Syntheses of substituted-1,2,4-triazoles

Starting from the readily available 3-phenylpropionitrile, 3-(or 5-)(2-phenethyl)-1,2,4-triazole 3 was prepared. Reaction of compounds 3 with diazomethane afforded 1-methyl-3-(2-phenethyl)-1,2,4-triazole (4) and 1-methyl-5-(2-phenethyl)-1,2,4-triazole (5) . Reaction of compound 3 with methanesulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride afforded only one of the expected isomer; namely compounds 6 , 7 and 8 respectively.     

Studies on the synthesis of heterocyclic compounds. Part IV. Further investigation of the pschorr reaction with some pyrazole derivatives

Thermal decomposition of the diazonium sulfate derived from N-methyl-(1-phenyl-3-methylpyrazol-5-yl)-2-aminobenzamide afforded products formulated as 1-phenyl-3-methyl[2]benzopyrano[4,3-c]pyrazol-5-one (yield 10%), 1,4-dimethyl-3-phenylpyrazolo[3,4-c]isoquinolin-5-one (yield 10%), N-methyl-(1-phenyl-3-methylpyrazol-5-yl)-2-hydroxybenzamide (yield 8%) and 4′-hydroxy-2,3′-dimethyl-1′-phenylspiro[isoindoline-1,5′-[2]-pyrazolin]-3-one (yield 20%). Decomposition of the diazonium sulfate derived from N-methyl-(1,3-diphenylpyrazol-5-yl)-2-aminobenzamide gave products formulated as 7,9-dimethyldibenzo[e,g]pyrazolo[1,5-a][1,3]-diazocin-10-(9H)one (yield 8%), 4-methyl-1,3-diphenylpyrazolo[3,4-c]isoquinolin-5-one (yield 7%) and 4′-hydroxy-2-methyl-1′,3′-diphenylspiro[isoindoline-1,5′-[2]pyrazolin]3-one (yield 10%). The spiro compounds 6a,b underwent thermal and acid-catalysed conversion into the hitherto unknown 2-benzopyrano[4,3-c]pyrazole ring system 7a,b in good yield. Analytical and spectral data are presented which supported the structures proposed.     

Nitroimidazoles. V . Synthesis of 1-methyl-2-(2-methyl-4-thiazolyl)nitroimidazoles

Reaction of readily available 2-methyl-4-formylthiazole ( 1 ) with glyoxal and ammonia gave 2-(2-methyl-4-thiazolyl)imidazole ( 2 ). Nitration of 2 with a mixture of nitric acid-sulfuric acid at 100° yielded 2-(2-methyl-4-thiazolyl)-4,5-dinitroimidazole ( 3 ) as the sole reaction product, while nitration at 65° afforded 2-(2-methyl-4-thiazolyl)-4-(or 5)-nitroimidazole ( 4 ). N-Methylation of compound 4 in the presence of base gave 1-methyl-2-(2-methyl-4-thiazolyl)4-nitroimidazole ( 6 ), whereas N-methylation with diazomethane afforded 1-methyl-2-(2-methyl-4-thiazolyl)-5-nitroimidazole ( 5 ). N-Methylation of compound 3 yielded 1-methyl-2-(2-methyl-4-thiazolyl)-3,5-dinitroimidazole ( 7 ) in high yield.     

Syntheses of substituted 1-methyl-2-(1,3,4-thiadiazol-2-yl)-4-nitropyrroles and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-4-nitropyrroles

Starting from readily available ethyl-4-nitropyrrole-2-carboxylate ( 1 ), substituted 1-methyl-2-(1,3,4-thiadiazol-2-yl)-4-nitropyrroles and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-4-nitropyrroles were prepared. The reaction of 1 with diazomethane gave ethyl 1-methyl-4-nitropyrrole-2-carboxylate ( 2 ). Reaction of compound 2 with hydrazine hydrate afforded the corresponding hydrazide 3 . The reaction of 3 with formic acid yielded 1-(1-methyl-4-nitropyrrole-2-carboxyl)-2-(formyl)hydrazine ( 7 ). Refluxing of the latter with phosphorus pentasulfide in xylene yielded compound 6 in 40% yield. Reaction of compound 7 with phosphorus pentoxide afforded compound 9 . Reaction of compound 3 with 1,1′-carboxyldiimidazole in the presence of triethylamine yielded 2-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-oxadiazoline-4(H)-5-one ( 11 ). Refluxing compound 3 with cyanogen bromide in methanol gave compound 12 . Compound 13 could be obtained through the reaction of compound 3 with carbon disulfide in basic medium. Alkylation of compound 13 afforded the correspanding alkylthio derivative 14 . Reaction of 1-methyl-4-nitropyrrole-2-carboxylic acid ( 15 ) with thiosemicarbazide and phosphorus oxychloride gave 2-amino-5-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-thiadiazole ( 16 ). Sandmeyer reaction of compound 16 yielded 2-chloro-5-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-thiadiazole ( 17 ). Refluxing of the latter with thiourea afforded 2-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-thiadiazoline-4(H)-5-thione ( 18 ). Alkylation of compound 18 gave the corresponding alkylthio derivative 19 . Oxidation of the latter with hydrogen peroxide in acetic acid yielded 2-(1-methyl-4-nitro-2-pyrrolyl)-5-methylsulfonyl-1,3,4-thiadiazole ( 20 ).     

