Copper-Mediated Trifluoromethylation of Benzylic Csp3 -H Bonds

Matthew Paeth; William Carson; Jheng-Hua Luo; David Tierney; Zhi Cao; Mu-Jeng Cheng; Wei Liu

doi:10.1002/chem.201802766

Copper-Mediated Trifluoromethylation of Benzylic Csp³ -H Bonds

Chemistry. 2018 Aug 9;24(45):11559-11563. doi: 10.1002/chem.201802766. Epub 2018 Jul 18.

Authors

Matthew Paeth¹, William Carson¹, Jheng-Hua Luo², David Tierney¹, Zhi Cao³, Mu-Jeng Cheng², Wei Liu¹

Affiliations

¹ Department of Chemistry and Biochemistry, Miami University, 651. E. High Street, Oxford, Ohio, 45056, USA.
² Department of Chemistry, National Cheng Kung University, 1 University Road, Tainan City, Taiwan.
³ Synfuels China, Beijing, 100195 and Institute of Coal Chemistry, Chinese Academy of Sciences, Taiyuan, Shanxi, 030001, P. R. China.

PMID: 29905985
DOI: 10.1002/chem.201802766

Abstract

Trifluoromethyl-containing compounds play a significant role in medicinal chemistry, materials and fine chemistry. Although direct C-H trifluoromethylation has been achieved on Csp² -H bonds, direct conversion of Csp³ -H bonds to Csp³ -CF₃ remains challenging. We report herein an efficient protocol for the selective trifluoromethylation of benzylic C-H bonds. This process is mediated by a combination Cu^III -CF₃ species and persulfate salts. A wide range of methylarenes can be selectively trifluoromethylated at the benzylic positions. A combination of experimental and theoretical mechanistic studies suggests that the reaction involves a radical intermediate and a Cu^III -CF₃ species as the CF₃ transfer reagent.

Keywords: C−H activation; copper; fluorination; late-stage diversification; trifluoromethylation.