Reed Udel 0060D 14257.Pdf

AROMATIC FUNCTIONALIZATION AND

HETEROCYCLE SYNTHESIS VIA ANILINE N-OXIDES

Hayley Reed

A dissertation submitted to the Faculty of the University of Delaware in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry and Biochemistry

Summer 2020

AROMATIC FUNCTIONALIZATION AND

HETEROCYCLE SYNTHESIS VIA ANILINE N-OXIDES

Hayley Reed

Approved: ______Brian J. Bahnson, Ph.D. Chair of the Department of Chemistry and Biochemistry

Approved: ______John Pelesko, Ph.D. Dean of the College of Arts and Sciences

Approved: ______Douglas J. Doren, Ph.D. Interim Vice Provost for Graduate and Professional Education and Dean of the Graduate College

I certify that I have read this dissertation and that in my opinion it meets the academic and professional standard required by the University as a dissertation for the degree of Doctor of Philosophy.

Signed: ______William J. Chain, Ph.D. Professor in charge of dissertation

Signed: ______Mary P. Watson, Ph.D. Member of dissertation committee

Signed: ______Klaus H. Theopold, Ph.D. Member of dissertation committee

Signed: ______Jacob R. LaPorte, Ph.D. Member of dissertation committee

ACKNOWLEDGMENTS

Graduate school has been one of the most difficult challenges of my life. I owe thanks to many people for the fact that I have made it through to the other side. To my advisor, Professor William Chain: Your advice, support and trust throughout these five years has made this possible. Thank you for the freedom and assistance that enabled me to pursue a non-traditional career path. It was not something you had to do and I will always be grateful for it. To my committee members, Professor Mary Watson, Professor Klaus Theopold, and Dr. Jacob LaPorte: Thank you for all your support throughout my Ph.D. career. I am grateful for all the guidance you provided. To Rachel Putnik, Elijah Hudson and Tyler Swanson: You were the best office mates and colleagues I could ask for. I will miss our time together. Good luck with the next three years. I wish you all the best. To Tyler Paul, Vedant Submaranian, and Steven Liu: You all have helped make this work possible. I hope you learned as much from me as I did from you. To Megan Hoerrner: If there is one person without whom I would not have been able to finish graduate school, it would be you. From recruitment weekend roommates to now, I cannot thank you enough for your friendship and support over these five years. I would not have made it through this part of my life without you. In addition to the challenges graduate school presented and the relationships formed during it, many people beyond the walls of the University of Delaware have had a hand in shaping who I am today.

To Mrs. Roach, Mrs. Wakefield, and Mr. Rockey: You were the teachers who told me that it was possible for a kid to be quiet and reserved but also capable and determined. You made up for all the teachers who doubted me. I hope all the future kids like me have someone like you to tell them that they belong. To Mrs. Mills: When you hired me as a lab aide in high school, you probably didn’t realize how many doors that would open for me. So many of my experiences and opportunities over the years can be traced back to that job. Thank you for your trust and support. To the Allens: I have known all of you for longer than I care to admit. I hope that one day I will be as smart as you think I am. To my grandmother: the childhood summers spent with you that were filled with Uno, puzzles, and water ice are some of the clearest memories I have. You are one of the major reasons I decided to swerve onto a different career path. I wish you could understand how big of an impact you had on who I am and who I want to be. To my brother Jordan: You are and have always been a high standard to which to hold myself. Maybe someday, I will reach it. To my mom: You have always had my back. Everything I do is possible because you have made it so.

To Ryan: I don’t even need to say. You just know.

TABLE OF CONTENTS

LIST OF TABLES ...... x LIST OF FIGURES ...... xii ABSTRACT ...... xvii

Chapter

1 APPLICATIONS OF ANILINE N-OXIDES IN SYNTHETIC CHEMISTRY ...... 1

1.1 Traditional Methods of Aromatic Functionalization ...... 3 1.2 The Synthetic Potential of Aniline N-Oxides ...... 8 1.3 An Overview of Synthetic Exploitation of N–O Bonds ...... 9 1.4 The Discovery of a Route for Aniline Functionalization ...... 14 1.5 Previous Investigations into Aniline N-Oxide Functionalization ...... 17 1.6 Possible Mechanisms of Functionalization ...... 20 1.7 Indoline Synthesis via Tandem Polonovski-Mannich Reaction ...... 22 1.8 Aim of This Dissertation ...... 24

REFERENCES ...... 26

2 SYNTHESIS OF HALOGENATED ANILINES BY TREATMENT OF N,N-DIALKYLANILINE N-OXIDES WITH THIONYL HALIDES ...... 34

2.1 Introduction ...... 34

2.1.1 Traditional Methods of Preparing Halogenated Anilines ...... 37 2.1.2 Exploiting N–O Bonds for Aromatic Halogenation ...... 38 2.1.3 Proposed Work ...... 41

2.2 Results and Discussion ...... 42

2.2.1 Synthesis of N,N-Dialkylaniline N-Oxides ...... 42 2.2.2 Optimization of Thionyl Bromide as Brominating Agent ...... 43 2.2.3 Scope of Bromination with Thionyl Bromide ...... 46 2.2.4 Optimization of Phosphoryl Chloride as a Chlorinating Agent .. 48 2.2.5 Optimization of Thionyl Chloride as a Chlorinating Agent ...... 49

2.2.6 Scope of Chlorination with Thionyl Chloride ...... 51 2.2.7 Mechanistic Investigations ...... 53

2.3 Conclusion ...... 57 2.4 Experimental ...... 58

2.4.1 General Information ...... 58 2.4.2 Synthesis of N,N-Dialkylanilines ...... 60 2.4.3 Oxidation of N,N-Dialkylanilines ...... 82 2.4.4 Bromination N,N-Dialkylaniline N-Oxides ...... 98 2.4.5 Chlorination N,N-Dialkylaniline N-Oxides ...... 118

REFERENCES ...... 137

3 PREPARATION OF TETRAHYDROQUINOLINE SCAFFOLDS FROM N,N-DIALKYLANILINE N-OXIDES VIA TANDEM POLONOVSKI- POVAROV CYCLIZATION SEQUENCE ...... 141

3.1 Introduction ...... 141

3.1.1 An Overview of Tetrahydroquinoline Synthesis ...... 142 3.1.2 Discovery of the Tandem Polonovski-Povarov Cyclization via Aniline N-Oxides ...... 144 3.1.3 Past Chain Group Work in Tetrahydroquinoline Synthesis ...... 147 3.1.4 Proposed Work ...... 148

3.2 Results and Discussion ...... 149

3.2.1 Synthesis of N,N-Dialkylaniline N-Oxide 3-Chlorobenzoic Acid Salts ...... 149 3.2.2 Polonovski-Povarov Cyclizations with N-Vinylpyrrolidone .... 150 3.2.3 Polonovski-Povarov Cyclizations with 2-Phenylpropene ...... 151 3.2.4 Derivatives of Tetrahydroquinoline Scaffolds ...... 153 3.2.5 Mechanistic Investigations ...... 154

3.3 Conclusion ...... 159 3.4 Experimental ...... 160

3.4.1 General Methods ...... 160 3.4.2 Synthesis of N,N-Dialkylanilines ...... 162 3.4.3 Oxidation of N,N-Dialkylanilines ...... 164 3.4.4 Polonovski-Povarov Cyclizations with N-vinylpyrrolidone ..... 179 3.4.5 Polonovski-Povarov Cyclizations with 2-Phenylpropene ...... 201 3.4.6 Derivatives of Tetrahydroquinoline Scaffolds ...... 209

vii

REFERENCES ...... 219

4 PREPARATION OF 2-SUBSTITUTED INDOLES VIA REARRANGEMENT OF N,N-DIMETHYLANILINE N-OXIDES ...... 223

4.1 Introduction ...... 223

4.1.1 An Overview of Indole Synthesis ...... 226 4.1.2 Methods of Preparing 2-Reverse Prenylated Indoles ...... 227 4.1.3 Use of N–O Bonds in Indole Synthesis ...... 230 4.1.4 Proposed Synthesis ...... 231

4.2 Results and Discussion ...... 232

4.2.1 Substrate Preparation ...... 232 4.2.2 Investigation of N-Demethylation Conditions ...... 234 4.2.3 Optimization of Aniline N-Oxide Functionalization ...... 235 4.2.4 Attempts at Enol Tautomerization ...... 238

4.3 Conclusion ...... 239 4.4 Experimental ...... 240

4.4.1 General Methods ...... 240 4.4.2 Synthesis of β-Keto Acids ...... 241 4.4.3 Functionalization of Aniline N-Oxides ...... 247

REFERENCES ...... 250

5 PREPARATION OF ARYL SULFOXIDES VIA ACTIVATION OF N,N- DIMETHYLANILINE N-OXIDES WITH ALKYLDISULFANIUM SALTS ...... 254

5.1 Introduction ...... 254

5.1.1 Methods of Forming Aryl C–S Bonds ...... 257 5.1.2 N–O Bond Cleavage in Aryl C–S Bond Formation ...... 259 5.1.3 Proposed Work ...... 261

5.2 Results and Discussion ...... 263

5.2.1 Substrate Preparation ...... 263 5.2.2 Optimization of Aniline N-Oxide Functionalization ...... 264

5.3 Conclusion ...... 268

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5.4 Experimental ...... 269

5.4.1 General Methods ...... 269 5.4.2 Preparation of Alkyldisulfanium Salts ...... 270 5.4.3 Functionalization with Alkyldisulfanium Salts ...... 272

REFERENCES ...... 275

Appendix

A SPECTRAL DATA FOR CHAPTER 2 ...... 279 B SPECTRAL DATA FOR CHAPTER 3 ...... 440 C SPECTRAL DATA FOR CHAPTER 4 ...... 539 D SPECTRAL DATA FOR CHAPTER 5 ...... 557

LIST OF TABLES

Table 1.1: Bond dissociation energy values for the N–O bond and others commonly found in organic molecules ...... 9

Table 1.2: Reagents for successful indoline formation ...... 23

Table 2.1: Optimization of bromination reaction temperature ...... 44

Table 2.2: Optimization of solvent, reaction concentration, and addition sequence ... 46

Table 2.3: Optimization of chlorination using phosphoryl chloride ...... 49

Table 2.4: Optimization of reaction temperature ...... 50

Table 2.5: Optimization of addition sequence and reaction concentration ...... 51

Table 2.6: Salt ion exchange experiments ...... 55

Table 4.1: Screened demethylation conditions ...... 235

Table 4.2: Optimization of acyl chloride generation using 2,2-dimethyl-3- butenoacetic acid and 4,N,N-trimethylaniline N-oxide ...... 236

Table 4.3: Optimization of acyl chloride generation and reaction solvent using 2,2- dimethylpropanoacetic acid and 4,N,N-trimethylaniline N-oxide ...... 237

Table 4.4: Optimization of reaction solvent in acyl chloride generation and subsequent diketene intermediate using 2,2-dimethylpropanoacetic acid and 4,N,N-trimethylaniline N-oxide ...... 238

Table 4.5: Conditions for investigated for shifting tautomerization equilibrium ...... 239

Table 5.1: Optimization of reaction temperature and reagent equivalents of reaction between alkyldisulfanium salt and 4,N,N-trimethylaniline N- oxide ...... 264

Table 5.2: Optimization of reaction solvent and reagent equivalents of reaction between alkyldisulfanium salt and 4,N,N-trimethylaniline N-oxide ..... 266

Table 5.3: Optimization of reagent equivalents of reaction between alkyldisulfanium salt and N,N-dimethylaniline N-oxide ...... 267

Table 5.4: Optimization of Lewis acid activation in reaction between alkyldisulfanium salt and N,N-dimethylaniline N-oxide ...... 268

LIST OF FIGURES

Figure 1.1: Examples of anilines and their derivatives found in bioactive molecules ... 2

Figure 1.2: Examples of anilines found in ligands ...... 3

Figure 1.3: Examples of common cross coupling reactions ...... 4

Figure 1.4: Common examples of electrophilic aromatic substitution ...... 5

Figure 1.5: Mechanism of electrophilic aromatic substitution ...... 6

Figure 1.6: Evolution of the Claisen rearrangement to aromatic aza-Claisen rearrangement ...... 7

Figure 1.7: Examples of N-oxides ...... 8

Figure 1.8: Aromatic functionalization via N-arylhydroxylamines and aniline N- oxides ...... 10

Figure 1.9: Examples of carbon–carbon bond formation via N-arylhydroxylamines .. 11

Figure 1.10: Examples of carbon–heteroatom bond formation via N- arylhydroxylamines ...... 12

Figure 1.11: Examples of aromatic functionalization via aniline N-oxides ...... 13

Figure 1.12: Proposed enolate aza-ortho-xylylene reaction ...... 15

Figure 1.13: Approach to generating aza-ortho-xylylenes via silyl protected anilines ...... 15

Figure 1.14: Arylation of N,N-dimethylaniline-N-oxides with trifluoromethanesulfonic acid and benzene ...... 16

Figure 1.15: Generating aza-ortho-xylylenes via aniline N-oxides ...... 17

Figure 1.16: Carbon–heteroatom bond formation via N,N-dimethylaniline N-oxides . 18

Figure 1.17: Carbon-carbon bond formation via N,N-dimethylaniline N-oxides ...... 19

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Figure 1.18: [3,3] rearrangements in N-arylhydroxylamines and aniline N-oxides ..... 20

Figure 1.19: SN2’ nucleophilic addition in N-arylhydroxylamines and aniline N- oxides ...... 21

Figure 1.20: Radical cleavage in aniline N-oxides ...... 22

Figure 1.21: Unexpected reagent dependent indoline formation ...... 23

Figure 1.22: Mechanism of Polonovski-Mannich reaction ...... 24

Figure 2.1: Examples of anilines halides in pharmaceuticals ...... 35

Figure 2.2: Examples of halogenated anilines in natural products ...... 35

Figure 2.3: Uses of aryl halides in transition metal catalysis ...... 36

Figure 2.4: Uses of aryl halides as organometallic reagent precursors ...... 37

Figure 2.5: Traditional methods of aromatic halogenation via electrophilic aromatic substitution and transition metal catalysis ...... 38

Figure 2.6: Halogenation of pyridine N-oxides, quinoline N-oxides, and isoquinoline N-oxides ...... 39

Figure 2.7: Halogenation of N-arylhydroxylamines ...... 40

Figure 2.8: Proposed mechanisms for halogenation via aniline N-oxides ...... 42

Figure 2.9: N-alkyl-N-methylaniline N-oxides not previously prepared and described by the Chain group ...... 43

Figure 2.10: Preliminary result for bromination using SOBr2 ...... 44

Figure 2.11: Scope of the bromination of aniline N-oxides ...... 48

Figure 2.12: Scope of the chlorination of aniline N-oxides ...... 53

Figure 2.13: Radical trapping experiment using BHT ...... 54

Figure 2.14: Hammett correlations for bromination of meta- and para-substituted N,N-dimethylaniline N-oxides ...... 56

Figure 2.15: Hammett correlations for chlorination of para-substituted N,N- dimethylaniline N-oxides ...... 57

xiii

Figure 3.1: Examples of compounds containing tetrahydroquinolines with useful applications ...... 142

Figure 3.2: Methods of preparing tetrahydroquinolines ...... 143

Figure 3.3: Preparation of 4-aminotetrahydroquinolines ...... 144

Figure 3.4: Proposed nucleophilic addition pathway based on N-arylhydroxylamine chemistry ...... 145

Figure 3.5: Summary of nucleophiles investigated ...... 145

Figure 3.6: Unexpected results in nucleophilic addition ...... 146

Figure 3.7: Proposed mechanism of tandem Polonovski-Povarov cyclizations ...... 147

Figure 3.8: Polonovski-Povarov cyclizations published by the Chain group ...... 148

Figure 3.9: Proposed alkenes to investigate...... 149

Figure 3.10: Preparation of N,N-dialkylaniline N-oxide 3-chlorobenzoic acid salts . 150

Figure 3.11: Scope of Polonovski-Povarov cyclizations with N-vinylpyrrolidone ... 151

Figure 3.12: Scope of Polonovski-Povarov cyclizations with 2-phenylpropene ...... 152

Figure 3.13: Reduction and alkylation of tetrahydroquinoline scaffolds ...... 153

Figure 3.14: N-oxidation and halogenation of tetrahydroquinoline scaffolds ...... 154

Figure 3.15: Reaction coordinate diagram for Polonovski-Povarov step-wise cyclization with N-vinylpyrrolidone produced from DFT computations ...... 156

Figure 3.16: Reaction coordinate diagram for Polonovski-Povarov concerted cyclization with N-vinylpyrrolidone produced from DFT computations ...... 157

Figure 3.17: Reaction coordinate diagram for Polonovski-Povarov step-wise cyclization with 2-phenylpropene produced from DFT computations . 158

Figure 3.18: Reaction coordinate diagram for Polonovski-Povarov concerted cyclization with 2-phenylpropene produced from DFT computations . 159

Figure 4.1: Examples of indoles in prescription medications ...... 224

xiv

Figure 4.2: Examples of indoles in natural products used in traditional medicines and cultures ...... 224

Figure 4.3: Examples of reverse prenylated indoles in bioactive compounds ...... 225

Figure 4.4: Examples of common indole syntheses ...... 227

Figure 4.5: Methodologies for 2-reverse prenylation of indoles ...... 228

Figure 4.6: Examples of 2-reverse prenylation of indoles from total syntheses ...... 229

Figure 4.7: Aniline N-oxides in indole synthesis ...... 230

Figure 4.8: Proposed route for C2 substituted indole synthesis ...... 231

Figure 4.9: N-arylhydroxylamine and aniline N-oxide precedent for the proposed 2- substitued indole synthesis ...... 232

Figure 4.10: Preparation of 2,2-dimethyl-3-butenoacetic acid ...... 233

Figure 4.11: Preparation of 2,2-dimethylpropanoacetic acid ...... 234

Figure 5.1: Examples of aryl sulfides in bioactive molecules ...... 255

Figure 5.2: Examples of aryl sulfides and sulfoxides in natural products ...... 255

Figure 5.3: Examples of aryl sulfones in pesticides ...... 256

Figure 5.4: Synthetic uses of aryl sulfoxides in transition metal catalysis, aromatic functionalization, and as chiral auxiliaries ...... 257

Figure 5.5: Preparation of aryl sulfoxides, sulfones, and sulfides ...... 258

Figure 5.6: Preparing aniline sulfoxides, sulfones, and sulfides ...... 259

Figure 5.7: Aryl C–S bond formation via N-arylhydroxylamines ...... 260

Figure 5.8: Aryl C–S bond formation via aniline N-oxides ...... 261

Figure 5.9: Cation-p cyclization using alkyldisulfanium salts ...... 262

Figure 5.10: Comparison of proposed work to previous functionalization work ...... 263

Figure 5.11: Synthesis of thioethers and methyldisulfanium salt ...... 263

Figure 5.12: Proposed mechanism of formanilide byproduct formation ...... 265

xvi

ABSTRACT

This dissertation focuses on the development of new methodologies for aromatic functionalization and heterocycle synthesis via the excision of the N–O bond in aniline N-oxides. Chapter 1 serves as an introduction to aromatic functionalization methods with a focus on those achieved through exploiting the cleavage of N–O bonds. Chapters 2 and 5 focus on the use of aniline N-oxides to prepare halogenated anilines and aryl sulfoxides. Chapters 3 and 4 concentrate on the synthesis of tetrahydroquinolines and indoles via aniline N-oxides.

Chapter 2 describes a metal-free method of preparing halogenated anilines from aniline N-oxides via activation of N-alkyl-N-methylaniline N-oxides with thionyl halides. A variety of aromatic substituents and substitution patterns as well as differentially N-substituted aniline N-oxides were tolerated. Treatment of aniline N- oxides with thionyl bromide selectively produced para-bromoanilines; treatment of aniline N-oxides with thionyl chloride preferentially synthesized ortho-chloroanilines.

Excitingly, this methodology does not require Lewis acids, exotic reagents, or activation of halogen sources. Preliminary mechanistic experiments suggest that para- halogenation occurs via a nucleophilic addition mechanism and ortho-halogenation occurs via a [3,3]-sigmatropic rearrangement.

xvii

Chapter 3 describes Polonovski-Povarov cyclizations to prepare tetrahydroquinoline scaffolds from aniline N-oxides and N-vinylpyrrolidone and 2- phenylpropene. Metal-free conditions to achieve these transformations are also disclosed. Derivatives of synthesized tetrahydroquinoline scaffolds were prepared.

Preliminary mechanistic investigations into both transformations indicate that the cyclization can occur via a concerted or stepwise Povarov reaction mechanism.

Chapter 4 describes efforts towards using aniline N-oxides and β-ketoacyl chlorides to prepare 2-substituted indoles, specifically 2-reverse prenylated indoles.

The use of β-ketoacyl chlorides would allow for a versatile methodology for preparing diverse 2-substiuted indoles beyond 2-reverse prenylated indoles. Preliminary investigations have not resulted in the synthesis of the desired indole products; however, further optimization of this methodology is ongoing.

Chapter 5 describes efforts towards preparing aryl sulfoxides from aniline N- oxides and alkyldisulfanium salts. The use of alkyldisulfanium salts to activate aniline

N-oxides would provide a metal-free method of preparing differentially substituted sulfoxides. Preliminary efforts have prepared few examples of aryl sulfoxides in low yields. No further optimization of this reaction is planned.

xviii

APPLICATIONS OF ANILINE N-OXIDES IN SYNTHETIC CHEMISTRY

Pharmaceuticals, natural products, and other biologically active molecules are amalgamations of diverse scaffolds. An aniline, an amine substituent directly bonded to an aromatic ring, is a scaffold commonly found in important compounds.

Systematic study of the preparation of aniline-containing compounds has contributed, and would continue to benefit, the field of synthetic organic chemistry as synthetic building blocks and to society as active pharmaceuticals.1 Via aryl diazonium salts, anilines are particularly useful in aromatic functionalization through nucleophilic aromatic substitution and cross coupling chemistry.2 Moreover, anilines are commonly used starting materials in heterocycle synthesis. For example, the Larock3 and Fischer4 indole syntheses and the Skraup-Doebner-Miller quinoline synthesis5 all transform aniline substrates into heterocycles. In addition, bioactive compounds currently prescribed to patients in the treatment of various medical conditions contain anilines or aniline derivatives (Figure 1.1).

CH3 O CH3 N S CH O N CH Cl N CH3 3 3 N H3C H HN H N OH S O N H N OCH H 2 3 O O O O

CH3 Cl N

metoclopramide (1-1) elobixibat (1-2) chloroquine (1-3), R = H hydroxychloroquine (1-4), R = OH Figure 1.1: Examples of anilines and their derivatives found in bioactive molecules

For example, metoclopramide (1-1) is marketed in the United States under brand names Reglan and Metozolv to treat heartburn and esophageal ulcers in people with gastroesophageal reflux disease; it also has been prescribed to treat nausea and vomiting caused by the slow stomach emptying commonly present in diabetes patients.6 Yearly prescriptions of metoclopramide have declined over the years from a peak of over six million prescriptions in 2008, but metoclopramide remains prevalent with patients in the United States receiving nearly two million prescriptions in 2017.7

Elobixibat (1-2) is an ileal bile acid transporter inhibitor approved for the treatment of chronic constipation in Japan, marketed under the brand name Goofice.8 Elobixibat has only recently been on the market in Japan, but as the flagship drug of Albireo

Pharmaceuticals, it helped drive the company’s initial public offering in 2017.9

Heterocycles such as quinolines can be prepared from anilines. Chloroquine

(1-3) and hydroxychloroquine (1-4), both quinoline-containing drugs, are used as a preventative and acute treatment for malaria and a treatment for autoimmune diseases and rheumatoid arthritis, respectively.10 During the global coronavirus pandemic in

2020, both drugs experienced renewed interest after being touted by the Trump

administration as potential, albeit unproven and potentially risky, treatments for

COVID-19.11 Beyond pharmaceuticals, synthetic chemists have found use for aniline- containing ligands (1-5 – 1-7) in transition metal-catalyzed transformations such as allylic oxidations and asymmetric Michael additions.12

H3C O O O Ph2P N NH HN

N PPh2 N N N N O O tBu tBu

1-5 1-6 1-7 Pd-catalyzed Pd-catalyzed Co-catalyzed allylic alkylations allylic alkylations Michael additions Figure 1.2: Examples of anilines found in ligands

1.1 Traditional Methods of Aromatic Functionalization

There are many known methods for the preparation and functionalization of aromatic systems.14–22 However, these traditional methods are difficult to apply to electron-rich substrates such as anilines due to the electron-donating character of such motifs.23 These shortcomings necessitate the development of efficient methods to prepare highly functionalized aniline substrates for use in organic synthesis.

For decades, the premier method of aromatic functionalization has been cross coupling chemistry, which forms new bonds in highly functionalized substrates in high chemoselectivity (Figure 1.3).13-17 First described in 1969, the Heck reaction couples aryl halides or triflates (1-8) and olefins (1-9) to form a new C–C bond (1-

10).14 Likewise, Sonogashira cross couplings combine alkynes (1-11) and aromatic

systems;15 Suzuki reactions prepare biaryls and alkylated aromatic rings (1-14) from boronic species (1-13) and activated aromatic systems.16 Formation of carbon– heteroatom bonds is possible via the Buchwald-Hartwig amination which produces anilines (1-16) from substituted amines (1-15) and aryl halides.17

1-9 1-15 R2 R3 R2 N H R2 Pd0 L PdCl R2 2 2 N ligand, base, solvent base, solvent R3 R1 R1 Heck Buchwald-Hartwig 1-10 Reaction Amination 1-16 X 1-11 R1 H R2 1-13 0 II 1-8 2 Pd or Pd R2B(R3) R X = Br, I, OTf 2 Cu(I) Pd0 R2 1 ligand, base, solvent ligand, base, solvent R R1 Sonogashira Suzuki 1-12 Cross Coupling Cross Coupling 1-14 Figure 1.3: Examples of common cross coupling reactions

The benefits of cross coupling chemistry are abundant: (1) they are generally high-yielding methodologies, (2) the catalysts employed have high tolerance for diverse functional groups, and (3) there are few problems with over-reactivity and stereoselectivity with respect to electron-rich substrates. Despite the synthetic utility of cross coupling chemistry, there remain limitations. Transition metal catalysts and ligands necessary for executing these transformations tend to be expensive. Cost- effective, metal-free functionalization methods free from toxicities associated with metals or additional purification to remove metal contamination are preferred in preparative pharmaceutical synthesis.18 Furthermore, cross coupling methodologies

require a pre-functionalized aromatic substrate. As such, starting material often needs to be prepared in-house using other traditional functionalization methods when not commercially available or affordable.

One long-established method, important enough to be a part of undergraduate organic chemistry curricula, is electrophilic aromatic substitution. Employing this methodology, a synthetic chemist can begin with otherwise unactivated aromatic rings

(1-17) and form diverse types of bonds (Figure 1.4).19-22 Friedel-Crafts alkylations and acylations20 and Vilsmeier-Haack formylations21 can be employed to substitute a carbonyl onto an aromatic ring to yield phenones (1-19) and benzaldehydes (1-20), respectively. In addition, aryl halides (1-21)22 and aryl nitrates (1-22)23 can be prepared from unactivated aromatic systems.

O 1-18 O Cl R2 O DMF, POCl3 AlCl3 then H2O H R1 R2 R1 Friedel-Crafts Vilsmeier-Haack Acylation/Alkylation Formylation 1-20 1-19

1-17 X Lewis acid, X HNO3, H2SO4 NO2 1 2 R R1 Halogenation Nitration 1-21 1-22 Figure 1.4: Common examples of electrophilic aromatic substitution

Yet, despite their utility to form various types of bonds, there are limitations to electrophilic aromatic substitution reactions.24 The types of transformations possible

are limited due to the stability of cationic intermediates (1-24) formed prior to rearomatization (Figure 1.5, eq 1). Although substrates with electron-rich substituents

(R = OR1, NR1R2) are able to better stabilize this cation, the stability comes at the cost of a predilection to over-reactivity and compromised regioselectivity (Figure 1.5, eq 2 and 3). Anilines fall into a class of compounds that are electron-rich; therefore, methods to functionalize anilines with control and selectivity are needed.

H E R1 E R1 E R1 (1)

1-23 1-24 1-25

R1 R2 R1 R2 R1 R2 R1 R2 N N N N H H E E E E (2)

1-26 1-27 1-28 1-29

H H E E E E (3) R1 R1 R1 R1 N N N N R2 R2 R2 R2 1-26 1-30 1-31 1-32 Figure 1.5: Mechanism of electrophilic aromatic substitution

For this reason, electron-rich functionality is a liability, but solutions specific for anilines have been identified. The traditional Claisen rearrangement (Figure 1.6, eq 1) has been modified to permit controlled functionalization of anilines.25 The nitrogenous analog of this rearrangement, the aza-Claisen rearrangement, was developed by replacing the oxygen in the allylic vinyl ether (1-33) with an amine (1-

35) and requires harsher conditions, like higher temperatures or Lewis acid activation, than the classical oxygen-based Claisen rearrangement (Figure 1.6, eq 2).26

This reactivity was extended to aniline substrates via an aromatic aza-Claisen rearrangement (Figure 1.6, eq 3).27 An ammonium ion is used to overcome the inherent stability of the aromatic system. This rearrangement offers a solution to prevent over-alkylation and to provide regiocontrol in the formation of functionalized aniline products; however, the aromatic aza-Claisen rearrangement remains an inefficient process as it requires elevated temperatures and only offers a means to C–C bond formation and carbon-based functionality on the aromatic system.

Claisen O Rearrangement O (1) 25−130 °C 1-33 1-34

Aza-Claisen R1 Rearrangement R1 N N (2) 175−250 °C 1-35 1-36

R2 Aromatic Aza-Claisen R1 R2 R1 N Rearrangement N (3) 3 R3 R 25−110 °C

1-37 1-38 Figure 1.6: Evolution of the Claisen rearrangement to aromatic aza-Claisen rearrangement

Traditional methods – cross coupling reactions, electrophilic aromatic substitution, and aromatic aza-Claisen rearrangements – can be used to functionalize the aromatic systems of anilines, but there are severe limitations. There is a need for

new metal-free, controlled, and efficient synthetic pathways for the functionalization anilines. Aniline N-oxides (1-39) are a class of compounds with great promise for use in aromatic functionalization (Figure 1.7).

H3C O H3C O O H3C N N N

N,N-dimethylaniline N-oxide (1-39) NMO (1-40) pyridine-N-oxide (1-41) aniline N-oxide tertiary amine N-oxide heteroaromatic N-oxide Figure 1.7: Examples of N-oxides

1.2 The Synthetic Potential of Aniline N-Oxides

Amine N-oxides, of which aniline N-oxides are a type, are defined by a coordinate covalent bond between nitrogen and oxygen, meaning both electrons in the bond come from a single atom, in this case the nitrogen. This bond renders the compound a hydrogen bond acceptor and allows it to act as a Brönsted or Lewis base.28 Beyond amine N-oxides like N-methylmorpholine N-oxide (NMO, 1-40), an oxidant used in conjunction with tetrapropylammonium perruthenate (TPAP), heteroaromatic N-oxides like pyridine N-oxide (1-41) are the other type of N-oxides most commonly encountered. Amine N-oxides are easily handled and bench stable, but some may be slightly hygroscopic.28-29 Aniline N-oxides have underexplored potential for aromatic functionalization via their N–O bond.

A comparison of bond dissociation energies (BDEs) of bonds found in organic molecules30 to the N–O bond of amine N-oxides28 explains the structural feature of

the aniline N-oxide that can be exploited (Table 1.1). Bonds in organic molecules are generally difficult to break (e.g. C–C, C–O, and C–H bonds) are all at least 20 kcal/mol greater in energy than a N–O bond. Bonds with BDEs more comparable to a

N–O bond are C–I and C–Br bonds, quintessential synthetic handles in organic synthesis.31 Aniline N-oxides can be employed for aromatic functionalization by utilizing N–O bond strength to relative other easily cleavable bonds with documented transformational use in organic chemistry.

Table 1.1: Bond dissociation energy values for the N–O bond and others commonly found in organic molecules

Bond Type C(sp3)–I N–O C(sp3)–Br C–N C–C C–O C–H BDE (kcal/mol) 51 65 68 73 88 91 104 Length (Å) 2.14 1.30 1.94 1.47 1.54 1.43 1.09

1.3 An Overview of Synthetic Exploitation of N–O Bonds

The potential of the N–O bond as a driving force for aromatic functionalization has been described in the literature; however, descriptions of exploitations of the N–O bond in N-arylhydroxylamines (1-42) are more common than those in aniline N-oxides

(Figure 1.8). These transformations are proposed to proceed through three different mechanistic pathways: (1) pericyclic rearrangement, (2) nucleophilic addition, and (3) radical cleavage and recombination.32 Regardless of the mechanistic pathway, these transformations form new C–C and carbon–heteroatom bonds on aromatic systems.

R2 O R2 O R2 N X N X NH N−O Bond Y Y proton Y (1) Excision transfer X R1 R1 H R1 O

1-42 1-43 1-44

R2 R2 R2 O O O R2 R3 R3 N R3 N X R3 N X N N−O Bond Y Y + Y (2) Activation Excision −H X R1 R1 R1 H R1 O 1-45 1-46 1-47 1-48 Figure 1.8: Aromatic functionalization via N-arylhydroxylamines and aniline N-oxides

There are limited examples in which N-arylhydroxylamines have been used for

C–C bond formation.33-34 Coates and Said have shown that alkyl-substituted b- ketoacid-activated N-arylhydroxylamines undergo a proposed [3,3]-sigmatropic rearrangement to form a new C–C bond in 40 to 82% yield (Figure 1.9, eq 1).34 In addition, Mao and Baldwin have demonstrated that 2-oxindole spirocycles can be prepared from N-arylhydroxylamine esters and subsequent derivatization (Figure 1.9, eq 2).35 However, the scope of these transformations is limited to migrating groups that are intrinsically able to undergo the rearrangement or others that require harsh reagents like strong bases to initiate the rearrangement and cleavage of the N–O bond.

In addition, much like the aza-Claisen rearrangements, N-arylhydroxylamine rearrangements often require high temperatures to functionalize the aromatic system.

R2 O O R2 O OH R2 N N NH O 3 toluene O [3,3] R R1 R1 R1 (1) R3 3 O 110 °C R −CO 30-90 min 2 1-49 1-50 1-51 40-82% O O O O H3CO N H3CO NH HN O KHMDS CO2H (2) THF, −78 °C 1-52 1-53 1-54 82% Figure 1.9: Examples of carbon–carbon bond formation via N-arylhydroxylamines

New C–O and C–N bond formation via N-arylhydroxylamines has been described in the literature.36-37 A [3,3]-sigmatropic rearrangement of O-acyl-N- arylhydroxylamines initiated by microwave heating forms new C–O bonds in 67 to

94% yield as described by Porzelle et al. (Figure 1.10, eq 1).37 Described by Porzelle et al., treatment of N-arylhydroxylamines with trichloroacetonitrile results in a reactive imidate that rearranges to give new C–N bonds in 15 to 86% yield (Figure

1.10, eq 2).38 Like those C–C bond forming rearrangements, these reactions have been mechanistically described as formal [3,3]-sigmatropic rearrangements and can be limited by the high temperatures or harsh reagents often necessary to facilitate these rearrangements.

O O O O O OR2 R2O R2O N R2O NH N O O toluene O OR2 R1 R1 R1 (1) MW, 110 °C O 3 h 1-55 1-56 1-57 67-94% 75-86%

O O OH 2 R N Cl3C N R2 NH H imidazole N CCl3 R1 R1 (2) DMF, 40 °C O 1-58 1-59 15-86% Figure 1.10: Examples of carbon–heteroatom bond formation via N- arylhydroxylamines

As a whole, these examples of N–O bond cleavage of N-arylhydroxylamines as a driving force for aromatic functionalization indubitably reinforce the belief that effective use of N–O bonds for this purpose is ripe for further study and expansion.

The application of methods to N-arylhydroxylamines often require prolonged exposure to elevated temperature, microwave heating, or other harsh reagents. In addition, while these transformations have the potential to be efficient, they demand careful consideration of N-substitution and sensitivity to the electronic character of the aromatic ring, as in electrophilic aromatic substitution. These shortcomings are aspects upon which aniline N-oxides can improve via their weak coordinate covalent

N–O bond.

Examples of aromatic functionalization via aniline N-oxides are rare other than those of N-arylhydroxylamines.38-41 In one example, activation of N,N- dimethylaniline-N-oxide with diketene to form benzylketone 1-62 in 38% yield is

described (Figure 1.11, eq 1).39 Spectroscopic data of this reaction supports a mechanism that involves homolytic cleavage of the N–O bond into radical pairs not a

[3,3] rearrangement as proposed with N-arylhydroxylamines. Acetic anhydride activates para-substituted aniline N-oxides (63) to form a new C–O bond upon rearrangement in 32 to 58% yield (Figure 1.11, eq 2).40 N,N-dimethylaniline-N-oxides are activated by an N-alkylacetonitrilium salt to yield new C–N bond in 38% yield

(Figure 1.11, eq 3).41 In all, very few methods employing aniline N-oxides for aromatic functionalization have been described.42

H3C H3C O O OH H3C CH3 H3C N O H3C N N O O CH3 (1) CH O CH2Cl2, 0 °C 3

1-60 1-61 1-62 38%

H3C H3C O O CH3 H3C CH3 H3C N H3C N N

Ac2O O O CH3 (2) −30 to 0 °C O

R R R 1-63 1-64 1-65 32-58%

H3C H3C CH O O CCl3 H3C 3 H3C N H3C N N CH3

Cl C N CH N N CCl3 3 3 CH 3 (3) O CH2Cl2, 0 °C

1-66 1-67 1-68 38% Figure 1.11: Examples of aromatic functionalization via aniline N-oxides

1.4 The Discovery of a Route for Aniline Functionalization

Despite evidence that aniline N-oxides are useful for aromatic functionalization, the discovery of their utility by the Chain group was not straightforward. Their incorporation as an arm of the group’s research program was incidental and serendipitous, as often is the case in research. It began with the search for a reaction analogous to an enolate ortho-quinone methide reaction proposed as a key step in total syntheses for premnalatifolin A and psiguadial A. The methodology, which involves using a fluoride source and precursor (1-69) to in situ generate an ortho-quinone methide (1-71) was developed, and ultimately published by the Chain group in 2015.43 Phenolic adduct (1-73) forms after a deprotected enol (1-72) adds onto the reactive ortho-quinone methide intermediate (Figure 1.12, eq 1). The group envisioned a nitrogen intermediate (1-75) analogous to an ortho-quinone methide (1-

71). A precursor (1-74) that could generate a reactive aza-ortho-xylylene species (1-

75) needed to be prepared. An aniline type adduct (1-76) would form after a deprotected enol (1-72) adds into the reactive aza-ortho-xylylene (Figure 1.12, eq 2).

The success of this endeavor rested on finding a precursor that would generate an aza- ortho-xylylene intermediate in a manner compatible with the enol deprotection.

OH 1-72 TMS TMS O R3 OH 1 2 O Cl O Cl 2 R R F R 1 (1) R1 R1 R O R3 1-69 1-70 1-71 1-73

OH 1-72 R1 R2 R2 R2 R4 3 N N 3 NH R conditions? R (2) X O R4 1-74 1-75 1-76 Figure 1.12: Proposed enolate aza-ortho-xylylene reaction

The initial precursor prepared by the group was a direct corollary to the published ortho-quinone methide generation: an N-silyl-protected aniline with an ortho-benzylic leaving group (1-77, Figure 1.12, eq 1).44 Treatment with fluoride would deprotect the nitrogen and eliminate the leaving group to form an aza-ortho- xylylene (1-79). However, despite their best efforts in preparing a precursor (1-77), researchers in the group were unable to generate 1-79 via N-silyl-protected anilines.

1-80 OH TMS Bn TMS Bn Bn Bn R2 1 N N N 1 NH R F R (1) LG LG O R2 1-77 1-78 1-79 1-81 Figure 1.13: Approach to generating aza-ortho-xylylenes via silyl protected anilines

The group’s next approach to generate the aza-ortho-xylylene was inspired by reactivity of aniline N-oxides reported by Shudo et al. in which a biaryl product was formed by treatment of N,N-dimethylaniline-N-oxide with trifuoromethanesulfonic

acid (TfOH) and benzene (Figure 1.14, eq 1).45 N,N-dimethylaniline N-oxide (1-82) is protonated by the strong acid to yield a doubly cationic species (1-83) from which a molecule of water is expelled. Benzene adds onto the intermediate (1-84) and after rearomatization yields biaryls N,N-dimethyl-4-phenylaniline (1-86) and N,N- dimethyl-2-phenylaniline (1-87) in 76% and 6% yield, respectively. In a separate experiment, 4,N,N-trimethylaniline N-oxide (1-88) is subjected to the same conditions and produces 4-benzyl-N,N-dimethylaniline in 4% yield (1-91, Figure 1.14, eq 2). The authors propose that the formation of 1-91 likely proceeds through an aza-para- xylylene intermediate (1-90) generated by the excision of the N–O bond.

H3C CH3 H3C CH3 N N H C CH H3C O H3C OH H3C CH3 3 3 + 2 N N H3C N H H3C N

PhH H H (1)

1-82 1-83 1-84 1-87 76% 1-85 1-86 76%

H3C CH3 N H C H C 3 O 3 OH2 H3C CH3 H3C N H3C N N H+ (2) PhH

CH3 CH3 1-90 1-91 1-88 1-89 4% Figure 1.14: Arylation of N,N-dimethylaniline-N-oxides with trifluoromethanesulfonic acid and benzene

Using this work as inspiration, the Chain group envisioned generating the aza- ortho-xylylene through the cleavage of a benzylic trimethylsilyl substituent and excision of an activated N–O bond upon treatment with a fluoride source (Figure 1.15,

eq 1). While testing this proposal using substrate 1-96 and trifluoroacetic anhydride

(TFAA) to activate the N–O bond for excision, the group was unable to produce the desired aza-ortho-xylylene intermediate or adduct; however, an unexpected hydroxylated aniline (1-97) was isolated in 50% yield (Figure 1.15, eq 2).43 This fortuitous finding suggests a different reaction pathway is favored over the desired aza-ortho-xylylene generation. Additionally, this pathway offers a new route for aromatic functionalization via aniline N-oxides using mild conditions: the activation of aniline N-oxides to form new C–O bonds. The use of other reagents needed to be investigated to discern what other bonds could be formed.

1-80 OH 2 2 R O R O R1 R2 R1 R2 1 1 F R2 1 R N LG R N LG N 1 N R F R (1) TMS TMS O R2

1-92 1-93 1-94 1-95

H3C CH3 N H3C O H3C N 1) TFAA, CH2Cl2, −78 °C TMS (2) TMS 2) TMAF, −78 °C

OH 1-96 1-97 50% Figure 1.15: Generating aza-ortho-xylylenes via aniline N-oxides

1.5 Previous Investigations into Aniline N-Oxide Functionalization

In 2014, the Chain laboratory described reagents for the activation of the N–O bond of aniline N-oxides which transfers functionality onto the aromatic ring upon its cleavage.46 TFAA, toluenesulfonyl chloride (TsCl), trifluoromethanesulfonic

anhydride (Tf2O), and phenyl isocyanate activate the N–O bond of mono-substituted

N,N-dimethylaniline N-oxides (1-98) to produce functionalized aniline products with new carbon–heteroatom bonds (Figure 1.16). Activation with TFAA produces aminophenols (1-99) in 38 to 94% yield. Reaction with TsCl prepares aniline tosylates (1-100) in 39 to 63% yield. Treatment with Tf2O yields aniline triflates (1-

101) in 28 to 95% yield. Activation of N,N-dimethylaniline N-oxide with phenyl isocyanate forms diarylamine (1-102) in 37% yield. Independent of the reagent used, both ortho- and para-functionalized products were isolated; however, the ortho- functionalized products were formed preferentially to para-functionalized products by ratios of 1.2:1 to 3:1.

H3C CH3 1) TFAA, CH Cl , 1) Tf O, CH Cl , H3C CH3 N 2 2 2 2 2 N −78 °C −78 °C OH OTf

R 2) NEt3, CH2Cl2 2) NEt3, CH2Cl2 R −78 to 0 °C −78 to 0 °C H3C O 1-99 H3C N 1-101 9 examples 8 examples up to 94% yield up to 95% yield R

N H C CH 1-98 3 3 C H3C CH3 N 1) TsCl, CH2Cl2, O N H OTs −78 to 23 °C N R 2) NEt3, CH2Cl2 NEt3, CH2Cl2, 0 °C −78 to 23 °C 1-100 1-102 4 examples 37% up to 63% yield Figure 1.16: Carbon–heteroatom bond formation via N,N-dimethylaniline N-oxides

In addition, a number of different reagents are able to functionalize the aromatic system of aniline N-oxides to form new C–C bonds (Figure 1.17). Reaction with ethyl malonyl chloride prepares benzyl esters (1-103) in 29 to 65% yield.45

Treatment with cyanoacetyl chloride forms newly functionalized aniline (1-105) in

37% yield from N,N-dimethylaniline N-oxide (1-104).47 Activation with diketene under similar conditions produces functionalized aniline 1-106 in 42% yield from

N,N-dimethylaniline N-oxide (1-104).45

H C CO2Et 3 O Cl H3C CH3 H3C N 1) N CH2Cl2, −78 °C CO Et (1) R R 2 2) NEt3, CH2Cl2 −78 to 23 °C 1-103 1-98 9 examples up to 65% yield

O CN Cl H3C CH3 1) N CH2Cl2, −78 °C CN (2) 2) NEt , CH Cl H C 3 2 2 3 O −78 to 23 °C H3C N 1-105 37%

O H3C CH3 1-104 1) O N CH2Cl2, −78 °C CH3 (3) 2) NEt3, CH2Cl2 O −78 to 23 °C 1-106 42% Figure 1.17: Carbon-carbon bond formation via N,N-dimethylaniline N-oxides

These transformations expand the scope of aromatic functionalizations possible using aniline N-oxides; however, the scope could be further elucidated.

Reaction tolerance for aromatic functional group substitution was investigated but not for the different aniline N-substitution patterns. Structurally and electronically diverse

N-alkyl-N-methylaniline N-oxides should be investigated alongside new functionalization reagents.

1.6 Possible Mechanisms of Functionalization

Mechanistic analysis of functionalization was not undertaken in the group’s prior work. Three mechanistic proposals can be found in the literature: (1) a [3,3]-

31 47 sigmatropic rearrangement, (2) an SN2’ type nucleophilic addition, and (3) homolytic cleavage of the N–O bond with subsequent recombination of the radical pairs.48 These proposals are described in reactions of N-arylhydroxylamines and aniline N-oxides.

The proposed [3,3]-sigmatropic rearrangement, is similar to those undergone by N-arylhydroxylamines described by Coates and Said in 1977 (Figure 1.18, eq 1).31

In this pathway, the N–O bond is broken and the newly functionalized aromatic carbon bond is formed in a concerted fashion (Figure 1.18, eq 2). This mechanism accounts for favored formation of the ortho-functionalized products, but not for the formation of para-functionalized anilines.45,46 Furthermore, the success of functionalization via this pathway would be limited to substrates able to undergo pericyclic reactions.

R2 O O R2 O OH R2 O OH R2 N N N NH H proton O O R3 transfer R3 R1 R1 R1 R1 (1) R3 R3 O O −CO2 1-107 1-108 1-109 1-110

R3 R2 R3 O R2 R3 O N X N R2 N X Y Y Y −H+ X R1 H R1 (2) R1 O

1-111 1-112 1-113 Figure 1.18: [3,3] rearrangements in N-arylhydroxylamines and aniline N-oxides

The SN2’-type nucleophilic addition pathway has been evidenced in N- arylhydroxylamine chemistry. When N-arylhydroxylamines are acylated, intermediate

1-114 is susceptible to nucleophilic attack in competition with [3,3]-sigmatropic rearrangements (Figure 1.19, eq 1).48 Similarly, activated aniline N-oxide 1-117 would be receptive to nucleophilic attack on its aromatic system (Figure 1.19, eq 2).

The nucleophile can be an inherent aspect of the activating reagent. Shudo et al. considered this pathway for their aniline N-oxides arylation methodology; however, it was dismissed as a viable pathway based on observed products and intermediates.44

Bz O CH3 Bz Bz N N NH O Nuc proton Nuc transfer H (1) Nuc

OCH3 OCH3 OCH3 1-114 1-115 1-116

3 R3 R2 R R2 R3 O N N R2 N LG Nuc Nuc −H+ R1 H R1 (2) R1 Nuc 1-117 1-118 1-119

Figure 1.19: SN2’ nucleophilic addition in N-arylhydroxylamines and aniline N-oxides

Taylor and co-workers proposed a radical mechanism for the preparation of aniline acetate (1-124, Figure 1.20, eq 1).49 Following homolytic cleavage of the aniline N-oxide N–O bond, the radical pairs recombine on the aromatic system of the aniline. This mechanistic pathway describes aromatic functionalizations involving other reagents similar to acetic anhydride (Figure 1.20, eq 2).

O CH3 3 3 3 2 3 R R O CH R 2 3 R R O CH3 3 R R N R2 N R2 N R2 N O N O + O CH3 O H O CH3 −H R1 (1) R1 R1 R1 R1 H O O

1-120 1-121 1-122 1-123 1-124

3 O R3 R3 R X R2 R3 O O R2 R3 O N 2 2 X 2 N R N X R N R Y N X Y Y Y H Y −H+ X R1 (2) R1 R1 R1 R1 H O

1-125 1-126 1-127 1-128 1-129 Figure 1.20: Radical cleavage in aniline N-oxides

The radical pathway is the easiest to experimentally eliminate through radical trapping experiments; however, experimentally differentiating between the [3,3] rearrangement and the SN2’ pathways will be challenging. Understanding the mechanism by which these functionalization methodologies occur allows for a better comprehension of the scope and limitations for this chemistry.

1.7 Indoline Synthesis via Tandem Polonovski-Mannich Reaction

While investigating ways to build highly functionalized aniline substrates from sequential aniline N-oxide functionalizations, a new type of reactivity in aniline N- oxides was discovered. When aniline N-oxide 1-130 was treated with TFAA, indoline heterocycle (1-131) was afforded in 21% yield, instead of the expected functionalized aniline (Figure 1.21, eq 1).43 Under optimized conditions, indolines (1-133) can be prepared from aniline N-oxide 1-132 by treatment with acetic anhydride in 47 to 61% yield (Figure 1.21, eq 2).46

H C H3C O 3 H C N N 3 1) TFAA, CH2Cl2, −78 °C CO2Et (1) CO Et 2 2) NEt3, CH2Cl2, −78 to 0 °C

1-130 1-131 21%

H C H3C O 3 H C N N 3 1) Ac2O, CH2Cl2, −78 °C CO2Et (2) CO2Et R 2) NEt3, CH2Cl2, −78 to 0 °C R

1-132 1-133 6 examples up to 61% yield Figure 1.21: Unexpected reagent dependent indoline formation

The above transformation depends on the acid-base pair formed by the activating reagent (Table 1.2).43 For example, treatment of the aniline N-oxide with

TFAA and Ac2O affords indoline products; however, treatment with Tf2O does not.

There results indicate that the reaction mechanism proceeds through an intermediate that can only be formed under certain conditions governed by the acidity and basicity of the acid-base pair. The lowest pKa value of the acid able to achieve the desired transformation resides somewhere between –0.25 and –14.

Table 1.2: Reagents for successful indoline formation

Conjugate Indoline Entry Reagent Acid-Base Pair Acid pKa Formation – 1 Ac2O AcOH/AcO 4.76 yes – 2 TFAA CF3CO2H/CF3CO2 –0.25 yes – 3 Tf2O TfOH/TfO –14 no

The proposed mechanism for this transformation involves generating an iminium ion (1-136) through a Polonovski-type acylation-elimination pathway (Figure

1.22). This ion results in N-demethylation in some reactions;50 however, the iminium ion is captured intramolecularly by ortho-nucleophilic functionality on the aromatic system. To form the indoline core, ester tautomerizes to an enol which adds onto the iminium ion in an intra-molecular Mannich reaction to form an indoline heterocycle.

This new method of reactivity offers insight into how the N–O bond of aniline N- oxides is exploited for applications beyond group transfer into the aromatic ring to produce heterocycle scaffolds.

