Oxidative Cross Dehydrogenative Coupling of <i>N</i> -Heterocycles with Aldehydes through C( <i>sp</i> <sup>3</sup> )–H Functionalization
Mo Chen, Austin M. Ventura, Soumik Das, Ammar Ibrahim, Paul M. Zimmerman, John Montgomery
Abstract
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( sp 3 )–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.