Pyrroles halogenation

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]. 

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. 

Gribble GW (2003) Naturally Occurring Halogenated Pyrroles and Indoles. Prog Hetero-cycl Chem 15 58... 

Several simple halogenated pyrroles are produced by marine organisms. Even though the oceans are richer in chloride than bromide, most marine halogenated compounds, of any type, contain bromine rather than chlorine. This is likely a consequence of the greater susceptibility of bromide to enzymatic oxidation by bromoperoxidase or other peroxidases. 

Compared to the number of halogenated pyrroles and indoles, the number of known halogenated carbazoles, carbolines, indolocarbazoles, and related compounds is much smaller <96MI1>, and the number of recently discovered examples of these types is fewer still. 

Although naturally occurring organohalogens represent a relatively new category of natural products, the discovery of such compounds has increased rapidly in recent years, and halogenated pyrroles and indoles are a major subset of this class. 

Of the more than 4500 known naturally occurring organohalogen compounds, a large fraction are alkaloids [1,3]. Most of these halogenated pyrroles, indoles, carbazoles, carbolines, tyrosines, and others have a marine origin. The present chapter surveys the occurrence, structure, and biosynthesis of these fascinating natural products. However, given their sheer number, this review focuses mainly on recent examples. 

Naturally occuring halogenated pyrroles and indoles 03PHC56. 

Naturally occurring halogenated pyrroles and indoles , Gribble, G. W., Prog. Heterocycl. Chem., 2003, 15, 58. 

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