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Exploration of Acyclic Diaminocarbenes as Transition Metal Ligands

Permanent Link: http://ufdc.ufl.edu/UFE0024905/00001

Material Information

Title: Exploration of Acyclic Diaminocarbenes as Transition Metal Ligands
Physical Description: 1 online resource (109 p.)
Language: english
Creator: Snead, David
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: carbene, catalysis, chiral, organometallic, palladium, rhodium
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy EXPLORATION OF ACYCLIC DIAMINOCARBENES AS TRANSITION METAL LIGANDS By David Robinson Snead May 2010 Chair: Sukwon Hong Major: Organic Chemistry Carbenes are an important class of spectator ligands, the most common of which are N-heterocyclic carbenes (NHCs). Lesser explored carbene ligands are acyclic diaminocarbenes(ADCs), which possess a degree of intrigue due to significant variations in electronic and steric parameters from NHCs. In this work, ADCs are explored, with a special emphasis on methods of complexation to metal centers. ADC ligands were built from chiral C_1-symmetric pyrrolidine subunits. Ureas 2-1 through 2-4 were synthesized from 2-substituted pyrrolidines, and X-ray analysis was obtained for these compounds. The location of the chiral substituents proximal to the oxygen atom of the carbonyl led to a reasonable hypothesis that these ADCs might be useful asymmetric ligands. Palladium complexes 2-15 and 2-18 were formed through oxidative addition of chloroamidinium precursors; however steric crowding created by the phosphine ligands caused the chiral groups to orient themselves away from the metal center, as observed by X-ray analysis. ADCs with substituents larger than benzyl were not able to be isolated with palladium, likely as a result of steric constraints. Complexes 2-15, 2-18, and 2-26 were tested in Suzuki reactions, but as the degree of ligand substitution increased, reactivity decreased. Access to a diversity of metal complexes from chloroamidiniums was restricted based on use of the oxidative addition methodology and also required the use of electron rich ligands like phosphines. As such, a new more general method of carbene generation was developed. Lithium-halogen exchange was applied to chloroamidiniums to give carbenoid intermediates. 13^C-NMR of the carbene in solution and formation of thiourea constitute proof, and after generation, Rh, Ir, Pd, and B complexes were produced. Interestingly, X-ray analysis of Rh-ADC complex 3-5 based on chiral C_1-symmetric pyrrolidine subunits demonstrated a change in conformational preference from the palladium compounds, as the methyl substituents were located proximal to the rhodium center. Rh-ADC complex 3-5 was tested in catalytic reactions and showed good reactivity in 1,4 conjugate addition of aryl boronic acids to cyclohexenone and in 1,2 addition of aryl boronic acids to aryl aldehydes. Notably, the ADC ligand performed better than NHC in 1,2 addition.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by David Snead.
Thesis: Thesis (Ph.D.)--University of Florida, 2010.
Local: Adviser: Hong, Sukwon.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0024905:00001

Permanent Link: http://ufdc.ufl.edu/UFE0024905/00001

Material Information

Title: Exploration of Acyclic Diaminocarbenes as Transition Metal Ligands
Physical Description: 1 online resource (109 p.)
Language: english
Creator: Snead, David
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: carbene, catalysis, chiral, organometallic, palladium, rhodium
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy EXPLORATION OF ACYCLIC DIAMINOCARBENES AS TRANSITION METAL LIGANDS By David Robinson Snead May 2010 Chair: Sukwon Hong Major: Organic Chemistry Carbenes are an important class of spectator ligands, the most common of which are N-heterocyclic carbenes (NHCs). Lesser explored carbene ligands are acyclic diaminocarbenes(ADCs), which possess a degree of intrigue due to significant variations in electronic and steric parameters from NHCs. In this work, ADCs are explored, with a special emphasis on methods of complexation to metal centers. ADC ligands were built from chiral C_1-symmetric pyrrolidine subunits. Ureas 2-1 through 2-4 were synthesized from 2-substituted pyrrolidines, and X-ray analysis was obtained for these compounds. The location of the chiral substituents proximal to the oxygen atom of the carbonyl led to a reasonable hypothesis that these ADCs might be useful asymmetric ligands. Palladium complexes 2-15 and 2-18 were formed through oxidative addition of chloroamidinium precursors; however steric crowding created by the phosphine ligands caused the chiral groups to orient themselves away from the metal center, as observed by X-ray analysis. ADCs with substituents larger than benzyl were not able to be isolated with palladium, likely as a result of steric constraints. Complexes 2-15, 2-18, and 2-26 were tested in Suzuki reactions, but as the degree of ligand substitution increased, reactivity decreased. Access to a diversity of metal complexes from chloroamidiniums was restricted based on use of the oxidative addition methodology and also required the use of electron rich ligands like phosphines. As such, a new more general method of carbene generation was developed. Lithium-halogen exchange was applied to chloroamidiniums to give carbenoid intermediates. 13^C-NMR of the carbene in solution and formation of thiourea constitute proof, and after generation, Rh, Ir, Pd, and B complexes were produced. Interestingly, X-ray analysis of Rh-ADC complex 3-5 based on chiral C_1-symmetric pyrrolidine subunits demonstrated a change in conformational preference from the palladium compounds, as the methyl substituents were located proximal to the rhodium center. Rh-ADC complex 3-5 was tested in catalytic reactions and showed good reactivity in 1,4 conjugate addition of aryl boronic acids to cyclohexenone and in 1,2 addition of aryl boronic acids to aryl aldehydes. Notably, the ADC ligand performed better than NHC in 1,2 addition.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by David Snead.
Thesis: Thesis (Ph.D.)--University of Florida, 2010.
Local: Adviser: Hong, Sukwon.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0024905:00001


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EXPLORATION OF ACYCLIC DIAMINOCARBENES AS TRANSITION METAL
LIGANDS




















By

DAVID ROBINSON SNEAD


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

UNIVERSITY OF FLORIDA

2010


































2010 David Robinson Snead



































To Stephanie









ACKNOWLEDGMENTS

Pursuit of the PhD and the opportunity to completely immerse myself into research

endeavors was a dream of mine, only made possible through the efforts and allowances of others.

To forget their help would be arrogant and inaccurate.

First and foremost, I would like to express my total and awe-filled gratitude to my wife,

Stephanie. At many times, I spent incredible amounts of time away from home at the laboratory.

This was a sacrifice not only on my part, but also and maybe mostly on her part. I thank her for

giving so much of herself, and for supporting me after long days with understanding,

conversation, or a meal. I am grateful not only for the allowance, but for the encouragement to

follow this pursuit which at times might seem incomprehensible. She made it possible to get

through this when I was discouraged and tired. I will always be thankful.

Secondly, I would like to thank my parents who steadfastly invested in their children's

success. Without all the preparation, wisdom, education, and love they bestowed, fulfillment of

the PhD would be impossible. I especially would like to thank my father for pushing and

challenging me in adolescence to instill a dogmatic sense of ambition, which I value and believe

to be a great asset.

I would like to thank my mentor, Sukwon Hong, for providing an exciting project to

explore, belief in my abilities, and the good character to help me fulfill my career aspirations. I

would also like to thank all of our wonderful Gainesville friends who enriched our lives with

smiles, jokes, and conversation. You will be the most memorable part of our Florida experiment.









TABLE OF CONTENTS



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

L IST O F T A B L E S .................................... .......................................................... ..................... 7

LIST O F FIG U RE S .................................................................8

A B S T R A C T ........................................... ................................................................. 1 1

CHAPTER

1 INTRODUCTION ................. .............. ........... ............................. 13

A cyclic D iam inocarb en es ............................................................................ .............. ... 13

2 BIS(2-ALKYLPYRROLIDIN-1-YL)METHYLIDENES AS CHIRAL ACYCLIC
D IA M IN O CA R B EN E LIG A N D S ............................................................. .....................17

Introduction .......... ......... ..................................................................................... 17
Ureas Stemming from 2-Substituted Pyrrolidine ....................................... ............... 18
U rea Crystal Structures .................. .................. ............... ............... ........... 19
Form ation of Palladium -AD C Com plexes ........................................ ........................ 23
Suzuki Cross-Coupling .................. .. .. .............. ... ................................28
C2-Symmetric Pyrrolidine Moieties and Attempts at Symmetrically Substituted Ureas .......32
Ureas with Non-Identical Amine Moieties Featuring (2S,5S)-trans-diphenylpyrrolidine .....35
Chlorination and Metalation of Ureas Based on (2S,5S)-trans-Diphenylpyrrolidine ............36
C conclusion and Sum m ary ............................................................................... ............... 37

3 LITHIUM-HALOGEN EXCHANGE: A NEW METHOD FOR DIAMINOCARBENE
FO R M A TIO N ................ ...................................... ............................39

Introduction ................. ......... ...... ........... .............................39
C arbene F orm ation and Proof............................................................................... ..............40
Binding Diaminocarbenes to Transition Metals and Boron ................................................42
Other Ligands Explored in Carbene Formation from the Lithium-Halogen Exchange .........59
Catalytic Activity of Rhodium Complexes Accessed Through Lithium-Halogen Exchange 68
ADC-Pd Complex 3-18 in the Suzuki Cross-Coupling..................................78
Steric and Electronic Measurements of ADC and NHC Compounds ..................................78
C on clu sion s an d Su m m ary .......................................................................... .....................8 1

4 E X PER IM EN TA L SE C TIO N ........................................................................ ..................83

G general R em arks .............................................................................83









General Procedure for Formation of Ureas Based on 2-Substituted Pyrrolidines ..................83
General Procedure for the Formation of Chloroamidinium Ions ......................................85
General Procedure for the Formation of Palladium Complexes ........................... .........87
General Procedure for Suzuki Cross-Coupling Reaction....................................................88
General Procedure for the Formation of Ureas from Carbamoyl Chlorides ..........................89
General Procedure for the Formation of Tri-Substituted Ureas from Isocyanates ...............90
General Procedure for the Methylation of Tri-Substituted Ureas .......................................91
General Procedure for Formation of Carbene 3-4 ...................................... ............... 91
General Procedure for Rhodium and Iridium Complex Formation............................92
General Procedure for 1,4 Conjugate Addition ........................................... ............... 97
General Procedure for Formation of Biaryl Methanols...................................................99
NM R of Carbene Intermediate ... ................................................................... 102

L IST O F R E FE R E N C E S ..................................................................................... ..................104

B IO G R A PH IC A L SK E T C H ......................................................................... ... ..................... 109









LIST OF TABLES


Table page

1-1 Calculated values of N-C-N bond angle and proton affinity (PA) for select
carb en es........ ................................ ................................................ 14

2-1 Crystal data and structure refinement for 2-1. ...................................... ............... 22

2-2 Crystal data and structure refinement for 2-2. ...................................... ............... 22

2-3 Crystal data and structure refinement for 2-15. ..................................... ............... 26

2-4 N-C-N bond angles and Pd-C bond lengths for select carbenes...............................28

2-5 Optimization of Suzuki cross-coupling reaction............................................................29

2-6 Suzuki cross-coupling of 2-23 and 2-24 with a variety of catalysts................................30

2-7 Exploration of substrate scope in Suzuki cross-coupling reaction. ...................................31

3-1 Crystal data and structure refinement for 3-5. ...................................... ............... 48

3-2 Crystal data and structure refinement for 3-6. ...................................... ............... 49

3-3 Crystal data and structure refinement for 3-9. ...................................... ............... 50

3-4 Crystal data and structure refinement for 3-13. ..................................... ............... 54

3-5 Attempts at transmetalating ADC ligand to rhodium. ...................................................... 59

3-6 1,4 Conjugate Addition of Boronic Acids to Cyclohexenone ............... ...... ..........70

3-7 1,2 Addition of arylboronic acids to o-anisaldehyde. ............... ................................ 71

3-8 1,2 Addition of phenylboronic acid to arylaldehydes....................................................72

3-9 1,2 Asymmetric addition of 1-naphthylboronic acid to o-anisaldehyde .........................76

3-10 Redox half potentials for some Ir(L)(COD)Cl complexes in CH2C12 (scan rate
100m V s- ). ................................................................................ 79

3-11 Calculated % VBurvalues for ADC ligands in complexes 3-5, 3-6, 3-9, and 3-13.
Calculated with Bondi radii scaled by 1.17, 3.5A radius of the sphere, and 2.1A
distance of the ligand from the sphere. NHC values reported by Cavallo......................80









LIST OF FIGURES


Figure pae

1-1 An N-heterocyclic carbene and some acyclic diaminocarbenes .............. .....................14

1-2 A comparison of electronic and steric parameters for NHC and ADC ligands ...............15

1-3 General method of preparation of carbene metal complexes via Ftirstner's route.............15

1-4 Some carbene metal complexes formed by oxidative addition of chloroamidinium
io n s ................. .................................. ............................ ................ 1 6

2-1 Potential conformers associated with carbenes designed about 2-substituted
p y rrolidin es. ............................................................ ................ 17

2-2 Unique abilities of a conformationally flexible ligands............... ........ ............... 18

2-3 Ureas from 2-substituted pyrrolidine derivatives. .................................. ...............18

2-4 Synthesis of urea 2-3 from condensation of (R)-(+)-2-isopropyl pyrrolidine................ 19

2-5 Potential conform ers of ureas 2-1 to 2-4 ......... ........................................ ................ 20

2-6 M molecular structure of urea 2-1......................................... .. .......................... ...............2 1

2-7 M molecular structure of urea 2-2...................... .... ................... ................. ............... 21

2-8 Chlorination of ureas with oxalyl chloride. ........ ....... ...................... ...............24

2-9 Complexation of chloroamidiniums to palladium. ................................. .................24

2-10 M olecular structure of com plex 2-15.......................................... ........................... 26

2-11 Chromium-ADC complex discovered by Herrmann. .............................. ................27

2-12 Preparation of (2S,5S)-trans-diphenylpyrrolidine .................................. .................33

2-13 Some attempts at urea formation with (2S,5S)-trans-diphenylpyrrolidine......................34

2-14 Synthetic attempt aimed at urea 2-39 using CDI. ....................................................... 34

2-15 Challenging secondary amines in desired urea production........................................35

2-16 Ureas from carbamoyl chlorides, acyl chlorides, and isocyanates. ..................................36

2-17 Chlorination of urea 2-50 and attempt at cationic ADC-Pd compound 2-57 ...................37










2-18 ADC-Pd complexes with 2-substituted pyrrolidines as mimics for ADC ligands
w ith C2-sym m etric pyrrolidines ............................................... .............................. 38

3-1 Envisioned synthesis of carbene intermediates through Li-X exchange .........................39

3-2 Classic methods to Form Organolithium Species. .......................................................40

3-3 Tentative proof of carbene intermediacy via lithium-halogen exchange.........................41

3-4 13C-NMR Spectrum of lithiated carbene intermediate 3-4' produced through
lithium -halogen exchange. ........................................................................ ....................43

3-5 2D gHMBC spectrum of lithiated carbene intermediate 3-4' produced through
lithium -halogen exchange. ........................................................................ ....................44

3-6 Formation of rhodium and iridium ADC complexes from chloroamidinium 3-1. ............45

3-7 Formation of rhodium and iridium NHC complexes from chloroamidinium 3-7. ............46

3-8 M olecular structure of com plex 3-5........................................................ .....................47

3-9 M olecular structure of com plex 3-6........................................................ ............... 47

3-10 M olecular structure of Com plex 3-9........................................ ............................ 48

3-11 Formation of piperidine based ADC rhodium complex from chloroamidinium 3-
1 1 ............................................................................................ 5 1

3-12 Synthesis of chiral ADC rhodium complexes 3-13 and 3-15. ........................................53

3-13 M olecular structure of com plex 3-13...................................................... .....................54

3-14 Synthesis of ADC palladium catalyst 3-18 .............. ..... ........... .................55

3-15 Attempt to create a frustrated Lewis pair with an ADC. .......................................... 60

3-16 Attempts at synthesis of ADC rhodium catalyst using chloroamidinium 3-36 ................60

3-17 Failure to produce lithiated ADC 3-4' from chloride salt 3-36. .......................................61

3-18 Observed differences in reactivity based upon counter-ion identity. .............................62

3-19 Diaminocarbene precursors which were unsuccessful in attempts complex with
rhodium using lithium-halogen exchange methodology .............................................62









3-20 Attempts at synthesis of a mixed pyridine-ADC rhodium complex .............................63

3-21 Trials to determine whether n-BuLi is effective in generation of carbene
interim ediacy w ith precursor 3-43. ............................................ ............................. 64

3-22 Formation of chlorinated dithiocarbamate tetrafluoroborate salts 3-51 and 3-52. ............65

3-23 Formation of chlorinated thiocarbamate tetrafluoroborate salt 3-55...............................66

3-24 Attempts at synthesis of rhodium complex 3-63 by changing counter-ion identity
and lithiation source .................................... .. .. ........ .. ............67

3-25 Use of a lithio-naphthalene solution to generate compound 3-5. .....................................68

3-26 Examples of catalysis with rhodium including cycloadditions, borylations,
carbenoid chemistry, C-H activation, 1,4 conjugate addition, and 1,2 addition to
a ld e h y d e s ....................... ..................... ......................... ................ 6 9

3-27 A plausible catalytic cycle for the 1,2 addition of aryboronic acids to aldehydes.............75

3-28 Attempts at synthesis of complexes 3-89 and 3-90 which might be expected to
show greater activity toward insertion reactions with olefins. ........................................77

3-29 Suzuki coupling to for tri-ortho-substituted product using catalyst 3-18........................78

3-30 Variable NHC ligands used in Plenio's study of electronic influence of aromatic
su b stitu e n ts ...................... .. ............. .. ......................................................7 9

3-31 G raphical illustration of % Bur ........................................................................ 80

3-32 Plot of redox potential vs. % VBur. .................................................................... 81









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

EXPLORATION OF ACYCLIC DIAMINOCARBENES AS TRANSITION METAL
LIGANDS

By

David Robinson Snead

August 2010

Chair: Sukwon Hong
Major: Chemistry

Carbenes are an important class of spectator ligands, the most common of which are N-

heterocyclic carbenes (NHCs). Lesser explored carbene ligands are acyclic

diaminocarbenes(ADCs), which possess a degree of intrigue due to significant variations in

electronic and steric parameters from NHCs. In this work, ADCs are explored, with a special

emphasis on methods of complexation to metal centers.

ADC ligands were built from chiral C 1-symmetric pyrrolidine subunits. Ureas 2-1

through 2-4 were synthesized from 2-substituted pyrrolidines, and X-ray analysis was obtained

for these compounds. The location of the chiral substituents proximal to the oxygen atom of the

carbonyl led to a reasonable hypothesis that these ADCs might be useful asymmetric ligands.

Palladium complexes 2-15 and 2-18 were formed through oxidative addition of chloroamidinium

precursors; however steric crowding created by the phosphine ligands caused the chiral groups to

orient themselves away from the metal center, as observed by X-ray analysis. ADCs with

substituents larger than benzyl were not able to be isolated with palladium, likely as a result of

steric constraints. Complexes 2-15, 2-18, and 2-26 were tested in Suzuki reactions, but as the

degree of ligand substitution increased, reactivity decreased.









Access to a diversity of metal complexes from chloroamidiniums was restricted based on

use of the oxidative addition methodology and also required the use of electron rich ligands like

phosphines. As such, a new more general method of carbene generation was developed.

Lithium-halogen exchange was applied to chloroamidiniums to give carbenoid intermediates.

13AC-NMR of the carbene in solution and formation of thiourea constitute proof, and after

generation, Rh, Ir, Pd, and B complexes were produced. Interestingly, X-ray analysis of Rh-

ADC complex 3-5 based on chiral C 1-symmetric pyrrolidine subunits demonstrated a change in

conformational preference from the palladium compounds, as the methyl substituents were

located proximal to the rhodium center. Rh-ADC complex 3-5 was tested in catalytic reactions

and showed good reactivity in 1,4 conjugate addition of aryl boronic acids to cyclohexenone and

in 1,2 addition of aryl boronic acids to aryl aldehydes. Notably, the ADC ligand performed

better than NHC in 1,2 addition.









CHAPTER 1
INTRODUCTION

Acyclic Diaminocarbenes

N-heterocyclic carbenes (NHCs) are of the most ubiquitous class of ligands, and their

presence has only grown since the discovery of isolable carbenes by Arduengo in 1991.1 The

emergence of NHCs is attributed to their ability to act as a more robust alternative to phosphines.

Many metal complexes incorporating NHCs are more stable against heat, moisture and oxygen

than their phosphine counterparts.

Carbenes, similarly to phosphines, show strong o-donor capacity, creating an analogy

between the two classes of ligands,2 but an advancement in the understanding of carbenes has

shown these ligands have a rich breadth of chemistry all their own and are much more than

simple "phosphine mimics".3 Carbenes are more basic than even the most electron-donating

phosphines.4 Additionally, they are less labile, and the lower liability is most likely due to bond

dissociation energies that are practically double that of even the most electron rich trialkyl

phosphines.3a,4a In some notable cases, carbene complexes have demonstrated higher activity

than even the best phosphine systems.5

Typically, carbenes used as ancillary ligands are located on a heterocyclic scaffolding

such as 1-1 shown below. Rare cases feature acyclic diaminocarbenes (ADCs) in which the

carbene ring has been dissolved (1-2 to 1-4). ADCs are a promising variant of NHCs possibly

representing the next generation of carbenes. ADCs feature a larger carbene N-C-N bond

angle with respect to regular NHCs, leading to a more basic carbene lone pair (Table 1).6 The

carbene's move toward linearity decreases the singlet triplet energy gap of the carbene frontier

molecular orbitals, l and bis(diisopropylamino) carbene 1-2 is the most basic carbene known to

date.











Ar-N N'Ar NT N N N NN N?

1-1 1-2 1-3 1-4

Figure 1-1. An N-heterocyclic carbene and some acyclic diaminocarbenes.

In addition to the increased donor capacity of ADCs, it is envisioned that ADCs could be

quite useful in asymmetric catalysis. The larger bond angle of these carbenes should place chiral

centers closer to metal coordination spheres than traditional NHCs, leading to a more efficient

transfer of chirality. Thus far, only one example of a chiral ADC complex exists.7a The goal of

this research was to explore novel chiral ADCs.

Table 1-1. Calculated values of N-C-N bond angle and proton affinity (PA) for select
carbenes

N N N_,N N _,N

-5 1-6 1-2


N-C-N Bond Angles () 106.0 116.3 121.0
Proton Affinity (kcal/mol) 271.4 278.9 282.9

ADCs have been relatively unexplored with respect to NHCs, and relatively few

examples of catalysis with ADCs exist. Slaughter and Firstner have both isolated metal

complexes with ADCs and then used them catalytically, and Thadani has shown in situ

generation of metal complexes with ADCs to be useful.7 The lack of proliferation is partially

caused by the difficulties associated from working with ADCs. Since they are more basic and

sterically hindered than the usual NHCs, extension of common methods for the preparation of

metal compounds do not always translate. Therefore, non-traditional modes of complexation are

sometimes necessary.









1060


Triplet NHC ADC


M
AE
B 1210

Singlet

-4-"N N

A

Figure 1-2. A comparison of electronic and steric parameters for NHC and ADC ligands. A)
Frontier molecular orbitals of carbenes. Triplet carbenes adopt a linear geometry
whereas singlet carbenes take on a bent geometry with 1200 angles. An NHC is a
typical singlet carbene, but an ADC has a larger carbene bond angle. As it moves
toward a more linear state, the HOMO rises in energy with the lone pair becoming
more donating as a result. B) The greater carbene bond angle of the ADC places the
N-substituents in closer proximity to the metal center.

Furstner and co-workers utilized chloroamidinium ions in a novel way to initiate

formation of metal complexes with ADCs.7c,d This route relied on three tasks: formation of

ureas, generation of chloroamidinium ions, and the ability to metalate chloroamidinium salts.

The chloroamidinium ions were formed by reacting ureas with oxalyl chloride, and the

chlorinated product underwent oxidative addition to electron-rich, palladium phosphine species.

NHC and ADC complexes were synthesized through this route, and the products were

demonstrated as useful in Suzuki Coupling, Heck Coupling, and Buchwald-Hartwig amination.

Previous research by Stone and Cavell gave precedent for this work.8

1) Toluene h \ @ O
(COCI)2 R PFe6
N N 60 OC RN Pd(PPh3)4 R-NCNR
R" R --R-^V'R c
YIC 2) AgPF6, CH2CI2 y Toluene Ph3P-Pd-PPh3
0 Cl 100 -C, 2h h
BF4e

Figure 1-3. General method of preparation of carbene metal complexes via Ftirstner's route.











-\ 'PF6
,-N, N-,N

Ph3P-Pd-PPh3
CI
Cl
1-7

N'N PF6N
/N-C-N,
Ph3P-Pd-PPh3
CI
Cl-0
1-10


PFK PF6
-,C N'Ph /N.'C- N
I I
Ph3P-Pd-PPh3 Ph3P-Pd-PPh3
I I
Cl Cl
1-8 1-9
N Fe MeOC FHe


Ph3P-Pd-PPh3 Ph3P-Pd-CI
I I
Cl PPh3
1-11 1-12


Figure 1-4. Some carbene metal complexes formed by oxidative addition of chloroamidinium
ions.









CHAPTER 2
BIS(2-ALKYLPYRROLIDIN-1-YL)METHYLIDENES AS CHIRAL ACYCLIC
DIAMINOCARBENE LIGANDS

Introduction

Potentially, ADCs based upon a 2-substituted pyrrolidine framework might demonstrate

interesting properties. Depending on the conformational preference of the chiral substituents, the

ligands might show an ability to influence stereochemical outcomes in catalysis. Alternatively,

potential rotation about the N-C bond of the carbene would provide a ligand capable of drastic

alterations in its steric profile (Figure 2-1). Complexes capable of conformational flexibility can



N-CN N N
M Q M M
A B C

Figure 2-1. Potential conformers associated with carbenes designed about 2-substituted
pyrrolidines. A) Adoption of a conformer with chiral groups situated close to the
metal center might afford a catalyst capable of displaying high enantioselectivities
and additionally is quite sterically hindered. B) A conformer with one chiral group
proximal to the metal center might promote some selectivity in catalytic reactions,
and is less intruding into the metal coordination sphere. C) The rotamer with both
substituents positioned away from the metal center is expected to display the lowest
levels of selectivity in catalysis and exhibits the least steric hindrance.

lead to high catalytic activity, as illustrated by Glorius and co-workers, since a transition metal

promoted transformation might require both an unhindered (open) or congested (closed)

environment during a catalytic cycle (Figure 2-2).9 For example oxidative addition is facilitated

by a non-crowded coordination sphere, whereas reductive elimination is promoted by a sterically

congested environment around the metal. Both processes are often important within the same

catalytic cycle, such as that known for the Suzuki cross-coupling reaction, and while the needs of

oxidative addition and reductive elimination appear to be at odds, they can be met with the use of

a conformationally flexible ligand.











A N N N N N
M M M


3 mol% Pd(OAc)2
K3P04, Toluene/THF
B Cl + (HO)2B \ 110C,16h \
3.6 mol% -

N N 96%

n OTFO
n=6

Figure 2-2. Unique abilities of conformationally flexible ligands. A) Potential conformers of a
bis-oxazoline based NHC where the leftmost structure is relatively non-hindered and
the structure on the right is most hindered. B) High catalytic activity of
conformationally flexible ligand.

Ureas Stemming from 2-Substituted Pyrrolidine

Commercially available amines such as (S)-(+)-2-methyl-pyrrolidine and (R)-(+)-2-

(diphenylmethyl)pyrrolidine were used along with (R)-(+)-2-isopropyl-pyrrolidine and (R)-(+)-2-

benzyl-pyrrolidine to give symmetrically substituted ureas stemming from 2-substituted

pyrrolidine derivatives. The mono-substituted pyrrolidines easily afforded ureas 2-1 to 2-4

(Figure 2-3).

N PhosnR R R = Me (71%) 2-1
2 NH Phosgee CHPh2 (84%, 72% with trisphosgene) 2-2
SCH2CI2, Et3N N N i-Pr (46%) 2-3
R 0 C to rt Bn (76%) 2-4

Figure 2-3. Ureas from 2-substituted pyrrolidine derivatives.

(R)-(+)-2-isopropyl-pyrrolidine was synthesized from valine, and amide 2-9 was prepared

by a known procedure (Figure 2-4).10 The carbonyl functionality of 2-9 was reduced with

LiAlH4 and protected in situ with Boc20 because of volatility of the corresponding amine.

Protected amine 2-10 was deprotected with 4M HC1 in dioxane, the excess HC1 was removed in









vacuo, and a phosgene solution was added to give urea 2-3. (R)-(+)-2-benzyl-pyrrolidine was

synthesized following the same procedure and leading to the related urea 2-4.

1) DMAP, DCC 2) AcOH
HO 0HO O CH2CI2 NaBH4
S Boc20, THF/H20 HO 0 0C, 12 h CH2C12
NH2 rt, 18h, 99% NHBoc 0 0 0 12 h
NH2 86%
2-5 2-6 O
0
0 f (CF3CO)20 1) LiAIH4, THF
S Toluene CH22 0 C to rt
0 NBoc NH
110 C, 4 h 0 OC to rt 2) Boc20, THF
0 98% 94% 97%
NHBoc
2-7 2-8 2-9
1)4M HCI in
NBoc Dioxane
2) Phosgene N N
Et3N, CH2Cl2
0 0C to rt
2-10 46% 2-3

Figure 2-4. Synthesis of urea 2-3 from condensation of (R)-(+)-2-isopropyl pyrrolidine.

Urea Crystal Structures

Crystal structures of ureas 2-1 and 2-2 were obtained to better understand conformational

preference of the alkyl substituents and to discern whether the ensuing carbenes might be

suitable as chiral ligands. Three different conformers, A, B, and C, are attainable as rotation

about the amide bond is possible (Figure 2-5). Conformer A places the aliphatic substituents in a

syn-relationship proximal to the carbonyl functionality. This isomer was expected to

predominate over B and C as it relieves steric hindrance associated with an alkyl substituent

located distal to the carbonyl group. Indeed, when a single crystal was obtained for ureas 2-1

and 2-2, isomer A was observed (Figures 2-6 and 2-7). Notably, the two pyrrolidine ring

systems are not coplanar. In the solid state, 2-1 demonstrates a dihedral angle of- 340 for N(2)-









C(1)- N(1)-C(2) and N(1)-C(1)-N(2)-C(7), and in urea 2-1 these dihedral angles are larger at

400

R 0 R 0


R R F
A B C

Figure 2-5. Potential conformers of ureas 2-1 to 2-4.

This twisting of the ring systems seems to indicate steric repulsion at carbons C(2)-C(7)

and C(2)-C(19) for 2-1 and 2-2 respectively and growing strain in the molecule. It also indicates

a lack of conjugation. The growing strain in the bulkier molecule becomes even more evident

when viewing the N(1)-C(1)-N(2) bond angle. The less hindered 2-1 possesses an N-C-N

bond angle of 116.57(9)0, but for urea 2-2 this value shrinks to 113.3(5)0, further deviating from

the ideal 1200 and pushing the methylene groups adjacent to nitrogen closer together.

If a similar conformational preference is assumed with carbenes, acyclic carbenes

stemming from 2-substituted pyrrolidines might make good asymmetric ligands. In the solid

state the ureas show a conformational preference for A over B and C, and there seems to be a

degree of repulsion between C(2) and C(7) in 2-1 and C(2) and C(19) in 2-2. An isomer of type

A should be even more favorable in the case of a carbene since the carbene generally shows a

higher level of conjugation due to the empty p-orbital centered on C(1). This increase in

conjugation and flatness of the carbene should decrease the twisting in the pyrrolidine ring

system, and therefore it should be less able to accommodate the strain induced from

conformations such as B and C.

























Figure 2-6. Molecular structure of urea 2-1. Selected bond lengths (A) and angles (0): O(1)-C(1)
1.2349(13), N(1)-C(1) 1.3733(13), N(2)-C(1) 1.3739(13), N(1)-C(1)-N(2) 116.57(9),
N(2)-C(1)-N(1)-C(2) 34.66(15), N(1)-C(1)-N(2)-C(7) 33.61(15).







C32B C34B
C4B CB C3B
C1OB C11B C3 C2BC
C12B+ 01B C30B C29B C28B
C9B C7B C5B N2B C23B C27B
C8B C7B^ N1B
C6B C1B C24B
C13B C18B CC22B C25B
C17B C19B C21B C26B
C14B C20B

C15B (" )C16B




Figure 2-7: Molecular structure of urea 2-2. Selected bond lengths (A) and angles (): O(1)-C(1)
1.242(6), N(1)-C(1) 1.372(6), N(2)-C(1) 1.373(7), N(1)-C(1)-N(2) 113.3(5), N(2)-
C(1)-N(1)-C(2) 40.0(8), N(1)-C(1)-N(2)-C(19) 43.0(8).











Table 2-1. Crystal data and structure refinement for 2-1.

Empirical formula C11 H20 N2 0
Formula weight 196.29

Temperature 173(2) K

Wavelength 0.71073 A
Crystal system Orthorhombic

Space group P212121
Unit cell dimensions a = 8.9984(7) A
b= 10.1229(8) A
c= 12.283(1) A

Volume 1118.86(15) A3


Density (calculated)

Absorption coefficient
F(000)

Crystal size

Theta range for data collection
Index ranges

Reflections collected

Independent reflections
Completeness to theta = 27.500
Absorption correction
Max. and min. transmission
Refinement method

Data / restraints / parameters
Goodness-of-fit on F2

Final R indices [I>2sigma(I)]
R indices (all data)

Absolute structure parameter
Largest diff. Deak and hole


1.165 Mg/m3
0.075 mm-1
432
0.20 x 0.20 x 0.18 mm3

2.61 to 27.50.
-1I 7612

2561 [R(int)= 0.0312]
100.0 %

Integration
0.9904 and 0.9851
Full-matrix least-squares on F2
2561/0 / 127
0.961

R1 = 0.0321, wR2 = 0.0744 [2149]
R1 = 0.0399, wR2 = 0.0763
-0.4(11)
0.165 and -0.264 e.A-3


Table 2-2. Crystal data and structure refinement for 2-2.

Empirical formula C35 H36 N2 0
Formula weight 500.66

Temperature 173(2) K


c= 90.

p= 90.
y = 90.


V











Wavelength
Crystal system
Space group
Unit cell dimensions


0.71073 A
Monoclinic
P2(1)
a= 16.0406(14) A
b= 10.8168(9) A
c = 56.512(5) A
9804.9(14) A3


Volume


o= 90.
p= 90.539(1).
y = 90.


Density (calculated)
Absorption coefficient
F(000)
Crystal size
Theta range for data collection
Index ranges
Reflections collected
Independent reflections
Completeness to theta = 25.000
Absorption correction
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I>2sigma(I)]
R indices (all data)
Absolute structure parameter
Largest diff. peak and hole


1.187 Mg/m3
0.071 mm-1
3752
0.19 x0.11 x0.05 mm3
1.08 to 25.000.
-9 40889
28710 [R(int) = 0.0496]
94.7 %
None
Full-matrix least-squares on F2
28710/1/2413
0.841
R1 = 0.0555, wR2 = 0.0884 [10696]
R1 = 0.1757, wR2 = 0.1230
0.8(10)
0.151 and -0.185 e.A-3


Formation of Palladium-ADC Complexes

Ureas were treated with a chlorinating agent such as oxalyl chloride or POC13 to generate

the chloroamidinium salts (Figure 2-8). Anion exchange was performed on these salts to make

them less hygroscopic, and the chloride anion was substituted with a tetrafluoroborate anion.

The isolated chloroamidinium salts were then reacted with Pd(PPh3)4 in toluene at 100 OC for

two hours, and the product was purified by recrystallization (Figure 2-9).









ClC BF4$
R O R R Cl R R CI R

N N Toluene or CCl4 CH2Cl2, 1 h A
60 C, 16 h C I,
R = Me (70%) 2-11
CHPh2 (52%) 2-12
i-Pr (61%) 2-13
Bn (57%) 2-14

Figure 2-8. Chlorination of ureas with oxalyl chloride.

Chloroamidiniums featuring primary alkyl substituents such as 2-11 (methyl group) and

2-14 benzyll group) afforded ADC-Pd complexes in good yield. However, more congested

secondary alkyl substituted carbene precursors 2-12 (CHPh2) and 2-13 (i-Pr) did not afford the

desired complex as an isolable substance.

BF4 RR R@
S RCI -R BF4
/ N N6 Pd(PPh3)4 O N ,N R = Me (65%)2-15
Toluene, 100 C I CHPh2 (Yield not obtained) 2-16
65% Ph3P-Pd-PPh3 i-Pr (Yield not obtained) 2-17
CI Bn (49%) 2-18

Figure 2-9. Complexation of chloroamidiniums to palladium.

The metal complexes of 2-15 and 2-18 were fully characterized by mass spectroscopy and NMR,

and a crystal structure of 2-15 was obtained as well. Unfortunately, conclusive NMR and mass

spectroscopy were not obtained for complexes 2-16 and 2-17.

