Potentiometric study on acid properties of some 4-hydroxy-6H-1,3-oxazin-6-ones. Structure-biological activity relationship

4-Hydroxy-6H-1,3oxazin-6-ones exhibit properties of weak OH acids. These compounds are readily methylated with diazomethane to give the corresponding 4-methoxy derivatives. According to the potentiometric titration data, the pK _a values of 2-methoxy-and 2-methylsulfanyl-substituted 4-hydroxy-6H-1,3-oxazin-6-ones range from 7.45 to 8.42, depending on the substituent in position 5 of the heteroring. 4-Hydroxy-6H-1,3-oxazin-6-ones in biological media exist mainly in the neutral form.     

Hetero-diels-alder reaction of N-cyanoaniline and pyridinium cyano-(ethoxycarbonyl)methylide with aroylketenes generated in situ in thermolysis of 6-aryl-2,2-dimethyl-1,3-dioxin-4-ones

We have used thermolysis of 6-aryl-2,2-dimethyl-1,3-dioxin-4-ones in the presence of N-cyanoaniline, pyridinium cyano(ethoxycarbonyl)methylide, and 4-hydroxybenzonitrile to obtain the corresponding 6-aryl-2-phenylamino-1,3-oxazin-4-ones, pyridinium ethoxycarbonyl(4-oxo-6-aryl-4H-1,3-oxazin-2-yl)methylides, and p-cyanophenyl esters of 3-aryl-3-oxopropanoic acids. We present the results of a preliminary investigation of the biological activity of these compounds. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 764–768, May, 2006.     

Preparation of fused 1,3-oxazine-2,4-diones as potential antitumor agents

A series of indole, thiophene and pyrrole-fused 1,3-oxazine-2,4-diones, 2-methyl-1,3-oxazin-4-ones and 2-dimethylamino-1,3-oxazin-4-ones were synthesized and evaluated as antitumor agents.     

Chemistry of oxalyl derivatives of methyl ketones. 40. Reaction of 5-aryl-2,3-dihydro-2,3-furandiones with aryl and aroyl cyanamides

Starting from 5-aryl-2,3-dihydro-2,3-furandiones and benzoyl cyanamide, 2-benzoylamino-6-aryl-1,3-oxazin-4-ones were obtained. It was shown that on reaction of o-chlorophenyl cyanamide with furandiones, 2-imino-3-(o-chlorophenyl)-5-phenacyliden-4-oxazolidones are formed which in acid medium rearrange to 3-(o-chlorophenyl)-5-phenacylideneimidazolidin-2,4-diones and on thermolysis in acid medium they form 2-(o-chloroanilino)-6-aryl-1,3-oxazin-4-ones.For Communication 39, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 166–169, February, 1985.     

Reactions of 2-alkylsulfanyl- and 2-alkoxy-4-hydroxy-6<Emphasis Type="Italic">H</Emphasis>-1,3-oxazin-6-ones with O-nucleophiles

Reactions of 2-alkylsulfanyl- and 2-alkoxy-4-hydroxy-6H-1,3-oxazin-6-ones with oxygen-centered nucleophiles were studied. 2-Alkoxy-4-hydroxy-6H-1,3-oxazin-6-ones reacted with water and alcohols to give the corresponding alkyl 3-amino-3-oxopropanoates as a result of opening of the oxazine ring at the C⁶-O bond, whereas their 2-alkylsulfanyl analogs turned out to be stable toward O-nucleophiles. The different reactivities of the title compounds were interpreted in terms of quantum-chemical calculations of their electronic structure.     

Heterocyclization of functionalized heterocumulenes with C,N-and C,O-binucleophiles: VI. Synthesis of carbofused 2,3-dihydro-1,3-oxazin-4-ones and 3,4-dihydro-1,3-oxazin-2-ones

Condensations of 1-phenyl-2,2,2-trifluoro-1-chloroethyl isocyanate and 1-chlorobenzyl isocyanate with cyclic 1,3-diketones yield respectively carbofused 2,3-dihydro-1,3-oxazin-4-ones and 3,4-dihydro-1,3-oxazin-2-ones.     

Facile and convenient synthesis of 2,6-disubstituted 4H-1,3-oxazin-4-one derivatives

Facile and convenient methods for the preparation of a variety of 2,6-disubstituted 4H-1,3-oxazin-4-ones 3 by three complementary methods are described. Treatment of the branched aliphatic imidate 2c,d with diketene 1 in the presence of a catalytic amount of acetic acid affords 2-substituted 6-methyl-1,3-oxazin-4-ones 3c,d , whereas the unbranched imidate 2b,e gave oxazines 3b,e and pyrimidines 4b,e (Method A). The reaction of acyl Meldrum's acid 5 with imidate 2 afford 2,6-disubstituted oxazine 3, though the alkylimidate with acetyl Meldrum's acid yielded 3 and 5-acetyl-1,3-oxazine-4,6-dione 8 (Method B). The cylodehydration of acylacetylcarboxamide 13 with acid, such as 70% perchloric acid or fluorosulfonic acid, afforded 1,3-oxazines 3 (Method C).     

