Abstract
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.
Highlights
The amide group is one of the most ubiquitous functional groups found in Nature
The traditional method of facile amide bond synthesis has been the coupling of reactive acid derivatives, such as acid chlorides or anhydrides, with amines, but these methods are poorly tolerated by other nucleophilic functional groups and generate waste
These considerations led us to explore the possibility of a lowtemperature amide synthesis pathway via the acceptorless dehydrogenative coupling.[10]
Summary
The amide group is one of the most ubiquitous functional groups found in Nature. The formation of the amide bond is a fundamental reaction with important utility in the synthesis of natural compounds, biologically active pharmaceutical drugs, short-chain peptides, industrial chemicals, and polymers such as nylons as well as in devising liquid organic hydrogen carrier systems.[1]. The high reaction temperature required for dehydrogenative amide bond formation is presumably due to the difficulty in the hydride abstraction from the reactant and the hemiaminal intermediate by the employed catalysts, en route to the Received: February 15, 2021 Revised: May 10, 2021 Published: June 7, 2021. The overall formation of amide and H2 from alcohol and amine is generally thermodynamically uphill, contributing toward the high required temperature for amide synthesis.
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