Synthesis and Anticancer Activity of Phosphinoylated and Phosphonoylated N-Heterocycles Obtained by the Microwave-Assisted Palladium Acetate‐Catalyzed Hirao Reaction

A literature survey showed that different derivatives with the 9‐phenyl‐9 H ‐carbazole or the dihydroindoline scaffold may be of biological activity including cytotoxic effect. Driven by this experience, P‐functionalized derivatives of these N ‐heterocycles were synthesized. Three N ‐heterocycles, 9‐(4‐bromophenyl)‐9 H ‐carbazole, 3‐bromo‐9‐phenyl‐9 H ‐carbazole and 1‐(5‐bromoindolin‐1‐yl)ethan‐1‐one, were coupled with dialkyl phosphites and diarylphosphine oxides using Pd(OAc) 2 (10 %) as the catalyst precursor and triethylamine as the base in ethanol under microwave irradiation. The excess of the Y 2 P(O)H reagent (Y=alkoxy, aryl) (30 %) served as the P‐ligand in its trivalent tautomeric form (Y 2 POH), hence there was no need for the usual P‐ligands meaning cost and environmental burden. Hence, the presented method is a “green” approach that proved to be more efficient than the preparation by the traditional method. The products, dialkyl phosphonates and tertiary phosphine oxides obtained in 58–84 % yields were characterized, one of them also by single crystal X‐ray analysis, and were subjected to in vitro biological activity evaluation. A (carbazol)yl‐phenylphosphonate, an N ‐phenyl‐(carbazol)yl‐phosphonate, a (carbazol)yl‐phenylphosphine oxide and an N ‐phenyl‐(carbazol)ylphosphine oxide revealed a significant cytotoxic activity on A549 human non‐small‐cell lung carcinoma and MonoMac‐6 acute monocytic leukemia cancer cells. The cytotoxic effect was significant as compared to that of the reference compounds.