Difluoroboronate Urea-Induced Acid Amplification for Insertion Chemistry

A Thesis

Presented in Partial Fulfillment of the Requirements for the degree of Master of Science in the Graduate School of The Ohio State University

By

Erica Dawn Couch, B. S.

Graduate Program in Chemistry

The Ohio State University

2014

Committee:

Professor Anita E. Mattson (Advisor)

Professor Claudia Turro

Copyright by

Erica Dawn Couch

2014

Abstract

Development of a new enhanced boronate urea that benefits from internal coordination of the urea carbonyl to a strategically placed Lewis acid has enabled a new direction in hydrogen bond donor (HBD) catalysis. Activation of α-nitrodiazocarbonyl compounds has elicited carbene- like reactivity, allowing for access to metal-free insertion reactions. Recent developments have utilized the difluroboronate urea with an organic acid cocatalytically to promote insertion reaction with aryldiazoacetates. These reactions are proposed to occur through a HBD induced heteroatom acidity amplification, facilitating protonation of the α-aryldiazoacetates, which can undergo a nucleophilic attack by the conjugate base. Understanding of the insertion mechanism has led to asymmetric cocatalytic variations of the insertion reactions utilizing both chiral acids with achiral

HBD catalyst and chiral HBD catalyst with an achiral acid. Work towards an asymmetric reaction has illuminated the one lacking feature of the boronate catalyst: its ability to achieve enantioselectivity, which has been an ongoing problem to advancements with these catalysts.

Herein, development of a new chiral catalyst design and a new metal-free approach to a selective insertion reaction are discussed.

! ii! ! Dedication

I would like to dedicate this work to my family. “Although we may not have it all together,

together we have it all.”

! iii! ! Acknowledgements

I would first like to thank my advisor, Anita Mattson, for affording me the opportunity to work in her lab. Her guidance and support has allowed me to accomplish more than I would have ever expected to in my short time here at The Ohio State University. I would also like to thank all of the other faculty and staff here at The Ohio State University, especially Professors Claudia

Turro for her help and guidance towards accomplishing my degree and James Stambuli for always being available to help and to humor.

I would like to thank my undergraduate advisor, LuAnne McNulty, for her constant advice in what to do next, whether it is in chemistry or in life, as well as my undergraduate department chair, Stacey O’Reilly, for her positivity that she was able to instill in me and several others throughout our undergraduate careers. I would also like to thank my high school chemistry teacher and softball coach, Dick “Doc” Hines, for never holding me back from being me, whether it was in a classroom or on the field.

Throughout my time at Ohio State, I have met several people who mean more to me than they will ever know. I first and foremost have to thank Tyler Auvil for all of his patience and guidance in training me and working with me on pretty much every project I ever touched during my time here. You have made me the chemist and person that I am today, and I don’t think that I will ever be able to repay for making my time here worth it. I would also like to thank Sonia So for being the best friend I could have asked for in grad school. I don’t know what I would have done in lab without our laughs, talks, and awkward run-ins! I am so happy that the majority of

! iv! ! my time overlapped with yours so that we were able to spend as much time together as we did, in the least creepy way possible. Josh Wieting for his entertainment in the lab, and his and his wife’s friendship outside of lab, “eat the brat, eat the brat!” Chi “Chip” Li for being an inspiration to work harder no matter what is going on around you, I didn’t expect for our friendship to grow as much as it did but I am happy to know that I will always have you to call.

Veronica for always being willing to run, and my first summer here, I will never forget it! Mike

“Moke” Visco just for always being here, you seriously are my new little brother and it’s goingt to be weird to walk around a room without having to walk around you. As well as several other really good friends I have met at my time here including: Luke “Lil Moke” McCroskey, Andrew

“Angrew” Schafer, Dr. Tom Fisher, Kelsey Miles, the Forsyth group lunch boys, Joe “Bro”

Castle, Greg Abernathy, Daniel Miller and several others.

Lastly, I would like to thank my family and friends for all of their love and support. My best friend, Danielle Wright, for being a friend at anytime of the day and night even if it took me months to call! My grandparents, especially my grandmas “mamaw” and “mammie” for always pushing me to be a better woman and for living as an example of what it meant to be better woman. I would like to thank my brothers for being them and being there they don’t know what they mean to me. My sister, Kristen, who even when I wished she was dead, I was praying that nothing would ever happen to her. I love you and I am happy we have become as good of friends as we have. Most importantly, however, I have to thank my parents. My dad for never hesitating to be there when I called and for always keeping me as his little girl, and my mom for not only being my biggest fan, but for being the bestest friend I will ever have.

! v! ! Vita

May 2008…………………………………………………………………... Anderson High School

May 2012………………………………………………………. B.S. Chemistry, Butler University

2012 to present……………………….… Graduate Research Assistant, The Ohio State University

Publications

Couch, E. D.; Auvil, T. J.; Mattson, A. E. “Urea-Induced Acid Amplification: A New Approach for Metal-Free Insertion Chemistry” Chem. Eur. J. 2014, 20, 8283 – 8287.

Field of study:

Chemistry

! vi! ! Table of Contents

Abstract ...... ii

Dedication ...... iii

Acknowledgements ...... iv

Vita ...... vi

List of Tables ...... x

List of Figures ...... xi

List of Schemes ...... xii

Chapter 1: Chiral Hydrogen Bond Donor Design and Development ...... 1

1.1 (Thio)urea Hydrogen Bond Donor Catalysts History ...... 2

1.1.1 Molecular Recognition ...... 2

1.1.2 History of Dual HBD Catalysis ...... 4

1.1.3 Chiral (thio)urea catalysis ...... 7

1.2 Design Strategies for Enhance Dual HBD Catalysts ...... 12

1.2.1 3,5-bis(trifluoromethylphenyl) Moiety in HBD Catalysis ...... 12

1.2.2 Chiral Acidifying Groups ...... 14

1.2.3 Internal Brønsted Acid Assistance ...... 17

1.2.4 Preorganizing and Acidifying Linkers ...... 19

1.3 Internal Lewis Acid-Assisted Dual HBD Catalysis: Boronate Ureas ...... 22

1.3.1 Catalytic Design Background ...... 22

! vii! ! 1.3.2 Catalytic Reactivity ...... 25

1.3.3 Catalyst Acidity ...... 33

1.4 Design Strategies for Enhance Internal Lewis Acid-Assisted Dual HBD Catalysis: Boronate

Ureas ...... 36

1.4.1 Strategies ...... 36

1.4.2 Synthesis ...... 38

1.4.3 New Avenues ...... 40

1.5 Experimental Section ...... 42

1.5.1 Preparation of Model Catalyst ...... 45

1.5.2 Prepartion of Oxazoline Containing Catalyst ...... 46

Chapter 2: Organocatalytic Acidity Amplification as a Strategy for Insertion Chemistry ...... 49

2.1 Heteroatom–Hydrogen Insertions by α-Diazocarbonyl Compounds ...... 50

2.1.1 Synthesis of Diazo Compounds ...... 50

2.1.2 X–H Insertion Reactions of Diazo Compounds ...... 53

2.1.3 X–H Insertion Mechanism ...... 57

2.2 Co-catalytic Reaction Strategies ...... 60

2.2.1 Phosphoric acid catalyzed reactions ...... 60

2.2.2 HBDs can increase acidity of Phosphoric acid-derived catalyst ...... 63

2.2.3 (Thio)urea-Brønsted Acid Co-catalytic Systems ...... 64

2.3 Difluoroboronate Ureas Catalyzed Insertion Reactions ...... 70

2.3.1 Introduction to a new approach to metal-free insertion reactions ...... 70

! viii! ! 2.3.2 HBD Catalyst Screen for the Organocatalytic X–H Insertion ...... 71

2.3.3 Organocatalytic X–H insertion optimization and substrate scope ...... 74

2.3.4 Plausible Mechanisms and Mechanistic Studies/Support ...... 75

2.3.5 New Avenue for Enantioselective X–H Insertion Reactions ...... 82

2.4 Experimental Section ...... 88

2.4.1 Standard Procedure for the Preparation of Boronate Ureas ...... 88

2.4.1.1 Standard Procedure for the Synthesis of Pinacol Boronate Ureas ...... 88

2.4.1.2 Standard Procedures for the Synthesis of Difluoroboronate Ureas ...... 89

2.4.1.3 Synthesis of Control Catalyst II-66 ...... 91

2.4.2 Synthesis of Novel α-Aryldiazoacetates ...... 93

2.4.3 General Procedure for the Organocatalytic O–H Insertion ...... 95

2.4.4 General Procedure for the Organocatalytic S–H Insertion ...... 102

2.5 Mechanistic Studies ...... 107

2.5.1 Evidence Against a Carbene Intermediate ...... 107

2.5.2 Evidence for X–H Bond Necessity ...... 108

2.5.3 Evidence Against Catalyst Deprotonation ...... 109

2.5.4 Synthesis of Chiral ortho-Borylbenzoic Acids ...... 113

2.5.4.1 Preparation of Sodium Borate ...... 113

2.5.4.2 General Procedure for the Preparation of Chiral ortho-Borylbenzoic Acids .... 114

References ...... 116

! ix! ! List of Tables

Table 2.1. Various aldehydes undergo a cocatalyzed one-pot Pictet-Spengler ...... 65

Table 2.2. Catalyst optimization screen ...... 73

Table 2.3. Solvent screen for X–H insertion reactions ...... 74

Table 2.4. Substrate scope for O–H insertion reaction ...... 76

Table 2.5 Substrate scope for S–H insertion reaction ...... 77

Table 2.6. Aryl-diazo compound scope for X–H insertion reactions ...... 78

Table 2.7. Cocatalyst screening optimization ...... 86

Table 2.8 Cocatalytic optimization for enantioselectivity ...... 87

! x! ! List of Figures

Figure 1.1. Early examples of hydrogen bond donors in molecular recognition ...... 3

Figure 1.2. Development of HBD catalysts ...... 13

Figure 1.3. Sulfinyl vs. common (thio)urea pKa values ...... 15

Figure 1.4. New acidifying linker catalyst design ...... 19

Figure 1.5 HBD catalyst structure related to its function ...... 23

Figure 1.6. New enhanced HBD catalyst design ...... 24

Figure 1.7. Popular (thio)urea pKa’s in DMSO ...... 33

Figure 1.8. Addition of CF3 group decreases the pKa ...... 34

Figure 1.9. Chiral catalyst design ...... 36

Figure 1.10. Chiral boronate urea catalyst targets ...... 37

Figure 2.1. HBD acidity amplification of biphenyl-2,2’-diol phosphoric acid ...... 63

! xi! ! List of Schemes

Scheme 1.1. Hine’s proposed HBD activation of glycolic epoxide ...... 5

Scheme 1.2. Kelly’s dual HBD catalyst promote Diels Alder reactions ...... 5

Scheme 1.3. Curran’s HBD promote Claisen rearrangements ...... 6

Scheme 1.4. Substituent effects of the thiourea increases reate of Diels-Alder reaction ...... 7

Scheme 1.5. Jacobsen’s (thio)urea design promotes asymmetric Strecker reactions ...... 8

Scheme 1.6. Takemoto’s thiourea promotes asymmetric conjugate addition of malonates to nitro olefins ...... 9

Scheme 1.7. Ricci’s thiourea promotion of the asymmetric conjugation of indole to nitroolefins 10

Scheme 1.8. Cinchona alkaloid derived catalyst promote enatioselective nitro-Michael addition 11

Scheme 1.9. (Thio)urea promoted asymmetric conjugate addition ...... 12

Scheme 1.10. Schreiner’s thiourea catalyzed Diesl-Alder reaction ...... 13

Scheme 1.11. Intramolecular N–H interaction prevents catalytic process ...... 15

Scheme 1.12. N-sulfinyl(thio)urea catalyzed Aza-Henry reactions reported by Ellman ...... 16

Scheme 1.13. Enhanced thiourea activation of the conjugate addition reaction ...... 17

Scheme 1.14. Quinolinium thioamide catalyst promotes addition of indoles to nitroalkenes ...... 18

Scheme 1.15. HBD catalyzed Mukaiyama-Mannich reaction ...... 19

Scheme 1.16. Synthesis of new quinazolines and benzothiadiazines HBD catalysts ...... 20

Scheme 1.17. Catalyst comparison in the hydrazination of α-ketoester ...... 21

Scheme 1.18. Aminobenzimidazole HBD promote conjugate addition reactions ...... 22

! xii! ! Scheme 1.19. Synthesis of enhanced HBD catalyst ...... 25

Scheme 1.20 Enhanced HBD catalyst promote the conjugate addition ...... 26

Scheme 1.21 Enhanced HBDs catalyze ring-opening of nitrocyclopropane carboxylates ...... 27

Scheme 1.22 Enhanced HBD catalyze formal [3+3] cycloaddition reactions ...... 28

Scheme 1.23 Proposed urea activation of nitro diazo compounds ...... 28

Scheme 1.24. HBD activiation of nitro diazo compounds for multicomponent coupling reactions29

Scheme1.25. Proposed catalytic cycle of multicomponent coupling reactions ...... 30

Scheme 1.26. Plausible catalytic cycle for the unsymmetric double arylation of nitrodiazoesters 32

Scheme 1.27 Lewis acid containing HBDs catalyze nitrodiazo ester and nitrocyclopropanes ..... 35

Scheme 1.28. Proposed synthesis of chiral boronate urea catalyst ...... 38

Scheme 1.29 Preparation of new chiral test catalyst ...... 38

Scheme 1.30. Proof of concept ...... 39

Scheme 1.31. Preparation of a chiral catalyst ...... 40

Scheme 1.32. Plausible design strategy to new chiral ureas ...... 41

Scheme 1.33 New avenue for chiral boronate ureas ...... 42

Scheme 2.1. First synthesized diazo compound and strategies towards accessing diazo compounds ...... 51

Scheme 2.2. Diazo group transfer examples ...... 52

Scheme 2.3. Metal-free example for dehydrogenation of hydrazine to diazo compound ...... 53

Scheme 2.4. Early example of X–H insertion reactions ...... 53

Scheme 2.5. Recent asymmetric N–H insertion reactions ...... 54

! xiii! ! Scheme 2.6. Zhou and coworkers demonstrate an asymmetric S–H insertion reaction ...... 55

Scheme 2.7. Further advancements in S–H insertion by the Zhou group ...... 56

Scheme 2.8. Fu’s work on asymmetric O–H insertion reactions ...... 56

Scheme 2.9. Zhou’s asymmetric O–H insetion into phenols ...... 57

Scheme 2.10. Commonly accepted X–H insertion mechanisms ...... 58

Scheme 2.11. Metal-free O–H insertion reaction ...... 59

Scheme 2.12 Propsed nitro diazo compound insertion mechanism ...... 60

Scheme 2.13. Akiyama’s proposal to achieve enantioselectivity using chiral phosphoric acids .. 61

Scheme 2.14. Chiral substituted phosphoric acid effects on rates, yields and enantioselectivity .. 62

Scheme 2.15. Chiral phosphoric acid substituents affect enantioselectivity ...... 62

Scheme 2.16. Cocatalytic asymmetric Pictet-Spengler ...... 64

Scheme 2.17. Proposed cocatalytic cycle of Pictet-Spengler reaction ...... 66

Scheme 2.18. Cocatalytic Povarov reaction ...... 67

Scheme 2.19. Ion-pairing studies with HBD catalyst ...... 68

Scheme 2.20. Bound cocatalytic ion pair possibilities ...... 68

Scheme 2.21. Optimal cocatalytic system for Povarov reaction ...... 69

Scheme 2.22. Covalently linked HBD activated Brønsted acid catalysed Pictet-Spengler ...... 70

Scheme 2.23. Previous HBD amplified insertion reaction and new HBD reaction ...... 70

Scheme 2.24. Potentail HBD catalysed X–H insertion mechanism ...... 71

Scheme 2.25. X–H insertion catalytic pathway ...... 80

Scheme 2.26. Evidence against the formation of a free carbene ...... 81

! xiv! ! Scheme 2.27. Evidence to which species is responsible for protonation ...... 82

Scheme 2.28 Plan for promoting chiral insertion reactions ...... 83

Scheme 2.29. Enhanced single HBD catalyst ...... 83

Scheme 2.30. Boronate ester assisted chiral carboxylic acids catalyze asymmetric trans- aziridinations ...... 84

Scheme 2.31. Synthesis of chiral boronate acids ...... 85

! xv! ! Chapter 1: Chiral Difluoroboronate Urea Design and Development

! 1! ! 1.1 (Thio)urea Hydrogen Bond Donor Catalysts History

Hydrogen bond donor (HBD) catalysts are becoming useful tools in the synthesis of vital synthetic building blocks.[1] Urea and thiourea scaffolds have become a family of particularly effective HBD catalysts. Despite its promise, the field of (thio)urea catalysis is being held back by significant challenges, including high catalyst loadings and limited reactivity patterns. To overcome these challenges, many advancements have been made to optimize the catalyst structure and performance.[1] Major tactics to improve catalyst reactivity have been made through augmentation of the HBD moiety’s acidity and stereocontrolling elements

1.1.1 Molecular Recognition

Inspiration for (thio)ureas as HBD catalysts can be found in early studies of diarylureas

(DAUs), which demonstrated a unique ability to recognize Lewis basic sites on guest molecules.

First used by Hart and coworkers to form clathrates, ditrityl ureas hydrogen bonded with an array of guest molecules containing amines, amides, alcohols, esters and other small hydrogen bond accepting functional groups. [2] A few years later, Etter and coworkers[3] exhibited the same type of co-crystallization with 1,3-bis(m-nitrophenyl)urea and a variety of function groups such as ethers, ketones, alcohols, sulfoxides, phosphine oxides, nitriles, and nitro groups (Figure 1.1).

! 2! ! Hart 1986

O O O O

(Ph)3C CPh3 Ph3C CPh3 Ph3C CPh3 Ph3C CPh3 N N N N N N N N H H H H H H H H O O Me N Me Me O H Me Me H Me N OMe H

Etter 1988

NO2 NO2 NO2 NO2 NO2 NO2 NO2 I-1 NO2 H O O O O

N N N N N N N N H H H H H H H H

O O N O O N S C Me Me Me

NMe2

Figure 1.1: Early examples of hydrogen bond donors in molecular recognition

Etter and coworkers were able to utilize IR spectroscopy and NMR spectroscopy to continue their investigation into urea-guest molecule recognition.[4] It was discovered that many ureas were unable to bind to guest molecules or were only able to bind to strong proton acceptor guest molecules. Lack of guest molecule recognition can be attributed to the self-aggregating abilities of the urea between the hydrogen bond accepting carbonyl oxygen (C=O) and the urea protons. Ureas capable of cocrystallizing with weak proton acceptors were found to only be ones substituted with electron-withdrawing groups in the meta position, like 1,3-bis(m-nitrophenyl) urea (I-1, Figure 1.1). Steric and pKa arguments were not enough to explain the lack of self- aggregation observed with meta substituted ureas. More strategically substituted rings and more acidic substituted ureas were found to not be as good of host molecules as the meta substituted ! 3! ! derivatives. Using the atom distances in the crystal lattice structures, it was discovered that m- withdrawing substituents prevent self-aggregation due to an intramolecular CH---O interaction between the weakly acidic ortho-C–H on the substituted aromatic ring and the urea carbonyl oxygen (I-1, Figure 1.1). This interaction instigates a distinct polarization of the urea, causing it to take on a nearly planar conformation, preventing self-aggregation. From these initial discoveries, Hart and Etter laid fundamental groundwork enabling the development of ureas as molecular recognition catalysts.

1.1.2 History of Dual HBD Catalysis

The first demonstration of deliberate dual HBD catalysis was reported in 1985. In this pioneering report, Hine and coworkers compared the relative rates of different phenolic dual

HBD catalysts in the activation of a glycolic epoxide for nucleophilic attack by diethylamine

(Scheme 1.1). [5] Their examination of the catalysts revealed, as the acidity of the phenol increased, so did its activity. To help explain this observation, one can look at the mechanism.

Upon attack of I-3, the C–O bond in the epoxide is displaced, causing the oxygen to become more basic. The more acidic the hydrogen atoms on the catalyst are better suited to stabilize the negative charge buildup on the oxygen in the transition state I-6. Stabilization of the transition state lowers the energy of activation, which causes an increase in the rate of the reaction. Hine also observed phenols capable of forming two bonds simultaneously (1,8-biphenylene diol I-5) afforded a 12 times greater rate enhancement than those phenols which could only form a single bond.

! 4! ! Hine 1985

OH OH O OH O O I-5 H O NEt2 δ− Et2NH O o H O 30 C O I-2 I-3 I-4 I-5 δ+ NHEt2 I-6

Scheme 1.1. Hine’s proposed HBD activation of glycolic epoxide

Kelly and coworkers wanted to utilize the findings of Hine’s I-5 as an approach to promote Diels-Alder reactions.[6] Their desired catalyst was envisioned to be both rigid, with the installation of propyl groups at the 2- and 7- positions of I-5 and acidic. Addition of electron- withdrawing substituents at the 4- and 5- positions caused an increase in the acidity from 8.00 of

I-5 to his optimal catalyst I-7 6.21. Without the addition of I-7, Diels-Alder adduct I-10 was afforded in only a 3% yield. However, with the addition of 0.4 equivalents of I-7, a 90% yield of

I-10 was observed after only 10 minutes.

Kelly 1990

OH OH Me Me Me O 0.4 equiv. I-7 90% with cat 3% without ambient temp 10 min COCH3 NO2 NO2 I-8 I-9 I-10 I-7

Scheme 1.2. Kelly’s dual HBD catalyst promote Diels Alder reactions

! 5! ! Curran and coworkers used 1 equivalent of I-11 to increase the rate of a Claisen rearrangement.[7] As the amount of catalyst was increased from 0 to 1 equivalent, I-13 was formed up to 22.4 times faster. The proposed transition state I-14 offers an explanation for the acceleration of the reaction. Urea I-11 can hydrogen bond to the oxygen’s partial negative charge during the reaction, lowering the energy of the transition state.

Proposed CF3 CF3 Transition State

O

C8H17O2C N N CO2C8H17 H H Ar O I-11 N H N Ar O O O H cat. cat (eq) 0.0 0.2 0.5 1.0 C6D6 Krel 1.0 2.7 5.0 22.4 MeO OMe OMe I-12 I-13 I-14

Scheme 1.3. Curran’s HBD promote Claisen rearrangements

In 2003, Schreiner and Wittkopp[8] reverted back to Kelly’s Diels-Alder reaction model to examine the effect of the substituents on the diaryl(thio)urea scaffold. HBD’s react similarly to

Lewis acids in promoting Diels-Alder reactions. The (thio)urea coordinates to the lone pair on the dienophile, lowering LUMO energy, which in turn increases the reaction rate. Kelly’s studies suggested the relative rates of these reactions were more dependent on the urea substituents rather than the reactants or solvent. Examination of the (thio)urea scaffold proved important; finding that rigidity, acidity and polarity of the catalyst all affected the rate of the reaction.

The installation of electron-withdrawing substituents at the meta- or para-positions ! 6! ! minimized the flexibility of the catalyst, reducing the entropic penalty in the transition state and maximizing the rate of the reaction. Installation of fluorine at the meta position provided rate enhancements up to 4.1 times (Scheme 1.4, entry 2), while installation of trifluoromethyl group increased the rate 5.9 times (Scheme 1.4, entry 3). However, the largest rate enhancement, greater than 8-fold, was found using just 1 mol% of 3,5-bis-(trifluoromethyl)phenyl thiourea with azachalcone I-16 and cyclopentadiene I-17 (Scheme 1.4, entry 4). Schreiner’s design experiment identified the 3,5-bis-(trifluoromethyl)phenyl moiety as an advantageous group in the activity of

(thio)ureas.

Cat. krel R1 R1 O 1 2 1.5 H H R = R = H N 1 mol% I-15 S R1= F, R2 = H 4.1 1 2 5.9 R2 N N R2 R = CF3, R = H O H H 1 2 8.2 I-15 R = R = CF3 I-16 I-17 N I-18

Scheme 1.4. Substituent effects of the thiourea increases rate of Diels-Alder reaction

1.1.3 Chiral (Thio)urea Catalysis

Sigman and Jacobsen reported an asymmetric Strecker reaction, the first demonstration of the promise of chiral (thio)urea catalysis. [9] The authors first attempted to use chiral Schiff base substituted thioureas as ligands on metal-centered catalyst, but later found the thioureas operated better in the absence of metal additives. Reacting N-allyl aldimines (I-19, Scheme 1.5) and HCN in the presence of their best catalyst I-21, they were able to isolate the appropriate Strecker adducts (I-20) in high yields and enantioselectivity >80%; the highest ever reported for this ! 7! ! reaction at the time of publication.

HCN O R2 2 mol % cat. N R2 F C N PhMe 3 R1 H -78 oC, 24 h R1 CN I-19 then TFAA I-20

R1 = Aryl, Alkyl R2 = Allyl, Benzyl

t-Bu S t-Bu O H H Ph N Ph N N N N N H H H H O N O N I-21 I-22 HO HO O 65-92% yield 65-99% yield 70-91% ee t-Bu OMe 77-97% ee t-Bu O t-Bu

Scheme 1.5. Jacobsen’s (thio)urea design promotes asymmetric Strecker reactions

Later, Jacobsen and coworkers further optimized the catalyst structure for the same reaction. [10] The bulky tert-butyl group was understood to be the essential element for high enantioselectivity. It was proposed the catalyst could bind to the imine lone pair to minimizing steric interaction between the catalyst and the large imine substituents. After screening of the

HBD and the salicylaldimine portion of the catalyst, Jacobsen, Vachal and Sigman found I-22, containing a urea HBD moiety and 5-pivaloyl-substituted salicylaldimine, functionalized best for an asymmetric Strecker reaction.

