Radical Relay Strategies for C–H Functionalization of Alcohols Dissertation Presented in Partial Fulfillment of the Requiremen

Radical Relay Strategies for C–H Functionalization of Alcohols

Dissertation

Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy

in the Graduate School of The Ohio State University

Kohki Mitchell Nakafuku

Graduate Program in Chemistry

The Ohio State University

2019

Dissertation Committee

David Nagib, Advisor

Craig Forsyth

Christopher Hadad

Jonathan Calede

Kohki Mitchell Nakafuku

2019

Abstract

C–H functionalization has the potential to bridge the gap between what is possible and practical in the realm of organic synthesis by providing a new mode of reactive manifold, allowing the C–H bond to become the new synthon for C–C and C–X bonds, and facilitating drug discovery via rapid synthesis of potential lead compounds. Despite high hopes, the development of new C–H functionalization methods is met with two distinct challenges: (1) most C–H bonds constitute part of the inert backbone of an organic molecule, so it is difficult to elicit sufficient reactivity from these bonds, and (2) C–H bonds are ubiquitous in organic molecules, so functionalization of one specific C–H bond is an enormous task.

The main subject of this dissertation is focused on the selective C–H functionalization of alcohols via hydrogen atom transfer strategy. In addition to the relevant background, herein are described five new reactions which were developed to provide solutions to the challenges of reactivity and selectivity in C–H functionalization.

In Chapter 1, a comprehensive review on directed, remote C–H functionalization, specifically focused on nitrogen-based radicals, is presented. Seminal works as well as recent advancements are exhibited to address the on-going challenges involved in C–H functionalization via selective hydrogen-atom transfer strategy.

In Chapter 2, method development toward C–H amination of alcohols via radical chaperone strategy is discussed. The inspiration and conception of an imidate radical strategy are presented, and its synthetic utility is demonstrated through its scopes and detailed mechanistic investigation including kinetic isotope effect study to understand the imidate radical-mediated hydrogen atom transfer.

In Chapter 3, development of catalytic C–H amination of alcohols is disclosed.

A series of mechanistic investigations, including kinetic profile, Hammett analysis, and robustness screen, are provided to elucidate the mechanism and scope of this novel catalytic C–H amination method.

In Chapter 4, development of a new synthetic method to access differentially substituted azoles is presented using an iterative hydrogen atom transfer strategy. Detailed computational and experimental data are presented to explain the mechanism of this unique oxidative cascade reaction.

In Chapter 5, development of photocatalytic system to harness imidate radical reactivity from an oxime imidate is presented. Using this newly developed strategy, difunctionalization of allylic alcohols was achieved, demonstrating different radical termination mechanisms to afford reactivity that is complementary to classical, two- electron strategies.

iii

Dedication

To my family

Acknowledgments

There are many people whom I would like to thank since graduate school would not have been possible without the support from them, but this brief acknowledgement section feels inadequate to express my gratitude. These past five years have been an extremely frustrating and challenging time. Yet, I am sure that I will look back upon this period of my life with fondness and nostalgia.

First and foremost, I am extremely grateful to my research advisor, Professor David

Nagib, for his valuable guidance, scholarly input, and consistent words of encouragement.

You are a person with an amicable and positive disposition. You were always available to chat in your office, sometimes for hours, to clarify my doubts despite your busy schedule.

I have learned so much more than chemistry. I will leave here with a PhD and life skills that I would not have mastered had I decided to not join your lab five years ago.

I would also like to thank my undergraduate research advisor Professor Ross

Widenhoefer and graduate mentor Dr. Robert Harris. Thank you for the warm and welcoming environment to join the lab and for making me a part of many exciting projects.

What I learned in the Widenhoefer lab as a synthetic organic chemist helped me tremendously during my time in graduate school. Robert, you were always open to questions and helped me fall in love with organic chemistry.

In my early years of schooling, I have had many inspiring teachers who have challenged me and taught me so much more than in textbooks. I specifically would like to thank Mrs. Judy Scroggins who was my academic tutor and life mentor. I cannot thank you enough for all your warm words of encouragements. You helped me learn English when my family moved to Cincinnati back in 2003. I cannot imagine spending an hour twice a week with someone who is so quiet and did not understand English very well. At no point did you show frustration; you were always filled with kindness and helped me with a smile.

Fifteen years ago, I never saw myself going to prestigious school like Duke or completing a PhD program at the Ohio State University. Thank you so much for helping me build the foundation of success and always being there for me for emotional support.

My graduate school career started in a windowless Evans Building and ended in a newly built CBEC, and it sure was filled with many ups and downs. But many people whom I met in the last five years really made all the tough time bearable and the exciting time so much more enjoyable. I thank all the Nagib group members, past and present, and wish them luck and success in all their future endeavors.

Dr. Lu Wang, thank you for deciding to do your post-doctoral research overseas with David. As one of four students to start the Nagib Lab, I learned so much from phenomenal chemist and am forever grateful for that. By action, you showed us how to approach not only chemistry, but also life. You always had a positive attitude even during tough times. Thank you for being a mentor that I always looked up to.

Andrew Chen, Sean Rafferty, and Leah Stateman, I had so much fun getting to know you personally in the last four years. You have laughed with me, celebrated with me,

vi lifted me up, and got me through graduate school. Thank you for your hard work in the lab and for your patience as I learned how to be a better a mentor and lab mates. I wish all three of you the best of luck. Now you three get to be senior students. You are no longer first-years!

Stacy Fosu, I still remember our time in Evans building when we were packing up the old lab space. At this point Jeremy, Ethan, and I were for sure joining the lab, but we were anxiously waiting to see if you were joining. All three of us were ecstatic when we found out from David that you were. You have been a chemist and a friend that I always looked up to. You always knew your goal and worked so hard. Working with you on a project was so much fun because things were getting done so much faster than I anticipated.

I am happy that we’ll be colleagues as medicinal chemists, and I cannot wait to see what an amazing and exciting thing you will be doing next.

Jeremy Lear, both of us definitely shared the same mentality to succeed, which made my first year so much fun and easy to come in everyday to work. Talking about chemistry with you is a moment that I enjoyed so much for the last five years. You had a unique skill to digest hard concepts and distill it down to its fundamentals. Your group meetings were always educational, and I always looked forward to your talks. Thank you for being a friend whom I could always rely on.

Ethan Wappes, I don’t even know where to start with you. I am so glad that you decided to come to OSU. You became my classmate, lab mate, friend, mentor, and most importantly lunch buddy. So many good and bad chemistry came out of our casual conversation, and I appreciated your constructive feedback. I always looked up to you as a

vii chemist and as a person. I think everyone in Nagib lab is so thankful for the effort you put in to finish projects, to become a mentor for younger students, and to be the leader for the lab. I definitely enjoyed working on multiple projects with you in the last five years.

A good support system is important for surviving and staying sane in graduate school, and for that, I want to thank Raj Singh, M.D. Ever since we met during the first day at Duke, you became my best friend. We were the only two among our close friend group to pursue a professional degree, and we often rant about how tough school was. Your encouraging phone calls, texts, as well as countless number of memes were always appreciated. I would not have been able to keep going without your support. I appreciate your effort to make a long road trip to visit me in Columbus. Talking to you served to help me stay balanced and focused. You have always been a fantastic friend of mine.

Aki Ishikawa, when I first saw you nine year ago in Marketplace on East Campus,

I never thought you would become this instrumental to my life. To this day, you still joke about how you always caught me staring at you. I am too shy to admit it, but I could not keep my eyes off you. Although certain circumstances kept us apart for the next year or so after that, every time I saw you, I wished that one day I was going to be lucky enough to find a girl like you. Now that you are my best friend, the love of my life, and my world, I have a lot to thank you for. Thank you for being my harshest critic while being supportive.

Thank you for letting me tell you all my problems, whether big or small. Thank you for sending many, many care packages throughout the last five years. Thank you for seeing the best in me and have faith in me when I did not. Thank you for motivating me and encouraged me to strive for excellence. Thank you for taking me out to go have fun. Thank

viii you for all the hugs and cuddles. Thank you for telling me when I'm wrong. Thank you for doing things that I like. Thank you for loving the people that I care about, although they somehow always end up liking you more than me. Thank you for trying to laugh at my jokes (you rarely laughed at my amazing puns, by the way). Thank you for talking to me every day for the last five years. Thank you for supporting my dreams and goals. Thank you for being the light of my life. Thank you for being you. You have been my best friend and have loved, supported, encouraged, entertained, and helped me get through this agonizing five years in the most positive way.

If I were to start writing a “Thank You” to my family, it would be much longer than this dissertation. So, I will try to keep it brief. Dad, it was never easy being a son of scientist.

You have taught me so much. I am most grateful for what you have given me through all the years of my life and many lessons you have taught me through your love. Thank you for all the opportunities that you have given to me, which often came with your sacrifice.

Thank you for being the Dad that I can always lean on. Mom, coming to America was a huge opportunity for me, but that came with many sacrifices you had to make as well. I would not have made it as far as I have without your love and support. Thank you for everything.

Vita

2010 – 2014……………………..Duke University, Durham, North Carolina B.S. in Chemistry with Honors, Global Health certificate

2014 – 2019……………………..The Ohio State University, Columbus, Ohio Ph.D. in Chemistry

Publications

Harris, R. J.; Nakafuku, K. M.; Widenhoefer, R. A. “Kinetics and Mechanism of the Racemization of Aryl Allenes Catalyzed by Cationic Gold(I) Phosphine Complexes.” Chem. Eur. J. 2014, 20, 12245.

Li, H., Harris, R. J.; Nakafuku, K. M.; Widenhoefer, R. A. “Kinetics and Mechanism of Allene Racemization Catalyzed by a Gold N-Heterocyclic Carbene Complex.” Organometallics, 2016, 35, 2242.

Wappes, E. A.†; Nakafuku, K. M.†; Nagib, D. A. “Directed β C–H Amination of Alcohols via Radical Relay Chaperones” J. Am. Chem. Soc. 2017, 139, 10204.

Stateman, L. M.; Nakafuku, K. M.; Nagib, D. A. “Remote C-H Functionalization via Selective Hydrogen Atom Transfer” Synthesis, 2018, 50, 1569.

Nakafuku, K. M.†; Fosu, S. C.†; Nagib, D. A. “Catalytic Alkene Difunctionalization via Imidate Radicals” J. Am. Chem. Soc. 2018, 140, 11202.

Stateman, L. M.; Wappes, E. A.; Nakafuku, K. M.; Edwards, K. M.; Nagib, D. A. “Catalytic β C–H Amination via an Imidate Radical Relay” Chem. Sci. 2019, 10, 2693.

Fields of Study

Major Field: Chemistry

Organic Chemistry

Table of Contents

Abstract ...... ii Dedication ...... iv Acknowledgments ...... v Vita ...... x List of Figures ...... xvi Chapter 1 C–H Functionalization via Hydrogen Atom Transfer ...... 1 1.1 Introduction: C–H Functionalization ...... 2 1.2 Early Inspiration for Directed C–H Functionalization ...... 3 1.3 Recent Advances in Directed C–H Functionalization ...... 5 1.4 General Strategy for Remote C–H Functionalization via HAT ...... 6 1.5 Remote C–H Functionalization via Nitrogen-Centered Radicals...... 11 1.5.1 N(sp3)-Radical Initiation ...... 11 1.5.2 N(sp2)-Radical Initiation ...... 28 1.6 Conclusion: Complimentary Reactivity Accessed via HAT ...... 37 Chapter 2C–H Amination via an Imidate Radical ...... 39 2.1 Synthesis of  Amino Alcohols ...... 40 2.2 Inspiration from Hofmann-Löffler-Freytag Reaction ...... 42 2.3 Radical Chaperone Strategy ...... 43 2.3.1 Aldimine as Radical Chaperone...... 45 2.3.2 Ketimine (Acyclic and Exocyclic) as Radical Chaperone ...... 48 2.3.3 Ketimine (Endocyclic) as Radical Chaperone ...... 50 2.3.4 Proof-of-Concept:  C–H Amination of Alcohols ...... 52 2.4 Nitrile as Radical Chaperone ...... 54 2.4.1 Imidate Single Electron Reactivity ...... 55 2.4.2 Trichloroacetimidate C–H Amination ...... 57

2.4.3 Synthetic Limitation Using Trichloroacetimidate...... 58 2.4.4 Benzimidate C–H Amination...... 59 2.4.5 Kinetic Isotope Effect ...... 60 2.4.6 Late-Stage Diversification of Oxazoline ...... 62 2.5 Experimental Section ...... 63 2.5.1 General Information ...... 63 2.5.2 Imidate Synthesis ...... 64 2.5.3 Imidate  C–H Amination ...... 80 2.5.4 Oxazoline Derivatization ...... 98 Chapter 3C–H Amination via Iodine Catalysis ...... 105 3.1 Introduction ...... 106 3.2 Investigating Catalytic Turnover ...... 106 3.3 Optimization of C–H Amination ...... 108 3.4 C–H Amination Scope ...... 109 3.5 Substrate Compatibility via Robustness Screening ...... 111 3.6 Mechanistic Difference between Stoichiometric and Catalytic Systems ...... 113 3.6.1 Rate of  C–H Amination ...... 113 3.6.2 HAT Regioselectivity ...... 114 3.6.3 Mechanistic Differences ...... 115 3.6.4 Hammett Analysis ...... 117 3.7 Experimental Section ...... 119 3.7.1 General Information ...... 119 3.7.2 Imidates Synthesis ...... 120 3.7.3 Catalytic Imidate  C–H Amination ...... 125 3.7.4 Mechanistic Probes ...... 129 Chapter 4 Synthesis of Azoles via Tandem Hydrogen Atom Transfer ...... 134 4.1 Introduction ...... 135 4.2 Construction of Oxazoles from Alcohols and Nitriles ...... 137 4.3 Iterative HAT-Mediated by Acetyl Radical ...... 138 4.3.1 Alcohol Scope ...... 139 4.3.2 Nitrile Scope ...... 140 4.4 Derivatization to Access Other Azoles ...... 141

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4.5 Proposed Mechanism ...... 143 4.6 Probing the Mechanism...... 144 4.7 Experimental Section ...... 145 4.7.1 General Information ...... 145 4.7.2 Imidate Synthesis ...... 146 4.7.3 Oxazole Synthesis ...... 163 4.7.4 Oxazole Derivatization ...... 176 Chapter 5 Development of Oxime Imidate Radical Precursor ...... 179 5.1 Introduction ...... 180 5.2 DFT-Calculation of Oxime Imidate BDEs ...... 181 5.3 Imidoyl Chloride as Radical Chaperone ...... 182 5.4 Oxime Imidate Synthesis ...... 184 5.5 Catalytic Imidate Radical Generation via Photoredox Catalyst ...... 185 5.6 Proposed Mechanism and Expanding Oxime Imidate Reactivity ...... 186 5.7 Radical Alkene Difunctionalization ...... 187 5.8 Hydroamination Scope ...... 189 5.9 Radical Clock Experiment...... 192 5.10 Aminoalkylation Scope ...... 193 5.11 Aryl Nitriles as Coupling Partners ...... 194 5.12 Overman Serendipitous Discovery ...... 196 5.13 Comparison to Other N(sp2) Radical Precursors ...... 197 5.14. Future Direction ...... 198 5.15 Experimental Section ...... 200 5.15.1 General Information ...... 200 5.15.2 General Procedure (GP) ...... 201 5.15.3 Imidoyl Chloride Synthesis ...... 203 5.13.4 Oxime Imidate Synthesis ...... 204 5.15.5 Hydroamination of Allylic Alcohols ...... 213 5.15.6 Oxazoline Hydrolysis ...... 221 5.15.7 Aminoalkylation of Allylic Alcohols ...... 226 5.15.8 Aminoarylation of Allylic Alcohols ...... 231 5.15.9. Miscellaneous Experiments ...... 234

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Bibliography ...... 236

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Table of Contents

Table 2-1 Proof-of-concept:  C–H amination of alcohols ...... 53 Table 2-2 Scope of trichloroacetimidate-mediated  C–H Amination...... 57 Table 2-3 Scope of benzimidate-mediated  C–H amination ...... 60 Table 3-1 Optimization of catalytic  C–H amination ...... 108 Table 3-2 Scope of trichloroacetimidate-mediated catalytic  C–H Amination...... 109 Table 3-3 Scope of benzimidate-mediated catalytic  C–H Amination ...... 110 Table 4-1 Optimization of iterative hydrogen atom transfer strategy ...... 139 Table 4-2 Scope of oxazoles via iterative hydrogen atom transfer: alcohol ...... 140 Table 4-3 Scope of oxazoles via iterative hydrogen atom transfer: nitrile ...... 141 Table 5-1 Scope of hydroamination of allylic alcohols ...... 191 Table 5-2 Scope of aminoalkylation of allylic alcohols ...... 194 Table 5-3 Scope of amino arylation of allylic alcohols ...... 196

List of Figures

Figure 1-1 Bond dissociation energy of common C(sp3)–H bonds...... 2 Figure 1-2 Different types of C–H bonds ...... 3 Figure 1-3 Inspiration from nature for selective C–H functionalization ...... 4 Figure 1-4 Regioselective steroid C–H functionalization via molecular templating ...... 5 Figure 1-5 Four elementary steps toward selective C–H functionalization...... 7 Figure 1-6 Fundamental principle of hydrogen atom transfer ...... 9 Figure 1-7 δ C–H amination via N-centered radicals, initiated by N–Cl/Br homolysis ... 12 Figure 1-8 δ C–H amination via in situ N–I formation and homolysis ...... 14 Figure 1-9 Modern improvements to Suárez’s HLF δ C–H amination ...... 15 Figure 1-10 Triiodide strategy for δ C–H amination of unactivated 2° C–H bonds ...... 16 Figure 1-11 δ C–H amination via azide-derived N-radicals and nitrenes ...... 17 Figure 1-12 δ C–H halogenation via N-radicals ...... 18 Figure 1-13 γ C–H halogenation of alcohols via N–Br homolysis ...... 20 Figure 1-14 C–H halogenation and xanthylation via N–X homolysis ...... 21 Figure 1-15 γ, δ-Amino-iodination of amides via amination/scission cascade ...... 21 Figure 1-16 Photoredox-catalyzed γ or δ C–H alkylation via PCET N–H oxidation ...... 23 Figure 1-17 functionalization of amines via metal-catalyzed N–F reduction ...... 24 Figure 1-18 δ C–H functionalization via N–S fragmentation ...... 25 Figure 1-19 δ C–H azidation via amidyl radicals from N–N precursor ...... 26 Figure 1-20 δ C–H functionalizations of amides via photoredox catalysis ...... 27 Figure 1-21 Rate of radical cyclization and H• atom reduction ...... 29 Figure 1-22 γ C–H functionalization via iminyl N(sp2) radicals ...... 30 Figure 1-23  C–H arylation via vinyl azide-derived N(sp2) radicals ...... 32 Figure 1-24  C–H functionalization of amines via amidyl radicals ...... 33 Figure 1-25  C–H amination of amines via N–OR reduction ...... 33 Figure 1-26 β C–H amination of alcohols via imidate radicals ...... 34 Figure 1-27 β C–H dihalogenation of alcohols via imidate iterative HAT ...... 35 Figure 1-28  C–H functionalization of ketones via iminyl radicals ...... 37 Figure 2-1  amino alcohols as privileged motifs ...... 40 Figure 2-2 Synthesis of  amino alcohol via direct  C–H amination of alcohols ...... 42 Figure 2-3 The Hofmann–Löffler–Freytag reaction mechanism ...... 43 Figure 2-4 Radical chaperone strategy toward C–H amination of alcohols ...... 44 Figure 2-5 Aldimine analogues as radical chaperones ...... 46 Figure 2-6 Hemiaminals under Suárez’s modified HLF condition ...... 47 Figure 2-7 Biased hemiaminals under Suárez’s modified HLF condition ...... 48 Figure 2-8 Acyclic and exocyclic ketimine analogues as radical chaperone ...... 50 Figure 2-9 Endocyclic ketimine as radical chaperone ...... 51 Figure 2-10 Geminal di-iodide formation via iterative HAT ...... 52

xv i

Figure 2-11 Design for β C-H amination using imidate radicals ...... 55 Figure 2-12 Discovery of β C–H amination chaperones ...... 56 Figure 2-13 Reactivity differences between trichloroacetimidate and benzimidate ...... 59 Figure 2-14 Kinetic isotope effect in imidate-mediated C–H amination ...... 61 Figure 2-15 Oxazoline derivatization: synthesis of β-amine family ...... 62 Figure 3-1 Strategy toward catalytic C–H amination ...... 106 Figure 3-2 Proposed catalytic cycle ...... 107 Figure 3-3 Robustness screen for catalytic and stoichiometric  C–H amination ...... 112 Figure 3-4 Kinetic profile of catalytic vs stoichiometric reaction ...... 114 Figure 3-5 Regioselectivity: 1,5- vs 1,6-HAT ...... 115 Figure 3-6 Diastereoselectivity: mechanistic probe ...... 117 Figure 3-7 Hammett analysis on 2-arylethanol imidates ...... 118 Figure 3-8 Hammett analysis on phenylethanol arylimidates ...... 119 Figure 4-1 Oxazole as an important chemical scaffold ...... 136 Figure 4-2 Oxazole synthesis from imidates...... 137 Figure 4-3 Acetyl hypoiodite playing a dual role ...... 138 Figure 4-4 Accessing a family of azoles via tandem HAT ...... 142 Figure 4-5 Proposed mechanism ...... 144 Figure 4-6 Mechanistic studies on iterative HAT ...... 145 Figure 5-1 Pre-oxidation of imidate to circumvent radical quenching ...... 181 Figure 5-2 BDE of ground and radical anion states of oxime imidates (in kcal/mol)..... 182 Figure 5-3 Derivatization of imidoyl chloride ...... 182 Figure 5-4 Alternative route to di-nitrophenyl imidoyl chloride ...... 184 Figure 5-5 Synthesis of oxime imidates ...... 185 Figure 5-6 Hydroamination of allyl alcohols via imidate radicals ...... 186 Figure 5-7 Proposed photocatalytic cycle ...... 187 Figure 5-8 Catalytic difunctionalization of allylic alcohols ...... 188 Figure 5-9 Uncatalyzed vs photocatalyzed hydroamination ...... 189 Figure 5-10 Radical clock experiments indicate:  addition > cyclization > SH2 ...... 193 Figure 5-11 Mechanistic support for radical–radical coupling ...... 195 Figure 5-12 Imidate complementary reactivities ...... 197 Figure 5-13 Comparison of N-centered radical precursors...... 198 Figure 5-14 Enantioselective  C–H amination of alcohols ...... 199

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Chapter 1 C–H Functionalization via Hydrogen Atom Transfer

Portions of this chapter are adapted from the following publication:

Stateman, L. M.; Nakafuku, K. M.; Nagib, D. A. “Remote C-H Functionalization via

Selective Hydrogen Atom Transfer” Synthesis, 2018, 50, 1569 – 1586. Copyright Thieme.

Reproduced with permission

Author contribution: The original review is divided based on types of radical initiation (e.g. nitrogen, carbon and oxygen). KMN wrote the sections on N(sp2)-radical initiation as well as sections on carbonyl diradical initiation, which is not covered in this dissertation. LMS wrote the sections on N(sp3)-radical initiation. KMN gathered and reviewed additional references since its publication.

1 1.1 Introduction: C–H Functionalization

Alkane, a saturated hydrocarbon scaffold, is the principal component of chemical feedstocks such as oil and natural gas. Despite their availability, there are still only few synthetically practical processes to directly convert these hydrocarbons into valuable chemical building blocks. While chemical cracking and thermal dehydrogenation of crude oil could deliver valuable olefins as primary building blocks, these indirect approaches are enormously energy intensive and offer little control over selectivity. Thus, the direct functionalization of ubiquitous carbon–hydrogen bonds (C–H) on organic molecules can be a powerful synthetic tool to construct new carbon–carbon (C–C) and carbon-heteroatom

(C–X) bond and to synthesize complex molecules.

However, the chemical inertness of alkane C–H bonds makes the functionalization challenging. Due to the strong covalent C–C and C−H bonds that keep the molecule together, C–H bonds are unreactive toward both homolytic and heterolytic cleavage. The typical bond dissociation energies (BDE)1 of C–H bonds are around 90 – 110 kcal/mol and they are considered to be non-acidic (pKa = 45 – 60) (Figure 1-1).

Figure 1-1 Bond dissociation energy of common C(sp3)–H bonds

In addition to a high energy barrier for C–H activation, the ubiquitous nature of C–

H bonds on a molecule makes the selective functionalization of chemically similar C–H

2 bonds challenging. In addition, there is a need for precise control over specific C−H bond in the presence of more conventional reactive functional groups. Thus, the ultimate solution to C–H functionalization is considered to be a holy grail of organic synthesis2, with a potential to revolutionize the way that chemists approach organic synthesis. Idealized C–

H functionalization methods, therefore, will be capable of rapidly introducing molecular complexity a high level of regio-, chemo-, and stereocontrol.

In the context of target-oriented synthesis, the application of C–H functionalization strategy has a tremendous impact on step economy3,4, atom economy5 as well as redox economy6, minimizing the overall effort required to arrive at the desired target. There is an intrinsic advantage to employing pre-existing C–H bonds, which does not require an independent preparation. C–H functionalization methods expand conventional chemical space and offer a unique opportunity to diversify complex structures without carrying out individual de novo syntheses by taking advantage of differences in their innate stereoelectronic properties (Figure 1-2).

Figure 1-2 Different types of C–H bonds

1.2 Early Inspiration for Directed C–H Functionalization

3 While the field of C–H functionalization has enjoyed a resurgence in the last decade or so, its fundamentals and implications were expressed explicitly by pioneers such as

Breslow7,8 and Barton9,10 several decades ago (Figure 1-3). Inspired by nature’s ability to convert stearic acid, a saturated fatty acid with an 18-carbon, selectively via a desaturate enzyme to oleic acid, where a degree of desaturation is introduced between C9 and C10,8

Breslow has pioneered the field of biomimetic chemistry. Using radical relay combined with chemical templating, Breslow was able to achieve site-selective C–H oxidation.

Similarly, Barton has opened the door for selective C–H hydroxylation reaction by an iron– oxo complex.

Figure 1-3 Inspiration from nature for selective C–H functionalization

Synthetic organic chemistry normally achieves selectivity by manipulation of the intrinsic reactivity of the substrate, but enzymes use a different principle, where the geometry of the enzyme–substrate complex determines enzymatic selectivity, overriding any normal selectivity. Breslow demonstrated the feasibility of this biomimetic strategy in

4 the synthetic setting using many different small molecules templates (Figure 1-4). For example, Breslow achieved selective abstraction of the C14 hydrogen atom within a steroid via the diradical of a benzophenone carbonyl, which was tethered to the C3 hydroxyl group via esterification. In this case, a subsequent, oxidative hydrogen atom transfer (HAT) adjacent to the resulting C-radical furnishes a remote olefin. This remote C–H functionalization has been extended toward other regioselective C–H oxidation chemistry via developing new linkers to facilitate the hydrogen atom transfer from one specific C–H bond that resulted in selective C–H chlorination, hydroxylation and olefination.

Figure 1-4 Regioselective steroid C–H functionalization via molecular templating

1.3 Recent Advances in Directed C–H Functionalization

5 Since Breslow’s series of observation and development of radical relay strategy for

C–H functionalization, a growing repertoire of directed C–H functionalization reactions has been reported lately, including C–H insertion11, arylation12,13, alkylation14,15, alkenylation16, amination17,18, hydroxylation19, borylation20, silylation20 and halogenation21–23. However, these methods often employ transition metal-catalysts and the application of robust hydrogen atom transfer (HAT) has played a much less significant role in advancing the fields of selective C–H functionalization. However, this HAT approach not only streamlines existing syntheses of useful molecular scaffolds, but also changes the way chemists think about chemical reactivity and plan chemical syntheses. Following sections of the chapter will outline the history, recent advances, and the principle of intramolecular HAT via N-centered radicals as a guide to demonstrate the utility of the

HAT-mediated C–H functionalization methods.

1.4 General Strategy for Remote C–H Functionalization via HAT

The typical synthetic method of remote, directed C–H functionalization via HAT reactions is divided into four distinct steps. Mechanistically, all intramolecular HAT reactions involve; (1) formation of a radical precursor; (2) initiation of the radical; (3) regioselective 1,5-HAT; and (4) termination via trapping of the relayed radical (Figure 1-

5).

Figure 1-5 Four elementary steps toward selective C–H functionalization

N-radical precursors (Figure 1-5, top left): The first step in promoting an intramolecular

HAT is the construction of a stable radical precursor that will enable access to the key, single-electron intermediate via mild methods. The most common form of HAT-initiation is from electronegative nitrogen- and oxygen-centered radical, although there are few examples of carbon-centered radicals.24 The remainder of this chapter specifically focuses on N-centered radical examples. As shown in Figure 1-5, there is a range of methods for accessing radical precursors. N(sp3)-centered radicals are typically accessed via SET reduction or homolysis of a weak N–X bond, where X is a halide or N2 or oxygen-based nucleofuge. During the infancy of N-radical precursor development, weak N–X bonds have

7 been pre-formed, but they are now typically generated in situ, since N–X bonds are often unstable. In the case for N(sp2) radical precursors, the generation of the N–X bonds involves multiple synthetic steps, which often limits the types of precursors that one could access. Similar to N(sp3)-radical, SET reduction or homolysis of N–X leads to the formation of N(sp2) radical, which often exhibit different chemical reactivity from its

N(sp3) counter-part.

Radical initiation (Figure 1-5, bottom left): The next step of the HAT mechanism is the generation of the radical intermediate. In the past, this has been the most constraining aspect of HAT chemistry, since typical strategies employ a combination of strong acid, high temperatures, unstable peroxides, toxic reagents, or energy-intensive UV light. These required harsh conditions rarely allow for functional-group compatible transformations, putting the synthetic potential of radical reactions in a negative light for a long time. More recently, however, earth abundant metals (e.g., Fe, Cu, Ni), benign hypervalent iodine reagents25,26, and visible-light-mediated photoredox catalysts27–31 have enabled controlled generation of radicals, harnessing inherent HAT reactivity.

1,5-HAT (Figure 1-5, top right): Despite the rapid, exergonic nature of many intramolecular radical translocation events, hydrogen atom abstraction frequently occurs with complete regioselectivity. The 1,5-HAT pathway is dictated by a pre-organized, six- membered transition state, with nearly linear C–H–X geometry (153° for O•)32. For the C• mediated process, there is a strong enthalpic preference for 1,5-HAT over 1,4- HAT (ΔΔH:

6.6 kcal/mol).33 In contrast, 1,5-HAT over 1,6- HAT selectivity stems from a lower entropic barrier (ΔΔS: 8.3 eu, 2.5 kcal/mol) in the O• pathway.34 As a consequence, the rate of 1,5-HAT is at least 10 times faster (2.7x107 s–1) than that of the 1,4- or 1,6-variants.35

8 Rare exceptions36 are cases where C5 lacks a hydrogen atom, when adjacent  C–H bonds are significantly weaker (e.g., benzylic, tertiary, α–oxy), or when geometry disfavors chair- like transition for 1,5-HAT. Otherwise, selective 1,5-HAT of an initiating radical offers access to a δ carbon radical.

Figure 1-6 Fundamental principle of hydrogen atom transfer

When considering the hydrogen atom transfer reaction, there are two main driving forces to be considered: thermodynamic and kinetic factors (Figure 1-6).

Thermodynamically favorable HAT involves formation of a stronger bond via abstraction of a weak C–H bond. For example, amminium radical cation undergoes thermodynamically-driven HAT since a weak benzylic C–H bond (90 kcal/mol) is abstracted while formation a much stronger N–H bond (105 kcal/mol). Another major

9 contributor to the efficiency of HAT is radical polarity. In 1999, Roberts reported the rate and selectivity of the hydrogen atom abstraction reactions depend on polar effects that operate in the transition state.37 Polarity matched hydrogen atom abstract contributes to the lowering of the kinetic barrier toward radical translocation. The polarity of a radical can be assigned via determining its corresponding cation and anion stability. An electrophilic radical is one that leads more easily to an anion by electron gain than to a cation by electron loss and vice versa for a nucleophilic radical. As an example, amminium radical cations are considered electrophilic since gaining of an electron will satisfy the octet on nitrogen atoms. Benzylic radicals are considered to be nucleophilic since loss of an electron leads to the formation of resonance-stabilized benzylic cations. Thus, the HAT example given in

Figure 1-6 is both a thermodaynamically and kinetically favored process. Throughout the chapter, the fundamentals of HAT reaction will be discussed to explain the inherent reactivity and selectivity of each N-centered radical transformation. Understanding both the thermodynamic and kinetic driving forces for HAT had led to optimized design of the radical precursors and multiple termination steps.

Radical trapping (Figure 1-5, bottom right):

The overall transformation, and the specific identity of the group that is incorporated via C–H functionalization, relies on the radical trap that is used to terminate the radical chain process. In this regard, radical-mediated processes offer a wide array of synthetic complementarity to transition-metal mediated approaches. For instance, unlike the strong reliance of metal system on aryl/alkyl halide/pseudohalide or organometallic species, radical traps can range from caged radicals (X•), to weakly bonded main group molecules (N–X, RSO2–X, Sn–H), metal salts (Cu–X, CuN3), and π-systems (alkenes,

10 arenes). This diversity of methods suitable for terminating HAT mechanisms allows for the widest scope of reactivity that is available for C–H functionalization and makes the strategy attractive toward late-stage functionalization of complex molecules.38

1.5 Remote C–H Functionalization via Nitrogen-Centered Radicals

N-centered radicals continue to predominate the realm of intramolecular HAT reactions. Due to the facile tunability of N-radical polarity via N-substitution39, the development of N-centered radicals flourished in the last century or so, which led to the advancement of many methods to initiate the radical process.40,41

1.5.1 N(sp3)-Radical Initiation

The earliest example of selective C–H functionalization via N-centered radical

HAT was reported by Hofmann in 1883 (Figure 1-7).42

Figure 1-7 δ C–H amination via N-centered radicals, initiated by N–Cl/Br homolysis

This N-radical reaction, known now as the Hofmann–Löffler–Freytag (HLF) reaction, arises from thermally-initiated homolysis of a cationic N-chloroamine.43,44 The resulting electrophilic amminium radical cation enables the abstraction of a hydrogen atom from the δ C–H bond, producing a new C-centered radical. The selectivity of this 1,5-HAT is governed by a chair-like transition state (see Chapter 2 for detailed mechanism). The ensuing nucleophilic δ C-radical is then trapped by recombination with a caged electrophilic Cl• (or propagation from N–Cl) to generate a δ chloride, which is then displaced via intramolecular cyclization. This strategy for accessing pyrrolidines directly from linear amines via δ C–H amination has enabled the streamlined synthesis of several natural products and their analogues. For instance, Löffler and Freytag, in 1909, used this reaction in the synthesis of nicotine from the corresponding linear N-bromoamine45, and

Corey, in 1958, employed this approach in the synthesis of a series of cycloaminated steroid derivatives.46 In 1979, Baldwin extended this method to the total synthesis of gelsemincine.47 Overall, the HLF reaction has played a pivotal role in demonstrating

12 feasibility of HAT strategy as a robust and selective radical-mediated C–H functionalization method that can be utilized on complex molecules.

Hofmann’s seminal report inspired further improvement of intramolecular HAT strategies to selectively achieve C–H amination reactions. In the original reports of the

HLF reaction, the use of refluxing sulfuric acid was required to generate the electrophilic

N-radical, which significantly reduced its functional group tolerance. Additionally, the preformation of N–Cl species limited the efficiency of this method. In 1985, Suárez and co-workers circumvented the need to pre-form and isolate the N-haloamine by generating

N–I in situ (Figure 1-8).48 By employing molecular iodine and a hypervalent iodine oxidant,

PhI(OAc)2, N–I is generated from AcO–I. The N–I bond that is generated in this Suárez- modification has the BDE of 38.0 kcal/mol, compared to 48 kcal/mol for the N-Cl bond and the ensuing weak N–I bond homolysis is initiated by visible light to generate the analogous electrophilic N-centered radical. The use of N-nitroamines, N-cianamines, and

N-phosphoroamidates allowed for polarization of the N-centered radical to facilitate rapid hydrogen atom transfer, eliminating the need for a strongly acidic condition. Through these rational reaction designs, Suárez demonstrated synthesis of bicyclic lactams via transannular C–H lactamization as well as the δ C–H amination of carbohydrates at the anomeric carbon are possible using a radical relay strategy.

Figure 1-8 δ C–H amination via in situ N–I formation and homolysis

Further modifications of this N-centered radical strategy were explored independently by the Herrera49 and Muñiz50 groups. Whereas the Suárez HLF reaction efficiently aminates weak C–H bonds (benzylic, tertiary, α-oxy), Herrera and coworkers investigated 1,5-HAT from primary C–H bonds. The challenge of this transformation arises from the high bond dissociation energy (BDE) of primary C–H bonds (>100 kcal/mol vs

1 90 kcal/mol, benzylic). Their solution involves adding PhI(OAc)2 oxidant to the reaction portion-wise to prevent undesired over-oxidized side products (e.g. amino C–H oxidation, instead of desired N-oxidation) via excess formation of I• species. Alternatively, divergent reactivity to access lactams was accomplished using slow addition of I2, where

C undergoes tri-iodination and amination, followed by hydrolysis, to yield pyrrolidin-2- ones (Figure 1-9). Also in 2015, Muñiz reported a catalytic variant of the Suárez reaction,

50 using 10 mol% of I2 and a benzoic-acid derived hypervalent iodine oxidant. This represents the first catalytic HLF reaction. Its utility is still limited to weaker benzylic and tertiary C–H bonds due to competitive C–H oxidation via I• species. In 2017, the Muñiz and Reiher groups reported a dual-catalytic method for δ C–H amination in which an

14 – organic photoredox catalyst allows for catalytic re-oxidation of the I to the I2 co-catalyst.

51 In this pathway, air serves as the terminal oxidant to reform I2 from the HI byproduct.

Figure 1-9 Modern improvements to Suárez’s HLF δ C–H amination

Although many HLF modifications are iodine-mediated, excess I2 generates undesired oxidized side-products, leading to poor selectivity for product formation in the case of C–H amination of unactivated secondary bonds. The rate of the desired N-radical

HAT becomes competitive with the rate of undesired HAT from I• when the BDE of the 

C–H bond becomes thermodynamically unfavorable for the hydrogen atom abstraction. In

2016, the Nagib group developed a solution that circumvents the build-up of excess I2 by generating it in situ via slow oxidation of NaI (Figure 1-10).52 In this approach, triiodide

– 7 –1 (I3 ) is generated in equilibrium upon combination of I2 and NaI (Keq = 10 M ), whereby

– 53 I scavenges I2 and limits side products derived from I2 oxidation. This triiodide-mediated approach is the first to enable δ C–H amination of amines with unactivated secondary C–

H bonds and serves to complement methods that are better suited for stronger C–H bonds.

Notably, this reaction is selective for δ secondary C–H functionalization, even in the

15 presence of weaker tertiary C–H bonds in the same molecule. The use of other sodium halide salts, NaCl and NaBr, facilitates interception of two key intermediates in the proposed mechanism: the N–Cl and the δ C-Br amines.

Figure 1-10 Triiodide strategy for δ C–H amination of unactivated 2° C–H bonds

Alkyl azides have been implemented as an alternative to N-haloamines as precursors to N-centered radicals, enabling similar reactivity (Figure 1-11). Kim and co- workers generated N-radicals by combination of alkyl azides and Bu3Sn•, followed by loss

54 of N2. The resultant, Sn-stabilized N-radical effectively performs a 1,5-HAT to yield the

δ C-radical, which is then trapped by Bu3SnD affording selective δ-deuteration. The neutral amminium radical is made more electrophilic by appending polarizable tributyl tin group, allowing for kinetically favorable HAT. This strategy was later applied by Gevorgyan and co-worker to make primary C-radical more electrophilic by installing a neighboring silyl group to achieve remote C–H desaturation of alcohols55 and amines56. Recently, metal- catalyzed variants have also been developed for conversion of azides into nitrenoids. Zhang and co-workers first employed this strategy using a Co(II) metalloporphyrin catalyst.57,58

Similarly, the Betley group reported a nitrene-mediated C–H amination of both activated

16 and unactivated C–H bonds δ to azides, using high-spin Fe(II) catalysts.59 The mechanism was proposed to occur either via intramolecular HAT from the imido radical, or via a closed-shell C–H insertion pathway.

Figure 1-11 δ C–H amination via azide-derived N-radicals and nitrenes

In addition to selective C–H aminations, N-centered radicals have also been employed to convert inert, distal C–H bonds into other functional groups. For example, intercepting the δ-halo intermediate of the HLF mechanism has been developed as an important method for installing a versatile halide group at the δ position via remote C–H functionalization (Figure 1-12).

Figure 1-12 δ C–H halogenation via N-radicals

Nikishin and co-workers reported the first δ C–H chlorination in 1985 using

60 stoichiometric CuCl2 and sodium persulfate. In 2015, Yu and Qin reported a modern variant to access δ chlorination using photoredox catalysis from the preformed N–Cl amine.61 Selective C–H bromination was obtained by Corey and co-workers using in situ generation of a trifluoroacetamide N–Br with acetyl hypobromite (AcO–Br).62 Less nucleophilic triflimide as well as bromide as a poor nucleofuge prevents cyclization, which results in the formation of the  bromide. In 2017, J.-Q. Yu and co-workers introduced a

Cu-catalyzed approach to δ bromination using Me3Si–N3 and NBS to generate transient

63 amidyl radicals and intercept their δ-C radicals. While the I2–mediated HLF reaction results in rapid cyclization of the δ iodide, early reports in 1989 by Suárez included the observation of a small amount of δ iodide remaining, as well as trace δ diiodide byproduct.64 Togo and co-workers demonstrated that these multi-iodination products could be harnessed in the synthesis of saccharides via a iterative C– H iodination of o-tosylamides at the benzylic position, followed by ring closure and hydrolysis to yield the sulfonamide product.26 More recently, Cook and co-workers reported the first δ C–H fluorination,

18 enabled by Fe-catalyzed transposition of a preformed N–F to a benzylic C–F.65 Strong N-

F bond (approximately 70 kcal/mol)66 is reduced by the iron-catalyst to generate the amidyl radical. This method remains site selective in the presence of benzylic C–H bonds of similar BDEs, which strongly supports the mechanism via 1,5-HAT radical generation.

