Synthesis and Reactivity of Aryl(trifluoromethyl)diazomethane Compounds by Kevin Chung Yin Ma A thesis presented to the University of Waterloo in fulfillment of the thesis requirement for the degree of Master of Science in Chemistry Waterloo, Ontario, Canada, 2020 © Kevin Chung Yin Ma 2020 Author’s Declaration I hereby declare that I am the sole author of this thesis. This is a true copy of the thesis, including any required final revisions, as accepted by my examiners. I understand that my thesis may be made electronically available to the public. ii Abstract Fluorine has a prominent role in organic chemistry and the pharmaceutical industry due to the unique properties it imparts. Naturally, trifluoromethyl groups (CF3) share similar qualities and many methods have been developed for its inclusion into molecules. Historically, indirect trifluoromethylation was used until the advent of more robust direct methods. Of the three categories, direct electrophilic trifluoromethylation has grown slowly until relatively recently since the introduction of the Togni reagent, a hypervalent iodine (HVI) compound. HVI compounds have found interest as safer and cheaper alternatives to traditional metal-based reagents and benziodoxoles in particular are used for ligand transfer reactions. Diazo groups are versatile functionalities that have a wide range of applications and syntheses. Apart from diazo group transfer reagents, hydrazones and their substituted derivatives serve as common precursors to diazo compounds. The Bamford-Stevens reaction of tosylhydrazones is one efficient pathway to the formation of diazoalkanes. The trifluoromethylation of diazo compounds and hydrazones as their precursors has found limited success and exploration into this area of research could serve useful towards the production of trifluoromethylated building blocks. A simultaneous diazotization and trifluoromethylation of arylaldehyde tosylhydrazones has been found and the conditions of this procedure are explored in various venues. Discussions behind its mechanism are also speculated upon due to the formation of various side products. The reactivity and application of these trifluoromethylated diazo compounds will be investigated towards the recent rise in visible light-mediated reactions, especially for diazo compounds. The blue light photocatalysis of aryl(trifluoromethyl)diazomethane compounds is explored in the context of cyclopropanation and has seen initial success. Further investigation will prove useful in understanding this new area of photochemistry of diazo compounds. iii Acknowledgements I would first like to sincerely thank my supervisor, Prof. Graham Murphy, for his continual support and guidance over the past three years. I am forever thankful for this opportunity and have learned much more than I would have ever expected. I would also like to thank my advisory committee, Prof. Michael Chong and Prof. Derek Schipper for all their support. I would like to further extend my gratitude to Prof. Michael Chong from whom I have learned many things in the classroom, in the lab, and in his chemistry magic shows. I would like to thank Jan Venne for all her support and assistance with NMR. I would also like to thank Dr. Richard Smith and Val Goodfellow for their help on mass spectrometry, as well as Julie Goll for allowing me use of the IR spectrometer. I would like to extend my gratitude to Dr. Laura Ingram, Dr. Kristina Lekin, and Prof. Monica Barra with whom I had the pleasure of working as a teaching assistant, it was a great learning experience. To the members of the Murphy lab, past and present, I thank you for the support and company I have been given throughout the years. It would not have been possible without you all. I owe my deepest gratitude to Avery To for all he has done for me. For the companionship, indulging in my endless questions, and assuaging my constant doubts, I do not have enough words to express my appreciation for everything and I truly thank him. I would also like to take this opportunity to thank Dr. Leanne Racicot, without whom this experience would have been less manageable, and I will fondly remember the steady support, guidance, and kindness she has given me. I would like to thank Fabio Cuzzucoli and Dr. Zhensheng Zhao for the encouragement and fun times shared in the lab. I would also like to thank Tristan Chidley, Islam Jameel, and Liam Britt for their assistance, ideas, and inspiring passion for chemistry. Lastly, I thank my friends and family for their continual support in keeping me hopeful towards this goal and the future. It has been quite the journey. iv Dedication For my loving family, Wency, John, and Brian v Table of Contents Author’s Declaration .............................................................................................................................. ii Abstract ................................................................................................................................................. iii Acknowledgements ............................................................................................................................... iv Dedication .............................................................................................................................................. v List of Figures ..................................................................................................................................... viii List of Schemes ...................................................................................................................................... x List of Tables ...................................................................................................................................... xiii List of Abbreviations .......................................................................................................................... xiv Chapter 1 : Fluorine and Trifluoromethyl Groups ................................................................................. 1 1.1 Fluorine Background ................................................................................................................. 1 1.2 Properties of Fluorine ................................................................................................................ 5 1.3 Physico-chemical and Conformational Effects of Fluorination ................................................ 7 1.4 Trifluoromethyl Groups (CF3) ................................................................................................. 11 1.5 Indirect Trifluoromethylation .................................................................................................. 16 1.6 Direct Trifluoromethylation .................................................................................................... 21 1.6.1 Nucleophilic Reagents ................................................................................................... 22 1.6.2 Radical Reagents ............................................................................................................ 27 1.6.3 Electrophilic Reagents ................................................................................................... 30 Chapter 2 : Hypervalent Iodine (HVI) ................................................................................................. 44 2.1 Background and Properties ...................................................................................................... 44 2.2 Reactivity and Applications .................................................................................................... 46 2.3 Benziodoxoles ......................................................................................................................... 50 2.4 Togni Reagent ......................................................................................................................... 54 Chapter 3 : Aryl(trifluoromethyl)diazomethane Compounds .............................................................. 58 3.1 History and Properties of Diazo Compounds .......................................................................... 58 vi 3.2 General Synthesis of Diazo Compounds ................................................................................. 61 3.3 Hydrazones and the Bamford-Stevens Reaction ...................................................................... 63 3.4 Proposal ................................................................................................................................... 70 3.5 Synthesis of Aryl(trifluoromethyl)diazomethanes ................................................................... 72 3.6 Other Side Products ................................................................................................................. 83 3.7 Discussion ................................................................................................................................ 89 3.8 Conclusions and Future Work ................................................................................................. 92 3.9 Experimental and Spectral Data ............................................................................................... 93 3.9.1 General Experimental Details......................................................................................... 93 3.9.2 General Procedure A: Synthesis of Tosylhydrazones .................................................... 95 3.9.3 General Procedure B: Synthesis of Aryl(trifluoromethyl)diazomethanes