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Development of New Chiral Diaminocarbene Ligands and Their Applications in Copper-Catalyzed Reactions

Permanent Link: http://ufdc.ufl.edu/UFE0041923/00001

Material Information

Title: Development of New Chiral Diaminocarbene Ligands and Their Applications in Copper-Catalyzed Reactions
Physical Description: 1 online resource (260 p.)
Language: english
Creator: Hirsch-Weil, Dimitri
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: acyclic, adc, alkylation, allylic, asymmetric, borylation, carbene, catalysis, chiral, copper, diaminocarbene, enantioselective, heterocyclic, isoquinoline, ligand, nhc
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: DEVELOPMENT OF NEW CHIRAL DIAMINOCARBENE LIGANDS AND THEIR APPLICATIONS IN COPPER-CATALYZED REACTIONS By Dimitri Hirsch-Weil August 2010 Chair: Sukwon Hong Major: Organic Chemistry N-Heterocyclic carbene (NHC) ligands are considered strong ?-donors and can be used in various catalytic reactions. Asymmetric catalysis using NHCs has been widely spread over the past 10 years. Comparing to chiral phosphine ligands, the choice of chiral NHCs still remains limited. Several designs have been developed such as attaching chiral alkyl groups directly to the nitrogen atoms, installing a chiral backbone on the NHC ring and using a chiral tethered group for second point metal binding. In this work, new designs were explored to further diversify the choice in chiral NHCs. C2-symmetric biisoquinoline-based diaminocarbene ligands were designed to create a chiral environment extended toward the metal center, which was confirmed by an X-ray structure. The concise ligand synthesis is highlighted by a modified Bischler-Napieralski cyclization of bisamides prepared from readily available chiral phenethylamines, and allows easy variation of the stereodifferentiating groups. The cyclohexyl-biisoquinoline based carbene-copper complex is an efficient catalyst for enantioselective SN2' allylic alkylation with Grignard reagents showing SN2' regioselectivity higher than 5:1 and enantioselectivity in the range of 68-77% ee. A novel acyclic diaminocarbene-copper complex has been prepared for the first time, conveniently from a chloroamidinium salt and Cu(I)-thiophenecarboxylate. The in situ generated acyclic diaminocarbene-Cu complex was characterized by 13C-NMR experiments using a 13C-labeled carbene precursor. The acyclic diaminocarbene-Cu complex is a highly efficient catalyst for SN2?-allylic alkylation with alkyl Grignard reagents, showing high SN2? selectivity. C1-symmetric monoisoquinoline based chiral diaminocarbene ligands were envisioned to expand the chiral pool of NHC structures and further optimize previously reported C2-symmetric biisoquinoline carbene ligands. This new ligand was synthesized from readily available chiral phenethylamine. The synthetic scheme allowed easy variation of the ligand structure within the final steps. Both C2 and C1-symmetric carbene ligands could be compared by their respective X-ray structures of Au(I) complexes. Monoisoquinoline based carbene ligand was tested in the copper-catalyzed borylation of alpha,beta-unsaturated amides giving good yields (80-99%) and enantioselectivities (85%) for various substrates.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Dimitri Hirsch-Weil.
Thesis: Thesis (Ph.D.)--University of Florida, 2010.
Local: Adviser: Hong, Sukwon.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2011-08-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0041923:00001

Permanent Link: http://ufdc.ufl.edu/UFE0041923/00001

Material Information

Title: Development of New Chiral Diaminocarbene Ligands and Their Applications in Copper-Catalyzed Reactions
Physical Description: 1 online resource (260 p.)
Language: english
Creator: Hirsch-Weil, Dimitri
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: acyclic, adc, alkylation, allylic, asymmetric, borylation, carbene, catalysis, chiral, copper, diaminocarbene, enantioselective, heterocyclic, isoquinoline, ligand, nhc
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: DEVELOPMENT OF NEW CHIRAL DIAMINOCARBENE LIGANDS AND THEIR APPLICATIONS IN COPPER-CATALYZED REACTIONS By Dimitri Hirsch-Weil August 2010 Chair: Sukwon Hong Major: Organic Chemistry N-Heterocyclic carbene (NHC) ligands are considered strong ?-donors and can be used in various catalytic reactions. Asymmetric catalysis using NHCs has been widely spread over the past 10 years. Comparing to chiral phosphine ligands, the choice of chiral NHCs still remains limited. Several designs have been developed such as attaching chiral alkyl groups directly to the nitrogen atoms, installing a chiral backbone on the NHC ring and using a chiral tethered group for second point metal binding. In this work, new designs were explored to further diversify the choice in chiral NHCs. C2-symmetric biisoquinoline-based diaminocarbene ligands were designed to create a chiral environment extended toward the metal center, which was confirmed by an X-ray structure. The concise ligand synthesis is highlighted by a modified Bischler-Napieralski cyclization of bisamides prepared from readily available chiral phenethylamines, and allows easy variation of the stereodifferentiating groups. The cyclohexyl-biisoquinoline based carbene-copper complex is an efficient catalyst for enantioselective SN2' allylic alkylation with Grignard reagents showing SN2' regioselectivity higher than 5:1 and enantioselectivity in the range of 68-77% ee. A novel acyclic diaminocarbene-copper complex has been prepared for the first time, conveniently from a chloroamidinium salt and Cu(I)-thiophenecarboxylate. The in situ generated acyclic diaminocarbene-Cu complex was characterized by 13C-NMR experiments using a 13C-labeled carbene precursor. The acyclic diaminocarbene-Cu complex is a highly efficient catalyst for SN2?-allylic alkylation with alkyl Grignard reagents, showing high SN2? selectivity. C1-symmetric monoisoquinoline based chiral diaminocarbene ligands were envisioned to expand the chiral pool of NHC structures and further optimize previously reported C2-symmetric biisoquinoline carbene ligands. This new ligand was synthesized from readily available chiral phenethylamine. The synthetic scheme allowed easy variation of the ligand structure within the final steps. Both C2 and C1-symmetric carbene ligands could be compared by their respective X-ray structures of Au(I) complexes. Monoisoquinoline based carbene ligand was tested in the copper-catalyzed borylation of alpha,beta-unsaturated amides giving good yields (80-99%) and enantioselectivities (85%) for various substrates.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Dimitri Hirsch-Weil.
Thesis: Thesis (Ph.D.)--University of Florida, 2010.
Local: Adviser: Hong, Sukwon.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2011-08-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0041923:00001


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DEVELOPMENT OF NEW CHIRAL DIAMINOCARBENE LIGANDS AND THEIR
APPLICATIONS IN COPPER-CATALYZED REACTIONS





















By

DIMITRI HIRSCH-WEIL


A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA

2010


































2010 Dimitri Hirsch-Weil


































To Catherine, Jean-Jacques and Jean









ACKNOWLEDGEMENTS

I would like to thank my mother for all the happiness she brings in my life. I will always

be grateful for the great education she gave me. My dad has always been present with me and

has given me a rich knowledge throughout my young years which helped me through tough

times.

My professor Sukwon Hong has been very supportive throughout my five years spent at

the University of Florida. He made himself available anytime I needed an advice or simply to

discuss about chemistry, I will always be thankful to him for that. He was a great mentor and

always trusted me in my work.

I want to thank especially David Snead for all the joyful moments spent inside and outside

the lab over the past years. Also, I want to thank all my group members: Kai Lang, Hwimin Seo,

Mike Rodig, Sebastien Inagaki and Jongwoo Park for interesting discussion about my work,

particularly Dr. Hwimin Seo who gave me invaluable training and advice in my chemistry.









TABLE OF CONTENTS
Page

A C K N O W LE D G E M EN T S ......... ................. .......................................................... 4

L IST O F TA B LE S ......... ..... ............. .................................................................... 7

L IST O F F IG U R E S ........ ............................................................... ................ ........... 9

L IST O F SC H E M E S................... ................................................ ................... ............. ..... 11

L IST O F A B B R E V IA T IO N S ......... ................. ......................................... ............................. 16

A B S T R A C T ............ ................... ............................................................. 18

CHAPTER

1 IN TRODU CTION ......... ........................... .................... ........... 20

1.1 N -H eterocyclic Carbene Background ........................................ ...................... 20
1.2 Chiral NHC ........................................... .................. ........... 22
1.2.1 Chiral Substituents at The Nitrogen Atoms .............................................. 22
1.2.2 B backbone C hirality......................................... ..... ............. .............. .... 28
1.3 Acyclic Carbene and Methods of Preparation .................................................... 35
1.4 C opper-C atalyzed A applications .............................................. ........... .............. 39
1.4.1 Copper-Catalyzed A llylic A lkylation ....................................... ............... ... 39
1.4.2 Copper-Catalyzed P-Borylation of a,P-Unsaturated Carbonyl Compounds.... 49

2 C2-SYMMETRIC BIISOQUINOLINE N-HETEROCYCLIC CARBENE LIGAND .... 53

2.1 Introduction: Ligand Design for C2-Symmetric Ligands............................................. 53
2.2 Bisoxazoline D erived N H C Ligand ........................................ .................. ...... 55
2.3 Bisimidazoline Derived NHC Ligand................................................. 58
2.4 Biisoquinoline Derived NHC Ligand.................... .......... .... .................. 60
2.4.1 Synthesis of Isopropyl, Isobutyl, Tert-Butyl and Cyclohexyl Alanine
Substituted A m ines ................... ... ................ ............ .......... .. 61
2.4.2 Cyclohexyl Substituted Amine Synthesis............................................. 62
2.4.3 Fused Cyclohexyl Substituted Amine Synthesis .......................................... 63
2.4.4 Phenyl Substituted A m ine Synthesis ........................................ ............... ... 67
2.4.5 Biisoquinoline Based Carbene Synthesis from Chiral Amine ......................... 69
2.4.6 Form ation of M etal Com plexes ................ ............ ...................................... 73
2.4.7 Application: Copper-Catalyzed Asymmetric Allylic Alkylation................. 76
2.4.8 Proposed Mechanism for The Copper-Catalyzed Allylic Alkylation.............. 80
2.4.9 Further Optimization of The Ligand Structure .......................................... 83









3 IN SITU GENERATION OF ACYCLIC DIAMINOCARBENE COPPER COMPLEX 91

3.1 Introduction: Discovery of The In Situ Generation of Aminocarbene Copper Complex
from C hloroim idazolium ............................................................... ................. 9 1
3.2 New In Situ Generation of ADC-Cu Complex and Application in Allylic Alkylation 93
3 .3 N M R E x p erim ents ....................................................................................................... 9 9

4 C1-SYMMETRIC MONOISOQUINOLINE N-HETEROCYCLIC CARBENE LIGAND
................................................................... .................... 105

4.1 Introduction: Ligand Design for Ci-Symmetric Ligands................ .................... 105
4.2 First A ttem pt U sing R 2=M e ................................................................................ ..... 106
4.3 Second A ttem pt U sing R 2=Ph ............................................................................. ... 109
4 .4 A chiral Side V ariation .......................................... ... ................ ...... .................. 111
4.5 Chiral Side Variation.... .................................................................................... 114
4.6 Gold BIQ and M IQ M etal Com plexes................................................ .................. .. 119
4.7 Application: Copper-Catalyzed P-Borylation of a,P-Unsaturated Carbonyl Compounds
........................ .............................................................. 123
4.8 Further Directions for MIQ or BIQ Ligands...... .............. ............................... 135

5 CON CLU SION ........................................................ ........... .. ............ .. 136

6 EXPERIM ENTAL SECTION .......................................................... .............. 138

6.1 G general R em arks ........... ...... .. ................................ .......................... .............. 138
6.2 C2-Symmetric NHC Ligands ........................................ 138
6.2.1 Bisoxazoline Derived NH C Ligand ..................................... .............. 138
6.2.2 Bisimidazoline Derived NHC Ligand................................. 141
6.2.3 Biisoquinoline Derived NHC Ligand ............................. ......... ..................... 144
6.2.4 Synthesis of the Substrates for The Copper-Catalyzed Allylic Alkylation.... 172
6.2.5 Products from The Copper-Catalyzed Allylic Alkylation ........................... 177
6.3 In Situ Generation of Acyclic Diaminocarbene-Copper Complex .......................... 181
6.3.1 Substrates and Catalysts Synthesis..................................................... 181
6.3.2 Products from The Copper-Catalyzed Allylic Alkylation ........................... 190
6.3.3 N M R Experim ents ...................................... ....................................... 193
6.3.4 Additional Experiments from Table 3-2 ............................................. .. 196
6.4 Ci-Symmetric Monoisoquinoline NHC Ligands ............................................... 198
6.4.1 Ligands Synthesis .................... ........................................ .............. 198
6.4.2 Gold Complexes Synthesis ........................... ........ .................. 225
6.4.3 Synthesis of The Substrates for The Copper-Catalyzed P-Borylation .......... 232
6.4.4 Products from The Copper-Catalyzed Borylation ....................................... 242

L IST O F R E FE R E N C E S .................................................................................. ............ 25 1

BIOGRAPHICAL SKETCH ............................................... 260









LIST OF TABLES

1-1 Asymmetric ring closing metathesis with various chiral NHC ruthenium complexes..... 30

1-2 Aerobic oxidative cyclization catalyzed by Stahl's and Kundig's ligands.................... 35

2-1 Optimization of the enzymatic kinetic resolution of rac-2-67 using lipase CALB.......... 66

2-2 Optimization of bisamide coupling using diethyl oxalate ......................................... 69

2-3 Optimization of the double Bischler-Napieralski cyclization................ .......... .... 72

2-4 Solvent optimization for the asymmetric allylic alkylation......................... ........... 77

2-5 Leaving group optimization for the asymmetric allylic alkylation............................. 78

2-6 Ligand structure optimization for the asymmetric allylic alkylation............................ 79

2-7 Grignard reagent survey for the asymmetric allylic alkylation ................................... 79

2-8 Substrate scope.............................................. .......... 80

2-9 Protection of the 0 alcohol of the bisamide compound ........................ ................ 87

2-10 Bisimine optimization for 0 substituted bisamides....................................................... 88

3-1 Allylic alkylation using chloroamidinium premixed with copper salt........................... 93

3-2 SN2' allylic alkylation catalyzed by copper carbene complexes ..................................... 94

3-3 Substrate scope.............................................. .......... 98

3-4 13C NMR experiments of the generation of copper carbene complex from
chloroam idinium .................................................................................................... 99

4-1 M onoam ide optim ization .................................................... ...................................... 107

4-2 Optimization of the Bischler-Napieralski cyclization................................................ 107

4-3 Optimization of imine formation .............. ...... .................. .................. .............. 108

4-4 Optimization of the imine condensation from the non-enolizable ketone...................... 109

4-5 Synthesis of disubstituted MIQ-NHC copper complexes........ ..... ...... ............ 111

4-6 Allylic alkylation with disubstituted MIQ-NHC copper complexes ........................... 112

4-7 Synthesis of monosubstituted MIQ-NHCs ........................... ....................... 113

4-8 Allylic alkylation using monosubstituted MIQ-NHCs .............................................. 114









4-9 Dependence between temperature and imidazolium ratio.......................................... 115

4-10 Allylic alkylation with two different isomers of 4-43 ..................... .............................. 119

4-11 Optimization of P-borylation for cinnamonitrile .................................................... 124

4-12 Ligand scope for cinnam onitrile ....................... ................................. .............. 125

4-13 Substrate scope..................... ........................ .................. .. .............. .. ........... .. 126

4-14 A m ide substrate optim ization ................................................ ............................. 127

4-15 Reaction condition optimization for N,N-dibenzylcinnamamide .................................. 129

4-16 P-borylation with different alkene configuration..... ............................ 130

4-17 Synthesis of additional MIQ-NHCs............................... .............. 131

4-18 Ligand scope for N,N-bis(4-methoxybenzyl)cinnamamide............... ...... ......... 132

4-19 Temperature effect on the copper-catalyzed borylation .............................................. 133

4-20 Substrate scope..................... ............................................ .. ..... .......... .. ........... .. 134









LIST OF FIGURES


Page

1-1 Electronic effects of the substituents for diaminocarbenes............................................. 20

1-2 Stable diam inocarbenes ...................................................... .................................. 2 1

1-3 B asic chiral carbene ligand fram ew ork................................................... ... ................. 22

1-4 Bisoxazoline derived NHC evolution ................. .................. ........ .............. 25

1-5 Major structure difference between NHC and ADC..................................... ............... 35

1-6 Proposed mechanism for 3-borylation of unsaturated ketones........................................ 52

2-1 C2-sym m etric ligand design .......................................................................... .............. 54

2-2 Tricyclic ligand design with variation of X ................................................................... 55

2-3 Fused cyclohexyl BIQ (trans 2-63 and cis 2-64 configuration) calculated with Chem3D
.......................................................................... 64
81
2-4 X-ray structure of Pd-carbene complex 2-103 ............. .............................................. 75

2-5 13C N M R of bisam ide 2-150 .......................... ...... .................................. .............. 89

2-6 13C NM R of bis(im idoyl) halide 2-156..................................... ......................... ......... 89

2-7 13C NM R of bisimine 2-100 ................................................................ .............. 90

3-1 X-Ray structure of chloroimidazolium-CuCl2 salt 3-283 ......................................... ....... 92

3-2 Direct 13C NMR monitoring (at -600C) of carbene-metal complex generation using 13C-
labeled chloroam idinium precursor 3-25 ...................................... ......... .............. 101

3-3 Direct 13C NMR monitoring at room temperature of carbene-metal complex generation
using 13C-labeled formamidinium 3-32 ............................. ......... 103

4-1 Increasing bulk around metal center by switching from C2-symmetric BIQ 2-2 to C1-
symmetric MIQ 4-1 carbene ligands................................ .............. 105

4-2 First design of the Ci-symmetric isoquinoline ligand 4-6 .................................... 106

4-3 1H NM R of the 4-39 (84:16) (Schem e 4-6, entry 1)...................................................... 116

4-4 1H NMR of 4-39 (51:49) (Scheme 4-6, entry 2)............................................... 116

4-5 1H NMR of the two diastereomers of 4-43......................... ..... .............. 118









4-6 Buried volume e for N H C ligand............................................................. .............. 120

4-7 X -ray structure of 4-4498 ......................... .................................................................. 12 1

4-8 X-ray structure of 4-4599........................................................... ........... ... 122

4-9 Proposed mechanism by Yun for 3-borylation of unsaturated substrates.................... 123

4-10 Proposed transition state with amide functionality............. .............. .............. 127

4-11 Proposed mechanism for 3-borylation with NHC ligand ............................................... 128

4-12 Proposed transition-state model for the asymmetric borylation. B = pinB- .................. 134









LIST OF SCHEMES

1-1 Synthesis of imidazolium and imidazolinium salts ......... ......... .... .............. 21

1-2 O ne pot synthesis of chiral im idazolium s............................................... ... ... .............. 23

1-3 Enantioselective copper-catalyzed 1,4-addition of zinc reagent using 1-21..................... 23

1-4 Synthesis of chiral [2.2]paracyclophane imidazoliums ................................... .............. 24

1-5 Ruthenium catalyzed asymmetric ketone hydrosilylation ........................................... 24

1-6 Enantioselective a-arylation of oxindole with 1-33 ..................................................... 24

1-7 Enantioselective a-arylation of oxindole with 1-34.................... ................... 25

1-8 Synthesis of the (-)-menthone-derived IBiox salt....................................................... 26

1-9 Enantioselective a-arylation of oxindole with 1-37 ............... .... .. ....................... 27

1-10 Synthesis of imidazolinium salts with restricted flexibility.................... .................. 27

1-11 Asymmetric hydrogenation of methyl 2-acetamidoacrylate with 1-52 ............................ 28

1-12 Tert-butyl substituted vicinal diam ine synthesis........................................... .............. 28

1-13 Synthesis of N-aryl substituted chiral imidazoliniums.................................... ............... 29

1-14 Synthesis of N-alkyl substituted chiral imidazoliniums ..................................................... 29

1-15 Synthesis and separation of meso and dl forms of bipiperidine ................................... 31

1-16 Synthesis and chiral resolution of bipiperidine...... ....................... ........... 32

1-17 Synthesis and separation of meso and dl forms of biisoquinoline............................ 32

1-18 Synthesis and chiral resolution of biisoquinoline................................. .................. .... 32

1-19 Asymmetric hydrosilylation using Rh and Ir complexes with NHC ligands based on
reduced biisoquinoline and bipiperidine framework ............................................ .. 33

1-20 Synthesis of chiral resolved seven-membered ring amidinium salts............................ 34

1-21 Formamidinium formation and deprotonation..................... ....... .............. 36

1-22 N -aryl acyclic carbene synthesis................................................ ........................... 37

1-23 Synthesis of metal free ADC and proposed mechanism............................................. 37

1-24 Synthesis of Chugaev-type ADC-Pd complexes with hydrazine or amine .................... 38









1-25 Pd complex formation from oxidative addition of chloroamidinium precursor .............. 38

1-26 Metal complex formation through lithium-halogen exchange from chloroamidinium
p re cu rso rs .................................. .......................................... ............... 3 9

1-27 General picture of the copper-catalyzed allylic alkylation ............................ ............. 40

1-28 First example of enantioselective copper-catalyzed allylic alkylation by Grignard
reagents ....... .................................. ......... .......... 40

1-29 First generation of phosphoramidite ligand applied in the allylic alkylation ................. 41

1-30 New condition with CuTC and second generation of phosphoramidite ligand applied for
the allylic alkylation ........................................ .......... 41

1-31 Third generation of phosphoramidite ligand applied in the allylic alkylation................ 42

1-32 Synthesis of syn and anti 1,2-dialkyl motifs .................................................. ... 43

1-33 Synthesis of chiral furanone.......................................................... ........................... 43

1-34 Allylic alkylation with allylic bromide containing nitrogen functional group ............... 44

1-35 Synthesis of bifunctional chiral building blocks from chiral protected P-amine ........... 44

1-36 Enantioselective preparation of a-substituted allylboronates................. .................... 45

1-37 Cu-catalyzed allylic alkylation using monodentate NHC ligands and proposed transition
state ..................................... ............. ............ 46

1-38 Cu-free enantioselective allylic alkylation on y-chloro-a,fl-unsaturated esters ............ 47

1-39 A nti selectivity w ith G rignard reagent.......................................................... .............. 47

1-40 Allylic alkylation with phenyl Grignard reagent using phosphine ligand ........................ 48

1-41 Allylic alkylation with phenyl Grignard reagent using monodentate NHC ligand .......... 48

1-42 First reported examples for P-borylation of unsaturated ketones .................................. 49

1-43 First asymmetric version using chiral josiphos phosphine ligand .................. .......... 50

1-44 Generation of quaternary centers using chiral phosphine ligands .................................. 50

1-45 First asymmetric version using chiral NHC ligands.................................... 51

1-46 Copper and MeOH free P-borylation of unsaturated ketones................ .................... 51

2-1 Retrosynthesis from trans-aminoindanol............................................................... .. 56









2-2 Synthesis from trans-aminoindanol ......... ....... ..................... 56

2-3 Decomposition pathway using chloromethyl ethyl ether.......................................... 57

2-4 Bisoxazoline-im idazolium synthesis ........................................... .................... ..... 57

2-5 B isim idazoline retrosynthesis ......................................................... .............. 58

2-6 B isim idazoline synthesis............................................................. ............. ...... ..... 59

2-7 B isim idazoline N H C synthesis ........................................................................................ 60

2-8 Bisdihydroisoquinoline-based carbene ligands ............. ............................... .......... 61

2-9 B iisoquinoline retrosynthesis......................................................... ....................... 61

2-10 Chiral amine synthesis from amino acids .............................................. 62

2-11 C yclohexyl am ine synthesis....................................................... ........................... 63

2-12 Racemic synthesis of the fused Cy amine rac-2-65 ................ .... ................ 64

2-13 A m ide synthesis for chiral resolution ........................................... .................. ...... 65

2-14 E ster synthesis for chiral resolution ......................................................................... ... 65

2-15 Non enzymatic kinetic resolution of secondary alcohol ............................................. 65

2-16 Scale up of the kinetic resolution of secondary alcohol with reused enzyme ................ 67

2-17 Reverse regioselectivity with phenyl substituted aziridine..................... .............. 67

2-18 Synthesis of (S)-1,2-diphenylethanamine........................................................ .. ....... 68

2-19 Bisam ide synthesis using oxalyl chloride................................................... ............. 70

2-20 Double Bischler-Napieralski cyclization .............. .............................................. ..... 70

2-21 Fragmentation of phenyl substituted bisnitrilium......... ..................................... 73

2-22 Imidazolium synthesis from chiral amine.......................... ............................. 73

2-23 Synthesis of Pd-BIQ-cinnamyl complex 2-103 ..... ............................................... 74

2-24 Copper complexes from C2-symmetric BIQ carbene ligands................ .................... 75

2-25 General scheme for allylic alkylation catalyzed by copper complexes using Grignard
reagents as nucleophiles................................ .. ........ .......... 76

2-26 Proposed mechanism for the asymmetric allylic alkylation .......................................... 81









2-27 Allylic alkylation using TC leaving group............................ ...... ........... ..... 82

2-28 Asymmetric allylic alkylation from a secondary alcohol pivalate............................ 82

2-29 Comparison between preformed (a) and in situ generated (b) copper carbene complex.. 83

2-30 Synthesis of the 7-OMe substituted BIQ carbene ligand 2-141 .............. .......... ..... 84

2-3 1 A llylic alkylation u sing 2-141 .......................................................................................... 84

2-32 Synthesis of the bis-OMe substituted BIQ carbene ligand 2-146................................. 85

2-33 B isam ide synthesis of norephedrine ............... ............ ....................... ............ ........ 86

2-34 Synthesis of the silylated bisamide ......................................................... .............. 87

3-1 Attempted synthesis of copper(II) BIQ-carbene complex 3-1....................................... 91

3-2 Comparison between catalysts 2-110 and 3-2 in the allylic alkylation of naphthyl
substrate 2-114 ......................................................................... ......... 92

3-3 Bispyrrolidine am idinium preparation ......... .. ............... .................. ............. ....... 96

3-4 Allylic alkylation using free carbene (Table 3-2, entry 8)......................................... 96

3-5 Comparison between catalysts 2-110 and 3-2 in the allylic alkylation of alkyl substrate 96

3-6 Enantioselective allylic alkylation using chiral ADC 3-12............................................ 97

3-7 Allylic alkylation of piperidine substrate with IMesCuCl catalyst 3-22 .......................... 98

3-8 Preparation of 13C-labeled chloroamidinium precursor 3-25.................................... 100

3-9 Preparation of 13C-labeled formamidinium precursor 3-32...................................... 102

3-10 Copper carbene complex generation involving cuprate-chloride exchange................... 103

3-11 Copper carbene complex generation involving Grignard-chloride exchange .............. 103

4-1 Retrosynthesis of the Ci-symmetric monoisoquinoline ligand ............. .............. 106

4-2 Monoimine synthesis from chiral isobutyl phenethylamine.............. ...... ........ 109

4-3 Imidazolium and copper complex synthesis for mesityl substituted imine................... 110

4-4 Asymmetric allylic alkylation using 4-15.............................. .............. 110

4-5 Attempted synthesis of the phenyl substituted isoquinoline 4-35 ................................. 114

4-6 Synthesis of 4-38 ............................................. ...... ......... ... ......... .... 115









4-7 Im idazolium synthesis of 4-43 ............................................. ............... ............... ....... 117

4-8 Synthesis of BIQ and MIQ gold complexes ............................................................. 120




















































15









LIST OF ABBREVIATIONS


Ac Acetyl.

ADC Acyclic diaminocarbene.

BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.

BIQ Biisoquinoline based carbene ligand.

Bn Benzyl.

Bpin Boron pinacolate.

B2pin2 Bispinacolate diboron.

CALB Candida Antarctica lipase B.

DCM Dichloromethane.

DFT Density functional theory.

DIAD Diisopropyl azodicarboxylate.

DMAP 4-Dimethylaminopyridine.

DME Dimethoxyethane.

DMF Dimethylformamide.

DMSO Dimethylsulfoxide.

dr diastereomeric ratio.

EDCI/EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide.

ee enantiomeric excess.

GC Gas chromatography.

HOBt Hydroxybenzotriazole.

Hoveyda-Grubbs 2nd generation (1,3-Bis-(2,4,6-trimethylphenyl)-2-
imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium.

HPLC High performance liquid chromatography.

(R)-(S)-Josiphos (R)- 1-[(Sp)-2-Diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine.

LAH Lithium aluminium hydride.









LDA

LiHMDS

MIQ

MsCI

MTBE

NCS

NHC

NMR

Piv

PMB

PMHS

PMP

Rac

SM

SMB

(R)-(S)-Taniaphos


TBDPS

TC

TFA

Tf2O

THF

TMS

TsCl

% VBur


Lithium diisopropylamide.

Lithium hexamethyldisilazide.

Monoisoquinoline based carbene ligand.

Mesylate chloride.

Methyl tert-butyl ether.

N-chlorosuccinimide.

N-heterocyclic carbene.

Nuclear magnetic resonance.

Pivalate.

para-methoxybenzyl.

Polymethylhydrosiloxane.

para methoxyphenyl.

Racemic.

Starting material.

Simulating moving bed.

(Rp)-1-[(S)-a-(Dimethylamino)-2-(diphenylphosphino)benzyl]-2-
diphenylphosphinoferrocene.

tert-Butyl diphenylsilyl.

Thiophenecarboxylate.

Trifluoroacetic acid.

Triflate anhydride.

Tetrahydrofuran.

Trimethylsilyl.

Tosylate chloride.

% buried volume.









Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy

DEVELOPMENT OF NEW CHIRAL DIAMINOCARBENE LIGANDS AND THEIR
APPLICATIONS IN COPPER-CATALYZED REACTIONS

By

Dimitri Hirsch-Weil

August 2010

Chair: Sukwon Hong
Major: Chemistry

N-Heterocyclic carbene (NHC) ligands are considered strong o-donors and can be used in

various catalytic reactions. Asymmetric catalysis using NHCs has been widely spread over the

past 10 years. Comparing to chiral phosphine ligands, the choice of chiral NHCs still remains

limited. Several designs have been developed such as attaching chiral alkyl groups directly to the

nitrogen atoms, installing a chiral backbone on the NHC ring and using a chiral tethered group

for second point metal binding. In this work, new designs were explored to further diversify the

choice in chiral NHCs.

C2-symmetric biisoquinoline-based diaminocarbene ligands were designed to create a

chiral environment extended toward the metal center, which was confirmed by an X-ray

structure. The concise ligand synthesis is highlighted by a modified Bischler-Napieralski

cyclization of bisamides prepared from readily available chiral phenethylamines, and allows easy

variation of the stereodifferentiating groups. The cyclohexyl-biisoquinoline based carbene-

copper complex is an efficient catalyst for enantioselective SN2' allylic alkylation with Grignard

reagents showing SN2' regioselectivity higher than 5:1 and enantioselectivity in the range of 68-

77% ee.









A novel acyclic diaminocarbene-copper complex has been prepared for the first time,

conveniently from a chloroamidinium salt and Cu(I)-thiophenecarboxylate. The in situ generated

acyclic diaminocarbene-Cu complex was characterized by 13C-NMR experiments using a 13C

labeled carbene precursor. The acyclic diaminocarbene-Cu complex is a highly efficient catalyst

for SN2'-allylic alkylation with alkyl Grignard reagents, showing high SN2' selectivity.

Ci-symmetric monoisoquinoline based chiral diaminocarbene ligands were envisioned to

expand the chiral pool of NHC structures and further optimize previously reported C2-symmetric

biisoquinoline carbene ligands. This new ligand was synthesized from readily available chiral

phenethylamine. The synthetic scheme allowed easy variation of the ligand structure within the

final steps. Both C2 and Ci-symmetric carbene ligands could be compared by their respective X-

ray structures of Au(I) complexes. Monoisoquinoline based carbene ligand was tested in the

copper-catalyzed borylation of a,P-unsaturated amides giving good yields (80-99%) and

enantioselectivities (85%) for various substrates.









CHAPTER 1
INTRODUCTION

1.1 N-Heterocyclic Carbene Background

N-heterocyclic carbenes (NHC) have been isolated for the first time by Arduengo et al. in

1991.1 NHCs are stabilized by the vicinal nitrogen atoms and exhibit singlet state configuration.

The two nitrogen lone pairs increase the energy of the empty p" orbital by mesomeric effects and

the carbene lone pair p, is stabilized by inductive effects of electronegative nitrogen atoms

(Figure 1-1). Those two effects increase the c-p, gap and favor the singlet state.2 NHCs are

strong o-donors and their metal complexes show better air and thermal stability than the

analogous phosphine complexes.3 As a result of these superior properties, carbene ligands are

replacing bulky electron-donating phosphine ligands in various catalytic reactions4 such as cross

coupling reactions,5 and olefin metathesis.6






1R2 Pn R2


Figure 1-1. Electronic effects of the substituents for diaminocarbenes

Recently, the discovery and isolation of several types of stable carbenes7 has been reported

(Figure 1-2). From four-, to seven-membered N-heterocyclic rings have been reported. Most of

the stable aminocarbenes reported are five-membered rings (1-2 to 1-8). This might be due to an

increase of stability compared to other ring sizes. In the carbene infancy, Arduengo et al.

reported an easy and practical synthesis of typical five-membered N-heterocyclic ring (Scheme

1-1).8












R R R-N NR RN N-R R N, N R
Ar-N N-Ar 0R RG NR'R RN NNRRR
vR R R

1-1 1-2 1-3 1-4 1-5 1-6

_-~~~ ~ ~ = ^ i /''*
-N NR R
S/ N N- R' N R N N N N R'N R
** "" a
1-7 1-8 1-9 1-10 1-11 1-12

Figure 1-2. Stable diaminocarbenes

Bisimines 1-13 were obtained by condensation of glyoxal and respective amines. Then,

either it was reduced to the corresponding diammonium salt 1-14 by NaBH4 or it was cyclized to

the imidazolium salt 1-15 using chloromethyl ethyl ether. The diammonium 1-14 was converted

to the imidazolinium 1-16 with triethyl orthoformate. This synthesis allows for a wide variation

of the starting amines.


Cl
S R-NH2 NaBH4 R-NH2 C0
0 O n-PrOH R-N N-R THF
60-70 "C HCI H2N-R
1-13 1-14

THF CI HC(OEt)3
rtEt I HCO2H



R-N NR R-N N-R
0 0
Cl CI
1-15 1-16

Scheme 1-1. Synthesis of imidazolium and imidazolinium salts









1.2 Chiral NHC

Asymmetric catalysis using chiral carbene ligands has exploded in the last 10 years.9 There

are two ways of introducing chirality into the carbene ligand framework (Figure 1-3).

R R

R* N C N R*

1-17

Figure 1-3. Basic chiral carbene ligand framework

The first method, reported by Herrmann et al.,10 involves attaching chiral substituents on

the nitrogen atoms. The second method, first developed by Grubbs et al.," uses a chiral

backbone which tethers two nitrogen atoms in saturated carbenes to relay chiral information to

the metal. Monodentate,12 bidentatel3 or multidentate chiral aminocarbene ligands have been

developed. An overview of monodentate aminocarbene ligands as well as their synthesis will be

discussed.

1.2.1 Chiral Substituents at The Nitrogen Atoms

This strategy is based on the introduction of N-substituents containing a chiral center on

the carbon attached to the nitrogen atom. In the first report by Herrmann, the chiral unit was

incorporated as a commercially available chiral amine 1-18. The imidazolium 1-19 was

synthesized in a one pot synthesis based on modified Arduengo's procedure (Scheme 1-2).14 This

synthesis can be used with various chiral amines to generate an array of chiral imidazoliums.

Those NHC ligands were tested in the hydrosilylation of acetophenone using rhodium complexes

but only poor enantioselectivity was observed with 1-19 (Ar = a-napht, 90% yield, 32% ee). The

chiral induction of these ligands remained low which is probably due to the rapid internal

rotation of the chiral substituents around the C-N axis. This leaves the active chiral space at the

metal center relatively ill-defined.









0

1) H H
toluene, rt
2) HCI, 3.3M

3) Oi\O
0 0
40 C, 12 h
79%


Ar N Ar

Me O Me
CI
1-19


Scheme 1-2. One pot synthesis of chiral imidazoliums

In other reactions, this rotation was beneficial and gave up to 62% ee in the addition of

zinc reagent to cyclohexenone 1-20 (Scheme 1-3).15 This reaction employed a silver-NHC

complex 1-21 as a transmetallating agent.

Ar N N ,Ar

Me Ag Me

0 Cl 0
1-21
CuTC
Et2Zn Et
Et2O, -78 C
1-20 16 h 1-22
99% yield, 62% ee

Scheme 1-3. Enantioselective copper-catalyzed 1,4-addition of zinc reagent using 1-21

In 2003, Andrus et al. reported the use of chiral planar [2,2]paracyclophane amines 1-25

and 1-26, obtained by chiral resolution,16 as precursor in the imidazolinium synthesis (Scheme

1-4).17 The amine 1-23 can be functionalized by Suzuki coupling using NHC 1-24 as ligand then

it was converted to the imidazolinium using Arduengo's conditions.

1-28 exhibited the best results in the ruthenium catalyzed ketone reduction (Scheme 1-5).18

The enantioselectivity stayed high for most aromatic substrates but it dropped to 58% ee for

some aliphatic substrates.


Ar
-NH2
Me

1-18

















Br
NH2



1-23


1-24 (2 mol%) 1) OPO
R-Bpin R H20/nPrOH
Pd(OAc)2 (2 mol%) K r/NH2 2) NaBH4/HCI
CsF, THF, 60 "C 3) HC(OEt)3
HCO2HINH4BF4

R = Ph, 92%, 1-25
o-MeOPh, 81%, 1-26


/ Q
BF4
R = Ph, 62%, 1-27
o-MeOPh, 51%, 1-28


Scheme 1-4. Synthesis of chiral [2.2]paracyclophane imidazoliums


1) Ph2SiH2
0.5 mol% RuCl2
1.2 mol% 1-28 o
AgOTf OH MeO
THF, rt, 16h
2) H20, HCI

1-29 1-30
98% yield, 97% ee


0
BF4
1-28


Scheme 1-5. Ruthenium catalyzed asymmetric ketone hydrosilylation

In 2001, Hartwig and co-workers reported the first enantioselective intramolecular a-

arylation with chiral carbene ligands. The best chiral NHC 1-33 was derived from (-)-

isopinocampheyl amine and produced all carbon quaternary centers in 76% ee (Scheme 1-6). In

this paper, carbene ligands gave better results than various chiral phosphines.19



r Me Pd(dba)2 (10 mol%) M
Br Me 1-33 (10 mol%) Me
NaOtBu N N
N O DME, 10C,40h O
N 0 N 0 (
Bn BF4
Bn
1-31 1-32 1-33

75% yield, 76% ee

Scheme 1-6. Enantioselective a-arylation of oxindole with 1-33









Following this report, Kundig et al. explored new bulky benzylamines derived NHCs 1-34

which showed increased enantioselectivity for the substrate 1-31 (Scheme 1-7). In a following

report, the reaction was extended to the formation of tertiary alkoxides as well as trisubstituted

tertiary amines by replacing the methyl group with protected heteroatoms.20



BrMe Pd(dba)2 (5 mol%) \
Br e 1-34(5 mol%) Me .
NaOtBu MeO OMe
N O DME, rt, 24 h
BnB
Bn
1-31 1-32 1-34
98% yield, 84% ee

Scheme 1-7. Enantioselective a-arylation of oxindole with 1-34

Glorius et al. developed a new series of ligand based on the bisoxazoline framework 1-4.21

Those ligands were applied in the Suzuki-Miyaura coupling and tetra-ortho-substituted biaryls

were synthesized for the first time from nonactivated aryl chlorides.22 The first ligand generation

1-35 was derived from natural amino acids and showed only 43% ee in the a-arylation of

oxindole. The second generation 1-36 consisted of a spiro cyclohexyl substitutent which was

representative of a flexible steric bulk (chair conformation).23 In the third generation 1-37, this

spiro compound was made chiral (Figure 1-4).24


O O


OTf OTf OTf
1-35 1-36 1-37
First generation Second generation Third generation

Figure 1-4. Bisoxazoline derived NHC evolution

Starting with a Bucherer-Bergs reaction,25 (-)-menthone 1-38 was converted to the

corresponding hydantoin 1-39 using potassium cyanide and ammonium carbonate. The urea









hydrolysis was realized under vigorous conditions using aqueous sulfuric acid at 150 OC, and this

was followed by reduction to the quaternary center amino alcohol 1-40 using sodium

borohydride combined with iodine. The bisamide 1-41 synthesis was achieved by coupling with

diethyloxalate. Then the alcohol moiety in 1-41 was substituted by chloride using thionyl

chloride. The bisoxazoline moiety 1-43 was produced under basic conditions at reflux in

excellent yields. Silver triflate in combination with chloromethyl pivalate, instead of the typical

chloromethyl ethyl ether developed by Arduengo, gave the imidazolium 1-37 in good yields

(Scheme 1-8). This alternative method was necessary to prevent ring opening of the oxazoline

ring by chloride counterion (Scheme 2-3).


S KCN, (NH4)2CO3 -NH 1)aq. H2SO4,150 C -OH
HN ____________
EtOH/H20, 60 *C 2) NaBH4/12
88% 65% '",
1-38 9 1-40
1-39

O tO OH H CI
OQEt N N '" 2 N N"
O Ot" N Otoluene, 60-90 C N
toluene, 90 C 0 H 5 h, 699% 0
18 h, 81% OH 5 % Cl
1-41 1-42

^ O 0-N CICH2OPiv 0O 0
NaOH N AgOTf N ,N'-
THF, reflux DCM, 60 C 0
19 h, 97% 12 h, 71% OTf
1-43 1-37

Scheme 1-8. Synthesis of the (-)-menthone-derived IBiox salt

This third generation imidazolium 1-37 was applied in the same a-arylation of oxindole

described previously (Scheme 1-9). Excellent ee and expansion to unactivated chloride substrate

1-44 was achieved.











Me S [Pd(allyl)CI]2 (2.5 mol%) / -
X Me 1-37 (5 mol%) Me N
[II /NaOtBu /
N DME, 50 "C, 12h o 0
N OTf
Bn
Bn Bn 1-32 -
1-37
X = Br, 1-31, 95% yield, 97% ee
X = CI, 1-44, 86% yield, 97% ee

Scheme 1-9. Enantioselective a-arylation of oxindole with 1-37

Herrmann and coworkers also developed a rigid chiral carbene structure based on the

isoquinoline framework (Scheme 1-10).26 Benzonitrile 1-45 was converted to the phenylethyl

amine 1-46 by addition of benzyl Grignard reagent followed by LAH reduction of the imine

formed in situ. The racemic amine rac-1-46 was resolved by recrystallization of ammonium salts

using tartaric acid as a chiral counterion. Then the amine 1-46 was transformed into a formamide

and subjected to a modified Bischler-Napieralski cyclization27 to yield the corresponding

monoimine 1-47. Then it was dimerized using Zinc and TMSC1 as coupling agent.28 The

resulting diamine 1-48 was obtained as a single diastereomer. Typical cyclization conditions

using triethyl orthoformate generated the desired imidazolium 1-49.

IN
1)PhCH2MgBr NH2 1)EtOCHO TM SCI

2)LAH Ph 2) (COCI)2, FeCl3 NH HN
2)LAH .H2S4/MeOH N Br-Br
3)(+)-tartaric acid 3) H2SO4MeOH H3CNeflux Ph Ph
1-45 1-46 1-47 85% 1-48

1) HBr, MeOH, rt, 12 h
2) CH(OEt)3, formic acid
neat, 100 *C, 60 h
81% N N
Ph a Ph
Br
1-49

Scheme 1-10. Synthesis of imidazolinium salts with restricted flexibility









The ligand 1-49 was tested in the iridium catalyzed hydrogenation of amidoacrylate 1-50

(Scheme 1-11). Excellent conversion was observed as well as modest enantioselectivity (60%

ee).



1-52 (1 mol%)
N H H2, 30 bar HN N, N
DCM, rt I C" 4
S16h O Ph I Ph
CIr
1-50 1-51 CI

99% yield, 60% ee 1-52

Scheme 1-11. Asymmetric hydrogenation of methyl 2-acetamidoacrylate with 1-52

1.2.2 Backbone Chirality

In order to transfer the chirality from the backbone to the front, the substituents off the

nitrogen atoms need to be rather bulky or restricted in movement for an effective interaction with

the chiral substituents at the back. C2-symmetric chiral vicinal diamines29 offer a good starting

point for the generation of those ligands. Phenyl or cyclohexyl substituted diamines are

commercially available but still relatively expensive (around $80 for Ig). Other substitution such

as tert-butyl required a three step synthesis using a chiral auxiliary (Scheme 1-12).30 The chiral

bisimine 1-54 was first synthesized by condensation of chiral amine 1-53 with glyoxal. Then

diastereoselective addition of Grignard reagent followed by removal of the auxiliary group

furnished the desired chiral diamine 1-56.


Ph 0 0 Ph Ph t-BuMgCI HCO2NH4
)-NH2 HCO2H M-N N, Et20,50 C NH Ph Pd(OH)2
Me MgSO4 Me Me 1 h, 77% NMeOH, 60 "C H2N NH2
DCM, rt Me Me 2 h, 60%
1-53 30 min 1-54 1-55 1-56
90%

Scheme 1-12. Tert-butyl substituted vicinal diamine synthesis










Using palladium catalyzed Buchwald-Hartwig coupling,31 various aryl groups could be

added on the nitrogen atoms of 1-57. Triethyl orthoformate furnished the desired imidazolinium

1-59 (Scheme 1-13).

R R ArBr R R HC(OEt)3 R R

H2N NH2 Pd(OAc)2 Ar-NH HN-Ar NH4BF4 ArN ,NAr
BINAP -Ar
NaOtBu
1-57 1-58 1-59 BF4

Scheme 1-13. Synthesis of N-aryl substituted chiral imidazoliniums

N-alkyl substituted imidazolinium salts were synthesized by another pathway because

primary amines would lead to dialkylated products (Scheme 1-14). Instead, secondary amine 1-

55 was converted to the aminal 1-60 followed by deprotection of the chiral groups which yield

the imidazole 1-61. Substitution using primary alkyl halides gave imidazoliniums 1-62.15


'-..H2C=0
-y
Ph Ph H2
e-NH HN- Et20,rt
Me Me 7
77%


HCO2NH4
Pd(OH)2
EtOH, 60 *C
6 h, 95%


RX -V
-K2C02 "
N NH DCM, rt R-NN-R
60-90% 0
X. X


1-55 1-60 1-61 1-62

Scheme 1-14. Synthesis of N-alkyl substituted chiral imidazoliniums

In 2001, Grubbs and co-workers reported the first enantioselective ruthenium olefin

methatesis bearing NHC ligands.32 The reaction consisted on a desymmetrization of achiral

trienes 1-63 by asymmetric ring closing metathesis (Table 1-1). In this first report, it was

observed that 1-66 prepared from (1R,2R)-diphenylethylenediamine showed higher

enantioselectivities than 1-68 prepared from (1R,2R)-1,2-diaminocyclohexane (entries 2 and 6).

Moreover, mono arylsubstituted 1-66 exhibited higher reactivity than symmetrically

substituted 1-65 (entry 1 and 2). Also if chloride ligands are exchanged in situ with iodides, the

enantioselectivity increased drastically (entries 2 and 3). The iodide ligand might have an









electronic effect.33 On the other hand, when a Ci-symmetric NHC ligand 1-67 was used,34 higher

enantioselectivity was observed compared to C2-symmetric versions with chloride ligand

entries2 and 4).

Table 1-1. Asymmetric ring closing metathesis with various chiral NHC ruthenium complexes
catalyst
O^-- (2 mol% without additive)
(4 mol% with additive) 0
additive
solvent, 40 C
1-63 1-64


catalyst

Ph Ph
Me /-( Me,
' N N


additive solvent yield (%) ee (%)


1 / ,Cl No DCM 67 15
Me-1 Me Ru Me Me
Cl' I'
PCy3 Ph
1-65

Ph Ph
iPr,
2 N PN No DCM 98 35

3 x PrRu P Nal THF 98 90
C ~Cy3 Ph
1-66
tBu tBu
4 B No DCM 98 82
SN 'C N-Me
S CI
5 ziPr lRu -- Nal THF 98 48
Cl I C Ph
PCy3
1-67

6 i No DCM 95 11
iPr,,
N. N-
7 Pr Nal THF 95 3
ClCy3 Ph

1-68


entry









Additionally, when iodide was added with 1-67, the inverse effect was observed, the

enantioselectivity decreased by 50% (entries 4 and 5). 1-67 could be synthesized by combining

the two methodologies developed previously (Schemes 3 and 4).

Other structures with backbone chirality were developed to further expand the field of

chiral NHC ligands. Tricylic carbene structures were first developed by Herrmann and co-

workers.35 Chiral imidazolinium ligands 1-84 and 1-83, derived from 2,2'-bipiperidine 1-73 and

partially reduced biisoquinoline 1-81, were prepared from achiral heterocyclic compounds.

Bipyridine 1-69 was first over reduced, using Ni/Al alloy,36 to give a mixture of meso and dl

2,2'-bipiperidine 1-70 in 83% yield (Scheme 1-15). The meso compound 1-71 was more soluble

in ethanol which allowed the isolation of the racemic bipiperidine hydrobromide salt 1-72 in

45% yield.

0 0
2 Br 2 Br
I NN i/Al alloy I I I I
IN NH HBr NH2 NH2 NH
KOH G N NaOH

SN H20/MeOH, rt N EtOH NH2 NH2 DM NH
S 3 d, 83% H Crt, 1 h
97%
46% 45%
1-69 1-70 1-71 1-72 rac-1-73

Scheme 1-15. Synthesis and separation of meso and dl forms of bipiperidine

In order to resolve rac-1-73, menthol based phosphine complexes were synthesized and

the two diastereomers 1-74 and 1-75 were separated by recrystallization (Scheme 1-16).35

Phenethylamine 1-76 was first converted to isoquinoline 1-77 using the Bischler-

Napieralski cyclization.37 Then reductive coupling of imines with the couple Zn/Me3SiCl

afforded the vicinal diamine 1-78.28 The dl-bishydroisoquinoline 1-80 was isolated from an

aqueous solution of hydrobromic acid in 44% yield (Scheme 1-17).










1)PCI3,DCM 1 HB
NH 2) I-Menthol 1) HBr INIH
3) S8 N 0 'NO 2) NaOH, DCM

I"NH "'N P" Np 98% NH


30% 25%
rac-1-73 1-74 1-75 SS-1-73

Scheme 1-16. Synthesis and chiral resolution of bipiperidine

1) O
EtO H Zn, TMSCI
reflux, 12 h -NH
NH2 99% Br Br

S2)PPA ,. N MeCN I NH
160 "C, 12 h 90%
92%
1-76 1-77 1-78
0 0
2 Br 2 Br

HBr NH2 NH2 NaOH NH
0+ D
rt, 8h NH2 '"NH2 DCM '"'NH
I 2 I 2 rt, 1 h
1 83%

37% 44%
1-79 1-80 rac-1-81

Scheme 1-17. Synthesis and separation of meso and dl forms of biisoquinoline

The resolution was achieved in high yield by using D-(+)-a-bromocamphor-7t-sulfonic acid

as a chiral counterion (Scheme 1-18).28c Both vicinal diamines 1-81 and 1-73 could be cyclized

into imidazolinium using triethyl orthoformate.

D-(+)-a-bromocamphor-
x-sulfonic acid ammonium Me NaOH, DCM
NH salt .,2NH2 O3S M NH

NH NH Br rt, 2 h NH
S Me 0 90%

rac-1-81 1-82 44% SS-1-81

Scheme 1-18. Synthesis and chiral resolution of biisoquinoline









Rhodium 1-83 and iridium 1-84 complexes were synthesized by transmetallation from

silver-NHC complexes. They were both tested in the asymmetric hydrosilylation of

acetophenone 1-29. Both showed good activity at low catalyst loadings. Low enantioselectivity

was observed which was probably due to the absence of transferrable groups from the ligand

backbone chirality (Scheme 1-19).35


H H H H

1)Ph2SiH2 N N N N
O 1 mol% 1-83 or 1-84 OH C
THF, -20 C, 16 h Rh Ir
2) pTsOH C D C 7
MeOH 99% yield 99% yield
1-29 1-30 28% ee 15% ee
1-83 1-84

Scheme 1-19. Asymmetric hydrosilylation using Rh and Ir complexes with NHC ligands based
on reduced biisoquinoline and bipiperidine framework

Stahl and co-workers were the first to report a seven member ring NHC.38 This ligand was

based on a torsional twist of the phenyl rings to relieve ring strains and induced a C2-symmetric

structure. This scaffold required chiral resolution at the amidinium stage which could be

troublesome. To overcome this difficulty, the chirality of the biphenyl diamine 1-85 was set by

adding two methyl substituents at the 6 and 6' positions (Scheme 1-20). This chiral amine was

resolved by simulated moving bed (SMB) chromatography which involves a series of preparative

column in series in order to separate close binary systems.39 As it was observed in the previous

example (Scheme 1-19), the backbone chirality was not sufficient to induce high

enantioselectivity. Grubbs and co-workers showed better results (Table 1-1) when the chiral

backbone was used as a relay for the substituents close to the metal sphere. Following this

strategy, phenyl groups were installed ortho to the nitrogen substituents by a Daugulis-Zaitsev40









coupling reaction developed recently by Stahl and co-workers.41 Then the acetyl directing group

was removed by strong basic conditions. Sequential addition of cyclohexyl aldehyde and LAH

gave the secondary amine 1-88 in 94% yield. Cyclization of this bisamine afforded the chiral

amidinium 1-89 (Scheme 1-20).

Phi Ph Ph
Pd(OAc)2 I I
NHAc AgOAc hNHAc 50% KOH/EtOH NH2
NHAc CF3CO2H, reflux NHAc 150 *C, pressure vessel NH2
16 h, 99% | 94% t Ph
P Ph Ph
1-85 1-86 1-87

Ph Ph
1) CyCHO
p-TsOH /Cy HC(OEt)3 /
toluene, reflux, 36 h N NH4BF4 N
2) LiAIH4 N8% N B
THF, 50 C, 2 h / Cy \-Cy
94%
Ph Ph
1-88 1-89


Scheme 1-20. Synthesis of chiral resolved seven-membered ring amidinium salts

The racemic version of this ligand was used in the aerobic intramolecular oxidative

amination of alkenes catalyzed by palladium complexes.42 Following this work, the chiral

amidinium 1-89 was tested in the asymmetric oxidative amination; this is the first report of the

use of NHC in this reaction (Table 1-2).43 In the best case, the product was obtained in 63% ee

but only 35% yield (entry 1). With Kundig's complex 1-93, only racemic product was obtained

using similar conditions (entry 2); but varying the base, which is known to facilitate substrate

oxidation by Pd(II), increased only the yield (entry 3).










Table 1-2. Aerobic oxidative cyclization catalyzed by Stahl's and Kundig's ligands
O 0
NH
5 mol% catalyst N
^1 atm 02
toluene, 50 *C, 18 h
1-90 1-91


entry catalyst additives yield ee


Ph Cy

1 / Cl- AgTFA 35% 63%
PI iPr2NEt, 3A MS
1 42
N- Cl
Ph Cy
Ph
1-92


2 tBu, N iPr2NEt, 3A MS 34% 0%
-0 tBu
3 6O Na2CO3 66% 7%

1-93

1.3 Acyclic Carbene and Methods of Preparation

Acyclic diaminocarbenes44 (ADC) are called acyclic because the nitrogen atoms

surrounding the carbene are not included within the same ring (Figure 1-5).

-R R
R-N cNR vs R-N cN'R

1-2/1-3 1-12

NHC ADC

Figure 1-5. Major structure difference between NHC and ADC

In 1996, Alder et al. reported the first ADC (Bis(diisopropylamino)carbene) 1-96 as a

crystalline solid stable both in the solid and solution state.45a ADCs have been shown to be more

electron donating than NHCs,46 and more sterically demanding resulting from a greater N-C-N









bond angle (121.00 vs 104.70).44a The lack of reports concerning ADC might be attributed to the

difficult preparation of acyclic carbenes and ADC-metal complexes.

In the first reports by Alder and co-workers,45 the amidinium 1-95 was synthesized through

intermolecular Vilsmeier-Haack chemistry (Scheme 1-21). This route often gives low yield along

with byproduct resulting from mixture of counterion from the formamidinium precursor. Alder

and co-workers found a recrystallization route by exchanging with hexafluorophosphate salts

which increased the yield and purity of the product formed. The amidinium 1-95 has a higher

pkA than imidazolium 1-2 (27.9 vs 22.3 in DMSO)47 so stronger bases are needed to deprotonate

those species such as LDA, LiHMDS and NaH in NH3 to give ADC complexes with a variety of

metals.46 At first glance, free carbene seem to be generated but the base counterion actually plays

a role in stabilizing the carbene from dimerization. All attempts to remove the metal ion from

ADC have been unsuccessful such as using crown ether to trap Li or K cations.

1) POCl3 LDA, THF
NH -Et20H LDANTHF NC
N 2) i-Pr2NH rt, 30 min
DCM 55%
25% .X
1-94 1-95 1-96

Scheme 1-21. Formamidinium formation and deprotonation

Bielawski et al. reported the first N-aryl acyclic diaminocarbene synthesis (Scheme

1-22).48 The formamidinium 1-98 was formed by mild basic dialkylation of the corresponding

formamidine 1-97 and the carbene 1-99 was obtained by deprotonation with sodium hydride.

Further metal complexation was possible with rhodium or ruthenium olefinn metathesis

catalyst).49












i-Pr i-Pr


.. a,.


i-rPr i-Pr I-
i-Pr i-Pr 2 CH31 i-Pr Me r e
N NH NaHCO3 ~NMe NaH/KOtBuN
CH3CN THF, 70C Ci
-Pr -P 110 C i-Pr I 77%
69% i
1-97 1-98 1-99

Scheme 1-22. N-aryl acyclic carbene synthesis

Bertrand and co-workers described a methodology using Hg(SiMe3)2 as a silylating agent

to form free acyclic diaminocarbenes 1-12 from chloroamidinium precursors 1-100 (Scheme

1-23).50 The proposed mechanism involves first a o-bond metathesis with generation of a

mercury derivative 1-101 and liberation of TMSC1. The chloride ion can then induce a fast

elimination of a second equivalent of TMSC1 followed by decomplexation of the metal to give

free carbene 1-12.

R R Hg(SiMe3)2 R R
N N N NR' N, NR + Hg(0) + 2 Me3Si-CI
R' !y 'R THF, -78 C R c R
Cl( Cl
1-100 1-12

-TMSCI -Hg


R R R R
I -TMSCI I I
N NR ------ R N'R
R' R R C R
Hg Hg
"Cl SiMe3
1-101 1-102

Scheme 1-23. Synthesis of metal free ADC and proposed mechanism

Alternative routes were developed to improve the free carbene synthesis as well as the

complex formation. Slaughter reported bidentate Chugaev-type ADC-metal complexes51 which


r









were synthesized by nucleophilic addition of either hydrazines 1-103 (a) or amine 1-107 (b) to

metal-bound isocyanide 1-106 (Scheme 1-24).


K2PdCl4
NH2 0 CIO4E
(a) 2 + R-N-C -
NH2 O H20, rt

1-103


H )O
N-N ClO4

H IP H
C cC
N N
R R
R=alkyl 1-104
65-85%


H H
excess
HCI N-N
1 "6 ,R
N- R R
H Cl' H
1-105
65-96%


q
Me-NH HN-Me
1-107

DCM, rt, 3 h
CH3CN, reflux, 2 h
65%


F3C Mes NMe CF3
SNC N C

H C Pd'CI H


1-106 1-108

Scheme 1-24. Synthesis of Chugaev-type ADC-Pd complexes with hydrazine or amine

Fiurstner et al. reported the synthesis of monodentate ADC Pd complex 1-111 through

oxidative addition of chloroamidinium precursor 1-110 which was easily synthesized from urea

1-109 (Scheme 1-25).52 Five and six member rings as well as dimethyl substituted ADCs were

synthesized through this route. Nickel complexes could also insert into the C-C1 bond. The main

drawback of this method is the incorporation of phosphine ligand into the ADC metal complex

limiting its applicability.


N N (COCI)2 Pd(PPh3)4 X
ON No --N-- N ON, C, No
I toluene toluene C
0 60 OC Cl 100 C Ph3P-Pd-PPh3
X 50% Cl
1-109 1-110 1-111

Scheme 1-25. Pd complex formation from oxidative addition of chloroamidinium precursor









Recently Hong et al. reported a general methodology of chloroamidinium activation by

lithium-halogen exchange (Scheme 1-26).53 Using this new methodology, a Pd complex without

phosphine ligand 1-116 was synthesized as well as Rh and Ir complexes 1-114 and 1-115.

n-BuLi
O N n -H\ (or t-BuLi)' N N
THF I
Cl -78 OC, 1 h Li M-CI
BF2 1-113
1-112
M = Rh (65%), Ir (71%)
1-114 1-115


I
Me2N-Pd-CI
(45%)
1-116


Scheme 1-26. Metal complex formation through lithium-halogen exchange from
chloroamidinium precursors

1.4 Copper-Catalyzed Applications

1.4.1 Copper-Catalyzed Allylic Alkylation

Typical palladium catalyzed allylic alkylation54 goes through a metal-allyl intermediate

which is usually attacked at the least hindered position. Generally soft nucleophiles are used such

as malonate, amine, alcohol and thiol. On the other hand, copper-catalyzed allylic alkylation55

proceed with high SN2'-selectivity and allow the use of hard nucleophiles such as Grignard

reagents,56'57 dialkyl zinc58 or aluminum reagent creating new tertiary or quaternary all carbon

stereogenic centers from simple linear allylic substrates (Scheme 1-27). The allylic alkylation

can lead to two types of product: the chiral y product 1-118 (branched compound) and/or the

achiral a product 1-119 (linear compound). Due to extensive research in this area, only Grignard

reagent as nucleophiles will be covered.









Cu (I or II)
carbene ligand
R' phosphoramidite R' Nu R'
R LG hard Nu: R"^ + R L Nu
1-117 -RMgBr 1-118 1-119
-R2Zn
-R3AI y product a product
(SN2') (SN2)

Scheme 1-27. General picture of the copper-catalyzed allylic alkylation

In 1995, Backvall reported the first enantioselective copper-catalyzed allylic alkylation.59

A thiolate ligand 1-122 with pendant amino group was used (Scheme 1-28). Excellent

regioselectivity and low ee were observed with ester leaving group in 1-120. In the transition

state proposed by the author, the second coordination site of the ligand binds to the leaving group

through magnesium ion.

n-BuMgl
Et20, 0 C
2 h Cy n- Bu
Cy.., OAc n-Bu, S. .NMe2
Cy<-OAc
1-122 (14 mol%) n-Bu Cu Mg-l
1-120 1-121 0 O
y:a 100:0 / 01
100% yield Transition state proposed by
Su 2 42% ee Backvall

1-122

Scheme 1-28. First example of enantioselective copper-catalyzed allylic alkylation by Grignard
reagents

After an extensive screening of phosphorus ligand, Alexakis et al. obtained good

enantioselectivity using a TADDOL phosphoramidite ligand 1-125 (Scheme 1-29).60 A chloride

leaving group in 1-123 was key to the success of this reaction, in the case of an acetate leaving

group such as 1-120 only racemic compound was produced. Moreover slow addition of the

Grignard reagent was crucial for the chirality.










EtMgBr Ph Ph
DCM, -78 OC Et O
PhICl Ph~ P-O N-
CuCN (1 mol%) O 0" o
1-123 1-125 (1 mol%) 1-124 Ph Ph Ph Me
y:a 94:6 1-125
100% yield
73% ee

Scheme 1-29. First generation of phosphoramidite ligand applied in the allylic alkylation

In a second generation system, CuCN was exchanged with CuTC which increased the ee

by 10% (Scheme 1-30, a). The reaction was expanded to aliphatic substrates with the help of a

second generation phosphoramidite ligand 1-128 which possessed a chiral binaphthol unit

(Scheme 1-30, b).56g


EtMgBr Ph Ph
DCM, -78 oC Et 0 0
(a) Ph Cl 1 h Ph P-0 N-
CuTC (1 mol%) Oh 0' 0
1-123 1-125 (1 mol%) 1-124 Ph Ph Ph Me
y:a 96:4
1-125
97% yield
82% ee



iPrMgBr Ph
DCM, -78 OC iPr ..o
(b) Cl 1 h Ph P-N
CuTC (1 mol%) 0
1-126 1-128 (1 mol%) 1-127 Ph
y:a 99:1
95% yield
74% ee

Scheme 1-30. New condition with CuTC and second generation of phosphoramidite ligand
applied for the allylic alkylation

For the third generation of phosphoramidite ligand 1-132, the binaphthol unit chirality and

the ortho OMe were found to increase drastically the ligand activity and selectivity (Scheme









1-31).56 If the OMe substituents were not present the enantioselectivity dropped to 55% ee with

a ratio of 79:21 between branched and linear products. On the other hand, if the atropoisomerism

is switched to (S), only 46% ee was obtained with a regioselectivity of 73:27. It was believed

that the OMe substituents act as pendant groups which would make this ligand bidentate. As an

application of the use of OMe substituents, 1-129 was converted to chiral cyclopentene 1-131 by

ring closing metathesis in a one pot process.



DCM, -78 C Ph one pot Ph (R
PhMgrC -O---------e ( -P-
Ph CuTC (1 mol%) PC (R) gP-N
1-132 (1 mol%) CY3 p (R) "
1-123 1-129 CI uPh 1-131R
y:a 97:3 PCy3 / OMe
79% yield
83% yield 1-130 93% ee 1-132
93% ee

Scheme 1-31. Third generation of phosphoramidite ligand applied in the allylic alkylation

Feringa and coworkers studied also the allylic alkylation and described the use of

commercially available Taniaphos ligand 1-134 in this reaction.56d Interestingly, a chloride

leaving group gave only linear product but aliphatic substrates with a bromide leaving group

gave 92-94% ee of SN2' products. In order to synthesize 1,2-dialkyl motifs, the author developed

a one pot process combining allylic alkylation and cross metathesis with methyl acrylate. The

subsequent product 1-135 can be subjected to copper-catalyzed enantioselective 1,4 addition of

Grignard reagents described in a previous report.61 Using the two enantiomers of this phosphine

ligand, syn and anti products could be obtained in excellent dr (Scheme 1-32).

Following this report, Feringa et al. extended the scope of this reaction to chiral allylic

esters 1-139.56c The temperature of the reaction was found to be a key element. If the reaction

was run at -85 OC, the major product was linear. Careful temperature optimization gave only the










branched product 1-140 (Scheme 1-33). This product gave chiral furanone 1-141 by ring closing

metathesis.


Ph -' Br

1-133


1) MeMgBr
CuBroMe2S (1 mol%)
1-134 (1.1 mol%)
DCM, -75 C, 4 h
2) Hoveyda-Grubbs
2nd generation (2 mol%)


OMe
DCM, rt, 36 h

\N


F PPh2
z^ Ph2P
ID 1 14",A -r i Lh


Me

Ph O
OMe
1-135

66% yield
98% ee


i i-i I dlaiiiJ iu Me
-- PPh2
Fe PCy2


(R,S)-1-137

Scheme 1-32. Synthesis of syn and anti 1,2-dialkyl motifs


EtMgBr
CuBr*MeS (5 mol%) Me
(R,S)-1-137 (6 mol%)
----------- phr
DCM, -75 C, 22 h OP
Et OMe
1-136
81% yield
dr 99:1


EtMgBr Me
CuBr*MeS (5 mol%) I
(S,R)-1-137 (6 mol%) Ph
DCM, -75 C, 22 h Et OMe
1-138
84% yield
dr:96:4


0
Ph -- O -Br

1-139


EtMgBr
CuBr*Me2S (0.5 mol%)
1-134

DCM, -73 C, 16 h


0 Et
Ph O

1-140
80% yield
98% ee


Hoveyda-Grubbs
2nd generation
DCM, reflux, 2 d oEt


1-141
78% yield
98% ee


Scheme 1-33. Synthesis of chiral furanone.

Toward the goal of making chiral building blocks, Feringa and coworkers expanded this

reaction to nitrogen substituted substrates with Boc and tosylate as protecting groups.62 Using

typical condition, the chiral protected amine 1-143 was obtained in 96% yield and 95% ee

(Scheme 1-34). Slow addition of the substrate (2.5 mL/60 min, 3M) was crucial to obtain high

ee.













O 1-1 Br
O=S=O

1 1-142


MeMgBr
CuBr-Me2S (5 mol%)
1-134 (6 mol%)

DCM, -75 C, 24 h


Scheme 1-34. Allylic alkylation with allylic bromide containing nitrogen functional group

This chiral protected amine was converted to several building blocks to show the

applicability of this reaction (Scheme 1-35).


0
Boc.N .

Ts Me
1-144
114 PdCI2, CuCI2
02, DMF/H20
rt, 82%

Mg, sonication
MeOH, rt, 90% Boc.N

Ts Me
1-143
/RuCI, Nal04
MeCN/CCI4/H20
rt, 79%


Boc- N OH

Ts Me
1-148


1)NaBH4, rt
2) HCI
77%


03, DCM/MeOH
-78 C
-------------]---^


1-147
1)NaBH4, rt
2) 60 *C vacuum
3) HCI
69%
11


Boc'N OH HN O
Ts Me Ts Me
1-146 1-149

Scheme 1-35. Synthesis of bifunctional chiral building blocks from chiral protected P-amine

P-Amino acid 1-146 was obtained in one step through Ru-catalyzed oxidation of the

terminal olefin 1-143 with NaI04.63 The tosylate protecting group could be selectively removed

to give 1-145 by treatment with magnesium under sonication.64 Catalytic Wacker oxidation

afforded the P-amino ketone 1-144 in 82% yield. A combined ozonolysis/reduction protocol


Boc--N

Ts Me

1-143

y:a 95:5
96% yield
95% ee


Boc-.N
H M
Me
1-145









transformed the olefin moiety into either 1,3-aminoalcohol 1-148 with both protecting groups on

the nitrogen atom or a tosylated amine 1-149 with Boc protected alcohol, depending on the

workup procedure. Direct quenching of the reaction mixture with 1 M aqeous HC1 gave

exclusively compound 1-148. In contrast, prior concentration of the reaction mixture at 60 C

(e.g., by removal of solvent in vacuo) led to a 1,5-migration of the Boc-group65 to the newly

formed alcohol, thus yielding compound 1-149.

Hall and co-workers reported boron substituted substrates 1-150 which could be subjected

to the allylic alkylation.45a Using phosphoramidite ligand 1-153, chiral allylic boronate esters 1-

151 could be readily converted to functionalized homoallylic alcohols 1-152 (Scheme 1-36).

0
F 2) J BF30Et2
O 1)1-153 (5.5 mol%) Ph OH
O CuTC (5 mol%) B -78 OC, 40 h Et
Cl B'o O Ph Et
DCM, -78 OC, 6 h Et 3) aq NaHCO3
-78 OC to rt
1-150 1-151 1-152

OMe 75% yield
18:1 E/Z
O *"I. 92% ee
P-N


W OMe

1-153

Scheme 1-36. Enantioselective preparation of a-substituted allylboronates

Okamoto et al. first reported the use of monodentate chiral NHC ligands in this reaction

(Scheme 1-37).66 Acetate and 2-pyridyl ether 1-154 were found to give better results as leaving

groups than chloride leaving group in 1-123 (different observation with phosphoramidite

ligands). Using the bisoxazoline based carbene ligand developed by Glorius,21 copper complex

1-156 was synthesized and tested in this reaction but only moderate ee was obtained (50%). 1-









157 gave better results (70%). A proposed transition state shows magnesium halide as counter

ion of the cuprate intermediate binding to the leaving group. Then the cuprate is brought close to

the double bond by some ionic interaction (Scheme 1-37).

n-HexMgBr
1-156 or 1-157 n-x 0 0
(1 mol%)Hex
N N N
TBSO O Et20, -20 OC TBSO-'
20h CuCI
1-154 2y:a 98:2
1-155 1-156
99% yield
50% ee


RN3 N x RN N

M Mg e Me
O~ Cl
1-157
Transition state proposed by Okamoto 99% yield
70% ee

Scheme 1-37. Cu-catalyzed allylic alkylation using monodentate NHC ligands and proposed
transition state

In another report, Hoveyda and co-workers reported a copper free enantioselective allylic

alkylation57b where carbene ligand was proposed to act as a Lewis base to activate Grignard

reagent (Scheme 1-38). By varying the NHC structure, 1-160 was found to be the most efficient

reagent in this reaction giving excellent enantioselectivities for various secondary alkyl Grignard

reagents. All carbon quaternary centers could be obtained using this metal free reaction

condition. The bidentate ligand design was found to be crucial for good regioselectivity in the

allylic alkylation. If the hydroxyl group of the ligand 1-160 was replaced by a proton or

protected with a methyl, only 2% of product formation was observed.









Ph Ph
O 1-160 O
Ce 5 d 5mol%
MeOCCI i5mol% MeO N ":1N
i-PrMgCI i-PrMe Me5
1-158 THF, -78 0C 1-159 HO ci
24 h
1-160
80% yield 1-160
97% ee

Scheme 1-38. Cu-free enantioselective allylic alkylation on y-chloro-a,f-unsaturated esters

One of the last challenges remaining was the use of aryl Grignard reagent as nucleophile.

When using this reagent, linear product was usually obtained as the only product. The first

example was reported by Alexakis et al. in 2001.52 When CuCN and TADDOL derived ligands

were used, 2-MeOC6H4MgBr was successfully added in good regioselectivity and modest 21%

ee. Kobayashi reported the use of a picolinoxy leaving group 1-161 to obtain high

regioselectivity in allylic alkylation with aryl Grignard reagents (Scheme 1-39).67 Even though

the reaction was stoichiometric in copper, excellent transfer of chirality was observed with a

chiral leaving group. Both Grignard reagent and copper source needed to match halide source to

generate in situ MgBr2. This Lewis acid could then activate the leaving group to facilitate its

displacement by the phenyl cuprate.



)N
O PhMgBr (2 equiv.) Ph
.O CuBr*Me2S -- M
=- THF, -60 to -40 C
1-161 1h 1-162

97% ee 83% yield
97% ee

Scheme 1-39. Anti selectivity with Grignard reagent

A catalytic version of this reaction was reported by Tomioka et al. using an

amidophosphane ligand 1-165 (Scheme 1-40).68a For symmetrical substrate 1-163, only SN2'









products were obtained whereas other unsymmetrical substrates ranged from 4:1 to 3:1 mixtures

of branched to linear products.

CuTC (2 mol%)
Br 1-165 (4 mol%) Br

Br DCM, -78 OC, 4 h PO \ PPh2

1-163 89% yield
80% ee 1-165


CuTC (2 mol%)
B 1-165 (4 mol%)
Br -
l1 B DCM, -78 OC, 4 h

1-166


Ph


-167
1-167


y:a 82:18
100% yield
71% ee


Scheme 1-40. Allylic alkylation with phenyl Grignard reagent using phosphine ligand

Tomioka and co-workers explored more ligand structures to generalize this reaction

(Scheme 1-41). Using chiral NHC 1-181 developed by Grubbs, they replaced the phenyl

substituents at the front by bulkier and more extended diarylmethyl.68b


Cl Br
1-166


(2 mol%) 1-168

DCM, -78 OC, 0.5 h


Scheme 1-41. Allylic alkylation with phenyl Grignard reagent using monodentate NHC ligand


Ph



1-167

y:a 93:7
96% yield
95% ee









This new monodentate NHC ligand 1-168 was found to be very successful in the aryl

Grignard addition to allylic substrates. High regioselectivity and enantioselectivity were

produced for various substrates.

1.4.2 Copper-Catalyzed P-Borylation of a,P-Unsaturated Carbonyl Compounds

Cu-catalyzed borylation incorporates a boron-ester in the 0 position of unsaturated

carbonyls69 which can be subsequently converted into useful functional groups.70 Hosomi (a) and

Miyaura (b) first reported independently this transformation (Scheme 1-42). Hosomi and co-

workers found catalytic conditions and showed that both phosphine ligand and DMF were

needed to achieve high yields.69q The reaction conditions were also successful on cyclic ketones.

Miyaura et al. reported reactions with a wider range of 1-171 from ketones, esters to nitriles.690'p

Miyaura introduced the base potassium acetate to activate the copper catalyst.


CuOTf (10 mol%)
O + BV O B Bu3P (11 mol%) O'B'O O
(a) 0 + B-B -- |
(a) Ph Ph 0d O DMF, rt, 10 h Ph Ph
96% yield
1-169 96% yield 1-170


CuCl I
O BO AcOK OB'O
(b) EWG + OB-B
(b) R0EWG 0 O DMF, rt, 16h R EWG
1-171 90% yield rac-1-172

EWG: ketones, esters
and nitriles
R: CH3, H
yield: 50-90% yield

Scheme 1-42. First reported examples for P-borylation of unsaturated ketones

Yun and co-workers disclosed a general methodology using chiral (R)-(S)-josiphos ligand

for the first asymmetric version of this reaction (Scheme 1-43).69b-g A protic reagent such as









methanol was discovered as a key component for increased yields.69b The reaction gave good

yields and ee from a wide range of acyclic and cyclic substrates.


CuCI (3 mol%)
josiphos (3 mol%)


NaOtBu (3 mol%) UB.U NaBO3 OH

EWG THF,rt,3-16 h EWG R EWG
MeOH (2 equiv.) R THF/H20 (1:1)
1-171 B2pin2 (1.1 equiv.) 1-172 1-173
90-98% yield EWG: ketones, esters,
nitriles and amides
R: Alkyl, Aryl

90-97% yield
72-99% ee

Scheme 1-43. First asymmetric version using chiral josiphos phosphine ligand

Recently, Shibasaki et al. reported the generation of tertiary organoboronic esters 1-175 in

cyclic ketones (Scheme 1-44).69h The use of MeOH with DMF (dimethylformamide) or DMSO

(dimethylsulfoxide) solvent drastically decreased the yields to 10%. Here the conditions are

more closely based on Miyaura's (Scheme 1-42(b)). The generation in situ of LiPF6 seems to be

crucial for rate acceleration as well as increased enantioselectivity.

CuPF6(CH3CN)4 (5 mol%) Me
1-176 (6 mol%) O e tBu
tBuOLi (7.5 mol%) N P

R B2pin2 (1.5 equiv.) Bpin N P
DMSO, rt, 12h nR tBu Me
1-174 1-175 1-176
R= Alkyl, Aryl
n= 0-2 (R,R)-quinoxP*

85-99% yield
70-98% ee

Scheme 1-44. Generation of quaternary centers using chiral phosphine ligands

Using chiral carbene ligands, Fernandez and co-workers disclosed the synthesis of chiral P

alcohol in 73% ee after oxidation of boron reagent using acyclic a,3-unsaturated esters as










substrates (Scheme 1-45).69i-1 The reaction conditions were the same as reported by Yun.69c

Chiral NHC 1-180 gave poor enantioselectivity while 1-181 (developed by Grubbs) increased ee

by two fold and Ci-symmetric NHC ligand 1-182 gave better results than its C2-symmetric

variant 1-181. By varying the ester group 1-183, enantioselectivity could be increased up to 73%.


(NHC)CuX (2 mol%)
0 O+ -B N NaOtBu (3 mol%) 0'BO NaBO3 OH 0
OEt O B2pin2 (1.1 equiv.) OEt THF/H20 (1:1) OEt
MeOH (2 equiv.)
1-177 THF, rt, 6 h 1-178 1-179

Ph Ph Ph Ph

N ^ N N N N 0


with: ^ OiBu
1-180 1-181 1-182 1-183
93% yield 96% yield 99% yield 99% yield
10% ee (R) 31% ee (S) 55% ee (R) 73% ee

Scheme 1-45. First asymmetric version using chiral NHC ligands

Hoveyda and co-workers reported a copper free reaction using NHC 1-186 as a Lewis base

(Scheme 1-46).71 The carbene ligand served as an activator for the diboron reagent. Good yields

were obtained for various cyclic and acyclic ketones. MeOH was discovered to be unnecessary

for this reaction when using NHC ligand.

1-186 (5 mol%)
with or without CuCI
0 No MeOH Bpin0 N
NaOtBu (5 mol%) O
B2pin2 (1.1 equiv.) 4
1-184 THF, 0 OC, 6h 1-185 1-186
92% yield

Scheme 1-46. Copper and MeOH free P-borylation of unsaturated ketones

Several mechanistic studies72 were realized and after compilation of most of them, here is a

proposed mechanism of this transformation (Figure 1-6). In a first stage, ligand, base and copper









are premixed to yield ligated copper alkoxide 1-187 which undergoes C-bond metathesis with

pinacolate diboron reagent. The newly formed borylated copper complex 1-188 inserts into the

a,p unsaturated alkene to give a 3,4 addition product 1-189. Then the C-copper bound species 1-

189 isomerizes to the O-copper bound enolate 1-190 which is more likely to undergo the next a-

bond metathesis due to the oxygen lone pairs. From this species, o-bond metathesis occurs either

with methanol or diboron reagent when present. In the first case, copper alkoxide 1-187 is

regenerated and a borylated product 1-172 is freed. On the other hand, borylated copper complex

1-188 is formed and a borylated boron enolate product 1-191 is synthesized which can be further

derivatized if needed.


CuX + NaOtBu + L
SL = NHC, phosphine


RO-Bpin


B2pin2


MeOH


LCu-Bpin
1-188


/ 0

Bpin OCuL BpinO RR2
R. RR R2 1-171
R R2R 2
CuL
1-190 1-189

Figure 1-6. Proposed mechanism for B-borylation of unsaturated ketones


Bpin 0









CHAPTER 2
C2-SYMMETRIC BIISOQUINOLINE N-HETEROCYCLIC CARBENE LIGAND

2.1 Introduction: Ligand Design for C2-Symmetric Ligands

Structural diversity is far from being fully explored or available with N-heterocyclic

carbene ligands. Key topological features ofNHC ligands that are desirable for asymmetric

catalysis still need to be identified. Thus, exploring new types of chiral carbene ligands,

especially focusing on creating an effective chiral space around the metal center, would be of

great use.

Limited successes so far with the current chiral carbene ligands might imply that the chiral

environment created by chiral directing groups either on the nitrogens or the backbone is too far

from the metal center to discriminate effectively between the two enantiotopic faces. To induce

more selectivity, chosen chiral carbene ligands have been optimized to furnish new ligands

(Figure 2-2). The chiral design developed by Grubbs accounts for over 90% ee in asymmetric

ring closing metathesis reactions (Figure 2-1).32,33 However a substrate dependence on

enantioselectivity in these reactions might suggest that the chiral space created by the ligand is

remote from the metal center and therefore less discriminating for less sterically demanding

substrates. In addition, the X-ray crystal structure shows that the aryl groups on the nitrogen

atoms are pointing orthogonal to the plane ofNHC-Ru. Therefore, it would be interesting to

extend and reposition the stereodifferentiating groups more toward the metal center. We

envisioned that this possibility could be explored through optimized structure (Figure 2-1) where

the chiral groups are installed within a ring structure which directs the components in a defined

position. From this design, we are hoping for an increase in selectivity.









R R


R I R Y R
M M

R R -

-- -=- > -------


2-1 2-2
Chiral groups can More defined structure may
rotate away from substrate induce more selectivity

Figure 2-1. C2-symmetric ligand design

Additionally, the X atom in the ligand structure 2-2 could be varied and different

properties could be obtained. In a first part, where X = O, we decided to optimize Glorius'

ligand23 by changing the chiral groups (Figure 2-2) to amino indanol 2-6 which would give more

bulk. Later, we wanted to add R groups on the phenyl ring to extend further the chiral pocket

toward the metal. The ligand 2-6 will be called the bisoxazoline derived NHC ligand. The ligand

2-3, which was first developed by Glorius, gave excellent results in the Suzuki reaction between

aryl chlorides and substituted boronic acids.22 In a second part, where X = N, the known

bisimidazoline ligand73 (Figure 2-2) could be converted by cyclization into a carbene ligand 2-7.

The latter would induce more donating character within the carbene structure thanks to the

donating effects from the nitrogen atoms. The known bisimine ligand 2-4 has been used for

allylic alkylation and showed modest activity.73 In a third part, where X = C, we decided to use

the frame of the biisoquinoline carbene ligand74 (Figure 2-2) and incorporate stereogenic centers

a to the nitrogen atoms and make an unsaturated carbene ligand 2-8.









Ligand A Ligand B Ligand C
X=O X=N X=C

R2 R2
0 0O1 1H H


Bn C' NBn N N NN
R1 R,

2-3 2-4 2-5




O O R2 R2

N NN
S .., 'NN RN N'
R C R, C'
R R1 ** R R
2-6 2-7 2-8
Bisoxazoline derived Bisimidazoline derived Biisoquinoline derived
NHC ligand NHC ligand NHC ligand

Figure 2-2. Tricyclic ligand design with variation of X

2.2 Bisoxazoline Derived NHC Ligand

Starting from trans-aminoindanol 2-12, the bisamide 2-11 was made followed by a

cyclization leading to the bisoxazoline 2-10. The imidazolium formation was carried out using

known procedures (Scheme 2-1). Two different ways were found to make the bisoxazoline

compound (Scheme 2-2). The trans-aminoindanol 2-12 was refluxed in toluene with diethyl

oxalate for 12 hours to lead to the bisamide 2-11 in 95% yield. Then it was reacted with mesylate

chloride in THF to give the O-mesylated product 2-13 in 90% yield. Biscyclization in an excess

of KOH in reflux methanol for 1 hour led to the bisoxazoline 2-10 in quantitative yield.

Moreover, another shorter path was discovered using Burgess reagent,75 but the overall yield was

diminished.



















NH2

1W ''",OH

2-12
trans amino indanol


Scheme 2-1. Retrosynthesis from trans-aminoindanol

toluene
NH2 reflux
S 0 0 12 h
2 +
2 "OH EtO OEt 95%

2-12


Burgess reagent
THF
60%


KOH
MeOH
reflux
1h
99%


4 h MsCI
90% Et3N
THF


OMsO O Ms

INH HN


2-10 2-13

Scheme 2-2. Synthesis from trans-aminoindanol

Then the focus was on the last step which is the imidazolium formation. Usually, the

common reagent is chloromethyl ethyl ether, but in this particular substrate, the chloride anion

liberated in the course of the reaction can attack the oxazoline ring 2-15 and regenerate an amide

2-17 (Scheme 2-3).


imidazolium
synthesis


2-10


OHO O HO
cyclization
NH HN


2-11


amide
synthesis









0 0 CI
U 0t 0o ci C0
Bn 2-14 Bn -n n C B B\n C OBn

C Bn r OEt Bn Bn0OEt Bn -OEt Bn
2-15 2-16 2-17

Scheme 2-3. Decomposition pathway using chloromethyl ethyl ether

For this reason, AgOTf was used to trap the chloride anion as an AgCl salt. As a trial, the

known bisoxazoline 2-14 was reacted with chloromethyl pivalate and AgOTf to yield the desired

imidazolium product 2-18 in 60% yield (Scheme 2-4).

AgOTf
Cl O O
O O O0

N N N N
Bn Bn CM B n "Bn
Bn Bn 40 oC, dark, 20 h Bn Bn
60% TfO
2-14 2-18
AgOTf

0 cl'-'r 0 0

.N N N^^ N N
DCM Tfe
40 'C, dark, 20 h Tf
2-10 35% 2-19


Scheme 2-4. Bisoxazoline-imidazolium synthesis

Unfortunately, it could not be reproduced for 2-10. The AgOTf salt seemed to be a very

sensitive reagent so a fresh bottle was used and stored in the glove box. This time the reaction

proceeded in 35% yield. After this success, reaction of the Pd-NHC metal complex with

imidazolium 2-19 was attempted. Known conditions reported by Glorius21'22 using KOtBu

followed by addition of Pd(II) was attempted but only starting materials were isolated. A

transmetallation route was also attempted using Ag20 but it also failed. Later it was found out

that the imidazolium 2-19 seemed to decompose over time and its synthesis was not reliable.









With all those issues, this project was stopped. We then decided to synthesize the bisimidazoline

derived NHC ligand variation 2-20. This ligand has nitrogen atoms instead of oxygen atoms

which should influence the electronic properties.

2.3 Bisimidazoline Derived NHC Ligand

Starting from commercially available amino acids 2-22 (Scheme 2-5), the corresponding

amino alcohol was obtained by reduction and converted to the bisamide 2-21. Then it was

cyclized in two consecutive steps to make the imidazoline moiety 2-4 which gave the

corresponding imidazolium by typical ring closing conditions.

R R R R
I I imidazolium
N N synthesis N

R R R
x
2-20 2-4



cyclization 0 O reduction O
HO /-OH H2N. OH
cNH HN amide
R R synthesis R
2-21 2-22

Scheme 2-5. Bisimidazoline retrosynthesis

Valine 2-23 was reduced with LAH to valinol 2-24 in a modest yield, and the amine 2-24

was coupled with diethyl oxalate to form the bisamide 2-25. Thionyl chloride was used to

convert the alcohols to chlorides. Using PC15, the amide 2-26 was converted to the imidoyl

chloride 2-27. The toluene was evaporated under vacuum followed by the addition of benzyl

amine in acetonitrile to give 2-28 or aniline to give 2-29 (Scheme 2-6). The yields were low but

the mechanism involved four nucleophilic substitutions and provided two new rings. So a 40%

yield represented actually a 65% yield for each ring formation.









LAH 0 0
0 THF
H reflux H2N OH EtO OEt
H2N OH re lux
12h toluene
S60% reflux, 12 h
2-23 2-24 97%




HO 0 OH SOC12 ci 0
H H toluene CY e CI
NH HN NH HN
90 C
12 h
2-25 97% 2-26

R R
Toluene Cl Cl RNH2 N N
PCI5s Cl / \ N Cl Et3N N
85 oC N CH3CN
5 h reflux, 12 h
2-27 -R= Bn, 40%, 2-28
R=Ph, 20%, 2-29

Scheme 2-6. Bisimidazoline synthesis

Unfortunately, the final step (Scheme 2-7) was not promising; both known conditions gave

a mixture of products. Moreover, the crude NMR did not show the characteristic imidazolium

peak between 8 and 10 ppm. 2-28 was the first bisimine synthesized and we supposed that the

lone pairs of the nitrogen atoms might be in conflict with the imidazolium synthesis. To solve

this issue, 2-29 was synthesized hoping that the phenyl substituents would delocalize these lone

pairs away from the imine moiety.

So far, electronegative atoms seemed to perturb either the imidazolium synthesis or the

complex formation. This led us to think the donating effect coming from the lone pairs of the

oxygen or nitrogen atoms is probably weaker than their electronegativity effect. So the third part

involving X = Csp2 (Figure 2-2) atoms instead of X = O or X = N atoms should inhibit electronic

effects and be closer in reactivity to a typical NHC.









