Science of Synthesis

Lishchynskyi, A.; Novák, P.; Grushin, V. V., Science of Synthesis: C-1 Building Blocks in Organic Synthesis, (2014) 2, 368.

Various sources of the trifluoromethyl group for trifluoromethylation reactions have been reviewed.[‌6‌] Nucleophilic, electrophilic, and radical trifluoromethylating reagents are known. To date, the most popular reagent for nucleophilic trifluoromethylation reactions is trimethyl(trifluoromethyl)silane (Ruppertʼs reagent),[‌3‌,‌4‌] originally reported in 1984.[‌7‌] Numerous polyfluorinated methanes can be used as a trifluoromethyl source.[‌6‌] However, most of these materials are believed to be ozone depleters and therefore they have been placed on the Montreal Protocol List and banned from the retail chemical market. Low-cost, nontoxic, and ozone-friendly trifluoromethane (fluoroform) is the most attractive and atom-economical trifluoromethyl source. Trifluoromethane is generated in large quantities (ca. 20 000–25 000 t per annum) as a side product in the manufacture of Teflon and should be destroyed or utilized because of its exceedingly high global warming potential.[‌8‌] The recent discovery of direct cupration of trifluoromethane using only inexpensive chemicals and furnishing (trifluoromethyl)copper(I) in nearly quantitative yield at room temperature and atmospheric pressure[‌9‌] is expected to open up new horizons for trifluoromethylation reactions on a larger scale. The reaction of copper(I) chloride and potassium tert-butoxide (1:2 mol/mol) in an aprotic dipolar solvent such as dimethylformamide gives quantitatively di-tert-butoxycuprate(I), which metalates trifluoromethane in a highly efficient and selective manner. Potassium, sodium, and methyl trifluoroacetates[‌6‌] as well as 2,2,2-trifluoroethanal (fluoral)[‌10‌] are inexpensive sources of the trifluoromethyl group. Methyl difluoro(fluorosulfonyl)acetate has been widely used in trifluoromethylation reactions since the original report by Chen and Wu.[‌11‌]

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References