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.     

SOME MONOCYCLIC AND SPIROCYCLIC FLUOROPHOSPHORANES CONTAINING 6- AND 7-MEMBERED RINGS

Abstract

The reaction of 2,2-dimethyl-(1,8-naphtho[c,d])-1,3,2-dioxysilenin (3) and 2,2-dimethyldibenzo-1,3,2-dioxysilepin (4) with (C₆H₅)₂PF₃ gave the expected monocyclic fluorophosphoranes. Reaction of the same siloxy compounds with PF₅ gave products which could not be purified but whose ¹⁹F nmr spectra suggested that the desired spirocyclic compounds were present in the impure products. Reaction of the siloxy compounds with C₆H₅PF₄ did not yield identifiable products. The ¹⁹F nmr spectra of the products obtained are discussed and structures are tentatively assigned.     

Synthesis and Antitumor Evaluation of Some Newly Synthesized Pyrazolopyrimidine and Pyrazolotriazolopyrimidine Derivatives

A series of novel pyrazolo[3,4-d]pyrimidine 2b, 3, 5b, pyrazolotetrazolopyrimidine 4, and pyrazolotriazolopyrimidine derivatives 6a,b–10a,b have been synthesized and characterized by elemental analysis and spectroscopic data. Furthermore, the cytotoxicity and in vivo antitumor evaluation of some prepared compounds have been assessed, and derivatives 1a and 6b revealed promising activity in comparison to that of Cisplatin.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Radioprotective and Antitumor Activity of Some Novel Amino Acids and Imidazoles Containing Thieno[2,3-d]pyrimidine Moiety

A variety of novel thieno[2,3-d]pyrimidine derivatives, comprising amino acids 3a–l, imidazothieno-pyrimidines 4A, 4b–h, and 7, were obtained via the reaction of 4-chloro-5,6-dimethylthieno[2,3-d]pyrimidine 1 with a variety of reagents. The structures of these compounds were confirmed by microanalysis, IR, ¹H NMR, and mass spectrometry. Some of the obtained compounds showed promising radioprotective and antitumor activities.     

Synthesis of Some Novel Fluorinated Pyrazolo[3,4‐b]Pyridines

Abstract

Reaction of 5‐amino‐3‐substituted pyrazoles (1a–c) and 5‐amino‐1,3‐disubstituted pyrazoles (1d–i) with fluorinated‐β‐diketones (2) results in the formation of the single isomer of pyrazolo[3,4‐b]pyridines (4a–h). A one‐pot procedure for the synthesis of title compounds starting from α‐cyanoacetophenones along with a possible mechanistic pathway for the formation of the title compounds is described.     

Studies in the Vilsmeier-Haack reaction,part VII: Synthesis and reaction of 3-methyl-1-phenyl-4-acetyl hydrazono 2-pyrazoline-5-one(-5-thione)

Summary The keto (thio) tautomers1–4 of the hydrazono pyrazolone, thiopyrazolone derivatives underwent simultaneous diformylation, chlorination (desulphurization) and ring closure under Vilsmeier reaction conditions giving the pyrazolo[3,4-c]pyrazole aminoacroleins (5,6). Treatment of5 and/or6 with proper reagents afforded the corresponding pyrazolo[3,4-c]pyrazoles with different heterocyclic systems at the 3-position.The structures of these compounds were confirmed by elemental analysis, IR and¹H-NMR spectroscopy. All synthesized compounds have been screened in vitro for their antibacterial activities against a number of Gram-positive and Gram-negative bacteria.

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Untersuchungen zur Vilsmeier-Haack Reaktion, 7. Mitt.: Synthese und Reaktionen von 3-Methyl-1-phenyl-4-acetylhydrazono-2-pyrazolin-5-on(-5-thion)

Zusammenfassung Die Keto-(Thio)-Tautomeren1–4 der Hydrazonopyrazolon-/Thiopyrazolon-Derivate gingen unter Vilsmeier-Bedingungen zugleich Diformylierung, Chlorierung (Entschwefelung) und Ringschluß zu Pyrazolo[3,4-c]pyrazol-aminoacroleinen5 und6 ein. Aus5 und/oder6 konnten die entsprechenden Pyrazolo[3,4-c]pyrazole mit verschiedenen heterocyclischen Systemen in 3-Position erhalten werden. Die Strukturen der Verbindungen wurden mittels Elementaranalyse, IR und¹H-NMR überprüft. Alle synthetisierten Verbindungen wurden in vitro bezüglich ihrer antibakteriellen Aktivität gegenüber einer Anzahl Gram-positiver und Gram-negativer Bakterien untersucht.

