The chemistry of phthalide-3-carboxylic acid - I decarboxylation in the presence of aldehydes

The decarboxylation of phthalide-3-carboxylic acid (3-oxo-l,3-dihydroisobenzofuran-1-carboxylic acid) has been studied in the melt, in dimethylsulfoxide, and in the presence of aromatic aldehydes. The latter are efficiently trapped to produce mixtures of 3-arylidene-phthalides and 3-(arylhydroxymethyl)phthalides. Kinetic and other evidence supports the proposal that this reaction occurs in a tight cyclic transition state.     

Regioselective C-H functionalization directed by a removable carboxyl group: palladium-catalyzed vinylation at the unusual position of indole and related heteroaromatic rings

The palladium-catalyzed oxidative vinylation of indole-3-carboxylic acids with alkenes effectively proceeds via directed C-H functionalization and decarboxylation to produce the corresponding 2-vinylated indoles. Similarly, pyrrole-, furan-, and thiophenecarboxylic acids also undergo decarboxylative vinylation.     

Pyoluteorin derivatives. II. Synthetic approaches to pyrrole ring substituted pyoluteorins

A method for the regiospecific synthesis of 3-substituted 2-aroylpyrroles is described. These pyrroles, which are structurally related to the naturally occurring antibiotic pyoluteorin, are prepared by a Friedel-Crafts aroylation of 4-substituted pyrrole-3-carboxylic acid esters with 2,6-dimethoxybenzoyl chloride. The carboalkoxy group is then removed by hydrolysis and decarboxylation to produce isomerically pure 3-substituted-2-(2′,6′-dimethoxybenzoyl)pyrroles ( 5 and 13 ). Conversion of these pyrroles into pyoluteorin-like compounds led to some unexpected products which arise from facile cleavage of the dihydroxybenzoyl portion of the molecules during chlorination.     

Studies on the fluorophore forming reactions of various catecholamines and tetrahydroisoquinolines with glyoxylic acid.

Strongly fluorescent 2-carboxymethyl-3,4-dihydro-7-hydroxyisoquinolin-6-ones are formed in high yields when catecholamines are reacted with glyoxylic acid. Formation of the fluorophores has been found to take place in two steps; i. e. via virtually non-fluorescent tetrahydroisoquinoline-1-carboxylic acids, which react to give the fluorophores in a subsequent, rapid reaction with glyoxylic acid. The rates of reaction (pseudo first-order) with glyoxylic acid for 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, and 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid show that introduction of a carboxyl group at either C-1 or C-3 in a tetrahydroisoquinoline highly facilitates the reaction with glyoxylic acid. This behaviour is discussed in terms of a mechanism involving both intramolecular acid catalysis by the C-1 or C-3-carboxyl groups during dehydration of the carbinolamine intermediate, and facilitation of the prototropic shifts of the resulting Schiff's base by decarboxylation.     

Analytical characterization of poly(pyrrole-3-carboxylic acid) films electrosynthesised on Pt, Ti and Ti/Al/V substrates

With the aim of developing a polymeric multilayer film for application in advanced biomaterials, as a first step poly(pyrrole-3-carboxylic acid) films (abbreviated as PPy-3-carbox) were electropolymerised from pyrrole-3-carboxylic acid solutions by cyclic voltammetry and chronoamperometry on platinum, titanium and Ti90Al6V4 substrates and characterised both electrochemically (cyclic voltammetry) and spectroscopically (X-Ray Photoelectron Spectroscopy, XPS). Electrochemical experiments showed that the potential range adopted for electropolymerization affects the polymer electroactivity, by analogy with unsubstituted polypyrrole. The combination of conventional and chemical derivation-XPS provided information on PPy-3-carbox surface structure, showing no significant difference between films grown on different substrates and an increase of the COOH groups amount (one group over three pyrrole rings, as an average) with respect to unsubstituted polypyrrole (PPy), as expected. Finally, a preliminary Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) investigation was performed in order to get further information on the polymer structure and electroactivity.     