H C 3 O H3C H3C N N 1) Ac2O, CH2Cl2, −78 °C OEt CO2Et 2) NEt , CH Cl , −78 to 0 °C O 3 2 2 1-134 1-138

Ac2O

H Base

O H3C H3C H3C N Ac N H N OEt OEt OEt

O O OH

1-135 1-136 1-137 Figure 1.22: Mechanism of Polonovski-Mannich reaction

1.8 Aim of This Dissertation

This dissertation builds upon the work of the Chain group in the area of aniline

N-oxide chemistry to expand the knowledge of what transformations are possible and how they occur. In Chapter 2, the methods for installing aromatic carbon–halogen

bonds are discussed. In Chapter 3, investigations in the mechanism of these transformations are presented. In Chapters 4 and 5, efforts towards the preparation of heterocycles using aniline N-oxides in heterocycle formation are described.

Specifically, the preparation of tetrahydroquinoline scaffolds and efforts towards the synthesis of substituted indoles are discussed in Chapter 4 and Chapter 5, respectively.

In Chapter 6, the efforts employing a possible [2,3] rearrangement with aniline N- oxides to install aryl C–S bonds are summarized. Collectively, the work described in this dissertation showcases the utility and potential of aniline N-oxides in the preparation of structurally diverse molecules and furthers our understanding of how these transformations proceed.

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SYNTHESIS OF HALOGENATED ANILINES BY TREATMENT OF N,N- DIALKYLANILINE N-OXIDES WITH THIONYL HALIDES

A portion of the work described here has been previously published (Reed, H.; Paul,

T. R.; Chain, W. J. J. Org. Chem. 2018, 83, 11359–11368.).

2.1 Introduction

Halogenated aromatic materials, and specifically halogenated anilines, have medicinal use as pharmaceutical agents, appear as substructures in many natural products, and are of great synthetic utility as building blocks in cross coupling chemistry, and magnesium-halogen and lithium-halogen exchange reactions.

Methodologies to prepare aryl halides are thus of wide utility and high impact.1

Halogenated anilines are found in a number of currently prescribed pharmaceuticals

(Figure 2.1); however, examples are relatively rare due to toxicities associated with halogenated compounds. For example, clenbuterol (2-1) is a bronchodilator approved to treat asthma in humans in Europe and airway obstruction in horses in the United

States.2 In addition, clenbuterol is abused by humans as an illicit anabolic steroid abused by athletes.3 Marketed by Sanofi Genzyme under the brand name Caprelsa, vandetanib (2-2) is an orally available kinase inhibitor used to treat thyroid cancer.4

H3C N OH H O N Cl N CH3 N CH3 CH3 H2N NH Cl

Br F clenbuterol (2-1) vandetanib (2-2) Figure 2.1: Examples of anilines halides in pharmaceuticals

In addition to pharmaceuticals, halogenated anilines are also found in isolated natural products, some of which have promising bioactivities (Figure 2.2). Isolated from Arctic bryozoan Securiflusta securifrons, the securamines (2-3 – 2-7) exhibit various degrees of cytotoxicity against different cancer cell lines including A2058

(skin), HT-29 (colon), MCF-7 (breast), and non-malignant MRC-5 lung fibroblasts.5

Isolated from the African shrub Putterlickia verrucose, maytansiol (2-8) exhibits no biological activity, but it is the parent alcohol of a series of maytanside esters including maytansine (2-9), an antitumor agent against with activity against cell growth of murine tumors.6

Br O R2 O H C O H H 3 OR Br R1 Cl N O H CO N OCH3 N 3 N N Br HO Br CH3 Cl Cl O OH HN CH HN CH N H C 3 N 3 N O 3 H3C H CH OCH O O 3 3 securamine J (2-3) securamine H (2-4): R1 = Br, R2 = Br maytansinol (2-8), R = H maytansine (2-9), securamine I (2-5): R1 = Br, R2 = H R = O CH securamine C (2-6): R1 = H, R2 = H 3 securamine E (2-7): R1 = H, R2 = Br N OCH3

CH3 O Figure 2.2: Examples of halogenated anilines in natural products

Beyond their prevalence in bioactive compounds and natural products, the carbon–halogen bond of the halogenated anilines has applications as a synthetic handle in organic chemistry as reaction partners in cross coupling chemistry7,8 and as precursors to organolithium10 and Grignard reagents.11 As discussed in the previous chapter, cross coupling chemistry is a premier method to build highly functionalized aromatic systems in high chemoselectivity and stereoselectivity (Figure 2.3).7 Aryl halides (2-10) offer a pathway to form new C–C, C–O, and C–N bonds as well as biaryl compounds. The diversity in functionalized substrates prepared is matched by the diversity in transition metal catalysts able to achieve these transformations.8

Functionalized Anilines:

R2 R3 R2 R3 R2 R3 N N N R4 Transition Metal R4 Catalysis: R4 R1 R1 R1 R2 R3 N Pd X Fe 2-11 2-12 2-13 Co 1 R Cu R2 R3 R2 R3 R2 R3 Ni N N R4 N R4 2-10 Sn O N R4 R5 R1 R1 R1

2-14 2-15 2-16

Figure 2.3: Uses of aryl halides in transition metal catalysis

When a reaction is featured prominently in undergraduate chemistry coursework, it can be considered a crucial fundamental reaction. Additions of

Grignard and organolithium reagents onto carbonyls are examples of such important reactions. Prepared from halides, these reagents have applications as building blocks

in organic synthesis through these nucleophilic additions and cross coupling reactions

(Figure 2.4);9 the work of Victor Grignard was recognized by the 1912 Nobel Prize in

Chemistry. Organolithium reagents (2-17) are prepared via lithium-halogen exchange;10 Grignard reagents (2-18) are produced via insertion of magnesium into a carbon–halogen bond.11

R2 R3 N Lithium-Halogen Li Exchange R1

R2 R3 2-17 N Organometallic Reagent Uses: X R1 Nucleophilic Additions

2-10 R2 R3 N Cross Couplings Magnesium Insertion MgX R1 2-18 Figure 2.4: Uses of aryl halides as organometallic reagent precursors

2.1.1 Traditional Methods of Preparing Halogenated Anilines

The importance of halogenated aromatic systems, especially those of anilines, begets the development of methods to prepare them. Halogenated anilines can be synthesized through electrophilic aromatic substitution12-14 and transition metal catalysis (Figure 2.5).15 Halogenation via electrophilic aromatic substitution proceeds using elemental dihalogen (X2) or N-halosuccinimide (NXS). Activation of X2 by

Lewis acidic metal salts (MX3) containing the same halogen is often but not always required to obtain the desired products (Figure 2.5, eq 1).13 Unactivated N-

halosuccinimides (NXS) are able to halogenate aromatic systems without additional reagents (Figure 2.5, eq 2).14 Either reagent produces regioisomer mixtures with little control of whether an ortho- or para-halogenated product dominates. The use of transition metal catalysis provides regiocontrol; however, the necessary catalysts can be expensive, problematic to source, and may require high reaction temperatures

(Figure 2.5, eq 3).15

R1 R2 R1 R2 R1 R2 N N N X2, MX3 X + (1) high temperatures X 2-19 2-20 2-21

R1 R2 R1 R2 R1 R2 N N N NXS X + (2) room temperature

X 2-19 2-20 2-21

R1 R2 R1 R2 transition metal R1 R2 N N catalysis N X or (3) high temperatures

X 2-19 2-20 2-21 Figure 2.5: Traditional methods of aromatic halogenation via electrophilic aromatic substitution and transition metal catalysis

2.1.2 Exploiting N–O Bonds for Aromatic Halogenation

Examples of aromatic halogenation via cleavage of N–O bonds in heteroaromatic N-oxides16-18 and N-arylhydroxylamines19-21 are found in the literature.

Although only distantly structurally analogous to aniline N-oxides, heteroaromatic N- oxides provide precedent that the N–O bond of aniline N-oxides can be leveraged for

aromatic chlorination and bromination via activation by suitable reagents.16 Treatment of pyridine N-oxides (2-22) with oxalyl halide (COX)2 and triethylamine (NEt3) produces 2-halopyridines (Figure 2.6, eq 1).17 Activation of quinoline N-oxides (2-25)

18 with phosphoryl halides (POX3) results in 2-haloquinolines (Figure 2.6, eq 2).

Reaction of isoquinoline N-oxides (2-28) with phosphoryl halides (POX3) results in 2- haloisoquinolines (Figure 2.6, eq 3).18 Collectively, all of the heteroaromatic N-oxide halogenation methods proceed at much lower reaction temperatures; however, only the aromatic 2-position has been halogenated and heteroaromatic halogenation is not a solution to the problem of aniline functionalization.

R1 R2 1 2 (COX)2, NEt3 R R N CH2Cl2, 0 °C N X (1) O 2-23, X = Cl, 75-93% 2-22 2-24, X = Br, 73-86%

R POX3, DMF R N CH2Cl2, 0 °C to rt N X (2) O 2-26, X = Cl, 20-96% 2-25 2-27, X = Br, 19-86%

POX , DMF R 3 R N N O CH2Cl2, 0 °C to rt X (3)

2-28 2-29, X = Cl, 43-89% 2-30, X = Br, 34-73% Figure 2.6: Halogenation of pyridine N-oxides, quinoline N-oxides, and isoquinoline N-oxides

Aromatic halogenation via N-arylhydroxylamine N–O bond cleavage has been described in the literature.19-21 Aromatic chlorination has been achieved by Ayyangar

et al. through treatment of ortho-substituted N-arylhydroxylamine (2-31) with thionyl chloride at 0 °C to give ortho-chloroanilines (2-32) in 71-85% yield (Figure 2.7, eq

1).19 McCord et al. describe reflux temperatures and hydrohalic acid preferentially producing para-haloanilines in 47-99% yield N-hydroxyl-1,2,3,4-tetrahydro-2- oxoquinoline (2-33) and ortho-haloanilines from in 50-55% when the para-position yield is blocked (Figure 2.7, eq 2).20 Treatment of an N-butylhydroxylamine (2-38) with thionyl bromide (SOBr2) produced ortho-brominated aniline 2-39 in 61% yield as described by Marx and Rassat (Figure 2.7, eq 3).21

O O OH 2 R N 2 SOCl2 R NH 1 R 1 Cl R (1) PhH or Et2O, 0 °C to rt

2-31 2-32 71-85%

O O O OH NH N conc. HX NH X or reflux X1 (2) X1 X1

X 2-33 2-34, X = Cl, 53-55% 2-36, X = Cl, 47-70% 2-35, X = Br, 50-54% 2-37, X = Br, 80-99%

tBu OH tBu N NH SOBr2, Et3N Br

CH2Cl2, 0 °C to rt (3)

tBu tBu

2-38 2-39 61% Figure 2.7: Halogenation of N-arylhydroxylamines

The halogenation of aromatic systems via N-arylhydroxylamines provides functionalized aniline substrates under mild conditions and common reagents;

however, the substrate tolerance of thionyl halides has not been tested and only regiocontrol for ortho-halogenation has been described. Hydrohalic acids require elevated temperatures and preferentially form para-halogenated products in a likely

SN2’ type mechanism.

2.1.3 Proposed Work

The existing body of literature supports the assertion that aniline N-oxides are suitable to achieve aromatic halogenation using common organic reagents like thionyl halides or phosphoryl halides at mild conditions. Aniline N-oxides will be activated with an electrophilic halogenating reagent; halogenation itself will occur via a [3,3] rearrangement (Figure 2.8, eq 1), nucleophilic addition (Figure 2.8, eq 2), or homolytic cleavage (Figure 2.8, eq 3) to produce ortho- and para-halogenated anilines. In this chapter, complementary methods of regiocontrolled preparation of para-bromoanilines and ortho-chloroanilines via treatment of aniline N-oxides with thionyl halides and experiments probing the reaction mechanism are described.

H3C H3C CH3 H3C CH3 O O N N H3C N S X X X −H+ (1) R1 H R1 R1

2-40 2-41 2-42

H3C H3C CH3 H3C CH3 O O N N H3C N S X X X −H+ (2) R1 H R1 R1 X 2-43 2-44 2-45

H C H C H C 3 H C CH 3 O O 3 O O 3 3 S H3C N N H3C N S H3C N X X X X −H+ (3) R1 H R1 R1 R1 2-46 2-47 2-48 2-49 Figure 2.8: Proposed mechanisms for halogenation via aniline N-oxides

2.2 Results and Discussion

2.2.1 Synthesis of N,N-Dialkylaniline N-Oxides

N-Alkyl-N-methylanilines (2-50) are prepared via reductive amination with sodium cyanoborohydride, paraformaldehyde and acetic acid in a similar procedure to that described by Chandrasekharam et al.22 This procedure generally results in complete conversion of the aniline into its respective N,N-dimethylaniline or N-alkyl-

N-methylaniline products and requires a quick, simple purification by column chromatography to isolate clean products as solid or oils. The N-alkyl-N- methylanilines were N-oxidized upon treatment with 3-chloroperbenzoic acid

(mCPBA) in a procedure similar to that described by Lewis et al. (Figure 2.9).23 This procedure requires simple addition sequences and easy purification by column

chromatography to quickly isolate the crystalline N,N-dimethylaniline N-oxides and the syrupy N-alkyl-N-methylaniline N-oxides in 40-90% yield.

1 1 R CH3 R O N mCPBA H3C N

2 CH Cl , 23 °C R 2 2 R2

2-50 2-51

H3C H C H C H3C H C H C H C O 3 O 3 O O 3 O 3 O 3 O H C N H C N 3 H3C N H3C N 3 H3C N H3C N H3C N

F CH3

Br Cl CF3 CN Br 2-52 2-53 2-54 2-55 2-56 2-57 2-58 63% 90% 79% 77% 84% 84% 71%

H C H C 3 O 3 O H3C CH3 H3C N H3C N H3C O O O H3C N H3C N H3C N N O

H3C

CO2CH3 CN 2-59 2-60 2-61 2-62 2-63 2-64 40% 69% 77% 77% 77% 71%

Figure 2.9: N-alkyl-N-methylaniline N-oxides not previously prepared and described by the Chain group

2.2.2 Optimization of Thionyl Bromide as Brominating Agent

First, we turned our attention to optimizing the preparation of bromoanilines using N,N-dimethylaniline N-oxide (2-65) and thionyl bromide (SOBr2). Initial attempts showed that the molar equivalents of SOBr2 could not be in excess of the aniline N-oxide as excess SOBr2 results in over-bromination (2-67) (Figure 2.10).

This product likely forms from reaction of the initial product, 4-bromo-N,N- dimethylaniline (2-66) with the excess SOBr2. Fortuitously, the reaction is selective

for the para-brominated product, no 2-bromo-N,N-dimethylaniline product was observed.

H3C CH3 H3C CH3 N N H3C O H3C N 1) SOBr2 (2 eq), CH2Cl2, 0 °C, 2 h Br

2) NEt3 (4.0 equiv),0 to 23 °C, 45 min

Br Br 2-65 2-66 2-67 27% 9%

Figure 2.10: Preliminary result for bromination using SOBr2

While limiting the equivalents of SOBr2, the optimal reaction temperature was investigated (Table 2.1). At 0, −40, −60, and −90 °C, moderate yields of the product were obtained (Table 2.1, entries 1, 2, 3, 5). The optimal reaction temperature was determined to be −78 °C at which 4-bromo-N,N-dimethylaniline (2-69) was obtained in 51% yield (Table 2.1, entry 5). Regardless of reaction temperature, only the para- brominated product was observed and isolated.

Table 2.1: Optimization of bromination reaction temperature

H3C CH3 N H3C O H3C N 1) SOBr2, CH2Cl2, temperature, 4 h

2) NEt3 (4.0 equiv), temp to 23 °C, 45 min

Br 2-68 2-69

Temperature Yield Entry (°C) 2-69 1 0 39% 2 −40 26% 3 −60 42% 4 -78 51% 5 −95 27%

The next reaction parameters to optimize are reaction concentration and solvent and reagent addition sequence (Table 2.2). Both dichloromethane (CH2Cl2) and tetrahydrofuran (THF) were screened at different concentrations of 0.2M and

0.5M N,N-dimethylaniline N-oxide (2-70) were used. THF produced a higher yield than CH2Cl2 (Table 2.2, entries 1 and 2). In THF, a concentration of 0.2M yielded more product than a concentration of 0.5M (Table 2.2, entries 1, 4, 5, 7). For the addition of the thionyl bromide, a single addition of neat SOBr2 produced the 4- bromoaniline (2-71) in 55% yield (Table 2.2, entry 1); a dropwise, two-part addition of a SOBr2 solution resulted in a 53% yield of the desired product (Table 2.2, entry 7).

Because there no advantage in reaction yield to using the slow addition, the simpler method was selected. To test the scope of this reaction, neat SOBr2 will be added all at once at the start of the reaction.

Table 2.2: Optimization of solvent, reaction concentration, and addition sequence

H3C CH3 N H3C O H3C N 1) SOBr2, solvent, −78 °C, 4 h

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min

Br 2-70 2-71 Concentration Yield Entry Solvent Addition Sequence 2-70 (M) 2-71

1 THF 0.2 Addition of SOBr2; then NEt3 55% 2 CH2Cl2 0.2 Addition of SOX2; then NEt3 51% 3 CH2Cl2 0.5 Slow addition SOBr2 solution; then NEt3 38% 4 THF 0.5 Slow addition SOBr2 solution; then NEt3 28% 5 THF 0.2 Slow addition SOBr2 solution; then NEt3 42% 6 CH2Cl2 0.5 Slow, two-step addition SOBr2; then NEt3 23% 7 THF 0.2 Slow, two-step addition SOBr2; then NEt3 53%

2.2.3 Scope of Bromination with Thionyl Bromide

Using the optimized reaction conditions, we investigated the scope and limitations of this reaction (Figure 2.13). The tolerance for aromatic substitution was tested using N,N-dimethylanilines. Wherever, the para-position was available for functionalization, bromination occurred at the para-position. The bromination of unsubstituted aromatic systems produced para-brominated products (2-75 and 2-76) in

55-56% yield. meta-Substituted N,N-dimethylaniline N-oxides were selectively para- brominated (2-77 – 2-83) in 39-66% yield. ortho-Substituted N,N-dimethylaniline N- oxides prepared para-brominated anilines (2-84 and 2-85) in 31-51% yield.

Bromination can be forced to occur at the ortho-position by using para-substituted

N,N-dimethylaniline N-oxides, producing 2-bromoanilines (2-86 – 2-90) in 10-37% yield. The unfavorability of ortho-bromination is reflected in its lower yields

compared to 4-bromoanilines indicating that para-bromination is significantly preferred, and different reaction mechanisms may be responsible for the formation of the different regioisomers. Because of the geometric requirement to undergo a [3,5]- rearrangement, it is likely that para-bromination occurs via a nucleophilic addition or radical mechanism. In differentially substituted N-alkyl-N-methylaniline N-oxides, we sought to expand the tolerance of the reaction beyond symmetric N,N-dimethylaniline

N-oxide substrates. Linear alkyl chains (2-93 and 2-95) were tolerated and produced para-bromoanilines in 53-59% yield. Sterically bulky N-substitution was well tolerated in 64% yield of isolated para-bromoaniline (2-94). Heterocyclic tetrahydroquinoline N-oxide produced the expected para-bromoaniline product (2-96) in 69% yield. Collectively, our investigations indicate this protocol demonstrates a quick, regioselective method for preparing bromoanilines in electronically and sterically diverse substrates.

2 H3C R 2 2 R O N H3C R N H3C N 1) SOBr2 (1.0 equiv), THF, −78 °C, 4 h or Br R1 2) NEt (4.0 equiv), −78 to 23 °C, 45 min 1 R1 3 R

2-72 Br 2-73 2-74

H3C CH3 H3C CH3 H3C CH3 H3C CH3 H3C CH3 H3C CH3 H3C CH3 N N N N N N N

CO2CH3 Br Cl OCH3 CH3 Br Br Br Br Br Br Br 2-75 2-76 2-77 2-78 2-79 2-80 2-81 55% 56% 50% 58% 61% 39% 66%

H3C CH3 H3C CH3 H3C CH3 H3C CH3 H3C CH3 H3C CH3 H3C CH3 N N N N N N N

F CH3 Br Br Br

CF3 CN Br Br Br Br Cl Br CN 2-82 2-83 2-84 2-85 2-86 2-87 2-88 48%* 49%* 31% 51% 37% 26% 10%

*uses CH2Cl2 as solvent

CH3 H3C CH3 H C CH H C H C H C H C N 3 3 3 3 3 3 N N CH3 N N CH3 N Br Br

CO2CH3 F Br Br Br Br 2-89 2-90 2-93 2-94 2-95 2-96 33% 26% 59% 64% 53% 69%

Figure 2.11: Scope of the bromination of aniline N-oxides

2.2.4 Optimization of Phosphoryl Chloride as a Chlorinating Agent

To find an analogous protocol for the preparation of chloroanilines, we first investigated phosphoryl chloride (POCl3) as a chlorinating reagent. When exposed to

POCl3, N,N-dimethylaniline N-oxide (2-92) yielded only the ortho-chloroaniline (2-

93); the para-chloroaniline product was not observed (Table 2.3). Excess POCl3 did not produce over-chlorination and a 2,4-dichloroaniline product. Increased reaction temperatures and reaction times did not significantly increase product yield (Table 2.3, entries 1-4). In addition, the use of purified POCl3 did not result in an appreciable

increase in yield (Table 2.3, entries 5-9). We turned our attention to a different reagent, thionyl chloride, to achieve this transformation.

Table 2.3: Optimization of chlorination using phosphoryl chloride

H3C CH3 H3C O N H3C N 1) POCl3, CH2Cl2, temperature, time Cl

2) NEt3 (4.0 equiv), temp to 23 °C, 45 min 2-98 2-97 Entry POCl3 (eq.) Temperature (°C) Time (h) Yield 2-98 1 0.9 -78 2 16% 2 1.0 -78 2 7% 3 1.0 0 2 8% 4 1.0 0 6 9% 5* 1.0 -78 2 10% 6* 1.0 0 2 7% 7* 2.0 -78 2 16% 8+ 2.0 -78 2 2% 9+ 2.0 23 18 3%

*reaction used distilled POCl3 + reactions used POCl3 from a new bottle and stored in a Schlenk flask

2.2.5 Optimization of Thionyl Chloride as a Chlorinating Agent

Because of the success seen in the use of SOBr2 as a brominating agent, thionyl chloride (SOCl2) was a promising option to explore to pursue chlorination methodology. We began with finding the optimal reaction temperature for the reaction of SOCl2 with N,N-dimethylaniline N-oxide (2-99) (Table 2.4). Independent of reaction temperature, the ortho-chlorinated product (2-100) was formed preferentially over the para-chlorinated product (2-101). No reaction temperature produced significantly higher yields than another. Because there was no substantially

higher yield at any particular temperature, we used a reaction temperature of −78 °C to further optimize other reaction parameters.

Table 2.4: Optimization of reaction temperature

H C CH H3C CH3 3 3 N H3C O N H3C N 1) SOCl2, CH2Cl2, temperature, 4 h Cl

2) NEt3 (4.0 equiv), temp to 23 °C, 45 min

2-100 Cl 2-99 2-101 Entry Temperature (°C) Yield (2-100:2-101)* 1 −40 22% (4.0:1) 2 −55 trace 3 −60 23% (5.9:1) 4 −78 15% (1.5:1) 5 −85 15% (6.6:1) * Product ratios obtained by 1H NMR.

Next, we investigated optimal reaction solvent and concentration, and reagent addition sequence (Table 2.5). THF (Table 2.5, entries 3, 4, and 6) produced higher yields of chloroaniline products than CH2Cl2 (Table 2.6, entries 1, 2, and 5) with the ortho-chloroaniline product (2-101) formed in a higher ratio to the para-chloroaniline product (2-102). The concentration of the aniline N-oxide (2-100) did not have a consistent effect on the product yield (Table 2.5, entries 3, 4, and 6), but the addition sequence of SOCl2 did. The optimal conditions involve using a dropwise, two-step addition of a SOCl2 solution to produce a 49% yield of chlorinated products in a ratio of 4.9:1 of ortho-chloroaniline (2-101) to para-chloroaniline (2-102) (Table 2.6, entry

6).

Table 2.5: Optimization of addition sequence and reaction concentration

H C CH H3C CH3 3 3 N H3C O N H3C N 1) SOCl2, solvent, −78 °C, 4 h Cl

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min

2-103 Cl 2-102 2-104 Concentration Yield Entry Solvent Addition Sequence 2-102 (M) (2-103:2-104)*

1 CH2Cl2 0.2 SOCl2 and Et3N at same time 6% (8.6:1) Slow addition SOCl2; 2 CH2Cl2 0.5 11% (2.4:1) then Et3N Slow addition SOCl ; 3 THF 0.5 2 31% (4.6:1) then Et3N Slow addition SOCl ; 4 THF 0.2 2 8% (3.3:1) then Et3N Slow, two-step addition SOCl2; 5 CH2Cl2 0.5 26% (3.8:1) then Et3N Slow, two-step addition SOCl ; 6 THF 0.2 2 49% (4.9:1) then Et3N * Product ratios obtained by 1H NMR.

2.2.6 Scope of Chlorination with Thionyl Chloride

Our next step was to investigate the scope of this reaction using the optimized reaction conditions (Figure 2.14). When both the ortho- and para-positions are available for chlorination, both regioisomers were obtained and, except in a few cases, isolated as a mixture; however, the ortho-chlorinated product was formed preferentially. Unsubstituted N,N-dimethyl-substituted aromatic systems gave chlorinated products (2-108 and 2-109) in 49-60% yield in ratios of 4.9:1 to 6.7:1 of ortho- to para-chlorinated products. 2,N,N,-trimethylaniline N-oxide produced a 1.3:1 mixture of ortho-chlorinated to para-chlorinated products (2-110) in 19% yield.

Treatment of 3,N,N-trimethylaniline N-oxide with SOCl2 prepared a mixture of 6-, 2-,

and 4-chloro-3,N,N-trimethylaniline (2-111) in a ratio of 2.9:1.5:1 in 54% yield; however, 3-methoxy-N,N-dimethylaniline N-oxide produced no para-chlorinated product but a 4.8:1 mixture of 6- and 2-chloro-3-methoxy-N,N-dimethylaniline (2-

112) in 43% yield. From para-substituted aniline N-oxides where only the ortho- position is available for chlorination, ortho-chloroanilines were obtained in 30-61% yield (2-113 – 2-118). Using differentially substituted N-alkyl-N-methylaniline N- oxides, we sought to expand the reaction scope beyond symmetric N,N- dimethylaniline N-oxides. Linear alkyl chains (2-119 and 2-122) were able to produce mixtures of ortho- and para-chloroanilines in 55-59% yield and similar ratios of about

3:1. Sterically bulky N-substitution is tolerated and produced ortho- and para- chlorinated products (2-120) in 65% yield and an undiminished ratio of 4.9:1.

Heterocyclic tetrahydroquinoline N-oxide produced ortho- and para-chlorinated products (2-121) in 61% yield and a ratio of 2.1:1. Overall, this methodology offers an efficient, controlled method to prepare diverse ortho-chloroanilines from aniline N- oxides under mild conditions.

2 2 2 R O H3C R H3C R H C N N N 3 1) SOCl (0.5 equiv), THF, −78 °C, 2h 2 Cl 2) SOCl (0.5 equiv), −78 °C, 2h 2 1 R1 R1 R 3) NEt3 (4.0 equiv), −78 to 23 °C 2-105 2-106 Cl 2-107

H3C CH3 H3C CH3 H3C CH3 H3C CH3 H3C CH3 N N N N N 2 6 6 Cl Cl Cl CH3 Cl 2 Cl 2 2 2

CH OCH 4 4 4 4 3 3 2-108 2-109 2-110 2-111 2-112 49% 60% 19% 54% 43% 4.9:1 6.7:1 1.3:1 2.9:1.5:1 4.8:1 (2-Cl:4-Cl) (2-Cl:4-Cl) (2-Cl:4-Cl) (6-Cl:2-Cl:4-Cl) (6-Cl:2-Cl)

H3C CH3 H3C CH3 H3C CH3 H3C CH3 H3C CH3 H3C CH3 N N N N N N Cl Cl Cl Cl Cl Cl

OCH3 CH3 CN Cl CO2CH3 F 2-113 2-114 2-115 2-116 2-117 2-118 61% 41% 33% 55% 40% 30%

CH3

H3C H3C H3C H3C N CH3 N N N CH3 Cl Cl 2 Cl 9 Cl 2 2

4 4 7 4 2-119 2-120 2-121 2-122 55% 65% 61% 59% 2.9:1 4.9:1 2.1:1 2.8:1 (2-Cl:4-Cl) (2-Cl:4-Cl) (9-Cl:7-Cl) (2-Cl:4-Cl)

Figure 2.12: Scope of the chlorination of aniline N-oxides

2.2.7 Mechanistic Investigations

To understand the different observed regioselectivities for bromination and chlorination, we sought to investigate by which mechanism these reactions proceed.

As discussed previously, there are three options: (1) a [3,3]-sigmatropic rearrangement, (2) a SN2’-type nucleophilic addition, and (3) homolytic cleavage of the N−O bond. The radical pathway via the homolytic cleavage of the N−O bond is the easiest to eliminate through radical trapping experiments. Treatment of N,N-

dimethylaniline N-oxide (2-121) with SOBr2 in the presence of 20 mol% butylated hydroxytoluene (BHT) produces the 4-bromoaniline product (2-122) in 55% yield

(Figure 2.15). In comparison to the yield of the reaction absent BHT, an unaffected yield indicates that the reaction mechanism does not generate a radical and proceeds via an [3,3] rearrangement or SN2’ mechanism.

H3C CH3 N H3C O H3C N 1) BHT (20 mol%), SOBr2, THF, −78 °C, 4h

2) NEt3, −78 to 23 °C, 45 min

Br 2-123 2-124 55% no BHT = 55% Figure 2.13: Radical trapping experiment using BHT

Next, we performed ion exchange experiments to help differentiate between the two remaining mechanistic pathways. In these experiments, the aniline N-oxide is treated with thionyl halides in the presence of lithium halide salts and the type and ratios of halogenated products was analyzed for mechanistic insight (Table 2.6). The lithium salts were added before (Table 2.6, entries 1 and 3) or after (Table 2.6, entries

2 and 4) to addition of the thionyl halide. For all the experiments except when LiCl was added after the addition of SOBr2 (Table 2.6, entry 2), a mixture of all halogenated products except the ortho-bromoaniline (2-124 – 2-126) were obtained.

In almost all experiments, the para-bromoaniline product (2-124) was formed in the greatest ratio (Table 2.7, entries 1-3). Unfortunately, no conclusive mechanistic insight can be gleaned from these experiments because it is impossible to know if the

lithium salt halide is adding onto the activated aniline N-oxide or the thionyl halide.

Further experiments need to be performed to conclusively ascertain the mechanism.

Table 2.6: Salt ion exchange experiments

H C CH H C CH H C 3 3 3 3 3 N H3C CH3 N O N H3C N 1) SOX2 (1.0 eq), LiY, THF, −78 °C, 4h Cl 2) NEt3 (4.0 eq), −78 to 23 °C

Br Cl 2-125 1-126 2-127 2-128 Yield Yield Yield Entry X Y Addition Order 2-125* 2-126* 2-127*

1 Br Cl LiCl then SOBr2 15% 9% 4% 2 Br Cl SOBr2 then LiCl 54% trace trace 3 Cl Br LiBr then SOCl2 20% 8% 3% 4 Cl Br SOCl2 then LiBr 14% 20% 5% *Product yields determined by 1H NMR.

In an effort to determine if the mechanism of this halogenation reaction follows a [3,3] rearrangement or an SN2’ pathway, Hammett correlations for both the bromination (Figure 2.15) and chlorination (Figure 2.16) reactions were analyzed. In the case of the bromination, the correlations for both meta- and para-substituted N,N- dimethylaniline N-oxides were analyzed and give insight into the formation of each regioisomer. For meta-substituted N,N-dimethylaniline N-oxides, only the para- brominated products were formed; for para-substituted N,N-dimethylaniline N- oxides, the products were ortho-brominated anilines. The differing � values, obtained from the slope of the trendlines, for the substitution patterns indicate that there likely are two different mechanisms is responsible for ortho- and para-bromination. For

ortho-bromination, the negative � value (� = –0.9436) indicates that there is a buildup of positive charge in the transition state which would be consistent with a [3,3] rearrangement mechanism. In contrast, para-bromination is unlikely to undergo a

[3,3] rearrangement due to the required geometry for that mechanism. The � value for para-bromination is neither positive nor significantly negative (� = –0.0527) indicating that there is no buildup of positive or negative charge in the transition state which is consistent with an SN2’ type mechanism.

0.20

0.10 y = -0.0527x CH 3 Cl R² = 0.1691 0.00 H Br -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 CN 0.7 0.8 CO2CH3 -0.10 CF3 Cl

) -0.20

H CO2CH3 /K

X -0.30 F Br

log(K -0.40

-0.50

-0.60 y = -0.9436x -0.70 R² = 0.7053 CN -0.80 !

Series1 para-substitution meta-substitution para-substitution Figure 2.14: Hammett correlations for bromination of meta- and para-substituted N,N- dimethylaniline N-oxides

In addition, the Hammett correlation for the chlorination of para-substituted

N,N-dimethylaniline N-oxides was analyzed (Figure 2.17). These substrates only produce ortho-chlorinated products, so their correlation gives insight into the mechanism for ortho-chlorination. Similar to the Hammett correlation for the

bromination of para-substituted aniline N-oxides, the � value for ortho-chlorination is negative (� = –0.2424) indicating a buildup of positive charge in the transition state and a likely [3,3]-sigmatropic rearrangement. Collectively, analysis of all Hammett correlations indicate that the ortho-halogenated products are likely obtained from a

[3,3]-sigmatropic rearrangement and the para-halogenated products are likely obtained through an SN2’ type mechanism. Further mechanistic experiments, such as kinetic studies, still need to be performed to confirm the proposed mechanism for the formation of each regioisomer.

0.15

0.10 OCH3

0.05 y = -0.2424x R² = 0.9665 )

H 0.00 H

-0.4/K -0.2 0 0.2 0.4 0.6 0.8 X

log(K -0.05

CO2CH3 -0.10

-0.15 CN

-0.20 !

Figure 2.15: Hammett correlations for chlorination of para-substituted N,N- dimethylaniline N-oxides

2.3 Conclusion

This work describes a set of complementary methods for the metal-free, regioselective preparation of halogenated anilines. Treatment of N-alkyl-N-

methylaniline N-oxides with SOBr2 preferentially prepares para-bromoanilines in up to 69% yield. Reaction of N-alkyl-N-methylaniline N-oxides with SOCl2 preferentially produces ortho-chloroanilines in up to 65% yield. This protocol is efficient and controlled and does not require exotic reagents, Lewis acids, or any activation of halogen sources. Preliminary mechanistic experiments have excluded a radical mechanism and Hammett correlations indicate that the ortho- and para- halogenated regioisomers are formed via different mechanisms. ortho-Halogenation proceeds through a [3,3]-sigmatropic rearrangement and para-halogenation occurs via an SN2’ mechanism. Further experiments to definitively determine the mechanism need to be performed.

2.4 Experimental

2.4.1 General Information

Commercial reagents and solvents were used as received with the following exceptions. Triethylamine, dichloromethane, ethyl ether, dimethylsulfoxide, tetrahydrofuran, hexane, toluene, N,N-dimethylformamide, and benzene were purified

24 by the method of Pangborn et al. Thionyl chloride (SOCl2) was purified by distillation over calcium hydride prior to use. Thionyl bromide was used without further purification. All reactions were performed in single-neck oven- or flame-dried round bottom flasks fitted with rubber septa under a positive pressure of nitrogen, unless otherwise noted. Air- and moisture-sensitive liquids were transferred via

syringe or stainless steel cannula. Organic solutions were concentrated by rotary evaporation at or below 35 °C at 10 Torr (diaphragm vacuum pump) unless otherwise noted. Proton (1H) and carbon (13C) nuclear magnetic resonance (NMR) spectra were recorded on Bruker AV400 CryoPlatform QNP or Bruker AVIII600 SMART NMR spectrometers at 23 °C. Proton chemical shifts are expressed in parts per million

(ppm, d scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR solvent (CHCl3: d 7.26, C6HD5: d 7.16). Carbon chemical shifts are expressed in parts per million (ppm, d scale) downfield from tetramethylsilane and are referenced to the carbon resonance of the NMR solvent (CDCl3: d 77.16, C6D6: d

128.06). Data are represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, app = apparent), integration, and coupling constant (J) in Hertz (Hz). Accurate mass measurements were obtained using an Agilent 1100 quaternary LC system coupled to an Agilent 6210 LC/MSD-

TOF fitted with an ESI or an APCI source, or Thermo Q-Exactive Orbitrap using electrospray ionization (ESI) or a Waters GCT Premier spectrometer using chemical ionization (CI). Compounds were isolated using flash column chromatography25 with silica gel (60-Å pore size, 40–63μm, standard grade, Silicycle) or basic alumina (60-Å pore size, 50–200 μm, Brockmann I, Acros Organics). Analytical thin-layer chromatography (TLC) was performed using glass plates pre-coated with silica gel

(0.25 mm, 60-Å pore size, 5–20 μm, Silicycle) impregnated with a fluorescent indicator (254 nm). TLC plates were visualized by exposure to ultraviolet light (UV),

then were stained by submersion in aqueous ceric ammonium molybdate solution

(CAM), ethanolic phosphomolybdic acid solution (PMA), acidic ethanolic p- anisaldehyde solution (anisaldehyde), or aqueous potassium permanganate solution

(KMnO4), followed by brief heating on a hot plate (215 °C, 10–15 s).

2.4.2 Synthesis of N,N-Dialkylanilines

H3C CH3 NH2 N

(CH2O)n, NaBH3CN, AcOH

THF, 50 °C 2-127 61%

Glacial acetic acid (6.1 mL, 100 mmol, 5.0 equiv) was added dropwise to a mixture of

1-aminonapthalene (3.0 g, 20. mmol, 1 equiv), paraformaldehyde (3.2 g, 100 mmol,

5.0 equiv), and sodium cyanoborohydride (6.6 g, 100 mmol, 5.0 equiv) in tetrahydrofuran (50 mL) at 23 °C. The resultant mixture was heated to 50 °C and stirred at that temperature for 18 h. The reaction mixture was cooled to 23 °C, then was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and diethyl ether (20 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2 × 20 mL). The combined organic layers were washed sequentially with water (2 × 30 mL), and saturated aqueous sodium chloride solution

(3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resulting oily residue was purified by flash column chromatography (silica gel, starting with 5% ethyl acetate–hexanes, grading to 10% ethyl acetate–hexanes) to afford 1-(N,N-dimethylamino)naphthalene

2-127 as an red-orange oil (2.09 g, 12.2 mmol, 61%): TLC 10% ethyl acetate–

1 hexanes, Rf = 0.66 (UV, KMnO4). H NMR (400 MHz, CDCl3) δ: 8.35 (m, 1H), 7.91

(m, 1H), 7.65-7.44 (overlapping multiplets, 4H), 7.15 (m, H), 2.99 (s, 6H). 13C NMR

(101 MHz, CDCl3) δ: 150.9, 134.9, 128.9, 128.4, 125.8, 125.7, 125.2, 124.2, 122.9,

45.3.

H3C CH3 NH2 N

(CH2O)n, NaBH3CN, AcOH

CO CH THF, 50 °C 2 3 CO2CH3 2-128 87%

Glacial acetic acid (5.1 mL, 89 mmol, 4.5 equiv) was added dropwise to a mixture of

3-aminobenzoate (3.0 g, 20 mmol, 1 equiv), paraformaldehyde (3.0 g, 100 mmol, 5.0 equiv), and sodium cyanoborohydride (6.2 g, 100 mmol, 5.0 equiv) in tetrahydrofuran

(50 mL) at 23 °C. The resultant mixture was heated to 50 °C and stirred at that temperature for 18 h. The reaction mixture was cooled to 23 °C, then was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and diethyl ether (20 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2 × 20 mL). The combined organic layers were washed sequentially with water

(2 × 30 mL), and saturated aqueous sodium chloride solution (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resulting oily residue was purified by flash column chromatography (silica gel, starting with 5% ethyl acetate–hexanes, grading to 10% ethyl acetate–hexanes) to afford methyl 3-N,N-dimethylaminobenzoate 2-128 as a

yellow oil (3.09 g, 17.2 mmol, 87%). TLC 10% ethyl acetate–hexanes, Rf = 0.27

1 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 7.41 – 7.36 (m, 2H), 7.29 (m, 1H),

13 6.90 (m, 1H), 3.90 (s, 3H), 2.99 (s, 6H). C NMR (101 MHz, CDCl3) d: 167.9, 150.5,

130.9, 129.1, 117.6, 116.8, 113.3, 52.2, 40.7. HRMS: ESI+ [M+H]+ Calcd. for

C10H14O2N: 180.1025. Found: 180.1018.

H3C CH3 NH2 N

(CH2O)n, NaBH3CN, AcOH

Br THF, 50 °C Br 2-129 92%

Glacial acetic acid (5.0 mL, 87 mmol, 4.8 equiv) was added dropwise to a mixture of

3-bromoaniline (3.1 g, 18 mmol, 1 equiv), paraformaldehyde (3.5 g, 120 mmol, 6.7 equiv), and sodium cyanoborohydride (5.6 g, 89 mmol, 4.9 equiv) in tetrahydrofuran

yellow oil (3.21 g, 16.0 mmol, 92%). Obtained as an orange-yellow oil (3.2 g, 92%).

1 TLC 10% ethyl acetate–hexanes, Rf = 0.53 (UV, KMnO4). H NMR (400 MHz,

13 CDCl3) d: 7.08 (t, J = 8.0 Hz, 1H), 6.83 (m, 2H), 6.63 (m, 1H), 2.94 (s, 6H). C NMR

+ (101 MHz, CDCl3) d: 151.7, 130.3, 123.5, 119.1, 115.1, 111.0, 40.5. HRMS: ESI

+ [M+H] Calcd. for C8H11NBr: 200.0075. Found: 200.0071.

H3C CH3 NH2 N

(CH2O)n, NaBH3CN, AcOH

Cl THF, 50 °C Cl 2-130 68%

Glacial acetic acid (6.4 mL, 110 mmol, 4.8 equiv) was added dropwise to a mixture of

3-chloroaniline ## (3.0 g, 23 mmol, 1 equiv), paraformaldehyde (3.7 g, 120 mmol, 5.2 equiv), and sodium cyanoborohydride (8.2 g, 130 mmol, 5.6 equiv) in tetrahydrofuran

(2.50 g, 16.1 mmol, 68%). Obtained as a yellow oil (2.50 g, 68%). TLC 10% ethyl

1 acetate–hexanes, Rf = 0.56 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 7.14 (m,

13 1H), 6.69 (m, 2H), 6.59 (dd, J1 = 8.5, J2 = 2.4 Hz, 1H), 2.95 (s, 6H). C NMR (101

+ + MHz, CDCl3) d: 151.6, 135.1, 130.1, 116.2, 112.3, 110.5, 40.5. HRMS: ESI [M+H]

Calcd. for C8H11NCl: 156.0580. Found: 156.0575.

H3C CH3 NH2 N

(CH2O)n, NaBH3CN, AcOH

OCH THF, 50 °C 3 OCH3 2-131 77%

Glacial acetic acid (7.3 mL, 130 mmol, 5.4 equiv) was added dropwise to a mixture of

3-methoxyaniline (3.0 g, 24 mmol, 1 equiv), paraformaldehyde (3.9 g, 130 mmol, 5.4 equiv), and sodium cyanoborohydride (7.9 g, 130 mmol, 5.4 equiv) in tetrahydrofuran

(100 mL) at 23 °C. The resultant mixture was heated to 50 °C and stirred at that temperature for 18 h. The reaction mixture was cooled to 23 °C, then was partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and diethyl ether

(40 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2 × 40 mL). The combined organic layers were washed sequentially with water

(2 × 60 mL), and saturated aqueous sodium chloride solution (3 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with 5% ethyl acetate–hexanes, grading to 10% ethyl acetate–hexanes) to afford 3-methoxy-N,N-dimethylaniline 2-131 as a yellow oil

(2.8 g, 18 mmol, 77% yield). TLC 10% ethyl acetate–hexanes, Rf = 0.40 (UV,

1 KMnO4). H NMR (400 MHz, CDCl3) d: 7.16 (t, J = 8.1 Hz, 1H), 6.37 (dd, J1 = 8.3, J2

13 = 2.3 Hz, 1H), 6.30 (m, 2H), 3.80 (s, 3H), 2.94 (s, 6H). C NMR (101 MHz, CDCl3) d: 160.7, 152.1, 129.8, 105.8, 101.4, 99.2, 55.2, 40.7. HRMS: ESI+ [M+H]+ Calcd. for

C9H14ON: 152.1075. Found: 152.1071.

H3C CH3 NH2 N

(CH2O)n, NaBH3CN, AcOH

CH THF, 50 °C 3 CH3 2-132 75%

Glacial acetic acid (8.5 mL, 150 mmol, 5.3 equiv) was added dropwise to a mixture of

3-methylaniline (3.0 g, 28 mmol, 1 equiv), paraformaldehyde (4.6 g, 150 mmol, 5.3 equiv), and sodium cyanoborohydride (9.3 g, 150 mmol, 5.3 equiv) in tetrahydrofuran

21.0 mmol, 75%). Obtained as a yellow oil (2.8 g, 75%). TLC 10% ethyl acetate–

1 hexanes, Rf = 0.59 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 7.16 (m, 1H), 6.59

13 (m, 3H), 2.95 (s, 6H), 2.35 (s, 3H). C NMR (101 MHz, CDCl3) d: 150.9, 138.8,

+ + 129.0, 117.7, 113.6, 110.0, 40.8, 22.0. HRMS: ESI [M+H] Calcd. for C9H14N:

136.1126. Found: 136.1122.

H3C CH3 NH2 N

(CH2O)n, NaBH3CN, AcOH

CF THF, 50 °C 3 CF3 2-133 65%

Glacial acetic acid (7.3 mL, 130 mmol, 6.8 equiv) was added dropwise to a mixture of

3-trifluoromethylaniline (3.1 g, 19 mmol, 1 equiv), paraformaldehyde (3.4 g, 110 mmol, 5.8 equiv), and sodium cyanoborohydride (7.7 g, 120 mmol, 6.3 equiv) in tetrahydrofuran (50 mL) at 23 °C. The resultant mixture was heated to 50 °C and stirred at that temperature for 18 h. The reaction mixture was cooled to 23 °C, then was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and diethyl ether (20 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2 × 20 mL). The combined organic layers were washed sequentially with water (2 × 30 mL), and saturated aqueous sodium chloride solution

2-133 as a yellow oil (2.34 g, 12.4 mmol, 65%). TLC 10% ethyl acetate–hexanes, Rf

1 = 0.51 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 7.32 (t, J = 8.0 Hz, 1H), 6.94 (d,

J = 7.6 Hz, 1H), 6.89 (m, 1H), 6.85 (dd, J1 = 8.4 Hz, J2 = 2.7 Hz, 1H), 3.00 (s, 6H).

13 C NMR (101 MHz, CDCl3) d: 150.5, 131.4 (q, J = 31.4 Hz), 129.5, 124.7 (q, J =

272.4 Hz), 115.2 (d, J = 1.5 Hz), 112.7 (q, J = 3.9 Hz), 108.5 (q, J = 4.0 Hz), 40.5.

+ + HRMS: ESI [M+H] Calcd. for C9H11NF3: 190.0844. Found: 190.0834.

H3C CH3 NH2 N

(CH2O)n, NaBH3CN, AcOH

CN THF, 50 °C CN 2-134 96%

Glacial acetic acid (7.3 mL, 120 mmol, 5.0 equiv) was added dropwise to a mixture of

3-aminobenzonitrile (3.2 g, 25 mmol, 1 equiv), paraformaldehyde (4.3 g, 140 mmol,

5.6 equiv), and sodium cyanoborohydride (8.0 g, 130 mmol, 5.2 equiv) in tetrahydrofuran (50 mL) at 23 °C. The resultant mixture was heated to 50 °C and stirred at that temperature for 18 h. The reaction mixture was cooled to 23 °C, then was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and diethyl ether (20 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2 × 20 mL). The combined organic layers were washed sequentially with water (2 × 30 mL), and saturated aqueous sodium chloride solution

grading to 10% ethyl acetate–hexanes) to afford 3-(N,N-dimethyl)-aminobenzonitrile

2-134 as a yellow oil (3.52 g, 24 mmol, 96% yield). TLC 10% ethyl acetate–hexanes,

1 Rf = 0.28 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 7.27 (m, 1H), 6.95 (m, 1H),

13 6.88 (m, 2H), 2.98 (s, 6H). C NMR (101 MHz, CDCl3) d: 150.3, 129.8, 119.9, 119.5,

+ + 116.3, 114.8, 112.8, 40.3. HRMS: ESI [M+H] Calcd. for C9H11N2: 147.0922. Found:

147.0917.

H3C CH3 NH2 N F (CH2O)n, NaBH3CN, AcOH F

THF, 50 °C 2-135 77%

Glacial acetic acid (7.3 mL, 130 mmol, 4.8 equiv) was added dropwise to a mixture of

2-fluoroaniline (3.0 g, 27 mmol, 1 equiv), paraformaldehyde (4.3 g, 140 mmol, 5.2 equiv), and sodium cyanoborohydride (8.6 g, 140 mmol, 5.2 equiv) in tetrahydrofuran

ethyl acetate–hexanes) to afford 2-fluoro-N,N-dimethylanilne 2-135 as a red-orange oil (2.90 g, 20.8 mmol, 77%). TLC 10% ethyl acetate–hexanes, Rf = 0.49 (UV,

1 KMnO4). H NMR (400 MHz, CDCl3) d: 7.08 – 6.98 (m, 2H), 6.95 – 6.84 (m, 2H),

13 2.84 (s, 6H). C NMR (101 MHz, CDCl3) d: 155.3 (d, J = 245.1 Hz), 140.9 (d, J = 8.6

Hz), 124.4 (d, J = 3.6 Hz), 121.3 (d, J = 7.8 Hz), 118.4 (d, J = 3.4 Hz), 116.2 (d, J =

+ + 20.9 Hz), 43.0 (d, J = 4.0 Hz). HRMS: ESI [M+H] Calcd. for C8H11NF: 140.0876.

Found: 140.0869.

H3C CH3 NH2 N CH3 (CH2O)n, NaBH3CN, AcOH CH3

THF, 50 °C 2-136 65%

Glacial acetic acid (8.0 mL, 140 mmol, 5.0 equiv) was added dropwise to a mixture of

2-methylaniline (3.0 g, 28 mmol, 1 equiv), paraformaldehyde (4.2 g, 140 mmol, 5.0 equiv), and sodium cyanoborohydride (8.8 g, 140 mmol, 5.0 equiv) in tetrahydrofuran

(90 mL) at 23 °C. The resultant mixture was heated to 50 °C and stirred at that temperature for 18 h. The reaction mixture was cooled to 23 °C, then was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and diethyl ether (20 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2 × 20 mL). The combined organic layers were washed sequentially with water

chromatography (silica gel, starting with 5% ethyl acetate–hexanes, grading to 10% ethyl acetate–hexanes) to afford 2,N,N-trimethylaniline 2-136 as a yellow oil (2.47 g,

1 18.3 mmol, 65%). TLC 10% ethyl acetate–hexanes, Rf = 0.65 (UV, KMnO4). H NMR

(400 MHz, CDCl3) δ 7.20 – 7.13 (m, 2H), 7.07 – 7.02 (m, 1H), 6.96 (td, J1 = 7.4 Hz,

13 J2 =1.3 Hz, 1H), 2.71 (s, 6H), 2.34 (s, 3H). C NMR (101 MHz, CDCl3) δ 152.8,

132.2, 131.2, 126.5, 122.6, 118.4, 44.3, 18.5. HRMS: ESI+ [M+H]+ Calcd. for

C9H14N: 136.1126. Found: 136.1120.

H3C CH3 NH2 N

(CH2O)n, NaBH3CN, AcOH

THF, 50 °C

Cl Cl 2-137 77%

Glacial acetic acid (6.4 mL, 110 mmol, 4.8 equiv) was added dropwise to a mixture of

4-chloroaniline (3.0 g, 23 mmol, 1 equiv), paraformaldehyde (3.6 g, 120 mmol, 5.2 equiv), and sodium cyanoborohydride (7.7 g, 120 mmol, 5.2 equiv) in tetrahydrofuran

chromatography (silica gel, starting with 5% ethyl acetate–hexanes, grading to 10% ethyl acetate–hexanes) to afford 4-chloro-N,N-dimethylanilne 2-137 as a white solid

(3.0 g, 19 mmol, 77% yield). mp 30-32 °C. TLC 10% ethyl acetate–hexanes, Rf =

1 0.57 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 7.17 (d, J = 9.1 Hz, 2H), 6.64 (d,

13 J = 9.1 Hz, 2H), 2.93 (s, 6H). C NMR (101 MHz, CDCl3) d: 149.3, 128.9, 121.5,

+ + 113.7, 40.8. HRMS: ESI [M+H] Calcd. for C8H11NCl: 156.0580. Found: 156.0577.

