PART I: PALLADIUM-PEPPSI-IPENTCl; A USEFUL CATALYST FOR CHALLENGING AMINATION REACTIONS PART II: GENERATION OF BENZYNES IN FLOW REACTORS FOLLOWED BY SUBSEQUENT DIELS-ALDER REACTIONS ABIR ALI KHADRA A DISSERTATION SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY GRADUATE PROGRAM IN CHEMISTRY YORK UNIVERSITY TORONTO, CANADA MAY, 2018 © ABIR ALI KHADRA, 2018 ABSTRACT: The first part of this research focuses on developing efficient methods to address challenging Buchwald –Hartwig amination reactions using Pd-NHC pre-catalysts. Specifically, we focused on: a) coupling of sterically hindered primary and secondary amines and b) coupling of 2-aminopyridine derivatives with aryl and heteroaryl halides. Although several approaches have been developed and proven to be effective for coupling of sterically hindered amines, they have limited utility and substrate scope. Pd-PEPPSI-IPentCl (Pyridine Enhanced Pre-catalyst Preparation Stabilization and Initiation) proved to be a very effective catalyst for coupling hindered primary and secondary amines under mild reaction conditions (i.e. Na-BHT (BHT = 2,6-Di-tert-butyl hydroxyl toluene), 80 °C, DME) tolerating base sensitive functional groups such as ester, keto, and nitrile groups. While the synthesis of 2-aminopyridine derivatives is commonly carried out by metal-catalyzed coupling of 2-halopyridines with aniline derivatives, the use of 2-aminopyridine as a nucleophilic partner in Pd catalysis is very difficult as these substrates tend to bind irreversibly to the palladium center and shut down the catalytic cycle. However, Pd-PEPPSI-IPentCl has been found to resist the binding of 2-aminopyridines, making it a very active catalyst for these couplings. The steric bulk of the 3-pentyl substituents on the aryl rings of the NHC ligand that drives the cross-coupling by facilitating reductive elimination also mitigates the poisoning effect of the 2-aminopyridine functionality in the starting material/and or products. We also found that placing electron-donating or electron-withdrawing substituents at the 6-position of the 2-aminopyridine ring reduces the poisoning effect and facilitate the catalytic cycle with mild bases (i.e. Na-BHT). ii The second part of this research investigated the formation of benzyne derivatives from ortho-trimethylsilyl triflates using tetra-n-butylammonium fluoride (TBAF) as the benzyne- forming trigger in the flow system. The numerous advantages of microfluidic devices enabled the formation of these species at room temperature which were immediately trapped in Diels-Alder reactions with five-membered heterocyclic dienes to generate bicyclic alkenes of biological interest. The yields of Diels-Alder reaction with benzynes follow the order: furans > pyrroles > thiophene. iii Dedications It is my genuine gratefulness and warmest regard that I dedicate this thesis to my friend Suzann Mansour, her kindness and devotion, her inspiration throughout the years of our friendship will not be forgotten. Suzann; you left incredible fingerprints of grace in my life, wish you were here. I also dedicate my work to my daughter Celina, I am truly thankful to have you in my life. iv ACKNOWLEDGMENTS First, I would like to express my special thanks to my supervisor Prof. Michael G. Organ for providing me with a golden opportunity to be one of his graduate students. The free environment that he provides to his students to work independently, to be creative and to develop problem- solving skills allowed me to be a much more confident chemist that I would imagine. Also, I would like to extend my thanks to Prof. Arturo Orellana for his constructive criticism, sharing his valuable knowledge in organic chemistry during my research evaluations at the end of each year, and during the problem sessions. His support and encouragement were extremely valuable especially when I became a new mother. In addition, I would like to thank Prof. Pierre Potvin for agreeing to be my research committee, his fruitful suggestions and advice in the lab during my CHEM 4000 course enabled me to be well prepared for graduate school. Next, I would like to thank Dr. Howard Hunter for his willingness to help and share his immense knowledge in NMR spectroscopy, his patience to answer my endless questions especially at the beginning of my studies, and his attempts to cheer me up whenever a reaction does not work. I would like to express my gratitude to my colleagues that I have had the pleasure to work with, especially to my best friends Sepideh Sharif who stood by me and helped me through the difficult times, to Xia Chen and many discussions about food and calorie counting, to Kristina Somerville- Rucker with her rare sense of humor, lovely spirit that forces you to