Direct Cyclization–Trifluoromethylthiolation to 4H-Chromen-4-ones

Key words

trichloroisocyanuric acid - intramolecular cyclization - chromenones

Significance

Reported is a general synthesis of 3-[(trifluoromethyl)thio]-4H-chromen-4-ones 2 from 1-(2′-hydroxyphenyl)-3-dimethylaminoprop-2-enones 1 and the active electrophilic trifluoromethylthio moiety generated from AgSCF₃and trichloroisocyanuric acid (TCCA). This synthetic approach leads to the direct introduction of the SCF₃ group into chromen-4-ones, which represents a very desirable technique to produce diverse molecules for the medicinal chemist. The screening of reaction conditions showed that the reaction is highly dependent on the solvent; for example, yields in THF were better than in DMF; however, no product was obtained for reactions that were carried out in MeCN, CH₂Cl₂, DMSO, MTBE or toluene. The reaction also showed dependency on the optimized amount of TCCA (1.5 equiv), and remarkable insensitivity to air and moisture. The synthetic utility of this reaction to synthesize other SCF₃-containing heterocycles such as a topopyrone C analogue was also investigated.

Comment

The trifluoromethylthio group is incorporated in many bioactive molecules such as the hypotensive agents losartan and nifedipine (L. M. Yagupolskii et al. J. Fluorine Chem. 2001, 109, 87). Classic approaches of introducing this group include an indirect, multistep method (A. E. Feiring J. Org. Chem. 1979, 44, 2907). Herein, an easy and direct synthetic route was used to accomplish the same result. A mechanism was presented without evidence. It includes the possibility of an intramolecular Michael addition–cyclization of 1, followed by enolate nucleophilic attack on the ⁺SCF₃ species, then a N,N-dimethylamine elimination process to produce 2.