A new base-induced ring transformation of pyrido[2,3-d]pyrimidines

8-Substituted 5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylates ( 3 ) rearranged to 8-substituted 7,8-dihydro-5-hydroxy-7-oxopyrido[2,3-d]pyrimidine-6-carboxaldehydes ( 5 ) when treated with sodium ethoxide in an aprotic polar solvent at room temperature. The 6-cyano analogue ( 18 ) also underwent ring transformation under the same mild conditions giving 7-amino-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxaldehyde ( 21 ). However, the ring transformations of the pyrido[2,3-d]pyrimidine bearing no N₈-substituent ( 12 ), ethyl 1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine- ( 14 ) and -quinoline-3-carboxylates ( 16 ) failed to occur. A mechanism is discussed.     

Synthesis and Properties of 6-Amino-7-hetaryl-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles

We have established that when 5-chloro-6-[cyano(2,3-dihydro-1-R-benzo[d]azol-2-yl)methyl]-2,3-pyrazinedicarbonitriles are reacted with nucleophilic reagents (aliphatic and aromatic amines, hydrogen sulfide), annelation of the five-membered ring occurs on the [b] face of the pyrazine with formation of 6-amino-7-hetaryl-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles and 6-amino-7-(1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyrazine-2,3-dicarbonitrile respectively. Further heating with excess of acylating reagent leads to formation of a novel heterocyclic system 1H-benzo[4,5]imidazo[1,2-c]pyrazino[2',3':4,5]pyrrolo[3,2-e]pyrimidine. Reaction of vicinal dinitriles with hydrazine hydrate leads to the novel system 1H-pyrrolo[2',3':5,6]pyrazino[2,3-d]pyridazine.     

Interaction of 3-p-toluoyl-1,2-dihydro-4H-pyrrolo-[2,1-c][1,4]benzoxazine-1,2,4-trione with benzylamine. Synthesis and crystal and molecular structure ofZ-3-(1-benzyl-2-hydroxy-4,5-dioxo-2-p-tolyltetrahydropyrrol-3-idene)-3,4-dihydro-2H-1,4-benzoxazin-2-one

3-p-Toluoyl-1,2-dihydro-4H-pyrrolo-[2,1-c][1,4]benzoxazine-1,2,4-trione reacts with benzylamine to yieldZ-3-(1-benzyl-2-hydroxy-4,5-dioxo-2-p-tolyltetrahydropyrrol-3-idene)-3,4-dihydro-2H-1,4-benzoxazin-2-one. The crystal and molecular structure of the latter compound was studied by X-ray structural analysis. Translated fromIzvestiya Akademii Nauk, Seriya Khimicheskaya, No. 3, pp. 566–569, March, 1997.     

Synthesis of 6-Amino-5-R2-7-(6-R1-4-oxo-3,4-dihydro-2-quinazolyl)-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles

It has been found that malonodinitrile and 2-(6-R¹-oxo-3,4-dihydro-2-quinazolyl)acetonitrile in the presence of triethylamine undergo hetarylation by 5,6-dichloro-2,3-pyrazinedicarbonitrile at the active methylene group to give the triethylammonium salt of 2-(3-chloro-5,6-dicyano-2-pyrazinyl)malononitrile or 5-chloro-6-cyano(6-R¹-4-oxo-1,2,3,4-tetrahydro-2-quinazolylidene)methyl-2,3-pyrazinedicarbonitriles. Reaction of these with primary amines leads to annelation of the pyrrole ring at the pyrazine [b] edge to give 6-amino-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3,7-tricarbonitriles and 6-amino-5-R²-7-(6-R¹-4-oxo-3,4-dihydro-2-quinazolyl)-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles respectively.     

The synthesis of a pyrido[2,3-c]pyridazine: A cinnoline related to 6-fluoronalidixic acid

An analog of the pyrido[2,3-c]pyridazine ring system, 1-ethyl-6-fluoro-1,4-dihydro-7-methyl-4-oxopyrido-[2,3-c]pyridazine-3-carboxylic acid ( 13 ), related to both Cinoxacin ( 1 ) and nalidixic acid ( 2 ), has been synthesized. The reductive ring closure of 2-chloro-α-diazo-6-methyl-5-nitro-β-oxo-3-pyridinepropanoic acid, ethyl ester ( 7 ), proved to be the key reaction providing entry into the ring system.     

