N.Aryl.f-methyl-~-alanines were synthesized by the reaction of aromatic amines with crotonic acid. The products were converted to dihydropyrimidine-2,4-dione derivatives. Alkylation, acylation, and oximation of l-arylpyrimidine-2,4-diones were carried out. Conformational analysis of the compounds obtained was carried out by dynamic NMR methods.
N-Substituted S-amino acids are frequently used for the synthesis of various nitrogen-containing heterocycles, particularly dihydropyrimidine-2,4-dione derivatives. It is known that 5-and 6-methyl-1-(1-naphthyl)dihydropyrimidine-2,4-diones and their 2-thiono analogs form stable conformers because of retarded rotation about the N-C bond and can be isolated in individual form by means of TLC [1, 2]. In the cited research a number of 1-aryl-6-methyldihydropyrimidine-2,4-diones and their 2-thiono analogs having various substituents in the 2 position of the aromatic ring and potentially capable of forming rotational isomers were synthesized and investigated by dynamic NMR methods. The energy characteristics of these processes have not been previously studied.
To synthesize N-substituted [3-methyl-13-alanines II, which are the starting compounds for obtaining dihydropyrimidine-2,4-diones, we used the alkylation of aromatic amines by crotonic acid via the Michael reaction. The resulting N-aryl-~methyl-~-atanines II are difficult-to-crystallize substances, and most of them were therefore isolated in the form of the hydrochlorides.
The dihydropyrimidine-2,4-diones and their 2-thiono analogs were synthesized by refluxing the corresponding N-aryl~methyl-~-alanines or their hydrochlorides with urea or alkali metal thiocyanates in glacial acetic acid for 14 h. The N-aryl-, Ncarbamoyl-, and N-thiocarbamoyl-t3-methyl-fl-alanines III and IV formed during the reaction were cyclized, without isolation, to pyrimidinedione derivatives with concentrated hydrochloric acid. The cyclization proceeds with high yields and is virtually complete after refluxing of the reaction mixture for 3-5 min. More prolonged refluxing, as, for example, in the synthesis of Vg and VIg, leads to cleavage of the ester bond and the formation of 1-(2-hydroxyphenyl)dihydropyrimidinedione derivatives. Decyclization and cyclization of the dihydrouracil ring proved to be a convenient method for the purification of V and VI. Compounds V and VI were dissolved by heating in 10% NaOH solution, and the undissolved impurities, particularly the Nsubstituted ureas, were removed by filtration. The aqueous solution of the sodium salt of the corresponding N-aryl.N-(thio)earbamoyl-t3-methyl-fl-alanine was acidified to pH 1-2 with concentrated HCI and refluxed for 3-5 min.
3-Methyldihydropyrimidine-2,4-diones VII were isolated in the alkylation of Vb, c with dimethyl sulfate. Acylation of the same compounds with benzoyl chloride also takes place at the amide N(3) atom, and 3-benzoyl derivatives VIIIb, c are formed as a result. The introduction of an alkyl or acyl group into dihydropyrimidinediones V leads to disappearance of the absorption bands of an NH bond at 3195-3230 cm -1, while yet another band of the carbonyl group of an acyl fragment appears in the spectra of VIIIb, c at 1760 cm -1. The presence of two or three clearly expressed absorption bands of carbonyl groups in the spectra of VIIb, c and VIIIb, c excludes the assumption of O-alkylation.
Reactions involving replacement of the oxygen atom of the oxo groups of dihydropyrimidine-2,4-diones by a hydroxyimino group have been heretofore unknown. This can be explained in part by the fact that the dihydropyrimidine ring, under the influence of strong nucleophiles, can undergo recyclization or undergo decomposition to amino acid derivatives such as hydrazides [3]. We synthesized 1-aryl-4-hydroxyimino-6-methyldihydropyrimidinediones IXb, c by heating the corresponding pyrimidine-2,4-diones Vb, c with hydroxylamine hydrochloride in a mixture of pyridine and 2-propanol; the products were obtained in 79-93% yields.