Nature http://doi.org/6kb (2015)

Credit: © 2015 NPG

The canon of synthetic chemistry has it that amides are relatively unreactive. This is usually explained by invoking resonance stabilization in which the nitrogen lone pair is donated into the anti-bonding (π*) orbital of the carbonyl, reducing its electrophilicity. This stability means that substrates containing amides can often be carried through multistep syntheses without significant concern. The amide bond is also the key structural component of proteins and yet nature is able to break them with ease using enzymes. Now, a team led by Neil Garg from the University of California, Los Angeles have developed a nickel-catalysed procedure for the conversion of amides to esters.

In line with the known stability of amides, previous approaches to this type of transformation have required the use of harsh acidic or basic conditions and a large excess of alcohol nucleophile — often used as reaction solvent. And, although metal-catalysed activation of carbon–heteroatom bonds in other carbonyl compounds has been reported, activation of the C–N bond in amides has not. Building upon their prior work on the activation of strong aryl–heteroatom bonds, Garg and co-workers turned to nickel catalysis. They began their study by performing density functional theory calculations to determine both the free-energy change for the methanolysis of a variety of N-substituted benzamides, and also the activation barrier for oxidative addition of the amide to an N-heterocyclic carbene–nickel catalyst. The calculations suggested that methanolysis of N-methyl-N-phenylbenzamides would be favourable both thermodynamically and kinetically and this was borne out experimentally — with the reaction producing an excellent yield of ester using only a small excess of methanol at just 80 °C.

Garg and co-workers also showed that their reaction conditions were applicable to a variety of electron-rich aryl, electron-poor aryl and heteroaryl amides, and that complex and sterically hindered alcohols could be used as nucleophiles. As it stands, however, reactions with alkyl amides have not been successful — though this also presents an opportunity for the chemoselective reaction of one amide in the presence of another.