Unambiguously confirmed structure of 2-phenacylidene-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one and 3-phenacylidene-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

To determine the structures of two isomeric products, 2-phenacylidene-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one (2) and 3-phenacylidene-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (3) obtained by condensation of 2,3-diaminopyridine (1) with ethyl benzoylpyruvate [1–3], these compounds were hydrolyzed to give 2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (4) and 3-methyl-1H-pyrido[2,3-b]pyrazin-2-one (5) , respectively [4,5]. Both hydrolysates 4 and 5 were hydrogenated to afford 2-methyl-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one (6) and 3-methyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (7) . The latter compound was identical with an unequivocally synthesized compound providing proof for the structures of all these compounds.     

Heterocycles structurally influenced by a side chain. X. Effect of temperature and side chain on the imine-enamine tautomerism in the quinoxalinone and pyridopyrazinone systems

3-(1-Benzoyl)ethyl-1H-pyrido[2,3-b]pyrazin-2-one ( 7 ), 3-(1-ethoxycarbonyl)ethyl-1H-pyrido[2,3-b]-pyrazin-2-one ( 8 ), and 3-(1-benzoyl)ethyl-1H-quinoxalin-2-one ( 9 ) exist only in the imine form due to the steric effect of the methyl substituent. As regards the imine-enamine tautomerism, 3-(β-carbonylmethylene) derivatives of 1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one such as 12 and 15–18 gradually change from the enamine form to the imine form with elevated temperatures; however, 3-(carbonylmethylene) derivatives of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one such as 10, 19 and 20 show little temperature effect. 2-Phenacylidene-1,2-dihydro-4H-pyrido[3,4-b]pyrazin-3-one ( 21 ) and 3-phenacylidene-3,4-dihydro-1H-pyrido[3,4-b]pyrazin-2-one ( 22 ), which exist in the enamine form, show no temperature effect.     

Azaindoles. V. Pyrido(4,3-b]indoles (γ-carbolines) fonctionnalisés sur leur sommet 4: Synthèse en une seule étape

In boiling diphenylether phenylhydrazine reacts with 1,2-dihydro-2-oxo-4-hydroxypyridines to give 3,4-dihydro-4-oxo(9H)-pyrido[4,3-b]indoles (γ-carbolines) in one step. Nucleophilic displacement of their 4-chloro derivatives by secondary amines affords both 3,4-disubstituted γ-carbolines and chlorination of 2,3-dimethyl-4-oxo(9H)pyrido[4,3-b]indoles, as well as methylation of 2-methyl-4-chloro-(9H)pyrido[4,3-b]indole leads to derivatives in the (3H)4-substituted pyrido[4,3-b] indole series.     

Reactions of Acylpyruvic Acids and 2,3-Dihydrofuran-2,3-diones with 2,3-Diaminopyridine

Acylpyruvic acids readily react with 2,3-diaminopyridine to form (Z)-3-acylmethylene-1H-3,4-di- hydropyrido[2,3-b]pyrazin-2-ones. 5-Aryl-2,3-dihydrofuran-2,3-diones which can be regarded as lactones derived from -enolized aroylpyruvic acids react with 2,3-diaminopyridine under mild conditions, yielding regioisomeric (Z)-2-aroylmethylene-4H-1,2-dihydropyrido[2,3-b]pyrazin-3-ones. The structure of the products and reaction chemoselectivity are discussed.     

2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indoles. II. Reversible transformation of 1-alkyl-2-(4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)cyclohexanol into 1-alkylidene-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles

Treatment of 2-(4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)-1-methylcyclohexanol ( 2a ) with acetic anhydride or methyl isocyanate gave 2-acetyl-2,3,4,9-tetrahydro-1-(6-oxoheptylidene)-1H-pyrido[3,4-b]indole ( 3 ) or 1,3,4,9-tetrahydro-N-methyl-1-(6-oxoheptylidene)-2H-pyrido[3,4-b]indole-2-carboxamide ( 4 ), respectively. Simpler analogues, 1-alkyl-4,9-dihydro-3H-pyrido[3,4-b]indoles, 7 , subjected to identical reaction conditions, gave 2-acetyl-1-alkylidene-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles 8 and 1,3,4,9-tetrahydro-N-methyl-1-alkyli-dene-2H-pyrido[3,4-b]indole-2-carboxamides 9 , respectively. A limited lanthanide shift reagent study to determine stereochemical assignments was also performed.     

