Boronate Urea Activation of Nitro Compounds a Dissertation

Boronate Urea Activation of Nitro Compounds

A Dissertation

Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University

Sonia Sung Young So, B. S.

Graduate Program in Chemistry

The Ohio State University

2014

Committee: Professor Anita E. Mattson (Advisor) Professor Craig J. Forsyth Professor Jovica Badjic

Sonia Sung Young So

2014

Abstract

Boronate ureas have been discovered as enhanced hydrogen bond donor (HBD) catalysts for the activation of various compounds containing nitro functional groups. The enhanced ability of boronate ureas to recognize and activate nitro compounds can be attributed to the internal coordination of the strategically placed boron to the urea carbonyl. Boronate ureas have elicited rate enhancements of up to 10 times that of traditional urea and thiourea HBD catalysts in the known addition of nitrogen heterocycles to nitroalkenes. This improvement in urea catalyst activity has allowed for the discovery of two new methodologies.

The urea activation of nitrocyclopropane carboxylates was discovered for nucleophilic ring opening by amine nucleophiles. The facile formation of !–amino acid precursors from nitrocyclopropane carboxylate precursors had never before been reported with HBD catalysts. This novel activation of nitrocyclopropane carboxylates led to the discovery of formal [3+3] dipolar cycloaddition reactions with nitrones for the efficient construction of oxazinanes. Additionally, boronate ureas have been demonstrated to activate nitrodiazoester compounds for N–H insertion/multicomponent coupling of anilines for the formation of !-aryl glycine compounds. Chiral phosphoric acid HBD catalysts were utilized for activation of nitrodiazoesters for stereoselective glycine formation. This methodology was expanded to develop double arylation of nitrodiazoesters through a transient N–H insertion intermediate. ii

Dedication

Everything leading up to and including this work is dedicated to my mom, whose

patience and strength are never ending.

This work is also dedicated to my husband for his support and encouragement through it

all.

iii

Acknowledgments

I would like to first thank my Ph.D. advisor, Professor Anita Mattson, for giving me the opportunity to achieve one of my life goals. Anita’s guidance and support has been integral in my development as a chemist and I am grateful for the knowledge she has imparted on me. I would like to thank Professor James Stambuli for being an advisor and an invaluable resource. I would also like to thank my undergraduate research advisor, Dr. Hamish Christie, without whom I never would have pursued chemistry. I respect and appreciate his mentorship and counsel and will continue to email him with the subject line, “update.”

I would be remiss if I did not acknowledge the impact my friendships have made on my experience in graduate school and in life. I must thank Tyler, who was there from the beginning, studying, columning, complaining right alongside me, for being like a brother to me through all the ups and downs. We made it. I want to thank all my friends, especially Erica, for making grad school a little easier. I will always cherish the memories of laughing uncontrollably, talking to Kamala, racing to grab the fire extinguisher, hearing Moke’s version of historical events, going to Moy’s, the movie theater laugh, that weird noise at group meeting, Josh’s story about the Hard Rock Café, the world’s most awkward elevator ride, that time I added rhodium to my vial, and so

iv many more. And, of course, I want to thank Elaine, for being so supportive and being the ultimate friend through the best and worst of it.

I want to take this opportunity to thank my brother, Victor, for taking on the role of an entire family, for raising me, protecting me, and for making sacrifices no one should have to…and now that it is all done, for being my friend.

I will never be able to thank my mom enough for showing me unconditional love and support. She has been an inspiration to me throughout my life and, after everything, continues to impress me.

Finally, I want to thank my husband, Tommy, for listening, advising, and showing me how to be who I want to be. He is ever patient and supportive, but true enough to tell me when I am wrong. He is the most important voice in my life, and I turn to him for science, math, history, song lyrics, and nearly everything else.

Vita

May 2005 ...... Mesquite High School

May 2009 ...... B.S. Biochemistry and Molecular Biophysics, University of Arizona

2009 to present ...... Graduate Program of Chemistry, The Ohio State University

Publications

• So, S. S.; Mattson, A. E. “Stereoselective N–H Insertion-Arylation Reactions of Nitrodiazoesters” Asian J. Org. Chem. 2013. DOI: 10.1002/ajoc.201300285. Invited contribution.

• So, S. S.; Oottikkal, S.; Badjic, J.; Hadad, C. M.; Mattson, A. E. “Urea-Catalyzed Activation of Nitrodiazoesters for N-H Insertion Reactions” J. Org. Chem. 2013. Submitted.

• Auvil, T. J.; So, S. S.; Mattson, A. E. “Double Arylation of Nitrodiazo Compounds Catalyzed by a Urea/Aniline Combination” Angew. Chem. Int. Ed. 2013. 52, 11317- 11320. (Highlighted in SynFacts)

• Hardman, A. M.; So, S. S.; Mattson, A. E. “Formal [3+2] Dipolar Cycloaddition Reactions of Nitrocyclopropane Carboxylates” Org. Biomol. Chem. 2013, 11, 5793- 5797

• Nickerson, D. M.; Angeles, V. V.; Auvil, T. J.; So, S. S.; Mattson, A. E. “Internal Lewis Acid Assisted Ureas: Tunable Hydrogen Bond Donor Catalysts” Chem. Commun. 2012, 49, 4289-4291. Invited Contribution

• So, S. S.; Mattson, A. E. “Urea Activation of !-Nitrodiazoesters: An Organocatalytic Approach to N–H Insertion Reactions” J. Am. Chem. Soc. 2012, 134, 8798-8801. (Highlighted in SynForm, Highlighted in SynFacts)

vi • So, S. S.; Auvil, T. J.; Garza, V. J.; Mattson, A. E. “Boronate Urea Activation of Nitrocyclopropanes” Org. Lett. 2012. 14, 444-447. (Highlighted in SynFacts)

• So, S. S.; Burkett, J. A.; Mattson, A. E. “Internal Lewis Acid Assisted Hydrogen Bond Donor Catalysis” Org. Lett. 2011, 4, 716-719.

Fields of Study

Major Field: Chemistry

Organic Chemistry

vii

Table of Contents Abstract ...... ii

Dedication ...... iii

Acknowledgments ...... iv

Vita ...... vi

List of Tables ...... xiii

List of Figures ...... xv

List of Schemes ...... xvii

Chapter 1: Boronate Ureas as Enhanced Hydrogen Bond Donor Catalysts ...... 1

1.1 Dual Hydrogen Bond Donor Catalysts: A History ...... 1

1.1.1 Ureas and Thioureas in HBD Catalysis ...... 3

1.1.2 Recent Advances in Asymmetric Dual HBD Catalysis ...... 6

1.1.3 Enhanced HBD Catalysts ...... 10

1.2 Ureas For Molecular Recognition ...... 15

1.2.1 Boronate Ureas for Molecular Recognition ...... 18

1.3 Internal Lewis Acid-Assisted Boronate Urea Catalysts ...... 20

1.3.1 Preparation of Boronate Ureas ...... 21

viii 1.3.2 Examination of Boronate Urea Structure and Features with Select NMR

Spectra ...... 23

1.4 Activation of Nitroalkenes for Conjugate Addition ...... 28

1.4.1 Scope of Addition of Nitrogen Heterocycles to Nitroalkenes ...... 31

1.4.2 Investigation into the Relative Rates of Urea Catalysts ...... 32

1.4.3 Asymmetric Addition to Nitroalkenes Using Chiral Boronate Ureas ...... 33

1.5 Activation of Nitrocyclopropane Carboxylates ...... 34

1.5.1 Development of Nucleophilic Ring-Opening Reactions ...... 36

1.5.2 Scope of Nucleophilic Ring-Opening Reactions ...... 39

1.5.3 Investigations into the Proposed Reaction Pathway ...... 41

1.5.4 Synthesis of 3-(1-Methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino)-5-(3-

trifluoromethyl-phenyl)-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-2-one ...... 43

1.6 Formal [3+3] Dipolar Cycloadditions ...... 45

1.6.1 Dipolar Cycloadditions of 1,1-Diestercyclopropanes ...... 45

1.6.2 Development of Cycloadditions of Nitrocyclopropane Carboxylates ...... 48

1.6.3 Nitrone and Nitrocyclopropane Substrate Scope of Oxazinane Formation ..... 50

1.6.4 Mechanistic Studies Probing the Stereochemical Outcome of Formal [3+3]

Dipolar Cycloaddition Reactions ...... 52

1.7 Summary ...... 53

1.8 Experimental: General Methods ...... 54

1.8.1 General Procedure for the Preparation of Boronate Urea Pinacol Esters I-53 56

1.8.2 Characterization of Boronate Urea Pinacol Esters I-53 ...... 56

1.8.3 General Procedure for the Preparation of Difluoroboronate Ureas I-54 ...... 58 ix 1.8.4 Characterization of Difluoroboronate Urea I-54 ...... 59

1.8.5 Synthesis of Chiral Boronate Urea I-57 ...... 61

1.8.6 General Procedure for Indole Additions to Nitroalkenes ...... 62

1.8.7 General Procedure for Nucleophilic Ring-Opening Reactions of

Nitrocyclopropane Carboxylates ...... 63

1.8.8 Characterization of Novel-!-Amino "-Nitroesters ...... 63

1.8.9 Characterization of Compounds Isolated in the Synthesis of I-75 ...... 66

1.8.10 General Procedure for Formal [3+3] Dipolar Cycloaddition Reactions of

Nitrocyclopropane Carboxylates and Nitrones ...... 70

1.8.11 Characterization of Novel Oxazinane Compounds ...... 71

References ...... 78

Chapter 2. Urea Activation of Nitrodiazo Compounds ...... 82

2.1 Fundamental Investigations of Nitrodiazoester Reactivity ...... 82

2.1.1 Cyclopropanation Reactions of Nitrodiazoesters ...... 83

2.1.2 Insertion Reactions of Nitrodiazoesters ...... 86

2.1.3 Investigations of Nitrocarbene Intermediates ...... 87

2.1.4 Synthesis of Nitrodiazoesters ...... 89

2.1.5 N–H Insertion Reactions of Diazocarbonyl Compounds ...... 90

2.2 HBD Activation of Nitrodiazoesters ...... 92

2.2.1 Anilines as N–H Insertion Partners ...... 93

2.2.2 HBD-Catalyzed Three-Component Coupling...... 97

2.3 Mechanistic Studies of N–H Insertion/Multicomponent Coupling Reaction ...... 100

2.3.1 Plausible Reaction Pathways ...... 100 x 2.3.2 Plausible Urea Activation Modes for N–H Insertion Reaction ...... 101

2.3.3 Computational Urea-Nitrodiazoester Binding ...... 103

2.3.4 Experimental Studies on Urea:Nitrodiazoester Binding ...... 105

2.3.5 Evidence Supporting Nucleophilic Addition Pathway B ...... 106

2.3.6 Mechanism of Glycine Formation ...... 109

2.3.7 Studies on the Role/Effects of Urea Catalysts on N–H Insertion ...... 112

2.4 Urea-Catalyzed Double Arylation Reactions of Ethyl Nitrodiazoacetate ...... 114

2.4.1 Background on Unsymmetric Diaryl Ester Formation ...... 115

2.4.2 Activation of Aryl Glycines for Exchange Reactions ...... 117

2.4.3 Optimization of Carbene Activator for Formation of Transient N–H Insertion

Intermediate ...... 119

2.4.4 Substrate Scope of Double Arylation Reaction ...... 121

2.4.5 Mechanistic Considerations of Transient N–H Insertion/Double Arylation ...123

2.5 Chiral Phosphoric Acid Catalysts for Stereoselective N–H Insertion Reactions ..124

2.5.1 Background on Phosphoric Acid Catalysis ...... 125

2.5.3 Optimization of Phosphoric Acid Catalyzed N–H Insertion/Multicomponent

Coupling ...... 129

2.5.4 Optimization and Scope of Stereoselective N–H Insertion/Multicomponent

Coupling Reaction ...... 131

2.6 Summary ...... 136

2.7 Experimental: General Methods ...... 138

2.7.1 General Procedure for the Urea Catalyzed N–H Insertion/Multicomponent

Reaction ...... 138 xi 2.7.2 Characterization of Novel Aryl Glycines ...... 138

2.7.3 Typical Procedure for Aryl Glycine Exchange Reaction for Formation of

Arylation Product II-79a ...... 145

2.7.4 Typical Procedure for the One-Pot Double Arylation Reaction of Ethyl

Nitrodiazoacetate ...... 145

2.7.5 Characterization of Novel Diaryl Esters ...... 146

2.7.6 Procedure for Binding Titration Experiment ...... 152

2.7.7 General Procedure for Stereoselective N–H Insertion/Multicomponent

Reaction ...... 154

2.7.8 HPLC Traces of Enantioenriched Glycines ...... 155

References ...... 162

Appendix A: X-ray Crystallographic Data for I-54a ...... 167

Appendix B: X-ray Crystallographic Data for I-95a ...... 179

Appendix C: Select NMR Spectra ...... 192

xii

List of Tables

Table 1.1. Boronate Urea-Catalyzed Addition of Indole to Nitrostyrene ...... 28"

Table 1.2. Catalyst Screen of Various Urea Derivatives ...... 30"

Table 1.3. Substrate Scope of Indole Addition to Nitrostyrene ...... 31"

Table 1.4. Catalyst Screen of Nucleophilic Ring-Opening Reaction of Nitrocyclopropane

Carboxylates ...... 38"

Table 1.5. Scope of Nucleophiles and Nitrocyclopropane Carboxylates for Urea-

Catalyzed Ring-Opening ...... 40"

Table 1.6. Optimization of Formal [3+3] Cycloadditions of Nitrocyclopropane

Carboxylates and Nitrones ...... 49"

Table 1.7. Substrate Scope of Formal [3+3] Dipolar Cycloaddition ...... 51"

Table 2.1. Rhodium-Catalyzed O–H Insertion Reactions of Nitrodiazoesters ...... 86

Table 2.2. Optimization of Difluoroboronate Urea-Catalyzed N–H Insertion Reaction ...95

Table 2.3. Catalyst Screen for N–H Insertion/Multicomponent Coupling Reaction ...... 96

Table 2.4. Substrate Scope for N–H Insertion ...... 98

Table 2.5. Binding Energies and Bond Distances of Complex II-37 with Various Urea

Derivatives ...... 104

Table 2.6. Initial Rate Studies of Urea Derivatives on N–H Insertion ...... 113

Table 2.7. Optimization of Glycine Exchange for Formation of Diaryl Esters ...... 118

Table 2.8. Optimization of Carbene Activator for Double Arylation Reaction ...... 120 xiii Table 2.9. Substrate Scope for Urea Catalyzed Transient N–H Insertion/Double Arylation

Reaction ...... 122

Table 2.10. Optimization of Phosphoric Acid Catalyzed N–H Insertion/Multicomponent

Coupling ...... 130

Table 2.11. Optimization of Stereoselective N–H Insertion/Multicomponent Coupling 132

Table 2.12 Observed Chemical Shifts of Binding Titration ...... 153!

xiv

List of Figures

Figure 1.1. Examples of Hart’s Cocrystallization of N,N’-Ditritylurea and Hydrogen

Bond Acceptor Molecules ...... 16"

Figure 1.2. Binding Motifs of Bis(m-nitrophenyl)urea ...... 18"

Figure 1.3. Enhanced Binding of Boronate Ureas to Acetate Anions ...... 19"

Figure 1.4. 11B NMR Data of Select Boronate Ureas ...... 19"

Figure 1.5. Boronate Urea Catalyst Design ...... 21"

Figure 1.6. Cocrystallization of Difluoroboronate Urea I-54a ...... 24"

Figure 1.7. pKa Values of Select Urea and Thiourea Catalysts ...... 26"

Figure 1.8. Select 1H NMR Spectra of Urea N–H Protons ...... 27"

Figure 1.9. Initial Rate Studies Comparing Various (Thio)Urea Catalysts in the Friedel-

Crafts Addition of Indole to Nitrostyrene ...... 32"

Figure 1.10. CB-1 Receptor Antagonist/Inverse Agonist Patented by Eli Lilly ...... 43"

Figure 2.1. NMR Titration with Difluoroboronate Urea II-40a and Nitrodiazoester II-1a

...... 105

Figure 2.2. a) Acyl Bond Formation To Access Aryl Esters b) Direct !-Arylation to

Access Aryl Esters c) General Catalytic Cycle for Aryl Coupling Reactions ...... 115

Figure 2.3 Best Fit Curve of Binding Titration Data ...... 153

Figure 2.4 Job Plot Analysis of Binding Titration ...... 154

xv Figure A.1 X-Ray Crystal Structure of Difluoroboronate Urea I-54a Cocrystallized With

Nitrobenzene ...... 169

Figure B.1 X-Ray Crystal Structure of Oxazinane I-95a ...... 171

Figure C.1 X-Ray Crystal Structure of Urea I-56c Cocrystallized with Nitrobenzene ...173

Figure D.1 X-Ray Crystal Structure of Ethyl-2-(1-methyl-1H-indol-3-yl)-2-(p-

tolylamino)acetate ...... 175

xvi

List of Schemes

Scheme 1.1. Bisphenol Dual Hydrogen Bond Donor Catalysts ...... 2"

Scheme 1.2. Early Examples of Urea and Thiourea Catalysis ...... 4"

Scheme 1.3. The Effect of Trifluoromethyl Substituents on Molecular Recognition ...... 5"

Scheme 1.4. Asymmetric Strecker Reaction Catalyzed by Jacobsen's Chiral Thiourea .... 6"

Scheme 1.5. (a) Takemoto's Thiourea with a Cyclohexane Diamine Chiral Scaffold (b)

Ricci's Thiourea with a (1R, 2S)-cis-1-Amino-2-Indanol Chiral Scaffold ...... 8"

Scheme 1.6. Cinchona Alkaloid Derived Chiral Thiourea Catalysts ...... 9"

Scheme 1.7. Ellman's N-Sulfinyl Derived Enhanced Catalysts ...... 11"

Scheme 1.8. (a) Seidel's Internally Coordinated Enhanced HBD Catalysts (b) Rawal’s

Chiral Squaramide Dual HBD Catalysts ...... 12"

Scheme 1.9. (a) Nájera’s Chiral Benzimidazole Dual HBD Catalysts (b) Takemoto’s

Internally Coordinated Benzothiadiazine Catalysts ...... 14"

Scheme 1.10. Synthesis of Boronate Ureas ...... 22"

Scheme 1.11. Modified Procedure for the Synthesis of Difluoroboronate Ureas ...... 23"

Scheme 1.12. Chiral Boronate Urea for Asymmetric Addition of 5-Methoxyindole to

Nitrostyrene ...... 33"

Scheme 1.13. Reactions of Nitrocyclopropane Carboxylates ...... 34"

Scheme 1.14. Thermally Promoted Ring-Opening of Nitrocyclopropanes (b) Lewis-acid

Activated Nitrocyclopropane Carboxylates for Ring-Opening Reactions ...... 36" xvii Scheme 1.15. Proposed Urea Activation of Nitrocyclopropane Carboxylates ...... 37"

Scheme 1.16. Plausible Reaction Pathways for Ring-Opening of Nitrocyclopropane

Carboxylates ...... 42"

Scheme 1.17. Reaction of Enantioenriched I-58a to Support Pathway B ...... 42"

Scheme 1.18. Synthesis of I-77 ...... 44"

Scheme 1.19. Proposed Cycloaddition Reactions of Nitrocyclopropane Carboxylates ... 45"

Scheme 1.20. (a) Kerr’s Formal [3+2] Cycloaddition With Indoles (b) Formal [3+3]

Cycloaddition with Nitrones ...... 47"

Scheme 1.21. Cycloaddition Reactions With (a) Aldehydes (b) Imines and (c) Silyl Enol

Ethers ...... 48"

Scheme 1.22. Plausible Mechanistic Pathways to Account for Stereoselectivity ...... 53"

Scheme 2.1. a) Early Work Demonstrating Decomposition of Nitrodiazoesters b)

Dailey’s Cyclopropanation Reactions of Nitrodiazoesters ...... 84

Scheme 2.2. Asymmetric Cyclopropanations with Nitrodiazoesters ...... 85

Scheme 2.3. Nitrocarbene Rearrangement to Acyl Nitroso Compounds for a) Ene

Reactions and b) Diels-Alder Reactions ...... 88

Scheme 2.4. Possible Routes for the Rearrangement of Nitrocarbenes to Acyl Nitroso

Compounds ...... 89

Scheme 2.5. a) Nitration of Diazo Compounds b) Perfluorinated Diazo Transfer Reagents

for the Synthesis of Nitrodiazo Compounds ...... 90

Scheme 2.6. a) First Example of N–H Insertion by Diazo Carbonyl Compounds b) First

N–H Insertion Reaction Using Catalysts for Activation of Diazo Compounds ...... 91

xviii Scheme 2.7. Merck's Synthesis of (+)-Thienamycin Using an Intramolecular N–H

Insertion Reaction ...... 91

Scheme 2.8. Mechanism for Insertion into Polar Bonds ...... 92

Scheme 2.9. Urea Activation Modes ...... 93

Scheme 2.10. Urea-Catalyzed N–H Insertion Reaction ...... 94

Scheme 2.11. Evidence for N–H Insertion ...... 101

Scheme 2.12. Role of Urea Catalyst on N–H Insertion Reaction ...... 102

Scheme 2.13. Total Energy Differences (#E) in kcal/mol Calculated at the B3LYP/6-

311++G**//B3LYP/6-31G* Level of Theory for Plausible Pathways of Urea-

Catalyzed N–H Insertion/Multicomponent Coupling Reaction ...... 107

Scheme 2.14. Evidence Suggesting Nitrocarbene is Not Accessed ...... 109

Scheme 2.15. Plausible Pathways for Glycine Formation ...... 110

Scheme 2.16. Possible Equilibria For Glycine Formation and Double Arylation ...... 114

Scheme 2.17. a) Buchwald’s Arylation of Ester Enolates Using Electron-Rich Phosphines

b) Hartwig’s Arylation of !-Amino Esters c) Hartwig’s Arylation with Mild Zinc

Reagents ...... 117

Scheme 2.18. Possible Pathways for Urea Catalyzed Arylation of Aryl Glycines ...... 124

Scheme 2.19. a) Terada’s Chiral Phosphoric Acid for Addition to Imines b) Akiyama’s

Chiral Phosphoric Acid Catalyzed Addition of Silyl Ketene Acetals to Imines ....126

Scheme 2.20. Phosphoric Acid Activation of Imines for Diazo Addition ...... 127

Scheme 2.21. a) Activation of Imines for Addition of O–H Insertion Ylide of Diazoesters

b) Activation of Imines for Addition of C–H Insertion Ylide of Diazoesters ...... 128

xix Scheme 2.22. SPINOL Phosphoric Acid for Enantioselective Protonation After Rhodium

Catalyzed N–H Insertion ...... 129

Scheme 2.23. Control Reaction Demonstration Direct Arylation Does Not Occur ...... 131

Scheme 2.24. Control Reactions Demonstrating Racemization/Enantioselective

Protonation Does Not Occur ...... 133

Scheme 2.25. Substrate Scope for Stereoselective N–H Insertion/Multicomponent

Coupling ...... 134

Chapter 1: Boronate Ureas as Enhanced Hydrogen Bond Donor Catalysts

Portions of this chapter appear in the following publications:

• So, S. S.; Burkett, J. A.; Mattson, A. E. “Internal Lewis Acid Assisted Hydrogen

Bond Donor Catalysis” Org. Lett. 2011, 4, 716-719

• So, S. S.; Auvil, T. J.; Garza, V. J.; Mattson, A. E. “Boronate Urea Activation of

Nitrocyclopropanes” Org. Lett. 2012 134, 8798-8801

• Hardman, A. M.; So, S. S.; Mattson, A. E. “Formal [3+2] Dipolar Cycloaddition

Reactions of Nitrocyclopropane Carboxylates” Org. Biomol. Chem. 2013, 11,

5793-5797

1.1 Dual Hydrogen Bond Donor Catalysts: A History

The field of organocatalysis has inundated the world of chemistry since its inception just two decades ago.1-3 The necessity of alternative methods for reaction development combined with the deep-seated understanding of fundamental rules of organic compounds and their reactivities have contributed to the rise and rapid dissemination of this emerging field. The excellent transformations achieved by main group and transition metals have no doubt made organometallic chemistry pervasive in the area of catalysis; and organic compounds have been found to offer a more comprehensive perspective in catalysis by providing interesting and complementary reactivities. Due to their many advantages, including low cost, low toxicity, and ease of handling, organocatalysts have been widely explored for the rational design of reaction 1 discovery.4-8 As such, many contributions in the field have led to the development of several subareas of study. Organocatalysts can be divided into two subclasses: covalent and noncovalent. While covalent organocatalysis has been dominated by enamine9-12 and iminium catalysis,13-17 noncovalent organocatalysis has centered on catalysis relying on hydrogen bonding interactions between donor and acceptor molecules.

The concept of using hydrogen bond interactions to catalyze reactions was perhaps first introduced by Hine and coworkers in 1985.18 In this influential paper, Hine and coworkers screened a variety of phenolic dual hydrogen bond donor (HBD) catalysts for the activation of glycolic epoxide I-1 for nucleophilic attack by diethylamine I-2

(Scheme 1.1a) to form I-3. When comparing the relative rates of the catalysts studied, it became apparent that increased acidity of the phenol correlated to increased activity.

Moreover, it was found that 1,8-biphenylene diol I-4 increased the rate of reaction 12 times greater than that of single HBD phenol. The significance of dual hydrogen bonding in catalysis was thus earnestly demonstrated in this early report. This finding was left largely unexplored until Kelly and coworkers reported using modified 1,8-biphenylene

pKa OH OH a) 1985 cat krel OH 8.00 O 30 ºC PhO + HNEt2 PhO NEt2 phenol 1 I-1 I-2 cat. I-3 I-4 12 I-4

b) 1990 OH OH O + 0.4 equiv 7 Me 10 min I-8 COMe I-5 I-6 pKa 90% 6.21 NO2 I-7 NO2

Scheme 1.1. Bisphenol Dual Hydrogen Bond Donor Catalysts 2 diol I-7 to catalyze the Diels-Alder reaction between cyclopentadiene I-5 and methyl vinyl ketone I-6 (Scheme 1.1b).19 Strategic installation of propyl groups in the 2- and 7- positions led to increased solubility of the catalyst, while electron-withdrawing NO2 groups in the 4- and 5- positions led to increased acidity (pKa (H2O) = 6.21) and higher activity compared to biphenylene-1,8-diol I-4 (pKa (H2O) = 8.00). With 0.4 equiv of I-7,

Diels-Alder adduct I-8 was formed in 90% yield after 10 minutes; only 3 % of the desired product was formed in the absence of catalyst. These seminal reports marked the beginning of the use of dual hydrogen bond donors as catalysts.

1.1.1 Ureas and Thioureas in HBD Catalysis

Ureas and thioureas have garnered significant attention for their use as dual hydrogen bonding noncovalent organocatalysts.20-23 In 1995, ureas were first discovered by Curran and coworker24 to enhance the rate of Claisen rearrangement of I-9 up to 22.4 times when compared to the reaction in the absence of a urea (Scheme 1.2a).25" Even substoichiometric amounts of urea I-10a provided significant rate enhancements; just 0.1 equiv of urea I-10a increased the rate of Claisen rearrangement 2.7 times compared to the reaction without urea. Curran and coworker discovered that a dimethylated version of catalyst I-10a provided no rate enhancements in otherwise identical reaction conditions.

Benzanilide catalyst I-10b, a single-hydrogen bond donor catalyst offered rate enhancements of only 1.6 times when 1.0 equivalents were used. This provided evidence that hydrogen bonding interactions were indeed responsible for the increased rate of reaction and that the dual HBD nature of the urea had benefits over a single HBD.

Interestingly, the corresponding thiourea was not as effective as I-10a, decomposing under the reaction conditions. Several years later, in 2003, Schreiner and coworker 3 reported the use of just 1 mol % of thiourea catalyst I-13 to enhance the rate of the Diels-

Alder reaction of cyclopentadiene I-5 and aza-chalcone I-12 (Scheme 1.2b).26 An investigation into the catalyst structure revealed that strategic placement of electron-

a) 1995 I-10a krel CF3 CF3 CF3 O O none 1 I-10a O O 0.1 equiv 2.7

C6D6 0.4 equiv 5.0 R N N R R N Ph H H H OMe 80 ºC OMe 1.0 equiv 22.4 R = CO2C8H17 I-10a I-10b I-9 I-11 1.0 equivI-10b 1.6

b) 2003 R1 R1 Ph H H O cat. krel pKa S N I-5 Ph I-13a 1.5 13.4 R2 N N R2 H H I-13 O I-13b 4.1 -- (1 mol %) I-13c 5.9 10.9 I-13a: R1 = R2 = H I-12 N I-14 I-13d 8.2 8.5 I-13b: R1 = F, R2 = H 1 2 I-13c: R = CF3, R = H I-13d: R1 = R2 = CF 3

Scheme 1.2. Early Examples of Urea and Thiourea Catalysis withdrawing groups were essential for obtaining moderate to good activities. Diphenyl thiourea I-13a was a poor catalyst while fluorinated catalyst I-13b provided moderate rate enhancements of up to 4.1 times. While installation of a trifluoromethyl group increased the rate further (I-13c, krel = 5.9), the optimal catalyst contained four electron- withdrawing groups (I-13d, krel = 8.2). It is important to note that no product inhibition was observed, a problem common to many catalytic systems.27 An analysis of the catalyst study indicated that rigidity was an important factor in affecting the activity of the thiourea. An internal hydrogen bond to the ortho hydrogen of thioureas containing aromatic rings with electron-withdrawing groups provides rigidity to the catalyst system.

4 Alkyl thioureas, lacking this internal rigidifying system, were found to have negligible effects on the desired Diels-Alder reaction. Through this work, Schreiner and coworker were able to conclude that thioureas are formidable HBD catalysts benefitting from increased solubility, when compared to their urea counterparts, and decreased

S R R I-13 (1 equiv) O O N N S R R H H H 23 ºC, R N N R H H [D8] toluene O O 1 2 I-15 I-13d:R = R = CF3 I-16 I-13e:R1 = R2 = Me

Scheme 1.3. The Effect of Trifluoromethyl Substituents on Molecular Recognition

aggregation. Additionally, Schreiner was able to identify the 3,5-bis-

(trifluoromethyl)phenyl moiety as a privileged group in urea activity. In a later report,

Schreiner and coworkers disclosed the importance of the ortho C-H group in hydrogen bonding.28 Complexation studies relying on 1H and 13C NMR spectroscopy revealed the involvement of the ortho C-H in binding to the substrate. This ortho C-H binding was found to be enhanced by the presence of the electron-withdrawing CF3 moiety. No shift was observed when lactone I-15 was added in equimolar amounts to thiourea I-13e, a structure containing no electron-withdrawing groups, suggesting no formation of I-16 was occurring (Scheme 1.3). Alternatively, the urea N–H protons and the ortho C–H protons of thiourea I-13d, a structure previously demonstrated to be an active catalyst, shifted significant amounts in the 1H NMR studies. The effect of the trifluoromethyl

5 group in leading to formation of complex I-16 as well as its significance as an important scaffold in various HBD catalysts is therefore well supported.

1.1.2 Recent Advances in Asymmetric Dual HBD Catalysis

While the development of achiral urea and thiourea catalysts was an important aspect of early development of the field, the necessity for asymmetric catalysis had not gone unnoticed. In response, several groups have made pioneering contributions to the development of chiral urea and thiourea catalysts. The Jacobsen group has been a leader in advancing asymmetric (thio)urea catalysis. Jacobsen and Sigman first reported an asymmetric Strecker reaction using chiral thiourea I-18 in just 2 mol % catalyst loading

(Scheme 1.4).29 The innovative catalyst design features a salicylaldehyde derived Schiff base along with a bulky amino acid component to impart excellent enantioselectivities on formation of Strecker product I-19 (78% yield, 91% ee). In a second communication, a library of 70 urea and thiourea compounds was synthesized and tested in an analogous

tBu S 1998 O H Ph N N 1. HCN, I-18 (2 mol %) N N F C N H H –78 ºC, PhMe, 24 h 3 O N Ph H 2. TFAA Ph CN I-17a I-19 I-18 HO 78%, 91% ee tBu OMe

Scheme 1.4. Asymmetric Strecker Reaction Catalyzed by Jacobsen's Chiral Thiourea

Strecker reaction.30 Several of the synthesized catalysts were identified as excellent catalysts for the asymmetric addition of HCN to various imines I-17. Polymer supported versions of the ureas and thioureas were also synthesized and tested. Very little changes 6 in reactivity or enantioselectivity were observed, even after ten catalyst recycles.

However, due to the need to separate the catalyst by column chromatography, slightly diminished yields of the desired amino acid products were isolated. Thus, the resin bound catalysts were found to be superior.

In 2003, Takemoto and coworkers introduced what would become another milestone in chiral thiourea catalyst structure design.31 Part of their design strategy was to capitalize on a bifunctional thiourea catalyst capable of activating both the electrophile

(via hydrogen bonding) as well as the nucleophile. Catalyst I-22 benefits from the 3,5- bis-(trifluoromethyl)phenyl thiourea backbone and a cyclohexane diamine moiety, which provides a chiral scaffold as well as a basic component for activation of the diethyl malonate nucleophile (Scheme 1.5a). These two components worked synergistically to afford Michael adduct I-23 in excellent yield and enantiomeric excess. Simple control experiments elegantly revealed the necessity of both the chiral amine and thiourea components on the same molecule. When a thiourea catalyst containing achiral cyclohexylamine instead of the (R,R)-1,2-cyclohexyldiamine scaffold was added to the reaction with triethylamine as an additive, moderate yields of the desired product were formed (57%) but with no enantioenrichment. When (R,R)-1,2-cyclohexyldiamine was added to the reaction by itself, moderate enantioselectivity was achieved (35%) but in poor yield (14%) These results indicated that high yields and enantioselectivities (86% yield, 93% ee) were obtained only when the 3,5-bis-(trifluoromethyl)phenyl thiourea moiety and the chiral tertiary amine work synergistically. This seminal report opened the door to access a variety of chiral urea and thiourea catalysts.

7 In 2005, Ricci and coworkers reported the successful installation of chiral 1,2- amino alcohols as excellent chiral scaffolds for the Friedel-Crafts addition of indole I-24 to nitroolefin I-20.32 This was the first account of enantioselective Friedel-Crafts alkylation of indoles. Their initial investigations surveyed the addition of various chiral

1,2-amino alcohols to 3,5-bis-(trifluoromethyl)phenyl isothiocyanate to obtain the corresponding chiral thiourea catalysts (Scheme 1.5b). Testing of the thioureas in inert solvents such as toluene and dichloromethane revealed that chiral thiourea I-25a, formed

a) 2003

NO2 CF3 Ph I-20 10 mol % EtO2C CO2Et cat. conv. (%) ee (%) cat. S + NO2 I-22a 86 93 24, PhMe Ph F3C N N O O I-22b 57 0 H H I-23 X EtO OEt 86%, 93% ee I-22a:X= NMe2 I-21 I-22b:X= H b) 2005

NO2 CF3 Ph 20 mol % NH cat. yield (%) ee (%) I-20 X cat. + I-25a 92 85 F3C N N –24 ºC NO2 I-25b 23 25 H H CH Cl , 72 h Ph I-25c 18 39 R 2 2 I-26 I-25a: X = S, R = OH N I-25d 15 0 I-25b: X = O, R = OH I-24 H I-25c: X = S, R = OTMS I-25d: X = S, R = H

Scheme 1.5. (a) Takemoto's Thiourea with a Cyclohexane Diamine Chiral Scaffold (b) Ricci's Thiourea with a (1R, 2S)-cis-1-Amino-2-Indanol Chiral Scaffold

by reaction with (1R,2S)-(+)-cis-1-amino-2-indanol, was indeed the most active and the most enantioselective catalyst, providing up to 92% conversion and 85% ee of desired adduct I-26. Interestingly, the corresponding urea catalyst I-25b formed the desired alkylation product in markedly lower yield and enantiomeric excess (23% conversion, 8 25% ee). Ricci and coworkers hypothesized that the alcohol moiety was, in fact, an important component of the catalyst by forming a hydrogen-bonded complex with the indolic proton and directing the nucleophilic attack onto the hydrogen-bonded nitroolefin.

To test the viability of such an interaction, catalyst I-25a was modified in 2 ways: (1) the alcohol functionality was protected with a sterically hindered trimethylsilyl group

(catalyst I-25c) and (2) the alcohol functionality was removed (catalyst I-25d). Both modified thioureas performed poorly in the reaction. Silylated catalyst I-25c yielded only 18% of the desired product, however in 39% ee, and catalyst I-25d produced 15% of

I-26 but with no enantioselectivity. These data suggest that the hydroxyl functional group is essential for obtaining both good yields and enantioselectivities.

In the same year as Ricci’s report on chiral amino alcohol derived thiourea catalysts, Soós,33 Connon,34 and Chen35 independently reported the use of cinchona alkaloids as chiral scaffolds for thioureas. The Soós group found installation of cinchona

2005 cat. yield (%) ee (%) CF3 O2N O O 10 mol % cat. I-28a 71 95 (R) S Ph Ph Ph Ph I-28b 93 96 (R) CH NO I-29 0 -- F3C N I-27 3 2 I-28c H I-30 I-28d 59 86 (S) I-28

N N N

H N OMe OMe H OMe N H H N H N N H OMe H H N N N N I-28a I-28b I-28c I-28d epiquinine amine dihydroepiquinine amine quinine amine epiquinidine amine

Scheme 1.6. Cinchona Alkaloid Derived Chiral Thiourea Catalysts

9 alkaloids to be an effective strategy for enantioselective nitro-Michael reactions (Scheme

1.6). While cinchona alkaloids had been previously reported to be effective catalysts in the conjugate addition of aromatic thiols to ",$-unsaturated systems by forming a chiral ion pair,36 their use in other reaction systems had yet to be fully explored. Soós and coworkers synthesized thiourea derivatives containing various quinine stereoisomers as chiral scaffolds to use as HBD catalysts. In the addition of nitromethane I-29a to chalcone I-27, bifunctional thiourea I-28a, derived from epiquinine amine, yielded 71% of the desired adduct I-30 in 95% ee. When epiquinine amine alone was tested in the reaction, 4% of I-30 was isolated in 42% ee. Dihydroepiquinine amine-derived thiourea

I-28b showed similar enantioselectivity (96% ee) but proved to be a more active catalyst

(93% yield). Notably, neither the quinine amine nor the quinine derived catalyst I-28c showed any catalytic activity. However, epiquinidine catalyst I-28d, a pseudo enantiomer of I-28a, afforded 59% of the nitro-Michael adduct in 86% ee (S-enantiomer).