Synthesis of 1H-thieno[3,4-c]pyrazoles,thieno[3,4-b]furans,selenolo[3,4-b]furans and pyrrolo[3,4-d]thiazoles

Starting from the readily available aryl 2-methyl-5-phenyl-3-furyl ketones, 5-methyl-1H-1-phenylpyrazole-4-yl ketones and 4-methyl-2-phenyl-5-thiazolylcarboxaldehyde, a series of 2-phenyl-4-arylthieno[3,4-b]-furan, 2-phenyl-4-(p-methoxyphenyl)selenolo[3,4-b]furan, 4-aryl-1H-1-phenylthieno[3,4-c]pyrazole and 5-benzyl-2-phenylpyrrolo[3,4-d]thiazole were prepared in high yield.     

Synthesis of brain-targeted 5-iodo-, 5-vinyl- and (E)-5-(2-iodovinyl)-2′-deoxyuridines coupled to a dihydropyridine ⇌ pyridinium salt redox chemical delivery system

5-Iodo-3′-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2′-deoxyuridine (15a) , 5-vinyl-3′-O-(1-methyl-1,4-di-hydropyridyl-3-carbonyl)-2′-deoxyuridine (15b) and (E)-5-(2-iodovinyl)-3′-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2′-deoxyuridine (15c) were synthesized for future evaluation as lipophilic brain-selective antiviral agents for the treatment of herpes simplex encephalitis. Quaternization of the 3′-O-(3-pyridylcarbonyl) compounds 10–11 using iodomethane afforded the corresponding 1-methylpyridinium salts 12–13 which were reduced with sodium dithionite to yield the corresponding 3′-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl) compounds 14–15.     

Research on nitrogen heterocyclic compounds. XV. Synthesis of 1H,4H-pyrazolo[4,3f]pyrrolo[1,2-a][1,4]diazepine derivatives

The synthesis of derivatives of 1H,4H-pyrazolo[4,3-f]pyrrolo[1,2-a][1,4]diazepine, a new tricyclic nitrogen-containing nucleus is reported. Condensation of arylaldehydes with 4-aminomethyl-1-phenyl-5-(1-pyrryl)pyrazole afforded the title compounds. Bischler-Napieralski intramolecular cyclization of 4-acetamidomethyl-1-phenyl-5-(1-pyrryl)pyrazole was also studied. The reaction led to 6-methyl-1-phenyl-1H,4H-pyrazolo[4,3-f]pyrrolo[1,2-a][1,4]diazepine or alternatively to 4-chloromethyl-1-phenyl-5-(1-pyrryl)pyrazole depending on the solvent used.     

Syntheses of substituted 2-(1-methyl-5-nitro-2-benzimidazolyl)quinolines

Reaction of N-methyl-2-amino-4-nitroaniline ( 1 ) with lactic acid afforded 2-(1-hydroxyethyl)-1-methyl-5-nitrobenzimidazole ( 2 ). Oxidation of compound 2 with chromic acid in acetic acid gave 2-acetyl-1-methyl-5-nitrobenzimidazole ( 3 ). Reaction of compound 3 with substituted 2-aminobenzaldehyde ( 4 ) under basic conditions yielded substituted 2-(1-methyl-5-nitro-2-benzimidazolyl)quinolines ( 5 ). Condensation and cyclization of o-aminoacetophenone (or substituted o-aminobenzophenones) with compound 3 under acetic condition afforded compound 7 . Condensation and cyclization of compound 1 with indole-3-carboxaldehyde ( 11 ) in ethanol in the presence of excess nitrobenzene gave 3-(1-methyl-5-nitro-2-benzimidazolyl)indole ( 12 ).     

