A new strategy for the synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines

A series of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines were prepared via oxidative cyclization of aldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-4-yl)hydrazones. Dimroth rearrangement of such a series yielded pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines.     

Methyl (5-oxopyrazol-3-yl)acetate <Emphasis Type="Italic">N</Emphasis>,<Emphasis Type="Italic">S</Emphasis>-ketene acetal as a new building block for the construction of pyrazolo[4,3-<Emphasis Type="Italic">c</Emphasis>]pyridines

Methyl (5-oxopyrazol-3-yl)acetate is added to methylthiocyanate C≡N bond in the presence of Ni(OAc)₂ giving a corresponding heterocyclic N,S-ketene acetal. The latter compound was used as a convenient synthon in the synthesis of new pyrazolo[4,3-c]pyridin-3-ones and pyrazolo[4,3-c]pyridine-3,6-diones.     

Stereoselective synthesis of dihydrothiadiazinoazines and dihydrothiadiazinoazoles and their pyrolytic desulfurization ring contraction

Intramolecular base catalyzed C-C bond formation led to exclusive stereoselective syntheses of trans-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines, trans-7,8-dihydro-6H-[1,2,4]triazino[3,4-b][1,3,4]thiadiazin-4-ones, and trans-3,4-dihydro-2H-[1,3,4]thiadiazino[2,3-b]quinazolin-10-one. trans-6,7-Dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines isomerize slowly in CDCl₃ and more rapidly in DMSO-d₆ into the corresponding cis-stereoisomers. The other trans-6,7-dihydro-[1,3,4]thiadiazines isomerize also in DMSO-d₆ into the corresponding cis-stereoisomers. Pyrolytic conversion of these heterocyclic condensed dihydrothiadiazines into their corresponding pyrazolo[5,1-b][1,2,4]triazoles, pyrazolo[5,1-c][1,2,4]triazin-4-ones and pyrazolo[4,3-b]quinazolin-9-ones via desulfurization ring contraction is described.     

Pyrolytic desulfurization ring contraction of condensed thiadiazines as a general route towards pyrazoloazines and pyrazoloazoles with a bridgehead (ring junction) nitrogen atom

Pyrolytic conversion of [1,2,4]triazino[3,4-b][1,3,4]thiadiazin-4-ones, [1,3,4]thiadiazino[2,3-b]quinazolin-10-ones and [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines into their corresponding pyrazolo[5,1-c][1,2,4]triazin-4-ones, pyrazolo[4,3-b]quinazolin-9-ones and pyrazolo[5,1-b][1,2,4]triazoles via desulfurization ring contraction is described. The starting condensed 1,3,4-thiadiazines were prepared from the corresponding readily available 4-amino-3-thioxo-1,2,4-triazin-5(4H)-ones, 3-amino-2,3-dihydro-2-thioxoquinazolin-4(1H)-one and 4-amino-3(2H)-thioxo-1,2,4-triazoles upon reaction with the appropriate α-haloketones in two steps, or directly in one step in ethylpyridinium tetrafluoroborate (ionic liquid, IL).     

A new route to pyrazolo[3,4-c] and [4,3-c]pyridinones via heterocyclization of vic-substituted hydroxamic acids of acetylenylpyrazoles

We report in this paper the synthesis of 6-substituted pyrazolo[4,3-c]pyridin-4-ones, 6-substituted 5-hydroxypyrazolo[4,3-c]pyridin-6-ones, 5-substituted pyrazolo[3,4-c]pyridin-7-ones and 5-substituted 6-hydroxypyrazolo[3,4-c]pyridin-7-ones by heterocyclization of vic-acetylenylpyrazol-hydroxamic acids under the influence of copper(I) salt in dimethylformamide or with organic bases in butanol or methanol.     

Synthesis and molecular structure of spirocyclic 2-oxindole derivatives of 2-amino-4H-pyran condensed with the pyrazolic nucleus

4,3′-Spiro[(6-amino-5-R-3-methyl-2H,4H-pyrano[2,3-c]pyrazolo)-2′-oxindoles] were synthesized based on the three-component condensation of isatins with 3-methyl-pyrazolone-5 and respective methylene active nitriles in the presence of basic catalysts. The molecular structure of the resulting compounds was proved unambiguously by X-ray diffraction.     

Azo-coupling of pyrazole-3(5)-diazonium chlorides with cyanothioacetamide: a convenient synthesis of pyrazolo[5,1-c][1,2,4]triazine-3-carbothioamides

Cyanothioacetamide reacts with pyrazole-3(5)-diazonium chlorides to afford pyrazolo[5,1-c][1,2,4]triazine-3-carbothioamides 5. The latter can be oxidized with H₂O₂ to give either pyrazolo[5,1-c][1,2,4]triazine-3-carboxamides or 1,2,4-thiadiazole derivatives, depending on the reaction conditions. The Hantzsch-type reaction of thioamides 5 with α-bromo ketones leads to 3-(thiazol-2-yl)pyrazolo[5,1-c][1,2,4]triazines.     

