Synthesis of 5-aryl-3-carbazoyl-1,3,4-oxadiazol-2(3H)-one. Derivatives and their ring transformation into 5-benzamido-1,2,4-triazolidine-3,5-dione derivatives

Some 5-aryl-3-carbazoyl-1,3,4-oxadiazol-2(3H)-one derivatives 6 and 9 have been synthesized in two ways. The expected thermal ring transformation into 2,5-disubstituted 1,3,4-oxadiazoles did not occur but, by acid hydrolysis of 5-aryl-3-[3-benzylidene-2-methyl(or phenyl)carbazoyl]-1,3,4-oxadiazol-2(3H)-ones 6 , a new ring transformation took place and the corresponding 4-benzamido-1-methyl(or phenyl)-1,2,4-triazolidine-3,5-dione derivatives 11 were formed. The 4-amino-1-phenyl-1,2,4-triazolidine-3,5-dione ( 19 ) has been prepared and its structure was confirmed by some reactions.     

Synthesis of isochroman-fused pyrazolone and pyrimidine derivatives

Unsubstituted 5 , and 2-aryl- 6a-c , or 2-(2-benzothiazolyl)-substituted 1,3-dihydroisochromano[4,3-c]pyrazol-3(2H)-ones 7a-f were prepared by the reactions of 3-ethoxyoxalyl- 2 , or 3-ethoxycarbonylisochroman-4-one 3 with hydrazine derivatives. The reactions with amidines gave 2-substituted 4-hydroxyisochromano[4,3-d]-pyrimidines 8a-c .     

Tetrazole compounds. 9. A new approach to tetrazolyl-substituted quinoline derivatives

The acid-catalyzed reaction of 1-aryl-5-(2-dimethylaminovinyl)-1H-tetrazoles 2 with arylamines suitably functionalized in the ortho-position resulted in Z-configurated transamination products which were cyclized to novel 3-tetrazolylquinolines by the action of sodium ethoxide. Thus, on reacting 2 with 2-aminoacetophenone or 2-aminobenzophenone, respectively, the 2-[2-(1-aryl-1H-tetrazol-5-yl)vinyl-amino]aryl ketones 3a-g were obtained, the cyclization of which gave 4-substituted 3-(1-aryl-1H-tetrazol-5-yl)quinolines 4 . In the case of the transamination products 3h-1 , prepared from 2 and methyl anthranilate, the ring closure afforded 3-(1-aryl-1H-tetrazol-5-yl)-1H-quinolin-4-ones 5 . Starting from 2 and anthranilonitrile 4-amino-3-(1-aryl-1H-tetrazol-5-yl)quinolines 10 were obtained via the corresponding intermediates 9 .     

Syntheses Based on 4-Chloro-1-[3,5-di(trifluoromethyl)phenyl]-, 4-Chloro-1-(2,4-difluorophenyl)-5-formyl-3-methyl-6,7-dihydroindazoles,and 4-Chloro-5-formyl-3-methyl-1-(2-pyridyl)-6,7-dihydroindazoles

Vilsmeier formylation of 1-[3,5-di(trifluoromethyl)phenyl]- and 1-(2,4-difluorophenyl)-3-methyl-4-oxo-4,5,6,7-tetrahydroindazoles gave the corresponding 1-aryl-4-chloro-5-formyl-3-methyl-6,7-dihydroindazoles. Reaction of the latter with amidines, o-phenylenediamine, hydrazine, or hydroxylamine gave a series of 1-aryl-3-methyl-6,6-dihydroindazoles annelated at positions 4 and 5. The reaction of 4-chloro-5-formyl-3-methyl-1-(2-pyridyl)-6,7-dihydroindazole with substituted anilines gave 5-arylaminomethylene-4-oxo- or 5-arylaminomethylene-4-arylimino-3-methyl-1-(2-pyridyl)-4,5,6,7-tetrahydroindazoles depending on the molar ratio of reagents and the nucleophilicity of the amines.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 740–750, May, 2005.     