Takemoto and coworkers reported another landmark catalyst structure design in 2003.[11]

Part of their design strategy was to capitalize on the bifunctionality of a catalyst capable of activating both the electrophile and the nucleophile. Their reports indicate that trans-1,2-

! 8! ! diaminocyclohexane derived thiourea I-26 was capable of the efficient promotion of asymmetric conjugate addition of malonates (I-24) to nitroolefins (I-23) with high enantioselectivity (93% ee). The bifunctional nature of I-26 benefits from the 3,5-bis-(trifluoromethyl)phenyl thiourea backbone introduced by Schreiner and cyclohexane diamine moiety to promote selectivity. The catalyst I-26 possesses a chiral scaffold with a basic heteroatom, which is presumed to assist in organization of the transition state leading to formation of the major enantiomer (Scheme 1.6).

The authors revealed through simple control experiments both the thiourea and dimethylamino group were necessary within the same molecule. If the thiourea possessed a cyclohexylamine instead of the cyclohexanediamine, only moderate yields of the desired product were formed. When only (R, R)-1,2-cyclohexyldiamine was added to the reaction, a decrease in enantioselectivity (35%) and poor yield (14%) resulted, perhaps due to weak hydrogen bonding capability. However, with the optimal thiourea backbone intact (I-26), a range of β-ketoester nucleophiles were compatible with the reaction at catalyst loadings as low as 2 mol % without affecting the enantioselectivity.

CF3 EtO C OMe 2 OMe CO2Et S EtO OEt NO2 10 mol % I-26 NO2 F3C N N O O H H o OMe PhMe, 23 C, 24 h OMe NMe2 I-26 I-24 I-23 I-25 87% yield 93% ee

Scheme 1.6. Takemoto’s thiourea promotes asymmetric conjugate addition of malonates to nitroolefins

Ricci reported the first enantioselective Friedel-Crafts addition with his optimal cis-1- amino-2-indanol derived (thio)urea I-30.[12] Using 20 mol % of I-30, afforded the addtion of I- ! 9! ! 28 to I-27 in a 92% yield of adduct I-29 in an 85% ee. Again, it was shown that both the

(thio)urea backbone and the heteroatom of the chiral scaffold, in this case an oxygen, proved crucial in accessing ideal catalyst performance. In order to demonstrate the necessity of the alcohol functionality, the same thiourea backbone was synthesized, but the alcohol functionality was protected or removed. In both cases, the modified thioureas performed poorly in the reaction yielding I-29 in 18% with 39% ee and 15% with no enantioselectivity, respectively. These results allowed the authors to propose the bifunctional mode of the catalyst in the transition state.

The alcohol can hydrogen bond with the indolic proton providing a facial selective addition to the hydrogen-bonded nitroolefin.

NH CF3

NO2 Ph 20 mol % I-30 S N H o CH2Cl2, -24 C, 72h NO2 Ph F3C N N I-27 I-28 H H I-29 OH I-30 92% yield 85% ee

Scheme 1.7. Ricci’s thiourea promotion of the asymmetric conjugation of indole to nitroolefins

In the same year as Ricci’s report, Soós[13] and Connon[14] independently reported another class of bifunctional (thio)ureas catalysts using chiral scaffolds derived from cinchona alkaloids

(I-33, Scheme 1.8). The cinchona alkaloid backbone contains both a basic quinidine moiety and a secondary alcohol in a distinct chiral environment. Both groups installed the thiourea functionality at the C-9 hydroxy group on the cinchona alkaloids and found the resulting catalysts

(I-34) offered improved yields and stereocontrol in select processes.

The Soós group applied catalyst I-34 in enantioselective nitro-Michael additions between nitromethane and I-31 (Scheme 1.8). The epiquinine amine derived thiourea I-33c yielded 71%

! 10! ! of the I-32 in 95% ee. Without the thiourea scaffold, I-33a alone only afforded 4% of I-32 with

42% ee. This result was further improved using the more active I-33d, resulting in similar ee at

96% but increased yield of 93%. Surprisingly, organocatalyst I-33b possessing the natural configuration provided no activity in this process.

R

OMe OMe O O2N 10 mol% cat O N H N H Ph Ph MeNO , 23 oC 2 Ph Ph R1 H I-31 I-32 N R2 N I-33 N H S N

a. R = H, R = OH, 4% yield, 42% ee 1 2 I-34 b. R1 = OH, R2 = H, no reaction c. R = CH=CH2, 71% yield, 95% ee F3C CF3 d. R = CH2CH3, 93% yield, 96% ee Scheme 1.8. Cinchona alkaloid derived catalyst promote enantioselective nitro-Michael addition

Connon and coworkers prepared a variety of (thio)urea-substituted derivatives of dihydroquinine (DHQ) and dihydroquinidine (DHQD) for the asymmetric conjugate addition of

I-36 to I-35 (Scheme 1.9). They found that with either epimerization of DHQ or DHQD at C-9 or substitution of the C-9 hydroxyl group with an aryl urea moiety without epimerization, led to only a small increase in enantioselectivity. However, with a combination of both modifications, an extremely active and selective catalyst was developed. In the presence of just 0.5 mol % of I-38, efficient conversion of I-35 to I-37 occurred under mild reaction conditions.

! 11! ! O O OMe H N NO2 O O S 0.5 mol % II-38 MeO OMe H S NO MeO OMe PhMe, 0 oC, 46 h 2 N I-35 (2 equiv.) N H I-37 S N I-36 92% yield 94% ee I-38

F3C CF3

Scheme 1.9. (Thio)urea promoted asymmetric conjugate addition

1.2 Design Strategies for Enhanced Dual HBD Catalysts

1.2.1 3,5-bis(trifluoromethylphenyl) Moiety in HBD Catalysis

Beginning with the early reports of Etter[15] and Kelly[6], HBD catalysts have been shown to benefit from the addition of electron withdrawing groups strategically positioned on the meta position of the diarylurea scaffold. Kelly and coworkers provided an improvement from Hine’s initial catalyst I-39 with the addition of nitro groups on I-40, while Etter and coworkers revealed the 1,3-bis-(meta-nitrophenyl)urea I-41 operated to improve the unsubstituted urea as a HBD catalyst. Further improvements of the catalysts by Curran and Wilcox found the substituents had substantial effects on the hydrogen bonding abilities of (thio)ureas. [16] Etter provided evidence that electron-withdrawing substituents at the meta position increased the reactivity of ureas.

Schreiner built from Etter’s, Curran’s and Wilcox’s findings by comparing a series of thioureas to their reactivity leading to the discovery of the 3,5-bis-(trifluoromethyl) phenyl moiety.

! 12! ! Hine (1985) Kelly (1990) Etter (1988)

NO2 NO2 OH OH NO2 NO2

O

nPr nPr N N OH OH H H I-39 I-40 I-41

Curran (1995) Schreiner (2002)

CF3 CF3 CF3 CF3

O S

C8H17O OC8H17 N N F3C N N CF3 H H H H O O I-42 I-43

Figure 1.2. Development of HBD catalysts

In 2002, Schreiner and coworkers clearly revealed the advantage of the 3,5-bis-

(trifluoromethyl) phenyl moiety in (thio)urea catalysis.[17] To support their spectroscopy data, they performed a Diels-Alder reaction of I-44 with I-45 (Scheme 1.10). With no catalyst, the reaction required elevated temperatures and extended reaction times, but with the addition of a

Lewis acid, the rate of the reaction was increased dramatically.[18] Similar to the results observed with the Lewis acid, the addition of thiourea I-43 afforded the desired product I-46 up to 8 times faster than the uncatalyzed process. During the course of their studies, a general trend was observed that suggested that the more electron deficient the (thio)urea, the better the yield of I-46.

O CF3 CF3 R2

R1 1 mol% II-43 S CDCl O R2 3 F3C N N CF3 R1 H H I-44 I-45 I-46 I-43

Scheme 1.10. Schreiner’s thiourea catalyzed Diels-Alder reaction ! 13! !

Since its introduction in 2002, the 3,5-bis-(trifluoromethyl)phenyl unit has become somewhat of a privileged structure in (thio)urea catalyst design, frequently leading to enhanced binding, higher yields and better stereoselectivity. It is proposed that the 3,5-bis-

(trifluoromethyl)phenyl functionality may partake in a number of roles to improve the catalytic activity, including increasing the (thio)urea acidity, rigidifying the catalyst structure, and enhancing the catalyst polarizibility. More specifically, Schreiner and coworkers recently reported the electron withdrawing nature of the CF3 groups enhances the acidity of the (thio)ureas nearly 5 orders of magnitude as compared to the unsubstitued version.[19] In the same report, the authors proposed another inherent advantage the scaffold possesses with its highly polarized ortho-CH bonds. This interaction allows for stronger catalyst-substrate interactions again attributing to the enhancement in reactivity and selectivity of many reactions.

1.2.2 Chiral Acidifying Groups

After establishing the 3,5-bis(trifluoromethyl)phenyl moiety increases polarity, polarizability, acidity, and π-π interactions, Schreiner and coworkers wanted to include amino acid-derived chiral oxazolines at the ortho-position for stereocontrol (I-47, Scheme 1.11).[20]

With a family of chiral thioureas, Schreiner and coworkers set out to promote the direct addition of I-45 to I-44 (Scheme 1.11). Their efforts were met with disappointment as all chiral catalysts prepared were found to be inactive in the cyanosilylation. The authors proposed a strong intramolecular hydrogen-bonding interaction between the nitrogen of the oxazoline and the thiourea N–H hydrogen was inhibiting the chiral scaffold from acting as a HBD catalyst I-47.

! 14! ! CF I-47 CF O OTMS 3 3 H S H CN + TMSCN F3C N N CF3 I-44 I-45 I-46 H H O N Intramolecular N H N R

Scheme 1.11. Intramolecular N—H interaction prevents catalytic process

Recognizing that the two most popular urea-based asymmetric catalysts either incorporated an acidifying group [21] or a chiral directing group [10] Ellman and coworkers developed a new class of HBD catalysts called N-sulfinyl ureas. [22] These catalysts contain an N- sulfinyl substituent which serves as both an acidifying agent and a chiral controlling element.

Measurements of pKa performed in DMSO of sulfinyl ureas I-48a and I-48b and (thio)urea I-49a and I-49b determined the sulfinyl group is 2-3 pKa units more acidifying than the commonly used

3,5-bis-(trifluoromethyl)phenyl moiety (Figure 1.3).

Sulfinyl urea acidifying affects Common acidifying linkers

CF3

O X I-48a X = O, pK = 15.5 I-49a X = O, pK = 18.1 X S N N I-48b X = S, pK = 11.2 I-49b X = S, pK = 13-14 H H F3C N N H H I-48 I-49

Figure 1.3. Sulfinyl vs. common (thio)urea pKa values

Acidity was not the sole factor of the success of N-sulfinyl ureas. Evidence for this was supported by Ellman and coworker’s finding that tert-butanesulfinyl urea catalyst I-50a was more ! 15! ! efficient than both thiourea derivative I-50b and sulfonyl derivative I-50c in catalytic aza-Henry reactions (Scheme 1.12).[20] Using 10 mol% of I-50a, the 1,2-addition of nitroethane to N-Boc benzaldimine was afforded in an excellent 99% yield with 83:17 dr and 94% ee. Further studies by Ellman and coworkers highlight multiple aspects, such as, steric size, electronics, solubility and stereochemistry of the sulfinyl urea catalyst as reasons for asymmetric induction. Using a

1,2-cyclohexanediamine-derived triisopropylphenyl (trisyl) sulfinyl urea catalyst, they reported the first highly enantioselective addition of thioacetic acids to both aryl and alkyl nitroalkene substrates with up to 96% ee and 95% yield.

10 mol% I-50 Boc Boc Boc 5 equiv EtNO HN HN N 2 + NO2 NO2 0.5 equiv i-Pr2NEt Ph Ph Ph MeCN, -40 oC, 32 h

Cat. X R1 R2 Yield (%) dr (X:X) %ee X I-50a O (R)-S(O)tBu OH 99 83:17 94

R1 N N I-50b S (R)-S(O)tBu OH 42 43:57 58 H H R2 I-50c SO tBu 35 26:74 16 I-50 O 2 OH

Scheme 1.12. N-sulfinyl(thio)urea catalyzed Aza-Henry reaction reported by Ellman

Using their optimized catalyst for the addition of thioacetic acid to trans-ß-nitrostyrene,

Ellman and coworkers were able to compare the reactivity of several N-sulfinyl ureas and compare them to Takemoto’s (thio)urea catalysts. [23] Takemoto’s less acidic urea catalyst was less reactive than his thiourea catalyst, but it improved enantioselectivity from 32% ee to 68% ee.

The high tunability of N-sulfinyl ureas facilitated catalyst optimization in a straightforward manner.

! 16! ! 1.2.3 Internal Bronsted Acid Assistance

Despite the many advancements made in the improvement of these HBD catalyst, issues such as high catalyst loadings and long reaction times remain a challenge. Other inventive methods to provide solutions to these problems have been presented. Internal activation of

(thio)ureas by Bronsted acids is one approach that led to increase reaction yields and improved stereocontrol.

280 fold increase with new catalyst design! New S-H interaction

CF3 NH H X NO2 H cat. S S N + vs. R N N N CF3 H NO H H N N 2 HO H H I-51 I-52 Ph HO I-53 I-54 I-55

Scheme 1.13. Enhanced thiourea activation of the conjugate addition reaction

Seidel and coworkers sought to invoke internal Bronsted acid assistance of (thio)ureas by replacing the frequently used 3,5-bis-(trifluoromethyl)phenyl group with a protonated 2-pyridyl substituent (Scheme 1.13).[24] It was expected that the pyridinium subunit I-55, when compared to the C-H—S hydrogen bond interaction present in I-54, would engage in enhanced intramolecular N-H—S interaction resulting increased thiourea polarization and improved catalyst activity. Indeed this approach proved effective: in a direct comparison to the I-54 and I-

55, Siedel and coworkers observed a rate acceleration of more than 280-fold when the conjugate addition of I-52 to I-51 was catalyzed by I-55. Further investigation of the catalyst structure revealed trends, such as, thioureas were more active and/or selective than their urea counterparts ! 17! ! and the more acidic a (thio)urea the more active and selective the catalyst. Unexpectedly, it was also found that a new quinolinium thioamide was the optimal catalyst in the addition of I-52 to I-

51. In these reactions, 5 mol% of thioamide (I-56) afforded conjugate addition products (I-50) in yields ranging from 80-96% and enantiocontrol up to 98% (Scheme 1.14).

BArF24 NH S

NO2 + 5 mol% I-56 Ph N N H 10h H NO2 HO HN I-51 I-52 Ph I-56 I-53 92% yield 94% ee

Scheme 1.14. Quinolinium thioamide catalyst promotes addition of indoles to nitroalkenes

Smith and coworkers also sought to improve the catalytic activity of (thio)ureas through internal Bronsted acid activation by mimicking the positive cooperativity observed with enzymes

(Scheme 1.15).[25] They envisioned this could be accomplished through an intramolecular urea activation of the thiourea I-57. The design is proposed to resemble nature in that it is flexible with a defined conformation to encourage cooperative binding to outweigh the entropic cost by enhancing the enthalpic contribution of the transition-state.

To study their new catalyst design, Smith and coworkers evaluated its effectiveness in a known HBD catalyzed Mukaiyama-Mannich reaction of I-58 and I-59. An initial screen of thiourea catalysts revealed pyrrolyl-1,2-cyclohexanediamine substituents were most effective, so a family of thioureas from the initial template was synthesized. Using their optimal catalyst I-57, they were able to obtain a 97% yield of I-60 as one enantiomer. To support the contribution of ! 18! ! the internal non-covalent interactions, Smith and coworkers deleted the internal activating group, which led to a decrease in both yield and enantioselectivity.

CF3 H NBoc OTBS 5 mol% I-54 NHBoc O + toluene CO2iPr Ph H OiPr 48h, -40 oC Ph N N minimize entropic cost in TS binding O H H I-55 I-56 I-57 with preoranized hydrogen-bonded S turn structure With optimal catalyst I-54, N N H H 97% conversion N Me Ph and >99% ee I-54

Scheme 1.15. HBD catalyzed Mukaiyama-Mannich reaction

1.2.4 Preorganizing and Acidifying Linkers

electron-withdrawing group CF less nucleophilic 3 heteroatom X1 S X2 vs

F3C N N N N H H H H N N Me Me Me Me

Figure 1.4. New acidifying linker catalyst design

Takemoto and coworkers sought to improve their (thio)urea catalyst design by utilizing an electron-withdrawing bridge to link the HBD functionality to its aryl scaffold.[26] The addition of the electron-withdrawing group bridge was envisioned to serve multiple purposes, including:

! 19! ! (i) holding the catalyst in a catalytically active form while at the same time (ii) increasing the acidity of the N-H protons. The hydrogen atoms would then be more accessible to lower the transition-state energy of the substrate-catalyst complex. Furthermore, the catalyst structure utilizes a guanidinium-based HBD moiety, removing the presence of a nucleophilic sulfur atom thereby preventing certain byproducts from forming.

H2N O O CO2H N R NH Me2N R R NH 2 N Cl isoamyl alcohol N N H H I-61 NMe2

H2N O O O O 1) ClSO2NCO S S 2) AlCl3 NH NH R R2N R R 3) POCl 3 N Cl N N NH2 isoamyl alcohol H o 130 C I-62 NR2

Scheme 1.16. Synthesis of new quinazolines and benzothiadiazines HBD catalysts

The synthesis of their two new HBD catalyst scaffolds, quinazolines (I-61) and benzothiadiazines (I-62), were accomplished in four steps from the corresponding anthranilic acid

(Scheme 1.16). Comparing the new catalyst with I-65a (Scheme 1.17) in the α-hydrazination of

I-63 with tert-butyl azodicarboxylate, it was found the quinazolines (I-61) were far superior in both yield and enantioselectivity (Scheme 1.17). Recognizing the sulfur atom readily undergoes nucleophilic addition to azodicarboxylate; the authors had previously used an “unlinked” bifunctional urea at lower temperatures to avoid this problem. However, even under the optimized “unlinked” urea reaction conditions, substituted quinazolines were able to surpass the

! 20! ! urea in both yield and selectivity.

Boc N O O N Boc O O cat 10 mol% OMe OMe toluene, RT N Boc NHBoc I-63 I-64

CF3 I-65 O I-61

X N R

F3C N N N N H H H H NMe2 NMe2 I-65a, X = S, Yield 22%, ee 83% I-61a, R = H: Yield = 93%, ee = 96% I-65b, X = O, Yield 99%, ee 87% I-61b, R = 8-F: Yield = quant, ee = 96% I-61c, R = 7-F: Yield = 98%, ee = 95% I-61d, R = 6-F: Yield = 99%, ee = 95% I-61e, R = 5-F: Yield = 93%, ee = 92%

Scheme 1.17. Catalyst comparison in the hydrazination of α-ketoester

Similar organocatalyst designs were developed by both the Nájera[27] and the Park and

Jew[28] groups with their reports of bifunctional 2-aminobenzimidazole scaffolds (I-66 and I-67,

Scheme 1.18). Again, the bond linker present in the benzimidazole core leads to an increased acidity and a structurally rigid scaffold, both of which can facilitate catalytst performance. The utility of both new catalyst structures (I-66 and I-67) was demonstrated in conjugate addition reactions of 1,3-dicarbonyl compounds to nitroolefins (Scheme 1.18). Nájera and coworkers utilized a chiral trans-cyclohexanediamine-benzimidazole organocatalyst I-66 in the presence of a cocatalyst, TFA, to observe high levels of yield and enantiocontrol. Park, Jew and coworkers successfully applied their cinchona-derived chiral 2-aminobenzimidazole I-67 catalyst to Michael additions of dimethyl malonate to nitroolefins.

! 21! !

Nájera Park and Jew

10 mol% I-66 MeO2C CO2Me MeO2C CO2Me O O 2 mol% I-67 10 mol% TFA NO 2 + NO toluene Ph 2 NO2 MeO OMe toluene Ph Ph

F3C CF3

N 96% yield NH 96% ee N N N 99% yield H H NH 93% ee NMe2 I-66 N N

I-67

OCH3

Scheme 1.18. Aminobenzimidazole HBD promote conjugate addition reactions

1.3 Internal Lewis Acid-Assisted Dual HBD Catalysis: Boronate Ureas

1.3.1 Catalytic Design Background

Ideas incorporated in host/guest molecule receptors have inspired the strategic installation of features on (thio)urea scaffolds able to improve their performance as catalysts. For example, in the late 1990s, Smith and coworkers developed a series of enhanced acetate binding agents by incorporating a Lewis acid within the urea framework. [29] The appropriate placement of a Lewis acid on the urea backbone was hypothesized to increase the activity of the HBD functionality by coordinating to the urea carbonyl oxygen causing a cooperative polarizing effect of the urea (I-

74, Figure 1.5). In this report, Smith and coworkers demonstrated how the favorable incorporate of boron into urea scaffolds polarizes the urea carbonyl resulting in an increased acetate binding by acidifying the hydrogen atoms and enhancing the ion-dipole interaction between the host and acetate through complex I-72.

! 22! ! To begin their studies, four boronate ureas were synthesized in two steps. The acetate ion-binding constant was then measured for each urea using 1H NMR spectroscopy and tetrabutylammonium acetate (TBAA). Comparing a test urea to the meta-boryl urea provided no relative increase in binding, a result that was not surprising because of the similar electronegativities between boron and hydrogen and a meta-substituted urea would not benefit from coordination of the Lewis acid. However, when a boronate urea was able to benefit from the internal Lewis acid coordination, a 19-fold tighter binding to the acetate was observed.

Furthermore, when the more withdrawing boron difluoride urea I-71 was present to strengthen the hydrogen bond donation ability, as well as generate a strong dipole, an 8-times stronger binding than I-70 was observed. Most importantly were the results validating a hydrogen bond interaction with the acetate was taking place by indicating the uncoordinated/trigonal boron atoms had no affinity for the acetate by 11B NMR.

New Lewis acid ureas

O O B F F O O B B O O O O

C8H17 C8H17 C8H17 C8H17 N N N N N N N N H H H H H H H H

I-68 Krel = 1 I-69 Krel = 19 Krel = 162 I-70 I-71

X R R Anticipated dipole effects N N H H X X X X B B O O O O

C8H17 C8H17 R N N N N H H H H I-72 I-73 I-74 Anion binding recognition

Figure 1.5. HBD catalyst structure related to its function

! 23! ! Taking into consideration advances made by both Smith [29] and Schreiner [17], our group was motivated to design an enhanced HBD catalyst that could benefit from both designs. It was envisioned that strategically placed internal Lewis acids onto the (thio)urea scaffold would enable the same polarization seen by Smith with his host guest molecule design, as well as allow for easy modification of the ligands on the Lewis acid. Simultaneous utilization of the 3,5-bis-

(trifluoromethyl)phenyl moiety discovered by Schreiner would also help in increasing the acidity of the urea protons, leading to the development of the optimal enhanced urea catalyst I-75 (Figure

1.6).

Variable Lewis Acid Easily Exchangeable Ligands F F CF3 L L B M O Variable X R Modular Chiral Scaffold Electronics R N N N N CF3 H H Rigid H H I-75 Conformation Increased Acidity

Figure 1.6. New enhanced HBD catalyst design

The optimal catalyst I-75 was prepared by first forming the pinacolboronate urea I-78 from 2-aminophenylboronic acid pinacol ester I-76 and 3,4-bis-(trifluoromethyl)phenyl isocyanate I-77 (Scheme 1.19). The treatment of I-78 with aqueous potassium bifluoride in methanol could be triturated in CH2Cl2 to provide urea I-79 with very little formation of the heterocyclic byproduct I-80.

! 24! ! CF CF3 O CF3 O O 3 B B MeCN aq. KHF2 O O + O MeOH N N CF N N CF3 NH2 N CF3 3 H H C BF K I-79 O I-77 H H 3 I-76 I-78

CF3 F F CF3 OH B + O H2O B N CF3 23 oC, 16 h N N CF3 N O H H H I-80 I-75

Scheme 1.19. Synthesis of enhanced HBD catalyst

1.3.2 Catalytic Reactivity

With the boronate urea I-75 prepared, its potential as an enhanced HBD catalyst was first evaluated using the nucleophilic addition of I-52 to I-51. [ 30 ] Since this reaction is well precedented in the literature, it allowed for a quick comparison of this new class of HBDs to existing catalysts. Using a 2,2,2-trifluoroethanaol additive, it was found the I-75 provided quantitative yield after 24 hours at 23 ºC. The examination of several Lewis acid assisted HBDs revealed the importance of both the boron and the choice of ligands that were placed onto the

Lewis acid. When the boron atom was replaced with silicon to afford silicate urea I-82 (Scheme

1.20), the yield decreased to 50% after 24 hours, even with higher catalyst loadings (20 mol%).