Synthesis of spiro[benzopyrazolonaphthyridine-indoline]-diones and spiro[chromenopyrazolopyridine-indoline]-diones by one-pot, three-component methods in water

The synthesis of spiro[benzo[h]pyrazolo[3,4-b][1,6]naphthyridine-7,3′-indoline]-2′,6(5H)-diones and spiro[chromeno[4,3-b]pyrazolo[4,3-e]pyridine-7,3′-indoline]-2′,6(6aH,10H)-diones via a one-pot, three-component reaction of 4-hydroxycoumarin or 4-hydroxy-1-methylquinolin-2(1H)-one, isatins and 1H-pyrazol-5-amines in water is reported.     

Construction of pyrazolo[3,4-b]pyridines and pyrazolo[4,3-c]pyridines by ring closure of 3-acylpyridine N-oxide tosylhydrazones

3-Acylpyridine N-oxide tosylhydrazones give good overall yields of a mixture of pyrazolo[3,4-b]pyridines and pyrazolo[4,3-c]pyridines when treated with an electrophilic additive and an amine base. (Z)-Hydrazones cyclize readily, while (E)-hydrazones fail to react under the reported conditions. The reaction takes place at room temperature, and moderate regiocontrol over the cyclization can be achieved by varying the electrophile/solvent combination.     

Intramolecular Cyclization of 4-Isocyanato-3-(2-naphthyl)-1-phenylpyrazole Under Friedel-Crafts Reaction Conditions

4-Isocyanato-3-(2-naphthyl)-1-phenylpyrazole cyclized under the influence of AlCl₃ to give 2H-benzo[h]pyrazolo[4,3-c]isoquinoline.     

Pyrazoles as building blocks in heterocyclic synthesis: Synthesis of pyrazolo [3,4-d]pyrimidine, pyrazolo[3,4-e][1,4]diazepine, pyrazolo [3,4-d][1,2,3]triazine and pyrolo [4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives

Several new pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4-e][1,4]diazepine, pyrazolo[3,4-d][1,2,3]triazine and pyrolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives were prepared by the reaction of the corresponding 5-amino-pyrazole-4-carbonitrile derivative with different organic reagents under different reaction conditions. Using IR, ¹H NMR, and mass spectra we have characterized all new compounds.     

Reactions with 5-aminopyrazoles. I. Synthesis of halogen-containing fused pyrazoles

5-Amino-3-phenylpyrazole (I) and 5-amino-4-bromo-3-phenylpyrazole (II) reacted with ethyl acetoacetate and acetylacetone to give various pyrazolo[1,5-a]pyrimidines IV-VI and with benzoins to give different fused pyrazoles, namely, imidazo[1,2-b]pyrazoles IX, pyrrolo[2,3-c]pyrazoles X and pyrazolo[4,3-b][1,4]oxazines XII. Diazotized II was coupled with active methylene-containing nitriles to afford pyrazolo[5,1-c]-as-triazines XIV.     

Synthesis and 13C-NMR study of pyrazolo[4,5-c] and pyrazolo[4,3-c benzazepines. III

The synthesis of pyrazolo[4,5-c][1]benzazepin-10-ones 10 and 13 and pyrazolo[4,3-c][1]benzazepin-10-ones 11 and 12 is reported. The structure of compounds 10-13 and that of their parent compounds 2-5 ensues from a ¹³C nmr study.     

Alkylation of 1-Alkyl-3-methyl-1,4-dihydropyrazolo[4,3-<Emphasis Type="Italic">c</Emphasis>]pyrazoles with Halocarboxylic Acids Esters

A preparative method for the synthesis of 1-alkyl-3-methyl-1,4-dihydropyrazolo[4,3-c]pyrazoles was developed. The alkylation of the obtained compounds with halocarboxylic acid esters was also investigated. A principal possibility of creating libraries of compounds based on pyrazolo[4,3-c]pyrazole derivatives was shown.     

Highly stereoselective [3+2]-cycloaddition reaction of stabilised N,N′-cyclic azomethine imines with 3-nitro-2-phenyl-2H-chromenes: Synthesis of tetrahydrochromeno[4,3-c]pyrazolo[1,2-a]pyrazol-11-ones

The reactions of 3-nitro-2-phenyl-2H-chromenes with 2-arylmethylidene-5-oxopyrazolidin-2-ium-1-ides proceeded diastereoselectively to afford the corresponding tetrahydrochromeno[4,3-c]pyrazolo[1,2-a]pyrazol-11-ones in good yields as a result of the 1,3-dipolar cycloaddition reaction of stabilised N,N′-cyclic azomethine imines at the Δ³-bond of the chromene system.     

