Amidation of Quinolin-2-yl Esters: Base‑, Catalyst‑, Metal‑, and Solvent-Free Conditions

An operationally simple yet efficient protocol is developed for the direct amidation of quinolin-2-yl esters under base-, metal-catalyst-, and solvent-free conditions. A simple heating of the ester with amine at 100 °C forms the product, amide, within 5 min to 10 h in 61-97% yield. The scope of both amine and ester substrates was explored (in total, 43 substrates). A broad range of alkyl amines, including amino acids (unprotected), anilines with electron-donating/withdrawing groups, and bulky groups (isopropyl), were found to be competent substrates. The practical utility of the method was demonstrated with the synthesis of the drug molecule moclobemide and two natural products, piperlotine A and piperlotine C. A comparative amidation study was conducted to find a possible factor for the high reactivity of quinolin-2-yl esters. The findings presented above reveal that the quinolin-2-yl ester scaffold can be exploited for the synthesis of amides and peptides under environmentally benign conditions.