The use of various cinchona alkaloid derivatives as chiral scaffolds demonstrates the need for highly tunable catalysts to obtain optimal reactivity and enantioselectivity.

1.1.3 Enhanced HBD Catalysts

Recent efforts in advancing the field of hydrogen bond donor catalysis have been directed toward the design of catalyst structures with enhanced reactivity. In this regard,

Ellman introduced the N-sulfinyl urea moiety as both a source of chirality and a method to enhance urea activity (Scheme 1.7).37 Using catalyst I-31a, Ellman was able to obtain nitro-Mannich adduct I-32 in 99% conversion with 94% ee and 83:17 dr of syn and anti diastereomers. N-Sulfinyl thiourea I-31b performed relatively poorly, affording only42% conversion to the desired product in 58% with 43:57 dr. Ellman concluded that N- 10 sulfinyl thiourea, as well as the even more acidic N-sulfonyl thiourea, exhibited diminished catalytic reactivity due to possible deprotonation by the i-PrNEt2 additive in the reaction. The hydroxyl group of the (1S,2R)-(–)cis-1-amino-2-indanol moiety was

2007 Boc conv. ee dr N 10 mol % Boc O X cat. HN cat. (%) (%) (syn:anti) Ph H S NO2 tBu N N I-17b 0.5 equiv Ph I-31a 99 94 83:17 H H R + i-Pr2NEt Me I-31b 42 58 43:57 MeCN I-31c 99 0 21:79 I-31a: X = O, R = OH I-32 NO2 –40 ºC I-31b: X = S, R = OH I-29b I-31c: X = O, R = H

Scheme 1.7. Ellman's N-Sulfinyl Derived Enhanced Catalysts

" again found to be essential. When the alcohol was removed (catalyst I-31c), excellent conversion to the desired product and good dr (99% conv., 21:79 dr) were observed but no enantioselectivity was attained. Additionally, it was important to have both the chiral sulfinyl moiety working in conjunction with the chiral (1S,2R)-(–)cis-1-amino-2-indanol group to obtain high enantioselectivities. When the urea (1S,2R)-(–)cis-1-amino-2- indanol group was replaced with cyclohexane, the enantiomeric excess dropped from

94% ee to 10% ee of aza-Henry product I-32. Interestingly, when the opposite enantiomer of tert-butanesulfinamide was used, a 29% decrease in enantiomeric excess was observed (89% ee versus 60% ee).

Following Ellman’s report on a novel strategy for developing enhanced HBD catalysts, Seidel reported the use of a quinolium thiamide functionality to catalyze the addition of indole I-24 to trans-$-nitrostyrene I-20 (Scheme 1.8a).38 The enhanced 11 catalyst structure stemmed from the original idea of adding a pyridinium component for the synthesis of an internally coordinated Brønsted-acid moiety. Seidel and coworkers were able to obtain excellent yields of desired product I-26 with internally coordinated thiourea I-33 (99%), however with only modest enantioselectivities (46% ee).

Intramolecular hydrogen bonding to the thiocarbonyl of catalyst I-33 was thought to increase the polarization of the N–H bonds, leading to enhanced acidity and activity.

While this was indeed a compelling strategy, quinolinium thioamide catalyst I-34 was found to be a more selective hydrogen bond donor catalyst. Although not a thiourea,

2008 NH BArF I-26 X 4 N I-24 H NO2 H S Ph S N NO2 0 ºC Ph N I-20 N N H cat yield (%) ee (%) H H 20 mol % HO HO HN cat I-33 99 46 I-33 I-34 I-34 92 94

2008 O O O O O O NO 2 + 2 mol % I-36 Ph F3C N N H HN CH2Cl2 I-20 I-35 NO2 H Ph

98% I-37 CF >99% ee 3 I-36 N

Scheme 1.8. (a) Seidel's Internally Coordinated Enhanced HBD Catalysts (b) Rawal’s Chiral Squaramide Dual HBD Catalysts thioamide I-34 was found to be an excellent HBD catalyst, affording indole addition product I-26 in the same high yield (92%) but with markedly higher stereoselectivity

(94% ee) than thiourea I-33 in otherwise identical reaction conditions. This novel

12 strategy of internal coordination to augment hydrogen bonding activity was an important milestone in HBD catalysis.

In 2008, Rawal and coworkers introduced the squaramide catalophore as another enhanced dual hydrogen bond donor that contrasts the thiourea backbone.39 While squaramides had been previously demonstrated to be active functionalities in molecular recognition studies,40-42 they had yet to be pursued as organocatalysts. Squaramide I-36, derived from 3,5-bis-trifluoromethyl benzyl amine and (–)-cinchonine, was found to catalyze the conjugate addition reaction of 1,3-dicarbonyl I-35 with nitroolefin I-20 to afford I-37 in excellent yield (98%) and greater than 99% enantiomeric excess (Scheme

1.8b). X-ray crystallographic analysis revealed that the distance between the N–H protons was, on average, ~0.6 Å longer than that of thioureas (2.72 Å vs. 2.13 Å), which

Rawal attributes to the enhanced activity of squaramide catalysts.

Benzimidazoles have recently garnered significant attention in the realm of HBD catalysis. Their ease of synthesis and documented molecular recognition properties made them attractive targets for development as catalysts. Nájera and coworkers successfully installed a trans-1,2-cyclohexane diamine chiral scaffold and were able to determine that the distance between the two N-H protons was between 2.41 and 2.61 Å.43 This finding suggested that benzimidazoles were well within the range of dual hydrogen bonding to dicarbonyl compounds. With 10 mol % of catalyst I-38 and 10 mol % of TFA as an additive, Nájera and coworkers were able to catalyze the conjugate addition of diethyl malonate I-21 to trans-$-nitrostyrene in 97% yield and 92% ee (Scheme 1.9a). The benzimidazole catalyst I-38 was found to be easily recyclable and reused with similar efficiency and enantioselective bias. Deprotonation of the dicarbonyl with the 13 cyclohexane diamine creates a protonated catalyst that has increased rigidity and planarity due to the benzimidazole moiety and can direct the resultant anionic dicarbonyl to the hydrogen-bonded nitroolefin to account for the stereochemical outcome of the reaction.

a) 2009

O O EtO2C CO2Et NO2 Ph + 10 mol % I-38 N EtO OEt NO2 10 mol % TFA, Ph I-20 I-21 N N PhMe I-23 H H 97%, 92% ee NMe2 I-38

b) 2011 O O O O X N 10 mol % yield ee OMe cat. OMe cat. (%) (%) N N H H I-39 N Boc PhMe NMe2 + BocHN I-41a 93 96 I-41b 82 84 N Boc I-42 I-41a: X = CO Boc N I-22a 22 83 I-41b: X = SO2 I-40

Scheme 1.9. (a) Nájera’s Chiral Benzimidazole Dual HBD Catalysts (b) Takemoto’s Internally Coordinated Benzothiadiazine Catalysts

Takemoto and coworkers incorporated several elements of recent developments in

HBD catalysis by synthesizing dual HBD catalysts that are bridged to an electron- withdrawing group.44 Quinazoline catalyst I-41a and benzothiadiazine catalyst I-41b benefit from both a chiral scaffold and internal coordination to a carbonyl (I-41a) or sulfonyl (I-41b) that acidifies the hydrogen bonding N–H protons (Scheme 1.9b). One motivation to develop this new class of dual HBD catalysts was to remove the sometimes problematically nucleophilic sulfur atom of traditional thiourea catalysts.45-47 In the hydrazination reaction of 1,3-dicarbonyl I-39 with di-tert-butyl diazodicarboxylate I-40, 14 quinazoline I-41a afforded the desired product I-42 in excellent yield and enantiomeric excess (93% yield, 96% ee). Benzothiadiazine catalyst I-41b exhibited slightly lower activity and enantioselectivity (82% yield, 84%), but both novel catalysts were far superior to thiourea I-22a, which yielded only 22% of the desired product (83% ee). The low reactivity of I-22a was attributed to catalyst decomposition due to reaction of the sulfur moiety with the azodicarboxylate.

1.2 Ureas For Molecular Recognition

Before their use in catalysis, ditrityl urea was documented in the early work of

Hart and coworkers to form clathrates with a variety of molecules containing hydrogen bond accepting functional groups (I-43a-d, Figure 1.1) in 1986.48 Four years later, Etter and coworkers relied on IR spectroscopy, solid state NMR spectroscopy, and X-ray crystallography to observe cocrystallization.49 Their extensive study in this area led to several X-ray crystallographic analyses that captured ureas hydrogen bonding to various guest molecules. Depending on the guest molecule, the urea carbonyl (C=O) IR stretching frequency was observed to shift from 1630 cm-1 (free urea) to 1700 cm-1

(bound urea). While obtaining melting points, the cocrystals cracked at temperatures below 200 °C, and then melted at the melting point of the urea host, providing further evidence that cocrystallization had occurred. In solution phase 1H NMR studies, a 1:1 binding of the urea to the host was observed in the cocrystals. In solid phase 13C NMR spectroscopy, significant downfield shifting of diagnostic peaks were observed.

However, throughout the course of their studies, it became apparent that many ureas were either incapable of binding to guest molecules or could only bind to guest molecules that were strong proton acceptors. According to Etter’s empirical hydrogen bond rules, “all 15 available proton donor and acceptor groups will be used in the hydrogen bond patterns of most organic molecules in the crystalline state.”50 Thus, ureas were found to readily self- aggregate by hydrogen bonding to the carbonyl oxygen of another urea molecule, diminishing the ability of the urea to hydrogen bond to guest molecules. In fact, several ureas were found to exist in this crystallographic state of aggregation even in the presence of guest molecules.

Tr = trityl

O O O O Tr Tr Tr Tr Tr Tr Tr Tr N N N N N N N N H H H H H H H H O N O OH H NH2 I-43a I-43b I-43c I-43d

Figure 1.1. Examples of Hart’s Cocrystallization of N,N’-Ditritylurea and Hydrogen Bond Acceptor Molecules

Of the ureas Etter studied, 1,3-bis(m-nitrophenyl)urea I-44 was found to be an

“all-purpose cocrystallizing agent.” While urea I-44 also self-aggregates in the absence of guest molecules, a competitive binding occurs in the presence of guest molecules. In the absence of guest molecules, several forms of self-aggregation can occur, one of which is shown in Figure 1.2 (I-44a). Each of the urea protons as well as the urea carbonyl were bound to a different urea molecule. A distance of 2.32 Å between the urea protons is indicative of a twisted conformation as planar ureas have a bonding distance of 2.05 Å.

In the presence of tetrahydrofuran, good crystals were obtained (I-44b, Figure 1.2). The carbonyl bond length was found to be 1.211 Å, which is consistent with the absence of

16 intermolecular hydrogen bonds formed during aggregation. The cocrystal structure was nearly planar, and the N---O bonding distance was 2.995 and 2.918 Å, suggesting dual hydrogen bonding was occurring.

Etter and coworkers offered an explanation for this unique ability of urea I-44 to cocrystallize even weak proton acceptors such as esters, ethers, and aromatic nitro compounds, using several observations. It was possible to implicate steric hindrance as the reason for urea I-43’s enhanced cocrystallizing ability if the m-NO2 groups were sterically encumbering and blocked self-aggregation, promoting cocrystallization.

However, this was not a likely factor since ureas containing –CF3, –CH3, and –OCH3 groups, which are similar in size to –NO2, were poor host molecules. An acidity argument was also ruled out as the p-NO2 urea derivatives were more acidic than the m-

NO2 ureas but were much poorer cocrystallizing agents. By ruling out steric hindrance and pKa arguments, they were able to narrow down the origin of this cocrystallizing phenomenon. In the presence of guest molecules, urea I-43 benefits from a special polarization resulting from an intramolecular CH---O interaction with the ortho H on the nitro aromatic ring and the urea carbonyl. This leads to an enhanced ability of the urea protons to hydrogen bond to various functional groups. This was corroborated by X-ray crystallography analysis as the ortho proton and the carbonyl oxygen have a bond distance of 2.30 Å, which is within the 2.40 Å limit generally accepted to indicate the presence of a C(H)---O bond.51 When urea I-44 was cocrystallized with N,N’-dimethyl- p-nitroaniline (I-44c, Figure 1.2), the urea was found to be nearly planar with an 8- membered hydrogen bonding framework. The hydrogen bonding distance between the

17 urea nitrogen and the nitro group oxygen was found to be 3.003 Å, a markedly shorter distance than the typical nitroaniline hydrogen bonding distance of 3.05 Å.52 This

NO2 NO2

O N NO2 NO2 H N N O O H H N N - O2N N N NO2 O O H H N+ H H O- O O N+ I-44c O I-44a I-44b NH2

Figure 1.2. Binding Motifs of Bis(m-nitrophenyl)urea

indicates a moderately strong hydrogen bonding interaction; strong hydrogen bonds are reported to have distances between 2.2-2.5 Å and weak interactions are reported to have distances between 3.2-4.0 Å.53 The installation of electron-withdrawing groups in the meta positions had a greater impact on the molecular recognition ability of the urea than ureas containing the same electron-withdrawing groups in the para positions. Etter’s discoveries laid the foundational framework for the use of ureas in molecular recognition and was also the inspiration for the use of ureas in catalysis.

1.2.1 Boronate Ureas for Molecular Recognition

The remarkable discovery that internal coordination of the carbonyl oxygen to the ortho proton of diaryl ureas enhances molecular recognition properties has served as inspiration for the design of boronate ureas. Smith’s investigation into the synthesis of ureas with enhanced hydrogen bonding abilities led to the discovery that the strategic 18 incorporation of boron onto the urea scaffold gave rise to a new family of internal Lewis acid assisted ureas that are better able to recognize anions.54#55 Boronate urea I-47 was found to recognize acetate anions with a binding constant 18.9 times stronger than that of urea I-45, a urea containing no boryl group for internal coordination (Figure 1.3). To rule

Bpin F F O Bpin B O O O C8H17 C H N N 8 17 C8H17 C8H17 N N N N N N H H H H H H H H

Me O O Me O O O O O O Bpin = O Me B O Me I-45 I-46 I-47 I-48 Krel = 1 Krel = 1.05 Krel = 18.9 Krel = 162

Figure 1.3. Enhanced Binding of Boronate Ureas to Acetate Anions

out electron-withdrawing effects, boronate urea I-46 was synthesized with the boryl group in the meta position, preventing internal coordination of the urea carbonyl, and was found to recognize acetate anions with the same relative binding as urea I-45. This

Bpin F F Bpin B O O O Me Me Me N N N N N N H H H H H H Me I-46 I-47 I-48 Me Bpin = O Me B Trigonal Boron Tetrahedral Boron Tetrahedral Boron O Me 11 11 11 B NMR = 12.3 ppm B NMR = –9.3 ppm B NMR = –15.2 ppm

Figure 1.4. 11B NMR Data of Select Boronate Ureas

19 polarization accounts for a 162-fold increase in binding to acetate anion when the ligands on boron were exchanged from pinacol to two fluorides56 (I-47 vs. I-48). An NMR analysis of the boronate ureas reveals evidence of internal coordination. Urea I-46, incapable of coordination to the urea carbonyl, produced an 11B NMR signal of 12.3 ppm, indicative of a trigonal boron signature.57 However, both boronate ureas I-47 and I-48, ureas capable of coordination, produced 11B NMR signals indicative of tetrahedral borons

(–9.3 ppm and –15.2 ppm, respectively, Figure 1.4). Thus, the augmented ability of boronate ureas to hydrogen bond to guest molecules can be attributed to the increased coordination of the carbonyl oxygen to the boron.

1.3 Internal Lewis Acid-Assisted Boronate Urea Catalysts

Drawing from these two reports, we set out to utilize boronate ureas as hydrogen bond donor (HBD) catalysts with enhanced activity. The possibility of applying the concept of internal Lewis acid assisted urea polarization toward organic catalysis intrigued us for two main reasons: (1) the potential to access an entirely new family of activated HBD catalysts and (2) the development of a class of HBDs containing several tunable parameters to facilitate the development of a highly active and stereoselective catalyst. The internal Lewis acid assisted urea catalyst structure was designed with several key features in mind. First, it was reasoned that the Lewis acid component could be altered to elicit different reactivities. Second, the enhanced activity afforded by the internal coordination could allow for installation of chiral scaffolds with relative ease and without diminished reactivity. Finally, the electronic nature of the catalyst could be finely adjusted in two ways: (1) by modification of the ligands on the Lewis acid as well as (2) introduction of functional groups on the aryl amino ring containing the Lewis acid 20 (Figure 1.5). While it was reasoned that internal Lewis acid assisted HBD catalysis was a promising avenue to explore, the study began with a number of uncertainties. There were concerns regarding the synthesis and stability of the activated ureas, and the potential issue of low catalyst turnover as a result of overly strong hydrogen bonding was also considered. Despite these concerns, we were excited by the potential surrounding internal Lewis acid assisted ureas and set out to investigate boronate ureas as new classes of enhanced HBD catalysts.

L = Ligands X = Lewis Acid

ﬁne-tune enhance coordination coordination to urea carbonyl

L L R = EWG R X R* = Chiral Scaffold O adjust electronic modify chiral R* nature of urea N N environment H H

increased hydrogen bonding ability "

Figure 1.5. Boronate Urea Catalyst Design

1.3.1 Preparation of Boronate Ureas

Investigations began with the synthesis of a family of boronate ureas (I-53 and I-

54) with varying electronic properties. It was essential that boronate urea catalysts were stable and easy to synthesize. Additionally, it was important that the catalysts were easily tunable so that several analogs could be synthesized with relative ease. Relying initially on Smith and coworker’s work,54,55 2-amino phenyl boronic acid I-49 was reacted with various isocyanates I-50, leading to the corresponding heterocycle I-51 (Scheme 1.10,

21 Method A). Refluxing in pinacol led to ligand exchange and formation of the corresponding boronate urea pinacol ester I-53, which upon heating in methanol with an aqueous solution of KHF2 afforded the difluoroboronate urea I-54. It was soon

Method A OH B(OH)2 O B Ar KHF2 + N C I-51 NH2 N N O Ar H I-49 I-50 BF2 Me O Me Bpin = O Ar Method B Me B HO OH N N O Me H H Bpin O I-54 Bpin + C O KHF2

NH2 N Ar Ar N N a: Ar = 3,5-(CF3)2Ph H H b: Ar = Ph I-52 I-50 I-53

Scheme 1.10. Synthesis of Boronate Ureas

discovered that 2-aminophenyl boronic acid pinacol ester I-52 could react with a variety of commercially available isocyanates I-50 to form the corresponding urea I-53 in just 4 hours (Method B). The urea was obtained as a highly stable white solid in excellent yields and high purity. The ligands on boron were then easily exchanged by subjecting the urea to an aqueous solution of potassium bifluoride. Using this procedure, boronate ureas I-53a, I-53b, and I-54b were readily synthesized. However, the synthesis of 3,5- bis-(trifluoromethyl)phenyl urea I-54a proved problematic and could not be isolated without significant impurities. Relying on crystallization techniques, the impurities were determined to be heterocycle I-51a and BF3K salt I-55a. We thus determined that during the exchange of pinacol for two fluorides using potassium bifluoride, an intermediate

22 trifluoroborate salt I-55 is formed. This BF3K salt urea is a stable white solid until washed with H2O, which removes an equivalent of KF and forms difluoroboronate urea

I-54. Washing with water proved to be nontrivial in the case of 3,5-bis-

(trifluoromethyl)phenyl trifluoroboronate urea I-55a. The corresponding heterocycle I-

OH Bpin BF3K BF2 O KHF O O H O B 2 H2O 2 N N N MeOH N N N N H H H H H H N O H I-53 I-55 I-54 I-51

CF 3 CF3 F

CF3 F

CF3 F a b c d e f

Scheme 1.11. Modified Procedure for the Synthesis of Difluoroboronate Ureas

51a was forming during the wash, due to hydrolysis of the difluoroboronate urea I-54a.

A modified procedure, whereby trifluoroboronate urea I-55a was dissolved in ethyl acetate and extracted with water, led to desired difluoroboronate urea I-54a with minimal

58 formation of I-51a. Washing the difluoroboronate urea with excess CH2Cl2 led to removal of any excess heterocycle I-51a. Using this modified procedure, a small library of boronate ureas was synthesized in up to a 10 g scale.

1.3.2 Examination of Boronate Urea Structure and Features with Select NMR

Spectra

An in-depth structural, NMR, and X-ray crystallographic analysis of difluoroboronate urea I-54a led us to elucidate its physical and molecular recognition

23 properties. While the insolubility of boronate ureas was concerning at first, it became evident that solubility was well-correlated to the hydrogen bonding properties of the solvent. Boronate ureas were found to be soluble in polar aprotic solvents (e.g. ethyl acetate, acetone, acetonitrile, dimethylsulfoxide, and nitrobenzene) and insoluble in solvents incapable of hydrogen bonding (e.g. hexanes, toluene, dichloromethane, and chloroform). Relying on these solubility data, we were able to successfully grow an X- ray quality crystal of boronate urea I-54a hydrogen bonding to nitrobenzene (Figure

1.6).58 From this crystallographic analysis, two very important properties of the urea were confirmed. First, the carbonyl bond length was determined to be 1.274 Å, significantly longer than the 1.212 Å bond length observed in urea carbonyls lacking internal coordination. This elongated carbonyl suggests that coordination to the internal

Lewis acid rigidifies the urea structure and enhances the hydrogen bond donating ability

1.274 Å

F F CF3 B O

N N CF3 H H

O- O 11B NMR = N+ 3.63 ppm (–14.47 ppm)*

Figure 1.6. Cocrystallization of Difluoroboronate Urea I-54a

24 of the urea protons. Second, the nitrobenzene solvent was not found to interact with the boron of the boronate urea. Instead, hydrogen bonding to the nitro group was the only interaction observed. Coordination of the urea carbonyl to the boron was also supported by a tetrahedral 11B NMR signal, which appeared at 3.63 ppm when referenced to

BF3OEt2 (–14.47 ppm when converted to BMe3 reference scale). Unfortunately, a 2D

NMR analysis of difluoroboronate urea I-54a to assign the urea proton peaks was inconclusive.

While the exact relationship between pKa and activity is not yet understood, there is certainly a trend between increased acidity of the urea protons and enhanced hydrogen bonding activity. When plotting some of the common urea and thiourea catalysts recently reported in the literature by their pKa values, it becomes apparent that many of

59 the catalysts have urea protons in the 12-14 pKa range (Figure 1.7). In fact, the highly active 3,5-bis-(trifluoromethyl)phenyl thiourea I-13d, was the most acidic catalyst reported with a pKa of 8.5. Thus, when difluoroboronate urea I-54a was found to have a

60 pKa of 7.5, we were excited to see its relative catalytic activity. In fact, when plotting the 1H NMR spectra of difluoroboronate urea I-54a and boronate urea pinacol ester I-53a with 3,5-bis-(trifluoromethyl)phenyl urea I-56c and thiourea I-16d a trend in N–H signal of the urea moiety was also apparent. The urea protons of I-54a are shifted downfield when compared to thiourea I-16d (11.27 and 10.65 ppm vs. 10.64 ppm, respectively,

Figure 1.8), suggesting that the acidity of protons correlates to 1H NMR chemical shifts.

The next most acidic urea in the series, boronate urea I-53a displayed urea proton signals

25 I-56c

I-22a I-18a

I-13a I-13d I-25a I-56b I-54a I-13c I-27a I-56a

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

F F CF3 CF3 CF3 N S B CF3 O S N N S OMe H H N N CF3 F3C N N CF3 H 26 I-13a H H H H I-13d F3C N N 13.4 I-54a 7.5 8.5 H H I-27a N CF CF CF CF3 CF3 3 3 3 12.39 S O O

tBu S N N N N CF3 F3C N N CF3 H H H H H H Et2N I-13c 10.9 I-56b 16.1 I-56c 13.8 N N H H O I-18a N CF3 CF3 O HO S S N N H H tBu OMe F3C N N F3C N N H H H H I-56a OH I-25a I-22a NMe2 18.3 18.7 12.98 13.65

Figure 1.7. pKa Values of Select Urea and Thiourea Catalysts

CF ! F F 3 B O

N N CF3 H! H

CF3 CF3 ! S

F3C N N CF3 H! H

CF3

27 Bpin ! O

O O Bpin = B N N CF3 H! H

CF3 CF3 ! O

F3C N N CF3 !H H !

Figure 1.8. Select 1H NMR Spectra of Urea N–H Protons

at 9.93 and 9.18 ppm, downfield of the corresponding urea proton signals of urea I-56c

1 (9.73 ppm). While there is no physical evidence for the relationship between pKa, H

NMR chemical shifts, and activity, a clear trend exists.

1.4 Activation of Nitroalkenes for Conjugate Addition

With the synthesis of boronate ureas established, and a small library of boronate ureas in hand, it was important to find a suitable reaction to test the catalytic activity of our new class of ureas. In this regard, we chose the nucleophilic addition of indole I-24 to nitroolefin I-20 as a test bed due to literature precedent demonstrating the success of urea and thiourea catalysts in this reaction.32!38!61!62

Using freshly recrystallized indole I-24, trans-!-nitrostyrene I-20, and 20 mol % of difluoroboronate urea 54a, Friedel-Crafts adduct I-26 was obtained in 64% yield after

24 h in dichloromethane (Table 1.1, entry 1).63 This moderate, but promising yield

I-54a (x mol %) HN NO2 Ph + N 24 h, 23 ºC I-20 I-24 H NO2 Ph entry mol % solvent additive yield (%) I-26 1 20 DCM -- 64 2 20 DCM TFE 100

3 20 DCM H2O 32 4 20 DCM MeOH 98 5 20 DCM 3Å MS 75 6 10 DCM TFE 99 7 10 PhMe TFE 53 8 10 MeOH -- 40 9 10 TFE -- 49 10 0 DCM TFE 8

Table 1.1. Boronate Urea-Catalyzed Addition of Indole to Nitrostyrene

" 28 helped confirm that boronate ureas could indeed act as catalysts. Addition of 3 Å molecular sieves increased the yield to 75%, while 1 equivalent of water decreased the yield to 32% (entries 5 and 3). Alcohol additives were found to increase formation of I-

26. MeOH (1 equiv) provided 98% of the desired adduct while 2,2,2-trifluoroethanol formed quantitative yields of I-26 (entries 4 and 2). A solvent screen helped determine

DCM to be the optimal solvent, yielding 91% of the desired adduct with 10 mol % of cat.

I-54a (entry 6). With 1 equivalent of TFE and 10 mol % of catalyst I-53a in toluene,

53% of the desired product was isolated. While 1 equivalent of methanol and 2,2,2- trifluoroethanol were effective additives, they were not effective as solvents (40% and

49%, respectively, entries 8 and 9). In the absence of catalyst, 8% of the Friedel-Crafts product was isolated (entry 10).

With highly active boronate urea catalyst I-54a in hand, attention was turned toward testing the limits of the reaction with respect to catalyst loadings (Table 1.2). We were pleased to find excellent yields of product can be obtained at catalyst loadings of just 2.5 mol % with I-54a (83% entry 2). Even just 1 mol % of difluoroboronate urea I-

54a afforded 63% of I-26 after 48 h. A more in-depth investigation into the internal

Lewis acid assisted urea structure allowed the identification of a key element of the catalyst design: the ligands on boron significantly influence the activity of the catalyst.

Difluoroboronate urea I-54a is considerably more active than the analogous pinacol ester

I-53a, which is able to provide only 41% of I-26 under identical reaction conditions

(entry 1 vs. entry 4, Table 1.2). Fine-tuning of the pinacol ester urea was achieved through the installation of an additional electron-withdrawing group on the amino phenyl

29 F F CF3 CF3 NO2 Ph cat. HN B Bpin O I-20 (x mol %) O

+ N N CF N N CF3 1 M CH Cl , 3 H H 2 2 NO2 H H 24 h, 23 ºC, Ph I-54a I-53a CF3CH2OH I-26 N H CF CF I-24 3 3 TMS F3C Bpin entry cat. mol % time (h) yield (%) O O 1 I-54a 10 24 99 N N CF3 N N CF3 2 I-54a 2.5 48 83 H H H H I-58 I-57 3 I-54a 1 48 63

4 I-53a 10 24 41 CF3 CF3 Bpin CF3 5 I-58 20 24 50 X 6 I-57 10 24 99 O

7 I-59 10 24 28 F3C N N CF3 N N CF3 H H 8 I-54a 10 24 43 H H I-56c:X = O 9 I-54b 10 24 80 I-59 I-13d:X = S

Table 1.2. Catalyst Screen of Various Urea Derivatives

borane side of the urea to afford the significantly more active catalyst I-57 (99%, entry

6). To examine the role of the Lewis acid on the catalyst activity, we tested the effect of a strategically placed silicon in the ortho position of the urea scaffold. The importance of the boron became apparent when 20 mol % of I-58 afforded only a 50% yield of I-26

(entry 5). Key control experiments further probing the catalyst activity revealed I-54a and I-57 provide enhanced yields in otherwise identical reaction conditions when directly compared to more conventional catalysts I-56c and I-13d (43% and 80%, respectively).

This significant finding demonstrates that internal Lewis acid activation of ureas is one strategy to overcome the low turnover rates that limit the synthetic utility of traditional urea catalysts. The reduced activity observed with control catalyst I-59, a urea unable to participate in internal Lewis acid coordination, provided further support for this improved method of urea activation (28%, entry 7).

30 1.4.1 Scope of Addition of Nitrogen Heterocycles to Nitroalkenes

To test the generality of internal Lewis acid assisted hydrogen bond donor catalysis, a brief investigation evaluating the scope of the reaction was carried out and the results are listed in Table 1.3. The process tolerates both electron-withdrawing and

R1 R1 I-54a (x mol %) HN

NO2 + R 1 M CH2Cl2, 24 h, I-26 N 23 ºC, CF CH OH I-20 H 3 2 NO2 I-24 R

entry R R1 product mol % time (h) yield (%) 1 Ph H I-26a 5 48 91

2 4-Br-C6H4 H I-26b 2.5 24 87 3 4-MeO-C6H4 H I-26c 5 24 88 4 n-pentyl H I-26d 10 48 64 5 cyclohexyl H I-26e 10 48 69 6 Ph 5-MeO I-26f 5 24 89 7 Ph 5-Br I-26g 10 48 70

Table 1.3. Substrate Scope of Indole Addition to Nitrostyrene

electron-donating substituents on the nitrostyrene; just 2.5 mol % and 5 mol % of I-54a afford excellent yields of corresponding products I-26b and I-26c after 24 h (87% and

88%, entries 2 and 3). Although alkyl nitroalkenes derived from hexanal and cyclohexanecarboxaldehyde proved to be more challenging electrophiles, good yields of the desired products were obtained after 48 h with 10 mol% of 54a (64% and 69%, entries 4 and 5). A short investigation of indoles revealed certain substituents are well- accommodated in the reaction. For example, more nucleophilic 5-methoxyindole I-24f afforded an 89% yield of the desired adduct with 5 mol% of I-54a after 24 h (entry 6).

31 The slightly less nucleophilic 5-bromoindole I-24g proved to be somewhat more sluggish yet afforded a good yield of product after 48 h (70%, entry 7).

1.4.2 Investigation into the Relative Rates of Urea Catalysts

Preliminary kinetic studies probing the activity of catalysts I-54a and I-53a were conducted in direct comparison to catalysts I-56c and I-13d. Using the method of initial

2345634*-$7*8* 2345'34*-$6*7* *%$/" *%." *%$&" !"#"$%&'()*+,"-".%&/()*0" *%2'" *%$." 12"#"'%/.()*$" !"#"$%&'()*&+","-%$'()*." *%$3" *%2" /0"#"-%-1()*$" *%$" *%$'" *%*/" !"#$%&'()* !"#$%&'()* *%*&" *%$" *%*." *%*'" *%*3" *" *" *" 3***" .***" &***" /***" $****" *" 2****" 3****" &****" 4****" $*****" $2****" $3****" $&****" +,-.*/01* +,-.*/01* 2345634*-$7*8* I-13d-5 mol % &%$*" *%2" !"#"$%&'()*'+")",%-.()*$" !"#"$%&'()&*+")",%&'()&'" *%*3" /0"#".%.1()*2" &%$" -."#"/%/,()&$" *%*'"

&%&*" *%*1" !"#$%&'()* !"#$%&'()* *%*-" &" &" '&&&" 0&&&" 1&&&" 2&&&" $&&&&" $'&&&" $0&&&" $1&&&" $2&&&" *" *" ,***" 2****" 2,***" -****" -,***" $****" )&%&*" )*%*-" +,-.*/01* +,-.*/01*

F F CF3 CF3 CF3 I-54a I-56c B k = O k = O obs obs -5 -1 3.6 x 10-4 s-1 3.3 x 10 N N CF3 F3C N N CF3 H H H H

CF3 CF3 CF3 I-53a I-13d Bpin k = O kobs = S obs -5 -1 2.4 x 10-4 s-1 7.8 x 10 s N N CF3 F3C N N CF3 H H H H

Figure 1.9. Initial Rate Studies Comparing Various (Thio)Urea Catalysts in the Friedel-Crafts Addition of Indole to Nitrostyrene

32 rates, the rate of the reaction was measured at several catalyst loadings. The results at 5 mol % are depicted in Figure 1.8 and show that there is strong evidence supporting boronate ureas as enhanced hydrogen bond donor catalysts. Most notably, the observed rate constant of difluoroboronate urea I-54a was found to be 3.6 x 10-4 s-1, a rate more than 10 times faster than the traditional urea catalyst I-56c. Pinacol ester I-53a has an observed rate constant of 2.4 x 10-4 s-1, more than 7 times faster than I-56c. Both I-54a and I-53a were also found to be nearly 5 times and 3 times faster, respectively, than thiourea I-13d. The reaction was found to be first order with respect to catalyst, as shown by the linear relationship between yield and concentration of catalyst.

1.4.3 Asymmetric Addition to Nitroalkenes Using Chiral Boronate Ureas

MeO 20 mol % I-57 HN NO2 OMe Bpin Ph + N O H –20 ºC, CH2Cl2, CF CH OH, 48 h I-20 I-24f 3 2 * NO2 N N Ph H H I-26f I-57 OH 64% yield 61% ee

Scheme 1.12. Chiral Boronate Urea for Asymmetric Addition of 5-Methoxyindole to Nitrostyrene

Initial investigations confirm asymmetric catalysis with internal Lewis acid assisted HBDs is an area filled with opportunity (Scheme 1.12). Under relatively unoptimized reaction conditions, cis-1,2-aminoindanol derived catalyst I-57 gave rise to

64% of I-26f with good enantioselectivity (61% ee). While excellent enantioselectivities can be achieved with many different chiral urea catalysts, it was important for us to demonstrate that (1) chiral variants of boronate ureas can be synthesized with relative

33 ease and (2) chiral boronate ureas are capable of affecting the stereochemical outcome of a bond-forming reaction.

1.5 Activation of Nitrocyclopropane Carboxylates

The activation of nitroalkenes for nucleophilic attack by nitrogen heterocycles was a choice platform for the successful introduction of boronate ureas as enhanced hydrogen bond donor catalysts. However, the urea activation of 1,2- and 1,4- electrophiles has been well-documented in the literature.1,21-23 Thus, motivated by our interest in discovering new reactions, we set out to develop novel modes of activation for bond-forming processes. While 1,1-diestercyclopropanes have been previously well studied for cycloadditions and ring-opening reactions,64-66 nitrocyclopropanes were relatively unexplored at the onset of our investigations.67,68 In 1990, Dailey and coworkers reported the acid or heat-catalyzed rearrangement of nitrocyclopropane carboxylate I-58a to isoxazoline N-oxide I-59a, reduction and hydrolysis to

Hydrolysis NH2 NH2 Reduction of Nitro Group Ph I-60a CO2H Ph I-61a CO2Me [H]

O- Nu H N+ NO2 H-Nu O ! NO2 Ph CO Me Ph CO Me CO2Me I-58a 2 2 Ph I-59a I-62 Nucleophilic Rearrangement [H] Ring-Opening -OH !

NO2 NO Ph OH Ph 2 I-64a I-63a Reduction Decarboxylation of Ester

Scheme 1.13. Reactions of Nitrocyclopropane Carboxylates

34 cyclopropanes I-60a and I-61a, and decarboxylation to I-63a (Scheme 1.13).69 Charette and coworkers led further investigations into the utility of nitrocyclopropanes, reporting the chemoselective reduction of the ester to alcohol I-64a.67 The nucleophilic ring- openings of nitrocyclopropanes were first reported by Seebach in 1987.70 At 60 ºC, nitrocyclopropane I-65 was readily opened by a variety of nucleophiles to the corresponding nitroester I-66. Sodium cyanide and was an excellent nucleophile in the reaction, affording the corresponding product I-66a in 81% after just 4 hours in DMF.

Aniline was found to be less reactive, affording ring-opened product I-66b in 95% after

21 hours in MeOH. Sodium methoxide proved to be a much worse nucleophile, requiring

96 hours to provide 96% yield of the corresponding nitroester I-66c.

