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.     

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.     

Studies in anthraquinone: Preparation of 2-substituted pyrimidoanthraquinones and related fused 1,2,4-triazolo,tetrazolo and pyrazolino derivatives

This paper describes the synthesis of 2-substituted-4(3H)-oxopyrimido[4,5-a]anthraquinone, 2-substi-tuted-4-hydrazinopyrimido[4,5-a]anthraquinones, several 2-substituted-1,2,4-triazolo[4,3-c]pyrimido[4,5-a]-anthraquinones tetrazolo[4,5-c]pyrimido[4,5-a]anthraquinones and pyrazolinopyrimidoanthraquinone derivatives.     

A new approach to the synthesis of pyrido[4,3-<Emphasis Type="Italic">b</Emphasis>]indole derivatives (γ-carbolines) <Emphasis Type="Italic">via</Emphasis> cyclization of enamino dinitriles

Reactions of 2-dicyanomethylidene-3-ethoxymethylidene-2,3-dihydroindole with various amines afforded enamino dinitriles and the corresponding pyrido[4,3-b]indoles (γ-carbolines). 3-Amino-4-cyano-5H-pyrido[4,3-b]indole reacted with cyclohexanone to give pentacyclic 13-amino-2,3,4,12-tetrahydro-1H-benzo[b]indolo[2,3-f]-1,8-naphthyridine. Alkylation of pyrido[4,3-b]indoles with various alkylating agents was studied.     

New polyazaheterocycles. 9-Methyl-di-s-triazolo[4,3-a:4,3-c]pyrimidine and 9-methyl-s-triazolo[4,3-c]tetrazolo[1,5-a]pyrimidine

9-Methyl-di-s-triazolo[4,3-a:4,3-c]pyrimidine and 9-methyl-s-triazolo[4,3-c]tetrazolo[1,5-a]pyrimidine have been synthetized from 4-hydrazino-7-methyl-s-triazolo[4,3-c]pyrimidine. Structural assignments based on nmr, ir and chemical manipulations are discussed.     

Azolopyrimidines and pyrimidoquinazolines from 4-chloropyrimidines

5-Cyano-3,4-dihydro-6-phenyl-2-substitutedpyrimidin-4-ones 1a-c reacted with phosphorus oxychloride to give the corresponding 4-chloropyrimidine derivatives IIa-c . Compounds IIa-c reacted with aniline and hydrazine to yield the 4-anilino, IIIa,e , and 4-hydrazino, IIIb-d derivatives. The 4-hydrazino analogues IIIb,c could be converted into the triazolo[4,3-c] and tetrazolo[4,5-c]pyrimidines IV and V by the action of carbon disulphide and nitrous acid, respectively. The reaction of IIb,c with phenylhydrazine afforded directly the 5-amino-4,6-diphenyl-6H-2-substitutedpyrazolo[3,4-d]pyrimidines VIa,b . The 4-chloro derivative IIa reacted with antrhanilic acid to form the 5-cyano-2,4-diphenyl-6-(o-carboxyphenylamino)pyrimidine VIII , which could be cyclised into the 4-cyano-1,3-diphenyl-10H-pyrimido[6,1-b]quinazolin-10-one IX by heating with acetic anhydride.     

Azaindoles. V. Pyrido(4,3-b]indoles (γ-carbolines) fonctionnalisés sur leur sommet 4: Synthèse en une seule étape

In boiling diphenylether phenylhydrazine reacts with 1,2-dihydro-2-oxo-4-hydroxypyridines to give 3,4-dihydro-4-oxo(9H)-pyrido[4,3-b]indoles (γ-carbolines) in one step. Nucleophilic displacement of their 4-chloro derivatives by secondary amines affords both 3,4-disubstituted γ-carbolines and chlorination of 2,3-dimethyl-4-oxo(9H)pyrido[4,3-b]indoles, as well as methylation of 2-methyl-4-chloro-(9H)pyrido[4,3-b]indole leads to derivatives in the (3H)4-substituted pyrido[4,3-b] indole series.     

The photo cycloaddition of alkenes to s-triazolo[4,3-b] and [2,3-b]pyridazines

s-Triazolo[4,3-b]pyridazine (I) reacted with cyclohexene under the influence of ultraviolet light to yield 4a,5,7,8,8a,9-hexahydro-9-methylene-6H-s-triazolo[1,5-a]indole (IV) and 9-cyanomethyl-4a,5,7,8,8a,9-hexahydro-6H-s-triazolo[1,5-a]indole (V). These products were formed by the addition of the alkene to the 1,8 positions of I with a concurrent cleavage of the N₄? N₅ bond. Similar additions were observed with cyclopentene and 2,3-dimethyl-1,3-butadiene. The isomeric s-triazolo[2,3-b]pyridazine (III) reacted with cyclohexene to form an isomer of IV, 4a,5,7,8,8a,9-hexahydro-9-methylene-6H-s-triazolo[4,3-a]indole (XV) and two [2 + 2] cycloadducts (XVI and XVII).     

