Azaindole derivatives. 67. Synthesis of N-substituted 1-benzyl-4-methyl-5-cyano-6-amino-7-azaindoles

N-substituted 1-benzyl-4-methyl-5-cyano-6-amino-7-azaindoles have been synthesized from the respective 1-benzyl-4-methyl-5-cyano-6-chloro(and 6-hydroxy)-7-azaindoles. The effect of the 5-cyano group on the oxidation-reduction processes accompanying nucleophilic replacement of chlorine in 6-chloro-7-azaindoles by primary and secondary amines has been considered. 7-Azaindoline compounds were dehydrogenated by chloranil to N-substituted 1-benzyl-4-methyl-5-cyano-6-amino-7-azaindoles.For communication 66, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 91–96, January, 1986.     

Azaindole derivatives. 59. Synthesis and chemical properties of 1-benzyl-4-dimethylamino-6-chloro-7-cyano-5-azaindoline

The condensation of 1-benzyl-2-cyanocarbamoylmethylene-pyrrolidine with tetramethylurea diethylacetal and subsequent cyclization gave 1-benzyl-4-dimethyl-amino-6-chloro-7-cyano-5-azaindoline, for which nucleophilic substitution and dehydrogenation reactions are described. The reactivity of this product is compared with that of 1-benzyl-6-chloro-7-cyano-5-azaindoline.See [1] for Communication 58.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 215–220, February, 1981.     

Derivatives of azaindoles. 65. Synthesis of 1-benzyl-4-methyl-5-cyano-6-hydroxy-7-azaindoline

Treatment of the ammonium (I) or benzylammonium salt of 2,6-dihydroxy-3-(-hydroxyethyl)-4-methyl-5-cyanopyridine (II) with a mixture of benzylamine and phosphorus pentoxide yielded 2-benzylamino-3-(-hydroxyethyl)-4-methyl-5-cyano-6-hydroxypyri-dine (III), which, when heated with phosphorus oxychloride, is converted to 1-benzyl-4-methyl-5-cyano-6-hydroxy-7-azaindoline (IV). The products of thermal fragmentation of II with benzylamine were studied by the method of chromato-mass spectrometry. In addition to compound III, N,N-dibenzylurea (V) and the dibenzylamide of malonic acid (VI) were preparatively isolated from the reaction products. The cyclization of I and II to 4-methyl-6-hydroxy-2,3-dihydro-7-azabenzofuran (VII) and 4-methyl-5-cyano-6-hydroxy-2,3-dihydro-7-azabenzofuran (VIII) was carried out. Heating VIII with benzylamine at 200–210°C led to compound III.For communication 64, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1105–1109, August, 1984.     

Azaindole derivatives. 66. 1,6-disubstituted 4-methyl-5-cyano-7-azaindolines

A general method was developed for the synthesis of 1,6-disubstituted 4-methyl-5-cyano-7-azalndolines from the readily available ammonium salt of 2,6-dihydroxy-3-(-hydroxyethyl)-4-methyl-5-cyanopyridine through the corresponding N-substituted ammonium salts and N-substituted 2-amino-3-(-hydroxyethyl)-4-methyl-5-cyano-6-hydroxypyridines with treatment of the latter by POCl₃. This method gives a 40% yield of 4-methyl-5-cyano-7-azaindoline compounds containing various aralkyl or alkyl substituents at N-1 and a hydroxy group or halogen atom at C-6 in three steps.For Communication 65, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 84–88, January, 1985.     

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.     

Azaindole derivatives. 61. Electrophilic substitution reactions in 1-benzyl-6-methoxy-7-cyano-5-azaindole and 6-oxo-5-azaindoline

The electrophilic substitution reactions (nitration, bromination, acylation, and the Mannich and Vilsmeier reactions) of 1-benzyl-6-methoxy-7-cyano-5-azaindole and the nitration and Vilsmeier reaction of 6-hydroxy-5-azaindoline were studied.See [1] for Communication 60.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 356–360, March, 1982.     

