Optimization of catalytic synthesis of thetrahydropyridines by multicomponent reaction.

The present work shows the optimization conditions for the synthesis of tetrahydropyridines, specifically ethyl 1-(p-tolyl)-4-((p-tolyl)amino)-2,6-diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate, by a multicomponent reaction between two equivalents of p-toluidine, two equivalents of benzaldehyde, and one equivalent of ethyl acetoacetate, assisted by an acid heterogeneous catalyst. The catalyst (5PMo@SiO₂) is constituted by commercial phosphomolybdic acid (5%) included in silica and was prepared by sol-gel technique.

Various parameters were tested: temperature (from room temperature to reflux); solvent (methanol, ethanol, acetonitrile, neat); volume of solvent (3, 5, 8 mL); time of addition of benzaldehyde (20, 40, 60 min); amount of ethyl acetoacetate (1, 1.5, 2 eq); and microwave irradiation.

The analysis of the results indicated that the optimal conditions are 2 mmol p-toluidine, 1 mmol ethyl acetoacetate, 2 mmol benzaldehyde, added after 40 min, 50 mg 5PMo@SiO₂, in 5 mL of methanol at reflux (66,5% yield, 7 h). Furthermore, the system exhibits good reproducibility when scaled up, which reinforces its synthetic potential.

The optimal conditions were employed to extend the reaction to other substituted anilines, aldehydes and alkyl acetoacetates with good to excellent yields (68-88%). We obtained ten different products, which were purified by recrystallization, and the melting points were constated by reported data.

The obtained compounds will be evaluated as antifouling additives in marine paints.