Exploration of the use of Palladium and Nickel to Catalyze Enolate Cross-coupling and the Enantioselective Mizoroki-Heck Reaction.
Palladium catalysis is a common synthetic tool utilized by organic chemists to create carbon-carbon bonds. We utilized palladium to catalyze the γ-arylation of α, β-unsaturated ketones, and esters. This work expands on palladium-catalyzed α-arylation chemistry and extends it to the vinylogous variation at the γ-position. We report the regioselective synthesis of mono-γ-arylated 7-methoxy-4-methylcoumarin. We also report efforts towards applying our reaction conditions to other α,β-unsaturated ketones and esters to expand the scope of our reaction conditions. In addition, we utilized palladium to catalyze the enantioselective asymmetric intramolecular Mizoroki-Heck reaction to produce potentially bioactive phenanthridinone analogs. We achieve this through the Birch-Heck sequence, a 4-step sequence that includes Birch reduction/alkylation of benzoic acid, acid chloride formation/amide formation, triflation, and then the enantioselective Mizoroki-Heck reaction. In this process, we report N-H and N-Me phenanthridinone analogs' synthesis. A protection/deprotection protocol was found to be the key to accessing phenanthridinone derivatives with N-H. Besides palladium catalysis, we also explored conducting the enantioselective Mizoroki-Heck reaction with nickel. Nickel catalysis is a relatively new research area that has recently demonstrated success with the enantioselective intramolecular Mizoroki-Heck reaction under mild conditions with high yields and ee values. We proposed that we may access a pathway that could increase our enantioselectivity under relatively mild conditions by using nickel. We report efforts to optimize the nickel catalyzed Heck reaction to minimize side products and to improve the yield of the desired 1,3-diene. In the synthesis of phenanthridinone analogs, we have demonstrated that the Birch-Heck sequence is a simple way of synthesizing chiral phenanthridinone derivatives with quaternary centers. In total, three areas of transition metal-catalyzed reactions were explored. This involved cross-coupling between enolates and aryl halides and between aryl halides and alkenes. Strategies for enantioselective synthesis were developed, and potentially bioactive phenanthridinone structures were constructed. Finally, the cross-coupling studies looked at both palladium and, the more cost-effective, nickel in the Mizoroki-Heck reaction.
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