Harnessing CO₂ Radical Anion-Mediated Electron Transfer for Scalable Copper-Catalyzed Cross-Coupling

The inherently sluggish single-electron transfer from copper(I) complexes to alkyl halides remains a central bottleneck in copper-catalyzed cross-coupling chemistry. Here, we introduce a conceptually distinct strategy that overcomes this limitation by harnessing the unique reactivity of the carbon dioxide radical anion (CO₂^·-) to undergo efficient single-electron transfer to alkyl bromides. The strategy relies on the generation of CO₂^·- via Cu-catalyzed C-H bond activation of the formate anion. CO₂^·- then undergoes an efficient single-electron transfer to alkyl bromides to generate alkyl radicals for subsequent Cu-catalyzed transformations. A broad range of unactivated alkyl bromides and structurally diverse nucleophiles─including heteroaryl amines, sulfonamides, anilines, sulfinates, and nitriles─are efficiently coupled to afford C(sp³)-N, C(sp³)-S, and C(sp³)-C bonds in good to excellent yields. The cost-effectiveness and simplicity of this protocol enable decagram-scale synthesis while facilitating rapid reaction optimization and library synthesis for late-stage diversification of drug molecules through high-throughput experimentation.