Ruthenium(II)-enabled para-selective C–H difluoromethylation of anilides and their derivatives
Chunchen Yuan1, Lei Zhu2, Changpeng Chen1, Xiaolan Chen1, Yong Yang3, Yu Lan*2（蓝宇）& Yingsheng Zhao*1（赵应声）
1 Key Laboratory of Organic Synthesis of Jiangsu Province College of Chemistry, Chemical Engineering, and Materials Science Soochow University, Suzhou,215123, China.
2 School of Chemistry and Chemical Engineering Chongqing University, Chongqing 40030, China.
3 Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Science, Qingdao 266000, China.
NATURE COMMUNICATIONS , (2018) 9:1189
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-CAr–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.