Designs, Syntheses, and Applications of N-Heterocyclic and Acyclic Diaminocarbene-Metal Complexes

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Designs, Syntheses, and Applications of N-Heterocyclic and Acyclic Diaminocarbene-Metal Complexes
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1 online resource (128 p.)
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english
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Inagaki, Sebastien M
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University of Florida
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Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Chemistry
Committee Chair:
Hong, Sukwon
Committee Members:
Schanze, Kirk S
Stewart, Jon D
Mcelwee-White, Lisa A
Sloan, Kenneth B

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Subjects / Keywords:
adc -- asymmetric -- carbene -- complexes -- ligand -- metal -- nhc -- synthesis
Chemistry -- Dissertations, Academic -- UF
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Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

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Abstract:
The design of a chiral isoquinoline-based N-heterocyclic carbene was revisited. Two ligands, one containing a Lewis base, were synthesized. The corresponding carbene-metal complexes were then used in different catalytic and asymmetric systems to seek greater reactivity and enantioselectivity. Acyclic diaminocarbene ligands have also a potential in asymmetric synthesis. However, their backbones make it more challenging to control their enantioselectivity. Simple achiral ADC-metal complexes could also achieve good reactivity with a new method of generating them in situ. A new ADC-iridium complex was synthesized and its X-ray structure was obtained showing the presence of only one conformer of the ligand.
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In the series University of Florida Digital Collections.
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Includes vita.
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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.
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by Sebastien M Inagaki.
Thesis:
Thesis (Ph.D.)--University of Florida, 2012.
Local:
Adviser: Hong, Sukwon.
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RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2014-05-31

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UFE0044115:00001


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1 DESIGN S SYNTHES E S, AND APPLICATION S OF N H ETEROCYCLIC AND ACYCLIC DIAMINO CARBENE METAL COMPLEXES By SEBASTIEN INAGAKI 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 2012

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2 2012 S bastien Inagaki

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3

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4 ACKNOWLEDGMENTS I wish to thank my advisor Sukwon Hong for his help througho ut my whole Ph D program. The fruitful discussions and his wise words were very helpful. He knew how to be patient and supportive with my work. I also want to thank my co workers: Dr. Dimitri Hirsh Weil, Dr. David Snead, and Dr. Hwimin Seo who I worked c losely with. Their work ethic was no doubt helpful to me and I will always appreciate their research skills. I finally thank my other co workers: Dr. Mike Rodig, Dr. Kai Lang, and Dr. Jongwoo Park for some interesting discussions I had with them.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 7 LIST OF FIGURES ................................ ................................ ................................ .......... 8 LIST OF SCHEMES ................................ ................................ ................................ ...... 12 ABSTRACT ................................ ................................ ................................ ................... 14 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .... 15 Electronic Properties of NHC Ligands ................................ ................................ ..... 15 Applications of NHC Metal Complexes as Catalysts ................................ .............. 16 Re cent Advances in the Synthesis of Chiral NHC Ligands ................................ ..... 18 Chirality on the Backbone ................................ ................................ ................. 18 Chirality on the Substituent of the Nitroge n Atom ................................ ............. 23 Chirality at the position from the nitrogen atom ................................ ...... 23 position from the nitrogen atom ................................ ....... 27 Ligands containing chiral planes ................................ ................................ 31 Synthesis of Acyclic Diaminocarbene Ligands ................................ ........................ 35 Formation of a Carbene Intermediate ................................ ............................... 35 ADC Metal Complexes by Functionalization of Isocyanide .............................. 36 First Isolation of a Free ADC ................................ ................................ ............ 37 ADC Metal Comple xes by Complexation of Free Carbene .............................. 38 ADC Metal Complexes by Oxidative Addition ................................ .................. 40 Applications of ADC Palladium Complexes in C oupling Reactions .................. 42 Aryl Substituted ADC Metal Complexes ................................ ........................... 42 Return to the Original Preparation ................................ ................................ .... 45 Chiral Acyclic Diaminocarbene Ligands ................................ ........................... 47 2 DESIGN, SYNTHESIS, AND APPLICATIONS OF CHIRAL N HETEROCYCLIC CARBENE METAL COMPLEXES ................................ ................................ .......... 49 Previous Designs of Chiral NHC Ligands ................................ ............................... 49 Improvement of the Original Design ................................ ................................ ....... 53 Synthesis of the New C 1 Symmetric Carbene Ligand ................................ ...... 55 Applications of the New C 1 Symmetric NHC Ligand ................................ ......... 56 Design of a Ligand Containing a Lewis Base ................................ .......................... 63 Experimental Section ................................ ................................ .............................. 69 General Remarks ................................ ................................ ............................. 69 Synthesis of Imidazolium ent 2 15dc ................................ ................................ 69

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6 Synthesis of Imidazolium ent 2 15ec ................................ ................................ 75 Borylation Reaction of Conjugated Ester 2 30 or Conjugated A mide 2 13a .. 81 Typical procedure ................................ ................................ ...................... 81 HPLC spectra for amide 2 14a ................................ ................................ ... 82 HPLC spectra for ester 2 31 ................................ ................................ ...... 83 1,2 Addition Reaction ................................ ................................ ....................... 83 Typical procedure ................................ ................................ ...................... 83 Characterization of 1,2 addition products (Table 2 3) ................................ 84 HPLC spectra for the ligand scope (Table 2 4) ................................ .......... 84 Asymme tric Allylic Alkylation ................................ ................................ ............ 86 Typical procedure ................................ ................................ ...................... 86 NMR spectra for the regioselectivity ................................ .......................... 86 HPLC spectra for the ligand scope ................................ ............................ 87 3 DESIGN, SYNTHESIS, AND APPLICATIONS OF CHIRAL AND ACHIRAL ACYCLIC DIAMINOCARBENE METAL COMPLEXES ................................ .......... 89 Achiral Acyclic Diaminocarbene Metal Complexes ................................ ................. 89 ADC Copper Catalyzed Allylic Alkylation ................................ .......................... 89 ADC Iridium Complex ................................ ................................ ....................... 93 Design and synthesis of an ADC iridium complex ................................ ..... 93 Hydroboration of alkenes ................................ ................................ ........... 97 Chiral Acyclic Diaminocarbene Precursors ................................ ........................... 101 Original Design of a Chiral Acyclic Diaminocarbene ................................ ...... 101 New Design of a Chiral Acyclic Diaminocarbene ................................ ............ 102 Experimental Section ................................ ................................ ............................ 105 ADC Copper Catalyzed Allylic Alkylation ................................ ........................ 105 Typical procedure for allylic alkylation ................................ ...................... 105 Characterizations of products 3 4a f ................................ ........................ 106 ADC Iridium Complexes ................................ ................................ ................. 107 Syntheses of iridium complexes ................................ ............................... 107 Typical procedure for the hydroboration ................................ .................. 111 NMR spectra ................................ ................................ ............................ 112 Chiral Acyclic Diaminocarbene Metal Complexes ................................ .......... 113 Synthesis of chloroamidinium salt 3 40 ................................ .................... 113 Syntheses of ADC metal complexes 3 41 and 3 42 ................................ 114 Suzuki cross coupling reaction ................................ ................................ 116 1,2 Addition of 1 naphthylboronic acid to o anisaldehyde ........................ 117 4 CONCLUSION ................................ ................................ ................................ ...... 119 LIST OF REFERENCES ................................ ................................ ............................. 121

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7 LIST OF TABLES Table page 1 1 Ligand scope for the desymmetrization of diynesulfonamide 1 36 ..................... 26 1 2 Carbene precursor scope for the conjugate addition of EtMgBr on enone 1 50 ................................ ................................ ................................ ....................... 29 2 1 Optimization of the reaction conditions ................................ ............................... 59 2 2 Base scope for the generation of the free carbene ................................ ............. 60 2 3 Substrate scope ................................ ................................ ................................ .. 61 2 4 Chiral ligand scope ................................ ................................ ............................. 62 3 1 Optimization of conditions for the copper catalyzed allylic alkylation .................. 90 3 2 Substrate scope for ADC copper catalyzed allylic alkylation .............................. 91

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8 LIST OF FIGURES Figure page 1 1 Structures of imidazolin 2 ylidene and imidazol 2 ylidene ................................ .. 15 1 2 The two ground states adopted by the NHC carbene and stabilization of the singlet state ................................ ................................ ................................ ........ 15 1 3 Structures of Grubbs catalysts ................................ ................................ ............ 16 1 4 NHC Ir catalyzed hydrogen transfer ................................ ................................ ... 16 1 5 Uses of NHC Pd catalysts in coupling reactions ................................ ................. 17 1 6 NHC gold catalyzed of cycloisomerization of 1,5 enyne ................................ ..... 17 1 7 Ruthenium catalyzed desymmetrization of triene 1 4 ................................ ......... 19 1 8 Ruthenium catalyzed AROCM of norbornene 1 14 ................................ ............ 21 1 9 Palladium catalyzed asymmetric diamination of conjugated dienes 1 17 ........... 22 1 10 Palladium catalyzed intramolecular arylation of amide 1 21 ........................... 22 1 11 s preparation of chiral imidazoliums ................................ ................... 23 1 12 Rhodium catalyzed hydrosilylation of acetophenone 1 25 ................................ 23 1 13 Czekelius chiral imidazolinium 1 27 ................................ ................................ .... 24 1 14 Substituent scope of NHC gold complex 1 35 ................................ .................... 25 1 15 lysts ................................ ................................ ............ 27 1 16 Rhodium catalyzed hydrosilylation of acetophenone 1 25 ................................ 27 1 17 Rhodium catalyzed hydrosilylation of pyruvic acid esters 1 44 .......................... 27 1 18 Copper catalyzed hydrosilylation of acetophenone 1 25 ................................ .... 28 1 19 Palladium catalyzed oxidative Heck reaction of enone 1 52 .............................. 30 1 20 Copper catalyzed conjugate addition of dialkylz inc to cyclic enones .................. 31 1 21 Ruthenium catalyzed AROM of norbonene 1 14 ................................ ................ 32 1 22 Gold catalyzed intramolecular hydroamination of 1 59 ................................ ....... 32

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9 1 23 Rhodium catalyzed 1,2 addition of arylboronic acids onto benzaldehyde derivatives ................................ ................................ ................................ .......... 35 1 24 Dimerization of imidazolinium 1 76 and formamidinium 1 78 ............................. 35 1 25 First ADC metal carbene synthesized ................................ ................................ 36 1 26 N C N bond angles of free carbenes and carbene copper complexes ............... 37 1 27 Deprotonation of formamidinium 1 83 ................................ ................................ 38 1 28 back donation of the metal to a C=O ligand ................................ .................... 40 1 29 Compa rison of CO frequencies between ADC and NHC Rh complexes ........... 40 1 30 Palladium catalyzed Heck reaction ................................ ................................ ..... 41 1 31 Common free NHC ligands ................................ ................................ ................. 42 1 32 P metal complexes ................................ 43 1 33 X ray structure of Rh complex 1 99 in its amphi conformatio n ........................... 43 1 34 ........ 44 1 35 gold complex 1 100 ................................ ................................ ................................ .... 45 1 36 gold complexes ................................ ................... 45 1 37 ADC gold catalyzed tandem reaction ................................ ................................ 46 1 38 Miyaura coupling ................................ ......... 47 1 39 The free rotation around the C N bond allowed for ADC ligands ........................ 47 1 40 catalyzed cyclization of 1 111 .............................. 48 1 41 catalyzed cyclization of 1 114 ....................... 48 2 1 Copper catal Cu complex ...................... 50 2 2 Copper catalyzed C 1 symmetric NHC ......................... 51 2 3 Origin of the chiral isoquinoline moiety for C 1 and C 2 symmetric ligands .......... 52 2 4 Retrosyn thesis for the preparation of the chiral isoquinoline moiety ................... 53 2 5 First rhodium catalyzed 1,2 addition ................................ ................................ ... 56

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10 2 6 NHC rhodium catalyzed asymmetric 1,2 addition ................................ ............... 57 2 7 addition ................................ .......... 57 2 8 Pd complexes in the asymmetric 1,2 addition ....................... 57 2 9 Copper catalyzed 1,2 addit ion ................................ ................................ ............ 58 2 10 Comparison of ligands ent 2 15dc and 2 15bc in the borylation of 2 13a ...... 63 2 11 New concept for the ring opening of the aziridine moiety ................................ ... 63 2 12 Calculated energy levels of protonated 1 methyl 4 phenyl 1,2,3 triazole ........... 66 2 13 Comparison of ligands ent 2 15ec and 2 15bc for the borylation of 2 30 ....... 67 2 14 Comparison of ligands ent 2 15ec and 2 15bc for the 1,2 addi tion ................... 67 2 16 HPLC spectra for the borylation of amide 2 14a ................................ ............. 82 2 17 HPLC spectra for the borylation of ester 2 31a ................................ ............... 83 2 18 HPLC spectra of the 1,2 addition product (racemic mixture) .............................. 84 2 19 HPLC spectra of the 1,2 addition product (Table 1, entry 1) .............................. 85 2 20 HPLC spectra of the 1,2 addition product (Table 1, entry 2) .............................. 85 2 20 HPLC spectra of the 1,2 addition product (Table 1, entry 3) .............................. 85 2 21 HPLC spectra of the 1,2 addition product (Table 1, entry 4) .............................. 86 2 22 NMR spectra of th e product of the AAA with ent 2 15ec ................................ .... 87 2 23 HPLC spectra of product 2 33 (racemic mixture) ................................ ................ 87 2 24 HPLC spectra of product 2 33 with ent 2 15ec ................................ .................. 88 2 25 HPLC spectra of product 2 33 with with ent 2 5aa ................................ ............. 88 2 26 HPLC spectra of product 2 33 with ent 2 15ec at 78 C ................................ .... 88 3 1 Catalytic activity of 3 2 in asymmetric allylic alkylation ................................ ....... 89 3 2 Possible conformers of the new acyclic diaminocarbene ligand ......................... 94 3 3 Thiourea formation: trapping method of carbene intermediate ........................... 95 3 4 X ray structures of complex 3 23a ................................ ................................ ...... 96

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11 3 5 X iridium complex ................................ ........... 97 3 6 .............................. 98 3 7 First rhodium catalyzed hydroboration ................................ ............................... 98 3 8 Mechanism of rhodium catalyzed hydroboration of terminal olefins ................... 99 3 9 Iridium catalyzed hydroboration of sty rene ................................ ....................... 100 3 10 Original design of a chiral ADC ligand ................................ .............................. 101 3 11 Preparation of the chiral ADC metal complex ................................ ................... 101 3 12 ADC palladium catalyzed Suzuki Miyaura coupling reaction ............................ 104 3 13 ADC rhodium catalyzed 1,2 addition re action ................................ .................. 104 3 14 Undesired conformations of the ADC metal complexes ................................ ... 105 3 15 NMR spectra of the hydroboration product ................................ ....................... 112 3 16 HPLC spectra of the Suzuki Miyaura coupling product ................................ .... 117 3 17 HPLC spectra of the 1,2 addition product ................................ ......................... 118 4 1 New chiral NHC pre cursors ................................ ................................ .............. 119 4 2 New ADC iridium complex 3 22a ................................ ................................ ...... 120 4 3 Chiral ADC ligand precursors ................................ ................................ ........... 120

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12 LIST OF SCHEMES Scheme page 1 1 ................................ ......................... 18 1 2 ruthenium complex ................................ ...... 20 1 3 gold complexes 1 32a h ............................. 24 1 4 ................................ ..................... 31 1 5 gold complex 1 61 ................................ ............... 33 1 6 Preparation of enantiopure atropisomer ( S ) 1 62 ................................ ............... 33 1 7 Preparation of enantiopure paracyclophane ( S p ) 1 70a ................................ ..... 34 1 8 1 71a e and 1 73a d ................................ 34 1 9 Formation of free acyclic diaminocarbene ................................ .......................... 37 1 10 Al ..................... 38 1 11 metal complexes ................................ ............. 39 1 12 Frs ................... 41 1 13 Preparation of neutral and cationic ADC palladium complexes .......................... 41 1 14 Use of ADC Pd complexes in coupling reactions ................................ ............... 42 1 15 and NHC palladium complexes .......................... 46 2 1 metal complexes ................................ .................... 49 2 2 C 1 symmetric NHC ligands and their metal complexes ... 50 2 3 Preparation of the chiral free amine 2 2 ................................ ............................. 52 2 4 Formation of structural isomers after Bischler Napieralski cyclization ................ 54 2 5 New target for the chiral isoquinoline moiety ................................ ...................... 54 2 6 Preparation of amine ent 2 2d ................................ ................................ ........... 55 2 7 Formation of imidazolium ent 2 15dc ................................ ................................ 55 2 8 New targets for the chiral amine containing a potential Lewis base ................... 64

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13 2 9 Synthesis of free amine ent 2 2e ................................ ................................ ....... 65 2 10 Synthesis of imidazolium ent 2 15ec ................................ ................................ 66 3 1 Evidence of the formation of the ADC copper complex ................................ ...... 92 3 2 Possible mechanisms for the formation of the ADC organocopper(I) ................. 93 3 3 Synthesis of ADC iridium complex ................................ ................................ ..... 95 3 4 Hydroboration of alkenes by a) Woods and b) Brown ................................ ........ 98 3 5 Preparation of the chiral pyrrolidine 3 27 ................................ .......................... 102 3 6 Synthe sis of chloroamidinium 3 40 ................................ ................................ ... 103 3 7 Formation of chiral ADC Pd 3 41 and ADC Rh 3 42 complexes ...................... 103

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14 Abstract of Dissertation Presented to the Graduate School o f the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy DESIGN S SYNTHES E S, AND APPLICATION S OF N H ETEROCYCLIC AND ACYCLIC DIAMINO CARBENE METAL COMPLEXES By Sbastien Inagaki May 201 2 Chair: Sukwon Hong Major: Chemistry The design of a chiral isoquinoline based N heterocyclic carbene was revisited. Two ligands one containing a Lewis base were synthesized The corresponding carbene metal complexes we re then used in different catalyti c and asymmetric systems to seek greater reactivity and enantioselectivity. Acyclic diamino carbene ligands have also a potential in asymmetric synthesis. However, their backbones make it more challenging to control their enantioselectivity. S imple achiral ADC metal complexes c ould also achieve good reactivity with a new method of generating them in situ. A new ADC iridium complex was synthesized and its X ray structure was obtained showing the presence of only one conformer of the ligand.

