1,4‐Dearomatization of Pyridines and Quinolines Enabled by the Carbodication Lewis Acid

Abstract

Abstract 1,4‐Dihydropyridines (DHPs) are valuable compounds in medicinal chemistry and organic synthesis. The most straightforward pathway for preparing 1,4‐DHPs is the direct 1,4‐reduction of pyridines and quinolines. However, existing strategies are not effective for pyridines with electron‐withdrawing substituents at the C2 position. To address this long‐standing issue, a new strategy has been developed that utilizes underexplored carbodications as the Lewis acids to activate pyridines. For the first time, pyridines with ‐CN and ‐ester substituents at the C2 position have been successfully converted to 1,4‐DHPs through direct reductive dearomatization in exclusive C4 selectivity. The potential utility of this 1,4‐DHP synthetic protocol is demonstrated with C5‐bromination, C5‐trifluoromethylation, C5‐deuteration, and C4‐deuteration of pyridines using the in situ generated 1,4‐DHPs as key intermediates.