H3C CH3 NH2 N

(CH2O)n, NaBH3CN, AcOH

THF, 50 °C

Br Br 2-138 90%

Glacial acetic acid (5.0 mL, 87 mmol, 5.1 equiv) was added dropwise to a mixture of

4-bromoaniline (3.0 g, 17 mmol, 1 equiv), paraformaldehyde (2.7 g, 90 mmol, 5.3 equiv), and sodium cyanoborohydride (5.6 g, 89 mmol, 5.2 equiv) in tetrahydrofuran

ethyl acetate–hexanes) to afford 4-bromo-N,N-dimethylanilne 2-138 as a white solid

(3.15 g, 15.7 mmol, 90%). mp 29-31 °C. TLC 10% ethyl acetate–hexanes, Rf = 0.45

1 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 7.30 (d, J = 9.1 Hz, 2H), 6.59 (d, J =

13 9.1 Hz, 2H), 2.92 (s, 6H). C NMR (101 MHz, CDCl3) d: 149.6, 131.8, 114.2, 108.6,

+ + 40.7. HRMS: ESI [M+H] Calcd. for C8H11NBr: 200.0075. Found: 200.0070.

H3C CH3 NH2 N

(CH2O)n, NaBH3CN, AcOH

THF, 50 °C

CN CN 2-139 65%

Glacial acetic acid (7.3 mL, 130 mmol, 5.2 equiv) was added dropwise to a mixture of

4-aminobenzonitrile (3.0 g, 25 mmol, 1 equiv), paraformaldehyde (3.9 g, 130 mmol,

5.2 equiv), and sodium cyanoborohydride (8.1 g, 130 mmol, 5.2 equiv) in tetrahydrofuran (50 mL) at 23 °C. The resultant mixture was heated to 50 °C and stirred at that temperature for 18 h. The reaction mixture was cooled to 23 °C, then was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and diethyl ether (20 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2 × 20 mL). The combined organic layers were washed sequentially with water (2 × 30 mL), and saturated aqueous sodium chloride solution

grading to 10% ethyl acetate–hexanes) to afford 4-(N,N-dimethyl)-aminobenzonitrile

2-139 as an orange-brown solid (2.43 g, 16.6 mmol, 65%). mp 72-74 °C. TLC 10%

1 ethyl acetate–hexanes, Rf = 0.29 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 7.47

(d, J = 9.0 Hz, 2H), 6.64 (d, J = 9.0 Hz, 2H), 3.04 (s, 6H). 13C NMR (101 MHz,

+ + CDCl3) d: 152.5, 133.5, 120.9, 111.5, 97.4, 40.1. HRMS: ESI [M+H] Calcd. for

C9H11N2: 147.0922. Found: 147.0917.

H3C CH3 NH2 N

(CH2O)n, NaBH3CN, AcOH

THF, 50 °C CO CH 2 3 CO2CH3 2-140 63%

Glacial acetic acid (5.6 mL, 98 mmol, 4.7 equiv) was added dropwise to a mixture of

4-aminobenzoate (3.1 g, 21 mmol, 1 equiv), paraformaldehyde (4.0 g, 130 mmol, 6.2 equiv), and sodium cyanoborohydride (6.7 g, 110 mmol, 5.2 equiv) in tetrahydrofuran

ethyl acetate–hexanes) to afford methyl 4-N,N-dimethylaminobenzoate 2-140 as a white solid (2.36 g, 13.2 mmol, 63%). mp 93-95 °C. TLC 10% ethyl acetate–

1 hexanes, Rf = 0.25 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 7.91 (d, J = 8.8 Hz,

2H), 6.65 (d, J = 8.7 Hz, 2H), 3.86 (d, J = 0.8 Hz, 3H), 3.04 (s, 6H). 13C NMR (101

+ + MHz, CDCl3) d: 167.8, 153.4, 131.4, 116.9, 110.8, 51.7, 40.2. HRMS: ESI [M+H]

Calcd. for C10H14O2N: 180.1025. Found: 180.1012.

H3C CH3 NH2 N

(CH2O)n, NaBH3CN, AcOH

THF, 50 °C

F F 2-141 77%

Glacial acetic acid (7.3 mL, 130 mmol, 4.8 equiv) was added dropwise to a mixture of

4-fluoroaniline ## (3.0 g, 27 mmol, 1 equiv), paraformaldehyde (4.2 g, 140 mmol, 5.2 equiv), and sodium cyanoborohydride (8.9 g, 140 mmol, 5.2 equiv) in tetrahydrofuran

ethyl acetate–hexanes) to afford 4-fluoro-N,N-dimethylanilne 2-141 as a yellow solid

(2.91 g, 20.9 mmol, 77%). mp 34-35 °C. TLC 10% ethyl acetate–hexanes, Rf = 0.34

1 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 6.95 (m, 2H), 6.68 (m, 2H), 2.90 (s,

13 6H). C NMR (101 MHz, CDCl3) d: 155.70 (d, J = 235.1 Hz), 147.61 (d, J = 1.8 Hz),

115.50 (d, J = 22.0 Hz), 114.04 (d, J = 7.4 Hz), 41.53. HRMS: ESI+ [M+H]+ Calcd. for C8H11NF: 140.0876. Found: 140.0869.

H3C CH3 NH2 N

(CH2O)n, NaBH3CN, AcOH

THF, 50 °C OCH 3 OCH3 2-142 74%

Glacial acetic acid (7.3 mL, 120 mmol, 5.0 equiv) was added dropwise to a mixture of

4-methoxyaniline (3.0 g, 24 mmol, 1 equiv), paraformaldehyde (3.8 g, 120 mmol, 5.0 equiv), and sodium cyanoborohydride (7.7 g, 120 mmol, 5.0 equiv) in tetrahydrofuran

chromatography (silica gel, starting with 5% ethyl acetate–hexanes, grading to 10% ethyl acetate–hexanes) to afford 4-methoxy-N,N-dimethylaniline 2-142 as a white solid (2.79 g, 18.5 mmol, 74% yield). TLC 10% ethyl acetate-hexanes, Rf = 0.45

1 (UV, KMnO4). H NMR (400 MHz, CDCl3) d 6.86 (d, J = 9.2 Hz, 2H), 6.77 (d, J =

13 8.8 Hz, 2H), 3.77 (s, 3H), 2.88 (s, 6H). C NMR (101 MHz, CDCl3) d 152.0, 145.9,

115.0, 114.7, 55.8, 41.9.

H3C CH3 NH2 N

(CH2O)n, NaBH3CN, AcOH

THF, 50 °C CH 3 CH3 2-143 62%

Glacial acetic acid (26.7 mL, 466 mmol, 4.99 equiv) was added dropwise to a mixture of 4-methylaniline (10.0 g, 93.3 mmol, 1 equiv), paraformaldehyde (14.0 g, 467 mmol, 5.00 equiv), and sodium cyanoborohydride (29.7 g, 472 mmol, 5.06 equiv) in tetrahydrofuran (160 mL) at 23 °C. The resultant mixture was heated to 50 °C and stirred at that temperature for 18 h. The reaction mixture was cooled to 23 °C, then was partitioned between saturated aqueous sodium bicarbonate solution (160 mL) and diethyl ether (80 mL). The layers were separated, and the aqueous layer was extracted with diethyl ether (2 × 80 mL). The combined organic layers were washed sequentially with water (2 × 120 mL), and saturated aqueous sodium chloride solution

(3 × 80 mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by

flash column chromatography (silica gel, starting with 1% ethyl acetate–hexanes, grading to 5% ethyl acetate–hexanes) to afford 4,N,N-trimeyhlaniline 2-143 as a yellow oil (7.8 g, 58 mmol, 62% yield). TLC 10% ethyl acetate-hexanes, Rf = 0.58

1 (UV, KMnO4). H NMR (400 MHz, CDCl3) d 7.07 (d, J = 8.1 Hz, 2H), 6.71 (d, J =

13 8.7 Hz, 2H), 2.91 (s, 6H), 2.27 (s, 3H). C NMR (101 MHz, CDCl3) d 148.9, 129.7,

126.2, 113.3, 41.2, 20.4. FTIR (neat) 3097, 2918, 2797, 1619, 1569, 1522, 1478,

1444, 1341, 1226, 1162, 1131, 947, 804, 686 cm-1. HRMS: ESI+ [M+H]+ Calcd. for

C9H14N: 136.1126. Found: 136.1122.

H3C H C NH O CH3 3 N CH3

NaBH3CN, AcOH

THF, 50 °C 2-144 50%

Glacial acetic acid (4.8 mL, 84 mmol, 3.0 equiv) was added dropwise to a mixture of

N-methylaniline (3.0 g, 28 mmol, 1 equiv), butyraldehyde (7.6 mL, 84 mmol, 3.0 equiv), and sodium cyanoborohydride (5.3 g, 84 mmol, 3.0 equiv) in tetrahydrofuran

(40 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2 × 40 mL). The combined organic layers were washed sequentially with water

(2 × 60 mL), and saturated aqueous sodium chloride solution (3 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried

solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with 1% ethyl acetate–hexanes, grading to 5% ethyl acetate–hexanes) to afford N-butyl-N-methylaniline 2-144 as a yellow oil (2.3 g,

1 14 mmol, 50% yield). TLC 10% ethyl acetate–hexanes, Rf = 0.75 (UV, KMnO4). H

NMR (400 MHz, CDCl3) δ 7.28 – 7.19 (m, 2H), 6.76 – 6.64 (m, 3H), 3.37 – 3.27 (m,

2H), 2.93 (s, 3H), 1.57 (m, 2H), 1.36 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR (101

+ MHz, CDCl3) δ 149.4, 129.2, 115.8, 112.1, 52.6, 38.4, 28.9, 20.5, 14.2. HRMS: ESI

+ [M+H] Calcd. for C11H18Nr: 164.1439. Found: 164.1433.

NH2 NH

NaBH3CN, AcOH

THF, 50 °C 2-145a 47%

Glacial acetic acid (9.2 mL, 160 mmol, 5.0 equiv) was added dropwise to a mixture of aniline (3.0 g, 32 mmol, 1 equiv), cyclohexanone (16.6 mL, 178 mmol, 5.6 equiv), and sodium cyanoborohydride (10.1 g, 161 mmol, 5.0 equiv) in tetrahydrofuran (100 mL) at 23 °C. The resultant mixture was heated to 50 °C and stirred at that temperature for

18 h. The reaction mixture was cooled to 23 °C, then was partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and diethyl ether (40 mL).

The layers were separated and the aqueous layer was extracted with diethyl ether (2 ×

40 mL). The combined organic layers were washed sequentially with water (2 × 60 mL), and saturated aqueous sodium chloride solution (3 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was

concentrated. The resultant oily residue was purified by flash column chromatography

(silica gel, starting with 5% ethyl acetate–hexanes, grading to 10% ethyl acetate– hexanes) to afford N-cyclohexylaniline 2-145a as a yellow oil (2.7 g, 15 mmol, 47%

1 yield). TLC 10% ethyl acetate–hexanes, Rf = 0.59 (UV, KMnO4). H NMR (400 MHz,

CDCl3) δ 7.16 (dd, J1 = 8.4 Hz, J2 = 7.4 Hz, 2H), 6.66 (t, J = 7.3 Hz, 1H), 6.62 – 6.57

(m, 2H), 3.52 (s, 1H), 3.27 (m, 1H), 2.07 (m, 2H), 1.77 (m, 2H), 1.70 – 1.62 (m, 1H),

13 1.45 – 1.31 (m, 2H), 1.29 – 1.09 (m, 3H). C NMR (101 MHz, CDCl3) δ 147.5,

+ + 129.4, 116.9, 113.2, 51.8, 33.6, 26.1, 25.2. HRMS: ESI [M+H] Calcd. for C12H18N:

176.1439. Found: 176.1430.

CH3 NH N

(CH2O)n, NaBH3CN, AcOH

THF, 50 °C 2-145a 2-145 64%

Glacial acetic acid (1.6 mL, 28 mmol, 4.9 equiv) was added dropwise to a mixture of

2-145a (1.0 g, 5.7 mmol, 1 equiv), paraformaldehyde (0.86 g, 29 mmol, 5.1 equiv), and sodium cyanoborohydride (1.8 g, 29 mmol, 5.1 equiv) in tetrahydrofuran (30 mL) at 23 °C. The resultant mixture was heated to 50 °C and stirred at that temperature for

18 h. The reaction mixture was cooled to 23 °C, then was partitioned between saturated aqueous sodium bicarbonate solution (30 mL) and diethyl ether (20 mL).

The layers were separated and the aqueous layer was extracted with diethyl ether (2 ×

20 mL). The combined organic layers were washed sequentially with water (2 × 30 mL), and saturated aqueous sodium chloride solution (3 × 20 mL). The combined

organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography

(silica gel, starting with 5% ethyl acetate–hexanes, grading to 10% ethyl acetate– hexanes) to afford N-cyclohexyl-N-methylaniline 2-145 as a yellow oil (0.69 g, 3.6

1 mmol, 64% yield). TLC 10% ethyl acetate–hexanes, Rf = 0.61 (UV, KMnO4). H

NMR (400 MHz, CDCl3) δ 7.25 – 7.20 (m, 2H), 6.78 (d, J = 8.6 Hz, 2H), 6.71 – 6.66

(m, 1H), 3.61 – 3.53 (m, 1H), 2.78 (s, 3H), 1.87 – 1.75 (m, 4H), 1.69 (d, J = 13.0 Hz,

13 1H), 1.53 – 1.29 (m, 5H), 1.19 – 1.08 (m, 1H). C NMR (101 MHz, CDCl3) δ

150.27, 129.21, 116.29, 113.21, 58.21, 31.28, 30.17, 26.34, 26.07. HRMS: ESI+

+ [M+H] Calcd. for C13H20N: 190.1596. Found: 190.1589.

CH 3 CH3 H3C H C NH CH 3 O 3 N CH3

(CH2O)n, NaBH3CN, AcOH

THF, 50 °C 2-146 43%

Glacial acetic acid (4.8 mL, 84 mmol, 3.0 equiv) was added dropwise to a mixture of

N-methylaniline (3.0 g, 28 mmol, 1 equiv), isovaleraldehyde (9.2 mL, 84 mmol, 3.0 equiv), and sodium cyanoborohydride (5.3 g, 84 mmol, 3.0 equiv) in tetrahydrofuran

(40 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2 × 40 mL). The combined organic layers were washed sequentially with water

(2 × 60 mL), and saturated aqueous sodium chloride solution (3 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with 1% ethyl acetate–hexanes, grading to 5% ethyl acetate–hexanes) to afford N-isopentyl-N-methylaniline 2-146 as a yellow oil

(2.2 g, 12 mmol, 43% yield). TLC 10% ethyl acetate–hexanes, Rf = 0.80 (UV,

1 KMnO4). H NMR (400 MHz, CDCl3) δ 7.27 – 7.20 (m, 2H), 6.69 (m, 3H), 3.37 –

3.29 (m, 2H), 2.92 (s, 3H), 1.61 (m, 1H), 1.46 (m, 2H), 0.96 (d, J = 6.6 Hz, 6H). 13C

NMR (101 MHz, CDCl3) δ 149.4, 129.3, 115.9, 112.2, 51.1, 38.3, 35.1, 26.3, 22.8.

+ + HRMS: ESI [M+H] Calcd. for C12H20N: 178.1596. Found: 178.1589.

CH3 NH N

(CH2O)n, NaBH3CN, AcOH

THF, 50 °C 2-147 76%

Glacial acetic acid (6.6 mL, 120 mmol, 5.1 equiv) was added dropwise to a mixture of

1,2,3,4-tetrahydroquinoline (3.0 g, 22 mmol, 1 equiv), paraformaldehyde (3.48 g, 120 mmol, 5.1 equiv), and sodium cyanoborohydride (7.3 g, 120 mmol, 5.1 equiv) in tetrahydrofuran (100 mL) at 23 °C. The resultant mixture was heated to 50 °C and stirred at that temperature for 18 h. The reaction mixture was cooled to 23 °C, then was partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and diethyl ether (40 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2 × 40 mL). The combined organic layers were washed

sequentially with water (2 × 60 mL), and saturated aqueous sodium chloride solution

(3 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with 5% ethyl acetate–hexanes, grading to 10% ethyl acetate–hexanes) to afford N-methyl-1,2,3,4-tetrahydroquinoline

2-147 as a yellow oil (2.5 g, 17 mmol, 76% yield). TLC 10% ethyl acetate–hexanes,

1 Rf = 0.71 (UV, KMnO4). H NMR (400 MHz, CDCl3) δ 7.08 (t, J = 7.7 Hz, 1H), 6.98

– 6.94 (m, 1H), 6.61 (m, 2H), 3.27 – 3.18 (m, 2H), 2.89 (s, 3H), 2.78 (t, J = 6.4 Hz,

13 2H), 1.99 (p, J = 6.3 Hz, 2H). C NMR (101 MHz, CDCl3) δ 146.9, 128.9, 127.2,

+ + 123.0, 116.3, 111.1, 51.4, 39.3, 27.9, 22.6. HRMS: ESI [M+H] Calcd. for C10H14N:

148.1126. Found: 148.1117.

2.4.3 Oxidation of N,N-Dialkylanilines

H3C CH3 H3C O N mCPBA H3C N

CH2Cl2, 23 °C Br Br 2-129 2-52 63%

A solution of 3-bromo-N,N-dimethylaniline 2-129 (1.0 g, 5.0 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA (77%, 0.99 g,

6.0 mmol, 1.2 eq) in dichloromethane (25 mL) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography (basic alumina, starting with dichloromethane grading to 2% methanol–dichloromethane) to yield 3-

bromo-N,N-dimethylaniline N-oxide 2-52 (0.68 g, 3.1 mmol, 63%) as a white solid.

1 mp 117-119 °C. TLC 20% ethyl acetate–hexanes, Rf = 0.00 (UV, KMnO4). H NMR

(400 MHz, CDCl3) d: 8.28 (m, 1H), 7.87 (m, 1H), 7.55 (m, 1H), 7.34 (t, J = 8.1 Hz,

13 1H), 3.57 (s, 6H). C NMR (101 MHz, CDCl3) d: 155.8, 132.3, 130.5, 124.1, 123.0,

+ + 118.8, 63.7. HRMS: ESI [M+H] Calcd. for C8H11ONBr: 216.0024. Found:

216.0017.

H3C CH3 H3C O N mCPBA H3C N

CH2Cl2, 23 °C Cl Cl 2-130 2-53 90%

A solution of 3-chloro-N,N-dimethylaniline 2-130 (0.99 g, 6.4 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA (77%, 2.04 g,

12.3 mmol, 1.93 eq) in dichloromethane (25 mL) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography (basic alumina, starting with dichloromethane grading to 2% methanol–dichloromethane) to yield 3- chloro-N,N-dimethylaniline N-oxide 2-53 as a tan solid (0.99 g, 5.77 mmol, 90%). mp

1 115-117 °C. TLC 20% ethyl acetate–hexanes, Rf = 0.00 (UV, KMnO4). H NMR (400

13 MHz, CDCl3) d: 8.13 (m, 1H), 7.80 (m, 1H), 7.45 – 7.35 (m, 2H), 3.57 (s, 6H). C

NMR (101 MHz, CDCl3) d: 155.8, 135.2, 130.2, 129.4, 121.3, 118.2, 63.7. HRMS:

+ + ESI [M+H] Calcd. for C8H11ONCl: 172.0529. Found: 172.0521.

H3C CH3 H3C O N mCPBA H3C N

CH2Cl2, 23 °C CF 3 CF3 2-133 2-54 79%

A solution of 3-trifluoromethyl-N,N-dimethylaniline 2-133 (1.01 g, 5.31 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA

(77%, 1.49 g, 8.71 mmol, 1.6 eq) in dichloromethane (25 mL) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography

(basic alumina, starting with dichloromethane grading to 2% methanol– dichloromethane) to yield 3-trifluoromethyl-N,N-dimethylaniline N-oxide 2-54 as a white solid (0.86 g, 4.19 mmol, 79%). mp 131-132 °C. TLC 20% ethyl acetate–

1 hexanes, Rf = 0.00 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 8.40 (m, 1H), 8.18

13 (m, 1H), 7.70 (m, 1H), 7.62 (m, 2H), 3.62 (s, 6H). C NMR (101 MHz, CDCl3) d:

155.3, 131.9 (q, J = 33.3 Hz), 130.0, 126.1 (q, J = 3.6 Hz), 123.5, 123.4 (q, J = 272.7

+ + Hz), 117.9 (q, J = 3.8 Hz), 63.8. HRMS: ESI [M+H] Calcd. for C9H11ONF3:

206.0793. Found: 206.0786.

H3C CH3 H3C O N mCPBA H3C N

CH2Cl2, 23 °C CN CN 2-134 2-55 77%

A solution of 3-(N,N-dimethyl-aminobenzonitrile 2-134 (1.0 g, 6.84 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA (77%, 1.82

g, 11.0 mmol, 1.60 eq) in dichloromethane (25 mL) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography (basic alumina, starting with dichloromethane grading to 2% methanol–dichloromethane) to yield 3-(N,N-dimethyl)-aminobenzonitrile N-oxide 2-55 as a white solid (0.85 g, 5.24 mmol, 77%). mp 140-142 °C. TLC 20% ethyl acetate–hexanes, Rf = 0.00 (UV,

1 KMnO4). H NMR (400 MHz, CDCl3) d: 8.44 (m, 1H), 8.25 (m, 1H), 7.72 (m, 1H),

13 7.62 (t, J = 8.0 Hz, 1H), 3.60 (s, 6H). C NMR (101 MHz, CDCl3) d: 155.5, 132.9,

+ + 130.3, 124.8, 124.5, 117.6, 113.6, 63.8. HRMS: ESI [M+H] Calcd. for C9H11ON:

163.0871. Found: 163.0863.

H3C CH3 H3C O N mCPBA H3C N F F CH2Cl2, 23 °C

2-135 2-56 84%

A solution of 2-fluoro-N,N-dimethylaniline 2-135 (1.03 g, 7.4 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA (77%, 1.93 g,

11.6 mmol, 1.57 eq) in dichloromethane (25 mL) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography (basic alumina, starting with dichloromethane grading to 2% methanol–dichloromethane) to yield 2- fluoro-N,N-dimethylaniline N-oxide 2-56 as an orange-brown solid (0.96 g, 6.18 mmol, 84%). mp 75-77 °C. TLC 20% ethyl acetate–hexanes, Rf = 0.00 (UV,

1 KMnO4). H NMR (400 MHz, CDCl3) d: 8.71 (m, 1H), 7.42 (m, 1H), 7.32 (m, 1H),

13 7.15 (m, 1H), 3.65 (d, J = 1.7 Hz, 6H). C NMR (101 MHz, CDCl3) d: 153.5 (d, J =

246.3 Hz), 141.3 (d, J = 9.9 Hz), 131.4 (d, J = 7.8 Hz), 125.3 (d, J = 3.6 Hz), 125.0,

116.5 (d, J = 22.5 Hz), 62.5 (d, J = 5.7 Hz). HRMS: ESI+ [M+H]+ Calcd. for

C8H11ONF: 156.0825. Found: 156.0817.

H3C CH3 H3C O N mCPBA H3C N CH 3 CH3 CH2Cl2, 23 °C

2-130 2-57 68%

A solution of 2-methyl-N,N-dimethylaniline 2-130 (0.51 g, 3.8 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA (77%, 0.96 g,

4.3 mmol, 1.1 eq) in dichloromethane (25 mL) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography (basic alumina, starting with dichloromethane grading to 2% methanol–dichloromethane) to yield

2,N,N-trimethylaniline N-oxide 2-57 as a yellow solid (0.39 g, 2.58 mmol, 68%). mp

1 69-71 °C. TLC 20% ethyl acetate–hexanes, Rf = 0.00 (UV, KMnO4). H NMR (400

MHz, CDCl3) δ 8.29 – 8.24 (m, 1H), 7.30 – 7.23 (m, 3H), 3.65 (s, 6H), 2.79 (s, 3H).

13 C NMR (101 MHz, CDCl3) δ 152.6, 134.1, 130.0, 129.2, 127.1, 120.9, 61.8, 22.5.

+ + HRMS: ESI [M+H] Calcd. for C9H14ON: 152.1075. Found: 152.1066.

H3C CH3 H3C O N mCPBA H3C N

CH2Cl2, 23 °C

Br Br 2-138 2-58 71%

A solution of 4-bromo-N,N-dimethylaniline 2-138 (1.01 g, 5.05 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA (77%, 1.80 g,

10.9 mmol, 2.16 eq) in dichloromethane (25 mL) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography (basic alumina, starting with dichloromethane grading to 2% methanol–dichloromethane) to yield 4- bromo-N,N-dimethylaniline N-oxide 2-58 as a white solid (0.78 g, 3.61 mmol, 71%).

1 mp 158-160 °C. TLC 20% ethyl acetate–hexanes, Rf = 0.00 (UV, KMnO4). H NMR

(400 MHz, CDCl3) d: 7.90 (d, J = 9.0 Hz, 2H), 7.59 (d, J = 9.0 Hz, 2H), 3.57 (s, 6H).

13 + C NMR (101 MHz, CDCl3) d: 153.8, 132.3, 123.0, 122.1, 63.7. HRMS: ESI

+ [M+H] Calcd. for C8H11ONBr: 216.0024. Found: 216.0016.

H3C CH3 H3C O N mCPBA H3C N

CH2Cl2, 23 °C

CO CH 2 3 CO2CH3 2-140 2-59 58%

A solution of Methyl 4-N,N-dimethylaminobenzoate 2-140 (1.01 g, 5.66 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA

(77%, 1.27 g, 7.65 mmol, 1.35 eq) in dichloromethane (25 mL) at 23 °C. The

resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography (basic alumina, starting with dichloromethane grading to 2% methanol–dichloromethane) to yield methyl 4-N,N-dimethylaminobenzoate N-oxide 2-

59 as a white solid (0.64 g, 3.28 mmol, 58%). mp 145-146 °C. TLC 20% ethyl

1 acetate–hexanes, Rf = 0.00 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 8.15 (d, J =

8.9 Hz, 2H), 8.09 (d, J = 8.9 Hz, 2H), 3.94 (s, 3H), 3.61 (s, 6H). 13C NMR (101 MHz,

+ + CDCl3) d: 165.9, 158.2, 131.0, 130.8, 120.5, 63.6, 52.6. HRMS: ESI [M+H] Calcd. for C10H14O3N: 196.0974. Found: 196.0966.

H3C CH3 H3C O N mCPBA H3C N

CH2Cl2, 23 °C

CN CN 2-139 2-60 69%

A solution of 4-(N,N-dimethyl)-aminobenzonitrile 2-139 (1.01 g, 6.84 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA (77%, 1.77 g, 10.6 mmol, 1.55 eq) in dichloromethane (25 mL) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography (basic alumina, starting with dichloromethane grading to 2% methanol–dichloromethane) to yield 4-(N,N-dimethyl)-aminobenzonitrile N-oxide 2-60 as a white solid (0.76 g, 4.7 mmol, 69%). mp 139-140 °C. TLC 20% ethyl acetate–hexanes, Rf = 0.00 (UV,

1 KMnO4). H NMR (400 MHz, CDCl3) d: 8.18 (d, J = 8.9 Hz, 2H), 7.80 (d, J = 9.0 Hz,

13 2H), 3.60 (s, 6H). C NMR (101 MHz, CDCl3) d: 158.2, 133.4, 121.6, 117.6, 113.5,

+ + 63.6. HRMS: ESI [M+H] Calcd. for C9H11ON2: 163.0871. Found: 163.0863.

CH3 CH3 H3C CH3 O H C N 3 mCPBA H3C N

CH2Cl2, 23 °C

2-146 2-61 79%

A solution of N-isopentyl-N-dimethylaniline 2-146 (0.44 g, 2.5 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA (77%, 0.77 g,

3.5 mmol, 1.4 eq) in dichloromethane (25 mL) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography (basic alumina, starting with dichloromethane grading to 2% methanol–dichloromethane) to yield N- isopentyl-N-dimethylaniline N-oxide 2-61 as a yellow syrup (0.38 g, 2.0 mmol, 79%).

1 TLC 20% ethyl acetate–hexanes, Rf = 0.00 (UV, KMnO4). H NMR (400 MHz,

CDCl3) δ 7.92 – 7.87 (m, 2H), 7.49 – 7.43 (m, 2H), 7.41 – 7.36 (m, 1H), 3.63 (m, 2H),

3.52 (s, 3H), 1.94 – 1.77 (m, 2H), 1.54 (m, 2H), 1.17 (m, 1H), 0.85 (dd, J = 13.5, 6.6

13 Hz, 6H). C NMR (101 MHz, CDCl3) δ 152.6, 129.1, 128.7, 121.0, 72.4, 62.4, 32.0,

+ + 26.3, 22.7, 22.6. HRMS: ESI [M+H] Calcd. for C12H20ON: 194.1545. Found:

194.1535.

CH3 O N mCPBA H3C N

CH2Cl2, 23 °C

2-145 2-62 66%

A solution of N-cyclohexyl-N-dimethylaniline 2-145 (0.50 g, 2.7 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA (77%, 0.82 g,

3.6 mmol, 1.4 eq) in dichloromethane (25 mL) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography (basic alumina, starting with dichloromethane grading to 2% methanol–dichloromethane) to yield N- cyclohexyl-N-dimethylaniline N-oxide 2-62 as a yellow syrup (0.36 g, 1.7 mmol,

1 66%). TLC 20% ethyl acetate–hexanes, Rf = 0.00 (UV, KMnO4). H NMR (400 MHz,

CDCl3) δ 7.89 – 7.84 (m, 2H), 7.43 (td, J = 7.3, 6.6, 1.4 Hz, 2H), 7.38 – 7.33 (m, 1H),

3.46 (s, 3H), 3.39 (m, 1H), 2.24 – 2.19 (m, 1H), 1.91 (m, 1H), 1.76 (m, 2H), 1.63 –

13 1.54 (m, 2H), 1.33 – 1.20 (m, 2H), 1.18 – 1.09 (m, 2H). C NMR (101 MHz, CDCl3)

δ 153.2, 128.8, 128.5, 121.5, 79.7, 57.5, 26.7, 26.6, 25.5, 25.4, 25.1. HRMS: ESI+

+ [M+H] Calcd. for C13H20ON: 206.1545. Found: 206.1534.

H3C CH3 O H C N 3 mCPBA H3C N

CH2Cl2, 23 °C

2-144 2-63 79%

A solution of N-butyl-N-dimethylaniline 2-144 (0.51 g, 3.1 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA (77%, 0.95 g,

4.2 mmol, 1.4 eq) in dichloromethane (25 mL each) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography (basic alumina, starting with dichloromethane grading to 2% methanol–dichloromethane) to yield N-butyl-N-dimethylaniline N-oxide 2-63 as a yellow syrup (0.44 g, 2.4 mmol,

1 79%). TLC 20% ethyl acetate–hexanes, Rf = 0.00 (UV, KMnO4). H NMR (400 MHz,

CDCl3) δ 7.93 – 7.88 (m, 2H), 7.49 – 7.43 (m, 2H), 7.40 – 7.36 (m, 1H), 3.68 – 3.56

(m, 2H), 3.52 (s, 3H), 1.96 – 1.85 (m, 2H), 1.26 (dddd, J = 17.1, 10.0, 4.1, 2.0 Hz,

13 2H), 0.86 (t, J = 7.2 Hz, 3H). C NMR (101 MHz, CDCl3) δ 152.6, 129.1, 128.7,

+ + 121.0, 73.5, 62.4, 25.6, 20.0, 14.0. HRMS: ESI [M+H] Calcd. for C11H18ON:

180.1388. Found: 180.1377.

CH CH3 3 N mCPBA N O

CH2Cl2, 23 °C

2-147 2-64 65%

A solution of N-methyl-1,2,3,4-tetrahydroquinoline 2-147 (0.99 g, 6.7 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA (77%, 1.75 g, 7.81 mmol, 1.16 eq) in dichloromethane (25 mL each) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography

(basic alumina, starting with dichloromethane grading to 2% methanol– dichloromethane) to yield N-methyl-1,2,3,4-tetrahydroquinoline N-oxide 2-64 as a tan

solid (0.71 g, 4.4 mmol, 65%). mp 118-120 °C. TLC 20% ethyl acetate–hexanes, Rf =

1 0.00 (UV, KMnO4). H NMR (600 MHz, CDCl3) δ 8.15 (dd, J1 = 8.4 Hz, J2 = 1.2 Hz,

1H), 7.35 – 7.31 (m, 1H), 7.24 (dt, J1 = 7.5 Hz, J2 = 1.2 Hz, 1H), 7.12 (dd, J1 = 7.7 Hz,

J2 = 1.4 Hz, 1H), 3.87 – 3.80 (m, 2H), 3.53 (s, 3H), 3.03 – 2.96 (m, 1H), 2.90 (m, 1H),

13 2.48 (m, 1H), 2.17 – 2.09 (m, 1H). C NMR (101 MHz, CDCl3) δ 149.96, 129.51,

128.64, 128.36, 128.14, 122.09, 69.50, 62.46, 26.23, 19.85. HRMS: ESI+ [M+H]+

Calcd. for C10H14ON: 164.1075. Found: 164.1065.

H3C CH3 H3C O N mCPBA H3C N

CH2Cl2, 23 °C

2-148 63%

A solution of N,N-dimethylaniline (2.02 g, 16.7 mmol, 1 equiv) in dichloromethane

(25 mL) was added drop-wise to a solution of mCPBA (77%, 4.39 g, 19.6 mmol, 1.17 eq) in dichloromethane (25 mL each) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography (basic alumina, starting with dichloromethane grading to 2% methanol–dichloromethane) to yield

N,N-dimethylaniline N-oxide 2-148 as a tan solid (1.61 g, 11.8 mmol, 71%). TLC 20%

1 ethyl acetate–hexanes, Rf = 0.00 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 7.97

13 (m, 2H), 7.48 (m, 2H), 7.41 (m, 1H), 3.59 (s, 6H). C NMR (101 MHz, CDCl3) d:

154.5, 129.3, 129.0, 120.0, 63.5.

H3C CH3 H3C O N mCPBA H3C N

CH2Cl2, 23 °C

2-127 2-149 61%

A solution of 1-(N,N-dimethyl)-aminonaphthalene 2-127 (1.00 g, 5.85 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA (77%, 1.52 g, 9.20 mmol, 1.57 equiv) in dichloromethane (25 mL each) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography

(basic alumina, starting with dichloromethane grading to 2% methanol– dichloromethane) to yield 1-(N,N-dimethyl)-aminonaphthalene N-oxide 2-149 (0.67 g,

3.6 mmol, 61%) as a tan solid. TLC 20% ethyl acetate–hexanes, Rf = 0.00 (UV,

1 KMnO4). H NMR (400 MHz, CDCl3) d: 9.07 (d, J = 8.8 Hz, 1H), 8.31(d, J = 7.6 Hz,

1H), 7.92 (m, 2H), 7.63 (m, 1H), 7.55 (m, 1H), 7.48 (m, 1H), 3.90 (s, 6H). 13C NMR

(101 MHz, CDCl3) d: 149.1, 135.7, 131.0, 129.5, 127.0, 126.2, 125.7, 125.3, 124.4,

118.3, 62.7.

H3C CH3 H3C O N mCPBA H3C N

CH2Cl2, 23 °C CO CH 2 3 CO2CH3 2-128 2-150 61%

A solution of methyl 3-(N,N-dimethyl)-aminobenzoate 2-128 (1.00 g, 5.58 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA

(77%, 1.63, 9.85 mmol, 1.76 equiv) in dichloromethane (25 mL each) at 23 °C. The

2-150 (0.66 g, 3.4 mmol, 61%) as a white solid. TLC 20% ethyl acetate–hexanes, Rf =

1 0.00 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 8.46 (m, 2H), 8.09 (dt, J1 = 7.6

13 Hz, J2 = 1.2 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 3.95 (s, 3H), 3.62 (s, 6H). C NMR

(101 MHz, CDCl3) d: 166.0, 155.1, 131.1, 130.2, 129.8, 125.3, 120.9, 63.7, 52.7.

H3C CH3 H3C O N mCPBA H3C N

CH2Cl2, 23 °C OCH 3 OCH3 2-131 2-151 86%

A solution of 3-methoxy-N,N-dimethylaniline 2-131 (1.02 g, 6.75 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA (77%, 1.90 g,

11.5 mmol, 1.70 eq) in dichloromethane (25 mL each) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography (basic alumina, starting with dichloromethane grading to 2% methanol–dichloromethane) to yield 3-methoxy-N,N-dimethylaniline N-oxide 2-151 (0.92 g, 5.82 mmol, 86%) as a

1 tan solid. TLC 20% ethyl acetate–hexanes, Rf = 0.00 (UV, KMnO4). H NMR (400

MHz, CDCl3) d: 7.87 (m, 1H), 7.32 (t, J = 8.4 Hz, 1H), 7.23 (m, 1H), 6.91 (m, 1H),

13 3.87 (s, 3H), 3.56 (s, 6H). C NMR (101 MHz, CDCl3) d: 160.5, 156.1, 156.0, 129.7,

115.2, 111.4, 106.2, 63.6, 55.8.

H3C CH3 H3C O N mCPBA H3C N

CH2Cl2, 23 °C CH 3 CH3 2-132 2-152 81%

A solution of 3,N,N-trimethylaniline 2-132 (0.98 g, 7.3 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA (77%, 1.96 g,

11.8 mmol, 1.6 eq) in dichloromethane (25 mL each) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography (basic alumina, starting with dichloromethane grading to 2% methanol–dichloromethane) to yield 3,N,N-trimethylaniline N-oxide 2-152 (0.89 g, 5.9 mmol, 81%) as a tan solid.

1 TLC 20% ethyl acetate–hexanes, Rf = 0.00 (UV, KMnO4). H NMR (400 MHz,

CDCl3) d: 7.92 (m, 1H), 7.62 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 7.32 (t, J = 7.6 Hz,

13 1H), 7.19 (d, J = 7.6 Hz, 1H), 3.56 (s, 6H), 2.42 (s, 3H). C NMR (101 MHz, CDCl3) d: 154.4, 139.7, 129.7, 128.9, 120.9, 116.7, 63.5, 21.7.

H3C CH3 H3C O N mCPBA H3C N

CH2Cl2, 23 °C

Cl Cl 2-137 2-153 91%

A solution of 4-chloro-N,N-dimethylaniline 2-137 (1.00 g, 6.55 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA (77%, 1.63 g,

9.85 mmol, 1.50 eq) in dichloromethane (25 mL each) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography (basic alumina, starting with dichloromethane grading to 2% methanol–dichloromethane) to yield 4-chloro-N,N-dimethylaniline N-oxide 2-153 (1.02 g, 5.94 mmol, 91%) as a

1 white solid. TLC 20% ethyl acetate–hexanes, Rf = 0.00 (UV, KMnO4). H NMR (400

13 MHz, CDCl3) d: 7.95 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 9.2 Hz, 1H), 3.57 (s, 6H). C

NMR (101 MHz, CDCl3) d: 153.2, 135.0, 129.3, 121.8, 63.7.

H3C CH3 H3C O N mCPBA H3C N

CH2Cl2, 23 °C

F F 2-141 2-154 97%

A solution of 4-fluoro-N,N-dimethylaniline 2-141 (1.00 g, 7.19 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA (77%, 1.89 g,

7.90 mmol, 1.10 eq) in dichloromethane (25 mL each) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography (basic alumina, starting with dichloromethane grading to 2% methanol–dichloromethane) to yield 4-fluoro-N,N-dimethylaniline N-oxide 2-154 (1.08 g, 6.96 mmol, 97%) as a

1 white solid. TLC 20% ethyl acetate–hexanes, Rf = 0.00 (UV, KMnO4). H NMR (400

13 MHz, CDCl3) d: 7.99 (m, 2H), 7.14 (m, 2H), 3.58 (s, 6H). C NMR (101 MHz,

CDCl3) d: 162.2 (d, J = 250 Hz), 150.4, 122.4 (d, J = 9.1 Hz), 115.8 (d, J = 23 Hz),

63.8.

H3C CH3 H3C O N mCPBA H3C N

CH2Cl2, 23 °C

OCH 3 OCH3 2-142 2-155 71%

A solution of 4-methoxy-N,N-dimethylaniline 2-142 (0.50 g, 3.3 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA (77%, 0.83 g,

4.8 mmol, 1.4 eq) in dichloromethane (25 mL each) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography (basic alumina, starting with dichloromethane grading to 2% methanol–dichloromethane) to yield 4-methoxy-N,N-dimethylaniline N-oxide 2-155 as a white solid (0.39 g, 2.4

1 mmol, 71%). TLC 20% ethyl acetate–hexanes, Rf = 0.00 (UV, KMnO4). H NMR

(400 MHz, CDCl3) d: 7.89 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 9.2 Hz, 2H), 3.83 (s, 3H),

3.56 (s, 6H).

H3C CH3 H3C O N mCPBA H3C N

CH2Cl2, 23 °C

CH 3 CH3 2-143 2-156 84%

A solution of 4-methyl-N,N-dimethylaniline 2-143 (1.00 g, 7.46 mmol, 1 equiv) in dichloromethane (25 mL) was added drop-wise to a solution of mCPBA (77%, 1.79 g,

10.8 mmol, 1.45 equiv) in dichloromethane (25 mL each) at 23 °C. The resultant solution was left stirring at 23 °C for 60 minutes. The solution was concentrated in vacuo to give a crude product, which was further purified using flash chromatography

(basic alumina, starting with dichloromethane grading to 2% methanol– dichloromethane) to yield 4-methyl-N,N-dimethylaniline N-oxide 2-156 as a tan solid

(0.95 g, 6.3 mmol, 84%). TLC 20% ethyl acetate–hexanes, Rf = 0.00 (UV, KMnO4).

1 H NMR (400 MHz, CDCl3) d: 7.84 (d, J = 7.2 Hz, 2H), 7.25 (d, J = 10.4 Hz, 2H),

3.55 (s, 6H), 2.38 (s, 3H).

2.4.4 Bromination N,N-Dialkylaniline N-Oxides

H3C CH3 H3C O N H3C N 1) SOBr2 (1.0 equiv), THF, −78 °C, 4 h

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min

2-148 Br 2-75 55%

Thionyl bromide (54 µL, 0.70 mmol, 1.0 equiv) was added dropwise to solution of the

N,N-dimethylaniline N-oxide 2-148 (96 mg, 0.70 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon

triethylamine (365 µL, 2.80 mmol, 4.0 equiv) was added. The cooling bath was removed and resultant mixture was allowed to warm to 23 °C and was stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford 4-bromo-N,N- dimethylaniline 2-75 as a white solid (77 mg, 0.38 mmol, 55% yield). mp 29-31 °C.

1 TLC: 10% ethyl acetate–hexanes, Rf = 0.45 (UV, KMnO4). H NMR (400 MHz,

13 CDCl3) d: 7.30 (d, J = 9.1 Hz, 2H), 6.59 (d, J = 9.1 Hz, 2H), 2.92 (s, 6H). C NMR

+ + (101 MHz, CDCl3) d: 149.6, 131.8, 114.2, 108.6, 40.7. HRMS: ESI [M+H] Calcd. for C8H11NBr: 200.0075. Found: 200.0069.

H3C CH3 H3C O N H3C N 1) SOBr2 (1.0 equiv), THF, −78 °C, 4 h

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min

2-149 Br 2-76 56%

Thionyl bromide (49 µL, 0.61 mmol, 1.0 equiv) was added dropwise to solution of the

1-(N,N-dimethyl)-aminonapthalene N-oxide 2-149 (111 mg, 0.608 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (317 µL, 2.43 mmol, 4.00 equiv) was added. The cooling

bath was removed and resultant mixture was allowed to warm to 23 °C and was stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography

(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 4- bromo-1-(N,N-dimethyl)-aminonapthalene 2-76 as a yellow oil (85 mg, 0.34 mmol,

1 56%). TLC 10% ethyl acetate–hexanes, Rf = 0.46 (UV, KMnO4). H NMR (400

MHz, CDCl3) d: 8.29 – 8.17 (m, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.56 (m, 2H), 6.93 (d, J

13 = 8.0 Hz, 1H), 2.88 (s, 6H). C NMR (101 MHz, CDCl3) d: 151.1, 132.9, 130.2,

129.7, 127.7, 127.2, 126.0, 124.7, 116.5, 114.8, 45.3. HRMS: ESI+ [M+H]+ Calcd. for

C12H13NBr: 250.0231. Found: 250.0225.

H3C CH3 H3C O N H3C N 1) SOBr2 (1.0 equiv), THF, −78 °C, 4 h

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min CO2CH3 CO2CH3 Br 2-150 2-77 50%

Thionyl bromide (54 µL, 0.70 mmol, 0.99 equiv) was added dropwise to solution of the methyl 3-N,N-dimethylaminobenzoate N-oxide 2-150 (138 mg, 0.706 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78

°C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.97 equiv) was added. The

100

cooling bath was removed and resultant mixture was allowed to warm to 23 °C and was stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography

(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the methyl 2-bromo-5-N,N-dimethylaminobenzoate 2-77 as a yellow oil (91.3 mg, 0.354

1 mmol, 50%). TLC 10% ethyl acetate–hexanes, Rf = 0.57 (UV, KMnO4). H NMR

(400 MHz, CDCl3) d: 8.20 (d, J = 2.0 Hz, 1H), 7.89 (dd, J1 = 8.5, J2 = 2.0 Hz, 1H),

13 7.01 (d, J = 8.5 Hz, 1H), 3.87 (s, 3H), 2.88 (s, 6H). C NMR (101 MHz, CDCl3) d:

166.0, 155.8, 135.7, 129.7, 124.5, 119.3, 116.9, 52.2, 43.7. HRMS: ESI+ [M+H]+

Calcd. for C10H13O2NBr: 258.0130. Found: 258.0123.

H3C CH3 H3C O N H3C N 1) SOBr2 (1.0 equiv), THF, −78 °C, 4 h

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min Br Br Br 2-52 2-78 59%

Thionyl bromide (54 µL, 0.70 mmol, 1.0 equiv) was added dropwise to solution of the

3-bromo-N,N-dimethylaniline N-oxide 2-52 (143 mg, 0.664 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 4.22 equiv) was added. The cooling

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(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the

3,4-dibromo-N,N-dimethylaniline 2-78 as a white solid (109 mg, 0.392 mmol, 59%).

1 mp 64-65 °C. TLC 10% ethyl acetate–hexanes, Rf = 0.47 (UV, KMnO4). H NMR

(400 MHz, CDCl3) d: 7.37 (d, J = 9.0 Hz, 1H), 6.92 (d, J = 3.0 Hz, 1H), 6.50 (dd, J1 =

13 9.0, J2 = 3.0 Hz, 1H), 2.92 (s, 6H). C NMR (101 MHz, CDCl3) d: 150.4, 133.4,

+ + 125.2, 116.9, 112.9, 110.0, 40.5. HRMS: ESI [M+H] Calcd. for C8H10NBr2:

277.9180. Found: 277.9185.

H3C CH3 H3C O N H3C N 1) SOBr2 (1.0 equiv), THF, −78 °C, 4 h

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min Cl Cl Br 2-53 2-79 61%

Thionyl bromide (54 µL, 0.70 mmol, 0.99 equiv) was added dropwise to solution of the 3-chloro-N,N-dimethylaniline N-oxide 2-53 (122 mg, 0.709 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.95 equiv) was added. The cooling

102

(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 4- bromo-3-chloro-N,N-dimethylaniline 2-79 as a white solid (101 mg, 0.431 mmol,

1 61%). mp 48-49 °C. TLC 10% ethyl acetate–hexanes, Rf = 0.50 (UV, KMnO4). H

NMR (400 MHz, CDCl3) d: 7.37 (d, J = 8.9 Hz, 1H), 6.75 (d, J = 3.0 Hz, 1H), 6.46

13 (dd, J1 = 9.0, J2 = 3.0 Hz, 1H), 2.93 (s, 6H). C NMR (101 MHz, CDCl3) d: 150.5,

+ + 134.7, 133.5, 113.7, 112.3, 107.7, 40.5. HRMS: ESI [M+H] Calcd. for C8H10NBrCl:

233.9685. Found: 233.9690.

H3C CH3 H3C O N H3C N 1) SOBr2 (1.0 equiv), THF, −78 °C, 4 h

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min OCH3 OCH3 Br 2-151 2-80 39%

Thionyl bromide (54 µL, 0.70 mmol, 0.97 equiv) was added dropwise to solution of the 3-methoxy-N,N-dimethylaniline N-oxide (2-151, 121 mg, 0.721 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.88 equiv) was added. The cooling

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(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 4- bromo-3-methoxy-N,N-dimethylaniline as a tan solid (2-80, 65 mg, 0.28 mmol, 39%

1 yield). mp 67-68 °C. TLC 10% ethyl acetate–hexanes, Rf = 0.55 (UV, KMnO4). H

NMR (400 MHz, CDCl3) d: 7.31 (d, J = 8.7 Hz, 1H), 6.25 (d, J = 2.8 Hz, 1H), 6.21

13 (dd, J1 = 8.7, J2 = 2.8 Hz, 1H), 3.89 (s, 3H), 2.95 (s, 6H). C NMR (101 MHz,

+ + CDCl3) d: 156.4, 151.4, 133.1, 106.2, 98.0, 97.2, 56.1, 40.8. HRMS: ESI [M+H]

Calcd. for C9H13ONBr: 230.0181. Found: 230.0175.

H3C CH3 H3C O N H3C N 1) SOBr2 (1.0 equiv), THF, −78 °C, 4 h

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min CH3 CH3 Br 2-152 2-81 66%

Thionyl bromide (54 µL, 0.70 mmol, 0.97 equiv) was added dropwise to solution of the 3-methyl-N,N-dimethylaniline N-oxide (2-152, 110 mg, 0.72 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.9 equiv) was added. The cooling

104

(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 4- bromo-3-methyl-N,N-dimethylaniline as a white solid (2-81, 103 mg, 0.479 mmol,

1 66%). mp 51-53 °C. TLC 10% ethyl acetate–hexanes, Rf = 0.41 (UV, KMnO4). H

NMR (400 MHz, CDCl3) d: 7.32 (d, J = 8.8 Hz, 1H), 6.59 (d, J = 3.1 Hz, 1H), 6.44

13 (dd, J1 = 8.8, J2 = 3.1 Hz, 1H), 2.91 (s, 6H), 2.35 (s, 3H). C NMR (101 MHz,

+ + CDCl3) d: 150.0, 138.0, 132.5, 115.0, 112.0, 111.5, 40.8, 23.5. HRMS: ESI [M+H]

Calcd. for C9H13NBr: 214.0231. Found: 214.0225.

H3C CH3 H3C O N H3C N 1) SOBr2 (1.0 equiv), CH2Cl2, −78 °C, 4 h

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min CF3 CF3 Br 2-54 2-82 48%

Thionyl bromide (54 µL, 0.70 mmol, 0.99 equiv) was added dropwise to solution of the 3-trifluoromethyl-N,N-dimethylaniline N-oxide (2-54, 145 mg, 0.706 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78

°C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.97 equiv) was added. The

105

(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 4- bromo3-trifluoromethyl-N,N-dimethylaniline as a yellow oil (2-82, 92 mg, 0.34 mmol,

1 48%). TLC 10% ethyl acetate–hexanes, Rf = 0.47 (UV, KMnO4). H NMR (400

MHz, CDCl3) d: 7.70 (d, J = 2.4 Hz, 1H), 7.38 (dd, J1 = 8.6, J2 = 2.3 Hz, 1H), 6.96 (d,

13 J = 8.6 Hz, 1H), 2.80 (s, 6H). C NMR (101 MHz, CDCl3) d: 149.2, 135.2, 130.1 (q,

J = 30.4 Hz), 123.3 (q, J = 273.5 Hz), 116.1, 111.2 (q, J = 5.8 Hz), 104.5 (q, J = 1.9

+ + Hz), 40.5. HRMS: ESI [M+H] Calcd. for C9H10NBrF3: 267.9949. Found: 267.9952.

