Some novel heterocyclic systems derived from 7-amino-2,3-dihydro-8-nitro-1H-pyrrolo[1,2-α]benzimidazole and the corresponding diamine

The preparation of 7-amino-2,3-dihydro-8-nitro-1H-pyrrolo[1,2-a]benzimidazole from 1,4-diacetamido-2,3-dinitrobenzene is described. Reaction of this compound with 2,5-dimethoxytetrahydrofuran produces 2,3-dihydro-8-nitro-7-N-pyrrolo-1H-pyrrolo[1,2-a]benzimidazole, which can be cyclised to produce two new heterocyclic ring systems, 9,10-dihydro-8H-pyrrolo[1,2-a]pyrrolo(1′,2′:1,2]imidazo[5,4-f]quinoxaline and 9,10-dihydro-8H-pyrrolo[2,1-c]pyrrolo[1′,2′:1,2]imidazo[4,5-h][1,2,4]benzotriazine. The corresponding diamine, 7,8-diamino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole undergoes a variety of condensation reactions to produce several new heterocyclic systems, for example, with formic acid, 1,7,8,9-tetrahydroimidazo-[4,5-e]pyrrolo[2,1-6]benzimidazole is formed and with diacetyl, 9,10-dihydro-2,3-dimethyl-8H-pyrrolo-[1′,2′:1,2]imidazo[5,4-y]quinoxaline is obtained.     

Fused polycyclic nitrogen-containing heterocycles 21. Condensation of 4-hydroxy-3,5-diphenyl-2-phenyliminothiazolidine with 5-fluoro-4-morpholino- and 4-(4-methylpiperazino)-1,2-phenylenediamines

The condensation of 4-hydroxy-3,5-diphenyl-2-phenyliminothiazolidine with 5-fluoro-4-morpholino- and 5-fluoro-4-(4-methylpiperazino)-1,2-phenylenediamines leads to region-isomeric thiazolo[3,4-a]quinoxalines differing in substituents in positions 7 and 8 of the benzene ring. From the ratio of isomers formed it follows that the mesomeric effect of a fluorine atom in 1,2-phenylenediamines is comparable with the influence of an aminosubstituent.     

Fused polycyclic nitrogen-containing heterocycles

The condensation of methyl phenylchloropyruvate with 1-phenyl-3-(2-pyridyl)thiourea and its 3-and 4-picolyl homologs affords the corresponding 4-hydroxythiazolidines, which react with o-phenylenediamine to give one of two possible thiazolo[3,4-a]quinoxalines containing the pyridyl-or picolylimine substituents at position 1. 3a-Hydroxy-3-phenylimino-1-(2-pyridyl)thiazolo[3,4-a]quinoxalin-4-(3H,5H)-one, which is a covalent hydrate of the final product, was isolated as an intermediate in this reaction.     

Synthesis and reactions of ethyl 3-acetyl-8-cyano-6,7-dimethylpyrrolo[1,2-a]pyrimidine-4-carboxylate and related compounds

The reactions of 3-acetyl-4-ethoxycarbonyl- or 3,4-diethoxycarbonylpyrrolo[1,2-a]pyrimidine derivatives 7a,b , which were prepared by condensation of the 2-aminopyrrole ( 4 ) with ethyl 3-ethoxymethylene-2,4-dioxovalerate ( 5a ) or ethyl ethoxymethyleneoxaloacetate ( 5b ), with diazomethane are described. Thus, reaction of 7a , with diazomethane gave ethyl 2a-acetyl-7-cyano-2a,3a-dihydro-5,6-dimethyl-3H -cyclopropa[e]pyrrolo[1,2-a]pyrimidine-3a-carboxylate ( 11 ) in 74% yield, which was readily transformed into the 1-pyrrol-2-yl-pyrrole ( 18 ) by treatment with potassium hydroxide. On the other hand, reaction of 7b with diazomethane afforded three products whose structures were assigned as diethyl 7-cyano-2a,3a-dihydro-5,6-dimethyl-3H-cyclopropa[e]pyrrolo[1,2-a]pyrimidine-2a,3a-carboxylate ( 20 ), 6-cyano-7,8-dimethyl-3a,3b,5,9a-tetrahydro-4H -aziridino[c]-1H or 3H-pyrazolo[3,4-e]pyrrolo[1,2-a]pyrimidine-3a,9a-dicarboxylates ( 21,22 ). Ring Transformation of 20 to 25 was not observed.     