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15 CHAPTER 1 INTROD UCTION Electronic Properties of NHC Ligands Carbenes derived from imidazolin 2 ylidene or imidazol 2 ylidene skeleton (Figure 1 1) c an exist either as a singlet or a triplet ground state. 1 However, the singlet state i s more f avored over the triplet one due to the neighboring nitrogen atoms (Figure 1 2) Indeed, their withdrawing character by inductive effect stabilize s the filled the C carbene Besides, their donation by resonance effect towards the empty p orbital of the C carbene further stabilize s the singlet state. When the gap between the two state s i s lower than a bout 40 kcal.mol 1 then the preference for the singlet state i s less important. 2, 3 Figure 1 1 Structures of imidazolin 2 ylidene and imidazol 2 ylidene Figure 1 2 The two ground states adopted by the NHC carbene and stabilization of the singlet state This stabilization from the nitrogen atoms ma k e s the carbenes air and moisture resistant. 4, 5 Besides, it confers on the m a more nucleophilic donor) than the phosphines meaning they have strong er bonding to metals All these features

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16 ma k e carbenes a new class of ligands of interest. Complexes with l ate transition metals have first been studied such as ruthenium, iridium, palladium, and gold. Applications of NHC Metal Complexes as Catalysts One of the most famous examples of a NHC ruthenium complex was the olefin metathes is performed by Grubbs in 1999 6 He modified his first generation catalyst by substituting one of the phosphine ligands by SIMes carbene (Figure 1 3 ) The new complex gave higher activity than its phosphine analo gue with a more extended substrate scope and in a lower catalyst loading. This difference in activity could be explained by the binding affinity between the phosphines versus the olefin Indeed, t he first generation catalyst had a better preference for bin ding to phosphines over olefins by four orders of magnitude than the second generation Figure 1 3 Structures of Grubbs catalysts a) first generation and b) second generation Hydrogen transfer was one of the first test reactions for NHC iridium complexes. In 2001, Nolan used cationic [Ir(cod)(py)(ICy)]PF 6 in very low catalyst loading (0.025 mol%) for the hydrogen transfer to ketones and alkenes in isopropanol with very good re activities (Figure 1 4 ) 7 Figure 1 4 NHC Ir catalyzed hydrogen transfer

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17 Also Nolan reported the use of imidazoliums as carbene precursors for palladium catalyzed coupling reactions such as Suzuki Miyaura, 8 Stille, 9 Kumada, 10 Hiyama, 11 or amination 12 reactions. He was able to use most of the time the less reactive coupling partners aryl chlorides, to obtain the desired products in good yields (Figure 1 5 ) Figure 1 5 Uses of NHC Pd catalysts in coupling reactions Finally, in collaboration with Malacria, Nolan studied the gold catalyzed of enyne cyclizations. 13 They were able to optimize the conditions to favor the form ation of only one constitutional isomer in good yield (Figure 1 6 ) Figure 1 6 NHC gold catalyzed of cycloisomerization of 1,5 enyne

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18 Recent Advances in the Synthesis of Chiral NHC Ligands NHC ligands can have their chiral sites either on their backbones or on the substituents of the n itrogen atoms. While the first choice is easy access from an optically active diamine, the source of chirality is far away from the metal. However, the second method requires more steps to obtain the desired material but the chiral site is closer to the me tal sphere. Chirality on t he Backbone One of the pioneers to design NHC ligands with the chirality on the backbone was Grubbs when he first reported the synthesis of imidazoliniums 1 3 in 2001. 14 He used co mmercially available chiral 1,2 disubstituted ethylenediamines that he arylated and then cyclized. In only two steps he was able to obtain a variety of optically pure imidazoliniums as carbene precursors (Scheme 1 1 ) Scheme 1 1. G in ium s The drawback of this design wa s to have the source of the chirality remote from the metal center. Therefore, the use of an ortho monosubstituted aryl group (e.g.: o methylphenyl or o isopropylphenyl) on the nitroge n atoms wa s required to relay the stereoinformation from the b ack of the ligand to the front. The authors used this design for the desymmetrization of achiral trienes 1 4 via the ruthenium catalyzed ring closing me tathesis obtaining up to 90% ee (Figure 1 7 )

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19 Figure 1 7 Ruthenium catalyzed desymmetrization of triene 1 4 The substituents at the 4 and 5 positions on Grubbs catalyst, not only ha d a role in the stereoinduction, but they also ma d e the catalyst more stable. I ndeed, Grubbs studied the substitution effect of the backbone with methyl groups. 15 He found out that the more substituted the backbone was, the closer the carbene was to the metal center due to the ligand being ele ctron rich. Therefore, the catalyst was more stable however less reactive when used in the ring closing metathesis reaction. In the same report, the author studied the effect of the bulkiness of the aryl group on the nitrogen atoms. He came to the conclusi on that the less bulky the aryl group was the less stable but more reactive the catalyst was. initial design and tried to balance between stability and reactivity of the catalyst without affec ting the stereoinduction. 16 His concept was to keep the aryl groups of the nitrogen atoms orthogonal to the plane of the imidazole moiety. He believed that the twisting of these groups due to the chiral geometry of t he backbone should be responsible for the lack of reactivity of the catalyst. He then decided to have only one asymmetric center on the backbone so that only one aryl group would be twisted. Therefore he could use a much amino acid, L valine.

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20 While the synthesis of the metal complexes require d more steps than the Grubbs one, it ha d good overall yields (Scheme 1 2) After arylation and reduction of the corresponding N substituted amino acid to the alcohol, the authors formed a su lfamidate 1 9 in order to open it with boc mesidine. Deprotection of diamine 1 10 and then cyclization gave imidazolinium 1 11 The ruthenium complex 1 13 wa s then obtained as a single isomer by a phosphine displacement in the presence of Hoveyda catalyst 1 12 In the case of the brominated version, a Suzuki coupling allows access to a more hindered ligand ( 1 13c ) before the formation of the imidazolinium. Scheme 1 ruthenium complex

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21 L ike Grubbs catalyst, the nitrogen atoms ha d ortho substituted aryl groups. However, the substituent surprisingly point ed towards the isopropyl group from the L valine, thus, away from the metal center. Nonetheless, the hindrance caused between the two prev ent ed any rotation of the aryl group hence locking the structure of the catalyst. Blechert tested his catalysts for the same desymmetrization of diene 1 4 but he 1 13c vs. 90% with 1 1 6 ). However, he used his own catalysts for the asymmetric ring opening cross metathesis (AROCM) of norbornene 1 14 (Figure 1 8 ). H e obtained better results in comparison with the Grubbs group not only in terms of enantioselectivity but also in terms of dia stereoselectivity (88% ee, E / Z ratio: >30/1 with 1 13c vs. 76% ee, E / Z ratio: 1/1 with complex 1 16 ). 17 Figure 1 8 Ruthenium catalyzed AROCM of norbornene 1 14 In 2008, Shi and co workers also got inspired from Grubbs design. 18 However, they noticed better enantioselectivity with di ortho substituted aryl groups rather than monosubstituted ones for the asymmetric diamination of conjugated diene s and triene (Figure 1 9 )

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22 Figure 1 9 Palladium catalyzed asymmetric diamination of conjugated diene s 1 17 Dorta and co workers also used the same chirality on the backbone of the imidazolinium moiety as Grubbs for their own catalyst. 19 However, they replaced the substituted phenyl groups on the nitrogen atoms with 1 naphthyl derivatives to obtain even more hindered ligands. They tested the corresponding palladium catalysts for the i arylation of amides (Figure 1 10 ) They obtained better enantioselectivity with bulky substituents (3 pentyl) at the 2 position of the naphthyl group. 20 After optimization they were able to form a quat ernary center at the benzylic position of a wide variety of 3 allyl oxindoles 1 22 Figure 1 10 Palladium catalyzed intramolecular arylation of amide 1 21 While the methodology looked attractive, the downside of it wa s the synthesis of its palladium catalyst. Indeed, the complexation of the free carbene on the metal generate d 3 stereoisomers ( R a R a 1 23, R a S a 1 23 and S a S a 1 23 ) that need ed to be separated.

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23 Chirality o n t he Substituent o f t he Nitrogen Atom Chirality at the position from the nitrogen atom In 1996, Herrmann was the first one to synthesize a chiral NHC ligand containing the chirality on the nitrogen atom. 21 He condensed enantiopur e 1 arylethylamine with glyoxal and formaldehyde to form the corresponding imidazolium 1 24 as a single isomer (Figure 1 11 ) Figure 1 11 After deprotonation of the imidazolium, h e complexed the correspond ing free carbene on rhodium and catalyzed the hydrosilylation of acetophenone with 90% yield and 33% ee (Figure 1 12 ) Figure 1 12 Rhodium catalyzed hydrosilylation of acetophenone 1 25 In 2011, Czekelius and co workers got inspired from a different design, but also originally created by Herrmann, to synthesize hindered Au(I) catalysts (Figure 1 13 ) 22, 23 Because of the linear coordination geometry of Au(I) and the potential anti addition of a nucleophile to the reactive site, a very bulky ligand had to surround the metal center to ould have this potential if the phenyl group pointing towards the metal c ould be further substituted.

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24 Figure 1 1 3 Czekelius chiral imidazolinium 1 2 7 Czekelius re visited the original synthesis and used bromobenzene for the Friedel Craft s a c ylation in order to perform a Suzuki coupling at a later stage (Scheme 1 3) Scheme 1 gold complexes 1 32a h

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25 Starting from phenylacetic acid 1 2 8 which wa s transformed into the corresponding acid chloride, the author perform ed an ary lation with bromobenze ne After reductive amination, the racemic mixture of the amine wa s resolved with (+) tartaric acid to obtain the ( R ) enantiomer 1 30 24 Then formylation and Bischler Napieralski cyclization afford ed the dihydroisoquinoline 1 31 Diamine 1 32 wa s then obtained as a single isomer after reductive dimerization in the presence of zinc and chlorotrimethylsilane. The new concept c ould now take place by further functionalizing the phenyl pendants wi th a Suzuki coupling (Figure 1 14 ) Czekelius was able to get seven new imidazoliniums 1 3 4 as carbene precursors, after cyclization with triethyl orthoformate. The corresponding gold complexes 1 3 5 were obtained by deprotonation of the five membered ring with potassium tert butoxide and treatment with AuCl Me 2 S Figure 1 1 4 Substituent scope of NHC gold complex 1 3 5 With these new highly hindered gold complexes, the authors tested their catalysts in the desymmetrization of diynesulfonamide 1 3 6 (Table 1 1) They screened all seven

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26 substituents improved the discrimination. All of them gave better enantioselectivity than the original ligand ( 1 3 5 a R 1 = H) with the best candidate being also the most hindered ( 1 3 5 f ). Table 1 1. Ligand scope for the desymmetrization of diynesulfonamide 1 3 6 Entry Catalyst Time (h) Yield (%) ee (%) 1 1 3 5 a 20 53 18 2 1 3 5 b 3 tra ces 22 3 1 3 5 c 14 52 45 4 1 3 5 d 6 36 34 5 1 3 5 e 7 37 39 6 1 3 5 f 3 77 51 7 1 3 5 g 6 50 30 8 1 3 5 h 14 63 40 F challenge wa s to have optically pure catalysts and easily accessible from cheap chiral sources. 25 He designed new non chelating NHC ligands based on commercially available chiral starting materials such as ( ) menthylamine or ( ) isopinocampheylamine (Figure 1 15 ) In only two steps, he c ould have access to chiral catalysts fr om these amines. He even came up with substituted cyclic acetals from cheap optically active aminodiols. In the end, he reported five different carbene rhodium complexes offering a variety of bulkiness. Herrmann then tested his rhodium complexes on the hyd rosilylation of acetophenone 1 25 (Figure 1 1 6 ) Only catalyst 1 3 9 offered some promising enantioselectivity (38%) as the other ones had too much ( 1 40 1 41 and 1 42 with thei r

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27 trans positioned phenyl groups) or not enough ( 1 3 8 with its simple methyl groups) hindrance around the metal center, offering poor discrimination. Figure 1 1 5 Figure 1 1 6 Rhodium catalyzed hydrosilylation of acetophenone 1 25 However, the se complexes being sterically more demanding were more efficient with less bulky substrates such as pyruvic acid esters 1 4 4 (Figure 1 1 7 ) T he hydrosilylation of the latter ones gave better results with up to 74% ee. Figure 1 1 7 Rhodium catalyzed hydrosilylation of pyruvic acid esters 1 4 4 Chirality at the position from the nitrogen atom For these previously described ligands, the source of chirality wa s closer to the metal center than the ones having their asymmetric carbons on the backbone. However,

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28 the chiral centers we posit ion (or both) from the nitrogen atoms. Gawley and co workers wanted to make this center even closer to the metal to increase even more the stereoinduction. In 2011, they were the first ones to report the synthesis of a non chelating NHC ligand bearing the asymmetric center at the position from the nitrogen atom. 26 They complexed their ligand with copper(I) and used the corresponding catalyst in the asymmetric hydrosilylation of acetophenone obtaining 96% ee (Figure 1 1 8 ) This C 2 symmet ric NHC ligand ha d creating a pocket and thus allowing the approach of the ketone only on its re face to the hydride. Figure 1 1 8 Copper catalyzed hydrosilylation of acetophenone 1 25 Another way of controlling the enantioselectivity without having a chiral center that close to the metal wa s to make the catalyst more rigid thus avoid ing the rotations around the C carbene metal bond or the nitrogen substitutent bond. This feature c ould be accomplishe d by using a bidentate ligand. In 2010, Alexakis, in collaboration with Mauduit, published a study about copper catalyzed asymmetric conjugate addition (ACA). 27 While the latter previously reported the synthesis of various chiral bidentate imidazoliniums ( 1 4 9 a f ), 28 the former tested them in the ACA reaction in addition to some C 2 symmetric NHC s ( 1 4 7 a c and 1 4 8 a e ) (Table 1 2) As Alexakis predicted in his study, not only the s terics is important for a good enantioselectivity, but also the chelating effect. Indeed, when he used the non chelating

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29 imidazoliums or some of the non hindered C 2 symmetric imidazoliniums, he saw a poor discrimination (9 42% ee). However, if he increased the steric demand of the N substitutents or if he used some chelating groups, then the enantioselectivity increased. precursors. The idea of a bidentate ligand that lock ed the st ructure of the corresponding metal complex led Jung and co workers to develop, in collaboration with Sakaguchi, a tridentate ligand. 29 Their original thought was to make a palladium complex more stable with an i ncreased electronic density around the metal center. Hence, those catalysts would be resistant even in nucleophilic solvents (water, acetonitrile, or alcohols). With three coordination sites from a tridentate ligand, this feature would be accomplished. The authors tested their new new catalysts in the oxidative Heck reaction (Figure 1 1 9 ). They obtained v ery good enantioselectivities (up to 98% ee) b ut unfortunately with moderate yields (31 61%). Table 1 2. Carbene precursor scope for the conjugate additio n of EtMgBr on enone 1 50 Entry Carbene precursor Conversion ee (%) 1 Ar = Ph 81 9 2 1 naphthyl 86 17 3 2 OMeC 6 H 4 75 42

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30 Table 1 2. Cont inued Entry Carbene precursor C onversion ee (%) 4 Ar = 1 naphthyl 92 68 5 2 naphthyl 82 17 6 2 Me C 6 H 4 87 63 7 2 i PrC 6 H 4 85 10 8 (8 MeO) 1 naphthyl >99 67 9 R = Me 87 68 10 i Pr 91 73 11 i Bu 85 74 12 t Bu 98 80 13 Ph 42 37 14 Bn 78 62 Figure 1 1 9 Palladium catalyzed oxidative Heck reaction of enone 1 5 2 In 2010, Sakaguchi further developed this design. 30 He tuned the chiral source as well as the non chiral part (substituent on the nitrogen of the azolium moiety) and was able to obtain a library of tridentate carbene precursors 1 57 (Scheme 1 4) The two step pre paration of these azoliums start ed amino alcohol 1 55 with chloroacetyl chloride to give the amide 1 56 which wa s then aminated with an N substituted imidazole or benzimidazole.

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31 Scheme 1 iums Sakaguchi tested those new azoliums in the copper catalyzed conjugate addition of dialkylzinc to cyclic enone. To his great surprise, he was able to obtain either enantiomer of the product with good enantioselectivity with the same chiral ligand (Figu re 1 20 ) Indeed, the copper source used as a pre catalyst affected the outcome of the selectivity. When the author used Cu(OTf) 2 as a copper source, he obtained the opposite enantiomer while using Cu(acac) 2 instead. Figur e 1 20 Copper catalyzed conjugate addition of dialkylzinc to cyclic enones Ligands containing chiral planes Not all chiral NHC ligands contain ed an asymmetric atom; they c ould have chiral planes instead. In 2011, Shi and co workers reported the synthesis and applications of an optic biphenyl scaffold (Figure 1 2 2 ) 31

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32 moiety. 32 The ruthenium complex showed excellent enantioselectivity (up to 98% ee) in the asymmetric ring opening metathesis (AROM) of norbonene 1 14 (Figure 1 21) Figure 1 21 Ruthenium catalyzed AROM of norbonene 1 14 In the same report, Shi also dimethoxybiphenyl system as a chiral plane and tested the corresponding gold complex 1 6 1 in the intramolecular hydroamination with up to 44% ee (Figure 1 22). Figure 1 22. Gold catalyzed intramolecular hydroa mination of 1 59 The preparation of such a catalyst require d six steps and even if the overall yield wa s decent (Scheme 1 5) the chiral starting material 1 62 need ed extra steps for its obtention (Scheme 1 6) Indeed,after Ullmann coupling with 2 iodo 3 m ethoxy 1 nitrobenzene 1 6 7 in the presence of copper(0) the dinitro compound was reduced to afford a racemic mixture of the corresponding diamine 1 62 T hen a chiral resol ution with a tartaric acid derivative was needed to give the ( S ) isomer. 33

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33 Scheme 1 5 gold complex 1 6 1 Scheme 1 6 Preparation of enantiopure atropisomer ( S ) 1 62 Another kind of chiral NHC s wit h chiral planes we re those based on substituted [2.2]paracyclophan disubstituted imidazoliniums exhibit ed an optical activity with the [2.2]paracyclophanes through chiral planes. This design was originally reported by Andrus in 2003 in collaboration with Ma. 34 Ma pursued the development of this type of NHC s by switching from imidazoliniums to imidazoliums and by introducing different substituents at different positions on t h e paracyclophane moiety. 35 The imidazolium version wa s of a very short access since it required only 2 steps: diimine formation and cyclization (Scheme 1 8) However, the chiral starting material (( S p ) 4 amino 12 bromo[2.2]paracyclophane)

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34 require d several steps for its preparation (Scheme 1 7) 36 First, paracyclophane 1 68 wa s dibrominated to afford a racemic mixture of pseudo ortho dibromo[2.2]paracyclophane 1 69 which wa s then kinetically resolved by amination to leave optically pure starting material of the S p isomer. Finally, another amination t ook place by palladium coupling to obtain the chiral desired compound ( S p ) 1 70 Scheme 1 7 Preparation of enantiopure paracyclophane ( S p ) 1 70a From this chiral starting material, the bromine atom c o uld further be functionalized with a Suzuki Miyaura coupling with various arylboronic acids to give pseudo ortho arylamino[2.2]paracyclophanes 1 70b e Following the same process, as previously described, the author was also able to form diferrent pseudo i pso arylamino[2.2]paracyclophanes 1 72c,d Scheme 1 8 1 71a e and 1 73a d

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35 Ma then tested those new imidazoliums in the rhodium catalyzed 1,2 addition of arylboronic acids onto benzald ehyde derivatives (Figure 1 23 ) NHC s were in situ generated after deprotonation of the corresponding imidazoliums with sodium tert butoxide. Carbene precursor 1 71a was the most promising in terms of enantioselectivity. After optimization, the author got high reactivity with moderate enantioselectivity. Figure 1 2 3 Rhodium catalyzed 1,2 addition of arylboronic acids onto benzaldehyde derivatives Synthesis of Acyclic Diaminocarbene Ligands Formation of a Carbene Intermedi ate In 1964 Wiberg and Buchler reported the first ADC intermediate formation. 37 They deprotonated formamidinium 1 78 with methyllithium and they isolated the tetraaminoethylene product 1 79 (Figure 1 24 ) They came t o the conclusion that in order to end up with this olefin, the intermediate had to be a carbene. Their reasoning 1 77 obtained after deprotonation of imidazolinium 1 76 (or also calle d zwitterion). 38 However, none of the groups were able to characterize or isolate the free carbene. Figure 1 24 Dimerization of imidazolinium 1 76 and formamidinium 1 78

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36 ADC Met al Complexes by Functionalization of Isocyanide Since ADC free species and their precursors had to be complexed on a metal before the carbene generation. In 1969, Richards and co workers functionalized an isocyanide ligand complexed on platinum by nucleophilic attack of a primary amine to form the first ADC metal complex ever reported (Figure 1 25 ) 39 They formed a platinum (II) salt from the reactio n between [PtCl 2 (MeNC)(PEt 3 )] and aniline. This work has been published only a year after the first preparation of an NHC metal complex. Figure 1 2 5 First ADC metal carbene synthesized From the n, different groups in the 1970 s used this method to prepare different types of ADC metal complexes. 40, 41 The advantage wa s to quickly obtain a variety of carbenes, with different electronic and steric propertie s, by changing the free amine or the isocyanide. However, this route only allow ed the use of late transition metals corresponding isocyanide metal complexes c ould be tedious. Wit h those limitations, another way to prepare an ADC metal complex was undertaken. The idea was to isolate the free carbene and then to complex it on a metal. However the challenge of this method was to avoid any dimerization of the free carbene.

