Nickel-Catalyzed Cross-Dehydrogenative Allylation of Aldehydes

Nucleophilic additions to aldehydes play a central role in synthetic chemistry. While additions of organometallic nucleophiles are commonly employed, alternative catalytic processes such as cross-electrophile couplings and reductive couplings involving various π-systems have also been developed and extensively used. In this study, we describe a complementary approach to aldehyde-alkene couplings via direct nickel-catalyzed cross-dehydrogenative coupling of aldehydes and alkenes. The process utilizes a combination of zinc powder and di-tert-butyl peroxide, enabling cross-dehydrogenative coupling to allow the synthesis of β,γ-unsaturated ketones through the catalytic union of acyl radicals and allylic radicals generated from the aldehyde and alkene substrates. An array of substrate combinations is demonstrated, and both experimental and computational studies support the involvement of a double hydrogen-atom-transfer (HAT) mechanism. Comparative analysis of di-tert-butyl peroxide with an alternate oxidant, 2-bromo-1,3-bis(trifluoromethyl)benzene, illustrates the substrate-dependent complementarity of the oxidants and shows an important interdependence of relative substrate concentrations. Quantum chemical estimates of the thermodynamics of the two simultaneous HAT events, generating acyl radicals and allylic radicals, show a correlation between calculated free energies of reaction and the optimal experimental protocol.