In 2008, Baran and co-workers developed an HAT-based strategy to access 1,3- diols via -oxygenation from N-bromocarbamates (Figure 1-13).67 Following photoinitiated homolysis of N–Br, an unusual 1,6-HAT occurs along with bromine C- radical trapping, affording the alkyl bromide. Although the HLF reaction typically undergoes 1,5-HAT, this carbamate tether promotes a seven-membered, cyclic transition state, affording the γ halide. Due to its reduced electrophilicity compared to other N- protecting group, the hydrogen atom abstraction from carbamate N-radical occurs only from a weak benzylic or tertiary C–H bond.39 The resulting alkyl bromide is then displaced, generating an iminocarbamate. This intermediate is hydrolyzed to unmask the 1,3-diol, providing access to a synthetically valuable motif in a one-pot synthesis from the N- bromocarbamate.

Figure 1-13 γ C–H halogenation of alcohols via N–Br homolysis

The useful features of the transformation are the unique chemo- and regioselectivity observed during the reaction with a substrate containing multiple tertiary C–H bonds.

White’s iron-catalyzed porphyrin chemistry results in the oxidation specifically at tertiary

68 C–Ha furthest away from electron-withdrawing carbamate group while an N-radical mediated strategy leads to diol as a single regioisomer via activation of C–Hb. In comparison, non-selective C–H oxidation using Curci conditions69, TFDO, an electrophilic dioxirane-analogue, indiscriminately provides a complex mixture of oxidized products, presumably oxidizing all the activated C–H bonds (C–Hc).

In 2017, Roizen and co-workers reported N–chlorosulfamates facilitate highly selective γ halogenation of secondary C–H bonds (Figure 1-14).70 This photoinitiated chlorination is γ selective even in the presence of weaker C–H bonds that are tertiary or α- heteroatoms. This robust γ selectivity, dictated by sulfamate geometry, was further extended to other γ C–H functionalizations via sulfamate ester-directed xanthylation of

C(sp3)–H bonds.71 Concurrently, Alexanian and co-workers achieved amide-directed  selective C–H xanthylation via thiocarbamylsulfenamide.72

Figure 1-14 C–H halogenation and xanthylation via N–X homolysis

In 2015, J.-Q. Yu and co-workers utilized amidyl radicals to functionalize both γ and δ C–H bonds in a single cascade reaction to generate iodolactams from alkyl amides

(Figure 1-15).63

Figure 1-15 γ, δ-Amino-iodination of amides via amination/scission cascade

This transformation begins with in situ conversion of an amide into its corresponding N–I intermediate by treatment with NIS. The thermal-induced homolysis

21 yields the corresponding N-radical. Following 1,5-HAT, iodination, and lactam formation, the mechanism then proceeds via an azido radical mediated β-scission of the C–N to form a terminal olefin. Subsequent N-centered radical 5-exo-trig cyclization and I• trapping yields the δ-iodo-γ-lactam. This selective dual-functionalization method converts two remote adjacent C–H bonds in a single chemical operation.

The common feature in all of the previously described mechanisms is the SET reduction or homolysis of a weak N–X to generate an N• intermediate, which results in the formation of an X• or weak N–X bond. However, these are great traps for the δ radical via progation mechanism. Thus, while there are several methods of accessing δ C–H functionalization with halides and heteroatoms, there is no other mechanistic pathway for accessing C–C formation via this N–X activating mechanism. In 2016, the Knowles73 and

Rovis74 groups overcame this synthetic challenge by circumventing the need for pre- installation, or in situ generation, of an N–X bond, which allowed for construction of - selective C–C bonds via amidyl radicals (Figure 1-16).

Figure 1-16 Photoredox-catalyzed γ or δ C–H alkylation via PCET N–H oxidation

This mechanism proceeds via a neutral amidyl radical, which is generated from oxidative proton-coupled electron transfer (PCET)75 by a combination of inorganic base and excited iridium photocatalyst. Concurrent deprotonation and oxidation via a photocatalyst generates the N-radical. As in the HLF reaction, the resulting amidyl radical undergoes a 1,5-HAT to form a carbon-centered radical. However, instead of undergoing typical X• trapping (since there is no halogen), the C-radical is trapped via 1,4-addition into a Michael acceptor (i.e. Giese radical addition76), producing a new C–C bond from a tertiary δ C–H bond. Reduction of the newly formed α-carbonyl C–radical provides a stabilized anion and the SET from photocatalyst regenerates the Ir(III) catalyst. The remote alkylation product is formed after the protonation of the anion. The success stems from avoiding the need for halogens (X2 or in situ N–X) to generate the N-radical, and thus non- halide-based trapping mechanisms is operative. In 2017, Rovis and co-workers extended

23 the method, wherein C–H alkylation occurs on the carbonyl side chain of the amide (rather than the N-substituent).77

The typical HLF reaction transforms the linear aliphatic N-haloamines either thermally or photolytically in a strong acidic media to generate N• and X•. The C• via 1,5-

HAT always recombine with the caged radicals X•, thus limiting the functionalization of amines to C–H halogenation, C–H amination, or C–H alkylation via PCET. To further expand the scope and maximize the synthetic potential of the HAT process, in 2019, Nagib and Zhu independently developed a copper-catalyzed  C–H arylation of amines, in which the generation of N-centered radicals from N–F radical precursor was coupled with the downstream copper-catalyzed cross-coupling reaction (Figure 1-17).78,79

Figure 1-17 functionalization of amines via metal-catalyzed N–F reduction

Using copper metal salt, neither the C-fluorination nor the N-arylation products were observed under their developed condition. Given the strong dependence of reaction efficiency, as well as the ready availability of enantioenriched bis-oxazoline ligands, Nagib and co-worker reported an example of asymmetric version of this  C–H arylation. Zhu

24 expanded the scope of this copper N–F strategy to readily install the CF3 group, utilizing

80 (bpy)Zn(CF3)2 as a stable transmetalating CF3 source.

The relatively harsh reaction conditions and the instability of the N-haloamines have limited to some extent its synthetic applications. In 2018, Studer and co-worker developed N-allylsulfonamides as a new precursor for HAT strategy.81 Using more stable, isolable N-radical precursor than N-haloamines, practical strategy for -selective amine functionalizations, including azidation, chlorination, bromination, trifluoromethylthiolation, phenylthiolation, cyanation, and alkenylation, were developed

(Figure 1-18).

Figure 1-18 δ C–H functionalization via N–S fragmentation

Mechanistically, radical initiation occurs by thermal decomposition of di(dodecanoyl) peroxide to provide the corresponding alkyl radical. The alkyl radical reacts with corresponding radical traps, which results in the formation of new radical species.

Ensuing radical then adds to the allyl sulfonamide that results in the fragmentation to give the desired amidyl radical. The electrophilic N-radical in turn undergoes 1,5-HAT to

25 generate the tertiary C-radical, which capture the radical trap and provide the - functionalization product via chain propagation mechanism.

Further expanding the scope of the HLF reaction, Zhu and co-workers interrogated

N-aminated dihydropyridines as a stable replacement of N–halo species to access a non- propagative mechanism for distal C–H functionalization (Figure 1-19).82

Figure 1-19 δ C–H azidation via amidyl radicals from N–N precursor

Using the radical polarity-reversal strategy37, they reasoned that if an electrophilic radical species (AcO•, generated from reduction of peroxide via Cu) abstracts the hydridic

C–H at the C4 of dihydropyridine, N-aminated dihydropyridines will fragment into amidyl radical and neutral pyridine leaving group. The N-radical undergoes 1,5-HAT from the benzylic C–H bond. This ensuing benzylic radical is captured by copper to generate a benzylic azide product via reductive elimination. High level of regioselectivity is derived from 1,5-HAT of an amidyl radical, even in the presence of other weak C–H bonds. This strategy was further expanded to oxidative trifluoromethylation. Instead of peroxide,

26 Togni’s reagent is used as a source of an electrophilic radical, generated from a copper reduction of I–CF3 bond. The electrophilic CF3• abstracts the C4 hydrogen atom of dihydropyridine, leading to radical fragmentation to generate N-centered radical, which undergoes 1,5-HAT to generate the benzylic radical. The ensuing radical participates in copper-mediated –hydride elimination to install activated styrene motif. Subsequently, another equivalent of CF3• engages in rapid -addition to form the benzylic radical, followed by –hydride elimination to complete the  trifluoromethylation of amides.

There have been many examples of reductive generation of the N–radical species.

In contrast, the oxidative radical generation is still limited to the PCET strategy that the group of Knowles and Rovis independently reported in 2016. In pursuit of developing a new oxidative strategy, Leonori and co-worker developed a method in which an N-radical is generated via decomposition of amide bearing a pendant carboxylic acid (Figure 1-20).83

Figure 1-20 δ C–H functionalizations of amides via photoredox catalysis

Mechanistically, in the presence of inorganic base, oxidizing organic photocatalyst facilitates decarboxylative fragmentation of carboxylate that results in the generation of an amidyl radical. At this point, enthalpically favored 1,5-HAT delivers the distal C–radical,

27 which displays nucleophilic character to undergo group-transfer with a electrophilic radical trap, such as N-fluorobenzene sulfonimide, oxidized succinimide, and hypervalent iodines, to furnish the δ-functionalized amides.

1.5.2 N(sp2)-Radical Initiation

Since the late 1960’s84, an iminyl (sp2) N-centered radicals attracted interest from the synthetic community as a way to generate a library of heterocycles via radical cyclization. Extensive kinetic studies by Newcomb and co-workers85 have shown that iminyl radicals exhibits complementary reactivity to N(sp3)-radicals; they undergo a much slower addition to olefins and reduction by an intermolecular H-atom relative to neutral aminyl radicals. This kinetic difference can be explained by their differences in radical character. EPR studies have demonstrated that the odd electron of N(sp2)-radicals resides in a -orbital on nitrogen orthogonal to the C=N -system.86–89 Delocalization of the N- radical in the p orbital results in less reactive radical compared to that of N(sp3) counterpart

(Figure 1-21).

Figure 1-21 Rate of radical cyclization and H• atom reduction

This distinct kinetic profile of the N(sp2)-centered radical allowed access to different synthetic avenues from that of N(sp3)-centered radical. While pioneering work from Forrester,90 Zard,91 Narasaka,92 and Weinreb93 have shown the synthetic utility of iminyl radicals by their addition into π-systems, there are only few reports on N(sp2) radical-based HAT reactions. The lengthy construction of radical precursor and the harsh conditions typically employed to generate iminyl radicals (strong oxidants, elevated temperatures) have likely limited an extensive exploration of this reactivity, even though

N(sp2) radical provides orthogonal reactivity to N(sp3) radical.

In 1979, an initial report by Forrester and co-workers demonstrated iminyl radicals are capable of performing 1,5-HAT to form a radical δ to N, and γ to an imine (Figure 1-

22, left).87 These radicals were generated by decomposition of oximes bearing a pendant carboxylic acid.94 Upon Cu-catalyzed, persulfate-mediated oxidation, and subsequent loss of CO2 and CO via radical fragmentation, the iminyl radical engages in several reactive pathways, including HAT from benzylic C–H bond and N-N dimerization. The resulting benzylic radical is oxidized by the copper catalyst and the benzylic cation is trapped by the

29 appending imine via intramolecular cyclization. Various tetralone derivatives were synthesized via this new iminyl-radical based approach, including pyridyl analogues.95

Figure 1-22 γ C–H functionalization via iminyl N(sp2) radicals

In 2011, the Chiba group reported a Cu-catalyzed benzylic oxygenation via iminyl radicals (Figure 1-22, left).96 The radical precursors were generated in situ by Grignard addition into nitriles to form aryl imines. Next, direct Cu-catalyzed oxidation under an O2 atmosphere facilitates 1,5-HAT of the iminyl radical to form a benzylic radical, which is subsequently trapped by O2 to provide a 1,4-keto-imine and upon hydrolysis affords the di-keto product.

In 2017, Nevado reported a mild, photoredox-catalyzed method to harness iminyl radicals.97 Employing acyl oximes as radical precursors, it was found that Ir photocatalysts could reduce the weak N–O bond of the oxime to generate an iminyl radical and benzoate

30 anion. Upon HAT, the δ C-radical could either result in C–N or C–C formation, depending on reaction conditions. In the former case, an oxidation event turns over the photocatalyst and allows for C–H amination via ring closure in the presence of DBU. On the other hand,

C–H arylation is observed in a CH3CN/H2O mixture when the radical first adds into an arene before oxidation by the catalyst.

Fu and co-workers98 have similarly employed an oxime for photoinduced iminyl radical formation.99 However, by designing a more easily reduced (2,4-dinitrophenol) nucleofuge, it was found that a metal catalyst is not needed. Instead, appending tertiary amines, which are excellent electron donors, are able to form an excited state complex with the dinitrophenyl group to promote photo-induced fragmentation. In their system, the resultant iminyl radical undergoes 1,5-HAT to generate an α-amino radical. Oxidation of this species affords a transient iminium species, which is trapped by the pendant imine. An additional oxidation facilitates the aromatization to heterocyclic product.

Typically, N(sp2) radical precursors are generated by either condensation of hydroxylamine onto a ketone or acylation of an oxime. However, in 2017 the Nevado group employed a synthetically distinct route to generate an iminyl radical (Figure 1-23)100 via radical addition (e.g. carbon radical101 and thionyl radical102) at -position of the azido styrene to generate an iminyl radical. Upon decarboxylative C–radical formation and addition into vinyl azide, the intermediary α-azido radical rapidly expels N2 to form an iminyl radical that promotes HAT and subsequent γ-arylation via -addition into an arene.

Figure 1-23  C–H arylation via vinyl azide-derived N(sp2) radicals

In 2012, the Chiba group reported the first use of an amidinyl radical in an HAT mechanism.103 These amidine radical precursors are readily derived from nitriles and amines and can be oxidized directly using a Cu catalyst and O2 as the terminal oxidant.

Upon HAT from tertiary or benzylic C–H bonds, the resulting  C-radical can be trapped in divergent ways to access either β-oxygenation or β-amination. In the former case, O2 serves as the trap, and an ensuing Cu-mediated fragmentation and cyclization affords oxazolines. In the latter case, by employing PhI(OAc)2 as the oxidant instead of O2, N-Ph amidines are converted into imidazolines via oxidation of  C-radical to cation, followed by N-cyclization (Figure 1-24).96

Figure 1-24  C–H functionalization of amines via amidyl radicals

This powerful method of converting an amine into a vicinal diamine via β C–H amination was further extended by the Chiba group in 2014 through the development of a redox-neutral variant.104 The use of amidoximes as a radical precursor allows for an oxidant-free approach, where the weak N–O bond serves as an internal oxidant for this transformation. In this case, the Cu metal reduces the weak bond, and the oxidized Cu later serves as a trap of the relayed radical, wherein oxidation allows for redox turnover of the

Cu catalyst along with formation of the imidazoline (Figure 1-25).

Figure 1-25  C–H amination of amines via N–OR reduction

In 2017, Nagib group reported a complementary strategy to convert alcohols into

β-amino alcohols by C–H amination via in situ generated imidate radicals (Figure 1-26).105

33 To achieve the goal of simplified access to an N(sp2) radical from an abundant functional group (e.g., an alcohol), we envisioned imidates as radical precursors. They are easily prepared in situ via nitrile condensation with alcohols,106 and their closed-shell reactivity is well understood (e.g., the Overman rearrangement).107 However, imidate radicals were previously only employed in π-addition cyclizations.108 Fortunately, under triiodide- mediated δ C–H amination conditions52, it was observed that the β C–H amination of a range of alcohols was possible via this imidate-based strategy.

Figure 1-26 β C–H amination of alcohols via imidate radicals

In the mechanism, the imidate forms an N–I bond in situ, which is homolytically cleaved by visible light to generate an N(sp2) radical. Ensuing 1,5- HAT translocates the radical to the β carbon, which is subsequently trapped by I• and displaced intramolecularly to afford an oxazoline product. Notably, benzylic, allylic, secondary, and even primary C–

H bonds are aminated in this approach. The identity of the imidate enables the amination

34 of these bonds of varying strength. For example, trichloroacetimidate promotes both benzylic and allylic aminations, quantitatively, while benzimidates enable C–H amination of stronger primary and secondary C–H bonds. As an illustration of its synthetic utility, the oxazoline intermediate can be hydrolyzed to a free β-amino alcohol or to a family of β amines substituted by nucleophilic ring opening reactions. Recently, catalytic variant was reported from the Nagib group109 and electrochemical strategy was reported from the Stahl group.110

Following the C–H amination of alcohols via imidate radical relay strategy,

Nagib and co-worker reported  C–H di-halogenation of alcohols via iterative HAT

(Figure 1-27).

Figure 1-27 β C–H dihalogenation of alcohols via imidate iterative HAT

Taking advantage of the non-nucleophilic appending imidate nitrogen, the iodo imidate that is formed after initial 1,5-HAT undergoes second HAT event instead of

35 nucleophilic displacement of the C–I bond, which results in the di-iodination of alcohols.

The generality of the scope was demonstrated on di-iodination, di-bromination, and mono- chlorination of cholic acid analogues, by simply changing the anion of the sodium salts employed. Due to the lack of other practical routes to access geminal-iodide species, its synthetic utility was investigated for these versatile handles synthesized from iterative

HAT process. First, aminolysis with NH3 affords  diiodo-alcohol. Acid-hydrolysis with

HBF4•H2O results in hydrolysis of the imidate to trichloroacetate group, leaving the di- iodide intact. Alternatively, reduction of one of the iodides by Zn in AcOH affords vinyl iodide via imidate elimination. From the  di-iodo-ester, hydrolysis to -oxy ketone is possible (AgBF4, Na2HPO4•H2O); or conversion to allyl alcohol, bearing a vinyl iodide, is realized via addition of AgOTf and K2HPO4, giving two complementary routes to both internal and external vinyl iodide species.

In 2018, Leonori and co-workers reported an oxidative decarboxylative generation of iminyl radical from oxime radical precursor with appending carboxylic acid (Figure 1-

28).111

Figure 1-28  C–H functionalization of ketones via iminyl radicals

The Fukuzumi acridinium photooxidant112 was used to initiate the SET oxidation of the carboxylate, which results in the fragmentation of precursor into N-radical, CO2, and acetone. Then, iminyl radical undergoes 1,5-HAT, generating the  C–radical. The ensuing nucleophilic δ C-radical is trapped by oxidants like NCS or Selectfluor to achieve δ- chlorination and δ-fluorination, respectively. The resulting radical from the oxidant closes the photoredox cycle by SET with the reduced photocatalyst. In the same year, Studer and co-worker extended the scope of this reaction to -alkylation reaction. In the presence of alkene radical trap, radical conjugate addition of nucleophilic -C radical results in – carbonyl radical, which readily undergoes reduction via reduced photooxidant. Upon protonation of the -carbonyl anion, an -alkylated product is isolated.

1.6 Conclusion: Complimentary Reactivity Accessed via HAT

Selective C–H functionalization via intramolecular HAT is a strategy that benefits from a mechanistically distinct pathway with complementary reactivity parameters to metal-based C–H activation routes. As new methods for mild radical-generation

37 continually give way to new reaction development, there is also a sustained expansion of our understanding of the inherent chemo-, regio-, and stereoselectivity patterns for HAT mechanisms. In pursuit of solving ongoing challenges, new radical precursors will likely need to be designed, allowing for more creative methods of trapping these relayed distal radicals.

To this end, we began our investigation on developing new classes of radical precursors that are able to direct the reactivity and selectivity for C–H functionalization of alcohols. Following chapters discuss the conceptions of the imidate radical strategy

(Chapter 2 & Chapter 3), its application (Chapter 4), and the development of oxime imidate radical strategy (Chapter 5).

38 Chapter 2 C–H Amination via an Imidate Radical

Portions of this chapter are adapted from the following publication:

Wappes, E. A.†; Nakafuku, K. M.†; Nagib, D. A. “Directed β C–H Amination of Alcohols via Radical Relay Chaperones” J. Am. Chem. Soc. 2017, 139, 10204 − 10207.

Author contribution: Preliminary investigation were done along with EAW (Section 2.1 to

2.3). Endocyclic ketimine was developed by KMN (Section 2.3.3). Imidate chemistry was co-developed with EAW (Section 2.4). Reaction scope was co-developed with EAW

(Section 2.4.2 & 2.4.4). Mechanistic study and late-stage diversification were led by KMN

(Section 2.4.5 & 2.4.6).

39 2.1 Synthesis of  Amino Alcohols

 amino alcohols are synthetically valuable motifs that are present in many small molecules such as natural products, pharmaceuticals, and asymmetric catalysts. The presence of two versatile functional groups (hydroxyl and amino groups) allows for further chemical manipulations to add complexity to the molecules (Figure 2-1).113

Figure 2-1  amino alcohols as privileged motifs

Many pharmaceutical compounds containing  amino alcohol motifs are being heavily studied as they have shown to be effective antibacterial and antifungal reagents.

Amine groups modulate the solubility of the drug, and hydroxyl groups participate in hydrogen bonding to biological receptors to provide entropic advantage for binding to the target. In addition, the acidity of amines is often in the range of physiological pH, a property essential for improving the bioavailability of drugs.17,18

Due to its chemical versatility and biological potency, various synthetic methods have been developed to effectively access this privileged organic framework. Notably, in

40 1996, Sharpless and co-workers developed dual functionalization of olefins to achieve asymmetric oxyamination using osmium catalyst114, although the regioselectivity is often a problem that can be circumvented only when the substrates are biased via electronic or steric influence. With the advancement of diastereo- and enantioselective syntheses of epoxides, cleavage of oxiranes by nitrogen nucleophiles has become one of the most investigated routes to vicinal amino alcohols, noticeably Jacobsen’s chromium salen complex system.115 Nucleophilic ring-opening reactions of carbonate116, aziridine117, and cyclic sulfates118 are investigated as well. While the reduction of amino acids119 yields  amino alcohols, the derivatization relies on the availability of amino acids, which limits the number of accessible analogues. More recently, Lin and co-workers developed reductive cross-coupling of sulfinyl imines and aldehydes to access the motif with excellent levels of both diastereo- and enantioselectivity.120

The majority of these methods developed relies heavily on the conversion of pre- functionalized groups derived from olefins or carbonyls, which are synthesized from feedstock alcohols. (Figure 2-2). Thus, we envisioned we could bypass this functional group manipulation and directly access the  amino alcohol via C-H functionalization of alcohols.

Figure 2-2 Synthesis of  amino alcohol via direct  C–H amination of alcohols

2.2 Inspiration from Hofmann-Löffler-Freytag Reaction

The Hofmann-Löffler-Freytag reaction, first reported in 1883, is the first remote

C–H functionalization method using 1,5-HAT to achieve pyrrolidine formation via a C–

H amination.42 Later in 1909, Löffler and Freytag extended the scope to simple secondary amines and demonstrated the synthetic utility of N-centered radicals.45 The Hofmann–

Löffler–Freytag reaction proceeds by the pre-formation a N-haloamine (Figure 2-3). The homolytic cleavage of a weak N–X bond under photolytic or thermal conditions generates a highly reactive electrophilic N-radical cation that undergoes 1,5-HAT to form a C-radical.

This C–radical abstracts halogen from another N-haloamine to propagate the radical chain reaction and form a C–X bond. The displacement of the C-X via intramolecular cyclization constructs the -amination product.

Figure 2-3 The Hofmann–Löffler–Freytag reaction mechanism

2.3 Radical Chaperone Strategy

We envisioned that we could achieve a highly regioselective  C–H amination of alcohols by combining a radical chaperone strategy with this intrinsic selectivity of the

Hofmann–Löffler–Freytag reaction. The premise of this chaperone strategy is based on induced intramolecularity.121 Nature employs specific enzymes as directing groups to bring the substrates close proximity to the binding pockets to efficiently catalyze reactions. For example, the decarboxylation of orotidine monophosphate to generate uridine

-16 -1 122 monophosphate occurs with a t1/2 of 78 million years (k = 2.8 x 10 s ) if un-catalyzed.

In the presence of OMP decarboxylase, however, the decarboxylation proceeds with k =

39 s-1. This is a rate enhancement of 1.4 x 1017. By bringing two reactive species close to each other, one could lower the transition state barrier and set an efficient energetic discrimination to favor the desired reaction pathway. Temporarily converting an intermolecular process to an intramolecular one allows for high degrees of regio- and stereo-control in a reaction as well as dramatic rate accelerations.121

43 Thus, in this strategy (Figure 2-4), there are four distinct steps for completing this radical chaperone strategy: (1) development of a robust chaperone, (2) formation of a radical precursor; (3) development of a C-H functionalization protocol; and (4) removal of a radical chaperone.

Figure 2-4 Radical chaperone strategy toward C–H amination of alcohols

Development of robust chaperone: Radical chaperones to be synthesized need to be easily accessible from commercial reagents via high-yielding chemical transformations.

Due to the facile tunability39 of N-substitution, the development of chaperone synthesis that incorporates derivatization step is crucial in determining the robust radical chaperone that facilitate this  C–H amination via radical relay.

Formation of a radical precursor: As discussed earlier, one of the most important steps for developing a new HAT-based method is the two-electron construction of a radical precursor that will enable access to the key, single-electron intermediate. We envisioned

44 that a base-mediated alkoxide addition into an imine carbon will generate a reactive N(sp3) atom that mimics the HLF reactivity.

Development of C-H functionalization protocol: Historically, the most limiting aspect of HAT chemistry is the use of strong acid, high temperatures, unstable peroxides, toxic reagents, or energy-intensive UV light to generate the N-radical species. For accessing the

HLF reactivity, Suárez modification, as well as further develoment by the group of Muñiz,

Herrera, and Nagib, cirumvents the use of those operationally limiting conditions and enables mild access to radical intermediates. Realizing that this oxidative C–H amination generates an equivalent of acid in the final cyclization step, new non-acidic HLF conditions need to be developed, as hemiaminals are acid-sensitive functional group.

Removal of radical chaperone: After the formation of C–N bond via radical relay, the collapse of the hemiaminal product via acid-hydrolysis reveals the desired free amino alcohol. Alternatively, Lewis-acid catalyzed hydrolysis of cyclic hemiaminal allows for more mild hydrolysis in the presence of acid-labile functional group.

2.3.1 Aldimine as Radical Chaperone

Due to its ease of synthesis and possibility of rapidly generating derivatives, we first decided to target aldehyde-derived imines as radical chaperones (Figure 2-5). In order to test this feasibility of this radical chaperone strategy, we introduced two substrate biases, kinetic and thermodynamic factor, that will facilitate the rate of HAT and the overall C–H amination reaction. First, to probe the rate of HAT and nucleophilic displacement of C–I by the appending nitrogen atom, an electronically differentiated protecting group was employed.39 Second, hemiaminals with steric and electronic bias were synthesized by

45 changing the R group at the central C atom, hoping to also incorporate the Thorpe-Ingold effect. Lastly, the alcohol substrates with various  C–H BDEs were used to facilitate the

C–H abstraction by the N-radical. Therefore, hemiaminals with combinations of these three factors were synthesized.

Figure 2-5 Aldimine analogues as radical chaperones

Upon subjecting these hemiaminals to oxidative modified Suárez-HLF reaction conditions48, instead of observing the formation of oxazolidine C–H amination product, we isolated imidates as major products (Figure 2-6). The proposed decomposition pathways involve both close and open shell mechanisms; base-mediated fragmentation of N–I species or radical -scission from oxidized N-centered radical. To our surprise, using other hemiaminal starting materials with smaller alkyl substituent also resulted in the formation

46 of the same imidate product even though less substituted alkene or less stable alkyl radical would form via proposed decomposition mechanisms.

Figure 2-6 Hemiaminals under Suárez’s modified HLF condition

In order to circumvent the decomposition pathway depicted in Figure 2-6, trifluoroacetaldehyde-derived hemiaminal was engaged to the same C–H amination protocol (Figure 2-7). We hypothesized that by placing the CF3 group at the central carbon, the hemiaminal will not only avoid the decomposition via base-mediated 2 e– pathway, but also may undergo more rapid hydrogen atom transfer by making the nitrogen inductively more electrophilic, consequently avoiding the -scission. However, this hemiaminal was unstable under the reaction condition, and the imine was observed in the crude reaction mixture. Cognizant of alkyl substituents on the central carbon leads to undesired reactivity,

47 benzaldehyde-derived hemiaminal was synthesized via the same alcohol addition method described above. Due to the presence of highly activated benzylic C–H bonds, which are also next to both an oxygen and a nitrogen atom, the hemiaminal undergoes the desired C–

H oxidation via I• species that results in the formation of fully substituted imidate.

Figure 2-7 Biased hemiaminals under Suárez’s modified HLF condition

2.3.2 Ketimine (Acyclic and Exocyclic) as Radical Chaperone

Understanding the undesired reactivity was driven by the presence of activated 

C–H bonds, imines derived from various ketones were invested for the  C–H amination of alcohols. From previous studies with aldimines (Section 2.3.1), alkyl substituents were purposely avoided as substituents on the ketones. Thus, this led to initially testing benzophenone-derived ketimines as a radical chaperone (Figure 2-8).

TiCl4-mediated tosyl amide condensation to benzophenone generates a desired imine. Subjecting this imine to alcohol addition protocol, however, only resulted in a trace amount of hemiaminal formation. Presumably, the imine carbon was too sterically congested by two flanking aromatic substituents. In order to reduce the steric demand and to increase the carbonyl electrophilicity for facile alcohol addition, ethyl (Z)-2-phenyl-2-

(tosylimino)acetate was synthesized via Lewis-acid promoted amide condensation to its

48 corresponding -keto ester. While imine formation proceeded smoothly, the alcohol addition did not lead to the desired hemiaminal product, only generating a trans- esterification product.

Next, we looked to form the exocyclic imine derived from isatin, which should allow for desired carbonyl reactivity by tuning the electrophilicity. Contrary to our hypothesis, the hemiaminal formation was sluggish, and when the isolated hemiaminal was subjected to oxidative C–H amination condition, electrophilic aromatic substitution was observed at C5 position of isatin backbone, which deterred us from pursuing this scaffold.

Existing as a hydrate, ninhydrin was proposed as our next targeted radical chaperone scaffold, and a hemiaminal radical precursor was synthesized via a two-step sequence of sulfonamide condensation and alcohol addition. Under Suárez’s modified HLF condition, this hemiaminal engages in the N-radical cyclization into -carbonyl -addition, which results in a ring-expansion product. As described in Figure 1-21, the rate of radical

cyclization is 1,000 times faster than hydrogen atom reduction. As such, there was a need to develop a more electrophilic N(sp3)-radical to favor what seems to be a kinetically challenging HAT event.

Figure 2-8 Acyclic and exocyclic ketimine analogues as radical chaperone

Throughout this radical chaperone designing, we have also investigated various N- protecting group (i.e. Ac, Boc, Bz, Tf, SO2R) for each scaffold, which yielded no more success than Ts protecting, a more common N-substituent for HLF chemistry.

2.3.3 Ketimine (Endocyclic) as Radical Chaperone

After observing sluggish alcohol addition and ring expansion via -carbonyl addition, our focus shifted to the synthesis of endocyclic ketimine. This newly designed imine has three unique features: 1) endocyclic ketimine would prevent undesired oxidation as we observed with ninhydrin; 2) the strategic placement of a trifluoromethyl substituent on imine carbon should increase the electrophilicity for facile alcohol addition; and 3) rapid structural diversification is enabled by a high-yielding three-step protocol.

50 Base-mediated tosylation of tert-butylamine generates mono-substituted sulfonamide, which undergoes metal-directed ortho-lithiation to forge a new C–C bond to yield the trifluoromethyl ketone. This then engages in acid-catalyzed dehydrative cyclization to form the desired imine (Figure 2-9).

Figure 2-9 Endocyclic ketimine as radical chaperone

To install the alcohol, no exogenous base was needed, and simply stirring alcohol in the presence of excess ketimine in MeCN at 23 °C for 1 hour resulted in the formation of the hemiaminal quantitatively (Figure 2-10). When the isolated hemiaminal was stirred with 3 equivalents of I2 and PhI(OAc)2 in MeCN, only trace amount of C–H amination oxazolidine product was formed. Instead, the majority of mass balance resided in the formation of  C–H di-iodination product. The nitrogen atom on the hemiaminal rendered non-nucleophilic via inductively withdrawing CF3 group and sulfonyl protecting group on the nitrogen atom. This resulted in the second oxidation of the nitrogen atom, instead of

51 intramolecular displacement of the C–I bond, to generate the geminal di-iodide species.

Intercepting an alkyl iodide intermediate is rarely observed in HLF literature.64,123

Figure 2-10 Geminal di-iodide formation via iterative HAT

2.3.4 Proof-of-Concept:  C–H Amination of Alcohols

With an intention to facilitate the intramolecular C–I displacement via the appending N-nucleophile, we stirred the hemiaminal, PhI(OAc)2, and I2 in MeCN with anhydrous K2HPO4. This exogenous base provided the buffered reaction media and allowed for cyclization reaction, overriding the propensity of the nitrogen atom to undergo the 2nd HAT. Encouraged by this optimized condition, the scope of  C–H amination of alcohols using this endocyclic ketimine as a radical chaperone was investigated (Table 2-

1). The substrate scope showed high level of diastereo- and regioselectivity, due to structural rigidity of [5,5]-fused radical chaperone backbone, as one can see in the X-ray crystal. Using simple linear 1-octanol, we exclusively isolated  C–H aminated product with no detectable region- or diastereo-isomers. Branched alcohol, such as 3-methyl

52 butanol, gives only -aminated product even when C–H bond is a weaker, tertiary bond.

Similarly, when  position is substituted with an electron-donating (OAc) or electron- withdrawing (ketone and ester) group, only -aminated product is observed.

Table 2-1 Proof-of-concept:  C–H amination of alcohols

O O S NaI, PhI(OAc)2, T NR NH K2HPO4 O Me R MeCN, Blue LED R O F3C > 20:1 b-selective

T NR T NR T NR O S O O Me O O Ph octyl F3C N Me O 72%, > 20:1 dr 50%, > 20:1 dr 75%, > 20:1 Me b-selective 2° b > 3° g 70%, > 20:1 dr

T NR T NR O T NR O O OAc O O Me OEt

55%, > 20:1 dr 45%, > 20:1 dr 44%, > 20:1 dr b C–H > g a- oxy b C–H > g a-EWG b C–H > g a-EWG

As discussed in Section 2.3, the ultimate step of the radical relay strategy is a facile removal of chaperone to reveal free  amino alcohol. In attempting to do so, we first engaged the oxazolidine into refluxing acid and base to see if the heterocycle would undergo hydrolysis to reveal desired  amino alcohol. However, due to the sterically encumbering and electronically deactivating CF3 group, the oxazolidine remained intact without any major degradation. This appending CF3 group also prevented a strategy using a strong Lewis acid to remove the chaperone. We next investigated the removal of the chaperone via a metal reductant such as SmI2 and Na° since the nitrogen atom is connected

53 to the sulfonyl protecting group, which makes the N–S bond susceptible to a single electron reduction. However, clean conversion to a free  amino alcohol was never achieved using metal reductants.

2.4 Nitrile as Radical Chaperone

We were cognizant that N-radicals, including those of hemiaminals, are prone to β- scission and an undesired, competitive oxidation reaction. Thus, we hypothesized that masking the central C of the chaperone within an imidate should obviate any undesired degradation. However, the imidate chemistry is predominated by the Overman rearrangement124, and imidate radical chemistry has only been studied by Glover’s group.108 In their original report, photolysis of N-bromoacetimidates generated the iminyl radicals, and the ensuing N-radical engages in 5-exo-trig cyclization to form the amino- bromination product (Figure 2-11, left). While there have not been any examples of imidate radical undergoing 1,5-HAT in the literature, inspired by analogous N(sp2)systems99,125,126, we envisioned that subjecting imidates under HLF conditions would result in the formation of oxazoline via similar 1,5-HAT mechanism, which can then be hydrolyzed to generate free  amino alcohols (Figure 2-11, right).

Figure 2-11 Design for β C-H amination using imidate radicals

2.4.1 Imidate Single Electron Reactivity

To test our hypothesis, we first synthesized three imidates of 2-phenylethanol by base-catalyzed addition into a nitrile (i.e. Cl3C–CN) or acid-mediated transimidation (i.e.

MeCN, PhCN). Each imidate was then subjected to our recently developed, triiodide-based

C−H amination conditions (Figure 2-12).52

Figure 2-12 Discovery of β C–H amination chaperones

Gratifyingly, these mild conditions (NaI, PhI(OAc)2) converted all three imidates

(II-S1, II-S2, II-S3) to the desired oxazoline heterocycles (II-4, II-5, II-6), albeit with varying reaction efficiencies (e.g., trace to quantitative), reflecting a difference in the stability of the imidate intermediates, as well as their respective N-centered radicals, demonstrating the first example of imidate radical undergoing 1,5-HAT. Fortunately, trichloroacetimidate II-S3 affords a C−H amination product II-6, quantitatively in 4 hours at 23 °C. Given its synthetic convenience and utility (e.g., Overman rearrangement),107 as well as the relative stability of this precursor and subsequent radical, we chose to further explore the Cl3C−CN chaperone in our β C−H amination protocol. Additionally, we expected the resultant oxazoline (bearing a −CCl3) to be primed for acidic hydrolysis, allowing direct isolation of free β-amino alcohols via an exceptionally simple process. We found that in situ subjection of crude oxazoline II-6 to HCl (aq) in MeOH facilitates hydrolysis and simple isolation via acid/base extraction of pure β-amino alcohol II-7 in

87% yield from II-S3. Unlike other directed C–H amination reactions using carbamates127 and sulfamate128,129 linkers, our method allows for direct isolation of unprotected amino

56 alcohols, which remains a challenge in metal-catalyzed reaction in part because the products can strongly chelate the metal and inhibit the catalytic cycle.130 Thus, a formal direct installation of ammonia via imidate-radical mediated C–H amination demonstrates an orthogonal reactivity unattainable by classical two-electron chemistry.

2.4.2 Trichloroacetimidate C–H Amination

With our new protocol in hand for the net installation of −NH2 to the β position of alcohols, we then subjected this method to various alcohols bearing a range of sterically and electronically diverse 2-phenylethanols and functionally rich molecules (Table 2-2).

Table 2-2 Scope of trichloroacetimidate-mediated  C–H Amination

57 This imidate radical-mediated C−H amination method exhibited remarkably efficient C–H amination, affording nearly quantitative oxazoline formation in all cases, typically with >80% isolated yields after acidic hydrolysis and purification via acid-base extraction. Aryl substitution, ortho-, meta-, and para, of either electronically donating or withdrawing groups is tolerated (II-8 – II-15, > 74% yield). Notably, heteroarenes such as

Lewis-basic pyridine II-16 and oxidative-labile thiophene II-17 are also tolerated. To prevent acid-mediated decomposition of the sensitive thiophene product, heterobenzyl amide II-17 was isolated via a milder TsOH-based hydrolysis to provide a trichloroacetamide (Ac* = C(O)CCl3), instead of the free amine. In further probing the generality of this transformation, we observed that alcohols with tertiary β C−H bonds are aminated efficiently (II-18, II-19). These tertiary C–H bond functionalizations are typically challenging to achieve using Pd-mediated C–H amination conditions.131 The impediment to developing efficient C-H activation by metal-catalysts arises from the steric congestion, and there are only a few reliable method to access tertiary C–H functionalization.132,133 Secondary alcohols are readily β-aminated, affording remarkably high diastereoselectivity (II-20 − II-22, >20:1 dr). We were pleased to find that both cholesterol and reduced ibuprofen are converted to their β-amino alcohol analogs (II-19,

II-22).

2.4.3 Synthetic Limitation Using Trichloroacetimidate

While investigating the limitation of this imidate-mediated radical functionalization protocol, isobutanol trichloroacetimidate II-24a (R = CCl3) under our C–H amination condition results in the formation of  alkyl iodide II-26 intermediate (Figure 2-13). The

58 trichloromethyl group is a sufficiently inductively electron-withdrawing group. The nucleophilicity of the imidate nitrogen is heavily distorted and the final 2-electron intramolecular displacement of the C–I bond is prevented. Gratifyingly, we were able to access C–H amination of the aliphatic substrate by replacing the CCl3 group to the Ph group for an imidate backbone. An inductively less withdrawing Ph group makes the imidate nitrogen nucleophilic enough to allow for efficient 2-electron cyclization reaction, resulting in an oxazoline product II-27, which was also hydrolyzed under HCl (aq) to reveal -amido alcohol product II-28.

Figure 2-13 Reactivity differences between trichloroacetimidate and benzimidate

2.4.4 Benzimidate C–H Amination

With a second-generation, benzimidate enabling β C−H amination of aliphatic alcohols, we sought to explore the scope and generality of this alternate benzimidate approach (Table 2-3). Notably, an alcohol with strong, primary β C−H bonds (BDE: 101

59 kcal/mol),1 such as ethanol, would result in the formation of a primary radical affords β- amido alcohol II-29. Longer alcohols with unactivated secondary β C−H bonds (II-31, II-

31) provide even greater efficiency. Many functionalities are tolerated under these mild, radical conditions, including ethers, esters, and imides (II-32 − II-34). Hydrolysis of II-32 in acidic conditions results in diol formation via desilylation, while II-33 and II-34 undergoes competitive N and O bezoyl group transfer. Secondary alcohols can also undergo β-amination (II-35, II-36), complementary to metal-mediated approaches. Lastly, subjecting enantiopure (S)-2-methyl-butanol to the C−H amination protocol provides amide II-37 with complete stereoablation (0% es), reinforcing the presence of planar radical or cationic intermediates.

Table 2-3 Scope of benzimidate-mediated  C–H amination

2.4.5 Kinetic Isotope Effect

60 As the imidate-mediated hydrogen atom transfer has not been reported in the literature, we investigated the presence of a kinetic isotope effect (KIE) in the β C−H amination (Figure 2-14). Three different deuterium-labeling studies were conducted: 1) An internal competition experiment involving a partially deuterated reagent, where the KIE is deduced from the ratio of proteo- and deuterio products; 2) an intermolecular competition experiment with 1:1 mixture of labeled and unlabeled reactants in a single flask, with the

KIE obtained from the ratio of products; and 3) independent initial rate studies to obtain the reaction rate constant for labeled and unlabeled reactants, with the KIE obtained from the ratio of kH and kD.