Tetrahydropyridoazepines and tetrahydropyridoazepinones from the corresponding dihydroquinolones

The p-toluenesulfonate of 7,8-dihydro-5(6H)quinoloneoxime( 3 ) was subjected of a Beckmann rearràngement. The resulting 2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepin-2-one ( 4 ) was reduced with lithium aluminum hydride affording 2,3,4,5-tetrahydro-1H-pyrido[3,2-b] azepine ( 5 ). 5,6-l)ihydro-8(7H)quinolone ( 7 ), obtained by oxidation of 5,6,7,8-tetrahydro-8-quinolinol ( 6 ), was converted into the p-toluenesulfonate of 5,6-dihydro-8(7H)quinolone oxitne ( 9 ). Similarly the latter compound could be rearranged into 2,3,4,5-letrahydro-1H-pyrido [2,3-b] azepin-2-one ( 10 ) which on reduction produced 2,3,4,5-tetrahydro-1H-pyrido [2,3-b] azepine ( 11 ).     

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 and transformations of 3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridines

Reactions of 2,5-dimethoxytetrahydrofuran with 3-aminothieno[2,3-b]pyridines afford a number of substituted 3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridines. The possibility of the reaction and the yield of the product are determined by the character of a substituent in position 2 of thieno[2,3-b]pyridine. The Curtius rearrangement of 2-acylazido-3(1H-pyrrol-1-yl)thieno[2,3-b]pyridines yields 4,5-dihydropyrido[3",2":4,5]thieno[2,3-e]pyrrolo[1,2-a]pyrazin-4-ones. The molecular and crystal structures of ethyl 4-methoxymethyl-6-methyl-3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridine-2-carboxylate were determined by X-ray diffraction analysis.     

New organic nitrates. II. Synthesis of 2H-pyrido[2,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazin-4(3H)-ones, 2H-thieno[2,3-e]-1,3-oxazin-4(3H)-ones and 2H-thieno[3,4-e]-1,3-oxazin-2,4(3H)-diones

The preparation and the physico-chemical characterization of 2H-pyrido[2,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazin-4(3H)-ones, 2H-thieno[2,3-e]-1,3-oxazin-4(3H)-ones and 2H-thieno[3,4-e]-1,3-oxazine-2,4(3H)-diones are reported.     

Cyclization reactions of 1,3-dibromopropan-2-ol, 2,3-dibromopropan-1-ol and 1-bromomethyloxirane with 6-amino-2,3-dihydro-2-thioxo-4(1H)-pyrimidinone

The cyclization reactions, carried out in strongly- or weakly-basic media, are described. Sometimes, 7-amino-2,3-dihydro-3-hydroxymethyl-5H-thiazolo[3,2-a]pyrimidin-5-one is separated out, together with 8-amino-3,4-dihydro-3-hydroxy-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one, as the principal product. A mechanism of reaction, during which the cyclizating agents are changed into oxirane derivatives, is proposed. The results of single-crystal X-ray investigations on 8-amino-3,4-dihydro-3-hydroxy-7-nitroso-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one (R = 0.035 for 1013 reflections), and on 7-hydroxymethyl-6,7-dihydrothiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidin-9(1H)-one (R = 0.027 for 1607 reflections) are reported.     

Synthesis of 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide

The reaction of methyl 2-bromo-6-(trifluoromethyl)-3-pyridinecarboxylate ( 1 ) with methanesulfonamide gave methyl 2-[(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridine-carboxylate ( 2 ). Alkylation of compound 2 with methyl iodide followed by cyclization of the resulting methyl 2-[methyl(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridinecarboxylate ( 3 ) yielded 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 4 ). The reaction of compound 4 with α,2,4-trichlorotoluene, methyl bromopropionate, methyl iodide, 3-trifluoromethylphenyl isocyanate, phenyl isocyanate and 2,4-dichloro-5-(2-propynyloxy)phenyl isothiocyanate gave, respectively, 4-[(2,4-dichlorophenyl)methoxy]-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide ( 5 ), methyl 2-[[1-methyl-2,2-dioxido-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4-yl]oxy]propanoate ( 6 ), 1,3,3-trimethyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 7 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 8 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-phenyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 9 ) and N-[2,4-dichloro-5-(2-propynyloxy)phenyl]-4-hydroxy-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2] thiazine-3-carboxamide 2,2-dioxide ( 10 ).     