Alkyl nitrate nitration of active methylene compounds. Nitration of 1-methyl4-piperidone, 1-methyl-2-pyrrolidinone and 1,3-dimethyl-2-pyrrolidinone

The reaction of 1-methyl-4-piperidone ( 1 ) with amyl nitrate in the potassium tert-butoxidetetrahydrofuran system gave dipotassium 5-methyl-2-oxo-1,3-piperidinedinitronate ( 4 ) in 78% yield. Similar treatment of 1-methyl-2-pyrrolidinone ( 2 ) afforded potassium 3-methyl-2-oxopyrrolidinenitronate ( 7 ) in 85% yield. In contrast, the nitration of 1,3-dimethyl-2-pyrrolidinone ( 3 ) led to opening of the lactam ring with the formation of amyl 2-aza-2-methyl-5-nitrohexanoate ( 10 ) in 40% yield. Acidification of disalt 4 did not cause ring opening but gave the dipolar ion of 1-methyl-3-nitro 4-hydroxy-5-aci-nitro-Δ³-tetrahydropyridinium (6).     

Syntheses of substituted-oxazolo-1,3,4-thiadiazoles, 1,3,4-oxadiazoles,and 1,2,4-triazoles

Starting from readily available methyl 5-methyloxazole-4-carboxylate ( 1 ) and 4-methyl-5-oxazolylcar-boxylic acid hydrazide ( 11 ) the title compounds were prepared. The reaction of compound 1 with hydrazine hydrate afforded the corresponding hydrazide 2 . The reaction of compound 2 with formic acid yielded 1-formyl-2-(5-methyloxazole-4-carboxyl)hydrazine ( 3 ). Refluxing of the latter with phosphorus pentasulfide in xylene gave compound 5 in 62% yield. The reaction of compound 3 with phosphorus pentoxide afforded compound 4 . Starting from hydrazide 11 , compounds 13 and 14 were prepared similarly. Reaction of compound 2 with substituted isothiocyanate yielded compound 9 which was cyclized in basic medium to 4-alkyl-5-(5-methyl-4-oxazolyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione ( 10 ). The isomer 19 was prepared similarly. Methylation and subsequent oxidation of compound 19 gave compound 21 . Reaction of the acid 7 with thiosemicarbazide in the presence of phosphorus oxychloride gave 2-amino-5-(5-methyl-4-oxazolyl)1,3,4-thiadiazole ( 8 ). 2-Amino-5-(4-methyl-5-oxazolyl)-1,3,4-thiadiazole ( 17 ) was prepared from acyl chloride 15 by the usual method.     

Reactions of 1,2-Dimethyl-5-nitroimidazole,novel methods of conversion of the 2-Methyl group to a nitrile

1, 2-Dimethyl-5-nitroimidazole( 1 )and N,N-dimethylformamide dicyclohexylacetal gave the 2-(β-dimethylaminovinyl) analog 2 and with iodine and pyridine gave the 2-(1-pyridinium)methyl compound 3 . Benzoyl chloride-triethylamine and 1 led to benzoylation of the 2-methyl group to give ketone 9 as the enol benzoate. Nitrous acid or nitrosylsulfuric acid with 9 or its enol ester afforded the oximinoketone 10 which was cleaved with thionyl chloride to give 2-cyano-1-methyl-5-nitroimidazole ( 11 ) in high overall yield. 1-Ethyl-2-methylbenzimidazole ( 22 ) was converted to 2-cyano-1-ethylbenzimidazole ( 25 ) similarly. Reaction of 1 with ethyl oxalyl chloride and triethylamine afforded ethyl 1-methyl-5-nitro-2-imidazolepyruvate ( 19 ) as the enol oxalate. Nitrous acid and 19 gave the oximino pyruvate 20 which effervesced on mild heating to give 2-cyano-1-methyl-5-nitroimidazole ( 11 ). The preparation of 1-methyl-5-nitro-2-imidazoleacetonitrile ( 39 ) is reported.     

Syntheses of 1-substituted 1,2,4-triazoles,imidazoles and benzimidazoles

Substituted 2-phenethyl-1,2,4-triazoles, 1-phenethylimidazoles 3 and 1-phenethylbenzimidazoles 5 were synthesized from the reaction of compound 8 with tri-n-butyltin hydride in good yield. The reaction of substituted-2-phenethyl halide with 1H-1,2,4-triazoles, imidazoles and benzimidazoles gave a low yield. The yield was increased by the use of substituted-2-phenethyl p-toluensulfonate.     

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 .     

