Copper‐Catalyzed Enantioconvergent Cross‐Coupling of Racemic Alkyl Bromides with Azole C(sp2)−H Bonds

• Published in: Angewandte Chemie International Edition Vol. 60; no. 1; pp. 380 - 384
• Main 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
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 04.01.2021; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Alkylation; Antifungal agents; asymmetric radical reactions; Azoles; Bonding; Bromides; Chemistry; Chemistry, Multidisciplinary; Copper; Cross coupling; Enantiomers; Halides; Heterocyclic compounds; High temperature; Hydrogen bonds; Oxadiazoles; Oxazoles; Physical Sciences; racemic alkyl bromides; Racemization; Science & Technology; Triazoles; HALIDES; C-H ALKYLATION; PALLADIUM; ACTIVATION; PHOTOREDOX; SECONDARY; BORONIC ESTERS; FUNCTIONALIZATION; HETEROARENES; azoles; alkylation; copper; racemic alkyl bromides; HYDROHETEROARYLATION; asymmetric radical reactions
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202009527

The development of enantioconvergent cross‐coupling of racemic alkyl halides directly with heteroarene C(sp2)−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(sp2)−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(sp2)−H bond and the involvement of alkyl radical species under the reaction conditions. The use of a cinchona‐alkaloid‐derived N,N,P‐ligand leads to the direct enantioconvergent coupling of racemic alkyl bromides with azole C(sp2)−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.