R R R R
I I I I
N N NN

S11 012 2X
R=Bn, 2-28 R=Bn, 2-30
R=Ph, 2-29 R=Ph, 2-31

CI O O
Method 1: AgOTf DCM
40 C, dark, 20 h

Method 2: CI O THF, rt

Scheme 2-7. Bisimidazoline NHC synthesis

2.4 Biisoquinoline Derived NHC Ligand

While our group was working on the BIQ (biisoquinoline) ligand 2-8,12d Herrmann and

coworkers reported the synthesis of the saturated version, 2-32, of our target structure. From the

saturated BIQ imidazolium, the unsaturated NHC-metal complexes were unexpectedly formed in

moderate yields. This oxidation happened during the preparation of NHC-Rh or Ir complexes 2-

34 and 2-35 via transmetallation with Ag20, when bromide was the counterion for the saturated

imidazolium salt 1-49 (Scheme 2-8).12g Their synthesis was based on the homocoupling of the

isoquinoline moiety (Scheme 1-10). Only phenyl substituted BIQ imidazolium was reported,

probably the diastereoselectivity ratio of this coupling reaction might decrease for other chiral

substituents. In contrast, our retrosynthesis scheme would allow a wide variety of chiral

substituents (Scheme 2-9).

A chiral amine 2-39 was synthesized from commercially available amino acids 2-22

followed by typical bisamide synthesis (Scheme 2-9). It was cyclized using Bischler-Napieralski

cyclization. Several R groups were tried such as isopropyl, isobutyl, tert-butyl, cyclohexyl,

methyl cyclohexyl, fused cyclohexyl and phenyl.










/ \ X=Br, 1-49 /\ / X=CI,2-32
1)Ag20 -H H 1)Ag20
NN 2) [M(COD)CI]2 N 2) [M(COD)Cl]2
Ph I Ph CH2C2 CHC
Cl-M Ph X Ph 2H


M = Rh (31%), 2-34
M = Ir (38%), 2-35

Scheme 2-8. Bisdihydroisoquinoline-based carbene ligands


imidazolium
synthesis
N. RN N N
R O R R R
CI
2-36 2-37


Bischler-Napieralski O O amide
cyclization (/ NH HN synthesis
NH HN--/
R R
2-38

H2N several steps
-" H2N OH


H H

N N
Ph I Ph
ClvM


M = Rh (64%), 2-33
M = Ir (52%), 1-52


R Ph
2-39 2-22

Scheme 2-9. Biisoquinoline retrosynthesis

2.4.1 Synthesis of Isopropyl, Isobutyl, Tert-Butyl and Cyclohexyl Alanine Substituted
Amines

The commercially available amino acid 2-23 was reduced by LAH to give the

corresponding amino alcohol 2-24 (Scheme 2-10). Then in a one pot process, the alcohol was

removed. First the amine 2-24 was protected with a tosylate group then the alcohol was

converted into a leaving group with mesylate chloride followed by the substitution of the alcohol

by the amine to form the aziridine 2-46. Addition of a phenyl cuprate, made in situ, onto the









aziridine moiety led mainly to the compound 2-50. Deprotection of the tosylated amine gave the

desired chiral amine 2-54. All these reactions could be run on a 10g-scale with no significant

drop in yield for various amino acids. Other conditions were tried for the deprotection of the

tosylate group such as Mg (sonication) in MeOH and Na with naphthalene. The Mg conditions

worked well only in a small scale and the Na conditions were very sensitive to air and moisture.

The reported procedure using Li (14 equiv.) and a catalytic amount of naphthalene was robust

and did not need extra precaution.

0 LAH 1) TsC
H2N OH THF H2 OH Et3N, 3 h
R reflux, 12 h R 2) MsCI
60% -25 OC to rt
R= i-Pr, 2-23 R= i-Pr, 2-24 12 h
R = i-Bu, 2-40 R = i-Bu, 2-43 80%
R = t-Bu, 2-41 R = t-Bu, 2-44
R = CH2Cy, 2-42 R = CH2Cy, 2-45


Ts PhMgBr
s Cul TsHN Li, Naphthalene H2N
N \ -
R THF, 3 h Ph THF, -78 C to rt R Ph
95% 12h
95%
R= i-Pr, 2-46 R= i-Pr, 2-50 R= i-Pr, 2-54
R = i-Bu, 2-47 R = i-Bu, 2-51 R = i-Bu, 2-55
R = t-Bu, 2-48 R = t-Bu, 2-52 R = t-Bu, 2-56
R = CH2Cy, 2-49 R = CH2Cy, 2-53 R = CH2Cy, 2-57

Scheme 2-10. Chiral amine synthesis from amino acids

2.4.2 Cyclohexyl Substituted Amine Synthesis

The cyclohexyl substituted amino acid being more expensive, the amine 2-62 was

synthesized by another route. (S)-Phenylglycine 2-58 was reduced to the corresponding alcohol

2-59. A 60:40 mixture of oxazolidines 2-60 were then formed by the addition of cyclohexyl

aldehyde (Scheme 2-11). Then addition of benzyl magnesium chloride gave only the

diastereomer 2-61. Mild hydrogenation was not strong enough to cleave the phenethyl alcohol 2-

61; therefore an autoclave was used to increase the hydrogen pressure up to 800 psi (54 atm) and









the temperature to 75 C to give the pure chiral amine 2-62. Here, it is interesting to note that the

chirality in the compound 2-62 is the opposite absolute configuration compared to the

compounds 2-54 to 2-57. The other enantiomer can be synthesized by using (R)-phenylglycine.

MgSO4

H2N OH THF H2N OH O -.
Sreflux, 12h 2DCM, rt
99%
O 60% OLJ 99%
2-58 2-59 2-60

H I Pd/C
,,, N H2, 800 psi H2N
THF, -30 C to rt EtOH Ph
4h OH 75 "C
71% 60%
2-61 2-62

Scheme 2-11. Cyclohexyl amine synthesis

2.4.3 Fused Cyclohexyl Substituted Amine Synthesis

To increase the steric bulk around the ligand, a cyclohexyl ring fused to the BIQ core was

proposed. Using Chem3D, the trans configuration 2-63 was rejected while the cis 2-64 was

preferred because the cyclohexyl ring seemed to sterically intrude more in this conformation

(Figure 2-3).

Rac-2-65 was first synthesized to make sure this pathway could work (Scheme 2-12).

Phenyl cuprate, made in situ, was added to cyclohexene oxide 2-66 which gave the trans alcohol

rac-2-67. Then this alcohol was replaced by an amine with an inversion of stereocenter using

Gabriel synthesis.76 Mitsonobu reaction77 was used to replace the secondary alcohol rac-2-67

with phthalimide in a SN2 pathway, and then rac-2-68 was reduced to the cis amine rac-2-65

using ethylene diamine.




















2-63


CI6

2-64


Figure 2-3. Fused cyclohexyl BIQ (trans 2-63 and cis 2-64 configuration) calculated with
Chem3D


2-65


OH
,,0 PhMgBr
O- Cul, THF Ph
0 oC, 12 h
91% yield


2-66


PPh3
DIAD
THF, rt


rac-2-67


0
N Ph H2N NH2
N Ph _P J
EtOH
reflux
82% yield
rac-2-68


Scheme 2-12. Racemic synthesis of the fused Cy amine rac-2-65

To resolve this racemic amine, the two diastereomers resulting of the amide coupling with

mandelic acid were synthesized (Scheme 2-13). Both compounds 2-69 and 2-70 could be


H2N Ph




rac-2-65









separated by column chromatography unfortunately the cleavage of the amide moiety to recover

the chiral amine was too harsh and the compound could not be isolated. Resolving at the alcohol

stage would be more economical thus we decided to study rac-2-67.


0


0


H2N Ph d-mandelic acid NH Ph H Ph
HOBt, EDCI HO + HO-
DMF, rt, 1 d Ph Ph

rac-2-65 2-69 2-70

Scheme 2-13. Amide synthesis for chiral resolution

The two esters 2-72 and 2-73 were first synthesized (Scheme 2-14), but unfortunately they

were not separable by chromatography.


HO--T

TsHN Ph


HOBt, EDCI Ph O Ph

DMF, rt, 1 d ",i0 NHTs


PhO Ph

+ NHTs


rac-2-67 2-71 2-72 2-73

Scheme 2-14. Ester synthesis for chiral resolution

Then using kinetic resolution,78 the pure chiral alcohol (1R,2S)-2-67 could be obtained by

replacing the alcohol moiety by a chloride 2-74 using Mitsonobu conditions (Scheme 2-15). This

reaction was very efficient but it used a large amount of chiral BINAP (2,2'-

bis(diphenylphosphino)-1,l'-binaphthyl) which made this process expensive for a large scale

synthesis.

Ph OH (S)-BINAP (0.4 eq) Ph Cl Ph OH
NCS (0.9 eq) +

STHF 0
rt, 20 min
rac-2-67 2-74 (1 R,2S)-2-67
45% yield
98% ee

Scheme 2-15. Non enzymatic kinetic resolution of secondary alcohol










Following this kinetic resolution example, other similar methodologies were researched.

Many studies reported enzymatic kinetic resolution for secondary alcohol using different lipases

such as CALB, PS30 and AK.79 Because CAL-B (Candida antarctica lipase B) also known as

Novozym 435 was widely used, this enzyme was chosen and different conditions were screened

(Table 2-1).

Table 2-1. Optimization of the enzymatic kinetic resolution of rac-2-67 using lipase CALB
CALB (220 mg/mmol)
OH vinyl acetate 5 eq OAc OH
solvent
temp

rac-2-67 2-75 (1S,2R)-2-67

ee of the unreacted alcohol was
entry solvent and conditions 24 h 48 h 72 h determined by chiral HPLC
using Whelk-O 1 column
S tBuOMe at 40 OC 80% ee 93% ee 96% ee Hex/iPrOH (5%), 0.5 mL/min, 8 215 nm
2 nPrOH at 40 OC 1% ee
3 DCM at 40 OC 1%ee

4 THF at 40 OC 20% ee
5 Hexane at rt 22% ee
tBuOMe at rt
6 after 24 h add 0.5 eq Et3N 34% ee 85% ee
and heat at at 40 C
1,2 diemthoxyethane
7 after 24 h add 0.5 eq Et3N 40% ee 72% ee
and heat at at 40 C

8 1,4 dioxane 13% ee


After careful screening, tBuOMe (MTBE) was chosen as the solvent and 40 C for the

temperature and this reaction could be done on a large scale. The enzyme coated on acrylic resin

could be reused by simple filtration and there was no need for careful buffering or temperature

control. No yields were reported for this table because the reactions were realized on a small

scale and only the enantioselectivity of the crude reaction mixture was monitored. Then it was









tried on a larger scale and the same enzyme was filtered and reused four times with only 1% ee

loss (Scheme 2-16).

CALB (220 mg/mmol)
S/ vinyl acetate 5 eq \Ac + OH
OH OAc ^ OH

tBuOMe (0.2 M), 45 C
48 h
rac-2-67 2-75 (1S,2R)-2-67
2g
Run 1: 750 mg, 37.5% yield, 99.4% ee
Run 2: 800 mg, 40% yield, 99% ee
Run 3: 800 mg, 40% yield, 99% ee
Run 4: 850 mg, 43% yield, 98.4% ee

Scheme 2-16. Scale up of the kinetic resolution of secondary alcohol with reused enzyme

Following the previous plan (Scheme 2-12), the single enantiomer (1S,2R)-2-67 was

converted to 2-65.

2.4.4 Phenyl Substituted Amine Synthesis

The previously reported synthesis of amines 2-39 (Scheme 2-10) could not be used

because the regioselectivity of the phenyl cuprate addition would be opposite (Scheme 2-17).

With alkyl substituents, the addition takes place on the least hindered carbon but with aryl

substituents the benzylic position is more reactive and electronic effects are more important than

steric effects in this case.

Ts PhMgBr
I Cul Ph HN-Ts
N \_ _
Ph"-, THF Ph

2-76 2-77

Scheme 2-17. Reverse regioselectivity with phenyl substituted aziridine

Different strategies were envisioned (Scheme 2-18). We decided to take advantage of the

existing chirality in 2-78 and find a way to remove the alcohol. First, the amine 2-78 was

protected with a tosylate group then Et3SiH associated with a Lewis acid was used to reduce the









benzylic alcohol 2-79. Unfortunately, only the starting material was isolated. Then, the aziridine

2-80 was made using Mitsonobu conditions and allowed for the formation of a more reactive C2-

symmetric benzylic position. Polymethylhydrosiloxane and Pd/C were used to ring open the

aziridine. The desired tosylated amine 2-82 was synthesized in 70% yield. Even though this

reaction worked well, four steps total are needed. A shorter path would be a good upgrade in

order to make more material.

H PPh Ts
Ph NH2 CI Ph PPh3 N
Et3N __S_
E t T s D IA D P h e P h
Ph OH DCM Ph OH THF
2-78 97% 2-79 rt, 90% 2-80
MeONa 0 Et3SiH PMHS
12h X BF30Et2 70% EtOH
99% EtO OEt DCM, 0 C Pd/C

0
HNO TsHN TsHN

Ph Ph Ph Ph
Ph Ph
2-81 2-82 2-82

MeOH /
Pd/C
48h H2 (400 psi)
77%

H2N

Ph Ph
1-46

Scheme 2-18. Synthesis of (S)-1,2-diphenylethanamine

As seen previously, a ring structure was more reactive toward hydrogenation. Using

diethyl carbonate, the oxazolidinone 2-81 was formed in a quantitative yield. Using an autoclave

for the hydrogenation, the desired amine 1-46 was produced in 77% yield. This pathway was two

steps shorter and gave an overall yield of 76%.









All the desired chiral phenethylamines 2-39 have been synthesized, now they can be used

in the synthesis of the C2-symmetric BIQ based carbene ligands 2-36. In chapter 4, the same

chiral phenethylamines could also be used in the synthesis of the Ci-symmetric MIQ

(monoisoquinoline) based carbene ligand 4-2.

2.4.5 Biisoquinoline Based Carbene Synthesis from Chiral Amine

Bisamides 2-38 could serve as precursors for a double Bischler-Napieralski cyclization

(Scheme 2-9). Following previous work (Scheme 2-6), we used diethyl oxalate as the coupling

agent (Table 2-2).

Table 2-2. Optimization of bisamide coupling using diethyl oxalate
O O

H2N EtO fEt 0 NHH
Solvent \=/ NH OEt
R Ph T C R R R
time


R = Ph (S), 2-54
R = Cy (S), 2-62
R = i-Pr, 1-46


R = Ph (S), 2-83
R = Cy (S), 2-84
R = i-Pr, 2-85


R = Ph (S), 2-86
R = Cy (S), 2-87
R = i-Pr, 2-88


bisamide monoamide
entry R solvent T C time yiel d yied
yield yield

1 Ph toluene 125 36 h 60%
2 Cy 1,4 dioxane 130 5d 18% 67%
3 i-Pr 1,4 dioxane 130 5 d 45%

4 Cy 1,4 dioxane 130 1d 25%
+ 4 A MS

5 i-Pr 1,4dioxane 130 1d 18%
+ 4 A MS
6 i-Pr neat 120 12 h 80%
7 Cy neat 120 12 h 20%

Typical conditions gave only the monoamide product 2-83 (entry 1). A more polar solvent

was used and the temperature was increased (entry 2) but only small amount of bisamide was

formed and the monoamide stayed predominant. Molecular sieves were also added to the


)









reaction mixture to trap the released ethanol but the yields stayed low (entries 4 and 5). When

neat conditions were used (entry 6), the yield was increased drastically for 2-86. Unfortunately,

2-87 with more bulky substituents still gave low yield using neat conditions (entry 7). For 2-86,

the neat condition was chosen but a better procedure was still needed for more bulky substituent

such as Cy. If the reactivity of the nucleophile is decreased by steric effects, then a more reactive

electrophile could be used such as oxalyl chloride (Scheme 2-19). This new reagent was more

efficient than diethyl oxalate but it required a quick column chromatography instead of a simple

filtration.

0 0

H2N Clh C cl0

-Ph NHHN
Et3N R R
THF

R = Ph, 70% yield, 2-88 Ph H 0
R = Cy, 70% yield. 2-87 sN
R = i-Bu, 81% yield, 2-90 NH 'Ph
R = CH2Cy, 91% yield, 2-91 O
2-89

Scheme 2-19. Bisamide synthesis using oxalyl chloride

With the bisamides in hand, the double Bischler-Napieralski cyclization could be

attempted (Table 2-3). This reaction consists of a double intramolecular electrophilic aromatic

substitution.



SR, XR R


NR XX

2-92 2-93
bis(imidoyl) chloride bis-nitrilium ion

Scheme 2-20. Double Bischler-Napieralski cyclization









In a first stage, the amide moiety is converted to an imidoyl chloride 2-92 which subsequently is

transformed into a nitrilium ion 2-93. Then the aromatic ring will attack this carbocation

(Scheme 2-20).

Different dehydrating agents have been used (most common are POC13, P205 and Tf2O) to

convert the amide into the nitrilium ion. Usually this reaction works best with electron donating

group on the aromatic ring. Few reports exist on the biscyclization and none describes a

successful biscyclization with absence of substituents on the phenyl rings. The main issue of the

double cyclization is the vicinal proximity of the two carbocations. Even if the reaction involves

a step wise process, each nitrilium ion will be destabilized by either an amide group or an imine.

Following reported conditions for the cyclization of mono amido-ester,80 a non chiral bisamide

2-94 was reacted with POC13 and ZnC12 to give no product (entry 1). The use of a Lewis acid

seems necessary to activate the nitrilium ion for an attack from the benzene ring. ZnC12 was

replaced by a stronger Lewis acid Zn(OTf)2 which gave product in 38% yield (entry 2). Then

those conditions were tried out on different substituted chiral bisamide (entries 3-5). The

bisamide 2-87 gave no reaction (entry 5), which was probably due to increased steric effects.

Previously, a bis(imidoyl) chloride (Scheme 2-6) was synthesized using PC15 as the dehydrating

agent, to make the precursor for bisimidazoline based carbene ligand. The latter reagent is

stronger than POC13 and was used in combination with Zn(OTf)2 in the Bischler-Napieralski

cyclization to yield the bisimine 2-98 in good yields (entries 8, 9, 11 and 12). The fused Cy

substituted bisamide gave a compound similar to the product by 1H NMR but the 13C NMR did

not show the characteristic imine peak around 160 ppm seeing in similar compounds (Figure

2-5).










Table 2-3. Optimization of the double Bischler-Napieralski cyclization
dehydrating
0 Oagent /
S Lewis acid
S NOH HN toluene N N
R R T C
12 h R R


R = H, 2-94
R = i-Bu, 2-90
R = i-Pr, 2-86
R = Cy, 2-87
R = Ph, 2-88
R = CH2Cy, 2-91


P N ONH Ph
O Ph
2-89
2-89


R = H, 2-95
R = i-Bu, 2-96
R = i-Pr, 2-97
R = Cy, 2-98
R = Ph, 2-99
R = CH2Cy, 2-100


-1N N

2-101


Lewis
acid (eq)
ZnCl2 (7)
Zn(OTf)2 (7)

Zn(OTf)2 (7)

Zn(OTf)2 (7)
Zn(OTf)2 (7)

Zn(OTf)2 (7)

Zn(OTf)2 (7)

Zn(OTf)2 (3)

Zn(OTf)2 (3)

Zn(OTf)2 (3)

Zn(OTf)2 (3)

Zn(OTf)2 (3)

Zn(OTf)2 (3)


T C

110
110

110

110
110

85

110

85

85

85

85

85

85


bisimine
yield
No reaction
38%

54%

41%
No reaction

12% monoimine

No reaction

61%

83%

No reaction

91%

90%

NR


On the other hand, the bisamide 2-88 reacted with major consumption of the starting

material to yield in the various conditions tried (Tf2O/DMAP, POCl3/Zn(OTf)2) a non polar

product. The latter could not be clearly identified but according to a reported paper, it could be

stilbene 2-102 (Scheme 2-21).27 This fragmentation may be driven by the formation of cyanogen

gas in the decomposition of 2-93.


entry

1
2

3

4
5

6

7

8

9

10

11

12

13


R

H
H

i-Bu

i-Pr
Cy

Cy

Ph

Cy

i-Pr

Ph

CH2Cy

i-Bu

Fused
Cy


dehydrating
agent (eq)

POCI3 (14)
POCI3 (14)

POCI3 (14)

POCI3 (14)
POCI3 (14)

POCI3 (14)

POCI3 (14)

PC15 (6)

PC15 (6)

PC15 (6)

PC15 (6)

PC15 (6)

PC15 (6)















+ NC-CN


2-102


H K
2-93

Scheme 2-21. Fragmentation of phenyl substituted bisnitrilium

The standard reaction of the bisimine with chloromethyl ethyl ether produced the C2-

symmetric BIQ imidazolium salts (Scheme 2-22). There was no problem with the closing of the

ring for this compound which enforced the hypothesis made about the electronics of this new

ligand being similar to typical NHC. The tert-butyl substituted BIQ-imidazolium compound was

synthesized by Dr Hwimin Seo.


oxalyl chloride
H2N Et3N
R THF
R Ph 0 C to rt, 12 h
2-39 80%
R= iBu, iPr, tBu, CH2Cy
inverse stereochemistry for Cy


PCl5
Zn(OTf)2 /
toluene N N
85 C, 12h
61% 2R R
2-37


NH HN
R R
2-38







THF, rt N N
12 h ?(
80% R R
CI 2-36


Scheme 2-22. Imidazolium synthesis from chiral amine

2.4.6 Formation of Metal Complexes

Two main methods can be used to make NHC metal complexes. First, the imidazolium can

be deprotonated with a base to make the aminocarbene and a metal is added to produce the metal









complex. Also a transmetallation route can be used where a carbene silver complex is

synthesized from the imidazolium salt and this silver complex is exchanged with another metal.

The latter was used in our project because this reaction was proved to be more efficient and

cleaner than the deprotonation route.

A NHC palladium complex 2-103 was synthesized by Dr Hwimin Seo (Scheme 2-23) and

its X-ray crystal structure was obtained to look at the orientation of the chiral groups (Figure

2-4).


/ / 3 1)Ag20, CH2Cl2
rt, 12 h
N N 2) [Pd(cinnamyl)CI]2 N N
Srt, 3h
CIG 53% (two steps) Pd


Ph
2-104 2-103

Scheme 2-23. Synthesis of Pd-BIQ-cinnamyl complex 2-103

In this structure, the chiral groups seem to be located in the axial position of the ring

structure which allows a wider coverage of the metal sphere. Also, the phenyl rings at the back

are twisted like atropoisomers. If this ring twist equilibrates in solution, two diastereomers

should be formed and two sets of peaks should be visible by 1H NMR. The imidazolium 2-104

only showed one set of peaks (see supporting information) which implied either only one

diastereomer exists in solution or the ring flip was too quick for the NMR time scale.

Interestingly, the solid state of this structure showed the chiral groups pointing in the same

direction of the phenyl rings. This BIQ-Pd complex was used in the synthesis of oxindoles by

amide a-arylation19'20'24 but only racemic product was obtained.














19 c18 C2 C27

C17 C22
C20
C28







C7 C1 C12 035 C34
C30








Q C1
C32










C15











Figure 2-4. X-ray structure of Pd-carbene complex 2-10381

After making the palladium complex, the synthesis of copper carbene complexes was

realized. Using the transmetallation route with Ag2O, five copper complexes were synthesized in

good yields (Scheme 2-24).



/ 1)Ag20, DCM
rt, 12 h

N N 2) CuCI. DCM R C R
R' R I R
R R rt, 1 h Cu
GI
C 6Cl
R=i-Bu, 2-104 R=i-Bu, 91%, 2-109
R=i-Pr, 2-105 R=i-Pr, 55%, 2-110
R=Cy, 2-106 R=Cy, 71%, 2-111
R=t-Bu, 2-107 R=t-Bu, 60%, 2-112
R=CH2Cy, 2-108 R=CH2Cy, 65%, 2-113


Scheme 2-24. Copper complexes from C2-symmetric BIQ carbene ligands









2.4.7 Application: Copper-Catalyzed Asymmetric Allylic Alkylation

As a reminder, two types of products can be obtained from the allylic alkylation. The

branched compound 1-118 which gives two enantiomers and the linear product 1-119 (Scheme

2-25).

R' Cu complex R' Nu R'
R WLG RMgBr R + R L Nu
1-117 1-118 1-119
y product a product
(SN2') (SN2)

Scheme 2-25. General scheme for allylic alkylation catalyzed by copper complexes using
Grignard reagents as nucleophiles.

The initial optimization of the reaction conditions was mostly performed with 3 mol% of

catalyst 2-109 on naphthyl substrates 2-114. The reaction protocol consisted of adding the

Grignard reagent to 2-109 to generate the cuprate complex in situ. Then the allylic substrate 2-

114 was added dropwise over 10 minutes. For the different solvents array, the acetate leaving

group was chosen and EtMgBr was used as a nucleophile (Table 2-4). THF gave inverse

regioselectivity (entry 6) as reported previously.55' DCM gave surprisingly a low y:a ratio (entry

4) compared to Alexakis' results.60 Et20 gave the best results at 0 OC (entry 1). Decreasing

further the temperature had a negative effect on the reaction yield (entries 2 and 3). MTBE gave

good regioselectivity but the yield dropped to 61% (entry 5). After this quick survey, Et20 was

chosen as the optimum solvent.

Different leaving groups were also used in the reaction conditions (Table 2-5). First, the

chloride leaving group 2-117 was tried (entry 1) to compare it with the results obtained with

phosphoramidite ligands.56 Surprisingly, the enantioselectivity was greatly decreased as well as

the regioselectivity. Then the phosphonate leaving group 2-118 was used (entry 2) because it

gives good results when bidentate carbene ligands are used for zinc reagent alkylations.58










Table 2-4. Solvent optimization for the asymmetric allylic alkylation
EtMgBr
OAc 3 mol% 2-109
solvent, temp
2-114 1 h 2-115
y product (SN2')


entry solvent temp (OC) yield (%) y: a % ee (y

1 Et20 0 98 77:23 70
2 Et20 -20 98 77:23 69

3 Et20 -78 10 65:35 74

4 CH2CI2 -78 45 50:50 72
5 MTBE 0 61 80:20 65

6 THF 0 15 44:66 38


2-116
a product (SN2)


Then a pyridyl leaving group 2-120 was used (entry 4) to compare with the best results using

another monodentate carbene ligand.66 This time the regioselectivity was good but the

enantioselectivity was similar to phosphonate leaving groups. This new BIQ ligand 2-109 seems

to be a good match for ester based leaving groups (entries 5-7) which was in contrast to the

previous reported papers. Benzoyl 2-121 and pivaloyl 2-122 substrates are bulkier (entries 6 and

7) which increased the desired regioselectivity. Benzoyl is also a better leaving group than

pivaloyl which seemed to decrease the enantioselectivity; similar trend was seen between acetate

2-114 and methyl carbonate 2-119.

Acetate and pivaloyl leaving groups were chosen as the best candidates for the ligand

structure screening (Table 2-6). For pivaloyl leaving group, the cyclohexyl complex 2-111 (entry

5) gave the best yield (99%) and enantioselectivity (72% ee). Interestingly, any other

substitutions such as tert-butyl 2-112, cyclohexyl alanine 2-113 and iso-butyl 2-109 gave similar

results (entries 4, 6 and 7).


N, N

Cu
Cl
2-109


)










Table 2-5. Leaving group optimization for the asymmetric allylic alkylation
EtMgBr
X 3 mol% 2-109 ~ (S) +
Et20,0C 0) C
lh
h 2-115 2-116
y product (SN2') a product (SN2)


entry substrate yield (%) y: a % ee

1 X= -Cl 2-117 98 66:34 35

0
2 11 2-118 98 53:47 45
-OP(OEt)2
0
3 ii 2-119 98 50:50 55
-OCOMe
-o N
4 2-120 80 74:26 46


0
5 I 2-114 98 77:23 70
--OCCHj

0
6 ii 2-121 99 84:16 58
-OCPh

7 II 2-122 68 88:12 61
-OCt-Bu


For acetate leaving group, 2-111 and 2-109 gave similar enantioselectivity (entries 1 and 3)

but the regioselectivity was superior for bulkier cyclohexyl. Once again, the iso-propyl 2-110

gave similar results as the other substitutions (entry 2). Other copper catalysts were synthesized

using CuBr and CuTC but the reaction results were indifferent to those changes. As a result from

all those optimizations, 2-111 was chosen in combination with pivaloyl leaving group in Et20 at

0 0C.

Other alkyl Grignard reagents can be used without significantly decreasing reaction yield,

regio-, or enantioselectivity (Table 2-7). However, use of phenyl Grignard reagent afforded the

SN2 product exclusively (entry 4).


CI
2-109










Table 2-6. Ligand structure optimization for the asymmetric allylic alkylation
EtMgBr
3 mlX 3 ol% L*CuCI *
Et2O,C + -C
1 h 2-115
y product (SN2') a pro(


2-116
Juct (SN2)


entry substrate catalyst yield (%) y: a % ee (config)
O
II
1 = -OCCH3 2-109 98 77:23 70 (S)
2 2-110 98 77:23 62(S)
3 2-111 98 83:17 73 (R)
O
II
4 -OCt-Bu 2-109 68 88:12 61(S)
5 2-111 99 90:10 72 (R)
6 2-112 80 85:15 62(S)
7 2-113 98 84:16 62(S)


NN, NN N
C C,
C ?\ c
Cl ICl


2-109


2-110


N,CN

SC2-111

2-111


\ C /\I
C2

2-112


N ,N-
C,
2 Cu


2-113


Table 2-7. Grignard reagent survey for the asymmetric allylic alkylation
RMgBr R

OPiv 3mol%2-111 R
SEt20, 0 C

2-122 lh 1-118 1-119
y product (SN2') a product (SN2)


entry

1

2

3

4


RMgBr

EtMgBr

nHexylMgBr

CyclopentylMgBr

PhenylMgBr


2-115

2-123

2-124

2-125


yield (%)

99

91

91

95


Y:a

88:12

85:15

84:16

<2:98


% ee

72

77

68

N/A


NC,



2-O
2-111










Then the substrate scope was explored (Table 2-8). The reaction was effective for the

formation of a quaternary chiral center (entry 5). The aryl substrates also tolerate electron

donating (entry 2) and electron withdrawing substituents (entry 3), as well as ortho-substituents

(entry 4).

Table 2-8. Substrate scope
R2 RMgBr R R2

R OPiv 3mol%2-111 R2R + R1 R
Et20, 0 C R1
1-117 1 h 1-118 1-119


y product (SN2')


a product (SN2)


ntry substrate


1 OPiv
S2-122


24 'OPiv

MeO5i 2-126

3 r "^ OPiv

i N 2-127



2-128
OMe


5 ^ OPiv
^ J. 2-129


RMgBr yield (%) y:a % ee


Et



Et



n-Hex



n-Hex


99 88:12


66 86:14 72


60 77:23


77 75:25 70


91 85:15 76


2.4.8 Proposed Mechanism for The Copper-Catalyzed Allylic Alkylation

To explain the regioselectivity and the enantioselectivity, a mechanism was proposed

(Scheme 2-26). This mechanism showed only monomeric copper species. Before adding the

substrate, the copper carbene complex was premixed with ethyl magnesium bromide which was

likely to form a cuprate (I) complex with two ethyl groups because using different copper

sources gave similar results. The cuprate complex could attack the allylic substrate in a SN2'


e


N N

C2-111



2-111










fashion to generate a copper (III) species 2-130.82 Then a reductive elimination could take place

to form the desired branched product 1-118. The copper (III) species 2-130 can also be

isomerized to the a position through a 7t-allyl complex 2-131, then another reductive elimination

can happen from the other intermediate 2-132 to produce the linear product 1-119. The

regioselectivity probably came from this isomerization. In this proposed mechanism, the leaving

group came back on the catalyst to replace one of the ethyl substituent. The active a-complex 2-

130 could be ligated to the carbene ligand, the ethyl group, the substrate and the leaving group.

This species would go to the 7t-allyl complex 2-131 by a precomplexation of the alkene. The

nature of the leaving group seemed to play a crucial role in the regioselectivity of the reaction

(Table 2-5).



Oxidative -
Addition
N NNN N tN
S C/Et RX EtMgX Ci Et C E R R
Et O A AcOA
ArH O Ar '\\ Ar Ar

2-130 2-131 2-132
x-allyl complex
Reductive Reductive
Elimination Elimination

Et
Ar" Ar. Et
H
1-118 1-119

Scheme 2-26. Proposed mechanism for the asymmetric allylic alkylation

In the first o-complex 2-130, the leaving group could influence a lot the coordination of the

alkene, which would change the ratio of linear: branched. To support this hypothesis, a bidentate

leaving group was used to minimize the coordination of the alkene which should yield a single

branched product. The trisubstituted allylic substrate 2-133 was protected with thiophene









carboxylate (TC) leaving group which can coordinate with the ester part as well as the thiophene

moiety. As expected, only one regioisomer 2-134 was isolated (Scheme 2-27).


Me 0 EtMgBr Me Et
0, 3 mol% 2-135 h
C a S/ Et20, 0 C, 1 h
2-133 2-134
SN2' Only
78% ee


N NN
Cu

TC 3
2-135


Scheme 2-27. Allylic alkylation using TC leaving group

To further support the first stage of this proposed mechanism (SN2'), a secondary alcohol

substrate 2-136 was used and the linear substitution product 2-116 was obtained as a major

product (Scheme 2-28).


OPiv



2-1 36
2-136


EtMgBr (1.5 equiv)
3 mol% 2-111


Et2O, 0 C
1 h


Et

call*


(SN2)
2-115


-Et (SN2')
1 (2-116

2-115 (SN2): 2-116 (SN2') = 22 : 78


Scheme 2-28. Asymmetric allylic alkylation from a secondary alcohol pivalate

The phenyl Grignard reagent gave mostly the linear compound which could be explained

by an increase stability of the bisphenylcuprate complex. If this species was more stable, it

would isomerize more readily to the least hindered o-complex 2-132 and deliver mostly the

linear compound 1-119.

During the course of this study, it was found out that premixing of the imidazolium, the

Grignard reagent and the copper source gave similar results to the preformed copper complex

(Scheme 2-29).









n-HexMgBr n-Hex
N6 OPiv 3 mol% 2-113 n
(a) O Piv
Et20, 0 C
2-122 1 h 2-123
95% yield, y:a 84:16
62% ee
n-HexMgBr
3 mol% 2-108 n-Hex
(b) ~OPiv 3 mol%CuC, C C
(b) Et2O, 0 -C c o
lh
2-122 2-123
95% yield, y:a 83:17
63% ee

Scheme 2-29. Comparison between preformed (a) and in situ generated (b) copper carbene
complex

The current best example of the tricyclic chiral diaminocarbene ligand gave up to 78% ee

for the asymmetric allylic alkylation of trisubstituted alkenes. But in order to use this new chiral

catalyst in the total synthesis of a natural product, the enantioselectivity should reach at least 85-

90% ee. That is why more structural changes were attempted on the ligand design.

2.4.9 Further Optimization of The Ligand Structure

As a first simple change, the electronics of the ligand were modified by putting OMe

substituents on the two phenyl moieties at the back of the structure (Scheme 2-30). Starting from

the aziridine 2-47, the anisole Grignard reagent was used to give the tosylated amine 2-137. Then

it was deprotected using the combination of Li/naphthalene. Using oxalyl chloride, the bisamide

2-139 was formed in 87% yield. A milder procedure was used for the Bischler-Napieralski

cyclization because some product decomposition was observed when using the PCl5/Zn(OTf)2

procedure. DMAP and Tf2O converted the amide 2-139 into the desired nitrilium ion by basic

conditions and yielded the bisimine 2-140 in 40% yield. 2-140 was cyclized into the imidazolium

2-141 using conventional procedure.












H2N OH 1) TsCl
S Et3N, 3h Ts BrMg
2) MsCI Cul
-25 OC to rt THF, 3 h
2-40 12 h 2-47 67%
80%



oxalyl chloride
Li Et3N
Li OMe THF,rt
naphthalene NH2 O 12T ,

THF -78 OC to rt 52%
12h
72% 2-138


\ /
00




N N .


CIlO

THF, rt
24 h
OnoL


NHTs OMe


2-137




0 HN -

HN O OMe

MeO /

2-139


/ \ / cl \
2-140 2-141

Scheme 2-30. Synthesis of the 7-OMe substituted BIQ carbene ligand 2-141

This new ligand was tested in the allylic alkylation. The branched compound was obtained

in 58% ee same as 2-109. More donating substituents on the aromatic rings seemed to have no

effect on the enantioselectivity for the allylic alkylation (Scheme 2-31).

EtMgBr
3 mol% 2-141 Et
OPiv 3 mol% CuTC O C
Et20, 0 -C
1 h
2-122 2-115

85% yield, y:a 99:1
58% ee


Scheme 2-31. Allylic alkylation using 2-141


Tf20
DMAP
toluene
95 C, 12 h
39%










Electron withdrawing substituents were not attempted because the Bischler-Napieralski

cyclization might be difficult with electron withdrawing groups on the phenyl rings. As it was

discussed earlier, the phenyl rings at the back are twisted due to a common repulsion of the

hydrogen atoms. If some substituents were to replace those hydrogen atoms, the rings would be

even more twisted and the chiral groups at the front will be even more extended. The same

synthesis was attempted with 3,5-dimethoxyphenyl Grignard reagent, but the synthesis of 2-146

was not successful (Scheme 2-32). It was probably due to steric effects, which were too large to

overcome.

^0


H2N OH 1)TsCI Ts c
Et3N, 3h s IMg NHTs
2) MsCI Cul
-25 *C tort THF, 3 h
2-40 12h 2-47 80% 2-142
80%


.O
Li 0
naphthalene NH2 2

THF -78 C to rt 0'O
12 h
54% 2-143


-0
Tf20 -
DMAP
toluene
85 C,12h N

90%

0-
2-145 0-

Scheme 2-32. Synthesis of the bis-OMe


oxalyl chloride
Et3N
THF, rt
12h
56%


-o ,o-
-0 O-
Cl O O- 0
6 to 15 eq


THF, rt to 50 C NN
24 h
No Reaction C
2-146


substituted BIQ carbene ligand 2-146









While working on the fused cyclohexyl 2-63, we also tried to synthesize ligands with

chiral groups in a and 0 position. Commercially available D-(+)-norephedrine 2-147 was used as

a cheap model compound. Even though, the a position was only substituted with a methyl

substituent, the p position was functional and there was a phenyl group for the Bischler-

Napieralski cyclization. The amine 2-147 was reacted with diethyl oxalate to give the bisamide

2-148 in excellent yields (Scheme 2-33).

0
EtOOEt
OH O OH Me R
-Me tNHO NH
toluene II
S N!H2 reflux Me 0 OH
2 h, 99%
2-147 2-148

Scheme 2-33. Bisamide synthesis of norephedrine

The alcohol 2-148 had to be protected to resist the harsh conditions of the Bischler-

Napieralski cyclization (Table 2-9). First, silicon reagent was used but with little or no success

(entries 1-2). DCM increased the reactivity of the starting material but only the monoprotected

bisamide was isolated (entry 2). The poor formation of bis-protected 2-149 was probably due to

the steric bulk of the tert-butyl diphenylsilyl groups. This large protecting group was used to

serve as a bulky chiral substituent. On the other hand, the alcohol was successfully protected

with an acetyl group (entry 3).

In order to protect the alcohol with a silicone group, the order of addition was reversed

(Scheme 2-34). Norephedrine 2-147 was protected with tert-butyl diphenylsilyl group then the

bisamide 2-149 formation needed oxalyl chloride as a coupling partner instead of diethyl oxalate.










Table 2-9. Protection of the 0 alcohol of the bisamide compound
protective agent
OH Me solvent OR Me
NH NH additives NH LN
NNH H NH
solvent M 0O
S Me 0 OH 12 h, rt Me O OR

2-148 R = TBDPS, 2-149
R= Ac, 2-150

entry protective agent solvent additives yield
Ph
1 tBu-Si-CI DMF Et3N NR
Ph
Ph
imidazole
2 tBu-Si-CI DCM mdAPo monoprotected
Ph

3 Ac20 DCM t3N 80%
DMAP


OH
HMe

~ H2

2-147

Et3N
THF,
78%

Ph-Si-Ph
O Me -e
NH) NHM

Me 0 0
Ph-Si-Ph
2-149


Ph
tBu-Si-CI
Ph
Et3N
DMAP
DCM, rt
86%


12h
/


Cl 0

O CI


Ph-Si-Ph
I
O Me

NH2

2-151
0 OEt

NHEtOOEt
toluene 2
reflux, 12 h
78%
Ph-Si-Ph


OEt
S Me 0

2-152


Scheme 2-34. Synthesis of the silylated bisamide

The Bischler-Napieralski cyclization was attempted using various methods (Table 2-10).

The milder condition using Tf2O/DMAP gave only decomposed products (entry 1). In the case of










the typical procedure PCl5/Zn(OTf)2, the starting materials decomposed also (entries 2 and 4).

The Lewis acid was removed to decrease the harshness of the reaction conditions, but even

though the starting material did not decompose only monocyclized product 2-155 was obtained

(entry 3). The O-acetyl protected amide only gave a product 2-156 very similar to bis(imidoyl)

chloride 2-92 (entry 5). The latter was stuck at this stage and would not cyclize. If some Lewis

acid was added afterward, it led to decomposed products.

Table 2-10. Bisimine optimization for 3 substituted bisamides

OR Me
OI cyclizing agents
NH NH I RO /-\ IOR
e O O toluene N N
Me 0 OR 85 C, 12h M
Me Me
R = TBDPS, 2-149
R = Ac, 2-150 R = TBDPS, 2-153
R = Ac, 2-154
entry R cyclizing agents yield notes
Ph
I I
1 tBu-Si-- MAOP N/A decomposed
Ph
Ph
I I PCl "5
2 tBu-i- Zn(OTf)2 N/A decomposed 0
Ph -I
Ph r NH
Ph. Ph. OM
3 tBu-Si-'- PCI5 81% monocyclized Si O Me
Ph >r h Me Si Ph
2-155

4 ]Zn(OTf)2 N/A decomposed
OAc X Me -
0 N ^ -
5 PCI5 68% bisimidoyl chloride =>e N N
', Me X OAc
2-156

The characterization of those compounds can be rather difficult sometimes, but a general

trend can be seen among them. The main difference between bisamide 2-150, bis(imidoyl) halide

2-156 and bisimine 2-100 is their 13C NMR. Their respective characteristic peaks are 160 ppm

(Figure 2-5), 139 ppm73 (Figure 2-6) and 164 ppm (Figure 2-7). This general trend was seen for

most of the compounds synthesized so far.













Bisamide 13C NMR


128.64


OAc 0 Me X

N N^NH
x MeO OAc

2-150


126.69


49.04


15.40
21.15
159.09 136.41
170.07 I 77.61










200 180 160 140 120 100 80 60 40 20 0
Chemical Shift (ppm)


Figure 2-5. 13C NMR of bisamide 2-150


Bisimidoyl chloride 13C NMR


127.99

S127.71


2-156


77.69


220 200 180 140 120 100 80 III III III III III III III III


220 200 180 140 120 100 80
Chemical Shift (ppm)


Figure 2-6. '3C NMR of bis(imidoyl) halide 2-156


63.07


60 40 20 0 -20


,i, ,











Bisimine 13C NMR


2-100


164.02


26.55


180 160 140 120 100 80 8' 60 40 20 0
Chemical Shift (ppm)


Figure 2-7. '3C NMR of bisimine 2-100

Those results marked the end of the trials for P-substituted BIQ based carbene ligands.


This substitution seemed to be too reactive and only lead to decomposition or synthesis of an


intermediate in the formation of the product.









CHAPTER 3
IN SITU GENERATION OF ACYCLIC DIAMINOCARBENE COPPER COMPLEX

3.1 Introduction: Discovery of The In Situ Generation of Aminocarbene Copper
Complex from Chloroimidazolium

In the previous chapter, the synthesis of a new chiral carbene ligand was reported as well

as its application in the copper-catalyzed allylic alkylation using Grignard reagent as a

nucleophile. The X-ray of the Pd carbene complex 2-103 was obtained by Dr. Hwimin Seo, but a

X-ray of the Cu carbene complex 2-110 would be more relevant in our copper catalyzed

research. Several trials were attempted with the complex 2-110 but with no success. In order to

increase the stability of this complex, the copper (II) complex 3-1 was attempted following the

same transmetallation procedure (Scheme 3-1).


1)AgO / /
/ / CH2C12
rt, 12 h

N N 2) CuC12 NN N uCl
N C C Cl> Y CuCI2
CH2CD12 2I2 I
H / \rt, h CU c
CI CI
2-105 3-1: Not Isolated 3-2 71% (X-ray)


Scheme 3-1. Attempted synthesis of copper(II) BIQ-carbene complex 3-1

But unexpectedly chloroimidazolium salt 3-2 was isolated and characterized by X-ray

crystallography (Figure 3-1). The silver complex was synthesized but instead of exchanging with

copper (II) chloride, it generated this BIQ chloroimidazolium 3-2.

Before obtaining the X-ray structure, this supposed complex 3-1 was used in the allylic

alkylation to compare with copper (I) complex 2-110 (Scheme 3-2). At that time, it was not

surprising to get similar results based on the fact that copper(II) can be reduced to copper(I)

complex in the presence of Grignard reagent. When the result of the X-ray came back and the










supposed copper (II) complex was found to be the chloroimidazolium 3-2, the results from the

allylic alkylation were now intriguing (Scheme 3-2).


Figure 3-1. X-Ray structure of chloroimidazolium-CuC12 salt 3-283


3 mol% Et

Nz OAc- catalyst 1
OAc
EtMgBr
2-114 Et20, 0C 2-115 (SN2')
lh


Catalyst = 2-110: 98% yield,
Catalyst = 3-2: 96% yield,


, .Et


2-116 a (SN2)


y: a = 78: 22, (62% ee)
y: a = 79: 21, (64% ee)


N N

Cl
CI
2-110




-8E
NN 0

CI /
3-2


Scheme 3-2. Comparison between catalysts 2-110 and 3-2 in the allylic alkylation of naphthyl
substrate 2-114

It seemed a Cu-carbene species was generated in situ from 3-2 and EtMgBr under the

allylic alkylation conditions. This new in situ generation is not useful for NHCs because their









imidazoliums can be easily synthesized and they can also be readily deprotonated to generate

various NHC-metal complexes.4 On the other hand, acyclic carbene metal complexes are more

challenging to synthesize (1.3 Acyclic Carbene and Methods of Preparation).4553

3.2 New In Situ Generation of ADC-Cu Complex and Application in Allylic Alkylation

Commercially available chloroamidinium 1-112 was used as a potential acyclic carbene

precursor (Table 3-1). To follow as closely as possible the procedure described previously

(Scheme 3-2), the chloroamidinium 1-112 was first stirred with a copper salt to generate an

intermediate 3-3 which would be similar to chloroimidazolium 3-2. Then it was combined with

the Grignard reagent to generate the hypothetical acyclic aminocarbene-copper species.

Table 3-1. Allylic alkylation using chloroamidinium premixed with copper salt
5 mol%

CuX L N

4h BF CUX
G4 4DCM, rt F CI CuX
1-112 3-3




0 EtMgBr

Et20, O0 C C
lh
2-122 2-115 y (SN2') 2-116 a (SN2)

entry CuX 3-3 yield a
1 CuCI2 Yes 85% 46: 54
2 CuCI Yes 75% 48: 52

3 CuCI2 No 10% 35: 65


The reaction yielded products in good yields, but with poor regioselectivity. Different

copper oxidation states could be used in this reaction (entries 1 and 2). The absence of










chloroamidinium gave low yield and poorer regioselectivity (entry 3). Even though the linear:

branched ratio was lower than seen with 3-2, the proof of concept was a success.

In order to increase the regioselectivity, the substrate was varied. It was found that alkyl

based substrates gave good regioselectivity (Table 3-2). The substrate 3-4 carried a PMB

protecting group to facilitate HPLC conditions in future chiral experiments.

Table 3-2. SN2' allylic alkylation catalyzed by copper carbene complexes



Cl BF4 Et
1-112 (5 mol%),.
MBOOA Cu Salt (5 mol%) PMBO + PMBOEt

EtMgBr
3-4 solvent, 0 "C, 1 h 3-5 Y (SN2') 3-6 a (SN2)


ligand precursor

1-112

1-112

1-112

1-112

1-112

1-112

none



S 3-7 (10 mol%)


Cu salt

CuCl2

CuCI

CuTC

CuTC

CuTC

none

CuTC

CuTC
(10 mol



CuTC


solvent

Et20

Et20

Et20

THF

DCM

Et20

Et20


yield

82%

81%

83%

37%

13%

25%

9%


Et20 71%


Y%)


Et20 57%


The premixing of chloroamidinium 1-112 with a copper source was not required (entries 1-

6). Cu(I) salts such as CuCl (entry 2) or CuTC (entry 3) also gave identical results to those with


entry

1

2

3

4

5

6

7


Y: a

93:7

93:7

94:6

68:32

50:50

94:6

19:81


90:10


92:8









CuC12. Changing the solvent to THF (entry 4) or DCM (entry 5) significantly decreased yield

and regioselectivity. Both the copper salt and the chloroamidinium were necessary for good

yields (entries 6 and 7). However, 1-112 without CuTC (entry 6) still managed to give high y

selectivity (y : a = 94:6) whereas CuTC without 1-112 (entry 7) showed very different selectivity

(y : a = 13:87).84 Commercially available 3-8 showed similarly high y selectivity (y : a = 94:6)

despite the slightly reduced yield (entry 9). Acyclic carbene 3-7 prepared by the reported

deprotonation protocol (Scheme 3-4) also gave a similar result (entry 8), which was consistent

with the idea of in-situ carbene generation.

Acyclic diaminocarbene 3-7 was made in situ from amidinium 3-11 following Alder's

procedure (Scheme 3-3).45b Pyrrolidine was first reacted with ethyl format in neat conditions to

yield quantitatively the formamide 3-9. Then the imidoyl chloride 3-10 was formed using POC13

and it was subsequently mixed with another equivalent of pyrrolidine. This reaction gave rise to

a mixture of amidiniums due to different counterions being present (Cl-, P2C12-). All those ions

were exchanged with hexafluorophosphate to yield the desired product 3-11 which precipited

from the solvent media.

The amidinium 3-11 was then reacted with fresh LDA to give a stock solution of free

carbene in THF which was used immediately (Scheme 3-4). Only 65 [L of this solution was

used in the following allylic alkylation which contained 2 mL of Et20, so the THF present was

almost negligible. To compare with ADC, chloroimidazolium 3-2 was reacted with the substrate

3-4 (Scheme 3-5).











0

C H OEt
NH
neat, 80 C
6h
99%


POCl3

DCM
-78 *C to rt
3-9 2h
3-9


^0

xO
3-10
3-10


1) I NH

Et3N

2) NH4PF6
water, 0 C
67% over 3 steps


CONQ
H PF60

3-11


Scheme 3-3. Bispyrrolidine amidinium preparation



-N1 ND + fresh LDA
H PF6
3-11 0


PMBO -OAc
3-4


- 20 oC, 30 min
stock solution of carbene
was made in THF


EtMgBr/CuTC
Et20, 0 C, 1 h


PMBO
3-5 y (SN2')


+ PMBO -Et

3-6 a (SN2)


71% yield, y: a = 90:10

Scheme 3-4. Allylic alkylation using free carbene (Table 3-2, entry 8)


5 mol%
Et
catalyst Et
PMBO- -OAc catat PMBO--
EtMgBr
3-4 Et20, 0 C 3-5 y (SN2')
lh


Catalyst = 2-110: 78% yield,
Catalyst = 3-2: 69% yield,


+ PMBO- --Et

3-6 a (SN2)


y: a = 94: 6, (50% ee)
y: a = 97: 3, (50% ee)


I
N N

Cl

2-110




N N 0
CuCl2
CI3-2
3-2


Scheme 3-5. Comparison between catalysts 2-110 and 3-2 in the allylic alkylation of alkyl
substrate


I









The enantioselectivity dropped to 50% probably due to decreased steric effects from the

substrate. The results were still similar between the isolated copper carbene complex 2-110 and

the chloroimidazolium 3-2.

This reaction was also tested with a chiral ADC 3-12 synthesized by Dr. David Snead

(Scheme 3-6). The enantioselectivity was good for a preliminary result. Unfortunately the major

compound was linear. Attempts to increase this ratio in favor of branched products did not

succeed.

Ph


Ph Cl N
Cl0 3-12 Et
\PMBO = OAc (5 mol%) ,. _
PMBO OAc CuTC (5 mol%) PMBO + PMBO Et

EtMgBr
3-4 Solvent, 0 OC 3-5 y (SN2') 3-6 a (SN2)
30 min
50% yield, y : a = 20:80, 40% ee

Scheme 3-6. Enantioselective allylic alkylation using chiral ADC 3-12

We decided to focus on achiral catalyst to study the scope of this reaction. This ADC-Cu

catalyst (1-112 with CuTC) showed excellent y selectivity for various allylic substrates (Table

3-3). Symmetrical dibenzoate substrate 3-13 could be used owing to high y selectivity (entry 1),

and quaternary centers could be generated from tri-substituted alkene substrates in high yields

(entries 3-5). E and Z substrates 3-15 and 3-16 reacted both efficiently (entries 2-4). The reaction

with piperidine substrate 3-17 was sluggish and 15 mol% of catalyst loading was required (entry

5). However, this ADC-Cu catalyst appears to be more reactive than the NHC-Cu catalyst85 3-22

which gave 24% yield of 3-21 under identical conditions (Scheme 3-7).










Table 3-3. Substrate scope


R2 LG

R1
1-117


ON IND
( BF4
1-112 CI (5 mol%)
CuTC (5 mol%)
EtMgBr
Et20, 0 C, 1 h


R2

R

1-118 (y, SN2')


entry substrate product yield


O O
II II
1 PMPCOx -OCPMP

3-13


MeO OAc


(E/Z = 80:20)
3-14
OAc

3-15


3-16
Ts N OAc


3-17


0
PMPCO- /

Et 3-18

MeO Et


3-19


3-20Et


3-20
I / `Et
3-20

Ts, N3.2

Et 3-21


[a] 15 mol % of chloroamidinium/CuTC


Ts 'N OAc



3-17


3-22 (15 mol%)

EtMgBr
Et20, 0 oC, 1 h


Ts"'N


Et
3-21
24% yield


Scheme 3-7. Allylic alkylation of piperidine substrate with IMesCuCl catalyst 3-22


84%




97%


95%




96%


93%









3.3 NMR Experiments

Several 13C NMR experiments were performed to characterize the copper species and

collect some indication that the copper carbene complex was really synthesized in situ (Table

3-4). The experiments consisted of mixing the chloroamidinium 1-112, a copper (I) source and

Grignard reagent in CD2C12 for some time. The premixing at room temperature (entry 1) showed

mostly decomposition of the starting material. Then it was stirred at 0 OC same as in the reaction

procedure for a short time and then cooled to -78 OC to trap the newly formed species and the

NMR was checked at -60 OC (entry 2). This time the chloroamidinium peak was visible but no

carbene peak was present. Those conditions were repeated with CuCl and phenyl Grignard which

has been reported to give stable cuprate complexes (entry 3).86 In this case the chloroamidinium

peak disappeared which meant it was completely converted into the metal carbene species or

something else, unfortunately no peak was observed in the >200 ppm region.

Table 3-4. 13C NMR experiments of the generation of copper carbene complex from
chloroamidinium
Grignard reagent (4 eq)
-N N[i CuX (1 eq) a ',N
ON ,N:> CD2C12 DN C'N4:>
D BBF4 temperature/time Cu carbene peak
chloroamidinium peak 13C NMR at T C /
1-1121 eq 3-23

entry CuX gnard temperature/time 13C NMR T C results

1 CuCI EtMgBr rt /10 min rt weak peaks, decomposition

2 CuBr EtMgBr 0 *C / 2 min -60 OC chloroamidinium peak still present
no carbene peak

3 CuCI PhMgBr 0 C / 5 min -60 C chloroamidinium peak gone but no carbene peak

4 CuC EtMgBr 0 C / 5 min -60 C chloroamidinium peak still present
no carbene peak

Those experiments were fruitful but not conclusive. The absence of carbene peak did not

necessarily mean the compound was not present; the acyclic aminocarbene bound to copper can









sometimes be rather weak in intensity.8 The solvent was replaced by THF-d8 which would be

more similar in nature to the solvent used in the reaction. Also it is less reactive with free

carbene than CD2C12 which can sometimes be acidic. The main issue to address was the weak

intensity of the carbene peak; it was resolved using 13C-labeled chloroamidinium precursor 3-25

(Scheme 3-8). The pyrrolidine was reacted with 13C-labeled phosgene to yield the desired urea 3-

24. It was then mixed with oxalyl chloride to give the 13C-labeled chloroamidinium 3-25 which

was synthesized by Dr David Snead. 13C-labeled chloroamidinium 3-25, CuCl and Grignard

reagent were mixed in THF-d8 and monitored by 13C NMR at low temperature (Figure 3-2).

1 O Cl ClO
S CI13 I 13c oxalyl chloride 13
N Et3N c i toluene, 60 *C CN L
H DCM, rt
82% 3-24 79% 3-25
made by Dr. David Snead

Scheme 3-8. Preparation of 13C-labeled chloroamidinium precursor 3-25

When a mixture of chloroamidinium 3-25 and CuCl was treated with PhMgBr, the starting

material 3-25 was fully converted to two species showing typical metal-carbene sp2 carbon

resonances at 206 and 217 ppm (Figure 3-2a).46 The 161 and 168 ppm resonances are assigned to

aryl and alkyl amidinium compounds, 3-28 and 3-25 respectively.88,89 We speculated that the

signals at 206 ppm and 217 ppm might be assigned to Cu-carbene complex 3-2790 and Mg-

carbene complex 3-26 respectively.91 These tentative assignments are supported by the following

observations: When chloroamidinium 3-25 was treated with PhMgBr in the absence of CuCl

(Figure 3-2b), the 216 ppm resonance appeared as the only carbene species 3-26. When this

mixture was further treated with CuCl (Figure 3-2c), the 216 ppm resonance was completely

converted to the resonance at 206 ppm 3-27. When a mixture of 3-25 and CuCl was treated with













EtMgBr (Figure 3-2d), the Cu-carbene resonance at 207 ppm 3-27 was again observed while the


216 ppm resonance was not detected in this case.


I CIO

s3-2
3-25


Y, Cie
13c


3-25


'Mg 'Cu'
(a) CuCI (1 equiv)
PhMgBr (4 equiv) C
THF-d 0
3-26 3-27


(a) 217 ppm 206 ppm

245 240 235 230 225 220 215 210 205 200 195 190 185 180 175 170 165 160 155 150 145
Chemical Shift (ppm)

CI xo
(b)PhMgBr (4 equiv) Mg Oo
3/N/ 'N Xo
1c \ 3-25&
THF-d8
3-26 G%'N
3.28
(b) 216 ppm 161 ppm 151 ppm

245 240 235 230 225 220 215 210 205 200 195 190 185 180 175 170 165 160 155 150 145
Chemical Shift (ppm)


(c)CuCI (1 equiv) cu Ph X s
Crude mixture 3'N 1N N
after step (b) TH- N j
THF-d'

(c) I206 ppm 161 ppm

245 240 235 230 225 220 215 210 205 200 195 190 185 180 175 170 165 160 155 150 145
Chemical Shift (ppm)


C9 CIS (d)CuCI(1eq) C Et X 9e C
C3 EtMgBr (4 equiv) c 1C 1c
THF-d\
3-25 3-27 3-29 3-25



(d) 207 ppm 168 ppm 150 ppm


245 240 235 230 225 220 215 210 205 200 195 190 185 180 175 170 165 160 155 150 145
Chemical Shift (ppm)


Figure 3-2. Direct '3C NMR monitoring (at -600C) of carbene-metal complex generation using

13C-labeled chloroamidinium precursor 3-25


In order to further support those findings, the '3C-labeled formamidinium ion 3-32 was


synthesized. The pyrrolidine was reacted with '3C-labeled ethyl format, followed by POCI3 and


another pyrrolidine to give the desired product (Scheme 3-9).










O 1) hNH H
13c 0 H 13c
NH 1 H N C N Et3N N
99% DCM 2) NH4PF6 PF6
67%
3-30 3-31 3-32

Scheme 3-9. Preparation of 13C-labeled formamidinium precursor 3-32

It would be useful for this work to generate the free carbene 3-33 with reported conditions

and then subject it to Grignard reagent as well as copper. The carbene peak would be expected to

shift downfield and be close to the values found before (Figure 3-2). When 13C-labeled

formamidinium 3-32 was reacted with fresh LDA in a NMR tube, a resonance peak at 235 ppm

appeared (Figure 3-3a) which was close to the reported value for free lithiated acyclic carbene 3-

33. When this mixture was further treated with PhMgBr, the 235 ppm peak was completely

converted to the resonance at 214 ppm (Figure 3-3b) which was very similar to the observed

resonance (Figure 3-2b). When this new mixture was treated with CuC1, the resonance at 214

ppm was fully converted to a new peak at 207 ppm (Figure 3-3c) which was in accordance with

the previous value (Figure 3-2c). Those findings further support the in situ generation of copper

carbene complex from chloroamidinium precursor.

One of the plausible mechanistic scenarios might involve metal-halide exchange between

chloroamidinium 1-112 and R2CuMgBr (Scheme 3-10).92 This process could involve first an

oxidative addition of the cuprate reagent into the carbon-chloride bond to form a copper(III)

complex 3-34 which upon reductive elimination would generate the copper(I) carbene complex

3-35. Another scenario could involve a two-step sequence of magnesium-chloride exchange93a

followed by transmetallation (Scheme 3-11).92b










(a) LDA
(1 equiv)
THF-d8
-78 C to rt


Li
13CN


H
N N

PF6
3-32


Crude mixture
after step (a)


(b) PhMgBr
(4 equiv)
THF-d8


130

0' NoN


(b) 214 ppm

245 240 235 230 225 220 215 210 205 200 195 190 185 180 175 170
Chemical Shift (ppm)


Crude mixture
after step (b)


(c) CuCI Cu
(1 equiv) 13

THF-d8 JN" 0 N
3-27


245 240 235 230 225 220 215 210 205 200 195 190 185 180 175 170
Chemical Shift (ppm)

Figure 3-3. Direct '3C NMR monitoring at room temperature of carbene-metal complex
generation using 13C-labeled formamidinium 3-32


CI BI
Cl B


1-112


R2CuMgBr
-----------
oxidative
F4 addition


3-34


------- O N, N + R-CI
reductive C
elimination Cu + MgBrBF4
R
3-35


Scheme 3-10. Copper carbene complex generation involving cuprate-chloride exchange


CON NB
I Y
Cl B


1-112


-RMgBr -__
sigma-bond
o methatesis
F4


3-36


CuCI --N r +M l
-.. .... ) +MgCI
magnesium-copper \NC N
exchange
Cu
R
3-35


Scheme 3-11. Copper carbene complex generation involving Grignard-chloride exchange


3-33

(a) 235 ppm


245 240 235 230 225 220 215 210 205 200 195 190 185 180 175 170
Chemical Shift (ppm)


207 ppm









This transformation allowed the conversion from easily synthesized chloroamidinium to

their respective copper complexes. While this project was studied, Dr David Snead developed a

similar concept but more general using lithium-halogen exchange (1.3Acyclic Carbene and

Methods of Preparation).53









CHAPTER 4
C1-SYMMETRIC MONOISOQUINOLINE N-HETEROCYCLIC CARBENE LIGAND

4.1 Introduction: Ligand Design for Ci-Symmetric Ligands

The enantiomeric excess in the asymmetric allylic alkylation was limited to 75% with

biisoquinoline-based carbene ligands 2-2 developed in Chapter 2, which is why these ligands

have to be improved. In this first design, we observed that the chiral carbene ligand 2-1

developed by Grubbs11 positioned the aryl groups at the front orthogonal to the plane by transfer

from the backbone chirality. We thought it would be interesting to bring the chiral groups closer

to the metal center using a tricyclic structure 2-2. It was clear that the BIQ ligand was rather

open on the other available quadrants compared to ligand 2-1 which included those trans phenyl

substituents at the back. In order to fill more efficiently the remaining quadrants, we conceived a

Ci-symmetric version of this ligand which was built on the same chiral isoquinoline core 4-1

(Figure 4-1).



R
RNN NN N I N N NN
C CC'
I R R R
R M R R M

R
R R


=>-~-- ------- -- ---- -- -


2-1 2-2 4-1

Figure 4-1. Increasing bulk around metal center by switching from C2-symmetric BIQ 2-2 to Ci-
symmetric MIQ 4-1 carbene ligands

The imidazolium 4-2 could be synthesized from bisimine 4-3 which resulted from imine

coupling of the ketone 4-4. The Bischler-Napieralski cyclization could be used to convert the









ketoamide 4-5 into the monoimine 4-4. This process should be easier than the previously

reported one because it involved only one ring closing. To finish, chiral phenethylamines 2-39

developed in Chapter 2 could be used to form the monoamide 4-5 (Scheme 4-1).


S imidazolium mine / R
R2 formation 2 coupling R2

N N-NR N N-R 3N O
3 3
R1 CIO R R,
4-2 4-3 4-4


Bishler-Napieralski / amide
cyclization O R2 synthesis -

NH O NH2
R1 R1
4-5 2-39

Scheme 4-1. Retrosynthesis of the Ci-symmetric monoisoquinoline ligand

4.2 First Attempt Using R2=Me

The first design consisted on using isobutyl chiral substituents 4-6 which showed good

results in the allylic alkylation (Figure 4-2).


Me

NN-R R = alkyl, aryl

ClI
4-6

Figure 4-2. First design of the Ci-symmetric isoquinoline ligand 4-6

The chiral phenethylamine 2-55 was coupled with pyruvic acid to give the monoamide 4-7

using EDCI and HOBt (Table 4-1). DCM was used as a solvent but only 50% yield was obtained

(entry 1). To increase the yield, bases were added into the reaction conditions (entries 2-3) but

the yield dropped because of an unknown byproduct which appeared in the reaction. The bases










were removed and a more polar solvent such as DMF was used instead of DCM (entry 4) with

better results.

Table 4-1. Monoamide optimization
EDCI 0 0
O O HOBt
NH2 base NH
O solvent
S0 rt, 12h

2-55 4-7

entry base solvent yield
1 No base DCM 51%
2 Et3N DCM 35%
3 DMAP DCM 30%

4 No base DMF 74%


To form the mono dihydroisoquinoline 4-8 (Table 4-2), the current best conditions

developed previously were used (entry 1) but only decomposition of product was observed. The

PC15 was replaced with weaker POC13 (entry 2) but the same result was obtained. Using a 5:3

combination of Tf2O and DMAP, the monoimine 4-9 was obtained in good yield (entry 3).

Table 4-2. Optimization of the Bischler-Napieralski cyclization

0o0

N reagents
solvent, time N 0
T oC

4-7 4-8


entry reagents solvent T *C/time yield

1 PCI5 / Zn(OTf)2 toluene 85 *C / 8 h decomposition
2 POC3 / Zn(OTf)2 toluene 85 C / 8 h decomposition

3 Tf20/DMAP DCM 60 C / 6 h 57%










With aryl amines (Table 4-3), different acid catalysts were used in combination with

dehydrating reagents, but only the starting material was isolated (entries 1-4). With aliphatic

amines, same result was obtained but the main issue in this case remained the bad solubility of

the protonated aliphatic amines (entries 5-9). As a last resort, more nucleophilic amines such as

methoxyamine or substituted hydrazine were used (entries 10-11). Only methoxyamine gave the

product 4-9 but in poor yield (entry 10). Yields could not be increased by longer reaction times

because the product was decomposing with excess heating. The methyl ketone moiety in the

compound 4-8 seemed unreactive which might result from enolization under acidic conditions.

Table 4-3. Optimization of imine formation

catalyst
additive
/ + NH2R /
N 0 sovent N N-R
S+ T C / time
4-8 4-9


NH2R

2,4,6-trimethylaniline

2,4,6-trimethylaniline

2,4,6-trimethylaniline

2,4,6-trimethylaniline

diphenylmethanamine

diphenylmethanamine

adamantylamine
adamantylamine

(R)-2-phenylglycinol

methoxyamine.HCI

1,1-diphenylhydrazine


catalyst

pTsOH

HCO2H

TiCl4

H2S04

pTsOH

HCO2H

HCO2H
TiCl4 (1 eq)

no catalyst

no catalyst

no catalyst


additive

4 A MS

no additive

MgSO4

no additive

4 A MS
no additive

no additive
Et3N

MgSO4

K2C03

K2C03


solvent

toluene

methanol

toluene

Si(OEt)4

toluene

ethanol

toluene
Et20

DCM

ethanol

ethanol


T *C/time

reflux/ 12 h

reflux/ 12 h

reflux/ 12 h

160 C/12 h

reflux/ 12 h

70 C /48 h

rt/ 12h
rt/ 12h

rt/ 12h

85 C / 1 h

85 C/1 h


yield

SM recovered

SM recovered

SM recovered

decomposition

SM recovered

SM recovered

SM recovered
SM recovered

SM recovered

17%

decomposition


entry

1

2

3

4

5

6

7
8

9

10

11










4.3 Second Attempt Using R2=Ph

This issue could be easily fixed by replacing pyruvic acid with phenylglyoxylic acid

(Scheme 4-2). Starting from the amine 2-55, it was coupled with 2-oxo-2-phenylacetic acid to

yield the desired monoamide 4-10. The Bischler-Napieralski cyclization went smoothly to give

the monoimine 4-11 in 85% yield.

0 0

HO
/\HO /O Tf20
S NH2 NH Ph DMAP /
--N 0
DCM, reflux
EDC, HOBt
DMF, t 12 h, 85%
DMF, rt
2-55 12 h, 61% 4-10 4-11


Scheme 4-2. Monoimine synthesis from chiral isobutyl phenethylamine

This imino-ketone 4-11 was non-enolizable and was submitted to the imine condensation

(Table 4-4). The typical conditions using pTsOH as a catalyst and molecular sieves or a Dean-

Stark apparatus to trap the water were first used but with no success (entries 1 and 2). Then the

stronger TiC14 was used stoichiometrically in combination with Et3N to give excellent yield of

the desired product 4-12 (entry 3).94

Table 4-4. Optimization of the imine condensation from the non-enolizable ketone


Y catalyst
additive
/ + NH2R/ s
N O N N-R
sovent
T C / time
/ R= Mes, 4-12


t- I I


entry NH2R catalyst additive

1 2,4,6-trimethylaniline pTsOH 4 A MS

2 diphenylmethanamine pTsOH Dean-Stark

3 2,4,6-trimethylaniline (5 eq) TiCI4 (1.2 eq) Et3N (2 eq)


R = CHPh2, 4-13

solvent T *C/time
toluene reflux/ 12 h

toluene reflux/ 12 h

toluene rt/12 h


yield

SM recovered

SM recovered

98%


F










Following this success, the bisimine was converted to the imidazolium 4-14 using typical

procedure and it was converted to the corresponding copper complex 4-15, by transmetallation

with silver, in good yield (Scheme 4-3).



\ / 1) Ag20
EtO Cl DCM, rt
12 h
N THF, rt 2) CuTC N'CN
S2d DCM,rt Cu
Cl 2 h C
TC


TC


4-12 4-14 4-15

Scheme 4-3. Imidazolium and copper complex synthesis for mesityl substituted imine

This complex was used in the allylic alkylation developed previously in order to compare

its efficiency with the BIQ based carbene copper complex (Scheme 4-4). Using the same

conditions, the Ci-symmetric copper complex 4-15 gave excellent regioselectivity compared to

the respective C2-symmetric copper complex 2-109. Unfortunately the enantioselectivity dropped

drastically.


007o


I70U


EtMgBr
EtgO, 0 C
Ih
lh [ (S)
3 mol%, 4-15 (
2-115
y product (SN2')


+ I

2-116
a product (SN2)


SN2' Only
92% yield, 35% ee
with 2-109: y: a = 88 : 12, 68% yield, 61% ee

Scheme 4-4. Asymmetric allylic alkylation using 4-15

In order to increase the enantioselectivity, the bulky side of this new ligand was modified

by changing the aryl amine in the imine condensation step (Table 4-5). Bulkier 2,6-

diisopropylaniline (entry 1) and meta substituted 3,5-dimethylaniline (entry 2) were successfully


YOPiv


2-122


I










condensed with the ketone moiety. Then they were converted to imidazolium and copper

complexes in good yields. 3,5-Dimethoxyaniline gave decomposed products (entry 3) as well as

very bulky triphenylaniline (entry 4).

4.4 Achiral Side Variation

Table 4-5. Synthesis of disubstituted MIQ-NHC copper complexes
/ NH2R/
SEtN /Y ,_\/ 12h
S TiC4 EtO CM, CAM

N 0 toluene, rt N N-R THF, rt N R 2) CuTC N R
12 h 2 d a DCM, rt
A B Cl 2h CuTC
4-11 C


entry NH2R A yield B yield C yield



1 H2N 70%, 4-16 77%, 4-20 70%, 4-22




2 H2N 45%, 4-17 86%, 4-21 74%, 4-23


OMe

3 H2N- decomposed, 4-18 N/A N/A

OMe
Ph

4 H2N- -Ph SM recovered, 4-19 N/A N/A

PhN


The two new complexes 4-22 and 4-23 were used in the allylic alkylation (Table 4-6).

Using more bulky substituents at the ortho position decreased the enantioselectivity from 35% to

23% (entry 1). Meta substitution gave results similar to those obtained with bulky diisopropyl

groups (entry 3). The carbene copper complex could also be synthesized in situ as it was

observed for the BIQ carbene ligand (Scheme 2-29); only the yield was slightly reduced (entry









2). The Ci-symmetric ligand 4-1 seemed to be optimum for this reaction with substituents

smaller than isopropyl and positioned at the ortho position.

Table 4-6. Allylic alkylation with disubstituted MIQ-NHC copper complexes
EtMgBr
Et20, 0 C
-Y Opiv lhO +
3 mol% (S) +
2-122 \ 2-115 2-116
y product (SN2') a product (SN2)

N-C-N-R
CuTC

entry R yield y: a ee



1 4-22 85% 99:1 23%





2a / \ 4-22 77% 99:1 23%




3 4-23 95% 99:1 20%


[a] The copper carbene complex was synthesized in situ
from premixing of C1-symmetric imidazolium
precursor, EtMgBr and CuTC for 10 minutes prior addition
of the substrate

Monosubstituted aryl amines should be less bulky and may give better enantioselectivity

(Table 4-7). Coordinating substituents such as pyridine 4-27 and sulfonic acid 4-29 failed to

form any products (entries 4 and 6). The synthesis of the monosubstituted isopropyl imidazolium

4-30 gave a mixture of diastereomers by NMR (entry 1) which was surprising considering that

the disubstituted isopropyl imidazolium 4-20 gave only one isomer. This diastereomeric mixture









issue would be discussed later in the chapter. Only 2-methyl and 2-methoxy aniline gave the

desired imidazolium as a single product (entries 2 and 5).

Table 4-7. Synthesis of monosubstituted MIQ-NHCs
/\ NH2R
T0I4 EtO Cl
Et3N
N toluene, rt N N-R THF, rt N-/ N-R
12h 2d
SCl
4-11 A B


entry NH2R A yield B yield atioomdaolium


1 H2 / 91%, 4-24 77%, 4-30 54:46

4-0-

2 H2N / 87%, 4-25 66%, 4-31 one isomer


Ph
3 H2N 89%, 4-26 68%, 4-32 40:60



4 H2N SM recovered, 4-27 N/A N/A
N-

MeO
5 ^ crude used 95% iom
S H2N in next step, 4-28 after 2 steps, 4-33 one isomer


HO3S
H6 2N / decomposed, 4-29 N/A N/A



The imidazoliums 4-31 and 4-33 were tested in the allylic alkylation (Table 4-8). The

regioselectivity stayed excellent but the enantioselectivity almost nullified which meant that this

monosubstitution was not intruding efficiently within the metal sphere (entries 1 and 2).









Table 4-8. Allylic alkylation using monosubstituted MIQ-NHCs
EtMgBr
^ OPiv Et2O, 0 C, h (S
CuTC (3 mol%) (S)

2-122 2 \ 2-115
S / y product (SN2')

N N'R
CI
3 mol%
entry R yield y: a ee


1 4-31 82% 99:1 2%

MeO

2 4-33 82% 99:1 2%


2-116
a product (SN2)


The achiral side of the ligand was locked with 2,4,6-trimethylaniline which gave the best

results so far. The chiral side was then modified using other chiral phenethylamines developed

previously in Chapter 2.

4.5 Chiral Side Variation

The (S)-1,2-diphenylethanamine 1-46 was reacted with phenylglyoxylic acid to give the

monoamide 4-34 (Scheme 4-5). Then the cyclization procedure gave the same non polar product

2-102 as the BIQ synthesis (Scheme 2-21).


- N H2


046
1-46


EDC, HOBt
DMF, rt
12 h, 79%


0
y 3NH Ph



4-34


Tf2O
DMAP
N 0
DCM, reflux
12h 0

4-35


Scheme 4-5. Attempted synthesis of the phenyl substituted isoquinoline 4-35









The cyclohexyl phenethylamine 2-62 was reacted with the carboxylic acid to give the

corresponding monoamide 4-36 in 60% yield. Then it was cyclized in quantitative yield using

toluene as a solvent instead of DCM. The bisimine 4-38 was obtained using mesitylamine

(Scheme 4-6).


0 0 Tf20O
HO Ph O DMAP PI
NH2 EDC, HOBt NH Ph to reflu
Cy DMF, rt, 12 h, 61% Cy 12 h, 99%
2-62 4-36 Cy 4-37



Ph
TiCl4 N N
Et3N
toluene, rt
12 h, 99% 4-38
Scheme 4-6. Synthesis of 4-38

When the cyclization from bisimine 4-38 to imidazolium 4-39 was attempted at different

temperatures (Table 4-9), different ratios of a and 0 were observed (entries 1 and 2). The same

results were observed previously (Table 4-7, entries 1 and 3). When the product mixture was

further heated in toluene at 120 OC for 2 hours, the ratio stayed unchanged.

Table 4-9. Dependence between temperature and imidazolium ratio

\- EtO CI
N \ THF, T C N N
NC 3 d, 62% -
Cy / C /
Cl
4-38 4-39 (a:P)
entry T C a: 3
1 rt 84:16
2 35 C 51 :49










The evidence of this mixture was obtained from the 'H NMR (Figure 4-3 and Figure 4-4).

The characteristic imidazolium signal area showed 2 peaks at 10.5 ppm and 11.8 ppm with

different ratio. Even though those peaks are acidic and may exchange, they are the only peaks

not overlapping in the spectrum.

10.48



NN N

OH
CI
4-39 (84:16) 11.75





0.18 1.00

12.5 12.0 11.5 11.0 10.5 10.0 9.5
Chemical Shift (ppm)

Figure 4-3. H NMR of the 4-39 (84:16) (Scheme 4-6, entry 1).

11.72


10.48




Cy0
C H

4-39 (51:49)




0.95 1.00

12.5 12.0 11.5 11.0 10.5 10.0 9.5
Chemical Shift (ppm)

Figure 4-4. H NMR of 4-39 (51:49) (Scheme 4-6, entry 2)

At first glance, the compound 4-39 possesses only one chiral center but an unexpected

atropoisomerism between the isoquinoline moiety and the imidazolium ring could explain this









phenomenon. With an opposite twist of the two phenyls at the back of the molecule, two

diastereomers could be synthesized and would be hard to separate. The bulk increase on the

isoquinoline moiety seemed to be responsible for the appearance of this mixture.

The fused Cy amine 2-65 failed to give C2-symmetric bisimine 2-101 but it could work in

this Ci-symmetric ligand. The bisimine 4-42 was successfully synthesized in good overall yield

(Scheme 4-7). The imidazolium synthesis gave again a mixture of diastereomers 4-43a and 4-

43p but this time they could be both isolated by column chromatography (separated spots).

Unfortunately, when this reaction was scaled up, only 4-431 was isolated.


' I-NH2

2-65


EDC, HOBt
DMF, rt
12 h, 76%


Ph O O Tf20 \
yN H DMAP -
SNH Ph toluene, 95 C /
12 h, 95% N O

4-40 4-41


H2N_ \ _\

TiCl4 N \
Et3N
toluene, rt
12 h, 96%
4-42


EtO Cl
THF, rt
2d


N"' N /

CIO
4-43a, 34% yield
4-431, 34% yield


Scheme 4-7. Imidazolium synthesis of 4-43

When looking at their respective NMR (Figure 4-5), the main difference is their

imidazolium peaks (a = 9.65 ppm, P = 10.34 ppm). The mass spectroscopy gave the same

molecular weight for both of them. X-ray could not be obtained so their structural difference

remain a mystery.



















N N

CIO
4-43P





10.34








1.03 1.00 1.08
U .1U U
i "' '.''.''. .''.'' .'' '' '' I' ''' ..'''...... ........ I. ..'' '''' '''
10 9 8 7 6 5 4 3 2 1 0
Chemical Shift (ppm)


* NON

Cli
4-43a


0.18 0.99 1.00 1.11
U U1 U iIU
10 9 8 7 6 5 4 3 2 1 0
Chemical Shift (ppm)


Figure 4-5. 'H NMR of the two diastereomers of 4-43









4-43a and 4-43p were tested in the allylic alkylation (Table 4-10) and gave different

enantioselectivities. This result proves that those two compounds are different and the various

ratio obtained for 4-39 (a:P) would probably lead to different enantioselectivities.

Table 4-10. Allylic alkylation with two different isomers of 4-43
4-43a or 4-43p (3.5 mol%)
OPiv CuTC (3 mol%) ( + -
EtMgBr (1.5 eq) c
2-122 Et2O, 0 C 2-115 2-116
I h
y product (SN2') a product (SN2)

entry ligand yield y: a ee
1 4-43a 90% 99: 1 27%

2 4-43p 90% 99: 1 40%


4.6 Gold BIQ and MIQ Metal Complexes

All of the reactions studied involved copper complexes. Unfortunately X-ray of those

complexes could never be obtained. Considering another metal complex in the same row, gold

was chosen as an alternative to obtain an X-ray structure. MIQ and BIQ gold complexes 4-44

and 4-45 were synthesized by transmetallation from silver complex (Scheme 4-8). Those

complexes could be purified by column chromatography.

X-ray structures were obtained for both complexes (Figure 4-7and Figure 4-8). Looking at

the front view of the complexes, it was clear that 4-44 was more demanding than 4-45. It was

interesting to note that the chiral substituents in both complexes were pointing in the axial

position. To further compare the ligand steric effects, the buried volumes95 were calculated

(Figure 4-6).9 This new parameter has been developed recently to quantify the steric effects

resulting from NHC when compared to phosphine ligand which used the Tolman cone angle.97

The buried volume gives a measure of the space occupied by the NHC ligand in the first

coordination sphere of the metal centre.


J










\Ph 1) Ag20 \Ph
Si-Pr DCM, rt, 12h h-Pr

0NqN 2)AuCI.Me2S NA N
/+ DCM, rt, 12h
/ I i-Pr 87% (two steps) l i-Pr
4-20 4-44

1) Ag20
DCM, rt, 12 h
(NDN 2) AuCI*Me2S NCN
DCM, rt, 12 h
CI0 79% (two steps) Cli
2-104 4-45

Scheme 4-8. Synthesis of BIQ and MIQ gold complexes

It is defined by two parameters being R (the radii of the coordination sphere) and d (the

atomic radii). The best correlation between %VBur and DFT calculations was found for R = 3.5

A. Recently, Nolan and co-workers disclosed a review on %VBur for an extensive list of NHC and

phosphine ligands.95c In this paper, they used d = 2 A for the atomic radii. For further

comparison with known complexes, we decided to use the same parameters.

Amount of Ligand Intruding
into Radius of Coordination
Sphere is %VBur

dC' R = 3.5 A

d=2A



Figure 4-6. Buried volume for NHC ligand









We found 42.8% for 4-44 and 33.2% for 4-45. Au-MIQ 4-44 was more demanding than

Au-BIQ 4-45 by 10%. This finding supported our design expressed by three quadrants around

the metal being occupied (Figure 4-1).


Figure 4-7. X-ray structure of 4-4498















C16 2 C12 C
C9 C5
C17 C11 C10 C4

C18
C25 C3

T C24 C19 2 i, C2
C26

C22

C27 C21
SAul C23






















Figure 4-8. X-ray structure of 4-4599










4.7 Application: Copper-Catalyzed p-Borylation of a,p-Unsaturated Carbonyl
Compounds

The allylic alkylation seems to give limited results with this new ligand design. Copper is

definitely a good choice for this ligand so the effort into finding a new application was directed

toward reactions catalyzed by this metal. After a few attempts, the copper-catalyzed P-borylation

of a,P-unsaturated carbonyl compounds was selected. An in situ catalyst generation was chosen

for ease of access. It consisted of a premixing of an imidazolium, a CuCl salt and NaOtBu in

THF at room temperature for 30 minutes. The base would deprotonate the imidazolium to form

an aminocarbene which would complex with CuCl followed by substitution of the halide to form

an alkoxide carbene-copper complex 1-187 which would be our active catalyst (Figure 1-6).

From previous work by Yun,69b methanol was used to regenerate the active complex in the

catalytic cycle (Figure 4-9).

CuCI + NaOtBu CuOt-Bu
L = phosphine
B2pin2
0
LCu-BPin R1 R2
1-188 1-171

B2pin2

Bpin O B CuL
L-CuOMe R, R2 -Bpn
1-187 1-189 CL R
41-189 1-190





Bpin 0
RR2 MeOH

1-172

Figure 4-9. Proposed mechanism by Yun for P-borylation of unsaturated substrates










The boron ester addition product 4-47 was found to be hard to isolate. Without any

purification, this intermediate was further treated with NaBO3 to give the P-alcohol substrate 4-

48. The yields and enantioselectivities reported would be for two consecutive steps. The

preliminary result was encouraging with 86% yield and 50% ee (Table 4-11, entry 1). KOtBu

and NaOtBu were equally efficient (entries 1 and 3). Polar, non polar solvents and other copper

salts did not affect the outcome of the reaction (entries 3-7). Decreasing the temperature did not

increase the enantioselectivity but the yield was decreased (entry 2). Absence of ligand gave

reduced yield (entries 8-10).

Table 4-11. Optimization of P-borylation for cinnamonitrile


SB-BN NaBO3 OH
0CN MeOH OB'O N 0 CN
base ,CN solvent/H20
copper salt rt, 3 h
4-46 ligand Cl,
solvent 4-47 4-48
T "c 4-14
T'C yield over 2 steps 4-14
12 h ee


entry ligand copper salt base solvent T C yield (%) ee (%)
1 4-14 CuCI NaOtBu THF rt 86 50
2 4-14 CuCI NaOtBu THF -70 50 50
3 4-14 CuCI KOtBu THF rt 84 50
4 4-14 CuCI KOtBu Et20 rt 84 51
5 4-14 CuBr.Me2S KOtBu THF rt 86 53
6 4-14 CuBr.Me2S KOtBu DCM rt 90 50
7 4-14 CuBr.Me2S KOtBu toluene rt 85 50
8 none CuCI NaOtBu THF rt 76 N/A
9 none CuCI NaOtBu THF -20 50 N/A

10 none CuCI NaOtBu THF -70 30 N/A


The various Clsymmetric ligands developed previously were tested in this reaction (Table

4-12). Fused cyclohexyl substitution 4-431 gave lower ee than isobutyl 4-14 (entries 2 and 1)

which was the inverse of the allylic alkylation results. Increased bulk on the achiral side 4-20









decreased the enantioselectivity (entry 5) as was observed in the allylic alkylation. Surprisingly,

the BIQ ligand 2-108 gave mostly racemic products which reinforced the need of this new C1-

symmetric ligand (entries 3 and 4). When using DCM, the yield was decreased resulting

probably from trace amount of hydrochloric acid present in the solvent (entries 5 and 6).

Table 4-12. Ligand scope for cinnamonitrile


/B-B
SB O NaBO3 OH
,CN MeOH CN
base solvent/H20
copper salt rt, 3 h
ligand yield over 2 steps
solvent ee
T oC
12 h

entry ligand copper salt base solvent T C yield (%) ee (%)
1 4-14 CuCI NaOtBu THF rt 86 50
2 4-431 CuCI NaOtBu THF rt 81 (-)38
3 2-108 CuCI NaOtBu THF rt 90 7
4 2-113 N/A NaOtBu THF rt 82 6
5 4-20 CuBr.Me2S KOtBu DCM rt 47 29
6 4-39 (84:16) CuBr.Me2S KOtBu DCM rt 46 49


From this small study, 4-14 gave the best results. The electron withdrawing groups from

the substrate 1-171 were varied to study their effect on this reaction (Table 4-13). The reaction

worked well for quaternary substrates 4-49 and 4-52 (entries 1 and 5). Ketone 4-49 gave lower

ee than nitrile 4-50 (entries 1 and 2). On the other hand, amide 4-55 increased the ee significantly

compared to nitriles and esters (entries 4, 5 and 8). Thioester 4-53 was unreactive toward this

reaction (entry 6).










Table 4-13. Substrate scope


B-B

MeOH
KOtBu
CuBr.Me2S
C1-i-Bu-IQ-Mes
THF, rt
12 h


NaBO3 HO EWG

THF/H20 R
rt, 3h
1-173
yield over 2 steps
ee


N N

Cl0

4-14


R1 EWG
entry yield (%) ee (%)
R2
0

1 4-49 82 40

Ph
2 -6CN
2 4-46 1 86 53


0




0
3 4-50 IO





4 4-51 NOEt


0
5 4-52 O Et




6 4-53 SNs


0
7 4-54 NNH2


0
8 4-55 N N 'Me
m Me


No reaction
SM recovered




83



93



No reaction
SM recovered



No reaction
SM recovered



60


R1 EWG

R2
1-171










A trend between the enantioselectivity and the functional group off the substrate seemed to

appear. The more electronegative the oxygen atom becomes the better the enantioselectivity is.

This is probably due to a stronger and tighter binding of the copper with the oxygen atom which

would be responsible for a closer transition state (Figure 4-10).


Figure 4-10. Proposed transition state with amide functionality

The amide functionality was the most promising. Thus substituents off the nitrogen atom

were varied to further increase the enantioselectivity (Table 4-14). Bigger groups such as Cy 4-

56 gave better yields but the same enantioselectivity (entry 2). The Weinreb amide 4-57 was

tested and gave excellent yields with satisfactory selectivity (entry 3).

Table 4-14. Amide substrate optimization

B-B
0 0 0 NaBO3 OH O
Ph NR MeOH N A. Ph N R,
I KOtBu THF/H20 I
R2 CuBr.Me2S rt, 3 h R2
R1 = R2 = Me, 4-55 4-14 R, = R2 = Me, 4-60
R1 = R2 = Cy, 4-56 THF, rt, 12 h R, = R2 = Cy, 4-61


R, = Me, F
R1 = R2 = I
RI = R2 = I


R2 = OMe, 4-57
Bn, 4-58
PMB, 4-59


R, = Me,
R1 = R2
R, = R2


R2 = OMe, 4-62
= Bn, 4-63
= PMB, 4-64


entry R1 R2 yield (%) ee (%)

1 Me Me 60 76

2 Cy Cy 86 75

3 Me OMe 99 78

4 Bn Bn 81 84

5 4-OMeBn 4-OMeBn 95 86










The latter would be interesting for further derivatization. The benzyl substrates for the first

time gave an enantioselectivity over 80% (entry 4) with excellent yields for PMB substituents

(entry 5).