H3C CH3 H3C O N H3C N 1) SOBr2 (1.0 equiv), CH2Cl2, −78 °C, 4 h

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min CN CN Br 2-55 2-83 50%

Thionyl bromide (54 µL, 0.70 mmol, 0.99 equiv) was added dropwise to solution of the 5-(N,N-dimethyl)-aminobenzonitrile N-oxide (2-55, 114 mg, 0.702 mmol, 1 equiv) in dichloromethane (4 mL) at –78 °C. The resultant mixture was stirred at –78 °C for

4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.97 equiv) was added. The

106

(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 2- bromo-5-(N,N-dimethyl)-aminobenzonitrile as a yellow oil (2-83, 81 mg, 0.27 mmol,

1 50%). mp 70-72 °C. TLC 5% ethyl acetate–hexanes, Rf = 0.21 (UV, KMnO4). H

NMR (400 MHz, CDCl3) d: 7.41 (d, J = 9.1 Hz, 1H), 6.87 (d, J = 3.2 Hz, 1H), 6.73

13 (dd, J1 = 9.1, J2 = 3.2 Hz, 1H), 2.97 (s, 6H). C NMR (101 MHz, CDCl3) d: 149.2,

133.3, 118.2, 117.6, 116.9, 115.7, 109.9, 40.4. HRMS: ESI+ [M+H]+ Calcd. for

C9H10N2Br: 225.0027. Found: 225.0020.

H3C CH3 H3C O N H3C N 1) SOBr2 (1.0 equiv), THF, −78 °C, 4 h F F 2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min

Br 2-56 2-84 26%

Thionyl bromide (54 µL, 0.70 mmol, 0.98 equiv) was added dropwise to solution of the 2-fluoro-N,N-dimethylaniline N-oxide (2-56, 111 mg, 0.715 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.92 equiv) was added. The cooling

107

(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 4- bromo-2-fluoro-N,N-dimethylaniline as a yellow oil (2-84, 40 mg, 0.18 mmol, 26%).

1 TLC 10% ethyl acetate–hexanes, Rf = 0.55 (UV, KMnO4). H NMR (400 MHz,

13 CDCl3) d: 7.15 (m, 2H), 6.75 (m, 1H), 2.82 (s, 6H). C NMR (101 MHz, CDCl3) d:

154.8 (d, J = 249.9 Hz), 140.2 (d, J = 8.5 Hz), 127.3 (d, J = 3.6 Hz), 119.5 (d, J = 40.4

Hz), 119.4 (d, J = 12.2 Hz), 112.0 (d, J = 9.4 Hz), 42.8 (d, J = 4.2 Hz). HRMS: ESI+

+ [M+H] Calcd. for C8H10NBrF: 217.9980. Found: 217.9984.

H3C CH3 H3C O N H3C N 1) SOBr (1.0 equiv), THF, −78 °C, 4 h 2 CH3 CH3 2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min

Br 2-57 2-85 51%

Thionyl bromide (54 µL, 0.70 mmol, 0.99 equiv) was added dropwise to solution of the 4-bromo-2,N,N-trimethylaniline N-oxide (2-57, 107 mg, 0.708 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.95 equiv) was added. The cooling

108

(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 2- bromo-2,N,N-trimethylaniline as a yellow oil (2-85, 77 mg, 0.36 mmol, 51%). TLC

1 10% ethyl acetate–hexanes, Rf = 0.63 (UV, KMnO4). H NMR (600 MHz, CDCl3) δ

7.28 (d, J = 2.1 Hz, 1H), 7.24 (dd, J1 = 8.5 Hz, J2 = 2.3 Hz, 1H), 6.88 (d, J = 8.5 Hz,

13 1H), 2.67 (s, 6H), 2.29 (s, 3H). C NMR (101 MHz, CDCl3) δ 152.0, 134.5, 133.8,

+ + 129.3, 120.2, 115.2, 44.2, 18.3. HRMS: ESI [M+H] Calcd. for C9H13NBr:

214.0231. Found: 214.0222.

H3C CH3 H3C O N H3C N 1) SOBr2 (1.0 equiv), THF, −78 °C, 4 h Br

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min

Cl Cl 2-86 2-153 37%

Thionyl bromide (54 µL, 0.70 mmol, 1.0 equiv) was added dropwise to solution of the

4-chloro-N,N-dimethylaniline N-oxide (2-153, 119 mg, 0.696 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 4.02 equiv) was added. The cooling

109

(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 2- bromo-4-chloro-N,N-dimethylaniline as a yellow oil (2-86, 58 mg, 0.25 mmol, 36%).

1 TLC 10% ethyl acetate–hexanes, Rf = 0.54 (UV, KMnO4). H NMR (400 MHz,

CDCl3) d: 7.55 (d, J = 2.5 Hz, 1H), 7.23 (dd, J1 = 8.6, J2 = 2.4 Hz, 1H), 7.00 (d, J =

13 8.6 Hz, 1H), 2.78 (s, 6H). C NMR (101 MHz, CDCl3) d: 150.8, 133.4, 128.2, 128.2,

+ + 121.2, 119.5, 44.3. HRMS: ESI [M+H] Calcd. for C8H10NBrCl: 233.9685. Found:

233.9680.

H3C CH3 H3C O N H3C N 1) SOBr2 (1.0 equiv), THF, −78 °C, 4 h Br

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min

Br Br 2-87 2-58 26%

Thionyl bromide (54 µL, 0.70 mmol, 1.0 equiv) was added dropwise to solution of the

4-bromo-N,N-dimethylaniline N-oxide (2-58, 150 mg, 0.696 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 4.02 equiv) was added. The cooling

110

(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the

2,4-dibromo-N,N-dimethylaniline as a yellow oil (2-87, 51 mg, 0.18 mmol, 26%).

1 TLC 10% ethyl acetate–hexanes, Rf = 0.62 (UV, KMnO4). H NMR (400 MHz,

CDCl3) d: 7.68 (d, J = 2.4 Hz, 1H), 7.36 (dd, J1 = 8.6, J2 = 2.3 Hz, 1H), 6.94 (d, J =

13 8.6 Hz, 1H), 2.77 (s, 6H). C NMR (101 MHz, CDCl3) d: 151.2, 136.1, 131.1, 121.7,

+ + 119.8, 115.4, 44.2. HRMS: ESI [M+H] Calcd. for C8H10NBr2: 279.9180. Found:

279.9158.

H3C CH3 H3C O N H3C N 1) SOBr2 (1.0 equiv), THF, −78 °C, 4 h Br

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min

CN CN 2-88 2-60 10%

Thionyl bromide (54 µL, 0.70 mmol, 1.0 equiv) was added dropwise to solution of the

3-(N,N-dimethyl)-aminobenzonitrile N-oxide (2-60, 114 mg, 0.702 mmol, 1 equiv) in dichloromethane (4 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.99 equiv) was added. The cooling

111

(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 3- bromo-4-(N,N-dimethyl)-aminobenzonitrile as a white solid (2-88, 20 mg, 0.07 mmol,

1 10%). TLC 5% ethyl acetate–hexanes, Rf = 0.23 (UV, KMnO4). H NMR (400 MHz,

CDCl3) d: 7.79 (d, J = 2.0 Hz, 1H), 7.51 (dd, J1 = 8.5 Hz, J2 = 2.0 Hz, 1H), 7.01 (d, J

13 = 8.4 Hz, 1H), 2.91 (s, 6H). C NMR (101 MHz, CDCl3) d: 155.7, 137.8, 132.1,

+ + 119.9, 118.3, 116.6, 105.4, 43.5. HRMS: ESI [M+H] Calcd. for C9H10N2Br:

225.0027. Found: 225.0030.

H3C CH3 H3C O N H3C N 1) SOBr2 (1.0 equiv), THF, −78 °C, 4 h Br

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min

CO2CH3 CO2CH3 2-89 2-59 33%

Thionyl bromide (54 µL, 0.70 mmol, 0.99 equiv) was added dropwise to solution of the methyl 3-N,N-dimethylaminobenzoate-N-oxide (2-59, 138 mg, 0.706 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78

°C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.97 equiv) was added. The

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(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the methyl 2-bromo-5-N,N-dimethylaminobenzoate as a yellow oil (2-89, 91.3 mg, 0.354

1 mmol, 50%). TLC 10% ethyl acetate–hexanes, Rf = 0.26 (UV, KMnO4). H NMR

(400 MHz, CDCl3) d: 7.42 (d, J = 8.9 Hz, 1H), 7.06 (d, J = 3.2 Hz, 1H), 6.65 (dd, J1 =

13 8.9, J2 = 3.2 Hz, 1H), 3.92 (s, 3H), 2.95 (s, 6H). C NMR (101 MHz, CDCl3) d:

167.6, 149.4, 134.5, 132.3, 116.5, 114.6, 106.9, 52.5, 40.5. HRMS: ESI+ [M+H]+

Calcd. for C10H13O2NBr: 258.0130. Found: 258.0135.

H3C CH3 H3C O N H3C N 1) SOBr2 (1.0 equiv), THF, −78 °C, 4 h Br

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min

F F 2-90 2-154 26%

Thionyl bromide (54 µL, 0.70 mmol, 0.99 equiv) was added dropwise to solution of the 4-fluoro-N,N-dimethylaniline-N-oxide (2-154, 110 mg, 0.709 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.95 equiv) was added. The cooling

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(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 2- bromo-4-fluoro-N,N-dimethylaniline as a yellow oil (2-90, 39 mg, 0.18 mmol, 26%).

1 TLC 10% ethyl acetate–hexanes, Rf = 0.56 (UV, KMnO4). H NMR (400 MHz,

CDCl3) d: 7.31 (dd, J1 = 8.1, J2 = 2.9 Hz, 1H), 7.06 (m, 1H), 6.99 (m, 1H), 2.75 (s,

13 6H). C NMR (101 MHz, CDCl3) d: 158.3 (d, J = 245.5 Hz), 148.4 (d, J = 3.0 Hz),

121.1 (d, J = 8.5 Hz), 120.9 (d, J = 25.0 Hz), 119.7 (d, J = 9.5 Hz), 114.8 (d, J = 21.6

+ + Hz), 44.7. HRMS: ESI [M+H] Calcd. for C8H10NBrF: 217.9981. Found: 217.9981.

H C H C 3 3 O N CH3 H3C N 1) SOBr2 (1.0 equiv), THF, −78 °C, 4 h

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min

Br 2-63 2-91 59%

Thionyl bromide (54 µL, 0.70 mmol, 0.99 equiv) was added dropwise to solution of the N-butyl-N-dimethylaniline N-oxide (2-63, 126 mg, 0.703 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.95 equiv) was added. The cooling

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(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 4- bromo-N-butyl-N-dimethylaniline as a yellow oil (2-91, 100 mg, 0.412 mmol, 59%).

1 TLC 10% ethyl acetate–hexanes, Rf = 0.71 (UV, KMnO4). H NMR (400 MHz,

CDCl3) δ 7.27 (d, J = 9.2 Hz, 2H), 6.54 (d, J = 9.0 Hz, 2H), 3.30 – 3.24 (m, 2H), 2.89

(s, 3H), 1.58 – 1.48 (m, 2H), 1.34 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (101

+ MHz, CDCl3) δ 148.3, 131.8, 113.7, 107.6, 52.6, 38.5, 28.8, 20.4, 14.1. HRMS: ESI

+ [M+H] Calcd. for C11H17NBr: 242.0544. Found: 242.0534.

H3C O N H3C N 1) SOBr2 (1.0 equiv), THF, −78 °C, 4 h

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min

Br 2-62 2-92 64%

Thionyl bromide (54 µL, 0.70 mmol, 0.99 equiv) was added dropwise to solution of the N-cyclohexyl-N-dimethylaniline N-oxide (2-62, 145 mg, 0.705 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.95 equiv) was added. The cooling

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(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 4- bromo-N-cyclohexyl-N-dimethylaniline as a yellow solid (2-92, 120 mg, 0.449 mmol,

1 64%). mp 45-47 °C. TLC 10% ethyl acetate–hexanes, Rf = 0.68 (UV, KMnO4). H

NMR (400 MHz, CDCl3) δ 7.27 (d, J = 9.3 Hz, 2H), 6.63 (d, J = 9.1 Hz, 2H), 3.49 (m,

1H), 2.73 (s, 3H), 1.87 – 1.80 (m, 2H), 1.79 – 1.67 (m, 3H), 1.47 – 1.31 (m, 4H), 1.12

13 (m, 1H). C NMR (101 MHz, CDCl3) δ 149.2, 131.8, 114.7, 107.9, 58.3, 31.3, 30.1,

+ + 26.3, 26.0. HRMS: ESI [M+H] Calcd. for C13H19NBr: 268.0701. Found: 268.0689.

CH CH3 3 H C H C 3 3 O N CH3 H3C N 1) SOBr2 (1.0 equiv), THF, −78 °C, 4 h

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min

Br 2-61 2-93 53%

Thionyl bromide (54 µL, 0.70 mmol, 0.99 equiv) was added dropwise to solution of the N-isopentyl-N-dimethylaniline N-oxide (2-61, 136 mg, 0.704 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.95 equiv) was added. The cooling

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(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 4- bromo-N-isopentyl-N-dimethylaniline as a yellow oil (2-93, 96 mg, 0.37 mmol, 53%).

1 TLC 10% ethyl acetate–hexanes, Rf = 0.74 (UV, KMnO4). H NMR (400 MHz,

CDCl3) δ 7.27 (d, J = 9.3 Hz, 2H), 6.54 (d, J = 9.1 Hz, 2H), 3.32 – 3.25 (m, 2H), 2.88

(s, 3H), 1.65 – 1.51 (m, 2H), 1.46 – 1.38 (m, 2H), 0.94 (d, J = 6.6 Hz, 6H). 13C NMR

(101 MHz, CDCl3) δ 148.3, 131.9, 113.8, 107.7, 51.1, 38.4, 35.0, 26.3, 22.8. HRMS:

+ + ESI [M+H] Calcd. for C12H19NBr: 256.0701. Found: 256.0690.

CH3 CH3 N N O 1) SOBr2 (1.0 equiv), THF, −78 °C, 4 h

2) NEt3 (4.0 equiv), −78 to 23 °C, 45 min

Br 2-64 2-94 69%

Thionyl bromide (54 µL, 0.70 mmol, 0.99 equiv) was added dropwise to solution of the N-methyl-1,2,3,4-tetrahydroquinoline N-oxide (2-64, 115 mg, 0.703 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78

°C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.95 equiv) was added. The cooling bath was removed and resultant mixture was allowed to warm to 23 °C and

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was stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography

(silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 2- bromo-4-fluoro-N,N-dimethylaniline as a yellow oil (2-94, 110 mg, 0.488 mmol,

1 69%). TLC 10% ethyl acetate–hexanes, Rf = 0.59 (UV, KMnO4). H NMR (400 MHz,

CDCl3) δ 7.13 (dd, J1 = 8.7 Hz, J2 = 2.5 Hz, 1H), 7.06 – 7.03 (m, 1H), 6.43 (d, J = 8.7

Hz, 1H), 3.23 – 3.17 (m, 2H), 2.85 (s, 3H), 2.73 (t, J = 6.5 Hz, 2H), 1.98 – 1.92 (m,

13 2H). C NMR (101 MHz, CDCl3) δ 145.8, 131.2, 129.7, 125.0, 112.5, 107.8, 51.2,

+ + 39.2, 27.8, 22.3. HRMS: ESI [M+H] Calcd. for C10H13NBr: 226.0231. Found:

226.0221.

2.4.5 Chlorination N,N-Dialkylaniline N-Oxides

H3C O H3C CH3 H C N N 3 1) SOCl (0.5 equiv), THF, −78 °C, 2h 2 Cl 2) SOCl2 (0.5 equiv), −78 °C, 2h 2

3) NEt (4.0 equiv), −78 to 23 °C 3 4 2-148 2-106 49% 4.9:1 (2-Cl:4-Cl)

A solution of thionyl chloride (52 µL, 0.70 mmol, 1.0 equiv) in tetrahydrofuran (1 mL) was added dropwise in two portions over a period of 2 h to a solution of the N,N- dimethylaniline N-oxide (2-148, 96 mg, 0.703 mmol, 1 equiv) in tetrahydrofuran (3

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mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 4.00 equiv) was added. The cooling bath was removed and resultant mixture was allowed to warm to 23 °C and stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford 2-106 as a yellow oil

(isolated as a mix of regioisomers, 4.9:1 (2-Cl:4-Cl), asterisk denotes minor peaks, 53

1 mg, 0.34 mmol, 49%). TLC 10% ethyl acetate–hexanes, Rf = 0.57 (UV, KMnO4). H

NMR (400 MHz, CDCl3) d: 7.35 (dd, J1 = 7.9, J2 = 1.6 Hz, 1H), 7.22 (dt, J1 = 8.1, J2 =

1.6 Hz, 1H), 7.17* (d, J = 9.1 Hz, 2H), 7.08 (dd, J1 = 8.1, J2 = 1.6 Hz, 1H), 6.95 (dt, J1

13 = 7.9, J2 = 1.6 Hz, 1H), 6.64* (d, J = 9.1 Hz, 2H), 2.93* (s, 6H), 2.82 (s, 6H). C

NMR (101 MHz, CDCl3) d: 150.5, 149.3*, 130.8, 130.4, 128.9*, 128.4, 127.5, 123.3,

+ + 120.1*, 113.7*, 43.9, 40.8*. HRMS: ESI [M+H] Calcd. for C8H11NCl: 156.0580.

Found: 156.0570.

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H3C O H3C CH3 H C N N 3 1) SOCl (0.5 equiv), THF, −78 °C, 2h 2 Cl 2) SOCl2 (0.5 equiv), −78 °C, 2h 2

3) NEt (4.0 equiv), −78 to 23 °C 3 4 2-149 2-107 60% 6.7:1 (2-Cl:4-Cl)

A solution of thionyl chloride (52 µL, 0.70 mmol, 1.0 equiv) in tetrahydrofuran (1 mL) was added dropwise in two portions over a period of 2 h to a solution of the 1-

(N,N-dimethyl)-aminonapthalene N-oxide (2-149, 132 mg, 0.703 mmol, 1 equiv) in tetrahydrofuran (3 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.98 equiv) was added. The cooling bath was removed and resultant mixture was allowed to warm to 23 °C and stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford 2-107 as 2 regioisomers.

2-chloro-1-(N,N-dimethyl)-aminonapthalene obtained as a colorless oil (75.3 mg, 0.37 mmol, 52%) and 4-chloro-1-(N,N-dimethyl)-aminonaphthalene as a yellow oil (11 mg, 0.056 mmol, 8%).

2-chloro-1-(N,N-dimethyl)-aminonapthalene: TLC 10% ethyl acetate–hexanes, Rf =

1 0.87 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 8.35 (m, 1H), 7.80 (m, 1H), 7.58

(d, J = 8.8 Hz, 1H), 7.50 (m, 2H), 7.37 (d, J = 8.8 Hz, 1H), 3.02 (s, 6H). 13C NMR

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(101 MHz, CDCl3) d: 145.4, 133.9, 133.3, 130.4, 128.6, 128.0, 126.6, 126.5, 126.1,

+ + 124.6, 42.9. HRMS: ESI [M+H] Calcd. for C12H13NCl: 206.0737. Found: 206.0727.

4-chloro-1-(N,N-dimethyl)-aminonaphthalene: TLC 10% ethyl acetate–hexanes, Rf =

1 0.47 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 8.26 (m, 2H), 7.62 – 7.51 (m,

2H), 7.47 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 2.88 (s, 6H). 13C NMR (101

MHz, CDCl3) d: 150.3, 131.7, 130.0, 126.9, 126.0, 126.0, 126.0, 125.0, 124.7, 114.2,

+ + 45.4. HRMS: ESI [M+H] Calcd. for C12H13NCl: 206.0737. Found: 206.0728.

H3C O H3C CH3 H3C N N 1) SOCl2 (0.5 equiv), THF, −78 °C, 2h CH3 H3C Cl 2) SOCl2 (0.5 equiv), −78 °C, 2h 2

3) NEt (4.0 equiv), −78 to 23 °C 3 4 2-57 2-108 19% 1.3:1 (2-Cl:4-Cl)

A solution of thionyl chloride (52 µL, 0.70 mmol, 0.98 equiv) in tetrahydrofuran (1 mL) was added dropwise in two portions over a period of 2 h to a solution of the 3- methyl-N,N-dimethylaniline N-oxide (2-57, 108 mg, 0.713 mmol, 1 equiv) in tetrahydrofuran (3 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.93 equiv) was added. The cooling bath was removed and resultant mixture was allowed to warm to 23 °C and stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The

121

resultant oily residue was purified by flash column chromatography (silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford 2-108 as a yellow oil

(isolated as a mix of regioisomers, 1.3:1 (6-Cl:4-Cl), asterisk denotes minor peaks, 23

1 mg, 0.13 mmol, 19%). TLC 10% ethyl acetate–hexanes, Rf = 0.89 (UV, KMnO4). H

NMR (400 MHz, CDCl3) d: 7.17 (d, J = 6.8 Hz, 1H), 7.13* (d, J = 2.0 Hz, 1H), 7.10*

(dd, J1 = 8.4, J2 = 2.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.96 (t, J = 7.2 Hz, 1H), 6.93*

(d, J = 8.4 Hz, 1H), 2.70 (s, 6H), 2.67* (s, 6H), 2.34 (s, 3H), 2.30* (s, 3H). 13C NMR

(101 MHz, CDCl3) δ 152.7*, 151.3, 134.0, 132.1, 131.2*, 130.8, 127.4*, 126.4*,

126.2, 122.5*, 119.6, 118.3*, 44.3*, 44.2, 18.4*, 18.3. HRMS: ESI+ [M+H]+ Calcd. for C9H13NCl: 170.0737. Found: 170.0727.

H3C O H3C CH3 H3C N N 1) SOCl2 (0.5 equiv), THF, −78 °C, 2h 2 Cl 2) SOCl2 (0.5 equiv), −78 °C, 2h 6

3) NEt (4.0 equiv), −78 to 23 °C H C CH3 3 3 4 2-152 2-109 54% 2.9:1.5:1 (6-Cl:2-Cl:4-Cl)

A solution of thionyl chloride (52 µL, 0.70 mmol, 0.98 equiv) in tetrahydrofuran (1 mL) was added dropwise in two portions over a period of 2 h to a solution of the

3,N,N-trimethylaniline N-oxide (2-152, 108 mg, 0.713 mmol, 1 equiv) in tetrahydrofuran (3 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.93 equiv) was added. The cooling bath was removed and resultant mixture was allowed to warm to 23 °C and stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous

122

sodium bicarbonate solution (4 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford 2-109 as a yellow oil

(isolated as a mix of regioisomers, (5.3:3.7:1 (6-Cl:2-Cl:4-Cl), asterisk denotes 2-Cl, plus denotes 4-Cl, 57 mg, 47%). TLC 10% ethyl acetate–hexanes, Rf = 0.64-54 (UV,

1 + KMnO4). H NMR (400 MHz, CDCl3) d: 7.22 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.8

Hz, 1H), 7.11* (t, J = 7.7 Hz, 1H), 6.94* (m, 2H), 6.87 (d, J = 2.0 Hz, 1H), 6.76 (dd,

+ + J1 = 8.0, J2 = 1.7 Hz, 1H), 6.58 (d, J = 3.1 Hz, 1H), 6.50 (dd, J1 = 8.8, J2 = 3.1 Hz,

1H), 2.91+ (s, 6H), 2.80 (s, 6H), 2.79* (s, 6H), 2.39* (s, 3H), 2.33+ (s, 3H), 2.31 (s,

13 + + 3H). C NMR (101 MHz, CDCl3) d: 150.9*, 150.1, 149.4 , 137.8*, 137.4, 136.2 ,

130.4, 129.3+, 128.9*, 126.6*, 125.2, 125.1*, 124.1, 122.1+, 120.9, 117.7*, 115.0+,

111.6+, 44.2*, 44.0, 40.9+, 21.3, 21.1*, 20.7+. HRMS: ESI+ [M+H]+ Calcd. for

C9H13NCl: 170.0737. Found: 170.0733.

4-chloro-3-methyl-N,N-dimethylaniline: Obtained as a yellow oil (8 mg, 7%). TLC

1 10% ethyl acetate–hexanes, Rf = 0.54 (UV, KMnO4). H NMR (400 MHz, CDCl3) d:

7.16 (d, J = 8.8 Hz, 1H), 6.58 (d, J = 3.0 Hz, 1H), 6.50 (dd, J1 = 8.8, J2 = 3.1 Hz, 1H),

13 2.91 (s, 6H), 2.33 (s, 3H). C NMR (101 MHz, CDCl3) d: 149.5, 136.2, 129.3, 122.1,

+ + 115.0, 111.6, 40.9, 20.7. HRMS: ESI [M+H] Calcd. for C9H13NCl: 170.0737.

Found: 170.0733.

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H3C O H3C CH3 H3C N N 1) SOCl2 (0.5 equiv), THF, −78 °C, 2h 2 Cl 2) SOCl2 (0.5 equiv), −78 °C, 2h 6

OCH3 3) NEt3 (4.0 equiv), −78 to 23 °C H3CO 2-151 2-110 43% 4.8:1 (6-Cl:2-Cl)

A solution of thionyl chloride (52 µL, 0.70 mmol, 1.0 equiv) in tetrahydrofuran (1 mL) was added dropwise in two portions over a period of 2 h to a solution of the 3- methoxy-N,N-dimethylaniline N-oxide (2-151, 116 mg, 0.693 mmol, 1 equiv) in tetrahydrofuran (3 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 4.04 equiv) was added. The cooling bath was removed and resultant mixture was allowed to warm to 23 °C and stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 2-110 as a yellow oil

(isolated as a mix of regioisomers, 4.9:1 (6-Cl:2-Cl), asterisk denotes minor peaks, 55

1 mg, 0.30 mmol, 43%). TLC 10% ethyl acetate–hexanes, Rf = 0.46 (UV, KMnO4). H

NMR (400 MHz, CDCl3) d: 7.24 (d, J = 8.7 Hz, 1H), 7.17* (t, J = 8.2 Hz, 1H), 6.74*

(dd, J1 = 8.2, J2 = 1.3 Hz, 1H), 6.65* (dd, J1 = 8.3, J2 = 1.3 Hz, 1H), 6.62 (d, J = 2.9

Hz, 1H), 6.49 (dd, J1 = 8.7 Hz, J2 = 2.9 Hz, 1H), 3.90* (s, 1H), 3.79 (s, 3H), 2.81* (s,

13 1H), 2.80 (s, 6H). C NMR (101 MHz, CDCl3) d: 159.1, 156.2*, 152.1*, 151.4,

124

131.0, 127.1*, 119.8, 116.5*, 112.4* 107.5, 107.0, 106.3*, 56.4*, 55.6, 44.1*, 43.8.

+ + HRMS: ESI [M+H] Calcd. for C9H13ONCl: 186.0686. Found: 186.0683.

H3C O H3C CH3 H C N N 3 1) SOCl (0.5 equiv), THF, −78 °C, 2h 2 Cl 2) SOCl2 (0.5 equiv), −78 °C, 2h

3) NEt3 (4.0 equiv), −78 to 23 °C

OCH3 OCH3 2-155 2-111 61%

A solution of thionyl chloride (52 µL, 0.70 mmol, 0.99 equiv) in tetrahydrofuran (1 mL) was added dropwise in two portions over a period of 2 h to a solution of the 4- methoxy-N,N-dimethylaniline N-oxide (2-155, 118 mg, 0.704 mmol, 1 equiv) in tetrahydrofuran (3 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.98 equiv) was added. The cooling bath was removed and resultant mixture was allowed to warm to 23 °C and stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 2-bromo-4-methoxy-

N,N-dimethylaniline as a yellow oil (2-111, 79 mg, 0.43 mmol, 61%). TLC 10% ethyl

1 acetate–hexanes, Rf = 0.38 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 7.03 (d, J =

8.8 Hz, 1H), 6.95 (d, J = 2.9 Hz, 1H), 6.78 (dd, J1 = 8.8, J2 = 2.9 Hz, 1H), 3.77 (s,

125

13 3H), 2.74 (s, 6H). C NMR (101 MHz, CDCl3) d: 155.6, 144.0, 129.5, 120.8, 116.1,

+ + 113.1, 55.8, 44.5. HRMS: ESI [M+H] Calcd. for C9H13ONCl: 186.0686. Found:

186.0685.

H3C O H3C CH3 H C N N 3 1) SOCl (0.5 equiv), THF, −78 °C, 2h 2 Cl 2) SOCl2 (0.5 equiv), −78 °C, 2h

3) NEt3 (4.0 equiv), −78 to 23 °C

CH3 CH3 2-156 2-112 41%

A solution of thionyl chloride (52 µL, 0.70 mmol, 0.98 equiv) in tetrahydrofuran (1 mL) was added dropwise in two portions over a period of 2 h to a solution of the 4- methyl-N,N-dimethylaniline N-oxide (2-156, 108 mg, 0.712 mmol, 1 equiv) in tetrahydrofuran (3 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.93 equiv) was added. The cooling bath was removed and resultant mixture was allowed to warm to 23 °C and stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 2-chloro-4-methyl-

N,N-dimethylaniline as a yellow oil (2-112, 49 mg, 0.29 mmol, 41%). TLC 10% ethyl

1 acetate–hexanes, Rf = 0.56 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 7.18 (d, J =

126

1.9 Hz, 1H), 7.02 – 6.95 (m, 2H), 2.78 (s, 6H), 2.27 (s, 3H). 13C NMR (101 MHz,

+ + CDCl3) d: 148.0, 133.3, 131.2, 128.2, 128.1, 119.9, 44.2, 20.5. HRMS: ESI [M+H]

Calcd. for C9H13NCl: 170.0737. Found: 170.0729.

H3C O H3C CH3 H C N N 3 1) SOCl (0.5 equiv), THF, −78 °C, 2h 2 Cl 2) SOCl2 (0.5 equiv), −78 °C, 2h

3) NEt3 (4.0 equiv), −78 to 23 °C CN CN 2-60 2-113 33%

A solution of thionyl chloride (52 µL, 0.70 mmol, 0.99 equiv) in tetrahydrofuran (1 mL) was added dropwise in two portions over a period of 2 h to a solution of the 4-

(N,N-dimethyl)-aminobenzonitrile N-oxide (2-60, 114 mg, 0.705 mmol, 1 equiv) in tetrahydrofuran (3 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.97 equiv) was added. The cooling bath was removed and resultant mixture was allowed to warm to 23 °C and stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 3-chloro-4-(N,N- dimethyl)-aminobenzonitrile as a yellow oil (2-113, 42 mg, 0.23 mmol, 33%). TLC

1 10% ethyl acetate–hexanes, Rf = 0.22 (UV, KMnO4). H NMR (400 MHz, CDCl3) d:

127

7.58 (d, J = 2.0 Hz, 1H), 7.46 (dd, J1 = 8.5, J2 = 2.0 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H),

13 2.92 (s, 6H). C NMR (101 MHz, CDCl3) d: 154.1, 134.5, 131.6, 126.5, 119.4, 118.5,

+ + 104.5, 43.1. HRMS: ESI [M+H] Calcd. for C9H10N2Cl: 181.0533. Found: 181.0530.

H3C O H3C CH3 H C N N 3 1) SOCl (0.5 equiv), THF, −78 °C, 2h 2 Cl 2) SOCl2 (0.5 equiv), −78 °C, 2h

3) NEt3 (4.0 equiv), −78 to 23 °C Cl Cl 2-153 2-114 55%

A solution of thionyl chloride (52 µL, 0.70 mmol, 1.0 equiv) in tetrahydrofuran (1 mL) was added dropwise in two portions over a period of 2 h to a solution of the 4- chloro-N,N-dimethylaniline N-oxide (2-153, 119 mg, 0.695 mmol, 1 equiv) in tetrahydrofuran (3 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 4.03 equiv) was added. The cooling bath was removed and resultant mixture was allowed to warm to 23 °C and stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 2,4-dichloro-N,N- dimethylaniline as a yellow oil (2-114, 73 mg, 0.38 mmol, 55%). TLC 10% ethyl

1 acetate–hexanes, Rf = 0.54 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 7.35 (d, J =

128

2.4 Hz, 1H), 7.17 (dd, J1 = 8.6, J2 = 2.5 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 2.79 (s, 6H).

13 C NMR (101 MHz, CDCl3) d: 149.3, 130.4, 128.9, 127.7, 127.5, 120.8, 43.9.

+ + HRMS: ESI [M+H] Calcd. for C8H10NCl2: 190.0190. Found: 190.0183.

H3C O H3C CH3 H C N N 3 1) SOCl (0.5 equiv), THF, −78 °C, 2h 2 Cl 2) SOCl2 (0.5 equiv), −78 °C, 2h

3) NEt3 (4.0 equiv), −78 to 23 °C

CO2CH3 CO2CH3 2-59 2-115 40%

A solution of thionyl chloride (52 µL, 0.70 mmol, 0.98 equiv) in tetrahydrofuran (1 mL) was added dropwise in two portions over a period of 2 h to a solution of the methyl 4-N,N-dimethylaminobenzoate N-oxide (2-59, 139 mg, 0.711 mmol, 1 equiv) in tetrahydrofuran (3 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.94 equiv) was added. The cooling bath was removed and resultant mixture was allowed to warm to 23 °C and stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the methyl 3-chloro-4-

N,N-dimethylaminobenzoate as a yellow oil (2-115, 61 mg, 0.28 mmol, 40%). TLC

1 10% ethyl acetate–hexanes, Rf = 0.41 (UV, KMnO4). H NMR (400 MHz, CDCl3) d:

129

8.00 (d, J = 2.1 Hz, 1H), 7.86 (dd, J1 = 8.5, J2 = 2.1 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H),

13 3.89 (s, 3H), 2.91 (s, 6H). C NMR (101 MHz, CDCl3) d: 166.2, 154.3, 132.5, 129.1,

+ + 126.5, 123.9, 118.8, 52.2, 43.3. HRMS: ESI [M+H] Calcd. for C10H13O2NCl:

214.0635. Found: 214.0625.

H3C O H3C CH3 H C N N 3 1) SOCl (0.5 equiv), THF, −78 °C, 2h 2 Cl 2) SOCl2 (0.5 equiv), −78 °C, 2h

3) NEt3 (4.0 equiv), −78 to 23 °C F F 2-154 2-116 30%

A solution of thionyl chloride (52 µL, 0.70 mmol, 0.98 equiv) in tetrahydrofuran (1 mL) was added dropwise in two portions over a period of 2 h to a solution of the 4- fluoro-N,N-dimethylaniline N-oxide (2-154, 111 mg, 0.712 mmol, 1 equiv) in tetrahydrofuran (3 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.93 equiv) was added. The cooling bath was removed and resultant mixture was allowed to warm to 23 °C and stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford the 2-chloro-4-fluoro-

N,N-dimethylaniline as a yellow oil (2-116, 37 mg, 0.22 mmol, 30%). TLC 10% ethyl

130

1 acetate–hexanes, Rf = 0.57 (UV, KMnO4). H NMR (400 MHz, CDCl3) d: 7.12 (m,

13 1H), 7.03 (m, 1H), 6.93 (m, 1H), 2.76 (s, 6H). C NMR (101 MHz, CDCl3) d: 158.1

(d, J = 244.3 Hz), 147.0 (d, J = 3.1 Hz), 129.2 (d, J = 10.3 Hz), 120.8 (d, J = 8.7 Hz),

117.9 (d, J = 25.3 Hz), 114.1 (d, J = 21.5 Hz), 44.2. HRMS: ESI+ [M+H]+ Calcd. for

C8H10NClF: 174.0486. Found: 174.0478.

H3C O H3C H C N N CH3 3 1) SOCl (0.5 equiv), THF, −78 °C, 2h 2 Cl 2) SOCl2 (0.5 equiv), −78 °C, 2h 2

3) NEt (4.0 equiv), −78 to 23 °C 3 4 2-63 2-117 55% 2.9:1 (2-Cl:4-Cl)

A solution of thionyl chloride (52 µL, 0.70 mmol, 0.98 equiv) in tetrahydrofuran (1 mL) was added dropwise in two portions over a period of 2 h to a solution of the N- butyl-N-dimethylaniline N-oxide (2-63, 126 mg, 0.706 mmol, 1 equiv) in tetrahydrofuran (3 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.93 equiv) was added. The cooling bath was removed and resultant mixture was allowed to warm to 23 °C and stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford 2-117 as a yellow oil

131

(isolated as a mix of regioisomers, 2.9:1 (2-Cl:4-Cl), asterisk denotes minor peaks, 77

1 mg, 0.39 mmol, 55%). TLC 10% ethyl acetate–hexanes, Rf = 0.70 (UV, KMnO4). H

NMR (400 MHz, CDCl3) δ 7.37 (dd, J1 = 7.9 Hz, J2 = 1.6 Hz, 1H), 7.22 (td, J1 = 7.7

Hz, J2 = 1.6 Hz, 1H), 7.17* (d, J = 9.1 Hz, 2H), 7.09 (dd, J1 = 8.1 Hz, J2 = 1.5 Hz,

1H), 6.96 (td, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H), 6.61* (d, J = 9.1 Hz, 2H), 3.33 – 3.27*

(m, 2H), 3.07 – 3.00 (m, 2H), 2.92* (s, 3H), 2.80 (s, 3H), 1.62 – 1.51* (m, 2H), 1.62 –

1.51 (m, 2H),1.41 – 1.28* (m, 2H), 1.41 – 1.28 (m, 2H), 0.95* (m, 3H), 0.95 (m, 3H).

13 C NMR (101 MHz, CDCl3) δ 150.2, 148.0*, 130.7, 129.0, 129.0*, 127.3, 123.2*,

121.3, 120.6*, 113.2*, 55.8, 52.7*, 40.9, 38.6*, 29.5, 28.8*, 20.5*, 20.4, 14.2, 14.1*.

+ + HRMS: ESI [M+H] Calcd. for C11H17NCl: 198.1050. Found: 198.1040.

O H3C H C N N 3 1) SOCl (0.5 equiv), THF, −78 °C, 2h 2 Cl 2) SOCl2 (0.5 equiv), −78 °C, 2h 2

3) NEt (4.0 equiv), −78 to 23 °C 3 4 2-62 2-118 65% 4.9:1 (2-Cl:4-Cl)

A solution of thionyl chloride (52 µL, 0.70 mmol, 0.98 equiv) in tetrahydrofuran (1 mL) was added dropwise in two portions over a period of 2 h to a solution of the N- cyclohexyl-N-dimethylaniline N-oxide (2-62, 145 mg, 0.706 mmol, 1 equiv) in tetrahydrofuran (3 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.93 equiv) was added. The cooling bath was removed and resultant mixture was allowed to warm to 23 °C and stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous

132

(isolated as a mix of regioisomers, 4.9:1 (2-Cl:4-Cl), asterisk denotes minor peaks,

103 mg, 0.462 mmol, 65%). TLC 10% ethyl acetate–hexanes, Rf = 0.82 (UV,

1 KMnO4). H NMR (600 MHz, CDCl3) δ 7.35 (dd, J1 = 7.9 Hz, J2 = 1.6 Hz, 1H), 7.19

– 7.16 (m, 1H), 7.15* (d, J = 9.0 Hz, 2H), 7.07 (dd, J1 = 8.1 Hz, J2 = 1.5 Hz, 1H), 6.91

(td, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H), 6.68* (d, J = 9.1 Hz, 2H), 3.52 – 3.46* (m, 1H),

3.14 (m, 1H), 2.74* (s, 3H), 2.71 (s, 3H), 1.84 (m, 1H), 1.87 – 1.73 (m, 3H), 1.69* (m,

1H), 1.65 – 1.58* (m, 3H), 1.45 (m, 3H), 1.39 – 1.30* (m, 3H), 1.29 – 1.20 (m, 3H),

13 1.11* (m, 3H). C NMR (101 MHz, CDCl3) δ 150.0, 148.8*, 130.7, 129.4, 129.2*,

128.9*, 127.0, 123.0, 122.7, 114.3*, 61.6, 58.5*, 33.8, 31.4*, 30.1*, 29.2, 26.3*, 26.2,

+ + 26.1, 26.0*. HRMS: ESI [M+H] Calcd. for C13H19NCl: 224.1206. Found: 224.1195.

CH3 CH3 N O N 1) SOCl (0.5 equiv), THF, −78 °C, 2h 2 Cl 2) SOCl2 (0.5 equiv), −78 °C, 2h 9

3) NEt (4.0 equiv), −78 to 23 °C 3 7 2-64 2-119 61% 2.1:1 (9-Cl:7-Cl)

A solution of thionyl chloride (52 µL, 0.70 mmol, 0.98 equiv) in tetrahydrofuran (1 mL) was added dropwise in two portions over a period of 2 h to a solution of the N-

133

methyl-1,2,3,4-tetrahydroquinoline N-oxide (2-64, 115 mg, 0.705 mmol, 1 equiv) in tetrahydrofuran (3 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.93 equiv) was added. The cooling bath was removed and resultant mixture was allowed to warm to 23 °C and stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford 2-119 as a yellow oil

(isolated as a mix of regioisomers, 2.2:1 (9-Cl:7-Cl), asterisk denotes minor peaks, 78

1 mg, 0.43 mmol, 61%). TLC 20% ethyl acetate–hexanes, Rf = 0.64 (UV, KMnO4). H

NMR (400 MHz, CDCl3) δ 7.18 – 7.15 (m, 1H), 7.01 – 6.98* (m, 1H), 6.97 – 6.94 (m,

1H), 6.91* (dt, J1 = 2.4 Hz, J2 = 1.0 Hz, 1H), 6.83 (t, J = 7.7 Hz, 1H), 6.48* (d, J = 8.7

Hz, 1H), 3.22 – 3.18* (m, 1H), 3.16 – 3.12 (m, 1H), 2.88* (s, 3H), 2.86 (s, 3H), 2.80

(t, J = 6.7 Hz, 2H), 2.73* (t, J = 6.6 Hz, 2H), 1.98 – 1.92* (m, 2H), 1.88 – 1.82 (m,

13 2H). C NMR (101 MHz, CDCl3) δ 146.0*, 145.4*, 131.4, 128.4 (2 resonances),

128.3, 128.0, 127.7*, 126.7*, 124.5*, 122.2, 120.7*, 112.0, 52.1, 51.2*, 42.9, 39.3*,

+ + 28.0, 27.8*, 22.3*, 17.1. HRMS: ESI [M+H] Calcd. for C10H13NCl: 182.0737.

Found: 182.0728.

134

CH3 CH3 H3C O H3C H C N N CH3 3 1) SOCl (0.5 equiv), THF, −78 °C, 2h 2 Cl 2) SOCl2 (0.5 equiv), −78 °C, 2h 2

3) NEt (4.0 equiv), −78 to 23 °C 3 4 2-61 2-120 59% 2.8:1 (2-Cl:4-Cl)

A solution of thionyl chloride (52 µL, 0.70 mmol, 0.98 equiv) in tetrahydrofuran (1 mL) was added dropwise in two portions over a period of 2 h to a solution of the N- isopentyl-N-dimethylaniline N-oxide (2-61, 137 mg, 0.711 mmol, 1 equiv) in tetrahydrofuran (3 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (365 µL, 2.80 mmol, 3.93 equiv) was added. The cooling bath was removed and resultant mixture was allowed to warm to 23 °C and stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with hexanes, grading to 1% ethyl acetate–hexanes) to afford 2-120 as a yellow oil

(isolated as a mix of regioisomers, 2.8:1 (2-Cl:4-Cl), asterisk denotes minor peaks, 89

1 mg, 0.42 mmol, 59%). TLC 10% ethyl acetate–hexanes, Rf = 0.75 (UV, KMnO4). H

NMR (400 MHz, CDCl3) δ 7.35 (dd, J1 = 7.9 Hz, J2 = 1.6 Hz, 1H), 7.22 – 7.17 (m,

1H), 7.15* (d, J = 9.1 Hz, 2H), 7.07 (dd, J1 = 8.1 Hz, J2 = 1.5 Hz, 1H), 6.93 (td, J1 =

7.6 Hz, J2 = 1.6 Hz, 1H), 6.59* (d, J = 9.1 Hz, 2H), 3.32 – 3.26* (m, 2H), 3.05 – 2.99

135

(m, 2H), 2.89* (s, 3H), 2.77 (s, 3H), 1.62 – 1.52* (m, 1H), 1.62 – 1.52 (m, 1H), 1.50 –

1.39* (m, 2H), 1.50 – 1.39 (m, 2H), 0.94* (d, J = 6.6 Hz, 6H), 0.90 (d, J = 6.5 Hz,

13 6H). C NMR (101 MHz, CDCl3) δ 150.2, 147.9*, 130.7, 129.0, 129.0*, 127.3,

123.2, 121.3, 120.6*, 113.3*, 54.4, 51.2*, 41.0, 38.4*, 36.2, 35.0*, 26.4, 26.3*, 22.9,

+ + 22.8*. HRMS: ESI [M+H] Calcd. for C12H19NCl: 212.1206. Found: 212.1196.

136

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14. (a) Tang, R.-J.; Milcent, T.; Crousse, B. J. Org. Chem. 2018, 83, 930–938. (b) Hirose, Y.; Yamazaki, M.; Nagata, M.; Nakamura, A.; Maegawa, T. J. Org. Chem. 2019, 84, 7405–7410. (c) Urones, B.; Martinez, A. M.; Rodiguez, N.; Arrayas, R. G.; Carretero, J. C. Chem. Commun. 2013, 49, 11044–11046. (d) Taumura, K.; Suzuki, T.; Nishida, Y.; Satsumabayashi, K.; Heraguchi, T. Chem. Lett. 2003, 32, 932–933. (e) Tretze, L. F.; Buhr, W.; Looft, J.; Grote, T. Chem. Eur. J. 1998, 4, 1554–1560.

15. (a) Petrone, D. A.; Ye, J.; Lautens, M. Chem. Rev. 2016, 116, 8003–8104. (b) Mostafa, M. A. B.; Bowley, R. M.; Racys, D. T.; Henry, M.C.; Sutherland, A. J. Org. Chem. 2017, 82, 7529–7537. (c) Bedford, R. B.; Haddow, M. F.; Mitchell, M. F.; Webster, R. L. Angew. Chem. Int. Ed. 2011, 50, 5524–5527. (d) Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.; Zhang, S.; Shi, Z. J. Amer. Chem. Soc. 2006, 128, 7416–7417.

16. (a) Zucker, S. P.; Wossidlo, F.; Weber, M.; Lentz, D.; Tzschucke, C. C. J. Org. Chem. 2017, 82, 5616–5635. (b) Krasnokutskaya, E. A.; Chudinov, A. A.; Filimov, V. D. Synthesis, 2018, 50, 1368–1372. (c) Dhiman, A. K.; Gupta, S. S.; Sharma, R.; Kumar, R.; Sharma, U. J. Org. Chem. 2019, 84, 12871–12880. (d) Hwang, H.; Kim, J.; Jeong, J.; Chang, S. J. Amer. Chem. Soc. 2014, 136, 10770–10776.

17. Chen, Y.; Huang, J.; Hwang, T.-L.; Chen, M. J.; Tedrow, J. S.; Farrell, R. P.; Bio, M. M.; Cai, S. Org. Lett. 2015, 17, 2948–2951.

18. (a) Wang, D.; Jia, H.; Wang, W.; Wang, Z. Tetrahedron Lett. 2014, 55, 7130–7132. (b) Wang, D.; Wang, Y.; Zhao, J.; Li, L.; Miao, L.; Wang, D.; Sun, H.; Yu, P. Tetrahedron 2016, 72, 5762–5768.

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19. Ayyangar, N. R.; Kalkote, U. R.; Nikrad, P. V. Tetrahedron Lett. 1982, 23, 1099–1102.

20. McCord, T. J.; Crawford, C. P.; Rabon, J. A.; Gage, L. D.; Winter, J. M.; Davis, A. C. J. Heterocyclic Chem. 1982, 19, 401–406.

21. Marx, L.; Rassat, A. Tetrahedron Lett. 2002, 43, 2613–2614.

22. Chandrasekharam, M.; Chiranjeevi, B.; Gupta, K.S.V.; Sridhar, B. J. Org. Chem., 2011, 76, 10229 – 10235.

23. Lewis, R. S.; Wisthoff, M. F.; Grissmerson, J.; Chain, W. J. Org. Lett. 2014,16, 3832–3835.

24. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518–1520. 25. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–2925.

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PREPARATION OF TETRAHYDROQUINOLINE SCAFFOLDS FROM N,N- DIALKYLANILINE N-OXIDES VIA TANDEM POLONOVSKI-POVAROV CYCLIZATION SEQUENCE

3.1 Introduction

The tetrahydroquinoline heterocyclic scaffold is present in many biologically active compounds;1 ciprofloxacin (3-1), an antibiotic of some note is one example

(Figure 3.1).2 There are myriad examples of natural products that contain tetrahydroquinolines. Martinelline (3-2) is an antitumor antibiotic originally isolated from the root of Martinella iquitosensis, a vine in the Amazon rainforest used in traditional medicine to treat various eye ailments.3 Galpinine (3-3), isolated from

Galipen officinalis, a shrubby tree which grows on the mountainsides of Venezuela, has exhibited anti-malarial activity.4 In addition to biologically important molecules, tetrahydroquinolines have been investigated as dyes in sensitized solar cells (3-4)5 and as tunable chiral ligands for asymmetric hydrogenation (3-5).6

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CH3

O H3C NH

F CO2H N O H N H O H2N N N N N O H H CH HN 3 O NH CH3 N N CH3 N H NH CH3 ciprofoxacin (3-1) martinelline (3-2) galipinine (3-3)

CH3 CO2H S * N R2 N H3C 1 N R PPh2 H3C CH3 3-5 3-4 Figure 3.1: Examples of compounds containing tetrahydroquinolines with useful applications

3.1.1 An Overview of Tetrahydroquinoline Synthesis

There are a number of ways to synthesize tetrahydroquinolines (Figure 3.2).7-13

Some methods employ hydrogen (H2) and expensive transition metal catalysts to hydrogenate substituted quinolines; however, the preparation of the quinoline starting materials is lengthy and inefficient (Figure 3.2, eq 1).8 Transition metal-catalyzed cross coupling chemistry can achieve ring closure via C–N bond formation9 or C–C bond formation,10 but these methods can require pre-functionalized aromatic systems and employ expensive and elevated temperature to achieve the transformation (Figure

3.2, eqs 2 and 3). The Povarov reaction is one of the most common ways to prepare tetrahydroquinolines; however, it is limited to electron-rich aniline and alkene substrates (Figure 3.2, eq 4).11 Other methods such as gold-catalyzed tandem hydroamination-hydrogenation (Figure 3.2, eq 5)12 and Lewis acid catalyzed ring expansion (Figure 3.2, eq 6)12 are rare and have limited substrate scope.

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Hydrogenation Povarov Reaction (1) R1 (4) R1 N H , catalyst acid catalysis 2 N 3-7 3-10

Tandem Ring Closure via Hydroamination C−N Bond Formation Hydrogenation 1 (2) R1 R1 R (5) N transition metal N gold catalysis NH2 catalysis H 3-8 3-6 3-11

C Ring Closure via C−C Bond Formation Ring Expansion 1 (3) R1 R (6) N transition metal Lewis acid or reduction H catalysis [N] 3-9 3-12 Figure 3.2: Methods of preparing tetrahydroquinolines

4-Aminotetrahydroquinolines are a type of substituted tetrahydroquinoline that have limited methods for their preparation (Figure 3.3).14-17 There are some reductive methods such as the reductive amination of a 4-oxotetrahydronquinoline (3-17)14 and reducing an imine 3-18;15 however, these methods require pre-functionalization at the tetrahydroquinoline 4-position (Figure 3.3, eq 1). The Povarov reaction has been employed to produce 4-aminotetrahydroqiunolines via Lewis acid catalysis (Figure

3.3, eq 2).16 There are examples in which N-arylimine have dimerized with themselves to produce tetrahydroquinolines in Povarov reactions.17 New methods that are robust, efficient, and tolerant to diverse substrates would be a welcome addition to the repertoire of methods available to prepare 4-aminotetrahydroquinolines.

