Enantioselective Synthesis of Atropisomeric Biaryls by Pd‐Catalyzed Asymmetric Buchwald–Hartwig Amination

• Published in: Angewandte Chemie International Edition 2021-09, Vol.60 (40), p.21718-21722
• Main Authors: Zhang, Peng, Wang, Xiao‐Mei, Xu, Qi, Guo, Chang‐Qiu, Wang, Peng, Lu, Chuan‐Jun, Liu, Ren‐Rong
• Format: Article
• Language: English
• Subjects: amidines; Amination; asymmetric catalysis; atropisomerism; Chemical synthesis; Coupling (molecular); Cross coupling; Enantiomers; Natural products; Palladium; Stereoselectivity
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202108747

N−C Biaryl atropisomers are prevalent in natural products and bioactive drug molecules. However, the enantioselective synthesis of such molecules has not developed significantly. Particularly, the enantioselective synthesis of N−C biaryl atropisomers by stereoselective metal‐catalyzed aryl amination remains unprecedented. Herein, a Pd‐catalyzed cross‐coupling strategy is presented for the synthesis of N−C axially chiral biaryl molecules. A broad spectrum of N−C axially chiral compounds was obtained with excellent enantioselectivities (up to 99 % ee) and good yields (up to 98 %). The practicality of this reaction was validated in the synthesis of useful biological molecules. A Pd‐catalyzed enantioselective amination of amidines has been developed for the synthesis of N−C biaryl atropisomers. A wide range of benzimidazole derivatives containing N−C axial chirality can be conveniently constructed in excellent yields and enantioselectivities by intramolecular amination.