Trifluoromethyl Ethers and –Thioethers as Tools for Medicinal Chemistry and Drug Discovery

Abstract

The ever-growing number of fluorinated compounds in medicinal and agrochemical applications has led to a remarkable positive emulation in research. The last few years have been the witness of several advances in the search of more effective and user-friendlier methods for the introduction of fluorine as substituent or of fluorinated groups on various structures. In particular, the synthesis of trifluoromethyl ethers and thioethers is receiving increasing attention due to the peculiar properties of the OCF3 and SCF3 groups. This review will cover the different methods for the preparation of trifluoromethyl ethers and thioethers, and will emphasize on the most recent developments, including the use of catalytic methods or of methodologies for trifluoromethylation or trifluoromethanesulfanylation.

Direct S-difluoromethylation of thiols using the Ruppert–Prakash reagent

“…Analogues to aryl and alphatic trifluoromethyl thioethers [1], difluoromethyl thioethers are promising synthons in medicinal chemistry and materials science. The SCF 2 H group has attracted considerable attention recently as it promises a unique lipophilic weak hydrogen bond donor property.…”

“…1 H,13 C and 19 F NMR spectra were recorded on Varian 500 MHz or 400 MHz NMR spectrometers 1. H NMR chemical shifts were determined relative to the signal of aThe mixture was stirred for 5 min under inert atmosphere in a microwave vial or a Schlenk flask.…”

“…The combined organic layers were then dried over anhydrous MgSO 4 , filtered and dried in a rotary evaporator. The resulting residue was purified by silica flash column chromatography using pentane or hexane/EtOAc gradient and the pure fractions were combined and rotary evaporated to obtain the pure difluoromethyl thioethers.Colorless oil (77.1 mg; 82% yield) 1. H NMR (399 MHz, CDCl 3 ) 7.25-7.21 (m, 1H), 7.17-7.15 (m, 2H), 6.67 (t, J = 57.0 Hz), 2.55 (s, 6H).…”

Rapid Dehydroxytrifluoromethoxylation of Alcohols

“…CF 3 O-containing pharmaceuticals and agrochemicals such as Delamanid, Riluzole, Sonidegib, Metaflumizone, and Indoxacarb have been continuously developed. The high demand for biologically active molecules has stimulated significant efforts to develop efficient methods for the installation of trifluoromethoxy functionality (Landelle et al., 2014, Lin et al., 2015, Tlili et al., 2016). However, the installation of such functionality remains a challenging task.…”

Electrophilic trifluoromethylthiolation of thiols with trifluoromethanesulfenamide

“…The triuoromethylthiol group CF 3 S-exhibits a remarkably high lipophilicity parameter, and is one of the key fragments in certain biologically relevant compounds. 13 The 2 0 -SCF 3 substituted uridine derivative was found to be a potent label for probing structure and function of RNA by 19 F NMR spectroscopy.…”