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.     

Synthèse de 5H-isoquino[6, 7-b][1, 6]naphtyridones-12 substituées sur leur sommet 10

Starting from 4-chloronicotinic and derivatives and 6-amino-5-methyl-2H-isoquinolin-1-one, subsequent cyclization of intermediates by sulfuric acid or trifluoromethanesulfonic acid and chlorination by phosphorus oxychloride gave 10-chloro-6-methyl-5H-isoquino[6,6-b][1,6]naphthyridin-12-ones. Cytotoxicity of the corresponding 10-(diethylamino-3)propylamino-6-methyl-5H-isoquino[6,7-b][1,6]naphthyridinh12-ones, compared to that of related 9-azaellipticine derivatives, showed that replacement of pyrrole by a pyridin-4-one nucleus resulted in loss of biological activity.     

Synthesis of diarylazolo[<Emphasis Type="Italic">a</Emphasis>]pyridines from [(<Emphasis Type="Italic">Z</Emphasis>)-2,4-diaryl-4-oxo-2-butenyl]azolium salts

A method for the synthesis of derivatives of [1, 3]thiazolo[3,2-a]pyridines, pyrido[2,1-b][1, 3]benzo-thiazole, [1, 3, 4]thiadiazolo[3,2-a]pyridine, and [1, 2, 4]triazolo[4,3-a]pyridine, which includes base initiated cyclization of quaternary azolium salts, formed by the interaction of (Z)-1,3-diaryl-4-bromo-2-buten-1-ones with 1-alkyl-1H-1,2,4-triazoles, 4-methyl-1,3-thiazole, 1,3-benzothiazole, and N-phenyl-1,3,4-thiadiazole-2-amine. Derivatives of 2-chloroimidazo[1,2-a]pyridine were obtained when 5-chloro-1-methyl-1H-imidazole was used.     

The Homoconjugated Electron-Releasing Carbonyl Group of 1-Methylbicyclo[2.2.1]hept-5-en-2-one. Regioselective syntheses of 5-chloro- and 6-chloro-1-methylbicyclo[2.2.1]hept-5-en-2-one

Syntheses of (±)-2-exo-cyano-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl acetate ( 1 ) and of (±)-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-one ( 2 ) are reported. The additon of PhSeCl to 1 afforded (±)-5-endo-chloro-2-exo-cyano-1-methyl-6-exo-(phenylselenenyl)-7-oxabicyclo[2.2.1]hept-2-endo-yl acetate ( 6 ), whereas 2 added to PhSeCl with the opposite regioselectivity giving (±)-6-endo-chloro-1-methyl-5-exo-(phenylselenenyl)-7-oxabicyclo[2.2.1]heptan-2-one ( 7 ). These adducts were converted into 5-chloro-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-one ( 9 ) and 6-chloro-1-methyl-7-oxabicyclo[2.2.1]hept-5-en-2-one ( 10 ), respectively.     

Fused s-triazino heterocycles. XVIII. 1,3,4,7,11c-Pentaazabenz[de]anthracene and 1,3,4,6,7,11c-hexaazabenz[de]anthracene. Two new ring systems

The reaction of 2-amino-4-chloro-6-methylpyrimidine ( 3a ) with trimethylacetyl chloride gave 4-chloro-6-methyl-2-trimethylacetamidopyrimidine ( 5 ). This latter compound with excess anthranilonitrile gave in one step 2-t-butyl-5-methyl-1,3,4,7,11c-pentaazabenz[de]anthracene ( 6a ). To prepare 2-t-butyl-5-dimethylamino-1,3,4,6,7,11c-hexaazabenz[de]anthracene ( 6b ) it was found necessary to first react 2-amino-4-chloro-6-dimethylamino -5 -triazine ( 3b ) with anthranilonitrile to yield the intermediate product 2-amino-4(2-cyanoanilino)-6-dimethylamino-s-triazine ( 4 ). Reaction of the latter with trimethylacetyl chloride gave 6b .     