smile no matter what. To my wise and loyal friend Zahra Vaziri who was always there for me especially during my pregnancy; to Dr. Jennifer Farmer and her valuable advices to cope stress; to an amazing friend Dr. George Achonduh; to Dr. Niloufar Hadie and her incredible sense of humor and her passion to live life to the maximum; to Matthew Pompeo and his unique professionalism; to Andrei Nikolaev and his passion to organic chemistry and willingness to participate in discussion on reaction mechanisms v for hours and hours; to Nour Bizzari and her distinct personality, to Jee Kwak and the smile that never leaves his face, to Dr. John Day and Dr. Gregory Price and their willingness to help me in the lab, and to my childhood best friend and cousin, Rami Valari Spasov who always reminded me to take care of myself and respect my needs when I was totally ignoring them. Finally, this work could not be completed without the support of my family, especially my father who taught me how to be determined, patient and to pursue my goals no matter what. To my precious mom who stayed with me for almost a year and took care of my daughter Celina, the love of my life; to my wise and forgiving brother Houssam, to my sophisticated, prestigious brother Hassan and to my youngest brother Ghaleb who taught me how to love myself and live life to the maximum, to the wise woman, my sister in law Kate Brooks-Khadra. Thank you for all your support, for enduring my unpredictable working hours and for being understandable for every time I was questioned about my graduating date. vi TABLE OF CONTENTS ABSTRACT……………….……………………………………....……………………………...ii DEDICATION…....……………………………………………..…………………………...…...iv ACKNOWLEDGEMENTS………………………………………..……………………….….…v TABLE OF CONTENTS…………………………………………………………………..……vii LIST OF TABLES…………………………………………………..……….…………………...x LIST OF FIGURES…………………………………………………..…….……………….…....xi LIST OF SCHEMES…………………………………………….……….….……………….…xiii LIST OF ABBREVIATIONS……………………………………………..……….………..…xvii PUBLICATIONS………………………………………………………………………………..xx PART I: PALLADIUM-PEPPSI-IPENTCl; A USEFUL CATALYST FOR CHALLENGING AMINATION REACTIONS CHAPTER 1-Introduction………………………….…….……………………….………….....1 1.1 Significance of Aniline Derivatives…………………………....……….…………………..…1 1.2 Synthesis of Aniline Derivatives………………………….……………….……………..…...3 1.2.1 Nucleophilic Aromatic Substitution…………………………….…….…………….….....3 1.2.2 Aniline Derivatives from Nitrobenzene.…..……………………..……………….….…...4 1.2.3 Aniline from Nitrobenzene and Grignard Reagents……..……………….…………....….5 1.3 Metal-Catalyzed Amination Reactions……………………………………….………….........9 1.3.1 Copper-Catalyzed C-N Bond Formation………………...…..............................................9 1.3.2 Palladium-Catalyzed C-N Bond Formation……………………..…………………….....12 1.3.2.1 Mechanism of Buchwald-Hartwig Amination……………………………….......13 1.4 Ligand Development in Palladium-Catalyzed Buchwald-Hartwig Amination………………………..…………………………………………...…………….……16 1.4.1 Phosphine Ligands……………….….…………………………………………………...17 1.4.1.1 Quantifying Electronic and Steric Properties of Phosphine Ligands………………….……………………………………………………...……………...17 1.4.1.2 Phosphine Ligands in Palladium-Catalyzed Amination…………………………..18 1.4.1.3 Deficiencies of Phosphine Ligands……………………..........................................27 vii 1.4.2 N-Heterocyclic Carbenes………………………………………………………….……..28 1.4.2.1 Steric Characteristics of NHC……………………………………….……….…..30 1.4.2.2 Electronic parameter of NHC Ligands…...…….......………………………..…...31 1.4.2.4 Pd-NHC Complexes in Buchwald Amination.…………………….……...….…..33 1.5 Challenges in C-N Bond Formation………..……………………………………………...…36 1.5.1 Synthesis of Sterically Hindered Aniline Derivatives……………………………….….36 1.5.2 Synthesis of 2-Aminopyridine Derivatives………………………………………….….39 1.6 Plan of study……...………………………………………………………………………..…43 1.6.1. Synthesis of Sterically Hindered Arylamines…..…………………….……………...…43 1.6.2 Synthesis of 2-Aminopyridine…….………………..…………………………….….…44 CHAPTER 2-Synthesis of Hindered Anilines…………………..…………….……………....45 2.1 Reaction Optimization……………………..………………….……………………………..45 2.2 Substrate Scope with Primary Amines…………………….…………………..…………….47 2.3 Substrate Scope with Secondary Amines…………………………….………………..…….48 2.4 Conclusion………………………………………………………...........................................52 CHAPTER 3-Reactions of 2-Aminopyridine in Cross-Coupling…………………...……….53 3.1 Catalyst Screening………………………………….………….…………………….………53 3.2 Coupling of Electron-Poor 2-Aminopyridines………………….…………………….……..56 3.3 Impact of the Size of the C6-Substituent on the Catalytic Cycle……………….…….……..57 3.4 Coupling of Cyano-Substituted-2-Aminopyridine……………………………………..……58 3.5 Poisoning Effect of the 2-Aminopyridine Coupled Product on Pd Catalyst…….…………..59 3.6