Pyrrole C-alkylation

A novel ionic liquid methodology for pyrrole C-alkylation is described (Equation 136) <20050L1231>. The pyrrole alkylation is achieved with various simple alkyl halides (1-bromopentadecane, l-(bromomethyl)-, l-(3-chloropropyl)- and l-(3-iodopropyl)benzenes, 2-(2-bromoethyl)- and 2-(3-bromopropyl)naphthalenes) and mesylates (3-phenylpropyl-, l-methyl-3-phenylpropyl-, 2-(2-naphthyl)ethyl- and 3-(2-naphthyl)propyl methanesulfonates) selectively at C(2)- and C(5)-positions in good yields with minimal by-products under relatively mild conditions in various ionic liquids. 2-(3-Phenylpropyl)pyrrole 569 was synthesized from pyrrole and l-bromo-3-phenylpropane in a mixed solvent system, [Bmim][SbF6] and MeCN, in 81% yield at 115°C for 44h with 5% yield of dialkylated compound. 

In C-alkylation of other compounds containing nitrogen atoms. Chi s group [35] has done a lot of work. They have described a novel approach for pyrrole C-alkylation in which [BMIM][SbFg] and CH CN as a mixture was onployed for the synthesis of 2-(3-phenylpropyl)pyrrole from pyrrole and 7-bromo-3-phenylpropane with the results that 81% yield was achieved at 115 C for 44 h with 5% yield of dialkylated compound. It is obvious that the ionic Uqnid demonstrated an important driving force in the regioselective alkylation of pyrrole. Moreover, it is worthy to be noted that in this reaction, no Lewis add/base catalysts were needed. 

As is the case with pyrroles, C-alkylation of indoles results in mixtures of products. Formylation and acylation, however, occur more readily. The Vilsmeier-Haack reaction furnishes indole-3-carbaldehyde heating with acetic anhydride produces 3-acetylindole. In the Houben-Hoesch acylation, substitution takes place in the 3-position. 

N-Alkylpyrroles may be obtained by the Knorr synthesis or by the reaction of the pyrrolyl metallates, ie, Na, K, and Tl, with alkyl haUdes such as iodomethane, eg, 1-methylpyrrole [96-54-8]. Alkylation of pyrroles at the other ring positions can be carried out under mild conditions with allyhc or hensylic hahdes or under more stringent conditions (100—150°C) with CH I. However, unless most of the other ring positions are blocked, poly alkylation and polymerisation tend to occur. N-Alkylation of pyrroles is favored by polar solvents and weakly coordinating cations (Na", K" ). More strongly coordinating cations (Li", Mg " ) lead to more C-alkylation. 

In another example of a radical process at the pyrrole C-2 position, it has been reported that reductive radical cycloaddition of l-(2-iodoethyl)pyrrole and activated olefins, or l-(oj-iodo-alkyl)pyrroles 34 lead to cycloalkano[a]pyrroles 35 via electroreduction of the iodides using a nickel(II) complex as an electron transfer catalyst <96CPB2020>. Thus, it appears the radical chemistry of pyrroles portends to be a fertile area of research in the immediate or near future. 

Whereas pyrrole was reported not to give N/H insertion by ketocarbenoids, such a reaction mode does occur with imidazole Copper-catalyzed decomposition of ethyl diazoacetate at 80 °C in the presence of imidazole gives ethyl imidazol- 1-ylacetate exclusively (93 %) small amounts of a C-alkylated imidazole were obtained additionally under purely thermal conditions 244). N/H insertion also takes place at benzimidazole 245 a). The reaction is thought to begin with formation of an N3-ylide, followed by N1 - C proton transfer leading to the formal N/H insertion product. Diazomalonic raters behave analogously however, they suffer complete or partial dealkoxycarbonylation under the reaction conditions 244) (Scheme 34). N-alkylation of imidazole and benzimidazole by the carbenoids derived from co-diazoacetophenone and 2-(diazoacetyl)naphthalene has also been reported 245 b>. 

Using this information in conjunction with a study into the preferred conformations of iminium ions generated from catalysts 12 and 21, Houk suggests that the additional steric bulk of the ferf-butyl group causes the benzyl arm of the catalyst to shield better the Si face of the C=C double bond - a requirement for high ees in an open transition state. For both the Diels-Alder and pyrrole/indole alkylation... 

