Radical Advances in C(sp3)−H Functionalization: Foundations for C–H Cross-Coupling

C−H functionalization reactions are playing an increasing role in the preparation and modification of complex organic molecules, including pharmaceuticals, agrochemicals, and polymer precursors. Radical C–H functionalization reactions, initiated by hydrogen-atom transfer (HAT) and proceeding via open-shell radical intermediates, have been expanding rapidly in recent years. These methods introduce strategic opportunities to functionalize C(sp3)−H bonds. Examples include synthetically useful advances in radical-chain reactivity and biomimetic radical-rebound reactions. A growing number of reactions, however, proceed via "radical relay" whereby HAT generates a diffusible radical that is functionalized by a separate reagent or catalyst. The latter methods provide the basis for versatile C–H cross-coupling methods with diverse partners. In the present review, highlights of recent radical-chain and radical-rebound methods provide context for a survey of emerging radical-relay methods, which greatly expand the scope and utility of intermolecular C(sp3)−H functionalization and cross coupling.