Condensed pyridazines. Part III. Rearrangement and ring cyclization during the thermolysis of (z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-methylacrylate

The thermolysis of (Z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-methylacrylate ( II ) provides a new synthetic route to pyrrolo[2,3-c-]pyridazines, specifically, methyl 3-chloro-1,6-dimethyl-4-oxo-1,4-dihydro-7H-pyrrolo[2,3-c]pyridazine-5-carboxylate ( III ) in 91% yield. Treatment of III with ozone provides an entry into the novel pyridazino[3,4-d][1,3]oxazine ring system, specifically, 3-chloro-1,7-dimethylpyridazino[3,4-d][1,3]oxazine-4,5-dione ( IV ) in 73% yield. Compound IV is smoothly hydrolyzed into 6-acetylamino-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazine-5-carboxylic acid ( V ) which is readily recyclized into IV by dehydration with acetic anhydride. Furthermore, IV undergoes a facile reductive ring opening reaction with sodium borohydride to give 3-chloro-6-ethylamino-1-methyl-4-oxo-1,4-dihydropyridazine-5-carboxylic acid ( VI ) in 95% yield.     

Synthesis of 2,3-dihydropyrido- and 2,3-dihydropyrimido-[1,4]diazepines from triaminopyridine and triaminopyrimidine

The reaction of 2,3,6-triaminopyridine 1 and 4,5,6-triaminopyrimidine 2 with one equivalent of the chal-cones 3, in acetic acid, leads to the formation of the 8-amino-2,3-dihydro-1H-pyrido[2,3-b][1,4]diazepine and 6-amino-2,3-dihydro-1H-pyrimido[4,5-b][1,4]diazepine derivatives 4 and 5 . The products were characterized by NMR techniques such as ¹³C, ¹H, and DEPT including selective ¹³C{¹H} decoupling experiments.     

Glycerol-1,2-carbonate: A mild reagent for the N-glycerylation of pyrazolecarboxylates

In this study, glycerol-1,2-carbonate was employed as a convenient reagent for the synthesis of more complex pyrazole-containing heterocyclic systems. 3-O-Tosylated glycerol-1,2-carbonate (TGC) was used for alkylation of NH-pyrazolecarboxylates. The obtained N-glycerylated pyrazoles were further treated with diverse nucleophiles for 2-oxo-1,3-dioxolane ring cleavage. The synthesized 1-(2,3-dihydroxypropyl)-1H-pyrazole-5-carboxylates were subsequently hydrolyzed and treated with p-toluenesulfonic acid, yielding a series of 6-(hydroxymethyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]ox-azin-4-ones.     

1,4-Cycloaddition reactions. II. Preparation of p-dioxino[2,3-g]furo[3,2-c] quinolines,p-dioxino[2,3-f] furo[3,2-c] quinolines,and [1,3] dioxolo[4,5-g] furo[3,2-c] quinolines from 2,3-dihydro-5-methylfuran and schiff bases

The boron trifluoride catalyzed 1,4-addition of 2,3-dihydro-5-methylfuran to N-(p-methoxy-benzylidene)-1,4-benzodioxan-6-amine (II) gave 2 pairs of epimers, 2,3,3a,4,5,8,9,11b-octahydro-4-(p-methoxyphenyl)-11b-methyl-p-dioxino[2,3-g]furo[3,2-c]quinoline (IIIa and b) and 2,3,7,8,8a,9.10,1la-octahydro-8-(p-methoxyphenyl)-11a-methyl-p-dioxino[2,3-f]furo[3,2-c]quinoline (IVa and b). When N-(p-methoxybenzylidene)-3,4-methylenedioxyaniline (V) was condensed with 2,3-dihydro-5-methylfuran in an analogous manner, a mixture of 2 epimers of 2,3,3a,4,5,10b-hexahydro-4-(p-methoxyphenyl)-10b-methyl[1,3]dioxolo[4,5-g]furo[3,2-c]quinoline (VIa and b) was isolated. Treatment of this mixture with sulfur afforded 6-(p-methoxyphenyl)-8-methyl-1,3-dioxolo[4,5-g]quinoline-7-ethanol (VIII). Structural assignments for all of the products were made from NMR spectra. None of the compounds possessed appreciable biological activity.     

