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

Area of Science:

• Organic Chemistry
• Catalysis
• Radical Chemistry

Background:

• Copper-catalyzed cross-coupling reactions are vital in organic synthesis.
• Sluggish single-electron transfer from copper(I) to alkyl halides is a key limitation.
• Developing efficient methods for C(sp3) functionalization is crucial.

Purpose of the Study:

• To overcome the bottleneck of sluggish single-electron transfer in copper catalysis.
• To develop a novel strategy for efficient alkyl bromide functionalization.
• To enable the formation of C(sp3)-N, C(sp3)-S, and C(sp3)-C bonds.

Main Methods:

• Generation of carbon dioxide radical anion (CO2•−) via Cu-catalyzed C-H activation of formate.
• Utilizing CO2•− for efficient single-electron transfer to alkyl bromides.
• Coupling of alkyl radicals with diverse nucleophiles.

Main Results:

• Successful formation of C(sp3)-N, C(sp3)-S, and C(sp3)-C bonds with good to excellent yields.
• Broad substrate scope including unactivated alkyl bromides and various nucleophiles.
• Demonstrated decagram-scale synthesis with cost-effectiveness and simplicity.

Conclusions:

• The developed protocol offers a distinct and efficient strategy for copper-catalyzed cross-coupling.
• This method overcomes previous limitations in single-electron transfer kinetics.
• Enables facile reaction optimization, library synthesis, and late-stage diversification of drug molecules.