     

1,3-Disubstitutedpyrazole-4-caboxaldehyde in Heterocyclic Synthesis: A Novel Synthesis of Pyridine-2(1H)-thione and Fused Nitrogen and/or Sulfur Heterocyclic Derivatives

Pyridine-2(1H)-thione 5 was synthesized from the reaction of 3-[3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl]-1-phenylpropenone (3) and cynothioacetamide (4). Compound 5 reacted with halogented compounds 6a–e to give 2-S-alkylpyridine derivatives 7a–e, which could be in turn cyclized into the corresponding thieno[2,3-b]-pyridine derivatives 8a–e. Compound 8a reacted with hydrazine hydrate to give 9. The latter compound reacted with acetic anhydride (10a), formic acid (10b), acetic acid, ethyl acetoacetate, and pentane-2,4-dione to give the corresponding pyrido[3′,2′:4,5]thieno-[3,2-d]pyrimidine 13a,b, pyrazolo[3′,4′:4,5]thieno[3,2-d]pyridine 14 and thieno[2,3-b]-pyridine derivatives 18 and 20, respectively. Alternatively, 8c reacted with 10a,b and nitrous acid to afford the corresponding pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine 24a,b and pyrido[3′,2′:4,5]thieno[3,2-d][1,2,3]triazine 26 derivatives, respectively. Finally compound 5 reacted with methyl iodide to give 2-methylthiopyridine derivative 27, which could be reacted with hydrazine hydrate to yield the corresponding pyrazolo[3,4-b]-pyridine derivative 29.     

Synthesis of some novel 5-substituted benzamido-6-arylamino-pyrazolo[3,4-D]pyrimidin-4-one derivatives for herbicidal activity

Abstract

Sixteen novel 3-methylthio-5-substituted benzamido-6-arylamino-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one derivatives (4a–p) were successfully synthesized from iminophosphoranes, aryl isocyanate, and substituted benzoylhydrazine. The structures of the title compounds were elucidated by FT-IR, ¹H NMR, ¹³C NMR, and HRMS. Herbicidal activity of the compounds 4a–p against Brassica napus (rape), Echinochloa crusgalli (barnyard grass), Cucumis sativus (cucumber), and Triticum aestivum (wheat) were determined. The results showed that 5-(2-chlorobenzamido)-6-phenylamino-3-methylthio-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4 (5H)-one (4c) displayed remarkable inhibition activity against the stalk and root of rape with 100% inhibition rate at the dosages of 10?mg/L and 100?mg/L, and 5-(4-nitrobenzamido)-6-phenylamino-3-methylthio-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4 (5H) -one (4d) exhibited excellent activity against the stalk and root of barnyard grass with 100% inhibition rate at the same dosages.     

2-HALOVINYL ARYL SULFONES: NEW COUPLING REAGENTS FOR CARBOXAMIDE FORMATION1

Abstract

E-2-Chlorovinyl p-nitrophenyl sulfone 6 and 2-bromo-2-trifluoromethylvinyl phenyl sulfone 7a reacted with carboxylic acids in the presence of a molar equiv of Et₃N affording the corresponding 2-acyloxyvinyl sulfones 8, 11, 17, 18, 22, 25, 28 and 29. The latter, on treatment with amines, gave amides 9, 13, 19, 23 and 26 and peptides 30 and 32. These reagents 6 and 7a were also used for the formation of N-methylanilides 13d, 13e, 19d, 23 and 26. Particularly, 6 was successfully used for synthesis of a macrocyclic lactam 23 involving a N-methylanilide moiety. The amidation reactions proceeded under essentially neutral conditions. Therefore, base-sensitive β-hydroxycarboxy-N-methylanilides such as 26, whose structural unit was involved in maytansine 5, could be prepared by the present method. The reagent 6 was also effective for the preparation of peptides such as Val-N-MeVal derivatives (e.g. 32), which were difficult to prepare by other methods.     

