ADVANCES IN THE SYNTHESIS OF INDAZOLES: REGIOSELECTIVE C-7 FUNCTIONALIZATION BY DIRECTED ORTHO METALATION AND PROGRESS TOWARDS INDAZOLE BASED AZABORINE COMPOUNDS By Fu Cullen A thesis submitted to the Department of Chemistry In conformity with the requirements for the degree of Master of Science Queen’s University Kingston, Ontario, Canada (January, 2017) Copyright © Fu Cullen, 2017 Abstract As one of the fundamental heterocyclic building blocks, indazole and its derivatives have spurred significant research interest and patented applications. In particular, C-7 substituted indazole derivatives are of prime interest due to their significant bioactivities. Azaborine molecules incorporating the B-N structural motif are also of prime interest to chemists and material scientists stemming from their distinctive photophysical properties. The aim of this thesis is to construct new azaborine targets incorporating the indazole framework using Directed ortho Metalation (DoM) reactions as a key step, as well as devise new methods for C-7 functionalization of indazole heterocycles using DoM reactions. Successful N-1 functionalization of indazoles enabled the subsequent Suzuki-Miyaura or Sonogashira cross coupling reactions to prepare C-3 substituted indazoles. Efforts in Directed ortho Metalation (DoM) reactions at the C-3 aryl groups of substituted indazoles towards azaborine targets were unsuccessful. Internal alkyne bearing substituted indazole was subjected to hydroboration conditions but without any conversion to the desired products. C-3 protected Indazoles bearing N- Directed Metalation Groups (DMGs) enabled their C-7 functionalization using DoM chemistry, and thereby led to the development of a new general route to these derivatives. ii Acknowledgements Aromatic and heteroaromatic molecules are arguably some of the most important chemical compounds to ever exist. Such is the way that nature had built the world, atom by atom, to form the stars, the planets, and life in the universe. By mastering these molecules - their properties, structures and reactivity, chemists can shape and enrich the human experience unlike any other: energy security, climate stability, alleviating poverty, economic prosperity, and preserving life itself are just some of the endeavors where we may find chemists playing such a pivotal role. I would like to express my utmost respect and gratitude towards Professor Wang and Professor Snieckus for their willingness to supervise the completion of my M.Sc. thesis. It is a privilege to explore the frontiers of organic synthesis under their guidance and patronage. I would like to thank Professor Macartney and Professor Zechel being members of my graduate supervisory committee, and especially to Professor Macartney for his internal review I would like to thank Professor Jerkiewicz, Professor Jessop and Professor Ross for being members of the examination committee. Finally, to my family, friends and the many professors, mentors, and teachers who helped to make a difference in my time spent here at Queen’s University, thank you! iii Table of Contents Abstract ......................................................................................................................................................... ii Acknowledgements ...................................................................................................................................... iii List of Schemes............................................................................................................................................. vi List of Figures ............................................................................................................................................. viii List of Tables ................................................................................................................................................ ix List of Abbreviations ..................................................................................................................................... x Chapter 1 Introduction ................................................................................................................................. 1 1.1 Indazoles ............................................................................................................................................. 1 1.1.1 Introduction to Indazoles ............................................................................................................. 1 1.1.2 Structure and Properties of Indazoles ......................................................................................... 2 1.1.3 Reactivity of Indazoles ................................................................................................................. 4 1.1.4 Bioactivity and Material Science Applications of Indazoles ......................................................... 8 1.1.5 C-7 Substituted Indazoles .......................................................................................................... 10 1.2 Organometallic Reactions ................................................................................................................. 13 1.2.1 The Directed ortho Metalation (DoM) Reaction: An Overview ................................................. 13 1.2.2 The DoM Reaction: Directed Metalation Groups (DMGs) ......................................................... 14 1.2.3 The DoM Reaction: Mechanism ................................................................................................. 16 1.2.4 The DoM Reaction: The Directed remote Metalation (DreM) ................................................... 20 1.2.5 Grignard Reactions: An Overview .............................................................................................. 23 1.3 N,C-Chelating Organoboron Compounds and Azaborines ............................................................... 24 1.3.1 Introduction to Azaborines ........................................................................................................ 24 1.3.2 Key advancement of Azaborines ................................................................................................ 26 1.3.3 Four-Coordinate Chelated Organoboron Compounds .............................................................. 30 1.3.4 Recently Synthesized Azaborines ............................................................................................... 37 Chapter 2 Indazole Based Azaborines and the DoM Reaction of Indazoles ............................................... 41 2.1 The DoM Approach towards Indazole-based Azaborines ................................................................. 41 2.1.1 Project Aims ............................................................................................................................... 41 2.1.2 N-1 Protection of 3-Iodo-1H-indazole ........................................................................................ 42 2.1.3 C-3 Functionalization of Indazoles via Suzuki-Miyaura Cross Coupling Reactions .................... 42 2.1.4 Directed ortho Metalation of N-Benzyl 3-Aryl Indazoles ........................................................... 45 2.1.5 Debenzylation Attempts ............................................................................................................ 47 iv 2.1.6 DoM of N-H 3-Aryl Indazoles ..................................................................................................... 49 2.1.7 DoM of N-1 Protected 3-Aryl Indazoles ..................................................................................... 51 2.2 C-7 Functionalization of Substituted Indazoles ................................................................................ 54 2.2.1 Project Aims ............................................................................................................................... 54 2.2.2 C-3 Protection of 1H-Indazole .................................................................................................... 55 2.2.3 N-1 Functionalization of 3-chloro-1H-Indazole .......................................................................... 56 2.2.4 Optimizing C-7 DoM Reaction Conditions ................................................................................. 56 2.2.5 DoM of Substituted Indazoles .................................................................................................... 59 2.3 Hydroboration Approach Towards Indazole Based N,C-Chelating Organoboron Compounds ........ 61 2.3.1 Project Aims ............................................................................................................................... 61 2.3.2 C-3 Functionalization of Indazoles via Sonogashira Cross Coupling Reactions ......................... 62 2.3.3 De-Silylation of 3-(TMS-Acetylene) Indazoles ............................................................................ 63 2.3.4 Hydroboration Reactions ........................................................................................................... 65 2.4 Conclusion and Future Work ............................................................................................................ 68 2.5 Experimental Section ........................................................................................................................ 70 2.5.1 General Information .................................................................................................................. 70 2.5.2 Representative