A convenient synthesis of novel pyridazino[3,4-b]quinoxaline and pyrazolo[3,4-b]quinoxaline utilizing 1,3-dipolar cycloaddition reaction

The reaction of 2,6-dichloroquinoxaline 4-oxide 4 with methylhydrazine gave 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 5, whose reaction with dimethyl acetylenedicarboxylate or 2-chloroacrylonitrile resulted in the 1,3-dipolar cycloaddition reaction to afford 7-chloro-3,4-bismethoxycarbonyl-1-methyl-1,2-dihydropyridazino[3,4-b]quinoxaline 6 or 6-chloro-3-hydroxymethylene-1-methyl-2,3-dihydro-1H-pyrazolo[3,4-b] quinoxaline hydrochloride 7, respectively.     

Tautomeric structure of 1-methyldihydropyridazino-[3,4-b]quinoxalines in solution

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 1 with ethyl 2-ethoxymethylene-2-cyano-acetate or ethoxymethylenemalononitrile gave 6-chloro-2-[2-(2-cyano-2-ethoxycarbonylvinyl)-1-methylhy-drazino]quinoxaline 4-oxide 3a or 6-chloro-2-[2-(2,2-dicyanovinyl)-1-methylhydrazino]quinoxaline 3b , respectively. The reaction of 3a with a base afforded 7-chloro-1-methyl-1,5-dihydropyridazino[3,4-b]quinoxaline 4 . From the NOE spectral data, the 1-methyldihydropyridazino[3,4-b]quinoxalines 2a, 2b and 4 were found to exist as the 1,5-dihydro form in a dimethyl sulfoxide or trifluoroacetic acid/dimethyl sulfoxide solution.     

Synthesis of pyridazino[3,4-b]quinoxalines and pyrazolo[3,4-b]-quinoxaline by 1,3-dipolar cycloaddition reaction

The pyridazino[3,4-b]quinoxalines 6a,b and pyrazolo[3,4-b]quinoxaline hydrochloride 9 were synthesized by the 1,3-dipolar cycloaddition reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 5 with dimethyl or diethyl acetylenedicarboxylate and 2-chloroacrylonitrile, respectively. The reaction mechanisms were postulated for the formation of 6a,b and 9 .     

Synthesis of mesoionic triazolo[4,3-a]quinoxalines

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 1 or 6-chloro-2-(1-methylhydrazino)-quinoxaline 5 with phenyl isothiocyanate under reflux in N,N-dimethylformamide gave 7-chloro-3-methyl-1,2,4-triazolo[4,3-a]quinoxalin-3-ium-1-thioate 4 , which was also obtained by refluxing of 6-chloro-2-[1-methyl-2-(N-phenylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 2b or 6-chloro-2-[1-methyl-2-(N-phenylthiocarbamoyl)hydrazino]quinoxaline 6 in N,N-dimethylformamide.     

A facile synthesis of novel 1,2-diazepino[3,4-b]quinoxalines by a 1,3-dipolar cycloaddition reaction

The 1,3-dipolar cycloaddition reaction of the quinoxaline 4-oxides 4a,b with 2-chloroacrylonitrile gave the 2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxalines 5a,b , respectively, which were converted into the 2,3,4,6-tetrahydro-1H-1,2-diazepino[3,4-b]quinoxalines 7a,b and 8a,b , respectively.     

A new synthesis of 1,5-dihydropyridazino[3,4-b]quinoxalines and 2-(pyrazol-4-yl)quinoxalines

The reaction of 6-chloro-2-(l-methylhydrazino)quinoxaline 1-oxide 3 with acetylenedicarboxylates gave the 8-chloro-1-memyl-1,5-dihydropyridazino[3,4-b]quinoxaline-3,4-dicarboxylates 4a,b and 2-(pyrazol-4-yl)quinoxaline 1-oxides 5a,b . The formation of compounds 4a,b would follow the 1,3-dipolar cycloaddition reaction, subsequent 1,2-hydrazino migration, and then dehydrative cyclization, while the production of compounds 5a,b would proceed via the addition of the hydrazino group to acetylene-dicarboxylate leading to the construction of a pyrazole ring, followed by rearrangement of the pyrazole ring. Compounds 5a,b were deoxidized with phosphoryl chloride/N,N-dimethylformamide to change into the 4-(quinoxalin-2-yl)pyrazole-3-carboxylates 8a,b .     