Exchanging the difluoroboryl urea with the analogous pinacol ester (I-78) dramatically reduced the yield to just 41% after 24 hours. It wasn’t until the addition of an electron-withdrawing group that the pinacol ester became an efficient catalyst I-81. Finally, Lewis acid assistance in the urea scaffold was confirmed as a viable strategy to increase the catalytic activity; conventional urea I-

43b and thiourea I-43a afforded only 43% and 80% yield, respectively, under otherwise identical conditions

! 25! ! F F CF3 B HN 10 mol% cat O NO2 + Ph N CH Cl , 23 oC N N CF3 H 2 2 H H CF CH OH, 24 h NO2 I-51 I-52 3 2 Ph 99% yield I-75 I-53

CF3 CF3 Me CF3 CF3 CF3 O O O O Me Me B F3C B Si O O O X

N N CF3 N N CF3 N N CF3 F3C N N CF3 H H H H H H H H I-78 I-81 I-82 I-43 41% yield 99% yield 50% yield I-43a, X = S: 80% yield I-43b, X = O: 43% yield

Scheme 1.20. Enhanced HBD catalyst promote a conjugate addition

After demonstrating the difluoroboronate urea catalysts offers improved reactivity over conventional ureas and thioureas, it was of interest to take advantage of the catalytic improvement in order to develop unprecedented reactivity modes. The first work from our group in this area was with the activation of nitrocyclopropane carboxylates I-83 (Scheme 1.21).[31]

Ring-opening reactions of I-83 is relatively understudied, with only a few successful reports, all of which involve metal catalysts or elevated temperatures. It was found using just 10 mol% of I-

75, nucleophilic addition of I-84 on I-83 afforded I-85 in 87% yield after 48 hours. This result compared favorably again to conventional urea I-43b, which afforded the I-85 in only a 67% yield under otherwise identical reaction conditions. Further investigation into nucleophiles and nitrocyclopropane carboxylates demonstrated high tolerance to both substituted anilines as well as substituted nitrocyclopropane carboxylates in this process.

! 26! ! Ph O NH Proposed Mode of 2 10 mol% cat Ph + OMe Activation CH Cl , CF CH OH N O 2 2 3 2 MeO2C o NH NO2 F 23 C, 48h Ph F O B I-84 I-85 CF I-83 O 3 N N F F CF3 CF3 CF3 H H B CF3 O O O N O

N N CF3 F3C N N CF3 H H H H CO2Me Ph 87% yield I-75 67% yield I-43b I-86

Scheme 1.21. Enhanced HBDs catalyze ring-opening of nitrocyclopropane carboxylates

The proposed mode of activation occurs through coordination of the I-75 with the nitrocyclopropane to generate complex I-86 (Scheme 1.21). This complex causes I-83 to be more susceptible to nucleophilic attack, allowing I-84 to open the ring in an SN2-type reaction pathway to form I-85. Inspired by this initial success of urea catalyzed ring-opening reactions of nitrocyclopropane carboxylates, our group continued with studies on formal [3 + 3] cycloaddition reactions of nitrocyclopropane carboxylates with nitrones.[32] In comparison with other ureas, I-75 outperformed I-43a and I-43b, as well as I-78, affording a 91% yield of the oxazinane I-89 in a

2:1 dr (Scheme 1.22).

! 27! ! F F CF3 Ph Ph O Ph B O 15 mol% cat N O + Ph N Ph Ph N O Toluene N N CF3 MeO2C H H H 24 h O2N CO2Me O 91% yield I-75 I-87 I-88 I-89

CF3 CF3 CF3 CF3 CF3 Bpin O S O

F3C N N CF3 F3C N N CF3 N N CF3 H H H H H H 75% yield 9% yield 27% yield I-43b I-43a I-78

Scheme 1.22. Enhanced HBD catalyze formal [3+3] cycloaddition reactions

Since the activation of electrophiles is the typical mode of activation for conventional

(thio)ureas, our group wanted to break away from this traditional reactivity pattern. It was envisioned that our boronate urea could facilitate the loss of nitrogen gas from a α-nitrodiazo compound I-90, leading to a reactive, yet stabilized α-nitrocarbene intermediate I-91 that could undergo N–H insertion to provide useful α-amino-α-nitroester products I-92 (Scheme 1.23).

Surprisingly, when the I-90 was subjected to conditions proposed to result in the urea-catalyzed insertion into the N-H bond of aniline, the multicomponent coupling product I-93 was observed.[33]

O O R1 R2 N N O 1 2 O R R O N N H H 1 NO2 H H Ar NH2 Ar NO2 EtO Ar2 EtO O O 1 EtO – N H NHAr – HNO 2 N 2 1 N2 H NHAr O I-90 I-91 I-92 I-93 OEt

Scheme 1.23. Proposed urea activation of nitro diazo compounds

! 28! ! With 20 mol% of I-75 present, I-95 was afforded in an 83% yield after 24 h at 40 °C

(Scheme 1.24). Compared to other urea catalysts, I-75 and traditional urea I-43b afforded modest yields, 61% and 58% respectively, while I-43a performed most poorly offering only a

27% yield.

NH2 CF O O O F F 3 NH2 B N O EtO O 20 mol% cat + EtO N 24 h NH N N CF3 H H N I-90 I-95 I- 83% yield I-75 84

CF3 CF3 CF3 CF3 CF3 Bpin O S O

F3C N N CF3 F3C N N CF3 N N CF3 H H H H H H

58% yield 27% yield 61% yield I-43b I-43a I-78

Scheme 1.24. HBD activation of nitro diazo compounds for multicomponent coupling reactions

Surprised by the multicomponent product I-95, an investigation into a plausible mechanism was undertaken. Through both experimental and computational studies, it is proposed that the diazo compound first inserts into the N–H bond of aniline then the addition of a second nucleophile, such as a aniline, occurs. The proposed pathway is through urea-activated intermediate I-96, which inserts stepwise into the N-H bond of aniline I-97. This is followed by the extrusion of nitrite, forming an iminium ion I-98 that can undergo nucleophilic attack

(Scheme 1.25).

! 29! ! O O CF N I-90 F F 3 EtO O B O N2 R N N CF3 H H N O I-75 H O O N N H R1 EtO O R N N O N I-96 H O O N 1 N H R EtO O H NH N2 I-97 Ph PhNH2

NO2

O NH2 PhNH2 O H EtO EtO N H Ph NH I-95 I-98

Scheme 1.25. Proposed catalytic cycle of multicomponent coupling reaction

Continuing with the initial successes of insertion reaction of diazo compounds, our group designed an autotandem organocascade double α-arylation of α-nitrodiazoesters (Scheme 1.26).

[ 34 ] In this reaction series, the I-75 has two sequential roles: first, activation of the α- nitrodiazoester I-96 for N-H insertion/multicomponent coupling and second, activation of the α- aminoester I-100 for α-arylation. It was found that 4-fluoroaniline acted as the best candidate for

N–H insertion, perhaps due to its good leaving group ability and its reduced participation in undesired side reactions. The proposed mechanism again begins with activation of the α- nitrodiazoester I-96, which inserts into the N–H bond of the 4-fluoroaniline I-97. Expulsion of nitrite allows for the first addition of 5-bromoindole to form transient insertion intermediate I-99.

This product is again activated by I-75, allowing for an assisted substitution of the N-bound 4-

! 30! ! fluoroaniline with 5-bromoindole I-101 to generate the desired double arylated ester product I-

102.

! 31! ! !

O NH

EtO

R HN OMe N O O 4-F-PhNH H Br + 2 NO O O 2 N EtO H R1 I-102 4-F-PhNH N N 2 EtO O 2 N I-90 Br N I-96 R O F F CF3 N B O R1 O I-75 NH H N N2 H EtO H N N CF3 N

32 4-F-Ph R H H H

! N O N–H Insertion α-Arylation OMe HN H H I-101 O O Cycle I Cycle II N N 1 N H R EtO O H NH I-97 Br Ph-4-F R R I-100 O I-98 N MeO Br N O O NH H 4-F-Ph H I-99 4-F-Ph N R1 NH N N N H H R1 EtO H H O H O HN H HNO2 Ph-4-F HN EtO EtO Br transient N–H insertion intermediate

Scheme 1.26. Plausible catalytic cycle for the unsymmetric double arylation of nitrodiazoesters

!

1.3.3 Catalyst Acidity

The correlation of (thio)urea acidity and activity has been of great interest. A report by

Schreiner and coworkers in 2012 investigated a pKa trend of several of the most popular

(thio)urea organocatalysts using Bordwell’s indicator method (Figure 1.7).[35]

I-43a O CF3 CF3 CF3 N CF S 3 O NH F3C N N CF3 H H F3C N N N H H S N CF3 OH pKa = 8.5 H I-106 I-104 pKa = 17.6 pKa = 12.4

CF3

S CF3 S N N CF3 S H H N N N N F3C N N H H I-103 H H O N N pKa = 10.7 I-105 I-107 pKa = 13.7 pKa = 19.6

Figure 1.7. Popular (thio)urea pKa’s in DMSO

The report was especially interested in the common 3,5-bis-(trifluoromethyl)phenyl moiety present in many (thio)urea organocatalysts. The benefits of this structural motif have been rationalized to increase the acidity of the double H-bonding organocatalysts, which strengthens the catalyst-substrate interaction through the strong σ-electron withdrawing ability of the CF3

! 33! groups. They found a direct correlation between the number of CF3 groups attached to the aromatic rings and the pKa of the urea. Each CF3 group was calculated to decrease the pKa by approximately 1.2 pK units. Using these measurements, Schreiner and coworkers determined the pKa of their thiourea to be 8.5, a pKa much lower than the common expectancy for a thiourea derivative. Following determination of the acidities of different (thio)urea catalysts, turnover frequencies (TOF) were calculated to quantify catalyst performance. Comparing I-104 (pka =

12.39), I-105 (pka = 13.65), and a catalyst not containing the CF3 groups (pka = 17.0) in a vinylogous aldol addition of γ-butenolide to benzaldehyde, it was found the TOF corresponded to acidity, 0.16 h-1, 0.13 h-1, and 0.08 h-1, respectively.

CF3 CF3 CF3 CF3

S S S S < < <

N N N N N N CF3 F3C N N CF3 H H H H H H H H 10.1 0.1 13.4 ± 0.1 12.1 ± 0.1 ± 8.5 ± 0.1

Figure 1.8. Addition of CF3 group decreases the pKa

Understanding that (thio)urea reactivity correlates to acidity, we were curious where on the pka chart diflouroboronate urea I-75 was positioned. It was anticipated that the internal Lewis acid assisted catalyst design would enable access to pKas below 8.5, a range not accessible with conventional (thio)urea catalysts. Indeed we were delighted to find I-75 had a pKa of 7.5 in

DMSO. Our group then compared a small family of internal Lewis acid assisted ureas to see how catalytic activity related to the acidity of these catalysts. [36] The two reaction platforms tested the

! 34! activation of ethyl nitrodiazoacetate (I) and the activation of nitrocyclopropane carboxylate (II), to investigate the effect of the Lewis acid (Scheme 1.27). In both cases, the more reactive catalysts were found to be most acidic with difluoroboronate urea possessing a 7.5 pKa and the urea palladacycle having a 6.8 pKa. Recalling from Schreiner and coworker’s paper, both of these pKa’s were considerably lower than more conventional urea (13.8) and thiourea (8.5).

NH2 O O O NH N 2 EtO O 20 mol% cat + EtO I N 24 h NH N I-90 I-95 I-84

Me Me CF3 CF CF CF F F 3 3 N N 3 OTf Me Me B Pd O O O N N CF 3 F3C N N CF3 N N CF3 H H H H H H I-108 I-75 I-43b I) 78% I) 83% I) 58% II)73% II) 87% II)65% Me Me PhPh Me Me Ph Ph CF3 CF3 Me CF3 P P OTf O O Me Me Ph Pt Ph B Si O O O

N N CF3 N N CF3 N N CF3 H H H H H H I-109 I-78 I-82 I) 65% I) 61% I) 35% II) 67% II)34% II) 31%

Ph O NH 2 10 mol% cat Ph + OMe II N O CH Cl , CF CH OH MeO2C 2 2 3 2 NH NO2 O 23 oC, 48h Ph I-85 I-87 I-84

Scheme 1.27. Lewis acid containing HBDs catalyze nitrodiazo ester and nitrocyclopropanes

! 35!

1.4 Design Strategies for Enhanced Internal Lewis Acid-Assisted Dual HBD Catalysis: Boronate Ureas

1.4.1 Strategies

With difluoroboronate ureas identified as promising enhanced HBD catalysts, we were interested in developing an enantioselective variant. There were several strategies considered for the preparation of a chiral, enantipure boronate urea, including: (1) adding chiral ligands onto boron, (2) utilizing a chiral acidifying group, such as Ellman’s chiral sulfinyl group [20] in place of

Schreiner’s 3,5-bis-(trifluoromethyl)phenyl moiety[17] or (3) introducing a chiral auxiliary attached to the aryl ring which hosts the Lewis acid. Wanting to keep the optimal elements of our catalyst, we opted to explore a urea with the 3,5-bis-(trifluoromethyl)phenyl moiety as well as the internal difluoroboryl moiety intact. The strategic installation of a chiral auxiliary ortho to the urea functionality would afford a catalyst prototype I-110 (Figure 1.9).

Chiral Ligands F F CF3 L L B B O X Addition of R a chiral scaffold R Modular Chiral Scaffold N N CF3 N N H H Xc H H I-110

Figure 1.9. Chiral catalyst design

Two types of auxilliaries were initially envisioned as potential sources of chirality because of their high modularity and ease of installation onto the aromatic core: imidazolines and oxazolines. While imidizoline auxiliaries can be derived from chiral C2 symmetric 1,2-diamines, chiral 1,2-diamines are more expensive and relatively difficult to access. However, oxazolines ! 36! are particularly attractive targets because of they can be easily accessed from a plethora of inexpensive amino acid-derived chiral 1,2-aminoalcohols. The reports by Schreiner[18] indicate the addition of the all amino acid-derived chiral oxazolines installed in the ortho-position to act as a stereocontrolling elements rendered (thio)ureas inactive catalysts for the cyanosilylation of aldehydes (vide supra). As mentioned previously (Scheme 1.11), the authors hypothesized an intramolecular H-bonding of the nitrogen lone pair on the chiral auxiliary to the adjacent thiourea proton considerably reduces the catalysts’ binding ability and prevents the (thio)urea from acting as a HBD catalyst. We were aware of their hypothesis, but we reasoned the addition of the difluoroboronate moiety our catalyst structure would possess a rigidifying element strong enough to modify the reactivity pattern of these catalysts. Although we envisioned placement of this auxiliary on the Lewis acid bearing phenyl substituent, we also considered the possibility of attaching the auxiliary to the 3,5-bis-(trifluoromethyl)phenyl unit (Figure 1.10).[18]

CF3 BF CF 2 3 O BF2 O N N CF3 H H

N N CF3 H H O N

HN N CF3 CF3 BF2 BF2 O R R O

N N CF3 N N CF3 H H H H N O O N

R Ph

Figure 1.10. Chiral boronate urea catalyst targets

The general synthetic route to the chiral boroate ureas is depicted in Scheme 2.28. First, the chiral auxilliary would be installed using known literature procedures (Step 1). The desired boron internal Lewis acid would be added via a Suzuki coupling reaction (Step 2). The formation

! 37! of the urea would be achieved through a reaction with the appropriate isocyanate (Step 3) then a boron ligand exchange would enable access to the desired difluoroboryl substituent (Step 4).

O Aux B Me O NH O Me 1 2 O 3 O Aux B Me Me Br Aux Br Me Me F3C NH NH2 O OH NH NH 2 2 Me Me 4 CF3

F F CF3 B O

N N CF3 H H Aux

Scheme 1.28. Proposed synthesis of chiral boronate urea catalyst

1.4.2 Synthesis

Before synthesis of I-110, a model catalyst was prepared in order to gain some insight into the potential reactivity of our proposed chiral catalyst designs. Treatment of anthranilic acid I-111 with triphosgene afforded isatoic anhydride I-112 in quantitative yield. I-112 was then subjected to L-phenylglycinol and zinc(II)chloride in refluxing chlorobenzene to afford I-113 in a 70% yield. Lastly, treatment with I-77 afforded I-114 in an overall 62% yield (Scheme 1.28).

I-77 F3C NCO CF3 H2N O O OH O O Ph triphosgene Ph CF3 OH O N N N CF3 H H ZnCl2 NH N O NH O N 2 H 2 I-114 I-111 90% yield I-112 I-113 Ph 99% yield 70% yield

Scheme 1.29. Preparation of new chiral test catalyst

! 38!

The catalytic efficiency of I-114 was examined in the conjugate addition of I-115 to I-51, a reaction studied extensively in our research group (Scheme 1.29). We were excited to see that when using 20 mol% I-115 in methylene chloride at –35 °C for 7 d, an 89% yield of I-116 was isolated with a 10% ee (Scheme 1.29). Given this result, we anticipated the addition of the difluoroboronyl moiety would rigidify the urea catalyst, preventing free rotation about the C–N bond and placing the auxiliary in close proximity to the active site of the urea resulting in a more selective catalyst.

I-114 CF3

O

MeO HN N N CF3 20 mol% I-114 OMe H H NO2 + Ph O N N CH2Cl2 H 89% yield, 10% ee -40 oC, 72 h NO2 I-51 I-115 Ph Ph I-116

CF3

O

N N CF3 H H

O N

Ph

F F CF3 B O

N N CF3 H H

O N

Ph

Scheme 1.30. Proof of concept

! 39! The synthesis of the desired chiral difluoroboronate urea commenced from commercially available 2-amino-3-bromobenzoic I-117 and triphosgene to form isatoic anhydride I-118 in quantitative yield (Scheme 1.30). Installation of the oxazoline was completed upon treatment of the isatoic anhydride with zinc(II)chloride and cis-1-amino-2-indanol I-119. Next, a palladium catalyzed Suzuki-Miyaura borylation was conducted using bis(pinacolato)diboron and potassium acetate in dioxane at 100 °C. Although low yielding, treatment of the resulting aniline I-120 with

I-77 afforded the heterocyclic compound I-121 as confirmed by 1H NMR spectroscopy and mass spectrometry. Smith and coworkers,[28b] as well as members of our group, have installed the desired fluoride ligands from similar heterocycles but all attempts to do so on I-121 were unsuccessful.

NH2 O O O O N OH B B N O O OH triphosgene O O O NH2 N O PdCl2(dppf) NH H 2 I-120 Br Br NH2 B O O 47% yield I-117 I-118 Br 99% yield I-119 70% yield CF3 O C CF3 OH F3C N BF2 B O N CF3 KHF2 I-77 N N CF3 N O H H H CF3 I-121 O N I-122 O N 88% yield

Scheme 1.31. Preparation of a chiral catalyst

1.4.3 New Avenues

Confident in the ability of oxazolines to operate as a good stereocontrol elements in our enhanced urea catalyst design, we have begun to explore the advantages of installing oxazoline

! 40! auxillaries to the meta-position (I-125). It was reasoned that moving the chiral auxiliary to the meta position will still allow for control the stereochemical outcome of reactions, but it would also be far enough away from the (thio)urea protons to avoid intramolecular H-bonding. A synthetic route to I-125 is outlined in Scheme 1.31.

!

NH2 CF3 OH BF2 O OH O O O B B Cs CO O O 2 3 O O N N CF3 H H Toluene N N NH2 I-125 Br Br I-124 O C I-123 NH2 F3C N

CF3 !

Scheme 1.32. Plausible design strategy to new chiral ureas

!

Work by Wang, Gao, and Liang has inspired a new direction of our chiral boronate urea catalyst design. [37] Their successful resolution of 4,4',6,6’-tetrakis-trifluoromethyl-bephenyl-2,2’- diamine (TF-BIPHAM) provided a route to chiral ligands which allowed for highly enantioselective hydrogenations of α-arylenamides and α-dehydroamino acid esters. Our strategy would be to build a TF-BIPHAM backbone by treating I-126 with Li-TMP and CBr4 (Scheme

1.32).[38] I-127 would undergo a nitration yielding I-128 which upon treatment with Cu/sulfolane

[39] and H2, Pd/C would give rise to I-129. Following Liang and coworkers prep to get resolve TF-

BIPHAM, enantiopure I-130 could be accessed. I-30 is envisioned as a backbone to the difluoroboronate urea.[38] In our hands, a successful bromonation of I-126 to I-127 followed by a nitration yielding I-128 have been completed. However, after only a few attempts, the cross- coupling step to form I-129 has not been accomplished and further work is necessary. This

! 41! desired catalyst would allow access to an easily modifiable backbone, as well as avoid the installation of an auxiliary with the potential to internally coordinate.

CF3

CF3 CF3 CF3

Br Br 1. Cu/sulfolane F3C NH2 Li-TMP H2SO4/HNO3 2. H , Pd/C F3C NH2 CBr4 96% 2 F C F C F C NO 3 94% 3 3 2 I-129 I-126 I-127 I-128

CF3

Resolution

CF3 F F CF3 B O

F3C N N F3C NH2 H H F3C F3C NH2 N R R I-131

CF3 CF3 I-130

Scheme 1.33. New avenue for chiral boronate ureas

In conclusion, the installation of oxazoline chiral auxillaries on boronate urea scaffolds has been explored as a strategy to access urea catalysts with enhanced reactivity and stereocontrol when compared to conventional (thio)urea catalysts. Our preliminary data supports the promise of this route, although obstacles in the synthetic route toward this new family of chiral catalyst must be addressed. Specifically, installation of the desired difluoroboryl substituent was unsuccessful thus far and new routes for its preparation must be explored.

1.5 Experimental Section

General Information. Methylene chloride (CH2Cl2), toluene (PhMe), diethyl ether (Et2O), tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and acetonitrile (MeCN) were purified

! 42! by passage through a bed of activated alumina.[40] Dioxane was purified by distillation after

[ 41 ] stirring in CaH2 for a minimum of 24 h. Pyridine, Et3N, i-PrNEt2, and N,N,N’- trimethylethylenediamine were purified by distillation using CaH2 as a dessicant. Purification of reaction products was carried out by flash chromatography using Aldrich 60 Å (40 - 63 µm).

Analytical thin layer chromatography was performed on EMD Chemicals 0.25 mm silica gel 60-

F254 plates. Visualization was accomplished with UV light and ceric ammonium molybdate stains followed by heating. Melting points (mp) were obtained on a Thermo Scientific Mel-temp apparatus and are uncorrected. Infrared spectra (IR) were obtained on a Perkin Elmer Spectrum

100R spectrophotometer. Infrared spectra for liquid products were obtained as a thin film on a

NaCl disk and spectra for solid products were collected by preparing a NaBr pellet containing the title compound. Proton nuclear magnetic resonances (1H NMR) were recorded in deuterated solvents on a Bruker Avance AVIII 400 (400 MHz) spectrometer. Chemical shifts are reported in parts per million (ppm, δ) using the solvent as internal standard (CHCl3 = δ 7.26; DMSO = δ

1 2.50; CH3OH = δ 3.31; (CH3)2CO = 2.05). H NMR splitting patterns are designated as singlet

(s), doublet (d), triplet (t), or quartet (q). Splitting patterns that could not be interpreted or easily visualized are designated as multiplet (m) or broad (br). Coupling constants are reported in Hertz

(Hz). Proton-decoupled carbon (13C NMR) spectra were recorded on a Bruker Avance AVIII

400 (100 MHz) spectrometer and are reported in ppm using the solvent as an internal standard

(CHCl3 = δ 77.16; DMSO = δ 39.52; CH3OH = δ 49.00; (CH3)2CO = 29.84). Proton decoupled fluorine (19F NMR) spectra were recorded on a Bruker Avance AVIII 400 (376 MHz) spectrometer and are reported in ppm using CF3C6H5 as an external standard (–63.72). Boron spectra (11B NMR) were recorded on a Bruker Avance DPX 500 (160 MHz) or Bruker Avance

AVIII 400 (128 MHz) spectrometer and are reported in ppm using BF3•OEt2 as an external standard (0.00). Electrospray mass spectra (ESI-MS) were obtained using a Bruker MicrOTOF

! 43! Mass Spectrometer. Unless otherwise noted, all other commercially available reagents and solvents were purchased and used without further purification.

! 44!

