Pyrrole Grignard reagents, 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. 

A number of instances have already been mentioned of reactions in which both N- and G-substitution occur. These are reactions of pyrroles with acid anhydrides (p. 64), alkylation and alkenylation of metallic derivatives of pyrroles (p. 66) and ethoxycarbonylation of metallic derivatives (p. 66 see also below). Most of the reactions of pyrrole Grignard reagents result in G-substitution, but occasionally N-substitution is also observed (p. 106). The Mannich reaction does not cause N-substitution (p. 70). Deuteration proceeds most easily at the nitrogen atom (p. 75), and reactions with metals (p. 61) cause displacement of hydrogen from nitrogen. 

As in pyrroles, the A-hydrogen in indoles is much more acidic (pK 16.2) than that of an aromatic amine (aniline has pK 30.7). Any very strong base will effect complete conversion of an A-unsubstituted indole into the corresponding indolyl anion, amongst the most convenient being sodium hydride, n-butyUithium or an alkyl Grignard reagent. 

Oddo reported that the organomagnesium derivatives of pyrrole, indole, skatole, and carbazole could be prepared in a single operation by mixing the parent heterocyclic compound with an alkyl halide and magnesium in anhydrous ether.23 The product formed was reported to be the same as that obtained by the more conventional procedure. However, this approach to the synthesis of the indole Grignard reagents does not seem to have been exploited in subsequent work. 

The NH pyrrole proton is acidic with a pATa of 17.5. As a consequence, bases such as NaH, Grignard reagents, n-BuLi, and NaOEt readily deprotonate pyrrole. For instance, alkylation of 4-nitro-pyrrole-2-ester was achieved by treatment of the pyrrole with sodium ethoxide in the presence of... 

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