Alkylation of pyrroles

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. 

Pyrroles do not react with alkyl halides in a simple fashion polyalkylated products are obtained from reaction with methyl iodide at elevated temperatures and also from the more reactive allyl and benzyl halides under milder conditions in the presence of weak bases. Alkylation of pyrrole Grignard reagents gives mainly 2-alkylated pyrroles whereas N-alkylated pyrroles are obtained by alkylation of pyrrole alkali-metal salts in ionizing solvents. 

Furthermore, Jana et al. developed a FeCl3-catalyzed C3-selective Friedel-Crafts alkylation of indoles, using allylic, benzylic, and propargylic alcohols in nitromethane as solvent at room temperature. This method can also be used for the alkylation of pyrrole (Scheme 4). The reactions were complete within 2-3 h without the need of an inert gas atmosphere leading to the C-3-substitution product exclusively in moderate to good yields [20]. 

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>. 

An interesting umpolung effect has been found in the alkylation of pyrroles with carbon nucleophiles via the endoperoxide (6.6)612). 

Alkylation of pyrroles, indoles and carbazoles under liquidiliquid two-phase conditions with an added organic solvent... 

The initial report within this area described the regiospecific alkylation of pyrroles using imidazolidinone 12 (20 mol%) as the catalyst [82]. A mixture of THF and water provided optimal reaction conditions, but low temperatures (-60 °C to -30 °C) were required to ensure the chemospecificity of the reaction. The functional group tolerance at the P-position of the substrate and A-substitution on the pyrrole nucleophile was explored (Scheme 15). It was noticed that subtle changes in the nature of the co-acid altered selectivities and this had to be modified depending on the substrates adopted. 

Flouk has also considered the alkylation reactions of pyrroles and indoles using the same class of catalyst. The report addresses the fact that while catalyst 12 provides high ees in the alkylation of pyrroles (Scheme 15), the same is not true of indoles and catalyst 21 is required instead (Scheme 16). A thorough examination of the accessible transition states for the reaction of iminium ion 184 with pyrrole and with indole led to the conclusion that the two reactions occur through different transition states. Pyrrole adopts a closed transition state reminiscent of that of the Diels-Alder reaction whereas indole adopts an open transition state (Fig. 19) [233]. 

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. 

The range of halides which are useful in the alkylation of pyrrole and indole can be predicted by reference to the well-known reactivity of halides and sulfonates towards SN2... 

Interestingly, enantioselective alkylation reactions [64] were also developed using, for instance, Cu(OTf)2, [65], [Cu(SbF6)2, Zn(OTf)2] [66], Cu(C104)2-6H20 [67] or Sc (OTf)3 [68] in combination with diverse chiral ligands. Remarkably, organocatalytic alkylations of pyrroles, indoles and anilines by 3-phenylpropenal have been also developed [69]. 

Scheme 4. Proposed mechanistic pathway for the stereoselective organo-catalyzed F-C alkylation of pyrroles.

As indicated from computational studies, the catalyst-activated iminium ion MM3-2 was expected to form with only the (E)-conformation to avoid nonbonding interactions between the substrate double bond and the gem-dimethyl substituents on the catalyst framework. In addition, the benzyl group of the imidazolidinone moiety should effectively shield the iminium-ion Si-face, leaving the Re-face exposed for enantioselective bond formation. The efficiency of chiral amine 1 in iminium catalysis was demonstrated by its successful application in several transformations such as enantioselective Diels-Alder reactions [6], nitrone additions [12], and Friedel-Crafts alkylations of pyrrole nucleophiles [13]. However, diminished reactivity was observed when indole and furan heteroaromatics where used for similar conjugate additions, causing the MacMillan group to embark upon studies to identify a more reactive and versatile amine catalyst. This led ultimately to the discovery of the second-generation imidazolidinone catalyst 3 (Fig. 3.1, bottom) [14],... 

For computational studies on the Friedel-Crafts alkylation of pyrroles and indoles catalyzed by chiral imidazolidinones, see R. Gordillo, J. Carter, K.N. Houk, Adv. Synth. Catal. 

General Procedure for Organocatalytic Friedel-Crafts Alkylation of Pyrroles [39]... 

Partial Rate Factors (Rel.ativetothe 2-Position of Pyrrole) for Diazonium Coupling and Alkylation of Pyrroles at 25°C... 

Much effort has been devoted to the alkylation of pyrroles and indoles with electrophilic alkenes. Such reactions can be catalyzed by acidic clays or Lewis acids. Indoles are alkylated as usual at C(3), and the alkylation of 3-substituted indoles has also been shown to take place at C(3) with subsequent migration occurring to C(2). 

Enantioselective organocatalytic (with tetrahydro-4//-imidazol-4-one-based catalysts of type 102nHX) 2-alkylation of pyrroles by, -unsaturated aldehydes generates 3-(pyrrol-2-yl) aldehydes 103 (Scheme 46) <2001JA4370, 2002JA1172, 200SJA1S0S1 and references therein>. 

Chiral 2-(3-oxoalkyl)pyrroles and 3-(3-oxoalkyl)indoles can also be accessed by reaction in the presence of 10 mol% of chiral bis(oxazoline)/metal complexes in CH2C12 in very high yields and with ee values over 90% <2005JA4154>. Alkylation of pyrrole and of substituted indoles with, -unsaturated acyl phosphonates <2003JA10780> or 2-acyl N-methylimidazoles catalyzed by a chiral bis(oxazolinyl)pyridine (pybox)/scandium(III) triflate complex also exhibits good enantioselectivity over a broad range of substrates <2005JA8942>. 

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