A versatile synthesis of pyrazolo[3,4-c]isoquinoline derivatives by reaction of 4-aryl-5-aminopyrazoles with aryl/heteroaryl aldehydes: the effect of the heterocycle on the reaction pathways

The reaction of 4-(3,4-dimethoxyphenyl)-5-aminopyrazoles 7A-D with aromatic and heterocyclic aldehydes in strong acidic media (trifluoroacetic or formic acid) has been studied. The initial azomethine derivatives 8 undergo cyclization similar to the Pictet-Spengler condensation to form the intermediate 4,5-dihydroisoquinolines 9 which readily dehydrogenate giving 5-aryl(heteroaryl)-pyrazolo[3,4-c]isoquinoline derivatives 10 as the final products. Whereas for benzaldehyde and its derivatives this one-pot synthesis presents a convenient general route to 5-aryl-pyrazolo[3,4-c]isoquinolines 10, in the case of heterocyclic aldehydes the product structure varies markedly with the structure of the aldehyde used: (i) 3-pyridyl-, 3-quinolyl-, 3-thienyl-, and 1,2,3-thiadiazolyl-5-carboxaldehydes give 5-heteroarylpyrazolo[3,4-c]isoquinolines; (ii) 1-methylbenzimidazolyl-2-carboxaldehyde gives only intermediate azomethine 8Dh, which does not cyclize; (iii) 1-R-3-indolylcarboxaldehydes (R = H, CH3, CH2Ph) eliminate the heteroaryl fragment resulting in 5-unsubstituted pyrazolo[3,4-c]isoquinolines 11. Thienyl-2-carboxaldehyde reacts by both pathways (i) and (iii) depending on the reaction conditions. The single crystal X-ray structures for 10Dj, 10Cd and 11D provide confirmation of the different types of products formed in these reactions. Mechanisms which explain these transformations are presented.     

A Facile method to transform trans-4-carboxy-3,4-dihydro-3-phenyl- 1(2H)-isoquinolones to indeno[1,2-c]isoquinolines

The indeno[1,2-c]isoquinolines are an important class of topoisomerase I inhibitors with anticancer activity. The condensation of Schiff bases with homophthalic anhydrides provides a mixture of cis- and trans-4-carboxy-3,4-dihydro-3-phenyl-1(2H)isoquinolones. Although the cis products can be readily converted to indeno[1,2-c]isoquinolines with thionyl chloride, the trans products do not afford indeno[1,2-c]isoquinolines using this method. The present report describes a route for conversion of the trans diastereomers to indeno[1,2-c]isoquinolines using selenoxide elimination and Friedel-Crafts cyclization chemistry.     

Synthesis of azolo[5,4-c]isoquinolines

Two pathways are presented for the synthesis of pyrazolo[5,4-c]isoquinoline derivatives: recyclization of 1-methyl-3-phenyl-4-cyano-6,7-dimethoxybenzo[c]pyrylium perchlorate upon treatment with hydrazine, and Bischler-Napieralski cyclization of substituted 5-amino-4-(3,4-dimethoxyphenyl)pyrazoles. A derivative of a new heterocyclic system, isoxazolo[5,4-c]isoquinoline, has also been obtained upon heating 5-amino-3-phenyl-4-(3,4-dimethoxyphenyl)isoxazole in a mixture of acetic anhydride and perchloric acid.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1092–1095, August, 1990.     

Synthesis of pyrazolo[3,4-c]isoquinoline and pyrazolo[3,4-b]pyridine derivatives from azomethines and CH-acidic compounds

Summary Donor substituted arylidene aminopyrazoles1a–c and CH-acidic 1,3-dicarbonyl compounds2a–e give in ethanol in an addition/cyclization reaction pyrazolo[3,4-c]isoquinolines4a–i and pyrazolo[3,4-b]pyridine derivatives5a,b, respectively. Using ethyl cyanoacetate as CH-acidic component, cinnamate6 and the cyano substituted pyrazolo[3,4-b]pyridine7 are formed.

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Synthese von Pyrazolo[3,4-c]isochinolin- und Pyrazolo[3,4-b]pyridin-Derivaten aus Azomethinen und CH-aciden Verbindungen

Zusammenfassung Die Reaktion der donorsubstituierten Aryliden-aminopyrazole1a–c mit den CH-aciden 1,3-Dicarbonylverbindungen2a–e führt in einer Additions/Cyclisierungsreaktion zu den Pyrazolo[3,4-c]isochinolin-4a–i bzw. Pyrazolo[3,4-b]pyridin-Derivaten5a,b. Verwendet man Cyanessigester als CH-acide Komponente, werden der Zimtsäureester6 und das cyanosubstituierte Pyrazolo[3,4-b]pyridin7 gebildet.

