Site-selective α-C(sp3)–H bond functionalization of amines/amides via 1,2-hydrogen atom transfer

Abstract

Site-selective functionalization of C(sp³)–H bonds represents a core challenge in modern organic synthesis. The strategy of nitrogen-centered radical-mediated 1,2-hydrogen atom transfer (1,2-HAT) provides an efficient new pathway for the precise α-C(sp³)–H bond functionalization of amines/amides. This article systematically reviews the latest research advances in this field, with a focus on the design and development of nitrogen radical precursors such as N-aroyloxyamides, N-aryloxyamides, N-alkoxyamides, and hydroxamic esters. It delves into the reaction mechanisms and the principles governing chemoselectivity in 1,2-HAT processes under photoredox catalysis, transition-metal-free conditions, and transition-metal synergistic catalysis. The review summarizes the applications of this strategy in the construction of C–C bonds and carbon–heteroatom bonds, highlighting its core advantages, including mild reaction conditions, excellent functional group tolerance, high site selectivity, and applicability in the late-stage functionalization of complex molecules. Finally, the current challenges in this field are analyzed, and future research directions and application prospects are discussed.