A study of the catalytic reductive products of 2,3-dihydro-6-methoxy-3-(6-nitroveratrylidene)-4H-benzopyran-4-one. Part II

Although the previously reported (1,2) chemical reduction of 2,3-dihydro-3-(6-nitroveratry-lidene)-4H-benzopyran-4-one with stannous chloride occurred with cyclization to the 6H-[1]-benzopyrano [4,3-b]quinoline ring system, the present study of the catalytic (palladium/carbon) reduction of 2,3-dihydro-6-methoxy-3-(6-nitroveratrylidene)-4H-benzopyran-4-one ( 1 ) (3) has indicated that other products in addition to the expected benzopyranoquinoline ( 3 ) may be isolated, depending upon the conditions of the reduction. The products of the reduction of 1 , isolated and structurally determined, include 2,9,10-trimethoxy-6H-[1]benzopyrano-[4,3-b]quinoline(3),2,9,10-trimethoxy-6a,7,12,12a-tetrahydro-6H-[1]benzopyrano[4,3-b]-quinoline (2), the N-oxide of 3 (6 ), and 6-hydroxy-2,9,10-trimethoxy-6H-[l]benzopyrano-[4,3-b Jquinoline ( 8 ).     

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.     

New approach to the functionalization of δ-carboline derivatives

The possibility of transformation of 3-cyano-1-p-nitrophenyl--carbolin-2-one into 2-amino-3-cyano-1-p-nitrophenyl-1H-pyrido[3,2-b]indole derivatives and 2-imino-3-cyano-1-p-nitrophenyl-5H-pyrido[3,2-b]indole derivatives (-carbolines) is demonstrated. Methylation of 1-p-nitrophenyl-2-piperidino-1H--carboline followed by treatment with acetone in an alkaline medium yields 4-acetonyl-5-methyl-1,4-dihydro-5H-pyrido[3,2-b]indole derivative. The rearrangement of 2-arylimino-3-cyano-1-p-nitrophenyl-5H-pyrido[3,2-b]indoles into 2-(aryl)nitrophenylamino-3-cyano-5H-pyrido[3,2-b]indoles was accomplished on heating above the melting point or on treatment with potassium tert-butoxide. The structures of the resulting compounds were proved by ¹H and ¹³C NMR spectroscopy and X-ray diffraction analysis.     

Synthesis of 1-substituted-2,3,4,9-tetrahydro-(2-oxopropyl)-1H-pyrido [3,4-b] indoles and their base-catalyzed rearrangements to N- [2-[2-(1-alkyl-3-oxobutenyl)-1H-indol-3-yl] ethyl]acetamides

The condensation of 1H-indole-3-ethanamides, 1 , with 2,4-pentanediones, 2 , gave enamines 3 . Acid catalyzed ring closure of 3 gave 1-(1-substituted-2,3,4,9-tetrahydro- (2-oxopropyl) -1H-pyrido [3,4-b] indoles 4 . Subsequent N-acetylation yielded 5 which sequentially produced 2,3-disubstituted indoles 6 and 7 resulting from C? N bond cleavage after treatment with sodium alkoxide in ethanol. Controlled catalytic hydrogenation of the latter gave saturated derivatives 8 and 9 .     

Synthesis of 17β-hydroxy-1′-H-5α-androst-2-eno[3,2-b]pyrrole and 17β-hydroxy-1′-H-5α-androst-3-eno[3,4-b]pyrrole from O-(2-hydroxyethyl)ketoxime precursors

Pyrrolosteroids such as 17β-hydroxy-1′-H-5α-androst-2-eno[3,2-b]pyrrole ( 1 ) and the novel 17β-hydroxy-1′-H-5α-androst-3-eno[3,4-b]pyrrole ( 12 ) can be synthesized from the corresponding O-(2-hydroxyethyl)ketoxime precursors. In the case of 1 , yields compare favourably with previously reported literature methods.     

A new method for the synthesis of novel 1-aryl-3-heteroaryl-1H-pyrazolo[3,4-b]quinoxalines

The reaction of 3-(2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline 4 with o-chlorobenzenediazonium chloride gave 3-[α-(o-chlorophenylhydrazono)-2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-ylmethyl]-2-oxo-1,2-dihydroquinoxaline 6 , whose refluxing in phosphoryl chloride/pyridine afforded 1-(o-chlorophenyl)-3-(2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-yl)-1H-pyrazolo[3,4-b]quinoxaline 7. The reactions of 6 and 7 with nitrous acid resulted in sulfur extrusion to provide 1-(o-chlorophenyl)-3-(4-methyl-4H-1,2,4-triazol-5-yl)1H-pyrazolo[3,4-b]quinoxaline 8 and 3-[α-(o-chlorophenylhydrazono)-4-methyl-4H-1,2,4-triazol-5-ylraethyl]-2-oxo-1,2-dihydroquinoxaline 9 , respectively.     

