Reactions of 3-methyl-1-(2-pyridyl)-4-chloro-5-formyl-6,7-dihydroindazole

The reactions of 3-methyl-1-(2-pyridyl)-, 3-methyl-1-phenyl-, and 3-methyl-1,6-diphenyl-4-chloro-5-formyl-6,7-dihydroindazoles with guanidine and benzo- and 3- and 4-pyridinecarbamidines gave the corresponding 8-substituted 1-methyl-3-(2-pyridyl)-and 1-methyl-3-phenyl-4,5-dihydropyrazolo[5,4-h]quinazolines. With acetic anhydride the same indazole derivatives gave the 4-acetoxy-5-formyl derivatives, and with hydroxylamine they gave4-chloro-5-hydroxyiminomethyl-6,7-dihydroindazoles. Thereactionof4-acetoxyl-1-(2-pyridyl)-5-formyl-6,7-dihydroindazole with hydroxylamine gave 8-methyl-6-(2-pyridyl)-4,5-dihydroisoxazolo[5,4-e]indazole, while dehydration of 5-hydroxyiminomethyl-3-methyl-4-chloro-6,7-dihydroindazole gave the 4-chloro-5-cyano derivative. The reaction of the latter with nucleophilic reagents was investigated.Riga Technical University, Riga, Latvia LV-1658. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1209–1213, September, 1998.     

Synthesis and reactions of 1-(2-pyridyl)-3-methyl-4-chloro-5-formyl-6,7-dihydroindazoles

The Vilsmeier formylation of 1-(2-pyridyl)-3-methyl-4-oxo-4,5,6,7-tetrahydroindazole and its 6-phenyl derivative gives 1-(2-pyridyl)-3-methyl-4-chloro-5-formyl-6,7-dihydroindazoles. Reactions of these derivatives with different N- and C-nucleophilic agents, including bisnucleophiles, were studied as a means of obtaining new 4- and 5-functional derivatives of indazole and its condensed systems.Riga Technical University, Riga LV-1658, Latvia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 768–773, June, 1998.     

Reactions of 2-Amino-4-methyl-6-(2-pyridyl)- and 2-Amino-4-methyl-6-phenyl-7,8-dihydroindazolo[4,5-d]thiazoles with Aldehydes

The reaction of 2-amino-4-methyl-6-(2-pyridyl)-7,8-dihydroindazolo[4,5-d]thiazole, obtained by treating 3-methyl-4-oxo-1-(2-pyridyl)-4,5,6,7-tetrahydroindazole with pyridinium bromide perbromide and then with thiourea, and 2-amino-4-methyl-6-phenyl-7,8-dihydroindazolo[4,5-d]thiazole with 4-bromo-, 4-fluoro-, 4-dimethylamino-, 4-methoxy-, 3,4-dimethoxy-, and 3,4-methylenedioxybenzaldehydes, furfural, pyridinecarbaldehyde, and thiophenecarbaldehyde gave the corresponding Schiff bases. The products of the condensation of these aminothiazoles with cinnamaldehyde, 1-(2-pyridyl)- and 4-chloro-1-(2,4-difluorophenyl)-5-formyl-3-methyl-6,7-dihydroindazoles, 2-formyl-dimedone, and 2-formyl-1,3-indanedione were also obtained.     

Synthesis and reactions of 1-(4-chloro-, 3-chloro-, 2-chloro-, 2,4-dichloro-, and 2,4-difluorophenyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazoles

Reaction of the potassium salt of 2-formyldimedone with hydrochlorides of 4-chloro-, 3-chloro-, 2-chloro-, 2,4-dichloro-, and 2,4-difluorophenylhydrazines gave the corresponding 2-arylhydrazinomethylene-dimedones which cyclized in acid media to 1-substituted 6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazoles. Oxidation of the latter with selenious acid gave the corresponding 4,5-dioxo-4,5,6,7-tetrahydroindazoles which were further converted into 3-aryl-5,5-dimethyl-4,5-dihydro-3H-pyrazolo[4,3-a]phenazines and 2,6-diaryl-4,4-dimethyl-4,5-dihydro-1H(3H)-indazolo[4,5-g]imidazoles.Riga Technical University, Riga LV-1658, Latvia; e-mail: marina@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, 533–539, April, 2000.     

