Synthesis of some 1-methyl-3-alkoxy-5-arylpyrrolecarboxylic acids and derivatives

By a combination of hydrolysis, decarboxylation, and methylation diethyl 1-methyl-3-hydroxy-5-phenylpyrrole-2,4-dicarboxylate was converted into 1-methyl-3-methoxy-5-phenyl-pyrrole-2,4-dicarboxylic acid (5) and into the isomeric compounds ethyl 1-methyl-2-phenyl-4-methoxypyrrole-3-carboxylate (4a) and ethyl 1-methyl-3-methoxy-5-phenylpyrrole-2-carboxylate (9a). 1-Methyl-2-phenyl-4-methoxypyrrole-3-carboxylic acid was synthesized both by the selective decarboxylation of 5 and by the hydrolysis of 4a. Hydrolysis of 9a, however, did not give the corresponding acid, but rather an oxidation product, 1-methyl-3-methoxy-5-hydroxy-5-phenyl-3-pyrrolin-2-onc (10a). Compound 10a was shown to arise from the air oxidation of the completely decarboxylated product, 1-methyl-2-phenyl-4-methoxypyrrole. Reduction of 9a with lithium aluminum hydride gave 1-methyl-3-methoxy-5-phenylpyrrole-2-methanol, which yielded 10a upon oxidation with silver oxide.     

Synthesis of some 5-aryl-2,2′-dipyrromethenes as analogs of prodigiosin

Three new dipyrromethenes have been synthesized as analogs of prodigiosin: 3-methoxy-5-phenyl-2,2′-dipyrromethene (10a) , 3-methoxy-4 -pentyl-5-phenyl-5′-methyl-2,2′-dipyrromethene (10b) , and 3-methoxy-4′-pentyl-5′-methyl-5-(2″-thienyl)-2,2′-dipyrromethene (10c). The Michael addition of ethyl glycinate to an appropriate arylidenemalonate, quenched with ethyl chloroformate and followed by a Dieckmann cyclization gave diethyl 1-ethoxycarbonyl-3-oxo-5-phenyl and thienylpyrrolidine-2,4-dicarboxylate, 2a and 2b. Methylation of the highly enolic keto-esters, followed by oxidation to N-ethoxycarbonylpyrroles led, after appropriate elaboration of the pyrrole nucleus, to 2-phenyl- and 2-thienyl-4-methoxypyrroles. The acid catalyzed condensation of these arylmethoxypyrroles with either pyrrole-2-carboxaldehyde or 5-methyl-4-pentylpyrrole-2-carboxaldehyde led to 10a, 10b and 10c.     

Efficient syntheses of ethyl 4-cyano-5-hydroxy-2-methyl-1H-pyrrole-3-carboxylate and ethyl (2Z)-(4-cyano-5-oxopyrrolidin-2-ylidene)ethanoate

Ethyl 2-chloroacetoacetate and its 4-chloro isomer react with cyanoacetamide in the presence of the mild, nonnucleophilic base, triethylamine under stoichiometric conditions to give high yields of ethyl 4-cyano-2-hydroxy-2-methyl-5-oxopyrrolidine-3-carboxylate and ethyl (4-cyano-2-hydroxy-5-oxopyrrolidin-2-yl)acetate, respectively. These, under acid-catalyzed dehydration conditions, afforded ethyl 4-cyano-5-hydroxy-2-methyl-1H-pyrrole-3-carboxylate and ethyl (2Z)-(4-cyano-5-oxopyrrolidin-2-ylidene)ethanoate, respectively. Similarly, the 4-chloro isomer reacted with ethyl cyanoacetate to give the novel product, diethyl 2-cyano-4-oxohexanedioate. The use of triethylamine enables access to a whole new library of pyrrole derivatives from easily accessible, commercially available starting materials. The reactions described in this Letter enable access to libraries of important pyrrole systems in any of the isotopically enriched forms.     