In a recent report by Hoveyda,71 it was shown that carbene-copper complexes did not need

methanol to be regenerated in the catalytic cycle with a,P-unsaturated ketones (Figure 4-11).

This probably resulted from higher reactivity of copper enolate 1-190 bearing strong C-donor

NHC compared to the less Lewis basic phosphine-based ligands.

1-187
CuCI + NaOtBu + NHC LCuOt-Bu
L = NHC

B-B2pin2
if
Bpin OBpin LCu-BPin R
R 1" R 1-188 Rj R2
1i 2 1-171
1-191




B2pin2

Bp CuL Bpin 0
Bpin OR %R2

R1 R2 CuL
1-190 1-189

Figure 4-11. Proposed mechanism for 3-borylation with NHC ligand

New optimizations were realized with the benzyl amide substrate 4-58 (Table 4-15). The

reaction proceeded very well without methanol (entries 1 and 2) which reinforced the advantage

of NHC over phosphine ligands. Other polar and apolar solvents increased slightly the ee but the

yield dropped a lot (entries 3-6 and 8). This was probably due to lower solubility. When using a

mixture of THF/Et20, the enantioselectivity stayed the same as when pure Et20 was used but the









yield was similar to pure THF (entry 7). The THF might coordinate to B2pin2 and facilitate the a

bond metathesis. Copper (II) salts were similarly effective in this reaction (entries 9 and 10).

Table 4-15. Reaction condition optimization for N,N-dibenzylcinnamamide




Ph N Bn MeOH ph N.Bn
I KOtBu solvent/H20 i
Bn copper salt rt, 3 h Bn
4-58 4-14 4-63
solvent
rt, 12 h

entry copper salt MeOH solvent yield (%) ee (%)
1 CuBr.Me2S Yes THF 81 84
2 CuBr.Me2S No THF 92 84
3 CuBr.Me2S No Et20 46 86
4 CuBr.Me2S No toluene 20 87
5 CuBr.Me2S No tBuOMe 33 86
6 CuBr.Me2S No DME 63 85
7 CuBr.Me2S No Et20/THF (1:1) 87 86
8 CuBr.Me2S No 1,4-dioxane 41 63
9 Cu(OTf)2 No THF 78 83
10 Cu(OAC)2 No THF 72 85

The optimization results with amide substrates were similar to those with cinnamonitrile

which showed the robustness of this new Ci-symmetric catalyst 4-14. For mechanistic studies,

the Z unsaturated amide 4-59 was synthesized and submitted to the Borylation reaction (Table

4-16). The catalyst favored the other enantiomer but in lower enantioselectivity (entries 1 and 2).

New imidazoliums were synthesized for further studies of the effect of the achiral moiety

(Table 4-17). 4-70 was synthesized for comparison with 4-14 (entry 2). Those two ligands differ

by the methyl in para position.









Table 4-16. j-borylation with different alkene configuration
OMe O OMe

0 0
O0 0 t NaB03 OHO
K MeOH OH O
Ph" N KOtBu THF/H20 Ph N
CuBr. Me2S rt, 3 h
4-14
THF
MeO rt, 12 h MeO
4-59 4-64

entry Z/E configuration yield (%) ee (%)

1 E 95 86 (S)
2 Z 80 -66 (R)

Lower ee for 4-70 would mean the methyl is needed in thepara position and bigger groups

could be incorporated for improvement. Similar ee would suggest that thepara position does not

interfere with the reaction. Higher ee would imply the para position obstructs the reaction. 4-69

was formed to increase the bulk between methyl and isopropyl (entry 1). 4-71 was made to study

inductive effect on the catalyst (entry 3). Anthracene substituted 4-72 would be interesting as a

facial bulk (entry 4). Aliphatic amines could also be used in the synthesis of this ligand (entry 5).

Those new imidazoliums were used in the copper-catalyzed borylation (Table 4-18). 4-70

gave slight better enantioselectivity than 4-14 which proved the additional methyl is decreasing

the ee (entries 1 and 3). The slight increase in bulk with ethyl substitution 4-69 gave the same

results (entry 4). A large increase in bulk with isopropyl in 4-20 decreased the enantioselectivity

(entry 2). Interestingly, the electron withdrawing substituents in 4-71 contributed to a 13% drop

in ee (entries 5 and 6). 4-33 and 4-72 did not improve the enantioselectivity in the borylation

reaction (entries 7 and 8).









Table 4-17. Synthesis of additional MIQ-NHCs
S0\ NH2R
S TiCI4
SEt3N EtOClI
N 0 toluene, rt N N-R THF, rt
12h 2d
4-11 A B


G N R

C01
CIO


entry NH2R A yield B yield

Et

1 H2N- 71%, 4-65 85%, 4-69

Et

2 H2 / 38%, 4-66 42%,4-70



CF3
3 H2N 80%, 4-67 71%, 4-71


CF3




4 H2N 75%, 4-68 90%, 4-72




5 PN h 74%, 4-13 90%, 4-73
5 Ph
Ph


This amide substrate may give a better transition state considering that BIQ based carbene

ligand 2-104 obtained 36% ee with 4-59 (entry 12) and 7% ee with 4-46 (Table 4-12, entry 3).

Two mixtures of 4-39 were tested in this reaction (entries 10 and 11). The difference in ee

supported the formation of two diastereomers. The three best ligands are the unhindered ortho

substituted ones (entries 1, 3 and 4).










Table 4-18. Ligand scope for N,N-bis(4-methoxybenzyl)cinnamamide
OMe OMe


SMeO NaBO3
O No MeOH ______ O_
Ph N NN KOtBu THF/H20 Ph" N
CuBr. Me2S rt, 3 h
Ligand
Jl J THF, rt, 12 h
MeO4 MeO
4-59 4-64


entry
1
2
3
4
5
6
7
8
9

10
11
12
13


ligand yield (%)
4-14 95
4-20 84
4-70 97
4-69 94
4-21 97
4-71 90
4-33 99
4-72 78
4-43p 90

4-39 (51:49) 88
4-39 (84:16) 90
2-104 80
4-73 80


ee (%)
86
82
88
88
64
51
67
72
55

56
75
36
62


Over the course of this study, inconsistencies were observed in the yields of this reaction.

After a careful screening of the reaction parameters, the temperature of the reaction was put at

fault (Table 4-19). From fall to winter, the room temperature decreased by 6 C and this small

drop had a dramatic effect on the yields (entries 1 and 3). To palliate this variation in yields, the

reaction temperature was increased to 40 C. Better yields were obtained without a drop in the

enantioselectivity (entries 4 and 5). Additionally, the reaction could be completed in 6 hours

instead of 12 hours (entries 5 and 6). Unfortunately, 4-69 only gave 85% ee (entries 1-3) instead

of 88% reported previously (Table 4-18, entry 4).









Table 4-19. Temperature effect on the copper-catalyzed borylation
0 OH 0
Ph A N'PMB B2pin2 NaBO3 Ph .NPMB
KOtBu THF/H20 P
PMB CuBr. Me2S 25 C, 3 h PMB
4-59 ligand 4-64
THF, T C, time

entry ligand T C MeOH time yield ee
1 4-69 21 No 12h 72% 85%
2 4-69 21 Yes 12 h 70% 85%
3 4-69 25-27 Yes 12 h 95% 86%
4 4-14 25-27 Yes 12 h 87% 85%
5 4-14 40 Yes 12 h 95% 85%
6 4-14 40 No 6h 92% 85%
7 4-14 40 No 2h 83% 85%


For reproducibility reasons, we decided to choose 4-14 as our ligand of choice for the

substrate scope (Table 4-20). The reaction tolerated electron-donating (entries 2 and 3), electron

withdrawing (entry 5) and meta substituents (entry 6), as well as aliphatic substituents (entries 6

and 7). Surprisingly, low yield and ee was obtained with ortho fluorine substitution (entry 4).

Combining our results and observations, we envisioned a working transition state

responsible for our selectivity (Figure 4-12). Using the X-ray structure 4-44, gold and chloride

atoms were replaced by copper and boron using reported bond lengths for similar complexes.100

Considering that MIQ carbene ligand blocks the three quadrants around the metal center and

giving the absolute configuration of the product, the substrate should approach from the bottom

left corner. The model i with Si-face attack by the boryl group is most likely to form the major

enantiomer (S) (Table 4-14, entry 1) where as model ii with attack on the Re-face would

encounter steric repulsion from the aryl substituents.










Table 4-20. Substrate scope
0
R "ANPMB

PMB


B2pin2 (1.1 equiv)

KOtBu (9 mol%)
CuBr.Me2S (3 mol%)
4-14 (3.5 mol%)
THF, 40 C, 6 h


NaBO3

THF/H20
rt, 3h


OH O

R.K N.PMB
PMB


entry SM/P R yield (%) ee (%) entry SM/P R yield (%) ee (%)

1 4-59/64 92 85 5 4-77/84 F 90 87


2 4-74/81 MeO 86 84 6 4-78/85 94 85

OMe

3 4-75/82 80 84 7 4-79/86 91 86

F

4 4-76/83 ,- 53 55 8 4-80/87 H3C-:- 99 75


Figure 4-12. Proposed transition-state model for the asymmetric borylation. B


pinB-









4.8 Further Directions for MIQ or BIQ Ligands

Over the course of this study, several BIQ or MIQ substituted carbene ligands were

synthesized. The pursuit of more bulky substitution is still needed to increase selectivity. P-

Substitution prevented the formation of the bisimine moiety as seen in fused cyclohexyl and

norephedrine. Ligands with only a-substitution should be pursued but a few substituents raise

issues. Aryl groups decompose the bisamide into cyanogens and stilbene (Scheme 2-21). Benzyl

substituents can also participate in the Bischler-Napieralski cyclization which can scramble the

chiral centers. Interesting results could be obtained by incorporation of quaternary centers at the

a position.









CHAPTER 5
CONCLUSION

Bisoxazoline and bisimidazoline based carbene ligand synthesis revealed some issues

either in the metal complex or the imidazolium formation. Concluding that the proximal

heteroatom next to the imidazolium rings were detrimental for N-heterocyclic carbene reactivity,

new all carbon based amino carbene ligands were synthesized with success.

New C2- (BIQ) and Ci-symmetric (MIQ) aminocarbene ligands were developed from the

same chiral phenethylamines which were synthesized in four steps from amino acids. Both

synthesis involved amide formation followed by Bischler-Napieralski cyclization. BIQ based

carbene ligands could accommodate any alkyl chirality a to the nitrogen atoms isopropyll,

isobutyl, tert-butyl, cyclohexyl, cyclohexyl alanine). Fused cyclohexyl with 0 chirality could not

be installed on this ligand. On the other hand, MIQ based carbene ligands could accept both

types of chirality as long as they possessed CH2 groups next to it (fused cyclohexyl and

isobutyl). Other groups such as cyclohexyl and tert-butyl gave mixture of diastereomers resulting

from hindered rotation.

BIQ based carbene ligands were successfully applied in the copper-catalyzed allylic

alkylation using Grignard reagent as nucleophiles. The highlight of this transformation was the

formation of an all carbon quaternary center in 91% yield, 85:15 (SN2'vs SN2) selectivity and

76% ee. MIQ based carbene ligands were used in the copper-catalyzed borylation of a,p

unsaturated amides with an average of 85% ee for alkyl and aryl substrates. The ligands gave

opposite results in those two reactions: BIQ gave 36% ee for the borylation and MIQ gave 35%

ee in the allylic alkylation. Those two results proved the need for diversity in ligand structure.

These ligands can be accessed readily from the same intermediate and used accordingly for

future applications.









While working on the BIQ copper complex characterization, we observed an in situ

carbene copper complex formation from chloroimidazolium. As our group was interested in the

development of new acyclic carbene ligands, we applied the methodology to this field. Using the

same copper-catalyzed allylic alkylation with Grignard reagent, we generated in situ the first

acyclic carbene copper complex which catalyzed efficiently the latter reaction. The carbene

cuprate complex was observed by low temperature NMR and based on characteristic metal-

carbene 13C NMR chemical shifts. This project was a typical example of serendipity in organic

chemistry.









CHAPTER 6
EXPERIMENTAL SECTION

6.1 General Remarks

All reactions were conducted in flame-dried glassware under an inert atmosphere of dry

argon. THF, CH2C2, Et20 and toluene were purified under positive pressure of dry nitrogen by

Meyer Solvent Dispensing System prior to use. All the chemicals used were purchased from

Sigma-Aldrich Co., Acros Organics and Strem Chemicals Inc. and were used as received without

further purification. NMR spectra were recorded using a Mercury-300 FT-NMR, operating at

300 MHz for H NMR and at 75.4 MHz for 13C NMR. All chemical shifts for 1H and 13C NMR

spectroscopy were referenced to residual signals from CDC13 (1H) 7.27 ppm and (13C ) 77.23

ppm. High resolution mass spectra were recorded on a GC/MS spectrometer or a TOF-LC/MS

spectrometer. Optical rotations were recorded on a Perkin-Elmer 241 polarimeter. Enantiomer

ratios were determined by chiral HPLC analysis (Shimadzu) using Chiral Technologies Chiralcel

OJ-H, Chiralpak IA and IB columns and Regis Technologies Whelk-01 column.

6.2 C2-Symmetric NHC Ligands

6.2.1 Bisoxazoline Derived NHC Ligand

N1 N2-bis((1R,2R)-2-hydroxy-2,3-dihydro-H-inden-1-yl)oxalamide (2-11)

OH 0 0 HQ

'- NH HN




In a flame dried Schlenk flask, 194 [L (1.42 mmol) of diethyl oxalate was added to a

suspension of 445 mg (2.98 mmol) of(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol in toluene

(10 mL). The reaction mixture was stirred at reflux for 12 h. It was cooled at room temperature









and hexane (5 mL) was added. The product was isolated by filtration on Buchner funnel and it

was washed with hexane (3 x 5 mL) to yield 478 mg (1.36 mmol, 95.5%) of N1,N2-bis((1R,2R)-

2-hydroxy-2,3-dihydro-lH-inden-l-yl)oxalamide.

1H NMR (300MHz ,DMSO-d6) 6 = 9.08 (d, J= 9.1 Hz, 2 H), 7.26 7.04 (m, 8 H), 5.36 (d,

J= 5.9 Hz, 2 H), 5.15 5.05 (m, 2 H), 4.57 4.45 (m, 2 H), 3.16 (dd, J= 7.3, 15.2 Hz, 2 H), 2.72

(dd, J= 7.6, 15.5 Hz, 2 H)

3C NMR (75MHz ,CHLOROFORM-d) 6 = 166.0, 146.6, 145.2, 133.1, 132.1, 130.1,

129.0, 82.3, 66.9, 44.2

Nli 2-bis((1R,2R)-2-methanesulfonate-2,3-dihydro-lH-inden-l-yl)oxalamide (2-13)

MsO 0 QMs

S"'NH HN




In a flame dried Schlenk flask, 55.0 [L of mesylate chloride (0.712 mmol) was added to a

suspension of 100 mg of N1,N2-bis((1R,2R)-2-hydroxy-2,3-dihydro-lH-inden-l-yl)oxalamide

(0.284 mmol) and 158 iL (1.14 mmol) of Et3N in THF (2 mL) at 0 C. The suspension was

stirred at room temperature for 4 h.4 mL of H20 was added and the solid was isolated by

filtration on Buchner funnel. It was washed with H20 (3 x 2 mL) to yield 117 mg (0.230 mmol,

82.0%) of N1,N2-bis((1R,2R)-2-methanesulfonate-2,3-dihydro- H-inden-l-yl)oxalamide.

H NMR (300MHz ,DMSO-d6) 6 = 9.51 (d, J= 8.5 Hz, 2 H), 7.35 7.24 (m, 6 H), 7.18 (s,

2 H), 5.52 5.40 (m, 4 H), 3.49 (dd, J= 6.9, 16.0 Hz, 2 H), 3.24 (s, 6 H), 3.16 3.03 (m, 2 H)

13C NMR (75MHz ,DMSO-d6) 6 = 160.9, 139.5, 138.8, 129.2, 128.1, 125.5, 124.3, 85.1,

59.5, 38.3, 37.1









(3aR,3'aR,8aS,8'aS)-8,8a,8',8'a-tetrahydro-3aH,3'aH-2,2'-biindeno[1,2-d]oxazole (2-

10)

'110 0
O)O

.'IN N



To a flame-dried Schlenk flask was added 268 mg (0.527 mmol) of N1,N2-bis((1R,2R)-2-

methanesulfonate-2,3-dihydro-1H-inden-l-yl)oxalamide, 440 mg (7.90 mmol) of potassium

hydroxide and 25 mL of methanol. The suspension was heated at 70 OC for 1 h. The reaction

mixture was concentrated under vacuum. The residue was extracted with DCM (10 mL) and

washed with H20 (2 x 10 mL), dried over anhydrous MgSO4, and the solvent was removed under

reduced pressure to yield 156 mg (0.494 mmol, 94.0%) of(3aR,3'aR,8aS,8'aS)-8,8a,8',8'a-

tetrahydro-3aH,3'aH-2,2'-biindeno[1,2-d]oxazole.

1H NMR (299MHz ,CHLOROFORM-d) 6 = 7.57 7.43 (m, 1 H), 7.36 7.12 (m, 3 H),

5.73 (d, J= 7.9 Hz, 1 H), 5.55 5.40 (m, 1 H), 3.54 3.23 (m, 2 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 155.3, 140.5, 139.6, 129.0, 127.6, 125.8,

125.4, 84.6, 77.2, 39.5

IBiox[(R,S)-indanol]-HOTf (2-19)







TfO

To a flame-dried Schlenk flask was added 460 mg (1.46 mmol) of (3aR,3'aR,8aS,8'aS)-

8,8a,8',8'a-tetrahydro-3aH,3'aH-2,2'-biindeno[1,2-d]oxazole, 449 mg (1.75 mmol) of silver









triflate and 5 mL of DCM. The reaction mixture was wrapped in aluminum foil to protect it from

the light and stirred for 5 min. 306 [iL (2.11 mmol) of chloromethyl pivalate was then added.

The mixture was stirred at 40 OC for 16 h. It was cooled to room temperature and DCM (10 mL)

followed by methanl (10 mL) were added to the flask. The suspension was filtered and

concentrated under vacuum. Silicagel column chromatography with a 98:2 mixture of DCM and

methanol as the eluent gave 230 mg (0.480 mmol, 32.9%) of Biox[(R,S)-indanol]-HOTf.

'H NMR (299MHz ,CHLOROFORM-d) 6 = 9.38 (s, 1 H), 7.75 (d, J= 7.6 Hz, 2 H), 7.38 -

7.15 (m, 6 H), 6.26 (d, J= 6.5 Hz, 2 H), 6.07 5.97 (m, 2 H), 3.54 3.33 (m, 4 H)

3C NMR (75MHz ,CHLOROFORM-d) 6 = 139.9, 135.1, 131.0, 129.1, 126.2, 125.5,

125.1, 114.5, 95.4, 67.1, 38.5

6.2.2 Bisimidazoline Derived NHC Ligand

Ni,N2-bis((S)-1-chloro-3-methylbutan-2-yl)oxalamide (2-26)


H
cI. N C
H 0


To a flame-dried Schlenk flask was added 100 mg (0.384 mmol) of N1,N2-bis((S)-l-

hydroxy-3-methylbutan-2-yl)oxalamide, 61.3 [L (0.845 mmol) of thionyl chloride and 2 mL of

toluene. The reaction mixture was stirred at 90 OC for 12 h. After cooling at room temperature,

the solution was poured onto cold 20% potassium hydroxide (4 mL). The mixture was extracted

with DCM (3 X 5 mL), washed with a saturated NaHCO3 solution (10 mL) and dried over

anhydrous sodium sulfate. The reaction mixture was concentrated under vacuum to yield 111 mg

(0.373 mmol, 97.2%) of N1,N2-bis((S)-l-chloro-3-methylbutan-2-yl)oxalamide (2-26).









'H NMR (300MHz ,CHLOROFORM-d) 6 = 7.54 (d, J= 9.1 Hz, 2 H), 3.93 (ddt, J= 4.2,

8.2, 9.6 Hz, 2 H), 3.78 3.60 (m, 4 H), 2.06 (dq, J= 6.8, 14.8 Hz, 2 H), 0.98 (d, J= 6.7 Hz, 6 H),

1.02 (d, J= 6.7 Hz, 6 H)

(4S,4'S)-l,l'-dibenzyl-4,4'-diisopropyl-4,4',5,5'-tetrahydro-1H,1'H-2,2'-biimidazole

(2-28)





N N

N N



To a flame-dried Schlenk flask was added 100 mg (0.336 mmol) of N1,N2-bis((S)-l-

chloro-3-methylbutan-2-yl)oxalamide, 175 mg (0.840 mmol) of PC15 and 5 mL of toluene. The

reaction mixture was stirred for 5 h at 85 C. After cooling to room temperature, the solution was

concentrated under vacuum and under inert atmosphere to give the crude imidoyl chloride as a

yellow oil. 5 mL of acetonitrile and 281 iL (2.02 mmol) of Et3N were added to the residue and

the mixture was stirred for 5 min. 81 [L (0.730 mmol) of benzylamine was then added and the

reaction mixture was stirred at reflux for 12 h. After cooling to room temperature, 25 mL of

water was added. The mixture was extracted with DCM (3 X 10 mL), and dried over anhydrous

sodium sulfate. The reaction mixture was concentrated under vacuum. Silicagel column

chromatography with a 95:5 mixture of ethyl acetate and methanol as the eluent gave 54 mg

(0.134 mmol, 40%) of (4S,4'S)-1,1'-dibenzyl-4,4'-diisopropyl-4,4',5,5'-tetrahydro-1H,1'H-2,2'-

biimidazole.









'H NMR (300MHz ,CHLOROFORM-d) 6 = 7.44 7.12 (m, 10 H), 4.67 4.40 (m, 4 H),

3.87 (td, J= 6.7, 10.4 Hz, 2 H), 3.33 (dd, J= 9.4, 10.8 Hz, 2 H), 2.92 (t, J= 9.7 Hz, 2 H), 1.75

(dq, J= 6.7, 13.3 Hz, 2 H), 0.94 (d, J= 6.7 Hz, 6 H), 0.84 (d, J= 6.7 Hz, 6 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 156.5, 137.9, 128.8, 128.1, 127.6, 71.5, 52.4,

51.6, 33.5, 19.4, 18.9

(4S,4'S)-4,4'-diisopropyl-1,1'-diphenyl-4,4',5,5'-tetrahydro-1H,1'H-2,2'-biimidazole

(2-29)





N N

N N.



To a flame-dried Schlenk flask was added 313 mg (1.05 mmol) of N1,N2-bis((S)-l-chloro-

3-methylbutan-2-yl)oxalamide, 550 mg (2.63 mmol) of PC15 and 15 mL of toluene. The reaction

mixture was stirred for 5 h at 85 C. After cooling to room temperature, the solution was

concentrated under vacuum and under inert atmosphere to give the crude imidoyl chloride as a

yellow oil. 15 mL of acetonitrile and 880 [iL (6.32 mmol) of Et3N were added to the residue and

the mixture was stirred for 5 min. 215 [iL (2.32 mmol) of aniline was then added and the reaction

mixture was stirred at reflux for 12 h. After cooling to room temperature, 75 mL of water was

added. The mixture was extracted with DCM (3 X 30 mL), and dried over anhydrous sodium

sulfate. The reaction mixture was concentrated under vacuum. Silicagel column chromatography

with ethyl acetate as the eluent gave 70 mg (0.187 mmol, 17.7%) of (4S,4'S)-4,4'-diisopropyl-

1,1'-diphenyl-4,4',5,5'-tetrahydro-1H, 1 'H-2,2'-biimidazole.









'H NMR (299MHz ,CHLOROFORM-d) 6 = 7.71 7.58 (m, 4 H), 7.50 (d, J= 7.1 Hz, 2

H), 7.29 7.18 (m, 4 H), 4.71 4.53 (m, J= 11.3 Hz, 1 H), 4.24 (t, J= 9.5 Hz, 2 H), 4.12 (dd, J=

9.2, 11.5 Hz, 2 H), 2.65- 2.48 (m, 1 H), 1.70 (d, J= 6.8 Hz, 6 H), 1.61 (d, J= 6.5 Hz, 6 H)

13C NMR (75MHz ,CHLOROFORM-d)6 = 153.6, 139.9, 128.4, 123.3, 119.5, 71.2, 53.8,

32.9, 19.6, 19.1, 1.2

6.2.3 Biisoquinoline Derived NHC Ligand

(S)-2-isobutyl-1-tosylaziridine (2-47).

Ts
N



To a flame-dried Schlenk flask was added 4.60 g (39.2 mmol) of (S)-2-amino-4-

methylpentan-1-ol 2-43, 22.0 mL (157 mmol) of triethylamine and 50 mL of CH2C12. The

reaction mixture was cooled to -25 C, and 8.40 g (44.0 mmol) of p-toluenesulfonyl chloride was

added. The cooled mixture was stirred for 2 h at -30 C and then for 1 h at room temperature.

The stirred mixture was cooled to -25 C, and 3.20 mL (41.5 mmol) of methanesulfonyl chloride

was added. After stirring for 2 h at -30 C, the reaction mixture was stirred for 10 h at room

temperature. The reaction solution was washed with 200 mL of 1 M aqueous HC1 solution and

then 100 mL of a saturated NaHCO3 solution. The organic solution was dried over anhydrous

MgSO4, and the solvent was removed under reduced pressure. Silicagel column chromatography

with a 6:1 solution of hexane and ethyl acetate as the eluent afforded 8.00 g (31.6 mmol, 80.5%)

of 2-47.

(S)-2-isopropyl-l-tosylaziridine (2-46)









Ts
N




6.50 g (27.2 mmol, 79.4 %) of 2-46 was obtained from 3.50 g (34.0 mmol) of (S)-2-amino-

3-methylbutan-l-ol 2-43.

(S)-4-methyl-1-phenylpentan-2-amine (2-55).


NH2



To a flame-dried Schlenk flask was added 1.90 g (10.0 mmol) of Cul and 20 mL of THF.

The reaction mixture was cooled to -30 C, and 33.0 mL of PhMgCl solution (2.0 M in THF)

was slowly added. After 30 min stirring at -30 C, 8.00 g (31.6 mmol) of 2-47 was added, and the

reaction temperature was slowly increased to room temperature. After 3 h, the reaction was

cautiously quenched by 50 mL of a saturated NH4Cl aqueous solution. The organic layer was

separated and dried over anhydrous MgSO4. All volatiles were removed in vacuo. Silicagel

column chromatography with a 3:1 mixture of hexane and ethyl acetate as the eluent gave 8.60 g

(25.9 mmol, 82.1 %) of 2-51.

To a flame-dried Schlenk flask was added 1.45 g (210.0 mmol) of Li and 30 mL of THF.

To the reaction mixture was added 0.190 g of naphthalene at room temperature. After 30 min,

the solution turned dark blue. 5.50 g (16.6 mmol) of (S)-4-methyl-N-(4-methyl-l-phenylpentan-

2-yl) benzenesulfonamide 2-51 was added at -78 C, and the reaction temperature was slowly

warmed to room temperature. After 12 h, the solution was transferred through a canula to

another flask to remove the unreacted Li. The solution was quenched by a saturated NH4Cl

solution and rinsed with water. To the organic solution was added 30 mL of 1 M HC1 aqueous









solution, and the organic layer was discarded. To the acidic aqueous solution was added 20 mL

of 20 % NaOH aqueous solution. Crude 2-55 was extracted by 60 mL of Et20 and dried over

anhydrous MgSO4. Evaporation of the solvent gave 2.80 g (15.8 mmol, 95.1 %) of 2-55.

(R)-3-methyl-1-phenylbutan-2-amine (2-54).

NH2




1.40 g (8.60 mmol, 83 %) of 2-54 was obtained from 2.50 g (10.4 mmol) of 2-46.

(S)-1-cyclohexyl-3-phenylpropan-2-amine (2-57)

S NH2



600 mg (2.76 mmol, 57%) of (S)-l-cyclohexyl-3-phenylpropan-2-amine was obtained

from 1.42g (4.84 mmol) of (S)-2-(cyclohexylmethyl)- 1-tosylaziridine.

1HNMR (300MHz ,CHLOROFORM-d) 6 = 7.39 7.02 (m, 5 H), 3.10 (br. s., 1 H), 2.78

(dd, J= 4.3, 13.3 Hz, 1 H), 2.41 (dd, J= 8.8, 13.5 Hz, 1 H), 1.80 1.62 (m, 4 H), 1.34 1.04 (m,

7 H), 1.04- 0.76 (m, 2 H)

3C NMR (75MHz ,CHLOROFORM-d) 6 = 140.0, 129.5, 128.6, 126.3, 49.9, 45.9, 45.5,

34.7, 34.4, 33.2, 26.9, 26.6, 26.5

(S)-1-cyclohexyl-2-phenylethanamine (2-62)

NH2





A flame-dried Schlenk flask was charged with 6.20 g (45.0 mmol) of (S)-2-amino-2-

phenylethanol 2-59, 9.00 g of MgSO4 and 50 mL of CH2C2. To the reaction mixture was added









5.00 mL (42.0 mmol) of cyclohexyl carboxaldehyde at room temperature. After stirring for 2 h,

the reaction mixture was filtered through a pad of celite. All volatiles were removed in vacuo. To

another flame-dried schlenk flask was added the filtrate and 20 ml of THF. 100 mL of

benzylmagnesium chloride solution (2.0 M in THF) was added to the reaction flask at -30 C.

The reaction mixture was slowly warmed to room temperature, and stirred for 4 h. The reaction

was quenched with 50 mL of a saturated NH4Cl solution, and the organic layer was separated

and dried over anhydrous MgSO4. After removal of the solvent under reduced pressure, silicagel

column chromatography with a 4:1 mixture of hexane and ethyl acetate as the eluent gave 9.70 g

(29.9 mmol, 66.4 %) of (S)-2-((S)-l-cyclohexyl-2-phenylethylamino)-2-phenylethanol 2-61.

A mixture of 9.70 g (29.9 mmol) of 2-61, 2.50 g of 10% Pd/C in 100 mL of ethanol was

stirred at 75 C for 48 h under 800 psi pressure of H2. The reaction solution was filtered through

a pad of celite, and the filtrate was concentrated under reduced pressure. The residue was

purified by slilicagel column chromatography using 5 % MeOH solution in CH2C12 as the eluent

to give 3.66 g (18.0 mmol, 60.2%) of 2-62.

trans-2-phenylcyclohexanol (rac-2-67)

HO Ph




To a cooled (0 oC), magnetically stirred solution of PhMgBr (89.0 mL, 89.0 mmol) and 40

mL of THF, 5.64 g (29.65 mmol) of Cul was added under argon followed by dropwise addition

of a solution of 5.0 mL (49.4 mmol) of cyclohexene oxide in 30 mL of THF. The reaction

mixture was stirred at room temperature for 12 h. A saturated solution of ammonium chloride

(20 mL) was slowly added and the mixture was extracted with diethyl ether (3 X 30mL), dried

with MgSO4 and concentrated under vacuum. The residue was purified by flash column









chromatography (silica gel, 1:4 ethyl acetate/hexane) to afford 7.90 g (44.8 mmol, 90.7%) of

trans-2-phenylcyclohexanol.

(1S,2R)-2-phenylcyclohexanol (1S,2R-2-67)

HQ Ph




To a flame-dried pressure vessel was added 2.00 g (11.4 mmol) of trans-2-

phenylcyclohexanol, 5.3 mL (57.1 mmol) of vinyl acetate, 2.5 g of CALB and 57 mL of

tBuOMe. The reaction mixture was heated at 45 C and stirred for 2 d. The enzyme CALB was

filtered off and could be reused while the solution was concentrated under vacuum. The residue

was purified by flash column chromatography (silica gel, 2.5:97.5 ethyl acetate/hexane) to afford

720 mg (4.11 mmol, 71.8% yield, 99.4% ee) of (1S,2R)-2-phenylcyclohexanol.

2-((1R,2R)-2-phenylcyclohexyl)isoindoline-,3-dione (2-68)



00
N Ph
O ^



To a flame dried Schlenk flask was added 500 mg (2.85 mmol) of (1S,2R)-2-

phenylcyclohexanol, 630 mg (4.28 mmol) of phthalimide, 1.12 g (4.28 mmol) of PPh3, 876 [L

(4.42 mmol) of DIAD and 10 mL (0.3M) of THF. The reaction mixture was stirred at room

temperature for 12 h and concentrated under vacuum. Silicagel column chromatography with a

97.5:2.5 mixture of hexane and ethyl acetate as the eluent gave 634 mg (2.08 mmol, 72.8%) of 2-

((1R,2R)-2-phenylcyclohexyl)isoindoline-1,3-dione.









(1R,2R)-2-phenylcyclohexanamine (2-65)

H2N Ph




To a flame dried Schlenk flask was added 585 mg (1.916 mmol) of 2-((1R,2R)-2-

phenylcyclohexyl)isoindoline-1,3-dione, 642 [iL (9.58 mmol) of ethylene diamine and 10 mL of

ethanol. The reaction mixture was stirred at 90 OC for 12 h. The suspension was filtered and the

solution was concentrated under reduced pressure. The residue was diluted in Et20 (20 mL) and

to the resulting organic solution was added 15 mL of 1 M HC1 aqueous solution, and the organic

layer was discarded. To the acidic aqueous solution was added 20 mL of 20 % NaOH aqueous

solution. The latter was extracted by 60 mL of Et20 and dried over anhydrous MgSO4.

Evaporation of the solvent gave 275 mg (1.57 mmol, 82.2%) of (1R,2R)-2-

phenylcyclohexanamine.

1H NMR (300MHz ,CHLOROFORM-d) 6 = 7.44 7.04 (m, 5 H), 3.66 (td, J= 4.5, 10.0

Hz, 1 H), 2.49 2.38 (m, 1 H), 2.18 2.05 (m, 1 H), 1.92 1.72 (m, 3 H), 1.62 1.35 (m, 4 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 143.5, 129.0, 128.1, 127.0, 74.6, 53.4, 34.7,

33.5, 26.3, 25.3

(2R,3R)-2,3-diphenyl- -tosylaziridine (2-80)

Ts
N

Ph 'Ph

To a flame dried Schlenk flask was added 500 mg (1.36 mmol) of N-((1R,2S)-2-hydroxy-

1,2-diphenylethyl)-4-methylbenzenesulfonamide, 535 mg (2.04 mmol) of PPh3, 416 [tL (2.10

mmol) of DIAD and 10 mL of THF. The reaction mixture was stirred at room temperature for 12

h. The suspension was concentrated un der vacuum. Silicalgel chromatography with a 5:1









mixture of hexane and ethyl acetate as eluent gave 400 mg (1.14 mmol, 84.2% yield) of

(2R,3R)-2,3-diphenyl-1-tosylaziridine.

H NMR (300MHz ,CHLOROFORM-d) 6 = 7.63 (d, J= 8.5 Hz, 1 H), 7.47 7.31 (m, 10

H), 7.20 (d, J= 8.2 Hz, 1 H), 4.27 (s, 2 H), 2.39 (s, 3 H)

(4R,5S)-4,5-diphenyloxazolidin-2-one (2-81)

0

HNO

Ph Ph

To a flame dried Schlenk flask was added 2.00 g (9.38 mmol) of(1S,2R)-2-amino-l,2-

diphenylethanol, 152 mg (2.80 mmol) of sodium methoxide and 36 mL (300 mmol) of diethyl

carbonate. The reaction mixture was stirred at 80 OC for 12 h. The reaction mixture was

concentrated under vacuum and the solid was washed with hexane (2 X 40 mL) to yield 2.24 g

(9.377 mmol, 99%) of (4R,5S)-4,5-diphenyloxazolidin-2-one.

'H NMR (299MHz ,CHLOROFORM-d) 6 = 7.23 7.01 (m, 6 H), 7.01 6.80 (m, 4 H),

5.94 (d, J= 8.2 Hz, 1 H), 5.64 (br. s., 1 H), 5.17 (d, J= 8.2 Hz, 1 H)

13C NMR (75MHz ,CHLOROFORM-d) 6= 151.9, 128.5, 128.3, 128.1, 127.1, 126.3, 82.5,

61.7

(S)-1,2-diphenylethanamine (1-46)

H2N

Ph Ph

7.83 g (32.7 mmol) of(4R,5S)-4,5-diphenyloxazolidin-2-one, 2.3g of 10% Pd/C and 175

mL of methanol were stirred at room temperature for 60 h under 400 psi pressure of H2. The

reaction solution was filtered through a pad of celite, and the filtrate was concentrated under









reduced pressure. The residue was diluted in Et20 (20 mL) and to the resulting organic solution

was added 15 mL of 1 M HC1 aqueous solution, and the organic layer was discarded. To the

acidic aqueous solution was added 20 mL of 20 % NaOH aqueous solution. The latter was

extracted by 60 mL of Et20 and dried over anhydrous MgSO4. Evaporation of the solvent gave

4.20 g (21.3 mmol, 65%) of (S)-l,2-diphenylethanamine.

1H NMR (300MHz ,CHLOROFORM-d) 6 = 7.44 7.19 (m, 10 H), 4.23 (dd, J= 4.9, 8.8

Hz, 1 H), 3.06 (dd, J= 5.0, 13.4 Hz, 1 H), 2.87 (dd, J= 8.9, 13.3 Hz, 1 H), 1.50 (br. s., 2 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 146.0, 139.4, 129.7, 128.7, 127.4, 126.7,

126.7, 57.9, 46.8

(S)-l-(4-methoxyphenyl)-4-methylpentan-2-amine (2-138)

H2N





0-

82 mg (0.395 mmol, 48.2%) of (S)-l-(4-methoxyphenyl)-4-methylpentan-2-amine was

obtained from 208 mg (0.825 mmol) of(S)-2-isobutyl-l-tosylaziridine.

'H NMR (299MHz ,CHLOROFORM-d) 6 = 7.17 6.99 (m, J= 8.5 Hz, 2 H), 6.89 6.72

(m, J= 8.5 Hz, 2 H), 3.76 (s, 3 H), 3.00 (br. s., 1 H), 2.70 (dd, J= 4.5, 13.6 Hz, 1 H), 2.48 2.26

(m, 1 H), 1.74 (tt, J= 6.5, 13.4 Hz, 1 H), 1.24 (t, J= 6.9 Hz, 2 H), 0.86 (d, J= 6.5 Hz, 3 H), 0.90

(d, J= 6.8 Hz, 3 H)

3C NMR (75MHz ,CHLOROFORM-d) 6 = 158.3, 131.8, 130.4, 114.0, 55.5, 50.7, 47.1,

44.2, 25.0, 23.7, 22.2

(S)-1-(3,5-dimethoxyphenyl)-4-methylpentan-2-amine (2-143)









H2N





0


163 mg (0.686 mmol, 43.2%) of (S)- 1 -(3,5-dimethoxyphenyl)-4-methylpentan-2-amine

was obtained from 75 mg (0.296 mmol) of (S)-2-isobutyl-l-tosylaziridine

'H NMR (299MHz ,CHLOROFORM-d) 6 = 6.44 6.19 (m, 3 H), 3.76 (s, 6 H), 3.10 2.97

(m, 1 H), 2.72 (dd, J= 4.2, 13.3 Hz, 1 H), 2.39 2.23 (m, 1 H), 1.74 (dt, J= 6.8, 13.9 Hz, 1 H),

1.31 1.22 (m, 2 H), 0.88 (d, J= 6.5 Hz, 3 H), 0.92 (d, J= 6.5 Hz, 3 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 161.0, 142.3, 107.5, 98.3, 55.5, 50.4, 47.3,

45.6, 25.1, 23.6, 22.3

N1, N2-bis((S)-4-methyl-l-phenylpentan-2yl)oxalamide (2-90).










In a flame-dried schlenk flask, 2.60 g (14.7 mmol) of 2-55 and 0.82 mL (6.00 mmol) of

diethyl oxalate were stirred at 120 C for 12h under Ar. After cooling to room temperature, the

solid residue was purified by column chromatography using silicagel (CH2CI2) to afford 1.13 g

(2.77 mmol, 46.2 %) of 2-90.

H NMR (300 MHz, CDC13) 6 ppm 7.31 7.12 (m, 12H), 4.18 (m, 2H), 2.79 (d, J = 4.8

Hz, 2H), 2.77 (d, J= 4.8 Hz, 2H), 1.59 (m, 2H), 1.34 (m, 4H), 0.88 (d, J= 6.6 Hz, 6H), 0.87 (d, J

= 6.6 Hz, 6H)









13C NMR (75 MHz, CDC13) 6 ppm 159.44, 137.65, 129.64, 128.64, 126.75, 49.38, 43.41,

41.65, 25.03, 23.36, 22.06

HRMS Calcd. for C26H37N202 [M+H]+: 409.2850, Found: 409.2826

[a]D24 -27.7(c 2.76, CHC13)

N1, N2-bis((R)-3-methyl-l-phenylbutan-2yl)oxalamide (2-86).



0 O 0





0.88 g (2.30 mmol, 80.0 %) of 2-86 was obtained from 0.988 g (6.05 mmol) of 2-54 and

0.394 ml (2.88 mmol) of diethyl oxalate.

H NMR (300 MHz, CDC13) 6 ppm 7.28 7.12 (m, 12H), 3.98 (m, 2H), 2.85 (dd, J= 5.8,

14.2 Hz, 2H), 2.67 (dd, J= 8.4, 14.1 Hz, 2H), 1.80 (m, 2H), 0.96 (d, J= 7.2 Hz, 6H), 0.94 (d, J=

6.9 Hz, 6H)

13C NMR (75 MHz, CDC13) 6 ppm 159.66, 138.18, 129.31, 128.64, 126.64, 56.60, 38.47,

31.02, 19.85, 17.62

HRMS Calcd. for C,,H,;,N02 [M+H]: 381.2537, Found: 381.2518

[a]D25 +16.5 (c 2.71, CHC13)

Ni,N2-bis((S)-1-cyclohexyl-2-phenylethyl)oxalamide (2-87).



















To a cooled, magnetically stirred solution of 2-62 (0.458 g, 2.25 mmol) and triethylamine

(0.350 mL, 2.53 mmol) in THF (28 mL) under argon, oxalyl chloride (0.096 mL, 1.09 mmol)

was added dropwise at 0 C. The reaction mixture was allowed to warm to room temperature and

was then stirred for 12 h. The reaction mixture was cooled to 0 C before quenching with water

(10 mL). The mixture was extracted with CHC13 (3 x 15 mL). The combined organic extracts

were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was

purified by flash column chromatography (silica gel, 3:1 chloroform/hexane) to afford 2-87

(0.349 g, 0.778 mmol, 70.7% yield).

1H NMR (300 MHz, CDC13) 6 ppm 7.27 7.09 (m, 12H), 3.95 (m, 2H), 2.88 (dd, J= 5.6,

14.0 Hz, 2H), 2.66 (dd, J= 8.3, 14.0 Hz, 2H), 1.78 1.58 (m, 10H), 1.44 (m, 2H), 1.24 1.02

(m, 10H)

13C NMR (75 MHz, CDC13) 6 ppm 159.54, 138.20, 129.34, 128.61, 126.59, 56.05, 40.98,

38.15, 30.31, 28.28, 26.45, 26.29, 26.24

HRMS Calcd. for C30H41N202 [M+H] : 461.3163, Found: 461.3164

[]D24 -24.4 (c 4.78, CHC13)

Ni,N2-bis((S)-1-cyclohexyl-3-phenylpropan-2-yl)oxalamide (2-91)

















90 mg (0.184 mmol, 91.1%) of N1,N2-bis((S)-1-cyclohexyl-3-phenylpropan-2-

yl)oxalamide was obtained from 90 mg (0.414 mmol) of (S)-1-cyclohexyl-3-phenylpropan-2-

amine, 65 [tL (0.460 mmol) of Et3N, 17.6 [IL (0.202 mmol) of oxalyl chloride and 4 mL of THF.

H NMR (300MHz ,CHLOROFORM-d) 6 = 7.33 7.10 (m, 11 H), 4.32 4.11 (m, 2 H),

2.78 (d, J= 6.4 Hz, 4 H), 1.89- 1.49 (m, 11 H), 1.43 1.05 (m, 11 H), 1.01 0.63 (m, 4 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 159.4, 137.7, 129.6, 128.6, 126.7, 48.7, 41.9,

41.6, 34.5, 34.0, 32.8, 26.7, 26.4, 26.3

N1i 2-bis((1R,2R)-2-phenylcyclohexyl)oxalamide (2-89)

Ph O OPh

O ", NH HN


260 mg (0.642 mmol, 91.0%) of N1,N2-bis((1R,2R)-2-phenylcyclohexyl)oxalamide was

obtained from 255 mg (1.45 mmol) of (1R,2R)-2-phenylcyclohexanamine, 216 [L (1.56 mmol)

of Et3N, 62 [L (0.709 mmol) of oxalyl chloride and 3 mL of THF.

H NMR (300MHz ,CHLOROFORM-d) 6 = 7.50 (d, J= 9.1 Hz, 2 H), 7.37 6.99 (m, 10

H), 4.27 (dq, J= 3.1, 9.4 Hz, 2 H), 2.93 (dt, J= 3.9, 11.9 Hz, 2 H), 2.02 1.63 (m, 12 H), 1.53 -

1.38 (m, 4 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 159.1, 142.7, 128.5, 127.5, 126.7, 50.5, 45.8,

31.1, 25.8, 25.7, 20.6








Nl,N2-bis((S)-1,2-diphenylethyl)oxalamide (2-88)


Oh

320 mg (0.713 mmol, 68.8%) of N1,N2-bis((S)-1,2-diphenylethyl)oxalamidewas obtained

from 419 mg (2.13 mmol) of (S)-1,2-diphenylethanamine, 330 iL (2.39 mmol) of Et3N, 90.0 [L

(1.037 mmol) of oxalyl chloride and 15 mL of THF.

H NMR (300MHz ,CHLOROFORM-d) 6 = 7.76 (d, J= 8.2 Hz, 2 H), 7.34 7.11 (m, 16

H), 7.08 6.95 (m, 4 H), 5.12 (q, J= 7.4 Hz, 2 H), 3.11 (d, J= 7.0 Hz, 4 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 159.0, 140.5, 136.9, 129.5, 128.8, 128.7,

127.9, 127.0, 126.8, 55.5, 42.8

Ni,N2-bis((S)-1-(4-methoxyphenyl)-4-methylpentan-2-yl)oxalamide (2-139)

0 0





NH HN


480 mg (1.02 mmol, 87.1%) of N1,N2-bis((S)-1-(4-methoxyphenyl)-4-methylpentan-2-

yl)oxalamide was obtained from 512 mg (2.47 mmol) of(S)-l-(4-methoxyphenyl)-4-

methylpentan-2-amine, 375 [L (2.76 mmol) of Et3N, 102 [L (1.18 mmol) of oxalyl chloride and

8 mL of THF.









'H NMR (300MHz ,CHLOROFORM-d) 6 = 7.19 (d, J= 9.7 Hz, 2 H), 7.07 6.99 (m, 4

H), 6.84 6.78 (m, 4 H), 4.13 (tq, J= 6.1, 9.1 Hz, 2 H), 3.76 (s, 6 H), 2.75 2.66 (m, 4 H), 1.65 -

1.51 (m, 2 H), 1.38 1.22 (m, 4 H), 0.86 (d, J= 5.0 Hz, 6 H), 0.84 (d, J= 4.7 Hz, 6 H)

13C NMR (75MHz ,CHLOROFORM-d) 6= 159.5, 158.5, 130.6, 129.6, 114.0, 55.4, 49.4,

43.3, 40.7, 25.0, 23.4, 22.1

Nl,N2-bis((S)-1-(3,5-dimethoxyphenyl)-4-methylpentan-2-yl)oxalamide (2-144)

I II I
O~ O



NH HN



96.8 mg (0.183 mmol, 56.0%) of N1,N2-bis((S)-l-(3,5-dimethoxyphenyl)-4-methylpentan-

2-yl)oxalamide was obtained from 163 mg (0.686 mmol) of(S)-1-(3,5-dimethoxyphenyl)-4-

methylpentan-2-amine, 105 [L (0.751 mmol) of Et3N, 28.8 [L (0.327 mmol) of oxalyl chloride

and 4 mL of THF.

'H NMR (300MHz ,CHLOROFORM-d) 6 = 7.23 (d, J= 9.7 Hz, 2 H), 6.34 6.26 (m, 6

H), 4.26 4.08 (m, 2 H), 3.74 (s, 12 H), 2.79 2.62 (m, 2 H), 1.67 1.50 (m, 2 H), 1.32 (ddd, J=

2.6, 5.5, 8.6 Hz, 4 H), 0.87 (d, J= 5.0 Hz, 6 H), 0.84 (d, J= 4.7 Hz, 6 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 161.0, 159.5, 139.9, 107.5, 99.0, 55.5, 49.2,

43.2, 41.9, 25.0, 23.4, 22.0

(3S, 3'S)-3,3'-diisobutyl-3,3',4,4'-tetrahydro-1,1'-biisoquinoline (2-96).


















To a flame dried schlenk flask was added 1.20 g (2.94 mmol) of 2-90 and 30 mL of

toluene. To this flask under nitrogen atmosphere was added 3.20 g (8.80 mmol) of Zn(OTf)2 and

3.70 g (18.0 mmol) of PC15. The reaction mixture was heated at 85 C for 12 h. After cooling to

room temperature, the reaction was quenched with 20mL of 30% aqueous ammonium hydroxide

solution. The solution was diluted with 100 mL of diethyl ether. The organic layer was separated

and dried over anhydrous MgSO4. After all volatiles were evaporated under reduced pressure,

0.930 g (2.50 mmol, 85.0 %) of 2-96 was purified by silicagel column chromatography with a

7:1 mixture of hexane and ethyl acetate as the eluent.

H NMR (300 MHz, CDC13) 6 ppm 7.35 7.14 (m, 8H), 3.84 (m, 2H), 2.93 (dd, J= 5.4,

15.9 Hz, 2H), 2.65 (dd, J= 11.2, 15.9 Hz, 2H), 1.98 1.79 (m, 4H), 1.53 (m, 2H), 0.97 (d, J=

6.0 Hz, 6H), 0.95 (d, J= 6.6 Hz, 6H)

13C NMR (75 MHz, CDC13)6 ppm 164.06, 137.51, 131.13, 128.67, 128.03, 127.08,

126.98, 55.28, 44.99, 31.59, 25.08, 23.39, 22,60

HRMS Calcd. for C26H32N2 [M+]: 372.2560, Found: 372.2581

[aD23 -72.7 (c 1.73, CHC13)

(3R, 3'R)-3,3'-diisopropyl-3,3',4,4'-tetrahydro-1,1'-biisoquinoline (2-97).


















2.10 g (6.10 mmol, 82.7 %) of 2-97 was obtained from 2.81 g (7.38 mmol) of 2-86, 8.1 g

(22.3 mmol) of Zn(OTf)2 and 9.2 g (44.2 mmol) of PCls.

1H NMR (300 MHz, CDC13) 6 ppm 7.33 7.13 (m, 8H), 3.48 (m, 2H), 2.78 2.74 (m,

4H), 2.23 (m, 2H), 1.13 (d, J= 6.9 Hz, 6H), 1.08 (d, J= 6.6 Hz, 6H)

13C NMR (75 MHz, CDC13) 6 ppm 164.15, 138.26, 131.00, 128.68, 127.98, 126.98,

126.87, 62.81, 33.07, 27.62, 19.94, 19.02

HRMS Calcd. for C,4H,,N, [M+]: 344.2247, Found: 344.2213

[aD25 +32.4 (c 2.43, CHC13)

(3S,3'S)-3,3'-dicyclohexyl-3,3',4,4'-tetrahydro-1,1'-biisoquinoline (2-98).




/ \
N N





0.357 g (0.841 mmol, 60.9%) of 2-98 was obtained from 0.619 g (1.38 mmol) of 2-87.

H NMR (300 MHz, CDC13) 6 ppm 7.26 7.05 (m, 8H), 3.40 (m, 2H), 2.69 (m, 4H), 1.93

- 1.54 (m, 12H), 1.29 1.09 (m, 10H)

13C NMR (75 MHz, CDC13), 6 ppm 163.86, 138.16, 130.85, 128.47, 127.79, 62.03, 42.92,

30.35, 29.18, 27.88, 26.81, 26.70, 26.57









HRMS Calcd. for C30H37N2 [M+H] : 425.2951, Found: 425.2957

[]D24 +6.2 (c 2.64, CHC13)

(3S,3'S)-3,3'-bis(cyclohexylmethyl)-3,3',4,4'-tetrahydro-1,1'-biisoquinoline (2-101)





N N




380 mg (0.839 mmol, 91.0%) of (3S,3'S)-3,3'-bis(cyclohexylmethyl)-3,3',4,4'-tetrahydro-

1,1'-biisoquinoline was obtained from 450 mg (0.921 mmol) of N1,N2-bis((S)-l-cyclohexyl-3-

phenylpropan-2-yl)oxalamide, 1.15 g (5.52 mmol) of PC15, 1.00 g (2.76 mmol) of Zn(OTf)2 and

45 mL of toluene.

1H NMR (300MHz ,CHLOROFORM-d) 6 = 7.44 7.04 (m, 8 H), 3.98 3.75 (m, 2 H),

2.93 (dd, J= 5.6, 15.8 Hz, 2 H), 2.64 (dd, J= 11.1, 15.8 Hz, 2 H), 1.98 1.48 (m, 16 H), 1.38 -

1.06 (m, 6 H), 1.06 0.75 (m, 4 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 164.0, 137.5, 131.1, 128.6, 128.0, 127.1,

126.9, 54.5, 43.5, 34.6, 34.1, 33.3, 31.6, 26.9, 26.6

(3S,3'S)-3,3'-diisobutyl-7,7'-dimethoxy-3,3',4,4'-tetrahydro-1,1'-biisoquinoline (2-140)









To a flame dried schlenk flask was added 105 mg (0.224 mmol) of N1,N2-bis((S)-1-(4-

methoxyphenyl)-4-methylpentan-2-yl)oxalamide and 4 mL of toluene. To this flask under argon

atmosphere was added 82 mg (0.672 mmol) of DMAP and 186 iL (1.34 mmol) of Tf2O. The

reaction mixture was heated at 95 C for 12 h. After cooling to room temperature, the reaction

was quenched with 10mL of a saturated solution of sodium carbonate. The solution was diluted

with 20 mL of DCM. The organic layer was separated and dried over anhydrous MgSO4. After

all volatiles were evaporated under reduced pressure, 38.0 mg (0.0878 mmol, 39.2 %) of

(3S,3'S)-3,3'-diisobutyl-7,7'-dimethoxy-3,3',4,4'-tetrahydro-1,1'-biisoquinoline was purified by

silicagel column chromatography with a 99:1 mixture of DCM and methanol as the eluent.

1H NMR (300MHz ,CHLOROFORM-d) 6 = 7.12 7.06 (m, 2 H), 6.94 6.81 (m, 4 H),

3.85 3.75 (m, 2 H), 3.67 (s, 6 H), 2.84 (dd, J= 5.4, 15.7 Hz, 2 H), 2.55 (dd, J= 11.1, 15.5 Hz, 2

H), 2.00 1.85 (m, 2 H), 1.79 (dt, J= 7.1, 13.7 Hz, 2 H), 1.48 (ddd, J= 6.6, 7.5, 13.5 Hz, 2 H),

0.92 (d, J= 3.5 Hz, 6 H), 0.94 (d, J= 3.5 Hz, 6 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 163.7, 158.4, 129.6, 129.2, 128.8, 116.8,

112.6, 55.6, 55.5, 44.9, 30.7, 25.0, 23.3, 22.6

(3S,3'S)-3,3'-diisobutyl-6,6',8,8'-tetramethoxy-3,3',4,4'-tetrahydro-1,1'-biisoquinoline

(2-145)






N/
)-^ O0




O









144 mg (0.292 mmol, 86.9%) of (3S,3'S)-3,3'-diisobutyl-5,6',8,8'-tetramethoxy-3,3',4,4'-

tetrahydro-1,1'-biisoquinoline was obtained from 177 mg (0.336 mmol) of N1,N2-bis((S)-1-(3,5-

dimethoxyphenyl)-4-methylpentan-2-yl)oxalamide, 246 mg (2.02 mmol) of DMAP, 470 [L

(3.36 mmol) of Tf2O and 17 mL of toluene.

H NMR (300MHz ,CHLOROFORM-d) 6 = 6.29 (s, 2 H), 6.15 6.04 (m, 2 H), 3.85 3.67

(m, 8 H), 3.35 3.27 (m, 6 H), 2.74 (dd, J= 4.5, 15.4 Hz, 2 H), 2.41 (dd, J= 11.7, 15.2 Hz, 2 H),

1.89- 1.74 (m, 4 H), 1.51 1.37 (m, 2 H), 0.90 (t, J= 6.2 Hz, 12 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 164.4, 161.8, 157.9, 142.4, 113.4, 104.7, 97.0,

55.5, 55.1, 54.2, 44.5, 32.9, 25.0, 23.6, 22.5

[6(S),8(S)-Diisobutyl-5,6,8,9-tetrahydro-6a,7a-diazadibenzo[c,g]fluorenium] chloride

(2-104)





N N

CI

A flame dried Schlenk flask was charged with 0.250 g (0.670 mmol) of 2-96, 0.140 mL

(1.49 mmol) of chloromethyl ethyl ether and 3 mL of THF. After 12 h, all volatiles were

evaporated in vacuo. The sticky residue was purified by silicagel column chromatography with a

10:1 mixture of CH2C2 and methanol as the eluent to afford 0.260 g (0.619 mmol, 92.4 %) of 2-

104.

H NMR (300 MHz, CDC13) 6 ppm 11.22 (s, 1H), 7.94 (d, J= 8.1 Hz, 2H), 7.43 7.31

(m, 6H), 5.21 (m, 2H), 3.42 (m, 2H), 3.01 (d, J= 15.9 Hz, 2H), 1.59 (m, 4H), 1.28 (m, 2H), 0.96

(d, J= 6.3 Hz, 6H), 0.94 (d, J= 6.3 Hz, 6H)









13C NMR (75 MHz, CDC13) 6 ppm 135.33, 132.20, 130.76, 130.18, 127.95, 124.55,

124.06, 53.60, 41.36, 33.15, 25.08, 23.22, 22.12

HRMS Calcd. for C27H33N2 [M-Cl]+: 385.2638, Found: 385.2637

[a]D24 -290.5 (c 1.38, CHC13)

[6(R),8(R)-Diisopropyl-5,6,8,9-tetrahydro-6a,7a-diazadibenzo[c,g]fluorenium]

chloride (2-105)





N N




0.091 g (0.230 mmol, 60.5 %) of 2-105 was obtained from 0.130 g (0.380 mmol) of 2-97.

1H NMR (300 MHz, CDC13): 6 ppm 11.23 (s, 1H), 7.94 (d, J= 7.8 Hz, 2H), 7.43 7.26

(m, 6H), 4.86 (m, 2H), 3.41 (dd, J= 4.8, 15.9 Hz, 2H), 3.20 (d, J= 15.9 Hz, 2H), 1.68 (m, 2H),

1.04 (d, J= 6.9 Hz, 6H), 0.94 (d, J= 6.6 Hz, 6H)

13C NMR (75 MHz, CDC13): 6 ppm 136.52, 132.61, 130.78, 129.82, 127.90, 124.44,

124.06, 123.90, 60.86, 31.91, 29.62, 19.83, 19.15

HRMS Calcd. for C25H29N2 [M-Cl]+: 357.2325, Found: 357.2309

[a]D25 -228.9 (c 0.88, CHC13)

[6(R),8(R)-Dicyclohexyl-5,6,8,9-tetrahydro-6a,7a-diazadibenzo[c,g]fluorenium]

chloride (2-106)














0 CIo


0.0750 g (0.159 mmol, 81.9 %) of 2-106 was obtained from 0.0822 g (0.194 mmol) of 2-

98.

H NMR (300 MHz, CDC13)6 ppm 11.31 (s, 1H), 7.92 (d, J= 7.2 Hz, 2H), 7.39 7.32

(m, 6H), 7.17 (m, 2H), 3.34 (dd, J= 5.5, 16.1 Hz, 2H), 3.20 (d, J= 15.9 Hz, 2H), 1.73 0.82 (m,

20H)

13C NMR (75 MHz, CDC13) 6 ppm 137.15, 132.78, 130.72, 129.89, 127.87, 124.50,

124.09, 123.98, 60.07, 38.31, 31.58, 29.52, 29.42, 25.87, 25.68, 25.55

HRMS Calcd. for C31H37N2 [M-Cl]+: 437.2957, Found: 437.2971

[a]D25 +212.1 (c 2.44, CHC13)

[6(R),8(R)- bis(cyclohexylmethyl)-5,6,8,9-tetrahydro-6a,7a-

diazadibenzo[c,g]fluorenium] chloride (2-108)










300 mg (0.598 mmol, 90.3%) of [6(R),8(R)- bis(cyclohexylmethyl)-5,6,8,9-tetrahydro-

6a,7a-diazadibenzo[c,g]fluorenium] chloride was obtained from 300 mg (0.662 mmol) of









(3S,3'S)-3,3'-bis(cyclohexylmethyl)-3,3',4,4'-tetrahydro-1,1'-biisoquinoline, 400 [L (4.04 mmol)

of chloromethyl ethylether and 33 mL of THF.

H NMR (500MHz ,CHLOROFORM-d) 6 = 11.18 (br. s., 1 H), 7.96 (d, J= 7.7 Hz, 2 H),

7.49 7.32 (m, 6 H), 5.27 (br. s., 2 H), 3.43 (d, J= 14.8 Hz, 2 H), 3.05 (d, J= 15.5 Hz, 2 H), 1.99

(br. s., 2 H), 1.79 1.56 (m, 12 H), 1.37 1.06 (m, 12 H)

13C NMR (126MHz ,CHLOROFORM-d) 6 = 135.4, 132.2, 130.7, 130.2, 127.9, 124.5,

124.1, 123.9, 53.1, 40.1, 34.4, 33.8, 33.0, 32.5, 26.4, 26.3, 26.2

[6(R),8(R)- diisobutyl-7,7'-dimethoxy -5,6,8,9-tetrahydro-6a,7a-

diazadibenzo[cg]fluorenium] chloride (2-141)

\ /
O O





N. N

SCl O

16.9 mg (0.0351 mmol, 80.0%) of 6(R),8(R)- diisobutyl-7,7'-dimethoxy -5,6,8,9-

tetrahydro-6a,7a-diazadibenzo[c,g]fluorenium] chloride was obtained from 19.0 mg (0.439

mmol) of (3S,3'S)-3,3'-diisobutyl-7,7'-dimethoxy-3,3',4,4'-tetrahydro-1,1'-biisoquinoline, 25.0

[L (0.267 mmol) of chloromethyl ethylether and 2 mL of THF.

[6(S),8(S)-Diisobutyl-5,6,8,9-tetrahydro-6a,7a-diazadibenzo[c,g]fluoren-5-ylidene]-

(r3 -cinnamyl)chloropalladium(0) (2-103)





















To a flame-dried Schlenk flask was added 0.250 g (0.450 mmol) of 2-104, 0.063 g (0.270

mmol) of Ag20 and 15 mL of CH2C12. The reaction mixture was stirred for 12 h at room

temperature and filtered through a pad of celite. The solvent of the filtrate was removed under

reduced pressure. To another flame-dried Schlenk flask was added the filtered silver complex,

0.110 g (0.220 mmol) of [Pd(cinnamyl)Cl]2 and 20 mL of CH2C2. The reaction mixture was

stirred for 3 h at room temperature and filtered through a pad of celite. The solvent was removed

under reduced pressure, and the residue was purified by silicagel column chromatography with

CH2C2 as the eluent to yield 0.150 g (0.240 mmol, 53.3 %) of 2-103. Four possible isomers can

exist according to the orientation of cinnamyl group. Crystals of an isomer were obtained by

slow diffusion of CH2C2 solution of 2-103 into hexanes, but the NMR spectra of the crystals

showed that there were at least two isomers in solution.

H NMR of the major isomer (300 MHz, CDC13) 6 ppm 7.86 7.76 (m, 2H) 7.47 (d, J=

7.5 Hz, 2H), 7.33 7.06 (m, 9H), 6.12 6.01 (m, 1H), 5.75 5.64 (m, 1H), 4.85 (d, J=12.6Hz,

1H), 4.55 (d, J= 11.4 Hz, 1H), 4.29 (d, J= 8.1 Hz, 1H), 3.51 3.34 (m, 2H), 3.02 2.93 (m,

2H), 2.32 (d, J= 14.7 Hz, 1H), 1.93 0.79 (m, 18H)

13C NMR of mixture of isomers (75 MHz, CDC13) 6 ppm 176.15, 175.15, 140.4, 140.28,

138.05, 133.21, 132.44, 132.19, 129.85, 129.73, 129.48, 129.35, 129.0, 128.87, 128.63, 128.52,

128.38, 127.48, 127.38, 127.05, 126.94, 126.86, 126.77, 126.59, 126.47, 126.43, 126.37, 124.97,









124.69, 123.95,0 123.84, 123.6, 111.53, 110.38, 109.3, 91.73, 69.93, 69.63, 69.14, 68.95, 52.99,

52.67, 44.13, 42.92, 41.83, 41.62, 33.92, 33.83, 33.36, 32.47, 25.41, 25.3, 25.2, 25.16, 24.17,

23.99, 23.84, 23.65, 22.97, 22.54, 22.32, 21.72

Anal. Calcd. for C36H41ClN2Pd: C, 67.18; H, 6.42; N, 4.35, Found: C, 66.83; H, 6.49; N,

4.27

[a]D23 -90 (c 1.12, CHC13)

X-ray experimental for 2-103

Data were collected at 173 K on a Siemens SMART PLATFORM equipped with A CCD

area detector and a graphite monochromator utilizing MoKa radiation (X = 0.71073 A). Cell

parameters were refined using up to 8192 reflections. A full sphere of data (1850 frames) was

collected using the co-scan method (0.30 frame width). The first 50 frames were re-measured at

the end of data collection to monitor instrument and crystal stability (maximum correction on I

was < 1 %). Absorption corrections by integration were applied based on measured indexed

crystal faces.

The structure was solved by the Direct Methods in SHELXTL6, and refined using full-

matrix least squares. The non-H atoms were treated anisotropically, whereas the hydrogen atoms

were calculated in ideal positions and were riding on their respective carbon atoms. The C27

methyl group was disordered and refined in two parts with their site occupation factors

dependently refined. Its isopropyl counter methyl group was not significantly disordered and

could not be resolved. The major disorder is in the C28-C36 ligand. It is completely disordered

and was refined with anisotropic displacement parameters and with the phenyl ring treated as an

idealized hexagon rigid body. A total of 338 parameters were refined in the final cycle of









refinement using 5574 reflections with I > 2o(I) to yield R1 and wR2 of 3.77% and 8.40%,

respectively. Refinement was done using F2

SHELXTL6 (2000). Bruker-AXS, Madison, Wisconsin, USA.

Crystal data and structure refinement for 2-103

Identification code 2-103

Empirical formula C36 H41 Cl N2 Pd

Formula weight 643.56

Temperature 173(2) K

Wavelength 0.71073 A

Crystal system Orthorhombic

Space group P2(1)2(1)2(1)

Unit cell dimensions

a = 5.6873(4) A a= 90.

b = 23.3061(18) A 3= 90.

c = 23.7168(18) A y= 900.

Volume 3143.6(4) A3

Z 4

Density (calculated) 1.360 Mg/m3

Absorption coefficient 0.702 mm-1

F(000) 1336

Crystal size 0.19 x 0.19 x 0.15 mm3

Theta range for data collection 1.72 to 27.500.

Index ranges -7








Reflections collected 20343

Independent reflections 7185 [R(int) = 0.0463]

Completeness to theta = 27.50099.7 %

Absorption correction Integration

Max. and min. transmission 0.9057 and 0.8827

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 7185/ 1 / 338

Goodness-of-fit on F2 0.972

Final R indices [I>2sigma(I)] R1 = 0.0377, wR2 = 0.0840 [5574]

R indices (all data) R1 = 0.0532, wR2 = 0.0877

Absolute structure parameter -0.02(3)

Largest diff. peak and hole 0.526 and -0.314 e.A-3

R1 = 2(||Fol |Fcl|) / I|Fol

wR2 = [I[w(Fo2 Fc2)2] / I[w(Fo2)2]]1/2

S =[[w(Fo2 Fc2)2] / (n-p)]1/2

w= 1/[C2(Fo2)+(m*p)2+n*p], p = [max(Fo2,0)+ 2* Fc2]/3, m & n are constants.

[6(S),8(S)-Diisobutyl-5,6,8,9-tetrahydro-6a,7a-diazadibenzo[c,g]fluoren-5-ylidene]-

chlorocopper(I) (2-109).










A flame dried Schlenk flask was charged with 0.200 g (0.360 mmol) of 2-104, 0.046 g

(0.200 mmol) of Ag20 and 5 mL of CH2C12. After stirring for 12 h, the reaction mixture was

filtered through a pad of celite. The solvent of the filtrate was removed under reduced pressure.

To another flame-dried Schlenk flask was added the filtered silver complex and 0.0340 g (0.340

mmol) of Cul. The reaction mixture was stirred for 2 h at room temperature. The reaction

solution was filtered through a pad of celite and evaporated to dryness. The residue was purified

quickly by silicagel column chromatography with CH2C2 as the eluent to yield 0.210 g (0.340

mmol, 94.4 %) of 2-109.

'H NMR (300 MHz, CDC13) 6 ppm 7.9 (dd, J= 1.8, 6.6 Hz, 2H), 7.32 7.24 (m, 6H),

4.78 (m, 2H), 3.36 (dd, J= 5.0, 15.5 Hz, 2H), 2.95 (d, J= 15.3 Hz, 2H), 1.74 (m, 2H), 1.38 (m,

2H), 1.27 (m, 2H), 0.97 (d, J= 6.6 Hz, 6H), 0.94 (d, J= 6.6 Hz, 6H)

13C NMR (75 MHz, CDC13) 6 132.49, 129.79, 127.4, 125.96, 124.10, 54.79, 42.82, 34.20,

25.00, 23.56, 22.40

Anal. Calcd. for C27H32ClCuN2: C, 67.06; H, 6.67; N, 5.79, Found: C, 67.13; H, 6.43; N,

5.71

[a]D23 -283.4 (c 0.48, CHC13)

[6(R),8(R)-Diisopropyl-5,6,8,9-tetrahydro-6a,7a-diazadibenzo[c,g]fluoren-5-

ylidene]chlorocopper(I) (2-110)


Cu /
CI









0.096 g (0.16 mmol, 55.2 %) of 2-110 was obtained from 0.150 g (0.290 mmol) of 2-105.

H NMR (300 MHz, CDC13) 6 ppm 7.88 (d, J= 7.4 Hz, 2H), 7.31 7.23 (m, 6H), 4.40 (m,

2H), 3.28 (dd, J= 4.2, 15.3 Hz, 2H), 3.15 (d, J= 15.6 Hz, 2H), 1.61 (m, 2H), 1.02 (d, J= 6.6 Hz,

6H), 0.88 (D, J= 6.9 Hz, 6H)

13C NMR (75 MHz, CDC13) 6 ppm 174.23, 133.24, 129.43, 129.18, 127.38, 126.22,

124.09, 124.01, 62.60, 33.07, 30.29, 21.45, 19.67

Anal Calcd. for C25H28ClCuN2: C, 65.92; H, 6.20; N, 6.15, Found: C, 66.38; H, 6.22; N,

5.98

[a]D23 -251.5 (c 2.20, CHC13)

[6(R),8(R)-Dicyclohexyl-5,6,8,9-tetrahydro-6a,7a-diazadibenzo[c,g]fluoren-5-

ylidene]chlorocopper(I) (2-111)





N cN

0Cu


0.240 g (0.450 mmol, 71.4 %) of 2-111 was obtained from 0.300 g (0.630 mmol) of 2-106.

1H NMR (300 MHz, CDC13) 6 ppm 7.88 (dd, J= 2.3, 6.2 Hz, 2H), 7.29 7.23 (m, 6H),

4.43 (m, 2H), 3.26 (dd, J= 5.0, 15.8 Hz, 2H), 3.16 (dd, J= 1.8, 15.6 Hz, 2H), 1.73 0.89 (m,

22H)

13C NMR (75 MHz, CDC13)6 ppm 133.36, 129.42, 129.09, 127.29, 126.32, 124.11,

124.00, 61.68, 38.15, 32.73, 31.43, 29.95, 26.09, 26.00, 25.89









Anal. Calcd. for C31H36ClCuN2: C, 69.51; H, 6.77; N, 5.23, Found: C, 69.42; H, 6.75; N,

4.83

[a]D23 +173.6 (c 0.78, CHC13).

[6(R),8(R)- bis(cyclohexylmethyl)-5,6,8,9-tetrahydro-6a,7a-diazadibenzo [c,g]fluoren-

5-ylidene]chlorocopper(I) (2-113)





N N

C u


36.5 mg (0.0648 mmol, 65.0%) of [6(R),8(R)- bis(cyclohexylmethyl)-5,6,8,9-tetrahydro-

6a,7a-diazadibenzo[c,g]fluoren-5-ylidene]chlorocopper(I) was obtained from 50 mg (0.0997

mmol) of [6(R),8(R)- bis(cyclohexylmethyl)-5,6,8,9-tetrahydro-6a,7a-

diazadibenzo[c,g]fluorenium] chloride, 13.9 mg (0.0598 mmol) of silver oxide, 10.9 mg (0.109

mmol) of copper chloride and 10 mL of DCM.

1H NMR (300MHz ,CHLOROFORM-d) 6 = 7.90 (d, J= 7.0 Hz, 2 H), 7.54 7.03 (m, 6

H), 4.84 (q, J= 6.2 Hz, 2 H), 3.35 (dd, J= 5.3, 15.2 Hz, 2 H), 3.10 2.79 (m, 2 H), 1.85 (d, J=

12.3 Hz, 2 H), 1.76 1.55 (m, 8 H), 1.46 1.09 (m, 12 H), 1.07 0.81 (m, 4 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 171.9, 132.5, 129.8, 129.1, 127.3, 126.0,

124.1, 54.0, 41.4, 34.3, 34.0, 33.1, 26.5, 26.2

6.2.4 Synthesis of the Substrates for The Copper-Catalyzed Allylic Alkylation

(E)-3-(2-methoxyphenyl)allyl pivalate (2-128)















Synthesis of (E)-ethyl 3-(2-methoxyphenyl)acrylate:

A flame-dried Schlenk flask was charged with 0.440 g (11.0 mmol) of NaH (60% in

mineral oil) and 20 mL of toluene. To this solution was added 2.0 mL (10.0 mmol) of triethyl

phosphonoacetate at 0 C. The temperature was slowly increased to room temperature for 30

min. To the reaction solution was added 1.2 mL (10.0 mmol) of o-anisole, and the solution was

heated to 60 C for 4 h. After cooling to room temperature, 20 mL of a saturated NH4Cl solution

was added to quench the reaction. The organic layer was extracted with 30 mL of Et20, and all

the volatiles were evaporated under reduced pressure to give crude (E)-ethyl 3-(2-

methoxyphenyl)acrylate.

Synthesis of (E)-3-(2-methoxyphenyl)prop-2-en-l-ol:

To a flame-dried Schlenk flask was added the crude (E)-ethyl 3-(2-methoxyphenyl)acrylate

and 20 mL of Et20. 20 mL of DIBALH (1.0 M solution in toluene) was slowly added to the

reaction solution at 0 C. The temperature was slowly increased to room temperature. After 3 h,

30 mL of 1M HC1 aqueous solution was added and the organic layer was separated. All volatiles

were removed under reduced pressure to give crude (E)-3-(2-methoxyphenyl)prop-2-en-l-ol.

Synthesis of (E)-3-(2-methoxyphenyl)allyl pivalate:

A flame-dried Schlenk flask was charged with 1.25 g (8.00 mmol) of the crude (E)-3-(2-

methoxyphenyl)allyl pivalate, 0.100 g (0.800 mmol) of 4-dimethylamino pyridine, 1.4 mL (10.0

mmol) of triethyl amine and 20 mL of CH2C2. To the reaction flask was added 1.0 mL (8.00

mmol) of pivaloyl chloride at 0 C. The reaction mixture was slowly warmed to room

temperature and stirred for 2 h. The reaction mixture was poured to a 20 mL of saturated









NaHCO3 aqeous solution, and the organic layer was separated. After evaporation of the solvent,

the residue was purified by silicagel column chromatography with a 5:1 mixture of hexane and

Et20 as the eluent to give 1.80 g (7.2 mmol, 65.5 %) of the pure product.

H NMR (300 MHz, CDC13) 6 ppm 7.49 (dd, J= 7.5, 1.6 Hz, 1 H), 7.24 7.32 (m, 1 H),

6.86 7.10 (m, 3 H), 6.35 (dt, J= 16.1, 6.3 Hz, 1 H), 4.79 (dd, J= 6.2, 1.4 Hz, 2 H), 3.88 (s, 3

H), 1.29 (s, 9 H)

13C NMR (75 MHz, CDC13) 6 ppm 178.21, 156.70, 128.95, 128.59, 128.33, 126.91,

125.23, 124.00, 120.53, 110.75, 65.35, 55.31, 38.70, 27.15

HRMS Calcd. for C15H20NaO3 [M+Na] : 271.1304, Found: 271.1332

(E)-3-(naphthalen-2-yl)allyl benzoate (2-121)

0





H NMR (300 MHz, CDC13) 6 ppm 8.13 8.19 (m, 2 H), 7.82 (dd, J= 7.92, 4.69 Hz, 4 H),

7.56 7.68 (m, 2 H), 7.44 7.54 (m, 4 H), 6.93 (d, J= 15.8 Hz, 1 H), 6.56 (dt, J= 15.8, 6.30 Hz,

1 H), 5.08 (dd, J= 6.5, 1.5 Hz, 2 H)

13C NMR (75 MHz, CDC13) 6 ppm 166.35, 134.23, 133.64, 133.47, 133.16, 132.96,

130.17, 129.64, 128.34, 128.25, 128.01, 127.63, 126.84, 126.29, 126.06, 123.57, 123.47, 65.54

HRMS Calcd. for C20H1602 [M]+: 288.1150, Found : 288.1141

(E)-3-(naphthalen-2-yl)allyl pivalate (2-122)

0









'H NMR (300 MHz, CDC13) 6 ppm 7.74 7.89 (m, 4 H), 7.62 (dd, J= 8.5, 1.7 Hz, 1 H),

7.42 7.54 (m, 2 H), 6.83 (d, J= 15.9 Hz, 1 H), 6.44 (dt, J= 15.9, 6.2 Hz, 1 H), 4.81 (dd, J= 6.2,

1.13 Hz, 2 H), 1.30 (s, 9 H)

13C NMR (75 MHz, CDC13) 6 ppm 178.31, 133.74, 133.59, 133.45, 133.10, 128.21,

127.98, 127.62, 126.69, 126.28, 126.00, 123.89, 123.47, 64.95, 38.80, 27.21

HRMS Calcd. for Ci8H20NaO2 [M+Na] : 291.1355, Found: 291.1318

(E)-3-(naphthalen-2-yl)but-2-enyl pivalate (2-129)

0





HH NMR (300 MHz, CDC13) 6 ppm 7.77 7.95 (m, 4 H), 7.61 (dd, J = 8.6, 1.86 Hz, 1 H),

7.41 7.55 (m, 2 H), 6.08 (td, J = 6.7, 1.2 Hz, 1 H), 4.86 (d, J= 6.9 Hz, 2 H), 2.25 (d, J= 0.6

Hz, 3 H), 1.26 (s, 9 H)

13C NMR (75 MHz, CDC13) 6 ppm 178.48, 139.65, 139.46, 133.26, 132.71, 128.09,

127.72, 127.43, 126.11, 125.80, 124.52, 124.07, 122.23, 61.68, 38.76, 27.18, 16.16

HRMS Calcd. for C19H22NaO2 [M+Na] : 305.1512, Found: 305.1473

(E)-3-(4-methoxyphenyl)allyl pivalate (2-126)

0

0 <

MeOO

H NMR (300 MHz, CDC13) 6 ppm 7.33 (m, 2 H), 6.86 (m, 2 H), 6.59 (d, J = 16.1 Hz, 1

H), 6.15 (dt, J= 15.8, 6.5 Hz, 1 H), 4.70 (dd, J= 6.5, 1.2 Hz, 2 H), 3.80 (s, 3 H), 1.24 (s, 9 H)









13C NMR (75 MHz, CDC13)6 ppm 178.27, 159.43, 133.31, 128.99, 127.72, 121.15,

113.90, 65.11, 55.12, 38.69, 27.12

HRMS Calcd. for C15H2003 [M]+: 248.1407, Found: 248.1410

(E)-3-(4-chlorophenyl)allyl pivalate (2-127)

0

0

CI

H NMR (300 MHz, CDC13) 6 ppm 7.28 7.35 (m, 4 H), 6.60 (d, J= 15.8 Hz, 1 H), 6.20 -

6.34 (m, J= 16.1, 6.2, 6.2 Hz, 1 H), 4.73 (dd, J= 6.2, 1.5 Hz, 2 H), 1.26 (s, 9 H)

13C NMR (75 MHz, CDC13) 6 ppm 178.07, 134.75, 133.49, 132.07, 128.63, 127.67,

124.23, 64.56, 38.70, 27.12

HRMS Calcd. for C14HI7C102 [M]+: 252.0917, Found: 252.0914

(E)-2-(3-(naphthalen-2-yl)allyloxy)pyridine (2-120)



ri0 N



(E)-2-(3-(naphthalen-2-yl)allyloxy)pyridine was prepared from (E)-3-(naphthalen-2-

yl)prop-2-en-l-ol by using a literature method5.

H NMR (300 MHz, CDC13) 6 ppm 8.21 (dd, J= 5.0, 2.1 Hz, 1 H), 7.74 7.91 (m, 4 H),

7.56 7.70 (m, 2 H), 7.40 7.53 (m, 2 H), 6.87 6.97 (m, 2 H), 6.83 (d, J= 8.2 Hz, 1 H), 6.62

(ddd, J= 16.0, 6.0, 5.9 Hz, 1 H), 5.08 (dd, J= 6.0, 1.0 Hz, 2 H)

13C NMR (75 MHz, CDC13) 6 ppm 146.85, 138.65, 134.09, 133.52, 133.13, 128.17,

127.99, 127.64, 126.63, 126.23, 125.91, 125.11, 123.59, 116.85, 111.25, 66.33









HRMS Calcd. for C18H16NO [M+H] : 262.1226, Found: 262.1232

1-(naphthalen-6-yl)allyl pivalate (2-136)

0







H NMR (300 MHz, CDC13) 6 ppm 7.81 7.90 (m, 4 H), 7.44 7.55 (m, 3 H), 6.42 (d, J=

5.6 Hz, 1 H), 6.10 (ddd, J= 17.2, 10.5, 5.7 Hz, 1 H), 5.25 5.43 (m, 2 H), 1.27 (s, 9 H)

13C NMR (75 MHz, CDC3) 6 ppm 177.27, 136.56, 136.46, 133.16, 133.03, 128.33,

128.05, 127.64, 126.19, 126.14, 126.02, 124.71, 116.65, 75.83, 40.17, 27.13

HRMS Calcd. for C18H2002 [M] : 268.1458, Found: 268.1465

6.2.5 Products from The Copper-Catalyzed Allylic Alkylation

Typical procedure for asymmetric Cu-heterocyclic carbene catalyzed allylic

substitution:

A flame-dried Schlenk flask was charged with a substrate (0.5 mmol), a copper catalyst (3

mol %) and 3 ml of a solvent. To this solution was added a Grignard reagent (0.75 mmol in

Et20) at a specified temperature. After 1 hr, the reaction was quenched by a saturated aqueous

NH4C1 solution and diluted by 20 mL of Et20. The organic layer was separated and the solvent

was evaporated under reduced pressure. Silicagel column chromatography with hexane as the

eluent gave a pure product. The regioselectivity was calculated by the integration ratio of the

protons shown on the two regioisomers by NMR spectra.



R R1 R3
H H









A racemic product was synthesized using IMes-Cu-Cl complex as the catalyst.

2-(pent-l-en-3-yl)naphthalene (2-115)





a 1

Ee was measured by chiral HPLC with a Whelk-01 column (UV 254 nm, 100% pentane,

0.2 mL/min). ts: 25.5, tR : 26.9

2-(non-l-en-3-yl)naphthalene (2-123-product)







H NMR (300 MHz, CDC13) 6 ppm 7.72 7.89 (m, 3 H), 7.63 (s, 1 H), 7.39 7.51 (m, 2

H), 7.35 (dd, J= 8.5, 1.7 Hz, 1 H), 5.97 6.11 (m, 1 H), 4.98 5.16 (m, 2 H), 3.42 (q, J= 7.6 Hz,

1 H), 1.81 (q, J= 7.5 Hz, 2 H), 1.24 1.35 (m, 8 H), 0.84 0.90 (m, 3 H)

13C NMR (75 MHz, CDC13) 6 ppm 142.42, 142.07, 133.62, 132.21, 127.96, 127.57,

126.28, 125.82, 125.19, 114.07, 49.96, 35.30, 31.77, 29.30, 27.55, 22.65, 14.09

HRMS Calcd. for C19H25 [M+H] : 253.1951, Found: 253.1966

Ee was measured by chiral HPLC with a Whelk-01 column (UV 254 nm, 100% pentane,

0.2 ml/min). t,: 26.0, t2: 28.2

2-(1-cyclopentylallyl)naphthalene (2-124-product)

















H NMR (300 MHz, CDC13) 6 ppm 7.81 7.92 (m, 2 H), 7.69 (s, 1 H), 7.39 7.56 (m, 3

H), 6.17 (ddd, J= 17.0, 10.2, 8.2 Hz, 1 H), 5.03 5.19 (m, 2 H), 3.23 (t, J= 9.3 Hz, 1 H), 2.30 -

2.47 (m, 1 H), 1.88 2.06 (m, 1 H), 1.38 1.78 (m, 6 H), 1.06 1.29 (m, 1 H)

13C NMR (75 MHz, CDC13) 6 ppm 142.45, 142.23, 133.94, 132.49, 128.21, 127.89,

126.76, 126.45, 126.11, 125.46, 114.65, 57.07, 44.92, 31.76, 25.61

HRMS Calcd. for C18H20 [M]+: 236.1560, Found: 236.1552

Ee was measured by chiral HPLC with a Whelk-01 column (UV 254 nm, 100% pentane,

0.2 mL/min). t,: 30.9, t2 : 34.0

(E)-2-(3-phenylprop-l-enyl)naphthalene (2-125-product)





'H NMR (300 MHz, CDC13) 6 ppm 7.66 7.82 (m, 4 H), 7.58 (dd, J= 8.5, 1.8 Hz, 1 H),

7.37 7.48 (m, 2 H), 7.18 7.37 (m, 5 H), 6.61 (d, J= 15.8 Hz, 1 H), 6.48 (dt, J= 15.8, 6.5 Hz, 1

H), 3.61 (d, J = 6.5 Hz, 2 H)

13C NMR (75 MHz, CDC13) 6 ppm 140.11, 134.91, 133.63, 132.74, 131.12, 129.69,

128.69, 128.50, 128.06, 127.83, 127.60, 126.20, 126.14, 125.71, 125.56, 123.55, 39.45

HRMS Calcd. for C19H16 [M]+: 244.1252, Found: 244.1245

2-(3-methylpent-l-en-3-yl)naphthalene (2-129-product)














Ee was measured by chiral HPLC with a Whelk-01 column (UV 254 nm, 100% pentane,

0.2 mL/min). t,: 32.8, t2 : 35.4

1-methoxy-4-(pent-l-en-3-yl)benzene (2-126-product)






MeO )

Ee was measured by chiral HPLC with a Chiralcel OJ-H column (UV 254 nm, hexane:

iPrOH = 99.5:0.5, 0.5 mL/min). t,: 15.6, t2 : 16.7

1-chloro-4-(non-l-en-3-yl)benzene (2-127-product)






Cl

H NMR (300 MHz, CDC13) 6 ppm 7.26 (m, 2 H), 7.10 (m, 2 H), 5.89 (ddd, J= 16.7,

10.6, 7.5 Hz, 1 H), 4.94 5.07 (m, 2 H), 3.20 (q, J= 7.4 Hz, 1 H), 1.57- 1.74 (m, 2 H), 1.19-

1.31 (m, 8 H), 0.83 0.90 (m, 3 H)

13C NMR (75 MHz, CDC13)6 ppm 143.07, 142.00, 131.68, 128.94, 128.46, 114.19, 49.22,

35.35, 31.74, 29.21, 27.40, 22.63, 14.06

HRMS Calcd. for C15H22C1 [M+H] : 237.1405, Found: 237.1408

Ee was measured by chiral HPLC with a Chiralcel OJ-H column (UV 215 nm, 100%

pentane, 0.2 mL/min). t,: 21.4, t2 : 22.4

1-methoxy-2-(non-l-en-3-yl)benzene (2-128-product)









OMe


H NMR (300 MHz, CDC13) 6 ppm 7.10 7.22 (m, 2 H), 6.80 6.95 (m, 2 H), 5.98 (ddd, J

= 17.1, 10.3, 7.6 Hz, 1 H), 4.93 5.06 (m, 2 H), 3.80 (s, 3 H), 3.73 (q, J= 7.5 Hz, 1 H), 1.60 -

1.73 (m, 2 H), 1.15 1.36 (m, 8 H), 0.80 0.91 (m, 3 H)

13C NMR (75 MHz, CDC3) 6 ppm 157.23, 142.35, 133.37, 128.02, 127.10, 120.86,

113.93, 110.96, 55.69, 42.37, 34.84, 32.07, 29.57, 27.78, 22.94, 14.37

HRMS Calcd. for C16H250 [M+H]+: 233.1900, Found: 233.1892

Ee was measured by chiral HPLC with a Chiralpak IA column (UV 254 nm, 100%

pentane, 0.2 mL/min). t,: 21.5 t2 : 22.4

6.3 In Situ Generation of Acyclic Diaminocarbene-Copper Complex

6.3.1 Substrates and Catalysts Synthesis

[6(R),8(R)-Diisopropyl-5,6,8,9-tetrahydro-6a,7a-

diazadibenzo[cg]fluoreniumchloride] copper (II) chloride (3-2).





NRN

CI

CuCl2


A flame dried Schlenk flask was charged with 0.100 g (0.254 mmol) of [6(R),8(R)-

Diisopropyl-5,6,8,9-tetrahydro-6a,7a-diazadibenzo[c,g]fluorenium] chloride (2-105), 0.036 g

(0.153 mmol) of Ag20 and 10 mL of CH2C12. After stirring for 12 h, the reaction mixture was









filtered through a pad of celite. The solvent of the filtrate was removed under reduced pressure.

To another flame-dried Schlenk flask was added the filtered silver complex and 0.038 g (0.279

mmol) of CuC12. The reaction mixture was stirred for 5 h at room temperature. The reaction

solution was filtered through a pad of celite and evaporated to dryness. The residue was purified

by recrystallization using a mixture of CH2Cl2:hexane to yield 0.090 g (0.182 mmol, 71.6 %) of

3-2.

