Synthesis of Substituted Pyrazolo[3,4‐b]Pyridines

The synthesis of different substituted pyrazolo[3,4‐b]pyridines by the reaction of 3‐amino‐5‐chloro‐1‐phenylpyrazole‐4‐carboxaldehyde 1 as starting material with some active methylene reagents has been reported.     

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.     

Novel Bisphosphonates Derived from 1H‐Indazole, 1H‐Pyrazolo[3,4‐b]Pyridine,and 1H‐Pyrazolo[3,4‐b]Quinoline

Novel tetraethyl ethylene‐1,1‐bisphosphonate esters derived from 1H‐indazole, 1H‐pyrazolo[3,4‐b]pyridine, and 1H‐pyrazolo[3,4‐b]quinoline were synthesized by a Michael addition reaction of tetraethyl ethylidene‐1,1‐bisphosphonate with the corresponding heterocycle, using conventional heating and microwave‐assisted methods. The microwave‐assisted method provides shorter reaction times and better yields. The hydrolysis of bisphosphonates afforded the corresponding bisphosphonic acids or salt, using concentrated hydrochloric acid or TMSBr/collidine, respectively. All new compounds were fully characterized, and their structures were assigned using ¹H, ³¹P, and ¹³C NMR and IR spectroscopies and mass spectrometry. The molecular structure of compound 6 was confirmed by X‐ray diffraction studies.     

Synthesis of Newly Substituted Pyrazoles and Substituted Pyrazolo[3,4‐b]Pyridines Based on 5‐Amino‐3‐Methyl‐1‐Phenylpyrazole

The reaction of the aminopyrazole 1 with benzenesulfonyl chloride, arenediazonium salt, chloroacetyl chloride, ethoxy methyleneamlononitrile and with ethyl 2‐cyano‐3‐ethoxyacrylate gave the substituted 3‐methyl‐1‐phenylpyrazole 2–5a,b . Compound 5b was cyclized to 6 and to 7 by treating it with AlCl₃ and with POCl₃, respectively. Compound 6 converted to 7 by boiling it in POCl₃/PCl₅. Compound 10b was produced through reaction of 9 with acetophenone. Reaction of 1 with benzylidinemalononitrile afforded 11 . New methods for preparation of 15 and 16 are described. The reaction of 8 with malononitrile, thiosemicarbazide, phenyl hydrazine and acetophenone afforded compounds 18–21 . The reaction of 21 with malononitrile gave 22 . Compounds 23–26 were produced upon reaction of 10a with malononitrile, phenyl hydrazine, thiosemicarbazide, semicarbazide and with benzaldehyde, respectively.     

Facile Route to Novel Pyrazolo[3,4‐d]pyrimidine,Imidazo[1,2‐b] pyrazole,Pyrazolo[3,4‐d][1,2,3]triazine,Pyrazolo[1,5‐c][1,3,5]triazine and Pyrazolo[1,5‐c][1,3,5]thiadiazine Derivatives

A regioselective synthesis of novel pyrazolo[3,4‐d]pyrimidines, imidazo[1,2‐b]pyrazoles, pyrazolo[3,4‐d][1,2,3]triazine, pyrazolo[1,5‐c][1,3,5]triazine and pyrazolo[1,5‐c][1,3,5]thiadiazine incorporating a thiazole moiety was described via the reactions of the versatile, readily accessible 5‐amino‐3‐(phenylamino)‐N‐(4‐phenylthiazol‐2‐yl)‐1H‐pyrazole‐4‐carboxamide ( 1 ) with each of DMF‐DMA, phenylisothiocyanate, chloroacetyl chloride, phenacyl bromide, benzoylisothiocyanate and formalin, respectively. All structures of the newly synthesized compounds were elucidated by elemental analysis and spectral data.     

Synthesis of Pyrazolo[3,4‐b]pyridin‐6‐ones

The procedures for the synthesis of substituted pyrazolo[3,4‐b]pyridine‐6‐ones and some of their properties are reviewed.     

Polycyclic N‐Heterocyclic Compounds. Part 79: Synthesis of 2,4‐Disubstituted 6,7‐Dihydro‐5H‐benzo[6,7]cyclohepta[1,2‐d]pyrimidines as Potential Antiplatelet Aggregators

Libraries of tricyclic 2‐substituted 4‐alkylamino‐6,7‐dihydro‐5H‐benzo[6,7]cyclohepta[1,2‐d]pyrimidines were synthesized as part of our research to develop new effective antiplatelet drugs. Several alkyl and aryl groups were used as substituents at the 2‐position. Evaluation of the effects of the newly synthesized compounds on collagen‐induced platelet aggregation revealed several promising antiplatelet candidates with potencies superior to aspirin.     

Synthesis and biological activity of new 1H‐Pyrazolo[3,4‐b]quinoxalines (flavazoles)

A novel series of flavazoles 3a‐1 were synthesized via dehydrative cyclization of a new series of 3‐[(α‐arylhydrazono)‐aroylmethyl]quinoxalin‐2(1H)‐ones 2a‐1 and their biological activity has been evaluated. The tautomeric structure of the precursors 2a‐1 has also been elucidated.     

