biostudies-literatureKar SEuropean Research Council7383-7393https://www.ebi.ac.uk/biostudies/studies/S-EPMC8218306biostudies-literatureUnknown11(12)The current existing methods for the amide bond synthesis <i>via</i> 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 <i>via</i> the dehydrogenative coupling method.ACS catalysisNear-Ambient-Temperature Dehydrogenative Synthesis of the Amide Bond: Mechanistic Insight and Applications.PMC8218306692775ERC AdG 692775Kar SBen-David YXie YZhou QQDiskin-Posner YMilstein DfalseNear-Ambient-Temperature Dehydrogenative Synthesis of the Amide Bond: Mechanistic Insight and Applications.The current existing methods for the amide bond synthesis <i>via</i> 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 <i>via</i> the dehydrogenative coupling method.2021-01-01T00:00:00Z2021 Jun2024-11-08T22:42:55.214Z2022-02-10T16:15:30.831ZS-EPMC82183063416890310.1021/acscatal.1c00728