Pyrazolo[5,4-h]quinazolines

The reaction of 1-phenyl- and 4-chloro-5-formyl-3-methyl-1-(2-pyridyl)-6,7-dihydroindazoles with carbamidinopyrrolidine, 4-carbamidinomorpholine, creatine, 2-carbamidinopyrazine, and 2-carbamidino-5-trifluoromethylpyridine gives the corresponding 3,8-substituted 1-methyl-4,5-dihydropyrazolo-[5,4-h]quinazolines and with 2-aminobenzimidazole gives 3-phenyl- and 3-(2-pyridyl)-1-methyl-4,5-dihydrobenzo[b]indazolo[4,5-e]imidazolo[1,2-a]pyrimidines.Riga Technical University, Riga LV-1658, Latvia; e-mail; marina@osi.lv . Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 962–965, July, 2000.     

Reactions of 4-Chloro-3-formylcoumarin with Arylhydrazines

The interaction of 3-formyl-4-coumarin with arylhydrazine hydrochlorides in the presence of sodium acetate gave the corresponding 3-arylhydrazonomethyl-4-chlorocoumarin, and with phenylhydrazine, 4-bromo- and 4-chlorophenylhydrazine hydrochlorides in the presence of two equivalents of triethylamine gave either 1-aryl- or 2-aryl[1]benzopyrano[4,3-c]pyrazol-4-ones depending on the reaction conditions. In reactions of 4-chloro-3-formylcoumarin with 2,4-dichloro-, 2,4-difluoro-, 2-hydroycarbonyl-, 4-nitro- and 3,5-di(trifluoromethyl)phenylhydrazine, 2-pyridyl- and 2-quinoxalylhydrazine in the presence of excess of triethylamine the 2-aryl[1]benzopyrano[4,3-c]pyrazol-4(2H)-ones were obtained exclusively. The structures of 1-phenyl- and 2-(2-pyridyl)[1]benzopyrano[4,3-c]pyrazolo-4(1H)ones were confirmed by X-ray crystallography. A simple method is proposed to distinguish between 1- and 2-substituted [1]benzopyrano[4,3-c]pyrazolo-4-ones on the basis of the ¹H NMR chemical shifts of the C(3)-H proton in two solvents - DMSO-d₆ and CDCl₃.     

3,6,6-trimethyl-4-oxo-1-(2-pyridyl)-4,5,6,7-tetrahydroindazole in Schmidt reaction and Beckmann rearrangement conditions for the 4-hydroxyimino derivative

Treatment of 3,6,6-trimethyl-4-oxo-1-(2-pyridyl)-4,5,6,7-tetrahydroindazole with sodium azide in acids gives 3,7,7-trimethyl-5-oxo-1-(2-pyridyl)-5,6,7,8-tetrahydro(4H)pyrazolo[4,3-b]azepine. Heating 1-(2-pyridyl)-3,6,6-trimethyl- and 1-phenyl-6,6-dimethyl-4-hydroxyimino-4,5,6,7-tetrahydroindazoles in polyphosphoric acid gives 1-phenyl-5,6-dimethyl- and 1-(2-pyridyl)-3,5,6-trimethyl-4-aminoindazole respectively: The reactions of the latter with 4-dimethylaminobenzaldehyde gave the 4-(4-dimethylaminobenzalamino) derivative and with 2-formyldimedone the 4-(4,4-dimethyl-2,6-dioxocyclohexylidenemethylamino) derivative.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 830–834, June, 2000.     

4,5-Dioxo-and 4-oxo-2,3-diaryl-5-diazo-6,6-dimethyl-4,5,6,7-tetrahydroindazoles

The oxidation of 2,3-diphenyl-, 3-(4-chlorophenyl)-2-phenyl-, 3-(4-dimethylaminophenyl)-2-phenyl-, 3-(4-methoxyphenyl)-2-phenyl-, 2-phenyl-3-(3-pyridyl)-, 3-phenyl-2-(2-pyridyl)-, and 3-(4-dimethylaminophenyl)-6,6-dimethyl-4-oxo-2-(2-pyridyl)-4,5,6,7-tetrahydroindazoles using H₂SeO₃ in acetic acid in the presence of sulfuric acid gave the corresponding 4,5-dioxo derivatives. Reaction of these with tosylhydrazine gave 4-oxo-5-tosylhydrazino derivatives which were decomposed by alkali to give the corresponding 2,3-diaryl-5-diazo-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazoles. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1829–1833, December, 2005     

5-Benzylidene- and 5-Aminomethyl-4-oxo-4,5,6,7-tetrahydroindazoles

The reaction of 3-methyl-4-oxo-4,5,6,7-tetrahydroindazoles with benzaldehydes gave 5-benzylidene-3-methyl-4-oxo-4,5,6,7-tetrahydroindazoles. Under Mannich conditions, 3-methyl-1-phenyl-4,5,6,7-tetrahydroindazole gave 5-aminomethyl-3-methyl-4-oxo-1-phenyl-4,5,6,7-tetrahydroindazoles.     

