1,3,4,6-Tetracarbonyl Compounds: V. Reaction of 1,6-Disubstituted 3,4-Dihydroxy-2,4-hexadiene-1,6-diones with 2,3-Diaminopyridine

1,6-Disubstituted 3,4-dihydroxy-2,4-hexadiene-1,6-diones having two contiguous -dicarbonyl fragments readily react with 2,3-diaminopyridine to give (2Z,3Z)-bis(acylmethylene)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazines.     

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.     

A convenient synthesis of (z)-3-(α-alkoxycarbonyl-α-cyanomethylene)-2-oxo-1,2,3,4-tetrahydroquinoxalines and related compounds

(Z)-3-(α-Alkoxycarbonyl-α-cyanomethylene)-2-oxo-1,2,3,4-tetrahydroquinoxalines 3 and (Z)-3-(α-alkoxycarbonyl-α-cyanomethylene)-3,4-dihydrobenzo[g]quinoxalin-2(1H)-ones 5 possessing various alkoxycarbonyl groups were prepared in good yields directly from the reaction of dialkyl (E)-2,3-dicyanobutendioates 1 with o-phenylenediamine ( 2 ) or with 2,3-diaminonaphthalene ( 4 ), respectively. Furthermore, 2,3-diaminopyridine ( 6 ) and 3,4-diaminopyridine ( 7 ) were reacted with the diethyl ester 1b to give (Z)-2-(α-cyano-α-ethoxycarbonylmethylene)-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one ( 8 ) and (Z)-3-(α-cyano-α-ethoxycarbonylmethylene)-3,4-dihydro-1H-pyrido[3,4-b]pyrazin-2-one ( 9 ), respectively. The structural studies of 3, 5, 8 , and 9 were carried out by nmr experiments in some details.     

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.     

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.     

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.     

The first synthesis of dihydro-3H-pyrido[2,3-b][1,4]diazepinols and a new alternative approach for diazepinone analogues

The first synthesis of a series of 2-aryl(heteroaryl)-4-trifluoromethyl-4,5-dihydro-3H-pyrido[2,3-b][1,4]diazepin-4-ols, where aryl = C₆H₅, 4-FC₆H₄, 4-ClC₆H₄, 4-BrC₆H₄, 4-CH₃C₆H₄, 4-OCH₃C₆H₄, 4,4′-biphenyl, 1-naphthyl and heteroaryl = 2-thienyl, 2-furyl obtained from the direct cyclocondensation reaction of 4-methoxy-1,1,1-trifluoroalk-3-en-2-ones with 2,3-diaminopyridine in 54-71% yield, is reported. Another alternative and efficient route for the synthesis of a series of 2-aryl(heteroaryl)-3H-pyrido[2,3-b][1,4]diazepin-4(5H)-ones from the reaction 4-methoxy-1,1,1-trichloroalk-3-en-2-ones with 2,3-diaminopyridine, in 54-70% yield, is also reported.     

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.     

Five-Membered 2,3-Dioxo Heterocycles: XLIV. Reaction of 3-Aroyl-1,2,4,5-tetrahydropyrrolo[1,2-a]- quinoxaline-1,2,4-triones with o-Phenylenediamines

The reaction of (Z)-3-phenacylidene-1,2,3,4-tetrahydroquinoxalin-2-ones with oxalyl chloride gives 3-aroyl-1,2,4,5-tetrahydropyrrolo[1,2-a]quinoxaline-1,2,4-triones which react with o-phenylenediamine to afford 8-aryl-6,7,9,14,15,16-hexahydroquinoxalino[1,2-a]pyrrolo[2,3-b][1,5]benzodiazepine-6,7,15-triones.     

Synthesis of 2,3-dihydro-5H-oxazolo[2,3-B]quinazolin-5-ones

Iodide-catalyzed ring expansion of 2-[(1-aziridinylcarbonyl)amino]benzoic acid methyl ester (2) gave 2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-one (3) in quantitative yield. Treatment of the dimethyl analog of 2 (9) with sodium iodide in acetone gave a mixture of the 2,3-dihydro-2,2-dimethyl- (10) and 2,3-dihydro-3,3-dimethyl-5H-oxazolo[2,3-b]quinazolin-5-ones (11). However, rearrangement of 9 with sulfuric acid produced only 10. Synthesis of 11 by another route for comparison is described, and the known syntheses of 2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-ones are reviewed.     

