A NOVEL SYNTHESIS OF 2-SUBSTITUTED-4H-THIENO [2,3-d][1,3] OXAZIN-4-ONE AND 2,3-DISUBSTITUTED THIENO [2,3-d]PYRIMIDIN-4(3H)-ONE DERIVATIVES

Abstract

The synthesis of acetic 2-{[1-methyl-2-(4-oxo-5,6,7,8-tetrahydro-4H-benzo [4,5]-thieno [2,3-d] [1,3-oxazin-2-yl)ethylidene]amino}-4,5,6,7-tetrahydrohenzo[b]thiophene ?3-carboxylic acid anhydride 5 and 2-(oxopropyl)-5,6,7,8-tetrahydro-4H-benzo-[4,5] thieno[2,3-d][1,3]oxazin-4-one 7, has been achieved in three steps from ethyl 2-amino-4,5,6,7-tetrahydrobenzo(b]thiophene-3-carboxlate 1 via the reaction with ethyl acetoacetate followed by hydrolysis and acetic anhydride-induced cyclization. The 2-substituent in compound 5 has two functional groups i.e. active methylene and acid anhydride which are suitably located for intramolecular transformation. Thermal and/or base catalyzed intramolecular cyclization of 5 afforded 2-(4-acetoxy-(hydroxyl)-2-methyl-5,6,7,8-tetrahydrobenzo[4,5] thieno[2,3-b]pyridin-3-yl)-5,6,7,8- tetrahydro-4H-benzo[4,5]thieno[2,3-d] [1,3]oxazin-4-one 10 and 9 respectively. Treatment of 5 with hydrazine hydrate, aromatic and/or heterocyclic amines induced the same intramolecular cyclization with a concomitant oxazine-pyrimidine interconversion to give 3-amino(aryl or heteryl)-2-(4-hydroxy-5,6,7,8-tetrdhydrobenzo-[4,5]thieno[2,3-b]pyridin-3-yl)-3,4,5,6,7,8-hexahydrobenzo[4,5] thieno[2,3-d] pyrimid in-4-one 11–14 respectively.     

Synthesis of 3-pyrrol-3′-yloxindoles with a carbamate function

By the reaction of methyl {4(3)-[2-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetyl]phenyl} carbamates with ethyl 3-aminocrotonate at boiling in the mixture toluene-anhydrous ethanol, 2: 1, ethyl 5-{3(4)-[(methoxycarbonyl)amino]phenyl}-2-methyl-4-(2-oxo-2,3-dihydro-1H-indol-3-yl)-1H-pyrrole-3-carboxylates were obtained. The condensation of methyl {3(4)-[2-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetyl] phenyl}carbamates with ethyl acetoacetate in the presence of ammonium acetate and 20 mol% of 1-methyl-3-butylimidazolium chloride or 1-methyl-3-octylimidazolium tetrafluoroborate at boiling in anhydrous ethanol led to the formation of the corresponding 3-pyrrol-3′-yloxindoles with a carbamate function.     

Synthesis of New Functionally Substituted Aryl- and Hetarylcarbamates Based on Ninhydrin

The condensation of methyl (ethyl) phenylcarbamates with ninhydrin in concentrated sulfuric acid gave dialkyl [1,3-dioxoindan-2,2-diyldi(4,1-phenylene)]biscarbamates. Treatment of the latter with hydrazine hydrate resulted in the transformation of the indandione fragment into phthalazinone. Ninhydrin reacted with methyl (hydroxyphenyl)carbamates in glacial acetic acid to produce dihydroxy derivative of oxotrihydroindeno[ 1,2-b][1]benzofuran possessing a carbamate group. Tandem reaction of ninhydrin with methyl (acetylphenyl) carbamates on heating in boiling glacial acetic acid, followed by addition of hydrazine hydrate in acetonitrile, afforded methyl (5-oxo-5H-indeno[1,2-c]pyridazin-3-yl)phenylcarbamates.     

Synthesis of Some 3-Substituted 1,2-Dihydroindoles

The reaction of 4-oxo-2-(2-oxo-1,2-dihydroindol-3-ylidene)hydrazone-1,3-thiazin-6-methyl carboxylate 2 with hydrazine hydrate in methanol gave 4-oxo-2-(2-oxo-1,2-dihydroindol-3-ylidene)hydrazone-1,3-thiazin-6-carbonylhydrazine 3. Furthermore, the reaction of 3 with carbon disulfide and then hydrazine hydrate afforded 3-[6-(4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4-oxo-1,3-thiazin-2-yl] hydrazone-1,3-dihydroindol-2-one 5. the latest reacted with DMAD to give {6-hydroxy-3-[4-oxo-2-(2-oxo-1,2-dihydroindol-3-ylidene)hydrazone-1,3-thiazin-6yl]-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-ylidene}methoxycarbonylmethylene 6.     