1.5.1 Preparation of Model Catalyst

I-77 F3C NCO CF3 H2N O O OH O O Ph triphosgene Ph CF3 OH O N N N CF3 H H ZnCl2 NH N O NH O N 2 H 2 I-114 I-111 90% yield I-112 I-113 Ph 99% yield 70% yield

O 2H-benzo[d][1,3]oxazine-2,4(1H)-dione: The literature procedure[42 was followed O 1 N O and the product was isolated as a light brown solid (99%). H NMR (400 MHz, H I-112 DMSO-d6) δ 11.73 (s, 1H); 7.92 (dd, J = 8.0, 1.6 Hz, 1H); 7.74 (m, 1H); 7.25 (m,

1H); 7.15 (d, J = 8.0 Hz, 1H); All spectra matched those previously reported in the literature.[42]

O 43 Ph (R)-2-(4-phenyl-4,5-dihydrooxazol-2-yl)aniline: The literature procedure was N 1 NH2 followed and the product was isolated as a white solid (70%). H NMR (400 MHz,

I-113 CDCl3) δ 7.74 (dd, J = 8.0, 1.4 Hz, 1H); 7.18-7.35 (6H); 6.64-6.69 (2H); 6.11 (s,

1H); 5.42 (dd, J = 9.8, 8.2 Hz, 1H); 4.65 (dd, J = 10.2, 8.2 Hz, 1H); 4.09 (t, J = 8.2 Hz, 1H). All spectra matched those previously reported in the literature.[44

CF3 (S-1-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(4-phenyl-4,5dihydrooxazol- O

N N CF3 2-yl)phenyl)urea: A flame-dried round bottom flask under N2 was H H O N I-114 charged with (R)-2-(4-phenyl-4,5-dihydrooxazol-2-yl)aniline (42.5 mg, Ph 0.178 mmol). Freshly purified acetonitrile (3 mL) was added to create a colorless solution. Last,

3,5-bis-trifluoromethylphenyl isocyanate (30.6 µL, 0.178 mmol) was introduced to the reaction ! 45! flask dropwise by syringe. Shortly after addition of the isocyanate, a white precipitate began to form. The reaction was allowed to stir at 23 °C for 4 h. The pure urea I-114 was isolated as a white solid after vacuum filtration followed by washing with hexanes. The solid was dried under vacuum (90%). FTIR (film) 2359, 1636, 1544, 1446, 1375, 1277, 1174, 1132, 1066 cm-1; 1H

NMR (400 MHz, CDCl3) δ 12.91 (s, 1H); 9.01 (dd, J = 8.4, 0.8 Hz, 1H); 8.50 (s, 1H); 7.90 (dd, J

= 8.0, 1.6 Hz, 1H); 7.71 (s, 2H); 7.55 (m, 1H); 7.38 (s, 1H); 7.27 (m, 3H); 7.19 (m, 1H); 6.95 (m,

2H); 5.05 (dd, J = 10.0, 8.4 Hz, 1H); 4.65 (dd, J =10.2, 8.6 Hz, 1H); 4.06 (t, J = 8.4, 1H); HRMS

(ESI): Mass calculated for C24H17F6N3NaO2 [M+Na]+, 516.1117. Found [M+Na]+, 516.1113.

1.5.2 Preparation of Oxazoline Containing Catalyst

NH2 O O O O N OH B B N O O OH triphosgene O O O NH2 N O PdCl2(dppf) NH H 2 I-120 Br Br NH2 B O O 47% yield I-117 I-118 Br 99% yield I-119 70% yield CF3 O C CF3 OH F3C N BF2 B O N CF3 KHF2 I-77 N N CF3 N O H H H CF3 I-121 O N I-122 O N 88% yield

O 8-bromo-2H-benzo[d][1,3]oxazine-2,4(1H)-dione: The literature procedure [45] was O 1 N O followed and the product was isolated as a light brown solid (99%). H NMR (400 H Br I-118 MHz, CDCl3) δ 8.09 (d, J = 7.6 Hz, 1H) 8.03 (s, 1H); 7.90 (d, J = 7.6 Hz, 1H); 7.20

(t, J = 8.0 Hz, 1H); All spectra matched those previously reported in the literature.[46]

! 46!

2-bromo-6-((3aS,8aR)-3a,8a-dihydro-8H-indeno[1,2-d]oxazol-2-yl)aniline:

N The literature procedure[47 was followed and the product was isolated as a white O

NH2 solid (70%). Rf = 0.90 (80:20 hexanes: ethyl acetate); FTIR (film) 2930, 2899, Br 16,28, 1602, 1577, 1540, 1477, 1458, 1424, 1357, 1311, 1279, 1250, 1236, 1166, 1070, 1059,

-1 1 1019, 1002 cm ; H NMR (400 MHz, CDCl3) δ 7.67 (dd, J = 8.0, 1.2 Hz, 1H); 7.49 (m, 1H);

7.46 (dd, J = 7.8, 1.4 Hz, 1H); 7.25 (m, 3H); 6.72 (br s, 2H); 6.50 (t, J = 8 Hz, 1H); 5.79 (d, J =

7.6 Hz, 1H); 5.39 (m, 1H); 3.49 (dd, J = 18, 6.8 Hz, 1H); 3.35 (dd, J = 17.8, 1.4 Hz,

13 1H); C NMR (100 MHz, CDCl3) δ 161.7, 143.9, 140.3, 137.8, 133.3, 127.2, 126.6, 125.6,

123.6, 123.4, 114.2, 108.3, 107.9, 79.7, 37.8; HRMS (ESI): Mass calculated for

C16H13BrN2NaO [M+Na]+, 351.0103. Found [M+Na]+, 351.0105.

2-((3S,8R)-3,8-dihydro-8H-indeno[1,2-d]oxazol-2-yl)-6-(4,4,5,5-tetramethyl-

N 1,3,2-dioxaborolan-2-yl)aniline. The literature procedure [48] was followed and O 1 NH2 I-120 the product was isolated as a yellow-white solid (47%). H NMR (400 MHz, B O O CDCl3) δ 7.71 (dd, J = 7.6, 1.6 Hz, 1H); 7.59 (dd, J = 7.4, 1.8 Hz, 1H); 7.40 (m,

1H); 7.16 (m, 3H); 6.47 (t, J = 7.6 Hz, 1H); 5.69 (d, J = 8.0 Hz, 1H); 5.27 (m, 1H); 3.40 (dd, J

=17.8, 6.6 Hz, 1H); 3.26 (dd, J = 17.6, 1.4, 1H); 1.25 (d, J = 2.4 Hz, 12H); 13C NMR (100 MHz,

CDCl3) δ 164.8, 155.0, 142.7, 140.7, 139.9, 133.8, 128.4, 127.5, 125.6, 125.4, 114.4, 108.3, 83.7,

81.1, 39.9, 25.1, 25.0;

CF3 2-(3,5-bis(trifluoromethyl)phenyl)-5-((3S,8R)-3,8-dihydro-8H- OH B N CF3 indeno[1,2]oxazol-2-yl)-1-hydroxy-1,4-dihydrobenzo[1,5,2]diazaborinin-

N O H 3-one. The same procedure to develop I-114 was followed and the product O N I-121

! 47! 1 was isolated as a white solid (88%). H NMR (400 MHz, CDCl3) δ 12.29 (s, 1H); 8.09 (dd, J =

7.8, 1.4 Hz, 1H); 7.90 (s, 1H); 7.83 (dd, J = 7.4, 1.4 Hz, 1H); 7.76 (s, 2H); 7.58 (m, 1H); 7.28 (d,

J = 2.8 Hz, 4H); 7.15 (t, J = 7.6 Hz, 1H); 5.87 (d, J = 8.0 Hz, 1H); 5.47 (m, 1H); 3.55 (dd, J = 18,

6.8 Hz, 1H); 3.43 (dd, J = 17.7, 1.4 Hz, 1H); HRMS (ESI): Mass calculated for

C25H16BF6N3NaO [M+Na]+, 554.1081 was not found. Instead, found [M+Na]+, 546.1423 do to an exchange with one methanol and 600.1505 do to an exchange with two equivalents of methanol.

! 48!

Chapter 2: Organocatalytic Acidity Amplification as a Strategy for Insertion

Chemistry

Portions of this chapter appear in

Couch,! E.! D.;! Auvil,! T.! J.;! Mattson,! A.! E.! “Organocatalytic! Acidity! Amplification:! A! New! Strategy!for!Insertion!Chemistry”!Chem.Eur.)J.)2014,)20,)8283Q8287.))!!

! 49!

Chapter 2: Organocatalytic Acidity Amplification as a Strategy for Insertion Chemistry

2.1 Heteroatom-Hydrogen Insertions by α-Diazocarbonyl Compounds

The decomposition of diazo compounds in the presence of heteroatom-hydrogen (X−H) bonds provides access to complex chemical structures. Transition metals have dominated the area of catalytic X−H insertion reactions and, until recently, technologies permitting asymmetric induction in these reactions had been troublesome. Even more recently, our group has reported the activation of α-nitrodiazoacetates by HBDs for catalytic N−H insertion/multicomponent coupling reactions, and we wanted to further investigate the power of (thio)urea catalysis for insertion reactions with more electron-rich α-diazocarbonyl compounds.[49] Although at the onset of our studies the potential mode of activation enabling ureas to catalyze insertion reaction of α- diazocarbonyl was not obvious to us, our investigation into X−Η insertion pathways commenced.

2.1.1 Synthesis of Diazo Compounds

Beginning with the first synthesis of ethyldiazoacetate in 1883,[50] diazo compounds have been recognized as versatile intermediates for a variety of chemical transformations (Scheme

2.1). Thermally or photochemically induced expulsion of molecular nitrogen can provide access to carbene intermediates through short-lived metal carbenoids, or exposure to acid can provide carbocation-like diazonium intermediates through protonation. These intermediates have the potential to undergo reactions like cyclopropanation, X−H (X= C, O, S, N, etc.) insertion reactions, and the formation of a variety of ylides. More than 100 years after the first synthesis of

! 50! a diazo compound, several procedures have enhanced structural and functional diversity of diazo carbonyl compounds (Scheme 2.1).[51] Although several methods are used in the synthesis of diazo compounds, two main strategies, (1) diazo group transfer and (2) dehydrogenation of hydrazones will be outlined.

Curtius 1883

O NOONa O N H3N 2 O O

1 2

NH2 H 2 1 2 diazo group R N2 dehydrogenation R COR R1 N transfer of hydrazones R1 H R2

Scheme 2.1. First synthesized diazo compound and strategies towards accessing diazo compounds

Diazo group transfer reaction occurs between the appropriate azide reagent and a methylene group. Installation of two strong electron acceptor substituents on the methylene group along with improvements of azide transfer agents have led to advancements in this method.

Charette and co-workers developed trifluoromethanesulfonyl azide, a powerful diazotransfer reagent, to directly install the diazo functionality onto α-nitrocarbonyl compounds, α- cyanocabonyl compounds, and α-sulfonylcarbonyl compounds.[52] Reaction of a hexane solution of trifluoromethanesulfonyl (trifyl) azide with ethyl nitroacetate in acetonitrile provided ethyl α- nitro-α-diazoacetate II-1 in 88% yield (Scheme 2.2). The scope of the reaction was expanded to prepare α-cyano-α-diazo-carbonyl compounds II-2, phenyl sulfonyl diazoacetophenone and

! 51! diethyl diazomalonate in high yields using trifyl azide. Taber and Tian utilized sulfonyl azides and DBU to prepare α-aryl-α-diazoketones.[53] The authors found 2,4,6-triisopropylbenzene- sulfonyl azide (TIBSA) in toluene provided II-3 in an 80% yield.

Charette 2000 II-1 Taber and Tian 2007 O O CF SO N (1.1 equiv) 3 2 3 NO2 NO2 EtO EtO pyridine (2 equiv) O N N CH3CN, hexanes 2 N S 20 C, 3-15 h N ° 88% yield O II-3

N2 Charette 2003 TIBSA (1.0 equiv) II-2 O DBU (3 equiv) O O O CF3SO2N3 (1.1 equiv) CN toluene CN PhO PhO pyridine (2 equiv) 80% yield CH3CN, hexanes N2 0 °C to RT, 14 h 93% yield

Scheme 2.2. Diazo group transfer examples

Dehydrogenation of hydrazones is another common strategy for synthesizing diazo compounds. Hydrazones are generally accessed from the corresponding ketone or aldehyde and hydrazine derivative. From here, a number of oxidizing reagents can be used, most commonly heavy-metal-based oxidants such as yellow mercury oxide, manganese dioxide, silver (I) oxide, and lead tetraacetate are used.[54] In 2007, Javed and Brewer offered a metal-free alternative method using “activated” DMSO to prepare diazo compounds via dehydrogenation of hydrazones.[55] Under their optimized conditions, isolation of stable diazo compounds can be accomplished via simple vacuum filtration. Subsequent treatment of the resulting diazo compound solution with a variety of carboxylic acids provided the corresponding esters in good yields.

! 52! Javed and Brewer (2007)

Ph H2N O R1= R2 = Ph; 88% yield N Oxalyl Chloride (1.05 equiv.) N2 i) filtration + Et N•HCl 1 2 3 H O R = Ph,R = H; 75% yield 1 2 R1 R2 DMSO (1.1 equiv.) R R ii) PhCO2H R1= 9-anth,R2 = H; 90% yield 1 2 Et3N (2.1 equiv.) (Precipitate) R R 1 2 R = Ph,R = CH3; 61% yield CH2Cl2, Et2O, -78 °C

Scheme 2.3. Metal-free example for dehydrogenation of hydrazone to diazo compound

2.1.2 X-H Insertion Reactions of Diazo Compounds

Diazo compounds provide access to an array of transformations such as X–H insertions, cyclopropanations, ylide formations, Wolff rearrangements, and α-diazocarbonyl compounds.

Several transition metals have been used to exploit the carbenoid intermediate, however, Cu(I) and Rh(II) complexes are the two most efficient catalysts for insertion reactions.[56] Peter Yates utilized copper metal in one of the first reports of X–H insertion reactions in 1952. [57] In the presence of the copper catalyst, no Wolff-rearrangement to the α-alkoxyketone product was formed. Treatment of α-diazoacetophenone with phenol, thiophenol, and aniline resulted in the corresponding insertion products in 63%, 67% and 33% yield respectively (Scheme 2.4).

Yates 1952

O H O X X = O, 63% yield H H Cu (0) H + X = S, 67% yield Neat, 60-80 °C X X = NH, 33% yield N2

Scheme 2.4. Early example of X−H insertion reactions

Since Yates’s initial report, X–H insertion chemistry has become well developed with the

! 53! synthesis of a variety of new C−X bond formation in a regio- and stereocontrolled manner.

Recent reports from the Fu and Zhou groups have revealed advances in the challenging area of asymmetric intermolecular N–H insertions reactions. In 2007, the Zhou group reported a chiral spiroindane-bis-oxazoline ligand II-4 for copper(I) catalyzed, asymmetric N-H insertions

(Scheme 2.5).[58] In the same year, the Fu group reported the use of a chiral bipyridyl ligand II-5 on copper(I) for the asymmetric insertion of α-diazocarbonyl compounds into the N−H bonds of carbamates (Scheme 2.5).[59] Both methods, although differing greatly in ligand structure, enabled access to highly enantioenriched α-aminoesters (up to 94% ee) in excellent yield.

Zhou Fu

5 mol % CuCl O O 7 mol % CuBr O H 6 mol % NaBArF 6 mol % AgSBF R1 6 N 6 mol % II-4 + R2 NH Ph t-BuO * Ph t-BuO 2 8 mol % II-5 t-BuO CH Cl , 25 ºC H Me 2 2 N2 DCE, 23 ºC BocHN

Me O Me Me Me Me N Ph Me 93% yield Fe Me 74% yield 96% ee N Ph N N 94% ee Fe Me O Me Me II-5 Me II-4 Me

Scheme 2.5. Recent asymmetric N−H insertion reactions

S–H insertions reactions of α-diazocarbonyl compounds provide access to sulfur- containing compounds found to have significant biological activities. Stereocontrol of the new C–

S bond would be advantageous, but asymmetric versions of these reactions have been the most ! 54! problematic among X–H insertions reactions.[60] Rationale for this difficulty can be explained by two problems inherent of metal catalyzed processes with sulfur. First, the high stability of free sulfonium ylides, relative to other heteroatomic ylides, leads to undesired reaction pathways.

Secondly, sulfur’s high affinity for coordination to late transition metals leads to decomposition of the catalyst. However, in 2009 Zhou and coworkers discovered that utilization of the same spiroindane-bis-oxazoline ligand used in their asymmetric N−H reactions (II-4) in combination with copper(I) could catalyze the asymmetric S–H insertion of benzylic mercaptans with high enantiomeric control (up to 85% ee).[61]

O O 5 mol % CuCl R2 6 mol % NaBArF 1 * R1 R2 R O 59-91% yield O + Ar SH 6 mol % II-4 S 44-85% ee N 2 CHCl3, 80 ºC Ar

Scheme 2.6. Zhou and coworkers demonstrate an asymmetric S−H insertion reaction

Recent reports from Zhou and coworkers further expanded on asymmetric S–H insertion reactions by using a Rh(II) and spirophosphoric acid (II-7) cocatalytic system.[62] The proposed mechanism involves the decomposition of the diazo compound to form a metal associated sulfonium ylide. After the free sulfonium ylide is released, it undergoes a spontaneous 1,2- hydrogen shift II-8 to provide the corresponding S–H insertion product. Enantiocontrol of the stereocenter is introduced by II-7 mediated chiral 1,3-proton transfer of the enol tautomer of the

S–H insertion product, providing up to 98% ee in the products.

! 55! O O 2 mol % II-6 Ar Ar * 49-91% yield MeO + R SH 2 mol % II-7 MeO 58-98% ee N S 2 cyclohexane, 25 ºC R

i-Pr i-Pr i-Pr i-Pr

i-Pr i-Pr H O Rh O O O O O OMe P P O Rh O OH O O H i-Pr i-Pr RS Ar i-Pr i-Pr 4 i-Pr i-Pr II-6 II-7 II-8

Scheme 2.7. Further advancements in S−H insertion by the Zhou group

Until recent reports by Fu and coworkers, asymmetric O–H insertion mechanisms had also been problematic. In 2006, Maier and Fu reported the first effective catalyst for enatioselective O–H insertions generating α-alkoxy and α-hydroxy carbonyl compounds in good enantiomeric excess (up to 98% ee).[ 63 ] The authors use a copper complex with chiral biazaferrocene ligand II-9 to couple a variety of alcohols with methyl α-diazo-α-phenylacetate in good to excellent yields and modest to excellent enantioselectivity.

Me Me 2 mol % Cu(OTf)2 Me Me O 4 mol % H2O O Fe Me Ar1 3.8 mol % II-9 1 + H OAr2 Ar N N MeO MeO DCE, 23 ºC Fe 2 Me Me N2 H OAr Me Me 85–98% yield (+)-II-9 21–98% ee Me

Scheme 2.8. Fu’s work on asymmetric O−H insertion reactions

! 56!

A year later Zhou and coworkers offered an improvement to Fu’s asymmetric O–H insertions with their report of the first efficient chiral catalyst for enantioselective insertion of carbenoids into O−H bond of phenols.[64] In high yields and enantioselectivities up to 99.6%, the insertion reaction of ethyl α-diazopropionate and phenol could be accomplished using a copper catalyst generated in situ. The addition of 5 Å molecular sieves to the optimized conditions provided their best yield of 87% and enantioselectivity of 99%.

H O O 5 mol % CuCl O 6 mol % NaBArF R2 + R2 68–88% yield R1O 6 mol % II-4 R1O 95–>99% ee N H O 2 5Å MS, CH2Cl2, 23 ºC R3 R3

Scheme 2.9. Zhou’s asymmetric O−H insertion into phenols.

2.1.3 X–H Insertion Mechanism

Many of these structural motifs prepared by X–H insertion reactions can be found in biologically active molecules or potential drug leads. The potential utility of diazo insertion chemistry in drug discovery drives the development of alternative, metal-free catalysts to control these useful reactivity patterns typically governed by transition metal catalysis. The advantages of metal-free catalyst systems include: (i) less toxicity and expense, (ii) the avoidance of intrinsic mechanistic problems linked to metals, and (iii) prevention of trace metals contaminating the products. The development of metal-free catalysts for diazo compound activation requires an understanding of the potential reaction pathways leading to the desired insertion products.[65]

Several insertion mechanisms have been considered, but three are generally accepted in carbene ! 57! insertion chemistry.[66] The first is a concerted mechanism in which the carbene inserts directly

[67] into the X–H bond in a single step (A, Scheme 2.10). Second, is a stepwise protonation of the carbene/diazo compound generating a carbocation/diazonium intermediate, which undergoes a subsequent nucleophilic attack by the heteroatomic counterion (B). Last, is a stepwise mechanism that first undergoes a nucleophilic attack on the electrophilic carbene to form an ylide intermediate, followed by a rapid 1,2-hydrogen shift (C).[68] These three potential pathways are generally considered when probing an X–H insertion mechanism.

H XR3

R1 R2

A

XR3 N2 H H XR3 HXR3 B R1 R2 R1 R2 R1 R2

C

H R3 1,2-H transfer X

R1 R2

Scheme 2.10. Commonly accepted X−H insertion mechanisms

In 2011, Crousse and coworkers reported the use of fluorinated alcohols to promote metal-free insertion reactions of diazocarbonyls into acid derivatives.[69] Their method provided efficient insertion into a variety of alkyl and aryl acids, resulting in the corresponding acetoxy esters (Scheme 2.11). The authors proposed that the fluorous alcohols’ inherent ionizing power and HBD ability could reinforce the acidity of the carboxylic acid. This increased acidity was suggested to then facilitate a protonation of the diazo compound and thus operating through

! 58! pathway B (Scheme 10). Although this discovery has greatly advanced the field of metal-free insertion chemistry, it requires the use of fluorous alcohols in superstoichiometric amounts; the field could greatly benefit from a catalytic variant with the potential to control the reaction’s stereochemical outcome.

O R O R R BocHN O CO2Et R O CO2Et N2 CO2Et R HFIP or TFE, RT R = H, Ph

R R

RO2S (R)2B O CO2Et O CO2Et

R

(OR)2P(O) O CO2Et

Scheme 2.11. Metal-free O−H insertion reaction

Previous research in our group revealed that select ureas and thioureas are feasible hydrogen bond donor (HBD) catalysts in N–H insertion/multicomponent coupling reactions with

α-nitrodiazoesters II-11 (Scheme 12). We hypothesized that our urea catalyst II-10 amplifies the electrophilicity of II-11 through well-precedented hydrogen bonding to the nitro group (Scheme

2.12). Mechanistic studies have provided evidence against the formation of a free carbene in these reactions, leading us to believe N–H insertion component proceeds through either mechanism B or C (Scheme 2.10). The proposed mechanistic pathway first involves activation of

II-11 by II-10 to form intermediate II-12, which can formally insert into N–H bond of aniline.

The insertion is then followed by the extrusion of nitrite, forming proposed iminium ion I-14 that can undergo Friedel-Crafts arylation with a second equivalent of aniline. ! 59! O O CF N II-11 F F 3 EtO O B O N2 R N N CF3 H H N O II-10 H O O N N H R1 EtO O R N N O N II-12 H O O N 1 N H R EtO O H NH N2 II-13 Ph PhNH2

NO2

O NH2 PhNH2 O H EtO EtO N H Ph NH II-15 II-14

Scheme 2.12. Proposed nitro diazo compound insertion mechanism

2.2 Co-catalytic Reaction Strategies

2.2.1 Phosphoric acid catalyzed reactions

Chiral Brønsted acids can serve as catalysts in a variety of enantioselective processes.[70]

Chiral phosphoric acid derived catalysts[71] are emerging as one promising family of Bronsted acid catalysts since their introduction about a decade ago by Akiyama et. al.[72] and Uraguchi and

Terada.[73] Early reports from Akiyama et. al. demonstrated a catalytic amount of a strong

Brønsted acid could promote both a Mannich-type and an aza-Diels-Alder reaction.[74] Building from their initial success, they hypothesized using the same reactions in the presence of a chiral

Brønsted acid, would foster an asymmetric response in the products (Scheme 2.13).

! 60! Akiyama 2004

HO chiral HO phosphoric OTMS acid N + HN OMe CO2Me R R II-16 II-17 II-18

Scheme 2.13. Akiyama’s proposal to achieve enantioselectivity using chiral phosphoric acids

Their studies began by reacting aldimines II-16 and silyl ketene acetals II-17 in the presence of readily prepared chiral phosphoric acid catalysts to afford II-18. Using a simple chiral phosphoric acid catalyst provided no enantioselectivity, so a library of 3,3’-substituted chiral phosphoric acid were synthesized.[24b] Addition of phenyl rings at the 3,3’ position provided 27% ee (II-22b, Scheme 2.14), and with the installation of 4-nitrophenyl groups, enantioselectivity was increased to 87% in a 96% yield after only 4 hours (II-22e). Continued optimization demonstrated only 10 mol% of the Brønsted acid catalyst was necessary, and the use of aromatic solvents led to higher enantioselectivies. A variety of aromatic aldehyde-derived aldimines with an essential ortho hydroxy group provided excellent yields with good to high enantioselectivities. Enantioselectivity arises from shielding of the phosphoric acid moiety by the diaryl groups during its interaction with the aldimine (II-19).

! 61! HO HO OTMS II-22 + H HN N OR NO2 CO2R R R R R II-19 II-20 II-21 O H Ar O N P O O Ar Ar t (h) Yield% ee% II-22a: H 22 57 0 O O II-22b: C H 20 100 27 P 6 5 II-23 O OH NO2 II-22c: 2,4,6-Me3C6H2 27 100 60

Ar II-22d: 4-MeOC6H4 46 99 52

II-22 II-22e: 4-NO2C6H4 4 96 87 ! !

Scheme 2.14. Chiral substituted phosphoric acid effects on rates, yields and enantioselectivity !

Uraguchi and Terada demonstrated a simple chiral phosphoric acid could selectively promote the addition of acetyl acetone to II-24 (Scheme 2.15).[25] They observed installation of

3,3’-bisdiaryl substituents increased enantioselectivity. Phenyl rings at the 3,3’-positions II-26b, increased selectivity to 56% ee, and para substituted phenyl rings II-26c-d, increased selectivity up to 95% ee. In the presence of just 1 mol% of their optimal catalyst II-26d, para-and ortho- substituted arylimines underwent addition with excellent yields (93-98%) and excellent enantioselectivity (92-98% ee). It is also important to note that up to 80% of II-26d could be recovered after the reaction, making these organocatalysts highly attractive.

