AlCl ₃ Catalyzed Groebke–Blackburn–Bienaymé Reaction for the Synthesis of Imidazo[1,2‐ <i>b</i> ]Isoquinolin‐3‐amine Derivatives: Design, Synthesis, and Selective COX‐II Inhibitors

Abstract The synthesis of imidazo[1,2‐ b ]isoquinolin‐3‐amine derivatives was accomplished by an AlCl 3 ‐catalyzed Groebke–Blackburn–Bienaymé (GBB) reaction, showing a direct and effective method for producing diverse heterocycles. A library of compounds (4a–4j) was synthesized by a multicomponent reaction involving isoquinolin‐3‐amine, aromatic aldehydes, and tert ‐butyl isocyanide in methanol at mild reaction conditions. The catalytic effects of different Lewis and Brønsted acids were analysed, with AlCl 3 proving to be the most efficient, with yields of up to 84%. Structural characterization was carried out by various spectroscopic methods (IR, NMR, and MS). The synthesized compounds were evaluated for their cyclooxygenase (COX) inhibitory activity, with compound 4a (4‐F) exhibiting the highest COX‐II selectivity (IC 50 = 1.14 ± 1.01 µM, SI = 15.0), followed by compound 4i (3‐Br, 5‐Cl) with an IC 50 of 1.01 ± 0.12 µM and SI = 13.2, surpassing celecoxib. Molecular modeling studies validated the binding interactions inside the COX‐I and COX‐II active sites, reinforcing their potential as anti‐inflammatory drugs.