     

Fluorinated pyrido[2,3-c]pyridazines. II. Synthesis and antibacterial activity of 1,7-disubstituted 6-fluoro-4(1H)-oxopyrido[2,3-c]pyridazine-3- carboxylic acids

Chemical modification of pyridonecarboxylic acid antibacterials with a 1,8-naphthyridine ring, such as enoxacin and tosufloxacin, to their 2-aza derivatives was studied. A new series of 1,7-disubstituted 6-fluoro-4(1H)-oxopyrido[2,3-c]pridazine-3-carboxylic acids (25-27) was prepared by a route involving either alkylation of ethyl 6-fluoro-4(1H)-oxo-7-(p-tolylthio)pyrido[2,3-c]pyridazine-3-carbox ylate (7) or intramolecular cyclization of ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-2-[2-(p-fluorophenyl)hydraz ono]acetate, (20), followed by displacement reaction with cyclic amines at C-7; the N-1 substituent in these compounds included of ethyl, 2-fluoroethyl and p-fluorophenyl groups, and the C-7 functional group comprised variously-substituted piperazines and pyrrolidines. Antibacterial activities of these compounds were markedly inferior to those of enoxacin and tosufloxacin.     

Synthesis and alkylation of pyrazolo[3,4-c]isoquinolines and hexahydrocyclohepta[d]pyrazolo[3,4-b]pyridines

The condensation of 1-acyl-2-(morpholin-4-yl)cycloalkenes with 3-amino-1-phenyl-1H-pyrazol-5(4H)-ones gave the corresponding 2,3,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinoline and 3,6,7,8,9,10-hexahydrocyclohepta[ d]pyrazolo[3,4-b]pyridine derivatives. Alkylation of 2,3,6,7,8,9-hexahydropyrazolo[3,4-c]-isoquinolines with alkyl halides occurred at the nitrogen atom in the 3-position. The structure of 7-methyl-2,5-diphenyl-2,3,6,7,8,9-hexahydro-1H-pyrazolo[3,4-c]isoquinolin-1-one was proved by X-ray analysis.     

Synthesis of substituted 1H-pyrrolo[3,2-c]quinolines

1H-2-Phenylpyrrolo[3,2-c]quinoline (1a) is made by thermal cyclization of quinol-4-yl hydrazone. Subsequent substitution of the C-3 hydrogen atom of the pyrrole ring of 1a with chlorine and a formyl group is easily achieved by reacting 1a with trichloroacetyl chloride and phosphorus oxychloride in DMF, respectively.     

A sequential Pummerer-Diels-Alder route for the generation and trapping of furo[3,4-c]pyridines: synthesis of heterocyclic analogues of 1-arylnaphthalene lignans

The Pummerer reaction of an o-benzoyl-substituted pyridylmethyl sulfoxide generates an alpha-thiocarbocation, the interception of which by a neighboring keto functionality produces an alpha-thio-substituted furo[3,4-c]pyridine as transient intermediate; the latter undergoes a Diels-Alder cycloaddition with an added dienophile. Base-induced ring opening of the cycloadduct followed by aromatization gives an isoquinoline derivative that may be looked upon as a heterocyclic analogue of 1-arylnaphthalene lignans. This procedure occurs readily with electron-poor dienophiles and the entire sequence can be run in one pot. The facility of the sequential Pummerer-Diels-Alder reaction hinges on the experimental conditions, the best results being obtained with heptafluorobutyric anhydride as the triggering agent in toluene containing a catalytic amount of p-toluenesulfonic acid. In the absence of a dienophile it is possible to isolate and characterize a rather unstable furo[3,4-c]pyridine derivative. An intramolecular variant of this protocol is also feasible with use of unactivated alkenyl tethers of variable length; however, the bridged cycloadducts are unisolable in these cases as they undergo spontaneous ring opening and aromatization to yield cycloalka[h]isoquinolines. The usefulness of the sequential Pummerer-Diels-Alder reaction is further demonstrated through the synthesis of a heterolignan with a built-in lactone ring via oxidation of the initial [4+2]-cycloadduct followed by extrusion of phenyl sulfinate and elaboration of the resulting hydoxylated isoquinoline derivative.     

