Trimethyl(trifluoromethyl)silane (Ruppert–Prakash Reagent)

One of the most widely used reagents for nucleophilic trifluoromethylation is trimethyl(trifluoromethyl)silane, TMSCF₃. The reagent has become widely referred to as the Ruppert–Prakash reagent, after Ruppert who introduced the material in 1984,¹ and Prakash who is largely responsible for popularizing its use.² The broad applicability of the TMSCF₃ makes it a popular reagent in syntheses of various medicinal targets.

In one example, a series of four tri- and tetraglutamic acid and glutamine peptides were created that incorporate a trifluoromethyl ketone group.³ The β-amino alcohol synthon was synthesized in five steps where the key step utilized TMSCF₃ to create the resultant trifluoromethylated silyl ether as a single diastereomer (Scheme 1). Two of the peptides in the report were shown to exhibit inhibitory activity against severe acute respiratory syndrome coronavirus protease (SARS-CoV 3CL^pro).

Another example usesTMSCF₃ in the synthesis of a non-steroidal selective androgen receptor modulator that displays excellent oral bioavailability and anabolic activity in muscle (Scheme 2).⁴ The compound also improved bone strength in a rat model of postmenopausal osteoporosis. Similarly, Hudson and coworkers used TMSCF₃ to create a selective glucocorticoid receptor modulator that demonstrated antiproliferative activity equal to the myeloma therapeutic, dexamethasone (Scheme 3).⁵

Commonly, an additional fluoride source (TBAF, CsF, etc.) is required to initiate the trifluoromethylation reaction. However, a recent report from Prakash detailed the trilfuoromethylation of carbonyl compounds using a new series of catalysts which do not require additional fluoride initiators or water-free conditions (Scheme 4).⁶

Another report from Prakash demonstrated the use of TMSCF₃ on N-unactivated imines to yield the corresponding trifluoromethylated amine. With a slight variation in the reaction conditions, difluoromethylated amines can also be prepared via HF elimination and reduction (Scheme 5).⁷

Despite its wide use, stereoselective trifluoromethylation using the Ruppert–Prakash reagent is still challenging. However, several groups have made significant progress in this arena. Dieter Enders has reported diastereoselective trifluoromethylation of α-alkylated dioxanones with good yields and high diastereo- and enantiomeric excesses.⁸ The acetonide group is easily removed to generate the 2-trifluoromethyl-1,2,3-triols (Scheme 6).

Shibata, Toru, and coworkers have reported an operationally simple method for enantioselective trifluoromethylation based on the combination of the ammonium bromide of a cinchona alkaloid, 1, and tetramethylammonium fluoride (TMAF).⁹ The reaction proceeds in modest to excellent yields with ee’s up to 93% (Scheme 7).