Synthesis of 3-Substituted Pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidines and Related Fused Thiazolo Derivatives

New ethyl 3-(substituted)-4-oxo-2-thioxo-1,2,3,4,5,6,7,8-octahydropyrido[4',3':4,5]thieno-[2,3-d]pyrimidine-7-carboxylates ( 3a , b ), ( 6 ),( 11-13 ), ethyl 3-methyl-5-oxo-2,3,6,9-tetrahydro 5 H -pyrido[4',3':4,5]thieno[2,3-d][1,3]thiazolo[3,2-a]pyrimidine-8(7H)-carboxylate ( 4 ), and ethyl 2-methyl-5-oxo-2,3,6,9-tetrahydro-5 H -pyrido[4',3':4,5]thieno[2,3-d][1,3]thiazolo[3,2-a]-pyrimidine-8(7H)-carboxylate ( 8 ) have been synthesized from diethyl 2-isothiocyanato-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3,6-dicarboxylate 1. The structure of these compounds as well as their intermediates have been established by their spectral data.     

An improved procedure for the preparation of 1-benzyl-1H-1,2,3-triazoles from benzyl azides

A procedure for the preparation of substituted 1-benzyl-1H-1,2,3-triazoles from benzyl azides under very mild conditions is described. The method provides improved yields and extends the scope of the Dimroth Reaction to other types of active methylene compound to those previously used. Benzyl azides react with active methylene compounds in dimethyl sulphoxide catalysed by potassium carbonate at 35–40° to give 1H-1,2,3-triazoles usually in good yield. Acetonitrile derivatives gave 5-amino-1H-1,2,3-triazoles whereas diethyl malonate gave 5-hydroxy-1H-1,2,3-triazoles. 1H-1,2,3-Triazole-4-carboxylate esters and 1H-1,2,3-triazole-4-ketones were obtained from ethyl acetoacetate and β-diketones respectively. Benzyl methyl ketone reacted to give a 5-methyl-4-phenyl-1H-1,2,3-triazole, but acetone and acetophenone failed to react. Other active methylene compounds which did not react under these reaction conditions included ethyl cyanoacetate, ethyl fluoroacetate and ethyl nitroacetate.     

Synthesis and structure of diethyl 2-oxo-1-oxaspiro[4,5]decane-3,4-dicarboxylate

Ethyl 1-oxaspiro[2,5]octane-2-carboxylate reacts with diethyl sodiomalonate in toluene to give diethyl 2-oxo-1-oxaspiro[4,5]decane-3,4-dicarboxylate, which on distillation under goes partial de-ethoxycarbonylation to give ethyl 2-oxo-1-oxaspiro[4,5]decane-4-carboxylate.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 28–32, January, 1991.     

Regioselective 1,3-Dipolar Cycloaddition Reactions of Unsymmetrical Münchnones (1,3-Oxazolium-5-olates) with 2- and 3-Nitroindoles. A New Synthesis of Pyrrolo[3,4-b]indoles

The unsymmetrical mesoionic münchnones 13 (3-benzyl-2-methyl-4-phenyl-1,3-oxazolium-5-olate) and 14 (3-benzyl-4-methyl-2-phenyl-1,3-oxazolium-5-olate) react with the N-protected 2- and 3-nitroindoles 1 (ethyl 2-nitroindole-1-carboxylate), 6 (3-nitro-1-(phenylsulfonyl)indole), and 17 (ethyl 3-nitroindole-1-carboxylate) in refluxing THF to afford in good to excellent yields the pyrrolo[3,4-b]indoles 15 (2-benzyl-1-methyl-3-phenyl-4-carboethoxy-2,4-dihydropyrrolo[3,4-b]indole), 16 (2-benzyl-3-methyl-1-phenyl-4-carboethoxy-2,4-dihydropyrrolo[3,4-b]indole), 18 (2-benzyl-1-methyl-3-phenyl-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole), and 19 (2-benzyl-3-methyl-1-phenyl-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole). In several cases the regiochemistry, which is opposite to that predicted by FMO theory, is very high and leads essentially to a single pyrrolo[3,4-b]indole; e.g., 6+13→19 in 74% yield.     

