Near-Ambient-Temperature Dehydrogenative Synthesis of the Amide Bond: Mechanistic Insight and Applications

The current existing
methods for the amide bond synthesis via acceptorless
dehydrogenative coupling of amines and
alcohols all require high reaction temperatures for effective catalysis,
typically involving reflux in toluene, limiting their potential practical
applications. Herein, we report a system for this reaction that proceeds
under mild conditions (reflux in diethyl ether, boiling point 34.6
°C) using ruthenium PNNH complexes. The low-temperature activity
stems from the ability of Ru–PNNH complexes to activate alcohol
and hemiaminals at near-ambient temperatures through the assistance
of the terminal N–H proton. Mechanistic studies reveal the
presence of an unexpected aldehyde-bound ruthenium species during
the reaction, which is also the catalytic resting state. We further
utilize the low-temperature activity to synthesize several simple
amide bond-containing commercially available pharmaceutical drugs
from the corresponding amines and alcohols via the
dehydrogenative coupling method.