Abstract
Amides are common functional groups that have been studied for more than a century1. They are the key building blocks of proteins and are present in a broad range of other natural and synthetic compounds. Amides are known to be poor electrophiles, which is typically attributed to the resonance stability of the amide bond1,2. Although amides can readily be cleaved by enzymes such as proteases3, it is difficult to selectively break the carbon–nitrogen bond of an amide using synthetic chemistry. Here we demonstrate that amide carbon–nitrogen bonds can be activated and cleaved using nickel catalysts. We use this methodology to convert amides to esters, which is a challenging and underdeveloped transformation. The reaction methodology proceeds under exceptionally mild reaction conditions, and avoids the use of a large excess of an alcohol nucleophile. Density functional theory calculations provide insight into the thermodynamics and catalytic cycle of the amide-to-ester transformation. Our results provide a way to harness amide functional groups as synthetic building blocks and are expected to lead to the further use of amides in the construction of carbon–heteroatom or carbon–carbon bonds using non-precious-metal catalysis.
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Acknowledgements
We are grateful to Boehringer Ingelheim, DuPont, Bristol-Myers Squibb, the Camille and Henry Dreyfus Foundation, the A. P. Sloan Foundation, the S. T. Li Foundation, the University of California, Los Angeles (UCLA), and the NIH-NIGMS (grant number GM036700 to K.N.H.) for financial support. We are grateful to the NIH (grant number F31 GM101951-02 to N.F.F.N.), the NSF (grant number DGE-1144087 to E.L.B.), the Foote Family (L.H., T.K.S. and X.H.), and the ACS Division of Organic Chemistry (L.H.) for fellowship support. Computations were performed with resources made available by the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the NSF (grant number OCI-1053575), as well as the UCLA Institute of Digital Research and Education (IDRE). This work was also supported by shared instrumentation grants from the NSF (grant number CHE-1048804) and the National Center for Research Resources (grant number S10RR025631).
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L.H., N.F.F.N., T.K.S., and E.L.B. designed and performed the experiments and analysed the experimental data; X.H., Y.-F.Y., and P.L. designed the computational studies and performed the analysis; K.N.H. and N.K.G. conceived and directed the investigations, and prepared the manuscript with contributions from all authors; all authors contributed to discussions.
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Hie, L., Fine Nathel, N., Shah, T. et al. Conversion of amides to esters by the nickel-catalysed activation of amide C–N bonds. Nature 524, 79–83 (2015). https://doi.org/10.1038/nature14615
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DOI: https://doi.org/10.1038/nature14615
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