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AROMATIC FUNCTIONALIZATION AND HETEROCYCLE SYNTHESIS VIA ANILINE N-OXIDES by Hayley Reed A dissertation submitted to the Faculty of the University of Delaware in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry and Biochemistry Summer 2020 © 2020 Hayley Reed All Rights Reserved AROMATIC FUNCTIONALIZATION AND HETEROCYCLE SYNTHESIS VIA ANILINE N-OXIDES by Hayley Reed Approved: __________________________________________________________ Brian J. Bahnson, Ph.D. Chair of the Department of Chemistry and Biochemistry Approved: __________________________________________________________ John Pelesko, Ph.D. Dean of the College of Arts and Sciences Approved: __________________________________________________________ Douglas J. Doren, Ph.D. Interim Vice Provost for Graduate and Professional Education and Dean of the Graduate College I certify that I have read this dissertation and that in my opinion it meets the academic and professional standard required by the University as a dissertation for the degree of Doctor of Philosophy. Signed: __________________________________________________________ William J. Chain, Ph.D. Professor in charge of dissertation I certify that I have read this dissertation and that in my opinion it meets the academic and professional standard required by the University as a dissertation for the degree of Doctor of Philosophy. Signed: __________________________________________________________ Mary P. Watson, Ph.D. Member of dissertation committee I certify that I have read this dissertation and that in my opinion it meets the academic and professional standard required by the University as a dissertation for the degree of Doctor of Philosophy. Signed: __________________________________________________________ Klaus H. Theopold, Ph.D. Member of dissertation committee I certify that I have read this dissertation and that in my opinion it meets the academic and professional standard required by the University as a dissertation for the degree of Doctor of Philosophy. Signed: __________________________________________________________ Jacob R. LaPorte, Ph.D. Member of dissertation committee ACKNOWLEDGMENTS Graduate school has been one of the most difficult challenges of my life. I owe thanks to many people for the fact that I have made it through to the other side. To my advisor, Professor William Chain: Your advice, support and trust throughout these five years has made this possible. Thank you for the freedom and assistance that enabled me to pursue a non-traditional career path. It was not something you had to do and I will always be grateful for it. To my committee members, Professor Mary Watson, Professor Klaus Theopold, and Dr. Jacob LaPorte: Thank you for all your support throughout my Ph.D. career. I am grateful for all the guidance you provided. To Rachel Putnik, Elijah Hudson and Tyler Swanson: You were the best office mates and colleagues I could ask for. I will miss our time together. Good luck with the next three years. I wish you all the best. To Tyler Paul, Vedant Submaranian, and Steven Liu: You all have helped make this work possible. I hope you learned as much from me as I did from you. To Megan Hoerrner: If there is one person without whom I would not have been able to finish graduate school, it would be you. From recruitment weekend roommates to now, I cannot thank you enough for your friendship and support over these five years. I would not have made it through this part of my life without you. In addition to the challenges graduate school presented and the relationships formed during it, many people beyond the walls of the University of Delaware have had a hand in shaping who I am today. iv To Mrs. Roach, Mrs. Wakefield, and Mr. Rockey: You were the teachers who told me that it was possible for a kid to be quiet and reserved but also capable and determined. You made up for all the teachers who doubted me. I hope all the future kids like me have someone like you to tell them that they belong. To Mrs. Mills: When you hired me as a lab aide in high school, you probably didn’t realize how many doors that would open for me. So many of my experiences and opportunities over the years can be traced back to that job. Thank you for your trust and support. To the Allens: I have known all of you for longer than I care to admit. I hope that one day I will be as smart as you think I am. To my grandmother: the childhood summers spent with you that were filled with Uno, puzzles, and water ice are some of the clearest memories I have. You are one of the major reasons I decided to swerve onto a different career path. I wish you could understand how big of an impact you had on who I am and who I want to be. To my brother Jordan: You are and have always been a high standard to which