Over two decades would pass before Charette and coworkers reported advancements to Seebach’s thermally activated ring-opening reaction of nitrocyclopropane carboxylates.71 They report that Lewis acids activate nitrocyclopropane carboxylate I-58a for ring-opening by aniline I-67a to form nitroester

I-62a. In the absence of a Lewis acid catalyst, 35% of the desired nitroester was formed after 17 h at room temperature. Using highly activating Lewis acids, such as AlCl3, resulted in high conversion (13% unreacted nitrocyclopropane I-58a) but poor yields of the nitroester (21%, entry 2). Instead, rearrangement product I-59a was formed in a majority 66% yield. Weak Lewis acids, such as Cu(OTf)2, gave low conversion (48%) to the desired product but with much less formation of isoxazoline N-oxide I-59a (7%, entry

3). Charette and coworkers found that Ni(ClO4)2•H2O was the optimal catalyst, affording

I-62a in 87% yield, with 3% rearrangement product and 10% unreacted nitrocyclopane.

35 These limited accounts of nitrocyclopropane reactivity made the HBD activation of nitrocyclopropanes an attractive methodology to pursue.

a) 1987

tBu NO2 tBu NO2 O 60 ºC O Nu conditions O O tBu OMe tBu OMe I-65 I-66

entry Nucleophile Solvent t (h) product yield 1 NaCN DMF 4 I-66a 81

2 PhNH2 MeOH 21 I-66b 95 3 NaOMe MeOH 96 I-66c 96

b) 2008 Ph O- NH2 NH NO NO 17 h, rt 2 N+ 2 + + O Ph CO Me CO Me 2 CH2Cl2 Ph CO2Me 2 Ph I-58a I-67a I-62a I-59a

entry Lewis acid I-58a (%) I-62a (%) I-59a (%) 1 -- 65 35 0

2 AlCl3 13 21 66 3 Cu(OTf)2 45 48 7 4 Ni(ClO4)2•6H2O 10 87 3

Scheme 1.14. Thermally Promoted Ring-Opening of Nitrocyclopropanes (b) Lewis-acid Activated Nitrocyclopropane Carboxylates for Ring-Opening Reactions

1.5.1 Development of Nucleophilic Ring-Opening Reactions

Encouraged by the enhanced capabilities of boronate ureas, specifically I-54a, to recognize nitro groups, we turned our attention toward the activation of nitrocyclopropane carboxylates for ring-opening reactions (Scheme 1.15). In contrast to

1,1-diestercyclopropanes, nitrocyclopropane carboxylates contain a valuable nitro group,

36 which itself is a synthetically useful group and can also be easily transformed into various other functionalities.72!73 Our investigation into the first organocatalytic activation of nitrocyclopropane carboxylates began with styrene-derived nitrocyclopropane I-58a, 10 mol % of boronate urea I-54a and aniline I-67a.74 At an optimal concentration of 1 M

CH2Cl2, with 1 equivalent CF3CH2OH at 23 ºC, 87% yield of ring-opened product I-62a as a 1:1 mixture of diastereomers. A survey of ureas and thioureas revealed that boronate

R N O H activated O O N H R + urea + N+ N O- ! O- Ph CO2Me Ph CO2Me I-58a I-68a

Scheme 1.15. Proposed Urea Activation of Nitrocyclopropane Carboxylates

urea I-54a was the most active catalyst for the activation of nitrocyclopropane carboxylate I-58a (Table 1.4). Boronate ureas containing fluoride ligands were generally more active than their pinacol ester counterparts: I-54a (87%) vs. I-53a (34%) and I-54d

(55%) vs. I-53d (29%). Silicate urea I-58 (31%) was comparable to boronate urea I-53d

(29%) but less active than boronate urea I-54a (87%). Chiral boronate urea I-57 afforded

35% of the desired product but gave no diastereoselectivity, possibility due to the readily epimerizable stereocenter containing the methyl ester and nitro group. Conventional urea and thiourea catalysts lacking an internally coordinated Lewis acid moiety were also found to be active catalysts in the ring-opening reaction. Urea I-69, a urea lacking

37 internal coordination that is otherwise analogous to boronate urea I-54a, afforded only

43% of the ring-opened product. Urea I-56c and thiourea I-13d were found to be more

Ph NH2 NH NO2 NO cat. (10 mol %) 2 + Ph CO2Me Ph CO2Me CH2Cl2, CF3CH2OH I-58a I-65a 23 ºC, 48 h I-62a

F F Bpin B O O Bpin O 1 1 O Ar1 Ar Ar Ar1 N N N N N N H H H H N N H H H H OH I-54a: 87% I-53a: 34% I-56c: 65% I-57: 35% F F F B Bpin S Bpin F F O O O 1 1 2 Ar Ar Ar2 Ar N N N N N N H H N N F H H H H H H I-54d: 55% I-53d: 29% I-13d: 80% I-53g: 46% F F F F F TMS O B O B O O Ph Ar1 Ar1 Ph N N N N H H N N H H N Me H H H I-54b: 38% I-58: 31% I-69: 43% I-70: 27%

Me CF3 CF3 O Me Bpin = B Ar1 = Ar2 = O Me Me CF 3

Table 1.4. Catalyst Screen of Nucleophilic Ring-Opening Reaction of Nitrocyclopropane Carboxylates

! active (65% and 80%, respectively). The effect of electron-withdrawing groups on the hydrogen-bonding capabilities of the urea was evident in a screen of select boronate ureas. Pinacol ester boronate urea I-53d afforded 29% yield of the desired product, while

I-53g was a much more active catalyst, providing 46% yield of I-62. The effect of electron-withdrawing groups was also evident in difluoroboronate ureas. The trend of I- 38 54a>I-54d>I-54b>I-68 (87%>55%>38%>27%) suggests that internal Lewis acid assistance working in combination with electron-withdrawing aryl rings offers enhanced activity of the urea catalyst. The lack of reactivity observed with difluoroboro acetamide

I-70 suggests that dual hydrogen bonding offered by urea catalysts is essential for obtaining high yields of the desired product. In addition to the mild reaction conditions afforded by urea catalysts, no rearrangement of I-58a to isoxazoline N-oxide I-59a was observed, a problem often observed with Lewis acid catalysis.

1.5.2 Scope of Nucleophilic Ring-Opening Reactions

Once the urea activation of nitrocyclopropane carboxylates for nucleophilic ring opening was established, various nucleophiles were tested to examine the scope of the reaction. With 10 mol % of difluoroboronate urea I-54a in CH2Cl2 at 23 ºC for 48 h, aniline afforded 87% of the corresponding nitroester I-62a. Electron rich p-anisidine I-

67b was an excellent nucleophile in the reaction, affording 90% of I-62b, while electron deficient p-bromoaniline I-67c afforded a moderate 58% yield of I-62c. Interestingly, phenyl hydrazine I-71 was highly active in this reaction, forming I-62d in 99% yield.

We were pleased to find that nitrogen heterocycles were tolerated, although primary amines, nucleophiles Charette and coworkers encountered to problematically complex with Lewis acid catalysts,71 were found to be inactive in the reaction. Piperidine I-72 afforded nitroester I-62e in 78% yield. Morpholine I-73 and indoline I-74 were much more active, affording nearly quantitative yields of the corresponding nitroesters I-62f and I-62g (95% and 99% yields, respectively).

39 I-54a (10 mol %) NR2 NO2 NO2 + R2NH Ph CO2Me CH2Cl2, CF3CH2OH Ph CO2Me (±)-I-58a I-67 23 °C, 48 h I-62 entry nitrocyclopropane amine product yield (%) 1 I-58a I-67a I-62a 87 2 I-58a I-67b I-62b 90 3 I-58a I-67c I-62c 58 4 I-58a I-71 I-62d 99 5 I-58a I-72 I-62e 78 nucleophiles 6 I-58a I-73 I-62f 95 7 I-58a I-74 I-62g 99 8 I-58b I-67a I-62h 77 9 I-58c I-67a I-62i 59

10 I-58d I-67a I-62j 99 nitro- 11 I-58e I-67a I-62k 76 cyclopropanes

NH2 NH2 NH2 NHNH2 nucleophiles O

N N N I-67a I-67b I-67c I-71 H I-72 H I-73 I-74 H OMe Br nitrocyclopropanes NO2 NO2

CO2Me CO2Me

I-58a Cl I-58b

NO2 NO2 NO2

CO2Me CO2Me CO2Me

I-58c I-58d I-58e CF3

Table 1.5. Scope of Nucleophiles and Nitrocyclopropane Carboxylates for Urea-Catalyzed Ring-Opening

With respect to the nitrocyclopropane carboxylate, the reaction was limited to only those that could be successfully isolated. Nitrocyclopropane carboxylates derived from electron-rich aromatic styrenes readily rearranged to the corresponding isoxazoline

N-oxide (I-59a), thus only those nitrocyclopropane carboxylates stable enough to isolate were tested in this reaction. Electron-deficient nitrocyclopropane carboxylate I-54b and

40 I-54c were less reactive than styrene-derived nitrocyclopropane I-54a, affording 77% and

59% yields, respectively. Naphthyl nitrocyclopropane I-54d was readily opened with aniline I-67a, affording nearly quantitative yields of nitroester I-62j. In addition to aromatic rings, nitrocyclopropane I-58e, derived from 1,3-butadiene, was a viable reactant. However, reduced yields of the ring-opened product I-62k were obtained (76% yield).

1.5.3 Investigations into the Proposed Reaction Pathway

The interesting reactivity afforded by urea activation of nitrocyclopropane carboxylates was of particular interest due to the application of the ring-opened products.

However, before we could proceed with utilizing the readily accessible !-amino-!- nitroester products, we were interested in determining the possible reaction mechanism of this transformation. We proposed that two possible pathways could occur, leading to two different stereochemical outcomes (Scheme 1.16). Starting with enantioenriched nitrocyclopropane I-58a, in Pathway A, an SN1-like ring-opening of urea-activated nitrocyclopropane intermediate I-68 would lead to carbocation I-75. The stereochemical information at both the !- and !- positions would be lost in formation of planar intermediates at those carbon centers. Addition of indoline I-74 would then afford rac-I-

76, which, upon proton transfer, would lead to rac-I-62g. Alternatively, in Pathway B, an SN2-like bimolecular ring-opening of ent-I-68 would lead to urea-stabilized I-76, with inversion at the ! stereocenter, but retention of enantioenrichment at the !-stereocenter.

Proton transfer would then lead to ent-I-62 as a mixture of diastereomers. To investigate these two plausible reaction pathways, enantioenriched ent-I-58a (89% ee) was

41 O O Ar Ar Ar N Ar N N N H Pathway A H H I-74 H - - - O - N NO O O + O 2 N+ NH N

Ph CO2Me Ph CO Me Ar Ph CO2Me 2 rac-I-76 rac-I-62g N O I-75 H SN1-type ring-opening O N H Ar N+ O- O Ph CO2Me Ar N Ar ent-I-68 N H H N I-74 O- H O- N NO2 NH N+

Pathway B Ph CO2Me Ph CO2Me ent-I-76 ent-I-62g SN2-type addition

Scheme 1.16. Plausible Reaction Pathways for Ring-Opening of Nitrocyclopropane Carboxylates

synthesized and reacted with indoline I-74 with 10 mol % of difluoroboronate urea I-54a under the optimized reaction conditions (Scheme 1.17). Ring-opened I-62g was isolated in 99% yield as a 1:1 mixture of diastereomers with complete inversion of stereochemistry, but with retention of enantiomeric excess (91% for each diastereomer).

Thus, an SN2-type reaction pathway (Pathway B) was favored over Pathway A.

O H N I-54a (10 mol %) N+ + O- N NO2 Ph CO2Me CH2Cl2, CF3CH2OH 23 °C, 24 h Ph CO2Me ent-I-58a 99% yield 89% ee I-74 ent-I-62g 99% yield,91% ee, 1:1 dr

Scheme 1.17. Reaction of Enantioenriched I-58a to Support Pathway B

! ! 42 1.5.4 Synthesis of 3-(1-Methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino)-5-(3- trifluoromethyl-phenyl)-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-2-one

Amide Formation O F CO 3 H ! N N N CF3 Nucleophilic H C CH Ring-Opening # " 3 3 Condensation F3C I-77 Eli Lilly

CB-1 receptor antagonist/inverse agonist -Treatment of obesity animal models -Treatment of depression and schizophrenia -Shown to reduce alcohol consumption -Good bioavailability -Selective for CB-1

Figure 1.10. CB-1 Receptor Antagonist/Inverse Agonist Patented by Eli Lilly

With our methodology to readily access !-amino-!-nitroesters, we envisioned that synthesis of CB-1 receptor antagonist/inverse agonist I-77 patented by Eli Lilly would be an attractive target to synthesize (Figure 1.10).75 The amino lactam was demonstrated to test positively in the treatment of obesity, depression, and schizophrenia. The drug target also showed reduced alcohol consumption in animal models. The good bioavailability of the drug, resulting from its good solubility in aqueous solutions, as well as its selectivity for the CB-1 receptor over the CB-2 receptor, makes it an attractive target as a potential orally administered medicine. Retrosynthetically speaking, we envisioned that the lactam functionality could form from condensation of a !-amino-!-amino ester, formed from reduction of the corresponding !-amino-!-nitro ester, which we hoped to synthesize using a urea-activated nitrocyclopropane ring-opening reaction.

43 Reaction of enantioenriched nitrocyclopropane carboxylate I-58c (90% ee,

Scheme 1.18) with 10 mol % of difluoroboronate urea I-54a and 4-

(trifluoromethoxy)aniline I-65d afforded the desired !-amino-!-nitro ester I-62l as a 1:1 mixture of diastereomers in 91% yield with 90% ee for each of the diastereomers.

Lactamization was achieved using HCl in methanol, affording the nitro lactam I-78 in an

F3CO NO 2 NH2 CO Me + 2 I-54a (10 mol %) NH NO2 I-58c F3CO CH2Cl2, CO2Me 90% ee I-65d CF3CH2OH I-62l CF3 23 °C 91% yield 90% ee CF3 1:1 dr

O F CO O 3 F3CO NO N 2 NH2 N a) CSA, I-79 HCl, MeOH Zn, HCl I-77 b) AlMe 43% over 2 steps 65 ºC 3 I-78 I-79 97% 92% O CF F3C N 3 CF3 Me I-80

Scheme 1.18. Synthesis of I-77

! excellent yield (97% yield). Chemoselective reduction of the nitro group using Zn and

HCl afforded the desired amino lactam I-79 in an excellent 92% yield. Condensation of

I-79 with 1-(6-(trifluoromethyl)pyridine-2-yl)ethanone I-80, formed the intermediate imine, which, upon methylation with trimethylaluminum, gave rise to the desired drug candidate I-77 in 43% yield. The application of the activation of nitrocyclopropanes toward the synthesis of I-77 demonstrates potential applications of boronate urea catalysis in drug discovery. 44 1.6 Formal [3+3] Dipolar Cycloadditions

The successful organocatalytic HBD-catalyzed formation of !-amino-!-nitro esters from their cyclopropane precursor was an important indication that ureas,

Ring-opening R R N O N O Nu H H H O O N O N + urea H R Nu H R Nu H N O- + N+ + NO ! O- N O- 2 Ph CO2Me Ph CO2Me Ph CO2Me Ph CO2Me I-58a I-68 I-81 I-62

Cycloaddition R R Nu N O N O E H H O O N E O N + urea H R Nu R Nu E N - + + H O ! N + NO2 O- N O- Ph CO Me 2 Ph CO Me Ph CO2Me Ph CO2Me 2 I-58a I-68 I-82 I-83 !

Scheme 1.19. Proposed Cycloaddition Reactions of Nitrocyclopropane Carboxylates

specifically boronate ureas, are well suited for the activation of nitrocyclopropanes carboxylates. Our mechanistic investigations revealed that the ring-opening reaction of nitrocyclopropane carboxylates was most likely occurring through a concerted, SN2-type mechanism, where an anion was generated in the !-position. We thus turned our attention toward utilizing this anionic intermediate to attack an electrophile. To this end, we began investigations for a dipolar cycloaddition reaction between nitrocyclopropane carboxylates I-58 and an appropriate dipolarophile.

1.6.1 Dipolar Cycloadditions of 1,1-Diestercyclopropanes

Owing to the similar reactivity they share with ","-unsaturated carbonyl compounds, the chemistry of 1,1-diestercyclopropanes has been proliferous in the 45 literature.64,65,76-78 Specifically, Lewis acid catalysts have been mainly relied upon to effect dipolar cycloadditions of 1,1-diestercyclopropanes to form a variety of cyclic molecules.79!!Of the many transformations found to occur with 1,1-diestercyclopropanes, a few select reports are outlined below to demonstrate the utility of cycloaddition reactions with donor acceptor cyclopropanes.

In 1997, Kerr and coworker reported the formation of I-85 as a side product during the nucleophilic ring-opening reaction of cyclopropane I-84 with indole I-24d.80

Two years later, they were able to capitalize on their discovery by utilizing Yb(OTf)3

(ytterbium triflate) to catalyze the cycloaddition reaction to afford fused indole I-85 in89% yield in a 1:5 cis:trans ratio (Scheme 1.20a).81 This interesting reactivity suggested that 1,1-diestercyclopropanes are “one-carbon homologs of electron-deficient olefins,” which led to further investigations of dipolar cycloaddition reactions.81

In 2003, Kerr and coworker reported the first homo [3+2] dipolar cycloaddition reaction of 1,1-diestercyclopropanes with nitrones (Scheme 1.20b).82 A survey of catalysts revealed that Yb(OTf)3 was far superior to common Lewis acids such as

Cu(OTf)2, Sc(OTf)3, TiCl4, and many others. Using nitrone I-86a, derived from 4- nitrotoluene, Kerr isolated 94% yield of 1,2-oxazinane I-88a as a single diastereomer.

The following year, Kerr reported the use of anhydrous MgI2 to catalyze the same

83 reaction, isolating 98% of I-88a with a 15:1 cis:trans diastereoselectivity. The MgI2 catalyst was also found to promote a one-pot, 3-component coupling reaction of an aldehyde, hydroxylamine, and cyclopropane to bypass the need to isolate the nitrone material. In a major breakthrough in 1,1-diestercyclopropane chemistry, Sibi and

46 Ph I-85 a) 1999 Me Me 89% yield CO Et Yb(OTf)2 (5 mol %) 1:5 cis:trans 2 + R CO2Et Ph CO2Et N I-84 H CH3CN, 13 kbar, 4h N H CO2Et I-24d H

MeO2C CO2Me b) -O R + Ph CO Me N cat. 2 a + O Kerr, 2003 Ph CO2Me conditions Ph H N O O b Kerr, 2004 Ph O R N I-87 N I-84 c I-86a: R = p-tol I-88a: R = p-tol Sibi, 2005 I-86b: R = Ph I-88b: R = Ph Ph Ph entry cat. mol % nitrone t (h) yield (%) cis:trans eecis/trans (%) a 1 Yb(OTf)3 5 I-86a 18 94 100:0 -- b 2 MgI2 10 I-86a 19 98 15:1 -- 3c Ni(ClO ) /I-87 30 I-86b 8 99 1:0.8 90/96 4 2 !

Scheme 1.20. (a) Kerr’s Formal [3+2] Cycloaddition With Indoles (b) Formal [3+3] Cycloaddition with Nitrones

coworkers were able to isolate 1,2-oxazinane I-88b in an excellent 91% ee and 97%

84 yield. Relying on 10 mol % of Ni(ClO4)2 and I-87 as a chiral ligand, Sibi was able to control the enantioselectivity of cyclization, however in a low cis:trans diastereomeric ratio (1:0.8).

In an extension to Kerr’s cycloaddition work with nitrones, Johnson and coworker used Sn(OTf)2 to catalyze the [3+3] reaction of cyclopropanes with aldehydes (Scheme

1.21a).85 When using enantioenriched cyclopropane I-80, they were able to quantitatively isolate tetrahydrofuran I-90 in greater than 100:1 cis:trans dr with 96% ee.

This excellent retention of ee was found to occur with a wide variety of aldehydes, although electron-poor aldehydes resulted in enantiomeric excesses as low as 93%. From this information, Johnson was able to rule out a pathway involving the Lewis acid- mediated opening of the cyclopropane to form a dipole intermediate. Instead, the cycloaddition was proposed to occur directly with the cyclopropane. In 2006, Tang and

47 coworkers found the cycloaddition to occur with imines I-91 with Sc(OTf)3 to form pyrrolidine I-92 in 85% yield with 24:1 cis:trans dr (Scheme 1.21b).86 Following these reports, the Cu(SbF6)2 catalyzed dipolar cycloaddition of silyl enol ether I-93 with cyclopropane I-80 was found to form cyclopentane I-94 in excellent yield and good diastereoselectivity (99% yield, 87:13 dr), further demonstrating the utility of cyclopropanes in cycloaddition chemistry (Scheme 1.21c).87

(a) 2005 O O Ph Ph CO2Et Sn(OTf)2 100% yield + 96% ee Ph CO2Et I-84 Ph H CO2Me >100:1 dr >99% ee I-89 I-90 CO2Me

H (b) 2006 Bn N Ph CO Et N Sc(OTf) Ph 2 + 3 OTBS 85% yield Ph CO Et 2 C H Cl-4 H 24:1 dr I-84 6 4 CO2Et I-91 I-92 CO2Et (c) 2009 Ph OTBS Ph CO2Et Cu(SbF ) OTBS + 6 2 99% yield Ph CO Et 2 Ph CO Et 87:13 dr I-80 12 h 2 I-93 I-94 CO2Et !

Scheme 1.21. Cycloaddition Reactions With (a) Aldehydes (b) Imines and (c) Silyl Enol Ethers

1.6.2 Development of Cycloadditions of Nitrocyclopropane Carboxylates

Despite several reports on cycloadditions of 1,1-diestercyclopropanes, the same types of reactions with nitrocyclopropanes have never been reported. At first glance, nitrocyclopropane carboxylates may seem strikingly similar to 1,1-diestercyclopropanes, however the addition of a nitro group not only forms an additional stereocenter but also introduces an important nitrogen functionality. Thus, we began our investigations by heating nitrocyclopropane I-58a with nitrone I-86b under various conditions. With 20

48 mol % of difluoroboronate urea I-54a in CH2Cl2, oxazinanes I-95a and I-95a’ were isolated in 35% yield as a 2:1 mixture of diastereomers when heated to 35 ºC for 24 h.88

Encouraged by this result, the reaction was heated to 100 ºC in toluene and 91% of the desired products were obtained (entry 1, Table 1.6). At this high temperature, decomposition of nitrone I-86b was observed, preventing full conversion to the desired products at higher temperatures and longer reaction times. Heating to 50 ºC in

Ph O Ph Ph O Ph O Ph N N NO N cat. (x mol %) 2 + + Ph CO2Me 24 h, conditions Ph Ph Ph CO Me ( ) I-58a 2 CO2Me ± I-86b NO2 NO2 I-95a 2:1 I-95a' Entry cat. mol % solvent temp (ºC) yield (%) F F I-54a I-56c B O 1 I-54a 20 CH2Cl2 35 35 O Ar1 Ar1 2 I-54a 20 PhMe 100 91 Ar1 N N N N H H 3 I-54a 20 CHCl3 50 79 H H 4 I-54a 20 CH3CN 50 36 Bpin I-53a S I-13d 5 I-54a 15 PhMe 80 91 O 1 1 6 I-54a 10 PhMe 80 74 1 Ar Ar Ar N N N N H H 7 I-53a 15 PhMe 80 27 H H 8 I-56c 15 PhMe 80 75 Me CF3 I-13d O Me 9 15 PhMe 80 9 Bpin = B Ar1 = O Me Me CF3 !

Table 1.6. Optimization of Formal [3+3] Cycloadditions of Nitrocyclopropane Carboxylates and Nitrones

! chloroform and acetonitrile afforded 79% and 36% yields, respectively. With toluene identified as the optimal solvent, heating the reaction to 80 ºC afforded the desired adducts in 91% with just 15 mol % of difluoroboronate urea I-54a. Lowering the catalyst loading to 10 mol % afforded 74% of I-95a/I-95a’. A brief screen of ureas identified difluoroboronate urea I-54a as a superior catalyst to boronate urea I-53a (91% vs. 27% 49 yields, entries 5 vs. 9). Traditional urea catalyst I-56c was a moderate catalyst in this reaction, affording 75% of the oxazinane products in otherwise identical reaction conditions. Surprisingly, 3,5-bis-(trifluoromethyl)phenyl thiourea I-13d performed poorly in the reaction, possibly due to decomposition of the catalyst under the reaction conditions (9%, entry 9).89,90 It should be noted that in all cases, a 2:1 ratio of I-95a:I-

95a’ was isolated.

1.6.3 Nitrone and Nitrocyclopropane Substrate Scope of Oxazinane Formation

With the optimized reaction conditions in hand, various nitrocyclopropane carboxylates I-54 and nitrones I-86 were tested for the formation of oxazinane I-95

(Table 1.7). While oxazinane I-95b was formed in a 2:1 dr, nitrone I-86a was an excellent 1,3-dipole reaction partner, affording oxazinane I-95a quantitatively as a 3:1 ratio of cis:trans diastereomers. Nitrones I-86c and I-86d, derived from p- chlorobenzaldehyde and cinnamaldehyde, reacted with nitrocyclopropane I-58a to afford the corresponding oxazinanes in 87% and 93% yields, respectively (entry 3 and 4).

Electron-rich nitrone I-86e was a much better dipole reaction partner than piperonal derived I-86f (47% yield of I-95f, 2:1 dr), affording I-95e in an excellent 96% yield in

4:1 dr. Formed from p-nitrotoluene and benzaldehyde, nitrone I-86g was moderately active, affording I-95g in 56% yield as a 2:1 mixture of diastereomers. Electron-poor nitrocyclopropane I-58b was a less reactive dipolarophile than naphthyl derived nitrocyclopropane I-58c, affording 67% and 99% yields of I-95h and I-95i, respectively.

Again, we were limited in scope to those nitrocyclopropane carboxylates and nitrones that could be isolated.

50 Ph O Ph Ph O Ph O R3 N N N 15 mol % I-54a NO2 + + R1 CO Me Ph Ph (±) 2 R2 toluene, 80 ºC, 24 h O2N CO2Me O2N CO2Me

entry cyclopropane nitrone product yield dr Ph O Ph 1 O Ph N N NO2 I-86a I-95a 100% 3:1 Ph CO Me p-Me-Ph 2 p-Me-Ph (±) I-58a O2N CO2Me

O Ph Ph O Ph 2 N N NO2 I-86b I-95b 92% 2:1 Ph CO2Me Ph Ph (±) I-58a O2N CO2Me

O Ph Ph O Ph 3 N N NO 2 I-86c I-95c 87% 2:1 Ph CO2Me p-Cl-Ph p-Cl-Ph (±) I-58a O2N CO2Me

O Ph Ph O Ph 4 N N NO 2 I-86d I-95d 93% 2:1 Ph CO2Me Ph Ph (±) I-58a O2N CO2Me

O Ph Ph O Ph 5 N N NO2 I-86e I-95e 96% 4:1 Ph CO2Me p-OMe-Ph p-OMe-Ph (±) I-58a O2N CO2Me

O Ph Ph O Ph N 6 N NO2 O I-86f O I-95f 47% 2:1 Ph CO2Me (±) I-58a O N CO2Me O O 2

7 p-Me-Ph O Ph NO2 O p-Me-Ph N N I-86f I-95g 56% 2:1 Ph CO2Me (±) I-58a Ph Ph O2N CO2Me

Ph O p-Cl-Ph 8 NO2 O Ph N N I-86b I-95h 67% 2:1 p-Cl-Ph CO2Me Ph (±) I-58b Ph O2N CO2Me

Ph O naphthyl 9 NO O Ph N 2 N I-86b naphthyl CO2Me I-95i 99% 2:1 p-Me-Ph (±) I-58c p-Me-Ph CO Me O2N 2

Table 1.7. Substrate Scope of Formal [3+3] Dipolar Cycloaddition

51 1.6.4 Mechanistic Studies Probing the Stereochemical Outcome of Formal [3+3]

Dipolar Cycloaddition Reactions

The interesting reactivity afforded by urea-catalyzed cycloadditions of nitrocyclopropane carboxylates with nitrones led us to investigate the stereochemical outcome of the oxazinane products. The major diastereomer I-95a, assigned from the X- ray crystal structure, differs from the minor diastereomer I-95a’ at the stereocenter containing the nitro group. This singular difference between the major and minor diastereomers led us to believe that the reaction was not proceeding through a concerted mechanism, coinciding with the findings of Johnson and Kerr regarding cycloaddition reactions of 1,1-diestercyclopropanes.85,91,92 Thus, a plausible step-wise mechanism was proposed, which can proceed through two different transition states leading to the two isolated diastereomers. In the first step of the mechanism, we propose that the urea catalyst hydrogen bonds to the nitro group of nitrocyclopropane I-58a, forming complex

I-96. Attack by the nucleophilic oxygen of nitrone I-86b leads to two possible chair-like intermediates. In Pathway A, the hydrogen bonded nitro group lies in the equatorial position of I-97, which we propose is preferred due to the presence of the large urea functionality. Cyclization affords I-97, where the nitro group and phenyl rings of the cyclopropane and nitrone share a cis-relationship. Alternatively, in Pathway A’, the nitro group lies in the axial position, opposite the phenyl rings, leading to I-95a’. When enantioenriched nitrocyclopropane I-58a (89% ee) was subjected to the optimized reaction conditions using difluoroboronate urea I-54a, a 2:1 mixture of I-95a:I-95a’ was isolated, each in 91% ee. This retention of enantioenrichment suggests that the stepwise,

52 nucleophilic addition of nitrone I-86b occurs in an SN2-type fashion leading to intermediates I-97 and I-97’.

H Ar Ph Ph O O A N H H H NO2 Ph N Ph Ph O N H O H H Ar CO2Me N N O I-95a Ph H I-97 major O O OMe Ph O Ph 91% ee N Ar Ar N N Ph H H O2N CO2Me

O O N H CO2Me H Ph Ph Ph O Ph Ph H O CO Me I-96 O H 2 Ph N Ph O H N N Ph OMe NO2 I-95a' Ph H N minor O O 91% ee (1R, 2S)-I-58a A' I-97' 89% ee Ph O Ph H H N N N Ar Ar Ph O2N CO2Me O !

Scheme 1.22. Plausible Mechanistic Pathways to Account for Stereoselectivity

1.7 Summary

The successful design of boronate urea catalysts as enhanced hydrogen bond donors has been demonstrated through the activation of nitroolefins and nitrocyclopropane carboxylates. When comparing the activities of traditional urea and thiourea catalysts containing two 3,5-bis(trifluoromethyl)phenyl rings in the addition of nitrogen heterocycles to trans-!-nitrostyrene to boronate ureas, difluoroboronate urea I-

54a provided enhanced yields and faster rates of reaction. The increased ability of

53 boronate ureas to hydrogen bond to and activate nitro groups allowed for the discovery of a new organocatalytic reaction: the nucleophilic ring-opening reaction of nitrocyclopropane carboxylates. Application of this methodology to the synthesis of a

CB-1 recepter antagonist/inverse agonist demonstrates the utility and importance of new reaction discovery. Extension of this work to include the activation of nitrocyclopropane carboxylates for formal [3+3] dipolar cycloaddition with nitrones led to the efficient synthesis of 1,2-oxazinanes containing an important nitro group. As the first organocatalytic cycloaddition reaction of nitrocyclopropanes, a broad scope of nitrocyclopropanes and nitrones were tolerated in the reaction, exhibiting modest cis:trans diastereoselectivities. These revelations in the fundamental reactivity of boronate ureas as HBD catalysts have opened the way for the rational design of new reactions.

1.8 Experimental: General Methods

Methanol was freshly distilled from CaH2 prior to use. Methylene chloride, tetrahydrofuran, toluene, diethyl ether, and acetonitrile were purified by passage through a bed of activated alumina.93 Purification of reaction products was carried out by flash chromatography using Aldrich 60 Å (40 - 63 !m) silica gel. Analytical thin layer chromatography was performed on EMD Chemicals 0.25 !m 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 54 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, !)

1 using the solvent as internal standard (CHCl3, ! 7.26 and DMSO, ! 2.50). 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

19 (CHCl3, ! 77.16; DMSO, ! 39.5). Proton decoupled fluorine ( F NMR) spectra were recorded on a Bruker Avance AVIII 400 (376 MHz) spectrometer and are reported in

11 ppm using CF3C6H5 as an external standard (–63.72). Boron spectra ( B 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

Mass Spectrometer. Gas Chromatography (GC) analysis data were obtained on Agilent

6850 Series GC System with a 7673 Series Injector. An HP-1 capillary 30 m column was employed (19091Z-413E). HPLC analyses were obtained on a Perkin Elmer Series 200

HPLC with multiple wavelength detector. Unless otherwise noted, all other commercially available reagents and solvents were purchased from Aldrich and used without further purification.

55 1.8.1 General Procedure for the Preparation of Boronate Urea Pinacol Esters I-53

To a flame-dried round bottom flask with stirbar under N2 was added 2- aminophenyl boronic acid pinacol ester I-52 (1 equiv). Freshly distilled acetonitrile (0.06

M) was added followed by isocyanate I-50 (1 equiv). Shortly after addition of the isocyanates, a white precipitate began to form. More acetonitrile was added if necessary to facilitate stirring. The reaction was allowed to stir at 23 ºC for 4 h. The pure boronate urea pinacol ester I-53 was isolated as a white solid after vacuum filtration followed by washing with hexanes.

1.8.2 Characterization of Boronate Urea Pinacol Esters I-53

Me Me I-53a: 1-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(4,4,5,5- Me Me CF O O 3 tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea was B O isolated as a white solid (85%). Rf = 0.94 (4:4:1 ethyl

N N CF3 H H 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) d 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-

13 7.34 (m, 2H); 7.08-7.04 (m, 1H); 1.24 (s, 12H); C NMR (100 MHz, DMSO d6) !

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 (d, J = 6 Hz, CF3), 155.61-155.5 (m), 83.0, 25.5 (the carbon bonded

94 11 to boron was not seen due to broadening) ; B NMR (160 MHz, DMSO d6) ! 26.0 (br

+ s); HRMS (ESI): Mass calculated for C21H21BF6N2O3 [M+H] , 475.1622. Found

[M+H]+, 475.1614.

56 Me Me I-53b: 1-phenyl-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Me Me

O O yl)phenyl)urea was isolated as a white solid (88%). IR (NaBr) B O 3130, 2986, 1639, 1599, 1573, 1472, 1387 cm-1; 1H NMR (400 N N H H MHz, DMSO d6) ! 9.36 (bs, 2H), 7.43 (d, J = 7.6 Hz, 3H); 7.33 (t,

J = 7.6 Hz, 2H); 7.26 (t, J = 6.8 Hz, 1H); 7.19 (d, J = 7.2 Hz, 1H); 7.08 (t, J = 7.2 Hz,

13 1H); 7.00 (t, J = 7.2 Hz, 1H); 1.20 (s, 12 H); C NMR (100 MHz, DMSO d6) ! 154.7,

141.4, 138.4, 133.8, 129.4, 129.3, 123.9, 123.0, 120.9, 117.4, 81.5, 26.0 (the carbon

94 11 bonded to boron was not seen due to broadening) ; B NMR (160 MHz, DMSO d6) !

+ 1.91 (br s); HRMS (ESI): Mass calculated for C19H23BN2NaO3 [M+Na] , 361.1697.

Found [M+Na]+, 361.1689.

Me Me I-53c: 1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- Me Me 1 O O CF3 3-(3-(trifluoromethyl)phenyl)urea. H NMR (400 MHz, DMSO B O d6) ! 9.64 (br s, 1H); 9.25 (br s, 1H); 8.01 (s, 1H); 7.61-7.53 (m, N N H H 2H); 7.49-7.47 (m, 1H); 7.40-7.38 (m, 1H); 7.38 (s, 2H); 7.05-7.01

13 (m, 1H); 1.23 (s, 12H); C NMR (100 MHz, DMSO d6) ! 153.8, 141.4, 139.5, 133.8,

129.7, 129.3, 129.0 (q, J = 87.6 Hz), 123.4 (q, J = 134.4 Hz), 123.2, 122.7, 119.1, 118.1,

115.7, 81.8, 25.2 (the carbon bonded to boron was not seen due to broadening)94; 11B

19 NMR (160 MHz, DMSO d6) ! 22.2; F NMR (376 MHz, DMSO d6) ! –61.3 (s); HRMS

+ + (ESI): Mass calculated for C20H22B1F1N2Na1O3 [M+Na] , 429.1571. Found [M+Na] ,

429.1568.

I-53d: 1-(3,5-difluorophenyl)-3-(2-(4,4,5,5-tetramethyl-1,3,2- Me Me Me Me dioxaborolan-2-yl)phenyl)urea. 1H NMR (400 MHz, DMSO O O F B O

N N F 57 H H d6) ! 9.67 (br s, 1H); 9.06 (br s, 1H); 7.51 (dd, J = 0.8, 7.2 Hz, 1H); 7.40-7.35 (m, 2H);

7.22-7.19 (m, 2H); 7.07-7.03 (m, 1H); 6.87-6.82 (m, 1H); 1.26 (s, 12H); 13C NMR (100

MHz, DMSO d6) ! 163.7 (d, J = 15.5 Hz), 161.3 (d, J = 15.6 Hz), 153.4, 142.0-141.7

(m), 134.2, 130.3, 122.7, 119.1, 102.1-101.8 (m), 97.4 (t, J = 26 Hz); 82.4, 24.9 (the carbon bonded to boron was not seen due to broadening)94; 11B NMR (160 MHz, DMSO

19 d6) ! 25.7; F NMR (376 MHz, DMSO d6) ! –109.75 (s); HRMS (ESI): Mass calculated

+ + for C19H21B1F2N2Na1O3 [M+Na] , 397.1509. Found [M+Na] , 397.1508.

Me Me I-53e: 1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Me Me yl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea. 1H NMR (400 O O B CF3 O MHz, DMSO d6) ! 9.70 (br s, 1H); 9.03 (br s, 1H); 7.70-7.65 N N H H (m, 4H); 7.52 (d, J = 1.7 Hz, 1H); 7.43-7.41 (m, 1H); 7.37-

13 7.34 (m, 1H); 7.06-7.02 (m, 1H); 1.26 (s, 12 H); C NMR (100 MHz, DMSO d6) !

