Acid-promoted direct electrophilic trifluoromethylthiolation of phenols

Abstract

The electrophilic aromatic ring trifluoromethylthiolation of various substituted phenols was accomplished using PhNHSCF₃ (N-trifluoromethylsulfanyl)aniline, (1) in the presence of BF₃·Et₂O (2) or triflic acid as the promoter. The functionalization was exclusively para-selective; phenols unsubstituted in both the ortho- and para positions solely gave the para-substituted SCF₃-products in all cases, while para-substituted phenols gave the ortho-substituted SCF₃-products. 3,4-Dialkyl substituted phenols yielded the corresponding products according to the Mills-Nixon effect, and estrone and estradiol furnished biologically interesting SCF₃-analogues. The highly reactive catechol and pyrogallol substrates gave the expected products smoothly in the presence of BF₃·Et₂O, whereas less reactive phenols required triflic acid. 2-Allylphenol gave the expected p-SCF₃ analogue, which underwent an addition/cyclization sequence and furnished a new di-trifluoromethylthio substituted 2,3-dihydrobenzofuran derivative. Some additional transformations of 4-(trifluoromethylthio)phenol with NBS, NIS, HNO₃, HNO₃/H₂SO₄ and 4-bromobenzyl bromide were performed giving bromo-, iodo-, nitro- and benzyl substituted products. The latter derivative underwent Suzuki–Miyaura coupling with phenylboronic acid.