Decarboxylation of pyrrole

Figure 8 Decarboxylation of pyrrole-2-carboxylate (a) and carboxylation of pyrrole (b) by pyrrole-2-carboxylate decarboxylase.

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. 

This synthesis of this widely used model compound uses a Knorr sequence as the first step the oligomerisation steps and the final cyclisation rest on side-chain reactivity of pyrrolylammonium salts (section 13.12) and the easy decarboxylation of pyrrole acids (section 13.14). 

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. 

Much interesting work has been done in the last ten years on the bridging of pyrrole and piperidine rings. Early in their work on this subject Clemo and Metcalfe (1937) prepared quinuclidine (V) by the reduction of 3-ketoquinuclidine (IV), the latter resulting from the hydrolysis and decarboxylation of the product (III) of a Dieckmann internal alkylation, applied to ethyl piperidine-l-acetate-4-carboxylate (II), itself made by condensing ethyl piperidine-4-carboxylate (I) with ethyl chloroacetate. 

Knorr reported the first pyrazole derivative in 1883. The reaction of phenyl hydrazine and ethylacetoacetate resulted in a novel stmcture identified in 1887 as l-phenyl-3-methy 1-5-pyrazolone 9. His interest in antipyretic compounds led him to test these derivatives for antipyretic activity which led to the discovery of antipyrine 10. He introduced the name pyrazole for these compounds to denote that the nucleus was derived from the pyrrole by replacement of a carbon with a nitrogen. He subsequnently prepared many pyrazole analogs, particularly compounds derived from the readily available phenyl hydrazine. The unsubstituted pyrazole wasn t prepared until 1889 by decarboxylation of liT-pyrazole-3,4,5-tricarboxylic acid. ... 

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. 

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. 

There are examples of ipso attack during the nitration of pyrroles, furans and thiophenes and in the corresponding benzo-fused systems. Reactions resulting in nitro-dealkylation, nitrodeacylation, nitro-decarboxylation and nitro-dehalogenation are to be found in the monograph reactivity chapters of CHEC. Treatment of the 3-azophenylindole (64) with nitric acid in acetic acid at room temperature gives 80% of the 3-nitroindole (65) (81JCS(P2)628). 

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. 

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. 

Decarboxylation of this dicarboxylic acid gave almost quantitavily the disered 3-chloro-4-(2 -nitro-3 -chlorophenyl)pyrrole MP 125°C. (recrystallized from benzene). 

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