Copper-catalyzed C-alkylation of secondary alcohols and methyl ketones with alcohols employing the aerobic relay race methodology.

By employing aerobic oxidation to aldehydes as a more effective alcohol activation strategy, ligand-free copper catalysts were found to be superior catalysts than other metals in aerobic dehydrative ß-alkylation of secondary alcohols and α-alkylation of methyl ketones using alcohols as the green alkylating reagents. Based on our mechanistic studies and also supported by the literature, we deduce that the newly-proposed relay race process rather than the conventional borrowing hydrogen-type mechanisms should be the most possible and a more rational mechanism for the aerobic C-alkylation reactions.

Discovery and mechanistic studies of a general air-promoted metal-catalyzed aerobic N-alkylation reaction of amides and amines with alcohols.

The thermodynamically unfavorable anaerobic dehydrogenative alcohol activation to aldehydes and hydridometal species is found to be the bottleneck in metal-catalyzed N-alkylations due to a general and unnoticed catalyst deactivation by amines/amides. Thus, different from the anaerobic dehydrogenation process in borrowing hydrogen or hydrogen autotransfer reactions that require noble metal complexes or addition of capricious ligands for catalyst activation, the water-producing, exothermic, metal-catalyzed aerobic alcohol oxidation is thermodynamically more favorable and the most effective and advantageous aldehyde generation protocol. This leads to a general and advantageous air-promoted metal-catalyzed aerobic N-alkylation methodology that effectively uses many simpler, less expensive, more available, and ligand-free metal catalysts that were inactive under typical anaerobic borrowing hydrogen conditions, avoiding the use of preformed metal complexes and activating ligands and the exclusive requirement of inert atmosphere protection. This aerobic method is quite general in substrate scope and tolerates various amides, amines, and alcohols, revealing its potentially broad utilities and interests in academy and industry. In contrast to the commonly accepted borrowing hydrogen mechanism, based on a thorough mechanistic study and supported by the related literature background, a new mechanism analogous to the relay race game that has never been proposed in metal-catalyzed N-alkylation reactions is presented.