Synthesis of 4H-1,3,4-oxadiazino[5,6-b]quinoxalines from 2-substituted quinoxaline 4-oxides

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 8 with acetic anhydride resulted in the intramolecular cyclization to give 8-chloro-2,4-dimethyl-4H-1,3,4-oxadiazino[5,6-b]quinoxaline 7a , while the reaction of compound 8 with acetic anhydride/pyridine or acetic anhydride/acetic acid afforded 3-(2,2-diacetyl-1-memymydrazmo)-7-chloro-2-oxo-1,2-dihydroquinoxaline 9 , effecting no intramolecular cyclization. The reaction of 2-(2-acetyl-1-methylhydrazino)-6-chloroquinoxaline 4-oxide 10a or 6-chloro-2-(1-methyl-2-trifluoroacetylhydrazino)quinoxaline 4-oxide 10b with phosphoryl chloride provided compound 7a or 8-chloro-4-memyl-2-trifluoromethyl-4H-1,3,4-oxadiazino[5,6-b]quinoxaline 7b , respectively. The reaction of compound 7b with phosphorus pentasulfide gave 7-chloro-3-(1-methyl-2-trifluoroacetylhydrazino)-2-thioxo-1,2-dihydroquinoxaline 11 , whose dehydration with sulfuric acid in acetic acid afforded 8-chloro-4-methyl-2-trifluoromemyl-4H-1,3,4-thiadiazino[5,6-b]quinoxaline 12 .     

Reaction of 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)]-hydrazinoquinoxaline 4-oxide with dimethyl acetylenedicarboxylate

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 4a with methyl or phenyl isothiocyanate gave 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7a or 6-chloro-2-[1-methyl-2-(N-phenylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7b , respectively, whose reaction with dimethyl acetylenedicarboxylate afforded 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-3-methyl-4-oxo-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8a or 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-4-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8b , respectively.     

A convenient synthesis of 5,14-methano-16-oxo-1,5,6-benzoxadiazonino[3,4-b]quinoxalines utilizing a 1,3-dipolar cycloaddition reaction and an intramolecular alcoholysis

The reaction of the hydrazones 5a-c with 2-chloroacrylonitrile produced the 1,2-diazepino[3,4-b]quinoxaline hydrochlorides 6a-c , which were transformed into the 5,6,7,13-tetrahydro-5,14-methano-16-oxo-1,5,6-benzoxadiazonino[3,4-b]quinoxalines 7a-c , respectively. The oxidation of 7a-c with diethyl azodicarboxylate afforded the 7,13-dihydro-5,14-methano-16-oxo-1,5,6-benzoxadiazonino[3,4-b]quinoxalines 8a-c , respectively. Compounds 7a-c and 8a-c were also obtained by a one-pot synthesis from 5a-c and 6a-c , respectively.     

A convenient synthesis of novel pyridazino[3,4-b]quinoxalines

Novel 4-chlorophenylhydrazono-3-oxo-1,2,3,4-tetrahydropyridazino[3,4-b]quinoxalines 10a-c were synthesized by the cyclization of the α-hydrazonohydrazides 8a-c. The chlorination of 10a with phosphoryl chloride afforded 3-chloro-4-[2-(o-chlorophenyl)hydrazino]pyridazino[3,4-b]quinoxaline 12.     