Methyl 3-cyclopropyl-3-oxopropanoate in the synthesis of heterocycles having a cyclopropyl substituent

Reactions of methyl 3-cyclopropyl-3-oxopropanoate with chloroacetone and ammonia, benzaldehyde and ammonia, and benzoquinone gave, respectively, methyl 2-cyclopropyl-5-methyl-1H-pyrrole-3-carboxylate, dimethyl 2,6-dicyclopropyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate, and methyl 2-cyclopropyl-5-hydroxy-1-benzofuran-3-carboxylate. Cyclization of methyl 3-cyclopropyl-3-oxopropanoate with ethyl chloro(arylhydrazono)ethanoates and other halohydrazones led to the formation of 3-substituted 1-aryl-5-cyclopropyl-1H-pyrazole-4-carboxylic acids, and 5-cyclopropyl-1-(quinolin-5-yl)-1H-1,2,3-triazole-4-carboxylic acid was obtained by reaction of the title compound with 5-azidoquinolines.     

Unprecedented base-promoted cascade transformation of a pyrimidinone derivative into a novel tricyclic bis-diazepinone

In the presence of strong bases (NaH, DBU, KOH), ethyl 4-chloromethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 4, is transformed into a novel tricyclic compound, diethyl 9-methyl-5-methylene-3,11-dioxo-2,3,4,5,6a,7,10,11-octahydro-1,6-methano[1,3]diazepino[1,7-e][1,3,5]triazocine-6,8(1H)-dicarboxylate, 5, as a result of a cascade reaction.     

The reduction of l-methyl-3-methoxy-5-arylpyrrole-2- and -4-carboxylic esters with selected reducing agents

Three new rnethoxypyrrole esters, ethyl 1-methyl-3-methoxy-5-phenylpyrrole-2-earboxylate, diethyl l-methyl-3-methoxy-5-phenylpyrrole-2,4-diearboxylate, and ethyl l-methyl-2-phenyl-4-methoxypyrrole-3-carboxylate were reduced with diborane/tetrahydrofuran, lithium aluminum hydride, and some related reducing agents. In each case diborane reduced the ethoxycarbonyl group to a methyl group and lithium aluminum hydride reduced it to a hydroxymethyl group.     

Synthesis of 5,8-dihydro-5-oxo-2-(3- or 4-pyridinyl)-pyrido[2,3-d]pyrimidine-6-carboxylic acids and the reinvestigation of the thermal cyclization of diethyl (2-hydroxy-4-pyrimidinyl)amino-methylenemalonate

Diethyl [2-(3- or 4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonates 5 prepared by the reaction between 2-(3- or 4-pyridinyl)-4-pyrimidinamines 3 and diethyl ethoxymethylenemalonate ( 4 ) were thermally cyclized to afford ethyl 5,8-dihydro-5-oxo-2-(3- or 4-pyridinyl)pyrido[2,3-d]pyrimidine-6-carboxylates 6 . The later were alkylated with ethyl iodide and then saponified to give 5,8-dihydro-8-ethyl-5-oxo-2-(3- or 4-pyridinyl)pyrido-[2,3-d]pyrimidine-6-carboxylic acids 2 . Thermal cyclization of diethyl (2-hydroxy-4-pyrimidinyl)amino-methylenemalonate ( 8 ) gave ethyl 1,6-dihydro-4,6-dioxo-4H-pyrimido[1,6-a]pyrimidine-3-carboxylate ( 10 ) instead of ethyl 5,8-dihydro-2-hydroxy-5-oxopyrido[2,3-d]pyrimidine-6-carboxylate ( 9 ) as previously claimed.     