Synthesis of novel dihydrothiazolo[3,2-a]pyrimidinone derivatives

Condensation of 2-amino-4-hydroxy-2-mercaptopyrimidine (2) hydrate and ethyl 4-bromocrotonate gave a mixture of ethyl 7-amino-2,3-dihydro-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-acetate (4) and 2a,3-dihydro-1-thia-5,8,8b-triazaacenaphthylene-4,7(2H)-dione (5) whereas reaction of 2 with 4-bromocrotononitrile afforded only 7-amino-2,3-dihydro-5-oxo-5H-thiazolo[3,2-a] pyrimidine-3-acetonitrile. Reaction of the tricycle 5 (which was isolated as a hemihydrate) with excess methyl iodide/potassium carbonate in dimethylformamide resulted in both ring hydrolysis and methylation to give 3,4-dihydro-1,7-dimethyl-4- [(methylthio)methyl]-2H-pyrimido[1,6-a]pyrimidine-2,6,8(1H,7H)-trione (10). Methylating 5 with excess methyl iodide/sodium methoxide in methanol also resulted in ring fragmentation and methylation but instead afforded methyl 7-methyl-amino-2,3-dihydro-5-oxo-7H-thiazolo[3,2-a]pyrimidine-3-acetate. The mechanistic aspects of these reactions are discussed.     

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.     

1,4-Cycloaddition reactions. III. Synthesis of furo[3,2-c]pyrido[2,3-g]quinolines,Furo[2,3-a] [4,7]phenanthrolines,Furo[3,2-c]pyrrolo[2,3-g]quinolines,Furo[3,2-c]pyrrolo[3,2-g]quinolines,and Furo[3,2-c]furo[2′,3′:4,5]pyrido[2,3-g]quinolines from 2,3-dihydro-5-methylfuran and schiff bases

The 1,4-cycloaddition of 2,3-dihydro-5-methylfuran (II) to 1-acetyl-1,2,3,4-te trahydro-6-[(p-hydroxybenzylidene)amino]quinoline (VIII) in the presence of boron trifluoride gave two pairs of epimers, namely dl-10-acetyl-2,3,3a,4,5,7,8,9,10,11b-decahydro-4-(p-hydroxyphenyl)-11b-methylfuro[3,2-c]pyrido[2,3-g]quinoline (IXa and b) and dl-8-acetyl-2,3,3a,4,5,8,9,10,11,-11c-decahydro-4-(p-hydroxyphenyl)-11c-methylfuro[2,3-a][4,7]phenanthroline (Xa and b). dl-9-Acetyl-3,3a,4,5,7,8,9,10b-octahydro-4-(p-hydroxyphenyl)-10b-methyl-2H-furo[3,2-c] pyrrolo-[2,3-g]quinoline (XIIIa) was the predominant product isolated from the reaction of II with 1-acetyl-5-[p-(hydroxybenzylidene)amino]indoline (XII). When 1-acetyl-6-[(p-hydroxybenzylidene)amino]indoline (XVI) was treated with 2,3-dihydro-5-methylfuran (II), two epimers of dl-7-acetyl-3,3a,4,5,7,8,9,10b-octahydro-4-(p-hydroxyphenyl)-10b-methyl-2H-furo[3,2-c]pyrrolo[3,2-g]quinoline (XVIIa and b) were obtained. dl-2,3,3a,4,5,6b,8,9,9a,10,11,12b-Dodecahydro-4,10-bis(p-methoxyphenyl)-6b,12b-dimethylfuro[3,2-c]furo[2′,3′:4,5]pyrido[2,3-g]quinoline (XX) was formed when 2,3-dihydro-5-methylfuran was allowed to react with N,N'-bis(p-methoxybenzylidene)-p-phenylcnediamine (XIX). Structure assignments were made from NMR spectra. None of the compounds exhibited appreciable biological activity.     

