BETA-AMINOMETHYLATION REACTIONS INVOLVING N-AZAHETEROARYL-SUBSTITUTED2,5-DIMETHYLPYRROLES - UNUSUAL EFFECTS OF ALPHA-AZA GROUPS

The reactions of a number of N-aryl- and N-alpha-azaheteroaryl-substit uted 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 pyr roles investigated cleanly afforded the corresponding single Mannich b ases, with the exception of the N-(2-pyrimidinyl) derivative which, in its reaction with the morpholine Mannich reagent, always gave the dou ble 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 Mann ich reagents, it proved impossible to bisaminoalkylate the N-aryl-2,5- dimethylpyrrole derivatives, whatever the amine and the reaction condi tions adopted, and the N-heteroaryl-2,5-dimethylpyrroles when the amin e was the 4-methylpiperazine, double substitution being achieved only with preformed Mannich salts. An explanation is offered for these unpr ecedented substituent and reagent effects in heteroaromatic aminoalkyl ation reactions.