Condensation reaction of 3,4-dibenzoyl-1-methyl-2,5-diphenylpyrrole and -1-phenylpyrazole with methylamine derivatives affording pyrrolo [3,4-c]pyridine and 2H-pyrazolo[3,4-c]- and [4,3-c]pyridines

The reaction of 3,4-dibenzoyl-1-methyl-2,5-diphenylpyrrole ( 1 ) and -1-phenylpyrazole ( 2 ) with methylamines ( 3a-c ) afforded pyrrolo[3,4-c]pyridine ( 4 ), and isomeric 2H-pyrazolo[3,4-c]pyridines ( 5a-c ) and [4,3-c]pyridines ( 6a-c ), respectively.     

Synthesis of novel ferrocenyl-containing pyrazolo[4,3-c]quinolines

Synthesis of novel ferrocenyl-substituted pyrazolo[4,3-c]quinolines via the Pictet-Spengler reaction is reported. Iminium intermediate formed by the condensation of pyrazole-based arylamine substrates with ferrocenecarboxaldehyde in acidic medium, undergoes 6-endo cyclization with sufficiently reactive aromatic moiety to form a pyrazolo[4,3-c]quinoline ring.     

First nucleophilic aromatic substitution of annelated pyrazole.

3-Chloropyrazolo[3,4-c]quinoline 5, 3-chloropyrazolo[3,4-c]isoquinoline 6, 1,2-dihydro-1,2-dimethylpyrazolo[3,4-c]quinolin-3-one 8, and 1,2-dihydro-1,2-dimethylpyrazolo[3,4-c]isoquinolin-3-one 10 were obtained by acid-induced nucleophilic aromatic substitution (S(N)H) of H-3 in N-hydroxypyrazolo[3,4-c]quinoline 1b and in N-hydroxy pyrazolo[3,4-c]isoquinoline 3b. In the acid-induced chlorination, 3b was far more reactive than 1b, whereas the related N-hydroxypyrazolo[4,3-c]quinoline 2b and N-hydroxypyrazolo[4,3-c]isoquinoline 4b were completely unreactive toward S(N)H under identical conditions.     

Synthesis of Several 2-Azafluorenones and 5H[1]Benzopyrano[3,4-c]Py Riding-Ones

Convenient syntheses of 2-azafluorenones 5a-f and 5H[1]benzopyrano[3,4-c]pyridin-5-ones 6a-b were performed by using intramolecular cyclization of 4-arylnicotinic acids 4a-F. 4a-f were obtained via permanganate oxidation from the corresponding of 4-arylpyridines 3a-f in good yields.     

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.     

Synthesis and electrophilic substitutions of novel pyrazolo[1,5-c]-1,2,4-triazolo[4,3-a]pyrimidines

5-Aryl-7-hydrazino-2-phenylpyrazolo[1,5-c]pyrimidines 1 were used as precursors for the preparation of a new series of 5-aryl-8-phenylpyrazolo[1,5-c]-1,2,4- triazolo[4,3-a]pyrimidines 2. The reactions of 2 with certain electrophilic reagents gave the respective 6-substituted derivatives 3-5 rather than the 7-isomeric products. Formylation of the key compounds 1 with ethyl formate yielded the formyl derivatives 6. Furthermore, boiling of compounds 1 with acetic acid afforded 7-acetylhydrazino-5-aryl-2-phenylpyrazolo[1,5-c]pyrimidines 7. Bromination of 7 yielded the dibromo- derivatives 8, while their iodination and nitration gave the monosubstituted derivatives 9 and 10, respectively. Also, treatment of 1 with boiling acetic anhydride yielded the triacetyl derivatives 11. The structure of synthesized products was confirmed by elemental analyses, IR, 1H NMR and MS spectra.     

