Synthetic utility of a heterocyclic o-aminoaldehyde: synthesis of pyrazolopyridopyrimidines, pyrazolonaphthyridines, and pyrazolopyrimidonaphthyridinones

Abstract  

A series of various polysubstituted pyrazolo[3,4-h][1,6]naphthyridines, benzo[b]pyrazolo[3,4-h][1,6]naphthyridines, and pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidines were synthesized by Friedl?nder condensation of 4-amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (o-aminoaldehyde) with active methylene compounds. The o-aminoaldehyde was functionalized to o-aminonitrile and o-aminocarboxamide with malononitrile and cyanoacetamide, respectively, which on condensation with monosubstituted ureas and acetic anhydride, respectively, afforded pyrazolo[3,4-h]pyrimido[4,5-b][1,6]naphthyridines.     

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.     

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.     

Beiträge zur Chemie der Enaminoketone, 2. Mitt.: Darstellung von Pyrazolo-pyridinen aus Enaminoketonen

Zusammenfassung Es wird über die Verwendung von Enaminoketonen zur Synthese von Pyrazolo[3,4-b]pyridinderivaten aus Aminopyrazolen berichtet. Mit Aminomethylencyclohexanon wird ein Pyrazolo[3,4-c]isochinolin erhalten. IR- und NMR-Spektren sowie Vergleiche mit bereits bekannten Substanzen bestätigen die Strukturen.

---

The application of enaminoketones in the synthesis of pyrazolo[3,4-b]pyridine derivatives from aminopyrazoles is reported. With aminomethylenecyclohexanone a pyrazolo[3,4-c]isoquinoline is obtained. The structures are proofed by IR- and NMR-spectra and by comparison with known substances.

     

Convenient regioselective reaction in presence of H<Subscript>3</Subscript>PW<Subscript>12</Subscript>O<Subscript>40</Subscript>: synthesis and characterization of pyrazolo[3,4-<Emphasis Type="Italic">b</Emphasis>]quinoline-3,5-diones

We describe regioselective synthesis of pyrazolo[3,4-b]quinoline derivatives by multicomponent reaction of dimedone, 5-aminopyrazolone, and aromatic aldehydes in presence of H₃PW₁₂O₄₀ as catalyst. When this multicomponent reaction was investigated without catalyst under reflux conditions, a mixture of products was obtained, while the reaction successfully proceeded to formation of pyrazolo[3,4-b]quinoline in presence of H₃PW₁₂O₄₀. Good product yield, short experimental time, and low-cost catalyst provide convenient synthesis for formation of pyrazolo[3,4-b]quinoline pharmacological compounds.     

Synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines

Starting from 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones, a synthesis pathway to the tricyclic pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines is described. Reaction of 1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-ones with phosphoryl chloride afforded the corresponding 4-chloro-1H-pyrazolo[3,4-d]pyrimidines. Treatment of these compounds with hydrazine hydrate at reflux temperature gave the hydrazino derivatives, which were subsequently cyclized to the titled compounds on heating with orthoesters in ethanol.     

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.     

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 of pyrazolo[4,3-<Emphasis Type="Italic">e</Emphasis>][1,2,4]triazolo[4,3-<Emphasis Type="Italic">c</Emphasis>]pyrimidines

Starting from 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones, a synthesis pathway to the tricyclic pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines is described. Reaction of 1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-ones with phosphoryl chloride afforded the corresponding 4-chloro-1H-pyrazolo[3,4-d]pyrimidines. Treatment of these compounds with hydrazine hydrate at reflux temperature gave the hydrazino derivatives, which were subsequently cyclized to the titled compounds on heating with orthoesters in ethanol. Correspondence: Abolghasem Davoodnia, Department of Chemistry, School of Sciences, Islamic Azad University, Mashhad Branch, Mashhad 91735-413, Iran.     

