From H to F: Strategies in Selective sp3 C-H Fluorination BY STEVEN P. BLOOM A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland March, 2015 ABSTRACT The replacement of a single hydrogen atom by fluorine can impart a unique set of chemical and physical properties onto organic molecules, oftentimes modifying their reactivity. In many instances, fluorination improves the metabolic stability of pharmaceuticals, amplifies the electronic properties of polymers, and heightens the efficiency of industrial solvents and surfactants. Despite these and others, fluorination methods have endeavored to become commonplace, a fact consistent with the lack of synthetically mild sources of atomic fluorine. Until recently, fluorination strategies have been predicated upon the use of harsh, unselective, and often destructive sources of fluorine, such as fluorine gas and explosive hypofluorites, limiting their synthetic utility. Over the last 20 years, the advent of bench-top stable N-F reagents have incurred a renaissance in the discovery of regio- and chemoselective methods for the direct incorporation of fluorine atoms into organic molecules. In this Dissertation, the applications of one such N-F compound, 1-chloromethyl-4- fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) is highlighted as a practical reagent for the monofluorination of unactivated sp3 C-H bonds of aliphatic, benzylic, and allylic containing compounds in conjunction with earth-abundant, inexpensive transition metals and commercially available photocatalysts. The use of Selectfluor in the α,α-difluorination of acid chloride derivatives and photocatalyzed ring opening-β-fluorination of cyclopropanols is ii likewise discussed. Mechanistic evidence suggests the involvement of putative carbon-centered radicals (or radical ions) during fluorination with Selectfluor acting as a versatile fluorine atom transfer reagent. Adviser: Professor Thomas Lectka Readers: Professor Gary H. Posner Professor Christopher Falzone iii FOR MY FAMILY & FRIENDS iv ACKNOWLEDGEMENTS First and foremost, I would like to extend my sincere gratitude to my adviser, Prof. Thomas Lectka. Tom, I will always be grateful for the opportunity to have been a member of your group. Over the last four years, not only have you provided me the chance to grow as an independent scientist, often allowing me pursue projects of my own interest in whatever manner I saw fit, but taught me to be a better writer, colleague, mentor, and above all else, a successful researcher. Perhaps more importantly Tom, you have inspired within me the ability to think creatively, and the courage to go after the really tough problems as they are often the most challenging, but equally the most rewarding. What is more, youʼve taught me not only how to excel when times are good and the research plentiful, but endure when things donʼt go exactly to plan and “Use the lemons you got to make lemonade”. Through all the good and bad experiences, I will always appreciate everything you have done for me, and be proud to call you a friend. I only hope that in wherever life takes me, and in whatever I do, I can continue to make you proud. I must also extend my thanks to both Prof. Gary H. Posner and Prof. Christopher Falzone. Prof. Posner, thank you for your constant support, providing both advice for my academic career, and in the laboratory with the use of your chemicals and equipment. I would also like to take a moment to thank you for your financial support as well. It is my distinct honor to have been a v recipient of the Gary H. Posner Fellowship, an award I will always hold dear. I wish you a well-deserved retirement, good health, and happiness in your future endeavors. Prof. Falzone, thank you for serving on my committee and allowing me to TA for you. You are an incredibly gifted teacher, and person. I have had the distinct pleasure of mentoring many of your past students in our laboratory, and honestly, they have been some of our most successful students, no doubt, a reflection on your prowess in the classroom. Finally, I would like to thank my family, and friends in particular Maxwell Ederer, David Goodwin, Katie Holmes, Ryan OʼDonnell, John Scheckelton, Alsion McQuicken, and Heather and Jesse Neu. All of you have made this a memorable journey, and some of the best years of my life. I hope you guys know I will always be there for you, even if I donʼt respond immediately, and wish you each a prosperous and intoxicating future. I would be remiss not to extend a much-deserved thank you to my fellow lab mates Cody Ross Pitts and Mark Struble as well. Thank you for reading my papers/correcting all my grammar, as well as lending an ear, and providing a much needed support