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.     

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 certain pyrazolo[3,4-d]pyrimidin-3-one nucleosides

Synthesis of the pyrazolo[3,4-d]pyrimidin-3-one congeners of guanosine, adenosine and inosine is described. Glycosylation of 3-methoxy-6-methylthio-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 13 ) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose ( 16 ) in the presence of boron trifluoride etherate gave 3-methoxy-6-methylthio-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 17 ) which, after successive treatments with 3-chloroperoxybenzoic acid and methanolic ammonia, afforded 6-amino-3-methoxy-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)one ( 18 ). The guanosine analog, 6-amino-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidine-3,4(2H,5H)-dione ( 21 ), was made by sodium iodide-chlorotrimethylsilane treatment of 6-amino-3-methoxy-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)one ( 19 ), followed by sugar deprotection. Treatment of the adenine analog, 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one ( 11 ), according to the high temperature glycosylation procedure yielded a mixture of N-1 and N-2 ribosyl-attached isomers. Deprotection of the individual isomers afforded 4-amino-3-hydroxy-1-βribofuranosylpyrazolo-[3,4-d]pyrimidine ( 26 ) and 4-amino-2-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-3(7H)-one ( 27 ). The structures of 26 and 27 were established by single crystal X-ray diffraction analysis. The inosine analog, 1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidine-3,4(2H,5H)-dione ( 28 ), was synthesized enzymatically by direct ribosylation of 1H-pyrazolo[3,4-d]pyrimidine-3,4(2H,5H)-dione ( 8 ) with ribose-1-phosphate in the presence of purine nucleoside phosphorylase, and also by deamination of 26 with adenosine deaminase.     

Synthesis of new imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one derivatives by iodocyclization of 6-alkenyl(alkynyl)-aminopyrazolo[3,4-d]pyrimidin-4(5H)-ones

6-Allyl(diallyl, prop-2-yn-1-yl)amino-1-R-pyrazolo[3,4-d]pyrimidin-4(5H)-ones reacted with iodine to give angularly fused 8-iodomethyl-7,8-dihydro-1-R-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-ones which were treated with sodium acetate to obtain 8-methylidene-1-R-7,8-dihydroimidazo[1,2-a]pyrazolo-[4,3-e]pyrimidin-4(6H)-ones as a result of elimination of hydrogen iodide. 8-Methylidene-1-R-7,8-dihydroimidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-ones were converted into 8-methyl-1-R-imidazo[1,2-a]pyrazolo-[4,3-e]pyrimidin-4(5H)-ones on heating to the melting point. 8-Methylidene-1-phenyl-7,8-dihydroimidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one underwent isomerization into linearly fused 6-methyl-1-phenyl-1,8-dihydro-4H-imidazo[1,2-a]pyrazolo[3,4-d]pyrimidin-4-one on heating in sulfuric acid.     

Synthesis of 1H-pyrazolo[3,4-e]-s-triazolo[3,4-c]-as-triazines, 8H-pyrazolo[3,4-e]tetrazolo[5,1-c]-as-triazine and 1,7-dihydro-8H-pyrazolo[3,4-e]-as-triazine derivatives

3-Hydrazino-7-methyl-5-phenyl-5H-pyrazolo[3,4-c]-as-triazine 1 underwent ring closure and/or condensation reaction with formic acid, acetic acid, acetic anhydride and benzoyl chloride to afford 1H-pyrazolo-[3,4-d]-s-triazolo[3,4-c]-as-triazines 2, 5 and 7a and/or N-acyl derivatives 3, 4 and 6 . N-Acyl derivatives 3 and 6 underwent cyclisation reaction on treatment with phosphoryl chloride to give 5 and 7a . 3-Methyl-1-phenyl-8-aryl-1H-pyrazolo[3,4-e]-s-triazolo[34,-c]-as-triazines 7 were also prepared by the reaction of the hydrazono derivatives 8 wit thionyl chloride. On treatment of 1 with nitrous acid gave the 8H-pyrazolo[3,4-e]tetrazolo-[5,1-c]-as-triazine 9 . Compound 1 underwent ring closure with carbon disulphide or ethyl chloroformate to 1,7-dihydro-8H-pyrazolo[3,4-e]-s-triazolo[3,4-c]-as-triazine derivatives 10 and 12 . Reaction of 1 with ethyl acetoacetate or acetylacetone gave 3-pyrazolo derivatives 13 and 14 .     

The acid-mediated intramolecular 1,3-dipolar cycloaddition of derived 2-nitro-1,1-ethenediamines for the synthesis of novel fused bicyclic isoxazoles

The discovery of a novel synthesis of new fused bicyclic isoxazoles, for example, N-methyl-3-phenyl-5,6-dihydro-4H-isoxazolo[3,4-c]azepin-8-amine (2a), N-methyl-3-phenyl-4,5-dihydroisoxazolo[3,4-c]pyridin-7-amine (2b) and N-methyl-3-phenyl-4H-pyrrolo[3,4-c]isoxazol-6-amine (2d) in high yield is reported. We speculate that the reaction proceeds via acid-mediated intramolecular 1,3-dipolar cycloaddition from 2-nitro-1,1-ethenediamines 1a,b,d.     