Cyclisierungsreaktionen zu Thiazolo[3,2—a]thieno[2,3-d]pyrimidinen

Cyclisation of 2-(-oxo-alkylthio)-thieno[2.3-d]pyrimidin-4(3H)-ones gave separable mixtures of the title substances and their [2.3-b]-isomers. The structure of the two isomers were be proved by comparison with a linear product synthesized by an unambiguous method. Similar cyclisations were achieved by reactions of 2-mercapto-thieno[2.3-d]pyrimidin-4(3H)-ones with chloroacetone, 1.2-dibromoethane or 1.3-dibromopropane.     

Synthesis and Transformations of 5-Substituted 2-Aryl-7H-[1,2,4]triazolo[3,2-b][1,3]thiazin-7-ones and 2-Aryl-2,3-dihydro-4H-[1,3]thiazino[3,2-a]benzimidazol-4-ones

3-Aryl-1,2,4-triazole-5-thiones react with dimethyl acetylenedicarboxylate and methyl 3-phenyl-propynoate to afford the corresponding 5-substituted 2-aryl-7H-[1,2,4]triazolo[3,2-b][1,3]thiazin-7-ones. Treatment of 2-aryl-2,3-dihydro-4H-[1,3]thiazino[3,2-a]benzimidazol-4-ones with alkalies leads to formation of 3-(benzimidazol-2-ylsulfanyl)-3-arylpropionic acids, their reaction with methyl p-toluenesulfonate yields 1-(3-methyl-2-thioxo-2,3-dihydro-1N-benzimidazol-1-yl)-3-phenyl-2-propen-1-one, and oxidation with hydrogen peroxide gives benzimidazole-2-sulfonic acid and 3-aryl-2-propenoic acids.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 1, 2005, pp. 109–114.Original Russian Text Copyright © 2005 by Britsun, Esipenko, Chernega, Lozinskii.     

Synthesen von 4-Amino-thieno[2,3—b]pyridinen

The Cyclization of 2-(1,1-dicyanovinylamino)-thiophenes2 by treatment with AlCl₃ yield 4-amino-5-cyano-thieno[2,3-b]pyridines3. 2-(1-acylvinyl-amino)-3-cyano-thiophenes7, obtainable from 2-amino-3-cyano-thiophenes and -diketones, react in the presence of AlCl₃ to form 4-acylamino-thieno[2,3-b] pyridines8. This reaction is connected with the transfer of the acyl group from C- to the N-atom. 4-Amino-5-cyano-thieno[2,3-b]pyridones-(6)11 are synthesized from 2-amino-3-cyano-thiophenes and ethyl cyano acetate in the presence of sodium ethoxide.

     

A Facile and Efficient Synthesis of Novel 1,2,4-Triazolo[5,1-b]quinazolin-9-one Derivatives

Summary.  A facile and efficient synthesis of a series of novel 1,2,4-triazolo[5,1-b]quinazolines is described. 2,3-Diaryl-2,3-dihydro-1H-1,2,4-triazolo[5,1-b]quinazolin-9-ones were obtained by reaction of 3-amino-2-arylamino-3H-quinazolin-4-ones with aromatic aldehydes as well as by ring closure of the corresponding anils. Treatment of 3-amino-2-arylamino-3H-quinazolin-4-ones with aromatic carboxylic acids afforded 2,3-diaryl-3H-1,2,4-triazolo[5,1-b]quinazolin-9-ones which could also be synthesized by dehydrogenation of the corresponding dihydro derivatives. Reaction of 3-amino-2-arylamino-3H-quinazolin-4-ones with diethyl malonate and acetylacetone gave 3-aryl-3,9-dihydro-9-oxo-1,2,4-triazolo[5,1-b]quinazolin-2-yl-acetic acid ethyl ester and 3-aryl-2-methyl-3H-1,2,4-triazolo[5,1-b]quinazolin-9-ones, respectively. The latter compounds were also prepared via reaction with acetic anhydride, whereas acetylation with acetic anhydride in the presence of pyridine afforded the acetyl derivatives. Received March 22, 2001. Accepted (revised) May 11, 2001     

A novel synthesis of aryl tethered imidazo[4,5-b]pyrazin-2-ones through in situ ring construction and contraction

An innovative synthesis of aryl tethered 1,3-dimethylimidazo[4,5-b]pyrazin-2-ones 4 and 6 has been delineated through base catalyzed ring transformation of 6-aryl-4-(piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1 and methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carboxylates 5 with 7-acetyl-1,3-dimethyllumazine 2 with subsequent ring contraction of the fused pyrimidine to an imidazole ring. An additional product, methyl [6-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-4-thiophen-2-ylpyran-2-ylidene]acetate 8b, was also isolated from the reaction of 5 and 2, as a minor constituent.     

