PART I: MECHANISTIC INSIGHT IN ALKYL-ALKYL AND ARYL-ARYL NEGISHI CROSS-COUPLING PART II: LARGE SCALE SYNTHESIS OF NHC PRECURSORS: 2,6-DI(3-PENTYL)ANILINE AND 2,6-DI(4-HEPTYL)ANILINE LUCAS C. McCANN A DISSERTATION SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY GRADUATE PROGRAM IN CHEMISTRY YORK UNIVERSITY TORONTO, ONTARIO OCTOBER 2015 © Lucas C. McCann, 2015 ABSTRACT Part I: An efficient method for alkyl-alkyl Negishi cross-coupling reaction of unactivated primary alkyl halides with higher-order zincate species (synthesized from dialkylzinc and a non-coordinating halide salt in situ) using Pd-PEPPSI-IPent (Pyridine-Enhanced Pre-catalyst Preparation Stabilization and Initiation) pre-catalyst has been developed. The method requires no additive (such as LiX) or use of a polar co-solvent (such as THF/DMI) and reactions proceed in THF solvent alone. The transmetalating species in alkyl-alkyl Negishi cross-coupling has been identified and the catalytic cycle has been amended to include the formation of the higher-order zincate species. Subsequent investigation into diarylzinc as reagents in Negishi cross-coupling have shown they transmetalate directly without the use of halide additive in THF alone producing arylzinc halide as a resting state. Once the dielectric of the solvent becomes sufficiently polar, coupling resumes, and the aryl moiety transmetalates to palladium. The optimized protocol using Pd-PEPPSI-IPent allowed for the coupling of a variety of alkyl- and aryl- organozinc reagents providing the corresponding products in good to quantitative yields. Moreover, the developed protocol is generally applicable and tolerant of a variety of functional groups including esters, and nitriles. Part II: An improved and efficient method for the preparation of sterically Cl Cl demanding Pd PEPPSI-IPent, IPent , IHept, and IHept pre-catalysts are presented and the results of optimization for the multi-gram synthesis of 2,6-disubstituted anilines is discussed. ii DEDICATION I wish to dedicate this work to my loving family. I thank my caring mother, Suzanne for always reminding me of the importance of education, and to prioritize it over everything else. I thank my father, Jeff for supporting me in whatever career path I chose to follow. Whether it was music, acting, carpentry or science (or even politics), I have never felt that I would disappoint you by following my heart. To Grand-mom and Grand-dad, for attending every birthday, Christmas pageant or football game, I remember you there at almost every single one. I was very proud I to tell both of you that I was successful in my PhD defense. To my three younger and, at times, supportive brothers Joel, Noah and Jacob, I owe special thanks. Being your older brother gave me the privilege of leading by example and, teaching me some of the most important life lessons I could ever have learned. I am honoured to call you band-mates. Mushy Callahan has kept me well-balanced and creatively centered throughout this degree. To my aunts: Mary-Lou and Virginia. I am grateful for your support and interest my academic achievement. I will pay forward your kindness and wisdom. Thank you. I warmly dedicate this work to my loving partner, Dr. Sherry Boodram. You have supported me in every dream, every endeavour, every practice, and every commitment. Our shared experience has made this a journey to remember for a life-time. iii ACKNOWLEDGEMENTS I would like to acknowledge Prof. Michael G. Organ for giving me a challenging and valuable project. I would not be where I am today if it were not for the opportunity you gave me, and for this, I am very grateful to you. I valued our discussions and the warm encouragement you have given me along the way. You have been a great mentor to me throughout this part of my life. I have been supported by great friends and esteemed colleagues within the Chemistry Department. I would like to specifically mention Jennifer Farmer, Matthew Pompeo, Abir Khadra – I enjoyed solving Thursday morning problem sets, troubleshooting our reactions and staying late at night to study for graduate courses together. Nilofar Hadei and George Achonduh provided clever office banter and both had made significant contributions to the project before I joined the group. To my lab mates, Endri Gjiri, Ka Hoi, Mahmoud Sayah, Debasis Mallik, Michael Tsimerman, Sepideh Sharif, Stefan Leenders, Xia Chen, Greg Price, Richard & Kristina Rucker, Chris Shruder, Chris Lombardi, Bruce Atwater and Nalin Chandrasoma, thank you for being a part of this. I would like to acknowledge the great faculty members that I have encountered over the last few years. Specifically, I would like to thank Prof. Arturo Orellano, Dr. Howard Hunter, Prof. Gino Lavoie, Prof. Ed