Oxidative Cross Dehydrogenative Coupling of <i>N</i>‑Heterocycles with Aldehydes through C(<i>sp</i>³)–H Functionalization

Existing methodologies for metal-catalyzed cross-couplings typically rely on preinstallation of reactive functional groups on both reaction partners. In contrast, C–H functionalization approaches offer promise in simplification of the requisite substrates; however, challenges from low reactivity and similar reactivity of various C–H bonds introduce considerable complexity. Herein, the oxidative cross dehydrogenative coupling of α-amino C(sp3)–H bonds and aldehydes to produce ketone derivatives is described using an unusual reaction medium that incorporates the simultaneous use of di-tert-butyl peroxide as an oxidant and zinc metal as a reductant. The method proceeds with a broad substrate scope, representing an attractive approach for accessing α-amino ketones through the formal acylation of C–H bonds α to nitrogen in N-heterocycles. A combination of experimental investigation and computational modeling provides evidence for a mechanistic pathway involving cross-selective nickel-mediated cross-coupling of α-amino radicals and acyl radicals.