Synthesis of novel acyclonucleosides. Reactions of 1-(2-oxopropyl)pyridazin-6-ones

Multi-substituted-1-(1-bromo-2-oxopropyl)pyridazin-6-ones 3, 4 , multi-substituted-1-(1,1-dibromo-2-oxopropyl)pyridazin-6-ones 7, 8 , and multi-substituted-1-(3-bromo-2-oxopropyl)pyridazin-6-ones 5, 6 were synthesized from the corresponding 1-(2-oxopropyl)pyridazin-6-ones 1, 2 by the selective bromination in acidic or neutral medium. And treatment of 1,1-dibromo-2-oxopropyl derivatives 7, 8 with aqueous potassium carbonate gave the corresponding pyridazin-6-ones 9, 10 by the dealkylation. Reaction of 1 with methanolic potassium cyanide afforded only the corresponding 4-methoxy derivative 11 , whereas reaction of 2 with methanolic potassium cyanide gave 4-methoxy derivative 12 and 2-cyano-2-hydroxypropyl derivative 13 . Reaction of 1 and 2 with hydroxylamine in methanol afforded the corresponding syn-2-hydroxyiminopropyl derivatives 14 and 15 .     

Pyridazine Derivatives and Related Compounds,Part 1. Some Reactions with 4-Cyano-5,6-Diphenyl-2,3-Dihydropyridazine-3-One

4-Cyano-5,6-diphenyl-2,3-dihydropyridazine-3-onc 1 reacts with phosphorous oxychloride to give 70% of the corresponding 3-chloro derivative 2. Treating 2 with anthranilic acid in butanol, 4-cyano-2,3-diphenyl-10H-pyridazino[6,1-b]quinoxaline-10-one, 3 was obtained. Compound 1 reacts with phosphorous pentasulphide to give 3-mercapto derivative 4, which was converted by acrylonitrile to S-(2-cyanoethyl)pyridazine derivative 5. Compound 4 reacts with ethyl bromoacetate and with phenacyl bromide gave the corresponding thieno[2,3-c] pyridazine derivatives 8, 9, Alkylation of 1 with ethyl chloroacetate afforded 3-0-carbethoxymethyl derivative 10. Compound 10 reacts with amines (aniline, hydrazine) to give the corresponding amide and acid hydrazide 13, 12 respectively. Hydrolysis of 10 with sodium hydroxide gave the corresponding acid derivative 11. Treating 1 with methyl iodide, 3-0-methyl derivative 14 was obtained, which was converted by ammonium acetate/acetic acid to 3-amino-4-cyano-5,6-diphenyl pyridazine 15. Compound 1 reacts with methyl magnesium iodide gave 4-acetyl derivative 16, which was reacted with hydrazine, phenyl hydrazine and with hydroxylamine to give the substituted I H pyrazolo [3,4-c] pyridazine 17 a,b and isoxazolo [5,4-c] pyridazine 18 derivatives respectively.     

Synthesis and Reactions of Some Heterocyclic Candidates Based on 2‐Amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene Moiety as Anti‐Arrhythmic Agents

In continuation of our previous work, a series of novel thiophene derivatives 4 , 5 , 6 , 8 , 9 , 9a , 9b , 9c , 9d , 9e , 10 , 10a , 10b , 10c , 10d , 10e , 11 , 12 , 13 , 14 , 15 , 16 were synthesized by the reaction of ethyl 2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carboxylate ( 1 ) or 2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carbonitrile ( 2 ) with different organic reagents. Fusion of 1 with ethylcyanoacetate or maleic anhydride afforded the corresponding thienooxazinone derivative 4 and N‐thienylmalimide derivative 5 , respectively. Acylation of 1 with chloroacetylchloride afforded the amide 6 , which was cyclized with ammonium thiocyanate to give the corresponding N‐theinylthiazole derivative 8 . On the other hand, reaction of 1 with substituted aroylisothiocyanate derivatives gave the corresponding thiourea derivatives 9a , 9b , 9c , 9d , 9e , which were cyclized by the action of sodium ethoxide to afford the corresponding N‐substituted thiopyrimidine derivatives 10a , 10b , 10c , 10d , 10e . Condensation of 2 with acid anhydrides in refluxing acetic acid afforded the corresponding imide carbonitrile derivatives 11 , 12 , 13 . Similarly, condensation of 1 with the previous acid anhydride yielded the corresponding imide ethyl ester derivatives 14 , 15 , 16 , respectively. The structures of newly synthesized compounds were confirmed by IR, ¹H NMR, ¹³C NMR, MS spectral data, and elemental analysis. The detailed synthesis, spectroscopic data, LD₅₀, and pharmacological activities of the synthesized compounds are reported.     

