Reductive Hydroxymethylation of 4‐Heteroarylpyridines

The activation of pyridinium salts with electron‐withdrawing heterocycles enables an iridium‐catalyzed reductive hydroxymethylation reaction to proceed smoothly, facilitating the preparation of useful 3D heteroaryl‐substituted functionalized piperidines. The methodology is used to prepare 3‐hydroxymethylated analogues of pharmaceutical agents. Mechanistically, formaldehyde acts as both a hydride donor and the electrophile, leading to the formation of two new carbon–hydrogen bonds and one new carbon–carbon bond under relatively mild conditions. Reductive functionalization: The activation of pyridinium salts with a 4‐heteroaryl group allows catalytic reductive hydroxymethylation, leading to the preparation of heterocyclic substituted 3‐hydroxymethylated piperidines (see scheme) with many uses in medicinal chemistry.