Radical cyclization via selective C–X bond transformation

Abstract

The selective cleavage and transformation of carbon–halogen bonds constitute pivotal fundamental transformations for constructing C–C bonds and assembling complex molecular skeletons in organic synthesis, serving as an essential platform for pharmaceutical molecules, natural products, and functional materials. Traditional transformations of carbon–halogen bonds proceed via ionic intermediates or organometallic complexes, which not only require harsh reaction conditions but also suffer from limitations in regioselectivity control and functional group tolerance. With the rapid advancement of radical chemistry, carbon–halogen bond activation strategies using carbon-centered radicals as intermediates have surmounted long-standing bottlenecks of conventional reaction modes owing to their distinct merits, including mild reaction conditions, excellent chemoselectivity, and diverse transformation pathways, thereby emerging as a key approach for constructing carbocyclic and heterocyclic frameworks. This review systematically summarizes recent advances in four radical activation pathways for carbon–halogen bonds: direct C–X bond homolysis, photoinduced electron transfer (PET), single-electron transfer (SET), and halogen atom transfer (XAT), covering their reaction mechanisms, catalytic systems, and substrate scopes. It highlights the progress in constructing five-, six-membered, and fused ring skeletons via intramolecular/intermolecular cyclization and cascade cyclization of carbon-centered radicals. The advantages and characteristics of diverse catalytic systems are systematically categorized, including metal catalysis, metal-free catalysis, photoenzymatic catalysis, and electrocatalysis. Furthermore, mechanistic investigations and control experiments are integrated to elucidate the intrinsic rules governing reaction selectivity, and the current state of the field is summarized in terms of substrate generality, stereoselectivity control, and the development of green catalytic systems. Finally, future perspectives in this area are proposed, aiming to provide theoretical guidance and innovative strategies for the design of radical cyclization reactions and the application of cyclic molecules.