Ring contraction reactions of 2,3-dihydro-4H-1,3-oxazin-4-ones under electrospray ionization conditions

The mass spectral behavior of 2,3-dihydro-4H-1,3-oxazin-4-ones has been investigated using electrospray ionization multi-stage mass spectrometry (ESI-MS(n)). All compounds showed a predominant retro-Diels-Alder (RDA) fragmentation pathway, and a novel ring contraction reaction by loss of isocynates was also found. The fragmentation mechanisms proposed for 4H-1,3-oxazin-4-ones are supported by ESI-MS/MS/MS spectra.     

Studies on condensation of chlorocarbonyl phenyl ketene with <Emphasis Type="Italic">N</Emphasis>-unsubstituted amides: synthesis of some new 1,3-oxazin-6-ones

A series of 1,3-oxazin-6-one derivatives has been synthesized upon treatment of N-unsubstituted amides with chlorocarbonyl phenyl ketene under reflux in toluene for several minutes. In this simple way, 2,5-disubstituted derivatives of 1,3-oxazin-6-ones have been obtained in high yields.     

Investigation of the Interaction of 5-Aryl-2,3-dihydro-2,3-furandiones with Compounds Containing C=N and C≡N Bonds Simultaneously

Aroylketenes, generated by the thermolysis of 5-aryl-2,3-dihydro-2,3-furandiones, react with S-methyl-N-cyano-N′-phenylisothiourea, N-cyano-N′,N′-dimethylformamidine, and N,N-bis(β-cyanoethyl)-cyanamide with the formation of 6-aryl-2-[(methylthio)(phenylamino)methylene]amino-, 6-aryl-2-dimethylaminomethyleneamino-, and 6-aryl-2-[N,N-bis(β-cyanoethyl)amino]-4H-1,3-oxazin-4-ones respectively. Modeling has been carried out of the interaction of benzoylketene with the indicated cyano compounds by the SSP MO LCAO semiempirical method using the MNDO-PM3 approach. A mechanism is proposed for the formation of substituted 4H-1,3-oxazin-4-ones. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1490–1501, October, 2005.     

Synthesis of 5-Alkyl(aryl)-2-alkylsulfanyl(alkoxy)-4-hydroxy-6H-1,3-oxazin-6-ones

Alkyl carbamates and S-alkyl thiocarbamates react with substituted malonyl dichlorides in boiling benzene to give the corresponding 2,5-substituted 4-hydroxy-6H-1,3-oxazin-6-ones. The reaction of S-methyl thiocarbamate with unsubstituted malonyl dichloride in boiling diethyl ether or benzene leads to formation of S-methyl (3-methylsulfanylaminocarbonyl-3-oxopropionyl)thiocarbamate and is not accompanied by cyclization, whereas in boiling toluene 4-hydroxy-2-methylsulfanyl-6H-1,3-oxazin-6-one is obtained.__________Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 3, 2005, pp. 468–472.Original Russian Text Copyright © 2005 by Lalaev, Yakovlev, Zakhs.     

A convenient synthesis of 1,3-oxazolidin-4-ones and 1,3-oxazin-4-ones

1,3-Oxazolidin-4-ones and 1,3-oxazin-4-ones were synthesized by formal cyclocondensation of imines with α- or β-hydroxy acids.     

Carboxyketenes from 4-hydroxy-1,3-oxazin-6-ones and Meldrum's acid derivatives

New 4-hydroxy-1,3-oxazin-6-ones 8 and 16 were prepared from chlorocarbonyl(phenyl)ketene and amides. The flash vacuum thermolysis (FVT) reactions of these compounds and the 4-methoxy derivative 17 were investigated by Ar matrix isolation IR spectroscopy and online mass spectrometry including MS/MS analysis. Carboxy(phenyl)ketene 10 is formed as the major product by thermal fragmentation of 4-hydroxy-1,3-oxazin-6-one 8. This takes place via the unstable 6-hydroxy tautomer 9. Another tautomer, the 5H-isomer 12, leads to the formation of benzoyl isocyanate 13 as a minor product together with phenylketene 14. Carboxy(phenyl)ketene 10 remains detectable at high FVT temperatures but undergoes thermal decarboxylation to phenylketene 14. The same carboxy(phenyl)ketene 10 is also produced in significant amounts by FVT of 5-phenyl-Meldrum's acid 18 via the unstable enol tautomer 19. A small amount of the unsubstituted carboxyketene 20 is observable on FVT of Meldrum's acid 1 itself.     

Synthesen von Heterocyclen, 76. Mitt.: Über eine Synthese von substituierten Barbitursäuren

Zusammenfassung Carbodiimide reagieren mit Malonylchlorid oder monosubstituierten Malonsäurechloriden zu Derivaten des 2-Imino-6-chlor-4-oxo-3,4-dihydro-2H-oxazins-(1,3), die in wäßrigen Medien eine Umlagerung zu 1,3-disubstituierten Barbitursäuren erfahren.