Synthesis of a novel analog of nalidixic acid: 1-Ethyl-1,4-dihydro-4-oxo-7-(trifluororaethyl)-1,8-naphthyridine- 3-carboxylic acid

Reaction of nalidixic acid ( 1 ) with thionyl chloride and subsequent treatment with ethanol gave a mixture of ethyl 1-ethyl-1,4-dihydro-4-oxo-7-(trichloromethyl)-1,8-naphthyridine-3-carboxylate ( 3 ) and diethyl 1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3,7-dicarboxylate ( 4 ). Ethyl1-ethyl-1,4-dihydro-4-oxo-7-(trichloromethyl)-1,8-naphthyridine-3-carboxylate ( 3 ) was reacted with antimony pentafluoride to afford 1-ethyl-1,4-dihydro-4-oxo-7-(trifluoromethyl)-l,8-naphthyridine-3-carboxylic acid ( 5 ).     

Five-membered dioxoheterocycles: XCIX. Reaction of 1-aryl-4-aroyl-5-methoxycarbonyl-1H-pyrrole-2,3-diones with indoles. Crystal and molecular structure of substituted 2-(indol-3-yl)pyrrole

1-Aryl-4-aroyl-5-methoxycarbonyl-1H-pyrrole-2,3-diones react with indole and 2-methylindole with the formation of methyl 1-aryl-3-aroyl-4-hydroxy-2-(1H-indol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylates. Crystal and molecular structure of methyl 3-benzoyl-4-hydroxy-2-(2-methyl-1H-indol-3-yl)-5-oxo-1-phenyl-2,5-dihydro-1H-pyrrole-2-carboxylate was examined.     

4-hydroxy-2-quinolones. 114. Synthesis and structure of 6-R-5-hydroxy-2,4-dioxo-2,3,4,6-tetrahydrobenzo-[<Emphasis Type="Italic">c</Emphasis>][2,7]naphthyridine-1-carbonitriles

Hydration of ethyl 1-R-4-dicyanomethyl-2-oxo-1,2-dihydroquinoline-3-carboxylate gives the corresponding substituted cyanoacetamides which are readily and quantitatively cyclized to 6-R-5-hydroxy-2,4-dioxo-2,3,4,6-tetrahydrobenzo[c][2,7]naphthyridine-1-carbonitriles in the presence of aqueous base. For Communication 113 see [1]. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 726–735, May, 2007.     

Five-membered 2,3-dioxo heterocycles: XCIII. Spiro heterocyclization of 4,5-diaroyl-1H-pyrrole-2,3-diones with acyclic enamine. Crystalline and molecular structure of substituted 1,7-diazaspiro[4.4]nonane

4,5-Diaroyl-1-aryl-1H-pyrrole-2,3-diones reacted with ethyl 3-amino-3-phenylprop-2-enoate to give ethyl 4-aroyl-1,6-diaryl-3-hydroxy-2-oxo-8-phenyl-1,7-diazaspiro[4.4]nona-3,6,8-triene-9-carboxylates. The crystalline and molecular structures of ethyl 4-benzoyl-3-hydroxy-1-(4-methylphenyl)-2-oxo-6,8-diphenyl-1,7-diazaspiro[4.4]nona-3,6,8-triene-9-carboxylate were determined by X-ray analysis.     