Synthesis of carpachromene and related isopentenylated derivatives of apigenin

Acacetin (4) on reaction with prenyl bromide in the presence of methanolic sodium methoxide yielded 6,8-di-C-prenyl-(5) and 6-C-prenyl-(10) derivatives. The former (5) formed the corresponding bisdihydropyrano derivative (8). Monomethyl derivative of 10 (12) gave monodihydropyrano derivative (13). DDQ reaction of 10 followed by methylation afforded di-O-methyl carpachromene (2); whereas that of 5 gave a mixture of 21 and 22.

Nuclear prenylation of apigenin (3) in a similar way gave 6,8-di-C-C-prenyl-(16), its 7-0-prenyl-(15) and 6-C-prenyl-(18) derivatives. DDQ reaction of 18 provided natural carpachromene.¹ The structure of the isopentylated apigenin isolated by Dreyer et al.² needs further consideration.     

Synthesis of novel acyclonucleosides. Reactions of 1-(1-bromo or 3-bromo-2-oxopropyl)pyridazin-6-ones

Reaction of 1-(3-bromo-2-oxopropyl)pyridazin-6-ones 1 and 2 with sodium azide at room temperature gave the corresponding 1-(3-azido-2-oxopropyl)pyridazin-6-ones 3 and 4 , whereas reaction of 1-(1-bromo-2-oxo-propyl)pyridazin-6-ones 5 and 6 with excess sodium azide afforded 4-azido-5-chloropyridazin-6-one 7 and 4,5-diazido-3-nitropyridazin-6-one 8 by dealkylation. Some 1-(2-hydroxypropyl)pyridazin-6-ones 9, 10, 11 were synthesized from the corresponding 1-(2-oxopropyl) derivatives 1, 2, 3 . 4,5-Dichloro-1-(2,3-dihydroxypropyl)-pyridazin-6-one 13 was also prepared from compound 9 via the corresponding 2,3-epoxypropyl derivative 12 . Treatment of compound 5 with thiourea gave 4,5-dichloro-1-(2-amino-4-methylthiazol-5-yl)pyridazin-6-one 14 . Reaction of compounds 1 and 2 with thiourea at 20° afforded the corresponding 3-formamidinylthio-2-oxo-propyl derivatives 15 and 16 , whereas treatment of compound 1 with thiourea at 45° gave 4,5-dichloro-1-[(2-aminothiazol-5-yl)methyl]pyridazin-6-one 17 . Compound 17 was also prepared from compound 15 by refluxing in ethanol.     

Synthesis and Reactions of Some Novel Nicotinonitrile,Thiazolotriazole, and Imidazolotriazole Derivatives for Antioxidant Evaluation

The novel 2-(1H)-pyridone, the lead compound of the pyridone derivative 1, reacted with an electrophilic reagent (ethyl chloroacetate) to give the corresponding ester 2. Condensation of compound 2 with thiosemicarbazide and/or hydrazine hydrate afforded the mercaptotriazole and the corresponding acetic acid hydrazide derivatives 3 and 4, respectively. The latter compound reacted with ethyl acetoacetate, ethyl cyanoacetate, and maleic anhydride to give compounds 5, 6, and 7, respectively. Alkylation of compound 3 with methyl iodide or chloroacetic acid afforded methylsulfanyltriazole and thiazolotriazole derivatives 8 and 9, respectively. Compound 8 reacted with glycine to afford the imidazotriazole derivative 10. Both compounds 9 and 10 reacted with glucose and benzaldehyde to give compounds 11, 12, 13, and 14, respectively. Some of the prepared products were selected and subjected to screening for their antioxidant activity.     

