Pyrrole, alkylation electrophilic aromatic

Alkylation of the C(2) or C(3) carbons of the pyrrole ring can be accomplished by electrophilic aromatic substitution. Such substitution reactions may be carried out on the neutral heterocycle or on a metal salt. The magnesium salts are of most synthetic importance for the alkylation of both pyrroles and indoles. As discussed in Section 3.05.1.2.7, there is a reversal of the preferred site of electrophilic substitution between pyrroles and indoles. Thus Friedel-Crafts-type substitution of pyrroles gives 2-aIkylpyrroles while similar reaction... 

Ozonolyses of tetrahydro-lH-pyrido-[4,3-fe]-indoles resulted in the formation of a nine-membered keto-lactam, which could either be isolated or in situ cyclized to dihydropyrrolo[3,2-( ]quinolones, which can be derivatized by electrophilic aromatic substitution, selectively on the pyrrole moiety. In the ozonolysis reaction, alkyl cin-noline betaines were formed as side products, most likely via Cl side products. ... 

The Houben-Hoesch reaction proceeds via a straightforward electrophilic aromatic substitution mechanism. Following protonation or Lewis acid activation of the alkyl nitrile, nucleophilic attack by the electron-rich pyrrole selectively at C(2) produces the resonance stabilized intermediate 1. Elimination of H" reestablishes the aromaticity of the pyrrole, resulting in imine 2, which is rapidly hydrolyzed to produce the ketone 3. ... 

Metal carbenes generated from the reaction of paUadium or ruthenium catalysts with a-diazo esters have also been found to be electrophilic enough to undergo electrophilic aromatic substitution with pyrrole. The Ru-catalyzed reaction leads to a 2-alkylated pyrrole upon rearomatization. In contrast, the Pd car-bene, in combination with a phosphoric acid cocatalysL generates an intermediate enolate, which subsequently combines with an imine electrophile to furnish a three-component adduct with good enantioselectivity and moderate S37i/a -selectivity (eq 6). 

In the previous sections, the reactions of nucleophilic alkyl and acyl radicals with electron-deficient aromatics via SOMO-LUMO interaction have been described. At this point, we introduce the reactions of electrophilic alkyl radicals and electron-rich aromatics via SOMO-HOMO interaction, though the study is quite limited. Treatment of ethyl iodoacetate with triethylborane in the presence of electron-rich aromatics (36) such as pyrrole, thiophene, furan, etc. produces the corresponding ethyl arylacetates (37) [50-54]. 

The high basicity and consequent electrophilic reactivity that hinder the determination of the reactivity of pyrrole relative to other aromatics facilitates reaction with unreactive electrophiles. This was utilized by Butler and co-workers, who measured partial rate factors for methyl substituents (Table 6.10) in coupling with benzenediazonium ions [77JCS(P2) 1452] and in alkylation by 4-(Af,ALdimethylamino)benzalde-hyde [76JCS(P2)696]. The selectivities of both reactions are remarkably similar. Reaction with p-X-benzenediazonium ions (X = OMe, CN, NO,... 

A number of transition metal complexes containing weakly basic (5-member ring) HDN-related ligands are known. The authenticated bonding modes of pyrrole (Pyr) and pyrrolyl ions (Pyl) -or their alkylated analogues- in mononuclear metal complexes are summarized in Fig. 6.1. Pyrrole is a 5-member aromatic heterocycle in which the lone pair is delocalized over the n system of the ring, and it is therefore an electron rich molecule that reacts readily with electrophiles but is not susceptible to nucleophilic attack. 

As noted in Chapters 2 and 11, a series of -q -arene complexes of osmium have been prepared, and the reactivity of these species has been studied extensively by Harman. The reactions of iq -arene complexes of Os(II) illustrate how strong backbonding can cause the uncoordinated portion of an aromatic system to be more susceptible to electrophilic attack than the corresponding free arene. ° Osmium(II) pentamine complexes of phenols, anilines, acetanilides, and anisoles react with electrophiles at the uncoordinated portion of the ring. For example, the simple phenol complex in Equation 12.78 reacts with Michael acceptors at the 4-position of the coordinated phenol in the presence of a mild tertiary amine base. This reactivity and selectivity for reaction at the 4-position is greater than the reactivity of free phenol. The reactions of electrophiles with aniline derivatives occur in a similar fashion and lead to products from alkylation of the aromatic ring predominantaly at the 4-position (Equation 12.79). Related reactions occur with complexes of electron-rich five-membered pyrrole and furan heterocycles. Examples of electrophilic attack on -q -pyrrole complexes of Os(II) are shown in Equation 12.80. ... 

Noteworthy points in the chapter on Electrophilic Substitution are the surprising findings, based on n.m.r. parameters of a model system, that the polar inductive effect of alkyl groups attached to p -carbon is zero (ref. 12). The correlation of the ortfto-directing effect in the metallation of aromatics (refs. 76—79) and a detailed study of the acylation of the pyrrole anion rationalizing the results on the HSAB principle (refs. 265, 266) are worthy of mention. 

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