Synthesis of 1-[3-methyl-2(3H)-benzazolon-5- or 6-yl]-4-{4-[cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-yl]methyleneoxyphenyl}piperazines

Reactions of 3-methyl-6-[4-(4-hydroxyphenyl)-1-piperazinyl]-2(3H)-benzoxazolone, 3-methyl-6-[4-(4-hydroxy-phenyl)-1-piperazinyl]-2(3H)-benzothiazolone and 1,3-dimethyl-5-[4-(4-hydroxyphenyl)-1-piperazinyl]-2(3H)-benzimidazolone with cis-{[2-(2,4-dichlorophenyl) -2-(1H-imidazol-1-ylmethyl)]-1,3-dioxolan-4-yl}methyl meth-anesulfonate in the presence of sodium hydride furnish the title compounds.     

Novel heterocycles. Synthesis of 2,3-dihydro-6-methyl-2-phenyl-4H,6H-pyrano[3,2-c][2,1]benzothiazin-4-one 5,5-dioxide and related compounds

The reaction of 2-chloro-4-(methylsulfonyl)benzoyl chloride ( 5 ) with 1-methyl-1H-2,1-benzothiazin-4-(3H)-one 2,2-dioxide ( 4 ) gave the O-benzoyl compound, 1-methyl-2,2-dioxido-1H-2,1-benzothiazin-4-yl 2-chloro-4-(methylsulfonyl)benzoate ( 6 ), which rearranged to give the C-benzoyl isomer, [2-chloro-4-(methylsulfonyl)phenyl] (4-hydroxy-1-mefhyl-2,2-dioxido-1H-2,1-benzothiazin-3-yl)methanone ( 7 ). The O-cinnamoyl compound 13 that resulted from the addition of 2,4-dichlorocinnamoyl chloride ( 11 ) to compound 4 rearranged to give the C-cinnamoyl compound, 3-(2,4-dichlorophenyl)-1-(4-hydroxy-1-methyl-2,2-dioxido-1H-2,1-benzothiazin-3yl)-2-propen-1-one ( 15 ). On the other hand, 1-methyl-2,2-dioxido-1H-2,1-benzothiazin-4-yl 3-phenyl-2-propenoate ( 19 ) (from cinnamoyl chloride ( 17 ) and compound 4 ) rearranged to give 2,3-dihydro-6-methyl-2-phenyl-4H,6H-pyrano[3,2-c][2,1]benzothiazin-4-one 5,5-dioxide ( 21 ), an example of a hitherto unknown ring system. Additional examples of this novel heterocycle were prepared from 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 23 ) and 1-methyl-1H-thieno[3,2-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 8 ).     

Retro-ene reactions in heterocyclic synthesis,III. A new route to 4,5-dihydrooxazoles and 5,6-dihydro-4H-1,3-oxazines

Methyl (E)-4,4-dimethyl-5-oxo-2-pentenoate ( 1 , X = O) reacted with 1,2- or 1,3-aminoalcohols 3 to yield oxazolidines 4a-c or tetrahydro-1,3-oxazines 4d,e. The corresponding imino ester 1 (X = NBu-t) also gave 4 on reaction with 3 . Compounds 4 on heating at 230° yielded 4,5-dihydrooxazoles 5a-c or 5,6-dihydro-4H-1,3-oxazines 5d,e along with methyl 4-methyl-3-pentenoate ( 6 ).     

Synthesis of 3,3′-(1,6-hexanediyl)bis-pyrimidine derivatives and 3,4-dithia[6.6](1.3)pyrimidinophane

Several 3,3′-(1,6-hexanediyl)bis[6-methyl-2,4(1H,3H)-pyrimidinedione] derivatives ( 4a, 4b , and 4c ) were synthesized from 1,6-(hexanediyl)bis[6-methyl-2H-1,3-oxazine-2,4(3H)-dione] (3) . Compound 4c was converted to 6, which reacted with thiourea giving thiuronium salt 7 . 3,3′-(1,6-Hexanediyl)bis [1-(2-mercaptoethyl)-6-methyl-2,4(1H,3H)-pyrimidinedione] (9) was obtained by the hydrolysis of 7 , and then 9 was oxidized to 12,22-dimethyl-3,4-dithia[6.6] (1.3)-1,2,3,4-tetrahydro-2,4-dioxopyrimidinophane (10) .     

