Development of Palladium-Catalyzed Decarboxylative Allylation of Electron-Deficient Sulfones: Method Development and Mechanistic Studies by Monica Anne Gill A thesis submitted to the Faculty of Graduate and Postdoctoral Affairs in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry Carleton University Ottawa, Ontario © 2015, Monica Anne Gill Abstract Palladium-catalyzed decarboxylative allylation is a powerful method of carbon-carbon bond construction. This methodology relies on an electron- withdrawing group to promote the reaction. The use of sulfones in decarboxylative allylation has been explored using the trifluoromethylsulfonyl (triflyl) group, as well as the bis(3,5-trifluoromethyl)phenylsulfonyl (BTMP) group. These substrates are highly reactive at room temperature (triflyl) and 50 oC (BTMP sulfones). A detailed mechanistic study using deuterium-labelled substrates was performed to understand the origin of the protonation side-product. It was proposed that a β- hydride elimination from the η1 allyl on palladium could generate a palladium hydride intermediate along with an allene. Although small amounts of deuterium incorporation were observed in the protonated products, the proposed mechanism could not be the major pathway. Using isotopically labelled ligand, however, all protonation was supressed. This suggests that the origin of the proton is actually from the ligand and that kinetic isotope effects may be responsible for inhibiting the protonation pathway with labelled ligand. ii Acknowledgments I would like to thank Dr. Jeff Manthorpe for giving me the chance to pursue my PhD in his lab. I always appreciated Jeff’s enthusiasm for organic chemistry as well as his vast knowledge of the subject. Some of my most fond lab memories are of group brainstorming at the chalkboard with Jeff and whoever else was in the lab at the time. During my time as a PhD student, I had the opportunity to train and mentor a large (18!) number of undergraduate researchers. In fact, three went on to pursue Master’s degrees in the Manthorpe lab. It was very rewarding to watch as the students grew from inexperienced undergrads to very capable graduate students. Han Kong, you were both an excellent colleague and friend. John Palko, your enthusiasm was refreshing. Sam Shields, I’m proud of the scientist you’ve become. Thank you to members of the DeRosa lab who unofficially adopted me into their group when I began and had no fellow graduate students in my lab. I value the friendship of both past and present members of that group. Also, thank you to members of the Miller lab, both past and present, who have been residents of the grad office 410. One never knows what is being discussed when one walks through the door, but you can be sure it’s interesting, and probably hillarious. Thank you to members of the Wang lab, both past and present, for their generous loan of so many chemicals to our group over the years. I would like to extend my thanks to Jim Logan for his expertise in fixing a wide array of electronics in our lab, as well as helping me out on occasion with my personal laptop. I’d also like to acknowledge the role of Peter Mosher in preventing iii Steacie from simply imploding on itself at any given time. Thank you to Tanya and Susa in stores for always being friendly faces and being up for a chat. Also, a huge thanks to Ann Anderson and Chantelle Gravelle (and Marilyn Stock before that) for all of their administrative assistance over the years. I would like to thank my former co-workers at BioVectra for their support of me over the years. I learned so much from all of you while working in research and development, and have never forgotten the lessons I learned while in industry. I am very grateful that I am able to continue to count you all amongst my friends. My family has always been very supportive of my desire to pursue my PhD. Thank you to my mother Elaine, and my sister Angela for their patience, support and understanding during the past years. My late father, Patrick, always encouraged my curious nature, and I know that was a major contributor to my scientific career. I would like to finish by acknowledging the huge role that my fiancé Vince has played in my life during my degree. The level of support that he has shown me and the sacrifices that he made so willingly so that I could complete the work I needed to do are nothing short of stunning. Whether it be cooking me meals or sitting with me in the lab until the wee hours of the morning, he did it without hesitation. Thank you from the bottom of my heart for believing in my abilities and having more faith in me than I ever had in myself. iv Table of Contents Abstract ..............................................................................................................ii Acknowledgments ............................................................................................. iii Table of Contents .............................................................................................. v List of Abbreviations ........................................................................................ viii List of Figures ....................................................................................................xi List of Schemes ................................................................................................xv List of Tables ................................................................................................... xix Chapter 1 : Introduction to Metal-Catalyzed Decarboxylative Allylation ................ 1 1.1 Metal-Catalyzed Cross-Coupling Reactions ................................................ 1 1.2 Palladium-Catalyzed Allylation .................................................................... 2 1.2.1 Initial Discovery using Stoichiometric Palladium ................................... 2 1.2.2 Early Catalytic Allylation and Regiochemistry ....................................... 3 1.2.3 Catalytic Enantioselective Allylation ...................................................... 4 1.3 Decarboxylative Variants ............................................................................. 5 1.4 Stereoselective DcA .................................................................................. 12 1.5 Applications of DcA in Total Synthesis ...................................................... 16 1.6 Mechanism of Metal-Catalyzed DcA ......................................................... 18 1.7 DcA with Non-Enolate Nucleophiles .......................................................... 25 1.8 Project Goals ............................................................................................. 25 Chapter 2 : Pd-Catalyzed Decarboxylative Allylation of α-Triflones .................... 27 2.1 Introduction ............................................................................................... 27 2.2 Attempts at Expanding Substrate Scope ................................................... 31 2.2.1 Preparation of Other Secondary Alkyllithiums ..................................... 31 2.2.2 Andersen Sulfoxide Approach ............................................................. 34 2.2.3 Ruppert-Prakash Reagent .................................................................. 36 2.2.4 Disulfide Approach .............................................................................. 37 2.2.5 Sequential Alkylation & Acylation ........................................................ 38 2.2.6 Insight Into Behavior of α-Triflyl Anions ............................................... 40 2.3 Extending Substrate Scope (Allylic ester) ................................................. 41 2.3.1 Substrate preparation .......................................................................... 41 v 2.3.2 Reductive Cleavage of Homoallylic Triflone ........................................ 42 2.4 Methylation of α-Triflyl Esters .................................................................... 43 2.5 Attempted Derivatization of Triflyl-Substituted Ambiphilic Alkenes ............ 46 2.6 Radical trap work ....................................................................................... 49 2.6.1 Preparation of appropriate substrate ................................................... 50 2.6.2 Attempts at radical and anionic cyclization of ambiphilic alkene ......... 51 2.7 Contemporary Work .................................................................................. 52 2.8 Experimental ............................................................................................. 54 Chapter 3 : Pd-Catalyzed Decarboxylative Allylation of BTMP Sulfones ............ 64 3.1 Alternate Electron-Withdrawing Group ...................................................... 64 3.2 Synthetic Approach ................................................................................... 65 3.3 Development of New Esterification Method ............................................... 73 3.3.1 Reaction Optimization ......................................................................... 73 3.3.2 Substrate Scope ................................................................................. 77 3.4 Optimization of Oxidation .......................................................................... 78 3.5 Optimization of Alkylation .......................................................................... 81 3.6 Early DcA Studies ....................................................................................