Synthesis of heierocyclic compounds from 2-phenyl-1, 2,3-triazole-4-formylhydrazine

2-Phenyl-1, 2, 3-triazole-4-formylhydrazine (2) was prepared by hydrazinolysis of the corresponding ester 1. Reaction of 2 with CS2/KOH gave the oxadiazole derivatives (3) which via, Mannich reaction with different dialkyl amines furnished 3-N, N-dialkyl derivatives (4a-c). Also, condensation of 2 with appropriate aromatic acid in POCl3 yielded oxadiazole derivatives (5a-c), or with aldehydes and ketones afforded hydrazones (6a-c). Cyclization of (6a-c) with acetic anhydride gave the desired dihydroxadiazole derivatives (7a-c). On the other hand, reaction of dithiocarbazate (8) with hydrazine hydrate gave the corresponding triazole derivative (9) which on treatment with carboxylic acids in refluxing POCl3 yielded s-triazole[3,4-b]-1, 3, 4-thiadiazole derivatives (10a-b). The structures of all the above compounds were confirmed by means of IR, 1H NMR, MS and elemental analysis.     

Rh(I)-catalyzed Pauson-Khand reaction of 1-phenylsulfonyl-1,2-octadien-7-yne derivatives

The Rh(I)-catalyzed PKR of 1-phenylsulfonyl-1,2-octadien-7-ynes and their aza derivatives exclusively produced the corresponding 9-phenylsulfonylbicyclo[4.3.0]nona-1,6-dien-8-ones and no 4-(phenylsulfonylmethylidene)bicyclo[3.3.0]oct-1-en-3-ones could be detected. Thus, the ring-closing pattern was found to be the same as those of the previously reported 3-phenylsulfonyl-1,2-octadien-7-yne derivatives. However, the formation of 4-(phenylsulfonylmethylidene)-7-oxabicyclo[3.3.0]oct-1-en-3-ones was observed as a minor product when the 5-oxa congeners were used. In addition, a larger ring-sized product, 10-phenylsulfonyl-5-azabicyclo[5.3.0]deca-1,7-dien-9-one derivative, was obtained from the 6-aza derivative of 1-phenylsulfonyl-1,2-nonadien-8-yne.     

Some transformations of 3-amino-4-alkoxycarbonyl-6-hydroxy-2H-1-benzopyran-2-ones. The synthesis of [1] benzopyrano[3,4-d]-[1,3]oxazine and [1] benzopyrano[3,4-d]pyrimidine derivatives

Acylation of 4-alkoxycarbonyl-3-amino-6-hydroxy-2H-1-benzopyran-2-one derivatives 3 and 4 gave under mild conditions the O-substituted derivatives 5–10, N,O -disubstituted derivative 11 and N,N-disubstituted derivative 12 . The compound 4 was transformed with benzoyl chloride under more drastic conditions into 13 , a derivative of a new heterocyclic system 2-benzopyrano[3,4-d][1,3]oxazine. The derivatives of 1-benzopyrano-[3,4-d]pyrimidine 19 and 20 were prepared either from 3 and 4 through the corresponding N-heteroarylformamidines 14 and 15 and N-heteroarylformamide oximes 17 and 18 or by cyclization of thiourea derivative 20 .     

Azines and Their Acyclic Derivatives as Transferers of One-carbon Fragment in Reactions with Pyrazolones

