Synthesis and pharmacological activity of 2-aryl-3-ethoxy-carbonyl-5-hydroxybenzofurans

Abstract

considerable number of 2-aryl-5-hydroxybenzofurans display antifungal [13], antibacterial [ii], ~-adrenoblocking [I0], anticonvulsant and psychotropic activity [2, 7]. For this reason, it was of interest to synthesize analogs of fenicarberan containing various substituents in the phenyl substituent, namely one or more methoxy groups, chlorine, bromine, or iodine atoms. Reaction of anisic acid [13], veratric acid, 3,5-dibromo- [14], 3,5-diiodo- [20], 3,5dichloro-4-methoxybenzoic acid [17], or 3,4,5-trimethoxybenzoic acid [15] with an excess of thionyl chloride gave the acid chlorides, which were treated without further purification with acetoacetic easter. There were obtained the known 4-methoxy [19] and 3,4,5-trimethoxybenzoylacetic ester [16], together with the novel 3,4-dimethoxy- (I), 3,5-dibromo-4-methoxy(II), 3,5-dichloro-4-methoxy- (III), and 3,5-diiodo-4-methoxybenzoylacetic esters (IV). Condensation of the substituted benzoylacetic esters with p-benzoquinone as described in [3] afforded 3-ethoxycarbonyl-5-hydroxybenzofurans, bearing in the 2-position the substituents4'~methoxy - (V), 3',4'-dimethoxy- (Vl), 3',4',5'-trimeth oxy- (VII), 3',5'-dibromo-4'methoxy- (VIII), 3',5'-dichloro-4'-methoxy- (IX), and 3',5'-diiodo-4'methoxyphenyl (X). As by-products in the condensation of (I-IV) with p-benzoquinone, there were isolated 2-16% of the diethyl 2,6-diarylbenzo[l,2-b:4,5-b]difuran-3,7-dicarboxylates (XI-XIV). Heating (V-X) in DM_F with formamide and Me2NH-HCI gave the 4-dimethylaminomethy ! derivatives. In the case of (VII), it was shown that the Mannich reaction when carried out with an equimolar amount of bisdimethylaminomethane in dioxane also gave the monoaminomethyl derivative (XVI). The use of an excess of bisdimethylaminomethane and increasing the reaction time resulted in the formation of the 4,6-bisdimethylaminomethyl derivatives (XXI-XXII). An exception was 2-(4'-methoxyphenyl)-3-ethoxycarbonyl-4-dimethylaminomethyl-5-hydroxybenzofuran (XX). Under the conditions for the synthesis of the disubstituted product (XXIII), we obtained high yields of the monosubstituted compound (XX) only. 2-(4-Methoxyphenyl)-3ethoxycarbonyl-4,6-bis(dimethylaminomethyl)-5-hydroxybenzofuran (XXIII) was only obtained when the aminomethylation of ()IX) with bisdimethylaminomethane was carried out in acetic acid.