The synthesis of substituted pyrazino[2,3-d]-1,2,4-triazolo[4,3-b]pyridazines

The synthesis of 1,2,4-triazolo[4,3-b]pyridazines and the unknown ring system, pyrazino[2,3-d]-1,2,4-triazolo[4,3-b]pyridazine, has been achieved. The preparation of the new tricyclic 1,2,4-triazole was accomplished first by ring closure of the triazole ring followed by formation of the pyrazine ring. Substitution of the pyrazino[2,3-d]-1,2,4-triazolo[4,3-b]pyridazine ring system was carried out in order to provide information of its reactivity and to provide a variety of interesting compounds for biological testing.     

A convenient synthesis of 1,2,4-triazolo[4,3,2-o,p]-[1,3]diazocino[4,5-b]quinoxalines via a 1,3-dipolar cycloaddition reaction and a ring transformation

The reaction of 6-chloro-2-hydrazinoquinoxaline 4-oxide 5 with triethyl orthoformate gave 7-chloro-1,2,4-triazolo[4,3-a]quinoxaline 5-oxide 6. The reaction of compound 6 with phenyl isocyanate afforded 7-chloro-4-phenylamino-1,2,4-triazolo[4,3-a]quinoxaline 7 , while the reaction of compound 6 with phenyl isothiocyanate resulted in deoxygenation to provide 7-chloro-1,2,4-triazolo[4,3-a]quinoxaline 8. However, the reaction of compound 6 with allyl isothiocyanate effected the 1,3-dipolar cycloaddition reaction, but not deoxygenation, to furnish 9-chloro-4,5-dihydroisoxazolo[2,3-a][1,2,4]triazolo[3,4-c]quinoxalin-5-ylmethylisothiocyanate 9. Moreover, the reduction of compound 9 with iron/acetic acid resulted in ring transformation to give 11 -chloro-7-hydroxy-4-thioxo-4,5,6,7,8,9-hexahydro-1,2,4-triazolo[4,3,2- o,p][1,3]diazocino[4,5-b]quinoxaline 10 , whose acetylation afforded 5-acetyl-11-chloro-7-hydroxy-4-thioxo-4,5,6,7,8,9-hexahydro-1,2,4-triazolo[4,3,2-o,p][1,3]diazocino[4,5-b]quinoxaline 11.     

Synthesis of some new derivatives of 4-hydrazino-5H-pyridazino[4,5-b]indole

This paper describes the synthesis of 1-chloro-4-hydrazino-5H-pyridazino[4,5-b]indole ( 4 ) and some of the triazoles ( 6–8 ), tetrazoles ( 10–11 ), triazolotetrazoles ( 9 ) and bis-tetrazoles ( 12 ) derived from it. All of these were previously unknown compounds. Treating 1,4-dioxo-1,2,3,4-tetrahydro-5H-pyridazino[4,5-b]indole ( 1 ) with phosphorus oxychloride gave 1,4-dichloro-5H-pyridazino[4,5-b]indole ( 2 ), which reacts regioselectively with hydrazine to give compound 4 . The reactions of 4 with formic and acetic acids gave 6-chloro-11 H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles ( 6a-6b ), respectively. Reaction of compound 6a with hydrazine gave 6-hydrazino-11H-1,2,4-triazolo[4,3–6]-pyridazino[4,5,-b]indole ( 8 ). This with nitrous acid gave 6-azido-11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]-indole ( 9 ). Compound 4 reacted with nitrous acid to give 6-chloro-11H-tetrazolo[4,5-b]pyridazino[4,5-b]-indole ( 10 ), which gave 1,4-diazydo-5H-pyridazino[4,5-b]indole ( 12 ), through successive reactions with hydrazine and nitrous acid. All compounds were characterized by elemental analysis, ir and ¹H-nmr spectra.     

Recherches en série azabenzodiazepine V. Synthése de bis s-triazolo[4,3-b:4,3-d] triaze'pines-1,2,4

Several new bis-s-triazolo[4,3-b:4,3-d]-1,2,4-triazepines were synthesized from appropriate 8-hydrazino-s-triazolo[4,3-b]-1,2,4-triazepines by condensation with formic and acetic acid.     

