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

• DOI: 10.1021/jacs.1c07726
• Publication Date: 2021-09-10T09:32:31Z
• Authors: Yu-Feng Zhang; Xiao-Yang Dong; Jiang-Tao Cheng; Ning-Yuan Yang; Li-Lei Wang; Fu-Li Wang; Cheng Luan; Juan Liu; Zhong-Liang Li; Qiang-Shuai Gu; Xin-Yuan Liu
• Keywords: 01 natural sciences; 0104 chemical sciences

α-Chiral alkyl primary amines are virtually universal synthetic precursors for all other α-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 α-chiral primary amines, but has hitherto remained rare due to the multifaceted difficulties in using ammonia and the underdeveloped C(sp3)-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, α-carbonyl alkyl, and α-cyano alkyl stereocenters. In addition, we have converted the masked α-chiral primary amines thus obtained to various synthetic building blocks, ligands, and drugs possessing α-chiral N-functionalities, such as carbamate, carboxylamide, secondary and tertiary amine, and oxazoline, with commonly seen α-substitution patterns. These results shine light on the potential of enantioconvergent radical cross-coupling as a general chiral carbon-heteroatom formation strategy.