Decarboxylation pyrrole acid

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. 

During a synthesis of lamellarin and related pyrrole alkaloids, Iwao et al. observed the Pd(OAc)2-mediated decarboxylative cyclization of pyrrole acid 52 to 53 [44]. Lesser amounts (12%) of the product from decarboxylation of 52 were isolated. 

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). 

Oxidation of sepiomelanin with potassium permanganate gave four pyrrolic acids, pyrrole-2,3,5- and 2,3,4-tricarboxylic acid, pyrrole-2,3-dicarboxylic acid (PDCA), and 2,3,4,5-pyrroletetracarboxylic acid (184, 204). On the other hand, the yield and number of PDCA increased when decarboxylated sepiomelanin was oxidized with permanganate. The origin of these pyrrolic acids was interpreted as resulting from the oxidative breakdown of various types of DHI units in the pigment backbone (184). 

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. 

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. ... 

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. 

Oxazolium oxides, which can be generated by cyclization of a-amido acids, give pyrroles on reaction with acetylenic dipolarophiles.144 These reactions proceed by formation of oxazolium oxide intermediates. The bicyclic adduct can then undergo a concerted (retro 4 + 2) decarboxylation. 

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>. 

Alder/retrograde Diels-Alder reaction sequence of a diaryl alkyne with a 3,6-dicarbomethoxy tetrazine. The resulting diazine (14) is then reduced, cleaved and cyclized with Zn/acetic acid to the 2,3,4,5-tetrasubstituted pyrrole (15), which is then N-alkylated with a-bromo-4-methoxyacetophenone to give a pentasubstituted pyrrole (16). The synthesis of lukianol A is completed by ester hydrolysis, decarboxylation, ring closure and deprotection. 

Reaction of the thia-amino acid 392 with trifluoroacetic anhydride gave the 2,2,2-trifluoro-l-[7-(trifluoromethyl)-l//-pyrrolo[l,2-c]-[l,3]thiazol-6-yl] ethanone pyrrole 395. The formation of the pyrrole can be rationalized by a sequence involving trifluoroacetylation of the enamine 392 affording dione 393 followed by loss of water and carbon dioxide to give the aromatic product 395. These decarboxylations afford fluorinated derivatives of heterocyclic skeletons known to exhibit interesting biological activity (Scheme 58) <2000T7267>. 

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). 

Likewise 3-amino-2-cyano-4-(3-methoxyphenyl)-A -carboethoxypyrrole is converted into 7-(3-methoxyphenyl)-pyrrolo[3,2- pyrimidin-4-one by, first decarboxylation, and then cyclization in refluxing formic acid <2006BMCL2091>. Replacing the 3-methoxyphenyl group on the pyrrole with a reduced pyrrole (a mimic of a ribofuranose ring) leads to a 4-aminopyrrolo[3,2- pyrimidine when treated with formamidine acetate <2006BMCL2662>. 

The anion formed from the acetyl methyl group under reaction conditions then attacks one of the carbethoxy groups to form a cylohexanone to give (74-4) as the isolated product. The free acid obtained on hydrolysis of the ester decarboxylates to give the (3-diketone (74-5). In a classic apphcation of the Knorr pyrrole synthesis, the diketone is then allowed to react with 2-aminopentan-3-one. Since the latter is unstable, it is generated in situ by reduction of the nitrosation product from diethyl ketone. There is thus obtained piquindone (74-6) [76], a compound that displays antipsychotic activity. 

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... 

---