142.8, 142.1, 134.2, 130.3, 125.9 (q, J = 3.8 Hz) 124.5 (q, J = 269.3 Hz), 122.6, 119.0,

118.9, 82.4, 25.0 (the carbon bonded to boron was not seen due to broadening)94; 11B

19 NMR (160 MHz, DMSO d6) ! 25.8; F NMR (376 MHz, DMSO d6) ! –60.19 (s);

+ HRMS (ESI): Mass calculated for C20H22B1F3N2Na1O3 [M+Na] , 429.1571. Found

[M+Na]+, 429.1576.

1.8.3 General Procedure for the Preparation of Difluoroboronate Ureas I-54

To a flame-dried round bottom flask with stirbar under N2 was added boronate urea pinacol ester I-53 (4.6 mmol, 1 equiv) and freshly distilled MeOH (30 mL). An aqueous solution of KHF2 (4.5 M, 18.4 mmol, 4 equiv) was introduced to the reaction flask, resulting in a white heterogeneous mixture. The reaction was heated to 50 ºC, and the solution turned clear and colorless. After 2 h, the reaction was cooled to 23 ºC and 58 concentrated. The white solid was dissolved in ethyl acetate (30 mL) and extracted four times with water (15 mL). The organic layer was dried and concentrated in a 500 mL round bottom flask. To the flask was added 250 mL CH2Cl2 and the mixture was allowed to stir rapidly at room temperature for 1 hour, after which the solid was filtered and washed with CH2Cl2 to afford difluoroboronate urea I-54.

1.8.4 Characterization of Difluoroboronate Urea I-54

F F CF3 I-54a: 1-(3,5-bis(trifluoromethyl)phenyl)-3-(2- B O (difluoroboryl)phenyl)urea (1.55 g, 3.11 mmol, 85%) as a

N N CF3 H H white powder. mp 205.3 – 205.9 ºC; IR (NaBr) 3628, 3345,

-1 1 2986, 1741, 1671, 1585, 1479, 1187, 1128, cm ; H NMR (400 MHz, DMSO d6) d

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

13 (m, 1H); 7.15-7.10 (m, 2H); C NMR (100 MHz, DMSO d6) d 154.5, 138.1, 137.4,

131.5, 131.2, 130.9, 130.6, 128.2, 124.7, 123.0, 123.0 (q, J = 267 Hz, CF3), 118.4, 115.4

(the carbon bonded to boron was not seen due to broadening)94; 11B NMR (160 MHz,

19 DMSO d6) d 3.63 (br s); F NMR (376 MHz, DMSO d6) ! –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 I-54b: 1-(2-(difluoroboryl)phenyl)-3-phenylurea was isolated as a B O white solid (82%). mp: 224.5-226.4 ºC; IR (NaBr) 3347, 3061, N N H H -1 1 1641, 1597, 1572, 1479 cm ; H NMR (400 MHz, DMSO d6)

! 10.69 (br s, 1H); 10.12 (br s, 1H); 7.45 (t, J = 7.2 Hz, 2H); 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); 13C NMR (100 MHz,

DMSO d6) ! 155.4, 138.7, 136.4, 131.5, 130.3, 129.0, 126.6, 125.1, 123.7, 116.1 (the 59 carbon bonded to boron was not seen due to broadening)72; 11B NMR (160 MHz, DMSO

19 d6) ! 3.39 (br s); F NMR (376 MHz, DMSO d6) d –133.4 (s). HRMS (ESI): Mass

+ + calculated for C13H11B1F2N2Na1O3 [M+Na] , 283.0825. Found [M+H] , 283.0815.

F F CF3 I-54c: 1-(2-(difluoroboryl)phenyl)-3-(3- B O 1 (trifluoromethyl)phenyl)urea. H NMR (400 MHz, DMSO d6) N N H H ! 10.78 (br s, 1H); 10.38 (br s, 1H); 7.78 (s, 1H); 7.71-7.70 (m,

2H); 7.63-7.62 (m, 1H); 7.40-7.38 (m, 1H); 7.31-7.29 (m, 1H); 7.29-7.14 (m, 2H);

13 C NMR (100 MHz, DMSO d6) ! 154.5, 137.5, 136.5, 130.5, 129.9 (q, J = 31.8 Hz),

128.1, 126.6, 124.3, 123.8 (q, J = 271 Hz), 122.0 (m), 119.0 (m), 115.2 (the carbon

94 11 bonded to boron was not seen due to broadening) ; B NMR (160 MHz, DMSO d6) !

19 3.63 (br s); F NMR (376 MHz, DMSO d6) ! –133.1 (s, 2F), –61.3 (s, 3f); HRMS (ESI):

+ + Mass calculated for C14H10B1F5N2Na1O1 [M+Na] , 351.0701. Found [M+H] , 351.0706.

F F F I-54d: 1-(2-(difluoroboryl)phenyl)-3-(3,5-difluorophenyl)urea B O was isolated as a white solid (72%). 1H NMR (400 MHz, N N F H H DMSO d6) ! 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) ! 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

72 11 to boron was not seen due to broadening) ; B NMR (160 MHz, DMSO d6) ! 3.22 (br

19 s); F NMR (376 MHz, DMSO d6) ! –108.7 (s, 2F), –132.8 (s, 2F).

60 F F I-54e: 1-(2-(difluoroboryl)phenyl)-3-(4- B CF3 O (trifluoromethyl)phenyl)urea was isolated as a white solid N N H H 1 (64%). H NMR (400 MHz, DMSO d6) ! 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 Hz, 1H); 7.06 (d, J = 7.6 Hz, 1H). 13C NMR

(100 MHz, DMSO d6) ! 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 carbon bonded to boron was

72 11 19 not seen due to broadening) ; B NMR (160 MHz, DMSO d6) ! 3.82 (br s); F NMR

(376 MHz, DMSO d6) ! –60.6 (s, 3F), –132.8 (s, 2F).

F F I-54f: 1-(2-(difluoroboryl)phenyl)-3-(4-fluorophenyl)urea was B F O isolated as a white solid (60%). 1H NMR (400 MHz, DMSO

N N H H d6) ! 10.70 (br s, 1H); 10.12 (br s, 1H); 7.55-7.15 (m, 6H);

13 7.15-6.93 (m, 2H); C NMR (100 MHz, DMSO d6) ! 159.9 (d, J = 241 Hz), 154.6,

137.7, 131.6 (d, J = 3 Hz), 130.5, 128.0, 125.5 (d, J = 4 Hz), 124.1, 116.0 (d, J = 23 Hz),

115.1, (the carbon bonded to boron was not seen due to broadening)72; 11B NMR (160

19 MHz, DMSO d6) ! 3.39 (br s); F NMR (376 MHz, DMSO d6) ! –116.4 (s, 1F), –

133.4 (s, 2F).

1.8.5 Synthesis of Chiral Boronate Urea I-57

I-57: 1-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-3-(2- Me Me Me Me (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea was O O B O synthesized following a modified procedure.95 A flame-dried

N N H H OH round bottom flask under N2 was charged with 2-aminophenyl boronic acid pinacol ester (500 mg, 2.29 mmol). Dichloromethane (5 mL) was added to 61 create a clear and colorless solution. Freshly distilled pyridine (368.2 µL, 4.57 mmol) was added and the solution was stirred for 10 minutes. 4-Nitrophenylchloroformate (469 mg, 2.33 mmol) was added and the solution stirred for 20 minutes, until gas evolution ceased. (1S, 2R)-(-)-cis-1-amino-2-indanol (400 mg, 2.68 mmol) was added, causing the solution to form a white solid. Immediately after, N,N-diisopropylethylamine (437.8 µL,

2.51 mmol) was added and the solution turned clear and yellow. After stirring for 30 minutes, the reaction was diluted with 100 mL of dichloromethane and washed with water until colorless. The organic layer was dried with Na2SO4, filtered, and concentrated to afford 990 mg of crude yellow crystals. This product was purified by column chromatography on silica gel (50:50 ethyl acetate/hexanes to 5:5:1 ethyl acetate/hexanes/methanol) to afford 6h as an off-white crystalline solid. Rf = 0.38 (4:4:1 ethyl acetate/hexanes/methanol); mp 115.5-116.7 ºC; IR (film) 3558, 3416, 3067, 2966,

-1 1 1640, 1573, 1475, 1385 cm ; H NMR (400 MHz, CDCl3) ! 9.67 (bs, 1H); 7.61 (d, J =

7.6 Hz, 1H); 7.21 (app t, J = 7.6 Hz, 2H); 7.12 (app t, J = 8.8 Hz, 2H); 7.04 (app t, J = 6.8

Hz, 2H); 6.96 (br s, 1H); 6.47 (br s, 1H); 5.11 (app t, J = 5.6 Hz, 1H); 4.39 (br s, 1H);

3.09 (dd, J = 7.6, 5.6 Hz, 1H); 2.84-2.79 (m, 1H); 2.44 (d, J = 15.6 Hz, 12 H); 13C NMR

(100 MHz, CDCl3) ! 157.3, 139.9, 133.3, 128.5, 127.4, 125.1, 123.7, 114.6, 81.2, 72.5,

11 68.3, 58.6, 39.3, 25.9, 25.4, 21.1, 18.7, 14.2; B NMR (160 MHz, CDCl3) ! 15.1 (br s);

+ HRMS (ESI): Mass calculated for C22H27BN2NaO4 [M+Na] , 417.1956. Found

[M+Na]+, 417.1943.

1.8.6 General Procedure for Indole Additions to Nitroalkenes

A dry screw-capped reaction containing a magnetic stir bar was charged with b- nitrostyrene (28 mg, 0.19 mmol) then catalyst (2.5 to 10 mol% see Table 1). The reaction 62 fitted with cap and septum and put under a positive pressure of N2. Freshly recrystallized indole (33 mg, 0.28 mmol) was added in one portion as a solid. Freshly distilled dichloromethane (0.19 mL) was added then trifluoroethanol (13 mL, 0.19 mmol). The reaction was allowed to stir for 24 hours. The reaction was immediately purified by flash column chromatography on silica gel.

1.8.7 General Procedure for Nucleophilic Ring-Opening Reactions of

Nitrocyclopropane Carboxylates

A dry, screw-capped reaction vial containing a magnetic stir bar was charged with nitrocyclopropane (0.170 mmol) and then catalyst (10 mol %). The reaction was fitted with cap and septum and put under a positive pressure of N2. Methylene chloride (0.340 mL, 0.50 M) was added followed by amine nucleophile (0.255 mmol) and trifluoroethanol (12.2 mL, 0.170 mmol). The reaction was allowed to stir for 48 hours.

The reaction was immediately purified by flash column chromatography on silica gel.

1.8.8 Characterization of Novel-!-Amino "-Nitroesters

I-62c: Methyl 4-((4-bromophenyl)amino)-2-nitro-4-

CO2Me phenylbutanoate was purified by column chromatography on

NH NO2 silica gel (5:95 ethyl acetate/hexanes to 20:80 ethyl

Br acetate/hexanes), yielding 38.8 mg (58%, 1:1 dr) of I-62c as a light yellow oil. Rf = 0.2 (20% ethyl acetate/hexanes); FTIR (film) 3055, 2987, 2306,

1 1756, 1565, 1423, 1265, 896, 738; H NMR (400 MHz, CDCl3, mixture of two diastereomers) ! 7.41-7.28 (m, 10H); 7.26-7.20 (m, 4H); 6.48-6.45 (m, 4H); 5.45-5.41

(m, 1H); 5.15-5.12 (m, 1H); 4.52-4.45 (m, 1H); 4.14-4.12 (m, 1H); 3.85 (s, 3H); 3.82 (s,

13 3H); 2.92-2.81 (m, 2H); 2.66-2.58 (m, 2H); C NMR (100 MHz, CDCl3, mixture of two 63 diastereomers) ! 165.1, 164.7, 145.3, 145.2, 140.6, 140.3, 132.1, 132.00, 131.97, 129.3,

129.1, 128.3, 128.1, 126.3, 125.9, 115.6, 115.4, 110.4, 110.2, 55.3, 54.8, 53.8, 38.4, 37.8;

+ + HRMS (ESI): Mass calculated for C17H17BrN2O4 [M] , 415.0264 Found [M+Na] ,

415.0273.

I-62d: Methyl 2-nitro-4-phenyl-4-(2-phenylhydrazinyl)butanoate

CO Me 2 was purified by column chromatography on silica gel (5:95 ethyl

NH NO2 HN acetate/hexanes to 20:80 ethyl acetate/hexanes), yielding 55.4 mg

(99%, 1:1 dr) of I-62d as a light yellow oil. Rf = 0.18 (20:80 ethyl acetate/hexanes); FTIR (film): 3054, 2987, 2305, 2254, 1600, 1564, 1422, 1266,

1 909, 739, 467; H NMR (400 MHz, CDCl3, mixture of two diastereomers) ! 7.31-7.24

(m, 13H); 7.20-7.17 (m, 2H); 6.98-6.88 (m, 5H); 5.65 (dd, J = 9.8, 4.4 Hz, 1H); 5.39 (t, J

= 6.6 Hz, 1H); 5.13 (dd, J = 10.3, 5.0 Hz, 1H); 4.92 (dd. J = 11.6, 3.5 Hz, 1H); 3.83 (s,

13 3H); 3.81 (s, 3H); 3.45-3.37 (m, 2H); 2.85-2.75 (m, 2H); C NMR (100 MHz, CDCl3, mixture of two diastereomers) ! 165.5, 165.2, 151.6, 151.3, 136.6, 136.2, 129.2, 128.5,

128.4, 128.2, 127.8, 127.8, 120.2, 119.8, 115.1, 114.5, 86.0, 85.9, 62.0, 61.7, 53.6, 53.6,

+ 32.6, 32.3; HRMS (ESI): Mass calculated for C15H20N2O5 [M+H] , 330.1448. Found

[M+H]+, 330.1438.

I-62f: Methyl 4-morpholino-2-nitro-4-phenylbutanoate was

CO Me 2 purified by column chromatography on silica gel (5:95 ethyl

N NO2 acetate/hexanes to 20:80 ethyl acetate/hexanes), yielding 48.5 mg O (95%, 1:1 dr) of I-62f as a light yellow oil. Rf = 0.2 (20:80 ethyl acetate/hexanes); FTIR (film) 3054, 2987, 2305, 2254, 1755, 1564, 1438, 1265, 117, 910.

1 H NMR (400 MHz, CDCl3, mixture of two diastereomers) ! 7.38-7.32 (m, 6H); 7.18- 64 7.13 (m, 4H); 5.54 (dd, J = 4.0, 8.0 Hz, 1H); 5.09 (dd, J = 4.0, 8.0 Hz, 1H); 3.85 (s, 3H);

3.79 (s, 3H); 3.68-3.62 (m, 8H); 3.52-3.49 (m, 1H); 3.44-3.42 (m, 1H); 3.13-3.05 (m,

13 1H); 2.96-2.89 (m, 1H); 2.58-2.38 (m, 6H); 2.35 (mc, 2H); 2.26 (mc, 2H). C NMR (100

MHz, CDCl3, mixture of two diastereomers) ! 165.5, 165.2, 136.3, 135.4, 128.6, 128.5,

128.4, 128.3, 128.34, 128.25, 128.2, 86.5, 85.6, 67.2, 67.1, 66.9, 65.6, 53.6, 53.6, 50.4,

+ 49.6, 32.5, 31.9; HRMS (ESI): Mass calculated for C15H20N2O5 [M+H] , 309.1445 Found

[M+H]+, 309.1435.

CF3 I-62i: Methyl 2-nitro-4-(phenylamino)-4-(3-

(trifluoromethyl)phenyl)butanoate was purified by column CO2Me chromatography on silica gel (5:95 ethyl acetate/hexanes to 20:80 NH NO2 ethyl acetate/hexanes), yielding 38.3 mg (59%, 1:1 dr) of I-62i as a light yellow oil. Rf = 0.2 (20:80 ethyl acetate/hexanes). FTIR (film): 3053, 2986,

1 1756, 1565, 1265; H NMR (400 MHz, CDCl3, mixture of two diastereomers) !

7.61-7.45 (m, 8H); 7.13 (t, J = 8.0 Hz, 4H); 6.76-6.72 (m, 2H); 6.55-6.53 (m, 4H); 5.48

(dd, J = 8.0, 4.0 Hz, 1H); 5.20 (dd, J = 8.0, 4.0 Hz, 1H); 4.66-4.57 (m, 2H); 4.09-4.05 (m,

2H); 3.84 (s, 3H); 3.82 (s, 3H); 2.88-2.77 (m, 2H); 2.70-2.64 (m, 1H); 2.61-2.53 (m, 1H);

13 C NMR (100 MHz, CDCl3, mixture of two diastereomers) !

165.1, 164.6, 145.7, 145.7, 142.6, 142.4, 131.5 (q, J = 26.0 Hz, CF3), 129.7, 129.6,

129.4, 129.4, 129.4, 125.19, 125.2-124.8 (m), 123.0-122.5 (m), 119.0, 118.9, 114.0,

113.8, 85.3, 85.2, 55.0, 54.4, 53.8, 53.8, 38.5, 38.1. HRMS (ESI): Mass calculated for

+ + C18H17F3N2NaO4 [M+Na] , 405.1033. Found [M+Na] , 405.1034.

65 I-62j: Methyl 4-(naphthalen-2-yl)-2-nitro-4-

CO2Me (phenylamino)butanoate was purified by column

NH NO2 chromatography on silica gel (5:95 ethyl acetate/hexanes to

20:80 ethyl acetate/hexanes), yielding 61.3 mg (99%, 1:1 dr) of I-62j as a light yellow oil. Rf = 0.2 (20:80 ethyl acetate/hexanes). FTIR (film):

-1 1 3054, 2987, 1756, 1603, 1564, 1422, 1265 cm ; H NMR (400 MHz, CDCl3, mixture of two diastereomers) ! 7.90-7.78 (m, 8H); 7.53-7.44 (m, 6H); 7.15-7.11 (m, 4H); 6.74-

6.62 (m, 2H); 5.52-5.48 (m, 4H); 5.50 (dd, J = 8.8, 5.2 Hz, 1H); 5.18 (dd, J = 8.8, 5.2 Hz,

1H); 4.74-4.67 (m, 2H); 4.16-4.15 (m, 2H); 3.85 (s, 3H); 3.81 (s, 3H); 3.01-2.92 (m, 2H);

13 2.77-2.66 (m, 2H); C NMR (100 MHz, CDCl3, mixture of two diastereomers) ! 165.3,

164.9, 146.3, 138.6, 138.2, 133.4, 133.2, 133.0, 129.4, 129.3, 129.2, 128.0, 128.0, 127.7,

127.7, 126.6, 126.5, 126.3, 126.2, 125.6, 125.0, 123.8, 118.7, 118.6, 114.1, 113.9, 85.5,

85.4, 76.7, 55.5, 54.9, 53.8, 53.8, 38.6, 38.0.

1.8.9 Characterization of Compounds Isolated in the Synthesis of I-75

NO2 I-58c: (1R,2S)-methyl 1-nitro-2-(3-(trifluoromethyl)phenyl)

CO2Me cyclopropanecarboxylate was prepared following a known

14 CF3 procedure. The product was purified by column chromatography on silica gel (hexanes to 5% diethyl ether in hexanes) yielding I-58c (21% yield, 90% ee) as a colorless liquid. Rf = 0.2 (5:95 ethyl acetate/hexanes); FTIR (film): 3474, 3058,

1 2958, 1748, 1550, 1440, 1200, 1130, 1074, 895, 740, 464; H NMR (400 MHz, CDCl3) !

7.57 (d, J = 4.0 Hz, 1H); 7.48-7.41 (m, 3H); 3.80 (t, J = 12 Hz, 1 H); 3.54 (s, 3H); 2.47

13 (dd, J = 8.0, 4.0 Hz, 1H); 2.28 (dd, J = 8.0, 4.0 Hz, 1H); C NMR (100 MHz, CDCl3 ) !

162.2, 133.3, 131.9, 131.1 (q, J = 30 Hz, CF3), 129.1, 125.3 (q, 4.0 Hz, CF3), 125.1 (q, 66 4.0 Hz, CF3), 122.4, 71.4, 53.3, 33.3, 20.7; HRMS (ESI): Mass calculated for

+ + 23 C12H10F3NO4Na [M+Na] , 312.0454. Found [M+Na] , 312.0445. [!]D = –39.4º (c 2.7,

CHCl3). HPLC (OD-H Chiralcel, 1% IPA in hexanes, 1.5 mL/min) tr 6.6 min (major), tr

7.1 min (minor).

F3CO I-76: (4R)-methyl 2-nitro-4-((4-(trifluoromethoxy)

NH NO2 phenyl)amino)-4-(3-(trifluoromethyl)phenyl)butanoate was

CO2Me formed from reaction of I-58c with 4-

CF3 (trifluoromethoxy)aniline I-65d according to the general procedure above. The product was purified by column chromatography on silica gel

(5:95 diethyl ether/hexanes) yielding 72.1 mg (91%) of I-76 as a yellow oil. Rf = 0.18

(20:80 ethyl acetate/hexanes); FTIR (film): 3055, 2987, 2685, 1515, 1422; 1H NMR (400

MHz, CDCl3) ! 7.60-7.56 (m, 4H); 7.53-7.49 (m, 4H) 6.98 (d, J = 8.0 Hz, 4H); 6.50 (d, J

= 8.0 Hz, 4H); 5.46 (dd, J = 8.0, 4.0 Hz, 1H); 5.18 (dd, J = 8.0, 4.0 Hz, 1H); 4.59-4.53

(m, 2H); 4.22-4.16 (m, 2H); 3.84 (s, 3H); 3.82 (s, 3H); 2.87-2.78 (m, 2H); 2.69-2.54 (m,

13 2H); C NMR (100 MHz, CDCl3) ! 165.0, 164.6, 144.5, 142.2, 141.9, 141.56-141.49

(m), 131.8 (d, J = 6.0 Hz), 131.2 (d, J = 6.0 Hz), 129.8, 129.8, 129.7, 129.4, 125.2-125.0

(m), 123.0-122.5 (m), 122.2, 121.8, 119.3, 114.4, 114.2, 85.3, 85.1, 55.3, 54.8, 53.9, 38.4,

+ 38.0; HRMS (ESI): Mass calculated for C19H16F6N2NaO5 [M+Na] , 489.0856. Found

+ 23 [M+Na] , 489.0876. [!]D = –11.1 º (c 1, MeOH).

O I-77: (3R,5R)-3-nitro-1-(4-(trifluoromethoxy)phenyl)-5-(3- F3CO NO2 N (trifluoromethyl)phenyl)pyrrolidin-2-one. To a 100 mL

round bottom flask equipped with stirbar was added 300 mg

CF3 67 of ring-opened product I-76 (0.643 mmol) followed by freshly distilled methanol (15 mL) under Ar. Dilute HCl (15 mL, 1M) was added and a white precipitate formed.

Upon heating to 65 ºC for 12 h, the precipitate dissolved and formed a brown oil. The reaction was cooled and extracted three times with CH2Cl2. The organic layers were combined, dried with Na2SO4, filtered, and concentrated. The product was obtained as a light yellow oil as a 1:1 mixture of diastereomers (251.3 mg, 90%) and used without further purification. Rf = 0.6 (45:55 ethyl acetate/hexanes); FTIR (film): 3054, 2987,

-1 1 1725, 1565, 1510, 1266 cm ; H NMR (400 MHz, CDCl3) ! 7.60-7.48 (m, 7H); 7.42-

7.35 (m, 5H); 7.26-7.11 (m, 4H); 5.63-5.54 (m, 3H); 5.35-5.31 (m, 1H); 3.40-3.28 (m,

13 2H); 2.87-2.79 (m, 1H); 2.59-2.52 (m, 1H); C NMR (100 MHz, CDCl3, mixture of two diastereomers) ! 163.9, 163.8, 147.2, 147.1, 139.7, 139.5, 134.7, 134.2, 132.1 (q, J = 33

Hz, CF3), 131.7 (q, J = 33 Hz, CF3), 130.3, 130.2, 129.8, 129.2, 125.9 (q, J = 3 Hz, CF3),

124.9, 124.9, 124.8, 124.1, 123.8 (q, J = 5 Hz, CF3), 123.1-123.0 (m), 122.2, 122.2,

121.7, 121.6, 119.0, 119.0, 85.2, 85.1, 61.7, 60.4, 34.8, 33.8; HRMS (ESI): Mass

+ + + 23 calculated for C18H12F6N2NaO4 [M+Na] , 457.0593. Found [M+Na] , 457.0571. [!]D

= –32.6 º (c 1.46, CHCl3).

I-79: 1-(6-(trifluoromethyl)pyridin-2-yl)ethanone. A flame-dried 100

F3C N mL round bottom flask was charged with 2-bromo-6-trifluoromethyl O pyridine (1.50 g, 6.64 mmol, ordered from Combi-blocks) under Ar. Dry diethyl ether

(30 mL) was added and the flask was then cooled to –78 ºC. Dropwise addition of 1.6 M nBuLi (4.56 mL, 7.30 mmol) occurred over 25 minutes. Freshly distilled dimethyl acetamide (0.617 mL, 6.64 mmol) was added dropwise and the reaction was allowed to warm to room temperature overnight. Water (25 mL) was added to quench the reaction 68 and was then extracted 3 times with dichloromethane. The organic layers were combined, dried with Na2SO4, filtered, and concentrated to yield a light brown oil. The compound was further purified by flash column chromatography (20:80 ethyl acetate/hexanes) yielding 0.59 g (47%) of I-79 as a colorless liquid. FTIR (film): 3053,

-1 1 2986, 2305, 2254, 1703, 1422, 1265, 910, 737, 651 cm ; H NMR (400 MHz, CDCl3) !

8.19 (d, J = 8.0 Hz, 1H); 8.02 (t, J = 7.6 Hz, 1H); 7.84 (d, J = 7.6 Hz, 1H); 2.74 (s, 3H);

13 C NMR (100 MHz, CDCl3) ! 198.9, 153.5, 147.7 (q, J = 35 Hz, CF3), 138.5, 123.6,

+ 123.5, 121.1 (q, J = 273 Hz, CF3), 25.5; HRMS (ESI): Mass calculated for C8H6F3NNaO

[M+Na]+, 212.0294. Found [M+Na]+, 212.0293.15

O I-75: (3R,5R)-1-(4-(trifluoromethoxy)phenyl)-5- F CO 3 H N N N CF3 (3-(trifluoromethyl)phenyl)-3-((2-(6-

H3C CH3 (trifluoromethyl)pyridin-2-yl)propan-2-

yl)amino)pyrrolidin-2-one. To a 25 mL flame- CF3 dried round bottom flask equipped with stir bar was added 1-(6-(trifluoromethyl)pyridin-

2-yl)ethanone I-79 (136 mg, 0.717 mmol) under Ar. Freshly distilled toluene (10 mL) was added followed by aminolactam I-78 (290 mg, 0.717 mmol). A catalytic amount of camphor sulfonic acid (10 mg) and 4Å molecular sieves were added (100 mg). The reaction was allowed to stir at 85 ºC for 48 hours. Upon cooling, the mixture was concentrated and then purified by flash column chromatography using basic alumina

(20:80 diethyl ether/hexanes to 50:50 diethyl ether/hexanes). The imine product was obtained as a light yellow oil (268 mg, 65%) and used without further purification. 1-(4-

(trifluoromethoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)-3-(1-(6 (trifluoromethyl) pyridine-2-yl)ethylidene)amino)pyrrolidin-2-one (50 mg, 0.087 mmol) was added to a 69 flame dried round bottom flask equipped with stirbar under Ar. Freshly distilled toluene

(4 mL) was added and the flask was cooled to 0 ºC. Dropwise addition of AlMe3 (0.13 mmol, 2.0 M in hexanes) occurred over 5 minutes. The solution turned deep red and was allowed to stir for 12 h. The reaction was quenched with H2O (5 mL) and the solution turned yellow. The solution was extracted three times with ethyl acetate. I-75 was obtained as a 1:1 mixture of diastereomers (43%) by flash column chromatography using silica gel (50:50 diethyl ether/hexanes).

1 cis-I-75: H NMR (400 MHz, CDCl3) ! 7.87-7.80 (m, 2H); 7.52-7.48 (m, 1 H); 7.47-7.40

(m, 1H); 7.39-7.31 (m, 3H); 7.25-7.20 (m, 2H); 7.05-7.01 (m, 1H); 5.03 (dd, J = 8.0, 4.0

Hz, 1H); 3.48 (dd, J = 10.8, 2.8 Hz, 1H); 2.81-2.77 (m, 1H); 1.88-1.79 (m, 1H); 1.56 (s,

13 3H); 1.53 (s, 3H); C NMR (100 MHz, CDCl3) 174.7, 167.1, 140.8, 137.7, 131.7, 129.9,

129.8, 124.9, 123.6, 122.9, 122.0, 121.9, 121.3, 118.2, 115.9, 60.1, 58.7, 55.4, 30.0, 29.7;

+ + HRMS (ESI): Mass calculated for C27H22F9N3O2 [M+H] , 592.1641. Found [M+H]

592.1632.

1 trans-I-75: H NMR (500 MHz, CDCl3) ! 7.85-7.78 (m, 2); 7.54-7.50 (m, 4H); 7.44-7.41

(m, 1H); 7.37 (s, 1H); 7.24-7.28 (m, 1H); 7.12-7.11 (m, 2H); 5.18 (d, J = 8.5 Hz, 1H);

3.66 (dd, J = 10.5, 8.0 Hz, 1H); 2.48-2.42 (m, 1H); 2.26-2.22 (m, 1H); 1.56 (s, 6H); 13C

NMR (125 MHz, CDCl3) ! 174.9, 167.1, 147.1 (q, J = 34 Hz, CF3), 145.9, 141.6, 137.8,

136.7, 131.8 (q, J = 34 Hz, CF3), 129.8, 128.4, 124.9-124.8 (m), 124.1, 122.7, 122.6-

122.5 (m), 122.0, 121.5, 120.4, 119.4, 118.18, 60.5, 58.3, 53.3, 40.4, 29.3, 27.9.

1.8.10 General Procedure for Formal [3+3] Dipolar Cycloaddition Reactions of

Nitrocyclopropane Carboxylates and Nitrones

70 A dry, screw-capped reaction vial containing a magnetic stir bar was charged with nitrocyclopropane carboxylate I-58 (0.136 mmol) and catalyst (0.0204 mmol). The vial was fitted with a cap and septum and placed under a positive pressure of Ar. Dry toluene

(272 !L) was added followed immediately by a nitrone I-86b (0.203 mmol). The reaction was allowed to stir at 80 ºC for 24 h and then immediately purified by flash column chromatography with silica gel. Select oxazinane products were further purified by recrystallization when noted.

1.8.11 Characterization of Novel Oxazinane Compounds

Ph O Ph I-95a: Methyl 4-nitro-2,6-diphenyl-3-(p-tolyl)-1,2-oxazinane-4- N p-Me-Ph carboxylate was isolated as a mixture of diastereomers. The O2N CO2Me following characterization is for the mixture of diastereomers: 1H NMR (400 MHz,

CDCl3) " 7.57#7.53 (m, 2.5H); 7.50-7.42 (m, 5.5H); 7.40-7.30 (m, 1.5H); 7.21-7.15 (m,

3.5H); 7.15-7.01 (m, 5H); 6.89-6.85 (m, 1H); 6.04 (s, 0.4H); 5.93 (s, 1H); 5.07-5.00 (m,

1.2H); 4.01 (s, 3H); 3.51 (s, 1H); 3.24-3.00 (m, 3H); 2.25 (s, 1H); 2.23 (s, 3H).

Recrystallization (1:3 CH2Cl2/hexanes) yielded the major diastereomer. The following characterization is for the major diastereomer. mp 195.0-196.0 °C; FTIR (film) 3054,

-1 2986, 1758, 1559, 1421, 1059, 735, 705 cm ; 1H NMR (400 MHz, CDCl3) " 7.57-7.54

(m, 2H); 7.50-7.43 (m, 5H); 7.19-7.15 (m, 2H); 7.11-7.08 (m, 2H); 7.03-7.01 (m, 2H);

6.88-6.85 (m, 1H); 5.95 (s, 1H); 5.02 (dd, J = 12, 2.4 Hz, 1H); 4.00 (s, 3H); 3.18-3.12 (m,

13 1H); 3.04-3.00 (m, 1H); 2.23 (s, 3H); C NMR (100 MHz, CDCl3) " 165.4, 147.7, 138.6.

138.0, 130.5, 129.1, 128.9, 128.8, 128.7, 126.5, 122.3, 116.0, 93.5, 78.5, 66.4, 54.4, 32.9,

+ 21.0; HRMS (ESI): Mass calculated for C25H24N2Na1O5 [M+Na] , 433.1758. Found [M+

Na]+ 433.1743. 71 Ph O Ph I-95b: Methyl 4-nitro-2,3,6-triphenyl-1,2-oxazinane-4-carboxylate was N

Ph isolated as a mixture of diastereomers. The following characterization is O2N CO2Me 1 for the mixture of diastereomers: H NMR (400 MHz, CDCl3) ! 7.60"7.42 (m, 10H);

7.26-7.08 (m, 11H); 6.89-6.84 (m, 1.5H); 6.07 (s, 0.5H); 5.98 (s, 1H); 5.08-5.00 (m,

1.5H); 4.01-4.01 (m, 3H); 3.54-3.54 (m, 1.5H); 3.26-3.01 (m, 3H). Recrystallization

(20:80 ethyl acetate/hexanes) yielded the major diastereomer. The following characterization is for the major diastereomer: mp 187.5-188.8 °C; FTIR (film) 3054,

-1 1 2987, 1559, 1421, 1265, 1180, 739, 705 cm ; H NMR (400 MHz, CDCl3) ! 7.59"7.56

(m, 4H); 7.52-7.42 (m, 3H); 7.25-7.16 (m, 5H); 7.12-7.09 (m, 2H); 6.90-6.85 (m, 1H);

5.99 (s, 1H); 5.04 (dd, J = 11.6, 2 Hz, 1H); 4.01 (s, 3H); 3.17 (dd, J = 14, 12 Hz, 1H);

13 3.01 (ddd, J = 13.6, 2.4, 0.8 Hz, 1H); C NMR (100 MHz, CDCl3) ! 165.4, 147.6, 137.9,

132.0, 128.9, 128.9, 128.7, 128.4, 126.5, 122.4, 116.1, 93.4, 78.5, 66.6, 54.5, 32.9;

+ + HRMS (ESI): Mass calculated for C24H22N2Na1O5 [M+Na] , 441.1421. Found [M+ Na]

441.1439.

Ph O Ph I-95c: Methyl 3-(4-chlorophenyl)-4-nitro-2,6-diphenyl-1,2- N p-Cl-Ph oxazinane-4-carboxylate as a mixture of diastereomers. The O2N CO2Me following characterization is for the mixture of diastereomers: 1H NMR (400 MHz,

CDCl3) ! 7.55-7.44 (m, 9H); 7.36-7.32 (m, 2H); 7.22-7.16 (m, 6H); 7.09-7.07 (m, 3H);

6.92-6.88 (m, 1H); 6.05 (s, 0.5H); 5.97 (s, 1H); 5.09-5.02 (m, 1.5H); 4.01 (s, 3H); 3.58 (s,

1.3H); 3.29-3.24 (m, 0.5H); 3.13-3.00 (m, 2H). Recrystallization (hexanes) yielded the major diastereomer. The following characterization is for the major diastereomer. mp

159.5-160.1°C; FTIR (film) 3054, 2987, 1758, 1560, 1492, 1421, 1265, 1093, 739 cm-1;

1 H NMR (400 MHz, CDCl3) ! 7.54-7.44 (m, 7H); 7.25-7.17 (m, 4H); 7.09-7.06 (m, 2H); 72 6.92-6.87 (m, 1H); 5.96 (s, 1H); 5.03 (dd, J = 10, 4.4, Hz, 1H)!4.01 (s, 3H); 3.09-3.07 (m,

13 2H); C NMR (100 MHz, CDCl3) ! 165.1, 147.4, 137.6, 135.1, 131.9, 130.5, 128.9,

128.9, 128.8, 128.6, 126.4, 122.7, 166.1, 93.2, 78.4, 66.1, 54.6, 54.6, 32.7; HRMS (ESI):

+ + Mass calculated for C24H21Cl1N2Na1O5 [M+Na] , 475.1031. Found [M+ Na] 475.1011.

Ph O Ph I-95d: Methyl 4-nitro-2,6-diphenyl-3-styryl-1,2-oxazinane-4- N

Ph carboxylate was isolated as a mixture of diastereomers. The O2N CO2Me following characterization is for the mixture of diastereomers: FTIR (film) 3054, 2987,

1755, 1599, 1558, 1494, 1422, 1265, 1058, 909, 737, 650 cm-1; 1H NMR (400 MHz,

CDCl3) ! 7.54-7.40 (m, 8H); 7.29-7.27 (m, 6H); 7.25-7.22 (m, 4H); 7.16-7.14 (m, 3H);

6.99-6.95 (m, 1.5H); 6.58 (s, 0.5H); 6.54 (s, 1H); 6.47-6.37 (m, 1.5H); 5.50-5.44 (m,

1.5H); 5.07-5.01 (m, 1.5H); 4.01 (s, 3H); 3.75 (s, 1.5H) 3.25-3.20 (m, 0.5H); 3.10-3.06

13 (m, 1H); 2.90-2.73 (m, 1.5H); C NMR (100 MHz, CDCl3) ! 164.9, 164.3, 147.8, 139.0,

138.3, 138.1, 128.1, 135.7, 135.6, 128.8, 128.8, 128.7, 128.7, 128.6, 128.5, 128.4, 128.4,

128.3, 126.8, 126.7, 126.4, 126.3, 122.9, 122.9, 118.4, 117.1, 116.6, 116.6, 94.2, 93.2,

78.7, 77.9, 67.7, 67.1, 54.4, 53.9, 33.7, 33.6; HRMS (ESI): Mass calculated for

+ + C26H24N2Na1O5 [M+Na] , 467.1577. Found [M+Na] 467.1562.