Composés sulfurés hétérocycliques. CII. Action de l'hydroxylamine sur les dihydro-1,2 benzothiazine-3,1 thiones-4

Hydroxylamine reacts with 1-alkyl-1,2-dihydro-3,1-benzothiazine-4thiones ( 1 ), giving 1-alky1-3-hydroxy-2,3-dihydro-1H-quinazoline-4-thiones ( 2 ). The same reagent, in neutral medium, converts 1-aryl-1,2-dihydro-3,1-benzothiazine-4-thiones ( 3 ) into 1-aryl-4-hydroxyimino-1,4-dihydro-2H-3,1-benzothiazines ( 4 ). In acidic medium, the same starting materials lead to 1-aryl-3-hydroxy-2-3-dihydro-1H-quinazoline-4-thiones ( 5 ). genrally with some quantity of the isomer 4 . Thiones 2 and 5 , as well as oximes 4 , heated at 200°, decomopose, yielding, in varying proportions, 1H-quinazoline-4-thiones ( 6 or 7 ), 1H-quinazoline-4-ones ( 9 ) and 2,3-dihydro-1H-quinazoline-4-thiones ( 11 ). Reacting with methyliodide, 1H-quinazoline-4-thiones ( 7 ) give 4-methylthioquinazolin-1-ium iodidies ( 12 ) which can be hydrolysed into 1H-quinazolin-4-ones ( 9 ). The latter are also obtained by reacting benzonitrile N-oxide with the corresponding thiones. 1-Aryl-1 H-quinazoline-4-thiones ( 7 ) react readily with nitrogen nucleophiles XNH₂ to give 1-aryl-4-imino-1,4-dihydro-quinazolines diversely substituted on the imino group. While thiones 7 are S- methylated by methyl iodide, the corresponding 1-aryl-1H-quinazolin-4-ones (9), with the same reagent, ungergo a N-methylation, yielding 1-aryl-3-methyl-4-oxo-3,4-dihydroquinazolin-l-ium iodides ( 18 ). Structure have been confirmed by uv, ir and nmr spectra.     

First asymmetric synthesis of 3-alkoxycarbonyl-2-amino-4-aryl-4H-naphtho[1,2-b]pyrans

The first asymmetric synthesis of 3-alkoxycarbonyl-2-amino-4-aryl-4H-naphtho[1,2-b]pyrans, by Michael addition of 1-naphthol to chirally modified arylidenecyanoacetates 6 and 7 , is described. Good yields and low diastereomeric excesses have been obtained in the 1,4-conjugate additions. The absolute stereochemistry at C-4 in major isomers of pyrans 8 and 9 has been assigned as 5 by X-ray analysis of major pyran 8 .     

Cascade cyclization of 3(5)-aminopyrazoles with aromatic aldehydes and cyclohexanediones

Three-component condensation of 5(3)-amino-3(5)-methylpyrazole with aromatic aldehydes and 1,3-cyclohexanedione afforded mixtures of 3-methyl-4-aryl-2,4,6,7,8,9-hexa hydro-5H-pyrazolo[3,4-b]quinolin-5-ones and 2-methyl-9-aryl-5,6,7,9-tetrahydro pyrazolo[5,1-b]quinazolin-8(4H)-ones. The reaction of 3-aminopyrazolo-4-carbonitrile and ethyl 3-aminopyrazolo-4-carboxylate with aldehydes and cyclo hexanedione or dimedome is regioselective and leads to the formation of partially hydrogenated pyrazolo [5,1-b]quinazolin-8-one systems. In all compounds the dihydroazine ring exists in the enamine tautomeric form.     

