A General Copper-Catalyzed Radical Cross-Coupling of Unactivated Alkyl Halides.

The first-row transition metal-catalyzed C(sp3)-carbon/heteroatom cross-coupling of unactivated alkyl halides is a powerful strategy for constructing diverse molecular frameworks. Copper-based systems dominate C(sp3)-N cross-coupling, likely owing to their strong propensity for reductive elimination, whereas other first-row transition metal catalysts have been reported only in rare cases. However, the intrinsically lower reducing capability of copper catalysts greatly limits their application to unactivated alkyl halides─particularly alkyl chlorides─in C(sp3)-N cross-coupling reactions. Here, we demonstrate a general copper-catalyzed C(sp3)-C/N cross-coupling of unactivated alkyl halides with diverse nucleophiles under mild thermal conditions. The success of this reaction relies on the use of anionic N,N,N-ligands to enhance the reducing capability of Cu(I) catalysts for the reduction of alkyl halides. This protocol accommodates a wide range of coupling partners, including primary to tertiary alkyl bromides and bench-stable chlorides, as well as primary and secondary alkyl iodides, and an array of nucleophiles (such as (hetero)aromatic amines, indoles, carbazoles, amides, azoles, and alkynes) with good functional-group compatibility. Furthermore, the present system provides a highly versatile platform for the late-stage functionalization of complex molecules.