A convenient synthesis of pyrazolo[3,4‐d]pyrimidine‐4,6‐dione and pyrazolo[4,3‐d]pyrimidine‐5,7‐dione derivatives

Pyrazolo‐[3,4‐d]pyrimidine‐4,6‐diones 5 and pyrazolo[4,3‐d]pyrimidine‐5,7‐diones 7 were synthesized by Curtius rearrangement of pyrazolic mono‐esters 2 and 3 followed by hetero‐cyclization via the ureas derivatives 4 and 6 under alkaline conditions.     

A stacked pyrazolo[3,4‐d]pyrimidine‐based flexible molecule: the effect of a bulky benzyl group on intermolecular stacking in comparison with methyl and ethyl groups

In the crystal structure of 1,1′‐(1,3‐propane­diyl)­bis(5‐benzyl‐6‐methyl­sulfanyl‐4,5‐di­hydro‐1H‐pyrazolo­[3,4‐d]­pyrimidin‐4‐one), C₂₉H₂₈N₈O₂S₂, the pairs of pyrazolo­[3,4‐d]­pyrimidine rings stack as a result of intramolecular π–π interactions between the heterocyclic rings. The folded mol­ecules are further stacked in pairs, due to intermolecular aromatic π–π interactions and C—H?O hydrogen bonds.     

Disappearance of intramolecular stacking due to one‐atom movement or increment of a `propyl­ene linker' in pyrazolo­[3,4‐d]­pyrimidine‐based ­flexible models

In the crystal structures of 4,6‐di­methyl­thio‐1‐[3‐(4,6‐di­methyl­thio‐2H‐pyra­zolo­[3,4‐d]­py­rimi­din‐2‐yl)­propyl]‐1H‐py­ra­­zolo­[3,4‐d]­py­rimi­dine, C₁₇H₂₀N₈S₄, and 1‐[4‐(4‐meth­oxy‐6‐methyl­thio‐1H‐pyra­zolo­[3,4‐d]py­rimi­din‐1‐yl)­butyl]‐5‐meth­yl‐6‐methyl­thio‐4,5‐di­hydro‐1H‐pyra­zolo­[3,4‐d]py­rimi­din‐4‐one, C₁₈H₂₂N₈O₂S₂, only intermolecular stacking due to aromatic π–π interactions between pyrazolo­[3,4‐d]­pyrimidinerings is present.     

Synthesis of trifluoromethylated pyrido[2,3‐d]pyrimidine‐2,4‐diones from 6‐aminouracils and trifluoromethylated pyrazolo[3,4‐b]‐pyridines from 5‐aminopyrazoles

5 or 7‐Trifluoromethyl‐1,2,3,4‐tetrahydropyrido[2,3‐d]pyrimidine‐2,4‐diones 3 , 5 , 10 , 13 and 4‐ or 6‐trifluoromethylpyrazolo[3,4‐b]pyridines 15 , 16 , 19 , 21 were prepared from 6‐aminouracils and 5‐aminopyrazoles, respectively, in good yields by the use of building blocks such as 4,4,4‐trifluoro‐1‐phenyl‐1,3‐butanedione, 1,1,1‐trifluoro‐4‐phenyl‐3‐buten‐2‐one, 4‐ethoxy‐1,1,1‐trifluoro‐3‐buten‐2‐one, and ethyl trifluoroacetoacetate.     

A stacked pyrazolo­[3,4‐d]­pyrimidine‐based flexible mol­ecule: the effect on stacking of a bulky iso­propyl group in comparison with a methyl/ethyl group

In the crystal structure of 1,3‐bis(4,6‐diiso­propyl­sulfanyl‐1H‐pyrazolo­[3,4‐d]­pyrimidin‐1‐yl)­propane, C₂₅H₃₆N₈S₄, the pairs of pyrazolo­[3,4‐d]­pyrimidine rings in the mol­ecule stack as a result of intramolecular π–π interactions between the heterocyclic rings. The crystal packing also exhibits an intermolecular C—H...π interaction between one methyl group of an iso­propyl group and a pyrazolo­[3,4‐d]­pyrimidine ring.     