Ph O Ph I-95e: Methyl 3-(4-methoxyphenyl)-4-nitro-2,6-diphenyl-1,2- N p-OMe-Ph oxazinane-4-carboxylate was isolated as a mixture of O2N CO2Me diastereomers. The following characterization is for the mixture of diastereomers: 1H

NMR (400 MHz, CDCl3) ! 7.55"7.41 (m, 8H); 7.20-7.15 (m, 3H); 7.10-7.07 (m, 3H);

6.89-6.85 (m, 1H); 6.77-6.68 (m, 3H); 6.01 (s, 0.25H); 5.94 (s, 1H); 5.07-5.00 (m, 1.3H);

4.00 (m, 3H); 3.89 (s, 1H); 3.73 (s, 1H); 3.71 (3H); 3.29-3.01 (m, 3H). The following characterization is for the major diastereomer. mp 186.1-188.5 °C; FTIR (film) 3054, 73 -1 1 2987, 1758, 1559, 1512, 1265, 1032, 896, 739 cm ; H NMR (400 MHz, CDCl3) ! 7.57-

7.42 (m, 7H); 7.28-7.16 (m, 2H); 7.11"7.09 (m, 2H); 6.90-6.86 (m, 1H); 6.75-6.73 (m,

2H); 5.94 (s, 1H); 5.03 (dd, J = 12, 2.4 Hz, 1H); 4.01 (s, 3H); 3.71 (s, 3H); 3.18-3.12 (m,

13 1H); 3.06-3.01 (m, 1H); C NMR (100 MHz, CDCl3) ! 165.4, 159.7, 147.7, 137.9,

131.9, 128.8, 128.8, 128.6, 126.4, 123.8, 122.3, 116.1, 113.7, 93.4, 78.4, 66.2, 54.9, 54.4,

+ 32.7; HRMS (ESI): Mass calculated for C25H24N2Na1O6 [M+Na] , 471.1527. Found

[M+Na]+ 471.1535.

Ph O Ph I-95f: Methyl 3-(benzo[d][1,3]dioxol-5-yl)-4-nitro-2,6- N O diphenyl-1,2-oxazinane-4-carboxylate was isolated as a mixture O N CO2Me O 2 of diastereomers. The following characterization is for the major diastereomer. mp 203.3-204.7 °C; FTIR (film) 3054, 2987, 1759, 1559, 1489,

-1 1 1421, 1264, 1041, 898, 739 cm ; H NMR (400 MHz, CDCl3) ! 7.54-7.40 (m, 5H); 7.23-

7.17 (m, 3H); 7.10-7.08 (m, 2H); 6.97-6.94 (m, 1H); 6.90-6.87 (m, 1H); 6.63-6.61 (m,

1H); 5.89-5.87 (m, 3H); 4.99 (dd, J = 12, 2 Hz, 1H); 3.99 (s, 3H); 3.17-3.10 (m, 1H);

13 3.03-3.00 (m, 1H); C NMR (100 MHz, CDCl3) ! 165.3, 148.0, 147.6, 147.5, 137.7,

128.9, 128.7, 126.5, 126.3, 125.4, 125.0, 122.4, 116.1, 110.7, 108.1, 101.1, 93.5, 78.4,

+ 66.2, 54.5, 32.7; HRMS (ESI): Mass calculated for C25H22N2Na1O7 [M+Na] , 485.1319.

Found [M+Na]+ 485.1311. p-Me-Ph O Ph I-95g: Methyl 4-nitro-3,6-diphenyl-2-(p-tolyl)-1,2-oxazinane-4- N

Ph carboxylate was isolated as a mixture of diastereomers. The O2N CO2Me following characterization is for the mixture of diastereomers. 1H NMR (400 MHz,

CDCl3) ! 7.63-7.53 (m, 6H), 7.51-7.42 (m, 4.5H), 7.27-7.21 (m, 4H), 7.01-6.95 (m, 6H);

6.02-6.02 (m, 0.5H), 5.93 (s, 1H), 5.08-5.02 (m, 1.5H), 4.01 (s, 3H), 3.53 (s, 1.5H), 3.53- 74 3.02 (m, 3H), 2.19, (s, 4.5H). The following characterization is for the major diastereomer. mp 181.3-183.9 °C; FTIR (film) 3054, 2987, 1759, 1558, 1454, 1422,

-1 1 1265, 1059, 745, cm ; H NMR (400 MHz, CDCl3) ! 7.60-7.54 (m, 4H); 7.50-7.41 (m,

3H); 7.23-7.31 (m, 3H); 7.00-6.95 (m, 4H); 5.92 (s, 1H); 5.03 (dd, J = 12, 2 Hz, 1H); 4.01

13 (s, 1H); 3.17-3.11 (m, 1H); 3.05-3.01 (m; 1H); 2.19 (s, 1H); C NMR (100 MHz, CDCl3)

! 165.4, 145.3, 138.0, 132.2, 131.9, 130.7, 129.2, 128.8, 128.8, 128.3, 126.5, 116.3, 93.5,

78.4, 66.8, 54.5, 32.9, 20.5, 14.1; HRMS (ESI): Mass calculated for C25H24N2Na1O5

[M+Na]+, 455.1578. Found [M+Na]+ 455.1571.

Ph O p-Cl-Ph I-95h: Methyl 6-(4-chlorophenyl)-4-nitro-2,3-diphenyl-1,2- N

Ph oxazinane-4-carboxylate was isolated as a mixture of diastereomers. O2N CO2Me The following characterization is for the mixture of diastereomers: FTIR (film) 3054,

-1 1 2956, 1758, 1598, 1559, 1492, 1265, 1091, 824, 739 cm ; H NMR (400 MHz, CDCl3) !

7.58-7.49 (m, 3H); 7.47-7.41 (m, 6H); 7.30 (s, 1.5H); 7.24-7.15 (m, 9H); 7.09-7.06 (m,

3H); 6.90-6.86 (m, 1.5H); 6.02 (s, 0.5H); 5.97 (s, 1H); 5.05-4.99 (m, 1.5H); 4.01 (s, 3H);

13 3.54 (s, 1.5H); 3.29-3.20 (m, 1H); 3.14-3.01 (m, 2H); C NMR (100 MHz, CDCl3) !

165.2; 164.0; 147.5; 147.5; 136.7; 136.3; 134.8; 132.5; 131.9; 130.6; 130.2; 130.0; 129.1;

129.0; 129.0; 128.8; 128.7; 128.7; 128.6; 128.5; 128.4; 128.0; 127.9; 127.7; 127.7; 127.5;

122.6; 116.2; 94.9; 93.2; 77.8; 66.7; 54.6; 53.7; 32.9; 32.8; HRMS (ESI): Mass calculated

+ + for C24H21Cl1N2Na1O5 [M+Na] , 475.1031. Found [M+Na] 475.1033.

Ph O naphthyl I-95i: Methyl 6-(naphthalen-2-yl)-4-nitro-2,3-diphenyl-1,2- N p-Me-Ph oxazinane-4-carboxylate was isolated as a mixture of O2N CO2Me diastereomers. The following characterization is for the mixture of diastereomers: 1H

NMR (400 MHz, CDCl3) ! 7.99-7.89 (m, 5.8H), 7.68-7.61 (m, 4.2H), 7.57-7.53 (m, 75 2.7H), 7.27-7.27 (m, 1.1H), 7.24-7.12 (m, 9.4H), 6.90-6.86 (m, 1.4H), 6.11 (s, 0.4H),

6.02 (s, 1H), 5.25-5.18 (m, 1.4H), 4.03 (s, 3H), 3.55 (s, 1.2H), 3.55-3.13 (m, 3.2H). The following characterization is for a mixture that contains 91% major diastereomer: mp

132.9-135.6 °C; FTIR (film) 3059, 2956, 1758, 1558, 1492, 1453, 1265, 1062, 738, 620

-1 1 cm ; H NMR (400 MHz, CDCl3) ! 8.00-7.88 (m, 4.4H); 7.68 -7.61 (m, 3.3H); 7.58-7.53

(m, 2.2H); 7.24-7.11 (m, 7.6H); 6.09-6.86 (m, 1.1H); 610 (s, 0.1H); 6.02 (s, 1H); 5.24-

5.18 (m, 1.1H); 4.04 (s, 3H); 3.55 (s, 0.3H); 3.31-3.24 (m, 1.1H); 3.17-3.13 (m, 1.1H);

13 C NMR (100 MHz, CDCl3) ! 165.4, 164.2 147.7, 147.7, 138.7, 135.6, 135.2, 133.4,

133.3, 133.2, 130.6, 130.2, 129.6, 129.2, 129.1, 128.9. 128.7, 128.7, 128.7, 128.2, 127.8,

126.6, 126.6, 126.5, 125.5, 125.4, 124.3, 124.2, 122.4, 116.1, 95.2, 93.5, 78.5, 77.8, 66.5,

65.9, 54.5, 53.6, 32.9, 32.8, 31.5, 22.6, 21.0 14.1; HRMS (ESI): Mass calculated for

+ + C29H26N2Na1O5 [M+Na] , 491.1578. Found [M+Na] 475.1578.

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Chapter 2. Urea Activation of Nitrodiazo Compounds

Portions of this chapter appear in the following publications:

• So, S. S.; Mattson, A. E. “Urea Activation of !-Nitrodiazoesters: An

Organocatalytic Approach to N–H Insertion Reactions” J. Am. Chem. Soc. 2012,

134, 8798-8801

• Auvil, T. J.; So, S. S.; Mattson, A. E. “Double Arylation of Nitrodiazo

Compounds Catalyzed by a Urea/Aniline Combination” Angew. Chem. Int. Ed.

2013, 52, 11317-11320

• So, S. S.; Mattson, A. E. “Phosphoric Acid-Catalyzed Enantioselective N–H

Insertion Reactions of Nitrodiazoesters” Asian J. Org. Chem. 2014, DOI:

10.1002/ajoc.201300285

• So, S. S.; Oottikkal, S.; Badjic, J.; Hadad, C. M.; Mattson, A. E. “Urea-Catalyzed

Activation of Nitrodiazoesters for N–H Insertion Reactions” J. Org. Chem. 2014,

Submitted

2.1 Fundamental Investigations of Nitrodiazoester Reactivity

First reported by Curtius1 in 1883 and made popular by Wolff2 in 1912, the chemistry of !-diazocarbonyl compounds is well documented in the chemistry literature.3-5 However, less is known about their !-nitrodiazo counterparts. Despite

! 82 limited accounts on the chemistry of !-nitrodiazo compounds, these nitrocarbene precursors have interesting reactivity and afford valuable building blocks containing the versatile nitro group. Nitrodiazo compounds containing electron-withdrawing substituents are significantly more stable than their nitrodiazomethane counterparts and are generally easy to use and prepare, making them attractive starting materials.6

Photolysis, thermolysis, and transition metal catalysts have been utilized to access nitrocarbene reactivity from nitrodiazo compounds. Cyclopropanation reactions using nitrocarbenes derived from nitrodiazo compounds are of particular interest due to the limited methods available to synthesize nitrocyclopropanes.7 Additionally, O–H insertion reactions are known to occur as well as interesting rearrangements leading to the highly reactive acyl nitroso species.8,9

2.1.1 Cyclopropanation Reactions of Nitrodiazoesters

The first known account of nitrodiazomethane and its reactivity was reported by

Schöllkopf and Markusch,10 however, they were unable to utilize the nitrocarbene intermediate to add to olefins for cyclopropanation reactions. They originally hypothesized that successful photolysis and thermolysis of nitrodiazomethane and various other !-nitro-!-diazoester compounds would lead to formation of a proposed nitrocarbene intermediate, which could be used in cyclopropanation reactions.10-14

Instead, fragmentation products of ethyl nitrodiazoacetate II-1a, formed by decomposition of the intermediate nitrocarbene II-2, were isolated under both photolytic and thermolytic reaction conditions (Scheme 2.1a). This discovery suggested that nitrocarbenes were short-lived and that it was difficult to control their reactivity. In 1988,

O’Bannon and Dailey advanced the synthetic utility of nitrodiazo compounds by relying ! 83 on Rh2(OAc)4 to generate the nitrocarbenoid from nitrodiazomethane. They relied on the formation of this stabilized intermediate to cyclopropanate isobutylene and cyclohexene.6

a) 1969

O O h! NO2 NO2 EtO EtO N2 + NO + N2O or " + CO + CO2 N2 II-1a II-2

b) 1989

O H NO2

NO2 Rh2(OAc)4 CO Et EtO + 2

N2 II-4a II-1a II-3a 75% yield 8:1 cis:trans !

Scheme 2.1. a) Early Work Demonstrating Decomposition of Nitrodiazoesters b) Dailey’s Cyclopropanation Reactions of Nitrodiazoesters

! Dailey and O’Bannon extended this work to include the generation of carbene-type intermediates derived from nitrodiazoester II-1a to cyclopropanate styrene II-3 to obtain nitrocyclopropane carboxylate II-4 as an 8:1 mixture of cis:trans diastereomers (Scheme

2.1b).

Since the early work of Dailey and Schöllkopf, there have been several more recent reports on the synthesis of nitrocyclopropanes using nitrodiazo derivatives.

Charette and coworkers have published extensive work using Rh(II) dimers as catalysts for the diastereoselective cyclopropanation of alkenes with !-nitro-!-diazocarbonyls.15-17!

In 2003, Charette and Wurz successfully reported asymmetric cyclopropanation of styrene using ethyl nitrodiazoester II-1a and dirhodium(II) tetrakis[methyl1- oxaazetidine-4(S)-carboxylate], Rh2(4S-MEAZ)4, to afford nitrocyclopropane II-4a in

! 84 76% yield and 33% ee as a 14:86 mixture of cis:trans diastereomers (Scheme 2.2, entry

1).18 Several other catalyst, nitrodiazo compound, and alkene combinations afforded only modest enantiomeric excesses. It wasn’t until the significant discovery of Zhang and coworkers in 2008 that a reliable strategy for asymmetric cyclopropanations of nitrodiazoesters was reported.3 A screen of several cobalt-porphyrin catalyst systems led

O O R1 NO2 1 R + cat. R R NO2 N2 II-5 II-3 II-4

entry R R1 catalyst (mol %) product yield (%) cis/trans % ee

1 OEt H Rh2(4S-MEAZ)4 II-4a 76 14:86 33

2 OEt NO2 II-5 (1 mol %) II-4b 90 91:9 94 3 PMP H II-6 (0.1 mol %) II-4c 81 98:2 91

Cl Me Me Me Cl Cl Me Cl H H Cl Cl tBu O Cl N O O tBu O O Cl NH HN tBu N tBu O O O N N Co N N O O

NH tBu HN Rh Rh II-6 O O O O tBu O H H O tBu O Me Me O Me Me N N tBu Cl II-5 O O Cl Cl Cl Cl Cl Cl Cl !

Scheme 2.2. Asymmetric Cyclopropanations with Nitrodiazoesters to the utilization of cobalt porphyrin II-5, a catalyst that produced nitrocyclopropane work in this area led to Charette’s discovery of chiral Rh(II) carboxylate ligated catalysts

! 85 that created chiral pockets for the enantioselective synthesis of cis-!-nitrocyclopropane carbonyls.19 The wide scope of this reaction included the isolation of cyclopropane II-4c in 91% yield with 93% ee and a 98:2 cis:trans ratio using Rh(II) catalyst II-6 (entry 3).

The development of efficient, reliable methods for the asymmetric synthesis of nitrocyclopropane carboxylates is an important breakthrough due to the numerous applications of these carbocycles both as synthetic building blocks and as functional groups in drug targets.7,20

2.1.2 Insertion Reactions of Nitrodiazoesters

Insertion reactions utilizing nitrodiazo compounds is a relatively unexplored area of chemistry. To the best of our knowledge, a single report on insertion into the O–H

15 bond of alcohols II-7 with 5 mol % of Rh2(OAc)4 catalyst exists in the literature.

During their efforts to synthesize nitrocyclopropane carboxylates from the corresponding

O O

Rh (OAc) (5 mol %) NO2 NO2 2 4 R + OH R R1 1 CH2Cl2, 2–4 h, 20 ºC OR N2 II-1 II-7 II-8 entry R R1 product yield (%)

1 OEt H2C=CH-CH2 II-8a 84

2 OEt PhCH2 II-8b 99 3 OEt t-Bu II-8c 45 4 OEt Cylopropylmethyl II-8d 87

5 OCH2Ph H2C=CH-CH2 II-8f 92

6 OCH2Ph PhCh2 II-8g 84 7 Ph H2C=CH-CH2 II-8h 78 !

Table 2.1. Rhodium-Catalyzed O–H Insertion Reactions of Nitrodiazoesters nitrodiazo compound, Charette and coworkers reported that nitrodiazo carbonyl II-1 afforded nitro alkoxy carbonyl II-8 in good yields. Allyl and benzyl alcohols were well- ! 86 tolerated, providing 84% and 99% yields of II-8a and II-8b, respectively (Table 2.1, entries 1 and 2). Alkyl alcohols were less reactive, but tert-butanol provided 45% of the insertion product II-8c and cyclopropylmethyl alcohol provided 87% of the desired product II-8d (entries 3 and 4). This singular account represents an opportune area that has been met with little exploration.

2.1.3 Investigations of Nitrocarbene Intermediates

Several attempts to trap nitrocarbenes have been unsuccessful due to the highly reactive nature of this species. Instead, fragmentation and degradation products resulting from reaction with solvent rendered the free nitrocarbene an elusive intermediate

(Scheme 2.1a). Carbene reactivity was achieved in the ability to cyclopropanate alkenes, however, an interesting reaction with hindered alkenes provided further insight into the generation of nitrocarbenes. Dailey’s investigations of nitrocarbene II-2 generated from

Rh2(OAc)4 catalysts or thermolysis of ethyl nitrodiazoacetate II-1a led to formation of hydroxamic acid 12 when treated with 2,3-dimethyl-2-butene II-11 (Scheme 2.3a).21

With sterically hindered alkenes, the nitrocarbene intermediate cannot be controlled for cyclopropanation, even with Rh(II) catalysts to stabilize the carbenoid. Instead, the nitrocarbene II-2 is believed to form acyl nitroso species II-10, a rearrangement product of singlet nitrocarbene, which can undergo an ene reaction with hindered alkenes to form the corresponding hydroxamic acid II-12. While there are still no reports providing direct evidence for the nitrocarbene species, several groups have worked to elucidate the structure and reactivity of acyl nitroso compound 10. Dailey and O’Bannon were able to apply this knowledge to offer further evidence for formation of nitroso 10 by reacting the in-situ generated nitrocarbene II-2 with 9,10-dimethylanthracene II-13 (Scheme 2.3b). ! 87

O O- O NO2 [Rh(II)] EtO2C NO2 + EtO2C N EtO EtO2C N

N2 or ! O II-1a II-2 II-9 II-10 O

a) ene reaction Me Me O Me O H II-10+ Me Me Me EtO2C N EtO C N Me Me Me 2 Me O O II-11 H II-12

b) Diels-Alder O EtO C O Me 2 EtO C N Me 2 O N Me O II-10 + Me Me II-13 Me II-14 !

Scheme 2.3. Nitrocarbene Rearrangement to Acyl Nitroso Compounds for a) Ene Reactions and b) Diels-Alder Reactions

! Isolation of Diels-Alder adduct II-14 provided evidence that nitroso II-10 was generated in the controlled decomposition of nitrodiazoester II-Ia. Computational studies revealed that formation of II-10 from nitrocarbene II-2 occurs with no barrier of reaction, suggesting that spontaneous rearrangement was eminent without the presence of a stabilizing metal complex. A mechanism for this rearrangement was proposed to proceed through N-oxirane intermediate II-15, based on ab initio calculations (Scheme 2.4).

However, due to the lack of direct observation of a nitrocarbene intermediate, it is still unclear whether formation of the nitroso compound II-10 forms via II-2 or through a concerted mechanism not involving a carbene. N-oxirane intermediate II-15 could still be accessed by rearrangement of II-16, formed by initial intramolecular attack by the

! 88 oxygen of the nitro group. In fact, Evans and coworkers could not explicitly rule out this pathway in their investigations on acyl nitroso reactivity.9

O O N EtO O O O II-2 O O N O O EtO O N N EtO N EtO II-1a O O N O O II-15 II-10 N EtO O N N II-16 !

Scheme 2.4. Possible Routes for the Rearrangement of Nitrocarbenes to Acyl Nitroso Compounds

2.1.4 Synthesis of Nitrodiazoesters

Early reports on the isolation of nitrodiazo compounds rely on the use of dinitrogen pentoxide to nitrate diazo compounds (Scheme 2.5a).11 Recently, diazo transfer reactions have become the preferred method to access nitrodiazo compounds due to the instability and unavailability of N2O5. Common diazo transfer reagents such as tosyl azide or mesyl azide are typically low-yielding in the diazotization of nitro compounds. It was reasoned that installation of more powerful electron-withdrawing substituents on the sulfonyl azide would lead to a more active diazo transfer reagent that could provide access to a wide range of nitrodiazo carbonyls in moderate to good yields.

Specifically, trifluoromethanesulfonyl azide (TfN3) has been reported as an efficient diazo transfer reagent.22 Ethyl nitroacetate II-20 was easily converted to the diazo compound II-1a in 88% yield using TfN3 II-21 after 15 hours (Scheme 2.5b). A large

! 89 a) O O H –20 ºC N O NO2 OtBu + 2 5 OtBu N CCl4 2 II-19 N2 II-17 II-18 48%

b) O O S F C N or O O 3 3 II-21 NO2 NO2 EtO EtO N2 F F O O II-20 II-1a F3C S N3 II-18 = 88% F F F F II-19 = 83% II-22 !

Scheme 2.5. a) Nitration of Diazo Compounds b) Perfluorinated Diazo Transfer Reagents for the Synthesis of Nitrodiazo Compounds

! scope of nitrodiazo-ketones and -esters were synthesized under mild conditions at room temperature using this method. Although TfN3 offers an efficient, high-yielding synthesis of nitrodiazo carbonyl compounds, the shelf-stable, more readily accessible perfluorobutanesulfonyl azide (NfN3) was recently introduced as a diazo transfer

23 reagent. Treatment of ethyl nitroacetate with NfN3 II-22 afforded diazo II-1a in 83% yield after just 30 minutes. Both diazo transfer reagents are stable at 0º C for several weeks and provide easy access to nitrodiazo carbonyls. Nitrodiazo carbonyls are relatively easy to handle and problems due to explosivity have not been reported.

2.1.5 N–H Insertion Reactions of Diazocarbonyl Compounds

Insertion reactions of diazo compounds have secured their place as a powerful tool in the arsenal of synthetic organic bond-forming reactions.24-26 One of the earliest examples of an insertion reaction was reported by Curtius in 1888.1 Under thermal conditions, Curtius was able to decompose ethyl diazoacetate II-23 for insertion into the ! 90 a) 1888 O O H2N H ! N EtO + EtO

II-23a N2 II-24a II-25a

b) 1952 O O H2N copper bronze H N + C H C17H35 17 35

N2 II-23b II-24a II-25b !

Scheme 2.6. a) First Example of N–H Insertion by Diazo Carbonyl Compounds b) First N–H Insertion Reaction Using Catalysts for Activation of Diazo Compounds

! N–H bond of aniline II-24a (Scheme 2.6a). The impact of this novel reaction pathway wasn’t fully capitalized upon until Yates applied copper bronze as a metal catalyst to control the decomposition of ethyl diazoacetate II-23b under mild conditions.27 Insertion into aniline afforded the "-amino ester II-25b (Scheme 2.6b). This milestone in diazo chemistry sparked the interest of the chemistry community, leading to several advancements in insertion reactions.28-32 Specifically, N–H insertion reactions have garnered significant attention and remains one of the most reliable and direct methods for synthesizing nitrogen heterocycles.33 However, the elegant transformation afforded by

H2N OH OH OH H H H H H H O Rh(II) O S NH N N O N2 CO2PNB O O CO H CO2PNB 2 II-26 II-27 II-28 (+)-thienamycin !

Scheme 2.7. Merck's Synthesis of (+)-Thienamycin Using an Intramolecular N–H Insertion Reaction

N–H insertion reactions was not always appreciated. In fact, it wasn’t until Cama and

Christensen (Merck) successfully relied on a rhodium-catalyzed intramolecular insertion ! 91 of diazoketone II-26 into the N–H bond of the !-lactam moiety that the appropriate attention was garnered.34,35 Although the first intramolecular N–H insertion reaction to form azacyclobutanes was reported in 1959, Merck’s large-scale isolation of (+)- thienamycin II-28 from just a few transformations of N–H insertion product II-27 truly demonstrated the amazing utility of this methodology.

The mechanism of this type of insertion reaction is generally accepted to occur through formation of an ylide intermediate (Scheme 2.8).5,33,36 When diazo compounds of the type II-29 reacts with a metal catalyst, generation of a metal carbenoid II-30 ensues. Insertion into polar bonds such as O–H and N–H bonds forms ylide II-32 after release of the metal catalyst. This is in contrast to insertion into nonpolar bonds such as

C–H bonds, where a one-step insertion occurs through a 3-centered cyclic transition state.37 1,2-Proton shift then forms the desired insertion product II-33.

1 R R1 1 H R R1 1 R R R R 1 [M] R R R2 XH R R M X N M 2 X 2 M H R H R2 X R2 II-29 II-30a II-30b II-31 II-32 II-33 !

Scheme 2.8. Mechanism for Insertion into Polar Bonds

2.2 HBD Activation of Nitrodiazoesters

The limited accounts on nitrodiazo chemistry inspired us to investigate the use of

HBD catalysis to elicit nitrocarbene-like reactivity. In particular, the lack of methodology regarding insertion chemistry of nitrodiazo compounds led us to focus our research efforts on N–H insertion reactions. We reasoned that the mild environment

! 92 generally accompanied by organocatalytic methods would allow for controlled reactivity of nitrodiazo compounds. Our new class of enhanced HBD boronate urea catalysts had

Typical Urea Activation Modes: New Reactivity Mode: New Reactivity Mode: 1,2-Acceptor 1,4-Acceptor Nitrocyclopropanes !-Nitrodiazoester O O O O Ar Ar Ar Ar Ar Ar Ar Ar N N N N N N N N H H H H H H H H O II-35 II-34 O O O O II-36 O- O II-37 N N N 1 H R O 4 + 3 CO R N R 2 N R2 OR5 !

Scheme II-9. Urea Activation Modes already previously demonstrated the ability to activate nitrocyclopropanes for both nucleophilic ring-opening reactions as well as formal [3+3] dipolar cycloadditions (II-36,

Scheme 2.9).38,39 Due to this impressive urea:nitro group recognition, we reasoned that the nitronate resonance form of nitrodiazoester would allow for an even more significant binding to boronate ureas (II-37, Scheme 2.9). This activation of the diazo compound could grant access to carbene-like reactivity for a wide variety of reactions including N–

H insertion.

2.2.1 Anilines as N–H Insertion Partners

Our investigation into harnessing urea activation of nitrodiazoester compounds for carbene-like reactivity began with a survey of anilines for N–H insertion reactions.40

With 20 mol % of a urea catalyst, we hypothesized that ethyl nitrodiazoacetate II-1a

! 93 could insert into the N–H bond of aniline, leading to "-nitroester II-38. Upon testing this hypothesis, it became apparent that reaction with 1 equivalent of aniline yielded no

Ar O NH2 N O O O H NH NO2 NH2 2 EtO urea Ph NO2 Ph O O N EtO EtO N H Ar N HN HN EtO O N Ph Ph N II-1a 2 II-37 II-38 II-39a !

Scheme 2.10. Urea-Catalyzed N–H Insertion Reaction products, recovering only nitrodiazoacetate II-1a. This initial result was disappointing, and it was unclear whether HBD catalysis was a viable method for the activation of nitrodiazo compounds. Despite this, we continued our investigation and were pleased to find that increasing the amount of aniline to 10 equivalents in toluene at 50 °C for 36 h did afford a reaction, however none of the anticipated product II-38 was observed. Upon closer inspection of the isolated products, it became apparent that "-aryl glycine II-39a was forming instead of "-nitroester II-38 (Scheme 2.10). This interesting, albeit unexpected, result led us to reason that N–H insertion was indeed occurring, followed by loss of HNO2 addition of a second equivalent of the amine nucleophile to form aryl glycine II-39a. This was the first example of urea activation of diazo compounds for controlled N–H insertion reactions. Driven by the synthetic utility of an organocatalytic single-flask process to access "-amino-"-aryl esters, we set out to further develop this N–

H insertion/multicomponent coupling process. At 40 °C with 10 equivalents of aniline, aryl glycine II-39a was isolated in 83% yield after 24 h (Table 2.2, entry 1). Excellent yields of product were obtained even at low loadings of difluoroboronate urea catalyst II-

! 94 O NH2 NH2 O NO2 II-40a (x mol%) EtO + 40 ºC, 1 M PhMe EtO N2 II-1a II-24a HN II-39a Ph entry II-40a (mol %) time (h) yield (%) 1 20 24 83 CF3 BF2 2 10 48 94 O 3 7.5 48 77 N N CF3 4 5 72 85 H H 5 2.5 72 73 II-40a 6 -- 24 8 !

Table 2.2. Optimization of Difluoroboronate Urea-Catalyzed N–H Insertion Reaction

40a by simply extending the reaction times. For instance, a 10 mol % loading of II-40a gave rise to 94% of II-39a after 48 h (entry 2). Even reducing the catalyst loading to just

5 mol % afforded an 85% yield of product after 72 h (entry 3). In the absence of an HBD catalyst just an 8% yield of II-39a was isolated (entry 4).

A brief screen of various urea catalysts was conducted for the insertion of ethyl nitrodiazoacetate II-1a into the N–H bond of aniline II-24a followed by Friedel Crafts addition of another molecule of aniline (Table 2.3). Catalyst II-40a was found to be the most active catalyst, giving 83% of the desired product. The corresponding boronate urea catalyst II-41a, containing a pinacol ester ligand in place of the difluoride, was slightly less active, generating 61% of the desired product. Removing one electron- withdrawing substituent decreased the yield to 72% (II-40a vs. II-40b).

Difluoroboronate urea catalyst II-40c, a catalyst with no trifluoromethyl groups, was found to have similar reactivity to catalyst II-41a, producing 61% of II-39a in otherwise identical reaction conditions. Single hydrogen bond donor II-44 was moderately active, generating only 33% of glycine II-39a, suggesting that dual hydrogen bonding is

! 95 NH2 O O NH2 cat. (20 mol %) NO2 EtO + EtO PhMe, 40 ºC, 24 h N2 HN II-39a II-1a II-24a Ph

BF 2 BF2 O BF2 O O O 1 1 Ar1 2 Ar Ar Ar N N Me N N N N H H N N H H H H H H II-40a: 83% II-40b: 72% II-42: 58% II-44: 33%

Bpin Bpin BF 2 S O O O 1 1 Ar1 Ph Ar Ar N N Ar1 N N N N H H N N H H H H H H II-41a: 61% II-40c: 61% II-43: 27% II-45: 27%

Me CF3 CF3 O Me Bpin = B Ar1 = Ar2 = O Me Me CF3 !

Table 2.3. Catalyst Screen for N–H Insertion/Multicomponent Coupling Reaction essential for enhanced activity of the urea catalyst. Boronate urea II-45, a catalyst that cannot coordinate the carbonyl oxygen to the boron Lewis acid center, was expected to have low reactivity due to the decreased acidity of the urea and, accordingly, produced only 27% of the desired product. The enhanced acidity of the N–H protons due to internal Lewis acid coordination as well as the installation of electron-withdrawing aryl rings supports the reactivity trends where II-40a>II-40b>II-40c>II-44 and II-41a>II-45.

Conventional urea catalysts II-42 and II-43 were active catalysts for this reaction, however, thiourea II-43 gave low yields of the desired product (27%), most likely due to decomposition of the catalyst under the reaction conditions. Urea II-42 was found to be more reactive and afforded yields comparable to boronate ureas (58%). This demonstrates that ethyl nitrodiazoacetate II-1a is capable of activation by ureas not

! 96 containing internal Lewis acids; therefore, suggesting that hydrogen bonding interactions are important in the reaction, not Lewis acid catalysis. In our attempts to further demonstrate whether hydrogen bonding plays an essential role, we sought to synthesize

N,N-dimethylated versions of boronate urea II-40a but have so far been unsuccessful in doing so.

2.2.2 HBD-Catalyzed Three-Component Coupling.

Encouraged by the success of HBD-catalyzed additions of two equivalents of aniline to ethyl nitrodiazoacetate II-1a, we set out to extend the utility of the method by developing it into a three-component coupling reaction (Table 2.4). More specifically, the reaction of II-1a, an amine for N–H insertion and a different nucleophile would allow access to a wide range of "-amino-"-aryl esters (II-39). A survey of anilines revealed that aniline (II-24a), p-fluoroaniline (II-24b), p-anisidine (II-24c), and p-toluidine (II-

24d) were successful N–H insertion partners. At this time, the reaction is specific for primary anilines; N-substituted anilines, alkyl amines, amides, and imides were unsuccessful and yielded no insertion products. With 20 mol % of urea catalyst II-40a and aniline II-24a as the nucleophilic component, insertion into p-fluoroaniline II-24b afforded aryl glycine II-39b in 72% yield. Controlling the stoichiometry allowed for selective insertion into the N–H bond of p-fluoroaniline over aniline. Insertion into the

N–H bonds of p-anisidine II-24c and p-toluidine II-24d afforded aryl glycines II-39c and

II-39d in 78% and 70% yields, respectively. With p-fluoroaniline as the N–H insertion component, various nucleophiles were found to be acceptable reaction partners. In solvent free conditions, 2,6-dimethylaniline II-46 and 2,6-diisopropylaniline II-47 were excellent nucleophiles, affording 91% and 96% yields of glycines II-39e and II-39f, ! 97 O O X NH2 20 mol % II-40a Nuc NO2 EtO EtO + + Nuc conditions HN II-1a N2 II-39 Ar

Me i-Pr NH NH NH NH NH NH2 2 2 2 2 2

F MeO Me Me i-Pr II-24a II-24b II-24c II-24d II-46 II-47

NHMe NEt2 MeO Cl Br

N N N N H H H H II-48 II-49 II-50a II-50b II-50c II-50d

Anilines for Nucleophilic Anilines: Nucleophilic Indoles: N-H Insertion: Me NH2 NH NH2 EtO2C EtO2C EtO2C Me 40 ºC, 40 ºC, 48 h, HN HN 24 h HN 4-F-Ph 40 ºC, Ph 4-F-Ph neat 48 h II-39a: 85% II-39e: 91% II-39i: 72% NH i-Pr 2 NH NH2 EtO2C EtO2C 40 ºC, EtO2C 40 ºC, HN i-Pr HN 48 h 4-F-Ph 30 ºC, 48 h, 4-F-Ph HN OMe 72 h 4-F-Ph neat II-39j: 95% II-39b: 72% II-39f: 96% NH NH2 H N EtO C Me 2 EtO2C HN 23 ºC, EtO2C 40 ºC, 23 ºC, 4-F-Ph 48 h HN 72 h Cl 4-OMe-Ph HN 48 h, 4-F-Ph neat II-39c: 78% II-39g: 85% II-39k:58% NH NH2 NEt2 EtO2C EtO2C EtO C 2 23 ºC, HN 40 ºC, HN 72 h, 4-F-Ph 4-Me-Ph 40 ºC, HN Br 48 h 48 h 4-F-Ph neat II-39d: 70% II-39h: 87% II-39l: 68% !

Table 2.4. Substrate Scope for N–H Insertion ! 98 respectively. It is reasoned that the steric bulk of the substituents in the 2- and 6- positions slow N–H insertion, leading to higher yields of insertion into p-fluoroaniline.

Substituted amines N-methylaniline II-48 and N,N-diethylaniline II-49 were also tolerated in the reaction, affording 85% and 87% yield of the corresponding glycines II-

39g and II-39h, respectively. In addition to aniline derivatives, indoles were found to operate well as nucleophiles in the coupling reaction. For example, the urea-catalyzed insertion of II-1a into p-fluoroaniline followed by reaction with indole II-50a provided a

72% yield of II-39i after 48 hours. Electron-rich 5-methoxyindole II-50b was an excellent nucleophile in the reaction in the formation of glycine II-39j (95%), while electron-poor 5-chloroindole II-50c and 5-bromoindole II-50d afforded lower yields of the corresponding glycines (58% and 68%, respectively). This methodology benefits from a wide scope of nucleophiles, however, insertion partners are currently limited to primary anilines. Testing of alkyl amines such as piperidine and morpholine resulted in decomposition of the starting nitrodiazoester, but no insertion products were isolated.

Protected amines such as tert-butyl carbamate and p-toluenesulfonamide were unsuccessful insertion partners and the starting nitrodiazoester was isolated. Other carbon nucleophiles such as silyl ketene acetals, silyl enol ethers, and enamines were unsuccessful nucleophilic reaction partners in the 3-component coupling reaction, mostly leading to addition of the nucleophile to the terminal nitrogen of the diazo compound. In general, sterically unhindered anilines and electron-rich aryl nucleophiles are best suited for the urea-catalyzed N–H insertion/multicomponent coupling reaction of nitrodiazoesters.

! 99 2.3 Mechanistic Studies of N–H Insertion/Multicomponent Coupling Reaction

The interesting reactivity afforded by nitrodiazoesters warranted significant investigation into the mechanistic pathway of insertion reactions. Especially intriguing was the role of the urea catalyst and the mode of activation of nitrodiazoesters to elicit carbene-like reactivity. As the first example of a HBD organocatalytic N–H insertion reaction, we were curious if the reaction was indeed proceeding through a carbene type intermediate or if a different pathway of insertion was prevailing. Together with experimentally gathered evidence and computational studies carried out in collaboration with Professor Christopher Hadad, we were able to rule out several possible pathways and propose a plausible mechanistic route to the N–H insertion/multicomponent coupling for the formation of "-aryl glycines II-39.