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37 First Isola tion of a Free ADC It was Alder who first reported the isolation of a free ADC in 1996. 42 Carbene 1 8 2 was obtained by deprotonation of the corresponding formamidinium salt with lithium diisopropylamide (Scheme 1 9 ) Salt 1 81 was synthesized from diisopropylformamide 1 80 with phosphorus oxychloride to form a chloroiminium adduct which was then subjected to a S N 2 type reaction with diisopropylamine. The dimerization of the free entity was prevented due to the steri c effect of the isopropyl groups. Scheme 1 9 Formation of free acyclic diamino carbene X ray analysis of carbene 1 8 2 showed, as expected, a wider N C N angle than its cyclic analogues (121.0 vs. <109 ) (Figure 1 2 6 ) Th at wider angle could therefore have the substituents on the nitrogen atoms closer to the metal center, making the complex more stable. Figure 1 2 6 N C N bond angles of free carbenes and carbene copper complexes 43 46 While Alder was able to isolate a free ADC, he quickly realized his method was limited. 47 Indeed, when he applied this procedure to formamidinium 1 83 he did

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38 observe, by NMR spectroscopy, formation of the corresponding carbene 1 8 4 but accompanied with the dimerization of the latter giving the ethene product 1 8 5 (Figure 1 2 7 ) Fi gure 1 2 7 Deprotonation of formamidinium 1 83 Alder proposed this dimerization due to the nucleophilic character of the free carbene. He reported that once carbene 1 8 4 was formed, it could attack the starting formamidinium 1 83 to g ive adduct 1 8 6 (Scheme 1 10) After deprotonation, the corresponding ethene 1 8 5 was formed. In the case of the tetraisopropylformamidinium, the hindrance of the alkyl groups wa s too important for the free carbene to attack the chloride salt. Scheme 1 10 ADC Metal Complexes by Complexation of Free Carbene In 2002, Herrmann and co workers reported the first complexation of an ADC on a metal via a free carbene 48 The authors described several methods to obtain the desired rhodium or iridium complexes. They either isolated the free carbene and complexed it on the metal, or use an internal base coming from the metal or from t he carbene

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39 precursor (Scheme 1 11) In the deprotonation case, they generated in situ the free carbene that they complexed on the metal. Scheme 1 1 1 of ADC metal complexes a) with isolated free car bene, b) with EtO ligand used as a base, and c) by t BuOH removal According to Herrmann, a simple way to measure the basicity of a carbene wa s to exchange the cyclooctadiene ligand of the corresponding metal complex with carbon monoxide and to measure the stretching frequency of the C=O bond by IR spectroscopy. He reported that this stretching frequency wa s directly related to the back donation of the carbene ligand. For example, if a ligand such as an ADC wa donor, then the carbon monoxide (which wa acceptor) w ould have its back donation increased (Figure 1 2 8 ) The anti bonding molecular orbital of the C=O ha d a better overlap with the metal d orbitals. Therefore, the electron enriched anti bonding ma de the bond length between the carbon and the oxygen atoms greater. Since the energy of the C=O bond wa s inversely proportional to its length, hence the longer the bond, the lower the energy (therefore the lower the wav enumber).

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40 Figure 1 2 8 back donation of the metal to a C=O ligand Herrmann measured the C=O stretching frequencies of 1 8 8 and saw the value was indeed lower than two of its cyclic analogues 1 89 and 1 90 by 19 and 24 cm 1 re spectively (Figure 1 29) Therefore, th is ADC ligan donor) than the NHC ones used in the experiment Figure 1 2 9 Comparison of CO frequencies between ADC and NHC Rh complexes ADC Metal Complexes by Oxidative Addition Another alternative to avoid this dimerization drawback was proposed by Frstner in 2005. He directly complexed the ligand on palladiu m through oxidative addition of chloroamidinium salt 1 92 with a palladium (0) source (Scheme 1 12) 49 The chloroamidinium can be obtained by oxygen displacement of the corresponding urea 1 91 in the p resence of a chlorinating agent (such as oxalyl chloride). The author was then able to obtain the same ADC ligand 1 84 complexed on a metal where Alder f ailed to isolate the free carbene.

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41 Scheme 1 1 2 Frstner a chloroamidinium on palladium (0) With the same method, Frstner formed the ADC palladium complex with the le ast sterically hindered carbene (we ll known to quickly dimerize) (Scheme 1 13) Moreover, depending on the counter ion of the chlor oamidinium salt, either neutral or cationic metal complex c ould be prepared ( 1 9 5 and 1 9 6 respectively) Scheme 1 1 3 Prepa ration of neutral and cationic ADC palladium complexes The author tested different ADC palladium complexes in the Heck reaction obtaining the desired coupled product 1 9 8 in good yields (Figure 1 3 0 ) Figure 1 30 Palladi um catalyzed Heck reaction

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42 Applications of ADC Palladium Complexes in Coupling Reactions Another breakthrough about the ADC metal complexes wa 2006. 50 He published the use of in situ gener ated ADC ligands then complexed on palladium for coupling reactions (Suzuki Miyaura, Sonogashira, and Heck) in good to excellent yields (Scheme 1 14) Scheme 1 1 4 Use of ADC Pd complexes in coupling reactions Aryl Substi tuted ADC Metal Complexes Hindered NHC ligands such as IAd, IMes, I t Bu, and IPr (Figure 1 31 ) have been widely used as ligands due to their stability. 51 53 The heavily hindered substituents prevent ed any possible dimerization. Since the acyclic analogues ha d a wider N C N bond angle, therefore those substituents on the nitrogen atoms should add even more stability to the carbene. Figure 1 31 Common free NHC ligands

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43 Bielawski and co workers got inspired from this feature and first reported the synthesis of diarylated ADC metal complexes with the stud y of their behavior. 54, 55 Since the substitutents on each nitrogen atom were different (one aryl and one alkyl groups) therefore, t he geo metry of such complexes could adopt different conformations. Indeed, the aryl groups c ould be both away ( anti ), both close ( syn ), or only one of them close ( amphi ) to the metal center (Figure 1 32 ) Figure 1 32 Possible metal complexes Initially, the authors thought the aryl groups would adopt the syn conformation, thus having the bulky groups the furthest away from each other. However, X ray structure of rhodium complex 1 99 showed a conform ation close to the amphi one (Figure 1 33 ). They postulated this rotation was the most favored due to some CH system of the aryl group. Besides, the 1,3 allylic strain between the substituents on the nitrogen atoms is at its lowest point when the methyl faces the aryl group. Figure 1 33 X ray structure of Rh complex 1 99 in its amphi conformation

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44 Bielawski measured the CO stretching frequency of the correspond ing dicarbonylrhodium complex. As expected, the value was higher 1 ) meaning the ligand was 1 88 1 ) which wa s a tetraalkyl substituted ADC. The aryl groups withdrew the electron density of the nitrogen atoms away from the C carbene However, the carbene wa s still more donating than the NHC ligands 1 89 and 1 90 1 1 ) respectively). Bielawski tested his ADC ligands complexed on ruthenium in the cross metathesis (CM) reactions in comparis on with their NHC equivalents (Fi gure 1 34 ). Figure 1 34 ruthenium complexes in cross metathesis While the ADC Ru complexes showed some reactivity, they did n o t have as good discrimination in terms of stereoselectivity as the NHC analogues. The author postulated the increase of sterics of the ADC prevent ed the isomerization of the CM

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45 product necessary to afford the ( E ) isomer. Indeed he took an aliquot from a crude mixture after CM reaction with an ADC Ru complex and he treated it with the NHC Ru analogue. He observed a change of the ratio in favor of the E isomer. Return to the Original Preparation Espinet and co workers came back to the original method of preparing ADC metal complexes with the functionalization of an is ocyanide metal complex. 56, 57 As seen in sterics of the substituents. To avoid this issue, Espinet wanted to lock the structure with some hydrogen bonding Indeed, in solution or in solid state, he observed that his corresponding hydrogen bond supported heterocyclic carbenes (HBHC) 1 100 showed a preferred conformation due to the hydrogen bonding betwee n the pyridine substituent and the hydrogen of the amine (Figure 1 3 5 ) Figure 1 3 5 hydrogen bond supported heterocyclic carbene ( HBHC ) gold complex 1 100 Two years later, Hashmi reported the synthesis of sever al ADC s (also called NAC: nitrogen acyclic carbene) complexed on gold following the same procedure as Richards in 1969 (Figure 1 36 ) 58 Figure 1 36 ADC gold complexes

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46 He obtained a large variety of complexes 1 103 in very good yields. However, this nucleophilic enough to attack the isonitrile moiety 1 102 Hashmi re ported the same year, an ADC gold catalyzed tandem reaction forming a tricyclic cage like structure 1 106 from diol 1 104 and an aniline derivative (or hydrazine derivative) (Figure 1 37 ). 59 Figure 1 37 ADC gold catalyzed tandem reaction In 2011, Hashmi extended this preparation to ADC and NHC palladium complexes ( 1 108 and 1 109 respectively) with a large variety of substituents on the nitrogen atom s (Scheme 1 15). 60 Scheme 1 1 5 and NHC palladium complexes Then, the author tested the activity of his new complexes in the Suzuki Miyaura cross coupling reaction (non optimi zed) (Figure 1 3 8 )

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47 Figure 1 3 8 Miyaura coupling However, in the same conditions, the NHC Pd analogue gave greater yield (79%). The author postulated the origin of this better activity mi ght be due to an improved stability and longer catalyst lifetime. Besides, coupling reactions were possible with phenyl chloride in the presence of these complexes while with the ADC Pd catalyst no desired product was observed Chiral Acyclic Diaminocarben e Ligands Unlike their NHC analogues, chiral source of chirality on the ir backbone s t have any. Therefore this source must be located on the substituent s of the nitrogen atoms However, because of this lack of ba ckbone, there is a free rotation allowed around the C carbene N bonds which prevent s a locked structure (Figure 1 3 9 ) Hence, the control of the enantioselectivity is more challen ging due to this new degree of freedom Fig ure 1 3 9 The free rotation around the C N bond allowed for ADC ligands Very few reports have been published about asymmetric catalysis with chiral ADC metal complexes.

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48 In 2011, Toste published the asymmetric gold cyclization of phenol substituted proparg yl pivalates 1 111 into chromene derivatives 1 113 61 He used BINAM based chiral ADC ligands, originally designed by Espinet, 57 to obtain the desired products in excel lent yields and excellent enantioselectivities (Figure 1 40 ) Figure 1 4 0 nantioselective gold catalyzed cyclization of 1 111 In 2012, Slaughter modified the structure of the previous ligand into a monometallic complex 1 115 and used it for the alkynylbenzaldeh yde cyclization (Figure 1 41 ) 62 He obtained the desired substituted isochromenes 1 116 in good yields and in excellent enantioselectivities. Figure 1 41 catalyzed cyclization of 1 114

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49 CHAPTER 2 DESIGN, SYNTHESIS, A ND APPLICATIONS OF CHIRAL N HETEROCYCLIC CARBENE METAL COMPLEXES Previous Designs of Chiral NHC Ligands In 2008, a new design of c hiral N HC ligands was reported by Hong. 63 The biisoquinoline based carbene contained its chirality to the nitrogen atom having an alkyl chain pointing towards the metal sphere Its preparation was only four steps awa y from a chiral amine 2 2 which was derivatized from the corresponding enantiopure amino acid 2 1 (Scheme 2 1) After bisamide 2 3 formation and Bischler Napieralski cyclization, the bisimine was subjected to another cyclization to form the imidazolium sa lt 2 4 Oxidative addition of the heterocycle with silver oxide followed by transmetallation gave the corresponding palladium(II) and copper(I) complexes Scheme 2 1. Preparation of NHC metal complexes This new ty pe of complexes have been tested for the a sym metric allylic alkylation with Grignard reagent s (Figure 2 1) The catalyst gave a good reactivity along a good regioselectivity ( vs. product) with a promising enantioselectivity.

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50 Figure 2 1. Copper NHC Cu complex A palladium complex X ray structure was obtained and showed the C 2 symmetry of the ligand thus blocking two quadrants of the metal coordination sphere. To further improve the enantio discrimination, a modification of the original ligand has been designed. Blocking three quadrants this time the C 1 symmetric monoisoquinoline based carbene was synthesized and reported in 2010 64 The chirality part still came from the same series of amines (which came from the enantiopure amino acids). However, instead of coupling it with oxalyl chloride to form the corresponding bisamide, it was treated with b enzoylformic acid to give an ketoam ide 2 9 (Scheme 2 2) Scheme 2 C 1 symmetric NHC ligands and their metal complexes

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51 After Bischler Napieralski cyclization and imine condensation, the new bisimine 2 11 was then cyclized. Transmeta llation as previously described was finally performed to obtain the C 1 symmetric NHC metal complex 2 12 For the imine formation, a bulky aniline derivative was used to block the two quadrants on the right side of the complex. Since th is condensation occur red at a late stage of the NHC synthesis, it was easy to tune the hindrance (as well as the electronic effects) the aromatic substituent could offer. An X ray structure for the gold complex showed indeed three quadrants being blocked by the chiral source a nd by the aniline derivative. Th ese C 1 symmetric ligands showed a good enantioselectivity in the borylation of acyclic unsaturated amides 2 13 ( Figure 2 2 ) Figure 2 2 Copper catalyzed C 1 symmetric NHC The source of chirality for both C 2 and C 1 symmetric ligands was from the amino ac ids. Therefore it was possible to obtain both enantiomers and to tun e the R substituent depending on the starting material used Also, since none of the transformations throughout the different syntheses epimerize d any intermediates, then the carbenes we re of high enantiopurity. However, the availability of the R substituent wa s dependent on the availability of the amino acids. Moreover, the synthesis called for

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52 the chiral source from the very first step. It was therefore difficult to extend the scope of th e ligand. The design had to be rethought so that more R substituents could be included in the scope with different electronic and steric effects. To see how to improve this feature, it was important to understand how the chiral free amine was prepared. Fir st, the amino acid 2 1 was reduced to the amino alcohol 2 16 (Scheme 2 3 ) The hydroxyl group was then activated for an intramolecular S N 2 reaction with the N Ts protected amine to form the corresponding azide 2 17 Next, the three membered ring was opened with phenylmagnesium bromide as the source of the benzene ring in the isoquinoline. Finally, the free amine 2 2 was obtained after N Ts cleavage in the presence of lithium. Scheme 2 3 Preparation of the chiral free ami ne 2 2 Overall the chiral amine, used for the preparation of C 1 and C 2 symmetric ligand s was derivatized from an amino acid and from phenylmagnesium bromide The natural starting material was the source of the chirality while the Grignard reagent was a building block for the isoquinoline moiety (Figure 2 3 ) Figure 2 3 Origin of the chiral isoquinoline moiety for C 1 and C 2 symmetric ligands

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53 Improvement of the Original Design Upon close r look at the chiral free amine, another similar preparation could also be suggested. Indeed, the structure of phenylalanine could be recognized with an R substituent at the position ( Figure 2 4 ) Therefore, the benzene ring for the isoquinoline c ould come from phenylalanine also responsible for the source of chirality. Besides, the R substituent c ould come from an organomet al l ic reagent. F igure 2 4 Retrosynthesis for the preparation of the chiral isoquinoline moiety With this new design, the sco pe would find a great extension Moreover, this preparation would still benefit from the original pathway that is to say allowing the access to bo th enantiomers and no possible epimerization of the chiral center. Last, the aziridine intermediate would be the common starting poi nt for all the different carbene precursors allowing the steric and electronic variations at the next stage (attack of the o rganometallic reagent). Therefore, it would only require two steps: ring opening and deprotection to obtain the free amine, common synthon for the C 1 and C 2 symmetric carbene syntheses. The original idea of an R scope was to increase its steric demand Th erefore the attention went to phenyl derivatives. However, a careful choice was important to make, keeping in mind that it had to be compatible with the subsequent steps to the aziridine formation For example, the Bischler Napieralski cyclization called f or a ring formation with the nitrogen atom and the ortho position of the benzyl group (Scheme 2 4 ) If the R

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54 group had such a carbon available then a competition w ould occur and would g i ve two different structural isomers. Scheme 2 4 Formation of structural isomers after Bischler Napieralski cyclization To avoid such an issue, ring B would have to be substituted on both ortho po sitions so that ring A only would cyclize with the amide moiety. One of the commercially avai lable Grignard reagents solving this problem was the 2,6 dimethylphenylmagnesium bromide. Hence, the two methyl groups would not only increase the hindrance but they would also block the ortho positions of ring B (Scheme 2 5 ) Scheme 2 5 New target for the chiral isoquinoline moiety The synthesis start ed with the reduction of L phenylalanine to L phenylalaninol 2 16a using standard conditions (Scheme 2 6 ) 65 Then, the aziridine 2 17a wa s formed with the same procedure as previously described. Next, the Grignard reagent was activat ed with an equivalent of copper (I) iodide to generate the corr esponding

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55 organocopper compound before addition of the aziridine. The free amine ent 2 2d was obtained by tosyl group removal with lithium. Scheme 2 6. Preparation of amine ent 2 2d Synthesis of the N ew C 1 Symmetric Carbene Ligand The free amine ent 2 2 d was first subjected to keto amide formation in the pre sence of benzoylformic acid (Scheme 2 7 ) Scheme 2 7 Formation of imidazolium ent 2 15dc

