Copper-Catalyzed Radical Cross-Coupling of Unactivated Alkyl Halides Enabled by Anionic N,N,N-Ligands

Copper-catalyzed cross-coupling of unactivated alkyl halides represents a powerful strategy for constructing C(sp³)-based molecular frameworks; yet its broader application has long been limited by the inherently low reducing capability of copper catalysts, especially toward unactivated alkyl chlorides. In this Synpacts article, we summarize our recently developed copper-catalyzed C(sp³)-C/N cross-coupling of unactivated alkyl halides under mild thermal conditions. The key to success is the employment of amide-derived anionic N,N,N-ligands, which significantly enhance the reducing ability of Cu(I) catalysts to enable the single-electron reduction of unactivated alkyl halides. The protocol accommodates primary to tertiary alkyl bromides, bench-stable alkyl chlorides, and alkyl iodides, alongside a broad range of nitrogen- and carbon-based nucleophiles (such as (hetero)aromatic amines, indoles, carbazoles, amides, azoles, and alkynes). The method features good functional-group tolerance and is applicable to late-stage functionalization of complex molecules, providing a practical platform for C(sp³)-C and C(sp³)-N bond construction.