Electrosynthesis of 4-bromosubstituted pyrazole and its derivatives

Electrosynthesis of 4-bromosubstituted pyrazole and its derivatives was carried out by bromination of initial pyrazoles on Pt anode in NaBr aqueous solutions under the conditions of diaphragm galvanostatic electrolysis. A donor substituent (Me or Et) in pyrazole ring was shown to promote to the bromination process, while an acceptor substituent (NO₂ or COOH) does not produce a significant effect to this process. Thus, the yield of 4-bromosubstituted derivatives from bromination of 3,5-dimethylpyrazole, 1,5-dimethylpyrazole, 3-nitropyrazole, pyrazole-3(5)-carboxylic acid, 1-methylpyrazole-3-carboxylic acid, 1-methylpyrazole-5-carboxylic acid, 1-ethylpyrazole-5-carboxylic acid, and 1-methylpyrazole-3,5-dicarboxylic acid amounted 70, 94, 88, 89, 84, 78, 89, and 84%, respectively.     

Amination of isomeric bromo-1-methylnitropyrazoles

A method was developed for the synthesis of 5-bromo-1-methyl-4-nitropyrazole from 1-methylpyrazole. In the reaction with 25% aqueous ammonia at 180–190 °C, 5-bromo-1-methyl-4-nitropyrazole is readily converted to 5-amino-1-methyl-4-nitropyrazole; the production of 4-amino-1-methyl-5-nitropyrazole from 4-bromo-1-methyl-5-nitropyrazole requires the presence of a copper catalyst; under the same conditions in the amination of 4-bromo-1-methyl-3-nitropyrazole, 4-amino-1-methyl-3-nitro- and 1-methyl-3-nitropyrazoles are formed in a 23 ratio.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1672–1675, December, 1983.     

Synthesis of pyrazolo[1,5-a]-pyrimidines by reaction of 3,5-diamino-4-nitropyrazole with acetoacetic ester in the presence of alkaline agents

Two major compounds are formed in the reaction of 3,5-diamino-4-nitropyrazole with acetoacetic ester: 2-amino-5-methyl-3-nitro-4,7-dihydropyrazolo[1,5-a]pyrimidin-7-one and 3-amino-5-(-hydroxycrotonyl)amino-4-nitropyrazole. The latter is converted to bicyclic dihydropyrazolo[1,5-a]-pyrimidinone in solutions with heating.State Science Center of the Russian Federation NIOPIK (Scientific Research Institute of Organic Intermediates and Dyes), Moscow 103787Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 73–77, January, 2000.     

Characteristic features of the reaction of 3(5)amino-5(3)-methylpyrazole with 1-nitroanthraquinone-2-carboxylic acid

In the reaction of 3(5)-amino-5(3)-methylpyrazole with 1-nitroanthraquinone-2-carboxylic acid in sulfolane at 150°C, 2-methyl-pyrazolo[5,1-b]naphtho[2,3-h]quinazoline-5,10,13-trione is formed with an admixture of 1-aminoanthraquinone-2-carboxylic acid and 1-aminoanthraquinone. Under similar conditions, from 4-amino-1,5-dimethylpyrazole, only 1-(1,5-dimethyl-4-pyrazolylamino)anthraquinone-1-carboxylic acid is formed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1191–1192, September, 1992.     

Efficient iodination of structurally varying pyrazoles in heterophase medium

A synthesis of 4-iodo-substituted pyrazoles by iodination of pyrazole and its derivatives in the heterophase (H₂O/CHCl₃ (CCl₄)) medium with the system KI-KIO₃ in the presence of H₂SO₄ additives was accomplished. The yields of 4-iodo-substituted pyrazoles in the iodination of pyrazole, 3,5-dimethylpyrazole, pyrazole-3(5)-carboxylic acid, 1-methylpyrazole-3-carboxylic acid, 1-methylpyrazole-5-carboxylic acid, 3-nitropyrazole, 1-methyl-3-nitropyrazole, 1-methylpyrazole, 1-ethylpyrazole, and 1-isopropylpyrazole were within 80–97%, whereas in the case of 3-nitropyrazole-5-carboxylic acid it was 32%.     