3-Oxo-4,4,4-trifluorobutyronitriles as building blocks of trifluoromethyl substituted heterocycles 2. Heterocyclization to 3-aryl-4-trifluoromethyl-2H-1-benzopyran-2-ones under hoesch reaction conditions

Resorcinol and 5-methylresorcinol, respectively, react with 3-oxo-2-aryl-4,4,4-trifluorobutyronitrile using zinc chloride as a catalyst in dibutyl ether under the Hoesch reaction conditions to give a low yield of 3-aryl-7-hydoxy-4-trifluoromethyl- or 3-aryl-5-hydroxy-7-methyl-4-trifluoromethyl-2H-l-benzopyran-2-ones. However, the related reaction with m-methoxyphenol was found to produce poor yields of 3-aryl-7-methoxy-4-trifluoromethyl-2H-1-benzopyran-2-one and its 3,4-dihydro-4-hydroxy derivative.     

L'isomérie géométrique d'amidines mono-substituées de l'acide benzothiazole-carboxylique-2. Isomères anti à carboxyle normal,isoméres syn à carboxyle énolisé

The condensation of methyl benzothiazole-2-iminicarboxylate with α-amino-acetic esters gives rise to amidines possessing only one (I) of the two possible tautomeric structures. Both syn and anti isomers have been characterized of the single tautomer. This is the first demonstration of geometrical isomerism around the imine group in amidines. The carboxylic esters and the free acids of the syn fro exist exclusively as the enol, whereas the anti derivatives prefer the carboxyl structure. The existence of these isomers has been confirmed by their IR., UV., and NMR. spectra as well as by the inversion of their configuration and the formation of cyclic derivatives.     

Regioselective arylation of 3-bromopyridine

The addition of aryl Grignard reagents to the 1-phenoxycarbonyl salt of 3-bromopyridine affords 2-aryl-5-bromo-1-phenoxycarbonyl-1,2-dihydropyridines and 4-aryl-3-bromo-1-phenoxycarbonyl-1,4-dihydropyridines. The crude dihydropyridines were aromatized with o-chloranil in refluxing toluene to give 4- and 6-aryl-3-bromopyridines. The regioselectivity of this two-step process, 6- vs. 4-substitution, was examined and found to be dependent upon the structure of the Grignard reagent. Unhindered aryl Grignard reagents, e.g., phenyl and 2-naphthyl, gave mainly 6-aryl-3-bromopyridines (49-52%) along with 9% of the 4-substituted isomer and less than 4% of the 2-aryl-3-bromopyridine. Hindered aryl Grignard reagents, e.g., o-tolyl and 1-naphthyl, are less regioselective. When a catalytic amount of cuprous iodide is present during the Grignard reaction, nearly exclusive 1,4-addition results. The crude 4-aryl-3-bromo-1,4-dihydropyridines were aromatized with p-chloranil to provide 4-aryl-3-bromopyridines in good yield and high isomeric purity. The sequential use of the cuprous iodide-catalyzed Grignard reaction and the “normal” Grignard reaction provided a regiospeci-fic synthesis of 3-bromo-6-(p-methoxyphenyl)-4-phenylpyridine from 3-bromopyridine.     

Synthesis of methyl 2-aryl-5-chlorosulfonyl-1,3-oxazole-4-carboxylates and their reactions with amines and amidines

Previously unknown methyl 2-aryl-5-chlorosulfonyl-1,3-oxazole-4-carboxylates have been synthesized. Their reactions with amines and amidines have yielded the corresponding sulfonamides and 6H,7H-[1,3]oxazolo-[5,4-d]pyrimidin-7-ones.     

New quinoxalines with nitrogen functions in the side chain. Potential inhibitors of 5-HT3

Starting with benzofuroxane 1 , 2-ethoxy-carbonyl-3-methylquinoxaline 1,4-dioxide 7 is obtained. From this compound different amides 5a-q and amino esters 6a-c are obtained. From 2-amino-3-cyanoquinoxaline 1,4-dioxide 7 , new amidines 9 , [5,4-b]pyrimido 10 and [6,5-b]diazepinoquinoxalines 11 were prepared.     