Pteridine. Teil LXXXI. Mechanismus der Photooxidation von 5,6-Dihydro-1,3-dimethyl-6-thioxopteridin-2,4(1H,3H)-dion

Mechanism of the Photooxidation of 5,6-Dihydro-1,3-dimethyl-6-thioxopteridine-2,4(1H,3H)-dione The mechanism of the photooxidation of 5,6-dihydro-1,3-dimethyl-6-thioxopteridine-2,4(1H,3H)-dione ( 9 ) has been investigated in dependence of the pH. Photooxidation of the anion species in weak alkaline solution takes place by singlet oxygen as well as the superoxide radical anion forming 1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxopteridine-6-sulfinate ( 5 ) as the first detectable reaction product. In acidic medium, a more complex photooxidation process is observed leading, in a radical-chain mechanism, to 6,6′-dithiobis[1,3-dimethylpteridine-2,4(1H,3H)-dione] ( 6 ).     

The first synthesis and X-ray structures of polyfluorinated 1,2-, 2,3- and 2,4a-dihydro-1,3-diazafluorenes

Acetic acid-catalyzed condensation of 2-amino-3-(1-imino-2,2,2-trifluoroethyl)-1,1,4,5,6,7-hexafluoroindene (1b) with acetone and cyclopentanone gives 5,6,7,8,9,9-hexafluoro-2,2-dimethyl-4-trifluoromethyl-2,3-dihydro-1,3-diazafluorene (2a) and 5,6,7,8,9,9-hexafluoro-4-trifluoromethyl-2,3-dihydro-1,3-diazafluorene-2-spiro-1′-cyclopentane (3a) together with small amounts of 5,6,7,8,9,9-hexafluoro-2,2-dimethyl-4-trifluoromethyl-1,2-dihydro-1,3-diazafluorene (2b) and 5,6,7,8,9,9-hexafluoro-4-trifluoromethyl-1,2-dihydro-1,3-diazafluorene-2-spiro-1′-cyclopentane (3b), respectively. When acted upon by (CH₃)₂SO₄ compounds 2, 3 were converted into corresponding fluorine-containing 1-methyl-1,2-dihydro-1,3-diazafluorenes 6, 7. 4a-Chloro-5,6,7,8,9,9-hexafluoro-2,2-dimethyl-4-trifluoromethyl-2,4a-dihydro-1,3-diazafluorene (8) has been synthesized by the interaction of compound 2 with SOCl₂. Solution of compound 2 as well as 8 in CF₃SO₃H-CD₂Cl₂ generated 5,6,7,8,9,9-hexafluoro-2,2-dimethyl-4-trifluoromethyl-1,2,3,4-tetrahydro-1,3-diazafluorene-4-yl cation (2c). The structures of compounds 2, 3, 6-8 have been determined by single crystal X-ray diffraction.     

Synthesis of 6-aryl-1,3-dimethyl-6,7-dihydro-6-azalumazin-7-(6H)ones and their conversion into 2-aryl-1,2,4-triazine-3,5-(2H,4H)odiones. A new synthesis of 1-aryl-6-azauracils

Treatment of 6-amino-5-arylazo-1,3-dimethyluracils with urea or N,N′-carbonyldiimidazole gave the respective 6-aryl-1,3-dimethyl-6,7-dihydro-6-azalumazin-7-(6H)ones, which were hydrolyzed with alkali to afford 2-aryl-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carboxylic acids (1-aryl-6-azauracil-5-carboxylic acids). Thermal decomposition of these carboxylic acids gave the corresponding 2-aryl-1,2,4-triazine-3,5-(2H,4H)diones (1-aryl-6-azauracils). Methylation of the latter with methyl iodide gave the corresponding 2-aryl-4-methyl-1,2,4-triazine-3,5-(2H,4H)diones (1-aryl-3-methyl-6-azauracils).     

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.     

[f]-Fused purine-2,6-diones: Synthesis of new [1,3,5]- and [1,3,6]-thiadiazepino-[3,2-f]-purine ring systems

Summary 6-Phenyl-1,3-dimethyl-2,4-dioxo-1,2,3,4,8,9-hexahydro-[1,3,5]-thiadiazepino-[3,2-f]-purine (5) was obtained by a three-step synthesis from 8-mercapto-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (1) and 2-(benzoylamino)-ethyl chloride (2)via 8-(benzoylaminoethylthio)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (3) and its chloromido derivative4. The analogous 9-phenyl-1,3-dimethyl-2,4-dioxo-1,2,3,4,6,7-hexahydro-[1,3,6]-thiadiazepino-[3,2-f]-purine (7) was synthesized either from compound1 and N-(2-chloroethyl)-benzimido chloridevia N-(chloroethyl)-S-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-7H-purin-8-yl)-benzothioimide (6), or alternatively from 7-(2-benzoylaminoethyl)-8-bromo-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (9), its 8-mercapto derivative10 and the corresponding chloroimido compound11 being the intermediates.Part of this paper was presented as a preliminary report at the Congress of Czech and Slovak Chemical Societies, Olomouc, Czech Republic, September 13–16, 1993     

Bildung von 5,6-Dihydro-1,3(4H)-thiazin-4-carbonsäure-estern aus 4-Allyl-1,3-thiazol-5(4H)-onen