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56 After Bischler Napieralski cyclization, the imine ent 2 11 d c was then obtained by condensation of the carbonyl compound ent 2 10 d with mesidine. Finally, another cyclization with chloromethyl ethyl ether afforded imidazolium ent 2 15 d c as a carbene precursor. Applications of the New C 1 S ymmetric NHC L igand With this new ligand precursor in hand, it was interesting to test its potenti al activity and enantioselectivity. An interesting reaction to have a look at was the 1,2 addition reaction. Miyaura publish ed the first rhodium catalyzed 1,2 addition to carbonyl derivatives in 1998 (Figure 2 5) 66 He also reported the use of a chiral ligand (( S ) MeO MOP) designed by Hayashi, 67 for the asymmetric version. He obtained the diaryl alcohol in 41% ee and 78% yield. Figure 2 5 First rhodium catalyzed 1,2 addition From then, different research groups improved the selectivity with various ligands (phosphoramidites 68 spirophosphites, 69 bicy clic dienes, 70, 71 or other chiral phosphines 72 ) and metals ( zinc, 73 palladium, 74 or iron 75 ) While high enantioselectivities 2005, Bolm reported an encouraging result with one of his [2.2]paracycloph ane containing imidazoliums as NHC precursors (Figure 2 6) 76

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57 Figure 2 6 NHC rhodium catalyzed asymmetric 1,2 addition For several years, this result was considered as the milest one for the asymmetric 1,2 addition with carbene ligands until two reports were published independently in 2010. First, Ma obtained the diaryl alcohol in a rhodium catalyzed system with his C 2 symmetric imidazoliums as previously discussed (Figure 2 7) 35 Figure 2 7 addition The same year, Shi reported the use of bis(carbene) palladium complexes catalyzing the 1,2 addition in moderate to g ood yields and in slightly higher enantioselectivity (Figure 2 8 ). 77 Figure 2 8 Pd complexes in the asymmetric 1,2 addition

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58 Also, a nother study from Ding and Wu i n 2008 showed the 1,2 addition could also be catalyzed by a copper(II) source in the presence of electron rich or bidentate phosphines (PAr 3 BINAP, dppb, or dppf) (Figure 2 9) 78 There were several advantages for u sing copper as a catalyst over palladium Not only the price but also the functional group tolerance were of interest. Indeed, the brominated or formylated substrates were not suitable for the arylation with palladium catalysts. Figure 2 9 Copper catalyzed 1,2 addition Since there was still room for improvement in th e enantioselectivity and the fact that the reaction could be catalyzed by a copper source, it was very encouraging to test the newly synthesized ligands. Bef ore testing chiral ligands, it was important to know whether the reaction could take place in the presence of a carbene instead of a phosphine Using the same moderate yield w ith isolated IMesCuCl (Table 2 1, entry 1). A base (entries 2 5) and a solvent (entries 6 8) scopes were then performed to optimize the yield but unfortunately without any success. It seemed a mild organic base would suit better than an inorganic (entries 2 4) or a stronger (entry 5) base. The reaction might need high boiling point solvent to process as in THF no reaction was observed (entry 6). However, polar media such as DMF or nitroethane gave decomposition (entries 7 and 8).

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59 Table 2 1 Optimization of the reaction conditions Entry Solvent Base Yield (%) 1 toluene NaOAc 46 2 toluene KOH <7 3 toluene LiOH <5 4 toluene CsF 29 5 toluene KO t Bu 10 6 THF NaOAc No reaction 7 DMF NaOAc decomposition 8 EtNO 2 NaOAc deco mposition The oxidation state of the copper source was then screened. While carbene copper(I) complexes could be easily obtained either by oxidation in the presence of silver oxide and then transmetalation or by generation of the free carbene with a bas e and complexation on a metal the copper(II) analogues were more tedious to prepare It has been reported that NHC Cu(II) complexes we re more stable with at least one O chelating ligand (OAc, OAlkyl) than halides. 79 Besides their formations were not possible to monitor by 1 H NMR analyses as the y were paramagnetic species Moreover, they were not stable enough to be purified by column chromatography. However, the preparation of IPrCu(OAc) 2 has been reported v ia complexation of the free carbene on the copper(II) diacetate. 80 Therefore IMesCu(OAc) 2 was then prepared the same way and its activity was compared between isolated and in situ generated complexes. In both cases a base was required to generate the free carbene thus the base used was screened too (Table 2 2)

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60 Table 2 2. Base scope for the generation of the free carbene Entry Base In situ generated vs. Isolated copper complex Yie ld (%) 1 LiHMDS In situ generated 16 2 n BuLi In situ generated 61 3 KO t Bu In situ generated 34 4 LiHMDS Isolated 72 5 n BuLi Isolated 61 It was encouraging to see the yield of the 1,2 addition product improved by switching from copper(I) to copper( II). Besides, the isolated NHC Cu complexes (entries 4 and 5) gave better activities than their in situ generated analogues (entries 1 3) Although generating in situ the catalyst might be appealing (not having to isolate the metal complex), the main the d rawback was the lack of control of its formation. Indeed, the base used to deprotonate the imidazolium might not completely react with the carbene precursor. Even if it did, the complexation might not be quantitative. In both cases, an excess of copper ace tate could still catalyze the reaction (background reaction). However, it was challenging to handle and to monitor the isolation (hence purity) of the NHC copper(II) complex. It was not possible to know whether the catalyst used was the desired species or mixed with an excess of copper acetate. This issue had to be kept in mind for the asymmetric reaction as free copper could hinder the enantioselectivity of the chiral ligands. The base used for the preparation of the latter ones had an important effect in terms of activity. This was probably due to the presence of the by product generated along with the complex. For example, both LiHMDS and KO t

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61 protic while n BuLi gave up a simple gas as its conjugate acid. A proton source might hin der the catalytic activity of the copper complex Other optimizations have been performed such as reaction time (36 hours) or counter anion of the bis(mesityl)imidazolium salt (PF 6 and BF 4 ). None of these new conditions improved the yield of the diarylme thanol (61%, 46%, and 51%, respectively). A substrate scope study was then undertaken with different boronic acids (Table 2 3 entries 1 4 ) and p fluorobenzaldehyde (entry 5 ). Unfortunately, the conditions used were very substrate specific. For example, whe n more hindered boronic acids were employed, a drop of the reactivity was observed (entries 2 and 3). Also, a more electron rich boronic acid (entry 4) or another electron deficient aldehyde (entry 5) did not give better results. Table 2 3. Substrate scop e Entry Ar 1 Ar 2 Yield (%) 1 61 2 56 3 12 4 a 2 2 5 no reaction a isolated IMesCuCl was used as the catalyst

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62 Finally a chiral ligand scope could take place in order to assess their enantios e lectivities (Table 2 4). It was inte resting to observe that C 2 symmetric ligand offered the product in low yield and enantioselectivity in contrast with its C 1 analogue which gave better enantiomeric excess (entries 1 and 2). However, too much hindrance in the ligand was detrimental to both yield and ee (entry 3). Finally, an isolated complex gave better results as its in situ generated counterpart (entry 4). An ee of 38% was a bit lower than the one reported by Shi (45%), however, no other groups published data with the same substrates: p ni trobenzaldehyde and phenylboronic acid. Table 2 4 Chiral ligand scope Entry NHC precursor Yield (%) ee (%) 1 28 <5 2 34 27 3 38 <3 4 a 62 38 a Isolated [(NHC) Cu (OAc) 2 ] complex was used instead of in situ generated

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63 Another test reaction was the copper catalyzed boryla tion of conjugated amide. This C 1 symmetric isoquinoline based ligand showed good enantioselectivity in the past. 64 Unfortunately, the extra hindrance brought by the new type of ligand was not enough t o increase the ee and gave similar results as its original carbene precursor (Figure 2 10) Figure 2 10 Comparison of ligands ent 2 15dc and 2 15bc in the bor yl ation of 2 13a Design of a Ligand Containing a Lewis Base The improvement made on the design of the C 1 symmetric ligand could allow access to more than alkyl or aryl substituents. Indeed the aziridine opening could be carried out with nucleophiles other than organometallic reagents such as amines, or alcohols (F igure 2 11). Figure 2 11 New concept for the ring opening of the aziridine moiety

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64 The introduction of a nitrogen atom could improve the efficiency of the ligand in terms of enantioselectivity Indeed, the new pendant co uld act as a potential Lewis base like an arm bringing the substrate (such as boron species) close to the metal center in a specific angle (bifunctional catalyst) A simple way to introduce a nitrogen atom was with sodium azide (Scheme 2 8 ) From there, th e azido group could either be reduced into the corresponding amine or a fter click chemistry, functionalized into a triazole moiety The great advantage to use th e latter one would be the tolerance to the different conditions to complete the ligand synthesi s due to the aromaticity of the heterocycle. Therefore this pathway was explored first. Scheme 2 8 New target s for the chiral amine containing a potential Lewis base The previous synthesis of the free amine ent 2 2 d cal led for a N tosyl protection before activation of the alcohol moiety. However, its removal by lithium reduction would not be compatible with the azido pendant. Therefore another protecting group was needed which did not require reducing conditions for its cleaving. The Boc group would be a good candidate as acidic conditions would take care of its removal. Besides,

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65 instead of forming an aziridine ring to reopen it with sodium azide, the mesylated alcohol adduct could simply be isolated and then subjected to an S N 2 reaction. Preparation of azide 2 28 was performed according to known procedures. 81 83 The synthesis started with L phenylalaninol that was N Boc protected (Scheme 2 9 ) Scheme 2 9 Synthesis of free amine ent 2 2e T he mesylated alcohol 2 2 7 was treated with sodium azide to afford the desired product 2 28 2 29 azide was the refore treated with phenylacetylene in the presence of copper sulfate, sodium ascorbate, and the ligand ( S ) MonoPhos. 84 Only one regioisomer was observed as predicted. Finally, deprotection of the te rt butyloxycarbonyl group with trifluoroacetic acid gave free amine ent 2 2e T he C 1 symmetric ligand precursor could be synthesized using the same conditions as previously described (Scheme 2 1 0 ) The most basic nitrogen atom of the triazole moiety was N 3 as Foces Foces calculated the energy levels for protonated forms of 1 methyl 4 phenyl 1,2,3 triazole (Figure 2 1 2 ). 85 Therefore, the Lewis base would coordinate to an electron deficient atom (such as boron) with the N 3 nitrogen atom.

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66 Scheme 2 1 0 Synthesis of imidazolium ent 2 15ec Figure 2 1 2 Calculated energy levels of protonated 1 methyl 4 phenyl 1,2,3 triazole The ligand precursor w as test ed in the copper catalyzed bor yl ation of conjugated ester, ethyl cinnamate (Figure 2 1 3 ) 64 The efficiency of this imidazolium was then compared to the original design of the C 1 symmetric ligand. In addition to the moderate yield (65% ), the enantioselectivity was also lower than the other candidate (25% vs. 55%).

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67 Figure 2 1 3 Comparison of ligands ent 2 15ec and 2 15bc for the bor yl ation of 2 30 The lower enantioselectivity showed that the ligand i s less discriminati ng Maybe the arm aim ed away from the metal center giving a wider angle for the substrate to approach the complex. Since this type of ligand did n o t show encouraging results for the bor yl ation, another reaction using boron reagents ( bo ronic acid s) was therefore tested: 1,2 addition of phenylboronic acid on substituted benzaldehyde (Figure 2 1 4 ) This addition has been previously tested with the original C 1 symmetric ligand 2 15bc Surprisingly, the and the starting material was recovered. Figure 2 1 4 Comparison of ligands ent 2 15ec and 2 15bc for the 1,2 addi tion

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68 Maybe the triazole moiety was too strong of a Lewis base and completely inhibited the reaction by coo rdinating it to the phenylboronic acid. Once coordinated, the complex would be hindered and no other boronic acid or benzaldehyde derivative could approach the metal center. This could also explain why the borylation got also a lower yield with the same ligand. Since the reactions using boron reagents might not be suitable for this type of ligand, a different reaction was tested: the asymmetric allylic alkylation (AAA). This time, t he magnesium could coordinate to both the triazole and the substrate restr aining the approach of the Grignard reagent onto the olefin. The ligand showed some enantioselectivity ( 26 %) but not as much as a C 2 symmetric one that gave 73 % ee (Figure 2 1 5 ) However, th e branched/linear ratio was very high (19/1) and the reactivity wa s good (87% yield). The enantioselectivity might be only due to the hindrance brought by the substituted triazole. Besides, it was lower than the C 2 symmetric cyclohexyl ligand since there is one extra methylene group bringing the bulkiness further away fr om the metal center. Figure 2 1 5 Comparison of ligands ent 2 15ec and 2 5aa for the AAA To see how selective the ligand precursor could be, the reaction temperature was lowered to 78 C while the other conditions remain ed the same. The observed ee went

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69 up to 45% (8% yield) but it was still lower than complex 2 5aa could offer. Besides, the regioselectivity was heavily affected ( 2.8/1) Experimental Section General Remark s All the reactions were conducted in flame dr ied glassware under an inert atmosphere of dry argon. THF, CH 2 Cl 2 and Et 2 O were passed through two packed columns of neutral alumina under positive pressure prior to use. All the chemicals used were purchased from Sigma Aldrich Co., Acros Organics and Str em Chemicals Inc. and were used as received without further purification except for styrene, p nitrobenzaldehyde and phenylboronic acid. Flash column chromatography was performed on 230 400 Mesh 60 Silica Gel (Whatman Inc.) NMR spectra were recorded usi ng a FT NMR machine, operating at 500 MHz or 300 MHz for 1 H NMR and at 126 MHz or 75 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) 7.26 ppm and ( 13 C) 77.23 ppm. Infrared spectra wer e obtained on a Perkin Elmer Spectrum RX 1 at 0.5 cm 1 resolution and are reported in wave numbers. High resolution mass spectra were recorded on a MALDI TOF spectrometer, an APCI TOF spectrometer, a DART spectrometer, or an ESI TOF spectrometer. Optical r otations were recorded on a Perkin Elmer 241 polarimeter. Enantiomer excesses were determined by chiral HPLC analysis (Shimadzu) using Chiral Technologies Chiralcel OJ H, Chiralpak IA and IB columns and Regis Technologies Whelk 01 column. Synthesis of Imid azolium ent 2 15dc L phenylalaninol (2 16a) : To a flame dried 500 m L three neck round bottom flask w ere added sodium borohydride (5.50 g, 145.3 mmol), THF ( 160 mL) and L

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70 phenylalanine (10.0 g, 60.5 mmol).T he flask was cooled to 0 C and a solution of iodine (15.4 g, 60.5 mmol) in THF ( 50 mL ) was added dropwise over 30 min utes After addition of the iodine was complete and gas evolution had ceased, the flask was heated to reflux for 18 h and then cooled to room temperature, and methanol was added until the mi xture became clear. After stirring 30 min utes the solvent was removed under reduced pressure leaving a white paste which was dissolved in 20% aqueous KOH (150 mL) The solution was stirred for 4 h ours and extracted with methylene chloride (x 3) The organ ic extracts were dried over sodium sulfate a nd concentrated under reduced pressure. The crude product was recrystallized from toluene to give 7.45 g (81%) of a white solid 1 H NMR (300 MHz, CDCl 3 35 7 .14 (m, 5 H), 3.62 (dd, J = 3.8, 10.6 Hz, 1 H), 3 .39 (dd, J = 7.1, 10.8 Hz, 1 H), 3.11 (dddd, J = 3.8, 5.2, 7.2, 8.7 Hz, 1 H), 2.79 (dd, J = 5.2, 13.4 Hz, 1 H), 2.51 (dd, J = 8.6, 13.4 Hz, 1 H), 2. 38 0 .91 (br s, 3 H). 13 C NMR (75 MHz, CDCl 3 mp 89 .7 93.2 C (lit. 86 mp 89 90 C ) [ ] D 20 = 21.0 ( c 1.0, CHCl 3 ) (lit. 87 [ ] D 20 = 21. 7 ( c 1.0, CHCl 3 ) ) ( S ) 2 benzyl 1 tosylaziridine ( 2 17a ). To a flame dried Schlenk f lask, were added L phenylalaninol (0.50 g, 3.31 mmol) and triethylamine (1.84 mL, 13.23 mmol) in methylene chloride (4.2 mL). The solution was cooled to 30C and tosyl chloride (0.69 g, 3.64 mmol) was added portion wise. The reaction mixture was stirred f or 2.5 hours at 30 C and then overnight at room temperature. The solution was cooled back to 30C and m ethanesulfonyl chloride (0.27 mL, 3.51 mmol) was added dropwise. The flask was warmed to room temperature and stirred for 6 hours. The reaction was que nched with a 1 M h ydrochloric acid aqueous solution. The organic layer was washed with a sodium

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71 bicarbonate saturated aqueous solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by colum n chromatography (silica gel, hexanes/ethyl acetate: 85/15) to give 0.49 g (63%) of a white solid. 1 H NMR (300 MHz, CDCl 3 J = 8.2 Hz, 2 H), 7.24 7.19 (m, 2 H), 7.18 7.12 (m, 3 H), 7.09 7.00 (m, 2 H), 3.00 2.90 (m, 1 H), 2.86 2.76 (m, 1 H), 2.74 2.64 (m, 2 H), 2.43 (s, 3 H), 2.16 (d, J = 4.4 Hz, 1 H). 13 C NMR (75 MHz, CDCl 3 128.6, 128.1, 126.7, 41.4, 37.7, 33.0, 21.8. HRMS ( m / z ): [M + H] + calcd for C 16 H 17 NO 2 S 288.1053; found, 288.1045. mp 91.3 92.6C ( S ) N (1 (2,6 dimethylphenyl) 3 phenylpropan 2 yl) 4 methylbenzenesul fonamide ( 2 21d ). To a flame dried Schlenk flask, was added a 1 M tetrahydrofuran solution of 2,6 dimethylphenylmagnesium bromide (2.44 mL, 2.44 mmol) in THF (4.3 mL). The solution was cooled to 0C and copper(I) iodide (0.07 g, 0.39 mmol) was added. The reaction mixture was stirred for 30 minutes at that te mperature and then cooled to 78C. A solution of aziridine ( 2 17a ) (0.35 g, 1.22 mmol) in tetrahydrofuran (2.7 mL) was added. The mixture was stirred for 15 minutes and then for 3.5 hours at 0C. The reaction was quenched with an ammonium chloride saturat ed aqueous solution. The aqueous phase was extracted with diethyl ether and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexanes/ethyl acetate: 9/1 to 4/1) to give 0.44 g (92%) of a white solid. 1 H NMR (300 MHz, CDCl 3 7.17 (m, 5 H), 7.09 6.92 (m, 5 H), 6.88 6.82 (m, 2 H), 4.29 (d, J = 6.4 Hz, 1 H), 3.52 (td, J = 6.4, 8.5 Hz, 1 H), 2.98 2.86 (m, 2 H), 2.84 2.68 (m, 2 H), 2.36 (s, 3 H), 2.09 (s, 6 H). 13 C NMR (75 MHz, CDCl 3 142.9, 136.9, 136.6, 134.5,

