New 1H-1-alkyl-6-methyl-3-phenyl-7-phenylazo-pyrazolo[5,1-c][1,2,4]triazoles through regioselective alkylation of 1H-6-methyl-3-phenyl-7-phenylazopyrazolo[5,1-c][1,2,4]triazoles

1H-1-Alkyl-6-methyl-3-phenyl-7-phenylazopyrazolo[5,1-c][1,2,4]triazoles (2aa-ad) were obtained by regioselective alkylation of 1H-6-methyl-3-phenyl-7-phenylazopyrazolo[5,1-c][1,2,4]triazoles (2a). 1H-1-Alkyl-6-methyl-3-phenyl-7-phenylazopyrazolo[5,1-c][1,2,4]triazoles 2aa and 2ab were also prepared by coupling phenyldiazonium chloride with 1H-1-alkyl-6-methyl-3-phenyl-pyrazolo[5,1-c][1,2,4]triazoles 1aa and 1ab. The new compounds were characterized by IR, UV-VIS, ¹H-NMR, ¹³C-NMR, and ¹⁵N-NMR spectroscopy and their structures and actual tautomeric forms were established unequivocally.      

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.     

Azo-coupling of pyrazole-3(5)-diazonium chlorides with cyanothioacetamide: a convenient synthesis of pyrazolo[5,1-c][1,2,4]triazine-3-carbothioamides

Cyanothioacetamide reacts with pyrazole-3(5)-diazonium chlorides to afford pyrazolo[5,1-c][1,2,4]triazine-3-carbothioamides 5. The latter can be oxidized with H₂O₂ to give either pyrazolo[5,1-c][1,2,4]triazine-3-carboxamides or 1,2,4-thiadiazole derivatives, depending on the reaction conditions. The Hantzsch-type reaction of thioamides 5 with α-bromo ketones leads to 3-(thiazol-2-yl)pyrazolo[5,1-c][1,2,4]triazines.     

A new method for the synthesis of novel 6-quinoxalinylpyrazolo[5,1-c][1,2,4]triazines

The reaction of the quinoxaline 1 with 4-ethoxycarbonyl-1H-pyrazole-5-diazonium chloride 7 at room temperature gave 3-[α-(4-ethoxycarbonyl-1H-pyrazol-5-ylhydrazono)methoxycarbonylmethyl]-2-oxo-1,2-dihydroquinoxaline 8. The pmr spectrum of 8 in deuteriodimethylsulfoxide supported the presence of two tautomers 8-I and 8-II. Refluxing of 8 in N,N-dimethylformamide or acetic acid resulted in cyclization to afford 8-ethoxycarbonyl-4-oxo-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)-1,4-dihydropyrazolo[5,1-c][1,2,4]triazine 9. Compound 9 was also obtained directly by the reaction of 1 with 7 under reflux in better yield. The reaction of 9 with hydrazine hydrate provided the hydrazinium salt 10 , while the reactions of 9 with triethyl and trimethyl orthoformates in the presence of 1,8-diazabicyclo[5,4,0]-7-undecene produced 8-ethoxycarbonyl-4-ethoxyl-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)pyrazolo[5,1-c][1,2,4]triazine 11a and 8-ethoxycarbonyl-4-methoxyl-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)pyrazolo[5,1-c][1,2,4]triazine 11b , respectively. The chlorination of 11a with phosphoryl chloride gave 3-(3-chloroquinoxalin-2-yl)-8-ethoxycarbonyl-4-ethoxylpyrazolo[5,1-c]-[1,2,4]triazine 12 , whose reaction with morpholine afforded 8-ethoxycarbonyl-4-ethoxyl-3-[3-(morpholin-4-yl)-quinoxalin-2-yl]pyrazolo[5,1-c][1,2,4]triazine 13.     

Synthesis and antiviral evaluation of some novel [1,2,4]triazolo[4,3-β][1,2,4]triazole nucleoside analogs

Ribosylation of 3-amino-5H-[1,2,4]triazolo[4,3-b][1,2,4]triazole ( 1 ) with l-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose and stannic chloride resulted in the following protected nucleoside analogs: 3-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 4 ), 3-amino-1-(2,3,5-tri-O-benzoyl-α-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 5 ), 3-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 5 ), and 3-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl) amino-5H-[1,2,4]triazolo[4,3-b]-[1,2,4]triazole ( 7 ). Compounds 4–6 were deprotected to 3-amino-1-β-D-ribofuranosyl[1,2,4]triazolo[4,3-b][1,2,4]-triazole ( 3 ), 3-amino-1-α-D-ribofuranosyl[1,2,4]triazolo[4,5-b][1,2,4]triazole ( 8 ), and 3-imino-2H-2-β-D-ribo-furanosyl[1,2,4]triazolo[4,3-b][1,2,4]triazole ( 9 ), while 7 could not be deprotected without decomposition. Compounds 1, 4, 6, 7 , and 9 were screened and found to have no antiviral activity.     

