Site‐Selective α─C─H Functionalization of Saturated Heterocycles via Copper‐Photoredox Catalysis

Site-selective α─C─H functionalization of saturated heterocycles is of particular importance in synthetic and medicinal chemistry, but the intrinsic chemical inertness of saturated heterocycles renders the transformation difficult. Furthermore, site-selectivity remains a significant challenge, especially among multiple C(sp³)─H bonds with comparable chemical properties. Herein, an unprecedented site-selective C_α─H functionalization of saturated heterocycles by copper-photoredox catalysis is described. This undirected approach exploits a novel copper photocatalyst to mediate both substrate activation and photoinduced energy transfer, enabling site-selective functionalization of cyclic C_α─H bonds in the presence of competitive C(sp³)─H bonds. Mechanistic studies reveal that the excellent site-selectivity stems from the coordination effect between the saturated heterocycle and copper/ligand complex, which makes the cyclic C_α─H bond more acidic and weaker in bond strength, thereby increasing the reactivity differences among similar C(sp³)─H bonds. The use of dual-role air bypasses exogenous HAT reagents and oxidants required in previous methods. This mild and sustainable protocol features broad substrate scope, excellent site-selectivity, and high functional group compatibility, providing a new and site-selective reactivity mode for rapid diversification of α─C─H bonds.