Remote C(sp3)–H Functionalization Enabled by Alkene-Relay Radical Migration

The selective functionalization of inert C(sp3)–H bonds, particularly at remote sites, represents a grand challenge in synthetic organic chemistry. Traditional methods often suffer from issues of regioselectivity, harsh reaction conditions, and limited substrate scope. This paper explores the burgeoning field of remote C(sp3)–H functionalization mediated by alkene-relay radical migration, an innovative strategy that leverages the reactivity of alkenes to steer radical intermediates to distant C–H bonds. We delve into the mechanistic underpinnings of this approach, which typically involves initial radical addition to an alkene, followed by a 1,n-hydrogen atom transfer (HAT) process from a remote C(sp3)–H bond to generate a new radical species. This newly formed radical can then undergo subsequent transformations, such as C–C or C–heteroatom bond formation. The review covers various catalytic systems, including photocatalytic, transition metal-catalyzed, and dual catalytic approaches, highlighting their efficacy in achieving site-selective azidation, fluoroalkylation, and cyclization reactions. We discuss the advantages of this strategy, such as mild reaction conditions, excellent regioselectivity, and the potential for late-stage functionalization of complex molecules. Furthermore, we examine the scope and limitations of current methodologies and propose future directions for this exciting area of synthetic chemistry, emphasizing the potential for designing novel radical cascades and expanding the utility of sustainable catalytic systems.