FUNCTIONALIZATION OF HETEROCYCLES: A METAL CATALYZED APPROACH VIA ALLYLATION AND C-H ACTIVATION A Dissertation Submitted to the Graduate Faculty of the North Dakota State University of Agriculture and Applied Science By Sandeepreddy Vemula In Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Major Department: Chemistry and Biochemistry October 2018 Fargo, North Dakota North Dakota State University Graduate School Title FUNCTIONALIZATION OF HETEROCYCLES: A METAL CATALYZED APPROACH VIA ALLYLATION AND C-H ACTIVATION By Sandeepreddy Vemula The Supervisory Committee certifies that this disquisition complies with North Dakota State University’s regulations and meets the accepted standards for the degree of DOCTOR OF PHILOSOPHY SUPERVISORY COMMITTEE: Prof. Gregory R. Cook Chair Prof. Mukund P. Sibi Prof. Pinjing Zhao Prof. Dean Webster Approved: November 16, 2018 Prof. Gregory R. Cook Date Department Chair ABSTRACT The central core of many biologically active natural products and pharmaceuticals contain N-heterocycles, the installation of simple/complex functional groups using C-H/N-H functionalization methodologies has the potential to dramatically increase the efficiency of synthesis with respect to resources, time and overall steps to key intermediate/products. Transition metal-catalyzed functionalization of N-heterocycles proved as a powerful tool for the construction of C-C and C-heteroatom bonds. The work in this dissertation describes the development of palladium catalyzed allylation, and the transition metal catalyzed C-H activation for selective functionalization of electron deficient N-heterocycles. Chapter 1 A thorough study highlighting the important developments made in transition metal catalyzed approaches for C-C and C-X bond forming reactions is discussed with a focus on allylation, directed indole C-2 substitution and vinylic C-H activation. Chapter 2 describes the development of a selective Tsuji-Trost allylation reaction of electron deficient heterocycles. The key issues addressed in this chapter include an extensive investigation of mechanistic details, and factors influencing selectivity control of tautomerizable heteroarenes to form linear N-allylated products. Chapter 3 describes the oxidative allylic C-H amidation reaction of N-heterocycles, an efficient and atom economic variant of traditional allylation. A simple protocol avoiding the use of expensive catalysts/ ligands or additives for allylation of N-heterocycles is demonstrated. Mechanistic investigation indicated the importance of Pd(II)/DMSO catalytic system for the allylic C-H activation, allowing for the efficient synthesis of -allylpalladium chloride catalysts. Chapter 4 describes a detailed investigation on the development of an unusual -bond directed indole C-2 amidation. A mechanism-based reaction optimization, and comparison of iii effectiveness of both Pd and Ni catalyst system indicated the effectiveness of NiCl2 for the -bond directed indole C-2 substitution. Mechanistic studies also shed light on the dual role of solvent system (DCE: DMSO), acting both as ligand (DMSO) and as an oxidant (DCE) for the regeneration of active Ni(II) catalyst. Chapter 5 describes the development of a ruthenium catalyst system for the synthesis of fused quinazolinones via vinylic C-H/amide N-H bond activation/alkyne annulation. This chapter also describes the utilization of quinazoline core as a masked pyridine template for the synthesis highly substituted pyridines via amide alcoholysis. iv ACKNOWLEDGEMENTS I would like to first thank Professor Gregory R. Cook for accepting me into your research group. Nothing of this would have been possible without your support and guidance throughout my stay in NDSU. You provided a work conditions composed of the right mix of freedom and flexibility, and the need for results and progress. I thank you for your patience and for encouraging me to remain in my doctoral studies through difficult times. I could not have asked for a better experience in graduate school, and I want you to know that I will forever appreciate all the time and effort you invested for me to reach this point. Thanks again! I would also like to thank Prof. Mukund P. Sibi, Prof. Pinjing Zhao and Prof. Dean Webster for being in my committee and helping in many ways to direct my research in the right path. A special thanks to Prof. Sibi for being there for me, whenever I needed any help. I have learned a lot from you and it was always a pleasure discussing with you in combined group meetings. Your passion for science and genuine interest in my progress inspired me to give the best in graduate school. I cannot proceed further without thanking Dr. Dinesh Kumar. You truly are the leader, who kept me motivated, and pushed my limits introducing to various aspects of chemistry. Much of what has been accomplished could not have been without your help and guidance. You are a great friend, mentor, and coworker. I will surely miss both personal and scientific discussions with you. I would like to thank all the supporting staff in the Department of Chemistry and Biochemistry for their help and support. A special thanks to Dr. Angel Ugrinov for his patience and help in solving X-ray crystal structures and helping with GCMS and HRMS. I would also like to thank Dr. John Bagu and Daniel Wanner for training me and helping me with NMR studies. I v am grateful to Wendy Leach, Linda Stoetzer, Dionna Martel, Amy Kain, Tina Exner, and Cole Larsen for their continuous help and for taking care of all my administrative requirements. I would also like to acknowledge NSF-ND EPSCoR for providing me with doctoral dissertation assistantship, and college of science, NDSU for providing multiple travel grants for attending conferences. I also like to thank past and present members of the Cook group. A special thanks to Michael Chhoun for being the best coworker in the lab and training me in lifting weights. I wish you nothing but success as you continue your career. I also extend my thanks to past and present members of Sibi group, Zhao group and Siva group for all their help, be it letting me borrow chemicals or answering all my questions, and for creating a healthy, competitive work environment. Life in graduate school would have been stressful without the support from my friends. A special thanks to Chandu, Eric, Rajith, Nandini, Naveen, Dayananda, and Sunil for all the professional and personal support. Most importantly, I’d like to thank my family and close friends for your unconditional love and support. My parents, sister and brother in law have always believed in me and encouraged in each and every step of my life. A special thanks to my wife (Anusha), you are my greatest gift, and meeting you was the best thing happened in my life. There’s nothing comparable to the love and devotion that you guys have given me. vi DEDICATION To my parents without whose love and support this would never have been possible vii TABLE OF CONTENTS ABSTRACT ................................................................................................................................... iii ACKNOWLEDGEMENTS ............................................................................................................ v DEDICATION .............................................................................................................................. vii LIST OF TABLES ....................................................................................................................... xiv LIST OF FIGURES ..................................................................................................................... xvi LIST OF SCHEMES................................................................................................................... xvii LIST OF ABBREVIATIONS ...................................................................................................... xxi CHAPTER 1. TRANSITION METAL CATALYZED FUNCTIONALIZATION OF TAUTOMERIZABLE N-HETEROCYCLES ................................................................................ 1 1.1. Introduction .......................................................................................................................... 1 1.2. Transition metal catalysis for functionalization ................................................................... 3 1.3. Tsuji-Trost allylation/ palladium catalyzed allylic substitution ........................................... 5 1.3.1. Early discovery/ C-C bond formation ........................................................................... 5 1.3.2. Mechanistic understanding of allylic alkylation ............................................................ 7 1.3.3. Allyl alcohols in the Tsuji-Trost reaction .................................................................... 10 1.4. Palladium catalyzed allylic C-H activation ........................................................................ 11 1.4.1. Allylic acetoxylation: development of catalytic allylic C-H activation reactions ....... 13 1.4.2. Palladium catalyzed allylic C-H oxidative C-C bond formation ................................. 15 1.5. Directed indole C-2 functionalization ................................................................................ 16 1.5.1. C-H activation for indole C-2 functionalization .......................................................... 16 1.5.2. Transition metal catalyzed directed dehydrogentative cross-coupling for C-C bond formation at indole C-2 position..................................................................................