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.
History
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.
Reagents
Trifluoromethyltrimethylsilane
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.
Sodium trifluoroacetate
Sodium trifluoroacetate as a reagent for trifluoromethylations was introduced by Matsui in 1981. In the original scope the substrate was an aromatic halide and the metal salt copper(I)iodide.
Trifluoromethane
Fluoroform (CF3H) has been employed as a trifluoromethylation reagent for aldehydes in combination with a strong base.
Trifluoroiodomethane
Trifluoroiodomethane is a reagent in aromatic coupling reactions. It has also been used with enones, for example with chalcone, a reaction catalysed by diethyl zinc and Wilkinson's catalyst:
Trifluoromethyl sulfone
Trifluoromethyl sulfone (PhSO2CF3) and trifluoromethyl sulfoxide (PhSOCF3) can be used for trifluoromethylations of electrophiles
Trifluoromethanesulfonyl chloride
Trifluoromethanesulfonyl chloride (or triflyl chloride, CF3SO2Cl) can be used in a highly efficient method to introduce a trifluoromethyl group to aromatic and heteroaromatic systems, including known pharmaceuticals such as Lipitor. The chemistry is general and mild, and uses a photoredox catalyst and a light source at room temperature.
Sodium trifluoromethanesulfinate
Sodium trifluoromethanesulfinate (CF3SO2Na) as a trifluoromethylation reagent was introduced by Langlois in 1991. The reaction requires t-butyl hydroperoxide and generally a metal and proceeds through a radical mechanism. The reagent has been applied with heterocyclic substrates
Umemoto reagents
Umemoto reagents are (trifluoromethyl)dibenzoheterocyclic salts, such as 5-(trifluoromethyl)dibenzothiophenium triflate and 5-(trifluoromethyl)dibenzothiophenium tetrafluoroborate.
Trifluoromethyl-metal reagents
Many CF3-containing metal complexes have been prepared, and some are useful for trifluoromethylation. The most obvious reagent is CF3Li, which can be generated by lithium-iodide exchange. This compound is however unstable even at low temperatures. It degrades to lithium fluoride and difluorocarbene. Trifluoromethyl copper(I) reagents are more useful. These reagents are generated in situ by reaction of CF3I with copper powder in polar solvents. Hg(CF3)2, prepared by decarboxylation of the trifluoroacetate, has proven useful for the trifluoromethylation of other metals.