Formation of Methyl 5,6-Dihydro-l, 3(4H)-thiazine-4-carboxyiates from 4-Allyl-l, 3-thiazol-5(4H)-ones . The reaction of N-[1-(N, N-dimethylthiocarbamoyl)-1-methyl-3-butenyl]benzamid ( 1 ) with HCl or TsOH in MeCN or toluene yields a mixture of 4-allyl-4-methyl-2-phenyl-1,3-thiazol-5(4H)-one ( 5a ) and allyl 4-methyl-2-phenyl-1,3-thiazol-2-yl sulfide ( 11 ; Scheme 3). Most probably, the corresponding 1,3-oxazol-5(4H)-thiones B are intermediates in this reaction. With HCl in MeOH, 1 is transformed into methyl 5,6-dihydro-4,6-dimethyl-2-phenyl-1,3(4H)-thiazine-4-carboxylate ( 12a ). The same product 12a is formed on treatment of the 1,3-thiazol-5(4H)-one 5a with HCl in MeOH (Scheme 4). It is shown that the latter reaction type is common for 4-allyl-substituted 1,3-thiazol-5(4H)-ones.     

Pyrimidine derivatives. IX . Synthesis of bromosubstituted 5-nitro-2,4(1H,3H)-pyrimidinedione derivatives

The following 5-nitro-2,4(1H,3H)-pyrimidinediones possessing bromo substituted side chains at the 1- and 6-positions were prepared by bromination of 3,6-dimethyl-1-(ω-hydroxyalkyl)-5-nitro-2,4(1H,3H)-pyrimidinediones 4a and 4b and its nitrates 2a and 2b . The three of mono-bromo derivatives are: 1-(ω-acetoxyalkyl and ω-hydroxyalkyl)-6-bromomethyl-3-methyl. 6a, 6b, 7a and 7b and 1-(ω-bromoalkyl)-3,6-dimethyl-2,4(1H,3H)- pyrimidinediones 8a and 8b . The one type dibromo derivatives are: 1-(ω-bromoalkyl)-6-bromomethyl-3-methyl-2,4(1H,3H)-pyrimidinediones 5a and 5b .     

Synthesis and antimicrobial testing of 2-amino-6-hydroxymethyl-4-(3H)pyrido[3,2-d]pyrimidinone

Synthesis of 2-amino-6-hydroxymethyl-4-(3H)pyrido[3,2-d]pyrimidinone ( 5 ) from 2-amino-6-methyl-4-(3H)-pyrido[3,2-d]pyrimidinone ( 2 ) was accomplished by selenium dioxide oxidation of 2 to the aldehyde 4 followed by sodium borohydride reduction. Compound 2 was available in four steps from 5-aminouracil or in two steps from 5-nitroisocytosine ( 3a ). Catalytic reduction of 4 or 5 gave a mixture of 2-amino-6-methyl-5,6,7,8-tetrahydro-4-(3H)pyrido[3,2-d]pyrimidinone ( 6a ) and the 6-hydroxymethyl compound 6b . These compounds showed only weak inhibitory activity in the coupled reactions catalyzed by 7,8-dihydro-6-hydroxymethylpterin pyrophosphokinase and 7,8-dihydropteroate synthetase from E. Coli. No significant antibacterial activity was observed.     

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.     

Five-membered 2,3-dioxo heterocycles: LXXVIII. Acylation of fischer’s base with aroylketenes. Crystalline and molecular structure of (1E, 3Z)-4-(4-chlorophenyl)-4-hydroxy-1-(1,3,3-trimethyl-2,3-dihydro-1H-indol-2-ylidene)but-3-en-2-one

Aroylketenes generated by thermolysis of 6-aryl-2,2-dimethyl-4H-1,3-dioxin-4-ones reacted with 1,3,3-trimethyl-2-methylidene-1,3-dihydro-2H-indole (Fischer’s base) to produce (1E,3Z)-4-aryl-4-hydroxy-1-(1,3,3-trimethyl-1,3-dihydro-2H-indol-2-ylidene)but-3-en-2-ones. The crystalline and molecular structures of (1E,3Z)-4-(4-chlorophenyl)-4-hydroxy-1-(1,3,3-trimethyl-2,3-dihydro-1H-indol-2-ylidene)but-3-en-2-one were determined by X-ray analysis.     

