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 substituted 5-oxo-1-thiocarbamoyl-3-pyrazoline-4-alkanoic acid derivatives

Cyclization of the 4-methyl-3-thiosemicarbazone of diethyl acetylsuccinate (1a) by the action of ammonium hydroxide followed by acidification afforded ethyl 3-methyl-1-methylthiocarbamoyl-5-oxo-3-pyrazoline-4-acetate (11a). Pmr spectral analyses using shift reagent, Eu(fod)₃, in deuteriochloroform indicated the presence also of approximately 15% of a second tautomer, ethyl 5-hydroxy-3-methyl-1-(methylthiocarbamoyl)pyrazole-4-acetate (11a'). 3-Methyl-1-methyl-thiocarbamoyl-5-oxo-pyrazoline-4-acetamide (11b) was prepared by extending the reaction time of 1a with ammonium hydroxide. Alkaline hydrolysis of 11a provided the corresponding acid 3-methyl-1-methylthiocarbamoyl-5-oxo-3-pyrazoline-4-acetie acid (11c). Regeneration of 11a was achieved by the reaction of ethyl 3-methyl-5-oxo-3-pyrazoline-4-acetate (IV) with methyl isothiocyanate. The latter reaction provided confirmation of structure for 11a. The preparation of other pyrazolin-5-ones by cyclization of thiosemicarbazones of ethyl formylsuccinate and ethyl acetylglutarate also is presented. All spectra are in accord with the proposed structures.     

Benzofuran derivatives. Part 3 On the reactivities of the intermediates in benzofuran synthesis

3-Methyl-5-nitrobenzofuran ( 2 ) and 3-methyl-5-nitrobenzofuran-2-carboxylic acid ( 3 ) were obtained by heating 2-acetyl-4-nitrophenoxyacetic acid ( 1 ) with various bases in acetic anhydride. It appeared that 3-hydroxy-3-methyl-5-nitro-2,3-dihydrobenzofuran-2-carboxylic acid ( 4 ) was the intermediate in the benzofuran synthesis. The properties of 4 were examined under various conditions. Using strong bases such as triethyl-amine in place of sodium acetate, 3-methyl-5-nitrobenzofuran-2-carboxylic acid ( 3 ) was obtained exclusively. However, in the presence of acetic acid in the reaction mixture 3-methyl-5-nitrobenzofuran ( 2 ) was obtained in good yield. The reaction pathways for the formation of 2 and 3 are discussed.     

Synthesis of 1,4-dihydro-2-methyl-4-oxo-3-quinolineglyoxylic acid and related compounds

The synthesis of 1,4-dihydro-1-methoxy or ethyl -2-methyl-4-oxo-3-quinolineglyoxylic acid derivatives are described. α-Acetoxy-1,4-dihydro-1-hydroxy-2-methyl-4-oxo-3-quinolineacetic acid esters ( 7a, 7a ), which are key intermediates, were prepared by catalytic hydrogenation of 2-acetoxy-3-acetyl-4-hydroxy-4-(2-nitrophenyl) crotonic acid lactone ( 6 ) in methanol or ethanol.     

Aromatization and chemoselective alkylation of 1-methyl-3,4-dihydro-β-carboline-3-carboxylic acid and its derivatives

Unprecedented aromatization was observed during N-alkylation reactions of 1-methyl-3,4-dihydro-β-carboline-3-carboxylic acid methyl ester, giving rise to 9-alkyl-1-methyl-β-carboline-3-carboxylic acid methyl esters. Inverse addition of base during a similar reaction resulted in a chemoselective alkylation to form novel 3-butyl-1-methyl-3,4-dihydro-β-carboline-3-carboxylic acid methyl ester as the major product in good yield.     

Syntheses of substituted 2-(1-methyl-5-nitro-2-benzimidazolyl)quinolines

Reaction of N-methyl-2-amino-4-nitroaniline ( 1 ) with lactic acid afforded 2-(1-hydroxyethyl)-1-methyl-5-nitrobenzimidazole ( 2 ). Oxidation of compound 2 with chromic acid in acetic acid gave 2-acetyl-1-methyl-5-nitrobenzimidazole ( 3 ). Reaction of compound 3 with substituted 2-aminobenzaldehyde ( 4 ) under basic conditions yielded substituted 2-(1-methyl-5-nitro-2-benzimidazolyl)quinolines ( 5 ). Condensation and cyclization of o-aminoacetophenone (or substituted o-aminobenzophenones) with compound 3 under acetic condition afforded compound 7 . Condensation and cyclization of compound 1 with indole-3-carboxaldehyde ( 11 ) in ethanol in the presence of excess nitrobenzene gave 3-(1-methyl-5-nitro-2-benzimidazolyl)indole ( 12 ).     

