Synthesis of 2-thioxoimidazolines via reaction of 1-unsubstituted 3-aminoquinoline-2,4-diones with isothiocyanates

3-Alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones react with alkyl/aryl isothiocyanates to give 3a-alkyl/aryl-1,2,3,3a-tetrahydro-9b-hydroxy-2-thioxo-5H-imidazo[4,5-c]quinolin-4(9bH)-ones in high yields. These compounds rearrange in boiling acetic acid or concd hydrochloric acid to give novel 4-(2-aminophenyl)-1H-imidazole-2(3H)-thiones, 1,3-bis(2-(2,3-dihydro-2-thioxo-1H-imidazol-5-yl)phenyl)ureas and minor N-(2-(2,3-dihydro-2-thioxo-1H-imidazol-4-yl)phenyl)acetamides. In the presence of ethanol, the starting compounds rearrange in boiling acetic acid to give ethyl 2-(2,3-dihydro-2-thioxo-1H-imidazol-4-yl)phenylcarbamates. All compounds were characterized by their ¹H, ¹³C, IR and MS spectra and some of them also by ¹⁵N NMR data. The structures of two compounds were supported by single-crystal X-ray diffraction.     

Intramolecular amidation: synthesis of novel imidazo[2,1-b][1,3,4]thiadiazole and imidazo[2,1-b][1,3]thiazole fused diazepinones

Novel heterocyclic systems 2-alkyl/aryl-9-(2-hydroxybenzylidene)-7,9-dihydro-8H-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-d][1,2]diazepin-8-one and 9-(2-hydroxy-benzylidene)-3,3-dimethyl-3,4,7,9-tetrahydro-2H-11-thia-4b,6,7,10-tetraazaindeno[1,2-a]azulene-1,8-dione are synthesized via an intramolecular amidation reaction. An interesting ring opening and cyclization of 2-alkyl/aryl-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde and 6,6-dimethyl-8-oxo-2-(2-oxo-2H-chromen-3-yl)-5,6,7,8-tetrahydroimidazo[2,1-b][1,3]benzothiazole-3-carbaldehyde are discussed.     

Reaction of 1-alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones with urea. Synthetic route to novel 3-(3-acylureido)-2,3-dihydro-1H-indol-2-ones, 4-alkylidene-1′H-spiro[imidazolidine-5,3′-indole]-2,2′-diones, and 3,3a-dihydro-5H-imidazo[4,5-c]quinoline-2,4-diones

1-Substituted 3-alkyl/aryl-3-amino-1H,3H-quinoline-2,4-diones react with urea in boiling acetic acid to give products depending on the type of substitution in position 3 and at the nitrogen atom of the 3-amino group. Starting compounds bearing a primary amino group in position 3 give 3-(3-acylureido)-2,3-dihydro-1H-indol-2-ones. Starting compounds bearing a secondary amino group in position 3 react according to the character of the other substituent in position 3. If there is a hydrogen atom α to the carbon atom C(3), 4-alkylidene-1′H-spiro[imidazolidine-5,3′-indole]-2,2′-diones arise. If a hydrogen atom is not present in this position, the reaction leads to 3,3a-dihydro-5H-imidazo[4,5-c]quinoline-2,4-diones. Reaction mechanisms for these transformations are proposed. All compounds were characterized by their ¹H, ¹³C, IR and atmospheric pressure chemical ionization mass spectra and some of them also by ¹⁵N NMR data.     

