Experimental and Theoretical Studies on Tetrahydropyridine Derivatives: Synthesis, Spectroscopic, SC‐XRD, Hirshfeld, DFT, ELF, LOL, ADMET, and Molecular Docking Studies

ABSTRACT Herein, we report the synthesis of methyl 4‐(2‐chloroacetoyloxy)‐1‐(2‐chloroacetyl)‐1,2,5,6‐tetrahydro‐2,6‐diphenylpyridine‐3‐carboxylate ( 3a ) and ethyl 4‐(2‐chloroacetoyloxy)‐1‐(2‐chloroacetyl)‐1,2,5,6‐tetrahydro‐2,6‐diphenylpyridine‐3‐carboxylate ( 3b ) from one‐pot multicomponent Mannich reaction followed by chloroacetylation. 1 H NMR and 13 C NMR were employed for preliminary structural characterization of the synthesized compounds. Further, single‐crystal x‐ray diffraction (SC‐XRD) analysis revealed that the heterocyclic tetrahydropyridine ring was found to be in boat form, with equatorial orientation of two phenyl rings at C‐2 and C‐6. The asymmetric units of both crystals are stabilized by the short contact of several C‐H···O interactions, and further, these interactions are evaluated by Hirshfeld surface analysis. To get a deeper understanding of the electronic properties of title compounds, density functional theory (DFT), electron localization function (ELF), and localized orbital locator (LOL) studies were employed to describe the electronic properties. The predicted HOMO—LUMO energy gaps for these compounds are calculated to be 3.06 and 3.01 eV, respectively, which favor charge transfer and indicate chemical reactivity. The physiochemical properties and molecular docking study were employed between the ligands 3a and 3b with EGFR and VEGFR kinase inhibitors. The study demonstrates that strong hydrogen bonding and hydrophobic interaction fall within the active site of macromolecule receptors.