Enehydrazine derivatives have been obtained by the reaction of 6-phenyl-1,2,4-triazine 4-oxide with pyrazolones 2, which on further heating with pyrazolones 2 are converted into the corresponding symmetrical or unsymmetrical derivatives of dipyrazolylmethane. Enehydrazine derivatives of 1,3-dimethyl-5-nitrosouracil and 1,3-dimethylimidazolidine interact with 3-methyl-1-phenyl-5-pyrazolone (2a) with the formation of dipyrazolylmethane derivative. On interacting compound 2a or 3-methyl-1-(p-nitrophenyl)-5-pyrazolone with 3,6-diphenyl-1,2,4-triazine 4-oxide 12 the corresponding 4,4'-bispyrazolones are formed, but the interaction of compound 12 with 3-(p-nitrophenyl)-1-phenyl-5-pyrazolone leads to dipyrazolylmethane derivative. Dipyrazolylmethane derivative is obtained on heating of fervenulin 4-oxide, 2,4-dihydroxy-5-nitropyrimidine, and 1,3,5-triazines: 6-azauracil, 5-azauracil, azacytosine, and 2,4-diamino-s-triazine with pyrazolone 2a.     

Synthesis of [1,5-A]Pyrimidinone Ring Derivatives

Cyclodehydrogenation of the benzalhydrazino derivatives 5 and 6 gave 6-cyano-7-(4-methoxyphenyl)- 2-phenyl-5-oxo-1,2,4-triazolo[1,5-a]pyrimidine (8) and 6-cyano-7-(4-methoxyphenyl)-4-methyl-2-phenyl- 5-oxo-1,2,4-triazolo[1,5-a]pyrimidine (9) respectively. Melhylation, acetylation and benzylation of 8 gave the corresponding N-methyl, acetyl and benzyl derivatives 10-12 . Methylation of 5 with dimethylsulfate gave 2-benzalhydrazino-5-cyano-3-methyl-6-(4-methoxyphenyl)-3,4-dihydropyrimidin-4-one (6) , of which the reaction with acetic anhydride in pyridine afforded the N-acetylbenzalhydrazino derivative 15 . The latter was also prepared from acetylation of 5 followed by medthylation with iodomethane. Acetylation of 5 with boiling acetic anhydride afforded the diacetyl derivative 16 , whereas its benzylation gave the mono-N-benzyl derivative 14 .     

Potential psychotropic agents. 7-Chloro-9-phenyl-3,3-diethyl-3H-pyrazolo-[5, 1-b]quinazolin-10-ium-2-olate and 9-Chloro-2,3,4,5-tetrahydro-1-methyl-3,3-diethyl-7-phenyl-1H-benzo-1,5,6-triazonine-2,4-dione

2-Amino-5-chloro-α-phenylbenzylidene hydrazone ( 1 ) or its methyl derivative 2 or acetyl derivative 10 react with diethylmalonic esters to give the corresponding malonyl derivatives 3, 4 and 8 . These esters were hydrolyzed to the acids 5 and 6 . Treating 5 with dehydrating agents the mesoionic compound 7-chloro-9-phenyl-3,3-diethyl-3H-pyrazolo[5,1-b]quinazolin-10-ium-2-olate (14) was obtained, while the methyl derivative 6 afforded the desired 9-chloro-2,3,4,5-tetrahydro-1-methyl-3,3-diethyl-7-phenyl-1H-benzo-1,5,6-triazonine-2,4-dione ( 17 ). Some derivatives of these compounds were also described. The structures of the new compounds were confirmed by an alternative synthesis and by mass and prnr spectral data.     

Synthesis with nitriles: synthesis of some new mercaptopyridazine, mercaptopyridazino[1,6-a]quinazoline and thiophene derivatives

2-(1-(4-Bromophenyl)-2-thiocyanatoethylidene)malononitrile (3) undergoes azo coupling with diazotized aromatic amines to afford arylhydrazone derivatives, which are readily cyclized to afford the corresponding 3(2H)-pyridazinimine derivatives upon reflux in aqueous NaOH. Under similar condition an o-cyanoarylhydrazone derivative was cyclized into 6H-pyridazino[1,6-a]quinazolin-6-imine, which in turn was easily transformed into 6H-pyridazino[1,6-a]quinazolin-6-one on reflux in ethanolic/HCl. Compound 3 afforded substituted 5-acetylthiophene derivatives upon reflux in AcOH/HCl mixtures.     