The X-ray crystal structure of complex 2-15 provides several key insights and depicts an

image of a somewhat strained molecule (Figure 2-10). In contrast to the urea crystal structure,

the methyl groups are positioned away from the metal center, apparently reducing steric

repulsions with the triphenyl phosphine ligands. Thus the phenyl rings of triphenyl phosphine

are staggered with respect to the chloride ligand yet eclipsed with regards to the carbene. This









close proximity and resulting repulsion certainly plays a role in the orientation of the methyl

groups.

Similarly to crystal structures obtained by Furstner's group,7c the plane of the carbene

created by N(1)-C(1)-N(2) is nearly orthogonal to the metal coordination plane defined by the

four ligands P(1), P(2), Cl(1), and C(1). The dihedral angles of N(2)-C(1)-N(1)-C(5) and N(1)-

C(1)-N(2)-C(10) are less than those observed with the corresponding urea. They are 12.6(5)

and 14.8(5) respectively, still showing a slight divergence from coplanarity and complete

conjugation; however, this is not unusual for acyclic diaminocarbenes.6c

The increased carbene bond angle [N(1)-C(1)-N(2)] is of the highest interest, and its value

is 123.7(2). This is one of the largest diaminocarbene bond angles known, and to the best of my

knowledge only one metal carbene complex shows a larger angle.6a'd The chromium complex 2-

19 has an N-C-N bond angle of 1250, although it is bound in qr2-fashion, and the author states

this increased hapticity enlarges the angle (Figure 2-11). The carbene bond angle of complex 2-

15 is 1.5 to 2.00 greater than analogous achiral complexes such as 1-10 prepared by Furstner

and co-workers. While small, this value is certainly not insignificant. The increase is most

likely caused by the increased repulsion due to methyl groups close proximity. The palladium

carbene bond length is 2.021(2) A.

An analysis and comparison to crystal structures from the work of Furstner and co-workers

leads to interesting conclusions. Larger bond angles lead to longer metal carbene bonds. The

longer bond is possibly caused by greater intrusion into the metal coordination sphere which

commonly promotes lower bond dissociation energies in NHCs.3a It is also possible the increase

in bond length comes from a carbene that is increasing in triplet character and that is potentially

destabilized by this change.







































Figure 2-10. Molecular structure of complex 2-15. Selected bond lengths (A) and angles ():
Pd(1)-C(1) 2.021(2), N(1)-C(1) 1.329(3), N(2)-C(1) 1.342(3), N(1)-C(1)-N(2)
123.7(2), N(2)-C(1)-N(1)-C(5) 12.6(5), N(1)-C(1)-N(2)-C(19) 14.8(5).

Table 2-3. Crystal data and structure refinement for 2-15.
Empirical formula C47 H50 B Cl F4 N2 P2 Pd
Formula weight 933.49
Temperature 173(2) K
Wavelength 0.71073 A
Crystal system Orthorhombic
Space group P212121
Unit cell dimensions a = 16.0636(8) A c= 900.
b = 16.2605(8) A p= 90.
c = 19.0326(9) A y= 90.
Volume 4971.4(4) A3
Z 4
Density (calculated) 1.247 Mg/m3
Absorption coefficient 0.538 mm-1











F(000)
Crystal size
Theta range for data collection
Index ranges
Reflections collected
Independent reflections
Completeness to theta = 25.000
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I>2sigma(I)]
R indices (all data)
Absolute structure parameter
Largest diff. peak and hole


1920
0.19 x0.13 xO.11 mm3
1.65 to 26.680.
-19 28914
9381 [R(int) = 0.0550]
99.9 %
Integration
0.9245 and 0.8844
Full-matrix least-squares on F2
9381/7/529
1.068
R1 = 0.0311, wR2 = 0.0818 [8716]
R1 = 0.0337, wR2 = 0.0828
0.017(18)
0.370 and -1.869 e.A-3


When bulky chloroamidiniums such as 2-12 and 2-13 are used, the corresponding carbene

ligands should exhibit N-C-N bond angles greater than that observed for complex 2-15 with

the relatively small methyl substituents. The larger carbene bond angles probably increase the

potential metal carbene bond length accounting for the difficulty in obtaining the more complex

compounds 2-16 and 2-17.



N N


OC 'C /O
ocyIrco
CO
2-19

Figure 2-11. Chromium-ADC complex prepared by Herrmann.









Table 2-4. N-C-N bond angles and Pd-C bond lengths for select carbenes.
PF G F PF6 PF
-N.N C'N -NCN-ph /N.C'N /N'CN
Ph3P-Pd-PPh PhP-Pd-PPh3 PhPP-Pd-PPh3 Ph3P-Pd-PPh3
Cl 1-7 CI 1-8 CI 1-9 CI 1-10
N-C-N Angles (0) 109.70 108.95 119.6 121.6
Pd-C Bond 1.9805 1.9687 2.005 2.003
Lengths (A)
N MeO
JPFC PF / BFE
N N B
ON, 'N` C* aNlc..N
Ph3P-Pd-PPh3 Ph3P-Pd-CI Ph3P-Pd-PPh3
CI 1-11 I I
PPh3 1-12 CI 2-15
N-C-N Angles (0) 122.3 124.0 123.7
Pd-C Bond 2.023 2.047 2.021
Lengths (A)

Suzuki Cross-Coupling

Palladium complexes of electron-rich, sterically demanding phosphines or NHC ligands

are effective catalysts for sterically demanding Suzuki couplings, and those ligands are believed

to stabilize a putative monoligated Pd complex."1 It is known that the oxidative addition step is

promoted by a highly o-donating ligand to stabilize the Pd" oxidation state whereas the reductive

elimination step can be accelerated by a sterically demanding ligand. Therefore, the highly c-

donating and bulky ADC ligand is perfect, meeting those exact requirements. In fact, Thadani

and co-workers reported that ADC-Pd complexes efficiently catalyze demanding Suzuki

couplings, and therefore application of chiral ADC-Pd complexes in the asymmetric Suzuki

coupling reaction is promising.7b Prior to our studies, Fiurstner and co-workers conducted some

preliminary work with the cationic palladium complexes in the Suzuki reaction. Using 1 mol %

of 1-7, phenyl boronic acid and 4-bromoacetophenone were coupled in 79% yield (Equation 2-

1). With catalyst 1-8, that yield improved to 89%.









In our work, application of the reported conditions led to low to moderate yields in the

coupling of simple substrates such as 2-20 and 2-21 and 2-20 and 2-22 with ADC complexes



S1 % [Pd] 1-7 -N ,N-..
+ 2 THF, K2C03 C(2-1)
Sreflux Ph3P-Pd-PPh3 (2-1)
(HO)2B Br 79% I
1-7



Qa Q.R' THF, BaR R' / BF^
+ I [Pd] 2-15 / / NF (2-2)
THF, Base /
reflux, 20 h Ph3P-Pd-PPh3
Br B(OH)2 2-15
CI 2-15


Table 2-5. Optimization of Suzuki cross-coupling reaction.
Entry Boronic Acid Aryl Bromide Base Mol % Yield (%)
n-Bu


1 I K2CO3 1 24
B(OH)2
2-20 2-21
2-21


2 2-20 ) K2CO3 1 50
Br
2-22
3 2-20 2-22 CsF 3 100


(Entries 1 and 2, Table 2-5). Optimizing the conditions by changing the base and increasing the

amount of catalyst resulted in significant gains in yield. Thus, the conformationally flexible,

chiral ADC-Pd complexes are active catalysts for sterically demanding Suzuki coupling

reactions. Hindered di-ortho and tri-ortho-substituted biaryls were produced in excellent yields

with catalysts 2-15 and 2-31. Attempting the very challenging synthesis of tetra-ortho-

substituted biaryls did not result in product formation (Entries 4 and 5, Table 2-7).













B(OH)2
2-23


[Pd] Cat.
CsF, THF
reflux, 20 h


2-24


(2-3)


Table 2-6. Suzuki cross-coupling of 2-23 and 2-24 with a variety of catalysts.

Entry Boronic Acid Aryl Bromide Catalyst Yield (%) Ee (%)


B(OH)2
2-23


2-23


2-23


2-23


2-23


OMe
Br
2-24


2-24








2-24








2-24




2-24


,C- NDN BF4

Ph3P-Pd-PPh3
CI 2-26


N C
I
Ph3P-Pd-PPh3
CI 2-15


Ph Ph


\ N
C-
Ph3P-Pd-PPh3
Cl 2-18


N.A.


BF4


Fe
BF4


BF`
Ph2HC CHPh2 BE4



Ph3P-Pd-PPh3
CI 2-16


N.A.


Pd(PPh3)4
aConditions: 3 mol % [Pd], 1 equiv ArBr, 1.2 equiv ArB(OH)2, 2.8 equiv CsF, THF, 100 C. Complex generated in
situ and used without further purification.










N R R's R R'
+ 3 mol % [Pd] (2-4)
STHF, CsF (2-4)

Br B(OH)2 reflux, 20 h
Br B(OH)2

Table 2-7. Exploration of substrate scope in Suzuki cross-coupling reaction.
Entry Boronic Acid Aryl Bromide Catalyst Yield (%)


1Me BN C 4e9
1 2-27 B(OH)2 Br 98
2-28 Ph3P-Pd-PPh3
Cl 2-26


2-23 B(OH)2



C OMe
2-30 B(OH)2



( : OMe
2-30 B(OH)2



S Me
2-27 B(OH)2




B(OH)2
2-20


2-29 Br


NO2
Br 2-31




2-29 Br


)?OMe
2-24 Br

n-Bu




Br
2-21


2-26




2-26




2-26




2-26



Ph2HC CHPh2 BF4



Ph3P-Pd-PPh3
Cl 2-16


The catalyst was varied when producing biaryl 2-25, and it is interesting to note that the

carbenes showing the most steric hindrance provided the lowest yields in Suzuki cross-coupling

reactions. This might be attributed to the observation that more hindered carbenes exhibit longer

Pd to carbene bonds, perhaps causing the ligands to become more labile. Although difficult to

isolate, catalyst 2-16 was generated in situ from chloroamidinium and Pd(PPh3)4 and tested in









catalysis resulting in 64% yield of 2-25 (Entry 4, Table 2-6). Pd(PPh3)4 was tested separately in

the Suzuki reaction, to ensure catalysis with 2-16 was not solely a result of residual Pd(PPh3)4

(Entry 5, Table 2-6).

A major goal of this program is to develop an asymmetric version of the Suzuki reaction.12

Using chiral catalysts such as 2-15, 2-16, and 2-18 substrates 2-23 and 2-24 were combined to

form a tri-ortho-substituted product, and the enantiomeric excess (ee) was determined by chiral

HPLC using a Chiralcel OJ-H column.12 The observed ee's were low and ranged from 3-4 %.

While this might be rationalized by the location of the chiral substituents, it was hoped that upon

dissociation of the phosphines at elevated temperature, the chiral centers might reposition

themselves proximal to the metal center in order to relieve steric strain.

C2-Symmetric Pyrrolidine Moieties and Attempts at Symmetrically Substituted Ureas

A potential problem associated with chiral ADCs made from 2-substituted pyrrolidine

subunits involved rotation about the bond linking nitrogen and the carbenoid carbon. Based on

the low enantioselectivities observed in the Suzuki cross-coupling, we focused on the synthesis

of ureas with a C2-axis of symmetry to minimize difficulties caused by rotation. Design of ureas

centered on the use of (2S,5S)-trans-diphenylpyrrolidine 2-37 as the chiral moiety.

The chiral amine was easily produced following a known procedure (Figure 2-12).13

Friedel-Crafts arylation of fumaryl chloride leads to enone 2-33, and the olefin is subsequently

hydrogenated using SnC12. Excellent enantioselectivity was observed for the CBS-catalyzed

reduction of the dione to a diol. Following reduction, the diol is cyclized to the amine in one-pot

with allyl amine. At this stage, the diastereomers were separated using column chromatography,

and the chiral tertiary amine was deprotected by refluxing in an acetonitrile-water mixture with

Wilkinson's Catalyst to afford enantiomerically pure amine 2-37.










Cll Benzene, AIC3 Ph SnCl2, 8N HCI Ph
rt, 2 h, 93% 11 EtOH, reflux
O O 1 h, 67% O
2-32 2-33 2-34
10 mol%
H OH
)Ph OH 1)MsCI, Et3N
P ph L.v.Ph CH2C2, -20 -C Ph (Ph3P)3RhCI
P\ Ph' N Ph "
10 mol% B(OMe)3 OH 2) CNH2 N MeCN/H20 (1:1)
br ve2 6H ^reflux, 5 h, 81 %
BH3SMe2 2-35 0 C to rt 2-36
THF, rt, 1 h 97%, ee 80%
Ph" Ph 93% de

Ph" ` N Ph
H
2-37

Figure 2-12. Preparation of (2S,5S)-trans-diphenylpyrrolidine

Urea formation was attempted in a condensation reaction using two equivalents of chiral

amine 2-37 with phosgene (Equation 2-3), but the simple condensation reaction did not give

urea. A product with 286 amu was recovered, which corresponds to carbamoyl chloride 2-38.

Changing the solvent to toluene and heating at temperatures up to 200 OC were ineffective in

changing the outcome, and various strategies were undertaken to produce urea 2-39 (Figure 2-

13). For example, amine 2-37 was deprotonated with n-BuLi and reacted with 2-38. Also, ferric

chloride was added to a solution of carbamoyl chloride 2-38 and chiral amine 2-37 in an effort to

help activate the electrophile. At one point, a phosgene derivative, carbonyl diimidazole (CDI),

was utilized to replace phosgene (Figure 2-14). None of these strategies led to the desired

Ph Phosgene Ph 0
Et3N, CH2CI2
2Et3N CH2CN2H JN ) CI (2-3)
NH rt, 24 h
90%
Ph Ph
2-37 2-38










Phosgene
Et3N, CH2CI2

500, 1000, 1500
and 2000 for 24 hr


Phosgene
A
-78 OC to rt,
CH2CI2, 24 h


Ph 0 Ph


2-39


Ph

2 bNH

Ph
2-37

Ph

2 N Li

Ph
2-40


Ph 0

N CI
S2-38
Ph

rrolidine
,N, CH2CI2
24 h




NP N

Ph 2-41


H
Ph AN, NPh
FeCl3,

THF
rt and reflux


2-39


Figure 2-13. Some attempts at urea formation with (2S,5S)-trans-diphenylpyrrolidine.


O

+ N N N
\z zi =N


1.1 eq


Ph 0

N N N Mel
SMeCN, 40 C
Ph
2-42


Ph O

LN N N-

Ph
2-43


Figure 2-14. Synthetic attempt aimed at urea 2-39 using CDI.


Ph 0 Ph

6NNQ

Ph Ph
2-39


Lie)
Ph N Ph

Ether
Ether


Ph Pt
2-39


Ph

NH

Ph
1 eq 2-37


THF
80 C, 24 h


Ph
Ph 2-42


H
Ph N Ph


Et3N


2-39









S= 0
Ph NH Triphosgene Ph N CI
S Et3N, CH2C2
Ph^ 72% ph
2-44 2-45

^^c-
)[ 'NN N cO

H Phosgene 2-47
Benzene +

2-46 N6CO
2-48

Figure 2-15. Challenging secondary amines in desired urea production.14

product 2-39, and it is believed that the hindered nature of the carbamoyl chloride caused a

second condensation to be difficult, as production of hindered ureas is known to be difficult

(Figure 2-15).14

Ureas with Non-Identical Amine Moieties Featuring (2S,5S)-trans-diphenylpyrrolidine

Carbenes incorporating 2-substituted pyrrolidine moieties showed a preference for

placement of the chiral substituents away from the metal center. Since the conformers could not

be effectively controlled, a C2-symmetric amine was needed, rendering rotation about the

nitrogen carbene bond insignificant. As a result, 2-37 was featured in the synthesis of several

ureas constructed from non-identical secondary amines.

Chiral amine 2-37 can be combined with a variety of electrophiles to make ureas. Figure

2-16 below shows reaction sequences where the pyrrolidine derivative is mixed with carbamoyl

chlorides, acyl halides, and isocyanates to form ureas. Ureas 2-41 and 2-49 were made from

carbamoyl chlorides; however, some hindered molecules such as diisopropyl carbamoyl chloride

failed to react with 2-37. Isocyanates react best with 2-37 leading to tri-N-substituted ureas









which can easily be methylated in high yield, as seen in the formation of 2-52 and 2-54. Also,

the amide precursor to a Bertrand type carbene, 2-50, was made from p-anisoyl chloride.15


Et3N, CH2CI2
60 C, 1 day
70%


Ph



Ph
2-41


Ph

NH

Ph
2-37


Ph

cNH

Ph
2-37


Ph

CNH

Ph
2-37

Ph

[NH

Ph
2-37


Ph

bNH

Ph
2-37


Et3N, CH2CI2
0 C to rt
1 d, 84%


Ph

N4 N
N
Ph
2-49


2-50


2-51


NaH, Mel
DMF, 40 C
97%




NaH, Mel
DMF, 40 C
92%


2-53


2-52


'Ph
2-54


Figure 2-16. Ureas from carbamoyl chlorides, acyl chlorides, and isocyanates.

Chlorination and Metalation of Ureas Based on (2S,5S)-trans-Diphenylpyrrolidine

Chlorination was conducted with the newly made ureas (Figure 2-17). Unlike ureas 2-1-

2-4, not all of the urea based on 2-37 chlorinated smoothly. Compound 2-41 took five days to

complete reaction, and the NMR spectrum of the product was difficult to reproduce. Urea 2-50

fragmented under the reaction conditions, and pieces of the molecule were isolated upon workup.

The mesityl substituted urea 2-54 did not provide the chlorinated product to an appreciable


Et3N, CH2CI2
0 C to rt
80%

0o,
"N /

MTBE, rt, 89%




MN r

MTBE, rt, 81%









extent either, but the slightly less hindered 2-52 chlorinates after several days at 60 OC. Urea 2-

49 chlorinates with exceeding ease in comparison to the other reagents, and after stirring

overnight, a nice, white, isolable solid is obtained. The desired ADC-Pd compound was not

isolated under oxidative addition conditions, however.

BFE
Ph 0 N | Ph CI N
PhN,.N 1) oxalyl chloride 2) AgBF4, CH2CI2 P O ..
N N N N
\I |Toluene, 60 C 1 h, RT, 75%
Ph 18h "Ph 2-55
2-49


e PhD
Ph BF4Cl N BF4
PhN B Pd(PPh3)4 NI

Toluene, 100 *C Ph C-Pd-N
'Ph 2-55 PPh3 2-56

Figure 2-17. Chlorination of urea 2-49 and attempt at cationic ADC-Pd compound 2-56.

Conclusion and Summary

Ureas are a logical entry point from which to reach acyclic diaminocarbenes. Ureas are

purified with relative ease and their synthesis is relatively straightforward. Amidinium salts on

the other hand can be difficult to purify and are sometimes difficult to make for non-simple

structures.6e Based on others' work, oxidative addition was taken advantage of to form ADC-Pd

complexes with the incorporation of triphenyl phosphine ligands.7c'd

Simple ureas constructed from 2-substituted chiral pyrrolidines were converted to

chloroamidinium salts and then bound to palladium. Interest in these ligands lay in their

potential for heightened activity and selectivity. The potential for conformational flexibility did

not improve the catalytic ability of the ADCs. Conversely, as the 2-position became more highly








substituted, catalyst activity decreased. Whether the substituents ever actually shift to create a
more sterically crowded environment under catalytic reaction conditions is unknown.





N N N N

Ph3P-Pd-PPh3 M
Cl 2-58

Figure 2-18. ADC-Pd complexes with 2-substituted pyrrolidines as mimics for ADC ligands
with C2-symmetric pyrrolidines. The steric interaction of the substituents toward the
back of the catalyst are detrimental.
We can presume that ureas of the type depicted in Figure 2-18 incorporating two C2-
symmetric pyrrolidine units would not be feasible ligands if the substituent has any significant
bulk. They can not avoid the detrimental interaction of substituents located distal to the metal
center that seems to account for the difficulty in isolating 2-16 and 2-17 and the also decreased
catalytic activity of complexes with increasing ADC substitution.









CHAPTER 3
LITHIUM-HALOGEN EXCHANGE: A NEW METHOD FOR DIAMINOCARBENE
FORMATION

Introduction

While the previously described methodology led to palladium complexes with carbenes,

several non-desirable features present themselves. Most importantly, the oxidative addition

procedure necessitates the use of electron donating ligands like phosphines and restricts the

diversity of catalysts that can be synthesized. Primarily, NHC chemistry was developed as an

alternative to phosphine use, but the insertion of Pd into the C-Cl bond of the chloroamidinium

does not take place in the absence of phosphines. The second drawback is that formation of

catalysts incorporating sterically demanding substituents such as those seen in chloroamidiniums

2-12 and 2-13 was not feasible. The difficulty arises from the intrusion of the triphenyl

phosphine ligand into the space occupied by ADC ligands, and it is manifested in the strained

orientation of the chiral substituents. In a related manner, the direction of the chiral substituents

of 2-substituted pyrrolidines is problematic. In being located distal to the metal center, the

ability of these directing groups to transfer chirality to substrate is minimized.16

The direct conversion of chloroamidiniums 2-11 to 2-14 into carbene synthons is ideal,

and it was envisioned that lithium-halogen exchange might accomplish this goal through a

reduction of the C-Cl bond (Figure 3-1).

R R R R R R
I I n-BuLi I I I I
RN 'R -n-BuC R'N N'R or R' NCN'R
CI BF4O Li BF4
+ LiBF4

Figure 3-1. Envisioned synthesis of carbene intermediates through Li-X exchange.

Organolithium reagents have played an important role in organic synthesis,17 and the

formation of these reagents proceeds through a number of routes including reduction with









metallic lithium,18 deprotonation with a lithiated base,19 lithium-halogen exchange,20 and

transmetalation.21 It is important to note that lithiation has been speculated to generate carbenoid

intermediates in reaction with R2CBr2 and in the Fritsch-Buttenberg-Wiechell rearrangement.22'23

Nevertheless, to the best of my knowledge, there have been no examples using lithium-halogen

exchange to form diaminocarbenes from chloroamidiniums.

Li, CloH8, THF
CI [Cr .] I-Li

A

n-BuLi
ci THF Li
-78 C
B


0 n-BuLi, TMEDA "N
CN:: -78 C, THF O-tBu
-tBu Li
C
SnMe3 MeLi L
THF
SOC
D

Figure 3-2. Classic methods to form organolithium species. A) Reduction with metallic lithium.
B) Lithium-halogen exchange. C) Deprotonation. D) Transmetalation.

Carbene Formation and Proof

As shown in Figure 3-1, formation of diaminocarbenes through lithium-halogen

exchange with chloroamidiniums is easily imagined. In his seminal research, Arduengo

demonstrated that diaminocarbenes react with elemental sulfur (Ss) to form thioureas (Figure 3-

3), and the formation of thioureas can be taken as a simple proof of carbene intermediates.

In the attempted formation of a putative carbene species, chloroamidinium 3-1 was added











1) n-BuLi, THF
SB -78 *C, 1 h
@ B G^ 2) Sulfur Y
3-1 C BF4 -78 C to rt, 12 h 3-2
N N 3-1 CI 3-2 S68%
A >n Sulfur N 68%
A Sufu ----- S = --------------------------------------------------------------
N N
SC Sulfur, THF
C ON NfY rt, 12 h No reaction
B *> (starting material
3-1 Cl B4 recovered)



Figure 3-3. Tentative proof of carbene intermediacy via lithium-halogen exchange. A) As
demonstrated by Arduengo and co-workers NHCs react with sulfur to produce
thioureas. B) Production of bis(pyrrolidine)thiourea through lithium-halogen
exchange. C) Control reaction showing that chloroamidinium does not react with
sulfur.

to a Schlenk flask under an argon atmosphere, and THF was added. The suspension was cooled

to -78 C, and at this point, 1.05 equivalents of n-BuLi was added. After approximately five

minutes the white precipitate disappeared, resulting in a clear suspension, indicating

consumption of the chloroamidinium salt and the possibility of a soluble carbene intermediate.

The reaction mixture was stirred for one hour at -78 C before elemental sulfur was introduced to

the solution. The yellowish suspension was allowed to slowly warm to room temperature and

was stirred for twelve hours. Upon purification, thiourea 3-2 was obtained in 68% yield,

suggesting ADC formation under lithium-halogen exchange conditions (Figure 3-3). Since the

chloroamidinium potentially could serve as an electrophile to be attacked by sulfur, a control

reaction was established without the presence of n-BuLi. In this case, thiourea 3-2 was not

obtained (Figure 3-3).

NMR studies were enlisted to further probe the nature of the intermediate generated in

situ (Equations 3-1 to 3-3). The lithium-halogen exchange reaction with chloroamidinium 3-1'

was carried out under an inert atmosphere of argon in THF-d8 in a sealed NMR tube. Data was









collected at -30 OC because the carbene decomposed too quickly at room temperature (within

five minutes). Both 1D and 2D techniques were utilized, where the 2D carbon trace was

obtained through indirect detection of the proton nucleus. Both spectra showed a strong signal at

232.9 ppm clearly indicating the presence of carbene and nicely corresponding to the known

value for the lithiated carbenoid species (Figures 3-4 and 3-5).24

O CH2Cl2 0
II 1 1
NH + 13 2 equiv Et3N 13cC
SCI/ o Cl 0 -C to rt, 12 h82% (3-
0.5 Equiv. a-
3-3'

0 1)(CICO)2 CI BFE
Toluene, RT, 16 h 13C
O Na / NQ 52% (3-2)
N__ N 2) AgBF4, CH2Cl2 52% (3-2)
3-3' rt, 1 h 3-1'


Cl BF4 1)n-BuLi Li F
13q, DF-7 13c BF4
THC, -78 (33)
ICJ N 2) -78 to -30 C (3-3)
3-1' 3-4'


In the 2D gHMBC spectrum, the carbene carbon (232.9 ppm) displayed couplings with

two protons at 3.47 and 3.66 ppm. The gDQCOSY spectrum revealed the sequence 3.47-1.89-

1.76-3.66. The carbons carrying these protons were detected in the gHMQC spectrum at 48.4,

26.5, 24.5 and 55.8 ppm, respectively. Therefore, the two proton resonances at 3.47 and 3.66

ppm can be assigned to the two protons at the C2 position of pyrrolidine, and this gHMBC

spectrum is consistent with the proposed carbene intermediate structure.

Binding Diaminocarbenes to Transition Metals and Boron

The evidence from thiourea formation and NMR experimental studies gave solid proof of

carbenoid generation, and the practical application of this methodology was sought. The



























-0




































0 CE
I^sa L
















0i




















Figure 3-4. 3C-NMR spectrum of lithiated carbene intermediate 3-4' produced through lithium-
halogen exchange.































o
r


















CD




cD
1- 1
(0





CN
,--





















O









































lithium-halogen exchange.
C)
O





















4 0
0





v









st-




































lithium-halogen exchange.









synthesis of potential catalysts was desired, and the formation of transition metal catalysts and

boron carbene adducts was attempted.

First, Group 9 metals were explored using [Rh(COD)Cl]2 and [Ir(COD)Cl]2 precursors.

Chloroamidinium 3-1 was added to a flame dried Schlenk flask in a glovebox under argon

atmosphere, and after removing the flask from the glovebox, THF was added. The suspension

was cooled to -78 C and followed by the addition of 1.05 equivalents of n-BuLi. After one

hour, either [Rh(COD)Cl]2 or [Ir(COD)Cl]2 was added, and the solution was slowly warmed to

room temperature, followed by a reaction period of twelve hours. The rhodium and iridium

complexes were purified through dissolution in ethyl acetate or dichloromethane respectively,

and then impurities were precipitated out of solution through the addition of hexanes. The

rhodium complex was isolated in 65% yield while the iridium complex was isolated in 71% yield

(Figure 3-6). It is important to note that the counter-ion identity proved to be important because

the chloride salt of chloroamidinium 3-1 did not react productively under the lithium-halogen

conditions. The metal complexes were fully characterized by NMR and high resolution mass

spectrometry, and proof of the assigned structure was demonstrated by X-ray analysis (Figures 3-

8 and 3-9).


1) n-BuLi, THF N N
O N ND -78 C, 1 h C C
2) [Rh(COD)CI]2 -Rh-CI
BF4 Cl -78 *C to rt, 12 h
3-1 65%
3-5

-8N N 1) n-BuLi, THF O N
O N N N-78 C, 1 h C NC
2) [Ir(COD)CI]2 -Cl
BF4 Ca -78 C to rt, 12 h
3-1 71%
3-6

Figure 3-6. Formation of rhodium and iridium ADC complexes from chloroamidinium 3-1.









The lithium-halogen exchange methodology was expanded in scope to include

commercially available chloroimidazolium salt 3-7. Upon treatment of chloroimidazolium 3-7

with n-BuLi, introduction of rhodium or iridium metals led to transition metal complexes (Figure

3-7). In this case, the chloride salt performed better than the BF4 salt. The metal complexes

were fully characterized by NMR and high resolution mass spectrometry, and proof of the

assigned structure was demonstrated by X-ray analysis (Figure 3-10).


/ 1) n-BuLi, THF N N
,N N. -78 'C, 1 h IC--
2) [Rh(COD)CI]2 -Rh-C
CIl Cl -78 C to rt, 12 h
3-7 58%
3-8

/ 1) n-BuLi, THF N N\
N N- -78 C, 1 h C--
E I 2) [Ir(COD)CI]2 C
Cl Cl -78 C to rt, 12 h
3-7 46%
3-9

Figure 3-7. Formation of rhodium and iridium NHC complexes from chloroamidinium 3-7.

Not surprisingly, the ADC complexes 3-5 and 3-6 showed larger N-C-N bond angles

of 117.9(2) and 118.4(4) respectively as compared to the carbene bond angle of 108.6(6) for

NHC complex 3-9. Also, the carbene bond length between carbon and transition metal was

longer for the ADCs when compared to the NHC iridium complex. ADC-Ir complex 3-6 showed

a carbene metal bond length of 2.045(5)A, and NHC-Ir complex 3-9 showed a carbene metal

bond length of 2.028(7)A suggesting that the ADC might be more sterically demanding than the

NHC. Where the imadazole ring is nearly flat, the ADC ligand in complexes 3-5 and 3-6 is not

planar. Instead the pyrrolidine rings are twisted showing torsion angles of approximately 260 in

complex 3-5.




























Figure 3-8. Molecular structure of complex 3-5. Thermal ellipsoids are drawn at the 50%
probability level. Selected bond lengths (A) and angles (0): Rhl-C9 2.022(2), Rhl-
Cll 2.3855(6), Rhl-C1 2.110(2), Rhl-C2 2.104(2), Rhl-C5 2.241(2), Rhl-C6
2.197(2), N1-C9-N2 117.90(18), N2-C9-N1-C10 25.68(32), N1-C9-N2-C14
26.69(30).


Figure 3-9. Molecular structure of complex 3-6. Thermal ellipsoids are drawn at the 50%
probability level. Selected bond lengths (A) and angles (0): Irl-C9 2.045(5), Irl-Cll
2.3713(11), Irl-C1 2.101(4), Irl-C2 2.104(4), Irl-C5 2.173(5), Irl-C6 2.189(4), N1-
C9-N2 118.4(4), N2-C9-N1-C10 16.84(62), N1-C9-N2-C14 30.48(63).



































Figure 3-10. Molecular structure of complex 3-9. Thermal ellipsoids are drawn at the 50%
probability level. Selected bond lengths (A) and angles (0): Irl-C9 2.028(7), Irl-Cll
2.3570(17), Irl-C1 2.113(7), Irl-C2 2.097(7), Irl-C5 2.197(7), Irl-C6 2.189(7), N1-
C9-N2 108.6(6).


Table 3-1. Crystal data and structure refinement for 3-5.

Empirical formula C17 H28 Cl N2 Rh
Formula weight 398.77
Temperature 173(2) K
Wavelength 0.71073 A
Crystal system Monoclinic
Space group P21/n
Unit cell dimensions a = 6.5715(6) A
b= 18.7963(18) A
c= 13.7990(13) A
Volume 1699.3(3) A3


Density (calculated)
Absorption coefficient
F(000)
Crystal size
Theta range for data collection


1.559 Mg/m3
1.158 mm-1
824
0.26 x0.13 x0.07 mm3
1.83 to 27.500.


o= 90.
p= 94.439(2).
y = 90.











Index ranges
Reflections collected
Independent reflections
Completeness to theta = 27.500
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I>2sigma(I)]
R indices (all data)
Largest diff. peak and hole


-8 11259
3899 [R(int) = 0.0697]
99.7 %
Numerical
0.9233 and 0.7528
Full-matrix least-squares on F2
3899/0/222
1.048
R1 = 0.0313, wR2 = 0.0795 [3490]
R1 = 0.0351, wR2 = 0.0816
1.034 and -0.948 e.A-3


Table 3-2. Crystal data and structure refinement for 3-6.

Empirical formula C17 H28 Cl Ir N2
Formula weight 488.06
Temperature 173(2) K
Wavelength 0.71073 A
Crystal system Monoclinic
Space group P2(1)/c
Unit cell dimensions a = 9.8235(9) A
b= 14.9332(14) A
c = 23.221(2) A
Volume 3405.0(5) A3


o= 90.
p= 91.616(2).
y = 90.


Density (calculated)
Absorption coefficient
F(000)
Crystal size
Theta range for data collection
Index ranges
Reflections collected

Independent reflections
Completeness to theta = 27.500
Absorption correction
Max. and min. transmission


1.904 Mg/m3
7.995 mm-'
1904
0.34 x 0.23 x 0.17 mm3
1.62 to 27.50.
-12 21406
7805 [R(int) = 0.0360]
99.8 %
Integration
0.3435 and 0.1719











Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 7805 / 0 / 379
Goodness-of-fit on F2 1.224
Final R indices [I>2sigma(I)] R1 = 0.0323, wR2 = 0.0747 [7041]
R indices (all data) R1 = 0.0370, wR2 = 0.0766
Largest diff. peak and hole 0.933 and -1.257 e.A-3


Table 3-3. Crystal data and structure refinement for 3-9.

Empirical formula C13 H22 Cl Ir N2
Formula weight 433.98
Temperature 173(2) K
Wavelength 0.71073 A
Crystal system Orthorhombic
Space group P2(1)2(1)2(1)
Unit cell dimensions a = 7.2770(15) A
b = 12.449(3) A
c= 15.738(3) A
Volume 1425.7(5) A3


Density (calculated)
Absorption coefficient
F(000)
Crystal size
Theta range for data collection
Index ranges
Reflections collected

Independent reflections
Completeness to theta = 27.500
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I>2sigma(I)]
R indices (all data)
Absolute structure parameter


2.022 Mg/m3
9.534 mm-1
832
0.20 x 0.02 x 0.01 mm3
2.09 to 27.50.
-9 9737
3271 [R(int) = 0.0628]
99.9 %
Integration
0.9107 and 0.2515
Full-matrix least-squares on F2
3271/0 / 154
1.046
R1 = 0.0296, wR2 = 0.0652 [3128]
R1 = 0.0320, wR2 = 0.0659
-0.021(13)


o= 90.
p= 90.
y = 90.










Largest diff. peak and hole


O
C NH + Cl C

0.5 Equi




O O
0
3-10



N N
BFO Cl
3-11


CH2CI2
2 equiv Et3N
01 0C to rt, 12 h
v. 74%


1) (CICO)2
Toluene, rt, 16 h
2) AgBF4, CH2C12
rt, 1 h
62%


1) n-BuLi, THF
-78 C, 1 h
2) [Rh(COD)CI]2
-78 C to rt, 12 h
61%


1.197 and -0.918 e.A-3



O N No
0
3-10



QNO
BF? Cl
BF4
3-11




3-R-CI

3-12


Figure 3-11. Formation of piperidine based ADC-rhodium complex 3-12.

In addition to the pyrrolidine based ADC ligand and the N-methyl substituted NHC,

several other ADC ligands were attached to rhodium. Piperidine based chloroamidinium 3-11

was synthesized and used as an ADC synthon after treatment with n-BuLi. Rhodium complex 3-

12 was obtained in 61% isolated yield (Figure 3-11).

Chiral chloroamidiniums 2-11 and 3-14 were also used as ADC precursors to further

demonstrate the scope of the new methodology (Figure 3-12). The usual method of carbene

formation from n-BuLi was utilized. Because [Rh(COD)Cl]2 was left after reaction, simple

precipitation of impurities was insufficient to purify ADC metal complexes 3-13 and 3-15.

Resultantly, silica gel chromatography on a short column was employed starting with a

3:1 mixture of hexanes to ethyl acetate and then quickly shifting to pure ethyl acetate as the

rhodium complex is slightly unstable on a silica gel column. After column chromatography, the

desired product was dissolved in dichloromethane and remaining impurities were precipitated









with hexanes. After filtration and evaporation of the filtrate, complexes 3-13 and 3-15 were

obtained in 65% and 60% yield. The metal complexes were fully characterized by NMR and

high resolution mass spectrometry, and proof of the assigned structure 3-13 was demonstrated by

X-ray analysis (Figure 3-13).

