A Novel Synthesis of Heterocyclic Analogues of Thioflavanones from Haloheteroaromatic Carboxylic Acids

Abstract

Thioflavanones (2-phenylthiochroman-4-ones), the thio analogues of flavanones, are an interesting class of heterocycles 1 because their biological activities sometimes can be improved. We recently investigated the anticancer effects of thioflavanone in MCF-7 human breast cancer cell lines and found that it inhibited cellular proliferation by inducing apoptosis with weak cytotoxicity. 2 The 3-cinnamylidene derivatives of thioflavanones showed antiproliferative effects 3 on mouse lymphoma cells, and the 3-chloromethylene derivatives of thiochroman-4-ones showed antifungal activities. 4 Thiochroman-4-ones have been generally synthesized by the Friedel-Crafts acylation of 3-arylmercaptopropanoic acids, which are prepared by adding thiophenols to α,βunsaturated esters or substituting 3-bromo (mesyl) esters with thiophenols and subsequent hydrolysis, with H2SO4 5 or polyphosphoric acid 6 in moderate yields. The cyclization of 3-arylthiopropanoic acids proceeded by a catalytic amount of Lewis acid, such as Bi(NTf2)3 or Yb(OTf)3, at 200 o C. 7 The direct cyclocondensation of thiophenols and 3-methyl2-butenoic acid with methanesulfonic acid resulted in thiochroman-4-ones, with the corresponding disulfides and enol thioethers obtained as minor products. 8 Another thioflavanone synthesis involved intramolecular cyclization of 2'-mercaptochalcones, which are prepared by the base catalyzed condensation of 2'-benzylthioacetophenones and benzaldehydes followed by subsequent debenzylation,