H NMR (300 MHz, CDC13) 6 ppm 7.97 (d, J=7.6 Hz, 1 H), 7.30 7.56 (m, 3 H), 4.56 -

4.75 (m, 1 H), 3.68 (dd, J=15.9, 5.4 Hz, 1 H), 3.27 (d, J=16.1 Hz, 1 H), 1.74 2.00 (m, 1 H),

1.03 (d, J=6.8 Hz, 3 H), 0.87 (d, J=6.8 Hz, 3 H).

13C NMR (75 MHz, CDC13) 6 ppm 132.8, 131.4, 129.7, 128.1, 126.1, 124.9, 123.3, 61.2,

31.7, 30.6, 20.6, 19.2

X-ray experimental for 3-2

Data were collected at 173 K on a Siemens SMART PLATFORM equipped with A CCD

area detector and a graphite monochromator utilizing MoKa radiation (X = 0.71073 A). Cell

parameters were refined using up to 8192 reflections. A full sphere of data (1850 frames) was

collected using the co-scan method (0.30 frame width). The first 50 frames were re-measured at

the end of data collection to monitor instrument and crystal stability (maximum correction on I

was < 1 %). Absorption corrections by integration were applied based on measured indexed

crystal faces.

The structure was solved by the Direct Methods in SHELXTL6, and refined using full-

matrix least squares. The non-H atoms were treated anisotropically, whereas the hydrogen atoms

were calculated in ideal positions and were riding on their respective carbon atoms. A total of









280 parameters were refined in the final cycle of refinement using 4548 reflections with I > 2o(I)

to yield R1 and wR2 of 3.45% and 7.82%, respectively. Refinement was done using F2

SHELXTL6 (2000). Bruker-AXS, Madison, Wisconsin, USA.

Crystal data and structure refinement for 3-2

Identification code 3-2

Empirical formula C25 H28 C13 Cu N2

Formula weight 526.38

Temperature 173(2) K

Wavelength 0.71073 A

Crystal system Orthorhombic

Space group P2(1)2(1)2(1)

Unit cell dimensions

a = 7.1072(5) A a= 90.

b = 17.4430(11) A 3= 90.

c = 19.5633(13) A y= 900.

Volume 2425.3(3) A3

Z 4

Density (calculated) 1.442 Mg/m3

Absorption coefficient 1.247 mm-1

F(000) 1088

Crystal size 0.26 x 0.09 x 0.09 mm3

Theta range for data collection 1.56 to 28.030.

Index ranges -8








Reflections collected 9852

Independent reflections 5109 [R(int) = 0.0340]

Completeness to theta = 28.03092.7 %

Absorption correction Integration

Max. and min. transmission 0.8961 and 0.7376

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 5109 / 0 / 280

Goodness-of-fit on F2 1.014

Final R indices [I>2sigma(I)] R1 = 0.0345, wR2 = 0.0782 [4548]

R indices (all data) R1 = 0.0408, wR2 = 0.0807

Absolute structure parameter 0.020(11)

Largest diff. peak and hole 0.314 and -0.275 e.A-3

R1 = 2(||Fol |Fcl|) / I|Fol

wR2 = [Y[w(Fo2 Fc2)2] / y[w(Fo2)2]]1/2

S =[[w(Fo2 Fc2)2] / (n-p)]1/2

w= 1/[Y2(Fo2)+(m*p)2+n*p], p = [max(Fo2,0)+ 2* Fc2]/3, m & n are constants.

(Z)-4-(4-methoxybenzyloxy)but-2-en-l-ol


O
HO 0


To a flame-dried Schlenk flask were added 1.25 g (14.16 mmol) of (Z)-2-buten-1,4-diol

and 5 mL (0.06 mmol) of a solution of TfOH in Et20 (10 aL in 10 mL of Et20). The reaction

mixture was cooled to 0 OC and a solution of 4-methoxybenzyl-2,2,2-trichloroacetimidate (0.67








g, 2.36 mmol) in DCM (1.2 mL) was added dropwise. After stirring over 2 hours at 0 OC, it was

quenched with 4 mL of a saturated solution of NaHCO3. The aqueous layer was extracted with

Et20 (3 x 5mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated

under reduced pressure. The residue was purified by flash column chromatography (silica gel,

from 2.3:1 to 1:1 Hexanes/EtOAc) to yield 0.40 g (1.90 mmol, 80%) of (Z)-4-(4-

methoxybenzyloxy)but-2-en-1 -ol.

H NMR (300 MHz, CDC13) 6 ppm 7.26 (d, J=8.21 Hz, 2 H), 6.88 (d, J=8.78 Hz, 2 H),

5.65 5.85 (m, 2 H), 4.45 (s, 2 H), 4.14 (d, J=5.95 Hz, 2 H), 4.05 (d, J=5.66 Hz, 2 H), 3.79 (s, 3

H), 2.32 (br. s, 1 H)

13C NMR (75 MHz, CDC13)6 ppm 159.5, 132.6, 130.1, 129.7, 128.4, 114.1, 72.4, 65.6,

58.8, 55.5

HRMS Calcd. for C12H1603 [M+Na]+: 231.0992, Found: 231.0991

(Z)-4-(4-methoxybenzyloxy)but-2-enyl acetate (3-4)

0
-K



To a flame-dried Schlenk flask were added 356 mg (1.71 mmol) of(Z)-4-(4-

methoxybenzyloxy)but-2-en-l-ol, 755 t-L (5.42 mmol) of Et3N, 44 mg (0.36 mmol) of DMAP,

205 t-L (2.17 mmol) of Ac20, and 18 mL of DCM. The reaction mixture was stirred at room

temperature over 12 hours. It was quenched with 10 mL of H20 and extracted with DCM (3 x 10

mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under

reduced pressure. The residue was purified by flash column chromatography (silica gel, 1:1

Hexanes/EtOAc) to yield 400 mg (1.60 mmol, 93%) of (Z)-4-(4-methoxybenzyloxy)but-2-enyl

acetate.









'H NMR (300 MHz, CDC13) 6 ppm 7.27 (d, J=8.80 Hz, 2 H), 6.88 (d, J=8.80 Hz, 2 H),

5.76 5.86 (m, 1 H), 5.64 5.75 (m, 1 H), 4.62 (dd, J=6.45, 0.88 Hz, 2 H), 4.45 (s, 2 H), 4.09

(dd, J=6.16, 1.17 Hz, 2 H), 3.80 (s, 3 H), 2.06 (s, 3 H)

13C NMR (75 MHz, CDC13)6 ppm 170.8, 159.3, 130.9, 130.1, 129.4, 126.6, 113.8, 72.1,

65.3, 60.3, 55.2, 20.9

HRMS Calcd. for C14HI804 [M+Na]+: 273.1097, Found: 273.1104

(Z)-but-2-ene-1,4-diyl bis(4-methoxybenzoate) (3-13)


0 O O
/


To a flame-dried Schlenk flask were added 54 mg (0.61 mmol) of(Z)-2-buten-l,4-diol,

212 tL (1.52 mmol) of Et3N, 15 mg (0.12 mmol) of DMAP, 10 mL of DCM, and dropwise 206

[tL (1.52 mmol) of 4-methoxybenzoylchloride. The reaction mixture was stirred at room

temperature over 17 hours. It was quenched with 6 mL of 30% NaOH solution and extracted

with DCM (3 x 8 mL). The combined organic extracts were dried over MgSO4, filtered, and

concentrated under reduced pressure. The residue was purified by flash column chromatography

(silica gel, 1:1 Hexanes/EtOAc) to yield 217 mg (0.61 mmol, quantitative yield) of 3-13.

SH NMR (300 MHz, CDC13) 6 ppm 8.00 (d, J=8.91 Hz, 4 H), 6.91 (d, J=8.91 Hz, 4 H),

5.93 (ddd, J=5.22, 3.98, 1.17 Hz, 2 H), 4.97 (d, J=5.26 Hz, 4 H), 3.86 (s, 6 H)

13C NMR (75 MHz, CDC13)6 ppm 166.2, 163.6, 131.8, 128.5, 122.5, 113.8, 60.5, 55.6

HRMS Calcd. for C20H2004 [M+Na] : 379.1152, Found: 379.1185

Ethyl 2-(1-tosylpiperidin-4-ylidene)acetate









0O

O N-0
0
0



To a flame-dried Schlenk flask was added 177 mg of NaH (60% in mineral oil, 4.42 mmol)

in 12 mL of toluene. To this suspensions at 0 OC was added dropwise 790 atL (3.95 mmol) of

triethyl phosphonoacetate. The reaction mixture was stirred 30 min at room temperature then

1.00 g (3.95 mmol) of 1-tosylpiperidin-4-one was added portionwise. It was stirred at 60 OC over

a day. The reaction mixture was quenched by 10 mL of H20 and extracted with Et20 (3 x 10

mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under

reduced pressure. The residue was purified by flash column chromatography (silica gel, from 1:0

to 4:1 Hexanes/EtOAc) to give 940 mg (2.9 mmol, 74%) of ethyl 2-(1-tosylpiperidin-4-

ylidene)acetate.

1H NMR (300 MHz, CDC13) 6 ppm 7.64 (d, J=8.20 Hz, 2 H), 7.31 (d, J=8.65 Hz, 2 H),

5.64 (s, 1 H), 4.11 (q, J=7.16 Hz, 2 H), 2.99 3.18 (m, 6 H), 2.42 (s, 2 H), 2.38 (t, J=6.34 Hz, 3

H), 1.24 (t, J=7.09 Hz, 3 H)

13C NMR (75 MHz, CDC13)6 ppm 166.0, 153.4, 143.7, 133.1, 129.7, 127.6, 115.9, 59.9,

47.3, 46.8, 35.8, 28.5, 21.5, 14.2

HRMS Calcd. for C16H21N04S [M+Na] : 346.1084, Found: 346.1086

2-(1-tosylpiperidin-4-ylidene)ethanol

0O

HO N-









To a flame-dried Schlenk flask were added 1.14 g (3.52 mmol) of ethyl 2-(1-

tosylpiperidin-4-ylidene)acetate and 38 mL of DCM. The reaction mixture was cooled at -78 C

and 10.6 mL (10.55 mmol) of DIBAL (1M in toluene) was added dropwise. It was stirred at -78

C for 2 hours. It was quenched with 20 mL of a saturated solution of NH4Cl and extracted with

DCM (3 x 30 mL). The combined organic extracts were filtered on a celite pad, dried over

MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash

column chromatography (silica gel, from 1:1.5 to 1:2.3 Hexanes/EtOAc) to yield 0.89 mg (3.17

mmol, 90%) of 2-(1-tosylpiperidin-4-ylidene)ethanol.

H NMR (300 MHz, CDC13) 6 ppm 7.62 (d, J=8.21 Hz, 2 H), 7.31 (d, J=8.49 Hz, 2 H),

5.42 (t, J=6.94 Hz, 1 H), 4.09 (d, J=6.79 Hz, 2 H), 2.98 3.09 (m, 4 H), 2.42 (s, 3 H), 2.37 (t,

J=5.80 Hz, 2 H), 2.29 (t, J=5.80 Hz, 2 H), 1.36 (br. s., 1 H)

13C NMR (75 MHz, CDC13) 6 ppm 143.55, 137.41, 133.08, 129.61, 127.58, 123.52, 58.08,

47.64, 47.08, 35.05, 27.76, 21.47

HRMS Calcd. for C14H19N03S [M+Na]+: 304.0978, Found: 304.0984

2-(1-tosylpiperidin-4-ylidene)ethyl acetate (3-17)

0



0


To a flame-dried Schlenk flask were added 489 mg (1.74 mmol) of 2-(1-tosylpiperidin-4-

ylidene)ethanol, 740 tL (5.31 mmol) of Et3N, 43 mg (0.36 mmol) of DMAP, 201 [L (2.13

mmol) of Ac20, and 18 mL of DCM. The reaction mixture was stirred at room temperature over

17 hours. It was quenched with 10 mL of H20 and extracted with DCM (3 x 10 mL). The

combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced









pressure. The residue was purified by flash column chromatography (silica gel, 1:1

Hexanes/EtOAc) to yield 548 mg (1.69 mmol, 97%) of 3-17.

H NMR (300 MHz, CDC13) 6 ppm 7.64 (d, J=8.21 Hz, 2 H), 7.31 (d, J=8.78 Hz, 2 H),

5.36 (t, J=6.94 Hz, 1 H), 4.51 (d, J=7.36 Hz, 2 H), 3.06 (q, J=6.23 Hz, 4 H), 2.37 2.49 (m, 5 H),

2.31 (t, J=5.52 Hz, 2 H), 2.01 (s, 3 H)

13C NMR (75 MHz, CDC13)6 ppm 171.1, 143.8, 140.1, 133.5, 129.9, 127.8, 118.9, 60.2,

47.7, 47.1, 35.3, 28.2, 21.7, 21.2

HRMS Calcd. for C16H21N04S [M+Na]+: 346.1084, Found: 346.1080

Pyrrolidine-l-carbaldehyde-13C (3-30)


13C
H N


To a flame-dried pressurized vessel were added 1.42 mL (17.29 mmol) of pyrrolidine and

1000 mg (16.38 mmol) of methyl formate-13C. The reaction mixture was stirred at 80 OC for 12

hours. It was warmed to room temperature and concentrated under reduced pressure to yield

1640 mg (16.38 mmol, 99%) of pyrrolidine-1-carbaldehyde-13C

H NMR (300 MHz, CDC13) 6 ppm 8.2 (d, J=188.8 Hz, 1 H), 3.4 (m, 4 H), 1.9 (m, 4 H)

13C NMR (75 MHz, CDC13) 6 ppm 160.7, 45.9, 43.0, 24.8, 24.1

HRMS Calcd. for C413CH9NO [M+H]+: 101.0790, Found: 101.0793

Piperidin-1-ylmethylidenepiperidinium hexafluorophosphate-13C (3-32)

H
13c



PF6









To a flame-dried Schlenk flask were added 467 [L (5.01 mmol) of phosphorus oxychloride

and 5 mL of DCM. To the reaction mixture at -78 C in a dry ice-acetone bath was added a

solution of 502 mg (5.01 mmol) of pyrrolidine-l-carbaldehyde-13C 3-30 in 2 mL of DCM. It was

warmed up to room temperature and stirred for 2 hours. Then it was cooled at 0 OC and a

solution of 693 [L (5.01 mmol) of triethyl amine and 412 [L (5.01 mmol) of pyrrolidine in 2.5

mL of DCM was added dropwise. It was stirred at room temperature for 2 hours. The reaction

mixture was extracted with cold H20 (3 x 2.5 mL), the combined aqueous layer was added to a

cold solution of 1600 mg (10.02 mmol) of ammonium hexafluorophosphate in 5 mL of H20. The

precipitate was filtered and washed with H20 (2 x 3 mL) and Et20 (2 x 5 mL). The yellowish

solid was dried under reduced pressure to yield 1000 mg (3.34 mmol, 67% yield) of piperidin-1-

ylmethylidenepiperidinium hexafluorophosphate-13C 3-32.

H NMR (300 MHz, CDC13) 6 ppm 7.81 (d, J=190.0 Hz, 1 H), 3.81 (dt, J=14.0, 7.0 Hz, 4

H), 2.01 (dt, J=13.2, 7.0 Hz, 4 H)

13C NMR (75 MHz, CDC13) 6 ppm 151.0, 54.2, 48.2, 25.8, 23.8

HRMS Calcd. for C813CH17F6N2P [M+H]+: 154.1420, Found: 154.1432

6.3.2 Products from The Copper-Catalyzed Allylic Alkylation

Typical procedure for the allylic alkylation:

A flame-dried Schlenk flask was charged with a copper source (5 mol %), 1-

(chloro(pyrrolidin-1-yl)methylene)pyrrolidinium tetrafluoroborate (5 mol%) and 1 mL of a

solvent. To this solution was added a Grignard reagent (0.22 mmol in Et20) at 0 OC. The mixture

reaction was stirred for 5 min at 0 OC. Then a solution of substrate (0.15 mmol) in 1 mL of Et20

was added over a 15 min period. After 1 hr, the reaction was quenched by a saturated aqueous

NH4C1 solution and extracted with Et20 (3 x 5 mL). The combined organic extracts were dried









over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by

flash column chromatography to give a pure product.

1-((2-ethylbut-3-enyloxy)methyl)-4-methoxybenzene (3-5)






MeO

H NMR (300 MHz, CDC13) 6 ppm 7.20 7.37 (m, 2 H), 6.87 (d, J=8.4 Hz, 2 H), 5.54 -

5.79 (m, 1 H), 4.98 5.23 (m, 2 H), 4.44 (s, 2 H), 3.80 (s, 3 H), 3.36 (d, J=6.4 Hz, 2 H), 2.12 -

2.42 (m, 1 H), 1.45 1.71 (m, 1 H), 1.13 1.37 (m, 1 H), 0.86 (t, J=7.4 Hz, 3 H)

13C NMR (75 MHz, CDC13) 6 ppm 159.1, 140.0, 130.7, 129.1, 115.5, 113.7, 73.2, 72.6,

55.2, 45.7, 24.0, 11.4

HRMS Calcd. for C14H2002 [M]+: 220.1463, Found: 220.1477.

2-ethylbut-3-enyl 4-methoxybenzoate (3-18)

0





MeO

H NMR (300 MHz, CDC13) 6 ppm 7.91 (d, J=8.78 Hz, 2 H), 6.83 (d, J=9.06 Hz, 2 H),

5.62 (ddd, J=17.06, 10.40, 8.21 Hz, 1 H), 5.00 5.09 (m, 2 H), 4.15 (dd, J=6.51, 1.98 Hz, 2 H),

3.77 (s, 3 H), 2.25 2.41 (m, 1 H), 1.44 1.60 (m, 1 H), 1.23 1.39 (m, 1 H), 0.86 (t, J=7.36 Hz,

3 H)

13C NMR (75 MHz, CDC13) 6 ppm 166.52, 163.50, 139.18, 131.76, 123.07, 116.68,

113.79, 67.37, 55.61, 45.13, 24.23, 11.61









HRMS Calcd. for C14Hi803 [M+Na] : 257.1148, Found: 257.1142

1-(2-ethylbut-3-enyl)-4-methoxybenzene (3-19)







MeO

H NMR (300 MHz, CDC13) 6 7.06 (d, J=9 Hz, 2 H), 6.81 (d, J=9 Hz, 2 H), 5.47 5.72 (m,

1 H), 4.73 5.04 (m, 2 H), 3.79 (s, 3 H), 2.43 2.70 (m, 2 H), 2.05 2.27 (m, 1 H), 1.36 1.52

(m, 1 H), 1.17 1.36 (m, 1 H), 0.87 (t, J=8 Hz, 3 H)

13C NMR (75 MHz, CDC13) 6 157.9, 142.6, 133.0, 130.3, 114.8, 113.7, 55.4, 47.7, 40.8,

27.0, 11.9

HRMS Calcd. for C13Hi80 [M+H] : 191.1430, Found: 191.1436

2,6-dimethyl-6-vinyldodec-2-ene (3-20)






H NMR (300 MHz, CDC13) 6 ppm 5.71 (dd, J=17.6, 10.9 Hz, 1 H), 5.05 5.15 (m, 1 H),

4.84 5.02 (m, J=15.9, 11.0, 1.6 Hz, 2 H), 1.82- 1.94 (m, 2 H), 1.69 (s, 3 H), 1.60 (s, 3 H), 1.21

- 1.34 (m, 12 H), 0.96 (s, 3 H), 0.86 0.92 (m, 3 H)

13C NMR (75 MHz, CDC13) 6 ppm 147.5, 130.9, 125.2, 111.3, 40.9, 40.8, 39.5, 32.0, 30.2,

25.7, 24.0, 22.9, 22.7, 22.6, 17.6, 14.1

HRMS Calcd. for C16H30 [M]+: 222.2348, Found: 223.2342

4-ethyl-l-tosyl-4-vinylpiperidine (3-21)














'H NMR (300 MHz, CDC13) 6 7.58 (m, J=8 Hz, 2 H) 7.26 (m, J=8 Hz, 2 H), 5.36 (dd,

J=18, 11 Hz, 1 H), 5.04 (d, J=ll Hz, 1 H), 4.77 (d, J=18 Hz, 1 H), 3.17 3.35 (m, 2 H), 2.55 -

2.71 (m, 2 H), 2.38 (s, 3 H), 1.59 1.76 (m, 2 H), 1.41 1.59 (m, 2 H), 1.22 (q, J=7 Hz, 2 H),

0.68 (t, J=7 Hz, 3 H)

13C NMR (75 MHz, CDC13) 6 143.4, 133.8, 129.8, 127.8, 115.1, 42.9, 38.1, 34.1, 33.6,

21.8, 7.7

HRMS Calcd. for C16H23N02S [M+H] : 294.1522, Found: 294.1499

6.3.3 NMR Experiments

Figure 3-2. Experiment (a)


QI CI
C 13C
N^^ N


CuCI (1 eq)
PhMgBr (4 eq)
THF-d8


--
"-C ( MgBr
Cu'
13C +
N N7


3-25 3-27 3-26

To a flame-dried Schlenk flask was added 20 mg (0.089 mmol) of 1-(chloro-1-

pyrrolidinylmethylene)-pyrrolidinium chloride, 8.9 mg (0.089 mmol) of copper (I) chloride and

750 tL of THF-ds. The reaction mixture was cooled to 0 OC and phenylmagnesium bromide

(0.36 mmol in THF) was added. It was stirred at 0 OC for 5 min then it was transferred to a

flame-dried NMR tube under argon via syringe. The NMR tube was cooled to -78 C in a dry

ice-acetone bath before being analyzed in the NMR instrument at -60 OC.

Figure 3-2. Experiment (b)


,Mg '
C13
N 'N









Cl Cl Ph X
N 10 PhMgBr (4 eq) Mg
NN THF-d0 GN' bCN

3-25 3-26 3-28

To a flame-dried Schlenk flask was added 10 mg (0.045 mmol) of 1-(chloro-1-

pyrrolidinylmethylene)-pyrrolidinium chloride and 750 aL of THF-ds. The reaction mixture was

cooled to 0 OC and phenylmagnesium bromide (0.18 mmol in THF) was added. It was stirred at 0

C for 5 min, and then it was transferred to a flame-dried NMR tube under argon via syringe.

The NMR tube was cooled to -78 C in a dry ice-acetone bath before being analyzed in the NMR

instrument at -60 C.

Figure 3-2. Experiment (c)


CuCI (1 eq) Cu,- gB
Crude mixture ( e' Ph X
from experiment b THF-d8 N N + / 1- N


3-27 3-29

To the NMR tube from experiment 2 was added 4.5 mg (0.045 mmol) of copper (I)

chloride at 0 OC. Then it was stirred at 0 OC for 5 min and cooled at -78 C in a dry ice-acetone

bath before being analyzed in the NMR instrument at -60 OC.

Figure 3-2. Experiment (d)


CI Cl CuCI (1 eq) -- t X
1 EtMgBr (4 eq) Cu MBr
N3 c- 3 + 13c G
o THF-d8 N N N
3-25 3-27 3-29









To a flame-dried Schlenk flask was added 10 mg (0.045 mmol) of 1-(chloro-1-

pyrrolidinylmethylene)-pyrrolidinium chloride, 4.4 mg (0.045 mmol) of copper (I) chloride and

750 tL of THF-ds. The reaction mixture was cooled to 0 OC, and ethylmagnesium bromide (0.18

mmol in THF) was added. It was stirred at 0 OC for 5 min, and then it was transferred to a flame-

dried NMR tube under argon via syringe. The NMR tube was cooled to -78 C in a dry ice-

acetone bath before being analyzed in the NMR instrument at -60 OC.

Figure 3-3. Experiment (a)

H LDA, 1 eq Li
13C ,, THF-d8 3C
1N" N __ 13N
< O -78 C to rt

PF6
3-32 3-33

To a flame-dried NMR tube was added 41.4 mg (0.138 mmol) of piperidin-1-

ylmethylidenepiperidinium hexafluorophosphate-13C. Then it was cooled at -78 OC in a dry ice-

acetone bath and 147 tL (0.94 M) of LDA followed by 750 tL of THF-ds. It was stirred at room

temperature for 5 min until dissolution of the suspension before being analyzed in the NMR

experiment at room temperature.

Figure 3-3. Experiment (b)

LiM
13C PhMgBr (4 eq) 13C


3-33 3-26
3-33 3-26









To the NMR tube from experiment 5 at -78 C in a dry ice-acetone bath was added 548 [tL

(1 M in THF) of phenyl magnesiumbromide and the reaction mixture was stirred for 5 min at

room temperature before being analyzed in the NMR experiment at room temperature.

Figure 3-3. Experiment (c)

"Mg C"Cu"
13C CuCI (1 eq) 13,
N" N 9-- 'No


3-26


3-27


To the NMR tube from experiment 6 at -78 C in a dry ice-acetone bath was added 14 mg

(0.138 mmol) of copper chloride and the reaction mixture was stirred for 5 min at room

temperature before being analyzed in the NMR experiment at room temperature.

6.3.4 Additional Experiments from Table 3-2

Table 3-2.Entry 8


N~o
3-11 H PF6
(0.1 eq)
Et
Pc + LDA (0.1 eq) M+ PMBOEt
PMBO^ Q-Oc Et PMRO^PMBO
CuTC (0.1 eq) P
34 EtMgBr (1.5 eq) 3-5(y) 3-6(a)
Et20, 0 oC, 1 h
Et2,0o 1 h 71% yield, y:a 90:10


To a flame-dried Schlenk flask were added 201 mg (0.674 mmol) of piperidin-1-

ylmethylidenepiperidinium hexafluorophosphate to a solution of 0.674 mmol (3 M in THF) of

LDA. The reaction mixture was stirred at -20 OC for 30 min. 65 [tL (0.022 mmol) of this carbene

solution generated in situ was added to a flame-dried Schlenk flask at 0 OC containing 110 tL (3









M in Et20) of ethyl magnesiumbromide, 4.2 mg (0.022 mmol) of copper thiophene-2-

carboxylate and 1 mL of Et20. The reaction mixture was stirred for 5 min then a solution of 55

mg (0.221 mmol) of (Z)-4-(4-methoxybenzyloxy)but-2-enyl acetate in 1 mL of Et20 was added

dropwise. After 1 hr, the reaction was quenched by a saturated aqueous NH4C1 solution and

extracted with Et20 (3 x 5 mL). The combined organic extracts were dried over MgSO4, filtered,

and concentrated under reduced pressure. The residue was purified by flash column

chromatography (silica gel, 1:0.05 Hexanes/EtOAc) to yield 33.9 mg (0.154 mmol, 71%, y:a

90:10) of 1-((2-ethylbut-3-enyloxy)methyl)-4-methoxybenzene.

Table 3-2. Entry 9


(0.05 eq) Et _
PMBO -/!^OAc CuTC (0.05 eq) PMBO PMBO-Et
3-4 EtMgBr (1.5 eq) 3-5(y) 3-6(a)
Et20, 0 C, 1 h
57% yield, y:a 92:8

To a flame-dried Schlenk flask were added 3.5 mg (0.011 mmol) of 1,3-Bis(2,4,6-

trimethyl-phenyl)imidazol-2-ylidene, 2.1 mg (0.011 mmol) of copper thiophene-2-carboxylate,

116 tL (3 M in Et20) of ethyl magnesiumbromide and 1 mL of Et20. The The reaction mixture

was stirred for 5 min at 0 OC then a solution of 58 mg (0.231 mmol) of (Z)-4-(4-

methoxybenzyloxy)but-2-enyl acetate in 1 mL of Et20 was added dropwise. After 1 hr, the

reaction was quenched by a saturated aqueous NH4C1 solution and extracted with Et20 (3 x 5

mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under

reduced pressure. The residue was purified by flash column chromatography (silica gel, 1:0.05









Hexanes/EtOAc) to yield 29 mg (0.131 mmol, 60%, y:a 92:8) of 1-((2-ethylbut-3-

enyloxy)methyl)-4-methoxybenzene.

6.4 Ct-Symmetric Monoisoquinoline NHC Ligands

6.4.1 Ligands Synthesis

(S)-N-(4-methyl-1-phenylpentan-2-yl)-2-oxo-2-phenylacetamide (4-10)

0 0

> NH






To a flame-dried Schlenk flask was added 2.21 g (12.5 mmol) of(S)-4-methyl-1-

phenylpentan-2-amine, 2.18 g (16.1 mmol) of HOBt, 3.09 g (16.2 mmol) of EDCI, 2.05 g (13.7

mmol) of 2-oxo-2-phenylacetic acid and 33 mL (0.377 M) of DMF. The reaction mixture was

stirred at room temperature for 12 h. It was quenched by 40 mL of water. The reaction mixture

was extracted with ethyl acetate (2 x 40 mL), washed with water (2 x 40 mL) and dried over

anhydrous MgSO4. All volatiles were removed in vacuo. Silicagel column chromatography with

a 95:5 mixture of hexane and ethyl acetate as the eluent gave 2.91 g (9.41 mmol, 75.3%) of(S)-

N-(4-methyl-1 -phenylpentan-2-yl)-2-oxo-2-phenylacetamide.

H NMR (299 MHz, CHLOROFORM-d) 6 = 8.18 8.29 (m, 2 H), 7.56 7.67 (m, 1 H),

7.41 7.51 (m, 2 H), 7.16- 7.36 (m, 5 H), 6.79 (d, J=9.3 Hz, 1 H), 4.30 4.46 (m, J=9.1, 6.0,

6.0, 3.0 Hz, 1 H), 2.75 2.97 (m, J=13.9, 6.2 Hz, 2 H), 1.67 (td, J=13.7, 6.7 Hz, 1 H), 1.43 (ddd,

J=8.9, 5.4, 3.5 Hz, 2 H), 0.93 (dd, J=6.5, 1.4 Hz, 6 H)

1C NMR (75 MHz, CHLOROFORM-d) 6 = 161.2, 137.5, 134.3, 131.1, 129.5, 128.4,

126.5, 48.6, 43.3, 41.6, 25.0, 23.2, 21.9








HRMS Calcd. for C20H23N02 [M+H] : 310.1802, Found: 310.1826

[a]20D- 22.20 (c 1.33, CHC13)

(S)-N-(1,2-diphenylethyl)-2-oxo-2-phenylacetamide (4-34)


0 0
NH Ph




265 mg (0.805 mmol, 71.9%) of (S)-N-(1,2-diphenylethyl)-2-oxo-2-phenylacetamide was

obtained from 200 mg (1.014 mmol) of(S)-1,2-diphenylethanamine, 167 mg (1.12 mmol) of 2-

oxo-2-phenylacetic acid, 253 mg (1.32 mmol) of EDCI, 180 mg (1.32 mmol) of HOBt and 2.5

mL of DMF.

'H NMR (300MHz ,CHLOROFORM-d) 6 = 8.41 8.08 (m, 2 H), 7.89 7.51 (m, 2 H),

7.51 7.11 (m, 12 H), 5.38 (q, J= 7.5 Hz, 1 H), 3.38 3.06 (m, 2 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 187.9, 161.3, 140.9, 137.2, 134.6, 133.5,

131.4, 129.6, 129.0, 128.7, 128.0, 126.9, 55.0, 42.9

(R)-N-(1-cyclohexyl-2-phenylethyl)-2-oxo-2-phenylacetamide (4-36)


Oo o
NH





460 mg (1.37 mmol, 54.0%) of (R)-N-(1-cyclohexyl-2-phenylethyl)-2-oxo-2-

phenylacetamide was obtained from 517 mg (2.54 mmol) of (R)-1-cyclohexyl-2-









phenylethanamine, 400 mg (2.66 mmol) of 2-oxo-2-phenylacetic acid, 634 mg (3.31 mmol) of

EDCI, 447 mg (3.31 mmol) of HOBt and 6.4 mL of DMF.

'H NMR (300MHz ,CHLOROFORM-d) 6 = 8.24 8.12 (m, 2 H), 7.70 7.56 (m, 1 H),

7.53 7.40 (m, 2 H), 7.38- 7.17 (m, 5 H), 6.86 (d, J= 9.7 Hz, 1 H), 4.29 4.13 (m, 1 H), 3.04

(dd, J= 5.3, 14.1 Hz, 1 H), 2.76 (dd, J= 8.8, 13.8 Hz, 1 H), 1.86 (t, J= 14.2 Hz, 4 H), 1.76 -

1.67 (m, 1 H), 1.65 1.51 (m, 1 H), 1.34 1.04 (m, 5 H)

13C NMR (75MHz ,CHLOROFORM-d) 6= 188.4, 161.6, 138.3, 134.5, 133.5, 131.3,

129.4, 128.7, 128.6, 126.6, 55.3, 41.3, 38.3, 30.4, 28.4, 26.5, 26.3

2-oxo-2-phenyl-N-((1R,2R)-2-phenylcyclohexyl)acetamide (4-40)

PhO 0

NH Ph


270 mg (0.878 mmol, 75.7%) of 2-oxo-2-phenyl-N-((1R,2R)-2-

phenylcyclohexyl)acetamide was obtained from 204 mg (1.16 mmol) of (1R,2R)-2-

phenylcyclohexanamine, 183 mg (1.22 mmol) of 2-oxo-2-phenylacetic acid, 290 mg (1.51

mmol) of EDCI, 204 mg (1.51 mmol) of HOBt and 2.8 mL of DMF.

'H NMR (300MHz ,CHLOROFORM-d) 6 = 8.06 7.96 (m, 2 H), 7.66 7.48 (m, 1 H),

7.48 7.14 (m, 8 H), 4.60 (dq, J= 3.2, 9.4 Hz, 1 H), 3.06 (dt, J= 4.0, 11.6 Hz, 1 H), 2.12 (d, J

15.0 Hz, 1 H), 2.06 1.66 (m, 5 H), 1.64 1.46 (m, 2 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 188.7, 161.7, 142.9, 134.4, 133.3, 131.2,

128.6, 128.5, 127.7, 126.7, 50.0, 45.6, 31.3, 25.9, 25.7, 20.8

(S)-(3-isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methanone (4-11)



















To a flame-dried Schlenk flask was added 400 mg (1.29 mmol) of (S)-N-(4-methyl-1-

phenylpentan-2-yl)-2-oxo-2-phenylacetamide, 472 mg (3.87 mmol) of DMAP and 50 mL (0.025

M) of toluene. The reaction mixture was cooled to 0 C, and 1.09 mL (6.45 mmol) of Tf2O was

slowly added. After 10 min stirring at 0 C, the reaction mixture was stirred at 90 C for 8 h. It

was quenched by 10 mL of a saturated Na2CO3 aqueous solution. The reaction mixture was

extracted with DCM (3 x 40 mL) and dried over anhydrous MgSO4. All volatiles were removed

in vacuo. Silicagel column chromatography with a 95:5 mixture of hexane and ethyl acetate as

the eluent gave 370 mg (1.27 mmol, 98.4%) of (S)-(3-isobutyl-3,4-dihydroisoquinolin-1-

yl)(phenyl)methanone.

H NMR (300 MHz, CHLOROFORM-d) 6 = 8.01 8.14 (m, 2 H), 7.54 7.69 (m, 1 H),

7.20 7.53 (m, 6 H), 3.84 3.98 (m, 1 H), 2.94 (dd, J=16.1, 5.6 Hz, 1 H), 2.68 (dd, J=16.0, 11.0

Hz, 1 H), 1.88 2.04 (m, J=13.5, 6.7, 6.7, 6.7, 6.7 Hz, 1 H), 1.70 1.84 (m, 1 H), 1.50 (ddd,

J=13.6, 7.0, 6.9 Hz, 1 H), 0.98 (dd, J=6.6, 2.2 Hz, 6 H)

13C NMR (75 MHz, CHLOROFORM-d) 6 =194.08, 164.15, 137.16, 135.74, 134.05,

131.72, 130.69, 128.71, 128.33, 127.33, 126.95, 126.62, 55.34, 44.50, 31.43, 25.03, 23.08, 22.80

HRMS Calcd. for C20H21NO [M+H]+: 291.1696, Found: 291.1700

[a]20D- 13.90 (c 1.21, CHC13)

(R)-(3-cyclohexyl-3,4-dihydroisoquinolin-l-yl)(phenyl)methanone (4-37)



















280 mg (0.882 mmol, 98.7%) of (R)-(3-cyclohexyl-3,4-dihydroisoquinolin-1-

yl)(phenyl)methanone was obtained from 300 mg (0.894 mmol) of 2(R)-N-(1-cyclohexyl-2-

phenylethyl)-2-oxo-2-phenylacetamide, 327 mg (2.68 mmol) of DMAP, 752 [L (4.47 mmol) of

Tf2O and 36 mL of toluene.

1H NMR (300MHz ,CHLOROFORM-d) 6 = 8.34 7.97 (m, 2 H), 7.82 7.56 (m, 1 H),

7.56 7.34 (m, 4 H), 7.34 6.96 (m, 2 H), 3.53 (dt, J= 6.3, 12.4 Hz, 1 H), 2.96 2.70 (m, 2 H),

2.05 (d,J= 11.4 Hz, 1 H), 1.94- 1.62 (m, 5 H), 1.49- 1.12 (m, 5 H)

3C NMR (75MHz ,CHLOROFORM-d) 6 = 194.0, 164.1, 138.0, 135.8, 134.0, 131.6,

130.7, 128.7, 128.3, 127.2, 127.1, 126.5, 62.4, 42.9, 30.1, 29.7, 28.2, 26.8, 26.7

((4aR,10bR)-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)(phenyl)methanone (4-41)



0

NN Ph


80 mg (0.276 mmol, 94.7%) of ((4aR,10bR)-1,2,3,4,4a, 1 Ob-hexahydrophenanthridin-6-

yl)(phenyl)methanone was obtained from 90 mg (0.292 mmol) of 2-oxo-2-phenyl-N-((1R,2R)-2-

phenylcyclohexyl)acetamide, 107 mg (0.878 mmol) of DMAP, 246 iL (1.46 mmol) of Tf2O and

12 mL of toluene.









'H NMR (299MHz ,CHLOROFORM-d) 6 = 8.17 8.03 (m, 2 H), 7.67 7.13 (m, 7 H),

3.90 (q, J= 4.7 Hz, 1 H), 2.96 2.80 (m, 1 H), 2.18 (d, J= 10.2 Hz, 1 H), 1.97- 1.35 (m, 7 H)

3C NMR (75MHz ,CHLOROFORM-d) 6 = 194.3, 165.4, 142.4, 135.7, 134.2, 132.1,

130.6, 128.8, 127.5, 127.2, 126.9, 125.8, 57.1, 37.6, 30.9, 29.0, 24.4, 22.3

(SE)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methylene)-3,5-

bis(trifluoromethyl)aniline (4-67)






N N `CF3



CF3

37.0 mg (0.0736 mmol, 79.5%) of (S,E)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-

yl)(phenyl)methylene)-3,5-bis(trifluoromethyl)aniline was obtained from 27.0 mg (0.0926

mmol) of (S)-(3-isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methanone, 25.6 [L (1.85 mmol)

of Et3N, 71.3 [L (0.460 mmol) of 3,5-bis(trifluoromethyl)aniline and 110 pL of TiC14 (1 M in

toluene).

IH NMR (300MHz ,CHLOROFORM-d) 6 = 7.95 (d, J= 7.4 Hz, 2 H), 7.55 7.34 (m, 4

H), 7.34 7.20 (m, 3 H), 7.20 7.01 (m, 3 H), 3.78 3.55 (m, 1 H), 2.63 (dd, J= 5.5, 16.0 Hz, 1

H), 1.88 1.65 (m, 1 H), 1.57 (dt, J= 6.7, 13.3 Hz, 1 H), 1.40- 1.15 (m, 1 H), 0.85 (d, J= 6.5

Hz, 3 H), 0.88 (d, J= 6.8 Hz, 3 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 163.0, 151.9, 136.3, 136.1, 132.0, 131.7,

131.1, 128.7, 128.0, 127.1, 125.7, 124.9, 121.3, 120.7, 116.9, 54.9, 44.2, 30.7, 24.5, 22.6, 22.4

HRMS Calcd. for C28H24F6N2 [M+H]+: 503.1916, Found: 503.1919









[a]32D- 43.40 (c 0.78, CHC13)

(SE)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methylene)-1,1-

diphenylmethanamine (4-13)





V/ Ph
N N
Ph



46.0 mg (0.100 mmol, 72.9%) of (S,E)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-

yl)(phenyl)methylene)- 1,1-diphenylmethanamine was obtained from 40.0 mg (0.137 mmol) of

(S)-(3-isobutyl-3,4-dihydroisoquinolin- 1 -yl)(phenyl)methanone, 37.9 iL (0.274 mmol) of Et3N,

118 iL (0.685 mmol) of diphenylmethanamine and 165 iL of TiC14(1 M in toluene).

H NMR (300MHz ,CHLOROFORM-d) 6 = 7.96 (d, J= 10.0 Hz, 2 H), 7.52 7.12 (m, 15

H), 6.94 (br. s., 1 H), 6.89- 6.55 (m, 1 H), 5.91 5.73 (m, 1 H), 4.09- 3.85 (m, 1 H), 3.13- 2.89

(m, 1 H), 2.83 2.65 (m, 1 H), 2.12 1.66 (m, 2 H), 1.58 1.41 (m, 1 H), 0.97 (d, J= 6.4 Hz, 6

H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 164.5, 144.2, 137.9, 137.7, 136.6, 136.0,

131.6, 130.6, 128.4, 128.3, 127.5, 127.4, 126.9, 70.0, 54.9, 44.8, 31.9, 31.6, 24.8, 23.0

HRMS Calcd. for C33H32N2 [M+H]+: 457.2638, Found: 457.2638

[a]32D- 88.80 (c 1.08, CHC13)

(SE)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methylene)anthracen-9-

amine (4-68)




















36.0 mg (0.0773 mmol, 75.0%) of (S,E)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-

yl)(phenyl)methylene)anthracen-9-amine was obtained from 30.0 mg (0.103 mmol) of (S)-(3-

isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methanone, 100 iL (0.723 mmol) of Et3N, 100 mg

(0.435 mmol) of anthracen-9-aminium chloride and 125 iL of TiC14(1 M in toluene).

'H NMR (300MHz ,CHLOROFORM-d) 6 = 8.27 (d, J= 6.7 Hz, 2 H), 8.14 7.86 (m, 3

H), 7.86 7.65 (m, 2 H), 7.65 7.45 (m, 3 H), 7.45 7.12 (m, 4 H), 7.03 (d, J= 7.6 Hz, 1 H),

6.95 6.76 (m, 1 H), 6.76 6.52 (m, 2 H), 3.29 (s, 1 H), 1.94 1.72 (m, J= 7.3 Hz, 1 H), 1.67 -

1.47 (m, 1 H), 1.19 (dt, J= 7.1, 13.7 Hz, 1 H), 0.99 0.82 (m, 2 H), 0.76 (t, J= 7.0 Hz, 6 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 168.0, 163.7, 143.7, 137.2, 131.8, 131.6,

131.4, 130.2, 129.2, 128.9, 127.8, 127.3, 126.9, 126.1, 125.4, 125.3, 125.2, 123.9, 121.7, 54.7,

30.8, 29.9, 24.5, 22.8, 22.7

HRMS Calcd. for C34H30N2 [M+H]+: 467.2482, Found: 467.2487

[a]28D- 252.90 (c 0.5, CHC13)

(S)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methylene)-2,6-

diisopropylaniline (4-16)




















217 mg (0.482 mmol, 70.6%) of (S)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-

yl)(phenyl)methylene)-2,6-diisopropylaniline was obtained from 200 mg (0.686 mmol) of(S)-(3-

isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methanone, 190 [tL (1.37 mmol) of Et3N, 647 itL

(3.43 mmol) of 2,6-diisopropylaniline and 820 [iL of TiC14 (1 M in toluene).

1H NMR (300 MHz, CHLOROFORM-d) 6 = 8.07 (d, J=6.5 Hz, 2 H), 7.42 7.58 (m, 3 H),

7.19- 7.26 (m, 1 H), 6.80 7.15 (m, 6 H), 3.54 (br. s., 1 H), 3.00 3.15 (m, 1 H), 2.78 (br. s., 1

H), 2.38 (dd, J=15.5, 4.7 Hz, 1 H), 1.84 (dt, J=13.1, 6.8 Hz, 2 H), 1.55 (dt, J=13.7, 7.1 Hz, 1 H),

0.80- 1.30 (m, 19 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 163.5, 163.2, 146.2, 137.4, 137.1, 136.7,

135.6, 131.0, 130.4, 128.6, 128.3, 127.5, 126.6, 125.7, 123.1, 121.7, 54.7, 44.2, 31.2, 28.5, 28.4,

24.5, 24.0, 23.0, 22.6, 20.9, 20.8

HRMS Calcd. for C32H38N2 [M+H] : 451.3108, Found: 451.3106

[a]20D- 8.70 (c 0.96, CHC13)

(S)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methylene)-2,4,6-

trimethylaniline (4-12)



















To a flame-dried Schlenk flask was added 204 mg (0.700 mmol) of (S)-(3-isobutyl-3,4-

dihydroisoquinolin-l-yl)(phenyl)methanone, 194 [L (1.40 mmol) of Et3N, 492 [L (3.50 mmol)

of mesitylamine and 8 mL (0.1 M) of toluene. The reaction mixture was cooled to 0 C, and 840

IL of TiC14 solution (1 M in toluene) was slowly added. After 10 min stirring at 0 C, the

reaction mixture was stirred at room temperature for 12 h. It was quenched by 4 mL of a

saturated NH4C1 aqueous solution. The reaction mixture was extracted with DCM (3 x 20 mL)

and dried over anhydrous MgSO4. All volatiles were removed in vacuo. Silicagel column

chromatography with a 99:1 mixture of hexane and ethyl acetate as the eluent gave 280 mg

(0.685 mmol, 97.8%) of (S)-N-((3-isobutyl-3,4-dihydroisoquinolin-l-yl)(phenyl)methylene)-

2,4,6-trimethylaniline.

H NMR (300 MHz, CHLOROFORM-d) 6 = 7.95 8.14 (m, 2 H), 7.40 7.58 (m, 3 H),

7.19 7.27 (m, 1 H), 7.01 7.14 (m, 3 H), 6.67 (br. s., 1 H), 6.55 (br. s., 1 H), 3.56 (dd, J=11.9,

5.4 Hz, 1 H), 2.46 (dd, J=15.5, 5.0 Hz, 1 H), 2.17 (s, 3 H), 2.10 (br. s., 3 H), 1.75 2.00 (m, 4 H),

1.52 1.63 (m, 1 H), 1.23 1.34 (m, 2 H), 0.91 (dd, J=10.7, 6.6 Hz, 6 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 165.6, 163.2, 145.7, 137.3, 136.9, 131.8,

131.0, 130.6, 128.6, 128.3, 127.9, 127.6, 127.4, 126.2, 126.0, 54.7, 44.4, 31.3, 30.3, 29.7, 24.5,

22.8, 22.6, 20.6

HRMS Calcd. for C29H32N2 [M+H] : 409.2638, Found: 409.2640

[a]20D- 28.20 (c 0.97, CHC13)









(S,E)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methylene)-3,5-

dimethylaniline (4-17)





V / \
N N





69.0 mg (0.175 mmol, 45.1%) of (S,E)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-

yl)(phenyl)methylene)-3,5-dimethylaniline was obtained from 113 mg (0.388 mmol) of(S)-(3-

isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methanone, 107 iL (0.776 mmol) of Et3N, 242 iL

(1.94 mmol) of 3,5-dimethylaniline and 465 |L of TiC14(1 M in toluene).

1H NMR (300MHz ,CHLOROFORM-d) 6 = 8.25 7.99 (m, 1 H), 7.93 (br. s., 1 H), 7.59

(d, J= 7.3 Hz, 1 H), 7.51 7.20 (m, 4 H), 7.17 7.04 (m, 2 H), 6.79 6.25 (m, 3 H), 3.99 3.61

(m, 1 H), 3.08 2.46 (m, 2 H), 2.39 2.04 (m, 6 H), 1.94 (dd, J= 6.7, 13.5 Hz, 1 H), 1.85 1.61

(m, 1 H), 1.50 (dd, J= 6.9, 13.6 Hz, 1 H), 1.03 0.77 (m, 6 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 164.3, 150.6, 137.7, 137.5, 136.4, 134.0,

131.7, 131.2, 130.7, 128.6, 128.3, 127.9, 127.3, 127.1, 126.5, 125.5, 118.5, 113.3, 55.3, 44.5,

31.4, 25.0, 24.8, 23.1, 22.8, 21.4

[a]29 27.40 (c 1.58, CHC13)

HRMS Calcd. for C28H30N2 [M+H]+: 395.2482, Found: 395.2484

(S,E)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methylene)-2,6-

dimethylaniline (4-66)



















99.0 mg (0.234 mmol, 68.2%) of (S,E)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-

yl)(phenyl)methylene)-2,6-dimethylaniline was obtained from 100 mg (0.343 mmol) of(S)-(3-

isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methanone, 94.9 [iL (0.686 mmol) of Et3N, 210 [tL

(1.72 mmol) of 2,6-dimethylaniline and 410 [iL of TiC14(1 M in toluene).

'H NMR (300MHz ,CHLOROFORM-d) 6 = 8.05 (d, J= 7.0 Hz, 1 H), 7.62 7.39 (m, 3

H), 7.35 7.17 (m, 2 H), 7.16 6.93 (m, 3 H), 6.91 6.60 (m, 3 H), 3.53 (td, J= 6.4, 12.2 Hz, 1

H), 2.41 (dd, J= 5.0, 15.5 Hz, 1 H), 2.22 2.04 (m, 3 H), 2.01 1.74 (m, 4 H), 1.63 1.50 (m, 1

H), 1.39- 1.18 (m, 2 H), 0.89 (d, J= 10.3 Hz, 3 H), 0.91 (d, J= 10.6 Hz, 3 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 165.7, 163.3, 148.4, 137.4, 131.3, 130.9,

128.9, 128.5, 127.8, 127.5, 126.5, 126.1, 123.0, 54.9, 44.9, 31.5, 24.8, 23.0, 22.9, 19.2, 18.5

HRMS Calcd. for C28H30N2 [M+H]+: 395.2482, Found: 395.2487

[al]32- 25.30 (c 1.58, CHC13)

(S,E)-2,6-diethyl-N-((3-isobutyl-3,4-dihydroisoquinolin-1-

yl)(phenyl)methylene)aniline (4-65)










26.0 mg (0.0615 mmol, 71.7%) of (S,E)-2,6-diethyl-N-((3-isobutyl-3,4-dihydroisoquinolin-

1-yl)(phenyl)methylene)aniline was obtained from 25.0 mg (0.0857 mmol) of (S)-(3-isobutyl-

3,4-dihydroisoquinolin-1-yl)(phenyl)methanone, 23.6 [L (0.171 mmol) of Et3N, 66.6 [L (0.428

mmol) of 2,6-diethylaniline and 103 iL of TiC14 (1 M in toluene).

'H NMR (300MHz ,CHLOROFORM-d) 6 = 8.04 (d, J= 6.7 Hz, 2 H), 7.59 7.39 (m, 3

H), 7.25- 7.18 (m, 1 H), 7.14 6.97 (m, 3 H), 6.95 6.69 (m, 3 H), 3.48 (dd, J= 5.1, 11.9 Hz, 1

H), 2.60 (dt, J= 7.6, 15.2 Hz, 1 H), 2.49 2.32 (m, 3 H), 1.95 1.70 (m, 1 H), 1.63 1.41 (m, 2

H), 1.34 1.04 (m, 5 H), 1.03 0.78 (m, 9 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 164.9, 163.3, 137.4, 137.3, 132.6, 131.7,

131.3, 130.8, 128.9, 128.6, 127.7, 126.5, 126.0, 124.9, 123.2, 54.8, 31.5, 29.9, 25.2, 24.7, 24.5,

23.0, 22.8, 13.5, 13.2

HRMS Calcd. for C30H34N2 [M+H]+: 423.2795, Found: 423.2795

[a]29D- 18.40 (c 0.79, CHC13)

(S,E)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methylene)-2-

isopropylaniline (4-24)




/ \
N N





42.0 mg (0.102 mmol, 71.7%) of (S,E)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-

yl)(phenyl)methylene)-2-isopropylaniline was obtained from 33.0 mg (0.113 mmol) of(S)-(3-









isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methanone, 31.0 [iL (0.226 mmol) of Et3N, 80.0

[iL (0.560 mmol) of 2-isopropylaniline and 136 [iL of TiC14 (1 M in toluene).

'H NMR (299MHz ,CHLOROFORM-d) 6 = 8.00 (d, J= 6.2 Hz, 2 H), 7.54 7.37 (m, 3

H), 7.33 7.23 (m, 1 H), 7.21 7.05 (m, 4 H), 7.00 6.77 (m, 2 H), 6.63 (br. s., 1 H), 3.80 3.62

(m, 1 H), 3.23 (br. s., 1 H), 2.67 (dd, J= 4.5, 14.7 Hz, 1 H), 1.88 1.65 (m, 1 H), 1.56 (dd, J=

6.4, 12.9 Hz, 1 H), 1.40 1.04 (m, 8 H), 1.02 0.72 (m, 6 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 164.1, 148.0, 140.0, 137.5, 136.6, 131.2,

130.7, 128.7, 128.7, 128.0, 127.1, 126.3, 125.2, 124.5, 119.0, 54.8, 53.7, 44.5, 31.4, 28.4, 24.7,

23.0, 22.7

(SE)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methylene)-2,4-

dimethylaniline (4-25)





-N N .




41.0 mg (0.104 mmol, 71.7%) of (S,E)-N-((3-isobutyl-3,4-dihydroisoquinolin-l-

yl)(phenyl)methylene)-2,4-dimethylaniline was obtained from 35.0 mg (0.120 mmol) of(S)-(3-

isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methanone, 33.0 [L (0.240 mmol) of Et3N, 75.0

[L (0.600 mmol) of 2,4-dimethylaniline and 144 iL of TiC14 (1 M in toluene).

SH NMR (300MHz ,CHLOROFORM-d) 6 = 8.04 7.90 (m, 2 H), 7.54 7.34 (m, 3 H),

7.32 7.21 (m, 1 H), 7.19 7.02 (m, 3 H), 6.83 (s, 1 H), 6.73 6.51 (m, 2 H), 3.84 3.62 (m, 1

H), 2.79 2.57 (m, 1 H), 2.34 2.07 (m, 7 H), 1.67 1.48 (m, 1 H), 1.39- 1.19 (m, 2 H), 0.94 -

0.80 (m, 6 H)









3C NMR (75MHz ,CHLOROFORM-d) 6 = 164.4, 146.6, 137.4, 136.6, 134.1, 133.4,

131.1, 130.8, 129.4, 128.7, 128.6, 128.1, 127.1, 126.3, 126.0, 118.8, 55.3, 54.9, 44.5, 31.3, 24.8,

23.0, 21.0, 18.5

(S,E)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methylene)biphenyl-2-amine

(4-26)






N N "


Ph

42.0 mg (0.0948 mmol, 71.7%) of (S,E)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-

yl)(phenyl)methylene)biphenyl-2-amine was obtained from 31.4 mg (0.107 mmol) of (S)-(3-

isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methanone, 30.0 pL (0.215 mmol) of Et3N, 91.0

mg (0.535 mmol) of biphenyl-2-amine and 129 iL of TiC14 (1 M in toluene).

H NMR (299MHz ,CHLOROFORM-d) 6 = 7.86 (d, J= 7.1 Hz, 2 H), 7.59 7.51 (m, 2

H), 7.49 7.29 (m, 5 H), 7.28 7.00 (m, 6 H), 6.93 6.76 (m, 2 H), 6.58 (d, J= 7.4 Hz, 1 H),

3.77 3.58 (m, 1 H), 2.68 (dd, J= 3.8, 16.0 Hz, 1 H), 1.97 1.70 (m, 1 H), 1.70 1.49 (m, 1 H),

1.40- 1.18 (m, 2H), 1.02 0.64 (m, 6 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 164.7, 163.8, 148.3, 140.3, 137.2, 136.4,

132.8, 131.1, 130.9, 130.7, 130.1, 129.8, 129.3, 129.0, 128.6, 128.0, 127.8, 127.4, 127.2, 126.7,

126.5, 124.4, 120.7, 115.8, 54.8, 44.5, 31.4, 24.7, 23.1, 22.7

(R,E)-N-((3-cyclohexyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methylene)-2,4,6-

trimethylaniline (4-38)



















204 mg (0.470 mmol, 99.6%) of (R,E)-N-((3-cyclohexyl-3,4-dihydroisoquinolin-1-

yl)(phenyl)methylene)-2,4,6-trimethylanilinewas obtained from 150 mg (0.472 mmol) of (R)-(3-

cyclohexyl-3,4-dihydroisoquinolin- 1 -yl)(phenyl)methanone, 130 [L (0.945 mmol) of Et3N, 332

[L (2.36 mmol) of 2,4,6-trimethylaniline and 570 iL of TiC14 (1 M in toluene).

'H NMR (299MHz ,CHLOROFORM-d) 6 = 8.07 (dd, J= 1.4, 7.9 Hz, 2 H), 7.63 7.39

(m, 3 H), 7.35 6.99 (m, 4 H), 6.71 (br. s., 1 H), 6.55 (br. s., 1 H), 3.22 (dt, J= 5.3, 13.9 Hz, 1

H), 2.44 (dd, J= 4.8, 15.6 Hz, 1 H), 2.19 (s, 6 H), 2.14 1.98 (m, 1 H), 1.89 (br. s., 1 H), 1.86 -

1.46 (m, 8 H), 1.40 1.00 (m, 5 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 165.7, 163.3, 145.8, 137.9, 137.6, 131.7,

131.0, 130.5, 128.6, 128.3, 128.0, 127.6, 126.7, 126.2, 125.4, 62.1, 42.6, 29.6, 29.4, 28.0, 26.7,

26.5, 20.7, 19.2, 18.2

(E)-N-(((4aR, 1bR)-1,2,3,4,4a,10b-hexahydrophenanthridin-6-yl)(phenyl)methylene)-

2,4,6-trimethylaniline (4-42)



Ph

N N



67.0 mg (0.164 mmol, 95.3%) of(E)-N-(((4aR,10bR)-1,2,3,4,4a,10b-

hexahydrophenanthridin-6-yl)(phenyl)methylene)-2,4,6-trimethylaniline was obtained from 50









mg (0.172 mmol) of ((4aR, 10bR)-1,2,3,4,4a, 10b-hexahydrophenanthridin-6-

yl)(phenyl)methanone, 48.0 [L (0.345 mmol) of Et3N, 121 [L (0.860 mmol) of 2,4,6-

trimethylaniline and 206 iL of TiC14 (1 M in toluene).

1H NMR (300MHz ,CHLOROFORM-d) 6 = 8.10 8.02 (m, 2 H), 7.57 7.41 (m, 3 H),

7.33 7.23 (m, 1 H), 7.18 7.02 (m, 3 H), 6.74 (br. s., 1 H), 6.50 (s, 1 H), 3.71 3.63 (m, 1 H),

2.50- 2.38 (m, 1 H), 2.32 2.11 (m, 8 H), 1.78- 1.57 (m, 4 H), 1.55- 1.43 (m, 1 H), 1.42- 1.20

(m, 3 H), 1.14 (d, J= 12.3 Hz, 1 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 166.2, 165.2, 146.4, 143.3, 137.8, 132.1,

131.5, 131.4, 128.9, 128.5, 128.2, 127.9, 127.5, 127.3, 126.3, 125.9, 125.1, 56.7, 38.0, 31.9, 27.1,

22.9, 20.8, 19.7, 18.2, 14.4

(S)-2-(3,5-bis(trifluoromethyl)phenyl)-5-isobutyl-l-phenyl-5,6-dihydro-2H-

imidazo[5,1-a]isoquinolin-4-ium chloride (4-71)





N- CCF3
NN


CP
CF3

21.0 mg (0.0381 mmol, 70.9%) of (S)-2-(3,5-bis(trifluoromethyl)phenyl)-5-isobutyl-1-

phenyl-5,6-dihydro-2H-imidazo[5, 1-a]isoquinolin-4-ium chloride was obtained from 27.0 mg

(0.0537 mmol) of (S,E)-N-((3-isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methylene)-3,5-

bis(trifluoromethyl)aniline and 29.8 [iL (0.322 mmol) of chloromethyl ethyl ether.









'H NMR (299MHz ,CHLOROFORM-d) 6 = 10.88 (br. s., 1 H), 8.32 6.48 (m, 12 H), 5.33

(br. s., 1 H), 3.56 (d, J= 16.7 Hz, 1 H), 3.06 (d, J= 15.6 Hz, 1 H), 2.03 1.61 (m, 3 H), 1.20 -

0.76 (m, 6 H)

13C NMR (75MHz ,CHLOROFORM-d) 6= 136.7, 134.7, 133.5, 133.1, 131.8, 131.8,

131.3, 131.0, 130.6, 129.9, 129.7, 127.8, 126.9, 124.7, 124.5, 124.0, 123.9, 114.3, 54.4, 41.6,

32.5, 24.9, 22.9, 21.7

HRMS Calcd. for C29H25F6N2 [M]+: 515.1916, Found: 515.1932

[a]32D-11.8o (c 0.65, CHC13)

(S)-2-benzhydryl-5-isobutyl-l-phenyl-5,6-dihydro-2H-imidazo[5,1-a]isoquinolin-4-

ium chloride (4-73)





N,,N Ph

CP Ph


30.0 mg (0.0594 mmol, 90.3%) of (S)-2-benzhydryl-5-isobutyl-l-phenyl-5,6-dihydro-2H-

imidazo[5,1-a]isoquinolin-4-ium chloride was obtained from 30.0 mg (0.0658 mmol) of (S,E)-N-

((3-isobutyl-3,4-dihydroisoquinolin-l-yl)(phenyl)methylene)-l,1-diphenylmethanamine and 36.5

[L (0.394 mmol) of chloromethyl ethyl ether.

H NMR (300MHz ,CHLOROFORM-d) 6 = 9.96 (s, 1 H), 7.85 7.49 (m, 2 H), 7.49 7.11

(m, 14 H), 7.11 6.88 (m, 2 H), 6.78 (d, J= 7.6 Hz, 1 H), 6.31 (s, 1 H), 5.68 (br. s., 1 H), 3.59

(br. s., 1 H), 2.97 (d, J= 16.1 Hz, 1 H), 1.64 1.37 (m, 3 H), 0.96 0.82 (m, 6 H)









3C NMR (75MHz ,CHLOROFORM-d) 6 = 136.1, 135.8, 132.0, 131.3, 130.3, 129.9,

129.8, 129.4, 129.2, 128.8, 128.5, 127.6, 125.8, 124.4, 122.9, 66.3, 53.8, 41.9, 32.5, 25.3, 23.2,

22.2

HRMS Calcd. for C34H33N2 [M]+: 469.2638, Found: 469.2641

[a]29D+ 36.60 (c 0.73, CHC13)

(S)-2-(anthracen-9-yl)-5-isobutyl-1-phenyl-5,6-dihydro-2H-imidazo[5,1-a]isoquinolin-

4-ium chloride (4-72)





N N


Cl1


20.0 mg (0.0388 mmol, 90.4%) of (S)-2-(anthracen-9-yl)-5-isobutyl-1-phenyl-5,6-dihydro-

2H-imidazo[5,1-a]isoquinolin-4-ium chloride was obtained from 20.0 mg (0.0429 mmol) of

(S,E)-N-((3-isobutyl-3,4-dihydroisoquinolin- 1-yl)(phenyl)methylene)anthracen-9-amine and 24.5

[L (0.264 mmol) of chloromethyl ethyl ether.

H NMR (300MHz ,CHLOROFORM-d) 6 = 10.51 (br. s., 1 H), 8.59 (s, 1 H), 8.09 (d, J=

8.5 Hz, 1 H), 7.96 (d, J= 8.5 Hz, 1 H), 7.73 7.33 (m, 8 H), 7.23 6.93 (m, 7 H), 5.94 (br. s., 1

H), 3.86 (br. s., 1 H), 3.19 (d, J= 11.7 Hz, 1 H), 1.85 (br. s., 1 H), 1.73 (br. s., 2 H), 1.06 (d, J=

5.6 Hz, 3 H), 1.09 (d, J= 5.6 Hz, 3 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 138.5, 132.4, 131.9, 131.3, 130.9, 130.8,

130.6, 130.1, 129.5, 129.4, 129.1, 128.7, 127.8, 126.6, 126.1, 125.3, 124.8, 123.7, 123.0, 121.9,

120.6, 54.3, 42.3, 33.0, 25.5, 23.3, 22.4









HRMS Calcd. for C35H31N2 [M] : 479.2482, Found: 479.2488

[a]28D+19.2 (c 0.7, CHC13)

(S)-2-(2,6-diisopropylphenyl)-5-isobutyl-l-phenyl-5,6-dihydro-2H-imidazo[5,1-

a]isoquinolin-4-ium chloride (4-20)









CI


60.0 mg (0.120 mmol, 75.5%) of (S)-2-(2,6-diisopropylphenyl)-5-isobutyl-1-phenyl-5,6-

dihydro-2H-imidazo[5,1-a]isoquinolin-4-ium chloride was obtained from 72.0 mg (0.159 mmol)

of ((S)-N-((3 -i sobutyl-3,4-dihydroisoquinolin- 1 -yl)(phenyl)methylene)-2,6-dii sopropylaniline

and 83.5 [L (0.954 mmol) of chloromethyl ethyl ether.

H NMR (300 MHz, CHLOROFORM-d) 6 = 10.63 (s, 1 H), 7.16 7.50 (m, 6 H), 6.79 -

7.16 (m, 6 H), 5.74 6.00 (m, 1 H), 3.70 (dd, J=16.1, 4.7 Hz, 1 H), 3.01 (d, J=16.4 Hz, 1 H),

2.53 (br. s., 1 H), 2.42 (dt, J=13.7, 6.8 Hz, 1 H), 2.27 (dt, J=13.3, 6.5 Hz, 1 H), 1.41 1.61 (m, 2

H), 0.41 1.36 (m, 18 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 145.9, 145.4, 137.2, 131.9, 131.5, 130.6,

130.3, 129.9, 129.7, 129.1, 128.1, 127.3, 125.6, 125.0, 124.7, 124.5, 124.0, 122.3, 53.1, 41.8,

32.9, 31.4, 29.1, 28.8, 26.0, 25.5, 24.8, 22.5, 22.3, 22.1

HRMS Calcd. for C33H39C1N2 [M]+: 463.3108, Found: 463.3108

[a]29D- 38.10 (c 0.90, CHCl3)









(S)-5-isobutyl-2-mesityl-l-phenyl-5,6-dihydro-2H-imidazo[5,1-a]isoquinolin-4-ium

chloride (4-14)





N IN

Cl


To a flame-dried Schlenk flask was added 225 mg (0.551 mmol) of (S)-N-((3-isobutyl-3,4-

dihydroisoquinolin-l-yl)(phenyl)methylene)-2,4,6-trimethylaniline, 256 [L (2.75 mmol) of

chloromethyl ethyl ether and 28 mL (0.02M) of THF. After 48 h, all volatiles were removed in

vacuo. Silicagel column chromatography with a 95:5 mixture of DCM and methanol as the

eluent gave 220 mg (0.481 mmol, 87.3%) of (S)-5-isobutyl-2-mesityl-l-phenyl-5,6-dihydro-2H-

imidazo[5,1 -a]isoquinolin-4-ium chloride.

'H NMR (299 MHz, CHLOROFORM-d) 6 = 10.35 (s, 1 H), 7.30 7.48 (m, 5 H), 7.04 -

7.24 (m, 4 H), 6.93 (s, 1 H), 6.76 (s, 1 H), 5.63 (br. s., 1 H), 3.64 (dd, J=16.0, 4.1 Hz, 1 H), 3.07

(d, J=15.9 Hz, 1 H), 2.18 (s, 3 H), 2.23 (s, 3 H), 1.90 (s, 3 H), 1.47 1.72 (m, 3 H), 0.99 (dd,

J=9.1, 6.2 Hz, 3 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 140.8, 136.8, 135.1, 134.4, 131.7, 130.6,

130.2, 129.8, 129.7, 129.3, 129.2, 128.9, 127.4, 125.8, 125.3, 124.4, 122.6, 53.5, 41.8, 32.7, 25.0,

22.8, 22.0, 21.0, 17.9

HRMS Calcd. for C30H33N2 [M]+: 421.2638, Found: 421.2646

[a]29 230 (c 1.06, CHC13)

(S)-2-(3,5-dimethylphenyl)-5-isobutyl-l-phenyl-5,6-dihydro-2H-imidazo[5,1-

a]isoquinolin-4-ium chloride (4-21)



















37.0 mg (0.0835 mmol, 84.5%) of ((S)-2-(3,5-dimethylphenyl)-5-isobutyl- -phenyl-5,6-

dihydro-2H-imidazo[5,1-a]isoquinolin-4-ium chloride was obtained from 39.0 mg (0.0988

mmol) of (S,E)-N-((3-isobutyl-3,4-dihydroisoquinolin-l-yl)(phenyl)methylene)-3,5-

dimethylaniline and 91.6 [L (0.988 mmol) of chloromethyl ethyl ether.

H NMR (299MHz ,CHLOROFORM-d) 6 = 10.59 (s, 1 H), 7.51 7.34 (m, 3 H), 7.31 -

7.21 (m, 4 H), 7.11 6.93 (m, 3 H), 6.85 (s, 2 H), 5.69 5.58 (m, 1 H), 3.53 (dd, J= 4.8, 16.1 Hz,

1 H), 3.02 (d, J= 15.6 Hz, 1 H), 2.18 (s, 6 H), 1.80 1.61 (m, 2 H), 1.56 1.44 (m, 1 H), 0.99 (d,

J= 6.2 Hz, 6 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 139.9, 135.9, 133.1, 132.0, 131.0, 130.8,

130.3, 129.8, 129.5, 129.1, 127.7, 126.1, 125.7, 124.5, 123.7, 122.9, 53.7, 41.9, 32.7, 25.2, 23.2,

22.0, 21.2

HRMS Calcd. for C29H31N2 [M]+: 407.2482, Found: 407.2487

[a]29D- 24.20 (c 0.7, CHC13)

(S)-2-(2,6-dimethylphenyl)-5-isobutyl-l-phenyl-5,6-dihydro-2H-imidazo[5,1-

a]isoquinolin-4-ium chloride (4-70)



















40.0 mg (0.0903 mmol, 47.8%) of (S)-2-(2,6-dimethylphenyl)-5-isobutyl-l-phenyl-5,6-

dihydro-2H-imidazo[5, 1-a]isoquinolin-4-ium chloride was obtained from 80.0 mg (0.189 mmol)

of (S,E)-N-((3-isobutyl-3,4-dihydroisoquinolin- -yl)(phenyl)methylene)-2,6-dimethylaniline and

105 [L (1.14 mmol) of chloromethyl ethyl ether.

'H NMR (299MHz ,CHLOROFORM-d) 6 = 10.60 (s, 1 H), 7.48 7.30 (m, 5 H), 7.26 -

7.07 (m, 6 H), 7.00 (d, J= 7.4 Hz, 1 H), 5.83 5.72 (m, 1 H), 3.75 3.61 (m, 1 H), 3.10 (dd, J=

2.0, 16.1 Hz, 1 H), 2.26 (s, 3 H), 1.99 (s, 3 H), 1.80 1.49 (m, 3 H), 1.04 (dd, J= 6.2, 8.5 Hz, 6

H)

3C NMR (75MHz ,CHLOROFORM-d) 6= 137.2, 136.0, 135.1, 132.2, 131.8, 131.1,

131.0, 130.6, 130.0, 129.5, 129.0, 127.7, 126.2, 125.6, 124.7, 122.9, 53.9, 42.1, 33.0, 29.9, 25.4,

23.2, 22.4, 18.4

HRMS Calcd. for C29H31N2 [M]+: 407.2482, Found: 407.2490

[a]29D- 38.80 (c 0.77, CHC13)

(S)-2-(2,6-diethylphenyl)-5-isobutyl-l-phenyl-5,6-dihydro-2H-imidazo[5,1-

a]isoquinolin-4-ium chloride (4-69)




















14.0 mg (0.0297 mmol, 85%) of ((S)-2-(2,6-diethylphenyl)-5-isobutyl-l-phenyl-5,6-

dihydro-2H-imidazo[5,1-a]isoquinolin-4-ium chloride was obtained from 15.0 mg (0.0355

mmol) of (S,E)-2,6-diethyl-N-((3-isobutyl-3,4-dihydroisoquinolin-1-

yl)(phenyl)methylene)aniline and 19.7 [L (0.213 mmol) of chloromethyl ethyl ether.

1H NMR (299MHz ,CHLOROFORM-d) 6 = 10.75 (s, 1 H), 7.47 7.29 (m, 6 H), 7.28 -

7.03 (m, 6H), 5.95 (d, J= 4.5 Hz, 1 H), 3.71 (dd, J= 4.2, 16.1 Hz, 1 H), 3.10 (d, J= 16.1 Hz, 1

H), 2.63 2.33 (m, 2 H), 2.05 (dd, J= 7.4, 15.3 Hz, 1 H), 1.83 1.41 (m, 4 H), 1.42- 1.17 (m, 5

H), 1.15- 0.94 (m, 7H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 141.2, 140.8, 137.3, 132.1, 131.4, 130.9,

130.5, 130.3, 130.0, 129.6, 129.4, 127.6, 126.9, 126.7, 126.0, 125.4, 124.7, 122.8, 53.6, 42.0,

33.0, 25.3, 24.6, 23.9, 23.1, 22.5, 15.0, 13.8

HRMS Calcd. for C31H35N2 [M]+: 435.2795, Found: 435.2801

[a]29D- 34.00 (c 0.92, CHC13)

(S)-5-isobutyl-2-(2-isopropylphenyl)-l-phenyl-5,6-dihydro-2H-imidazo[5,1-

a]isoquinolin-4-ium chloride (4-30)



















25.0 mg (0.0547 mmol, 85.0%) of (S)-5-isobutyl-2-(2-isopropylphenyl)-l-phenyl-5,6-

dihydro-2H-imidazo[5,1-a]isoquinolin-4-ium chloride was obtained from 30.0 mg (0.0744

mmol) of (S,E)-N-((3-isobutyl-3,4-dihydroisoquinolin-l-yl)(phenyl)methylene)-2-

isopropylaniline and 65.0 [L (0.744 mmol) of chloromethyl ethyl ether.

(S)-2-(2,4-dimethylphenyl)-5-isobutyl-l-phenyl-5,6-dihydro-2H-imidazo[5,1-

a]isoquinolin-4-ium chloride (4-31)








CIo

22.0 mg (0.0497 mmol, 66.7%) of (S)-2-(2,4-dimethylphenyl)-5-isobutyl-l-phenyl-5,6-

dihydro-2H-imidazo[5,1-a]isoquinolin-4-ium chloride was obtained from 30.0 mg (0.0744

mmol) of (S,E)-N-((3-isobutyl-3,4-dihydroisoquinolin-l-yl)(phenyl)methylene)-2,4-

dimethylaniline and 65.0 [L (0.744 mmol) of chloromethyl ethyl ether.

H NMR (300MHz ,CHLOROFORM-d) 6 = 10.49 (br. s., 1 H), 7.53 7.17 (m, 8 H), 7.17 -

6.78 (m, 4 H), 5.66 (br. s., 1 H), 3.68 3.54 (m, 1 H), 3.06 (d, J= 15.8 Hz, 1 H), 2.27 (s, 6 H),

1.81 1.60 (m, 2 H), 1.58 1.46 (m, 1 H), 1.08 0.88 (m, 6 H)









3C NMR (75MHz ,CHLOROFORM-d) 6 = 141.4, 136.9, 132.4, 132.1, 130.8, 130.6,

130.5, 130.0, 129.5, 128.9, 128.0, 127.7, 125.9, 125.7, 124.6, 123.0, 53.9, 42.0, 32.9, 25.3, 23.3,

22.2, 21.4, 17.9

(S)-5-isobutyl-2-(2-methoxyphenyl)-l-phenyl-5,6-dihydro-2H-imidazo[5,1-

a]isoquinolin-4-ium chloride (4-33)






NCIO N




23.0 mg (0.0517 mmol, 66.7%) of (S)-5-isobutyl-2-(2-methoxyphenyl)-l-phenyl-5,6-

dihydro-2H-imidazo[5,1-a]isoquinolin-4-ium chloride was obtained from 15.8 mg (0.0544

mmol) of (S)-(3-isobutyl-3,4-dihydroisoquinolin-1-yl)(phenyl)methanone.

H NMR (300MHz ,CHLOROFORM-d) 6 = 10.44 (s, 1 H), 7.52 7.16 (m, 9 H), 7.16 -

6.98 (m, 2 H), 6.98 6.68 (m, 2 H), 5.78 5.59 (m, 1 H), 3.68 (s, 3 H), 3.59 (dd, J= 4.8, 16.3 Hz,

1 H), 3.04 (d, J= 15.0 Hz, 1 H), 1.85 1.63 (m, 2 H), 1.60 1.43 (m, 1 H), 0.99 (d, J= 6.2 Hz, 3

H), 1.03 (d, J= 6.4 Hz, 3 H)

3C NMR (75MHz ,CHLOROFORM-d) 6 = 153.9, 137.2, 132.5, 132.0, 130.6, 130.3,

129.9, 129.2, 128.9, 127.7, 126.0, 125.6, 124.5, 123.2, 122.0, 121.3, 112.3, 56.0, 53.9, 42.0, 33.1,

25.2, 23.4, 22.3

(4aR,8aR)-2-mesityl-1-phenyl-4a,5,6,7,8,8a-hexahydro-2H-imidazo[1,5-

f]phenanthridin-4-ium chloride (4-43)











SPh

CN N




15.0 mg (0.0357 mmol, 36.5%) of (4aR,8aR)-2-mesityl-l-phenyl-4a,5,6,7,8,8a-hexahydro-

2H-imidazo[1,5-J]phenanthridin-4-ium chloride (4-43a) and 15.0 mg (0.0357 mmol, 36.5%) of

(4aR,8aR)-2-mesityl-1-phenyl-4a,5,6,7,8,8a-hexahydro-2H-imidazo[1,5-J]phenanthridin-4-ium

chloride (4-430) were obtained from 40.0 mg (0.0980 mmol) of(E)-N-(((4aR,10bR)-

1,2,3,4,4a, 10b-hexahydrophenanthridin-6-yl)(phenyl)methylene)-2,4,6-trimethylaniline and 55.0

[iL (0.590 mmol) of chloromethyl ethyl ether.

(4-43a):

H NMR (300MHz ,CHLOROFORM-d) 6 = 9.65 (s, 1 H), 7.53 7.15 (m, 7 H), 7.15 6.98

(m, 2 H), 6.88 (s, 2 H), 5.20- 5.01 (m, 1 H), 3.55 3.38 (m, 1 H), 2.26 (s, 3 H), 2.19 1.89 (m, 8

H), 1.89 1.70 (m, 2 H), 1.70 1.44 (m, 4 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 141.4, 136.3, 135.7, 134.5, 131.0, 130.8,

130.0, 129.6, 129.1, 127.9, 127.5, 126.9, 125.6, 125.2, 122.6, 56.1, 38.9, 29.9, 28.0, 27.6, 22.1,

21.3, 18.1, 17.9

HRMS Calcd. for C30H31N2 [M]+: 419.2482, Found: 419.2517

[a]20D- 0.70 (c 1.08, CHCl3)

(4-43P)

1H NMR (300MHz ,CHLOROFORM-d) 6 = 10.39 (s, 1 H), 7.48 7.29 (m, 5 H), 7.20 (d, J

= 7.0 Hz, 2 H), 7.09 (d, J= 3.2 Hz, 2 H), 6.86 (s, 2 H), 5.27 5.06 (m, 1 H), 3.51 3.29 (m, 1 H),

2.24 (s, 3 H), 2.16- 1.91 (m, 9 H), 1.89- 1.68 (m, 2 H), 1.67-1.51 (m, 3 H)









3C NMR (75MHz ,CHLOROFORM-d) 6 = 141.2, 137.0, 136.4, 135.5, 134.6, 130.9,

130.6, 130.0, 129.7, 129.6, 129.3, 127.9, 127.5, 126.6, 125.8, 125.1, 122.7, 56.1, 38.9, 28.2, 27.6,

22.4, 22.2, 21.3, 18.3, 18.0

HRMS Calcd. for C30H31N2 [M]+: 419.2482, Found: 419.2516

[a]20D- 5.40 (c 1.08, CHC13)

6.4.2 Gold Complexes Synthesis

(S)-chloro(2-(2,6-diisopropylphenyl)-5-isobutyl-1-phenyl-5,6-dihydro-2H-imidazo[5,1-

a] isoquinolin-4-ium-3-yl)aurate(I) (4-44)






N N

Au



To a flame-dried Schlenk flask was added 33.0 mg (0.0661 mmol) of (S)-2-(2,6-

diisopropylphenyl)-5-isobutyl-1-phenyl-5,6-dihydro-2H-imidazo[5,1-a]isoquinolin-4-ium

chloride, 9.20 mg (0.0396 mmol) of Ag20 and 1.3 mL (0.05M) of DCM. After stirring for 12 h,

the reaction mixture was filtered through a pad of celite. The solvent of the filtrate was removed

under reduced pressure. To another flame-dried Schlenk flask was added the filtered silver

complex, 22.0 mg (0.0747 mmol) of AuCl*Me2S and 1.3 mL (0.05M) of DCM. The reaction

mixture was stirred for 12 h at room temperature. The reaction solution was filtered through a

pad of celite and evaporated to dryness. The residue was dissolved in ether and the solid was

discarded. Then the ethereal solution was concentrated and additional impurities were washed

away with hexane to yield 40.0 mg (0.0574 mmol, 86.8 %) of (S)-chloro(2-(2,6-









diisopropylphenyl)-5-isobutyl-1-phenyl-5,6-dihydro-2H-imidazo[5, 1-a]isoquinolin-4-ium-3-

yl)aurate(I).

H NMR (300MHz ,DICHLOROMETHANE-d2) 6 = 7.41 6.80 (m, 12 H), 5.08 (q, J=

6.2 Hz, 1 H), 3.47 (dd, J= 5.6, 15.8 Hz, 1 H), 2.99 (d, J= 16.1 Hz, 1 H), 2.71 2.50 (m, 1 H),

2.29 (dt, J= 6.6, 13.4 Hz, 1 H), 1.77 (dt, J= 6.5, 13.3 Hz, 1 H), 1.56 0.53 (m, 20 H)

13C NMR (75MHz ,DICHLOROMETHANE-d2) 6 = 170.7, 147.1, 146.7, 133.4, 132.5,

131.0, 131.0, 130.8, 130.2, 130.1, 129.4, 129.3, 128.4, 127.6, 125.6, 125.3, 124.8, 124.7, 55.1,

43.5, 34.1, 29.3, 29.1, 26.6, 26.1, 25.2, 23.7, 23.6, 22.9, 22.6

HRMS Calcd. for C33H39ClN2Au [M+NH4]+: 712.2727, Found: 712.2739

[a]29D- 12.80 (c 0.84, CHC13)

X-ray experimental for 4-44

Data were collected at 100 K on a Bruker DUO system equipped with an APEX II area

detector and a graphite monochromator utilizing MoKa radiation (X = 0.71073 A). Cell

parameters were refined using up to 9999 reflections. A hemisphere of data was collected using

the co-scan method (0.50 frame width). Absorption corrections by integration were applied based

on measured indexed crystal faces.

The structure was solved by the Direct Methods in SHELXTL6, and refined using full-

matrix least squares. The non-H atoms were treated anisotropically, whereas the hydrogen atoms

were calculated in ideal positions and were riding on their respective carbon atoms. The

asymmetric unit consists of two chemically equivalent but crystallographically independent. The

data was checked for higher symmetry, in specific checked for the possibility of the space group

being P21/m. No possible solution was found. Additionally, the two molecules in the asymmetric

unit do not have neither a mirror symmetry nor an inversion symmetry. A total of 679 parameters









were refined in the final cycle of refinement using 11154 reflections with I > 2o(I) to yield R1

and wR2 of 2.32% and 4.24%, respectively. Refinement was done using F2

SHELXTL6 (2000). Bruker-AXS, Madison, Wisconsin, USA.

Crystal data and structure refinement for 4-44

Identification code 4-44

Empirical formula C33 H38 Au Cl N2

Formula weight 695.07

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system Monoclinic

Space group P2(1)

Unit cell dimensions

a = 12.074(12) A a= 90.

b = 11.168(12) A 3= 93.82(2).

c = 22.31(2) Ay = 900.

Volume 3002(5) A3

Z 4

Density (calculated) 1.538 Mg/m3

Absorption coefficient 5.013 mm-1

F(000) 1384

Crystal size 0.15 x 0.13 x 0.03 mm3

Theta range for data collection 1.69 to 27.500.

Index ranges -15








Reflections collected 31564

Independent reflections 12574 [R(int) = 0.0246]

Completeness to theta = 27.50 100.0 %

Absorption correction Nnumerical

Max. and min. transmission 0.8642 and 0.5221

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 12574 / 1 / 679

Goodness-of-fit on F2 0.919

Final R indices [I>2sigma(I)] R1 = 0.0232, wR2 = 0.0424 [11154]

R indices (all data) R1 = 0.0300, wR2 = 0.0442

Absolute structure parameter 0.006(4)

Largest diff. peak and hole 1.341 and -0.688 e.A-3

R1 = 2(||Fol |Fcl|) / 2IFol

wR2 = [I[w(Fo2 Fc2)2] / y[w(Fo2)2]]1/2

S =[[w(Fo2 Fc2)2] / (n-p)]1/2

w= 1/[Y2(Fo2)+(m*p)2+n*p], p = [max(Fo2,0)+ 2* Fc2]/3, m & n are constants.

[6(S),8(S)-Diisobutyl-5,6,8,9-tetrahydro-6a,7a-diazadibenzo[c,g]fluoren-5-ylidene]-

chloroaurate(I) (4-45)










To a flame-dried Schlenk flask was added 15.0 mg (0.0356 mmol) of [6(S),8(S)-diisobutyl-

5,6,8,9-tetrahydro-6a,7a-diazadibenzo[c,g]fluorenium] chloride, 4.80 mg (0.0207 mmol) of

Ag20 and 700 iL (0.05M) of DCM. After stirring for 12 h, the reaction mixture was filtered

through a pad of celite. The solvent of the filtrate was removed under reduced pressure. To

another flame-dried Schlenk flask was added the filtered silver complex, 12.0 mg (0.0407 mmol)

of AuCl*Me2S and 1.3 mL (0.05M) of DCM. The reaction mixture was stirred for 12 h at room

temperature. The reaction solution was filtered through a pad of celite and evaporated to dryness.

The residue was purified by silicagel column chromatography with a 70:30 mixture of hexane

and ethyl acetate as the eluent gave 17.0 mg (0.0275 mmol, 77.2%) of [6(S),8(S)]-diisobutyl-

5,6,8,9-tetrahydro-6a,7a-diazadibenzo[c,g]fluoren-5-ylidene]- chloroaurate(I).

'H NMR (300MHz ,CHLOROFORM-d) 6 = 7.87 (d, J= 7.0 Hz, 2 H), 7.39 7.12 (m, 6

H), 5.02 4.78 (m, 2 H), 3.29 (dd, J= 5.4, 15.4 Hz, 2 H), 2.94 (d, J= 15.2 Hz, 2 H), 1.83 1.60

(m, 1 H), 1.49- 1.36 (m, 2 H), 1.31 1.23 (m, 2 H), 0.95 (dd, J= 6.7, 9.7 Hz, 12 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 166.3, 132.3, 129.6, 129.2, 127.2, 125.5,

124.0, 123.7, 54.5, 41.9, 33.3, 24.9, 23.5, 21.9

HRMS Calcd. for C27H33ClN2Au [M]+: 616.1920, Found: 616.1959

[a]29D- 266.50 (c 0.32, CHC13)

X-ray experimental for 4-45

Data were collected at 100 K on a Bruker DUO system equipped with an APEX II area

detector and a graphite monochromator utilizing MoKa radiation (X = 0.71073 A). Cell

parameters were refined using up to 9999 reflections. A hemisphere of data was collected using

the co-scan method (0.50 frame width). Absorption corrections by integration were applied based

on measured indexed crystal faces.









The structure was solved by the Direct Methods in SHELXTL6, and refined using full-

matrix least squares. The non-H atoms were treated anisotropically, whereas the hydrogen atoms

were calculated in ideal positions and were riding on their respective carbon atoms. The

asymmetric unit consists of the complex and a disordered dichloromethane solvent molecule.

The latter molecules was disordered and could not be modeled properly, thus program

SQUEEZE, a part of the PLATON package of crystallographic software, was used to calculate

the solvent disorder area and remove its contribution to the overall intensity data. Judging by the

total count of electrons calculated by program SQUEEZE, it looks like the solvent exists in about

80% occupancy and disordered by the 21 screw axis of symmetry along the a-axis. A total of 281

parameters were refined in the final cycle of refinement using 6106 reflections with I > 2o(I) to

yield R1 and wR2 of 2.01% and 5.62%, respectively. Refinement was done using F2

P. van der Sluis & A.L. Spek (1990). SQUEEZE, Acta Cryst. A46, 194-201

SHELXTL6 (2000). Bruker-AXS, Madison, Wisconsin, USA.

Spek, A.L. (1990). PLATON, Acta Cryst. A46, C-34

Crystal data and structure refinement for 4-45

Identification code 4-45

Empirical formula C27 H32 Au Cl N2

Formula weight 616.96

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system Orthorhombic

Space group P2(1)2(1)2(1)

Unit cell dimensions









a = 9.4129(6) A a= 90.

b = 16.7290(11) A 3= 900.

c = 17.6201(12) A y = 900.

Volume 2774.6(3) A3

Z 4

Density (calculated) 1.477 Mg/m3

Absorption coefficient 5.413 mm-1

F(000) 1216

Crystal size 0.28 x 0.17 x 0.13 mm3

Theta range for data collection 1.68 to 27.500.

Index ranges -12
Reflections collected 43949

Independent reflections 6356 [R(int) = 0.0281]

Completeness to theta = 27.500 100.0 %

Absorption correction Nnumerical

Max. and min. transmission 0.5441 and 0.3165

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 6356 / 0 / 281

Goodness-of-fit on F2 0.849

Final R indices [I>2sigma(I)] R1 = 0.0201, wR2 = 0.0562 [6106]

R indices (all data) R1 = 0.0216, wR2 = 0.0569

Absolute structure parameter 0.009(6)

Largest diff peak and hole 1.156 and -1.026 e.A-3









R1 = 2(||Fol |Fcl|) / IFol

wR2 = [Y[w(Fo2 Fc2)2] / y[w(Fo2)2]]1/2

S = [[w(Fo2- Fc2)2] / (n-p)] 1/2

w= 1/[o2(Fo2)+(m*p)2+n*p], p = [max(Fo2,0)+ 2* Fc2]/3, m & n are constants.

