I. P. Yakovlev

Reaction of 4-hydroxy-6H-1,3-oxazin-6-ones with guanidine. Synthesis of new 1,3,5-triazine derivatives

Abstract2-(2-Furyl)- and 2-(2-thienyl)-5-alkyl-4-hydroxy-6H-1,3-oxazin-6-ones react with guanidine in methanol in the presence of an equimolar amount of sodium methoxide to give previously unknown sodium 4-amino-6-hetaryl-1,3,5-triazin-2-ylacetates. The reactions of 2-(2-furyl)- and 2-(2-thienyl)-5-phenyl-4-hydroxy-6H-1,3-oxazin-6-ones with guanidine under analogous conditions are accompanied by decarboxylation, yielding 4-benzyl-6-hetaryl-1,3,5-triazin-2-amines. The corresponding decarboxylation products are also obtained by treatment of sodium 2-(4-amino-6-hetaryl-1,3,5-triazin-2-yl)propionates with aqueous HCl.

Reactions of 2-alkylsulfanyl- and 2-alkoxy-4-hydroxy-6H-1,3-oxazin-6-ones with O-nucleophiles

Reactions of 2-alkylsulfanyl- and 2-alkoxy-4-hydroxy-6H-1,3-oxazin-6-ones with oxygen-centered nucleophiles were studied. 2-Alkoxy-4-hydroxy-6H-1,3-oxazin-6-ones reacted with water and alcohols to give the corresponding alkyl 3-amino-3-oxopropanoates as a result of opening of the oxazine ring at the C6-O bond, whereas their 2-alkylsulfanyl analogs turned out to be stable toward O-nucleophiles. The different reactivities of the title compounds were interpreted in terms of quantum-chemical calculations of their electronic structure.

Reaction of methyl thiocarbamate with nonsubstituted malonyl dichloride. Effect of conditions on reaction direction

The reaction of methyl thiocarbamate with malonyl dichloride at low temperatures provides an N-substituted thiocarbamate, whereas prolonged boiling in high-boiling solvents gives rise to 4-hydroxy-2-(methylsulfanyl)-6H-1,3-oxazin-6-one that was also prepared by treatment of the N-substituted thiocarbamate with malonyl chloride in toluene and chlorobenzene.

Potentiometric study on acid properties of some 4-hydroxy-6H-1,3-oxazin-6-ones. Structure-biological activity relationship

Abstract4-Hydroxy-6H-1,3oxazin-6-ones exhibit properties of weak OH acids. These compounds are readily methylated with diazomethane to give the corresponding 4-methoxy derivatives. According to the potentiometric titration data, the pKa values of 2-methoxy-and 2-methylsulfanyl-substituted 4-hydroxy-6H-1,3-oxazin-6-ones range from 7.45 to 8.42, depending on the substituent in position 5 of the heteroring. 4-Hydroxy-6H-1,3-oxazin-6-ones in biological media exist mainly in the neutral form.

Synthesis of 2-aryl(hetaryl)-4H-1,3,4-oxadiazine-5,6-diones

Aromatic and heteroaromatic acid hydrazides reacted with oxalyl chloride in benzene or chloroform to give previously unknown 2-aryl(hetaryl)-4H-1,3,4-oxadiazine-5,6-diones whose structure was confirmed by the NMR, IR, and mass spectra. According to the spectral data and the results of quantumchemical calculations, the products exist mainly in the lactam form.

Reaction of 2,5-substituted 4-hydroxy-6H-1,3-oxazin-6-ones with benzimidazol-2-ylhydrazine