Synthesis of s-triazolo[4,3-b]pyridazine C-nucleosides

A one step synthesis of s-triazolo[4,3-b]pyridazine using 3-chloro-6-hydrazinopyridazine and an appropriate thioformimidate is described. Applying this procedure to 5-O-benzoyl-1-benzylthio-1-formimidate-D-ribofuranose, 5′ benzoyl-6-chloro-3β-D-ribofuranosyl-s-triazolo[4,3-b]pyridazine was obtained. Substitutions of chlorine by nucleophilic reagents afforded some derivatives of a new series of C-nucleo-sides. Structural determination including anomeric configuration assignment is discussed based mainly on ¹H nmr spectroscopy.     

Synthesis of 4- and 5-(s-triazolo[4,3-b]pyridazinyl-3)-substituted cyclic polyols

4( R )-(6-Chloro-s-triazolo[4,3-b]pyridazinyl-3)-1,4-furanoses 10 and 11 , 5( R )-(6-chloro-s-triazolo[4,3-b]pyridazinyl-3)-1,5-pyranose 13 , and 2(S),3( R )-dihydro-5-(6-chloro-s-triazolo[4,3-b]pyridazinyl-3)-2,3-O-isopropylidenefuran ( 12 ) were prepared by cyclization of hydrazones 6–9 obtained from 6-chloro-3-hydrazinopyridazine ( 1 ) and aldofuranoses 2, 3 and 4 , and aldopyranose 5 .     

NMR study on the tautomeric equilibria between the hydrazone imine and diazenyl enamine forms in side chained quinoxalines: Solvent effects and temperature dependence

The reaction of 7-chloro-4-ethoxycarbonylmethylene-4,5-dihydro-1,2,4-triazolo[4,3-a]quinoxaline 6 with 4-ethoxycarbonyl-1-methyl-1H-pyrazole-5-diazonium chloride or 4-cyano-1,3-dimethyl-1H-pyrazole-5-diazonium chloride gave 7-chloro-4-[α-(4-ethoxycarbonyl-1-methyl-1H-pyrazol-5-ylhydrazono)-ethoxycarbonylmethyl]-1,2,4-triazolo[4,3-a]quinoxaline 8a or 7-chloro-4-[α-(4-cyano-1,3-dimethyl-1H-pyrazol-5-ylhydrazono)ethoxycarbonylmethyl]-1,2,4-triazolo[4,3-a]quinoxaline 8b , respectively, while the reaction of 7-chloro-4-ethoxycarbonylmethylene-4,5-dihydrotetrazolo[1,5-a]quinoxaline 7 with 4-ethoxycarbonyl-1-methyl-1H-pyrazole-5-diazonium chloride or 4-cyano-1,3-dimethyl-1H-pyrazole-5-diazomum chloride provided 7-chloro-4-[α-(4-ethoxycarbonyl-1-methyl-1H-pyrazol-5-ylhydrazono)ethoxycarbonylmethyl]tetrazolo[1,5-a]quinoxaline 9a or 7-chloro-4-[α-(4-cyano-1,3-dimethyl-1H-pyrazol-5-ylhydrazono)ethoxycarbonylmethyl]tetrazolo[1,5-a]quinoxaline 9b , respectively. Compounds 8a,b and 9a,b showed the tautomeric equilibria between the hydrazone imine C and diazenyl enamine D forms in dimethyl sulfoxide and/or trifluoroacetic acid, and the effects of solvent and temperature on the tautomer ratios of C to D were studied by the nmr measurements in a series of mixed trifluoroacetic acid/dimethyl sulfoxide media (compounds 8a,b and 9a,b ) and at various temperatures (compounds 8a,b ).     

Synthèse et étude physicochimique des 1,2,4-triazolo[4,3-a]-pyridines et des 1,2,4-triazolo[2,3-a]pyridines

The synthesis of 1,2,4-triazolo[4,3-a] and [2,3-a]pyridines 7, 8 was achieved by cyclization of 2-hydrazino-8-nitropyridine 3a with formic acid. The 4,5,6,7-tetrahydro-1,2,4-triazolo[2,3-a]pyridine 13 and 8-amino-1,2,4-triazolo[2,3-a]pyridine 9 were obtained by catalytic hydrogenation. The reduction of triazolo pyridine 8 using stannous chloride led to the intermediate compound 10 which with acetic anhydride afforded 8-acetylamino-5-chloro-1,2,4-triazolo[2,3-a]pyridine 10a . The structure of the derivatives was determined by ¹H-nmr (DMSO-d₆).     