Pyridazines. XXXIV. Electron-impact induced fragmentation of some s-triazolo[4,3-b] pyridazines,tetrazolo[1,5-b] pyridazines and related compounds

Mass spectra of several 4-triazolo[4,3-b]pyridazines and tetrazolo[1,5-b]pyridazines were examined in order to establish their fragmentation patterns. Two distinct patterns could be observed upon electron impact of s-triazolo[4,3-b]pyridazines and tetrazolo[1,5-b]pyridazines. Azidotetrazolopyridazines show a loss of six nitrogens. This can be accounted for by a path proceeding via a molecular ion with a bis-tetrazolo structure.     

Polyazasteroids II.. 1,2,4-Triazolol[3′,4′:2,3]pyrimido[4,5-c]quinolin- 11(12H)ones,imidazo[2′,1′:2,3]pyrimido[4,5-c]quinolin-11(12H)ones and 2,3-dihydroimidazo[2′,1′:2,3] pyrimido[4,5-c]quinolin-11(12H)ones

Starting with 2-substituted quinoline-3,4-dicarboxylic acids, a series of substituted 1,2,3,4-tetrahydropyrimido[4,5-c]quinolinone-3-thiones were obtained. The latter compounds were converted to the three novel polyazasteroid series: 1,2,4-Triazolo[3′,4′:2,3]pyrimido[4,5-c]-quinolin-11(12H)ones, imidazo[2′,1′:2,3]pyrimido[4,5c]quinolin-11(12H)ones and 2,3-dihydroimidazo[2′,1′:2,3]pyrimido[4,5-c]quinolin-11(12H)ones. The intermediate 3-hydrazino-1,2-dihydropyrimido[4,5-c]quinolinones and nitrous acid gave the 3-azido derivatives rather than the tetrazolo compounds.     

Pyridazines. XXXV. Preparation of some novel pyrimido[4,5-c]pyridazine derivatives from 3-alkylamino- and 3-arylamino-4-pyridazinecarboxamides

Facile syntheses of pyrimido[4,5-c]pyridazine-5,7(6H,8H)diones 4 , pyrimido[4,5-c]pyridazin-5(8H)-ones 7–10 , and dihydropyrimido[4,5-c]pyridazin-5(6H)ones 5,6 starting from 3-chloro-4-pyridazinecarbonitrile 1 via aminocarbonitriles 2 and aminocarboxamides 3 are described. In addition, a convenient access to the new aminopyridazinecarbonitrile 11 from the chloronitrile 1, employing the tetrazolo[1,5-b]pyridazine 12 as the key intermediate, is reported.     

Studies on the synthesis and interconversion of isomeric triazolotheinopyrimidines. Part II. Effect of 5-substituents on the dimroth rearrangement of 1,2,4-triazolo[4,3-c]thieno[3,2-e]pyrimidines

The triazolothienopyrimidines obtained by the cyclization of 4-hydrazino-2-phenylthieno[2,3-d]pyrimidines with triethyl orthoformate or formic acid presumed to be the triazolo[2,3-c] isomers are now assigned the 5-phenyl-1,2,4-triazolo[4,3-c]thieno[3,2-e]pyrimidine structure. While these [4,3-c]triazoles resist isomerization under acidic conditions, they undergo isomerization to 5-phenyl-1,2,4-triazolo[2,3-e]thieno[3,2-e]pyrimidines under basic conditions.     

Synthesis and reactivity of 1,2,4-triazolo[1,5-c]quinazolines

The preparation of 1,2,4-triazolo[1,5-c]quinazolines 4a-d , 5 , 8a-d by cyclocondensation of 1a-c with carboxylic acids and carboxylic anhydrides, respectively, is described. By different pathways, the 5-thioxo-5,6-dihydro-1,2,4-triazolo[1,5-c]quinazolines 4a-d react with hydrazine hydrate or amines with the formation of 5-substituted 1,2,4-triazolo[1,5-c]quinazolines 9 and 10a-d . Cyclocondensation of 9 with carboxylic acids, carboxylic anhydrides, and nitrous acid, respectively, leads to the new anellated heterocycles bis-1,2,4-triazolo[4,3-a:1,5-c]quinazoline 13 and tetrazolo [1,5-a]-1,2,4-triazolo[1,5-c]quinazoline ( 14 ).     

Synthesis of 3-amino-5H-pyrimido[5,4-b]indol-4-one derivatives

Starting with ethyl 3-aminoindole-2-carboxylate, the synthesis of 3-amino-5H-pyrimido[5,4-b]indole-2,4-dione 5 , 3-amino-5H-pyrimido[5,4-b]indol-4-one 10 and some related compounds is described. Preliminary results about the inhibition of platelet aggregation by these compounds is reported.     

