Discovery and Mechanistic Studies of a General Air-Promoted Metal-Catalyzed Aerobic N-Alkylation Reaction of Amides and Amines with Alcohols

Abstract

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.

Homogeneous, Heterogeneous and Nanocatalysis

“…The same group also reported findings in the area of air-promoted metal-catalyzed aerobic N-alkylation. 58 Their method is rather general in catalyst and substrate scope and uses many simpler, cheaper, readily available ligand-free metal catalysts and a wide range of amines, amides and alcohols which behave with respect to activities more effectively than those under conventional anaerobic conditions. Although a few N-alkylation reactions have been carried out under aerobic conditions and found to be more efficient than the anaerobic reactions, the role played by air in such reactions remains to be fully elucidated.…”

Comparative Assessment of DFT Performances in Ru- and Rh-Promoted σ-Bond Activations

“…This process is considered to be crucial in the aerobic N-alkylation reactions of amides and amines with alcohols. 62,63 Density functional theory (DFT) has achieved significant success in the field of transition metal chemistry. 64−74 Due to the wide occurrence of Ru-and Rh-catalyzed reactions, more accurate DFT treatment and modeling are highly desirable.…”

Oxidation and Reduction

“…The method was general in substrate scope and tolerated various amides, amines, and alcohols. 266 The oxidation of primary alkyl aryl sulfones by O 2 in THF resulted in formation of the corresponding carboxylic acids in fair to excellent yield in the presence of a base used for double deprotonation of the sulfones. The method was used for the convenient synthesis of 13 C-labelled carboxylic acids.…”