Synthesis of Some New Thiazoles and Pyrazolo[1,5-a]pyrimidines Containing an Antipyrine Moiety

Ethyl 2-{2-[4-(2,3-dimethyl-5-oxo-1-phenyl-3-(pyrazolin-4-yl)]-2-cyano-1-(phenylamino)vinylthio}-acetate, 2-[4-(2,3-dimethyl-5-oxo-1-phenyl-(3-pyrazolin-4-yl))(1,3-thiazol-2-yl)]2-(4-oxo-3-phenyl-(1,3-thiazoilidin-2-ylidene))ethanenitrile, 2-[4-(2,3-dimethyl-5-oxo-1-phenyl(3-pyrazolin-4-yl))(1,3-thiazol-2-yl)]-2-(4-methyl-3-phenyl(1,3-thiazolin-2-ylidene))ethanenitrile, 2-(5-acetyl-4-methyl-3-phenyl(1,3-thiazolin-2-ylidene))-2-[4-(2,3-dimethyl-5-oxo-1-phenyl(3-pyrazolin-4-yl))(1,3-thiazol-2-yl)]ethanenitrile, and ethyl 2-(cyano(4-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)thiazol-2-yl)methylene)-2,3-dihydro-4-methyl-3-phenylthiazole-5-carboxylate were synthesized by treatment of 2-(4-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)thiazol-2-yl)-3-mercapto-3-(phenylamino)-acrylonitrile with appropriate halo ketones or halo esters. Also, 4-{2-[5,7-dimethyl-2-(phenylamino)(7a-hydropyrazolo[1,5-a]pyrimidin-3-yl](1,-thiazol-4-yl)}-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one derivatives were synthesized via reaction of 4-{2-[5-amino-3-(phenylamino)pyrazolin-4-yl](1,3-thiazol-2-yl)}-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one with β-diketone or β-keto ester. All synthesized compound were established by elemental analysis, spectral data, and alternative synthesis whenever possible.     

Reactions of 1,2,4-triazole derivatives with a “model” thiirane

Reactions of 3-mono- and 3,5-disubstituted 1,2,4-triazoles with a “model” thiirane, 8-bromo-1,3-dimethyl-7-(thiiran-2-ylmethyl)-3,7-dihydro-1H-purine-2,6-diones proceed at the positions N¹ and N² of the triazole ring and yield 7-(5-R-3-R′-1,2,4-triazol-1-yl)methyl- and/or 7-(5-R′-3-R-1,2,4-triazol-1-yl)methyl-1,3-dimethyl-6,7-dihydro[1,3]thiazolo[2,3-f]-purine-2,4-(1H,3H)-diones. 3-Methylsulfonyl-1,2,4-triazole reacted regiospecifically at the position N¹ forming 1,3-dimethyl-7-[(3-methyl-sulfonyl-1,2,4-triazole-1-yl)-methyl]-6,7-dihydro[1,3]thiazolo-[2,3-f]purine-2,4(1H,3H)-dione.     

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.     

Synthesis of 7-iodo(arylsulfanyl)methyl-7,8-dihydro-[1,3]thiazolo[2,3-i]purinium pentaiodide (perchlorates) and their transformation into 4-amino-5-(1,3-thiazol-2-yl)imidazole derivatives

Intramolecular electrophilic cyclization of 6-allylsulfanylpurine by the action of iodine and arenesulfenyl chlorides gave 7-iodomethyl-7,8-dihydro[1,3]thiazolo[2,3-i]purin-6-ium pentaiodide and 7-arylsulfanylmethyl-7,8-dihydro[1,3]thiazolo[2,3-i]purin-6-ium perchlorates, respectively. 7-Iodomethyl-7,8-dihydro-[1,3]thiazolo[2,3-i]purin-6-ium iodide reacted with sodium and potassium alkoxides to produce alkyl N-[5-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-4-yl]formimidates, and its reaction with secondary cyclic amines afforded 5-(4-methyl-1,3-thiazol-2-yl)-N-[morpholin-4-yl(or piperidin-1-yl)methylidene]-1H-imidazol-4-amines. Successive treatment of 7-arylsulfanylmethyl-7,8-dihydro[1,3]thiazolo[2,3-i]purin-6-ium perchlorates with sodium acetate and morpholine led to the formation of 5-(4-arylsulfanylmethyl-4,5-dihydro-1,3-thiazol-2-yl)-N-(morpholin-4-ylmethylidene)-1H-imidazol-4-amines.     