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.     

Reactivity of 7-amino-3-tert-butyl-4-oxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carbonitrile

By reaction of carbonyl compounds with 7-amino-3-tert-butyl-4-oxo-4,6-dihydropyrazolo[5,1-c]-[1,2,4]triazine-8-carbonitrile 3-tert-butyl-8-R-4,6,9,10-tetrahydropyrimido[4′,5′:3,4]pyrazolo[5,1-c][1,2,4]-triazine-4,10-diones and (3-tert-butyl-4-oxo-8-cyano-4,6-dihydropyrazolo[5,1-c][1,2,4]triazin-7-yl)acetamide were obtained.     

A convenient synthesis of novel spiro[benzoxazole-2′,4(1H,3′H)-pyrazolo[5,1-c][1,2,4]triazines] by ring transformation of novel pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzoxazepines

Novel pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzoxazepines 5, 6 and 8 were synthesized, and these compounds were converted into novel spiro[benzoxazole-2′,4(1H,3′H)-pyrazolo[5,1-c][1,2,4]triazines] 7 and 9 by ring transformation.     

Synthesis of new halo-substituted pyrazolo[5,1-c][1,2,4]triazines

Ethyl 3-tert-butyl-4-oxo-7-X-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carboxylates (X = H, Cl, Br) were synthesized for the first time by diazotization of 7-amino-3-tert-butyl-4oxo-8-ethoxycarbonyl-6H-pyrazolo[5,1-c][1,2,4]triazines with tert-butyl nitrite in the presence of trimethylsilyl halides. A new method was developed: a reaction between 7-amino-3-tert-butyl-4-oxo-6H-pyrazolo[5,1-c][1,2,4]triazine-8-carboxylic acid and I₂/TEA followed by treatment with NaBH₄ led to a mild decarboxylation. The acid reacts with N-halosuccinimides to give novel 8-halo-substituted derivatives. The amino groups of the latter were acylated by treatment with trifluoroacetic anhydride to give monoacylation products.

     

Synthetic approaches to 5,7-disubstituted imidazo[5,1-f][1,2,4]triazin-4-amines

The preparation of 5,7-disubstituted imidazo[5,1-f][1,2,4]triazin-4-amines, exemplified by 5-[3-(benzyloxy)phenyl]-7-cyclobutylimidazo[5,1-f][1,2,4]triazin-4-amine, was developed through a linear and three convergent synthetic strategies, with the latter providing the greatest flexibility for diversification at the 5-position at the last step of the synthesis.     

Solution-phase parallel synthesis of new 2H-pyrimido-[4,5-e][1,2,4]triazin-3-ylidenecyanamides

A practical synthesis of 2H-pyrimido[4,5-e][1,2,4]triazin-3-ylidenecyanamides has been developed. The key step is the coupling reaction of an aryldiazonium salt with 1-cyano-3-(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-ylamino)-2-methylisothiourea followed by intramolecular cyclization. A library of 2H-pyrimido[4,5-e][1,2,4]triazin-3-ylidenecyanamides was prepared in two steps from 6-aminouracils using this method.     

Anodic formation of 3,6-diaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles and 2(3-aryl-5-methyl-1H-[1,2,4]triazol-1-yl)-5-aryl-1,3,4-thiadiazoles

3,6-Disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles together with the unknown systems 2-(3-aryl-5-methyl-1H-[1,2,4]triazol-1-yl)-5-aryl-1,3,4-thiadiazoles were obtained by anodic oxidation, under aprotic conditions, of aryl aldehyde N-(5-aryl-1,3,4-thiadiazol-2-yl) hydrazones. Mechanistic proposals are given.     

Synthesis and reactivity of ethyl 7-amino-3-tert-butyl-4-thioxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carboxylate

Treatment of ethyl 7-amino-3-tert-butyl-4-oxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carboxylate with P₂S₅ in pyridine gave ethyl 7-amino-3-tert-butyl-4-thioxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carboxylate which was subjected to acylation, decarboxylation, and hydrazinolysis.     

