Synthesis of 3,5-difunctionalized 1-methyl-1H-pyrazolo[3,4-b]pyridines involving palladium-mediated coupling reactions

Indirect iodination of 2-chloro-nicotinonitrile gave 2-chloro-5-iodonicotinonitrile, which was cyclized with methylhydrazine to lead to 3-amino-5-iodopyrazolo[3,4-b]pyridine. Position 3 was then protected by pivaloyl group and the resulting 5-iodo-3-pivaloylaminopyrazolo[3,4-b]pyridine was engaged in palladium-promoted coupling reactions with various reagents to give 3-pivaloylamino-5-substituted compounds. Deprotection and iododediazoniation followed by cross-coupling reactions in position 3 afforded novel unsymmetrical 3,5-disubstituted pyrazolo[3,4-b]pyridine species.     

Convenient syntheses of pyrazolo[3,4-b]pyridin-6-ones using either microwave or ultrasound irradiation

An efficient synthesis of 12 pyrazolo[3,4-b]pyridin-6-one derivatives was achieved using either microwave or ultrasound irradiation, resulting in yields of 40-60% and 60-95%, respectively. Under our conditions, these reactions occurred with notably reduced reaction times as compared to literature reports involving traditional heating. Furthermore, these reactions were highly regioselective and produced only one pyrazolo[3,4-b]pyridin-6-one isomer, whose identity was confirmed by NOESY spectroscopy.     

Microwave-assisted chemoselective synthesis of novel pyrazolo[3,4-b]thieno[3,4-e]pyridines: substitution induced axial chirality

A microwave-assisted chemoselective synthesis of novel pyrazolo[3,4-b]thieno[3,4-e]pyridines has been achieved via tandem Michael addition–cyclization–tautomerization–oxidative aromatization sequence of reactions. Compounds with ortho-substituted phenyl rings exhibited axial chirality due to restricted rotation around C–C single bond.     

Regioselective formylation of pyrazolo[3,4-b]pyridine and pyrazolo[1,5-a]pyrimidine systems using Vilsmeier-Haack conditions

Regioselective formylation behavior has been found in the reaction of pyrazolo[3,4-b]pyridines and pyrazolo[1,5-a]pyrimidines via Vilsmeier-Haack conditions. While the 4,5- and 6,7-dihydro derivatives afforded pyrazolo[3,4-b]pyridine-5-carbaldehydes and 4,7-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarbaldehydes, respectively, the aromatic analogs rendered the pyrazolo[1,5-a]pyrimidine-3-carbaldehyde only, and no reaction took place at the pyrazolopyridine derivatives.     

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).     

Synthesis of Some New Pyrazolo[3,4-b]Pyridlne and Pyrazolo[3,4-d]Pyrimidine Derivatives1

Several pyrazolo[3,4-b]pyridine (3,4) and pyrazolo-[3,4-d]pyrimidine (5-13) derivatives were prepared using 5-amino-l-(5-ethyl-5H-1,2,4-triazino[5,6-b]-indol-3-yl)-lH-pyrazole-4-carbonitrile (2) . The pyridine derivatives 3 and 4 were obtained by reaction of 2 with malononitrile and ethyl cyanoacetate, respectively, while pyrimidine analogs 5-13 were synthesized cither by a one-step or multi-step sequence.     

An alternative synthetic approach for the synthesis of biologically relevant 1,4-disubstituted pyrazolo[3,4-d]pyrimidines

A versatile approach for the synthesis of 1,4-disubstituted pyrazolo[3,4-d]pyrimidines has been developed. Starting from commercially available allopurinol, TBAF mediated N1-functionalization and subsequent C4 nucleophilic substitution, under microwave assisted- or standard heating conditions, granted access to highly functionalized pyrazolo[3,4-d]pyrimidines of potential biological interest.     

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.     

Facile synthesis of 1-substituted 4,5-diaminopyrazoles and its application toward the synthesis of pyrazolo[3,4-b]pyrazines

1-Substituted 5-aminopyrazole-4-carbonylazides were prepared from the appropriate 5-aminopyrazole-4-carboxylates. The acyl azides undergo a Curtius rearrangement followed by quenching with alcohols to form the corresponding carbamates. The 1-substituted 5-amino-4-benzyloxycarbonylaminopyrazoles were unblocked by catalytic hydrogenolysis to give the desired 4,5-diaminopyrazoles. These 4,5-diaminopyrazoles were immediately condensed with glyoxal to afford 1-substituted pyrazolo[3,4-b]pyrazines.     

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.     

Convenient synthesis of pyrazolo[3,4-b]pyridin-3-ones and pyrazolo[3,4-b]pyridine-5-carbaldehyde using vinamidinium salts

An expedient method for the synthesis of 2-phenyl-5-aryl-2,3-dihydropyrazolo[3,4-b]pyridin-3-ones and 2-phenyl-3-oxo-2,3-dihydropyrazolo[3,4-b]pyridine-5-carbaldehyde in a single-step via condensation of vinamidinium salts with 3-amino-1-phenyl-2-pyrazolin-5-one is described.     

Synthesis of fully substituted pyrazolo[3,4-b]pyridine-5-carboxamide derivatives via a one-pot four-component reaction

A one-pot four-component reaction of an aliphatic or aromatic amine, diketene, an aromatic aldehyde and 1,3-diphenyl-1H-pyrazol-5-amine in the presence of p-toluenesulfonic acid as a catalyst has been developed. In this reaction, a new class of fully substituted pyrazolo[3,4-b]pyridine-5-carboxamide derivatives is produced under mild reaction conditions and in good yields at ambient temperature.     

