Pyrrole carboxylic acids, decarboxylation

Pyrrole Carboxylic Acids and Esters. The acids are considerably less stable than benzoic acid and often decarboxylate readily on heating. However, electron-withdrawing substituents tend to stabilize them toward decarboxylation. The pyrrole esters are important synthetically because they stabilize the ring and may also act as protecting groups. Thus, the esters can be utilized synthetically and then hydrolyzed to the acid, which can be decarboxylated by heating. Often P-esters are hydrolyzed more easily than the a-esters. 

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. 

A marginal, although interesting chemical route to PPy is the decomposition of 3-bromopyrrole and 3,4-dibromopyrrole. " These chemicals can be easily obtained, either from the decarboxylation of the corresponding 2-pyrrole carboxylic acids, or by deprotection of the N-silylated precursors. They are quite stable in solutions, but do polymerize very quickly in the pure state, with evolvement of gaseous hydrobromic acid. The resulting polymers have been produced and characterized. They were found to correspond to doped PPy, very likely by bromide ions. 

The most striking property of pyrrole-carboxylic acids having the carboxyl group directly attached to the nucleus is their ready decarboxylation. This occurs when the acids are heated under a variety of conditions the ease varies with the character of other substituents present. Melting is usually accompanied by decarboxylation, and preparative procedures have used decarboxylation by heating at reduced pressure so, by heating in glycerol, 2-aminoethanol and alkali, and distillation from weakly acid solution ... 

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. 

Grignard reagent from, acylation, 4, 237 nitration, 4, 211 reactivity, 4, 71-72 synthesis, 4, 149, 237, 341, 360 Pyrrole-3-carboxylic acids acidity, 4, 71 decarboxylation, 4, 286 esterification, 4, 287 esters... 

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. ... 

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... 

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. 

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... 

Pyrrole-2-carboxylic acid easily loses the carboxylic group thermally. Pyrrole-3-carboxylic acid and furan-2- and -3-carboxylic acids also readily decarboxylate on heating to about 200°C. Thiophene-carboxylic acids require higher temperatures or a copper-quinoline catalyst. In furans, 2-carboxylic acid groups are lost more readily than 3-carboxylic acid groups (Scheme 64). 

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.

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-... 

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