Synthesis and Crystal Structure of exo-4-（3,4-Dichlorophenyl）-8-ethyl-3,3a,4,5,8, 12d-hexahydro-2H-furo[3,2-c]indolo[3,2-f]quinoline

The title compound exo-4-(3,4-dichlorophenyl)-8-ethyl-3,3a,4,5,8,12d-hexahydro-2H-furo[3,2-c]indolo[3,2-f]quinoline (C25H22Cl2N2O, Mr = 437.35) was synthesized and crystallized. The crystal belongs to tetragonal, space group I4(1)/a with a = 17.4903(3), b = 17.4903(3), c = 28.3403(5) , Z = 16, V = 8669.6(3) 3, Dc = 1.340 g·cm-3, μ(MoKɑ) = 0.319 mm-1, F(000) = 3648, R = 0.0429 and wR = 0.711 for 2714 observed reflections I > 2σ(I). X-ray analysis reveals that atoms C(1), C(2), C(3), C(4), C(5) and N(1) on the new pyridine ring are slightly distorted, forming a distorted boat conformation.     

Properties of 4H-[1]benzopyrano[3,4-c]-[1,2,5]-selenodiazol-4-one

4H-[1]benzopyrano[3,4-c][1,2,5]selenodiazol-4-one has been synthesized by the reaction of 3,4-diaminocoumarin with selenous acid and its reaction with several nucleophiles (alkali, ammonia, amines, hydrazine hydrate) and its nitration have been studied. Using PMR spectroscopy, a comparative kinetic study of the opening of the lactone ring in 6,8-dinitro-4H-[1]benzopyrano[3,4-c][1,2,5]seleno- and thiadiazol-4-ones has been carried out.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 128–133, January, 1991.     

Novel heterocyclic systems based on 8-R-4,5-dihydro-4,4-dimethyl-[1,2]dithiolo[3,4-c]quinoline-1-thiones

Based on the reaction of 8-R-4,5-dihydro-4,4-dimethyl[1,2]dithiolo[3,4-c]quinoline-1-thiones with oxalyl chloride followed by the reactions of 1,3-dipolar cycloaddition and diene synthesis with participation of acetylenedicarboxylic acid dimethyl ester, we have developed approaches to synthesis of novel polycondensed heterocyclic systems: [1,2]dithiolo[3,4-c]pyrrolo[3,2,1-ij]quinoline-4,5-dione, 6-(1,3-dithiol-2-ylidene)-1,2-dioxo-5-thioxo-7H-pyrrolo[3,2,1-ij]quinoline and 4,5-dioxospiro(pyrrolo)-[3,2,1-ij]thiopyrano[2,3-c]quinoline-11,2′-[1,3]dithiole. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 610–615, April, 2006.     

Synthesis of pyrimido [4,5-c] pyridazine (4-deazafervenulin), pyrazolo[3,4-d] pyrimidine and 6-(pyrazino-1-yl)pyrimidine derivatives

The synthesis of several pyrimido[4,5-c]pyridazine (4-deazafervenulin) ( 1 ), pyrazolo[3,4-d]-pyrimidine ( 2 ) and 6-(pyrazino-1-yl)pyrimidine ( 9 ) analogs has been accomplished from 6-hydrazinouracil ( 3 ). This compound could not be used as starting material for the preparation of indolo[3,2-c]pyridazino[3,4-d]pyrimidine derivatives ( 8 ) because it yielded the corresponding hydrazones ( 7 ).     

Investigations on furopyridines. 10. Synthesis of 4-N-substituted 1H-furo[3,4]pyridin-3-ones

2-Amino or 2-hydrazino derivatives of pyridine or pyridinopyrazole were obtained by amination or hydrazination of 2-chloro-3-cyano-4-methoxy-6-methylpyridine. Acid hydrolysis of these derivatives leads to heterocyclization with formation of 4-amino-1H-furo[3,4-c]pyridines or pyrazolo[3,4-b]pyridine. The possibility to synthesize 4-arylamino-1H-furo[3,4-c]-pyridines from 4-chloro-6-methyl-1H-furo[3,4-c]-pyridine has been shown.V. S. Pustovoit All-Russian Oil-Bearing Crops Research Institute, Krasnodar 350038, Russia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 61–66, January, 1999.     

Polarized ethylene. V. Synthesis of 1-substituted indolizine,pyrazolo[1,5-a]pyridine,and their related compounds using methoxyethylene derivatives

The reaction of pyridinium or isoquinolinium N-ylides with methoxy-substituted ethylenes gave the corresponding indolizine and pyrrolo[2,1-a]isoquinoline derivatives bearing acetyl, aroyl, cyano, ester group at the 1-position in one step. Pyrazolo[1,5-a]pyridine, pyrazolo[1,5-a]quinoline, and pyrazolo[5,1-a]isoquinolines were also synthesized in good yields from the corresponding aromatic N-imines and methoxyethylene derivatives.