Preparation of 6-chloropyrazolo[3,4-b]pyridine-5-carbaldehydes by Vilsmeier-Haack reaction and its use in the synthesis of heterocyclic chalcones and dipyrazolopyridines

Novel 6-chloropyrazolo[3,4-b]pyridine-5-carbaldehydes 5 have been synthesized from the 4,5-dihydropyrazolo[3,4-b]pyridine-6-ones 4 via Vilsmeier-Haack reaction. Further treatment of carbaldehydes 5 with acetophenones 6 and hydrazine hydrate afforded chalcone analogues 7 and dipyrazolo[3,4-b:4′,3′-e]pyridines 8, respectively.     

Synthesis of derivatives of a new heterocyclic system pyrazolo[3,4-b]pyrido[1′,2′: 1,2]imidazo[4,5-d]pyridine

1-[4-Aminoarylpyrazolo[3,4-b]pyridin-5-yl]pyridinium chlorides undergo cyclization under reflux in tert-butanol in the presence of an excess of potassium tert-butoxide to form tetracyclic derivatives of pyrazolo[3,4-b]pyrido[1′,2′:1,2]imidazo[4,5-d]pyridine. The reaction scheme of the processes is proposed. The structures of the reaction products were confirmed by physicochemical methods. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 710–714, April, 2006.     

Regioselective synthesis of fused benzopyrazolo[3,4-b]quinolines under solvent-free conditions

New 6,8-dihydro-5H-benzo[f]pyrazolo[3,4-b]quinolines 6 have been obtained in a novel solvent-free three-component reaction involving β-tetralone along with 5-aminopyrazoles 1 and benzaldehydes 2. The isomeric 6,10-dihydro-5H-benzo[h]pyrazolo[3,4-b]quinolines 9 could not be prepared in a similar fashion directly from α-tetralone, but were obtained by the reaction of amines 1 with benzylidene-derivative 10 of α-tetralone in similar conditions. The yields of quinolines obtained via this novel protocol were good and the reaction times varied from few minutes to just few seconds.     

Preparation of new pyrido[3,4-b]thienopyrroles and pyrido[4,3-e]thienopyridazines

Two new types of pyrido-fused tris-heterocycles (1a,b and 2a,b) have been prepared from 3-aminopyridine in five/six steps. A synthetic strategy for the preparation of the novel pyrido[3,4-b]thieno[2,3- and 3,2-d]pyrroles (1a,b) and pyrido[4,3-e]thieno[2,3- and 3,2-c]pyridazines (2a,b) has been studied. The Suzuki cross coupling of the appropriate 2- and 3-thienoboronic acids (3,4) and 4-bromo-3-pyridylpivaloylamide (9) afforded the biaryl coupling products (10,11) in high yields (85%). Diazotization of the hydrolysed (2-thienyl)-coupling product (12) and azide substitution gave the 3-azido-4-(2-thienyl)pyridine intermediate (72%, 14). 3-Azido-4-(3-thienyl)pyridine (15) was prepared by exchanging the previous order of reactions. The desired β-carboline thiophene analogues (1a,b) were obtained via the nitrene by thermal decomposition of the azido precursors (14,15). By optimising conditions for intramolecular diazocoupling, the corresponding pyridazine products (72-83%, 2a,b) were afforded.     

Synthesis and functionalisation of 1H-pyrazolo[3,4-b]pyridines involving copper and palladium-promoted coupling reactions

A convenient route to novel 3-iodo-1H-pyrazolo[3,4-b]pyridines via iododediazonation of 3-amino-1H-pyrazolo[3,4-b]pyridines, which are obtained by copper-catalysed cyclisation of 2-chloro-3-cyanopyridine with hydrazines. We describe also efficient coupling reactions from 3-iodo derivatives with various reagents according to Suzuki, Heck, Stille, and Sonogashira conditions.     

Iron(III) chloride catalysed three-component Grieco condensation: Synthesis of tetrahydropyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidines/quinazolines

Three-component Grieco condensation reaction of 3-aminopyrazolo[3,4-b]pyridine, formaldehyde/benzaldehyde and electron rich alkenes in presence of iron(III) chloride gave tetrahydropyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidines/quinazolines in single pot. The sequence of reactions is formation of di-azadiene in situ and the subsequent regioselective addition of alkenes in aza-Diels Alder type reaction. The structure and stereochemistry of the products were confirmed by spectral data and single crystal X-ray crystallography.     

New chemistry of diazafulvenium methides: one way to pyrazoles

Diazafulvenium methides generated from the solution pyrolysis of pyrazolo[1,5-c][1,3]thiazole-2,2-dioxides participate in [8π+2π] cycloadditions giving pyrazolo[1,5-a]pyridine derivatives. 1-Methyl-diazafulvenium, generated under flash vacuum pyrolysis reaction conditions, undergoes an intramolecular sigmatropic [1,8]H shift giving 1-vinyl-1H-pyrazoles.     

Synthesis of 1H-pyrazolo[3,4-d]pyrimidines via solid-phase Aza-Wittig/electrocyclic ring closure reaction

An elegant solid-phase synthetic route of pyrazolo[3,4-d]pyrimidine derivatives via Aza-Wittig/electrocyclic ring closure reaction was developed and validated. By manipulating the R group from the primary amine building block, one can easily prepare the library of pyrazolo[3,4-d]pyrimidine derivatives.