Solid-phase synthesis of 4(1H)-quinolone and pyrimidine derivatives based on a new scaffold-polymer-bound cyclic malonic acid ester

An efficient method for the preparation of polymer-bound cyclic malonic acid ester starting from Merrifield resin has been developed. Reaction of the resin-bound cyclic malonic acid ester with triethyl orthoformate and subsequent double substitution with nucleophilic reagents, such as arylamine, urea, thiourea, 2-aminobenzothiazoles, or isothiosemicarbazones, afforded the corresponding polymer-bound substituted aminomethylene cyclic malonic acid esters, which upon thermal treament led to 4(1H)-quinolones, 3-substituted uracils and thiouracils, 4H-pyrimido[2,1-b]benzothiazol-4-ones, and 1-(N-alkylidene or benzylideneamino)-1,6-dihydro-2-methylthio-6-oxo-pyrimidines, depending on the structures of the nucleophilic reagents.     

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.     

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.     

A Facile Solid Phase Synthesis of 2—Alkylthio—4（1H）—quinolones

The resin-bound cyclic malonic acid ester 2 reacted with aryl isothiocyanate and alkyl halides to afford the key intermediate arylthioaminomethylene cyclic malonic ester resin 3.Subsequently,resin 3 proceeded thermal cyclizaiton giving the 2-alkylthio-4(1H)-quinolones in good yields and excellent purties.     

A [4 + 2] cycloaddition strategy to pyridine boronic ester derivatives

Alkynylboronate cycloadditions of 1,4-oxazin-2-ones and 2-pyrazinones provide a direct and regioselective route to functionalized pyridine boronic ester derivatives.     

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).     

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.     

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.     

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.     

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.     

Convenient Solid-phase Synthesis of Benzothiazole Derivatives

Resin-bound cyclic malonic ester 1 reacted with aryl isothiocynate, then was treated with bromine, followed by cleavage from the resin under perchloric acid to give benzothiazoles 4.     

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.     

Synthesis and reactivity of 4-hydroxy-5-methyl-2-(2-oxo-2<Emphasis Type="Italic">H</Emphasis>-chromen-3-yl)-6<Emphasis Type="Italic">H</Emphasis>-1,3-oxazin-6-ones

4-Hydroxy-6H-1,3-oxazin-6-ones with a coumarin fragment in position 2 of the oxazine ring were synthesized. Their hydrolysis, alcoholysis, and hydrazinolysis afforded a number of new coumarin derivatives containing malonamic acid and 1,2,4-triazole residues. The low stability of the title compounds toward oxygencentered nucleophiles was interpreted by quantum chemical calculations.     

Investigation of the Diels-Alder cycloadditions of 2(H)-1,4-oxazin-2-ones

[Reaction: see text]. A variety of 5-chloro-2(H)-1,4-oxazin-2-ones bearing a range of substituents at their 3- and 6-positions undergo Diels-Alder cycloaddition as a 2-azadiene component with electron-rich, electron-deficient, and electron-neutral dienophiles. These reactions proceed with moderate regio- and stereoselectivity to afford relatively stable and readily isolable bridged bicyclic lactone cycloadducts. Chemical manipulation of these cycloadducts affords highly substituted and functionally rich piperidines. The regio- and stereochemical preferences of the cycloadditions of 5-chloro-2(H)-1,4-oxazin-2-ones are investigated computationally using density functional theory (B3LYP/6-31G).     

Transformations of nitrates (nitro esters) of amino alcohols involving both functions. 1. Reaction with alkali metal hydrogen carbonates

The reaction of nitrates (nitro esters) of amino alcohols with alkali metal hydrogen carbonates yielding oxazolidin-2-ones and tetrahydro-1,3-oxazin-2-ones was discovered. A large number of both known and newly synthesized nitrates of amino alcohols with various structures were involved in this reaction, and the optimum reaction conditions were found. New oxazolidin-2-ones and tetrahydro-1,3-oxazin-2-ones were synthesized. Two more transformations were found for a few examples. One of the reactions gives nitramino alcohols, whereas another reaction affords polymers.     

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.     

Reaction of 6-aryl-2,2-dimethyl-1,3-dioxin-4-ones with cyanoamino compounds

Aroylketenes have been generated by thermolysis of 6-aryl-2,2-dimethyl-1,3-dioxin-4-ones. They take part in a 1,4-cycloaddition reaction at the CN bond of N-aryl or N,N-dialkyl-N-cyanoamines and of N'-phenyl-N-cyanoguanidine to form the corresponding 2-N-aryl-amino, 2-N,N-dialkylamino, and 2-N-phenylguanidino-6-aryl-1,3-oxazin-4-ones. p-Aminobenzonitrile and cyanoacetamide are acylated by aroylketenes to form the p-cyanophenylamide of p-toluylacetic acid and the cyano-acetamide of benzoylacetic acid.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1265–1268, September, 1989.     

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.     

Solid Phase Synthesis of Ethyl β-Substituted Indolepropionates

A facile solid phase synthesis of ethyl β-substituted indolepropionates is reported. Condensation between indole, polymer-supported cyclic malonic acid ester and aldehyde yielded the trimolecular adducts, which was cleaved by pyridine/EtOH to release the final products in good yield with high purity.