Features of the reaction of 3,4-dihydroxy-6-oxo-2,4-alkadienoic acid esters with acetone and <Emphasis Type="Italic">p</Emphasis>-toluidine

Three-component reactions of 3,4-dihydroxy-6-oxo-2,4-alkadienoic acids with acetone and p-toluidine were studied; their specific feature was the formation of the regioisomeric esters of 4-hydroxy-2,2-dimethyl-1-(4-methylphenyl)-5-(2-oxoalkyliden)-2,5-dihydro-1H-pyrrole-3-carboxylic acids and [4-alkanoyl-3-hydroxy-5,5-dimethyl-1-(4-methylphenyl)-1,5-dihydro-2H-pyrrol-2-ylidene]acetic acid. Structure of the synthesized compounds was discussed based on the data of IR and ¹H NMR spectroscopy and X-ray diffraction analysis.     

Electrosynthesis of 4-iodopyrazole and its derivatives

Electrosynthesis of 4-iodo-substituted pyrazoles has been accomplished by iodination of the corresponding precursors on a Pt-anode in aqueous solutions of KI under conditions of the diaphragm galvanostatic electrolysis. Efficiency of the process depends on the donor-acceptor properties of substituents and their positions in the pyrazole ring. Thus, iodination of pyrazole, 3,5-dimethylpyrazole, 3-nitropyrazole, 1-methylpyrazole, 1,3-dimethylpyrazole, pyrazole-3(5)-carboxylic acid or methyl esters furnished 4-iodo derivatives in 57, 86, 2, 5, 35, 30, and 40% yields, respectively.     

Reaction of Ethoxymethylenemalonate with Cyanothioacetamide in the Presence of Triethylamine: Formation of 1,5-Diamino-2,4-dicyano-5-thioxopenta-1,3-diene-1-thiolate and Unexpected Aminomethylation Result

The reaction of cyanothioacetamide with ethoxymethylenemalonate and triethylamine in ethanol upon heating is non-selective and leads to the formation of a mixture of triethylammonium 1,5-diamino-2,4-dicyano-5-thioxopenta-1,3-diene-1-thiolate and triethylammonium 6-oxo-3-cyano-5-ethoxycarbonyl-1H-pyridin-2-thiolate with a predominance of the latter. When treating with primary amines and 37% formalin in boiling aqueous alcohol, the reaction product gives only 4-(1,3,5-thiadiazinan-2-ylidene)-2-(3,4-dihydro-2H-1,3,5-thiadiazin-6-yl)pent-2-enedinitrile instead of the expected pyrido[2,1-b][1,3,5]thiadiazine derivatives. Triethylammonium 6-oxo-3-cyano-5-ethoxycarbonyl-1H-pyridin-2-thiolate does not react under these conditions.     

Studies With Pyrazol-3-Carboxylic Acid Hydrazide: The Synthesis of New Pyrazolyloxadiazole and Pyrazolyltriazole Derivatives

A simple and versatile method for the synthesis of pyrazol-3-yl-1,3,4-oxadiazole, pyrazol-3-yl-1,2,4-triazole, (1,5-diphenylpyrazol-3-yl)-(3,5-dimethyl-1-carbonyl)pyrazole, and (1,5-diphenylpyrazol-3-yl)-(5-hydroxy-3-metheyl-1-carbonyl)pyrazole derivatives from 1,5-diphenylpyrazole-3-carboxylic acid hydrazide has been developed.     

New Iodo- and Nitro-substituted Pyrroles

Treating 2,5-dimethyl-4-ethoxycarbonyl- and 2,5-dimethyl-4-carboxypyrroles with iodine furnished 3-iodo-2,5-dimethyl-4-ethoxycarbonyl- and 3,4-diiodo-2,5-dimethylpyrroles. It was established that 3-iodo-2,5dimethyl-4-ethoxycarbonylpyrrole reacted at heating with silver nitrite to afford 2,5-dimethyl-3-nitro-4-ethoxycarbonylpyrrole, and the same reagent oxidized 3,4-diiodo-2,5-dimethylpyrrole to give 3,4-diiodo-2-methyl-5-formylpyrrole.     

