SYNTHESIS AND REACTIONS OF 2,3-DIHYDRO- 5-ARYL-5H,6H-THIAZOLO[3,2-b]-2,4-DIAZAFLUORENE-3,6-DIONES OF POTENTIAL BIOLOGICAL ACTIVITIES

Abstract

1,2,3,4-Tetrahydro-l-aryl-3,9-dioxo-2,4-diazafluorenes (2) and 1,2,3,4-tetrahydro-1-aryl-9-oxo-3-thi-oxo-2,4-diazafluorenes (3) were newly synthesized. Compounds 3 reacted with chloroacetic acid, α-bromopropanoic acid, or B-bromopropanoic acid in the presence of fused sodium acetate and acetic anhydride to give 2,3-dihydro-5-aryl-5H,6H-thiazolo[3,2-b]2,4-diazafluorene-3,6-diones (4), 2-methyl-2,3-dihydro-5-aryl-5H,6H-thiazolo[3,2-b]2,4-diazafluorene-3,6-diones (5) and 2,3-dihydro-6-aryl-6H,7H-thiazino[3,2-b]2,4-diazafluorene-4,7-diones (6), respectively.

2,3-Dihydro-2-arylmethylene-5-aryl-5H,6H-thiazolo[3,2-b]2,4-diazafluorene-3,6-diones (7) were prepared by the reaction of compounds (3) with chloroacetic acid and aromatic aldehydes in the presence of fused sodium acetate and acetic anhydride or by the reactions of (4) with aromatic aldehydes in the presence of acetic anhydride.

2-(Arylhydroazono)-5-aryl-2,3-dihydro-5H,6H-thiazolo[3,2-b]2,4-diazafluorene-3,6-diones (8) were synthesized by coupling (4) with aryldiazonium salts in the presence of pyridine.     

O-Protected 3-hydroxy-oxazolidin-2,4-diones: novel precursors in the synthesis of alpha-hydroxyhydroxamic acids

O-Protected 3-hydroxyoxazolidin-2,4-diones have been prepared in a novel one-pot reaction by subsequent treatment of cyanohydrins with 1,1'-carbonyldiimidazole and O-protected hydroxylamines followed by acidic hydrolysis of the intermediate 4-imino-oxazolidin-2-ones. Decarbonylation of O-protected 3-hydroxyoxazolidin-2,4-diones by catalytic amounts of sodium methoxide, lithium hydroxide, sodium carbonate and caesium carbonate in methanol afforded O-protected alpha-hydroxyhydroxamic acids in excellent yields. Their deprotection provided a series of novel alpha-hydroxyhydroxamic acids.     

Conventional and microwave-assisted conversion of substituted 3-amino-oxazolidin-2,4-diones into N',N'-disubstituted alpha-hydroxyhydrazides

Substituted 3-amino-oxazolidin-2,4-diones have been prepared by reacting cyanohydrins or alpha-hydroxyesters subsequently with 1,1'-carbonyldiimidazole and 1,1-disubstituted hydrazines followed by acidic hydrolysis in case of the intermediate 3-amino-4-imino-oxazolidin-2-ones. Conventional and microwave-assisted syntheses of N',N'-disubstituted alpha-hydroxyhydrazides have been accomplished by reacting substituted 3-amino-oxazolidin-2,4-diones with catalytic amounts of sodium methoxide in methanol.     

Five-membered 2,3-dioxoheterocycles. 10. Reaction of 5-aryl-2,3-dihydrofuran-2,3-diones with N-substituted ureas and their thio and seleno analogs

3-Aryl-5-phenacylideneimidazolidine-2,4-diones, 3-aryl-5-phenacylidene-4-oxoimidazolidine-2-thiones, and 5-phenacylidene-4-oxoimidazolidine-2-selenones were obtained from 5-aryl-2,3-dihydrofuran-2,3-diones and arylureas, arylthioureas, and selenoureas respectively in glacial acetic acid. In the reaction of 5-aryl-2,3-dihydrofuran-2,3-diones with cyanoguanidine in 98% acetic acid 5-phenacylideneimidazolidine-2,4-diones were isolated, and in anhydrous acetic acid 2-imino-3-amidino-5-phenacylidene-4-oxazolidones were isolated. When heated in a water-dioxane solution of hydrochloric acid, the latter are converted into 5-phenacylideneimidazolidine-2, 4-diones.For Communication 9, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1411–1413, October, 1988.     