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R2 Reductive R2 R2 N N N Amination Reduction R3 R3 O N N (1) 1 1 1 R NaBH3CN R LAH or H2 R R4 3-17 3-16 3-18

R2 R2 Povarov R3 R3 N Reaction HN R4 R3 N Lewis acid catalysis N (2) R1 dimerization R1 R5 R4

3-19 3-20 3-21 Figure 3.3: Preparation of 4-aminotetrahydroquinolines

3.1.2 Discovery of the Tandem Polonovski-Povarov Cyclization via Aniline N- Oxides

The incorporation of tetrahydroquinoline synthesis into the Chain group’s aniline N-oxide research program was serendipitous. We were investigating how to leverage a nucleophilic addition pathway with aniline N-oxides as seen in N- arylhydroxylamine chemistry (Figure 3.4, eq 1).18 Successful nucleophilic addition onto activated aniline N-oxides would be dependent on selecting a suitable reagent to activate the N–O bond; the resultant leaving group required sufficiently slow rates of transfer onto the aromatic ring (3-27) and discouraged elimination to form an iminium ion (3-26) in order to give enough time for a nucleophile to attack the activated aniline

N-oxide (Figure 3.4, eq 2). Based on our preliminary observations, we selected di- tert-butyl dicarbonate (Boc2O) as a suitable activating reagent as group transfer was generally not observed with this reagent.

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Bz O CH3 Bz Bz N N NH Nucleophilic O Nuc proton Nuc Addition transfer H (1) Nuc

OCH3 OCH3 OCH3 3-23 3-24 3-25

R2 2 2 Group OBoc 2 R R CH3 H C N R CH3 N N Transfer or 3 Nucleophilic N Addition OBoc s Nuc (2) 1 R1 R1 Elimination R R1 3-26 3-27 3-28 3-29 Figure 3.4: Proposed nucleophilic addition pathway based on N-arylhydroxylamine chemistry

We tested the ability of different nucleophiles to engage the activated aniline

N-oxide (3-31) (Figure 3.5). Heteroaromatic nucleophiles furan (3-32) and indole (3-

33) were unable to efficiently engage the activated aniline N-oxide at C2 (3-31).

Additions of stronger silicon-based nucleophiles, Ruppert-Prakash reagent (3-34),19 and allyl trimethylsilane (3-35), onto the aromatic ring at C2 were unsuccessful as well. Sodium azide (3-36) and sodium cyanide (3-37), the strongest nucleophiles we tested, did not produce the desired nucleophilic addition product.

Nucleophiles

CH3 O N H C H3C 3 O OBoc H3C CH3 H C N N H3C N Boc2O, DMAP 3 3-32 3-33 Nuc CH2Cl2 R R R TMS TMS F3C 3-30 3-31 3-34 3-35 3-38

NaN3 NaCN 3-36 3-37

Figure 3.5: Summary of nucleophiles investigated

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Our investigations yielded two unexpected discoveries (Figure 3.6). When the activated aniline N-oxide was treated with sodium cyanide, the tert-butyl carbonate

(OBoc) group transfers onto the aromatic ring and upon heating cleaves to give an aminophenol (3-42) (Figure 3.6, eq 1). Unfortunately, this discovery casts doubt upon the suitability of Boc2O as an activating reagent to achieve nucleophilic addition. The more synthetically useful discovery was that treatment of the activated aniline N-oxide

(3-44) with allyl trimethylsilane (3-45) and a Lewis acid led to the formation of a tetrahydroquinoline (3-46). Two Lewis acids were particularly promising in that regard; 3-46 was isolated in 36% yield when using tin(IV) chloride as the Lewis acid and in 31% yield with chlorotrimethylsilane (TMSCl) (Figure 3.6, eq 2).

H C H3C 3 OBoc H3C CH3 H3C CH3 O N N H3C N H3C N Boc2O, DMAP NaCN OBoc 40 °C OH (1) CH2Cl2, 0 °C 23 °C

OCH3 OCH3 OCH3 OCH3 3-39 3-40 3-41 3-42

3-45 H C TMS H3C 3 OBoc H3C O N H C N H3C N 3 Boc2O, DMAP SnCl4 or TMSCl TMS

CH2Cl2, 0 °C −78 to 23 °C (2)

3-43 3-44 3-46 SnCl4, 36% TMSCl ,31% Figure 3.6: Unexpected results in nucleophilic addition

This transformation proceeds via a proposed tandem Polonovksi-Povarov reaction (Figure 3.7). After activation of the aniline N-oxide by Boc2O, a Lewis acid

(SnCl4 or TMSCl) coordinates to and activates the carbonyl for elimination with tert-

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butoxide (-OtBu) to produce an iminium ion (3-52) in a Polonovski reaction. An alkene (3-48) is able to react with this iminium ion in a step-wise Povarov reaction to produce a tertrahydroquinoline (3-56) via a cationic intermediate (3-54). In addition, it is mechanistically possible for the cyclization to proceed through a concerted [4+2] cycloaddition.

R2 R2 O N X H3C N mCBA 1) Boc2O, DMAP, 0 °C Y 2) Lewis acid, −78 to 23 °C 1 R1 R X Y 3-47 3-48 3-49

OtBu

H R2 R2 H C O O O 2 O O R2 2 H3C N H3C N R N L.A. N X OtBu L.A. OtBu Boc2O Y R1 R1 R1 R1 3-48 3-50 3-51 3-52 3-53

R2 R2 R2 N X N X N X Y -H+ Y Y R1 R1 H R1

3-56 3-55 3-54 Figure 3.7: Proposed mechanism of tandem Polonovski-Povarov cyclizations

3.1.3 Past Chain Group Work in Tetrahydroquinoline Synthesis

The group began investigating what scope of alkenes undergo this cyclization and published five examples of alkenes that formed tetrahydroquinolines with para- substituted aniline N-oxides (Figure 3.8).20 Treatment of activated aniline N-oxides

(3-57) with SnCl4 and ethyl vinyl ether (3-58) produced 4-ethoxytetrahydroquinolines

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in 42-78% yield (Figure 3.8 eq, 1). Cyclic vinyl ethers (3-60 and 3-61) prepared tetrahydroquinolines (3-62 and 3-63) in 42-74% yield (Figure 3.8, eq 2). Aromatic benzofuran (3-64) and SnCl4 furnished tetrahydroquinolines (3-65) in 41-87% yield

(Figure 3.8, eq 3). Substituted allyl trimethylsilanes (3-66) produced tetrahydroquinolines (3-67) in 31-92% yield (figure 3.8, eq 4).

3-60 3-61 3-58 O O or H3C OEt H3C H3C N N N SnCl4, CH2Cl2 SnCl4, CH2Cl2 (1) OEt O O (2) −94 to −78 to 23 °C −94 to −78 to 23 °C

R1 H C 3 OBoc R1 R1 3-59 H3C N 3-62 3-63 42-78% yield 49-74% yield 42-72% yield 6 examples 6 examples 5 examples

1 3-66 R O 3-64 2 3-57 2 R H3C R TMS N H3C O SnCl4, CH2Cl2 SnCl4, CH2Cl2 N (4) TMS (3) −94 to 23 °C −78 to 23 °C

CO2CH3 R1 3-67 3-65 31-92% yield 41-87% yield 4 examples 8 examples Figure 3.8: Polonovski-Povarov cyclizations published by the Chain group

3.1.4 Proposed Work

To build upon the group’s work in tetrahydroquinoline synthesis, we sought to expand the scope of the reaction in three areas: (1) inclusion of ortho-, meta- and differentially N-substituted aniline N-oxides, (2) cyclizations with enamines and styrenes, and (3) achieving the Polonovski-Povarov reaction under metal-free conditions. We employed N-vinylpyrrolidone (3-69) to prepare 4-

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aminotetrahydroquinolines (3-70) and 2-phenylpropene (3-71) to prepare 4- phenyltetrahydroquinolines (3-72) (Figure 3.9).

H3C 3-69 O 3-71 N 2 R2 2 R OBoc R N O H C N N SnCl4 or TMSCl 3 SnCl4 or TMSCl Ph N 1 −78 to 23 °C −78 to 23 °C 1 CH R R1 R 3

3-70 3-68 3-72 Figure 3.9: Proposed alkenes to investigate.

3.2 Results and Discussion

3.2.1 Synthesis of N,N-Dialkylaniline N-Oxide 3-Chlorobenzoic Acid Salts

As described in Chapter 2, N-alkyl-N-methylanilines (3-72) are prepared from their respective anilines or N-methylanilines via reductive amination with sodium cyanoborohydride, paraformaldehyde and acetic acid in a similar procedure to that described by Chandrasekhram et al.21 These N-alkyl-N-methylanilines (3-72) were oxidized to their respective N-oxides (3-73) in 79 to 99% yield using a similar procedure to that described by Lewis et al. and discussed in Chapter 2 (Figure 3.10).22

In this procedure, N-oxidation occurs at 0 °C instead of 23 °C and requires no column chromatography as the aniline N-oxide is isolated as a 3-chlorobenzoic acid (mCBA) salt.

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(·mCBA) 1 1 H3C R R N O OH mCPBA H3C N Cl · O 2 CH Cl , 0 °C R 2 2 R2

3-72 3-73

H C 3 O H3C H3C H3C O H3C O H C N O O 3 H3C N H3C N H3C N H3C N · ·mCBA ·mCBA mCBA H3C ·mCBA F ·mCBA

Cl F 3-76 3-77 3-78 98% 94% 97% 3-74 3-75 95% 91%

H3C O H3C O H3C O H3C N H C H3C N H3C N 3 O O H C N H C N ·mCBA ·mCBA ·mCBA 3 3 ·mCBA ·mCBA CN CF3 CH3 CO2CH3 3-79 3-80 3-81 3-82 3-83 88% 88% 96% 96% 97%

Figure 3.10: Preparation of N,N-dialkylaniline N-oxide 3-chlorobenzoic acid salts

3.2.2 Polonovski-Povarov Cyclizations with N-Vinylpyrrolidone

First, we turned our attention to Polonovski-Povarov cyclizations using N- vinylpyrrolidone (3-85) and aniline N-oxides activated using Boc2O and 4- dimethylaminopyridine (DMAP) (Figure 3.11). With N,N-dimethylaniline N-oxide, both SnCl4 and TMSCl produced the tetrahydroquinoline (3-87) in 82% and 71% yield, respectively. SnCl4 was used to investigate the scope of the reaction.

Electronically diverse para-substituted N,N-dimethylaniline N-oxides prepared tetrahydroquinolines (3-88 – 3-95) in 37-89% yield. ortho-Substituted N,N- dimethylaniline N-oxides produced tetrahydroquinoline products (3-96 and 3-97) in

26-27% yield. meta-Substituted N,N-dimethylaniline N-oxides synthesized regioisomeric mixtures of tetrahydroquinoline products (3-99 – 3-102) in 50-91%

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yield with cyclization occurring at the more sterically hindered ortho-position preferentially. The sterically bulky N-cyclohexyl-N-methylaniline N-oxide produces the kinetically favored iminium ion which successfully undergoes the Povarov reaction to produce the tetrahydroquinoline (3-98) in 58% yield.

R2 O 2 O H3C N mCBA 1) Boc2O, DMAP, R N O CH2Cl2, 0 °C N R1 N 2) SnCl4, 3-85 R1 3-85 −78 to 23 °C 3-84 3-86

H3C H3C H3C H3C H3C H3C N O N O N O N O N O N O

N N N N N N

3-87 CN Cl CF3 NO2 CO2CH3 82% (SnCl4) 3-88 3-89 3-90 3-91 3-92 71% (TMSCl) 37% 83% 85% 38% 84%

H3C H3C H3C H3C H3C N O N O N O N O N O

H3C F N N N N N

F Br CH3 3-93 3-94 3-95 3-96 3-97 84% 89% 65% 26% 27%

Cy H3C H3C H3C H3C N O N O N O N O N O

N N N N N

CN CF3 CH3 CO2CH3 3-98 3-99 3-100 3-101 3-102 58% 81% 68% 50% 91% 2.58:1 2.42:1 1.55:1 2.09:1 6-CN:8-CN 6-CF3:8-CF3 6-CH3:8-CH3 6-CO2CH3:8-CO2CH3 Figure 3.11: Scope of Polonovski-Povarov cyclizations with N-vinylpyrrolidone

3.2.3 Polonovski-Povarov Cyclizations with 2-Phenylpropene

Next, we turned our attention to developing a reaction protocol and substrate scope for the Polonovski-Povarov cyclizations between aniline N-oxides (3-104) and

2-phenylpropene (3-103) (Figure 3.12). 4-(N,N-dimethylamino)-benzonitrile N-oxide

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prepared tetrahydroquinoline 3-106 in 71% yield using SnCl4 and in 76% yield using

TMSCl which was selected to investigate the scope of this reaction. Cyclized tetrahydroquinoline product (3-106 – 3-109) was obtained from electronically diverse para-substituted N,N-dimethylaniline N-oxides in 50% to 76% yield. When 3-(N,N- dimethylamino)-benzonitrile N-oxide was subjected to the reaction conditions, a regioisomeric mixture of 6- and 8- substituted tetrahydroquinolines (3-120) was isolated in 50% yield. Unlike the cyclization with N-vinylpyrrolidone, the less sterically hindered ortho- position was cyclized preferentially by 2-phenylpropene.

Finally, the sterically bulky N-cyclohexyl-N-methylaniline N-oxide produced the kinetically favored iminium ion and furnished a tetrahydroquinoline (3-121) in 60% yield.

2 R O R2 CH3 N H3C N mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C Ph 2) TMSCl, 3-103 1 CH R1 R 3 −78 to 23 °C 3-103 3-104 3-105

H3C H3C H3C H3C N N N N Ph Ph Ph Ph

CH3 CH3 CH3 CH3

CN CH3 Cl CF3 3-106 3-107 3-108 3-109 76% (TMSCl) 75% 50% 61% 71% (SnCl4)

H3C Cy N N Ph Ph

CH3 CH3 6 NC 8 3-110 3-111 50% 60% 1.14:1 6-CN:8-CN

Figure 3.12: Scope of Polonovski-Povarov cyclizations with 2-phenylpropene

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3.2.4 Derivatives of Tetrahydroquinoline Scaffolds

We sought to showcase the synthetic utility of the synthesized tetrahydroquinoline scaffolds by derivatizing them. In a procedure similar to that described by Assimomytisa et al., the pyrrolidone ring of tetrahydroquinoline 3-112 was reduced using lithium aluminum hydride (LAH) to prepare a pyrrolidine ring (3-

113) in 93% yield (Figure 3.13, eq 1).23 An enolate alkylation of the lactam of 3-112 using lithium diisopropylamide (LDA) and methyl iodide produced two diastereomers

(3-114 and 3-115) in a combined yield of 49% (Figure 3.13, eq 2).

H3C H3C N N O LAH (1) N THF, 0 to 23 °C N

3-112 3-113 93%

H3C H3C H3C N O 1) LDA, THF, −78 °C N O N O (2) N N CH3 N CH3 2) CH I, −78 to 23 °C 3 H H H H

3-112 3-114 3-115 29% 20% Figure 3.13: Reduction and alkylation of tetrahydroquinoline scaffolds

In addition, we halogenated these complex tetrahydroquinoline scaffolds using our N-oxidation and halogenation protocol discussed in Chapter 2 (Figure 3.14).24

Tetrahydroquinoline scaffold 3-116 was N-oxidized with mCPBA to yield N-oxide (3-

117) in 63% yield, which was subsequently reacted with thionyl bromide to obtain the brominated product (3-118) in 29% yield (Figure 3.14, eq 1). N-Oxide 3-120 was obtained from tetrahydroquinoline 3-119 in 83% yield and subsequently treated with

153

SOCl2 to produce chlorinated product 3-121 in 34% isolated yield (Figure 3.14, eq 2).

Tetrahydroquinoline scaffold 3-122 was treated with mCPBA to prepare N-oxide 3-

123 in 74% yield which was subjected to SOCl2 to prepare a chlorinated tetrahydroquinoline scaffold (3-124) in 32% isolated yield (Figure 3.14, eq 3).

H C H C 3 H3C 3 N O N O O N mCPBA O 1) SOBr2, THF, −78 °C N N N CH2Cl2, 23 °C 2) NEt3, −78 to 23 °C (1)

Br 3-116 3-117 3-118 63% 29% (NMR)

H C H3C 3 H3C N O O N O N O mCPBA 1) SOCl2, THF, −78 °C Cl N N N CH2Cl2, 23 °C 2) NEt3, −78 to 23 °C (2)

Cl Cl Cl 3-119 3-120 3-121 83% 34%

H C H3C 3 H3C N O N N Ph mCPBA Ph 1) SOCl2, THF, −78 °C Cl Ph CH CH 3 CH3 3 CH2Cl2, 23 °C 2) NEt3, −78 to 23 °C (3)

CN CN CN 3-122 3-123 3-124 74% 32% Figure 3.14: N-oxidation and halogenation of tetrahydroquinoline scaffolds

3.2.5 Mechanistic Investigations

We looked to computational chemistry for an answer to the thermodynamic and kinetic favorability of the different regioisomers seen in the cyclizations with N- vinylpyrrolidone and 2-phenylpropene with a meta-substituted aniline N-oxide. To reduce the number of computations, only the portion of the reaction pathway involving the Povarov reaction was investigated. Because the cyclizations favored different

154

regioisomers when different alkenes were used, the formation of the iminium ion is unlikely to be responsible for the observed regioselectivity of the reaction. Another assumption necessary to compare the relative energies of both regioisomers’ intermediates and transition structures is to set the energies of the iminium ions of both regioisomers equal to zero.

First, we constructed a reaction coordinate diagram for the relative energies of the intermediates and transition structures for a step-wise Povarov cyclization with N- vinylpyrrolidone (Figure 3.15). In the first transition structure, the 6-CN regioisomer is 12 kcal/mol lower in energy than the 8-CN regioisomer. Reaction intermediate 3-

126 has a calculated 17.2 kcal/mol energy difference between the regioisomers. The final transition structure and intermediate 3-129 maintain an energy difference of approximately 17 kcal/mol between the regioisomers. The completed reaction coordinate diagrams for both regioisomers show that the overall exothermic reaction has both thermodynamic and kinetic favorability to prepare the more sterically hindered tetrahydroquinoline.

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H3C H3C H3C N TS1 N O TS2 N O O (3-126) (3-128) Key N N N NC NC NC H 6-CN 8 6 8 6 8 6 8-CN 3-125 3-127 3-129 2.58:1 6-CN:8-CN

23.3

11.3 0 -1.9 -7.2 -12.3 E (kcal/mol)

-19.4 -24.4 -29.0

reaction progress Figure 3.15: Reaction coordinate diagram for Polonovski-Povarov step-wise cyclization with N-vinylpyrrolidone produced from DFT computations

In addition, we constructed a reaction coordinate diagram for a concerted cyclization of N-vinylpyrrolidone and the iminium ion (3-130) (Figure 3.16). The energies of the transition structure for each regioisomers have a difference of 14.1 kcal/mol and confirm the thermodynamically and kinetically of the 6-nitrile regioisomer. Because the activation energies of the two mechanistic pathways are within 0.5-2.6 kcal/mol of each other, we are unable to determine if the reaction proceeds step-wise or in a concerted fashion.

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H3C H3C N TS1 N O O (3-131) Key N N NC NC H 6-CN 8 6 8 6 8-CN 3-130 3-132 2.58:1 6-CN:8-CN

22.8

0 8.7

-12.3 E (kcal/mol)

-29.0

reaction progress Figure 3.16: Reaction coordinate diagram for Polonovski-Povarov concerted cyclization with N-vinylpyrrolidone produced from DFT computations

Next, we turned our attention to assembling a reaction coordinate diagram for both regioisomers resulting from the step-wise Povarov cyclization using 2- phenylpropene (Figure 3.17). The reaction coordinate diagram is expected to have smaller energy differences between the regioisomers due to the smaller ratio between the two regioisomers. The calculated energies of the transition structures and intermediates had an energy difference no greater than 2.4 kcal/mol between the two regioisomers. Neither regioisomer was consistently lower in energy than the other.

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These results align with the observed regioisomer ratio of 1.14:1 in the isolated product.

H3C H3C H3C N TS1 N TS2 N 3-134 3-136 Key CH3 CH Ph CH 3 Ph NC 3 NC Ph NC H 6-CN 8 6 8 6 8 6 8-CN 3-133 3-135 3-137 1.14:1 6-CN:8-CN

5.6 2.4 0 -0.9 3.7 -1.0 -3.3 -15.0 E (kcal/mol) -15.1

reaction progress Figure 3.17: Reaction coordinate diagram for Polonovski-Povarov step-wise cyclization with 2-phenylpropene produced from DFT computations

Additionally, we constructed a reaction coordinate diagram for a concerted cyclization for both regioisomers (Figure 3.18). The calculated energies for each transition structure and intermediate were both 0.1 kcal/mol. Neither regioisomer was lower in energy than the other in both the transition state and intermediate. We were once again unable to determine if the cyclization proceeds in a concerted or step-wise mechanism, because of the similar activation energies required by both mechanisms.

The reaction coordinate diagrams for both mechanisms were agreement that neither

158

regioisomer produced from the cyclization with 2-phenylpropene was kinetically or thermodynamically favored.

H3C H3C N TS1 N 3-139 Key CH3 Ph CH Ph NC 3 NC H 6-CN 8 6 8 6 8-CN 3-138 3-140 1.14:1 6-CN:8-CN

6.5 0 6.4

-15.0 E (kcal/mol) -15.1

reaction progress Figure 3.18: Reaction coordinate diagram for Polonovski-Povarov concerted cyclization with 2-phenylpropene produced from DFT computations

3.3 Conclusion

This chapter describes Polonovksi-Povarov cyclizations with N- vinylpyrrolidone and 2-phenylpropene to prepare functionalized tetrahydroquinoline scaffolds. Treatment of N-alkyl-N-methylaniline N-oxides with Boc2O and DMAP followed by SnCl4 and N-vinylpyrrolidone prepared tetrahydroquinolines in up to 91% yield. Two examples of these tetrahydroquinolines were derivatized via reduction and

159

alkylation as well as our N-oxidation and halogenation reactions. Treatment of N- alkyl-N-methylaniline N-oxides with Boc2O and DMAP followed by TMSCl and 2- phenylpropene prepares tetrahydroquinolines in up to 76% yield using metal-free conditions. One of these tetrahydroquinoline scaffolds was subject to our N-oxidation and halogenation methodology. The observed regioselectivity of the Polonovski-

Povarov cyclizations with meta-substituted aniline N-oxides was rationalized using

DFT calculations.

3.4 Experimental

3.4.1 General Methods

Commercial reagents and solvents were used as received with the following exceptions. Triethylamine, dichloromethane, and tetrahydrofuran were purified by the method of Pangborn et al.25 Trimethylsilyl chloride (TMSCl) was purified by distillation over calcium hydride prior to use. All reactions were performed in single- neck oven- or flame-dried round bottom flasks fitted with rubber septa under a positive pressure of nitrogen, unless otherwise noted. Air- and moisture-sensitive liquids were transferred via syringe or stainless-steel cannula. Organic solutions were concentrated by rotary evaporation at or below 35 °C at 10 Torr (diaphragm vacuum pump) unless otherwise noted. Proton (1H) and carbon (13C) nuclear magnetic resonance (NMR) spectra were recorded on Bruker AV400 CryoPlatform QNP or

Bruker AVIII600 SMART NMR spectrometers at 23 °C. Proton chemical shifts are

160

expressed in parts per million (ppm, d scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR solvent (CHCl3: d 7.26). Carbon chemical shifts are expressed in parts per million (ppm, d scale) downfield from tetramethylsilane and are referenced to the carbon resonance of the NMR solvent

(CDCl3: d 77.16). Data are represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, app = apparent), integration, and coupling constant (J) in Hertz (Hz). Accurate mass measurements were obtained using an Agilent 1100 quaternary LC system coupled to an Agilent

6210 LC/MSD-TOF fitted with an ESI or an APCI source, or Thermo Q-Exactive

Orbitrap using electrospray ionization (ESI) or a Waters GCT Premier spectrometer using chemical ionization (CI). Compounds were isolated using flash column chromatography26 with silica gel (60-Å pore size, 40–63μm, standard grade, Silicycle) or basic alumina (60-Å pore size, 50–200 μm, Brockmann I, Acros Organics).

Analytical thin-layer chromatography (TLC) was performed using glass plates pre- coated with silica gel (0.25 mm, 60-Å pore size, 5–20 μm, Silicycle) impregnated with a fluorescent indicator (254 nm). TLC plates were visualized by exposure to ultraviolet light (UV), then were stained by submersion in aqueous ceric ammonium molybdate solution (CAM), ethanolic phosphomolybdic acid solution (PMA), acidic ethanolic p-anisaldehyde solution (anisaldehyde), or aqueous potassium permanganate solution (KMnO4), followed by brief heating on a hot plate (215 °C, 10–15 s).

161

3.4.2 Synthesis of N,N-Dialkylanilines

H3C CH3 NH2 N

NaBH3CN, (CH2O)n, AcOH

THF, 50 °C

CF3 CF3 3-141 47%

Glacial acetic acid (14.6 mL, 244 mmol, 10 equiv) was added dropwise to a mixture of

4-trifluoromethylaniline (3.0 g, 24 mmol, 1 equiv), paraformaldehyde (7.7 g, 240 mmol, 10 equiv), and sodium cyanoborohydride (15.3 g, 244 mmol, 10 equiv) in tetrahydrofuran (100 mL) at 23 °C. The resultant mixture was heated to 50 °C and stirred at that temperature for 18 h. The reaction mixture was cooled to 23 °C, then was partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and diethyl ether (40 mL). The layers were separated, and the aqueous layer was extracted with diethyl ether (2 × 50 mL). The combined organic layers were washed sequentially with water (2 × 80 mL), and saturated aqueous sodium chloride solution

(3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with 5% ethyl acetate–hexanes, grading to 10% ethyl acetate–hexanes) to afford 4-trifluoromethyl-N,N- dimethylaniline as a white solid (3-141, 1.66 g, 11 mmol, 47% yield). TLC 10% ethyl

1 acetate-hexanes, Rf = 0.59 (UV, KMnO4). mp 64-66 °C. H NMR (400 MHz,

13 CDCl3) d 7.45 (d, J = 8.7 Hz, 2H), 6.70 (d, J = 8.7 Hz, 2H), 3.01 (s, 6H). C NMR

(101 MHz, CDCl3) d 152.4, 126.4 (q, J = 4.0 Hz), 125.3 (q, J = 270 Hz), 117.6 (q, J =

162

33 Hz), 111.2, 40.3. FTIR (neat) 2900, 2824, 1653, 1623, 1566, 1540, 1349, 1325,

-1 + + 1232, 1159, 1072 cm . HRMS: ESI [M+H] Calcd. for C9H11F3N: 190.0844. Found:

190.0840.

H3C CH3 NH2 N

NaBH3CN, (CH2O)n, AcOH

THF, 50 °C

NO2 NO2 3-142 34%

Glacial acetic acid (13.7 mL, 217 mmol, 9.9 equiv) was added dropwise to a mixture of 4-nitroaniline (3.0 g, 22 mmol, 1 equiv), paraformaldehyde (6.6 g, 220 mmol, 10 equiv), and sodium cyanoborohydride (13.7 g, 217 mmol, 9.9 equiv) in tetrahydrofuran (100 mL) at 23 °C. The resultant mixture was heated to 50 °C and stirred at that temperature for 18 h. The reaction mixture was cooled to 23 °C, then was partitioned between saturated aqueous sodium bicarbonate solution (120 mL) and diethyl ether (50 mL). The layers were separated, and the aqueous layer was extracted with diethyl ether (2 × 50 mL). The combined organic layers were washed sequentially with water (2 × 50 mL), and saturated aqueous sodium chloride solution

(3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with 5% ethyl acetate–hexanes, grading to 10% ethyl acetate–hexanes) to afford 4-nitro-N,N-dimethylaniline as a yellow solid (3-142, 1.22 g, 7.5 mmol, 34% yield). TLC 10% ethyl acetate-hexanes,

1 Rf = 0.17 (UV, KMnO4). mp 161-163 °C. H NMR (400 MHz, CDCl3) d 8.13 (d, J =

163

13 9.4 Hz, 2H), 6.61 (d, J = 9.4 Hz, 2H), 3.12 (s, 6H). C NMR (101 MHz, CDCl3) d

154.3, 137.0, 126.2, 110.3, 40.4. FTIR (neat) 2921, 1916, 1613, 1581, 1483, 1455,

-1 + + 1348, 1233, 1118, 1068, 821, 751 cm . HRMS: ESI [M+H] Calcd. for C8H11N2O2:

167.0821. Found: 167.0816.

3.4.3 Oxidation of N,N-Dialkylanilines

H3C CH3 H3C N O H3C N mCPBA ·mCBA

CH2Cl2, 0 °C

Cl Cl 2-137 3-74 95% meta-Chloroperbenzoic acid (77%, 2.38 g, 10.6 mmol, 1.10 equiv) was added to a solution of 4-chloro-N,N-dimethylaniline (2-137, 1.50 g, 9.64 mmol, 1 equiv) in dichloromethane (10 mL) cooled to 0 °C. The resultant solution was left stirring at 0

°C for 1 hour after which basic alumina (5.8 g) was added and stirred for an additional

(15 min). The slurry was filtered and concentrated, then reslurried with ethyl acetate and dried azeotropically (20 mL, 3 iterations) to yield 4-chloro-N,N-dimethylaniline

N-oxide 3-chlorobenzoic acid as a white solid (3-74, 3.02 g, 9.20 mmol, 95% yield).

1 mp 107-109 °C. H NMR (400 MHz, CDCl3) d 8.05 (t, J = 1.9 Hz, 1H), 7.94 (dt, J1 =

7.70 Hz, J2 = 1.4 Hz, 1H), 7.90 (d, J = 9.1 Hz, 2H), 7.49 (d, J = 9.2 Hz, 2H), 7.47 –

13 7.44 (m, 1H), 7.34 (t, J = 7.8 Hz, 1H), 3.84 (s, 6H). C NMR (101 MHz, CDCl3) d

169.3, 151.2, 135.9, 135.0, 134.3, 132.0, 130.0, 129.8, 129.5, 127.9, 121.4, 62.2.

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FTIR (neat) 3031, 1653, 1559, 1457, 833, 764, 554 cm-1. HRMS: ESI+ [M+H]+

Calcd. for C8H11ClNO: 172.0524. Found: 172.0522.

H3C CH3 H3C N O H3C N mCPBA ·mCBA

CH2Cl2, 0 °C

F F 2-141 3-75 91% meta-Chloroperbenzoic acid (77%, 2.66 g, 11.9 mmol, 1.10 equiv) was added to a solution of 4-fluoro-N,N-dimethylaniline (2-141, 1.50 g, 10.8 mmol, 1 equiv) in dichloromethane (10 mL) cooled to 0 °C. The resultant solution was left stirring at 0

°C for 1 hour after which basic alumina (6.2 g) was added and stirred for an additional

(15 min). The slurry was filtered and concentrated, then reslurried with ethyl acetate and dried azeotropically (20 mL, 3 iterations) to yield 4-fluoro-N,N-dimethylaniline N- oxide 3-chlorobenzoic acid as a white solid (3-75, 3.05 g, 9.78 mmol, 91% yield). mp

1 108-110 °C. H NMR (400 MHz, CDCl3) d 8.05 (t, J = 1.9 Hz, 1H), 7.97 – 7.92 (m,

3H), 7.45 (ddd, J1 = 8.0 Hz, J2 = 2.2 Hz, J3 = 1.1 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H),

13 7.22 – 7.16 (m, 2H), 3.85 (s, 6H). C NMR (101 MHz, CDCl3) d 169.4, 162.7 (d, J =

250 Hz), 148.7 (d, J = 3.0 Hz), 153.3, 134.2, 131.9, 130.0, 129.5, 127.9, 122.0 (d, J =

9.1 Hz), 116.6 (d, J = 23 Hz), 62.3. FTIR (neat) 1725, 1659, 1501, 1298, 1073, 759

-1 + + cm . HRMS: ESI [M+H] Calcd. for C8H11FNO: 156.0819. Found: 156.0818.

165

H3C CH3 H3C N O mCPBA H3C N ·mCBA CH2Cl2, 0 °C

3-76 97% meta-Chloroperbenzoic acid (77%, 3.05 g, 13.6 mmol, 1.10 equiv) was added to a solution of N,N-dimethylaniline (1.50 g, 12.4 mmol, 1 equiv) in dichloromethane (10 mL) cooled to 0 °C. The resultant solution was left stirring at 0 °C for 1 hour after which basic alumina (6.8 g) was added and stirred for an additional (15 min). The slurry was filtered and concentrated, then reslurried with ethyl acetate and dried azeotropically (20 mL, 3 iterations) to yield N,N-dimethylaniline N-oxide 3- chlorobenzoic acid as a white solid (3-76, 3.53 g, 12.0 mmol, 97% yield). mp

1 106-108 °C. H NMR (400 MHz, CDCl3) d 8.06 (t, J = 1.9 Hz, 1H), 7.97 – 7.91 (m,

3H), 7.55 – 7.46 (m, 3H), 7.45 (ddd, J1 = 8.0 Hz, J2 = 2.2 Hz, J3 = 1.1 Hz, 1H), 7.33 (t,

13 J = 7.8 Hz, 1H), 3.88 (s, 6H). C NMR (101 MHz, CDCl3) d 169.5, 152.4, 135.5,

134.2, 131.8, 130.0, 129.9, 129.8, 129.4, 127.9, 119.7, 61.9. FTIR (neat) 3409, 1700,

-1 + + 1684, 1652, 1559, 1540, 759, 716 cm . HRMS: ESI [M+H] Calcd. for C8H12NO:

138.0913. Found: 138.0911.

H3C CH3 H3C N O mCPBA H3C N H3C ·mCBA H3C CH2Cl2, 0 °C

2-136 3-77 95% meta-Chloroperbenzoic acid (77%, 2.76 g, 12.3 mmol, 1.11 equiv) was added to a solution of 2,N,N-trimethylaniline (2-136, 1.50 g, 11.1 mmol, 1 equiv) in

166

dichloromethane (10 mL) cooled to 0 °C. The resultant solution was left stirring at 0

°C for 1 hour after which basic alumina (6.3 g) was added and stirred for an additional

(10 min). The slurry was filtered and concentrated, then reslurried with ethyl acetate and dried azeotropically (20 mL, 3 iterations) to yield 2,N,N-trimethylaniline N-oxide

3-chlorobenzoic acid as a red-orange syrup (3-77, 3.27 g, 10.6 mmol, 95%). 1H NMR

(400 MHz, CDCl3) d 8.02 (t, J = 1.9 Hz, 1H), 7.92 (dt, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H),

7.87 – 7.83 (m, 1H), 7.42 (ddd, J1 = 7.9 Hz, J2 = 2.2 Hz, J3 = 1.2 Hz, 1H), 7.35 – 7.27

13 (m, 4H), 3.98 (s, 6H), 2.82 (s, 3H). C NMR (101 MHz, CDCl3) d 169.8, 149.6,

136.1, 135.1, 134.0, 131.5, 131.0, 130.1, 129.9, 129.3, 127.8, 127.4, 119.7, 60.3, 22.5.

FTIR (neat) 3415, 3069, 1709, 1677, 1572, 1427, 1298, 1073, 851, 789, 714 cm-1.

+ + HRMS: ESI [M+H] Calcd. for C9H14NO: 152.1070. Found: 152.1067.

H3C CH3 H3C N O mCPBA H3C N F F ·mCBA CH2Cl2, 0 °C

2-135 3-78 97% meta-Chloroperbenzoic acid (77%, 2.66 g, 11.9 mmol, 1.10 equiv) was added to a solution of 2-fluoro-N,N-dimethylaniline (2-135, 1.50 g, 10.8 mmol, 1 equiv) in dichloromethane (10 mL) cooled to 0 °C. The resultant solution was left stirring at 0

°C for 2 hours after which basic alumina (6.2 g) was added and stirred for an additional (10 min). The slurry was filtered and concentrated, then reslurried with ethyl acetate and dried azeotropically (20 mL, 3 iterations) to yield 2-fluoro-N,N- dimethylaniline N-oxide 3-chlorobenzoic acid as a red-orange syrup (3-78, 3.28 g,

167

1 10.5 mmol, 97% yield). H NMR (400 MHz, CDCl3) d 8.61 (td, J1 = 8.6 Hz, J2 = 1.8

Hz, 1H), 8.06 (t, J = 1.9 Hz, 1H), 7.95 (dt, J1 = 7.7 Hz, J2 = 1.3 Hz, 1H), 7.46 (m, 2H),

7.38 – 7.30 (m, 2H), 7.22 (ddd, J1 = 12.9 Hz, J2 = 8.1 Hz, J3 = 1.4 Hz, 1H), 3.90 (s,

13 6H). C NMR (101 MHz, CDCl3) d 169.1, 153.2 (d, J = 250 Hz), 139.5 (d, J = 8.1

Hz), 135.0, 134.2, 132.0 (d, J = 8.1), 132.0, 130.0, 129.5, 127.9, 125.8 (d, J = 4.0 Hz),

124.4, 117.2 (d, J = 22 Hz), 61.2 (d, J = 6.1 Hz). FTIR (neat) 3421, 1684, 1653, 1559,

-1 + + 1457, 850, 758, 716 cm . HRMS: ESI [M+H] Calcd. for C8H11FNO: 156.0819.

Found: 156.0817.

H3C CH3 H3C N O mCPBA H3C N ·mCBA

CH2Cl2, 0 °C NC NC 2-134 3-79 88% meta-Chloroperbenzoic acid (77%, 4.37 g, 19.4 mmol, 1.10 equiv) was added to a solution of 3-(N,N-dimethylamino)benzonitrile (2-134, 2.60 g, 17.6 mmol, 1 equiv) in dichloromethane (19 mL) cooled to 0 °C. The resultant solution was left stirring at 0

°C for 2 hours after which basic alumina (10.4 g) was added and stirred for an additional (10 min). The slurry was filtered and concentrated, then reslurried with ethyl acetate and dried azeotropically (20 mL, 3 iterations) to yield 3-(N,N- dimethylamino)benzonitrile N-oxide 3-chlorobenzoic acid as a pale beige-white solid

1 (3-79, 5.01 g, 15.7 mmol, 88% yield). mp 102-104 °C. H NMR (400 MHz, CDCl3) d

8.33 (dd, J1 = 2.5 Hz, J2 = 1.4 Hz, 1H), 8.26 (ddd, J1 = 8.4 Hz, J2 = 2.5 Hz, J3 = 1.1

Hz, 1H), 8.04 (t, J = 1.9 Hz, 1H), 7.94 (dt, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H), 7.78 (dt, J1 =

168

7.7 Hz, J2 = 1.3 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.48 (ddd, J1 = 8.0 Hz, J2 = 2.2 Hz,

13 J3 = 1.1 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 3.85 (s, 6H). C NMR (101 MHz, CDCl3) d 169.1, 153.8, 134.5, 134.3, 133.5, 132.2, 130.9, 130.0, 129.6, 127.9, 124.7, 124.1,

117.3, 114.1, 62.4. FTIR (neat) 3402, 3020, 2234, 1740, 1572, 1426, 1073, 758 cm-1.

+ + HRMS: ESI [M+H] Calcd. for C9H11N2O: 163.0866. Found: 163.0863.

H3C CH3 H3C N O mCPBA H3C N ·mCBA

CH2Cl2, 0 °C F3C F3C 2-133 3-80 88% meta-Chloroperbenzoic acid (77%, 4.56 g, 20.3 mmol, 1.10 equiv) was added to a solution of N,N-dimethyl-3-trifluoromethyl-aniline (2-133, 3.44 g, 18.3 mmol, 1 equiv) in dichloromethane (26 mL) cooled to 0 °C. The resultant solution was left stirring at 0 °C for 2 hours after which basic alumina (12 g) was added and stirred for an additional (10 min). The slurry was filtered and concentrated, then reslurried with ethyl acetate and dried azeotropically (20 mL, 3 iterations) to yield N,N-dimethyl-3- trifluoromethyl-aniline N-oxide 3-chlorobenzoic acid as a pale beige-white solid (3-

1 80, 5.83 g, 16.1 mmol, 88% yield). mp 92-94 °C. H NMR (400 MHz, CDCl3) d 8.27

(m, 1H), 8.19 (m, 1H), 8.06 – 8.04 (m, 1H), 7.95 (dt, J1 = 7.7 Hz, J2 = 1.3 Hz, 1H),

7.75 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.47 (m, 1H), 7.34 (t, J = 7.8 Hz,

13 1H), 3.88 (s, 6H). C NMR (101 MHz, CDCl3) d 169.3, 153.5, 134.8, 134.2, 132.4

(q, J = 33 Hz), 132.1, 130.6, 130.0, 129.5, 127.9, 126.8 (q, J = 4.0 Hz), 123.5, 123.3

(q, J = 270 Hz), 117.5 (q, J = 4.0 Hz), 62.3. FTIR (neat) 3427, 3016, 1691, 1572,

169

1461, 1326, 1172, 1129, 1073, 758, 717 cm-1. HRMS: ESI+ [M+H]+ Calcd. for

C9H11F3NO: 206.0787. Found: 206.0784.

H3C CH3 H3C N O mCPBA H3C N ·mCBA

CH2Cl2, 0 °C H3C H3C 2-132 3-81 96% meta-Chloroperbenzoic acid (77%, 2.73 g, 12.2 mmol, 1.10 equiv) was added to a solution of 3,N,N-trimethylaniline (2-132, 1.50 g, 11.1 mmol, 1 equiv) in dichloromethane (10 mL) cooled to 0 °C. The resultant solution was left stirring at 0

°C for 1 hour after which basic alumina (6.3 g) was added and stirred for an additional

(15 min). The slurry was filtered and concentrated, then reslurried with ethyl acetate and dried azeotropically (20 mL, 3 iterations) to yield 3,N,N-trimethylaniline N-oxide

3-chlorobenzoic acid as a red-brown solid (3-81, 3.28 g, 10.6 mmol, 96% yield). mp

1 64-66 °C. H NMR (400 MHz, CDCl3) d 8.05 (t, J = 1.8 Hz, 1H), 7.95 (dt, J1 = 7.7

Hz, J2 = 1.3 Hz, 1H), 7.78 (t, J = 2.0 Hz, 1H), 7.64 (dd, J1 = 8.4 Hz, J2 = 2.6 Hz, 1H),

7.44 (ddd, J1 = 8.0 Hz, J2 = 2.2 Hz, J3 = 1.1 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.32 (t,

J = 7.8 Hz, 1H), 7.27 – 7.24 (m, 1H), 3.86 (s, 6H), 2.44 (s, 3H). 13C NMR (101 MHz,

CDCl3) d 169.6, 152.2, 140.3, 135.8, 134.1, 131.7, 130.6, 129.9, 129.5, 129.4, 127.9,

120.3, 116.4, 61.8, 21.8. FTIR (neat) 3407, 3019, 1572, 1462, 1427, 1298, 909, 759

-1 + + cm . HRMS: ESI [M+H] Calcd. for C9H14NO: 152.1070. Found: 152.1068.

170

H3C CH3 H3C N O mCPBA H3C N ·mCBA

CH2Cl2, 0 °C H3CO2C H3CO2C 2-128 3-82 99% meta-Chloroperbenzoic acid (77%, 1.96 g, 8.54 mmol, 1.10 equiv) was added to a solution of methyl 3-(N,N-dimethylamino)benzoate (2-128, 1.44 g, 7.84 mmol, 1 equiv) in dichloromethane (10 mL) cooled to 0 °C. The resultant solution was left stirring at 0 °C for 3 hours after which basic alumina (5.1 g) was added and stirred for an additional (10 min). The slurry was filtered and concentrated, then reslurried with ethyl acetate and dried azeotropically (20 mL, 3 iterations) to yield methyl 3-(N,N- dimethylamino)benzoate N-oxide 3-chlorobenzoic acid as a pale yellow solid (3-82,

1 2.79 g, 7.93 mmol, 99% yield). mp 139-141 °C. H NMR (400 MHz, CDCl3) d 8.42

(dd, J1 = 2.4 Hz, J2 = 1.4 Hz, 1H), 8.39 (ddd, J1 = 8.2 Hz, J2 = 2.6 Hz, J3 = 1.0 Hz,

1H), 8.14 (dt, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 8.06 (t, J = 1.9 Hz, 1H), 7.95 (dt, J1 = 7.7

Hz, J2 = 1.3 Hz, 1H), 7.65 (t, J = 8.1 Hz, 1H), 7.47 – 7.44 (m, 1H), 7.33 (t, J = 7.9 Hz,

13 1H), 3.97 (s, 3H), 3.88 (s, 6H). C NMR (101 MHz, CDCl3) d 169.3, 165.7, 153.1,

135.1, 134.2, 132.0, 131.7, 130.9, 130.3, 130.0, 129.5, 127.9, 124.9, 120.5, 62.2, 52.9.

FTIR (neat) 3469, 1725, 1710, 1572, 1298, 1074, 759 cm-1. HRMS: ESI+ [M+H]+

Calcd. for C10H14NO3: 196.0968. Found: 196.0966.

171

CH3 N mCPBA O H3C N ·mCBA CH2Cl2, 0 °C

2-145 3-83 82% meta-Chloroperbenzoic acid (77%, 1.98 g, 8.83 mmol, 1.10 equiv) was added to a solution of N-cyclohexyl-N-methylaniline (2-145, 1.50 g, 7.92 mmol, 1 equiv) in dichloromethane (10 mL) cooled to 0 °C. The resultant solution was left stirring at 0

°C for 3 hours after which basic alumina (5.1 g) was added and stirred for an additional (10 min). The slurry was filtered and concentrated, then reslurried with ethyl acetate and dried azeotropically (20 mL, 3 iterations) to yield N-cyclohexyl-N- methylaniline N-oxide 3-chlorobenzoic acid as an orange-red syrup (3-83, 2.35 g, 6.49

1 mmol, 82% yield). H NMR (400 MHz, CDCl3) d 8.03 (t, J = 1.9 Hz, 1H), 7.92 (dt, J1

= 7.7 Hz, J2 = 1.4 Hz, 1H), 7.83 – 7.78 (m, 2H), 7.48 (m, 2H), 7.45 – 7.42 (m, 1H),

7.40 (ddd, J1 = 8.0 Hz, J2 = 2.2 Hz, J3 = 1.2 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 3.84 (s,

3H), 3.67 (tt, J1 = 11.7 Hz, J2 = 3.4 Hz, 1H), 2.34 (dt, J1 = 12.0 Hz, J2 = 3.6 Hz, 1H),

1.93 (m, 1H), 1.83 – 1.74 (m, 2H), 1.69 – 1.51 (m, 3H), 1.29 – 1.07 (m, 3H). 13C

NMR (101 MHz, CDCl3) d 169.5, 149.6, 136.5, 134.0, 131.2, 129.9, 129.5, 129.3,

129.2, 127.8, 121.3, 80.8, 55.4, 26.9, 26.5, 25.3, 25.3, 24.9. FTIR (neat) 3068, 2937,

2859, 1699, 1684, 1569, 1456, 843, 759, 720 cm-1. HRMS: ESI+ [M+H]+ Calcd. for

C13H20NO: 206.1539. Found: 206.1536.

172

H3C CH3 H3C N O H3C N mCPBA ·mCBA

CH2Cl2, 0 °C

CN CN 2-139 3-143 80% meta-Chloroperbenzoic acid (77%, 2.55 g, 11.4 mmol, 1.11 equiv) was added to a solution of 4-(N,N-dimethyl)-aminobenzonitrile (2-139, 1.50 g, 10.3 mmol, 1 equiv) in dichloromethane (12 mL) cooled to 0 °C. The resultant solution was left stirring at 0

°C for 1 hour after which basic alumina (8.1 g) was added and stirred for an additional

(15 min). The slurry was filtered and concentrated, then reslurried with ethyl acetate and dried azeotropically (20 mL, 3 iterations) to yield 4-(N,N-dimethyl)- aminobenzonitrile N-oxide 3-chlorobenzoic acid as a white solid (3-143, 2.64 g, 8.28

1 mmol, 80% yield). mp 123-125 °C. H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 9.0

Hz, 2H), 8.03 (t, J = 1.9 Hz, 1H), 7.92 (dt, J1 = 7.7 Hz, J2 = 1.3 Hz, 1H), 7.84 (d, J =

9.0 Hz, 2H), 7.47 (ddd, J1 = 8.0 Hz, J2 = 2.2 Hz, J3 = 1.1 Hz, 1H), 7.34 (t, J = 7.9 Hz,

13 1H), 3.83 (s, 6H). C NMR (101 MHz, CDCl3) δ 169.1, 156.3, 134.7, 134.3, 133.8,

132.1, 129.9, 129.5, 127.9, 121.3, 117.3, 114.2, 62.3. FTIR (neat) 3420, 3030, 1700,

-1 + + 1681, 1653, 1559, 759 cm . HRMS: ESI [M+H] Calcd. for C9H11N2O: 163.0866.

Found: 163.0863.

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H3C CH3 H3C N O H3C N mCPBA

CH2Cl2, 0 °C

CF3 CF3 3-141 3-144 92% meta-Chloroperbenzoic acid (77%, 2.30 g, 10.1 mmol, 1.10 equiv) was added to a solution of 4-trifluoromethyl-N,N-dimethylaniline (3-141, 1.76 g, 9.15 mmol, 1 equiv) in dichloromethane (13 mL) cooled to 0 °C. The resultant solution was left stirring at

0 °C for 1 hour after which basic alumina (6.0 g) was added and stirred for an additional (15 min). The slurry was filtered and concentrated, then reslurried with ethyl acetate and dried azeotropically (20 mL, 3 iterations) to yield 4-trifluoromethyl-

N,N-dimethylaniline N-oxide 3-chlorobenzoic acid as a beige-white solid (3-144, 3.08

1 g, 8.53 mmol, 92% yield). mp 126-128 °C. H NMR (400 MHz, CDCl3) δ 8.12 (d, J

= 8.6 Hz, 2H), 8.05 (t, J = 1.9 Hz, 1H), 7.94 (dt, J1 = 7.7 Hz, J2 = 1.3 Hz, 1H), 7.80 (d,

J = 8.7 Hz, 2H), 7.46 (ddd, J1 = 8.0 Hz, J2 = 2.2 Hz, J3 = 1.1 Hz, 1H), 7.34 (t, J = 7.8

13 Hz, 1H), 3.86 (s, 6H). C NMR (101 MHz, CDCl3) δ 169.3, 155.5, 134.8, 134.3,

132.4 (q, J = 67 Hz), 132.1, 130.0, 129.5, 127.9, 127.1 (q, J = 4.0 Hz), 123.3 (q, J =

270 Hz), 120.8, 62.2. FTIR (neat) 3446, 1652, 1646, 1638, 1559, 1137, 848, 761, 608

-1 + + cm . HRMS: ESI [M+H] Calcd. for C9H11F3NO: 206.0787. Found: 206.0785.

174

H3C CH3 H3C N O H3C N mCPBA

CH2Cl2, 0 °C

NO2 NO2 3-142 3-145 79% meta-Chloroperbenzoic acid (77%, 1.82 g, 7.94 mmol, 1.10 equiv) was added to a solution of 4-nitro-N,N-dimethylaniline (3-142, 1.22 g, 7.24 mmol, 1 equiv) in dichloromethane (12 mL) cooled to 0 °C. The resultant solution was left stirring at 0

°C for 1 hour after which basic alumina (6.0 g) was added and stirred for an additional

(15 min). The slurry was filtered and concentrated, then reslurried with ethyl acetate and dried azeotropically (20 mL, 3 iterations) to yield 4-nitro-N,N-dimethylaniline N- oxide 3-chlorobenzoic acid as a yellow solid (3-145, 1.98 g, 5.84 mmol, 79% yield). mp 109-111 °C. 1H NMR (400 MHz, Chloroform-d) δ 8.39 (d, J = 9.3 Hz, 2H), 8.21

(d, J = 9.3 Hz, 2H), 8.04 (t, J = 1.9 Hz, 1H), 7.93 (dt, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H),

7.48 (ddd, J1 = 8.0 Hz, J2 = 2.2 Hz, J3 = 1.1 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 3.87 (s,

13 6H). C NMR (101 MHz, CDCl3) δ 169.1, 157.6, 148.3, 134.3, 132.3, 130.0, 129.6,

127.9, 125.2, 121.7, 62.5. FTIR (neat) 3447, 1653, 1635, 1557, 1457 cm-1. HRMS:

+ + ESI [M+H] Calcd. for C8H11N2O3: 183.0764. Found: 183.0762.