Figure 2-14 Kinetic isotope effect in imidate-mediated C–H amination

A large primary KIE (8.1) was observed from intramolecular H and D competition in the imidate derived from 2-phenylethan-2-d-1-ol, suggesting HAT is likely product- determining step for this reaction. Similarly, intermolecular competition between deuterium labeled and non-labeled substrates yielded KIE values of 4.5, and the initial rate

61 study resulted in kH/kD of 2.1, suggesting HAT is likely involved in the rate-limiting step of the reaction.134–136

2.4.6 Late-Stage Diversification of Oxazoline

A synthetic advancement of our radical chaperone strategy is the intermediacy of an oxazoline that can be easily derivatized to many, useful synthetic functionalities.137 To demonstrate the wide utility of this transformation, the β C−H amination products were converted to several valuable motifs (Figure 2–15).

Figure 2-15 Oxazoline derivatization: synthesis of β-amine family

62 First, in situ hydrolysis of the oxazoline with TsOH provides acetamide II-38 as a complementary product to the unprotected β amino alcohols shown in Table 2-1 (via HCl hydrolysis). Next, subjecting II-38 to NaOH afforded oxazolidinone II-39. Importantly, oxazoline II-6 could be isolated in 88% yield, enabling several further modifications. For example, nucleophilic ring-opening of oxazoline II-6 provides access to a family of β- amines, including thioester II-40 (via KSAc) and halides II-41 – II-43 (via Me3Si-X). In an attempt to achieve fluorination using various fluoride nucleophile, no reaction was observed. Subjecting hydroxyacetamide II–38 to deoxyfluorination resulted in re- formation of oxazoline II-6. A two-step protocol using Me3Si–I to first convert the oxazoline II-6 to alkyl iodide II-41 and nucleophilic displacement by NaN3 in DMF results in azide II-44. Deoxygenation of II-6 via II-41 using Raney Ni results in the formation of alkane II-45, in addition to the full reduction of the trichloromethyl group into an acetyl group. DDQ oxidation provides a unique method of synthesizing oxazole II-46 from an alcohol and nitrile.

2.5 Experimental Section

2.5.1 General Information

All chemicals and reagents were purchased from Sigma-Aldrich, Alfa Aesar, Acros, TCI,

Combi-Blocks, or ChemImplex. MeCN was distilled over calcium hydride before use.

CH2Cl2, THF, Et2O and DMF were dried and degassed with nitrogen using an Innovative

Technology solvent system. For flash column chromatography, Silicycle F60 (230-400 mesh) silica gel or a CombiFlash Automated Flash Chromatograph was used. For

63 preparative thin-layer chromatography (PTLC) and thin layer chromatography (TLC) analyses, Merck silica gel 60 F254 plates were used and visualized under UV (254 nm) and

1 19 KMnO4. Melting points were determined using an Electrotherman IA9000. H, F, and

13C NMR spectra were recorded using a Bruker AVIII 400 MHz, AVIII 600 MHz, or AVIII

700 MHz NMR spectrometer. 1H NMR and 13C NMR chemical shifts are referenced with

1 13 1 respect to CDCl3 ( H: residual CHCl3 at δ 7.26, C: CDCl3 triplet at δ 77.16), CD2Cl2 ( H:

13 1 residual CH2Cl2 at δ 5.32, C: CD2Cl2 quintet at δ 53.84), CD3OD ( H: residual CH3OH

13 1 13 at δ 3.31, C: CD3OD septet at δ 49.00), or CD3CN ( H: residual CH3CN at δ 1.94, C:

1 CH3CN at δ 118.26). H NMR data are reported as chemical shifts (δ ppm), multiplicity (s

= singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, app t = apparent triplet, app q = apparent quartet, app qd = apparent quartet of doublets), coupling constant (Hz), relative integral. 19F and 13C NMR data are reported as chemical shifts (δ ppm). High resolution mass spectra were obtained using Bruker

MicrOTOF (ESI). IR spectra were recorded using a Thermo Fisher Nicolet iS10 FT-IR and are reported in terms of frequency of absorption (cm–1). The diastereomeric ratio of the hydroamination product was determined by 1H NMR analysis of the crude reaction mixture.

2.5.2 Imidate Synthesis

Phenethyl acetimidate (II-S1): Trifluoroethyl acetimidate hydrochloride

(0.2 g, 0.3 mmol) was suspended in MeCN (4 mL) to which 2-phenylethanol

(0.15 g, 0.15 mL, 0.3 mmol) was added. After completion and workup, the crude material was purified (silica gel, hexanes with 1% Et3N) to yield imidate II-S1 (28 mg) as mixture with 2-phenyethanol and the hydrolyzed ester (1 : 0.18 : 0.16 TM : alcohol : ester). Rf: 0.08

64 1 (20% Ethyl acetate/hexanes). H NMR (600 MHz, CDCl3): δ = 7.31 (t, J = 7.5 Hz, 2H),

7.27 – 7.22 (m, 3H), 6.90 (bs, 1H), 4.29 (t, J = 6.5 Hz, 2H), 3.00 (t, J = 7.1 Hz, 2H), 2.00

13 (s, 3H). C NMR (100 MHz, CDCl3): δ = 169.8, 138.7, 129.0, 128.5, 126.4, 66.1, 35.2.

+ HRMS (ESI-TOF) m/z: calc’d for C10H14NO [M+H] 164.1075, found 164.1087.

Phenethyl benzimidate (II-S2): Trifluoroethyl benzimidate hydrochloride

(0.1 g, 0.4 mmol) was suspended in MeCN (2 mL) to which 2-phenylethanol

(51 mg, 50 μL, 0.4 mmol) was added. After completion and workup, the crude material was purified (silica gel, hexanes with 1% Et3N) to yield imidate II-S2 (46 mg, 49%) as a

1 clear oil. Rf: 0.12 (10% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.65 –

7.63 (m, 2H), 7.42 – 7.32 (m, 3H), 7.29 – 7.25 (m, 3H), 7.20 – 7.17 (m, 1H), 4.46 (t, J =

13 6.9 Hz, 2H), 3.08 (t, J = 6.8 Hz, 2H). C NMR (100 MHz, CDCl3): δ = 167.9, 138.7, 132.9,

131.0, 129.1, 128.6 (2C), 126.8, 126.5, 66.7, 35.3. HRMS (ESI-TOF) m/z: calc’d for

+ –1 C15H16NO [M+H] 226.1232, found 226.1229. IR (film) cm : 3303, 3034, 3024, 2943,

1631, 1577.

Phenethyl 2,2,2-trichloroacetimidate (II-S3): Phenylethanol (2 g, 1.96

mL, 16.4 mmol) was dissolved in CH2Cl2 (50 mL) to which trichloroacetonitrile (3.54 g, 2.46 mL, 24.5 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene

(0.26 g, 0.25 mL, 1.7 mmol) were added. Upon completion (monitored by TLC) the reaction was concentrated and loaded directly onto silica gel and purified (hexanes, 1%

Et3N) to yield imidate II-S3 (4.4 g, 100%) as a white solid. Rf: 0.63 (20% Ethyl

1 acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.29 (bs, 1H), 7.33 – 7.22 (m, 5H), 4.50

65 13 (t, J = 6.9 Hz, 2H), 3.10 (t, J = 6.9 Hz, 2H). C NMR (100 MHz, CDCl3): δ = 163.0, 137.8,

129.2, 128.6, 126.7, 91.6, 70.0, 34.8. HRMS (ESI-TOF) m/z: calc’d for C10H10Cl3NONa

[M+Na]+ 287.9726, found 287.9708. IR (film) cm–1: 3337, 3025, 2948, 1660, 1602.

4-methoxyphenethyl 2,2,2-trichloroacetimidate (II-S8): 2-(4-

methoxyphenyl)ethan-1-ol (0.1 g, 0.7 mmol) was dissolved in

CH2Cl2 (10 mL) to which trichloroacetonitrile (0.14 g, 0.1 mL, 0.1 mmol) and 1,8-

Diazabicyclo(5.4.0)undec-7-ene (0.01 g, 0.01 mL, 0.07 mmol) were added. Upon completion (monitored by TLC) the reaction was concentrated and loaded directly onto silica gel and purified (hexanes, 1% Et3N) to yield imidate II-S8 (0.18 g, 92%) as a white

1 solid. Rf: 0.25 (10% Ethyl acetate/hexanes). H NMR (600 MHz, CDCl3): δ = 8.29 (bs,

1H), 7.19 (d, J = 7.9 Hz, 2H), 6.84 (d, J = 7.3 Hz, 2H), 4.45 (t, J = 7.0 Hz, 2H), 3.79 (s,

13 3H), 3.03 (t, J = 6.9 Hz, 2H). C NMR (100 MHz, CDCl3): δ = 162.9, 158.5, 130.2, 129.8,

+ 114.0, 91.6, 70.2, 55.3, 33.9. HRMS (ESI-TOF) m/z: calc’d for C11H12Cl3NONa [M+Na]

317.9831, found 317.9814. IR (film) cm–1: 3324, 2936, 2936, 2838, 1658, 1668, 1582. MP:

54 – 56 °C.

4-fluorophenethyl 2,2,2-trichloroacetimidate (II-S9): 2-(4-

fluorophenyl)ethan-1-ol (0.2 g, 1.4 mmol) was dissolved in CH2Cl2

(10 mL) to which trichloroacetonitrile (0.3 g, 0.21 mL, 2.1 mmol) and 1,8-

Diazabicyclo(5.4.0)undec-7-ene (0.022 g, 0.022 mL, 0.15 mmol) were added. Upon completion (monitored by TLC) the reaction was concentrated and loaded directly onto silica gel and purified (hexanes, 1% Et3N) to yield imidate II-S9 (0.38 g, 94%) as a

66 1 colorless oil. Rf: 0.42 (10% Ethyl acetate/hexanes). H NMR (600 MHz, CDCl3): δ = 8.28

(bs, 1H), 7.25 – 7.22 (m, 2H), 7.00 – 6.97 (m, 2H), 4.47 (t, J = 6.6 Hz, 2H), 3.06 (t, J = 6.8

13 1 Hz, 2H). C NMR (150 MHz, CDCl3): δ = 162.9, 161.9 (d, JCF = 244.4 Hz), 133.5 (d,

4 3 2 19 JCF = 3.2 Hz), 130.7 (d, JCF = 7.7 Hz), 115.4 (d, JCF = 21.0 Hz), 91.5, 69.9, 34.1. F

NMR (564 MHz, CDCl3): δ = – 116.57. HRMS (ESI-TOF) m/z: calc’d for C10H10Cl3FNO

[M+H]+ 283.9812, found 283.9817. IR (film) cm–1: 3651, 3339, 2968, 2881, 1662, 1509,

1304.

4-(trifluoromethyl)phenethyl 2,2,2-trichloroacetimidate (II-

S10): 2-(4-(trifluoromethyl)phenyl)ethanol (400 mg, 2.1 mmol) was dissolved in CH2Cl2 (5 mL) to which trichloroacetonitrile (462 mg, 0.32 mL, 3.2 mmol) and 1,8-Diazabicyclo(5.4.0)undec-7-ene (0.032 g, 31 uL, 0.21 mmol) were added.

Upon completion (monitored by TLC) the reaction was concentrated and loaded directly onto silica gel and purified (hexanes, 1% Et3N) to yield imidate II-S10 (660 mg, 93%) as

1 a colorless oil. Rf: 0.45 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.32

(bs, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.40 (t, J = 9.0 Hz, 2H), 4.52 (t, J = 6.5 Hz, 2H), 3.15 (t,

13 2 J = 6.8 Hz, 2H). C NMR (100 MHz, CDCl3): δ = 162.8, 142.0, 129.2 (q, JCF = 32.4 Hz),

3 1 19 125.5 (q, JCF = 3.7 Hz), 124.4 (q, JCF = 271.9 Hz), 91.4, 69.3, 34.7. F NMR (376MHz,

+ CDCl3): δ = – 62.4. HRMS (ESI-TOF) m/z: calc’d for C11H9Cl3F3N2ONa [M+Na]

355.9600, found 355.9582. IR (neat) cm–1: 3326, 2980, 2971, 1891, 2360, 2343, 1701,

1662, 1618, 1469, 1393, 1323, 1167, 1132, 1099, 1065, 1001, 942, 849, 802.

67 2-methylphenethyl 2,2,2-trichloroacetimidate (II-S11): 2-(2-

methylphenyl)ethanol (371 mg, 2.7 mmol) was dissolved in CH2Cl2 (5 mL) to which trichloroacetonitrile (0.592 g, 0.852 mL, 4.1 mmol) and 1,8-

Diazabicyclo(5.4.0)undec-7-ene (0.042 g, 41 uL, 0.27 mmol) were added. Upon completion (monitored by TLC) the reaction was concentrated and loaded directly onto silica gel and purified (hexanes, 1% Et3N) to yield imidate II-S11 (0.621 g, 82%) as a

1 colorless oil. Rf: 0.65 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.31

(bs, 1H), 7.25 – 7.15 (m, 4H), 4.49 (t, J = 7.2 Hz, 2H), 3.12 (t, J = 7.2 Hz, 2H), 2.40 (s,

13 3H). C NMR (100 MHz, CDCl3): δ = 163.0, 136.6, 135.8, 130.4, 129.8, 126.9, 126.2,

+ 91.6, 62.2, 32.0, 19.6. HRMS (ESI-TOF) m/z: calc’d for C11H12Cl3NONa [M+Na]

301.9882, found 301.9858. IR (neat) cm–1: 3339, 2928, 2867, 2360, 2343, 1764, 1659,

1465, 1383, 1303, 1074, 999, 864, 825, 794.

2-chlorophenethyl 2,2,2-trichloroacetimidate (II-S12): 2-(2-

chlorophenyl)ethanol (705 mg, 4.5 mmol) was dissolved in CH2Cl2 (5 mL) to which trichloroacetonitrile (0.98 g, 0.68 mL, 6.8 mmol) and 1,8-

Diazabicyclo(5.4.0)undec-7-ene (0.069 g, 68 uL, 0.45 mmol) were added. Upon completion (monitored by TLC) the reaction was concentrated and loaded directly onto silica gel and purified (hexanes, 1% Et3N) to yield imidate II-S12 (1.2 g, 90%) as a

1 colorless oil. Rf: 0.64 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.30

(bs, 1H), 7.38 – 7.16 (m, 4H), 4.53 (t, J = 7.0 Hz, 2H), 3.24 (t, J = 7.0 Hz, 2H). 13C NMR

(100 MHz, CDCl3): δ = 162.9, 135.4, 134.3, 131.6, 129.6, 128.3, 126.9, 91.5, 68.3, 32.5.

68 + HRMS (ESI-TOF) m/z: calc’d for C10H9Cl4NONa [M+Na] 321.9336, found 321.9319. IR

(neat) cm–1: 3338, 2957, 2368, 1664, 1474, 1383, 1307, 1080, 1004, 794, 750, 655.

2-(trifluoromethyl)phenethyl 2,2,2-trichloroacetimidate (II-S13): 2-

(2-(trifluoromethyl)phenyl)ethanol (400 mg, 2.1 mmol) was dissolved in CH2Cl2 (5 mL) to which trichloroacetonitrile (0.455 g, 0.32 mL, 3.2 mmol) and 1,8-

Diazabicyclo(5.4.0)undec-7-ene (0.032 g, 32 uL, 0.21 mmol) were added. Upon completion (monitored by TLC) the reaction was concentrated and loaded directly onto silica gel and purified (hexanes, 1% Et3N) to yield imidate II-S13 (0.267 g, 80%) as a

1 colorless oil. Rf: 0.62 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.33

(bs, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.49 – 7.48 (m, 2H), 7.37 – 7.31 (m, 1H), 4.52 (t, J =

13 6.3 Hz, 2H), 3.30 (s, 3H). C NMR (100 MHz, CDCl3): δ = 162.8, 136.3, 132.3, 131.8,

2 3 1 129.1 (q, JCF = 26.9 Hz), 126.2 (q, JCF = 5.7 Hz), 124.6 (q, JCF = 270.7 Hz), 91.5, 69.3,

19 31.6. F NMR (376 MHz, CDCl3): δ = – 59.5. HRMS (ESI-TOF) m/z: calc’d for

+ –1 C11H9Cl3F3NONa [M+Na] 333.9780, found 333.9756. IR (neat) cm : 3348, 2964, 2363,

1662, 1449, 1317, 1163, 1107, 1085, 997, 797, 775, 645.

3-methoxyphenethyl 2,2,2-trichloroacetimidate (II-S14): 2-(3-

methoxyphenyl)ethan-1-ol (0.2 g, 1.3 mmol) was dissolved in

CH2Cl2 (10 mL) to which trichloroacetonitrile (0.29 g, 0.2 mL, 2.0 mmol) and 1,8-

Diazabicyclo(5.4.0)undec-7-ene (0.02 g, 0.02 mL, 0.13 mmol) were added. Upon completion (monitored by TLC) the reaction was concentrated and loaded directly onto silica gel and purified (hexanes, 1% Et3N) to yield imidate II-S14 (0.37 g, 95%) as a clear

69 1 colorless oil. Rf: 0.36 (10% Ethyl acetate/hexanes). H NMR (600 MHz, CDCl3): δ = 8.29

(bs, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.84 (t, J = 1.9 Hz, 1H), 6.78

(dd, J = 8.2, 2.6 Hz, 1H), 4.50 (t, J = 6.9 Hz, 2H), 3.80 (s, 3H), 3.07 (t, J = 6.9 Hz, 2H).

13 C NMR (150 MHz, CDCl3): δ = 163.0, 159.9, 139.4, 129.6, 121.6, 114.9, 112.3, 91.6,

+ 70.0, 55.3, 34.9. HRMS (ESI-TOF) m/z: calc’d for C11H12Cl3NO2Na [M+Na] 317.9831, found 317.9819. IR (film) cm–1: 3331, 2952, 2887, 2832, 1660, 1584.

3-methylphenethyl 2,2,2-trichloroacetimidate (II-S15): 2-(3-

methylphenyl)ethanol (613 mg, 4.5 mmol) was dissolved in CH2Cl2

(5 mL) to which trichloroacetonitrile (0.98 g, 0.68 mL, 6.8 mmol) and 1,8-

1 colorless oil. Rf: 0.61 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.28

(bs, 1H), 7.22 – 7.18 (m, 1H), 7.11 – 7.04 (m, 3H), 4.49 (t, J = 7.0 Hz, 2H), 3.06 (t, J = 7.0

13 Hz, 2H), 2.33 (s, 3H). C NMR (100 MHz, CDCl3): δ = 163.0, 138.2, 137.6, 130.1, 128.5,

127.5, 126.2, 91.6, 70.1, 34.7, 21.5. HRMS (ESI-TOF) m/z: calc’d for C11H12Cl3NONa

[M+Na]+ 301.9882, found 301.9918. IR (neat) cm–1: 3345, 2969, 2935, 2886, 1667, 1466,

1376, 1158, 1127, 956, 814.

2-(pyridin-2-yl)ethyl 2,2,2-trichloroacetimidate (II-S16): 2-(2-

pyridyl)ethanol (0.55 g, 0.51 mL, 4.5 mmol) was dissolved in CH2Cl2

(5 mL) to which trichloroacetonitrile (0.98 g, 0.68 mL, 6.8 mmol) and 1,8-

70 Diazabicyclo(5.4.0)undec-7-ene (0.069 g, 68 uL, 0.45 mmol) were added. Upon completion (monitored by TLC) the reaction was concentrated and loaded directly onto silica gel and purified (Hexanes → 40% Ethyl acetate/hexanes) to yield imidate II-S16

1 (1.16 g, 96%) as a yellow oil. Rf: 0.59 (10% Isopropanol/CH2Cl2). H NMR (400 MHz,

CDCl3): δ = 8.55 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 8.29 (bs, 1H), 7.61 (td, J = 7.7, 1,9 Hz,

2H), 7.25 (d, J = 7.7 Hz, 2H), 7.14 (ddd, J = 7.6, 4.9, 1.1 Hz, 1H), 4.66 (t, J = 6.6 Hz, 2H),

13 3.25 (t, J = 6.6 Hz, 2H). C NMR (100 MHz, CDCl3): δ = 162.8, 158.0, 149.6, 136.4,

+ 123.8, 121.8, 91.5, 68.7, 37.1. HRMS (ESI-TOF) m/z: calc’d for C9H9Cl3N2ONa [M+Na]

288.9678, found 288.9657. IR (neat) cm–1: 3339, 2980, 2902, 2360, 2343, 1701, 1655,

1472, 1382, 1301, 1250, 1150, 1079, 1001, 962, 829, 794.

2-(thiophen-2-yl)ethyl 2,2,2-trichloroacetimidate (II-S17): 2-

(thiophen-2-yl)ethan-1-ol (577 mg, 1.6 mmol) was dissolved in CH2Cl2

(5 mL) to which trichloroacetonitrile (0.338 g, 0.23 mL, 2.3 mmol) and 1,8-

Diazabicyclo(5.4.0)undec-7-ene (0.024 g, 24 uL, 0.45 mmol) were added. Upon completion (monitored by TLC) the reaction was concentrated and loaded directly onto silica gel and purified (hexanes, 1% Et3N) to yield imidate II-S17 (0.366 g, 86%) as a white

1 solid. Rf: 0.63 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.32 (bs,

1H), 7.17 (dd, J = 5.0, 1.3 Hz, 1H), 6.96 – 6.92 (m, 2H), 4.51 (t, J = 6.7 Hz, 2H), 3.31 (t, J

13 = 6.7 Hz, 2H). C NMR (100 MHz, CDCl3): δ = 162.9, 139.7, 127.0, 125.9, 124.2, 91.5,

+ 69.6, 29.0. HRMS (ESI-TOF) m/z: calc’d for C8H8Cl3NOSNa [M+Na] 293.9290, found

293.9329. IR (neat) cm–1: 3323, 2980, 2892, 2360, 2342, 1661, 1470, 1443, 1393, 1308,

71 1277, 1243, 1090, 1065, 991, 822, 795. MP: 35 – 36 °C

2-phenylbutyl 2,2,2-trichloroacetimidate (II-S18): 2-phenylbutan-1-

ol (676 mg, 4.5 mmol) was dissolved in CH2Cl2 (5 mL) to which trichloroacetonitrile (0.98 g, 0.68 mL, 6.8 mmol) and 1,8-Diazabicyclo(5.4.0)undec-7-ene

(0.069 g, 68 uL, 0.45 mmol) were added. Upon completion (monitored by TLC) the reaction was concentrated and loaded directly onto silica gel and purified (hexanes, 1%

Et3N) to yield imidate II-S18 (1.26 g, 95%) as a colorless oil. Rf: 0.67 (20% Ethyl

1 acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.23 (bs, 1H), 7.33 – 7.20 (m, 5H), 4.45

– 4.36 (m, 2H), 3.03 – 2.96 (m, 1H), 1.99 – 1.88 (m, 1H), 1.78 – 1.67 (m, 1H), 0.88 (t, J =

13 7.4 Hz, 3H). C NMR (100 MHz, CDCl3): δ = 163.1, 141.7, 128.5, 128.2, 126.8, 91.6,

+ 73.2, 46.6, 25.3, 12.0. HRMS (ESI-TOF) m/z: calc’d for C12H14Cl3NONa [M+Na]

316.0039, found 316.0043. IR (neat) cm–1: 3336, 2967, 2883, 2363, 2336, 1659, 1466,

1376, 1300, 1156, 1129, 951, 819.

2-(4-isobutylphenyl)propyl 2,2,2-trichloroacetimidate (II-

S19): Lithium aluminum hydride (367 mg, 9.7 mmol) was suspended in dry THF (10 mL) in a 50 mL flask and then cooled to 0 °C. To this flask, was added alcohol (0.5 g, 2.4 mmol) dissolved in THF (10 mL) dropwise. After addition, the solution was warmed to room temperature and allowed to stir for 4 hours. Upon completion, the solution was quenched according to the Fieser workup reproduced here. After cooling the reaction to 0 °C, H2O (0.37 mL) was added slowly, followed by 15% NaOH (0.37 mL), and finally H2O (1.11 mL). This solution was warmed to room temperature and allowed to

72 stir for 15 minutes. MgSO4 was added and stirred for an additional 15 minutes. Finally, the solution was filtered and the mixture concentrated to yield the alcohol. Crude alcohol was dissolved in CH2Cl2 (5 mL) to which trichloroacetonitrile (520 mg, 0.361 mL, 3.6 mmol) and 1,8-Diazabicyclo(5.4.0)undec-7-ene (37mg, 36 µL, 0.24mmol) were added. Upon completion (monitored by TLC) the reaction was concentrated and loaded directly onto silica gel and purified (hexanes, 1% Et3N) to isolate trichloroacetimidate II-S19 was isolated as a colorless oil (1.3 g, 80% over 2 steps). Rf: 0.48 (10% Ethyl acetate/hexanes).

1 H NMR (400 MHz, CDCl3): δ = 8.23 (bs, 1H), 7.19 – 7.17 (m, 2H), 7.09 – 7.07 (m, 2H),

4.39 (dd, J = 10.5, 6.1 Hz, 1H), 4.27 (dd, J = 10.5, 7.7 Hz, 1H), 3.25 (m, 1H), 2.44 (d, J =

7.2 Hz, 2H), 1.89 – 1.79 (m, 1H), 1.39 (d, J = 7.0 Hz, 3H), 0.89 (d, J = 6.7 Hz, 6H). 13C

NMR (150 MHz, CDCl3): δ = 163.1, 140.2, 140.1, 129.3, 127.3, 91.7, 74.6, 45.2, 38.5,

+ 30.4, 22.5, 18.0. HRMS (ESI-TOF) m/z: calc’d for C15H20Cl3NONa [M+Na] 358.0508, found 358.0482. IR (film) cm–1: 3340, 2952, 2941, 2866, 1662, 1299.

4-fluorophenethyl 2,2,2-trichloroacetimidate (II-S20): 2,3-dihydro-

1H-inden-2-ol (0.25 g, 1.9 mmol) was dissolved in CH2Cl2 (10 mL) to which trichloroacetonitrile (0.4 g, 0.28 mL, 2.8 mmol) and 1,8-Diazabicyclo(5.4.0)undec-

7-ene (0.029 g, 0.028 mL, 0.19 mmol) were added. Upon completion (monitored by TLC) the reaction was concentrated and loaded directly onto silica gel and purified (hexanes, 1%

Et3N) to yield imidate II-S20 (0.44 g, 85%) as a colorless oil. Rf: 0.35 (10% Ethyl

1 acetate/hexanes). H NMR (600 MHz, CDCl3): δ = 8.34 (bs, 1H), 7.26 – 7.24 (m, 2H), 7.21

– 7.18 (m, 2H), 5.70 – 5.67 (m, 1H), 3.43 (dd, J = 17.0, 6.7 Hz, 2H), 3.19 (dd, J = 17.0, 3.4

13 Hz, 2H). C NMR (150 MHz, CDCl3): δ = 162.7, 140.4, 126.9, 124.8, 91.8, 80.1, 39.3.

73 + HRMS (ESI-TOF) m/z: calc’d for C11H11Cl3NO [M+H] 277.9906, found 277.9888. IR

(film) cm–1: 3640, 3336, 2978, 2895, 1655, 1302.

1,1,1-trifluoro-3-phenylpropan-2-yl 2,2,2-trichloroacetimidate (II-

S21): 1,1,1-trifluoro-3-phenylpropan-2-ol (0.9 g, 4.7 mmol) was dissolved in CH2Cl2 (30 mL) to which trichloroacetonitrile (1.02 g, 0.71 mL, 7.1 mmol) and 1,8-

Diazabicyclo(5.4.0)undec-7-ene (0.14 g, 0.14 mL, 0.93 mmol) were added. Upon completion (monitored by TLC) the reaction was concentrated and loaded directly onto silica gel and purified (hexanes, 1% Et3N) to yield imidate II-S21 (0.79 g, 50%) as a yellow

1 oil. Rf: 0.63 (10% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.49 (bs, 1H),

7.30 – 7.23 (m, 5H), 5.86 – 5.75 (m, 1H), 3.25 – 3.12 (m, 2H). 13C NMR (100 MHz,

1 CDCl3): δ = 161.6, 134.5, 129.6, 128.7, 127.4, 123.7 (q, JCF = 282.1 Hz), 90.6, 74.7 (q,

2 3 19 3 JCF = 31.8 Hz), 34.4 (q, JCF = 1.4 Hz). F NMR (376 MHz, CDCl3): δ = – 76.60 (d, JHF

+ = 5.6 Hz). HRMS (ESI-TOF) m/z: calc’d for C12H12Cl3F3NO [M+H] 333.9780, found

333.9777. IR (film) cm–1: 3341, 2997, 2978, 2878, 1673, 1266.

3-trichloroacetimidatyl cholesterol (II-S22):

Cholesterol (193 mg, 0.5 mmol) was dissolved in

CH2Cl2 (1 mL) to which trichloroacetonitrile (0.11 g,

0.75 mL, 0.75 mmol) and 1,8-

Diazabicyclo(5.4.0)undec-7-ene (69 mg, 68 uL, 0.5 mmol) were added. Upon completion

(monitored by TLC) the reaction was concentrated and loaded directly onto silica gel and purified (hexanes, 1% Et3N) to yield imidate II-S22 (220 mg, 83%) as a white solid. Rf:

74 1 0.72 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.23 (bs, 1H), 5.42 –

5.41 (m, 1H), 4.81 – 4.72 (m, 1H), 2.55 – 2.50 (m, 1H), 2.46 – 2.40 (m, 1H), 2.07 – 0.94

(m, 29H), 0.92 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 1.8 Hz, 3H), 0.86 (d, J = 1.9 Hz, 3H), 0.69

13 (s, 3H). C NMR (100 MHz, CDCl3): δ = 162.2, 139.6, 123.1, 92.1, 79.1, 56.9, 56.3, 50.2,

42.5, 39.9, 39.7, 37.5, 37.1, 36.9, 36.4, 35.9, 32.1, 32.0, 28.4, 28.2, 27.2, 24.4, 24.0, 23.0,

+ 22.7, 21.2, 19.5, 18.9, 12.0. HRMS (ESI-TOF) m/z: calc’d for C29H46Cl3NONa [M+Na]

552.2543, found 552.2542. IR (neat) cm–1: 3340, 2980, 2883, 2360, 2343, 1763, 1654,

1464, 1440, 1382, 1301, 1249, 1135, 1071, 1000, 963, 829, 794. MP: 158 – 159 °C.

isobutyl 2,2,2-trichloroacetimidate (II-24a): Isobutanol (0.815 g, 1.01

mL, 11 mmol) was dissolved in CH2Cl2 (20 mL) to which trichloroacetonitrile (2.38 g, 1.65 mL, 16.5 mmol) and 1,8-Diazabicyclo(5.4.0)undec-7- ene (167 mg, 0.165 mL, 1.1 mmol) were added. Upon completion (monitored by TLC) the reaction was concentrated and loaded directly onto silica gel and purified (hexanes, 1%

Et3N) to yield imidate II-24a (2.2 g, 93%) as a yellow oil. Rf: 0.71 (20% Ethyl

1 acetate/hexanes). H NMR (600 MHz, CDCl3): δ = 8.20 (bs, 1H), 4.06 (d, J = 6.7, 2H),

13 2.11 (m, J = 6.7 Hz, 1H), 1.01 (d, J = 6.7 Hz, 6H). C NMR (150 MHz, CDCl3): δ = 163.3,

+ 91.9, 75.6, 27.8, 19.1. HRMS (ESI-TOF) m/z: calc’d for C6H10Cl3NONa [M+Na]

239.9726, found 239.9715. IR (neat) cm–1: 3346, 2961, 2875, 1733, 1662, 1471, 1379,

1311, 1289, 1077, 710, 648.

isobutyl benzimidate (II-24b): isobutanol (8.64 g, 10.8 mL, 116 mmol) and

benzonitrile (1 g, 1 mL, 9.7 mmol) were mixed and acetyl chloride (6.09 g,

75 5.54 mL, 77.6 mmol) was added dropwise. After 24 hours, the mixture was concentrated yielding a white solid. The salt was suspended in Et2O and a saturated solution of NaHCO3 was added dropwise until the salt dissolved completely. Upon dissolution, the solution was stirred for five minutes and then diluted with H2O. The organic phase was separated and the aqueous phase was extracted with Et2O (2 x 10 mL). The combined organic phase was dried over MgSO4 and concentrated to isolate imidate II-28b as a clear oil (1.17 g, quant.).

1 Rf: 0.26 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.75 (bs, 3H), 7.48

– 7.40 (m, 3H), 4.04 (t, J = 3.4 Hz, 2H), 2.19 – 2.09 (m, 1H), 1.05 (t, J = 6.8 Hz, 6H). 13C

NMR (100 MHz, CDCl3): δ = 168.0, 133.2, 131.0, 128.6, 126.8, 72.4, 28.0, 19.5. HRMS

+ –1 (ESI-TOF) m/z: calc’d for C11H16NO [M+H] 178.1232, found 178.1246. IR (film) cm :

3274, 2956, 2871, 1631, 1327.

Ethyl benzimidate (II-S29): ethanol (5.36 g, 6.79 mL, 116 mmol) and benzonitrile (1 g, 1 mL, 9.7 mmol) were mixed and acetyl chloride (6.09 g, 5.54 mL, 77.6 mmol) was added dropwise. After 24 hours, the mixture was concentrated yielding a white solid. This hydrochloride salt (0.5 g) was subjected to basic workup to yield imidate II-

1 S29 as a clear oil (0.33 g, 87%). Rf: 0.21 (20% Ethyl acetate/hexanes), H NMR (400 MHz,

CDCl3): δ = 7.75 (d, J = 6.9 Hz, 2H), 7.71 (bs, 1H), 7.48 – 7.39 (m, 3H), 4.33 (q, J = 6.8

13 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H). C NMR (100 MHz, CDCl3): δ = 168.0, 133.2, 130.9,

128.6, 126.8, 61.9, 14.4.

Propyl benzimidate (II-S30): propanol (7 g, 8.75 mL, 116 mmol) and benzonitrile (1 g, 1 mL, 9.7 mmol) were mixed and acetyl chloride (6.09 g, 5.54 mL, 77.6

76 mmol) was added dropwise. After 24 hours, the mixture was concentrated yielding a white solid. Upon basic workup, imidate II-S30 was isolated as a clear oil (1.57 g, 99%). Rf: 0.24

1 (20% Ethyl acetate/hexanes). H NMR (600 MHz, CDCl3): δ = 7.75 (d, J = 5.7 Hz, 2H),

7.71 (bs, 1H), 7.47 – 7.40 (m, 3H), 4.23 (t, J = 6.0 Hz, 2H), 1.87 – 1.81 (m, 2H), 1.06 (t, J

13 = 7.4 Hz, 3H). C NMR (100 MHz, CDCl3): δ = 168.1, 133.2, 130.9, 128.6, 126.8, 67.7,

+ 22.2, 10.8. HRMS (ESI-TOF) m/z: calc’d for C10H14NO [M+H] 164.1075, found

164.1094. IR (film) cm–1: 3289, 2965, 2961, 1631, 1326.

Pentyl benzimidate (II-S31): pentanol (10.27 g, 12.66 mL, 116 mmol)

and benzonitrile (1 g, 1 mL, 9.7 mmol) were mixed and acetyl chloride

(6.09 g, 5.54 mL, 77.6 mmol) was added dropwise. After 24 hours, the mixture was concentrated yielding a white solid. Upon basic workup, imidate II-S31 was isolated as a

1 clear oil (1.82 g, 98%). Rf: 0.26 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3):

δ = 7.73 (bs, 3H), 7.48 – 7.39 (m, 3H), 4.28 (bs, 2H), 1.82 (quint, J = 7.0 Hz, 2H), 1.51 –

13 1.36 (m, 4H), 0.94 (t, J = 7.2 Hz, 3H). C NMR (150 MHz, CDCl3): δ = 168.7, 133.2,

130.9, 128.6, 126.8, 66.3, 28.6, 28.5, 22.6, 14.1. HRMS (ESI-TOF) m/z: calc’d for

+ –1 C12H18NO [M+H] 192.1388, found 192.1402. IR (film) cm : 3275, 2952, 2936, 2856,

1631, 1577.

5-((tert-butyldimethylsilyl)oxy)pentyl benzimidate (II-S32):

trifluoroethyl benzimidate hydrochloride (0.2 g, 0.8 mmol) was suspended in MeCN (4 mL) to which alcohol (182 mg, 0.8 mmol) was added. After completion and workup, the crude material was purified (silica gel, hexanes with 1% Et3N)

77 to yield imidate II-S32 as a clear oil (130 mg, 48%). Rf: 0.28 (20% Ethyl acetate/hexanes).

1 H NMR (600 MHz, CDCl3): δ = 7.76 (bs, 1H), 7.72 (bs, 2H), 7.47 – 7.44 (m, 1H), 7.43 –

7.40 (m, 2H), 4.29 (bs, 2H), 3.65 (t, J = 6.3 Hz, 2H), 1.83 (q, J = 7.1 Hz, 2H), 1.63 – 1.52

13 (m, 4H), 0.89 (s, 9H), 0.05 (s, 6H). C NMR (150 MHz, CDCl3): δ = 168.1, 133.2, 130.9,

128.6, 126.9, 66.2, 63.2, 32.7, 28.7, 26.1, 22.8, 18.5, – 5.1. HRMS (ESI-TOF) m/z: calc’d

+ –1 C18H32NO2Si [M+H] 322.2202, found 322.2183. IR (film) cm : 3307, 2936, 2926, 2854,

1634, 1578.

Methyl 4-(imino(phenyl)methoxy)butanoate (II-S33): trifluoroethyl

benzimidate hydrochloride (0.2 g, 0.8 mmol) was suspended in MeCN

(4 mL) to which methyl 4-hydroxybutanoate (98.6 mg, 0.8 mmol) was added. After completion and workup, the crude material was purified (silica gel, 10% ethyl acetate/hexanes with 1% Et3N) to yield imidate II-S33 as a clear oil (52 mg, 28%). Rf: 0.30

1 (50% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.79 (bs, 1H), 7.72 (d, J =

6.0 Hz, 2H), 7.48 – 7.39 (m, 3H), 4.32 (t, J = 5.7 Hz, 2H), 3.68 (s, 3H), 2.53 (t, J = 7.5 Hz,

13 2H), 2.19 – 2.13 (m, 2H). C NMR (150 MHz, CDCl3): δ = 173.6, 167.8, 132.8, 131.0,

+ 128.6, 126.8, 65.1, 51.7, 31.1, 24.3. HRMS (ESI-TOF) m/z: calc’d for C12H16NO3 [M+H]

222.1130, found 222.1137. IR (film) cm–1: 3305, 2948, 2936, 2846, 1729, 1632, 1577.

4-(1,3-dioxoisoindolin-2-yl)butyl benzimidate (II-S34):

trifluoroethyl benzimididate hydrochloride (575 mg, 2.4 mmol) was suspended in MeCN (2 mL) to which 2-(4-hydroxybutyl)isoindoline-1,3-dione (260 mg, 1.2 mmol) was added. After completion (3 hours) and workup, the crude material was

78 purified (silica gel, hexanes to 30% ethyl acetate in hexanes) to yield imidate II-S34 (352 mg, 91%) as a white solid, or the crude material can be purified via trituration in cold

1 hexanes with a slightly lower yield (82%). Rf: 0.27 (50% Ethyl acetate/hexanes). H NMR

(400 MHz, CDCl3): δ = 7.85 (dd, J = 5.4, 3.1 Hz, 2H), 7.85 – 7.60 (m, 3H), 7.71 (dd, J =

5.5, 3.0 Hz, 2H), 7.47 – 7.38 (m, 3H), 4.31 (bs, 2H), 3.81 – 3.77 (m, 2H), 1.90 – 1.88 (m,

13 4H). C NMR (100 MHz, CDCl3): δ = 168.6, 168.0, 134.1, 132.9, 132.3, 131.0, 128.6,

+ 126.8, 123.4, 65.6, 37.9, 26.4, 25.7. HRMS (ESI-TOF) m/z: calc’d for C19H19N2O3 [M+H]

323.1396, found 323.1383. IR (neat) cm–1: 3314, 2954, 1765, 1702, 1638, 1578, 1468,

1444, 1397, 1323, 1246, 1173, 1077, 948, 860. MP: 86 °C

Cyclopentyl benzimidate (II-S35): trifluoroethyl benzimidate hydrochloride

(0.2 g, 0.8 mmol) was suspended in MeCN (4 mL) to which alcohol (72 mg,

76 μL, 0.8 mmol) was added. After completion and workup, the crude material was purified

(silica gel, hexanes with 1% Et3N) to yield imidate S39 as a clear oil (99 mg, 63%). Rf:

1 0.23 (20% Ethyl acetate/hexanes). H NMR (600 MHz, CDCl3): δ = 7.73 (d, J = 7.0 Hz,

2H), 7.65 (bs, 1H), 7.46 – 7.39 (m, 3H), 5.33 (bs, 1H), 2.00 – 1.94 (m, 2H), 1.92 – 1.88 (m,

13 2H), 1.84 – 1.78 (m, 2H), 1.68 – 1.63 (m, 2H). C NMR (150 MHz, CDCl3): δ = 167.0,

133.7, 130.8, 128.5, 126.9, 78.0, 32.9, 24.1. HRMS (ESI-TOF) m/z: calc’d for C12H16NO

[M+H]+ 190.1232, found 190.1241. IR (film) cm–1: 3275, 2953, 2866, 1628, 1577.

sec-butyl benzimidate (II-S36): sec-butanol (8.63 g, 10.66 mL, 116 mmol)

and benzonitrile (1 g, 1 mL, 9.7 mmol) were mixed and acetyl chloride (6.09 g, 5.54 mL, 77.6 mmol) was added dropwise. After 24 hours, the mixture was concentrated

79 yielding a white solid. Upon basic workup, imidate II-S36 was isolated as a clear oil (0.28

1 g, 16%). Rf: 0.15 (10% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.76 –

7.72 (m, 3H), 7.47 – 7.39 (m, 3H), 5.10 – 5.02 (m, 1H), 1.85 – 1.64 (m, 2H), 1.35 (d, J =

13 6.3 Hz, 3H), 1.00 (t, J = 7.5 Hz, 3H). C NMR (150 MHz, CDCl3): δ = 167.5, 133.8, 130.8,

+ 128.5, 126.8, 73.1, 29.1, 19.2, 9.9. HRMS (ESI-TOF) m/z: calc’d for C11H16NO [M+H]

178.1232, found 178.1247. IR (film) cm–1: 3307, 3300, 2936, 2874, 1628, 1577.