Unequivocal syntheses of 6-methyl- and 6-phenylisoxanthopterin

Although 6-methyl- ( 1 ) and 6-phenylisoxanthopterin ( 2 ) have previously been synthesized, the requirement of high purity necessary for immunological testing has necessitated our development of the first reported synthesis of these compounds by unequivocal methods. In the process of so doing four new pyrazines, ethyl 3-amino-5-chloro-6-methyl-2-pyrazinecarboxylate ( 11 ), N,N-dimethyl-N'-(6-chloro-3-cyano-5-phenylpyrazin-2-yl)methanimidamide ( 16 ), 2-amino-3-ethoxycarbonyl-5-phenylpyrazine 1-oxide ( 19 ), and ethyl 3-amino-5-chloro-6-phenyl-2-pyrazinecarboxylate ( 20 ) were synthesized. Four new pteridines, 7-methoxy-6-methyl-2,4-pteridinediamine ( 7 ), 7-methoxy-6-phenyl-2,4-pteridinediamine ( 17 ), 2-amino-7-ethoxy-6-methyl-4(3H)-pteridinone ( 12 ), and 2-amino-7-ethoxy-6-phenyl-4(3H)-pteridinone ( 21 ) have also been synthesized enroute to these isoxanthopterins.     

New approach to the synthesis of substituted 5-arylcarbamoyl-3-cyano-6-methylpyridine-2(1h)-thiones. Molecular and crystal structure of 2-allylthio-3-cyano-5-(2-methoxyphenylcarbamoyl)-6-methyl-4-(5-methyl-2-furyl)-1,4-dihydropyridine

Morpholinium 5-arylcarbamoyl-3-cyano-6-methyl-4-(5-methyl-2-furyl)-1,4-dihydropyridine-2-thiolates have been obtained by the interaction of enamines of acetoacetanilides with 5-methyl-2-furfurylidenecyanothioacetamide. Alkylation of the salts gives thioethers and oxidation gives the corresponding substituted pyridine-2(1H)-thiones. The structure of 2-allylthio-3-cyano-5-(2-methoxyphenylcarbamoyl)-6-methyl-4-(5-methyl-2-furyl)-1,4-dihydropyridine was studied by X-ray crystallographic analysis. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 51–58, January, 2006.     

Synthesis of 6′-carbamoylmethylthio-5′-cyano-1′,4′-dihydro-3,4′-bipyridine-3′-carboxylic and 6′-carbamoylmethylthio-5′-cyano-1′,4′-dihydro-4,4′-bipyridine-3′-carboxylic esters and investigation of their stability. 2. Esters of 6′-carbamoylmethyl-thio-5′-cyano-1′,4′-dihydro-4,4′-bipyridine-3-carboxylic acids

The stability of solutions of esters of 6′-carbamoylmethylthio-5′-cyano-2′-methyl-1′,4′-dihydro-4,4′-bipyridine-3′-carboxylic acids was investigated by HPLC. The corresponding esters of 6′-carbamoylmethylthio-5′-cyano-4,4′-bipyridine-3′-carboxylic acids,esters of 8-cyano-5-methyl-3-oxo-7-(4-pyridyl)-2,3-dihydro-7H-thiazolo-[3,2-a]pyridine-6-carboxylic acids, methyl 3-amino-2-carbamoyl-6-methyl-4-(4-pyridyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate, and methyl 3-amino-2-carbamoyl-6-methyl-4-(4-pyridyl)-thieno[2,3-b]pyridine-5-carboxylate were synthesized as standard compounds (typical impurities). Analysis by HPLC was realized under the conditions of reverse-phase chromatography. It was established that solutions of the investigated compounds (with mixtures of acetonitrile with phosphate buffer, having pH values of not less than 3 and not more than 5, as solvents) are stable for one month when the solutions are stored in a place protected against light. It is also necessary to use chromatographic systems in which the aqueous components have pH 3–5 during determination of the purity of the esters of 6′-carbamoylmethylthio-5′-cyano-2′-methyl-1′,4′-dihydro-4, 4′-bipyridine-3′-carboxylic acid by HPLC in order to separate the analyzed sorbates and their typical impurities more completely. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 841–848, June, 2007.     

5-Cyano-6-aryluracil and 2-thiouracil derivatives as potential chemotherapeutic agents. IV

A series of 5-cyano-6-aryluracils and 2-thiouracils 1a-h has been prepared and alkylated to 1,3-dialkyluracils 2a-d and 2-alkylthiouracils, 3, 4 and 6 , by electrophilic substitution with alkyl halides. Reaction of 1b with dibromoethane and 1,3-dibromopropane gave the corresponding bicyclic products, 7-aryl-6-cyano-2,3-dihydrothiazolo[3,2-a]pyrimidin-5-ones 5a,b and 8-aryl-7-cyano-3,4-dihydro-2H-pyrimido[2,3-b][1,3]thiazin-6-ones 5c-g . Nucleophilic substitution on 6 with hydrazine led to 7 which on refluxing with formic acid gave 5-aryl-6-cyano-8-methyl-s-triazolo[3,4-b]pyrimidin-7-ones ( 9 ), while with acetic and propionic acids only 2-acylhydrazino-3-methyl-4-oxo-5-cyano-6-arylpyrimidines 8a,b were isolated. The hydrazine 7 undergoes cyclization with acetylacetone and methyl dimethylmercaptoacrylate providing 2-(pyrazol-1-yl)-3-methyl-4-oxo-5-cyano-6-substituted pyrimidines 10 , and 11 . Some of the compounds were screened for antibacterial-, antifungal- and antiviral activities and a few of them showed significant chemotherapeutical activities.     

