Abstract: | 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. |