Synthesis of new functionally substituted hetarylcarbamates from methyl {4-[(2<Emphasis Type="Italic">E</Emphasis>)-3-(4-methoxyphenyl)-prop-2-enoyl]phenyl}carbamate

Three-component condensation of methyl {4-[(2E)-3-(4-methoxyphenyl)prop-2-enoyl]phenyl}- carbamate with ninhydrin and L-proline in methanol–water (10: 1) afforded methyl {4-[1,3-dioxo-1′- (4-methoxyphenyl)-1,1′,2′,3,5′,6′,7′,7a′-octahydrospiro[indene-2,3′-pyrrolizin]-2′-ylcarbonyl]phenyl}carbamate. Heating of methyl {4-[(2E)-3-(4-methoxyphenyl)prop-2-enoyl]phenyl}carbamate with isatin and benzylamine in methanol gave methyl {4-[4′-(4-methoxyphenyl)-2-oxo-5′-phenyl-1,2-dihydrospiro[indole-3,2′-pyrrolidin]-3′-ylcarbonyl]phenyl}carbamate. The condensation of methyl {4-[(2E)-3-(4-methoxyphenyl)prop-2- enoyl]phenyl}carbamate with sarcosine and 11H-indeno[1,2-b]quinoxalin-11-one generated in situ from ninhydrin and o-phenylenediamine in boiling ethanol led to the formation of methyl {4-[4′-(4-methoxyphenyl)-1′-methyl-11,11a-dihydro-5aH-spiro[benzo[b]phenazine-6,2′-pyrrolidin]-3′-ylcarbonyl]phenyl}carbamate.     

Synthesis and antimicrobial activity of some derivatives of (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide

(7-Hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide (2) was prepared from (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid ethyl ester (1) and 100% hydrazine hydrate. Compound 2, is the key intermediate for the synthesis of several series of new compounds such as Schiff's bases 3a-l, formic acid N'-[2-(7-hydroxy-2-oxo-2H- chromen-4-yl)acetyl] hydrazide (4), acetic acid N'-[2-(7-hydroxy-2-oxo-2H-chromen-4- yl)-acetyl] hydrazide (5), (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid N'-[2-(4- hydroxy-2-oxo-2H-chromen-3-yl)-2-oxoethyl] hydrazide (6), 4-phenyl-1-(7-hydroxy-2- oxo-2H-chromen- 4-acetyl) thiosemicarbazide (7), ethyl 3-{2-[2-(7-hydroxy-2-oxo-2H- chromen-4-yl)-acetyl]hydrazono}butanoate (8), (7-hydroxy-2-oxo-2H-chromen-4-yl)- acetic acid N'-[(4-trifluoromethylphenylimino)methyl] hydrazide (9) and (7-hydroxy-2- oxo-2H-chromen-4-yl)acetic acid N'-[(2,3,4-trifluorophenylimino)-methyl] hydrazide (10). Cyclo- condensation of compound 2 with pentane-2,4-dione gave 4-[2-(3,5- dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-7-hydroxy-2H-chromen-2-one (11), while with carbon disulfide it afforded 7-hydroxy-4-[(5-mercapto-1,3,4-oxadiazol-2-yl)methyl]-2H- chromen-2-one (12) and with potassium isothiocyanate it gave 7-hydroxy-4-[(5- mercapto-4H-1,2,4-triazol-3-yl)methyl]-2H-chromen-2-one (14). Compound 7 was cyclized to afford 2-(7-hydroxy-2-oxo-2H-chromen-4-yl)-N -(4-oxo-2-phenylimino- thiazolidin-3-yl) acetamide (15).     