Reaction of ethyl 4-aryl-6-bromomethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates with N-methylmorpholinium 3-cyano-1,4-dihydro- and 3-cyano-1,4,5,6-tetrahydropyridine-2-thiolates

Alkylation of N-methylmorpholinium 4-Ar¹-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates using ethyl 4-Ar-6-bromomethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates (10 % KOH, DMF) gives mixtures of diastereomers of ethyl 4-Ar-6-[(4-Ar¹-3-cyano-1,4,5,6-tetrahydropyridin-2-ylthio)methyl]-1-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates in overall 30-58 % yield. Under these conditions the N-methylmorpholinium 4-Ar1-5-(N-Ar²-carbamoyl)-3-cyano-6-methyl-1,4-dihydropyridine-2-thiolates undergo aromatization of the dihydropyridine ring to give ethyl 4-Ar-6-[4-Ar¹-5-(N-Ar²-carbamoyl)-3-cyano-6-methylpyridin-2-ylthio)methyl]-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates (37-51 %). In the absence of KOH, only the substituted pyridine-2(1 H)-thione is formed as a product of oxidation of the dihydropyridine ring in the starting substrate. Some of the alkylation products obtained possess weak or moderate antibacterial activity towards the specific strains of Escherichia coli and Bacillus subtilis but are inactive towards Candida albicans and Staphylococcus aureus.     

Reaction of 3-acetonyl-5-cyano-1,2,4-thiadiazole with phenylhydrazine hydrochlorides: indolization and phenylpyrazolation

Treatment of 3-acetonyl-5-cyano-1,2,4-thiadiazole (1) with 4-methyl or 4-methoxyphenylhydrazine hydrochloride provided 5-cyano-3-(2,5-dimethylindol-3-yl)-1,2,4-thiadiazole (2) or 5-cyano-3-(5-methoxy-2-methylindol-3-yl)-1,2,4-thiadiazole (3) as the sole product, respectively. In contrast, treatment of 1 with phenylhydrazine hydrochloride resulted in the formation of 5-cyano-3-(2-methylindol-3-yl)-1,2,4-thiadiazole (4) and the unexpected 5-cyano-3-(3,5-dimethyl-1-phenylpyrazol-4-yl)-1,2,4-thiadiazole (5). In a similar manner, when 1 was treated with 4-chlorophenylhydrazine hydrochloride, indolization was suppressed by phenylpyrazolation giving rise to 5-cyano-3-(5-chloro-2-methylindol-3-yl)-1,2,4-thiadiazole (6) and 5-cyano-3-[1-(4-chlorophenyl)-3,5-dimethylpyrazol-4-yl]-1,2,4-thia diazole (7). The reaction mechanism is discussed. Compounds 4, 5 and 6 exhibited weak antimicrobial activity against Helicobacter pylori.     

6-Amino-5-cyano-1H,4H-pyrazolo[3,4-b]pyrans

The reaction of 3-methyl-1-phenyl-5-pyrazolene with arylideneamino nitriles in alcohol leads to the formation of 3-methyl-4(1-aryl-2,2-dicyanoethyl)-5-pyrazolones, which are readily cyclized in the presence of bases to the corresponding 6-amino-5-cyano-3-methyl-4-aryl- 1H,4H-pyrazolo[3,4-b]pyrans. The structures of the intermediate and final products were confirmed by the IR, UV, PMR, and mass spectra.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 801–806, June, 1982.     

Synthesis and Properties of 7-Acetyl-8-aryl-9-cyano-3-hydroxy-6-methyl-3,4-dihydro-2H,8H-pyrido[2,1-<Emphasis Type="Italic">b</Emphasis>][1,3]thiazines

7-Acetyl-8-aryl-2-(1-chloro-2-hydroxy-3-propyl)thio-9-cyano-6-methyl-1,4-dihydropyridines were obtained by treatment of 1,4-dihydropyridine-2(3H)-thiones with epichlorohydrin in the presence of sodium bicarbonate. When treated with NaOMe, these compounds are readily intramolecularly alkylated with formation of 7-acetyl-8-aryl-3-hydroxy-9-cyano-6-methyl-3,4-dihydro-2H,8H-pyrido[2,1-b]-[1,3]thiazines. We have studied amination of 2-(1-chloro-2-hydroxy-3-propyl)thio-1,4-dihydropyridines and acylation of 3-hydroxy-3,4-dihydro-2H,8H-pyrido[2,1-b][1,3]thiazines. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1394–1399, September, 2005.     