New Synthesis of Pyrazolo[3,4‐b][1,4,5]benzothiadiazepine, ‐[1,4,5]benzoxadiazepine, ‐[1,4,5]benzotriazepine and Pyrazolo[3,4‐b]quinoxaline Derivatives

New pyrazolo[3,4‐b][1,4,5]benzothiadiazepine and its analogues 3 have been obtained by reaction of 4‐nitrosopyrazoles 1 with 2‐aminothiophenol 2a and its analogues 2b,c . Under fused conditions, dipyrazolyl derivatives 7a was obtained with a trace amount of quinoxaline 5a . On the other hand, 5b and 7b were obtained in equal amounts. A proposed pathway is presented.     

Synthesis,Characterization, and Antioxidant Evaluation of Some Novel Pyrazolo[3,4‐c][1,2]diazepine and Pyrazolo[3,4‐c]pyrazole Derivatives

5‐Hydrazineyl‐3‐methyl‐1H‐pyrazole ( 1 ) was used as a starting material for the synthesis of novel pyrazolo[3,4‐c][1,2]diazepine derivatives 3 , 4 , and 6a,b by its reaction with acetylacetone, ethyl acetoacetate, and isatylidene derivatives 5a,b , respectively. Also, pyrazolo[3,4‐c][1,2]diazepine derivative 11 was synthesized via multicomponent reaction of 1 , benzaldehyde, and malononitrile. Moreover, compound 1 was used for synthesis novel pyrazolo[3,4‐c]pyrazole derivative 7 by its reaction with isatin. In addition, pyrazolo[3,4‐c]pyrazole derivatives 18a–c were synthesized by treatment of 2‐cyano‐N′‐(3‐methyl‐1H‐pyrazol‐5‐yl)acetohydrazide ( 13 ) with aromatic aldehydes 16a–c . The newly synthesized compounds were valeted by means of analytical and spectral data. All newly synthesized compounds were screened for their antioxidant activities. Compounds 3 , 13 , 18b , and 18c showed higher radical‐scavenging activities.     

Facile and Regioselective Synthesis of Substituted 1H‐Pyrazolo[3,4‐b]quinolines from 2‐Fluorobenzaldehydes and 1H‐Pyrazol‐5‐amines

The present article concerns the scope and limitations of the regioselective condensation of 2‐fluorobenzaldehydes with 1H‐pyrazol‐5‐amines, leading to the synthesis of substituted 1H‐pyrazolo[3,4‐b ]quinolines ( PQ ), in the presence of a base catalyst (DABCO and 2,4,6‐trimethylpyridine). A method to obtain these nitrogen heterocycles with fluorine or trifluoromethyl substituents in different positions in the carbocyclic ring was developed as a part of a systematic research on the influence of fluorine‐containing substituents on the parameters of PQ . Those compounds, characterized by high‐fluorescence intensity, have been tested as emitters for the organic light‐emitting diodes since 1997. The functionalization of PQ causes changes in various parameters, for example, HOMO and LUMO levels, which are important for the adjustment of fabricated organic light‐emitting diodes. One of the easiest methods of PQ preparation, namely, the condensation of substituted anilines with 5‐chloro‐1H‐pyrazole‐4‐carbaldehydes, is not regioselective. The method described in this study allows synthesizing of 1H‐pyrazolo[3,4‐b ]quinolines with good yields and high selectivity – only the expected isomer is obtained. As various different 2‐fluorobenzaldehydes are commercially available, and 1H‐pyrazol‐5‐amines with different substituents are easy to prepare, the method could be a good alternative to the already known procedures. All possible mechanisms of the reaction were also thoroughly studied.     

Selective Synthesis of New Tetracyclic Coumarin‐fused Pyrazolo[3,4‐b]pyridines and Pyrazolo[3,4‐b]pyridin‐6(7H)‐ones

A three‐component reaction for the synthesis of new coumarin‐fused tetracyclic system from 4‐hydroxycoumarin, aldehydes, and 5‐aminopyrazoles/5‐aminoisoxazole is described. In the presence of acetic acid, 4,7‐dihydro‐1H‐pyrazolo[3,4‐b]pyridines ( 4 ) and pyrazolo[3,4‐b]pyridines ( 5 ) were obtained in acetonitrile and dimethylsulfoxide medium, respectively. The reaction gave rise to 4,5‐dihydro‐1H‐pyrazolo[3,4‐b]pyridin‐6(7H)‐ones ( 6 ) in acetic acid–ethanol combination system, which involved the C–O bond cleavage. 4‐Hydroxy‐6‐methyl‐2H‐pyran‐2‐one and acenaphthylene‐1,2‐dione were also examined, affording the corresponding C–O bond cleavage products. Mechanism indicates that the reaction is reversible in acetic acid–ethanol combination system.     