A Versatile Synthesis,PM3‐Semiempirical,Antibacterial, and Antitumor Evaluation of Some Bioactive Pyrazoles

This research work describes the synthesis and biological properties of some novel isolated or fused heterocyclic ring systems with pyrazole, for example; enaminones containing pyrazolone ring photochromic functional unit, 4‐[(4‐chlorophenylamino)methylene]‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐5(4H)‐one (3) and some analogous derivatives 4, 9, and 10, also as pyrazolo[3,4‐b]pyridine, pyrazolo[3,4‐b]quinoline, pyrazolo[3′,4′:4,5]thieno[2,3‐c]pyrazoline and pyrazolo[3,4‐c]pyrazole were synthesized and characterized. Newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, mass spectral data and quantum mechanical calculations. Selected products were tested for their antibacterial and antitumor agents.     

Synthesis,Reactions, and Pharmacological Evaluations of Some Novel Pyridazolopyridiazine Candidates

Herein, we report the synthesis, characterization, and preliminary pharmacological activity of a new series of substituted pyrazolopyridazine derivatives. Compound 1 was reacted with ethoxymethylene malononitrile 2 in refluxing ethanol to give the corresponding compound 3 , which was treated with hydrazine hydrate or formamide to give pyrazolo[3,4‐c]pyrazole 4 and pyrazolo pyrimidine 5 derivatives, respectively. Also, compound 3 was reacted with NH₄SCN or carbon disulphide or ethyl acetoacetate to yield the corresponding pyrazolo derivatives 6 , 7 , 8 , respectively. Additionally, compound 3 was reacted with triethyl orthoformat in acetic anhydride to give 9 , which was treated with hydrazine hydrate to give hydrazino derivative 10 . The latter compound transformed into the pyrazolo[4,3‐e][1,2,4]triazolo[1,5‐c]‐pyrimidine 11 via refluxing with acetic anhydride. Finally, compound 9 was reacted with benzoic acid hydrazide or mercapto acetic acid to give compounds 12 and 13 , respectively. The latter compound was treated with refluxing ethanolic sodium ethoxide solution to afford the pyrazolothiazolopyrimidine 14 . Some of the compounds exhibited better activities as anti‐inflammatory and antimicrobial agents than the reference controls. The detailed synthesis, spectroscopic data, anti‐inflammatory, and antimicrobial activities of the synthesized compounds was reported.     

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.     

Cyclic guanidines: Synthesis of 4,6,7,8-tetrahydro-1H-imidazo[1,2-a]pyrazolo[3,4-d]pyrimidin-7-ones and 1,4,6,7,8,9-hexahydropyrazolo[3′,4′:4,5]pyrimido[2,1-c] [1,2,4]triazin-7-ones

The synthesis of potential platelet aggregation inhibitors 4,6,7,8-tetrahydroimidazo[1,2-a]pyrazolo[3,4-d]-pyrimidin-7-ones and 1,4,6,7,8,9-hexahydropyrazolo[3′,4′:4,5]pyrimido[2,1-c] [1,2,4]triazin-7-ones derivatives is described starting from 4,6-dichloropyrazolo[3,4-d]pyrimidines.     

Synthesis of derivatives of pyrazolo[1,5-a]pyrrolo[1,2-c][1,3,6]-benzotriazocine,a new class of compounds with potential CNS activity

The synthesis of derivatives of pyrazolo[1,5-a]pyrrolo[1,2-c][1,3,6]benzotriazocine was obtained by the reaction of arylaldehydes with some 1-(2-aminophenyl)-5-(pyrrol-1-yl)pyrazoles, as hydrochlorides. Characterization of this new class of compounds was effected with ir, pmr and ¹³C nmr spectral data.     

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.     

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 ad Some Conversions of Partially Hydrogenated 1-Aminopyrano(thiopyrano)[4,3-d]pyrazolo[3,4-b]pyridines and Pyrazolo[3,4-c]isoquinolines

We have synthesized derivatives of pyrano(thiopyrano)[4,3-d]pyrazolo[3,4-b]pyridine and pyrazolo[3,4-c]isoquinoline, and we have also carried out some conversions with them.     