The [4+2]-cycloaddition of ketene containing both acyl and imidoyl groups to aldehyde: Synthesis,crystal and molecular structure of 1-p-bromophenyl-4-p-toluoyl-1, 3-dihydro-5H-[1,3]oxazino[4,3-c][1,4]benzoxazine-3,5-dione

Thermal decarboxylation of 3-p-toluoyl-1,2-dihydro-4H-pyrrolo[5,1-c][1,4]benzoxazine-1, 2,4-trione resulted in 2-oxo-2H-1,4-benzoxazin-3-yl(p-toluoyl)ketene; the latter under-goes [4+2]-cycloaddition withp-bromobenzaldehyde to form 1-p-bromophenyl-4-p-toluoyl-1, 3-dihydro-5H-[1,3]oxazino[4,3-c][1,4] benzoxazine-3,5-dione. The crystal and molecular structure of the latter has been studied by X-ray analysis.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1633–1636, September, 1993.     

Synthesis and reactions of 2-deoxy-β-D-ribofuranosyl derivatives of 3-aryl-4H-pyrrolo[2,3-d]pyrimidin-4-imines

Summary 3-Aryl-7-(2-deoxy--D-erythro-pentofuranosyl)-3,7-dihydro-4H-pyrrolo[2,3-d]-pyrimidin-4-imines (4) as well as 4-arylamino-7-(2-deoxy--D-erythro-pentofuranosyl)-2-methyl-5-phenyl-7H-pyrrolo[2,3-d]pyrimidines (7) have been synthesized by glycosylation of the sodium salt of the corresponding nucleobases with 2-deoxy-3,5-di-O-p-toluyl--D-erythro-pentofuranosyl chloride (2) followed by subsequent deprotection with sodium methoxide in methanol. The deprotected nucleoside4 undergoes aDimroth rearrangement on reflux for 24 h in water to furnish the 4-arylamino nucleoside7.

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Synthese und Reaktionen von 2-Deoxy--D-ribofuranosylderivaten von 3-Aryl-4H-pyrrolo[2,3-d]pyrimidin-4-iminen

Zusammenfassung 3-Aryl-7-(2-deoxy--D-erythro-pentafuranosyl)-3,7-dihydro-4H-pyrrolo[2,3-d]-pyrimidin-4-imine (4) und 4-Arylamino-7-(2-deoxy--D-erythro-pentofuranosyl)-2-methyl-5-phenyl-7H-pyrrolo[2,3,-d]pyrimidine (7) wurden durch Glycosylierung der Natriumsalze der entsprechenden Nucleosidbasen mit 2-Deoxy-3,5-di-O-p-toluyl--D-erythro-pentofuranosylchlorid (2) und anschließende Entfernung der Schutzgruppe mit Natriummethoxid in Methanol hergestellt. Das entschützte Nucleosid4 ergibt bei 24-stündigem Erhitzen in Wasser unter Rückfluß über eineDimroth-Umlagerung das 4-Aminonucleosid7.

     

Some novel heterocyclic systems derived from 7-amino-2,3-dihydro-8-nitro-1H-pyrrolo[1,2-α]benzimidazole and the corresponding diamine

The preparation of 7-amino-2,3-dihydro-8-nitro-1H-pyrrolo[1,2-a]benzimidazole from 1,4-diacetamido-2,3-dinitrobenzene is described. Reaction of this compound with 2,5-dimethoxytetrahydrofuran produces 2,3-dihydro-8-nitro-7-N-pyrrolo-1H-pyrrolo[1,2-a]benzimidazole, which can be cyclised to produce two new heterocyclic ring systems, 9,10-dihydro-8H-pyrrolo[1,2-a]pyrrolo(1′,2′:1,2]imidazo[5,4-f]quinoxaline and 9,10-dihydro-8H-pyrrolo[2,1-c]pyrrolo[1′,2′:1,2]imidazo[4,5-h][1,2,4]benzotriazine. The corresponding diamine, 7,8-diamino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole undergoes a variety of condensation reactions to produce several new heterocyclic systems, for example, with formic acid, 1,7,8,9-tetrahydroimidazo-[4,5-e]pyrrolo[2,1-6]benzimidazole is formed and with diacetyl, 9,10-dihydro-2,3-dimethyl-8H-pyrrolo-[1′,2′:1,2]imidazo[5,4-y]quinoxaline is obtained.     

