Synthesis and Properties of Ring-Deactivated Deuterated (Hydroxymethyl)pyrroles

A sequence, based on a Mitsunobu displacement at the hydroxymethyl position of deuterium-labeled, N-substituted 2-(hydroxymethyl)pyrroles, is reported as a general procedure to determine the ability of the N-substituent to deactivate the heterocycle. An SN2 mechanism, in this reaction, has been shown to be favored over reaction via an azafulvenium intermediate, by employing N-(trifluoromethyl)sulfonyl as the deactivating group. Deuterium-labeling studies have demonstrated that suppression of contributions to the reaction from an azafulvenium intermediate is less effective with other deactivating groups, and the order for deactivation is triflyl > mesyl > BOC ≈ acetyl. The attachment of an electron-withdrawing group onto the nitrogen of a 2-formyl[formyl-d]pyrrole has also been shown to allow reduction to give a 2-(hydroxymethyl[methylene-d 1])pyrrole of high configurational purity. The utility of the N-triflyl group to deactivate a pyrrole was demonstrated with the preparation of deuterium-labeled porphobilinogen precursor.