Environmentally friendly and efficient: iron-mediated reduction of 3-methyl-5-aryl-1,2,4-oxadiazoles to benzamidines

A new synthetic method is described for the mild and selective reduction of 3-methyl-5-aryl-1,2,4-oxadiazoles to amidines employing iron powder in aqueous medium. Its application is demonstrated in the synthesis of 1, a potent and selective urokinase-type plasminogen activator (uPA) inhibitor.     

Synthesis of 5-substituted 1-aryl-1H-pyrazole-4-acetonitriles, 4-methyl-1-phenyl-1H-pyrazole-3-carbonitriles and pharmacologically active 1-aryl-1H-pyrazole-4-acetic acids

Lithium aluminum hydride reduction of 5-substituted or unsubstituted ethyl or methyl 1-aryl-1H-pyrazole-4-carboxylates gave, generally in excellent yields, 5-substituted or unsubstituted 1-aryl-1H-pyrazole-4-methanols which afforded the corresponding 1-aryl-4-(bromomethyl)-1H-pyrazoles with hydrobromic acid in acetic acid solution. These crude intermediates gave by reaction with potassium cyanide in dimethylsulfoxide solution 1-aryl-1H-pyrazole-4-acetonitriles only in the case of 5-unsubstituted compounds, otherwise mixtures of 5-substituted 1-aryl-1H-pyrazole-4-acetonitriles and 4-methyl-1-phenyl-1H-pyrazole-3-carbonitriles were generally obtained. Acetonitriles IIIa,b,i,l gave in excellent yields the corresponding 1-aryl-1H-pyrazole-4-acetic acids Va,b,i,l by alkaline hydrolysis. Compounds Vb,i,l showed in the writhing test appreciable analgesic properties, associated with low acute toxicity; moreover, compound VI exhibited a statistically significant antiinflammatory activity in the carrageenan-induced edema assay.     

Synthesis of 2-Aryl-1H-s-Triazolo[1, 5-a] Benzimidazoles

2-Aroylaminobenzimidazoles (2) have been converted into 1(2-benzimidazolyl)-5-aryl-1H-tetrazoles (4) by treatment with PCl₅ followed by azidation with NaN₃ in aqueous acetone solution. Pyrolysis of 4 in diphenylether yielded 2-aryl-1H-s-triazolo [1,5-a] benzimidazoles (6). The product of benzylation of 6a has been characterised. A reasonable pathway for the formation of 6 from 4 has been suggested.     

Facile synthesis of fluorine-containing [4-aryl-4,5-dihydro-5-imino-1,3,4-thiadiazol-2-ylaryl]methanone, 2-amino-4-aryl-5-arylazothiazoles and 3-aroyl-4-acetyl/benzoyl-5-methyl-1-phenylpyrazoles through N-aryl-α-oxo-α-arylethanehydrazonoyl bromide

N-Aryl-α-oxo-α-arylethanehydrazonoyl bromides 2 react with potassium thiocyanate in ethanol leading to the formation of [4-aryl-4,5-dihydro-5-imino-1,3,4-thiadiazol-2-ylaryl]methanone 5 in quantitative yield. Treatment of 2 with thiourea and β-diketones affords 2-amino-4-aryl-5-arylazothiazoles 4 and 3-aroyl-4-acetyl/benzoyl-5-methyl-1-phenylpyrazoles 6 in 65–70 and 60–70% yields respectively. Compound 5 has also been subjected to acetylation and chloroacetylation. All the compounds are characterized by their analytical and spectral (ir, ¹H-nmr and ms) data. Mass fragmentation patterns of these compounds are discussed.     