Electrophilic heterocyclization of 6-alken(yn)ylsulfanyl-pyrazolo[3,4-<Emphasis Type="Italic">d</Emphasis>]pyrimidin-4(5<Emphasis Type="Italic">H</Emphasis>)-ones

6-Allylsulfanyl-1-arylpyrazolo[3,4-d]pyrimidin-4(5H)-ones react with iodine and sulfuric acid to give angular pyrazolothiazolopyrimidine derivatives. The reaction of 6-(prop-2-yn-1-ylsulfanyl)-1-(4-tolyl)-pyrazolo[3,4-d]pyrimidin-4(5H)-one with sulfuric acid gives angularly fused pyrazolo[4,3-e][1,3]thiazolo-[3,2-a]pyrimidin-4-one, whereas in the reaction with sodium methoxide linearly fused pyrazolo[3,4-d][1,3]-thiazolo[3,2-a]pyrimidin-4-one was formed. Linearly fused pyrazolo[3′,4′:4,5]pyrimido[2,1-b][1,3]thiazole derivatives were also obtained by reaction of 1-aryl-6-(3-phenylprop-2-en-1-ylsulfanyl)pyrazolo[3,4-d]pyrimidin-4(5H)-ones with sulfuric acid.     

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.     

Iodocyclization of 6-allylamino-4,5-dihydropyrazolo[3,4-d]pyrimidines

6-Allylamino-1-R-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidines treated with iodine in the presence of potassium carbonate are converted into 6-allylamino-1-R-1H-pyrazolo[3,4-d]pyrimidines that at further reaction with iodine undergo the cyclization into 6-iodomethyl-1-R-1,6,7,8-tetrahydroimidazo [1,2-a]pyrazolo[3,4-d]-pyrimidin-5-ium iodide of a linear structure. In the absence of potassium carbonate alongside the mentioned linear products 8-iodo-methyl-1-R-1,4,5,6,7,8-hexahydroimidazo[1,2-a]pyrazolo[4,3-e] pyrimidin-9-ium iodides of an angular structure have been obtained.     

Synthesis of arylamino-substituted pyrazolo[3,4-d][1,2,4]triazolo[4,3-a]pyrimidinones,pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidinones,and their thermal isomerization

The reaction of 1-(4-oxo-1-R-5H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-arylthiosemicarbazides with methyl iodide gave rise to 1,2,4-triazolo-pyrazolopyrimidinones of linear structure, and with dicyclohexylcarbodiimide the products had angular and linear structure. The heating of compounds obtained higher than their melting point resulted in their isomerization into 7-aryl-amino-1-R-1,8-dihydro-4H-pyrazolo[3,4-d]-[1,2,4]triazolo[1,5-a]pyrimidin-4-ones.     

Synthesis of 2-Methyl-7-phenyl-5,8-dihydro-4<Emphasis Type="Italic">H</Emphasis>-pyrzylo-[5,1-<Emphasis Type="Italic">d</Emphasis>][1,2,5]triazepin-4-one

An approach is developed to the synthesis of 2-methyl-7-phenyl-5,8-dihydro-4H-pyrazolo[5,1-d]-[1,2,5]triazepin-4-one, based on the recyclization of 2-methyl-6-phenyl-4H-pyrazolo[5,1-c][1,4]oxazin-4-one with hydrazine.     

Microwave assisted synthesis of 2,3-dihydro-4H-benzo[4,5]thiazolo[3,2-a]furo[2,3-d]pyrimidin-4-ones and 6,7-dihydro-5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-ones using Mn(OAc)3

2-Hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one 2a and 7-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one 2b, were obtained in high yields under mild conditions from the cyclization reactions of bis-(2,4,6-trichlorophenyl) malonate and 2-aminobenzothiazole or 2-aminothiazole, respectively. A new class of compounds, 2,3-dihydro-4H-benzo[4,5]thiazolo[3,2-a]furo[2,3-d]pyrimidin-4-ones and 6,7-dihydro-5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-ones, were synthesized via the microwave assisted radical addition of compounds 2a and 2b to various alkenes using manganese(III) acetate. A preliminary acetylcholine esterase (AchE) inhibition test of compound 4e showed excellent (92%) inhibitory potential, comparable with the standard drug Donapezil®.     

Synthesis of 2-hetaryl-6H-pyrazolo[3,4-d]-1,2,3-triazoles

A novel efficient synthesis of 2-hetaryl-4-methyl-6-phenyl-6H-pyrazolo[3,4-d]-1,2,3-triazoles was achieved by the reaction of 5-amino-3-methyl-4-nitroso-1-phenyl-1H-pyrazole with heterocyclic amines followed by air oxidation in the presence of cupric acetate.     