2-methylbutyl benzimidate (II-S37): trifluoroethyl benzimidate hydrochloride (0.2 g, 0.8 mmol) was suspended in MeCN (4 mL) to which alcohol (74 mg,

90 μL, 0.8 mmol) was added. After completion and workup, the crude material was purified

(silica gel, hexanes with 1% Et3N) to yield imidate II-S37 as a clear oil (100 mg, 63%). Rf:

1 0.43 (20% Ethyl acetate/hexanes). H NMR (600 MHz, CDCl3): δ = 7.75 (bs, 3H), 7.47 –

7.45 (m, 1H), 7.43 – 7.40 (m, 2H), 4.14 (bs, 1H), 4.07 (bs, 1H), 1.95 – 1.88 (m, 1H), 1.62

– 1.55 (m, 1H), 1.35 – 1.28 (m, 1H), 1.05 (d, J = 6.8 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H). 13C

NMR (150 MHz, CDCl3): δ = 168.3, 133.2, 130.9, 128.6, 126.8, 70.9, 34.5, 26.5, 16.8,

+ 11.5. HRMS (ESI-TOF) m/z: calc’d for C12H18NO [M+H] 192.1388, found 192.1404. IR

(film) cm–1: 3309, 2978, 2877, 1629, 1577.

2.5.3 Imidate  C–H Amination

General Procedure for  C–H amination reaction (GP):

To a 2-dram vial equipped with PTFE septa cap and magnetic stir bar imidate105 (0.4 mmol), iodobenzene diacetate (1.2 mmol), and NaI (1.2 mmol) was added. This vial was evacuated and backfilled with N2 (3x). Dry acetonitrile (4 mL) was degassed using a freeze-pump-

80 thaw technique (3x), then added to the vial under N2. The reaction was irradiated with two

23 W compact fluorescent light bulbs for 2 hours and monitored using TLC. Hydrolysis and acid/base extraction. Upon completion, the mixture was concentrated in a round- bottom flask, then methanol (4 mL) and 2M HCl (0.8 mL) was added. After stirring for 2 hours, 25 mL of CHCl3 and 10 mL of H2O was added. The aqueous layer was washed with

CHCl3 (5 x 25 mL). The combined organic fractions were rewashed with H2O (10 mL).

The combined aqueous layer was poured into a round bottom, diluted with CHCl3 (25 mL), and finally 6M NaOH (10 mL) was added and stirred for 30 minutes. The aqueous layer was washed with CHCl3 (5 x 25 mL) and the combined organic solution was dried over

MgSO4 and concentrated.

2,4-diphenyl-4,5-dihydrooxazole (II-5): Benzimidate II-S2 (22.5 mg, 0.1

mmol) was subjected to GP with the following changes. After two hours, the reaction was removed from the light and concentrated. A crude yield of 71% was determined via 1H NMR (1,2 dichloroethane as an internal standard). The crude mixture was washed with Na2S2O3, extracted with CH2Cl2, dried over MgSO4, and concentrated.

The crude oil was purified via column chromatography (silica gel, 5% Ethyl

Acetate/hexanes) to yield oxazoline II-5 (9 mg, 42%) as a clear oil. Rf: 0.18 (10% Ethyl

1 acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.06 – 8.04 (m, 2H), 7.53 – 7.49 (m,

1H), 7.46 – 7.42 (m, 2H), 7.38 – 7.27 (m, 5H), 5.40 (dd, J = 10.0, 8.2 Hz, 1H), 4.80 (dd, J

13 = 10.2, 8.3 Hz, 1H), 4.28 (appt, J = 8.3 Hz, 1H). C NMR (100 MHz, CDCl3): δ = 164.9,

142.6, 131.7, 128.9, 128.6, 128.5, 127.8, 127.8, 126.9, 75.0, 70.3. HRMS (ESI-TOF) m/z:

81 + –1 calc’d for C15H14NO [M+H] 224.1075, found 224.1078. IR (film) cm : 3055, 3026, 2967,

2896, 1644, 1494.

4-phenyl-2-(trichloromethyl)-4,5-dihydrooxazole (II-6):

Trichloroacetimidate II-S3 (106.6 mg, 0.4 mmol) was subjected to GP with the following changes. Upon completion, the mixture was poured over 20% Na2S2O3 (15 mL) and washed with CH2Cl2 (3 x 25 mL). The combined organic layers were dried over

MgSO4 and concentrated. The crude material was purified (SiliaFlash® 150 Å, 1% Ethyl acetate/hexanes) to yield oxazoline II-6 as a clear oil (93 mg, 88%). Oxazoline yield by

1 1 H NMR: 100%. Rf: 0.26 (10% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ =

7.41 – 7.37 (m, 2H), 7.35 – 7.31 (m, 1H), 7.28 – 7.25 (m, 2H), 5.43 (dd, J = 10.1, 8.2 Hz,

1H), 5.00 (dd, J = 10.2, 8.6 Hz, 1H), 4.51 (app t, J = 8.4 Hz, 1H). 13C NMR (100 MHz,

CDCl3): δ = 163.8, 140.3, 129.2, 128.4, 126.7, 86.7, 78.4, 70.2. HRMS (ESI-TOF) m/z:

+ –1 calc’d for C10H9Cl3NO [M+H] 263.9750, found 263.9756. IR (film) cm : 3024, 2936,

2895, 1699, 1658, 1537.

2-amino-2-phenylethan-1-ol (II-7): Trichloroacetimidate II-S3 (106.4

mg, 0.4 mmol) was subjected to GP After workup, β-amino alcohol II-7

1 was isolated as a white solid (48.2 mg, 87%). Oxazoline yield by H NMR: 100%. Rf: 0.08

1 (30% Isopropanol/CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.38 – 7.27 (m, 5H), 4.05

(dd, J = 8.2, 4.4 Hz, 1H), 3.74 (dd, J = 10.7, 4.5 Hz, 1H), 3.55 (dd, J = 10.7, 8.3 Hz, 1H),

13 1.90 (bs, 3H). C NMR (100 MHz, CDCl3): δ =143.0, 128.8, 127.7, 126.6, 68.2, 57.7.

82 + HRMS (ESI-TOF) m/z: calc’d for C8H12NO [M+H] 138.0919, found 138.0944. IR (film) cm–1: 3363, 3282, 3006, 2896, 2861, 1598, 1555.

2-amino-2-(4-methoxyphenyl)ethan-1-ol (II-8):

Trichloroacetimidate II-S8 (117.8 mg, 0.4 mmol) was subjected to GP.

After workup, β-amino alcohol II-8 was isolated as a white solid (54 mg, 80%). Oxazoline

1 1 yield by H NMR: 100%. Rf: 0.04 (30% Isopropanol/CH2Cl2). H NMR (600 MHz,

CDCl3): δ = 7.25 – 7.23 (m, 2H), 6.89 – 6.87 (m, 2H), 3.99 (dd, J = 8.2, 4.4 Hz, 1H), 3.79

(s, 3H), 3.69 (dd, J = 10.4, 3.9 Hz, 1H), 3.52 (dd, J = 10.7, 8.3 Hz, 1H), 2.13 (bs, 3H). 13C

NMR (150 MHz, CDCl3): δ = 159.1, 135.1, 127.7, 114.2, 68.3, 56.9, 55.4. HRMS (ESI-

+ –1 TOF) m/z: calc’d for C9H14NO2 [M+H] 168.1025, found 168.1040. IR (film) cm : 3316,

3272, 2900, 2833, 1606, 1509.

2-amino-2-(4-fluorophenyl)ethan-1-ol (II-9): Trichloroacetimidate II-

S9 (114 mg, 0.4 mmol) was subjected to GP. After workup, β-amino alcohol II-9 was isolated as a colorless oil that slowly crystallized into a white solid (54.1

1 1 mg, 88%). Oxazoline yield by H NMR: 95%. Rf: 0.05 (30% Isopropanol/CH2Cl2). H

NMR (600 MHz, CDCl3): δ = 7.31 – 7.29 (m, 2H), 7.04 – 7.01 (m, 2H), 4.04 (dd, J = 8.1,

4.4 Hz, 1H), 3.70 (dd, J = 10.8, 4.4 Hz, 1H), 3.52 (dd, J = 10.8, 8.2 Hz, 1H), 2.12 (bs, 3H).

13 1 4 C NMR (150 MHz, CDCl3): δ = 162.3 ( JCF = 245.4 Hz), 138.6 ( JCF = 3.1 Hz), 128.2

3 2 19 ( JCF = 7.7 Hz), 115.6 ( JCF = 20.9 Hz), 68.2, 56.8. F NMR (564 MHz, CDCl3): δ = –

+ 115.2. HRMS (ESI-TOF) m/z: calc’d for C8H11FNO [M+H] 156.0825, found 156.0844.

IR (film) cm–1: 3329, 3273, 3040, 2979, 2903, 2830, 1597. MP: 104 – 106 °C.

2-amino-2-(4-(trifluoromethyl)phenyl)ethan-1-ol (II-10)

: Trichloroacetimidate II-S10 (134 mg, 0.4 mmol) was subjected to GP.

After workup, β-amino alcohol II-10 was isolated as a white solid (62 mg, 76%). Oxazoline

1 1 yield by H NMR: 98%. Rf: 0.14 (30% Isopropanol/CH2Cl2). H NMR (400 MHz, CDCl3):

δ = 7.61 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 4.14 (dd, J = 7.8, 4.3 Hz, 1H), 3.76

(dd, J = 10.7, 4.3 Hz, 1H), 3.56 (dd, J = 10.6, 7.9 Hz, 1H), 1.89 (bs, 3H). 13C NMR (100

2 3 MHz, CDCl3): δ = 147.0, 130.0 ( JCF = 32.4 Hz), 127.1, 125.7 ( JCF = 3.8 Hz), 122.9, 68.1,

19 57.1. F NMR (376MHz, CDCl3): δ = – 62.5. HRMS (ESI-TOF) m/z: calc’d for

+ –1 C9H11F3NO [M+H] 206.0793, found 206.0799. IR (neat) cm : 3336, 3283, 3029, 2929,

2818, 1621, 1422, 1322, 1282, 1172, 1123, 1111, 1083, 1061, 1044, 1016, 958, 892, 838

MP: 106 – 109 °C.

2-amino-2-(o-tolyl)ethan-1-ol (II-11): Trichloroacetimidate II-S11 (112

mg, 0.4 mmol) was subjected to GP. After workup, β-amino alcohol II-11

1 was isolated as a white solid (53 mg, 89%). Oxazoline yield by H NMR: 99%. Rf: 0.03

1 (30% Isopropanol/CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.38 (d, J = 7.4 Hz, 1H),

7.24 – 7.15 (m, 3H), 4.30 (dd, J = 8.3, 4.7 Hz, 1H), 3.70 (dd, J = 10.7, 4.0 Hz, 1H), 3.51

13 (dd, J = 10.7, 8.4 Hz, 1H), 2.37 (s, 3H), 2.04 (bs, 3H). C NMR (100 MHz, CDCl3): δ =

141.0, 135.4, 130.8, 127.3, 126.5, 125.3, 67.2, 53.1, 19.4. HRMS (ESI-TOF) m/z: calc’d

+ –1 for C9H14NO [M+H] 152.1075, found 152.1099. IR (neat) cm : 3334, 3279, 3226, 2918,

2502, 1588, 1487, 1455, 1361, 1093, 1043, 980, 893. MP: 100 – 102 °C.

84 2-amino-2-(2-chlorophenyl)ethan-1-ol (II-12): Trichloroacetimidate II-

S12 (120 mg, 0.4 mmol) was subjected to GP. After workup, β-amino alcohol II-12 was isolated as a white solid (56 mg, 82%). Oxazoline yield by 1H NMR:

1 100%. Rf: 0.11 (30% Isopropanol/CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.48 (dd, J

= 7.7, 1.6 Hz, 1H), 7.36 (dd, J = 7.8, 1.3 Hz, 1H), 7.30 – 7.26 (m, 1H), 7.20 (dt, J = 7.6,

1.6 Hz, 1H), 4.50 (dd, J = 8.1, 4.2 Hz, 1H), 3.82 (dd, J = 10.7, 4.0 Hz, 1H), 3.57 (dd, J =

13 10.8, 7.8 Hz, 1H), 2.08 (bs, 3H). C NMR (100 MHz, CDCl3): δ = 140.0, 133.2, 129.9,

+ 128.6, 127.5, 127.3, 66.1, 53.8. HRMS (ESI-TOF) m/z: calc’d for C8H11ClNO [M+H]

172.0529, found 172.0536. IR (neat) cm–1: 3329, 3277, 2923, 2809, 1589, 1471, 1455,

1435, 1360, 1133, 1102, 1046, 1039, 983, 949, 896, 813, 749. MP: 76 – 78 °C.

2-amino-2-(2-(trifluoromethyl)phenyl)ethan-1-ol (II-13):

Trichloroacetimidate II-S13 (134 mg, 0.4 mmol) was subjected to GP.

After workup, β-amino alcohol II-13 was isolated as a white solid (61 mg, 74%). Oxazoline

1 1 yield by H NMR: 100%. Rf: 0.31 (30% Isopropanol/CH2Cl2). H NMR (400 MHz,

CDCl3): δ = 7.67 (dd, J = 13.5, 7.9 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz,

1H), 4.47 (dd, J = 8.0, 3.8 Hz, 1H), 3.75 (dd, J = 10.8, 4.0 Hz, 1H), 3.57 (dd, 10.7, 8.3,

13 2 1H), 2.10 (bs, 3H). C NMR (100 MHz, CDCl3): δ = 142.1, 132.4, 128.1 (q, JCF = 29.8

3 1 4 Hz), 127.9, 127.6, 126.0, (q, JCF = 5.9 Hz), 124.5 (q, JCF = 274.1 Hz), 67.4, 52.5 (d, JCF

19 = 2.2 Hz). F NMR (375 MHz, CDCl3): δ = – 58.4. HRMS (ESI-TOF) m/z: calc’d for

+ –1 C9H11F3NO [M+H] 206.0793, found 206.0793. IR (neat) cm : 3350, 3281, 3076, 2893,

2828, 1609, 1456, 1311, 1148, 1107, 1044, 989, 899, 771, 757. MP: 51 – 55 °C.

85 2-amino-2-(3-methoxyphenyl)ethan-1-ol (II-14):

Trichloroacetimidate II-S14 (117.8 mg, 0.4 mmol) was subjected to

GP. After workup, β-amino alcohol II-14 was isolated as a colorless oil (61.2 mg, 92%).

1 1 Oxazoline yield by H NMR: 92%. Rf: 0.1 (30% Isopropanol/CH2Cl2). H NMR (400 MHz,

CDCl3): δ = 7.27 – 7.23 (m, 1H), 6.90 – 6.88 (m, 2H), 6.81 – 6.79 (m, 1H), 4.00 (dd, J =

8.2, 4.3 Hz, 1H), 3.79 (s, 3H), 3.71 (dd, J = 10.8, 4.3 Hz, 1H), 3.54 (dd, J = 10.8, 8.2 Hz,

13 1H), 2.32 (bs, 3H). C NMR (100 MHz, CDCl3): δ = 159.9, 144.5, 129.7, 118.9, 112.8,

+ 112.4, 68.0, 57.5, 55.3. HRMS (ESI-TOF) m/z: calc’d for C9H14NO2 [M+H] 168.1025, found 168.1040. IR (film) cm–1: 3326, 3257, 2998, 2877, 2834, 1609, 1581.

2-amino-2-(m-tolyl)ethan-1-ol (II-15): Trichloroacetimidate II-S15

(112 mg, 0.4 mmol) was subjected to GP. After workup, β-amino alcohol II-15 was isolated as a white solid (51 mg, 84%). Oxazoline yield by 1H NMR:

1 97%. Rf: 0.03 (30% Isopropanol/CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.24 – 7.22

(m, 1H), 7.14 – 7.09 (m, 3H), 4.01 (dd, J = 8.2, 4.5 Hz, 1H), 3.73 (dd, J = 10.6, 4.5 Hz,

1H), 3.55 (dd, J = 10.6, 8.3 Hz, 1H), 2.36 (s, 3H), 1.86 (bs, 3H). 13C NMR (100 MHz,

CDCl3): δ = 142.9, 138.5, 128.7, 128.4, 127.3, 123.6, 68.2, 57.4, 21.6. HRMS (ESI-TOF)

+ –1 m/z: calc’d for C9H14NO [M+H] 152.1075, found 152.1094. IR (neat) cm : 3190, 3106,

3022, 2949, 2926, 2872, 2672, 2114, 1568, 1445, 1398, 1366, 1315, 1169, 1049, 895. MP:

84 – 85 °C

2-amino-2-(pyridin-2-yl)ethan-1-ol (II-16): Trichloroacetimidate II-S16

(109 mg, 0.4 mmol) was subjected to GP. Upon completion, the mixture

86 was diluted with H2O (1 mL) and 50% aq. HBF (50 ul, 0.8 mmol) was added and the reaction was allowed to stir for 3 hr. Upon completion, the reaction was poured into a separatory funnel containing a 1:1 mixture of saturated NaHCO3 and 20% Na2S2O3 (15 mL). The aqueous phase was washed with ethyl acetate (3 x 15 mL) and the combined organic solution was dried over MgSO4 and concentrated. The crude material was purified

(silica gel, Hexanes → 60% Ethyl acetate/hexanes) to yield trichloroacetamide II-16 as a

1 white solid (74 mg, 65%). Oxazoline yield by H NMR: 97%. Rf: 0.10 (50% Ethyl

1 acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.56 (ddd, J = 4.9, 1.6, 0.9, 1H), 8.27

(bs, 1H), 7.74 (td, J = 11.6, 1.8, Hz, 1H), 7.43 (d, J = 7.8, Hz, 1H), 7.30 (ddd, J = 7.6, 4.9,

1.1, 1H), 5.09 – 5.06 (m, 1H), 4.19 – 4.16 (m, 1H), 4.02 – 3.96 (m, 1H), 3.66 (bs, 1H). 13C

NMR (100 MHz, CDCl3): δ = 162.2, 157.2, 149.2, 137.7, 123.6, 123.3, 92.6, 65.2, 56.0.

+ HRMS (ESI-TOF) m/z: calc’d for C9H9Cl3N2O2Na [M+Na] 304.9627, found 304.9612.

2-amino-2-(thiophen-2-yl)ethan-1-ol (II-17): Trichloroacetimidate II-

S17 (109 mg, 0.4 mmol) was subjected to GP. Upon completion, the

mixture was diluted with H2O (1 mL) and p-toluenesulfonic acid monohydrate (380.4 mg, 2.0 mmol) was added and the reaction was allowed to stir for 1 hr. Upon completion, the reaction was poured into a separatory funnel containing a 1:1 mixture of saturated NaHCO3 and 20% Na2S2O3 (15 mL). The aqueous phase was washed with ethyl acetate (3 x 15 mL) and the combined organic solution was dried over MgSO4 and concentrated. The crude material was purified (silica gel, Hexanes → 20% Ethyl acetate/hexanes) to yield trichloroacetamide II-17 as a white solid (97 mg, 84%).

1 1 Oxazoline yield by H NMR: 95%. Rf: 0.49 (50% Ethyl acetate/hexanes). H NMR (400

87 MHz, CDCl3): δ = 7.37 (bs, 1H), 7.30 (dd, J = 5.1, 1.2 Hz, 1H), 7.08 (td, J = 3.5, 1.0 Hz,

1H), 7.02 (dd, J = 3.5, 5.1 Hz, 1H), 5.38 – 5.34 (m, 1H), 4.06 (dd, J = 6.1, 4.0 Hz, 1H),

13 1.90 (t, J = 6.1 Hz, 1H). C NMR (100 MHz, CDCl3): δ = 161.7, 140.4, 127.4, 125.8,

+ 125.7, 92.6, 65.4, 52.9. HRMS (ESI-TOF) m/z: calc’d for C8H8Cl3NO2SNa [M+Na]

309.9239, found 309.9227. IR (neat) cm–1: 3443, 3178, 2981, 2884, 1698, 1545, 1454,

1379, 1278, 1085, 1042, 906, 824. MP: 127 – 130 °C.

2-amino-2-phenylbutan-1-ol (II-18): Trichloroacetimidate II-S18 (118 mg,

0.4 mmol) was subjected to GP with the following changes: the crude mixture was concentrated in a round-bottom flask, then methanol (4 mL) and 2M HCl (0.8 mL) was added and stirred for 5 hours at 50 °C, after workup, β-amino alcohol II-18 was

1 isolated as a white solid (65 mg, 97%). Oxazoline yield by H NMR: 97%. Rf: 0.19 (30%

1 Isopropanol/CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.41 – 7.34 (m, 4H), 7.27 – 7.23

(m, 1H), 3.70 – 3.64 (m, 5H), 1.92 – 1.67 (m, 5H), 0.72 (t, J = 7.5 Hz, 3H). 13C NMR (100

MHz, CDCl3): δ = 144.6, 128.6, 126.8, 126.0, 71.1, 59.7, 32.0, 7.9. HRMS (ESI-TOF) m/z:

+ –1 calc’d for C10H16NO [M+H] 166.1232, found 166.1246. IR (neat) cm : 3378, 3308, 3057,

2967, 2939, 2876, 1569, 1442, 1307, 1234, 1182, 1067, 1053, 990, 807. MP: 53 – 54 °C.

2-amino-2-(4-isobutylphenyl)propan-1-ol (II-19):

Trichloroacetimidate II-S19 (134.7 mg, 0.4 mmol) was subjected to GP with the following changes: the crude mixture was concentrated in a round-bottom flask, then methanol (4 mL) and 2M HCl (0.8 mL) was added and stirred for 2 hours at 50 °C, after workup, β-amino alcohol II-19 was isolated as a white solid (69 mg, 83%). Oxazoline

88 1 1 yield by H NMR: 90%. Rf: 0.08 (30% Isopropanol/CH2Cl2). H NMR (600 MHz, CDCl3):

δ = 7.34 (d, J = 8.3 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 3.61 (d, J = 10.8 Hz, 1H), 3.55 (d, J

= 10.6 Hz, 1H), 2.46 (d, J = 7.1 Hz, 2H), 1.89 – 1.83 (m, 1H), 1.44 (s, 3H), 0.90 (d, J = 6.8

13 Hz, 6H). C NMR (150 MHz, CDCl3): δ = 143.9, 140.4, 129.3, 125.1, 71.8, 56.0, 45.1,

+ 30.3, 27.2, 22.5. HRMS (ESI-TOF) m/z: calc’d for C13H22NO [M+H] 208.1701, found

208.1706. IR (film) cm–1: 3321, 3266, 2947, 2918, 2863, 1604.

1-amino-2,3-dihydro-1H-inden-2-ol (II-20): Trichloroacetimidate II-S20

(111.6 mg, 0.4 mmol) was subjected to GP with the following changes: the crude mixture was concentrated in a round-bottom flask, then methanol (4 mL) and 6M

HCl (0.3 mL) was added and stirred for 5 hours at 50 °C, after workup, β-amino alcohol

1 II-20 was isolated as a white solid (48.2 mg, 81%). Oxazoline yield by H NMR: 97%. Rf:

1 0.03 (30% Isopropanol/CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.32 – 7.23 (m, 4H),

4.38 (td, J = 5.5, 3.0 Hz, 1H), 4.32 (d, J = 5.4 Hz, 1H), 3.09 (dd, J = 16.5, 5.7 Hz, 1H),

13 2.94 (dd, J = 16.3, 2.9 Hz, 1H), 2.36 (bs, 3H). C NMR (100 MHz, CDCl3): δ = 144.1,

141.1, 128.1, 127.1, 125.6, 124.0, 72.8, 58.6, 39.5. HRMS (ESI-TOF) m/z: calc’d for

+ –1 C9H12NO [M+H] 150.0919, found 150.0930. IR (film) cm : 3340, 3265, 3062, 2979,

2898, 2755, 2730, 1580, 1473. MP: 129 – 130 °C.

cis-3-amino-1,1,1-trifluoro-3-phenylpropan-2-ol (II-21):

Trichloroacetimidate II-S21 (133.6 mg, 0.4 mmol) was subjected to GP with the following changes: the reaction was stirred in a heating block at 50 °C for 14 hours.

Upon completion, the crude mixture was concentrated in a round-bottom flask and the

89 crude oxazoline yield of 79% was determined by 1H NMR (DCE, 32 μL, as internal standard). The sample was concentrated and then methanol (4 mL) and 2M HCl (0.8 mL) was added and stirred for 12 hours at 50 °C, after workup, β-amino alcohol II-21 was

1 isolated as a white solid (46.7 mg, 57%). Rf: 0.46 (10% MeOH/CH2Cl2). H NMR (600

MHz, CD3OD): δ = 7.39 – 7.38 (m, 2H), 7.35 – 7.33 (m, 2H), 7.29 – 7.27 (m, 1H), 4.08 (d,

13 J = 5.7 Hz, 1H), 4.00 (dq, J = 5.9, 7.2 Hz, 1H). C NMR (150 MHz, CD3OD): δ = 142.7,

1 2 19 129.5, 128.8, 128.4, 126.5 (q, JCF = 283.2 Hz), 74.5 (q, JCF = 28.6 Hz), 56.4. F NMR

3 (565 MHz, CD3OD): δ = – 77.01 (d, JHF = 6.1 Hz). HRMS (ESI-TOF) m/z: calc’d for

+ –1 C9H11F3NO [M+H] 206.0793, found 206.0804. IR (film) cm : 3344, 3289, 2968, 2891,

1766, 1590, 1271. MP: 115 – 122 °C.

4- trichloroacetamidyl cholesterol (II-22):

Trichloroacetimidate II-S22 (212 mg, 0.4 mmol) was subjected

to GP with the following changes: upon completion, the mixture

was concentrated, then methanol (4 mL), 2M HCl (0.8 mL), tetrabutylammonium chloride (111 mg, 0.4mmol) were added. After stirring for 24 hours, the reaction was diluted with CH2Cl2 (10 mL) and aqueous sodium thiosulfate (20% w/w) was added. The aqueous layer was washed with CH2Cl2 (3 x 25 mL). The combined organic layer was dried over MgSO4 and concentrated. The crude product was purified (hexanes,

1% Et3N) to yield trichloroacetamide II-22 (186 mg, 85%) as a white solid. Oxazoline

1 1 yield by H NMR: 100%. Rf: 0.26 (20% Ethyl acetate/hexanes). H NMR (400 MHz,

CDCl3): δ = 7.06 (d, J = 6.0 Hz, 1H), 5.88 (dd, J = 4.9, 2.2 Hz, 1H), 4.46 (t, J = 5.3 Hz,

1H), 3.87 – 3.83 (m, 1H), 2.21 – 2.14 (m, 2H), 2.02 (dt, J = 12.6, 3.4 Hz, 1H), 1.88 –1.81

90 (m, 3H), 1.72 – 1.65 (m, 1H), 1.63 – 0.94 (m, 23H), 0.91 (d, J = 6.6 Hz, 3H), 0.87 (d, J =

13 1.4 Hz, 3H), 0.86 (d, J = 2.8 Hz, 3H), 0.67 (s, 3H). C NMR (100 MHz, CDCl3): δ = 162.5,

137.9, 131.7, 93.1, 77.4, 71.1, 60.9, 57.0, 56.2, 50.4, 42.4, 39.7, 39.6, 36.3, 36.1, 35.9, 32.4,

31.8, 28.3, 28.2, 25.7, 24.4, 24.0, 23.0, 22.7, 21.0, 20.7, 18.9, 12.0. HRMS (ESI-TOF) m/z:

+ –1 calc’d for C29H46Cl3NO2Na [M+Na] 568.2492, found 568.2485. IR (neat) cm : 3430,

3380, 2980, 2970, 2938, 2866, 1703, 1500, 1471, 1378, 1247, 1175, 1075, 946, 819, 759.

MP: 200.0 °C (decomposed).

2-iodo-2-methylpropyl 2,2,2-trichloroacetimidate (II-30):

Trichloroacetimidate II-28a (87.4 mg, 0.4 mmol) was subjected to GP with the following changes: the crude mixture was concentrated in a round-bottom flask and a crude 1H NMR was taken (iPrOAc as an internal standard) which indicated a crude yield of 53% of tertiary alkyl iodide imidate II-30 by integrating a singlet corresponding to - oxy methylene around 4.2 ppm (see below for crude 1H NMR spectra). The presence of alkyl iodide was further confirmed via HRMS.

N-(1-hydroxy-2-methylpropan-2-yl)benzamide (II-32): Benzimidate II-

28b (70.4 mg, 0.4 mmol) was subjected to GP with the following changes: solid NaHCO3 (67.2 mg, 0.8 mmol) was added to the reaction mixture. Upon completion

(24 hours) the crude mixture was concentrated in a round-bottom flask and a crude 1H

NMR was taken (DCE as an internal standard) which indicated a crude oxazoline yield of

62%. THF (4 mL) and 2M HCl (0.8 mL) were added to the crude reaction which was then stirred for 17 hours at 50 °C, after workup, β-amido alcohol II-32 was isolated as a white

91 1 solid (29 mg, 38%). Rf: 0.24 (50% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ

= 7.75 – 7.72 (m, 2H), 7.53 – 7.49 (m, 1H), 7.46 – 7.41 (m, 2H), 6.16 (bs, 1H), 4.64 (t, J =

13 4.8 Hz, 1H), 3.70 (d, J = 3.8 Hz, 2H), 1.42 (s, 6H). C NMR (150 MHz, CDCl3): δ = 168.5,

135.1, 131.8, 128.8, 127.0, 70.9, 56.7, 25.0. HRMS (ESI-TOF) m/z: calc’d for C11H16NO2

[M+H]+ 194.1181, found 194.1191. IR (film) cm–1: 3292, 3158, 3057, 2980, 2899, 2895,

2849, 1626, 1554. MP: 83 – 85 °C.

N-(2-hydroxyethyl)benzamide (II-33): Benzimidate hydrochloride II-S33

(18.7 mg, 0.1 mmol) was subjected to GP with the following changes: upon completion

(24 hours) the crude mixture was concentrated in a round-bottom flask and a crude 1H

NMR was taken (DCE as an internal standard) which indicated a crude oxazoline yield of

45%. MeOH (0.5 mL) and 2M HCl (0.5 mL) were added to the crude reaction which was then stirred for 12 hours at room temperature, after workup, β-amido alcohol II-33 was

1 isolated as a white solid (7 mg, 42%). Rf: 0.20 (5% MeOH/CH2Cl2). H NMR (400 MHz,

CDCl3): δ = 7.79 – 7.77 (m, 2H), 7.52 – 7.48 (m, 1H), 7.44 – 7.40 (m, 2H), 6.70 (bs, 1H),

3.83 (t, J = 5.0 Hz, 2H), 3.63 (appq, J = 5.3 Hz, 2H), 2.78 (bs, 1H). 13C NMR (150 MHz,

CDCl3): δ = 168.7, 134.4, 131.8, 128.7, 127.1, 62.5, 43.0. HRMS (ESI-TOF) m/z: calc’d

+ –1 for C9H12NO2 [M+H] 166.0868, found 166.0878. IR (film) cm : 3327, 3289, 3056, 2969,

2936, 2868, 1632, 1535. MP: 59 – 61 °C.

N-(1-hydroxypropan-2-yl)benzamide (II-34): Benzimidate II-S34 (64.6 mg,

0.04 mmol) was subjected to GP with the following changes: upon completion (ca 5 hours), the crude mixture was concentrated in a round-bottom flask and a crude 1H NMR was taken

92 (DCE as an internal standard) which indicated a crude oxazoline yield of 82%. Then THF

(2 mL) and 2M HCl (1.0 mL) was added and stirred for 12 hours at room temperature, after workup, β-amido alcohol II-34 was isolated as a white solid (50.4 mg, 70%). Rf: 0.09 (50%

1 Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.78 – 7.76 (m, 2H), 7.52 – 7.48

(m, 1H), 7.45 – 7.40 (m, 2H), 6.33 (bs, 1H), 4.31 – 4.25 (m, 1H), 3.78 (dd, J = 10.8, 3.6

Hz, 1H), 3.65 (dd, J = 10.9, 5.8, 1H), 2.80 (bs, 1H), 1.29 (d, J = 6.9 Hz, 3H). 13C NMR

(100 MHz, CDCl3): δ = 168.2, 134.5, 131.8, 128.7, 127.1, 67.3, 48.3, 17.3. HRMS (ESI-

+ –1 TOF) m/z: calc’d for C10H13NO2Na [M+Na] 202.0844, found 202.0859. IR (film) cm :

3343, 2971, 2936, 2875, 1629, 1537. MP: 103 – 105 °C.

N-(1-hydroxypentan-2-yl)benzamide (II-35): Benzimidate II-S35

(75.3 mg, 0.04 mmol) was subjected to GP with the following changes: upon completion

(ca 5 hours), the crude mixture was concentrated in a round-bottom flask and a crude 1H

NMR was taken (DCE as an internal standard) which indicated a crude oxazoline yield of

79%. Then THF (2 mL) and 2M HCl (1.0 mL) was added and stirred for 12 hours at room temperature, after workup, β-amido alcohol II-35 was isolated as a white solid (52 mg,

1 64%). Rf: 0.13 (50% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.77 – 7.75

(m, 2H), 7.51 – 7.46 (m, 1H), 7.42 – 7.38 (m, 2H), 6.42 (d, J = 7.4 Hz, 1H), 4.19 – 4.11

(m, 1H), 3.76 (dd, J = 10.9, 3.8 Hz, 1H), 3.66 (dd, J = 11.1, 5.4 Hz, 1H), 3.08 (bs, 1H),

1.66 – 1.52 (m, 2H), 1.47 – 1.37 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (150 MHz,

CDCl3): δ = 168.4, 134.6, 131.7, 128.7, 127.1, 65.7, 52.2, 33.6, 19.5, 14.1. HRMS (ESI-

+ –1 TOF) m/z: calc’d for C12H17NONa [M+Na] 230.1157, found 230.1162. IR (film) cm :

3282, 2937, 2936, 2865, 1631, 1530. MP: 95 – 97 °C.

N-(1,5-dihydroxypentan-2-yl)benzamide (II-36): Benzimidate II-

S36 (32.4 mg, 0.2 mmol) was subjected to GP with the following changes: upon completion (ca 5 hours), the crude mixture was concentrated in a round-bottom flask and a crude 1H NMR was taken (DCE as an internal standard) which indicated a crude oxazoline yield of 80%. Then THF (1 mL) and 2M HCl (0.5 mL) was added and stirred for

7 hours at room temperature, then saturated NaHCO3 (10 mL) was added and stirred for 12 hours. The crude mixture was extracted with ethyl acetate (4 x 20 mL) and dried over

MgSO4. Upon concentration, the crude material was purified via column chromatography

(silica gel, 4% → 5% MeOH/CH2Cl2) and β-amido alcohol II-36 was isolated as a white

1 solid (14 mg, 62%). Rf: 0.20 (10% MeOH/CH2Cl2). H NMR (600 MHz, CDCl3): δ = 7.80

– 7.79 (m, 2H), 7.52 – 7.49 (m, 1H), 7.45 – 7.42 (m, 1H), 6.70 (d, J = 6.9 Hz, 1H), 4.24 –

4.19 (m, 1H), 3.81 (dd, J = 11.1, 3.6 Hz, 1H), 3.77 – 3.71 (m, 3H), 2.78 (bs, 1H), 1.99 (bs,

13 1H), 1.82 – 1.68 (m, 4H). C NMR (150 MHz, CDCl3): δ = 168.5, 134.5, 131.8, 128.8,

+ 127.2, 65.8, 62.7, 52.2, 28.7, 28.1. HRMS (ESI-TOF) m/z: calc’d for C12H18NO3 [M+H]

224.1287, found 224.1292. IR (film) cm–1: 3329, 3275, 3052, 2916, 2853, 1632, 1534. MP:

87 – 89 °C.

Methyl 3-benzamido-4-hydroxybutanoate (II-37): Benzimidate II-

S37 (22.4 mg, 0.1 mmol) was subjected to GP with the following changes: upon completion (ca 5 hours), the crude mixture was concentrated in a round-bottom flask and a crude 1H NMR was taken (DCE as an internal standard) which indicated a crude oxazoline yield of 68%. Then MeOH (1 mL) and 2M HCl (0.5 mL) was added and stirred

94 for 3 hours at room temperature, then solid NaOMe (130 mg, 20 equiv.) was added and diluted with 2 mL of CHCl3 and stirred for 6 hours. The crude mixture was extracted with ethyl acetate (4 x 20 mL) and dried over MgSO4. Upon concentration, the crude material was purified via column chromatography (silica gel, 1% → 3% MeOH/CH2Cl2) and β- amido alcohol II-37 was isolated in low yield and an oily residue. (Note: Other attempts at hydrolysis yield mixtures of ester and amide. Other basic reaction conditions also yield

1 a mixture of an open amide and ring-closed lactam.). Rf: 0.49 (10% MeOH/CH2Cl2). H

NMR (600 MHz, CDCl3): δ = 8.04 – 8.02 (m, 2H), 7.57 – 7.55 (m, 1H), 7.45 – 7.43 (m,

2H), 4.54 – 4.46 (m, 2H), 3.71 – 3.67 (m, 1H), 3.69 (s, 3H), 2.27 – 2.23 (m, 1H), 2.04 –

13 1.99 (m, 1H), 1.82 (bs, 3H). C NMR (150 MHz, CDCl3): δ = 166.4, 133.0, 130.1, 129.6,

+ 128.4, 61.5, 52.1, 51.8, 33.7. HRMS (ESI-TOF) m/z: calc’d for C12H15NO4Na [M+Na]

260.0899, found 260.0897.

(S)-2-(2-(2-phenyl-4,5-dihydrooxazol-4-yl)ethyl) isoindoline-

1,3-dione (II-38’): Benzimidate II-S38 (64.5 mg, 0.2 mmol) was

subjected to GP with the following changes: Upon completion (ca

4 hours), the crude mixture was concentrated in a round-bottom flask and a crude 1H NMR was taken (DCE as an internal standard) which indicated a crude oxazoline yield of 85%.

The crude reaction mixture was concentrated and loaded directly onto silica gel and purified (silica gel, Hexanes → 50% Ethyl acetate/hexanes) to yield the target oxazoline

II-38’ (49 mg, 77%) as an off-white viscous oil. (Note: Attempted hydrolysis with HCl led to a complex mixture, due to benzoyl transfer between OH and NH2. Other hydrolysis condition yields complex mixtures as well. Because of this inconsistent result, we decided

95 to isolate the oxazoline product. Trace amounts of both amide and ester were isolated after

1 hydrolysis.) Rf: 0.56 (50% Ethyl acetate/hexanes). H NMR (600 MHz, CDCl3): δ = 7.85

(dd, J = 5.7, 3.7, 2H), 7.78 (d, J = 8.1, 2H), 7.72 (dd, J = 5.4, 3.0, 2H), 7.43 (t, 1H), 7.33

(t, 2H), 4.54 (t, J = 9.0 Hz, 1H), 4.34 (q, J = 7.8 Hz, 1H), 4.10 (t, J = 8.1 Hz, 1H), 3.99 –

3.94 (m, 1H), 3.88 – 3.84 (m, 1H), 2.15 – 2.09 (m, 1H), 1.97 – 1.91 (m, 1H). 13C NMR

(150 MHz, CDCl3): δ = 168.6, 164.1, 134.0, 132.5, 131.4, 128.4, 128.4, 127.8, 123.4, 72.6,

+ 650, 35.5, 34.6. HRMS (ESI-TOF) m/z: calc’d for C19H17N2O3 [M+H] 321.1239, found

321.1220. IR (film) cm–1: 3445, 2970, 1738, 1435, 1365, 1228, 1217, 1047.

N-(2-hydroxycyclopentyl)benzamide (II-39): Benzimidate II-S39 (37.2 mg,

0.2 mmol) was subjected to GP with the following changes: the reaction was run at 50 °C. Upon completion (ca 24 hours), the crude mixture was concentrated in a round-bottom flask, and a crude 1H NMR was taken (DCE as an internal standard) which indicated a crude oxazoline yield of 63%. THF (1 mL) and 2M HCl (0.5 mL) was added and stirred for 24 hours at 50 °C. The crude reaction mixture was purified via column chromatography (silica gel, 20% Ethyl acetate/hexanes) to yield β-amido alcohol II-39 as

1 a white solid (18 mg, 45%). Rf: 0.32 (5% MeOH/CH2Cl2). H NMR (600 MHz, CD3OD):

δ = 7.84 – 7.83 (m, 2H), 7.54 – 7.51 (m, 1H), 7.47 – 7.44 (m, 2H), 4.22 (td, J = 4.8, 2.2 Hz,

1H), 4.18 (ddd, J = 9.9, 7.9, 4.6 Hz, 1H), 2.05 – 2.00 (m, 1H), 1.98 – 1.85 (m, 2H), 1.80 –

13 1.71 (m, 1H), 1.67 – 1.59 (m, 1H). C NMR (100 MHz, CD3OD): δ = 170.1, 135.9, 132.6,

129.5, 128.3, 73.2, 56.2, 33.6, 29.4, 21.2. HRMS (ESI-TOF) m/z: calc’d for C12H16NO2

[M+H]+ 206.1181, found 206.1187. IR (film) cm–1: 3286, 3237, 3065, 2917, 2848, 1628,

1536.

