Copper‐Catalyzed Enantioconvergent Cross‐Coupling of Racemic Alkyl Bromides with Azole C(sp2)−H Bonds. Issue 1 (28th October 2020)

• Record Type: Journal Article
• Authors: Su, Xiao‐Long; Ye, Liu; Chen, Ji‐Jun; Liu, Xiao‐Dong; Jiang, Sheng‐Peng; Wang, Fu‐Li; Liu, Lin; Yang, Chang‐Jiang; Chang, Xiao‐Yong; Li, Zhong‐Liang; Gu, Qiang‐Shuai; Liu, Xin‐Yuan
• Is Part Of: Angewandte Chemie international edition. Volume 60:Issue 1(2021)
• Page Start: 380
• Page End: 384
• Publication Date: 2020-10-28
• Subjects: alkylation -- asymmetric radical reactions -- azoles -- copper -- racemic alkyl bromides; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202009527
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: The development of enantioconvergent cross‐coupling of racemic alkyl halides directly with heteroarene C(sp 2 )−H bonds has been impeded by the use of a base at elevated temperature that leads to racemization. We herein report a copper(I)/cinchona‐alkaloid‐derived N, N, P ‐ligand catalytic system that enables oxidative addition with racemic alkyl bromides under mild conditions. Thus, coupling with azole C(sp 2 )−H bonds has been achieved in high enantioselectivity, affording a number of potentially useful α‐chiral alkylated azoles, such as 1, 3, 4‐oxadiazoles, oxazoles, and benzo[ d ]oxazoles as well as 1, 3, 4‐triazoles, for drug discovery. Mechanistic experiments indicated facile deprotonation of an azole C(sp 2 )−H bond and the involvement of alkyl radical species under the reaction conditions. Abstract : The use of a cinchona‐alkaloid‐derived N, N, P ‐ligand leads to the direct enantioconvergent coupling of racemic alkyl bromides with azole C(sp 2 )−H bonds by copper catalysis. The key to success is the ligand‐enabled facile oxidative addition at approximately room temperature that suppresses product racemization at elevated temperature. This method provides a range of enantioenriched α‐chiral alkylated azoles.