Trifluoromethylation

Trifluoromethylation in organic chemistry describes any organic reaction that introduces a trifluoromethyl group in an organic compound. Trifluoromethylated compounds are of some importance in pharmaceutical industry and agrochemicals. Several notable pharmaceutical compounds have a trifluoromethyl group incorporated: fluoxetine, mefloquine, Leflunomide, nulitamide, dutasteride, bicalutamide, aprepitant, celecoxib, fipronil, fluazinam, penthiopyrad, picoxystrobin, fluridone, norflurazon, sorafenib and triflurazin. A relevant agrochemical is trifluralin. The development of synthetic methods for adding trifluoromethyl groups to chemical compounds is actively pursued in academic research. The first to investigate trifluoromethyl groups in relationship to biological activity was F. Lehmann in 1927. An early review appeared in 1958. An early synthetic method was developed by Frédéric Swarts in 1892, based on antimony fluoride. In this reaction benzotrichloride was reacted with SbF3 to form PhCF2Cl and PhCF3. In the 1930s Kinetic Chemicals and IG Farben replaced SbF3 with HF. The McLoughlin-Thrower reaction (1968) is an early coupling reaction using iodofluoroalkanes, iodoaromatic compounds and copper. In 1969 Kobayashi & Kumadaki adapted their protocol for trifluoromethylations. Preparation of the trifluoromethyltrimethylsilane was reported by Ingo Ruppert in 1984. In 1989, Prakash and Olah first reported activation of TMSCF3 by fluoride to perform nucleophilic trifluoromethylation of carbonyl compounds. In the same year, Stahly described similar reactions for the synthesis of trifluoromethylated phenols and anilines. Since then TMSCF3 has been widely used as a nucleophilic trifluoromethylating agent. An example is the trifluoromethylation of cyclohexanone in THF using tetrabutylammonium fluoride. The substrates can be aryl halides. Potassium (trifluoromethyl)trimethoxyborate for this purpose has been synthesised from B(OMe)3, CF3SiMe3 and KF. Aryl functionalization by C-H activation has also been reported.