Direct arylation of strong aliphatic C-H bonds

Despite the widespread success of transition-metal-catalysed cross-coupling methodologies, considerable limitations still exist in reactions at sp³-hybridized carbon atoms, with most approaches relying on prefunctionalized alkylmetal or bromide coupling partners^1,2. Although the use of native functional groups (for example, carboxylic acids, alkenes and alcohols) has improved the overall efficiency of such transformations by expanding the range of potential feedstocks^3-5, the direct functionalization of carbon-hydrogen (C-H) bonds-the most abundant moiety in organic molecules-represents a more ideal approach to molecular construction. In recent years, an impressive range of reactions that form C(sp³)-heteroatom bonds from strong C-H bonds has been reported^6,7. Additionally, valuable technologies have been developed for the formation of carbon-carbon bonds from the corresponding C(sp³)-H bonds via substrate-directed transition-metal C-H insertion⁸, undirected C-H insertion by captodative rhodium carbenoid complexes⁹, or hydrogen atom transfer from weak, hydridic C-H bonds by electrophilic open-shell species^10-14. Despite these advances, a mild and general platform for the coupling of strong, neutral C(sp³)-H bonds with aryl electrophiles has not been realized. Here we describe a protocol for the direct C(sp³) arylation of a diverse set of aliphatic, C-H bond-containing organic frameworks through the combination of light-driven, polyoxometalate-facilitated hydrogen atom transfer and nickel catalysis. This dual-catalytic manifold enables the generation of carbon-centred radicals from strong, neutral C-H bonds, which thereafter act as nucleophiles in nickel-mediated cross-coupling with aryl bromides to afford C(sp³)-C(sp²) cross-coupled products. This technology enables unprecedented, single-step access to a broad array of complex, medicinally relevant molecules directly from natural products and chemical feedstocks through functionalization at sites that are unreactive under traditional methods.