Recyclization of 1,3-dialkyl-6-nitro-1<Emphasis Type="Italic">H</Emphasis>-imidazo[4,5-<Emphasis Type="Italic">b</Emphasis>]pyridine-2,5(3<Emphasis Type="Italic">H</Emphasis>,4<Emphasis Type="Italic">H</Emphasis>)-diones into imidazole derivatives

Treatment of 5-amino-1,3-dialkyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-ones with sodium nitrite in aqueous HCl gave 1,3-dialkyl-1H-imidazo[4,5-b]pyridine-2,5(3H,4H)-diones which were nitrated with potassium nitrate in sulfuric acid to 6-nitro derivatives, and the latter underwent recyclization into 4-amino-1,3-dialkyl-5-(1H-pyrazol-5-yl)-2,3-dihydro-1H-imidazol-2-ones by the action of hydrazine hydrate.     

Five-membered dioxoheterocycles: XCIX. Reaction of 1-aryl-4-aroyl-5-methoxycarbonyl-1H-pyrrole-2,3-diones with indoles. Crystal and molecular structure of substituted 2-(indol-3-yl)pyrrole

1-Aryl-4-aroyl-5-methoxycarbonyl-1H-pyrrole-2,3-diones react with indole and 2-methylindole with the formation of methyl 1-aryl-3-aroyl-4-hydroxy-2-(1H-indol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylates. Crystal and molecular structure of methyl 3-benzoyl-4-hydroxy-2-(2-methyl-1H-indol-3-yl)-5-oxo-1-phenyl-2,5-dihydro-1H-pyrrole-2-carboxylate was examined.     

Structure and catalytic activity of organopalladium(II) complexes based on 4,5-dihydro-1H-imidazol-5-one derivatives

The paper describes preparation of a chiral bidentate ligand - 2-(2-bromophenyl)-4,5-dihydro-1H-imidazol-5-one, and a tridentate ligand - 2-bromo-1,3-bis(4,5-dihydro-1H-imidazol-5-on-2-yl)benzene, whose oxidative addition reaction with Pd(0) giving neutral organopalladium(II) complexes has been studied. The structure of these complexes was studied by means of NMR spectroscopy and X-ray diffraction. After transformation of the neutral organopalladium(II) complexes into the corresponding ionic species the latter were studied as enantioselctive catalysts for asymmetric Friedel-Crafts alkylation and Michael addition.     

Five-membered 2,3-dioxoheterocycles: XCVI. Reactions of 3-aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5h)-triones with substituted 1,3,3-trimethyl-2-azaspiro[4.5]dec-1-enes

3-Aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones react with 1,3,3,7,9-pentamethyl-2-azaspiro-[4.5] deca-1,6,9-trien-8-one and 2′,5′,5′-trimethyl-4′,5′-dihydro-4H-spiro[naphthalene-1,3′-pyrrol]-4-one providing 3-aroyl-2-hydroxy-3a-{(3,3,7,9-tetramethyl-8-oxo-2-azaspiro[4.5]deca-1,6,9-trien-1-yl)methyl}pyrrolo[1,2-a-quinoxaline-1,4(3a H,5H)-diones and 3-aroyl-2-hydroxy-3a-{(5′,5′-dimethyl-4-oxo-4′,5′-dihydro-4H-spiro[naphthalene-1,3′-pyrrol]-2′-yl)methyl}pyrrolo[1,2-a]-quinoxaline-1,4(3aH,5H)-diones.     

Reaction of methyl 1-bromocyclopentane- and -cyclohexanecarboxylates with zinc and 2-arylmethylideneindan-1,3-diones

Methyl 1-bromocyclopentanecarboxylate and methyl 1-bromocyclohexanecarboxylate reacted with zinc and 2-arylmethylideneindan-1,3-diones to give methyl-1-[(aryl)(1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-methyl]cyclopentane(or cyclohexane)carboxylates and 4′-aryl-2′H-spiro[cyclopentane(or cyclohexane)-1,3′-indeno[ 1,2-b]pyran]-2′,5′(4′H)-diones.     