group throughout graduate school. Good luck in the rest of your graduate school careers, I know youʼll do great things. For all those whose support has made this possible, I dedicate this dissertation to you. vi PUBLICATIONS DRAWING UPON THIS DISSERTATION (1) Bloom, S.; Bume, D. D.; Pitts, C. R.; Lectka, T. “A Site-Selective Approach to β-Fluorination: Photocatalyzed Ring Opening of Cyclopropanols. Angew. Chem. 2015, submitted (2) Bloom, S.; McCann, M.; Lectka, T. "Photocatalyzed Benzylic Fluorination: Shedding “Light” on the Involvement of Electron Transfer" Org. Lett. 2014, 16, 6338-6341. (3) Griswold, A.; Bloom, S.; Lectka, T. "A Chelating Nucleophile Plays a Starring Role: 1, 8- Naphthyridine- Catalyzed Polycomponent α,α- Difluorination of Acid Chlorides" J. Org. Chem. 2014, 79, 9830-9834. (4) Bloom, S.; Knippel, J. L.; Holl, M. G.; Barber, R.; Lectka, T. "A cooperative allylic fluorination: combination of nucleophilic and electrophilic fluorine sources" Tetrahedron Lett. 2014, 55, 4576-4580. (5) Pitts, C. R.; Bloom, S.; Woltornist, R.; Auvenshine, D. J.; Ryzhkov, L. R.; Siegler, M. A.; Lectka, T. "Direct, Catalytic Monofluorination of sp3 C-H Bonds: A Radical- Based Mechanism with Ionic Selectivity" J. Am. Chem. Soc. 2014, 136, 9780-9791 (6) Bloom, S.; Knippel, J. L.; Lectka, T. "A photocatalyzed aliphatic fluorination" Chem. Sci. 2014, 5, 1175-1178. vii (7) Bloom, S.; Sharber, S. A.; Holl, M. G.; Knippel, J. L.; Lectka, T. "Metal- Catalyzed Benzylic Fluorination as a Synthetic Equivalent to 1, 4- Conjugate Addition of Fluoride" J. Org. Chem. 2013, 78, 11082-11086. (8) Bloom, S.; Pitts, C. R.; Woltornist, R.; Griswold, A.; Holl, M. G.; Lectka, T. "Iron(II)-Catalyzed Benzylic Fluorination" Org. Lett. 2013, 15, 1722- 1724. (9) Bloom, S.; Pitts, C. R.; Miller, D.; Haselton, N.; Holl, M. G.; Urheim, E.; Lectka, T. "A Polycomponent Metal-Catalyzed Aliphatic, Allylic, and Benzylic Fluorination" Angew. Chem. Int. Ed. 2012, 51, 10580-10583. (10) Bloom, S.; Scerba, M. T.; Erb, J.; Lectka, T. "Tricomponent Catalytic α,α-difluorination of Acid Chlorides" Org. Lett. 2011, 13, 5068-5071. viii TABLE OF CONTENTS Title Page i Abstract ii Dedication iv Acknowledgements v Publications Drawing Upon this Dissertation vii Table of Contents ix List of Schemes xiv List of Figures xvii List of Tables xix List of Equations xxi CHAPTER 1: INTRODUCTION 1.1) Introduction to Organofluorine Chemistry 1 1.2) Properties of Fluorine 2 1.3) Medicinal Applications of Organofluorine Compounds 4 1.4) Synthesis of Organofluorine Compounds 6 CHAPTER 2: TRICOMPONENT CATALYTIC α,α- DIFLUORINATION OF ACID CHLORIDES 2.1) α-Fluorination of Carbonyl-Containing Compounds 13 2.2) Tricomponent Methodology 15 2.3) Concluding Remarks 19 ix CHAPTER 3: A CHELATING NUCLEOPHILE PLAYS A STARRING Role: 1,8-NAPHTHYRIDINE-CATALYZED POLYCOMPONENT α,α-DIFLUORINATION OF ACID CHLORIDES 3.1) Introduction to Chelating Nucleophiles 20 3.2) Optimized Tricomponent Methodology 21 3.3) Mechanistic Insight 25 3.4) Concluding Remarks 28 CHAPTER 4: A POLYCOMPONENT METAL-CATALYZED ALIPHATIC, ALLYLIC, AND BENZYLIC FLUORINATION 4.1) Introduction to sp3 C-H Fluorination 29 4.2) Metal Catalyzed Methodology 30 4.3) Mechanistic Insight 35 4.4) Concluding Remarks 36 CHAPTER 5: IRON(II)-CATALYZED BENZYLIC FLUORINATION 5.1) Introduction to Benzylic Fluorination 37 5.2) Metal Catalyzed Methodology 38 5.3) Computational Insight 42 5.4) Concluding Remarks 42 CHAPTER 6: METAL-CATALYZED BENZYLIC FLUORINATION AS A SYNTHETIC EQUIVALENT TO 1,4-CONJUGATE ADDITION OF FLUORIDE x 6.1) Introduction to β-fluorination 44 6.2) Metal Catalyzed Methodology 45 6.3) Mechanistic Insight 49 6.4) Concluding Remarks 51 CHAPTER 7: DIRECT, CATALYTIC MONOFLUORINATION OF sp3 C-H BONDS: A RADICAL-BASED MECHANISM WITH IONIC SELECTIVITY 7.1) Mechanism for the copper(I) Catalyzed Fluorination of Alkanes 52 7.2) Simplified Protocol 56 7.3) Loss of Fluoride from copper(I)-Selectfluor Interaction 59 7.4) UV-Vis and EPR Analyses Indicate copper(II) Species 61 7.5) Initiation by Single-Electron Transfer 68 7.6) Involvement of Alkyl Radicals 74 7.7) Inductions period 79 7.8) Rate dependence 82 7.9) KIE 83 7.10) Proposed Mechanism 86 7.11) Role of Valence Bond “Ionicity” in Reaction Selectivity 88 7.12) Polar Effect 90 7.13) Concluding Remarks 95 xi CHAPTER 8: A COOPERATIVE ALLYLIC FLUORINATION: COMBINATION OF NUCLEOPHILIC AND ELECTROPHILIC FLUORINE SOURCES 8.1) Introduction to Allylic Fluorination 96 8.2) Allylic Fluorination Methodology 98 8.3) Mechanistic Insight 102 8.4) Concluding Remarks 104 CHAPTER 9: A PHOTOCATALZED ALIPHATIC FLUORINATION 9.1) Introduction to Photocatalysis 105 9.2) Photocatalyzed Methodology 106 9.3) Mechanistic Insight 111 9.4) Concluding Remarks