L. N. Ovsyannikova, B. Lalaev, I. Yakovlev
May 22, 2016
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Journal
Russian Journal of Organic Chemistry
Abstract
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)