Synthesis of new pyrazolo[1,5‐a]pyrimidines and pyrazolo[3,4‐b]pyridines

While 3(5)‐aminopyrazole reacts with enaminonitrile to yield pyrazolo[1,5‐a]pyrimidines, 3‐amino‐5‐pyrazolone reacts with the same reagents to yields pyrazolo[3,4‐b]pyridines.     

Regioselective synthesis of some novel pyrazoles,isoxazoles, pyrazolo[3,4‐d]pyridazines and isoxazolo[3,4‐d]pyridazines pendant to benzimidazole

2‐Acetyl‐1‐methyl‐1H‐benzimidazole reacts with dimethylformamide‐dimethyl‐acetal (DMF‐DMA) to afford the corresponding E‐1‐(1‐methyl‐1H‐benzimidazol‐2‐yl)‐3‐N,N‐dimethylaminoprop‐2‐enone. The latter compound reacts regioselectively with some nitrilimines and nitrile oxides to afford the corresponding pyrazole and isoxazole derivatives, respectively. These reaction products react with hydrazine hydrate to give the novel pyrazolo[3,4‐d]pyridazine and isoxazolo[3,4‐d]pyridazine derivatives, respectively.     

One pot syntheses of thiazol‐2‐hydrazone,pyridino[2,3‐d]pyridazine,pyrazolo[3,4‐d]pyridazine,and isoxazolo[4,5‐d]pyridazine derivatives

Reactions of the pyridazine derivatives 1a–c with phenyl isothiocyanate followed by heterocyclization with ethyl chloroacetate gave the thiazolidinone derivatives 6a–c . The reactivity of 6a towards some chemical reagents was studied. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:258–262, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10026     

Three‐Component Synthesis of Spiro[indoline‐3,4′‐pyrazolo[3,4‐b]pyridines] under Microwave Irradiation

A domino three‐component strategy with high efficiency for the synthesis of spiro[indoline‐3,4′‐pyrazolo[3,4‐b ]pyridines] from easily available isatins, pyrazol‐5‐amines and β‐ketonitriles under microwave heating. During reaction process, HOAc plays dual roles as reaction media as well as a Brønsted acid‐promoter. Flexible structural modification, broad functional group compatibility and mild reaction conditions make this strategy a useful and attractive process of library generation for drug discovery.     

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 novel pyrazolo[3,4‐d]pyridazine,pyrido[1,2‐a]benzimidazole,pyrimido[1,2‐a]benzimidazole and triazolo[4,3‐a]pyrimidine derivatives

4‐Acetyl‐5‐methyl‐1‐phenyl‐1H‐pyrazole reacts with dimethylformamide dimethylacetal (DMF‐DMA) to afford the corresponding (E)1‐(5‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)‐3‐(N,N‐dimethylamino)‐2‐propen‐1‐one. The latter product undergoes regioselective 1,3‐dipolar cycloaddition with nitrilimines and nitrile oxides to afford the novel 3‐aroyl‐4‐(5‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)carbonyl‐1‐phenylpyrazole and 3‐aroyl‐4‐(5‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)carbonyl isoxazole derivatives, respectively. It reacts also with 1H‐benzimidazole‐2‐acetonitrile, 2‐aminobenzimidazole and 3‐amino‐1,2,4‐triazole to afford the novel pyrido[1,2‐a]benzimidazole, pyrimido[1,2‐a]benzimidazole and the triazolo[4,3‐a]pyrimidine derivatives, respectively. The reaction of 3‐aroyl‐4‐(5‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl) carbonyl‐1‐phenylpyrazole derivatives with hydrazine hydrate led to a new pyrazolo[3,4‐d]pyridazine derivatives.     

Studies on uracils: A facile one‐pot synthesis of pyrazolo[3,4‐d]pyrimidines

The reaction of 6‐hydrazino uracils 1 and nitrones 2 result in an efficient one‐pot synthesis of pyrazolo[3,4‐d]pyrimidines 3 in excellent yields. The isolation of the by‐product aniline from the reaction mixture supported the plausible mechanism for the formation of pyrazolo[3,4‐d]pyrimidines.     