Reaction of 2-dimethylaminomethylene-1,3-diones with dinucleophiles. VI. Synthesis of ethyl or methyl 1,5-disubstituted 1H-pyrazole-4-carboxylates

Reaction of ethyl or methyl 3-oxoalkanoates with N,N-dimethylformamide dimethyl acetal gave, generally in excellent yields, a series of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates II which reacted with phenylhydrazine to afford the esters of 5-substituted 1-phenyl-1H-pyrazole-4-carboxylic acids III in high yields. Esters III were hydrolyzed to the relative 5-substituted 1-phenyl-1H-pyrazole-4-carboxylic acids which were converted by heating to 5-substituted 1-phenyl-1H-pyrazoles in excellent yields. Reaction of II with methylhydrazine afforded in general a mixture of 3- and 5-substituted ethyl 1-methyl-1H-pyrazole-4-carboxylates with the exception of IIg , which gave in high yield methyl 5-benzyl-1-methyl-1H-pyrazole-4-carboxylate, which was hydrolyzed to the relative pyrazolecarboxylic acid. This afforded by heating 5-benzyl-1-methyl-1H-pyrazole in quantitative yield.     

含吡唑1,2,4-三唑噻二嗪衍生物的合成及抑菌活性

1-苯基-3-甲基-5-氯-4-吡唑甲醛与4-氨基-5-取代苯基-1,2,4-三唑-3-硫酮缩合生成4-(1-苯基-3-甲基-5-氯吡唑次甲亚胺基)-5-(取代苯基)-2H-1,2,4-三唑-3(4H)-硫酮,再烷基加成化为新型含吡唑基5,6-2H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪衍生物。 化合物结构经¹H NMR、IR以及元素分析确认。 初步生物活性测试结果表明,在100 mg/L浓度下,化合物8a(3-(2-甲基苯基)-6-(5-氯-2-甲基-4-苯基吡唑)-7-(4-硝基苯基)-5H-1,2,4-三唑[3,4-b][1,3,4]噻二嗪)对黄瓜炭疽病的抑制率达90%。     

Reactions of 6-Amino-5-Cyano-3-Methyl-1,4-Diphenyl-1H 4H-Pyrano[2,3-C]Pyrazole and its Methanimidate

Reaction of 6-amino-5-cyano-3-methyl-1,4-diphenyl- 1H,4H-pyrano[2,3-c]pyrazole 1 with triethyl orthoformate in acetic anhydride gave its methanimidate 2, which reacts with primary aliphatic and aromatic amines to give 4,6-dihydro-3-methyl-1,4-diphenyl-6- (alkyl)pyrazolo[4′,3′:5,6]pyrano[2,3-d]pyrimidine-5(lH)- imine 3 and the starting compound 1 , respectively. Treatment of 1 with o-aminophenol gave 5-(2-benzoxalyl)- 1,4-dihydro-3-methyl-1,4-diphenylpyrano[2,3-c]pyrazol- 6-amine 9.     

Alkylating nucleosides. 3. The reaction of 3,5-dimethylpyrazole nucleosides with N-bromosuccinimide

Bromination of 3,5-dimethylpyrazole nucleosides with N-bromosuccinimide gave the corresponding 4-bromo-3,5-dimethylpyrazole, 3-methyl-5-(bromomethyl)pyrazole and 4-bromo-3-methyl-5-(bromomethyl)pyrazole nucleosides. Structural assignments were made on basis of analytical and ¹ H nmr spectral data. All of the bromomethylpyrazole nucleosides described showed cytostatic activity against HeLa cell sultures.     

Uncommon Heterocyclization into a Pyrazole System of <Emphasis Type="Italic">Z</Emphasis>-3-(2-Naphthyl)-3-chloro-2-propenal Semicarbazone and Thiosemicarbazone

By reaction of Z-3-(2-naphthyl)-3-chloro-2-propenal with semicarbazide hydrochloride and thiosemicarbazide the corresponding semicarbazone and thiosemicarbazone were obtained that underwent a heterocyclization into a pyrazole system with elimination of amide moieties and with migration of the naphthyl fragment into the position 4 of the pyrazole ring. The alkylation of 4-(2-naphthyl)pyrazole synthesized with 2-nitropentachloro-1,3-butadiene afforded 1,1-bis[4-(2-naphthyl)-pyrazol-1-yl]-2-nitrotrichloro-1,3-butadiene.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 5, 2005, pp. 753–755.Original Russian Text Copyright © 2005 by Vashkevich, Potkin, Kozlov.     

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 ).     

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.