Directed meta-Selective Bromination of Arenes with Ruthenium Catalysts

• Published in: Angewandte Chemie International Edition Vol. 54; no. 50; pp. 15284 - 15288
• Main Authors: Yu, Qingzhen, Hu, Le'an, Wang, Yue, Zheng, Shasha, Huang, Jianhui
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 07.12.2015; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: bromination; Chemistry; Chemistry, Multidisciplinary; CH activation; meta-selective; Physical Sciences; radical processes; Science & Technology; HALIDES; ACTIVATION; BOND HALOGENATION; ALKYL; COMPLEXES; SECONDARY; C-H HALOGENATION; radical processes; FUNCTIONALIZATION; CROSS-COUPLING REACTIONS; C-H activation; LIGANDS; meta-selective; bromination; CH activation
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201507100

A Ru‐catalyzed direct CH activation/meta‐bromination of arenes bearing pyridyl, pyrimidyl, and pyrazolyl directing groups has been developed. A series of bromo aryl pyridines and pyrimidines have been synthesized, and further coupling reactions have also been demonstrated for a number of representative functionalized arenes. Preliminary mechanistic studies have revealed that this reaction may proceed through radical‐mediated bromination when NBS is utilized as the bromine source. This type of transformation has opened up a new direction for the radical non‐ipso functionalization of metal with regard to future CH activation development that would allow the remote functionalization of aromatic systems. A method for direct ruthenium‐catalyzed­ meta‐bromination of arenes bearing various pyridyl or pyrimidyl directing groups (DGs) is reported. This procedure is demonstrated in the concise synthesis of Vismodegib, and mechanistic studies suggest that bromination proceeds through radical intermediates.