2.3.1 Plausible Reaction Pathways

In light of the discovery of this unexpected, yet useful, urea-catalyzed multicomponent coupling of diazo compounds, the plausible reaction pathway was considered more closely. Several experimental observations collected during the substrate scope study afforded clues that offered initial direction to our mechanistic studies (Scheme 2.11).

First, direct C–H insertion was ruled out as the first step of the reaction pathway because no reaction was observed between II-1a and nucleophilic heterocycles lacking N–H bonds available for insertion, such as diethylaniline II-49 or indole II-50a, and all starting materials were easily recovered (Observation 1). Not only was II-24b, the insertion component, required for the reaction, the success of the reaction hinged on the concentration of the aniline derivative. The best yields were obtained in the presence of at least 3 equivalents of 4-fluoroaniline; anything less afforded reduced yields ! 100 (Observation 2). These experimental observations led us to reason that N–H insertion was the first bond-forming event in the reaction pathway.

Observation 1 O 20 mol % II-40a 20 mol % II-40a no reaction: no reaction: NO2 EtO recovered starting NEt recovered starting materials 2 materials N2 II-49 II-1a N II-50a H Observation 2 NH II-24b yield 2 O NH (%) O MeO 20 mol % (equiv)

NO2 II-40a EtO + + EtO 1 equiv 3 N 2 equiv 10 N H HN 2 F 4-F-Ph 3 equiv 21 OMe II-1a II-24b II-50b II-39j 5 equiv 48

Conclusion: Observation 1: Observation 2: N–H Insertion C–H Insertion Aniline is Occurs First, Does Not Occur Essential then Arylation

Scheme 2.11. Evidence for N–H Insertion

2.3.2 Plausible Urea Activation Modes for N–H Insertion Reaction

With evidence suggesting that N–H insertion is the first step in the reaction pathway, the specifics of this step were more closely considered. Reexamination of the catalyst screen allowed us to focus the results into two observations. Observation 1 of

Scheme 2.12 outlines a control experiment in which two molecules of aniline (one molecule acting as the N–H insertion partner and one molecule acting as the nucleophilic component) reacted with II-1a without a urea catalyst and afforded just 8% of the desired product II-39a: this demonstrated the importance of the urea (entry 1). Additionally, our results outlined in Observation 2 led us to determine that the boronate ureas were likely acting through hydrogen bonding and not Lewis acid interactions. The diminished, yet still moderate, activities of 3-(trifluoromethyl)phenyl difluoroboronate urea II-40b and ! 101 phenyl difluoroboronate urea II-40c imply that the boron moiety was most likely participating in internal coordination to the urea carbonyl, and not activation of the reaction substrate. We suspect that the electron-withdrawing effects of the

NH2 R O O F F NH2 B NO2 O EtO + 20 mol % EtO N2 HN N N R1 cat. Ph H H II-1a II-24a II-39a II-40a entry cat. R R1 % yield 1 ------8 Observation 1 F F B 2 II-40a CF3 CF3 83 O 3 II-40b CF3 H 72 Observation 2 N Me 4 II-40c H H 61 H 5 II-44 -- -- 33 II-44

Conclusion: Observation 2: Conclusion: Ureas Observation 1: Ureas Boronate Ureas Activate II-1a Through Urea is Essential Activate II-1a. Have Varying HB Interactions Activity

Scheme 2.12. Role of Urea Catalyst on N–H Insertion Reaction trifluoromethyl groups affect the hydrogen bond donating ability of the ureas (72% and

61% yields, entries 3 and 4, respectively), leading to slightly diminished results when compared to 3,5-bis(trifluoromethyl)phenyl difluoroboronate urea II-40a (83%, entry 2).

Not surprisingly, acetamide urea II-44, a single-hydrogen bond donor catalyst afforded just 33% of the desired product, further providing evidence that hydrogen bonding, specifically dual hydrogen bonding, was a necessary component of the boronate urea catalyst for obtaining high yields of the desired product II-40a.

! 102 2.3.3 Computational Urea-Nitrodiazoester Binding

Having established its necessity, two roles that the urea catalyst may play were hypothesized: (1) urea activation of the aniline or (2) urea activation of the nitrodiazoester. Little experimental evidence suggesting direct activation of the aniline with the urea catalyst was found. On the other hand, urea:nitrodiazoester binding was readily observed by 1H NMR spectroscopy (Figure 2.1). Given the literature precedent for urea:nitro group recognition, our own data suggesting urea:nitrodiazoester binding, and the lack of reactivity in the absence of a urea catalyst, we reasoned that coordination of the urea catalyst II-40a to ethyl nitrodiazoacetate II-1a forms complex II-37 to initiate the catalytic cycle and set out to collect additional computational and experimental data supporting this theory.

To further explore the role of urea catalysis in the activation of nitrodiazoesters, a detailed computational investigation at the B3LYP/6-311++G**//B3LYP/6-31G* level of theory was carried out on the proposed complexes of nitrodiazoester II-1a with various urea derivatives to understand the mode and strength of complexation. Out of several possible isomers of the complex considered, the most stable complex (II-37, Table 2.5) has two hydrogen bonds between the nitro group of nitrodiazoester II-1a and the urea.

The calculated energetics of the complexation show that the most stable complex II-37 is formed between the nitrodiazoester and urea II-40a, followed by pinacol ester boronate urea II-41a. The enhanced acidity of II-40a (pKa (DMSO) = 7.5) and II-41a (pKa

(DMSO) = 9.5), due to the intramolecular coordination between boron and oxygen, results in stronger hydrogen-bonded complexes with nitrodiazoester II-1a. The structural parameters of the complex II-37 with various urea derivatives are given in Table 2.5. ! 103 O O O Ar N urea EtO O H N EtO O N O N2 N O H N II-1a N II-37 Ar

II-40a II-41a F F CF3 CF3 Me Me B Bpin Bpin = O O O Me B O Me

N N CF3 N N CF3 H H H H

CF3 II-42 CF3 CF3 II-43 CF3 II-51 O O S Ph Ph N N F3C N N CF3 F3C N N CF3 H H H H H H

entry urea C=X C–N N–H H--O N–O !E !H !G

1.37 1.02 2.00 1.23 1 1.27 –9.8 –13.8 –1.5 II-40a 1.35 1.02 2.12 1.24 1.39 1.01 2.01 1.23 2 1.23 –7.0 –10.7 –0.2 II-41a 1.38 1.01 2.21 1.24 1.02 2.37 1.22 3 1.66 1.38 –3.4 –8.8 +3.3 II-43 1.02 2.15 1.25 1.01 2.06 1.26 4 1.22 1.39 –3.9 –8.2 +2.3 II-42 1.01 2.98 1.22 1.01 2.18 1.23 5 1.23 1.39 –6.4 –8.0 +1.9 II-51 1.01 2.18 1.24 aThe various bond distances of the hydrogen bonded complex is given in Å.

Table 2.5. Binding Energies and Bond Distances of Complex II-37 with Various Urea Derivatives

The shortest hydrogen bond (2.00 and 2.12 Å) is formed between nitrodiazoester II-1a and urea II-40a, followed by II-40a (2.01 and 2.21 Å). The enhanced hydrogen-bond donating ability of the urea derivative II-40a is also reflected in shorter C–N and longer

C=O bonds of the urea complex (C–N = 1.37, 1.35 Å and C=O = 1.27 Å) when compared to urea II-42 (C–N = 1.38 Å and C=O = 1.22 Å) and urea II-51 (C–N = 1.39 Å and C=O

= 1.22 Å), which are incapable of benefitting from internal coordination. X-Ray crystallography confirmed that the carbonyl bond length of urea II-40a (1.274 Å) is

! 104 indeed significantly longer than that of urea II-42 (1.221 Å) when hydrogen bonded to nitrobenzene. Thus, the analysis confirms that urea II-40a is in fact a more enhanced hydrogen bond donor in the formation of complex II-37.

2.3.4 Experimental Studies on Urea:Nitrodiazoester Binding

The interaction of nitrodiazoester II-1a with difluoroboronate urea II-40a was readily observed with 1H NMR spectroscopy (Figure 2.1). An observed shift in the N–H proton signals of the urea by 1H NMR allowed for a direct correlation to the binding affinity of difluoroboronate urea II-40a to the nitro group of nitrodiazoester II-1a. At

B) HA HB F F CF3 h B O No parameters g N N CF3 H H Current Data Parameters f O O NAME 6-59-M N EXPNO 1 O e N 2 Current Data Parameters OEt NAME 6-59-K EXPNO 1 d

entry II-1a (mM) HA (ppm) HB (ppm) Current Data Parameters NAME 6-59-I c a 0 10.3007 9.7393 EXPNO 2 b 0.98 10.3619 9.8249 No parameters b c 1.92 10.4026 9.8822 d 4.72 10.4559 9.9513 Current Data Parameters a e 11.57 10.4871 9.9910 NAME 6-59-E EXPNO 1 f 20.45 10.5152 10.0234 No parameters 10.6 10.5 10.4 10.3 10.2 10.1 10.0 9.9 9.8 ppm g 10.5446 10.0575 Scale: 0.1005 ppm/cm, 50.25 Hz/cm 42.41 h 92.67 10.5751 10.0945

Current Data Parameters NAME 6-59-A EXPNO 2 Figure 2.1. NMR Titration with Difluoroboronate Urea II-40a and Nitrodiazoester II-1a

this time, we are unable to assign protons HA and HB. Extensive 2D NMR experimentation has yielded inconclusive results and we have been unsuccessful in definitively assigning the urea N–H protons. Following the diagnostic shifts of HA and

! 105 HB upon titration of 0 to 262 equivalents of nitrodiazoester II-1a enabled the calculation

–1 –1 of an apparent experimental binding constant of 245 ± 22 M for HA and 295 ± 30 M for HB in acetone-d6. A Job plot analysis supported a 1:1 binding stoichiometry of urea

II-40a and nitrodiazoester II-1a. This apparent binding supports our hypothesis that ureas are capable of hydrogen bonding to nitrodiazoesters. Additionally, both urea protons shift upon titration with nitrodiazoester II-1a, suggesting that dual hydrogen bonding was indeed occurring. !

2.3.5 Evidence Supporting Nucleophilic Addition Pathway B

With evidence suggesting that urea-activation of nitrodiazoesters through hydrogen-bonding interactions initiates the reaction, two plausible reaction steps were considered: (1) an N–H insertion reaction pathway proceeding through a hydrogen- bonding stabilized carbene (Pathway A, Scheme 2.13) or (2) a polar reaction pathway proceeding through a nucleophilc addition of aniline to activated nitrodiazoester complex

II-37 (Pathway B). Density functional theory (DFT) calculations provided support for a preferred polar reaction pathway, as opposed to a pathway proceeding through a carbene.

This evidence was achieved through calculating the reaction energies associated with difluoroboronate urea II-40a, pinacol ester boronate urea II-41a, 3,5- bis(trifluoromethyl)phenyl thiourea II-43, 3,5-bis(trifluoromethyl)phenyl urea II-42, and unsubstituted diphenyl urea II-51 for the N–H insertion/multicomponent coupling of nitrodiazoester II-1a with two anilines. As shown in Scheme 2.13, Pathway A is proposed to proceed with loss of N2 through TS-I to form urea-stabilized nitrocarbene intermediate II-54. The N–H insertion of carbene II-54 into aniline II-24a through TS-II gives rise to zwitterionic species II-52, which forms urea-stabilized !-nitroester II-53 ! 106

Pathway B: Nucleophilic Addition R R R N O N O N O H H H O O TS-III O O O O O B N N N H R N H R N –N N H R Ar Ar EtO O 2 EtO O EtO O N N H H N II-37 II-52 HN II-53 NH2 Ar N Ar +

O Pathway A: Carbene Insertion NO2 EtO R R R

N2 A N O N O N O H II-1a H H O O O O TS-II O O N TS-I N N N H R N H R N H R EtO O –N2 EtO O EtO O N II-37 II-54 H2N II-52 N Ar

entry urea II-37 TS-I II-54 TS-II II-52 TS-III II-53 1 -- 0 32.3 32.8 -- –33.2 31.8 –54.8 2 II-40a –9.8 23.9 20.4 25.4 –49.8 21.6 –63.2 3 II-41a –7.0 24.1 20.8 25.0 –45.2 22.1 –61.8 4 II-43 –3.4 24.9 21.0 22.2 –48.0 23.0 –62.4 5 II-42 –3.9 24.6 20.4 22.9 –48.4 22.5 –62.4 6 II-51 –6.4 27.2 21.7 25.0 –43.6 25.8 –60.2

Scheme 2.13. Total Energy Differences (!E) in kcal/mol Calculated at the B3LYP/6-311++G**//B3LYP/6-31G* Level of Theory for Plausible Pathways of Urea-Catalyzed N–H Insertion/Multicomponent Coupling Reaction

! after proton transfer. With our most active urea catalyst difluoroboronate urea II-40a,

TS-I has a calculated !E of 23.9 kcal/mol. Insertion of II-54 into the N–H bond of aniline occurs with an activation barrier of 5.0 kcal/mol to generate urea complex II-52

(–49.9 kcal/mol). The carbene-free mechanism to access "-amino-"-nitroester II-53 is outlined in Pathway B. From complex II-37, nucleophilic attack by aniline forms zwitterionic species II-52, providing access to nitroester II-53 after a proton transfer.

When compared to Pathway A, TS-III has a lower activation barrier than TS-I (21.6 vs.

23.9). Although the activation barriers are close, the differential does not change. The ! 107 trend is the same, independent of method of calculation or solvation effects. Taken collectively, the experimental and computational data support the preference for polar reaction Pathway B.

Experimentally, several observations further suggested that a nucleophilic addition reaction pathway was preferred over a pathway proceeding through a carbene

(Scheme 2.14). Again, it was very interesting to observe the reliance of the reaction on the presence of aniline derivatives. In the absence of an N–H insertion partner, electron- rich aromatic rings, such as 5-methoxyindole and N,N-diethylaniline, were unable to react with II-1a and all starting materials could be recovered (C, Scheme 2.14). Efforts to cyclopropanate styrene with II-1a under the influence of urea catalysis was also met with no success and, at 30 °C after 24 h, II-1a, styrene and the difluroboronate urea II-40a were completely recovered (D). Similarly, all of our attempts at O–H insertion reactions were met with complete recovery of II-1a (E). Even any attempt at inserting into the N–

H bond of a variety of aliphatic amines produced no reaction and only decomposition of the starting diazoester was observed (F). Further evidence of the preferred reaction pathway surfaced from the lack of reactivity of II-1a combined with boronate urea II-

40a. At 23 °C, a temperature in which the title N–H insertion/arylation reaction is observed, there are no new products observed and all of II-1a is recovered (A). Heating of the same control reaction lacking an N–H insertion partner to 30 °C resulted in only slight decomposition of II-1a after 48 hours (B). Although probing the mechanism via the direct observation of a nitrocarbene intermediate would be ideal, the well-documented rearrangement of nitrocarbenes to the N-acyl nitroso species prevent study of the reaction mechanism via this method. The broad lack of reactivity in the absence of anilines, ! 108 combined with the recovery of II-1a in the presence of II-40a but no aniline, led us to reason the reaction pathway was likely proceeding through a nucleophilic addition reaction pathway and not through the formation of a carbene intermediate.

MeO

N C H no reaction 20 mol % II-40a 30 °C, PhMe

20 mol % II-40a A D Ph II-1a no reaction 23 ºC, 48 h, PhMe O 20 mol % II-40a 30 °C, PhMe NO2 EtO

N2 85% II-1a; 20 mol % II-40a B II-1a E 15% Ph OH no reaction decomposition 30 ºC, 48 h, PhMe 20 mol % II-40a 30 °C, PhMe

R NH2 F no reaction 20 mol % II-40a 30 °C, PhMe

Scheme 2.14. Evidence Suggesting Nitrocarbene is Not Accessed

2.3.6 Mechanism of Glycine Formation

With evidence suggesting a polar N–H insertion reaction pathway, our attention turned toward elucidating the reaction mechanism for the formation of observed glycine products II-39. Three different routes for the conversion of !-amino-!-nitroester II-53 to the isolated aryl glycine products II-39 were considered (Scheme 2.15a). Through

Pathway C, direct N-addition of aniline II-24a to nitroester II-53 would afford

– protonated aminal II-55 with loss of NO2 . Alternatively, through Pathway D loss of

– NO2 facilitated by the formation of iminium II-54, allows for addition of the nucleophile ! 109

a) Pathway E R O N O NH2 H –HNO2 O O EtO N N H R II-58 HN EtO O Ph II-24a II-52 H2N II-24a Ph

O O H2 NH2 N II-24a II-24a O EtO Ph EtO HN Pathway D II-54 HN Pathway D' EtO II-55 Ph Ph II-57 HN Ph II-24a Pathway C

–NO –NO2 II-24a 2 2 R PathwayNO C'

PathwayD – N O O H NH2 H O O O N N EtO Ph N H R EtO O EtO HN II-56 Ph HN HN Ph II-53 Ph II-39a

entry urea II-53 II-54 II-55 II-56 II-52 II-58 II-57 II-39 1 -- –54.8 9.9 2.5 –49.6 –33.2 –15.3 6.5 –57.9 2 II-40a –63.2 –25.1 –32.5 –55.1 –49.8 –20.8 –28.6 –63.4 3 II-41a –61.8 –13.6 –21.0 –53.5 –45.2 –19.2 –17.0 –61.8 4 II-43 –62.4 –21.3 –28.6 –54.5 –48.0 –20.1 –24.6 –62.8 5 II-42 –62.4 –21.7 –29.1 –54.5 –48.4 –20.2 –25.1 –62.8 6 II-51 –60.2 –12.2 –19.6 –53.0 –43.6 –18.7 –15.6 –61.3

b) N,N-diethylaniline No reaction; O only recovered II-53' NO2 A. 23 ºC EtO B. 40 ºC aniline No reaction; O only recovered II-53' Bn II-53' 5-methoxyindole No reaction; only recovered II-53'

Scheme 2.15. (a) Plausible Pathways for Glycine Formation (b) Model Study With "-Benzyloxy-"-Nitroester to yield II-55, which we propose is in equilibrium with iminium II-54. would allow for a

Friedel-Crafts type of addition by aniline to yield aryl glycine II-39. Lastly, carbene II- ! 110 58 could be formed from loss of HNO2 from zwitterionic intermediate II-52 (Pathway E).

In all cases, it was calculated that N-attack was preferred over Friedel-Crafts-tyupe addition of the aromatic nucleophile (Pathway D’ and Pathway C’); however, after proton transfer, aminal II-56 is energetically less stable than glycine II-39a, by 8.3 kcal/mol.

Thus, reversible formation of iminium II-54 could lead to thermodynamically stable aryl glycine II-39a. Of the three routes considered, the higher energetic state of carbene II-58

(–20.8 kcal/mol) compared to nitroester II-53 (62.3 kcal/mol) makes Pathway E unlikely.

Wen comparing the energetics of Pathway C and Pathway D, it is difficult to assign a clear preferred pathway. Both pathways seem plausible and, at this time, all of our efforts to experimentally probe the conversion of nitroester II-53 to glycine II-39a have been prevented by the apparent unstable nature of the "-amino-"-nitroester II-53; we have been unable to isolate or independently prepare this species. As a model study, we probed the reactivity of "-alkoxy-"-nitroester II-53’ as a suitable alternative to "-amino-

"-nitroester II-53 (Scheme II-15b). Subjecting II-53’ with N,N-diethylaniline and 20 mol % of urea II-40a at 23 ºC yielded no reaction and only II-53’ was recovered.

Heating the reaction mixture to 40 ºC still afforded no desired product, although slight decomposition (<10 %) of the starting material was observed. Aniline was also unsuccessful in substituting the NO2 group. We observed no formation of products of N- attack or C-attack and only the starting II-53’ was recovered. Even the more nucleophilic 5-methoxyindole did not add to the "-alkoxy-"-nitroester II-53’ at 23 ºC nor at 40 ºC. These experimental data suggest that SN2-type substitution of the nitro group

– by aryl nucleophiles in the reaction system is unlikely. Instead, loss of NO2 and

! 111 formation of an iminium type intermediate is a more feasible reaction pathway. Efforts to directly probe the mechanism of glycine formation are continuing.

2.3.7 Studies on the Role/Effects of Urea Catalysts on N–H Insertion

We have calculated the energies of transition states, intermediates, and products involved in the insertion reaction in the presence of different ureas and compared these values with the insertion reaction in the absence of a urea catalyst. The analysis of the insertion of nitrodiazoester II-1a into the N–H bond of aniline II-24a in the absence of a urea catalyst shows that the transition states and intermediates are less stable when compared to urea-catalyzed reactions. For example, zwitterion II-52 without a urea catalyst is less stable by 16.6 kcal/mol (Scheme 2.13: entry 1, –33.2 kcal/mol vs. entry 2,

–49.8 kcal/mol). Similarly, formation of nitroester II-53 is less favorable by 8.4 kcal/mol than compared with urea II-40a (–54.8 kcal/mol vs. –63.2 kcal/mol). However, the energetics of the reaction without a urea catalyst are such that it is feasible for the reaction to proceed, albeit with less efficiency. This is corroborated by the 8% yield of aryl glycine II-39a (Scheme 2.12) observed when nitrodiazoester II-1a is reacted with aniline II-24a, but without catalyst.

We were able to study the effect of the urea catalyst structure on the N–H insertion reaction of nitrodiazoester II-1a, aniline II-24a, and another equivalent of aniline II-24a for the formation of glycine II-39a (Table 2.6). Initial rate studies demonstrate that urea II-40a is capable of providing rate enhancements up to 8.4 times

–5 –1 –5 (kobs = 9.19 x 10 s ) when compared to the traditional thiourea II-43 (kobs = 1.10 x 10

–1 –5 –1 s ) and urea II-42 (kobs = 1.38 x 10 s ) in the formation of glycine II-39a (entry 1 vs.

! 112 entry 3 and entry 4). Boronate urea II-41a was found to provide the slowest rate of

–5 –1 reaction (kobs = 0.77 x 10 s ). These data are supported by our DFT calculations.

O NH2 NH2 O NO2 cat. (20 mol %) EtO + EtO N PhMe, 40 ºc, 24 h 2 HN II-39a II-1a II-24a

-5 -1 entry cat. yield (%) kobs x 10 , s 1 II-40a 83 9.19 2 II-41a 61 0.77 3 II-43 27 1.10 4 II-42 58 1.38

Table 2.6. Initial Rate Studies of Urea Derivatives on N–H Insertion

Among the urea derivatives, the most stable nucleophilic addition intermediate II-53 is generated in the the presence of urea derivative II-40a, which forms the strongest hydrogen-bonded complex II-37 with nitrodiazoester II-1a. In the multicomponent coupling of two molecules of aniline II-24a with nitrodiazoester II-1a, the formation of glycine II-39a is most stabilized (–63.4 kcal/mol, Scheme 2.12, entry 2) in the presence of urea II-40a. Boronate urea II-41a provided the highest yield of the N–H insertion product II-39a (83%), followed by boronate urea II-41a (61%), urea II-42 (58%), and thiourea II-43 (27%). Contradictory to the experimentally isolated low yield of glycine product II-39a observed with thiourea II-43, calculated energetics for the reaction with thiourea II-43 does not show markedly less stable intermediates or transition states compared to other urea derivatives. The decomposition of the catalyst under the reaction

! 113 conditions could be a possible explanation for the low yield of N–H inserted product in the case of thiourea II-43.

2.4 Urea-Catalyzed Double Arylation Reactions of Ethyl Nitrodiazoacetate

The new reactivity afforded by enhanced HBD boronate urea catalysts prompted further exploration of the activation of nitrodiazoesters. After closer inspection of the reaction mechanism, we became interested in further manipulation of the glycine formation step. In particular, we asked the following question: “If aminal II-56 could equilibrate to II-39a by releasing aniline II-24a and forming iminium II-54, could an analogous equilibrium occur to form double arylation product II-61 (Scheme 2.16)?” If the equilibrium did in fact occur, we hoped to capitalize on this process to add a second nucleophile to the system to form unsymmetric diaryl esters. Having already previously

Glycine Formation

NH2 O O O H II-24a II-24a N EtO Ph EtO EtO HN HN HN II-56 Ph II-54 Ph Ph II-39a

NH2 Double Arylation Product O

NH2 NH2 EtO O O II-24a II-24a EtO EtO II-60 HN II-39a Ph II-59 NH2 !

Scheme 2.16. Possible Equilibria For Glycine Formation and Double Arylation established that direct arylation of nitrodiazoester II-1a does not occur, the overall transformation of nitrodiazoester II-1a to doubly arylated ester II-60 would then occur

! 114 through a transient N–H insertion intermediate. In this way, we hoped to use aniline as a carbene activator. That is, both a urea HBD catalyst and an N–H insertion partner would work in tandem to effect this cascade41-48 transformation.!

2.4.1 Background on Unsymmetric Diaryl Ester Formation

"-Arylation reactions of carbonyl compounds have been of considerable interest to the chemistry community.49-51 The construction of these privileged structures52-55 has classically relied on radical reactions, stoichiometric amounts of metal reagents, and dianion coupling reactions that focused on formation of the acyl bond (Figure 2.2a).56

However, the limited scope and harsh reaction conditions of many of these reactions made them impractical for the broad synthesis of "-aryl carbonyl compounds. It wasn’t

a) c) II-67 O O O R1 Ar X 1 Ar [L M0] Ar R + OR RO n OR 1 II-63 Ar II-66 II-61 R II-62 II-63 X O LnM R1 O RO II-68 Ar b) O Ar LnM Ar + R1 OR Ar OR II-70 1 II-64 R OM II-65 II-63 R1 RO II-69 !

Figure 2.2. a) Acyl Bond Formation To Access Aryl Esters b) Direct "-Arylation to Access Aryl Esters c) General Catalytic Cycle for Aryl Coupling Reactions

! until the late 1990s that reliable cross coupling methodology was developed, shifting focus to direct arylation of the "#position of the carbonyl (Figure 2.2b).51,57-59 While the

! 115 intramolecular "-arylation reaction of ketones was reported as early as 1973 by

Semmelhack and coworkers, the intermolecular "-arylation of ketones wasn’t discovered until Miura,60 Buchwald,61 and Hartwig62 independently reported this transformation in

1997. Relying mostly on transition metals and preformed enolates, the general catalytic cycle begins with oxidative insertion into the aryl–halide bond of II-67, followed by transmetalation with the enolate II-69 and reductive elimination to form desired "-aryl ester I-63 (Figure 2.2c). Despite this breakthrough in arylation reactions, efficient methods for the synthesis of diarylated esters had yet to be reported. In fact, double arylation of the same aryl group was an undesired side reaction during the mono arylation reaction of carbonyl compounds. Further development of this methodology is required for the reliable addition of two different aryl groups to the ester moiety.

The arylation of esters was considerably more difficult than their ketone counterparts for several reasons. The lower reactivity and sensitivity to base made the development of this methodology more difficult. Ester enolates were prone to Claisen reactions, a competing pathway that was minimized by use of hindered ester materials and always in large excess. However, in 2001, Buchwald and Moradi were able to effect

63 arylation of esters by relying on bulky electron-rich phosphine ligands and Pd(OAc)2.

A typical example is shown in Scheme 2.17a. Efficient arylation of ester II-67 with naphthyl bromide II-68a led to the formation of !-aryl ester II-72 in 83% yield.

Arylation of !-amino ester derivatives was achieved by Hartwig and coworkers in 2003.64

Relying on 5 mol % of Pd(OAc)2 and 5 mol % of Q-Phos ligand II-76, tetra-substituted ester II-75 was isolated in 85% yield (Scheme 2.17b). To circumvent the need for

! 116 a) 3.0 mol % Pd(dba)2 O Br 6.3 mol % II-73 O + PCy2 Et OEt OtBu 2.5 equiv LiHMDS NMe2 PhMe, RT, –80 ºC Et II-67 II-68a 83% II-72 II-73

b) O MeO PtBu2 Br 5 mol % Pd(OAc)2, Me O Ph Fe Ph O + 5 mol % QPhos, N MeO O Ph Ph 3.3 equiv K2CO3 Me Ph Ph 80 ºC II-75 N II-74 II-68b 85% Ph II-76: Q-Phos

c) O MeO2C Br 1 mol % Pd(dba) O Me 2 OtBu + 1 mol % Q-Phos OtBu ZnBr!THF MeO2C II-78 THF, RT Me II-77 II-68c 87% !

Scheme 2.17. a) Buchwald’s Arylation of Ester Enolates Using Electron-Rich Phosphines b) Hartwig’s Arylation of "- Amino Esters c) Hartwig’s Arylation with Mild Zinc Reagents

! strongly basic conditions, Hartwig and coworkers relied on zinc enolates (II-77) to undergo arylation coupling reactions with just 1 mol % of Pd(dba)2 and 1 mol % of Q-

Phos (Scheme 2.17c).65 Despite these significant advances in coupling reactions to form

!-aryl esters, a simple, broad method for the unsymmetric double arylation of esters has yet to be uncovered.!

2.4.2 Activation of Aryl Glycines for Exchange Reactions

Investigation into the equilibrium process outlined in Scheme II-16 began with step-wise consideration of the total reaction sequence. We first needed to establish that glycine II-39a could lose aniline to form an extended iminium species like II-59 for a second nucleophile to add. With aryl glycine II-39b and 10 mol % of difluoroboronate urea II-40a, 91% of the exchange product II-79a was isolated after 24 h at 60 ºC in toluene (Table 2.7, entry 1).66 Changing the solvent to 1,2-dichloroethane slightly ! 117 NH2 O NH2 O xx mol % cat. EtO EtO + HN Me Me conditions II-79a NH 2 Me Me F II-39b II-46 NH2

entry cat. mol % solvent temp. (ºC) t (h) yield (%) 1 II-40a 10 PhMe 60 24 91 2 II-40a 10 DCE 60 24 95 3 II-40a 10 DCE 40 24 69 4 II-40a 10 DCE 23 48 27 5 II-40a 10 DCE 60 12 75 6 II-40a 5 DCE 60 24 39 7 II-40a 5 DCE 60 48 92 8 II-40a 2.5 DCE 60 48 82 9 II-40a 0 DCE 60 24 0 10 II-41a 10 DCE 60 24 23 11 II-42 10 DCE 60 24 79 12 II-80 10 DCE 60 24 69 13 II-81 10 DCE 60 24 34

O O P Si O OH HO OH II-80 II-81 !

Table II-7. Optimization of Glycine Exchange for Formation of Diaryl Esters increased the yield to 95% (entry 2). Decreasing the temperature to 40 ºC afforded lower yields (69%), while further cooling to 23 ºC yielded only 27% of the desired adduct after

48 h (entries 3 and 4). Reducing the reaction time to 12 h afforded the diarylated ester in

75% yield (entry 5). A catalyst loading study revealed that even 2.5 mol % of II-40a afforded 82 % yield of the desired product after 48 h (entry 8). A brief survey of HBD catalysts confirmed that hydrogen bond interactions catalyzed the exchange reaction.

! 118 While boronate urea pinacol ester II-41a and silane diol II-81 afforded low yields (23% and 34%, entries 10 and 13, respectively), urea II-42 and phosphoric acid II-81 were respectably active catalysts (79% and 69%, entries 11 and 12, respectively). Notably, no exchange occurred in the absence of a catalyst (entry 9).

2.4.3 Optimization of Carbene Activator for Formation of Transient N–H Insertion

Intermediate

With confirmation that aryl glycines II-39 could be activated by urea catalysts to lose N-bound aniline and add a different aryl nucleophile, we set out to develop a one-pot cascade reaction utilizing an aniline/urea cocatalyst system. Under reaction conditions previously optimized for N–H insertion, 20 mol % of difluoroboronate urea II-40a, an aniline activator, and 5-methoxyindole was added in Step 1. In Step 2, 5-bromoindole and more urea catalyst was added to afford diarylated ester II-82. A survey of aniline activators revealed that p-fluoroaniline II-24b was the most effective in forming the transient N–H insertion intermediate followed by p-anisidine and p-toluidine (77%, 71%,

46%; entries 1, 2, and 3, respectively, Table 2.8). 2,6-Dimethylaniline did not act as an activator of nitrodiazoester II-1a, affording none of the desired product, most likely due to the steric hindrance of the methyl groups in the ortho positions that prevent N–H insertion. Importantly, in the absence of an aniline activator, none of the desired product

II-82 was isolated (entry 5). This suggests that the transient formation of the N–H insertion product was essential for the double arylation reaction mechanism. When all reagents were added in one step, only 20 % of the desired product was isolated along with a mixture of addition products (entry 6). Once the appropriate conditions for Step 1 were established, we turned our attention toward testing the limits of Step 2. After 48 h, ! 119 Single-Flask Step 1 Step 2 H N O MeO Br O

NO2 EtO EtO N N H H OMe N2 X mol % II-40a, X mol % II-40a Br II-1a 40 ºC, activator N II-82k

Step 1 Step 2 entry mol % activator t (h) mol % solvent t (h) temp. (°C) yield (%)

1a 20 p-fluoroaniline 72 20 -- 24 60 77 2a 20 p-anisidine 72 20 -- 24 60 71 3a 20 p-toluidine 72 20 -- 24 60 46 4a 20 2,6-dimethylaniline 72 20 -- 24 60 0 5a 20 -- 72 20 -- 24 60 0 6b 20 p-fluoroaniline 72 ------20 7c 20 p-fluoroaniline 48 10 DCE 24 60 90 8c 20 p-fluoroaniline 48 -- DCE 24 60 71 9c -- p-fluoroaniline 48 10 DCE 24 60 11 10d 20 p-fluoroaniline 48 10 DCE 24 60 48

aReactions run in toluene (1 M); bAll reagents added in one step cReactions run without solvent; c1.5 equiv p-ﬂuoroaniline !

Table 2.8. Optimization of Carbene Activator for Double Arylation Reaction under solvent free conditions, with p-fluoroaniline and 20 mol % of II-40a as the optimized cocatalyst, an additional 10 mol % of the urea catalyst II-40a and 5- bromoindole were added with 1,2-dichloroethane as the solvent. After 24 h at 60 ºC, an excellent 90 % yield of ester II-82 was isolated (entry 7). When no additional urea catalyst was added, a moderate 71% yield of the double arylation product was formed

(entry 8). The 11% yield of II-82 formed when no catalyst was added is attributed to the background rate of N–H insertion; all the aryl glycine formed in Step 1 was arylated in

Step 2 with 10 mol % of difluoroboronate urea II-40a (entry 9). When the aniline ! 120 activator loading was reduced to 1.5 equiv, a reduced 48% yield was isolated (entry 10).

Attempts to make the reaction catalytic with respect to the aniline activator were unsuccessful due to the cross arylation that occurred when more than one nucleophile was present in the reaction system.

2.4.4 Substrate Scope of Double Arylation Reaction

With the optimized reaction conditions in hand, including difluoroboronate urea catalyst II-40a and p-fluoroaniline activator II-24b, we were able to apply the double arylation methodology to the synthesis of a broad scope of diaryl esters II-82 (Table 2.9).

With aniline II-24a as the first nucleophile, a variety of anilines were tolerated as the second nucleophile. 2,6-Dimethylaniline, 2,6-diisopropylaniline, N,N-diethylaniline, and

N-methylaniline afforded the corresponding esters II-82a (91%), II-82b (87%), II-82c

(94%), and II-82d (99%) yields, without competing nitrogen attack. Electron-deficient nucleophile o-iodoaniline afforded only modest yields of ester II-82d while electron-rich

3,5-dimethoxyaniline afforded an excellent 98% yield of II-82f. This suggests that the electronic nature of the nucleophile is important for activity. Knowing that electron-rich aryl nucleophiles afforded high yields of the desired products, we suspected indoles would be active reaction partners for double arylation. Indole, 5-methoxyindole, and N- methylindole aryl nucleophiles efficiently afforded the corresponding "-indoyl-"-aryl esters II-82g-j (86%-98% yields). Bisindoyl esters II-82k-o were also readily formed using this methodology (75%-97% yields). Through step-wise addition of the reagent, the double arylation of nitrodiazoester II-1a occurred with relative ease and reliability with a wide variety of aniline and indole nucleophiles.

! 121 O 2 1 R O R 1 O 20 mol % II-40a R EtO NO p-ﬂuoroaniline 10 mol % II-40a EtO 2 + R1 EtO HN 40 ºC, 48 h DCE, 60 ºC, 24 h N2 II-82 II-1a F 2 II-39 R

NH2 NH2 NH2 NH2 NH2 O O O O O

EtO EtO EtO EtO EtO

II-82a II-82b II-82c II-82d II-82e Me Me 91% iPr iPr 87% 94% 99% I 56%

NH2 NHMe NEt2 NHMe NH2 122

NH2 NEt2 NH2 NH2 NH2 O O O O O

EtO EtO EtO EtO EtO II-82g II-82h II-82i II-82j MeO OMe 86% 96% 95% 98% II-82f OMe 98% N HN HN N Me Me NH2

H NH NH NH NH N O O O O O EtO EtO EtO EtO EtO

Br Br OMe Br OMe N HN HN N HN Me Me II-82k II-82l II-82m II-82n II-82o 86% 92% 75% 97% 97% !