R 2 mol% II-26 R Yield% ee% Boc II-26a: H 92 12 Boc HN O O N 1.1 equiv acac P * Ac II-26b: Ph 95 56 R O OH R H CH2Cl2 rt, 1h Ac II-26c: 4-Biph 88 90

II-24 II-25 R II-26d: 4-(β-Naph)-C6,H4 99 95 II-26

Scheme 2.15. Chiral phosphoric acid substituents affect enantioselectivity

! 62!

2.2.2 HBDs can increase acidity of Phosphoric acid-derived catalyst

The relationship between acidity and reactivity/selectivity has been well studied and demonstrated in organocatalysis.[19-28] Cheng et. al. recently reported computationally predicted pKa values for several known Brønsted acid catalysts ranging in pKa from -9.06 to 12.18, and used these results to design new catalysts with the appropriate acidity levels.[75] The authors proposed a self-assembly of organocatatlysts in situ through noncovalent interactions could be a potential pathway for asymmetric catalysis. For example, biphenyl-2,2’-diol phosphoric acid II-

27 has a pKa of 3.58, and upon binding with Schreiner’s thiourea II-28 or squaramide II-29, the complexes have pKas of -1.15 and -2.36, respectively (Figure 2.1). The HBD interaction lowers the pKa often leading to enhanced reactivity of the Bronsted acid catalyst.

CF3

S F C 3 CF S 3 H S N N H N H N H H H CF O O O O 3 O O P P P O OH O OH O OH

II-27 II-28 II-29

3.58 -1.15 -2.36

Figure 2.1. HBD acidity amplification of biphenyl-2,2’-diol phosphoric acid

In earlier reports, Cheng and coworkers calculated that HBDs have the potential to reduce

[76] the pKa of proline up to 9 units in nonpolar solvents such as toluene. Cocatalytic systems using

! 63! chiral diols, Schreiner’s thiourea, and guanidinium salts have been shown to dramatically increase reaction rates and diastereo- and/or enantioselectivity in proline-catalyzed reactions. The initial formation of proline-cocatalyst HBD complex has been proposed to be the cause of the higher activity and selectivity of proline. A direct correlation can be drawn between the affects a HBD has on the pKa of an acid and their synergistic activity, which is why several reports on asymmetric cooperation of cocatalytic systems have recently arisen.

2.2.3 (Thio)urea-Brønsted Acid Co-catalytic Systems

Although there are numerous examples of cocatalytic systems,[ 77 ] the Bronsted acid/(thiourea) cocatalysis work accomplished independently by the Jacobsen and Seidel groups will mainly be discussed. In 2009, Jacobsen and coworkers published their findings on an enantioselective protio-Pictet-Spengler reaction promoted by a chiral thiourea and benzoic acid co-catalytic system (Scheme 2.16).[78]

NH 2 thiourea 20 mol% NH BzOH (20 mol%) N X H RCHO (1.1 equiv) N R toluene, RT X H II-30 II-31

Scheme 2.16. Cocatalytic asymmetric Pictet-Spengler

A screen of the catalyst structure for one-pot imine formation and thiourea-catalyzed

Pictet-Spengler found II-33? to be the optimal catalyst (Table 2.1). Synthesis of II-33 can be easily accomplished in 3 steps and, in the presence of benzoic acid, afford the desired product in

74% yield and 94% ee. Using the optimal reaction conditions, it was found a large number of

! 64! variably substituted benzaldehydes and less electron-rich tryptamines were tolerable in the methodology. Aliphatic aldehydes also demonstrated reactivity in the cyclization, but it was noted that unlike the aryl substrates, cyclization with aliphatic aldehydes occurred without the acid additive and in high enantioselectivity.

NH 2 II-33 20 mol% NH BzOH (20 mol%) MeO N RCHO (1.1 equiv) H MeO N R toluene, RT H II-32 II-34

R t (h) Yield% ee%

p-ClC6H4 66 78 94 CF3 p-FC6H4 78 81 92 Me I-Pr S p-BrC H 74 79 94 6 4 N Bn N N CF3 m-BrC6H4 19 87 94 H H O o-BrC6H4 11 74 95 II-33

p-MeC6H4 92 78 85 Ph 70 94 86

Table 2.1. Various aldehydes undergo a cocatalyzed one-pot Pictet-Spengler

The proposed reaction pathway begins with initiation of imine protonation by II-35 activated benzoic acid complex II-36 (Scheme 2.17). After protonation of the imine, the ion-pair

II-38 is formed; it is likely through II-38 that the enantioselectivity arises. Finally, after cyclization and subsequent aromatization of II-39, the two catalysts can be introduced back into the catalytic cycle.

! 65! O S HO product + R R* BzOH N N H H S R R* II-35 S N N N H R R* H H N N

O O R H H N H II-36 O O H H II-39 S

R R* H N N N H H R O O N

NH R N H II-37 II-38

Scheme 2.17. Proposed cocatalytic cycle of Pictet-Spengler reaction

Later in 2010, Jacobsen and coworkers further explored their cocatalytic methodology with a computational analysis in the context of an asymmetric Povarov reaction.[79] An extensive amount of chiral (thio)ureas and Brønsted acids were evaluated to determine the best cocatalyst combination for the Povarov reaction between imine II-40 and 2,3-dihydrofuran II-41 (Scheme

2.18). The arrangement of bifunctional sulfinamido urea II-34 and ortho-nitrobenzenesulfonic acid (NBSA) in a 2:1 ratio provided the product in high enantioselectivity. All parts of the catalyst were found to be crucial to the reactivity and selectivity of the reaction. In the presence of a thiourea without the sulfinamide group, a catalytic reaction occurred but in lower selectivity.

The opposite was the case when a phosphinic amide was present without the urea moiety, modest selectivity was observed, but reduced reactivity was observed. The acid without the (thio)urea catalyst provided a racemic mixture of product.

! 66! CF3

II-43 (10 mol%) S O NBSA (5 mol%) N + HN toluene, 48h, 4 °C F3C N N Ph H H H Ph O HN O II-41 S II-40 II-43 II-42 95% conversion 83% ee

Scheme 2.18. Cocatalytic Povarov reaction

Using 1H NMR spectroscopy, Jacobsen and coworkers performed the reaction in the presence of catalytic quantities of HOTf and monitored the reaction kinetics. These studies revealed a first-order dependence of II-41 and HOTf and a zeroth-order of the II-40; indicating a quantitative protonation of the II-40 by HOTf forming a partially insoluble salt II-45 (Scheme

2.19). Upon treatment of the in situ formed II-45 with a HBD, the reaction mixture became homogeneous due the formation of a more organic-soluble ion pair II-46. To demonstrate a HBD interaction occurs, both achiral thiourea II-44 and chiral thiourea II-43 were added to II-45. An increase in solubility of II-45 by a factor of 4 was observed in the presence of II-44 and an over one fold increase seen in the presence of II-43. Further examination with 1H NMR demonstrated a 0.14 ppm up-field shift using II-43; suggesting a greater charge separation between the iminium ion and the triflate anion. This is noticeably different compared to II-44, which shifts the formal proton 0.92-ppm down-field, indicating a tight ion-binding interaction. These two studies provide evidence that an ion pair can be formed in solution, which provides an enhanced reactive intermediate iminium ion for reaction.

! 67! CF3 CF 3 O

O H + N F3C N N • CF SO 3 3 H H F3C N N H H H Ph H N O O II-44 II-45 S Ph H F3C O II-46 Scheme 2.19. Ion-pairing studies with HBD catalyst

The ability to predict the enantiodetermining steps of a reaction, and the transitions states involved during these steps, is crucial to the rational design of new and improved chiral catalysts.

Seidel and coworkers designed a covalently linked, chiral thiourea-Brønsted acid catalyst which is able to promote the first catalytic asymmetric Povarov reaction with secondary aromatic amines.[80] With their new catalyst design, they anticipated an increase in acidity of the acid portion of the catalyst through a conjugate base stabilization by the attached thiourea II-47

(Scheme 2.20). This would allow for two different types of substrate/catalyst ion pairs to occur.

The first would be a simple protonation of a substrate, which could form a rigid ion pair with the bound thiourea-conjugate base complex II-48. A second pathway would be the catalyst promoting a condensation reaction of two substrates, which would then be tethered together in a cationic pair. The tethered substrates would decrease the potential for the conjugate base to interact with the cation, causing the formation an ion-pair II-49.

Ion pair type 1 Ion pair type 2

S S substrate 1 S Ar Ar Ar N N substrate N N substrate 2 N N substrate 1 substrate H H H H H * -H2O H H * * substrate 2 X II-48 XH X II-47 II-49

Scheme 2.20. Bound cocatalytic ion pair possibilities

! 68! Extensive structural screening of the catalyst revealed the thiourea derivative with a tethered tetrabromo benzoic acid derivative (II-54, Scheme 2.21) to be the best catalyst. A crystal structure revealed the enhanced acidity of II-54 could be contributed to an internal hydrogen bonding interaction between the N–H amide and the sulfur. This polarization provides a stronger anion-binding site that interacts with the carboxylate anion of a neighboring II-54. With optimal catalyst II-54 in hand, the Povarov reaction was tolerant of indolines (II-50) substituted in the 5-position with various enamides (II-51) and electronically diverse aldehydes (II-52) giving rise to II-53 in high yields and enantioselectivity.

CF3

S R

R O N N CF3 II-54 H H + + RCHO O N O NH N N H N R Br COOH II-54 II-50 II-51 II-52 II-53 Br Br Br Scheme 2.21. Optimal cocatalytic system for Povarov reaction!!

Even more recently, Seidel and coworkers built from Jacobsen’s initial success of Pictet-

Spengler reactions with modified tryptamine, and utilized their same linked co-catalytic system to accomplish the reaction with unmodified tryptamine (Scheme 2.22).[81] In the presence of II-54, differently substituted benzaldehydes were tested to find that electron-withdrawing groups at the para position provided high yields and enantioselectivities. Benzaldehyde itself was also able to afford the desired product in good selectivity, but electron-donating groups at the para position were reported as poor substrates.

! 69! NH2 II-54 (10 mol%) NBoc + RCHO + (Boc) O N 2 H PhMe (0.05 M) N R H 1.1 equiv 2.2 equiv II-55 3 Å MS, rt, 48 h II-56

Scheme 2.22. Covalently linked HBD activated Brønsted acid catalyzed Pictet-Spengler

2.3 Difluoroboronate Urea Catalyzed Insertion Reactions

2.3.1 Introduction to New Approach to Metal-Free insertion reactions

Previous studies in our group have utilized boronate ureas to activate nitrodiazo compounds II-57 for N–H insertion reactions. More recently, however, our studies have turned to urea-activated insertion reactions involving more basic diazo compounds, such as aryldiazoacetates II-59. It was unclear to us at the beginning of our studies how II-58 would effect the reaction, but much to our surprise, we found that our boronate urea was an excellent tool for select O−H and S−H insertion reactions.[82]

Activation of Activation of Nitro Diazo Comounds Aryl Diazo Compounds O NO RO 2 RX–H II-57 N2 O O Ar1 Ar2 ArNH2 N N Ar RO Nuc H H II-59 N II-58 2 O O Ar Nuc RO RO X NHAr R

Scheme 2.23. Previous HBD amplified insertion reaction and new HBD reaction

! 70!

Investigation into the mechanism, in conjunction with recent reports of HBD/Brønsted acid cocatalytic systems, allowed us to propose that difluoroboronate urea II-10 (Scheme 2.24) has the capability of amplifying the acidity of Brønsted acids. It is feasible that upon complexation of II-10 via hydrogen bonding to an acidic functionality (X−H), complex II-60 could be formed. This would initiate the protonation the diazo compound II-61 (Scheme 2.24).

Finally, upon expulsion of nitrogen gas and addition of the conjugate base to the diazonium ion

II-62, the HBD can return into the catalytic cycle.

O O CF F F 3 X R1 H R Ar1 Ar2 O B N N OR2 -N R1 O 2 N H H H OR2 N H 1 X Ar X N N CF3 R N H H H X H R H N II-62 II-10 II-60 II-61 O Ar2

Scheme 2.24. Potential HBD catalyzed X−H insertion mechanism

2.3.2 HBD Catalyst Screen for the Organocatalytic X-H Insertion

Our studies commenced by testing a variety of HBD catalysts for the insertion of α- aryldiazoester II-63a (Table 2.2) into the O–H bond of acetic acid and the S−H bond of thiophenol. We were initially met with disappointment when conventional urea II-65a and thiourea II-65b were found to be completely inactive, even with prolonged reaction times (up to 2 weeks) and elevated temperatures (up to 50 °C). Pinacolboronate ureas were also inactive catalysts for the X–H insertion reaction. Not all too surprisingly, our first observation of catalysis

! 71! occurred when electron withdrawing substituents were incorporated into the difluoroboronate urea scaffold; at 2.5 mol % loading difluoroboronate ureas II-65d and II-65e showed mediocre conversion to the O–H insertion product II-64a (68% and 75% yield), while the optimal HBD II-

10 gave rise to II-64a in 91% yield. Moreoever, we found that catalyst loadings for this reaction had a substantial effect on its overall efficiency; higher catalyst loadings provided lower yields, which we attributed to both solubility and self- aggregation of II-10. Very similar results were observed under slightly different reaction conditions for the insertion of II-63a into the S−H bond

[83] of thiophenol. Only select ureas benefiting from both internal boron activation and appropriate electron-withdrawing substitution patterns, II-65d and II-65e, provided the insertion product II-

67a in 78% and 77% yield, while optimal catalyst II-10 provided II-67a in 90% yield.

Because only difluoroboronate ureas were operational as catalysts, we were curious if the reaction was proceeding through Lewis acid activation via heteroatom coordination to the active boron atom present in our catalyst scaffold. Attempts to synthesize a N,N-dimethylated analogue of II-10, for use as a Lewis acid control, have been unsuccessful to date. However, the use of difluoroboronate acetanilide II-66 (<5% yield by 1H NMR spectroscopy) as a control catalyst provided sufficient evidence against Lewis acid catalysis, and is perhaps a better control due to an amide’s decreased Lewis basicity relative to a urea’s. The lack of reactivity of control catalyst II-66 suggests that the hydrogen-bonding urea functionality is also necessary component of the catalyst structure, and simple Lewis acid catalysis at boron is unlikely.

! 72! MeO MeO O O 2.5 mol % cat + AcOH OMe OMe PhMe (1.2 equiv.) H OAc II-63a N 23 ºC, 24 h 2 II-64a

Effect of Urea Structure on Catalysis:

CF3 CF3 F F F F B B X O O R R

F3C N N CF3 N N N N H H H H H H X=O, II-65a: <5% yield[a] R=H, II-65c: 6% yield[a] II-65f: <5% yield [a] [a] X=S, II-65b: <5% yield R=3,5-F2, II-65d: 68% yield R=4-CF3, II-65e: 75% yield F F CF F F 3 B B Catalyst Loading: O O 2.5 mol%: 91% yield N Me N N CF3 [a] H H 0 mol%: <5% yield Me II-10 II-66: <5% yield[a]

MeO MeO O O 2.5 mol % cat + PhSH OMe OMe PhCF (1.2 equiv.) 3 H SPh II-63a N 23 ºC, 12 h 2 II-67a

Effect of Urea Structure on Catalysis:

CF3 CF3 F F F F B B X O O R R

F3C N N CF3 N N N N H H H H H H X=O, II-65a: <5% yield[a] R=H, II-65c: 6% yield[a] II-65f: <5% yield [a] [a] X=S, II-65b: <5% yield R=3,5-F2, II-65d: 78% yield R=4-CF3, II-65e: 77% yield F F CF F F 3 B B Catalyst Loading: O O 2.5 mol%: 90% yield N Me N N CF3 [a] H H 0 mol%: <5% yield Me II-10 II-66: <5% yield[a]

Table 2.2. Catalyst optimization screen

! 73!

2.3.3 Organocatalytic X-H Insertion Optimization and Substrate Scope

With our best catalyst in hand, our study for the optimal reaction conditions began.

Utilizing the most active aryldiazo compound II-63a, insertion into the X−H bond of thiophenol and acetic acid began with a solvent screen. In the presence of 10 mol% of II-10, it was found t-

BuOMe was a poor solvent (10%, entry 1, Table 2.3) while, toluene (68%, entry 2) and chlorinated solvents, such as CHCl3 and 1,2-dichloroethane (DCE), provided moderate yields (58 and 67%) of II-67a at 23 °C after 24 hours. It wasn’t until the use of α,α,αQTrifluorotoluene

(PhCF3) that a higher yield of II-67a (85%) was observed. With this knowledge, a solvent screen of toluene (91%), MTBE (<5 %), DCE (54%), PhCF3 (90 %) and CHCl3 (45%) was used in the insertion into acetic acid. Although comparable results were seen for toluene (entry 6) and PhCF3

(entry 9), a smaller background rate was observed in toluene (<5%).

MeO MeO MeO O PhSH AcOH O 10 mol% II-10 O 10 mol% II-10

OMe OMe OMe 23 ºC, 24 h H SPh 23 ºC, 24 h H OAc II-63a N2 II-67a II-64a

entry solvent yield entry solvent yield 1 t-BuOMe 10% 6 PhMe 77% 2 PhMe 68% 7 MTBE <5%

3 CHCl3 58% 8 DCE 51%

4 DCE 67% 9 PhCF3 75%

5 PhCF3 85% 10 CHCl3 45%

Table 2.3. Solvent screen for X−H insertion reactions

! 74! Further optimization provided shorter reaction times and lower catalyst loadings of 2.5 mol% were tolerated for S−H insertion reactions, providing II-67a in 90% yield after 12 hours at

23 °C. However, insertion of II-63a into the O−H bond of acetic acid took 24 hours to go to completion, but a decrease in the amount of catalyst actually provided an increase in yield. When

2.5 mol% of II-10 was used, II-64a was afforded in a 91% yield. It is important to note that in both cases, without the addition of II-10, no product of any appreciable amount is afforded even after extended reaction times (up to 2 weeks).

Utilizing the optimal conditions, the scope of the organocatalytic insertion reaction was examined. II-63a inserted readily into a variety of acidic O−H and S−H bonds (Table 2.4).

Aliphatic carboxylic acids efficiently underwent insertion to afford α-acyloxy esters II-64a-c

(Table 2.4). The steric hindrance of the acid had little effect on the insertions efficiency; even the sterically hindered pivalic acid was a viable O−H insertion partner. Electron-rich, electron-poor, and sterically encumbered benzoic acids underwent insertion giving rise to II-64d-h in 53–93 % yield. Diazo compound II-63a also inserted into the O−H bonds of α-amino acids, although we observed no diastereoselectivity in the products (II-64i-k) under the examined reaction conditions. Importantly, the N-terminus of the amino acid required protection as the tert-butyl carbamate in order for the insertion to proceed.

! 75!

O–H Insertion: MeO O MeO O O 2.5 mol % II-10 OMe + OMe H O HO R PhMe, 23 ºC, 24 h O II-64 II-63a N2 R

Carboxylic Acids: R= H, II-64d: 93% R= Me, II-64a: 91% O R= 4-OMe, II-64e: 92% O [a] R= i-Pr, II-64b: 88%[a] HO R= 2-OMe, II-64f: 58% HO R R R= 2,6-Me2, II-64g: 86% R= t-Bu, II-64c: 88%[b] R= 4-CF3, II-64h: 53%

O [c] [a] NHBoc R= Me, II-64i: 82% R= i-Pr, II-64j: 85% R= Ph, II-64k: 83% HO 1:1 dr 1:1 dr 1:1 dr R

Table 2.4. Substrate scope for O−H insertion reaction

Mercaptans operated well in catalytic S−H insertion reactions (Table 2.5) and good yields of the products II-67 could be isolated. Thiophenols were efficient substrates for S−H bond insertion, irrespective of the electronic nature of their substituents, providing the insertion products II-67a-e. Even alkyl thiols were accommodated under the reaction conditions affording

S−H insertion products II-67f and g in good yield. Thioacids, which are problematic in S−H

[84] insertions catalyzed BF3·OEt2, were tolerated, providing only the S-bound insertion adducts

II-67h and i.

! 76! S–H Insertion: MeO MeO O O 2.5 mol % 10 + HS R OMe OMe PhCF3, 23 ºC, 12 h H S N2 II-67 II-63a R

Mercaptans: R= H, II-67a: 90% R= i-Pr, II-67f: 73% SH HS R R= 2-OMe, II-67b: 91% R= Bn, II-67g: 69%

R R= 2-Me, II-67c: 88%

R= 4-F, II-67d: 79% O R= Me, II-67h: 42% R= Ph, II-67i: 54% R= 2-Np, II-67e: 87% HS R

Table 2.5. Substrate scope for S−H insertion reaction

A variety of α-aryldiazoacetates easily inserted into boronate urea-activated O−H and

S−H bonds. The efficiency of the insertions was heavily dependent on the diazo compounds’ aryl substituents. As a general trend, electron-donating groups sped up the reaction, whereas electron- withdrawing substituents rendered the insertions more sluggish. Ethyl phenyldiazoacetate (II-

63b) rapidly inserted into acetic acid in the presence of II-10 (Table 2.6, entry 1), whereas longer reaction times and 50 °C reaction temperatures were required to insert into thiophenol’s S−H bond (entry 6). The introduction of halogens onto the aryldiazo compounds was tolerated. For example, diazoester II-63c inserted into acetic acid providing II-64d in an 89 % yield (entry 2).

Similarly, II-63c underwent insertion efficiently into thiophenol to afford II-67k (81 %, entry 7).

Halogens as the sole substituent were also accepted; II-63d underwent both O−H and S−H insertion at room temperature, albeit longer reaction times were required to provide II-64n and

II-67l in 57 and 72 %, respectively (entries 3 and 8). As was expected, inductively donating groups facilitated the insertion process; both acetic acid and thiophenol underwent insertion by

! 77! II-63e more efficiently than II-63b, providing 10 % higher yields in each of the studied insertion reactions (entries 4 and 9). Unfortunately, the electron poor α-aryldiazoester, methyl 4-

(trifluoromethyl)phenyldiazoacetate was inoperable in both insertion reactions, plausibly due to its relatively poor basicity. The heteroaryl α-diazoester II-63f also operated well in the insertion reactions; insertion of II-63f into acetic acid provided the α-acetoxyester II-64p in 50 % yield

(entry 5), whereas insertion into thiophenol occurred efficiently providing II-67n in 91 % (entry

10).

O O O Ar AcOH Ar PhSH Ar RO RO RO II-64 2.5 mol % II-10 2.5 mol % II-10 H OAc II-63 N2 II-67 H SPh entry II-64 yield[a] (%) aryldiazoester II-63 entry II-67 yield[a] (%)

O

[b,c] 1 II-64l 66% EtO II-63b 6 II-67j 65%

N2 OMe O 2 II-64m 89%d II-63c 7 II-67k 81% MeO

N2 Br Br O 3 II-64n 57% II-63d 8 II-67l 75%[b] EtO

N2 Me O 4 II-64o 76% II-63e 9 II-67m 72%[c] MeO

N2

O NBoc

5 II-64p 50% MeO II-63f 10 II-67n 91%

N2

Reactions performed at 0.5 M with respect to 3, see supporting information for elaborative experimental details. The X–H insertion conditions are identical to those in Scheme 4 unless otherwise noted [a] Yields are of isolated product [b] 72 h reaction time [c] 50 ºC reaction temperature [d] 48 h reaction time.

Table 2.6. Aryl-diazo compound scope for X−H insertion reactions

! 78! 2.3.4 Plausible Mechanisms and Mechanistic Studies/Support

Our working hypothesis of the catalytic cycle is depicted in Scheme 2.25. The process is thought to begin with coordination of II-10 to the acidic heteroatom (X−H), forming II-60. This complexation enables the amplification of the acidity of the organic acid, which in the presence of a Brønsted basic diazo compound II-63 undergoes a proton transfer through species II-68. The proton transfer, converting II-68 to II-61, may be rate determining in this process, because it has been shown that α-aryldiazoacetate hydrolysis occurs through a general acid-catalyzed A-SE2

[85, mechanism, although additional studies are required to provide tangible evidence in this case.

86] The catalytic cycle would conclude with the diazonium species in II-61 reacting with the urea- stabilized anion (X-) to generate the observed insertion products (II-62). The weak interaction of

II-61 would then free the urea to re-enter into the catalytic cycle.

! 79! O

O Ar1 Ar2 R1 N N OR2 H H X–H II-63 N2 X II-60 H

O F F CF3 R1 B OR2 O H X–H Insertion N II-68 X H Ar2 N N CF3 N N H H H N O II-10 Ar1

-N2 O R1 O R1 OR2 OR2 N H H X N X H Ar2 N II-62 II-61 H N O Ar1

Scheme 2.25. X−H insertion catalytic pathway

More concrete insight into the proposed reaction pathway was collected through the execution of strategically selected experiments (Scheme 2.26 and II-27). We first attempted to trap a potential donor/acceptor carbene intermediate through an intramolecular cyclopropanation

[87] of the olefin in the cinnamyl alcohol-derived α-aryldiazoacetate II-63g (Scheme 2.26). When

II-63g was subjected to the standard O−H insertion reaction conditions, we observed only formation of the α-acetoxyester II-64q. Importantly, when acetic acid was omitted from the reaction, under otherwise identical reaction conditions, we observed no reaction after 48 h at 23

°C. Moreover, when II-63g was subjected to high temperatures in PhCF3, reaction conditions

[88] known to generate free carbenes from aryldiazoacetates, 87% of exo-(±)-II-69 was isolated as a single diastereomer. Collectively, this data contends the formation of a free donor/acceptor

! 80! carbene intermediate under the optimal reaction conditions.