Nowadays, studies in the field of biologically active azines occupy a leading position in the chemistry of heterocyclic compounds. Among diazines, pyrimidine derivatives have been studied in most detail, whereas such pyrimidine hetero analogs as oxo derivatives of unsaturated 1,3-oxazines have been poorly explored. Many 1,3-oxazin-6-ones are used as starting compounds for the synthesis of various acyclic and heterocyclic systems that are difficult or even impossible to obtain by other methods. They may be regarded as structural analogs of natural pyrimidine compounds which are crucial for many physiological processes in living matter; some 1,3-oxazin-6-one derivatives exhibit antimicrobial, antifungal, antiviral, and antitumor activity. Therefore, search for new biologically active compounds among products of reactions of 2,5-substituted 4-hydroxy-6H-1,3-oxazin-6-ones with nucleophiles is an important problem of modern organic chemistry. We previously [1‒8] synthesized 1,3-oxazines with various substituents in the 2-positions and showed that some of them possess various biological activities such as analgesic, sedative, and antimicrobial. However, their reactions with some nucleophiles were not studied. Herein we report for the first time the reaction of 2,5-disubstituted 4-hydroxy-6H-1,3-oxazin-6-ones 1a– 1d with benzimidazol-2-ylhydrazine (2). The reactions were carried out in anhydrous methanol at room temperature under continuous stirring for 40‒48 h, and the products were 1,2,4-triazole derivatives 3a–3d resulting from opening of the oxazine ring and subsequent recyclization involving the hydrazine moiety. The structure of 3a–3d was confirmed by H and C NMR, IR, and UV spectra. 2-[1-(1H-Benzimidazol-2-yl)-3-(4-nitrophenyl)1H-1,2,4-triazol-5-yl]propanoic acid (3a). A mixture of 1 g of 4-hydroxy-5-methyl-2-(4-nitrophenyl)-6H1,3-oxazin-6-one (1a) and 0.6 g of benzimidazol-2ylhydrazine (2) in 25 mL of anhydrous methanol was stirred for 48 h at room temperature. The precipitate was filtered off, washed with three portions of ethyl acetate, recrystallized from ethyl acetate, and dried. Yield 1.2 g (80%), mp 143‒145°C. UV spectrum: λmax 280 nm. IR spectrum, ν, cm: 3400 w (O‒H), 3200‒2950 br (C‒H), 1700 s (C=O), 1550 s (C=N). H NMR spectrum, δ, ppm: 1.66 d (3H, CH3), 5.00 q (1H, CHCH3), 6.92 t (1H), 7.19 t (1H), 7.59 d (1H), 8.20 d (1H), 8.26 d (2H), 8.34 d (2H), 9.03 s (1H), 10.47 s (1H). C NMR spectrum, δC, ppm: 15.35 (CH3), 21.93 (CH), 113.80‒135.30 (Carom), 148.91‒ 160.89 (triazole, imidazole), 172.78 (COOH). 2-[1-(1H-Benzimidazol-2-yl)-3-(4-methoxyphenyl)-1H-1,2,4-triazol-5-yl]propanoic acid (3b)

Synthesis and Reactivity of 4-Hydroxy-5-methyl-2-(2-oxo- 2H-chromen-3-yl)-6H-1,3-oxazin-6-ones

Abstract4-Hydroxy-6H-1,3-oxazin-6-ones with a coumarin fragment in position 2 of the oxazine ring were synthesized. Their hydrolysis, alcoholysis, and hydrazinolysis afforded a number of new coumarin derivatives containing malonamic acid and 1,2,4-triazole residues. The low stability of the title compounds toward oxygencentered nucleophiles was interpreted by quantum chemical calculations.

Features of reactions of 1,3-oxazin-6-ones with 2-hydrazinyl-1,3-benzothiazole

Reaction of 2,5-substituted 4-hydroxy-6Н-1,3-oxazin-6-ones with 2-hydrazinyl-1,3-benzothiazole in anhydrous polar solvent (methanol) without heating led to the formation of new derivatives of 1,2,4-thiazoles. Screening of biologic activity was performed.

Synthesis of 4-hydroxy-5-methyl-2-[2-(4-oxo-4H-chromen-3-yl)ethenyl]-6H-1,3-oxazin-6-ones and their reaction with hydrazine

Abstract4-Hydroxy-6H-1,3-oxazin-6-ones containing a 3-vinylchromone fragment in the 2-position were synthesized. The direction of their reactions with hydrazine hydrate was found to depend on the solvent nature. The reaction in protic solvents (methanol, acetic acid) resulted in recyclization of both oxazine ring to 1,2,4-triazole and pyranone ring to pyrazole. Aprotic acetonitrile favored attack of hydrazine exclusively on the oxazine ring, while the 3-vinylchromone fragment remained intact.

Synthesis and Antifungal Activity of New 2-[(z)-1-(3,5-diaryl-1,3,4-thiadiazol-2(3h)-ylidene)methyl]-3,5-diaryl-1,3,4-thiadiazol-3-ium Chlorides

Methods for synthesizing new heterocyclic compounds based on 1,3,4-thiadiazoles were developed. It was shown that these compounds possessed pronounced antifungal activity and could be recommended for further investigation as potential antimicrobial agents with fungicidal activity.