Deoxygenative radical cross-coupling of C(sp3)−O/C(sp3)−H bonds enabled by hydrogen-bond interaction

Abstract

Abstract Building C(sp3)-rich architectures using simple and readily available starting materials will greatly advance modern drug discovery. C(sp3)−H and C(sp3)−O bonds are commonly used to strategically disassemble and construct bioactive compounds, respectively. However, the direct cross coupling of these two chemical bonds to form new C(sp3)−C(sp3) bonds is rarely explored in existing literature. Conventional methods for forming C(sp3)−C(sp3) bonds via radical-radical coupling pathways often suffer from poor selectivity, severely limiting their practicality in synthetic applications. In this study, we present a single electron transfer (SET) strategy that enables the cleavage of amine a-C−H bonds and heterobenzylic C−O bonds to form new C(sp3)−C(sp3) bonds without the catalysis of transition metals. Preliminary mechanistic studies have revealed that a hydrogen bond interaction facilitates the cross-coupling of two radicals with high chemoselectivity. This methodology features a broad substrate scope range from primary to tertiary alcohols and exhibits high functional group compatibility. Most importantly, it provides an effective approach to a variety of aza-heterocyclic unnatural amino acids and bioactive molecules.