A facile synthesis of enol type acyl cyanides via a 1,3-dipolar cycloaddition reaction and a cyano group migration

The reaction of 7-chlorotetrazolo[1,5-a]quinoxaline 5-oxide 4a or 7-chloro-1,2,4-triazolo[4,3-a]quinoxaline 5-oxide 4b with 2-chloroacrylonitrile gave 7-chloro-4-(2-cyano-2-hydroxyvinyl)tetrazolo[1,5-a]quinoxaline 5a or 7-chloro-4-(2-cyano-2-hydroxyvinyl)-1,2,4-triazolo[4,3-a]quinoxaline 5b , respectively. Alcoholysis of compound 5a or 5b afforded 7-chloro-4-ethoxycarbonylmethylene-4,5-dihydrotetrazolo[1,5-a]quinoxaline 6a or 7-chloro-4-ethoxycarbonylmethylene-4,5-dihydro-1,2,4-triazolo[4,3-a]quinoxaline 6b , respectively. Compounds 5a,b were found to exist as a syn and anti mixture of the enol form, while compounds 6a,b occurred as the enamine and methylene imine forms. The tautoraeric character and/or D-H exchange of the vinyl protons are described for compounds 5a,b and 6a,b .     

Reactions of 3-chloro-6-hydrazinopyridazine with michael-retro-michael reagents

Although pyrazole formation results from treatment of 3-chloro-6-hydrazinopyridazine ( 2 ) with both ethoxymethylenemalononitrile and ethyl (ethoxymethylene)cyanoacetate, 6-chlorotriazolo[4,3-b]pyridazine ( 5 ) was produced (75% yield) when 2 was treated with diethyl ethoxymethylenemalonate. Treatment of 2 with diethyl acetylmalonate ( 8 ) gave both 6-chloro-3-methyltriazolo[4,3-b]pyridazine ( 10 ) and 5-hydroxy-3-methyl-1-(6-chloro-3-pyridazinyl)-1H-pyrazole-4-carboxylic acid ethyl ester ( 12 ). Pyrazole 12 was initially isolated as a salt of triazolopyridazine 10 .     

Synthesis of tricyclic and tetracyclic thieno[3,2-f]-1,4-thiazepines

Treatment of 5-methylthio-2,3-dihydrothieno[3,2-f]-1,4-thiazepine ( 9 ) with acylhydrazines gave 5,6-dihydrothieno[3,2-f]-1,2,4-triazolo[4,3-d][1,4]thiazepines 10, 11 , and that of 9 with ethyl anthranilate gave 5,6-dihydrothieno[3′,2′:6,7][1,4]thiazepino[5,4-b]quinazolin-8-one ( 14 ). Reaction of 9 with hydrazine hydrate or 4-chlorophenylhydrazine afforded 5-hydrazino compounds 12, 15 , which were subsequently cyclized to ethyl 5,6-dihydrothieno[3,2-f]-1,2,4-triazolo[4,3-d][1,4]thiazepine-3-carboxylate ( 13 ), 2-(4-chlorophenyl)-5,6-dihydrothieno[3,2-f]-1,2,4-triazolo[4,3-d][1,4]thiazepin-3(2H)-one ( 16 ) and 2-(4-chlorophenyl)-6,7-dihydro-2H-thieno[3,2-f][1,2,4]triazino[4,3-d][1,4]thiazepine-3,4-dione ( 17 ). New thieno-anellated heterocycles were prepared with the aim of studying their affinity for the benzodiazepine receptors.     

Synthesis of 8-tert-Butyl-9-oxo-1,2,4-triazolo[4,5-b]-1,2,4-triazolo[3,4-c]-1,2,4-triazine

8-tert-Butyl-9-oxo-1,2,4-triazolo[4,5-b]-1,2,4-triazolo[3,4-c]-1,2,4-triazine has been synthesized by the interaction of 6-tert-butyl-3-hydrazino-1,2,4-triazolo[3,4-c]-1,2,4-triazin-5-one with formic acid. The conditions of carrying out the reaction are discussed. Spectral characteristics are given.     