Using the lithium-halogen exchange method for preparing carbenes in place of the

oxidative addition of chloroamidiniums results in several advantages of note. Most importantly,

sterically demanding ligands previously not accessible through the oxidative addition route

become available as seen in compound 3-15. The oxidative addition route requires the use of

bulky phosphines that intrude into the space occupied by the NHC and ADC ligands as seen in

the crystal structure of compound 2-15 that resulted in lengthened carbene metal bonds. Chiral

centers were repositioned toward the back of the metal complex indicating that this positioning

was more favorable than the opposite location which directs the substituents toward the metal.

Palladium complexes stemming from chloroamidinium 2-12 could not be isolated most likely

due to extreme steric constraints. Without the incorporation of bulky phosphine, ligands coming

from 2-12 become feasible suggesting the lithium-halogen exchange route is amenable to a

greater variety of ligands than those obtained through oxidative addition.

The second point of interest relates to the first point and involves the repositioning of the

chiral substituents so that they are oriented toward the metal center instead of distal to the

coordination sphere. When examining the crystal structure of 3-13, this repositioning is noticed,

again insinuating the decreased steric restraints operating upon the square planar rhodium

system. By reorienting the chiral centers, there is a greater chance the ligands can transfer their

chirality to substrates.










1)n-BuLi, THF \N N,
WN N -78 C, 1 h C
U 2) [Rh(COD)CI]2
BE Cl -78 "C to rt, 12 h -CI
2-11 65%
3-13


Y N Nr (CICO)2 N N
Toluene, rt, 16 h
Ph Ph Ph 75% Ph Ph Cl Ph
2-2 3-14


Cl 1)n-BuLi, THF Y N 'CN
N-.N -78 -C, h P h Ph
( -D T2) [Rh(COD)CI]2 Ph P
PPh Cl p,'Ph -78 OC to rt, 12 h --Rh-CI
Ph Ph 60%
3-14
3-15

Figure 3-12. Synthesis of chiral ADC rhodium complexes 3-13 and 3-15.

As mentioned previously, a major goal of this research effort was to develop a

methodology providing a more general route to divergent metal complexes than possible through

the oxidative addition pathway. With this in mind, the research moved beyond Group 9 metals

and into Group 10. Chloroamidinium 3-1 was transformed into a carbene species with use of t-

BuLi in place of n-BuLi, and then dimeric palladacycle 3-17 was added to the THF solution

(Figure 3-14).25 The use ofn-BuLi led to lower yields. The resultant suspension was allowed to

slowly warm to room temperature and then was stirred for twelve hours. At the end of the

reaction time, compound 3-18 was first purified by silica gel chromatography using pure ethyl

acetate as the eluent and then followed by 5% methanol in dichloromethane. The ensuing solid

was further purified by precipitating the product from ethyl acetate with hexanes, giving 3-18 in

45% yield.













C9A


C15A


C19A


C5A


Figure 3-13. Molecular structure of complex 3-13. Thermal ellipsoids are drawn at the 50%
probability level. Selected bond lengths (A) and angles (0): RhlA-CIA 2.052(3),
RhIA-CllA 2.3928(7), RhlA-C16A 2.105(3), RhlA-C17A 2.136(3), N1A-C1A-
N2A 117.8(2), C7A-N2A-C1A-N1A 34.0(4), C2A-N1A-C1A-N2A 20.1(4).


Table 3-4. Crystal data and structure refinement for 3-13.

Empirical formula C19 H32 Cl N2 Rh
Formula weight 426.83
Temperature 100(2) K
Wavelength 0.71073 A
Crystal system Monoclinic
Space group P2(1)
Unit cell dimensions a = 10.4422(9) A
b= 11.9880(10) A
c= 15.3266(13) A
Volume 1914.3(3) A3


Density (calculated)
Absorption coefficient
F(000)
Crystal size


c= 90.
p= 93.8320(10).
y= 90.


1.481 Mg/m3
1.033 mm-'
888
0.41 x 0.20 x 0.09 mm3










Theta range for data collection
Index ranges
Reflections collected
Independent reflections
Completeness to theta = 27.500
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I>2sigma(I)]
R indices (all data)
Absolute structure parameter
Largest diff. peak and hole


1.33 to 27.50.
-13 13908
8304 [R(int) = 0.0176]
99.1%
Numerical
0.9127 and 0.6755
Full-matrix least-squares on F2
8304/1 /467
1.034
R1 = 0.0260, wR2 = 0.0649 [8132]
R1 = 0.0265, wR2 = 0.0652
0.03(2)
1.667 and -0.982 e.A-3


N

3-16




ON N

BF4 CI
3-1


PdCl2
MeOH, rt, 5 h
79%




1) t-BuLi, THF
-78 "C, 1 h
2) [Pd] 3-17
-78 C to rt, 12 h
45%


/ \
N CI1
SPd 'PdN


3-17



N ,N

d-C
3-1 N

3-18


Figure 3-14. Synthesis of ADC palladium complex 3-18.

Several metal precursors were explored before ultimately finding that dimeric palladacycle

3-17 was suitable for catalyst synthesis. Difficulty was experienced in trying to form either Pdo

or Pd" complexes because as explained by Herrmann and co-workers, Pdo has little electron

affinity for very strong o-donors, and ADCs act as effective reducing agents for Pd", forming ill

defined Pdo species.6b [Pd(allyl)]2, PdC12, Pd(MeCN)4(BF4)2, Pd(PPh3)2C12, Pd(dba)2, and









phospha-palladacycle 3-25 were investigated, but none led to the desired ADC palladium


species.


o
BF) CI
3-1



BF4 Cl
3-1







QUO



BF? Cl
3-1
ON N











Doy
BF4O Cl
3-1
ON, N





BF4 Cl
3-1


BF C'I
3-1


1) n-BuLi, THF
-78 C, 1 h
2) [Pd] 3-17
-78 *C to rt, 12 h
17%

1) n-BuLi, THF
-78 C, 1 h
2) [Pd(allyl)CI]2
-78 oC to rt, 12 h



1) n-BuLi, THF
-78 C, 1 h
2) PdCI2
-78 *C to rt, 12 h




1) n-BuLi, THF
-78 C, 1 h X
2) Pd(NCMe)4(BF4)2
-78 C to rt, 12 h



1) n-BuLi, THF
-78 C, h X
2) Pd(PPh3)2Cl2
-78 C to rt, 12 h


yNd N






Pd-C
N



I I
Cl No
3-19



CI-Pd-CI
CI-Pd-CI
cNo
3-20


S2BF

MeCN-Pd-NCMe
NCMe
3-21


BF4

Ph3P-Pd-PPh3
Cl
3-22


QO
BF4 Cl
3-1


1) n-BuLi, THF
-78 C, 1 h
2) Pd(dba)2
-78 C to rt, 12 h


ND


(3-9)


(3-4)





(3-5)


(3-6)







(3-7)






(3-8)


3-23









t-Bu
P(OAr)2 Ar Ar
O' ArO OAr
-Bu + Pd(MeCN)2C12 Tl \CI t-Bu(3-10)
reflux, 8 h Pd Pd
82% t-Bu 'CIl P-O
t-Bu / ArO OAr
3-24
t-Bu 3-25

ArO OAr
N// IN/ 1)n-BuLi, THF opP CI
-78C .1I -X P f .. (3-11)
(0 2) [Pd] 3-25 -Bu C
BF4 C -78 C to rt, 12 h / N
3-1 3-26
t-Bu
Ruthenium complexes with ADCs were desired, but they proved to be difficult to isolate.

First, catalyst synthesis was attempted by displacement of a tricyclohexyl phosphine ligand from

Grubbs First Generation metathesis catalyst (Equation 3-12). Lithiated carbene was generated

from n-BuLi, and then Grubbs catalyst was added to the solution. Upon warming the reaction

mixture to room temperature, the color changed from purple to an orangish-brown color as

expected, but quickly, a black sludge was formed. Only decomposition products were detected

by NMR in a result similar to that obtained by Herrmann and co-workers when working with

ruthenium and ADC ligands.6d Other complex formation was attempted with precursors other

than Grubbs First Generation by Hwimin Seo, a group member; however none of these trials

resulted in successful isolation of an ADC ruthenium complex.

ADC adducts were able to be formed with main group elements in addition to transition

.No 1) n-BuLi, THF O
h -78 C, 1 h X N (3-12)
G 2) PCy3 C,I H
BF4 CI Cl I H-
3-1 Cl'Ru= 3-1 cIr Ph Crc' I Ph
PCy3 PCY3
-78 C to rt, 12 h 3-27










ON ND
BF4 Cl
3-1



N N
BF4 CI
3-1


1) n-BuLi, THF
-78 "C, 1 h
X
2) [Ru(Cymene)CI]2
-78 C to rt, 12 h


1) n-BuLi, THF
-78 C, 1 h
2) PCy3
Cl,. I H
Ru-
i-Pr"'

-78 *C to rt, 12 h


S1) n-BuLi, THF N (3-1
SN-78 -C, 1 h X C Y(3-15)
BF4 C 2) RuCl2(Pyridine)4 I
31 -78 -C to rt, 12 h CI"Ru
3-1 Cl N(Py)3
3-30

metals. After generation of ADC 3-4 from chloroamidinium, the electrophilic boron trifluoride

etherate was introduced to the reaction mixture. The ADC easily completed with boron, and the

ensuing product was purified on a short silica gel column with a 1:1 mixture of hexanes and

ethyl acetate, giving the adduct in 81% (Equation 3-16). Compound 3-31 was characterized by

'H and 13C NMR as well as elemental analysis and mass spectrometry. Transmetalation of the

carbene from boron to rhodium was attempted, but it was not successful (Table 3-5). ADC

boron compound 3-31 was recovered after the reaction showing the stability of the carbene boron

bond.


1) n-BuLi, THF
-78 C, 1 h
2) BF3*Et20
-78 C to rt, 12 h


ON NO
BF4 CI
3-1


N
C-BF3
31N 81%
3-31


(3-16)


SRu.,CI
CN '3'CI8

0 3-28


(3-13)


(3-14)










\ 0
[Rh], THF, A (3-17)
C-BF3 C-M-L, (3-17)

0 3-31 0

Table 3-5. Attempts at transmetalating ADC ligand to rhodium.
Entry Metal Precursor Temperature Additive Yield
1 [Rh(COD)Cl]2 70 -NR
2 [Rh(COD)Cl]2 110 NR
3 [Rh(COD)Cl]2 110 Ag20 NR
4 [Rh(COD)OH]2 110 NR

The work of Tamm and colleagues showed that NHCs acting in conjunction with

tris(pentafluorobenzene) borate functioned to activate small molecules like diatomic hydrogen

through dissociation of the carbene boron bond.26 Steric repulsion caused by the joining of 3-32

and 3-33 creates a frustrated Lewis pair (Figure 3-15). With the idea that this type of boron

carbene molecule might be a useful species for transferring an ADC to a transition metal through

transmetalation, the synthesis of compound 3-34 from tris(pentafluorobenzene) borate was

attempted, but it was not accessed. It was believed that if formed, compound 3-34 might behave

similarly to 3-32 and 3-33, with the dissociation of the carbene boron bond in the presence of a

metal source leading to a metal carbene bond.

Other Ligands Explored in Carbene Formation from the Lithium-Halogen Exchange

Success was observed when conducting metal complexation with ADC and NHC ligands

featuring a low degree of functionality and mostly alkyl substituents. Ligand structure was

varied more drastically, however, to understand the scope of methodology for carbene generation

from chlorinated precursors, and unfortunately several classes of ligands did not fare well. This

section details these efforts.









t-Bu t-Bu
N Toluene, H2 HB(C6F5)3
C: + B(C6F5)3 rt, 10min H
N 3-33 N
t-Bu t-Bu 82%
3-32

c .. 0 1)n-BuLi, THF
N N -78 C, 1 h X C-B(C
CODT 2) B(C6F5)3 B(CF
BF4 Cl -78 -C to rt, 12 h /- 3
3-1 0 3-34

Figure 3-15. Attempt to create a frustrated Lewis pair with an ADC.

First, the identity of the chloroamidinium's counter-ion is important but for what reason

is not clear. Bis(pyrrolidine) chloroamidinium 3-36 was synthesized in the laboratory, but anion

exchange was not performed so that the counter-ion remained as chloride. Attempts at formation

of rhodium complex 3-5 failed from this precursor (Figure 3-16). After converting 3-36 to the

tetrafluoroborate salt, synthesis of 3-5 succeeded. 13C labeled chloroamidinium 3-36' was used

in an NMR experiment to understand why the chloride version of 3-1 did not form the rhodium


ON ND (CICO)2
Toluene, rt, 16 h
0 79% Cl Cl
3-35 3-36

S /\ 1)n-BuLi, THF
\ N N D -78 C, 1 h A CI.
33 2) [Rh(COD)CI]2 /l C Rh
Cl Cl -78 C to rt, 12 h
3-36 3-37

Figure 3-16. Attempts at synthesis of ADC rhodium catalyst using chloroamidinium 3-36.

catalyst, and it was seen that the carbene was not formed under these circumstances (Figure 3-

17). A similar dependence on the identity of the counter-ion was observed when working with

NHC precursor 3-38. In this instance, however, the chloride anion was preferential to

tetrafluoroborate (Figure 3-18).














Some seemingly simple alkyl-based diaminocarbenes did not perform well under the


lithium-halogen exchange conditions. Neither bis(dimethyl) chloroamidinium 3-39 nor


bis(morpholine) chloroamidinium 3-40 showed evidence of binding to rhodium. Both reactions


were run twice, and after twelve hours of reaction time, [Rh(COD)Cl]2 was recovered in


quantitative amounts. Based on data from Alder and co-workers,6b it was believed that the


carbene stemming from 3-39 might quickly dimerize even at low temperature. After all, the


successful ligand stemming from 3-1 dimerizes within three hours in THF at -78 C.27 Likewise,


a chiral chloroamidinium with a low degree of functionality developed by a co-worker, Hwimin


Seo, failed to ligate to a rhodium center under the identical lithium-halogen exchange conditions.




1 05
Cl CI 1) nBu-LI Li
100 .CN THF, -78C CN'
095
3-36' 3-4'
0.90
085
0o80
0.75
0.70
065
060


,0.50;
E 045
0.40
0.35
0.30
025;
0.20


010




A 005
230 220 210 200 190 180 170 160 150 140 130 10 110 100 90 80 70 60 50 40 30 20 10 0
Chemical Shif (ppm)



Figure 3-17. NMR taken at -60 C of chloride salt 3-36' under Li-X exchange conditions.










/- 1) n-BuLi, THF N N
,N N. -78 'C, 1 h C'
SY 2) [Rh(COD)CI]2 R -Rh-CI
CIE Cl -78 C to rt, 12 h
3-7 58%
3-8

/ 1) n-BuLi, THF N N
N N -78 C, 1 h 'C
BD Y 2) [Rh(COD)CI]2 -Rh-CI
BF4 C-78 C to rt, 12 h
3-38
3-8

Figure 3-18. Observed differences in reactivity based upon counter-ion identity.

Iron catalysts exhibit an abundance of dative bonds to nitrogen containing ligands, and so

the potential of pyridine-based ADCs was of special interest.28 Chloroamidinium




II o 0 -

PF6 CI BF4 C
O,
3-39 340 BF4 CI
3-41

Figure 3-19. Diaminocarbene precursors which were unsuccessful in attempts to complex with
rhodium using lithium-halogen exchange methodology.

3-42 was previously noted for its simple preparation and isolation. Treatment of 3-42 with n-

BuLi followed by addition of [Rh(COD)Cl]2 did not yield the desired product, however (Figure

3-20). Initially, the chloride salt was used because the chloroamidinium was simple to obtain as

a nice, white solid, whereas the tetrafluoroborate salt was a nearly intractable, colorless oil.

Resultantly, when 3-42 failed to give the proper product, tetrafluoroborate salt 3-44 was

examined, but it also did not yield the rhodium complex.










\ N 1)n-BuLi, THFN N
N N -78 C, 1 h 'N, c
C N 2) [Rh(COD)C1]2 -Rh-Cl N 0
C 32 -78 C to RT, 12 h 33
3-42 3-43


SN 1) n-BuLi, THF N
N -78 C, 1 hX N ,N
CI N 2) [Rh(COD)CI]2 i-Rh-CI N,,
BFE -78 "C to RT, 12 h
BF4 3-44 3-43



Y 1)t-BuLi, THF \ N N
N -78 C, 1 h
E CI N 2) [Rh(COD)CI]2 Rh-CIN
BF4 -78 *C to RT, 12 h I
3-44 3-43

Figure 3-20. Attempts at synthesis of a mixed pyridine-ADC rhodium complex.

In an attempt to pinpoint the problem with catalyst formation, the reaction was dissected

into two halves, as either the lithium-halogen exchange or the metal binding might be

problematic. After addition of n-BuLi to 3-44 in THF and thirty minutes of stirring, sulfur was

added to the reaction mixture. Thiourea 3-45 was not isolated. In a separate trial,

trifluoroborane diethyletherate was also used as an electrophile to trap the ADC after generation

with n-BuLi, but again, the expected product was not observed (Figure 3-21). This led us to

believe that the problem with rhodium complex formation lay with the lithium-halogen

exchange.

One possible scenario was that a lithium aggregate was formed, diminishing the reactivity

of the lithiated carbene. Clustered organo-lithium species are known to lower reactivity, and

breaking the aggregate is a common method for increasing rate of reaction.29 HMPA is one of

the most effective additives to deconstruct the tetrameric phenyl-lithium structure, and so it was









used in conjunction with the lithiation of pyridine based chloroamidinium 3-44. The addition of

HMPA did not prove to be effective in the formation of borate 3-46 (Equation 3-18).


| 1) n-BuLi, THF Y
SN N -78 OC,1h N N
cT I N 2) Sulfur X
EC N -78 C to rt, 12 h S N
BF4 3-44 3-45


T I 1)n-BuLi, THF
N N -78 "C, 1 h N
Cl N 2) BF3-Et20 BF3
BF4 3-44 -78 "C to rt, 12 h 3-46

Figure 3-21. Trials to determine whether n-BuLi is effective in generation of carbene
intermediacy with precursor 3-44.

I 1) n-BuLi, THF, HMPA
NYN -78 *C,_1h N-- 1- (3-18)
CI N. 2) BF3*Et20O BF3 N
BE -78 C to rt, 12 h
BF4 3-44 3-46


In previous projects, formation of sterically hindered tetra-substituted ureas was found to

be very challenging, and this has been observed in other research groups as well.14 A potential

strategy to circumvent this obstacle is to pursue N,Xcarbenes instead of diaminocarbenes, where

Xequals sulfur or oxygen. The use of divalent sulfur or oxygen would effectively eliminate the

strain observed in the ADC ligands, and this methodology might allow the use of 2,5 trans-

diphenylpyrrolidine or other C2-symmetric amines as chiral building blocks.

Ph Ph,,
K N. X1)n-BuLi, THF R X
N XR ..... ...... RX' (3-19)
Ph BF2) [Rh(COD)C]2 -Rh-l Ph
h B-78 C to rt
X = S, O









N,S carbene precursors 3-49 and 3-50 were synthesized quite easily from the nucleophilic

attack on carbon disulfide by a secondary amine. After isolation of the dithiocarbamate salt,

ethyl iodide was added to give the alkylated product in high yield (Figure 3-22). Thiocarbamate

3-54 leading to a possible N,O carbene was made by addition of pyrrolidine to phenyl

chlorothionoformate (Figure 3-23). All of these molecules were easily chlorinated by adding

oxalyl chloride to a solution of the dithiocarbamate or thiocarbamate in toluene and stirring the

reaction mixture at room temperature for twenty four hours.

The first carbene synthons investigated were chlorinated dithiocarbamates 3-51 and 3-52.

Both were subjected to n-BuLi in THF at -78 C, which was followed by the addition of

[Rh(COD)Cl]2. At the end of the reaction period, quantitative amounts of the rhodium precursor

were recovered (Equations 3-20 and 3-21). A switch from the tetrafluoroborate anion to the

chloride anion was explored but did not produce an affirmative result.

R






R R
A O EtiEtoH M
R NaOa RT,0 I 2
NH + CS2 R'-N S
R RT II N



S m S
R = i-Pr (80%) 3-49
(CH2)4 (78%) 3-50




R 1)(CICO)2 R
R R
R'N SNa RT, 30 R1N IS






2) AgBF4, CH2CI2 e
S RTminh C B
R = i-Pr (37%) 3-51
(CH2)4 (90%) 3-52
Figure 3-22. Formation of chlorinated dithiocarbamate tetrafluoroborate salts 3-51 and 3-52.
I Toluene, RT, 16 h I
R-'N ii S2) AgBF4, CH2C12 R (9 Y E)
S RT, 1 h Cl BF4

R = i-Pr (37%) 3-51
(CH2)4 (90%) 3-52

Figure 3-22. Formation of chlorinated dithiocarbamate tetrafluoroborate salts 3-51 and 3-52.










NH + C O'"Ph CH2CI2, Et3N. O N P
s RT NY Ph
83% S
3-53 3-54
3-54

1) (CICO)2
N 0 -O Toluene, RT, 16 h .N Oph
O ph 2) AgBF4, CH2CI2 OB Ph
S RT, 1 h4 Cl
3-54 80% 3-55

Figure 3-23. Formation of chlorinated thiocarbamate tetrafluoroborate salt 3-55.


Y 1) n-BuLi, THF S
N SN- -78 C, 1 h X C (3-20)
S 2) [Rh(COD)CI]2 -h-CI
Cl BF4 -78 C to RT, 12h \
3-51 3-56

N 1) n-BuLi, THF '
-78 C, 1 h X S C (3-21)
SY E 2) [Rh(COD)CI]2 -Rh-CI
Cl BF4 -78 OC to RT, 12 h L\L
3-52 3-57

Next, attention was paid to the chlorinated carbamate, 3-55. Again, treatment with n-

BuLi followed by addition of [Rh(COD)Cl]2 failed to produce the desired rhodium complex, and

salts with the tetrafluoroborate or chloride counter-ion were both investigated (Figure 3-24).

Two different fragments of the carbamate appear upon isolation of the reaction byproducts. One

featured a pyrrolidine unit without any aromatic signal in 'H NMR, whereas the other product

showed only aromatic peaks, looking quite similar to phenol. Based on this information it

seemed as though the n-BuLi might be attacking the chlorinated molecule with phenoxide

ejected as a suitable leaving group. With this hypothesis in hand, t-BuLi was substituted as the

reducing agent, but no complex was isolated. Thiocarbamate formation was tested with the

chlorinated carbamate to test the efficacy of lithium-halogen exchange, but addition of elemental











NOph
S 'Y Ph
BF4E CI
3-55



ON O, 0,
Co Ph
Cl CI
3-59


1) n-BuLi, THF
-78 C, 1 h
2) [Rh(COD)CI]2
-78 "C to rt, 12 h


1) n-BuLi, THF
-78 C, 1 h
2) [Rh(COD)CI]2
-78 C to rt, 12 h


R'C ph
C-Rh-CI
x- 3-58


N'C-O ph
h-Rh-CI
3-58


1) t-BuLi, THF I"C Ph
S-78 C, 1 h h
S O'Ph 2) [Rh(COD)CI]2 Rh-C
BF CI -78 OC to rt, 12 h 3-58
3-55

Figure 3-24. Attempts at synthesis of rhodium complex 3-58 by changing counter-ion identity
and lithiation source.

O ,.1) n-BuLi, THF -
ON Ph -0780C,1h N 0Ph (3-22)
N OPh 2) [Rh(COD)CI]2 ph
BF4CI -78 OC to rt, 12 h S
3-55 3-54

sulfur to the putative lithio-carbene species did not produce the desired product (Equation 3-22).

With some of the difficulties in obtaining a usable carbene, a different method for

reduction of the carbon-chlorine bond was sought. One such possibility involved the

application of metallic lithium and naphthalene to create a radical anionic naphthalene species

(Figure 3-25).18 Crucial to production of the radical anion was activation of the lithium granules

by crushing with a spatula once inside the Schlenk flask. If activated outside an inert

atmosphere, the freshly exposed surface quickly oxidized giving a sluggish lithium species. The

initially dark green lithio-naphthalene solution was added to the simple chloroamidinium 3-1,

and although the green color disappeared, the chloroamidinium never dissolved. The presence of

the chloroamidinium was somewhat troubling since normally the chloroamidinium dissolves as it









transforms into a carbenoid species. Not unexpectedly, complex 3-5 was not isolated after

addition of [Rh(COD)Cl]2.

Li
G -
QcQ ] TLithium ,
O THF, rt


1) Li, C1oH8 X rNC
THF, -78 C X
(D 2) [Rh(COD)CI]2 [ -Rh-CI
BF4 Cl -78 C to rt, 12 h
3-1 3-5

Figure 3-25. Use of a lithio-naphthalene solution to generate compound 3-5.

Catalytic Activity of Rhodium Complexes Accessed Through Lithium-Halogen Exchange

Rhodium complexes function as diverse catalysts capable of a range of transformations

effective in C-C and C-X bond formation (Figure 3-26).30 Among these reactions rhodium is

especially known for its ability to effect cycloadditions,30'31 afford carbenoids from diazonium

ylides,32 and promote C-H activation.33 Recently, rhodium has also gained attention for

insertion reactions such as 1,4 conjugate addition34,35 and 1,2 migratory insertion.36,37 The 1,4

conjugate addition is particularly effective due to the high degree of enantioselectivity, low

catalyst loadings, and mild conditions employed in catalysis, with the work of Hayashi and co-

workers playing a large role in the achievements.

Catalysis with rhodium was explored since access to these complexes along with iridium

was most straightforward. With the rhodium complexes, catalysis involving transmetalation of a

boronic acid seemed to work well, and conjugate addition ofboronic acids to enones was

explored first using cyclohexenone 3-60 as the standard substrate (Equation 3-23). Rhodium

ADC complex 3-5, boronic acid, and potassium hydroxide were added to a Schlenk flask under









OMe OH
0-A


0

P[ Cyclohexenone
Ph PPhB(OH)2



N/N





w- -
NN


o-An
PhB(




[Rh]


isaldehyde /Ts
OH)2 TsN NTs
NTs

butadiene


^ Octane
? ~i(PinB)2
0 0 R1
MeO N2


K6 BPin


O O

MeO O

WR2


Figure 3-26. Examples of catalysis with rhodium including cycloadditions, borylations,
carbenoid chemistry, C-H activation, 1,4 conjugate addition, and 1,2 addition to
aldehydes.

argon atmosphere, followed by a 10:1 mixture of THF and water respectively. After addition of

the solvent, distilled and degassed cyclohexenone was added to the solution. The yellowish

reaction mixture was heated to 40 OC for thirty minutes, and as it neared completion, the aqueous

phase separated from the organic layer. The solvent was evaporated and the residue was purified

by silica gel column chromatography using a 4:1 mixture of hexanes to ethyl acetate.

Arylboronic acids functioned very well under these conditions (Table 3-6, entries 1-6),

giving product in excellent yields and short reaction times. With a vinylboronic acid (entry 7), a

longer reaction time was necessary, and the yield was not as high. This might be expected

however, as the enone could be regenerated easily to make a highly conjugated product.

Extension of the methodology to include alkylboronic acids (entry 8) did not result in successful


m









isolation of the product. The catalyst was investigated with a more challenging heterocyclic

substrate, 3-69. The reaction was run under conditions similar to those used for conjugate

addition to cyclohexenone; however, more time was needed (Equation 3-24).

ADC complex 3-5 also fared well in another reaction involving transmetalation, the 1,2

addition of arylboronic acids to aldehydes (Table 3-7). Under an inert atmosphere of argon, the

catalyst, aldehyde, boronic acid, and base were combined, and then a 3.5:1 mixture of 1,2-

dimethoxyethane and water was added. The reaction was heated at 80 OC for varying times

before purification by silica gel chromatography.




S RB(OH)2d -CI (3-23)
+ R ) [340 C, 30 min -
3-60
3-5

Table 3-6. 1,4 Conjugate Addition of Boronic Acids to Cyclohexenone
Entry ArB(OH)2 Time Isolated Yield (%)

1 /\ B(OH)2 20 min 98
3-61

2 -/ B(OH)2 20 min 96
3-62

3 MeO / B(OH)2 30 min 90
3-63

4 F B(OH)2 20 min 98
3-64
B(OH)2
5 3-65 30 min 98



6 \B(OH)2 20 min 97
3-66










//B(OH)2
Ph- 3-67


B(OH)2
3-68


+ PhB(OH)2


O


N
CO2Et
3-69


OMe O

eN H


+ ArB(OH)2


2% [Rh] 3-5, KOH
THF/H20 (10:1)
40 C, 2 d
66%


1.5 mol% [Rh]
2 equiv. KOtBu
DME/H20 (3.5:1)
80 'C, 1 h


0


N Ph
CO2Et
3-70


OMe OH
'N Ar


Table 3-7. 1,2 Addition of arylboronic acids to o-anisaldehyde.
Entry Catalyst Aldehyde Boronic Acid
OMe 0 B(OH)2

1 [Rh(COD)Cl]2 H 3
3-71 3-61
2 Rh(IMes)(COD)Cl
3 3-5


3-5


L -RhCI

3-5


Yield (%)


4 3-5


B(OH)2 3-65



B(OH)2


6 -3-66


5 3-5




6 3-5


12 h


12 h


(3-24)


(3-25)


B(OH)2



F 3-64











7 3-5


B(OH)2



OMe 3-63


The effectiveness of the bis(pyrrolidine) ADC as a ligand was compared directly to IMes

and 1,4-cyclooctadiene (COD) and showed a higher level of catalytic activity (entries 1-3). In

conjunction with 2-methoxybenzaldehyde, 3-5 afforded product in 92% yield while

Rh(IMes)(COD)Cl and [Rh(COD)Cl]2 gave 80% and 62% yield respectively. While COD was

easily the best ligand in 1,4 conjugate addition reactions, it did not compete as successfully in the

1,2 addition. This result demonstrates the potential of ADCs as viable ligands and alternates to

NHCs and phosphines.


O 1.5 mol% [Rh] 3-5 OH
H + PhB(OH)2 2equiv. KOtBu
DME/H20 (3.5:1)
80 C, 1 h



Table 3-8. 1,2 Addition of phenylboronic acid to arylaldehydes.
Entry Benzaldehyde Boronic Acid Time
Cl 0 B(OH)2

S3-72 3-61
0
F3C y H
2 lh


ONC,NC


3-5h-
3-5


(3-26)


Yield (%)


95




41


3-73


O
H
F e 3-74


7h 87









0

4 H 8h 46
Cl 3-75
0

5 [ H 7h 0
02N 3-76


6 H H 7h 0
S3-77


The insertion worked with a variety ofboronic acids as coupling partners. Both electron

deficient and rich aryl rings transferred with the same efficacy (entries 6 and 7), and mono-ortho-

substituted aryl rings reacted with excellent activity (entries 4 and 5). The aldehyde proved to

be the most sensitive variable examined (Table 3-8). A substituent in the ortho-position capable

of coordinating to a metal center or alternatively an electron withdrawing group seemed to

promote success. For example, simple benzaldehyde and 4-methoxybenzaldehyde did not react

under the catalytic conditions investigated; however, the broad scope of boronic acid tolerance

helps to overcome this limitation in the synthesis of diaryl methanol products.

A plausible catalytic cycle is shown below and based on the thoroughly investigated

cycle for 1,4 conjugate addition (Figure 3-27).30 Presumably, the first step is exchange of

chloride for an alkoxide.38 Formation of a rhodium hydroxo or alkoxo intermediate has proven

crucial in the acceleration of reaction rates.38a It is believed that the transmetalation

preferentially proceeds from the hydroxo or alkoxo complex due to the oxophilic nature of the

boronic acid. Following ligand exchange is transmetalation, coordination of the aldehyde, and

insertion of the aryl group into the aldehyde. The newly formed alkoxide undergoes either

protonolysis or remains on the metal to start the next catalytic cycle.









It is of interest to note that there is precedent for the transmetalation step to be initiated

from an intermediate involving q/-6 coordination of the boronic acid.39 Electron rich metal

complexes bind olefins tighter and at a quicker rate than less electron rich metal centers.40

Potentially, the ADC complex is more active in the 1,2 addition of arylboronic acids to

aldehydes because it is more efficient in the transmetalation step. Alternatively, the difference in

reactivity between the ADC and NHC metal complex might be attributed to a quicker rate of

exchange of chloride for t-butoxide. In examining the structures of ADC-Ir complex 3-6 and

NHC-Ir complex 3-9, it is seen that the Ir-Cl bond is longer in the ADC complex, ostensibly

because the greater electron density coming from the ADC weakens the Ir-Cl bond, making

exchange for t-butoxide more facile.

The 2-bis(alkylpyrrolidino)methylidine ligands were briefly tested in the asymmetric 1,2

addition to aldehydes (Table 3-5). The most active substrates, o-anisaldehyde and 1-

naphthylboronic acid, were used since 3-15 tends to exhibit sluggish reactivity. With both 3-13

and 3-15 slightly lower yields were obtained, and catalyst 3-15 imparted 12% ee. With NHC

ligands, the highest selectivity observed thus far is 38% ee to the best of my knowledge.37d,41

The aforementioned results demonstrate the viability of ADC-Rh complex 3-5 in catalysis

involving insertion of aryl groups into double bonds. Because transition metals bind alkenes

more tightly when they are electron rich, it seemed reasonable to infer that an ADC

metal complex might work well in catalysis with olefinic substrates such as 2,3-dihydrofuran 3-

78 that do not bind well to metal centers. To understand the boundaries and capabilities of

catalysis with the ADC complex, the unprecedented Rh-catalyzed 1,2 addition of

naphthylboronic acid to 2,3-dihydrofuran was tested (Equation 3-28). The catalyst was not

active enough to promote the reaction in conditions favoring either reformation of the double








bond or protonolysis. The synthesis of the bis(ethylene) and bis(cyclooctene) versions of 3-5

were attempted in order to make a more active metal center; however, neither complex was able

to be isolated (Figure 3-28).





L-R'h-CI
^- 3-5


Ph /PhB(OH)2
Ar^O 0 ONND

KOtBu -Ot




O N ,.ND N-c- r
-Rh- Ph Rh-OtBu

r hA B(OH)2






Ar-H L h-Ph tBuOB(OH)2


Figure 3-27. A plausible catalytic cycle for the 1,2 addition of aryboronic acids to aldehydes.

OMe O B(OH)2 1.5 mol% [Rh] OMe OH
1 .H 1 2 equiv. KOtBu
H + '(3-27)
DME/H20 (3.5:1)
S3-71 80 C, 1 h
3-65









Table 3-9. 1,2 Asymmetric addition of 1-naphthylboronic acid to o-anisaldehyde.
Entry Catalyst Time Yield (%) ee (%)

N'C, Nr

1 1 h 71 2
--Rh-CI
3-13


N C, N

2 Ph Ph Ph'"Ph 16h 75 12
L-Rh-CI
3-15




+ NpB(OH)2 1.5 mol% [RhL3-5 C N- (3-28)
O THF/H20 (10:1) C
3-78 KOH, 70 OC, 12 h 3-79
3-5

With the electron rich ADC, 3-5 might be expected to perform exceptionally well in

catalytic cycles involving oxidative addition. As such, low-pressure hydrogenation was

investigated (Equation 3-29).42 3-5 and coumarin 3-82 were loaded into a Schlenk flask under an

argon atmosphere. Dichloromethane was added and the argon was exchanged for hydrogen at

one atmosphere of pressure by bubbling the gas through the CH2C2 solution. The reaction

proceeded overnight, but isolation of starting material showed that the enone failed to be

reduced.

Recently, a report appeared covering the cross-coupling of aryltosylates with arylboronic

acids. Wu and co-workers nicely demonstrated that electron-rich, Rh(NHC)(COD) complexes

catalyzed the reaction, which makes use of readily available phenols with a functional group less









sensitive than triflate.43 Since ADCs are even more donating than NHCs, we believed they

might be more effective in the cross-coupling.

Rhodium compound 3-5, an aryltosylate, a boronic acid, and cesium fluoride were

combined in a Schlenk flask. Anhydrous toluene under an argon atmosphere was added to the

solids, and the suspension was then heated to 120 OC and stirred for thirty hours. After purifying

the products of the reaction mixture by silica gel chromatography, the aryltosylate was recovered

in quantitative yields, giving evidence that a reaction did not take place (Equation 3-30).


BF4? CI
3-1




QNNQ
ON N

BF4 Cl
3-1


1) n-BuLi, THF
-78 C, 1 h
2) [Rh(COE)CI]2
-78 *C to rt, 12 h




1) n-BuLi, THF
-78 C, 1 h
2) [Rh(C2H4)CI]2
-78 C to rt, 12 h


Figure 3-28. Attempts at synthesis of complexes 3-80 and 3-81 which might be expected to show
greater activity toward insertion reactions with olefins.