1-(3,4-二甲氧基）苯乙基-3-环氧丙基-5-氰基-6-甲基脲嘧啶的合成及晶体结构

标题化合物1-（3，4-二甲氧基）苯乙基-3-环氧丙基-5-氰基-6-甲基脲嘧啶是 由1-（3，4-二甲氧基）苯乙基-5-氰基-6-甲基脲嘧啶在NaOH水溶液中与环氧氯丙 烷反应制得。结构通过单晶X射线衍射分析确定，其晶体属于单斜晶系，空间群 P2_1/a, 晶胞参数：a = 1.09(10) nm, b = 1.43(10) nm, c = 1.20(8) nm, V = 1.868 nm~3，Z = 4, D_c = 1.32 Mg/m~3, F(000) = 784。并用波谱法对分离得 到的副产物进行了结构表征。     

Synthesis and chemical properties of 8-aryl-7-acyl-1-6-dimethyl-6-hydroxy-4-cyano-5,6,7,8-tetrahydro-3(2H)-isoquinolinones and isoquinolinethiones

8-Aryl-7-acetyl-1, 6-dimethyl-6-hydroxy-4-cyano-5, 6, 7, 8-tetrahydro-3(2H)-isoquinolinones and -isoquinolinethiones and their sodium salts were obtained by the reaction of cyanoacetamide and cyanothioacetamide with 3-aryl-2, 4-diacetyl-5-methyl-5-hydroxycyclohexanonesinbasicrnedium. 8-Aryl-7-acetyl-6-methoxycarbonyl-1, 6-dimethyl-4-cyano-5, 6, 7, 8-tetrahydro-3(2H)-isoquinolinones were obtained by the reaction of acetyl chloride and the above isoquinolinone sodium salts. The reaction of iodoacetamide and the above isoquinolinethione sodium salts yielded 8-aryl-7-acetyl-3-carbamoylmethylthio-1, 6-dimethyl-4-cyano-5, 6, 7, 8-tetra-hydroisoquinolines, which were cyclized into 1-amino-6-aryl-7-acetyl-2-carbamoyl-5, 8-dimethyl-8-hydroxy-6, 7, 8, 9-tetrahydrothiophene[2,3-c]isoquinolines in basic medium.     

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 ).     

7-azaindole derivatives

A new method for synthesizing 5- and 7-azaindoles is given, -Chlorobutyronitrile and malonyl chloride give 2, 4, 6-trichloro-3-(ß-chloroethyl) pyridine, which is cyclized with ammonia to 4, 6-dichloro-7-azaindoline and 4, 6-dichloro-5-azaindoline. 6-Chloro derivatives of 7-azaindolines are not dehydrogenated by chlorainil, but 2, 3-dichloro-S, 6-dicyanobenzoquinone converts them to 6-chloro-7-azaindoles. It is shown that sodium in liquid ammonia is an effective means of dehydrogenating the 5-azaindoline to 5-azaindole. In this case, dehydrogenation of 4, 6-dichloro-7-azaindoline is followed by dehalogenation.For Part IX see [1].     

Efficient synthesis of 5-substituted 2-aryl-6-cyanoindolizines via nucleophilic substitution reactions

2-Aryl-6-cyano-7-methyl-5-indolizinones were successfully converted into 2-aryl-5-chloro-6-cyano-7-methylindolizines. The obtained 5-chloroindolizines readily underwent nucleophilic substitution at position 5 leading in high yields to novel 5-functionalised indolizines.     

Azaindole derivatives. 60. Nucleophilic substitution reactions in 6-chloro-5-azaindolines

Reactions involving nucleophilic substitution of the halogen atoms in 1-benzyl-6-chloro-7-cyano-5-azaindoline by alkoxy groups and residues of various amines were investigated. The effect of electron-acceptor substituents on the saponification of the alkoxy groups to give hydroxy groups is demonstrated. The effect of the character of the fusion of the pyridine and pyrrole rings on the ease of nucleophilic substitution is examined.See [1] for Communication 59.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1648–1653, December, 1981.