Selective protodeboronation: synthesis of 4-methyl-2-thiopheneboronic anhydride and demonstration of its utility in Suzuki-Miyaura reactions

An efficient synthesis of 4-methyl-2-thiopheneboronic anhydride is reported. Regioselective lithiation of 3-methylthiophene followed by reaction with triisopropylborate and hydrolysis provides a 92:8 ratio of 4-methyl-2-thiopheneboronic acid (1) and regioisomeric 2-methyl-3-thiopheneboronic acid (3). The undesired regioisomer is selectively protodeboronated with concentrated acid to provide only the desired 4-methyl-2-thiopheneboronic acid (1). The title compound is isolated by dehydration/crystallization and employed in several Suzuki-Miyaura reactions.     

Extraction of scandium ions by 1-alkyl-3-methyl-2-pyrazolin-5-ones from perchlorate solutions

The extraction of perchloric acid and the two-phase partition of 1-alkyl-3-methyl-2-pyrazolin-5-ones (AMPs) in the system water-chloroform-perchloric acid are studied. These reagents can extract scandium cations from weak acid solutions in the presence of perchlorate ions. 1-Alkyl-3-methyl-2-pyrazolin-5-ones separate aqueous perchloric acid solutions into a pair of liquid phases. Scandium ions concentrate in the lower phase, which has a small volume.     

Analytical aspects of cyanobacterial volatile organic compounds for investigation of their production behavior

In order to fully understand the role of volatile organic compounds (VOCs) under natural conditions, an adaptable analytical method was developed as the first step. β-Ionone, β-cyclocitral, 2-methyl-1-butanol and 3-methyl-1-butanol were simultaneously analyzed in addition to geosmin and 2-MIB using GC/MS with SPME. The slight modification of a known method allowed the simultaneous detection and quantification of these VOCs. The SIM of the 3-methyl-1-butanol was always accompanied by a shoulder peak, suggesting the presence of two compounds. In order to separate both compounds, the GC/MS conditions were optimized, and the additional peak was identified as 2-methyl-1-butanol by direct comparison of the authentic compound, indicating that the Microcystis strain always produces a mixture of 2-methyl-1-butanol and 3-methyl-1-butanol. Furthermore, it was found that 2-methyl-1-butanol and 3-methyl-1-butanol were predominant in the dissolved fractions. β-Cyclocitral was easily oxidized to provide the oxidation product, 2,6,6-trimethylcyclohexene-1-carboxylic acid, which causes the blue color formation of cyanobacteria as a consequence of acid stress. The intact acid could be satisfactorily analyzed using the usual GC/MS without derivatization.     

Highly sensitive simultaneous quantification of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid in human plasma using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry

Indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid are uremic toxins that accumulate in renal failure and have been reported to decrease the activities of the drug-metabolizing enzyme cytochrome P450 3A and the drug transporter organic anion transporting polypeptides 1B, respectively. In this study, we established and validated an assay for simultaneous quantification of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid in human plasma. The samples were pretreated by solid-phase extraction, and measured by ultra-high-performance liquid chromatography–tandem mass spectrometry. The validation results for this assay were within the acceptable limits recommended by the US Food and Drug Administration, with a lower limit of quantitation of 0.05 μg/mL for both indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid. Recovery rates of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid corrected by internal standard were 100.7–101.9 and 100.2–101.3%, respectively. Matrix effects of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid corrected by internal standard were 101.1–105.5 and 97.0–103.8%, respectively. The validated assay was used to analyze indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid concentrations in the plasma samples of healthy volunteers and patients with chronic kidney disease. All the measured plasma indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid concentrations were within the calibration ranges. This novel method may contribute to predicting the activities of drug-metabolizing enzymes and drug transporters in individual patients.     

Synthesis of new polydentate tweezers ligands of amido-amine type

A series of new tweezers amido-amine ligands containing pyrrole, bipyrrole, and dipyrrolylmethane fragments were synthesized by reaction of 2-thioxothiazolidin-3-yl derivatives of α-pyrrolecarboxylic acids {5-[1-(5-carboxy-3-methyl-4-phenyl-1H-pyrrol-2-yl)-1-methylethyl]-4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid, 5-[(5-carboxy-3-methyl-4-phenyl-1H-pyrrol-2-yl)phenylmethyl]-4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid, 5-(5-carboxy-3-methyl-4-phenyl-1H-pyrrol-2-yl)-4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid, and 3,4-dimethyl-pyrrole-2,5-dicarboxylic acid} with o-phenylenediamine. All compounds obtained were characterized by elemental analysis, NMR and mass spectra.     