Synthesis of aromatic carbamates derivatives with a chromen-2-one fragment

Condensation of methyl N-(3-hydroxyphenyl)carbamate with ethyl trifluoromethylacetoacetate, 2-methoxyethyl acetoacetate in the presence of conc. sulfuric acid, and also with acetonedicarboxylic acid formed in situ from citric acid under the action of conc. sulfuric acid afforded chromene derivatives. The esterification of 2-{7-[(methoxycarbonyl)amino]-2-oxo-2H-chromen-4-yl}acetic acid with methanol in the presence of TsOH provided the corresponding ester. The oxidation of its α-methylene group with selenium dioxide led to the formation of methyl 2-{7-[(methoxycarbonyl)amino]-2-oxo-2H-chromen-4-yl}-2-oxo-acetate entering into a condensation with o-phenylenediamine resulting in a derivative with a dihydroquinoxaline fragment. The reaction of phenyl N-(4-formylphenyl)carbamate with 3-acetyl-2H-chromen-2-one in butanol in the presence of catalytic quantity of piperidine and acetic acid furnished 4-[(E)-3-oxo-2H-chromen-3-yl)-1-propenyl]phenyl N-phenylcarbamate.     

Some chemical transformations of alkyl (4-aminophenyl)carbamates

Azo coupling of diazonium salts derived from alkyl (4-aminophenyl)carbamates with ethyl α-methylacetoacetate gave ethyl 5-alkoxycarbonylamino-1H-indole-2-carboxylates. The condensation of aminophenylcarbamates with aromatic aldehydes in ethanol afforded the corresponding Schiff bases. Cyclohexyl {4-[(4-methoxyphenyl)methylidene]aminophenyl}carbamate reacted with chloroacetyl chloride in dioxane in the presence of triethylamine to produce cyclohexyl {4-[3-chloro-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]phenylcarbamate, and the reaction of benzyl {4-[(4-nitrophenyl)methylidene]aminophenyl}carbamate with sulfanylacetic acid in DMF led to the formation of benzyl {4-[2-(4-nitrophenyl)-4-oxo-1,3-thiazolidin-3-yl]-phenyl}carbamate.     

Synthesis of azoles from 3-[(3-hydrazino-3-oxopropyl)anilino]-and 3-[(3-hydrazino-3-oxopropyl)-4-methylanilino]propane hydrazides

Condensation of 3-[(3-hydrazino-3-oxopropyl)anilino]-and 3-[(3-hydrazino-3-oxopropyl)-4-methylanilino]propane hydrazides with 2,4-pentanedione, phenyl isocyanate or phenyl isothiocyanate (with subsequent work up of the semicarbazides obtained by base), and carbon disulfide gave respectively: 1-(3,5-dimethyl-1H-1-pyrazolyl)-3-[3-(3,5-dimethyl-1H-1-pyrazolyl)-3-oxopropylanilino]-1-propanone, 3-(2-{[2-(5-oxo-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]anilino}ethyl)-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-5-one and its thio analog, and 5-(2-{[2-(2-thioxo-2,3-dihydro-1,3,4-oxadiazol-5-yl)ethyl]anilino}ethyl)-2,3-dihydro-1,3,4-oxadiazole-2(3H)-thione plus their methyl derivatives. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1353–1358, September, 2007.     

Synthesis of N-arylcarbamates with tetrazole fragment and some their derivatives

Reactions of methyl(ethyl) N-(2-cyanophenyl)carbamates with sodium azide in dimethylformamide at 80–90°C in the presence of anhydrous CdCl₂ afforded the corresponding N-arylcarbamates with a 1,2,3,4-tetrazole fragment. The acylation of methyl N-[2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]carbamate with acetic anhydride followed by the condensation of the obtained N-acyl derivative with thiophene-2-carbaldehyde in the KOH methanol solution led to the formation of methyl N-(2-{1-[3-(2-thienyl)-2-propenoyl]-1H-1,2,3,4-tetrazol-5-yl}phenyl)carbamate. The reaction of cyclohexyl N-(4-aminophenyl)carbamate with a triethyl orthoformate and sodium azide in glacial AcOH yielded cyclohexyl N-[4-(1H-1,2,3,4-tetrazol-1-yl)phenyl]carbamate.     