Microwave synthesis of new azolyl-substituted thiazolo[5,4-<Emphasis Type="Italic">d</Emphasis>]thiazoles

One-pot condensation of dithiooxamide with 4,5-dichloro-1,2-thiazole-3-carbaldehyde and 5-phenyl-1,2-oxazole-3-carbaldehyde, followed by oxidation of intermediate 2,5-dihydro[1,3]thiazolo[5,4-d]-[1,3]thiazoles with selenium dioxide, afforded previously unknown 2,5-bis(4,5-dichloro-1,2-thiazol-3-yl)- and 2,5-bis(5-phenyl-1,2-oxazol-3-yl)[1,3]thiazolo[5,4-d][1,3]thiazoles as first representative of bis-isothiazolyl- and bis-isoxazolyl thiazolothiazoles.     

Thieno[2,3-d]pyrimidin-4-ones 1. Condensation of 2,3-dimethyl- and 2,3-tri-, 2,3-tetra-, and 2,3-pentamethylene-7,8-dihydro-pyrrolo[1,2-a]thieno[2,3-d]pyriminidin-4(6H)-ones with aromatic aldehydes and furfural

2,3-Dimethyl- and 2,3-tri-, 2,3-tetra-, and 2,3-pentamethylene-substituted 8-arylidene-6,7-dihydro-pyrrolo[1,2-a]thieno[2,3-d]pyrimidin-4-ones were synthesized by the reaction of 2,3-dimethyl- and 2,3-tri-, 2,3-tetra-, and 2,3-pentamethylene-7,8-dihydropyrrolo[1,2-a]thieno[2,3-d]pyrimidin-4(6H)-ones with benzaldehyde, its 4-dimethylamino-, 3,4-dimethoxy-, and 3,4-methylenedioxy derivatives and also furfural in the presence of NaOH.     

Thermolyzed products of naphth[1,2-d]imidazo[2,1-b]-thiazole-2,3-dione

Themolysis of naphth[1,2-d]imidazo[2,1-b]thiazole-2,3-dione ( 1 ) in dimethylformamide gave an intermediate 2-isocyanatonaphtho[1,2-d]thiazole ( 2 ), which underwent [4 + 4] cyclodimerization to yield dinaphtho-[1″,2″:4,5;1′″,2′″:4′,5′]dithiazolo[3,2-a:3′,2′-e]-1,3,5,7-tetrazocine-9,19-dione ( 3 ). The possible [4 + 2] cycloadduct, 3-(2-naphtho-[1,2-d]-thiazolyl)naphtho[1′,2′:4,5]thiazolo[3,2-a]-1,3,5-triazine-2,4-dione ( 4 ), an usual dimer type of heterocyclic isocyanates was not produced. Discrimination between the two isomers was established on the basis of spectral analyses.     

Synthesis of novel spiro[benzo[4,5]thiazolo[3,2-a]chromeno[2,3-d]pyrimidine-14,3′-indoline]-1,2′,13(2H)-triones via three component reaction

A new and efficient method for the synthesis of hitherto unreported spiro[benzo[4,5]thiazolo[3,2-a]chromeno[2,3-d]pyrimidine-14,3′-indoline]-1,2′,13(2H)-triones was developed via the Domino Knoevenagel condensation–Michael addition–intermolecular cyclization sequences of isatin derivatives, cyclohexane-1,3-diones, and 2-hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ones, employing 12-tungstophosphoric acid (H₃PW₁₂O₄₀) as an effective and inexpensive catalyst.     

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 ).     

New heterocyclic structures. [1,3]Thiazino[3,2-a]purine and [1,2,3]triazolo[4,5-d][1,3]thiazino[3,2-a]pyrimidine

Derivatives of two new molecular structures, namely, [1,3]thiazino[3,2-a]purine and [1,2,3]triazolo[4,5-d]-[1,3]thiazino[3,2-a]pyrimidine, were synthesized together with other heterocyclic compounds. Retrosynthetic analysis of their molecular skeletons suggested a simple way of obtaining 3,4-dihydro-7,8-diamino-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one, which is a useful intermediate for their synthesis. This intermediate and the thiazole homologue were obtained directly by reaction of 5,6-diamino-2,3-dihydro-2-thioxo-4(lH)-pyrimidi-none with 1,3- or 1,2-dibromoalkane, 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.     