03-8
3-82


OMe



OTs
3-84


Me

+

B(OH)2
3-62


3 mol% [Rh] 3-5
1 atm H2
CH2CI2, rt, 16 h




2 mol% [Rh] 3-5
CsF, Toluene
120 C, 30 h


3-83


3-85


L-Rh-CI
3-5







3-5


(3-29)







(3-30)


3-80


O
N


CI
Rh 81
S'Cl-
3-81









ADC-Pd Complex 3-18 in the Suzuki Cross-Coupling

Although palladacycles of type 3-18 are not typically used in the Suzuki cross-coupling

reaction, it was investigated to see the effects of the ADC ligand in the absence of triphenyl

phosphine. With toluene at reflux, the conditions employed when using 2-15 and 2-26, low yield

of the binaphthyl product was obtained. Using the harsher conditions developed by Iyer and co-

workers, 3-87 was formed in 78% yield (Figure 3-29).44


B(OH)2 Br
OMe 3 mol% [Pd] 3-18
CsF, Toluene OMe
reflux, 20 h
3-65 3-86 25% 3-87


B(OH)2 Br
OMe 3 mol% [Pd] 3-18
K3P04, DMF OMe
120 C, 2 d
3-65 3-86 78% / 3-87



3-18

Figure 3-29. Suzuki coupling to form triortho-substituted product using catalyst 3-18.

Steric and Electronic Measurements of ADC and NHC Compounds

Iridium complexes 3-6 and 3-9 were further characterized using cyclic voltametry to measure the

diaminocarbenes' donor properties. As discussed by Plenio and co-workers, electrochemistry

and the measurement of reduction potentials gives a more precise understanding of electronic

characteristics than measurement of v(CO) of M(NHC)(CO)2C1 complexes and calculation of the

Tolman electronic parameter (TEP) since most NHCs fall within a 3 cm1 range.45 Lower

reduction potentials indicate stronger donor ligands, as more electron rich ligands ease the

oxidation of the iridium center from IrI to Ir". ADC iridium complex 3-6 exhibited an E1/2 of









0.422 V and NHC iridium complex showed a E1/2 of 0.765 V, clearly demonstrating the superior

donor properties of the ADC ligand. Plenio and co-workers synthesized a variety of NHC

ligands, and when bound to metal, these complexes yielded E1/2 values spanning from 0.591 to

0.920 V, clearly delineating the electronic spectrum of carbene ligands (Table 3-10). ADCs fall

well below the range observed for even the most donating NHC. The electronic properties for

bis(diisopropylamino)carbene were previously reported;6d however donor power only accounts

for half of the puzzle when determining carbene properties.

NHC NHC =\ R = NEt2, 3-88a
-Ir-C N,'CN Me, 3-88b
I R / R Br,3-88c
SO2Ar,3-88d

Figure 3-30. Variable NHC ligands used in Plenio's study of electronic influence of aromatic
substituents.

Table 3-10. Redox half potentials for some Ir(L)(COD)Cl complexes in CH2C12 (scan rate
100mVs'-).
Complex E1/2 [V] Complex E1/2 [V]



S-r-C 0.422 3-88b, R = Me 0.735
3-6
3-88c, R= Br 0.838
.N N-
C'
-Ir-CI 0.765
I 3-88d, R = SO2Ar 0.910
3-9

3-88a, R = NEt2 0.591 Ir(PCy3)(COD)C1 0.948

Thus far, steric parameters of ADCs have not been disclosed. Cavallo and co-workers

developed an excellent model aiding the determination of a ligand's steric bulk. It is known as

percent volume buried, or % yVur and is a metric for how much of a ligand lies within a set radius

representing the coordination sphere of a metal (Figure 3-31).46













NAmount of Ligand Intruding
into Radius of Coordination
-- M -M Sphere is % VBur



Figure 3-31. Graphical illustration of % VBur

Table 3-11. Calculated % VBurvalues forADC ligands in complexes 3-5, 3-6, 3-9, and 3-13.
Calculated with Bondi radii scaled by 1.17, 3.5A radius of the sphere, and 2.1A
distance of the ligand from the sphere. NHC values reported by Cavallo.46
Ligand 0% VBur Ligand 0% VBur

N N R-Nc N-R
-Rh-CI 27.9 25.4
3-5 R = Me(saturated)



-I 28.0 R =Et 26.0


-N ,N.
C----
l 25.3 R= IMes 31.6

3-9

NC, rN
29.7 R = DIPr 33.6
h^-Rh-CI
3-13


N N 30.1 R= Adamantyl 36.1



One might expect that the larger carbene bond angle of ADCs might cause them to have

higher % VBur values than NHCs. With the ADCs explored thus far; however, the % VBur has









been considerably lower than typical NHCs. This could reasonably be expected since the

pyrrolidine rings exhibit a low degree of substitution. Complexes 3-6, 3-9, and 3-13 show %

VBur values of 28.0, 25.3, and 29.7 % respectively, while IMes possesses a percentage of 31.6

(Table 3-11).

Conclusions and Summary

The methodology developed provides a solid platform for the synthesis and exploration of

ADC ligands. Despite the benefits of the lithium-halogen exchange, several drawbacks still

exist. The process as of now is not applicable to all chloroamidinium precursors. Particularly,

functionalized molecules and NXtype carbenes were not formed, and alkyl-based ureas tend to

fare best.

A1


nortS gly Donating/Sterically
Demanding


NY,


N^c.N/-


Strongly Donating/ Less
Sterically Demanding


Less 3Lrongiy
Donating/Sterically Demanding


Adm-N C' NNAdm
'Ad


Mes N C N-Mes
o.s


4


r--\
Me-N cN-Me




Less Strongly Donating/Less
Sterically Demanding


El/2 [V]

Figure 3-32. Plot of redox potential vs. % VBur. Carbenes that are both strongly donating and
sterically demanding are as of yet uninvestigated.









ADC structures have only just begun to be investigated, and measurement of reduction

potentials and % VBur give a logical means of tuning ADC properties. The combined

information from cyclic voltametry and % VBur data paints a picture of a ligand possessing quite

distinct characteristics from those of the well-known NHC basis set. Promising results showing

the potential of ADCs has been demonstrated, but truly exceptional catalytic activity has not yet

been achieved. Perhaps one needs to draw deeper into the well of available catalytic reactions

and further from those known to work well with NHCs to realize the desired outcomes of ADCs.

Clearly by expanding into other quadrants of the graph in Figure 3-32, through single factor

variation of either sterics or electronics, considerable changes in catalytic reactivity might be

observed.









CHAPTER 4
EXPERIMENTAL SECTION

General Remarks

All reactions were conducted in flame-dried glassware under an inert atmosphere of dry

argon. THF, CH2C2, and Et20 were passed through two packed columns of neutral alumina

under positive pressure of dry nitrogen prior to use. Toluene was passed through an alumina

column and a copper (II) oxide column under positive pressure of dry nitrogen prior to use. All

other chemicals were commercially available and were used as received without further

purification. NMR spectra were recorded using a FT-NMR machine, operating at 300 MHz for

1H NMR and at 75.4 MHz for 13C NMR. All chemical shifts for 1H and 13C NMR spectroscopy

were referenced to residual signals from CDC13 (1H) 7.27 ppm and (13C ) 77.23 ppm. High

resolution mass spectra were recorded on a GC/MS spectrometer or a TOF-LC/MS spectrometer.

General Procedure for Formation of Ureas Based on 2-Substituted Pyrrolidines.

A pyrrolidine derivative (8.82 mmol), triethyl amine (26.4 mmol), and CH2C12 (17.6 mL)

were added to a flame dried Schlenk flask, and the solution was stirred and cooled to 0 OC.

Phosgene (4.4 mmol, 2.32 mL) was slowly added in the form of a 20 wt% solution in toluene,

and the Schlenk flask was sealed to prevent loss of gaseous phosgene. The reaction was

vigorously stirred for 4 hours at which point extra phosgene (2.2 mmol, 1.16 mL) was added to

ensure complete reaction of the amine. Stirring continued for an additional 4 hours, and then the

reaction was quenched with water. The aqueous layer was extracted with CH2C12 (20 mL x 3),

dried with MgSO4, and concentrated. The crude product was purified by silica gel column

chromatography (hexanes, ethyl acetate, 1:1) to give the pure urea.

-0O









Bis(2S)-Methylpyrrolidine Urea. 1H NMR (300 MHz, CDC13) 6 = 1.15 (d, J= 6.30 Hz,

3H), 1.36-1.43 (m, 1H), 1.61-1.74 (m, 1H), 1.76-1.83 (m, 1H), 2.01-2.12 (m, 1H), 3.23-3.37 (m,

2H), 3.89- 4.02 (m, 1H); 13C NMR (CDC13, 75 MHz) 6 = 21.0, 25.5, 49.7, 54.0, 161.5; HRMS

Calcd. for CliH20N20 [M+H] : 197.1648, Found: 197.1643.

Ph/Ph O Ph Ph


2-2
Bis(2R)-Diphenylmethylpyrrolidine Urea. 1H NMR (300 MHz, CDC13) 6 = 1.45 1.72

(m, 4 H), 1.70 2.01 (m, 4 H), 2.45 2.65 (m, 2 H), 2.98 3.21 (m, 2 H), 3.99 (d, J= 10 Hz, 2

H), 5.19- 5.36 (m, 2 H), 5.38 5.86 (m, 1 H), 7.04 7.46 (m, 20 H). 13C NMR (75 MHz,

CDC13)6= 14.5, 24.0, 28.6, 55.5, 69.6, 127.7, 127.9, 128.5, 128.6, 129.0, 129.1, 129.2,

139.3, 140.3, 152.5. HRMS Calcd. for C35H36N2C1 [M+H] : 519.2562, Found: 519.2585.

N-Boc

2-10

(2R)-(Isopropyl)-N-(tert-Butyloxycarbonyl)pyrrolidine. To a flame dried 3-neck round

bottom flask, pyrrolidinone 2-9 (15.7 mmol, 2.0 g) and THF (78 mL) were added. The solution

was cooled to 0 C, and lithium aluminum hydride (31.4 mmol, 1.195 g) was added portion wise

over 10 minutes. The reaction mixture was stirred at this temperature for half an hour before

warming to room temperature. After an additional 30 minutes, the reaction was heated to reflux

and stirred for 3.5 hours. The reaction was quenched with 1.2 mL of water followed by 2.4 mL

of a 10 % NaOH solution, and lastly 3 mL of water was added. Lithium salts were removed by

filtering over a celite bed. Boc20 was added to the THF filtrate, and the solution was stirred

overnight. Volatiles were removed and the crude product was purified by column

chromatography (hexanes/ethyl acetate, 4:1) to give 2-10 (3.24 g, 97%). 1H NMR (300 MHz,









CDC13) 6 = 0.76 (d, J= 6.9 Hz, 3H), 0.83 (d, J= 7.2 Hz, 3H), 1.42 (s, 9H), 1.63-1.79 (m, 4H),

1.94-2.23 (m, 1H), 3.14-3.22 (m, 1H), 3.36-3.70 (m, 2H). 13C NMR (75 MHz, CDC13) 6 = 17.4,

20.0, 23.8, 24.5, 26.0, 26.9, 28.8, 30.2, 31.1, 47.2, 62.5, 78.6, 154.5. HRMS Calcd. for

C12H23N02 [M+Na] : 236.1621, Found: 236.1606.

0


2-3
Bis(2R)-Diphenylmethylpyrrolidine Urea. Boc-protected amine 2-10 (4.69 mmol, 1.00

g) and ether (1 mL) were added to a flame dried Schlenk flask and cooled to 0 OC. Slowly, 4M

HC1 in dioxane (23.5 mmol, 5.87 mL) was added to the vigorously stirred solution. The reaction

was stirred at room temperature for 3 hours, and a white salt precipitated out of solution. Solvent

was removed in situ, and the solid was washed twice with ether. The solid was dried in vacuo,

and the general procedure described above was used for formation of urea 2-3 (0.271 g, 46 %).

'H NMR (300 MHz, CDC13) 6 = 0.78 (d, J= 7 Hz, 3 H), 0.86 (d, J= 7 Hz, 3 H), 1.44 1.95 (m,

4 H), 1.95- 2.18 (m, 1 H), 3.21 (m, 1 H), 3.28 3.47 (m, 1 H), 3.91 4.14 (m, 1 H). 13C NMR

(75 MHz, CDC13) 6 = 13.6, 16.5, 19.7, 25.7, 30.3, 50.9, 62.6, 162.4. HRMS Calcd. for

C12H23N02 [M+H] : 253.2274, Found: 253.2264.

General Procedure for the Formation of Chloroamidinium Ions.

Urea 2-1 (2.09 mmol, 0.400 g) was mixed with toluene (10.45 mL) in a flame dried

Schlenk flask. To this solution was added oxalyl chloride (2.51 mmol, 0.212 mL), and the

reaction mixture was heated to 60 OC. The reaction was stirred overnight at which point, a

brown, oily residue precipitated out of solution. The reaction was cooled to room temperature

and the toluene was siphoned off. The oily residue was washed twice with ether, dissolved in

CH2C12 (12 mL), and AgBF4 (2.09 mmol, 0.407 g) was added. The reaction was stirred for 1









hour. After this time, the CH2C12 was filtered off into a dry Schlenk flask under an argon

atmosphere. Volatiles were removed resulting in an off white solid (0.4445 g, 70%).


N' N BF4
CI
2-11
Bis(2S)-Methylpyrrolidine Chloroamidinium Tetrafluoroborate 2-11. 'H NMR (300

MHz, CDCl3) 6 = 1.39 (d, 6 H), 1.63 1.88 (m, 2 H), 2.11 (dd, J= 5, 1 Hz, 4 H), 2.25 2.56 (m,

2 H), 3.68 3.90 (m, 2 H), 3.90 4.13 (m, 2 H), 4.20 4.56 (m, 2 H). 13C NMR (75 MHz,

CDC13) 6 = 20.3, 25.4, 33.5, 55.9, 62.4, 152.7. HRMS Calcd. for ClIH20N2C1 [M+H]:

215.1310, Found: 215.1310.



N BF4
Ph CIPh Ph/"Ph
Ph Ph
2-12

Bis(2R)-Diphenylmethylpyrrolidine Chloroamidinium Tetrafluoroborate 2-12. 'H

NMR (300 MHz, CDC13) 6 = 1.45 1.72 (m, 4 H), 1.70 2.01 (m, 4 H), 2.45 2.65 (m, 2 H),

2.98 3.21 (m, 2 H), 3.99 (d, J= 10 Hz, 2 H), 5.19 5.36 (m, 2 H), 5.38 5.86 (m, 1 H), 7.04 -

7.46 (m, 20 H). 13C NMR (75 MHz, CDC13) 6 = 14.5, 24.0, 28.6, 55.5, 69.6, 127.7, 127.9,

128.5, 128.6, 129.0, 129.1, 129.2, 139.3, 140.3, 152.5. HRMS Calcd. for C35H36N2C1

[M+H]+: 519.2562, Found: 519.2585.



N BF4
CI/
2-13
Bis(2R)-Isopropylpyrrolidine Chloroamidinium Tetrafluoroborate 2-13. 'H NMR

(300 MHz, CDC13) 6 = 0.82 (br. s., 3 H), 0.91 (br. s., 3 H), 1.32 (br. s., 1 H), 2.09 (br. s., 4 H),

3.68 (br. s., 2 H), 4.27 (br. s., 1 H). 13C NMR (75 MHz, CDC13) 6 = 13.12, 16.04, 19.46, 24.98,









25.38, 30.56, 49.13, 57.65, 58.24, 71.73, 153.48, 156.42. HRMS Calcd. for C15H28N2C1

[M+H]+: 271.1936, Found: 271.1928.

General Procedure for the Formation of Palladium Complexes.

Amidinium chloride 2-11 (0.140 mmol, 0.0408 g) was added to a flame dried Schlenk

flask along with toluene (10 mL). To the suspension was added Pd(PPh3)4 (0.140 mmol, 0.1623

g). The yellow solution was heated to 100 OC and quickly turned deep red in color. The reaction

was stirred for two hours at which point, a yellow solid precipitated from solution. The mixture

was allowed to cool to room temperature, and the toluene was evaporated. Pentane was added to

the resulting solid (10 mL x 2) which was stirred for 1 hour before being decanted. CH2C12 was

used to dissolve the product and insoluble salts were filtered off. Pentane was layered on top of

the filtrate to purify the product by recrystallization (0.078 g, 65 %).

"" + BF4
ON N
Ph3P-Pd-PPh3
C1 2-15
Bis(Triphenylphosphine)-(2S)-Methylpyrrolidinecarbene Palladium Chloride 2-15.

H NMR (300 MHz, CDC13) 6 = 0.54 (d, J= 7 Hz, 1 H), 0.76 0.96 (m, 5 H), 1.21 1.34 (m, 1

H), 1.42 1.60 (m, 2 H), 1.60 1.79 (m, 2 H), 1.79 2.01 (m, 1 H), 3.70 4.07 (m, 3 H), 4.85 (q,

J= 9 Hz, 1 H), 7.06 7.28 (m, 2 H), 7.28 7.51 (m, 2 H), 7.53 7.81 (m, 25 H). 13C NMR (75

MHz, CDC13) 6 = 14.0, 20.2, 20.9, 21.7, 22.6, 22.9, 30.0, 32.1, 34.3, 57.1, 59.0, 129.2, 129.3,

129.3, 129.8, 130.0, 132.0, 132.2, 134.6, 187.2. HRMS Calcd. for C47H40N2P2ClPd [M+H]+:

845.2181, Found: 845.2152.









Ph Ph

,, + BF4

Ph3P-Pd-PPh3
CI 2-18
Bis(Triphenylphosphine)-(2R)-Methylpyrrolidinecarbene Palladium Chloride 2-15.

H NMR (300 MHz, CDCl3) 6 = 1.00 1.51 (m, 4 H), 1.53 2.13 (m, 5 H), 2.49 2.72 (m, 2 H),

2.96 (dd, J= 14, 5 Hz, 2 H), 3.66 3.85 (m, 2 H), 4.28 4.48 (m, 2 H), 5.49 (ddd, J= 11, 6, 6

Hz, 2 H), 6.81 7.85 (m, 40 H). 13C NMR (75 MHz, CDC13) 6 = 22.8, 25.9, 40.0, 54.4, 71.5,

126.8, 128.5, 128.8, 129.1, 130.2, 131.6, 132.4, 134.3, 134.7, 135.3, 137.1, 185.8.

General Procedure for Suzuki Cross-Coupling Reaction

Boronic acid 2-23 (0.269 mmol, 0.0464 g), aryl bromide 2-24 (0.221 mmol, 0.524 g),

palladium complex 2-15 (0.0066 mmol, 0.0060 g), and CsF (0.619 mmol, 0.0940 g) 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 hours. After this time, the reaction mixture was diluted with water and

extracted with ethyl acetate (3.5 mL x 3). The organic layers were combined, dried with MgSO4,

and concentrated. The crude product was purified by column chromatography (hexanes/ethyl

acetate, 50:1) resulting in pure biaryl (0.0619 g, 99%) with spectra that match those reported in

the literature. 1H NMR (CDC13, 300 MHz) 6 = 3.79 (s, 3H), 7.2-7.4 (m, 5H), 7.46-7.54 (m, 3H),

7.67 (t, J= 6.9 Hz, 1H), 7.92 (d, J= 6.3 Hz, 1H), 7.98- 8.04 (m, 3H). 13C NMR (75 MHz,

CDCl3)6 = 154.54, 134.51, 134.21, 133.65, 132.91, 129.42, 128.94, 128.39, 128.17, 127.76,

127.67, 126.34, 126.12, 125.8 1, 125.64, 125.52, 125.43, 123.50, 113.71, 56.61. HRMS Calcd.

for C21H160 [M+H] : 284.1201, found, 284.1225.









General Procedure for the Formation of Ureas from Carbamoyl Chlorides

Chiral amine 2-37 (0.672 mmol, 0.150 g), triethyl amine (1.345 mmol, 0.188 mL),

pyrrolidine carbamoyl chloride (1.01 mmol, 0.111 mL), and CH2C12 (1.2 mL) were mixed in a

flame dried Schlenk flask. The solution was warmed to 60 OC and heated overnight. The

reaction was diluted with water and extracted with CH2C12 (3 mL x 3). The organic fractions

were collected, dried with MgSO4, and concentrated. The crude product was purified by column

chromatography (hexanes/ethyl acetate, 2:1) to give 2-41 (0.152 g, 70%).

Ph

N4

Ph
2-41
(2S, 5S)-Diphenylpyrrolidine Pyrrolidine Urea 2-41. 'H NMR (300 MHz, CDC13) 6 =

1.40-1.56 (m, 2H), 1.62-1.74 (m, 2H), 1.76-1.83 (m, 2H), 2.38-2.50 (m, 2H), 3.08-3.38 (m, 4H),

5.35-5.39 (m, 2H), 7.18-7.36 (m, 10H); 13C NMR (75 MHz, CDC13) 6 = 25.1, 25.5, 34.2, 34.5,

63.5, 63.8, 125.5, 125.8, 126.7, 127.0, 128.3, 128.4, 128.6, 144.5, 144.8, 159.1.

Ph

N

Ph N
2-49
N,N-Methyl,Pyridine-(2S, 5S)-Diphenylpyrrolidine Urea 2-49. 1H NMR (300 MHz,

CDC13) 6 = 8.32 (br. s., 1 H), 7.72 7.45 (m, 1 H), 7.25 (br. s., 10 H), 7.02 6.78 (m, 1 H), 6.67

(d, J= 7.6 Hz, 1 H), 5.27 (br. s., 1 H), 5.01 (br. s., 2 H), 2.84 (br. s., 3 H), 2.58 2.29 (m, 2 H),

1.85 (br. s., 2 H). 13C NMR (75MHz, CDC13) 6 = 158.7, 156.3, 148.0, 144.0, 137.4, 128.7,

127.3, 126.2, 117.4, 114.5, 64.3, 34.9









Ph 0


'Ph OMe
2-50
Anisoyl (2S, 5S)-Diphenylpyrrolidine Amide 2-50. 'H NMR (300 MHz, CDC13) 6 =

1.89-2.01 (m, 2H), 2.57-2.87 (m, 2H), 3.81 (s, 3H), 5.44 (d, J= 6.3 Hz, 1H), 5.82 (d, J= 5.7 Hz,

1H), 6.77 (d, J= 8.7 Hz, 2H), 7.12 (d, J= 7.5 Hz, 2H), 7.21-7.59 (m, 10H); 13C NMR (75 MHz,

CDC13) 6 =31.8, 34.2, 55.6, 62.3, 65.1, 133.5, 125.9, 127.2, 128.8, 130.5, 143.9, 144.5, 160.6,

171.4.

General Procedure for the Formation of Tri-Substituted Ureas from Isocyanates


Ph 0


Ph 2-51

3,5-Dimethylaniline (2S, 5S)-Diphenylpyrrolidine Urea 2-51. 3,5-dimethylphenyl

isocyanate (0.448 mmol, 0.063 mL) and MTBE (2 mL) were added to a flame dried Schlenk

flask. To this solution was added drop wise chiral amine 2-37 (0.448 mmol, 0.100 g) dissolved

in MTBE (2 mL). After five minutes, a white precipitate formed, and the reaction was stirred for

5 hours. The reaction was quenched with water and extracted with CH2C2 (3 mL x 3). The

organic layers were collected, dried with MgSO4, and concentrated. The crude product was

purified by column chromatography (hexanes/ethyl acetate 4:1) to give the pure urea (0.148 g,

89%) as a white solid. 'HNMR (300 MHz, CDC13) 6 = 1.79-1.84 (m, 2H), 2.16 (s, 6H), 2.51-

2.60 (m, 2H), 5.12-5.60 (br. s., 2H), 6.01 (s, 1H), 6.57 (s, 1H), 6.72 (s, 2H), 7.25-7.44 (m, 10H);

13C NMR (75 MHz, CDC13)6 = 21.5, 62.2, 117.1, 124.7, 129.3, 138.6, 138.9, 153.5.









General Procedure for the Methylation of Tri-Substituted Ureas


Ph U -i


Ph 2-52
N,N-Methyl-3,5-Dimethylaniline (2S, 5S)-Diphenylpyrrolidine Urea 2-52. Urea 2-51

(0.329 mmol, 0.122 g) was combined with DMF (3.3 mL) in a flame dried Schlenk flask.

Sodium hydride (0.494 mmol, 0.0197 g) was added to this solution and it was stirred at room

temperature for 45 minutes. After this point, methyl iodide (0.494 mmol, 0.031 mL) was added,

the reaction was heated to 40 OC, and the reaction mixture was stirred overnight. The reaction

was quenched with water and extracted with CH2C12. The organic fractions were combined,

dried with MgSO4, and concentrated. The crude product was purified by column

chromatography (hexanes/ethyl acetate, 4:1) to afford the pure product (0.119 g, 94%). 1H NMR

(300 MHz, CDC13) 6 = 1.62-1.68 (m, 2H), 2.23-2.40 (s, 8H), 2.80 (s, 3H), 6.38 (s, 2H), 6.84 (s,

1H), 7.11-7.38 (m, 10H); 13C NMR (75 MHz, CDC13) 6 = 21.4, 38.9, 63.5, 123.5, 126.2, 127.1,

128.5, 138.8, 145.1, 145.4, 159.7.

General Procedure for Formation of Carbene 3-4

Li


3-4
Lithium-Bis(Pyrrolidine)Carbene 3-4. To a Schlenk flask in a glovebox, 100 mg (0.364

mmol) of chloroamidinium 3-1 was added, and the flask was connected to a Schlenk line outside

the glovebox. THF (2 mL) was added, and the suspension was cooled to -78 C with a dry-

ice/acetone bath. After cooling, 2.5M n-BuLi in hexanes (0.153mL) was added. After 5

minutes, the suspension turned to a clear and slightly yellowish solution upon formation of









carbene. The solution proceeded to stir at -78 C for a total of 1 hour. 1H NMR (300MHz, THF-

ds) 6 = 3.56 (br. s., 8 H), 1.70 (br. s., 8 H). 13C NMR (75MHz, THF-ds) 6 = 233.8.

S




Bis(Pyrrolidine)thiourea 3-2. Carbene generation was followed as described above.

After formation of carbene, 100 mg (3.125 mmol) of sulfur was added, and the reaction was

allowed to slowly warm to room temperature. The resulting suspension stirred for 12 hours,

diluted with ether, and filtered over a bed of celite. The filtrate was concentrated and purified by

silica-gel chromatography (2:1 hexanes/ethyl acetate). After removal of solvent, 45 mg (0.245

mmol) of a colorless crystal resulted (68% yield). 1H and 13C NMR matched the values found in

literature.47

General Procedure for Rhodium and Iridium Complex Formation

Generation of carbene as described for 3-4 was followed. After stirring for 1 hour at -78 C,

[M(COD)C1]2 (0.5 equiv.) was added, and the reaction slowly warmed to room temperature.

Stirring at room temperature proceeded for 12 hours, at which point, solvent was evaporated. To

remove any remaining [M(COD)C1]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 then transferring 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. The product is sufficiently soluble in hexanes.



N
5 CI/

3-5








Chloro(ql4-1,5-cyclooctadiene)-bis(pyrrolidinecarbene)rhodium(I) 3-5. 1H NMR

(300MHz, CDC13) 6 = 4.80 (br. s., 4 H), 4.44 (br. s., 2 H), 3.40 (br. s., 4 H), 3.18 (m, 2 H), 2.52 -

2.17 (m, 4 H), 2.10 1.71 (m, 12 H). 13C NMR (75MHz, CDC13) 6 = 216.8, 216.2, 96.7, 96.6,

68.3, 68.1, 55.7, 51.9, 32.8, 28.9, 26.5, 24.9. HRMS Calcd. for C17H28N2Rh [M-C1]+: 363.1302,

Found: 363.1312.


0. ,
NCI

3-6
Chloro(q4-1,5-cyclooctadiene)-bis(pyrrolidinecarbene)iridium(I) 3-6. H NMR

(300MHz, CDC13) 6 = 4.53 (br. s., 2 H), 4.35 (br. s., 4 H), 4.23 (br. s., 2 H), 3.48 (br. s., 4 H),

3.03 2.68 (m, 2 H), 2.40 2.00 (m, 4 H), 1.86 (br. s., 8 H), 1.71 1.40 (m, 4 H). 13C NMR

(75MHz, CDC13)6 = 211.7, 81.4, 54.7, 52.0, 33.4, 29.5, 25.7. HRMS Calcd. for C34H56N4lr2C1

[2M+C1] : 941.3436, Found: 941.3376.




3-8 Il

Chloro(q4-1,5-cyclooctadiene)-(1,3-dimethylimidazolidin-2-ylidene)iridium(I) 3-8. 1H

NMR (300MHz, CDC13) 6 = 4.92 (br. s., 2 H), 4.64 (br. s., 2 H), 3.54 3.43 (m, 8 H), 3.33 3.18

(m, 2 H), 2.47 2.19 (m, 4 H), 2.00 1.74 (m, 4 H). 13C NMR (75MHz, CDC13) 6 = 213.2,

212.6, 99.2, 99.1, 68.3, 68.1, 51.7, 37.4, 33.1, 28.9. HRMS Calcd. for C13H22N2Rh [M-Cl]:

309.0833, Found: 309.0834.




3-9 C









Chloro(q4-1,5-cyclooctadiene)-(1,3-dimethylimidazolidin-2-ylidene)iridium(I) 3-9. 1H

NMR (300MHz, CDC13) 6 = 4.51 (br. s., 2 H), 3.55 (br. s., 4 H), 3.40 (s, 6 H), 2.98 (br. s., 2 H),

2.16 (br. s., 4 H), 1.78 1.54 (m, 4 H). 13C NMR (75MHz, CDC13) 6 = 207.9, 85.0, 52.0, 52.0,

37.2, 33.6, 29.5. HRMS Calcd. for C2,,H44N4Ir2C1 [2M+C1]+: 833.2495, Found: 833.2419.


N)


3-12 CI

Chloro(ql4-1,5-cyclooctadiene)-bis(piperidinecarbene)rhodium(I) 3-12. 1H NMR

(300MHz, CDC13) 6 = 4.81 (br. s., 2 H), 3.88-3.82 (m, 8 H), 3.17 (br. s., 2 H), 2.27 (br. s., 4 H),

1.82 (m, 4 H), 1.62 (br. s., 12 H). 13C NMR (75MHz, CDC13) 6 = 222.3, 221.7, 97.7, 97.6, 68.1,

67.9, 54.0, 32.8, 28.9, 26.7, 24.5. HRMS Calcd. for C19H32N2Rh [M-Cl] : 391.1615, Found:

391.1612.


c N ^
C-N

3-13 Cl

Chloro(ql4-1,5-cyclooctadiene)-bis((S)-2-methylpyrrolidine)rhodium(I) 3-13. 1H NMR

(300MHz, CDC13) 6 = 6.42 (br. s., 1 H), 5.93 (br. s., 1 H), 5.57 (br. s., 0.4 H), 5.09 4.62 (m, 2.3

H), 4.23 3.70 (m, 1.4 H), 3.28 (br. s., 5 H), 1.82 (br. s., 22 H). 13C NMR (75MHz, CDC13) 6 =

97.0, 97.0, 68.6, 68.4, 66.9, 66.7, 63.3, 61.9, 51.2, 50.9, 34.9, 33.2, 33.0, 32.6, 31.6, 31.1, 29.8,

29.3, 28.6, 28.3, 25.0, 23.3, 23.0, 21.0, 20.5, 14.3. HRMS Calcd. for C19H32N2Rh [M-Cl]:

391.1615, Found: 391.1616. [a]D26 -182.6 (c 8.3 mg/mL CHC13).
















3-15
Chloro(q4-1,5-cyclooctadiene)-bis((R)-2-diphenylmethylpyrrolidine)rhodium(I) 3-15.

H NMR (300MHz, CDC13) 6 = 7.53 (d, J= 7.3 Hz, 2 H), 7.47 7.11 (m, 12 H), 6.96 (t, J= 6.6

Hz, 1 H), 6.69 6.51 (m, 1 H), 5.71 (d, J= 3.8 Hz, 1 H), 4.81 (br. s., 2 H), 4.36 (d, J= 6.2 Hz, 1

H), 3.20- 2.99 (m, 2 H), 2.93 (dd, J= 5.3, 10.0 Hz, 1 H), 2.83 2.60 (m, 2 H), 2.49 2.12 (m, 3

H), 2.12 1.84 (m, 3 H), 1.84 1.40 (m, 7 H), 1.39- 1.13 (m, 4 H). 13C NMR (75MHz, CDC13)

6 = 222.5, 221.9, 143.3, 143.2, 142.8, 142.6, 142.0, 141.6, 131.0, 129.9, 129.4, 129.3, 129.1,

129.0, 128.8, 128.6, 128.5, 128.4, 128.3, 128.0, 127.5, 127.4, 127.3, 127.1, 126.8, 126.7, 126.5,

126.2, 126.2, 98.1, 98.0, 97.8, 97.7, 78.6, 70.8, 69.5, 69.3, 69.1, 67.7, 67.5, 60.6, 60.0, 56.1, 55.8,

54.5, 54.1, 53.3, 49.0, 32.9, 32.8, 31.2, 31.2, 28.7, 28.6, 28.1, 26.7, 26.0, 25.8, 24.9, 23.8, 21.3,

14.4. HRMS Calcd. for C43H48N2Rh [M-Cl]+: 695.2867, Found: 695.2868.


N /C
dC N
N 3-18


Chloro(il2-N,N-dimethylbenzylamine)-bis(pyrrolidinecarbene)palladium(II) 3-18. To

a Schlenk flask in a glovebox, 0.055 g (0.2 mmol) of chloroamidinium 3-1 was added, and the

flask was connected to a Schlenk line outside the glovebox. THF (2 mL) was added, and the

suspension was cooled to -78 C with a dry-ice/acetone bath. After cooling, 1.7M t-BuLi in

hexanes (0.235 mL) was added. After 5 minutes, the suspension turned to a clear and slightly

yellowish solution upon formation of carbene. The solution proceeded to stir at -78 C for a total

of 1 hour. After stirring for 1 hour at -78 C, 0.055 g (0.1 mmol) palladium(r2-N,N-








dimethylbenzylamine)chloride dimer was added, and the reaction slowly warmed to room

temperature. Stirring at room temperature proceeded for 12 hours, at which point, solvent was

evaporated. To remove any remaining metal precursor, the product was purified by

chromatography on a short pad of silica-gel. Columns were run starting with ethyl acetate and

then transferring to 2.5% MeOH in DCM. 1H NMR (300MHz, CDC13) 6 = 6.93 (br. s., 2 H),

6.82 (m, 1 H), 6.64 (d, J= 7.0 Hz, 1 H), 3.74 (br. s., 10 H), 2.66 (s, 6 H), 1.85 (br. s., 8 H). 13C

NMR (75MHz, CDC13) 6 = 204.3, 150.3, 148.6, 135.2, 125.8, 123.6, 122.3, 71.9, 50.0, 25.8.

HRMS Calcd. for C18H28N3Pd [M]+: 392.1320, Found: 392.1328.


Q
C-BF3

0 3-31

N,N,N',N'-bis(tetramethylene)-2-formamidinium trifluoroborate 3-31. Generation of

carbene as described for 3-4 was followed with 0.50g (1.82 mmol) of chloroamidinium 3-1.

After stirring for 30 minutes at -78 C, 0.23 mL (1.82 mmol) of BF3*Et20 was added, and the

reaction slowly warmed to room temperature. Stirring at room temperature proceeded for 12

hours, at which point, solvent was evaporated. The product was purified by silica gel

chromatography (1:1 hexanes:ethyl acetate). H NMR (300MHz, CDC13) 6 = 3.59 (br. s., 8 H),

1.73 (br. s., 8 H). 13C NMR (75MHz, CDC13) 6 = 180.3, 52.8, 25.4. 19F NMR (282MHz, CDC13)

6 = 138.95 (q, J= 45 Hz). Anal Calcd for C9H16N2BF3: C, 49.13; H, 7.33; N, 12.73. Found: C,

49.374; H, 7.528; N, 12.591.









General Procedure for 1,4 Conjugate Addition


3-Phenyl Cyclohexanone. To a flame dried Schlenk flask under argon, 126 mg (1.04

mmol) of phenyl boronic acid, 29 mg (0.52 mmol) of potassium hydroxide, and 2 mg (0.0052

mmol) of rhodium catalyst 3-5 were added. 1 mL of THF and 0.1 mL of water was added, and

to the reaction mixture, 50 mg (0.52 mmol) of cyclohexenone was added. The solution was

heated to 40 OC. The mixture was stirred for thirty minutes and monitored by TLC (Rf 0.63, 2:1

hexanes/ethyl acetate). The solution was diluted with 10 mL of diethyl ether and washed twice

with a 10% aqueous solution of NaOH. The organic layer was dried and concentrated, and then

purified by silica-gel chromatography (4:1 hexanes/ethyl acetate) to isolate the product as a clear

oil in 98% yield. Spectroscopic values matched those reported in the literature.48 1H NMR

(300MHz, CDC13) 6 = 7.39 7.28 (m, 2 H), 7.28 7.15 (m, 3 H), 3.12 2.89 (m, 1 H), 2.66 -

2.26 (m, 4 H), 2.25 1.99 (m, 2 H), 1.95 1.65 (m, 2 H). 13C NMR (75MHz, CDC13) 6 = 211.3,

144.6, 128.9, 126.9, 126.8, 49.2, 45.0, 41.4, 33.0, 25.8.

