Novel Synthesis of Thioflavones and Their Pyridyl Analogs from 2-Mercaptobenzoic(nicotinic) Acid

Abstract

Thioflavones have the skeleton of a thiochromen-4-one ring, which serves as a building block for biologically active molecules. Thioflavones have drawn much attention because of their various pharmacological activities such as antimalarial, antiviral, and antimicrobial activity. They also inhibit the proliferation of tumor cells while thioflavonoids, such as 3’,4’-dimethoxythioflavone, relax vascular contraction by activation of the EGF receptor. Several types of synthetic reactions for thioflavones and their heterocyclic analogs have been described in the literature. Among them, a tandem reaction using 2’-substituted chalcones and ynones allows for the efficient synthesis of thioflavones and their heterocyclic analogs. Three types of 2’-substituted chalcones, which were prepared from the condensation of arylaldehydes and 2’-substituted acetophenones, were converted to thioflavones by the following methods (Scheme 1(a)): (i) Treatment of 3-aryl-1-[2-(t-butylsulfanyl)phenyl]prop-2-en-1-ones with 3 equiv. iodine and NaHCO3 at reflux in EtCN. 7 (ii) Cyclization of 2’-tosyloxychalcones with 5 equiv. sulfur in the presence of Et3N in DMSO at 80 °C. This method produced thioflavones together with (Z)-thioaurones as byproducts. (iii) Cu-catalyzed cyclization of 2’-iodo(bromo)chalcones using 2 equiv. potassium ethyl xanthogenate followed by the sequential oxidation of thioflavanone intermediates using H2SO4 in DMSO at 80 °C. The coupling of 2-(methylthio)benzoyl chlorides and arylacetylenes with 2.5 equiv. AlCl3 in CH2Cl2, followed by the addition of chloride, afforded the 2’-(methylthio)β-chlorochalcone intermediates. These intermediates underwent sequential 1,4-addition of sulfur atom and demethylation by chloride anion to yield the thioflavones (Scheme 1(b)). Similarly, sequential addition of NaSH-elimination-SNAr reaction to 2’-halo-β-chlorochalcones, in the presence of 2 equiv. Cs2CO3 in DMSO at 140 °C, also afforded the thioflavones (Scheme 1(b)). On the other hand, the 1,4-addition of 1-(2-methoxyphenyl)-3-phenylprop-2-yn-1-ones with sodium sulfide nonahydrate produced 3-mercapto-1-(2-methoxyphenyl)-3-