The synthesis of 11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles,11H-tetrazolo[4,5-b]pyridazino[4,5-b]indoles and 1,2,4-triazolo[3,4-f]-1,2,4-triazino[4,5-a]indoles

This paper describes the synthesis of the previously unknown 11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles (2) and 11H-tetrazolo[4,5-b]pyridazino[4,5-b]indoles (3) from 4-hydrazino-5H-pyridazino[4,5-b]indoles (1) , as well as the synthesis of 1,2,4-triazolo[3,4-f]-1,2,4-triazino-[4,5-a]indoles (10) from 2-indolecarbohydrazide (4) . Compounds 2 were obtained by acylation of compounds 1 , followed of thermal cyclization and compounds 3 by treating compounds 1 with nitrous acid. The reactions of compound 4 with formic acid or ethyl orthoformiate gave 1,2-dihydro-1-oxo-1,2,4-triazino[4,5-a]indole (6) . Treating this last compound with phosphorus oxychloride or phosphorus pentasulfide, followed by hydrazine, gave 1-hydrazino-1,2,4-triazino-[4,5-a]indole (9) . Acylation of this last compound, followed of cyclization gave compounds 10 . All the compounds were characterized by elemental analysis and ir and ¹H-nmr spectra.     

Synthesis of 4-hydrazino-5H-pyrimido[5,4-b]indole and related compounds

This paper describes the synthesis of two 4-amino-5H-pyrimido[5,4-b]indoles 5 , 4-hydrazino-5H-pyrimido[5,4-b]indole 6 , two 1,2,4-triazolo[4,3-c]pyrimido[5,4-b]indoles 8 , and tetrazolo[4,5-c]pyrimido[5,4-b]indole 10 . Starting with ethyl 3-aminoindole-2-carboxylate 1 , 5H-pyrimido[5,4-b]indol-4-one 2 was obtained (80%) by condensing with formamide. Reactions of 2 with phosphorus oxychloride and phosphorus pentasulfide gave respectively, 4-chloro-5H-pyrimido[5,4-b]indole 3 (70%) and 5H-pyrimido[5,4-b]indole-4-thione 4 (80%). Compound 3 reacted with amines (morpholine, piperidine) to give the respective 4-amino-5H-pyrimido[5,4-b]-indoles 5 , and compound 4 reacted with hydrazine to give 4-hydrazino-5H-pyrimido[5,4-b]indole 6 (80%). Two hydrazones of 6 (benzylidene, isopropylidene) 7 were also prepared (90%). Compound 6 reacted with formic and acetic acids to give (65–75%) the respective 1,2,4-triazolo[4,3-c]pyrimido[5,4-b]indoles 8 and with nitrous acid to give tetrazolo[4,5-c]pyrimido[5,4-b]indole 9 (85%). All the new compounds 2 to 9 were characterized by elemental analysis and spectral data (ir, nmr).     

1,2,3-Triazolo[4,5-d]-1,2,4-triazolo[4,3-b]pyridazines

Some new 1,2,3-triazolo[4,5-d]-1,2,4-triazolo[4,3-b]pyridazines were prepared starting from the corresponding 1,2,3-triazolo[4,5-d]pyridazines via the formation of the 1,2,4-triazole ring, by condensation of an appropriate monocarbon fragment with the 4-hydrazino substituent and the nitrogen atom in the 5 position of the heterocycle. Condensation of 4-phenylhydrazino substituted derivatives with formic acid gave zwitterionic compounds.     

Reaction of azole condensed quinoxaline N-oxides with acetic anhydride

The reaction of 7-chlorotetrazolo[1,5-α]quinoxaline 5-oxide 6a with acetic anhydride gave 7-chloro-5-(7-chlorotetrazolo[1,5-α]quinoxalin-4-yl)-4,5-dihydro-4-oxotetrazolo[1,5-α]quinoxaline 7a , while the reaction of 7-chloro-1,2,4-triazolo[4,3-α]quinoxaline 5-oxide 6b with acetic anhydride afforded 7-chloro-5-(7-chloro-1,2,4-triazolo[4,3-α]quinoxalin-4-yl)-4,5-dihydro-4-oxo-1,2,4-triazolo[4,3-α]quinoxaline 7b and 7-chloro-4,5-dihydro-4-oxo-1,2,4-triazolo[4,3-α]quinoxaline 8b . The reaction of compound 6a or 6b with acetic anhydride/acetic acid provided 7-chloro-4,5-dihydro-4-oxo-tetrazolo[1,5-α]quinoxaline 8a or compound 8b , respectively.     