Recherches en série triazépine-1,2,4: II — Etude de la réaction de l'acétylacétate d'éthyle avec les diamino-3,4 oxo-5 dihydro-4,5 triazines-1,2,4

The reaction of 3,4-diamino-5-oxo-4,5-dihydro-l,2,4-triazine or its 6-methyl or 6-phenyl substituted derivatives and ethyl acetoacetate gave three compounds: 4,7-dioxo-9-methyl-1,4,6,7-tetrahydro-as-triazino[4,3-b]-1,2,4-triazepine in poor yield, isomeric 4,9-dioxo-7-methyl-1,4,8,9-tetrahydro-as -triazino[4,3-b]-1,2,4-triazepine and by competitive cyclisation, 2-methyl-7-oxo-3,7-dihydro-s-triazolo[3,2-c]-1,2,4-triazine. By condensation of 3-methylamino-4-amino-5-oxo-4,5-dihydro-1,2,4-triazine with ethyl acetoacetate, the formation of 4,9-dioxo-7,10-dimethyl-4,8,9,10-tetrahydro-as-triazino[4,3-b]-1,2,4-triazepine was strongly favored.     

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.     

Palladium-catalyzed reaction of methyl 5-amino-4-chloro-2-methylthiopyrrolo[2,3-<Emphasis Type="Italic">d</Emphasis>]-pyrimidine-6-carboxylate with arylboronic acids. Synthesis of 1,3,4,6-tetraazadibenzo[<Emphasis Type="Italic">cd,f</Emphasis>]-azulene heterocyclic system

Densely substituted methyl 5-amino-4-aryl-7-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine-6-carboxy- lates were synthesized by the palladium-catalyzed cross-coupling reaction of methyl 5-amino-4-chloro-7-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate with arylboronic acids using Pd(OAc)₂/dicyclohexyl(2-biphenyl)phosphine/K₃PO₄ as a catalyst system. Reaction of methyl 5-amino-4-chloro-7-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate with 2-formylphenyl- boronic acid led to a novel heterocyclic system – 1,3,4,6-tetraazadibenzo[cd,f]azulene.     

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 ).     

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.     

Condensed pyridazines. Part III. Rearrangement and ring cyclization during the thermolysis of (z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-methylacrylate

The thermolysis of (Z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-methylacrylate ( II ) provides a new synthetic route to pyrrolo[2,3-c-]pyridazines, specifically, methyl 3-chloro-1,6-dimethyl-4-oxo-1,4-dihydro-7H-pyrrolo[2,3-c]pyridazine-5-carboxylate ( III ) in 91% yield. Treatment of III with ozone provides an entry into the novel pyridazino[3,4-d][1,3]oxazine ring system, specifically, 3-chloro-1,7-dimethylpyridazino[3,4-d][1,3]oxazine-4,5-dione ( IV ) in 73% yield. Compound IV is smoothly hydrolyzed into 6-acetylamino-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazine-5-carboxylic acid ( V ) which is readily recyclized into IV by dehydration with acetic anhydride. Furthermore, IV undergoes a facile reductive ring opening reaction with sodium borohydride to give 3-chloro-6-ethylamino-1-methyl-4-oxo-1,4-dihydropyridazine-5-carboxylic acid ( VI ) in 95% yield.     

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.     

1H and 13C NMR studies of 7-azaindole and related compounds

The ¹H and ¹³C chemical shifts, proton-proton coupling constants, and one-bond carbon-hydrogen coupling constants have been obtained for 7-azaindole, 1-methyl-7-azaindole, their corresponding methyl iodide salts, and the related compound 7-methyl-7H-pyrrolo [2,3-b]pyridine. are different from those of either 7-azaindole or 1-methyl-7-azaindole.     

Fluorénacènes et fluorénaphènes Synthèses dans la série des indéno-fluorènes,XVI. Méthyl-5-, diméthyl-5, 6- et diphényl-5, 6-dihydro-11, 12-indéno [2.1-a] fluorène

Starting from 2-methyl- and from 2,3-dimethyl-1,4-diphenyl-butadiene-1, 3 respectively, the 5-methyl- and the 5,6-dimethyl-11, 12-dihydro-indeno[2.1-a]fluorene are synthesized in 4 steps. The 5, 6-diphenyl-11, 12-dihydro-indeno[2.1-a]fluorene is obtained by reduction of the already known 11, 12-dioxoderivative. Accesorily a new preparation of the unsubstituted hydrocarbon is described.     

