meso-2,3-dibromosuccinic acid as a temperature-dependent catalyst for the selective synthesis of syn and anti-highly functionalized tetrahydropyridines: experimental and theoretical study

This study reports the flexible synthesis of syn-anti isomers of highly functionalized tetrahydropyridines under controlled temperature conditions. The present catalytic system employs cost-effective meso-2,3-dibromosuccinic acid in a one-pot, multicomponent process involving both aromatic aldehydes, anilines, and 1,3-dicarbonyl compounds to produce a structurally diverse tetrahydropyridines. The current catalyst, meso-2,3-dibromosuccinic acid, demonstrates a unique capability for selective synthesis of syn:anti tetrahydropyridine isomers. Unlike other reported catalysts, it enables exclusive formation of the syn isomer at low temperatures (5 °C) and allows tunable syn:anti ratios at moderate temperatures (25 °C). Moreover, at 65 °C, meso-2,3-dibromosuccinic acid exclusively yields the anti isomer highlighting its distinct advantage in controlling product selectivity. Other notable features of this method include simple work-up procedure, the absence of transition metal catalysts, high structural diversity of the products, and excellent product yields. Thermodynamics, kinetics, aromaticity, frontier orbitals, and ¹H NMR in gas, ethanol, and chloroform phase at different temperature are studied using density functional theory. According to the thermodynamics, aromaticity and energy gap results the anti isomer is more stable than syn one, but the latter have lower activation energy than the former, therefore, the rate constant of formation of syn isomer is several times of anti form at low temperatures.