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72 129.6, 129.4, 128.7, 128.7, 127.2, 127.2, 126.9, 126.6, 55.4, 47.0, 38.4, 21.7, 20.5 mp 118.8 120.4 C ( S ) 1 (2,6 dimethylphenyl) 3 phenylpropan 2 amine ( ent 2 2d ). To a flame dried Schlenk flask was added lithium(0) (0.11 g 15.4 mmol) and naphthalene (5.6 mg, 44x10 3 mmol) in tetrahydrofuran (4.7 mL). After 30 minutes of stirring at room temperature, the solution turned deep green and was then cooled to 78C. To t he reaction mixture was a dded a solution of sulfonamide 2 21d (0.43 g, 1.1 mmol) in THF (2 mL) dropwise. Next, the solution was slowly warmed to room temperature and stirred overnight. The reaction mixture was canula transferred to an Erlenmeyer flask in a n ice bath. The solution was quenched with water and the aqueous layer was extracted with diethylether (x 3). To purify the free amine, the organic phase was extracted with a 1M hydrochloride solution (x 3) and after neutralization of the aqueous layer wit h a saturated solution of NaHCO 3 the phase was back extracted with ether (x 3). The combined organic layers were dried over MgSO 4 filtered, and concentrated under reduced pressure to afford 0.24 g (92%) of a light yellow oil. 1 H NMR (300 MHz, CDCl 3 .35 7.16 (m, 6 H), 7.02 (s, 2 H), 3. 38 3 .23 (m, 1 H), 2. 87 2 .70 (m, 3 H), 2.63 (dd, J = 8.8, 13.3 Hz, 1 H), 2.33 (s, 6 H), 1.15 (br. s, 2 H). 13 C NMR (75 MHz, CDCl 3 137.2, 136.6, 129.4, 128.7, 128.6, 126.5, 126.2, 53.5, 44.8, 37.6, 20.8 HRMS (m/z): [M + H] + calcd for C 17 H 21 N, 240.1747; found, 240.1755. ( S ) N (1 (2,6 dimethylphenyl) 3 phenylpropan 2 yl) 2 oxo 2 phenylacetamide ( ent 2 9d). To a flame dried Schlenk flask, were added benzoylformic acid (0. 061 g, 0 4 1 mmol) and 1 h ydroxybenzo triazole hydrate (0. 0 5 5 g, 0 4 1 mmol) in methylene chloride ( 4 mL). The solution was stirred for 30 minutes at room temperature and amine

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73 ent 2 2 d (0. 098 g, 0 4 1 mmol), and 4 dimethylaminopyridine ( 5 mg, 0. 04 mmol) were added to the mixture. The flask was then cooled to 0 C and a solution of N N dicyclohexylcarbodiimide (0. 093 g, 0 45 mmol) in methylene chloride ( 3 mL) was added dropwise. The reaction mixture was stirred at 0 C for 1 hour and then at room temperature overnight. The solvent was evaporated a nd the white solid was suspended in ethyl acetate and filtered through a plug of Celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, hexanes/ethyl acetate: 85 / 15 ) to give 0.1 4 g ( 92 %) of a white s olid. 1 H NMR (300 MHz, CDCl 3 (d, J = 7.3 Hz, 2 H), 7. 59 7 .49 (m, 1 H), 7. 43 7 .15 (m, 7 H), 7. 05 6 .92 (m, 4 H), 4. 68 4 .45 (m, 1 H), 3. 04 2 .87 (m, 4 H), 2.32 (s, 6 H). 13 C NMR (75 MHz, CDCl 3 161.3, 137.9, 137.0, 134.9, 134.4, 133.3, 131.2, 129.3, 128.7, 128.6, 128 .5, 126.8, 126.6, 51.3, 41.1, 34.6, 20.6. HRMS (m/z): [M + H] + calcd for C 25 H 25 NO 2 372.1958; found, 372.1938. IR (cm 1 ): 3328, 3021, 1656, 1596, 1535, 1449, 1233. mp 125 .9 127.0 C ( S ) (3 (2,6 dimethylbenzyl) 3,4 dihydroisoquinolin 1 yl)(phenyl)methanone ( ent 2 10d). To a flame dried Schlenk flask, were added ketoamide ent 2 9 d ( 0.61 g, 1.63 mmol) and 4 dimethylaminopyridine ( 0.60 g, 4 9 mmol) in toluene ( 65 mL). The solution was cooled to 0 C and triflic anhydride ( 1 .4 mL, 8 2 mmol) was added dropwise. Th e reaction mixture was then heated to 90 C and stirred for 14 hours. The solution was cooled to room temperature and quenched with a sodium carbonate saturated aqueous solution. The aqueous phase was extracted with methylene chloride and the combined organ ic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column

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74 chromatography (silica gel, hexanes/ethyl acetate: 9 /1) to give 0 50 mg (8 7 %) of a yellow solid. 1 H NMR (300 MHz, CDCl 3 J = 1.2, 7.3 Hz, 2 H), 7. 62 7.54 (m, 1 H), 7.48 7.40 (m, 2 H), 7. 40 7 .32 (m, 2 H), 7. 26 7 .15 (m, 2 H), 7. 09 6 .99 (m, 3 H), 4. 12 3 .97 (m, 1 H), 3.30 (dd, J = 5.9, 13.8 Hz, 1 H), 3.02 (dd, J = 8.9, 13.9 Hz, 1 H), 2.82 (dd, J = 6.0, 15.8 Hz, 1 H), 2.73 (dd, J = 11.1, 15.8 Hz, 1 H), 2.32 (s, 6 H). 13 C NMR (75 MHz, CDCl 3 128.7, 128.5, 128.5, 127.4, 126.7, 126.4, 57.8, 35.1, 30.6, 20.8. HRMS (m/z): [M + H] + calcd for C 25 H 23 NO, 354 .1852; found, 354.1850. IR (cm 1 ): 3068, 3025, 2955, 2365, 2250, 1676, 1617, 1598, 1578, 1450, 1321, 1215. mp 103 .7 105.8 C ( S ) N ((3 (2,6 dimethylbenzyl) 3,4 dihydroisoquinolin 1 yl)(phenyl)methylene) 2,4,6 trimethylaniline ( ent 2 11dc). To a flame dried Schlenk flask, were added dihydroisoquinolin e ent 2 10 d ( 0.15 g, 0. 42 mmol), triethylamine ( 0.12 m L 0. 85 mmol), and 2,4,6 t rimethylaniline ( 0.30 m L 2 .1 2 mmol) in toluene ( 7 mL). To the solution was then added dropwise a 1M solution of titanium(IV) tetra chloride in toluene ( 0.51 m L 0. 51 mmol). The reaction mixture was stirred overnight at room temperature. The solution was quenched with an ammonium chloride saturated aqueous solution and the aqueous phase was extracted with methylene chloride. The combin ed organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexanes/ethyl acetate: from 99 / 1 to 97 / 3 ) to give 0 1 8 g ( 90% ) of a yellow oil 1 H NMR (300 MHz, CDCl 3 8.07 (d, J = 7.9 Hz, 2 H), 7.57 7.38 (m, 3 H), 7.23 7.14 (m, 1 H), 7.14 6.96 (m, 5 H), 6.92 (d, J = 7.3 Hz, 1 H), 6.82 6.64 (m, 1 H), 6.57 6.41 (m, 1 H), 3.80 3.62 (m, 1 H), 3.26 (d, J = 11.4 Hz, 1 H), 2.79 (dd, J = 11.0, 13.9 Hz, 1

PAGE 75

75 H), 2.42 1.99 (m, 1 5 H) 13 C NMR (75 MHz, CDCl 3 146.0, 137.2, 136.4, 132.1, 131.4, 130.9, 128.9, 128.5, 128.5, 128.1, 127.9, 126.5, 126.2, 66.0, 31.8, 30.5, 22.9, 20.8, 20.7 ( S ) 5 (2,6 dimethylbenzyl) 2 mesityl 1 phenyl 5,6 dihydro 2 H im idazo[5,1 a ]isoquinolin 4 ium chloride ( ent 2 15dc ). To a flame dried Schlenk flask, were added imine ent 2 11 d c ( 90 0 mg, 0.167 mmol) and chloromethyl ethyl ether ( 106 L, 1 15 mmol) in tetrahydrofuran ( 9 mL). The solution was stirred for a day at room te mperature. Any volatiles were evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate then methylene chlo ride/methanol: 9/1) to give 0.10 g ( quantitative yield ) of a white solid. 1 H NMR (300 MHz CDCl 3 8.95 8.80 (m, 1 H), 7.49 7.09 (m, 10 H), 7.07 6.92 (m, 2 H), 6.83 (s, 1 H), 6.71 (s, 1 H), 6.15 6.01 (m, 1 H), 4.01 (dd, J = 6.0, 16.0 Hz, 1 H), 3.25 3.10 (m, 2 H), 2.98 (dd, J = 5.3, 14.7 Hz, 1 H), 2.20 (s, 9 H), 1.92 (s, 3 H), 1.86 (s, 3 H) 13 C NMR (75 MHz, CDCl 3 141.1, 137.6, 136.4, 134.2, 132.7, 132.4, 130.9, 130.6, 130.5, 130.1, 129.9, 129.5, 129.3, 127.9, 127.5, 126.4, 125.7, 124.7, 54.0, 34.0, 32.9, 22.9, 20.4, 17.9. Synthesis of Imidazolium ent 2 15ec ( S ) tert butyl (1 hydroxy 3 phenylpropan 2 yl)carbamate (2 2 6 ) To a round bottom flask, were added L phenylalaninol (4 g, 26.45 mmol) in ethanol (52 mL) and di tert butyl dicarbonate (6.06 g, 27.77 mmol). The reaction was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure. The crude material was recrystallized in hexanes to afford 6.18 g (93%) of a white solid. 1 H NMR (300 MHz, CDCl 3 7.07 (m, 5 H), 4.71 (br. s., 1 H), 4.00 3.79 (m, 1 H),

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76 3.75 3.62 (m, 1 H), 3.60 3.49 (m, 1 H), 2.84 (d, J = 7.0 Hz, 1 H), 2.25 (br. s., 1 H), 1.42 (s, 9 H). 13 C NMR (75 MHz, CDCl 3 156.4, 138.0, 129.6, 128.7, 126.6, 79.9, 64.3, 53.9, 37.6, 2 8.5. HRMS ( m / z ): [M + Na] + calcd for C 14 H 21 NO 3 274.1414; found, 274.1423. ( S ) 2 (( tert butoxycarbonyl)amino) 3 phenylpropyl methanesulfonate (2 2 7 ) To a flame dried S chlenk flask was added alcohol 2 2 6 ( 4 .0 g, 15 .9 2 mmol) in methylene chloride ( 5 0 mL). T he solution was then cooled to 0 C and to the mixture were added triethylamine ( 2 4 4 mL, 17 51 mmol) and methanesulfonyl chloride ( 1 .3 0 mL 16 71 mmol) in methylene chloride (30 mL) dropwise. The solution was stirred for 1 hour at 0 C then overnight at room temperature. Next, 30 mL of water were added and the aqueous phase was extracted 3 times with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexanes/ethyl acetate: 1/1) to give 4.57 g (8 8 %) of a white solid. 1 H NMR (300 MHz, CDCl 3 7.12 (m, 5 H), 4.72 (br. s., 1 H), 4.32 4.19 (m, 1 H), 4.16 4.02 (m, 2 H), 3.02 (s, 3 H), 2.94 2.78 (m, 2 H), 1.42 (s, 9 H) 13 C NMR (75 MHz, CDCl 3 136.8, 129.4, 129.0, 127.2, 80.2, 70.0, 51.0, 37.5, 37.4, 28.5. HRMS ( m / z ): [M + Na] + calcd for C 15 H 23 NO 5 S, 352.1189; found, 352.1195. IR (cm 1 ): 3363, 2980, 1751, 1682, 1524, 1458, 1355, 1281, 1167, 1058, 984, 971, 841, 752, 703. ( S ) tert butyl (1 azido 3 phenylpropan 2 yl)carbamate (2 2 8 ) To a flame dried Schlenk flask, w ere added 2 2 7 ( 4 0 0 g, 1 2 14 mmol) and sodium azide (0.97 g, 15.0 mmol) in DMF (15 mL). The reaction mixture was heated to 6 0C and stirred at that temperature overnight. After the solut ion cooled to room temperature, water was added

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77 and the aqueous phase was extracted s ix times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, hexanes/ethyl acetate: 1/1) to afford 2.54 g ( 76%) of a white solid. 1 H NMR (300 MHz, CDCl 3 7.10 (m, 5 H), 4.64 (br. s., 1 H), 4.07 3.87 (m, 1 H), 3.42 (dd, J = 4.4, 12.3 Hz, 1 H), 3.31 (dd, J = 4.4, 12.3 Hz, 1 H), 2.88 (dd, J = 6.4, 13.2 Hz, 1 H), 2.78 (dd, J = 7.9, 13.5 Hz, 1 H), 1.43 (s, 9 H). 13 C NMR (75 MHz, CDCl 3 3, 129.5, 128.9, 127.0, 80.0, 53.3, 51.6, 38.4, 28.6. HRMS ( m / z ): [M + Na] + calcd for C 14 H 20 N 4 O 2 299.1478; found, 299.1489. IR (cm 1 ): 3338, 2977, 2374, 2102, 1686, 1509, 1459, 1364, 1251, 1168, 1053, 1026, 742, 701. [ D 20 11.9 ( c 1.01, CHCl 3 ) ( S ) tert butyl (1 phenyl 3 (4 phenyl 1 H 1,2,3 triazol 1 yl)propan 2 yl)carbamate (2 2 9 ) To a sample vial were added copper(II)sulfate pentahydrate ( 11 2 mg, 44 9 x 10 3 mmol) and sodium ascorbate ( 44 4 mg, 0.22 mmol) in distilled water ( 9.6 mL). To th e sample vial was added ( S ) MonoPhos ( 18 0 mg, 50 0 x 10 3 mmol) in dimethylsulfoxide ( 3 2 mL). The resulting solution was vigorously stirred for 15 minutes. The solution was then added to a round bottom flask containing a solution of azide 2 2 8 ( 1.24 g, 4 49 mmol) and phenylacetylene ( 1 0 mL, 8 98 mmol) in a DMSO/H 2 O mixture ( 24 mL DMSO/H 2 O: 1/3). The reaction mixture was vigorously stirred at room temperature for 20 hours and diluted with 60 mL of water. The aqueous phase was extracted with methylene chlo ride and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was recrystallized in ethanol with some drops of water to give 1 55 g ( 91 %) of a white solid. 1 H NMR (300 MHz, CDCl 3 J = 7.0 Hz, 2 H), 7.74 (s, 1 H), 7.49 7.40

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78 (m, 2 H), 7.39 7.31 (m, 3 H), 7.30 7.22 (m, 3 H), 4.83 (br. s., 1 H), 4.54 (d, J = 5.0 Hz, 2 H), 4.36 4.21 (m, 1 H), 3.01 2.76 (m, 2 H), 1.39 (s, 9 H). 13 C NMR (75 MHz, CDCl 3 130.7, 129.5, 129.1, 129.0, 128.4, 127.2, 125.9, 121.0, 80.2, 69.9, 52.2, 38.2, 28.5. HRMS ( m / z ): [M + Na] + calcd for C 22 H 26 N 4 O 2 401.1948; found, 401.1959. IR (cm 1 ): 3370, 2978, 2375, 1686, 1509, 1250, 1170, 1057, 764, 697. D 20 0.9 ( c 1, CHCl 3 ) ( S ) 1 phenyl 3 (4 phenyl 1 H 1,2,3 triazol 1 yl)propan 2 amine ( ent 2 2e) To a flame dried Schlenk flask, was added triazole 2 26 (1.02 g, 2.69 mmol) in a 1:1 mixture of methylene chloride and trifluoroacetic acid (26 mL). The reaction mixture was stirred for 2 hours at room temperature and the volatiles were evaporated under reduced pressure. To the crude product was added a 1M aqueous sodium hydroxide solution in methylene chloride and stirred for 15 minutes. The aqueous phase was extracted with methylene ch loride and the combined organic layers were dried over sodium sulfate, further purification (0.75 g, quantitative yield). 1 H NMR (300 MHz, CDCl 3 7.78 (m, 3 H), 7.4 9 7.39 (m, 2 H), 7.38 7.30 (m, 3 H), 7.30 7.20 (m, 3 H), 4.49 (dd, J = 4.1, 13.5 Hz, 1 H), 4.26 (dd, J = 7.9, 13.8 Hz, 1 H), 3.63 (ddt, J = 4.1, 5.4, 8.2 Hz, 1 H), 2.89 (dd, J = 5.3, 13.5 Hz, 1 H), 2.64 (dd, J = 8.2, 13.5 Hz, 1 H), 1.32 (br. s., 2 H). 13 C NMR (75 MHz, CDCl 3 137.7, 130.8, 129.5, 129.1, 129.0, 128.4, 127.1, 125.9, 120.9, 100.0, 56.7, 53.1, 41.8. HRMS ( m / z ): [M + Na] + calcd for C 17 H 18 N 4 301.1424; found, 301.1432. IR (cm 1 ): 3358, 3304, 3091, 3034, 2926, 2346, 1750, 1610, 1467, 1442, 1226, 1084, 1054, 975, 830, 767,749, 697. D 20 12.3 ( c 1.0, CHCl 3 ).