Table 2.9. Substrate Scope for Urea-Catalyzed Transient N–H Insertion/Double Arylation Reaction 2.4.5 Mechanistic Considerations of Transient N–H Insertion/Double Arylation

The two step double arylation cascade reaction of nitrodiazoester II-1a occurs through a transient N–H insertion that has already been mechanistically studied. After formation of the aryl glycine, DFT calculations suggest that the urea catalyst hydrogen bonds to the ester carbonyl and the amine. This hydrogen bonding facilitates loss of aniline, allowing 5-bromoindole to add. This process is thought to occur in one of two possible pathways (Scheme 2.18). In Pathway A, an SN2-type nucleophilic attack of 5- bromoindole to release p-fluoroaniline affords the desired diaryl ester II-82k. In

Pathway B, formation of iminium II-84 facilitates loss of p-fluoroaniline, allowing for 5- bromoindole to attack. In order to determine the possible mechanistic route, enantioenriched II-32j (52% ee) was subjected to the reaction conditions. Diaryl ester II-

82k was isolated as a racemic mixture with no enantiomeric enrichment. When comparing the pathways, a direct displacement mechanism would result in inversion of stereochemistry but retention of enantiomeric excess, while formation of an iminium would result in racemization. The racemic diaryl ester suggested that an iminium intermediate (Pathway B) was likely dominating. However, it was still possible that an

SN2-type reaction (Pathway A) was occurring if racemization of the glycine occurred before reaction with 5-bromoindole. In order to determine whether the loss of enantiomeric excess was stemming from a) racemization of the glycine or b) formation of a planar intermediate, we subjected enantioenriched II-82k to the reaction conditions in the absence of the 5-bromoindole nucleophile. Isolation of the racemic glycine suggested to us that deprotonation of the relatively acidic "-proton and reprotonation could be responsible for the loss of ee. Alternatively, the presence of the urea catalyst could ! 123 Br H N N O H

EtO

Pathway A OMe Br H HN N NH O OEt II-82k Step 2 EtO O 0% ee H HN OMe R HN N H OMe N F F O R II-32j Br 52% ee Pathway B NH O N H EtO II-84 OMe

Scheme 2.18. Possible Pathways for Urea Catalyzed Arylation of Aryl Glycines facilitate loss of p-fluoroaniline by formation of iminium II-84. p-Fluoroaniline could then re-attack the planar intermediate, resulting in racemization. From our experimental evidence, it is unclear which of these racemization pathways is dominating.

2.5 Chiral Phosphoric Acid Catalysts for Stereoselective N–H Insertion Reactions

Due to the widespread prevalence and importance of aryl glycines in many natural products and drug targets,67-70 there is a perpetual need for improved, efficient, and stereoselective methods for the preparation of aryl glycines.71-77 For example, since the discovery of vancomycin, many aryl glycine containing glycopeptides such as oritavancin, dalbavancin, and telavancin, have been identified as potent antibiotics. The urea-catalyzed N–H insertion/multicomponent coupling of nitrodiazoesters has proven to be a reliable method for the construction of the aryl glycine nucleus, however, stereoselective insertion reactions have so far been unsuccessful with urea catalysts. ! 124 With the indisputable success of phosphoric acids as hydrogen bond donors, we turned our attention toward applying phosphoric acid catalysts in the activation of nitrodiazoesters.

2.5.1 Background on Phosphoric Acid Catalysis

While ureas and phosphoric acids are both well-known HBD catalysts, their acidities and modes of action differ significantly and, at the onset of our studies, it was unclear if phosphoric acid derivatives would be capable of catalyzing reactions of nitrodiazo compounds. Our interest in exploring phosphoric acid-catalyzed glycine formation from II-1a was two-fold. First, prior to our investigations, phosphoric acid- derived catalysis had not been capitalized on for reactions of nitrodiazo compounds. In fact, several reports on the use of phosphoric acids as cocatalysts with transition metal catalysts indicates that phosphoric acids were specifically demonstrated not to activate diazo compounds (vide infra). Second, we reasoned that chiral phosphoric acids may enable us to control the stereochemical outcome of the multicomponent coupling, thus affording access to enantioenriched aryl glycines II-39. To assess the potential of phosphoric acid catalyzed multicomponent coupling reactions of II-1a, we initiated studies probing the addition of p-fluoroaniline and 5-methoxyindole to II-1a under the influence of a catalytic amount of racemic II-80.

Phosphoric acids have been extensively used to promote organocatalytic transformations since their introduction in 2004 by both the Terada and Akiyama groups.41,78-83 As an extension to the already established Brønsted acid catalysis afforded by ureas and thioureas, Terada and Uraguchi introduced a new family of chiral phosphoric acids found to catalyze the Mannich reaction of N-Boc-protected imine II-86 ! 125 and acetyl acetone II-87 (Scheme 2.19a).84 After optimization, excellent yields and enantiomeric excesses were obtained of the !-aminoketone II-88 with 4-biphenyl substituted phosphoric acid II-85a. Simultaneously, Akiyama and coworkers published their results on the Mannich-type reaction of aldimine II-89 with silyl ketene acetal II-90

(Scheme 2.19b).85 Using a similar BINOL-derived chiral backbone, they were able to isolate Mannich product II-91 in quantitative yield, with excellent syn:anti selectivity and enantioselectivity with phosphoric acid II-85b, substituted with 4-nitrophenyl in the 3- and 3’-positions. a) 2 mol % Boc Boc N O O II-85a NH II-88 R + Ac Me Me CH Cl Ph 88% yield, Ph H 2 2 90% ee rt, 1 h O II-86 II-87 Ac O P O OH b) HO HO

OTMS 10 mol % II-91 R II-85b N H HN 100% yield II-85a: R = 4-biphenyl OEt CO2Et 87:13 syn:anti II-85b: R = 4-NO2C6H4 Ph H + PhMe, 24 h Me –78 ºC Ph 96% ee II-89 II-90 Me !

Scheme 2.19. a) Terada’s Chiral Phosphoric Acid for Addition to Imines b) Akiyama’s Chiral Phosphoric Acid Catalyzed Addition of Silyl Ketene Acetals to Imines

! Following the introductory reports on chiral phosphoric acid catalysis and their activation of imines for hydrophosphonylation reactions, cycloadditions, transfer hydrogenation, and Friedel-Crafts reactions, phosphoric acids were also found to be effective activating agents for various functional groups in the presence of diazo compounds. Terada and coworkers used BINOL-based phosphoric acid II-85c to catalyze the addition of ethyl diazoacetate II-23a to imine II-92 (Scheme 2.20).86

! 126 Ph R O HN O O O EtO2C H 2 mol % II-85c N Ph EtO2C P + Ph rt, 5 h O OH N2 Ph H N2 II-23a II-92 II-93 R 59%, 90% ee II-85c: R = 9-phenanthrenyl !

Scheme 2.20. Phosphoric Acid Activation of Imines for Diazo Addition

Deprotonation reforms the diazo moiety to afford "-amino diazoester II-93 in 59% yield and 90% ee. Although the phosphoric acid catalyst features a Lewis basic phosphoryl oxygen, it is unclear whether deprotonation is occurring by the catalyst or a different

Lewis basic atom in the reaction. It should be noted that the phosphoric acid catalyst was compatible with diazo functionalities; that is, the phosphoric acid did not decompose the diazoester II-23a nor did it activate the diazo for further reaction. In 2008, Hu and coworkers reported the use of chiral phosphoric acid catalysts for the multicomponent

87 reaction of diazo compounds, an O–H insertion partner, and imines. With Rh2OAc4 to catalyze the insertion of diazoester II-94 into the O–H bond of 9-anthracenyl alcohol II-

95, phosphoric acid II-85d directed attack of the resultant ylide to the imine II-96. This effective strategy resulted in multicomponent coupling product II-97 in 95% yield with excellent stereocontrol (92% ee, Scheme 2.21a). In a direct extension of this work, Hu and coworkers reported the multicomponent coupling reaction of diazo compounds, a C–

H insertion partner, and imines. Surprisingly, rhodium dimer catalysts only led to pyrrole

C–H insertion products. However, screening several transition metal catalysts led to the

3 discovery that [PdCl(! -C3H5)2] was effective in forming a C–H insertion zwitterionic intermediate for trapping with chiral phosphoric acid activated imine II-96 (Scheme 2.

! 127 a) 2 mol % Ph Ph OCH2Ar Rh2(OAc)4 MeO2C Ph N CO2Me + + Ar OH 5 mol % PhHN Ph R N2 Ph H II-85d, 95% yield II-94 II-95 II-96 CH Cl , 0 ºC II-97 Ar = 9-anthryl 2 2 92% ee O O P b) 5 mol % O OH 3 PhHN CO2Me MeO C Ph Ph [{PdCl(! -C3H5)}2] 2 N + 10 mol % II-85d Ph R + Ph N II-85d: R = 2,4,6-iPr3C6H2 2 N Ph H H 5 mol % HN II-94 II-98 II-96 L-tartaric acid II-9954% –20 ºC, THF 5:95 syn:anti 98% ee !

Scheme 2.21. a) Activation of Imines for Addition of O–H Insertion Ylide of Diazoesters b) Activation of Imines for Addition of C–H Insertion Ylide of Diazoesters

! 21b). Relying on TRIP-BINOL based phosphoric acid II-85d as a cocatalyst, multicomponent coupling product II-97 was isolated in 54% yield as a 5:95 mixture of syn:anti diastereomers in 98% ee. It was essential that 5 mol % of L-tartaric acid was added to the reaction mixture, although it is unclear what the role of the acid additive is in obtaining high yields of the desired product.88

In addition to the use of phosphoric acids as cocatalysts for the activation of imines for transition metal catalyzed diazo coupling reactions, chiral phosphoric acids have also been used in limited accounts as catalysts for enantioselective protonations.

With diazoester II-94, Hu and coworkers relied on 1 mol % of [Rh2(TPA)4] to catalyze

N–H insertion into II-100, leading to an ylide intermediate that was selectively protonated by spiroindane phosphoric acid catalyst II-101.89 "-Amino ester II-102 was formed in excellent yield and enantioselectivity (94% yield, 92% ee, Scheme 2.22) after just 1 minute of reaction time. The use of chiral dirhodium catalysts provided only low to modest enantioselectivities. Again, this report demonstrates that phosphoric acids do

! 128 not act as catalysts in the insertion reactions of diazo compounds, however there have been accounts of phosphoric acids acting as reaction partners.33

R NHBoc O MeO C Ph 1 mol % [Rh2(TPA)4] 2 OMe O P + BocNH 1 mol % II-101 OH 2 Ph O N2 O R CHCl3, 25 ºC II-94 II-100 1 min II-102 94%, 92% ee II-101: R = 2-naphthyl !

Scheme 2.22. SPINOL Phosphoric Acid for Enantioselective Protonation After Rhodium Catalyzed N–H Insertion

2.5.3 Optimization of Phosphoric Acid Catalyzed N–H Insertion/Multicomponent

Coupling

Chiral phosphoric acids have been demonstrated to operate as excellent HBD catalysts for the activation of imines in the presence of diazoesters. However, no such activation of the diazoester moiety itself has been reported, thus we set out to study the possible activation of nitrodiazo compounds for N–H insertion reactions. Early into our investigations, we were delighted to find racemic BINOL-derived phosphoric acid II-80 catalyzed the insertion/multicomponent coupling of II-1a with p-fluoroaniline II-24b and

5-methoxyindole II-50b to afford II-39j in 62% yield after 24 h at 40 ºC, (Table 2.10, entry 1). The modest yield of II-39j at slightly elevated temperatures (40 ºC) was largely due to the formation of ethyl-2,2-bis(5-methoxy-1H-indol-3-yl)acetate II-103, the product of equivalents of 5-methoxyindole adding to II-1a, in 26% yield. Experimental evidence suggests double arylation product II-103 is formed via a second arylation of II-

! 129 39j, not the direct addition of two equivalents of 5-methoxyindole to II-1a (Scheme 2.23,

Control Reaction 1). The undesired double arylation was minimized by reducing the

O NH O NH2 O O NO2 EtO EtO + II-80 P HN O OH N2 F conditions R II-1a II-24b II-80 II-39 F (±) entry time (h) temp (ºC) mol % solvent Nu prod yield (%) 1 24 40 20 PhMe II-50b II-39j 62 2 48 23 20 PhMe II-50b II-39j 95 3 48 23 20 DCE II-50b II-39j 63 4 48 23 20 MTBE II-50b II-39j 71 5 48 23 20 THF II-50b II-39j 78 6 48 23 10 PhMe II-50b II-39j 61 7 72 23 50 PhMe II-50b II-39j 62 8 48 23 0 PhMe II-50b II-39j 13 9 48 23 20 PhMe II-50b II-39j 69 10 48 23 20 PhMe II-50a II-39i 95 11 48 23 20 PhMe II-50d II-39l 37 !

Table 2.10. Optimization of Phosphoric Acid Catalyzed N–H Insertion/Multicomponent Coupling reaction temperature: excellent yields of II-39j were obtained after 48 h in 1 M toluene at

23 ºC (95%, entry 2). A solvent screen confirmed toluene as the optimal solvent. Lower yields of II-39j were isolated if the reactions were conducted in ethereal or halogenated solvents (entries 3-5). The loadings of catalyst (±)-II-80 could be reduced, however, longer reaction times were required to achieve high yields. For example, after 48 h, 10 mol % of (±)-II-80 gave rise to glycine II-39j in 61% yield (entry 6). Just 5 mol % of

(±)-II-80 provided a 62% yield of II-39j after 72 h (entry 7). In the absence of a phosphoric acid catalyst, just 13 % of N–H insertion/multicomponent coupling product

! 130 H Control Reaction 1 N O O MeO EtO II-103 NO2 20 mol % II-80 EtO + 0 % yield OMe N N 40 ºC, 48 h 2 H OMe II-1a II-50b HN !

Scheme 2.23. Control Reaction Demonstration Direct Arylation Does Not Occur

II-39j was formed (entry 8). The reaction was found to accommodate a variety of N–H insertion partners and aryl nucleophiles. For instance, product II-39m was isolated in high yield from the coupling of II-1a, p-anisidine II-24c and 5-methoxyindole II-50

(96% yield, entry 9). Facilitated by 20 mol % of (±)-II-80, p-fluoroaniline and indole formed glycine II-39i in a moderate 69% yield (entry 10). Less electron-rich arylating agents resulted in lower yields. Nucleophilic reaction partner 5-bromoindole gave rise to

37% of II-39l after 48 h at 23 ºC (entry 11).

2.5.4 Optimization and Scope of Stereoselective N–H Insertion/Multicomponent

Coupling Reaction

With a phosphoric acid-catalyzed synthesis of racemic II-39j established, we became curious if an enantiopure catalyst could control the absolute stereochemistry of glycines II-39. Our inspiration was embedded in the great success of chiral phosphoric acid catalysis. Although there were concerns regarding the sensitivity of glycines II-39 to racemization, we remained optimistic that the mild reaction conditions identified in Table

2.10 would provide the ideal environment for administering enantiocontrol. A survey of chiral phosphoric catalysts found that select BINOL-based catalysts provided the most promising results. For example, after 72 h at 0 ºC in 1 M toluene, 20 mol % of phenyl substituted phosphoric acid catalyst II-85e provided desired glycine II-39j in 55% yield ! 131 and a low, but encouraging, 6% enantiomeric excess (Table 2.11, entry 1). Further catalyst exploration found a slight increase in enantiomeric excess (10% ee) with 1-

O NH MeO 20 mol % NH2 cat. EtO * II-1a + + N 0 °C HN F H OMe II-24b II-50b (+)-II-39j F

catalyst: Ph Ph R II-85e: R = Ph II-85f: R = 1-naphthyl O O II-85a: R = 4-biphenyl P O O OH II-85g: R = 3,5-(CF3)2C6H3 O II-85c: R = 9-phenanthrenyl P II-85h: R = 9-anthracenyl HO O R II-104 entry cat. solvent (M) er yield (%) 1 II-85e PhMe 1 53:47 55 2 II-85f PhMe 1 55:45 42 3 II-85a PhMe 1 52:48 25 4 II-85g PhMe 1 50:50 48 5 II-85c PhMe 1 62:38 40 6 II-85h PhMe 1 56:44 36 7 II-104 PhMe 1 50:50 30

8 II-85c CH2Cl2 1 62:38 50 9 II-85c CH3CN 1 55:45 10 10 II-85c CPME 1 63:37 51 11 II-85c MTBE 0.5 70:30 49 12 II-85c MTBE 0.25 76:24 24

Table 2.11. Optimization of Stereoselective N–H Insertion/Multicomponent Coupling naphthyl substituted catalyst II-85f, while catalysts II-85a and II-85g provided poor enantiomeric enrichment (entries 3-5). The effect of catalyst structure on stereocontrol became evident when 9-phenanthrenyl substituted phosphoric acid II-85c afforded glycine II-39j in 40% yield with 62:38 er (entry 6). The BINOL-backbone was essential for achieving the best stereocontrol in this study as VAPOL-derived catalyst II-104 ! 132 resulted in no enantiomeric excess (entry 7). With phenanthrenyl phosphoric acid II-85c identified as the choice catalyst in this study, the reaction conditions were further optimized; both solvent and concentration dramatically affected the outcome of the reaction. Dichloromethane, acetonitrile and cyclopentyl methyl ether (CPME) provided modest enantioselectivities (24-28% ee, entries 8-10). Methyl tert-butyl ether (MTBE) was found to be the optimal solvent providing up to 52% ee of II-39j at a concentration of 0.25 M under the influence of 20 mol % of catalyst II-85c (entry 12).

In order to test if glycine II-39j was sensitive to racemization, leading to low isolated enantiomeric excess, we subjected enantioenriched II-39j (20% ee) to the reaction conditions with 20 mol % of racemic phosphoric acid II-80 (Scheme 2.24,

Control Reaction 2). Isolation of II-39j with retention of enantioenrichment (20% ee) suggested that the glycines formed did not racemize. A second control experiment

Control Reaction 2

O NH O NH

NH2 EtO 20 mol % II-80 EtO + HN HN F 0.5 M MTBE OMe 0 ºC, 120 h OMe F II-24b F (+)-II-39j (+)-II-39j 20% ee 20 % ee Control Reaction 3 NH O NH O

NH2 EtO 20 mol % II-85c EtO + HN HN F 0.5 M MTBE OMe OMe II-24b 0 ºC, 120 h F F (±)-II-39j (±)-II-39j 0 % ee 0% ee

Scheme 2.24. Control Reactions Demonstrating Racemization/Enantioselective Protonation Does Not Occur

! 133 confirmed that enantioenrichment was arising during the course of the reaction, and not from selective protonation after glycine formation. Racemic II-39j was subjected to the reaction conditions with 20 mol % of chiral phosphoric acid catalyst II-85c. After 120 h, racemic glycine II-39j was isolated, providing evidence that the chiral catalyst was demonstrating enantiocontrol during the C–C bond forming step of the reaction.

A brief study of the scope of the stereoselective N–H insertion/multicomponent coupling reaction was explored with catalyst (R)-II-85c (Scheme 2.25). In 0.5 M MTBE, in the presence of 20 mol % of (R)-II-85c, glycine II-39j was formed in 49% yield and

phenanthrenyl O Nu O O NH2 O NO2 20 mol % (R)-II-85c * Nu EtO + EtO P O OH N2 0.5 M MTBE, HN R Ar (R)-II-85c II-1a 0 ºC, 120 h phenanthrenyl

NH O NH O NH O

EtO EtO EtO HN HN HN OMe Br F F F II-39jR II-39i II-39l 49% yield, 30:70 er 63% yield, 47:53 er 52% yield, 35:65 er

NH NMe O NH O O

EtO EtO EtO HN HN HN OMe OMe OMe Me Me II-39m II-39n II-39o 88% yield, 35:65 er 60% yield, 32:68 er 61% yield, 50:50 er

Scheme 2.25. Substrate Scope for Stereoselective N–H Insertion/Multicomponent Coupling

! 134 40% ee. Interestingly, product II-39i was accessed in 63% yield but only 6% ee. High yields and promising levels of enantiocontrol were found for the synthesis of II-39l (52% yield and 30% ee). 5-Methoxyindole was well tolerated in multicomponent couplings of

II-1a with both p-anisidine and p-toluidine giving rise to II-39m and II-39n in good yields, respectively. When utilizing N-methylindole, no stereocontrol was observed in the formation of glycine II-39o (61% yield, 0% ee).

2.6 Summary

The impressive ability of boronate ureas to recognize urea groups through hydrogen bonding interactions was essential in discovering new HBD-catalyzed reactions. The efficient N–H insertion/multicomponent coupling of nitrodiazoester II-1a, an aniline molecule, and a second aryl nucleophile was a key discovery in the reactions of diazo compounds. Harnessing the reactivity of nitrodiazoesters was especially remarkable due to their incompatibility with many traditional modes of activation.

Mechanistic studies to determine the specific bond forming steps suggested that N–H insertion does not occur through a nitrocarbene intermediate, but rather through nucleophilic attack of the urea-activated diazo compound. Formation of the aryl glycine by loss of HNO2 is not fully understood, however, investigation into this mechanistic pathway led us to discover the ability of ureas to catalyze the loss of the N-aryl moiety.

Further development of this exchange reaction led to the use of the aryl glycine as a transient N–H insertion intermediate for the double arylation of nitrodiazoesters. In a one-pot cascade reaction, difluoroboronate urea II-40a catalyzed the formation of germinal diaryl esters in excellent yields (15 examples, 56-99% yields). Through urea activation of nitrodiazoesters, the valuable aryl glycine and diaryl ester moieties were ! 135 easily accessed. To further demonstrate the impressive nature of this transformation, a stereoselective variant of the reaction was performed using chiral phosphoric acid catalysts. BINOL-derived phosphoric acids have previously been established to be active

HBD catalysts for a variety of reactions. However, they had never been used to activate diazo compounds. In fact, phosphoric acid catalysts had specifically been demonstrated to activate imines in the presence of diazo esters, without reacting with the diazo functionality. In our N–H insertion/multicomponent coupling reaction of nitrodiazo esters, chiral phosphoric acids were found to not only catalyze the insertion reaction, but also impart stereoselectivity. These foundational discoveries have demonstrated that ureas and phosphoric acids are especially capable of harnessing the reactivity of nitrodiazo esters.

2.7 Experimental: General Methods

Methylene chloride and acetonitrile were purified by passage through a bed of activated alumina.90 Purification of reaction products was carried out by flash chromatography using Aldrich 60 Å (40 - 63 !m) or Alfa Aesar 58 Å 60 mesh activated neutral aluminum oxide powder that was deactivated to Brockmann Activity II.

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. 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, ") ! 136 1 using the solvent as internal standard (CDCl3, ! 7.26 and DMSO, ! 2.50). H NMR splitting patterns are designated as singlet (s), doublet (d), triplet (t), or quartet (q).

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

19 (CDCl3, ! 77.16; DMSO, ! 39.5). Proton decoupled fluorine ( F NMR) spectra were recorded on a Bruker Avance AVIII 400 (376 MHz) spectrometer and are reported in

11 ppm using CF3C6H5 as an external standard (–63.72). Boron spectra ( B 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

Mass Spectrometer. An HP-1 capillary 30m column was employed (19091Z-413E).

HPLC analyses were obtained on a Perkin Elmer Series 200 HPLC with multiple wavelength detector. p-Fluoroaniline, aniline, and N-methylindole were freshly distilled before use. 1,1’-Binaphthyl-2,2’-diyl hydrogen phosphate was purchased from Alfa

Aesar and used without further purification. (R)-3,3’Bis(9-phenanthryl)-1,1’- binaphthalene-2,2’-diyl hydrogen phosphate was purchased from Aldrich and used without further purification. (S)-3,3’-Bis(9-phenanthryl)-1,1’-binaphthalene-2,2’-diyl hydrogen phosphate and other (S)-BINOL based phosphoric acids were synthesized according to the literature.91 Caution: While we have not experienced any problems handling ethyl nitrodiazoacetate, appropriate care should be exercised when handling any diazo compound. ! 137 2.7.1 General Procedure for the Urea Catalyzed N–H Insertion/Multicomponent

Reaction

A dry, screw-capped reaction vial containing a magnetic stir bar was charged with ethyl nitrodiazoacetate II-1a (30.0 mg, 0.189 mmol) and catalyst II-40a (15.0 mg, 0.038 mmol). The reaction was fitted with cap and septum and put under a positive pressure of

Ar. Toluene (189 mL) was added if necessary. Nucleophile 1 and nucleophile 2 were added immediately and the reaction was allowed to stir at the indicated temperature and duration. The reactions were immediately purified by flash column chromatography with a minimal amount of basic alumina or silica gel.

2.7.2 Characterization of Novel Aryl Glycines

NH2 II-39a: Purified by column chromatography on basic alumina O

EtO (20:80 diethyl ether/hexanes to 100% diethyl ether), yielding 42.4 HN mg (83%) of II-39a as a light yellow oil. Rf = 0.81 (100% diethyl ether); FTIR (film) 3051, 2982, 1731, 1604, 1507, 1266, 1178, 1023, 734 cm -1; 1H NMR

(400 MHz, CDCl3) ! 7.27-7.25 (m, 2H); 7.14-7.10 (m, 2H); 6.71-6.64 (m, 3H); 6.58-

6.56 (m, 2H); 4.95 (d, J = 6.4 Hz, 1H); 4.82 (d, J = 6.0 Hz, 1H); 4.27-4.19 (m, 1H); 4.17-

13 4.09 (m, 1H); 3.7 (br s, 2H); 1.21 (t, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3) !

172.3, 146.4, 146.3, 129.2, 128.3, 127.4, 117.9, 115.3, 113.4, 61.6, 60.3, 14.1; HRMS

+ + (ESI): Mass calculated for C16H18N2O2 [M+Na] , 293.1260. Found [M+Na] , 293.1263.

II-39b: The reaction was allowed to stir neat at 23 ºC for 72 hours NH2 O with 4-fluoroaniline (179 mL, 1.89 mmol) and N,N-diethylaniline EtO HN (151 mL, 0.945 mmol). The reaction was immediately purified

! 138 by flash column chromatography with a minimal amount of basic alumina (5:95 diethyl ether/hexanes to 100% diethyl ether), yielding 61.2 mg of II-39b (94%). Rf = 0.21

(20:80 ethyl acetate/hexanes); FTIR (film) 3053, 2974, 2932, 1732, 1612, 1511, 1376,

-1 1 1314, 1267, 1194, 1078, 1023, 909, 820, 736 cm ; H NMR (400 MHz, CDCl3) ! 7.28-

7.26 (m, 2H); 6.86-6.81 (m, 2H); 6.64-6.62 (m, 2H); 6.53-6.50 (m, 2H); 4.88 (d, J = 6.4

Hz, 1H); 4.64 (d, J = 6.4 Hz, 1H); 4.28-4.20 (m, 1H), 4.15-4.07 (m, 1H); 3.34 (q, J =

14.0, 6.8 Hz, 4H); 1.23 (t, J = 7.2 Hz, 3H); 1.15 (t, J = 7.2 Hz, 6H) ; 13C NMR (100 MHz,

CDCl3) ! 172.5, 156.0 (d, J = 233.9 Hz), 147.8, 142.8 (d, J = 1.5 Hz), 128.2, 123.4, 115.6

(d, J = 22.4 Hz), 114.2 (d, J = 24.9 Hz), 111.7, 61.5, 60.8, 44.3, 14.1, 12.6; HRMS (ESI):

+ + Mass calculated for C20H25F1N2O2 [M+Na] , 367.1792. Found [M+Na] , 367.1789.

II-39c: The reaction was allowed to stir at 23 ºC for 72 hours in NH2 O

EtO toluene (189 µL) with p-anisidine (162.9 mg, 1.32 mmol) and HN aniline (17.2 µL, 0.189 mmol). The reaction was immediately

OMe purified by flash column chromatography with a minimal amount of neutral alumina (5:95 ethyl acetate/hexanes to 50% ethyl acetate), yielding 78% of II-

1 39c. Rf = 0.81 (100% diethyl ether); H NMR (400 MHz, CDCl3) ! 7.26-7.24 (m, 2H);

6.72 (d, J = 8.4 Hz, 2H); 6.64 (d, J = 8.4 Hz, 2H); 6.54 (d, J = 9.2 Hz, 2H); 4.88 (d, J =

5.2 Hz, 1H), 4.53 (d, J = 4.8 Hz, 1H); 4.23-4.17 (m, 1H); 4.16-4.10 (m, 1H); 3.71 (s, 3H);

13 3.67 (br s, 2H); 1.21 (t, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3) ! 172.7, 152.5,

146.5, 140.6, 128.4, 127.7, 115.4, 115.0, 114.9, 61.6, 61.3, 55.9, 14.2; HRMS (ESI):

+ + Mass calculated for C17H20Na1N2O3 [M+Na] , 323.1366. Found [M+Na] , 323.1365.

! 139 NH2 II-39d: The reaction was allowed to stir at 40 ºC for 48 hours in O

EtO toluene (189 µL) with p-toludine (101.3 mg, 0.945 mmol) and HN aniline (17.2 µL, 0.189 mmol). The reaction was immediately Me purified by flash column chromatography with a neutral alumina (5:95 ethyl acetate/hexanes to 50% ethyl acetate), yielding 70% of II-39d. Rf = 0.3 (35:65 ethyl acetate/hexanes); FTIR (film) 3390, 3055, 2986, 1734, 1654, 1515, 1374, 1264, 1046,

1 cm-1; H NMR (400 MHz, CDCl3) ! 7.26-7.24 (m, 2H); 6.93 (d, J = 8.0 Hz, 2H); 6.65-

6.63 (m, 2H); 6.50-6.48 (m, 2H); 4.92 (d, J = 6.0 Hz, 1H); 4.67 (d, J = 6.0 Hz, 1H); 4.26-

4.18 (m, 1H); 4.17-4.08 (m, 1H); 3.68 (br s, 2H); 3.20 (s, 3H); 1.21 (t, J = 6.8 Hz, 3H);

13 C NMR (100 MHz, CDCl3) ! 172.6, 146.5, 144.1, 129.8, 128.4, 127.6, 127.2, 115.4,

113.7, 61.6, 60.7, 20.5, 14.2; HRMS (ESI): Mass calculated for C17H20Na1N2O2

[M+Na]+, 307.1417. Found [M+Na]+, 307.1416.

Me II-39e: The reaction was allowed to stir neat at 40 ºC for 48 hours

NH2 O with 2,6-dimethylaniline (234 mL, 1.89 mmol) and p- EtO Me HN fluoroaniline (179 mL, 1.89 mmol). The reaction was

F immediately purified by flash column chromatography with a minimal amount of basic alumina (20:80 diethyl ether/hexanes to 100% diethyl ether), yielding 54.4 mg of II-39e (91%). Rf = 0.78 (100% diethyl ether); FTIR (film) 3394,

3095, 2925, 1729, 1624, 1510, 1490, 1368, 1314, 1193 cm-1; 1H NMR (400 MHz,

CDCl3) d 7.03 (s, 2H); 6.88-6.77 (m, 2H); 6.53-6.49 (m, 2H); 4.82 (d, J = 6.4 Hz, 1H);

4.64 (d, J = 6.0 Hz, 1H); 4.28-4.20 (m, 1H); 4.14-4.06 (m, 1H); 3.59 (br s, 2H); 2.17 (s,

13 6H); 1.22 (t, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3) d 172.5, 156.0 (d, J = 234

Hz), 142.9, 142.8 (d, J = 1.9 Hz), 127.1, 126.4, 122.0, 115.6 (d, J = 22.4 Hz), 114.2 (d, J ! 140 = 7.3 Hz), 61.5, 61.1, 17.7, 14.1; HRMS (ESI): Mass calculated for C18H21F1N2O2

[M+Na]+, 339.1479. Found [M+Na]+, 339.1480.

iPr II-39f: The reaction was allowed to stir neat at 40 ºC for 48 hours

NH2 O with 2,6-diisopropylaniline (1.89 mmol) and p-fluoroaniline (179 EtO iPr HN µL, 1.89 mmol). The reaction was immediately purified by flash

F column chromatography with a minimal amount of basic alumina

(20:80 diethyl ether:hexanes to 100% diethyl ether), yielding 96% of II-39f. Rf = 0.78

(100% diethyl ether); FTIR (film) 3401, 2962, 2927, 2870, 1731, 1624, 1510, 1466,

1 1308, 1280 cm-1; H NMR (400 MHz, CDCl3) ! 7.09 (s, 2H); 6.87- 6.82 (m, 2H); 6.55-

6.52 (m, 2H); 4.90 (d, J = 6.8 Hz, 1H); 4.55 (d, J = 8.8 Hz, 1H); 4.27- 4.20 (m, 1H); 4.18-

4.10 (m, 1H); 3.76 (br s, 2H); 2.93-2.86 (m, 2H,); 1.27-1.21 (m, 15 H); 13C NMR (100

MHz, CDCl3) ! 172.6, 156.1 (d, J = 234 Hz), 143.0, 140.4, 132.7, 126.6, 121.9, 115.6 (d,

J = 22.4 Hz), 114.3 (d, J = 7.3 Hz), 61.7, 61.3, 28.1, 22.4, 14.1; HRMS (ESI): Mass

+ + calculated for C22H29F1N2O2Na1 [M+Na] , 395.2105. Found [M+Na] , 395.2091.

H II-39g: The reaction was allowed to stir neat at 23 ºC for 48 N O Me hours with p-fluoroaniline (179 µL, 1.89 mmol) and N- EtO HN methylaniline (204.6 µL, 1.89 mmol). The reaction was

F immediately purified by flash column chromatography with a minimal amount of silica gel (5:95 ethyl acetate:hexanes to 50:50 ethyl acetate:hexanes), yielding 85% of II-39g. Rf = 0.21 (20:80 ethyl acetate/hexanes); FTIR (film) 3053, 2986,

1 1732, 1614, 1510, 1421, 1265, 909 cm-1; H NMR (400 MHz, CDCl3) ! 7.28-7.25 (m,

2H); 6.85-6.80 (m, 2H); 658-6.56 (m, 2H); 6.52-6.48 (m, 2H); 4.88 (d, J = 5.6 Hz, 1H);

4.69 (d, J = 5.2 Hz, 1H); 4.26-4.24 (m, 1H), 4.24-4.08 (m, 1H), 3.75 (br s, 1H), 2.82 (s, ! 141 13 3H), 1.23 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) ! 172.5, 156.0 (d, J = 233.9

Hz), 149.5, 142.8 (d, J = 1.5 Hz), 128.3, 125.7, 115.6 (d, J = 22.4 Hz), 114.2 (d, J = 24.9

Hz), 112.7, 61.7, 61.0, 30.7, 14.2; HRMS (ESI): Mass calculated for C17H19F1N2O2Na

[M+Na]+, 325.1323. Found [M+Na]+, 325.1329.

NEt2 II-39h: The reaction was allowed to stir at 30 ºC for 48 hours in O

EtO toluene (189 mL) with p-anisidine (233 mg, 1.89 mmol) and N,N- HN diethylaniline (151 mL, 0.945 mmol). The reaction was F immediately purified by flash column chromatography with a minimal amount of basic alumina (5:95 diethyl ether/hexanes to 50:50 diethyl ether/hexanes), yielding 64.0 mg of

II-39h (95%). Rf = 0.8 (100% diethyl ether); FTIR (film) 3045, 2973, 2932, 2832, 1732,

-1 1 1612, 1514, 1374, 1268, 1238, 1181 cm ; H NMR (400 MHz, CDCl3) d 7.30-7.28 (m,

2H); 6.75-6.72 (m, 2H); 6.64-6.62 (m, 2H); 6.57-6.55 (m, 2H); 4.89 (d, J = 6.8 Hz, 1H);

4.47 (d, J = 6.8 Hz, 1H); 4.27-4.19 (m, 1H); 4.15-4.07 (m, 1H); 3.72 (s, 3H); 3.34 (q, J =

14.0, 6.8 Hz, 4H); 1.23 (t, J = 6.8 Hz, 3H) 1.15 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz,

CDCl3) d 172.8, 152.3, 147.7, 140.8, 128.2, 123.9, 114.8, 114.7, 111.7, 61.3 61.2, 55.7,

+ 44.3, 14.1, 12.6; HRMS (ESI): Mass calculated for C21H28N2O3 [M+H] , 357.2173.

Found [M+H]+, 357.2181.

O NH II-39i: The reaction was allowed to stir at 40 ºC for 48 hours in

EtO toluene (189 mL) with p-fluoroaniline (179 mL, 1.89 mmol) and HN indole (22.1 mg, 0.189 mmol). The reaction was immediately F purified by flash column chromatography on silica gel (5:95 ethyl acetate:hexanes to

20:80 ethyl acetate:hexanes), yielding 72% of 7e. Rf = 0.4 (75:25 diethyl ether:hexanes);

FTIR (film) 3466, 3054, 2986, 1734, 1654, 1509, 1265, cm-1; 1H NMR (400 MHz, ! 142 CDCl3) ! 8.12 (br s, 1H); 7.82 (d, J = 8.0 Hz, 1H); 7.38 (d, J = 8.4 Hz, 1H); 7.24-7.22 (m,

2H); 7.17 (t, J = 8.0 Hz, 1H); 6.84 (t, J = 8.8 Hz, 2H); 6.59-6.55 (m, 2H); 5.32 (d, J = 5.6

Hz, 1H); 4.65 (d, J = 5.2 Hz, 1H); 4.28-4.23 (m, 1H); 4.16-4.11 (m, 1H); 1.21 (t, J = 7.2

13 Hz, 3H); C NMR (100 MHz, CDCl3) ! 172.7, 156.2 (d, J = 234.2 Hz), 143.0, 136.6,

125.9, 123.0 (d, J = 48.7 Hz), 119.9 (d, J = 59.3 Hz), 115.9, 115.7, 114.5, 114.4, 112.7,

+ 111.5, 61.8, 55.0, 14.2; HRMS (ESI): Mass calculated for C18H17F1NaN2O2 [M+Na] ,

335.1166. Found [M+Na]+, 335.1163.

O NH II-39j: The reaction was allowed to stir at 40 ºC for 48 hours in

EtO toluene (189 mL) with p-fluoroaniline (179 mL, 1.89 mmol) and HN OMe 5-methoxyindole (27.8 mg, 0.189 mmol). The reaction was F immediately purified by flash column chromatography on silica gel (20:80 ethyl acetate:hexanes to 100% ethyl acetate), yielding 95% of II-39j. Rf = 0.2 (35:65 ethyl acetate:hexanes); FTIR (film) 3395, 2969, 1724, 1508, 1277, 1210, 1173, 1031 cm-1; 1H

NMR (400 MHz, CDCl3) ! 8.20 (br s, 1H); 7.26-7.22 (m, 2H); 7.16 (d, J = 2.4 Hz, 1H);

6.91-6.84 (m, 3H); 6.60-6.58 (m, 2H); 5.29 (d, J = 2.8 Hz, 1H); 4.63 (d, J = 3.2 Hz, 1H);

4.31-4.23 (m, 1H); 4.19-4.14 (m, 1H); 3.87 (s, 3H); 1.23 (t, J = 7.2 Hz, 3H); 13C NMR

(100 MHz, CDCl3) ! 172.7, 156.3 (d, J = 267.4 Hz), 154.5, 143.1, 131.7, 126.3, 123.9,

116.2 (d, J = 7.7 Hz), 115.8 (d, J = 22.3 Hz), 114.5 (d, J = 7.3 Hz), 113.0, 112.2 (d, J =

16.1 Hz), 101.3, 61.7, 56.0, 55.1, 14.3; HRMS (ESI): Mass calculated for

+ + C19H19FN2NaO3 [M+Na] , 365.1272. Found [M+Na] , 365.1269.