0





3-(p-Tolyl)-Cyclohexanone. Spectroscopic values matched those reported in the

literature.4 1HNMR (300MHz, CDC13) 6 = 7.27 7.01 (m, 4 H), 3.16 2.86 (m, 1 H), 2.69 -

2.39 (m, 4 H), 2.35 (s, 4 H), 2.23 2.02 (m, 2 H), 1.93 1.68 (m, 2 H). 13C NMR (75MHz,

CDCl3) 6 =211.3, 141.7, 136.4, 129.6, 126.7, 49.3, 44.6, 41.4, 33.1, 25.8, 21.2.














SOMe

3-(p-Anisoyl) Cyclohexanone. Spectroscopic values matched those reported in the

literature.4 1H NMR (300MHz, CDC13) 6 = 7.22 7.04 (d, J = 7.6 Hz, 2 H), 6.96 6.75 (d, J=

7.6 Hz, 2 H), 3.77 (s, 3 H), 3.06 2.81 (m, 1 H), 2.64 2.24 (m, 4 H), 2.22 1.93 (m, 2 H), 1.91 -

1.61 (m, 2 H). 13C NMR (75MHz, CDCl3)6 = 211.4, 158.5, 136.8, 127.7, 114.2, 55.5, 49.4, 44.2,

41.4, 33.2, 25.7.

0



aF

3-(p-Fluorophenyl) Cyclohexanone. Spectroscopic values matched those reported in the

literature.4 1H NMR (300MHz, CDC13) 6 = 7.25 7.06 (m, 2 H), 6.97 (t, J = 8.2 Hz, 2 H), 3.08 -

2.86 (m, 1 H), 2.63 2.24 (m, 4 H), 2.21 1.93 (m, 2 H), 1.90 1.66 (m, 2 H). 13C NMR

(75MHz, CDC3) 6 = 210.9, 163.3, 160.1, 140.3, 128.3, 128.2, 115.7, 115.5, 49.2, 44.2, 41.3,

33.1, 25.6.

0






3-(1-Naphthyl) Cyclohexanone. Spectroscopic values matched those reported in the

literature.49 1H NMR (300MHz, CDC13) 6 = 8.05 (d, J= 7.9 Hz, 1 H), 7.88 (d, J= 7.6 Hz, 1 H),

7.77 (d, J= 7.9 Hz, 1 H), 7.63 7.30 (m, 4 H), 3.86 (t, J= 11.1 Hz, 1 H), 2.82 2.73 (m, 1 H),

2.71 2.40 (m, 3 H), 2.36 2.10 (m, 2 H), 1.98 (t, J= 10.8 Hz, 2 H). 13C NMR (75MHz, CDC13)









6= 211.5, 140.3, 134.2, 131.1, 129.3, 127.5, 126.5, 125.9, 125.8, 123.0, 122.7, 48.8, 41.7, 39.6,

32.5, 25.8.

0






3-(o-Tolyl)-Cyclohexanone. Spectroscopic values matched those reported in the

literature.5 1H NMR (300MHz, CDC13) 6 = 7.43 7.03 (m, 4 H), 3.23 (d, J= 8.8 Hz, 1 H), 2.61

- 2.36 (m, 4 H), 2.34 (s, 3 H), 2.18 (td, J= 2.5, 6.5 Hz, 1 H), 2.09 1.95 (m, 1 H), 1.93 1.73 (m,

2 H). 13C NMR (75MHz, CDCl3)6 = 211.4, 142.6, 135.3, 130.9, 126.7, 126.6, 125.3, 48.6, 41.5,

40.5, 32.2, 26.0, 19.5.

General Procedure for Formation of Biaryl Methanols

MeOH




2-Methoxyphenyl-Phenyl-methanol. To a flame dried Schlenk flask under argon, 50 mg

(0.364 mmol) of o-anisaldehyde, 89 mg (0.728 mmol) of phenyl boronic acid, 83 mg (0.728

mmol) of potassium tert-butoxide, and 2 mg (0.0052 mmol) of rhodium catalyst 3-5 were added.

1.22 mL of DME and 0.33 mL of water were added, and the solution was heated to 40 OC. The

mixture was stirred for one hour and monitored by TLC (Rf 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 and concentrated, and then purified by silica-gel

chromatography (8:1 hexanes/ethyl acetate) to isolate the product as a clear oil in 92% yield.

Spectroscopic values matched those reported in the literature.51 H NMR (300MHz, CDC13) 6 =

7.49 7.11 (m, 8 H), 7.07 6.82 (m, 2 H), 6.07 (s, 1 H), 3.78 (s, 3 H), 3.32 (br. s., 1 H). 13C









NMR (75MHz, CDC13) 6 = 156.9, 143.5, 132.2, 129.7, 129.0, 128.4, 128.1, 127.4, 126.8, 121.1,

115.6, 111.0, 72.4, 55.7. HRMS Calcd. for C14H130 [M-OH] : 197.0989, Found: 197.0994.

Me OH f




2-Methoxyphenyl-Naphthalen-l-yl Methanol. 1H NMR (299MHz, CDC13) 6 = 8.05 (d,

J= 7.4 Hz, 1 H), 7.96 7.79 (m, 2 H), 7.71 (d, J= 7.1 Hz, 1 H), 7.60 7.39 (m, 3 H), 7.37 7.22

(m, 1 H), 7.11 6.78 (m, 4 H), 3.91 (s, 3 H), 3.22 (br. s., 1 H). 13C NMR (75MHz, CDC13) 6 =

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 Calcd. for C8isH50 [M-OH]+: 247.1177, Found: 247.1176.

Me OH




2-Methoxyphenyl-o-Tolyl Methanol. 1H NMR (299MHz, CDC13) 6 = 7.66 7.46 (m, 1

H), 7.43 7.13 (m, 4 H), 7.12 6.83 (m, 3 H), 6.32 (s, 1 H), 3.88 (s, 3 H), 3.00 (br. s., 1 H), 2.27

(s, 3 H). 13C NMR (75MHz, CDC13) 6 = 157.3, 140.8, 135.8, 131.5, 130.4, 129.1, 128.1, 127.5,

126.8, 126.2, 121.0, 110.7, 68.5, 55.7, 19.5. HRMS Calcd. for C15Hi50 [M-OH]+: 211.1176,

Found: 211.1185.

Me OH


OMe

2-Methoxyphenyl-4-Methoxyphenyl Methanol. 1H NMR (300MHz, CDC13) 6 = 7.60 -

7.17 (m, 4 H), 7.11 6.73 (m, 4 H), 6.05 (s, 1 H), 3.79 (s, 6 H), 3.30 (br. s., 1 H). 13C NMR

(75MHz, CDC13)6 = 159.0, 156.9, 136.0, 132.6, 128.8, 128.1, 127.8, 121.0, 113.8, 111.0, 71.7,

55.6, 55.5. HRMS Calcd. for C15H1402 [M-OH]+: 226.0994, Found: 226.0987.













4-Fluorophenyl-2-Methoxyphenyl Methanol. 1H NMR (300MHz, CDC13) 6 = 7.55 -

7.19 (m, 4 H), 7.13 6.79 (m, 4 H), 6.03 (br. s., 1 H), 3.80 (s, 3 H), 3.27 (br. s., 1 H). 13C NMR

(75MHz, CDC13) 6 = 163.8, 160.6, 156.8, 139.4, 139.4, 132.1, 129.1, 128.5, 128.4, 127.8, 121.1,

115.3, 115.0, 111.0, 71.7, 55.6. HRMS Calcd. for C14H1302F [M] : 232.0900, Found: 232.0886.

CI OH

&~I-0

2-Chlorophenyl-Phenyl Methanol. Spectroscopic values matched those reported in the

literature. 1HNMR (299MHz, CDC13) 6 = 7.62 (dd, J= 1.4, 7.6 Hz, 1 H), 7.51 7.11 (m, 8 H),

6.37 6.05 (m, 1 H), 2.88 2.58 (m, 1 H). 13C NMR (75MHz, CDC13) 6 = 142.5, 141.3, 132.7,

129.8, 129.0, 128.7, 128.3, 128.0, 127.4, 127.2, 72.9. HRMS Calcd. for C13HIoC1 [M-OH]+:

201.0446, Found: 201.0472.

OH


F

4-Fluorophenyl-Phenyl Methanol. Spectroscopic values matched those reported in the

literature.52 1H NMR (300MHz, CDC13) 6 = 7.45 7.18 (m, 7 H), 7.09 6.85 (m, 2 H), 5.74 (s, 1

H), 2.63 (br. s., 1 H). 13C NMR (75MHz, CDC13) 6 = 164.0, 160.7, 143.8, 139.8, 139.7, 130.1,

128.8, 128.6, 128.5, 128.4, 127.9, 126.7, 115.6, 115.3, 75.8. HRMS Calcd. for C13H9F [M-

OH] : 185.0761, Found: 185.0772.









OH
F3C Z


CF3

3,5-Bis(Trifluoromethyl)phenyl-Phenyl Methanol. 1H NMR (300MHz, CDC13) 6 = 7.87

(s, 2 H), 7.79 (s, 1 H), 7.55 7.19 (m, 5 H), 5.91 (s, 1 H), 2.50 (br. s., 1 H). 13C NMR (75MHz,

CDC13) 6 = 146.3, 142.6, 132.1, 131.7, 129.3, 128.8, 126.9, 126.7, 121.7, 121.6, 75.5. HRMS

Calcd. for C15H10F6 [M]: 320.0636, Found: 320.0623.

NMR of Carbene Intermediate

The carbene was generated at -78 C, in THF-ds, and analyzed by NMR spectroscopy at -

30 C. First, gHMBC, gHMQC and gDQCOSY experiments were run in about 30 minutes, to

quickly characterize the carbene, presumed unstable. The carbene carbon, at 232.9 ppm,

displayed couplings in the gHMBC spectrum with two protons, at 3.47 and 3.66 ppm, both

triplets. The gDQCOSY spectrum revealed the sequence 3.47-1.89-1.76- 3.66. The carbons

carrying these protons were detected in the gHMQC spectrum at 48.4, 26.5, 24.5 and 55.8

correspondingly. The non-equivalence of the alpha positions in the tetrahydropyrrole moiety

indicates restricted rotation about the carbene carbon nitrogen bond.

NMR spectra were recorded on a Varian Inova spectrometer, operating at 500 MHz for

H and 125 MHz for 13C, and equipped with a 5 mm indirect detection probe, with z-axis

gradients. The 1H and 13C chemical shifts were referenced to internal tetramethylsilane. The

solvent was THF-ds, and the temperature -30 C. The gHMBC experiment was run with the

standard vnmr pulse sequence. 2048 points were acquired in f2, on a spectral window from 0.1 to

4.3 ppm. The acquisition time was 0.49 s, with a relaxation delay of 0.5 s. 512 increments were









acquired in fl, for a spectral window from 0 to 300 ppm, in 1 transient per increment. The total

experiment time was 9 minutes.

The gHMQC experiment was run with the standard vnmr pulse sequence. 1024 points were

acquired in f2, on a spectral window from 0.5 to 4.0 ppm. The acquisition time was 0.29 s, with a

relaxation delay of 1 s. 256 increments were acquired in fl, for a spectral window from 10 to 80

ppm, in 1 transient per increment. The total experiment time was 6 minutes.

The gDQCOSY experiment was run with the standard vnmr pulse sequence. 2048 points

were acquired in f2, on a spectral window from 0.64 to 3.64 ppm. The acquisition time was 0.64

s, with a relaxation delay of 1 s. 512 increments were acquired in fl, in 1 transient per increment.

The total experiment time was 16 minutes.









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BIOGRAPHICAL SKETCH

David Snead was born in Charlotte, North Carolina on December 31st of 1982, and grew

up in Raleigh, North Carolina. After graduating from St. Timothy's-Hale Episcopal High School

in 2001, he attended the University of North-Carolina at Chapel Hill where he majored in

chemistry. Upon graduation, David married Stephanie Leigh Elder on May 21st of 2005. David

went on to pursue his PhD in organic chemistry at the University of Florida under the

supervision of Dr. Sukwon Hong, and will pursue postdoctoral opportunities at MIT and

Argonne National Laboratories in hopes of attaining a research professorship.





PAGE 1

1 EXPLORATION OF ACYCLIC DIAMINOCARBENES AS TRANSITION METAL LIGANDS By DAVID ROBINSON SNEAD A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DE GREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2010

PAGE 2

2 2010 David Robinson Snead

PAGE 3

3 To Stephanie

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4 ACKNOWLEDGMENTS Pursuit of the PhD and the opportunity to completely immerse myself into rese arch endeavors was a dream of mine, only made possible through the efforts and allowances of others. To forget the ir help would be arrogant and inaccurate. First and foremost, I would like to express my total and awe filled gratitude to my wife, Stephanie. A t many times, I spent incredible amounts of time away from home at the laboratory. This was a sacrifice not only on my part, b ut also and maybe mostly on her part. I thank her for giving so much of herself, and for supporting me after long days with u nderstanding, conversation, or a meal. I am grateful not only for the allowance, but for the encouragement to follow this pursuit which at times m ight seem incomprehensible. She made it possible to get through this when I was discouraged and tired. I wi ll always be thankful. Secondly, I would like to thank my parents who steadfastly invested in their success. Without all the preparation, wisdom, education, and love they bestowed fulfillment of the PhD would be impossible. I especially woul d like to tha nk my father for pushing and challenging me in adolescence to instill a do gmatic sense of ambition which I value and believe to be a great asset I would like to thank my mentor, Sukwon Hong, for providing an exciting project to explore, beli ef in my abilities, and the good character to help me fulfill my career aspirations. I would also like to thank all of our wonderful Gainesville friends who enriched our lives with smiles, jokes, and conversation. You will be the most memorable part of o ur Florida experiment.

PAGE 5

5 TABLE OF CONTENTS p age ACKNOWLEDGMENTS ................................ ................................ ................................ ............... 4 LIST OF TABLES ................................ ................................ ................................ ........................... 7 LIST OF FIGURES ................................ ................................ ................................ ......................... 8 ABSTRACT ................................ ................................ ................................ ................................ ... 11 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .................. 13 Acyclic Diaminocarbenes ................................ ................................ ................................ ....... 13 2 BIS(2 ALKYLPYRROLIDIN 1 YL)METHYLIDENES AS CHIRAL ACYCLIC DIAMINOCARBENE LIGANDS ................................ ................................ ........................ 17 Introduction ................................ ................................ ................................ ............................. 1 7 Ureas Stemming from 2 Substituted Pyrrolidine ................................ ................................ ... 1 8 Urea Crystal Structures ................................ ................................ ................................ ........... 1 9 Formation of Palladium ADC Complexes ................................ ................................ ............. 2 3 Suzuki Cross Coupling ................................ ................................ ................................ ........... 2 8 C 2 Symmetric Pyrrolidine Moieties and Attempts at Symmetrically Substituted Ureas ....... 3 2 Ureas with Non Identical Amine Moieties Featuring (2 S ,5 S ) trans diphenylpyrrolidine ..... 3 5 Chlorination and Metalation of Ureas Based on (2 S ,5 S ) trans Diphenylpyrrolidine ............ 3 6 Conclusion and Summary ................................ ................................ ................................ ....... 3 7 3 LITHIUM HALOGEN EXCHANGE: A NEW METHOD FOR DIAMINOCARBENE FORMATION ................................ ................................ ................................ ......................... 3 9 Introduction ................................ ................................ ................................ ............................. 3 9 Carbene Formation and Proof ................................ ................................ ................................ 4 0 Binding Diaminocarbenes to Transition Metals and Boron ................................ ................... 4 2 Other Ligands Explored in Carbene F ormation from the Lithium Halogen Exchange ......... 5 9 Catalytic Activity of Rhodium Complexes Accessed Through Lithium Halogen Exchange 6 8 ADC Pd Complex 3 18 in the Suzuki Cross Coupling ................................ .......................... 7 8 Steric and Electronic Measurements of ADC and NHC Compounds ................................ .... 7 8 Conclusion s and Summary ................................ ................................ ................................ ..... 8 1 4 EXPERIMENTAL SECTION ................................ ................................ ................................ 8 3 General Remarks ................................ ................................ ................................ .................... 8 3

PAGE 6

6 General Procedure for Formation of Ureas Based on 2 Substituted Pyrrolidines. ................. 8 3 General Procedure for the Formation of Chloroamidinium Ions. ................................ ........... 8 5 General Procedure for the Formation of Palladium Complexes. ................................ ............ 8 7 General Procedure for Suzuki Cross Coupling Reaction ................................ ....................... 8 8 General Procedure for the Formation of Ureas from Carbamoyl Chlorides .......................... 8 9 General Procedure for the Formation of Tri Substituted Ureas from Isocyanates ................. 9 0 General Procedure for the Methylation of Tri Substituted Ureas ................................ .......... 9 1 General Procedure for Formation of Carbene 3 4 ................................ ................................ .. 9 1 General Procedure for Rhodium and Iridium Complex Formation ................................ ........ 9 2 General Procedure for 1,4 Conjugate Addition ................................ ................................ ...... 9 7 General Procedure for Formation of Biaryl Methanols ................................ .......................... 9 9 NMR of Carbene Intermediate ................................ ................................ ............................. 102 LIST OF REFERENCES ................................ ................................ ................................ ............. 1 04 BIOGRAPHICAL SKETCH ................................ ................................ ................................ ....... 109

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7 LIST OF TABLES Table page 1 1 Calculated values of N C N bon d angle and proton affinity (PA) for select carbenes ................................ ................................ ................................ .............................. 14 2 1 Crystal data and structure refinement for 2 1 ................................ ................................ ... 22 2 2 Crystal dat a and structure refinement for 2 2 ................................ ................................ ... 22 2 3 Crystal data and structure refinement for 2 15 ................................ ................................ 26 2 4 N C N bond angles and Pd C bond lengths for select carbenes. ................................ .. 28 2 5 Optimization of Suzuki cross coupling reaction. ................................ ............................... 29 2 6 Suzuki cross coupling of 2 23 and 2 24 with a variety of catalysts. a ................................ 30 2 7 Exploration of substrate scope in Suzuki cross coupling reaction. ................................ ... 31 3 1 Crystal data and structure refinement for 3 5 ................................ ................................ ... 48 3 2 Crystal data and structure refinement for 3 6 ................................ ................................ ... 49 3 3 Crystal data and stru cture refinement for 3 9 ................................ ................................ ... 50 3 4 Crystal data and structure refinement for 3 13 ................................ ................................ 54 3 5 Attempts at transmetalating ADC ligan d to rhodium. ................................ ....................... 59 3 6 1,4 Conjugate Addition of Boronic Acids to Cyclohexenone ................................ ........... 70 3 7 1,2 Addition of arylboronic acids to o anisaldehyde. ................................ ........................ 71 3 8 1,2 Addition of phenylboronic acid to arylaldehydes. ................................ ....................... 72 3 9 1,2 Asymmetric addition of 1 naphthylboroni c acid to o anisaldehyde. ........................... 76 3 10 Redox half potentials for some Ir(L)(COD)Cl complexes in CH 2 Cl 2 (scan rate 100mVs 1 ). ................................ ................................ ................................ ......................... 79 3 11 Calculated % V Bur values for ADC ligands in complexes 3 5 3 6 3 9 and 3 13 Calculated with Bondi radii scaled by 1.17, 3.5 radius of the sphere, and 2.1 distance of the ligand from the sphere. NHC values reported by Cavallo ........................ 80

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8 LIST OF FIGURES Figure page 1 1 An N heterocyclic carbene and some acyclic diaminocarbenes ................................ ........ 14 1 2 A comparison of electronic and steric param eters for NHC and ADC ligands. ................ 15 1 3 General method of preparation of carbene metal complexes via Frstner's route. ............ 15 1 4 Some carbene metal complexes formed by oxidative addition of chloroamidinium ions. ................................ ................................ ................................ ................................ .... 16 2 1 Potential conformers associated with carbenes des igned abo ut 2 substituted pyrrolidines. ................................ ................................ ................................ ....................... 17 2 2 Unique abilities of a conf ormationally flexible ligands. ................................ .................... 18 2 3 Ureas from 2 substituted pyrrolidine derivatives. ................................ ............................. 18 2 4 Synthesis of urea 2 3 from condensation of ( R ) (+) 2 isopropyl pyrrolidine. ................... 19 2 5 Potential conformers of ureas 2 1 to 2 4 ................................ ................................ ........... 20 2 6 Molecular structure of urea 2 1 ................................ ................................ ......................... 21 2 7 Molecular structure of urea 2 2 ................................ ................................ ......................... 21 2 8 Chlorination of ureas with oxalyl chloride. ................................ ................................ ....... 24 2 9 Complexation of chloroamidiniums to palladium. ................................ ............................ 24 2 10 Molecular structure of complex 2 15 ................................ ................................ ................ 26 2 1 1 Chromium ADC complex discovered by Herrmann. ................................ ........................ 27 2 1 2 Preparation of (2 S ,5 S ) trans diphenylpyrrolidine ................................ ............................. 33 2 1 3 Some attempts at urea formation with (2 S ,5 S ) trans diphenylpyrrolidine. ....................... 34 2 1 4 Synthetic attempt aimed at urea 2 39 using CDI. ................................ .............................. 34 2 1 5 Challenging secondary amines in desired urea production. ................................ ............... 35 2 1 6 Ureas from carbamoyl chlorides, acyl chlorides, and isocyanates. ................................ ... 36 2 1 7 Chlorination of urea 2 50 and attempt at cationic ADC Pd compound 2 5 7 ................... 37

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9 2 1 8 ADC Pd complexes with 2 substituted pyrrolidines as mimics for ADC ligands with C 2 symmetric pyrrolidines. ................................ ................................ ........................ 38 3 1 Envisioned synthesis of carbene intermediates through Li X exchange. .......................... 39 3 2 Classic methods to Form Organolithium Species. ................................ ............................. 40 3 3 Tentative proof of carbene intermediacy via lithium halogen exchange. .......................... 41 3 4 13 C NMR Spectrum of lithiated carbene intermediate 3 produced through lithium halogen exchange. ................................ ................................ ................................ 43 3 5 2D gHMBC spectrum of lithiated carbene intermediate 3 4 produced through lithium halogen exchange. ................................ ................................ ................................ 44 3 6 Formation o f rhodium and iridium ADC complexes from chloroamidinium 3 1 ............ 45 3 7 Formation of rhodium and iridium NHC complexes from chloroamidinium 3 7 ............ 46 3 8 Molecular structure of complex 3 5 ................................ ................................ .................. 47 3 9 Molecular structure of complex 3 6 ................................ ................................ .................. 47 3 1 0 Molecular s tructure of Complex 3 9 ................................ ................................ ................. 48 3 1 1 Formation of piperidine based ADC rhodium complex from chloroamidinium 3 11 ................................ ................................ ................................ ................................ ....... 5 1 3 1 2 Synt hesis of chiral ADC rhodium complexes 3 13 and 3 15 ................................ ........... 53 3 1 3 Molecular structure of complex 3 13 ................................ ................................ ................ 54 3 1 4 Synthesis of ADC palladium catalyst 3 18 ................................ ................................ ....... 55 3 1 5 Attempt to create a frustrated Lewis pair with an ADC. ................................ ................... 60 3 1 6 Attempts at synthesis of ADC rhodium catalyst using chloroamidinium 3 36 ................ 60 3 1 7 Failure to produce lithiated ADC 3 4 from chloride salt 3 ................................ ....... 61 3 1 8 Observed differences in reactivity based upon counter ion identity. ................................ 62 3 1 9 Diaminocar bene precursors which were unsuccessful in attempts complex with rhodium using lithium halogen exchange methodology. ................................ ................... 62

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10 3 2 0 Attempts at synthesis of a mixed pyridine ADC rhodium complex. ................................ 63 3 2 1 Trials to determine whether n BuLi is effective in generation of carbene intermediacy with precursor 3 43 ................................ ................................ ..................... 64 3 2 2 Formation of chlorinated dithiocarbamate tetrafluoroborate salts 3 51 and 3 52 ............ 65 3 2 3 Formation of chlorinated thiocarbamate tetrafluoroborate salt 3 55 ................................ 66 3 2 4 Attempts at synthesis of rhodium complex 3 63 by changing counter ion identity and lithiation source. ................................ ................................ ................................ .......... 67 3 2 5 Use of a lithio naphthalene solution to generate compound 3 5 ................................ ...... 68 3 2 6 Examples of catalysis with rhodium including cycloadditions, borylations, carbenoid chemistry, C H activation, 1,4 conjugate addition, and 1,2 addition to aldehydes. ................................ ................................ ................................ ........................... 69 3 2 7 A plausible catalytic cycle for the 1,2 addition of aryboronic acids to aldehydes. ............ 75 3 2 8 Attempts at s ynthesis of complexes 3 89 and 3 90 which might be expected to show greater activity toward insertion reactions with olefins. ................................ .......... 77 3 2 9 Suzuki coupling to for tri ortho substituted product us ing catalyst 3 18 ......................... 78 3 3 0 substituents. ................................ ................................ ................................ ........................ 79 3 3 1 Graphical illustration of % V Bur ................................ ................................ ........................ 80 3 3 2 Plot of redox potential vs. % V Bur ................................ ................................ ..................... 81

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11 Abstract of Dissertation Presented to the Graduate School of the Uni versity of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy EXPLORATION OF ACYCLIC DIAMINOCARBENES AS TRANSITION METAL LIGANDS By David Robinson Snead A ug ust 2010 Chair: Sukwon Hong Major: Ch emistry Carbenes are an important class of spectator ligands, the most common of which are N heterocyclic carbenes (NHCs). Lesser explored carbene ligands are acyclic diaminocarbenes(ADCs), which possess a degree of intrigue due to significant variations in electronic and steric parameters from NHCs. In this work, ADCs are explored, with a special emphasis on methods of complexation to metal centers. ADC ligands were built from chiral C _1 s ymmetric pyrrolidine subunits. Ureas 2 1 through 2 4 were synth esized from 2 substituted pyrrolidines, and X ray analysis was obtained for these compounds. The location of the chiral substituents proximal to the oxygen atom of the carbonyl led to a reasonable hypothesis that these ADCs might be useful asymmetric liga nds. Palladium complexes 2 15 and 2 18 were formed through oxidative addition of chloroamidinium precursors; however steric crowding created by the phosphine ligands caused the chiral groups to orient themselves away from the metal center, as observed by X ray analysis. ADCs with substituents larger than benzyl were not able to be isolated with palladium, likely as a result of steric constraints. Complexes 2 15 2 18 and 2 26 were tested in Suzuki rea ctions, but as the degree of ligand substitution in cr eased, reactivity decreased.

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12 Access to a diversity of metal complexes from chloroamidiniums was restricted based on use of the oxidative addition methodology and also required the use of electron rich ligands like phosphines. As such, a new more general m ethod of carbene generation was developed. Lithium halogen exchange was applied to chloroamidiniums to give carbenoid intermediates. 13 ^ C NMR of the carbene in solution and formation of thiourea constitute proof, and after generation, Rh, Ir, Pd and B c omplexes were produced. Interestingly, X ray analysis of Rh ADC complex 3 5 based on chiral C _1 symmetric pyrrolidine subunits demonstrated a change in conformational preference from the palladium compounds, as the methyl substituents were located proxima l to the rhodium center. Rh ADC complex 3 5 was tested in catalytic reactions an d showed good reactivity in 1,4 conjugate addition of aryl boronic ac ids to cyclohexenone and in 1,2 addition of aryl boronic acids to aryl aldehydes. Notably, the ADC ligand p erformed better than NHC in 1,2 addition.

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13 CHAPTER 1 INTRODUCTION Acyclic Diaminocarbenes N heterocyclic carbenes (NHC s ) are of the most ubiquitous class of ligands, and their presence has only grown since the discovery of isolab le carbenes by Arduengo in 1991 1 The emergence of NHCs is attributed to their ability to act as a more robust alternative to phosphines Many metal complexes incorporating NHCs are more stable against heat, moisture and oxygen than their phosphine counterparts. C arbenes similarly to phosphines, donor capacity creating an analogy between the two classes of ligands, 2 but a n a dvancement in the und erstanding of carbenes has shown these ligands have a rich breadth of chemistry all their own and are much more than s 3 Carbenes are more basic than even the most elect ron donating phosphines 4 Additionally, they are less labile, and t he lower lability is most likely due to bond dissociation energies that are practically double that of even the most electron rich tria lkyl phosphines 3a,4a In some notable cases, carbene complexes have demonstrated higher activity than even the b est phosphine systems 5 Typically, carbenes used as ancillary ligands are located on a heterocyclic scaffolding such as 1 1 shown below. Ra re cases feature a cyclic diamino carbenes (ADCs) in which the carbene ring has been dissolved ( 1 2 to 1 4 ). ADCs are a promising variant of NHCs possibly representing the next generation of carbenes. ADCs feature a larger carbene N C N bond angle with res pect to regular NHCs leading to a more basic carbene lone pair (Table 1) 6 The molecular orbitals, 1j and bis(diisopropylamino) carbene 1 2 is the most basic carbene known to date.

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14 Figure 1 1 An N heterocyclic carbene and some acyclic diaminocarbenes In addition to the increased donor capacity of ADCs, it is envisioned that ADCs could be quite useful in asymmetric catalys is. The larger bond angle of these carbenes should place chiral centers closer to metal coordination spheres than traditional NHCs leading to a more efficient transfer of chirality Thus far, only one example of a chiral ADC complex exists 7a The goal of this research was to explore novel chiral ADCs. Table 1 1. Calculated values of N C N bond angle and proton affinity (PA) for select carbenes N C N Bond Angles () 106.0 116.3 121.0 Proton Affinity (kcal/mol) 271.4 278.9 282.9 ADCs have been relatively un explored with respect to NHCs, and relatively few examples of catalysis wi th ADCs exist. Slaughter and F rstner have both isolated metal compl exes with ADCs and then used them catalytically, and Thadani has shown in situ generation of metal complexes with ADCs to be useful 7 The lack of proliferation is partially caused by the difficulties associated from working with ADCs. Since they are more basic and sterically hindered than the usual NHCs, extension of common methods for the preparation of metal compounds do not always translate. Therefore, non traditional modes of complexation are sometimes necessary.

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15 Figure 1 2 A comparison of electronic and steric parameters for NHC and ADC ligands A) Frontier molecular orbitals of carbenes. Triplet carbenes adopt a linear geometry whereas singlet carbenes take on a bent geometry with 120 angles. An NHC is a t ypical singlet carbene, but an ADC has a larger ca rbene bond angle. As it moves toward a more linear state, the HOMO rises in energy with the lone pair becoming more donating as a result B) The greater carbene bond angle of the ADC places the N substitu ents in closer proximity to the metal center. Frstner and co workers utilized chloroamidinium ions in a novel way to initiate format ion of metal complexes with ADC s 7c,d This route relied on three tasks: formation of ureas, generation of chloroamidinium ions and the ability to metalate chloroamidinium salts. The chloroamidinium ions were formed by reacting ureas with oxalyl chloride, and the chlorinated product underwent oxidative addition to electron rich, palladium phosphine species. NHC and ADC com plexes were synthesized through this route, and the products were demonstrated as useful in Suzuki Coupling Heck Coupling and Buchwald Hartwig amination. Previous research by Stone and Cavell gave precedent for this work 8 Figure 1 3 General method of preparation of carbene met al complexes via Frstner's route

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16 Figure 1 4 Some carbene metal complexes formed by oxidative addition of chloroamidinium ions

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17 CHAPTER 2 BIS(2 ALKYLPYRROLIDIN 1 YL)METHYLIDENES AS C HIRAL ACYCLIC DIAMINOCARBENE LIGAN DS Introduction Potentially, ADCs based upon a 2 sub stituted pyrrolidine framework might demonstrate int eresting properties. Depending on the conformational preference of the chiral substituents, the ligands might show an ability to influence stereochemical outcomes in catalysis. Alternatively, potential rotation about the N C bond of the carbene would prov ide a ligand capable of drastic alterations in its steric profile (Figure 2 1) Complexes capable of conformational flexibility can Figure 2 1. Potential conformers associated with carbenes designed about 2 substitute d pyrrolidines. A) Adoption of a conformer with chiral groups situated close to the metal center might afford a catalyst capable of displaying high enantioselectivities and additionally is quite sterically hindered. B) A conformer with one chiral group pr oximal to the metal center might promote some selectivity in catalytic reactions, and is less intruding into the metal coordination sphere. C) The rotamer with both substituents positioned away from the metal center is expected to display the lowest level s of selectivity in catalysis and exhibits the least steric hindrance. lead to high catalytic activity, as illustrated by Glorius and co workers since a transition metal promoted transformation might require both an unhindered (open) or congested (closed) environment during a catalytic cycle (Figure 2 2 ). 9 For example oxidative addition is facilitated by a non crowded coordination sphere, whereas reductive elimination is promoted by a sterically congested environment around the metal. Both processes are often important within the same catalytic cycle, such as that known for the Suzuki cross coupling reaction, and while the needs of oxidative addition and reductive elimination appear to be at odds, they can be met with the use of a conformationally flexibl e ligand.

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18 Figure 2 2 Unique abilities of conformationally flexible ligands. A) Potential conformers of a bis oxazoline based NHC where the leftmost structure is relatively non hindered and the structure on the right is most hindered. B) High catalytic activity of conformationally flexible ligand. Ureas Stemming from 2 Substituted Pyrrolidine Commercially available amines such as ( S ) (+) 2 methyl pyrrolidine and ( R ) (+) 2 (diphenylmethyl)pyrrolidine were used a long w ith ( R ) (+) 2 isopropyl pyrrolidine and ( R ) (+) 2 benzyl pyrrolidine to give symmetrically substituted ureas stemming from 2 substituted pyrrolidine derivatives. T he mono substituted pyrrolidines easily afforded ureas 2 1 to 2 4 ( Figure 2 3 ). Figure 2 3 Ureas from 2 substituted pyrrolidine d erivatives. ( R ) (+) 2 isopropyl pyrrolidine was synthesized from valine, and amide 2 9 was prepared by a known procedure ( Figure 2 4 ). 10 The carbonyl functionality of 2 9 was red uced with LiAlH 4 and protected in situ with Boc 2 O because of volatility of the corresponding amine. Protected amine 2 1 0 was deprotected with 4M HCl in dioxane, the excess HCl was removed in

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19 vacuo and a phosgene solution was added to give urea 2 3 ( R ) (+) 2 benzyl pyrrolidine was synthesized following the same procedure and leading to the related urea 2 4 Figure 2 4 Synthesis of u rea 2 3 from c onde nsation of ( R ) (+) 2 isopropyl p yrrolidine Urea Crystal Structures Crystal structures of ureas 2 1 and 2 2 were obtained to better understand conformational preference of the alkyl substituents and to discern whether the ensuing carbenes might be suitable as chiral ligands Three different conformers, A B and C are attainable as rotation about the amide bond is possible (Figure 2 5 ). Conformer A places the aliphatic substituents in a syn relationship proximal to the carbonyl functionality. This isomer was expected to predominate over B and C as it relieves steric h indrance associated with an alkyl substituent located distal to the carbonyl group. Indeed, when a single crystal was obtained for ureas 2 1 and 2 2 isomer A was observed (Figures 2 6 and 2 7 ). Notably the two pyrrolidine ring systems are not coplanar. In the solid state, 2 1 demonstrates a dihedral angle of ~ 34 for N(2)

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20 C(1) N(1) C(2) and N(1) C(1) N(2) C(7), and in urea 2 1 these dihedral angles are larger at ~ 40. Figure 2 5 Potential conformers of ur eas 2 1 to 2 4 This twisting of the ring systems seems to indicate steric repulsion at carbons C(2) C(7) and C(2) C(19) for 2 1 and 2 2 respectively and growing strain in the molecule. It also indicates a lack of conjugation. The growing strain i n the bulkier molecule becomes even more evident when viewing the N(1) C(1) N(2) bond angle. The less hindered 2 1 possesses an N C N bond angle of 116.57 (9) but for urea 2 2 this value shrinks to 113.3 (5) further deviating from the ideal 120 and pushing the methylene groups adjacent to nitrogen closer together If a similar conformational preference is assumed with carbenes, acyclic carbenes stemming from 2 substituted pyrrolidines might make good asymmetric ligands. In the solid state the ureas show a conformational preference for A over B and C and there seems to be a degree of repulsion between C(2) and C(7) in 2 1 and C(2) and C(19) in 2 2 An isomer of type A should be even more favorable in the case of a carbene since the carbene generally sho w s a higher level of conjugation due to the empty p orbital centered on C(1). This increase in conjugation and flatness of the carbene should decrease the twisting in the pyrrolidine ring system, and therefore it should be less able to accommodate the str ain induced from conformations such as B and C

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21 Figure 2 6 Molecular structure of urea 2 1 Selected bond lengths () and angles (): O(1) C(1) 1.2349(13), N(1) C(1) 1.3733(13), N(2) C(1) 1.3739(13), N(1) C(1) N(2) 116.57(9) N(2) C(1) N(1) C(2) 3 4 .66( 1 5), N(1) C(1) N(2) C(7) 33.61( 15) Figure 2 7 : Molecular structure of urea 2 2 Selected bond lengths () and angles (): O(1) C(1) 1.242(6), N(1) C(1) 1.372(6), N(2) C(1) 1.373(7), N(1) C(1) N(2 ) 113.3(5), N(2) C(1) N(1) C(2) 40.0(8), N(1) C(1) N(2) C(19) 43.0 ( 8 )

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22 Table 2 1 Crystal data and structure refinement for 2 1 Empirical formula C11 H20 N2 O Formula weight 196.29 Temperature 173(2) K Wavelength 0.71073 Crystal system Ort horhombic Space group P2 1 2 1 2 1 Unit cell dimensions a = 8.9984(7) = 90. b = 10.1229(8) = 90. c = 12.283(1) = 90. Volume 1118.86(15) 3 Z 4 Density (calculated) 1.165 Mg/m 3 Absorption coefficient 0.075 mm 1 F(000) 432 Crystal size 0.20 x 0.20 x 0.18 mm 3 Theta range for data collection 2.61 to 27.50. Index ranges Reflections collected 7612 Independent reflections 2561 [R(int) = 0.0312] Completeness to theta = 27.50 100.0 % Absorption correction Integration Max. and min. transmission 0.9904 and 0.9851 Refinement method Full matrix least squares on F 2 Data / restraints / parameters 2561 / 0 / 127 Goodness of fit on F 2 0.961 Final R indices [I>2sigma(I)] R1 = 0.0321, wR2 = 0.074 4 [2149] R indices (all data) R1 = 0.0399, wR2 = 0.0763 Absolute structure parameter 0.4(11) Largest diff. peak and hole 0.165 and 0.264 e. 3 Table 2 2 Crystal data and structure refinement for 2 2 Empirical formula C35 H36 N2 O Formula w eight 500.66 Temperature 173(2) K

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23 Wavelength 0.71073 Crystal system Monoclinic Space group P2(1) Unit cell dimensions a = 16.0406(14) = 90. b = 10.8168(9) = 90.539(1). c = 56.512(5) = 90. Volume 9804.9(14) 3 Z 14 Den sity (calculated) 1.187 Mg/m 3 Absorption coefficient 0.071 mm 1 F(000) 3752 Crystal size 0.19 x 0.11 x 0.05 mm 3 Theta range for data collection 1.08 to 25.00. Index ranges Reflections collected 40889 Independent r eflections 28710 [R(int) = 0.0496] Completeness to theta = 25.00 94.7 % Absorption correction None Refinement method Full matrix least squares on F 2 Data / restraints / parameters 28710 / 1 / 2413 Goodness of fit on F 2 0.841 Final R indices [ I>2sigma(I)] R1 = 0.0555, wR2 = 0.0884 [10696] R indices (all data) R1 = 0.1757, wR2 = 0.1230 Absolute structure parameter 0.8(10) Largest diff. peak and hole 0.151 and 0.185 e. 3 Formation of Palladium ADC Complexes Ureas were treated with a c hlorinating agent such as oxalyl chloride or POCl 3 to generate the chloroamidinium salts ( Figure 2 8 ). Anion exchange was performed on these salts to make them less hygroscopic, and the chloride anion was substituted with a tetrafluoroborate anion. The i solated chloroamidinium salts were the n reacted with Pd(PPh 3 ) 4 in toluene at 100 C for two hours and the product was purified by recrystallization ( Figure 2 9 ).

