Synthesis of 1H-pyrazolo[3,4-e]-s-triazolo[3,4-c]-as-triazines, 8H-pyrazolo[3,4-e]tetrazolo[5,1-c]-as-triazine and 1,7-dihydro-8H-pyrazolo[3,4-e]-as-triazine derivatives

3-Hydrazino-7-methyl-5-phenyl-5H-pyrazolo[3,4-c]-as-triazine 1 underwent ring closure and/or condensation reaction with formic acid, acetic acid, acetic anhydride and benzoyl chloride to afford 1H-pyrazolo-[3,4-d]-s-triazolo[3,4-c]-as-triazines 2, 5 and 7a and/or N-acyl derivatives 3, 4 and 6 . N-Acyl derivatives 3 and 6 underwent cyclisation reaction on treatment with phosphoryl chloride to give 5 and 7a . 3-Methyl-1-phenyl-8-aryl-1H-pyrazolo[3,4-e]-s-triazolo[34,-c]-as-triazines 7 were also prepared by the reaction of the hydrazono derivatives 8 wit thionyl chloride. On treatment of 1 with nitrous acid gave the 8H-pyrazolo[3,4-e]tetrazolo-[5,1-c]-as-triazine 9 . Compound 1 underwent ring closure with carbon disulphide or ethyl chloroformate to 1,7-dihydro-8H-pyrazolo[3,4-e]-s-triazolo[3,4-c]-as-triazine derivatives 10 and 12 . Reaction of 1 with ethyl acetoacetate or acetylacetone gave 3-pyrazolo derivatives 13 and 14 .     

A novel crystalline tetrazolo-azido isomer pair: Pyrido[ 2,3-e] tetrazolo[5,1-c]-as-triazine and 3-azidopyrido[2,3-e]-as-triazine; the synthesis of tetrazolo[5,1-c] benzo-as-triazine and pyrido[2,3-e]-s-triazolo[3,4-c] -as-triazine

The deoxygenated derivative of 3-azidobenzo-as-triazine 1-oxide (II) exists in solution predominantly as 3-azidobenzo-as-triazine form (IVa) but in the crystalline state as tetrazolo[5,]-c]-benzo-as-triazine (IVb), a new fused heteroaromatie ring system. With the pyrido[2,3-e]-as-triazine derivatives, however, both 3-azidopyrido[2,3-e]-as-triazine (X) and pyrido[2,3-e] tetra-zolo[5,1-e]-as-triazine (XI) can be isolated in crystalline form, and these are interconvertible. Another new ring system, the pyrido[2,3-e] triazolo [3,4-c]-as-triazine (XVII) and its derivatives has also been synthesized.     

Reactions with 5-aminopyrazoles. I. Synthesis of halogen-containing fused pyrazoles

5-Amino-3-phenylpyrazole (I) and 5-amino-4-bromo-3-phenylpyrazole (II) reacted with ethyl acetoacetate and acetylacetone to give various pyrazolo[1,5-a]pyrimidines IV-VI and with benzoins to give different fused pyrazoles, namely, imidazo[1,2-b]pyrazoles IX, pyrrolo[2,3-c]pyrazoles X and pyrazolo[4,3-b][1,4]oxazines XII. Diazotized II was coupled with active methylene-containing nitriles to afford pyrazolo[5,1-c]-as-triazines XIV.     

N-bromosuccinimide in heterocyclic synthesis. Synthesis of pyrazolo[3,4-d]pyrimidines,Pyrimido[5,4-e]-as-triazines,and pyrimido[4,5-c]pyridazines from 6-arylidenehydrazino-1,3-dimethyluracil derivatives

Reactions of 6-arylidenehydrazino-1,3-dimethyluracil derivatives with N-bromosuccinimide leading to pyrazolo[3,4-d]pyrimidines, pyrimido[5,4-e]-as-triazines, and pyrimido[4,5-c]pyridazines are described.     