Preparation of novel heterocyclic systems from isatoic anhydrides

Isatoic anhydride ( 1a ) and 5-chloroisatoic anhydride ( 1b ) were treated with 2-(1-methylhydrazino)ethanol ( 2 ) to produce 2-aminobenzoic acid 2-(2-hydroxyethyl)-2-methylhydrazide ( 3a ) and its 5-chloro analog 3b , respectively. Treatment of 3a and 3b with carbon disulfide gave, respectively, 2,3-dihydro-3-[(2-hydroxyethyl)methylamino]-2-thioxo-4-(1H)quinazolinone ( 4a ) and its 6-chloro analog 4b . Compounds 4a and 4b afforded 5,6-dihydro-5-methyl-2-thioxo-4H,8H-[1,3,5,6]oxathiadiazocino[4,5-b]quinazolin-8-one ( 5a ) and its 10-chloro analog 5b , respectively, upon treatment with thiophosgene. Compound 5a could be produced directly from 3a and thiophosgene. Treatment of 4a and 4b with trifluoroacetic anhydride followed by potassium carbonate gave 3,4-dihydro-4-methyl-2H,6H-[1,3,4]thiadiazino[2,3-b]quinazolin-6-one ( 7a ) and its 8-chloro analog 7b , respectively. Treatment of 4a with thionyl chloride also gave 7a , but 4b and thionyl chloride afforded a mixture of 7b and 8-chloro-3,4-dihydro-4-methyl-2H,6H-[1,3,4]oxadiazino[2,3-b]quinazolin-6-one ( 10 ). The dimethyl analogs of 4a and 4b ( 13a and 13b ) upon treatment with thiophosgene afforded 3,4-dihydro-2,2,4-trimethyl-2H,6H-[1,3,4]oxadiazino[2,3-b]quinazolin-6-one ( 14a ) and its 8-chloro analog 14b , respectively.     

Halogenation of Imidazo[4,5-<Emphasis Type="Italic">b</Emphasis>]pyridin-2-one Derivatives

Chlorination and bromination of 2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one and its N-methyl-substituted derivatives in acetic acid at 90–95°C leads to formation of the corresponding 5,6-dichloro(dibromo)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-ones. Iodination of the same substrates with ICl under analogous conditions yields 6-iodo derivatives. Chlorination of 6-iodo-1,3-dimethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one is accompanied by replacement of the iodine atom by chlorine with formation of 5,6-dichloro-1,3-dimethyl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one. Bromination of 6-bromo- and 6-chloro-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-ones gives 5,6-dibromo- and 5-bromo-6-chloro-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-ones, respectively.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 4, 2005, pp. 586–589.Original Russian Text Copyright © 2005 by Yutilov, Lopatinskaya, Smolyar, Gres’ko.     

Comparative kinetic studies on the synthesis of quinoxalinone derivatives and pyrido[2,3-b]pyrazinone derivatives by the hinsberg reaction

Kinetic studies on the anelation of quinoxalinone derivatives 3a-c and pyrido[2,3-b]pyrazinone derivatives 5a-c and 6a-c synthesized by the Hinsberg reaction is reported. o-Phenylenediamine or 2,3-diaminopyridine were treated with bifunctional carbonyl compounds such as glyoxylic, pyruvic and benzoylformic acids under different experimental conditions. When pyridopyrazine derivatives were synthesized both position isomers were achieved applying regioselective reactions. Mixture were avoided by looking for special experimental conditions that led unambiguously to only one of the components of the classic “Hinsberg mixture”. Quinoxalinone derivatives 3a-c were obtained at room temperature in good yields (>90%) using anhydrous methanol or ethanol as solvents. On the other hand, only pyrido[2,3-b]pyrazin-3(4H)-one ( 5a ) was regioselectively attained in aqueous buffer of pH 7 while 3-methylpyridopyrazinone derivatives were regioselectively separated using anhydrous methanol for one isomer, 5b , and anhydrous chloroform for the other isomer, 6b , at room temperature. Yields were higher than 80%. Reactions with benzoylformic acid did not give good yields and only 2-phenylpyrido[2,3-b]pyrazin-3(4H)-one ( 5c ) could be obtained using anhydrous chloroform (yield <30%) as the solvent. Steric hindrance exerted by the phenyl group of the benzoylformic acid is supposed to be responsible of our difficulties to obtain 2-phenylpyrido[2,3-b]pyrazin-3(4H)-one ( 5c ) in good yields applying this technique. The other isomer, 3-phenyl[2,3-b]pyrazin-2(1H)-one ( 6c ) was always formed together with the former isomer and could not be isolated from the mixture, when other solvents than chloroform were used as the reaction media.