Carboxylation of indoles and pyrroles with CO2 in the presence of dialkylaluminum halides

The Lewis acid-mediated carboxylation of arenes with CO₂ has been successfully applied to 1-substituted indoles and pyrroles by using dialkylaluminum chlorides instead of aluminum trihalides. Thus, the carboxylation of 1-methylindoles, 1-benzyl-, and 1-phenylpyrroles proceeds regioselectively with the aid of an equimolar amount of Me₂AlCl under CO₂ pressure (3.0 MPa) at room temperature to afford the corresponding indole-3-carboxylic acids and pyrrole-2-carboxylic acids in 61-85% yields, while the same treatment of 1,2,5-trimethylpyrrole affords the 3-carboxylic acid in 52% yield.     

How Effective Is the Single-point Energy Calculation in Investigating the Reaction Mechanisms？ New Decarboxylation Mechanism of Pyrrole-2-carboxylic Acid by Full Optimization with CPCM Solvation Model

The decarboxylation of pyrrole-2-carboxylic acid in acid solutions was elucidated by full optimization with the CPCM solvation model at the B3LYP/6-31 l＋＋G（d,p） level. Compared with the single-point energy calculation, CPCM full optimization is better to model solvent environments to gain reasonable reaction mechanisms. The π interactions play a significant role in the decarboxylation of pyrrole-2-carboxylic acid （R）. Firstly, the a hydrogen is protonated, but all of the carbonyl hydration pathways bear relatively higher energy barriers. The carbonyl group can rove over the pyrrole ring, but it does not lead to the speciation of pyrrole and protonated carbon dioxide for the latter is an energy-rich species. The decarboxylation mechanism proposed here is that, the protonated pyrrole-2-carboxylic acid （RH） decarboxylates via direct C-C bond cleavage with the aid of a water molecule to accommodate the proton on the carbonyl group.     

Mechanistic observations in the gewald syntheses of 2-aminothiophenes

The Gewald syntheses were employed to prepare a series of 2-amino-3-carboethoxythiophenes, and the syntheses of two of these, namely, the 3,4-trimethylene ( 1f ) and 3,4-tetramethylene ( 1g ) derivatives, were examined in detail. In two preparations of 1f , octahydro-6a-(4-morpholinyl)-2-thioxocyclopenta[b]pyrrole-3-carboxylic acid ( 7 ) was a co-product. The structure of 7 was ascertained from its 300 MHz ¹H nmr and ¹³C nmr spectra, and by its conversion to 1,4,5,6-tetrahydro-2-mercaptocyclopenta[b]pyrrole-3-carboxylic acid ethyl ester ( 8 ). Isolation of 7 and other observations led to postulated mechanisms for three of the Gewald thiophene syntheses.     

Dimers of formic acid, acetic acid, formamide and pyrrole-2-carboxylic acid: an ab initio study

The intermolecular hydrogen bonds in dimers of formic acid, acetic acid, and formamide were investigated. Additionally, three configurations of the pyrrole-2-carboxylic acid (PCA) dimer were studied to analyze how the pyrrole pi-electron system influences the carboxylic groups connected by double O-H...O hydrogen bonds. The ab initio calculations for the systems investigated were performed at MP2/6-311++G(d,p), MP2/aug-cc-pVDZ, and MP2/aug-cc-pVTZ//MP2/aug-cc-pVDZ levels of theory. The "atoms in molecules" theory of Bader was used and the analysis of the critical points was performed to study the nature of hydrogen bonds. The decomposition of the total interaction energy applied here reveals that the delocalization energy term is a particularly important attractive contribution in these systems, more important in the case of systems forming homonuclear O-H...O double hydrogen bonds than in the case of those connected through heteronuclear N-H...O bonds. Because the systems analyzed may be formally classified as the resonance-assisted hydrogen bonds (RAHBs), it seems that the dominant contribution from the delocalization interaction energy term is a distinguished feature of such interactions.     

4-hydroxy-2-quinolones. 96. Synthesis and properties of 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid

Alkaline hydrolysis of the ethyl ester of 4-(cyanoethoxycarbonylmethyl)-2-oxo-1,2-dihydroquinoline-3-carboxylic acid is accompanied by decarboxylation with loss of two molecules of CO₂ and leads to 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 887–893, June, 2006.     