O NH II-39k: The reaction was allowed to stir at 40 ºC for 48 hours in

EtO toluene (189 mL) with p-fluoroaniline (179 mL, 1.89 mmol) and 5- HN

Cl F ! 143 chloroindole (47.6 mg, 0.189 mmol). The reaction was immediately purified by flash column chromatography on silica gel (20:80 ethyl acetate:hexanes to 100% ethyl acetate),

1 yielding 58% of II-39k. Rf = 0.2 (35:65 ethyl acetate:hexanes); H NMR (400 MHz,

CDCl3) " 8.19 (br s, 1H); 7.81 (d, J = 2.0 Hz, 1H); 7.30-7.28 (m, 1H); 7.20-7.17 (m, 2H);

6.87-6.83 (m, 2H); 6.57-6.55 (m, 2H); 5.26 (d, J = 4.0 Hz, 1H); 4.68 (d, J = 6.0 Hz, 1H);

4.30-4.22 (m, 1H); 4.17-4.12 (m, 1H); 1.23 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz,

CDCl3) " 172.1, 156.2 (d, J = 234 Hz), 142.7, 135.0, 126.8, 125.9, 124.4, 123.0, 119.2,

115.7 (d, J = 22.4 Hz), 114.4 (d, J = 7.3 Hz), 112.5, 112.4, 61.8, 54.9, 29.7, 14.1; HRMS

+ + (ESI): Mass calculated for C18H16Cl1F1N2O2 [M+Na] , 369.0777. Found [M+Na] ,

369.0763.

O NH II-39l: The reaction was allowed to stir at 40 ºC for 48 hours in

EtO toluene (189 mL) with p-fluoroaniline (179 mL, 1.89 mmol) and 5- HN Br bromoindole (61.6 mg, 0.189 mmol). The reaction was F immediately purified by flash column chromatography on silica gel (20:80 ethyl acetate:hexanes to 100% ethyl acetate), yielding 68% of II-39l. Rf = 0.2 (35:65 ethyl acetate:hexanes); FTIR (film) 3448, 3054, 2986, 1734, 1654, 1509, 1458, 1265 cm-1; 1H

NMR (400 MHz, CDCl3) " 8.19 (br s, 1H); 7.81 (d, J = 2.0 Hz, 1H); 7.30-7.28 (m, 1H);

7.20-7.17 (m, 2H); 6.87-6.83 (m, 2H); 6.57-6.55 (m, 2H); 5.26 (d, J = 4.0 Hz, 1H); 4.68

(d, J = 6.0 Hz, 1H); 4.30-4.22 (m, 1H); 4.17-4.12 (m, 1H); 1.23 (t, J = 6.8 Hz, 3H); 13C

NMR (100 MHz, CDCl3) " 172.1, 156.2 (d, J = 234 Hz), 142.7, 134.9, 126.8, 125.9,

124.4, 123.0, 119.2, 115.7 (d, J = 22.4 Hz), 114.4 (d, J = 7.3 Hz), 112.5, 112.4, 61.8,

+ 43.7, 29.7, 14.1; HRMS (ESI): Mass calculated for C18H16Br1F1Na1N2O2 [M+Na] ,

413.0271. Found [M+Na]+, 413.0273. ! 144 2.7.3 Typical Procedure for Aryl Glycine Exchange Reaction for Formation of

Arylation Product II-79a

NH2 A dry, screw-capped reaction vial containing a magnetic stir bar O

EtO was charged with II-39b (40.0 mg, 0.139 mmol), catalyst II-40a,

2,6-dimethylaniline (51.3 mL, 0.416 mmol), and DCE (139 mL). Me Me

NH2 The reaction stirred according to the indicated time and temperature and was immediately purified by flash column chromatography on neutral alumina (20:80 ethyl acetate:hexanes to 100% ethyl acetate). Rf = 0.15 (35:65 ethyl acetate/hexanes); FTIR (film) 3454, 3374, 3223, 3046, 2979, 1723, 1624, 1507, 1287,

-1 1 1161 cm ; H NMR (400 MHz, CDCl3) ! 7.10 (app d, J = 8.4 Hz, 2H); 6.88 (s, 2H); 6.62

(app d, J = 8.4 Hz, 2H); 4.77 (s, 1H); 4.23-4.14 (m, 2H); 3.56 (br s, 4H); 2.14 (s, 6H);

13 1.26 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) ! 173.7, 145.4, 141.8, 129.6,

129.5, 128.7, 128.4, 121.8, 115.2, 60.9, 55.7, 17.8, 14.3; HRMS (ESI): Mass calculated

+ + for C18H23N2O2 [M+H] , 299.1754. Found [M+H] , 299.1757.

2.7.4 Typical Procedure for the One-Pot Double Arylation Reaction of Ethyl

Nitrodiazoacetate

A dry, screw-capped reaction vial containing a magnetic stir bar was charged with ethyl nitro diazoacetate II-1a (100.0 mg, 0.629 mmol). The reaction was fitted with cap and septum and put under a positive pressure of Ar. Catalyst II-40a (49.8 mg, 0.126 mmol) was added, followed immediately by aniline (57.3 mL, 0.629 mmol) and 4- fluoroaniline (297.9 mL, 3.14 mmol). The reaction was allowed to stir at 40 ºC for 48 hours. The second nucleophile (1.89 mmol) was added followed by catalyst II-40a (24.9 mg, 0.0629 mmol) and DCE (314 mL), and the reaction stirred at 60 ºC for 24 h. The ! 145 reaction was immediately purified by flash column chromatography with a minimal amount of basic alumina or silica gel.

2.7.5 Characterization of Novel Diaryl Esters

NH2 II-82b: The compound was isolated (189.8 mg, 87%) by flash O

EtO column chromatography on neutral alumina (20:80 ethyl

acetate:hexanes to 100% ethyl acetate). Rf = 0.2 (35:65 ethyl iPr iPr acetate/hexanes); FTIR (film) 3461, 3372, 3223, 2962, 2872, NH2

-1 1 1724, 1628, 1514, 1466, 1280, 1226, 1173 cm ; H NMR (400 MHz, CDCl3) ! 7.10 (app d, J = 8.4 Hz, 2H); 6.99 (s, 2H); 6.62 (app d, J = 8.4 Hz, 2H); 4.84 (s, 1H); 4.27-4.12 (m,

2H); 3.70 (br s, 2H); 3.60 (br s, 2H); 2.91 (sep., J = 6.8 Hz, 2 H), 1.27-1.22 (m, 15H); 13C

NMR (100 MHz, CDCl3) ! 173.9, 145.3, 139.4, 132.5, 129.8, 129.5, 128.8, 123.2, 115.2,

+ 60.9, 56.4, 28.2, 22.5, 14.3; HRMS (ESI): Mass calculated for C22H31N2O2 [M+H] ,

355.2380. Found [M+H]+, 355.2379.

NH2 II-82c: The compound was isolated (193.0 mg, 94%) by flash O

EtO column chromatography on neutral alumina (5:95 ethyl

acetate:hexanes to 50:50 ethyl acetate:hexanes). Rf = 0.38 (35:65

ethyl acetate/hexanes; FTIR (film) 3461, 3378, 2977, 1724, 1612, NEt2

-1 1 1516, 1278, 1182 cm ; H NMR (400 MHz, CDCl3) ! 7.14-7.10 (m, 4H); 6.63-6.59 (m,

4H); 4.80 (s, 1H); 4.18 (q, J = 7.2 Hz, 2H); 3.60 (br s, 2H); 3.31 (q, J = 7.2 Hz, 4H); 1.25

13 (t, J = 7.2 Hz, 3H); 1.13 (t, J = 7.2 Hz, 6H); C NMR (100 MHz, CDCl3) ! 173.8, 146.8,

145.2, 129.6, 129.4, 129.3, 125.8, 115.1, 111.6, 60.8, 55.4, 44.3, 14.2, 12.6; HRMS

+ + (ESI): Mass calculated for C20H27N2O2 [M+H] , 327.2067. Found [M+H] , 327.2069.

! 146 NH2 II-82d: The compound was isolated (176.5 mg, 99%) by flash O

EtO column chromatography on neutral alumina (20:80 ethyl

acetate:hexanes to 100% ethyl acetate). Rf = 0.2 (35:65 ethyl

acetate/hexanes); FTIR (film) 3373, 3223, 2983, 1723, 1618, NHMe

-1 1 1516, 1281, 1157, 1023 cm ; H NMR (400 MHz, CDCl3) !! 7.12 (app d, J = 8.4 Hz,

2H); 7.09 (app d, J = 8.0 Hz, 2H); 6.62 (app d, J = 8.8 Hz, 2H); 6.55 (app d, J = 8.8 Hz,

2H); 4.80 (s, 1H); 4.18 (q, J = 7.2 Hz, 2H); 3.61 (br s, 3H); 2.81 (s, 3H), 1.25 (t, J = 7.2

13 Hz, 3H); C NMR (100 MHz, CDCl3) !! 173.7, 148.4, 145.4, 129.7, 129.5, 129.4, 128.1,

115.3, 112.5, 61.0, 55.7, 30.9, 14.3; HRMS (ESI): Mass calculated for C17H21N2O2

[M+H]+, 285.1598. Found [M+H]+, 285.1598.

II-82e: The compound was isolated (138.6 mg, 56%) by flash NH2 O column chromatography on neutral alumina (20:80 ethyl EtO

acetate:hexanes to 100% ethyl acetate). Rf = 0.11 (35:65 ethyl

I acetate/hexanes); FTIR (film) 3439, 3362, 2947, 1721, 1616, NH2 -1 1 1507, 1285, 1170 cm ; H NMR (400 MHz, CDCl3) !! 7.55 (s, 1H); 7.10.-7.02 (m, 3H);

6.70-6.60 (m, 3H); 4.73 (s, 1H); 4.17 (q, J = 7.2 Hz, 2H); 4.04 (br s, 2H); 3.63 (br s, 2H);

13 1.24 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) !! 173.1, 145.9, 145.6, 138.8,

131.1, 129.7, 129.5, 128.9, 115.4, 114.7, 84.2, 61.2, 55.0, 14.3; HRMS (ESI): Mass

+ + calculated for C16H17I1N2O2 [M+H] , 397.0407. Found [M+H] , 397.0410.

NH2 II-82f: The compound was isolated (204.2 mg, 98%) on neutral O

EtO alumina (20:80 ethyl acetate:hexanes to 100% ethyl acetate). Rf MeO OMe = 0.2 (35:65 ethyl acetate/hexanes); FTIR (film) 3444, 3364,

NH2 ! 147 -1 1 3056, 2974, 2940, 1725, 1616, 1513, 1465, 1274, 1195 cm ; H NMR (400 MHz,

CDCl3) ! 7.09 (app d, J = 8.0 Hz, 2H); 6.56 (app d, J = 8.0 Hz, 2H); 5.90 (s, 2H); 5.15

(s, 1H); 4.24-4.06 (m, 2H); 3.71 (s, 6H); 3.61 (br s, 4H); 1.19 (t, J = 6.8 Hz, 3H); 13C

NMR (100 MHz, CDCl3) ! 174.5, 158.4, 147.0, 144.8, 130.2, 129.8, 115.0, 108.2, 92.0,

+ 60.5, 55.6, 45.2, 14.5; HRMS (ESI): Mass calculated for C18H22N2NaO4 [M+Na] ,

353.1472. Found [M+Na]+, 353.1465.

NEt2 II-82g: The compound was isolated (197.0 mg, 86%) on neutral O

EtO alumina (5:95 ethyl acetate:hexanes to 50:50 ethyl

acetate:hexanes). Rf = 0.63 (20:80 ethyl acetate/hexanes); FTIR N Me (film) 3054, 2972, 2931, 1728, 1611, 1514, 1364, 1265, 1155,

-1 1 1025 cm ; H NMR (400 MHz, CDCl3) ! 7.50 (d, J = 7.2 Hz, 1H); 7.29-7.24 (m, 3H);

7.20 (dt, J = 6.8, 0.8 Hz, 1H); 7.09-7.03 (m, 2H); 6.62 (app d, J = 8.8 Hz, 1H); 5.12 (s,

1H); 4.27-4.13 (m, 2H); 3.75 (s, 3H); 3.33 (q, J = 7.2 Hz, 4H); 1.27 (t, J = 7.2 Hz, 3H);

13 1.14 (t, J = 7.2 Hz, 6H); C NMR (100 MHz, CDCl3) !! 173.8, 147.1, 137.2, 129.3,

127.9, 127.3, 125.5, 121.8, 119.4, 119.1, 113.3, 111.9, 109.3, 61.0, 48.1, 44.4, 32.9, 14.4,

+ + 12.8; HRMS (ESI): Mass calculated for C23H29N2O2 [M+H] , 365.2224. Found [M+H] ,

365.2222.

II-82h: The compound was isolated (196.1 mg, 96%) by flash NH2 O column chromatography on neutral alumina (20:80 ethyl EtO

acetate:hexanes to 100% ethyl acetate). Rf = 0.1 (35:65 ethyl OMe HN acetate/hexanes); FTIR (film) 3396, 3044, 2991, 2939, 1722,

-1 1 1619, 1513, 1292, 1155, 1022 cm ; H NMR (400 MHz, CDCl3) !!8.00 (br s, 1H); 7.24-

7.18 (m, 3H); 7.14 (d, J = 2.8 Hz, 1H); 6.89 (d, J = 2.4 Hz, 1H); 6.83 (dd, J = 8.8 Hz, 2.4 ! 148 Hz, 1H); 6.63 (app d, J = 8.8 Hz); 5.08 (s, 1H); 4.27-4.13 (m, 2H); 3.78 (s, 3H); 3.62 (br

13 s, 2H); 1.26 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) !! 173.5 154.1, 145.5,

131.6, 129.4, 128.7, 127.2, 124.0, 115.3, 114.2, 112.4, 112.0, 101.2, 61.1, 56.0, 48.4,

+ 14.38; HRMS (ESI): Mass calculated for C19H20N2NaO3 [M+Na] , 347.1366. Found

[M+Na]+, 347.1362.

NH2 I-82i: The compound was isolated (175.9 mg, 95%) by flash O

EtO column chromatography on neutral alumina (20:80 ethyl

acetate:hexanes to 100% ethyl acetate). Rf = 0.1 (35:65 ethyl HN acetate/hexanes); FTIR (film) 3375, 3052, 2980, 1720, 1621,

-1 1 1512, 1458, 1174, 1022 cm ; H NMR (400 MHz, CDCl3) ! 8.10 (br s, 1H); 7.45 (d, J =

7.2 Hz, 1H); 7.32 (d, J = 8.0 Hz, 1H); 7.20 (app d, J = 8.4 Hz, 2H); 7.19-7.12 (m, 2H);

7.07-7.03 (m, 1H); 5.13 (s, 1H); 4.26-4.13 (m, 2H); 3.70 (br s, 2H); 3.85 (br s, 2H); 1.25

13 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) ! 173.5, 145.1, 136.4, 129.5, 129.1,

126.8, 123.2, 122.3, 119.7, 119.3, 115.5, 114.5, 111.3, 61.1, 48.4, 14.3; HRMS (ESI):

+ + Mass calculated for C18H18N2NaO2 [M+Na] , 317.1260. Found [M+Na] , 317.1255.

NH2 II-82j: The compound was isolated (189.7 mg, 98%) by flash O

EtO column chromatography on neutral alumina (5:95 ethyl

acetate:hexanes to 100% ethyl acetate). Rf = 0.1 (35:65 ethyl N Me acetate/hexanes); FTIR (film) 3454, 3370, 3081, 2979, 2932,

-1 1 1725, 1618, 1511, 1475, 1289, 1157 cm ; H NMR (400 MHz, CDCl3) ! 7.45 (d, J = 8.0

Hz, 1H); 7.28 (d, J = 8.0 Hz, 1H); 7.24-7.17 (m, 3H); 7.05 (t, J = 7.2 Hz, 1H); 7.02 (s,

1H); 6.63 (app d, J = 8.4 Hz, 2H); 5.12 (s, 1H); 4.27-4.11 (m, 2H); 3.74 (s, 3H); 3.65 (br

13 s, 2H); 1.26 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) !! 173.6, 145.6, 137.2, ! 149 129.4, 128.9, 127.9, 127.2, 121.8, 119.3, 119.2, 115.3, 112.9, 109.3, 61.1, 48.3, 32.8,

+ 14.3; HRMS (ESI): Mass calculated for C19H20N2NaO2 [M+Na] , 331.1417. Found

[M+Na]+, 331.1410.

II-82k: The compound was isolated (232.4 mg, 86%) by flash O NH

EtO column chromatography on silica gel (5:95 ethyl acetate:hexanes

HN OMe to 100% ethyl acetate). Rf = 0.2 (35:65 ethyl acetate/hexanes); Br FTIR (film) 3406, 3119, 2982, 2938, 1719, 1487, 1459, 1210,

-1 1 1175 cm ; H NMR (400 MHz, CDCl3) ! 8.17 (br s, 1H); 8.00 (br s, 1H); 7.78 (s, 1H);

7.23 (dd, J = 8.4, 1.6 Hz, 1H); 7.19 (d, J = 8.8 Hz, 1H); 7.12 (d, J = 8.4 Hz, 1H); 7.05 (d,

J = 2.4 Hz, 1H); 6.98 (dd, J = 8.4, 2.4 Hz, 2H); 6.85 (dd, J!"!#$#, 2.4 Hz, 1H), 5.38 (s,

1H); 4.24 (q, J = 7.2 Hz, 2H); 3.79 (s, 3H); 1.29 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,

CDCl3) !! 173.5, 154.2, 135.1, 131.7, 128.5, 127.0, 125.1, 124.8, 124.2, 122.0, 113.3,

112.97, 112.92, 112.90, 112.5, 112.2, 101.4, 61.4, 56.0, 40.8, 14.4; HRMS (ESI): Mass

+ + calculated for C21H19BrN2NaO3 [M+Na] , 449.0471. Found [M+Na] , 449.0466.

Me II-82l: The compound was isolated (187.0 mg, 92%) by flash O N column chromatography on silica gel (5:95 ethyl acetate:hexanes to EtO

100% ethyl acetate). Rf = 0.3 (35:65 ethyl acetate/hexanes); FTIR

HN (film) 3400, 3058, 2980, 2938, 1719, 1619, 1541, 1469, 1379, 1277,

-1 1 1175, 1132, cm ; H NMR (400 MHz, CDCl3) ! 8.03 (br s, 1H); 7.64 (dd, J = 8.0, 0.8

Hz, 2H); 7.30 (d, J = 4.0 Hz, 1H); 7.28 (d, J = 4.0 Hz, 1 H); 7.23 (dd, J = 6.8, 0.8 Hz,

1H); 7.21-7.14 (m, 1H); 7.13-7.05 (m, 3H); 6.98 (s, 1H); 5.51 (s, 1H); 4.21 (q, J = 7.2

13 Hz, 2H); 3.67 (s, 3H); 1.26 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) !! 173.7,

137.3, 136.5, 128.1, 127.2, 126.8, 123.4, 122.2, 121.8, 119.6, 119.5, 119.4, 119.2, 113.9, ! 150 112.2, 111.3, 109.4, 61.2, 40.7, 32.8, 14.4; HRMS (ESI): Mass calculated for

+ + C21H20N2NaO2 [M+Na] , 355.1417. Found [M+Na] , 355.1419.

II-82m: The compound was isolated (229.8 mg, 92%) by flash O NH

EtO column chromatography on silica gel (5:95 ethyl acetate:hexanes to

Br 100% ethyl acetate). Rf = 0.2 (35:65 ethyl acetate/hexanes); FTIR HN (film) 3409, 3111, 3057, 2981, 1718, 1458, 1179, 1097, 1020 cm-1;

1 H NMR (400 MHz, CDCl3) ! 8.07 (br s, 1H); 8.05 (br s, 1H); 7.69 (d, J = 2.0 Hz, 1H);

7.61 (d, J = 8.0 Hz, 1H); 7.35 (d, J = 8.0 Hz, 1 H); 7.26 (dd, J = 8.8, 2.0 Hz, 1H); 7.23-

7.16 (m, 2H); 7.13-7.05 (m, 3H); 5.43 (s, 1H); 4.23 (q, J = 7.2 Hz, 2H); 1.28 (t, J = 7.2

13 Hz, 3H); C NMR (100 MHz, CDCl3) !! 173.6, 136.5, 135.1, 128.4, 126.6, 125.0, 124.9,

123.4, 122.3, 122.0, 119.7, 119.3, 113.2, 113.1, 112.94, 112.91, 111.5, 61.5, 40.7, 14.3;

HRMS (ESI): Mass calculated for C20H17BrN2NaO2 [M+Na]+, 419.0366. Found [M+Na]+,

419.0371.

O NH II-82n: The compound was isolated (212.6 mg, 97%) by flash

EtO column chromatography on silica gel (20:80 ethyl acetate:hexanes

OMe to 100% ethyl acetate). Rf = 0.1 (35:65 ethyl acetate/hexanes); HN FTIR (film) 3406, 2983, 2935, 1718, 1581, 1485, 1457, 1212,

-1 1 1173, 1096, 1022 cm ; H NMR (400 MHz, CDCl3) ! 8.05 (br s, 1H); 7.94 (br s, 1H);

7.64 (d, J = 8.0 Hz, 1H); 7.34 (d, J = 8.0 Hz, 1H); 7.23-7.17 (m, 2H); 7.11-7.06 (m, 4H);

6.87-6.84 (m, 1H); 5.46 (s, 1H); 4.26-4.20 (m, 2H); 3.80 (s, 3H); 1.28 (t, J = 7.2 Hz, 3H);

13 C NMR (100 MHz, CDCl3) !! 173.6, 154.2, 136.5, 131.7, 127.2, 126.8, 124.2, 123.5,

122.3, 119.7, 119.5, 119.5, 113.8, 113.6, 112.5, 112.1, 111.4, 101.4, 61.2, 56.0, 40.9,

! 151 + 14.4; HRMS (ESI): Mass calculated for C21H20N2NaO3 [M+Na] , 371.1366. Found

[M+Na]+, 371.1369.

O NH II-82o: The compound was isolated (250.6 mg, 97%) by flash

EtO column chromatography on silica gel (5:95 ethyl acetate:hexanes to

Br 100% ethyl acetate). R = 0.3 (35:65 ethyl acetate/hexanes); FTIR N f Me (film) 3401, 3056, 2980, 1720, 1462, 1326, 1173, cm-1; 1H NMR

(400 MHz, CDCl3) ! 8.08 (br s, 1H); 7.79 (d, J = 2.0 Hz, 1H); 7.61 (d, J = 8.0 Hz, 1H);

7.30 (d, J = 8.4 Hz, 1 H); 7.27-7.22 (m, 2H); 7.18 (d, J = 8.4 Hz, 1H); 7.14-7.06 (m, 2H);

6.99 (s, 1H); 5.44 (s, 1H); 4.24 (dq, J = 7.2, 0.8 Hz, 2H); 3.72 (s, 3H); 1.29 (t, J = 7.2 Hz,

13 3H); C NMR (100 MHz, CDCl3) !! 173.5, 137.3, 135.1, 128.5, 128.0, 127.1, 125.2,

124.7, 122.1, 122.0, 119.5, 119.3, 113.7, 113.1, 112.8, 111.8, 109.5, 61.4, 40.6, 32.9,

+ 14.4; HRMS (ESI): Mass calculated for C21H19BrN2NaO2 [M+Na] , 433.0522. Found

[M+Na]+, 433.0527.

2.7.6 Procedure for Binding Titration Experiment

Urea II-40a was dried overnight in a vacuum dessicator with P2O5. To an NMR tube was added 500 µL of a 1.136 mM solution of host (urea II-40a) in dry acetone (d6).

Stock solutions of guest (ethyl nitrodiazoacetate II-1a) in acetone (d6) were made of the following concentrations: (A) 0.5 M, (B) 0.25 M, (C) 0.05 M. Diagnostic host shifts

(urea N–H protons) were followed by 1H NMR (500 MHz) as aliquots of the guest solution were added and were fitted to a 1:1 binding model.

! 152 Binding Titration (Urea 6a:3) Guest Guest II-1a Urea II- Guest II- entry H1 (ppm) H2 (ppm) Solution added (uL) 40a (mM) 1a (mM) A -- -- 1.136 0.000 10.3007 9.7393 B C 5 1.125 0.495 10.3243 9.7737 C C 5 1.114 0.980 10.3619 9.8249 D C 5 1.103 1.456 10.3809 9.855 E C 5 1.092 1.923 10.4026 9.8822 F C 5 1.082 2.381 10.4205 9.9108 G B 5 1.072 4.717 10.4559 9.9513 H B 5 1.062 7.009 10.4798 9.9806 I B 5 1.052 11.574 10.4871 9.991 J B 5 1.042 16.055 10.4996 10.0042 K A 5 1.033 20.455 10.5152 10.0234 L A 5 1.023 29.279 10.5342 10.0425 M A 5 1.014 42.411 10.5446 10.0575 N A 10 0.996 63.596 10.5601 10.0777 O A 10 0.979 92.672 10.5751 10.0945 P A 10 0.963 129.237 10.587 10.1062 Q A 15 0.939 175.620 10.5875 10.106 R A 25 0.902 236.111 10.5872 10.1063 !

Table 2.12 Observed Chemical Shifts of Binding Titration

Figure 2.3 Best Fit Curve of Binding Titration Data

! 153 Job Plot:

Urea II-40a was dried overnight in a vacuum dessicator with P2O5. Stock solutions of a

12.6 mM solution of host (urea II-40a) and guest (ethyl nitrodiazoacetate II-1a) in acetone (d6) were made. The stock solutions were added to 10 NMR tubes in the following Host (II-40a):Guest (II-1a) solutions: 500:0, 450:50, 400:100, 350:150,

300:200, 250:250, 200:300, 150:350, 100:400, 50:450. Diagnostic host shifts were obtained by 1H NMR were used to determine the concentration of the Host-Guest

Complex ([C]) using the equation

[C] = [H]0 (!obs – !0)/(!max – !0) where [H]0 is the pre-equilibrium host concentration, !obs is the observed N–H chemical shift, !0 is the N–H chemical shift without guest, and !max is the N–H chemical shift of the completely bound host.

'! &#$! &! %#$! !"#$ %! "#$! "! "! "#&! "#(! "#)! "#*! %! %#&! %&'$()*+,-&.$ !

Figure 2.4 Job Plot Analysis of Binding Titration

! 154 2.7.7 General Procedure for Stereoselective N–H Insertion/Multicomponent

Reaction

A dry, screw-capped reaction vial containing a magnetic stir bar was charged with ethyl nitrodiazoacetate II-1a (40.0 mg, 0.251 mmol), solvent (251 mL), catalyst II-80

(17.5 mg, 0.050 mmol), p-fluoroaniline (238 mL, 2.51 mmol), and 5-methoxyindole (184 mg, 1.25 mmol) under Ar. The reaction was allowed to stir at the indicated time and temperature.

2.7.8 HPLC Traces of Enantioenriched Glycines

23 R H Racemic II-39j [!] = +0.997º (c 0.775, MeOH) ; HPLC N D O (OD-H) Daicel Chiralcel, 20:80 isopropanol:hexanes, 0.7 EtO HN OMe mL/min) 254 nm, tr :19 min, tr :22 min.

! 155 II-39jR (R-Catalyst)

II-39j (S-Catalyst)

! 156 H II-39i HPLC: Daicel Chiralcel OD-H 20:80 isopropanol:hexanes, N O flow rate = 1mL/min, 220 nm, t = 13 min, t = 14 min EtO minor major HN

Racemic II-39i

II-39i*

! 157 23 H II-39l: [!]D = +2.2º (c 1.25, MeOH); HPLC: Daicel Chiralcel, N O OD-H 20:80 isopropanol:hexanes, flow rate = 0.7 mL/min, 254 EtO HN Br nm, tminor = 12.13 min, tmajor = 13.70 min.

Racemic II-39l

II-39l*

! 158

23 O NH II-39m: [!]D = +8.1º (c 1.1, MeOH); HPLC (OD-H) Daicel

EtO Chiralcel, 20:80 isopropanol:hexanes, 0.7 mL/min) 254 nm, HN OMe tminor:28 min, tmajor :32 min. OMe Racemic II-39m

II-39m*

! 159 O NH Glycine II-39n was purified by flash column chromatography

EtO (5:95 ethyl acetate:hexanes to 30:70 ethyl acetate:hexanes). Rf = HN 1 OMe 0.3 (35:65 ethyl acetate:hexanes); H NMR (400 MHz, CDCl3) Me ! 8.11 (br s, 1H); 7.26-7.22 (m, 2H); 7.16 (d, J = 2.4 Hz, 1H);

6.99-6.90 (m, 2H); 6.88 (d, J = 8.8 Hz, 1H); 6.60-6.57 (m, 2H); 5.33 (s, 1H); 4.54 (br s,

1H); 4.30-4.23 (m, 1H); 4.19-4.13 (m, 1H); 3.89 (s, 3H); 2.23 (s, 3H); 1.24 (t, J = 7.2 Hz,

13 3H); C NMR (100 MHz, CDCl3) ! 172.9, 154.5, 144.5, 131.7, 129.9, 127.5, 126.4,

123.8, 113.7, 113.0, 112.5, 112.2, 101.3, 61.6, 56.0, 54.8, 20.5, 14.3; FTIR (film) cm-1

3408, 3051, 2984, 1734, 1617, 1489; HRMS (ESI): Mass calculated for C20H23N2O3

[M+H]+, 339.1703. Found [M+H]+, 339.1691. HPLC (OD-H) Daicel Chiralcel, 20:80 isopropanol:hexanes, 0.7 mL/min) 254 nm, tmajor:20 min, tr :23 min.

Racemic II-39n

! ! ! ! ! ! ! !

! 160 II-39n*

O NMe II-39o: HPLC (OJ) Daicel Chiralcel 50:50 hexanes:isopropanol,

EtO flow rate = 1 mL/min, 254 nm, tminor = 55 min, tmajor = 66 min HN

OMe II-39o

! 161 H II-104: Purified by flash column chromatography (10:90 ethyl N O acetate:hexanes to 30:70 ethyl acetate:hexanes). Rf = 0.1 (35:65 EtO 1 O ethyl acetate/hexanes); H NMR (400 MHz, CDCl3) ! 7.94 (br O HN s, 2H), 7.25 (d, J = 8.4 Hz, 2H); 7.11 (dd, J = 8.8, 2.4 Hz,

4H); 6.86 (dd, J = 8.8, 2.4 Hz, 2H); 5.4 (s, 1H); 4.24 (q, J = 7.2 Hz, 2H); 3.81 (s, 6 H);

13 1.29 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) ! 173.5, 154.2, 131.7, 127.3,

124.2, 113.6, 112.6, 112.0, 101.4, 61.2, 56.0, 41.0, 14.5; FTIR (film) cm-1 3474, 3053,

+ 2986, 1734, 1486, 1265; HRMS (ESI): Mass calculated for C22H22N2Na1O3 [M+Na] ,

401.1472. Found [M+Na]+, 401.1458.

! 162

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! 167

Appendix A: X-ray Crystallographic Data of I-54a

The ORTEP plot is drawn with 50% probability ellipsoids for the non-hydrogen atoms. The hydrogen atoms are drawn with an artificial radius.

168 !

Figure A.1 X-Ray Crystal Structure of Difluoroboronate Urea I-54a Cocrystallized With Nitrobenzene

169

Appendix B: X-Ray Crystallographic Data of I-95a

The Ortep plot was drawn with 50% probability displacement ellipsoids and the hydrogen atoms were drawn with an artificial radius. Note: This crystal contains a single enantiomer. The correct absolute configuration of the molecule cannot be determined from the X-ray data.

170 ! Figure B.1 X-Ray Crystal Structure of Oxazinane I-95a

171

Appendix C: X-Ray Crystallographic Data of I-56c

The Ortep plot was drawn with 50% probability displacement ellipsoids and the hydrogen atoms were drawn with an artificial radius.

172 !

Figure C.1 X-Ray Crystal Structure of Urea I-56c Cocrystallized with Nitrobenzene

173

Appendix D: X-Ray Crystallographic Data of Ethyl 2-(1-methyl-1H-indol-3-yl)-2-(p-

tolylamino)acetate

The Ortep plot was drawn with 50% probability displacement ellipsoids and the hydrogen atoms were drawn with an artificial radius.

174 ! Figure D.1 X-Ray Crystal Structure of Ethyl 2-(1-methyl-1H-indol-3-yl)-2-(p-tolylamino)acetate

175

Appendix E: Select NMR Spectra

176 ppm 1 2 3 4 5

7.096

7.115

7.133

2.11

7 7.152

1.07

7.280

1.00 7.299

7.402

7.420

1.04

7.958 −

8 2.00 8.111 9

10.652 1.01

11 1.00 11.275 bis(trifluoromethyl)phenyl) (difluoroboryl)phenyl)urea − − (2 − (3,5 3 − 1

177 ppm 10 20 30 40 50 60 70 80 90

100

115.406 −

118.398 110

118.972

121.682

122.989 124.394

120

124.562

127.105

128.169 130.586

130 130.884

131.213

131.542

137.477 138.095 140

150 154.433 bis(trifluoromethyl)phenyl) − (difluoroboryl)phenyl)urea 160 − (3,5 (2 − − 1 3

178 ppm

1 12.03 1.249 2 3 4

7.043

7.046

7.061 7.064

7.079

7.082

7.366

7.370

1.01

7.384 7

7.388 2.03

7.409 1.01

1.01 7.411 7.429

2.02

7.508 tramethyl-1,3,2-

3 7.512

CF 7.527

7.530

7.696 9 1.00

8.162 N H

Me 9.180 O O Me

B N H 1.00 9.932 O Me Me 10 dioxaborolan-2-yl)phenyl)urea 11 1-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(4,4,5,5-te

179 ppm

3.031

3.034

3.038

3.040 2

3.066

3.068

3.072

3.074

1.02

3.143

1.06 3.173

3.178

3.208

4.018

5.026 3.00

4 5.032

5.056

5.061

5.999

6.880

1.02

7.096 5

7.099

7.118

7.121

7.164

7.182

te 1.00

6 7.186

7.204

7.222

7.227

1.02 7.235

2.04

7.240 7

5.29 7.245

3.18 7.259

Ph 4.26 7.441 Me

2 7.459 CO

7.480 N

2 8 N

7.484 O

7.495 Ph Ph

7.499

7.516

7.520 7.561 )-4-nitro-2,3,6-triphenyl-1,2-oxazinane-4-carboxyla 9

7.562 ,6

R 7.580

7.584 7.591 methyl (3 methyl

180

ppm

1.196 1

3.15 1.214 1.231

3.668

4.088

4.106

4.115

4.124 3

4.133

4.142

4.151

1.86 4.169

4.185

4.203

1.08

4.212 4

4.220 1.06

4.229

4.238

4.247

4.265 0.91

4.812

1.00

4.827

4.937

4.953

6.553

6.555

6.569

6.574 6.577

6 6.638

6.643

6.654

2.00 6.659

3.03 6.666

6.669

6.685

2.05 6.687 7

6.689 2.88

6.703

6.705

6.708

7.099

7.104

7.118 8

7.121

7.139

7.250

7.260 7.271 9

181

ppm

1.214

1.231 2.99

1.249

3.868

4.110

4.128 2

4.136

4.145

4.154

4.163 4.172

3 4.190

4.230

4.248

4.257

3.07 4.266

4.275 4 1.21

4.284 1.00

4.293

0.93

4.311

4.627

4.635

5.286 1.00

5.293

6.565

6.570 6.575

6 6.581 -indol-3-yl)acetate

H 6.587

6.593

O 1.99

6.598

3.35

6.835 NH

6.845 7 1.07

6.850 1.72

NH 6.857

O 6.866

O 6.882 6.888

8 F

6.904 1.00

6.910

7.155

7.161

7.218

7.240 9

7.254

7.259 ethyl 2-((4-fluorophenyl)amino)-2-(5-methoxy-1 8.200

182

ppm

1.273 1

1.291 3.14 1.308

3.718

4.210

4.211

3.03 4.228 4.229

4 4.245

2.03

4.247

4.263

4.265

5.439

6.987 5

7.078

1.00 7.081

7.095

7.098 7.101

7.115

7.118 7.168 -indol-3-yl)acetate

H 7.189

1.14

7.215 2.18

7.218 7 Me 1.19

7.236 2.41

1.05 7.247

1.11 7.252

O 1.01 HN 7.269

O 7.273

8 1.01 7.296

-indol-3-yl)-2-(1-methyl-1 7.316

7.601

7.603 7.621

9 7.625

7.787

7.792 8.081 ethyl 2-(5-bromo-1

183

ppm

1.236 1

3.27 1.254

1.272

2 6.08 2.141 3.561

3 4.148

4.158

4.163 4.08

4.166

4.176

4.181 4

2.09

4.193

4.198

4.208

1.00

4.211 4.216

4.226

4.773

6.603

6.610

6.615

6 6.626

l)acetate

6.631

6.638 1.97

6.883

2.06 6.884

2 7 2.07

7.082

7.088

7.093 7.105

2 7.109

NH 7.115 8 O O 9 ethyl 2-(4-amino-3,5-dimethylphenyl)-2-(4-aminopheny

184