Synthesis and properties of 4a-substituted 6,8-dimethylpyrimido-[5,5-e][1,2,4]-triazine-3,5,7-triones

Azev, Yu. A.; Mudretsova, I. I.; Sidorov, E. O.; Pidemskii, E. L.; Goloneva, A. G.; Александрова, Г. А.

doi:10.1007/bf00758763

Cited by 2 publications

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“…Indeed, even a short-time heating of fervenul-3-one with indole in boiling butanol leads to the formation of a (4a)-indolyl derivative [12]. Under the conditions of acid catalysis, this reaction proceeds in ethanol at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…Due to the high reactivity, fervenul-3-one interacts with "aromatic" C-nucleophiles (in contrast to fervenulin, which is inert to these compounds). Indeed, the heating of fervenul-3-one in ethanol in the presence of a hydrochloric acid with phenylhydrazine (or related hydrazones) leads to the formation of the corresponding 4a-substituted derivatives XIVb -XIVe [12]. Fervenul-3-one-4-N-oxides XII and XIII proved to be significantly less reactive with respect to the aforementioned C-nucleophiles.…”

Section: Methodsmentioning

confidence: 99%

“…It is interesting to note that prolonged heating of compounds XII and XIII with indoles in the absence of acid catalyst leads to the formation of 2,3,4,4a,5,6,7,8-octahydro-6,8-dimethylpyrimido [5,4-e] [1,2,4]triazine-3,5,7-trione-4-hydroxy-4a-indolyl derivatives (XVa), XVb) [14]. Heating of the 4-hydroxy derivatives XV in ethanol solution of hydrochloric acid leads to the corresponding derivatives of fervenul-3-one XIV [12].…”

Section: Methodsmentioning

confidence: 99%

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Structure and spectral characteristics of fervenulin and 2-methylfervenulin-3-one 4-N-oxides: Features of the transformations of fervenulin-3-one and its 4-N-oxide with C-nucleophiles

Azev¹,

Gabel

Lork

et al. 2006

Pharm Chem J

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The structures of crystalline fervenulin, 2-methylfervenulin-3-one (MSD-92), and their 4-N-oxides were studied using x-ray diffraction and 1 H and 13 C NMR spectroscopy techniques. A comparative analysis of the spectroscopic data and the chemical reactivity of pyrimidotriazine antibiotics and their analogs allowed the reactive centers of these biologically active compounds, ways of their activation, and mechanisms of transformation to be elucidated.As is known, 3-substituted derivatives of the antibiotic fervenulin exhibit transformation into xanthine [1] and azauracil [2] derivatives as a result of the nucleophilic attack of formamide at C-8a, and of OH ion at the C-5 atom of the pyrimidotriazine nucleus, respectively. On heating with indoles in the presence of acids, fervenulin attaches the indole moiety at the C-4a atom with the formation of stable indolyl derivatives [3]. However, fervenulin 4-N-oxide reacts with nucleophiles in a different manner. For example, the interaction of this oxide with CH acids (acetylacetone, dimedone, and acetoacetic, malonic, cyanoacetic, and nitroacetic esters, etc.) in anhydrous DMSO in the presence of triethylamine at 20 -25°C leads to a high yield of the corresponding derivatives of 1,3-dimethyl-5-nitroso-6-hydrazinouracil [4,5].Thus, the available experimental data indicate that the presence of a 4-N-oxide function in the fervenulin nucleus leads to a dramatic change in the reactivity of pyrimidotriazines. However, there are almost no data on the structure of 4-N-oxides and their spectral characteristics, although this information would be useful for the identification and char-acterization of reactive centers, ways of their activation, and mechanisms of chemical transformation of these compounds.In order to fill this gap, we have synthesized crystals of 4-N-oxides of fervenulin and 2-methylfervenulin-3-one and studied them by x-ray diffraction and 1 H and 13 C NMR spectroscopy techniques in order to elucidate the role of 3-oxoand 4-N-oxide groups in the reactivity of these compounds.The simplest pathway to the synthesis of fervenulin-4-oxide (V) is via the nitrosation of 6-hydrazinouracil I, followed by cyclization of the intermediate 5-nitroso-6-hydrazinouracil (IV) with ortho-formic ester (Scheme 1, path A) [6]. The disadvantages of this method are (i) multistage procedure, (ii) long synthesis time, and (iii) low yield of the target product. In order to avoid these drawbacks, we have previously developed a simple "one-pot" method for the synthesis of fervenulin-4-N-oxide (V) by means of the sequential treatment of the initial hydrazinouracil (I) in acetic acid solution with glyoxylic acid and sodium nitrite (Scheme 1, Path B) [7].Ichiba et al.[8] used fervenulin-4-oxide for the synthesis of fervenul-3-one (X) and its 2-methyl derivative (XI) (Scheme 2, path A). We oxidized fervenulin-4-oxide by gaseous chlorine in aqueous acetic acid solution [9] and obtained 4-N-oxide of fervenul-3-one (XII) (Scheme 2, Path B) 398 0091-150X/06/4007-0398

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Structure and spectral characteristics of fervenulin and 2-methylfervenulin-3-one 4-N-oxides: Features of the transformations of fervenulin-3-one and its 4-N-oxide with C-nucleophiles

Azev¹,

Gabel

Lork

et al. 2006

Pharm Chem J

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“…Cinnoline was found to react with 1,2-diaminoethane in the presence of Ag(C 5 H 5 N) 2 MnO 4 to produce dimer 5 10 as a single product. Under the same conditions, 1,3-dimethyllumazine adds a nucleophile to the internuclear bond 11 to give derivative 7 in 9% yield (Scheme 2). ¶ α α ω ω † An analogy to the reaction reported appears to be the cycloaddition of bifunctional nucleophiles to azinium cations.…”

mentioning

confidence: 99%

Reaction of 6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione with α,ω-diamines as the first example of tandem nucleophilic substitution in neutral azines

Besedin

Gulevskaya

Пожарский

2000

Mendeleev Communications

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Synthesis and properties of 4a-substituted 6,8-dimethylpyrimido-[5,5-e][1,2,4]-triazine-3,5,7-triones

Cited by 2 publications

References 1 publication

Structure and spectral characteristics of fervenulin and 2-methylfervenulin-3-one 4-N-oxides: Features of the transformations of fervenulin-3-one and its 4-N-oxide with C-nucleophiles

Structure and spectral characteristics of fervenulin and 2-methylfervenulin-3-one 4-N-oxides: Features of the transformations of fervenulin-3-one and its 4-N-oxide with C-nucleophiles

Reaction of 6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione with α,ω-diamines as the first example of tandem nucleophilic substitution in neutral azines

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