Phosphine-catalyzed β-C(sp³)-H Functionalization of Cyclic Amines via a Halogen Based Frustrated Radical Pairs Approach

Abstract

The precise functionalization of saturated nitrogen-containing heterocycles is a cornerstone of modern drug discovery.While strategies targeting the α-C(sp 3 )-H bond are well-established, functionalization at the distal β-position remains a formidable challenge, typically plagued by harsh conditions and reliance on noble metals. Herein, we report a metal-free, phosphine-catalyzed strategy for the β-position C(sp³)-H functionalization of cyclic amines, enabled by a novel frustrated radical pairs (FRPs) mechanism. Guided by density functional theory (DFT) calculations, we identified a thermodynamically stable yet reactively potent "spoke-shaped" adduct derived from tris(2,6-dimethoxyphenyl)phosphine as the key catalytic species. Unlike traditional frustrated Lewis pairs (FLPs) systems based on boron or aluminum, this halogen-based system operates via a single electron transfer (SET) pathway to overcome the kinetic barriers of bond activation. This protocol features broad functional group tolerance, enabling diverse transformations (including sulfuration and heteroarylation) under unified, mild conditions. Furthermore, the utility of this method is demonstrated through the late-stage modification of complex pharmaceutical agents, offering a robust platform for the synthesis of bioactive amine derivatives.