A new method for the synthesis of 4H-1,3,4-thiadiazino[5,6-b]quinoxalines

The reaction of 6-chloro-2-[1-methyl-2-(Mmemylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 5 with acetic anhydride or trifluoroacetic anhydride resulted in dehydrative cyclization to give 2-(N-acetyl)-memylamino-8-chloro-4-methyl-4H-1,3,4-thiadiazino[5,6-b]quinoxaline 6 or 8-chloro-2-(N-trifluoroacetyl)methylamino-4-methyl-4H-1,3,4-thiadiazino[5,6-b]quinoxaline 9 , respectively. The oxidation of compound 6 or 9 with 2-fold molar amount of m-chloroperbenzoic acid afforded the 4H-1,3,4-thiadiazino-[5,6-b]quinoxaline 1,1-dioxide 8 or 13 , respectively. The acetyl group of compound 6 was hardly hydrolyzed, but the trifluoroacetyl group of compound 9 was easily hydrolyzed to change into 8-chloro-4-methyl-2-memylamino-4H-1,3,4-thiadiazino[5,6-b]quinoxaline 10 . The acylation of compound 10 with acetic anhydride, trifluoroacetic anhydride, phenyl isocyanate, and chloroacetyl chloride furnished the 2-(N-acetyl)methylamino 6 , 2-(N-trifluoroacetyl)methylamino 9 , 2-(1-methyl-3-phenylureido) 11 , and 2-(N-chloroacetyl)methylamino 12 derivatives, respectively.     

A new method for the synthesis of novel 1-aryl-3-heteroaryl-1H-pyrazolo[3,4-b]quinoxalines

The reaction of 3-(2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline 4 with o-chlorobenzenediazonium chloride gave 3-[α-(o-chlorophenylhydrazono)-2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-ylmethyl]-2-oxo-1,2-dihydroquinoxaline 6 , whose refluxing in phosphoryl chloride/pyridine afforded 1-(o-chlorophenyl)-3-(2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-yl)-1H-pyrazolo[3,4-b]quinoxaline 7. The reactions of 6 and 7 with nitrous acid resulted in sulfur extrusion to provide 1-(o-chlorophenyl)-3-(4-methyl-4H-1,2,4-triazol-5-yl)1H-pyrazolo[3,4-b]quinoxaline 8 and 3-[α-(o-chlorophenylhydrazono)-4-methyl-4H-1,2,4-triazol-5-ylraethyl]-2-oxo-1,2-dihydroquinoxaline 9 , respectively.     

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.     

A new synthesis of novel 1-aryl-3-heteroaryl-1H-pyrazolo[3,4-b]quinoxalines via a Key Intermediate

The chlorination of the α-hydrazonoester 4 with phosphoryl chloride/pyridine gave 3-[α-(o-chlorophenylhydrazono)methoxycarbonylmethyl]-2-chloroquinoxaline 5 , whose cyclization with 1,8-diazabicyclo[5,4,0]-7-undecene afforded 3-methoxycarbonyl-1-(o-chlorophenyl)-1H-pyrazolo[3,4-b]quinoxaline 6 . The reaction of 6 with hydrazine hydrate provided 3-hydrazinocarbonyl-1-(o-chlorophenyl)-1H-pyrazolo[3,4-b]quinoxaline 7 , whose reactions with methyl and allyl isothiocyanates furnished 3-(2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-yl)-1-(o-chlorophenyl)-1H-pyrazolo[3,4-b]quinoxaline 2 and 3-(4-allyl-2,3-dihydro-3-thioxo-4H-1,2,4-triazol-5-yl)-1-(o-chloropheny)-1H-pyrazolo[3,4-b]quinoxaline 8 , respectively. Moreover, the reactions of 7 with triethyl orthoformate and orthoacetate gave 1-(o-chlorophenyl)-3-(1,3,4-oxadiazol-5-yl)-1H-pyrazolo-[3,4-b]quinoxaline 9a and 1(o-chlorophenyl)-3-(2-methyl-1,3,4-oxadiazol-5-yl)-1H-pyrazolo[3,4-b]quinoxaline 9b , respectively.     

Tautomeric structure of dihiydropyridazino-[3,4-b]quinoxalines in solution and solid state

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide (1) with -diketone abd -ketoesters gave the dihydropyridazino[3,4-b]quinoxalines (IIIa-d), which were found to exist as the 1,5-dihydro form in solution and solid state by NMR spectoscopy and x-ray analysis.Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1245–1252, September, 1995.     