Syntheses of 2-acetyl-3-hydroxy-1-n-propylpyrrole from isomaltol and 1-n-alkyl-3-hydroxy-2-methyl-4-pyridones from maltol

2-Acetyl-3-hydroxyfuran (2) reacts with n-propylamine affording 2-acetyl-3-hydroxy-1-n-propylpyrrole (3) in 63% yield. The transformation of 2-methyl-3-hydroxy-4-pyrone (4) into 1-n-alkyl-3-hydroxy-2-methyl-4-pyridones is achieved by benzylation of the 3-hydroxyl group whereupon the product reacts with ammonia and the corresponding pyridone is obtained. The pyridone is alkylated with alkyl bromides and after hydrobromic acid in acetic acid cleavage of the 3-position ether function, 1-n-alkyl-3-hydroxy-2-methyl-4-pyridones are obtained in 48% overall yield.     

Crystallographic and ab initio theoretical studies of (2R,3R)-1-methyl-5-oxo-2-phenyltetrahydro-1H-pyrrole-3-carboxylic acid. The comparison of chiral (I) and racemic (II) structure

Crystal and molecular structures of (2R,3R)-1-methyl-5-oxo-2-phenyltetrahydro-1H-pyrrole-3-carboxylic acid (I) and (2R^*,3R^*)-1-methyl-5-oxo-2-phenyltetrahydro-1H-pyrrole-3-carboxylic acid (II) are presented. The alternative packings were studied using ab initio quantum-chemical methods. Energies of hydrogen bonds for real and model cases are discussed. Infinite chains of molecules instead of carboxylic acid dimers were observed.     

Synthesis of two naturally occurring 3-methyl-2,5-dihydro-1-benzoxepin carboxylic acids

[structures: see text] Two naturally occurring 3-methyl-2,5-dihydro-1-benzoxepin carboxylic acids, 6-hydroxy-3-methyl-8-(phenylethyl)-2,5-dihydro-1-benzoxepin-9-carboxylic acid (radulanin E) (1) and 9-hydroxy-3-methyl-2,5-dihydro-1-benzoxepin-7-carboxylic acid (2), were synthesized using Stille coupling followed by Mitsunobu cyclization.     

Expedient Lewis acid catalyzed synthesis of a 3-substituted 5-arylidene-1-methyl-2-thiohydantoin Library

An efficient and rapid solution phase combinatorial synthesis of a 3-substituted 5-arylidene-1-methyl-2-thiohydantoin library was developed. The salient feature for this library production procedure is the addition of the Lewis acid catalyst, indium(III) trifluoromethanesulfonate, which serves to facilitate the direct condensation of aldehydes with 3-substituted 1-methyl-2-thiohydantoins. Use of this Lewis acid catalyst has resulted in faster reaction times, higher conversions and better purity profiles for these condensation reactions as compared to traditional uncatalyzed reactions. The resulting 315 member library of 3-substituted 5-arylidene-1-methyl-2-thiohydantoin is described.     

Synthesis of the (Z) and (E) isomers of 1,2-diaryl-3-methyl-4,5-dioxo-3-pyrrolidinecarboxylic acid esters. Structural assignment by nmr and mass spectroscopy

Reaction of N-benzylideneaniline, 1a , with 3-methyl-2-oxobutanedioic acid diethyl ester, 2a , produced isomeric 3-methyl-4,5-dioxo-1,2-diphenyl-3-pyrrolidinecarboxylic acid ethyl esters, 3a and 3b . The higher melting isomer, 3a , was shown to have the (Z) configuration by nmr spectroscopy. The (Z) and (E) isomers of 3-methyl-4,5-dioxo-1,2-diphenyl-3-pyrrolidinecarboxylic acid methyl esters, 3c and 3d , were prepared from 1a and 3-methyl-2-oxobutanedioic acid dimethyl ester, 2b . The higher melting isomer, 3c , was shown to have the (Z) configuration. Similarly, N-benzylidene-p-toluidine, 1b , reacted with 2a to form (Z) and (E) isomers of 3-methyl-4,5-dioxo-1-(4-methylphenyl)-2-phenyl-3-pyrrolidinecarboxlic acid ethyl esters, 3e and 3f . Assignment of the ¹³C carbonyl carbon nmr chemical shift was made by preparing 2-methyl-3-oxobutanedioic-1-¹³C acid diethyl ester, 4 , and from it the corresponding (Z) and (E) isomers of 3-methyl-4,5-dioxo-1,2-diphenyl-3-pyrrolidinecarboxylic ¹³C acid ester, 5a and 5b . The mass spectra of the (Z) isomers exhibit prominent ions corresponding to the masses of the Schiff bases used to make them, and ions corresponding to the loss of ArNCOCO from the parent ion. The (E) isomers 3b, 3d and 5b exhibit a prominent ion of mass 264; 3f gives mass 278, corresponding to the loss of the carboalkoxy group.     