Synthesis of 1-(1,3-dialkyl-2-oxo-2,3-dihydro-1<Emphasis Type="Italic">H</Emphasis>-imidazo-[4,5-<Emphasis Type="Italic">b</Emphasis>]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic acids

Nitration of 2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one gave its 5-nitro derivative which was subjected to alkylation with dimethyl sulfate, diethyl sulfate, and benzyl(dimethyl)phenylammonium chloride. The resulting 1,3-dimethyl-, 1,3-diethyl-, and 1,3-dibenzyl-5-nitro-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-ones were reduced to the corresponding 1,3-dialkyl-5-amino-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-ones, and the latter reacted with itaconic acid to produce 1-(1,3-dialkyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic acids. 1-(2-Oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic acid was obtained by analogous reaction with 5-amino-2,3-dihydro-1H-imidazo[4,5-b]-pyridin-2-one.     

Synthesis of novel 1-(2,3-dihydro-5H-4,1-benzoxathiepin-3-yl)-uracil and -thymine, and their corresponding S-oxidized derivatives

On the basis of molecular variations on isosteric replacements from the prototype 1-(2,3-dihydro-5H-1,4-benzodioxepin-3-yl)-5-fluorouracil a series of 3-(2,3-dihydro-5H-4,1-benzoxathiepin-3-yl)-uracil or -thymine O,N-acetals was prepared. The nature of the cis- and trans-sulfoxide isomers was established by means of their conformational analyses carried out with Sybyl and after comparing the theoretical results with the ¹H NMR responses of the target molecules. (RS)-3-(1,1-Dioxo-2,3-dihydro-5H-4,1-benzoxathiepin-3-yl)thymine and (1S*,3S*)-1-(1-oxo-3,5-dihydro-2H-4,1-benzoxathiepin-3-yl)thymine were found to be inhibitors of the MCF-7 cell growth.     

Azines and azoles: CXXVI. First example of a novel heterocyclic system: Pyrimido[1,6-<Emphasis Type="Italic">a</Emphasis>][1,5]benzodiazepines

4-Hydroxy-5-(2-R-2,3-dihydro-1H-1,5-benzodiazepin-4-yl)-2H-1,3-thiazine-2,6-diones readily undergo acylation at the N¹ atom of the benzodiazepine system by the action of acetic anhydride. Heating of the acetylated products in boiling dimethylformamide leads to the formation of 75–93% of the corresponding 7-acetyl-6-R-6,7-dihydropyrimido[1,6-a][1,5]benzodiazepine-1,3-diones that are derivatives of hitherto unknown fused heterocyclic system, pyrimido[1,6-a][1,5]benzodiazepine. 4-Hydroxy-5-(2-R-2,3-dihydro-1H-1,5-benzodiazepin-4-yl)-2H-1,3-thiazine-2,6-diones are converted into 1-(2-aminophenyl)-6-(2-R-vinyl)uracils on heating in boiling DMF.     

Unexpected course of rearrangement of substituted S-(1(3H)-isobenzofuranone-3-yl)isothiuronium bromides

Three series of S-(1(3H)-isobenzofuranone-3-yl)isothiuronium bromides differing in substitution at the isothiuronium moiety (none, one or two methyl groups) and at the benzene ring were prepared and characterized. These salts were then treated with various bases (acetate, triethylamine, Na₂CO₃) to give either 1-hydroxy-3-oxo-1,3-dihydro-2H-isoindol-2-carbothioamides or the product of S to N isobenzofuranone-3-yl migration, i.e., 1,3-dimethyl-1-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thioureas. If ammonia was used in reaction with N,N′-dimethyl isothiuronium salts then 3-hydroxy-2,3-dihydro-1H-isoindol-1-ones were formed together with 1,3-dimethyl-1-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thioureas in parallel reaction with the yields increasing with ammonia concentration. The formation of isoindolones takes place in two steps with an aldehyde intermediate, which can be trapped with N,N-dimethylhydrazine.     