Reaction of 2-bromomethyl-1,3-thiaselenole with thiourea: en route to the first representatives of 2-(organylsulfanyl)-2,3-dihydro-1,4-thiaselenines

The regioselective reaction of 2-bromomethyl-1,3-thiaselenole 1 with thiourea is accompanied by rearrangement, expanding the ring to afford the corresponding six-membered isothiuronium salt, 2-[amino(imino)methyl]sulfanyl-2,3-dihydro-1,4-thiaselenine hydrobromide 2, a synthon of the 2,3-dihydro-1,4-thiaselenin-2-ylthiolate anion. The latter was used for the synthesis of the first representatives of 2-(organylsulfanyl)-2,3-dihydro-1,4-thiaselenines 3a–g, bis(2,3-dihydro-1,4-thiaselenin-2-yl) disulfide 5 and 1,6-bis(2,3-dihydro-1,4-thiaselenin-2-ylsulfanyl)hexane 6.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones VII. Synthesis of 2H,5H-[1]benzothiopyrano[4,3-b]pyran and 2H,5H-thiopyrano[4,3-b]pyran derivatives

The dipolar 1,4-cycloaddition of dichloroketerie to N,N-disubslituled 3-aminomethylene-2,3-dihydro-4-thiochromanones and 3-aminomethylenetelrahydro-4-thiopyranones gave N,N-disubstituted 4-amino-3,3-diehloro-3,4-dihydro-2H,5H-[1]benzolhiopyrano[4,3-b]pyran-2-ones and 4-amino-3,3-dichloro-3,4,7,8-tetrahydro-2H,5H-thiopyrano[4,3-b]pyran-2-ones, respectively, only in the ease of aromatic or strong hindering aliphatic N-substitution. The adducts gave N,N′-disubstituted 4-amino-3-chloro-2H,5H-[1]benzothiopyrano[4,3-b]pyran-2-ones and 4-amino-3-chloro-7,8-dihydro-2H,5H-thiopyrano[4,3-b]pyran-2-ones, respectively, by dehydro-chlorination with DBN. By chromatography on neutral alumina, 3-(2,2-dichloroethylidene)-2,3-dihydro-4-thiochromanone was isolated as an unstable liquid from the reaction between dichloroketerie and 3-diethylaminornethylene-2,3-dihydro-4-thiochromanone.     

Unexpected Direction of Iodocyclization of 3-Allylthio-5-phenyl-4H-1,2,4-triazole

The reaction of 3-allylthio-5-phenyl-4H-1,2,4-triazole with iodine to give a mixture of 5,6-dihydro-5-iodomethyl-3-phenyl[1,3]thiazolo[2,3-c][1,2,4]triazole, 6,7-dihydro-6-iodo-3-phenyl-5H-[1,2,4]triazolo[3,4-b][1,3]thiazine, 5,6-dihydro-6-iodomethyl-2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazole, and 6,7-dihydro-6-iodo-2-phenyl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine has been studied. The structure of the products obtained was established using ¹H NMR spectroscopy of their dehydriodination products.     

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.     

Synthesis of Benzofuro[3,2-e][1,4]diazepines

A synthesis of 4-N-oxides and of 3-hydroxy derivatives of 1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-ones and of 2,3-dihydro-1H-benzofuro[3,2-e][1,4]diazepines is described. Condensation of 2-acetyl- and 2-benzoyl-3-ethoxycarbonylaminobenzofurans with acrylonitrile gave derivatives of 1,2-dihydro- and of 1,2,3,4-tetrahydrobenzofuro[3,2-b]pyridine.