Simple Pyrroles

The pyrrole ring is widely distributed in nature. It occurs in both terrestrial and marine plants and animals [1-3]. Examples of simple pyrroles include the Pseudomonas metabolite pyrrolnitrin, a recently discovered seabird hexahalogenated bipyrrole [4], and an ant trail pheromone. An illustration of the abundant complex natural pyrroles is konbu acidin A, a sponge metabolite that inhibits cyclin-dependent kinase 4. The enormous reactivity of pyrrole in electrophilic substitution reactions explains the occurrence of more than 100 naturally occurring halogenated pyrroles [2, 3]. 

As will be seen in this chapter and in the rest of the book, the Heck reaction and its numerous variations represent a fantastically powerful set of tools available to the heterocyclic chemist. Although most Heck chemistry that involves pyrroles is intramolecular or entails synthesis of the pyrrole ring, a few intermolecular Heck reactions of pyrroles are known. Simple pyrroles (pyrrole, A-methylpyrrole, A-(phenylsulfonyl)pyrrole) react with 2-chloro-3,6-dialkylpyrazines under Heck conditions to give mixtures of C-2 and C-3 pyrrole-substituted pyrazines in low... 

Bullock E (1958) The structure of pyrrole salts and the basic strengths of some simple pyrroles. Can J Chem 36, 1686-1690. 

An additional impetus for pyrrole and indole research derives from the recognition of the physiological significance of these ring systems. In the case of pyrroles the early work centered around hemin from hemoglobin and the bile pigments. The structure of chlorophyll was also shown to be pyrrole-derived. The biosynthetic connection between simple pyrroles and the macrocyclic hemin and chlorin have remained of interest up to the present (75ACR201). 

Most of the known natural brominated pyrrole alkaloids are found in sponges, and several new examples were isolated since the first survey (1). Reviews are available that discuss the occurrence and syntheses of these metabolites (1236-1238). The Papua New Guinea sponge Agelas nakamurai has yielded the new simple pyrroles 1222 and 1223 (1239). The dibromo analog (1224) of 1223 along with enantiomeric lactams 1225/1226, which were separated by chiral HPLC, and... 

The extended cyclic enolate derived from a simple pyrrol-3-en-2-one (butenolac-tam) has been deuterated at the 5-position with very high diastereoselectivity if the (g) nitrogen atom carries a a-methyl-p-methoxybenzyl group (de > 99 l).27 A similar diastereoselective protonation has been observed in a pyrrol-3-en-2-one formed by dearomatizing cyclization of a pyrrole. 

A small number of simple pyrroles such as 2.5 and 2.6 occur naturally. Far more important are the tetramic pyrrole derivatives (porphyrins) such as chlorophyll-a 2.7 and haem 2.8. 

Simple pyrroles frequently give complex breakdown products. Oxidation with oxygen (UV-irradiation, a photosensitizer, or an radical initiator) produces hydroxypyrrolones <1991JOC6942, 1999TL4519, 2002TA601>. For example, pyrrole 152 (30 C) leads to 5-hydroxy-l,5-dihydro-27/-pyrrol-2-one 153 <2003T8499>. 

Recently, evidence for the transient ex istence of cation-radicals from simple pyrroles and indoles has been furnished by the observation of anodic regiospecific cyanation of these heterocycles.455 Both heterocycles are preferentially cyanated at the 2-position. Methyl side chains at these positions are also activated to cyanation and deuteration. Indole cation-radicals have been generated by photoionization in an aqueous medium.456 Unsubstituted at N, their lifetime in neutral solution is 10-6sec before they lose the N-proton however, it is longer in more acidic conditions.456 The photophysical properties of indole, its cation-radical, and neutral radical have been the subject of a recent theoretical analysis.457 On anodic oxidation of 2,3-diphenyl indole in acetonitrile, the initially formed cation-radicals dimerize to a product identified, primarily on the basis of 13C NMR, as 3-(5-indolyl)-indolenine (141).458... 

A trace constituent in the venoms of the myrmicines Atta texana, A. cephalotes, A. sexdens, and Acromyrmex octospinosus is methyl 4-methylpyrrole-2-carboxylate (X) ( 13, L4, lj[). This simple pyrrole... 

Although an impressive number of alkaloids have been isolated from plant sources, only a few contain simple pyrrole rings. These include a series of tropane alkaloids from the bark of Erythroxylum vacciniifoUum, for example, 82, that share as common structural features a methylpyrrole moiety <2005JNP1153> methyl-(5-formyl-l//-pyrrole-2-yl) -hydroxybutyrate 83 from sweet chestnut seeds <2002MI22> and solsodomine A 84 and B 85 from the fresh berries of Solanum sodomaeum L. <1998JNP848>. The latter are the first pyrrole alkaloids from the genus Solanum. 

The last class of Schiff base macrocycles to be discussed in this subsection are the only ones which can truly be called expanded porphyrins. This is because in all cases reliance is not made on simple pyrroles but on linked polypyrroles. The first... 

Other compounds which have been isolated from the fermentation broths of S. disthallicus are netropsin (Fig. 2) and a simple pyrrole derivative devoid of biological activity. Netropsin (synonium congocidin) was reported in 195115, ... 

Although most Heck chemistry that involves pyrroles is intramolecular or entails synthesis of the pyrrole ring, a few intermolecular Heck reactions of pyrroles are known. Simple pyrroles (pyrrole, 7V-methylpyrrole, 7V-(phenylsulfonyl)pyrrole) react with... 

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