Synthesis,structure, and properties of pyrazolo[4,3-b]quinuclidine derivatives

It was shown by means of ¹H and ¹³C NMR spectroscopy that the reaction of 2-arylmethylene-3-oxoquinuclidines with hydrazine hydrate gives 4a-hydroxy-7-aryl-4a,5,7,7a-tetrahydropyrazolo[4,3-b]quinuclidines, which are stable in the crystalline state but undergo dehydration to the corresponding 7-aryl-6H-7,7a-dihydropyrazolo[4,3-b]quinuclidines in solutions. The latter undergo cleavage to 3-(4-piperidyl)-5-arylpyrazoles when they are heated in an alkaline medium.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1248–1256, September, 1985.     

A Novel Synthesis of 3,4-Discubstituted-1H-pyrazolo[3,4-b]quinolines

A simple and efficient synthesis of pyrazolo[3,4-b] quinolines is described. The synthesis involves reaction of 2-amino-3-cyanoquinoline-4-carboxylates(1) with hydrazine hydrate to give regioselectively only pyrazolo[3,4-b]quinolines (2). No formation of pyridazino quinolines (3) is observed.     

Reactions of nucleophilic substitution of 4-aryl-5-carbomethoxy-6-methyl-2-chloro-3-cyanopyridines

Methods of synthesis of 5-carbomethoxy-substituted pyrazolo[3,4-b]pyridines and 3H-imidazo[4,5-b]pyridines by their reaction with hydrazine hydrate or as a result of Hofmann rearrangement of the corresponding 2-aminopyridines were developed based on 4-aryl-3-carbamoyl(or cyano)-5-carbomethoxy-6-methyl-2-chloropyridines.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.12, pp. 1646–1650, December 1992.     

PYRAZOLONES AS VERSATILE PRECURSORS FOR THE SYNTHESIS OF FUSED AND BINARY HETEROCYCLES

The reaction of pyrazolone bearing a β-ketoester moiety with aliphatic dibasic functional reagents in ethanol afforded the binary ring heterocycles 2, 6, and 10. Whereas, when using an excess of the dibasic reagent, the dipyrazolo [3,4-c: 3′, 4′-f] [1,2]diazepine derivative 5 was, obtained. On the other hand, when compound 1 reacted with hydrazine hydrate in acetic acid, it furnished the pyrazolo[3,4-b]pyridine derivative 7 in which the hydrazine hydrate acts as a monofunctional reagent. Also, the reaction of 1 with m-anisidine according to Knorr synthesis gave the α,β-unsaturated ketone derivative 9 in lieu of the anticipated quinolone derivative 8. Furthermore, treatment of compound 1 with aromatic dibasic functional reagents afforded 11 and 13. Eventually, compound 11 was annelated through its reaction with ammonium carbonate to give pyrazolo[3,4-b]pyrido[6,5-b]benzodiazepin 12.     

Nucleophilic substitution reactions in 2-chloropyridines and 2,5-dioxo-1,2,5,7-tetrahydro-1H-furo[3,4-b]pyridines

3-Cyano- and 3-carbamoyl-2-chloropyridines react with hydrazine hydrate to form substituted 3-amino-1H-pyrazolo[3,4-b]pyridines and 3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridines. Hydrazine hydrate reacts with 3-carbamoyl-2-chloro-5-oxo-5,7-dihydrofuro[3,4-b]pyridine to form substituted 3,5-dioxo-2,3,5,7-tetrahydro-1H-pyrazolo[3,4-b]furo[3,4-e]pyridine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1218–1222, September, 1992.     

General synthesis of: 5-substituted-3-acyl-4-carbethoxypyrazoles 3,6-subslituted-5-carbethoxy-4(h)pyridazinones and 3,7-substitutedpyrazoio[3,4-d] pyridazine-4(5h)ones via reactions between 2-hydroxy,methoxy, and acetoxy-3(2h)furanones and hydrazine

Synthesis of substituted 3-acyl-4-carbethoxypyrazoles, 5-earbethoxy-4(1H)pyridazinones and pyrazolo[3,4-d]pyridazine-4(5H)ones is described. They involve the reaction of the 2,5-substituted-4-earbelhoxy-2-hydroxy, methoxy and acetoxy-3(2H)furanones with hydrazine hydrate. The reaction was found to be dependent on the hydroxy, methoxy or acetoxy substituents of these furanones and proceeds with ring opening followed by cy clisation. Pyrazoles were formed with hydroxy or methoxy substituents while pyridazinones are afforded with acetoxy group. The pyrazoles so formed were readily converted to pyrazolo[3,4-d] pyridazinones by condensation with excess hydrazine.     