Pyrimidine derivatives and related compounds. 38. Synthesis of 1,3-oxazine-2,4-diones and their reaction with nucleophiles. Ring transformation of 1,3-oxazines to pyrimidines

5,6-Unsubstituted 1,3-oxazine-2,4-diones ( 3 ) and 6-unsubstituted 5-methyl-1,3-oxazine-2,4-diones ( 4 ) were prepared by reduction of the corresponding 6-chloro derivatives ( 1 and 2 ). Treatment of 6-chloro-3-methyl-1,3-oxazine-2,4-dione ( 1a ) with sodium azide, sodium cyanide, secondary amines and aniline gave the corresponding 6-substituted compounds ( 7, 9, 10 and 11 ) while the reaction of 1a and 2a,b with primary aliphatic amines such as methylamine and ethylamine caused a ring transformation to pyrimidine ring system giving barbituric acids ( 13a-d ).     

Synthesis of 4-[Alkylsulfanyl(sulfonyl)methyl]isoxazoles and -1<Emphasis Type="Italic">H</Emphasis>-pyrazoles from 3-[(Alkylsulfanyl)methyl]- pentane-2,4-diones

New 4-[(alkylsulfanyl)methyl]- and 4-[(alkanesulfonyl)methyl]isoxazoles and -1H-pyrazoles were synthesized by reactions of 3-[(alkylsulfanyl)methyl]- and 3-[(alkanesulfonyl)methyl]pentane-2,4-diones with hydroxylamine and hydrazine, phenylhydrazine, semicarbazide, or thiosemicarbazide, respectively. The heterocyclization of 3-[(alkylsulfanyl)methyl]pentane-2,4-diones with thiosemicarbazide and semicarbazide hydrochloride was accompanied by elimination of amide or thioamide group. 3-[(Alkanesulfonyl)methyl]pentane- 2,4-diones were found to exist in solution as enol tautomers; they were prepared by oxidation of the corresponding 3-[(alkylsulfanyl)methyl]pentane-2,4-diones with hydrogen peroxide in acetic acid in the presence of a catalytic amount of sulfuric acid.     

Reaction of 3-aminoquinoline-2,4-diones with nitrourea. Synthetic route to novel 3-ureidoquinoline-2,4-diones and imidazo[4,5-c]quinoline-2,4-diones

1-Unsubstituted 3-alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones react with 1-substituted and 1,1-disubstituted ureas in boiling acetic acid to give 2,6-dihydro-imidazo[1,5-c]quinazoline-3,5-diones. In contrast, the reaction of these amines with nitrourea in dioxane affords novel 3-alkyl/aryl-3-ureido-1H,3H-quinoline-2,4-diones or 9b-hydroxy-3a-alkyl/aryl-3,3a,5,9b-tetrahydro-1H-imidazo[4,5-c]quinoline-2,4-diones, which can smoothly be dehydrated to 3a-alkyl/aryl-3,3a-dihydro-5H-imidazo[4,5-c]quinoline-2,4-diones. All three types of products can be converted to 2,6-dihydro-imidazo[1,5-c]quinazoline-3,5-diones by refluxing in acetic acid.     

Reaction of 3-chloroquinoline-2,4-diones with ethanolamine and rearrangement of the reaction products

The reaction of tertiary α-chloroketones with ethanolamine has not been hitherto described in the literature. Herein, we describe the reaction of tertiary 3-chloroquinoline-2,4-diones with ethanolamine to give novel 3-(2-hydroxyethylamino)quinoline-2,4-diones. These compounds provide 3-(2-oxooxazolidin-3-yl)quinoline-2,4(1H,3H)-diones and new compounds with dimeric character after reaction with triphosgene. Molecular rearrangement proceeds during the reaction of 3-(2-hydroxyethylamino)quinoline-2,4-diones with isocyanic acid. Three types of reaction products arise: 2-(2-hydroxyethyl)imidazo[1,5-c]quinazoline-3,5-diones, 3-(2-hydroxyethyl)-3,3a-dihydro-2H-imidazo[4,5-]quinoline-4(5H)diones and primarily 5-hydroxy-1-(hydroxyethyl)-1′H-spiro[imidazolidine-5,3′-indole]-2,2′-diones. The reaction mechanism and product stereochemistry are discussed. The ¹H, ¹³C and ¹⁵N NMR spectra of the prepared compounds were measured, and all resonances were assigned from appropriate two-dimensional experiments.     