N-(3-hydroxybutan-2-yl)benzamide (II-40): Benzimidate II-S40 (71.3 mg,

0.4 mmol) was subjected to GP with the following changes: upon completion

(ca 12 hours), the crude mixture was concentrated in a round-bottom flask and a crude 1H

NMR was taken (DCE as an internal standard) which indicated a crude oxazoline yield of

88%. Methanol (4 mL) and 2M HCl (0.8 mL) were added to the crude reaction which was then stirred for 12 hours at 50 °C, after workup, the crude material was purified via column chromatography (silica gel, 1% → 2% MeOH/CH2Cl2) β-amido alcohol II-40 was isolated as a white solid and an inseparable mixture of diastereomers (49 mg, 63%, d.r. 1:1). Rf:

1 0.17 (5% MeOH/CH2Cl2). H NMR (600 MHz, CDCl3): Diastereomers (a + b) δ = 7.77 –

7.74 (m, 2Ha), 7.77 – 7.74 (m, 2Hb), 7.50 – 7.45 (m, 1Ha), 7.50 – 7.45 (m, 1Hb), 7.41 –

7.37 (m, 2Ha), 7.41 – 7.37 (m, 2Hb), 6.58 – 6.53 (m, 1Ha), 6.58 – 6.53 (m, 1Hb), 4.22 –

4.14 (m, 1Ha), 4.13 – 4.05 (m, 1Hb), 3.97 – 3.96 (m, 1Ha) 3.85 – 3.82 (m, 1Hb) 3.13 (bs,

1Ha), 2.87 (bs, 1Hb), 1.27 (d, J = 6.8 Hz, 3Hb), 1.22 (d, J = 6.3 Hz, 3Ha), 1.20 (d, J = 6.9

13 Hz, 3Hb), 1.19 (d, J = 6.5 Hz, 3Ha). C NMR (150 MHz, CDCl3): δ = 168.0, 167.9, 134.7,

134.6, 131.61, 131.56, 128.6, 127.14, 127.11, 127.08, 70.8, 70.3, 51.1 (2C), 20.8, 19.2,

+ 18.2, 14.3. HRMS (ESI-TOF) m/z: calc’d for C11H15NO2Na [M+Na] 216.1000, found

216.1006. IR (film) cm–1: 3293, 2970, 2936, 2870, 1627, 1553, 1525. MP: 84 – 86 °C.

N-(1-hydroxy-2-methylbutan-2-yl)benzamide (II-41): Benzimidate II-S41

(38.3 mg, 0.2 mmol) was subjected to GP with the following changes: upon completion (25 hours), the crude mixture was concentrated in a round-bottom flask, and a crude 1H NMR was taken (DCE as an internal standard) which indicated a crude oxazoline

97 yield of 66%. THF (1 mL) and 2M HCl (0.5 mL) was added and stirred for 24 hours at

50 °C. The crude reaction mixture was purified via column chromatography (silica gel,

25% Ethyl acetate/hexanes) to yield β-amido alcohol II-41 as a white solid (18 mg, 45%).

1 Rf: 0.29 (50% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.74 – 7.72 (m,

2H), 7.53 – 7.49 (m, 1H), 7.45 – 7.41 (m, 2H), 6.10 (bs, 1H), 4.85 (bs, 1H), 3.74 (q, J =

11.0 Hz, 1H), 1.95 – 1.88 (m, 1H), 1.79 – 1.70 (m, 1H), 1.31 (s, 3H), 0.97 (t, J = 7.5 Hz,

13 3H). C NMR (150 MHz, CDCl3): δ = 168.6, 135.1, 131.8, 128.8, 127.0, 69.4, 59.6, 29.4,

+ 22.3, 8.1. HRMS (ESI-TOF) m/z: calc’d for C12H18NO2 [M+H] 208.1338, found 208.1343.

IR (film) cm–1: 3369, 3296, 3053, 2938, 2918, 2849, 1639, 1524.

2.5.4 Oxazoline Derivatization

2,2,2-trichloro-N-(2-hydroxy-1-phenylethyl)acetamide (II-42):

Trichloroacetimidate II-S3 (106.6 mg, 0.4 mmol) was subjected to GP with the following changes. Upon completion, the mixture was diluted with H2O (1 mL) and p- toluenesulfonic acid monohydrate (380.4 mg, 2.0 mmol) was added and the reaction was allowed to stir for 45 minutes. Upon completion, the reaction was poured into a separatory funnel containing a 1:1 mixture of saturated NaHCO3 and 20% Na2S2O3 (15 mL). The aqueous phase was washed with ethyl acetate (3 x 15 mL) and the combined organic solution was dried over MgSO4 and concentrated. The crude material was purified (silica gel, 10 → 20% Ethyl acetate/hexanes) to yield hydroxyacetamide II-42 as a white solid

1 (92 mg, 81%). Rf: 0.32 (25% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.46

(bs, 1H), 7.43 – 7.38 (m, 2H), 7.36 – 7.32 (m, 3H), 5.06 (dt, J = 8.0, 4.0 Hz, 1H), 4.06 –

13 3.96 (m, 2H), 1.76 (dd, J = 6.9, 5.4 Hz, 1H). C NMR (100 MHz, CDCl3): δ = 161.9, 137.6,

98 129.2, 128.5, 126.6, 92.7, 65.6, 56.8. HRMS (ESI-TOF) m/z: calc’d for C10H13Cl3NO2Na

[M+Na]+ 303.9675, found 303.9673. IR (film) cm–1: 3457, 3183, 3021, 2936, 1699, 1540.

MP: 107 – 109 °C.

4-phenyloxazolidin-2-one (II-43): Hydroxyacetamide II-42 (20 mg, 0.7 mmol)

was dissolved in MeCN (2 mL) and 6 M NaOH (1.5 mL) was added. The reaction was stirred for three hours and then extracted with CH2Cl2., dried over MgSO4, and concentrated to yield oxazolidinone II-43 as a white solid (11.6 mg, 100%). Rf: 0.26

1 (50% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.42 – 7.31 (m, 5H), 6.29

(bs, 1H), 4.95 (dd, J = 8.0, 7.1 Hz, 1H), 4.72 (t, J = 8.7, 1H), 4.17 (dd, J = 8.6, 6.8 Hz, 1H).

13 C NMR (150 MHz, CDCl3): δ = 160.1, 139.7, 129.3, 128.8, 126.1, 72.3, 56.4. HRMS

+ –1 (ESI-TOF) m/z: calc’d for C9H10NO2 [M+H] 164.0712, found 164.0740. IR (film) cm :

3259, 3148, 2950, 2909, 2840, 1729, 1718, 1595. MP: 138 – 139 °C.

2-phenyl-2-(2,2,2-trichloroacetamido)ethyl ethanethioate (II-44): To a

solution of oxazoline II-6 (53 mg, 0.2 mmol) in DMF (1 mL) was added potassium thioacetate (46mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 72 hours. The reaction was poured into water and extracted with CH2Cl2.

The organic layer was concentrated and loaded directly onto silica gel and purified

(SiliaFlash® 150 Å, Hexanes → 3% Ethyl acetate/hexanes) to yield the target thioester II-

44 (39 mg, 57%) as an off-white solid. (Note: Potassium thioacetate should be washed thoroughly with hexanes to remove trace amount of thioacetic acid. The reaction does not

1 work in the presence of thioacetic acid.) Rf: 0.44 (30% Ethyl acetate/hexanes). H NMR

99 (400 MHz, CDCl3): δ = 7.43 (bs, 1H), 7.31 – 7.21 (m, 5H), 4.96 – 4.91 (m, 1H), 3.42 (dd,

J = 14.6, 10.6 Hz, 1H), 3.06 (dd, J = 14.6, 4.0 Hz, 1H), 2.30 (s, 3H). 13C NMR (100 MHz,

CDCl3): δ = 197.9, 161.8, 139.4, 129.2, 128.6, 126.3, 92.6, 56.8, 34.3, 30.7. HRMS (ESI-

+ – TOF) m/z: calc’d for C12H12Cl3NO2SNa [M+Na] 361.9552, found 361.9521. IR (neat) cm

1: 3297, 3064, 2980, 2889, 2361, 1693, 1541, 1492, 1398, 1269, 1129, 1093, 1070, 958,

859, 818. MP: 108– 110 °C.

2,2,2-trichloro-N-(2-iodo-1-phenylethyl)acetamide (II-45): To a 2-dram

vial equipped with PTFE septa cap and magnetic stir bar, was added hexamethyldisilane (0.4 mmol) and I2 (0.4 mmol) under N2. The reaction was refluxed for

2 hours. After cooling to room temperature, this in situ generated Me3Si–I was added to a solution of oxazoline II-6 (53 mg, 0.2 mmol) in CH2Cl2 (1 mL) and stirred for 12 hours

(99% yield by 1H NMR). The reaction was concentrated and loaded directly onto silica gel and purified (acidic aluminum oxide, Hexanes → 50% CH2Cl2/hexanes) to yield the target iodide II-45 (34 mg, 43%) as a white solid. (Note: Aluminium oxide, acidic was used to effectively isolate the desired product. By crude NMR, the reaction yields quantitative iodide species, however, unknown byproduct (~ 5.9ppm, singlet) co-elutes with both tautomers when silica gel is used. Aluminum oxide avoids this issue) Rf: 0.49 (20% Ethyl

1 acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.46 – 7.32 (m, 5H), 7.18 (bs, 1H), 5.11

– 5.06 (m, 1H), 3.69 (dd, J = 10.8, 5.5 Hz, 1H), 3.60 (dd, J = 10.4, 6.1 Hz, 1H). 13C NMR

(100 MHz, CDCl3): δ = 161.3, 138.3, 129.3, 128.9, 126.2, 92.5, 55.3, 9.9. HRMS (ESI-

+ – TOF) m/z: calc’d for C10H9Cl3INONa [M+Na] 413.8692, found 413.8662. IR (neat) cm

100 1: 3246, 3065, 2918, 1673, 1557, 1528, 1495, 1452, 1420, 1339, 1269, 1216, 1179, 1088,

849, 815, 765. MP: 92 – 94 °C

N-(2-bromo-1-phenylethyl)-2,2,2-trichloroacetamide (II-46): To a

solution of oxazoline II-6 (53 mg, 0.4 mmol) in CH2Cl2 was added Me3Si–Br

(53.l, 0.4 mmol). The reaction mixture was stirred at room temperature for 5 min. The reaction was concentrated and loaded directly onto silica gel and purified (silica gel,

Hexanes → 20% Ethyl acetate/hexanes) to yield the target bromide II-46 (53 mg, 77%) as a white solid.

1 Rf: 0.44 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.44 – 7.32 (m,

5H), 7.24 (bs, 1H), 5.31 – 5.26 (m, 1H), 3.85 (dd, J = 10.8, 4.9 Hz, 1H), 3.77 (dd, J = 10.8,

13 6.0 Hz, 1H). C NMR (100 MHz, CDCl3): δ = 161.5, 137.4, 129.2, 128.9, 126.4, 92.5,

+ 55.2, 35.8. HRMS (ESI-TOF) m/z: calc’d for C10H9BrCl3NONa [M+Na] 365.8831, found

365.8802. IR (neat) cm–1: 3294, 2980, 2920, 2851, 1691, 1524, 1422, 1266, 1203, 1163,

1024, 971, 861, 840, 822. MP: 117 – 120 °C

2,2,2-trichloro-N-(2-chloro-1-phenylethyl)acetamide (II-47):

Method A: To a solution of oxazoline II-6 (105 mg, 0.4 mmol) in Et2O was added HCl in ether (2M). The reaction mixture was stirred at room temperature for 5 min.

The reaction mixture was poured into saturated aqueous NH4Cl and extracted with CH2Cl2

(3 x 25 mL). The organic fraction was dried over MgSO4, concentrated, and purified (silica gel, Hexanes → 10% Ethyl acetate/hexanes) to yield the target chloride II-47 (120 mg,

99%) as a white solid. Method B: To a solution of oxazoline II-6 (53 mg, 0.2 mmol) in

101 CH2Cl2 was added Me3Si–Cl (51 l, 0.4 mmol). The reaction mixture was stirred at room temperature for 1 hr. The reaction was concentrated and loaded directly onto silica gel and purified (silica gel, Hexanes → 20% Ethyl acetate/hexanes) to yield the target chloride II-

1 47 (51 mg, 85%) as a white solid. Rf: 0.44 (20% Ethyl acetate/hexanes). H NMR (400

MHz, CDCl3): δ = 7.44 – 7.33 (m, 5H), 7.28 (bs, 1H), 5.32 – 5.28 (m, 1H), 3.99 (dd, J =

13 11.6, 4.8 Hz, 1H), 3.91 (dd, J = 11.6, 5.7 Hz, 1H). C NMR (100 MHz, CDCl3): δ = 161.6,

137.0, 129.2, 128.8, 126.6, 92.5, 55.7, 47.1. HRMS (ESI-TOF) m/z: calc’d for

+ –1 C10H9Cl4NONa [M+Na] 321.9336, found 321.9316. IR (neat) cm : 3288, 3059, 3030,

2981, 2966, 1692, 1528, 1493, 1428, 1270, 1101, 1051, 879, 822. MP: 125 – 126 °C.

2,2,2-trichloro-N-(2-azido-1-phenylethyl)- acetamide (II-48):

To a 2-dram vial equipped with PTFE septa cap and magnetic stir bar was added acetamide II-45 (39.2 mg, 0.1 mmol), NaN3 (13.0 mg, 0.2 mmol), and DMF (0.5 mL). The reaction was stirred at room temperature for 12 hours. Upon completion

(monitored by TLC), the crude reaction was poured into water and extracted with CH2Cl2.

The organic layer was concentrated and loaded directly onto silica gel and purified (Silica,

Hexanes → 10% Ethyl acetate/hexanes) to yield the target azide II-48 (26.2 mg, 85%) as

1 a white solid. Rf: 0.48 (20% Ethyl acetate/hexanes). H NMR (600 MHz, CDCl3): δ = 7.43

– 7.34 (m, 5H), 7.16 (bs, 1H), 5.15 (dt, J = 7.8, 5.1 Hz, 1H), 3.83 (dd, J = 12.7, 5.0 Hz,

13 1H), 3.77 (dd, J = 12.6, 5.2 Hz, 1H). C NMR (125 MHz, CDCl3): δ = 16106, 137.3, 129.4,

+ 128.9, 126.6, 92.5, 54.9, 54.6. HRMS (ESI-TOF) m/z: calc’d for C10H9Cl3N4ONa [M+Na]

328.9740, found 328.9740. IR (neat) cm–1: 3299, 3068, 2937, 2085, 1688, 1533, 1495,

1445, 1259, 1220, 1097, 820, 762, 701, 637.MP: 78 – 80 °C

102

N-(1-phenylethyl)acetamide (II-49): To a 2-dram vial equipped with PTFE

septa cap and magnetic stir bar, was added the iodide II-45 (39.2 mg, 0.1 mmol), excess Raney Nickel (washed with isopropyl alcohol prior to reaction), and isopropyl alcohol (2 mL). The reaction was stirred at 80 °C for 15 min. Upon completion

(monitored by TLC), the crude reaction was filtered through a pad of celite and washed thoroughly with ethyl acetate. The filtrate was concentrated to yield acetamide II-49 (16.3 mg, quant.) as a white solid. (Note: Trichloromethyl is fully reduced to a methyl group.)

1 Rf: 0.29 (Ethyl acetate). H NMR (400 MHz, CDCl3): δ = 7.35 – 7.23 (m, 5H), 5.87 (bs,

1H), 5.12 (q, J = 7.4 Hz, 1H), 1.97 (s, 3H), 1.48 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz,

CDCl3): δ = 169.2, 143.3, 128.8, 127.5, 126.3, 48.9, 23.5, 21.8. HRMS (ESI-TOF) m/z:

+ –1 calc’d for C10H13NONa [M+Na] 186.0895, found 186.0900. IR (neat) cm : 3258, 3071,

2980, 1639, 1548, 1491, 1443, 1374, 1301, 1279, 1216, 1137, 1027, 741, 701. MP: 75 –

77 °C.

4-phenyl-2-(trichloromethyl)oxazole (II-50): To a solution of oxazoline II-6

(53 mg, 0.2 mmol) in CH2Cl2 was added 2,3-dichloro-5,6-dicyano-1,4- benzoquinone (182 mg, 0.8 mmol). The reaction mixture was stirred at 50°C for 16 hr. The reaction was concentrated and loaded directly onto silica gel and purified (silica gel,

Hexanes → 5% Ethyl acetate/hexanes) to yield the target oxazole II-50 (40 mg, 76%) as a

1 white solid. Rf: 0.70 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.01

(s, 1H), 7.78 – 7.76 (m, 2H), 7.46 – 7.41 (m, 2H), 7.40 – 7.35 (m, 1H). 13C NMR (100

MHz, CDCl3): δ = 159.3, 142.1, 135.7, 129.7, 129.1, 129.0, 126.0, 85.7. HRMS (ESI-TOF)

103 + –1 m/z: calc’d for C10H6Cl3NONa [M+Na] 283.9413, found 283.9401. IR (neat) cm : 3146,

3124, 2919, 2850, 1557, 1489, 1448, 1324, 1225, 1118, 1067, 1028, 983, 942, 852, 805,

790. MP: 84 – 85°C.

104 Chapter 3 C–H Amination via Iodine Catalysis

Portions of this chapter are adapted from the following publication:

Stateman, L. M.; Wappes, E. A.; Nakafuku, K. M.; Edwards, K. M.; Nagib, D. A.

“Catalytic β C–H amination via an imidate radical relay” Chem. Sci. 2019, 10, 2693 – 2699.

Author Contribution: KMN mentored and worked on a team that developed an iodine- catalyzed C–H amination of alcohols. Major contribution on substrates (Section 3.4) and robustness screen (Section 3.5).

105 3.1 Introduction

Selectively replacing an unbiased C–H bond with a valuable functional group in a molecule still remains a synthetic challenge. Considering 84% of pharmaceutical compounds contain at least one nitrogen atom138, selective incorporation of a nitrogen atom by C–H amination is an especially important transformation. Among recent advances toward directed C(sp3)–H functionalization of alcohol analogues, there remain few methods to synthesize  amino alcohols by C–H amination. Also, despite recent advances in C–H amination via HAT, there remain few catalytic variants of this transformation. To complement state-of-the-art, metal-catalyzed nitrenoid and C–H insertion pathways for remote C–H amination, we sought to employ a radical-based approach that entails 1,5-

HAT from an imidate radical (Figure 3-1).

Figure 3-1 Strategy toward catalytic C–H amination

3.2 Investigating Catalytic Turnover

106 With the hopes of expanding the synthetic utility of our previously reported C–H amination strategy that requires super-stoichiometric amount of oxidants105, we proposed development of a catalytic variant via continually recycling an iodine atom in a catalytic fashion (Figure 3-2). We envisioned that I2 acts as a pre-catalyst and is oxidized by

PhI(OAc)2 to generate AcO–I. This electrophilic iodine source halogenates imidate III-A, which is followed by N–I bond homolysis of imidate III-B to generate the imidate radical

III-C and I•. 1,5-HAT of imidate radical III-C results in the formation of imidate III-D, which undergoes radical coupling to form imidate III-E. In the presence of another equivalent of PhI(OAc)2, alkyl hypervalent iodine is generated; the nucleofugality is enhanced by 1010 – 1012 times when the iodine group is replaced by a hypervalent iodine group.139 This results in the formation of oxazoline III-F and a turn-over of iodine catalytic cycle.

Figure 3-2 Proposed catalytic cycle

107 3.3 Optimization of C–H Amination

In accord with our design, we were pleased to find the catalytic  C–H amination of imidate III-1 by HAT is indeed possible with 5 mol% I2 and 1.2 equiv. PhI(OAc)2, affording oxazoline III-2 in 95% yield (Table 3-1).

Table 3-1 Optimization of catalytic  C–H amination

This new thermal protocol requires polar, aprotic solvents (e.g. DMF, MeCN), whereas other solvents (e.g. CH2Cl2, PhMe) afford inferior yields due to incomplete conversion (entries 1 – 4). Although rigorous degassing is not essential, an N2 atmosphere was found to be superior to an aerobic one (entry 5). Although alkali iodide salts (e.g. NaI,

CsI) are competent sources of iodine for this reaction, they are less efficient than more soluble I2 reagent (entries 6 and 7). Finally, photolysis (entry 8) or non-photolytic initiation at room temperature (entry 9) afford reactivity, albeit with less efficiency than standard thermal initiation at 50 °C.

108 3.4 C–H Amination Scope

As shown in Table 3-2, a wide range of imidates undergo the radical relay mechanism via an iodine-catalyze thermal condition.

Table 3-2 Scope of trichloroacetimidate-mediated catalytic  C–H Amination

For trichloroacetimidate derived from Cl3C–CN, a range of electronically diverse 2- phenylethanol derivatives could be selectively aminated at the  position. These benzylic

C–H aminations (III-3 – III-10) are amenable to both electronically rich and deficient substituents (i.e. OMe, Me, F, CF3) as well as sterically differentiated o-, m-, and p- substitution pattern. Additionally, medicinally relevant heteroarenes (thiophene, pyridine,

109 III-11 – III-12) and tertiary C–H of an ibuprofen analog (III-13) are tolerated. Acyclic and cyclic secondary alcohols are efficiently aminated with excellent diastereoselectivity (up to >20:1 d.r.; III-14, III-15). Finally, the allylic C–H of a cholesterol analog is also efficiently and stereo-selectively aminated (III-16), with no other regioisomer present.

The C–H amination of aliphatic C–H bonds were investigated using benzimidate

(Table 3-3). This catalytic protocol is also suitable for the regioselective amination of primary, secondary, and tertiary C–H bonds (III-17 – III-21). Similarly, secondary alcohols are tolerated, although greater diastereoselectivity is observed for cyclic versus acyclic cases (III-19, > 1:1 d.r. vs. III-20, > 20:1 d.r.).

Table 3-3 Scope of benzimidate-mediated catalytic  C–H Amination

As a testament to the synthetic utility provided by these mild, catalytic conditions, several functional groups that were not previously tolerated in our stoichiometric protocol

110 can now be aminated (III-22 – III-26). Most interestingly, the reactive -systems of alkenes and alkynes are now amenable as substrates. In the presence of stoichiometric amount of electrophilic halogen source (e.g. NCS, NIS), imidates containing -systems often undergo halocyclization.140,141 By having AcO-I in catalytic amount in the reaction,

N-oxidation overrides undesired alkene oxidation to prevent deleterious oxidation degradation. For example, whereas alkene III-25 was previously accessible in only 43% yield under the stoichiometric, photochemical protocol; these catalytic, thermal conditions provide amination in 88% yield. Additionally, alkynes III-26, which had previously not been tolerated (0%), are now suitable substrates for this  amination (63% yield).

3.5 Substrate Compatibility via Robustness Screening

The limitation that often deters the incorporation of newly reported synthetic methods is a lack of information regarding its application beyond the idealized condition developed. In 2017, Glorius and co-worker142–144 have coined the term “robustness screen”, a simple analytical method in which exogenous functional groups are added to the reaction to rapidly assess the scope and limitations of a chemical reaction beyond its initial report.

In practice, they introduce additives with labile functional groups to the reaction and then assess the stability in the reaction by quantitatively calculating the yield of the reaction and that of the remaining additives. This approach will provide data that directly correlate to tolerance and limitations of a chemical transformation. Without de novo construction of substrates containing desired functional group, this analytical method provides rapid investigation into limitation of the method (Figure 3-3).

111

Figure 3-3 Robustness screen for catalytic and stoichiometric  C–H amination

With the optimized condition in hand, we undertook a robustness screen for an iodine-catalyzed  C–H amination reaction. Subjecting pentyl benzimidate to the catalytic

C–H amination protocol with various exogenous additives, gratifyingly, we discovered that the reaction condition tolerates many heterocycles (e.g. pyrrole, benzofuran, benzothiofuran, quinoline, isoquinoline, indole) as well as reactive functional groups (e.g. tertiary alkene, allylic alcohol, free OH, N-oxide). Additives had minimal effect on the efficiency of the reaction and were fully recovered at the end of the reaction.

112 3.6 Mechanistic Difference between Stoichiometric and Catalytic Systems

3.6.1 Rate of  C–H Amination

To study the kinetic profile for oxazoline formation, side-by-side reactions of the amination of pentyl benzimidate III-1 were quenched at time points and analyzed the rate of oxazoline III-2 by 1H NMR. In the stoichiometric reaction, less soluble sources of iodide

NaI in MeCN did not afford product as rapidly or efficiently (likely due to slower generation of I2). In the catalytic system, the use of more soluble I2 in a polar solvent DMF affords a higher initial concentration of the active oxidant, AcO–I. As a result, more than

85% of oxazoline III-2 is formed within 10 min, whereas the stoichiometric condition forms only 10% of oxazoline III-2. Moreover, thermal (vs. photolytic) initiation to generate imidate radical affects the efficiency of an AcOI-based, two-electron reactivity.

The greater thermolytic stability of AcOI over photolytic stability allows for higher concentration of the active oxidant under catalytic thermal condition.

113

Reaction Kinetic Profiles 100

60 (%)

2 50 -

III 40

Yield Yield 30

10 stoich. 5 mol% 10 mol% 20 mol% 0 0 5 10 15 20 25 30 35 40 45 50 Time (minutes)

Figure 3-4 Kinetic profile of catalytic vs stoichiometric reaction

3.6.2 HAT Regioselectivity

To gain a deeper understanding of this reaction mechanism, we conducted a series of competitive rate studies interrogating various stereoelectronic effects. First, we probed the regioselectivity of the imidate radical-mediated amination in the presence of weaker

C–H bonds. Although our reaction design is based on the entropic and enthalpic favorability of 1,5-HAT, there are notable examples of 1,6-HAT mediated pathways that are governed by substrate geometry70 or thermodynamics.145,146 To test the influence of the

114 latter, the  selectivity of this C–H amination was investigated for alcohols bearing a weaker  C–H bond (Figure 3-5). Thus, benzimidates from 3-phenylpropyl alcohol and isoamyl alcohol were synthesized via transimidation accordingly.

Figure 3-5 Regioselectivity: 1,5- vs 1,6-HAT

In each case,  selectivity (via 1,5-HAT) was observed in preference to  selectivity

(via 1,6-HAT). Even when the  C–H bond is significantly weaker (benzylic: 90 vs. secondary: 98 kcal/mol), the  amine III-27a is still preferentially formed (2:1  selectivity). However, when  C–H bond is only marginally weaker (3° :96 vs. 2° :98 kcal

/mol), the  amine III-28a is obtained exclusively (>20:1  selectivity). The remaining imidate is converted to -diiodide product via iterative hydrogen atom transfer123, which is also generated via selective HAT.

3.6.3 Mechanistic Differences

Next, we investigated the observed diastereoselectivity of the  C–H amination by employing cis and trans isomers of 2-phenyl-cyclohexanol III-29 as stereochemical probes in the formation of  amino alcohol III-30 (Figure 3-6). Whereas the trichloroacetimidate

115 of cis-III-29 does not afford C–H amination (likely because the imidate radical is conformationally constrained to the opposite side of the ring), trans-III-29 efficiently undergoes HAT (since the imidate radical and  C–H are on the same side of the cyclohexane ring). Interestingly, these catalytic conditions afford greater diastereoselectivity (5:1 d.r.) than the stoichiometric protocol (2:1 d.r.). Moreover,  benzyl iodide intermediate III-31 was observed for the first time, only in the catalytic case. Taken together, these results suggest divergent mechanisms are operative in the radical trapping steps of these two protocols. A possible explanation is that the higher oxidant concentration of the (super)stoichiometric method more rapidly oxidizes the benzyl radical to a cation, which is unselectively cyclized to afford the thermodynamically favored cis-III-30 product in only a 2:1 excess. On the other hand, a stepwise iodine trapping and subsequent cyclization mechanism under the low oxidant concentration of the catalytic conditions allow for greater 5:1 diastereoselectivity. This likely occurs via slower conversion of the observed alkyl iodide intermediate III-31, which enables greater overall stereocontrol.

116

Figure 3-6 Diastereoselectivity: mechanistic probe

3.6.4 Hammett Analysis

Finally, we examined the nature of the HAT mechanism via a Hammett study.

By varying substituents of 2-arylethanol imidates, we determined a linear free- energy relationship exists between initial reaction rates and the electronics of the para-substituents. As shown in Figure 3-7, we observed reaction acceleration with p-OMe and p-Me groups, whereas p-CF3 and p-NO2 substituents decrease product formation relative to the parent 2-Ph-ethanol. The resulting negative slope () of the

Hammett equation is consistent with other HAT-mediated C−H functionalizations.27

In this case, we propose intramolecular HAT (which we have shown to be rate- limiting, with primary KIE values up to 8)12 is enabled by an electrophilic N- centered radical, gaining electron density in the transition state, as an N-H  bond is formed. At the same time, the carbon atom loses electron density in the transition

117 state as the ensuing C-centered radical is formed. Thus, electron-releasing groups at the para-position stabilize this transition state by electron donation, while electron- withdrawing groups have the opposite effect. The resultant stabilization by donating groups thus reasonably explains the observed reaction rate acceleration.

σp Hammett Correlation 1

0.5 p-OMe

p-Me H 0 -0.5 0 0.5 1

p-CF 3 p-NO log (yield log (yield X/yield H) -0.5 2

-1 σp Figure 3-7 Hammett analysis on 2-arylethanol imidates

We have also conducted a Hammett analysis of the catalytic C–H amination reaction by varying substituents of benzimidate (Figure 3-8). We determined that there is no free-energy relationship between initial reaction rates and the electronics of the para- substituents. A very minor correlation can be attributed to the slight increase in the nucleophilicity of the imidate nitrogen, which results in more efficient C–I displacement to form the product. More nucleophilic p-OMe benzimidate results in slightly faster product formation. As a more electron-withdrawing group (i.e. p-CF3) is installed, a more complex reaction mixture is observed. Presumably, the imidate undergoes competitive hydrolysis to ester as well as decomposition to nitrile and alcohol. Therefore, the oxazoline

118 yield is dramatically impacted, resulting in a non-linear correlation with the remaining data points (p = 0.54).

σp Hammett Correlation 1.5

p-OMe H 1 p-Br

p-CF3

0.5 log (yield log (yield X/yield H)

0 -0.5 0 0.5 1 σp Figure 3-8 Hammett analysis on phenylethanol arylimidates

3.7 Experimental Section

3.7.1 General Information

All chemicals and reagents were purchased from Sigma-Aldrich, Alfa Aesar, Acros,

TCI, Combi-Blocks, or ChemImplex. MeCN was distilled over calcium hydride before use.

CH2Cl2, THF, Et2O and DMF were dried and degassed with nitrogen using an Innovative

Technology solvent system. For flash column chromatography, Silicycle F60 (230-400 mesh) silica gel or a CombiFlash Automated Flash Chromatograph was used. For preparative thin-layer chromatography (PTLC) and thin layer chromatography (TLC) analyses, Merck silica gel 60 F254 plates were used and visualized under UV (254 nm) and

1 19 KMnO4. Melting points were determined using an Electrotherman IA9000. H, F, and

13C NMR spectra were recorded using a Bruker AVIII 400 MHz, AVIII 600 MHz, or AVIII

700 MHz NMR spectrometer. 1H NMR and 13C NMR chemical shifts are referenced with

119 1 13 1 respect to CDCl3 ( H: residual CHCl3 at δ 7.26, C: CDCl3 triplet at δ 77.16), CD2Cl2 ( H:

13 1 residual CH2Cl2 at δ 5.32, C: CD2Cl2 quintet at δ 53.84), CD3OD ( H: residual CH3OH

13 1 13 at δ 3.31, C: CD3OD septet at δ 49.00), or CD3CN ( H: residual CH3CN at δ 1.94, C:

1 CH3CN at δ 118.26). H NMR data are reported as chemical shifts (δ ppm), multiplicity (s

For characterization of imidate III-S3 – III-S5, III-S7 – III-S14, III-S16, III-S17, III-S19

– III-S21, III-S23 and amino alcohol III-3 – III-5, III-7 – III-14, III-16, III-17, III-19 –

III-21, III-23, refer to Chapter 2, Section 2.5

3.7.2 Imidates Synthesis

3-methoxyphenethyl 2,2,2-trichloroacetimidate (III-S6): To a

round-bottom flask containing a stir bar, 2-(3- methoxyphenyl)ethan-1-ol (0.2 g, 1.3 mmol), trichloroacetonitrile (196 ml, 2.0 mmol, 1.5 equiv.) and 1,8-diazabicyclo(5.4.0)undec-7-ene (19 ml, 0.1 mmol, 0.1 equiv.) and CH2Cl2

(0.1 M) were added. Upon completion, the solution was concentrated and directly loaded onto silica gel and purified (silica gel, hexanes with 1% Et3N) to yield imidate III-S6 (0.37

1 g, 95%) as a clear colorless oil. Rf: 0.36 (10% Ethyl acetate/hexanes). H NMR (400 MHz,

120 CDCl3) δ: 8.29 (bs, 1H), 7.22 (t, J = 7.8 Hz, 1H), 6.88 – 6.84 (m, 2H), 6.88 – 6.84 (m, 1H),

13 4.50 (t, J = 6.9 Hz, 2H), 3.80 (s, 3H), 3.07 (t, J = 6.9 Hz, 2H). C NMR (100 MHz, CDCl3)

δ: 162.9, 159.8, 139.4, 129.6, 121.5, 114.9, 112.3, 91.6, 69.9, 55.3, 34.9.

phenylpropan-2-yl 2,2,2-trichloroacetimidate (III-S15): To a round-

bottom flask containing a stir bar, 1-phenylpropan-2-ol (998 mg, 7.3 mmol), trichloroacetonitrile (1.1 ml, 11 mmol, 1.5 equiv.) and 1,8-diazabicyclo(5.4.0)undec-7-ene

(105 l, 0.7 mmol, 0.1 equiv.) and CH2Cl2 (0.1 M) were added. Upon completion, the solution was concentrated and directly loaded onto silica gel and purified (silica gel, hexanes with 1% Et3N) to yield trichloroacetimidate III-S15 (1.77 g, 86%) as a clear oil.

1 Rf: 0.42 (10% Ethyl acetate/hexanes) H NMR (400 MHz, CDCl3) δ: 8.24 (bs, 1H), 7.31 –

7.20 (m, 5H), 5.29 – 5.21 (m, 1H), 3.10 (dd, J = 13.8, 6.7 Hz, 1H), 2.89 (dd, J = 13.8, 6.2

13 Hz, 1H), 1.35 (d, J = 5.9 Hz, 3H). C NMR (100 MHz, CDCl3) δ: 162.2, 137.6, 129.8,

128.4, 126.6, 92.0, 41.9, 18.6.

4-cyclohexylbutyl benzimidate (III-S18): To a 2-dram vial

equipped with a stir bar was added 4-cyclohexylbutan-1-ol (569 mg,

0.607 ml, 4 mmol), benzonitrile (412 l, 4 mmol), triflic acid (425 l, 4.8 mmol), and dry toluene (0.5 M). The vial was sealed and heated to reflux for 24 hours. Upon completion, the vial was cooled to room temperature and evaporated to dryness. The salt was suspended in Et2O and a saturated solution of NaHCO3 was added dropwise until the salt dissolved completely. Upon dissolution, the solution was stirred for five minutes and then diluted with H2O. The organic phase was separated, and the aqueous phase was extracted with

121 Et2O (2 x 10 mL). The combined organic phase was dried over MgSO4 and concentrated.

The product was purified by column chromatography (5% Ethyl acetate/hexanes with 1%

Et3N) to yield imidate III-S18 (772 mg, 78%) as a colorless oil. Rf: 0.2 (20% Ethyl

1 acetate/hexanes). H NMR (400 MHz, CDCl3) δ: 7.74 (bs, 3H), 7.49 – 7.38 (m, 3H), 4.25

(bs, 2H), 1.87 – 1.61 (m, 8H), 1.39 – 1.09 (m, 7H), 0.99 – 0.84 (m, 2H). 13C NMR (100

MHz, CDCl3) δ: 168.3, 133.2, 130.9, 128.6, 126.8, 66.7, 37.6, 34.0, 33.5 (2C), 26.8, 26.5,

26.3.

6-chlorohexylbenzimidate (III-S22): To a 2-dram vial equipped

with a stir bar was added 6-chlorohexan-1-ol (546 mg, 0.534 mL, 4 mmol), benzonitrile (412 l, 4 mmol), triflic acid (425 l, 4.8 mmol), and dry toluene (0.5

M). The vial was sealed and heated to reflux for 24 hours. Upon completion, the vial was cooled to room temperature and evaporated to dryness. The salt was suspended in Et2O and a saturated solution of NaHCO3 was added dropwise until the salt dissolved completely.

Upon dissolution, the solution was stirred for five minutes and then diluted with H2O. The organic phase was separated, and the aqueous phase was extracted with Et2O (2 x 10 mL).

The combined organic phase was dried over MgSO4 and concentrated. The product was purified by column chromatography (5% Ethyl acetate/hexanes with 1% Et3N) to yield

1 imidate III-S22 (852 mg, 89%) as a colorless oil. Rf: 0.30 (20% Ethyl acetate/hexanes). H

NMR (600 MHz, CDCl3) δ: 7.73 (bs, 3H), 7.47 – 7.40 (m, 3H), 4.27 (bs, 2H), 3.54 (t, J =

13 6.7 Hz, 2H), 1.85 – 1.79 (m, 4H), 1.53 – 1.51 (m, 4H). C NMR (150 MHz, CDCl3) δ:

168.2, 133.0, 130.9, 128.6, 126.8, 66.0, 45.1, 32.6, 28.7, 26.8, 25.7; HRMS (ESI-TOF) m/z:

122 + calc’d for C13H19ClNO [M+H] 240.1155, found 240.1153. IR (film) cm–1: 3325, 3076,

2934, 1630, 1331, 1081.

4,4,4-trifluorobutyl benzimidate (III-S24): To a 2-dram vial equipped

with a stir bar was added 4,4,4-trifluorobutan-1-ol (512 mg, 0.423 mL, 4 mmol), benzonitrile (412 l, 4 mmol), triflic acid (425 l, 4.8 mmol), and dry toluene (0.5

Upon dissolution, the solution was stirred for five minutes and then diluted with H2O. The organic phase was separated, and the aqueous phase was extracted with Et2O (2 x 10 mL).

The combined organic phase was dried over MgSO4 and concentrated. The product was purified by column chromatography (5% Ethyl acetate/hexanes with 1% Et3N) to yield

1 imidate III-S24 (485 mg, 53%) as a colorless oil. Rf: 0.13 (20% Ethyl acetate/hexanes). H

NMR (400 MHz, CDCl3) δ: 7.87 (bs, 1H), 7.70 (bs, 2H), 7.53 – 7.41 (m, 3H), 4.36 (bs,

13 2H), 2.37 – 2.25 (m, 2H), 2.12 – 2.05 (m, 2H). C NMR (100 MHz, CDCl3) δ: 168.1,

1 2 132.5, 131.2, 128.7, 126.7, 125.9 (q, JCF = 276.0 Hz), 64.5, 31.1 (q, JCF = 29.2 Hz), 21.8

3 19 (d, JCF = 2.9 Hz). F (376 MHz, CDCl3) δ: – 66.4 (t, J = 10.8 Hz). HRMS (ESI-TOF)

+ –1 m/z: calc’d for C11H13F3NO [M+H] 232.0949, found 232.0962. IR (film) cm : 3313, 3071,

2950, 1631, 1328, 1250.

oct-7-en-1-yl benzimidate (III-S25): To a 2-dram vial equipped

with a stir bar was added trifluoroethyl benzimidate hydrochloride

123 (240 mg, 1 mmol.), oct-7-en-1-ol (128 mg, 0.152 ml, 1 mmol) and MeCN (0.2 M). The reaction was heated to 50 °C and stirred until consumption of starting imidate (monitored by 1H NMR). Upon completion, the vial was cooled to room temperature and evaporated to dryness. The salt was suspended in Et2O and a saturated solution of NaHCO3 was added dropwise until the salt dissolved completely. Upon dissolution, the solution was stirred for five minutes and then diluted with H2O. The organic phase was separated, and the aqueous phase was extracted with Et2O (2 x 10 mL). The combined organic phase was dried over

MgSO4 and concentrated. The product was purified by column chromatography (5% Ethyl acetate/hexanes with 1% Et3N) to yield imidate III-S25 (185 mg, 80%) as a colorless oil.

1 Rf: 0.28 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3) δ: 7.79 – 7.73 (m, 3H),

7.68 – 7.38 (m, 3H), 5.88 – 5.75 (m, 1H), 5.04 – 4.91 (m, 2H), 4.27 – 4.24 (t, J = 7.0 Hz,

2H), 2.10 – 2.02 (m, 2H), 1.86 – 1.77 (m, 2H), 1.54 – 1.35 (m, 6H). 13C NMR (100 MHz,

CDCl3) δ: 163.5, 138.9, 131.3, 128.41, 128.35, 128.1, 114.6, 72.7, 66.9, 36.0, 33.8, 29.0,

+ 25.5. HRMS (ESI-TOF) m/z: calc’d for C15H22NO [M+H] 232.1701, found 232.1701. IR

(film) cm–1: 3296, 3063, 2966, 2902, 1634, 1336,

hex-5-yn-1-yl benzimidate (III-S26): To a 2-dram vial equipped with

a stir bar was added trifluoroethyl benzimidate hydrochloride (240 mg,

1 mmol.), hex-5-yn-1-ol (98 mg, 0.110 ml, 1 mmol) and MeCN (0.2 M). The reaction was heated to 50 °C and stirred until consumption of starting imidate (monitored by 1H NMR).

Upon completion, the vial was cooled to room temperature and evaporated to dryness. The salt was suspended in Et2O and a saturated solution of NaHCO3 was added dropwise until the salt dissolved completely. Upon dissolution, the solution was stirred for five minutes

124 and then diluted with H2O. The organic phase was separated, and the aqueous phase was extracted with Et2O (2 x 10 mL). The combined organic phase was dried over MgSO4 and concentrated. The product was purified by column chromatography (20% Ethyl acetate/hexanes) to yield imidate III-S26 (219 mg, 100%) as a colorless solid. Rf: 0.13

1 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3) δ: 7.80 – 7.66 (m, 3H), 7.49 –

7.39 (m, 3H), 4.30 (t, J = 6.1 Hz, 2H), 2.29 (td, J = 10.7, 2.8 Hz, 2H), 1.98 – 1.90 (m, 3H),

13 1.79 – 1.70 (m, 2H). C NMR (100 MHz, CDCl3) δ: 164.0, 131.5, 128.44, 128.41, 127.9,

83.8, 72.5, 68.9, 65.9, 34.9, 29.8, 15.6. HRMS (ESI-TOF) m/z: calc’d for C13H16NO

[M+H]+ 202.1232, found 232.1223. IR (film) cm–1: 3293, 3258, 3072, 2941, 1628, 1333,

1297.

3.7.3 Catalytic Imidate  C–H Amination

To a 2-dram vial equipped with PTFE septa cap and magnetic stir bar was added imidate (0.4 mmol, 1 equiv.) and PhI(OAc)2 (154.6 mg, 0.48 mmol, 1.2 equiv.). This vial was evacuated and backfilled with N2 (3x). A degassed stock solution of I2 in dry DMF (2 mL, 0.01 M, 0.05 equiv.) was added to the vial under N2. The reaction was heated to 50°C

(by placing vial in an aluminum heating block) and stirred for 4 hours. Upon completion, the reaction was cooled, transferred to a round-bottom flask, and concentrated in vacuo.