Features of reactions of polyfluorinated ethyl 4-oxo-2-pnenyl-4H-chromene-3-carboxylates with N-nucleophiles

Ethyl 5,6,7,8-tetrafluoro-4-oxo-2-phenyl-4H-chromene-3-carboxylate in reactions with primary amines is characterized by a chromone-coumarin rearrangement affording 3-[amino(phenyl)methylene]-6,7,8-trifluoro-2H-chromene-2,4(3H)-diones, and ethyl 4-oxo-2-phenyl-5,6,7,8-tetrafluoro-4H-chromene-3-carboxylate characteristically adds the amine at the C² site of the flavone furnishing 3-amino-3-phenyl-2-(2,3,4,5-tetrafluoro-6-hydroxybenzoyl)acrylates which depending on the substituent at the amino group are capable of intramolecular cyclization into 3-[(alkylamino)(phenyl)methylene]-5,6,7,8-tetrafluoro-2H-chromene-2,4(3H)-dione or in the case of benzylamine substituent, into ethyl 1-benzyl-5-hydroxy-4-oxo-2-phenyl-6,7,8-trifluoro-1,4-dihydroquinoline-3-carboxylate. The main process in the reaction of tri- and tetrafluoroflavones with secondary amine (1-methylpiperazine) is the nucleophilic substitution at the C⁷ of flavone. In the reaction with 1,2-phenylenediamine 3-[(2-aminophenyl)amino]-3-phenyl-2-(2,3,4,5-tetrafluoro-6-hydroxybenzoyl)acrylate was obtained from tetrafluoroflavone and 1H-benzimidazol-2-yl(3,4,5-trifluoro-2-hydroxyphenyl)methanone, from trifluoroflavone.     

Synthesis and crystal structure of ethyl 1-benzyl-2-hydroxy-5-methyl-3-oxo-2-phenacyl-2,3-dihydropyrrole-4-carboxylate

Reaction of 5-phenyl-2,3-dihydro-2,3-furandione with ethyl 3-benzylamino-2-butenoate, resulting in ethyl 1-benzyl-2-hydroxy-5-methyl-3-oxo-2-phenacyl-2,3-dihydropyrrole-4-carboxylate and benzylamide ofN-benzoylpyruvic acid, was studied. The structure of the pyrrole derivative was confirmed by X-ray analysis.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1552–1555, August, 1995.     

Crystal structure of phenylhydrazine with diacetyl substituted ketol of the cyclohexane series

The reaction of 2,4-diacetyl-5-hydroxy-5-methyl-3-phenylcyclohexanone-1 with phenylhydrazine is conducted, and the crystal structures of its products, 1-(6-hydroxy-3,6-dimethyl)-2,4-diphenyl-4,5,6,7-tetrahydro-2H-indazol-5-yl)ethane-1-one and 1-(2-hydroxy-2-methyl-6-phenyl-4-(2-phenylhydrazono)-5-(1-(2-henylhydrazono)ethyl)cyclohexyl)ethane-1-one, are determined by single crystal XRD.     

Five-membered 2,3-Dioxoheterocycles: LIX. Reaction of 3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones with Acyclic β-Enaminoesters. Crystal and Molecular Structure of Ethyl 3-Benzoyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,3-dihydro-1H-pyrrolo-2-spiro-3′-(5-methyl-2-oxo-2,3-dihydro-1H-pyrrolo-4-carboxylate)

3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones react with substituted alkyl 3-amino-2-propenoates to form substituted alkyl 3-aroyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,5-dihydro-1H-pyrrole-2-spiro-3′-(2-oxo-2,3-dihydro-1H-pyrrole-4-carboxylates). Crystal and molecular structure of ethyl 3-benzoyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,5-dihydro-1H-pyrrole-2-spiro-3′-(5-methyl-2-oxo-2,3-dihydro-1H-pyrrole-4-carboxylate) was investigated.     

An improved synthesis and some reactions of diethyl 4-oxo-4H-pyran-2,5-dicarboxylate

The reaction of ethyl 2-(dimethylamino)methylene-3-oxobutanoate with diethyl oxalate in the presence of sodium hydride in THF gave diethyl 4-oxo-4H-pyran-2,5-dicarboxylate, from which 4-oxo-4H-pyran-2,5-dicarboxylic and 4-oxo-1-phenyl-1,4-dihydropyridine-2,5-dicarboxylic acids and their derivatives were obtained in good yields.