Diazepines II. A new synthesis of 4h-pyrrolo[ 1,2-α] -[1,41] benzodiazepine

A convenient synthesis of a 4H-pyrroIo[1,2-α][1,4 ]benzodiazepine is described. 2,5-Di-methoxy-2-melhyl-5-phthalimidomethyltetrahydrofuran ( 3 ) was prepared starting from 2-methyl-5-phthalimidomelhylfuran ( 1 ). The condensation of 2-amino-5-chlorobenzophcnone with 3 to give 5-chloro-2-(2-methyl-5-phthalimidomethylpyrro]-1-yl)benzophenone ( 4 ), the treatment of which with hydrazine hydrate afforded 8-chloro-1-methyl-4H-pyrrolo[1,2-α] [1,4]benzodiazepine ( 5 ).     

Structure moléculaire et propriétés moléculaires de quatre isomères de formule C8H10N4

The molecular structures of the three Meyer isomers [3-methyl-3-(5′-amino-3′-methyl-l-pyrazolyl)acrylonitrile; acetylacetonitrile azine; 2,5-dimethyl-7-aminopyrazolo[1,5-a]pyrimidine] have been compared with that of the fourth isomer, 2,7-dimethyl-5-amino-pyrazolo[1,5-a]pyrimidine. The CNDO/2 and CNDO/S calculations utilizing these geometries have been accomplished. These include electronic transitions, dipole moments, ionisation potentials, charge densities, bond ordres and total energies. The calculated values have been compared to some experimental data. Uv spectra, ¹³C chemical shifts, ¹H-¹H coupling constants and relative stability of the four isomers are included.     

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.     

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 .     

Synthesis, 1H- and 13C-NMR spectra,crystal structure and ring openings of 1-methyl-6,9-epoxy-9-aryl-5,6,9,10-tetrahydro-1H-imidazo [3,2-e] [2H-1,5] oxazocinium methanesulfonate

The methanesulfonic acid catalyzed reaction of 1-(4-chloro- and 2,4-dichlorophenyl)-2-(1-methyl-2-imida-zolyl)ethanones 1a and 1b with glycerol produced cis- and trans-{2-haloaryl-2-[(1-methyl-2-imidazolyl)methyl]-4-hydroxymethyl}-1,3-dioxolanes 2a and 2b with a 2:1 cis/trans ratio. Besides these five-membered ketals, the reaction of 1a with glycerol afforded a small amount of trans-{2-(4-chlorophenyl)-2-[(1-methyl-2-imidazolyl)methyl]-5-hydroxy}-1,3-dioxane ( 3a , 7%). The reaction of methanesulfonyl chloride with cis-1 formed the corresponding methanesulfonates, cis- 4 , which rapidly cyclized to the title compounds 5 . Base-catalyzed ring opening of 5 furnished 1-methyl-5,6-dihydro-6-hydroxymethyl-8-(4-chloro- and 2,4-dichlorophenyl)-1H-imidazo[3,2-d][1,4]oxazepinium methanesulfonates 7 . Acid-catalyzed hydrolyses of 5 or 7 provided 1-methyl-2-[(4-chloro- and 2,4-dichloro)phenacyl]-3-[(2,3-dihydroxy)-1-propyl]imidazolium salts 12 . Structure proofs were based on extensive ¹H and ¹³C chemical shifts and coupling constants and structures of 3a and 5a were confirmed by single crystal X-ray crystallography.     

Synthesis of Sulfur Heterocycles by Thio-<Emphasis Type="Italic">Claisen</Emphasis> Rearrangement

Summary. 7-Chloro-4-hydroxydithiocoumarin was alkylated with allylic halides under phase transfer catalysis condition in the presence of TBAB or BTEAC in chloroform-aqueous NaOH (1%) at room temperature. 2,3-Dichloroprop-2-ene on similar treatment with 7-chloro-4-hydroxydithiocoumarin afforded 2-methylthieno[2,3-b]thiochromen-4-one in 65% yield. The S-alkylated thiochromen-4-ones were then refluxed in quinoline to give 7-chloro-2,3-dihydrothieno[2,3-b]thiochromen-4-ones or 7-chloro-2,3,4-trihydrothiopyrano[2,3-b]thiochromen-5-ones or 7-chloro-2,3-dihydro-3-vinylthieno[2,3-b]thiochromen-4-one.