Meerwein arylation of methyleneglutaronitrile with anthraquinone diazonium hydrogensulfate. Synthesis of an enolizable benzanthrone lactone

The Meerwein reaction of 1-anthraquinone diazonium hydrogensulfate with 2-methyleneglutaronitrile in methanol yielded predominantly 3-hydroxy-4-(1-anthraquinone)-1,3-butanedicarbonitrile ( 5 ), while the corresponding 2-methyleneglutaric acid diethyl ester furnished a derivative of 1-(anthraquinone)butanolide 10. Catalytic dehydrocyanation of 5 was effected with Dowex-50 to furnish 3-oxo-4-(anthraquinone)butanecarbo-nitrile ( 6 ). Both nitriles 5,6 gave in a double cyclization reaction a benzanthrone lactone 12 from which a crystalline derivative of the enol form was isolated, the structure of which was elucidated by ¹H- and ¹³C-nmr spectra. The methylene group of the lactone ring underwent coupling reactions with aromatic diazonium salts to form hydrazone derivatives.     

Synthesis of piperidine analogs of 1-(3-chlorophenyl)piperazine,a well known serotonin ligand

Synthesis of arylpiperideines 3a-3d and arylpiperidines 4a-4d as analogs of a well known serotonin ligand 1-(3-chlorophenyl)piperazine is reported. Starting aryllithium derivatives were treated with 1-methyl-piperdin-4-one to provide the corresponding hydroxy derivatives 6a and 6b. N-Methylpiperideine derivatives 3a and 3c were obtained by their dehydration while the corresponding N-unsubstituted compounds 3b and 3d were prepared indirectly by a three-step procedure. Hydrogenation of piperideine 3a provided the corresponding piperidine derivative 4a which after demethylation yielded 4b. Similar 4-pyridyl derivatives 4c and 4d were prepared by a similar strategy via the corresponding methoxy derivatives.     

Synthesis, reactions and biological evaluation of some new naphtho[2,1-b]furan derivatives bearing a pyrazole nucleus

Vilsmeier formylation of 2-(1-phenylhydrazonoethyl)naphtho[2,1-b]furan (2) gave 3-naphtho[2,1-b]furan-2-yl-1-phenyl-1H-pyrazole-4-carbaldehyde (3), which was reacted with C- and N-nucleophiles to afford naphthofuranpyrazol derivatives 4-8. Treatment of 2-[(3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene]-malononitrile (4a) with reactants having active hydrogen and Et?N gave the corresponding pyrazoline, pyran and chromene addition product derivatives 10, 12 and 13, consisting of three different connected heterocyclic moieties. Reaction of 1-((3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl) methylene)-2-phenylhydrazone (6b) with AcONa and ethyl bromoacetate or chloroacetone afforded the thiazolidinone and methylthiazole derivatives 14 and 15, respectively. In addition, intramolecular cyclization of 6d with Ac?O afford the corresponding 1,3,4-thiadiazol-2-yl acetamide derivative 16. The structures of the synthesized compounds were confirmed by IR, 1H-NMR/13C-NMR and mass spectral studies. Compound 14 showed promising effects against the tested Gram positive and negative bacteria and fungi.     

Synthesis, properties, and redox behavior of mono-, bis-, and tris[1,1,4,4,-tetracyano-2-(1-azulenyl)-3-butadienyl] chromophores binding with benzene and thiophene cores

Mono-, bis-, tris-, and tetrakis(1-azulenylethynyl)benzene and mono- and bis(1-azulenylethynyl)thiophene derivatives 5-10 have been prepared by Pd-catalyzed alkynylation of ethynyl arenes with 1-iodoazulene derivative or the 1-ethynylazulene derivative with tetraiodobenzene and iodothiophenes under Sonogashira-Hagihara conditions. Compounds 5-10 reacted with tetracyanoethylene in a [2+2] cycloaddition reaction to afford the corresponding 1,1,4,4,-tetracyano-2-(5-isopropyl-3-methoxycarbonyl-1-azulenyl)-3-butadienyl chromophores 12-16 in excellent yields, except for the reaction of the tetrakis(1-azulenylethynyl)benzene derivative. 1,1,4,4,-Tetracyano-2,3-bis(1-azulenyl)butadiene (17) was also prepared by the similar reaction of bis(1-azulenyl)acetylene (11) with tetracyanoethylene (TCNE). The redox behavior of novel azulene derivatives 12-17 was examined by cyclic voltammetry (CV) and differential pulse voltammetry (DPV), which revealed multistep electrochemical reduction properties. Moreover, a significant color change was observed by visible spectroscopy under electrochemical reduction conditions.     