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The reaction between carbodiimides and malonyl chloride or monosubstituted malonyl chlorides yields derivatives of 6-chloro-2-imino-3,4-dihydro-2H-(1,3)-oxazin-4-on, which in aqueous solution are readily rearranged to 1,3-disubstituted barbituric acids.

     

Conversion of N-acyl-4-acyloxy-beta-lactams into 1,3-oxazin-6-ones: two consecutive pseudopericyclic processes

N-Acyl-4-acyloxy-beta-lactams are converted into 1,3-oxazin-6-ones under basic conditions. This transformation is believed to proceed via N-acylazetones, which rearrange to the final products by a sequence of two electrocyclic processes. The calculated (RHF and B3LYP) transition structures of both concerted reactions are shown to present characteristic pseudopericyclic orbital topologies.     

Reaction of Phenylmalonyl Dichloride with 3-Phenylpropynamide and Transformations of the Product by the Action of Some Nucleophiles

Phenylmalonyl dichloride reacted with 3-phenylpropynamide to give 4-hydroxy-5-phenyl-2-phenylethynyl-6H-1,3-oxazin-6-one. Treatment of the latter with hydrazine afforded 3,5-disubstituted 1,2,4-triazole. Reactions of 4-hydroxy-5-phenyl-2-phenylethynyl-6H-1,3-oxazin-6-one with methanol and ethanol led to formation of the corresponding malonamic acid esters. The structure of the products was proved by the ¹H and ¹³C NMR and IR spectra, quantum-chemical calculations (PM3, MNDO, MINDO3), and some chemical transformations.__________Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 5, 2005, pp. 815–819.Original Russian Text Copyright © 2005 by Komarov, Yakovlev, Zakhs, Prep’yalov.     

Solid Phase Synthesis of 2-Substituted 1,3-Oxazin-6-ones Using Resin-bound Cyclic Malonic Acid Ester

A facile solid phase synthesis of 2-substituted 1,3-oxazin-6-ones using polymer-supported Meldrum‘s acid has been reported. Reaction of the resin-bound cyclic malonic acid ester with triethyl orthoformate and subsequent double substitution with amide, afforded the corresponding polymer-supported acylaminomethylene cyclic malonic acid ester, which upon thermal treatment led to 1, 3-oxazin-6-ones in good yields and with high purity.     

Novel Synthesis of Acylaminomethylene Meldrum's Acids and Their Thermolysis to 4-Methylthio-and 4-Amino-2-aryl-6H-1,3-oxazin-6-ones

Bismethylthiomethylene Meldrum's acid reacts with amides in the presence of potassium hydroxide to afford methylthioacylaminomethylene Meldrum's acid 5. Aminolysis of 5 gives aminoacylaminomethylene Meldrum's acids 7. Thermolysis of 5 and 7 supplies a novel synthetic method of 4-methylthio- and 4-amino-2-aryl-6H-1,3-oxazin-6-ones.     

Reaction of 2,3-Dihydro-1,5-benzothiazepines and Phenylacetyl Chloride in the Presence of Triethylamine： A New Aspect on the Formation Mechanism of Dihydro-1,3-oxazin-4-one Derivatives

2a,4-Disubstituted 2,2a,3,4-tetrahydro-2-phenyl-1H-azeto[2,1-d][ 1,5]benzothiazepin-1-ones, as well as 2-substi-tuted 2,3-dihydro-3-phenylacetyl-2-styryl-benzothiazoles and 4a,6-disubstituted 3- .benzyl-4a,5-d/hydro-2-phenyl-1H,6H-[1,3]oxazino[2,3-d][1,5]benzothiazepin-1-ones, were obtained from the reaction of 2,4-disubstituted 2,3-dihydro-1,5-benzothiazepines with phenylacetyl chloride in the presence of triethylamine. The mechanism for the formation of 4a,5-dihydro-1H,6H-[1,3]oxazino[2,3-d][1,5]benzothiazepin-1-ones, 2,3-dihydro-1,3-oxazin-4-one derivatives, was suggested.     

Novel salicylaldehyde-based mineral-supported expeditious synthesis of benzoxazin-2-ones

One-pot montmorillonite K-10 clay supported reactions of either salicylaldehyde/2-hydroxyacetophenone hydrazones and aryl-/alkylureas or salicylaldehydes/2-hydroxyacetophenone and 4-aryl-/alkylsemicarbazides expeditiously yield 3,4-dihydro-4-hydrazino-2H-benz[e]-1,3-oxazin-2-ones (9) via cycloisomerization of the intermediate salicylaldehyde/2-hydroxyacetophenone 4-aryl-/alkylsemicarbazones (5) under solvent-free microwave irradiation. Under the same conditions, hydrazines (9) readily underwent reductive dehydrazination on alumina-supported copper(II) sulfate to furnish 2H-benz[e]-1,3-oxazin-2-ones (10).