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24 Figure 2 8 Chlorination of ureas with oxalyl chloride. Chloroamidiniums featuring primary alkyl substituents such as 2 11 (methyl group) and 2 14 (benzyl group) afforded ADC Pd complexes in good yield. However, more congested secondary alkyl substituted carbene precursors 2 12 (CHPh 2 ) and 2 13 ( i Pr) did not afford the desired complex as an isolable substance. Figure 2 9 Complexation of chloroamidiniums to palladium. The metal complexes of 2 1 5 and 2 1 8 were fully characterized by mass spectroscopy and NMR, and a cryst al structure of 2 1 5 was obtained as well. Unfortunately, conclusive NMR and mass spectroscopy were not obtained for complexes 2 1 6 and 2 1 7 The X r ay crystal structure of complex 2 1 5 provides several key insights and depicts an image of a somewhat s trained molecule (Figure 2 10 ) In contrast to the urea crystal structure, the me thyl groups are positioned away from the metal center apparently reducing steric repulsions with the triphenyl phosphine ligands Thus the phenyl rings of triphenyl phosphi ne are staggered with respect to the chloride ligand yet eclipsed with regards to the carbene. This

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25 close proximity and resulting repulsion certainly plays a role in the orientation of the methyl groups. Similarly to crystal structures obtained by Frs group, 7c the plane of the carbene created by N(1) C(1) N(2) is nearly orthogonal to the metal coordination plane defined by the four ligands P(1), P(2), Cl(1), and C(1) The dihedral angles of N(2) C(1) N(1) C(5) and N(1) C(1) N(2) C(10) are less t han those observed with the cor responding urea. They are 12.6(5) and 14.8(5) respectively, still showing a slight divergence from coplanarity and complete conjugation; however, this is not unusual for acyclic diaminocarbenes. 6c The increased carbene bo nd angle [N(1) C(1) N(2)] is of the highest interest, and its value is 123.7 (2) This is one of the largest diaminocarbene bond angles known, and to the best of my knowledge only one metal carbene complex shows a larger angle. 6a,d The chromium complex 2 1 9 has an N C N bond angle of 125, although it is bound in 2 fashion, and the author states this increased hapticity enlarges the angle (Figure 2 11). The carbene bond angle of complex 2 1 5 is ~ 1.5 to 2.0 greater than analogous achiral complexes suc h as 1 1 0 prepared by Frstner and co workers. While small, this value is certainly not insignificant. The increase is most likely caused by the increased repulsion due to methyl groups close proximity. The palladium carbene bond length is 2.021 (2) An analysis and comparison to crystal structures from the work of Frstner and co workers leads to interesting conclusions. Larger bond angles lead to longer metal carbene bonds. The longer bond is possibly caused by greater intrusion into the metal coo rdination sphere which commonly promotes lower bond dissociation energies in NHCs. 3a It is also possible the increase in bond length comes from a carbene that is increasing in triplet character and that is potentially destabilized by this change.

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26 Figure 2 10 Molecular structure of complex 2 1 5 Selected bond lengths () and angles (): Pd(1) C(1) 2.021(2), N(1) C(1) 1.329(3), N(2) C(1) 1.342(3), N(1) C(1) N(2) 123 .7( 2), N(2) C(1) N(1) C(5) 12.6(5 ), N(1) C(1) N(2) C(19) 14 .8(5 ) Table 2 3 Crystal data and structure refinement for 2 15 Empirical formula C47 H50 B Cl F4 N2 P2 Pd Formula weight 933.49 Temperature 173(2) K Wavelength 0.71073 Crystal system Orthorhombic Space group P212121 Unit cell dimens ions a = 16.0636(8) = 90. b = 16.2605(8) = 90. c = 19.0326(9) = 90. Volume 4971.4(4) 3 Z 4 Density (calculated) 1.247 Mg/m 3 Absorption coefficient 0.538 mm 1

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27 F(000) 1920 Crystal size 0.19 x 0.13 x 0.11 mm 3 Theta range for data collection 1.65 to 2 6.68. Index ranges Reflections collected 28914 Independent reflections 9381 [R(int) = 0.0550] Completeness to theta = 25.00 99.9 % Absorption correction Integration Max. and min. transmission 0.9245 and 0.8844 Refinement method Full matrix least squares on F 2 Data / restraints / parameters 9381 / 7 / 529 Goodness of fit on F 2 1.068 Final R indices [I>2sigma(I)] R1 = 0.0311, wR2 = 0.0818 [8716] R indices (all data) R1 = 0.0337, wR2 = 0.0828 Absolute str ucture parameter 0.017(18) Largest diff. peak and hole 0.370 and 1.869 e. 3 When bulky chloroamidiniums such as 2 1 2 and 2 1 3 are used, the corresponding carbene ligands should exhibit N C N bond angles greater than that observed for complex 2 1 5 w ith the relatively small methyl substituents. The larger carbene bond angles probably increase the potential metal carbene bond length accounting for the difficulty in obtaining the more complex compounds 2 1 6 and 2 1 7 Figure 2 11 Chromium ADC complex prepared by Herrmann.

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28 Table 2 4 N C N bond angles and Pd C bond lengths for select carbenes. N C N Angles () 109.70 108.95 119.6 121.6 Pd C Bond Lengths () 1.9805 1.9687 2.005 2.003 Suzuki Cross Coupling Palladium complexes of electron rich, sterically demanding phosphines or NHC ligands are effective catalysts for sterically demanding Suzuki couplings, and those ligands are believed to stabilize a putative monoligated Pd complex 11 It is known that the oxidative addition step is donating ligand to stabilize the Pd II oxidation state whereas the reductive elimination step can be accelerated by a sterically demanding ligand. donating and bulky ADC ligand is perfect, meeting those exact requirements. In fact, Thadani and co workers reported that ADC Pd complexes efficiently catalyze demanding Suzuki coupling s and therefore application of chiral ADC Pd complexes in the asymmetric Suzuki coupling reaction is promising. 7b Prior to our studies, Frstner and co workers conducted some preliminary work with the cationic palladium complexes in the Suzuki reaction. Using 1 mol % of 1 7 phenyl boronic acid and 4 bromoacetophenon e were coupled in 79% yield ( Equation 2 1 ). With catalyst 1 8 that yield improved to 89%. N C N Angles () 122.3 124.0 123.7 Pd C Bond Lengths () 2.023 2.047 2.021

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29 In our work, application of the reported conditions led to low to moderate yields in the coupling of simple substrates such as 2 2 0 and 2 2 1 an d 2 2 0 and 2 2 2 with ADC complexes Table 2 5 Optimization of Suzuki cross coupling reaction. (Entries 1 and 2, Table 2 5 ). Optimizing the conditions by changing the base and increasing the amount of catalyst resulted in si gnificant gains in yield. Thus, the conformationally flexible, chiral ADC Pd complexes are active catalyst s for sterically demanding Suzuki coupling reactions. Hindered di ortho and tri or tho substituted biaryls were produced in excellent yields with cat alysts 2 1 5 and 2 3 1 Attempting the very challenging synthesis of tetra ortho substituted biaryls did not resul t in product forma tion (Entries 4 and 5, Table 2 7 ). Entry Boronic Acid Aryl Bromide Base Mol % Yield (%) 1 K 2 CO 3 1 24 2 2 20 K 2 CO 3 1 50 3 2 20 2 22 CsF 3 100

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30 Table 2 6. Suzuki cross coupling of 2 23 and 2 24 w ith a variety of catalysts. a a Conditions: 3 mol % [Pd], 1 equiv ArBr, 1. 2 equiv ArB(OH) 2 2.8 equiv CsF, THF, 100 C. b Complex generated in situ and used without further purification. Entry Boronic Acid Aryl Bromide Catalyst Yield (%) Ee (%) 1 2 3 4 5 2 23 2 23 2 23 2 23 2 24 2 24 2 24 2 24 Pd(PPh 3 ) 4 99 95 85 64 b 45 N.A. 4 4 3 N.A.

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31 Table 2 7. Exploration of substrate scope in Suzuki cross coupling reaction. Entry Boronic Acid Aryl Bromid e Catalyst Yield (%) 1 98 2 2 26 93 3 2 26 75 4 2 26 NR 5 2 26 NR 6 95 The catalyst was varied when producing biaryl 2 25 and it is interesting to note that the carbenes showing the most steric hindrance provided the lowest yields in Suzuki cross coupling reactions. This might be attributed to the observation that more hindered carbenes exhibit longer Pd to carbene bonds, perhaps causing the ligands to become more labile Although difficult to isolate, catalyst 2 16 was generated in situ from chloroamidinium and Pd(P Ph 3 ) 4 and tested in

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32 catalysis resulting in 64% yield of 2 25 (Entry 4, Table 2 6 ). Pd(PPh 3 ) 4 was tested separately in the Suzuki reaction, to ensure catalysis with 2 16 was not solely a result of residual Pd(PPh 3 ) 4 (Entry 5, Table 2 6 ). A major goal of th is program is to develop an asymmetric version of the Suzuki reaction. 12 Using chiral catalysts such as 2 15 2 16 and 2 18 substrates 2 2 3 and 2 2 4 were combined to form a tri ortho substituted product, and the enantiomeric excess (ee) was determined by chiral HPLC using a Chiralcel OJ H column. 12 4 %. While this might be rationalized by the location of the chiral substituents, it was hoped that upon dissociation of the phosphines at elevated temperature, the chiral centers might reposition themselves proximal to the metal center in order to relieve steric strain. C 2 Symmetric Pyrrolidine Moieties and Attempts at Symmetrically Substituted Ureas A potential probl em associated with chiral ADCs made from 2 substituted pyrrolidine subunits involved rotation about the bond linking nitrogen and the carbenoid carbon. Based on the low enantioselectivities observed in the Suzuki cross coupling, we focused on the synthesi s of ureas with a C 2 axis of symmetry to minimize difficulties caused by rotation. Design of ureas centered on the use of (2 S ,5 S ) trans diphenylpyrrolidine 2 3 7 as the chiral moiety. The chiral amine was easily produced follo win g a known procedure (Fig ure 2 12 ). 13 Friedel Crafts arylation of fumaryl ch loride leads to enone 2 33 and the olefin is subsequently hydrogenated using SnCl 2 E xcellent enantioselectivity was observed for the CBS catalyzed reduction of the dione to a diol. Following reduction, the diol is cyclized to the amine in one pot with allyl amine At this stage, the diastereomers were separated using column chromatography, and the chiral tertiary amine was deprotected by refluxing in an acetonitrile water mixture with yst to afford enantiomerically pure amine 2 37

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33 Figure 2 12 Preparation of (2 S ,5 S ) trans diphenylpyrrolidine Urea formation was attempted in a condensation reaction using two equivalents of chiral amine 2 37 with phosg ene ( Equation 2 3 ) but t he simple condensation reaction did not give urea A product with 286 amu was recovered, which corresponds to carbamoyl chloride 2 3 8 Changing the solvent to toluene and heating at temperatures up to 200 C were ineffec tive in c hanging the outcome, and v arious strategies were undertaken to produce urea 2 39 (Figure 2 13 ) For example, amine 2 37 was deprotonated with n BuLi and reacted with 2 3 8 Also, ferric chloride was added to a solution of carbamoyl chloride 2 3 8 and chira l amine 2 37 in an effort to help activate the electrophile. At one point, a phosgene derivative, carbonyl diimidazole (CDI), was utilized to rep lace phosgene (Figure 2 14) N one of these strategies led to the desired

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34 Figure 2 13 Some attempts at urea formation with (2 S ,5 S ) trans diphenylpyrrolidine. Figure 2 14. Synthetic attempt aimed at urea 2 39 using CDI.

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35 Figure 2 1 5 Challenging secondary amines in desired urea production. 14 product 2 39 and it is believed that the hindered nature of the carbamoyl chloride caused a second condensation to be difficult, as pro duction of hindered ureas is known to be difficult (Figure 2 15). 14 Ureas with Non Identical Amine Moieties Featuring (2 S ,5 S ) trans diphenylpyrrolidine Carbenes incorporating 2 substituted pyrrolidine moieties showed a preference for placement of the chira l substituents away from the metal center. Since the conformers could not be effectively controlled, a C 2 symmetric amine was needed, rendering rotation about the nitrogen carbene bond insignificant. As a result, 2 37 was featured in the synthesis of sev eral ureas constructed from non identical secondary amines. Chiral amine 2 37 can be combined with a variety of electrophiles to make ureas. Figure 2 16 below shows reaction sequences where the pyrrolidine derivative is mixed with carbamoyl chlorides, ac yl halides, and isocyanates to form ureas. Ureas 2 41 and 2 49 were made from carbamoyl chlorides; however, some hindered molecules such as diisopropyl carbamoyl chloride failed to react with 2 37 Isocyanates react best with 2 37 leading to tri N substi tuted ureas

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36 which can easily be methylated in high yield, as seen in the formation of 2 5 2 and 2 5 4 Also, the amide precursor to a Bertrand type carbene, 2 5 0 was made from p anisoyl chloride. 15 Figure 2 16. Ureas fr om carbamoyl chlorides, acyl chlorides, and isocyanates Chlorination and Metalation of Ureas Based on ( 2 S ,5 S ) trans Diphenylpyrrolidine Chlorina tion was conducted with the newly made ureas (Figure 2 1 7 ). Unlike ureas 2 1 2 4 not all of the urea based o n 2 37 chlorinated smoothly. Compound 2 41 took five days to complete reaction, and the NMR spectrum of the product was difficult to reproduce. Urea 2 5 0 fragmented under the reaction conditions, and pieces of the molecule were isolated upon workup. The mesityl substituted urea 2 5 4 did not provide the chlorinated product to an appreciable

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37 extent either, but the slightly less hindered 2 5 2 chlorinates after several days at 60 C. Urea 2 49 chlorinates with exceeding ease in comparison to the other reage nts, and after stirring overnight, a nice, white, isolable solid is obtained. The desired ADC Pd compound was not isolated under oxidative addition conditions, however. Figure 2 17. Chlorination of urea 2 49 and attemp t at cationic ADC Pd compound 2 56 Conclusion and Summary Ureas are a logical entry point from which to reach acyclic diaminocarbenes. Ureas are purified with relative ease and their synthesis is relatively straightforward. Amidinium salts on the other hand can be difficult to purify and are sometimes di fficult to make for non simple structures. 6 e Pd complexes with the incorporation of triphenyl phosphine ligands. 7 c,d Simple ureas constructed from 2 substituted chiral pyrrolidines were converted to chloroamidinium salts and then bound to palladium. Interest in these ligands lay in the ir potential for heightened activity and selectivity. The potential for conformational flexibility did not improve the catalytic ability of the ADCs. Conversely, as the 2 position became more highly

PAGE 38

38 substituted, catalyst activity decreased. Whether the substituents ever actually shift to create a more sterically crowded environment under catalytic reaction conditions is unknown. Figure 2 18. ADC Pd complexes with 2 substituted pyrrolidines as mimics for ADC ligands with C 2 symmetric pyrrolidines. The steric interaction of the substituents toward the back of the catalyst are detrimental. We can presume that ureas of the type depicted in Figure 2 18 incorporating two C 2 symmetric pyrrolidine units would not be feasibl e ligands if the substituent has any significant bulk They can not avoid the detrimental interaction of substituents located distal to the metal center that seems to account for the difficulty in isolating 2 16 and 2 17 and the also decreased catalytic a ctivity of complexes with increasing ADC substitution.

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39 CHAPTER 3 LITHIUM HALOGEN EXCHANGE: A NEW METHOD FOR DIAMI NOCARBENE FORMATION Introduction While the previously described methodology led to palladium complexes with carbenes several non desira ble features present themselves. Most importantly the oxidative addition procedure necessitates the use of electron donating ligands like phosphines and restricts the diversity of catalysts that can be synthesized. Primarily, NHC chemistry was developed as an alternative to phosphine use, but the insertion of Pd into the C Cl bond of the chloroamidinium does not take place in the absence of phosphines. The second drawback is that formation of catalysts incorporating sterically demanding substituents suc h as those seen in chloroamidiniums 2 1 2 and 2 1 3 was not feasible. The difficulty arises from the intrusion of the triphenyl phosphine ligand into the space occupied by ADC ligands, and it is manifested in the strained orientation of the chiral substit ue nts In a related manner the direction of the chiral substituents of 2 substituted pyrrolidines is problematic. In being located distal to the metal center, the ability of these directing groups to transfer chir ality to substrate is minimized. 16 The d irect conversion of chloroamidiniums 2 1 1 to 2 1 4 into carbene synthons is ideal, and it was envisioned that lithium halogen exchange might accomplish this goal through a reduction of the C Cl bond (Figure 3 1). Figure 3 1. Envisioned synthesis of car bene intermediates through Li X exchange. Organolithium reagents have played an important role in organic synthesis, 17 and the formation of these reagents proceeds through a number of routes including reduction with

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40 metallic lithium, 18 deprotonation with a lithiated base, 19 lithium halogen exchange, 20 and trans metalation 21 It is important to note that lithiation has been speculated to generate carbenoid intermediates in reaction with R 2 CBr 2 and in the Fritsch Buttenberg Wiechell rearrangement. 22 23 Nevertheles s, to the best of my knowledge, there have been no examples using lithium halogen exchange to form diaminocarbenes from chloroamidiniums F igure 3 2. Classic methods to form organolithium s pecies. A) Reduction with met allic lithium. B) Lithium halogen exchange. C) Deprotonation. D) Trans metalation Carbene Formation and Proof As shown in Figure 3 1 formation of diaminocarbenes through lithium halogen exchange with chloroamidiniums is easily imagined. In his semina l research, Arduengo demonstrated that diaminocarbenes react with elemental sulfur (S 8 ) to form thioureas (Figure 3 3 ) and the formation of thioureas can be taken as a simple proof of carbene intermediates. In the attempted formation of a putative carbe ne species, c hloroamidinium 3 1 was added

PAGE 41

41 Figure 3 3. Tentative proof of carbene intermediacy via lithium halogen exchange. A) As demonstrated by Arduengo and co workers NHCs react with sulfur to produce thioureas. B) Production of bis(pyrrolidine)thiourea through lithium halogen exchange. C) Control reaction showing that chloroamidinium does not react with sulfur. to a Schlenk flask under an argon atmosphere, and THF was added. The suspension was cooled to 78 C, an d at this point, 1.05 equivalents of n BuLi was added. After approximately five minutes the white precipitate disappeared, resulting in a clear suspension, indicating consumption of the chloroamidinium salt and the possibility of a soluble carbene interme diate. The reaction mixture was stirred for one hour at 78 C before elemental sulfur was introduced to the solution. The yellowish suspension was allowed to slowly warm to room temperature and was stirred for twelve hours. Upon purification, thiourea 3 2 was obtained in 68% yield suggesting ADC formation under lithium halogen exchange conditions (Figure 3 3 ) Since the chloroamidinium potentially could serve as an electrophile to be attacked by sulfur, a control reaction was established without the p resence of n Bu Li. In this case thiourea 3 2 was not obtained (Figure 3 3 ) NMR studies were enlisted to further probe the nature of the intermediate generated in situ ( Equation s 3 1 to 3 3 ) The lithium halogen exchange reaction with chloroamidinium 3 1 was carried out under an inert atmosphere of argon in THF d 8 in a sealed NMR tube. Data was

PAGE 42

42 collected at 30 C because the carbene decomposed too quickly at room temperature (within five minutes). Both 1D and 2D techniques were utilized, where the 2 D carbon trace was obtained through indirect detection of the proton nucleus. Both spectra showed a strong signal at 232.9 ppm clearly indicating the presence of carbene and nicely corresponding to the known value for the lithiated carbenoid species (Figu re s 3 4 and 3 5) 24 In the 2D gHMBC spectrum, the carbene carbon (232.9 ppm) displayed couplings with two proton s at 3.47 and 3.66 ppm The gDQCOSY spectrum revealed the sequence 3.47 1.89 1.76 3.66. The carbons carryin g these protons were detected in the gHMQC spectrum at 48.4, 26.5, 24.5 and 55.8 ppm, respectively. Therefore, the two proton resonances at 3.47 and 3.66 ppm can be assigned to the two protons at the C2 position of pyrrolidine, and this gHMBC spectrum is c onsistent with the proposed carbene intermediate structure. Binding Diaminocarbenes to Transition Metals and Boron The evidence from thiourea formation and NMR experimental studies gave solid proof of carbenoid generation, and the practical application o f this methodology was sought. The

PAGE 43

43 Figure 3 4. 13 C NMR s pectrum of lithiated carbene intermediate 3 4 produced through lithium halogen exchange.

PAGE 44

44 Figure 3 5. 2D gHMBC spectrum of lithiated carbene intermediate 3 4 produc ed through lithium halogen exchange.

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45 synthesis of potential catalysts was desired, and the formation of transition metal catalysts and boron carbene adducts was attempted. First, Group 9 metals were explored using [Rh(COD)Cl] 2 and [Ir(COD)Cl] 2 precursor s. Chloroamidinium 3 1 was added to a flame dried Schlenk flask in a glovebox under argon atmosphere, and after removing the flask from the glovebox, THF was added. The suspension was cooled to 78 C and followed by the addition of 1.05 equivalents of n BuLi After one hour, either [Rh(COD)Cl] 2 or [Ir(COD)Cl] 2 was added, and the solution was slowly warmed to room temperature, followed by a reaction period of twelve hours. The rhodium and iridium complexes were purified through dissolution in ethyl acet ate or dichloromethane re spectively and then impurities were precipitated out of solution through the addition of hexanes. The rhodium complex was isolated in 65% yield while the iridium complex wa s isolated in 71% yield (Figure 3 6 ). It is important to note that the counter ion identity proved to be important because the chloride salt of chloroamidinium 3 1 did not react productively under the lithium halogen conditions. The metal complexes were fully characterized by NMR and high resolution mass spect rometry, and proof of the assigned structure was demonstrated by X ray analysis (Figures 3 8 and 3 9 ). Figure 3 6. Formation of rhodium and iridium ADC complexes from chloroamidinium 3 1

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46 The lithium halogen exchange methodology was expanded in scope to include commercially available chloro imidazolium salt 3 7 Upon treatment of chloro imidazolium 3 7 with n BuLi, introduction of rhodium or iridium metals led to transition metal complexes ( Figure 3 7 ). In this case, the chloride salt performed better than the BF 4 salt. The metal complexes were fully characterized by NMR and high resolution mass spectrometry, and proof of the assigned structure was demonstrated by X ray analysis (Figure 3 10 ) Figure 3 7. Formation of rhodium and iridium NHC complexes from chloroamidinium 3 7 Not surprisingly, the ADC complexes 3 5 and 3 6 showed larger N C N bond angles of 117.9 (2) and 118.4 (4) respectively as compared to the carbene bond a ngle of 108.6 (6) for NHC complex 3 9 Also, the carbene bond length between carbon and transition metal was longer for the ADCs when compare d to th e NHC iridium complex. ADC Ir c omplex 3 6 showed a carbene metal bond length of 2.045 (5) and NHC Ir comp lex 3 9 showed a carbene metal bond length of 2.028 (7) suggesting that the ADC might be more sterically demanding than the NHC. Where the imadazole ring is nearly flat, the ADC ligand in complexes 3 5 and 3 6 is not planar. Instead the pyrrolidine rings are twisted showing torsion angles of approximately 26 in complex 3 5

PAGE 47

47 Figure 3 8. Molecular structure of complex 3 5 Thermal ellipsoids are drawn at the 50% probability level. Selected bond lengths () and angles (): Rh1 C9 2.022(2), Rh1 Cl1 2.3855 (6), Rh1 C1 2.110(2), Rh1 C2 2.104(2), Rh1 C5 2.241(2), Rh1 C6 2.197(2), N1 C9 N2 117.90(18), N2 C9 N1 C10 25.68(32), N1 C9 N2 C14 26.69(30). Figure 3 9 Molecular structure of complex 3 6 Thermal ellipsoids are drawn at the 50% probability level. Sel ected bond lengths () and angles (): Ir1 C9 2.045(5), Ir1 Cl1 2.3713(11), Ir1 C1 2.101(4), Ir1 C2 2.104(4), Ir1 C5 2.173(5), Ir1 C6 2.189(4), N1 C9 N2 118 .4(4), N2 C9 N1 C10 16.84(62), N1 C9 N2 C14 30.48(63).

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48 Figure 3 10. Molecular structure of c ompl ex 3 9 Thermal ellipsoids are drawn at the 50% probability level. Selected bond lengths () and angles (): Ir1 C9 2.028(7), Ir1 Cl1 2.3570(17), Ir1 C1 2.113(7), Ir1 C2 2.097(7), Ir1 C5 2.197(7), Ir1 C6 2.189(7), N1 C9 N2 108.6(6). Table 3 1. Crystal d ata and structure refinement for 3 5 Empirical formula C17 H28 Cl N2 Rh Formula weight 398.77 Temperature 173(2) K Wavelength 0.71073 Crystal system Monoclinic Space group P21/n Unit cell dimensions a = 6.5715(6) = 90. b = 18.7963(18) = 94.439(2). c = 13.7990(13) = 90. Volume 1699.3(3) 3 Z 4 Density (calculated) 1.559 Mg/m 3 Absorption coefficient 1.158 mm 1 F(000) 824 Crystal size 0.26 x 0.13 x 0.07 mm 3 Theta range for data collection 1 .83 to 27.50.

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49 Index ranges Reflections collected 11259 Independent reflections 3899 [R(int) = 0.0697] Completeness to theta = 27.50 99.7 % Absorption correction Numerical Max. and min. transmission 0.9233 and 0.752 8 Refinement method Full matrix least squares on F 2 Data / restraints / parameters 3899 / 0 / 222 Goodness of fit on F 2 1.048 Final R indices [I>2sigma(I)] R1 = 0.0313, wR2 = 0.0795 [3490] R indices (all data) R1 = 0.0351, wR2 = 0.0816 Largest diff. peak and hole 1.034 and 0.948 e. 3 Table 3 2 Crystal data and structure refinement for 3 6 Empirical formula C17 H28 Cl Ir N2 Formula weight 488.06 Temperature 173(2) K Wavelength 0.71073 Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 9.8235(9) = 90. b = 14.9332(14) = 91.616(2). c = 23.221(2) = 90. Volume 3405.0(5) 3 Z 8 Density (calculated) 1.904 Mg/m 3 Absorption coefficient 7.995 mm 1 F(000) 1904 Crystal size 0.34 x 0.2 3 x 0.17 mm 3 Theta range for data collection 1.62 to 27.50. Index ranges Reflections collected 21406 Independent reflections 7805 [R(int) = 0.0360] Completeness to theta = 27.50 99.8 % Absorption correction Integr ation Max. and min. transmission 0.3435 and 0.1719

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50 Refinement method Full matrix least squares on F 2 Data / restraints / parameters 7805 / 0 / 379 Goodness of fit on F 2 1.224 Final R indices [I>2sigma(I)] R1 = 0.0323, wR2 = 0.0747 [7041] R indi ces (all data) R1 = 0.0370, wR2 = 0.0766 Largest diff. peak and hole 0.933 and 1.257 e. 3 Table 3 3. Crystal data and structure refinement for 3 9 Empirical formula C13 H22 Cl Ir N2 Formula weight 433.98 Temperature 173(2) K Wavelength 0 .71073 Crystal system Orthorhombic Space group P2(1)2(1)2(1) Unit cell dimensions a = 7.2770(15) = 90. b = 12.449(3) = 90. c = 15.738(3) = 90. Volume 1425.7(5) 3 Z 4 Density (calculated) 2.022 Mg/m 3 Absorption coefficient 9.534 mm 1 F(000) 832 Crystal size 0.20 x 0.02 x 0.01 mm 3 Theta range for data collection 2.09 to 27.50. Index ranges Reflections collected 9737 Independent reflections 3271 [R(int) = 0.0628] Completeness to theta = 27.50 99.9 % Absorption correction Integration Max. and min. transmission 0.9107 and 0.2515 Refinement method Full matrix least squares on F 2 Data / restraints / parameters 3271 / 0 / 154 Goodness of fit on F 2 1.046 Final R indices [I>2sig ma(I)] R1 = 0.0296, wR2 = 0.0652 [3128] R indices (all data) R1 = 0.0320, wR2 = 0.0659 Absolute structure parameter 0.021(13)

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51 Largest diff. peak and hole 1.197 and 0.918 e. 3 Figure 3 11. Formation of piperi dine based ADC rhodium complex 3 12 In addition to the pyrrolidine based ADC ligand and the N methyl substituted NHC, several other ADC ligands were attached to rhodium. Piperidine based chloroamidinium 3 11 was synthesized and used as an ADC synthon aft er treatment with n BuLi. Rhodium complex 3 12 was obtained in 61% isolated yield (Figure 3 11). Chiral chloroamidiniums 2 11 and 3 14 were also used as ADC precursors to further demonstrate the scope of the new methodology (Figure 3 12) The usual me thod of carbene formation from n BuLi was utilized. Because [Rh(COD)Cl] 2 was left after reaction, simple precipitation of impurities was insufficient to purify ADC metal complexes 3 13 and 3 15 Resulta ntly, silica gel chromatography on a short column w as empl oyed starting with a 3:1 mixture of hexanes to ethyl acetate and then quickly shifting to pure ethyl acetate as the rhodium complex is slightly unstable on a silica gel column. After column chromatography, the desired product was dissolved in dichl oromethane and remaining impurities were precipitated

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52 with hexanes. After filtration and evaporation of the filtrate, complexes 3 13 and 3 15 were obtained in 65 % and 60% yield. The metal complexes were fully characterized by NMR and high resolution mass spectrometry, and proof of the assigned structure 3 13 was demonstrated by X ray analysis (Figure 3 13). Using the lithium halogen exchange method for preparing carbenes in place of the oxidative addition of chloroamidiniums results in several advantag es of note. Most importantly, sterically demanding ligands previously not accessible through the oxidative addition route become available as seen in compound 3 15 The oxidative addition route requires the use of bulky phosphines that intrude into the s pace occupied by the NHC and ADC ligands as seen in the crystal structure of compound 2 15 that resulted in lengthened carbene metal bonds. Chiral centers were repositioned toward the back of the metal complex indicating that this positioning was more fav orable than the opposite location which directs the substituents toward the metal. Palladium complexes stemming from chloroamidinium 2 12 could not be isolated most likely due to extreme steric constraints. Without the incorporation of bulky phosphine, l igands coming from 2 12 become feasible suggesting the lithium halogen exchange route is amenable to a greater variety of ligands than those obtained through oxidative addition. The second point of interest relates to the first point and involves the repo sitioning of the chiral substituents so that they are oriented toward the metal center instead of distal to the coordination sphere. When examining the crystal structure of 3 13 this repositioning is noticed, again insinuating the decreased steric restra ints operating upon the square planar rhodium system. By reorienting the chiral centers, there is a greater chance the ligands can transfer their chirality to substrates.

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53 Figure 3 12. Synthesis of chiral ADC rhodium co mplexes 3 13 and 3 15 As mentioned previously, a major goal of this research effort was to develop a methodology providing a more general route to divergent metal complexes than possible through the oxidative addition pathway. With this in mind, the res earch moved beyond Group 9 metals and into Group 10. Chloroamidinium 3 1 was transformed into a carbene species with use of t BuLi in place of n BuLi, and then dimeric palladacycle 3 17 was added to the THF solution (Figure 3 14). 25 The use of n BuLi led to lower yields. The resultant suspension was allowed to slowly warm to room temperature and then was stirred for twelve hours. At the end of the reaction time, compound 3 18 was first purified by silica gel chromatography using pure ethyl acetate as the eluent and then followed by 5% methanol in dichloromethane. The ensuing solid was further purified by precipitating the product from ethyl acetate with hexanes, giving 3 18 in 45% yield.

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54 Figure 3 13. Molecular structure of complex 3 13 Thermal ell ipsoids are drawn at the 50% probability level. Selected bond lengths () and angles (): Rh1A C1A 2.052(3), Rh1A Cl1A 2.3928(7) Rh1A C16A 2.105(3), Rh1A C17A 2.136(3) N1A C1A N2A 117.8(2), C7A N2A C1A N1A 34 0(4), C2A N1A C1A N2A 20.1(4 ) Table 3 4. Crystal data and structure refinement for 3 13 Empirical formula C19 H32 Cl N2 Rh Formula weight 426.83 Temperature 100(2) K Wavelength 0.71073 Crystal system Monoclinic Space group P2(1) Unit cell dimensions a = 10.4422(9) = 90. b = 11.9880(10) = 93.8320(10). c = 15.3266(13) = 90. Volume 1914.3(3) 3 Z 4 Density (calculated) 1.481 Mg/m 3 Absorption coefficient 1.033 mm 1 F(000) 888 Crystal size 0.41 x 0.20 x 0.09 mm 3

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55 Theta range for data collection 1.33 to 27.50. Index ranges Reflections collected 13908 Independent reflections 8304 [R(int) = 0.0176] Completeness to theta = 27.50 99.1 % Absorption correction Numerical Max. and min. transmission 0.9127 and 0 .6755 Refinement method Full matrix least squares on F 2 Data / restraints / parameters 8304 / 1 / 467 Goodness of fit on F 2 1.034 Final R indices [I>2sigma(I)] R1 = 0.0260, wR2 = 0.0649 [8132] R indices (all data) R1 = 0.0265, wR2 = 0.0652 Abso lute structure parameter 0.03(2) Largest diff. peak and hole 1.667 and 0.982 e. 3 Figure 3 14. Sy nthesis of ADC palladium complex 3 18 Several metal precursors were explored before ultimately finding that dimeri c palladacycle 3 17 was suitable for catalyst synthesis. Difficulty was experienced in trying to form either Pd 0 or Pd II complexes because as explained by Herrmann and co workers Pd 0 has little electron donors, and ADCs act as effective reducing agents for Pd II forming ill defined Pd 0 species. 6b [Pd(allyl)] 2 PdCl 2 Pd(MeCN) 4 (BF 4 ) 2 Pd(PPh 3 ) 2 Cl 2 Pd(dba) 2 and

PAGE 56

56 phospha palladacycle 3 25 were investigated, but none led to the desired ADC palladium species.