MeO 2.5 mol % II-10 O AcOH (1.2 equiv.) O Ph MeO PhMe, 23 ºC O 24 h H OAc II-64q: 89% yield O MeO

II-63g N2 Ph O exo-(±)-II-69:

PhCF3, 100 ºC 87% yield 30 min Ph O

H

Scheme 2.26. Evidence against the formation of a free carbene

Further support of the proposed mechanism, depicted in Scheme 2.27, can be seen when the X−H bond is not present for HBD activation. For example, when triethylammonium acetate or sodium benzoate were utilized under the optimal reaction conditions, no reaction was observed

(Scheme 2.27a). Similarly, when sodium thiophenolate was added to the standard S−H insertion conditions, the expected product was not formed in any appreciable amount, demonstrating that the X−H bond is crucial for the insertion to occur. Confident that the reaction was proceeding through an initial protonation event, we were also curious if the catalyst could be involved in a direct protonation of the α-aryldiazoester. To probe this question, the most active diazo compound surveyed during our studies (II-63a) was subjected to one equivalent of catalyst II-10 in [D3]acetonitrile for 24 h at 23 °C (Scheme 2.31b). Under these conditions, we were unable to detect formation of II-70, the product known to form from deprotonation and isomerization of the

[89] urea catalyst, to any measureable extent by 1H NMR spectroscopy.

! 81! (a) 10 mol % II-10 MeO 10 mol % II-10 O No AcOH, Et3N NaOAc No Reaction PhMe, 23 ºC II-63a OMe PhMe, 23 ºC Reaction 24 h N2 24 h

(b) CF3 F F CF3 B II-63a (1 equiv.) F F O B N CF CD3CN, 23 ºC 3 N N CF3 H H 24 h N O II-70 II-10 H Scheme 2.27. Evidence to which species is responsible for protonation

In summary, we have discovered that difluoroboronate ureas are unique metal-free catalysts for O−H and S−H insertion reactions of aryldiazoacetates. This innovative approach for diazo insertion chemistry is believed to occur through hydrogen bonding to suitable functionalities giving a urea-induced organic-acid enhancement. The reaction tolerates an assortment of carboxylic acids and thiols, enabling the efficient preparation of a wide array of α- acyloxyesters and α-mercaptoesters under mild reaction conditions.

2.3.5 New Avenue for Enantioselective X−H Insertion Reactions

Urea-induced organic acid amplification as a tool for metal-free, enantioselective C−C bond formation through chemical insertion technologies is of current interest in our laboratory.

The new approach was to promote the insertion of aryldiazo compounds into C−H and X−H bonds with enantiocontrol, through the utilization of a chiral cocatalyst (Scheme 2.28). By using a chiral acid whose conjugate base is non-nucleophilic, it was envisioned our HBD catalyst could hydrogen bond to its conjugate base, initiating protonation of diazo compound. After formation of the diazonium ion, a chiral ion pair II-72 would ideally allow for a selective addition of any nucleophile in solution II-73.

! 82!

O R B O HO O O O R R R N N I-71 R O H H R R OR diazo activation OR N2 via interupted R I-63 O–H insertion O R B I-73 O O O O R R OR I-72 H

Scheme 2.28. Plan for promoting chiral insertion reactions

The plan was to use catalysts that were previously developed in our group, internal

Lewis acid assisted benzoic acid derivative II-77 (Scheme 2.29).[90 ] It is predicated that formation of borate II-78 would be generated upon deprotonation of species II-77; this hypothesis was later supported in a report by Maruoka and coworkers.[91] This catalyst platform would provide a proton source with a non-nucleophilic conjugate base to test our hypothesis.

HN O O O O NO2 B B 20 mol% II-65 -H + O O N NO H CH2Cl2 2 23 °C, 24 h II-74 II-75 II-76 II-77 OH II-78 O

Scheme 2.29. Enhanced single HBD catalyst

The report by Maruoka et. al. also provided a route for chiral, enantiopure boronate acids.

In 2012, Maruoka used boryl benzoic acid II-82 with chiral diols to form chiral boronate acids in

! 83! situ (Scheme 2.30).[91] The boronate ester assisted chiral carboxylic acids were able to catalyze a trans-aziridination of N-Boc II-79 and N-benzyl imines with N-phenyldiazoacetamide II-80.

Their studies started with commercially available (R,R)-diethyl tartrate II-83 and (S, S)- hydrobenzoin II-84. These C2-symmetric chiral diols provided evidence the reaction was enantioselective when II-84 provided 44 % ee. Testing of C1-symmetric diols II-85 synthesized in one step from (S)-1,1-diaryl-2-phenylethanediols, unexpectedly exceeded that of the C2- symmetric diols. Using what they found to be their optimal catalyst, II-85e, afford 92% ee in a

64% yields at –20 °C.

O Boc 10 mol% II-82 Boc N 12 mol% diol O B(OH)2 + NHPh N Ph CH Cl , MS 4Å Ph NHPh N2 2 2 COOH 0 °C, 2-4 h II-79 II-80 II-81 II-82

EtO C OH Ph OH 2 Ph OH II-85a: Ar = Ph; 52% yield, -60% ee II-85b: Ar = 4-PhC6H4; 51% yield, -70% ee EtO2C OH Ph OH Ar OH II-85c: Ar = 3,5-tBu2C6H3; 50% yield, -70% ee Ar II-85d: Ar = 2-MeC6H4; 40% yield, 47% ee II-85e: Ar = 2-PhC6H4; 63% yield, 89% ee II-83 II-84 II-85 44% yield 50% yield 0% ee 44% ee

Scheme 2.30. Boronate ester assisted chiral carboxylic acids catalyze asymmetric trans- aziridinations

Inspired by the data collected in our own laboratory, and Maruoka’s enantioselective boronate acid catalysed reaction, we initiated our studies by synthesizing three easily prepared boronate acids, which we hoped would validate our method. Exposing II-82 to (S, S)-2,3- butanediol, (S, S) hydrobenzoin, and reverse α,α,α,α-tetraaryl-1,3-dioxolane-4,5- dimethanols

(TADDOL) in diethyl ether for 2 hours produced the corresponding boronate acids, II-86, II-87, and II-88, respectively (Scheme 2.31).

! 84!

Me Me Me OH O O B(OH)2 B Me OH II-86 O Et O COOH 2 OH Ph OH Ph Ph Ph OH O Et O O 2 B O II-87 OMe Ph OH OH Ph Ph Ph Ph Ph OH MeO Ph Ph OMe OMe O O B Et2O O II-88

OH

Scheme 2.31. Synthesis of chiral boronate acids

Our first set of reaction conditions utilized 1.2 equivalents of II-86, 2.5 mol% of II-10, and 2 equivalents of II-89 (Table 2.7). After 24 hours, we found that there were equal amounts of the desired C−H insertion product II-90 and undesired O−H insertion of the boronate acid product II-91. Using catalytic amounts of II-86 (10 mol%), we could reduce the amount of II-91 and simultaneously increase the amount of II-90. It is important to note, without the addition of any II-86, no reaction took place. Also, without the addition of HBD II-10, only II-91 was formed.

! 85! MeO O MeO MeO O O II-10 OMe H R N + II-86 OMe + O O OMe O 0.25 M Toluene R N2 B II-89 23 °C, 24 h O II-63a NH II-90 II-91

entry II-86 (eq) II-10 (eq) Yield (%) II-90 Yield (%) II-91

1 1.2 2.5 40 % 37% F F CF3 B O 2 0.10 2.5 56% 8%

N N CF3 3 0 2.5 0 0 H H II-10 4 0.10 0 0 7% Table 2.7. Cocatalyst screening optimization

A solvent screen revealed the use of chlorinated solvents provided no reaction (Table 2.8, entry 1), while toluene (entry 2) and PhCF3 (entry 3) afforded modest yields. However, ethereal solvents were found to be the best solvents for this reaction (entry 4). Lastly, the addition of excess nucleophile (entry 5) drove the reaction to completion. Using 5 equivalents of pyrrole in a

0.25M solution of THF, II-90 was isolated in 78% yield at 23 °C after 24 hours. However, no enantioselectivity was observed for any of the three chiral boronate acids at this temperature.

When temperatures were lowered to 4 °C, –30 °C and –55 °C, we were disappointed to find no enantioselectivity was observed under the optimized conditions. Re-optimization of the solvent surprisingly resulted in the use of acetone to consistently provide 12% ee at –30 °C, but only in the presence of II-10 and cocatalyst II-87 (entry 5).

! 86! MeO O MeO O MeO II-10 (2.5 mol%) O OMe H R N boronate acid (10 mol%) + OMe + O O OMe O 0.25 M Solvent R N2 B II-89 O II-63a NH II-90 II-91

entry temp (°C) solvent time (h) acid II-89 (eq) Yield (%) II-90 Yield (%) II-91 1 23 DCM 24 II-86 2 <5 <5

2 23 PhMe 24 II-86 2 56 8

3 23 PhCF3 24 II-86 2 61 7 4 23 THF 24 II-86 2 68 8

5 23 THF 24 II-86 5 78 5 6 -30 Acetone 48 II-87 5 62, 12% ee! <5

Table 2.8. Cocatalytic optimization for enantioselectivity

With a promising enantioselectivity established in the formation of II-90, further optimization of the reaction conditions could lead to a potential method for metal-free, enantioselective insertion reaction. Synthesizing new chiral diols, as well as, changing the equivalents of boronate acid in solution may help with the selectivity of the reaction. Other proposed methods to achieve selectivity that have been attempted in our group involve synthesizing chiral diazo ester compounds, which unfortunately have not provided us with any selectivity to date. Also, a completed synthesis of a chiral boronate urea would help to promote many asymmetric reactions and is still ongoing in our lab.

! 87!

2.4 Experimental Section

2.4.1 Standard Procedure for the Preparation of Boronate Ureas

Bpin O O F F B MeCN B + O 1. KHF2 O O R R R NH C 2 2. H2O N N N N N H H H H

2.4.1.1 Standard Procedure for the Synthesis of Pinacol Boronate Ureas

1-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(4,4,5,5-tetramethyl-1,3,2-

CF O O 3 B dioxaborolan-2-yl)phenyl)urea (I-78): A flame-dried round bottom flask O

N N CF3 H H under N2 was charged with 2-aminophenyl boronic acid pinacol ester (600 mg, 2.74 mmol). Freshly distilled acetonitrile (30 mL) was added to create a colorless solution.

Last, 3,5-bis-trifluoromethylphenyl isocyanate (473 mL, 2.74 mmol) was introduced to the reaction flask dropwise by syringe. Shortly after addition of the isocyanate, a white precipitate began to form. The reaction was allowed to stir at 23 °C for 4 h. The pure boronate urea pinacol ester 6 was isolated as a white solid after vacuum filtration followed by washing with hexanes.

The solid was dried under vacuum (83%). Rf = 0.94 (4:4:1 ethyl acetate:hexanes:methanol); mp

215.2 – 216.9 ºC; IR (NaBr) 3415, 3132, 2985, 1640, 1600, 1581, 1476, 1184, 1129, cm-1; 1H

NMR (400 MHz, DMSO d6) δ 9.93 (br s, 1H); 9.19 (br s, 1H); 8.16 (s, 2H); 7.69 (s, 1H); 7.52-

7.50 (m, 1H); 7.42-7.34 (m, 2H); 7.08-7.04 (m, 1H); 1.24 (s, 12H); 13C NMR (100 MHz, DMSO d6) d 154.0, 142.2, 141.7, 134.7, 131.2 (q, J = 33 Hz, CCF3), 130.8, 123.8 (q, J = 271 Hz, CF3),

123.4, 119.7, 119.4, 115.6, 83.0, 25.5, (the carbon bonded to boron was not seen due to

[92] 11 broadening) ; B NMR (160 MHz, DMSO d6) δ 26.0 (br s); HRMS (ESI): Mass calculated for

+ + C21H21BF6N2O3 [M+H] , 475.1622. Found [M+H] , 475.1614. ! 88!

2.4.1.2 Standard Procedure for the Synthesis of Difluoroboronate Ureas[93]

F F CF3 II-10: A flame-dried round bottom flask under N2 was charged with B O

N N CF3 boronate urea pinacol ester (I-78, 4.6 mmol) and freshly distilled MeOH H H

(30 mL). KHF2 (4.5 M, 18.4 mmol) was introduced to the reaction flask dropwise by syringe, resulting in a white heterogenous mixture, and the reaction was heated to 50 °C. Shortly after heating, the reaction became a colorless solution. After 2 h at 50 °C, the reaction was cooled to

23 °C and concentrated. The white solid was filtered and washed several times with water to afford the potassium trifluoroboryl urea salt (92%). The urea salt (1.95 g, 4.29 mmol) was dissolved in ethyl acetate (15 mL) and extracted twice with water (5 mL). The organic layer was dried and concentrated in a 500 mL round bottom flask. To the flask was added 250 mL DCM and the mixture was allowed to stir rapidly at room temperature for 1 hour, after which the solid was filtered and washed with DCM to afford difluoroboryl urea II-10 (1.55 g, 3.11 mmol, 85%) as a white powder. mp 205.3 – 205.9 ºC; IR (NaBr) 3628, 3345, 2986, 1741, 1671, 1585, 1479,

-1 1 1187, 1128, cm ; H NMR (400 MHz, DMSO d6) δ 11.27 (br s, 1H); 10.65 (br s, 1H); 8.11 (s,

2H); 7.96 (s, 1H); 7.42-7.40 (m, 1H); 7.32-7.28 (m, 1H); 7.15-7.10 (m, 2H); 13C NMR (100

MHz, DMSO d6) δ 154.4, 138.1, 137.5, 131.0 (q, J = 33 Hz, CCF3), 130.6, 128.2, 124.6, 123.0,

123.0 (q, J = 271 Hz, CF3), 118.4, 115.4, (the carbon bonded to boron was not seen due to

[90] 11 19 broadening) ; B NMR (160 MHz, DMSO d6) δ 3.63 (br s); F NMR (376 MHz, DMSO d6) d –61.7 (s, 6F), –132.8 (s, 1F), –132.9 (s, 1F); HRMS (ESI): Mass calculated for C21H21BF6N2O3

[M+H]+, 419.0572. Found [M+H]+, 419.0580.

F F II-65c: The procedure for II-10 was followed and the product was isolated as a B O

N N white powder (82% - 2 steps from 2-aminophenylboronic acid pinacol ester). H H

1 H NMR (400 MHz, DMSO d6) δ 10.69 (br s, 1H); 10.12 (br s, 1H); 7.45 (t, J = 7.2 Hz, 2H); ! 89! 7.42-7.34 (m, 3H); 7.26 (t, J = 7.2 Hz, 2H); 7.09 (t, J = 7.2 Hz, 1H); 7.03 (d, J = 7.2 Hz, 1H);

13 C NMR (100 MHz, DMSO d6) δ 154.5, 137.7, 135.4, 130.5, 129.3, 128.0, 125.6, 124.1, 122.7,

115.1, (the carbon bonded to boron was not seen due to broadening)[90]; 11B NMR (160 MHz,

19 DMSO d6) δ 3.39 (br s); F NMR (376 MHz, DMSO d6) d –133.4 (s).

F F F II-65d: The procedure for II-10 was followed and the product was isolated B O as a white powder (73% - 2 steps from 2-aminophenylboronic acid pinacol N N F H H 1 ester). H NMR (400 MHz, DMSO d6) δ 11.00 (br s, 1H); 10.46 (br s, 1H); 7.39 (d, J = 6.8 Hz,

1H); 7.29 (t, J = 7.2 Hz, 1 H); 7.18-7.10 (m, 4H); 7.06 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz,

DMSO d6) δ 162.4 (dd, J = 243, 15 Hz), 154.3, 138.4 (t, J = 14 Hz), 137.4, 130.5, 128.2, 124.5,

115.4, 105.5 (d, J = 29 Hz), 100.7 (t, J = 26 Hz), (the carbon bonded to boron was not seen due to

[90] 11 19 broadening) ; B NMR (160 MHz, DMSO d6) δ 3.22 (br s); F NMR (376 MHz, DMSO d6)

δ –108.7 (s, 2F), –132.8 (s, 2F).

F F II-65e: The procedure for II-10 was followed and the product was isolated B CF O 3 as a white powder (64% - 2 steps from 2-aminophenylboronic acid pinacol N N H H 1 ester). H NMR (400 MHz, DMSO d6) δ 10.95 (br s, 1H); 10.48 (br s, 1H); 7.83 (d, J = 8.4 Hz,

2H); 7.62 (d, J = 8.4 Hz, 2H); 7.39 (d, J = 6.8 Hz, 1H); 7.29 (t, J = 7.6 Hz, 1H); 7.12 (t, J = 7.2

13 Hz, 1H); 7.06 (d, J = 7.6 Hz, 1H). C NMR (100 MHz, DMSO d6) δ 154.4, 139.6, 137.5, 130.6,

128.2, 126.5 (q, J = 4 Hz), 125.3 (q, J = 33 Hz), 124.5, 124.1 (q, J = 273 Hz), 122.2, 115.3 (the

[90] 11 carbon bonded to boron was not seen due to broadening) ; B NMR (160 MHz, DMSO d6) δ

19 3.82 (br s); F NMR (376 MHz, DMSO d6) δ –60.6 (s, 3F), –132.8 (s, 2F).

! 90!

2.4.1.3 Synthesis of Control Catalyst II-66

H3C CH3 F F H3C H3C CH3 B CH3 O O CH 1. Ac O O O KHF 3 2 B 2 B O N CH3 O CH3 2. MeI, K2CO3 MeOH, 23 ºC CH3 N CH3 NH2 II-66 CH3

H3C CH3 N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide: A flame- H3C CH3 O O B O dried round bottom flask under argon was charged with 2-aminophenyl boronic

N CH3 H acid pinacol ester (2.00 g, 9.13 mmol) and dissolved in dry CH2Cl2 (25 mL).

Acetic anhydride (1.04 mL, 11.0 mmol) was then added slowly at 23 ºC and the solution was stirred at 23 ºC for 16 h. After the reaction was complete (determined by TLC, Rf = 0.08 in 100%

EtOAc) the reaction mixture was concentrated and residual acetic acid was removed azeotropically with toluene via rotary evaporation to provide N-(2-(4,4,5,5-tetramethyl-1,3,2-

1 dioxaborolan-2-yl)phenyl)acetamide. H NMR (400 MHz, CDCl3) δ 10.7 (br s, 1H); 7.94-7.63

(m, 2H); 7.29 (br s, 1H); 7.10 (app t, J = 7.2 Hz, 1H); 1.92 (br s, 3H); 1.36 (s, 12H).

H3C CH3 N-methyl-N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)acetamide: H3C CH3 O O B [4] O A modified version of a previously reported procedure was used. The crude N-

N CH3

CH3 (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide was placed back under argon and DMF (50 mL) was added and stirred rapidly. To the vigorously stirred solution was added K2CO3 (2.52 g, 18.3 mmol) followed by iodomethane (1.71 mL, 27.5 mmol) at 23 ºC.

The reaction mixture was allowed to stir vigorously at 23 ºC for 5 h and quenched with H2O (25 mL). The reaction mixture was extracted with Et2O (3 x 50 mL), washed with water (3 x 15 mL) and brine (15 ml), and dried with MgSO4. The solution was concentrated and the solid was dried

! 91! under vacuum to provide N-methyl-N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)acetamide (1.26 g, 50% - 2 Steps). Rf = 0.62 (100% ethyl acetate); IR (film) 3054,

-1 1 2983, 1654, 1600, 1446, 1382, 1354, 1322, 1265, 1144 cm ; H NMR (400 MHz, CDCl3) δ 7.83

(dd, J = 7.6, 1.6 Hz, 1H); 7.50 (dt, J = 7.6, 1.6 Hz, 1H); 7.35 (dt, J = 7.6, 1.2 Hz, 1H); 7.15 (dd, J

13 = 8.0, 0.8 Hz, 1H); 3.20 (s, 3H); 1.74 (s, 3H); 1.31 (s, 12H); C NMR (100 MHz, CDCl3) δ

170.3, 149.8, 136.8, 132.6, 127.9, 127.4, 84.0, 37.3, 24.8, 24.7, 22.3 (the carbon bonded to boron

[3] 11 was not seen due to broadening) ; B NMR (160 MHz, CDCl3) δ 30.4 (br s); HRMS (ESI):

+ + Mass calculated for C15H22BNaNO3 [M+Na] , 298.1588. Found [M+Na] , 298.1585.

F F II-66: N-methyl-N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- B O

N CH3 yl)phenyl)acetamide (500 mg, 1.82 mmol) was suspended in MeOH (20 mL) under

CH3 argon and aq. KHF2 (4.5 M, 1.41 mL, 6.36 mmol) was added at 23 ºC. After 18 h at 23 ºC the solution was concentrated to afford an off-white solid that was transferred to a separatory funnel with CH2Cl2. Water (50 mL) was added and the aqueous layer was extracted with CH2Cl2 (3 x 50 mL). The product then crystallized from the aqueous layer overnight to afford N-(2-

(difluoroboranyl)phenyl)-N-methylacetamide as colorless needles which were collected in vacuo

-1 1 (218 mg, 61%). IR (film) 1643, 1613, 1225, 1031 cm ; H NMR (400 MHz, DMSO d6) δ 7.51-

7.46 (1H); 7.46-7.39 (m, 2H); 7.37-7.31 (m, 1H); 3.65 (s, 3H); 2.63 (s, 3H); 13C NMR (100 MHz,

DMSO d6) δ 171.9, 139.5, 130.5, 128.4, 126.9, 115.3, 36.3, 23.1 (the carbon bonded to boron

[3] 11 19 was not seen due to broadening) ; B NMR (160 MHz, DMSO d6) δ 2.29 (br s); F NMR (376

+ MHz, DMSO d6) δ –132.0 (s); HRMS (ESI): Mass calculated for C9H10BF2NNaO [M+Na] ,

220.0717. Found [M+H]+, 220.0719.

! 92! % 2.4.2 Synthesis of Novel α-Aryldiazoacetates

OMe II-63c: A flame-dried 100 mL round bottom flask was charged with 2-(2- O MeO bromo-4-methoxyphenyl)acetic acid (1.00 g, 4.08 mmol) and placed under N2 Br

N2. To the flask was then added methanol (40 mL) and Amberlyst-15 (1.3 g) at 23 ºC. The reaction mixture was stirred at 23 ºC for 72 h, then filtered and concentrated to provide the crude ester. The residue was purified on silica gel (5:95 diethyl ether:hexanes) to provide methyl 2-(2- bromo-4-methoxyphenyl)acetate as a colorless oil (0.84 g, 79%). 1H NMR (400 MHz, CDCl3) δ

7.19 (d, J = 8.8 Hz, 1H); 7.12 (d, J = 2.8 Hz, 1H); 6.83 (dd, J = 8.8, 2.8 Hz, 1H); 3.79 (s, 3H);

3.73 (s, 2H); 3.71 (s, 3H). All spectral data match those previously reported.[7]

Methyl 2-(2-bromo-4-methoxyphenyl)acetate (0.83 g, 3.2 mmol) was added to a flame- dried 25 mL round bottom flask under a N2 atmosphere, dissolved in MeCN (11 mL) and p-

ABSA (921 mg, 3.84 mmol) was added at 23 ºC. The reaction mixture was cooled to 0 ºC and

DBU (0.67 mL, 4.5 mmol) was added dropwise. The reaction mixture was allowed to warm to 23

ºC and stirred at 23 ºC for 24 h. Upon completion of the reaction, water (10 mL) was added and the reaction mixture was extracted with diethyl ether (3 x 50 mL). The organic layers were combined and washed with saturated aq. NH4Cl and dried with MgSO4. The organic layer was concentrated and the resulting residue was purified on silica gel (5:95 diethyl ether:hexanes) to obtain methyl 2-(2-bromo-4-methoxyphenyl)-2-diazoacetate as a! tacky yellow solid (753 mg,

83%). Rf = 0.6 (10:90 ethyl acetate:hexanes); FTIR (film) 3059, 3006, 2952, 2842, 2093, 1698,

1599, 1559, 1496, 1439, 1260, 1160, 1032 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.8

Hz, 1H); 7.17 (d, J = 2.8 Hz, 1H); 6.92 (dd, J = 8.8, 2.4 Hz, 1H); 3.82 (s, 3H); 3.81 (s, 3H); 13C

NMR (100 MHz, CDCl3) δ 160.6, 133.8, 118.2, 118.1, 117.7, 114.3, 113.7, 55.7, 52.2, (the diazo carbon was not observed); HRMS (ESI): Mass calculated for C10H9BrN2NaO3 [M+Na]+,

306.9689. Found [M+Na]+, 306.9685.

! 93! ! MeO II-63g: A flame-dried 50 mL round bottom flask was charged with 4- O

O Ph methoxyphenylacetic acid (500 mg, 3.00 mmol) and placed under N2. N2 To the flask was then added cinnamyl alcohol (807 mg, 6.0 mmol), DMAP (37 mg, 0.30 mmol) and CH2Cl2 (15 mL) at 23 ºC. The solution was cooled to 0 ºC and a separate solution of DCC (3 mL, 1.0 M, 3.0 mmol) was added dropwise to the reaction mixture over 5 min. The reaction mixture was allowed to warm to 23 ºC and stirred for 18 h, then filtered, and concentrated. The residue was purified on silica gel (7:93 ethyl acetate:hexanes) to provide cinnamyl 2-(4- methoxyphenyl)acetate as a white solid (697 mg, 82%). FTIR (film) 3028, 2935, 2837, 1730,

1612, 1512, 1449, 1376, 1033 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.40-7.30 (m, 4H); 7.30-7.21

(m, 3H); 6.89 (app d, J = 8.8 Hz, 2H); 6.61 (d, J = 16.0 Hz, 1H); 6.28 (dt, J = 16.0, 6.0 Hz, 1H);

4.77 (dd, J = 6.0, 1.2 Hz, 2H); 3.81 (s, 3H); 3.63 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 171.8,

158.9, 136.3, 134.2, 130.4, 128.7, 128.2, 126.7, 126.2, 123.2, 114.2, 65.4, 55.4, 40.6; HRMS

(ESI): Mass calculated for C18H18NaO3 [M+Na]+, 305.1148. Found [M+Na]+, 305.1148.