Synthesis of new imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one derivatives by iodocyclization of 6-alkenyl(alkynyl)-aminopyrazolo[3,4-d]pyrimidin-4(5H)-ones

6-Allyl(diallyl, prop-2-yn-1-yl)amino-1-R-pyrazolo[3,4-d]pyrimidin-4(5H)-ones reacted with iodine to give angularly fused 8-iodomethyl-7,8-dihydro-1-R-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-ones which were treated with sodium acetate to obtain 8-methylidene-1-R-7,8-dihydroimidazo[1,2-a]pyrazolo-[4,3-e]pyrimidin-4(6H)-ones as a result of elimination of hydrogen iodide. 8-Methylidene-1-R-7,8-dihydroimidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-ones were converted into 8-methyl-1-R-imidazo[1,2-a]pyrazolo-[4,3-e]pyrimidin-4(5H)-ones on heating to the melting point. 8-Methylidene-1-phenyl-7,8-dihydroimidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one underwent isomerization into linearly fused 6-methyl-1-phenyl-1,8-dihydro-4H-imidazo[1,2-a]pyrazolo[3,4-d]pyrimidin-4-one on heating in sulfuric acid.     

Bridgehead nitrogen heterocycles. VI. The reaction of 1-amino- and 1,2-diaminopyridinium salts with β-dicarbonyl compounds

1,2-Diaminopyridinium iodide underwent reaction with ethyl acetoacetate to form 1,4-dihydro-2-methyl-4-oxopyrido[1,2-a]pyrimidin-1-ium iodide, and with acetyl acetone it gave 2,4-dimethylpyrido[1,2-a]pyrimidin-5-ium iodide. Though 2-acetylcyclohexanone gave the corresponding 5-methyl-1,2,3,4-tetrahydropyrido[1,2-a]quinazolin-11-ium iodide, no reaction was observed with 2,6-dimethyl-3,5-heptanedione, 1-benzoylacetone, 1,3-diphenyl-1,3-propanedione and its p-methoxyphenyl derivative. However, 1-aminopyridinium iodide and acetyl acetone in the presence of base gave 3-acetyl-2-methylpyrazolo[1,5-a]pyridine and 1-amino-2-methylpyridinium iodide yielded the corresponding 3-acetyl-2,7-dimethylpyrazolo[1,5-a]pyridine. With ethyl acetoacetate, the latter salt formed 3-ethoxycarbonyl-2,7-dimethylpyrazolo[1,5-a]pyridine but with 2,6-dimethyl substituents in the pyridine ring no condensation occurred. Reaction of 1-amino-2-methylpyridinium iodide with benzaldehyde gave N-benzalimino-2-methylpyridinium iodide which, on treatment with base, resulted in the formation of 2-picoline and benzonitrile, providing a convenient method of deamination.     

The Use of 4-(Bromomethylene)-5,5-dimethyl-1,3-dioxolan-2-one as “Masked” α-Bromo-α'-Hydroxy Ketone in the Synthesis of Heterocyclic Systems

4-(Bromomethylene)-5,5-dimethyl-1,3-dioxolan-2-one was obtained on the basis of the readily obtainable 4-methylene-5,5-dimethyl-1,3-dioxolan-2-one. It forms 2-imidazo[1,2-a]pyridin-2-yl-2-propanol with 2-aminopyridine, 11a-hydroxy-1,1-dimethyl-3-oxo-1,5,11,11a-tetrahydro[1,3]oxazolo[3,4-a]pyrido[1,2-d]-10-pyrazinium bromide with 2-(aminomethyl)pyridine, and the corresponding derivative of 4-hydroxyoxazolidin-2-one with 2-(3,4-dimethoxyphenyl)ethylamine. The last product was converted by intramolecular amidoalkylation without isolation into 10b-(bromomethyl)-8,9-dimethoxy-1,1-dimethyl-1,5,6,10b-tetrahydro[1,3]oxazolo[3,4-a]isoquinolin-3-one.     