3-acyl-1,2,3,4-tetrahydropyridine-2,4-diones: Synthesis and chemical properties

N-Substituted 6-methyl-1,2,3,4-tetrahydropyridine-2,4-diones reacted with aliphatic carboxylic acid chlorides in the presence of pyridine or triethylamine to give the corresponding 4-O-acyl derivatives which underwent O,C-migration of the acyl group by the action of 2 equiv of triethylamine and a catalytic amount of 2-hydroxy-2-methylpropanenitrile. Reactions of 3-acyl-6-methyl-1,2,3,4-tetrahydropyridine-2,4-diones thus formed with aliphatic and aromatic amines gave the corresponding enamino derivatives at the side acyl group. Enamino derivatives at the C⁴ =O group were obtained by transformation of 3-acyl-1,2,3,4-tetrahydropyridine-2,4-diones into 3-acyl-4-methoxy-6-methyl-1,2-dihydropyridin-2-ones via alkylation with dimethyl sulfate and subsequent treatment with amines.     

Quinazolines 1. Synthesis and chemical reactions of 6-chlorosulfonyl-quinazoline-2,4-diones

Treatment of quinazoline-2,4-dione and its symmetrical 1,3-dialkyl derivatives with chlorosulfonic acid gave the corresponding 6-chlorosulfonylquinazoline-2,4-diones. Reaction of the compounds obtained with nucleophilic agents (water, ammonia, aliphatic and cyclic amines) gave the corresponding free 2,4-dioxoquinazoline-6-sulfonic acids, 6-sulfamidoquinazoline-2,4-diones, and 2,4-dioxoquinazoline-6-sulfonic acid amides. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 420–427, March 2008.     

1,3,4,6-Tetracarbonyl Compounds: VI. Synthesis of 2-Substituted 6-Aryl-3,4-dihydroxy-6-oxo-2,4-hexadienoic Acid Esters and Amides

The Knoevenagel reaction of 5-aryl-2,3-dihydrofuran-2,3-diones with ethyl cyanoacetate or malonodinitrile yields 2-substituted 6-aryl-3,4-dihydroxy-6-oxo-2,4-hexadienoic acid esters or amides which exhibit biological activity. The structure of the products is discussed, taking into account the structure of known 3,4-dihydroxy-6-oxo-2,4-hexadienoic acid esters and 1,6-diaryl-3,4-dihydroxy-2,4-hexadiene-1,6-diones.     

Diphenylparabanic acid as a synthon for the synthesis of α-diketones and α-ketocarboxylic acids

Diphenylparabanic acid was found to react with >2 equiv of organolithiums at -78 °C to effectively give the corresponding symmetrical α-diketones. However, upon treatment with 1 equiv of organolithium, the parabanic acid gave mainly 5-substituted 5-hydroxyimidazolidine-2,4-diones. On the other hand, Grignard reagents were less reactive toward the parabanic acid at low temperature, and selectively gave the corresponding 5-hydroxyimidazolidine-2,4-diones even if more than 1 equiv of the reagents was used. A tandem process in which the parabanic acid was first reacted with a Grignard reagent and then reacted in one-pot with an organolithium effectively gave the unsymmetrical α-diketone. 5-Substituted 5-hydroxyimidazolidine-2,4-diones were useful as versatile precursors for preparing α-ketocarboxylic acids as well as unsymmetrical α-diketones.     

Synthesis and antiphospholipase activity of 3,5-disubstituted thiotetronic acid derivatives

The condensation of 3-acetyltetrahydrothiophene-2,4-dione with aromatic aldehydes in the presence of piperidine as a catalyst gave a series of 5-arylmethylidene-3-acetyltetrahydrothiophene-2,4-diones. The reaction with excess aldehyde (2.5 equiv) led to the formation of bis-condensation products, 5-arylmethylidene-3-(3-aryl-1-oxoprop-2-enyl)tetrahydrothiophene-2,4-diones. Analogous 3,5-disubstituted tetrahydrothiophene-2,4-dione derivatives with different aryl groups in the ring and the side chain were synthesized by two-step condensation with the use of differently substituted aromatic aldehydes. Catalytic hydrogenation of both mono-and bis-adducts resulted in the reduction of the side-chain double C=C bond, while ionic hydrogenation with triethylsilane in trifluoroacetic acid in the presence of lithium perchlorate involved both the double C=C bond and carbonyl group in the side chain. The isolated products showed an appreciable effect on the activity of two secretory phospholipases A₂ from various sources.     

