Lewis Acids as Mild and Effective Catalysts for the Synthesis of 3,5‐Bis[(hetero)arylidene]piperidin‐4‐ones

The aldol‐crotonic condensation reactions of N‐alkyl‐ and NH‐piperidin‐4‐one derivatives with (hetero)aromatic aldehydes promoted by Lewis acids or bases were examined. This comparative study has revealed three effective catalytic systems based on Lewis acids, i.e., LiClO₄ and MgBr₂ (in the presence of tertiary amine), and BF₃⋅Et₂O, for the synthesis of N‐alkyl‐substituted 3,5‐bis(heteroarylidene)piperidin‐4‐ones, including those bearing acid‐ or base‐labile groups both in the (hetero)aromatic groups and in the alkyl substituent at the N‐atom. The highest reaction rate was observed for LiClO₄‐mediated synthesis. Both MgBr₂‐ and LiClO₄‐mediated syntheses were inefficient in the case of NH‐piperidin‐4‐one, while BF₃⋅Et₂O provided the final compounds in high yields. This catalyst is especially advantageous as it allows simultaneous condensation and deprotection in the case of O‐protected piperidin‐4‐one.