A new type of deoxygenation of quinoxaline N-oxides

The reaction of 6-chloro-2-[2-(p-chlorobenzylidene)-1-methylhydrazino]quinoxaline 4-oxide 3a or 2-[2-(p-bromobenzylidene)-1-methylhydrazino]-6-chloroquinoxaline 4-oxide 3b with dimethyl acetylenedicarboxylate under reflux in N,N-dimethylformamide resulted in deoxygenation to give 6-chloro-2-[2-(p-chlorobenzylidene)-1-methylhydrazino]quinoxaline 4a or 2-[2-(p-bromobenzilidene)-1-methylhydrazino]-6-chloroquinoxaline 4b , respectively, while the reaction of compound 3a or 3b with dimethyl acetylenedicarboxylate under reflux in dioxane precipitated dimethyl 8-chloro-4-[2-(p-chlorobenzyli-dene)-1-methylhydrazino]-3aH-isoxazolo[2,3-a]quinoxaline-2,3-dicarboxylate 6a or dimethyl 4-[2-(p-bromobenzylidene)-1-methylhydrazino]-8-chloro-3aH-isoxazolo[2,3-a]quinoxaline-2,3-dicarboxylate 6b , respectively. Further refluxing of compound 6a or 6b in N,N-dimethylformamide provided compound 4a or 4b , respectively.     

A convenient synthesis of 1,4-dihydro-4-oxopyridazino[3,4-b]quinoxalines by a ring transformation of 1,2-diazepino[3,4-b]quinoxalines

The reaction of the 1,2-diazepino[3,4-b]quinoxalines 2a,b or 3a,b with N-bromosuccinimide/water resulted in ring transformation to give the 1,4-dihydro-4-oxopyridazino[3,4-b]quinoxalines 4a,b , respectively.     

A Convenient Synthetic Approach to Newly Condensed Pyrazoloazines Based on Pyrazolo[3,4-b]pyridine

The reaction of 6-amino-5-cyano-3-methyl-1H-1-phenylpyrazolo[3,4-b]pyridine ( 2 ) and 6,7-dihydro-3-methyl-6-oxo-1H-1-phenylpyrazolo[3,4-b)]pyridine-5-carbonitrile ( 3 ) and 5-amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]-1H-pyrazolo[4′,3′-e]pyridine ( 12 ) with different reagents have been conducted to give newly condensed pyrazoloazines.     

A convenient synthesis of 2-amino-4H-1,3,4-oxadiazino[5,6-b]-quinoxaline derivatives

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 5 with a 2-fold molar amount of ethyl chloroglyoxalate gave ethyl 8-chloro-4-methyl-4H-1,3,4-oxadiazino[5,6-b]quinoxaline-2-carboxylate 6 , whose reaction with hydrazine hydrate afforded the C₂-hydrazinocarbonyl derivative 7 . The reaction of compound 7 with nitrous acid provided the C₂-acylazide derivative 8 , which was converted into the C₂-amino 9 , C₂-carbamate 11a-c, 12a,b , and C₂-ureido 13a-c, 14 derivatives. The mass spectral fragmentation patterns were examined for compounds 10–14 , wherein the molecular ion peak did not appear in the mass spectra of compounds 10c, 11a-c, 12a,b, 13c , and 14.     

Synthesis and biological activity of 1,5-dihydropyridazino-[3,4-b]quinoxalines and a new class of quinolones

A new class of quinolones, 1,4-dihydro-4-oxopyridazino[3,4-b]quinoxaline-3-carboxylic acids and related compounds, were synthesized via oxidation of 1,5-dihydropyridazino[3,4-b]quinoxalines obtained from 2-hydrazinoquinoxaline 4-oxides. Some of the 1,5-dihydropyridazino[3,4-b]quinoxalines, 1,4-dihydro-4-oxopyridazino[3,4-b]quinoxaline-3-carboxylic acids, and related compounds showed biological activity.