Synthesis of new tricyclic ring systems containing the pyrimido[5, 4-b][1, 4]oxazine skeleton

Synthesis of derivatives 4 and 6 of two novel tricyclic ring systems, 1, 2, 4-triazolo[3, 4-c]pyrimido[5, 4-b]-[1, 4]oxazine and imidazo[1, 2-c]pyrimido[5, 4-b][1, 4]oxazine, respectively is described. Although the parent pyrimido[5, 4-b]oxazines possess positive inotropic activity, the tricyclic compounds are practically inactive.     

Synthesis of 1-hydrazinopyridazino[4,5-b]quinoxaline and related compounds

This paper describes the synthesis of 1-hydrazinopyridazino[4,5-b]quinoxaline ( 10 ), tetrazolo[4,3-b]pyridazino[4,5-b]quinoxaline ( 11 ) and some 1,2,4-triazolo[4,3-b]pyridazino[4,5-b]quinoxalines 13 . Starting with 2-ethoxycarbonyl-3-methylquinoxaline 1,4-dioxide ( 1 ), 1,2-dihydro-1-oxopyridazino[4,5-b]quinoxaline ( 5 ) was prepared by three different ways: (a) chlorination of 1 in acetic acid gave 2-ethoxycarbonyl-3-dichloromethylquinoxaline 1,4-dioxide, which reacts with an excess of hydrazine to give about 60% of 5 ; (b) oxidation of 1 with selenium dioxide gave 90% of 2-ethoxycarbonyl-3-formylquinoxaline 1,4-dioxide ( 3 ), which reacts with hydrazine to give 5 (63%); (c) compound 3 was treated with hydrazine to give 1,2-dihydro-1-oxopyridazino-[4,5-b]quinoxaline 1,4-dioxide ( 4 ) (70%), which by reduction with sodium dithionite gave 5 (80%). Compound 5 reacts with phosphorus pentasulfide or the Lawesson reagent to give 1,2-dihydro-1-thiocarbonylpyridazino[4,5-b]quinoxaline ( 9 ), which treated with hydrazine gave 5 (80%). This last compound reacts with nitrous acid to give 11 . Some hydrazones 12 from 10 are described. Heating the aldehyde hydrazones 12a,c,d with dimethylsulfoxide some 1,2,4-triazolo[4,3-b]pyridazino[4,5-b]quinoxalines 13 were obtained. Compound 13a was also obtained in the reaction of 10 with benzoyl chloride. Reaction of 3 with phenylhydrazine gave 1,2-dihydro-1-oxo-2-phenylpyridazino[4,5-b]quinoxaline ( 6 ). Reactions of 5 with acetic anhydride and dimethylsulfate gave, respectively, 1-acetoxypyridazino[4,5-b]quinoxaline ( 8 ) and 1,2-dihydro-1-oxo-2-methylpyridazino-[4,5-b]quinoxaline ( 7 ). All the compounds were characterized by elemental analysis and ¹H-nmr spectra. Compounds 5 and 10 showed antihypertensive activity in rats.     

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 1- and 3-amino-5-t-butyl-1H- and -3H-v-triazolo[4,5-d]pyrimidines as hetaryne precursors

The synthesis of the title compounds 6 and 8 has first been accomplished by reaction of O-mesitylsulfonyl-hydroxylamine with 5-t-butyl-3H-v-triazolo[4,5-d]pyrimidine ( 5 ) whose preparation is reported in detail. However the preferred route for the synthesis of the 3-amino derivative 8 is based upon the preparation of 3-benzylideneamino-5-t-butyl-3H-v-triazolo[4,5-d]pyrimidine ( 10 ), followed by the removal of the benzylidene protecting group. This critical step was effected by treatment of 10 with dilute hydrochloric acid, in the presence of 2,4-dinitrophenylhydrazine. The diazotization of 5-amino-4-hydrazino-2-t-butylpyrimidine gave predominantly the tetrazolo[1,5-c]-pyrimidine 13 along with a small amount of compound 8.     

Efficient synthesis of pyrimido[5,4‐c]pyridazines and of thiino[2,3‐d]pyrimidines based on an aza‐wittig reaction/heterocyclization strategy

A simple one‐pot and efficient method is described for the synthesis of pyrimido[5,4‐c]pyridazines 5 and of thiino[2,3‐d] pyrimidines 15 by a domino process involving an aza‐Wittig reaction/heterocyclization. The iminophosphorane 2 reacted with phenylisocyanate, followed by heterocyclization on addition of amines to give the corresponding guanidine intermediates 4 . The guanidine intermediates were cyclized in the presence of catalytic amount of sodium ethoxide to pyrimido[5,4‐c]pyridazines 5 . Similarly, iminophosphorane 12 reacted with phenylisocyanate and amines to give thiino[2,3‐d]pyrimidines 15 in moderate yields. Furthermore, pyridazino[4,3‐d]oxazines 10 and thiino[2,3‐d]oxazines 19 were synthesized by the intremolecular aza‐Wittig reaction of phosphazenes 2 and 12 , respectively, with acid chlorides followed by heterocylization via imidoyl chloride intermediates. J. Heterocyclic Chem., (2012).     

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 ).