Rh(I)-katalysierte Umlagerungen von 3,4-Diacycloxy-1,5-hexadiinen; synthese von (E)-4-acyloxymethyliden-2-cyclopenten-1-onen

Rh(I)-Catalysed Rearrangements of 3,4-Diacyloxy-1,5-hexadiynes; Synthesis of (E)-4-Acyloxymethyliden-2-cyclopenten-1-ones The 3,4-diacyloxy-1,5-hexadiynes 3, 6 and 8 which were synthesized according to a known, slightly modified procedure react with [Rh(CO)₂Cl]₂ at 100° in chloroform with formation of the (E)-4-acyloxymethyliden-2-cyclopenten-1-ones 4, 7 and 9 (Schemes 2, 3 and 4), respectively. DL - and meso- 3 as well as trans- and cis- 8 , give the same (E)-isomers 4 and 9 , respectively. 3,4-Diacetoxy-3, 4-dimethyl-1, 6-diphenyl-1,5-hexadiyne ( 10 ) produces with the same catalyst 2,6-diacetoxy-3, 4-dimethyl-1,6-diphenylfulvene ( 11 ) (Scheme 5). A mechanism for the formation of the cyclopentenones is proposed in Scheme 6.     

Synthesis and biological activity of 1,5-dihydropyridazino-[3,4-b]quinoxalines and a new class of quinolones

A new class of quinolones, 1,4-dihydro-4-oxopyridazino[3,4-b]quinoxaline-3-carboxylic acids and related compounds, were synthesized via oxidation of 1,5-dihydropyridazino[3,4-b]quinoxalines obtained from 2-hydrazinoquinoxaline 4-oxides. Some of the 1,5-dihydropyridazino[3,4-b]quinoxalines, 1,4-dihydro-4-oxopyridazino[3,4-b]quinoxaline-3-carboxylic acids, and related compounds showed biological activity.     

C,O-dialkylation of Meldrum's acid: synthesis and reactivity of 1,3,7,7-tetramethyl-4H,10H-6,8,9-trioxa-2-thiabenz[f]azulen-5-one

Reaction of Meldrum's acid with 3,4-bis(chloromethyl)-2,5-dimethylthiophene (1) or 3,4-bis(bromomethyl)-2,5-dimethylthiophene (2) produces the kinetically favored C,O-dialkylation product, 1,3,7,7-tetramethyl-4H,10H-6,8,9-trioxa-2-thiabenz[f]azulen-5-one (4). Recrystallization of 4 from refluxing methanol results in the methanolysis product 5-(4-methoxymethyl-2,5-dimethylthiophen-3-ylmethyl)-2,2-dimethyl[1,3]dioxane-4,6-dione (5). Attempts to isomerize 4 to the thermodynamically favored C,C-dialkylation product, 1,3-dimethyl-5,6-dihydro-4H-cyclopenta[c]thiophene(2-spiro-5)2,2-dimethyl-4,6-dione (8), result in the formation of 1,3-dimethyl-7,8-dihydro-4H-thieno[3,4-c]oxepin-6-one (6). The transformation occurs via a retro-Diels-Alder elimination of acetone followed by hydrolysis and decarboxylation of the resulting ketene. The ketene is trapped by tert-butyl alcohol, furnishing 1,3-dimethyl-6-oxo-7,8-dihydro-4H,6H-thieno[3,4-c]oxepine-7-carboxylic acid tert-butyl ester (7). All compounds are characterized spectroscopically as well as by X-ray crystallography of products 4-7.     

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.     

