Decarboxylation of pyrrole-2-carboxylic acid

Oxidative decarboxylation of pyrrole-2-carboxylic acids Reaction of pyrrolc-2-carboxylic acids such as 1 and 2 with singlet oxygen in i-PrOH or CH3CN and water (3 1) results in 5-hydroxy-3-pyrrolin-2-ones in high yield. 

The mechanisms of the acid-catalysed decarboxylation of pyrrole-2-carboxylic acid and mesitoic acid have been investigated at the B3LYP/6-311G (d, p) level of theory. A polarizable continuum model has been established in order to evaluate the effects of solvents on these reactions. The results of the calculations indicate that the first step of the acid-catalysed decarboxylation of the pyrrole-2-carboxylic acid has two possible pathways the proton of H30 attacks either the a-carbon atom or the carboxyl oxygen atom. The subsequent process of forming a four-membered ring TS is the ratedetermining step. The computational results show that both pathways are favoured. 

The main feature of the reactivity of pyrrole-2-carboxylic acids is the ease with which the carboxyl group is removed. Thermal decarboxylation is a preparatively useful reaction. 

Scheme 9 Mechanism of decarboxylation via addition of water to the carboxyl group of pyrrole-2-carboxylic acid. Reprinted with permission from Reference 73. Copyright 2009 American Chemical Society.

We have presented evidence that pyrrole-2-carboxylic acid decarboxylates in acid via the addition of water to the carboxyl group, rather than by direct formation of C02.73 This leads to the formation of the conjugate acid of carbonic acid, C(OH)3+, which rapidly dissociates into protonated water and carbon dioxide (Scheme 9). The pKA for protonation of the a-carbon acid of pyrrole is —3.8.74 Although this mechanism of decarboxylation is more complex than the typical dissociative mechanism generating carbon dioxide, the weak carbanion formed will be a poor nucleophile and will not be subject to internal return. However, this leads to a point of interest, in that an enzyme catalyzes the decarboxylation and carboxylation of pyrrole-2-carboxylic acid and pyrrole respectively.75 In the decarboxylation reaction, unlike the case of 2-ketoacids, the enzyme cannot access the potential catalysis available from preventing the internal return from a highly basic carbanion, which could be the reason that the rates of decarboxylation are more comparable to those in solution. Therefore, the enzyme cannot achieve further acceleration of decarboxylation. In the carboxylation of pyrrole, the absence of a reactive carbanion will also make the reaction more difficult however, in this case it occurs more readily than with other aromatic acid decarboxylases. 

Heterocyclic compounds containing a nitrogen atom commonly undergo N-alkylation or C-alkylation. N-Methyl pyrrole can be prepared by interaction of methyl iodide with potassium pyrrole (40%). N-Carbethoxy pyrrole is made from chloroformic ester and potassium pyrrole. The C-alkylation of pyrroles has been discussed. 3-Alkylindoles are made by the alkylation and decarboxylation of indole-2-carboxylic acid. The conditions for alkylation of pyrrolidine are analogous to those employed for the alkylation of a secondary amine. Thus, pyrrolidine on treatment with n-butyl bromide and potassium hydroxide in boiling benzene is con-... 

Irradiation of the potassium salt of the substituted cyclopenta[b]pyrrole-2-carboxylic acid 389 results in formation of the central piperazine core of 390 following decarboxylation (Equation 104) <20010L537, 2003JA10664>. 

Pyrrole-2-carboxylic acid esters have been prepared from ethyl chloroformate and pyrrolylmagnesium bromide1 2 or pyrrolyllithium,3 by hydrolysis and decarboxylation of dimethyl pyrrole-1,2-dicarboxylate followed by re-esterification of the 2-acid4 and by oxidation of pyrrole-2-carboxaldehyde followed by esterification with diazomethane.4... 

Pyrrole-2-carboxylate decarboxylase attains equilibrium in the course of either decarboxylation or carboxylation (Fig. 8). The decarboxylation of 100 mM pyrrole-2-carboxylate was in equilibrium after Ih, resulting in an equilibrium constant of 0.3 M." Due to this balanced equilibrium, the enzyme also catalyzed the reverse carboxylation of pyrrole after the addition of HCO3, leading to a similar equilibrium constant of 0.4 M and a shift of the [pyrrole]/[pyrrole-2-carboxylate] ratio toward the acid. 

By the hydrolysis of esters 81a-c, the corresponding acids 83a-c were formed. The 2-[3-(trifluoromethyl)phenyl]-4//-furo[3,2-7]pyrrole-5-carboxylic acid 83a was decarboxylated in acetic anhydride to 4-acetyl-2-[3-(trifluoromethyl)-phenyl]furo[3,2-7]pyrrole 84 (see 10.01.05.1.2, Scheme 7). 

Anodic oxidation of l,3-diaryl-5-methyl-A2-pyrazoline-5-carboxylic acids in CH3CN-Et4NBF4 proceeded with decarboxylation to the aromatized pyrazoles in high yield.414 Similarly, electrochemical oxidation of N-acetyl-2,3-substituted A4-pyrroline-2-carboxylic acids in water-tetrahydrofuran (3 1) containing KOH forms the corresponding pyrroles (80-98%).415... 

Difluoropyrrole (58) has been extensively used in the syntheses of octafluor-oporphyrins and other calyx( )pyrroles. This was first accessed by Leroy and Wakselman by barium-promoted copper chromite decarboxylation of 3,4-difluor-opyrrole-2-carboxylic acid in quinoline at 200°C. The acid was prepared in four steps beginning with a cycloaddition reaction of the protected aziridine 59 and chlorotrifluoroethylene (Fig. 3.26). 

The most convenient laboratory method for the preparation of 2,4-dimethyl-5-carbethoxypyrrole is that given above. A cheaper method of obtaining large quantities consists in the partial hydrolysis of 2,4-dimethyl-3,5-dicarbethoxypyrrole with sulfuric acid, followed by decarboxylation. The ester has been obtained also by the alcoholysis of 5-trichloroaceto-2,4-dimethyl-pyrrole in the presence of sodium ethylate. The free acid has been obtained fronii-[2,4-dimethylpyrrole-5]-2,4-dimethylpyrrole-5-carboxylic acid and from 2,4-dimethylpyrrole-5-aldehyde. ... 

In an effort to explore the chemistry of pyrrolodiazines and their quatemized salts (see Section 6.2.2.2), Alvarez-Builla and co-workers prepared a series of pyrrolo[l,2-c]pyrimidines via methodology developed in their laboratory <99JOC7788>. Cyclocondensation of tosylmethyl isocyanide with substituted pyrrole-2-carboxaldehydes 17 produced pyrimidine derivatives 18 sifter removal of the tosyl group. The key to this procedure was the use of tosylmethyl isocyanide, which provided a relatively easily removed tosyl group in comparison to the more problematic decarboxylation of a carboxylic acid functionality. 

American workers needed to prepare the bis-amino acid 1 and adopted a literature procedure in which two equivalents of diethyl acetamidomalonate were to be alkylated with one equivalent of l,4-dichloro-2-butyne using two equivalents of sodium ethoxide in hot ethanol. Hydrolysis and decarboxylation of the dialkylated malonate would then give 1. This alkylation reaction was carried out, but ten equivalents of sodium ethoxide were used rather than two. This resulted in formation of ethyl 5-methylpyrrole-2-carboxylate in ca. 40% yield. Further study showed that the reaction to produce the pyrrole required equimolar amounts of the acetamidomalonate and the dichlorobutyne, excess of sodium ethoxide, and heating. No pyrrole was formed at room temperature. 

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