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H3C CH3 H3C N O H3C N mCPBA ·mCBA

CH2Cl2, 0 °C

CO2CH3 CO2CH3 2-140 3-146 92% meta-Chloroperbenzoic acid (77%, 1.39 g, 6.14 mmol, 1.10 equiv) was added to a solution of methyl 4-N,N-dimethylaminobenzoate (2-140, 1.00 g, 5.58 mmol, 1 equiv) in dichloromethane (6 mL) cooled to 0 °C. The resultant solution was left stirring at 0

°C for 1 hour after which basic alumina (3.6 g) was added and stirred for an additional

(15 min). The slurry was filtered and concentrated, then reslurried with ethyl acetate and dried azeotropically (20 mL, 3 iterations) to yield methyl 4-(N,N- dimethylamino)benzoate N-oxide 3-chlorobenzoic acid as a beige-white solid (3-146,

1 1.81 g, 5.14 mmol, 92% yield). mp 138-139 °C. H NMR (400 MHz, CDCl3) δ 8.

8.19 (d, J = 9.0 Hz, 2H)., 8.07 – 8.01 (m, 3H), 7.94 (dt, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H),

7.47 – 7.43 (m, 1H), 7.34 (t, J = 7.8 Hz, 1H), 3.95 (s, 3H), 3.86 (s, 6H). 13C NMR

(101 MHz, CDCl3) δ 169.3, 165.6, 156.1, 135.1, 134.2, 131.9, 131.7, 131.2, 130.0,

129.5, 127.9, 120.1, 62.1, 52.8. FTIR (neat) 3456, 1718, 1655, 1558, 1288, 761 cm-1.

+ + HRMS: ESI [M+H] Calcd. for C10H14NO3: 196.0968. Found: 196.0966.

176

H3C CH3 H3C N O H3C N mCPBA ·mCBA

CH2Cl2, 0 °C

Br Br 2-138 3-147 85% meta-Chloroperbenzoic acid (77%, 1.86 g, 8.30 mmol, 1.11 equiv) was added to a solution of 4-bromo-N,N-dimethylaniline (2-138, 1.50 g, 7.50 mmol, 1 equiv) in dichloromethane (11 mL) cooled to 0 °C. The resultant solution was left stirring at 0

°C for 1 hour after which basic alumina (6.7 g) was added and stirred for an additional

(15 min). The slurry was filtered and concentrated, then reslurried with ethyl acetate and dried azeotropically (20 mL, 3 iterations) to yield 4-bromo-N,N-dimethylaniline

N-oxide-3-chlorobenzoic acid as a pale orange solid (3-147, 2.38 g, 6.39 mmol, 85%

1 yield). mp 121-123 °C. H NMR (400 MHz, CDCl3) δ 8.04 (t, J = 1.9 Hz, 1H), 7.94

(dt, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H), 7.84 (d, J = 9.1 Hz, 2H), 7.64 (d, J = 9.2 Hz, 2H),

7.45 (ddd, J1 = 8.0 Hz, J2 = 2.2 Hz, J3 = 1.1 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 3.82 (s,

13 6H). C NMR (101 MHz, CDCl3) δ 169.4, 151.8, 135.3, 134.2, 132.8, 131.9, 129.9,

129.4, 127.9, 123.9, 121.7, 62.1. FTIR (neat) 3572, 3030, 1658, 1642, 1566, 1072,

-1 + + 829, 763, 553 cm . HRMS: ESI [M+H] Calcd. for C8H11BrNO: 216.0019. Found:

216.0017.

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H3C CH3 H3C N O H3C N mCPBA ·mCBA

CH2Cl2, 0 °C

CH3 CH3 2-143 3-148 91% meta-Chloroperbenzoic acid (77%, 2.31 g, 10.2 mmol, 1.10 equiv) was added to a solution of 4,N,N-trimethylaniline (2-143, 1.25 g, 9.21 mmol, 1 equiv) in dichloromethane (9 mL) cooled to 0 °C. The resultant solution was left stirring at 0

°C for 1 hour after which basic alumina (5.8 g) was added and stirred for an additional

(15 min). The slurry was filtered and concentrated, then reslurried with ethyl acetate and dried azeotropically (20 mL, 3 iterations) to yield 4,N,N-trimethylaniline N-oxide-

3-chlorobenzoic acid as a pale yellow solid (3-148, 2.58 g, 8.38 mmol, 91% yield).

1 mp 113-115 °C. H NMR (400 MHz, CDCl3) δ 8.06 – 8.03 (m, 1H), 7.95 (dt, J1 = 7.7

Hz, J2 = 1.3 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.46 – 7.41 (m, 1H), 7.33 (d, J = 7.8

Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 3.87 (s, 6H), 2.39 (s, 3H). 13C NMR (101 MHz,

CDCl3) δ 169.6, 149.9, 140.1, 135.6, 134.2, 131.7, 130.3, 130.0, 129.4, 127.9, 119.4,

61.8, 21.0. FTIR (neat) 3028, 1559, 1652, 1070, 761, 556 cm-1. HRMS: ESI+ [M+H]+

Calcd. for C9H14NO: 152.1070. Found: 152.1068.

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3.4.4 Polonovski-Povarov Cyclizations with N-vinylpyrrolidone

H3C O H3C N O H3C N mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C N 2) N-vinylpyrrolidone, SnCl4, −78 to 23 °C 3-76 3-87 82%

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.60 equiv) was added to a solution of

N,N-dimethylaniline-N-oxide 3-chlorobenzoic acid (3-76, 294 mg, 1.00 mmol, 1 equiv) and 4-(dimethylamino)pyridine (12 mg, 0.010 mmol, 0.10 equiv) in dichloromethane cooled to 0 °C. The resultant solution was stirred at 0 °C for 2 hours.

The solution was cooled to -78 °C, then N-vinylpyrrolidone (267 µL, 2.50 mmol, 2.50 equiv) and tin (IV) chloride (1M solution in heptane, 0.25 mL, 0.25 mmol, 0.25 equiv) was added. The reaction solution was slowly warmed to 23 °C and stirred at that temperature for 18 hours. The reaction was partitioned between saturated aqueous sodium bicarbonate solution (4 mL) and dichloromethane (5 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 ´ 5 mL). The combined organic layers were dried over sodium sulfate, and the dried solution was concentrated. The resultant oily residue was purified by flash chromatography (silica gel, grading from 30% ethyl acetate-hexanes to ethyl acetate, followed by 2% methanol-dichloromethane) to afford N-(1-methyl-1,2,3,4-tetrahydroquinoline)- pyrrolidone as a pale yellow solid (3-87, 189 mg, 0.821 mmol, 82% yield). TLC 50%

1 ethyl acetate-hexanes, Rf = 0.14 (UV, KMnO4). mp 77-79 °C. H NMR (400 MHz,

CDCl3) d 7.14 (m, 1H), 6.87 (dt, J1 = 7.6 Hz, J2 = 1.3 Hz, 1H), 6.70 – 6.60 (m, 2H),

179

5.42 (dd, J1 = 9.4 Hz, J2 = 5.9 Hz, 1H), 3.38 – 3.30 (m, 1H), 3.26 – 3.17 (m, 2H), 3.12

(m, 1H), 2.88 (s, 3H), 2.53 – 2.46 (m, 2H), 2.14 (m, 1H), 2.01 (m, 3H). 13C NMR

(101 MHz, CDCl3) d 175.6, 147.6, 128.6, 127.7, 119.9, 116.9, 111.9, 49.6, 48.0, 43.6,

39.5, 31.6, 26.8, 18.4. FTIR (neat) 2949, 1683, 1603, 1501, 1419, 1327, 1284, 747,

-1 + + 569 cm . HRMS: ESI [M+H] Calcd. for C15H21N2O: 231.1497. Found: 231.1486.

H3C O H3C N O H3C N mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C N

2) N-vinylpyrrolidone, SnCl4, −78 to 23 °C CN CN 3-143 3-88 36%

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.73 equiv) was added to a solution of

4-(N,N-dimethylamino)benzonitrile-N-oxide 3-chlorobenzoic acid (3-143, 303 mg,

0.951 mmol, 1 equiv) and 4-(dimethylamino)pyridine (12 mg, 0.010 mmol, 0.10 equiv) in dichloromethane cooled to 0 °C. The resultant solution was stirred at 0 °C for 2 hours. The solution was cooled to -78 °C, then N-vinylpyrrolidone (267 µL,

2.63 mmol, 2.50 equiv) and tin (IV) chloride (1M solution in heptane, 0.25 mL, 0.25 mmol, 0.26 equiv) was added. The reaction was partitioned between saturated aqueous sodium bicarbonate solution (4 mL) and dichloromethane (5 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 ´ 5 mL).

The combined organic layers were dried over sodium sulfate, and the dried solution was concentrated. The resultant oily residue was purified by flash chromatography

(silica gel, grading from 30% ethyl acetate-hexanes to ethyl acetate followed by 2%

180

methanol-dichloromethane) to afford N-(1-methyl-1,2,3,4-tetrahydroquinoline-7- carbonitrile)-pyrrolidone as a white solid (3-88, 91 mg, 0.36 mmol, 36% yield). TLC

1 50% ethyl acetate-hexanes, Rf = 0.05 (UV, KMnO4). mp 120-122 °C. H NMR (400

MHz, CDCl3) d 7.37 (dd, J1 = 8.6 Hz, J2 = 2.0 Hz, J3 = 0.6 Hz, 1H), 7.05 (dd, J1 = 1.9

Hz, J2 = 1.2 Hz, 1H), 6.53 (d, J = 8.7 Hz, 1H), 5.34 (dd, J1 = 10.3 Hz, J2 = 5.3 Hz,

1H), 3.56 – 3.51 (m, 1H), 3.33 (dt, J1 = 12.2 Hz, J2 = 4.7 Hz, 1H), 3.26 – 3.20 (m,

1H), 3.16 – 3.11 (m, 1H), 2.97 (s, 3H), 2.57 – 2.48 (m, 2H), 2.12 – 2.00 (m, 4H). 13C

NMR (101 MHz, CDCl3) d 175.8, 149.8, 133.1, 130.5, 120.7, 119.9, 111.1, 97.8, 49.3,

47.6, 43.3, 39.0, 31.3, 25.7, 18.3. FTIR (neat) 2959, 2884, 2831, 2211, 1679, 1607,

-1 + + 1519, 1423, 1336, 1286, 759 cm . HRMS: ESI [M+H] Calcd. for C15H18N3O:

256.1450. Found: 256.1435.

H3C O H3C N O H3C N mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C N

2) N-vinylpyrrolidone, SnCl4, −78 to 23 °C Cl Cl 3-74 3-89 83%

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.60 equiv) was added to a solution of

4-chloro-N,N-dimethylaniline-N-oxide 3-chlorobenzoic acid (3.74, 329 mg, 1.00 mmol, 1 equiv) and 4-(dimethylamino)pyridine (12 mg, 0.010 mmol, 0.10 equiv) in dichloromethane cooled to 0 °C. The resultant solution was stirred at 0 °C for 2 hours.

The solution was cooled to -78 °C, then N-vinylpyrrolidone (267 µL, 2.50 mmol, 2.50 equiv) and tin (IV) chloride (1M solution in heptane, 0.25 mL, 0.25 mmol, 0.25 equiv)

181

was added. The reaction solution was slowly warmed to 23 °C and stirred at that temperature for 18 hours. The reaction was partitioned between saturated aqueous sodium bicarbonate solution (4 mL) and dichloromethane (5 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 ´ 5 mL). The combined organic layers were dried over sodium sulfate, and the dried solution was concentrated. The resultant oily residue was purified by flash chromatography (silica gel, grading from 30% ethyl acetate-hexanes to ethyl acetate followed by 2% methanol-dichloromethane) to afford N-(7-chloro-1-methyl-1,2,3,4- tetrahydroquinoline)-pyrrolidone as a yellow oil (3-89, 219 mg, 0.827 mmol, 83%

1 yield). TLC 50% ethyl acetate-hexanes, Rf = 0.14 (UV, KMnO4). H NMR (400

MHz, CDCl3) d 7.06 (dd, J1 = 8.7, 2.4 Hz, 1H), 6.81 (dd, J1 = 2.5 Hz, J2 = 0.9 Hz,

1H), 6.51 (d, J = 8.8 Hz, 1H), 5.37 (dd, J1 = 9.6 Hz, J2 = 6.0 Hz, 1H), 3.34 (m, 1H),

3.26 – 3.11 (m, 3H), 2.86 (s, 3H), 2.53 – 2.45 (m, 2H), 2.14 – 1.99 (m, 4H). 13C NMR

(101 MHz, CDCl3) d 175.6, 146.1, 128.4, 127.0, 121.7, 121.5, 113.1, 49.6, 47.8, 43.4,

39.5, 31.5, 26.6, 18.4. FTIR (neat) 2949, 1681, 1598, 1502, 1461, 1420, 1324, 1284,

-1 + + 1210, 1111, 804, 616, 573 cm . HRMS: ESI [M+H] Calcd. for C14H18ClN2O:

265.1108. Found: 265.1094.

182

H3C O H3C N O H3C N mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C N

2) N-vinylpyrrolidone, SnCl4, −78 to 23 °C CF3 CF3 3-144 3-90 85%

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.60 equiv) was added to a solution of

N,N-dimethyl-4-trifluoromethyl-aniline-N-oxide 3-chlorobenzoic acid (3-144, 362 mg,

1.00 mmol, 1 equiv) and 4-(dimethylamino)pyridine (12 mg, 0.010 mmol, 0.10 equiv) in dichloromethane cooled to 0 °C. The resultant solution was stirred at 0 °C for 2 hours. The solution was cooled to -78 °C, then N-vinylpyrrolidone (267 µL, 2.50 mmol, 2.50 equiv) and tin (IV) chloride (1M solution in heptane, 0.25 mL, 0.25 mmol,

0.25 equiv) was added. The reaction solution was slowly warmed to 23 °C and stirred at that temperature for 18 hours. The reaction was partitioned between saturated aqueous sodium bicarbonate solution (4 mL) and dichloromethane (5 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 ´ 5 mL).

The combined organic layers were dried over sodium sulfate, and the dried solution was concentrated. The resultant oily residue was purified by flash chromatography

(silica gel, grading from 30% ethyl acetate-hexanes to ethyl acetate followed by 2% methanol-dichloromethane) to afford N-(7-trifluoromethyl-1-methyl-1,2,3,4- tetrahydroquinoline)-pyrrolidone as a yellow oil (3-90, 254 mg, 0.851 mmol, 85%

1 yield). TLC 50% ethyl acetate-hexanes, Rf = 0.14 (UV, KMnO4). mp 76-78 °C. H

NMR (400 MHz, CDCl3) d 7.34 (dd, J1 = 8.7 Hz, J2 = 2.2 Hz, 1H), 7.04 (d, J = 2.2

Hz, 1H), 6.58 (d, J = 8.7 Hz, 1H), 5.38 (dd, J1 = 9.7 Hz, J2 = 5.5 Hz, 1H), 3.46 (m,

183

1H), 3.31 – 3.19 (m, 2H), 3.11 (m, 1H), 2.94 (s, 3H), 2.57 – 2.44 (m, 2H), 2.17 – 2.09

13 (m, 1H), 2.06 – 1.93 (m, 3H). C NMR (101 MHz, CDCl3) d 175.7, 149.4, 125.9 (q, J

= 4.0 Hz), 125.0 (q, J = 270 Hz), 124.3 (q, J = 4.0 Hz), 119.3, 117.9 (q, J = 32 Hz),

110.9, 49.2, 47.8, 43.6, 39.1, 31.5, 26.2, 18.5. FTIR (neat) 2935, 1687, 1619, 1526,

1421, 1328, 1283, 1214, 1139, 1101, 1078, 814, 576 cm-1. HRMS: ESI+ [M+H]+

Calcd. for C15H18F3N2O: 299.1371. Found: 299.1356.

H3C O H3C N O H3C N mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C N

2) N-vinylpyrrolidone, SnCl4, −78 to 23 °C NO2 NO2 3-145 3-91 38%

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.60 equiv) was added to a solution of

N,N-dimethyl-4-nitro-aniline-N-oxide 3-chlorobenzoic acid (3-145, 339 mg, 1.00 mmol, 1 equiv) and 4-(dimethylamino)pyridine (12 mg, 0.010 mmol, 0.10 equiv) in dichloromethane cooled to 0 °C. The resultant solution was stirred at 0 °C for 2 hours.

184

concentrated. The resultant oily residue was purified by flash chromatography (silica gel, grading from 30% ethyl acetate-hexanes to ethyl acetate followed by 2% methanol-dichloromethane) to afford N-(1-methyl-7-nitro-1,2,3,4- tetrahydroquinoline)-pyrrolidone as a yellow solid (3-91, 104 mg, 0.378 mmol, 38%

1 yield). TLC 50% ethyl acetate-hexanes, Rf = 0.08 (UV, KMnO4). mp 182-183 °C. H

NMR (400 MHz, CDCl3) d 8.05 (dd, J1 = 8.0 Hz, J2 = 1.5 Hz, 1H), 7.73 (dd, J1 = 2.7

Hz, J2 = 1.2 Hz, 1H), 6.52 (d, J = 9.2 Hz, 1H), 5.41 – 5.35 (m, 1H), 3.65 – 3.58 (m,

1H), 3.40 (dt, J1 = 12.5 Hz, J2 = 4.7 Hz, 1H), 3.25 – 3.17 (m, 2H), 3.05 (s, 3H), 2.59 –

13 2.48 (m, 2H), 2.14 – 2.01 (m, 4H). C NMR (101 MHz, CDCl3) d 175.9, 151.5,

137.1, 125.8, 123.2, 118.9, 110.0, 49.5, 47.7, 43.4, 39.3, 31.4, 25.7, 18.5. FTIR (neat)

2955, 1678, 1606, 1527, 1422, 1303, 1265, 1226, 1172, 1111, 750 cm-1. HRMS: ESI+

+ [M+H] Calcd. for C14H18N3O3: 276.1348. Found: 276.1333.

H3C O H3C N O H3C N mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C N

2) N-vinylpyrrolidone, SnCl4, −78 to 23 °C CO2CH3 CO2CH3 3-146 3-92 84%

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.60 equiv) was added to a solution of

4-(N,N-dimethylamino)benzoate-N-oxide 3-chlorobenzoic acid (3-146, 352 mg, 1.00 mmol, 1 equiv) and 4-(dimethylamino)pyridine (12 mg, 0.010 mmol, 0.10 equiv) in dichloromethane cooled to 0 °C. The resultant solution was stirred at 0 °C for 2 hours.

The solution was cooled to -78 °C, then N-vinylpyrrolidone (267 µL, 2.50 mmol, 2.50

185

equiv) and tin (IV) chloride (1M solution in heptane, 0.25 mL, 0.25 mmol, 0.25 equiv) was added. The reaction solution was slowly warmed to 23 °C and stirred at that temperature for 18 hours. The reaction was partitioned between saturated aqueous sodium bicarbonate solution (4 mL) and dichloromethane (5 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 ´ 5 mL). The combined organic layers were dried over sodium sulfate, and the dried solution was concentrated. The resultant oily residue was purified by flash chromatography (silica gel, grading from 30% ethyl acetate-hexanes to ethyl acetate followed by 2% methanol-dichloromethane) to afford N-(methyl-1-methyl-1,2,3,4- tetrahydroquinoline-7-carboxylate)-pyrrolidone as a yellow oil (3-92, 241 mg, 0.836

1 mmol, 84% yield). TLC 50% ethyl acetate-hexanes, Rf = 0.11 (UV, KMnO4). H

NMR (400 MHz, CDCl3) d 7.81 (dd, J1 = 8.7 Hz, J2 = 1.9 Hz, 1H), 7.52 (d, J = 2.1

Hz, 1H), 6.55 (d, J = 8.8 Hz, 1H), 5.36 (dd, J1 = 9.4 Hz, J2 = 5.3 Hz, 1H), 3.83 (s, 3H),

3.49 – 3.44 (m, 1H), 3.34 – 3.29 (m, 1H), 3.17 (m, 2H), 2.98 (s, 3H), 2.62 – 2.44 (m,

13 2H), 2.17 – 2.10 (m, 1H), 2.05 – 2.00 (m, 3H). C NMR (101 MHz, CDCl3) d 175.7,

167.4, 150.5, 130.9, 129.2, 118.5, 117.3, 110.4, 51.7, 49.2, 47.9, 43.8, 39.1, 31.6, 26.3,

18.5. FTIR (neat) 2948, 1703, 1680, 1608, 1523, 1423, 1318, 1290, 1267, 1210, 1144,

-1 + + 1115, 769 cm . HRMS: ESI [M+H] Calcd. for C16H21N2O3: 289.1552. Found:

289.1540.

186

H3C O H3C N O H3C N mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C N

2) N-vinylpyrrolidone, SnCl4, −78 to 23 °C F F 3-75 3-93 85%

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.60 equiv) was added to a solution of

4-fluoro-N,N-dimethylaniline-N-oxide 3-chlorobenzoic acid (3-75, 311 mg, 1.00 mmol, 1 equiv) and 4-(dimethylamino)pyridine (12 mg, 0.010 mmol, 0.10 equiv) in dichloromethane cooled to 0 °C. The resultant solution was stirred at 0 °C for 2 hours.

The solution was cooled to -78 °C, then N-vinylpyrrolidone (267 µL, 2.50 mmol, 2.50 equiv) and tin (IV) chloride (1M solution in heptane, 0.25 mL, 0.25 mmol, 0.25 equiv) was added. The reaction solution was slowly warmed to 23 °C and stirred at that temperature for 18 hours. The reaction was partitioned between saturated aqueous sodium bicarbonate solution (4 mL) and dichloromethane (5 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 ´ 5 mL). The combined organic layers were dried over sodium sulfate, and the dried solution was concentrated. The resultant oily residue was purified by flash chromatography (silica gel, grading from 30% ethyl acetate-hexanes to ethyl acetate followed by 2% methanol-dichloromethane) to afford N-(7-fluoro-1-methyl-1,2,3,4- tetrahydroquinoline)-pyrrolidone as a white solid (3-93, 210 mg, 0.846 mmol, 85%

1 yield). TLC 50% ethyl acetate-hexanes, Rf = 0.17 (UV, KMnO4). mp 93-95 °C. H

NMR (400 MHz, CDCl3) d 6.84 (m, 1H), 6.61 (ddd, J1 = 9.2 Hz, J2 = 3.1 Hz, J3 = 1.1

Hz, 1H), 6.54 (dd, J1 = 9.0 Hz, J2 = 4.6 Hz, 1H), 5.42 (dd, J1 = 9.8 Hz, J2 = 6.3 Hz,

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1H), 3.34 – 3.24 (m, 2H), 3.21 – 3.12 (m, 2H), 2.85 (s, 3H), 2.55 – 2.47 (m, 2H), 2.15

13 – 1.94 (m, 4H). C NMR (101 MHz, CDCl3) d 175.5, 155.5 (d, J = 240 Hz), 144.1 (d,

J = 1.0 Hz), 121.6 (d, J = 6.1 Hz), 115.0 (J = 22 Hz), 113.7 (J = 23 Hz), 113.0 (J = 7.1

Hz), 49.9, 47.9, 43.2, 39.8, 31.3, 26.6, 18.4. FTIR (neat) 2950, 1682, 1506, 1461,

1423, 1284, 1271, 1208, 805, 694, 671 cm-1. HRMS: ESI+ [M+H]+ Calcd. for

C14H18FN2O: 249.1403. Found: 249.1389.

H3C O H3C N O H3C N mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C N

2) N-vinylpyrrolidone, SnCl4, −78 to 23 °C Br Br 3-147 3-94 89%

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.60 equiv) was added to a solution of

4-bromo-N,N-dimethylaniline-N-oxide 3-chlorobenzoic acid (3-147, 373 mg, 1.00 mmol, 1 equiv) and 4-(dimethylamino)pyridine (12 mg, 0.010 mmol, 0.10 equiv) in dichloromethane cooled to 0 °C. The resultant solution was stirred at 0 °C for 2 hours.

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concentrated. The resultant oily residue was purified by flash chromatography (silica gel, grading from 30% ethyl acetate-hexanes to ethyl acetate followed by 2% methanol-dichloromethane) to afford N-(7-bromo-1-methyl-1,2,3,4- tetrahydroquinoline)-pyrrolidone as a pale-yellow oil (3-94, 275 mg, 0.889 mmol,

1 89% yield). TLC 50% ethyl acetate-hexanes, Rf = 0.14 (UV, KMnO4). H NMR (400

MHz, CDCl3) d 7.20 (ddd, J1 = 8.8 Hz, J2 = 2.4 Hz, J3 = 0.7 Hz, 1H), 6.94 (dd, J1 =

2.5 Hz, J2 = 1.1 Hz, 1H), 6.47 (d, J = 8.8 Hz, 1H), 5.38 (dd J1 = 9.6 Hz, J2 = 5.9 Hz,

1H), 3.36 – 3.30 (m, 1H), 3.26 – 3.13 (m, 3H), 2.86 (s, 3H), 2.55 – 2.44 (m, 2H), 2.14

13 – 1.98 (m, 4H). C NMR (101 MHz, CDCl3) d 175.6, 146.5, 131.4, 129.8, 122.0,

113.5, 108.7, 49.5, 47.8, 43.5, 39.4, 31.5, 26.5, 18.4. FTIR (neat) 2879, 1681, 1593,

1500, 1461, 1419, 1324, 1283, 1209, 1104, 802, 731, 682 cm-1. HRMS: ESI+ [M+H]+

Calcd. for C14H18BrN2O: 309.0603. Found: 309.0587.

H3C O H3C N O H3C N mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C N

2) N-vinylpyrrolidone, SnCl4, −78 to 23 °C CH3 CH3 3-148 3-95 61%

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.60 equiv) was added to a solution of

4,N,N-trimethylaniline-N-oxide 3-chlorobenzoic acid (3-148, 328 mg, 1.00 mmol, 1 equiv) and 4-(dimethylamino)pyridine (12 mg, 0.010 mmol, 0.10 equiv) in dichloromethane cooled to 0 °C. The resultant solution was stirred at 0 °C for 2 hours.

The solution was cooled to -78 °C, then N-vinylpyrrolidone (267 µL, 2.50 mmol, 2.50

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equiv) and tin (IV) chloride (1M solution in heptane, 0.25 mL, 0.25 mmol, 0.25 equiv) was added. The reaction solution was slowly warmed to 23 °C and stirred at that temperature for 18 hours. The reaction was partitioned between saturated aqueous sodium bicarbonate solution (4 mL) and dichloromethane (5 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 ´ 5 mL). The combined organic layers were dried over sodium sulfate, and the dried solution was concentrated. The resultant oily residue was purified by flash chromatography (silica gel, grading from 30% ethyl acetate-hexanes to ethyl acetate followed by 2% methanol-dichloromethane) to afford N-(1,7-dimethyl-1,2,3,4-tetrahydroquinoline)- pyrrolidone as a red orange oil (3-95, 150 mg, 0.614 mmol, 61% yield). TLC 50%

1 ethyl acetate-hexanes, Rf = 0.29 (UV, KMnO4). H NMR (400 MHz, CDCl3) d 6.94

(dd, J1 = 8.3 Hz, J2 = 2.0 Hz, 1H), 6.69 (m, 1H), 6.56 (d, J = 8.3 Hz, 1H), 5.40 (dd, J1

= 9.0 Hz, J2 = 6.3 Hz, 1H), 3.29 – 3.20 (m, 2H), 3.20 – 3.09 (m, 2H), 2.84 (s, 3H),

13 2.54 – 2.46 (m, 2H), 2.20 (s, 3H), 2.14 – 1.95 (m, 4H). C NMR (101 MHz, CDCl3) d 175.6, 145.6, 129.2, 128.2, 126.3, 120.2, 112.3, 49.9, 47.9, 43.6, 39.7, 31.6, 27.1,

20.5, 18.4. FTIR (neat) 2947, 2814, 1682, 1618, 1510, 1460, 1420, 1318, 1283, 1207,

-1 + + 758 cm . HRMS: ESI [M+H] Calcd. for C15H21N2O: 245.1654. Found: 245.1643.

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H3C O H3C N O H3C N mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C H3C H3C N 2) N-vinylpyrrolidone, SnCl4, −78 to 23 °C 3-77 3-96 26%

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.61 equiv) was added to a solution of

2,N,N-trimethylaniline-N-oxide 3-chlorobenzoic acid (3-77, 327 mg, 0.997 mmol, 1 equiv) and 4-(dimethylamino)pyridine (12 mg, 0.010 mmol, 0.10 equiv) in dichloromethane cooled to 0 °C. The resultant solution was stirred at 0 °C for 2 hours.

The solution was cooled to -78 °C, then N-vinylpyrrolidone (267 µL, 2.50 mmol, 2.51 equiv) and tin (IV) chloride (1M solution in heptane, 0.25 mL, 0.25 mmol, 0.25 equiv) was added. The reaction solution was slowly warmed to 23 °C and stirred at that temperature for 18 hours. The reaction was partitioned between saturated aqueous sodium bicarbonate solution (4 mL) and dichloromethane (5 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 ´ 5 mL). The combined organic layers were dried over sodium sulfate, and the dried solution was concentrated. The resultant oily residue was purified by flash chromatography (silica gel, grading from 30% ethyl acetate-hexanes to ethyl acetate followed by 2% methanol-dichloromethane) to afford N-(1,9-dimethyl-1,2,3,4-tetrahydroquinoline)- pyrrolidone as a red orange oil (3-96, 60 mg, 0.25 mmol, 26% yield). TLC 50% ethyl

1 acetate-hexanes, Rf = 0.16 (UV, KMnO4). H NMR (400 MHz, CDCl3) d 7.06 – 7.00

(m, 1H), 6.88 – 6.82 (m, 2H), 5.40 (dd, J1 = 8.9 Hz, J2 = 7.1 Hz, 1H), 3.28 – 3.20 (m,

2H), 3.15 – 3.03 (m, 2H), 2.71 (s, 3H), 2.48 (dd, J1 = 8.9 Hz, J2 = 7.2 Hz, 2H), 2.28

191

13 (s, 3H), 2.08 – 1.84 (m, 4H). C NMR (101 MHz, CDCl3) d 175.5, 149.0, 131.7,

130.5, 126.8, 125.6, 122.2, 50.3, 48.1, 43.2, 42.4, 31.5, 21.0, 18.7, 18.3. FTIR (neat)

2946, 1683, 1594, 1470, 1420, 1284, 795, 768, 565, 511 cm-1. HRMS: ESI+ [M+H]+

Calcd. for C15H21N2O: 245.1654. Found: 245.1641.

H3C O H3C N O H3C N mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C F F N 2) N-vinylpyrrolidone, SnCl4, −78 to 23 °C 3-78 3-97 27%

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.61 equiv) was added to a solution of

2-fluoro-N,N-dimethylaniline-N-oxide 3-chlorobenzoic acid (3-78, 310 mg, 0.995 mmol, 1 equiv) and 4-(dimethylamino)pyridine (12 mg, 0.010 mmol, 0.10 equiv) in dichloromethane cooled to 0 °C. The resultant solution was stirred at 0 °C for 2 hours.

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methanol-dichloromethane) to afford N-(9-fluoro-1-methyl-1,2,3,4- tetrahydroquinoline)-pyrrolidone as a yellow oil (3-97, 67 mg, 0.27 mmol, 27% yield).

1 TLC 50% ethyl acetate-hexanes, Rf = 0.17 (UV, KMnO4). H NMR (400 MHz,

CDCl3) d 6.94 – 6.85 (m, 1H), 6.73 – 6.66 (m, 2H), 5.37 (dd, J1 = 9.6 Hz, J2 = 5.6 Hz,

1H), 3.29 – 3.17 (m, 3H), 3.07 (m 1H), 2.98 (d, J = 2.7 Hz, 3H), 2.49 (m, 2H), 2.08 –

13 1.92 (m, 4H). C NMR (101 MHz, CDCl3) d 175.7, 152.9 (d, J = 244 Hz), 137.1 (d, J

= 9.1 Hz), 126.3 (d, J = 3.0 Hz), 122.8 (d, J = 3.0 Hz), 119.3 (d, J = 8.1 Hz), 115.7 (d,

J = 22 Hz), 50.8, 48.1 (d, J = 3.0 Hz), 43.5, 42.7 (d, J = 11 Hz), 31.5, 24.7, 18.4.

FTIR (neat) 2951, 1686, 1613, 1489, 1423, 1285, 1239, 782, 730, 636, 569 cm-1.

+ + HRMS: ESI [M+H] Calcd. for C14H18FN2O: 249.1403. Found: 249.1391.

O 1) Boc O, DMAP, CH Cl , 0 °C N O H3C N mCBA 2 2 2

2) N-vinylpyrrolidone, SnCl4, N −78 to 23 °C

3-83 3-98 58%

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.57 equiv) was added to a solution of

N-cyclohexyl-N-dimethylaniline-N-oxide 3-chlorobenzoic acid (3-83, 366 mg, 1.01 mmol, 1 equiv) and 4-(dimethylamino)pyridine (12 mg, 0.010 mmol, 0.10 equiv) in dichloromethane cooled to 0 °C. The resultant solution was stirred at 0 °C for 2 hours.

The solution was cooled to -78 °C, then N-vinylpyrrolidone (267 µL, 2.50 mmol, 2.48 equiv) and tin (IV) chloride (1M solution in heptane, 0.25 mL, 0.25 mmol, 0.25 equiv) was added. The reaction solution was slowly warmed to 23 °C and stirred at that

193

temperature for 18 hours. The reaction was partitioned between saturated aqueous sodium bicarbonate solution (4 mL) and dichloromethane (5 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 ´ 5 mL). The combined organic layers were dried over sodium sulfate, and the dried solution was concentrated. The resultant oily residue was purified by flash chromatography (silica gel, grading from 30% ethyl acetate-hexanes to ethyl acetate followed by 2% methanol-dichloromethane) to afford N-(1-cyclohexyl-1,2,3,4-tetrahydroquinoline)- pyrrolidone as a yellow oil (3-98, 174 mg, 0.583 mmol, 58% yield). TLC 50% ethyl

1 acetate-hexanes, Rf = 0.22 (UV, KMnO4). H NMR (400 MHz, CDCl3) d 7.11 (m,

1H), 6.86 (dt, J1 = 7.4 Hz, J2 = 1.4 Hz, 1H), 6.72 – 6.67 (m, 1H), 6.58 (td, J1 = 7.4 Hz,

J2 = 1.0 Hz, 1H), 5.33 (dd, J1 = 8.7 Hz, J2 = 5.6 Hz, 1H), 3.58 (m, 1H), 3.27 – 3.19 (m,

2H), 3.13 (m, 1H), 2.48 (td, J1 = 8.0 Hz, J2 = 7.6 Hz, J3 = 1.5 Hz, 2H), 2.12 – 1.91 (m,

4H), 1.91 – 1.64 (m, 5H), 1.56 – 1.29 (m, 4H), 1.20 – 1.08 (m, 1H). 13C NMR (101

MHz, CDCl3) d 175.5, 146.2, 128.7, 128.1, 119.9, 115.7, 111.5, 56.4, 48.6, 44.0, 39.6,

31.7, 30.3, 29.0, 27.0, 26.4, 26.3, 26.1, 18.5. FTIR (neat) 2929, 2854, 1684, 1601,

1495, 1454, 1419, 1316, 1283, 1170, 744, 558 cm-1. HRMS: ESI+ [M+H]+ Calcd. for

C19H27N2O: 299.2123. Found: 299.2108.

194

H3C O H3C H C N N O 3 mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C N 2) N-vinylpyrrolidone, SnCl4, 6 −78 to 23 °C 8 NC CN 3-79 3-99 81% 2.58:1 6-CN: 8-CN

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.60 equiv) was added to a solution of

3-(N,N-dimethylamino)benzonitrile-N-oxide 3-chlorobenzoic acid (3-79, 319 mg, 1.00 mmol, 1 equiv) and 4-(dimethylamino)pyridine (12 mg, 0.010 mmol, 0.10 equiv) in dichloromethane cooled to 0 °C. The resultant solution was stirred at 0 °C for 2 hours.

The solution was cooled to -78 °C, then N-vinylpyrrolidone (267 µL, 2.50 mmol, 2.50 equiv) and tin (IV) chloride (1M solution in heptane, 0.25 mL, 0.25 mmol, 0.25 equiv) was added. The reaction solution was slowly warmed to 23 °C and stirred at that temperature for 18 hours. The reaction was partitioned between saturated aqueous sodium bicarbonate solution (4 mL) and dichloromethane (5 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 ´ 5 mL). The combined organic layers were dried over sodium sulfate, and the dried solution was concentrated. The resultant oily residue was purified by flash chromatography (silica gel, grading from 30% ethyl acetate-hexanes to ethyl acetate followed by 2% methanol-dichloromethane) to afford 3-99 as a yellow oil (isolated as mix of regioisomers, 2.65:1 (6-CN:8-CN) asterisk denotes minor peaks, 206 mg, 0.807 mmol,

1 81% yield). TLC 50% ethyl acetate-hexanes, Rf = 0.10 (UV, KMnO4). H NMR (400

MHz, CDCl3) d 7.16 (dd, J1 = 8.5 Hz, J2 = 7.5 Hz, 1H), 6.89 (dd, J1 = 7.5 Hz, J2 =

1.1 Hz, 1H), 6.83* (m, 2H), 6.77 (dd, J1 = 8.6 Hz, J2 = 1.0 Hz, 1H), 6.69* (d, J = 1.2

195

Hz, 1H), 5.33* (m, 1H), 5.30 (m, 1H), 3.39* (m, 1H), 3.27 – 3.20* (m, 2H), 3.27 –

3.20 (m, 2H), 3.15* (m, 1H), 3.04* (m, 1H), 2.99 – 2.92 (m, 1H), 2.90 (s, 3H), 2.85*

(s, 3H), 2.50 – 2.29* (m, 2H), 2.50 – 2.29 (m, 2H), 2.23 – 2.15 (m, 1H), 2.13 – 1.89*

13 (m, 4H), 2.13 – 1.89 (m, 3H). C NMR (101 MHz, CDCl3) d 175.6*, 174.9, 147.6,

147.2*, 129.2, 127.3*, 124.7*, 121.2 (2 signals), 120.8, 119.5*, 117.7*, 115.6, 113.9*,

112.8, 111.9*, 49.1*, 47.6, 47.6*, 46.8, 46.0, 43.1*, 39.2, 38.9*, 31.1*, 30.9, 27.3,

25.7*, 18.3, 18.2*. FTIR (neat) 2928, 2240, 1683, 1589, 1496, 1415, 1284, 790, 567

-1 + + cm . HRMS: ESI [M+H] Calcd. for C15H18N3O: 2561450. Found: 256.1435.

H3C O H3C H C N N O 3 mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C N 2) N-vinylpyrrolidone, SnCl4, 6 −78 to 23 °C 8 CF3 F3C 3-80 3-100 68% 2.42:1 6-CF3: 8-CF3

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.60 equiv) was added to a solution of

N,N-dimethyl-3-trifluoromethyl-aniline-N-oxide 3-chlorobenzoic acid (3-80, 362 mg,

196

were separated, and the aqueous layer was extracted with dichloromethane (2 ´ 5 mL).

The combined organic layers were dried over sodium sulfate, and the dried solution was concentrated. The resultant oily residue was purified by flash chromatography

(silica gel, grading from 30% ethyl acetate-hexanes to ethyl acetate followed by 2% methanol-dichloromethane) to afford 3-100 as a yellow oil (isolated as mix of regioisomers, 2.42:1 (6-CF3:8-CF3) asterisk denotes minor peaks, 204 mg, 0.685

1 mmol, 68% yield). TLC 50% ethyl acetate-hexanes, Rf = 0.11 (UV, KMnO4). H

NMR (400 MHz, CDCl3) d 7.20* (m, 1H), 6.91* (m, 1H), 6.89 (m, 1H), 6.82 (dd, J1 =

8.0 Hz, J2 = 1.6 Hz, 1H), 6.77* (d, J = 8.4 Hz, 1H), 6.73 (d, J = 1.6 Hz, 1H), 5.38*

(m, 1H), 5.38 (m, 1H), 3.39 (m, 1H), 3.33 – 3.18* (m, 2H), 3.33 – 3.18 (m, 2H), 3.08

(m, 1H), 3.00* (m, 1H), 2.96 (s, 1H), 2.89* (s, 3H), 2.84 – 2.76* (m, 1H), 2.47 (m,

1H), 2.47* (m, 2H), 2.38 – 2.31 (m, 1H), 2.28* (m, 1H), 2.16 – 2.06 (m, 1H), 2.04 –

1.95* (m, 2H), 2.04 – 1.95 (m, 2H), 1.91 – 1.77* (m, 1H), 1.91 – 1.77 (m, 1H). 13C

NMR (101 MHz, CDCl3) d 175.6, 174.5*, 147.3, 147.2*, 130.7 (q, J = 31 Hz), 129.6*

(q, J = 29 Hz), 129.3*, 127.5, 125.7*, 123.0*, 123.2 (q, J = 1.0 Hz), 115.3* (q, J = 1.0

Hz), 114.5, 112.9* (q, J = 6.1 Hz), 112.7 (q, J = 4.0 Hz), 107.8 (q, J = 4.0 Hz), 49.3,

47.7, 47.4*, 46.0*, 45.1*, 43.3, 39.1*, 39.1, 31.5*, 31.3, 26.7*, 26.1, 18.5*, 18.3.

FTIR (neat) 2829, 1687, 1598, 1511, 1421, 1333, 1307, 1285, 1214, 1164, 1117, 729

-1 + + cm . HRMS: ESI [M+H] Calcd. for C15H18F3N2O: 299.1371. Found: 299.1356.

197

H3C O H3C H C N N O 3 mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C N 2) N-vinylpyrrolidone, SnCl4, 6 −78 to 23 °C 8 CH3 H3C 3-81 3-101 47% 1.55:1 6-CH3: 8-CH3

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.60 equiv) was added to a solution of

3,N,N-trimethylaniline-N-oxide 3-chlorobenzoic acid (3-81, 328 mg, 1.00 mmol, 1 equiv) and 4-(dimethylamino)pyridine (12 mg, 0.010 mmol, 0.10 equiv) in dichloromethane cooled to 0 °C. The resultant solution was stirred at 0 °C for 2 hours.

The solution was cooled to -78 °C, then N-vinylpyrrolidone (267 µL, 2.50 mmol, 2.50 equiv) and tin (IV) chloride (1M solution in heptane, 0.25 mL, 0.25 mmol, 0.25 equiv) was added. The reaction solution was slowly warmed to 23 °C and stirred at that temperature for 18 hours. The reaction was partitioned between saturated aqueous sodium bicarbonate solution (4 mL) and dichloromethane (5 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 ´ 5 mL). The combined organic layers were dried over sodium sulfate, and the dried solution was concentrated. The resultant oily residue was purified by flash chromatography (silica gel, grading from 30% ethyl acetate-hexanes to ethyl acetate followed by 2% methanol-dichloromethane) to afford 3-101 as a red orange oil (isolated as mix of regioisomers, 1.55:1 (6-CH3:8-CH3) asterisk denotes minor peaks, 114 mg, 0.466

1 mmol, 47% yield). TLC 50% ethyl acetate-hexanes, Rf = 0.20 (UV, KMnO4). H

NMR (400 MHz, CDCl3) d 7.11 (dd, J1 = 8.4 Hz, J2 = 7.4 Hz, 1H), 6.79* (dd, J1 = 7.6

Hz, J2 = 1.0 Hz, 1H), 6.55 (t, J = 8.5 Hz, 2H), 6.51* (m, 1H), 6.47* (d, J = 1.5 Hz,

198

1H), 5.41* (dd, J1 = 9.2 Hz, J2 = 6.0 Hz, 1H), 5.24 (dd, J1 = 4.7 Hz, J2 = 3.3 Hz, 1H),

3.37 – 3.30 (m, 1H), 3.26 – 3.20 (m, 2H), 3.26 – 3.20* (m, 2H), 3.17* (m, 2H), 2.96

(s, 3H), 2.90* (s, 3H), 2.83 (m, 1H), 2.51* (m, 2H), 2.46 (m, 2H), 2.31* (s, 3H), 2.24*

(m, 1H), 2.20 (m, 1H), 2.14 (s, 3H), 2.12 – 1.83 (m, 3H), 2.12 – 1.83* (m, 3H). 13C

NMR (101 MHz, CDCl3) d 175.6*, 174.6, 147.5*, 147.4, 138.4*, 138.2, 128.8,

127.7*, 118.6, 117.8*, 117.1*, 116.8, 112.6*, 109.6, 49.7*, 47.8*, 47.6, 47.3, 45.7,

43.7*, 39.7, 39.5*, 31.7*, 31.6, 28.7, 27.0*, 21.8*, 19.3, 18.7, 18.4*. FTIR (neat)

2923, 1680, 1592, 1493, 1416, 1317, 1283, 1267, 1210, 731 cm-1. HRMS: ESI+

+ [M+H] Calcd. for C15H21N2O: 245.1654. Found: 245.1639.

H3C O H3C H C N N O 3 mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C N 2) N-vinylpyrrolidone, SnCl4, 6 −78 to 23 °C 8 CO2CH3 H3CO2C 3-82 3-102 91% 2.09:1 6-CO2CH3: 8-CO2CH3

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.60 equiv) was added to a solution of methyl 3-(N,N-dimethylamino)benzoate-N-oxide 3-chlorobenzoic acid (3-82, 352 mg,

0.25 equiv) was added. The reaction solution was slowly warmed to 23 °C and stirred at that temperature for 18 hours. The reaction was partitioned between saturated

199

aqueous sodium bicarbonate solution (4 mL) and dichloromethane (5 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 ´ 5 mL).

The combined organic layers were dried over sodium sulfate, and the dried solution was concentrated. The resultant oily residue was purified by flash chromatography

(silica gel, grading from 30% ethyl acetate-hexanes to ethyl acetate followed by 2% methanol-dichloromethane) to afford 3-102 as a yellow oil (isolated as mix of regioisomers, 2.04:1 (6-CO2CH3:8-CO2CH3) asterisk denotes minor peaks, 262 mg,

0.909 mmol, 91% yield). TLC 50% ethyl acetate-hexanes, Rf = 0.16 (UV, KMnO4).

1 H NMR (400 MHz, CDCl3) d 7.30* (dd, J1 = 7.9 Hz, J2 = 1.6 Hz, 1H), 7.26*

(apparent s, 1H), 7.20 (t, J = 8.0 Hz, 1H), 6.95 (dd, J1 = 7.6 Hz, J2 = 1.0 Hz, 1H),

6.90* (dd, J1 = 7.8 Hz, J2 = 1.0 Hz, 1H), 6.75 (dd, J1 = 8.4 Hz, J2 = 1.1 Hz, 1H), 5.55

(t, J = 5.5 Hz, 1H), 5.43* (dd, J1 = 9.6 Hz, J2 = 6.0 Hz, 1H), 3.89* (s, 3H), 3.79 (s,

3H), 3.44 – 3.35 (m, 1H), 3.28 – 3.22* (m, 2H), 3.28 – 3.22 (m, 2H), 3.13 – 3.02* (m,

1H), 3.13 – 3.02 (m, 1H), 2.94* (s, 3H), 2.94 (s, 3H), 2.92 – 2.88* (m, 1H), 2.52 –

2.47 (m, 1H), 2.38 (dd, J = 8.5, 7.5 Hz, 2H), 2.15* (m, 1H), 2.15 (m, 1H), 2.08 –

1.96* (m, 3H), 2.08 – 1.96 (m, 1H), 1.90* (m, 1H), 1.90 (m, 1H), 1.67* (m, 1H). 13C

NMR (101 MHz, CDCl3) d 175.6*, 174.8, 169.5, 167.6*, 147.7, 147.5*, 133.1,

130.3*, 128.9, 127.3*, 124.8*, 117.8, 117.7*, 117.3, 114.5, 112.6*, 52.6, 52.2*, 49.5*,

48.0*, 47.8, 46.5, 45.8, 43.4*, 39.7, 39.4*, 31.6, 31.5*, 27.1, 26.4*, 18.4, 18.4*. FTIR

(neat) 2950, 1720, 1682, 1589, 1416, 1317, 1284, 1267, 1209, 1114, 769, 737 cm-1.

+ + HRMS: ESI [M+H] Calcd. for C16H21N2O3: 289.1552. Found: 289.1536.

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3.4.5 Polonovski-Povarov Cyclizations with 2-Phenylpropene

H C H3C 3 O N H3C N mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C Ph CH3 2) TMSCl, 2-phenylpropene, −78 to 23 °C CN CN 3-143 3-106 76%

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.60 equiv) was added to a solution of

4-(N,N-dimethylamino)benzonitrile-N-oxide 3-chlorobenzoic acid (3-143, 319 mg,

2.60 equiv) and trimethylsilyl chloride (127 µL, 1.00 mmol, 1.00 equiv) were added.

The reaction solution was slowly warmed to 23 °C and stirred at that temperature for

18 hours. The reaction was partitioned between saturated aqueous sodium bicarbonate solution (4 mL) and dichloromethane (5 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 ´ 5 mL). The combined organic layers were dried over sodium sulfate, and the dried solution was concentrated. The resultant oily residue was purified by flash chromatography (silica gel, grading from

1% ethyl acetate-hexanes to 3% ethyl acetate-hexanes) to afford 1,4-dimethyl-

1,2,3,4-tetrahydroquinoline-7-carbonitrile as a pale yellow solid (3-106, 199 mg, 0.758 mmol, 76% yield). TLC 10% ethyl acetate-hexanes, Rf = 0.27 (UV, KMnO4). mp

1 107-109 °C. H NMR (400 MHz, CDCl3) d 7.39 (dd, J1 = 8.7 Hz, J2 = 2.0 Hz, 1H),

7.29 – 7.25 (m, 2H), 7.23 (d, J = 2.0 Hz, 1H), 7.22 – 7.17 (m, 1H), 7.07 – 7.01 (m,

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2H), 6.57 (d, J = 8.7 Hz, 1H), 3.26 – 3.20 (m, 1H), 3.09 – 3.03 (m, 1H), 2.94 (s, 3H),

13 2.25 – 2.20 (m, 1H), 1.98 – 1.91 (m, 1H), 1.69 (s, 3H). C NMR (101 MHz, CDCl3) d 148.8, 148.3, 132.1, 131.9, 129.2, 128.5, 127.0, 126.4, 121.3, 110.3, 96.9, 47.5, 40.9,

38.9, 37.1, 29.2. FTIR (neat) 3055, 2926, 2211, 1606, 1523, 1493, 1415, 1334, 1316,

+ + 1206, 809, 765, 701. HRMS: ESI [M+H] Calcd. for C18H19N: 263.1548. Found:

263.1533.

H C H3C 3 O N H3C N mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C Ph CH3 2) TMSCl, 2-phenylpropene, −78 to 23 °C CH3 CH3 3-148 3-107 76%

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.60 equiv) was added to a solution of

4,N,N-trimethylaniline-N-oxide 3-chlorobenzoic acid (3-148, 318 mg, 1.00 mmol, 1 equiv) and 4-(dimethylamino)pyridine (12 mg, 0.010 mmol, 0.10 equiv) in dichloromethane cooled to 0 °C. The resultant solution was stirred at 0 °C for 2 hours.

The solution was cooled to -78 °C, then 2-phenylpropene (338 µL, 2.60 mmol, 2.60 equiv) and trimethylsilyl chloride (127 µL, 1.00 mmol, 1.00 equiv) were added. The reaction solution was slowly warmed to 23 °C and stirred at that temperature for 18 hours. The reaction was partitioned between saturated aqueous sodium bicarbonate solution (4 mL) and dichloromethane (5 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 ´ 5 mL). The combined organic layers were dried over sodium sulfate, and the dried solution was concentrated. The

202

resultant oily residue was purified by flash chromatography (silica gel, grading from

0.5% ethyl acetate-hexanes to 1% ethyl acetate-hexanes) to afford 1,4,7-trimethyl-4- phenyl-1,2,3,4-tetrahydroquinoline as a clear yellow oil (3-107, 190 mg, 0.756 mmol,

1 76% yield). TLC 10% ethyl acetate-hexanes, Rf = 0.66 (UV, KMnO4). H NMR (400

MHz, CDCl3) d 7.32 – 7.26 (m, 2H), 7.22 – 7.16 (m, 3H), 6.99 (dd, J1 = 8.3 Hz, J2 =

2.1 Hz, 1H), 6.81 (d, J = 2.1 Hz, 1H), 6.64 (d, J = 8.3 Hz, 1H), 3.12 (m, 1H), 2.98 (m,

1H), 2.90 (s, 3H), 2.23 (m, 1H), 2.22 (s, 3H), 2.05 (m, 1H), 1.76 (s, 3H). 13C NMR

(101 MHz, CDCl3) d 150.8, 144.4, 129.8, 129.3, 128.0, 128.0, 127.4, 125.7, 125.3,

111.4, 47.9, 41.1, 39.7, 39.4, 30.0, 20.6. FTIR (neat) 3022, 2964, 2918, 2870, 2820,

1616, 1599, 1511, 1493, 1465, 1444, 1325, 1210, 801, 764, 701. HRMS: ESI+ [M+H]+

Calcd. for C18H22N: 252.1752. Found: 252.1739.