Design,synthesis, and antimicrobial activity of some new pyrazolo[3,4‐d]pyrimidines

2‐Benzyl‐ and 2‐aryloxymethyl‐3‐amino‐1‐phenyl‐pyrazolo[3,4‐d]pyrimidine‐4‐ones 5a–f have been synthesized by reacting the corresponding arylacetylamino derivatives 3a–f with hydrazine hydrate. Thionation of compounds 5d–f by action of P₂S₅ in pyridine yielded 2‐aryloxy‐methyl‐3‐amino‐1‐pheny‐lpyrazolo[3,4‐d]pyrimidin‐4‐thions 6a–c . 2,5‐Diphenyl‐2,3‐dihydro‐1H‐pyrazolo[5′,1′:4:5]pyrazolo[3,4‐d]pyrimidine‐8‐one ( 8 ) was also obtained via reaction of ethyl‐2‐cinnamoylamino‐1‐phenyl‐pyrazole‐4‐car‐boxylate ( 7 ) with hydrazine hydrate. The prepared compounds were screened in vitro for their antimicrobial activity. Some of the tested compounds were found to be active at 100 μg/ml compared with reference compounds (Ampicillin and Trivid) as antibacterial agents and claforan as antifungal agent. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:530–534, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10187     

Synthesis of 1,4,5,6‐tetrahydropyrazolo[3,4‐d]pyrido[3,2‐b]azepine

The synthesis of 7,8‐dihydro‐5(6H)‐quinolinone ( 3 ) from commercially available 3‐amino‐2‐cyclohexen‐1‐one ( 1 ) and 3‐(dimethylamino)acrolein ( 4 ) in 23% yield avoids the preparation of propynal ( 2 ). Conversion of 5‐(4‐methylphenylsulfonyl)‐6,7,8,9‐tetrahydro‐5H‐pyrido[3,2‐b]azepine ( 12 ) to 6‐(4‐methylphenylsulfonyl)‐1,4,5,6‐tetrahydropyrazolo[3,4‐d]pyrido[3,2‐b]azepine ( 24 ) is described. Removal of the N‐(4‐methylphenylsulfonyl) group with 40% sulfuric acid in acetic acid gave the tricyclic azepine 26. Application of a similar series of reactions to 5‐(4‐nitrobenzoyl)‐6,7,8,9‐tetrahydro‐5H‐pyrido[3,2‐b]‐azepine ( 13 ) afforded 6‐(4‐nitrobenzoyl)‐1,4,5,6‐tetrahydropyrazolo[3,4‐d]pyrido[3,2‐b]azepine ( 25 ).     

An efficient synthesis of pyrazolo[3,4‐b]pyrrolo[2,3‐d]pyridines from 5‐aminopyrazoles and cyclic β‐keto ester

5‐Chloroethylpyrazolo[3,4‐b]pyridines were synthesized by condensation of 5‐aminopyrazoles with α‐acetyl γ‐butyrolactone followed by cyclization treating with phosphorous oxychloride. 5‐Chloroethyl‐pyrazolo[3,4‐b]pyridines, thus obtained, were then converted to the corresponded tricyclic pyrazolo[3,4‐b]‐pyrrolo[2,3‐d]pyridines by treating with some primary amines.     

Convenient one pot synthesis of 5‐unsubstituted pyrazolo [3,4‐c]isoquinolines

The convenient one pot synthesis of pyrazolo[3,4‐c]isoquinolines 1 from 5‐aminopyrazoles 2 and paraformaldehyde in formic or trifluoroacetic acids is described.     

Synthesis of Polysubstituted Pyrazolo[3,4‐b]pyridine‐3‐Carbohydrazide and Pyrazolo[3,4‐d]pyridazine Derivatives

5‐Amino‐4‐formyl pyrazole carboxylate gave facile reactions with malononitrile, hydrazine, and ketones in the presence of piperidine furnished substituted pyrazolo[3,4‐b]pyridines and pyrazolo[3,4‐b]quinolones. The pyridazine sulfonamides were obtained by the reaction of 5‐chloro 4‐formyl pyrazole carboxylate with sulfonamide derivatives.