Synthesis of 3-amino-3,4-dihydroquinazolin-4-one derivatives from anthranilic acid hydrazide and dicarboxylic acids

Treatment of anthranilic acid hydrazide with 2 equiv of ethoxalyl chloride gave the corresponding diester which underwent cyclization in acetic anhydride to produce ethyl 3-(ethoxalylamino)-4-oxo-3,4-dihydroquinazoline-2-carboxylate. Acylation of anthranilic acid hydrazide first with succinic anhydride and then with ethoxalyl chloride led to the formation of 4-[2-(2-{[ethoxy(oxo)acetyl]amino}benzoyl)hydrazino]-4-oxobutanoic acid whose cyclization in acetic acid afforded N-(2-ethoxycarbonyl-4-oxo-3,4-dihydroquinazolin-3-yl)succinamic acid, while in acetic anhydride ethyl 3-(2,5-dioxopyrrolidin-1-yl)-4-oxo-3,4-dihydroquinazoline-2-carboxylate was obtained. The latter was brought into reactions with amines and hydrazine hydrate and alkaline hydrolysis. Acylation of 2-[2-(2-aminobenzoyl)hydrazinocarbonyl]benzoic acid with ethoxalyl chloride gave ethyl N-[2-(phthalimidocarbamoyl)phenyl]oxamate, and with succinic anhydride, 3-[4-oxo-3-phthalimido-3,4-dihydroquinazolin-2-yl]propionic acid. 4-[2-(2-Aminobenzoyl)hydrazino]-4-oxobutanoic acid reacted with phthalic anhydride in boiling acetic acid to give phthalazino[1,2-b]quinazoline-5,8-dione via elimination of succinic acid residue.     

Synthesis of fluorinated 2,6-heptanediones and 2-oxa-6- azabicyclo[2.2.2]octanes from 1,4-dihydropyridines

Electrophilic fluorination of Hantzsch-type 1,4-dihydropyridines with Selectfluor^® led to the formation of new fluorinated 2,6-heptanediones - dialkyl 2,4-diacetyl-2,4-difluoro-3-phenylpentanedioates. Novel 2,6-heptanedione derivatives in reaction with hydrazine hydrate easily form 6-amino-4,7-difluoro-3-hydroxy-1,3-dimethyl-5-oxo-8-phenyl-2-oxa-6-azabicyclo[2.2.2]octanes instead of the corresponding diazepine derivatives. The obtained 2-оxa-6-azabicyclo[2,2,2]octanes are thermally stable at the temperatures below 50°С. At higher temperatures rearrangement of 2-oxa-6-azabicyclo[2,2,2]octanes offers new fluorine-containing pyrazolinone derivatives - alkyl esters of 2-fluoro-2-((4-fluoro-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)(phenyl)methyl)-3-oxobutanoates.     

Synthesis of New Polyheterocyclic Compounds Based on Chalcones

Russian Journal of Organic Chemistry - The reaction of methyl N-{4-[2-(2-oxo-2,3-dihydro-1H-indol-3-ylidene)acetyl]phenyl}carbamate with tosylmethyl isocyanide in tetrahydrofuran in the presence of...     

Synthesis of 1,2,3,4,6,7,8,9-octahydropyrimido[4,5-b]quinoline-2,4-dione

In the presence of hydrazine hydrate or sodium ethylate, ethyl 2-[(N-phenylcarbamoyl)amino]-5,6,7,8-tetrahydroquinoline-3-carboxylate is converted to 3-amino- or 3-phenyl-1,2,3,4,6,7,8,9-octahydropyrimido[4,5-b]quinoline-2,4-dione. Compounds analogous to the latter are also obtained during heating of 2-amino-5,6,7,8-tetrahydroquinoline-3-carboxylic arylamides with phenyl isocyanate or from their N-phenylcarbamoyl derivatives.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1114–1117, August, 1989.     

Synthesis of methyl esters of 5-aroyl-6-aryl-2-oxo-1,2,3,6-tetra-hydropyrimidine-4-carboxylic acids

Methyl esters of 5-aroyl-6-aryl-2-oxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acids were synthesized from three component mixtures of methyl esters of aroylpyruvic acids, urea, and substituted benzaldehydes. 8-Hydroxy-4,5-diphenyl-3,4-dihydropyrimido[4,5-d]pyridazin-2(1H)-one was synthesized by the reaction of 5-benzoyl-2-oxo-6-phenyl-1,2,3,6-tetrahydropyrimidin-4-carboxylate with hydrazine hydrate.     

4,5-Dihydropyrazolo[3,4-f]quinazolines

By reaction of 6-dimethylamino-5-oxo-2-phenyl-5,6,7,8-tetrahydroquinazoline with hydrazine, phenylhydrazine, 4-bromo-, 4-chlorophenylhydrazines, and also reaction of 6-dimethylaminomethylene-5-oxo-2-(4-pyridyl)-5,6,7,8-tetrahydroquinazoline with hydrazine, 4-methoxy- and 2-carboxyphenylhydrazines, we have obtained the corresponding 7-phenyl(4-pyridyl)-substituted 1H(2H)- or 1-aryl-4,5-dihydropyrazolo[3,4-f]quinazolines. Methylation of 7-phenyl-4,5-dihydro-1(2H)-pyrazolo[3,4-f]quinazoline by methyl iodide led to its 2-methyl derivative.     