Reaction of 3,4,6-trioxoalkanoic acid esters with 2,4-dinitrophenylhydrazine

Methyl 3,4,6-trioxoalkanoates (3,4-dihydroxy-6-oxo-2,4-alkadienoates) reacted with 2,4-dinitrophenylhydrazine to give methyl 3,6-bis[(2,4-dinitrophenyl)hydrazinylidene]-4-oxoalkanoates or methyl {5-alkyl-2-hydroxy-1-(2,4-dinitroanilino)-3-oxo-2,3-dihydro-1H-pyrrol-2-yl }acetates. Alkyl 3,6-bis[(2,4-dinitrophenyl) hydrazinylidene]-4-oxoalkanoates were also synthesized by reaction of disodium 1-alkoxy-1,6-dioxoalka-2,4-diene-3,4-diolates with 2,4-dinitrophenylhydrazine.     

Synthesis of novel 1,3-oxazino[6,5-b]indole-2,4-(3H,9H)-dione and 2H-1,3,5-oxadiazino[3,2-a]indole-2,4-(3H)-dione from oxindoles

Two novel tricyclic ring systems were designed as serine protease inhibitors and synthesized from oxindoles; the first series, 1,3-oxazino[6,5-b]indole-2,4-(3H,9H)-diones, were prepared from 2,3-dihydro-2-oxo-(1H)-indole-3-carboxamides and phosgene in tetrahydrofuran with triethylamine. The second, a 2H-1,3,5-oxadiazino[3,2-a]indole-2,4-(3H)-dione was made using a similar cyclization on 2,3-dihydro-2-oxo-N-phenyl-(1H)-indole-1-carboxamide.     

Nucleophilic trifluoromethylation of RF-containing 4-quinolones, 8-aza- and 1-thiochromones with (trifluoromethyl)trimethylsilane

Reactions of N-substituted 2-polyfluoroalkyl-4-quinolones and 8-aza-5,7-dimethyl-2-polyfluoroalkylchromones with (trifluoromethyl)trimethylsilane proceed mainly as a 1,4-nucleophilic trifluoromethylation to give N-substituted 2,2-bis(polyfluoroalkyl)-2,3-dihydroquinolin-4(1H)-ones and 5,7-dimethyl-2,2-bis(polyfluoroalkyl)-2,3-dihydro-4H-pyrano[2,3-b]pyridin-4-ones after acid hydrolysis. Similar reaction with 2-trifluoromethyl-4H-thiochromen-4-one proceeds as a 1,2-addition to give 2,4-bis(trifluoromethyl)-4H-thiochromen-4-yl trimethylsilyl ether.     

Five-membered 2,3-dioxo heterocycles: LII. Reactions of 5-aryl-4-(quinoxalin-2-yl)-2,3-dihydrofuran-2,3-diones with Schiff bases and dicyclohexylcarbodiimide. Crystalline and molecular structure of substituted 2-(4-oxo-3,4-dihydro-2<Emphasis Type="Italic">H</Emphasis>1,3-oxazin-5-yl)quinoxalines

Aroyl(quinoxalinyl)ketenes generated by thermolysis of 5-aryl-4-(quinoxalin-2-yl)-2,3-dihydrofuran-2,3-diones react with N-benzylideneanilines and N,N’-dicyclohexylcarbodiimide according to the [4+2]-cycloaddition pattern where the aroylketene acts as diene, and C=N component, as dienophile, to give 3-aryl-2-(2,3,6-triaryl- and 6-aryl-3-cyclohexyl-2-cyclohexylimino-4-oxo-3,4-dihydro-2H-1,3-oxazin-5-yl)quinoxalines. The structure of two cycloaddition products was proved by X-ray analysis.