Reaction of 2,6-dibutylaminohepta-2,5-dien-4-one with malononitrile

Malononitrile reacted with the title compound to give 6-amino-5-cyano-2-(3,3-dicyano-2-methylallylidene-4-methyl-2H-pyran (3). Treatment of 3 with hot 80% sulfuric acid yielded 4,7-dimethyl-56-hydroxy-2(1H)quinolone. With concentrated aqueous sodium hydroxide, 3 gave 5-amino-3,6-dicyano-4,7-dimethyl-2(1H)quinolone and 5-amino-6-carbamoyl-3-cyano-4,7-dimethyl-2(1H)quinolone. The reaction of 3 with hydrochloric in acetic acid gave a mixture of 6-amino-3,7-dicyano-2,8-dimethyl-4-quinolizone and 3-cyano-4-methyl-6-(3,3-dicyano-2-methylallyl)-2-pyrone. Compound 3 also reacted with methylamine, butylamine and piperidine to give 8-amino-5-cyano-4-methyl-2-pyridone, 6-bulylamino-5-cyano-4-methyl-2-pyridone and 5-eyano-4-methyl-6-piperidino-2-pyridone respectively.     

Synthesis and structure of hydrazones obtained by the reaction of 2-[6-methyl-2,4-dioxo-1-(thietan-3-yl)-1,2,3,4-tetrahydropyrimidin-3-yl]acetic acide hydrazide with β-dicarbonyl compounds

Reaction of 2-[6-methyl-2,4-dioxo-1-(thietan-3-yl)-1,2,3,4-tetrahydropyrimidin-3-yl]acetic acid hydrazide with β-dicarbonyl compounds proceeds regioselectively; the structure of the formed hydrazones is governed by the structure of the β-dicarbonyl reaction component. The reaction with acetyl- and propionylacetone afforded 3-[2-(5-alkyl-3-methyl-1H-pyrazol-1-yl)-2-oxoethyl]-6-methyl-1-(thietan-3-yl)pyrimidin-2,4(1H,3H)-diones, with aroylacetones, 5-hydroxypyrazoline derivatives which are present in DMSO solutions in E′ conformation with respect to the amide bond. The condensation products with acetoacetic acid derivatives have a linear structure and consist of mixtures of E,Z- and E′,Z′-isomers owing to the geometric and conformational isomerism.     

Synthesis and Biological Evaluation of Some Novel N,N ′-Bis-(1,2,4-Triazin-4-Yl)Dicarboxylic Acid Amides and Some Fused Rings with 1,2,4-Triazine Ring

Some of novel N , N '-bis-(1,2,4-triazin-4-yl)dicarboxylic acid amides ( 2-5 ) and thiadiazolo[2,3- b ][1,2,4]triazin-7-yl carboxylic acid derivatives ( 6 , 7 ) were prepared by heating 4-amino-6-methyl-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine ( 1 ) with different dicarboxylic acids (oxalic, malonic, fumaric, maleic, succinic, and phthalic acids respectively) in POCl 3 . Refluxing 1 with 1-chloro-2,4-dinitrobenzene in DMF yielded 3-methyl-6-nitro-10 H -benzo[1,2,4]thiadiazino[2,3- c ][1,2,4]triazin-4-one ( 8 ). Condensation of 1 with 2,4-pentandione in refluxing acetic acid furnished 6-methyl-4-(1-methyl-3-oxobut-1-enylamino)-3-thioxo-3,4-dihydro-2 H -[1,2,4]triazin-5-one ( 9 ). 3,8-D imethyl[1,2,4] triazino[3,4- b ][1,3,4]thiadiazine-4,7-dione ( 11 ) was prepared by refluxing 1 with 2-bromopropionyl bromide in anhydrous benzene to afford the corresponding N -acetylated derivative 10 , which was cyclized by using triethylamine. Also, some triazinylquinazolinones 13a , b were obtained by fusion of 1 with 6-bromo(and/or 6,8-dibromo)-2-methyl-3,1-benzoxazin-4 H -ones.     

Catalyzed liquid-phase oxidation of dialkylthiophenes

The oxidation of 3-methyl-2-ethylthiophene with molecular oxygen in glacial acetic acid in the presence of a cobalt-bromide catalyst was investigated. It was established that there is a dependence of the rate of oxidation of this compound on its concentration, on the catalyst (cobalt acetate) concentration, and on the initiator (NaBr) concentration. The principal oxidation products are 3-methyl-2-acetothienone (III) and 1-(3-methyl-2-thienyl) ethyl acetate, which were isolated and characterized. The reactivity of 3-methyl-2-ethylthiophene in the oxidation reaction is higher than that of 4-methyl-2-ethylthiophene.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 758–761, June, 1981.