The reaction of methyl pyrrole-2-carboxylate with epoxides

Potassium methyl pyrrole-2-carboxylate and styrene oxide are shown to yield trans-1-styrylpyrrole-2-carboxylic acid (dry conditions) and 1-(2-hydroxy-2-phenylethyl)pyrrole-2-carboxylic acid (moist conditions). The hydroxy acid yields 1H-3-phenyl-3,4-dihydropyrrolo[2.1-c]-[1.4]oxazin-1-one, on treatment with polyphosphoric acid. Vinyl acids were also obtained from the potassium pyrrole ester and ethylene oxide, propylene oxide, and cis- and trans-stilbene oxide; the latter two compounds yielded stereospecific products. A pyrrolo[2.1-c]-[1.4]benzoxazinone was obtained from cyclohexene oxide. The photo chemical isomerization of the trans-1-styryl acid and the attempted conversion into lactones is described.     

An intramolecular oxo Diels-Alder approach to 1-oxo-1,2,3,3a,4,7a-hexahydro-pyrano[3,4-c]pyrrole-4-carboxylic acid ethyl esters

The diastereoselective synthesis of a series of 1-oxo-1,2,3,3a,4,7a-hexahydro-pyrano[3,4-c]pyrrole-4-carboxylic acid ethyl esters via an oxo Diels-Alder reaction is described. Ab initio calculations predicted the products of the exo cycloaddition to be the thermodynamic products while the products resulting from the endo cycloaddition were predicted to be the kinetic products. The calculations were born out by experimental data.     

Decarboxylation of a benzo[b] thiophene-2-carboxylic acid

5-Hydroxy-3-methylbenzo[b]thiophene-2-carboxylic acid can be decarboxylated by refluxing with 48% hydrobromic acid for 30 minutes. Yield and quality of the product are better than for the previously used copper-quinoline decarboxylation. The 5-methoxy analog of the above acid is stable to decarboxylation under these conditions; however, it demethylates readily under the reaction conditions, and the phenol thus afforded decarboxylates.     

Synthesis of enantiopure (R,R)- and (S,S)-cis-2,3-propanoprolines

A novel approach to the synthesis of an enantiopure bicyclic proline analogue, hexahydrocyclopenta[b]pyrrole-6a(1H)-carboxylic acid (‘2,3-propanoproline’), has been developed. The method relied on tandem Strecker-nucleophilic cyclization reaction of 2-(2-bromoethyl)cyclopentanone. The overall synthetic scheme included six steps and resulted in 18% overall yield of both enantiomers of the title amino acid.     

Production of anticancer polyenes through precursor-directed biosynthesis

The biosynthesis of the pyrrolyl moiety of the fungal metabolite rumbrin originates from pyrrole-2-carboxylic acid. In an effort to produce novel derivatives with enhanced biological activity a series of substituted pyrrole-2-carboxylates were synthesised and incubated with the producing organism, Auxarthron umbrinum. Several 4-halo-pyrrole-2-carboxylic acids were incorporated into the metabolite yielding three new derivatives: 3-fluoro-, 3-chloro- and 3-bromo-isorumbrin, which were generated in milligram quantities enabling cytotoxicity assays to be conducted. The 3-chloro- and 3-bromo-isorumbrins had improved activity against HeLa cells compared with rumbrin; 3-bromoisorumbrin also showed dramatically improved activity towards a lung cancer cell line (A549).     

The van Alphen rearrangement. Thermal,catalytic, and photolytic transformation of 3,3,5-triphenylpyrazolenine-4-carboxylic acid esters

The thermal, catalytic, and acid-catalyzed transformation of 3,3,5-triphenylpyrazolenine-4-carboxylic acid esters was studied. The thermal and acid-catalyzed isomerization of the pyrazolenines leads not only to pyrazoles but also to isopyrazoles. A mechanism involving a 1,5-suprafacial sigmatropic shift is proposed for the isomerization. It is shown that the migration of substituents from the 4 position of the pyrazolenine ring, which has been previously proposed as a variant of the van Alphen rearrangement, does not occur.     

