Beta-Aminomethylation Reactions Involving N-Azaheteroaryl-Substituted 2,5-Dimethylpyrroles: Unusual Effects of alpha-Aza Groups

The reactions of a number of N-aryl- and N-alpha-azaheteroaryl-substituted 2,5-dimethylpyrroles with Mannich reagents formed by formaldehyde and a secondary cyclic amine have been investigated in aqueous acetic acid at various temperatures and different Mannich reagent : pyrrole ratios. Using a 1:1 Mannich reagent : pyrrole molar ratio, all the pyrroles investigated cleanly afforded the corresponding single Mannich bases, with the exception of the N-(2-pyrimidinyl) derivative which, in its reaction with the morpholine Mannich reagent, always gave the double Mannich base, unless the reaction was stopped after a few minutes. On the other hand, even in the presence of a large excess of the Mannich reagents, it proved impossible to bisaminoalkylate the N-aryl-2,5-dimethylpyrrole derivatives, whatever the amine and the reaction conditions adopted, and the N-heteroaryl-2,5-dimethylpyrroles when the amine was the 4-methylpiperazine, double substitution being achieved only with preformed Mannich salts. An explanation is offered for these unprecedented substituent and reagent effects in heteroaromatic aminoalkylation reactions.