Oxidative carbon-carbon bond formation: a synergy of enamine and Pd(II) catalysis

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DESCRIPTION (provided by applicant): Selective oxidation of organic chemicals is one of the most critical challenges facing the chemical and pharmaceutical industries today. Over the past 10 years, many groups have endeavored to couple known and novel oxidation processes to the world's most abundant oxidant, molecular oxygen. One challenging area of research in this field is the palladium(ll) mediated oxidative coupling of carbon nucleophiles with unactivated olefins. Concurrent with aerobic oxidation research, organocatalysis, particularly iminium/enamine catalysis, has garnered significant attention from the synthetic community and has proven to be extremely effective at catalyzing reactions with high levels of enantiocontrol under very mild conditions. The proposed study involves a synergy of these two concepts: to successfully merge enamine catalysis with Pd(ll) chemistry to catalyze the oxidative coupling of relatively weak a-carbonyl nucleophiles with unactivated olefins under aerobic conditions. The ultimate goal of this proposal entails probing the mechanism of the reaction and rendering it catalytic in both amine and palladium while being capable of inducing high levels of enantioselectivity. The proposed reaction proceeds via condensation of a secondary amine with a molecule containing an alkene tethered carbonyl to generate an enamine. Electrophilic activation of the tethered alkene by a palladium(ll) source leads to carbon-carbon bond formation. Hydrolysis of the resulting iminium ion with concomitant p-hydride elimination of the palladium affords the oxidatively coupled product. The newly generated Pd(0) can be reoxidized by O2 to Pd(ll) which can re-enter the catalytic cycle. It is expected that use of chiral, enantioenriched secondary amines will enable high enantiocontrol. Chiral secondary amines that have the dual role of palladium ligand will also be investigated for their potential in asymmetric reactions. The design of efficient and benign oxidative chemical transformations is critical for the development of an environmentally sustainable worldwide economy, and therefore, the health of all living things. In this application, we propose the design of a powerful yet mild chemical reaction that uses molecular oxygen as the sole oxidant and generates water as the only byproduct.