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57 Ruthenium complexes with ADCs were desired, but they proved to be difficult to isolate. F irst catalyst synthesis was attempted by displacement of a tricyclohexyl phosphine ligand from Grubbs First Generation metathesis catalyst ( Equation 3 12 ). Lithiate d carbene was generated from n BuLi, and then Grubbs catalyst was added to the solution. Upon warming the reaction mixture to room temperature, the color changed from purple to an orangis h brown color as expected, but quickly, a black sludge was formed. Only decomposition products were detected by NMR in a result similar to that obtained by Herrmann and co workers when working with ruthenium and ADC ligands. 6d Other complex formation was attempted with precursors other than Grubbs First Generation by Hwi min Seo, a group member; however none of these trials resulted in successful isolation of an ADC ruthenium complex. ADC adducts were able to be formed with main group elements in addition to transition

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58 metals. After generation of ADC 3 4 from chloroamidinium, the electrophilic boron trifluoride etherate was introduced to the reaction mixture. The ADC easily complexe d with boron, and the ensuing product was purified on a short silica gel column with a 1:1 mixture of hexanes and ethyl acetate, giving the adduct in 81% ( Equation 3 16 ). Compound 3 31 was characterized by 1 H and 13 C NMR as well as elemental analysis and mass spectrometry. Trans metalation of the carbene from boron to rhodium was attempt ed, but it was not successful (Table 3 5 ). ADC boron compound 3 31 was recovered after the reaction showing the stability of the carbene boron bond.

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59 Table 3 5 Attempts at trans metalat ing ADC ligand to rhodium Entry Metal Precursor Temperature Additive Yield 1 [Rh(COD)Cl] 2 70 NR 2 [Rh(COD)Cl] 2 110 NR 3 [Rh(COD)Cl] 2 110 Ag 2 O NR 4 [Rh(COD)OH] 2 110 NR The work of Tamm and colleagues showed that NHCs acting in conjunction with tris(pentafluorobenzene) borate functioned to activate small molecules like diatomic hydrogen through dissociation of the carbene boron bond. 26 Steric repulsion caused by t he joining of 3 32 and 3 33 creates a frustrated Lewis pair (Figure 3 15) With the idea that this type of boron carbene molecule might be a useful species for transferring an ADC to a transition metal through trans metalation the synthesis of compound 3 34 from tris(pentafluorobenzene) borate was attempted, but it was not accessed. It was believed that if formed, compound 3 34 might behave similarly to 3 32 and 3 33 with the dissociation of the carbene boron bond in the presence of a metal source leadin g to a metal carbene bond. Other Ligands Explored in Carbene Formation from the Lithium Halogen Exchange Success was observed when conducting metal complexation with ADC and NHC ligands featuring a low degree of functionality and mostly alkyl substituent s. Ligand structure was varied more drastically, however, to understand the scope of methodology for carbene generation from chlorinated precursors, and unfortunately several classes of ligands did not fare well. This section details these efforts.

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60 Figure 3 15. Attempt to create a frustrated Lewis pair with an ADC. ion is important but for what reason is not clear. Bis(pyrrolidine) chloroamidinium 3 36 was synthesi zed in the laboratory, but anion exchange was not performed so that the counter ion remained as chloride. Attempts at formation of rhodium complex 3 5 failed from this precursor (Figure 3 16 ) After converting 3 36 to the tetrafluoroborate salt synthesi s of 3 5 succeeded. 13 C labeled chloroamidinium 3 36 was used in an NMR experiment to understand why the chloride version of 3 1 di d not form the rhodium Figure 3 16. Attempts at synthesis of ADC rhodium catalyst using chloroamidinium 3 36 catalyst, and it was seen t hat the carbene was not formed under these circumstances (Figure 3 17). A similar dependence on the identity of the counter ion was observed when working with NHC precursor 3 38 In this instance, however, the chloride anion was preferential to tetrafluo roborate (Figure 3 18).

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6 1 Some seemingly simple alkyl based diaminocarbenes did not perform well under the lithium halogen exchange conditions. Neither bis(dimethyl) chloroamidinium 3 39 nor bis(morpholine) chloroamidinium 3 40 showed evidence of binding t o rhodium. Both reactions were run twice, and after twelve hours of reaction time, [Rh(COD)Cl] 2 was recovered in quantitative amounts. Based on data from Alder and co workers 6b it was believed that the carbene stemming from 3 39 might quickly dimerize e ven at low temperature. After all, the successful ligand stemming from 3 1 dimerizes within three hours in THF at 78 C. 27 Likewise, a chiral chloroamidinium with a low degree of functionality developed by a co worker Hwimin Seo, failed to ligate to a rh odium center under the identical lithium halogen exchange conditions. Figure 3 17. NMR taken at chloride salt 3 36 under Li X exchange conditions

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62 Figure 3 18. Observed differences in reactivity based upo n counter ion identity. Iron catalysts exhibit an abundance of dative bonds to nitrogen containing ligands, and so the potential of pyridine based ADCs was of special interest. 28 Chloroamidinium Figure 3 19. Diaminocar bene precursors which were unsuccessful in attempts to complex with rhodium using lithium halogen exchange methodology. 3 42 was previously noted for its simple preparation and isolation. Treatment of 3 42 with n BuLi followed by addition of [Rh(COD)Cl] 2 did not yield the desired product, however (Figure 3 20) Initially, the chloride salt was used because the chloroamidinium was simple to obtain as a nice, white solid, whereas the tetrafluoroborate salt was a nearl y intractable, colorless oil. Resultan tly, w hen 3 42 failed to give the proper product, tetrafluoroborate salt 3 44 was examined, but it also did not yield the rhodium complex

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63 Figure 3 20. Attempts at synthesis of a mixed pyridine ADC rhodium complex. In an attempt to pinpoint the problem with catalyst formation, the reaction was dissected into two halves, as either the lithium halogen exchange or the metal binding might be problematic. After addition of n BuLi to 3 44 in THF and thirty minutes of stirri ng, sulfur was added to the reaction mixture. Thiourea 3 45 was not isolated In a separate trial, trifluoroborane diethyletherate was als o used as an electrophile to trap the ADC after generation with n BuLi, but again, the expecte d product was not obse rved (Figure 3 21 ). This led us to believe that the problem wit h rhodium complex formation lay with the lithium halogen exchange. One possible scenario was that a lithium aggregate was formed, diminishing the reactivity of the lithiated carbene. Cluste red organo lithium species are known to lower reactivity, and breaking the aggregate is a common method for increasing rate of reaction. 29 HMPA is one of the most effective additives to deconstruct the tetrameric phenyl lithium structure, and so it was

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64 used in conjunction with the lithiation of pyridine based chloroamidinium 3 44 The addition of HMPA did not prove to be effective in the formation of borate 3 46 (Equation 3 18). Figure 3 21. Trials to determine whether n BuLi is effective in generation of carbene intermediacy with precursor 3 4 4 In previous projects, formation of sterically hin dered tetra substituted ureas was found to be very challenging, and this has been observed in other research groups as well 14 A potential strategy to circumvent this obstacle is to pursue N X carbenes instead of diaminocarbenes, where X equals sulfur or oxygen The use of divalent sulfur or oxygen w ould effectively eliminate the strain observed in the ADC ligands, and this methodology might allow the use of 2,5 trans diphenylpyrrolidine or other C 2 symmetric amines as chiral building blocks.

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65 N S carbene precurso rs 3 49 and 3 5 0 were synthesized quite easily from the nucleophilic attack on carbon disulfide by a secondary amine. After isolation of the dithiocarbamate salt, ethyl iodide was added to give the alkylated product in high yield (Figure 3 22) Thiocarba mate 3 54 leading to a possible N O carbene was made by addition of pyrrolidine to phenyl chlorothionoformate (Figure 3 23) All of these molecules were easily chlorinated by adding oxalyl chloride to a solution of the dithiocarbamate or thiocarbamate in toluene and stirring the reaction mixture at room temperature for twenty four hours. The first carbene synthons investigated were chlorinated dithiocarbamates 3 51 and 3 52 Both were subjected to n BuLi in THF at 78 C, which was followed by the additi on of [Rh(COD)Cl] 2 A t the end of the reaction period, quantitative amounts of the rhodium precursor were recovered (Equations 3 20 and 3 21). A switch from the tetrafluoroborate anion to the chloride anion was explored but did not produce an affirmative result. Figure 3 22. Formation of chlorinated dithiocarbamate tetrafluoroborate salts 3 51 and 3 52

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66 Figure 3 23. Formation of chlorinated thiocarbamate tetrafluoroborate salt 3 55 Next, attention was paid to the chlorinated carbamate, 3 55 Again, treatment with n BuLi followed by addition of [Rh(COD)Cl] 2 failed to produce the desired rhodium complex, and salt s with the tetrafluoroborate or chloride counter ion were both investigated (Figure 3 24). Two different fragments of the carbamate appear up on isolation of the reaction by products. One featured a pyrrolidine unit without any aromatic signal in 1 H NMR, w hereas the other product showed only aromatic peaks, looking quite similar to phenol. Based on this information it seemed as though the n BuLi might be attacking the chlorinated molecule with phenoxide ejected as a suitable leaving group. With this hypot hesis in hand, t BuLi was substituted as the reducing agent, but no complex was isolated. Thiocarbamate formation was tested with the chlorinated carbamate to test the efficacy of lithium halogen exchange, but addition of elemental

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67 Figure 3 24. Attempts at synthesis of rhodium complex 3 58 by changing counter ion identity and lithiation source. sulfur to the putative lithio carbene species did not produce the desired product (Equation 3 22). With some of the difficulties in obtaining a usable carbene, a different method for reduction of the carbon chlorine bond was sought. One such possibility involved the application of metallic lithium and naphthalene to create a radical a nionic naph thalene species (Figure 3 25) 18 Crucial to production of the radical anion was activation of the lithium granules by crushing with a spatula once inside the Schlenk flask. If activated outside an inert atmos phere, the freshly exposed surface quickly oxidized giving a sluggish lithium species. The initially dark green lithio naphthalene solution was added to the simple chloroamidinium 3 1 and although the green color disappeared, the chloroamidinium never di ssolved The presence of the chloroamidinium was somewhat troubling since normally the chloroamidinium dissolves as it

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68 transforms into a carbenoid species. Not unexpectedly, complex 3 5 was not isolated after addition of [Rh(COD)Cl] 2 Figure 3 25. Use of a lithio naphthalene solution to generate compound 3 5 Catalytic Activity of Rhodium Complexes Accessed Through Lithium Halogen Exchange Rhodium complexes function as diverse catalysts capable of a range of transform ations effective in C C and C X bond formation (Figure 3 26) 30 Among these reactions rhodium is esp ecially known for its ability to effect cycloaddition s, 30 31 afford carbenoids from diazonium ylides, 32 and prom ote C H activation. 33 Recently, rhodium has also gained attention for insertion reactions such as 1,4 conjugate addition 34 35 and 1,2 migratory insertion. 36 37 The 1,4 conjugate addition is particularly effective due to the high degree of enantioselectivity, low catalyst loadings, and mild condi tions employed in catalysis, with the work of Hayashi and co workers playing a large role in the achievements Catalysis with rhodium was explored since access to th ese complexes along with iridium was most straightfor ward. With the rhodium complexes, catalysis involving trans metalation of a boronic acid seemed to work well, and conjugate addition of boronic acids to enones was explored first using cyclohexenone 3 60 as the standard substrate (Equation 3 23). Rhodium ADC complex 3 5 boronic acid, and potassium hydroxide were added to a Schlenk flask under

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69 Figure 3 26. Examples of catalysis with rhodium including cycloadditions, borylations, carbenoid chemistry, C H activation, 1,4 conjugate addition, and 1,2 addition to aldehydes. argon atmosphere, followed by a 10:1 mixture of THF and water respectively. After addition of the solvent, distilled and degassed cyclohexenone was added to the solution. The yellowish reaction mixture w as heated to 40 C for thirty minutes, and as it neared completion, the aqueous phase separated from the organic layer. The solvent was evaporated and the residue was purified by silica gel column chromatography using a 4:1 mixture of hexanes to ethyl ace tate. Arylboronic acids functioned very well under these conditions ( Table 3 6, entries 1 6) giving product in excellent yields and short reaction times. With a vinylboronic acid (entry 7), a longer reaction time was necessary and the yield was not as high. This might be expected however, as the enone could be regenerated easily to make a highly conjugated product. Extension of the methodology to include alkylboronic acids (entry 8) did not result in successful

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70 isolation of the product. The catalyst was investigated with a more challenging heterocyclic substrate, 3 69 The reaction was run under conditions similar to those used for conjugate addition to cyclohexenone; how ever, more time was needed ( Equation 3 24 ). ADC complex 3 5 also fared well in another reaction involving trans metalation the 1,2 addition of arylboronic acids to aldehydes (Table 3 7 ). Under an inert atmosphere of argon, the catalyst, aldehyde, boronic acid, and base were combined, and then a 3.5:1 mixture of 1,2 dimethoxyethane a nd water was added. The reaction was heated at 80 C for varying times before purification by silica gel chromatography. Table 3 6 1,4 Conjugate Addition of Boronic Acids to Cyclohexenone Entry ArB(OH) 2 Time Isolate d Yield (%) 1 20 min 98 2 20 min 96 3 30 min 90 4 20 min 98 5 30 min 98 6 20 min 97

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71 7 12 h 59 8 12 h 0 Table 3 7 1,2 Addition of arylboronic a cids to o anisaldehyde. Entry Catalyst Aldehyde Boronic Acid Yield (%) 1 [Rh(COD)Cl] 2 62 2 Rh(IMes)(COD)Cl 80 3 3 5 92 4 3 5 96 5 3 5 92 6 3 5 83

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72 7 3 5 83 The effectiveness of the bis(pyrrolidine) ADC as a ligand was compared directly to IMes and 1,4 cyclooctadiene (COD) and sho wed a higher level of catalytic activity ( e ntries 1 3) In conjunction with 2 methoxybenzaldehyde, 3 5 afforded product in 92% yield while Rh(IMes)(COD)Cl and [Rh(COD)Cl] 2 gave 80 % and 62% yield respectively. While COD was easily the best ligand in 1,4 conjuga te addition reactions, it did not compete as successfully in the 1,2 addition. This result demonstrates the potential of ADCs as viable ligands and alternates to NHCs and phosphines. Table 3 8 1,2 Addition of phenylbor onic acid to arylaldehydes. Entry Benzaldehyde Boronic Acid Time Yield (%) 1 1 h 95 2 1 h 41 3 7 h 87

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73 4 8 h 46 5 7 h 0 6 7 h 0 The insertion worked with a variety of boronic acids as coupling partners. Both electron deficient and rich aryl rings trans ferred with the same efficacy (e ntries 6 and 7), and mono ortho substituted aryl rings re acted with excellent activity (e ntries 4 and 5). The aldehyde proved to be the most sensitive variable examined (Table 3 8 ) A substituent in the ortho position cap able of coordinating to a metal center or alternatively an electron withdrawing group seemed to promote success. For example, simple benzaldehyde and 4 methoxybenzaldehyde did not react under the cata lytic conditions investigated; however, the broad scope of boronic acid tolerance helps to overcome this limitation in the synthesis of diaryl methanol products. A plausible catalytic cycle is shown below and based on the thoroughly investigated cycle for 1,4 conjugate addition (Figure 3 27). 30 Presumably, the first step is exchange of chloride for an alkoxide. 38 Formation of a rhodium hydroxo or alkoxo intermediate has proven crucial in the acceleration of reaction rates. 38 a It is believed that the trans metalation preferentially proceeds from the hydroxo or alkoxo complex due to the oxophilic nature of the boronic acid. Following ligand exchange is trans metalation coordination of the aldehyde, and insertion of the a ryl group into the aldehyde. The newly formed alkoxide undergoes either protonolysis or remains on the metal to start the next catalytic cycle.

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74 It is of interest to note that there is precedent for the trans metalation step to be initiated from an inter mediate involving 6 coordination of the boronic acid. 39 Electron rich metal complexes bind olefins tighter and at a quicker rate than less electron rich metal centers. 40 Potentially, the ADC complex is more active in the 1,2 addition of arylboronic acids to aldehydes beca use it is more efficient in the trans metalation step. A lternatively, the difference in reactivity between the ADC and NHC metal complex might be attributed to a quicker rate of exchange of chloride for t butoxide. In examining the structures of ADC Ir co mplex 3 6 and NHC Ir complex 3 9 it is seen that the Ir Cl bond is longer in the ADC complex, ostensibly because the greater electron density coming from the ADC weakens the Ir Cl bond, making exchange for t butoxide more facile. The 2 bis(alkylpyrrolidi no)methylidine ligands were briefly tested in the asymmetric 1,2 addition to aldehydes (Table 3 5). The most active substrates, o anisaldehyde and 1 naphthylboronic acid, were used since 3 15 tends to exhibit sluggish reactivity. With both 3 13 and 3 15 slightly lower yields were obtained, and catalyst 3 15 imparted 12% ee. With NHC ligands, the highest selectivity observed thus far is 38% ee to the best of my knowledge. 37 d, 41 The aforementioned results demons trate the viability of ADC Rh complex 3 5 in catalysis involving insertion of aryl groups into double bonds. Because transition metals bind alkenes more tightly when they are electron rich, it seemed reasonable to infer that an ADC metal complex might wo rk well in catalysis with olefinic substrates such as 2,3 dihydrofuran 3 78 that do not bind well to metal centers. To understand the boundaries and capabilities of catalysis with the ADC complex, the unprecedented Rh catalyzed 1,2 addition of naphthylbor onic acid to 2,3 dihydrofuran was tested (Equation 3 28). The catalyst was not active enough to promote the reaction in conditions favoring either reformation of the double

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75 bond or protonolysis. The synthesis of the bis(ethylene) and bis(cyclooctene) ver sions of 3 5 were attempted in order to make a more act ive metal center; however, neither complex was able to be isolated (Figure 3 28 ) Figure 3 27. A plausible catalytic cycle for the 1,2 addition of aryboronic acids to aldehydes.

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76 Table 3 9 1,2 Asymmetric addition of 1 naphthylboronic acid to o anisaldehyde. Entry Catalyst Time Yield (%) e e (%) 1 1 h 71 2 2 16 h 75 12 With the electron rich ADC, 3 5 might be expected to perform exceptionally well in catalytic cycles involving oxidative addition. As such, low pressure hydrogenation was investigated (Equation 3 29 ). 42 3 5 and coumarin 3 82 were loaded into a Schlenk flask under an argon atmosphere. Dichloromethane was added and the argon was exchanged for hydrogen at one atmosphere of pressure by bubbling the gas through the CH 2 Cl 2 solution. The reaction proceeded overni ght, but isolation of starting material showed that the enone failed to be reduced. Recently, a report appeared covering the cross coupling of aryltosylates with arylboronic acids. Wu and co workers nicely demonstrated that electron rich, Rh(NHC)(COD) co mplexes catalyzed the reaction, which makes use of readily available phenols with a functional group less

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77 sensitive than triflate. 43 Since ADCs are even more donating than NHCs, we believed they might be more effective in the cross coupling. Rhodium compo und 3 5 an aryltosylate, a boronic acid, and cesium fluoride were combined in a Schlenk flask. Anhydrous toluene under an argon atmosphere was added to the solids, and the suspension was then heated to 120 C and stirred for thirty hours. After purifyin g the products of the reaction mixture by silica gel chromatography, the aryltosylate was recovered in quantitative yields, giving evidence that a reaction did not take place (Equation 3 30). Figure 3 28 Attempts at syn thesis of complexes 3 8 0 and 3 81 which might be expected to show greater activity toward insertion reactions with olefins.

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78 ADC Pd Complex 3 18 in the Suzuki Cross Coupling Although pall adacycle s of type 3 18 are not typically used in the Suzuki cross coupling reaction, it was investigated to see the effects of the ADC ligand in the absence of triphenyl phosphine. With toluene at reflux, the conditions employed when using 2 15 and 2 26 low yield of the binaphthyl product was obtained. Using the harsher conditions developed by Iyer and co workers 3 87 was formed in 78% yield (Figure 3 29 ). 44 Figure 3 29 Suzuki coupling to for m tri ortho substituted p roduct using catalyst 3 18 Steric and Electronic Measurements of ADC and NHC Compounds Iridium complexes 3 6 and 3 9 were further characterized using cyclic voltametry to measure the co worker s electrochemistry and the measurement of reduction potentials gives a more precise understanding of electronic characteristics than measurement of (CO) of M(NHC)(CO) 2 Cl complexes and calculation of the Tolman electronic parameter (TEP) since most NHCs fall within a 3 cm 1 range. 45 Lower reduction potentials indicate stronger donor ligands, as more electron rich ligands ease the oxidation of the irid ium center from Ir I to Ir II ADC iridium complex 3 6 exhibited a n E 1/2 of

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79 0.422 V and NHC iridium complex showed a E 1/2 of 0.765 V, clearly demonstrating the superior donor properties of the ADC ligand. Plenio and co workers synthesized a variety of NHC ligands, and when bound to metal, these complexes yielded E 1/2 values spanning from 0.591 to 0.920 V clearly delineating the electronic spectrum of carbene ligands (Table 3 10 ) ADCs fall well below the range observed for even the most donating NHC. The electronic properties for bis(diisopropylamino)carbene were previously reported; 6d however donor power only accounts for half of the puzzle when determining carbene properties. Figur e 3 30 Variable NHC ligands used i substituents. Table 3 10 Redox half potentials for some Ir(L)(COD)Cl complexes in CH 2 Cl 2 (scan rate 100mVs 1 ). Complex E 1/2 [V] Complex E 1/2 [V] 0.422 3 88b R = Me 0.735 0.765 3 88c R = Br 3 88d R = SO 2 Ar 0.838 0.910 3 88a R = NEt 2 0.591 Ir(PCy 3 )(COD)Cl 0.948 Thus far, steric parameters of ADCs have not been disclosed. Cavallo and co workers developed an exce percent volume buried, or % V Bur and is a metric for how much of a ligand lies within a set radius representing the coordinatio n sphere of a metal (Figure 3 31 ). 46

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80 Figure 3 31. Graphical illustration of % V Bur Table 3 11 Calculated % V Bur values for ADC ligands in complexes 3 5 3 6 3 9 and 3 13 Calculated with Bondi radii scaled by 1.17, 3.5 radius of the sphere, and 2.1 distance of the ligand from the sphere. NHC values reported by Cavallo. 46 Ligand % V Bur Ligand % V Bur 27.9 R = Me(saturated) 25.4 28.0 R = Et 26.0 25.3 R = IMes 31.6 29.7 R = DIPr 33.6 30.1 R = Adamantyl 36.1 One might expect that the larger carbene bond angle of ADCs might cause them to have higher % V Bur values than NHCs. With the ADCs explored thus far; however, the % V Bur has

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81 been considerably lower than typical NHCs. This could reasonably be expected since the pyrrolidine rings exhibit a low de gree of substitution. Complexes 3 6 3 9 and 3 13 show % V Bur values of 28.0, 25.3, and 29.7 % respectively, while IMes possesses a percentage of 31.6 (Table 3 11 ). Conclusions and Summary The methodology developed provides a solid platform for the synth esis and exploration of ADC ligands. Despite the benefits of the lithium halogen exchange, several drawbacks still exist. The process as of now is not applicable to all chloroamidinium precursors. Particularly, functionalized molecules and N X type carb enes were not formed, and alkyl based ureas tend to fare best. Figure 3 32. Plot of redox potential vs. % V Bur Carbenes that are both strongly donating and sterically demanding are as of yet uninvestigated.

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82 ADC structures have only just begun to be investigated, and measurement of reduction potentials and % V Bur give a logical means of tuning ADC properties. The combined information from cyclic voltametry and % V Bur data paints a picture of a ligand possessing quite distinct characteristics from those of the well known NHC basis set. Promising results showing the potential of ADCs has been demonstrated, but truly exceptional catalytic activity has not yet been achieved. Perhaps one needs to draw deeper into the well of available catalytic react ions and further from those known to work well with NHCs to realize the desired outcomes of ADCs. Clearly by expanding into other quadrants of the graph in Figure 3 32, through single factor variation of either sterics or electronics, considerable changes in catalytic reactivity might be observed.

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83 CHAPTER 4 EXPERIMENTAL S ECTION General Remarks All reactions were conducted in flame dried glassware under an inert atmosphere of dry argon. THF, CH 2 Cl 2 and Et 2 O were passed through two packed columns of neu tral alumina under positive pressure of dry nitrogen prior to use. Toluene was passed through an alumina column and a copper (II) oxide column under positive pressure of dry nitrogen prior to use. A ll other chemicals were commercially available and were u sed as received without further purification. NMR spectra were recorded using a FT NMR machine, operating at 300 MHz for 1 H NMR and at 75.4 MHz for 13 C NMR. All chemical shifts for 1 H and 13 C NMR spectroscopy were referenced to residual signals from CDCl 3 ( 1 H ) 7.27 ppm and ( 13 C ) 77.23 ppm. High resolution mass spectra were recorded on a GC/MS spectrome ter or a TOF LC/MS spectrometer General Procedure for Formation of Ureas Based on 2 Substituted Pyrrolidines. A pyrrolidine derivative (8.82 mmol), trieth yl amine (26.4 mmol), and CH 2 Cl 2 (17.6 mL) were added to a flame dried Schlenk flask, and the solution was stirred and cooled to 0 C. Phosgene (4.4 mmol, 2.32 mL) was slowly added in the form of a 20 wt% solution in toluene, and the Schlenk flask was sea led to prevent loss of gaseous phosgene. The reaction was vigorously stirred for 4 hours at which point extra phosgene (2.2 mmol, 1.16 mL) was added to ensure complete reaction of the amine. Stirring continued for an additional 4 hours, and then the reac tion was quenched with water. The aqueous layer was extracted with CH 2 Cl 2 (20 mL x 3), dried with MgSO 4 and concentrated. The crude product was purified by silica gel column chromatography (hexanes, ethyl acetate, 1:1) to give the pure urea.

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84 Bis (2 S ) M ethylpyrrolidine Urea. 1 H NM R ( 300 MHz, CDCl 3 = 1.15 (d, J = 6.30 Hz, 3H), 1.36 1.43 (m, 1H), 1.61 1.74 (m, 1H), 1.76 1.83 (m, 1H), 2.01 2.12 (m, 1H), 3.23 3.37 (m, 2H), 3.89 4.02 (m, 1H); 13 C NMR (CDCl 3 75 MHz) 21.0, 25.5, 49.7, 54.0, 161.5; HRMS Calcd. for C 11 H 20 N 2 O [M+H] + : 197.1648, Found : 197.1643. Bis (2 R ) Diphenylm ethylpyrrolidine Urea. 1 H NMR (300 MHz, CDCl 3 ) = 1.45 1.72 (m, 4 H), 1.70 2.01 (m, 4 H), 2.45 2.65 (m, 2 H), 2.98 3.21 (m, 2 H), 3.99 (d, J = 10 Hz, 2 H), 5.19 5.36 (m, 2 H), 5.38 5.86 (m, 1 H), 7.04 7.46 (m, 20 H). 13 C NMR (75 MHz, CDCl 3 ) = 14.5, 24.0, 28.6, 55.5, 69.6, 127.7, 127.9, 128.5, 128.6, 129.0, 129.1, 129.2, 139.3, 140.3, 152.5. HRMS Calcd. for C 35 H 36 N 2 Cl [M+H] + : 519.2562, Found: 519.2585. (2 R ) ( I sopropyl ) N ( tert Butylo xycarbony l)pyrrolidine To a flame dried 3 neck round bottom flask, pyrrolidinone 2 9 (15.7 mmol, 2.0 g) and THF (78 mL) were added. The solution was cooled to 0 C, and lithium aluminum hydride (31.4 mmol, 1.195 g) was added portion wise over 10 minutes. The re action mixture was stirred at this temperature for half an hour before warming to room temperature. After an additional 30 minutes, the reaction was heated to reflux and stirred for 3.5 hours. The reaction was quenched with 1.2 mL of water followed by 2. 4 mL of a 10 % NaOH solution, and lastly 3 mL of water was added. Lithium salts were removed by filtering over a celite bed. Boc 2 O was added to the THF filtrate, and the solution was stirred overnight. Volatiles were removed and the crude product was pu rified by column chromatography (hexanes/ethyl acetate, 4:1) to give 2 10 (3.24 g, 97%) 1 H NMR ( 300 MHz,

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85 CDCl 3 = 0.76 (d, J = 6.9 Hz, 3H), 0.83 (d, J = 7.2 Hz, 3H), 1.42 (s, 9H), 1.63 1.79 (m, 4 H), 1.94 2.23 (m, 1H), 3.14 3.22 (m, 1 H), 3.36 3.70 (m, 2 H) 13 C NMR (75 MHz, CDCl 3 ) = 17.4, 20.0, 23.8, 24.5, 26.0, 26.9, 28.8, 30.2, 31.1, 47.2, 62.5, 78.6, 154.5. HRMS Calcd. for C 12 H 2 3 NO 2 [M+Na] + : 236.1621, Found: 236.1606. Bis (2 R ) Diphenylm ethylpyrrolidine Urea. Boc protected amine 2 10 (4. 69 mmol, 1.00 g) and ether (1 mL) were added to a flame dried Schlenk flask and cooled to 0 C. Slowly, 4M HCl in dioxane (23.5 mmol, 5.87 mL) was added to the vigorously stirred solution. The reaction was stirred at room temperature for 3 hours, and a white salt precipitated out of solution. Solvent was removed in situ, and the solid was washed twice with ether. The soli d was dried in vacuo, and the general procedu re described above was used for formation of urea 2 3 (0.271 g, 46 %) 1 H NMR (300 MHz, CDCl 3 ) 0.78 (d, J = 7 Hz, 3 H), 0.86 (d, J = 7 Hz, 3 H), 1.44 1.95 (m, 4 H), 1.95 2.18 (m, 1 H), 3.21 (m, 1 H), 3. 28 3.47 (m, 1 H), 3.91 4.14 (m, 1 H). 13 C NMR (75 MHz, CDCl 3 ) = 13.6, 16.5, 19.7, 25.7, 30.3, 50.9, 62.6, 162.4. HRMS Calcd. for C 12 H 2 3 NO 2 [M+H] + : 253.2274, Found: 253.2264. General Procedure for the Formation of Chloroamidinium Ions. Urea 2 1 (2 .09 mmol, 0.400 g) was mixed with toluene (10.45 mL) in a flame dried Schlenk flask. To this solution was added oxalyl chloride (2.51 mmol, 0.212 mL), and the reaction mixture was heated to 60 C. The reaction was stirred overnight at which point, a brow n, oily residue precipitated out of solution. The reaction was cooled to room temperature and the toluene was siphoned off. The oily residue was washed twice with ether, dissolved in CH 2 Cl 2 (12 mL), and AgBF 4 (2.09 mmol, 0.407 g) was added. The reaction was stirred for 1

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86 hour. After this time, the CH 2 Cl 2 was filtered off into a dry Schlenk flask under an argon atmosphere. Volatiles were removed resulting in an off white solid (0.4445 g, 70%). Bis (2 S ) Methylpyrrolidi ne Chloroamidinium Tetrafluorob orat e 2 11 1 H NMR (300 MHz, CDCl 3 ) 1.39 (d, 6 H), 1.63 1.88 (m, 2 H), 2.11 (dd, J = 5, 1 Hz, 4 H), 2.25 2.56 (m, 2 H), 3.68 3.90 (m, 2 H), 3.90 4.13 (m, 2 H), 4.20 4.56 (m, 2 H). 13 C NMR (75 MHz, CDCl 3 ) = 20.3, 25.4, 33.5, 55.9, 62.4, 152.7. HRMS Calcd. for C 11 H 20 N 2 Cl [M+H ] + : 215.1310, Found: 215.1310. Bis(2 R ) Diphenylmethylpyrrolidine Chloroamidinium Tetrafluoroborate 2 12. 1 H NMR (300 MHz, CDCl 3 ) = 1.45 1.72 (m, 4 H), 1.70 2.01 (m, 4 H), 2.45 2.65 (m, 2 H), 2.98 3.21 (m, 2 H), 3.99 (d, J = 10 Hz, 2 H), 5.19 5.36 (m, 2 H), 5.38 5.86 (m, 1 H), 7.04 7.46 (m, 20 H). 13 C NMR (75 MHz, CDCl 3 ) = 14.5, 24.0, 28.6, 55.5, 69.6, 127.7, 127.9, 128.5, 128.6, 129.0, 129.1, 129.2, 139.3, 140.3, 152.5. HRMS Calcd. for C 35 H 36 N 2 Cl [M+H] + : 519.2562, Found: 519.2585. Bis(2 R ) Isopropylpyrrolidine Chloroamidinium Tetrafluoroborate 2 13. 1 H NMR (300 MHz, CDCl 3 ) = 0.82 (br. s., 3 H), 0.91 (br. s., 3 H), 1.32 (br. s., 1 H), 2.09 (br. s., 4 H), 3.68 (br. s., 2 H), 4.27 (br. s., 1 H). 13 C NMR (75 MHz, CDCl 3 ) = 13.12, 16.04, 19.46, 24.98,

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87 25.38, 30.56, 49.13, 57.65, 58.24, 71.73, 153.48, 156.42. HRMS Calcd. for C 15 H 2 8 N 2 Cl [M+H] + : 271.1936, Found: 271.1928. General Procedure for the Formation of Palladium Complexes. Amidinium chloride 2 11 (0.140 mmol, 0.04 08 g) was added to a flame dried Schlenk flask along with toluene (10 mL) To the suspension was added Pd(PPh 3 ) 4 (0.140 mmol, 0.1623 g) The yellow solution was heated to 100 C and quickly turned deep red in color. The reaction was stirred for two hour s at which point, a yellow solid precipitated from solution. The mixture was allowed to cool to room temperature, and the toluen e was evaporated. Pentane was added to the resulting solid (10 mL x 2) which was stirred for 1 hour before being decanted. CH 2 Cl 2 was used to dissolve the product and insoluble salts w ere filtered off. Pentane was layered on top of the filtrate to purify the product by recr ystallization (0.078 g, 65 %). Bis(Triphenylphosphine) (2 S ) Methylpyrrolidinecarbene Palladium Chloride 2 15 1 H NMR (300 MHz, CDCl 3 ) = 0.54 (d, J = 7 Hz, 1 H), 0.76 0.96 (m, 5 H), 1.21 1.34 (m, 1 H), 1.42 1.60 (m, 2 H), 1.60 1.79 (m, 2 H), 1.79 2.01 (m, 1 H), 3.70 4.07 (m, 3 H), 4.85 (q, J = 9 Hz, 1 H), 7.06 7.28 (m, 2 H), 7.28 7.51 (m, 2 H), 7.53 7.81 (m, 25 H). 13 C NMR (75 MHz, CDCl 3 ) = 14.0, 20.2, 20.9, 21.7, 22.6, 22.9, 30.0, 32.1, 34.3, 57.1, 59.0, 129.2, 129.3, 129.3, 129.8, 130.0, 132.0, 132.2, 134.6, 187.2. HRMS Calcd. for C 47 H 40 N 2 P 2 ClPd [M+H] + : 845.2181, Found: 845.2152.