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 and reactivity of 2-(benzothiazol-2-yl)-1-bromo-1,2-ethanedione-1-arylhydrazones

The novel, highly versatile 2-(benzothiazol-2-yl)-1-bromo-1,2-ethanedione-1-arylhydrazones 3 were prepared and their behavior toward some nucleophiles was investigated. Thus, reaction of 3 with the sodium salt of malononitrile afforded the aminopyrazolecarbonitriles 5 that undergo cyclocondensation with hydrazine, formic acid, and formamide to give the corresponding pyrazolo[3,4-d]pyridazine 6, pyrazolo[3,4-d]pyrimidinone 7, and pyrazolo[3,4-d]pyrimidine 8 derivatives, respectively. Similarly, reactions of 3 with each of acetylacetone, dibenzoylmethane, and benzoylacetonitrile afforded the corresponding pyrazole derivatives 9, 10, and 11, respectively. The latter products undergo cyclocondensation with hydrazine to afford the corresponding pyrazolo[3,4-d]pyridazines 12, 13, and 14, respectively. © 1997 John Wiley & Sons, Inc.     

Synthesis,Reactions, and Characterization of 6-Amino-4-(Benzo[b]Thiophen-2-YL)-2-Thioxo-1, 2-Dihydropyridine-3, 5-Dicarbonitrile

Abstract

Benzothiophene -2- carbaldehyde 1 reacted with 2-cyanoethanethioamide 2 in 1:2 molar ratios to give the corresponding 6-amino-4-(benzo[b]thiophen-2-yl)-2-thioxo-1, 2-dihydropyridine-3,5-dicarbonitrile 6. The synthetic potentiality of compound 6 was investigated via its reaction with active halogen-containing reagents to afford the corresponding thieno[2,3-b]pyridine derivatives 11a,b, 14, 16, and 19. Also, compound 6 reacted with hydrazine hydrate to give the pyrazolo[3,4-b]pyridine derivative 21. Compound 21 condensed with 4-(2-thienyl)benzaldehyde to afford pyrazolo[3,4-b]pyridine derivative 23. Structural elucidation of all the newly synthesized heterocyclic compounds was based on elemental analyses, IR, ¹H NMR, and mass spectra.

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.     

Synthesis,reactions, and antimicrobial activity of some novel pyrazolo[3,4-d]pyrimidine,pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine,and pyrazolo[4,3-e][1,2,4]triazolo[3,4-c]pyrimidine derivatives

Treatment of N-phenyl-substituted benzenecarbo-hydrazonoyl chlorides 1a - d with malononitrile in sodium ethoxide solution gave 5-amino-4-cyanopyrazole derivatives 2 - 5 . Compounds 2 - 5 were converted to formidate derivatives 6 - 9 upon treatment with TEOF in acetic anhydride. The reaction of the latter products 6 - 9 with hydrazine hydrate gave imino-amino derivatives 10 - 13 , which was converted to hydrazino derivatives 14 - 17 by refluxing with hydrazine hydrate. Hydrazino as well as imino-amino derivatives undergo condensation, cyclization, and cycloaddition reactions to give pyrazolo[3,4-d]pyrimidine 18 - 21 , pyrazolo[4,3-e][1,2,4]triazolo-[3,4-c]pyrimidine 22 - 27 , and pyrazolo[3′,4′:4,5]pyrimido[1,6-b][1,2,4]triazine 42 - 44 derivatives. Antimicrobial studies are performed using two Gram-positive bacteria and two Gram-negative bacteria. Data indicated that compounds 5 , 28D , 29B , and 31D are exploring elevated antibacterial effects against all strains tested. Compound 28D is the most promising antibacterial agent against the delicate bacterial strain Bacillus subtilis and Pseudomonas aeruginosa with high effectiveness (low minimum inhibitory concentration [MIC] value) 40 and 60 μg/mL, respectively.     

