Oxidative Cross Dehydrogenative Coupling of N-Heterocycles with Aldehydes through C(sp3)–H Functionalization

15 June 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Existing methodologies for metal-catalyzed cross-couplings typically rely on pre-installation 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 CH bonds introduce considerable complexity. Herein, the oxidative cross dehydrogenative coupling of alpha-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 -amino ketones through the formal acylation of unactivated CH bonds in N-heterocycles. A combination of experimental investigation and computational modelling provides evidence for a mechanistic pathway involving cross-selective nickel-mediated cross-coupling of -amino radicals and acyl radicals.

Keywords

nickel
C-H activation
coupling
dehydrogenative
oxidative

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