3-Aminopyrazolo[4,3-c]pyridine-4,6-dione as a precursor for novel pyrazolo[4,5,1-ij][1,6]naphthyridines and pyrido[4’,3’:3,4]pyrazolo[1,5-a]pyrimidines

The versatile, 3-aminopyrazolo[4,3-c]pyridine-4,6-dione (2) was synthesized and allowed to react with aldehydes, aryldiazonium chlorides, chalcones and enaminones to afford regioselectively the novel pyrazolo[4,3-c]pyridine derivatives 4a-c, pyrazolo[4,5,1-ij][1,6] naphthyridines 9a-d and pyrido[4’,3':3,4]pyrazlo[1,5-a]pyrimidines 19a-i. The structure of all the newly synthesized compounds was assigned from elemental analysis and spectral data. Also, the mechanistic aspects for the formation of the newly synthesized compounds is discussed.     

Synthesis and herbicidal activity of novel 6-arylthio-3-methylthio-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones

A series of pyrazolo[3,4-d]pyrimidine-4-one derivatives was conveniently synthesized via tandem aza-Wittig and annulation reactions of the corresponding iminophosphoranes, arylisocyanate, and substituted thiophenols. The structures of the target compounds were confirmed by IR, ¹H NMR, ¹³C NMR, LC-MS, and elemental analysis. The preliminary bioassay demonstrated that some title compounds such as 6-(3-chlorophenylthio)-1-phenyl-3-methylthio-5-(4-chlorophenyl)-1H-pyrazolo[3,4-d]-pyrimidin-4(5H)-one and 6-(4-fluorophenylthio)-1-phenyl-3-methylthio-5-(3-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one showed good inhibition activities against the root of Brassica napus (rape) and Echinochloa crusgalli (barnyard grass) at a dosage of 100 mg/L.     

Heterocycles from Pyrazoloylhydroximoyl Chloride: Synthesis of Certain Quinoxaline,Benzothiadiazine, Benzoxadiazine,Quinazolinone, Imidazo[1,2-a]pyridine,Imidazo[1,2-a]pyrimidine,Isoxazole, Pyrazolo[3,4-d]pyridazine and Pyrrolidino[3,4-d]isoxazolin-4,6-dione Derivatives

3-Ethoxycarbonyl-5-methyl-1-(4-methylphenyl)-4-pyrazoloylhydroximoyl chloride (1) reacted with o-phenylenediamine, o-aminothiophenol, o-aminophenol and methyl anthranilate to afford 3-nitrosoquinoxaline, benzothiadiazine, benzoxadiazine, and 3-hydroxyquinazoline, respectively. Imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine and isoxazole derivatives were obtained via the reaction of 1 with 2-aminopyridine, 2-aminopyrimidine and the appropriate active methylene compounds, respectively. Pyrazolo[3,4-d]pyridazines, and pyrrolidino[3,4-d]isoxazolines derivatives were also synthesized. The structures of the newly synthesized compounds were established on the basis of spectral data and alternate synthesis whenever possible.     

Unexpected formation of 4,5-dihydro-1H-pyrazolo[3,4-b]pyridine derivatives as a potent antitubercular agent and its evaluation by green chemistry metrics

Abstract

The present study describes L-hydroxy proline catalyzed unpredicted formation of 4,5-dihydro-1H-pyrazolo[3,4-b]pyridines instead of expected 4,7-dihydro-1H-pyrazolo[3,4-b]pyridines in aqueous ethanol at ambient temperature through one-pot three-component reaction. Furthermore, this protocol was evaluated using green chemistry metrics indicating green relevance of the present synthetic methodology. Most of the synthesized compounds were evaluated for their antitubercular activity against Mycobacterium tuberculosis H37RV strain, showing excellent results based on minimum inhibitory concentrations (MIC). Among the screened derivatives 4f, 4i, and 4j exhibited antitubercular activity with promising MIC value of 1.6?μg/mL.     

Novel Synthesis of N-Arylpyrrole,Pyrrolo[1,2-a]quinazoline,and Pyrrolo[3,4-d]pyridazine Derivatives

Phenacyl-malononitrile derivatives 1a,b react with dimethyl formamide dimethyl acetal (DMFDMA) in refluxing toluene to afford the enaminones 2a,b respectively. Compounds 2a and 2b react with the aromatic amines (aniline, p-toluidine, p-anisidine) in refluxing ethanol to afford the pyrroles 4a–f and with anthranilonitrile and methyl anthranilate to afford the pyrrolo[1,2-a]quinazolines 5a,b and 6a,b respectively. The pyrrole derivatives 4a–f react with hydrazine hydrate and phenyl hydrazine in refluxing ethanol to afford the pyrrolo[3,4-d] pyridazine derivatives 7a–f and 8a–f respectively.     