Heterocyclizations of 5-methylpyrazol-3-amine with unsaturated arylaliphatic carboxylic acid derivatives

Cyclocondensation of 5-methylpyrazol-3-amine with methyl cinnamate and arylmethylidenemalonic acids in DMF and methanol leads to the formation of 7-aryl-2-methyl-6,7-dihydropyrazolo[1,5-a]-pyrimidin-5(4H)-ones. Arylmethylidenemalonic acids react with the title amine at a ratio of 1:2 in nitrobenzene to give 4-aryl-3,5-dimethyl-1,7-dihydrodipyrazolo[3,4-b:4′,3′-e]pyridines. Heterocyclizations of 5-methylpyrazol-3-amine with 5-arylmethylidene-2,2-dimethyl-1,3-dioxane-4,6-diones or their precursors, para-substituted benzaldehydes and 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum’s acid) in all solvents (methanol, DMF, and nitrobenzene) give the corresponding 4-aryl-3-methyl-2,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-ones. The structure of 3-methyl-4-(4-nitrophenyl)-2,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-one was proved by X-ray analysis.     

Enolethers. XX . Synthesis of azepino[4,5-b]quinoxalines and pyridopyrazino[2,3-d]azepines

1,6-Diethoxy-1,5-hexadiene-3,4-dione ( 1 ) reacts with primary amines 3 and ammonia respectively in a molar ratio of 1:1 to give mainly aminoalkyl- and small amounts of bis(aminoalkyl)-1,5-hexadiene-3,4-diones 4 and 2 , respectively. On heating in dichlorobenzene above 150° the mixtures of 2 and 4 cyclize to yield 1-alkyl-1H-azepine-4,5-diones 5 by elimination of ethanol or amine. 3H-3-Alkylazepino[4,5-b]-quinoxalines 7, 8, 10 and 12 are easily accessible by condensation of the diketones 5a and b with various substituted o-phenylenediamines 6, 9 and 3,3′,4,4′-tetraaminobiphenyl ( 11 ) in p-xylene or n-butanol. 8-Isopropylpyridopyrazino[2,3-d]azepines 14 were obtained by condensation of 5b with pyridinediamines 13 in p-xylene. The azepine-4,5-diones 5a-c can be hydrogenated selectively by sodium borohydride in ethanol at room temperature to give the azepin-4-ol-5-ones 15a-c .     

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.     

Some Conversions of Thiazoline Carboxylic Acid Esters

We have carried out solvolysis of the previously described ethyl esters of 3-methyl(aryl)-4-methyl-2-thioxothiazoline-5-carboxylic acids, leading to the corresponding acids without breaking down the heterocycle. We synthesized a series of novel esters from the latter by treatment with dimethyl sulfate or reactive halides. Of these, only in the case of the ethyl ester of 3,4-dimethyl-2-thioxothiazoline-5-carboxylic acid did we obtain the hydrazinolysis product (the hydrazide), from which we synthesized novel hydrazones by treatment with aldehydes and ketones.     

Formation of the benzo[f]pyrazolo[3,4-c][1,2,5]-triazepine system in the template reaction of o-amino-o′-halophenylazopyrazoles

The substance isolated from the template cyclization of 4-(2-bromo-4-methyl-1-phenylazo)-5-amino-3-methyl-1-propylpyrazole was identified by spectroscopic methods as 5-(2-bromo-4-methylphenyl)-3,7-dimethyl-1-propyl-1,5-dihydrobenzo[f]-pyrazolo[3,4-c][1,2,5]triazepine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 802–804, June, 1979.     

Stereoselective synthesis of highly enantioenriched 3-methyl-2-cyclohexen-1-ones possessing an asymmetric quaternary carbon as C-4 or C-6: a sugar template approach

The 1,4-addition of the enolate generated from α-methylated acetoacetate incorporated at C-4 of methyl 6-deoxy-2,3-di-O-(tert-butyldimethylsilyl)-α-d-glucopyranoside to methyl vinyl ketone, followed by aldol condensation of the resulting 1,4-addition product under two base-mediated conditions, provided 4-O-functionalized d-glucose derivatives with high diastereoselectivity. These products install a 3-methyl-2-cyclohexen-1-one-4- (or -6-) carboxylic acid as the O-4 ester, in which C-4 or C-6 is an asymmetric quaternary carbon. Removal of the sugar template from those aldol condensation products provided synthetically useful 3,6-dimethyl-2-cyclohexen-1-one-6-carboxylic acid and 3,4-dimethyl-2-cyclohexen-1-one-4-carboxylic acid derivatives both in high enantioenriched forms.