6.4.3 Synthesis of The Substrates for The Copper-Catalyzed P-Borylation

2-chloro-N,N-bis(4-methoxybenzyl)acetamide

0O



0
Cl I
N





To a flame-dried Schlenk flask was added 618 [L (7.77 mmol) of 2-chloroacetyl chloride

and 16 mL (0.5 M) of THF. The reaction mixture was cooled to 0 oC and 2.00 g (7.77 mmol) of

bis(4-methoxybenzyl)amine was added dropwise followed by 1.08 mL (7.77 mmol) of Et3N. The

reaction mixture was stirred at room temperature for 12 h. It was diluted with 20 mL of Et20 and

washed with IN HC1 (2 x 15 mL) followed by a saturated NaHCO3 aqueous solution (2 x 15

mL). It was dried over anhydrous MgSO4. All volatiles were removed in vacuo to yield 2.55 g

(7.62 mmol, 98.1%) of 2-chloro-N,N-bis(4-methoxybenzyl)acetamide.

'H NMR (300MHz ,CHLOROFORM-d) 6 = 7.22 6.97 (m, 4 H), 6.84 (d, J= 8.5 Hz, 2

H), 6.88 (d, J= 8.5 Hz, 2 H), 4.50 (s, 2 H), 4.40 (s, 2 H), 4.12 (s, 2 H), 3.78 (s, 3 H), 3.80 (s, 3

H)









3C NMR (75MHz ,CHLOROFORM-d) 6 = 167.2, 159.6, 129.9, 128.8, 128.1, 127.8,

114.7, 114.3, 55.6, 55.5, 49.8, 48.0, 41.7

HRMS Calcd. for C18H20C1NO3 [M+H]+: 334.1204, Found: 334.1208

Diethyl 2-(bis(4-methoxybenzyl)amino)-2-oxoethylphosphonate

0





O'P N
O


ol o

To a flame-dried Schlenk flask was added 970 mg (2.90 mmol) of 2-chloro-N,N-bis(4-

methoxybenzyl)acetamide and 1.26 mL (7.25 mmol) of triethyl phosphite. The reaction mixture

was stirred at 100 oC for 60 h. After cooling at room temperature, it was washed with hexane (3 x

5 mL) and concentrated in vacuo to yield 1.13 g (2.59 mmol, 89.3%) of diethyl 2-(bis(4-

methoxybenzyl)amino)-2-oxoethylphosphonate.

H NMR (300MHz ,CHLOROFORM-d) 6 = 7.19 7.11 (m, 2 H), 7.06 (d, J= 8.8 Hz, 2

H), 6.93 6.73 (m, 4 H), 4.52 (d, J= 5.6 Hz, 4 H), 4.24 4.06 (m, 4 H), 3.77 (s, 3 H), 3.79 (s, 3

H), 3.13 (s, 1 H), 3.06 (s, 1 H), 1.39 1.22 (m, 6 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 165.7, 159.4, 159.2, 129.6, 129.2, 128.4,

128.3, 127.9, 114.6, 114.2, 62.9, 62.8, 55.6, 50.4, 48.0, 34.8, 33.1, 16.6, 16.5

HRMS Calcd. for C22H30N06P [2M+H]+: 871.3616, Found: 871.3720

(Z)-N,N-bis(4-methoxybenzyl)-3-phenylacrylamide (Z-4-59)
















0



To a flame-dried Schlenk flask was added 150 mg (1.012 mmol) of (Z)-cinnamic acid, 137

mg (1.012 mmol) of HOBt and 7 mL (0.14 M) of DCM. The reaction mixture was stirred 30

minutes at room temperature. 12.0 mg (0.100 mmol) of DMAP and 260 mg (1.012 mmol) of

bis(4-methoxybenzyl)amine were then added. The reaction mixture was cooled to 0 oC and a

solution of 209 mg (1.012 mmol) of DCC in 5 mL (0.2 M) of DCM was added dropwise. The

reaction was stirred 1 h at 0 oC and 12 h at room temperature. The reaction mixture was

concentrated and 15 mL of ethyl acetate was added and the white solid was filtered off. The ethyl

acetate solution was concentrated. Silicagel column chromatography with a 75:25 mixture of

hexane and ethyl acetate as the eluent gave 245 mg (0.633 mmol, 62.5%) of (Z)-N,N-bis(4-

methoxybenzyl)-3-phenylacrylamide.

H NMR (300MHz ,CHLOROFORM-d) 6 = 7.42 (d, J= 7.3 Hz, 2 H), 7.35 7.13 (m, 5

H), 7.01 (d, J= 8.2 Hz, 2 H), 6.96 6.80 (m, 4 H), 6.70 (d, J= 12.6 Hz, 1 H), 6.23 (d, J= 12.6

Hz, 1 H), 4.55 (s, 2 H), 4.35 (s, 2 H), 3.83 (s, 3 H), 3.86 (s, 3 H)

1C NMR (75MHz ,CHLOROFORM-d) 6 = 169.2, 159.4, 159.3, 135.6, 133.9, 130.6,

128.9, 128.8, 128.8, 128.7, 128.7, 128.4, 123.6, 114.4, 114.1, 55.5, 50.0, 45.9

HRMS Calcd. for C25H25N03 [M+H]+: 388.1907, Found: 388.1905

N-methoxy-N-methylcinnamamide (4-57)











N



940 mg (4.92 mmol, 95.9%) of N-methoxy-N-methylcinnamamide was obtained from 1.25

g (10.3 mmol) of DMAP, 1.37 g (6.66 mmol) of DCC, 500 mg (5.13 mmol) ofN,O-

dimethylhydroxylammonium chloride and 986 mg (6.66 mmol) of trans-cinnamic acid.

H NMR (300MHz ,CHLOROFORM-d) 6 = 7.74 (d, J= 15.8 Hz, 1 H), 7.62 7.52 (m, 2

H), 7.45 7.29 (m, 3 H), 7.04 (d, J= 15.8 Hz, 1 H), 3.76 (s, 3 H), 3.30 (s, 3 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 167.2, 143.6, 135.4, 130.0, 129.0, 128.2,

116.0, 62.1, 32.7

HRMS Calcd. for CllH13N02 [M+H]+: 192.1019, Found: 192.1024

N,N-dicyclohexylcinnamamide (4-56)

0

N





400 mg (1.28 mmol, 37.9%) ofN,N-dicyclohexylcinnamamide was obtained from 42 mg

(0.344 mmol) of DMAP, 765 mg (3.71 mmol) of DCC, 455 mg (3.37 mmol) of HOBt, 670 iL

(3.37 mmol) of dicyclohexylamine and 500 mg (3.37 mmol) of trans-cinnamic acid.

HH NMR (300MHz ,CHLOROFORM-d) 6 = 7.80 7.43 (m, 3 H), 7.43 7.15 (m, 3 H),

6.84 (d, J= 15.2 Hz, 1 H), 3.56 (br. s., 2 H), 2.26 (br. s., 2 H), 1.80 (br. s., 6 H), 1.64 (br. s., 6

H), 1.48- 1.21 (m, 4 H), 1.18 (br. s., 2 H)









13C NMR (75MHz ,CHLOROFORM-d) 6 = 166.5, 140.9, 136.0, 129.4, 128.9, 127.8,

121.3, 57.6, 56.1, 32.3, 30.6, 26.6, 25.7

HRMS Calcd. for C21H29NO [M+H]+: 312.2322, Found: 312.2320

N,N-bis(4-methoxybenzyl)cinnamamide (4-59)

0
O
N O



0

To a flame-dried Schlenk flask was added 60.2 mg (2.51 mmol) of sodium hydride and 2

mL (1.3 M) of DMF. A solution of 100 mg (0.679 mmol) of trans-cinnamide in 2 mL (0.33 M)

of DMF was then added dropwise at room temperature. The reaction mixture was heated to 70 C

for 1 h. Then 276 [L (2.04 mmol) of 1-(chloromethyl)-4-methoxybenzene was added dropwise

to the reaction mixture. It was stirred at 70 C for 2 h. It was cooled to room temperature and

quenched by 10 mL of water. The reaction mixture was extracted with Et2O (2 x 15 mL), washed

with water (2 x 15 mL) and dried over anhydrous MgSO4 All volatiles were removed in vacuo.

Silicagel column chromatography with a 80:20 mixture of hexane and ethyl acetate as the eluent

gave 260 mg (0.671 mmol, 98.8%) of N,N-bis(4-methoxybenzyl)cinnamamide.

H NMR (300MHz ,CHLOROFORM-d) 6 = 7.84 (d, J= 15.2 Hz, 1 H), 7.55 7.40 (m, 2

H), 7.40 7.07 (m, 7 H), 7.02 6.76 (m, 5 H), 4.62 (s, 2 H), 4.52 (s, 2 H), 3.80 (s, 6 H)

1C NMR (75MHz ,CHLOROFORM-d) 6 = 167.2, 159.4, 159.2, 143.8, 135.5, 130.0,

129.9, 129.8, 129.0, 128.9, 128.1, 117.7, 114.6, 114.2, 55.5, 49.5, 48.2

HRMS Calcd. for C25H25N03 [M+H] : 388.1907, Found: 388.1926

N,N-dibenzylcinnamamide (4-58)

















197 mg (0.602 mmol, 88.7%) of NN-dibenzylcinnamamide was obtained from 60.2 mg

(2.51 mmol) of sodium hydride, 100 mg (0.679 mmol) of trans-cinnamide and 242 iL (2.04

mmol) of benzyl bromide.

H NMR (300MHz ,CHLOROFORM-d) 6 = 7.87 (d, J= 15.2 Hz, 1 H), 7.56 7.17 (m, 15

H), 6.92 (d, J= 15.2 Hz, 1 H), 4.73 (s, 2 H), 4.62 (s, 2 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 167.4, 144.1, 137.6, 137.0, 135.4, 129.9,

129.2, 129.0, 128.9, 128.6, 128.1, 128.0, 127.7, 126.8, 117.5, 50.3, 49.1

HRMS Calcd. for C23H21NO [M+H]+: 328.1696, Found: 328.1704

N,N-dimethylcinnamamide (4-55)

0
r-^ ^ 'NO
N



90.0 mg (0.514 mmol, 75.7%) of N,N-dimethylcinnamamide was obtained from 60.2 mg

(2.51 mmol) of sodium hydride, 100 mg (0.679 mmol) of trans-cinnamide and 127 iL (2.04

mmol) of methyl iodide.

IH NMR (300MHz ,CHLOROFORM-d) 6 = 7.67 (d, J= 15.2 Hz, 1 H), 7.59 7.46 (m, 2

H), 7.46 7.22 (m, 3 H), 6.89 (d, J= 15.5 Hz, 1 H), 3.17 (s, 3 H), 3.06 (s, 3 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 166.9, 142.5, 135.6, 129.7, 129.0, 128.0,

117.7, 37.6, 36.1

HRMS Calcd. for ClIH13NO [M+H]+: 176.1070, Found: 176.1068









General procedure for the Horner-Wadsworth-Emmons olefination for aryl

substrates

To a flame-dried Schlenk flask was added 1.10 mmol of sodium hydride and 1.6 mL (0.7

M) of THF. The reaction was cooled to 0 oC and a solution of 0.919 mmol of diethyl 2-(bis(4-

methoxybenzyl)amino)-2-oxoethylphosphonate in 1.6 mL (0.7 M) of THF was added dropwise.

The reaction mixture was stirred at room temperature for 1 h. 1.10 mmol of aryl aldehyde was

then added and the mixture was stirred for 12 h at room temperature. It was quenched by 4 mL of

water. The reaction mixture was extracted with Et20 (2 x 10 mL), washed several times with

water (2 x 5 mL) and dried over anhydrous MgSO4. All volatiles were removed in vacuo.

Silicagel column chromatography with a mixture of hexane and ethyl acetate as the eluent gave

the desired (E)-a,P-unsaturated amide.

(E)-N,N-bis(4-methoxybenzyl)-3-(4-methoxyphenyl)acrylamide (4-74)

0



O O



H NMR (300MHz ,CHLOROFORM-d) 6 = 7.79 (d, J= 15.2 Hz, 1 H), 7.40 (d, J= 7.9

Hz, 2 H), 7.30 7.00 (m, 4 H), 7.00 6.70 (m, 7 H), 4.60 (s, 2 H), 4.50 (s, 2 H), 3.92 3.64 (m, 9

H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 167.5, 161.1, 159.3, 159.2, 143.5, 130.0,

129.6, 129.0, 128.1, 115.2, 114.5, 114.4, 114.2, 55.5, 49.4, 48.1

HRMS Calcd. for C26H27NO4 [M+H]: 418.2013, Found: 418.2009

(E)-N,N-bis(4-methoxybenzyl)-3-(2-methoxyphenyl)acrylamide (4-75)


















H NMR (299MHz ,CHLOROFORM-d) 6 = 8.08 (d, J= 15.3 Hz, 1 H), 7.40 (d, J= 7.6

Hz, 1 H), 7.30 7.01 (m, 6 H), 6.95 6.80 (m, 6 H), 4.61 (s, 2 H), 4.50 (s, 2 H), 3.85 3.74 (m, 9

H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 167.6, 159.0, 158.9, 158.2, 139.1, 130.7,

129.8, 129.2, 128.9, 127.9, 124.3, 120.6, 118.5, 114.2, 113.9, 111.1, 55.4, 55.3, 49.2, 47.9

HRMS Calcd. for C26H27N04 [M+H] : 418.2013, Found: 418.2008

(E)-3-(4-fluorophenyl)-N,N-bis(4-methoxybenzyl)acrylamide (4-77)

O



F O


H NMR (300MHz ,CHLOROFORM-d) 6 = 7.78 (d, J= 15.5 Hz, 1 H), 7.43 (dd, J= 5.6,

8.5 Hz, 2 H), 7.31 7.06 (m, 4 H), 7.00 (t, J= 8.5 Hz, 2 H), 6.93 6.68 (m, 5 H), 4.60 (s, 2 H),

4.50 (s, 2 H), 3.78 (s, 3 H), 3.78 3.75 (m, 3 H)

3C NMR (75MHz ,CHLOROFORM-d) 6 = 167.0, 165.4, 162.0, 159.4, 159.2, 142.5,

131.7, 130.0, 129.9, 129.8, 129.7, 128.8, 128.0, 117.5, 116.2, 115.9, 114.6, 114.2, 55.5, 49.5,

48.2


HRMS Calcd. for C25H24FN03 [M+H] : 406.1813, Found: 406.1818

(E)-N,N-bis(4-methoxybenzyl)-3-m-tolylacrylamide (4-78)


.0









0O


H NMR (300MHz ,CHLOROFORM-d) 6 = 7.85 (d, J= 15.2 Hz, 1 H), 7.40 7.05 (m, 8

H), 7.05 6.77 (m, 5 H), 4.64 (s, 2 H), 4.55 (s, 2 H), 3.79 (s, 6 H), 2.34 (s, 3 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 167.3, 159.4, 159.3, 144.0, 138.6, 135.5,

130.8, 130.1, 129.8, 128.9, 128.8, 128.2, 125.3, 117.5, 114.6, 114.2, 55.5, 49.5, 48.1, 21.6

HRMS Calcd. for C26H27N03 [M+H]+: 402.2064, Found: 402.2045

(E)-3-cyclohexyl-N,N-bis(4-methoxybenzyl)acrylamide (4-79)

0

N


O0


To a flame-dried Schlenk flask was added 200 mg (0.459 mmol) of diethyl 2-(bis(4-

methoxybenzyl)amino)-2-oxoethylphosphonate, 146 [L (0.834 mmol) of Hunig's base, 36.0 mg

(0.834 mmol), 51.0 [L (0.417 mmol) of cyclohexanecarbaldehyde and 3 mL (0.15 M) of

acetonitrile. It was stirred at room temperature for 12 h. The reaction mixture was extracted with

ethyl acetate (2 x 10 mL), washed with water (2 x 10 mL) and dried over anhydrous MgSO4. All

volatiles were removed in vacuo. Silicagel column chromatography with a 70:30 mixture of








hexane and ethyl acetate as the eluent gave 140 mg (0.356 mmol, 85.4%) of (E)-3-cyclohexyl-

N,N-bis(4-methoxybenzyl)acrylamide.

'H NMR (300MHz ,CHLOROFORM-d) 6 = 7.12 (t, J= 7.6 Hz, 4 H), 6.97 (dd, J= 7.0,

15.0 Hz, 1 H), 6.84 (dd, J= 8.4, 12.2 Hz, 4 H), 6.22 (d, J= 15.0 Hz, 1 H), 4.52 (s, 2 H), 4.40 (br.

s., 2 H), 3.77 (s, 3 H), 3.76 (s, 3 H), 2.18 2.03 (m, 1 H), 1.81 1.58 (m, 5 H), 1.30 1.05 (m, 5

H)

3C NMR (75MHz ,CHLOROFORM-d) 6 = 167.7, 159.3, 159.1, 152.9, 130.0, 128.9,

128.1, 118.0, 114.4, 114.1, 55.4, 49.3, 47.8, 41.0, 32.2, 26.1, 25.9

HRMS Calcd. for C25H31N03 [M+H]+:394.2377, Found: 394.2393

(E)-N,N-bis(4-methoxybenzyl)but-2-enamide (4-80)

0O




,-4





H NMR (300MHz ,CHLOROFORM-d) 6 = 7.16 (d, J= 7.6 Hz, 2 H), 7.12 6.93 (m, 3

H), 6.82 (d, J= 8.2 Hz, 2 H), 6.87 (d, J= 8.5 Hz, 2 H), 6.30 (d, J= 15.0 Hz, 1 H), 4.53 (br. s., 2

H), 4.40 (br. s., 2 H), 3.77 (s, 3 H), 3.78 (s, 3 H), 1.85 (d, J= 6.7 Hz, 3 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 167.3, 159.3, 159.2, 142.9, 129.9, 128.9,

128.0, 122.0, 114.5, 114.1, 55.5, 49.2, 47.7, 18.5

HRMS Calcd. for C20H23N03 [M+H]+: 326.1751, Found: 326.1735









6.4.4 Products from The Copper-Catalyzed Borylation

General procedure for copper-catalyzed borylation of a,P-unsaturated substrates:

To a flame-dried Schlenk flask was added copper (I) bromide-dimethylsulfide complex (3

mol%), NHC ligand (3.5 mol%), potassium tert-butoxide (9 mol%) and THF (0.16 M). The

reaction mixture was stirred for 30 minutes at room temperature. Then bis(pinacolato)diboron

(0.178 mmol) was added followed by substrate (0.162 mmol) and methanol (0.324 mmol) when

used. Then the reaction mixture was stirred at room temperature for 12 h or at 40 oC for 6 h.

NaBO3*(H20)4 (0.810 mmol) and water (0.16 M) were added and the reaction mixture was

stirred an additional 3 h at room temperature. The suspension was then extracted with Et20 (3 x

10 mL), dried with MgSO4 and concentrated in vacuo. Silicagel column chromatography with a

mixture of hexane and ethyl acetate as the eluent gave the chiral 1 alcohol.

The racemic compound was obtained by using IMes as racemic NHC ligand.

3-hydroxy-3-phenylpropanenitrile (4-48)

OH
CN




H NMR (300MHz ,CHLOROFORM-d) 6 = 7.53 7.24 (m, 5 H), 4.98 (t, J= 6.3 Hz, 1 H),

3.10 (br. s., 1 H), 2.71 (d, J= 6.2 Hz, 2 H)

13C NMR (75MHz ,CHLOROFORM-d) 6= 141.3, 129.1, 129.0, 125.8, 117.7, 70.1, 28.1

HRMS Calcd. for C9H9NO [M+H] : 148.0757, Found: 148.0753

Ee was measured by chiral HPLC with a OJ-H column (UV 215 nm, 10%

isopropanol/hexane, 1.0 ml/min). ti: 25.6, t2: 30.4

Ethyl 3-hydroxy-3-phenylpropanoate (4-51-product)









OH 0

OEt



H NMR (299MHz ,CHLOROFORM-d) 6 = 7.49 7.17 (m, 5 H), 5.13 (dd, J= 4.2, 8.2

Hz, 1 H), 4.18 (q, J= 7.1 Hz, 2 H), 3.34 (br. s., 1 H), 2.83 2.62 (m, 2 H), 1.26 (t, J= 7.1 Hz, 3

H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 172.6, 142.7, 128.7, 128.0, 125.9, 70.5, 61.1,

43.6, 14.4

HRMS Calcd. for CllH1403 [M+Na]: 217.0835, Found: 217.0830

Ee was measured by chiral HPLC with a Whelk-01 column (UV 215 nm, 10%

isopropanol/hexane, 1.0 ml/min). ti: 7.69, t2: 8.92

3-hydroxy-N,N-dimethyl-3-phenylpropanamide (4-60)

OH O

I



H NMR (299MHz ,CHLOROFORM-d) 6 = 7.47 7.17 (m, 5 H), 5.13 (dd, J= 3.1, 9.1

Hz, 1 H), 4.79 (br. s., 1 H), 2.93 (s, 3 H), 2.97 (s, 3 H), 2.73 2.58 (m, 2 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 172.5, 143.2, 128.7, 127.7, 125.9, 70.6, 42.1,

37.3, 35.4

HRMS Calcd. for C11H15N02 [M+H] : 194.1176, Found: 194.1172

Ee was measured by chiral HPLC with a Whelk-01 column (UV 215 nm, 30%

isopropanol/hexane, 1.5 ml/min). ti: 7.58, t2: 10.4

3-hydroxy-N-methoxy-N-methyl-3-phenylpropanamide (4-62)









OH 0

\= N
/ O

H NMR (300MHz ,CHLOROFORM-d) 6 = 7.55 7.18 (m, 5 H), 5.15 (d, J= 9.1 Hz, 1

H), 4.29 4.22 (m, 1 H), 3.62 (s, 3 H), 3.20 (s, 3 H), 2.92 2.75 (m, 2 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 173.5, 143.3, 128.7, 127.8, 126.0, 70.4, 61.5,

40.7, 32.1

HRMS Calcd. for CllH15NO3 [M+Na]+: 232.0944, Found: 232.0948

Ee was measured by chiral HPLC with a IB column (UV 215 nm, 5% isopropanol/hexane,

1.4 ml/min). t: 12.2, t2: 14.5

N,N-dicyclohexyl-3-hydroxy-3-phenylpropanamide (4-61)

OH 0







H NMR (300MHz ,CHLOROFORM-d) 6 = 7.54 7.23 (m, 5 H), 5.12 (d, J= 9.1 Hz, 1

H), 4.99 (br. s., 1 H), 3.34 (t, J= 11.6 Hz, 1 H), 3.13 2.81 (m, 1 H), 2.78 2.49 (m, 2 H), 2.45

(br. s., 2 H), 1.92 1.69 (m, 4 H), 1.61 (br. s., 4 H), 1.49 (t, J= 12.5 Hz, 4 H), 1.33 0.98 (m, 6

H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 171.6, 143.5, 128.6, 127.6, 126.1, 70.8, 57.8,

56.4, 43.7, 31.2, 30.5, 30.1, 26.8, 26.0, 25.6, 25.4

HRMS Calcd. for C21H31N02 [M+H] : 330.2428, Found: 330.2423









Ee was measured by chiral HPLC with a Whelk-01 column (UV 215 nm, 10%

isopropanol/hexane, 1.0 ml/min). ti: 11.8, t2: 22.4

N,N-dibenzyl-3-hydroxy-3-phenylpropanamide (4-63)

OH O

N





1H NMR (299MHz ,CHLOROFORM-d) 6 = 7.49 7.17 (m, 13 H), 7.17 7.05 (m, 2 H),

5.29 5.20 (m, 1 H), 4.84 (d, J= 2.8 Hz, 1 H), 4.75 (d, J= 14.7 Hz, 1 H), 4.54 (d, J= 15.0 Hz, 1

H), 4.48 4.33 (m, 2 H), 2.88 2.77 (m, 2 H)

3C NMR (75MHz ,CHLOROFORM-d) 6 = 173.2, 143.1, 137.0, 136.0, 129.3, 129.0,

128.7, 128.5, 128.1, 127.8, 127.8, 126.6, 126.0, 70.9, 50.1, 48.4, 41.9

HRMS Calcd. for C23H23N02 [M+H]: 346.1802, Found: 346.1802

Ee was measured by chiral HPLC with a Whelk-01 column (UV 215 nm, 30%

isopropanol/hexane, 1.5 ml/min). ti: 12.2, t2: 19.0

3-hydroxy-N,N-bis(4-methoxybenzyl)-3-phenylpropanamide (4-64)

OH O

N


10 0


H NMR (300MHz ,CHLOROFORM-d) 6 = 7.45 7.23 (m, 5 H), 7.14 (d, J= 8.5 Hz, 2

H), 7.01 (d, J= 8.8 Hz, 2 H), 6.95 6.79 (m, 4 H), 5.22 (br. s., 1 H), 4.87 (d, J= 2.9 Hz, 1 H),









4.61 (d, J= 14.7 Hz, 1 H), 4.45 (d, J= 14.4 Hz, 1 H), 4.30 (d, J= 4.1 Hz, 2 H), 3.81 (s, 3 H),

3.81- 3.79 (m, 3 H), 2.87 2.75 (m, 2 H)

3C NMR (75MHz ,CHLOROFORM-d) 6 = 172.6, 159.1, 159.0, 142.9, 129.6, 128.8,

128.4, 127.6, 127.4, 125.7, 114.3, 114.0, 70.6, 55.3, 49.0, 47.2, 41.6

HRMS Calcd. for C25H27N04 [M+H] : 406.2013, Found: 406.2011

Ee was measured by chiral HPLC with a Whelk-01 column (UV 215 nm, 30%

isopropanol/hexane, 1.5 ml/min). ti: 19.9, t2: 31.2

3-hydroxy-N,N-bis(4-methoxybenzyl)-3-(4-methoxyphenyl)propanamide (4-81)

OH O



0 0
"0&


H NMR (299MHz ,CHLOROFORM-d) 6 = 7.36 7.29 (m, 2 H), 7.17 (d, J= 8.5 Hz, 2

H), 7.05 (d, J= 8.8 Hz, 2 H), 6.99 6.83 (m, 6 H), 5.20 (t, J= 5.5 Hz, 1 H), 4.84 (br. s., 1 H),

4.65 (d, J= 14.4 Hz, 1 H), 4.48 (d, J= 14.7 Hz, 1 H), 4.34 (d, J= 4.2 Hz, 2 H), 3.97 3.76 (m, 9

H), 2.81 (d, J= 6.2 Hz, 2 H)

3C NMR (75MHz ,CHLOROFORM-d) 6 = 172.9, 159.3, 159.2, 159.2, 135.3, 129.9,

129.1, 127.8, 127.2, 114.6, 114.2, 114.0, 70.5, 55.5, 49.2, 47.4, 41.9

HRMS Calcd. for C26H29N05 [M+H] : 436.2118, Found: 436.2105

Ee was measured by chiral HPLC with a Whelk-01 column (UV 215 nm, 40%

isopropanol/hexane, 1.5 ml/min). ti: 26.6, t2: 47.2

3-hydroxy-N,N-bis(4-methoxybenzyl)-3-(2-methoxyphenyl)propanamide (4-82)


















1H NMR (299MHz ,CHLOROFORM-d) 6 = 7.59 (d, J= 7.6 Hz, 1 H), 7.36 6.68 (m, 11

H), 5.47 (d, J= 8.5 Hz, 1 H), 5.03 (d, J= 3.4 Hz, 1 H), 4.66 (d, J= 14.4 Hz, 1 H), 4.47 4.15 (m,

3 H), 3.81 (s, 3 H), 3.80 (s, 3 H), 3.71 (s, 3 H), 2.99 (dd, J= 2.4, 16.0 Hz, 1 H), 2.69 (dd, J= 8.8,

15.9 Hz, 1 H)

3C NMR (75MHz ,CHLOROFORM-d) 6 = 173.5, 159.3, 159.2, 155.7, 131.3, 129.8,

129.2, 128.3, 128.0, 127.9, 126.7, 121.0, 114.5, 114.2, 110.2, 66.1, 55.5, 55.5, 55.3, 49.1, 47.2,

39.6

HRMS Calcd. for C26H29NO5 [M+H] : 436.2118, Found: 436.2108

Ee was measured by chiral HPLC with a Whelk-01 column (UV 215 nm, 40%

isopropanol/hexane, 1.5 ml/min). ti: 27.5, t2: 54.3

3-(4-fluorophenyl)-3-hydroxy-N,N-bis(4-methoxybenzyl)propanamide (4-84)

OH O



F 0 O
\O

H NMR (300MHz ,CHLOROFORM-d) 6 = 7.38 7.20 (m, 2 H), 7.19 6.80 (m, 10 H),

5.15 (dd, J= 4.3, 7.8 Hz, 1 H), 4.90 (br. s., 1 H), 4.58 (d, J= 14.4 Hz, 1 H), 4.43 (d, J= 14.7 Hz,

1 H), 4.28 (d, J= 2.3 Hz, 2 H), 3.79 (d, J= 2.1 Hz, 6 H), 2.77 2.69 (m, 2 H)


.0









13C NMR (75MHz ,CHLOROFORM-d) 6 = 172.7, 159.4, 159.3, 138.9, 129.9, 129.0,

127.8, 127.7, 127.6, 115.6, 115.3, 114.6, 114.3, 70.3, 55.5, 55.5, 49.3, 47.5, 41.8

HRMS Calcd. for C25H26FN04 [M+H]+: 424.1919, Found: 424.1916

Ee was measured by chiral HPLC with a Whelk-01 column (UV 215 nm, 40%

isopropanol/hexane, 1.5 ml/min). ti: 12.3, t2: 16.4

3-hydroxy-N,N-bis(4-methoxybenzyl)-3-m-tolylpropanamide (4-85)

0O



OH O

N


O
I

H NMR (300MHz ,CHLOROFORM-d) 6 = 7.34 6.95 (m, 8 H), 6.95 6.72 (m, 4 H),

5.18 (br. s., 1 H), 4.83 (d, J= 2.9 Hz, 1 H), 4.61 (d, J= 14.7 Hz, 1 H), 4.45 (d, J= 14.4 Hz, 1 H),

4.30 (d, J= 3.8 Hz, 2 H), 3.81 (d, J= 2.1 Hz, 6 H), 2.85 2.73 (m, 2 H), 2.34 (s, 3 H)

13C NMR (75MHz ,CHLOROFORM-d) 6 = 173.0, 159.4, 159.3, 143.1, 138.3, 129.9,

129.1, 128.6, 128.5, 127.9, 126.6, 123.0, 114.6, 114.3, 70.9, 55.6, 55.5, 49.3, 47.4, 42.0, 21.7

HRMS Calcd. for C26H29NO4 [M+H] : 344.1856, Found: 344.1859

Ee was measured by chiral HPLC with a Whelk-01 column (UV 215 nm, 40%

isopropanol/hexane, 1.5 ml/min). ti: 15.1, t2: 23.9

3-cyclohexyl-3-hydroxy-N,N-bis(4-methoxybenzyl)propanamide (4-86)


















1H NMR (300MHz ,CHLOROFORM-d) 6 = 7.22 6.98 (m, 4 H), 6.98 6.69 (m, 4 H),

4.66 4.41 (m, 2 H), 4.36 (d, J= 4.4 Hz, 2 H), 4.25 (d, J= 2.6 Hz, 1 H), 3.82 (s, 3 H), 3.80 (s, 3

H), 2.58 (d, J= 2.1 Hz, 1 H), 2.48 (d, J= 9.7 Hz, 1 H), 1.87 (br. s., 1 H), 1.81 1.58 (m, 4 H),

1.43- 1.10 (m, 4 H), 1.10 0.98 (m, 2 H)

3C NMR (75MHz ,CHLOROFORM-d) 6 = 173.8, 159.4, 159.3, 129.9, 129.3, 128.1,

127.9, 114.6, 114.2, 72.6, 55.6, 55.5, 49.3, 47.4, 43.2, 36.8, 29.2, 28.6, 26.7, 26.4, 26.3

HRMS Calcd. for C25H33N04 [M+H]+:412.2482, Found: 412.2482

Ee was measured by chiral HPLC with a Whelk-01 column (UV 215 nm, 5%

isopropanol/hexane, 1.5 ml/min). ti: 84.9, t2: 94.5

3-hydroxy-N,N-bis(4-methoxybenzyl)butanamide (4-87)

0/



OH 0

N






H NMR (300MHz ,CHLOROFORM-d) 6 = 7.20 6.98 (m, 4 H), 6.96 6.78 (m, 4 H),

4.58 (d, J= 14.7 Hz, 1 H), 4.43 (d, J= 14.4 Hz, 2 H), 4.38 4.22 (m, 3 H), 3.80 (s, 6 H), 2.57

(dd, J= 2.6, 16.4 Hz, 1 H), 2.42 (dd, J= 9.4, 16.7 Hz, 1 H), 1.23 1.18 (m, 3 H)









3C NMR (75MHz ,CHLOROFORM-d) 6 = 173.4, 159.4, 159.3, 129.9, 129.2, 128.0,

127.9, 114.7, 114.3, 64.7, 55.6, 55.5, 49.2, 47.3, 41.2, 22.5

Ee was measured by chiral HPLC with a IA column (UV 215 nm, 10%

isopropanol/hexane, 1.2 ml/min). ti: 16.6, t2: 23.1









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(81) Thermal ellipsoids are drawn at the 50% probability level. Inserted structure (PdClC9H9
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(A) and angles (0): Pd-C1 2.031(3), Pd-Cl 2.359(8), Pd-C28 2.053(8), Pd-C29
2.086(7), Pd-C30 2.267(6), N1-C1-N2 104.3(2), C9-C4-C2-C3 26.6.










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C20-C15-C3-C2 21.6

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(96) The calculations used SambVcal2a'b with the following parameters: radius of sphere, 3.5 A;
distance from sphere, 2 A; mesh step, 0.05 A.










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(98) Thermal ellipsoids are drawn at the 50% probability level. The inserted structure shows the
front view of the complex. Selected bond lengths (A) and angles (0): Aul-C1 2.289(2),
Aul-C1 1.988(4), N2-C1-N1 105.0(3), C8-C9-C10-C11 21.0, C28-C18-N1-C1 80.6.

(99) Thermal ellipsoids are drawn at the 50% probability level. The inserted structure shows the
front view of the complex. Selected bond lengths (A) and angles (0): Aul-C1
2.2829(10), Aul-C1 1.985(4), N2-C1-N1 104.6(3), C8-C9-C10-C11 23.3

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BIOGRAPHICAL SKETCH

Dimitri Hirsch-Weil was born in Paris, France in 1982, and grew up in Nimes, France.

After graduating from Alphonse Daudet High School in 2000, he spent two years in preparatory

classes for chemistry school entry's exam at Alphonse Daudet High School. He then joined the

Ecole Superieure de Chimie Physique Electronique de Lyon (CPE), France where he spent two

years majoring in organic chemistry. For his one year internship, he was hired by

GlaxoSmithKline in Upper Merrion, Pennsylvania to work in their medicinal chemistry

department. This rich experience led him to pursue a PhD in organic chemistry under the

supervision of Sukwon Hong at the University of Florida.





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1 DEVELOPMENT OF NEW C HIRAL DIAMINO CARBENE LIGANDS A ND THEIR APPLICATIONS IN COPP ER CATALYZED REACTIONS By DIMITRI HIRSCH WEIL A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLME NT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2010

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2 2010 Dimitri H irsch W eil

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3 To Catherine Jean Jacques and J ean

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4 ACKNOWLEDGEMENT S I would like to thank my mother for all the happiness she brings in my life. I will always be grateful for the great education she gave me. My dad has always been present with me and has given me a rich know ledge throughout my young years which helped me through tough times. My professor Su kwon Hong has been very supportive throughout my five years spent at the University of Florida. He made himself available anytime I needed an advice or simply to discuss about chemistry, I will always be thankful to him for that. He was a great mentor and always trusted me in my work. I want to thank especially David Snead for all the joyful moments spent inside and outside the lab over the past years. Also I want to thank all my group members: Kai Lang, Hwimin Seo, Mike Rodig, Sebastien Inagaki and Jongw oo Park for interesting discussion about my work particularly Dr. Hwimin Seo who gave me invaluable training and advice in my chemistry.

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5 TABLE OF CONTENTS P age ACKNOWLEDGEMENT S ................................ ................................ ................................ ............ 4 LIST OF TABLES ................................ ................................ ................................ .......................... 7 LIST OF FIGURES ................................ ................................ ................................ ........................ 9 LIST OF SCHEMES ................................ ................................ ................................ ..................... 11 LIST OF ABBREVIATIONS ................................ ................................ ................................ ....... 16 ABSTRACT ................................ ................................ ................................ ................................ .. 18 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ ............ 20 1.1 N H eterocyclic C arbene Background ................................ ................................ .......... 20 1.2 Chiral NHC ................................ ................................ ................................ .................. 22 1.2.1 Chiral Substituents at The Nitrogen Atoms ................................ ..................... 22 1.2.2 Backbone Chirality ................................ ................................ ........................... 28 1.3 Acyclic Carbene and Methods of Preparation ................................ ............................. 35 1.4 Copper Catalyzed Applications ................................ ................................ ................... 39 1.4.1 Copper Catalyzed Ally lic Alkylation ................................ .............................. 39 1.4.2 Copper Unsaturated Carbonyl Compounds .... 49 2 C 2 SYMMETRIC BIISOQUINOLINE N HETEROCYCLIC CARBENE LIGAND .... 53 2.1 Introduction: Ligand Design for C 2 Symmetric Ligands ................................ ............. 53 2.2 Bisoxazoline Derived NHC Ligand ................................ ................................ ............. 55 2.3 Bisimidazoline Deri ved NHC Ligand ................................ ................................ .......... 58 2.4 Biisoquinoline Derived NHC Ligand ................................ ................................ ........... 60 2.4.1 Synthesis of Isopropyl, Isobutyl, Tert Butyl and Cyclohexyl Ala nine Substituted Amines ................................ ................................ .......................... 61 2.4.2 Cyclohexyl Substituted Amine Synthesis ................................ ........................ 62 2.4.3 Fused Cyclohexyl Substituted Amine Synthesis ................................ ............. 63 2.4.4 Phenyl Substituted Amine Synthesis ................................ ............................... 67 2.4.5 Biisoquinoline Based Carbene Synthesis from Chiral Amine ......................... 69 2.4.6 Formation of Metal Complexes ................................ ................................ ....... 73 2.4.7 Application: Copper Catalyzed Asymmetric Allylic Alkylation ..................... 76 2.4.8 Proposed Mechanism for The Copper Catalyzed Allylic Alkylation .............. 80 2.4.9 Further Optimization of The Ligand Structure ................................ ................ 83

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6 3 IN SITU GENERATION OF ACYCLIC DIAMINOCARBENE COPPER COMPLEX 91 3.1 Introduction: Discovery of The In Situ Generation of Aminocarbene Copper Complex from Chloroimidazo lium ................................ ................................ .............................. 91 3.2 New In Situ Generation of ADC Cu Complex and Application in Allylic Alkylation 93 3.3 NMR Experiments ................................ ................................ ................................ ....... 99 4 C 1 SYMMETRIC MONOISOQUINOLINE N HETEROCYCLIC CARBENE LIGAND ................................ ................................ ................................ ................................ ......... 105 4.1 Introduction: Ligand Design for C 1 Symmetric Ligands ................................ ........... 105 4.2 First Attempt Using R 2 =Me ................................ ................................ ....................... 106 4.3 Second Attempt Using R 2 =Ph ................................ ................................ .................... 109 4.4 Ach iral Side Variation ................................ ................................ ................................ 111 4.5 Chiral Side Variation ................................ ................................ ................................ .. 114 4.6 Gold BIQ and MIQ Metal Complexes ................................ ................................ ....... 119 4.7 Application: Copper Unsaturated Carbonyl Compounds ................................ ................................ ................................ ................................ .... 123 4.8 Further Directions for MIQ or BIQ Ligands ................................ .............................. 135 5 CONCLUSION ................................ ................................ ................................ ............... 136 6 EXPERIMENTAL SECTION ................................ ................................ ........................ 138 6.1 General Remarks ................................ ................................ ................................ ........ 138 6.2 C 2 Symmetric NHC Ligands ................................ ................................ ..................... 138 6.2.1 Bisoxazoline Derived NHC Ligand ................................ ............................... 138 6.2.2 Bisimidazoline Derived NH C Ligand ................................ ............................ 141 6.2.3 Biisoquinoline Derived NHC Ligand ................................ ............................. 144 6.2.4 Synthesis of the Substrates for The Copper Catalyzed Allylic Alky lation .... 172 6.2.5 Products from The Copper Catalyzed Allylic Alkylation ............................. 177 6.3 In Situ Generation of Acyclic Diaminoc arbene Copper Complex ............................ 181 6.3.1 Substrates and Catalysts Synthesis ................................ ................................ 181 6.3.2 Products from The Copper Catalyzed Allylic Alkylati on ............................. 190 6.3.3 NMR Experiments ................................ ................................ ......................... 193 6.3.4 Additional Experiments from Table 3 2 ................................ ........................ 196 6.4 C 1 Symmetric Monoisoquinoline NHC Ligands ................................ ....................... 198 6.4.1 Ligands Synthesis ................................ ................................ .......................... 198 6.4.2 Gold Complexes S ynthesis ................................ ................................ ............ 225 6.4.3 Synthesis of The Substrates for The Copper Catalyzed Borylation ........... 232 6.4.4 Products from The Copper Catalyzed Borylation ................................ ......... 242 LIST OF REFERENCES ................................ ................................ ................................ ............ 251 BIOGRAPHICAL SKETCH ................................ ................................ ................................ ...... 260

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7 LIST OF TABLES 1 1 Asymmetric ring closing metathesis with various chiral NHC ruthenium complexes ..... 30 1 2 ....................... 35 2 1 Optimization of the enzymatic kinetic resolution of rac 2 67 using lipase CALB .......... 66 2 2 Optimization of bisamide coupling using diethyl oxalate ................................ ................ 69 2 3 Optimization of the double Bischler Napieralski cyclization ................................ ........... 72 2 4 Solvent optimization for the asymmetric allylic alkylation ................................ .............. 77 2 5 Leaving group optimization for the asymmetric allylic alkylation ................................ ... 78 2 6 Ligand structure optimization for the asymmetric allylic alkylation ................................ 79 2 7 Grignard re agent survey for the asymmetric allylic alkylation ................................ ........ 79 2 8 Substrate scope ................................ ................................ ................................ .................. 80 2 9 Protection of t ................................ .................... 87 2 10 ................................ ........................... 88 3 1 Allylic alkylation using chloroamidinium premixed with copper salt .............................. 93 3 2 S N 2' allylic alkylation catalyzed by copper carbene complexes ................................ ....... 94 3 3 Substrate scope ................................ ................................ ................................ .................. 98 3 4 13 C NMR experiments of the generation of copper carbene complex from chloroamidinium ................................ ................................ ................................ ............... 99 4 1 Monoamide optimization ................................ ................................ ................................ 107 4 2 Optimization of the Bischler Napieralski cyclization ................................ ..................... 107 4 3 Optimization of imine formation ................................ ................................ .................... 108 4 4 Optimization of the imine condensation from the non enolizable ketone ...................... 109 4 5 Synthesis of disubstituted MIQ NHC copper complexes ................................ ............... 111 4 6 Allylic alkylation with disubstituted MIQ NHC copper complexes .............................. 112 4 7 Synthesis of monosubstituted MIQ NHCs ................................ ................................ ..... 113 4 8 Allylic alkylation using monosubstituted MIQ NHCs ................................ ................... 114

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8 4 9 Dependence between temperature and imidazolium ratio ................................ .............. 115 4 10 Allylic alkylation with two different isomers of 4 43 ................................ .................... 119 4 11 borylation for cinnamonitrile ................................ ............................ 124 4 12 Ligand scope for cinnamonitrile ................................ ................................ ..................... 125 4 13 Substrate scope ................................ ................................ ................................ ................ 126 4 14 Amide substrate optimization ................................ ................................ ......................... 127 4 15 Reaction condition optimization for N N dibenzylcinnamamide ................................ ... 129 4 16 borylation with different alkene configuration ................................ ............................ 130 4 17 Synthesis of additional MIQ NHCs ................................ ................................ ................ 131 4 18 Ligand scope for N N bis(4 m ethoxybenzyl)cinnamamide ................................ ............ 132 4 19 Temperature effect on the copper catalyzed borylation ................................ ................. 133 4 20 Substrate scope ................................ ................................ ................................ ................ 134

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9 LIST OF FIGURES Page 1 1 Electronic effects of the substituents for diaminocarbenes ................................ ............... 20 1 2 Stable di aminocarbenes ................................ ................................ ................................ .... 21 1 3 Basic chiral carbene ligand framework ................................ ................................ ............. 22 1 4 Bisoxazoline derived NHC evolution ................................ ................................ ............... 25 1 5 Major structure difference between NHC and ADC ................................ ......................... 35 1 6 Propo borylation of unsaturated ketones ................................ ......... 52 2 1 C 2 symmetric ligand design ................................ ................................ .............................. 54 2 2 Tricyclic ligand design with vari ation of X ................................ ................................ ...... 55 2 3 Fused cyclohexyl BIQ ( trans 2 63 and cis 2 64 configuration) calculated with Chem3D ................................ ................................ ................................ ................................ ........... 64 2 4 X ray structure of Pd carbene complex 2 103 81 ................................ ............................... 75 2 5 13 C NMR of bisamide 2 150 ................................ ................................ ............................. 89 2 6 13 C NMR of bis(imidoyl) hali de 2 156 ................................ ................................ ............. 89 2 7 13 C NMR of bisimine 2 100 ................................ ................................ .............................. 90 3 1 X Ray structure of chloroimidazolium CuCl 2 salt 3 2 83 ................................ .................. 92 3 2 Direct 13 C NMR monitoring (at 60C) of carbene metal complex generation using 13 C labeled chloroamidinium precursor 3 25 ................................ ................................ ........ 101 3 3 Direct 13 C NMR monitoring at room temperature of carbene metal complex generation using 13 C labeled formamidinium 3 32 ................................ ................................ .......... 103 4 1 Increasing bulk around metal center by switching from C 2 symmetric BIQ 2 2 to C 1 symmetric MIQ 4 1 carbene ligands ................................ ................................ ............... 105 4 2 First design of the C 1 symmetric isoquinoline ligand 4 6 ................................ .............. 106 4 3 1 H NMR of the 4 39 (84:16) (Scheme 4 6, entry 1). ................................ ...................... 116 4 4 1 H NMR of 4 39 (51:49) (Scheme 4 6, entry 2) ................................ ............................. 116 4 5 1 H NM R of the two diastereomers of 4 43 ................................ ................................ ..... 118

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10 4 6 Buried volume for NHC ligand ................................ ................................ ....................... 120 4 7 X ray structure of 4 44 98 ................................ ................................ ................................ 121 4 8 X ray structure of 4 45 99 ................................ ................................ ................................ 122 4 9 borylation of unsaturated substrates ....................... 123 4 10 Proposed transition state with amide functionality ................................ ......................... 127 4 11 borylat ion with NHC ligand ................................ ............... 128 4 12 Proposed transition state model for the asymmetric borylation. B = pinB ................... 134

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11 LIST OF SCHEMES 1 1 Synthesis of imidazolium and imidazolinium salts ................................ .......................... 21 1 2 One pot synthesis of chiral imidazoliums ................................ ................................ ......... 23 1 3 Enantioselective copper catalyzed 1,4 addition of zinc reagent using 1 21 ..................... 23 1 4 Synthesis of chiral [2.2]paracyclophane imidazoliums ................................ .................... 24 1 5 Ruthenium catalyzed asymmetric ketone hydrosilylation ................................ ................ 24 1 6 arylation of oxindole with 1 33 ................................ .......................... 24 1 7 arylation of oxindole with 1 34 ................................ .......................... 25 1 8 Synthesis of the ( ) menthone derived IBiox salt ................................ ............................. 26 1 9 arylation of oxindole with 1 37 ................................ .......................... 27 1 10 Synthesis of imidazolinium salts with restricted flexibility ................................ .............. 27 1 11 Asymmetric hydrogenation of methyl 2 acetamidoacrylate with 1 52 ............................ 28 1 12 Tert butyl substituted vicinal diamine synthesis ................................ ............................... 28 1 13 Synthesis of N aryl substituted chiral imidazoliniums ................................ ..................... 29 1 14 Synthesis of N alkyl substituted chiral imidazoliniums ................................ ................... 29 1 15 Synthesis and separation of meso and dl forms of bipiperidine ................................ ....... 31 1 16 Synthesis and chiral resolution of bipiperidine ................................ ................................ 32 1 17 Synthesis and separation of meso and dl forms of biisoquinoline ................................ .... 32 1 18 Synthesis and chiral resolution of biisoquinoline ................................ ............................. 32 1 19 Asymmetric hydrosilylation using Rh and Ir complexes with NHC ligands based on reduced biisoquinoline and bipiperidine framework ................................ ........................ 33 1 20 Synthesis of chiral resolved seven m embered ring amidinium salts ................................ 34 1 21 Formamidinium formation and deprotonation ................................ ................................ .. 36 1 22 N aryl acyclic carbene synthesis ................................ ................................ ....................... 37 1 23 Synthesis of metal free ADC and proposed mechanism ................................ ................... 37 1 24 Synthesis of Chugaev type ADC Pd complexes with hydrazine or amine ...................... 38

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12 1 25 Pd complex formation from oxidative addition of chloroamidinium precursor ............... 38 1 26 Metal complex formation through lithium halogen exchange from chloroamidinium precursors ................................ ................................ ................................ .......................... 39 1 27 General picture of the copper catalyzed allylic alkylation ................................ ............... 40 1 28 Firs t example of enantioselective copper catalyzed allylic alkylation by Grignard reagents ................................ ................................ ................................ ............................. 40 1 29 First generation of phosphoramidite ligand applied in the allylic alkylation ................... 41 1 30 New condition with CuTC and second generation of phosphoramidite ligand applied for the allylic alkylation ................................ ................................ ................................ .......... 41 1 31 Third generation of phosp horamidite ligand applied in the allylic alkylation .................. 42 1 32 Synthesis of syn and anti 1,2 dialkyl motifs ................................ ................................ ..... 43 1 33 Synthesis of ch iral furanone. ................................ ................................ ............................. 43 1 34 Allylic alkylation with allylic bromide containing nitrogen functional group ................. 44 1 35 Synthesis of bifunct amine .............. 44 1 36 substituted allylboronates ................................ ........... 45 1 37 Cu catalyzed allylic alkylation using monodentate NHC ligands and proposed transition state ................................ ................................ ................................ ................................ ... 46 1 38 Cu free enantioselective allylic alkylation on chloro unsaturated esters ................ 47 1 39 Anti selectivity with Grignard reagent ................................ ................................ .............. 47 1 40 Allylic alkylation with phenyl Grignard reagent using phosphine ligand ........................ 48 1 41 Allylic alkylation with phenyl Grignard reagent using monodentate NHC ligand .......... 48 1 42 First reported example borylation of unsaturated ketones ................................ ..... 49 1 43 First asymmetric version using chiral josiphos phosphine ligand ................................ .... 50 1 44 Genera tion of quaternary centers using chiral phosphine ligands ................................ .... 50 1 45 First asymmetric version using chiral NHC ligands ................................ ......................... 51 1 46 Copp borylation of unsaturated ketones ................................ ........... 51 2 1 Retrosynthesis from trans aminoindanol ................................ ................................ .......... 56

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13 2 2 Synthesis from trans a minoindanol ................................ ................................ .................. 56 2 3 Decomposition pathway using chloromethyl ethyl ether ................................ .................. 57 2 4 Bisoxazoline imidazolium synthesis ................................ ................................ ................ 57 2 5 Bisimidazoline retrosynthesis ................................ ................................ ........................... 58 2 6 Bisimidazoline synthesis ................................ ................................ ................................ ... 59 2 7 B isimidazoline NHC synthesis ................................ ................................ ........................ 60 2 8 Bisdihydroisoquinoline based carbene ligands ................................ ................................ 61 2 9 Biisoquinoline retrosynthesis ................................ ................................ ............................ 61 2 10 Chiral amine synthesis from amino acids ................................ ................................ ......... 62 2 11 Cyclohexyl amine synthesis ................................ ................................ .............................. 63 2 12 Racemic synthesis of the fused Cy amine rac 2 65 ................................ ......................... 64 2 13 Amide synthesis for chiral resolution ................................ ................................ ............... 65 2 14 Ester syn thesis for chiral resolution ................................ ................................ .................. 65 2 15 Non enzymatic kinetic resolution of secondary alcohol ................................ ................... 65 2 16 Scale up of the kinetic resol ution of secondary alcohol with reused enzyme .................. 67 2 17 Reverse regioselectivity with phenyl substituted aziridine ................................ ............... 67 2 18 Synthes is of ( S ) 1,2 diphenylethanamine ................................ ................................ ......... 68 2 19 Bisamide synthesis using oxalyl chloride ................................ ................................ ......... 70 2 20 Double Bischler Napieralski cyclizatio n ................................ ................................ .......... 70 2 21 Fragmentation of phenyl substituted bisnitrilium ................................ ............................. 73 2 22 Imidazolium synthesis from chiral amine ................................ ................................ ......... 73 2 23 Synthesis of Pd BIQ cinnamyl complex 2 103 ................................ ................................ 74 2 24 Copper complexes from C 2 symmetric BIQ carbene ligands ................................ ........... 75 2 25 General scheme for allylic alkylation catalyzed by copper complexes using Grignard reagents as nucleophiles. ................................ ................................ ................................ ... 76 2 26 Proposed mechanism for the asymmetric allylic alkylation ................................ ............. 81

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14 2 27 Allylic alkylation using TC leaving group ................................ ................................ ........ 82 2 28 Asymmetric allylic alkylation from a secondary alco hol pivalate ................................ .... 82 2 29 Comparison between preformed (a) and in situ generated (b) copper carbene complex .. 83 2 30 Synthesis of the 7 OMe substituted BIQ carbene ligand 2 141 ................................ ....... 84 2 31 Allylic alkylation using 2 141 ................................ ................................ .......................... 84 2 32 Synthesis of the bis OMe substituted B IQ carbene ligand 2 146 ................................ ..... 85 2 33 Bisamide synthesis of norephedrine ................................ ................................ ................. 86 2 34 Synthesis of the silylated bisamide ................................ ................................ ................... 87 3 1 Attempted synthesis of copper(II) BIQ carbene complex 3 1 ................................ .......... 91 3 2 Comparison between catalysts 2 110 and 3 2 in the allylic alkylation of n aphthyl substrate 2 114 ................................ ................................ ................................ .................. 92 3 3 Bispyrrolidine amidinium preparation ................................ ................................ .............. 96 3 4 Allylic alkylation using free carbene (Table 3 2, ent ry 8) ................................ ................ 96 3 5 Comparison between catalysts 2 110 and 3 2 in the allylic alkylation of alkyl substrate 96 3 6 Enantioselective all ylic alkylation using chiral ADC 3 12 ................................ ............... 97 3 7 Allylic alkylation of piperidine substrate with IMesCuCl catalyst 3 22 .......................... 98 3 8 Prepa ration of 13 C labeled chloroamidinium precursor 3 25 ................................ .......... 100 3 9 Preparation of 13 C labeled formamidinium precursor 3 32 ................................ ............ 102 3 10 Co pper carbene complex generation involving cuprate chloride exchange ................... 103 3 11 Copper carbene complex generation involving Grignard chloride exchange ................ 103 4 1 Retrosynthesis of the C 1 symmetric monoisoquinoline ligand ................................ ....... 106 4 2 Monoimine synthesis from chiral isobutyl phenethylamine ................................ ........... 109 4 3 Imidazolium and copper complex synthesis for mesityl substituted imine .................... 110 4 4 Asymmetric allylic alkylation using 4 15 ................................ ................................ ....... 110 4 5 Attempted synthesis of the phenyl substituted isoquinoline 4 35 ................................ .. 114 4 6 Synthesis of 4 38 ................................ ................................ ................................ ............. 115

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15 4 7 Imidazolium synthesis of 4 43 ................................ ................................ ........................ 117 4 8 Synthesis of BIQ and MIQ gold complexes ................................ ................................ ... 120

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16 LIST OF ABBREVIATION S Ac Acetyl ADC Acyclic diaminocarbene. BINAP 2,2' bis (diphenylphosphino) 1,1' binaphthyl. BIQ Biisoquinoline based carbene ligand. Bn Benzyl. Bpin Boron pinacolate. B 2 pin 2 Bispinacolate diboron. CALB Candida Antarctica lipase B. DCM Dichloromethane. DFT Density functional theory. DIAD Diisopropyl azodicarb oxylate DMAP 4 Dimethylaminopyridine. DME Dimethoxyethane. DMF Dimethylformamide. DMSO Dimethylsulfoxide. dr diastereomeric ratio. EDCI/EDC 1 ethyl 3 (3 dimethylaminopropyl) carbodiimide. ee enantiomeric excess. GC Gas chromatography. HOBt Hydroxybenzotri azole. Hoveyda Grubbs 2 nd generation (1,3 Bis (2,4,6 trimethylphenyl) 2 imidazolidinylidene)dichloro(o isopropoxyphenylmethylene)ruthenium HPLC High performance liquid chromatography. ( R ) ( S ) Josiphos ( R ) 1 [( S P ) 2 Diphenylphosphino)ferrocenyl]ethyldicycl ohexylphosphine LAH Lithium aluminium hydride.

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17 LDA Lithium diisopropylamide. LiHMDS Lithium hexamethyldisilazide. MIQ Monoisoquinoline based carbene ligand. MsCl Mesylate chloride. MTBE Methyl tert butyl ether. NCS N chlorosuccinimide. NHC N heterocyclic carbene. NMR Nuclear magnetic resonance. Piv Pivalate. PMB para methoxybenzyl. PMHS Polymethylhydrosiloxane. PMP para methoxyphenyl Rac Racemic. SM Starting material. SMB Simulating moving bed. ( R ) ( S ) Taniaphos ( R P ) 1 [( S ) (Dimethylamino) 2 (diphenylphosphino)benzyl] 2 diphenylphosphinoferrocene TBDPS tert Butyl diphenylsilyl. TC Thiophenecarboxylate. TFA Trifluoroacetic acid. Tf 2 O Triflate anhydride. THF Tetrahydrofuran. TMS Trimethylsilyl. TsCl Tosylate chloride. % V Bu r % buried volume.

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18 Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy DEVELOPMENT OF NEW CHIRAL DIAMINOCARBENE LIGANDS A ND THEIR APPLICATIONS IN COPPER CATALYZE D REACTIONS By Dimitri Hirsch Weil August 2010 Chair: Sukwon Hong Major: Chemistry N Heterocyclic carbene (NHC) ligands are considered strong donors and can be used in various catalytic r eactions Asymmetric catalysis using NHC s has been widely spread over the past 10 year s. Comparing to chiral phosphine ligands the choice of chiral NHC s still re mains limited Several designs have been develo ped such as attaching chiral alkyl groups directly to the nitrogen atoms, installing a chiral backbone on the NHC ring and using a chiral tethered group for second point metal binding. In this work, n ew designs were explored to further diversify the choice in chiral NHCs. C 2 symmetric biisoquinoline based diaminocarbene ligands were designed to create a chiral environment extended toward the metal center, which was confirmed by an X ray structure. The concise ligand synthesis is highlighted by a modified Bi schler Napieralski cyclization of bisamides prepared from readily available chiral phenethylamines, and allows easy variation of the stereodifferentiating groups. The cyclohexyl biisoquinoline based carbene copper complex is an efficient catalyst for enant ioselective S N 2' allylic alkylation with Grignard reagents showing S N 2' regioselectivity h igher than 5:1 and enantioselectivity in the range of 68 77% ee

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19 A novel acyclic diaminocarbene copper complex has been prepared for the first time, conveniently from a chloroamidinium salt and Cu(I) thiophenecarboxylate. The in situ generated acyclic diaminocarbene Cu complex was characterized by 13 C NMR experiments using a 13 C labeled carbene precursor. The acyclic diaminocarbene Cu complex is a highly efficient cata lyst for S N allylic alkylation with alkyl Grignard reagents, showing high S N C 1 symmetric monoisoquinoline based chi ral diaminocarbene ligands were envisioned to expand the chiral pool of NHC structures and further optimize previously reported C 2 sym metric biisoquinoline carbene ligands. This new ligand was synthesized from readily available chiral phenethylamine. The synthetic scheme allowed easy variation of the ligand structure within the final steps. Both C 2 and C 1 symmetric carbene ligands could be compared by their respective X ray structures of Au (I) complexes. M onoisoquinoline based carbene ligand was tested in the copper catalyze d borylation unsaturated amides giving good yields (80 99%) and enantioselectivities (85%) for various substrates

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20 CHAPTER 1 INTRODUCTION 1.1 N H eterocyclic C arbene B ackground N heterocyclic carbenes (NHC) have been isolated for the first time by Arduengo et al. in 1991. 1 NHCs are stabilized by the vicinal nitrogen atoms and exhibit singlet state configuration. The t wo nitrogen lone pairs increase the energy of the empty p orbital by mesomeric effects and the carbene lone pair p is stabilized by inductive effects of elect ronegative nitrogen atoms ( Figure 1 1 ) p gap and favor the singlet state. 2 NHCs are donors and their metal complexes show better air and thermal stability than the analogous phosphine co mplexes 3 As a result of these superior properties, carbene ligands are replacing bulky electron donating phosphine ligands in various catalytic reactions 4 such as cross coupling reactions 5 and olefin metathesis. 6 Figure 1 1 Electronic effects of the substituents for diaminocarbenes Recently, the discovery and isolation of several types of stable carbenes 7 has been reported ( Figure 1 2 ). From four to seven me mbered N heterocyclic rings have been reported. Most of the stable aminocarbenes reported are five membered rings ( 1 2 to 1 8 ) This might be due to an increase of stability compared to other ring sizes. In the carbene infancy, Arduengo et al. reported an easy and practical synthesis of typical five membered N heterocyclic ring ( Scheme 1 1 ). 8

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21 Figure 1 2 Stable diaminocarbenes Bisimines 1 13 were obtained by conde nsation of glyoxal and respective amines. Then, either it was reduced to the corresponding diam m onium salt 1 14 by NaBH 4 or it was cyclized to the imidazolium salt 1 15 using chloromethyl ethyl ether. The diam m onium 1 14 was converted to the imidazolinium 1 16 with triethyl orthoformate. This synthesis allows for a wide variation of the starting amines. Scheme 1 1 Synthesis of imidazolium and imidazolinium salt s

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22 1.2 Chiral NHC A symmetric ca talysis using chiral carbene ligands has exploded in the last 10 years 9 There are two ways of introducing chirality into the carbene ligand framework ( Figure 1 3 ) Figure 1 3 Basic chiral carbene ligand framework The first method reported by Herrmann et al., 10 involves attaching chiral substituents on the nitrogen atoms. The second method first developed by Grubbs et al., 11 uses a chiral backbone which tethers two nitrogen atoms in saturated carbenes to relay chiral information to the metal. M onodentate, 12 bidentate 13 or multidentate chiral amino carbene ligands have been developed. An overview of monodentate amino carbene ligands as well as their synthesis will be discussed. 1.2.1 Chiral Substituents at T he N itrogen A toms This strategy is based on the introduction of N substituents containing a chiral center on the carbon attached to the nitrogen atom. In the first report by Herrmann, the chiral unit was incorporated as a commercially available chiral amine 1 18 The imidazolium 1 19 was synthesized in a Scheme 1 2 ). 14 This synthesis can be used with various chiral amines to generate an arr ay of chiral imidazoliums. Those NHC ligands were tested in the hydrosilylation of acetophenone using rhodium complexes but only poor enantioselectivity was observed with 1 19 napht, 90% yield, 32% ee). T he chiral induction of these ligands remained low which is probably due to the rapid internal rotation of the chiral substituents around the C N axis. This leaves the active chiral space at the metal cent e r relatively i ll defined.

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23 Scheme 1 2 One pot synthesis of chiral imidazoliums I n other reactions, this rotation was beneficial and gave up to 62% ee in the addition of zinc reagent to cyclohexenone 1 20 ( Scheme 1 3 ). 15 This reaction employed a silver NHC complex 1 21 as a transmetallating agent Scheme 1 3 Enantioselective copper catalyze d 1,4 addition of zinc reagent using 1 21 In 2003, Andrus et al. reported the use of chiral p lanar [2,2]paracyclophane amines 1 25 and 1 26 obtained by chiral resolution, 16 as precursor in the imidazolinium synthesis ( Scheme 1 4 ). 17 The amine 1 23 c an be functionalized by Suzuki coupling using NHC 1 24 as ligand then 8 1 28 exhibited the best results in the ruthenium catalyzed ketone reduction ( Scheme 1 5 ). 18 The enantioselectivity stayed high for most aromatic substrates but it dropped to 58% ee for some aliphatic substrates.

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24 Scheme 1 4 Synthesis of chiral [2 .2]paracyclophane imidazolium s Scheme 1 5 Ruthenium catalyzed asymmetric ketone hydrosilylation In 2001, Hartwig and co workers reported the first enantioselective intramolecu arylation with chiral carbene lig ands. The best chiral NHC 1 33 wa s derived from ( ) isopinocampheyl amine and produced all carbon quaternary centers in 76% ee ( Scheme 1 6 ). In this paper, carbene ligands gave better result s than various chiral phosphines. 19 Scheme 1 6 arylation of oxindole with 1 33

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25 Following this report, Kundig et al. explored new bulky benzylamines derived NHCs 1 34 w hich showed increased enantioselectivity for the substrate 1 31 ( Scheme 1 7 ). In a following report, the reaction was extended to the formation of tertiary alkoxides as well as trisubstituted tertiary amines by replacing the methy l group with protected heteroatoms 20 Scheme 1 7 arylation of oxindole with 1 34 Glorius et al. developed a new series of ligand based on the bisoxazoline framework 1 4 21 Those ligands were applied in the Suzuki Miyaura coupling and t etra ortho substituted biaryls were synthesized fo r the first time from nonactivated aryl chlorides. 22 The first ligand generation 1 35 was derived from natural amino acids and showed only 43% ee in the arylation of oxindole The second generation 1 36 consisted of a spiro cyclohexyl substitutent which w as representative of a flexible steric bulk (chair conformation). 23 In the third generation 1 37 this spiro compound was made chiral ( Figure 1 4 ). 24 Figure 1 4 Bi s oxazoline derived NHC evolution Starting with a Bucherer Bergs reaction, 25 ( ) menthone 1 38 was converted to the corresponding hydantoin 1 39 using potassium c yanide and ammonium carbonate. The urea

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26 hydrolysis was realized under vigorous conditions usin g aqueous sulfuric acid at 150 C, and this was followed by reduction to the quaternary center amino alcohol 1 40 using sodium borohydride combined with iodine. The bisamide 1 41 synthesis was achieved by coupling with diethyloxalate. Then the alcohol moie ty in 1 41 was substituted by chloride using thionyl chloride. The bisoxazoline moiety 1 43 was produced under basic conditions at reflux in excellent yields. Silver triflate in combination with chloromethyl pivalate, instead of the typical chloromethyl et hyl ether developed by Arduengo, gave the imidazolium 1 37 in good yields ( Scheme 1 8 ). This alternative method was necessary to prevent ring opening of the oxazoline ring by chloride counterion ( Scheme 2 3 ) Scheme 1 8 Synthesis of the ( ) menthone derived IBiox s alt This third generation imidazolium 1 37 was applied in the same arylation of oxindole described previously ( Scheme 1 9 ). Excellent ee and expansion to unactivated ch loride substrate 1 44 was achieved.

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27 Scheme 1 9 Enantiose lective arylation of oxindole with 1 37 Herrmann and coworkers also developed a rigid chiral carbene structure based on the isoquinoline framework ( Scheme 1 10 ). 26 Benzonitrile 1 45 was converted to the phenylethyl amine 1 46 by addition of benzyl Grignard reagent followed by LAH reduction of the imine formed in situ The racemic amine rac 1 46 was reso lved by recrystallization of ammo nium salts using tartaric acid as a chiral counterion. Then the amine 1 46 was transformed into a formamide and subjected to a modified Bischler Napieralski cyclization 27 to yield the corresponding monoimine 1 47 Then it was dimerized using Zinc and TMSCl as coupling agent. 28 The resulting diamine 1 48 was obtained as a single diastereomer. Typical cyc lization conditions using triethyl orthoformate generated the desired imidazolium 1 49 Scheme 1 10 Synthesis of imidazolinium salts with restricted flexibility

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28 The ligand 1 49 was test ed in the iridium catalyzed hydrogenation of amidoacrylate 1 50 ( Scheme 1 11 ). Excellent conversion was observed as well as modest enantioselectivity (60% ee). Scheme 1 11 Asymmetric hydrogenation of m ethyl 2 a cetamidoacrylate with 1 52 1.2.2 Backbone C hirality In order to transfer the chirality from the backbone to the front, the substituents off the nitrogen atoms need to be rather bulky or restricted in movement fo r an effective interaction with the chiral substituents at the back. C 2 symmetric chiral vicinal diamines 29 offer a good starting point for the generation of those ligands. Phenyl or cyclohexyl substituted diamines are commercially available but still relat ively expensive (around $80 for 1g). Other substitution such as tert butyl required a three step synthesis using a chiral auxiliary ( Scheme 1 12 ). 30 The chiral bisimine 1 54 wa s first synthesized by condensation of chiral amine 1 5 3 with glyoxal. Then diastereoselective addition of Grignard reagent followed by removal of the auxiliary group furnished the desired chiral diamine 1 56 Scheme 1 12 Tert butyl substit uted vicinal diamine synthesis

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29 Using palladium catalyzed Buchwald Hartwig coupling, 31 various aryl groups c ould be added on the nitrogen atoms of 1 57 Triethyl orthoformate furnished the desired imidazolinium 1 59 ( Scheme 1 13 ). Scheme 1 13 Synthesis of N aryl substituted chiral imidazoliniums N alkyl substituted imidazolinium salts were synthesized by another pathway because primary amines would lead to dialky lated products ( Scheme 1 14 ). Instead, secondary amine 1 55 was converted to the aminal 1 60 followed by deprotection of the chiral groups which yield the imidazole 1 61 Substitution usi ng primary alkyl halide s gave imidazolinium s 1 62 15 Scheme 1 14 Synthesis of N alkyl substituted chiral imidazoliniums In 2001, Grubbs and co workers reported the first enantioselective rutheniu m olefin methatesis bearing NHC ligands. 32 The reaction consisted on a desymmetrization of achiral trienes 1 63 by asymmetric ring closing metathesis ( Table 1 1 ). In this first report, it was observed that 1 66 prepared from (1 R ,2 R ) diphenylethylenediamine showed higher enantioselectivities than 1 68 prepared from (1 R ,2 R ) 1,2 diaminocyclohexane (entries 2 and 6). Moreover, mono aryl substituted 1 66 exhibited higher reactivity than symmetrically substituted 1 65 (entry 1 and 2). Als o if chloride ligands are exchanged in situ with iodides, the enantioselectivity increased drastically (entries 2 and 3). The iodide ligand might have an

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30 electronic effect. 33 On the other hand, when a C 1 symmetric NHC ligand 1 67 was used, 34 higher enantiose lectivity was observed compared to C 2 symmetric versions with chloride ligand (entries2 and 4). Table 1 1 Asymmetric ring closing metathesis with various chiral NHC ruthenium complexes

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31 Ad ditionally, when iodide was added with 1 67 the inverse effect was observed, the enantioselectivity decreased by 50% (entries 4 and 5). 1 67 could be synthesized by combining the two methodologies developed previously (Schemes 3 and 4). Other structures with backbone chirality were developed to further expand the field of chiral NHC ligands. Tricylic carbene structures were first developed by Herrmann and co workers. 35 Chiral imidazolinium ligands 1 84 and 1 83 derived from 2,2 bipiperidine 1 73 and part ially reduced biisoquinoline 1 81 were prepared from achiral heterocyclic compounds. Bipyridine 1 69 was first over reduced, using Ni/Al alloy, 36 to give a mixture of meso and dl 2,2 bipiperidine 1 70 in 83% yield ( Scheme 1 15 ). The meso compound 1 71 was more soluble in ethanol which allowed the isolation of the racemic bipiperidine hydrobromide salt 1 72 in 45% yield. Scheme 1 15 Synthesis and separation of meso and dl forms of bipiperidine In order to resolve rac 1 73 menthol based phosphine complexes were synthesized and the two diastereomers 1 74 and 1 75 were separated by recrystallization ( Scheme 1 16 ). 35 Phenethylamine 1 76 was first converted to isoquinoline 1 77 using the Bischler Napieralski cyclization. 37 Then reductive coupling of imines with the couple Zn/Me 3 SiCl afforded the vicinal diamine 1 78 28 The dl bishydroisoquinoline 1 80 was isolated from an aqueous solution of hydrobromic acid in 44% yield ( Scheme 1 17 ).

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32 Scheme 1 16 Synthesis and chiral resolution of bipiperidine Scheme 1 17 Synthesis and separation of meso and dl forms of biisoquinoline The resolution was achieved in high yield by using D ( +) bromocamphor sulfonic acid as a chiral counterion ( S cheme 1 18 ). 28 c Both vicinal diamines 1 81 and 1 73 could be cyclized into imidazolinium using triethyl orthoformate. S cheme 1 18 Synthesis and chiral resolution of biisoquinoline

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33 Rhodium 1 83 and iridium 1 84 complexes were synthesized by transmetallation from silver NHC complexes. They were both tested in the asymmetric h ydrosilylation of acetophenone 1 29 Both showed good activity at low catalyst loadings. Low enantioselectivity was observed which was probably due to the absence of transferrable groups from the ligand backbone chirality ( Scheme 1 19 ). 35 Scheme 1 19 Asymmetric hydrosilylation using Rh and Ir complexes with NHC ligands based on reduced biisoquinoline and bipiperidine framework Stahl and co workers were the first to report a seven member ring NHC. 38 This ligand was based on a torsional twist of the phenyl rings to relieve ring strains and induced a C 2 symmetric structure. This scaffold required chiral resolution at the amidinium s tage which could be troublesome. To overcome this difficulty, the chirality of the biphenyl diamine 1 85 was set by Scheme 1 20 ). This chiral amine was resolved by simulate d moving bed (SMB) chromatography which involves a series of preparative column in series in order to separate close binary systems. 39 As it was observed in the previous example ( Scheme 1 19 ), the backbone chirality was not suffici ent to induce high enantioselectivity. Grubbs and co workers showed better results ( Table 1 1 ) when the chiral backbone was used as a relay for the substituents close to the metal sphere. Following this strategy, phenyl groups wer e installed ortho to the nitrogen substituents by a Daugulis Zaitsev 40

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34 coupling reaction developed recently by Stahl and co workers. 41 Then the acetyl directing group was removed by strong basic conditions. Sequential addition of cyclohexyl aldehyde and LAH gave the secondary amine 1 88 in 94% yield. Cyclization of this bisamine afforded the chiral amidinium 1 89 ( Scheme 1 20 ). Scheme 1 20 Syn thesis of chiral res olved seven membered ring amidinium salts The racemic version of this ligand was used in the aerobic intramolecular oxidative amination of alkenes catalyzed by palladium complexes. 42 Following this work, the chiral amidinium 1 89 was tested in the asymmetri c oxidative amination; this is the first report of the use of NHC in this reaction ( T able 1 2 ). 43 In the best case, the product was obtained in 63% ee complex 1 93 only racemic product w as obtained using similar conditions (entry 2) ; but varying the base, which is known to facilitate substrate oxidation by Pd(II), increased only the yield (entry 3).

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35 T able 1 2 Aerobic oxidative cyclization ca 1.3 Acyclic C arbene and M ethods of P reparation Acyclic diaminocarbenes 44 (ADC) are called acyclic because the nitrogen atoms surrounding the carbene are not included within the same ring ( Figure 1 5 ). Figure 1 5 Major structure difference between NHC and ADC In 1996, Alder et al. reported the first ADC (Bis(diisopropylamino)carbene) 1 96 as a crystalline solid stable both in the solid and solution state. 45 a ADCs have been shown to be more electron donating than NHCs 46 and more sterically demanding resulting from a greater N C N

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36 bond angle (121.0 vs 104.7). 44a The lack of reports concerning ADC might be at tributed to the difficult preparation of acyclic carbenes and ADC metal complexes In the first reports by Alder and co workers, 45 the amidinium 1 95 was synthesized through intermolecular Vilsmeier Haack chemistry ( Scheme 1 21 ). This route often gives low yield along with byproduct resulting from mixture of counterion from the formamidi ni um precursor. Alder and co workers found a recrystallization route by exchanging with hexafl uorophosphate salts which increased the yield and purity of the product formed. The amidi ni um 1 9 5 has a higher pkA than imidazolium 1 2 (27.9 vs 22.3 in DMSO) 47 so stronger bases are needed to deprotonate those species such as LDA, LiHMDS and NaH in NH 3 to give ADC complexes with a variety of metals 46 At first glance, free carbene seem to be generated but the base counterion actually plays a role in stabilizing the carbene from dimerization. All attempts to remove the metal ion from ADC have been unsuccessful such as using crown ether to trap Li or K cations. Scheme 1 21 Formamidinium formation and deprotonation Bielawski et al. reported the first N aryl acyclic diaminocarb ene synthesis ( Scheme 1 22 ). 48 The formamidinium 1 98 was formed by mild basic dialkylation of the corresponding formamidine 1 97 and the carbene 1 99 was obtained by deprotonation with sodium hydride. Further metal complexation wa s po ssible with rhodium or r uthenium (olefin metathesis catalyst). 49

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37 Scheme 1 22 N aryl acyclic carbene synthesis Bertrand and co workers described a methodology using Hg(SiMe 3 ) 2 as a si l y lating agent to form free acyclic diaminocarbenes 1 12 from chloroamidinium precursors 1 100 ( Scheme 1 23 ). 50 bond metathesis with generation of a mercury derivative 1 101 and liberation of TMSCl. The chloride ion can then induce a fast elimination of a second equivalent of TMSCl followed by decomplexation of the metal to give free carbene 1 12 Scheme 1 23 Synthesis o f metal free ADC and proposed mechanism Alternative routes were developed to improve the free carbene synthesis as well as the complex formation. Slaughter reported bidentate Chugaev type ADC metal complexes 51 which

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38 were synthesized by nucleophilic addition of either hydrazines 1 103 (a) o r amine 1 107 (b) to metal bound isocyanide 1 106 ( Scheme 1 24 ). Scheme 1 24 Synthesis of Chugaev type ADC Pd complexes with h ydrazine or amine Frstner et al. reported the synthesis of monodentate ADC Pd complex 1 111 through oxidative additio n of chloroamidinium precursor 1 110 which was easily synthesized from urea 1 109 ( Scheme 1 25 ). 52 Five and six m ember rings as well as dimethyl substituted ADCs were synthesized through this route. Nickel complexes could also insert into the C Cl bond. The main drawback of this method is the incorporation of phosphine ligand into the ADC metal complex limiting its a pplicability. Scheme 1 25 Pd complex formation from oxidative addition of chloroamidinium precursor

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39 Recently Hong et al. reported a general methodology of chloroamidinium activation by lithium halogen exchange ( Scheme 1 26 ). 53 Using this new methodology, a Pd complex without phosphine ligand 1 116 was synthesized as well as Rh and Ir complexes 1 114 and 1 115 Scheme 1 26 Metal complex formation through lithium halogen exchange from chloroamidinium precursors 1.4 Copper C atalyze d A pplication s 1.4.1 Copper C atalyze d Allylic A lkylation Typical palladium catalyzed allylic alkylation 54 goes through a metal a llyl intermediate which is usually attacked at the least hindered position. Generally soft nucleophiles are used such as malonate, amine, alcohol and thiol. On the other hand, copper catalyze d allylic alkylation 55 proceed with high S N 2' selectivity and all ow the use of hard nucleophiles such as Grignard reagents 56 57 dialkyl zinc 58 or aluminum reagent creating new tertiary or quaternary all carbon stereogenic centers from simple linear allylic substrates ( Scheme 1 27 ) The allyl ic al kylation 1 118 (branched compound) and/or the 1 119 (linear compound). Due to extensive research in this area, only Grignard reagent as nucleophiles will be covered.

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40 Scheme 1 27 General picture of the copper catalyze d allylic alkylation In 1995, Bckvall reported the first enantioselective copper catalyze d allylic alkylation. 59 A thiolate ligand 1 122 with pendant am ino group was used ( Scheme 1 28 ). Excellent regioselectivity and low ee were observed with ester leaving group in 1 120 In the transition state proposed by the author, the second coordination site of the ligand binds to the leavi ng group through magnesium ion. Scheme 1 28 First example of enantioselective copper catalyze d allylic alkylation by Grignard reagents After an extensive screening of phosphorus ligand, Alexakis et al. obtained good enantioselectivity using a TADDOL phosphoramidite ligand 1 125 ( Scheme 1 29 ). 60 A c hloride leaving group in 1 123 was key to the success of this reaction, in the case of an acetate leaving group such as 1 120 only racemic compound was produced. Moreover slow addition of the Grignard reagent was crucial for the chirality.

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41 Scheme 1 29 First generation of phosphoramidite ligand applied in the allylic alkylation In a second generation system, CuCN was exchanged with CuTC which increased the ee by 10% ( Scheme 1 30 a). The reaction was expanded to aliphatic substrates with the help of a second generation phosphor amidite ligand 1 128 which possessed a chiral binaphthol unit ( Scheme 1 30 b). 56 g Scheme 1 30 New condition with CuTC and s ec ond generation of phosphoramidite ligand applied for the allylic alkylation For the third generation of phosphoramidite ligand 1 132 the binaphthol unit chirality and the ortho OMe were found to increase drastically the ligand activity and selectivity ( Scheme

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42 1 31 ). 56 f If the OMe substituent s were not present the enantioselectivity dropped to 55% ee with a ratio of 79:21 between branched and linear products On the other hand, if the atropoisomeris m is switched to (S), only 46% ee was obtained with a regioselectivity of 73:27. It was believed that the OMe substituents act as pendant groups which would make this ligand bidentate. As an application of the use of OMe substituents 1 129 was converted t o chiral cyclopentene 1 131 by ring closing metathesis in a one pot process. Scheme 1 31 Third generation of phosphoramidite ligand applied in the allylic alkylation Feringa and cowork ers studied also the allylic alkylation and described the use of commercially available Taniaphos ligand 1 134 in this reaction. 56 d Interestingly, a chloride leaving group gave only linear product but aliphatic substrates w ith a bromide leaving group gave 92 94% ee of S N 2' products In order to synthesize 1,2 dialkyl motifs, the author developed a one pot process combining allyl ic alkylation and cross metathesis with methyl acrylate. The subsequent product 1 135 can be subje cted to copper catalyze d enantioselective 1,4 addition of Grignard reagents described in a previous report. 61 Using the two enantiomers of this phosphine ligand, syn and anti products could be obtained in excellent dr ( Scheme 1 32 ) Following this report, Feringa et al. extended the scope of this reaction to chiral allylic esters 1 139 56 c The temperature of the reaction was found to be a key element. If the reaction was run at 85 C, the major pro duct was linear. Careful temperature optimization gave only the

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43 branched product 1 140 ( Scheme 1 33 ). This product gave chiral furanone 1 141 by ring closing metathesis. Scheme 1 32 Synthesis of syn and anti 1,2 dialkyl motifs Scheme 1 33 Synthesis of chiral furanone. Toward the goal of making chiral building blocks Feringa and co workers e xpanded this reaction to nitrogen substituted substrates with Boc and tosylate as protecting groups 62 Using typical condition, the chiral protected amine 1 143 was obtained in 96% yield and 95% ee ( Scheme 1 34 ). Slow addition of t he substrate (2.5 mL/60 min, 3M) was crucial to obtain high ee.

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44 Scheme 1 34 Allylic alkylation with allylic bromide containing nitrogen functional group This chiral protected amine was converted to several building blocks to show the applicability of this reaction ( Scheme 1 35 ). Scheme 1 35 Synthesis of bifunctional chiral building block s fr amine Amino acid 1 146 was obtained in one step through Ru catalyzed oxidation of the terminal olefin 1 143 with NaIO 4 63 The tosylate protecting group could be selectively removed to give 1 145 by treatment with magnesium under soni cation. 64 Catalytic Wacker oxidation amino ketone 1 144 in 82% yield. A combined ozonolysis/reduction protocol

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45 transformed the olefin moiety into either 1,3 aminoalcohol 1 148 with both protecting groups on the nitrogen atom or a tosylated am ine 1 149 with Boc protected alcohol depending on the workup procedure. Direct quenching of the reaction mixture with 1 M aq eous HCl gave exclusively compound 1 148 In contrast, prior concentration of the reaction mixture at 60 C (e.g., by removal of so lvent in vacuo) led to a 1,5 migration of the Boc group 65 to the newly formed alcohol, thus yielding compound 1 149 Hall and co workers reported boron substituted substrates 1 150 which could be subjected to the allylic alkylation 45a Using phosphoramidit e ligand 1 153 chiral allylic boronate esters 1 151 could be readily converted to functionalized homoallylic alcohols 1 152 ( Scheme 1 36 ). Scheme 1 36 Enanti oselective p reparation of s ubstituted a llylboronates Okamoto et al. first reported the use of monodentate chiral NHC ligands in this reaction ( Scheme 1 37 ). 66 Acetate and 2 pyridyl ether 1 154 were found to give better results as leaving groups than chlor ide leaving group in 1 123 (different observation with phosphoramidite ligands). Using the bisoxazoline based carbene ligand developed by Glorius, 21 copper complex 1 156 was synthesized and tested in this reaction but only moderate ee was obtained (50%). 1

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46 157 gave better results (70%). A proposed transition state shows magnesium halide as counter ion of the cuprate intermediate binding to the leaving group. Then the cuprate is brought close to the double bond by some ionic interaction ( Scheme 1 37 ). Scheme 1 37 Cu catalyze d allylic alkylation using monodentate NHC ligands and proposed transition state In another report, Hoveyda a nd co workers reported a copper free enantioselective allylic alkylation 57 b where carbene ligand was proposed to act as a Lewis base to activate Grignard reagent ( Scheme 1 38 ). By varying the NHC s tructure, 1 160 was found to be the most efficient reagent in this reaction giving excellent enantioselectivities for various secondary alkyl Grignard reagents. All carbon quaternary centers could be obtained using this metal free reaction condition. The b identate ligand design was found to be crucial for good regioselectivity in the allylic alkylation. If the hydroxyl group of the ligand 1 160 was replaced by a proton or protected with a methyl, only 2% of product formation was observed.

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47 Scheme 1 38 Cu free enantioselective allylic alkylation on c hloro u nsaturated e sters One of the last challenges remaining was the use of aryl Grignard reagent as nucleophile. When usin g this reagen t, linear product wa s usually obtained as the only product The first example was reported by Alexakis et al. in 2001. 52 When CuCN and TADDOL derived ligand s were used, 2 MeOC 6 H 4 MgBr was successfully added in good regio sele ctivity and modest 21% ee. Kobayashi reported the use of a picolinoxy leaving group 1 161 to obtain high regioselectivity in allylic alkylation with aryl Grignard reagents ( Scheme 1 39 ). 67 Even though the reaction was stoichiometri c in copper, excellent transfer of chirality was observed with a chiral leaving group. Both Grignard reagent and cop per source needed to match halide source to generate in situ MgBr 2 T his Lewis acid could then activate the leaving group to facilitate its displacement by the phenyl cuprate. \ Scheme 1 39 Anti selectivity with Grignard reagent A catalytic version of this reaction was reported by Tomioka et al. using an amidophosphane ligan d 1 165 ( Scheme 1 40 ). 68 a For symmetrical substrate 1 163 only S N 2

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48 products were obtained wherea s other unsymmetrical substrates ranged from 4:1 to 3:1 mixtures of branched to linear products. Scheme 1 40 Allylic alkylation with phenyl Grignard reagent using phosphine ligand Tomioka and co workers explored more ligand structures to generalize this reaction ( Scheme 1 41 ) Using chiral N HC 1 181 developed by Grubbs, they replaced the phenyl substituents at the front by bulkier and more extended diarylmethyl. 68 b Scheme 1 41 Allylic alkyl ation with phenyl Grignard reagent using monodentate NHC ligand

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49 This new monodentate NHC ligand 1 168 was found to be very successful in the aryl Grignard addition to allylic substrates. High regioselectivity and enantioselectivity were produced for variou s substrates. 1.4.2 Copper Unsaturated Carbonyl C ompounds Cu catalyzed borylation incorporates a boron carbonyls 69 which can be subsequently converted in to useful functional groups. 70 Hosomi (a) and Miyaura (b) first reported independently this transformation ( Scheme 1 42 ). Hosomi and co workers found catalytic conditions and showed that both phosphine ligand and DMF were needed to achieve high yields. 69 q The reaction conditions were also successful on cyclic ketones. Miyaura et al. reported reactions with a wider range of 1 171 from ketones, esters to nitriles. 69 o,p Miyaura introduced the base potassium ace tate to activate the copper catalyst. Scheme 1 42 borylation of unsaturated ketones Yun and co workers disclosed a general methodology using chiral (R) ( S ) josiphos ligand for the first asymmetric version of this reaction ( Scheme 1 43 ) 69 b g A protic reagent such as

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50 methanol was discovered as a ke y component for increased yields. 69 b The reaction gave good yields and ee from a wide range of acyclic and cyclic substrates. Scheme 1 43 First asymmetric version using chiral josiphos phosphine ligand Rec ently, Shibasaki et al. reported the generation of tertiary organoboronic esters 1 175 in cyclic ketones ( Scheme 1 44 ) 69 h The use of MeOH with DMF (dimethylformamide) or DMSO (dimethylsulfoxide) s olvent drastically decreased the yields to 10%. Here the conditions are more closely Scheme 1 42 (b)). The generation in situ of LiPF 6 seems to be crucial for rate acceleration as well as increased enantioselec tivity. Scheme 1 44 Generation of quaternary centers using chiral phosphine ligands Using chiral carbene ligands, Fernndez and co alcohol in 73% ee after oxidation of boron reagent using acyclic unsaturated esters as

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51 substrates ( Scheme 1 45 ) 69 i l The reaction conditions wer e the same as reported by Yun. 69 c C hiral NHC 1 180 gave poor enantioselectivity while 1 181 ( developed by G rubbs ) increased ee by two fold and C 1 symmetric NHC ligand 1 182 gave better results than its C 2 symmetric variant 1 181 By varying the ester group 1 183 enantioselectivit y could be increased up to 73%. Scheme 1 45 First asymmetric version using chiral NHC ligands Hoveyda and co workers reported a copper free reaction using NHC 1 186 as a Lewis base ( Scheme 1 46 ). 71 The carbene ligand served as an activator for the diboron reagent. Good yields were obtained for various cyclic and acyclic ketones. MeOH was discovered to be unnecessary for this reaction when using NHC ligand. Scheme 1 46 Copper and Me O borylation of unsaturated ketones Several mechanistic studies 72 were realized and after compilation of most of them, here is a proposed mechanism of this transformation ( Figure 1 6 ). In a first stage, ligand, base and copp er

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52 are premixed to yield ligated copper alkoxide 1 187 bond metathesis with pinacolate diboron reagent. The newly formed borylated copper complex 1 188 inserts into the 1 189 Then the C copper bound species 1 189 isomerizes to the O copper bound enolate 1 190 bond metathesis occurs either with methanol or diboron reagent when p resent In the first case, copper alkoxide 1 187 is regenerated and a borylated product 1 172 is freed. On the other hand, borylated copper complex 1 188 is formed and a borylated boron enolate product 1 191 is synthesized which can be further derivatized if needed. Figure 1 6 borylation of unsaturated ketones

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53 CHAPTER 2 C 2 SYMMETRIC BIISOQUINO LINE N HETEROCYCLIC CARBENE LIGAND 2.1 Introduction : Ligand D esign for C 2 Symmetric L igands Structural diversity is far from being fully explored or available with N heterocy clic carbene ligands. Key topo logical features of NHC ligands that are desirable for asymmetric catalysis still need to be identified. Thus, exploring new types of chiral carbene ligands, especially focusing on creating an effective chiral space around the metal center, would be of great use. Limited successes so far with the current chiral carbene ligands might imply that the chiral environment created by chiral directing groups either on the nitrogens or the backbone is too far from the metal center to discriminate effectively between the two enantiotopic faces. To induce more selectivity, chosen chiral carbene ligands have been optimized to furnish new ligands ( Figure 2 2 ). The chiral design d eveloped by Grubbs accounts for ove r 90% ee in asymmetric ring closin g metathesis reactions ( Figure 2 1 ). 32 33 However a substrate dependence on enantioselectivity in these reactions might suggest th at the chiral space created by the ligand is remote from the metal center and therefore less discriminating for less sterically demanding substrates. In addition, the X ray crystal structure shows that the aryl groups on the nitrogen atoms are pointing ort hogonal to the plane of NHC Ru Therefore, it would be interesting to extend and reposition the stereodifferentiating groups more toward the metal center. We envisioned that this possibility could be explored through optimized structure ( Figure 2 1 ) where the chiral groups are installed within a ring structure which directs the components in a defined position. From this design, we are hoping for an increase in selectivity.