Synthesis of 2,8-disubstituted 1,2,4-triazolo[5,1-i]purines

This paper describes the preparation of 2-aryl-8-fluorobenzyl-1,2,4-triazolo[5,1-i]purines 2 , starting from 2-aryl-7,8-diamino-1,2,4-triazolo[1,5-c]pyrimidines 9 . Our synthetic procedure represents the first example of a feasible approach for the synthesis of 2,8-disubstituted triazolo[5,1-i]purines. New syntheses of 5-amino-3-arylpyrimido[5,4-e]1,2,4-triazines 12 and 8-fluorobenzyl-6-hydrazinopurines 15 are also reported.     

1,2,4-Triazines. VI. Imidazo[1,2-b]-as-triazines

Imidazo[1,2-b]-as-triazines were obtained in high yields by heating substituted glyoxaldoximes with 1,2-diaminoimidazoles in the presence of hydrochloric acid. Phenylglyoxal hydrate in a similar reaction afforded a mixture of 2- and 3-diphenyl-6-arylimidazo[1,2-b]-as-triazines. α-Ketoacids and 1,2-diaminoimidazoles in the presence of hydrochloric acid afforded 2,6-disubstituted-4H-imidazo[1,2-b]-as-triazin-3-ones.     

Azinotriazines. I. Synthesis and spectral data of pyrido[3,2-e] -as-triazines

A series of pyrido[3,2-e]-as-triazines (VI) was prepared via acid-catalyzed cyclization of suitable 2-substituted 3-aminopyridines obtained by reduction of the corresponding 3-nitro-pyridines. Cyclization of 3-amino-2-hydrazinopyridines (III) with triethyl orthoformate and hydrochloric acid, or cyclodehydration of 2-(2-acetylhydrazino)-3-aminopyridines (IV) with alcoholic hydrogen chloride gave 1,2-dihydropyrido[3,2-e]-as-triazine hydrochloride (V). Mild dehydrogenation with alkaline potassium ferricyanide yielded heteroaromatic pyrido[3,2-e]-as-triazines (VI), for which ultraviolet and nmr spectral data are reported.     

Synthesis and hydroxydeamination in the series of 6-aryl- and 6-benzoimidazolyl-7-aminoazolo[5,1-c]-1,2,4-triazines

The replacement of the amino group with the hydroxy group was examined in the series of 6-aryl- and 6-benzoimidazolyl-7-aminoazolo[5,1-c]-1,2,4-triazines. These reactions provide a convenient synthetic procedure for the preparation of fused azolo[5,1-c]-1,2,4-triazin-7-ones.     

Azinotriazines. II Cyclizations leading to pyrido[3,4-e] - and [4,3-e]-as-triazines. Ring interconversion of a pyrido-as-triazine 1-oxide to a pyridotriazole

Treatment of 4-chloro-3-nitropyridine (I) with hydrazine hydrate followed by catalytic reduction gave 3-amino-4-hydrazinopyridine (III). Acid-catalyzed cyclizations of III and subsequent dehydrogenation gave pyrido[3,4-e]-as-triazines (V). Treatment of I with guanidine followed by base-catalyzed cyclization gave 3-aminopyrido[4,3-e]-as-triazine 1-oxide (VII). The 1-oxide function was removed by reduction and subsequent dehydrogenation gave the 3-amino derivative (IX). On treatment with hot alkali VII rearranged to a triazolo[4,5-c]pyridine (X). The ultraviolet and nmr spectra of derivatives of the title ring systems are reported.     

Azolo[5,1-<Emphasis Type="Italic">c</Emphasis>]-1,2,4-triazines as a new class of antiviral compounds

Synthetic methods, reactivity, and the properties of a new class of antiviral compounds, pyrazolo-, imidazo-, 1,2,4-triazolo[5,1-c]-1,2,4-triazinones, tetrazolo[5,1-b]-1,2,4-triazinones, and azoloannulated amino-1,2,4-triazines having structural similarity with biogenic purines and capable of mimicking them in metabolic processes are considered. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 967–995, May, 2008.     