Synthesis of 1,2-diazepino[3,4-b]quinoxalines and pyrido[3′,4′:9,8][1,5,6]oxadiazonino[3,4-b]quinoxalines via a 1,3-dipolar cycloaddition reaction

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 8 with furfural, 3-methyl-2-thiophene-carbaldehyde, 2-pyrrolecarbaldehyde, 4-pyridinecarbaldehyde and pyridoxal hydrochloride gave 6-chloro-2-[2-(2-furylmethylene)-1-methylhydrazino]quinoxaline 4-oxide 5a , 6-chloro-2-[1-methyl-2-(3-methyl-2-thienyl-methylene)hydrazino]quinoxaline 4-oxide 5b , 6-chloro-2-[1-methyl-2-(2-pyrrolylmethylene)hydrazino]quinoxa-line 4-oxide 5c , 6-chloro-2-[1-methyl-2-(4-pyridylmethylene)hydrazino]quinoxaline 4-oxide 5d and 6-chloro-2-[2-(3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridylmethylene)-1-methylhydrazino]quinoxalme 4-oxide 5e , respectively. The reaction of compound 5a or 5b with 2-chloroacrylonitrile afforded 8-chloro-3-(2-furyl)-4-hydroxy-1-methyl-2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6a or 8-chloro-4-hydroxy-1-methyl-3-(3-methyl-2-thienyl)-2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6b , respectively, while the reaction of compound 5e with 2-chloroacrylonitrile furnished 11-chloro-7,13-dihydro-4-hydroxy-methyl-5,14-methano-1,7-dimethyl-16-oxopyrido[3′,4′:9,8][1,5,6]oxadiazonino[3,4-b]quinoxaline 7.     

Prins-Reaktionen mit Arylaldehyden, 2. Mitt. Diene

By 1,4-addition of arylaldehydes to 2,3-dimethyl-1,3-butadiene in the presence of sulfuric acid 2-aryl-4,5-dimethyl-3,6-dihydro-2H-pyrans are obtained. From 1,3-butadiene and isoprene beside the corresponding 3,6-dihydro-2H-pyrans by reaction with two more molecules aldehydetrans-2,4,7-triphenyl-4a,7,8,8a-tetrahydro-4H,5H-pyrano[4,3-d-1,3-dioxines are formed. With 1,3-cyclohexadiene, however, 1,2-addition of benzaldehyde is observed to givecis-r-2,c-4-diphenyl-4a,5,6,8a-tetrahydro-1,3-benzodioxane.     

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.     

Die Struktur des Adduktes aus 3-Dimethylamino-2,2-dimethyl-2H-azirin und 3-Methyl-2,4-diphenyl-1,3-oxazolium-5-olat. Vorläufige Mitteilung

Structure of the adduct from 3-dimethylamino-2,2-dimethyl-2H-azirine and 3-methyl-2,4-diphenyl-1,3-oxazolium-5-olate 3-Dimethylamino-2,2-dimethyl-2H-azirine ( 1 ) reacts with 3-methyl-2,4-diphenyl-1,3-oxazolium-5-olate ( 5a ) to give a 1:1 adduct ( 7 ) in a 88% yield. Its crystal structure has been determined by X-ray analysis (direct methods) and refined with 1056 structure amplitudes to R = 0,032. The crystal system is monoclinic, space group P2₁/c, with unit cell dimensions a = 10.663, b = 9,828, c = 18,592 Å, and β = 90,63°. It is obvious that 4-dimethylamino-5,5-dimethyl-2-[α-(N-methyl-benzamido)benzyliden]-Δ³-1,3-oxazoline ( 7 ) arises from an addition of 1 to the valence-polaromeric ketene form 5b of the mesoionic oxazolone 5a (Scheme 3).     

On the oxidation of N-methylpyrimidinium salts

Oxidation of 1,2-dihydro-1,3-dimethyl-2-oxopyrimidinium bisulfate ( 1 ⁺·HSO) with hydrogen peroxide in acetic acid in the presence of potassium iodide gave 1,3-dimethyl-5-iodouracil (65-70%), 1,3-dimethyluracil (10-15%) and 3-methyl-2,4-oxazolidinedione (10-15%). Similar results were obtained on oxidation of the iodide ( 1⁺·I^? ). Oxidation of 1-methyl-4-phenylpyrimidinium iodide or oxidation of 1-methyl-4-phenylpyrimidinium methylsulfate in the presence of potassium iodide gave 1,6-dihydro-5-iodo-1-methyl-6-oxo-4-phenylpyrimidine.     

An improved synthesis of 3,6-diamino-1,2,4,5-tetrazine. I

Treatment of 1,3-diaminoguanidine monohydrochloride ( 1 ) with 2,4-pentanedione ( 2 ) in alcohols under carefully controlled conditions gave 3,6-diamino-1,2-dihydro-1,2,4,5-tetrazine monohydrochloride ( 3 ) in 45-50% yields along with 3,5-dimethyl-1H-pyrazole ( 4 ) and its hydrochloride 5 . Oxidation of 3 with sodium perborate produced 3,6-diamino-1,2,4,5-tetrazine ( 6 ) in quantitative yield.