Trifluoromethylation
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.
The development of synthetic methods for adding trifluoromethyl groups to chemical compounds is actively pursued in academic research.
[11] In 1989, Prakash and Olah first reported activation of TMSCF3 by fluoride to perform nucleophilic trifluoromethylation of carbonyl compounds.
[34] In coupling reactions between aromatic compounds and metal-trifluoromethyl complexes the metal is usually copper, Pd and Ni are less prominent.
A palladium acetate catalysed reaction described in 1982 used zinc powder with the main intermediate believed to be CF3ZnI with Pd(0) is the active catalyst.
[44] Reagents such as bromotrifluoromethane and haloform have been used for this purpose[45][46][47] but in response to the Montreal Protocol alternatives such as trifluoroiodomethane have been developed as replacement.
[48][49] One particular combination is CF3I / triethylborane[50][51] Other reagents that generate the CF3 radical are sodium trifluoromethanesulfinate and bis(trifluoroacetyl) peroxide.
[54] It was, however, widely believed that the trifluoromethyl anion is a transient species and thus cannot be isolated or observed in the condensed phase.
Contrary to the popular belief, the CF3 anion, with [K(18-crown-6)]+ as a countercation, was produced and characterized by Prakash and coworkers.
[55] The challenges associated with observation of CF3 anion are alluded to its strong basic nature and its tendency to form pentacoordinated silicon species, such as [Me3Si(CF3)2]− or [Me3Si(F)(CF3)]−.
The reactivity of fluoroform in combination with a strong base such as t-BuOK with carbonyl compounds in DMF is an example.
Substrates are thiols, alcohols, phosphines, (hetero) arenes,[71] unactivated olefins[72] and unsaturated carboxylic acids.
[73] The reaction mechanism of electrophilic trifluoromethylations has been described as controversial with polar substitution or single electron transfer as likely candidates.
[74][75] Ruppert's reagent has been used for this purpose in an asymmetric induction approach to functionalise chiral amino acid derivates,[76] saccharides,[77] and steroids.