Condensed as-triazines. Synthesis of 7-aryl-8H-[1,4]thiazino[2,3-e]-1,2,4-triazin-3(2H)-one

Ring closure of 6-amino-3-oxo-as-triazine-5-thione with α-haloketones provides the thiazino[2,3-e]-1,2,4-triazines which dehydrate via an unusual pathway to give 7-aryl-8H[1,4]thiazino[2,3-e]-1,2,4-triazin-3(2H)-ones.     

Ring transformation of 1,5-benzoxazepines into spirobenzoxazoles. Synthesis of pyrazolo[1′,5′:3,4][1,2,4]triazino-[5,6-b][1,5]benzoxazepines and spiro[benzoxazole-2′(3′H),4(1H)-pyrazolo[5,1-c][1,2,4]triazines]

The reactions of the 3-substituted 4-amino-8-ethoxycarbonyl[5,1-c][1,2,4]triazines 1 and 2 with o-amino-phenol hydrochloride gave the pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzoxazepines 5 and 8 . The alkylation of 5 with methyl iodide and isopropyl iodide afforded the 6-alkoxylpyrazolo[1′,5′:3,4][1,2,4]triazino-[5,6-b][1,5]benzoxazepines 6a and 6b , respectively. Refluxing of 5, 6a, 6b and 8 in hydrochloric acid/acetic acid resulted in ring transformation to produce the spiro[benzoxazole-2′(3′H),4(1H)pyrazolo[5,1-c][1,2,4]-triazines] 7a, 7b and 9 . The screening data of the above compounds was described.     

The synthesis of 7,8-dihydroimidazo[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines, 8,9-dihydro-7H-pyrimido[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines and 7,8,9,10-tetrahydro[1,3]diazepino[1,2-e]pyrazolo[1,5-a]triazines

Cyclic hydrazino amidines were converted to the corresponding aminopyrazolyl derivatives. Ring closure between the amino groups of pyrazoline moieties and NH groups of cyclic amidines afforded the following ring systems: 7,8-Dihydroimidazo[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines, 8,9-dihydro-7H-pyrimido[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines and 7,8,9,10-tetrahydro[1,3]diazepino[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines.     

4-Azapteridines. 2. spectral,chromatographic, and X-Ray crystallographic studies concerning the mode of covalent addition to the pyrazino[2,3-e]-as-triazine ring system

The first examples of the unknown pyrazino[2,3-e]-as-triazine ring system, that is, the 6,7-dihydroxy-5,6,7,8-tetrahydropyrazino[2,3-e]-as-triazines, have been prepared by ring closure of selected 5,6-diamino-as-triazines with 40% aqueous glyoxal. These 4-azapteridines experience a novel exchange process with alcohols at the C(7)-position. When dissolved in alcohol and stirred at room temperature, the 7-alkoxy, 6-hydroxy analogues are formed and isolated. In fact, during ring closure, if alcohols are used as the solvent, only the latter compounds are obtained. Initially, cyclization of the ortho-diamino-as-triazines with glyoxal proceeds in a stereoselective manner giving rise to both the cis and trans adducts. A single-crystal X-ray diffraction study has determined the predominant and most stable adduct to be the trans (R,R or S,S) isomer. Spectroscopy (nmr) has verified the intermediacy of the cis adduct, but because of the aforementioned exchange process only the trans isomer is isolated. The site of exchange on these σ-adducts has been rigorously established as C(7). A plausible reaction mechanism by which this exchange process occurs is presented.     