Transaminations of enaminones:A Synthesis of tricyclic,N-aryl, 1,2,3-triazole-fused pyridones

1-Phenylmethyl- and 1-(4-methoxyphenylmethyl)-5-chloro-1,2,3-triazole-4-carbonyl chlorides acylated the pyrrolidine enamines of cyclopentanone and cyclohexanone, and the resulting enaminones underwent transaminations with aryl amines under acidic conditions. The products then cyclized under basic conditions to linearly fused, tricyclic 3-phenylmethyl- and 3-(4-methoxyphenylmethyl)-4-aryl-8-oxo-4,5,6,7-tetrahydrocyclopenta[6]-1,2,3-triazolo[4,5-e]pyridines, and to 5,6,7,8-tetrahydro-4-aryl-3H-1,2,3-triazolo[4,5-b]quinolin-9(4H)-ones. Similar transaminations afforded the related 8-phenyl- and 8-(3-chlorophenyl)-1,5,7,8-tetrahydro-1-(phenylmethyl)-4H-thieno[3,4-e]-1,2,3-triazolo[4,5-b]pyridin-4-ones. Phase-transfer and catalytic hydrogenolyses of some of these intermediates furnished 4-aryl-8-oxo-4,5,6,7-tetrahydrocyclopenta[b]-1,2,3-triazolo[4,5-e]pyridines and 4-aryl-5,6,7,8-tetrahydro-3H,2,3-triazolo[4,5-b]quinoline-9-(4H)-ones. The 3-(4-methoxyphenylmethyl)-4-aryl intermediates were sterically crowded. Two protons from the methoxyphenylmethylphenylmethylgroups were dramatically shielded because of anisotropic effects exerted by the 4-aryl substituents.     

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.     

微波促进下3-(2-苯并呋喃基)-4-氨基-5-巯基-1,2,4-三唑

微波辐射条件下, 首先由2-苯并呋喃甲酰肼依次与二硫化碳和水合肼反应合成3-(2-苯并呋喃基)-4-氨基-5-巯基- 1,2,4-三唑, 进一步在微波辐射条件下由4-氨基-5-巯基-1,2,4-三唑分别与芳甲酸/芳氧基乙酸、α-溴代苯乙酮及芳醛反应以较高产率制得了相应的1,2,4-三唑并[3,4-b]-1,3,4-噻二唑、1,2,4-三唑并[3,4-b]-1,3,4-噻二嗪及4-芳亚甲基亚胺基-5-巯基-1,2,4-三唑. 产物结构经IR, ¹H NMR, MS及元素分析进行了表征.     

Studies in the field of pyridazine compounds, 20. 6H-1,2,4-Triazino[4,3—b]1,2,4-triazolo[3,4—f]pyridazine,a novel angular ring system

The novel ring system, 6H-1,2,4-triazino[4,3—b]1,2,4-triazolo[3,4—f]-pyridazine was prepared either by ring closure of1-(1-ethoxycarbonylethylene)-2-(1,2,4-triazolo[4,3—b]pyridazinyl-6)-hydrazine derivatives (4, 5, 7) in polyphosphoric acid or of a hydrazine15 derived from pyridazino-1,2,4-triazine under the action of triethyl orthoformate. Compound8 showed a positive inotropic effect.

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Über Pyridazinring enthaltende Verbindungen, 20. 6H-1,2,4-Triazino[4,3—b]1,2,4-triazolo[3,4—f]pyridazin, ein neues angulares Ringsystem

Zusammenfassung Das neue Ringsystem 6H-1,2,4-Triazino[4,3—b]1,2,4-triazolo[3,4—f]-pyridazin wurde entweder durch Ringschluß der1-(1-Ethoxycarbonylethylen)-2-(1,2,4-triazolo[4,3—b]pyridazinyl-6)-hydrazin-Derivate(4, 5, 7) 4, 5, 7 in Polyphosphorsäure, oder aus einem von Pyridazino-1,2,4-triazin abgeleiteten Hydrazin15 durch Ringschluß mit Orthoameisensäuretriethylester hergestellt. Verbindung8 zeigte einen positiven inotropen Effekt.