Iodination of pyrroles

Direct iodination of pyrrole 358 with Nal and I2 (H2O, reflux, 3 h) gave the 5-iodopyrrole 359 in excellent yield (Scheme 81) <2004T11283>. This compound was involved in the synthesis of a new terpyrrolic analog of DPQ (dipyrrolylquinoxaline) 360. 

In their studies towards the synthesis of lukianol A, Wong et al. observed the regioselective zp o-iodination of pyrrole 187 followed by Sonogashira coupling to give 189 in quantitative yield overall [109]. lodopyrrole 188 also undergoes Suzuki couplings with arylboronic acids. 

Many heterocyclic compounds can be halogenated with H2O2/HX. Examples include tetra-iodination of pyrrole in 80% yield with H2O2 and KI at 45°C [270], monochlorination of 3-aminopyridine with H2O2/HCI at 80°C giving the 2-chloro-product [271], and of the more active 3-bromo-2,4-dihydroxypyridine at ambient temperature giving the 6-chloro-product. Several substituted quinolines have also been chlorinated, including 3-hydroxy [272], 8-hydroxy [273], 8-amino [274] and 8-methoxy-4-hydroxy [275]. 

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. 

Additional kinetic evidence supporting molecular iodine as an iodinating species is sparse. Li325 found that the iodination of tyrosine in acetate buffers at 25 °C showed the mixed inverse dependence on iodide ion concentration noted above, so that part of the reaction appeared to involve the molecular species. Subsequently, Doak and Corwin326 found that the kinetics of the iodination of (N-Me)-4-carboethoxy-2,5-dimethyl- and (N-Me)-5-carboethoxy-2,4-dimethyl-pyrroles in phosphate buffers in aqueous dioxane at 26.5 °C obeyed equation (162), viz. 

A type Ilac synthesis of functionalized pyrroles was developed that adapted the Larock indole synthesis <06OL5837>. For example, treatment of iodoacrylate 19 and trimethylsilylphenylacetylene 20 with palladium acetate led to the formation of pyrrole-2-carboxylate 21 with excellent regioselectivity. 19 was prepared by iodinating (N-iodosuccinimide) the corresponding commercially available dehydroamino ester. 

A Sml2-induced reductive cyclization of (V-(alkylketo)pyrroles provided an entry into medium ring 1,2-annelated pyrroles <06EJO4989>. An oxidative radical alkylation of pyrroles with xanthates promoted by triethylborane provided access to a-(pyrrol-2-yl)carboxylic acid derivatives <06TL2517>. An oxidative coupling of pyrroles promoted by a hypervalent iodine(III) reagent provided bipyrroles directly <060L2007>. 

Iodine has been reported to possess a mild Lewis acidity and can activate carbonyl groups. It can for example catalyze the addition of pyrroles to cf,]3-unsaturated ketones (Scheme 85) [224], A mixture of pyrrol and 3 equiv. of ketone gave disub-stituted products in up to 92% yield in 10 min with 10 mol% of iodine. In cases when only 1.1 equiv. of ketone was apphed in the reaction, mono- and disubstituted products were isolated in few minutes in up to 95% yield in a ratio between 1 1 and up to 1 5. A-Alkylated pyrroles also participated in the reaction in good yields. 

In an extension of atom-transfer radical reactions to heterocyclic systems, Byers has introduced a novel methodology for the addition of electron-deficient radicals to unprotected pyrroles and indoles in a stannane-fi ee, non-oxidative process <99TL2677>. For exanqrle, photochemical reaction of pyrrole (33) with etl l iodoacetate (34) in presence of thiosulfiite as an iodine reductant, phase transfer catalyst and propylene oxide led to high yields of the 2-alkylated pyrrole 35 <99TL2677>. 

The iodination of substituted pyrroles can be carried out with iodine-potassium iodide, iodine-iodic acid or iodine and mercury(II) oxide. The tendency towards polyiodination is... 

Doak and Corwin94 have studied the kinetics of the iodination of some trisubstituted derivatives of pyrrole and A-methylpyrrole. Both free iodine and hypoiodous acid are supposed to be the iodinating agents in this reaction. The similar reactivity exhibited by pyrrole and A-rn ethyl py rrole contradicts the hypothesis previously proposed,95 that the great reactivity of pyrroles in iodination may be due to a reaction either of the dissociated anion or the pyrrolenine tautomer. 

There are no quantitative studies to permit direct comparison of the reactivity of indole in electrophilic substitution with that of pyrrole. However, the available data indicate that the reactivity at position 3 of indole does not differ very much from that of the 2-position of pyrrole. For instance, indole is reported to be 50 times more reactive than aniline in the iodination reaction.107... 

Molecular iodine-promoted Michael addition is a simple and efficient method for generating 2-pyrrolyl-2-phenyl-l-nitroalkanes in good yields (Scheme 67) [86]. Cr+3-Catsan (Cr+3 exchanged commercially available montmorillonite clay) and ZnCl2, which were first used as Lewis acids for Michael reactions of pyrrole, showed different selectivity under the same conditions [221], In general, while the reactions catalyzed by Cr+3-Catsan... 

Acetylation of pyrrole is difficult because if forms a 2 1 complex with stannic chloride (29CB226). Hence, under the conditions used for the other five-membered rings (i.e., acetic anhydride in the presence of one hundredth molar equivalent of stannic chloride or iodine), no reaction occurs, and only 20% acetylation is obtained if the molar proportion of the catalyst is reduced 10-fold. The effect of complex formation also shows up in the inhibition of stannic chloride-catalyzed acetylation of fu-ran or thiophene, on addition of pyrrole (67MI4). Catalyzed acetylation of 2-cyano-, 2-formyl-, or 2-methoxycarbonylpyrrole gives mainly 4-substitution (67CJC897) indicating that the catalyst must also be coordinated with the substrate l-methyl-3-nitropyrrole acetylates only in the 5-posi-tion (57CJC21). 

Clauson-Kaas) are perhaps the most utilized methods for the de novo synthesis of pyrroles. Recent advances include the following novel approaches to 1,4-diketones Stetter addition of aldehydes to chalcones <07SC1109> ruthenium-catalyzed isomerization of 1,4-alkynediols <07TL5115> and Zn/iodine-mediated dimerization of a-bromoketones <07TL7215>. 

Another unexpected side reaction occurred in the attempted deprotection of pyrrole acetal 70 <07OL4785>. Treatment of 70 with iodine (mild Lewis acid) led to the formation of the novel pyrrole macrocycle, cyclononatripyrrole 71. 

Hypervalent iodine(lll) was shown to catalyze the direct cyanation of iV-tosylpyrroles and -indoles under mild conditions, without the need for any prefunctionalization <2007JOC109>. Phenyliodine(m) bis(trifluoroacetate)-induced oxidative regioselective coupling of pyrroles in the presence of bromotrimethylsilane gave a series of electron-rich bipyrroles <2007S2913>. 

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