Synthesis of Some New Polyfused Thienothiophenes Part 4: Synthesis of Thienopyrimidine,Thienotriazine, Thienoimidazotriazine,Thienotriazolotriazine, and Thienotetrazolotriazine Derivatives

3,4-Diamino-2,5-dicarboxamidothieno(2,3-b)thiophene 1 was allowed to react with CS 2 , carbonyl compounds, ethyl chloroformate, S,S-acetals, and oxallyl chloride to give thienopyrimidines 2-6 and thieno-1,4-diazepine 7 . Treatment of compound 1 with nitrous acid afforded compound 8 , which converted into the corresponding chloro derivative 9 by using PCl 5 . Compound 9 was reacted with amino reagents to afford the corresponding thienoimidazotriazines 10 and 11 , thienotriazolotriazines 12 and 13 and 4-hydrazinothienotriazine 14 . Treatment of compound 14 with aldehydes, triethyl orthoformate, CS 2 , nitrous acid and ylidenemalononitriles, afforded thienotriazolotriazine 16-18 , thienotetrazolotriazine 19 , and 4-pyrazolyl-thienotriazine 20-22 derivatives respectively.     

Cyclization of diketones to pyridazine and furan derivatives

Condensation of (±)-2,3-bis(3,4-dimethoxybenzoyl)butane-1,4-dione 1 with different hydrazine bases afforded the corresponding pyridazines 2 and 3 . Refluxing the diketone 1 with methanolic hydrogen chloride yielded the corresponding 3,4-dimethylfuran derivative 5 . Reaction of acetonylacetone 6 with p-sulfamylphenylhydrazine afforded the corresponding 3,6-dimethyl-1H-pyridazine derivative 7 . Reaction of 7 with the appropriate isocyanate and isothiocyanate yielded the corresponding benzenesulfonylurea 8 and thiourea 9 derivatives respectively. The structures of the compounds synthesized were affirmed by microanalyses and spectral studies.     

Part 1: Synthesis of Polyfused Heterocyclic Systems Derived From 3-Phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4- b ][1,3,4]thiadiazepine-6,8-dione

3-Phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4- b ][1,3,4]thiadiazepine-6,8-dione ( 1 ) was condensed with o -aminothiophenol, 2-amino-ethanol or cystamine to afford compounds 2-4 respectively. Treatment of compound 1 with dimethylthiomethylenemalononitrile yielded the corresponding pyrano[3,2- f ][1,2,4]triazolo[3,4- b ]-[1,3,4]thiadiazepine derivative 5 . 7-[5-Amino-1,3-dithiolan-2-ylidene]-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4- b ][1,3,4]thiadiazepine-6,8-dione ( 6 ) was obtained by treating compound 1 with CS 2 and chloroacetonitrile. Thiation of compound 1 gave the corresponding thioanalog 7 , which in turn was condensed with malononitrile to give 3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4- b ][1,3,4]thiadiazepine-6-one-8-ylidenemalononitrile ( 8 ). On treating compound 8 with benzaldehyde or p -nitrobenzaldehyde, pyrano[1,2,4]triazolo[1,3,4]thiadiazepin derivatives 9a , b , respectively, were obtained. Compound 8 was treated with CS 2 and methyl iodid to give the corresponding dithiomethylmethylene derivative 10 which was subjected to react with aniline to give pyrido[1,2,4]triazolo[1,3,4]thiadiazepine derivative 11 . Compound 8 was treated with 3-aminopyridine, o -aminothiophenol, or o -phenylenediamene to yield compounds 12 and 13a , b respectively. Finally, tertiary amines or activated phenols were condensed with compound 8 to yield compounds 14 and 15a , b respectively.