Hydrolysis and acid/base extraction. To the flask, was added methanol (4 mL) and 2M

HCl (0.8 mL). After stirring for 2 hours, 25 mL of CHCl3 and 10 mL of H2O was added.

The aqueous layer was washed with CHCl3 (5 x 25 mL). The combined organic fractions were rewashed with H2O (10 mL). The combined aqueous layer was poured into a round bottom, diluted with CHCl3 (25 mL), and finally 6M NaOH (10 mL) was added and stirred

125 for 30 minutes. The aqueous layer was washed with CHCl3 (5 x 25 mL) and the combined organic solution was dried over MgSO4 and concentrated to yield the pure amino alcohol.

To a flame-dried Schlenk flask equipped with a stir bar, was added I2 (50.8 mg, 0.2 mmol) and dry DMF (20 mL). The resulting solution was degassed via a free-pump-thawed protocol three times. The solution was warmed to room temperature under N2 and used directly in the amination protocol.

2-amino-2-(m-methoxyphenyl)ethan-1-ol (III-6):

Trichloroacetimidate III-S6 (119 mg, 0.4 mmol) was subjected to GP.

Upon reaction completion, the mixture was cooled to room temperature and the solvent was removed in vacuo. The crude mixture was subjected to the hydrolysis protocol to yield amino alcohol III-6 (46.0 mg, 69%) as a colorless solid. Oxazoline yield by 1H NMR: 96%.

i 1 Rf: 0.10 (30% PrOH in CH2Cl2). H NMR (600 MHz, CDCl3) δ: 7.29 – 7.27 (m, 1H), 6.92

– 6.90 (m, 2H), 6.83 – 6.82 (m, 1H), 4.02 (dd, J = 8.1, 4.3 Hz, 1H), 3.82 (s, 3H), 3.74 (dd,

J = 10.8, 4.3 Hz, 1H), 3.56 (dd, J = 10.8, 8.2 Hz, 1H), 2.40 (bs, 3H). 13C NMR (150 MHz,

CDCl3) δ: 159.9, 144.5, 129.7, 118.9, 112.8, 112.4, 68.0, 57.5, 55.3.

5-methyl-4-phenyl-2-(trichloromethyl)-4,5-dihydrooxazole (III-15):

Trichloroacetimidate III-S15 was subjected to GP. Analysis of the crude 1H

NMR (with 1 equiv. DCE standard) indicates 88% of the target oxazoline III-15 (3:1 d.r.).

1 Rf: (major) 0.39 (minor) 0.33 (10% ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): major diastereomer δ: 7.39 – 7.37 (m, 2H), 7.34 – 7.31 (m, 1H), 7.25 – 7.24 (m, 2H), 4.88

126 – 4.82 (m, 2H), 1.59 (d, J = 6.1 Hz, 3H). Minor diastereomer δ: 7.42 – 7.29 (m, 3H), 7.19

– 7.17 (m, 2H), 5.47 (d, J = 9.6 Hz, 1H), 5.33 (dq, J = 9.6, 6.6 Hz, 1H), 1.01 (d, J = 6.6 Hz,

13 3H). C NMR (150 MHz, CDCl3) δ: 162.9, 140.1, 129.1, 128.4, 126.6, 88.4, 20.6.

N-(4-cyclohexyl-1-hydroxybutan-2-yl)benzamide (III-18):

Benzimidate III-S18 (104 mg, 0.4 mmol) was subjected to GP. Upon reaction completion, the mixture was cooled to room temperature and the solvent was removed in vacuo. The crude mixture was subjected to the hydrolysis protocol to yield amino alcohol III-18 (90.4 mg, 82%) as a colorless solid. Oxazoline yield by 1H NMR:

1 95%. Rf: 0.69 (10% Methanol/dichloromethane). H NMR (400 MHz, CD3CN) δ: 7.74 (bs,

3H), 7.49 – 7.38 (m, 3H), 4.25 (bs, 2H), 1.87 – 1.61 (m, 8H), 1.39 – 1.09 (m, 7H), 0.99 –

13 0.84 (m, 2H). C NMR (150 MHz, CD3CN) δ: 168.0, 136.1, 132.1, 129.4, 128.1, 65.8,

50.4, 39.5, 35.2, 34.7, 33.5, 27.3, 27.1, 27.0. HRMS (ESI-TOF) m/z: calc’d for

+ –1 C17H25NO2Na [M+Na] 284.1626, found 284.1607. IR (film) cm : 3213, 3075, 2924, 2850,

1634, 1553.

N-(6-chloro-1-hydroxyhexan-2-yl)benzamide (III-22):

Benzimidate III-S22 (96 mg, 0.4 mmol) was subjected to GP. Upon reaction completion, the mixture was cooled to room temperature and the solvent was removed in vacuo. The crude mixture was subjected to the hydrolysis protocol to yield amino alcohol III-22 (91.7 mg, 90%) as an off-white solid. Oxazoline yield by 1H NMR:

1 92%. Rf: 0.63 (10% Methanol/dichloromethane). H NMR (400 MHz, CD3CN) δ: 7.82 (m,

2H), 7.54 – 7.51 (m, 1H), 7.47 – 7.44 (m, 1H), 6.81 (bs, 1H), 4.10 – 4.02 (m, 1H), 3.59 (t,

127 J = 6.7 Hz, 2H), 3.58 – 3.53 (m, 2H), 3.01 (t, J = 5.9 Hz, 1H), 1.87 – 1.73, (m, 2H), 1.70 –

13 1.62 (m, 1H), 1.59 – 1.42 (m, 3H). C NMR (100 MHz, CD3CN) δ: 168.1, 136.1, 132.2,

129.4, 128.1, 65.2, 52.8, 46.1, 33.2, 31.1, 24.2. HRMS (ESI-TOF) m/z: calc’d for

+ –1 C13H18ClNO2Na [M+Na] 278.0924, found 278.0909. IR (film) cm : 3305, 3245, 3081,

2921, 1728, 1637.

N-(4,4,4-trifluoro-1-hydroxybutan-2-yl)benzamide (III-24):

Benzimidate III-S24 (96 mg, 0.4 mmol) was subjected to GP. Upon reaction completion, the mixture was cooled to room temperature and the solvent was removed in vacuo. The crude mixture was subjected to the hydrolysis protocol to yield amino alcohol III-24 (46.6

1 mg, 47%) as a yellow solid. Oxazoline yield by H NMR: 77%. Rf: 0.63 (10%

1 Methanol/dichloromethane). H NMR (400 MHz, CD3CN) δ: 7.81 – 7.78 (m, 2H), 7.56 –

7.52 (m, 1H), 7.49 – 7.45 (m, 2H), 7.04 (bs, 1H), 4.45 – 4.37 (m, 1H), 3.69 – 3.54 (m, 2H),

13 3.18 (bs, 1H), 2.65 – 2.47 (m, 2H). C NMR (100 MHz, CD3CN) δ: 167.7, 135.6, 132.4,

1 3 2 129.5, 128.1, 128.0 (q, JCF = 276.1 Hz), 64.2, 47.5 (q, JCF = 3.8 Hz), 39.6 (q, JCF = 27.6

19 Hz). F NMR (564 MHz, CD3CN) δ: –59.2 (t, J = 11.2 Hz). HRMS (ESI) m/z: calc’d for

+ –1 C11H12F3NO2Na [M+Na] 270.0718, found 270.0713. IR (film) cm : 3370, 3296, 3070,

2918, 2850, 1637, 1537.

4-(hex-5-en-1-yl)-2-phenyl-4,5-dihydrooxazole (III-25):

Benzimidate III-S25 (23 mg, 0.1 mmol) was subjected to GP. Upon reaction completion, the mixture was cooled to room temperature and the solvent was removed in vacuo. The crude mixture was purified via column chromatography (silica gel,

128 10% EtOAc, Hexanes) to give oxazoline III-25 (17.4 mg, 76%) as a colorless oil.

1 1 Oxazoline yield by H NMR: 88%. Rf: 0.38 (20% Ethyl acetate/hexanes). H NMR (400

MHz, CD3CN) δ: 7.95 – 7.93 (m, 2H), 7.49 – 7.44 (m, 1H), 7.42 – 7.38 (m, 2H), 5.81 (ddt,

J = 17.1, 10.2, 6.7 Hz, 1H), 5.03 – 4.93 (m, 2H), 4.48 (dd, J = 9.4, 8.1 Hz, 1H), 4.33 – 4.21

(m, 1H), 4.02 (t, J = 7.9 Hz, 1H), 2.11 – 2.06 (m, 2H), 1.81 – 1.71 (m,1 H), 1.61 –1.36 (m,

13 5H); C NMR (100 MHz, CD3CN) δ: 163.5, 138.9, 131.3, 128.41, 128.35, 128.1, 114.6,

+ 72.7, 66.9, 36.0, 33.8, 29.0, 25.5. HRMS (ESI-TOF) m/z: calc’d for C15H20NO [M+H]

230.1545, found 230.1545.

4-(but-3-yn-1-yl)-2-phenyl-4,5-dihydrooxazole (III-26): Benzimidate

III-S26 (20 mg, 0.1 mmol) was subjected to GP. Upon reaction completion, the mixture was cooled to room temperature and the solvent was removed in vacuo. The crude mixture was purified via column chromatography (silica gel, 10%

EtOAc/hexanes) to give oxazoline III-26 (11.2 mg, 56%) as a colorless oil. Oxazoline yield

1 1 by H NMR: 63%. Rf: 0.38 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CD3CN) δ:

7.95 – 7.93 (m, 2H), 7.49 –7. 45 (m, 1H), 7.42 – 7.38 (m, 2H), 4.53 (dd, J = 9.5, 8.2 Hz,

1H), 4.45 – 4.37 (m, 1H), 4.09 (t, J = 7.9 Hz, 1H), 2.41 (td, J = 7.2, 2.6 Hz, 2H). 13C NMR

(100 MHz, CD3CN) δ: 164.0, 131.5, 128.44, 128.41, 127.9, 83.8, 72.5, 68.9, 65.9, 34.9,

+ 29.8, 15.6. HRMS (ESI-TOF) m/z: calc’d for C13H14NO [M+H] 200.1075, found

200.1086. IR (film) cm–1: 3308, 3225, 3086, 2929, 2851, 2244, 1731, 1627.

3.7.4 Mechanistic Probes

129 3-phenylpropyl benzimidate (III-S27): To a 2-dram vial equipped

with a stir bar was added 3-phenyl-propanol (569 mg, 1.2 mmol), benzonitrile (124 l, 1.2 mmol), triflic acid (39 l, 1.4 mmol), and dry toluene (0.5 M).

The vial was sealed and heated to reflux for 24 hours. Upon completion, the vial was cooled to room temperature and evaporated to dryness. The salt was suspended in Et2O and a saturated solution of NaHCO3 was added dropwise until the salt dissolved completely.

Upon dissolution, the solution was stirred for five minutes and then diluted with H2O. The organic phase was separated, and the aqueous phase was extracted with Et2O (2 x 10 mL).

The combined organic phase was dried over MgSO4 and concentrated. The product was purified by column chromatography to yield imidate III-S27 (150 mg, 49%) as a clear oil.

1 Rf: 0.16 (20% Ethyl acetate/hexanes). H NMR (600 MHz, CDCl3) δ: 7.75 (bs, 3H), 7.49

– 7.46 (m, 1H), 7.44 – 7.42 (m, 2H), 7.32 – 7.29 (m, 2H), 7.25 – 7.24 (m, 2H), 7.22 – 7.20

(m, 1H), 4.31 (bs, 2H), 2.84 (t, J = 7.7 Hz, 2H), 2.18 – 2.14 (m, 2H). 13C NMR (150 MHz,

CDCl3) δ: 168.3, 141.7, 133.0, 131.0, 128.59, 128.56, 126.8 (2C), 126.1, 65.4, 32.6, 30.5.

+ HRMS (ESI-TOF) m/z: calc’d for C16H18NO [M+H] 240.1388, found 240.1390. IR (film) cm–1: 3337, 3062, 3026, 2949, 2887, 2859, 1633, 1602, 1578.

isopentyl benzimidate (III-S28): 3-methylbutanol (1.71 g, 2.11 mL,

19.4 mmol) and benzonitrile (1 g, 1 mL, 9.7 mmol) were dissolved in 2.4 mL of HCl in dioxanes (4M, 9.6 mmol). The reaction was stirred for 2 days and then concentrated. The salt was suspended in Et2O and a saturated solution of NaHCO3 was added dropwise until the salt dissolved completely. Upon dissolution, the solution was stirred for five minutes and then diluted with H2O. The organic phase was separated, and the aqueous phase was

130 extracted with Et2O (2 x 10 mL). The combined organic phase was dried over MgSO4 and concentrated. The product was purified by column chromatography to yield imidate III-

1 S28 (0.31 g, 17%) as a clear oil. Rf: 0.34 (20% Ethyl acetate/hexanes). H NMR (400 MHz,

CDCl3) δ: 7.73 (bs, 3H), 7.48 – 7.39 (m, 3H), 4.32 (bs, 2H), 1.90 – 1.80 (m, 1H), 1.71 (app

13 q, J = 6.8 Hz, 2H), 0.99 (d, J = 6.7 Hz, 6H). C NMR (150 MHz, CDCl3) δ: 168.4, 133.1,

130.9, 128.5, 126.8, 64.8, 37.6, 25.4, 22.7. HRMS (ESI-TOF) m/z: calc’d for C12H18NO

[M+H]+ 192.1388, found 192.1393. IR (film) cm–1: 3337, 2956, 2929, 2870, 1633, 1579.

4-isopropyl-2-phenyl-4,5-dihydrooxazole (III-28a): Rf: 0.44 (20% ethyl

1 acetate/hexanes). H NMR (400 MHz, CDCl3) δ: 7.96 – 7.94 (m, 2H), 7.47

– 7.38 (m, 3H), 4.43 – 4.37 (m, 1H), 4.16 – 4.07 (m, 2H), 1.91 – 1.85 (m, 1H), 1.03 (d, J =

13 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H). C NMR (100 MHz, CDCl3) δ: 163.5, 131.3, 128.41,

128.39, 128.1, 72.8, 70.2, 33.0, 19.1, 18.2. HRMS (ESI-TOF) m/z: calc’d for C12H16NO

[M+H]+ 190.1232, found 190.1242. IR (film) cm–1: 2970, 2925, 2856, 1643.

2,2-diiodo-3-methylbutyl benzimidate (III-28c): Rf: 0.36 (20% Ethyl

1 acetate/hexanes). H NMR (400 MHz, CDCl3) δ: 8.03 (bs, 1H), 7.82 (d,

J = 7.0 Hz, 2H), 7.53 – 7.41 (m, 3H), 4.82 (bs, 2H), 1.75 – 1.69 (m, 1H), 1.10 (d, J = 6.4

+ Hz, 6H). HRMS (ESI-TOF) m/z: calc’d for C12H16I2NO [M+H] 443.9321, found

443.9309.

cis-2-phenylcyclohexyl 2,2,2-trichloroacetimidate (cis-III-29): To a round-

bottom flask containing a stir bar, cis-2-phenylcyclohexanol (264 mg, 1.5

mmol), trichloroacetonitrile (231 l, 2.3 mmol, 1.5 equiv.) and 1,8-

131 diazabicyclo(5.4.0)undec-7-ene (30 l, 0.2 mmol, 0.1 equiv.) and CH2Cl2 (0.1 M) were added. Upon completion, the solution was concentrated and directly loaded onto silica gel and purified (silica gel, hexanes with 1% Et3N) to yield trichloroacetimidate cis-III-29 (40

1 mg, 8%) as a colorless oil. Rf: 0.37 (10% Ethyl acetate/hexanes). H NMR (400 MHz,

CDCl3) δ: 8.07 (bs, 1H), 7.33 – 7.30 (m, 2H), 7.28 – 7.23 (m, 2H), 7.20 – 7.16 (m, 1H),

5.27 (bs, 1H), 2.87 (dt, J = 12.9, 2.9 Hz, 1H), 2.36 – 2.31 (m, 1H), 2.21 (app qd, J = 13.0,

3.6 Hz, 1H), 1.98 – 1.93 (m, 1H), 1.84 – 1.80 (m, 1H), 1.72 – 1.57 (m, 3H), 1.54 – 1.43 (m,

13 1H). C NMR (100 MHz, CDCl3) δ: 162.0, 143.1, 128.3, 128.1, 126.5, 92.2, 78.7, 47.2,

29.2, 26.2, 26.1, 20.3.

trans-2-phenylcyclohexyl 2,2,2-trichloroacetimidate (trans-III-29): To a

round-bottom flask containing a stir bar, trans-2-phenylcyclohexanol (494 mg,

2.8 mmol). trichloroacetonitrile (421 l, 4.2 mmol, 1.5 equiv.) and 1,8- diazabicyclo(5.4.0)undec-7-ene (45 l, 0.3 mmol, 0.1 equiv.) and CH2Cl2 (0.1 M) were added. Upon completion, the solution was concentrated and directly loaded onto silica gel and purified (silica gel, hexanes with 1% Et3N) to yield trichloroacetimidate trans-III-29

1 (245 mg, 27%) as a colorless oil. Rf: 0.51 (10% Ethyl acetate/hexanes). H NMR (400 MHz,

CDCl3) δ: 8.05 (bs, 1H), 7.27 – 7.23 (m, 4H), 7.19 – 7.14 (m, 1H), 5.14 – 5.08 (m, 1H),

2.86 (ddd, J = 12.3, 10.9, 3.8 Hz, 1H), 2.40 – 2.36 (m, 1H), 2.02 – 1.97 (m, 1H), 1.94 –

13 1.89 (m, 1H), 1.85 – 1.80 (m, 1H), 1.69 – 1.37 (m, 4H). C NMR (100 MHz, CDCl3) δ:

162.2, 143.1, 128.3, 127.8, 126.5, 91.9, 81.5, 50.0, 34.0, 30.9, 26.0, 24.8.

132 cis-2-(trichloromethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole (cis-III-

1 30): Rf: 0.55 (10% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3) δ: 7.43

– 7.36 (m, 4H), 7.31 – 7.27 (m, 1H), 5.02 (t, J = 3.5 Hz, 1H), 2.23 – 2.17 (m, 1H), 2.11 –

13 2.04 (m, 1H), 1.99 – 1.90 (m, 2H), 1.75 – 1.61 (m, 4H). C NMR (100 MHz, CDCl3) δ:

161.6, 145.6, 128.8, 127.5, 125.4, 88.8, 87.3, 74.3, 34.0, 25.3, 17.8, 16.1.

trans-2-(trichloromethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole (trans-

1 III-30): Rf: 0.30 (10% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3) δ:

7.62 – 7.60 (m, 2H), 7.38 – 7.24 (m, 3H), 4.56 – 4.51 (m, 1H), 3.05 – 3.02 (m,

1H), 2.41 – 2.35 (m, 2H), 1.94 – 1.83 (m, 2H), 1.75 – 1.68 (m, 1H), 1.58 – 1.46 (m, 1H),

1.40 – 1.29 (m, 1H).

2-iodo-2-phenylcyclohexyl 2,2,2-trichloroacetimidate (III-31): 1H NMR

(400 MHz, CDCl3) δ: 5.66 (bs) (diagnostic peak). HRMS (ESI-TOF) m/z:

+ calc’d for C17H22Cl3N2O2 [M–I+DMF] 391.0747, found 391.0742.

133 Chapter 4 Synthesis of Azoles via Tandem Hydrogen Atom Transfer

Portions of this chapter are adapted from the following publication:

Chen, A. D. †; Herbort, J. H. †; Wappes, E. A.†; Nakafuku, K. M.; Mustafa, D. N.; Nagib, D. A. “Radical Cascade Synthesis of Azoles via Tandem Hydrogen Atom Transfer” Manuscript Submitted.

Author Contribution: KMN initiated and supervised a team that developed a streamlined synthesis of oxazoles from alcohols and nitriles. Derivatization of oxazoles were developed by KMN and DNM.

134 4.1 Introduction

5-membered heterocycles containing nitrogen and oxygen atoms are considered as prime scaffolds for drug discovery.147 The unique structural features of oxazole moieties endow their derivatives diverse weak interactions such as hydrogen bonds,  stacking, and hydrophobic effect. Thus, oxazole-based compounds display potential applications in fields such as medicinal, agricultural, supramolecular as well as materials sciences.

Especially, in medicinal chemistry, oxazole compounds readily bind with a variety of enzymes and receptors in biological systems and show broad biological activities. As a bioisostere of more commonly occurring thiazole, imidazoles, and tetrazoles138, oxazoles had been extensively studied. Some clinical candidates had demonstrated wide range of biological activities such as antibacterial, antifungal, antiviral, antitubercular, anticancer, and anti-inflammatory effect (Figure 4-1).148

135

Figure 4-1 Oxazole as an important chemical scaffold

Considering their biological importance and potential, the synthesis of oxazole has been of great interest to the synthetic community. Classical synthetic route to oxazoles often involved intramolecular oxidative cyclization of acyclic precursors (e.g. amides), which is generated from carbonyls and amines. The diversification of oxazole has been limited to either de novo synthesis of the individual amide precursors or post- functionalization via metal-catalyzed reactions, with limited regio-functionalization. The classic methods, including Robinson–Gabriel reaction or the Hantzsch and Conforth cyclizations often are limited due to harsh reaction conditions, long reaction times, less substrate scope or modest to poor yields. Given the pharmacological value of heteroarenes, and the broad availability of the reagents used in this approach, we wondered if we could apply the imidate radical-mediated strategy for synthesis of oxazoles.

136 4.2 Construction of Oxazoles from Alcohols and Nitriles

As described in Chapter 2, we recently disclosed that the radical-mediated  C-H amination of alcohols offers a complementary approach to accessing N-containing heterocycles (i.e. oxazoline).149 In our first-generation approach (Figure 4-2A), we prepared aryl imidates in a two-step protocol, entailing trifluoroethanol addition into benzonitrile, followed by transimidation with the desired alcohol. The imidate was then converted to an oxazole via another two-step protocol, entailing  C-H amination to form an oxazoline, followed by oxidative aromatization with DDQ. Each of these four steps was carried out sequentially and involved discrete product isolation. To improve this strategy, we then sought to further streamline both the imidate formation as well as its direct conversion to oxazole (Figure 4-2 B).

Figure 4-2 Oxazole synthesis from imidates

Mechanistically speaking, the first oxidation to oxazoline involves intramolecular

1,5-HAT from benzylic C–H bond, and the second oxidation occurs via DDQ-mediated intermolecular HAT from -amino C–H bond (Figure 4-3).

137

Figure 4-3 Acetyl hypoiodite playing a dual role

Thus, an iterative HAT strategy seemed plausible as both the directed  C–H amination and the ensuing aromatization to oxazole are C-H oxidations involving electrophilic radical, which could conceivably be carried out using the same reagent. In pursuit of such a reagent, we decided to investigate acetyl hypoiodite AcO–I, which undergoes homolytic cleavage to form a HAT reagent. We have previously demonstrated that the AcO–I is capable of generating oxazoline C–H amination product from imidates via stoichiometric105 and catalytic method109, in which AcO–I acted as an electrophilic iodine source. Thus, we reasoned that if the concentration of the electrophilic iodine and the acetyl radical could be balanced, then direct formation of oxazole from imidate should be possible via an iterative hydrogen atom strategy without the need to isolate the oxazoline intermediate.

4.3 Iterative HAT-Mediated by Acetyl Radical

138 We tested the tandem oxidation strategy using NaI and PhI(OAc)2 in MeCN at

23 °C for 8 hrs. We observed quantitative formation of oxazoline IV-2 from imidate IV-I.

However, as shown in Table 4-1, solvents played a significant role in facilitating the tandem oxidation reaction via acetyl radical. Less polar solvents (e.g. DCE and PhMe) facilitated a second HAT in the proposed radical cascade to form oxazole IV-3.

Encouraged by the high mass balance in the NaI/PhI(OAc)2, a more solubilizing alkali iodide salts was subjected, from which CsI emerged as the most efficient reagent.

Table 4-1 Optimization of iterative hydrogen atom transfer strategy

4.3.1 Alcohol Scope

Having developed an efficient, tandem oxidative method to enable  C-H amination and an ensuing HAT to convert imidates to oxazoles directly, we investigated the generality of this radical cascade. As shown in Table 4-2, a broad range of alcohols can be employed,

139 including functional groups that are both electron-withdrawing and electron-releasing.

These diverse substituents may be at the ortho (IV-4 – IV-5), meta (IV-7 – IV-9), or para

(IV10 – IV-15) positions of various 2-phenylethanol analogs. Additionally, a pyridyl alcohol affords the heteroarene IV-6. Interestingly, the secondary alcohol, tetrahydronaphthalen-2-ol, enables a triple C-H oxidation, wherein formation of both a second and third aromatic ring affords the naphthyl-fused oxazole IV-16.

Table 4-2 Scope of oxazoles via iterative hydrogen atom transfer: alcohol

4.3.2 Nitrile Scope

We then investigated the generality of the nitrile component for this iterative HAT strategy (Table 4-3). Since a broad range of sterically and electronically diverse nitriles are commercially available, we tested a range of substitution patterns on the benzonitrile fragment. Again, OMe, CF3, and several halide substituents were tolerated (IV-17 – IV-

140 21), indicating minimal effect of electronics on efficiency of the tandem oxidative protocol.

Polyaromatic nitriles (IV-22 – IV-24), including 1- and 2-naphthylenes as well as 4- biphenyl, were also amenable to this iterative HAT transformation. Notably, there was no additional halogenated oxazoles observed in this strategy, which is in contrast to a non- directed benzylic bromination approach that results in bromo-oxazoles from its corresponding amide.150

Table 4-3 Scope of oxazoles via iterative hydrogen atom transfer: nitrile

4.4 Derivatization to Access Other Azoles

Having demonstrated the broad synthetic utility of this radical cascade in accessing

2,4-bis-aryl-oxazoles, we questioned if this approach could also streamline access to other classes of five- membered heteroarenes from imidate (Z = O) and amidine (Z = N) IV-25

(Figure 4-4). In order to synthesize alkyl oxazole via our tandem method, pivalimidate was

141 synthesized from corresponding nitrile and alcohol. Gratifyingly, the oxidation condition yielded 77% of oxazole product IV-26.

To improve upon the first-generation synthesis of oxazole IV-27 from trichloroacetimidate via two-step protocol, which yielded 67% of IV-27 over 2 steps, phenylethanol trichloroacetimidate was engaged in a tandem oxidation condition to yield

65% of desired oxazole in a single step using an operationally much simpler system.

Figure 4-4 Accessing a family of azoles via tandem HAT

Inspired by amidine chemistry from Chiba and co-workers, we became interested in investigating amidine in our tandem oxidation. Interesting, electron-rich amidines engage in triple oxidation in which amidine is converted into iodinated-imidazole at C5 position. Both 2-Ar and 2-CCl3 amidines engaged in this tandem oxidation to iodo- imidazole IV-28 and IV-29.

Encouraged by the reactivity of 2-trichloromethylbenzoxazoles to various N-based nucleophiles at C2 position for the synthesis of N-substitute benzoxazole151, we subjected oxazole IV-27 to differentially substituted alkyl amines. Expecting an addition-elimination

142 mechanism to displace CCl3 at C2 by amines, we were surprised to find that amides (IV-

30 – IV-33) were instead isolated via a chloride-displacement and ensuing hydrolysis of the remaining gem-di-chloride.

4.5 Proposed Mechanism

Our proposed mechanism for the radical cascade conversion of imidate A (derived from combination of an alcohol and nitrile) to an oxazole is shown in Figure 4-5.

Heterolytic cleavage of acetyl hypoiodite by imidate A results in the formation of the N- halo imidate B. Upon photo-initiate homolytic cleavage to generate N-radical C, the ensuing radical undergoes 1,5-HAT to form C-radical D. This undergoes -iodination, resulting in the formation of E, which engages in cyclization to form oxazoline F. In a non- polar solvent like toluene, the O-I bond of acetyl hypoiodite homolytically cleaves to generate the acetyl radical. This electrophilic radical generates -amino C-radical G via kinetically favorable HAT. Radical propagation followed by rapid aromatization results in the formation of oxazole I.

143

Figure 4-5 Proposed mechanism

4.6 Probing the Mechanism

Addition experiments discussed below seem to confirm the acetyl-radical mediated iterative hydrogen atom transfer to construct the oxazole scaffold. While sterically small

Me (IV-4) and Cl (IV-5) groups were tolerated in this iterative oxidation reaction, a sterically-encumbering group slowed down the reaction; we discovered that substrates with an ortho-CF3 group do not engage in the second oxidation reaction and only oxazoline IV-

33 was isolated. To further investigate the effect of steric component on the second HAT, we independently synthesized both diastereomers IV-35 and IV-36 via previously reported diastereoselective catalytic  C–H amination method.109 When both diastereomers were subjected to CsI/PhI(OAc)2, only the cis-isomer went to full conversion, and the reaction with trans-isomer was sluggish and did not yield oxazole IV-37. We reasoned that in cis- diastereomer, the -amino C–H bond is sterically more accessible for hydrogen atom

144 abstraction by acetyl radical; in trans-diastereomer, approaching acetyl radical has disfavored steric interaction with the syn-methyl C–H bonds.

Figure 4-6 Mechanistic studies on iterative HAT

4.7 Experimental Section

4.7.1 General Information

All chemicals and reagents were purchased from Sigma-Aldrich, Alfa Aesar, Acros,

TCI, Combi-Blocks, or ChemImplex. MeCN was distilled over calcium hydride before use.

CH2Cl2, THF, Et2O and DMF were dried and degassed with nitrogen using an Innovative

1 19 KMnO4. Melting points were determined using an Electrotherman IA9000. H, F, and

13C NMR spectra were recorded using a Bruker AVIII 400 MHz, AVIII 600 MHz, or AVIII

145 700 MHz NMR spectrometer. 1H NMR and 13C NMR chemical shifts are referenced with

1 13 1 respect to CDCl3 ( H: residual CHCl3 at δ 7.26, C: CDCl3 triplet at δ 77.16), CD2Cl2 ( H:

13 1 residual CH2Cl2 at δ 5.32, C: CD2Cl2 quintet at δ 53.84), CD3OD ( H: residual CH3OH

13 1 13 at δ 3.31, C: CD3OD septet at δ 49.00), or CD3CN ( H: residual CH3CN at δ 1.94, C:

1 CH3CN at δ 118.26). H NMR data are reported as chemical shifts (δ ppm), multiplicity (s

4.7.2 Imidate Synthesis

General Procedure to Prepare Benzimidates (GP1)

To a 4-dram vial containing a stir bar was added alcohol (1 equiv.), nitrile (1.1 equiv.),

PhMe (0.5 M), and triflic acid (1.2 equiv.). The solution was heated to 110 °C and stirred.

After 24 h the solution was cooled to room temperature, and then stored at -15 °C until crystallization of the hydrotriflate salt was observed. The salt was then isolated via filtration and washed with cold hexanes and Et2O; residual solvent was removed under vacuum. The salt was suspended in Et2O (0.1 M), and NaHCO3 (sat. aqueous) was added dropwise until the dissolution of the salt observed (typically ~5 minutes). The aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried over

146 Na2SO4, concentrated under vacuum, and then used as is, or purified via column chromatography (silica gel treated with 1% Et3N/hexanes to avoid hydrolysis).

General Procedure for Transimidation (GP2)

Step 1: To a pressure tube equipped with a stir bar was added nitrile (1 equiv.), trifluoroethanol (12 equiv.), and acetyl chloride (8 equiv.). The solution was heated to 80

°C and stirred. After 48 h the reaction was cooled to room temperature and carefully vented, which immediately induced precipitation of the benzimidate hydrochloride salt. The benzimidate salt was collected via filtration with cold hexanes.

Step 2: To a 2-dram vial equipped with a stir bar was added trifluoroethyl benzimidate hydrochloride salt (1 equiv.), alcohol (1 equiv.), and MeCN (0.16 M). The reaction was heated to 50 °C and stirred. Reaction progress was monitored by consumption of starting trifluoroethyl benzimidate via crude 1H NMR. Upon completion, the solution was concentrated and the resulting crude solid was suspended in dry Et2O and subjected to the free-base protocol from GP1. The crude reaction mixture was then purified via column chromatography (silica gel treated with 1% Et3N in hexanes to avoid hydrolysis).

2-methylphenethyl benzimidate (IV-S4): 2-(o-tolyl)ethan-1-ol (0.14 g,

1.0 mmol) was subjected to GP2, with acidification after transimidation to facilitate removal of unconsumed alcohol (see below). Upon completion, the free-based crude was concentrated, dissolved in dry Et2O, and acidified with 2M HCl in Et2O. Upon precipitation, the hydrochloride salt was isolated via filtration, and washed with cold hexanes and Et2O, yielding the benzimidate salt (0.17 g, 63%) as a white solid. The

147 benzimidate salt was free-based according to GP1; no purification was needed, yielding

1 benzimidate IV-S4 (0.14 g, 98%) as a clear oil. Rf: 0.38 (30% Ethyl acetate/hexanes). H

NMR (600 MHz, CDCl3): δ = 7.76 (bs, 1H), 7.71 (d, J = 7.4 Hz, 2H), 7.47 – 7.44 (m, 1H),

7.42 – 7.39 (m, 2H), 7.28 – 7.26 (m, 1H), 7.19 – 7.14 (m, 3H), 4.49 (t, J = 7.0 Hz, 2H),

13 3.14 (t, J = 7.0 Hz, 2H), 2.40 (s, 3H). C NMR (150 MHz, CDCl3): δ = 168.0, 136.7, 136.6,

133.0, 131.0, 130.4, 129.7, 128.6, 126.8, 126.7, 126.1, 65.8, 32.5, 19.6. HRMS (ESI-TOF)

+ + –1 m/z: calc’d for C16H18NO [M+H] 240.1383, found 240.1388. IR (film) (cm ): 3330,

3061, 3022, 2950, 2359, 2341, 1717, 1632, 1577, 1492, 1447, 1392, 1329, 1295, 1272,

1164, 1075, 1027, 1000, 973.

2-chlorophenethyl benzimidate (IV-S5): 2-(2-chlorophenyl)ethan-1-ol

(0.47 g, 3.0 mmol) was subjected to GP1 without isolation of the hydrotriflate salt, as no precipitation was observed. The crude reaction was free-based according to GP1. Purification via column chromatography (silica gel, 1% ethyl acetate/hexanes with 1% Et3N to 20% ethyl acetate/hexanes), yielded benzimidate IV-S5

1 (0.32 g, 41%) as a yellow oil. Rf: 0.31 (30% Ethyl acetate/hexanes). H NMR (600 MHz,

CDCl3): δ = 7.80 (bs, 1H), 7.70 (d, J = 6.6 Hz, 2H), 7.45 – 7.34 (m, 5H), 7.24 – 7.16 (m,

13 2H), 4.44 (m, 2H), 3.28, (t, J = 6.8 Hz, 2H). C NMR (100 MHz, CDCl3): δ = 168.1,

136.3, 134.4, 132.8, 131.3, 131.0, 129.7, 128.6, 128.1, 126.9, 126.8, 65.1, 33.0. HRMS

+ – (ESI-TOF) m/z: calc’d for C15H15ClNO [M+H] 260.0837, found 260.0842. IR (film) cm

1: 3330, 3059, 2948, 1633.

148 2-(pyridin-2-yl)ethyl benzimidate (IV-S6): 2-(pyridin-2-yl)ethan-1-ol

(0.79 mL, 7.0 mmol) was subjected to GP1, with the following modifications: additional triflic acid (1.4 mL, 15 mmol) was used, reaction temperature was 100 °C instead of 110 °C, and sufficient precipitation was achieved at 23 °C. After filtration, the benzimidate bis hydrotriflate salt was isolated (3.7 g, 100%) as a brown solid.

A portion of the benzimidate salt (1.5 g, 2.8 mmol) was free-based according to GP1; final purification was done via column chromatography (silica gel, 10% ethyl acetate/hexanes with 1% Et3N to 50% ethyl acetate/hexanes with 1% Et3N), yielding benzimidate IV-S6

1 (0.30 g, 46%) as a yellow oil. Rf: 0.1 (50% Ethyl acetate/hexanes). H NMR (600 MHz,

CDCl3): δ = 8.57 (d, J = 4.7 Hz, 1H), 7.81 (m, 1H), 7.65 (bs, 1H), 7.61 (td, J = 7.6, 1.7 Hz,

2H), 7.46 – 7.42 (m, 1H), 7.39 – 7.37 (m, 2H), 7.27 (d, J = 2.7 Hz, 1H) 7.14 (ddd, J = 7.5,

13 4.9, 1.0 Hz, 1H), 4.67 (bs, 2H), 3.31 (t, J = 6.6 Hz, 2H). C NMR (100 MHz, CDCl3): δ =

158.9, 149.6, 136.4, 132.9, 131.0, 128.6, 126.8, 123.6, 121.6, 65.3, 37.7. HRMS (ESI-TOF)

+ –1 m/z: calc’d for C14H15N2O [M+H] 227.1179, found 227.1178. IR (film) cm : 3283, 2922,

1633.

3-methylphenethyl benzimidate (S7): 2-(m-tolyl)ethan-1-ol (0.55 g, 4.0

mmol) was subjected to GP1. After filtration, the benzimidate salt was

isolated (0.40 g, 25%) as a white solid. A portion of the benzimidate salt

(0.29 g, 0.8 mmol) was free-based according to GP1; no purification was needed, yielding benzimidate S7 (0.17 g, 100%) as an off-white solid. Rf: 0.46 (30% Ethyl acetate/hexanes).

1 H NMR (400 MHz, CDCl3): δ = 7.85 – 7.78 (m, 1H), 7.69 (bs, 2H), 7.49 – 7.37 (m, 3H),

7.21 (t, J = 7.5 Hz, 1H), 7.15 – 7.09 (m, 2H), 7.08 – 7.02 (m, 1H), 4.49 (bs, 2H), 3.09 (t, J

149 13 = 7.1 Hz, 2H), 3.34 (s, 3H). C NMR (100 MHz, CDCl3): δ = 169.0, 138.5, 138.1, 132.9,

132.2, 131.0, 130.0, 128.8, 128.6, 128.5, 127.5, 127.3, 126.8, 126.2, 66.8, 35.2, 21.5.

+ + HRMS (ESI-TOF) m/z: calc’d for C16H18NO [M+H] 240.1383, found 240.1388. IR (film) cm–1: 3325, 3025, 2950, 2359, 2341, 1670, 1632, 1577, 1489, 1447, 1392, 1329, 1295,

1164, 1078, 1027, 1000, 973.

3-(trifluoromethyl)phenethyl benzimidate (IV-S8): 2-(3-

(trifluoromethyl)phenyl)ethan-1-ol (0.76 g, 4.0 mmol) and benzonitrile

(0.45 mL, 4.4 mmol) were subjected to GP1. After filtration, the benzimidate salt was isolated (0.97 g, 55%) as a white solid. A portion of the benzimidate salt (0.50 g, 1.1 mmol) was free-based according to GP1; no purification was needed, yielding benzimidate IV-S8 (0.31 g, 96%) as an off-white oil. Rf: 0.46 (30% Ethyl

1 acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.83 (bs, 1H), 7.74 – 7.61 (m, 2H), 7.59

(s, 1H), 7.54 – 7.47 (m, 2H), 7.47 – 7.37 (m, 4H), 4.63 – 4.39 (m, 2H), 3.19 (t, J = 6.6 Hz,

13 2H). C NMR (150 MHz, CDCl3): δ = 168.1, 139.7, 132.6, 132.5, 131.1, 129.0, 128.6,

19 126.7, 126.1, 123.5, 123.4, 66.2, 35.1. F NMR (376 MHz, CDCl3): δ = – 62.6. HRMS

+ + – (ESI-TOF) m/z: calc’d for C16H15F3NO [M+H] 294.1100, found 294.1093. IR (film) (cm

1): 3334, 3061, 2953, 2359, 1633, 1578, 1492, 1470, 1448, 1392, 1330, 1321, 1197, 1160,

1118, 1071, 1028, 1001, 781, 693.

3-methoxyphenethyl benzimidate (IV-S9): 2-(3-

methoxyphenyl)ethan-1-ol (0.15 g, 1.0 mmol) was subjected to GP2,

with acidification after transimidation to facilitate removal of

150 unconsumed alcohol (see below). Upon completion, the free-based crude was concentrated, dissolved in dry Et2O, and acidified with 2M HCl in Et2O. Upon precipitation, the hydrochloride salt was isolated via filtration, and washed with cold hexanes and Et2O, yielding the benzimidate salt (0.16 g, 66%) as a white solid. The benzimidate salt was free- based according to GP1; no purification was needed, yielding benzimidate IV-S9 (0.14 g,

1 98%) as a clear oil. Rf: 0.46 (30% Ethyl acetate/hexanes). H NMR (600 MHz, CDCl3): δ

= 7.76 (bs, 1H), 7.70 (d, J = 7.3 Hz, 2H), 7.47 – 7.44 (m, 1H), 7.39 – 7.42 (m, 2H), 7.24 (t,

J = 7.9 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 6.86 – 6.87 (m, 1H), 6.79 (dd, J = 8.2, 2.5 Hz,

1H), 4.51 (t, J = 6.5 Hz, 2H), 3.80 (s, 3H), 3.11 (t, J = 6.9 Hz, 2H). 13C NMR (150 MHz,

CDCl3): δ = 167.8, 159.8, 140.3, 132.9, 131.0, 129.5, 128.6, 126.8, 121.5, 114.8, 112.1,

+ + 66.6, 55.3, 35.4. HRMS (ESI-TOF) m/z: calc’d for C16H18NO2 [M+H] 256.1332, found

256.1329. IR (film) (cm–1): 3330, 2952, 2834, 2359, 2341, 1717, 1633, 1601, 1578, 1487,

1448, 1392, 1328, 1294, 1257, 1164, 1151, 1077, 1057, 1041, 1028, 995, 975, 925.

