Pyrrole esters

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. 

In 1985, in the course of their interest in nitroalkane chemistry, Barton and Zard reported the base-catalyzed reaction of nitroalkenes with a-isocyanoacetates leading to pyrrole esters having an ideal substitution pattern for the synthesis of porphyrins and bile... 

The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus base-induced formation of enolate 9 is followed by Michael addition to the nitroalkene and cyclization of nitronate 10 to furnish 11 after protonation. Loss of nitrous acid and aromatization affords pyrrole ester 12. 

Under mercuration conditions, pyrrole itself reacts with a mixture of Hg(OAc)2, PdCh, LiBr, CO, EtOH, and Cu(OAc)2 to give 2-(ethoxycarbonyl)pyrrole, but in only 4% yield [115]. In contrast, using the thallation-palladium modification of the Heck reaction, Monti and Sleiter have prepared pyrrole ester 159 in high yield [111]. 

Ligand directed palladation of 2-(dimethylaminomethyl)-l-(phenylsulfonyl)pyrrole (165) leads to the isolable palladium complex 166. Exposure of 166 to CO yields pyrrole ester 167 in good... 

An intramolecular oxo-Diels-Alder reaction leads to the synthesis of reduced pyrano[3,4-f]pyrrole esters. When benzene is chosen as reflux solvent, /ra r-substituted products form, whereas air-substituted derivatives are favored in refluxing toluene solvent (see Section 10.06.2.1.2) <2003T8955>. 

The isomeric 5 -ethoxycarbonylthieno[3,2-6 jpyrrole (47) was acylated at C-2 to give 2-acyIthieno[3,2-6]pyrrole ester (48), which is not surprising. 

By addition of carbocyclic, acyclic and heterocyclic enamino ester to nitroalkenes and subsequent expulsion of the nitro group, pyrrole ester and fused derivatives are accessible82 (equation 58). 

These dienes are transformed into pyrrole esters on treatment with ethyl glycine hydrochloride in hot pyridine, e.g. equation 4566. 

N-Arylation of ethyl l/f-pyrrole-2-carboxylate under Chan and Lam conditions <1998TL2933, 1998TL2941>, by reaction with 4-methoxyphenylboronic acid in the presence of cupric acetate and either triethylamine or pyridine at room temperature, gave the pyrrole ester 190 in good yield (Equation 40) <1999T12757>. 

Heating a mixture of diastereomeric oxaziridine 44 at 70 °C for 3h resulted in formation of pyrrole ester 46 as the only product <2002TA437>. Hydroxy imine 45 was suggested as an intermediate with transformation. Treatment with... 

Gabriele er al. have described the cycloamination of aminoalkynes 247 leading to pyrroles 248 [153, 154], and in the presence of carbon monoxide to pyrrole esters 249 [155]. 

The PAs are not toxic until they are metabolized in the liver. Dehydro genation by P-450 enzymes forms toxic pyrrolic metabolites. These pyrrolic metabolites either undergo hydrolysis to pyrrolic alcohols or destroy surrounding tissues. Both the pyrrolic esters (primary metabolites) and the pyrrolic alcohols (secondary metabolites) have antimitotic effects and are responsible for the damage to cells in the liver (Abbott, 1988). 

The main feature within this group is the ease with which loss of the carboxyl group occurs. Simply heating pyrrole acids causes loss of carbon dioxide in what is essentially ip o-displacement of carbon dioxide by proton. This facility is of considerable relevance to pyrrole synthesis since several of the ring-forming routes (e.g. see 16.16.1.2 and 16.16.1.6) produce pyrrole esters, in which the ester function may not be required ultimately. 

The total synthesis of (+ )-dehydroheliotridine (4), a toxic metabolite of the pyrrolizidine alkaloids (e.g. lasiocarpine and heliotrine), has also been described.2 The pyrrole ring was obtained by reaction of l,6-dihydroxy-2,5-dicyanohexa-l,3,5-triene-l,6-dicarboxylic ester (5) with j3-alanine, which afforded the N-substituted pyrrole ester (6), together with the appropriate amide of oxalic acid. Careful hydrolysis of (6) with dilute alkali afforded the related tricarboxylic acid, which was converted, by Dieckmann cyclization, hydrolysis and decarboxylation, into the keto-acid (7). Esterification of (7) with diazomethane, followed by reduction with lithium aluminium hydride, finally afforded ( )-dehydroheliotridine (4), identical, except in optical rotation, with dehydroheliotridine obtained earlier by Culvenor et al.3... 

Benzylic, allylic or pyrrolic esters if the acyloxy moiety is a good leaving group. 

During the past few years, the polyoxygenated 2,3,4-triarylpyrrole natural products known collectively as the lamellarins have been amongst the most thoroughly studied class of natural products. An interesting cyclocondensation reaction between imine 1 and nitroalkene ester 2 led to highly functionalized pyrrole ester 3, an intermediate which was converted to lamellarin L <04AG(E)866>. A similar reaction with a nitrocoumarin Michael acceptor proved to be less effective. 

Pyrroles (10) can be made the same way, the cyclisation being carried out with ammonia, but an alternative strategy is particularly valuable for carbonyl-substituted pyrroles. Pyrrole esters such as (15) are needed for the synthesis of porphyrins (as in haemoglobin), chlorins (as in chlorophyll), and corrins (vitamin B 2). Ester (IS) has the haem side chain and can be converted by hydrolysis and decarboxylation into a pyrrole (16) with a reactive free position (H in 16). 

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