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54 Figure 2 1 C 2 symmetric ligand design Additionally the X atom in the ligand structure 2 2 could be varied and different properties could be obtained In a first part, where X = O, w ligand 23 by changing the chiral groups ( Figure 2 2 ) to amino indanol 2 6 which would give more bulk. Later, we wanted to add R groups on the phenyl ring to extend further the chiral pocket toward the metal The ligand 2 6 will be called the bis oxazolin e derived NHC ligand. The ligand 2 3 which was first developed by Glorius gave excellent results in the Suzuki reaction between aryl chlorides and substituted boronic acids. 22 In a second part, w here X = N, t he known bisimidazoline ligand 73 ( Figure 2 2 ) could be converted by cyclization into a carbene ligand 2 7 The latter would induce more donating character within the carbene structure thanks to the donating effects fro m the nitrogen atoms The known bisimine ligand 2 4 has been used for allylic alkylation and showed modest activity. 73 In a third part, where X = C, we decided to use the frame of the biisoquinoline carbene ligand 74 ( Figure 2 2 ) and incorporate stereogenic centers 2 8

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55 Figure 2 2 Tricyclic ligand design with variation of X 2.2 Bisoxazoline Derived NHC L igand Starting from trans aminoindanol 2 12 the bisamide 2 11 was made followed by a cyclization leading to the bisoxazoline 2 10 The imidazolium formation was carried out using known procedures ( Scheme 2 1 ). Two different ways were found to make the bisoxazoline compound ( Scheme 2 2 ). The trans aminoindanol 2 12 was refluxed in toluene with diethyl oxalate for 12 hours to lead to the bisamide 2 11 in 95% yield. Then it w as reacted with mesylate chloride in THF to give the O mesylated product 2 13 in 90% yield B iscyclization in an excess of KOH in reflux methanol for 1 hour l ed to the bisoxazoline 2 10 in quantitative yield. Moreover, another shorter path was discovered u sing Burgess reagent 75 but the overall yield was diminished.

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56 Scheme 2 1 Retrosynthesis from trans aminoindanol Scheme 2 2 Synthesis from trans aminoindanol Then the focus was on the last step which is the imidazolium formation. Usually, the common reagent is chloromethyl ethyl ether, but in this particular substrate, the chloride anion liberated in the course of the reaction can attack the oxazoline ring 2 15 and regenerate an amide 2 17 ( Scheme 2 3 ).

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57 Scheme 2 3 Decomposition pathway using chloromethyl ethyl ether For this reason, AgOTf was used to trap the chloride anion as an AgCl salt. As a trial, the known bisoxazoline 2 14 was reacted with chloromethyl pivalate and AgOTf to yield the desired imidazolium product 2 18 in 60% yield ( Scheme 2 4 ). Scheme 2 4 Bisoxazoline imidazolium synthesis Unfortunately, it could not be reproduced for 2 10 The AgOTf salt seemed to be a very sensitive reagent so a fresh bottle was used and st ored in the glove box. This time the reaction proceeded in 35% yield. After this success, reaction of the Pd NHC metal complex with imidazolium 2 19 was attempted. Known conditions reported by Glorius 21 22 using KO t Bu followed by addition of Pd(II) was attempted but only starting materials were isolated A transmetallation route was also attempted using Ag 2 O but it also failed. Later it was found out that the imidazolium 2 19 seemed to decomp ose over time and its synthesis was not reliable.

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58 With all those issues, this project was stopped. We then decided to synthesize the bisimidazoline derived NHC ligand variation 2 20 This ligand has nitrogen atoms instead of oxygen atoms which should influ ence the electronic properties. 2.3 Bisimidazoline Derived NHC L igand Starting from commercially available amino acids 2 22 ( Scheme 2 5 ), the correspon ding amino alcohol was obtained by reduction and converted to the bisamide 2 21 Th en it was cyclized in two consecutive steps to make the imidazoline moiety 2 4 which gave the corresponding imidazolium by typical ring closing conditions Scheme 2 5 Bisimidazoline ret rosynthesis Valine 2 23 was reduced with LAH to valinol 2 24 in a modest yield, and the amine 2 24 was coupled with diethyl oxalate to form the bisamide 2 25 Thionyl chloride was used to convert the alcohol s t o chlorides. Using PCl 5 the amide 2 26 was co nverted to the imidoyl chloride 2 27 The toluene was evaporated under vacuum followed by the addition of benzyl amine in acetonitrile to giv e 2 28 or aniline to giv e 2 29 ( Scheme 2 6 ) The yields were low but the mechanism involv ed four nucleop hilic substitutions and provided two new rings. So a 40% yield represented actually a 65% yield for each ring formation.

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59 Scheme 2 6 Bisimidazoline synthesis Unfortunately the final step ( Scheme 2 7 ) was not promising ; both known conditions gave a mixture of products. Moreover, the crude NMR did not show the characteristic imidazolium peak between 8 and 10 ppm. 2 28 was the first bisimine synthesi zed and we supposed that the lone pairs of the nitrogen atoms might be in conflict with the imidazolium synthesis. To solve this issue, 2 29 was synthesized hoping that the phenyl substituents would delocalize these lone pairs away from the imine moiety. So far, electronegative atoms seem ed to perturb either the imidazolium synthesis or the complex formation. This led us to think the donating effect coming from the lone pairs of the oxygen or nitrogen atoms is probably weaker than their electronegativity e ffect. So the third part involving X = Csp 2 ( Figure 2 2 ) atoms instead of X = O or X = N atoms should inhibit electronic effects and be closer in reactivity to a typical NHC

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60 Scheme 2 7 Bisimidazoline NHC synthesis 2.4 Biisoquinoline Derived NHC L igan d While our group was working on the BIQ (biisoquinoline) ligand 2 8 12 d Herrmann and coworkers reported the synthesis of the saturate d version 2 32 of our target structure. From the saturated BIQ imidazolium, the unsaturated NHC metal complexes were unexpectedly formed in moderate yields This oxidation happened during the preparation of NHC Rh or Ir complexes 2 34 and 2 35 via transm etallation with Ag 2 O when bromide was the counterion for the saturated imidazolium salt 1 49 ( Scheme 2 8 ). 12 g Their synthesis wa s based on the homocoupling of the isoquinoline moiety ( Scheme 1 10 ). Only phenyl substituted BIQ imidazolium was reported, probably the diastereoselectivity ratio of this coupling reaction might decrease for other chiral substituents. In contrast, our retro synthesis scheme would allow a wide vari et y of chiral substituents ( Scheme 2 9 ). A chiral amine 2 39 was synthesized from commercially available amino acids 2 22 followed by typical bisamide synthesis ( Scheme 2 9 ) It was cyclized using Bischl er Napieralski cyclization. Several R groups were tried such as isopropyl, isobutyl, tert butyl, cyclohexyl methyl cyclohexyl, fused cyclohexyl and phenyl.

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61 Scheme 2 8 Bisdihydroisoquin oline based carbene ligands Scheme 2 9 Biisoquinoline retrosynthesis 2.4.1 Synthesis of Isopropyl, I sobutyl, T ert Butyl and Cyclohexyl Alanine S ubstituted A mines The co mmercially available a mino acid 2 23 w as reduced by LAH to give the corresponding amino alcohol 2 24 ( Scheme 2 10 ) Then in a one pot process, the alcohol was removed. First the amine 2 24 was protected with a tosylate group then the alcohol was conver ted into a leaving group with mesylate chloride followed by the substitution of the alcohol by the amine to form the aziridine 2 46 Addition of a phenyl cuprate made in situ on to the

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62 aziridine moiety led mainly to the compound 2 50 Deprotection of the tosylate d amine gave the desired chiral amine 2 54 All these reactions c ould be run on a 10g scale with no significant drop in yield for various amino acids Other conditions were tried for the deprotection of the tosylate group such as Mg (sonication) in MeOH and Na with naphthalene. The Mg conditions worked well only in a small scale and the Na conditions were very sensitive to air and moisture. The reported procedure using Li (14 equiv.) and a catalytic amount of naphthalene was robust and did not need extra precaution. Scheme 2 10 Chiral amine synthesis from amino acids 2.4.2 Cyclohexyl Substituted Amine S ynthesis The cyclohexyl substituted amino acid being more expensive, the amine 2 62 was synthesized by another route. ( S ) Phenylglycine 2 58 was reduced to the corresponding alcohol 2 59 A 60:40 mixture of oxazolidines 2 60 were then formed by the addition o f cyclohexyl aldehyde ( Scheme 2 11 ). Then addition of b enzyl magnesium chloride gave only the diastereomer 2 61 Mild hydrogenation was not strong enough to cleave the phenethyl alcohol 2 61 ; therefore an autoclave was used to increase the hydrogen pressure up to 800 psi (54 atm) and

PAGE 63

63 the temperature to 75 C t o give the pure chiral amine 2 62 Here, it is interesting to note that the chirality in the compound 2 62 is the opposite absolute configuration compared to the compounds 2 54 to 2 57 The other enantiomer can be synthesized by using ( R ) phenylglycine. Scheme 2 11 Cyclohexyl amine synthesis 2.4.3 Fused Cyclohexyl S ubstituted Amine S ynthesis To increase the steric bulk around the ligand, a cyclohexyl ring fused to the BIQ core was proposed. U sing C hem3D, the trans configuration 2 6 3 was rejected while the cis 2 6 4 was preferred because the cyclohexyl ring seemed to sterically intrude more in this conformation ( Figure 2 3 ). Rac 2 65 was first synthesized to make sure this pathway could work ( Scheme 2 12 ). Phenyl cuprate, made in situ was added to cyclohexene oxide 2 66 which gave the trans alcohol rac 2 67 Then this alcohol was replaced by an amine with an inversion of stereocenter using Gab riel synthesis. 76 Mitsonobu reaction 77 was used to replace the secondary alcohol rac 2 67 with phthalimide in a S N 2 pathway, and then rac 2 68 was reduced to the cis amine rac 2 65 using ethylene diamine.

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64 Figure 2 3 Fused c yclohexyl BIQ ( trans 2 63 and cis 2 64 configuration) calculated with Chem3D Scheme 2 12 Racemic synthesis of the fused Cy amine rac 2 65 To resolve this racemic ami ne, the two diastereomers resulting of the amide coupling with mandelic acid were synthesized ( Scheme 2 13 ). Both compounds 2 69 and 2 70 could be

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65 separated by column chromatography unfortunately the cleavage of the amide moiety t o recover the chiral amine was too harsh and the compound could not be isolated Resolving at the alcohol stage would be more economical thus we decided to study rac 2 67 Scheme 2 13 Amide synthesis for chiral resolution The two esters 2 72 and 2 73 were first synthesized ( Scheme 2 14 ), but unfortunately they were not separable by chromatography. Scheme 2 14 Ester synthesis for chiral resolution Then using kinetic resolution, 78 the pure chiral alcohol (1R,2S) 2 67 could be obtained by replacing the alcohol moiety by a chloride 2 74 using Mitsonobu conditions ( Scheme 2 15 ). This reaction was very efficient but it used a large amount of chiral BINAP ( 2,2' bis(diphenylphosphino) 1,1' binaphthyl ) which made this process expensive for a large scale synthesis. Scheme 2 15 Non enzymatic kinetic resolution of secondary alcohol

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66 Following this kinetic resolution example, other similar methodologies were researched. Many studies reported enzymatic kinetic resolution for secondary alcohol using different lipases such as CALB, PS30 and AK. 79 Because CAL B ( Candida antarctica lipase B) also known as Novozym 435 wa s widely used, this enzyme was chosen and different conditions were screened ( Table 2 1 ). Table 2 1 Optimization of the enzymatic kinetic resolution of rac 2 67 using l ipase CALB After careful screening, t BuOMe (MTBE) was chosen as the solvent and 40 C for the temperature and t his reacti on could be done on a large scale. T he en zyme coated on acrylic resin could be reused by simple filtration and there wa s no need for careful buffering or temperature control. No yields were reported for this table because the reactions were realized on a small scale and only the ena ntioselectivity of the crude reaction mixture was monitored. Then it was

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67 tried on a larger scale and the same enzyme was filtered and reused four times with only 1% ee loss ( Scheme 2 16 ). Scheme 2 16 Scale up of the kinetic resolution of seco ndary alcohol with reused enzyme Following the previous plan ( Scheme 2 12 ) the single enantiomer (1S,2R) 2 67 was converted to 2 65 2.4.4 Phenyl S ubsti tute d Amine S ynthesis The previous ly reported synthesis of amine s 2 39 ( Scheme 2 10 ) could not be used because the regioselectivity of the phenyl cuprate addition would be opposite ( Scheme 2 17 ). With alk yl substituents, the addition takes place on the least hindered carbon but with aryl substituents the benzylic position is more reactive and electronic effects are more important than steric effects in this case Scheme 2 17 Reverse regioselectivity wi t h phenyl substituted aziridine Different strategies were envisioned ( Scheme 2 18 ). We decided to take advantage of the existing chirality in 2 78 and find a way t o remove the alcohol. First, the amine 2 78 was protected with a tosylate group then Et 3 SiH associated with a Lewis acid was used to reduce the

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68 benzylic alcohol 2 79 Unfortunately, only the starting material was isolated Then, the aziridine 2 80 was made using Mitsonobu conditions and allowed for the formation of a more reactive C 2 symmetric benzylic position. P olymethylhydro sil oxa ne and Pd/C were used to ring open the aziridine. The desired tosylated amine 2 82 was synthesized in 70% yield. Even though t his reaction worked well, four steps total are needed. A shorter path would be a good upgrade in order to make more material. Scheme 2 18 Synthesis of ( S ) 1,2 diphenylethanamine As seen pr eviously, a ring structure was more reactive toward hydrogenation. Using diethyl carbonate, the oxazolidinone 2 81 was formed in a quantitative yield. Using an autoclave for the hydrogenation the desired amine 1 46 was produced in 77% yield. This pathw ay was two steps shorter and gave an overall yield of 76%.

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69 All th e desired chiral phenethylamines 2 39 have been synthesized, now they can be used in the synthesis of the C 2 symmetric BIQ based carbene ligands 2 36 In chapter 4 the same chiral phenethyla mines could also be used in the synthesis of the C 1 symmetric MIQ (monoisoquinoline) based carbene ligand 4 2 2.4.5 Biisoquinoline Based C arbene S ynthesis from Chiral A mine Bisamide s 2 38 could serve as precursor s for a double Bischler Napieralski cyclization ( Scheme 2 9 ). Following previous work ( Scheme 2 6 ), we used diethyl oxalate as the coupling agent ( Table 2 2 ). Table 2 2 Optimizat ion of bisamide coupling using diethyl oxalate Typical conditions gave only the monoamide product 2 83 (entry 1). A more polar solvent was used and the temperature was increased (entry 2) but only small amount of bisamide was formed an d the monoamide stayed predominant. Molecular sieves were also added to the

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70 reaction mixture to trap the released ethanol but the yields stayed low (entries 4 and 5). When neat conditions were used (entry 6), the yield was increased drastically for 2 86 U nfortunately, 2 87 with more bulky substituents still gave low yield using neat conditions (entry 7). For 2 86 the neat condition was chosen but a better procedure was still needed for more bulky substituent such as Cy. If the reactivity of the nuc leophil e is decreased by steric effects then a more reactive electrophile could be used such as oxalyl chloride ( Scheme 2 19 ). This new reagent was more efficient than diethyl oxalate but it required a quick column chromatography instea d of a simple filtration. Scheme 2 19 Bisamide synthesis using oxalyl chloride With the bisamide s in hand, the double Bischler Napieralski cyclization could be a ttempted ( Table 2 3 ) This reaction consists of a double intramolecular electrophilic aromatic substitution. Scheme 2 20 Double Bischler Napieralski cyclization

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71 In a first stage, the amide moiety is converted to an imidoyl chloride 2 92 which subsequently is transformed into a nitrilium ion 2 93 Then the aromatic ring will attack this carbocation ( Scheme 2 20 ). Different dehydrating agents have been used (m ost common are POCl 3 P 2 O 5 and Tf 2 O) to convert the amide into the nitrilium ion. Usually this reaction works best with electron donating group on the aromatic ring. Few reports exist on the biscyclization and none describes a successful biscyclization wit h absence of substituents on the phenyl rings. The main issue of the double cyclization is the vicinal proximity of the two carbocations. Even if the reaction involves a step wise process, each nitrilium ion will be destabilized by either an amide group or an imine. Following reported conditions for the cyclization of mono amido ester, 80 a non chiral bisamide 2 94 was reacted with POCl 3 and ZnCl 2 to give no product (entry 1). The use of a Lewis acid seems necessary to activate the nitrilium ion for an attack from the benzene ring. ZnCl 2 was replaced by a stronger Lewis acid Zn(OTf) 2 which gave product in 38% yield (entry 2). Then those conditions were tried out on different substituted chiral bisamide (entries 3 5). The bisamide 2 87 gave no reaction (entry 5 ), which was probably due to increased steric effects Previously, a bis ( imidoyl ) chloride ( Scheme 2 6 ) was synthesized using PCl 5 as the dehydrating agent, to make the precursor for bisimidazoline based carbene ligand. The latte r reagent is stronger than POCl 3 and was used in combination with Zn(OTf) 2 in the Bischler Napieralski cyclization to yield the bisimine 2 98 in good yields (entries 8, 9, 11 a nd 12). The fused Cy substituted bis amide gave a compound similar to the product by 1 H NMR but the 13 C NMR did not show the characteristic imine peak around 160 ppm seeing in similar compounds ( Figure 2 5 )

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72 Table 2 3 Optimization of the double Bischler Napierals ki cyclization On the ot her hand, the bisamide 2 88 reacted with major consumption of the starting material to yield in the various conditions tried (Tf 2 O/DMAP, POCl 3 /Zn(OTf) 2 ) a non polar product. The latter could not be clearly iden tified but according to a reported paper, it could be stilbene 2 102 ( Scheme 2 21 ). 27 This fragmentation may be driven by the formation of cyanogen gas in the decomposition of 2 93

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73 Scheme 2 21 Fragment ation of phenyl substituted bis nitrilium The standard reaction of the bisimine with chloromethyl ethyl ether produced the C 2 symmetric BIQ imidazolium salts ( Scheme 2 22 ). There was no problem with the closing of the ring for this compound which enforced the hypothesis made about the electronics of this new ligand being similar to typical NHC. The tert butyl substituted BIQ imidazolium compound was synthesi zed by Dr Hwimin Seo. Scheme 2 22 Imidazolium synthesis from chiral amine 2.4.6 Formation of Metal C omplex es Two main methods can be used to make NHC metal complexes. First, the imidazolium c an be deprotonated with a base to make the amino carbene and a metal is added to produce the metal

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74 complex. Also a transmetallation route can be used where a carbene silver complex is synthesized from the imidazolium salt and this silver complex is exchange d with another metal. The latter was used in our project because this reaction was proved to be more efficient and cleaner than the deprotonation route. A NHC palladium complex 2 103 was synthesized by Dr Hwimin Seo ( Scheme 2 23 ) and its X ray crystal structure was obtained to look at the orientation of the chiral groups ( Figure 2 4 ). Scheme 2 23 Synthesis of Pd BIQ cinnamyl complex 2 1 03 In this structure, the chiral groups seem to be located in the axial position of the ring structure which allows a wider coverage of the metal sphere. Also, the phenyl rings at the back are twisted like atropoisomers. If this ring twist equilibrates in solution, two diastereomers should be formed and two sets of peaks should be visible by 1 H NMR. The imidazolium 2 104 only showed one set of peaks (see supporting information) which implied either only one diastereomer exists in solution or the ring flip w as too quick for the NMR time scale. Interestingly, the solid state of this structure showed the chiral groups pointing in the same direction of the phenyl rings. This BIQ Pd complex was used in the synthesis of oxindoles by arylation 19 20 24 but only racemic product was obtained.

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75 Figure 2 4 X ray struc ture of Pd carbene complex 2 10 3 81 After making the palladium complex, the synthesis of copper carbene complexes was realized Using the transmetallation route with Ag 2 O, five copper complexes w ere synthesized in good yields ( Scheme 2 24 ). Scheme 2 24 Copper complexes from C 2 symmetric BIQ carbene ligands

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76 2.4.7 Application: Copper C atalyze d A symmetric A lly lic A lkylation As a reminder, two types of products can be obtained from the allylic alkylation. The branched compound 1 118 which gives two enantiomers and the linear product 1 119 ( Scheme 2 25 ). Scheme 2 25 General scheme for allylic alkylation catalyzed by copper complexes using Grignard reagents as nucleophiles. The initial optimization of the reaction conditions was mostly performed with 3 mol% of catalyst 2 109 on naphthyl substrates 2 114 The reaction protocol consisted of adding the Grignard reagent to 2 109 to generate the cuprate complex in situ Then the allylic substrate 2 114 was added dropwise over 10 minutes. For the different solvent s array, the acetate leaving group was chosen and EtMgBr was used as a nucleophile ( Table 2 4 ). THF gave inverse regioselectivity (entry 6) as reported previously. 55 c 60 Et 2 O gave the best results at 0 C (entry 1). Decreasing further the temperature had a negative effect on the reaction yield (entries 2 and 3 ). MTBE gave good regioselectivity but the yield dropped to 61% (entry 5) After this quick survey, Et 2 O was chosen as the optimum solvent. Different leaving groups were also used in the reaction conditions ( Table 2 5 ). First, the chloride leaving group 2 117 was tried (entry 1) to compare it with the results obtained with phosphoramidite ligands 56 Surprisingly, the enantioselectivity was greatly decreased as well as the regioselectivity. Then the phosphonate leaving group 2 118 was used (entry 2) because it gives good results when bidentate carbene ligands are used for zinc reagent alkylations. 58

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77 Table 2 4 Solvent opt imization for the asymmetric allylic alkylation Then a pyridyl leaving group 2 120 was used (entry 4) to compare with the best results using another monodentate carbene ligand. 66 This time the regiosele ctivity was good but the enantioselectivity was similar to phosphonate leaving groups. This new BIQ ligand 2 109 seems to be a good match for ester based leaving groups (entries 5 7) which was in contrast to the previous reported papers. Benzoyl 2 121 and pivaloyl 2 122 substrates are bulkier (entries 6 and 7) which increased the desired regioselectivity. Benzoyl is also a better leaving group than pivaloyl which seemed to decrease the enantioselectivity; similar trend was seen between acetate 2 114 and met hyl carbonate 2 119 Acetate and pivaloyl leaving groups were chosen as the best candidates for the ligand structure screening ( Table 2 6 ). For pivaloyl leaving group, t he cyclohexyl complex 2 111 (entry 5) gave the best yield (9 9%) and enantioselectivity (7 2% ee). Interestingly, any other substitutions such as tert butyl 2 112 cyclohexyl alanine 2 113 and iso butyl 2 109 gave similar results (entries 4, 6 and 7).

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78 Table 2 5 Leaving group optimization for the asymmetric allylic alkylation For acetate leaving group, 2 111 and 2 109 gave similar enantioselectivity (entries 1 and 3) but the regioselectivity was superior for bulkier cyclohexyl. Once again, the iso pro pyl 2 110 gave similar results as the other substitutions (entry 2). Other copper catalysts were synthesized using CuBr and CuTC but the reaction results were indifferent to those changes. As a result from all those optimizations, 2 111 was chosen in combi nation with pivaloyl leaving group in Et 2 O at 0 C Other alkyl Grignard reagents can be used without significantly decreasing reaction yield, regio or enantioselectivity ( Table 2 7 ). However, use of phenyl Grignard reagent affo rded the S N 2 product exclusively (entry 4).

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79 Table 2 6 Ligand structure optimization for the asymmetric allylic alkylation Table 2 7 Grigna rd reagent survey for the asymmetric allylic alkylation

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80 Then the substrate scope was explored ( Table 2 8 ). T he reaction was effective for the formatio n of a quaternary chiral center (entry 5). The aryl substra tes also toler ate electron donating (entry 2) and electron withdrawing subs tituents (entry 3) as well as ortho substituents (entry 4) Table 2 8 Substrate scope 2.4.8 Proposed M echanism for T he Copper C atalyze d Allylic A lkylation To explain the regioselectivity and the enantioselectivity, a mechanism was proposed ( Scheme 2 26 ). This mechanism showed only monomeric copper species. Before adding the substrate, the copp er carbene complex was premixed with ethyl magnesium bromide which was likely to form a cuprate (I) complex with two ethyl groups because using different copper sources gave similar results. The cuprate complex could attack the allylic substrate in a S N 2'

PAGE 81

81 fashion to generate a copper (III) species 2 130 82 Then a reductive elimination could take place to form the desired branched product 1 118 The copper (III) species 2 130 can also be allyl complex 2 131 then another reductive elimination can happen from the other intermediate 2 132 to produce the linear product 1 119 The regioselectivity probably came from this isomerization. In t his proposed mechanism, the leaving complex 2 130 could be l igated to the carbene ligand, the ethyl group, the substrate and the leaving group. This species would go to t allyl complex 2 131 by a precomplexation of the alkene. The nature of the leaving group seemed to play a crucial role in the regioselectivity of the reaction ( Table 2 5 ). Scheme 2 26 Proposed mechanism for the asymmetric allylic alkylation complex 2 130 the leaving group could influence a lot the coordination of the alkene, which would change the ratio of linear: branched To support this hy pothesis, a bidentate leaving group was used to minimize the coordination of the alkene which should yield a single branched product. The trisubstituted allylic substrate 2 133 was protected with thiophene

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8 2 carboxylate (TC) leaving group which can coordinat e with the ester part as well as the thiophene moiety. As expected, only one regioisomer 2 134 was isolated ( Scheme 2 27 ). Scheme 2 27 Allylic alkylation using TC leaving group To further support the first stage of this proposed mechanism (S N 2'), a secon dary alcohol substrate 2 136 was used and the linear substitution product 2 116 was obtained as a major product ( Scheme 2 28 ) Scheme 2 28 Asymmetric allylic alkylation from a secondary alcohol pival ate The phenyl Grignard reagent gave mostly the linear compound which could be explained by an increase stability of the bisphenylcuprate complex. If this species was more stable, it would is omerize more readily to the least complex 2 132 and deliver mostly the linear compound 1 119 During the course of this study, it was found out that premixing of the imidazoli um, the Grignard reagent and the copper source g a ve similar results to the preformed copper complex ( Scheme 2 29 ).

PAGE 83

83 Scheme 2 29 Comparison between preformed (a ) and in situ generated (b) copper carbene complex The current best example of the tricyclic chiral diaminocarbene ligand gave up to 78% ee for the asymmetric allylic alkylation of trisubstituted alkenes. But in order to use this new chiral catalyst in the total synthesis of a natural product, the enantioselectivity should reach at least 85 90% ee. That is why more structural changes were attempted on the ligand design. 2.4.9 Further Optimization of The Ligand S tructure As a first simple change, the electronics o f the ligand were modified by putting OMe substituents on the two phenyl moieties at the back of the structure ( Scheme 2 30 ). Starting from the aziridine 2 47 the anisol e Grignard reagent was used to give the tosylated amine 2 13 7 Then it was deprotected using the combination of Li/naphthalene. Using oxalyl chloride, the bisamide 2 139 was formed in 87% yield. A milder procedure was used for the Bischler Napieralski cyclization because some product decomposition was observed when using the PCl 5 /Zn(OTf) 2 procedure DMAP and Tf 2 O converted the amide 2 139 into the desired nitrilium ion by basic con ditions and yielded the bisimine 2 140 in 40% yield. 2 140 was cyclized into the imidazolium 2 141 using conventiona l procedure.

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84 Scheme 2 30 Synthesis of the 7 OMe substituted BIQ carbene ligand 2 141 This new ligand was tested in the allylic alkylation. The branched compound was obtained in 5 8% ee same as 2 109 More d onating substituents on the aromatic rings seemed to h ave no effect on the enantioselectivity for the allylic alkylation ( Scheme 2 31 ). Scheme 2 31 Allylic alk ylation using 2 141

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85 Electron withdrawing substituents were not attempted because the Bischler Napieralski cyclization might be difficult with electron withdrawing groups on the phenyl rings. As it was discussed earlier, the phenyl rings at the back are twi sted due to a common repulsion of the hydrogen atoms. If some substituents were to replace those hydrogen atoms, the rings would be even more twisted and the chiral groups at the front will be even more extended. The same synthesis w as attempted with 3,5 d imethoxy phenyl Grignard reagent, but the synthesis of 2 146 was not successful ( Scheme 2 32 ) It was probably due to steric effects which were too large to overcome. Scheme 2 32 Synthesis of the bis OMe substituted BIQ carbene ligand 2 146

PAGE 86

86 While working on the fused cyclohexyl 2 63 we also tried to synthesize ligands with (+) norephedrine 2 147 was used as henyl group for the Bischler Napieralski cyclization. The amine 2 147 was reacted with diethyl oxalate to give the bisamide 2 148 in excellent yields ( Scheme 2 33 ). Scheme 2 33 Bisamide synthesis of norephedrine The alcohol 2 148 had to be protected to resist the harsh conditions of the Bischler Napieralski cyclization ( Table 2 9 ). First, silicon reagent was used but with little or no success (entries 1 2). DCM increased the reactivity of the starting material but only the mo noprotected bisamide was isolat ed (entry 2). The poor formation of bis protected 2 149 was probably due to the steric bulk of the tert butyl diphenylsilyl groups T his large protecting group was used to serve as a bulky chiral substituent. On the other hand, the alcohol was successfully protected with an acetyl group (entry 3) In order to protect the alcohol with a silicone group, the order of addition was reversed ( Scheme 2 34 ). Norephedrine 2 147 was protected with tert butyl diphenylsilyl group then the bisamide 2 149 formation needed oxalyl chloride as a coupling partner instead of diethyl oxalate.

PAGE 87

87 Table 2 9 Protection of t Scheme 2 34 Synthesis of the silylated bisamide The Bischler Napieralski cyclization was attempted using various methods ( Table 2 10 ). The milder condition using Tf 2 O/DMAP gave only decomposed products (entry 1). In the case of

PAGE 88

88 the typical procedure PCl 5 /Zn(OTf) 2 the starting materials decomposed also (entries 2 and 4). The Lewis acid was removed to dec rease the harshness of the reaction conditions, but even though the starting material did not decompose only monocyclized product 2 155 was obtained (entry 3). The O acetyl protected amide only gave a product 2 156 very similar to bis ( imidoyl ) chloride 2 9 2 (entry 5). The latter was stuck at this stage and would not cyclize. If some Lewis acid was added afterward, it led to decomposed products. Table 2 10 The characterization of those compounds can be rather difficult sometimes but a general trend can be seen among them. The main difference between bisamide 2 150 bis ( imidoyl ) halide 2 156 and bisimine 2 100 is their 13 C NMR. Their respec tive characteristic peaks are 160 ppm ( Figure 2 5 ) 139 ppm 73 ( Figure 2 6 ) and 164 ppm ( Figure 2 7 ). This general trend was seen for most of the compounds synthesized so f ar.

PAGE 89

89 Figure 2 5 13 C NMR of bisamide 2 150 Figure 2 6 13 C NMR of bis ( imidoyl ) halide 2 156

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90 Figure 2 7 13 C NMR of bis imin e 2 100 substituted BIQ based carbene ligands. This substitution seemed to be too reactive and only lead to decomposition or synthesis of an intermediate in the formation of the product.

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91 CHAPTER 3 IN SITU GENERATION O F ACYC LIC DIAMINOCARBENE C OPPER COMPLEX 3.1 Introduction : Discovery of T he I n S itu G eneration of A minocar bene Copper C omplex from C hloroimidazolium In the previous chapter, the synthesis of a new chiral carbene ligand was reported as well as its application in the c opper catalyze d allylic alkylation using Grignard reagent as a nucleophile. The X ray of the Pd carbene complex 2 103 was obtained by Dr. Hwimin Seo, but a X ray of the Cu carbene complex 2 110 would be more relevant in our copper catalyzed research Sever al trials were attempted with the complex 2 110 but with no success. In order to increase the stability of this complex, the copper (II) complex 3 1 was attempted following the same transmetallation procedure ( Scheme 3 1 ). Scheme 3 1 Attempted synthesis of copper (II) BIQ carbene complex 3 1 But unexpectedly chloroimidazolium salt 3 2 was isolated and characterized by X ray crystallography ( Figure 3 1 ). The silver complex was synthesized but instead of exchanging with copper (II) chloride, it generated this BIQ chloroimidazolium 3 2 Before obtaining the X ray structure, this supposed complex 3 1 was used in the allylic alkylation to com pare with copper (I) complex 2 110 ( Scheme 3 2 ). At that time, it was not surprising to get similar results based on the fact that copper(II) can be reduced to copper(I) complex in the presence of Grignard reagent. When the result of the X ray came back and the

PAGE 92

92 supposed copper (II) complex was found to be the chloroimidazolium 3 2 the results from the allylic alkylation were now intriguing ( Scheme 3 2 ). Figure 3 1 X Ray structure of chloroimidazolium CuCl 2 salt 3 2 83 Scheme 3 2 Comparison between catalysts 2 110 and 3 2 in the allylic alkylation of naphthyl substrate 2 114 It seemed a Cu carbene species was generated in situ from 3 2 and EtMgBr under the allylic alkylation conditions. This new in situ generation is not useful for NHCs because their

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93 imidazoliums can be easily synthesized and they can also be readily deprotonated to generat e various NHC metal complexes. 4 On the other hand, acyclic carbene metal complexes are more challenging to synthesize ( 1.3 Acyclic C arbene and M ethods of P reparation ). 45 53 3.2 New I n S itu Generation of ADC Cu Complex and Application in Allylic A lkylation Commercially available chloroamidinium 1 112 was used as a potential acyclic carbene precursor ( Table 3 1 ). To follow as closely as possible the procedure described previously ( Scheme 3 2 ), the chloroamidinium 1 112 was first stirred with a copper salt to generate an intermediate 3 3 which would be similar to chloroimidazolium 3 2 Then it was combined with the Grignard reagent to generate the hypothetic al acyclic aminocarbene copper species. Table 3 1 Allylic alkylation using chloroamidinium premixed with copp er salt The reaction yielded products in good yields, but with poor regioselectivity. Different copper oxidation states could be used in this reaction (entries 1 and 2). The absence of

PAGE 94

94 chloroamidinium gave low yield and poorer regiose lectivity (entry 3). Even though the linear: branched ratio was lower than seen with 3 2 the proof of concept was a success. In order to increase the regioselectivity, the substrate was varied. It was found that alkyl based substrates gave good regio selec tivity ( Table 3 2 ). The substrate 3 4 carried a PMB protecting group to facilitate HPLC conditions in future chiral experiments. Table 3 2 S N 2 allylic alkylation catalyzed by coppe r carbene complexes The premixing of chloroamidinium 1 112 with a copper source was not required (entries 1 6). Cu(I) salts such as CuCl (entry 2) or CuTC (entry 3) also gave identical results to those with

PAGE 95

95 CuCl 2 Changing the solvent to THF (entry 4) or DCM (entry 5) significantly decreased yield and regioselectivity. Bo th the copper salt and the chloroamidinium were necessary for good yields (entries 6 and 7 ) However, 1 112 selectiv 1 112 (entry 7 ) showed very different selectivity 84 Commercially available 3 8 selectiv despite th e slightly reduced yield (entry 9). A cyclic carbene 3 7 prepared by the r eported deprotonation protocol ( Scheme 3 4 ) also gave a similar result (entry 8), which wa s consistent with the idea of in situ carbene generation Acyclic d iaminoc arbene 3 7 was made in situ from amidinium 3 11 procedure ( Scheme 3 3 ). 45 b Pyrrolidine was first reacted with ethyl formate in neat conditions to yield quantitatively the f ormamide 3 9 Then the imidoyl chloride 3 10 was formed using POCl 3 and it was subsequently mixed with another equivalent of pyrrolidine. This reaction gave rise to a mixture of amidiniums due to different counterions being present (Cl PO 2 Cl 2 ). All thos e ions were exchanged with hexafluorophosphate to yield the desired product 3 11 which precipited from the solvent media. The amidinium 3 11 was then reacted with fresh LDA to give a stock solution of free carbene in THF which was used immediately ( Scheme 3 4 ). Only 65 L of this solution was used in the following allylic alkylation which contained 2 mL of Et 2 O, so the THF present was almost negligible. To compare with ADC, chloroimidazolium 3 2 was reacted with the substrate 3 4 ( Scheme 3 5 ).

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96 Scheme 3 3 Bispyrrolidine amidinium preparation Scheme 3 4 Allylic alkyla tion using free carbene ( Table 3 2 entry 8) Scheme 3 5 Comparison between catalysts 2 110 and 3 2 in the allylic alkylation of alkyl substrate

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97 The enantiosele ctivity dropped to 50% probably due to decreased steric effects from the substrate. The results were still similar between the isolated copper carbene complex 2 110 and the chloroimidazolium 3 2 This reaction was also tested with a chiral ADC 3 12 synthes ized by Dr. David Snead ( Scheme 3 6 ). The enantioselectivity was good for a preliminary result. Unfortunately the major compound was linear. Attempts to increase this ratio in favor of branched products did not succeed. Scheme 3 6 Enantioselective allylic alkylation using chiral ADC 3 12 We decided to focus on achiral catalyst to study the scope of this reaction. This ADC Cu catalyst ( 1 112 with CuTC) show ed ex for various allylic substrates ( Table 3 3 ). Symmetrical dibenzoate substrate 3 13 c ould 1 ), and quaternary centers c ould be generated from tri substituted alkene sub strates in high yield s (entries 3 5). E and Z substrates 3 15 and 3 16 reacted both efficiently (entries 2 4). The reaction with piperidine substrate 3 17 was sluggish and 15 mol% of catalyst loading was required (entry 5). However, this ADC Cu catalyst ap pears to be more reactive than the NHC Cu catalyst 85 3 22 which gave 24% yield of 3 21 under identical conditions ( Scheme 3 7 ).

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98 Table 3 3 Substrate scope Scheme 3 7 Allylic alkylation of piperidine substrate with IMesCuCl catalyst 3 22

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99 3.3 NMR E xperiments Several 13 C NMR experiments were performed to characterize the copper species and collect so me indication that the copper carbene complex was really synthesized in situ ( Table 3 4 ). The experiments consisted of mixing the chloroamidinium 1 112 a copper (I) source and Grignard reagent in CD 2 Cl 2 for some t ime. The premixing at r oom t emperature (entry 1) showed mostly decomposition of the starting material. Then it was stirred at 0 C same as in the reaction procedure for a short time and then cooled to 78 C to trap th e newly formed species and the NMR was checked at 60 C (entry 2). This time the chloroamidinium peak was visible but no carbene peak was present. Those conditions were repeated with CuCl and phenyl Grignard which has been reported to give stable cuprate complexes (entry 3). 86 In this case the chloroamidinium peak disappeared which meant it was completely converted into the metal carbene species or something else unfortunately no peak was observed in the >200 ppm region. Table 3 4 13 C NMR experi ments of the generation of copper carbene complex from chloroamidinium Those experiments were fruitful but not conclusive. The absence of carbene peak did not necessarily mean the compound was not present; the acyclic amino carbene boun d to copper can

PAGE 100

100 sometimes be rather weak in intensity. 87 The solvent was replaced by THF d 8 which would be more similar in nature to the solvent used in the reaction. Also it is less reactive with free carbene than CD 2 Cl 2 which can sometimes be acidic. The main issue to address was the weak intensity of the carbene peak; it was resolved using 13 C labeled chloroamidinium precursor 3 25 ( Scheme 3 8 ). The pyrrolidine was reacted with 13 C labeled phosgene to yield the desired urea 3 24 It was then mixed with oxalyl chloride to give the 13 C labeled chloroamidinium 3 25 which was synthesized by Dr David Snead. 13 C labeled chloroamidinium 3 25 CuCl and Grignard reagent were mixed in THF d 8 and monitored by 13 C NMR at low temperature ( Figure 3 2 ). Scheme 3 8 Preparation of 13 C labeled chloroamidinium precursor 3 25 When a mixture of chloroamidinium 3 25 and CuCl was treated with PhMgBr, the star ting material 3 25 was fully converted to two species showing typical metal carbene sp 2 carbon resonances at 206 and 217 ppm ( Figure 3 2 a). 46 The 161 and 168 ppm resonances are assigned to aryl and alkyl amidinium compounds, 3 28 and 3 25 respectively. 88 89 We speculated that the signals at 206 ppm and 217 ppm might be assigned to Cu carbene complex 3 27 90 and Mg carbene complex 3 26 respectively. 91 These tentative assignments are supported by the follo wing observations: When chloroamidinium 3 25 was treated with PhMgBr in the absence of CuCl ( Figure 3 2 b), the 216 ppm resonance appeared as the only carbene species 3 26 When this mixture was further treated with CuCl ( Figure 3 2 c), the 216 ppm resonance wa s completely convert ed to the resonance at 206 ppm 3 27 When a mixture of 3 25 and CuCl was treated with

PAGE 101

101 EtMgBr ( Figure 3 2 d), the Cu carbene resonance at 207 ppm 3 27 was ag ain observed while the 216 ppm resonance was not detected in this case. Figure 3 2 Direct 13 C NMR monitoring (at 60C) of carbene metal complex generation using 13 C labeled chloroamidi nium precursor 3 25 In order to further support those findings, the 13 C labeled formamidinium ion 3 32 was synthesized. The pyrrolidine was reacted with 13 C labeled ethyl formate, followed by POCl 3 and another pyrrolidine to give the desired product ( Scheme 3 9 ).

PAGE 102

102 Scheme 3 9 Preparation of 13 C labeled formamidinium precursor 3 32 It would be useful for this work to generate the free carbene 3 33 with reported con ditions and then subject it to Grignard reagent as well as copper. The carbene peak would be expected to shift downfield and be close to the values found before ( Figure 3 2 ). When 13 C labeled formamidinium 3 32 was reacted with fr esh LDA in a NMR tube, a resonance peak at 235 ppm appeared ( Figure 3 3 a) which was close to the reported value for free lithiated acyclic carbene 3 33 When this mixture was further treated with PhMgBr, the 235 ppm peak was compl etely converted to the resonance at 214 ppm ( Figure 3 3 b) which was very similar to the observed resonance ( Figure 3 2 b). When this new mixture was treated with CuCl, the resonance at 214 ppm was fully co nverted to a new peak at 207 ppm ( Figure 3 3 c) which was in accordance with the previous value ( Figure 3 2 c). Those findings further support the in situ generation of copper carbene complex from chloroami dinium precursor. One of the plausible mechanistic scenarios might involve m etal halide exchange between chloroamidinium 1 112 and R 2 CuMgBr ( Scheme 3 10 ) 92 This process could involve first an oxidative addition of the cuprate rea gent into the carbon chloride bond to form a copper(III) complex 3 34 which upon reductive elimination would generate the copper(I) carbene complex 3 35 Another scenario could involve a two step sequence of magnesium chloride exchange 93 a followed by transm etallation ( Scheme 3 11 ). 92 b

PAGE 103

103 Figure 3 3 Direct 13 C NMR monitoring at r oom t emperature of carbene metal complex generation usi ng 13 C labeled formamidinium 3 32 Scheme 3 10 Copper carbene complex generation involving cuprate chloride exchange Scheme 3 11 Copper carbene complex generation involving Grignard chloride exchange

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104 This transformation allowed the conversion from eas il y synthesized chloroamidinium to their respective copper complexes. While this project was studied, Dr David Snead dev eloped a similar concept but more general using lithium halogen exchange ( 1.3 Acyclic C arbene and M ethods of P reparation ) 53

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105 CHAPTER 4 C 1 SYMMETRIC MONOISOQUI NOLINE N HETEROCYCL IC CARBENE LIGAND 4.1 Introduction : Ligand D esign for C 1 Symmetric L igands The enantiomeric excess in the asymmetric allylic alkylation was limited to 75% with biisoquinoline based carbene ligands 2 2 developed in C hapter 2 which is why these ligands have to be improved. In this first design, we observed that the chiral carbene ligand 2 1 developed by Grubbs 11 positioned the aryl groups at the front orthogonal to the plan e by transfer from the backbone chirality. We thought it would be interesting to bring the chiral groups closer to the metal center using a tricyclic structure 2 2 It was clear that the BIQ ligand was rather open on the other available quadrants compared to ligand 2 1 which included those trans phenyl substitue nts at the back. In order to fill more efficiently the remaining quadrants, we conceived a C 1 symmetric version of this ligand which was built on the same chiral isoquinoline core 4 1 ( Figure 4 1 ). Figure 4 1 Increasing bulk around metal center by switching from C 2 symmetric BIQ 2 2 to C 1 symmetric MIQ 4 1 carbene ligands The imidazolium 4 2 could be synthesized from bisimine 4 3 which resulted from imine coupli ng of the ketone 4 4 T he Bischler Napieralski cyclization could be used to convert the

PAGE 106

106 ketoamide 4 5 into the monoimine 4 4 This process should be easier than the previously reported one because it involve d only o ne ring closing. To finish, chiral phenet hyl amines 2 39 developed in C hapter 2 could be used to form the monoamide 4 5 ( Scheme 4 1 ). Scheme 4 1 Retrosynthesis of the C 1 symmetric mono isoquinoline liga nd 4.2 First Attempt U sing R 2 =Me The first design consisted on using isobutyl chiral substituents 4 6 which showed good results in the allylic alkylation ( Figure 4 2 ). Figure 4 2 First design of the C 1 symmetric isoquinoline ligand 4 6 The chiral phenethylamine 2 55 was coupled with pyruvic acid to give the monoamide 4 7 using EDCI and HOBt ( Table 4 1 ) DCM was used as a solvent but only 50% yield was obtained (entry 1). To increase the yield, bases were added into the reaction conditions (entries 2 3) but the yield dropped because of an unknown byproduct which appeared in the reaction. The bases

PAGE 107

107 were removed and a more polar solvent such as DMF was used instead of DCM (entry 4) with better results. Table 4 1 Monoamide optimization To form the mono dihydroisoquinoline 4 8 ( Table 4 2 ), the curren t best conditions developed previously were used (entry 1) but only decomposition of product was observed. The PCl 5 was replaced with weaker POCl 3 (entry 2) but the same result was obtained. Using a 5:3 combination of Tf 2 O and DMAP the monoimine 4 9 was o btained in good yield (entry 3). Table 4 2 Optimization of the Bischler Napieralski cyclization

PAGE 108

108 With aryl amines ( Table 4 3 ) different acid catalysts were us ed in combination with dehydrating reagents, but only the starting material was isolated (entries 1 4). With aliphatic amines, same result was obtained but the main issue in this case remained the bad solubility of the protonated aliphatic amines (entries 5 9). As a last resort, more nucleophilic amine s such as methoxyamine or substituted hydrazine were used (entries 10 11). Only methoxyamine gave the product 4 9 but in poor yield (entry 10). Yields could not be increased by longer reaction times because th e product was decomposing with excess heating T he methyl ketone moiety in the compound 4 8 seemed unreactive which might result from enolization under acidic conditions. Table 4 3 Optimization of imine forma tion

PAGE 109

109 4.3 Second Attempt U sing R 2 =Ph This issue could be easily fixed by replacing pyruvic acid with phenylglyoxylic acid ( Scheme 4 2 ). Starting from the amine 2 55 it was coupled with 2 oxo 2 phenylacetic acid to yield the desired monoamide 4 10 The Bischler Napieralski cyclization went smoothly to give the monoimine 4 11 in 85% yield. Scheme 4 2 Monoimine synthesis from chiral isobutyl phen ethylamine This imino ketone 4 11 was non enolizable and was submitted to the imine condensation ( Table 4 4 ). The typical conditions using pTsOH as a catalyst and molecular sieves or a Dean Stark apparatus to trap the water were f irst used but with no success (entries 1 and 2). Then the stronger TiCl 4 was used stoichiometrically in combination with Et 3 N to give excellent yield of the desired product 4 12 (entry 3). 94 Table 4 4 Optimiza tion of the imine condensation from the non enolizable ketone

PAGE 110

110 Following this success, the bisimine was converted to the imidazolium 4 14 using typical procedure and it was converted to the corresponding copper complex 4 15 by transmet allation with silver, in good yield ( Scheme 4 3 ). Scheme 4 3 Imidazolium and copper complex synthesis for mesityl substituted imine This complex was used in th e allylic alkylation developed previously in order to compare its efficiency with the BIQ based carbene copper complex ( Scheme 4 4 ). Using the same conditions, the C 1 symmetric copper complex 4 15 gave excellent regioselectivity c ompare d to the respective C 2 symmetric copper complex 2 109 Unfortunately the enantioselectivity dropped drastically. Scheme 4 4 Asymmetric allylic alkylation using 4 15 In order to i ncrease the enantioselectivity, the bulky side of this new ligand was modified by changing the aryl amine in the imine condensation step ( Table 4 5 ). Bulkier 2,6 diisopropylaniline (entry 1) and meta substituted 3 ,5 dimethylanilin e (entry 2) were successfully

PAGE 111

111 condensed with the ketone moiety. Then they were converted to imidazolium and copper complexes in good yields. 3,5 D imethoxyaniline gave decomposed products (entry 3) as well as very bulky triphenylaniline (entry 4). 4.4 Achiral S ide V ariation Table 4 5 Synthesis of disubstituted MIQ NHC copper complexes The two new complexes 4 22 and 4 23 were used in the allylic alkylation ( Table 4 6 ). Using more bulky substituents at the ortho position decreased the enantioselectivity from 35% to 23% (entry 1). Meta substitution gave results similar to those obtained with bulky diisopropyl groups (entry 3). The carbene copper complex could also be synt hesized in situ as it was observed for the BIQ carbene ligand ( Scheme 2 29 ) ; only the yield was slightly reduced (entry

PAGE 112

112 2). The C 1 symmetric ligand 4 1 seemed to be optimum for this reaction with substituents smaller than isopropy l and positioned at the ortho position. Table 4 6 Allylic alkylation with disubstituted MIQ NHC copper complexes Monosubstituted aryl amines should be less bulky and may give better ena ntioselectivity ( Table 4 7 ). Coordinating substituents such as pyridine 4 27 and sulfonic acid 4 29 failed to form any products (entries 4 and 6). The synthesis of the monosubstituted isopropyl imidazolium 4 30 gave a mixture of d iastereomers by NMR (entry 1) which was surprising considering that the disubstituted isopropyl imidazolium 4 20 gave only one isomer. This diastereomeric mixture

PAGE 113

113 issue would be discussed later in the chapter. Only 2 methyl and 2 methoxy aniline gave the d esired imidazolium as a single product (entries 2 and 5). Table 4 7 Synthesis of monosubstituted MIQ NHCs The imidazoliums 4 31 and 4 3 3 were tested in the allylic alkylation ( Table 4 8 ). The regioselectivity stayed excellent but the enantioselectivity almost nullified which meant that this monosubstitution was not intruding efficiently within the metal sphere (entries 1 and 2).

PAGE 114

114 Table 4 8 Allylic alkylation using monosubstituted MIQ NHCs The achiral side of the ligand was locked with 2,4,6 trimethylaniline which gave the best results so far. The chiral side was then modified using other chiral p henethylamines developed previously in C hapter 2 4.5 Chiral Side V ariation The ( S ) 1,2 diphenylethanamine 1 46 was reacted with phenylglyoxylic acid to give the monoamide 4 34 ( Scheme 4 5 ). Then the cyclization procedure gave the sa me non polar product 2 102 as the BIQ synthesis ( Scheme 2 21 ). Scheme 4 5 Attempted synthesis of the phenyl substituted isoquinoline 4 35

PAGE 115

115 The cyclohexyl pheneth ylamine 2 62 was reacted with the carboxylic acid to give the corresponding monoamide 4 3 6 in 60% yield. Then it was cyclized in quantitative yield using toluene as a solvent instead of DCM. The bisimine 4 38 was obtained using mesitylamine ( Scheme 4 6 ). Scheme 4 6 Synthesis of 4 38 When the cyclization from bisimine 4 38 to imidazolium 4 39 was attempted at different temperatures ( Table 4 9 ), different ratios were observed (entries 1 and 2). The s ame results were observed previously ( Table 4 7 entries 1 and 3). When the product mixture was further heated in toluene at 120 C for 2 hours, the ratio st ayed unchanged. Table 4 9 Dependence between temperature and imidazolium ratio

PAGE 116

116 The evidence of this mixture was obtained from the 1 H NMR ( Figure 4 3 and Figure 4 4 ). The characteristic imidazolium signal area showed 2 peaks at 10.5 ppm and 11.8 ppm with different ratio. Even though those peaks are acidic and may exchange, they are the only peaks not overlapping in the spectrum. Figure 4 3 1 H NMR of the 4 39 (84:16) ( Scheme 4 6 entry 1). Figure 4 4 1 H NMR of 4 39 (51:49) ( Scheme 4 6 entry 2) At first glance, the compound 4 39 possesses only one chiral center but an unexpected atropoisomerism between the isoquinoline moiety and the imidazolium ring could explain this

PAGE 117

117 phenomenon. With an opposite twist of the two phenyls at the back of the molecule two diastereomers could be synthesized and would be hard to separate. The bulk increase on the isoquinoline moiety seemed to be responsible for the appearance of this mixture. The fused Cy amine 2 65 fa iled to give C 2 symmetric bisimine 2 101 but it could work in this C 1 symmetric ligand. The bisimine 4 42 was successfully synthesized in good overall yield ( Scheme 4 7 ). The imidazolium synthesis gave again a mixture of diastereo mers 4 and 4 but this time they could be both isolated by column chromatography (separated spots). Unfortunately, when this reaction was scaled up only 4 was isolated. Scheme 4 7 Imidazolium synthesis of 4 43 When looking at their respective NMR ( Figure 4 5 ), the main difference is their the same molecular weight for both o f them. X ray could not be obtained so thei r structural difference remain a mystery.

PAGE 118

118 Figure 4 5 1 H NMR of the two diastereomers of 4 43

PAGE 119

119 4 and 4 were tested in the allylic alkyl ation ( Table 4 10 ) and gave different enantioselectivities. This result proves that those two compounds are different and the various ratio obtained for 4 would probably lead to different enantioselectivities. Table 4 10 Allylic alkylation with two different isomers of 4 43 4.6 Gold BIQ and MIQ Metal C omplexes All of the reactions studied involved copper complexes. U nfortunately X ray of those complexes c oul d never be obtained. Considering another metal complex in the same row gold was chosen as an al ternative to obtain an X ray structure. MIQ and B IQ gold complexes 4 44 and 4 45 were synthesized by transmetallation from silver complex ( Scheme 4 8 ). Those complexes could be purified by column chromatography. X ray structures were obtained for both complexes ( Figure 4 7 and Figure 4 8 ). Looking at the front view of the complexes, it w as clear that 4 44 was more demanding than 4 45 It was interesting to note that the chiral substituents in both complexes were pointing in the axial position. To further compare the ligand steric effects the buried volumes 95 were calculated ( Figure 4 6 ) 96 This new parameter has been developed recently to quantify the steric effects resulting from NHC when compared to phosphine ligand which used the Tolman cone angle. 97 The buried volume gives a measure of the space occupied by the NHC ligand in the first coordination sphere of the metal centre

PAGE 120

120 Scheme 4 8 Synthesis of BIQ and MIQ gold complexes It is defined by two parameters being R (the radii of the coordinatio n sphere) and d (the atomic radii). The best correlation between % V Bur and DFT calculations was found for R = 3.5 Recently, Nolan and co workers disclosed a review on % V Bur for an extensive list of NHC and phosphine ligands. 95 c In this paper, they used d = 2 for the atomic radii. For further comparison with known complexes, we decided to use the same parameters. Figure 4 6 Buried volume for NHC liga nd

PAGE 121

121 We found 42.8% for 4 44 and 33.2% for 4 45 Au MIQ 4 44 was more demanding than Au BIQ 4 45 by 10%. This finding supported our design exp ressed by three quadrants around the metal being occupied ( Figure 4 1 ). Figure 4 7 X ray structure of 4 44 98

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122 Figure 4 8 X ray structure of 4 45 99

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123 4.7 Application: Copper C Unsaturated Carbonyl C ompounds The allylic alkylation seems to give limited results with this new ligand design. Copper is definitely a good choice for this ligand so the effort into finding a new application was directed towar d reactions catalyzed by this metal. After a few attempts, the copper borylation unsaturated carbonyl compounds was selected. An in situ catalyst generation was chosen for ease of access. It consisted of a premixing of an imidazolium, a CuCl salt and NaO t Bu in THF at r oom t emperature for 30 minutes. The base would deprotonate the imidazolium to form a n amino carbene which would complex with CuCl followed by substitution of the halide to form an alkoxide carbene copper complex 1 187 which w ould be our active catalyst ( Figure 1 6 ). From previous work by Yun, 69 b methanol was used to regenerate the active complex in the catalytic cycle ( Figure 4 9 ). Figure 4 9 borylation of unsaturated substrates

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124 The boron ester addition product 4 47 was found to be hard to isolate. Without any purification, this intermediate w as further treated with NaBO 3 alcohol substrate 4 48 The yields and enantioselectivities reported would be for two consecutive steps. The preliminary result was encouraging with 86% yield and 50% ee ( Table 4 11 ent ry 1). KO t Bu and NaO t Bu were equally efficient (entries 1 and 3). Polar, non polar solvents and other copper salts did not affect the outcome of the reaction (entries 3 7). Decreasing the temperature did not increase the enantioselectivity but the yield wa s decreased (entry 2). Absence of ligand gave reduced yield (entries 8 10). Table 4 11 borylation for cinnamonitrile The various C 1 symmetric ligands developed previously were tested in this reaction ( Table 4 12 ). Fused cyclohexyl substitution 4 gave lower ee than isobut yl 4 14 (en tries 2 and 1 ) which was the inverse of the allylic alkylation result s Increased bulk on the achiral side 4 20

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125 decreased the e nantioselectivity (entry 5) as was observed in the allylic alkylation. Surprisingly, the BIQ ligand 2 108 gave mostly racemic products which reinforced the need of this new C 1 symmetric ligand (entries 3 and 4). When using DCM, the yield was decreased resulting probably from trace amount of hydrochloric acid present in the solvent (entries 5 and 6). Table 4 12 Ligand scope for cinnamonitrile From this small study, 4 14 gave the best results. The electron withdrawing groups from the substrate 1 171 were varied to study their effect on this reaction ( Table 4 13 ). The reaction worked well for quaternary substrates 4 49 and 4 52 (entries 1 and 5). Ketone 4 49 gave lower ee than nitrile 4 50 (entries 1 a nd 2). On the other hand, amide 4 55 increased the ee significantly compared to n itriles and esters (entries 4, 5 and 8). Thioester 4 53 was unreactive toward this reaction (entry 6).

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126 Table 4 13 Substrate scope

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127 A trend between the enantioselectivity and the functio nal group off the substrate seemed to appear. The more electronegative the oxygen atom becomes the better the enantioselectivity is. This is probably due to a stronger and tighter binding of the copper with the oxygen atom which would be responsible for a closer transition state ( Figure 4 10 ). Figure 4 10 Proposed transition state with amide functionality The amide functionality was the most promising T hus subs tituents off the nitrogen atom were varied to further increase the enantioselectivity ( Table 4 14 ). Bigger groups such as Cy 4 56 gave better yields but the same enantioselectivity (entry 2). The Weinreb amide 4 57 was tested and gave excellent yields with satisfactory selectivity (entry 3). Table 4 14 Amide substrate optimization

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128 The latter would be interesting for further derivatization. The benzyl substrates f or the first time gave an enantioselectivity over 80% (entry 4) with excellent yields for PMB substituents (entry 5). In a recent report by Hoveyda, 71 it was shown that carbene copper complexes did not need methanol to be r unsaturated ketones ( Figure 4 11 ). This probably resulted from higher reactivity of copper enolate 1 190 donor NHC compared to the less Lewis basic phosphine based ligand s. Figure 4 11 P borylation with NHC ligand New optimizations were realized with the benzyl amide substrate 4 58 ( Table 4 15 ). The rea ction proceeded very well without methanol (entries 1 and 2) which reinforced the advantage of NHC over phosphine ligands. Other polar and apolar solvents increased slightly the ee but the yield dropped a lot (entries 3 6 and 8). This was probably due to l ower solubility. When using a mixture of THF/Et 2 O, the enantioselectivity stayed the same as when pure Et 2 O was used but the

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129 yield was similar to pure THF (entry 7). The THF might coordinate to B 2 pin 2 and facilitate the bond metathesis. Copper (II) salts were similarly effective in this reaction (entries 9 and 10). Table 4 15 Reaction condition o ptimization for N N dibenzylcinnamamide The optimization results with amide substrates were similar to those with cinnamonitrile which showed the robustness of this new C 1 symmetric catalyst 4 14 For mechanistic studies, the Z unsaturated amide 4 59 was synthesized and submitted to the Borylation reaction ( Table 4 16 ). The catalyst favored the other enantiomer but in lower enantioselectivity (entries 1 and 2). New imidazoliums were synthesized for further studies of the effect of the achiral moiety ( Table 4 17 ). 4 70 was synthesized for comparison with 4 14 (entry 2). Those two ligands differ by the methyl in para position.

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130 Table 4 16 borylation with different alkene configuration Lower ee for 4 70 would mean the methyl is needed in the para position and bigger groups could be incorporated for improvement. Similar ee would suggest that the para position does not interfere with the reaction. Higher ee would imply the para position obstructs t he reaction. 4 69 was formed to increase the bulk between methyl and isopropyl (entry 1). 4 71 was made to study inductive effect on the catalyst (entry 3). Anthracene substituted 4 72 would be interesting as a facial bulk (entry 4). Aliphatic amines could also be used in the synthesis of this ligand (entry 5). Those new imidazoliums were used in the copper catalyzed borylation ( Table 4 18 ). 4 70 gave slight better enantioselectivity than 4 14 which proved the additional methyl is decreasing the ee (entries 1 and 3). The slight increase in bulk with ethyl substitution 4 69 gave the same results (entry 4). A large increase in bulk with isopropyl in 4 20 decreased the enantioselectivity (entry 2). Interestingly, the electron withdrawi ng substituents in 4 71 contributed to a 13% drop in ee (entries 5 and 6). 4 33 and 4 72 did not improve the enantioselectivity in the borylation reaction (entries 7 and 8).

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131 Table 4 17 Synthesis of additiona l MIQ NHCs This amide substrate may give a better transition state considering that BIQ based carbene ligand 2 104 obtained 36% ee with 4 59 (entry 12) and 7% ee with 4 46 ( Table 4 12 entry 3). Two mixtures of 4 39 were tested in this reaction (entries 10 and 11). The difference in ee supported the formati on of two diastereomers. The three best ligands are the unhindered ortho substituted ones (entries 1, 3 and 4).

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132 Table 4 18 Ligand scope for N N bis(4 methoxybenzyl)cinnamamide Over the course of this study, inconsistencies were observed in the yields of this reaction. After a careful screening of the reaction parameters, the temperature of the reaction was put at fault ( Table 4 19 ). From fall to winter, the room temperature decreased by 6 C and this small drop had a dramatic effect on the yield s (entries 1 and 3). To palliate this variation in yields, the reaction temperature was increased to 40 C. Better yields were obtained without a drop in the enantioselectivity (entries 4 and 5). Additionally, the reaction could be completed in 6 hours instead of 12 hours (entries 5 and 6). Unfortunately, 4 69 only gave 85% ee (entries 1 3) instead of 88% reported previously ( Table 4 18 entry 4).

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133 Table 4 19 Temperature effect on the copper catalyze d borylation For reproducibility r easons, we decided to choose 4 14 as our ligand of choice for the substrate scope ( Table 4 20 ). The reaction tolerated electron donating (entries 2 and 3 ), electron withdrawing (entry 5) and meta substituents (entry 6 ), as well as aliphatic substituents (entries 6 and 7). Surprisingly, low yield and ee was obtained with ortho fluorine substitution (entry 4). Combining our results and observations, we envisioned a working transition state responsible for our selectivity ( Figure 4 12 ). Using the X ray structure 4 44 gold and chloride atoms were replaced by copper and boron using reported bond lengths for similar complexes. 100 Considering that MIQ carbene ligand blocks the three quadrants around the metal cent er and giving the absolute configuration of the product, the substrate should approach from the bottom left corner. The model i with Si face attack by the boryl group is most likely to form the major enantiomer ( S ) ( Table 4 14 e ntry 1 ) where as model ii with attack on the Re face would encounter steric repulsion from the aryl substituents.

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134 Table 4 20 Substrate scope Figure 4 12 Proposed transition state model for the asymmetric borylation B = pinB

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135 4.8 Further D irections for MIQ or BIQ L igands Over the course of this study, several BIQ or MIQ substituted carbene ligands were synthesized. The pursuit of more bulky substitution is still needed to increase selectivity. S ubstitution prevented the formation of the bisimine moiety as seen in fused cyclohexyl and substitution should be pursued but a few substituents raise issues. A ryl groups decompose the bisamide into cyanogens and stilbe ne ( Scheme 2 21 ). Benzyl substituents can also participate in the Bischler Napieralski cyclization which can scramble the chiral centers. Interesting results could be obtained by incorporation of quaternary centers at the on.

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136 CHAPTER 5 CONCLUSION Bisoxazoline and bisimidazoline based carbene ligand synthesis revealed some issues either in the metal complex or the imidazolium formation. Concluding that the proximal heteroatom next to the imidazolium rings were detrimental for N hete rocyclic carbene reactivity, new all carbon based amino carbene ligands were synthesized with success. New C 2 (BIQ) and C 1 symmetric (MIQ) amino carbene ligands were developed from the same chiral phenethylamines which were synthesized in four steps from amino acids. Both synthesis involved amide formation followed by Bischler Napieralski cyclization. BIQ based carbene ligand s isobutyl, tert butyl, cyclohexyl, cyclohexyl alanine). Fu be installed on this ligand. On the other hand, MIQ based carbene ligand s could accept both types of chirality as long as they possessed CH 2 groups next to it (fused cyclohexyl and isobutyl). Other groups such as c yclohexyl and tert butyl gave mixture of diastereomers resulting from hindered rotation. BIQ based carbene ligand s were successfully applied in the copper catalyze d allylic alkylation using Grignard reagent as nucleophiles. The highlight of this transforma tion was the formation of an all carbon quaternary center in 91% yield, 85:15 ( S N 2' vs S N 2 ) selectivity and 76% ee. MIQ based carbene ligand s were used in the copper catalyze unsaturated amides with an average of 85% ee for alkyl and aryl substrates. The ligands gave opposite results in those two reactions: BIQ gave 36% ee for the borylation and MIQ gave 35% ee in the allylic alkylation. Those two results pr oved the need for diversity in lig and structure. These ligands can be accessed readily fro m the same intermediate and used accordingly for future applications.

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137 While working on the BIQ copper complex characterization, we observed an in situ carbene copper complex formation from chloroimidazolium. As our group was interested in the development of new acyclic carbene ligands, we applied the methodology to this field. Using the same copper catalyze d allylic alkylation with Grignard reagent, we generated in sit u the first acyclic carbene copper complex which catalyzed efficiently th e latter reaction. The carbene cuprate complex was observed by low temperature NMR and based on characteristic metal carbene 13 C NMR chemical shifts. This project wa s a typical exampl e of serendipity in organic chemistry.

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138 CHAPTER 6 EXPERIMENTAL SECTION 6.1 General R emarks All reactions were conducted in flame dried glassware under an inert atmosphere of dry argon. THF, CH 2 Cl 2 Et 2 O and toluene were purified under positive pressure of dry nitrogen by Meyer Solvent Dispensing System prior to use. All the chemicals used were purchased from Sigma Aldrich Co., Acros Organics and Strem Chemicals Inc. and were used as received without further purification. NMR spectra were recorded using a Mercury 300 FT NMR, operating at 300 MHz for 1 H NMR and at 75.4 MHz for 13 C NMR. All chemical shifts for 1 H and 13 C NMR spectroscopy were referenced to residual signals from CDCl 3 ( 1 H ) 7.27 ppm and ( 13 C ) 77.23 ppm. High resolution mass spectra were recorded on a GC/MS spectrometer or a TOF LC/MS spectrometer. Optical rotations were recorded on a Perkin Elmer 241 polarimeter. Enantiomer ratios were determined by chiral HPLC analysis (Shimadzu) using Chiral Technologies Chiralcel OJ H, Chiralpak IA and IB columns and Regi s Technologies Whelk 01 column. 6.2 C 2 S ymmetric NHC L igands 6.2.1 Bisoxazoline Derived NHC L igand N 1, N 2 bis((1 R ,2 R ) 2 hydroxy 2,3 dihydro 1H inden 1 yl)oxalamide (2 11) In a flame dried Schlenk flask, 194 L (1.42 mmol) of diethyl oxalate was added t o a suspension of 445 mg (2.98 mmol) of (1 R 2 R ) 1 amino 2,3 dihydro 1H inden 2 ol in toluene (10 mL). The reaction mixture was stirred at reflux for 12 h. It was cooled at room temperature

PAGE 139

139 and hexane (5 mL) was added. The product was isolated by filtration on Buchner funnel and it was washed with hexane (3 x 5 mL) to yield 478 mg (1.36 mmol, 95.5%) of N 1, N 2 bis((1 R ,2 R ) 2 hydroxy 2,3 dihydro 1H inden 1 yl)oxalamide 1 H NMR (300MHz ,DMSO d 6 ) = 9.08 (d, J = 9.1 Hz, 2 H), 7.26 7.04 (m, 8 H), 5.36 (d, J = 5.9 Hz, 2 H), 5.15 5.05 (m, 2 H), 4.57 4.45 (m, 2 H), 3.16 (dd, J = 7.3, 15.2 Hz, 2 H), 2.72 (dd, J = 7.6, 15.5 Hz, 2 H) 13 C NMR (75MHz ,CHLOROFORM d) = 166.0, 146.6, 145.2, 133.1, 132 .1, 130.1, 129.0, 82.3, 66.9, 44.2 N 1 N 2 bis((1 R ,2 R ) 2 methanesulfonate 2,3 dihydro 1H inden 1 yl)oxalamide (2 13) In a flame dried Schlenk flask, 55.0 L of mesylate chloride ( 0.712 mmol) was added to a suspension of 100 mg of N 1, N 2 bis((1 R ,2 R ) 2 hydro xy 2,3 dihydro 1H inden 1 yl)oxalamide ( 0.284 mmol) and 158 L (1.14 mmol) of Et 3 N in THF ( 2 mL ) at 0 C. The suspension was stirred at ro om temperature for 4 h.4 mL of H 2 O was added and the solid was isolated by filtration on Buchn er funnel. It was washed with H 2 O (3 x 2 mL) to yield 117 mg ( 0.230 mmol, 82.0 %) of N 1, N 2 bis((1 R ,2 R ) 2 methanesulfonate 2,3 d ihydro 1H inden 1 yl)oxalamide 1 H NMR (300MHz ,DMSO d 6 ) = 9.51 (d, J = 8.5 Hz, 2 H), 7.35 7.24 (m, 6 H), 7.18 (s, 2 H), 5.52 5.40 (m, 4 H), 3.49 (dd, J = 6.9, 16.0 Hz, 2 H), 3.24 (s, 6 H), 3.16 3.03 (m, 2 H) 13 C NMR (75MHz ,DMSO d 6 ) = 160.9, 139 .5, 138.8, 129.2, 128.1, 125.5, 124.3, 85.1, 59.5, 38.3, 37.1

PAGE 140

140 (3a R ,3'a R ,8a S ,8'a S ) 8,8a,8',8'a tetrahydro 3aH,3'aH 2,2' biindeno[1,2 d]oxazole (2 10) To a flame dried Schlenk flask was added 268 mg (0.527 mmol) of N 1, N 2 bis((1 R ,2 R ) 2 methanesulfonate 2,3 dihydro 1H inden 1 yl)oxalamide 440 mg (7.90 mmol) of potassium hydroxide and 25 mL of methanol. The suspension was heated at 70 C for 1 h. The reaction mixture was concentrated under vacuum. The residue was extracted with DCM (10 mL) and washed with H 2 O (2 x 10 mL), dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure to yield 156 mg (0.494 mmol, 94.0% ) of (3a R ,3'a R ,8a S ,8'a S ) 8,8a,8',8'a tetrahydro 3aH,3'aH 2, 2' biindeno[1,2 d]oxazole 1 H NMR (299MHz ,CHLOROFORM d) = 7.57 7 .43 (m, 1 H), 7.36 7.12 (m, 3 H), 5.73 (d, J = 7.9 Hz, 1 H), 5.55 5.40 (m, 1 H), 3.54 3.23 (m, 2 H) 13 C NMR (75MHz ,CHLOROFORM d) = 155.3, 140.5, 139.6, 129.0, 127.6, 125.8, 125.4, 84.6, 77.2, 39.5 IBiox[ ( R S ) indanol ] HOTf (2 19) To a flame dr ied Schlenk flask was added 460 mg (1.46 mmol) of (3a R ,3'a R ,8a S ,8'a S ) 8,8a,8',8'a tetrahydro 3aH,3'aH 2, 2' biindeno[1,2 d]oxazole, 449 mg (1.75 mmol) of silver

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141 triflate and 5 mL of DCM. The reaction mixture was wrapped in aluminum foil to protect it from t he light and stirred for 5 min. 306 L (2.11 mmol) of chloromethyl pivalate was then added. The mixture was stirred at 40 C for 16 h. It was cooled to room temperature and DCM (10 mL) followed by methanl (10 mL) were added to the flask. The suspension was filtered and concentrated under vacuum. Silicagel column chromatography with a 98:2 mixture of DCM and methanol as the eluent gave 230 mg (0.480 mmol, 32.9%) of IBiox[( R S ) indanol]HOTf 1 H NMR (299MHz ,CHLOROFORM d) = 9.38 (s, 1 H), 7.75 (d, J = 7.6 H z, 2 H), 7.38 7.15 (m, 6 H), 6.26 (d, J = 6.5 Hz, 2 H), 6.07 5.97 (m, 2 H), 3.54 3.33 (m, 4 H) 13 C NMR (75MHz ,CHLOROFORM d) = 139.9, 135.1, 131.0, 129.1, 126.2, 125.5, 125.1, 114.5, 95.4, 67.1, 38.5 6.2.2 Bisimidazoline Derived NHC L igand N 1, N 2 bis( ( S ) 1 chloro 3 methylbutan 2 yl)oxalamide (2 26) To a flame dried Schlenk flask was added 100 mg (0.384 mmol) of N 1, N 2 bis( ( S ) 1 hydroxy 3 methylbutan 2 yl)oxalamide 61.3 L (0.845 mmol) of thionyl chloride and 2 mL of toluene. The reaction mixture was sti rred at 90 C for 12 h. After cooling at room temperature, the solution was poured onto cold 20% potassium hydroxide (4 mL). The mixture was extracted with DCM (3 X 5 mL), washed with a saturated NaHCO 3 solution (10 mL) and dried over anhydrous sodium sulf ate. The reaction mixture was concentrated under vacuum to yield 111 mg (0.373 mmol, 97.2%) of N 1, N 2 bis(( S ) 1 chloro 3 methylbutan 2 yl)oxalamide (2 26)

PAGE 142

142 1 H NMR (300MHz ,CHLOROFORM d) = 7.54 (d, J = 9.1 Hz, 2 H), 3.93 (ddt, J = 4.2, 8.2, 9.6 Hz, 2 H), 3 .78 3.60 (m, 4 H), 2.06 (dq, J = 6.8, 14.8 Hz, 2 H), 0.98 (d, J = 6.7 Hz, 6 H), 1.02 (d, J = 6.7 Hz, 6 H) (4 S ,4' S ) 1,1' dibenzyl 4,4' diisopropyl 4,4',5,5' tetrahydro 1H,1'H 2,2' biimidazole (2 28) To a flame dried Schlenk flask was added 100 mg (0.33 6 mmol) of N 1, N 2 bis(( S ) 1 chloro 3 methylbutan 2 yl)oxalamide 175 mg (0.840 mmol) of PCl 5 and 5 mL of toluene. The reaction mixture was stirred for 5 h at 85 C. After cooling to room temperature, the solution was concentrated under vacuum and under iner t atmosphere to give the crude imidoyl chloride as a yellow oil. 5 mL of acetonitrile and 281 L (2.02 mmol) of Et 3 N were added to the residue and the mixture was stirred for 5 min. 81 L (0.730 mmol) of benzylamine was then added and the reaction mixture was stirred at reflux for 12 h. After cooling to room temperature, 25 mL of water was added. The mixture was extracted with DCM (3 X 10 mL), and dried over anhydrous sodium sulfate. The reaction mixture was concentrated under vacuum Silicagel column chrom atography with a 95:5 mixture of ethyl acetate and methanol as the eluent gave 54 mg (0.134 mmol, 40%) of (4 S ,4' S ) 1,1' dibenzyl 4,4' diisopropyl 4,4',5,5' tetrahydro 1H,1'H 2,2' biimidazole

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143 1 H NMR (300MHz ,CHLOROFORM d) = 7.44 7.12 (m, 10 H), 4.67 4.40 (m, 4 H), 3.87 (td, J = 6.7, 10.4 Hz, 2 H), 3.33 (dd, J = 9.4, 10.8 Hz, 2 H), 2.92 (t, J = 9.7 Hz, 2 H), 1.75 (dq, J = 6.7, 13.3 Hz, 2 H), 0.94 (d, J = 6.7 Hz, 6 H), 0.84 (d, J = 6.7 Hz, 6 H) 13 C NMR (75MHz ,CHLOROFORM d) = 156.5, 137.9, 128.8, 128. 1, 127.6, 71.5, 52.4, 51.6, 33.5, 19.4, 18.9 (4 S ,4' S ) 4,4' diisopropyl 1,1' diphenyl 4,4',5,5' tetrahydro 1H,1'H 2,2' biimidazole (2 29) To a flame dried Schlenk flask was added 313 mg (1.05 mmol) of N 1, N 2 bis(( S ) 1 chloro 3 methylbutan 2 yl)oxalamide, 550 mg (2.63 mmol) of PCl 5 and 15 mL of toluene. The reaction mixture was stirred for 5 h at 85 C. After cooling to room temperature, the solution was concentrated under vacuum and under inert atmosphere to give the crude imidoyl chloride as a yellow oil. 15 mL of acetonitrile and 880 L (6.32 mmol) of Et 3 N were added to the residue and the mixture was stirred for 5 min. 215 L (2.32 mmol) of aniline was then added and the reaction mixture was stirred at reflux for 12 h. After cooling to room temperature, 75 mL of water was added. The mixture was extracted with DCM (3 X 30 mL), and dried over anhydrous sodium sulfate. The reaction mixture was concentrated under vacuum Silicagel column chromatography with ethyl acetate as the eluent gave 70 mg (0.187 mmol, 17.7%) of (4 S ,4' S ) 4,4' diisopropyl 1,1' diphenyl 4,4',5,5' tetrahydro 1H,1'H 2,2' biimidazole

PAGE 144

144 1 H NMR (299MHz ,CHLOROFORM d) = 7.71 7.58 (m, 4 H), 7.50 (d, J = 7.1 Hz, 2 H), 7.29 7.18 (m, 4 H), 4.71 4.53 (m, J = 11.3 Hz, 1 H), 4.24 (t, J = 9.5 Hz, 2 H), 4.12 (dd, J = 9.2, 11.5 Hz, 2 H), 2.65 2.48 (m, 1 H), 1.70 (d, J = 6.8 Hz, 6 H), 1.61 (d, J = 6.5 Hz, 6 H) 13 C NMR (75MHz ,CHLOROFORM d) = 153.6, 139.9, 128.4, 123.3, 119.5, 71.2, 53.8, 32.9, 19.6, 19.1, 1.2 6.2.3 Biisoquinoline Derived NHC L igand ( S ) 2 isobutyl 1 tosylaziridine ( 2 47 ). To a flame dried Schlenk flask was added 4.60 g (39.2 mmol) of ( S ) 2 amino 4 methylpentan 1 ol 2 43 22.0 mL (157 mmol) of triethylamine and 50 mL of CH 2 Cl 2 The reaction mixture was cooled to 25 and 8.40 g (44 .0 mmol) of p toluenesulfonyl chloride was added. The cooled mixture was stirred for 2 h at 30 and then for 1 h at room temperature. The stirred mixture was cooled to 25 and 3.20 mL (41.5 mmol) of methanesulfonyl chloride was added. After stirring for 2 h at 30 the reaction mixture was stirred for 10 h at room temperature. The reaction solution was washed with 200 mL of 1 M aqueous HCl solution and then 100 mL of a saturated NaHCO 3 solution. The organic solution was dried over anhydrous MgSO 4 and the solvent was removed under reduced pressure. Silicagel column chromatography with a 6:1 solution of hexane and ethyl acetate as the eluent afforded 8.00 g (31.6 mmol, 80.5%) of 2 47 ( S ) 2 isopropyl 1 tosylaziridine ( 2 46 )

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145 6.50 g (27.2 mmol, 79. 4 %) of 2 46 was obtained from 3.50 g (34.0 mmol) of ( S ) 2 amino 3 methylbutan 1 ol 2 43 ( S ) 4 methyl 1 phenylpentan 2 amine ( 2 55 ). To a flame dried Schlenk flask was added 1.90 g (10.0 mmol) of CuI and 20 mL of THF. The reaction mixture was cooled to 30 and 33.0 mL of PhMgCl solution (2.0 M in THF) was slowly added. After 30 min stirring at 30 8.00 g (31.6 mmol) of 2 47 was added, and the reaction temperature was slowly increased to room temperature. After 3 h, the reaction was cautiously quenched by 50 mL of a saturated NH 4 Cl aqueous solution. The organic layer was separated and dried over anhydrous MgSO 4 All volatiles were removed in vacuo. Silicagel column chromatography with a 3:1 mixture of hexane and ethyl acetate as the eluent gave 8.60 g (25.9 mmol, 82.1 %) of 2 51 To a flame dried Schlenk flask was added 1.45 g (210.0 mmol) of Li and 30 mL of THF. To the reaction mixture was added 0.190 g of naphthalene at room temperature. After 30 min, the solution turned dark blue. 5.50 g (16 .6 mmol) of ( S ) 4 methyl N (4 methyl 1 phenylpentan 2 yl) benzenesulfonamide 2 51 was added at 78 and the reaction temperature was slowly warmed to room temperature. After 12 h, the solution was transferred through a canula to another flask to remove the unreacted Li. The solution was quenched by a saturated NH 4 Cl solution and rinsed with water. To the organic solution was added 30 mL of 1 M HCl aqueous

PAGE 146

146 solution, and the organic layer was discarded. To the acidic aqueous solution was added 20 mL of 20 % NaOH aqueous solution. Crude 2 55 was extracted by 60 mL of Et 2 O and dried over anhydrous MgSO 4 Evaporation of the solvent gave 2.80 g (15.8 mmol, 95.1 %) of 2 55 ( R ) 3 methyl 1 phenylbutan 2 amine ( 2 54 ). 1.40 g (8.60 mmol, 83 %) of 2 54 was obtai ned from 2.50 g (10.4 mmol) of 2 46 ( S ) 1 cyclohexyl 3 phenylpropan 2 amine (2 57) 600 mg (2.76 mmol, 57%) of ( S ) 1 cyclohexyl 3 phenylpropan 2 amine was obtained from 1.42g (4.84 mmol) of ( S ) 2 (cyclohexylmethyl) 1 tosylaziridine 1 H NMR (300MHz ,CHLO ROFORM d) = 7.39 7.02 (m, 5 H), 3.10 (br. s., 1 H), 2.78 (dd, J = 4.3, 13.3 Hz, 1 H), 2.41 (dd, J = 8.8, 13.5 Hz, 1 H), 1.80 1.62 (m, 4 H), 1.34 1.04 (m, 7 H), 1.04 0.76 (m, 2 H) 13 C NMR (75MHz ,CHLOROFORM d) = 140.0, 129.5, 128.6, 126.3, 49.9, 45.9, 45. 5, 34.7, 34.4, 33.2, 26.9, 26.6, 26.5 ( S ) 1 cyclohexyl 2 phenylethanamine ( 2 6 2 ) A flame dried Schlenk flask was charged with 6.20 g (45.0 mmol) of ( S ) 2 amino 2 phenylethanol 2 59 9.00 g of MgSO 4 and 50 mL of CH 2 Cl 2 To the reaction mixture was added

PAGE 147

147 5.00 mL (42.0 mmol) of cyclohexyl carboxaldehyde at room temperature. After stirring for 2 h, the reaction mixture was filtered through a pad of celite. All volatiles were removed in vacuo. To another flame dried schlenk flask was added the filtrate and 2 0 ml of THF. 100 mL of benzylmagnesium chloride solution (2.0 M in THF) was added to the reaction flask at 30 The reaction mixture was slowly warmed to room temperature, and stirred for 4 h. The reaction was quenched with 50 mL of a saturated NH 4 Cl so lution, and the organic layer was separated and dried over anhydrous MgSO 4 After removal of the solvent under reduced pressure, silicagel column chromatography with a 4:1 mixture of hexane and ethyl acetate as the eluent gave 9.70 g (29.9 mmol, 66.4 %) of ( S ) 2 (( S ) 1 cyclohexyl 2 phenylethylamino) 2 phenylethanol 2 61 A mixture of 9.70 g (29.9 mmol) of 2 61 2.50 g of 10% Pd/C in 100 mL of ethanol was stirred at 75 for 48 h under 800 psi pressure of H 2 The reaction solution was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The residue was purified by slilicagel column chromatography using 5 % MeOH solution in CH 2 Cl 2 a s the eluent to give 3.66 g (18.0 mmol, 60.2%) of 2 62 t rans 2 phenylcyclohexanol (rac 2 67) To a cooled (0 C) magnetically stirred solution of PhMgBr (89.0 mL, 89.0 mmol) and 40 mL of THF, 5.64 g (29.65 mmol) of CuI was added under argon followed by dropwise addition of a solution of 5.0 mL (49.4 mmol) of cyclohexene oxide in 30 mL of THF. The reaction mixture was stirred at room temperature for 12 h. A saturated solution of ammonium chloride (20 mL) was slowly added and the mixture was extracted wit h diethyl ether (3 X 30mL), dried with MgSO 4 and concentrated under vacuum. The residue was purified by flash column

PAGE 148

148 chroma tography (silica gel, 1:4 ethyl acetate /hexane) to afford 7.90 g (44.8 mmol, 90.7%) of t rans 2 phenylcyclohexanol (1 S ,2 R ) 2 phenylcy clohexanol (1 S ,2 R 2 67) To a flame dried pressur vessel was added 2.00 g (11.4 mmol) of trans 2 phenylcyclohexanol, 5.3 mL (57.1 mmol) of vinyl acetate, 2.5 g of CALB and 57 mL of t BuOMe. The reaction mixture was heated at 45 C and stirred for 2 d. The enzyme CALB was filtered off and could be reused while the solution was concentrated under vacuum. The residue was purified by flash column chroma tography (silica gel, 2.5:97.5 ethyl acetate /hexane) to afford 720 mg (4.11 mmol, 71.8% yield, 99.4% ee) of ( 1 S ,2 R ) 2 phenylcyclohexanol 2 ((1 R ,2 R ) 2 phenylcyclohexyl)isoindoline 1,3 dione (2 68) To a flame dried Schlenk flask was added 500 mg (2.85 mmol) of (1 S ,2 R ) 2 phenylcyclohexanol 630 mg (4.28 mmol) of phthalimide, 1.12 g (4.28 mmol) of PPh 3 876 L (4 .42 mmol) of DIAD and 10 mL (0.3M) of THF. The reaction mixture was stirred at room temperature for 12 h and concentrated under vacuum. Silicagel column chromatography with a 97.5:2.5 mixture of hexane and ethyl acetate as the eluent gave 634 mg (2.08 mmol 72.8%) of 2 ((1 R ,2 R ) 2 phenylcyclohexyl)isoindoline 1,3 dione

PAGE 149

149 (1 R ,2 R ) 2 phenylcyclohexanamine (2 65) To a flame dried Schlenk flask was added 585 mg (1.916 mmol) of 2 ((1 R ,2 R ) 2 phenylcyclohexyl)isoindoline 1,3 dione 642 L (9.58 mmol) of ethylene d iamine and 10 mL of ethanol. The reaction mixture was stirred at 90 C for 12 h. The suspension was filtered and the solution was concentrated under reduced pressure. The residue was diluted in Et 2 O (20 mL) and to the resulting organic solution was added 15 mL of 1 M HCl aqueous solution, and the organic layer was discarded. To the acidic aqueous solution was added 20 mL of 20 % NaOH aqueous solution. The latter was extracted by 60 mL of Et 2 O and dried over anhydrous MgSO 4 Evaporation of the solvent gave 275 mg (1.57 mmol, 82.2%) of (1 R ,2 R ) 2 phenylcyclohexanamine 1 H NMR (300MHz ,CHLOROFORM d) = 7.44 7.04 (m, 5 H), 3.66 (td, J = 4.5, 10.0 Hz, 1 H), 2.49 2.38 (m, 1 H), 2.18 2.05 (m, 1 H), 1.92 1.72 (m, 3 H), 1.62 1.35 (m, 4 H) 13 C NMR (75MHz CHLOROFORM d) = 143.5, 129.0, 128.1, 127.0, 74.6, 53.4, 34.7, 33.5, 26.3, 25.3 (2 R ,3 R ) 2,3 diphenyl 1 tosylaziridine (2 80) To a flame dried Schlenk flask was added 500 mg (1.36 mmol) of N ((1 R ,2 S ) 2 hydroxy 1,2 diphenylethyl) 4 methylbenzenesulfonami de 535 mg (2.04 mmol) of PPh 3 416 L (2.10 mmol) of DIAD and 10 mL of THF. The reaction mixture was stirred at room temperature for 12 h. The suspension was concentrated un der vacuum. Silicalgel chromatography with a 5:1

PAGE 150

150 mixture of hexane and ethyl ace tate as eluent gave 400 mg (1.14 mmol, 84.2% yield) of (2 R ,3 R ) 2,3 diphenyl 1 tosylaziridine 1 H NMR (300MHz ,CHLOROFORM d) = 7.63 (d, J = 8.5 Hz, 1 H), 7.47 7.31 (m, 10 H), 7.20 (d, J = 8.2 Hz, 1 H), 4.27 (s, 2 H), 2.39 (s, 3 H) (4 R ,5 S ) 4,5 diphenyloxazolidin 2 one (2 81) To a flame dried Schlenk flask was added 2.00 g (9.38 mmol) of (1 S ,2 R ) 2 amino 1,2 diphenylethanol 152 mg (2.80 mmol) of sodium methoxide and 36 mL (300 mmol) of diethyl carbonate. The reaction mixture was stirred at 80 C for 12 h. The reaction mixture was concentrated under vacuum and the solid was washed with hexane (2 X 40 mL) to yield 2.24 g (9.37 7 mmol, 99%) of (4 R ,5 S ) 4,5 diphenyloxazolidin 2 one 1 H NMR (299MHz ,CHLOROFORM d) = 7.23 7.01 (m, 6 H), 7.01 6.80 (m, 4 H), 5.94 (d, J = 8.2 Hz, 1 H), 5.64 (br. s., 1 H), 5.17 (d, J = 8.2 Hz, 1 H) 13 C NMR (75MHz ,CHLOROFORM d) = 151.9, 128.5, 128.3, 128.1, 127.1, 126.3, 82.5, 61.7 ( S ) 1,2 diphenylethanamine (1 46) 7.83 g (32. 7 mmol) of (4 R ,5 S ) 4,5 diphenyloxazolidin 2 one 2.3g of 10% Pd/C and 175 mL of methanol were stirred at room temperature for 60 h under 400 psi pressure of H 2 The reaction solution was filtered through a pad of celite, and the filtrate was concentrated u nder

PAGE 151

151 reduced pressure. The residue was diluted in Et 2 O (20 mL) and to the resulting organic solution was added 15 mL of 1 M HCl aqueous solution, and the organic layer was discarded. To the acidic aqueous solution was added 20 mL of 20 % NaOH aqueous solut ion. The latter was extracted by 60 mL of Et 2 O and dried over anhydrous MgSO 4 Evaporation of the solvent gave 4.20 g (21.3 mmol, 65%) of ( S ) 1,2 diphenylethanamine 1 H NMR (300MHz ,CHLOROFORM d) = 7.44 7.19 (m, 10 H), 4.23 (dd, J = 4.9, 8.8 Hz, 1 H), 3.06 (dd, J = 5.0, 13.4 Hz, 1 H), 2.87 (dd, J = 8.9, 13.3 Hz, 1 H), 1.50 (br. s., 2 H) 13 C NMR (75MHz ,CHLOROFORM d) = 146.0, 139.4, 129.7, 128.7, 127.4, 126.7, 126.7, 57.9, 46.8 ( S ) 1 (4 methoxyphenyl) 4 methylpentan 2 amine (2 138 ) 82 mg (0.395 mmol 48.2% ) of ( S ) 1 (4 methoxyphenyl) 4 methylpentan 2 amine was obtained from 208 mg (0.825 mmol) of ( S ) 2 isobutyl 1 tosylaziridine 1 H NMR (299MHz ,CHLOROFORM d) = 7.17 6.99 (m, J = 8.5 Hz, 2 H), 6.89 6.72 (m, J = 8.5 Hz, 2 H), 3.76 (s, 3 H), 3.00 ( br. s., 1 H), 2.70 (dd, J = 4.5, 13.6 Hz, 1 H), 2.48 2.26 (m, 1 H), 1.74 (tt, J = 6.5, 13.4 Hz, 1 H), 1.24 (t, J = 6.9 Hz, 2 H), 0.86 (d, J = 6.5 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 3 H) 13 C NMR (75MHz ,CHLOROFORM d) = 158.3, 131.8, 130.4, 114.0, 55.5, 50.7 47.1, 44.2, 25.0, 23.7, 22.2 ( S ) 1 (3,5 dimethoxyphenyl) 4 methylpentan 2 amine (2 143)

PAGE 152

152 163 mg (0.686 mmol, 43.2%) of ( S ) 1 (3,5 dimethoxyphenyl) 4 methylpentan 2 amine was obtained from 75 mg (0.296 mmol) of ( S ) 2 isobutyl 1 tosylaziridine 1 H NMR (29 9MHz ,CHLOROFORM d) = 6.44 6.19 (m, 3 H), 3.76 (s, 6 H), 3.10 2.97 (m, 1 H), 2.72 (dd, J = 4.2, 13.3 Hz, 1 H), 2.39 2.23 (m, 1 H), 1.74 (dt, J = 6.8, 13.9 Hz, 1 H), 1.31 1.22 (m, 2 H), 0.88 (d, J = 6.5 Hz, 3 H), 0.92 (d, J = 6.5 Hz, 3 H) 13 C NMR (75MHz ,CHLOROFORM d ) = 161.0, 142.3, 107.5, 98.3, 55.5, 50.4, 47.3, 45.6, 25.1, 23.6, 22.3 N 1, N 2 bis(( S ) 4 methyl 1 phenylpentan 2yl)oxalamide ( 2 90 ). In a flame dried schlenk flask, 2.60 g (14.7 mmol) of 2 55 and 0.82 mL (6.00 mmol) of diethyl oxalate were stirred at After cooling to room temperature, the solid residue was purified by column chromatography using silicagel ( CH 2 Cl 2 ) to afford 1.13 g (2.77 mmol, 46.2 %) of 2 90 1 H NMR (300 MHz, CDCl 3 ) ppm 7.31 7.12 (m, 12H), 4.18 (m, 2H), 2. 79 (d, J = 4.8 Hz, 2H), 2.77 (d, J = 4.8 Hz, 2H), 1.59 (m, 2H), 1.34 (m, 4H), 0.88 (d, J = 6.6 Hz, 6H), 0.87 (d, J = 6.6 Hz, 6H)

PAGE 153

153 13 C NMR (75 MHz, CDCl 3 ) ppm 159.44, 137.65, 129.64, 128.64, 126.75, 49.38, 43.41, 41.65, 25.03, 23.36, 22.06 HRMS Calcd. for C 2 6 H 3 7 N 2 O 2 [M+H] + : 409.2850, Found: 409.2826 D 24 c 2.76, CHCl 3 ) N 1, N 2 bis(( R ) 3 methyl 1 phenylbutan 2yl)oxalamide ( 2 86 ). 0.88 g (2.30 mmol, 80.0 %) of 2 86 was obtained from 0.988 g (6.05 mmol) of 2 54 and 0.394 ml (2.88 mmol) of diethyl o xalate. 1 H NMR (300 MHz, CDCl 3 ) ppm 7.28 7.12 (m, 12H), 3.98 (m, 2H), 2.85 (dd, J = 5.8, 14.2 Hz, 2H), 2.67 (dd, J = 8.4, 14.1 Hz, 2H), 1.80 (m, 2H), 0.96 (d, J = 7.2 Hz, 6H), 0.94 (d, J = 6.9 Hz, 6H) 13 C NMR (75 MHz, CDCl 3 ) ppm 159.66, 138.18, 129. 31, 128.64, 126.64, 56.60, 38.47, 31.02, 19.85, 17.62 HRMS Calcd. for C 24 H 33 N 2 O 2 [M+H] + : 381.2537, Found: 381.2518 D 25 +16.5 ( c 2.71, CHCl 3 ) N 1, N 2 bis(( S ) 1 cyclohexyl 2 phenylethyl)oxalamide ( 2 87 ).

