Copper-catalyzed Aerobic Oxidative Synthesis Of α-ketoamides From Methyl Ketones, Amines And NIS

The-ketoamides are natural products possessing biological activity. They arealso important intermediates in organic synthesis. Because of its unique pharmacuticaland physiological activity, α-ketoamides attract great interest to organic chemists andmedicinal chemists. In view of the importance of the α-ketoamides, quite a lot ofsynthetic methods has been developed.We have developed a simple, convenient and efficient method toward thesynthesis of-ketoamides. In the presence of copper catalyst, the simple methylketone reacted with amine and NIS in the air, affording a series of α-ketoamides. Thisprotocol avoided the use of expensive catalyst and harsh conditions generally adoptedin the conventional method, and could be conducted in gram scale. The optimizedreaction conditions were as follows:2.2equivalents of amine,1.2equivalents of NIS,toluene as the solvent, at room temperature and in the open air. It was found that,when acetophenone substituents are electron-withdrawing groups, the yields arehigher. While the yields decrease slightly when the substituents on the aryl rings areelectron-donating groups. The heterocyclic substrates also gave satisfactory results,but with relatively lower yields. The scope of amine component was also examined.Both the primary and secondary amines were efficient for the reaction. The yields ofthe secondary amines are higher, the corresponding yields decreased for the primaryamines. Reactions with primary amines produced-ketoamides and amideby-products. Copper-catalyzed aerobic oxidation mechanism for the formation ofα-ketoamides was proposed. The reaction features inexpensive catalyst, readilyavailable starting materials, mild conditions (room temperature), the use of air as themolecular oxygen source (not oxygen balloon).