Synthesis of Fused Isolated Azoles and N-Heteroaryl Derivatives Based on 2-Methyl-3,4-dihydrothieno[3,4-d]pyrimidin-5-amine

In this work, we report the synthesis and characterization of new compounds derived from thieno[d]pyrimidines. The formation of isolated and fused thieno[d]pyrimidine derivatives was achieved via reacting 5-amino-(2-methyl)thieno[3,4-d]pyrimidin-4(3H)-one (3) with some selected reagents. The starting compound (2) was prepared in a quantitative yield using a modified procedure by conversion of the cyano group in 1 to the amide via hydrolysis using concentrated H₂SO₄. Methylthieno[3,4-d]pyrimidin-5-yl (8, 9, and 18), 3-phenylthieno[3,4-e][1,2,4]triazolo[4,3-c]pyrimidines (11–15) and tetrazolo[1,5-c]thieno[3,4-e]pyrimidine (16) have been synthesized in excellent isolated yield. The interaction of N-acetyl derivative 19 with benzaldehyde and/or some nitroso compounds afforded the chalcones and Schiff's bases derivatives 20 and 26a and c respectively. The latter compounds were used as key intermediates in the synthesis of N-acetylpyrazol-3-yl (21a and 21b), 6-phenylpyrimidine-2-(one)thione (22a and b), pyrazolo-1-carbothioamide (25), and thiazolidinone andβ β-lactam derivatives 28a and 28c and 30a and 30c respectively. The structures of these compounds were established by elemental analysis, infrared (IR), mass spectrometry (MS), and NMR spectral analysis.     

2-[4-(2-Thienyl)-1,3-thiazol-2-yl]ethanenitrile in Heterocyclic Synthesis of Biological Interist

Abstract

Thiazolylacetonitrile was used in the synthesis of coumarin, pyrazolo[4,3]pyrimidines, 1,3,4-thiadiazolines, aminothiophenes, and thiazoles in a good yields. Also, pyrazolo[4,5-d]triazolino[4,5-a]pyrimidines, pyrazolo[4,5-d]thiazolino[3,2-a]pyrimidines, and pyrazolo[4,5-d]tetrazolino[1,5-a]pyrimidines were synthesized from pyrazolo[4,5-d]pyrimidine. Structures of the newly synthesized were elucidated by elemental analysis, spectral data, and alternative synthesis routes whenever possible. Some synthesized compounds were tested for their antimicrobial activity.     

A Novel Synthesis of N-Aryl-6-methylsulfanyl-4-pyrimidinones and Purine Analogues: The Reaction of Dimethyl N-Cyanodithioiminocarbonate with Cyanoacetanilides

Abstract

A novel and efficient method for the synthesis of N-aryl-6-methylsulfanyl-4-oxopyrimidine-5-carbonitriles via the reaction of dimethyl N-cyanodithioiminocarbonate with substituted cyanoacetanilides has been investigated. (3)N-Aryl-2,5-diamino-7H-pyrazolo[3,4-d]-pyrimidin-4(3H)-one have also been prepared from the reaction of 6-sulfanylthio-N-aryl-4-pyrimidinones with hydrazines.     

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.     

A New Efficient Synthesis of 4-Alkoxy-1,6-diaryl-1H-pyrazolo[3,4-d]pyrimidine Derivatives

A new synthesis of 4-methoxy (or ethoxy)-1,6-diaryl-1H-pyrazolo[3,4-d]pyrimidine derivatives is described. An efficient one-step methodology for the title compounds was achieved by using 5-amino-1-aryl-1H-pyrazole-4-carbonitriles with arylaldehydes in CH₃OH or C₂H₅OH and NaOH at 60 °C. The new compounds were obtained in moderate to good yields as stable solids and easily purified by filtration.     

Reactions of Hydrazonoyl Halides 571: Reactions of 1‐Bromo‐2‐(5‐Chlorobenzofuranyl)Ethanedione‐1‐Phenylhydrazone

Pyrrolo[3,4‐c]pyrazole‐4,6‐diones, pyrazoles, pyrazolo[3,4‐d]pyridazines, and pyrazolo[3,4‐d]pyrimidines were prepared via 1‐bromo‐2‐(5‐chlorobenzofuran‐2‐yl)ethanedione‐1‐phenylhydrazone with N‐arylmalemides and active methylene. All newly synthesized compounds were confirmed by elemental analysis and spectral data.