Synthesis of aliphatic α-ketoamides from α-substituted methyl ketones via a Cu-catalyzed aerobic oxidative amidation

alpha-Ketoamides are an important key functional group and have been used as versatile and valuable intermediates and synthons in a variety of functional group transformations. Synthetic methods for making aryl alpha-ketoamides as drug candidates have been greatly improved through metal-catalyzed aerobic oxidative amidations. However, the preparation of alkyl alpha-ketoamides through metal-catalyzed aerobic oxidative amidations has not been reported because generating alpha-ketoamides from aliphatic ketones with two alpha-carbons theoretically provides two distinct alpha-ketoamides. Our strategy is to activate the alpha-carbon by introducing an N-substituent at one of the two alpha-positions. The key to this strategy is how heterocyclic compounds such as triazoles and imidazoles affect the selectivity of the synthesis of the alkyl alpha-ketoamides. From this basic concept, and by optimizing the reaction and elucidating the mechanism of the synthesis of aryl alpha-ketoamides via a copper-catalyzed aerobic oxidative amidation, we prepared fourteen aliphatic alpha-ketoamides in high yields (48-84%).