PAGE 79

79 ( S ) 2 oxo 2 phenyl N (1 phenyl 3 (4 phenyl 1 H 1,2,3 triazol 1 yl)propan 2 yl)acetamide ( ent 2 9e) To a flame dried Schlenk flask, were added benzoylformic acid (0.17 g, 1.11 mmol) and 1 h ydroxybenzotriazole hydrate (0.15 g, 1.11 mmol) in methylene chloride (7 mL). The solution was stirred for 30 minutes at room temperature and amine ent 2 2e (0.31 g, 1.11 mmol), and 4 dimethylaminopyridine (14 mg, 0.11 mmol) were added to the mixture. The flask was then cool ed to 0 C and a solution of N N dicyclohexylcarbodiimide (0.25 g, 1.22 mmol) in methylene chloride (5 mL) was added dropwise. The reaction mixture was stirred at 0 C for 1 hour and then at room temperature overnight. The solvent was evaporated and the white solid was suspended in ethyl acetate and filtered through a plug of Celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, hexanes/ethyl acetate: 3/2) to give 0.12 g (58%) of a white solid. 1 H NMR (300 MHz, CDCl 3 (dd, J = 1.3, 8.4 Hz, 2 H), 7.84 7.77 (m, 4 H), 7.60 (tt, J = 1.3, 7.4 Hz, 1 H), 7.46 7.40 (m, 5 H), 7.38 7.32 (m, 2 H), 7.31 7.27 (m, 2 H), 5.24 (br. s, 1 H), 4.79 4.69 (m, 1 H), 4.65 (dd, J = 4.9, 14.1 Hz, 1 H), 4.58 (dd, J = 6.2, 14.1 Hz, 1 H), 3.01 (dd, J = 7.1, 14.0 Hz, 1 H), 2.96 (dd, J = 7.3, 14.1 Hz, 1 H). 13 C NMR (75 MHz, CDCl 3 187.3, 162.1, 148.2, 136.1, 134.8, 133.1, 131.3, 130.5, 129.5, 129.2, 129.1, 128.8, 128.5, 127.6, 126.0, 120.9, 51.1, 49.4, 37.8. HRMS ( m / z ): [M + Na] + calcd for C 25 H 22 N 4 O 2 433.1635; found, 433.1642. ( S ) phenyl(3 ((4 phenyl 1 H 1,2,3 triazol 1 yl)met hyl) 3,4 dihydroisoquinolin 1 yl)methanone ( ent 2 10e) To a flame dried Schle nk flask, were added ketoamide ent 2 9e (84 mg, 0.204 mmol) and 4 dimethylaminopyridine (75 mg, 0.613 mmol) in toluene (8 mL). The solution was cooled to 0 C and triflic anhydrid e (0.34 mL, 2.04 mmol) was

PAGE 80

80 added dropwise. The reaction mixture was then heated to 90 C and stirred for 14 hours. The solution was cooled to room temperature and quenched with a sodium carbonate saturated aqueous solution. The aqueous phase was extracted w ith methylene chloride and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexanes/ethyl acetate: 1/1) to give 68.4 mg (85%) of a beige solid. 1 H NMR (300 MHz, CDCl 3 7.95 7.82 (m, 3 H), 7.81 7.69 (m, 2 H), 7.59 7.49 (m, 2 H), 7.46 7.29 (m, 1 0 H), 4.9 3 ( dd J = 4.8 13.7 Hz, 1 H), 4.8 3 ( d J = 5.6 13.7 Hz, 1 H), 4.25 4.06 (m, 1 H), 2.95 ( dd J = 5. 6, 16.4 Hz, 1 H), 2.81 2.63 (m 1 H) ( S E ) 2,4,6 trim ethyl N (phenyl(3 ((4 phenyl 1 H 1,2,3 triazol 1 yl)methyl) 3,4 dihydroisoquinolin 1 yl)methylene)aniline ( ent 2 11ec ) To a flame dried Schlenk flask, were added dihydroisoquinolin e ent 2 10e (68 mg, 0.174 mmol), triethylamine (4 9 0.349 mmol), and 2,4, 6 t rimethylaniline (122 0.871 mmol) in toluene (3 mL). To the solution was then added dropwise a 1M solution of titanium(IV) tetrachloride in toluene (209 0.209 mmol). The reaction mixture was stirred overnight at room temperature. The solution was quenched with an ammonium chloride saturated aqueous solution and the aqueous phase was extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexanes/ethyl acetate: from 1/0 to 3/1) to give 88.8 mg (quantitative yield) of a yellow solid. ( S ) 2 mesityl 1 phenyl 5 ((4 phenyl 1 H 1,2,3 triazol 1 yl)methyl) 5,6 dihydro 2 H imidazo[5,1 a ]isoquinolin 4 iu m chloride ( ent 2 15ec) To a flame dried S chlenk

PAGE 81

81 flask, were added imine ent 2 11ec (84.6 mg, 0.167 mmol) and chloromethyl ethyl ether (92 L, 0.996 mmol) in tetrahydrofuran (8 mL). The solution was stirred for a day at room temperature. Any volatiles wer e evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate then methylene chloride/methanol: 9/1) to give 70.8 mg (76%) of a beige solid. 1 H NMR (300 MHz, CDCl 3 7.85 (d, J = 7.3 Hz, 2 H), 7.48 7.42 (m, 2 H), 7.40 7.33 (m, 4 H), 7.30 (d, J = 7.1 Hz, 2 H), 7.23 (d, J = 7.4 Hz, 2 H), 7.15 7.08 (m, 2 H), 6.90 (s, 1 H), 6.72 (s, 1 H), 6.38 (br. s., 1 H), 4.93 (dd, J = 7.3, 13.7 Hz, 1 H), 4.88 (dd, J = 5.1, 13.7 Hz, 1 H), 3.76 (dd, J = 4.3, 16.7 Hz, 1 H), 3.33 (d, J = 16.6 Hz, 1 H), 2.22 (s, 3 H), 2.13 (s, 3 H), 1.82 (s, 3 H). 13 C NMR (75 MHz, CDCl 3 148.7, 141.3, 136.5, 135.2, 134.8, 131.1, 131.0, 130.5, 130.4, 130.1, 130.0, 129.9, 129.8, 129.8, 129.5, 128.9, 128.9, 128.3, 128.2, 126.4, 126.1, 125.2, 125.0, 122.5, 122.4, 54.2, 51.3, 30.8, 21.2, 18.1, 18.0. HRMS ( m / z ): [M] + calcd for C 35 H 32 N 5 52 2.2652; found, 522.2664. IR (cm 1 ): 3422, 2957, 2237, 1610, 1542, 1476, 1438, 1364, 1341, 1217, 1078, 1042, 912, 856, 769, 731, 697. Borylation Reaction of Conjugated Ester 2 30 or Conjugated Amide 2 13a Typical procedure To a flame dried Schlenk flask w as added copper(I) bromide dimethylsulfide complex (3 mol%), NHC ligand precursor (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) w as added followed by amide (0.162 mmol) and methanol (0.324 mmol). Then the reaction mixture was stirred at 40C for 6 h. NaBO 3 2 O) 4 (0.810 mmol) and water (0.16 M) were added and the reaction mixture

PAGE 82

82 was stirred an additional 3 h at room temperature. Th e suspension was then extracted with Et 2 O (3 x 10 mL), dried over MgSO 4 and concentrated under reduced pressure Silicagel column chromatography with a mixture of hexane and ethyl acetate as the 1 H NMR (300 MHz, CDCl 3 : 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) 13 C NMR (75 MHz, CDCl 3 172.6, 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 ( m / z ): [M + H ] + calcd for C 25 H 27 NO 4 406.2013; found, 406.2011 HPLC spectra for amide 2 14a The enantiomeric e xcess was measured b y chiral HPLC with a Whelk 01 column (UV 215 nm, 30% isopropanol/hexane, 1.5 mL/min). a) b ) c) Figure 2 16. HPLC spectra for the borylation of amide 2 14a a) racemic mixture b) w ith ent 2 15dc and c) w ith 2 15bc

PAGE 83

83 HPLC spectra for ester 2 31 a ) b) c) Figure 2 17. HPLC spectra for the borylation of e ster 2 3 1 a a) racemic mixture, b) w ith ent 2 15ec and c) w ith 2 15bc 1,2 Addition Reaction Typical procedure In a flame dried Schlenk flask, were added IMes HCl (8.2 mg, 0.024 mmol), copper(II) diacetate (3.6 mg, 0.02 mmol) and toluene (3 mL). The mixture was cooled to 78 C and a solution of n BuLi (15 L, 1.6M in hexane) was slowly added. After 30 minutes of stirring at room temperature, p nitrobenzaldehyde (30 mg, 0.2 mmol), phenylboronic acid (48.8 mg, 0.4 mmol), and sodium acetate (49.2 mg, 0.6 mmol) were added (in the case of an isolated copper complex, the latter and toluene were added with the other reagents). The solution was stirred for 24 hours at reflux temperature. Then the flask was cooled to room temperature and water was added to the black mixture. The aqueous phase was extracted with methylene chloride (x 3) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated

PAGE 84

84 under reduce pressure. The crude material was purified by column chromatography (Silica gel, hexanes/ethyl acetate: 90/10) to afford the desired product ( 27.5 mg, 60%) as a white solid. Characterization of 1,2 addition products (Table 2 3) (4 nitrophenyl)(phenyl)methanol 1 H NMR (300 MHz, CDCl 3 : 8.16 (d, J = 8.8 Hz, 2 H), 7.56 (d, J = 8.2 Hz, 2 H), 7.41 7.29 (m, 5 H), 5.89 (s, 1 H), 2.60 (br. s., 1 H) Naphthalen 1 yl(4 nitrophenyl)methanol 1 H NMR (300 MHz, CDCl 3 : 8.16 (d, J = 8.8 Hz, 2 H), 8.07 7.96 (m, 1 H), 7.93 7.79 (m, 2 H), 7. 59 (dd, J = 0.8, 9.1 Hz, 2 H), 7.53 7.43 (m, 4 H), 6.56 (s, 1 H), 2.65 (br. s, 1 H) Mesityl(4 nitrophenyl)methanol 1 H NMR (300 MHz, CDCl 3 : 8.15 (d, J = 9.1 Hz, 2 H), 7.47 (dd, J = 1.1, 9.1 Hz, 2 H), 6.88 (s, 2 H), 6.39 6.32 ( s 1 H), 2.29 (s, 3 H ), 2.28 (br. s., 1 H), 2.22 (s, 6 H) (4 methoxyphenyl)(4 nitrophenyl)methanol 1 H NMR (300 MHz, CDCl 3 : 7.41 7.36 (m, 2 H), 7.36 7.30 (m, 2 H), 7.30 7.19 (m, 3 H), 7.06 6.91 (m, 1 H), 6.89 (d, J = 8.2 Hz, 1 H), 6.06 (s 1 H ), 3.81 (s, 3 H), 3.0 9 3.03 (br. s. 1 H) HPLC spectra for the ligand scope (Table 2 4) The enantiomeric excess was determined by HPLC analysis with a chiral column (Chiralcel IA; hexanes/2 propanol, 9:1; flow rate 1mL/min; t R 11.7 and 13.6 min). Figure 2 18. HPLC spectra of the 1,2 addition product (racemic mixture)

PAGE 85

85 Figure 2 19. HPLC spectra of the 1,2 addition product (Table 1, entry 1) Figure 2 2 0 HPLC spectra of the 1,2 addition product (Table 1, entry 2 ) Figure 2 2 0 HPLC spectra of the 1,2 addition product (Table 1, entry 3 )

PAGE 86

86 Figure 2 2 1 HPLC spectra of the 1,2 addition product (Table 1, entry 4) Asymmetric Allylic Alkylation Typical procedure To a flame dried Schlenk flask were added C uTC (3 mol%), chloroamidinium salt ent 2 15ec (3 mol%) and 1 mL of diethyl ether. To this solution was added an ethylmagnesium chloride solution (0.27 mmol, 2M in Et 2 O) at 0C. The mixture reaction was stirred for 5 min at 0C. In the case of catalyst 2 5a a the complex was added just before the Grignard reagent. Then a solution of substrate 2 3 2 (0. 18 mmol) in 1 mL of Et 2 O was added over a 15 min period. After 1 hour, 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 chrom atography to give the alkylated products 2 33 and 2 34 NMR spectra for the regioselectivity T he regioselectivity (S N 2': S N 2) was determined by 1 H NMR. The integration values of the olefinic proton signal of the two regioisomers were compared.

PAGE 87

87 Figure 2 2 2 NMR spectra of the product of the AAA with ent 2 15ec a) at 0 C and b) at 78 C HPLC spectra for the ligand scope Enatiomeric excess was measured by chiral HPLC with a Whelk O1 column (UV 254 nm, 100% pentane, 0.2 mL/min). t S : 25.5 min, t R : 26.9 min. Figure 2 2 3 HPLC spectra of product 2 33 ( racemic mixture ) a ) b )

PAGE 88

88 Figure 2 2 4 HPLC spectra of product 2 33 w ith ent 2 15ec Figure 2 2 5 HPLC spectra of product 2 33 w ith w ith ent 2 5 a a Figure 2 2 6 HPLC spectra of product 2 33 with ent 2 15ec at 78 C

PAGE 89

89 CHAPTER 3 DESIGN, SYNTHESIS, AND APPLICATIONS OF CHIRAL AND ACHIRAL A CYCLIC DIAMINO CARBENE METAL COMPLEXES Achiral Acyclic Diaminocarbene Metal Complexes ADC Copper C atalyzed Allylic Alkylation 88 as their cyclic analog ue s, they had the advantage to be better don or s and more sterically demanding due to a wider N C N angle 42, 48 However, the free ligands were less stable than the NHC ones making their preparation more challenging. It had been observed that asymmetric allylic alkylation (AAA) of protected diol 3 1 a could be cata lyzed by a mixture of a chloroimidazolium and a copper(I) source (Figure 3 1 ) Although it gave lower yield than its isolated complex, it still afforded a similar branched:linear product ratio and above all, it gave the same enantioselectivity. Figure 3 1 Catalytic activity of 3 2 in asymmetric allylic alkylation This example showed the generation of a carbene copper complex having similar behavior as its isolated counterpart. This new in situ generation might be interes ting to explore with the acyclic version, known to be more challenging to isolate. Indeed,

PAGE 90

90 s ubstituting chloroimidazolium 3 2 by commercially available chloroamidinium 3 6 gave better reactivity in the same conditions (Table 3 1 entry 1). This promising r esult led to optimizing the reaction conditions starting with the copper source. T he oxidation state of as similar results with either CuCl or CuTC were observed (entries 1 3). CuTC (copper th iophene 2 carboxylate) being easier to handle than CuCl (air and moisture more stable and molecular weight nearly twice more important) was chosen as the copper source for further scopes. Table 3 1 Optimization of conditions for the copper catalyzed all ylic alkylation Entry Carbene precursor Copper salt Yield (%) Branched : linear 1 CuCl 2 82 93 : 7 2 CuCl 81 93 : 7 3 CuTC 83 94 : 6 4 CuTC 71 90 : 10 5 IMes CuTC 57 92 : 8 6 3 6 25 94 : 6 7 CuTC 9 13 : 87 Then, it was interesting to investigate the carbene source. For example, when corresponding prepared free carbene was used in the presence of CuTC, the results were similar (entry 4). Howe ver, if a more sterically demanding cyclic free carbene (IMes) was used, then the reactivity dropped but still with the same branched/linear ratio (entry 5). Finally, the background reaction was also studied. While the absence of copper source gave lower r eactivity, the magnesium could still catalyze the reaction giving

PAGE 91

91 same ratio in the products (entry 6). 89 However, if the carbene source was removed then linear product 3 5a was the major one but in low yield (entry 7) 90 Other substrates have also been tested in the allylic alkylation giving good branched/linear ratios (Table 3 2 ). Table 3 2 Substrate scope for ADC copper catalyzed allylic alkylation Entry Substrate 3 1b f Yield (%) Branched : linear 1 84 9 8 : 2 2 97 98 : 2 3 95 98 : 2 4 96 98 : 2 5 93 (with 15 mol% of 3 6 ) 98 : 2 Generation of products c ontaining a quaternary center was obtained in good yields with this methodology (entries 3 5). The E / Z geometry of the olefin did not interfere with the outcome of the product ratio or with the reactivity (entries 2 4). Protected piperidine 3 1f required h igher catalyst loading, probably due to the nitrogen atom that could coordinate to the copper complex. 13 C NMR experi ments allowed for the evidence of the generation of an ADC copper complex with 13 C labeled chloroamidinium 3 8 (Scheme 3 1) When the salt was first mixed with phenylmagnesium bromide, a new downfield signal ( = 216 ppm) was observed. It then shifted slightly upfield ( = 206 ppm) once copper(I) chloride was

PAGE 92

92 added to the mixture. The first signal could be attributed to the carbene magnesium complex 3 9 while the second one could stand for the ADC copper complex 3 10 91, 92 Similar observations could be done by substituting chloroamidinium 3 8 by the corresponding fo rmamidinium 3 11 After generation of the free carbene in the presence of LDA, 42 the ligand was treated with PhMgBr ( = 213 ppm). Then copper(I) chloride was added to the mixture and the signal shifted upfield as previously observed ( = 207 ppm). Th ese experiment s confirmed the formation of a carbene that could complex on copper. Sche me 3 1 Evidence of the formation of the ADC copper complex a) from chloroamidinium 3 8 and b) from formamidinium 3 11 proposed (Scheme 3 2 ). A plausible scenario would be the gener ation of a homocuprate (R 2 CuMg Br ) formed from two equivalents of the Grignard reagent and the copper source. 93 It would then undergo oxidative addition in the presence of the chloroamidinium salt to give a coppe r(III) adduct. After reductive elimination, it would then form the ADC organocopper(I) complex. Another mechanism would be first the formation of a carbene magnesium complex ( after magnesium halide exchange from

PAGE 93

93 the Grignard reagent ) followed by transmeta lation with the copper salt. 94, 95 Finally, the same ADC organocopper(I) complex would be obtained after halide displacement with a second equivalent of the Grignard reagent. Scheme 3 2 Possible mechanisms for the formation of the ADC organocopper(I) ADC Iridium C omplex Design and synthesis of an ADC iridium complex The main drawback of the ADC ligands over their cyclic analogues wa s their degree of free dom due to the free C carbene N rotation. Indeed, as seen previously they c ould adopt different conformers 55, 96 It could be suggested that the same complex might have different acitivitie s depending on the conformer used. To avoid this issue, a new design was conceived where two substituents, one on each nitrogen atom, would have some affinity to each other. Thus, the ligand would become more rigid and would slow down any rotations. An aff inity stacking interact i on between two aromatic rings would be a good choice since the N C N bond angle of an ADC ligand is approximately 120 42 making the two facing each other. However, the other two

PAGE 94

94 subst ituents of the nitrogen atoms would have to be sterically demanding enough to avoid formations of undesired conform ers of the complex (Figure 3 2) Figure 3 2 Possible conformers of the new acyclic diamino carbene ligand From previous attempts of making this type of ADC metal complexes it had been noticed that if the bulky group contained a terti ary center alpha to the nitrogen, then the isop ropyl and cyclohexyl substituents as sterically demanding groups have been explored. As for the aromatic moiety, the simple phenyl group was first taken into account and would later be modified. The synthesis start ed with a Buchwald Hartwig coupling betwee n alk ylamine 3 17 and bromobenzene. The aniline derivative 3 18 w as then divided in two batches. The first one was converted into the corresponding formamidine 3 20 in the presence of DMF. The second batch was silylated in order to favor the formation of t he formamidinium ( 3 21 ) The condensation indeed occurred to afford the chloride salt Finally, the free carbene was generated in situ with lithium hexamethyldisilazane and then complexed on iridium to afford the desired product 3 22

PAGE 95

95 Scheme 3 3 Synthesis of ADC iridium complex Surprisingly, the cyclohexyl substituted iridium complex 3 22 b Decomposition of the formamidinium into the amine precursor was observed instead. A simple way to see if the fre e carbene was formed wa s to treat the salt with sulfur after deprotonation which did not take into account the hindrance of the metal The resulting product would be the corresponding thiourea (Figure 3 3) 97 Once again, the latter instead It could be suggested that once formed, back. Figure 3 3 Thiourea f ormation: trapping method of carbene intermediate

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96 An X ray structure of complex 3 23 a was obtained and a s expected, the conformation was syn (phenyl groups away from the metal) (Figure 3 4) The N C N bond angle was 116.44 wide and the C carbene Ir bond wa s 2.044 long However, the two phenyl groups did not face to each other but instead they would be slightly displaced (the planes orthogonal to each ring form ed an angle of 46.3) T his feature (parallel displaced geometry) was very common in 98 100 The measured centroid centroid distance was 3.607 and the angle formed between two vectors one normal to one of the rings and the oth er one passing through the two centroids was 29.02. These data were complexes with aromatic nitrogen containg ligands. 100 He calculated these same data for more than 4,800 structures and he observed a maximum peak in the distribution at 3.8 and 27. The values found for complex 3 23a s ones and could therefore suggest a possible stacking with a parallel displaced geometry Figure 3 4 X ray structure s of complex 3 23 a The only other X ray structure of an ADC iridium complex was obtained by Bielawski in 2010 (Figure 3 5). 55 The conformation of his ligand was also syn : the two

