Bromination-Dehydrobromination of 4-Aryl-5-nitro-6-phenyl-3,4-dihydropyrimidin-2(1H)-ones

Abstract

Depending on the conditions, bromination of 4-aryl-5-nitro-6-phenyl-3,4-dihydropyrimidine-2(1H)-ones and subsequent dehydrobromination gives either 4-aryl-5-nitro-6-phenylpyrimidin-2(1H)-ones or their mixtures with the corresponding 4-aryl-5-bromo-6-methoxy-5-nitro-6-phenyltetrahydropyrimidin-2-ones which are formed as two diastereoisomers.Some 4-aryl-5-nitro-3,4-dihydropyrimidin-2(1H)-ones exhibit an appreciable biological activity, specifically as calcium channel modulators [1]. We recently found that several 4-aryl-5-nitro-6-phenyl-3,4-dihydropyrimidin-2(1H)-one derivatives show a high antiarrhythmic activity [2]. According to the data of [3], the stability of the heterocyclic fragment in 1,4(or 3,4)-dihydropyrimidines and structurally related 1,4-dihydropyridines to aromatization is important for their biological activity. Therefore, it seemed to be reasonable to examine the behavior of 4-aryl-5-nitro-6-phenyl-3,4-dihydropyrimidin-2(1H)-ones I in dehydrogenation and oxidation reactions which could result in aromatization of the heteroring.The present communication reports on the bromination and subsequent dehydrobromination of dihydropyrimidinones Ia-Ic. This two-step technique is widely used for aromatization of dihydropyrimidinones [4]. Here, the first step (i.e., bromination) is usually determining. It was shown that the ease of bromination of 4,6-diphenyldihydropyrimidin-2-ones depends on the substituent in position 5 of the heteroring. The bromination of 4,6-diphenyldihydropyrimidin-2-ones having such substituent in position 5 as ethoxycarbonyl, aroxy, or nitro group requires more severe conditions as compared to the corresponding 5-unsubstituted and 5-alkyl derivatives [4][5][6]. For example, compound Ia undergoes bromination with bromine in boiling acetic acid, and the subsequent dehydrobromination yields pyrimidinone IIa [5].Taking into account these findings, we performed bromination of 3-chlorophenyl derivative Ib on heating in acetic acid, and the bromination product was isolated and treated with pyridine in boiling methanol. As a result, we obtained 4-(3-chlorophenyl)-5-nitro-6-phenylpyrimidin-2(1H)-one (IIb) in good yield (Scheme 1). Unlike compounds Ia and Ib, 4-(4-methoxyphenyl)-5-nitro-6-phenyl-3,4-dihydropyrimidin-2(1H)-one (Ic) readily reacted with an equimolar amount of bromine both in acetic acid and in chloroform at room temperature. However, the reaction involved only the methoxyphenyl group to give 4-(3-bromo-4-methoxyphenyl)-5-nitro-6-phenyl-3,4-dihydropyrimidin-2(1H)-one (Id). This is consistent with published data on ready bromination of para-substituted anisoles [7]. The subsequent bromination of compound Id with an equimolar amount of bromine in acetic acid on heating, followed by dehydrobromination, afforded a mixture of products containing 4-(3-bromo-4-methoxyphenyl)-5-nitro-6-phenylpyrimidin-2(1H)-one (IId) and dibromo derivatives (according to the data of elemental analysis and mass spectrometry). We succeeded in isolating compound IId and a mixture of dibromo derivatives, but ...