Details

Autor(en) / Beteiligte

• Xiao, Haiwen
• Liu, Zhonglin
• Shen, Haigen
• Zhang, Benxiang
• Zhu, Lin
• Li, Chaozhong

Titel

Copper-Catalyzed Late-Stage Benzylic C(sp3)–H Trifluoromethylation

Ist Teil von

• Chem, 2019-04, Vol.5 (4), p.940-949

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Direct trifluoromethylation of C(sp3)–H bonds, especially in late stages, remains a formidable challenge. Herein, we describe the copper-catalyzed benzylic C(sp3)–H trifluoromethylation. With Cu(I) or Cu(II) as the catalyst, (bpy)Zn(CF3)2 (bpy = 2,2′-bipyridine) as the CF3 source, and NFSI (or Selectfluor) as the oxidant, site-selective benzylic C(sp3)–H trifluoromethylation is successfully implemented in high efficiency under mild conditions. The protocol not only exhibits broad substrate scope and wide functional-group compatibility but also allows efficient late-stage C(sp3)–H trifluoromethylation of natural products or drug derivatives. [Display omitted] •Direct benzylic C–H trifluoromethylation enabled by copper catalysis•Broad substrate scope and wide functional-group compatibility•Late-stage modification of natural products and drug derivatives The introduction of trifluoromethyl groups into organic molecules is of paramount importance in pharmaceuticals and agrochemicals because of their profound effect on properties such as lipophilicity, permeability, and metabolic stability. However, direct C(sp3)–H trifluoromethylation, which is most atom economical, remains a formidable challenge, and only a few examples with limited substrate scope and low to moderate efficiency have been reported to date. In this article, we introduce the copper-catalyzed benzylic C(sp3)–H trifluoromethylation with the easily available (bpy)Zn(CF3)2 complex as the CF3 source. This unprecedented protocol not only exhibits a high efficiency and broad substrate scope but also allows the late-stage trifluoromethylation of bioactive molecules or natural product derivatives. Because the procedure is operationally simple and the conditions are mild, the method should find immediate application in the synthesis of important trifluoromethylated molecules. Trifluoromethylated molecules are of paramount importance in pharmaceuticals and agrochemicals, but methods of making them by direct C(sp3)–H trifluoromethylation are extremely rare. In this issue of Chem, Li and coworkers describe a copper-catalyzed late-stage benzylic C–H trifluoromethylation with broad substrate scope and functional-group tolerance. The reaction may serve the late-stage modification of drug candidates.