Ruthenium(II)-enabled para-selective C–H difluoromethylation of anilides and their derivatives

• Published in: Nature communications Vol. 9; no. 1; pp. 1189 - 10
• Main Authors: Yuan, Chunchen, Zhu, Lei, Chen, Changpeng, Chen, Xiaolan, Yang, Yong, Lan, Yu, Zhao, Yingsheng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.03.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 119/118; 140/131; 140/146; 639/638/403/934; 639/638/549/933; 639/638/77/888; Aromatic compounds; Chelation; Chemical engineering; Chemistry; Complex compounds; Derivatives; Drug discovery; Fluorination; Fluorine; Heterocyclic compounds; Humanities and Social Sciences; multidisciplinary; Pharmaceutical sciences; Ruthenium; Ruthenium compounds; Science; Science (multidisciplinary); Substrates
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03341-6

Transition-metal-catalyzed direct site-selective functionalization of arene C–H bonds has emerged as an innovative approach for building the core structure of pharmaceutical agents and other versatile complex compounds. However, para -selective C–H functionalization has seldom been explored, only a few examples, such as steric-hindered arenes, electron-rich arenes, and substrates with a directing group, have been reported to date. Here we describe the development of a ruthenium-enabled para -selective C–H difluoromethylation of anilides, indolines, and tetrahydroquinolines. This reaction tolerates various substituted arenes, affording para -difluoromethylation products in moderate to good yields. Results of a preliminary study of the mechanism indicate that chelation-assisted cycloruthenation might play a role in the selective activation of para -C Ar –H bonds. Furthermore, this method provides a direct approach for the synthesis of fluorinated drug derivatives, which has important application for drug discovery and development. Selective para-functionalization of substituted arenes is a formidable challenge in homogeneous catalysis. Here, the authors achieved the para-selective C-H difluoromethylation of anilides, indolines and tetrahydroquinolines with a ruthenium catalyst in good yields and apply it to the synthesis of bioactive compounds.