5-thiazolyl derivatives of 4-aryl-3,4-dihydropyrimidin-2(1H)-ones

Abstract

As shown by calculations by means of the PASS software [1], the 5-(1,3-thiazol-4-yl) derivatives of 4-aryl-3,4-dihydropyrimidin-(1H)-2-ones are promising subjects in the search for physiologically active substances. Moreover, there are few publications on the synthesis of 4-aryl-3,4-dihydropyrimidin-(1H)-2-ones containing a heterocyclic fragment at position 5 [2-4], and their synthesis will make it possible to develop substantially the theories about such systems. The most obvious way of constructing the 1,3-thiazole ring is the Hantsch reaction, the starting materials for which must be the ω-bromoacetyl derivatives of compounds produced by the Biginelli reaction. It is known that the related 4-aryl-5-ethoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-ones, also produced by the Biginelli reaction, are brominated at the methyl group with the formation of 6-bromomethyl and 6,6-dibromomethyl derivatives [5-7]. We studied the bromination of the 5-acetyl derivatives of 4-aryl-3,4dihydropyrimidin-2(1H)-ones 1 and 2 in order to determine how the presence (or absence) of the 6-methyl group in these molecules would affect the course of bromination. As found, the 6-methyl derivative 1 does not react with bromine in acetic acid at room temperature (the initial compound is recovered completely on dilution of the reaction mixture with water), while the low solubility of the compound does not permit the reaction in chloroform or alcohol. At the same time, the bromination of compound 1 in acetic acid with heat leads to resinification of the mixture. Earlier [8, 9] we showed that by inserting a 1-alkyl substituent it is possible to eliminate the possibility of amide–imidol tautomerism in 5-acetyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones, affecting the processes involving removal of the acetyl group, and to increase their solubility significantly, and this should make it possible to realize bromination under mild conditions. This was confirmed during the bromination of the 1,6-dimethyl derivative 2; nevertheless, a complex mixture is formed both in chloroform and in acetic acid due, probably, to crossed bromination of both the acetyl group and the 6-methyl group. We assumed that the absence of a methyl group at position 6 of the heterocycle would make it possible to minimize the contribution from the bromination paths. Compounds 3a,b corresponded fully to such a model. Our assumptions were fully confirmed; the reaction of compounds 3a,b with bromine take place at a sufficiently high rate in chloroform at room temperature. Although according to H NMR spectroscopy the bromination products represent mixtures of substances the main products among them are the ω-bromoacetyl derivatives in which we are interested, since the direct use of these mixtures in reaction with thioamides made it possible to obtain moderate yields of the corresponding thiazoles 4a-d.