Bis-Pyrazolones as azodienophiles

Lead tetraacetate oxidations of 2,3,3a,4,6,7,7a,8-octahydrobenzo[1,2-c:4,5-c']dipyrazolo-3,7-dione and 2,3,3a,4,5,5a,6,7-octahydrobenzo[2,1-c:3,4-c']dipyrazolo-3,6-dione in the presence of 1,3-cyclopentadiene, 1,3-cyclohexadiene, 2,3-dimethyl-1,3-butadiene or 1,4-diphenyl-1,3-butadiene have yielded octahydrodipyridazino[1,2-a:1,2-a']benzo[1,2-c:4,5-c']dipyrazolo-6,14-diones and octahydrodipyridazino[1,2-a:1,2-a']benzo[2,1-c:3,4-c']dipyrazolo-6,9-diones. In one of the eight Diels-Alder reactions two isomeric products were isolated.     

Imidazo[1,5-a]- and Thiazolo[3,4-a]quinoxalines Based on 3-(a-Thiocyanobenzyl)quinoxalin-2(1H)-one

When 3-(a-thiocyanobenzyl-2(1H)-one is heated, competing processes of [a]-annelation of the imidazole or thiazole rings occurs with formation of imidazo[1,5-a]- and thiazolo[3,4-a]quinoxalin-4(5H)-ones.     

Synthesis of 1,2-diazepino[3,4-b]quinoxalines and pyrido[3′,4′:9,8][1,5,6]oxadiazonino[3,4-b]quinoxalines via a 1,3-dipolar cycloaddition reaction

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 8 with furfural, 3-methyl-2-thiophene-carbaldehyde, 2-pyrrolecarbaldehyde, 4-pyridinecarbaldehyde and pyridoxal hydrochloride gave 6-chloro-2-[2-(2-furylmethylene)-1-methylhydrazino]quinoxaline 4-oxide 5a , 6-chloro-2-[1-methyl-2-(3-methyl-2-thienyl-methylene)hydrazino]quinoxaline 4-oxide 5b , 6-chloro-2-[1-methyl-2-(2-pyrrolylmethylene)hydrazino]quinoxa-line 4-oxide 5c , 6-chloro-2-[1-methyl-2-(4-pyridylmethylene)hydrazino]quinoxaline 4-oxide 5d and 6-chloro-2-[2-(3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridylmethylene)-1-methylhydrazino]quinoxalme 4-oxide 5e , respectively. The reaction of compound 5a or 5b with 2-chloroacrylonitrile afforded 8-chloro-3-(2-furyl)-4-hydroxy-1-methyl-2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6a or 8-chloro-4-hydroxy-1-methyl-3-(3-methyl-2-thienyl)-2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6b , respectively, while the reaction of compound 5e with 2-chloroacrylonitrile furnished 11-chloro-7,13-dihydro-4-hydroxy-methyl-5,14-methano-1,7-dimethyl-16-oxopyrido[3′,4′:9,8][1,5,6]oxadiazonino[3,4-b]quinoxaline 7.     

New polyheterocyclic series based on 4,5,6,7-tetrahydrothieno[2,3-c]pyridine

4,8-Dimethyl-6,7,8,9-tetrahydropyrido[4′,3′:4,5]thieno[2,3-e][1,2,4]triazolo[3,4-a]-4H-pyrimidin-5-ones, 7-methyl-2,3,6,7,8,9-hexahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrrolo[1,2-a]-1H, 10H-pyrimidin-10-one, 8-methyl-1,2,3,4,7,8,9,10-octahydropyrido[4′,3′:4,5]thieno[2,3-d]-11H-pyrimidin-11-one, and 9-methyl-2,3,4,5,8,9,10,11-octahydro[4′,3′:4,5]thieno[2,3-d]azepino-[1,2-a]-1H, 12H-pyrimidin-12-one which consist four new heterocyclic ring systems were synthesized from 2-amino-3-carbethoxy-5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine.     

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.     

An efficient synthesis of 1,3-diaryl-pyrrolo[1,2-<Emphasis Type="Italic">a</Emphasis>]quinoxalines from 2-(1h-pyrrol-1-yl)phenylamines

The condensation of 1,3-diaryl-4-bromo-2-buten-1-ones with o-phenylenediamine leads to 2-[2,4-diaryl-1H-pyrrol-1-yl]phenylamines. Heating solutions of these compounds in formic acid leads to formylation and intramolecular condensation to give 1,3-diarylpyrrolo[1,2-a]quinoxalines. The acylation of 2-[2,4-diphenyl-1H-pyrrol-1-yl]phenylamine with acetic anhydride in acetic acid leads to an acetamide, which readily cyclizes to give 4-methyl-1,3-diphenylpyrrolo[1,2-a]quinoxaline upon heating with POCl₃.