Bromopyrrols

Treatment of pyrrole, 1-methyl-, 1-benzyl- and 1-phenyl-pyrrole with one mole of A -bromosuccinimide in THF results in the regiospecific formation of 2-bromopyrroles. Chlorination with IV-chlorosuccinimide is less selective (8UOC2221). Bromination of pyrrole with bromine in acetic acid gives 2,3,4,5-tetrabromopyrrole and iodination with iodine in aqueous potassium iodide yields the corresponding tetraiodo compound. 

The Heck cyclization of bromopyrrole 77 and the corresponding oxidative Heck cyclization of desbromopyrrole 78 was studied <06SL3081>. While the Heck cyclization of 77 led to a mixture of [3.3.l]bicycle 79 and [3.2.2]bicycle 80 under a variety of conditions, the oxidative Heck cyclization of 78 led solely to the desired building block 79. The latter has previously been utilized in a total synthesis of dragmacidin F. 

The sulfamate ester variant of this chemistry has already been shown to be a very powerful protocol for the syntheses of 1,3-amino alcohols and related /3-amino acids (Equation (90)), as well as iminium ion equivalents (Equation (91)). The further showcases of this chemistry are the total syntheses of the bromopyrrole alkaloids, manzacidins A and C (Scheme 13).234 The cyclic sulfamidate 129 was obtained diastereospecifically from sulfamate 128 using intramolecular rhodium-catalyzed G-H insertion. It was then found to react with sodium azide in NfN-dimethylformamide at room temperature after introduction of the Boc-activating group to afford the 1,3-diamino precursor 130 in 78% yield over 3 steps. Four subsequent manipulations afford the target structure 131. 

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. 

The power of Muchowski s method is seen by the fact that these bromopyrroles can be subjected to bromine-lithium exchange to afford the versatile 3-lithio species that can be quenched with a variety of electrophiles in good to excellent yields [18-21]. This is illustrated by a synthesis of verrucarin E (11) [19]. 

Noteworthy is the fact that one can utilize the appropriate bromopyrrole (e.g., 48) in conjunction with the desired Grignard reagent in a one-step operation to afford the corresponding substituted pyrroles (e.g., 49) [43]. The mixed pyrrole-pyridine heterocycle 50 was made in this fashion [45]. 

Using 2-bromopyrrole 72, Burgess has synthesized 2-arylpyrroles 73 in excellent yield [61], The resulting hydrolyzed pyrroles 74 were used to prepare 3,5-diaryl BODIPY dyes. 

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. 

Another type of C—N bond formation was achieved via stereospecific C—H activation in the synthesis of bromopyrrole alkaloids, manzacidins A and C... 

Scheme 17.43 Bromopyrrole alkaloid assembly, highlighting sulfamate ester oxidation.

Substituted Pyrroles from N-tert-Butoxycarbonyl-2-bromopyrrole ... 

Other examples of N-substituted 3-bromopyrroles that have been successfully derivatized at the 3-position include either 4- or 5-substituted-3-bromo-l-tosylpyrroles 5 (90TL6785 91T7615) 3-bromo-l-tritylpyrrole 6 (91UP1) and the bromo-azafulvene dimer , which leads to 4-substituted pyrrole-2-carboxaldehydes 8 after reaction with electrophiles and hydrolysis (88TL3215). 

Mar. ALKAL. 3-alkylpyridine, azirine, azacyclodecanes, p-carboline, C, or C22 bromopyrrole, guanidine, halotyrosine, (bis)imidazole, (bis)indole, imidazoiyi pyrroloazBpine, indolizidine, pept. alkal., pyridazine. high high... 

Table 5 Reaction of bromopyrroles with (NSCijs (2equiv) in refluxing carbon tetrachioride...

Bromopyrroles are accessible from metallic derivatives quenched with bromine [62MI2 77MI1]. 

CAi90) 123047). The isolation of 2-chloro-5-formylpyrrole from the Vilsmeier-Haack formylation of 2-bromopyrrole (75JOC3161) can be rationalized in terms of an addition-elimination reaction of the intermediate azafulvenium cation (Scheme 82). Displacement... 

Although very few terrestrial plant alkaloids contain halogen, brominated alkaloids have been reported from the marine environment. From the Okinawan marine sponge Hymemacidon sp., several bromopyrrole alkaloids have been described, e.g., tauroacidins A and B, Fig. (35) [262], konbuacidin A, Fig. (36) [263] and spongiacidins A-D [264]. Several species of sponges contain hymenialdisine, Fig. (37), which has been shown as a potent inhibitor of nuclear factor kappa B and interleukin-8 production in vitro [265,266]. 

A new bromopyrrole alkaloid 15 along with racemic 16 was isolated from the Japanese marine sponge Homaxinellct sp. They exhibit weak cytotoxic activity against P-388 lymphocytic leukemia cells with ED50 values of 21.5 pg/ml and 30 pg/ml, respectively [34]. 

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