Synthesis of some new pyrimidine selanyl derivatives

The targeted synthesis of 2-(methylsulfanyl)-6-(furan-2-yl)-4(3H)-selenoxo -pyrimidine-5-carbonitrile failed due to the formation 1-methyl-2-methylsulfanyl-6-oxo -4-(furan-2-yl)-1,6-dihydropyrimidine-5-carbonitrile. A new series of 5,6,7,8-tetrahydro-1-benzo thieno[2,3-d]pyrimidine-4-yl substituted selanyl derivatives were prepared by the reaction of sodium diselenide with 4-chloro-5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidine followed by the reaction with chloroacetic acid derivatives such as ethyl chloroacetate, chloroacetamide or chloroacetonitrile. Hydrazinolysis of ethyl (5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidine- 4-ylselanyl)acetate with hydrazine hydrate gave the corresponding hydrazino derivative. The latter reacted with ethyl acetoacetate, acetylacetone, diethyl malonate, ethoxymethylenemalononitrile or ethyl 2-cyano-3-ethoxyacetate to afford 5-methyl-2-[2-(5,6,7,8-tetrahydro-1-benzothieno [2,3-d]pyrimidine-4-ylselanyl)acetyl]-2,4-dihydropyrazol-3-one, 1-(3,5-dimethylpyrazol-1-yl)-2- (5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidin-4-ylselanyl)ethanone, 1-[2-(5,6,7,8-tetrahydro -1-benzothieno[2,3-d]pyrimidine-4-ylselanyl)acetyl]-2,4-dihydropyrazolidine-3,5-dione and 5-Amino-1-[2-(5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidin-4-ylselanyl)acetyl]-1H-pyrazol -4-yl substituted carbonitrile or ethyl carboxylate, respectively. The structure of the novel compounds was confirmed by spectroscopic tools (IR, ¹H NMR ¹³C NMR and mass spectra) and elemental analysis.     

Ring Transformation of 7-Nitro-1-(4-nitrophenyl)-4,5-dihydro-1H-imidazo- and -[1,2,3]triazolo[4,5-c]pyridin-4-ones

Nitration of 1-phenyl-4,5-dihydroimidazo- and -1,2,3-triazolo[4,5-c]pyridin-4-ones initially occurs at the para position of the phenyl ring, and the subsequent nitration yields the corresponding 7-nitro-1-(4-nitrophenyl) derivatives. Treatment of the latter with hydrazine hydrate leads to formation of 1-(4-aminophenyl)-7-methyl-4,5-dihydroimidazo- and -1,2,3-triazolo[4,5-d]pyridazin-4-ones.     

Synthesis and Anticancer Evaluation of 2-{4-[5-(5-Substituted arylpyrimidin-2-yl)-1H-pyrazol-3-yl]-phenyl}thiazolo[4,5-b]pyridine Derivatives

Russian Journal of General Chemistry - In the present study a new series of 2-{4-[5-(5-substituted arylpyrimidin-2-yl)-1H-pyrazol-3-yl] phenyl}thiazolo[4,5-b]pyridine derivatives (11a–11j)...     

3-Methylidene-2,4-dioxo-4-pentafluorophenylbutanoates in the Synthesis of Heterocycles

3-Ethoxy- and 3-arylaminomethylidene-2,4-dioxo-4-pentafluorophenylbutanoates undergo cyclization by the action of hydrazine hydrate and phenylhydrazine to give ethyl 4-pentafluorobenzoylpyrazole-5-carboxylates. The reaction of 3-ethoxymethylidene-2,4-dioxo-4-pentafluorophenylbutanoate with o-phenylene-diamine leads to formation of 3-[2-(2-aminophenylamino)-1-pentafluorobenzoylethenyl]-1,2-dihydroquinoxa-lin-2-one. 3-Arylaminomethylidene-2,4-dioxo-4-pentafluorophenylbutanoates react with o-phenylenediamine to afford 3-(1-aryl-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinolin-3-yl)-1,2-dihydroquinoxalin-2-ones and/or 3-(2-arylamino-1-pentafluorobenzoylethenyl)-1,2-dihydroquinoxalin-2-ones.