PAGE 154

154 To a cooled, magnetically stirred solution of 2 6 2 (0.458 g, 2.25 mmol) and triethylamine (0.350 mL, 2.53 mmol) in THF (28 mL) under argon, oxalyl chloride (0.096 mL, 1.09 mmol) was then stirred for 12 h. The rea (10 mL). The mixture was extracted with CHCl 3 (3 x 15 mL). The combined organic extracts were dried over MgSO 4 filtered, and concentrated under reduced pressure. The residue was purified by fl ash column chromatography (silica gel, 3:1 chloroform/hexane) to afford 2 87 (0.349 g, 0.778 mmol, 70.7% yield). 1 H NMR (300 MHz, CDCl 3 ) ppm 7.27 7.09 (m, 12H), 3.95 (m, 2H), 2.88 (dd, J = 5.6, 14.0 Hz, 2H), 2.66 (dd, J = 8.3, 14.0 Hz, 2H), 1.78 1.5 8 (m, 10H), 1.44 (m, 2H), 1.24 1.02 (m, 10H) 13 C NMR (75 MHz, CDCl 3 ) ppm 159.54, 138.20, 129.34, 128.61, 126.59, 56.05, 40.98, 38.15, 30.31, 28.28, 26.45, 26.29, 26.24 HRMS Calcd. for C 30 H 41 N 2 O 2 [M+H] + : 461.3163, Found: 461.3164 D 24 24.4 ( c 4.78, C HCl 3 ) N 1, N 2 bis(( S ) 1 cyclohexyl 3 phenylpropan 2 yl)oxalamide (2 91)

PAGE 155

155 90 mg (0.184 mmol, 91.1%) of N 1, N 2 bis(( S ) 1 cyclohexyl 3 phenylpropan 2 yl)oxalamide was obtained from 90 mg (0.414 mmol) of (S) 1 cyclohexyl 3 phenylpropan 2 amine 65 L (0.460 mm ol) of Et 3 N, 17.6 L (0.202 mmol) of oxalyl chloride and 4 mL of THF. 1 H NMR (300MHz ,CHLOROFORM d) = 7.33 7.10 (m, 11 H), 4.32 4.11 (m, 2 H), 2.78 (d, J = 6.4 Hz, 4 H), 1.89 1.49 (m, 11 H), 1.43 1.05 (m, 11 H), 1.01 0.63 (m, 4 H) 13 C NMR (75MHz ,CHLOROFORM d) = 159.4, 137.7, 129.6, 128.6, 126.7, 48.7, 41.9, 41.6, 34.5, 34.0, 32.8, 26.7, 26 .4, 26.3 N 1, N 2 bis((1 R ,2 R ) 2 phenylcyclohexyl)oxalamide (2 89) 260 mg (0.642 mmol, 91.0%) of N 1, N 2 bis((1 R ,2 R ) 2 phenylcyclohexyl)oxalamide was obtained from 255 mg (1.45 mmol) of (1 R ,2 R ) 2 phenylcyclohexanamine 216 L (1.56 mmol) of Et 3 N, 62 L (0.709 mmol) of oxalyl chloride and 3 mL of THF. 1 H NMR (300MHz ,CHLOROFORM d) = 7.50 (d, J = 9.1 Hz, 2 H), 7.37 6.99 (m, 10 H), 4.27 (dq, J = 3.1, 9.4 Hz, 2 H), 2.93 (dt, J = 3.9, 11.9 Hz, 2 H), 2.02 1.63 (m, 12 H), 1.53 1.38 (m, 4 H) 13 C NMR (75MHz ,CHLOROFORM d) = 159.1, 142.7, 128.5, 127.5, 126.7, 50.5, 45.8, 31.1, 25.8 25.7, 20.6

PAGE 156

156 N 1, N 2 bis(( S ) 1,2 diphenylethyl)oxalamide (2 88) 320 mg (0.713 mmol, 68.8%) of N 1, N 2 bis(( S ) 1,2 diphenylethyl)oxalamide was obtained from 419 mg (2.13 mmol) of ( S ) 1,2 diphenylethanamine 330 L (2.39 mmol) of Et 3 N, 90.0 L (1.037 mmol) of oxalyl chloride and 15 mL of THF. 1 H NMR (300MHz ,CHLOROFORM d) = 7.76 (d, J = 8.2 Hz, 2 H), 7.34 7.11 (m, 16 H), 7.08 6.95 (m, 4 H), 5.12 (q, J = 7.4 Hz, 2 H), 3.11 (d, J = 7.0 Hz, 4 H) 13 C NMR (75MHz ,CHLOROFORM d) = 159.0, 140.5, 136.9, 129.5, 128.8, 128.7, 127.9, 127.0, 126.8, 55.5, 42.8 N 1, N 2 bis(( S ) 1 (4 methoxyphenyl) 4 methylpentan 2 yl)oxalamide (2 139) 480 mg ( 1.02 mmol, 87.1 %) of N 1, N 2 bis(( S ) 1 (4 methoxyphenyl) 4 methylpentan 2 yl)oxalamide was obtained from 512 mg ( 2.47 mmol) of ( S ) 1 (4 methoxyphenyl) 4 methylpentan 2 amine 375 L ( 2.76 mmol) of Et 3 N, 102 L ( 1.18 mmol) of oxalyl chloride and 8 mL of THF.

PAGE 157

157 1 H NMR (300MHz ,CHLOROFORM d) = 7.19 (d, J = 9.7 Hz, 2 H), 7.07 6.99 (m, 4 H), 6.84 6.78 (m, 4 H), 4.13 (tq, J = 6.1, 9.1 Hz, 2 H), 3.76 (s, 6 H), 2.75 2.66 (m, 4 H), 1.65 1.51 (m, 2 H), 1.38 1.22 (m, 4 H), 0.86 (d, J = 5.0 Hz, 6 H), 0.84 (d, J = 4.7 Hz, 6 H) 13 C NMR (75MHz ,CHLOROFORM d) = 159.5, 158.5, 130.6, 129.6, 114.0, 55.4, 49.4, 43.3, 40.7, 25.0, 23.4, 22.1 N 1, N 2 bis(( S ) 1 (3,5 dimethoxyphenyl) 4 methylpentan 2 yl)oxalamide (2 144) 9 6 8 mg (0.183 mmol, 56.0 %) of N 1, N 2 bis(( S ) 1 (3,5 dimethoxyphenyl) 4 methylpent an 2 yl)oxalamide was obtained from 163 mg (0.686 mmol) of ( S ) 1 (3,5 dimethoxyphenyl) 4 methylpentan 2 amine 105 L (0.751 mmol) of Et 3 N, 28.8 L (0.327 mmol) of oxalyl chloride and 4 mL of THF. 1 H NMR (300MHz ,CHLOROFORM d) = 7.23 (d, J = 9.7 Hz, 2 H) 6.34 6.26 (m, 6 H), 4.26 4.08 (m, 2 H), 3.74 (s, 12 H), 2.79 2.62 (m, 2 H), 1.67 1.50 (m, 2 H), 1.32 (ddd, J = 2.6, 5.5, 8.6 Hz, 4 H), 0.87 (d, J = 5.0 Hz, 6 H), 0.84 (d, J = 4.7 Hz, 6 H) 13 C NMR (75MHz ,CHLOROFORM d) = 161.0, 159.5, 139.9, 107 .5, 99.0, 55.5, 49.2, 43.2, 41.9, 25.0, 23.4, 22.0 (3 S S ) diisobutyl tetrahydro biisoquinoline ( 2 96 ).

PAGE 158

158 To a flame dried schlenk flask was added 1.20 g (2.94 mmol) of 2 90 and 30 mL of toluene. To this flask under nitrogen atmosphe re was added 3.20 g (8.80 mmol) of Zn(OTf) 2 and 3.70 g (18.0 mmol) of PCl 5 The reaction mixture was heated at 85 for 12 h. After cooling to room temperature, the reaction was quenched with 20mL of 30% aqueous ammonium hydroxide solution. The solution was diluted with 100 mL of diethyl ether. The organic layer was separated and dried over anhydrous MgSO 4 After all volatiles were evaporated under reduced pressure, 0.930 g (2.50 mmol, 85.0 %) of 2 96 was purified by silicagel column chromatography with a 7:1 mixture of hexane and ethyl acetate as the eluent. 1 H NMR (300 MHz, CDCl 3 ) ppm 7.35 7.14 (m, 8H), 3.84 (m 2H), 2.93 (dd, J = 5.4, 15.9 Hz, 2H), 2.65 (dd, J = 11.2, 15.9 Hz, 2H), 1.98 1.79 (m, 4H), 1.53 (m, 2H), 0.97 (d, J = 6.0 Hz, 6H), 0.95 (d, J = 6.6 Hz, 6H) 13 C NMR (75 MHz, CDCl 3 ) ppm 164.06, 137.51, 131.13, 128.67, 128.03, 127.08, 126.98, 55.28, 4 4.99, 31.59, 25.08, 23.39, 22,60 HRMS Calcd. for C 26 H 32 N 2 [M + ]: 372.2560, Found: 372.2581 D 23 72.7 ( c 1.73, CHCl 3 ) (3 R R ) diisopropyl tetrahydro biisoquinoline ( 2 97 ).

PAGE 159

159 2.10 g (6.10 mmol, 82.7 %) of 2 97 was obtained from 2.81 g (7.38 mmol) of 2 86 8.1 g (22.3 mmol) of Zn(OTf) 2 and 9.2 g (44.2 mmol) of PCl 5 1 H NMR (300 MHz, CDCl 3 ) ppm 7.33 7.13 (m, 8H), 3.48 (m, 2H), 2.78 2.74 (m, 4H), 2.23 (m, 2H), 1.13 (d, J = 6.9 Hz, 6H), 1.08 (d, J = 6.6 Hz, 6H) 13 C NMR (75 MHz, CD Cl 3 ) ppm 164.15, 138.26, 131.00, 128.68, 127.98, 126.98, 126.87, 62.81, 33.07, 27.62, 19.94, 19.02 HRMS Calcd. for C 24 H 28 N 2 [M + ]: 344.2247, Found: 344.2213 D 25 +32.4 ( c 2.43, CHCl 3 ) (3 S ,3' S ) 3,3' dicyclohexyl 3,3',4,4' tetrahydro 1,1' biisoquinoline ( 2 98 ). 0.357 g (0.841 mmol, 60.9%) of 2 98 was obtained from 0.619 g (1.38 mmol) of 2 87 1 H NMR (300 MHz, CDCl 3 ) ppm 7.26 7.05 (m, 8H), 3.40 (m, 2H), 2.69 (m, 4H), 1.93 1.54 (m, 12H), 1.29 1.09 (m, 10H) 13 C NMR (75 MHz, CDCl 3 ), ppm 163.86, 138.16, 130.85, 128.47, 127.79, 62.03, 42.92, 30.35, 29. 18, 27.88, 26.81, 26.70, 26.57

PAGE 160

160 HRMS Calcd. for C 30 H 37 N 2 [M+H] + : 425.2951, Found: 425.2957 D 24 c 2.64, CHCl 3 ) (3 S ,3' S ) 3,3' bis(cyclohexylmethyl) 3,3',4,4' tetrahydro 1,1' biisoquinoline (2 101) 380 mg (0.839 mmol, 91.0%) of (3S,3'S) 3,3' bis(cyclohexylmethyl) 3,3',4,4' tetrahydro 1,1' biisoquinoline was obtained from 450 mg (0.921 mmol) of N1,N2 bis((S) 1 cyclohexyl 3 phenylpropan 2 yl)oxalamide 1.15 g (5.52 mmol) of PCl 5 1.00 g (2.76 m mol) of Zn(OTf) 2 and 45 mL of toluene. 1 H NMR (300MHz ,CHLOROFORM d) = 7.44 7.04 (m, 8 H), 3.98 3.75 (m, 2 H), 2.93 (dd, J = 5.6, 15.8 Hz, 2 H), 2.64 (dd, J = 11.1, 15.8 Hz, 2 H), 1.98 1.48 (m, 16 H), 1.38 1.06 (m, 6 H), 1.06 0.75 (m, 4 H) 13 C NMR (75MHz ,CHLOROFORM d) = 164.0, 137.5, 131.1, 128.6, 128.0, 127. 1, 126.9, 54.5, 43.5, 34.6, 34.1, 33.3, 31.6, 26.9, 26.6 (3 S ,3' S ) 3,3' diisobutyl 7,7' dimethoxy 3,3',4,4' tetrahydro 1,1' biisoquinoline (2 140)

PAGE 161

161 To a flame dried schlenk flask was added 105 mg (0.224 mmol) of N 1, N 2 bis(( S ) 1 (4 methoxyphenyl) 4 methylp entan 2 yl)oxalamide and 4 mL of toluene. To this flask under argon atmosphere was added 82 mg (0.672 mmol) of DMAP and 186 L (1.34 mmol) of Tf 2 O. The reaction mixture was heated at 95 for 12 h. After cooling to room temperature, the reaction was quenched with 10mL of a saturated solution of sodium carbonate. The solution was diluted with 20 mL of DCM. The organic layer was separated and dried over anhydrous MgSO 4 After all volatiles were evaporated under reduced pressure, 38.0 mg (0.0878 mmol, 39.2 %) of (3 S ,3' S ) 3,3' diisobutyl 7,7' dimethoxy 3,3',4,4' tetrahydro 1,1' biisoquinoline was purified by silicagel column chromatography with a 99:1 mixture of DCM and methanol as the eluent 1 H NMR (300MHz ,CHLOROFORM d) = 7.12 7.06 (m, 2 H), 6.94 6.81 (m, 4 H), 3.85 3.75 (m, 2 H), 3.67 (s, 6 H), 2.84 (dd, J = 5.4, 15.7 Hz, 2 H), 2.55 (dd, J = 11.1, 15.5 Hz, 2 H), 2.00 1.85 (m, 2 H), 1.79 (dt, J = 7.1, 13.7 Hz, 2 H), 1.48 (ddd, J = 6.6, 7.5, 13.5 Hz, 2 H), 0.92 ( d, J = 3.5 Hz, 6 H), 0.94 (d, J = 3.5 Hz, 6 H) 13 C NMR (75MHz ,CHLOROFORM d) = 163.7, 158.4, 129.6, 129.2, 128.8, 116.8, 112.6, 55.6, 55.5, 44.9, 30.7, 25.0, 23.3, 22.6 (3 S ,3' S ) 3,3' diisobutyl 6,6',8,8' tetramethoxy 3,3',4,4' tetrahydro 1,1' biisoquinol ine (2 145)

PAGE 162

162 144 mg (0.292 mmol, 86.9%) of (3 S ,3' S ) 3,3' diisobutyl 5,6',8,8' tetramethoxy 3,3',4,4' tetrahydro 1,1' biisoquinoline was obtained from 177 mg (0.336 mmol) of N 1, N 2 bis(( S ) 1 (3,5 dimethoxyphenyl) 4 methylpentan 2 yl)oxalamide 246 mg (2.02 mmol) of DMAP, 470 L (3.36 mmol) of Tf 2 O and 17 mL of toluene. 1 H NMR (300MHz ,CHLOROFORM d) = 6.29 (s, 2 H), 6.15 6.04 (m, 2 H), 3.85 3.67 (m, 8 H), 3.35 3.27 (m, 6 H), 2.74 (dd, J = 4.5, 15.4 Hz, 2 H), 2.41 (dd, J = 11.7, 15.2 Hz, 2 H), 1.89 1.74 (m, 4 H), 1.51 1.37 (m, 2 H), 0.90 (t, J = 6.2 Hz, 12 H) 13 C NMR (75MHz ,CHLOROFORM d) = 164.4, 161.8, 157.9, 142.4, 113.4, 104.7, 97.0, 55.5, 55.1, 54.2, 44.5, 32.9, 25.0, 23.6, 22.5 [6( S ),8( S ) Diisobutyl 5,6,8,9 tetrahydro 6a,7a diazadibenzo[c,g]fluorenium] chloride (2 104) A flame dried Schlenk flask was charged with 0.250 g (0.670 mm ol) of 2 96 0.140 mL (1.49 mmol) of chloromethyl ethyl ether and 3 mL of THF. After 12 h, all volatiles were evaporated in vacuo. The sticky residue was purified by silicagel column chromatography with a 10:1 mixture of CH 2 Cl 2 and methanol as the eluent t o afford 0.260 g (0.619 mmol, 92.4 %) of 2 104 1 H NMR (300 MHz, CDCl 3 ) ppm 11.22 (s, 1H), 7.94 (d, J = 8.1 Hz, 2H), 7.43 7.31 (m, 6H), 5.21 (m, 2H), 3.42 (m, 2H), 3.01 (d, J = 15.9 Hz, 2H), 1.59 (m, 4H), 1.28 (m, 2H), 0.96 (d, J = 6.3 Hz, 6H), 0.94 ( d, J = 6.3 Hz, 6H)

PAGE 163

163 13 C NMR (75 MHz, CDCl 3 ) ppm 135.33, 132.20, 130.76, 130.18, 127.95, 124.55, 124.06, 53.60, 41.36, 33.15, 25.08, 23.22, 22.12 HRMS Calcd. for C 2 7 H 33 N 2 [M Cl] + : 385.2638, Found: 385.2637 D 24 290.5 ( c 1.38, CHCl 3 ) [6( R ),8( R ) Diisopro pyl 5,6,8,9 tetrahydro 6a,7a diazadibenzo[ c g ]fluorenium] chloride ( 2 105) 0.091 g (0.230 mmol, 60.5 %) of 2 105 was obtained from 0.130 g (0.380 mmol) of 2 97 1 H NMR (300 MHz, CDCl 3 ): ppm 11.23 (s, 1H), 7.94 (d, J = 7.8 Hz, 2H), 7.43 7.26 (m, 6H) 4.86 (m, 2H), 3.41 (dd, J = 4.8, 15.9 Hz, 2H), 3.20 (d, J = 15.9 Hz, 2H), 1.68 (m, 2H), 1.04 (d, J = 6.9 Hz, 6H), 0.94 (d, J = 6.6 Hz, 6H) 13 C NMR (75 MHz, CDCl 3 ): ppm 136.52, 132.61, 130.78, 129.82, 127.90, 124.44, 124.06, 123.90, 60.86, 31.91, 29.62 19.83, 19.15 HRMS Calcd. for C 25 H 29 N 2 [M Cl] + : 357.2325, Found: 357.2309 D 25 228.9 ( c 0.88, CHCl 3 ) [6( R ),8( R ) Dicyclohexyl 5,6,8,9 tetrahydro 6a, 7a diazadibenzo[ c g ]fluorenium] chloride ( 2 106)

PAGE 164

164 0. 0750 g (0.159 mmol, 81.9 %) of 2 106 was obtained f rom 0.0822 g (0.194 mmol) of 2 98 1 H NMR (300 MHz, CDCl 3 ) ppm (s, 1H), 7.92 (d, J = 7.2 Hz, 2H), 7.39 7.32 (m, 6H), 7.17 (m, 2H), 3.34 (dd, J = 5.5, 16.1 Hz, 2H), 3.20 (d, J = 15.9 Hz, 2H), 1.73 0.82 (m, 20H) 13 C NMR (75 MHz, CDCl 3 ) ppm 13 7.15, 132.78, 130.72, 129.89, 127.87, 124.50, 124.09, 123.98, 60.07, 38.31, 31.58, 29.52, 29.42, 25.87, 25.68, 25.55 HRMS Calcd. for C 31 H 37 N 2 [M Cl] + : 437.2957, Found: 437.2971 D 25 +212.1 ( c 2.44, CHCl 3 ) [6( R ),8( R ) bis(cyclohexylmethyl) 5,6,8,9 tetrahy dro 6a,7a diazadibenzo[ c g ]fluorenium] chloride (2 108) 300 mg (0.598 mmol, 90.3%) of [6( R ),8( R ) bis(cyclohexylmethyl) 5,6,8,9 tetrahydro 6a,7a diazadibenzo[ c g ]fluorenium] chloride was obtained from 300 mg (0.662 mmol) of

PAGE 165

165 (3 S ,3' S ) 3,3' bis(cyclohexylm ethyl) 3,3',4,4' tetrahydro 1,1' biisoquinoline 400 L (4.04 mmol) of chloromethyl ethylether and 33 mL of THF. 1 H NMR (500MHz ,CHLOROFORM d) = 11.18 (br. s., 1 H), 7.96 (d, J = 7.7 Hz, 2 H), 7.49 7.32 (m, 6 H), 5.27 (br. s., 2 H), 3.43 (d, J = 14.8 Hz, 2 H), 3.05 (d, J = 15.5 Hz, 2 H), 1.99 (br. s., 2 H), 1.79 1.56 (m, 12 H), 1.37 1.06 (m, 12 H) 13 C NMR (126MHz ,CHLOROFORM d) = 135.4, 132.2, 130.7, 130.2, 127.9, 124.5, 124.1, 123.9, 53.1, 40.1, 34.4, 33.8, 33.0, 32.5, 26.4, 26.3, 26.2 [6( R ),8( R ) diisobutyl 7,7' dimethoxy 5,6,8,9 tetrahydro 6a,7a diazadibenzo[ c g ]fluorenium] chloride (2 141) 16.9 mg (0.0351 mmol, 80.0%) of 6( R ),8( R ) diisobutyl 7,7' dimethoxy 5,6,8,9 tetrahydro 6a,7a diazadibenzo[ c g ]fluorenium] chloride was obtained from 19.0 mg (0.439 mmol) of (3S,3'S) 3,3' diisobutyl 7,7' dimethoxy 3,3',4,4' tetrahydro 1,1' biisoquinoline 25.0 L (0.267 mmol) of chloromethyl et hylether and 2 mL of THF. [6( S ),8( S ) Diisobutyl 5,6,8,9 tetrahydro 6a,7a diazadibenzo[ c g ]fluoren 5 ylidene] ( 3 cinnamyl)chloropalladium(0) ( 2 103)

PAGE 166

166 To a flame dried Schlenk flask was added 0.250 g (0.450 mmol) of 2 104 0.063 g (0.270 mmol) of Ag 2 O an d 15 mL of CH 2 Cl 2 The reaction mixture was stirred for 12 h at room temperature and filtered through a pad of celite. The solvent of the filtrate was removed under reduced pressure. To another flame dried Schlenk flask was added the filtered silver comple x, 0.110 g (0.220 mmol) of [Pd(cinnamyl)Cl] 2 and 20 mL of CH 2 Cl 2 The reaction mixture was stirred for 3 h at room temperature and filtered through a pad of celite. The solvent was removed under reduced pressure, and the residue was purified by silicagel c olumn chromatography with CH 2 Cl 2 as the eluent to yield 0.150 g (0.240 mmol, 53.3 %) of 2 103 Four possible isomers can exist according to the orientation of cinnamyl group. Crystals of an isomer were obtained by slow diffusion of CH 2 Cl 2 solution of 2 103 into hexanes, but the NMR spectra of the crystals showed that there were a t least two isomers in solution. 1 H NMR of the major isomer (300 MHz, CDCl 3 ) ppm 7.86 7.76 ( m, 2H) 7.47 (d, J = 7.5 Hz, 2H), 7.33 7.06 (m, 9H), 6.12 6.01 (m, 1H), 5.75 5.64 (m, 1H), 4.85 (d, J =12.6Hz, 1H), 4.55 (d, J = 11.4 Hz, 1H), 4.29 (d, J = 8.1 Hz, 1H), 3.51 3.34 (m, 2H), 3.02 2.93 (m, 2H), 2.32 (d, J = 14.7 Hz, 1H), 1.93 0.79 (m, 18H) 13 C NMR of mixture of isomers (75 MHz, CDCl 3 ) ppm 176.15, 175.15, 140.4, 140.28, 138.05, 133.21, 132.44, 132.19, 129.85, 129.73, 129.48, 129.35, 129.0, 128.87, 128.63, 128.52, 128.38, 127.48, 127.38, 127.05, 126.94, 126.86, 12 6.77, 126.59, 126.47, 126.43, 126.37, 124.97,

PAGE 167

167 123.84, 123.6, 111.53, 110.38, 109.3, 91.73, 69.93, 69.63, 69.14, 68.95, 52.99, 52.67, 44.13, 42.92, 41.83, 41.62, 33.92, 33.83, 33.36, 32.47, 25.41, 25.3, 25.2, 25.16, 24.17, 23.99, 23.84, 23 65, 22.97, 22.54, 22.32, 21.72 Anal. Calcd. for C 36 H 41 ClN 2 Pd: C, 67.18; H, 6.42; N, 4.35, Found: C, 66.83; H, 6.49; N, 4.27 D 23 90 ( c 1.12, CHCl 3 ) X ray experimental for 2 103 Data were collected at 173 K on a Siemens SMART PLATFORM equipped with A CCD area detector and a graphite monochromator utilizing MoK radiation ( = 0.71073 ). Cell parameters were refined using up to 8192 reflections. A full sphere of data (1850 frames) was collected using the scan method (0.3 frame width). The first 50 fram es were re measured at the end of data collection to monitor instrument and crystal stability (maxim um correction on I was < 1 %). Absorption corrections by integration were applied based on measured indexed crystal faces. The structure was solved by the Direct Methods in SHELXTL6, and refined using full ma trix least squares. The non H atoms were treated anisotropically, whereas the hydrogen atoms were calculated in ideal positions and were riding on their respective carbon atoms. The C27 methyl group was disordered and refined in two parts with their site occupatio n factors dependently refined. Its isopropyl counter methyl group was not significantly disorde red and could not be resolved. The major diso rder is in the C28 C36 ligand. It is completely disorde red and was refined with anisotropic displacement parameters and with the phenyl ring treated as an idealized hexagon rigid body. A total of 338 parameters were refined in the final cycle of

PAGE 168

168 refinement using 5574 reflections with I > 2 (I) to yield R 1 and wR 2 of 3.77 % and 8.40 %, respectively. Refinement was done using F 2 SHELXTL6 (2000). Bruker AXS, Madison, Wisconsin, USA. Crystal data and structure refinement for 2 103 Identification code 2 103 Empirical formula C36 H41 Cl N2 Pd Fo rmula weight 643.56 Temperature 173(2) K Wavelength 0.71073 Crystal system Orthorhombic Space group P2(1)2(1)2(1) Unit cell dimensions a = 5.6873(4) = 90. b = 23.3061(18) = 90. c = 23.7168(18) = 90. Volume 3143.6(4) 3 Z 4 Density (c alculated) 1.360 Mg/m 3 Absorption coefficient 0.702 mm 1 F(000) 1336 Crystal size 0.19 x 0.19 x 0.15 mm 3 Theta range for data collection 1.72 to 27.50. Index ranges

PAGE 169

169 Reflections collected 20343 Independent reflections 7185 [R(int ) = 0.0463] Completeness to theta = 27.50 99.7 % Absorption correction Integration Max. and min. transmission 0.9057 and 0.8827 Refinement method Full matrix least squares on F 2 Data / restraints / parameters 7185 / 1 / 338 Goodness of fit on F 2 0.972 Fi nal R indices [I>2sigma(I)] R1 = 0.0377, wR2 = 0.0840 [5574] R indices (all data) R1 = 0.0532, wR2 = 0.0877 Absolute structure parameter 0.02(3) Largest diff. peak and hole 0.526 and 0.314 e. 3 R1 = (||F o | |F c ||) / |F o | wR2 = [ w(F o 2 F c 2 ) 2 ] / w F o 2 2 ]] 1/2 S = [ w(F o 2 F c 2 ) 2 ] / (n p)] 1/2 w= 1/[ 2 (F o 2 )+(m*p) 2 +n*p], p = [max(F o 2 ,0)+ 2* F c 2 ]/3, m & n are constants. [6( S ),8( S ) Diisobutyl 5,6,8,9 tetrahydro 6a,7a diazadibenzo[ c g ]fluoren 5 ylide ne] chlorocopper(I) ( 2 109 ).

PAGE 170

170 A flame dried Schlenk flask was charged with 0.200 g (0.360 mmol) of 2 104 0.046 g (0.200 mmol) of Ag 2 O and 5 mL of CH 2 Cl 2 After stirring for 12 h, the reaction mixture was filtered through a pad of celite. The solvent of the filtrate was removed under reduced pressure. To another flame dried Schlenk flask was added the filtered silver complex and 0.0340 g (0.340 mmol) of CuI. The reaction mixture was stirred for 2 h at room temperature. The reaction solution was filtered through a pad of celite and evaporated to dryness. The residue was purified quickly by silicagel column chromatography with CH 2 Cl 2 as the eluent to yield 0.210 g (0.340 mmol, 94.4 %) of 2 109 1 H NMR (300 MHz, CDCl 3 ) ppm 7.9 (dd, J = 1.8, 6.6 Hz, 2H), 7 .32 7.24 (m, 6H), 4.78 (m, 2H), 3.36 (dd, J = 5.0, 15.5 Hz, 2H), 2.95 (d, J = 15.3 Hz, 2H), 1.74 (m, 2H), 1.38 (m, 2H), 1.27 (m, 2H), 0.97 (d, J = 6.6 Hz, 6H), 0.94 (d, J = 6.6 Hz, 6H) 13 C NMR (75 MHz, CDCl 3 ) 132.49, 129.79, 127.4, 125.96, 124.10, 54.7 9, 42.82, 34.20, 25.00, 23.56, 22.40 Anal. Calcd. for C 27 H 32 ClCuN 2 : C, 67.06; H, 6.67; N, 5.79, Found: C, 67.13; H, 6.43; N, 5.71 D 23 283.4 ( c 0.48, CHCl 3 ) [6( R ),8( R ) Diisopropyl 5,6,8,9 tetrahydro 6a,7a diazadibenzo[ c g ]fluoren 5 ylidene]chlorocopper( I) ( 2 110)

PAGE 171

171 0.096 g (0.16 mmol, 55.2 %) of 2 110 was obtained from 0.150 g (0.290 mmol) of 2 105 1 H NMR (300 MHz, CDCl 3 ) ppm 7.88 (d, J = 7.4 Hz, 2H), 7.31 7.23 (m, 6H), 4.40 (m, 2H), 3.28 (dd, J = 4.2, 15.3 Hz, 2H), 3.15 (d, J = 15.6 Hz, 2H), 1.61 (m, 2H), 1.02 (d, J = 6.6 Hz, 6H), 0.88 (D, J = 6.9 Hz, 6H) 13 C NMR (75 MHz CDCl 3 ) ppm 174.23, 133.24, 129.43, 129.18, 127.38, 126.22, 124.09, 124.01, 62 .60, 33.07, 30.29, 21.45, 19.67 Anal Calcd. for C 25 H 28 ClCuN 2 : C, 65.92; H, 6.20; N, 6.15, Found: C 66.38; H, 6.22; N, 5.98 D 23 251.5 ( c 2.20, CHCl 3 ) [6( R ),8( R ) Dicyclohexyl 5,6,8,9 tetrahydro 6a,7a diazadibenzo[ c g ]fluoren 5 ylidene]chlorocopper(I) ( 2 111) 0.240 g (0.450 mmol, 71.4 %) of 2 111 was obtained from 0.300 g (0.630 mmol) of 2 106 1 H NMR (300 MHz, CDCl 3 ) ppm 7.88 (dd, J = 2.3, 6.2 Hz, 2H), 7.29 7.23 (m, 6H), 4.43 (m, 2H), 3.26 (dd, J = 5.0, 15.8 Hz, 2H), 3.16 (dd, J = 1.8, 15.6 Hz, 2H), 1.73 0.89 (m, 22H) 13 C NMR (75 MHz, CDCl 3 ) ppm 133.36, 129.42, 129.09, 127.29, 126.32, 12 4.11, 124.00, 61.68, 38.15, 32.73, 31.43, 29.95, 26.09, 26.00, 25.89

PAGE 172

172 Anal. Calcd. for C 31 H 36 ClCuN 2 : C, 69.51; H, 6.77; N, 5.23, Found: C, 69.42; H, 6.75; N, 4.83 D 23 +173.6 ( c 0.78, CHCl 3 ). [6( R ),8( R ) bis(cyclohexylmethyl) 5,6,8,9 tetrahydro 6a,7a diaz adibenzo[ c g ]fluoren 5 ylidene]chlorocopper(I) (2 113) 36.5 mg (0.0648 mmol, 65.0%) of [6( R ),8( R ) bis(cyclohexylmethyl) 5,6,8,9 tetrahydro 6a,7a diazadibenzo[ c g ]fluoren 5 ylidene]chlorocopper(I) was obtained from 50 mg (0.0997 mmol) of [6( R ),8( R ) bis (cyclohexylmethyl) 5,6,8,9 tetrahydro 6a,7a diazadibenzo[ c g ]fluorenium] chloride 13.9 mg (0.0598 mmol) of silver oxide, 10.9 mg (0.109 mmol) of copper chloride and 10 mL of DCM. 1 H NMR (300MHz ,CHLOROFORM d) = 7.90 (d, J = 7.0 Hz, 2 H), 7.54 7.03 (m, 6 H), 4.84 (q, J = 6.2 Hz, 2 H), 3.35 (dd, J = 5.3, 15.2 Hz, 2 H), 3.10 2.79 (m, 2 H), 1.85 (d, J = 12.3 Hz, 2 H), 1.76 1.55 (m, 8 H), 1.46 1.09 (m, 12 H), 1.07 0.81 (m, 4 H) 13 C NMR (75MHz ,CHLOROFORM d) = 171.9, 132.5, 129.8, 129.1, 127.3, 126.0, 124.1, 54.0, 41.4, 34.3, 34.0, 33.1, 26.5, 26.2 6.2.4 Synthesis of the S ubstrates for The Copper C atalyze d Allylic A lkylation ( E ) 3 (2 methoxyphenyl)allyl pivalate (2 128)

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17 3 Synthesis of ( E ) ethyl 3 (2 methoxyph enyl)acrylate: A flame dried Schlenk flask was charged with 0.440 g (11.0 mmol) of NaH (60% in mineral oil) and 20 mL of toluene. To this solution was added 2.0 mL (10.0 mmol) of triethyl phosphonoacetate at 0 The temperature was slowly increased to r oom temperature for 30 min. To the reaction solution was added 1.2 mL (10.0 mmol) of o anisole, and the solution was heated to 60 for 4 h. After cooling to room temperature, 20 mL of a saturated NH 4 Cl solution was added to quench the reaction. The organ ic layer was extracted with 30 mL of Et 2 O, and all the volatiles were evaporated under reduced pressure to give crude ( E ) ethyl 3 (2 methoxyphenyl)acrylate Synthesis of ( E ) 3 (2 methoxyphenyl)prop 2 en 1 ol: To a flame dried Schlenk flask was added the cr ude ( E ) ethyl 3 (2 methoxyphenyl)acrylate and 20 mL of Et 2 O. 20 mL of DIBALH (1.0 M solution in toluene) was slowly added to the reaction solution at 0 The temperature was slowly increased to room temperature. After 3 h, 30 mL of 1M HCl aqueous solution was added and the organic layer was separated. All volatiles were removed under reduced pressure to give crude ( E ) 3 (2 methoxyphenyl)prop 2 en 1 ol Synthesis of ( E ) 3 (2 methoxyphenyl)allyl pivalate: A flame dried Schlenk flask was charged with 1.25 g (8.00 mmol) of the crude ( E ) 3 (2 methoxyphenyl)allyl pivalate 0.100 g (0.800 mmol) of 4 dimethylamino pyridine, 1.4 mL (10.0 mmol) of triethyl amine a nd 20 mL of CH 2 Cl 2 To the reaction flask was added 1.0 mL (8.00 mmol) of pivaloyl chloride at 0 The reaction mixture was slowly warmed to room temperature and stirred for 2 h. The reaction mixture was poured to a 20 mL of saturated

PAGE 174

174 NaHCO 3 aqeous solution, and the organic layer was separated. After evaporation of the solvent, the residue was purif ied by silicagel column chromatography with a 5:1 mixture of hexane and Et 2 O as the eluent to give 1.80 g (7.2 mmol, 65.5 %) of the pure product. 1 H NMR (300 MHz, CDCl 3 ) ppm 7.49 (dd, J = 7.5, 1. 6 Hz, 1 H), 7.24 7.32 (m, 1 H), 6.86 7.10 (m, 3 H), 6. 35 (dt, J = 16. 1 6. 3 Hz, 1 H), 4.79 (dd, J = 6. 2 1.4 Hz, 2 H), 3.88 (s, 3 H), 1.29 (s, 9 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 178.21, 156.70, 128.95, 128.59, 128.33, 126.91, 125.23, 124.00, 120.53, 110.75, 65.35, 55.31, 38.70, 27.15 HRMS Calcd. for C 15 H 20 NaO 3 [M+Na] + : 271.1304, Found: 271.1332 ( E ) 3 (naphthalen 2 yl)allyl benzoate (2 121) 1 H NMR (300 MHz, CDCl 3 ) ppm 8.13 8.19 (m, 2 H), 7.82 (dd, J = 7.92, 4.69 Hz, 4 H), 7.56 7.68 (m, 2 H), 7.44 7.54 (m, 4 H), 6.93 (d, J = 15.8 Hz, 1 H), 6.56 (dt, J = 15.8, 6.30 Hz, 1 H), 5.08 (dd, J = 6. 5 1. 5 Hz, 2 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 166.35, 134.23, 133.64, 133.47, 133.16, 132.96, 130.17, 129.64, 128.34, 128.25, 128.01, 127.63, 126.84, 126.29, 126.06, 123.57, 123.47, 65.54 HRMS Calcd. for C 20 H 16 O 2 [ M] + : 288.1150, Found : 288.1141 ( E ) 3 (naphthalen 2 yl)allyl pivalate (2 122)

PAGE 175

175 1 H NMR (300 MHz, CDCl 3 ) ppm 7.74 7.89 (m, 4 H), 7.62 (dd, J = 8. 5 1.7 Hz, 1 H), 7.42 7.54 (m, 2 H), 6.83 (d, J = 15. 9 Hz, 1 H), 6.44 (dt, J = 15. 9 6.2 Hz, 1 H), 4.81 ( dd, J = 6.2, 1.13 Hz, 2 H), 1.30 (s, 9 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 178.31, 133.74, 133.59, 133.45, 133.10, 128.21, 127.98, 127.62, 126.69, 126.28, 126.00, 123.89, 123.47, 64.95, 38.80, 27.21 HRMS Calcd. for C 18 H 20 NaO 2 [M+Na] + : 291.1355, Found: 291.131 8 ( E ) 3 (naphthalen 2 yl)but 2 enyl pivalate (2 129) 1 H NMR (300 MHz, CDCl 3 ) ppm 7.77 7.95 (m, 4 H), 7.61 (dd, J = 8. 6 1.86 Hz, 1 H), 7.41 7.55 (m, 2 H), 6.08 (td, J = 6.7, 1. 2 Hz, 1 H), 4.86 (d, J = 6. 9 Hz, 2 H), 2.25 (d, J = 0.6 Hz, 3 H), 1.2 6 (s, 9 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 178.48, 139.65, 139.46, 133.26, 132.71, 128.09, 127.72, 127.43, 126.11, 125.80, 124.52, 124.07, 122.23, 61.68, 38.76, 27.18, 16.16 HRMS Calcd. for C 19 H 22 NaO 2 [M+Na] + : 305.1512, Found : 305.1473 ( E ) 3 (4 methoxyphenyl )allyl pivalate (2 126) 1 H NMR (300 MHz, CDCl 3 ) ppm 7.33 (m, 2 H), 6.86 (m, 2 H), 6.59 (d, J = 16.1 Hz, 1 H), 6.15 (dt, J = 15.8, 6. 5 Hz, 1 H), 4.70 (dd, J = 6. 5 1. 2 Hz, 2 H), 3.80 (s, 3 H), 1.24 (s, 9 H)

PAGE 176

176 13 C NMR (75 MHz, CDCl 3 ) ppm 178.27, 159.43 133.31, 128.99, 127.72, 121.15, 113.90, 65.11, 55.12, 38.69, 27.12 HRMS Calcd. for C 15 H 20 O 3 [M] + : 248.1407, Found : 248.1410 ( E ) 3 (4 chlorophenyl)allyl pivalate (2 127) 1 H NMR (300 MHz, CDCl 3 ) ppm 7.28 7.35 (m, 4 H), 6.60 (d, J = 15.8 Hz, 1 H), 6 .20 6.34 (m, J = 16.1, 6. 2 6. 2 Hz, 1 H), 4.73 (dd, J = 6. 2 1. 5 Hz, 2 H), 1.26 (s, 9 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 178.07, 134.75, 133.49, 132.07, 128.63, 127. 67, 124.23, 64.56, 38.70, 27.12 HRMS Calcd. for C 14 H 17 ClO 2 [M] + : 252.0917, Found: 252.0914 ( E ) 2 (3 (n aphthalen 2 yl)allyloxy)pyridine (2 120) ( E ) 2 (3 (naphthalen 2 yl)allyloxy)pyridine was prepaired from ( E ) 3 (naphthalen 2 yl)prop 2 en 1 ol by using a literature method 1 5 1 H NMR (300 MHz, CDCl 3 ) ppm 8.21 (dd, J = 5.0 2. 1 Hz, 1 H), 7.74 7.91 (m, 4 H), 7.56 7.70 (m, 2 H), 7.40 7.53 (m, 2 H), 6.87 6.97 (m, 2 H), 6.83 (d, J = 8.2 Hz, 1 H), 6.62 (ddd, J = 16.0 6.0, 5. 9 Hz, 1 H), 5.08 (dd, J = 6.0, 1.0 Hz, 2 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 146.85 138.65 134.09 133.52 133.13 128 .17 127.99 127.64 126.63 126.23 125.91 125.11 123.59 116.85 111.25 66.33

PAGE 177

177 HRMS Calcd. for C 18 H 16 NO [M+H] + : 262.1226, Found : 262.1232 1 (naphthalen 6 yl)allyl pivalate (2 136) 1 H NMR (300 MHz, CDCl 3 ) ppm 7.81 7.90 (m, 4 H), 7.44 7.55 (m, 3 H), 6.42 (d, J = 5. 6 Hz, 1 H), 6.10 (ddd, J = 17.2, 10. 5 5.7 Hz, 1 H), 5.25 5.43 (m, 2 H), 1.27 (s, 9 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 177.27, 136.56, 136.46, 133.16, 133.03, 128.33, 1 28.05, 127.64, 126.19, 126.14, 126.02, 124.71, 116.65, 75.83, 40.17, 27.13 HRMS Calcd. for C 18 H 20 O 2 [M] + : 268.1458, Found: 268.1465 6.2.5 Products from The Copper C atalyze d Allylic A lkylation Typical procedure for asymmetric Cu heterocyclic carbene catalyzed allylic substitution : A flame dried Schlenk flask was charged with a su bstrate (0.5 mmol), a copper catalyst (3 mol %) and 3 ml of a solvent. To this solution was added a Grignard reagent (0.75 mmol in Et 2 O) at a specified temperature. After 1 hr, the reaction was quenched by a saturated aqueous NH 4 Cl solution and diluted by 20 mL of Et 2 O. The organic layer was separated and the solvent was evaporated under reduced pressure. Silicagel column chromatography with hexane as the eluent gave a pure product. The regioselectivity was calculated by the integration ratio of the protons shown on the two regioisomers by NMR spectra.

PAGE 178

178 A racemic product was synthesized using IMes Cu Cl complex as the catalyst. 2 (pent 1 en 3 yl)naphthalene (2 115) Ee was measured by chiral HPLC with a Whelk 01 column (UV 254 nm, 100% pentane, 0.2 mL/mi n). t S : 25.5, t R : 26.9 2 (non 1 en 3 yl)naphthalene (2 123 product) 1 H NMR (300 MHz, CDCl 3 ) ppm 7 .72 7.89 (m, 3 H), 7.63 (s, 1 H), 7.39 7.51 (m, 2 H), 7.35 (dd, J = 8. 5 1.7 Hz, 1 H), 5.97 6.11 (m, 1 H), 4.98 5.16 (m, 2 H), 3.42 (q, J = 7. 6 Hz, 1 H), 1.81 (q, J = 7. 5 Hz, 2 H), 1.24 1.35 (m, 8 H), 0.84 0.90 (m, 3 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 142.42, 142.07, 133.62, 132.21, 127.96, 127.57, 126.28, 125.82, 125.19, 114.07, 49.96, 35.30, 31.77, 29.30, 27.55, 22.65, 14.09 HRMS Calcd. for C 19 H 25 [M+H] + : 253.1951, Found: 253.1966 Ee was measured by chiral HPLC with a Whelk 01 column (UV 254 nm, 100% pentane, 0.2 ml/min). t 1 : 26.0, t 2 : 2 8.2 2 (1 cyclopentylallyl)naphthalene (2 124 product)

PAGE 179

179 1 H NMR (300 MHz, CDCl 3 ) ppm 7.81 7.92 (m, 2 H) 7.69 (s, 1 H), 7.39 7.56 (m, 3 H), 6.17 (ddd, J = 1 7.0 10. 2 8.2 Hz, 1 H), 5.03 5.19 (m, 2 H), 3.23 (t, J = 9.3 Hz, 1 H), 2.30 2.47 (m, 1 H), 1.88 2.06 (m, 1 H), 1.38 1.78 (m, 6 H), 1.06 1.29 (m, 1 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 142.45, 1 42.23, 133.94, 132.49, 128.21, 127.89, 126.76, 126.45, 126.11, 125.46, 114.65, 57.07, 44.92, 31.76, 25.61 HRMS Calcd. for C 18 H 20 [M] + : 236.1560, Found: 236.1552 Ee was measured by chiral HPLC with a Whelk 01 column (UV 254 nm, 100% pentane, 0.2 mL/min). t 1 : 30.9, t 2 : 34.0 ( E ) 2 (3 phenylprop 1 enyl)naphthalene (2 125 product) 1 H NMR (300 MHz, CDCl 3 ) ppm 7.66 7.82 (m, 4 H), 7.58 (dd, J = 8.5, 1. 8 Hz, 1 H), 7.37 7.48 (m, 2 H), 7.18 7.37 (m, 5 H), 6.61 (d, J = 15.8 Hz, 1 H), 6.48 (dt, J = 15.8, 6. 5 Hz, 1 H), 3.61 (d, J = 6. 5 Hz, 2 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 140.11, 134.91, 133.63, 132.74, 1 31.12, 129.69, 128.69, 128.50, 128.06, 127.83, 127.60, 126.20, 126.14, 125.71, 125.56, 123.55, 39.45 HRMS Calcd. for C 19 H 16 [M] + : 244.1252, Found : 244.1245 2 (3 methylpent 1 en 3 yl ) naphthalene (2 129 product)

PAGE 180

180 Ee was measured by chiral HPLC with a Whel k 01 column (UV 254 nm, 100% pentane, 0.2 mL/min). t 1 : 32.8, t 2 : 35.4 1 methoxy 4 (pent 1 en 3 yl)benzene (2 126 product) Ee was measured by chiral HPLC with a Chiralcel OJ H column (UV 254 nm, hexane: iPrOH = 99.5:0.5, 0.5 mL/min). t 1 : 15.6, t 2 : 16.7 1 chloro 4 (non 1 en 3 yl)benzene (2 127 product) 1 H NMR (300 MHz, CDCl 3 ) ppm 7.26 (m, 2 H), 7.10 (m, 2 H), 5.89 (ddd, J = 16.7, 10.6, 7.5 Hz, 1 H), 4.94 5.07 (m, 2 H), 3.20 (q, J = 7.4 Hz, 1 H), 1.57 1.74 (m, 2 H), 1.19 1.31 (m, 8 H), 0.83 0.90 (m, 3 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 143.07, 142.00, 131.68, 128.94, 128.46, 114.19, 49.22, 35.35, 31.74, 29.21, 27.40, 22.63, 14.06 HRMS Calcd. for C 15 H 22 Cl [M+H] + : 237.1405, Found: 237.1408 Ee was measured by chiral HPLC with a Chiralcel OJ H col umn (UV 215 nm, 100% pentane, 0.2 mL/min). t 1 : 21.4 t 2 : 22.4 1 methoxy 2 (non 1 en 3 yl)benzene (2 128 product)

PAGE 181

181 1 H NMR (300 MHz, CDCl 3 ) ppm 7.10 7.22 (m, 2 H), 6.80 6.95 (m, 2 H), 5.98 (ddd, J = 17.1, 10.3, 7.6 Hz, 1 H), 4.93 5.06 (m, 2 H), 3.80 (s, 3 H), 3.73 (q, J = 7. 5 Hz, 1 H), 1.60 1.73 (m, 2 H), 1.15 1.36 (m, 8 H), 0.80 0.91 (m, 3 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 157.23, 142.35, 133.37, 128.02, 127.10, 120.86, 113.93, 110.96, 55.69, 42.37, 34.84, 32.07, 29.57, 27.78, 22.94, 14.37 HRMS Calcd. for C 16 H 25 O [M+H] + : 233.1900, Found: 233.1892 Ee was measured by chiral HPLC with a Chiralpak IA column (UV 254 nm, 100% pentane, 0.2 mL/min). t 1 : 21.5 t 2 : 22.4 6.3 I n S itu Generation of A cyclic D iamino carbene C opper C omplex 6.3.1 Substrat es and Catalysts S ynthesis [6( R ),8( R ) Diisopropyl 5,6,8,9 tetrahydro 6a,7a diazadibenzo[ c g ]fluoreniumchloride] copper (II) chloride ( 3 2 ). A flame dried Schlenk flask was charged with 0.100 g (0.254 mmol) of [6( R ),8( R ) Diisopropyl 5,6,8,9 tetrahydro 6a ,7a diazadibenzo[ c g ]fluorenium] chloride ( 2 105 ), 0.036 g (0.153 mmol) of Ag 2 O and 10 mL of CH 2 Cl 2 After stirring for 12 h, the reaction mixture was

PAGE 182

182 filtered through a pad of celite. The solvent of the filtrate was removed under reduced pressure. To anot her flame dried Schlenk flask was added the filtered silver complex and 0.038 g (0.279 mmol) of CuCl 2 The reaction mixture was stirred for 5 h at room temperature. The reaction solution was filtered through a pad of celite and evaporated to dryness. The r esidue was purified by recrystallization using a mixture of CH 2 Cl 2 :h exane to yield 0.090 g (0.182 mmol, 71.6 %) of 3 2 1 H NMR (300 MHz, CDCl 3 ) ppm 7.97 (d, J =7.6 Hz, 1 H), 7.30 7.56 (m, 3 H), 4.56 4.75 (m, 1 H), 3.68 (dd, J =15.9, 5.4 Hz, 1 H), 3.27 (d, J =16.1 Hz, 1 H), 1.74 2.00 (m, 1 H), 1.03 (d, J =6.8 Hz, 3 H), 0.87 (d, J =6.8 Hz, 3 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 132.8, 131.4, 129.7, 128.1, 126.1, 124.9, 123. 3, 61.2, 31.7, 30.6, 20.6, 19.2 X ray experimental for 3 2 Data were collected at 173 K on a Siemens SMART PLATFORM equipped with A CCD area detector and a graphite monochromator utilizing MoK radiation ( = 0.71073 ). Cell parameters were refined using up to 8192 reflections. A full sphere of data (1850 frames) was collected using the s can method (0.3 frame width). The first 50 frames were re measured at the end of data collection to monitor instrument and crystal stability (maximum correction on I was < 1 %). Absorption corrections by integration were applied based on measured indexed crystal faces. The structure was solved by the Direct Methods in SHELXTL6, and refined us ing full matrix least squares. The non H atoms were treated anisotropically, whereas the hydrogen atoms were calculated in ideal positions and were riding on their re spective carbon at oms. A total of

PAGE 183

183 280 parameters were refined in the final cycle of refinement using 4548 reflections with I > 2 (I) to yield R 1 and wR 2 of 3.45 % and 7.82 %, respectively. Refinement was done using F 2 SHELXTL6 (2000). Bruker AXS, Madison, Wisconsin USA. Crystal data and structure refinement for 3 2 Identification code 3 2 Empirical formula C25 H28 Cl3 Cu N2 Formu la weight 526.38 Temperature 173(2) K Wavelength 0.71073 Crystal system Orthorhombic Space group P2(1)2(1)2(1) Unit cell dimensions a = 7.1072(5) = 90. b = 17.4430(11) = 90. c = 19.5633(13) = 90. Volume 2425.3(3) 3 Z 4 Density (calc ulated) 1.442 Mg/m 3 Absorption coefficient 1.247 mm 1 F(000) 1088 Crystal size 0.26 x 0.09 x 0.09 mm 3 Theta range for data collection 1.56 to 28.03. Index ranges

PAGE 184

184 Reflections collected 9852 Independent reflections 5109 [R(int) = 0 .0340] Completeness to theta = 28.03 92.7 % Absorption correction Integration Max. and min. transmission 0.8961 and 0.7376 Refinement method Full matrix least squares on F 2 Data / restraints / parameters 5109 / 0 / 280 Goodness of fit on F 2 1.014 Final R indices [I>2sigma(I)] R1 = 0.0345, wR2 = 0.0782 [4548] R indices (all data) R1 = 0.0408, wR2 = 0.0807 Absolute structure parameter 0.020(11) Largest diff. peak and hole 0.314 and 0.275 e. 3 R1 = (||F o | |F c ||) / |F o | wR2 = [ w(F o 2 F c 2 ) 2 ] / w F o 2 2 ]] 1/2 S = [ w(F o 2 F c 2 ) 2 ] / (n p)] 1/2 w= 1/[ 2 (F o 2 )+(m*p) 2 +n*p], p = [max(F o 2 ,0)+ 2* F c 2 ]/3, m & n are constants. ( Z ) 4 (4 methoxybenzyloxy)but 2 en 1 ol To a flame dried Schlenk flask were added 1.25 g (14.16 mmol) of ( Z ) 2 buten 1,4 diol and 5 mL (0.06 mmol) of a solution of TfOH in Et 2 mL of Et 2 O). Th e reaction mixture was cooled to 0 C and a solution of 4 methoxybenzyl 2,2,2 trichloroacetimidate (0.67

PAGE 185

185 g, 2.36 mmol) in DCM ( 1.2 mL ) was added dropwise. After stirring over 2 hours at 0 C, it was quenched with 4 mL of a saturated solution of NaHCO 3 The aqueous layer was extracted with Et 2 O (3 x 5 mL ). The combined organic layers were dried over Na 2 SO 4 filtered, and concentra ted under reduced pressure. The residue was purified by flash column chromatography (silica gel, from 2.3:1 to 1:1 Hexanes/EtOAc) to yield 0.40 g (1.90 mmol, 80%) of ( Z ) 4 (4 methoxybenzyloxy)but 2 en 1 ol. 1 H NMR (300 MHz, CDCl 3 ) ppm 7.26 (d, J =8.21 Hz, 2 H), 6.88 (d, J =8.78 Hz, 2 H), 5.65 5.85 (m, 2 H), 4.45 (s, 2 H), 4.14 (d, J =5.95 Hz, 2 H), 4.05 (d, J =5.66 Hz, 2 H), 3.79 (s, 3 H), 2.32 (br. s, 1 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 159.5, 132.6, 130.1, 129.7, 128.4, 114.1, 72.4 65.6, 58.8, 55.5 HRMS Calcd. for C 12 H 16 O 3 [M+Na] + : 231.0992, Found: 231.0991 ( Z ) 4 (4 methoxybenzyloxy)but 2 enyl acetate ( 3 4 ) To a flame dried Schlenk flask were added 356 mg (1.71 mmol) of ( Z ) 4 (4 methoxybenzyloxy)but 2 en 1 of Et 3 N, 44 mg (0.36 mmol) of DMAP, 2 O, and 18 mL of DCM. The reaction mixture was stirred at room temperature over 12 hours. It was quenched with 10 mL of H 2 O and extracted with DCM (3 x 10 mL ). The combined organic extracts were dried over MgSO 4 filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 1:1 Hexanes/EtOAc) to yield 400 mg (1.60 mmol, 93%) of ( Z ) 4 (4 methoxybenzyloxy)but 2 enyl acetate.

PAGE 186

186 1 H NMR (300 MHz, CDCl 3 ) ppm 7.27 (d, J =8.80 Hz, 2 H), 6.88 (d, J =8.80 Hz, 2 H), 5.76 5.86 (m, 1 H), 5.64 5.75 (m, 1 H), 4.62 (dd, J =6.45, 0.88 Hz, 2 H), 4.45 (s, 2 H), 4.09 (dd, J =6.16, 1.17 Hz, 2 H), 3.80 (s, 3 H), 2.06 (s, 3 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 170.8, 159.3, 130.9, 130.1, 129.4, 126.6, 113.8, 72.1, 65.3, 60.3, 55.2, 20.9 HRMS Calcd. for C 14 H 18 O 4 [M+Na] + : 273.1097, Found: 273.1104 ( Z ) but 2 ene 1,4 diyl bis(4 methoxybenzoate) ( 3 13 ) To a flame dried Schlenk flask were added 54 mg (0.61 mmol) of ( Z ) 2 buten 1 ,4 diol, 3 N, 15 mg (0.12 mmol) of DMAP, 10 mL of DCM, and dropwise 206 methoxybenzoylchloride. The reaction mixture was stirred at room temperature over 17 hours. It was quenched with 6 mL of 30% NaOH solution an d extracted with DCM (3 x 8 mL ). The combined organic extracts were dried over MgSO 4 filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 1:1 Hexanes/EtOAc) to yield 217 mg (0.61 mmol, qua ntitative yield) of 3 13 1 H NMR (300 MHz, CDCl 3 ) ppm 8.00 (d, J =8.91 Hz, 4 H), 6.91 (d, J =8.91 Hz, 4 H), 5.93 (ddd, J =5.22, 3.98, 1.17 Hz, 2 H), 4.97 (d, J =5.26 Hz, 4 H), 3.86 (s, 6 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 166.2, 163.6, 131.8, 128.5, 122.5, 113.8, 60.5, 55.6 HRMS Calcd. for C 20 H 20 O 4 [M+Na] + : 3 79.1152, Found: 379.1185 Ethyl 2 (1 t osylpiperidin 4 ylidene)acetate

PAGE 187

187 To a flame dried Schlenk flask was added 177 mg of NaH (60% in mineral oil, 4.42 mmol) in 12 mL triethy l phosphonoacetate. The reaction mixture was stirred 30 min at room temperature then 1.00 g (3.95 mmol) of 1 tosylpiperidin 4 one was added portionwise. It was stirred at 60 C over a day. The reaction mixture was quenched by 10 mL of H 2 O and extracted wit h Et 2 O (3 x 10 mL ). The combined organic extracts were dried over MgSO 4 filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, from 1:0 to 4:1 Hexanes/EtOAc) to give 940 mg (2.9 mmol, 74%) of ethyl 2 (1 tosylpiperidin 4 ylidene)acetate. 1 H NMR (300 MHz, CDCl 3 ) ppm 7.64 (d, J =8.20 Hz, 2 H), 7.31 (d, J =8.65 Hz, 2 H), 5.64 (s, 1 H), 4.11 (q, J =7.16 Hz, 2 H), 2.99 3.18 (m, 6 H), 2.42 (s, 2 H), 2.38 (t, J =6.34 Hz, 3 H), 1.24 (t, J =7.09 Hz, 3 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 166.0, 153.4, 143.7, 133.1, 129.7, 127.6, 115.9, 59.9, 47.3, 46.8, 35.8, 28.5, 21.5, 14.2 HRMS Calcd. for C 16 H 21 NO 4 S [M+Na] + : 346.1084, Found: 346.1086 2 (1 t osylpiperidin 4 ylidene)ethanol

PAGE 188

188 To a flame dried Schlenk flask were added 1.14 g (3.52 mmol) of ethyl 2 (1 tosylpiperidin 4 ylidene)acetate and 38 mL of DCM. The reaction mixture was cooled at 78 C and 10.6 mL (10.55 mmol) of DIBAL (1M in toluene) was added dropwise. It was stirred at 78 C for 2 hours. It was que nched with 20 mL of a saturated solution of NH 4 Cl and extracted with DCM (3 x 30 mL ). The combined organic extracts were filtered on a celite pad, dried over MgSO 4 filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, from 1:1.5 to 1:2.3 Hexanes/EtOAc) to yield 0.89 mg (3.17 mmol, 90%) of 2 (1 tosylpiperidin 4 ylidene)ethanol. 1 H NMR (300 MHz, CDCl 3 ) ppm 7.62 (d, J=8.21 Hz, 2 H), 7.31 (d, J=8.49 Hz, 2 H), 5.42 (t, J=6.94 Hz, 1 H), 4.09 (d, J=6.79 Hz, 2 H), 2.98 3.09 (m, 4 H), 2.42 (s, 3 H), 2.37 (t, J=5.80 Hz, 2 H), 2.29 (t, J=5.80 Hz, 2 H), 1.36 (br. s., 1 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 143.55, 137.41, 133.08, 129.61, 127.58, 123.52, 58.08, 47.64, 47.08, 35.05, 27.76, 21.47 HRMS Calcd. for C 14 H 19 NO 3 S [M+Na] + : 304.0978, Found: 304.0984 2 (1 tosylpiperidin 4 ylidene)ethyl acetate ( 3 17 ) To a flame dried Schlenk flask were added 489 mg (1.74 mmol) of 2 (1 tosylpiperidin 4 3 N, 43 mg (0.36 mmol) of mmol) of Ac 2 O, and 18 mL of DCM. The reaction mixture was stirred at room temperature over 17 hours. It was quenched with 10 mL of H 2 O and extracted with DCM (3 x 10 mL ). The combined organic extracts were dried over MgSO 4 filtered, an d concentrated under reduced

PAGE 189

189 pressure. The residue was purified by flash column chromatography (silica gel, 1:1 Hexanes/EtOAc) to yield 548 mg (1.69 mmol, 97%) of 3 17 1 H NMR (300 MHz, CDCl 3 ) ppm 7.64 (d, J =8.21 Hz, 2 H), 7.31 (d, J =8.78 Hz, 2 H), 5.36 (t, J =6.94 Hz, 1 H), 4.51 (d, J =7.36 Hz, 2 H), 3.06 (q, J =6.23 Hz, 4 H), 2.37 2.49 (m, 5 H), 2.31 (t, J =5.52 Hz, 2 H), 2.01 (s, 3 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 171.1, 143.8, 140.1, 133.5, 129.9, 127.8, 118.9, 60.2, 47.7, 47.1, 35.3, 28.2, 21.7, 21.2 H RMS Calcd. for C 16 H 21 NO 4 S [M+Na] + : 346.1084, Found: 346.1080 P yrrolidine 1 carbaldehyde 13 C (3 30 ) To a flame dried pressurized vessel were added 1.42 m L (1 7 29 mmol) of pyrrolidine and 1000 mg (16.38 mmol) of methyl formate 13 C. The reaction mixture wa s stirred at 80 C for 1 2 hours. It was warmed to room temperature and concentrated under reduced pressure to yield 1640 mg (16.38 mmol, 99%) of pyrrolidine 1 carbaldehyde 13 C 1 H NMR (300 MHz, CDCl 3 ) ppm 8.2 (d, J =188.8 Hz, 1 H), 3.4 (m, 4 H), 1.9 (m, 4 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 160.7, 45.9, 43.0, 24.8, 24.1 HRMS Calcd. for C 4 13 CH 9 NO [M+ H ] + : 101 0790 Found: 101.0793 Piperidin 1 ylmethylidenepiperidinium hexafluorophosphate 13C ( 3 32)

PAGE 190

190 To a flame dried Schlenk flask were added 467 (5.01 mmol) of phosphorus oxychloride and 5 mL of DCM. To the reaction mixture at 78 C in a dry ice acetone bath was added a solution of 502 mg (5.01 mmol) of pyrrolidine 1 carbaldehyde 13 C 3 30 in 2 mL of DCM. It was warmed up to room temperature and stirred for 2 hours. Then it was cooled at 0 C and a solution of 693 (5.01 mmol) of triethyl amine and 412 (5.01 mmol) of pyrrolidine in 2.5 mL of DCM was added dropwise. It was stirred at room temperature f or 2 hours. The reaction mixture was extracted with cold H 2 O (3 x 2.5 mL), the combined aqueous layer was added to a cold solution of 1600 mg (10.02 mmol) of ammonium hexafluorophosphate in 5 mL of H 2 O. The precipitate was filtered and washed with H 2 O (2 x 3 mL) and Et 2 O (2 x 5 mL). The yellowish solid was dried under reduced pressure to yield 1000 mg (3.34 mmol, 67% yield) of p iperidin 1 ylmethylidenepiperidinium hexafluorophosphate 13 C 3 32 1 H NMR (300 MHz, CDCl 3 ) ppm 7.81 (d, J =190.0 Hz, 1 H), 3.81 (dt, J =14.0, 7.0 Hz, 4 H), 2.01 (dt, J =13.2, 7.0 Hz, 4 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 151.0, 54.2, 48.2, 25.8, 23.8 HRMS Calcd. for C 8 13 CH 17 F 6 N 2 P [M+ H ] + : 154.1420 Found: 154.1432 6.3.2 Products from The C opper C atalyze d A llylic A lkylation Typical procedure for the allylic alkylation: A flame dried Schlenk flask was charged with a copper source (5 mol %), 1 (chloro(pyrrolidin 1 yl)methylene)pyrrolidinium tetrafluoroborate (5 mol%) and 1 mL of a solvent. To this solution was added a Grignard reagent (0.22 mmol in Et 2 O) at 0 C. The mixture reaction was stirred for 5 min at 0 C. Then a solution of substrate (0.15 mmol) in 1 mL of Et 2 O was added over a 15 min period. After 1 hr, the reaction was quenched by a saturated aqueous NH 4 Cl solution and extracted with Et 2 O (3 x 5 mL). The combined organic extracts were dried

PAGE 191

191 over MgSO 4 filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography to give a pure product. 1 ((2 ethylbut 3 eny loxy)methyl) 4 methoxybenzene ( 3 5 ) 1 H NMR (300 MHz, CDCl 3 ) ppm 7.20 7.37 (m, 2 H), 6.87 (d, J =8.4 Hz, 2 H), 5.54 5.79 (m, 1 H), 4.98 5.23 (m, 2 H), 4.44 (s, 2 H), 3.80 (s, 3 H), 3.36 (d, J =6.4 Hz, 2 H), 2.12 2.42 (m, 1 H), 1.45 1.71 (m, 1 H), 1.13 1.37 (m, 1 H), 0.86 (t, J =7.4 Hz, 3 H) 13 C NMR (75 MH z, CDCl 3 ) ppm 159.1, 140.0, 130.7, 129.1, 115.5, 113.7, 73.2, 72.6, 55.2, 45.7, 24.0, 11.4 HRMS Calcd. for C 14 H 2 0 O 2 [M] + : 220.1463, Found: 220.1477. 2 ethylbut 3 enyl 4 methoxybenzoate ( 3 18 ) 1 H NMR (300 MHz, CDCl 3 ) ppm 7.91 (d, J =8.78 Hz, 2 H), 6.8 3 (d, J =9.06 Hz, 2 H), 5.62 (ddd, J =17.06, 10.40, 8.21 Hz, 1 H), 5.00 5.09 (m, 2 H), 4.15 (dd, J =6.51, 1.98 Hz, 2 H), 3.77 (s, 3 H), 2.25 2.41 (m, 1 H), 1.44 1.60 (m, 1 H), 1.23 1.39 (m, 1 H), 0.86 (t, J =7.36 Hz, 3 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 166.52, 163.50, 139.18, 131.76, 123.07, 116.68, 113.79, 67.37, 55.61, 45.13, 24.23, 11.61

PAGE 192

192 HRMS Calcd. for C 14 H 18 O 3 [M+Na] + : 257.1148, Found: 257.1142 1 (2 ethylbut 3 enyl) 4 methoxybenzene ( 3 19) 1 H NMR (300 MHz, CDCl 3 ) 7.06 (d, J =9 Hz, 2 H), 6.81 (d, J =9 Hz, 2 H), 5.47 5.72 (m, 1 H), 4.73 5.04 (m, 2 H), 3.79 (s, 3 H), 2.43 2.70 (m, 2 H), 2.05 2.27 (m, 1 H), 1.36 1.52 (m, 1 H), 1.17 1.36 (m, 1 H), 0.87 (t, J =8 Hz, 3 H) 13 C NMR (75 MHz, CDCl 3 ) 157.9, 142.6, 133.0, 130.3, 114.8, 113.7, 55.4 47.7, 40.8, 27.0, 11.9 HRMS Calcd. for C 1 3 H 18 O [M+H] + : 191.1430, Found: 191.1436 2,6 dimethyl 6 vinyldodec 2 ene ( 3 20 ) 1 H NMR (300 MHz, CDCl 3 ) ppm 5.71 (dd, J =17.6, 10.9 Hz, 1 H), 5.05 5.15 (m, 1 H), 4.84 5.02 (m, J =15.9, 11.0, 1.6 Hz, 2 H), 1. 82 1.94 (m, 2 H), 1.69 (s, 3 H), 1.60 (s, 3 H), 1.21 1.34 (m, 12 H), 0.96 (s, 3 H), 0.86 0.92 (m, 3 H) 13 C NMR (75 MHz, CDCl 3 ) ppm 147.5, 130.9, 125.2, 111.3, 40.9, 40.8, 39.5, 32.0, 30.2, 25.7, 24.0, 22.9, 22.7, 22.6, 17.6, 14.1 HRMS Calcd. for C 1 6 H 30 [M] + : 222.2348, Found: 223.2342 4 ethyl 1 tosyl 4 vinylpiperidine ( 3 21 )

PAGE 193

193 1 H NMR (300 MHz, CDCl 3 ) 7.58 (m, J =8 Hz, 2 H) 7.26 (m, J =8 Hz, 2 H), 5.36 (dd, J =18, 11 Hz, 1 H), 5.04 (d, J =11 Hz, 1 H), 4.77 (d, J =18 Hz, 1 H), 3.17 3.35 (m, 2 H), 2.55 2.71 (m, 2 H), 2.38 (s, 3 H), 1.59 1.76 (m, 2 H), 1.41 1.59 (m, 2 H), 1.22 (q, J =7 Hz, 2 H), 0.68 (t, J =7 Hz, 3 H) 13 C NMR (75 MHz, CDCl 3 ) 143.4, 133.8, 129.8, 127.8, 115.1, 42.9, 38.1, 34.1, 33.6, 21.8, 7.7 HRMS Calcd. for C 16 H 2 3 NO 2 S [M+H] + : 294.1 522, Found: 294.1499 6.3.3 NMR E xperiments Figure 3 2 Experiment (a ) To a flame dried Schlenk flask was added 20 mg (0.089 mmol) of 1 (chloro 1 pyrrolidinylmethylene) pyrrolidinium chloride, 8.9 mg (0.089 mmol) of copper (I) chloride and d 8 T he reaction mixture was cooled to 0 C and phenylmagnesium bromide (0.36 mmol in THF) was added. It was stirred at 0 C for 5 min then it was transferred to a flame dried NMR tube under argon via syringe. The NMR tube was cooled to 78 C in a dry ice acet one bath before being analyzed in the NMR instrument at 60 C. Figure 3 2 Experiment (b )

PAGE 194

194 To a flame dried Schlenk flask was added 10 mg (0.045 mmol) of 1 (chloro 1 pyrrolidinylmethylene) pyrrolidinium chloride and 75 d 8 The reaction mixture was cooled to 0 C and phenylmagnesium bromide (0.18 mmol in THF) was added. It was stirred at 0 C for 5 min, and then it was transferred to a flame dried NMR tube under argon via syringe. The NMR tube was cooled to 7 8 C in a dry ice acetone bath before being analyzed in the NMR instrument at 60 C. Figure 3 2 Experiment (c ) To the NMR tube from experiment 2 was added 4.5 mg (0.045 mmol) of copper (I) chloride at 0 C. Then it was stirred at 0 C for 5 min and c ooled at 78 C in a dry ice acetone bath before being analyzed in the NMR instrument at 60 C. Figure 3 2 Experiment ( d )

PAGE 195

195 To a flame dried Schlenk flask was added 10 mg (0.045 mmol) of 1 (chloro 1 pyrrolidinylmethylene) pyrrolidinium chloride, 4.4 mg (0.045 mmol) of copper (I) chloride and d 8 The reaction mixture was cooled to 0 C, and ethylmagnesium bromide (0.18 mmol in THF) was added. It was stirred at 0 C for 5 min, and then it was transferred to a flame dried NMR tube under argon via syringe. The NMR tube was cooled to 78 C in a dry ice acetone bath before being analyzed in the NMR instrument at 60 C. Figure 3 3. Experiment (a ) To a flame dried NMR tube was added 41.4 mg (0.138 mmol) of p iperidin 1 ylmethylidenepiperidiniu m hexafluorophosphate 13 C Then it was cooled at 78 C in a dry ice acetone bath and 147 d 8 It was stirred at room temperature for 5 min until dissolution of the suspension before being analyzed in the NMR experiment at room temperature. Figure 3 3. Experiment (b )

PAGE 196

196 To the NMR tube from experime nt 5 at 78 C in a dry ice (1 M in THF) of phenyl magnesiumbromide and the reaction mixture was stirred for 5 min at room temperature before being analyzed in the NMR experiment at room temperature. Figure 3 3. Experiment (c) To the NMR tube from experiment 6 at 78 C in a dry ice acetone bath was added 14 mg (0.138 mmol) of copper chloride and the reaction mixture was stirred for 5 min at room temperature before being analyzed in the NMR experiment at room temperature. 6.3.4 A dditional Experiments from T able 3 2 Table 3 2. E ntry 8 To a flame dried Schlenk flask were added 201 mg (0.674 mmol) of p iperidin 1 ylmethylidenepiperidinium hexafluorophosphate to a solution of 0.674 mmol (3 M in THF) of LDA. The reaction mixture was s tirred at solution generated in situ was added to a flame

PAGE 197

197 M in Et 2 O) of ethyl magnesiumbromide, 4.2 mg (0.022 mmol) of copper thiophene 2 carboxylate and 1 mL of Et 2 O. The reaction mixture was stirred for 5 min then a solution of 55 mg (0.221 mmol) of ( Z ) 4 (4 methoxybenzyloxy)bu t 2 enyl acetate in 1 mL of Et 2 O was added dropwise. After 1 hr, the reaction was quenched by a saturated aqueous NH 4 Cl solution and extracted with Et 2 O (3 x 5 mL). The combined organic extracts were dried over MgSO 4 filtered, and concentrated under reduced pressure. The residue was purified by flash column c hromatography (silica gel, 1:0.05 Hexanes/EtOAc) to yield 33.9 mg (0.154 m 90:10) of 1 ((2 ethylbut 3 enyloxy)methyl) 4 methoxybenzene Table 3 2. E ntry 9 To a flame dried Schlenk flask were added 3.5 mg (0.011 mmol) of 1,3 Bis(2,4,6 trimethyl phenyl)imidazol 2 ylidene, 2.1 mg (0.011 mmol) of copper thiophene 2 c arboxylate, 2 O) of ethyl magnesiumbromide and 1 mL of Et 2 O. The The reaction mixture was stirred for 5 min at 0 C then a solution of 58 mg (0.231 mmol) of ( Z ) 4 (4 methoxybenzyloxy)bu t 2 enyl acetate in 1 mL of Et 2 O was added dropwise. Af ter 1 hr, the reaction was quenched by a saturated aqueous NH 4 Cl solution and extracted with Et 2 O (3 x 5 mL). The combined organic extracts were dried over MgSO 4 filtered, and concentrated under reduced pressure. The residue was purified by flash column c hromatography (silica gel, 1:0.05

PAGE 198

198 Hexanes/EtOAc) to yield 1 ((2 ethylbut 3 enyloxy)methyl) 4 methoxybenzene 6.4 C 1 Symmetric M onoisoquinoline NHC L igand s 6.4.1 Ligands S ynthesis ( S ) N (4 methyl 1 phenylpentan 2 yl) 2 oxo 2 phenylacetamide ( 4 10 ) To a flame dried Schlenk flask was added 2.21 g (12.5 mmol) of ( S ) 4 methyl 1 phenylpentan 2 amine 2.18 g (16.1 mmol) of HOBt, 3.09 g (16.2 mmol) of EDCI, 2.05 g (13.7 mmol) of 2 oxo 2 phenylacetic acid and 33 mL (0.377 M) of DMF. The reaction mixture was stirred at room tempera ture for 12 h. It was quenched by 40 mL of water. The reaction mixture was extracted with ethyl acetate (2 x 40 mL), washed with water (2 x 40 mL) and dried over anhydrous MgSO 4 All volatiles were removed in vacuo. Silicagel column chromatography with a 9 5:5 mixture of hexane and ethyl acetate as the eluent gave 2.91 g (9.41 mmol, 75.3%) of ( S ) N (4 methyl 1 phenylpentan 2 yl) 2 oxo 2 phenylacetamide 1 H NMR (299 MHz, CHLOROFORM d ) = 8.18 8.29 (m, 2 H), 7.56 7.67 (m, 1 H), 7.41 7.51 (m, 2 H), 7.16 7.36 (m, 5 H), 6.79 (d, J =9.3 Hz, 1 H), 4.30 4.46 (m, J =9.1, 6.0, 6.0, 3.0 Hz, 1 H), 2.75 2.97 (m, J =13.9, 6.2 Hz, 2 H), 1.67 (td, J =13.7, 6.7 Hz, 1 H), 1.43 (ddd, J =8.9, 5.4, 3.5 Hz, 2 H), 0.93 (dd, J =6.5, 1.4 Hz, 6 H) 13 C NMR (75 MHz, CHLOROFORM d ) = 161.2, 137.5, 134.3, 131.1, 129.5, 128.4, 126.5, 48.6, 43.3, 41.6, 25.0, 23.2, 21.9

PAGE 199

199 HRMS Calcd. for C 2 0 H 23 NO 2 [M+H] + : 310 1802 Found: 310.1826 20 D 22.2 ( c 1.33, CHCl 3 ) ( S ) N (1,2 diphenylethyl) 2 oxo 2 phenylacetamide (4 34) 265 mg (0.805 mmo l, 71.9%) of ( S ) N (1,2 diphenylethyl) 2 oxo 2 phenylacetamide was obtained from 200 mg (1.014 mmol) of ( S ) 1,2 diphenylethanamine 167 mg (1.12 mmol) of 2 oxo 2 phenylacetic acid 253 mg (1.32 mmol) of EDCI, 180 mg (1.32 mmol) of HOBt and 2.5 mL of DMF. 1 H NMR (300MHz ,CHLOROFORM d) = 8.41 8.08 (m, 2 H), 7.89 7.51 (m, 2 H), 7.51 7.11 (m, 12 H), 5.38 (q, J = 7.5 Hz, 1 H), 3.38 3.06 (m, 2 H) 13 C NMR (75MHz ,CHLOROFORM d) = 187.9, 161.3, 140.9, 137.2, 134.6, 133.5, 131.4, 129.6, 129.0, 128.7, 128.0, 126.9, 55.0, 42.9 ( R ) N (1 cyclohexyl 2 phenylethyl) 2 oxo 2 phenylacetamide (4 36) 460 mg (1.37 mmol, 54.0%) of (R) N (1 cyclohexyl 2 phenylethyl) 2 oxo 2 phenylacetamide was obtained from 517 mg (2.54 mmol) of (R) 1 cyclohexyl 2

PAGE 200

200 phenylethanamine 400 mg (2.66 mmol) of 2 oxo 2 phenylacetic acid 634 mg (3.31 mmol) of EDCI, 447 mg (3.31 mmol) of HOBt and 6.4 mL of DMF. 1 H NMR (300MHz ,CHLOROFORM d) = 8.24 8.12 (m, 2 H), 7.70 7.56 (m, 1 H), 7.53 7.40 (m, 2 H), 7.38 7.17 (m, 5 H), 6.86 (d, J = 9.7 Hz, 1 H), 4.29 4.13 (m, 1 H), 3.04 (dd, J = 5.3, 14.1 Hz, 1 H), 2.76 (dd, J = 8.8, 13.8 Hz, 1 H), 1.86 (t, J = 14.2 Hz, 4 H), 1.76 1.67 (m, 1 H ), 1.65 1.51 (m, 1 H), 1.34 1.04 (m, 5 H) 13 C NMR (75MHz ,CHLOROFORM d) = 188.4, 161.6, 138.3, 134.5, 133.5, 131.3, 129.4, 128.7, 128.6, 126.6, 55.3, 41.3, 38.3, 30.4, 28.4, 26.5, 26.3 2 oxo 2 phenyl N ((1 R ,2 R ) 2 phenylcyclohexyl)acetamide (4 40) 270 mg (0.878 mmol, 75.7%) of 2 oxo 2 phenyl N ((1R,2R) 2 phenylcyclohexyl)acetamide was obtained from 204 mg (1.16 mmol) of (1R,2R) 2 phenylcyclohexanamine 183 mg (1.22 mmol) of 2 oxo 2 phenylacetic acid 290 mg (1.51 mmol) of EDCI, 204 mg (1.51 mmol) of HOBt and 2.8 mL of DMF. 1 H NMR (300MHz ,CHLOROFORM d) = 8.06 7.96 (m, 2 H), 7.66 7.48 (m, 1 H), 7.48 7.14 (m, 8 H), 4.60 (dq, J = 3.2, 9.4 Hz, 1 H), 3.06 (dt, J = 4.0, 11.6 Hz, 1 H), 2.12 (d, J = 15.0 Hz, 1 H), 2.06 1.66 (m, 5 H), 1.64 1.46 (m, 2 H) 13 C NMR (75MHz ,CHLOROFORM d) = 188.7, 161.7, 142.9, 134.4, 133.3, 131.2, 128.6, 128.5, 127.7, 126.7, 50.0, 45.6, 31.3, 25.9, 25.7, 20.8 ( S ) (3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methanone ( 4 11 )

PAGE 201

201 T o a flame dried Schlenk flask was added 400 mg (1.29 mmol) of ( S ) N (4 methyl 1 phenylpentan 2 yl) 2 oxo 2 phenylacetamide 472 mg (3.87 mmol) of DMAP and 50 mL (0.025 M) of toluene. The reaction mixture was cooled to 0 C and 1.09 mL (6.45 mmol) of Tf 2 O was slowly added. After 10 min stirring at 0 the reaction mixture was stirred at 90 C for 8 h. It was quenched by 10 mL of a saturated Na 2 CO 3 aqueous solution. The reaction mixture was extracted with DCM (3 x 40 mL) and dried over anhydrous MgSO 4 All volatiles were removed in vacuo. Silicagel column chromatography with a 95:5 mixture of hexane and ethyl acetate as the eluent gave 370 mg (1.27 mmol, 98.4%) of ( S ) (3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methan one 1 H NMR (300 MHz, CHLOROFORM d ) = 8.01 8.14 (m, 2 H), 7.54 7.69 (m, 1 H), 7.20 7.53 (m, 6 H), 3.84 3.98 (m, 1 H), 2.94 (dd, J =16.1, 5.6 Hz, 1 H), 2.68 (dd, J =16.0, 11.0 Hz, 1 H), 1.88 2.04 (m, J =13.5, 6.7, 6.7, 6.7, 6.7 Hz, 1 H), 1.70 1.84 (m, 1 H), 1.50 (ddd, J =13.6, 7.0, 6.9 Hz, 1 H), 0.98 (dd, J =6.6, 2.2 Hz, 6 H) 13 C NMR (75 MHz, CHLOROFORM d ) =194.08, 164.15, 137.16, 135.74, 134.05, 131.72, 130.69, 128.71, 128.33, 127.33, 126.95, 126.62, 55.34, 44.50, 31.43, 25.03, 23.08, 22.80 HRMS Calcd. for C 20 H 21 NO [M+H] + : 291.1696 Found: 291.1700 20 D 13.9 ( c 1.21, CHCl 3 ) ( R ) (3 cyclohexyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methanone (4 37)

PAGE 202

202 280 mg (0.882 mmol, 98.7%) of ( R ) (3 cyclohexyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methanone was obtained from 300 mg (0.894 mmol) o f 2 ( R ) N (1 cyclohexyl 2 phenylethyl) 2 oxo 2 phenylacetamide 327 mg (2.68 mmol) of DMAP, 752 L (4.47 mmol) of Tf 2 O and 36 mL of toluene. 1 H NMR (300MHz ,CHLOROFORM d) = 8.34 7.97 (m, 2 H), 7.82 7.56 (m, 1 H), 7.56 7.34 (m, 4 H), 7.34 6.96 (m, 2 H), 3.53 (dt, J = 6.3, 12.4 Hz, 1 H), 2.96 2.70 (m, 2 H), 2.05 (d, J = 11.4 Hz, 1 H), 1.94 1.62 (m, 5 H), 1.49 1.12 (m, 5 H) 13 C NMR (75MHz ,CHLOROFORM d) = 194.0, 164.1, 138.0, 135.8, 134.0, 131.6, 130.7, 128.7, 128.3, 127.2, 127.1, 126.5, 62.4, 42.9, 30.1, 29.7, 28.2, 26.8, 26.7 ((4a R ,10b R ) 1,2,3,4,4a,10b hexahydrophenanthridin 6 yl)(phenyl)methanone (4 41) 80 mg (0.276 mmol, 94.7%) of ((4a R ,10b R ) 1,2,3,4,4a,10b hexahydrophenanthridin 6 yl)(phenyl)methanone was obtained from 90 mg (0.292 mmol ) of 2 oxo 2 phenyl N ((1 R ,2 R ) 2 phenylcyclohexyl)acetamide 107 mg (0.878 mmol) of DMAP, 246 L (1.46 mmol) of Tf 2 O and 12 mL of toluene.