4-fluorophenethyl benzimidate (IV-S10): 2-(4-fluorophenyl)ethan-

1-ol (0.50 mL, 4.0 mmol) was subjected to GP1. After filtration, the benzimidate salt was isolated (1.4 g, 91%) as a white solid. A portion of the benzimidate salt (0.89 g, 2.3 mmol) was free-based according to GP1. Purification via column chromatography (silica gel, 10% ethyl acetate/hexanes with 1% Et3N to 30% ethyl acetate/hexanes) yielded benzimidate IV-S10 (0.23 g, 41%) as a white solid. Rf: 0.23 (30%

1 Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.81 (bs, 1H), 7.68 (d, J = 7.5

Hz, 2H), 7.48 – 7.39 (m, 3H), 7.26 (m, 2H), 7.00 (m, 2H), 4.19 (bs, 2H), 3.16 (t, J = 6.8

13 1 Hz, 1H). C NMR (100 MHz, CDCl3): δ = 167.9, 161.8 (d, JC-F = 243.9 Hz), 134.4 (d,

151 4 3 2 JC-F = 2.7 Hz), 132.8, 131.0, 130.5 (d, JC-F = 8.0 Hz), 128.6, 126.7, 115.3 (d, JC-F = 21.5

19 Hz), 66.6, 34.5. F NMR (376 MHz, CDCl3): δ = – 118.1. HRMS (ESI-TOF) m/z: calc’d

+ + –1 for C15H15FNO [M+H] 244.1132, found 244.1137. IR (film) cm : 3335, 3066, 1629

MP: 53 – 54°C.

4-chlorophenethyl benzimidate (IV-S11): 2-(4-chlorophenyl)ethan-

1-ol (0.62 g, 4.0 mmol) was subjected to GP1. After filtration, the benzimidate salt was isolated (1.4 g, 84%) as a white solid. A portion of the benzimidate salt (0.26 g, 0.6 mmol) was free-based according to GP1; no purification was needed, yielding benzimidate IV-S11 (0.16 g, 100%) as an off-white solid. 1H NMR (400 MHz,

CDCl3): δ = 7.71 – 7.62 (m, 2H), 7.49 – 7.37 (m, 2H), 7.32 – 7.26 (m, 2H), 7.25 – 7.20 (m,

13 2H), 4.49 (t, J = 6.7 Hz, 2H), 3.09 (t, J = 5.0 Hz, 2H). C NMR (100 MHz, CDCl3): δ =

167.9, 137.2, 132.7, 133.4, 131.1, 130.5, 128.7, 128.6, 126.7, 63.4, 34.7. HRMS (ESI-TOF)

+ + –1 m/z: calc’d for C15H15ClNO [M+H] 260.0837, found 260.0842. IR (film) (cm ): 3332,

2964, 2923, 2360, 2341, 1627, 1576, 1490, 1475, 1410, 1396, 1339, 1186, 1162, 1107,

1079, 1060, 1026, 1014, 974, 922.

4-bromophenethyl benzimidate (S12): 2-(4-bromophenyl)ethan-1-

ol (2.4 g, 12.0 mmol) was subjected to GP1, with the following modifications: dry DCE (20 mL) instead of PhMe, and a reaction temperature of 80 °C instead of 110 °C. After filtration, the benzimidate salt was isolated (2.9 g, 53%) as a white solid. A portion of the benzimidate salt (2.2 g, 4.9 mmol) was free-based according to GP1; no purification was needed, yielding benzimidate IV-S12 (1.3 g, 85%) as an off-white

152 1 solid. H NMR (400 MHz, CDCl3): δ = 7.82 (bs, 1H), 7.71 – 7.58 (m, 2H), 7.49 – 7.36 (m,

5H), 7.21 – 7.16 (m, 2H), 4.51 (t, J = 6.3 Hz, 2H), 3.08 (t, J = 6.7 Hz, 2H). 13C NMR (100

MHz, CDCl3): δ = 168.2, 137.8, 132.7, 131.6, 131.1, 130.9, 128.6, 126.7, 120.4, 66.4, 34.7.

+ + HRMS (ESI-TOF) m/z: calc’d for C15H15BrNO [M+H] 304.0332, found 304.0326. IR

(film) (cm–1): 3331, 3060, 2965, 2896, 2866, 2359, 2341, 1627, 1575, 1485, 1457, 1407,

1394, 1334, 1300, 1292, 1185, 1162, 1106, 1082, 1069, 1059, 1026, 1010, 1001, 973, 921.

MP: 83 – 84 °C.

4-iodophenethyl benzimidate (IV-S13): 2-(4-iodophenyl)ethan-1-ol

(0.99 g, 4.0 mmol) was subjected to GP1. After filtration, the benzimidate salt was isolated (1.4 g, 70%) as a white solid. A portion of the benzimidate salt (0.57 g, 1.1 mmol) was free-based according to GP1; no purification was needed, yielding benzimidate IV-S13 (0.40 g, 100%) as an off-white solid. 1H NMR (400 MHz,

CDCl3): δ = 7.82 (bs, 1H), 7.72 – 7.60 (m, 4H), 7.50 – 7.37 (m, 3H), 7.09 – 7.02 (m, 2H),

13 4.60 – 4.38 (m, 2H), 3.07 (t, J = 6.7 Hz, 2H). C NMR (150 MHz, CDCl3): δ = 168.1,

138.4, 137.6, 132.7, 131.2, 131.0, 128.6, 126.7, 91.8, 66.3, 34.8. HRMS (ESI-TOF) m/z:

+ –1 calc’d for C15H15INO [M+H] 352.0193, found 352.0176. IR (film) (cm ): 3058, 2950,

2888, 2362, 2342, 1633, 1577, 1484, 1447, 1397, 1330, 1297, 1183, 1165, 1080, 1062,

1028, 1000, 976. MP: 79 – 80 °C.

4-(trifluoromethyl)phenethyl benzimidate (IV-S14): 2-(4-

(trifluoromethyl)phenyl)ethan-1-ol (0.76 g, 4.0 mmol) was subjected to GP1. After filtration, the benzimidate salt was isolated (1.1 g, 62%) as a white solid. A

153 portion of the benzimidate salt (0.72 g, 1.6 mmol) was free-based according to GP1; no purification was needed, yielding benzimidate IV-S14 (0.47 g, 99%) as a white solid. 1H

NMR (400 MHz, CDCl3): δ = 7.82 (bs, 1H), 7.72 – 7.56 (m, 2H), 7.50 – 7.36 (m, 5H), 7.22

– 7.15 (m 2H), 4.51 (t, J = 6.3 Hz, 2H), 3.08 (t, J = 6.7 Hz, 2H). 13C NMR (100 MHz,

2 CDCl3): δ = 168.0, 143.0, 132.6, 131.1, 129.4, 129.0 (q, JCF = 33.0 Hz), 128.7, 126.7,

3 1 19 125.5 (q, JCF = 3.7 Hz), 124.43 (q, JCF = 272.0 Hz), 66.1, 35.1. F NMR (376 MHz,

+ + CDCl3): δ = – 62.4. HRMS (ESI-TOF) m/z: calc’d for C16H15F3NO [M+H] 294.1100, found 294.1088. IR (film) (cm–1): 3337, 2955, 2894, 2359, 2341, 1628, 1617, 1576, 1496,

1448, 1419, 1397, 1324, 1187, 1168, 1153, 1124, 1110, 1086, 1063, 1027, 1017, 1000,

974, 957, 924. MP: 83 – 84 °C.

4-(trifluoromethoxy)phenethyl benzimidate (S15): 2-(4-

(trifluoromethoxy)phenyl)ethan-1-ol (0.94 g, 4.5 mmol) was subjected to GP1. After filtration, the benzimidate salt was isolated (1.4 g, 68%) as a white solid. A portion of the benzimidate salt (0.76 g, 1.7 mmol) was free-based according to

GP1; no purification was needed, yielding benzimidate IV-S15 (0.52 g, 99%) as an off-

1 white solid. H NMR (400 MHz, CDCl3): δ = 7.83 (bs, 1H), 7.73 – 7.57 (m, 2H), 7.50 –

7.37 (m, 3H), 7.37 – 7.29 (m, 2H), 7.16 (d, J = 7.9 Hz, 2H), 4.62 – 4.42 (m, 2H), 3.13 (t, J

13 = 6.7 Hz, 2H). C NMR (150 MHz, CDCl3): δ = 168.2, 148.0, 137.6, 132.7, 131.1, 130.4,

1 19 128.6, 126.7, 121.1, 120.6 (q, JCF = 256.6 Hz), 66.4, 34.6. F NMR (376 MHz, CDCl3):

+ + δ = – 57.9. HRMS (ESI-TOF) m/z: calc’d for C16H15F3NO2 [M+H] 310.1049, found

310.1044. IR (film) (cm–1): 3332, 2966, 2896, 2359, 2342, 1627, 1577, 1507, 1474, 1448,

154 1399, 1339, 1259, 1211, 1195, 1152, 1108, 1080, 1058, 1027, 1018, 1001, 974, 920. MP:

61 – 62 °C.

1,2,3,4-tetrahydronaphthalen-2-yl benzimidate (IV-S16): 1,2,3,4-

tetrahydronaphthalen-2-ol (0.30 g, 2.0 mmol) was subjected to GP2 Step

2, with the following modifications: a reaction temperature of 60 °C instead of 50 °C, and

2 equivalents of trifluoroethanol benzimidate was used. Final purification was done via column chromatography (silica gel, 1% ethyl acetate/hexanes with 1% Et3N to 20% ethyl acetate/hexanes with 1% Et3N), yielding the imidate IV-S16 (0.27 g, 52%) as a clear oil.

Note: The transimidation is temperature sensitive; at 50 °C the alcohol is not consumed, and at 80 °C, the imidate decomposes into benzamide. Multiple columns may be needed to

1 obtain pure benzimidate. Rf: 0.26 (20% Ethyl acetate/hexanes). H NMR (400 MHz,

CDCl3): δ = 7.83 (bs, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.46 – 7.38 (m, 3H), 7.15 – 7.09 (m,

4H), 5.48 (bs, 1H), 3.28 (dd, J = 16.8, 5.1 Hz, 1H), 3.16 – 3.00 (m, 2H), 2.91 (td, J = 16.7,

13 6.7 Hz, 1H), 2.25 – 2.09 (m, 2H). C NMR (100 MHz, CDCl3): δ =167.2, 136.0, 134.4,

134.3, 130.9, 129.6, 128.7, 128.6, 126.8, 126.0, 126.0, 70.6, 34.6, 27.8, 26.7. HRMS (ESI-

+ –1 TOF) m/z: calc’d for C17H18NO [M+H] 252.1383, found 252.1378. IR (film) cm : 3328,

3018, 1630.

phenethyl 4-methoxybenzimidate (IV-S17): 4-

methoxybenzonitrile (1 g, 7.5 mmol) was subjected to GP1. After

filtration, the crude benzimidate salt was isolated as a white solid. A portion of the benzimidate salt (1.0 g, 2.5 mmol) was free-based according to GP1.

155 Purification via column chromatography (silica gel, 10% ethyl acetate/hexanes with 1%

Et3N to 25% ethyl acetate/hexanes) yielded benzimidate IV-S17 (0.52 g, 82%) as a white

1 solid. Rf: 0.09 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.67 (bs,

1H), 7.66 (d, J = 8.7 Hz, 2H), 7.35 – 7.30 (m, 4H), 7.26 – 7.22 (m, 1H), 6.92 – 6.88 (m,

2H), 4.49 (t, J = 6.8 Hz, 2H), 3.84 (s, 3H), 3.13 (t, J = 6.8 Hz, 2H). 13C NMR (100 MHz,

CDCl3): δ = 167.4, 161.8, 138.7, 129.1, 128.52, 128.46, 126.5, 125.3, 113.8, 66.5, 55.5,

+ 35.3. HRMS (ESI-TOF) m/z: calc’d for C16H18NO2 [M+H] expected 256.1338, found

256.1319. IR (film) cm–1: 3276, 2996, 2955, 2922, 2835, 1624, 1604, 1509.

phenethyl 4-bromobenzimidate (IV-S18): 4-bromobenzonitrile was

subjected to GP2, yielding the corresponding TFE-benzimidate (1.43 g, 82%) as a white solid. A portion of the TFE-benzimidate salt (2 reactions at 0.2 g scale) was freebased according to GP2 Step 2. Purification via column chromatography (silica gel, 10% ethyl acetate/hexanes with 1% Et3N) yielded benzimidate S18 (0.25 g, 65%) as a

1 white solid. Rf: 0.09 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.80

(bs, 1H), 7.55 – 7.50 (m, 4H), 7.34 – 7.23 (m, 5H), 4.52 (t, J = 6.8 Hz, 2H), 3.11 (t, J = 6.8

13 Hz, 2H). C NMR (100 MHz, CDCl3): δ = 167.1, 138.5, 131.8, 129.1, 128.6, 128.4, 126.6,

+ 125.6, 66.9, 35.2. HRMS (ESI-TOF) m/z: calc’d for C15H15BrNO [M+H] expected

304.0337, found 304.0315. IR (film) cm–1: 3336, 3085, 3032, 2969, 2951, 2931, 2891,

2861, 1639, 1586. MP: 57 – 59 °C.

phenethyl 4-(trifluoromethyl)benzimidate (IV-S19): 4-

trifluoromethylbenzonitrile (0.5 mL, 0.64 mL, 3.7 mmol) was

156 subjected to GP1. After filtration, the crude benzimidate salt was isolated. The benzimidate salt was free-based according to GP1. Purification via column chromatography (silica gel,

5% ethyl acetate/hexanes with 1% Et3N), yielded benzimidate IV-S19 (0.65 g, 59%) as a

1 white solid. Rf: 0.22 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.94

(bs, 1H), 7.78 (bs, 2H), 7.66 (d, J = 8.3 Hz, 2H), 7.36 – 7.29 (m, 4H), 7.27 – 7.23 (m, 1H),

13 4.54 (bs, 2H), 3.14 (t, J = 6.7 Hz, 2H). C NMR (150 MHz, CDCl3): δ = 166.9, 138.5,

136.1, 132.7 (2J = 32.8 Hz), 129.0, 128.5, 127.1, 126.6, 125.5, 122.9, 67.1, 35.1. HRMS

+ (ESI-TOF) m/z: calc’d for C16H15F3NO [M+H] expected 294.1106, found 294.1099. IR

(film) cm–1: 3335, 3059, 3026, 2962, 2893, 1638, 1577, 1541. MP: 62.5 – 63.5 °C.

phenethyl 3-chlorobenzimidate (IV-S20): 3-chlorobenzonitrile was

subjected to GP2, yielding the corresponding TFE-benzimidate (0.54 g,

54%) as a white solid. A portion of the TFE-benzimidate salt (0.2 g) was subjected to GP2 Step 2. Purification via column chromatography (silica gel, 10% ethyl acetate/hexanes with 1% Et3N) yielded benzimidate IV-S20 (0.18 g, 96%) as a white solid.

1 Rf: 0.15 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.83 (bs, 1H), 7.63

(bs, 1H), 7. 53 – 7.51 (m, 1H), 7.43 (ddd, J = 8.0, 2.1, 1.1 Hz, 1H), 7.36 – 7.29 (m, 5H),

7.26 – 7.24 (m, 1H), 4.53 (t, J = 6.9 Hz, 2H), 3.12 (t, J = 6.8 Hz, 2H). 13C NMR (100 MHz,

CDCl3): δ = 166.7, 138.4, 134.7, 131.0, 129.8, 129.1, 128.6, 128.4, 127.2, 126.6, 124.9,

+ 67.0, 35.2. HRMS (ESI-TOF) m/z: calc’d for C15H15ClNO [M+H] expected 260.0842, found 260.0835. IR (film) cm–1: 3338, 3062, 3029, 2958, 2895, 2859, 1632, 1595, 1566.

MP: 35 – 36 °C.

157 phenethyl 3-bromo-4-fluorobenzimidate (IV-S21): 3-bromo-4-

fluorobenzonitrile (2 g, 14.5 mmol) was subjected to GP2 Step 1,

yielding the corresponding TFE-benzimidate (1.63 g, 67%) as a white solid. A portion of the TFE-benzimidate salt (0.17 g) was subjected to GP2 Step 2.

Purification via column chromatography (silica gel, 10% ethyl acetate/hexanes with 1%

Et3N), yielded benzimidate IV-S21 (0.12 g, 87%) as a white solid. Rf: 0.12 (20% Ethyl

1 acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.89 (bs, 1H), 7.77 (bs, 1H), 7.59 (m,

1H), 7.35 – 7.23 (m, 5H), 7.13 (t, J = 8.4 Hz, 1H), 4.49 (bs, 2H), 3.12 (t, J = 6.9 Hz, 2H).

13 C NMR (100 MHz, CDCl3): δ = 162.0, 159.5, 138.3, 132.7, 130.5, 129.1, 128.7, 127.8,

19 126.7, 116.5 (d, J = 22.8 Hz), 109.4 (d, J = 22.1), 66.9, 35.2. F NMR (376 MHz, CDCl3):

+ δ = – 103.5. HRMS (ESI-TOF) m/z: calc’d for C15H14BrFNO [M+H] expected 322.0243, found 322.0215. IR (film) cm–1: 3362, 3057, 3026, 2956, 2942, 2883, 1900, 1641, 1597,

1584. MP: 58 – 58.8 °C.

phenethyl 1-naphthimidate (IV-S22): 1-naphthonitrile (0.5 g, 3.3

mmol) was subjected to GP1. After filtration, the crude benzimidate salt

was isolated. The benzimidate salt was free-based according to GP1.

Purification was done via column chromatography (silica gel, 10% ethyl acetate/hexanes with 1% Et3N) yielding benzimidate IV-S22 (0.12 g, 13%) as a clear oil. Rf: 0.34 (20%

1 Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.91 – 7.85 (m, 3H), 7.62 (bs,

1H), 7.54 – 7.42 (m, 4H), 7.33 – 7.31 (m, 4H), 7.28 – 7.24 (m, 1H), 4.66 (t, J = 6.8 Hz,

13 2H), 3.16 (t, J = 6.8 Hz, 2H). C NMR (100 MHz, CDCl3): δ = 170.2, 138.7, 133.7, 130.3,

129.8, 129.2, 128.6, 128.5, 127.1, 126.6, 126.3, 125.7 (2C), 125.3. 125.0, 67.1, 35.3.

158 + HRMS (ESI-TOF) m/z: calc’d for C19H17NONa [M+Na] expected 298.1208, found

298.1209. IR (film) cm–1: 3317, 3057, 3027, 2954, 2915, 2893, 1950, 1629.

phenethyl 2-naphthimidate (IV-S23): 2-naphthonitrile (0.5 g, 3.3

mmol) was subjected to GP1. After filtration, the crude benzimidate

salt was isolated. A portion of the benzimidate salt (0.75 g, 1.8 mmol) was free-based according to GP1. Purification via column chromatography (silica gel, 10% ethyl acetate/hexanes with 1% Et3N) yielded benzimidate S24 (0.12 g, 25%) as a white

1 solid with a minor ester impurity (ca. 10%). Rf: 0.11 (20% Ethyl acetate/hexanes). H NMR

(400 MHz, CDCl3): δ = 8.21 (bs, 1H), 7.91 – 7.85 (m, 3H), 7.76 (dd, J = 8.5, 1.6 Hz, 1H),

7.57 – 7.51 (m, 2H), 7.37 – 7.32 (m, 4H), 7.29 – 7.24 (m, 1H), 4.57 (t, J = 6.8 Hz, 2H),

13 3.19 (t, J = 6.9 Hz, 2H). C NMR (100 MHz, CDCl3): δ = 167.6, 138.7, 134.5, 132.9,

130.0, 129.2, 129.1, 128.6, 128.4, 127.8, 127.6, 127.3, 126.8, 126.6, 123.6, 66.8, 35.4.

+ HRMS (ESI-TOF) m/z: calc’d for C19H18NO [M+H] expected 276.1388, found 276.1374.

IR (film) cm–1: 3335, 3060, 3031, 2951, 2893, 2854, 1638, 1599, 1552. MP: 66 – 68 °C.

phenethyl [1,1'-biphenyl]-4-carbimidate (IV-S24): 4-

phenylbenzonitrile (1 g, 5.6 mmol) was subjected to GP1. After filtration, the crude benzimidate salt was isolated. A portion of the benzimidate salt (0.5 g,

1.1 mmol) was free-based according to GP1. Final purification via column chromatography (silica gel, 10% ethyl acetate/hexanes with 1% Et3N), yielded benzimidate

1 IV-S24 (0.12 g, 36%) as a white solid. Rf: 0.09 (20% Ethyl acetate/hexanes). H NMR (400

MHz, CDCl3): δ = 7.85 (bs, 1H), 7.75 – 7.73 (m, 2H), 7.64 – 7.60 (m, 4H), 7.48 – 7.44 (m,

159 2H), 7.40 – 7.36 (m, 1H), 7.33 (d, J = 4.3 Hz, 4H), 7.27 – 7.23 (m, 1H) 4.56 (t, J = 6.2 Hz,

13 2H), 3.15 (t, J = 6.8 Hz, 2H). C NMR (100 MHz, CDCl3): δ = 167.3, 143.8, 140.2, 138.7,

129.1, 129.0, 128.6, 128.0, 127.4, 127.31, 127.29, 127.26, 126.5, 66.7, 35.3. HRMS (ESI-

+ TOF) m/z: calc’d for C21H20NO [M+H] expected 302.1545, found 302.1538. IR (film) cm–1: 3335, 3062, 3030, 2942, 1629, 1607, 1582. MP: 116 – 118 °C.

Phenethyl pivalimidate (IV-S26): 2-phenylethan-1-ol (0.82 mL, 8.0

mmol) and pivalonitrile (0.97 mL, 8.8 mmol) were subjected to GP1.

After filtration, the pivalimidate salt was isolated (680 g, 24%) as a white solid. A portion of the pivalimidate salt (420 mg, 1.2 mmol) was free-based according to GP1. Purification via column chromatography (silica gel, 20% ethyl acetate/hexanes with 1% Et3N), yielded pivalimidate IV-S26 (100 mg, 44%) as a clear oil. Note: The phenethyl pivalimidate hydrotriflate salt took over a week to precipitate out at -15 °C. Alkyl imidates are generally more hydrolytically unstable than their corresponding arylimidates. As such, column chromatography for this substrate was done quickly, in less than 3 minutes. The crude freebased material can be used without any observable difference in reactivity. Rf: 0.42

1 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.30 – 7.20 (m, 5H), 6.90

(Br s, 1H), 4.29 (t, J = 6.7 Hz, 2H), 3,00 (t, J = 6.7 Hz, 2H), 1.14 (s, 9H). 13C NMR (100

MHz, CDCl3): δ = 179.2, 138.8, 129.14, 128.4, 126.4, 66.5, 37.9, 35.3, 27.8. HRMS (ESI-

+ –1 TOF) m/z: calc’d for C13H20NO [M+H] 206.1539, found 206.1543. IR (film) cm : 3028,

2958, 2871, 1726, 1639.

160 N-methyl-N-phenethyl-4-(trifluoromethyl)benzimidamide (IV-

S28): To a 2-dram vial equipped with stirbar and N-methyl phenethylamine (0.54 g, 4.0 mmol) and PhMe (4.5 mL) at 0 °C, was added AlMe3 (25% w/w in hexanes, 2.7 mL, 6.2 mmol) dropwise. The reaction was stirred and warmed to room temperature for 15 minutes. 4-trifluorobenzonitrile (1.0 g, 6.0 mmol) in PhMe (1.0 mL) was added dropwise, and then brought to 110 °C for 24 h. The reaction was quenched with H2O, extracted with ethyl acetate, and then purified via column chromatography

(silica gel with 1% Et3N, 20% ethyl acetate/hexanes to 97% ethyl acetate/3% NEt3) yielding amidine IV-S28 (0.31 g, 25%) as a yellow oil. Rf: 0.29 (3% Et3N/ethyl acetate).

1 H NMR (400 MHz, CDCl3): δ = 7.56 (d, J = 8.0 Hz, 2H), 7.30 – 7.26 (m, 2H), 7.25 – 7.20

(m, 2H), 7.16 (d, J = 7.9 Hz, 2H), 7.04 (d, J = 6.7 Hz, 2H), 3.42 (t, J = 7.0 Hz, 2H), 2.94

13 (s, 3H), 2.83 (t, J = 7.2 Hz, 2H). C NMR (150 MHz, CDCl3): δ = 168.1, 142.1, 140.1,

2 3 138.8, 130.9 (q, JCF = 32.7 Hz), 129.0, 128.6, 128.0, 127.1, 126.6, 126.2, 125.6 (q JCF =

1 19 3.7 Hz), 123.9 (q, JCF = 272.7 Hz), 53.2, 36.1, 34.3. F NMR (376 MHz, CDCl3): δ = –

+ + 62.8. HRMS (ESI-TOF) m/z: calc’d for C17H18F3N2 [M+H] 307.1417, found 307.1405.

IR (film) cm–1: 3367, 3027, 2345, 2115, 1685, 1618, 1585, 1570, 1520, 1496, 1478, 1454,

1406, 1364, 1322, 1665, 1123, 1065, 1030.

2,2,2-trichloro-N-methyl-N-phenethylacetimidamide (IV-S29): To a

250 mL round bottom flask containing a stir bar, N-methyl-phenethylamine

(0.68 g, 5.0 mmol) and CH2Cl2 (50 mL) were added trichloroacetonitrile (1.0 mL, 10 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.5 mL, 1.0 mmol). The solution was stirred at 23 °C and monitored by TLC until consumption of amine. Upon completion, the

161 solution was concentrated and directly loaded onto silica gel (treated with 1% Et3N in hexanes) and purified, yielding amidine IV-S29 (0.5 g, 36%) as an orange oil. 1H NMR

(400 MHz, CDCl3): δ = 7.68 (br s, 1H), 7.34 – 7.27 (m, 2H), 7.25 – 7.19 (m, 3H), 3.79 –

13 3.71 (m, 2H), 3.12 (s, 3H), 3.01 – 2.93 (m, 2H). C NMR (100 MHz, CDCl3): δ = 179.2,

138.8, 129.14, 129.10, 128.4, 66.5, 37.9, 35.3, 27.8. HRMS (ESI-TOF) m/z: calc’d for

+ + –1 C11H17Cl3N2 [M+H] 279.0217, found 279.0215. IR (film) cm : 3315, 2922, 1709, 1619,

1573, 1522, 1488, 1449, 1426, 1373, 1328, 1310, 1258, 1168, 1071, 1029, 1008.

1-phenylpropan-2-yl benzimidate (IV-34): 1-phenyl-2-propanol (0.273 g,

2.0 mmol) was combined with trifluoroethanol benzimidate (hydrochloride salt) (1.16 g, 4.8 mmol) in MeCN (8 mL) and stirred at 60 °C for 16h. The solvent was evaporated, and the residue was freebased according to GP1. The crude product was purified via column chromatography (silica gel, 5% ethyl acetate/hexanes with 1% Et3N) to yield benzimidate IV-34 (0.20 g, 0.84 mmol, 42%) as a clear oil. Note: the transimidation is temperature sensitive; at 50 °C the alcohol is not consumed, and at 80 °C, the imidate decomposes into benzamide. Multiple columns may be needed to obtain pure benzimidate.

1 Rf: 0.37 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 7.75 (bs, 1H), 7.68

(d, J = 7.2 Hz, 2H), 7.47 – 7.38 (m, 3H), 7.30 – 7.27 (m, 4H), 7.25 – 7.20 (m, 1H), 5.40

(bs, 1H), 3.14 (dd, J = 13.6, 6.4 Hz, 1H), 2.94 (dd, J = 13.7, 6.4 Hz, 1H) 1.37 (d, J = 6.2

13 Hz, 3H). C NMR (100 MHz, CDCl3): δ =167.3, 138.3, 133.5, 130.8, 129.7, 128.4, 126.8,

+ 126.4, 72.4, 42.4, 19.3. HRMS (ESI-TOF) m/z: calc’d for C16H18NO [M+H] 240.1383, found 240.1376. IR (film) cm–1: 3026, 3018, 2926, 1630.

162 4.7.3 Oxazole Synthesis

General Procedure for Tandem Oxidation (GP3):

To a 2-dram vial containing a stir bar were added: imidate (0.2 mmol, 1 equiv.),

CsI (0.6 mmol, 3 equiv.), and PhI(OAc)2 (0.6 mmol, 3 equiv.). This was followed by evacuation and backfilling of the headspace with N2, three times. Degassed PhMe (0.1 M, degassing method described below) was then added, and the solution was stirred under visible irradiation (2 x 23W CFL bulbs) with two fans maintaining ambient temperature

(23 °C vs. 35 ºC without). Reaction progress was monitored by TLC. Upon completion, the crude reaction was quenched with 10% aq. Na2S2O3 and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, concentrated, and then purified via column chromatography (silica gel with ethyl acetate and hexanes).

2,4-diphenyl-4,5-dihydrooxazole (IV-2): To a 10 mL round bottom flask and

stir bar was added benzimidate 1 (0.4 g, 1.8 mmol), and PhI(OAc)2 (0.7 g, 2.2 mmol). This vial was evacuated and backfilled with N2 (3x). A degassed stock solution of

I2 (47 mg, 0.018 mmol) in dry DMF (4.5 mL) was added to the flask under N2. The reaction was heated to 50°C (by placing vial in an aluminum heating block) and stirred for 2 hours.

Upon completion, the reaction was quenched with 10% aq. Na2S2O3, extracted with

EtOAc, and washed with H2O. The crude was then purified via column chromatography

(silica gel treated with 1% Et3N in hexanes), yielding oxazoline IV-2 (0.34 g, 85%) as a

1 light yellow oil. H NMR (400 MHz, CDCl3): δ = 8.07 – 8.02 (m, 1H), 7.47 – 7.41 (m,

2H), 7.39 – 7.25 (m, 5H), 5.39 (dd, J = 10.2, 8.2 Hz, 1H), 4.80 (dd, J = 10.0, 8.4 Hz, 1H),

4.28 (app t, J = 8.3 Hz, 1H).

163

2,4-diphenyloxazole (IV-3): phenethyl benzimidate (45 mg, 0.2 mmol)

was subjected to GP3. Purification via column chromatography, yielded

oxazole 3 (43 mg, 97%) as an off-white solid. Rf: 0.48 (10% Ethyl

1 acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.16 – 8.10 (m, 2H), 7.97 (s, 1H), 7.86

13 – 7.80 (m, 2H), 7.53 – 7.38 (m, 6H), 7.37 – 7.31 (m, 1H). C NMR (100 MHz, CDCl3): δ

= 162.10, 142.19, 133.56, 131.31, 130.54, 128.90, 128.26, 127.69, 126.68, 125.80. HRMS

+ + – (ESI-TOF) m/z: calc’d for C15H12NO [M+H] 222.0913, found 222.0920. IR (film) (cm

1): 2924, 2852, 2360, 2341, 1553, 1487, 1146, 1339, 1290, 1274, 1157, 1123, 1069, 1022,

942, 929. MP: 94 - 96 °C.

2-phenyl-4-(o-tolyl)oxazole (IV-4): Benzimidate IV-S4 (48 mg, 0.2

mmol) was subjected to GP3. Purification via column chromatography

yielded oxazole IV-4 (44 mg, 94%) as an off-white solid. Rf: 0.45 (5% Ethyl

1 acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.21 8.08 (m, 2H), 7.98 – 7.88 (m, 1H),

7.82 (s, 1H), 7.56 – 7.40 (m, 3H), 7.34 – 7.26 (m, 3H), 2.51 (s, 3H). 13C NMR (100 MHz,

CDCl3): δ = 161.1, 141.2, 135.8, 135.4, 131.0, 130.6, 130.5, 128.9, 128.9, 128.1, 127.7,

+ + 126.7, 126.2, 21.9. HRMS (ESI-TOF) m/z: calc’d for C16H14NO [M+H] 236.1070, found

236.1067.IR (film) cm–1: 3177, 3059, 2926, 2359, 2341, 1556, 1488, 1462, 1448, 1378,

1339, 1288, 1262, 1235, 1134, 1111, 1081, 1066, 1043, 1023, 934. M.P 65 – 66 °C.

4-(2-chlorophenyl)-2-phenyloxazole (IV-5): Benzimidate IV-S5 (52 mg,

0.2 mmol) was subjected to GP3. Purification via column chromatography

164 1 yielded oxazole IV-5 (33 mg, 63%) as a tan solid. Rf: 0.45 (5% Ethyl acetate/hexanes). H

NMR (400 MHz, CDCl3): δ = 8.41 (s, 1H), 8.28 (dd, J = 7.8, 1.7 Hz, 1H), 8.16 – 8.12 (m,

2H), 7.52 – 7.45 (m, 4H), 7.41 – 7.37 (td, J = 7.9, 1.3 Hz, 1H), 7.28 – 7.24 (m, 1H). 13C

NMR (100 MHz, CDCl3): δ = 160.9, 138.2, 137.4, 131.7, 130.6, 130.4, 130.1, 130.0, 128.9,

+ + 128.8, 127.5, 127.2, 126.7. HRMS (ESI-TOF) m/z: calc’d for C17H12NO [M+H]

256.0524, found 256.0517. IR (film) cm–1: 3191, 3045, 1611. M.P 89 – 91 °C.

2-phenyl-4-(pyridin-2-yl)oxazole (IV-6): Benzimidate IV-S6 (45 mg, 0.2

mmol) was subjected to GP3, with the following modifications: addition of

K2HPO4 (40 mg, 0.2 mmol). Purification via column chromatography yielded oxazole IV-6 (22 mg, 49%) as a tan solid. Rf: 0.25 (30% Ethyl acetate/hexanes).

1 H NMR (400 MHz, CDCl3): δ = 8.61 (dq, J = 4.8, 0.8 Hz, 1H), 8.31 (s, 1H), 8.01 (dt, J =

7.7, 1.0 Hz, 1H), 7.78 (td, J = 7.7, 1.8 Hz, 1H), 7.52 – 7.45 (m, 3H), 7.23 (ddd, J = 7.6,

13 4.8, 1.2 Hz, 1H). C NMR (100 MHz, CDCl3): δ = 162.2, 151.0, 149.7, 142.4, 137.0,

+ 130.7, 128.9, 127.5, 126.7, 122.9, 120.5. HRMS (ESI-TOF) m/z: calc’d for C15H11NO

[M+H]+ 223.0866, found 223.0871. IR (film) cm–1: 3121, 3058, 1607, 1576. M.P 94 – 95

°C.

2-phenyl-4-(m-tolyl)oxazole (IV-7): Benzimidate IV-S7 (48 mg, 0.2

mmol) was subjected to GP3. Purification via column chromatography yielded oxazole IV-7 (44 mg, 94%) as a white solid. Rf: 0.45 (10% Ethyl acetate in

1 hexanes). H NMR (400 MHz, CDCl3): δ = 8.19 – 8.07 (m, 2H), 7.96 (s, 1H), 7.70 – 7.65

(m, 1H), 7.64 – 7.58 (m, 1H), 7.53 – 7.42 (m, 3H), 7.35 – 7.29 (t, H = 7.7 Hz, 1 H), 7.18 –

165 13 7.12 (m, 1H), 2.42 (s, 3H). C NMR (150 MHz, CDCl3): δ = 162.4, 142.3, 138.6, 133.6,

131.2, 130.5, 129.1, 128.9, 128.8, 127.7, 126.7, 126.5, 122.9, 21.6. HRMS (ESI-TOF) m/z:

+ + –1 calc’d for C16H14NO [M+H] 236.1070, found 236.1067. IR (film) (cm ): 3058, 2920,

2857, 2359, 2341, 1616, 1598, 1555, 1488, 1448, 1337, 1275, 1113, 1081, 1060, 1023,

960, 932. MP: 50 – 51 °C.

2-phenyl-4-(3-(trifluoromethyl)phenyl)oxazole (IV-8): Benzimidate

IV-S8 (59 mg, 0.2 mmol) was subjected to GP3. Purification via column chromatography yielded oxazole IV-8 (43 mg, 77%) as a white solid. Rf: 0.38

1 (10% Ethyl acetate in hexanes). H NMR (400 MHz, CDCl3): δ = 8.17 – 8.09 (m, 3H), 8.03

(s, 1H), 8.03 – 7.98 (m, 1H), 7.62 – 7.52 (m, 2H), 7.52 – 7.46 (m, 3H). 13C NMR (150

2 MHz, CDCl3): δ = 162.4, 141.0, 134.2, 132.2, 131.4 (q, JCF = 32.3 Hz), 130.8, 129.4,

3 1 3 129.0, 126.7, 124.8 (q, JCF = 3.8 Hz), 124.22 (q, JCF = 272.3 Hz), 122.6 (q, JCF = 4.0

19 Hz). F NMR (376 MHz, CDCl3): δ = – 62.8. HRMS (ESI-TOF) m/z: calc’d for

+ + –1 C16H11F3NO [M+H] 290.0787, found 290.0789. IR (film) (cm ): 2359, 2341, 1620

,1558, 1491, 1479, 1448, 1341, 1317, 1284, 1277, 123, 1169, 1157, 1107, 1094, 1060,

1022, 956, 931. MP: 70 – 72 °C.

4-(3-methoxyphenyl)-2-phenyloxazole (IV–9): Benzimidate IV-S9

(51 mg, 0.2 mmol) was subjected to GP3. Purification via column

chromatography yielded oxazole IV-9 (50 mg, 100%) as a white solid.

1 Rf: 0.28 (10% Ethyl acetate in hexanes). H NMR (600 MHz, CDCl3): δ = 8.14 – 8.12 (m,

2H), 7.98 (s, 1H), 7.50 – 7.47 (m, 3H), 7.42 (dd, J = 2.5, 1.4 Hz, 1H), 7.39 (dt, J = 7.6, 1.2

166 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 6.89 (ddd, J = 8.1, 2.6, 1.0 Hz, 1H), 3.89 (s, 3H). 13C

NMR (150 MHz, CDCl3): δ = 162.0, 160.2, 142.1, 133.8, 132.6, 130.6, 129.9, 128.9, 127.6,

+ + 126.7, 118.2, 114.2, 111.1, 55.5. HRMS (ESI-TOF) m/z: calc’d for C16H14NO2 [M+H]

252.1019, found 252.1021. IR (film) (cm–1): 3061, 2999, 2935, 2833, 2360, 2341, 1609,

1591, 1571, 1555, 1489, 1465, 1447, 1431, 1337, 1320, 1303, 1280, 1245, 1212, 1177,

1079, 1043, 1023, 960, 932. MP: 67 – 68 °C.

4-(4-fluorophenyl)-2-phenyloxazole (IV-10): Benzimidate IV-S10 (49

mg, 0.2 mmol) was subjected to GP3. Purification via column

chromatography yielded oxazole IV-10 (41 mg, 85%) as an off-white

1 solid. Rf: 0.35 (5% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.12 (m, 2H),

7.92 (s, 1H), 7.80 (dd, J = 8.9, 5.4 Hz, 2H), 7.48 (m, 3H), 7.13 (t, J = 8.8 Hz, 2H). 13C

1 4 NMR (100 MHz, CDCl3): δ = 162.8 (q, JC-F = 247.2 Hz), 162.1, 141.3, 133.2 (q, JC-F =

3 2 19 1.1 Hz), 130.6, 128.9, 127.6, 127.5 (q, JCF = 8.0 Hz), 126.6, 115.9 (q, JCF = 21.8 Hz). F

+ NMR (376 MHz, CDCl3): δ = –114.68. HRMS (ESI-TOF) m/z: calc’d for C15H11FNO

[M+H]+ 240.0819, found 240.0830. IR (film) cm–1: 3132, 3059, 1718, 1610, 1556. MP:

104 – 105 °C.

4-(4-chlorophenyl)-2-phenyloxazole (IV-11): Benzimidate IV-S11 (42

mg, 0.2 mmol) was subjected to GP3. Purification via column

chromatography yielded oxazole IV-11 (39 mg, 94%) as a white solid.

1 Rf: 0.50 (5% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.14 – 8.09 (m, 2H),

7.96 (s, 1H), 7.86 – 7.75 (m, 2H), 7.52 – 7.46 (m, 3H), 7.42 – 7.39 (m, 2H). 13C NMR (100

167 MHz, CDCl3): δ = 162.2, 141.2, 133.9, 133.7, 130.7, 129.8, 129.1, 128.9, 127.5, 127.1,

+ + 126.7. HRMS (ESI-TOF) m/z: calc’d for C15H10NNaO [M+Na] 378.0343, found

378.0374. IR (film) (cm–1): 3364, 3120, 3057, 2959, 2923, 2852, 1657, 1609, 1565, 1555,

1486, 1449, 1404, 1340, 1312, 1292, 1271, 1121, 1103, 1068, 191, 1059, 1024, 1013, 942,

932, 829. MP: 129 °C.

4-(4-bromophenyl)-2-phenyloxazole (IV-12): Benzimidate IV-S12

(61 mg, 0.2 mmol) was subjected to GP3. Purification via column

chromatography yielded oxazole IV-12 (59 mg, 98%) as a white solid.

1 Rf: 0.53 (5% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.08-8.14 (m, 2H),

7.97 (s, 1H), 7.68-7.73 (m, 2H), 7.53-7.59 (m, 2H), 7.45-7.52 (m, 3H). 13C NMR (100

MHz, CDCl3): δ = 162.26, 141.25, 133.72, 132.03, 130.69, 130.28, 128.94, 127.47, 127.34,

+ + 126.69, 122.08. HRMS (ESI-TOF) m/z: calc’d for C15H11BrNO [M+H] 300.0019, found

300.0022. IR (film) (cm–1): 3369, 3181, 3055, 2952, 2853, 1726, 1659, 1606, 1589, 1577.

MP: 137 – 138 °C.

4-(4-iodophenyl)-2-phenyloxazole (IV-13): Benzimidate IV-S13 (70

mg, 0.2 mmol) was subjected to GP3. Purification via column

chromatography yielded oxazole IV-13 (64 mg, 93%) as a white solid.

1 Rf: 0.45 (10% Ethyl acetate in hexanes). H NMR (400 MHz, CDCl3): δ = 8.12 – 8.10 (m,

2H), 7.98 (s, 1H), 7.78 – 7.75 (m, 2H), 7.59 – 7.56 (m, 2H), 7.50 – 7.46 (m, 3H). 13C NMR

(100 MHz, CDCl3): δ = 162.1, 141.2, 137.8, 133.7, 130.7, 130.6, 128.8, 127.4, 127.3,

+ + 126.6, 93.4. HRMS (ESI-TOF) m/z: calc’d for C15H11INO [M+H] 347.9880, found

168 347.9869. IR (film) (cm–1): 2360, 2342, 1157, 1473, 1447, 1396, 1338, 1267, 1120, 1100,

1063, 1022, 1005, 940, 932. MP: 156 °C.