Cinnamyl 2-(4-methoxyphenyl)acetate (500 mg, 1.77 mmol) was added to a flame-dried 25 mL round bottom flask under a N2 atmosphere, dissolved in MeCN (5 mL) and p-ABSA (850 mg,

3.54 mmol) was added at 23 ºC. The reaction mixture was cooled to 0 ºC and DBU (0.37 mL, 2.5 mmol) was added dropwise. The reaction mixture was allowed to warm to 23 ºC and stirred at 23

ºC for 48 h. Water (10 mL) was added and the reaction mixture was extracted with diethyl ether

(3 x 30 mL). The organic layers were combined and washed with saturated aq. NH4Cl and dried with MgSO4. The organic layer was concentrated and the resulting residue was purified on silica gel (1:99 diethyl ether:hexanes) to obtain cinnamyl 2-diazo-2-(4-methoxyphenyl)acetate as a light orange solid (362 mg, 66%). Rf = 0.5 (10:90 ethyl acetate:hexanes); FTIR (film) 3036, 2954,

2934, 2084, 1698, 1514, 1255, 1153, 1032 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.44-7.38 (m,

4H); 7.37-7.30 (m, 2H); 7.30-7.25 (m, 1H); 6.95 (app d, J = 8.8 Hz, 2H); 6.69 (d, J = 16.0 Hz,

! 94! 1H); 6.34 (dt, J = 16.0, 6.4 Hz, 1H); 4.92 (dd, J = 6.4, 1.2 Hz, 2H); 3.81 (s, 3H); 13C NMR (100

MHz, CDCl3) δ 165.7, 158.3, 136.3, 134.6, 128.8, 128.3, 126.8, 126.2, 123.4, 117.0, 114.8, 65.6,

55.5, (the diazo carbon was not observed); HRMS (ESI): Mass calculated for C18H16N2NaO3

[M+Na]+, 331.1053. Found [M+Na]+, 331.1052.

%

2.4.3 General Procedure for the Organocatalytic O-H Insertion

A dry, screw-capped reaction vial, equipped with a magnetic stir bar, was charged with aryldiazoacetate (0.364 mmol), catalyst (0.0091 mmol, 2.5 mol %), and placed under a N2 atmosphere. Toluene (1.45 mL) was added and the reaction was degassed by bubbling N2 through the solution for 5 min at 23 ºC. The appropriate carboxylic acid (0.437, 1.2 equiv.) was added in one portion and the reaction mixture was allowed to stir for 24 h at 23 ºC and then immediately purified by flash column chromatography on silica gel.

!

MeO II-64a: The compound was isolated as a clear solid (79 mg, 91%) by flash O OMe column chromatography on silica gel (5:95 ethyl acetate:hexanes to 20:80 O O

CH3 ethyl acetate:hexanes). Rf = 0.42 (20:80 ethyl acetate:hexanes); FTIR (film)

3057, 2957, 2840, 1751, 1612, 1515, 1458, 1438, 1428, 1374, 1235, 1179, 1034 cm-1; 1H NMR

(400 MHz, CDCl3) δ 7.38 (app d, J = 8.4 Hz, 2H); 6.91 (app d, J = 8.8 Hz, 2H); 5.88 (s, 1H);

3.81 (s, 3H); 3.719 (s, 3H); 2.18 (s, 3H); 13C NMR(100MHz, CDCl3)

δ 170.5, 169.7, 129.3, 126.0, 114.4, 74.3, 55.5, 52.7, 20.9; HRMS (ESI): Mass calculated for

C12H14NaO5 [M+Na]+, 261.0733. Found [M+Na]+, 261.0726.

MeO O II-64b: 36 h reaction time. The compound was isolated as a colorless oil (85

OMe O O mg, 88%) by flash column chromatography on silica gel (5:95 ethyl

H C CH 3 3 acetate:hexanes to 20:80 ethyl acetate:hexanes). Rf = 0.50 (20:80 ethyl

! 95! acetate:hexanes); FTIR (film) 2974, 2839, 1741, 1613, 1586, 1514, 1468, 1438, 1388, 1340,

1305, 1250, 1218, 1177, 1149, 1034 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.39 (app d, J = 8.8 Hz,

2H); 6.91 (app d, J = 8.8 Hz, 2H); 5.87 (s, 1H); 3.81 (s, 3H); 3.71 (s, 3H); 2.69 (sep, J = 7.0 Hz,

13 1H); 1.23 (AB d, Jab = 6.8 Hz, Δδ = 0.06, 3H); C NMR (100 MHz, CDCl3) δ 176.6, 169.8,

160.4, 129.2, 126.2, 114.3, 74.0, 55.5, 52.6, 33.9, 19.1, 18.8; HRMS (ESI): Mass calculated for

C14H18NaO5 [M+Na]+, 289.1046. Found [M+Na]+, 289.1046.

MeO O II-64c: 72 h reaction time. The compound was isolated as colorless solid (90

OMe O O mg, 88%) by flash column chromatography on silica gel (5:95 ethyl

H3C CH3 CH3 acetate:hexanes to 20:80 ethyl acetate:hexanes). Rf = 0.58 (20:80 ethyl acetate:hexanes); FTIR (film) 2958, 2873, 2839, 2108, 1758, 1737, 1613, 1586, 1514, 1480,

1462, 1438, 1397, 1345, 1271, 1251, 1217, 1176, 1145, 1034 cm-1; 1H NMR (400 MHz, CDCl3)

δ 7.39 (app d, J = 8.8 Hz, 2H); 6.91 (app d, J = 11.2 Hz, 2H); 5.83 (s, 1H); 3.81 (s, 3H); 3.70 (s,

3H); 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.1, 169.8, 160.4, 129.0, 126.3, 114.4, 74.0,

55.4, 52.6, 38.9, 27.18; HRMS (ESI): Mass calculated for C15H20NaO5 [M+Na]+, 303.1203.

Found [M+Na]+, 303.1205.

! MeO O II-64d: The compound was isolated as a white solid (101 mg, 93%) by flash

OMe O O column chromatography on silica gel (5:95 ethyl acetate:hexanes to 20:80

ethyl acetate:hexanes). Rf = 0.43 (20:80 ethyl acetate:hexanes); FTIR (film)

2954, 2838, 2359, 1755, 1723, 1613, 1585, 1514, 1492, 1452, 1438, 1348, 1316, 1288, 1249,

121.9, 1175, 1108, 1070, 1033 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.12 (app d, J = 6.4 Hz, 2H);

7.60-7.56 (1H); 7.51-7.43 (4H); 6.95 (app d, J = 8.8 Hz, 2H); 6.12 (s, 1H); 3.83 (s, 3H); 3.76 (s,

3H); 13C NMR (100 MHz, CDCl3) δ 169.7, 166.1, 160.5, 133.8, 133.6, 130.3, 129.5, 128.6,

126.2, 114.4, 74.7, 55.5, 55.8; HRMS (ESI): Mass calculated for C17H16NaO5 [M+Na]+,

! 96! 323.0890. Found [M+Na]+, 323.0888.

MeO II-64e: The compound was isolated as a light yellow oil (110 mg, 92%) by O OMe flash column chromatography on silica gel (5:95 ethyl acetate:hexanes to O O

20:80 ethyl acetate:hexanes). Rf = 0.32 (20:80 ethyl acetate:hexanes); FTIR

OMe (film) 3004, 2954, 2839, 2359, 2341, 2047, 1755, 1715, 1607, 1583, 1514,

1462, 1439, 1251, 1218, 1099 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.07 (app d, J = 8.8 Hz, 2H);

7.49 (app d, J = 8.8 Hz, 2H); 6.96-6.91 (4H); 6.09 (s, 1H); 3.86 (s, 3H); 3.83 (s, 3H); 3.75 (s, 3H);

13C NMR (100 MHz, CDCl3) δ 169.9, 165.8, 163.9, 160.5, 132.2, 129.3, 126.4, 121.8, 114.4,

113.8, 74.5, 55.6, 55.5, 52.7; HRMS (ESI): Mass calculated for C18H18NaO6 [M+Na]+,

353.0996. Found [M+Na]+, 353.0997.

MeO O II-64f: 36 h reaction time. The compound was isolated as a colorless oil (70

OMe O O mg, 58%) by flash column chromatography on silica gel (5:95 ethyl

MeO acetate:hexanes to 20:80 ethyl acetate:hexanes). Rf = 0.21 (20:80 ethyl acetate:hexanes); FTIR (film) 3003, 2954, 2839, 2046, 1731, 1600, 1583, 1514, 1492,1461, 1435,

1242, 1177, 1129, 1074, 1028 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, 8.0, 1.8 Hz, 1H);

7.49 (app d, J = 8.4 Hz, 3H); 7.01-6.96 (2H); 6.93 (app d, J = 8.8 Hz, 2H); 6.11 (s, 1H); 3.90 (s,

3H); 3.82 (s, 3H); 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.8, 165.1, 160.4, 160.0, 134.3,

132.4, 129.2, 126.4, 120.3, 118.9, 114.3, 112.2, 74.4, 56.1, 55.4, 52.3; HRMS (ESI): Mass calculated for C13H18NaSO3 [M+Na]+, 353.0996. Found [M+Na]+, 353.0995.

! MeO II-64g: The compound was isolated as a colorless oil (102 mg, 86%) by flash O

OMe O O column chromatography on silica gel (5:95 ethyl acetate:hexanes to 20:80

Me Me ethyl acetate:hexanes). Rf = 0.46 (20:80 ethyl acetate:hexanes); FTIR (film)

! 97! MeO 2955, 2839, 2109, 1756, 1731, 1613, 1586, 1514, 1465, 1437, 1383, 1347, O OMe 1306, 1244, 1217, 1177, 1111, 1071, 1032 cm-1; 1H NMR (400 MHz, O O CDCl3) δ 7.43 (app d, J = 8.8 Hz, 2H); 7.20 (t, J = 7.6Hz, 1H); 7.03 (app d, J

CF3 = 7.2 Hz, 2H); 6.91 (app d, J = 8.8 Hz, 2H); 6.13 (s, 1H); 3.81 (s, 3H); 3.78

(s, 3H); 2.38 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 169.6, 169.4, 160.5, 135.9, 132.7, 129.8,

129.4, 125.8, 114.4, 74.8, 55.4, 52.7, 20.0; HRMS (ESI): Mass calculated for C19H20NaO5

[M+Na]+, 351.1203. Found [M+Na]+, 351.1196. II-64h: The compound was isolated as a white solid (76 mg, 53%) by flash column chromatography on silica gel (5:95 ethyl acetate:hexanes to

20:80 ethyl acetate:hexanes). Rf = 0.41 (20:80 ethyl acetate:hexanes); FTIR (film) 2955, 2840,

1755, 1726, 1612, 1530, 1514, 1452, 1347, 1249, 1218, 1175, 1108, 1070, 1031 cm-1; 1H NMR

(400 MHz, CDCl3) δ 8.22 (app d, J = 8.4 Hz, 2H); 7.72 (app d, J = 8.0 Hz, 2H); 7.48 (app d, J =

8.8 Hz, 2H); 6.96 (app d, J = 8.8 Hz, 2H); 6.13 (s, 1H); 3.84 (s, 3H); 3.76 (s, 3H); 13C NMR (100

MHz, CDCl3) δ 169.4, 164.9, 160.7, 135.0 (q, J = 32.8 Hz, CCF3), 132.7, 130.5, 129.4, 125.8,

125.6 (q, J = 3.8 Hz), 123.7 (q, J = 271.1 Hz, CF3), 114.5, 75.1, 55.5, 52.9; HRMS (ESI): Mass calculated for C18H15F3NaO5 [M+Na]+, 391.0764. Found [M+Na]+, 391.0761.

!

MeO II-64i: The compound was isolated as a colorless oil (109 mg, 82%) by flash O OMe column chromatography on silica gel (5:95 ethyl acetate:hexanes to 20:80 O O

BocHN Me ethyl acetate:hexanes). Rf = 0.22 (20:80 ethyl acetate:hexanes); FTIR (film)

3380, 2978, 2935, 2839, 1748, 1714, 1612, 1586, 1515, 1455, 1366, 1251, 1218, 1161, 1114,

1069, 1032, cm-1; 1H NMR (400 MHz, CDCl3, mixture of two diastereomers) δ 7.36 (app dd, J =

8.8 Hz, 2H); 7.35 (app d, J = 9.2 Hz, 2H); 6.90 (app d, J = 8.8 Hz, 2H); 6.90 (app d, J = 8.8 Hz,

2H); 5.91 (s, 1H); 5.90 (s, 1H); 5.04 (br m, 2H); 4.43 (br m, 2H); 3.81 (s, 3H); 3.80 (s, 3H); 3.71

(s, 3H); 3.70 (s, 3H);1.51 (d, J = 7.2 Hz, 3H); 1.42 (d, J = 7.2 Hz, 18H); 1.39 (s, 3H); 13C NMR

(100 MHz, CDCl3) δ 173.1, 173.1, 172.7, 169.3, 169.1, 160.6, 160.5, 155.2, 155.1, 129.3, 129.2,

! 98! 125.7, 125.5, 114.4, 114.3, 80.0, 74.7, 55.4, 52.7, 52.7, 49.5, 49.2, 28.4, 28.4, 18.6; HRMS (ESI):

Mass calculated for C18H25NaNO7 [M+Na]+, 390.1523. Found [M+Na]+, 390.1526.

! MeO O II-64j: 48 h reaction time. The compound was isolated as a colorless oil (122

OMe O O mg, 85%) by flash column chromatography on silica gel (5:95 ethyl

CH BocHN 3 acetate:hexanes to 20:80 ethyl acetate:hexanes). Rf = 0.37 (20:80 ethyl CH3 acetate:hexanes); FTIR (film) 3386, 2965, 1749, 1715, 1612, 1514, 1366, 1250, 1175, 1154, 1034 cm-1; 1H NMR (400 MHz, CDCl3, mixture of two diastereomers) δ 7.37-7.35 (4H); 6.91-6.88

(4H); 5.91 (s, 1H); 5.87 (s, 1H); 5.01 (br m, 2H); 4.35 (br m, 2H); 3.80 (s, 3H); 3.80 (s, 3H); 3.71

(s, 3H); 3.70 (s, 3H); 2.35 (br m, 1H); 2.18 (br m, 1H); 1.43 (s, 9H); 1.40 (s, 9H); 1.03 (d, J = 6.8

Hz, 3H); 1.00 (d, J = 7.2 Hz, 3H); 0.96 (d, J = 6.8 Hz, 3H); 0.85 (d, J = 6.8 Hz, 3H);13C NMR

(100 MHz, CDCl3) δ 172.1, 171.7, 169.3, 169.1, 160.5, 160.5, 155.8, 155.7, 129.3, 129.2, 125.8,

125.5, 114.3, 114.3, 79.9, 74.8, 74.6, 58.7, 58.3, 55.4, 52.7, 52.6, 31.3, 28.4, 28.4, 19.1, 19.1,

17.5, 17.2; HRMS (ESI): Mass calculated for C20H29NaNO7 [M+Na]+, 418.1836. Found

[M+Na]+, 418.1839.

! MeO O II-64k: 36 h reaction time. The compound was isolated as a light yellow oil

OMe O O (130 mg, 83%) by flash column chromatography on silica gel (5:95 ethyl

BocHN acetate:hexanes to 20:80 ethyl acetate:hexanes). Rf = 0.28 (20:80 ethyl acetate:hexanes); FTIR (film) 3381, 2976, 2839, 2253, 1747, 1713, 1613, 1586, 1514, 1455,

1392, 1367, 1250, 1218, 1170, 1054, 1031 cm-1; 1H NMR (400 MHz, CDCl3, mixture of two diastereomers) δ 7.41-721 (m, 12H); 6.87 (app d, J = 8.8 Hz, 2H); 6.82 (app d, J = 8.8 Hz,

2H);5.90 (s, 1H); 5.90 (s, 1H); 5.54-5.45 (4H); 3.78 (s, 3H); 3.77 (s, 3H); 3.70 (s, 3H); 3.57 (s,

3H); 1.44 (s, 9H); 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.7, 170.4, 168.9, 168.8, 160.5,

154.9, 154.8, 136.5, 136.3, 129.2, 128.9, 128.8, 128.6, 128.5, 127.6, 127.4, 125.4, 125.3, 114.3,

114.2, 80.3, 80.2, 75.2, 75.0, 57.9, 57.6, 55.4, 55.4, 52.7, 52.5, 28.4, 28.4; HRMS (ESI): Mass ! 99! calculated for C23H27NaNSO7 [M+Na]+, 452.1680. Found [M+Na]+, 452.1676.

O II-64l: The compound was isolated as a light yellow solid (53 mg, 66%) by flash

OEt O O column chromatography on silica gel (5:95 ethyl acetate:hexanes to 20:80 ethyl

CH3 acetate:hexanes). Rf = 0.64 (20:80 ethyl acetate:hexanes); FTIR (film) 2983, 1744,

1496, 1456, 1372, 1336, 1233, 1181, 1083, 1055, 1026, 960, 925 cm-1; 1H NMR (400 MHz,

CDCl3) δ 7.50-7.46 (2H); 7.40-7.38 (3H); 5.91 (s, 1H); 4.26- 4.11 (2H); 2.20 (s, 3H); 1.22 (t, J =

7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.5, 169.0, 134.1, 129.3, 128.9, 127.7, 74.7, 61.8,

20.9, 14.1; HRMS (ESI): Mass calculated for C12H14NaO4 [M+Na]+, 245.0784. Found

[M+Na]+, 245.0786.

MeO Br II-64m: The compound was isolated as a colorless oil (102 mg, 89%) by O OMe flash column chromatography on silica gel (5:95 ethyl acetate:hexanes to O O

CH 3 20:80 ethyl acetate:hexanes). Rf = 0.39 (20:80 ethyl acetate:hexanes); FTIR

(film) 3006, 2954, 2841, 1747, 1605, 1568, 1497, 1462, 1439, 1372, 1346, 1287, 1230, 1182,

1054, 1031, 978 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.8 Hz, 1H); 7.14 (d, J = 2.4

Hz, 1H); 6.87 (dd, 8.4, 2.6, 1H); 6.37 (s, 1H); 3.80 (s, 3H); 3.74 (s, 3H); 2.16 (s, 3H); 13C NMR

(100 MHz, CDCl3) δ 170.2, 169.3, 160.8, 130.3, 125.9, 124.9, 118.5, 114.1, 73.1, 55.7, 52.8,

20.7; HRMS (ESI): Mass calculated for C12H13NaBrO5 [M+Na]+, 338.9839. Found [M+Na]+,

338.9836.

! Br O II-64n: 48 h reaction time. The compound was isolated as a dark yellow oil

OEt O O (62.5 mg, 57%) by flash column chromatography on silica gel (5:95 ethyl

CH3 acetate:hexanes to 20:80 ethyl acetate:hexanes). Rf = 0.49 (20:80 ethyl acetate:hexanes); FTIR (film) 2982, 2360, 1745, 1593, 1489, 1444, 1406, 1372, 1341, 1232,

! 100! 1210, 1180, 1070, 1012 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.52 (app d, J = 8.4 Hz, 2H); 7.35

(app d, J = 8.4 Hz, 2H); 5.86 (s, 1H); 4.24-4.12 (2H); 2.19 (s, 3H); 1.22 (t, J = 7.2 Hz, 3H); 13C

NMR (100 MHz, CDCl3) δ 170.3, 168.5, 133.1, 132.1, 129.3, 123.5, 74.0, 62.0, 20.8, 14.1;

HRMS (ESI): Mass calculated for C12H13NaBrO4 [M+Na]+, 322.9889. Found [M+Na]+,

322.9891.

Me II-64o: The compound was isolated as a colorless oil (61.5 mg, 76%) by flash O OMe column chromatography on silica gel (5:95 ethyl acetate:hexanes to 20:80 O O

CH3 ethyl acetate:hexanes). Rf = 0.52 (20:80 ethyl acetate:hexanes); FTIR (film)

3481, 3030, 2954, 1747, 1615, 1516, 1436, 1372, 1347, 1274, 1235, 1177, 1113, 1056, 979, 931 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.35 (app d, J = 8.4 Hz, (2H); 7.20 (app d, J = 7.6 Hz, 2H);

3.90 (s, 1H); 3.71 (s, 3H); 2.36 (s, 3H); 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.5,

169.6, 139.4, 131.0, 129.6, 127.8, 74.5, 52.7, 21.3, 20.8; HRMS (ESI): Mass calculated for

C12H14NaO4 [M+Na]+, 245.0784. Found [M+Na]+, 245.0786.

II-64p: The compound was isolated as a green solid (62.2 mg, 50%) by flash

O BocN OMe column chromatography on silica gel (5:95 ethyl acetate:hexanes to 10:90 ethyl O O acetate:hexanes). R = 0.5 (20:80 ethyl acetate:hexanes); FTIR (film) 3054, CH3 f

2979, 2954, 2360, 1740, 1609, 1570, 1453, 1371, 1223, 1156, 1092, 1049 cm-1; 1H NMR (400

MHz, CDCl3) δ 8.16 (d, J = 8.4 Hz, 1H); 7.72 (m, 1H); 7.69 (m, 1H); 7.36 (m, 1H); 7.29 (m,

1H); 6.25 (s, 1H); 3.75 (s, 3H); 2.20 (s, 3H); 1.67 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.5,

169.1, 149.4, 135.7, 128.1, 125.9, 125.1, 123.2, 120.0, 115.5, 113.7, 84.4, 68.3, 52.9, 28.3,

20.8; HRMS (ESI): Mass calculated for C18H21NaNO6 [M+Na]+, 370.1261. Found [M+Na]+,

3701264.

% ! 101! 2.4.4 General Procedure for the Organocatalytic S-H Insertion

A dry, screw-capped reaction vial, equipped with a magnetic stir bar, was charged with aryldiazoacetate (0.485 mmol), catalyst (0.012 mmol, 2.5 mol %), and placed under a N2 atmosphere. PhCF3 (0.97 mL) was added and the reaction was degassed by bubbling N2 through the solution for 5 min at 23 ºC. The appropriate thiol (0.533, 1.1 equiv.) was added in one portion and the reaction mixture was allowed to stir for 12 h at 23 ºC and then immediately purified by flash column chromatography on silica gel.

OMe O II-67a: The compound was isolated as a white solid (125.7 mg, 90%) by flash

MeO S column chromatography on silica gel (5:95 diethyl ether:hexanes to 15:85

diethyl ether:hexanes). Rf = 0.15 (5:95 ethyl acetate:hexanes); FTIR (film)

3003, 2951, 2838, 1737, 1607, 1509, 1443, 1251, 1154, 1027 cm-1; 1H NMR (400 MHz, CDCl3)

δ 7.41-7.33 (m, 4H); 7.29-7.24 (m, 3H); 6.85 (app d, J = 8.8 Hz, 2H); 4.88 (s, 1H); 3.80 (s, 3H);

3.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.2, 159.8, 134.0, 132.7, 129.9, 129.1, 128.1,

127.7, 114.2, 55.8, 55.4, 52.8; HRMS (ESI): Mass calculated for C16H16SNaO3 [M+Na]+,

311.0712. Found [M+Na]+, 311.0714.

OMe II-67b: The compound was isolated as a white solid (141.0 mg, 91%) by O MeO flash column chromatography on silica gel (5:95 diethyl ether:hexanes to S

MeO 15:85 diethyl ether:hexanes). Rf = 0.12 (5:95 ethyl acetate:hexanes); FTIR

(film) 2934, 1733, 1580, 1509, 1466, 1245, 1026 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.37 (app d, J = 8.7 Hz, 2H); 7.30 (dd, J = 7.5, 1.6 Hz, 1H); 7.28-7.23 (m, 1H); 6.88-6.80 (m, 4H); 5.05 (s,

1H); 3.89 (s, 3H); 3.78 (s, 3H); 3.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.4, 159.6, 159.0,

134.1, 129.8, 129.7, 127.9, 121.9, 121.1, 114.1, 110.9, 56.0, 55.4, 53.3, 52.7; HRMS (ESI): Mass calculated for C17H18NaSO4 [M+Na]+, 341.0818. Found [M+Na]+, 341.0814. ! 102!

