Abstract An alternative and general one‐pot synthesis of a library of novel imidazol‐2‐yl‐1 H ‐quinolin‐2‐one derivatives was performed in 70 % aqueous acetic acid by the direct reaction of 2‐chloroquinolin‐3‐carbaldehyde with aromatic o ‐diamines. Experiments showed that adding Amberlyst ® ‐15 (20 % w/w) to the reaction media increased both the speed of reaction as well as the yield of products. Both DFT theoretical calculations and X‐ray diffraction studies confirmed the proposed structures and the more stable conformation of the obtained products. Antitumor studies against sixty different cancer cell lines showed the potential of these kinds of compounds.