Highly regioselective 4-hydroxy-1-methylpiperidine mediated aromatic nucleophilic substitution on a perfluorinated phthalimide core

[Display omitted] •1-Methyl-4-hydroxypiperidine mediated highly regioselective SNAr protocol was developed.•The inherent regioselectivities were modified towards the less favoured bioactive regioisomer.•The optimal condition could be utilized for gram scale synthesis. A tertiary amine-mediated highly regioselective aromatic nucleophilic substitution (SNAr) protocol was developed in the assemblies of perfluorinated phtalimide with primary or secondary amines as inputs. Application of 1-methyl-4-hydroxypiperidine as additive, formation of the less favoured, bioactive regioisomer was facilitated, modifying their ratios from the initial 8–36% to 81–91%. After optimization, a facile gram scale syntheses were accomplished and isolated the desired analogues in up to 63% yield.