Synthesis of Some 1,3-Thiazole, 1,3,4-Thiadiazole, Pyrazolo[5,1-c]-1,2,4-triazine, and 1,2,4-Triazolo[5,1-c]-1,2,4-triazine Derivatives Based on the Thiazolo[3,2-a]benzimidazole Moiety

3-(3-Methylthiazolo[3,2-a]benzimidazol-2-yl)-3-oxopropionitrile was synthesized by refluxing ethyl 3-methylthiazolo[3,2-a]benzimidazole-2-carboxylate, acetonitrile, and sodium hydride. Treatment of 3-(3-methylthiazolo[3,2-a]benzimidazol-2-yl)-3-oxopropionitrile with phenyl isothiocyanate, in the presence of KOH, furnished the corresponding potassium salt which was converted into thioacetanilide derivative upon neutralization. The thioacetanilide derivative reacts with α-chloroacetylacetone and ethyl α-chloroacetoacetate to give the 1,3-thiazole derivatives, while the reaction of the'thioacetanilide derivative with hydrazonyl chlorides gave 1,3,4-thiadiazole derivatives. On the other hand, 3-(3-methylthiazolo[3,2-a]benzimidazol-2-yl)-3-oxopropionitrile reacted with the diazonium salt of both 3-phenyl-5-amino-(1H)-pyrazole and 5-amino-l,2,4-(1H)-triazole to afford the corresponding hydrazones. The latter hydrazones underwent an intramolecular cyclization upon boiling in pyridine to give pyrazolo[5,1-c]-1,2,4-triazine and 1,2,4-triazolo[5,1-c]-1,2,4-triazine derivatives. Moreover, the behavior of thiazolo[3,2-a]benzimidazol-3(2H)-one towards phenyl isothiocyanate followed by the reaction with α-chloroketones or hydrazonyl chlorides was investigated. Some of the latter compounds exhibited moderate effects against some bacterial and fungal species.     

5H-Thiazolo [3,2-b]- and 2H-Thiazolo [2,3-c]-as-triazines

Derivatives of the 5H-thiazolo[3,2-b]- and 2H-thiazolo[2,3-c]-as-triazine systems were synthesized via condensation of tetrahydro-I-methyl-as-triazine-3(2H)-thione with ethylene dibromide and ethyl bromoacetate, respectively. An hypothesis is given for the formation of the [3,2-b] system in one of these reactions and the [2,3-c] system in the other. Structure proof was accomplished by an unequivocal synthesis of one of the [2,3-c] derivatives.     

Synthesis of Some 1,3-Thiazole, 1,3,4-Thiadiazole, Pyrazolo[5,1-c]-1,2,4-triazine, and 1,2,4-Triazolo[5,1-c]-1,2,4-triazine Derivatives Based on the Thiazolo[3,2-a]benzimidazole Moiety

Summary. 3-(3-Methylthiazolo[3,2-a]benzimidazol-2-yl)-3-oxopropionitrile was synthesized by refluxing ethyl 3-methylthiazolo[3,2-a]benzimidazole-2-carboxylate, acetonitrile, and sodium hydride. Treatment of 3-(3-methylthiazolo[3,2-a]benzimidazol-2-yl)-3-oxopropionitrile with phenyl isothiocyanate, in the presence of KOH, furnished the corresponding potassium salt which was converted into thioacetanilide derivative upon neutralization. The thioacetanilide derivative reacts with α-chloroacetylacetone and ethyl α-chloroacetoacetate to give the 1,3-thiazole derivatives, while the reaction of the'thioacetanilide derivative with hydrazonyl chlorides gave 1,3,4-thiadiazole derivatives. On the other hand, 3-(3-methylthiazolo[3,2-a]benzimidazol-2-yl)-3-oxopropionitrile reacted with the diazonium salt of both 3-phenyl-5-amino-(1H)-pyrazole and 5-amino-l,2,4-(1H)-triazole to afford the corresponding hydrazones. The latter hydrazones underwent an intramolecular cyclization upon boiling in pyridine to give pyrazolo[5,1-c]-1,2,4-triazine and 1,2,4-triazolo[5,1-c]-1,2,4-triazine derivatives. Moreover, the behavior of thiazolo[3,2-a]benzimidazol-3(2H)-one towards phenyl isothiocyanate followed by the reaction with α-chloroketones or hydrazonyl chlorides was investigated. Some of the latter compounds exhibited moderate effects against some bacterial and fungal species.     

