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.     

Microwave-assisted and iodine mediated synthesis of 5-n-alkyl-cycloalkane[d]-pyrazolo[3,4-b]pyridines from 5-aminopyrazoles and cyclic ketones

5-n-Alkylcycloalkane[d]pyrazolo[3,4-b]pyridines were prepared by a microwave-assisted cyclocondensation reaction between 5-aminopyrazoles and cyclic ketones under solvent-free conditions and catalyzed by iodine. This procedure provides a simple one-step and environmentally friendly methodology with good yields for the synthesis of these compounds.     

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.     

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 novel dipyrazolo[3,4-b:3,4-d]pyridines and study of their fluorescence behavior

A convenient route was successfully developed for the synthesis of novel heterocycles such as pyrazolo[3,4-h][1,6]naphthyridine and dipyrazolo[3,4-b:3,4-d]pyridine (DPP) from pyrazolo[3,4-b]pyridine in good yield. The DPP derivatives synthesized were further studied for their fluorescence properties.     

Synthesis of pyrazolo[3,4-d]-4,5-dihydropyrimidin-6-ones

A small library of hitherto unprepared pyrazolo[3,4-d]-4,5-dihydropyrimidin-6-ones was synthesized on a preparative scale. The synthesis starts with a substituted 5-aminopyrazole that reacts with an isocyanate to give the corresponding urea. The latter undergoes a chlorotrimethylsilane-promoted [5+1] cyclocondensation with an aldehyde yielding the title pyrazolo[3,4-d]-4,5-dihydropyrimidin-6-one. Both synthetic steps are high-yielding (74–94%). The intermediates and the target compounds were isolated by simple crystallization. Ketones with the exception of isatin do not react with the open-chain urea intermediates.     

Synthesis of condensed tricyclic pyrazolo[3,4-b]thieno[2,3-d]pyridine and related isostere derivatives

In this paper we report the synthesis of an isosteric series of new heterotricyclic derivatives, corresponding to pyrazolo[3,4-b]thieno[2,3-d]pyridine ( 1 ), pyrazolo[3,4-b]furano[2,3-d]pyridine ( 2 ) and pyrazolo[3,4-b]pyrrolo[2,3-d]pyridine ( 3 ). These functionalized compounds were obtained, in high overall yield, by an ‘one-pot’ reaction of the chloroester intermediate 4 , possessing the pyrazolo[3,4-b]pyridine system, with an adequate α-hetero-acetyl ester derivative, in SNAr/Dieckman cyclization type consecutive reactions.     

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.     

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.     

Microwave-assisted protocols for the expedited synthesis of pyrazolo[1,5-a] and [3,4-d]pyrimidines

General, high-yielding MAOS protocols for the expedited synthesis of functionalized pyrazolo[1,5-a]pyrimidines and pyrazolo[3,4-b]pyrimidines, as well as their pyrazole precursors, are described amenable to an iterative analogue library synthesis strategy for lead optimization.     

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.     

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.     

Synthesis of 3-aryl-6H-isoxazolo[3,4-d]pyrazolo[3,4-b]pyridines and 3-aryl-6H-isoxazolo[5,4-d]pyrazolo[3,4-b]pyridines

The synthesis and characterization of a number of 3-aryl-6H-isoxazolo[3,4-d]pyrazolo[3,4-b]pyridines and 3-aryl-6H-isoxazolo[5,4-d]pyrazolo[3,4–6]pyridines from common precursors, 5-benzoyl-4-chloro-1H-pyrazolo-[3,4-b]pyridines, has been described. The structures were determined by unambiguous chemical synthesis and by isolation and ¹³C nmr analysis of some key, isolated, intermediates. The ability of these compounds to displace [3H]flunitrazepam from CNS binding sites was also observed.     

Synthesis of chromeno[3,4-b]pyrrol-4(3H)-ones by cyclocondensation of 1,3-dicarbonyl compounds with 4-chloro-3-nitrocoumarin

The base-mediated cyclocondensation of 1,3-dicarbonyl compounds with 4-chloro-3-nitrocoumarin provides a convenient approach to various chromeno[3,4-b]pyrrol-4(3H)-ones.     

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.     

Nucleophilic cyclization of 3-alkynylquinoxaline-2-carbonitriles into pyrido[3,4-b]quinoxalines

3-Alkynylquinoxaline-2-carbonitriles have been synthesized from 3-chloroquinoxaline-2-carbonitrile via the Sonogashira reaction. Treatment of 3-alkynylquinoxaline-2-carbonitriles with an alkylamine or ammonia has been shown to produce stable enamines, e.g., (Z)-3-(2-aryl-2-aminovinyl)quinoxaline-2-carbonitriles. Their base-induced cyclization gave the previously unknown pyrido[3,4-b]quinoxalin-1(2H)-imines or pyrido[3,4-b]quinoxalin-1-amines. 3-Alkynylquinoxaline-2-carbonitriles were directly transformed into pyrido[3,4-b]quinoxalin-1(2H)-imines by heating with an alkylamine and K₂CO₃ in DMF. The ionization constants, and absorption and fluorescent properties of the resulted pyrido[3,4-b]quinoxalin-1(2H)-imines were measured.     

Polysubstituted 2,3-dihydrofuro[2,3-b]pyridines and 3,4-dihydro-2H-pyrano[2,3-b]pyridines via microwave-activated inverse electron demand Diels-Alder reactions

Polysubstituted 2,3-dihydrofuro[2,3-b]pyridines and 3,4-dihydro-2H-pyrano[2,3-b]pyridines have been synthesized from 1,2,4-triazines using the inverse electron Diels-Alder reaction. For this purpose, 3-methylsulfanyl-1,2,4-triazines were reacted with several nucleophiles allowing the formation of appropriately substituted alkynes to undergo the intramolecular inverse electron demand Diels-Alder reaction. Sealed-tube microwave activation of the cycloaddition reaction has proved to be very efficient and allowed shorter reaction times. This strategy enabled an efficient synthesis of 3-hydroxy-2,3-dihydrofuro[2,3-b]pyridines and 4-hydroxy-3,4-dihydro-2H-pyrano[2,3-b]pyridines with several points of diversity on the bicyclic scaffold.     

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 of pyridazino[3,4-b]quinoxalines and pyrazolo[3,4-b]-quinoxaline by 1,3-dipolar cycloaddition reaction

The pyridazino[3,4-b]quinoxalines 6a,b and pyrazolo[3,4-b]quinoxaline hydrochloride 9 were synthesized by the 1,3-dipolar cycloaddition reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 5 with dimethyl or diethyl acetylenedicarboxylate and 2-chloroacrylonitrile, respectively. The reaction mechanisms were postulated for the formation of 6a,b and 9 .