Enantioconvergent Cu-Catalyzed Radical C-N Coupling of Racemic Secondary Alkyl Halides to Access α-Chiral Primary Amines

alpha-Chiral alkyl primary amines are virtually universal synthetic precursors for all other alpha-chiral N-containing compounds ubiquitous in biological, pharmaceutical, and material sciences. The enantioselective amination of common alkyl halides with ammonia is appealing for potential rapid access to alpha-chiral primary amines, but has hitherto remained rare due to the multifaceted difficulties in using ammonia and the underdeveloped C(sp(3))-N coupling. Here we demonstrate sulfoximines as excellent ammonia surrogates for enantioconvergent radical C-N coupling with diverse racemic secondary alkyl halides (>60 examples) by copper catalysis under mild thermal conditions. The reaction efficiently provides highly enantioenriched N-alkyl sulfoximines (up to 99% yield and >99% ee) featuring secondary benzyl, propargyl, alpha-carbonyl alkyl, and alpha-cyano alkyl stereocenters. In addition, we have converted the masked alpha-chiral primary amines thus obtained to various synthetic building blocks, ligands, and drugs possessing alpha-chiral N-functionalities, such as carbamate, carboxylamide, secondary and tertiary amine, and oxazoline, with commonly seen alpha-substitution patterns. These results shine light on the potential of enantioconvergent radical cross-coupling as a general chiral carbon-heteroatom formation strategy.

Automated summary

This study demonstrates the successful use of sulfoximines as ammonia surrogates for enantioconvergent radical C-N coupling with diverse racemic secondary alkyl halides, achieving high yields and enantioselectivity. The obtained alpha-chiral primary amines can be converted to various synthetic building blocks, ligands, and drugs, highlighting the potential of enantioconvergent radical cross-coupling as a general chiral carbon-heteroatom formation strategy.