Transformation of 6‐methylthiopyrimidines. Preparation of new pyrimidine derivatives and fused azolopyrimidines

2,4‐Diamino‐6‐methylthiopyrimidines 1 reacted with sodium methoxyde and benzylamine to give the corresponding 6‐methoxypyrimidine and 6‐benzylaminopyrimidine derivatives 2 and 4 respectively. The reaction of 1 with hydrazine hydrate, in ethanol, gave 6‐hydrazino derivatives 6. However, by treating pyrimidines 1 in boiling hydrazine hydrate 3,6‐diamino‐4‐hydrazino‐1H‐pyrazolo[3,4‐d]pyrimidine 5 was obtained. The 6‐hydrazinopyrimidines 6 could be converted into the pyrazolo[3,4‐d], triazolo[4,3‐c] and tetrazolo‐[1,5‐c]pyrimidines 7, 8 and 9 by the action of heating, trimethyl orthoformate and nitrous acid, respectively.     

Studies on the reactions of cyclic oxalyl compounds with hydrazines or hydrazones : Synthesis and reactions of 4‐benzoyl‐1‐(3‐nitrophenyl)‐5‐phenyl‐1H‐pyrazole‐3‐carboxylic acid

The 1H‐pyrazole‐3‐carboxylic acid 2 , obtained from the furan‐2,3‐dione 1 and N‐Benzylidene‐N'‐(3‐nitrophenyl) hydrazine, was converted via reactions of its acid chloride 3 with various alcohols or N‐nucleo‐philes into the corresponding ester or amide derivatives 4 or 5 , respectively. Nitrile 6 and anilino‐pyrazole acid 7 derivatives of 2 were also obtained by dehydration of 5a in a mixture of SOCl₂ with DMF and reduction of 2 with sodium polysulphide, respectively. While cyclocondensation reactions of 2 or 7 with phenyl hydrazine or hydrazine hydrate and 6 with only anhydrous hydrazine lead to derivatives of pyrazolo[3,4‐d]‐pyridazinone 8 and pyrazolo[3,4‐d]pyridazine amine 9 , respectivel. The reaction of 2 with 2‐hydrazinopyri‐dine provided hydrazono‐pyrazole acid derivative 10 , which was decarboxylated to give hydrazono‐pyra‐zole derivative 11 . Pyrazolo[4,3‐d]oxazinone 12 and 2‐quinolyl pyrazolo[3,4‐d]pyridazine 13 derivatives were also prepared by cyclocondensation reactions of 2 with hydroxylamine hydrochloride and 7 with acetaldehyde, respectively.     

Synthesis, reactions and biological activity of 2-substituted 3-cyano-4,6-dimethylpyridine derivatives

The reaction of 2-chloro-4,6-dimethylpyridine-3-carbonitrile with hydrazine hydrate, hydroxylamine, and anthranilic acid afforded the corresponding pyrazolo, isoxazolo, and pyridoquinazoline derivatives. Alkylation of 2-mercapto-4,6-dimethylpyridine-3-carbonitrile with ethyl chloroacetate or phenacyl bromide followed by cyclization in NaOH gave thienopyridine derivatives. Diazotization of ethyl 3-amino-4,6-dimethylthiеno[2,3-b]pyridine-2-carboxylate followed by the reaction with thiourea, guanidine carbonate, and hydroxylamine hydrochloride gave the corresponding thienopyridine derivatives. The biological activity of some new compounds has been discussed. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 43–51, Januar, 2009.     

3-Formylchromones IV. The rearrangement of 3-formylchromone enamines as a simple, facile route to novel pyrazolo[3,4-b]pyridines and the synthetic utility of the latter

One-pot and facile preparations of 6-(2-hydroxy-5-R-benzoyl)-4-methyl-2-R1- pyrazolo[3,4-b]pyridines 4a-o are described, using the reaction of 3-formyl chromones 1 with 5-amino-1-R1-pyrazoles 2. An enamine-intermediate 2-ethyloxy-6-R-3-(3-methyl-1- phenylpyrazol-5-ylaminomethylene)chroman-4-one 3 was isolated at lower temperatures. Acyloxy-derivatives 5 of compounds 4 were obtained by acylation with acid chlorides or acid anhydrides. Coumarins 6 substituted at the 3- and 4-positions were prepared from the pyrazolo[3,4-b]pyridines 4 by condensation reactions and hydrazones 7 were formed from their reaction with 2,4-dinitrophenyl hydrazine. Reactions under microwave irradiation proceeded significantly faster and with high yields.     

