Deoxygenative radical cross-coupling of C(sp 3 )-O/C(sp 3 )-H bonds promoted by hydrogen-bond interaction.

Building C(sp 3 )-rich architectures using simple and readily available starting materials will greatly advance modern drug discovery. C(sp 3 )-H and C(sp 3 )-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 C(sp 3 )-C(sp 3 ) bonds is rarely explored in existing literature. Conventional methods for forming C(sp 3 )-C(sp 3 ) 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 α-C - H bonds and heterobenzylic C - O bonds to form C(sp 3 )-C(sp 3 ) bonds. Preliminary mechanistic studies reveal a hydrogen bond interaction between substrates and phosphoric acid facilitates the cross-coupling of two radicals with high chemoselectivity. This methodology provides an effective approach to a variety of aza-heterocyclic unnatural amino acids and bioactive molecules.