Lee-Ruff, Prof. Lever, Prof. Leznoff and Prof. Philip Johnson for their insight and encouragement. Lastly, I would thank the administrative staff in the Chemistry Office, Mary Mamais, Magy Baket and Natasha Bissoon, thanks for finding that TA-ship or meeting room every time, without fail. iv TABLE OF CONTENTS Abstract..........................................................................................................................i Dedication................................................................................................................... iii Acknowledgements ..................................................................................................... .iv Table of Contents..........................................................................................................v List of Tables................................................................................................................ix List of Figures..............................................................................................................xii List of Schemes............................................................................................................xiii List of Abbreviations...................................................................................................xvi PART I: MECHANISTIC INSIGHT IN ALKYL-ALKYL AND ARYL-ARYL NEGISHI CROSS-COUPLING.....................................................................................1 Chapter 1:Evidence for High-Order Zincates in Alkyl-alkyl Negishi Cross- coupling............ ............................................................................................................ 2 1.1 Background Information .................................................................................. 3 1.1.1 Selected Highlights in the History of Cross-coupling .......................................... 3 3 3 1.1.2 Transition Metal Mediated C(sp )-C(sp ) Cross-coupling ................................... 4 1.1.3 Oxidative Addition to an Organohalide ............................................................... 7 1.1.4 Reductive Elimination Step................................................................................... 8 1.1.5 Transmetalation .................................................................................................... 9 1.1.6 The Active TM in Suzuki-Miyaura Cross-coupling ............................................ 10 1.1.7 Difficulties in Alkyl-alkyl Cross-coupling .......................................................... 12 1.1.8 Negishi Cross-coupling ...................................................................................... 14 1.1.9 The Synthesis of Organozinc Reagents ............................................................... 15 1.1.10 The Importance of Salt By-products in Negishi Cross-coupling ........................ 17 1.1.11 Evidence for the Isolation of a Higher-order Zincate Species ........................... 22 1.2 Plan of Study .................................................................................................. 26 1.3 Results and Discussion .................................................................................. 27 2- + 1.3.1 Spectrometric Titration – The Formation of [EtZnBr3] 2[PPh4] ................... 27 1.3.2 Evaluation of the Reactivity of 13 Relative to Other Alkylzincs ......................... 30 1.3.3 The Importance of the Cation in the Reactivity of Zincates ............................... 32 v 1.3.4 The Reactivity of Di(tetra-n-butylammonium)ethylzinc Tribromide (17) in Negishi Cross-coupling ................................................................................................................ 38 1.3.5 The Proposed Catalytic Cycle of Alkyl-alkyl Negishi Cross-coupling ............... 44 1.4 Conclusion ..................................................................................................... 45 Chapter 2:Experimental Procedures ...................................................................... 47 2.1 General Experimental .................................................................................... 48 2.2 Synthetic Procedures ...................................................................................... 49 38a 2.2.1 General procedure for the Preparation of Organozinc Halides .................... 49 2.2.2 General Negishi Cross-coupling Procedures A and B ....................................... 52 2.2.3 General Negishi Cross-coupling Procedure C ................................................... 52 2.2.4 General Negishi Cross-coupling Procedure D .................................................. 53 2.2.5 General Negishi Cross-coupling Procedure E ..................................................