A new method for the synthesis of novel 6-quinoxalinylpyrazolo[5,1-c][1,2,4]triazines

The reaction of the quinoxaline 1 with 4-ethoxycarbonyl-1H-pyrazole-5-diazonium chloride 7 at room temperature gave 3-[α-(4-ethoxycarbonyl-1H-pyrazol-5-ylhydrazono)methoxycarbonylmethyl]-2-oxo-1,2-dihydroquinoxaline 8. The pmr spectrum of 8 in deuteriodimethylsulfoxide supported the presence of two tautomers 8-I and 8-II. Refluxing of 8 in N,N-dimethylformamide or acetic acid resulted in cyclization to afford 8-ethoxycarbonyl-4-oxo-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)-1,4-dihydropyrazolo[5,1-c][1,2,4]triazine 9. Compound 9 was also obtained directly by the reaction of 1 with 7 under reflux in better yield. The reaction of 9 with hydrazine hydrate provided the hydrazinium salt 10 , while the reactions of 9 with triethyl and trimethyl orthoformates in the presence of 1,8-diazabicyclo[5,4,0]-7-undecene produced 8-ethoxycarbonyl-4-ethoxyl-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)pyrazolo[5,1-c][1,2,4]triazine 11a and 8-ethoxycarbonyl-4-methoxyl-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)pyrazolo[5,1-c][1,2,4]triazine 11b , respectively. The chlorination of 11a with phosphoryl chloride gave 3-(3-chloroquinoxalin-2-yl)-8-ethoxycarbonyl-4-ethoxylpyrazolo[5,1-c]-[1,2,4]triazine 12 , whose reaction with morpholine afforded 8-ethoxycarbonyl-4-ethoxyl-3-[3-(morpholin-4-yl)-quinoxalin-2-yl]pyrazolo[5,1-c][1,2,4]triazine 13.     

Synthesis and in vitro anticancer activity of pyrazolo[1,5-a]pyrimidines and pyrazolo[3,4-d][1,2,3]triazines

A novel series of pyrazolo[1,5-a]pyrimidines 14a–j and pyrazolo[1,5-a]quinazolines 18a, b were synthesized via condensation of 5-amino-1H-pyrazoles 10a, b with 3-(dimethylamino)-1-aryl-prop-2-en-1-ones 11a–e and 2-((dimethylamino)methylene)-5,5-dimethylcyclohexane-1,3-dione (15), respectively, in glacial acetic acid. Finally, treatment of 10a, b with sodium nitrite (NaNO₂) afforded pyrazolo[3,4-d]triazines 20a, b. Structures of compounds were confirmed by their spectral data. These compounds were screened for their in vitro cytotoxic activities against human cancer cell lines (HepG-2 and MCF-7) using 3-[4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The results reveal that, the compounds 14b and 14h were the most potent in comparison with doxorubicin. The structure–activity relationship was discussed.     

Synthesis of some novel pyrazolo[1,5-a]quinazolines and their fused derivatives

New pyrazolo[1,5-a]quinazoline-3-carbonitriles 4a,b were obtained via cyclocondensation of 5-amino-3-cyanomethyl-1H-pyrazole-4-carbonitrile (1) with enaminones of 1,3-cyclohexanedione derivatives 2a,b in refluxing glacial acetic acid. Condensation of compounds 4a,b with various aromatic aldehydes furnished the corresponding arylidene derivatives 6a–j. On the other hand, condensation of 4a,b with o-hydroxybenzaldehydes yielded the polyheterocyclic compounds 10a–h. Coupling of compounds 4a,b with aryldiazonium chlorides led to formation of 2-arylhydrazono derivatives 12a–h. Also, reaction of compounds 4a,b with phenyl isothiocyanate, followed by addition of ethyl chloroacetate and chloroacetonitrile, afforded the polyheterocyclic compounds based on pyrazolo[1,5-a]quinazoline core. The reaction of compounds 4a,b with phenyl isothiocyanate and elemental sulfur gave the thiazole-2-thione derivatives 25a,b. The reaction of enamines of compounds 4a,b with each of hydrazine hydrate and guanidine hydrochloride afforded pyrazolo[4″,3″:5′,6′]pyrido[4′,3′:3,4]pyrazolo[1,5-a]quinazolin-8-ones 30a,b and pyrimido[5″,4″:5′,6′]pyrido[4′,3′:3,4]pyrazolo[1,5-a]quinazolin-9(10H)-ones 33a,b, respectively. The structures of all the newly synthesized compounds were elucidated by elemental analyses and spectral data. The plausible mechanisms have been postulated to account for their formation.