Tautomerism of Aza heterocycles: V. Structure of the spontaneous transformation products of 5-methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo-[4,3-c]pyridin-3-one in crystal and solution

5-Methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one exists as zwitterion with a proton localized on the nitrogen atom of the piperidine ring and negative charge delocalized over the pyrazololate fragment. The compound is stable in crystal but ustable in solution. Its chromatographic purification and attempts to recrystallize or synthesize by condensation of phenylhydrazine with alkyl 1-methyl-4-oxopiperidin-3-carboxylate on heating in alcohols or benzene lead to the formation of a complex mixture of products. Among these products, we isolated and identified 3a,3a′-methylenebis(5-methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one), 1-methyl-3-(2-phenylhydrazinylidene)pyrrolidin-2-one, and 5-methyl-2-phenyl-3,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine. The structure of methyl 3-(2-phenylhydrazinylidene)-4,5-dihydro-3H-pyrrole-2-carboxylate and 3a,5-dimethyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one was proved by NMR spectroscopy. 3a,5-Dimethyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one was isolated as hydrochloride hydrate whose structure was determined by X-ray analysis.     

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.     

Syntheses of 6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one,an isostere of oxanosine,and the guanosine analog 6-amino-1-(β-d-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one via ring closure of pyrazole-5-thioureido intermediates

6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one ( 4 ), an isostere of the nucleoside antibiotic oxanosine has been synthesized from ethyl 5-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)pyrazole-4-carboxylate ( 6 ). Treatment of 6 with ethoxycarbonyl isothiocyanate in acetone gave the 5-thioureido derivative 7 , which on methylation with methyl iodide afforded ethyl 1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-5-[(N'-ethoxycarbonyl-S-methylisothiocarbamoyl)amino]pyrazole-4-carboxylate ( 8 ). Ring closure of 8 under alkaline media furnished 6-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one ( 10 ), which on deisopropylidenation afforded 4 in good yield. 6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 5 ) has also been synthesized from the AICA riboside congener 5-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)pyrazole-4-carboxamide ( 12 ). Treatment of 12 with benzoyl isothiocyanate, and subsequent methylation of the reaction product with methyl iodide gave 1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-5-[(N'-benzoyl-S-methylisothiocarbamoyl)amino]pyrazole-4-carboxamide ( 15 ). Base mediated cyclization of 15 gave 6-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 14 ). Deisopropylidenation of 14 with aqueous trifluoroacetic acid afforded 5 in good yield. Compound 4 was devoid of any significant antiviral or antitumor activity in culture.     

Synthesis of 1H-thieno[3,4-c]pyrazoles,thieno[3,4-b]furans,selenolo[3,4-b]furans and pyrrolo[3,4-d]thiazoles

Starting from the readily available aryl 2-methyl-5-phenyl-3-furyl ketones, 5-methyl-1H-1-phenylpyrazole-4-yl ketones and 4-methyl-2-phenyl-5-thiazolylcarboxaldehyde, a series of 2-phenyl-4-arylthieno[3,4-b]-furan, 2-phenyl-4-(p-methoxyphenyl)selenolo[3,4-b]furan, 4-aryl-1H-1-phenylthieno[3,4-c]pyrazole and 5-benzyl-2-phenylpyrrolo[3,4-d]thiazole were prepared in high yield.     

Regiospecific synthesis of 6-aryl-3-cyano-5-alkylamino/arylamino-1-p-tolyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-ones via iminophosphorane-mediated annulation

An efficient and straightforward approach to the synthesis of 6-aryl-3-cyano-5-alkylamino-1-p-tolyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-ones 8 has been developed from the readily commercially available starting materials 4-methylaniline and malononitrile in five steps. The key to the pyrazolo[4, 3-d]pyrimidin-7(6H)-ones relies on an iminophosphorane-mediated annulation, followed by a nucleophilic addition with amines. The structures of the title compounds are clearly characterized by IR, ¹H NMR, MS, elemental analysis or X-ray diffraction crystallography.     

5-Amino-N-(2,2-dialkoxyethyl)pyrazole-4-carboxamides in the synthesis of 7-sulfanyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]diazepin-4-ones

5-Amino-N-(2,2-dialkoxyethyl)pyrazole-4-carboxamides obtained by hydrolytic cleavage of 5-(2,2-diethoxyethyl)pyrazolo[3,4-d]pyrimidin-4-ones or by condensation of 3-(dimethylamino)-N-(2,2-dimethoxyethyl)-2-cyanoacrylamides with alkylhydrazines in formic acid react with benzylthiol or thiophenols to afford 7-benzyl(aryl)sulfanyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]diazepin-4-ones.     

A Convenient Synthetic Approach to Newly Condensed Pyrazoloazines Based on Pyrazolo[3,4-b]pyridine

The reaction of 6-amino-5-cyano-3-methyl-1H-1-phenylpyrazolo[3,4-b]pyridine ( 2 ) and 6,7-dihydro-3-methyl-6-oxo-1H-1-phenylpyrazolo[3,4-b)]pyridine-5-carbonitrile ( 3 ) and 5-amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]-1H-pyrazolo[4′,3′-e]pyridine ( 12 ) with different reagents have been conducted to give newly condensed pyrazoloazines.