Catalytic Metalloradical System for Radical 1,6-C(sp3)–H Amination with Concurrent Control of Site-, Chemo-, and Enantio-selectivity

Abstract

A catalytic radical process has been developed via metalloradical catalysis (MRC) for 1,6-C(sp³)–H amination with concurrent control of site-, chemo-, and enantioselectivity. Supported by an optimal D₂-symmetric chiral amidoporphyrin ligand, the Co(II)-based metalloradical system effectively catalyzes chemoselective amination of propargylic, allylic, and benzylic C–H bonds at 1,6- over 1,5-positions of alkoxysulfonyl azides, achieving high enantioselectivity. This Co(II)-catalyzed process, which operates at room temperature, is applicable to a broad range of alkoxysulfonyl azides with a high tolerance of functional groups, enabling the efficient construction of six-membered sulfamidates in high yields with excellent enantioselectivities. Comprehensive experimental investigations, complemented by computational studies, elucidate the stepwise radical mechanism underlying this transformation. The resulting six-membered cyclic sulfamidates from the enantioselective radical process can undergo stereospecific ring-opening reactions with various nucleophiles, affording γ-functionalized α-chiral amines in high yields while retaining the original enantiopurity. Since alkoxysulfonyl azides are readily synthesized from widely available alcohols through a nucleophilic azide transfer, this union of the radical and ionic processes constitutes a versatile 1,3-difunctionalization of alcohols.