A Facile and Efficient Synthesis of Novel 1,2,4-Triazolo[5,1- b ]quinazolin-9-one Derivatives

 A facile and efficient synthesis of a series of novel 1,2,4-triazolo[5,1-b]quinazolines is described. 2,3-Diaryl-2,3-dihydro-1H-1,2,4-triazolo[5,1-b]quinazolin-9-ones were obtained by reaction of 3-amino-2-arylamino-3H-quinazolin-4-ones with aromatic aldehydes as well as by ring closure of the corresponding anils. Treatment of 3-amino-2-arylamino-3H-quinazolin-4-ones with aromatic carboxylic acids afforded 2,3-diaryl-3H-1,2,4-triazolo[5,1-b]quinazolin-9-ones which could also be synthesized by dehydrogenation of the corresponding dihydro derivatives. Reaction of 3-amino-2-arylamino-3H-quinazolin-4-ones with diethyl malonate and acetylacetone gave 3-aryl-3,9-dihydro-9-oxo-1,2,4-triazolo[5,1-b]quinazolin-2-yl-acetic acid ethyl ester and 3-aryl-2-methyl-3H-1,2,4-triazolo[5,1-b]quinazolin-9-ones, respectively. The latter compounds were also prepared via reaction with acetic anhydride, whereas acetylation with acetic anhydride in the presence of pyridine afforded the acetyl derivatives.     

Tetrahydrocyclopenta[e]pyrido[3,2-b][1,4]diazepine and -cyclopenta[e]pyrido[2,3-b][1,4]diazepine derivatives

In pursuing the study on compounds obtained by condensation of N-monoalkylated aromatic and hetero-aromatic diamines with α- and β-ketoesters, 7,8,9,10-tetrahydrocyclopenta[e]pyrido[3,2-b][1,4]diazepin-6(5H)-ones 4a, 4b and 5,7,8,10-tetrahydrocyclopenta[e]pyrido[2,3,-b][l,4]diazepin-9H)-ones 5a, 5b were prepared starting from 2,3-diaminopyridine or 2,3-diamino-5-chloropyridine and ethyl 2-oxo-cyclopentanecarboxylate. Compounds 4a,b and 5a,b suffer thermally induced ring contraction to the imidazolone derivatives 8a,b and 7a,b respectively and are unsuitable for preparing diazepinone derivatives. Thus the methylated diazepinones 15, 17 and 18 , stable on heating, were prepared. Compound 17 was transformed into the clozapine analogue 22 , through the diazepinthione 20 and its S-methyl derivative 21 .     

Heterotricyclic systems. Part I. Synthesis of new dipyridopyrazines

Pursuing our previous research on azaquinoxalinones (1,2-dihydropyrido[2,3-b]/[3,4-b]pyrazinones) we prepared, through a reductive cyclization of N-(3′-nitropyridin-2′-yl)piperidine-2-carboxylic acids 3a-c , a set of derivatives of a new tricyclic structure, 7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-ones 4a-c. Starting from these compounds we obtained substituted amides 5a-c and, from 4a , the amidines 6a-c. In the synthesis of 6 , a dehydrogenation reaction occurred giving rise to 7. The compounds 9 and 10 , characterized by a different ring-fusion between the pyridine and pyrazine rings, were synthesized in a similar manner.     

Synthesis of a New Series of Imidazo-[1,5-a]pyrido[2,3-e]pyrazines as Potential Ligands for the GABA Receptor Complex

Summary.  Starting from 2-chloro-3-nitropyridine, 2-isopropyl-1,4-dihydropyrido[2,3-b]pyrazin-2(3H),3-dione was synthesized. This compound was reacted with potassium tert-butoxide and diethyl chlorophosphate to afford an intermediate dihydropyrido[2,3-b]pyrazin-2-ylphosphate derivative which in turn furnished the desired 1,2,4-oxadiazolylimidazo[1,5-a]pyrido[2,3-e]pyrazine derivatives with 5-alkyl-3-isocyanomethyl-1,2,4-oxadiazoles in the presence of additional tert-butoxide. The title compounds are potential ligands for the γ-aminobutyric acid A/benzodiazepine receptor complex. Received November 26, 2001. Accepted December 3, 2001     

An orthogonal protection strategy for the synthesis of 2-substituted piperazines

Tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-ones are readily prepared from the bis-carbamate protected piperazine-2-carboxylic acids and serve as orthogonally protected piperazines from which a variety of 2-substituted piperazines can be prepared. Sodium benzylate and sodium phenoxides react at the C-5 carbon of the oxazolidinone to yield 2-(benzyloxymethyl)piperazines and 2-(phenoxymethyl)piperazines, respectively. The tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-ones also provide convenient scaffolds from which 2-benzyl- and 2-phenethylpiperazines are prepared.