Synthesis of heterocycles. Part VI. Synthesis and antimicrobial activity of some 4-amino-5-aryl-1,2,4-triazole-3-thiones and their derivatives

4-Amino-5-aryi-1,2,4-triazole-3-thiones I react with acid chlorides to yield 4-acylamino-5-aryl-1,2,4-triazole-3-thiones II. Compounds I also react with methylene iodide, chloroacetonitrile and methyl bromoacetate to give bis-(4-amino-5-aryl-1,2,4-triazol-3-ylthio)methanes III, 4-amino-5-aryl-3-cyanomethylthio-1,2,4-triazoles IV and 4-amino-5-aryl-3-carbomethoxymethylthio-1,2,4-triazoles V, respectively. Compounds V react with hydrazine hydrate to give the corresponding acid hydrazides VI which in turn condenses with acid chlorides and aldehydes to afford respectively 1-[(4-amino-5-aryl-1,2,4-triazol-3-ylthio)acetyl]-2-aroylhydrazines VII and aryl methylene (4-amino-5-aryl-1,2,4-triazol-3-ylthio)acethydrazones VIII. The antimicrobial activities of the above compounds were screened against different strains of bacteria and fungi.     

Synthesis of 6-amino-2-aryl-1,2-dihydro-3H-pyrido[2,3-d]pyrimidin-4-one derivatives

This paper reports the synthesis of new pyrido[2,3-d]pyrimidin-4-one derivatives as diuretic agents. Starting with 1,2-dihydro-5-nitro-2-oxo-3-pyridinecarboxylic acid 1 , ethyl 2-ethoxy-5-nitro-3-pyridincarboxylate 4 was obtained. Compound 4 reacts with ammonia, methylamine or S-methylpseudothiourea to give the respective 2-amino-5-nitro-3-pyridinecarboxamide derivatives 5 and 6 or 2-methylthio-6-nitro-3H-pyrido[2,3-d]pyrimidin-4-one 8. Treating carboxamide 5 with arylaldehydes and zinc dichloride, new 2-aryl-1,2-dihydro-6-nitro-3H-pyrido[2,3-d]pyrimidin-4-ones 9 were synthetised. These compounds reduced with iron(II) hydroxide gave 6-amino-2-aryl-1,2-dihydro-3H-pyrido[2,3-d]pyrimidin-4-ones 10 as expected.     

5-Cyano-6-aryluracil and 2-thiouracil derivatives as potential chemotherapeutic agents. IV

A series of 5-cyano-6-aryluracils and 2-thiouracils 1a-h has been prepared and alkylated to 1,3-dialkyluracils 2a-d and 2-alkylthiouracils, 3, 4 and 6 , by electrophilic substitution with alkyl halides. Reaction of 1b with dibromoethane and 1,3-dibromopropane gave the corresponding bicyclic products, 7-aryl-6-cyano-2,3-dihydrothiazolo[3,2-a]pyrimidin-5-ones 5a,b and 8-aryl-7-cyano-3,4-dihydro-2H-pyrimido[2,3-b][1,3]thiazin-6-ones 5c-g . Nucleophilic substitution on 6 with hydrazine led to 7 which on refluxing with formic acid gave 5-aryl-6-cyano-8-methyl-s-triazolo[3,4-b]pyrimidin-7-ones ( 9 ), while with acetic and propionic acids only 2-acylhydrazino-3-methyl-4-oxo-5-cyano-6-arylpyrimidines 8a,b were isolated. The hydrazine 7 undergoes cyclization with acetylacetone and methyl dimethylmercaptoacrylate providing 2-(pyrazol-1-yl)-3-methyl-4-oxo-5-cyano-6-substituted pyrimidines 10 , and 11 . Some of the compounds were screened for antibacterial-, antifungal- and antiviral activities and a few of them showed significant chemotherapeutical activities.     

Synthesis and nmr study of 7-aryl-1,2,4-triazolo-[1,5-a]-1, 3,5-triazines

The reactionof N-(1,2,4)-triazol-5-yl)amidines with ethyl orthoformate is a convenient method for the fusion of a triazine ring to the triazole ring. An NMR study showed that the heterocyclic compounds obtained are 7-aryl-1,2,4-triazolo-[1,5- a]-1,3,5-triazines.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 10, pp. 2386–2388, October, 1989.