Facile synthesis and antifungal activity of 3-substituted 4-amino-8-ethoxycarbonylpyrazolo[5,1-c][1,2,4]triazines and pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzodiazepines

The reactions of the pyrazole-5-diazonium salt 3 with malononitrile and ethyl cyanoacetate gave 4-amino-3-cyano-8-ethoxycarbonylpyrazolo[5,1-c][1,2,4]triazine 7 and 4-amino-3,8-bisethoxycarbonylpyrazolo[5,1-c]-[1,2,4]triazine 8 , whose reactions with p-chloroaniline hydrochloride afforded 4-amino-8-ethoxycarbonyl-3-(p-chlorophenyl)amidinopyrazolo[5,1-c][1,2,4]triazine 9 and 4-amino-8-ethoxycarbonyl-3-(p-chlorophenyl)car-bamoylpyrazolo[5,1-c][1,2,4]triazine 10 , respectively. The reactions of 7 and 8 with o-phenylenediamine di-hydrochloride provided 9-ethoxycarbonyl-13H-spiro[benzimidazole-2′(3′H),6(5H)-pyrazolo[1,5′:3,4][1,2,4]tri-azino[5,6-b][1,5]benzodiazepine] hydrochloride 11a and 9-ethoxycarbonyl-6-oxo-13H-5,6-dihydropyrazolo-[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzodiazepine 12 , respectively. The antifungal activity of the above compounds was described.     

The synthesis and properties of pyridazino[4,3-e] -as-triazines and pyridazino[4,5-e] -as-triazines,two novel condensed pyridazine ring systems

The compounds prepared in the novel pyridazino[4,3-e]-as-triazine ring system are: 8-chloro-4-methyl-3,4-dihydropyridazino[4,3-e]-as-triazine ( 21 ), 8-chloro-2,4-dimethyl-3,4-dihydropyridazino[4,3-e]-as-triazine ( 23 ), 8-chloro-2-ethyl-4-methyl-3,4-dihydropyridazino[4,3-e]-as- triazine ( 24 ), 4-methyl-3,4-dihydropyridazino[4,3-e]-as-triazine-8-thione ( 25 ), 4-methyl-3,4-dihydropyridazino[4,3-e]-as-triazine ( 26 ), 2,4-dimethyl-3,4-dihydropyridazino[4,3-e]-as-triazine ( 27 ), and 2-ethyl-4-methyl-3,4-dihydropyridazino[4,3-e]-as-triazine ( 28 ). In the novel pyridazino[4,5-e]-as-triazine ring system the following compounds were prepared: 1,2-dihydropyridazino[4,5-e]-as-triazine ( 31 ), 3-methyl-1,2-dihydropyridazino[4,5-e]-as-triazine ( 32 ), 3-ethyl-1,2-dihydropyridazino[4,5-e]-as-triazine ( 33 ), and 1-methyl-1,2-dihydropyridazino[4,5-e]-as-triazine ( 35 ). The preparation of a number of previously unreported intermediates and compounds for structure proof are also described.     

Reactions with heterocyclic diazonium salts: New routes for the synthesis of pyrazolo[1,5-c]-1,2,4-triazoles and pyrazolo[1,5-c]-as-triazines

3-Phenylpyrazole-5-(liazonium chloride ( 1 ) couples with α-chloro derivatives of acetylacetone, ethyl acetoacetate and aceto-o-anisidine to yield the corresponding pyrazole-5-yl hydrazonyl chloride derivatives 2a-c . Compounds 2a,b were cyclised to yield either the pyrazolo[1,5-c]-1,2,4-triazole derivatives 3a,b or the pyrazolo[1,5-c]-as-triazines 4a,b depending on the applied reaction conditions. Compound 2c cyclised only into 3c under different cyclization conditions. The pyrazolo[1,5-c]-as-triazine derivatives 4c-e could be prepared via condensation of 2a with potassium cyanide. Compound 2d reacted with aromatic thioles and with sodium benzene-sulphonate to yield the pyrazolo[1,5-c]-as-triazine derivatives 6a-d . Compound 1 reacted with activated double bond systems to yield pyrazolo[1,5-c]-as-triazines 8a,b and 9 .