PAGE 97

97 mesityl groups being away from the metal center. However, the C carbene Ir bond was longer than the one of 3 23a (2.061(4) ) suggesting a possible weaker bond. Also the N C N bond angle wa s wider (1 18.9(4) ), this could be du e to less or more hindrance between the two mesityl groups. Figure 3 5. X iridium complex With the isopropyl substituted metal complex in hands, iridium catalyzed reactions coul d be tested. Hydroboration of alkenes Hydroboration of alkenes with dioxaborinane derivatives have first been reported by Woods in 1966 with TMDB (4,4,6 trimethyl 1,3,2 dioxaborinane) 101 He performed the hydrob oration on 1 octene and he obtained the terminal product as the sole regioisomer in 28% yield (Scheme 3 4 a) ). Brown also hydroborated mono and disubstituted alkene s (terminal or not) with catecholborane in better yields (Scheme 3 4 b) ). 102

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98 Scheme 3 4 Hydroboration of alkenes by a) Wo o ds and b) Brown For both examples high temperatures were required (100C) and the terminal products were obtained due to the sterics of th e boration reagent s and to the electronic effect of the alkene. In order to use milder conditions, the reaction could be catalyzed by transition metals oxidative addition with catecholborane, by isolating the resulting product (Figure 3 6 ). 103 Figure 3 6 The n in 1985, Nth first report ed the hydroboration of 1 octene with catecholborane. 104 The desired product was obtained in 78% yield, in only 25 min, and at room temperature (Figure 3 7 ) Besides, keto ne and nitrile functional groups were tolerated through the process. Figure 3 7 First rhodium catalyzed hydroboration

PAGE 99

99 While the regioselectivity might be identical whether a metal was used or not, the mechanism did n o t remain the s ame. Indeed, Nth porposed a mechanism that had later been confirmed by Evans with extra study (Figure 3 8 ). 104, 105 After oxidative borane, the olefin would b i nd to the metal. Then followed a hydride migration from rhodium to the alkene. Finally, reductive elimination gave the hydroborated product with regeneration of the catalyst. Figure 3 8 Mechan ism of rhodium catalyzed hydroboration of terminal olefins Evans went more in depth about the mechanistic study and proved by isotope labeling that it wa s indeed a hydride (and not a boron) migration. He also concluded that the reductive e l imination could n o t occur from a secondary alkyl group but only from a primary one. Hence, the terminal olefin was always functionalized at the primary carbon. Besides, he also studied the hydroboration of styr ene In this particular case, the regioselectivity wa s inverte d that is to say, the secondary carbon was bound to the

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100 boron. This was explained by the migration of the hydride exclusively at the primary carbon, thus generating a benzylic alkyl rhodium complex. The regioselectivity outcome of the hydroboration of sty rene was also dependent on the boron reagent employed Indeed, when Miyaura used more sterically demanding pinacolborane, he obtained a 1 / 0.5 mixture of the linear/branched products in the 106 When he catalyzed the same reaction with [Ir(cod)Cl] 2 in the presence of a bidentate phosphine (dppm, dppe, or dppb) or with some cationic iridium complexes, he exclusively obtained the linear product. It was then interesting to compare t he behavior of the newly made iridium complex 3 23 a Unfortunately, d espite the low reactivity of the catalyst, the regioselectivity was ear/branched ratio of 1/0.56 (Figure 3 9 ). When compared with other NH C and ADC iridium complexes, IMes Ir (cod)Cl w as the most regioselective ( linear product only ) Besides, electronic effects of the carbene ligand had an impact on the product distribution as they gave different results Figure 3 9 Iridium catalyzed hydroboration of styrene

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101 Chiral Acyclic Diaminocarbene Precursors The use of chiral acyclic diaminocarbenes as ligands in the asymmetric catalysis explored Indeed, while the ADC s we re thought to be more donor towards the metal than the N HC ana logues they still remained less rigid T he free rotation around the C carbene N bond allow ed more degrees of freedom which could cause a decrease in the efficiency towards the stereo selectivity of the corresponding ligand. Original Design of a Chiral Acyclic Diaminocarbene The original thought was to form an ADC ligand containing a C 2 sy m metric disubstituted pyr r olidine (Figure 3 10 ) Hence, the rotation around the C carbene N bond would n o t have any effect since the re w ou l d always be a chiral center (with the same absolute configuration) pointing towards th e metal center. Such a geometry would block two quadrants diametrically opposed, hence giving a C 2 symmetry to the ligand. Figur e 3 10 Original design of a chiral ADC ligand The ADC metal complex would either be generated 1) from deprotonation of the formamidinium 3 25 and complexation of the newly formed carbene on the metal or 2) from metal halide exchange of the chloroamidiniu m 3 26 (Figure 3 1 1 ) Both salts would be obtained from the chiral 2,5 disubstituted pyrrolidine 3 27 Figure 3 1 1 Preparation of the chiral ADC metal complex

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102 The chiral pyrrolidine 3 27 was prepared according to known procedure s (Scheme 3 5 ). 107, 108 First, succinyl chloride wa s converted to the corresponding diphenyl ketone 3 29 in the presence of phenylmagneium bro m ide via the corresponding Weinreb amide 3 28 After CBS reduction into diol 3 30 the protected pyrrolidine 3 31 could be obtained by activation of the alcohols and S N 2 reactions with allylamine. Wilkinson reagent allowed the formation of chiral pyrrolidine 3 27 Scheme 3 5 Preparation of the chiral pyrrolidine 3 27 U nfortunately, the formation of form amidinium 3 25 or of the chloroamidinium precursor, the corresponding urea was not successful This might be due to the high hindrance of the product Therefore, the original design was revisited and a simpler one was then investigated with only one chiral center on each pyrrolidine moiety. New Design of a Chiral Acyclic Diaminocarbene The chiral monosubsituted py rro lidine 3 37 was synthesized from known procedure s. 49, 109, 110 It started with the N Boc protection of L phenylalanine, to allow 3 33 (Scheme 3 6 ). The ketone moiety was then completely reduced to a methylene group in the presence

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103 of sodium borohydride. After a reflux in toluene, the lactam 3 3 5 was formed via decarboxylation and release of acetone. 3 3 5 was then deprotected with TFA in methylene c hloride to give the free lactam 3 36 which was next reduced to the corresponding amine 3 37 without erosion of the enantiopurity during the whole synthesis. The substituted amine was then treated with phosgene to give urea 3 38 The chloroamidinium 3 39 was then obtained by subjecting the urea in the presence of oxalyl chloride. An anion exchange was subsequentially performed with AgBF 4 been noted the BF 4 counter ion g a ve more stability to the complex than the chloride one. 49 Scheme 3 6 Synthesis of chloroamidinium 3 40 At this stage, chloroamidinium salt was complexed on either palladium(0) by oxidative addition or on rhodium via formation of the free carbene (Scheme 3 7 ) 49, 111 Scheme 3 7 Formation of ch iral ADC Pd 3 41 and ADC Rh 3 42 complexes

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104 Once the ADC palladium complex 3 41 was obtained, it was then tested for the asymmetric Suzuki reaction. This coupling was of interest since ADC ligands were strong donors whom feature favored the oxidative addition of the catalyst with aryl halide. 112 Besides, these ligands brought more hindrance around the metal sphere, due to their wider N C N angle (in respect to NHCs), which could make the reductive elimination easier. These two properties were well illustrated by Thadani as he obtai ned the desired products of the coupling reactions in good to excellent yields in the presence of a simple ADC ligand (Scheme 1 14). 50 As expected, the activity of the ADC Pd complex 3 41 was good (85%), but unfortunately the enantioselectivity was nearly inexistent (Scheme 3 1 2 ) Figure 3 1 2 ADC palladium cata lyzed Suzuki Miyaura coupling reaction With the ADC rhodium complex 3 42 the 1,2 addition reaction of 1 naphthylboronic acid to o anisaldehyde was tested (Figure 3 1 3 ). Again, while the activity of the complex was good in low catalyst loading, the enantio not observed. Figure 3 1 3 ADC rhodium catalyzed 1,2 addition reaction

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105 Th e lack of enantioselectivity might be d ue to too much freedom around the C carbene N bond. The expected conformer A might not be the most stable (Figure 3 1 4 ). However, w hile conformer B with the two chiral centers at the back (away from the metal) w ould be very sterically demanding it w ould be nonetheless possible that only one of them remained at the back w i th the other one point ing towards the front (conformer C ) This conformation could be the result of a lack of enantioselectivity for both Suzuki coupling and 1,2 addition in these conditions Figure 3 1 4 Undesired conformations of the ADC met al complex es Experimental Section ADC Copper Catalyzed Allylic Alkylation Typical procedure for allylic alkylation To a flame dried Schlenk flask w ere added CuTC (5 mol%), chloroamidinium salt 3 6 (5 mol%) and 1 mL of diethyl ether To this solution was ad ded a n ethylmagnesium bromide (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 3 1 (0.15 mmol) in 1 mL of Et 2 O was added over a 15 min period. After 1 h ou r, 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 chromatography to give a pure product 3 4

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106 Characte rizations of products 3 4a f 1 ((2 ethylbut 3 enyloxy)methyl) 4 methoxybenzene (3 4a). 1 H NMR (300 MHz, CDCl 3 ) : 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, 2H), 4.44 (s, 2H), 3.80 (s, 3 H), 3.36 (d, J = 6.4 H z, 2 H), 2.12 2.42 (m, 1 H), 1.45 1.71 (m, 1H), 1.13 1.37 (m, 1 H), 0.86 (t, J = 7.4 Hz, 3 H) 13 C NMR (75 MHz, CDC l 3 159.1, 140.0, 130.7, 129.1, 115.5, 113.7, 73.2, 72.6, 55.2, 45.7, 24.0, 11.4 HRMS ( m / z ): [M + H] + calcd for C 14 H 20 O 2 220.1463; f ound 220.1477. 2 ethylbut 3 enyl 4 methoxybenzoate ( 3 4b ). 1 H NMR (300 MHz, CDCl 3 ) : 7.91 (d, J = 8.78 Hz, 2H), 6.8 3 (d, J = 9.06 Hz, 2H), 5.62 (ddd, J = 17.06, 10.40, 8 .21 Hz, 1H), 5.00 5.09 (m, 2 H), 4.15 (dd, J = 6.51, 1.9 8 Hz, 2 H), 3.77 (s, 3H), 2.25 2.41 (m, 1H), 1.44 1.60 (m, 1H), 1.23 1.39 (m, 1 H), 0.86 (t, J = 7.36 Hz, 3 H) 13 C NMR (75 MHz, CDCl 3 1 66.52, 163.50, 139.18, 131.76, 123.07, 116.68, 113.79, 67.37, 55.61, 45.13, 24.23, 11.61 HRMS ( m / z ): [M + H] + calcd for C 14 H 18 O 3 257.1148; f ound 257.1142. 1 (2 ethylbut 3 enyl) 4 methoxybenzene ( 3 4c ). 1 H NMR (300 MHz, CDCl 3 ) : 7.06 (d, J = 9 Hz, 2H), 6.81 (d, J = 9 Hz, 2H), 5.47 5.72 (m, 1H), 4.73 5.04 (m, 2H), 3.79 (s, 3H), 2.43 2.70 (m, 2H), 2.05 2.27 (m, 1H), 1.36 1.52 (m, 1H), 1.17 1.36 (m, 1H), 0.87 (t, J = 8 Hz, 3H). 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 ( m / z ): [M + H] + calcd for C 13 H 18 O 191.1430; f ound 191.1436. 3 ethyl 3,7 dimethylocta 1,6 diene ( 3 4d ). 1 H NMR (300 MHz, CDCl 3 ) : 5.71 (dd, J = 17.6, 10.9 Hz, 1H), 5.05 5.15 (m, 1 H), 4.84 5.02 (m, J = 15.9, 11 .0, 1.6 Hz, 2H), 1.82 1.94 (m, 2 H ), 1.69 (s, 3H), 1.60 (s, 3 H), 1.21 1.34 (m, 4 H), 0.96 (s, 3H), 0.86 0.92 (m, 3 H) 13 C NMR (75 MHz, CDCl 3 14 7.5, 130.9, 125.2, 111.3, 40.9

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107 32.0, 30.2, 25.7, 24.0 22.6, 17.6, 14.1 HRMS ( m / z ): [M + H] + calcd for C 1 2 H 22 166 1722 ; found, 166 1719 4 ethyl 1 tosyl 4 vinylpiperidine (3 4f). 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, 3H), 1.59 1.76 (m, 2H), 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 ( m / z ): [M + H] + calcd for C 16 H 23 NO 2 S, 294.1522; found, 294.1499. ADC Iridium Complexes Synthes e s of i ridium complex es N isopropylaniline ( 3 18 a ). To an oven dried high pressure flask, were added Pd(dba) 2 (0.22 g, 0.38 mmol) and () BINAP (0.35 g, 0.57 mmol) in toluene (18 mL). The solu tion was stirred for 30 minutes under a nitrogen atmosphere. Then to the reaction mixture were added bromobenzene (2 mL, 19.0 mmol), isopropylamine (1.8 mL, 20. 9 mmol), sodium tert butoxide (2.56 g, 26.6 mmol), and toluene (18 mL). The solution was stirre d for 2 days at 10 0C The mixture was filtered over a plug of Celite and rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexanes/ethyl acetate: 3/1) to g ive 1.88 g (73%) of a yellow oil. 1 H NMR (300 MHz, CDCl 3 J = 7.7 Hz, 2H), 6.66 (tt, J = 1.3, 7.3 Hz, 1H), 6.58 (td, J = 1.0, 7.7 Hz, 2H), 3.62 (spt, J = 6.2 Hz, 1H), 3.42 ( br s 1H), 1.20 (dd, J = 1.0, 6.3 Hz, 6H). 13 C NMR (75 MHz, CDCl 3 IR (cm 1 ): 3401 2967, 1604, 1508, 1318, 1256, 1179, 748, 693. HRMS ( m / z ): [M + H] + calcd for C 9 H 13 N, 136.1121; found, 136.1125.

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108 N isopropyl 1,1,1 trimethyl N phenylsilanamine ( 3 19 a ). To a flame dried Schlenk flask, was added N isopropylaniline (1.0 g, 7.40 mmol) in tet rahydrofuran (10 mL). The solution was cooled to 78C and a 1.6 M solution of n butyl lithium in hexane (5.5 mL, 8.88 mmol) was added dropwise. Then, the reaction mixture was slowly warmed to room temperature and stirred for 1 hour. Next, chlorotrimethyls ilane (1.4 mL, 1.21 g) was added dropwise and the reaction was stirred at room temperature for 5 days. Any volatiles were evaporated under reduced pressure and diethyl ether was added to the residual oil forming a while solid which was then filtered over a plug of Celite. The filtrate was concentrated under reduced pressure and the crude product was purified by distillation giving 1.41 g (95%) of a colorless oil. 1 H NMR (500 MHz, CDCl 3 7.21 (m, J = 7.4 Hz, 2H), 7.12 (s, 1H), 7.01 (dd, J = 1.2, 8.4 Hz, 2H), 3.59 (spt, J = 6.7 Hz, 1H), 1.05 (d, J = 6.7 Hz, 6H), 0.06 (s, 9H). 13 C NMR (126 MHz, CDCl 3 145.4, 132.2, 128.2, 124.4, 48.8, 24.0, 0.9. IR (cm 1 ): 2966, 1597, 1490, 12 50, 1045, 918, 833, 703. HRMS ( m / z ): [M + H] + calcd for C 12 H 21 NSi, 208.1516; found, 208.1523. Synthesis of N isopropyl N phenylformamide ( 3 20 a ) To a flame dried Schlenk flask, were added N isopropylaniline (1.0 g, 7.40 mmol) in tetrahydrofuran (10 mL) an d acetic formic anhydride (0.98 g, 11.10 mmol) dropwise. The solution was stirred for 2 days at room temperature and then quenched with a 1 M sodium hydroxide aqueous solution at 0C The aqueous phase was extracted with diethyl ether and the combined orga nic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by distillation to give 1.20 g (99%) of a yellow oil. 1 H NMR (500 MHz, CDCl 3 7.46 7.34 (m, 3H), 7.19 7.13 (m, 2H), 4.80 (spt, J = 6.8 Hz, 1H), 1.20 (d, J = 6.9 Hz,

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109 6H); Minor isomer: 8.45 8.41 (m, 1H), 7.45 7.35 (m, 3H), 7.19 7.14 (m, 2H), 4.11 (spt, J = 6.8 Hz, 1H), 1.28 (d, J = 6.7 Hz, 6H). 13 C NMR (126 MHz, CDCl 3 isomer: 162.5, 138. 4, 129.7, 129.0, 128.2, 45.8, 21.0; Minor isomer: 162.5, 129.2, 129.1, 128.0, 51.5, 22.7. IR (cm 1 ): 2977, 2936, 2876, 1669, 1595, 1497, 1370, 1296, 1257, 1120, 703 HRMS ( m / z ): [M + H] + calcd for C 10 H 13 NO, 164.1070; found, 164.1064. B is( N phenyl N isoprop yl)amidinium chloride ( 3 21 a ). To a flame dried S chlenk flask, were added formamide ( 3 20 a ) ( 1.0 g, 6.13 mmol) in toluene (6.1 mL) and oxalyl chloride ( 0.80 mL 9.44 mmol ) dropwise, at 78 C. After 20 min of stirring the yellow solution wa s stirred at roo m temperature for 2 hours. Next, any volatiles were evaporated under reduced pressure. The resulting yellow solid wa s then dissolved in methylene chloride (4.1 mL) and t he solution wa s cooled to 78 C To the reaction mixture was added dropwise a solution of protected amine ( 3 19 a ) ( 1.27 g, 6.13 mmol ) in methylene chloride (2 mL) The reaction wa s slowly warmed to room temperature and stirred overnight. Any volatiles were evaporated under reduced pressure and the crude product wa s purified by flash column c hromatography (silica gel, hexanes/ ethyl acetate : 1/1 then methylene chloride/methanol 97/3 ). The solid wa s then dissolved in a minimum amount of methylene chloride and precipitated with diethyl ether which wa s rinsed several times with diethyl ether to gi ve 1.24 g (64%) of a white solid. 1 H NMR (500 MHz, CDCl 3 7.05 (m, 2H), 7.04 6.99 (m, 4H), 6.73 6.69 (m, 4H), 5.12 (quin, J = 6.6 Hz, 2H), 1.25 (d, J = 6.6 Hz, 12H). 13 C NMR (126 MHz, CDCl 3 134.1, 129.5, 129.1, 129.1, 61.0, 21.9 IR (cm 1 ): 3420, 3352, 163 6, 1590, 1503, 1453, 1110, 700. HRMS ( m / z ): [M] + calcd for C 19 H 25 N 2 281.20; found, 281.2020.