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88 Bis(Triphenylphosphine) (2 R ) Met hylpyrrolidinecarbene Palladium Chloride 2 15. 1 H NMR (300 MHz, CDCl 3 ) = 1.00 1.51 (m, 4 H), 1.53 2.13 (m, 5 H), 2.49 2.72 (m, 2 H), 2.96 (dd, J = 14, 5 Hz, 2 H), 3.66 3.85 (m, 2 H), 4.28 4.48 (m, 2 H), 5.49 (ddd, J = 11, 6, 6 Hz, 2 H), 6.81 7.85 (m, 40 H). 13 C NMR (75 MHz, CDCl 3 ) 22.8, 25.9, 40.0, 54.4, 71.5, 126.8, 128.5, 128.8, 129.1, 130.2, 131.6, 132.4, 134.3, 134.7, 135.3, 137.1, 185.8. General Procedure for S uzuki Cross Coupling Reaction Boronic acid 2 23 (0.269 mmol, 0.0464 g), aryl bromide 2 24 (0.221 mmol, 0.524 g), palladium complex 2 15 (0.0066 mmol, 0.0060 g), and CsF (0.619 mmol, 0.0940 g) 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 hours. A fter this time, the reaction mixture was diluted with water and extracted with 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 acetat e, 50:1) resulting in pure biaryl (0.0619 g, 99%) with spectra that match those reported in the literature 1 H NMR (CDCl 3 = 3.79 (s, 3H), 7.2 7.4 (m, 5H), 7.46 7.54 (m, 3H), 7.67 (t, J = 6.9 Hz, 1 H), 7.92 (d, J = 6.3 Hz, 1H), 7.98 8.04 (m, 3H ). 13 C NMR (75 MHz, CDCl 3 ) 154.54, 134.51, 134.21, 133.65, 132. 91, 129.42, 128.94, 128.39, 128.17, 127.76, 127.67, 126.34, 126.12, 125.8 1, 125.64, 125.52, 125.43, 123.50, 113.71, 56.61. HRMS Calcd. for C 21 H 16 O [M+H] + : 284.1201, found, 284.1225

PAGE 89

89 Gener al Procedure for the Formation of Ureas from Carbamoyl Chlorides Chiral amine 2 37 ( 0.672 mmol, 0.150 g), triethyl amine (1.345 mmol, 0.188 mL), pyrrolidine carbamoyl chloride (1.01 mmol, 0.111 mL), and CH 2 Cl 2 (1.2 mL) were mixed in a flame dried Schlenk f lask. The solution was warmed to 60 C and heated overnight. The reaction was diluted w ith water and extracted with CH 2 Cl 2 (3 mL x 3) The organic fractions were collected, dried with MgSO 4 and concentrated. The crude product was purified by column ch romatography (hexanes/ethyl acetate, 2:1) to give 2 41 (0.152 g, 70%). (2 S 5 S ) Diphenylp yrrolidine Pyrrolidine Urea 2 41 1 H NMR ( 300 MHz, CDCl 3 ) = 1.40 1.56 (m, 2H), 1.62 1.74 (m, 2H), 1.76 1.83 (m, 2H), 2.38 2. 50 (m 2H), 3.08 3.38 (m, 4H), 5.35 5.39 (m, 2H), 7.18 7.36 (m, 10H); 13 C NMR ( 75 MHz, CDCl 3 ) 25.1, 25.5, 34.2, 34.5, 63.5, 63.8, 125.5, 125.8, 126.7, 127.0, 128.3, 128.4, 128.6, 144.5, 144.8, 159.1 N,N Methyl,Pyridine (2 S 5 S ) Diphenylpyrrolidine Urea 2 49 1 H NMR ( 300 MHz, CDCl 3 ) = 8.32 (br. s., 1 H), 7.72 7.45 (m, 1 H), 7.25 (br. s., 10 H), 7.02 6.78 (m, 1 H), 6.67 (d, J = 7.6 Hz, 1 H), 5.27 (br. s., 1 H), 5.01 (br. s., 2 H), 2.84 (br. s., 3 H), 2.58 2.29 (m, 2 H), 1.85 (br. s., 2 H). 13 C NMR (75MHz, CDCl 3 ) = 158.7, 156.3, 148.0, 144.0, 137.4, 128.7, 127.3, 126.2, 117.4, 114.5, 64.3, 34.9

PAGE 90

90 A nisoyl (2 S 5 S ) Diphenylpyrrolidine Amide 2 50 1 H NMR ( 300 MHz, CDCl 3 = 1.89 2.01 (m, 2H), 2.57 2.87 (m, 2H), 3.81 (s, 3H), 5.44 (d, J = 6.3 Hz, 1H), 5.82 (d, J = 5.7 Hz, 1H), 6.77 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 7.5 Hz, 2H), 7.21 7.59 (m, 10H) ; 13 C NMR ( 75 MHz, CDCl 3 ) = 31.8, 34.2, 55.6, 62.3, 65.1, 133.5, 125.9, 127.2, 128.8, 130 .5, 143.9, 144.5, 160.6, 171.4 General Procedure for the Formation of Tri Subst ituted Ureas from Isocyanates 3,5 Dimethylaniline (2 S 5 S ) Diphenylpyrrolidine Urea 2 51 3,5 dimethylphenyl isocyanate (0.448 mmol, 0.063 m L) and MTBE (2 mL) were added to a flame dried Schlenk flask. To this solution was added drop wise chiral amine 2 3 7 (0.448 mmol, 0.100 g) dissolved in MTBE (2 mL). After five minutes, a white precipitate formed, and the reaction was stirred for 5 hours. The reaction was quenched with water and extracted with CH 2 Cl 2 (3 mL x 3). The organic layers were collected, dried with MgSO 4 and concentrated. The crude product was purified by column chromatography (hexanes/ethyl acetate 4:1) to give the pure urea (0.148 g, 89%) as a white solid. 1 H NMR ( 300 MHz, CDCl 3 = 1.79 1.84 (m, 2H), 2.16 (s, 6H), 2.51 2.60 (m, 2H), 5.12 5.60 (b r. s., 2H), 6.01 (s, 1H), 6.57 ( s, 1H), 6.72 (s, 2H), 7.25 7.44 (m, 10H); 13 C NMR ( 75 MHz, CDCl 3 ) = 21.5, 62.2, 117.1, 124.7, 129.3, 138.6, 138.9, 153.5.

PAGE 91

91 General Procedure for the Meth yla tion of Tri Substituted Ureas N,N Methyl 3,5 Dimethyl aniline (2 S 5 S ) Diphenylpyrrolidine Urea 2 52 Urea 2 51 (0.329 mmol, 0.122 g) was combined with DMF (3.3 mL) in a flame dried Schlenk flask. Sodium hydride (0.49 4 mmol, 0.0197 g) was added to this solution and it was stirred at room temperature for 45 minutes. After this point, methyl iodide (0.494 mmol, 0.031 mL) was added, the reaction was heated to 40 C, and the reaction mixture was stirred overnight. The re action was quenched with water and extracted with CH 2 Cl 2 The organic fractions were combined, dried with MgSO 4 and concentrated. The crude product was purified by column chromatography (hexanes/ethyl acetate, 4:1) to afford the pure product (0.119 g, 9 4%). 1 H NMR ( 300 MHz, CDCl 3 = 1.62 1.68 (m, 2H), 2.23 2.40 (s, 8H), 2.80 (s, 3H), 6.38 (s, 2H), 6.84 (s, 1H), 7.11 7.38 (m, 10H) ; 13 C NMR ( 75 MHz, CDCl 3 ) = 21.4, 38.9, 63.5, 123.5, 126.2, 127.1, 128.5, 138.8, 145.1, 145.4, 159.7 General Procedure for Formation of C arbene 3 4 Lithi um Bis(Pyrrolidine)Carbene 3 4. To a Schlenk flask in a glovebox, 100 mg (0.364 mmol) of chloroamidinium 3 1 was added, and the flask was connected to a Schlenk line outside the glovebox. THF (2 mL) was added, and the suspension was cooled to 78 C with a dry ice/acetone bath. After cooling, 2.5M n BuLi in hexanes (0.153mL) was added. After 5 minutes, the suspension turned to a clear and slightly yellowish solution upon formation of

PAGE 92

92 carbene. The solution proceeded to stir at 78 C for a total o f 1 hour. 1 H NMR (300MHz, THF d 8 ) = 3.56 (br. s., 8 H), 1.70 (br. s., 8 H). 13 C NMR (75MHz, THF d 8 ) = 233.8. Bis(Pyrrolidine)thiourea 3 2. Carbene generation was followed as described above After formation of car bene, 100 mg (3.125 mmol) of sulfur was added, and the reaction was allowed to slowly warm to room temperature. The resulting suspension stirred for 12 hours, diluted with ether, and filtered over a bed of celite. The filtrate was concentrated and purifi ed by silica gel chromatography (2:1 hexanes/ethyl acetate). After removal of solvent, 45 mg (0.245 mmol) of a colorless crystal resulted (68% yield). 1 H and 13 C NMR matched the values found in literature. 47 General Procedure for Rhodium and Iridium Comple x Formation Generation of carbene as described for 3 4 was followed. After stirring for 1 hour at 78 C, [M(COD)Cl] 2 (0.5 equiv.) was added, and the reaction slowly warmed to room temperature. Stirring at room temperature proceeded for 12 hours, at whic h point, solvent was evaporated. To remove any remaining [M(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 then transferring 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. The product is sufficiently soluble in hexan es.

PAGE 93

93 Chloro ( 4 1,5 cyclooctadiene ) bis ( pyrrolidine carbene ) rhodium ( I ) 3 5. 1 H NMR (300MHz, CDCl 3 ) = 4.80 (br. s., 4 H), 4.44 (br. s., 2 H), 3.40 (br. s., 4 H), 3.18 (m, 2 H), 2.52 2.17 (m, 4 H), 2.10 1.71 (m, 12 H). 13 C NMR (75MHz, CDCl 3 ) = 216.8, 216.2, 96.7 96.6, 68.3, 68.1, 55.7, 51.9, 32.8, 28.9, 26.5, 24.9. HRMS Calcd. for C 17 H 28 N 2 Rh [M Cl ] + : 363.1302 Found: 363.1312 Chloro 4 1,5 cyclooctadiene ) bis ( pyrrolidine carbene ) iridium ( I ) 3 6. 1 H NMR (300MHz, CDCl 3 ) = 4.53 (br. s., 2 H), 4.35 (br. s., 4 H ), 4.23 (br. s., 2 H), 3.48 (br. s., 4 H), 3.03 2.68 (m, 2 H), 2.40 2.00 (m, 4 H), 1.86 (br. s., 8 H), 1.71 1.40 (m, 4 H). 13 C NMR (75MHz, CDCl 3 ) = 211.7, 81.4, 54.7, 52.0, 33.4, 29.5, 25.7. HRMS Calcd. for C 34 H 56 N 4 Ir 2 Cl [2M+Cl ] + : 941.3436 Found : 941.3376 Chloro 4 1,5 cyclooctadiene ) (1,3 dimethyl imidazolidin 2 ylidene ) iridium ( I ) 3 8. 1 H NMR (300MHz, CDCl 3 ) = 4.92 (br. s., 2 H), 4.64 (br. s., 2 H), 3.54 3.43 (m, 8 H), 3.33 3.18 (m, 2 H), 2.47 2.19 (m, 4 H), 2.00 1.74 (m, 4 H). 13 C NMR (75MHz, CDCl 3 ) = 213.2, 212.6, 99.2, 99.1, 68.3, 68.1, 51.7, 37.4, 33.1, 28.9. HRMS Calcd. for C 13 H 22 N 2 Rh [M Cl ] + : 309.0833 Found: 309.0834

PAGE 94

94 Chloro 4 1,5 cyclooctadiene ) (1,3 dimethyl imidazolidin 2 ylidene ) iridium ( I ) 3 9. 1 H NMR (300MHz, CDCl 3 ) = 4.51 (br. s., 2 H), 3.55 (br. s., 4 H), 3.40 (s, 6 H), 2.98 (br. s., 2 H), 2.16 (br. s., 4 H), 1.78 1.54 (m, 4 H) 13 C NMR (75MHz, CDCl 3 ) = 207.9, 85.0, 52.0, 52.0, 37.2, 33.6, 29.5. HRMS Calcd. for C 26 H 44 N 4 Ir 2 Cl [ 2M+Cl ] + : 833.2495 Found: 833. 2419 Chloro ( 4 1,5 cyclooctadiene ) bis ( piperidine carbene ) rhodium ( I ) 3 12 1 H NMR (300MHz, CDCl 3 ) = 4.81 (br. s., 2 H), 3.88 3.82 (m, 8 H), 3.17 (br. s., 2 H), 2.27 (br. s., 4 H), 1.82 ( m, 4 H), 1.62 (br. s., 12 H) 13 C NMR (75MHz, CDCl 3 ) = 222.3, 221.7, 97.7, 97.6 68.1, 67.9, 54.0, 32.8, 28.9, 26.7, 24.5 HRMS Calcd. for C 19 H 32 N 2 Rh [M Cl ] + : 391.1615 Found: 391.1612 Chloro ( 4 1,5 cyclooctadiene ) bis ( (S) 2 methylpyrrolidine) rhodium ( I ) 3 13. 1 H NMR (300MHz, CDCl 3 ) = 6.42 (br. s., 1 H), 5.93 ( br. s., 1 H), 5.57 (br. s., 0.4 H), 5.09 4.62 (m, 2.3 H), 4.23 3.70 (m, 1.4 H), 3.28 (br. s., 5 H), 1.82 (br. s., 22 H). 13 C NMR (75MHz, CDCl 3 ) = 97.0, 97.0, 68.6, 68.4, 66.9, 66.7, 63.3, 61.9, 51.2, 50.9, 34.9, 33.2, 33.0, 32.6, 31.6, 31.1, 29.8, 29 .3, 28.6, 28.3, 25.0, 23.3, 23.0, 21.0, 20.5, 14.3. HRMS Calcd. for C 19 H 32 N 2 Rh [M Cl ] + : 391.1615 Found: 391.1616 D 26 182.6 ( c 8.3 mg/mL CHCl 3 ).

PAGE 95

95 Chloro ( 4 1,5 cyclooctadiene ) bis ( ( R ) 2 diphenyl methylpyrrolidine) rhod ium ( I ) 3 15 1 H NMR (300MHz, CDCl 3 ) = 7.53 (d, J = 7.3 Hz, 2 H), 7.47 7.11 (m, 12 H), 6.96 (t, J = 6.6 Hz, 1 H), 6.69 6.51 (m, 1 H), 5.71 (d, J = 3.8 Hz, 1 H), 4.81 (br. s., 2 H), 4.36 (d, J = 6.2 Hz, 1 H), 3.20 2.99 (m, 2 H), 2.93 (dd, J = 5.3, 1 0.0 Hz, 1 H), 2.83 2.60 (m, 2 H), 2.49 2.12 (m, 3 H), 2.12 1.84 (m, 3 H), 1.84 1.40 (m, 7 H), 1.39 1.13 (m, 4 H). 13 C NMR (75MHz, CDCl 3 ) = 222.5, 221.9, 143.3, 143.2, 142.8, 142.6, 142.0, 141.6, 131.0, 129.9, 129.4, 129.3, 129.1, 129.0, 128.8, 128.6, 128.5, 128.4, 128.3, 128.0, 127.5, 127.4, 127.3, 127.1, 126.8, 126.7, 126.5, 126.2, 126.2, 98.1, 98.0, 97.8, 97.7, 78.6, 70.8, 69.5, 69.3, 69.1, 67.7, 67.5, 60.6, 60.0, 56.1, 55.8, 54.5, 54.1, 53.3, 49.0, 32.9, 32.8, 31.2, 31.2, 28.7, 28.6, 28.1, 2 6.7, 26.0, 25.8, 24.9, 23.8, 21.3, 14.4. HRMS Calcd. for C 43 H 48 N 2 Rh [M Cl ] + : 695.2867 Found: 695.2868 2 N,N dimethylbenzylamine) b is(pyrrolidinecarbene)palladium (II) 3 18. To a Schlenk flask in a glovebox, 0.055 g (0.2 mmol) of chloroamidinium 3 1 was added, and the flask was connected to a Schlenk line outside the glovebox. THF (2 mL) was added, and the suspension was cooled to 78 C with a dry ice/acetone bath. After cooling, 1.7M t BuLi in hexanes (0.235 mL) was added. After 5 minutes, the suspension turned to a clear and slightly yellowish solution upon formation of carbene. The solution p roceeded to stir at 78 C for a total of 1 hour. After stirring for 1 hour at 78 C, 0.055 g (0.1 mmol) 2 N,N

PAGE 96

96 dimethylbenzylamine) chloride dimer was added, and the reaction slowly warmed to room temperature. Stirring at room temperature proceeded for 12 hours, at which point, solvent was evaporated. To remove any remaining metal precursor the p roduct was purified by chromatography on a short pad of silica gel. Columns were run starting with ethyl acetate and then transferring to 2.5% MeOH in DCM. 1 H NMR (300MHz, CDCl 3 ) = 6.93 (br. s., 2 H), 6.82 (m, 1 H), 6.64 (d, J = 7.0 Hz, 1 H), 3.74 (br. s., 10 H), 2.66 (s, 6 H), 1.85 (br. s., 8 H). 13 C NMR (75MHz, CDCl 3 ) = 204.3, 150.3, 148.6, 135.2, 125.8, 123.6, 122.3, 71.9, 50.0, 25.8. HRMS Calcd. for C 18 H 28 N 3 Pd [M ] + : 392.1320 Found: 392.1328 N,N,N ,N bis(tetramethylene) 2 formamidinium trifl uoroborate 3 31. Generation of carbene as described for 3 4 was followed with 0.50g (1.82 mmol) of chloroamidinium 3 1 After stirring for 30 minutes at 78 C, 0.23 mL (1.82 mmol) of BF 3 2 O was added, and the reaction slowly warmed to room temperature Stirring at room temperature proceeded for 12 hours, at which point, solvent was evaporated. The product was purified by silica gel chromatography (1:1 hexanes:ethyl acetate). 1 H NMR (300MHz, CDCl 3 ) = 3.59 (br. s., 8 H), 1.73 (br. s., 8 H). 13 C NMR (75MHz, CDCl 3 ) = 180.3, 52.8, 25.4. 19 F NMR (282MHz, CDCl 3 ) = 138.95 (q, J = 45 Hz). Anal Calcd for C 9 H 16 N 2 BF 3 : C, 49.13; H, 7.33; N, 12.73. Found: C, 49.374; H, 7.528; N, 12.591.

PAGE 97

97 General Procedure f or 1,4 Conjugate Addition 3 Phenyl Cyclohexanone. To a flame dried Schlenk flask under argon, 126 mg (1.04 mmol) of phenyl boronic acid, 29 mg (0.52 mmol) of potassium hydroxide, and 2 mg (0.0052 mmol) of rhodium catalyst 3 5 were added. 1 mL of THF an d 0.1 mL of water was added, and to the reaction mixture, 50 mg (0.52 mmol) of cyclohexenone was added. The solution was heated to 40 C. The mixture was stirred for thirty minutes and monitored by TLC (R f 0.63, 2:1 hexanes/ethyl acetate). The solution was diluted with 10 mL of diethyl ether and washed twice with a 10% aqueous solution of NaOH. The organic layer was dried and concentrated, and then purified by silica gel chromatography (4:1 hexanes/ethyl acetate) to isolate the product as a clear oil in 98% yield. Spectroscopic values matched those reported in the literature. 48 1 H NMR (300MHz, CDCl 3 ) = 7.39 7.28 (m, 2 H), 7.28 7.15 (m, 3 H), 3.12 2.89 (m, 1 H), 2.66 2.26 (m, 4 H), 2.25 1.99 (m, 2 H), 1.95 1.65 (m, 2 H). 13 C NMR (75MHz, CDCl 3 ) = 211.3, 144.6, 128.9, 126.9, 126.8, 49.2, 45.0, 41.4, 33.0, 25.8. 3 (p Tolyl) Cyclohexanone. Spectroscopic values matched those reported in the literature. 4 1 H NMR (300MHz, CDCl 3 ) = 7.27 7.01 (m, 4 H), 3.16 2.86 (m, 1 H), 2.69 2.39 (m, 4 H), 2.35 (s, 4 H), 2.23 2.02 (m, 2 H), 1.93 1.68 (m, 2 H). 13 C NMR (75MHz, CDCl 3 ) = 211.3, 141 .7, 136.4, 129.6, 126.7, 49.3, 44.6, 41.4, 33.1, 25.8, 21.2.

PAGE 98

98 3 ( p Anisoyl) Cyclohexanone. Spectroscopic values matched those reported in the literature. 4 1 H NMR (300MHz, CDCl 3 ) = 7.22 7.04 (d, J = 7.6 Hz, 2 H), 6.96 6.75 (d, J = 7.6 Hz, 2 H), 3.7 7 (s, 3 H), 3.06 2.81 (m, 1 H), 2.64 2.24 (m, 4 H), 2.22 1.93 (m, 2 H), 1.91 1.61 (m, 2 H). 13 C NMR (75MHz, CDCl 3 ) = 211.4, 158.5, 136.8, 127.7, 114.2, 55.5, 49.4, 44.2, 41.4, 33.2, 25.7. 3 ( p Fluorophenyl) Cyclohexanone. Spectroscopic values matched those reported in the literature. 4 1 H NMR (300MHz, CDCl 3 ) = 7.25 7.06 (m, 2 H), 6.97 (t, J = 8.2 Hz, 2 H), 3.08 2.86 (m, 1 H), 2.63 2.24 (m, 4 H), 2.21 1.93 (m, 2 H), 1.90 1.66 (m, 2 H). 13 C NMR (75MHz, CDCl 3 ) = 210.9, 163.3, 160.1, 140.3, 128.3, 128.2, 115.7, 115.5, 49.2, 44.2, 41.3, 33.1, 25.6. 3 (1 Naphthyl) Cyclohexanone. Spectroscopic values matched those reported in the literature. 49 1 H NMR (300MHz, CDCl 3 ) = 8.05 (d, J = 7.9 Hz, 1 H), 7.88 (d, J = 7.6 Hz, 1 H), 7.77 (d, J = 7.9 Hz, 1 H), 7.63 7.30 (m, 4 H), 3.86 (t, J = 11.1 Hz, 1 H), 2.82 2.73 (m, 1 H), 2.71 2.40 (m, 3 H), 2.36 2.10 (m, 2 H), 1.98 (t, J = 10.8 Hz, 2 H). 13 C NMR (75MHz, CDCl 3 )

PAGE 99

99 = 211.5, 140.3, 134.2, 131.1, 129.3, 127.5, 126.5, 125.9, 125.8, 123.0, 122.7, 48.8, 41.7, 39.6, 32.5, 25.8. 3 (o Tolyl) Cyclohexanone. Spectroscopic values matched those reported in the literature. 50 1 H NMR (300MHz, CDCl 3 ) = 7.43 7.03 (m, 4 H), 3.23 (d, J = 8.8 Hz, 1 H), 2.61 2.36 (m, 4 H), 2.34 (s, 3 H), 2.18 (td, J = 2.5, 6.5 Hz, 1 H), 2.09 1.95 (m, 1 H), 1.93 1.73 (m, 2 H). 13 C NMR (75MHz, CDCl 3 ) = 211.4, 142.6, 135.3, 130.9, 126.7, 126.6, 125.3, 48.6, 41.5, 40.5, 32.2, 26.0, 19.5. General Procedure for Formation of Biaryl Methanols 2 Methoxyphenyl Phenyl m ethanol To a flame dried Schlenk flask under argon, 50 mg (0.364 mmol) of o anisaldehyde, 89 mg (0.728 mmol) of phenyl boronic acid, 83 mg (0.728 mmol) of potassium tert butoxide, and 2 mg (0.0052 mmol) of rhodium catalyst 3 5 were added. 1.22 mL of DME and 0.33 mL of water were added, and the solution was heated to 40 C. The mixture was stirred for one hour and monitored by TLC (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 e xtracted three times. The organic layer was dried and concentrated, and then purified by silica gel chromatography (8:1 hexanes/ethyl acetate) to isolate the product as a clear oil in 92% yield. Spectroscopic values matched those reported in the literatu re. 51 1 H NMR (300MHz, CDCl 3 ) = 7.49 7.11 (m, 8 H), 7.07 6.82 (m, 2 H), 6.07 (s, 1 H), 3.78 (s, 3 H), 3.32 (br. s., 1 H). 13 C

PAGE 100

100 NMR (75MHz, CDCl 3 ) = 156.9, 143.5, 132.2, 129.7, 129.0, 128.4, 128.1, 127.4, 126.8, 121.1, 115.6, 111.0, 72.4, 55.7. HRMS Calcd. for C 14 H 13 O [M OH ] + : 197.0989 Found: 197.0994 2 Methoxyphenyl Naphthalen 1 yl M ethanol 1 H NMR (299MHz, CDCl 3 ) = 8.05 (d, J = 7.4 Hz, 1 H), 7.96 7.79 (m, 2 H), 7.71 (d, J = 7.1 Hz, 1 H), 7.60 7.39 (m, 3 H), 7.37 7.22 (m, 1 H), 7.11 6.78 (m, 4 H), 3.91 (s, 3 H), 3.22 (br. s., 1 H). 13 C NMR (75MHz, 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 Calcd. for C 18 H 15 O [M OH ] + : 247.1177 Found: 247.1176 2 Methoxyphenyl o Tolyl M et hanol 1 H NMR (299MHz, CDCl 3 ) = 7.66 7.46 (m, 1 H), 7.43 7.13 (m, 4 H), 7.12 6.83 (m, 3 H), 6.32 (s, 1 H), 3.88 (s, 3 H), 3.00 (br. s., 1 H), 2.27 (s, 3 H). 13 C NMR (75MHz, CDCl 3 ) = 157.3, 140.8, 135.8, 131.5, 130.4, 129.1, 128.1, 127.5, 126.8, 126.2, 121.0, 110.7, 68.5, 55.7, 19.5. HRMS Calcd. for C 15 H 15 O [M OH ] + : 211.1176 Found: 211.1185 2 Methoxyphenyl 4 Methoxyphenyl M ethanol. 1 H NMR (300MH z, CDCl 3 ) = 7.60 7.17 (m, 4 H), 7.11 6.73 (m, 4 H), 6.05 (s, 1 H), 3.79 (s, 6 H), 3.30 (br. s., 1 H) 13 C NMR (75MHz, CDCl 3 ) = 159.0, 156.9, 136.0, 132.6, 128.8, 128.1, 127.8, 121.0, 113.8, 111.0, 71.7, 55.6, 55.5. HRMS Calcd. for C 15 H 14 O 2 [M OH ] + : 226.0994 Found: 226.0987

PAGE 101

101 4 Fluorophenyl 2 Methoxyphenyl M ethanol 1 H NMR (300MHz, CDCl 3 ) = 7.55 7.19 (m, 4 H), 7.13 6.79 (m, 4 H), 6.03 (br. s., 1 H), 3.80 (s, 3 H), 3.27 (br. s., 1 H). 13 C NMR (75MHz, CDCl 3 ) = 163.8, 160.6, 156.8, 139.4, 139.4, 132.1, 129.1, 128.5, 128.4, 127.8, 121.1, 115.3, 115.0, 111.0, 71.7, 55.6. HRMS Calcd. fo r C 14 H 13 O 2 F [M ] + : 232.0900 Found: 232.0886 2 Chlorophenyl Phenyl M ethanol Spectroscopic values matched those reported in the literature. 1 H NMR (299MHz, CDCl 3 ) = 7.62 (dd, J = 1.4, 7.6 Hz, 1 H), 7.51 7.11 (m, 8 H), 6.37 6.05 (m, 1 H), 2.88 2 .58 (m, 1 H). 13 C NMR (75MHz, CDCl 3 ) = 142.5, 141.3, 132.7, 129.8, 129.0, 128.7, 128.3, 128.0, 127.4, 127.2, 72.9. HRMS Calcd. for C 13 H 10 Cl [M OH ] + : 201.0446 Found: 201.0472 4 Fluorophenyl Phenyl M ethanol Spectroscopic values matched those report ed in the literature. 52 1 H NMR (300MHz, CDCl 3 ) = 7.45 7.18 (m, 7 H), 7.09 6.85 (m, 2 H), 5.74 (s, 1 H), 2.63 (br. s., 1 H). 13 C NMR (75MHz, CDCl 3 ) = 164.0, 160.7, 143.8, 139.8, 139.7, 130.1, 128.8, 128.6, 128.5, 128.4, 127.9, 126.7, 115.6, 115.3, 75.8. HRMS Calcd. for C 13 H 9 F [M OH ] + : 185.0761 Found: 185.0772

PAGE 102

102 3,5 B is (Trifluoromethyl)phenyl Phenyl M ethanol 1 H NMR (300MHz, CDCl 3 ) = 7.87 (s, 2 H), 7.79 (s, 1 H), 7.55 7.19 (m, 5 H), 5.91 (s, 1 H), 2.50 (br. s., 1 H). 13 C NMR (75MHz, CDCl 3 ) = 146.3, 142.6, 132.1, 131.7, 129.3, 128.8, 126.9, 126.7, 121.7, 121.6, 75.5. HRMS Calcd. for C 15 H 10 F 6 [M ] + : 320.0636 Found: 320.0623 NMR of Carbene Intermediate The carbene was generated at 78 C, in THF d 8 and analyzed by NMR spectroscopy at 30 C. First, gHMBC, gHMQC and gDQCOSY experiments were run in about 30 minutes, t o quickly characterize the carbe ne, presumed unstable. The carbene carbon, at 232.9 ppm, displayed couplings in the gHMBC spectrum with two protons, at 3.47 and 3.66 ppm, both t riplets. The gDQCOSY spec trum revealed the sequence 3.47 1.89 1.7 6 3.66. The carbons car ry ing these protons were detected in the gHMQC spectr um at 48.4, 26.5, 24.5 and 55.8 correspondingly. The non equivalence of the alpha positions in the tetrahydropyrro le moiety indicates res tricted rotation about the carbe ne carbon nitrogen bond. NMR spectra were recorded on a Varian Inova spectrometer, operating at 500 MHz for 1 H and 125 MHz for 13 C, and equipped with a 5 mm indirect detection probe, with z axis gra dients. The 1 H and 13 C chemical shifts were referenced to internal tetramethylsilane. The solvent was THF d 8 and the temperature 30 C. The gHMBC experiment was run with the standard vnmr pulse sequence. 2048 points were acquired in f2, on a spectral wi ndow from 0.1 to 4.3 ppm. The acquisition time was 0.49 s, with a relaxation delay of 0.5 s. 512 increments were

PAGE 103

103 acquired in f1, for a spectral window from 0 to 300 ppm, in 1 transient per increment. The total experiment time was 9 minutes. The gHMQC exper iment was run with the standard vnmr pulse sequence. 1024 points were acquired in f2, on a spectral window from 0.5 to 4.0 ppm. The acquisition time was 0.29 s, with a relaxation delay of 1 s. 256 increments were acquired in f1, for a spectral window from 10 to 80 ppm, in 1 transient per increment. The total experiment time was 6 minutes. The gDQCOSY experiment was run with the standard vnmr pulse sequence. 2048 points were acquired in f2, on a spectral window from 0.64 to 3.64 ppm. The acquisition time wa s 0.64 s, with a relaxation delay of 1 s. 512 increments were acquired in f1, in 1 transient per increment. The total experiment time was 16 minutes.

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104 LIST OF REFERENCES 1 ) (a) Angew. Chem. Int. Ed 2007 46 2768 2813. (b) Clavier, H.; Nolan, S. P. Annu. Rep. Prog. Chem. 2007, 103, 193 222. (c) Glorius, F. Top. Organomet. Chem. 2007, 21, 1 20. (d) Nolan, S. P., Ed. N heterocyclic Carbenes in Synthesis ; Wiley VCH: Weinheim, Germ an y, 2006. (e) Garrison, J. C.; You ngs, W. J. Chem. Rev 2005 105 3978 4008. (f) P eris, E. V.; Crabtree, R. H. Coord. Chem. Rev. 2004 248 2239 2246. (g) Crudden, C. M.; Allen, D. P. Coord. Chem. Rev. 2004 248 2247 2273. (h) Herrmann, W. A. Angew. Chem. Int. Ed 2002 41 1290 1309. (i) Carbene Chemistry, from F leeting I ntermediates to P owerful R eagents ; Bertrand, G. Ed.; Marcel Denker: New York, 2002, 153 230. (j) Bourissou, D.; Guerret, O.; Gabbai, F. P.; Bertrand, G. Chem. Rev. 2000 100 39 91. (k) Arduengo, A. J. III Acc. Chem. Res 1999 32 913 921. (l) Arduengo A. J. III ; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991 113 361 363. 2 ) Green, J. C.; Scur, R. G.; Arnold, P. L.; Cloke, G. N. Chem. Commun. 1997 1963 1964. 3 ) (a) Diez Gonzalez, S.; Nolan, S. P. Coord. Chem. Rev 2007 251, 874 883. (b) Crabtree, R. H. J. Organomet. Chem. 2005 690 5451 5457. (c) Alder, R. W.; Blake, M. E.; Chaker, L.; Harvey, J. N.; Pao lini, F.; Schtz, J. Angew. Chem. Int. Ed 2004 43 5896 5911. 4 ) (a) Rogers, M. M.; Stahl, S. S. Top. Organomet. Chem. 2007, 21, 21 46. (b) Chianese, A. R.; Kovacevic, A.; Zeglis, B. M.; Faller, J. W.; Crabtree, R. H. Organometallics 2004 23 2461 246 8. (c) Chianese, A. R.; Li, X.; Janzen, M. C.; Faller, J. W.; Crabtree, R. H. Organometallics 2003 22 1663 1667. 5 ) (a) Trnka, T. M.; Morgan, J. P.; Sanford, M. S.; Wilhelm, T. E.; Scholl, M.; Choi, T. L.; Ding, S.; Day, M. W.; Grubbs, R. H. J. Am. C hem. Soc. 2003 125 2546 2558. (b) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001 123 6543 6549. 6 ) (a) Grey, G. D.; Herdtweck, E.; Herrmann, W. A. J. Organomet. Chem. 2006, 691, 2465 2478. (b) Frey, G. D.; Herrmann, W. A. J. Orga nomet. Chem. 2005, 690 5876 5880. (c) Alder, R. W.; Blake, M. E.; Chaker, L.; Harvey, J. N.; Paolini, F.; Schatz, J. Angew. Chem.,Int. Ed. 2004, 43, 5896 5911. (d) Herrmann, W. A.; Ofele, K.; Preysing, D.; Herdtweck, E. J. Organomet. Chem. 2003, 684, 235 248. (e) Alder, R. W.; Blake, M. E.; Bufali, S.; Butts, C. P.; Orpen, A. G.; Schutz, J.; Williams, S. J. J. Chem Soc., Perkin Trans. 1, 2001, 1586 1593. (f) Alder, R. W.; Allen, P. R.; Murray, M.; and Orpen, A. G. Angew. Chem., Int. Ed. 1996, 35 1121 1 123. 7 ) (a) Wanniarachchi, Y. A.; Slaughter, L. M. Chem. Commun. 2007, 3294 3296. (b) Dhudshia, B.; Thadani, A. N. Chem. Commun. 2006, 668 670. (c) Kremzow, D.; Seidel, G.; Lehmann, C. W.; Frstner, A. Chem. Eur. J. 2005 11, 1833 1853 (d) Frstner, A.; Seidel, G.; Kremzow, D.; Lehmann, C. W. Organometallics 2003, 22, 907 909.

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108 4 4 ) Iyer, S.; Jayanthi, A. Synlett 2003, 8, 1125 11 28. 4 5 ) (a) Leuthu er, S.; Schwarz, D.; Plenio, H. Chem. Eur. J. 2007, 13, 7195 7203. (b) S ner, M.; Plenio, H. Angew. Chem., I nt. Ed. 2005, 44, 6885 6888. (c) S ner, M.; Plenio, H. Chem. Commun. 2005, 5417 5419. 4 6 ) (a) Poater, A.; Cosenza, B.; Correa, A.; Giudice, S.; Ragone, F.; Scarano, V.; Cavallo, L. Eur. J. Inorg. Chem. 2009, 1759 1766. (b) http://www.molnac.unisa.it/OMtools.php (c) Kelly, R. A., III; Clavier, H.; Giudice, S.; Scott, N. M.; Stevens, E. D.; Bordner, J.; Samardjiev, I.; Hof f, C. D.; Cavallo, L.; Nolan, S. P. Organometallics 2008, 27, 202 210. (d) Dorta, R.; Stevens, E. D.; Scott, N. M.; Costabile, C.; Cavallo, L.; Hoff, C. D.; Nolan, S. P. J. Am. Chem. Soc. 2005, 127, 2485 2495. (e) Hillier, A. C.; Sommer, W. J.; Yong, B. S.; Petersen, J. L.; Cavallo, L.; Nolan, S. P. Organometallics 2003, 22, 4322 4326. 4 7 ) Yang, D.; Chen, Y.; Zhu, N. Org. Lett. 2004, 6, 1577 1580. 4 8 ) Lu, X.; Lin, S. J. Org. Chem. 2005, 70, 9651 9653. 4 9 ) Cho, C. S.; Motofusa, S.; Ohe, K.; Uemura, S .; Sang, C. J. Org. Chem. 1995, 60, 883 888. 5 0 ) Hayashi, T.; Tokunaga, N.; Yoshida, K.; Han, J. W. J. Am. Chem. Soc. 2002, 124, 12102 12103. 5 1 ) Kuriyama, M.; Shimazawa, R.; Enomota, T.; Shirai, R. J. Org. Chem. 2008, 73, 6939 6942. 5 2 ) Trindade A. F.; Gois, P. M. P.; Veiros, L. F.; Andre, V.; Duarte, M. T.; Afonso, C. A. M.; Caddick, S.; Cloke, F. G. N.. J. Org. Chem. 2008, 73, 4076 4086.

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109 BIOGRAPHICAL SKETCH David Snead was born in Charlotte, North Carolina on December 31st of 1982, and gre w Hale Episcopal High School in 2001, he attended the University of North Carolina at Chapel Hill where he majored in chemistry. Upon graduation, David married Stephanie Leigh Elder on Ma y 21st of 2005. David went on to pursue his PhD in organic chemistry at the University of Florida under the supervision of Dr. Sukwon Hong, and w ill pursue postdoctoral opportunities at MIT and Argonne National Laboratories in hopes of attaining a research professorship