Synthesis and keto-enol tautomerism of 6-alkyl-1-alkoxypyridine-2,4-diones

Reactions of 2,2-dimethyl-5-(3-oxoalkanoyl)-1,3-dioxane-4,6-diones with alkoxyamines proceed regioselectively at the β′-keto group of the side acyl chain affording the corresponding tricarbonyl imines whose boiling in toluene leads to the formation of products of intramolecular cyclization, N-alkoxy-2,4-dioxopyridine-3-carboxylic acids. The decarboxylition of the obtained pyridine-3-carboxylic acids in mesitylene at 160–165°C gives in the preparative yield N-alkoxypyridine-2,4-diones. Proceeding from the IR and NMR spectra the problems of the keto-enol and imine-enamine tautomerism were discussed for the series of 5-acyl derivatives of the Meldrum acid and the obtained N-alkoxypyridine-2,4-diones.     

A convenient synthesis of new pyrido[3,2-e][1,4]diazepine-2,5-diones and pyrido[2,3-e][1,4]diazepine-2,5-diones

A convenient synthesis of a series of pyrido[3,2-e][1,4]-diazepine-2,5-diones 8 and pyrido[2,3-e][1,4]diazepine-2,5-diones 9, is reported using the condensation of α-amino acid methyl ester derivatives with 1H-pyrido[3,2-d][1,3]oxazine-2,4-dione and 1H-pyrido[2,3-d][1,3]oxazine-2,4-dione. Compounds 8 and 9 were also synthesized by peptide coupling of α-amino acid methyl ester derivatives with β-amino acids (2 or 3) followed by the cyclisation in tetrahydrofuran with sodium hydride (NaH).     

Direct synthesis of 3-(diaminomethylidene)chromane-2,4-diones from 3-formylchromones and hydroxylamine

3-(Diaminomethylidene)chromane-2,4-diones were synthesized from 4-oxo-4H-chromene-3-carbaldehyde and hydroxylamine in the presence of sodium hydroxide without isolation of intermediate products. Reflux of 3-(diaminomethylidene)chromane-2,4-dione in acetic anhydride gives rise to their monoacetyl derivatives at one of the amino groups.     

Synthesis of 6-Aroyl-3,3,5,5-tetramethyl-2,3,5,6-tetrahydropyran-2,4-diones and Their Reaction with Phenylhydrazine

Methyl 4-bromo-3-oxo-2,2,4-trimethylpentanoate reacts with zinc and arylglyoxals yielding 6-aroyl-3,3,5,5-tetramethyl-2,3,5,6-tetrahydropyran-2,4-diones. The latter with phenylhydrazine afford 6-(1-aryl-2-phenylhydrazonomethyl)-3,3,5,5-tetramethyl-2,3,5,6-tetrahydropyran-2,4-diones.     

Annelation of 3,4-dihydroisoquinolines by 3-acyl-5,5-dimethylthiopyran-2,4-diones. Synthesis and properties of 8-aza-17-thia-d-homogona-12,17a-diones

We have used annelation of 3,4-dihydroisoquinolines by 3-acyl-5,5-dimethylthiopyran-2,4-diones to obtain the corresponding 8-aza-17-thia-D-homogonanes, which are novel representatives of heterosteroids. We have studied the tautomerism of 3-acylthiopyran-2,4-diones using NMR spectroscopy and H/D-isotope exchange. We have obtained 2H-isotopomers of 3-acylthiopyran-2,4-diones.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1572–1583, October, 2004.     

Polyfunctional imidazoles: II. Synthesis and reactions with nucleophilic reagents of 1-substituted 2,4-dichloro-1<Emphasis Type="Italic">H</Emphasis>-imidazole-5-carbaldehydes

1-Alkyl(aryl)imidazolidine-2,4-diones reacted with Vilsmeier-Haack reagent affording 1-alkyl(aryl)-2,4-dichloro-1H-imidazole-5-carbaldehydes whose reactions with sodium azide, sodium alkoholates, with phenols, thiols, and secondary cycloalkylamines led to the substitution of chlorine in the position 2 of the imidazole ring. The reaction with primary amines resulted in the condensation products at the aldehyde group.     

Quinazolines. 2*. unsymmetric 1,3-dialkyl-6-chlorosulfonyl- quinazoline-2,4-diones in nucleo- philic substitution reactions

The corresponding 6-chlorosulfonylquinazoline-2,4-diones were synthesized by the reactions of 1-methylquinazoline-2,4-dione and its 3-alkyl-substituted derivatives with chlorosulfonic acid. Treatment of the products with nucleophilic agents (water or ammonia, aliphatic and cyclic amines) gave 2,4-dioxoquinazolin-6-sulfonic acids or their amides.