Typical electrophilic reactions, such as nitration, halogenation with a Lewis acid (as a carrier ), Friedel-Crafts C-alkylation and -acylation, that work well with benzene, cannot be applied to pyrrole, because heating with strong acids, or a Lewis acid, destroys the heterocycle. However,... 

For example, during N-alkylation of pyrrole under conventional alkaline conditions C-alkylation also occurs at positions 2 and 3. Thus the Grignard derivative of pyrrole122 reacting with dimethyl sulfate in HMPA gives a mixture of mono- and dimethylation products. The first example of pyrrole benzylation under PT conditions was reported by Jonczyk and Makosza.123 The /V-benzyl compound was the major product. 

Wang et al.122 have described methylation and alkylation of pyrrole and obtained mono-N-alkylation products with yields of 30-85%. An increase in the ratio of N- versus C-alkylation of pyrrole (and of other heterocyclic compounds bearing an acidic hydrogen atom) has been observed by Guida and Mathre,124 who carried out the reaction with t-BuOK, 18-crown-6 (10%), and diethyl ether. 

A classical method for preparing C-acylated pyrroles involves the acylation of pyrrylmagnesium bromide. In general, tightly coordinated TV-pyrryl and indolyl salts, exemplified by their Grignard derivatives, undergo preferential C-acylation and C-alkylation (Scheme 3) (81TL4647). 

Pyrroles give polyalkylated products on reaction with methyl iodide at elevated temperatures and the more reactive ally and benzyl halides under milder conditions in the presence of weak bases. Alkylation of pyrrole Grignard reagents gives mainly 2-alkylated pyrroles whereas A-alkylated pyrroles are obtained by alkylation of pyrrole alkali metal salts in ionizing solvents (see Section 3.3.1.3.1). Pyrrolenines are formed by the C-alkylation of the Grignard derivatives of polyalkylated pyrroles. Alkylation occurs at positions 2 and 3, although the former predominates. 

These observations have been interpreted in terms of the hard-soft acid-base theory (77CJC4112), in which the salts of the harder cations, such as the Li+ ion, lead to C-alkylation, whilst the salts of the soft cations, such as the quaternary ammonium salts, are TV-alkylated. This interpretation is particularly relevant in understanding the reactivity of the heteroaryl-magnesium salts. The Mg2+ ion is a harder cation than the Li+ ion and, with the more strongly associated Grignard compounds, C-alkylation predominates. Generally, the pyrrole... 

The oxidation of indoles and pyrroles by Fe(III) ions is less predictable than other chemical oxidations. 2-Methyl- and 3-methyl-indoles, respectively, yield (187) and (188), and whilst pyrroles may form pyrrole black , the rate of oxidation of pyrrole and of 1-methylpyrrole appears to be relatively slow. C-Alkyl and electron-donating substituents enhance the formation of oligimers, e.g. (189) -> (190) and (191) -> (192), and although electron-withdrawing substituents reduce the susceptibility of the pyrrole ring to oxidation, acyl- and alkoxycarbonyl-pyrroles of the type (193) are readily oxidized to the thermochromic dimer (194), which is in equilibrium with the dimer (195) via the monomeric pyrrolyl radical (72BCJ3584). 

The [3 + 2] addition of type llbd is a significant method for synthesis of both simple and complex pyrrole derivatives. One manifestation of this pattern is seen in the base-catalyzed condensation of tosylmethyl isocyanide with alkenes having strong electron-accepting substituents. The aromatization by elimination of the arenesulfinic add occurs under the reaction conditions (equation 117) (72TL5337). This reaction can be applied to the synthesis of 2,3,4-trisubstituted pyrroles by using C-alkylated tosylmethyl isocyanides or AT-tosyl-methyl-S- methylthioimidates <77H(7)77, 81JHC1127). 

Alkylation of carbazole has not been studied systematically but isolated preparative examples suggest that N- alkylation can be carried out as for pyrroles and indoles. No complication from competing carbon alkylation occurs. N- Alkylation of the anion of isoindole does not seem to have been investigated. One might expect serious competition from C- alkylation because of the favorable benzenoid conjugation of the resonance structure with charge on carbon (equation 161). 

The mass spectra of pyrrole, four C-alkyl, and two A-alkyl derivatives are to be found in the American Petroleum Institute catalog of mass spectral data.318 Other publications report the most abundant fragment peaks of some N- and C-substituted pyrroles.313,314... 

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