to hold myself. Maybe someday, I will reach it. To my mom: You have always had my back. Everything I do is possible because you have made it so. To Ryan: I don’t even need to say. You just know. v TABLE OF CONTENTS LIST OF TABLES ......................................................................................................... x LIST OF FIGURES ...................................................................................................... xii ABSTRACT ............................................................................................................... xvii Chapter 1 APPLICATIONS OF ANILINE N-OXIDES IN SYNTHETIC CHEMISTRY ..................................................................................................... 1 1.1 Traditional Methods of Aromatic Functionalization ................................. 3 1.2 The Synthetic Potential of Aniline N-Oxides ............................................ 8 1.3 An Overview of Synthetic Exploitation of N–O Bonds ............................ 9 1.4 The Discovery of a Route for Aniline Functionalization ........................ 14 1.5 Previous Investigations into Aniline N-Oxide Functionalization ........... 17 1.6 Possible Mechanisms of Functionalization ............................................. 20 1.7 Indoline Synthesis via Tandem Polonovski-Mannich Reaction ............. 22 1.8 Aim of This Dissertation ......................................................................... 24 REFERENCES ............................................................................................................. 26 2 SYNTHESIS OF HALOGENATED ANILINES BY TREATMENT OF N,N-DIALKYLANILINE N-OXIDES WITH THIONYL HALIDES ............ 34 2.1 Introduction ............................................................................................. 34 2.1.1 Traditional Methods of Preparing Halogenated Anilines ........... 37 2.1.2 Exploiting N–O Bonds for Aromatic Halogenation .................... 38 2.1.3 Proposed Work ............................................................................ 41 2.2 Results and Discussion ............................................................................ 42 2.2.1 Synthesis of N,N-Dialkylaniline N-Oxides ................................. 42 2.2.2 Optimization of Thionyl Bromide as Brominating Agent .......... 43 2.2.3 Scope of Bromination with Thionyl Bromide ............................. 46 2.2.4 Optimization of Phosphoryl Chloride as a Chlorinating Agent .. 48 2.2.5 Optimization of Thionyl Chloride as a Chlorinating Agent ........ 49 vi 2.2.6 Scope of Chlorination with Thionyl Chloride ............................. 51 2.2.7 Mechanistic Investigations .......................................................... 53 2.3 Conclusion ............................................................................................... 57 2.4 Experimental ........................................................................................... 58 2.4.1 General Information .................................................................... 58 2.4.2 Synthesis of N,N-Dialkylanilines ................................................ 60 2.4.3 Oxidation of N,N-Dialkylanilines ............................................... 82 2.4.4 Bromination N,N-Dialkylaniline N-Oxides ................................. 98 2.4.5 Chlorination N,N-Dialkylaniline N-Oxides ............................... 118 REFERENCES ........................................................................................................... 137 3 PREPARATION OF TETRAHYDROQUINOLINE SCAFFOLDS FROM N,N-DIALKYLANILINE N-OXIDES VIA TANDEM POLONOVSKI- POVAROV CYCLIZATION SEQUENCE ................................................... 141 3.1 Introduction ........................................................................................... 141 3.1.1 An Overview of Tetrahydroquinoline Synthesis ....................... 142 3.1.2 Discovery of the Tandem Polonovski-Povarov Cyclization via Aniline N-Oxides ...................................................................... 144 3.1.3 Past Chain Group Work in Tetrahydroquinoline Synthesis ...... 147 3.1.4 Proposed Work .......................................................................... 148 3.2 Results and Discussion .......................................................................... 149 3.2.1 Synthesis of N,N-Dialkylaniline N-Oxide 3-Chlorobenzoic Acid Salts .................................................................................. 149 3.2.2 Polonovski-Povarov Cyclizations with N-Vinylpyrrolidone .... 150 3.2.3 Polonovski-Povarov Cyclizations with 2-Phenylpropene ......... 151 3.2.4 Derivatives of Tetrahydroquinoline Scaffolds .......................... 153 3.2.5 Mechanistic Investigations

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