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110 I ridium complex ( 3 22 a ). To a flame dried S chlenk flask, was added amidinium ( 3 21 a ) (75 mg, 0.24 mmol) in tetrahydrofuran (3 mL). The reaction mixture was cooled to 78 C and a 1 M solution of LiHMDS in tetrahydrofuran ( 026 mL, 0.26 mmol ) was added dropwise The flask wa s warmed to room temperature and stirred for 30 minutes. Then, [Ir(cod)Cl] 2 complex (80 mg, 0.12 mmol ) was added at 78 C. The solution wa s slowly warmed to room temp erature and stirred overnight. Any volatiles were evaporated under reduced pressure. The crude product wa s purified by flash column chromatography (silica gel, hexanes/ ethyl acetate : 4/1) to give iridium complex ( 3 22 a ) as a yellow solid. Crystal s for X ra y analysis were obtained by slow diffusion of hexanes in highly concentrated solution of the iridium complex in DCM. 1 H NMR (500 MHz, CDCl 3 6.83 (m, 6 H), 6.73 6.54 (m, 4 H), 6.22 (d, J = 7.7 Hz, 2 H), 4.67 4.55 (m, 2 H), 3.38 3.25 (m, 2 H), 2.36 2.21 (m, 4 H), 1.85 1.75 (m, 2 H), 1.75 1.64 (m, 2 H), 1.19 (d, J = 6.7 Hz, 6 H), 1.09 (d, J = 6.7 Hz, 6 H) 13 C NMR (75 MHz, CDCl 3 143.9, 129.8, 129.2, 128.6, 128.3, 126.0, 82.6, 59.5 52.3, 33.5, 29.6, 22.5, 22.2. HRMS ( m / z ): [M] + calcd for C 27 H 34 IrN 2 579.2347; found, 579.2374. Iridium complex A : In a glove box, a 10 mL Schlenk flask was charged with chloroamidinium chloride (0.10 g, 0.36 mmol) Outside the glove box, was added THF (2 mL) and the solution was cooled to 78C. A solution of n BuLi (1.6M in hexanes, 0.24 mL, 0.38 mmol) was slowly added and the reaction mixture was stirred over 1 hour at that same temperature. Finally complex [Ir(cod)Cl] 2 (0.12 g, 0.18 mmol) was added and the solution was stirred overnight at room temperature. Any volatiles were evaporated under reduced pressure and the crude was purified by column chromatography ( s ilica gel, hexanes/EtOAc : from 2/1 to 1/1) to give 0.13 g (73%) of a

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111 yellow solid. 1 H NMR (500 MHz CDC l 3 ) : 4.57 4.45 (m, 2 H), 3.55 ( m 4 H), 3.41 (s, 6 H), 3.04 2.93 (m, 2 H), 2.24 2.10 (m, 4 H), 1.79 1.68 (m, 2 H), 1.66 1.54 (m, 2 H) 13 C NMR (126 MHz CDC l 3 ) : 207.9, 84.9, 52.0 33.6, 29.5 Iridium complex B : The same procedure as above was u sed starting from 2 c hloro 1,3 dimethylimidazolinium chloride to give complex 3 X as a yellow solid ( 17% yield ) 1 H NMR (500 MHz CDC l 3 4. 57 ( br. s. 2 H), 4.42 4.34 (m, 2 H), 4. 27 ( br. s. 2 H), 3. 4 8 ( br. s. 4 H), 2.94 2.85 (m, 2 H), 2.24 2.09 (m, 4 H), 1.88 (br. s., 8 H), 1.69 1.60 (m, 2 H), 1.58 1.49 (m, 2 H) 13 C NMR (126 MHz, CDCl 3 211.9, 81.6, 51.9, 33.5, 29.5 Iridium complex [IMesIr(cod)Cl] : The same procedure as for complex 3 22a was used starting from IMesHCl to afford [IMesIr( cod)Cl] as a bright orange solid (quantitative yield). 1 H NMR ( 3 00 MHz CDC l 3 7.40 7.21 (m, 2 H), 7.12 6.92 (m, 4 H), 4.30 4.06 (m, 2 H), 3.08 2.91 (m, 2 H), 2.36 (s, 12 H), 2.17 (s, 6 H), 1.84 1.63 (m, 4 H), 1.42 1.17 (m, 4 H) Typical p ro cedure for the hydroboration To a flame dried Schlenk flask, were added iridium complex 3 23a ( 18.5 mg, 0.0 3 mmol) pinacolborane (0.174 L, 1.2 mmol), freshly distilled styrene (115 L, 1.0 mmol) and toluene (3 ml). The mixture was then stirred at room te mperature over 24 hours The reaction was quenched with methanol (1 mL) and water (3 mL). T he product was extracted with diethyl ether, and dried over MgSO 4 Purification on column c hromatography (S ilica gel hexanes/ethyl acetate: 90/10) gave 70 mg of the product (30%) as a light yellow oil Linear product: 1 H NMR (500 MHz CDC l 3 ): 7.33 7.12 (m, 5 H), 2.84 2.72 ( t J = 8.1 Hz, 2 H), 1.25 (s, 12 H), 1.20 1.14 ( t J = 8.2 Hz, 2 H) 13 C NMR (126 MHz CDC l 3 ) : 144.6, 128.5, 128.4, 125.5, 83.3, 30.2, 25.0 Branched

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112 product: 1 H NMR (300 MHz CDC l 3 ): 7.31 7.09 (m, 5 H), 2.43 (q, J = 7.6 Hz, 1 H), 1.33 (d, J = 7.6 Hz, 3 H), 1.21 (s, 6 H), 1.20 (s, 6 H) 13 C NMR ( 75 MHz CDC l 3 ) : 144.1, 128.5, 128.0, 125.7, 83.5, 29.3, 20.9, 11.7. NMR spectra Figure 3 15. NMR spectra of the hydroboration product

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113 Chiral Acyclic Diaminocarbene Metal Complexes Synthesis of chloroamidinium salt 3 40 B is(( R ) 2 benzylpyrrolidin 1 yl)methanone (3 38 ) To a flame dried Schlenk flask, were added pyrrolidine 3 3 7 ( 1 18 g, 7 34 mmol) and triethylamine ( 3.0 mL, 21 5 mmol) in methylene chloride ( 15 mL). The solution was cooled to 0C and a 20% solution of phosgene in toluene ( 2.0 mL, 3.80 mmol) was added dropwise. The reaction mixture was stirred 40 minutes at 0C and then overnight at room temperature. The solution was quenched wi th water and the aqueous phase was extracted with meth ylene chloride. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexanes/ethyl acetate: 3/2) to afford 0.97 g (76%) of a p ale yellow oil. 1 H NMR (300 MHz, CDCl 3 7.09 (m, 10 H), 4.28 (dd, J = 3.4, 6.3 Hz, 2 H), 3.45 3.05 (m, 6 H), 2.60 (dd, J = 8.8, 12.9 Hz, 2 H), 1.90 (td, J = 2.6, 5.7 Hz, 2 H), 1.84 1.44 (m, 8 H). 13 C NMR (75 MHz, CDCl 3 ): 161.6, 139.4, 129.9, 128.3, 126.2, 59.6, 50.2, 40.8, 30.7, 25.5 HRMS ( m / z ): [M + H ] + calcd for C 23 H 28 N 2 O 349.2274; found 349.2279. ( R Z ) 2 benzyl 1 ((( R ) 2 benzylpyrrolidin 1 yl)chloromethylene)pyrrolidin 1 ium tetrafluoroborate (3 40 ) To a flame dried Schlenk flask, were added urea 3 38 (0.22 g, 0.62 mmol) and ox alyl chloride ( 63 L, 0.74 mmol) in toluene ( 3 mL) T he reaction mixture was heated to 50 C and stirred overnight. The solution was cooled to room temperature and the toluene resting on top of the precipitate was removed with a syringe. The oily residue was washed twice wit h diethyl ether, dissolved in copious amounts of tetrahydrofuran and precipitated with pentanes as a slightly orange solid.

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114 Any volatiles were evaporated under reduced pressure, then methylene chloride ( 4 mL) and silver(I) tetrafluoroborate ( 0.12 g, 0 62 mmol) were added to the solid. The reaction was stirred for 1 h. After this time, the methylene chloride was removed by filtration and transferred into a flame dr ied Schlenk flask under an argon atmosphere, and the solids were washed with methylene chlorid e collecting the organics. Volatiles were removed, and the solid was dissolved with generous amounts of tetrahydrofuran The product was precipitated with diethyl ether, resulting in 0.16 g (57%) of a pale brown solid 1 H NMR (300 MHz, CDCl 3 7.34 7.1 1 (m, 10 H), 4.48 ( br s 2 H), 3.82 ( br s 4 H), 3.08 (dd, J = 3.5, 14.6 Hz, 2 H), 2.82 ( br s 2 H), 2.11 ( br s 4 H), 2.04 1.82 (m, 4 H). 13 C NMR (75 MHz, CDCl 3 129.5, 12 9.1, 128.9, 128.6, 127.5, 67.4, 56.3, 40.3, 30.4, 24.9. HRM S ( m / z ): [M BF 4 ] + calcd for C 23 H 28 BClF 4 N 2 367.1936 ; found 367.1973. Syntheses of ADC metal complexes 3 41 and 3 42 C hlorobis (( R ) 2 benzylpyrrolidinyl)methylidenebistriphenylphosphinepalladium tetrafluoroborate (3 41 ) To a flame dried Schlenk flas k, w ere added chloroamidinium 3 40 (50 mg, 0.11 mmol) and t etrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol) in toluene (8 mL). The solution was heated for 3 hours at 100C. The mixture was allowed to cool to room temperature and any volatiles were e vaporated under reduced pressure. Pentane was added to the resulting solid, which was stirred for 1 h before being decanted. Methylene chloride was used to dissolve the product, and insoluble salts were filtered off. Pentane was layered on top of the filtr ate to purify the product by recrystallization (57 mg, 48%). 1 H NMR (300 MHz, CD 2 Cl 2 : 7.83 7.63 (m, 5 H), 7.54 ( br s 10 H),

PAGE 115

115 7.50 7.31 (m, 6 H), 7.31 7.01 (m, 17 H), 7.01 6.80 (m, 4 H), 5.49 (dt, J = 5.6, 11.5 Hz, 2 H), 4.48 4.28 (m, 2 H), 3.85 3.66 (m, 2 H), 2.96 (dd, J = 4.8, 13.9 Hz, 2 H), 2.72 2.49 (m, 2 H), 2.13 1.96 (m, 1 H), 1.9 6 1.81 (m, 2 H), 1.81 1.52 (m, 3 H), 1.43 ( br s 1 H), 1.34 1.01 (m, 3 H). 13 C NMR (75 MHz, CD 2 Cl 2 : 185.8, 137.1, 135.3, 134.7, 134.3, 132.4, 131.6, 130.2, 129.1, 128.8, 128.5, 126.8 71.5, 54.3, 40.0, 25.8, 22.8. HRMS ( m / z ): [M BF 4 ] + calcd for C 59 H 5 8 BClF 4 N 2 P 2 Pd 997.2810; found 997.2817. Chloro( 4 1,5 cyclooctadiene)bis(( R ) 2 benzylpyrrolidinyl) methylidenerhodium(I) (3 42) To a Schlenk flask in a glovebox was added 100 mg (0.364 mmol) of bis(pyrrolidinyl)chloroamidinium tetrafluoroborate ( 3 40 ) a nd the flask was connected to a Schlenk line outside the glovebox. THF (2 mL) was added, and the suspension was cooled to 78C with a dry ice/acetone bath. After cooling, 2.5 M n BuLi clear and slightly yellowish solution upon formation of carbene. After stirring for 1 h at 78C, [Rh( cod )Cl] 2 (89.6 mg, 0.182 mmol) was added, and the reaction slowly warmed to room temperature. Stirring at room temperature proceeded for 12 h, at which po int, solvent was evaporated. To remove any remaining [Rh( cod )Cl] 2 the product was purified by chromatography on a very short pad of silica gel. Columns were run starting with a mixture of 2:1 hexanes/ethyl acetate and proceeding to pure ethyl acetate. The complexes showed very slight decomposition on silica gel, so the product was further purified by dissolving the product in ethyl acetate and then precipitating impurities with addition of hexanes, giving 94 mg ( 3 6%) of complex. The product is sufficiently soluble in hexanes. 1 H NMR (300 MHz, CDCl 3 7.57 7.41 (m, 2H), 7.39 7.08 (m, 8H), 6.58 6.40 (m, 1H), 6.26 (td, J = 3.2, 6.9 Hz, 1H), 5.20 5.01 (m, 1H), 4.89 (br s, 1H), 4.41 4.20

PAGE 116

116 (m, 1H), 3.77 3.54 (m, 2H), 3.54 3.34 (m, 2H), 3.34 3.11 (m, 4H), 3.02 (dd, J = 4.4, 13.5 Hz, 1H), 2.77 (dd, J = 10.4 13.6 Hz, 1H), 2.70 2.54 (m, 2H), 2.54 2.22 (m, 4H), 2.19 1.57 (m, 9H) 13 C NMR (75 MHz, CDCl 3 218.9, 218.3, 161.6, 139.8, 139.4, 138.9, 130.0, 129.9, 129.4, 128.8, 128.5, 128.3, 126.8, 126.3, 126.2, 97.5, 97.4, 97.3, 69.7, 69.4, 68.5, 68.1, 66.7, 66 .5, 59.6, 52.2, 52.0, 50.3, 42.1, 40.9, 40.8, 33.2, 32.9, 30.7, 29.9, 29.0, 28.7, 28.1, 26.6, 25.5, 24.8, 23.2 HRMS ( m / z ): [M Cl ] + calcd for C 31 H 40 ClN 2 Rh 543.2241 ; found 543.2248 Suzuki c ross c oupling r eaction 1 Naphthylboronic acid (46.4 mg, 0.269 m mol), 1 bromo 2 methoxynaphthalene (52.4 mg, 0.221 mmol), palladium complex 3 41 0.619 mmol) were added to a flame dried Schlenk flask. THF (3.5 mL) was added to the solids, and the reaction was heated at reflux for 16 h. After this time, the reaction mixture was diluted with water and extracted w ith ethyl acetate (3.5 mL x 3). The organic layers were combined, dried with MgSO 4 and concentrated. The crude product was purified by column chromatography (hexanes/ethyl acetate, 50:1), resulting in pure biaryl (59.7 mg, 95%). Enantiomeric excess was de termined by HPLC analysis using a chiral column (Chiralcel OJ H; hexane/2 propanol, 4:1; flow rate 1 mL/min; t R 8.5 and 13.5 min). 1 H NMR (300 MHz, CDCl 3 8.12 7.82 (m, 4H), 7.74 7.58 (m, 1H), 7.55 7.41 (m, 3H), 7.41 7.13 (m, 5H), 3.78 (s, 3H). 13 C NMR (75 MHz, CDCl 3 154.9, 134.8, 134.5, 134.0, 133.2, 129.7, 129.3, 128.7, 128.5, 128.1, 128.0, 126.6, 126.4, 126.1, 125.9, 125.8, 125.8, 123.8, 123.5, 1 14.1, 57.0. HRMS ( m / z ): [M] + calcd for C 21 H 16 O 284.1196 ; found 284.1190.

PAGE 117

117 a ) b ) Figure 3 16. HPLC spectra of the Suzuki Miyaura coupling product a) racemic mixture a nd b) with 3 41 1,2 A ddition of 1 n aphthylboronic a cid to o a nisaldehyde To a flame dried Schlenk flask under argon were added 50.0 mg (0.364 mmol) of o anisaldehyde, 125 mg (0.728 mmol) of 1 naphthylboronic acid, 82.6 mg (0.728 mmol) of potassium tert ) of rhodium catalyst 3 42 Then 1.22 mL of DME and 0.33 mL of water were added, and the solution was heated to 80C. The mixture was stirred for 1 h and monitored by T LC (R f 0.38, 4:1 hexanes/ethyl acetate). The solution was diluted with 10 mL of diethyl ether and 10 mL of water and was then extracted three times. The organic layer was dried, concentrated, and then purified by silica gel chromatography (8:1 hexanes/ethyl acetate) to isolate the product as a clear oil (92 mg, 8 6%yield). Enantiomeric excess was determined by HPLC analysis with a chiral column (Chiralcel IA; hexanes/2 propanol, 9:1; flow rate 1mL/min; t R 12.5 and 13.8min). 1 H NMR (300 MHz, CDCl 3 8.05 (d, J = 7.4 Hz, 1H), 7.96 7.79 (m, 2H), 7.71 (d, J = 7.1Hz, 1H), 7.60 7.39 (m, 3H), 7.37 7.22 (m, 1H), 7.11 6.78 (m, 4H), 3.91 (s, 3H), 3.22 (br s, 1H). 13 C NMR (75 MHz, CDCl 3 157.2, 138.4, 134.0, 131.6, 131.3, 129.2, 128.9, 128.7, 128.3, 126 .2, 125.7, 124.6, 124.5, 121.1, 110.8, 68.6, 55.8. HRMS ( m / z ): [M OH ] + calcd for C 18 H 16 O 2 247.1177 ; found 247.1176.

PAGE 118

118 a ) b ) Figure 3 17. HPLC spe ctra of the 1,2 addition product a) racemic mixture and b) with 3 42

PAGE 119

119 CHAPTER 4 CONCLUSION An improvement of t he original design of the isoquinoline based ligand allowed access to a larger variety of the R substituent (Figure 4 1). The steric and electronic properties could be tuned at a later stage of the preparation. Although ent 2 15dc gave good enantioselectiv ity for borylation (85% ee), it did not surpass the one of the original design. Carbene precursor ent 2 15ec with its triazole moiety showed some enantioselectivity in the asymmetric allylic alkylation (up to 45%). A n X ray structure would give pre cious information about the orienta tion of the chiral group and certain types of reactions could be targeted from there. Figure 4 1. New chiral NHC precursors The achiral ADC iridium complex was successfully obtained (Fi gure 4 2) Its X ray structure showed the syn conformation of the carbene as expected and a possible stacking (parallel displaced) Unfortunately, t he catalysis of the hydroboration gave moderate results in terms of regioselectivity (linear/branched: 1/0.58) Therefore, other iridium catalyzed reactions needed to be tested. Finally, the chiral ADC lig and precursor was also prepared (Figure 4 3). The drawback of the C N bond rotation still remained a challenge in order to obtain some enantioselectivity. Again, a wider screening of reactions had to be performed to seek for its potential.

PAGE 120

120 Figure 4 2. New ADC iridium complex 3 22 a Figure 4 3. Chiral ADC ligand precursors

PAGE 121

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128 BIOGRAPHICAL SKETCH Sbastien Inagak i was born in Cholet, France. After graduating from high school in Cholet (Lyce Sainte Marie) in 1999, he moved next to Paris (Cergy Pontoise, France) for his undergraduate study. He obtained a Master degree in organic chemistry from the University of Cer gy Pontoise under the supervision of Professor Thierry Brigaud, in 2005. He also graduated from ESCOM (Ecole Suprieure de Chimie Organique et Minrale) where he obtained a Master degree in chemical engineering, the same year. Sbastien then moved to Gaine sville, FL in 2006, to pursue his PhD in organic chemistry at the University of Florida under the supervision of Professor Sukwon Hong. He received his Ph.D. in the spring of 2012