A new synthesis of 2,8-disubstituted pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines

A practical synthesis of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines, which are key intermediates in the preparation of adenosine receptor antagonists, is developed. The method allows introduction of a variety of aryl substituents at position 2 of the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine system via cyclocondensation of 5-amino-4-iminopyrazolo[3,4-d]pyrimidine with benzaldehydes accompanied with oxidation by iodobenzene diacetate. Some unexpected reactions are observed and the structures of the products are confirmed using NMR spectroscopy and X-ray crystallography.     

Preparation of novel pyridine-fused tris-heterocycles; pyrido[4,3-e]pyrrolo-/pyrido[4,3-e]furano[2,3-c]pyridazines and pyrido[3,4-b]pyrrolo[3,2-d]pyrrole

Three novel pyrido-fused tris-heterocycles have been prepared based on a Suzuki coupling and subsequent cyclisation approach. Pyrido[4,3-e]pyrrolo[2,3-c]pyridazine (3b, 77%) and pyrido[4,3-e]furano[2,3-c]pyridazine (5b, 76%) were obtained by intramolecular diazocoupling. Successful diazocoupling of furan (5b) is thus reported for the first time by NOBF₄ generation of the diazonium intermediate. N-TIPS-pyrido[3,4-b]pyrrolo[3,2-d]pyrrole (TIPS-4b) was synthesised by thermal cyclisation of pyridyl nitrene in considerably higher yield (71%) than previously experienced from similar cyclisations, due to TIPS-activation.     

Tautomerism of Aza heterocycles: V. Structure of the spontaneous transformation products of 5-methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo-[4,3-c]pyridin-3-one in crystal and solution

5-Methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one exists as zwitterion with a proton localized on the nitrogen atom of the piperidine ring and negative charge delocalized over the pyrazololate fragment. The compound is stable in crystal but ustable in solution. Its chromatographic purification and attempts to recrystallize or synthesize by condensation of phenylhydrazine with alkyl 1-methyl-4-oxopiperidin-3-carboxylate on heating in alcohols or benzene lead to the formation of a complex mixture of products. Among these products, we isolated and identified 3a,3a′-methylenebis(5-methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one), 1-methyl-3-(2-phenylhydrazinylidene)pyrrolidin-2-one, and 5-methyl-2-phenyl-3,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine. The structure of methyl 3-(2-phenylhydrazinylidene)-4,5-dihydro-3H-pyrrole-2-carboxylate and 3a,5-dimethyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one was proved by NMR spectroscopy. 3a,5-Dimethyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one was isolated as hydrochloride hydrate whose structure was determined by X-ray analysis.     

Synthesis of dihydrochromeno[4,3-b]pyrazolo[4,3-e]pyridin-6(7H)-ones involving one-pot three-component tandem Knoevenagel–Michael reaction catalyzed by n-tetrabutylammonium tribromide (TBATB)

The synthesis of dihydrochromeno[4,3-b]pyrazolo[4,3-e]pyridin-6(7H)-ones was achieved through one-pot three-component reaction from 4-hydroxycoumarin, aldehydes, and 3-amino-5-methyl-pyrazole in acetonitrile using 5 mol % TBATB as the catalyst under reflux condition. The product formation is through tandem Knoevenagel–Michael reaction followed by concomitant cyclization. Simple reaction procedure, shorter reaction time, good yields, avoidance of aqueous work-up, and column chromatographic separation are some of the salient features of the present protocol.     

A Novel Synthesis of 1‐Aryl‐6‐bromo‐3‐(5‐ethylthio‐4‐phenyl‐4H‐1,2,4‐triazol‐3‐yl)‐1H‐pyrazolo[4,3‐b]quinolin‐9(4H)‐ones via Thermal Cyclization of 4‐Azidopyrazoles

2‐Aryl‐hydrazononitriles 3a , 3b , 3c were prepared by coupling 3‐ethylthio‐5‐cyanomethyl‐4‐phenyl‐1,2,4‐triazole ( 1 ) with diazonium salts 2a , 2b , 2c . Reacting 3a , 3b , 3c with both ethyl bromoacetate ( 4a ) and 4‐bromobenzyl bromide ( 4b ) in DMF, in the presence of K₂CO₃, at 80 °C for 3–4 h, gave the corresponding 4‐amino‐pyrazoles 6a , 6b , 6c , 6d , 6e , 6f . Diazotization of 6a , 6b , 6c , 6d , 6e , 6f , followed by reaction with NaN₃, leads to the formation of 4‐azidopyrazoles 8a , 8b , 8c , 8d , 8e , 8f , a new heterocyclic ring system. Interestingly, fusion of 4‐azidopyrazoles 8d , 8e , 8f at temperature higher than their melting points with 5 °C for 2 min did not give the expected fused pyrazolo[4,3‐c]isoxazoles 9 but furnished instead the novel pyrazolo[4,3‐b]quinolinones 10a , 10b , 10c , in high yields.