Efficient Synthesis of 14C‐Labeled 1H‐Pyrazolo[3,4‐d]pyrimidine and Related [4.3.0]‐Bicyclic Pyrimidino Systems

In support of a research program aimed at discovering purine‐related anticancer drug candidates, a method for the ¹⁴C‐labeling of pyrazolopyrimidines utilizing the readily available labeled starting material, sodium [¹⁴C]formate, has been developed with a good overall yield. This new method was proven to be general in the preparation of other related [4.3.0]heterocycles containing N, O, and S atoms. A concise synthesis of a model compound, 8‐aza‐7‐deaza‐5′‐[¹⁴C]noraristeromycin, was achieved utilizing this methodology as a key step.     

Ionic Liquid as an Efficient Promoting Medium for Synthesis of Bis‐Pyrazolo[3,4‐b:4′,3′‐e]Pyridines

The preparation of a series of bis‐pyrazolo[3,4‐b:4′,3′‐e]pyridines by the reaction of 5‐aminopyrazole with aldehydes in ionic liquid [bmim]Br is described. This new method has the advantages of easier work‐up, milder reaction conditions, high yields and environmental friendliness compared with other methods.     

New Triheterocyclic Ring System. Synthesis of Functionalized Pyrazolo[3,4‐d]Pyrimido[1,2‐b][1,2,4,5]Tetrazine Derivatives

New functionalized pyrazolo[3,4‐d]pyrimido[1,2‐b][1,2,4,5]tetrazine derivatives 6a‐q were synthesized via reaction of the hydrazonoyl halides 1a‐q with 5‐amino‐1‐phenyl‐6‐thioxo‐pyrazolo[3,4‐d]pyrimidin‐4‐one 2 and its 2‐methylthio derivative 3 . The mechanism and the regioselectivity of the studied reactions have been discussed.     

Synthesis and Biological Activity of Some New Pyrazolo[3,4‐b]Pyrazines

New derivatives of pyrazolo[3,4‐b]pyrazine and related heterocycles were prepared starting from 6‐amino‐3‐methyl‐1‐phenyl‐1H‐pyrazolo[3,4‐b]pyrazine‐5‐carbonitrile ( 2 ) and using the key intermediates 4 , 5 , 6 , 14 , 15 and 16 . Some of the prepared compounds were evaluated for their antifungal and antibacterial activities.     

Synthesis and Properties of 2,3‐Dihydro‐1H‐corannuleno[2,3‐cd]pyridine (=2,3‐Dihydro‐1H‐dibenzo[1,10 : 6,7]fluorantheno[3,4‐cd]pyridine) Derivatives: Heterocyclic peri‐Anellated Corannulenes

The anellation of a 6‐membered ring to the 2,3‐position of corannulene (=dibenzo[ghi,mno]fluoranthene; 1 ) leads to curved aromatic compounds with a significantly higher bowl‐inversion barrier than corannulene (see Fig. 1). If the bridge is −CH₂−NR−CH₂−, a variety of linkers can be introduced at the N(2) atom, and the corresponding curved aromatics act as versatile building blocks for larger structures (see Scheme). The locked bowl, in combination with an amide bond (see 9 and 10 ), gives rise to corannulene derivatives with chiral ground‐state conformations, which possess the ability to adapt to their chiral environment by shifting their enantiomer equilibrium slightly in favor of one enantiomeric conformer. Rim annulation of corannulene seems to display a significantly lower electron‐withdrawing effect than facial anellation on [5,6]fullerene‐C₆₀‐I_h, as determined by an investigation of the basicity at the N‐atom of CH₂−NR−CH₂ (see 4 vs. 15 in Fig. 2).     

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 ).     

Efficient New Synthesis of N‐Arylbenzo[b]furo[3,2‐d]pyrimidin‐4‐amines and Their Benzo[b]thieno[3,2‐d]pyrimidin‐4‐amine Analogues via a Microwave‐Assisted Dimroth Rearrangement

A useful and rapid access to libraries of N‐arylbenzo[b]furo[3,2‐d]pyrimidin‐4‐amines ( 1 ) and their novel benzo[b]thieno[3,2‐d]pyrimidin‐4‐amine analogues ( 2 ) was investigated for the first time. Title compounds were obtained via microwave‐accelerated condensation and Dimroth rearrangement of suitable anilines with N′‐(2‐cyanaryl)‐N,N‐dimethylformimidamides obtained by reaction of benzo[b]furane and benzo[b]thiophene precursors with N,N‐dimethylformamide dimethyl acetal. This work also demonstrates that well‐controlled parameters offer comfortable use of microwave technology and are both safe and beneficial to the environment. Some products obtained in this article exhibit interesting in vitro antiproliferative effects.     

An Efficient Synthesis of Pyrazolo[3,4‐b]Pyridine Derivatives in Aqueous Media

A series of pyrazolo[3,4‐b]pyridines was synthesized by the reaction of 5‐aminopyrazole with benzylidenemalononitrile in aqueous media. The structures were characterized by IR, ¹H NMR, and elemental analysis and were further confirmed by X‐ray diffraction analysis.