OMe O II-67c: The compound was isolated as a colorless oil (128.4 mg, 88%) by

MeO S flash column chromatography on silica gel (5:95 diethyl ether:hexanes to

Me 15:85 diethyl ether:hexanes). Rf = 0.19 (5:95 ethyl acetate:hexanes); FTIR

(film) 3003, 2951, 2839, 1738, 1608, 1510, 1462, 1251, 1151, 1033 cm-1; 1H NMR (400 MHz,

CDCl3) δ 7.39 (app d, J = 8.7 Hz, 2H); 7.35 (app d, J = 7.7 Hz, 1H); 7.23-7.16 (m, 2H); 7.16-

7.09 (m, 1H); 6.87 (app d, J = 8.7 Hz, 2H); 4.84 (s, 1H); 3.82 (s, 3H); 3.67 (s, 3H); 2.41 (s, 3H);

13C NMR (100 MHz, CDCl3) δ 171.3, 159.8, 140.5, 133.3, 133.0, 130.5, 129.8, 128.1, 127.7,

126.6, 114.2, 55.4, 54.9, 52.7, 20.7; HRMS (ESI): Mass calculated for C17H18NaSO3 [M+Na]+,

325.0869. Found [M+Na]+, 325.0867.

OMe O II-67d: The compound was isolated as a light yellow solid (117.1 mg, 79%)

MeO S by flash column chromatography on silica gel (5:95 diethyl ether:hexanes to

F 15:85 diethyl ether:hexanes). Rf = 0.15 (5:95 diethyl ether:hexanes); FTIR

(film) 3003, 2954, 2839, 1738, 1609, 1589, 1511, 1490, 1461, 1438, 1291, 1252, 1178, 1153 cm-

1; 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 2H); 7.31 (app d, J = 8.8 Hz, 2H); 6.96 (m, 2H); 6.84

(app d, J = 8.8 Hz, 2H); 4.78 (s, 1H); 3.80 (s, 3H); 3.66 (s, 3H); 13C NMR (100 MHz, CDCl3)

δ 171.1, 164.4 (d, J = 247.6 Hz), 159.8, 136.2 (d, J = 8.2 Hz), 129.9, 128.6 (d, J = 3.4 Hz),

19 127.5, 116.2 (d, J = 21.6 Hz), 114.2, 56.5, 55.4, 52.8; F NMR (376 MHz, CDCl3) d –112.6 (s);

HRMS (ESI): Mass calculated for C16H15FSNaO3 [M+Na]+, 329.0618. Found [M+Na]+,

329.0607.

OMe O II-67e: The compound was isolated as a white solid (143.4 mg, 87%) by

MeO S flash column chromatography on silica gel (5:95 diethyl ether:hexanes to

! 103! 15:85 diethyl ether:hexanes). Rf = 0.22 (35:65 ethyl acetate:hexanes); FTIR (film) 3053, 2953,

2839, 1734, 1606, 1508, 1437, 1340, 1248, 1149, 1030 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.87-

7.83 (m, 1H); 7.83-7.77 (m, 1H); 7.77-7.71 (m, 2H); 7.51-7.37 (m, 5H); 6.86 (app d, J = 8.8 Hz,

2H); 5.00 (s, 1H); 3.79 (s, 3H); 3.66 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.2, 159.8, 133.7,

132.7, 131.7, 131.4, 129.9, 129.6, 128.6, 127.8, 127.7, 127.6, 126.64, 126.58, 114.3, 55.7, 55.4,

52.8; HRMS (ESI): Mass calculated for C20H18NaSO3 [M+Na]+, 361.0869. Found [M+Na]+,

361.0861.

OMe II-67f: The compound was isolated as a colorless oil (90.1 mg, 73%) by flash O

MeO S Me column chromatography on silica gel (5:95 diethyl ether:hexanes to 15:85

Me diethyl ether:hexanes). Rf = 0.22 (5:95 ethyl acetate:hexanes); FTIR (film)

2958, 1738, 1607, 1511, 1459, 1250, 1149, 1032 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.40 (app d, J = 8.7 Hz, 2H); 6.86 (app d, J = 8.8 Hz, 2H); 4.61 (s, 1H); 3.80 (s, 3H); 3.72 (s, 3H); 2.88

13 (sep, J = 6.7 Hz, 1H); 1.25 (AB d, Jab = 6.7 Hz, Δδab = 0.01, 6H); C NMR (100 MHz, CDCl3)

δ 172.0, 159.6, 129.7, 128.5, 114.2, 55.4, 52.8, 50.9, 35.7, 23.24, 23.20; HRMS (ESI): Mass calculated for C13H18NaSO3 [M+Na]+, 277.0869. Found [M+Na]+, 277.0863.

OMe O II-67g: The compound was isolated as a colorless oil (101.3 mg, 69%) by

MeO S flash column chromatography on silica gel (5:95 diethyl ether:hexanes to

15:85 diethyl ether:hexanes). Rf = 0.15 (5:95 diethyl ether:hexanes); FTIR

(film) 3014, 2951, 2842, 1732, 1605, 1501, 1456, 1255, 1166, 1024 cm-1; 1H NMR (400 MHz,

CDCl3) δ 7.36-7.22 (m, 7H); 6.87 (app d, J = 8.8 Hz, 2H); 4.39 (s, 1H); 3.80 (s, 3H); 3.68 (AB d,

13 Jab = 13.6 Hz, Δδab = 0.15, 2H); 3.68 (s, 3H); C NMR (100 MHz, CDCl3) δ 171.5, 159.6, 137.4,

129.9, 129.2, 128.7, 127.8, 127.4, 114.2, 55.4, 52.8, 51.0, 36.3; HRMS (ESI): Mass calculated for

C17H18SNaO3 [M+Na]+, 325.0869. Found [M+Na]+, 325.0872.

! 104! II-67h: The compound was isolated as a colorless oil (51.3 mg, 42%) by flash OMe O

MeO column chromatography on silica gel (5:95 diethyl ether:hexanes to 15:85 S O 1 Me diethyl ether:hexanes). Rf = 0.34 (5:95 diethyl ether:hexanes); H NMR (400

MHz, CDCl3) δ 7.31 (app d, J = 8.8 Hz, 2H); 6.86 (app d, J = 8.8 Hz, 2H); 5.27 (s, 1H); 3.79 (s,

3H); 3.73 (s, 3H); 2.34 (s, 3H); All spectral data match those previously reported.[8]

OMe II-67i: The compound was isolated as a colorless oil (83.6 mg, 54%) by flash O

MeO S O column chromatography on silica gel (5:95 diethyl ether:hexanes to 15:85

Ph diethyl ether:hexanes). Rf = 0.15 (5:95 diethyl ether:hexanes); FTIR (film)

3004, 2954, 2839, 1741, 1665, 1608, 1511, 1446, 1253, 1212, 1174, 1031 cm-1; 1H NMR (400

MHz, CDCl3) δ 7.96-7.92 (m, 2H); 7.60-7.54 (m, 1H); 7.47-7.38 (m, 4H); 6.89 (app d, J = 8.8

Hz, 2H); 5.45 (s, 1H); 3.80 (s, 3H); 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.5, 170.9,

159.9, 136.2, 133.9, 129.9, 128.8, 127.5, 126.7, 114.5, 55.4, 53.2, 50.7; HRMS (ESI): Mass calculated for C17H16SNaO4 [M+Na]+, 339.0662. Found [M+Na]+, 339.0661.

II-67j: Reaction was performed at 50 ºC for 72 h. The compound was isolated as a O

EtO S colorless oil (86.4 mg, 65%) by flash column chromatography on silica gel (5:95

diethyl ether:hexanes to 10:90 diethyl ether:hexanes). Rf = 0.26 (5:95 ethyl acetate:hexanes); 1H NMR (400 MHz, CDCl3) δ 7.47-7.43 (m, 2H); 7.40-7.36 (m, 2H); 7.34-7.28

(m, 3H); 7.28-7.25 (m, 3H); 4.90 (s, 1H); 4.12 (m, 2H); 1.17 (t, J = 7.1 Hz, 3H); All spectral data match those previously reported.[9]

Br OMe O II-67k: The compound was isolated as a colorless oil (144.2 mg, 81%) by

MeO S flash column chromatography on silica gel (5:95 diethyl ether:hexanes to

! 105! 15:85 diethyl ether:hexanes). Rf = 0.20 (5:95 ethyl acetate:hexanes); FTIR (film) 3066, 3006,

2947, 2842, 1738, 1597, 1486, 1239, 1027 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.8

Hz, 1H); 7.44-7.38 (m, 2H); 7.30-7.25 (m, 3H); 7.08 (d, J = 2.8 Hz, 1H); 6.86 (dd, J = 8.8, 2.8

Hz, 1H); 5.43 (s, 1H); 3.78 (s, 3H); 3.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.8, 159.9,

133.4, 133.1, 130.9, 129.1, 128.3, 127.3, 124.9, 118.1, 114.1, 55.7, 54.4, 52.9; HRMS (ESI):

Mass calculated for C16H15NaBrSO3 [M+Na]+, 388.9817. Found [M+Na]+, 388.9819.

Br II-67l: Reaction was performed at 50 ºC for 12 h. The compound was isolated O EtO as a colorless oil (123.4 mg, 72%) by flash column chromatography on silica S

gel (5:95 diethyl ether:hexanes). Rf = 0.24 (5:95 ethyl acetate:hexanes); FTIR

(film) 3058, 2980, 2935, 1738, 1585, 1487, 1439, 1271, 1148, 1072 cm-1; 1H NMR (400 MHz,

CDCl3) δ 7.44 (app d, J = 8.4 Hz, 2H); 7.40-7.34 (m, 2H); 7.31 (app d, J = 8.4 Hz, 2H); 7.27 (app d, J = 2.8 Hz, 2H); 4.83 (s, 1H); 4.13 (AB dq, Jab = 10.8, 7.2 Hz, Δδ = 0.02, 2H); 1.17 (t, J = 7.2

Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.1, 135.0, 133.4, 133.1, 131.9, 130.4, 129.2, 128.4,

122.5, 62.0, 56.0, 14.1; HRMS (ESI): Mass calculated for C16H15NaBrSO2 [M+Na]+, 372.9868.

Found [M+Na]+, 372.9866.

Me II-67m: 72 h reaction time. The compound was isolated as a white solid (99.6 O MeO mg, 75%) by flash column chromatography on silica gel (5:95 diethyl S

ether:hexanes to 10:90 diethyl ether:hexanes). Rf = 0.36 (5:95 ethyl acetate:hexanes); FTIR (film) 3051, 2946, 1739, 1582, 1512, 1434, 1331, 1147, 1089 cm-1; 1H

NMR (400 MHz, CDCl3) δ 7.41-7.37 (m, 2H); 7.34 (app d, J = 8.0 Hz, 2H); 7.29-7.24 (m, 3H);

7.17-7.12 (app d, J = 8.0 Hz, 2H); 4.91 (s, 1H); 3.67 (s, 3H); 2.34 (s, 3H); 13C NMR (100 MHz,

CDCl3) δ 171.1, 138.3, 134.1, 132.7, 132.6, 129.5, 129.1, 128.5, 128.0, 56.2, 52.8, 21.3; HRMS

(ESI): Mass calculated for C16H16NaSO2 [M+Na]+, 295.0763. Found [M+Na]+, 295.0766. ! 106!

O NBoc II-67n: The compound was isolated as a light yellow oil (169.8 mg, 88%) by

MeO S flash column chromatography on silica gel (5:95 diethyl ether:hexanes to 10:90

diethyl ether:hexanes). Rf = 0.26 (5:95 ethyl acetate:hexanes); FTIR (film)

3055, 2977, 1730, 1568, 1451, 1367, 1257, 1151, 1084, 1021 cm-1; 1H NMR (400 MHz, CDCl3)

δ 8.16 (br d, J = 8.0 Hz, 1H); 7.70 (d, J = 7.2 Hz, 1H); 7.63 (s, 1H); 7.43-7.38 (m, 2H); 7.37-7.32

(m, 1H); 7.31-7.27 (m, 4H); 5.13 (d, J = 0.8 Hz, 1H); 3.72 (s, 3H); 1.65 (s, 9H); 13C NMR (100

MHz, CDCl3) δ 170.9, 149.5, 135.7, 133.6, 133.5, 129.1, 128.7, 128.5, 125.5, 125.0, 123.0,

119.6, 115.5, 114.5, 84.1, 52.8, 47.9, 28.3; HRMS (ESI): Mass calculated for C22H23NaNSO4

[M+Na]+, 420.1240. Found [M+Na]+, 420.1241.

% % 2.5 Mechanistic Studies

2.5.1 Evidence Against a Carbene Intermediate

II-64q: A dry, screw-capped reaction vial equipped with a magnetic MeO O

O Ph stir bar was charged with II-63g (112.1 mg, 0.364 mmol), AcOH (3.6 O O

CH3 mg, 0.0091 mmol), and placed under an atmosphere of N2. Toluene

(1.45 mL) was added, the reaction mixture was stirred at 23 ºC for 5 min, and then acetic acid

(25.0 mL, 0.267 mmol) was added. The reaction was allowed to stir at 23 ºC for 24 h at 23 ºC and immediately purified by flash column chromatography on silica gel (15:90 ethyl acetate:hexanes) to obtain 4q as a colorless oil (109.6 mg, 89%). Rf = 0.30 (20:80 ethyl acetate:hexanes); FTIR

(film) 3026, 2957, 2838, 1747, 1731, 1613, 1514, 1446, 1372, 1235, 1176, 1035 cm-1; 1H NMR

(400 MHz, CDCl3) δ 7.41 (app d, J = 8.8 Hz, 2H); 7.34-7.21 (5H); 6.92 (app d, J = 8.8 Hz, 2H);

! 107! 6.51 (dt, J = 16.0, 1.2 Hz, 1H); 6.18 (dt, J = 15.6, 6.4 Hz, 1H); 5.93 (s, 1H); 4.84-4.73 (m, 2H);

3.81 (s, 3H); 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.5, 169.0, 160.5, 136.2, 134.3,

129.3, 128.7, 128.2, 126.8, 126.0, 122.5, 114.4, 74.4, 66.0, 55.4, 20.9; HRMS (ESI): Mass calculated for C20H20NaO5 [M+Na]+, 363.1203. Found [M+Na]+, 363.1203.

MeO exo-(±)-II-69: A dry, screw-capped reaction vial, equipped with a magnetic stir bar

O and a reflux condenser was charged with II-63g (74.8 mg, 0.243 mmol) and O

H dissolved in PhCF3 (1.22 mL) under an atmosphere of N2. The reaction was warmed to 100 ºC for 30 min behind a blast shield and immediately purified by flash column chromatography on silica gel (25:75 ethyl acetate:hexanes) to obtain exo-II-69 as a white solid

(59.0 mg, 87%). Rf = 0.21 (20:80 ethyl acetate:hexanes); FTIR (film) 3038, 2965, 2908, 2838,

1766, 1611, 1517, 1460, 1374, 1296, 1251, 1195, 1130 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.14-

7.09 (m, 5H); 6.86-6.82 (m, 2H); 6.73 (app d, J = 8.8 Hz, 2H); 4.61 (dd, J = 9.2, 4.4 Hz, 1H);

4.49 (d, J = 9.2 Hz, 1H); 3.72 (s, 3H); 3.03 (app t, J = 4.4 Hz, 1H); 2.67 (d, J = 4.4 Hz, 1H); 13C

NMR (100 MHz, CDCl3) δ 175.9, 159.3, 134.0, 131.9, 128.2, 128.0, 127.1, 121.8, 113.9, 68.5,

55.3, 39.6, 35.4, 27.9; HRMS (ESI): Mass calculated for C18H16NaO3 [M+Na]+, 303.0992.

Found [M+Na]+, 303.0986.

2.5.2 Evidence For X–H Bond Necessity

MeO O 10 mol % II-10 AcOH, Et3N OMe No PhMe, 23 ºC Reaction N2 24 h

A dry, screw-capped reaction vial, equipped with a magnetic stir bar, was charged with aryldiazoacetate (0.364 mmol), catalyst (0.0364 mmol, 10 mol %), and placed under a N2 ! 108! atmosphere. Toluene (1.45 mL) was added and the reaction was degassed by bubbling N2 through the solution for 5 min at 23 ºC. Triethylamine (0.437, 1.2 equiv.) was added to the reaction slowly. Acetic acid (0.437, 1.2 equiv.) was added in one portion and the reaction mixture was allowed to stir for 24 h at 23 ºC. The reaction was quenched slowly with water and immediately purified by flash column chromatography on silica gel.

MeO 10 mol % II-10 O NaOAc No OMe PhMe, 23 ºC Reaction N2 24 h

A dry, screw-capped reaction vial, equipped with a magnetic stir bar, was charged with aryldiazoacetate (0.364 mmol), catalyst (0.0364 mmol, 10 mol %), and placed under a N2 atmosphere. Toluene (1.45 mL) was added and the reaction was degassed by bubbling N2 through the solution for 5 min at 23 ºC. Sodium acetate (0.437, 1.2 equiv.) was added in one portion and the reaction mixture was allowed to stir for 24 h at 23 ºC. The reaction was quenched with water and immediately purified by flash column chromatography on silica gel.

2.5.3 Evidence Against Catalyst Deprotonation

CF3 NBu F F CF3 4 F F B n-Bu NOAc O 4 B EtOAc, 2 weeks N CF3 N N CF3 H H N O H

! 109! [2b] CF3 II-70: According to the report of Smith et al., the boronate urea II-10 was NBu4 F F B dissolved in EtOAc and t-butylammonium acetate was added. After several N CF3

N O H weeks small cubes crystallized from the solution to afford II-70: FTIR (film)

-1 1 3193, 2966, 1651, 1583, 1373, 1275, 1129 cm ; H NMR (400 MHz, CDC3N) d 7.99 (s, 2H);

7.65 (s, 1H); 7.36 (d, J = 7.2 Hz, 1H); 7.25 (br s, 1H); 7.09 (td, J = 8.0, 1.6 Hz, 1 H); 6.85 (td, J =

7.2, 0.8 Hz, 1 H); 6.69 (d, J = 8.0 Hz, 1H); 3.10-3.02 (8H); 1.64-1.53 (8H); 1.34 (sep, J = 7.2 Hz,

13 8H); 0.96 (t, J = 7.2 Hz, 12H); C NMR (100 MHz, CD3CN) d 156.9, 147.4, 142.5 (t, J = 4.4

Hz), 131.7, 130.9 (q, J = 32.5 Hz), 129.4 (br), 128.0, 125.0 (q, J = 269.9 Hz), 121.3, 117.3 (sep, J

= 3.9 Hz), 113.2, 59.3 (t, J = 1.9 Hz), 24.3, 20.3 (t, J = 1.3 Hz), 13.8 (the carbon bonded to boron

[3] 11 19 was not seen due to broadening) ; B NMR (160 MHz, CD3CN) d 3.78 (br s); F NMR (376

MHz, CD3CN) d –63.17 (s, 6F), –138.2 (s, 1F), –138.4 (s, 1F); HRMS (ESI): Mass calculated for

– – C15H8BF8N2O [M–Bu4N] , 395.0610. Found [M–Bu4N] , 395.0606.

! 110!

The crystal structure has been deposited at the Cambridge Crystallographic Data Centre (CCDC

991177). The data can be obtained free of charge via the Internet at www.ccdc.cam.ac.uk/conts/retrieving.html.

Ortep Diagram of Isomerized Difluoroboronate Urea II-70:

!

! 111! ppm 6.8 6.9 7.0 Scale: 0.1034 ppm/cm, 41.37 Hz/cm 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 9.0 9.1 9.2

! 112! 2.5.4 Synthesis of Chiral ortho-Borylbenzoic Acids

2.5.4.1 Preparation of Sodium Borate

CH3 Na H3C CH3 CH3 B(OH) O 2 O pinacol B O O PhMe, reflux Na O A O

CH H C 3 Na 3 CH3 Sodium 4',4',5',5'-tetramethyl-3-oxo-3H-spiro[benzo[c][1,2]oxabor- CH3 O O B O ole-1,2'-[1,3,2]dioxaborolan]-1-uide: Sodium 2-boronobenzoate (2.00

O A g, 10.6 mmol) and pinacol (1.43 g, 12.1 mmol were added to a 100 mL flame-dried flask equipped with a Dean Stark trap and a reflux condensor. Toluene (25 mL) was then added to the reaction pot and the heterogeneous mixture was heated reflux with vigorous stirring for 24 h. The reaction mixture was then allowed to cool to room temperature and the solvent was removed in vacuo. The excess pinacol was removed by trituration of the resulting white solid in ether. This afforded A as a white powder, 2.86 g

(quant.), decomposed 331.2 – 333.6 ºC; IR (KBr) 2975, 1679, 1451, 1152, 1088 cm-1; 1H

NMR (400 MHz, DMSO-d6) δ 7.38 (d, 1H, J = 7.2 Hz); 7.33-7.24 (m, 2H); 7.13 (m, 1H);

13 1.09 (s, 12H); C NMR (100 MHz, DMSO-d6) δ 173.1, 138.1, 130.1, 128.7, 125.7,

122.2, 77.66 25.5 (the carbon bonded to boron was not seen due to broadening)[90] 11B

NMR (160 MHz, DMSO-d6) δ 10.4 (br s); HRMS (ESI): Mass calculated for C13H16BO4

[M–Na]–, 247.1147. Found [M–Na]–, 247.1147.

R R R R O B(OH)2 O HO OH B O O Et2O, 23 ºC, 2 h

OH OH II-82

! 113!

2.5.4.2 General Procedure for the Preparation of Chiral ortho-Borylbenzoic Acids

A modified version of the procedure described by Maruoka et al. was used 2-

(dihydroxyboryl)-benzoic acid (1.1 equiv.), freshly washed with HCl (3 M), and chiral

1,2-diol (1.0 equiv.) were added to a 4 mL flame-dried vial. Et2O (2 mL) was then added to the reaction pot and the heterogeneous mixture was stirred at 23 ºC for 2 h. The reaction mixture was then concentrated and stirred in CH2Cl2 for 10 min. The insoluble material was removed and the filtrate was concentrated to afford II-86, II-87 and II-88.

Me Me 2-((4R,5R)-4,5-dimethyl-1,3,2-dioxaborolan-2-yl)benzoic acid: (97 %) O O B O light-yellow oil; IR (KBr) 3163, 3066, 2973, 1686, 1600, 1569, 1493, 1446,

OH -1 1 II-86 1375, 1353, 1311, 1260, 1221 cm ; H NMR (400 MHz, CDCl3) δ 11.64 (br s, 1H); 8.02-7.91 (1H); 7.80-7.30 (3H); 4.24 (s, 2H); 1.44 (s, 6H); 13C NMR (100 MHz,

CDCl3) δ 173.7, 133.1, 132.5, 132.2, 129.8, 129.3, 81.0, 20.8 (the carbon bonded to

[90] 11 boron was not seen due to broadening) B NMR (160 MHz, CDCl3) δ 30.4 (br s).

Ph Ph 2-((4R,5R)-4,5-diphenyl-1,3,2-dioxaborolan-2-yl)benzoic acid: (XX %) O O B O white solid; IR (KBr) 3063, 3032, 2913, 2675, 1682, 1600, 1569, 1496,

OH -1 1 II-87 1454, 1345 cm ; H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 7.6 Hz, 1H); 7.78 (dd, J = 7.2, 0.4 Hz, 1H); 7.69 (td, J = 7.6, 1.2 Hz, 1H); 7.57 (td, J = 7.6, 1.6 Hz,

13 1H); 7.45-7.38 (8H); 7.38-7.31 (2H); 5.37 (s, 2H); C NMR (100 MHz, CDCl3) δ 173.7,

140.2, 133.4, 132.52, 13.47, 130.0, 129.6, 128.9, 128.5, 126.3, 87.5 (the carbon bonded to

[90] 11 boron was not seen due to broadening) B NMR (160 MHz, CDCl3) δ 34.9 (br s). ! 114!

MeO(Ph)2C C(Ph)2OMe 2-((4S,5S)-4,5-bis(methoxydiphenylmethyl)-1,3,2-dioxaborolan-2- O O B O yl)benzoic acid: (99 %) white solid; IR (KBr) 3068, 2938, 2834, 1704,

OH II-88 1597, 1494, 1446, 1372, 1346, 1265, 1227, 1200 cm-1; 1H NMR (400

MHz, CDCl3) δ 9.87 (br s, 1H); 7.92 (d, J = 7.6 Hz, 1H); 7.45 (td, J = 7.6, 1.6 Hz, 1H);

7.39-7.32 (9H); 7.32-7.27 (6H); 7.26-7.16 (7H); 5.59 (s, 2H); 3.02 (s, 6H); 13C NMR

(100 MHz, CDCl3) δ 169.7, 141.1, 140.9, 136.2, 135.5, 131.0, 130.9, 130.7, 129.7, 128.7,

128.1, 127.8, 127.7, 83.6, 79.0, 52.2 (the carbon bonded to boron was not seen due to

[90] 11 broadening) B NMR (160 MHz, CDCl3) δ 32.6 (br s).

! 115!

!

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