PAGE 203

203 1 H NMR (299MHz ,CHLOROFORM d) = 8.17 8.03 (m, 2 H), 7.67 7.13 (m, 7 H), 3.90 (q, J = 4.7 Hz, 1 H), 2.96 2.80 (m, 1 H), 2.18 (d, J = 10.2 Hz, 1 H), 1.97 1.35 (m, 7 H) 13 C NMR (75MHz ,CHLOROFORM d) = 194.3, 165.4, 142.4, 135.7, 134.2, 132.1, 130.6, 128.8, 127.5, 127.2, 126.9, 125.8, 57.1, 37.6, 30.9, 29.0, 24.4, 22.3 ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 3,5 bis(trifluoromethyl)aniline ( 4 67 ) 37.0 mg (0.0736 mmol, 79.5%) of ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 3,5 bis(trifluoromethyl)aniline was obtained from 27.0 mg (0.0926 mmol) of ( S ) (3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methanone 25.6 L (1.85 mmol) of Et 3 N, 71.3 L (0.460 mmol) of 3 5 bis(trifluoromethyl)aniline and 110 L of TiCl 4 (1 M in toluene) 1 H NMR (300MHz ,CHLOROFORM d) = 7.95 (d, J = 7.4 Hz, 2 H), 7.55 7.34 (m, 4 H), 7.34 7.20 (m, 3 H), 7.20 7.01 (m, 3 H), 3.78 3.55 (m, 1 H), 2.63 (dd, J = 5.5, 16.0 Hz, 1 H), 1.88 1.65 (m, 1 H), 1.57 (dt, J = 6.7, 13.3 Hz, 1 H), 1.40 1.15 (m, 1 H), 0.85 (d, J = 6.5 Hz, 3 H), 0.88 (d, J = 6.8 Hz, 3 H) 13 C NMR (75MHz ,CHLOROFORM d) = 163.0, 151.9, 136.3, 136.1, 132.0, 131.7, 131.1, 128.7, 128.0, 127.1, 125.7, 124.9, 121.3, 120.7, 116.9, 54.9, 44.2, 30.7, 24.5, 22.6, 22.4 HRMS Calcd. for C 28 H 24 F 6 N 2 [M+H ] + : 503.1916 Found: 503.1919

PAGE 204

204 32 D 43.4 ( c 0.78, CHCl 3 ) ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 1,1 diphenylmethanamine ( 4 13 ) 46.0 mg (0.100 mmol, 72.9%) of ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phe nyl)methylene) 1,1 diphenylmethanamine was obtained from 40.0 mg (0.137 mmol) of (S) (3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methanone 37.9 L (0.274 mmol) of Et 3 N, 118 L (0.685 mmol) of diphenylmethanamine and 165 L of TiCl 4 (1 M in toluene). 1 H NMR (300MHz CHLOROFORM d) = 7.96 (d, J = 10.0 Hz, 2 H), 7.52 7.12 (m, 15 H), 6.94 (br. s., 1 H), 6.89 6.55 (m, 1 H), 5.91 5.73 (m, 1 H), 4.09 3.85 (m, 1 H), 3.13 2.89 (m, 1 H), 2.83 2.65 (m, 1 H), 2.12 1.66 (m, 2 H), 1.58 1.41 (m, 1 H), 0.97 (d, J = 6.4 Hz, 6 H) 1 3 C NMR (75MHz ,CHLOROFORM d) = 164.5, 144.2, 137.9, 137.7, 136.6, 136.0, 131.6, 130.6, 128.4, 128.3, 127.5, 127.4, 126.9, 70.0, 54.9, 44.8, 31.9, 31.6, 24.8, 23.0 HRMS Calcd. for C 33 H 32 N 2 [M+H ] + : 457.2638 Found: 457.2638 32 D 88.8 ( c 1.08, CHCl 3 ) ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene)anthracen 9 amine ( 4 68 )

PAGE 205

205 36.0 mg (0.0773 mmol, 75.0%) of ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene)anthracen 9 amine was obtained from 30.0 mg (0.103 mmol) of (S) (3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methanone 100 L (0.723 mmol) of Et 3 N, 100 mg (0.435 mmol) of anthracen 9 aminium chloride and 125 L of TiCl 4 (1 M in toluene). 1 H NMR (300MHz ,CHLOROFORM d) = 8.27 (d, J = 6.7 Hz, 2 H), 8.14 7.86 (m, 3 H), 7.86 7.65 (m, 2 H), 7.65 7.45 (m, 3 H), 7.45 7.12 (m, 4 H), 7.03 (d, J = 7.6 Hz, 1 H), 6.95 6.76 (m, 1 H), 6.76 6.52 (m, 2 H), 3.29 (s, 1 H), 1.94 1.72 (m, J = 7.3 Hz, 1 H), 1.67 1.47 (m, 1 H), 1.19 (dt, J = 7.1, 13.7 Hz, 1 H), 0.99 0.82 (m, 2 H), 0.76 (t, J = 7.0 Hz, 6 H) 13 C NMR (75MHz ,CHLOROFORM d) = 168.0, 163.7, 143.7, 137.2, 131.8, 131.6, 131.4, 130.2, 129.2, 128.9, 127.8, 127.3, 126.9, 126.1, 125.4, 125.3, 125.2, 123.9, 121.7, 54 .7, 30.8, 29.9, 24.5, 22.8, 22.7 HRMS Calcd. for C 34 H 30 N 2 [M+H ] + : 467.2482 Found: 467.2487 28 D 252.9 ( c 0.5, CHCl 3 ) ( S ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 2,6 diisopropylaniline ( 4 16 )

PAGE 206

206 217 mg (0.482 mmol, 70.6%) of ( S ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 2,6 diisopropylaniline was obtained from 200 mg (0.686 mmol) of ( S ) (3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methanone 190 L (1.37 mmol) of Et 3 N, 647 L (3.43 mmol) of 2,6 diisopropylan iline and 820 L of TiCl 4 (1 M in toluene). 1 H NMR (300 MHz, CHLOROFORM d ) = 8.07 (d, J =6.5 Hz, 2 H), 7.42 7.58 (m, 3 H), 7.19 7.26 (m, 1 H), 6.80 7.15 (m, 6 H), 3.54 (br. s., 1 H), 3.00 3.15 (m, 1 H), 2.78 (br. s., 1 H), 2.38 (dd, J =15.5, 4.7 Hz, 1 H), 1.84 (dt, J =13.1, 6.8 Hz, 2 H), 1.55 (dt, J =13.7, 7.1 Hz, 1 H), 0.8 0 1.30 (m, 19 H) 13 C NMR (75MHz ,CHLOROFORM d) = 163.5, 163.2, 146.2, 137.4, 137.1, 136.7, 135.6, 131.0, 130.4, 128.6, 128.3, 127.5, 126.6, 125.7, 123.1, 121.7, 54.7, 44.2, 31.2, 28.5, 28.4, 24.5, 24.0, 23.0, 22.6, 20.9, 20.8 HRMS Calcd. for C 32 H 38 N 2 [ M+H] + : 451.3108 Found: 451.3106 20 D 8.7 ( c 0.96, CHCl 3 ) ( S ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 2,4,6 trimethylaniline ( 4 12 )

PAGE 207

207 To a flame dried Schlenk flask was added 204 mg (0.700 mmol) of ( S ) (3 isobutyl 3,4 dihydroiso quinolin 1 yl)(phenyl)methanone 194 L (1.40 mmol) of Et 3 N, 492 L (3.50 mmol) of mesitylamine and 8 mL (0.1 M) of toluene. The reaction mixture was cooled to 0 C and 840 L of TiCl 4 solution (1 M in toluene) was slowly added. After 10 min stirring at 0 the reaction mixture was stirred at room temperature for 12 h. It was quenched by 4 mL of a saturated NH 4 Cl aqueous solution. The reaction mixture was extracted with DCM (3 x 20 mL) and dried over anhydrous MgSO 4 All volatiles were removed in vacuo. Silicagel column chromatography with a 99:1 mixture of hexane and ethyl acetate as the eluent gave 280 mg (0.685 mmol, 97.8%) of ( S ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 2,4,6 trimethylaniline 1 H NMR (300 MHz, CHLOROFORM d ) = 7. 95 8.14 (m, 2 H), 7.40 7.58 (m, 3 H), 7.19 7.27 (m, 1 H), 7.01 7.14 (m, 3 H), 6.67 (br. s., 1 H), 6.55 (br. s., 1 H), 3.56 (dd, J =11.9, 5.4 Hz, 1 H), 2.46 (dd, J =15.5, 5.0 Hz, 1 H), 2.17 (s, 3 H), 2.10 (br. s., 3 H), 1.75 2.00 (m, 4 H), 1.52 1. 63 (m, 1 H), 1.23 1.34 (m, 2 H), 0.91 (dd, J =10.7, 6.6 Hz, 6 H) 13 C NMR (75MHz ,CHLOROFORM d) = 165.6, 163.2, 145.7, 137.3, 136.9, 131.8, 131.0, 130.6, 128.6, 128.3, 127.9, 127.6, 127.4, 126.2, 126.0, 54.7, 44.4, 31.3, 30.3, 29.7, 24.5, 22.8, 22.6, 20.6 HRMS Calcd. for C 2 9 H 32 N 2 [M+H] + : 409.2638 Found: 409.2640 20 D 28.2 ( c 0.97, CHCl 3 )

PAGE 208

208 ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 3,5 dimethylaniline (4 17) 69.0 mg (0.175 mmol, 45.1%) of ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 3,5 dimethylaniline was obtained from 113 mg (0.388 mmol) of ( S ) (3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methanone 107 L (0.776 mmol) of Et 3 N, 242 L (1.94 mmol) of 3 5 di meth ylaniline and 465 L of TiCl 4 (1 M in toluene). 1 H NMR (300MHz ,CHLOROFORM d) = 8.25 7.99 (m, 1 H), 7.93 (br. s., 1 H), 7.59 (d, J = 7.3 Hz, 1 H), 7.51 7.20 (m, 4 H), 7.17 7.04 (m, 2 H), 6.79 6.25 (m, 3 H), 3.99 3.61 (m, 1 H), 3.08 2.46 (m, 2 H), 2.39 2.04 (m, 6 H), 1.94 (dd, J = 6.7, 13.5 Hz, 1 H), 1.85 1.61 (m, 1 H), 1.50 (dd, J = 6.9, 13.6 Hz, 1 H), 1.03 0.77 (m, 6 H) 13 C NMR (75MHz ,CHLOROFORM d) = 164.3, 150.6, 137.7, 137.5, 136.4, 134.0, 131.7, 131.2, 130.7, 128.6, 128.3, 127.9, 127.3, 127.1, 126.5, 125.5, 118.5, 113.3, 55.3, 44.5, 31.4, 25.0, 24.8, 23.1, 22.8, 21.4 29 D 27.4 ( c 1.58, CHCl 3 ) HRMS Calcd. for C 28 H 30 N 2 [M+H] + : 395.2482 Found: 395.2484 ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 2,6 dimethylaniline (4 66)

PAGE 209

209 99.0 mg (0.234 mmol, 68.2%) of ( S E ) N ((3 isobutyl 3,4 d ihydroisoquinolin 1 yl)(phenyl)methylene) 2,6 dimethylaniline was obtained from 100 mg (0.343 mmol) of ( S ) (3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methanone 94.9 L (0.686 mmol) of Et 3 N, 210 L (1.72 mmol) of 2,6 dimethylaniline and 410 L of TiCl 4 (1 M in toluene). 1 H NMR (300MHz ,CHLOROFORM d) = 8.05 (d, J = 7.0 Hz, 1 H), 7.62 7.39 (m, 3 H), 7.35 7.17 (m, 2 H), 7.16 6.93 (m, 3 H), 6.91 6.60 (m, 3 H), 3.53 (td, J = 6.4, 12.2 Hz, 1 H), 2.41 (dd, J = 5.0, 15.5 Hz, 1 H), 2.22 2.04 (m, 3 H), 2.01 1.74 (m, 4 H), 1.63 1.50 (m, 1 H), 1.3 9 1.18 (m, 2 H), 0.89 (d, J = 10.3 Hz, 3 H), 0.91 (d, J = 10.6 Hz, 3 H) 13 C NMR (75MHz ,CHLOROFORM d) = 165.7, 163.3, 148.4, 137.4, 131.3, 130.9, 128.9, 128.5, 127.8, 127.5, 126.5, 126.1, 123.0, 54.9, 44.9, 31.5, 24.8, 23.0, 22.9, 19.2, 18.5 HRMS Calcd for C 28 H 30 N 2 [M+H ] + : 395.2482 Found: 395.2487 32 D 25.3 ( c 1.58, CHCl 3 ) ( S E ) 2,6 diethyl N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene)aniline (4 65)

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210 26.0 mg (0.0615 mmol, 71.7%) of ( S E ) 2,6 diethyl N ((3 isobutyl 3,4 dihydroiso quinolin 1 yl)(phenyl)methylene)aniline was obtained from 25.0 mg (0.0857 mmol) of ( S ) (3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methanone 23.6 L (0.171 mmol) of Et 3 N, 66.6 L (0.428 mmol) of 2,6 diethylaniline and 103 L of TiCl 4 (1 M in toluene). 1 H NMR (300MHz ,CHLOROFORM d) = 8.04 (d, J = 6.7 Hz, 2 H), 7.59 7.39 (m, 3 H), 7.25 7.18 (m, 1 H), 7.14 6.97 (m, 3 H), 6.95 6.69 (m, 3 H), 3.48 (dd, J = 5.1, 11.9 Hz, 1 H), 2.60 (dt, J = 7.6, 15.2 Hz, 1 H), 2.49 2.32 (m, 3 H), 1.95 1.70 (m, 1 H), 1.63 1.41 (m, 2 H), 1.3 4 1.04 (m, 5 H), 1.03 0.78 (m, 9 H) 13 C NMR (75MHz ,CHLOROFORM d) = 164.9, 163.3, 137.4, 137.3, 132.6, 131.7, 131.3, 130.8, 128.9, 128.6, 127.7, 126.5, 126.0, 124.9, 123.2, 54.8, 31.5, 29.9, 25.2, 24.7, 24.5, 23.0, 22.8, 13.5, 13.2 HRMS Calcd. for C 3 0 H 34 N 2 [M+H ] + : 423.2795 Found: 423.2795 29 D 18.4 ( c 0.79, CHCl 3 ) ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 2 isopropylaniline (4 24) 42.0 mg (0.102 mmol, 71.7%) of ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl )methylene) 2 isopropylaniline was obtained from 33.0 mg (0.113 mmol) of ( S ) (3

PAGE 211

211 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methanone 31.0 L (0.226 mmol) of Et 3 N, 80.0 L (0.560 mmol) of 2 isoprop ylaniline and 136 L of TiCl 4 (1 M in toluene). 1 H NMR (2 99MHz ,CHLOROFORM d) = 8.00 (d, J = 6.2 Hz, 2 H), 7.54 7.37 (m, 3 H), 7.33 7.23 (m, 1 H), 7.21 7.05 (m, 4 H), 7.00 6.77 (m, 2 H), 6.63 (br. s., 1 H), 3.80 3.62 (m, 1 H), 3.23 (br. s., 1 H), 2.67 (dd, J = 4.5, 14.7 Hz, 1 H), 1.88 1.65 (m, 1 H), 1.56 (dd, J = 6.4, 12.9 Hz, 1 H), 1.40 1.04 (m, 8 H), 1.02 0.72 (m, 6 H) 13 C NMR (75MHz ,CHLOROFORM d) = 164.1, 148.0, 140.0, 137.5, 136.6, 131.2, 130.7, 128.7, 128.7, 128.0, 127.1, 126.3, 125.2, 124.5, 119.0, 54.8, 53.7, 44.5, 31.4, 28.4, 24.7, 23.0, 22.7 ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 2,4 dimethylaniline (4 25) 41.0 mg (0.104 mmol, 71.7%) of ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 2,4 dimethylaniline was obtained from 35.0 mg (0.120 mmol) of ( S ) (3 is obutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methanone 33.0 L (0.240 mmol) of Et 3 N, 75.0 L (0.600 mmol) of 2,4 dimethylaniline and 144 L of TiCl 4 (1 M in toluene). 1 H NMR (300MHz ,CHLOROFORM d) = 8.04 7.90 (m, 2 H), 7.54 7.34 (m, 3 H), 7.32 7.21 (m, 1 H), 7.19 7.02 (m, 3 H), 6.83 (s, 1 H), 6.73 6.51 (m, 2 H), 3.84 3.62 (m, 1 H), 2.79 2.57 (m, 1 H), 2.34 2.07 (m, 7 H), 1.67 1.48 (m, 1 H), 1.39 1.19 (m, 2 H), 0.94 0.80 (m, 6 H)

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212 13 C NMR (75MHz ,CHLOROFORM d) = 164.4, 146.6, 137.4, 136.6, 134.1, 133.4, 131.1, 130.8, 129.4, 128.7, 128.6, 128.1, 127.1, 126.3, 126.0, 118.8, 55.3, 54.9, 44.5, 31.3, 24.8, 23.0, 21.0, 18.5 ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)me thylene)biphenyl 2 amine (4 26) 42.0 mg (0.0948 mmol, 71.7%) of ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene)biphenyl 2 amine was obtained from 31.4 mg (0.107 mmol) of ( S ) (3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methanone 30.0 L (0.215 mmol) of Et 3 N, 91.0 mg (0.535 mmol) of biphenyl 2 amine and 129 L of TiCl 4 (1 M in toluene). 1 H NMR (299MHz ,CHLOROFORM d) = 7.86 (d, J = 7.1 Hz, 2 H), 7.59 7.51 (m, 2 H), 7.49 7.29 (m, 5 H), 7.28 7.00 (m, 6 H), 6.93 6.76 (m, 2 H), 6.58 (d, J = 7.4 Hz, 1 H), 3.77 3.58 (m, 1 H), 2.68 (dd, J = 3.8, 16.0 Hz, 1 H), 1.97 1.70 (m, 1 H), 1.70 1.49 (m, 1 H), 1.40 1.1 8 (m, 2 H), 1.02 0.64 (m, 6 H) 13 C NMR (75MHz ,CHLOROFORM d) = 164.7, 163.8, 148.3, 140.3, 137.2, 136.4, 132.8, 131.1, 130.9, 130.7, 130.1, 129.8, 129.3, 129.0, 128.6, 128.0, 127.8, 127.4, 127.2, 126.7, 126.5, 124.4, 120.7, 115.8, 54.8, 44.5, 31.4, 24. 7, 23.1, 22.7 ( R E ) N ((3 cyclohexyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 2,4,6 trimethylaniline (4 38)

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213 204 mg (0.470 mmol, 99.6%) of ( R E ) N ((3 cyclohexyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 2,4,6 trimethylaniline was obtained from 150 mg (0.472 mmol) of ( R ) (3 cyclohexyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methanone 130 L (0.945 mmol) of Et 3 N, 332 L (2.36 mmol) of 2,4,6 trimethylaniline and 570 L of TiCl 4 (1 M in toluene). 1 H NMR (299MHz ,CHLOROFORM d) = 8.07 (dd, J = 1.4, 7.9 Hz, 2 H), 7.63 7.39 (m, 3 H), 7.35 6.99 (m, 4 H), 6.71 (br. s., 1 H), 6.55 (br. s., 1 H), 3.22 (dt, J = 5.3, 13.9 Hz, 1 H), 2.44 (dd, J = 4.8, 15.6 Hz, 1 H), 2.19 (s, 6 H), 2.14 1.98 (m, 1 H), 1.89 (br. s., 1 H), 1.86 1.4 6 (m, 8 H), 1.40 1.00 (m, 5 H) 13 C NMR (75MHz ,CHLOROFORM d) = 165.7, 163.3, 145.8, 137.9, 137.6, 131.7, 131.0, 130.5, 128.6, 128.3, 128.0, 127.6, 126.7, 126.2, 125.4, 62.1, 42.6, 29.6, 29.4, 28.0, 26.7, 26.5, 20.7, 19.2, 18.2 ( E ) N (((4a R ,10b R ) 1,2,3, 4,4a,10b hexahydrophenanthridin 6 yl)(phenyl)methylene) 2,4,6 trimethylaniline (4 42) 67.0 mg (0.164 mmol, 95.3%) of ( E ) N (((4a R ,10b R ) 1,2,3,4,4a,10b hexahydrophenanthridin 6 yl)(phenyl)methylene) 2,4,6 trimethylaniline was obtained from 50

PAGE 214

214 mg (0.172 m mol) of ((4a R ,10b R ) 1,2,3,4,4a,10b hexahydrophenanthridin 6 yl)(phenyl)methanone 48.0 L (0.345 mmol) of Et 3 N, 121 L (0.860 mmol) of 2,4,6 trimethylaniline and 206 L of TiCl 4 (1 M in toluene). 1 H NMR (300MHz ,CHLOROFORM d) = 8.10 8.02 (m, 2 H), 7.57 7.41 (m, 3 H), 7.33 7.23 (m, 1 H), 7.18 7.02 (m, 3 H), 6.74 (br. s., 1 H), 6.50 (s, 1 H), 3.71 3.63 (m, 1 H), 2.50 2.38 (m, 1 H), 2.32 2.11 (m, 8 H), 1.78 1.57 (m, 4 H), 1.55 1.43 (m, 1 H), 1.42 1.20 (m, 3 H ), 1.14 (d, J = 12.3 Hz, 1 H) 13 C NMR (75MHz ,CHLOROFORM d) = 166.2, 165.2, 146.4, 143.3, 137.8, 132.1, 131.5, 131.4, 128.9, 128.5, 128.2, 127.9, 127.5, 127.3, 126.3, 125.9, 125.1, 56.7, 38.0, 31.9, 27.1, 22.9, 20.8, 19.7, 18.2, 14.4 ( S ) 2 (3,5 bis(trifl uoromethyl)phenyl) 5 isobutyl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride ( 4 71 ) 21.0 mg (0.0381 mmol, 70.9%) of ( S ) 2 (3,5 bis(trifluoromethyl)phenyl) 5 isobutyl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride was obtained from 27.0 mg (0.0537 mmol) of ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 3,5 bis(trifluoromethyl)aniline and 29.8 L (0.322 mmol) of chloromethyl ethyl ether

PAGE 215

215 1 H NMR (299MHz ,CHLOROFORM d) = 10.88 (br. s., 1 H), 8.32 6.48 (m, 12 H), 5.33 (br. s., 1 H), 3.56 (d, J = 16.7 Hz, 1 H), 3.06 (d, J = 15.6 Hz, 1 H), 2.03 1.61 (m, 3 H), 1.20 0.76 (m, 6 H) 13 C NMR (75MHz ,CHLOROFORM d) = 136.7, 134.7, 133.5, 133.1, 131.8, 131.8, 131.3, 131.0, 130.6, 129.9, 129.7, 127.8, 126.9, 124.7, 124.5, 124.0, 123.9, 114.3, 54.4, 41.6, 32.5, 24.9, 22.9, 21.7 HRMS Calcd. for C 29 H 25 F 6 N 2 [M ] + : 515.1916 Found: 515.1932 32 D 11.8 ( c 0.65, CHCl 3 ) ( S ) 2 benzhydryl 5 isobutyl 1 phenyl 5,6 dihydro 2H imidazo[5 ,1 a ]isoquinolin 4 ium chloride ( 4 73 ) 30.0 mg (0.0594 mmol, 90.3%) of ( S ) 2 benzhydryl 5 isobutyl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride was obtained from 30.0 mg (0.0658 mmol) of ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 1,1 diphenylmethanamine and 36.5 L (0.394 mmol) of chloromethyl ethyl ether 1 H NMR (300MHz ,CHLOROFORM d) = 9.96 (s, 1 H), 7.85 7.49 (m, 2 H), 7.49 7.11 (m, 14 H), 7.11 6.88 (m, 2 H), 6.78 (d, J = 7.6 Hz, 1 H), 6.31 (s, 1 H), 5.68 (br. s., 1 H), 3.59 (br. s., 1 H), 2.97 (d, J = 16.1 Hz, 1 H), 1.64 1.37 (m, 3 H), 0.96 0.82 (m, 6 H)

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216 13 C NMR (75MHz ,C HLOROFORM d) = 136.1, 135.8, 132.0, 131.3, 130.3, 129.9, 129.8, 129.4, 129.2, 128.8, 128.5, 127.6, 125.8, 124.4, 122.9, 66.3, 53.8, 41.9, 32.5, 25.3, 23.2, 22.2 HRMS Calcd. for C 34 H 33 N 2 [M ] + : 469.2638 Found: 469.2641 29 D + 36.6 ( c 0.73, CHCl 3 ) ( S ) 2 (anthracen 9 yl) 5 isobutyl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride ( 4 72 ) 20.0 mg (0.0388 mmol, 90.4%) of ( S ) 2 (anthracen 9 yl) 5 isobutyl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride was obtained from 20. 0 mg (0.0429 mmol) of ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene)anthracen 9 amine and 24.5 L (0.264 mmol) of chloromethyl ethyl ether 1 H NMR (300MHz ,CHLOROFORM d) = 10.51 (br. s., 1 H), 8.59 (s, 1 H), 8.09 (d, J = 8.5 Hz, 1 H), 7.96 (d, J = 8.5 Hz, 1 H), 7.73 7.33 (m, 8 H), 7.23 6.93 (m, 7 H), 5.94 (br. s., 1 H), 3.86 (br. s., 1 H), 3.19 (d, J = 11.7 Hz, 1 H), 1.85 (br. s., 1 H), 1.73 (br. s., 2 H), 1.06 (d, J = 5.6 Hz, 3 H), 1.09 (d, J = 5.6 Hz, 3 H) 13 C NMR (75MHz ,CHLOROFORM d) = 138.5, 132.4, 131.9, 131.3, 130.9, 130.8, 130.6, 130.1, 129.5, 129.4, 129.1, 128.7, 127.8, 126.6, 126.1, 125.3, 124.8, 123.7, 123.0, 121.9, 120.6, 54.3, 42.3, 33.0, 25.5, 23.3, 22 .4

PAGE 217

217 HRMS Calcd. for C 35 H 31 N 2 [M ] + : 479.2482 Found: 479.2488 28 D +19.2 ( c 0.7, CHCl 3 ) ( S ) 2 (2,6 diisopropylphenyl) 5 isobutyl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride ( 4 20 ) 60.0 mg (0.120 mmol, 75.5%) of ( S ) 2 (2,6 diisoprop ylphenyl) 5 isobutyl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride was obtained from 72.0 mg (0.159 mmol) of ( ( S ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 2,6 diisopropylaniline and 83.5 L (0.954 mmol) of chlorometh yl ethyl ether 1 H NMR (300 MHz, CHLOROFORM d ) = 10.63 (s, 1 H), 7.16 7.50 (m, 6 H), 6.79 7.16 (m, 6 H), 5.74 6.00 (m, 1 H), 3.70 (dd, J =16.1, 4.7 Hz, 1 H), 3.01 (d, J =16.4 Hz, 1 H), 2.53 (br. s., 1 H), 2.42 (dt, J =13.7, 6.8 Hz, 1 H), 2.27 (dt, J =13.3, 6.5 Hz, 1 H), 1.41 1.61 (m, 2 H), 0.41 1.36 (m, 18 H) 13 C NMR (75MHz ,CHLOROFORM d) = 145.9, 145.4, 137.2, 131.9, 131.5, 130.6, 130.3, 129.9, 129.7, 129.1, 128.1, 127.3, 125.6, 125.0, 124.7, 124.5, 124.0, 122.3, 53.1, 41.8, 32.9, 31.4, 29.1, 28.8, 26.0, 25.5, 24.8, 22.5, 22.3, 22.1 HRMS Calc d. for C 33 H 39 ClN 2 [M ] + : 463.3108 Found: 463.3108 29 D 38.1 ( c 0.90, CHCl 3 )

PAGE 218

218 ( S ) 5 isobutyl 2 mesityl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride ( 4 14 ) To a flame dried Schlenk flask was added 225 mg (0.551 mmol) of ( S ) N ((3 i sobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 2,4,6 trimethylaniline 256 L (2.75 mmol) of chloromethyl ethyl ether and 28 mL (0.02M) of THF. After 48 h, all volatiles were removed in vacuo. Silicagel column chromatography with a 95:5 mixture of DCM and methanol as the eluent gave 220 mg (0.481 mmol, 87.3%) of ( S ) 5 isobutyl 2 mesityl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride 1 H NMR (299 MHz, CHLOROFORM d ) = 10.35 (s, 1 H), 7.30 7.48 (m, 5 H), 7.04 7.24 (m, 4 H), 6.93 (s, 1 H), 6.76 (s, 1 H), 5.63 (br. s., 1 H), 3.64 (dd, J =16.0, 4.1 Hz, 1 H), 3.07 (d, J =15.9 Hz, 1 H), 2.18 (s, 3 H), 2.23 (s, 3 H), 1.90 (s, 3 H), 1.47 1.72 (m, 3 H), 0.99 (dd, J =9.1, 6.2 Hz, 3 H) 13 C NMR (75MHz ,CHLOROFORM d) = 140.8, 136.8, 135.1, 134.4, 131.7, 130.6, 130.2, 129.8, 129.7, 129.3, 129.2, 128.9, 127.4, 125.8, 125.3, 124.4, 122.6, 53.5, 41.8, 32.7, 25.0, 22.8, 22.0, 21.0, 17.9 HRMS Calcd. for C 30 H 33 N 2 [M ] + : 421.2638 Fo und: 421.2646 29 D 23 ( c 1.06, CHCl 3 ) ( S ) 2 (3,5 dimethylphenyl) 5 isobutyl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride (4 21)

PAGE 219

219 37.0 mg (0.0835 mmol, 84.5%) of ( ( S ) 2 (3,5 dimethylphenyl) 5 isobutyl 1 phenyl 5,6 dihydro 2H imida zo[5,1 a ]isoquinolin 4 ium chloride was obtained from 39.0 mg (0.0988 mmol) of ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 3,5 dimethylaniline and 91.6 L (0.988 mmol) of chloromethyl ethyl ether 1 H NMR (299MHz ,CHLOROFORM d) = 10.59 (s, 1 H), 7.51 7.34 (m, 3 H), 7.31 7.21 (m, 4 H), 7.11 6.93 (m, 3 H), 6.85 (s, 2 H), 5.69 5.58 (m, 1 H), 3.53 (dd, J = 4.8, 16.1 Hz, 1 H), 3.02 (d, J = 15.6 Hz, 1 H), 2.18 (s, 6 H), 1.80 1.61 (m, 2 H), 1.56 1.44 (m, 1 H), 0.99 (d, J = 6.2 Hz, 6 H) 13 C NMR (75MHz ,CHLOROFORM d) = 139.9, 135.9, 133.1, 132.0, 131.0, 130.8, 130.3, 129.8, 129.5, 129.1, 127.7, 126.1, 125.7, 124.5, 123.7, 122.9, 53.7, 41.9, 32.7, 25.2, 23.2, 22.0, 21.2 HRMS Calcd. for C 29 H 31 N 2 [M ] + : 407.2482 Found: 407.2487 29 D 24.2 ( c 0.7, CHCl 3 ) ( S ) 2 (2,6 d imethylphenyl) 5 isobutyl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride (4 70)

PAGE 220

220 40.0 mg (0.0903 mmol, 47.8%) of ( S ) 2 (2,6 dimethylphenyl) 5 isobutyl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride was obtained from 80 .0 mg (0.189 mmol) of ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 2,6 dimethylaniline and 105 L (1.14 mmol) of chloromethyl ethyl ether. 1 H NMR (299MHz ,CHLOROFORM d) = 10.60 (s, 1 H), 7.48 7.30 (m, 5 H), 7.26 7.07 (m, 6 H), 7.00 (d, J = 7.4 Hz, 1 H), 5.83 5.72 (m, 1 H), 3.75 3.61 (m, 1 H), 3.10 (dd, J = 2.0, 16.1 Hz, 1 H), 2.26 (s, 3 H), 1.99 (s, 3 H), 1.80 1.49 (m, 3 H), 1.04 (dd, J = 6.2, 8.5 Hz, 6 H) 13 C NMR (75MHz ,CHLOROFORM d) = 137.2, 136.0, 135.1, 132.2, 131.8, 131.1, 131.0, 130.6, 130.0, 129.5, 129.0, 127.7, 126.2, 125.6, 124.7, 122.9, 53.9, 42.1, 33.0, 29.9, 25.4, 23.2, 22.4, 18.4 HRMS Calcd. for C 29 H 31 N 2 [M ] + : 407.2482 Found: 407.2490 29 D 38.8 ( c 0.77, CHCl 3 ) ( S ) 2 (2,6 diethylphenyl) 5 isobutyl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride (4 69)

PAGE 221

221 14.0 mg (0.0297 mmol, 85%) of ( ( S ) 2 (2,6 diethylphenyl) 5 isobutyl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 iu m chloride was obtained from 15.0 mg (0.0355 mmol) of ( S E ) 2,6 diethyl N ((3 isobutyl 3,4 dihydroisoquinolin 1 y l)(phenyl)methylene)aniline and 19.7 L (0.213 mmol) of chloromethyl ethyl ether. 1 H NMR (299MHz ,CHLOROFORM d) = 10.75 (s, 1 H), 7.47 7.29 (m, 6 H), 7.28 7.03 (m, 6 H), 5.95 (d, J = 4.5 Hz, 1 H), 3.71 (dd, J = 4.2, 16.1 Hz, 1 H), 3.10 (d, J = 16.1 Hz, 1 H), 2.63 2.33 (m, 2 H), 2.05 (dd, J = 7.4, 15.3 Hz, 1 H), 1.83 1.41 (m, 4 H), 1.42 1.17 (m, 5 H), 1.1 5 0.94 (m, 7 H) 13 C NMR (75MHz ,CHLOROFORM d) = 141.2, 140.8, 137.3, 132.1, 131.4, 130.9, 130.5, 130.3, 130.0, 129.6, 129.4, 127.6, 126.9, 126.7, 126.0, 125.4, 124.7, 122.8, 53.6, 42.0, 33.0, 25.3, 24.6, 23.9, 23.1, 22.5, 15.0, 13.8 HRMS Calcd. for C 31 H 35 N 2 [M ] + : 435.2795 Found: 435.2801 29 D 34.0 ( c 0.92, CHCl 3 ) ( S ) 5 isobutyl 2 (2 isopropylphenyl) 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride (4 30)

PAGE 222

222 25.0 mg (0.0547 mmol, 85 .0 %) of ( S ) 5 isobutyl 2 (2 isopropylphenyl) 1 phen yl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride was obtained from 30.0 mg (0.0744 mmol) of ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 2 isopropylaniline and 65.0 L (0.744 mmol) of chloromethyl ethyl ether. ( S ) 2 (2,4 di methylphenyl) 5 isobutyl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride (4 31) 22 .0 mg (0.0 497 mmol, 66.7 %) of ( S ) 2 (2,4 dimethylphenyl) 5 isobutyl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride was obtained from 30. 0 mg (0.0744 mmol) of ( S E ) N ((3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 2,4 dimethylaniline and 65.0 L (0.744 mmol) of chloromethyl ethyl ether. 1 H NMR (300MHz ,CHLOROFORM d) = 10.49 (br. s., 1 H), 7.53 7.17 (m, 8 H), 7.17 6.78 (m, 4 H), 5.66 (br. s., 1 H), 3.68 3.54 (m, 1 H), 3.06 (d, J = 15.8 Hz, 1 H), 2.27 (s, 6 H), 1.81 1.60 (m, 2 H), 1.58 1.46 (m, 1 H), 1.08 0.88 (m, 6 H)

PAGE 223

223 13 C NMR (75MHz ,CHLOROFORM d) = 141.4, 136.9, 132.4, 132.1, 130.8, 130.6, 130.5, 130.0, 129.5, 12 8.9, 128.0, 127.7, 125.9, 125.7, 124.6, 123.0, 53.9, 42.0, 32.9, 25.3, 23.3, 22.2, 21.4, 17.9 ( S ) 5 isobutyl 2 (2 methoxyphenyl) 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride (4 33) 23.0 mg (0.0517 mmol, 66.7%) of ( S ) 5 isobutyl 2 (2 methoxyphenyl) 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride was obtained from 15.8 mg (0.0544 mmol) of ( S ) (3 isobutyl 3,4 dihydroisoquinolin 1 yl)(phenyl)methanone 1 H NMR (300MHz ,CHLOROFORM d) = 10.44 (s, 1 H), 7.52 7.16 (m, 9 H), 7.16 6.98 (m, 2 H), 6.98 6.68 (m, 2 H), 5.78 5.59 (m, 1 H), 3.68 (s, 3 H), 3.59 (dd, J = 4.8, 16.3 Hz, 1 H), 3.04 (d, J = 15.0 Hz, 1 H), 1.85 1.63 (m, 2 H), 1.60 1.43 (m, 1 H), 0.99 (d, J = 6.2 Hz, 3 H), 1.03 (d, J = 6.4 Hz, 3 H) 13 C NMR (75MHz ,CHLOROFORM d) = 153.9, 137.2, 132.5, 132.0, 130.6, 130.3, 129.9, 129.2, 128.9, 127.7, 126.0, 125.6, 124.5, 123.2, 122.0, 121.3, 112.3, 56.0, 53.9, 42.0, 33.1, 25.2, 23.4, 22.3 (4a R ,8a R ) 2 mesityl 1 phenyl 4a,5,6, 7,8,8a hexahydro 2H imidazo[1,5 f ]phenanthridin 4 ium chloride (4 43)

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224 15.0 mg (0.0357 mmol, 36.5%) of (4a R ,8a R ) 2 mesityl 1 phenyl 4a,5,6,7,8,8a hexahydro 2H imidazo[1,5 f ]phenanthridin 4 ium chloride ( 4 and 15.0 mg (0.0357 mmol, 36.5%) of (4a R ,8a R ) 2 mesityl 1 phenyl 4a,5,6,7,8,8a hexahydro 2H imidazo[1,5 f ]phenanthridin 4 ium chloride ( 4 were obtained from 40.0 mg (0.0980 mmol) of ( E ) N (((4a R ,10b R ) 1,2,3,4,4a,10b hexahydrophenanthridin 6 yl)(phenyl)methylene) 2,4,6 trimethylaniline and 55.0 L (0.590 mmol) of chloromethyl ethyl ether. (4 1 H NMR (300MHz ,CHLOROFORM d) = 9.65 (s, 1 H), 7.53 7.15 (m, 7 H), 7.15 6.98 (m, 2 H), 6.88 (s, 2 H), 5.20 5.01 (m, 1 H), 3.55 3.38 (m, 1 H), 2.26 (s, 3 H), 2.19 1.89 (m, 8 H), 1.89 1.70 (m, 2 H), 1.70 1.44 (m, 4 H) 13 C NMR (75MHz ,CHLOROFORM d) = 141.4, 136.3, 135.7, 134.5, 131.0, 130.8, 130.0, 129.6, 129.1, 127.9, 127.5, 126.9, 125.6, 125.2, 122.6, 56.1, 38.9, 29.9, 28.0, 27.6, 22.1, 21.3, 18.1, 17.9 HRMS Calcd. for C 30 H 31 N 2 [M ] + : 4 19.2482 Found: 419.2517 20 D 0.7 ( c 1.08, CHCl 3 ) (4 1 H NMR (300MHz ,CHLOROFORM d) = 10.39 (s, 1 H), 7.48 7.29 (m, 5 H), 7.20 (d, J = 7.0 Hz, 2 H), 7.09 (d, J = 3.2 Hz, 2 H), 6.86 (s, 2 H), 5.27 5.06 (m, 1 H), 3.51 3.29 (m, 1 H), 2.24 (s, 3 H), 2.16 1.91 (m, 9 H), 1.89 1.68 (m, 2 H), 1.67 1.51 (m, 3 H)

PAGE 225

225 13 C NMR (75MHz ,CHLOROFORM d) = 141.2, 137.0, 136.4, 135.5, 134.6, 130.9, 130.6, 130.0, 129.7, 129.6, 129.3, 127.9, 127.5, 126.6, 125.8, 125.1, 122.7, 56.1, 38.9, 28.2, 27.6, 22.4, 2 2.2, 21.3, 18.3, 18.0 HRMS Calcd. for C 30 H 31 N 2 [M ] + : 419.2482 Found: 419.2516 20 D 5.4 ( c 1.08, CHCl 3 ) 6.4.2 Gold Complexes S ynthesis ( S ) chloro(2 (2,6 diisopropylphenyl) 5 isobutyl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium 3 yl)aurate(I) ( 4 44 ) To a flame dried Schlenk flask was added 33.0 mg (0.0661 mmol) of ( S ) 2 (2,6 diisopropylphenyl) 5 isobutyl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium chloride 9.20 mg (0.0396 mmol) of Ag 2 O and 1.3 mL (0.05M) of DCM. After stirring for 12 h, the reaction mixture was filtered through a pad of celite. The solvent of the filtrate was removed under reduced pressure. To another flame dried Schlenk flask was added the filtered silver 2 S and 1.3 mL (0.05 M) of DCM. The reaction mixture was stirred for 12 h at room temperature. The reaction solution was filtered through a pad of celite and evaporated to dryness. The residue was dissolved in ether and the solid was discarded. Then the ethereal solution was c oncentrated and additional impurities were washed away with hexane to yield 40.0 mg (0.0574 mmol, 86.8 %) of ( S ) chloro(2 (2,6

PAGE 226

226 diisopropylphenyl) 5 isobutyl 1 phenyl 5,6 dihydro 2H imidazo[5,1 a ]isoquinolin 4 ium 3 yl)aurate(I). 1 H NMR (300MHz ,DICHLOROMET HANE d 2 ) = 7.41 6.80 (m, 12 H), 5.08 (q, J = 6.2 Hz, 1 H), 3.47 (dd, J = 5.6, 15.8 Hz, 1 H), 2.99 (d, J = 16.1 Hz, 1 H), 2.71 2.50 (m, 1 H), 2.29 (dt, J = 6.6, 13.4 Hz, 1 H), 1.77 (dt, J = 6.5, 13.3 Hz, 1 H), 1.56 0.53 (m, 20 H) 13 C NMR (75MHz ,DIC HLOROMETHANE d 2 ) = 170.7, 147.1, 146.7, 133.4, 132.5, 131.0, 131.0, 130.8, 130.2, 130.1, 129.4, 129.3, 128.4, 127.6, 125.6, 125.3, 124.8, 124.7, 55.1, 43.5, 34.1, 29.3, 29.1, 26.6, 26.1, 25.2, 23.7, 23.6, 22.9, 22.6 HRMS Calcd. for C 33 H 39 ClN 2 Au [M+NH 4 ] + : 712.2727 Found: 712.2739 29 D 12.8 ( c 0.84, CHCl 3 ) X ray experimental for 4 44 Data were collected at 100 K on a Bruker DUO system equipped with an APEX II area detector and a graphite monochromator utilizing MoK radiation ( = 0.71073 ). Cell pa rameters were refined using up to 9999 reflections. A hemisphere of data was collected using the scan method (0.5 frame width). Absorption corrections by integration were applied based on measured indexed crystal faces. The structure was solved by the Direct Methods in SHELXTL6, and refined us ing full matrix least squares. The non H atoms were treated anisotropically, whereas the hydrogen atoms were calculated in ideal positions and were riding on their respective carbon atoms. The asymmetric unit consi sts of two chemically equivalent but cry stallographically independent. The data was checked for higher symmetry, in specific checked for the possibility of the space group being P2 1 /m. N o possible solution was found. Additionally, the two molecules in the asymmetric unit do not have neither a mirror symme try nor an inversion symmetry. A total of 679 parameters

PAGE 227

227 were refined in the final cycle of refinement using 11154 reflections with I > 2 (I) to yield R 1 and wR 2 of 2.32% and 4.24%, respectively. Refinement was done using F 2 SHELXTL6 (2000). Bruker AXS, Madison, Wisconsin USA. Crystal data and structure refinement for 4 44 Identification code 4 44 Empirical formula C33 H38 Au Cl N2 Formula weight 695.07 Temperature 100(2) K Wavelength 0.71073 Crysta l system Monoclinic Space group P2(1) Unit cell dimensions a = 12.074(12) = 90. b = 11.168(12) = 93.82(2). c = 22.31(2) = 90. Volume 3002(5) 3 Z 4 Density (calculated) 1.538 Mg/m 3 Absorption coefficient 5.013 mm 1 F(000) 1384 Crystal size 0.15 x 0.13 x 0.03 mm 3 Theta range for data collection 1.69 to 27.50. Index ranges

PAGE 228

228 Reflections collected 31564 Independent reflections 12574 [R(int) = 0.0246] Completeness to theta = 27.50 100.0 % Absorption correction Nnumerical Max. and min. transmission 0.8642 and 0.5221 Refinement method Full mat rix least squares on F 2 Data / restraints / parameters 12574 / 1 / 679 Goodness of fit on F 2 0.919 Final R indices [I>2sigma(I)] R1 = 0.0232, wR2 = 0.0424 [11154] R indices (all data) R1 = 0.0300, wR2 = 0.0442 Absolute structure parameter 0.006(4) Largest diff. peak and hole 1.341 and 0.688 e. 3 R1 = (||F o | |F c ||) / |F o | wR2 = [ w(F o 2 F c 2 ) 2 ] / w F o 2 2 ]] 1/2 S = [ w(F o 2 F c 2 ) 2 ] / (n p)] 1/2 w= 1/[ 2 (F o 2 )+(m*p) 2 +n*p], p = [max(F o 2 ,0)+ 2* F c 2 ]/3, m & n are constants. [6( S ),8( S ) Diisobutyl 5,6,8,9 tetrahydro 6a,7a diazadibenzo[ c g ]fluoren 5 ylide ne] chloroaurate(I) ( 4 45 )

PAGE 229

229 To a flame dried Schlenk flask was added 15.0 mg (0.0356 mmol) of [6( S ),8( S ) d iisobutyl 5,6,8,9 tetrahydro 6a,7a diazadibenzo[ c g ]fluorenium] chloride 4.80 mg (0.0207 mmol) of Ag 2 O and 700 L (0.05M) of DCM. After stirring f or 12 h, the reaction mixture was filtered through a pad of celite. The solvent of the filtrate was removed under reduced pressure. To another flame dried Schlenk flask was added the filtered silver complex, 12.0 mg (0.0407 mmol) 2 S and 1.3 mL (0 .05M) of DCM. The reaction mixture was stirred for 12 h at room temperature. The reaction solution was filtered through a pad of celite and evaporated to dryness. The residue was purified by silicagel column chromatography with a 70:30 mixture of hexane an d ethyl acetate as the eluent gave 17.0 mg (0.0275 mmol, 77.2%) of [6( S ),8( S ) ] d iisobutyl 5,6,8,9 tetrahydro 6a,7a diazadibenzo[ c g ]fluoren 5 ylidene] chloroaurate(I) 1 H NMR (300MHz ,CHLOROFORM d) = 7.87 (d, J = 7.0 Hz, 2 H), 7.39 7.12 (m, 6 H), 5.02 4.78 (m, 2 H), 3.29 (dd, J = 5.4, 15.4 Hz, 2 H), 2.94 (d, J = 15.2 Hz, 2 H), 1.83 1.60 (m, 1 H), 1.49 1.36 (m, 2 H), 1.31 1.23 (m, 2 H), 0.95 (dd, J = 6.7, 9.7 Hz, 12 H) 13 C NMR (75MHz ,CHLO ROFORM d) = 166.3, 132.3, 129.6, 129.2, 127.2, 125.5, 124.0, 123.7, 54.5, 41.9, 33.3, 24.9, 23.5, 21.9 HRMS Calcd. for C 27 H 33 ClN 2 Au [M ] + : 616.1920 Found: 616.1959 29 D 266.5 ( c 0.32, CHCl 3 ) X ray experimental for 4 45 Data were collected at 100 K o n a Bruker DUO system equipped with an APEX II area detector and a graphite monochromator utilizing MoK radiation ( = 0.71073 ). Cell parameters were refined using up to 9999 reflections. A hemisphere of data was collected using the scan method (0.5 frame width). Absorption corrections by integration were applied based on measured indexed crystal faces.

PAGE 230

230 The structure was solved by the Direct Methods in SHELXTL6, and refined using full matrix least squares. The non H atoms were treated anisotropically whereas the hydrogen atoms were calculated in ideal positions and were riding on their respective carbon atoms The asymmetric unit consists of the complex and a disordered dichloromethane solvent molecule. The latter molecules was disordered and could n ot be modeled properly, thus program SQUEEZE, a part of the PLATON package of crystallographic software, was used to calculate the solvent disorder area and remove its contribution to the overall intensity data. Judging by the total count of electrons calc ulated by program SQUEEZE, it looks like the solvent exists in about 80% occupancy and disordered by the 2 1 screw axis of symmetry along the a axis. A total of 281 parameters were refined in the final cycle of refinement using 6106 reflections with I > 2 (I) to yield R 1 and wR 2 of 2.01% and 5.62 %, respectively. Refinement was done using F 2 P. van der Sluis & A.L. Spek (1990). SQUEEZE, Acta Cryst. A46, 194 201 SHELXTL6 (2000). Bruker AXS, Madison, Wisconsin, USA. Spek, A.L. (1990). PLATON, Acta Cryst. A46 C 34 Crystal data and structure refinement for 4 45 Identification code 4 45 Empirical formula C27 H32 Au Cl N2 Formula weight 616.96 Temperature 100(2) K Wavelength 0.71073 Crystal system Orthorhombic Space group P2(1)2(1)2(1) Unit cell dimensi ons

PAGE 231

231 a = 9.4129(6) = 90. b = 16.7290(11) = 90. c = 17.6201(12) = 90. Volume 2774.6(3) 3 Z 4 Density (calculated) 1.477 Mg/m 3 Absorption coefficient 5.413 mm 1 F(000) 1216 Crystal size 0.28 x 0.17 x 0.13 mm 3 Theta range for data collection 1.68 to 27.50. Index ranges Reflections collected 43949 Independent reflections 6356 [R(int) = 0.0281] Completeness to theta = 27.50 100.0 % Absorption correction Nnumerical Max. and min. transmission 0.5441 and 0.3165 Refinement method Full matr ix least squares on F 2 Data / restraints / parameters 6356 / 0 / 281 Goodness of fit on F 2 0.849 Final R indices [I>2sigma(I)] R1 = 0.0201, wR2 = 0.0562 [6106] R indices (all data) R1 = 0.0216, wR2 = 0.0569 Absolute structure parameter 0.009(6) Largest dif f. peak and hole 1.156 and 1.026 e. 3

PAGE 232

232 R1 = (||F o | |F c ||) / |F o | wR2 = [ w(F o 2 F c 2 ) 2 ] / w F o 2 2 ]] 1/2 S = [ w(F o 2 F c 2 ) 2 ] / (n p)] 1/2 w= 1/[ 2 (F o 2 )+(m*p) 2 +n*p], p = [max(F o 2 ,0)+ 2* F c 2 ]/3, m & n are constants. 6.4.3 S ynthesis of T he S ubstrates for The C opper C atalyze d B orylation 2 chloro N N bis(4 methoxybenzyl)acetamide To a flame dried Schlenk flask was added 618 L (7.77 mmol) of 2 chloroacetyl chloride and 16 mL (0.5 M) of THF. The reaction mixture was cooled to 0 C and 2.00 g (7.77 mmol) of bis(4 methoxybenzyl)amine was added dropwise followed by 1.08 mL (7.77 mmol) of Et 3 N. The reaction mixture was stirred at room temperature for 12 h. It was diluted with 20 mL of Et 2 O and washed with 1N HCl (2 x 15 mL) followed by a saturated NaHCO 3 aqueous solution (2 x 15 mL). It was dried over anh ydrous MgSO 4 All volatiles were removed in vacuo to yield 2.55 g (7.62 mmol, 98.1%) of 2 chloro N N bis(4 methoxybenzyl)acetamide 1 H NMR (300MHz ,CHLOROFORM d) = 7.22 6.97 (m, 4 H), 6.84 (d, J = 8.5 Hz, 2 H), 6.88 (d, J = 8.5 Hz, 2 H), 4.50 (s, 2 H), 4.40 (s, 2 H), 4.12 (s, 2 H), 3.78 (s, 3 H), 3.80 (s, 3 H)

PAGE 233

233 13 C NMR (75MHz CHLOROFORM d) = 167.2, 159.6, 129.9, 128.8, 128.1, 127.8, 114.7, 114.3, 55.6, 55.5, 49.8, 48.0, 41.7 HRMS Calcd. for C 18 H 20 ClNO 3 [M+H ] + : 334.1204 Found: 334.1208 Diethyl 2 (bis( 4 methoxybenzyl)amino) 2 oxoethylphosphonate To a flame dried Schlenk flask was added 970 mg (2.90 mmol) of 2 chloro N N bis(4 methoxybenzyl)acetamide and 1.26 mL (7.25 mmol) of triethyl phosphite. The reaction mixture was stirred at 100 C for 60 h. Af ter cooling at room temperature, it was washed with hexane (3 x 5 mL) and concentrated in vacuo to yield 1.13 g (2.59 mmol, 89.3%) of d iethyl 2 (bis(4 methoxybenzyl)amino) 2 oxoethylphosphonate 1 H NMR (300MHz ,CHLOROFORM d) = 7.19 7.11 (m, 2 H), 7.06 (d, J = 8.8 Hz, 2 H), 6.93 6.73 (m, 4 H), 4.52 (d, J = 5.6 Hz, 4 H), 4.24 4.06 (m, 4 H), 3.77 (s, 3 H), 3.79 (s, 3 H), 3.13 (s, 1 H), 3.06 (s, 1 H), 1.39 1.22 (m, 6 H) 13 C NMR (75MHz ,CHLOROFORM d) = 165.7, 159.4, 159 .2, 129.6, 129.2, 128.4, 128.3, 127.9, 114.6, 114.2, 62.9, 62.8, 55.6, 50.4, 48.0, 34.8, 33.1, 16.6, 16.5 HRMS Calcd. for C 22 H 30 NO 6 P [2M+H ] + : 871.3616 Found: 871.3720 ( Z ) N N bis(4 methoxybenzyl) 3 phenylacrylamide ( Z 4 59 )

PAGE 234

234 To a flame dried Schlenk fla sk was added 150 mg (1.012 mmol) of ( Z ) cinnamic acid, 137 mg (1.012 mmol) of HOBt and 7 mL (0.14 M) of DCM. The reaction mixture was stirred 30 minutes at room temperature. 12.0 mg (0.100 mmol) of DMAP and 260 mg (1.012 mmol) of bis(4 methoxybenzyl)amine were then added. The reaction mixture was cooled to 0 C and a solution of 209 mg (1.012 mmol) of DCC in 5 mL (0.2 M) of DCM was added dropwise. The reaction was stirred 1 h at 0 C and 12 h at room temperature. The reaction mixture was concentrated and 15 mL of ethyl acetate was added and the white solid was filtered off. The ethyl acetate solution was concentrated. Silicagel column chromatography with a 75:25 mixture of hexane and ethyl acetate as the eluent gave 245 mg (0.633 mmol, 62.5%) of ( Z ) N N bis( 4 methoxybenzyl) 3 phenylacrylamide 1 H NMR (300MHz ,CHLOROFORM d) = 7.42 (d, J = 7.3 Hz, 2 H), 7.35 7.13 (m, 5 H), 7.01 (d, J = 8.2 Hz, 2 H), 6.96 6.80 (m, 4 H), 6.70 (d, J = 12.6 Hz, 1 H), 6.23 (d, J = 12.6 Hz, 1 H), 4.55 (s, 2 H), 4.35 (s, 2 H), 3 .83 (s, 3 H), 3.86 (s, 3 H) 13 C NMR (75MHz ,CHLOROFORM d) = 169.2, 159.4, 159.3, 135.6, 133.9, 130.6, 128.9, 128.8, 128.8, 128.7, 128.7, 128.4, 123.6, 114.4, 114.1, 55.5, 50.0, 45.9 HRMS Calcd. for C 25 H 25 NO 3 [M+H ] + : 388.1907 Found: 388.1905 N methoxy N methylcinnamamide ( 4 57 )

PAGE 235

235 940 mg (4.92 mmol, 95.9%) of N methoxy N methylcinnamamide was obtained from 1.25 g (10.3 mmol) of DMAP, 1.37 g (6.66 mmol) of DCC, 500 mg (5.13 mmol) of N O dimethylhydroxylammonium chloride and 986 mg (6.66 mmol) of trans cinn amic acid. 1 H NMR (300MHz ,CHLOROFORM d) = 7.74 (d, J = 15.8 Hz, 1 H), 7.62 7.52 (m, 2 H), 7.45 7.29 (m, 3 H), 7.04 (d, J = 15.8 Hz, 1 H), 3.76 (s, 3 H), 3.30 (s, 3 H) 13 C NMR (75MHz ,CHLOROFORM d) = 167.2, 143.6, 135.4, 130.0, 129.0, 128.2, 116.0, 62.1, 32.7 HRMS Calcd. for C 11 H 13 NO 2 [M+ H ] + : 192.1019 Found: 192.1024 N N dicyclohexylcinnamamide ( 4 56 ) 400 mg (1.28 mmol, 37.9%) of N N dicyclohexylcinnamamide was obtained from 42 mg (0.344 mmol) of DMAP, 765 mg (3.71 mmol) of DCC, 455 mg (3.37 mmol) of HOBt, 670 L (3.37 mmol) of dicyclo hexylamine and 500 mg (3.37 mmol) of trans cinnamic acid. 1 H NMR (300MHz ,CHLOROFORM d) = 7.80 7.43 (m, 3 H), 7.43 7.15 (m, 3 H), 6.84 (d, J = 15.2 Hz, 1 H), 3.56 (br. s., 2 H), 2.26 (br. s., 2 H), 1.80 (br. s., 6 H), 1.64 (br. s., 6 H), 1.48 1.21 (m, 4 H), 1.18 (br. s., 2 H)

PAGE 236

236 13 C NMR (75MHz ,CHLOROFORM d) = 166.5, 140.9, 136.0, 129. 4, 128.9, 127.8, 121.3, 57.6, 56.1, 32.3, 30.6, 26.6, 25.7 HRMS Calcd. for C 21 H 29 NO [M+H ] + : 312.2322 Found: 312.2320 N N bis(4 methoxybenzyl)cinnamamide ( 4 59 ) To a flame dried Schlenk flask was added 60.2 mg (2.51 mmol) of sodium hydride and 2 mL (1.3 M) of DMF. A solution of 100 mg (0.679 mmol) of trans cinnamide in 2 mL (0.33 M) of DMF was then added dropwise at room temperature. The reaction mixture was heated to 70 C for 1 h. Then 276 L (2.04 mmol) of 1 (chloromethyl) 4 methoxybenzene was added d ropwise to the reaction mixture. It was stirred at 70 C for 2 h. It was cooled to room temperature and quenched by 10 mL of water. The reaction mixture was extracted with Et 2 O (2 x 15 mL), washed with water (2 x 15 mL) and dried over anhydrous MgSO 4 All v olatiles were removed in vacuo. Silicagel column chromatography with a 80:20 mixture of hexane and ethyl acetate as the eluent gave 260 mg (0.671 mmol, 98.8%) of N N bis(4 methoxybenzyl)cinnamamide 1 H NMR (300MHz ,CHLOROFORM d) = 7.84 (d, J = 15.2 Hz, 1 H), 7.55 7.40 (m, 2 H), 7.40 7.07 (m, 7 H), 7.02 6.76 (m, 5 H), 4.62 (s, 2 H), 4.52 (s, 2 H), 3.80 (s, 6 H) 13 C NMR (75MHz ,CHLOROFORM d) = 167.2, 159.4, 159.2, 143.8, 135.5, 130.0, 129.9, 129.8, 129.0, 128.9, 128.1, 117 .7, 114.6, 114.2, 55.5, 49.5, 48.2 HRMS Calcd. for C 25 H 25 NO 3 [M+H ] + : 388.1907 Found: 388.1926 N N dibenzylcinnamamide ( 4 58 )

PAGE 237

237 197 mg (0.602 mmol, 88.7%) of N N dibenzylcinnamamide was obtained from 60.2 mg (2.51 mmol) of sodium hydride, 100 mg (0.679 mm ol) of trans cinnamide and 242 L (2.04 mmol) of benzyl bromide. 1 H NMR (300MHz ,CHLOROFORM d) = 7.87 (d, J = 15.2 Hz, 1 H), 7.56 7.17 (m, 15 H), 6.92 (d, J = 15.2 Hz, 1 H), 4.73 (s, 2 H), 4.62 (s, 2 H) 13 C NMR (75MHz ,CHLOROFORM d) = 167.4, 144.1, 137.6, 137.0, 135.4, 129.9, 129.2, 129.0, 128.9, 128.6, 128.1, 128.0, 127.7, 126.8, 117.5, 50.3, 49.1 HRMS Calcd. for C 23 H 21 NO [M+H ] + : 328.1696 Found: 328.1704 N N dimethylcinnamamide ( 4 55 ) 90.0 mg (0.514 mmol, 75.7%) of N N dimethylcinnamamide was obtained from 60.2 mg (2.51 mmol) of sodium hydride, 100 mg (0.679 mmol) of trans cinnamide and 12 7 L (2.04 mmol) of methyl iodide. 1 H NMR (300MHz ,CHLOROFORM d) = 7.67 (d, J = 15.2 Hz, 1 H), 7.59 7.46 (m, 2 H), 7.46 7.22 (m, 3 H), 6.89 (d, J = 15.5 Hz, 1 H), 3.17 (s, 3 H), 3.06 (s, 3 H) 13 C NMR (75MHz ,CHLOROFORM d) = 166.9, 142.5, 135.6, 129.7, 129.0, 128.0, 117.7, 37.6, 36.1 HRMS Calcd. for C 11 H 13 NO [M+H ] + : 176.1070 Found: 176.1068

PAGE 238

238 General procedure for the Horner Wadsworth Emmons olefination for aryl substrates To a flame dried Schlenk flask was added 1.10 mmol of sodium hydride and 1.6 mL (0.7 M) of THF. The reaction was cooled to 0 C and a solution of 0.919 mmol of d iethyl 2 (bis(4 methoxybenzyl)amino) 2 oxoethylphosphonate in 1.6 mL (0.7 M) of THF was added dropwise. The reaction mixture was stirred at room temperature for 1 h. 1.10 mmol of aryl aldehyde was then added and the mixture was stirred fo r 12 h at room temperature. It was quenched by 4 mL of water. The reaction mixture was extracted with Et 2 O (2 x 10 mL), washed several times with water (2 x 5 mL) and dried over anhydrous MgSO 4 All volatiles were removed in vacuo. Silicagel column chromat ography with a mixture of hexane and ethyl acetate as the eluent gave the desired ( E ) unsaturated amide. ( E ) N N bis(4 methoxybenzyl) 3 (4 methoxyphenyl)acrylamide ( 4 74 ) 1 H NMR (300MHz ,CHLOROFORM d) = 7.79 (d, J = 15.2 Hz, 1 H), 7.40 (d, J = 7.9 Hz, 2 H), 7.30 7.00 (m, 4 H), 7.00 6.70 (m, 7 H), 4.60 (s, 2 H), 4.50 (s, 2 H) 3.92 3.64 (m, 9 H) 13 C NMR (75MHz ,CHLOROFORM d) = 167.5, 161.1, 159.3, 159.2, 143.5, 130.0, 129.6, 129.0, 128.1, 115.2, 114.5, 114.4, 114.2, 55.5, 49.4, 48.1 HRMS Calcd. for C 26 H 27 NO 4 [M+H ] + : 418.2013 Found: 418.2009 ( E ) N N bis(4 methoxybenzyl) 3 (2 methoxyphenyl)acrylamide ( 4 75 )

PAGE 239

239 1 H NMR (299MHz ,CHLOROFORM d) = 8.08 (d, J = 15.3 Hz, 1 H), 7.40 (d, J = 7.6 Hz, 1 H), 7.30 7.01 (m, 6 H), 6.95 6.80 (m, 6 H), 4.61 (s, 2 H), 4.50 (s, 2 H), 3.85 3.74 (m, 9 H) 13 C NMR (75MHz ,CHLOROFORM d) = 167.6, 159.0, 158.9, 158.2, 139.1, 130.7, 129.8, 129.2, 128.9, 127.9, 124.3, 120.6, 118.5, 114.2, 113.9, 111.1, 55.4, 55.3, 49.2, 47.9 HRMS Calcd. for C 26 H 27 NO 4 [M+H ] + : 418.2013 Found: 418.2008 ( E ) 3 (4 fluorophenyl) N N bis(4 methoxybenzyl)acrylamide ( 4 77 ) 1 H NMR (300MHz ,CHLOROFORM d) = 7.78 (d, J = 15.5 Hz, 1 H), 7.43 (dd, J = 5.6, 8.5 Hz, 2 H), 7.31 7.06 (m, 4 H), 7.00 (t, J = 8.5 Hz, 2 H), 6.93 6.68 (m, 5 H), 4.60 (s, 2 H), 4.50 (s, 2 H), 3.78 (s, 3 H), 3.78 3.75 (m, 3 H) 13 C NMR (75MHz ,CHLOROFORM d) = 167.0, 165.4, 162.0, 159.4, 159.2, 142.5, 131.7, 130.0, 129.9, 129.8, 129.7, 128.8, 128.0, 117.5, 116.2, 115.9, 114.6, 114.2, 55.5, 49.5, 48.2 HRMS Calcd. for C 25 H 24 FNO 3 [M+H ] + : 406.1813 Found: 406.1818 ( E ) N N bis(4 methoxybenzyl) 3 m tolylacrylamide ( 4 78 )

PAGE 240

240 1 H NMR (300MH z ,CHLOROFORM d) = 7.85 (d, J = 15.2 Hz, 1 H), 7.40 7.05 (m, 8 H), 7.05 6.77 (m, 5 H), 4.64 (s, 2 H), 4.55 (s, 2 H), 3.79 (s, 6 H), 2.34 (s, 3 H) 13 C NMR (75MHz ,CHLOROFORM d) = 167.3, 159.4, 159.3, 144.0, 138.6, 135.5, 130.8, 130.1, 129.8, 128.9, 128.8, 128.2, 125 .3, 117.5, 114.6, 114.2, 55.5, 49.5, 48.1, 21.6 HRMS Calcd. for C 26 H 27 NO 3 [M+H ] + : 402.2064 Found: 402.2045 ( E ) 3 cyclohexyl N N bis(4 methoxybenzyl)acrylamide ( 4 79 ) To a flame dried Schlenk flask was added 200 mg (0.459 mmol) of d iethyl 2 (bis(4 metho xybenzyl)amino) 2 oxoethylphosphonate (0.834 mmol), 51.0 L (0.417 mmol) of cyclohexanecarbaldehyde and 3 mL (0.15 M) of acetonitrile. It was stirred at room temperature for 12 h. The reaction mixture was extra cted with ethyl acetate (2 x 10 mL), washed with water (2 x 10 mL) and dried over anhydrous MgSO 4 All volatiles were removed in vacuo. Silicagel column chromatography with a 70:30 mixture of

PAGE 241

241 hexane and ethyl acetate as the eluent gave 140 mg (0.356 mmol, 85.4%) of ( E ) 3 cyclohexyl N N bis(4 methoxybenzyl)acrylamide 1 H NMR (300MHz ,CHLOROFORM d) = 7.12 (t, J = 7.6 Hz, 4 H), 6.97 (dd, J = 7.0, 15.0 Hz, 1 H), 6.84 (dd, J = 8.4, 12.2 Hz, 4 H), 6.22 (d, J = 15.0 Hz, 1 H), 4.52 (s, 2 H), 4.40 (br. s., 2 H), 3.77 (s, 3 H), 3.76 (s, 3 H), 2.18 2.03 (m, 1 H), 1.81 1.58 (m, 5 H), 1.30 1.05 (m, 5 H) 13 C NMR (75MHz ,CHLOROFORM d) = 167.7, 159.3, 159.1, 152.9, 130.0, 128.9, 128.1, 118.0, 114.4, 114.1, 55.4, 49.3, 47.8, 41.0, 32.2, 26.1, 25.9 HRMS Calcd. for C 25 H 31 NO 3 [M+H ] + : 394.2377 Found: 394.2393 ( E ) N N bis(4 methoxybenzyl)but 2 enamide ( 4 80 ) 1 H NMR (300MHz ,CHLOROFORM d) = 7.16 (d, J = 7.6 Hz, 2 H), 7.12 6.93 (m, 3 H), 6.82 (d, J = 8.2 Hz, 2 H), 6.87 (d, J = 8.5 Hz, 2 H), 6.30 (d, J = 15.0 Hz, 1 H), 4.53 (br. s., 2 H), 4.40 (br. s., 2 H), 3.77 (s, 3 H), 3.78 (s, 3 H), 1.85 (d, J = 6.7 Hz 3 H) 13 C NMR (75MHz ,CHLOROFORM d) = 167.3, 159.3, 159.2, 142.9, 129.9, 128.9, 128.0, 122.0, 114.5, 114.1, 55.5, 49.2, 47.7, 18.5 HRMS Calcd. for C20H23NO3 [M+H ] + : 326.1751 Found: 326.1735

PAGE 242

242 6.4.4 Products from T he C opper C atalyze d B orylation General procedur e for copper catalyze unsaturated substrates: To a flame dried Schlenk flask was added copper (I) bromide dimethylsulfide complex (3 mol%), NHC ligand (3.5 mol%), potassium tert butoxide (9 mol%) and THF (0.16 M). The reaction mixture was stirred for 30 minutes at room temperature. Then bis(pinacolato)diboron (0.178 mmol) was added followed by substrate (0.162 mmol) and methanol (0.324 mmol) when used. Then the reaction mixture was stirred at room temperature for 12 h or at 40 C for 6 h. NaBO 3 2 O) 4 (0.810 mmol) and water (0.16 M) were added and the reaction mixture was stirred an additional 3 h at room temperature. The suspension was then extracted with Et 2 O (3 x 10 mL), dried with MgSO 4 and concentrated in vacuo. Silicagel column chr omatography with a The racemic compound was obtained by using IMes as racemic NHC ligand. 3 hydroxy 3 phenylpropanenitrile ( 4 48 ) 1 H NMR (300MHz ,CHLOROFORM d) = 7.53 7.24 (m, 5 H), 4.98 (t, J = 6.3 Hz, 1 H), 3.10 (br. s., 1 H), 2.71 (d, J = 6.2 Hz, 2 H) 13 C NMR (75MHz ,CHLOROFORM d) = 141.3, 129.1, 129.0, 125.8, 117.7, 70.1, 28.1 HRMS Calcd. for C 9 H 9 NO [M+H ] + : 148.0757 Found: 148.0753 Ee was measured by chiral HPLC with a OJ H column (UV 215 nm, 10% isopropanol/hexane, 1.0 ml/min). t 1 : 25.6, t 2 : 30.4 Ethyl 3 hydroxy 3 phenylpropanoate ( 4 51 product )

PAGE 243

243 1 H NMR (299MHz ,CHLOROFORM d) = 7.49 7.17 (m, 5 H), 5.13 (dd, J = 4.2, 8.2 Hz, 1 H), 4.18 (q, J = 7.1 Hz, 2 H), 3.3 4 (br. s., 1 H), 2.83 2.62 (m, 2 H), 1.26 (t, J = 7.1 Hz, 3 H) 13 C NMR (75MHz ,CHLOROFORM d) = 172.6, 142.7, 128.7, 128.0, 125.9, 70.5, 61.1, 43.6, 14.4 HRMS Calcd. for C 11 H 14 O 3 [M+Na ] + : 217.0835 Found: 217.0830 Ee was measured by chiral HPLC with a W helk 01 column (UV 215 nm, 10% isopropanol/hexane, 1.0 ml/min). t 1 : 7.69, t 2 : 8.92 3 hydroxy N N dimethyl 3 phenylpropanamide ( 4 60 ) 1 H NMR (299MHz ,CHLOROFORM d) = 7.47 7.17 (m, 5 H), 5.13 (dd, J = 3.1, 9.1 Hz, 1 H), 4.79 (br. s., 1 H), 2.93 (s, 3 H), 2.97 (s, 3 H), 2.73 2.58 (m, 2 H) 13 C NMR (75MHz ,CHLOROFORM d) = 172.5, 143.2, 128.7, 127.7, 125.9, 70.6, 42.1, 37.3, 35.4 HRMS Calcd. for C 11 H 15 NO 2 [M+H ] + : 194.1176 Found: 194.1172 Ee was measured by chiral HPLC with a Whelk 01 column (UV 215 n m, 30% isopropanol/hexane, 1.5 ml/min). t 1 : 7.58, t 2 : 10.4 3 hydroxy N methoxy N methyl 3 phenylpropanamide ( 4 62 )

PAGE 244

244 1 H NMR (300MHz ,CHLOROFORM d) = 7.55 7.18 (m, 5 H), 5.15 (d, J = 9.1 Hz, 1 H), 4.29 4.22 (m, 1 H), 3.62 (s, 3 H), 3.20 (s, 3 H), 2.9 2 2.75 (m, 2 H) 13 C NMR (75MHz ,CHLOROFORM d) = 173.5, 143.3, 128.7, 127.8, 126.0, 70.4, 61.5, 40.7, 32.1 HRMS Calcd. for C 11 H 15 NO 3 [M+Na ] + : 232.0944 Found: 232.0948 Ee was measured by chiral HPLC with a IB column (UV 215 nm, 5% isopropanol/hexane, 1. 4 ml/min). t 1 : 12.2, t 2 : 14.5 N N dicyclohexyl 3 hydroxy 3 phenylpropanamide ( 4 61 ) 1 H NMR (300MHz ,CHLOROFORM d) = 7.54 7.23 (m, 5 H), 5.12 (d, J = 9.1 Hz, 1 H), 4.99 (br. s., 1 H), 3.34 (t, J = 11.6 Hz, 1 H), 3.13 2.81 (m, 1 H), 2.78 2.49 (m, 2 H), 2.45 (br. s., 2 H), 1.92 1.69 (m, 4 H), 1.61 (br. s., 4 H), 1.49 (t, J = 12.5 Hz, 4 H), 1.33 0.98 (m, 6 H) 13 C NMR (75MHz ,CHLOROFORM d) = 171.6, 143.5, 128.6, 127.6, 126.1, 70.8, 57.8, 56.4, 43.7, 31.2, 30.5, 30.1, 26.8, 26.0, 25.6, 25.4 HRMS Calcd. for C 21 H 31 NO 2 [M+H ] + : 330.2428 Found: 330.2423

PAGE 245

245 Ee was measured by chiral HPLC with a Whelk 01 column (UV 215 nm, 10% isopropanol/hexane, 1.0 ml/min). t 1 : 11.8, t 2 : 22.4 N N dibenzyl 3 hydroxy 3 phenylpropanamide ( 4 63 ) 1 H NMR (299MHz ,CHLOROFORM d) = 7.49 7.17 (m, 13 H), 7.17 7.05 (m, 2 H), 5.29 5.20 (m, 1 H), 4.84 (d, J = 2.8 Hz, 1 H), 4.75 (d, J = 14.7 Hz, 1 H), 4.54 (d, J = 15.0 Hz, 1 H), 4.48 4.33 (m, 2 H), 2.88 2.77 (m, 2 H) 13 C NMR (75MHz ,CHLOROFORM d) = 173.2, 143.1, 137.0, 136.0, 129.3, 129.0, 128.7, 128.5, 128.1, 127.8, 127.8, 126.6, 126.0, 70.9, 50.1, 48.4, 41.9 HRMS Calcd. for C 23 H 23 NO 2 [M+H ] + : 346.1802 Found: 346.1802 Ee was measured by chiral HPLC with a Whelk 01 column (UV 215 nm, 30% isopropanol/hexane, 1.5 ml/min). t 1 : 12.2, t 2 : 19.0 3 hydroxy N N bis(4 methoxybenzyl) 3 phenylpropanamide ( 4 64 ) 1 H NMR (300MHz ,CHLOROFORM d) = 7.45 7.23 (m, 5 H), 7.14 (d, J = 8.5 Hz, 2 H), 7.01 (d, J = 8.8 Hz, 2 H), 6.95 6.79 (m, 4 H), 5.22 (br. s., 1 H), 4.87 (d, J = 2.9 Hz, 1 H),

PAGE 246

246 4.61 (d, J = 14.7 Hz, 1 H), 4.45 (d, J = 14.4 Hz, 1 H), 4.30 (d, J = 4.1 Hz, 2 H), 3.81 (s, 3 H), 3.81 3.79 (m, 3 H), 2.87 2.75 (m, 2 H) 13 C NMR (75MHz ,CHLOROFORM d) = 172.6, 159.1, 159.0, 142.9, 129.6, 128.8, 128.4, 127.6, 127.4, 125.7, 114. 3, 114.0, 70.6, 55.3, 49.0, 47.2, 41.6 HRMS Calcd. for C 25 H 27 NO 4 [M+H ] + : 406.2013 Found: 406.2011 Ee was measured by chiral HPLC with a Whelk 01 column (UV 215 nm, 30% isopropanol/hexane, 1.5 ml/min). t 1 : 19.9, t 2 : 31.2 3 hydroxy N N bis(4 methoxybenzyl) 3 (4 methoxyphenyl)propanamide ( 4 81 ) 1 H NMR (299MHz ,CHLOROFORM d) = 7.36 7.29 (m, 2 H), 7.17 (d, J = 8.5 Hz, 2 H), 7.05 (d, J = 8.8 Hz, 2 H), 6.99 6.83 (m, 6 H), 5.20 (t, J = 5.5 Hz, 1 H), 4.84 (br. s., 1 H), 4.65 (d, J = 14.4 Hz, 1 H), 4.48 (d, J = 14.7 Hz, 1 H), 4.34 (d, J = 4.2 Hz, 2 H), 3.97 3.76 (m, 9 H), 2.81 (d, J = 6.2 Hz, 2 H) 13 C NMR (75MHz ,CHLOROFORM d) = 172.9, 159.3, 159.2, 159.2, 135.3, 129.9, 129.1, 127.8, 127.2, 114.6, 114.2, 114.0, 70.5, 55.5, 49.2, 47.4, 41.9 HRMS Calcd. fo r C 26 H 29 NO 5 [M+H ] + : 436.2118 Found: 436.2105 Ee was measured by chiral HPLC with a Whelk 01 column (UV 215 nm, 40% isopropanol/hexane, 1.5 ml/min). t 1 : 26.6, t 2 : 47.2 3 hydroxy N N bis(4 methoxybenzyl) 3 (2 methoxyphenyl)propanamide ( 4 82 )

PAGE 247

247 1 H NMR (299 MHz ,CHLOROFORM d) = 7.59 (d, J = 7.6 Hz, 1 H), 7.36 6.68 (m, 11 H), 5.47 (d, J = 8.5 Hz, 1 H), 5.03 (d, J = 3.4 Hz, 1 H), 4.66 (d, J = 14.4 Hz, 1 H), 4.47 4.15 (m, 3 H), 3.81 (s, 3 H), 3.80 (s, 3 H), 3.71 (s, 3 H), 2.99 (dd, J = 2.4, 16.0 Hz, 1 H), 2.69 (dd, J = 8.8, 15.9 Hz, 1 H) 13 C NMR (75MHz ,CHLOROFORM d) = 173.5, 159.3, 159.2, 155.7, 131.3, 129.8, 129.2, 128.3, 128.0, 127.9, 126.7, 121.0, 114.5, 114.2, 110.2, 66.1, 55.5, 55.5, 55.3, 49.1, 47.2, 39.6 HRMS Calcd. for C 26 H 29 NO 5 [M+H ] + : 436.2118 Found: 436.2108 Ee was measured by chiral HPLC with a Whelk 01 column (UV 215 nm, 40% isopropanol/hexane, 1.5 ml/min). t 1 : 27.5, t 2 : 54.3 3 (4 fluorophenyl) 3 hydroxy N N bis(4 methoxybenzyl)propanamide ( 4 84 ) 1 H NMR (300MHz ,CHLOROFORM d) = 7.38 7 .20 (m, 2 H), 7.19 6.80 (m, 10 H), 5.15 (dd, J = 4.3, 7.8 Hz, 1 H), 4.90 (br. s., 1 H), 4.58 (d, J = 14.4 Hz, 1 H), 4.43 (d, J = 14.7 Hz, 1 H), 4.28 (d, J = 2.3 Hz, 2 H), 3.79 (d, J = 2.1 Hz, 6 H), 2.77 2.69 (m, 2 H)

PAGE 248

248 13 C NMR (75MHz ,CHLOROFORM d) = 1 72.7, 159.4, 159.3, 138.9, 129.9, 129.0, 127.8, 127.7, 127.6, 115.6, 115.3, 114.6, 114.3, 70.3, 55.5, 55.5, 49.3, 47.5, 41.8 HRMS Calcd. for C 25 H 26 FNO 4 [M+H ] + : 424.1919 Found: 424.1916 Ee was measured by chiral HPLC with a Whelk 01 column (UV 215 nm, 40% isopropanol/hexane, 1.5 ml/min). t 1 : 12.3, t 2 : 16.4 3 hydroxy N N bis(4 methoxybenzyl) 3 m tolylpropanamide (4 85) 1 H NMR (300MHz ,CHLOROFORM d) = 7.34 6.95 (m, 8 H), 6.95 6.72 (m, 4 H), 5.18 (br. s., 1 H), 4.83 (d, J = 2.9 Hz, 1 H), 4.61 (d, J = 14.7 Hz, 1 H), 4.45 (d, J = 14.4 Hz, 1 H), 4.30 (d, J = 3.8 Hz, 2 H), 3.81 (d, J = 2.1 Hz, 6 H), 2.85 2.73 (m, 2 H), 2.34 (s, 3 H) 13 C NMR (75MHz ,CHLOROFORM d) = 173.0, 159.4, 159.3, 143.1, 138.3, 129.9, 129.1, 128.6, 128.5, 127.9, 126.6, 123.0, 114.6 114.3, 70.9, 55.6, 55.5, 49.3, 47.4, 42.0, 21.7 HRMS Calcd. for C 26 H 29 NO 4 [M+H ] + : 344.1856 Found: 344.1859 Ee was measured by chiral HPLC with a Whelk 01 column (UV 215 nm, 40% isopropanol/hexane, 1.5 ml/min). t 1 : 15.1, t 2 : 23.9 3 cyclohexyl 3 hydroxy N N bis(4 methoxybenzyl)propanamide (4 86)

PAGE 249

249 1 H NMR (300MHz ,CHLOROFORM d) = 7.22 6.98 (m, 4 H), 6.98 6.69 (m, 4 H), 4.66 4.41 (m, 2 H), 4.36 (d, J = 4.4 Hz, 2 H), 4.25 (d, J = 2.6 Hz, 1 H), 3.82 (s, 3 H), 3.80 (s, 3 H), 2.58 (d, J = 2.1 Hz, 1 H), 2.48 (d, J = 9.7 Hz, 1 H), 1.87 (br. s., 1 H), 1.81 1.58 (m, 4 H), 1.43 1.10 (m, 4 H), 1.10 0.98 (m, 2 H) 13 C NMR (75MHz ,CHLOROFORM d) = 173.8, 159.4, 159.3, 129.9, 129.3, 128.1, 127.9, 114.6, 114.2, 72.6, 55.6, 55.5, 49.3, 47.4, 43.2, 36.8, 29.2, 28.6, 26.7, 26.4, 26.3 HRMS Calcd. for C 25 H 33 NO 4 [M+H ] + : 412.2482 Found: 412.2482 Ee was measured by chiral HPLC with a Whelk 01 column (UV 215 nm, 5% isopropanol/hexane, 1.5 ml/min). t 1 : 84.9, t 2 : 94.5 3 hydroxy N N bis(4 methoxybenzyl)butanamide (4 87) 1 H NMR (300MHz ,CHLOROFORM d) = 7.20 6.98 (m, 4 H), 6.96 6.78 (m, 4 H), 4.58 (d, J = 14.7 Hz, 1 H), 4.43 (d, J = 14.4 Hz, 2 H), 4.38 4.22 (m, 3 H), 3.80 (s, 6 H), 2.57 (dd, J = 2.6, 16.4 Hz, 1 H), 2.42 (dd, J = 9.4, 16.7 Hz, 1 H), 1.23 1.18 (m 3 H)

PAGE 250

250 13 C NMR (75MHz ,CHLOROFORM d) = 173.4, 159.4, 159.3, 129.9, 129.2, 128.0, 127.9, 114.7, 114.3, 64.7, 55.6, 55.5, 49.2, 47.3, 41.2, 22.5 Ee was measured by chiral HPLC with a IA column (UV 215 nm, 10% isopropanol/hexane, 1.2 ml/min). t 1 : 16.6, t 2 : 23.1

PAGE 251

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258 ( 82 ) (a) Gschwind R. M. Chem. Rev. 2008, 108 3029 3053. (b) Bartholomew, E. R.; Bertz, S. H.; Cope, S.; Murphy, M.; Ogle C. A. J. Am. Chem. Soc. 2008, 130 11244 11245. ( 83 ) Thermal ellipsoids are drawn at the 50% probability level. Selecte d bond lengths () and angles (): Cl1 C1 1.680(2), Cu1 Cl2 2.1069(8), Cu1 Cl3 2.0963(9), N1 C1 N2 109.6(2), C20 C15 C3 C2 21.6 ( 84 ) The alpha selectivity with CuTC alone (without a donating ligand) has been reported. Alexakis, A.; Croset, K. Org. Lett 200 2 4 4147 4149. ( 85 ) Kaur, H.; Zinn, F. K. ; Stevens, E. D.; Nolan, S. P. Organometallics 2004, 23 1157 1160. ( 86 ) He, X.; Olmstead, M. M.; Power P. P. J. Am. Chem. Soc. 1992, 114 9668 9670. ( 87 ) Tapu, D.; Dixon, D. A.; Roe, C. Chem. Rev. 2010, 109 3385 3407. ( 88 ) V. ; Wilhelm, R. Green Chem 2005, 7 844 848 ( 89 ) Gnis son, Y.; Lauth de Viguerie, N.; Andr, C.; Baltas, M. ; Gorri chon, L. Tetrahedron: Asymmetry 2005, 16, 1017 1023 ( 90 ) Welle, A.; Dez Gonzlez, S.; Tinant, B.; Nolan, S. P.; Riant, O. Org. Lett 2006, 8 6059 6062. ( 91 ) ( a) Lee Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128 15604 15605 (b) Arduengo, A. J., III.; Dias, H. V. R.; Davidson, F.; Harlow, R. L. J. Organomet. Chem 1993 462 13 18. ( 92 ) Whitesides, G. M.; Fisher Jr, W. F.; Filippo Jr, J. S.; Bashe, R. W.; House, H. O. J. Am. Chem. Soc 1969 91 4871 4882. ( 93 ) (a) Abarbri, M.; Thibonnet, J.; Brillon, L.; Dehmel, F.; Rottlnder, M.; Knochel, P. J. Org. Chem 2000, 65 4618 4634. (b) Boymond, L.; Rottlnder, M.; Cahiez, G.; Knochel, P. Angew. Chem. Int. Ed 1998, 37 1701 1703. ( 94 ) (a) Esquivias, J.; Arrays, R, G.; Carretero, J. C. J. Org. Chem. 2005 70 7451 7454 (b) Takeda, N.; Hamaki, H.; Tokitoh N. Chem. Lett. 2004, 33 134 135. ( 95 ) (a) Poater, A.; Cosenza, B.; Corre a, A.; Giudice, S.; Ragone, F.; Scarano, V.; Cavallo, L. Eur. J. Inorg. Chem. 2009 1759 1766 ( b ) http://www.molnac.unisa.it/OMtools.php (c) Clavier, H.; Nolan, S. P. Chem. Commun. 2010, 46 841 861. (d) Gaillard, S.; Bantreil, X.; Slawin A. M. Z.; Nolan S. P. Dalton Trans., 2009, 6967 6971. ( 96 ) The calculations used Samb V ca 12 a,b with the following parameters: radius of sphere, 3.5 ; distance from sphere, 2 ; mesh step, 0.05

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259 ( 97 ) Tolman, C. A. C hem. Rev. 1977, 77 313 348 ( 98 ) Thermal ellipsoids are drawn at the 50% probabilit y level. The inserted structure show s the front view of the complex. Selected bond lengths () and angles (): Au1 Cl1 2.289(2), Au1 C1 1.988(4), N2 C1 N1 105.0(3), C8 C9 C1 0 C11 21.0, C28 C18 N1 C1 80.6. ( 99 ) Thermal ellipsoids are drawn at the 50% probabilit y level. The inserted structure show s the front view of the complex. Selected bond lengths () and angles (): Au1 Cl1 2.2829(10), Au1 C1 1.985(4), N2 C1 N1 104.6(3), C8 C9 C10 C11 23.3 ( 100 ) (a) Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. Organometallics 2006, 25, 2405 2408. ( b ) Laitar, D. S.; Mller, P.; Sadighi, J. P. J. Am. Chem. Soc. 2005, 127 17196 17197.

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260 BIOGRAPHICAL SKETCH Dimitri Hirsch Weil was bor n in Paris, France in 1982, and grew up in Nmes, France. After graduating from Alphonse Daudet High School in 2000, he spent two years in preparatory He then joined the Ecole Supri eure de Chimie Physique Electronique de Lyon (CPE), France where he spent two years majoring in organic chemistry. For his one year internship, he was hired by GlaxoSmithKline in Upper Merrion, P ennsylvania to work in their medicinal chemistry department. This rich experience led him to pursue a PhD in organic chemistry under the supervision of Sukwon Hong at the University of Florida.