Halogenated pyrroles

Pyrrole halogenates so readily that unless controlled conditions are used, stable tetrahalopyrroles are the only isolable products.Attempts to monohalogenate simple alkylpyrroles fail, probably because of side-chain halogenation and the generation of extremely reactive pyrrylalkyl halides (section 13.12). 

In many ways the chemistry of indole is that of a reactive pyrrole ring with a relatively unreactive benzene ring standing on one side—electrophilic substitution almost always occurs on the pyrrole ring, for example. But indole and pyrrole differ in one important respect. In indole, electrophilic substitution is preferred in the 3-position with almost all reagents whereas it occurs in the 2-position with pyrrole. Halogenation, nitration, sulfonation, Friedel—Crafts acylation, and alkylation all occur cleanly at that position. 

Halogenation reactions usually involve pyrroles with electronegative substituents. Mixtures are usually obtained and polysubstitution products, ie, tetrahalopyrroles, predominate. The monohalopyrroles are difficult to prepare and are not very stable in air or light. 

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

The chemistry of pyrrole is similar to that of activated benzene rings. In general, however, the heterocycles are more reactive toward electrophiles than benzene rings are, and low temperatures are often necessary to control the reactions. Halogenation, nitration, sulfonation, and Friedel-Crafts acylation can all be accomplished. For example ... 

By introducing reasonable values (about 2 for nitrogen, 4 for oxygen) for the electron affinity parameter relative to carbon, 8, and for the induced electron affinity for adjacent atoms (32/8i = Vio), we have shown that the calculated permanent charge distributions for pyridine, toluene, phenyltrimethylammonium ion, nitrobenzene, benzoic acid, benzaldehyde, acetophenone, benzo-nitrile, furan, thiophene, pyrrole, aniline, and phenol can be satisfactorily correlated qualitatively with the observed positions and rates of substitution. For naphthalene and the halogen benzenes this calculation does not lead to results... 

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]. 

Although pyrrolyl halides are well-known compounds, their instability to acid, alkali, and heat precludes their commercial availability. Since pyrrole is a very reactive, Jt-excessive heterocycle, it undergoes halogenation extremely readily [6, 7], For example, the labile 2-bromopyrrole, which decomposes above room temperature, is a well-known compound, as are A-aIkyl-2-halopyrroles, readily prepared by direct halogenation, usually with NBS for the synthesis of bromopyrroles [8, 9], The 2-halopyrrole is usually the kinetic product but the 3-halopyrrole is often the thermodynamic product, and this property of halopyrroles can be exploited in synthesis. For example, A-benzylpyrrole (1) can be dibrominated to give 2 as the kinetic product, which rearranges to 3 upon treatment with acid [10, 11]. Other A-alkyl-2,5-dibromopyrroles are available in this fashion. 

If the pyrrole is substituted with an electron-withdrawing group, then more vigorous halogenation conditions are required, but the products are usually more stable than simple halogenated pyrroles. For example, the bromination of pyrrole-2-carboxylic acid (12) yields the 4,5-dibromo isomer (13) in excellent yield [22]. Similarly, the bromination of 4-chloropyrrole-2-carboxylic acid furnishes 5-bromo-4-chIoropyrrole-2-carboxylic acid in 90% yield [23]. 

Although V-protected 2-lithiopyrroles are readily generated and many types are known [6, 26], these intermediates have not generally been employed to synthesize halogenated pyrroles. One exception is the synthesis of the two natural seabird hexahalogenated bipyrroles 15 and 17,... 

Halogenated pyrroles can serve as the aryl halide in Stille couplings with organotin reagents. Scott has used this idea to prepare a series of 3-vinylpyrroles, which are important building blocks for the synthesis of vinyl-porphyrins, bile pigments, and indoles [77]. Although 3-chloro-and 3-bromopyrroles fail completely or fared poorly in this chemistry, 3-iodopyrroles 101 work extremely well to yield 3-vinylpyrroles 102. 

Like pyrrole, indole is a very reactive jt-excessive heterocycle and reacts with halogens and other electrophiles extremely rapidly [1]. Nature has exploited this property to produce more than 300 halogenated indoles, mainly bromoindoles in marine organisms. A few examples are illustrated below. Chapter 2 contains references to reviews of these natural organohalogens. 

In all of the halogenation reactions, it is noteworthy that no substitution of the aromatic ring occurs with aryl ketones, even in the case of ir-electron-excessive pyrroles [21 ] or thiophenes [20,23]. 

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