H C H3C 3 O N H3C N mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C Ph CH3 2) TMSCl, 2-phenylpropene, −78 to 23 °C Cl Cl 3-74 3-108 50%

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.60 equiv) was added to a solution of

4-chloro-N,N-dimethylaniline-N-oxide 3-chlorobenzoic acid (3-74, 328 mg, 1.00 mmol, 1 equiv) and 4-(dimethylamino)pyridine (12 mg, 0.010 mmol, 0.10 equiv) in dichloromethane cooled to 0 °C. The resultant solution was stirred at 0 °C for 2 hours.

The solution was cooled to -78 °C, then 2-phenylpropene (338 µL, 2.60 mmol, 2.60 equiv) and trimethylsilyl chloride (127 µL, 1.00 mmol, 1.00 equiv) were added. The

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reaction solution was slowly warmed to 23 °C and stirred at that temperature for 18 hours. The reaction was partitioned between saturated aqueous sodium bicarbonate solution (4 mL) and dichloromethane (5 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 ´ 5 mL). The combined organic layers were dried over sodium sulfate, and the dried solution was concentrated. The resultant oily residue was purified by flash chromatography (silica gel, grading from

0.5% ethyl acetate-hexanes to 1% ethyl acetate-hexanes) to afford 7-chloro-1,4- dimethyl-4-phenyl-1,2,3,4-tetrahydroquinoline as a yellow oil (3-108, 135 mg, 0.497

1 mmol, 50% yield). TLC 10% ethyl acetate-hexanes, Rf = 0.62 (UV, KMnO4). H

NMR (400 MHz, CDCl3) d 7.29 – 7.24 (m, 2H), 7.21 – 7.15 (m, 1H), 7.09 (m, 3H),

6.93 (d, J = 2.6 Hz, 1H), 6.56 (d, J = 8.8 Hz, 1H), 3.15 – 3.10 (m, 1H), 3.00 – 2.94 (m,

1H), 2.87 (s, 3H), 2.20 (ddd, J1 = 13.4 Hz, J2 = 5.9 Hz, J3 = 3.9 Hz, 1H), 1.99 (ddd, J1

13 = 13.5 Hz, J2 = 9.6 Hz, J3 = 4.2 Hz, 1H), 1.71 (s, 3H). C NMR (101 MHz, CDCl3) d

149.6, 144.9, 131.0, 128.2, 128.1, 127.4, 127.2, 126.0, 120.7, 112.1, 47.6, 41.3, 39.4,

38.5, 29.7. FTIR (neat) 3056, 3023, 2967, 2933, 1596, 1504, 1465, 1444, 1405, 1327,

+ + 1262, 1220, 1115, 801, 764, 700. HRMS: ESI [M+H] Calcd. for C17H19N:

272.1206. Found: 272.1193.

204

H C H3C 3 O N H3C N mCBA 1) Boc2O, DMAP, CH2Cl2, 0 °C Ph CH3 2) TMSCl, 2-phenylpropene, −78 to 23 °C CF3 CF3 3-144 3-109 61%

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.60 equiv) was added to a solution of

N,N-dimethyl-4-trifluoromethyl-aniline-N-oxide 3-chlorobenzoic acid (3-144, 362 mg,

2.60 equiv) and trimethylsilyl chloride (127 µL, 1.00 mmol, 1.00 equiv) were added.

The reaction solution was slowly warmed to 23 °C and stirred at that temperature for

0.5% ethyl acetate-hexanes to 1% ethyl acetate-hexanes) to afford 1,4-dimethyl-4- phenyl-7-trifluormethyl-1,2,3,4-tetrahydroquinoline as a yellow oil (3-109, 185 mg,

0.606 mmol, 61% yield). TLC 10% ethyl acetate-hexanes, Rf = 0.60 (UV, KMnO4).

1 H NMR (400 MHz, CDCl3) d 7.40 (dd, J1 = 8.7 Hz, J2 = 1.8 Hz, 1H), 7.31 – 7.26 (m,

3H), 7.23 – 7.18 (m, 1H), 7.10 (m, 2H), 6.65 (d, J = 8.7 Hz, 1H), 3.20 (dt, J1 = 11.0

Hz, J2 = 4.8 Hz, 1H), 3.04 (ddd, J1 = 11.7 Hz, J2 = 10.3 Hz, J3 = 4.0 Hz, 1H), 2.94 (s,

205

13 3H), 2.24 (m, 1H), 2.02 (m, 1H), 1.76 (s, 3H). C NMR (101 MHz, CDCl3) d 149.0,

148.3, 128.5, 128.3, 127.1, 126.1, 125.4 (q, J = 272 Hz), 125.0 (q, J = 3.0 Hz), 124.9

(q, J = 4.0 Hz), 117.0 (q, J = 32 Hz), 109.9, 47.4, 41.0, 39.0, 37.7, 29.5. FTIR (neat)

3058, 3028, 2969, 2936, 2839, 1617, 1525, 1493, 1445, 1395, 1330, 1286, 1282, 1221,

+ + 1134, 1105, 1062, 810, 765, 701, 576. HRMS: ESI [M+H] Calcd. for C18H19NF3:

306.1470. Found: 306.1455.

H C H3C 3 O 1) Boc2O, DMAP, N H3C N mCBA CH Cl , 0 °C 2 2 Ph 2) TMSCl, 2-phenylpropene, CH3 6 −78 to 23 °C 8 CN NC 3-79 3-110 50% 1.14:1 8-CN: 6-CN

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.60 equiv) was added to a solution of

206

resultant oily residue was purified by flash chromatography (silica gel, grading from

1% ethyl acetate-hexanes to 3% ethyl acetate-hexanes) to afford 3-110 as a colorless oil (isolated as a mixture of regioisomers 1.09:1 8-CN:6-CN (asterisk denotes major peaks),132 mg, 0.503 mmol, 50% yield). TLC 10% ethyl acetate-hexanes, Rf = 0.37

1 (UV, KMnO4). H NMR (400 MHz, CDCl3) d 7.42 – 7.37 (m, 1H), 7.34 – 7.30* (m,

2H), 7.28 (d, J = 1.4 Hz, 1H), 7.26 – 7.22* (m, 3H), 7.22 – 7.17 (m, 1H), 7.15* (dd, J1

= 8.4 Hz, J2 = 7.6 Hz, 1H), 7.12 – 7.05 (m, 2H), 7.01 (d, J = 7.8 Hz, 1H), 6.98 – 6.91

(m, 1H), 6.89* (t, J = 1.5 Hz, 1H), 6.88 – 6.84* (m, 1H), 6.81 (dd, J1 = 8.4 Hz, J2 =

1.2 Hz, 1H), 3.32* (ddd, J1 = 11.7 Hz, J2 = 10.2 Hz, J3 = 3.0 Hz, 1H), 3.22 (ddd, J1 =

11.7 Hz, J2 = 6.1 Hz, J3 = 4.3 Hz, 1H), 3.17 – 3.10* (m, 1H), 3.09 – 3.02 (m, 1H),

2.98* (s, 3H), 2.91 (s, 3H), 2.28 – 2.22 (m, 1H), 2.22 – 2.15* (m, 1H), 2.02 – 1.96 (m,

13 1H), 2.02 – 1.96* (m, 1H), 1.96* (s, 3H), 1.71 (s, 3H). C NMR (101 MHz, CDCl3) d

149.6, 148.7*, 147.5, 146.3*, 134.4*, 133.0, 128.8*, 128.6*, 128.3, 128.3*, 127.5,

127.2, 127.0*, 126.3, 126.2*, 126.1*, 123.1, 119.2, 115.7, 113.3*, 112.8, 110.9*, 47.6,

47.3*, 42.0, 41.6, 41.3*, 40.1, 39.0*, 37.6*, 29.2*, 27.5. FTIR (neat) 3083, 3059,

3024, 2932, 2225, 1598, 1582, 1494, 1445, 1325, 1302, 1262, 1222, 786, 762, 739,

+ + 701. HRMS: ESI [M+H] Calcd. for C18H19N2: 263.1548. Found: 263.1535.

207

1) Boc2O, DMAP, O CH2Cl2, 0 °C N H3C N mCBA 2) TMSCl, 2-phenylpropene, Ph −78 to 23 °C CH3

3-83 3-111 60%

Di-tert-butyl dicarbonate (597 µL, 2.60 mmol, 2.60 equiv) was added to a solution of N-cyclohexyl-N-methylaniline-N-oxide 3-chlorobenzoic acid (3-83, 362 mg, 1.00 mmol, 1 equiv) and 4-(dimethylamino)pyridine (12 mg, 0.010 mmol, 0.10 equiv) in dichloromethane cooled to 0 °C. The resultant solution was stirred at 0 °C for 2 hours. The solution was cooled to -78 °C, then 2-phenylpropene (338 µL, 2.60 mmol, 2.60 equiv) and trimethylsilyl chloride (127 µL, 1.00 mmol, 1.00 equiv) were added. The reaction solution was slowly warmed to 23 °C and stirred at that temperature for 18 hours. The reaction was partitioned between saturated aqueous sodium bicarbonate solution (4 mL) and dichloromethane (5 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 ´ 5 mL). The combined organic layers were dried over sodium sulfate, and the dried solution was concentrated. The resultant oily residue was purified by flash chromatography (silica gel, grading from 0.25% ethyl acetate-hexanes to 0.5% ethyl acetate-hexanes) to afford 1-cyclohexyl-4-methyl-4-phenyl-7-trifluormethyl-1,2,3,4-tetrahydroquinoline as a yellow oil (3-111, 183 mg, 0.599 mmol, 60% yield). TLC 10% ethyl

1 acetate-hexanes, Rf = 0.78 (UV, KMnO4). H NMR (400 MHz, CDCl3) d 7.29 – 7.24

(m, 2H), 7.19 – 7.10 (m, 4H), 7.03 (dd, J1 = 7.7 Hz, J2 = 1.7 Hz, 1H), 6.76 (dt, J1 = 8.4

Hz, J2 = 1.0 Hz, 1H), 6.60 (td, J1 = 7.4 Hz, J2 = 1.1 Hz, 1H), 3.63 (m, 1H), 3.15 (m, 1H), 2.82 (m, 1H), 2.17 (m, 1H), 1.95 (m, 1H), 1.89 – 1.78 (m, 3H), 1.73 (s, 3H), 1.71 – 1.64 (m, 2H), 1.49 – 1.32 (m, 3H), 1.18 – 1.06 (m, 1H). 13C NMR (101 MHz,

CDCl3) d 150.0, 145.3, 129.6, 128.4, 128.0, 127.5, 127.4, 125.7, 115.0, 111.0, 56.7,

208

41.0, 38.5, 38.2, 29.7, 29.5, 29.3, 26.4, 26.2, 26.1. FTIR (neat) 3157, 3028, 2931, 2853, 1599, 1496, 1448, 1342, 1313, 1172, 763, 739, 703. HRMS: ESI+ [M+H]+

Calcd. for C22H28N: 306.2222. Found: 306.2205.

3.4.6 Derivatives of Tetrahydroquinoline Scaffolds

H3C H3C N N O LAH

N THF, 0 to 23 °C N

3-87 3-113 93%

A solution of N-(1-methyl-1,2,3,4-tetrahydroquinoline)-pyrrolidone (3-87, 150 mg,

0.650 mmol, 1 equiv.) in tetrahydrofuran (26 mL) was added to an emulsion of lithium aluminum hydride (123 mg (3.23 mmol, 4.97 equiv) in tetrahydrofuran (13 mL) cooled to 0 °C. The reaction mixture was slowly warmed to 23 °C and stirred for 3 h.

The excess lithium aluminum hydride was quenched with water (20 mL). The layers were partitioned with dichloromethane (20 mL) and the aqueous layer was extracted with CH2Cl2 (2 ´ 20 mL). The organic layers were combined, dried over Na2SO4, and concentrated to yield N-(1-methyl-1,2,3,4-tetrahydroquinoline)-pyrrolidine as a dark orange oil (3-113, 131 mg, 0.606 mmol, 93% yield). TLC 50% ethyl acetate-hexanes,

1 Rf = 0.10 (UV, KMnO4). H NMR (400 MHz, CDCl3) d 7.13 (m, 1H), 7.05 (dd, J1 =

7.3 Hz, J2 = 1.7 Hz, 1H), 6.59 – 6.52 (m, 2H), 3.65 – 3.57 (m, 1H), 3.26 (t, J = 3.7 Hz,

1H), 3.15 – 3.09 (m, 1H), 2.93 (s, 3H), 2.69 (m, 2H), 2.43 (m, 2H), 2.17 – 2.10 (m,

13 1H), 1.84 (m, 1H), 1.78 – 1.69 (m, 4H). C NMR (101 MHz, CDCl3) d 145.7, 130.1,

128.6, 122.9, 114.4, 110.5, 61.0, 51.5, 46.7, 38.7, 25.7, 23.5. FTIR (neat) 3064, 3027,

209

2963, 2872, 2783, 2711, 1605, 1573, 1508, 1452, 1430, 1331, 1201, 1123, 1000, 742.

+ + HRMS: ESI [M+H] Calcd. for C14H21N2: 217.1705. Found: 217.1699.

H3C H3C H3C N O 1) LDA, THF, −78 °C N O N O N N CH3 N CH3 2) CH I, −78 to 23 °C 3 H H H H

3-87 3-114 3-115 29% 20% n-Butyllithium (0.65 mL, 1.80 M in hexanes, 1.18 equiv) was added to a solution of diisopropylamine (181 µL, 1.28 mmol, 1.28 equiv) in tetrahydrofuran (10 mL) cooled to -78 °C. The resultant solution was stirred for 15 min at -78 °C after which a solution of N-(1-methyl-1,2,3,4-tetrahydroquinoline)-pyrrolidone (3-87, 246 mg, 1.07 mmol, 1 equiv.) in tetrahydrofuran (1 mL) was added. The solution was stirred for 90 minutes at which time iodomethane (133 µL, 2.14 mmol, 2.00 equiv) was added. The reaction solution was slowly warmed to 23 °C and stirred for 2 h. The excess lithium diisopropylamide was quenched with saturated aqueous ammonium chloride solution

(10 mL). The layers were partitioned, and the aqueous layer was extracted with

CH2Cl2 (3 ´ 10 mL). The organic layers were combined, dried over Na2SO4, and concentrated. The resultant oily residue was purified by flash chromatography (silica gel, grading from 10% ethyl acetate-hexanes to 60% ethyl acetate-hexanes) to yield

S5-methyl-N-(1-methyl-1,2,3,4-tetrahydroquinoline)-pyrrolidone as a white solid (3-

114, 76 mg, 0.31 mmol, 29% yield) and R5-methyl-N-(1-methyl-1,2,3,4- tetrahydroquinoline)-pyrrolidone as a yellow oil (3-115, 52 mg, 0.21 mmol, 20% yield).

210

S5-methyl-N-(1-methyl-1,2,3,4-tetrahydroquinoline)-pyrrolidone (3-114): TLC 50%

1 ethyl acetate-hexanes, Rf = 0.25 (UV, KMnO4). mp 97-99 °C. H NMR (400 MHz,

CDCl3) d 7.13 (m, 1H), 6.83 (dt, J1 = 7.5 Hz, J2 = 1.4 Hz, 1H), 6.66 – 6.59 (m, 2H),

5.41 (dd, J1 = 9.2 Hz, J2 = 5.9 Hz, 1H), 3.38 – 3.31 (m, 1H), 3.22 – 3.12 (m, 2H), 3.06

– 3.00 (m, 1H), 2.88 (s, 3H), 2.59 (m, 1H), 2.22 – 2.12 (m, 2H), 2.07 – 1.99 (m, 1H),

13 1.63 – 1.57 (m, 1H), 1.25 (d, J = 7.2 Hz, 3H). C NMR (101 MHz, CDCl3) d 178.1,

147.6, 128.6, 127.9, 119.9, 116.8, 111.9, 49.6, 48.1, 41.7, 39.5, 37.3, 27.4, 26.9, 16.4.

FTIR (neat) 3027, 2960, 2871, 2820, 1685, 1603, 1504, 1454, 1420, 1327, 1291, 1264,

+ + 1208, 749. HRMS: ESI [M+H] Calcd. for C15H21N2O: 245.1654. Found: 245.1648.

R5-methyl-N-(1-methyl-1,2,3,4-tetrahydroquinoline)-pyrrolidone (3-115): TLC 50%

1 ethyl acetate-hexanes, Rf = 0.14 (UV, KMnO4). H NMR (400 MHz, CDCl3) d 7.12

(m, 1H), 6.84 (dt, J1 = 7.5 Hz, J2 = 1.4 Hz, 1H), 6.63 (m, 2H), 5.40 (dd, J1 = 9.6 Hz, J2

= 6.0 Hz, 1H), 3.33 (m, 1H), 3.22 – 3.11 (m, 2H), 3.09 – 3.01 (m, 1H), 2.87 (s, 3H),

2.59 – 2.49 (m, 1H), 2.21 (m, 1H), 2.16 – 2.06 (m, 1H), 2.03 (m, 1H), 1.55 (dq, J1 =

13 12.5 Hz, J2 = 8.8 Hz, 1H), 1.27 (d, J = 7.2 Hz, 3H). C NMR (101 MHz, CDCl3) d

177.8, 147.5, 128.5, 127.1, 120.0, 116.8, 111.8, 49.6, 47.9, 41.4, 39.4, 37.3, 27.7, 26.6,

16.5. FTIR (neat) 3027, 2960, 2929, 2871, 1685, 1603, 1503, 1454, 1423, 1327, 1295,

+ + 1264, 1208, 749. HRMS: ESI [M+H] Calcd. for C15H21N2O: 245.1654. Found:

245.1648.

211

H C H3C 3 N O mCPBA O N O

N N CH2Cl2, 23 °C

3-87 3-117 63%

A solution of N-(1-methyl-1,2,3,4-tetrahydroquinoline)-pyrrolidone (3-87, 203 mg,

0.881 mmol, 1 equiv) in dichloromethane (2 mL) was added to a solution of meta- chloroperbenzoic acid (77%, 217 mg, 0.968 mmol, 1.10 equiv) in dichloromethane (3 mL) at 23 °C and stirred for 90 minutes. The solution was concentrated and purified by flash chromatography (basic alumina, dichloromethane followed by 5% methanol– dichloromethane) to yield N-(1-methyl-1,2,3,4-tetrahydroquinoline N-oxide)- pyrrolidone as a white solid (3-117, 136 mg, 0.552 mol, 63%). TLC 50% ethyl

1 acetate-hexanes, Rf = 0.00 (UV, KMnO4). mp 99-101 °C. H NMR (400 MHz,

CDCl3) d 7.93 (d, J = 8.3 Hz, 1H), 7.41 (m, 1H), 7.32 (m, 1H), 7.08 (dd, J1 = 7.8 Hz,

J2 = 1.2 Hz, 1H), 5.50 (dd, J1 = 10.0 Hz, J2 = 6.3 Hz, 1H), 3.90 – 3.81 (m, 2H), 3.64

(s, 3H), 3.40 – 3.34 (m, 1H), 3.12 – 3.07 (m, 1H), 2.97 (m, 1H), 2.54 – 2.49 (m, 2H),

13 2.07 (m, 4H). C NMR (101 MHz, CDCl3) d 176.0, 149.7, 129.7, 129.1, 127.9,

127.0, 121.4, 67.7, 61.9, 46.8, 43.2, 31.2, 22.7, 18.3. FTIR (neat) 3206, 2948, 1676,

1489, 1453, 1420, 1286, 1224, 767, 676. HRMS: ESI+ [M+H]+ Calcd. for

C14H19N2O2: 247.1447. Found: 247.1440.

212

H3C H3C N O O N O 1) SOBr2, THF, −78 °C N N 2) NEt3, −78 to 23 °C

Br 3-117 3-118 28% (NMR)

Thionyl bromide (41 µL, 0.51 mmol, 1.0 equiv) was added dropwise to solution of the

N-(1-methyl-1,2,3,4-tetrahydroquinoline-N-oxide)-pyrrolidone (3-117, 126 mg, 0.510 mmol, 1 equiv) in tetrahydrofuran (4 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 4 h whereupon triethylamine (284 µL, 2.04 mmol, 4.00 equiv) was added. The cooling bath was removed, and resultant mixture was allowed to warm to

23 °C and was stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated, and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with 15% acetone–hexanes, grading to 25% acetone–hexanes) to afford N-(7-bromo-1-methyl-1,2,3,4-tetrahydroquinoline)- pyrrolidone (3-118, isolated as a mixture, asterisk denotes minor peaks, 55 mg, 28%

1 NMR yield). TLC 50% ethyl acetone–hexanes, Rf = 0.41 (UV, KMnO4). H NMR

(400 MHz, CDCl3) d 7.18 (ddd, J1 = 8.8 Hz, J2 = 2.5 Hz, J3 = 0.7 Hz, 1H), 7.14* (m,

1H), 6.92 (dd, J1 = 2.4 Hz, J2 = 1.1 Hz, 1H), 6.87* (dt, J1 = 7.6 Hz, J2 = 1.3 Hz, 1H),

6.67 – 6.59* (m, 1H), 6.45 (d, J = 8.8 Hz, 1H), 5.42* (dd, J1 = 9.4 Hz, J2 = 5.9 Hz,

1H), 5.36 (dd, J1 = 9.6 Hz, J2 = 5.9 Hz, 1H), 3.33 (m, 1H), 3.33* (m, 1H), 3.26 – 3.19

213

(m, 2H), 3.26 – 3.19* (m, 1H), 3.19 – 3.08 (m, 1H), 3.19 – 3.08* (m, 2H), 2.87* (s,

3H), 2.85 (s, 3H), 2.49 (m, 2H), 2.49* (m, 2H), 2.17 – 2.08 (m, 1H), 2.17 – 2.08* (m,

13 1H), 2.07 – 1.95 (m, 3H), 2.07 – 1.95* (m, 3H). C NMR (101 MHz, CDCl3) d

175.5, 175.4*, 147.5*, 146.3, 131.1, 129.7, 128.5*, 127.5*, 121.2, 119.8*, 116.7*,

113.3, 111.8*, 108.5, 49.5*, 49.3, 47.8*, 47.6, 43.5*, 43.3, 39.3*, 39.2, 31.5*, 31.3,

26.7*, 26.4, 18.3, 18.3*. FTIR (neat) 2948, 2826, 1684, 1594, 1500, 1460, 1419,

+ + 1325, 1283, 1210, 1104, 803. HRMS: ESI [M+H] Calcd. for C17H18BrN2O:

309.0603. Found: 309.0596.

H C H3C 3 N O O N O mCPBA N N CH2Cl2, 23 °C

Cl Cl 3-89 3-120 83%

A solution of N-(7-chloro-1-methyl-1,2,3,4-tetrahydroquinoline)-pyrrolidone (3-89,

196 mg, 0.740 mmol, 1 equiv) in dichloromethane (2 mL) was added to a solution of meta-chloroperbenzoic acid (77%, 245 mg, 1.09 mmol, 1.47 equiv) in dichloromethane (3 mL) at 23 °C and stirred for 90 minutes. The solution was concentrated and purified by flash chromatography (basic alumina, dichloromethane followed by 5% methanol–dichloromethane) to yield N-(7-chloro-1-methyl-1,2,3,4- tetrahydroquinoline N-oxide)-pyrrolidone as a pale yellow solid (3-120, 172 mg, 0.613 mmol, 83% yield). TLC 50% ethyl acetate-hexanes, Rf = 0.00 (UV, KMnO4). mp

1 54-56 °C. H NMR (400 MHz, CDCl3) d 7.89 (d, J = 9.0 Hz, 1H), 7.38 (ddd, J1 = 9.0

214

Hz, J2 = 2.4 Hz, J3 = 0.9 Hz, 1H), 7.05 (dd, J1 = 2.5 Hz, J2 = 1.1 Hz, 1H), 5.47 (dd, J1

= 9.9 Hz, J2 = 6.3 Hz, 1H), 3.93 – 3.87 (m, 2H), 3.66 (s, 3H), 3.43 – 3.33 (m, 2H),

3.12 (m, 1H), 2.94 (m, 1H), 2.55 – 2.49 (m, 2H), 2.12 – 2.05 (m, 2H). 13C NMR (101

MHz, CDCl3) d 175.9, 147.6, 135.2, 129.8, 129.2, 127.4, 123.0, 67.4, 61.6, 46.4, 43.0,

30.9, 22.3, 18.2. FTIR (neat) 3182, 2949, 1683, 1577, 1473, 1419, 1285, 1196, 1119,

+ + 854, 729, 554. HRMS: ESI [M+H] Calcd. for C14H18ClN2O2: 281.1057. Found:

281.1051.

H C 3 H3C O N O N O 1) SOCl2, THF, −78 °C Cl N N 2) NEt3, −78 to 23 °C

Cl Cl 3-120 3-121 34%

A solution of thionyl chloride (46 µL, 0.50 mmol, 1.0 equiv) in tetrahydrofuran (1 mL) was added dropwise in two portions over a period of 2 h to a solution of the N-(7- chloro-1-methyl-1,2,3,4-tetrahydroquinoline-N-oxide)-pyrrolidone (3-120, 140 mg,

0.499 mmol, 1 equiv) in tetrahydrofuran (3 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 2 h whereupon triethylamine (278 µL, 1.99 mmol, 4.00 equiv) was added. The cooling bath was removed, and resultant mixture was allowed to warm to 23 °C and stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated, and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried

215

solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, grading from 15% acetone-hexanes to 20% acetone-hexanes) to afford N-(7,9-dichloro-1-methyl-1,2,3,4-tetrahydroquinoline)- pyrrolidone as a pale-yellow oil (3-121, 50 mg, 0.17 mmol, 34% yield). TLC 50%

1 acetone-hexanes, Rf = 0.52 (UV, KMnO4). H NMR (400 MHz, CDCl3) d 7.23 (d, J

= 2.4 Hz, 1H), 6.87 (d, J1 = 2.5 Hz, 1H), 5.36 (dd, J1 = 9.3 Hz, J2 = 6.7 Hz, 1H), 3.30

– 3.21 (m, 2H), 3.19 – 3.13 (m, 1H), 3.06 (m, 1H), 2.87 (s, 3H), 2.52 – 2.46 (m, 2H),

13 2.02 (m, 3H), 1.89 (m, 1H). C NMR (101 MHz, CDCl3) d 175.6, 145.6, 130.4,

129.7, 128.4, 127.2, 126.0, 50.2, 47.9, 43.0, 42.4, 31.2, 21.3, 18.3. FTIR (neat) 2950,

1686, 1554, 1469, 1442, 1417,1284, 1269, 1167, 1118, 865, 812. HRMS: ESI+

+ [M+H] Calcd. for C14H17Cl2N2O: 299.0718. Found: 299.0713.

H C H3C 3 N O N Ph mCPBA Ph CH 3 CH3 CH2Cl2, 23 °C

CN CN 3-106 3-123 74%

A solution of 4-dimethyl-1,2,3,4-tetrahydroquinoline-7-carbonitrile (3-106, 280 mg,

1.07 mmol, 1 equiv) in dichloromethane (2 mL) was added to a solution of meta- chloroperbenzoic acid (77%, 266 mg, 1.18 mmol, 1.10 equiv) in dichloromethane (3 mL) at 23 °C and stirred for 60 minutes. The solution was concentrated and purified by flash chromatography (basic alumina, dichloromethane followed by 5% methanol– dichloromethane) to yield 1,4-dimethyl-1,2,3,4-tetrahydroquinoline-7-carbonitrile N-

216

oxide as a white solid (3-123, mixture of diastereomers, asterisk denotes minor diastereomer, 220 mg, 0.791 mmol, 74% yield). TLC 10% ethyl acetate-hexanes, Rf

1 = 0.00 (UV, KMnO4). mp 65-67 °C. H NMR (400 MHz, CDCl3) d 8.47 (d, J = 8.7

Hz, 1H), 8.38* (d, J = 8.4 Hz, 1H), 7.68 (m, 1H), 7.68* (m, 1H), 7.37 – 7.27 (m, 4H),

7.37 – 7.27* (m, 4H), 7.07 (m, 2H), 7.07* (m, 2H), 3.93 (m, 1H), 3.93* (m, 1H), 3.75

(m, 1H), 3.75* (m, 1H), 3.59 (s, 3H), 3.58* (s, 3H), 2.65 (m, 1H), 2.59* (m, 1H), 2.39

13 (m, 1H), 2.29* (m, 1H), 1.86* (s, 3H), 1.83 (s, 3H). C NMR (101 MHz, CDCl3) d

153.3*, 152.8, 146.9*, 146.9, 137.9, 137.6*, 134.2, 134.0*, 131.6, 131.6*, 129.0,

128.8*, 127.3, 127.2*, 126.9*, 126.7, 123.7, 123.6*, 117.6, 117.6*, 113.2*, 113.1,

66.3, 65.5*, 62.6, 53.4*, 41.8, 41.0*, 37.0*, 36.6, 29.5*, 29.1. FTIR (neat) 3239,

3026, 2973, 2231, 1602, 1495, 1478, 1444, 900, 848, 765, 732, 702. HRMS: ESI+

+ [M+H] Calcd. for C18H19N2O: 279.1497. Found: 279.1491.

H C 3 H3C O N N Ph 1) SOCl2, THF, −78 °C Cl Ph CH CH3 3 2) NEt3, −78 to 23 °C

CN CN 3-123 3-124 32%

A solution of thionyl chloride (56 µL, 0.76 mmol, 1.0 equiv) in tetrahydrofuran

(1 mL) was added dropwise in two portions over a period of 2 h to a solution of the 4- dimethyl-1,2,3,4-tetrahydroquinoline-7-carbonitrile-N-oxide (3-123, 212 mg, 0.763 mmol, 1 equiv) in tetrahydrofuran (3 mL) at –78 °C. The resultant mixture was stirred at –78 °C for 2 h whereupon triethylamine (425 µL, 3.05 mmol, 4.00 equiv) was

217

added. The cooling bath was removed, and resultant mixture was allowed to warm to

23 °C and stirred at that temperature for 45 min. The resultant mixture was diluted with saturated aqueous sodium bicarbonate solution (4 mL), the layers were separated, and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organic layers were dried over anhydrous sodium sulfate and the dried solution was concentrated. The resultant oily residue was purified by flash column chromatography

(silica gel, starting with 1% ethyl acetate–hexanes, grading to 5% ethyl acetate– hexanes) to afford 9-chloro-4-dimethyl-1,2,3,4-tetrahydroquinoline-7-carbonitrile as a yellow solid (3-124, 72 mg, 0.24 mmol, 32% yield). TLC 10% ethyl acetate-hexanes,

1 Rf = 0.40 (UV, KMnO4). mp 106-107 °C. H NMR (400 MHz, CDCl3) d 7.49 (d, J =

2.0 Hz, 1H), 7.31 – 7.27 (m, 2H), 7.24 – 7.20 (m, 2H), 7.05 – 7.01 (m, 2H), 3.26 –

3.21 (m, 1H), 3.01 (s, 3H), 2.84 – 2.78 (m, 1H), 2.24 – 2.19 (m, 1H), 1.94 – 1.89 (m,

13 1H), 1.69 (s, 3H). C NMR (101 MHz, CDCl3) d 149.2, 147.5, 137.5, 133.2, 130.2,

128.5, 126.7, 126.5, 123.5, 119.0, 101.8, 48.8, 43.1, 41.9, 36.7, 29.1. FTIR (neat)

3057, 3023, 2970, 2938, 2221, 1596, 1513, 1493, 1419, 1325, 1226, 828, 766, 701.

+ + HRMS: ESI [M+H] Calcd. for C18H18ClN2: 297.1159. Found: 297.1152.

218

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PREPARATION OF 2-SUBSTITUTED INDOLES VIA REARRANGEMENT OF N,N-DIMETHYLANILINE N-OXIDES

4.1 Introduction

The nitrogenous heterocycle indole represents one of the most commonly found heterocycles in bioactive compounds and natural products.1 In addition, indoles can be found in ligands used both in transition metal catalysis2 and metal complexes with biological activity.3 Many pharmaceuticals currently prescribed in the US4-8 and potential therapeutics contain indole scaffolds (Figure 4.1).9-10

Sumatriptan (4-1), also known as Imitrex, is a selective serotonin receptor agonist currently prescribed as a rescue medication to treat migraines and cluster headaches;4 in 2017, medical professional prescribed sumatriptan to patients over eight million times.5 Indomethacin (4-2), a non-steroidal anti-inflammatory drug sold under the brand names Indocid and Indocin, treats severe pain, stiffness, and swelling associated with osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis;6 patients received about 1.3 million prescriptions of indomethacin in 2017.7

Delaviridine (4-3), a non-nucleoside reverse transcriptase inhibitors sold under the brand name Rescriptor, treats HIV and reduces a patient’s chances of developing

AIDS by decreasing the amount HIV in their blood.8

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O H C O Cl CH3 3 O N CH3 NH N O S N N N HN NH CH3 S CH3 H CO O 3 OH NH O N H O H3C CH3 sumatriptan (4-1) indomethacin (4-2) delaviridine (4-3) Figure 4.1: Examples of indoles in prescription medications

A number of natural products that have a history in indigenous cultures and traditional medicines contain indoles (Figure 4.2).9-11 Ibogaine (4-4) is an indole alkaloid isolated from the rainforest shrub in West Africa, Tabernanthe iboga. The bark and roots of the shrub have been used to create a near-death experience in religious ceremonies of some indigenous cultures.9 In Western medicine, ibogaine has been studied as a potential treatment for opioid addiction.10 Reserpine (4-5) was isolated from the East Asian flower Ravolfia serpentia, a plant used in traditional medicine to treat insanity, fever, and snake bites.11 Resperine has been used to treat high blood pressure by causing a patient’s heartbeat to slow and blood vessels to relax through slowing the activity of the nervous system; however, it is no longer available in the US.12

OCH3 O CH3 H N N OCH3 H3CO O H CO N H OCH3 N 3 H H H OCH O 3 OCH3 ibogaine (4-4) reserpine (4-5) Figure 4.2: Examples of indoles in natural products used in traditional medicines and cultures

224

There are particular types of substituted indoles like 2-reverse prenylated indoles that are a target of the synthetic community due to their bioactivity and potential as therapeutics (Figure 4.3).13 Gypsetin (4-6) is an acylCoA:cholesterol acyltransferase inhibitor with potential as a drug discovery lead.14 Brevianamide S (4-

7) is a potential antitubercular therapeutic with antibacterial activity.15 Fellutanines B and C (4-8 and 4-9), isolated from cultures of Penicillium fellutanum, have shown anticancer activity.16 Ambiguine H (4-10), a potential antimicrobial agent isolated from Fischerella ambigua,17 and fumigaclavine C (4-11), a potential anti-cancer therapeutic isolated from marine-derived fungus Aspergillus Fumigatus,18 both contain

2-reverse prenylated indoles.

H3C O H O H3C N R H N N OH HN HN O N HO H R N O NH H3C CH3 O H NH R= N CH O 3 CH3 gypsetin (4-6) brevianamide S (4-7)

H3C CH3 O N R CH3 H NH H C H NH 3 AcO H3C N H HN HN H C CH3 CH3 CH 3 CH3 O CH CH3 3 N N H H fellutanine B, R = H (4-8) ambiguine H (4-10) fumigaclavine C (4-11) fellutanine C (4-9)

R = H3C CH3

Figure 4.3: Examples of reverse prenylated indoles in bioactive compounds

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4.1.1 An Overview of Indole Synthesis

The preparation of indoles has a long-documented history. For over a century, many different indole syntheses using organic reagents19 and transition metal methods20 have been described. The most common methods to prepare indoles include the Bartoli, Fischer, Larock, and Madelung indole syntheses (Figure 4.5). The

Bartoli synthesis uses nitroarenes (4-12) and vinyl Grignard reagents (4-13) to prepare substituted indoles (4-14) at low temperatures; however, organometallic reagents tolerate a limited substrate scope and N-substitution must be installed in an additional step (Figure 4.5, eq 1).21 The Fischer method prepares substituted indoles from the acid catalyzed reaction of a ketone (4-16) and an arylhydrazine (4-15) (Figure 4.5, eq

2).22 The Larock methodology uses transition metal catalysis to prepare a substituted indole (4-20) from an ortho-iodoaniline (4-18) and an alkyne (4-19) (Figure 4.5, eq 3).

Unfortunately, palladium catalysts can be costly and require functionalized aniline substrates and elevated temperatures.23 The Madelung synthesis intramolecularly prepares substituted indoles (4-22) from ortho-alkylanilides (4-21) using strong bases and elevated temperatures (Figure 4.5, eq 4).24 Despite the number of different indole syntheses that have been described, certain substitution patterns such as 2-reverse prenylated indoles, remain difficult to prepare.

226

Bartoli Indole R3 R3 Synthesis R1 + R2 R1 R2 MgX solvent (1) NO2 N low temperature H 4-12 4-13 4-14

2 3 R NH2 Fischer Indole R N O Synthesis R3 1 + 3 3 R R R catalytic acid (2) R1 N [3,3] rearrrengement R2 4-15 4-16 4-17

2 4 R R3 R NH Larock Indole Synthesis I + R1 R3 0 II (3) R1 Pd or Pd N 4 R ligand, base, MCl R2 4-18 4-19 4-20

O Madelung Indole R3 R2 NH Synthesis R1 R2 (4) R3 strong base 1 N R high temperature H 4-21 4-22 Figure 4.4: Examples of common indole syntheses

4.1.2 Methods of Preparing 2-Reverse Prenylated Indoles

2-Reverse prenylated indole alkaloids are some of the most challenging natural product targets in total synthesis.25 Methodologies to prepare these 2-reverse prenylated indoles are especially scarce and have limited scope (Figure 4.6).26-29

Casnati and Pochini describe a rearrangement of an N-prenylated indole (4-23) using trifluoroacetic acid (TFA) to produce a 2-reverse prenylated indole (4-24) in 50% yield; however, the 2-prenylated indole (4-25) is also produced in equal yield (Figure

4.6, eq 1).26 Kawasaki et al. employed a Claisen rearrangement of indole 4-28 to produce a 2-reverse prenylated 3-oxindole (4-29) in 32% yield and a 2-prenylated 3- oxindole (4-30) in 20% yield (Figure 4.6, eq 2).27 Similarly, Plieninger et al. prepared

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2-reverse prenylated 3-thioindole (4-34) from a thia-Claisen rearrangement of indole thioether 4-33 in 53% yield (Figure 4.6, eq 3).28 Recently, Chen et al. employed microwave heating to install 2-reverse prenyl functionality in indoles in a tandem N- alkylation-aza-Cope rearrangement and subsequent Wittig reaction in 37-85% yield

(Figure 4.6, eq 3).29

CH3 N H3C TFA CH + 3 CH3 (1) 4-23 24 h N N H H CH3 H C 3 4-24 4-25 50% 50%

4-27 CH3 CH O 3 O O O H3C HO CH3 CH CH3 3 + CH3 (2) N TsOH, MgSO4 N N 80 °C N Ac Ac Ac CH Ac 3 4-26 4-29 4-30 4-28 32% 20%

4-32 CH3 CH H C SH 3 FSO CH 3 Br CH3 S 3 3 S NaOAc K2CO3 H3C CH3 CH3 (3) N acetone, 0 °C PhH, 2 h H N N H H 4-31 4-33 4-34 88% 53%

1) CH CN Br 3 rt-50 °C Ph3PCH3Br N 5-80 min O nBuLi 1 + R1 R1 R CH 3 N CH3 N CH3 N 2) iPrOH/H2O CH3 THF, 0 °C to rt CH3 (4) 2 2 R2 CH MW 100 °C R R 3 1.5 h 4-35 4-36 4-37 4-38 11 examples R1 = H, R2 = Ms 37-85% yield quant. Figure 4.5: Methodologies for 2-reverse prenylation of indoles

With the limited examples of indole 2-reverse prenylation methodologies, targeted methods to prepare 2-reverse prenylated indoles can be found in the total

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syntheses of indole alkaloids (Figure 4.7).30-31 In the synthesis of gypsetin,

Schkeryantz et al. used tert-butyl hypochlorite (tBuOCl) and prenyl-9-BBN (4-41) to prepare a 2-reverse prenylated indole (4-43) was prepared in 95% yield (Figure 4.7, eq

1).30 In the synthesis of okaramine N, Baran et al. treated indole 4-44 with palladium

(II) acetate to achieve an intramolecular 2-reverse prenylation in 44% yield (Figure

4.7, eq 2).31 Overall, the limited substrate scope and undesirable byproduct formation found in existing 2-reverse prenylation methodologies necessitates the development of a robust, tolerant, selective, and efficient method for the preparation of synthetically interesting 2-reverse prenylated indoles.

4-41 CH3

H C CO2CH3 3 CO2CH3 CO CH H3CO2C 2 3 PhthHN 9-BBN proton tBuOCl NHPhth PhthHN Cl H transfer NHPhth (1) H3C CH3 CH3 NEt3, THF CH3 −78 °C N N N N H H 4-39 4-40 4-42 4-43 95%

H3C H3C CH CH3 3 N N

FmocHN 1 equiv Pd(OAc) FmocHN 2 H H3CO2C H CO C H 3 2 O AcOH:dioxane:H2O (2) H N N O 1 atm O2 H 25 °C, 16 h

N H N CH3 H3C CH3 H CH3 4-44 4-45 44% Figure 4.6: Examples of 2-reverse prenylation of indoles from total syntheses

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4.1.3 Use of N–O Bonds in Indole Synthesis

There are two examples of aniline N-oxides being used for indole synthesis and both employ transition metal catalysis (Figure 4.8).32-33 Huang et al. described a

Larock-type indole synthesis in which N,N-dialkylaniline N-oxides (4-46) and symmetric substituted alkynes (4-47) are treated with catalytic amounts of a rhodium catalyst and silver hexafluoroantimonate(V) to produce N-alkyl-2,3-diarylindoles (4-

50) in 40-92% yield (Figure 4.8, eq 1).32 Li et al. describe very similar reaction conditions and starting materials to prepare 2,3-diaryl and 2,3-dialkyl indoles in 22-

95% yield; however, the 2,3-dialkylindoles were produced in lower yields than the

2,3-diarylindole substrates (Figure 4.8, eq 2).33 Although these methodologies use expensive transition metal catalysts and are not well suited for preparing 2- reverseprenylated indoles, they testify to the ability of aniline N-oxides to contribute a method to synthesize 2-reverse prenylated indoles.

R2 3 O R3 [RhCp*Cl2]2 (5 mol%) R 2 R N AgSbF6 (30 mol%) + R1 R4 1 CyCO2H (2 equiv) N R 4 (1) R CH3OH, 60 °C, 24 h R2 4-46 4-47 4-48 32 examples 40-92%

R2 3 O R3 [RhCp*Cl2]2 (5 mol%) R 2 R N AgBF6 (2 equiv) + R1 R4 1 MesCO2H (1 equiv) N R 4 (2) R tBuOH, 115 °C, 10 h R2 4-49 4-50 4-51 44 examples 22-95% Figure 4.7: Aniline N-oxides in indole synthesis

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4.1.4 Proposed Synthesis

We proposed a metal-free and general synthesis of 2-substituted indoles from aniline N-oxides in three steps (Figure 4.9). This synthetic route offers the advantage of being tailorable to any desired 2-substituted indole (4-59). The first step in this route is the activation of an aniline N-oxide (4-52) by a substituted β-keto acyl chloride (4-53) to produce a reactive intermediate (4-54), which will readily excise the

N–O bond to produce functionalized aniline 4-56 (Figure 4.9, eq 1). This aniline substrate can be N-demethylated and undergo a subsequent enamine cyclization to form the desired 2-substituted indole (4-59) (Figure 4.9, eq 2). As 2-reverse prenylated indoles are of specific interest to the synthetic community, a β-keto acyl chloride (4-61) can be prepared exclusively for the synthesis of 2-reverse prenylated indoles (4-63) (Figure 4.9, eq 3).

2 4-53 2 R R 2 2 O O O O OH R CH3 R CH3 H3C N H3C N N N O N−O Bond R3 + R3 Cl R3 Excision −H (1) R1 R1 R1 H R1 3 Activation R O O 4-52 4-54 4-55 4-56

2 2 2 3 R CH3 R R R N NH Enamine Demethylation Cyclization N R3 R3 (2) R1 R1 O O R1

4-57 4-58 4-59

4-61 O O CH3 H3C 2 R 2 R2 O R CH3 H C N Cl N 3 H3C CH3 N H3C CH3 (3)

R1 R1 R1 O 4-60 4-62 4-63 Figure 4.8: Proposed route for C2 substituted indole synthesis

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The key aniline N-oxide functionalization step in this synthesis is precedented in the literature (Figure 4.10).34-35 In N-arylhydroxylamine chemistry, a successful rearrangements employing a similar 1,3-dicarbonyl compound to produce a similar product (4-66) has been described (Figure 4.10, eq 1).34 Likewise in aniline N-oxide chemistry, treatment of N,N-dimethylaniline N-oxides with diketene (4-68) and acyl chlorides 4-72 produces a structurally similar products (Figure 4.10, eq 2).

R2 O O R2 O OH R2 N N NH 3 O toluene O [3,3] R R1 R1 R1 (1) R3 R3 O 110 °C −CO2 30-90 min 4-64 4-65 4-66 40-82%

H3C 4-68 H3C O O OH H3C CH3 H3C N O H3C N N O O [3,3] CH3 (2) CH3 O CH2Cl2, 0 °C −CO2

4-67 4-69 4-70 38%

O 4-72 H C EWG 3 O Cl H3C CH3 H3C N 1) N CH2Cl2, −78 °C EWG (3) R R 2) NEt3, CH2Cl2 −78 to 23 °C 4-71 4-73 EWG = CN, CO2Et 37-65% yield Figure 4.9: N-arylhydroxylamine and aniline N-oxide precedent for the proposed 2- substitued indole synthesis

4.2 Results and Discussion

4.2.1 Substrate Preparation

2,2-Dimethyl-3-butenoacetic acid (4-80), the substrate needed to synthesize 2- reverse prenylated indoles, was prepared from ethyl isobutyrate (4-74) in five steps

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(Figure 4.11).36 An aldol reaction between ethyl isobutyrate and acetaldehyde produced ethyl 3-hydroxy-2,2-dimethylbutanoate (4-75) in 66% yield. The alcohol was subsequently activated with para-toluenesulfonyl chloride (TsCl) and eliminated using 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) to prepare alkene 4-77 in 48% yield over two steps. An addition of the lithium enolate of ethyl acetate onto 4-77 in a

Claisen condensation produced β-keto ester 4-79 in 75% yield. This β-keto ester was saponified with sodium hydroxide (NaOH) to furnish β-keto acid (4-80) in 74% yield.

This compound will be used in situ to generate an acyl chloride, which will activate the aniline N-oxide.

O 1) LDA, THF, O OH O OTs O −78 °C, 30 min TsCl DBU CH3 EtO EtO CH EtO CH EtO 3 pyr, 23 °C, 60 h 3 130 °C, 5 h CH 2) acetaldehyde, H C CH H C CH H C CH 3 −78 °C, 30 min 3 3 3 3 3 3 4-74 4-75 4-76 4-77 66% 54% 90%

O O O O O 1) LDA, THF, −78 °C, 45 min NaOH EtO HO EtO CH3 2) O −78 to 23 °C, 2 h THF/H2O, 50 °C H3C CH3 H3C CH3 4-78 EtO 4-79 4-80 75% H3C CH3 74% 4-77 Figure 4.10: Preparation of 2,2-dimethyl-3-butenoacetic acid

2,2-Dimethylpropanoacetic acid was synthesized for the purpose of reaction optimization. This simpler substrate was prepared in a shorter synthetic sequence

(Figure 4.12). In the first step, treatment of the lithium enolate of ethyl acetate (4-81) with pivaloyl chloride (4-82) generated ethyl 2,2-dimethylpropanoacetate (4-83) in

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96% yield. This ester underwent saponification with NaOH to prepare 2,2- dimethylpropanoacetic acid (4-84) in 67% yield.

O O O O O 1) LDA, THF, −78 °C, 45 min NaOH CH3 CH3 EtO HO EtO CH3 2) O −78 to 23 °C, 2 h THF/H2O, 50 °C H3C CH3 H3C CH3 CH3 4-81 Cl 4-83 4-84 H3C CH3 96% 67% 4-82 Figure 4.11: Preparation of 2,2-dimethylpropanoacetic acid

4.2.2 Investigation of N-Demethylation Conditions

We began by screening N-demethylation conditions using simple aniline (4-86) or aniline N-oxide (4-85) substrates to find condition suitable for use on functionalized aniline substrate 4-57 (Table 4.1).37 Neither treatment of N,N-dimethylaniline oxide with iron (II) sulfate heptahydrate nor N,N-dimethylaniline with di-tert-butyl dicarbonate (Boc2O) produced the desired N-methylaniline product (Table 4.1, entries

1 and 2). Reaction of 4,N,N-trimethylaniline with titanium (IV) chloride produced impure product (4-87 (Table 4.1, entry 3). I-9BBN was unable to produce more than trace demethylated product at elevated temperatures (Table 4.1, entries 4 and 5).

Iodine (I2) and calcium oxide (CaO) in tetrahydrofuran (THF) and methanol (CH3OH) produced impure 4,N-dimethylaniline from 4,N,N-trimethylaniline (Table 4.1, entry

6);38 however, these conditions did not successfully produce demethylated product from other aniline substrates (Table 4.1, entries 7-9). Investigations into finding

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suitable demethylation conditions were not pursued any further due to problems encountered in other steps in the proposed indole synthesis.

Table 4.1: Screened demethylation conditions

H C 3 O H3C CH3 N N H3C H H3C N or conditions 2 R R

4 4-85 4-86 4-87 Starting Entry R Conditions Yield 4-87 Material

1 4-85 H FeSO4∙7H2O, CH3OH, 23 °C, 3 h No product Boc O, CH Cl , 23 °C, 6 h 2 4-86 H 2 2 2 No reaction then 30 °C, 14 h TiCl , CH Cl , 0 °C, 30 min 3 4-86 4-CH 4 2 2 7.0:1 4-86:4-87 3 then 23 °C, 14 h 4 4-86 H I-9BBN, CH2Cl2 37 °C, 18 h Trace product 5 4-86 H I-9BBN, DCE, 70 °C, 18 h Trace product I , CaO, THF, CH OH, 0 °C, 6 h 6 4-86 4-CH 2 3 4-87 (impure) 3 then 23 °C, 14 h 7 4-86 H I2, CaO, THF, CH3OH, 0 °C, 3 h No reaction I , CaO, THF, CH OH, 23 °C, 22 8 4-86 H 2 3 No reaction h I , CaO, THF, CH OH, 50 °C, 20 9 4-86 2-CH 2 3 Trace product 3 h

4.2.3 Optimization of Aniline N-Oxide Functionalization

First, the conditions for in situ acyl chlorination of the β-keto acid were investigated using the 2,2-dimethyl-3-butenoacetic acid (4-88) substrate and 4,N,N- trimethylaniline N-oxide (4-90) (Table 4.2). Thionyl chloride (SOCl2) did not prepare any functionalized product (Table 4.2, entries 1 and 2). When using oxalyl chloride

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((COCl)2), the enol tautomer (4-92) of the expected ketone product (4-93) was observed (Table 4.2, entries 3-6). The optimal conditions from these initial investigations produced the reverse prenylated enol 4-92 in 19% yield (Table 4.2, entry 3).

Table 4.2: Optimization of acyl chloride generation using 2,2-dimethyl-3-butenoacetic acid and 4,N,N-trimethylaniline N-oxide

H3C O H3C N 4-90

CH H3C CH3 H3C CH3 Acid Chloride 3 N H C CH N H C CH O O Formation O O 3 3 3 3 Conditions −78 °C, 1 h HO Cl O OH then NEt3, 23 °C, 4 h H3C CH3 H3C CH3 4-88 4-89 CH3 CH3 4-91 4-92 4-89 Yield Yield Entry Acid Chloride Conditions Equiv 4-91 4-92

1 SOCl2, NEt3, 23 °C, 18 h 1.1 ------2 SOCl2, py, 23 °C, 18 h 0.82 ------3 (COCl)2, py, cat. DMF, 23 °C, 18 h 1.2 --- 19% 4 (COCl)2, py, cat. DMF, 23 °C, 18 h 1.1 --- 9% 5 (COCl)2, py, cat. DMF, 23 °C, 1 h 1.1 --- 5%

Further optimizations of this reaction used 2,2-dimethylpropanoacetic acid (4-

93) and 4,N,N-trimethylaniline N-oxide (4-95) (Table 4.3). In addition to the enol product (4-96), chlorinated aniline (4-97) and aniline N-oxide deoxygenation (4-98) byproducts were observed and isolated. Using oxalyl chloride as the limiting reagent lowered the amount of chloroaniline byproduct observed (Table 4.3, entries 1 and 2).