New heterocyclic systems based on 1-hydrazino-5,6,7,8-tetrahydro[2,7]naphthyridine: 7,8,9,10-tetra-hydro[1,2,4]triazolo[3,4-a]- and 7,8,9,10-tetra-hydro[1,2,4]triazolo[5,1-a][2,7]naphthyridines

Methods have been developed for the synthesis of new substituted 7,8,9,10-tetrahydro[1,2,4]triazolo-[3,4-a][2,7]naphthyridines from 3-chloro-1-hydrazino-7-methyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carbonitrile. It was shown that on heating in an amine (ethanolamine, pyrrolidine, 2-hydroxy-propylamine), they undergo a Dimroth rearrangement at the triazole fragment, being converted into 7,8,9,10-tetrahydro[1,2,4]triazolo[5,1-a][2,7]naphthyridine derivatives.     

The first stable examples of compounds containing both diazonium and acyl azide,and synthesis of a new pyrazino[2′,3′:3,4]pyrazolo[5,1-c][1,2,4]triazin-4(6H)-one heterocyclic system

The first stable compound containing both N₂⁺BF₄^? and CON₃ functional groups – 8-azidocarbonyl-3-(tert-butyl)-4-oxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-7-diazonium tetrafluoroborate was synthesized, and its stability and reactivity discussed. The Curtius rearrangement of 7-azido-3-(tert-butyl)-4-oxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carbonylazide was investigated, and the synthesis of a novel heterocyclic system –pyrazino[2′,3′:3,4]pyrazolo[5,1-c][1,2,4]triazin-4(6H)-one is described.     

A facile synthesis and highly atom economic 1,3-dipolar cycloaddition of hexahydropyrido[3,4-c][1,5]benzothiazepines with nitrile oxide: stereoselective formation of hexahydro[1,2,4]oxadiazolo[5,4-d]pyrido[3,4-c][1,5]benzothiazepines

A series of new 2-methyl-11-aryl-4-[(E)-arylmethylidene]-1,2,3,4,11,11a-hexahydropyrido[3,4-c][1,5]benzothiazepines were obtained by the reaction of o-aminothiophenol and (E)-1-methyl-3,5-bis(arylidene)-4-piperidones in the presence of a catalytic amount of acetic acid under solvent-free microwave irradiation. These dipolarophiles undergo a highly atom economic 1,3-dipolar cycloaddition with nitrile oxide to afford a series of novel 6-methyl-1-phenyl-8-aryl-4-[(E)-arylmethylidene]-4,5,6,7,7a,8-hexahydro[1,2,4]oxadiazolo[5,4-d]pyrido[3,4-c][1,5]benzothiazepines stereoselectively.     

4-Aryl-3-(methanesulfonyl)pyrazolo[5,1-<Emphasis Type="Italic">c</Emphasis>][1,2,4]triazines and their transformations

Coupling of 3-alkyl-4-aryl-1H-pyrazole-5-diazonium chlorides with methylene-active methyl phenacyl sulfones afforded new pyrazolo[5,1-c][1,2,4]triazine derivatives via cyclization of the corresponding intermediate 1-aryl-2-(hetarylhydrazinylidene)-2-(methanesulfonyl)ethanones. The reactivity of the methanesulfonyl group on C³ of pyrazolo[5,1-c][1,2,4]triazines toward some nucleophiles was studied.     

Regioselectivity of cyclization of 1-(6-methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)-4-arylthiosemicarbazides by treating with methyl iodide and dicyclohexylcarbodiimide

1-(6-Methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)-4-arylthiosemicarbazides treated with methyl iodide in the presence of sodium acetate in ethanol convert into 6-methyl-3-arylamino[1,2,4]-triazolo[4,3-b][1,2,4]triazin-7(1H)-ones. In reaction with dicyclohexylcarbodiimide 6-methyl-3-arylamino[1,2,4]triazolo[3,4-c][1,2,4]triazin-5(1H)-ones were obtained which at heating in alcohol solution in the presence of sodium acetate or at 262–272°C underwent the Dimroth rearrangement to give 3-methyl-7-arylamino[1,2,4]triazolo[5,1-c][1,2,4]-triazin-4(8H)-ones.     

A new strategy for the synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines

A series of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines were prepared via oxidative cyclization of aldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-4-yl)hydrazones. Dimroth rearrangement of such a series yielded pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines.     

3,5-Disubstituted 6H-pyrrolo[1,2-c][1,2,3]triazoles from Morita-Baylis-Hillman adducts of propargyl aldehydes

A simple method for synthesizing several 6H-pyrrolo[1,2-c][1,2,3]triazole derivatives having a methoxycarbonyl or an acetyl group at C-5 position and 7,8-dihydro-4H-[1,2,3]triazolo[1,5-a]indol-5(6H)-ones via an intramolecular 1,3-dipolar cycloaddition reaction of azido enynes, which were readily obtained from the Morita-Baylis-Hillman acetates of propargyl aldehydes with sodium azide, has been developed.