2-phenyl-4-(4-(trifluoromethyl)phenyl)oxazole (IV-14):

Benzimidate S14 (59 mg, 0.2 mmol) was subjected to GP3. Purification

via column chromatography yielded oxazole IV-14 (49 mg, 84%) as a

1 white solid. Rf: 0.43 (5% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.16 –

8.10 (m, 2H), 8.05 (s, 1H), 7.98 – 7.92 (d, J = 8.0 Hz, 2H), 7.72 – 7.66 (d, J = 8.3 Hz, 2H),

13 7.53 – 7.47 (m, 3H). C NMR (100 MHz, CDCl3): δ = 162.5, 141.0, 134.8, 134.6, 130.8,

2 3 130.1 (q, JCF = 32.4 Hz), 129.0, 127.4, 126.7, 125.9, 125.9 (q, JCF = 3.8 Hz), 124.3 (q,

1 19 JCF = 272.0 Hz). F NMR (376 MHz, CDCl3): δ = – 62.56. HRMS (ESI-TOF) m/z: calc’d

+ + –1 for C16H11F3NO [M+H] 290.0787, found 290.0789. IR (film) (cm ): 2359, 2342, 1620,

1558, 1450, 1415, 1335, 1166, 1156, 1110, 1076, 1065, 943, 930. MP: 145 – 146 °C.

2-phenyl-4-(4-(trifluoromethoxy)phenyl)oxazole (IV-15):

Benzimidate IV-S15 (62 mg, 0.2 mmol) was subjected to GP3.

Purification via column chromatography yielded oxazole IV-15 (57

1 mg, 94%) as a white solid. Rf: 0.53 (5% Ethyl acetate/hexanes). H NMR (400 MHz,

CDCl3): δ = 8.10-8.15 (m, 2H), 7.97 (s, 1H), 7.83-7.89 (m, 2H), 7.46-7.51 (m, 3H), 7.27-

13 7.32 (m, 2H). C NMR (150 MHz, CDCl3): δ = 162.3, 149.1, 141.0, 133.7, 130.7, 130.1,

1 19 129.0, 127.5, 127.2, 126.7, 121.4, 120.7 (q, JCF = 257.4 Hz). F NMR (376 MHz, CDCl3):

+ + δ = –57.8. HRMS (ESI-TOF) m/z: calc’d for C16H11F3NO2 [M+H] 306.0736, found

169 306.0737. IR (film) (cm–1): 3054, 2983, 2928, 2111, 2029, 2008, 1963, 1574, 1499, 1450.

MP: 95.7 °C.

2-phenylnaphtho[1,2-d]oxazole (IV-16): Benzimidate IV-S16 (50 mg,

0.2 mmol) was subjected to GP3, with the following modifications:

additional CsI (208 mg, 0.8 mmol), PhI(OAc)2 (258 mg, 0.8 mmol), and

PhMe (3 mL). Purification via column chromatography yielded oxazole IV-16 (37 mg,

1 75%) as an off-white solid. Rf: 0.35 (5% Ethyl acetate/hexanes). H NMR (400 MHz,

CDCl3): δ = 8.62 (d, J = 8.2 Hz, 1H), 8.35 (m, 2H), 7.97 (d, J = 8.2 Hz, 1H), 7.80 (d, J =

8.8 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.70 – 7.67 (m, 1H), 7.57 – 7.51 (m, 4H). 13C NMR

(100 MHz, CDCl3): δ = 162.4, 148.2, 137.8, 131.4, 131.2, 129.0, 128.7, 127.7, 127.5,

+ 127.1, 126.7, 126.1, 125.5, 122.4, 110.9. HRMS (ESI-TOF) m/z: calc’d for C17H12NO

[M+H]+ 264.0913, found 264.0917. IR (film) cm–1: 3068, 2924, 1639, 1551. M.P 133 –

134 °C.

2-(4-methoxyphenyl)-4-phenyloxazole (IV-17): Benzimidate IV-

S17 (51 mg, 0.2 mmol) was subjected to GP3. Purification via column chromatography yielded oxazole IV-17 (38 mg, 76%) as a white solid. Rf: 0.50

1 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.08 – 8.04 (m, 2H), 7.92

(s, 1H), 7.83 – 7.80 (m, 2H), 7.45 – 7.41 (m, 2H), 7.35 – 7.31 (m, 1H), 7.01 – 6.98 (m, 2H),

13 3.88 (s, 3H). C NMR (100 MHz, CDCl3): δ 162.1, 161.5, 141.9, 133.0, 131.4, 128.8,

+ 128.3, 128.1, 125.7, 120.5, 114.3, 55.5. HRMS (ESI-TOF) m/z: calc’d for C16H14NO2

170 [M+H]+ expected 252.1025, found 252.1019. IR (film) cm–1: 3042, 2969, 2920, 2843,

1613, 1592. MP: 95 – 96 °C.

2-(4-bromophenyl)-4-phenyloxazole (IV-18): Benzimidate IV-S18

(61 mg, 0.2 mmol) was subjected to GP3. Purification via column chromatography yielded oxazole IV-18 (55 mg, 92%) as a white solid. Rf: 0.65 (20% Ethyl

1 acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.01 – 7.97 (m, 3H), 7.82 – 7.80 (m,

2H), 7.64 – 7.60 (m, 2H), 7.46 – 7.41 (m, 2H), 7.37 – 7.32 (m, 1H). 13C NMR (150 MHz,

CDCl3): δ 161.2, 142.4, 133.8, 132.2, 131.1, 128.9, 128.4, 128.1, 126.6, 125.8, 125.0.

+ + HRMS (ESI-TOF) m/z: calc’d for C15H11BrNO [M+H] expected 300.0024, found

299.9998. IR (film) cm–1: 3120, 3078, 3058, 3026, 2981, 1600, 1551. MP: 143 – 145 °C.

4-phenyl-2-(4-(trifluoromethyl)phenyl)oxazole (IV-19):

Benzimidate IV-S19 (59 mg, 0.2 mmol) was subjected to GP3.

Purification via column chromatography yielded oxazole IV-19 (45 mg, 77%) as a white

1 solid. Rf: 0.40 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.25 – 8.23

(m, 2H), 8.02 (s, 1H), 7.84 – 7.82 (m, 2H), 7.76 – 7.73 (m, 2H), 7.47 – 7.43 (m, 2H), 7.38

13 2 – 7.34 (m, 1H). C NMR (150 MHz, CDCl3): δ = 160.7, 142.7, 134.3, 132.2 ( J = 32.0

Hz), 130.9, 130.8, 129.0, 128.6, 126.9, 126.0 (3J = 4.3 Hz), 125.86, 125.85 (1J = 272.5 Hz),

+ + 123.1. HRMS (ESI-TOF) m/z: calc’d for C16H11F3NO [M+H] expected 290.0793, found

290.0822. IR (film) cm–1: 2981, 2923, 2890, 1659, 1620, 1587, 1563. MP: 143 – 144 °C.

171 2-(3-chlorophenyl)-4-phenyloxazole (IV-20): Benzimidate IV-S20

(52 mg, 0.2 mmol) was subjected to GP3. Purification via column chromatography yielded oxazole IV-20 (59 mg, 89%) as a low-melting yellow solid. Rf:

1 0.69 (20% Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 8.13 – 8.12 (m, 1H),

8.02 – 7.99 (m, 1H), 7.98 (s, 1H), 7.83 – 7.81 (m, 2H), 7.46 – 7.42 (m, 4H), 7.37 – 7.33

13 (m, 1H). C NMR (100 MHz, CDCl3): δ = 160.7, 142.4, 135.0, 133.9, 131.0, 130.5, 130.2,

+ 129.3, 128.9, 128.4, 126.7, 125.8, 124.7. HRMS (ESI-TOF) m/z: calc’d for C15H11ClNO

[M+H]+ expected 256.0529, found 256.0526. IR (film) cm–1: 3123, 3062, 2981, 2881,

1587, 1549.

2-(3-bromo-4-fluorophenyl)-4-phenyloxazole (IV-21):

Benzimidate IV-S21 (52 mg, 0.2 mmol) was subjected to GP3.

Purification via column chromatography yielded oxazole IV-21 (51 mg, 81%) as a white

1 solid. Rf: 0.65 (20% Ethyl acetate/hexanes). H NMR (600 MHz, CDCl3): δ = 8.34 (dd, J

= 6.5, 2.1 Hz, 1H), 8.04 (ddd, J = 8.6, 4.7, 2.1 Hz, 1H), 7.96 (s, 1H), 7.82 – 7.80 (m, 2H),

7.45 – 7.43 (m, 2H), 7.37 – 7.34 (m, 1H), 7.22 (app t, J = 8.3 Hz, 1H). 13C NMR (150 MHz,

1 CDCl3): δ = 161.3, 159.8 ( JCF = 35 Hz), 142.5, 133.9, 132.0, 130.9, 128.9, 128.5, 127.4

3 4 2 2 ( JCF = 7.7 Hz), 125.8, 125.3 ( JCF = 4.2 Hz), 117.1 ( JCF = 23.1 Hz), 109.9 ( JCF = 21.8

+ + Hz). HRMS (ESI-TOF) m/z: calc’d for C15H10BrFNO [M+H] expected 317.9930, found

317.9915. IR (film) cm–1: 3145, 3092, 3034, 2981, 1603, 1585, 1557. MP: 101 – 102 °C.

2-(naphthalen-1-yl)-4-phenyloxazole (IV-22): Benzimidate IV-S22

(55 mg, 0.2 mmol) was subjected to GP3. Purification via column

172 chromatography yielded oxazole IV-22 (44 mg, 86%) as a yellow solid. Rf: 0.55 (20%

1 Ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ = 9.47 – 9.44 (m, 1H), 8.27 (dd, J

= 7.3, 1.2 Hz, 1H), 8.08 (s, 1H), 8.00 – 7.98 (m, 1H), 7.95 – 7.92 (m, 3H), 7.71 – 7.67 (m,

1H), 7.61 – 7.56 (m, 2H), 7.50 – 7.46 (m, 2H), 7.40 – 7.35 (m, 1H). 13C NMR (100 MHz,

CDCl3): δ = 161.9, 142.1, 134.1, 133.3, 131.42, 131.39, 130.4, 128.9, 128.7, 128.3, 128.0,

127.7, 126.5, 126.4, 125.9, 125.1, 124.1. HRMS (ESI-TOF) m/z: calc’d for C19H14NO

[M+H]+ expected 272.1075, found 272.1103. IR (film) cm–1: 3145, 3048, 2979, 2923, 1587,

1542. MP: 70 – 72 °C.

2-(naphthalen-2-yl)-4-phenyloxazole (IV-23): Benzimidate IV-

S23 (61 mg, 0.2 mmol) was subjected to GP3. Purification via column chromatography yielded oxazole IV-23 (43 mg, 67%; corrected yield, contains ca.

10% inseparable iodinated oxazole) as a white solid. Rf: 0.61 (20% Ethyl acetate/hexanes).

1 H NMR (400 MHz, CDCl3): δ = 8.62 (s, 1H), 8.23 (dd, J = 8.5, 1.7 Hz, 1H), 8.02 (s, 1H),

7.98 – 7.94 (m, 2H), 7.89 – 7.86 (m, 3H), 7.57 – 7.54 (m, 2H), 7.48 – 7.44 (m, 2H), 7.38 –

13 7.34 (m, 1H). C NMR (100 MHz, CDCl3): δ = 162.2, 142.4, 134.3, 133.7, 133.2, 131.3,

128.91, 128.89, 128.7, 128.3, 128.0, 127.4, 126.9, 126.6, 125.8, 125.0, 123.7. HRMS (ESI-

+ TOF) m/z: calc’d for C19H14NO [M+H] expected 272.1075, found 272.1049. IR (film) cm–1: 3059, 2980, 2887, 1609, 1586, 1549.

2-([1,1'-biphenyl]-4-yl)-4-phenyloxazole (IV-25): Benzimidate IV-

S25 (60 mg, 0.2 mmol) was subjected to GP3. Purification via column chromatography yielded oxazole IV-25 (40 mg, 67%) as a white solid. Rf: 0.66 (20% Ethyl

173 1 acetate/hexanes). H NMR (600 MHz, CDCl3): δ = 8.21 – 8.19 (m, 2H), 7.99 (s, 1H), 7.86

– 7.84 (m, 2H), 7.73 – 7.71 (m, 2H), 7.67 – 7.65 (m, 2H), 7.49 – 7.44 (m, 4H), 7.41 – 7.38

13 (m, 1H), 7.37 – 7.34 (m, 1H). C NMR (150 MHz, CDCl3): δ = 162.0, 143.2, 142.3, 140.4,

133.6, 131.3, 129.1, 128.9, 128.3, 128.0, 127.6, 127.3, 127.1, 126.5, 125.8. HRMS (ESI-

+ TOF) m/z: calc’d for C21H16NO [M+H] expected 298.1232, found 298.1247. IR (film) cm–1: 3056, 3038, 2981, 2919, 2850, 1610, 1576. MP: 161 – 163 °C.

2-(tert-butyl)-4-phenyloxazole (IV-26): Pivalimidate IV-S26 (41 mg, 0.2 mmol) was subjected to GP3. Purification via column chromatography yielded oxazole

1 IV-26 (31 mg, 77%) as a clear yellow oil. Rf: 0.29 (5% Ethyl acetate/hexanes). H NMR

(400 MHz, CDCl3): δ = 7.80 (s, 1H), 7.75 – 7.71 (m, 2H), 7.41 – 7.36 (m, 2H), 7.30 – 7.26

13 (m, 1H), 1.43 (s, 9H). C NMR (100 MHz, CDCl3): δ =171.7, 140.4, 132.9, 131.7, 128.8,

+ 127.9, 125.7. 34.0, 28.7. HRMS (ESI-TOF) m/z: calc’d for C13H16NO [M+H] 202.1226, found 202.1238. IR (film) cm–1: 3033, 2970, 1724, 1564.

4-phenyl-2-(trichloromethyl)oxazole (IV-27): Trichloroacetimidate IV-

S27 (53.3 mg, 0.2 mmol) was subjected to GP3, with the following modifications: NaI instead of CsI as the source of iodide, and a 50:50 mixture of PhMe/CHCl3 instead of PhMe as solvent. Purification via column chromatography yielded oxazole IV-27 (33 mg, 63%)

1 as a yellow solid. Rf: 0.43 (10% Ethyl acetate in hexanes). H NMR (400 MHz, CDCl3):

δ = 8.01 (s, 1H), 7.80 – 7.74 (m, 2H), 7.47 – 7.40 (m, 2H), 7.40 – 7.37 (m, 1H).

174 5-iodo-1-methyl-4-phenyl-2-(4-(trifluoromethyl)phenyl)-1H-

imidazole (IV-28): Amidine IV-S28 (61 mg, 0.2 mmol) was subjected to GP3, with the following modifications: additional CsI (2 mg, 0.8 mmol) and

PhI(OAc)2 (258 mg, 0.8 mmol). Purification via column chromatography yielded imidazole IV-28 (59 mg, 68%) as a white solid. Rf: 0.35 (10% Ethyl acetate in hexanes).

1 H NMR (400 MHz, CDCl3): δ = 7.99 – 7.92 (m, 2H), 7.77 (q, J = 8.5 Hz, 4H), 7.47 – 7.40

13 (m, 2H), 7.37 – 7.30 (m, 1H), 3.77 (s, 3H). C NMR (150 MHz, CDCl3): δ = 149.6, 144.9,

2 3 134.3, 133.8, 131.2 (q, JCF = 32.7 Hz), 129.4, 128.4, 127.8, 127.7, 125.8 (q, JCF = 3.8

1 Hz), 124.0 (q, JCF = 273.5 Hz), 72.4, 36.5. HRMS (ESI): m/z calculated for C17H13F3IN2

[M+H]+: 429.0070, found 429.0063. IR (film): 2981, 2361, 2342, 2160, 1977, 1616, 1528,

1481, 1459, 1444, 1378, 1325, 1165, 1120, 1106, 1073, 1013, 955, 850. MP: 156.7 °C.

5-iodo-1-methyl-4-phenyl-2-(trichloromethyl)-1H-imidazole (IV-29):

Amidine IV-S29 (61 mg, 0.2 mmol) was subjected to GP3, with the following modifications: additional CsI (2 mg, 0.8 mmol) and PhI(OAc)2 (258 mg, 0.8 mmol). Purification via column chromatography yielded imidazole IV-29 (25 mg, 32%) as

1 an orange solid. Rf: 0.28 (10% Ethyl acetate in hexanes). H NMR (400 MHz, CDCl3): δ =

8.56 – 8.49 (m, 2H), 7.59 – 7.52 (m, 1H), 7.52 – 7.45 (m, 2H), 3.58 (s, 3H). 13C NMR (150

MHz, CDCl3): δ = 164.5, 158.3, 145.5, 132.8, 129.9, 129.3, 129.0, 111.6, 30.1. HRMS

(ESI): The molecule was not amenable to HRMS analysis and fragmented into a number of species. IR (film): 3315, 2922, 1709, 1619, 1572, 1522, 1488, 1448, 1426, 1373, 1328,

1310, 1258, 1168, 1071, 1029, 1008. MP: 99.0 – 100 °C.

175 5-methyl-2,4-diphenyloxazole (IV-37): In addition to the two-step protocol,

the following procedure was used to go directly from (36) to (38). 36 (47.9 mg,

0.2 mmol), N-iodo succinimide (180 mg, 0.8 mmol), and potassium phosphate dibasic(69.7 mg, 0.4 mmol) were added to an 8 mL vial with septa cap which was degassed and charged with toluene. After completion and workup, the crude material was purified (silica gel) to

1 yield oxazole 38 (27 mg, 56%) as a white solid. Rf: 0.28 (5% Ethyl acetate/hexanes). H

NMR (400 MHz, CDCl3): δ = 8.10 – 8.07 (m, 2H), 7.76 – 7.74 (m, 2H), 7.49 – 7.43 (m,

13 2H), 7.35 – 7.31 (m, 1H), 2.62 (s, 3H). C NMR (100 MHz, CDCl3): δ = 159.5, 144.1,

136.1, 132.6, 130.1, 128.8, 128.7, 127.8, 127.4, 127.0, 126.3, 12.1. HRMS (ESI-TOF) m/z:

+ –1 calc’d for C16H14NO [M+H] 236.1070, found 236.1065. IR (film) cm : 3089, 2915, 1615,

1597, 1555. MP: 71 – 73 °C.

4.7.4 Oxazole Derivatization

General Procedure for Derivatization of Trichloromethyl Oxazoles (GP4):

To a 2-dram vial equipped with a stir bar was added oxazole IV-27 (0.2 mmol, 1 equiv.), NaH2PO4∙H2O (0.6 mmol, 3 equiv.), amine (0.8 mmol, 4 equiv.), and MeCN (0.1

M). The reaction was stirred at 80 °C and progress was monitored by TLC. Upon completion, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, concentrated, and then purified via column chromatography (silica gel with ethyl acetate and hexanes).

N-benzyl-4-phenyloxazole-2-carboxamide (IV-30): Oxazole IV-27

(44 mg, 0.2 mmol) and benzylamine (44 μL, 0.8 mmol were subjected

176 to GP4. Purification via column chromatography (silica gel, hexanes to 20% ethyl acetate/hexanes) yielded oxazole IV-30 (30 mg, 53%) as a white solid. Rf: 0.26 (20% Ethyl

1 acetate in hexanes). H NMR (400 MHz, CDCl3) δ: 8.04 (s, 1H), 7.74 – 7.71 (m, 2H), 7.44

13 – 7.31 (m, 9H), 4.67 (d, J = 6.1 Hz, 2H). C NMR (100 MHz, CDCl3) δ: 155.2, 142.0,

137.3, 136.1, 130.0, 129.0(4), 129.0(2), 128.9, 128.2, 128.0, 125.8, 43.8. HRMS (ESI): m/z calculated for C17H14N2O2Na [M+Na]: 301.0953, found 301.0933. IR (neat): 3272, 3136,

3110, 3058, 3031, 2917, 1667, 1579, 1526, 1346, 1262, 1204, 1185, 938, 763, 722. MP:

137.1 – 138.5 °C.

Morpholino(4-phenyloxazol-2-yl)methanone (IV-31): Oxazole IV-

27 (44 mg, 0.2 mmol) and morpholine (68 μL, 0.8 mmol) were subjected to GP4. Purification via column chromatography (silica gel, hexanes to 20% ethyl acetate/hexanes) yielded oxazole IV-31 (37 mg, 71%) as a brown solid. Rf: 0.15 (20%

1 Ethyl acetate in hexanes). H NMR (400 MHz, CDCl3) δ: 8.02 (s, 1H), 7.75 – 7.73 (m, 2H),

7.45 – 7.41 (m, 2H), 7.38– 7.34 (m, 1H), 4.38 – 4.35 (m, 2H), 3.85 – 3.79 (m, 6H). 13C

NMR (100 MHz, CDCl3) δ: 155.4, 154.5, 141.5, 135.0, 130.2, 129.0, 128.9, 125.8, 67.2,

66.9, 47.7, 43.4. HRMS (ESI): m/z calculated for C14H14N2O3Na [M+Na]: 281.0902, found

281.0897. IR (neat): 3140, 3115, 3026, 3018, 2963, 2922, 2853, 1635, 1533, 1430, 1271,

1171, 1110, 1021, 947. MP: 82.3 – 84.1 °C.

(4-phenyloxazol-2-yl)(pyrrolidin-1-yl)methanone (IV-32): Oxazole

IV-27 (44 mg, 0.2 mmol) and pyrrolidine (66 μL, 0.8 mmol) were subjected to GP4. Purification via column chromatography (silica gel, 100% hexanes to

177 20% ethyl acetate/hexanes) yielded oxazole IV-32 (41 mg, 85%) as a yellow solid. Rf: 0.15

1 (20% Ethyl acetate in hexanes). H NMR (400 MHz, CDCl3) δ: 8.01 (s, 1H), 7.78 – 7.76

(m, 2H), 7.45 – 7.41 (m, 2H), 7.37– 7.32 (m, 1H), 4.15 (t, J = 6.8 Hz, 2H), 3.72 (t, J = 6.9

13 Hz, 2H), 2.08 – 2.01 (m, 2H), 1.99 – 1.92 (m, 2H). C NMR (100 MHz, CDCl3) δ: 155.6,

154.8, 141.7, 134.9, 130.5, 129.0, 128.7, 125.8, 49.3, 47.4, 26.7, 24.0. HRMS (ESI): m/z calculated for C14H14N2O2Na [M+Na]: 269.0953, found 265.0955. IR (neat): 3133, 3105,

3043, 2977, 2923, 2876, 1654, 1540, 1431, 1340, 1305, 1295, 1165, 1115, 1071, 943, 819,

759, 694, 679. MP: 116.4 – 118.9 °C.

178 Chapter 5 Development of Oxime Imidate Radical Precursor

Portions of this chapter are adapted from the following publication:

Nakafuku, K. M.†; Fosu, S. C.†; Nagib, D. A. “Catalytic Alkene Difunctionalization via

Imidate Radicals” J. Am. Chem. Soc. 2018, 140, 11202 – 11205. Copyright The American

Chemical Society. Reproduced with permission.

Author Contribution: KMN conceived and designed a photoredox-catalyzed difunctionalization of allylic alcohols (Section 5.1 to 5.7). SCF and KMN co-investigated various radical termination strategies (Section 5.8, 5.10, & 5.11). Dual catalytic system was conceived and developed by KMN (Section 5.14).

179 5.1 Introduction

In pursuit of alcohol -functionalization using oxidative imidate radical strategy, the system using a halide-based radical initiator (i.e. AcO–I) results in C–H halogenations or amination via initial halogenation. Thus, the required pre-activation of an N-atom via formation of weak N–X bond presents a challenge in accessing a C–C bond forming reaction (Figure 5-1, top). Attempts to C–H alkylate the carbon radical in the presence of a radical acceptor such as methyl acrylate provides oxazoline exclusively due to rapid

C–I formation. In order to expand the synthetic scope and value of imidate radical reactions, there was a need to develop a new radical precursor. While Knowles and Rovis have developed PCET-based direct N–H oxidation to generate aminyl radical to circumvent the need for a halogen-activator, we envisioned pre-oxidizing the imidate by covalently attaching a non-propagative leaving group on the nitrogen atom (Figure 5-1, bottom). This reductive strategy uses single electron reduction to facilitate the mesolytic cleave to generate the imidate radical and the leaving group anion, ultimately preventing radical recombination. This similar strategy has been incorporated in aminyl92,152, imidyl153 and amidyl154 radicals to generate its respective single-electron species via single electron transfer reduction of the substrate. New strategic development of pre-oxidized imidate radical precursors would enable new catalytic methods to efficiently generate nitrogen- centered radicals to provide a solution to  C–H functionalization of alcohols via HAT.

180

Figure 5-1 Pre-oxidation of imidate to circumvent radical quenching

5.2 DFT-Calculation of Oxime Imidate BDEs

To test the feasibility of SET reduction process, we performed a series of DFT calculations (using (ωB97X-D/6-31G(D)) to estimate the BDE of four different oxime imidates, which contains different activating groups that result in different nucleophuge upon mesolytic cleavage of the N–O bond (Figure 5-2). In their ground state, the BDEs of oxime imidates range from 32 to 53 kcal/mol, which are on par with other iminyl radical variants.99 Gratifyingly, a single electron reduction to generate radical anion species results in a dramatic decrease in its BDE compared to its ground state. Detailed mechanisms of the SET reduction is currently underway; preliminary calculations suggest that the benzene backbone of the oxime imidate seems to be the electron-sink that results in elongation and fragmentation of the N–O bond upon SET.

181

Figure 5-2 BDE of ground and radical anion states of oxime imidates (in kcal/mol)

5.3 Imidoyl Chloride as Radical Chaperone

We envisioned that oxime imidates could readily be accessed by the combination of alcohols and imidoyl chlorides in a modular and tunable manner to access radical precursors with variable N−OR bond strengths. Imidoyl chlorides with various O- protecting groups were synthesized via following synthetic strategies (Figure 5.3).

Figure 5-3 Derivatization of imidoyl chloride

182 In the case of phenoxy and methoxy leaving group on the nitrogen atom, two step protocol involving benzoylation and dehydration using PCl5 yielded the desired imidoyl chloride in over 90% yields over two steps. This can be scaled up to a 100 mmol scale reaction. Derivatization on the N-leaving group as well as imidate backbone can easily be achieved by employing different hydroxylamine or N-protecting group. For installation of an acetate leaving group, condensation of hydroxylamine hydrochloride on to a benzaldehyde followed by -chlorination resulted in the formation of (Z)-N- hydroxybenzimidoyl chloride. In the presence of acetyl chloride, the imidoyl chloride was quantitatively acylated to give desired imidoyl chloride.

The installation of dinitrophenol leaving required a development of modified synthetic route (Figure5-4). When benzoyl chloride and O-(2,4- dinitrophenyl)hydroxylamine were stirred in standard basic condition, 2,4-dinitrophenol was isolated as the major product. Presumably, the Lossen rearrangement155 from the benzoylated O-(2,4-dinitrophenyl)hydroxylamine resulted in the formation isocyanate as well as 2,4-dinitrophenol as the leaving group. In order to avoid the formation of the benzoylated O-(2,4-dinitrophenyl)hydroxylamine under basic conditions, generation of desired benzoylated arylhydroxylamine under acidic condition was considered. Our modified reaction condition required initial Boc protection of O-(2,4- dinitrophenyl)hydroxylamine, followed by benzoylation to generate the tertiary amine species. Deprotection of Boc group under acidic condition using TFA prevented the Lossen rearrangement and allowed for facile isolation of the N-(2,4-dinitrophenoxy)benzamide.

The amide was then subjected to dehydrative chlorination using POCl3 and PCl5 in refluxing toluene to allow for the isolation of the imidoyl chloride.

183

Figure 5-4 Alternative route to di-nitrophenyl imidoyl chloride

5.4 Oxime Imidate Synthesis

With four representative imidoyl chlorides in hands, oxime imidates were synthesized from propanol and NaH in THF via addition elimination mechanism (Figure

5-5). While oxime imidates V-i and V-iv were isolated via column chromatography, attempts to synthesized oxime imidates from V-ii and V-iii turned out unfruitful.

Electrophilic carbon atoms labeled in green undergo competitive alkoxide addition, which made the clean isolation of the corresponding imidates challenging.

Oxime imidates V-i and V-iv were subjected to a cyclic voltammetry experiment, which is a commonly employed method for measuring the standard reduction potential of organic substrates. The electrochemical measurement was carried out in a three-electrode electrochemical cell, consisting of a glassy carbon disk working electrode, an Ag/AgCl, and a platinum wire counter electrode. V-i showed a sign of irreversible catalytic current around – 2.5 V vs SCE, while V-iv showed much lower reduction potential around – 1.6

184 V vs SCE. Attracted by stability and reactivity of V-iv, we decided to continue the study using the (Z)-N-phenoxybenzimidoyl chloride as the radical chaperone.

Figure 5-5 Synthesis of oxime imidates

5.5 Catalytic Imidate Radical Generation via Photoredox Catalyst

In developing a catalytic strategy to harness the reactivity of imidate radicals, we proposed oxime imidate may be selectively reduced by a single-electron via photocatalyst and upon mesolytic cleavage, the N-centered radical and phenoxide anion are formed. To test the feasibility of this strategy, oxime imidate V-S1 was synthesized from imidoyl chloride and allylic alcohol. SET reduction of V-S1 results in the formation of N-centered radical that would engage in radical 5-exo-trig cyclization to form oxazoline V-S1’. The most suitable/active photoredox catalyst was investigated based on its redox profiles

Ru(II)/Ru(I) (Figure 5-6). For example, using Ru(bpy)3Cl2 (E = – 1.3 V vs SCE) did not afford any product due to a thermodynamically unfavorable single electron transfer. However, we

185 identified [Ir(ppy)2(dtbbpy)]PF6 as the most suitable photocatalyst for this transformation, where the reduction potential of Ir(III)/Ir(II) matches the redox potential of imidate V-S1.

Figure 5-6 Hydroamination of allyl alcohols via imidate radicals

5.6 Proposed Mechanism and Expanding Oxime Imidate Reactivity

In our proposed mechanism, photo-excitation of a catalyst (IrIII to *IrIII) precedes reductive quenching by a tertiary amine to provide a strong reductant (IrII). We postulated that single-electron reduction of an allyl imidate V-A to its radical anion, and subsequent mesolytic cleavage, could then afford an imidate radical V-B and regenerated photocatalyst

(IrIII). Next, rapid, 5-exo-trig cyclization13 of the N-centered radical would provide V-C, which contains a C• adjacent to the new C−N bond. Doubly allylic C–H bond in 1,4-

186 cylcohexadine allows for the terminal H• reduction, which results in the formation of oxazoline product V-D (Figure 5-7).

Figure 5-7 Proposed photocatalytic cycle

In order to elucidate the reactivity of this photoredox-catalyzed imidate radical generation form oxime imidate, a Stern-Volmer quenching study was performed. The study suggested that the stoichiometric single electron donor N,N’-diisopropylethylamine is able to sufficiently quench the photo-exicited to state of Iridium catalyst, with the Stern-Volmer constant of 80 M–1. Oxime imidate as well as 1,4-cyclohexadiene was shown to be ineffective quencher, suggesting inability of iridium photocatalyst to directly engage in

SET event with the substrate.

5.7 Radical Alkene Difunctionalization

Complex organic molecular structures are of great importance as they promote the development of new medicines, agrochemicals, and biotechnologies.156 Considering step economy3,4, atom economy5 as well as redox economy6, minimizing the material and time

187 input required to structure the desired molecular complexity are preferred. Thus, in synthetic chemistry, the rapid generation of complex molecular frameworks from simple starting materials remains an important goal. One solution is a radical cascade reaction that allow multiple chemical steps to occur one after another in a defined sequence to form multiple bonds, often alongside the generation of a complex molecules, in a single operation. Enabled by new nitrogen-centered radical generation via mesolytic cleavage of oxime imidate using photoredox catalyst, radical alkene difunctionalization is a valuable synthetic tool to rapidly achieve molecular complexity in a single step (Figure 5-8).

Figure 5-8 Catalytic difunctionalization of allylic alcohols

We postulated that three distinct mechanisms could be employed to intercept the

C-radical. For instance, homolytic substitution (SH2) of a radical trap containing a weak

C−H bond may provide hydroamination.157 Alternatively, intermolecular radical π- addition of alkenes would afford aminoalkylation.76 Lastly, a rare, radical−radical coupling mechanism could incorporate γ–arenes in a net, aminoarylation. Upon combination with a variety of intermolecular radical traps, a resulting α-substituted oxazoline may be hydrolyzed under acidic conditions to afford a family of 1,2- amino alcohols. Importantly,

188 each of these three radical termination mechanisms affords reactivity that is complementary to classic, two-electron strategies.

For example, radical hydroamination is an excellent alternative to traditional amination strategies (Figure 5-9). Much of the challenge involved in accomplishing 2 e– hydroamination resides in the innate thermodynamic barrier of transforming relatively stable amine and olefin reaction components into what are often less stable amine adducts.

An effective solution to correcting such unfavorable energetics has been realized in the use of electrophilic N-centered radicals as the nitrogen source. The direct oxidation of the amine to its electrophilic radical cation circumvents this energetic impasse and makes the

C–N bond formation kinetically favorable process.

Figure 5-9 Uncatalyzed vs photocatalyzed hydroamination

5.8 Hydroamination Scope

Having developed a strategy for efficient imidate generation, we decided to investigate the scope of hydroamination reaction using 1,4-cyclohexadiene as the terminal

H• reductant (Table 5-1). We found that allyl alcohols with both terminal and internal

189 olefins are hydroaminated smoothly (V-1 – V-3), as well as trisubstituted olefins (V-4).

These results illustrate that primary, secondary, benzylic, and tertiary radicals are all viable intermediates in the translocation of an imidate N-centered radical to a γ C-radical. If chloro- or silyl-substituted olefins are employed (gray circles), products bearing heteroatom functionality at three adjacent carbons are obtained (V-5 − V-6). Several natural products are also hydroaminated (V-7 − V-9), including those containing multiple alkenes−demonstrating chemoselectivity of this protocol for allyl alcohols.

190 Table 5-1 Scope of hydroamination of allylic alcohols

In the case of secondary alcohols, exclusive syn-diastereoselectivity (>20:1) is observed in all cases (V-10 - V-14), likely due to geometric constraints of the five- membered oxazoline intermediate. Interestingly, and complementary to our previous studies on H atom abstraction by imidate radicals,105 hydroamination outcompetes β C−H abstraction−even of weak, allyl or benzyl C−H bonds (V-12, V-13, highlighted with gray circles). Additionally, 5-exo-trig (vs 6-exo-trig) cyclization is solely observed. In fact,

191 using homoallylic alcohol as a substrate results only in the formation of the HAT product

(i.e. reduce oxime imidate).

Under this mild photoredox-catalyzed condition, the imidate of gibberellic ester is also efficiently converted to its β amino-alcohol (V-14) to exhibiting the mildness of the reaction condition while illustrating chemoselectivity in the presence of esters, lactones, and unprotected allyl alcohols. Interestingly, amidoximes also engaged in this hydroamination reaction (V-15). However, the reaction stalled at low conversion due to the kinetically slow SET reduction of electron rich amidoximes (~ > 1.6V vs SCE).

5.9 Radical Clock Experiment

The robust reactivity observed for these imidate radicals in the case of hydroamination via SH2 led us to question if other trapping mechanisms might also be viable by this catalytic pathway. The reactivity was initially studied by synthesizing the oxime imidate from (E)-octa-2,7-dien-1-ol. When the oxime imidate was subjected to radical cyclization reaction in the presence of 1,4-cyclohexadiene, cyclopentane was isolated. However, when acrylate was used as the terminal radical quencher, alkylation product was isolated and none of cyclopentane resulting from 5-exo-trig was observed in the crude reaction mixture. We successfully demonstrated that the rate of SH2 via cyclohexadiene is much slower than alkene trap using methyl acrylate (Figure 5-10).

192 Ph Ph N N O O ( )3 aminoalkylation MeO C MeO2C 2 acrylate traps faster 33 % than cyclization

CO2Me X

Ph Ph Ph N OPh N N [Ir] 5 -1 O kcyc > 1 x 10 s O O

hydroamination Ph Ph S 2 is slower H N N than cyclization O 3 ( ) O

H H

not observed 66 %

Figure 5-10 Radical clock experiments indicate:  addition > cyclization > SH2

5.10 Aminoalkylation Scope

With an increased efficiency of the imidate radical formation by higher photocatalyst loading and an increased effective concentration of an alkene radical trap, we were able to demonstrate alkenes are capable partners in a three-component radical coupling of imidates, alkenes, and an H atom (from oxidized electron donor) (Table 5-2).

Notably, both acrylates (V-16 – V-18) and styrenes (V-19 – V-23) function as capable partners to effect a three-component radical coupling. In these cases, both 1,1- and 1,2- disubstitution is tolerated, as well as incorporation of heteroarenes, such as 2- and 4- vinylpyridines. Although tertiary radicals (from trisubstituted allyl alcohols) afford greater

193 efficiency in this radical π-addition, simple allyl alcohols (that incorporate a primary radical intermediate) are also suitable for this aminoalkylation (e.g., V-20 vs V-21).

Table 5-2 Scope of aminoalkylation of allylic alcohols

5.11 Aryl Nitriles as Coupling Partners

In the hopes of incorporating an aryl trap within this cascade, we sought to develop an aminoarylation by a radical−radical coupling mechanism. In 1984, Arnold and co- workers demonstrated that under UV light, 1,4-dicyanobenzene and 2-methylpropene engages in photo-induced electron transfer. The first step of this transformation involves the photochemical excitation of 1,4-dicyanobenzene to its excited singlet state. This enhances its oxidizing properties so that it undergoes electron transfer from the olefin to give the corresponding olefin radical cation and cyanoarene radical anion. Two radical

194 species undergoes radical-radical recombination, with the cation quenched via nucleophilic attack by MeOH (Figure 5-11).

Figure 5-11 Mechanistic support for radical–radical coupling

We hypothesized that a radical anion of the arene is photocatalytically generated concurrently with formation of the imidate radicals, both through reductive quenching mechanisms. The ensuing cyclohexadienyl radical and the translocated alkyl radical selectively combine with one another to afford the observed products in preference to dimerization of either radicals. This was realized by aminoarylation with various aryl precursors, such as dicyano-benzene (DCB; V-24 − V-25), 4-cyano-pyridine (V-26), 4- sulfonylbenzene (V-27), 4-methylester, and perfluorinated analog (V-29) (Table 5-3).

195 Table 5-3 Scope of amino arylation of allylic alcohols

5.12 Overman Serendipitous Discovery

To further understand the reactivity of the oxime imidate, we also investigated its

2-electron chemistry, as allyl imidate reactivity is dominated by a synthetically valuable reaction wherein allyl imidates are rapidly converted to allyl amines by sigmatropic rearrangement, known as Overman rearrangement. When the oxime imidate V-S4 was treated with a palladium Lewis acid, we indeed observed [3+3] rearrangement product V-

30 as well as a 1,3-rearranged amide product. None of these products were observed under a photoredox-catalyzed difunctionalization condition; exclusively V-S5’ was isolated

(Figure 5-12).

196

Figure 5-12 Imidate complementary reactivities

5.13 Comparison to Other N(sp2) Radical Precursors

We were also intrigued by the complementarity of imidate radical reactivity with other N-centered radicals, such as those of imines and amides. First, they are synthetically orthogonal, as these imidate-based radicals are accessed from alcohols, whereas iminyl and amidyl radicals are derived from ketones or acid chlorides, respectively (Figure 5-13).

Moreover, we noted each of these N-centered radical precursors reacts differently. For example, a competition between all three radical precursors exclusively results in cyclization of the imidate radical. In this case, only oxazoline V-S1’ is formed among all three possible hydroamination products, with both the imine and amide radical precursors remaining. For iminyl precursor, interestingly, clean C=N isomerization from (E) to (Z) is observed, instead of radical reactivity.

This competitive hydroamination of the imidate (versus iminyl or amidyl) precursor

II III is also observed even with a strongly reducing catalyst, like Ir(ppy)3 (Ir /*Ir = −2.2 V vs

SCE). Kinetically, SET reduction of oxime imidate is much faster than that of oxime and

197 amide since no reduction of neither oxime nor amide is observed even in the presence of a photocatalyst that is capable of reducing the N–O bond.

Figure 5-13 Comparison of N-centered radical precursors

5.14. Future Direction

Having developed the first catalytic reaction of an imidate radical, we sought to expand this oxime imidate radical system to a general strategy toward  C–H functionalization of alcohols. Especially, using a co-operative photoredox and transition metal catalysis, there are ample opportunities to modulate the oxidation state of transition metal species that can open new pathways for efficient syntheses. To this end, we became interested in  functionzalization of alcohols via photoredox and copper dual catalytic system, termed metallaphotoredox catalysis.158 By merging the capacity of photoredox reactions to form imidate radicals from oxime imidates with the propensity of copper to 1) oxidize alkyl radicals159–161 and 2) participate in reductive elimination162 to form carbon–

198 heteroatom bonds, we envisioned highly enantioselective C–H amination of alcohols using

Ir and Cu dual catalytic system (Figure 5-14). Instead of utilizing a stoichiometric amount of tri-alkylamine as an electron donor, the reduction of the excited state Ir(III)* to strongly reducing Ir(II) is coupled with the oxidation of Cu(I) to Cu(II). The ensuing Ir(II) species reduces an oxime imidate to afford an imidate radical. This then undergoes  selective

HAT to form a carbon radical that is enantioselectively trapped by the Cu(II)L* species.

The resulting copper-metallocycle engages in reductive elimination to yield an oxazoline that may be hydrolyzed under acidic conditions to afford chiral  amino alcohols.

Figure 5-14 Enantioselective  C–H amination of alcohols

The architecture of the imidate substitution proves to be crucial in this C–N bond formation. Concurrently, ligand investigation as well as additive effects are being investigated toward a more stereoselective  amination reaction.

199

5.15 Experimental Section

5.15.1 General Information