Addition of a solution of 4-94 to the aniline N-oxide solution decreased the yield of

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chloroaniline byproduct (Table 4.3, entry 4). Both diethyl ether (Et2O) and dichloromethane (CH2Cl2) proved to be viable reaction solvents with comparable yields in enol product (4-96) and minimal chloroaniline byproduct (4-97) formation

(Table 4.3, entries 4-5); however, further optimization attempts did not result in higher yields. Next, we looked into methods to increase the reactivity of the acyl chloride intermediate in an effort to increase the reaction yield.

Table 4.3: Optimization of acyl chloride generation and reaction solvent using 2,2- dimethylpropanoacetic acid and 4,N,N-trimethylaniline N-oxide

H3C O H3C N 4-95

H3C CH3 H3C CH3 N N CH H3C CH3 O O (COCl)2 O O 3 cat. DMF −78 °C, 1 h R CH3 CH3 CH3 HO Cl OH H C CH solvent, 23 °C H C CH then NEt3, 23 °C, 4 h 3 3 time 3 3 4-93 4-94 CH3 CH3

4-96 4-97 (R = Cl) 4-98 (R = H) 4-94 Step 1 4-95 Yield Yield Yield Entry Solvent Equiv Time Equiv 4-96 4-97 4-98

1 1.1 1 h 1 CH2Cl2 16% 42% 8% 2 1.2 4 h 1 CH2Cl2 25% 13% 23% 3 1 4 h 1.2 CH2Cl2 33% 33% 7% 4* 1 4 h 1.2 CH2Cl2 36% 8% 6% 5* 1 4 h 1.2 THF 27% 10% 12% 6* 1 4 h 1.2 Et2O 39% 5% 7% * solution of 4-94 was added to solution of 4-95

Because diketene has precedented reactivity with aniline N-oxides,35a we treated 2,2-dimethylpropanoacetyl chloride with triethylamine (NEt3) to generate the strained diketene intermediate (4-100) in situ (Table 4.4). Different solvents (Table

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4.4, entries 2-4) and reagent equivalents were tested. Using CH2Cl2 as the reaction solvent and 4-101 as the limiting reagent, the enol product was isolated in 44% yield

(Table 4.4, entry 2). Although much could still be done to optimize this reaction, we turned our attention to shifting the equilibrium of the enol tautomer towards the ketone.

Table 4.4: Optimization of reaction solvent in acyl chloride generation and subsequent diketene intermediate using 2,2-dimethylpropanoacetic acid and 4,N,N-trimethylaniline N-oxide

H3C O H3C N 4-101

1) (COCl)2 cat. DMF H3C CH3 H3C CH3 N N CH H3C CH3 O O solvent 3 23 °C, 1 h CH3 −78 °C, 1 h R CH3 CH3 HO O CH3 O OH 2) NEt CH3 then NEt , 23 °C, 4 h H3C CH3 3 3 23 °C, 18 h CH CH 4-99 4-100 3 3 4-102 4-103 (R = Cl) 4-104 (R = H) 4-100 4-101 Yield Yield Yield Entry Solvent Equiv Equiv 4-102 4-103 4-104

1 1 1 CH2Cl2 9% 0% 10% 2 1.3 1 CH2Cl2 44% 7% 23% 3 1.5 1 Et2O trace trace trace 4 1.2 1 THF 3% trace trace

4.2.4 Attempts at Enol Tautomerization

Different conditions were employed to attempt to force the equilibrium of tautomerization from the enol (4-105) to the ketone (4-106) (Table 4.5). Neither acid

(Table 4.5, entries 1-4), base (Table 4.5, entries 5 and 6), nor elevated temperature

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(Table 4.5, entry 7) were successful in shifting the equilibrium by any amount. We believe that the steric bulk of the tert-butyl group locks the substrate in a confirmation in which the enol O-H bond is stabilized and very resistant to tautomerization.

Because of the difficulties encountered with this tautomerization and the N- demethylation, the final step of our proposed indole synthesis, the enamine cyclization, was not investigated.

Table 4.5: Conditions for investigated for shifting tautomerization equilibrium

H3C CH3 H3C CH3 N N H3C CH3 H3C CH3 conditions CH3 CH3 OH O

CH3 CH3 4-105 4-106 Entry Conditions Yield 4-107

1 sat. NH4Cl, 23 °C, 24 h No reaction 2 1M HCl, 23 °C, 24 h No reaction 3 1M HCl, 50 °C, 24 h No reaction 4 HFIP, 23 °C, 24 h No reaction 5 NEt3, 23 °C, 24 h No reaction 6 NaOH, 23 °C, 24 h No reaction 7 50 °C, 24 h No reaction

4.3 Conclusion

We have made progress towards the synthesis of 2-substituted indoles and specifically 2-reverse prenylated indoles. Two β-keto acid substrates used to activate the aniline N-oxides were prepared: (1) 2,2-dimethyl-3-butenoacetic acid in 5 steps in

18% overall yield and (2) 2,2-dimethylpropanoacetic acid in 2 steps in 64% overall

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yield. The rearrangement of 4,N,N-trimethylaniline N-oxide with in situ generated

2,2-dimethyl-3-butenoacyl chloride proceeded in 19% yield and 2,2-dimethyl- propanoacyl chloride proceeded in 44% yield. Suitable conditions for successful N- demethylation and enamine cyclization of functionalized aniline substrates were not obtained.

4.4 Experimental

4.4.1 General Methods

Commercial reagents and solvents were used as received. Triethylamine, dichloromethane, ethyl ether, tetrahydrofuran, and N,N-dimethylformamide were purified by the method of Pangborn et al.39 All reactions were performed in single- neck oven- or flame-dried round bottom flasks fitted with rubber septa under a positive pressure of nitrogen, unless otherwise noted. Air- and moisture-sensitive liquids were transferred via syringe or stainless steel cannula. Organic solutions were concentrated by rotary evaporation at or below 35 °C at 10 Torr (diaphragm vacuum pump) unless otherwise noted. Proton (1H) and carbon (13C) nuclear magnetic resonance (NMR) spectra were recorded on Bruker AV400 CryoPlatform QNP or

Bruker AVIII600 SMART NMR spectrometers at 23 °C. Proton chemical shifts are expressed in parts per million (ppm, d scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR solvent (CHCl3: d 7.26). Carbon chemical shifts are expressed in parts per million (ppm, d scale) downfield from

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tetramethylsilane and are referenced to the carbon resonance of the NMR solvent

6210 LC/MSD-TOF fitted with an ESI or an APCI source, or Thermo Q-Exactive

Orbitrap using electrospray ionization (ESI) or a Waters GCT Premier spectrometer using chemical ionization (CI). Compounds were isolated using flash column chromatography40 with silica gel (60-Å pore size, 40–63μm, standard grade, Silicycle) or basic alumina (60-Å pore size, 50–200 μm, Brockmann I, Acros Organics).

4.4.2 Synthesis of β-Keto Acids

O 1) LDA, THF, O OH −78 °C, 30 min CH3 EtO EtO CH3 CH 2) acetaldehyde, H C CH 3 −78 °C, 30 min 3 3 4-74 4-75 66%

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To a solution of diisopropylamine (35.0 mL, 250 mmol, 1.1 equiv) in THF (150 mL) cooled to –78 °C, n-butyllithium (2.5 M in hexanes, 100 mL, 250 mmol, 1.1 equiv) was added dropwise. The resultant solution was stirred at –78 °C for 15 minutes.

Ethyl isobutyrate (4-74, 30.5 mL, 227 mmol, 1 equiv) was added dropwise to the solution which then stirred for 30 minutes at –78 °C. Acetaldehyde (17.7 mL, 318 mmol, 1.4 equiv) was added dropwise and the resultant solution was stirred at –78 °C for 30 minutes. The reaction mixture was quenched with sat. aq. NH4Cl solution (120 mL) and warmed to 23 °C. The mixture was extracted with ethyl acetate (3 ´ 200 mL). The organic layers were combined and washed sequentially with 1M HCl (2 ´

200 mL) and brine (200 mL). The organic layer was dried over Na2SO4 and concentrated give a crude oil which was purified by flash column chromatography

(silica gel, starting with 5% ethyl acetate–hexanes grading to 20% ethyl acetate– hexanes) to yield ethyl 3-hydroxy-2,2-dimethylbutanoate (4-75, 23.8 g, 150 mmol,

1 66%) as a yellow oil. TLC 20% ethyl acetate–hexanes, Rf = 0.32 (KMnO4). H NMR

(400 MHz, CDCl3) δ 4.16 (q, J = 7.1 Hz, 2H), 3.85 (q, J = 6.4 Hz, 1H), 1.24 (t, J = 5.8

13 Hz, 3H), 1.14 (s, 3H), 1.13 (s, 3H). C NMR (101 MHz, CDCl3) δ 178.0, 72.6, 60.8,

47.1, 22.6, 19.9, 17.8, 14.3.

O OH O OTs TsCl EtO CH EtO CH 3 pyr, 23 °C, 60 h 3 H3C CH3 H3C CH3 4-75 4-76 54%

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para-Toluenesulfonyl chloride (13.1 g, 68.7 mmol, 1.10 equiv) was added to a solution of ethyl 3-hydroxy-2,2-dimethylbutanoate (4-75, 10.0 g, 62.4 mmol, 1 equiv) in pyridine (20.2 mL, 251 mmol, 4.0 equiv) at 23 °C. The resultant solution was stirred for 60 h at 23 °C after which the reaction was quenched with 1M HCl (60 mL) and extracted with ethyl acetate (3 ´ 140 mL). The organic layers were combined and washed sequentially with 1M HCl (2 ´ 60 mL) and brine (60 mL). The organic layer was dried over Na2SO4 and concentrated to yield a crude oil which was purified by flash column chromatography (silica gel, starting with 5% ethyl acetate–hexanes grading to 10% ethyl acetate–hexanes) to yield ethyl 3-(4-methylbenzenesulfonate)-

2,2-dimethylbutanoate (4-76, 10.5 g, 33.7 mmol, 54%) as a colorless oil. TLC 20%

1 ethyl acetate–hexanes, Rf = 0.55 (UV, KMnO4). H NMR (400 MHz, CDCl3) δ 7.78

(d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 4.95 (q, J = 6.4 Hz, 1H), 4.32 – 3.83 (m,

2H), 2.44 (s, 3H), 1.22 (d, J = 6.4 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H), 1.12 (s, 3H), 1.11

13 (s, 3H). C NMR (101 MHz, CDCl3) δ 175.0, 144.6, 134.6, 129.8, 127.8, 83.1, 61.1,

+ 47.0, 21.9, 21.8, 19.6, 16.6, 14.2. HRMS ESI C15H23O5S Calcd. 315.1266. Found

315.1272.

O OTs O DBU EtO CH EtO 3 130 °C, 5 h H3C CH3 H3C CH3 4-76 4-77 90%

A solution of ethyl 3-(4-methylbenzenesulfonate)-2,2-dimethylbutanoate (4-76, 5.02 g, 16.0 mmol, 1 equiv) in DBU (3.6 mL, 24 mmol, 1.5 equiv) was stirred at 130 °C for

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5 h after which the solution was cooled to 23 °C and diluted with Et2O (60 mL). The organic solution was washed with 1M HCl (40 mL), sat. aq. NaHCO3 solution (30 mL), and brine (20 mL). The organic layer was dried over Na2SO4 and concentrated to yield ethyl 2,2-dimethyl-3-butenoate (4-77, 2.05 g, 14.4 mmol, 90%) as a yellow

1 oil. TLC 20% ethyl acetate–hexanes, Rf = 0.85 (KMnO4). H NMR (400 MHz,

CDCl3) δ 6.03 (dd, J1 = 17.5 Hz, J2 = 10.6 Hz, 1H), 5.13 – 5.02 (m, 2H), 4.12 (q, J =

13 7.1 Hz, 2H), 1.29 (s, 6H), 1.24 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, CDCl3) δ

+ 176.5, 142.8, 112.8, 60.8, 44.9, 24.7, 14.3. HRMS ESI C8H15O2 Calcd. 143.1072.

Found 143.1074.

O O O 1) LDA, THF, −78 °C, 45 min EtO EtO CH3 2) O −78 to 23 °C, 2 h H3C CH3 4-78 EtO 4-79 H3C CH3 75% 4-77

To a solution of diisopropylamine (3.0 mL, 21 mmol, 1.1 equiv) in THF (10 mL) cooled to –78 °C, n-butyllithium (1.96 M in hexanes, 11 mL, 21 mmol, 1.1 equiv) was added dropwise. The resultant solution was stirred at –78 °C for 15 minutes. Ethyl acetate (4-78, 2.1 mL, 21 mmol, 1.1 equiv) was added dropwise to the solution which then stirred for 45 minutes at –78 °C. Ethyl 2,2-dimethyl-3-butenoate (4-77, 1.00 g,

7.00 mmol, 1 equiv) was added dropwise and the resultant solution was stirred at –78

°C for 30 minutes then 23 °C for 2 hours. The reaction mixture was quenched with sat. aq. NH4Cl solution (40 mL). The mixture was extracted with ethyl ether (3 ´ 30 mL). The organic layers were combined and washed sequentially with sat. aq. NH4Cl

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(2 ´ 30 mL) and brine (2 ´ 30 mL). The organic layer was dried over Na2SO4 and concentrated to give a crude oil which was purified by flash column chromatography

(silica gel, starting with 1% ethyl ether–hexanes grading to 10% ethyl ether–hexanes) to yield ethyl aceto-2,2-dimethylbutenoate (4-79, 0.97 g, 5.2 mmol, 75%) as a yellow

1 oil. TLC 20% ethyl acetate–hexanes, Rf = 0.67 (UV, KMnO4). H NMR (400 MHz,

CDCl3) δ 6.03 (dd, J1 = 17.5, J2 = 10.6 Hz, 1H), 5.12 – 5.03 (m, 2H), 4.12 (q, J = 7.1

13 Hz, 2H), 1.29 (s, 6H), 1.24 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, CDCl3) δ 176.5,

+ 142.8, 112.8, 60.8, 44.9, 24.7, 14.3. HRMS ESI C10H17O3 Calcd. 185.1178. Found

185.0807.

O O O O NaOH EtO HO THF/H2O, 50 °C H3C CH3 H3C CH3

4-79 4-80 74%

A solution of sodium hydroxide (0.50 g, 12 mmol, 3.3 equiv) in water (5 mL) was added to a solution of ethyl aceto-2,2-dimethylbutenoate (4-79, 0.70 g, 3.8 mmol, 1 equiv) in THF (5 mL). The resultant mixture was heated to 50 °C and stirred at that temperature for 18 hours. The reaction mixture was acidified to a pH of 2-3 with 1M

HCl and extracted with CH2Cl2 (3 ´ 10 mL). The organic layers were combined and washed with brine (20 mL) and dried over Na2SO4 and concentrated to give 3- hydroxy-2,2-dimethyl-3-butenoacetic acid (4-80, 0.44 g, 2.7 mmol, 74%) as a yellow

1 oil. H NMR (400 MHz, CDCl3) δ 5.96 – 5.83 (m, 1H), 5.27 – 5.05 (m, 2H), 2.11 (s,

+ 2H), 1.22 (s, 6H). HRMS ESI C8H13O3 Calcd. 157.0859. Found 157.0865.

245

O O O 1) LDA, THF, −78 °C, 45 min CH3 EtO EtO CH3 2) O −78 to 23 °C, 2 h H3C CH3 CH3 4-81 Cl 4-83 H3C CH3 96% 4-82

To a solution of diisopropylamine (3.9 mL, 30 mmol, 3.0 equiv) in THF (20 mL) cooled to –78 °C, n-butyllithium (1.86 M in hexanes, 16 mL, 30 mmol, 3.0 equiv) was added dropwise. The resultant solution was stirred at –78 °C for 15 minutes. Ethyl acetate (4-81, 2.9 mL, 30 mmol, 3.0 equiv) was added dropwise to the solution which then stirred for 45 minutes at –78 °C. Trimethylacetyl chloride (4-82, 1.2 mL, 10 mmol, 1 equiv) was added dropwise and the resultant solution was stirred at –78 °C for 30 minutes then 23 °C for 2 hours. The reaction mixture was quenched with sat. aq. NH4Cl (60 mL). The mixture was extracted with ethyl ether (3 ´ 60 mL). The organic layers were combined and washed sequentially with sat. aq. NH4Cl (2 ´ 60 mL) and brine (2 ´ 60 mL). The organic layer was dried over Na2SO4 and concentrated to give a crude oil which was purified by flash column chromatography

(silica gel, starting with 1% ethyl ether–hexanes grading to 10% ethyl ether–hexanes) to yield ethyl 2,2,2-trimethylacetoacetate (4-83, 1.65 g, 9.60 mmol, 96%) as a pale

1 yellow oil. TLC 20% ethyl acetate–hexanes, Rf = 0.75 (UV, KMnO4). H NMR (400

MHz, CDCl3) δ 4.19 (q, J = 7.1 Hz, 2H), 3.54 (s, 2H), 1.26 (t, J = 7.2 Hz, 3H), 1.17 (s,

13 9H). C NMR (101 MHz, CDCl3) δ 208.3, 167.9, 61.4, 44.1, 26.2.

246

O O O O NaOH CH3 CH3 EtO HO THF/H2O, 50 °C H3C CH3 H3C CH3

4-83 4-84 67%

A solution of sodium hydroxide (0.74 g, 19 mmol, 3.2 equiv) in water (10 mL) was added to a solution of 2,2,2-trimethylacetyl chloride (4-83, 1.01 g, 5.85 mmol, 1 equiv) in THF (10 mL). The resultant mixture was heated to 50 °C and stirred at that temperature for 18 hours. The reaction mixture was acidified to a pH of 2-3 with 1M

HCl and extracted with CH2Cl2 (3 ´ 20 mL). The organic layers were combined and washed with brine (20 mL) and dried over Na2SO4 and concentrated to give 2,2,2- trimethylacetoacetic acid (4-84, 0.57 g, 3.92 mmol, 67%) as a yellow oil. 1H NMR

13 (400 MHz, CDCl3) δ 3.61 (s, 2H), 1.20 (s, 9H). C NMR (101 MHz, CDCl3) δ 188.8,

170.8, 68.1, 42.1, 26.1.

4.4.3 Functionalization of Aniline N-Oxides

H3C O H3C N 4-90 H3C CH3 N H C CH O O (COCl)2, py, O O 3 3 cat. DMF CH3 HO Cl CH2Cl2 −78 °C, 1 h OH H3C CH3 H3C CH3 23 °C 18 h then NEt3, 23 °C, 4 h 4-88 4-89 CH3

4-92 19% Oxalyl chloride (208 µL, 2.43 mmol, 1.59 equiv), pyridine (196 µL, 2.43 mmol, 1.59 equiv), and DMF (10 µL, 0.13 mmol, 0.11 equiv) were added to solution of 2,2- dimethyl-3-butenoacetic acid (4-88, 280 mg, 1.86 mmol, 1.2 equiv) in CH2Cl2 (3 mL) at 23 °C and stirred at that temperature for 18 hours. The reaction solution was cooled

247

to -78 °C and a solution of 4-methyl-N,N-dimethylaniline-N-oxide (4-90, 231 mg,

1.53 mmol, 1 equiv) in CH2Cl2 (1 mL) was added and the reaction solution stirred at

-78 °C for 1 hour. Triethylamine (595 µL, 4.26 mmol, 2.79 equiv) was added to the reaction at -78 °C. The reaction was slowly warmed to 23 °C and stirred at that temperature for 4 hours. The reaction solution was concentrated. The resultant oily residue was purified by flash column chromatography (silica gel, starting with hexanes, grading to 2% ethyl acetate–hexanes) to afford 4-92 (87 mg, 0.35 mmol,

1 19%) as a yellow oil. TLC 20% ethyl acetate–hexanes, Rf = 0.32 (KMnO4). H NMR

(400 MHz, CDCl3) δ 6.99 – 6.95 (m, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 1.6

Hz, 1H), 6.41 (s, 1H), 5.96 – 5.90 (m, 1H), 5.21 – 5.14 (m, 2H), 2.71 (s, 6H), 2.28 (s,

13 3H), 1.38 (s, 6H). C NMR (101 MHz, CDCl3) δ 162.9, 159.2, 143.2, 143.1, 132.0,

+ 127.2, 124.0, 119.0, 114.8, 114.3, 43.7, 26.1, 20.6. HRMS ESI C16H24ON Calcd.

246.1858. Found 248.1863.

H3C O H3C N 4-95 H3C CH3 N H C CH O O (COCl)2 O O 3 3 cat. DMF CH3 CH3 CH3 CH3 HO Cl CH2Cl2 −78 °C, 1 h OH H3C CH3 H3C CH3 23 °C 4 h then NEt3, 23 °C, 4 h 4-93 4-94 CH3

4-96 36%

Oxalyl chloride (94 µL, 1.1 mmol, 1.1 equiv) and DMF (10 µL, 0.1 mmol, 0.1 equiv) were added to solution of 2,2-dimethyl-propanoacetic acid (4-93, 149 mg, 1.03 mmol,

1 equiv) in CH2Cl2 (5 mL) at 23 °C and stirred at that temperature for 4 hours. The

248

reaction solution was added dropwise to a solution of 4-methyl-N,N-dimethylaniline-

N-oxide (4-95, 185 mg, 1.22 mmol, 1.18 equiv) in CH2Cl2 (3 mL) cooled to -78 °C.

The restultant solution was stirred at -78 °C for 1 hour. Triethylamine (261 µL, 2.00 mmol, 1.94 equiv) was added to the reaction at -78 °C. The reaction was slowly warmed to 23 °C and stirred at that temperature for 4 hours. The reaction solution was concentrated. The resultant oily residue was purified by flash column chromatography

(silica gel, starting with hexanes, grading to 2% ethyl acetate–hexanes) to afford 4-96

(88 mg, 0.38 mmol, 36%) as a yellow oil. TLC 20% ethyl acetate–hexanes, Rf = 0.20

1 (KMnO4). H NMR (400 MHz, CDCl3) δ 6.98 (dd, J1 = 8.5, J2 = 1.6 Hz, 1H), 6.93 (d,

J = 8.2 Hz, 1H), 6.88 (d, J = 1.7 Hz, 1H), 6.36 (s, 1H), 2.71 (s, 6H), 2.28 (s, 3H), 1.29

13 (s, 6H). C NMR (101 MHz, CDCl3) δ 163.0, 161.8, 143.0, 132.0, 127.1, 124.0,

119.0, 113.2, 43.72, 28.8, 20.6.

249

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PREPARATION OF ARYL SULFOXIDES VIA ACTIVATION OF N,N- DIMETHYLANILINE N-OXIDES WITH ALKYLDISULFANIUM SALTS

5.1 Introduction

A number of molecules with practical applications like bioactive molecules,1-5 natural products,6-8 and pesticides9-11 contain sulfur functional groups. Additionally, in synthetic chemistry, sulfoxides have been used as synthetic handles for transition metal catalysis,12-13 aromatic functionalization, 14 and asymmetric synthesis.15-18

Many pharmaceuticals contain sulfur functional groups bound to anilines (Figure 5.1).

Chloropromazine (5-1) is a treatment for symptoms from schizophrenia, bipolar disorder, or other psychotic disorders sold under the brand names Thorazine and

Largactil;1 acepromazine (5-2) is a dopamine receptor agonist that was an antipsychotic drug used in humans in the 1950s but is now commonly prescribed to animals as a sedative and antiemetic.2 Rufloxacin (5-3) is a quinoline antibiotic containing an aryl sulfide.3 Another dopamine receptor agonist, thiethylperazine (5-

4), is prescribed as an antiemetic and antipsychotic drug under the brand name

Torecan.4 Thioridazine (5-5) treats symptoms of schizophrenia and was often prescribed after multiple other ineffective medications had been until its manufacturer,

Novartis, withdrew it from the market due to severe side effects.5

254

S S S O O F EtS N H CS N R N OH 3

N N CH3 CH3 N N S N N H3C N CH3 CH3 chloropromazine, R = Cl (5-1) rufloxacin (5-3) thiethylperazine (5-4) thioridazine (5-5) acepromazine, R = COCH3 (5-2) Figure 5.1: Examples of aryl sulfides in bioactive molecules

In addition to pharmaceuticals, there are examples of natural products that contain aryl sulfides and sulfoxides (Figure 5.2). Shermilamine A (5-6) is a natural product isolated from the marine invertebrate Trididemnum sp.6 Rubroflavin (5-7) and oxyrubflavin (5-8) are natural pigments isolated from the dried fruit bodies of the

North American puffball fungus, Calvatia rubroflava.7 Bagremycins D (5-9) and C

(5-10) are glioma cell agonists isolated from mangrove-derived actinomycete bacteria.8

O O NH2 HN CH3 N N O O H R S Br N S O CH3

RS OH N O H OH NH2 N

shermilamine A (5-6) rubroflavin, R = SCH3 (5-7) bagremycin D, R = H (5-9) oxyrubroflavin, R = SOCH3 (5-8) bagremycin C (5-10) R = O

H3C NH O Figure 5.2: Examples of aryl sulfides and sulfoxides in natural products

255

In addition, aryl sulfones are found in pesticides and herbicides (Figure 5.3).9

Sulfometuron-methyl (5-11) is a general use pesticide, sold under the brand names

Oust Weed Killer and DPX-5648, that is used to control annual and perennial grasses and broad-leaved weeds.10 Rimsulfuron (5-12) is a xenobiotic and herbicide which can become an environmental contaminant with heavy use.11

O H O H N O H3C N O O O S O S

HN N CH3 O S HN N OCH3 H CO 3 O N N

CH3 OCH3 sulfometuron-methyl (5-11) rimsulfuron (5-12) Figure 5.3: Examples of aryl sulfones in pesticides

Aryl sulfoxides have applications in synthetic organic chemistry (Figure 5.4).

Sulfoxides have been used as coupling partners to prepare biaryl sulfoxides (5-14) and sulfides (5-15) as well as biaryl compounds (5-16) through transition metal catalysis12 and metal-free conditions13 (Figure 5.4, eq 1). Via a [3,3]-sigmatropic rearrangement, aryl sulfoxides have been employed as a synthetic handle for aromatic functionalization (Figure 5.4, eq 2).14 Aryl sulfoxides are be used to impart stereochemistry within a molecule through kinetic resolutions,15 intramolecular conformational control,16 and asymmetric synthesis.17 Unique aniline sulfoxides have been synthesized for use as chiral auxiliaries in transition metal catalysis (Figure 5.4, eq 3).18

256

O S S R1 R3 R1 R3 O Transition Metal S 5-14 5-15 (1) R2 Catalysis 1 R R3

5-13 R1

5-16

5-18 [3,3] R2 O R2 Sigmatropic S X Rearrangement S R2 S 1 X R1 (2) R R1 X X = OR, NH2 5-17 or CH2TMS 5-19 5-20

H C CH3 EtO C 3 2 CO Et N O Pd(OAc)2, dppf H C CH3 2 CO Et 3 S 2 Ag2CO3 N O CO Et 2 S (3) I CH3CN, 60 °C

5-21 5-22 Figure 5.4: Synthetic uses of aryl sulfoxides in transition metal catalysis, aromatic functionalization, and as chiral auxiliaries

5.1.1 Methods of Forming Aryl C–S Bonds

Methodologies to form new aryl C–S bonds depend on the desired oxidation level of sulfur (i.e. aryl sulfoxides, sulfones, or sulfides) in the product (Figure 5.5).

Aryl sulfoxides (5-24) have been prepared using sodium sulfonates and palladium catalysis; symmetrically substituted sulfoxides have been isolated using by using thionyl chloride (Figure 5.5, eq 1);19 however, methods for directly preparing aryl sulfoxides via C–S bond formation are rare. Aryl sulfones (5-28) are synthesized using transition metal catalysis with alkylsulfonyl chlorides and sodium alkylsulfonates (Figure 5.5, eq 2).20 Transition metal-catalyzed cross coupling reactions between aryl halides or triflates and thiols have been used to prepare aryl

257

sulfides (5-32) (Figure 5.5, eq 3). 21 The methods have employed different transition metal catalysts such as copper,22 palladium,23 nickel,24 and iron.25

SOCl2 Pd2dba3 O H 10 mol% H2O ligand I 1 S 1 R R2 R (1) or R1 Cs2CO3 RSO2Na O TfOH 5-23 5-24 S 5-25 2 tBuO2C R 5-26

R2SO Cl 2 2 O O R SO2Na H [RuCl (p-cymene)] X 2 2 S CuI, L-proline R1 R2 R1 R1 (2) K2CO3, solvent base, solvent CH CN, 115 °C, 15 h 5-27 3 5-28 rt to 90 °C 5-29 X = Br, I

X S 2 2 Transition Metal R 1 + R 1 R HS Catalysis R (3) 5-30 5-31 5-32 X = Cl, Br, I, OTf R2 = alkyl, aryl Figure 5.5: Preparation of aryl sulfoxides, sulfones, and sulfides

Methods for installing sulfur functionality onto aniline substrates are limited

(Figure 5.6). Aniline sulfoxides (5-35) are prepared from aniline substrates (5-33) using organolithium reagents and thio- or amino-sulfoxide (5-34); however, the use of organolithium and Grignard reagents as well as a limited substrate scope render this methodology ill-suited for broad application (Figure 5.6, eq 1).16,18b,26 Aniline sulfones (5-38) have been synthesized from anilines (5-36) and sodium alkylsulfonates

(5-37) treated with iridium catalysis or electric potential; these methods offer a broader substrate scope, but they require expensive catalysts and reagents, or specialized equipment.27 Treatment of anilines or aniline bromides (5-39) with harsh

258

organolithium reagents and alkyl disulfides (5-40) yielded aniline sulfides (5-41), but the limited substrate scope and harsh reagents prevents broad application of these methods.28

2 2 CH R CH3 R 3 N 1) nBuLi, sBuLi, or Mg0 N O X S R3 1 2) O 1 R R (1) S Y R3 5-33 5-35 X = H, Br, I 5-34 Y = SR3 or NTsR4

Ir cat., KS2O8 Bu4NHSO4 2 3 2 3 R R CH3CN/H2O R R N N O blue LEDs O O + S S 4 4 R (2) R1 NaO R or R1 C/Pt electrodes undivided, 10 mA 5-36 5-37 5-38 Bu4NBF4 CH3CN/H2O

R2 R3 R2 R3 N 1) nBuLi or sBuLi N X S R4 1 2) 1 R R4 S R (3) S R4

5-39 5-40 5-41 X = H, Br Figure 5.6: Preparing aniline sulfoxides, sulfones, and sulfides

5.1.2 N–O Bond Cleavage in Aryl C–S Bond Formation

There are few examples of aryl C–S bond formation that exploit the N–O bond in N-arylhydroxylamines (Figure 5.7). Novak and Liu described treating N- arylhydroxylamines (5-42) with alkylthionyl chlorides (5-43) and preparing aniline sulfonyl compounds (5-44) in 14-34% yield via a proposed [3,3] rearrangement to

(Figure 5.7, eq 1).29 Heesing et al. employed a nucleophilic addition of glutathione (5-

46) onto sulfonate salts of N-arylhydroxylamines (5-45) and to produce an aniline

259

sulfide (5.47) (Figure 5.7, eq 2).30 No methods for the direct preparation of aryl sulfoxides using N-arylhydroxylamines have been reported.

O 5-43 O S O R Cl OH Ph N NEt3 Ph NH O O S −70 °C R (1)

5-42 5-44 4 examples 14-34%

Ac GSH (5-46) Ac OSO3 N NH GSH SH SG O O O 1 H (2) R1 CH3CN/H2O, 20 °C R N HO N OH H NH 5-45 5-47 2 O Figure 5.7: Aryl C–S bond formation via N-arylhydroxylamines

Few examples using aniline N-oxides to achieve aryl C–S bond formation have been described (Figure 5.8). Single aniline N-oxide substrates have been treated with sulfurous acid31 (Figure 5.8, eqs 1 and 2) or sulfur dioxide32 (Figure 5.8, eq 3) to form new C–S bonds on the aromatic system. Although limited, these examples show the potential of exploiting the N–O bond of aniline N-oxides to form new aryl C–S bonds and synthesize aniline sulfoxides.

260

H3C CH3 N H3C H3C CH3 O N H3C N H2SO3 SO H 3 (1)

SO3H 5-48 5-49 5-50

H3C H3C CH3 O N H3C N SO3H

H2SO3 (2) SO3H

O CH3 N N CH H3C CH3 3 5-51 5-52

H3C H H C H3C O 3 H H3C N H3C N H3C N SO2 SO3 (3)

SO3 5-48 5-53 5-54 60% 20% Figure 5.8: Aryl C–S bond formation via aniline N-oxides

5.1.3 Proposed Work

The reagents we proposed to prepare aryl sulfoxides from aniline N-oxides are alkyldisulfanium salts (5-56), which have been described by Schevenels et al. to initiate a cation-pi cyclization of polyenes (5-55) (Figure 5.9).33 In this reaction, the alkyldisulfanium salt acts as an electrophilic source of sulfur and is attacked by an olefin in the polyene which produces a cationic intermediate (5-58) that undergoes a cascade cyclization to produce a tricyclic compound (5-61). The strongly electrophilic nature these reagents make them ideal candidates to activate aniline N-oxides to be able to prepare aryl sulfoxides.

261

R SbCl S 6 5-56 H C S H3C 3 R Cl H CH NO , 5 min R 3 2 S

H3C CH3 H3C CH3 5-55 5-57 R = CH3, 42% R = Et, 52% R = CH2CH2CF3, 55%

H3C H3C H3C

H R R RS S S H3C CH3 H3C CH3 H3C CH3 S R Cl 5-55 5-58 5-59 5-56

H3C H3C H -H+ H H R R S S

H3C CH3 H3C CH3 5-61 5-60

Figure 5.9: Cation-p cyclization using alkyldisulfanium salts

Based on the Chain group’s prior work in aniline N-oxide chemistry, the ability of electrophilic reagents to activate the N–O bond for excision is well precedented. In that work, the N–O bond is excised via a [3,3] rearrangement, nucleophilic addition, or radical mechanisms (Figure 5.10, eq 1).34 The proposed aniline sulfoxide synthesis differs from our prior work in that it has limited mechanistic possibilities. The N–O bond can be excised in a [2,3] rearrangement or by homolytic cleavage (Figure 5.10, eq 2). Despite having fewer mechanistic pathways for functionalization, alkyldisulfanium salts have potential as an effective reagent for preparing aniline sulfoxides.

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2 2 2 R R R 2 O O O R CH3 H3C N H3C N X H3C N X N Y N−O Bond Y Y Activation Excision −H+ X (1) R1 R1 R1 H R1 O 5-61 5-62 5-63 5-64

5-66 2 R3 2 R SbCl R 3 2 2 O S 6 O R H3C R H3C R H C N H C N S N O N O 3 S 3 N−O Bond 3 R Cl S + S Excision R3 −H R3 R1 R1 R1 H R1 (2) Activation [2,3] or radical 5-65 5-67 5-68 5-69 Figure 5.10: Comparison of proposed work to previous functionalization work

5.2 Results and Discussion

5.2.1 Substrate Preparation

Alkyldisulfanium salts were prepared using the procedures described by

Schevenels et al. (Figure 5.11).33 1,2-Ethandithiol was treated with sodium hydride

(NaH) and an iodoalkane (iodomethane or iodoethane) to produce dithioethers 5-71 and 5-72 in 81% and 87% yield, respectively. Dithioether 5-71 was treated with chlorine gas in 1,2-dichloroethane and antimony (V) chloride to prepare methyldisulfanium salt (5-73) in 98% yield.

Cl 2 R NaH, R-I ClCH2CH2Cl, −30 °C S SbCl6 HS SH R S S R S THF, 0 to 23 °C then SbCl5 R Cl −30 to 23 °C 5-70 5-71, R = CH3, 81% 5-73 5-72, R = Et, 87% R = CH3 98% Figure 5.11: Synthesis of thioethers and methyldisulfanium salt

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5.2.2 Optimization of Aniline N-Oxide Functionalization

Both the methyldisulfanium salt (5-75) and 4,N,N-trimethylaniline N-oxide (5-

74) were used to optimize the reaction. In addition to the desired aryl sulfoxide (7-

76), the reaction produces a formanilide byproduct (5-77). Temperature, reagent equivalents, and reaction time were the initial reaction parameters screened to increase the yield of the sulfoxide product and minimize the byproduct formation (Table 5.1).

The most successful conditions employed used dichloromethane (CH2Cl2) and kept the reaction mixture at –40 °C for 17 hours (Table 5.1, entries 9 and 10).

Table 5.1: Optimization of reaction temperature and reagent equivalents of reaction between alkyldisulfanium salt and 4,N,N-trimethylaniline N-oxide

H3C S SbCl6 O S CH H3C O H3C Cl H3C 3 CH 5-75 N O 3 H3C N H N 1) CH2Cl2, temp, time S CH3 2) NEt3, temp to 23 °C, 45 min

CH CH3 3 CH3 5-74 5-76 5-77 Equiv Equiv Temp Time Equiv Yield Yield Entry 5-74 5-75 (°C) (h) NEt3 5-76 5-77 1 1 1.1 -78 4 3.8 9% 12% 2 1 1.1 0 4 3.8 trace 20% 3 1 1.1 23 4 4.0 6% 11% 4 1 1.1 0 to 23 17 3.8 trace 35% 5 1 1.1 23 17 3.9 22% 50% 9 1 1.1 -40 17 3.9 19% 23% 10 1 1.0 -40 17 1.0 20% 34% 11 1 1.1 -25 17 1.1 trace 14%

264

It is believed that the formanilide byproduct results from a Mannich-type addition followed by a Pummerer rearrangement35 (Figure 5.12). In the proposed mechanism, the N–O bond is excised in an elimination to produce iminium ion 5-79 onto which the sulfur adds. This resulting sulfoxide (5-80) is activated and undergoes a Pummerer rearrangement to produce formanilide (5-84). This formanilide has readily formed in initial optimization studies; therefore, successfully mitigating its formation is key to a high yielding synthesis of the desired aryl sulfoxide.

NEt3 NEt3 H H O O CH3 H3C H3C CH3 H3C CH3 H3C N S N S N S N S CH3 S−O Bond O Activation LG

CH3 CH3 CH3 CH3 5-78 5-79 5-80 5-81

O OH H2O

H3C H3C CH3 H3C CH3 N H proton N S N S transfer + HSCH3

CH3 CH3 CH3 5-84 5-83 5-82

Figure 5.12: Proposed mechanism of formanilide byproduct formation

Next, we looked to find the optimal reaction solvent (Table 5.2). Using our best previously determined conditions, the reactivity of methyldisulfanium salt (5-86) and 4,N,N-trimethylaniline N-oxide (5-85) in different solvents was tested. As no

265

other solvents produced isolable product (Table 5.2, entries 2-6), CH2Cl2 remained the best solvent choice (Table 5.2, entry 1).

Table 5.2: Optimization of reaction solvent and reagent equivalents of reaction between alkyldisulfanium salt and 4,N,N-trimethylaniline N-oxide

H3C S SbCl6 O S CH H3C O H3C Cl H3C 3 CH 5-86 N O 3 H3C N H N 1) solvent, temp, time S CH3 2) NEt3, temp to 23 °C, 45 min

CH CH3 3 CH3 5-85 5-87 5-88 Equiv Equiv Temp Time Equiv Yield Yield Entry Solvent 5-85 5-86 (°C) (h) NEt3 5-87 5-88 1 1 1.1 CH2Cl2 -40 17 3.9 19% 23% 2 1 1.1 CH3NO2 -23 4 3.9 trace trace 3 1 1.1 CH3NO2/CH2Cl2 -23 4 4.0 trace trace 4 1 1.1 CH3CN -25 17 1.0 trace trace 5 1 1.1 THF -40 17 1.0 trace trace 6 1 1.0 DME -40 17 1.0 trace trace

We looked at the reaction of N,N-dimethylaniline N-oxide (5-89) and methyldisulfanium salt (5-90) to determine if the difficulties in increasing the yield we were experiencing were specific to the 4,N,N-trimethylaniline N-oxide (5-85). Using the optimal solvent, temperature and reaction length, we looked at equivalents of different reagents (Table 5.3). Although the desired aryl sulfoxide (5-91) was prepared, the isolated yield was not greater than that of the 4,N,N-trimethylaniline N- oxide indicating that the low product yields had another cause.

266

Table 5.3: Optimization of reagent equivalents of reaction between alkyldisulfanium salt and N,N-dimethylaniline N-oxide

H3C S SbCl6 S CH H3C O H3C Cl H3C 3 5-90 N O H3C N 1) CH2Cl2, −40 °C, 17 h S CH3 2) NEt3, −40 to 23 °C, 45 min 5-89 5-91 Equiv Entry Equiv 5-89 Equiv 5-90 Yield 5-91 NEt3 1 1 1.1 1.0 18% 2 1 1.2 4.0 11% 3 2.0 1 0 trace

Finally, we looked at Lewis acid activation in an effort to increase the yield of the reaction (Table 5.4). The reaction mixture of N,N-dimethylaniline N-oxide (5-92) and methyldisulfanium salt (5-93) was treated with different Lewis acids; however, none offered improvement on the yield. Only copper (I) iodide (CuI), copper (I) bromide (CuBr), and aluminum chloride (AlCl3) produced any isolable aryl sulfoxide

(Table 5.4, entries 4, 5, and 9). Due to the lack of success in increasing the yield of this reaction, this project was abandoned.

267

Table 5.4: Optimization of Lewis acid activation in reaction between alkyldisulfanium salt and N,N-dimethylaniline N-oxide

H3C S SbCl6 S CH H3C O H3C Cl H3C 3 5-93 N O H3C N 1) LA, CH2Cl2, −40 °C, 17 h S CH3 2) NEt3, −40 to 23 °C, 45 min 5-92 5-94 Yield Entry Lewis Acid (LA) 5-94 1 none 18%

2 BF3×OEt2 trace 3 BBr3 trace 4 CuI 9% 5 CuBr 5%

6 InCl3 trace

7 TiCl4 none

8 SnCl4 none

9 AlCl3 4%

5.3 Conclusion

This work describes the preparation of aryl sulfoxides from N,N- dimethylaniline N-oxide and 4,N,N-trimethylaniline N-oxide by treatment with methyldisulfanium salt in 22% and 18% yield, respectively. However, the reactions remained low yielding despite efforts to increase the yield and decrease the amount of the formanilide reaction byproduct.

268

5.4 Experimental

5.4.1 General Methods

Commercial reagents and solvents were used as received with the following exceptions. 1,2-dichloroethane was purified by distillation over calcium hydride.

Triethylamine, dichloromethane, ethyl ether, and tetrahydrofuran were purified by the method of Pangborn et al.36 All reactions were performed in single-neck oven- or flame-dried round bottom flasks fitted with rubber septa under a positive pressure of nitrogen, unless otherwise noted. Air- and moisture-sensitive liquids were transferred via syringe or stainless steel cannula. Organic solutions were concentrated by rotary evaporation at or below 35 °C at 10 Torr (diaphragm vacuum pump) unless otherwise noted. Proton (1H) and carbon (13C) nuclear magnetic resonance (NMR) spectra were recorded on Bruker AV400 CryoPlatform QNP or Bruker AVIII600 SMART NMR spectrometers at 23 °C. Proton chemical shifts are expressed in parts per million

(ppm, d scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR solvent (CHCl3: d 7.26). Carbon chemical shifts are expressed in parts per million (ppm, d scale) downfield from tetramethylsilane and are referenced to the carbon resonance of the NMR solvent (CDCl3: d 77.16). Data are represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, app = apparent), integration, and coupling constant (J) in

Hertz (Hz). Compounds were isolated using flash column chromatography37 with silica gel (60-Å pore size, 40–63μm, standard grade, Silicycle) or basic alumina (60-Å

269

pore size, 50–200 μm, Brockmann I, Acros Organics). Analytical thin-layer chromatography (TLC) was performed using glass plates pre-coated with silica gel

(0.25 mm, 60-Å pore size, 5–20 μm, Silicycle) impregnated with a fluorescent indicator (254 nm). TLC plates were visualized by exposure to ultraviolet light (UV), then were stained by submersion in aqueous ceric ammonium molybdate solution

(CAM), ethanolic phosphomolybdic acid solution (PMA), acidic ethanolic p- anisaldehyde solution (anisaldehyde), or aqueous potassium permanganate solution

(KMnO4), followed by brief heating on a hot plate (215 °C, 10–15 s).

5.4.2 Preparation of Alkyldisulfanium Salts

NaH, CH3-I HS SH H C S S CH THF, 0 to 23 °C 3 3 5-70 5-71 81%

1,2-ethanedithiol (5-70, 6.72 mL, 80.1 mmol, 1 equiv) was added dropwise to a suspension of NaH (60% dispersion in mineral oil, 10.2 g, 255 mmol, 3.18 equiv) cooled to 0 °C. Methyl iodide (12.0 mL, 193 mmol, 2.41 equiv) was slowly added dropwise to the suspension to prevent quick evolution of gas. The resultant suspension was slowly warmed to 23 °C and stirred for 18 hours. Reaction contents were quenched with saturated aqueous ammonium chloride solution (80 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (2 x 80 mL). The organic layers were combined and dried over Na2SO4, filtered, and concentrated. The crude oil was purified by flash chromatography (silica gel, hexanes

270

to 10% dichloromethane–hexanes) to give 1,2-bis(methylthio)ethane as a yellow oil

(5-71, 7.9 g, 65 mmol, 81%). TLC 25% dichloromethane–hexanes, Rf = 0.33

1 13 (KMnO4). H NMR (400 MHz, CDCl3) δ 2.72 (s, 4H), 2.14 (s, 6H). C NMR (101

MHz, CDCl3) δ 33.8, 15.7.

NaH, Et-I

HS SH THF, 0 to 23 °C Et S S Et

5-70 5-72 87%

1,2-ethanedithiol (5-70, 3.36 mL, 40.0 mmol, 1 equiv) was added dropwise to a suspension of NaH (60% dispersion in mineral oil, 4.80 g, 120 mmol, 3.00 equiv) cooled to 0 °C. Ethyl iodide (7.70 mL, 96.0 mmol, 2.40 equiv) was slowly added dropwise to the suspension to prevent quick evolution of gas. The resultant suspension was slowly warmed to 23 °C and stirred for 18 hours. Reaction contents were quenched with saturated aqueous ammonium chloride solution (40 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (2 x 40 mL). The organic layers were combined and dried over Na2SO4, filtered, and concentrated. The crude oil was purified by flash chromatography (silica gel, hexanes to 30% ethyl acetate–hexanes) to give 1,2-bis(ethylthio)ethane as a yellow oil (5-72,

1 5.2 g, 35 mmol, 87%). TLC 25% dichloromethane–hexanes, Rf = 0.29 (KMnO4). H

NMR (400 MHz, CDCl3) δ 2.73 (s, 4H), 2.57 (q, J = 7.4 Hz, 4H), 1.26 (t, J = 7.4 Hz,

13 6H). C NMR (101 MHz, CDCl3) δ 31.7, 26.1, 14.9.

271

Cl2 H3C ClCH2CH2Cl, −30 °C S SbCl6 R S S R S then SbCl5 H3C Cl −30 to 23 °C 5-71 5-73 98%

Chlorine gas (0.45 g, 6.4 mmol, 1 equiv) was bubbled into a weighed flask containing

1,2-dichloroethane (10 mL) cooled to -30 °C. 1,2-bis(methylthio)ethane (5-71, 0.94 g, 7.7 mmol, 1.2 equiv) was added slowly at -30 °C and the resultant mixture was stirred at -30 °C for 5 minutes. A freshly prepared solution of SbCl5 (0.89 mL, 7.0 mmol, 1.1 equiv) in CH2Cl2 (1 mL) was added to the reaction mixture at -30 °C. The reaction mixture was warmed to 23 °C and stirred for 1 hour. The mixture was stored in the freezer for 2 hours. The precipitate was collected by filtration and washed with

1:1 hexanes/dichloromethane to afford 5-73 as a yellow powder (3.1 g, 6.3 mmol,

98%). mp 119-121 °C.

5.4.3 Functionalization with Alkyldisulfanium Salts

H3C S SbCl6 O S CH H3C O H3C Cl H3C 3 CH 5-75 N O 3 H3C N H N 1) CH2Cl2, −40 °C, 17h S CH3 2) NEt3, −40 to 23 °C, 45 min

CH CH3 3 CH3 5-74 5-76 5-77 30% 34%

A solution of 4,N,N-trimethylaniline N-oxide (5-74, 80 mg, 0.53 mmol, 1 equiv) in CH2Cl2 (1 mL) was added to a mixture of 5-75 (268 mg, 0.545 mmol, 1.0 equiv) in CH2Cl2 (3 mL) at -40 °C. The resultant mixture was stirred at -40 °C for 17 hours. Triethylamine (70 µL, 0.50 mmol, 0.94 equiv) was added and the reaction

272

mixture was warmed to 23 °C over 45 minutes. Reaction mixture was filtered and concentrated to a crude oil which was subsequently purified by flash chromatography

(silica gel, 10% ethyl acetate–hexanes) to give 4,N,N-trimethylaniline 2- sulfurylmethane (5-76, 21 mg, 0.11 mmol, 20%) and N-methyl-N-(4-methylphenyl)- formanilide (5-77, 26 mg, 0.18 mmol, 34%).

4,N,N-trimethylaniline 2-sulfurylmethane (5-76): TLC 30% ethyl acetate–

1 hexanes, Rf = 0.51 (KMnO4). H NMR (400 MHz, CDCl3) δ 7.88 – 7.83 (m, 1H),

7.43 – 7.37 (m, 1H), 7.32 (d, J = 8.1 Hz, 1H), 3.31 (s, 3H), 2.75 (s, 6H), 2.38 (s, 3H).

13 C NMR (101 MHz, CDCl3) δ 151.5, 136.4, 135.4, 135.3, 129.7, 123.5, 46.4, 42.7,

21.0.

N-methyl-N-(4-methylphenyl)-formanilide (5-77): TLC 30% ethyl acetate–

1 hexanes, Rf = 0.39 (KMnO4). H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.21 (d, J =

8.2 Hz, 2H), 7.06 (d, J = 8.3 Hz, 2H), 3.29 (s, 3H), 2.36 (s, 3H). 13C NMR (101 MHz,

CDCl3) δ 162.5, 139.8, 136.5, 130.3, 122.7, 32.4, 21.0.

H3C S SbCl6 S CH H3C O H3C Cl H3C 3 5-90 N O H3C N 1) CH2Cl2, −40 °C, 17 h S CH3 2) NEt3, −40 to 23 °C, 45 min 5-89 5-91 18%

A solution of N,N-dimethylaniline-N-oxide (5-89, 67 mg, 0.49 mmol, 1 equiv) in CH2Cl2 (1 mL) was added to a mixture of 5-90 (278 mg, 0.565 mmol, 1.1 equiv) in

CH2Cl2 (3 mL) at -40 °C. The resultant mixture was stirred at -40 °C for 17 hours.

273

Triethylamine (70 µL, 0.50 mmol, 1.0 equiv) was added and the reaction mixture was warmed to 23 °C over 45 minutes. Reaction mixture was filtered and concentrated to a crude oil which was subsequently purified by flash chromatography (silica gel, 10% ethyl acetate–hexanes) to give N,N-dimethylaniline 2-sulfurylmethane (5-91, 16 mg,

1 0.88 mmol, 18%). TLC 30% ethyl acetate–hexanes, Rf = 0.51 (KMnO4). H NMR

(400 MHz, CDCl3) δ 8.06 (dd, J1 = 7.9 Hz, J2 = 1.5 Hz, 1H), 7.60 (td, J1 = 7.8 Hz, J2 =

1.5 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 3.32 (s, 3H), 2.79 (s,

6H).

274

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Appendix A

SPECTRAL DATA FOR CHAPTER 2

279

Appendix B

SPECTRAL DATA FOR CHAPTER 3

440

Appendix C

SPECTRAL DATA FOR CHAPTER 4

539

Appendix D

SPECTRAL DATA FOR CHAPTER 5

557