Polycondensed heterocycles. I. Synthesis of 11-oxo-5H, 11H-pyrrolo[2,1-c][1,4]benzothiazepine,Derivative of a novel ring system

The synthesis of the title compound 4 by cyclization of 1-(2-ethoxycarbonylthiobenzyl)pyrrole 9 , prepared by treating with ethyl chloroformate the 1-(2-mercaptobenzyl)pyrrole 7 previously obtained by debenzylation of 1-(2-benzylthiobenzyl)pyrrrole 6 , failed. On the other hand 4 was successfully synthesized by intramolecular cyclization of 1-(2-mercaptobenzyl)pyrrole-2-carboxylic acid 15 by DMAP -catalyzed DCC method. The pyrrole 6 and 1-(2-benzylthiobenzyl)pyrrole-2-carboxaldehyde 11 were useful as starting materials to obtain 1-(2-benzylthiobenzyl)pyrrole-2-carbonitrile 13 , which was hydrolyzed to corresponding amide 16 . Debenzylation of 16 afforded 1-(2-mercaptobenzyl)pyrrole-2-carboxyamide 17 , whose hydrolysis led to required acid 15 .     

Theoretical studies of the quinolinic acid to nicotinic acid mononucleotide transformation

Quinolinate phosphoribosyl transferase (QPRTase) is an essential enzyme that catalyzes the transformation of quinolinic acid (QA) to nicotinic acid mononucleotide (NAMN), a key step on the de novo pathway for nicotinamide adenine dinucleotide (NAD) biosynthesis. We describe herein a theoretical study of the intrinsic energetics associated with the possible mechanistic pathways by which QA forms NAMN. Our main interest is in probing the decarboxylation step, which is intriguing since the product is a vinylic anion, not unlike the reaction catalyzed by orotidine 5'-monophosphate (OMP) decarboxylase, an enzyme whose mechanism is under fierce debate. Our calculations indicate that a path involving a quinolinic acid mononucleotide (QAMN) intermediate is the most energetically attractive, favoring decarboxylation. We also find that the monocarboxylate form of QAMN will decarboxylate much more favorably energetically than will the dicarboxylate form of QAMN. Furthermore, our calculations indicate that decarboxylation is not a likely first step; the substrate in such a mechanism would prefer to decarboxylate at the C3 position, not the desired C2 position. We also discuss our results in the context of existing experimental data.     

Phenazines-IV The synthesis of 3-aminophenazine-1-, 3-aminophenazine-2-and 8-aminophenazine-1-carboxylic acids

The oxidative cyclization in boiling nitrobenzene of 4,6-diaminodiphenylamine-2-carboxylic acid gave 3-aminophenazine-1-carboxylic acid. 4,6-Diaminodiphenylamine-3-carboxylic acid underwent decarboxylation, but the methyl ester gave methyl 3-aminophenazine-2-carboxylate from which the acid was obtained. 2,4-Diaminodiphenylamine-3′-carboxylic acid gave a mixture of 7-aminophenazine-2- and 8-aminophenazine-1-carboxylic acids from which the pure acids were separated and oriented. 8-Aminophenazine-1-carboxylic acid, together with some 1,8-diamino-acridone, was also obtained from 3′,6-diaminodiphenylamine-2-carboxylic acid.     

Polycondensed heterocycles. II. A new preparative route to 11-Oxo-5H,11H-pyrrolo[2,1-c][1,4]benzothiazepine

6-Methylthio-10-oxo-5H,10H-pyrrolo[1,2-b]isoquinoline 11 was isolated in an attempted synthesis of 11-oxo-5H,11H-pyrrolo[2,1-c][1,4]benzothiazepine 1 from 1-(2-methylthiobenzyl)pyrrole-2-carboxylic acid chloride 9 , obtained using as starting material o-methylthiobenzyl bromide 3 and passing through 1-(2-methylthiobenzyl)pyrrole-2-carbonitrile 5 , by cyclization with aluminum chloride. However the successful demethylation with sodium in dimethylacetamide of 1-(2-methylthiobenzyl)pyrrole-2-carboxyamide 12 , formed by hydrolysis of nitrile 5 , allowed us to prepare by another way the corresponding thiol 13 and consequently the 1-(2-mercaptobenzyl)pyrrole-2-carboxylic acid 14 , which when subjected to intramolecular ring closure by CDI in place of DCC gave 1 in higher yield, 69% instead of 43%. Finally, the direct cyanation of 1-(2-ethoxycarbonylthiobenzyl)pyrrole 16 , prepared utilizing the 1-(2-mercaptobenzyl)pyrrole 15 obtained by demethylation of the corresponding thioanisol 4 which was carried out as above, afforded the unexpected 1-(2-ethylthio-benzyl)pyrrole-2-carbonitrile 17 .