Intermolecular Enantioselective Benzylic C(sp3)−H Amination by Cationic Copper Catalysis

• Published in: Angewandte Chemie International Edition Vol. 62; no. 24; pp. e202304427 - n/a
• Main Authors: Dai, Ling, Chen, Ying‐Ying, Xiao, Li‐Jun, Zhou, Qi‐Lin
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 12.06.2023; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Amides; Amination; Amines; Asymmetric Catalysis; Benzylamines; Catalysis; Cations; Chemical synthesis; Chemistry; Chemistry, Multidisciplinary; Copper; C−H Amination; Enantiomers; Functional groups; Hydrogen; Oxidants; Oxidizing agents; Physical Sciences; Radicals; Science & Technology; Substrates; Asymmetric Catalysis; ASYMMETRIC-SYNTHESIS; C-H Amination; HYDROCARBONS; BONDS; Benzylamines; AMIDATION; ALLYLIC OXIDATION; OLEFINS; NITRENE TRANSFER-REACTIONS; Copper; Radicals; C−H Amination
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202304427

Chiral benzylic amines are privileged motifs in pharmacologically active molecules. Intramolecular enantioselective radical C(sp3)−H functionalization by hydrogen‐atom transfer has emerged as a straightforward, powerful tool for the synthesis of chiral amines, but methods for intermolecular enantioselective C(sp3)−H amination remain elusive. Herein, we report a cationic copper catalytic system for intermolecular enantioselective benzylic C(sp3)−H amination with peroxide as an oxidant. This mild, straightforward method can be used to transform an array of feedstock alkylarenes and amides into chiral amines with high enantioselectivities, and it has good functional group tolerance and broad substrate scope. More importantly, it can be used to synthesize bioactive molecules, including chiral drugs. Preliminary mechanistic studies indicate that the amination reaction involves benzylic radicals generated by hydrogen‐atom transfer. A highly enantioselective intermolecular benzylic C(sp3)−H bond amination by using a chiral cationic copper catalyst and oxidant di‐tert‐butyl peroxide is reported. This mild, straightforward method can be used to transform an array of feedstock alkylarenes and amides into chiral amines with high enantioselectivities, and it has good functional group tolerance and a broad substrate scope.