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.     

1- and 2-(4-Hydroxycarbonylphenyl)-4-oxo-4,5,6,7-tetrahydroindazoles

Reactions of 4-hydrazinobenzoic acid with 2-formyl- and 2-acetyldimedones were utilized to synthesize 6,6-dimethyl- and 3,6,6-trimethyl-1-(4-hydroxycarbonylphenyl)-4-oxo-4,5,6,7-tetrahydroindazoles corre-spondingly, and the reaction with 2-cyano-3-ethoxy-5,5-dimethylcyclohex-2-en-1-one gave 2-(4-hydroxy-carbonylphenyl)-3-amino-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydroindazole. Riga Technical University, Riga LV-1658. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 516–519, April, 1997.     

3-Aryl- and 2,3-Diaryl-4-oxo-4,5,6,7-tetrahydroindazoles. 1. Reactions of Phenyl- and Tosylhydrazones of Dimedone and Cyclohexane-1,3-dione with Substituted Benzaldehydes

Sixteen 3-aryl-4-oxo-2-phenyl-4,5,6,7-tetrahydroindazoles were obtained from the reaction of the phenylhydrazones of dimedone and cyclohexane-1,3-dione with 3-bromo-, 4-bromo-, 4-chloro-, 4-fluoro-, 2-hydroxy-, 4-hydroxy-, 4-methoxy-, 2-nitro-, 3-nitro-, 4-nitro-, and 4-dimethylamino-benzaldehydes. The interaction of the tosylhydrazones of dimedone and cyclohexane-1,3-dione with the substituted benzaldehydes gave thirteen 3-aryl-4-oxo-4,5,6,7-tetrahydroindazoles. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1662–1668, November 2005.     

4-(3-Cyanopyridin-2-ylthio)acetoacetates in synthesis of heterocycles

Substituted 2-amino-4-aryl-3-cyano-5-oxo-5,6-dihydro-4H-pyrano[2,3-d]pyrido[3",2":4,5]thieno[3,2-b]pyridines were synthesized by the reactions of 4-hydroxy-1H-thieno[2,3-b;4,5-b]dipyridin-2-ones with arylidenemalononitriles or by the three-component reactions of hydroxythienodipyridinones with aldehydes and malononitrile in DMF in the presence of triethylamine. Methods for syntheses of substituted 3-alkoxycarbonyl-6-amino-4-aryl-2-(3-cyanopyridin-2-ylthiomethyl)-4H-pyrans were developed on the basis of the reactions of 4-(3-cyanopyridin-2-ylthio)acetoacetates and arylidenemalononitriles or aldehydes and malononitrile. Ethyl 4-(3-cyanopyridin-2-ylthio)acetoacetate and 4-methoxybenzylidenecyanothioacetamide were used for the synthesis of 6-(pyridin-2-ylthiomethyl)-3-cyanopyridine-2(1H)-thione.     

6,7-亚甲二氧基-9-甲基-1(2H,4H)-吖啶酮衍生物的合成

以5-芳基-1,3-环基环己二酮为原料合成了8个未见报道的吖啶酮衍生物,其结构均经元素分析,IR和^1H NMR光谱确证。其中3-呋喃基-6,7-亚甲二氧基-9-甲基-1(2H,4H)-吖啶醇对一些肿瘤细胞有抑制作用。     

Nucleophilic substitution in 1-alkyl-4,5-dichloro-3-nitropyridazin-6-ones

Treatment of 1-alkyl-4,5-dichloro-3-nitropyridazin-6-one with C-nucleophiles and with ambident nucleophiles (2-azahetarylacetonitriles) leads to a selective substitution of a chorine atom by the quaternary carbon atom of the carbanion formed from a substituted acetonitrile. The pK_a of the CH-acid 2-(1-alkyl-5-chloro-3-nitro-6-oxo-1,6-dihydro-4-pyridazinyl)malononitrile was determined by potentiometric titration. Reaction of 2-(1-alkyl-5-chloro-3-nitro-6-oxo-1,6-dihydro-4-pyridazinyl)-2-hetarylacetonitriles with primary amines gives 6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-7-ones. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 556–564, April, 2006.     