Aminoethyl derivatives of 4-substituted pyrazolo[3,4-d]pyrimidines

New 3-aminoethyl derivatives of pyrazolo[3,4-d]pyrimidine were synthesized by reduction of 3-cyanomethylpyrazolo[3,4-d]pyrimidines with hydrazine hydrate in the presence of Raney nickel in alcohol.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 846–847, June, 1972.     

Synthesis and properties of 2-ethoxycarbonyl-3-amino-2,3-dehydroquinuclidine

The reduction of 2-ethoxycarbonyl-3-oxoquinuclidine oxime hydrochloride leads to 2-ethoxycarbonyl-3-amino-2,3-dehydroquinuclidine, from which pyrimido[5,4-b]quinuclidine derivatives were obtained by reaction with formamide, methyl isocyanate, and phenyl isothiocyanate. It is shown that 7-hydroxypyrazolo[4,3-b]quinuclidine is formed in the reaction of 2-ethoxycarbonyl-3-acetamido-2,3-dehydroquinuclidine with hydrazine hydrate.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 971–974, July, 1983.     

Reactions of 2-aryl (hetaryl) methylene-3-oxoquinuclidines with bifunctional nucleophilic reagents

The reactions of 2-aryl(hetaryl)methylene-3-oxoquinuclidines with hydrazine hydrate, thiourea, and phenylhydrazine gave, respectively, 7-phenyl-7,7a,dihydropyrazolo[3,4-b]quinuclidine, 7-(4-methoxyphenyl)-7,7a-dihydropyrazolo[3,4-b]quinuclidine, 7-(2-thienyl)-7,7a-dihydropyrazolo-[3,4-b]quinuclidine, 3,3-azinobis (2-benzylidenequinuclidine), 3,3-azinobis[2-(4-methoxybenzylidene)quinuclidine], 6-thio-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-b]quinuclidine, 2-benzylidene -3-oxoquinuclidine phenylhydrazone, and 2-(4-methoxybenzylidene)-3-oxoquinuclidine phenylhydrazone. The structures of the compounds were confirmed by the IR and ¹H and ¹³C NMR spectra.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 793–797, June, 1982.     

Efficient Protocol for Synthesis of Pyrazolo[3,4-a]acridines

A new class of pyrazolo[3,4-a]acridines have been prepared. The synthon acridones were obtained in very good yield by a one-pot reaction of 2-amino-5-chloro or nitro substituted benzophenones with 1,3-cyclic diketones in the presence of freshly prepared Eaton’s reagent without solvent, using Friedländer synthesis. The intermediates were reacted with ethylformate followed by hydrazine hydrate to afford pyrazolo[3,4-a]acridines. All of the compounds were purified by recrystallization only, and no chromatographic workup was required. The structures of the synthesized compounds were deduced by spectroscopic techniques, including single-crystal x-ray diffraction.     

New heterocyclic syntheses from hydrazidoyl halides. Convenient syntheses of fused pyrimidines,pyridazines, and quinazolines

Aminocyanopyrazole derivatives and pyrazolo[2,3-a]quinazolones were obtained in good yields from hydrazidoyl halides and malononitrile. Pyrazolo[3,4-d]pyridazine and pyridazo[4′,5′: 1,2]pyrazolo[1,5-a]quinazoline derivatives were synthesized in quantitative yields by reaction of hydrazine hydrate with 2 and 16 , respectively. A novel ring system, a 3-substituted tetrahydro derivative of 7-oxo-6H,8H-pyridazo[3′,4′,5′-c'd']-pyrazolo[3,4-d]pyrimidine was prepared by reaction of 6 with dimethyl carbonate. Pyrazolo[3,4-d]pyrimidine-4,6-dithiones were obtained in good yields by reaction of 2 with carbon disulfide. The structures of the products were assigned and confirmed on the basis of their elemental analyses, spectral data, and alternate synthesis wherever possible. The structures of the parent fused heterocyclic systems discussed in this work are summarized in Scheme 1 .     

Reactions of 3-aroylacrylates with α-aminoazoles*

Dihydro derivatives of pyrazolo[3,4-b]pyridine-, pyrazolo[1,5-a]pyrimidine-, and [1,2,4]triazolo-[1,5-a]pyrimidinecarboxylates have been prepared by cyclocondensation of β-aroylacrylates with 5-aminopyrazoles and 3-amino-1,2,4-triazole. Heating dihydro[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylates with hydrazine hydrate led to recyclization of the pyrimidine ring to form 6-arylpyridazin-3(2H)-ones.