Enantioselective nickel-catalysed electrochemical cross-dehydrogenative amination

Abstract

Enantio-enriched amines are found in a wide range of bioactive natural products and pharmaceutical agents. However, radical-based asymmetric cross-dehydrogenative amination via electrochemical oxidative C–H/N–H coupling to facilitate catalytic C(sp3)–N bond formation remains a largely unsolved challenge in organic synthesis. In the present study, we present nickel-catalysed, anodically coupled electrolysis for the stereoselective, cross-dehydrogenative amination of acylimidazoles, with commercially available nitrogen nucleophiles as coupling partners to access structurally diverse α-amino carbonyls. This method involves the coupling of an electrogenerated nickel-bound α-keto radical species and an aminyl radical to provide a stereoselective approach for the cross-dehydrogenative amination. The utility of this anodic oxidative strategy has been highlighted through the stereoselective synthesis of (+)-γ-secretase inhibitor, (+)-flamprop-methyl and (+)-flamprop-isopropyl. Developing reaction conditions for radical–radical cross-dehydrogenative amination reactions is challenging. Now a nickel-catalysed asymmetric electrochemical cross-dehydrogenative amination reaction between acylimidazoles and nitrogen nucleophiles is developed to access structurally diverse α-amino carbonyls that can be used to synthesize (+)-γ-secretase inhibitor, (+)-flamprop-methyl and (+)-flamprop-isopropyl.