3-(Benzimidazolyl-2)-2-iminocoumarins in Reactions with Aromatic Aldehydes

Interaction of 3-(benzimidazolyl-2)-2-iminocoumarins with aromatic aldehydes in the presence of piperidine gave the corresponding 7-aryl-7H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidines. The 3-diethylamino derivatives of this series fluoresce effectively in alcohol solutions.     

1-(2-Quinoxalyl)-, 1-[3,5-Di(trifluoromethyl)phenyl]-, 1-(2-Carboxyphenyl)-, and 1-Ethoxycarbonyl-4-oxo-4,5,6,7-tetrahydroindazoles

The corresponding 1-(2-quinoxalyl)-, 1-[3,5-di(trifluoromethyl)phenyl]-, and 1-ethoxycarbonyl-3-methyl-4-oxo-4,5,6,7-tetrahydroindazoles have been obtained from reactions of 2-acetyl-1,3-cyclohexanedione, its 5,5-dimethyl and 5-(2-furyl) derivatives, with 2-hydrazinoquinoxaline, 3,5-di(trifluoromethyl)phenylhydrazine, and ethoxycarbonylhydrazine. On interaction with ethoxycarbonylhydrazine the intermediate 2-[1-(-ethoxycarbonyl)hydrazino]ethylidene-1,3-cyclohexanediones were also isolated. From the potassium salt of 2-formyldimedone and 2-carboxyphenylhydrazine hydrochloride, 2-(2-carboxyphenyl)hydrazinomethylene-5,5-dimethyl-1,3-cyclohexanedione was obtained, the cyclization of which in ethanol in the presence of HCl led to 1-(2-carboxyphenyl)- and 1-(2-ethoxycarbonylphenyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazole.     

Novel Aspects of the Reaction of 3-(Benzimidazol-2-yl)-2-iminocoumarins with Aromatic Aldehydes

The reaction of 3-(benzimidazol-2-yl)-2-iminocoumarins with aromatic aldehydes has been studied. The condensation products 7-aryl-7H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidines or 3-(benzimidazol-2-yl)coumarins are formed depending on the nature of the substituent in the starting 2-iminocoumarin and aldehyde. In DMF medium, 7-aryl-7H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidines isomerize to the corresponding 7-aryl-14H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidines. The effect of the substituent on the isomerization process has been studied and the reaction mechanisms are discussed.     

Synthesis and molecular structure of 4-nitro-9-phenyl-1H-and 9-hydroxy-3-oxo-9-phenyl-2,3-dihydro-9H-indeno-[2,1- c ]pyridines and 3,7-diphenyl-3a, 4,5,6-tetrahydroindeno[2,1- c ]isoxazolo[5,4- d ]pyridine

The 4-nitro derivatives and an oxidation by-product, 9-hydroxy-2-methyl-3-oxo-9-phenyl-2,3-dihydro-9H-indeno[2,1-c]pyridine were obtained by the nitration of N-alkyl-9-phenyl-2,3-dihydro-1H-indeno-[2,1-c]pyridines with sodium nitrite in acetic acid. Their molecular structures were studied by X-ray structural analysis. The product of [2+3] cycloaddition, 5-methyl-3,7-diphenyl-3a, 4,5,6-tetrahydroindeno[2,1-c]isoxazolo[5,4-d]pyridine, was obtained by the interaction of 2-chloro-1-hydroxy-2-phenylazomethine with 2-methyl-9-phenyl-2,3-dihydro-1H-indeno[2,1-c]pyridine. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1390–1399, September, 2007.     

One-step synthesis of 5-acetyl-2-amino-4-aryl-3-cyano-4H-pyrano[3,2-b]indoles. Molecular and crystal structure of 5-acetyl-2-amino-4-(4"-chloro-3"-nitrophenyl)-3-cyano-4H-pyrano[3,2-b]indole

A one-step procedure was developed for the synthesis of 5-acetyl-2-amino-4-aryl-3-cyano-4H-pyrano[3,2-b]indoles involving the three-component reaction of 1-acetylindol-3(2H)-one with aromatic aldehydes and malononitrile in ethanol in the presence of triethylamine as the catalyst. The structure of 5-acetyl-2-amino-4-(4"-chloro-3"-nitrophenyl)-3-cyano-4H-pyrano[3,2-b]indole was established by X-ray diffraction analysis.