Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Conversion of amides to esters by the nickel-catalysed activation of amide C–N bonds


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Amide-bond cleavage using transition-metal catalysis.
Figure 2: Experimental and computational study of amide-bond activation during the conversion of benzamides 7 to methyl benzoate 8a.
Figure 3: Scope of our methodology.
Figure 4: Computational study of catalytic cycle.
Figure 5: Selective amide-bond cleavage processes.


  1. Greenberg, A., Breneman, C. M. & Liebman, J. F. (eds) The Amide Linkage: Structural Significance in Chemistry, Biochemistry, and Materials Science (Wiley, 2003)

    Google Scholar 

  2. Pauling, L., Corey, R. B. & Branson, H. R. The structure of proteins: two hydrogen-bonded helical configurations of the polypeptide chain. Proc. Natl Acad. Sci. USA 37, 205–211 (1951)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  3. Brix, K. & Stöcker, W. (eds) Proteases: Structure and Function (Springer, 2013)

    Book  Google Scholar 

  4. Corey, E. J. & Cheng, X.-M. The Logic of Chemical Synthesis (Wiley, 1995)

    Google Scholar 

  5. Hudlicky, T. & Reed, J. W. The Way of Synthesis: Evolution of Design and Methods for Natural Products (Wiley, 2007)

    Google Scholar 

  6. Van Vranken, D. L. &. Weiss. G. A. Introduction to Bioorganic Chemistry and Chemical Biology (Garland Science, 2013)

    Google Scholar 

  7. Spletstoser, J. T., White, J. M., Tunoori, A. R. & Georg, G. I. Mild and selective hydrozirconation of amides to aldehydes using Cp2Zr(H)Cl: scope and mechanistic insight. J. Am. Chem. Soc. 129, 3408–3419 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nahm, S. & Weinreb, S. M. N-methoxy-N-methylamides as effective acylating agents. Tetrahedron Lett. 22, 3815–3818 (1981)

    Article  CAS  Google Scholar 

  9. Blangetti, M., Rosso, H., Prandi, C., Deagostino, A. & Venturello, P. Suzuki–Miyaura cross-coupling in acylation reactions, scope and recent developments. Molecules 18, 1188–1213 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tatamidani, H., Kakiuchi, F. & Chatani, N. A new ketone synthesis by palladium-catalyzed cross-coupling reactions of esters with organoboron compounds. Org. Lett. 6, 3597–3599 (2004)

    Article  CAS  PubMed  Google Scholar 

  11. Dineen, T. A., Zajac, M. A. & Myers, A. G. Efficient transamidation of primary carboxamides by in situ activation with N,N-dialkylformamide dimethyl acetals. J. Am. Chem. Soc. 128, 16406–16409 (2006)

    Article  CAS  PubMed  Google Scholar 

  12. Stephenson, N. A., Zhu, J., Gellman, S. H. & Stahl, S. S. Catalytic transamidation reactions compatible with tertiary amide metathesis under ambient conditions. J. Am. Chem. Soc. 131, 10003–10008 (2009)

    Article  CAS  PubMed  Google Scholar 

  13. Keck, G. E., McLaws, M. D. & Wager, T. T. A direct and mild conversion of tertiary aryl amides to methyl esters using trimethyloxonium tetrafluoroborate: a very useful complement to directed metalation reactions. Tetrahedron 56, 9875–9883 (2000)

    Article  CAS  Google Scholar 

  14. Nishimoto, S.-i., Izukawa, T. & Kagiya, T. Photo-induced ring-opening reactions of 1-(2-naphthoyl)aziridine in various solvents. Bull. Chem. Soc. Jpn 55, 1484–1488 (1982)

    Article  CAS  Google Scholar 

  15. White, E. H. The chemistry of N-alkyl-N-nitrosoamides. II. A new method for the deamination of aliphatic amines. J. Am. Chem. Soc. 77, 6011–6014 (1955)

    Article  CAS  Google Scholar 

  16. Guthrie, J. P., Pike, D. C. & Lee, Y.-C. Equilibrium constants and heats of formation of methyl esters and N,N-dimethyl amides of substituted benzoic acids. Can. J. Chem. 70, 1671–1683 (1992)

    Article  CAS  Google Scholar 

  17. Tasker, S. Z., Standley, E. A. & Jamison, T. F. Recent advances in homogeneous nickel catalysis. Nature 509, 299–309 (2014)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mesganaw, T. & Garg, N. K. Ni- and Fe-catalyzed cross-coupling reactions of phenol derivatives. Org. Process Res. Dev. 17, 29–39 (2013)

    Article  CAS  Google Scholar 

  19. Rosen, B. M. et al. Nickel-catalyzed cross-couplings involving carbon–oxygen bonds. Chem. Rev. 111, 1346–1416 (2011)

    Article  CAS  PubMed  Google Scholar 

  20. Blakey, S. B. & MacMillan, D. W. C. The first Suzuki cross-couplings of aryltrimethylammonium salts. J. Am. Chem. Soc. 125, 6046–6047 (2003)

    Article  CAS  PubMed  Google Scholar 

  21. Zhang, X.-Q. & Wang, Z.-X. Nickel-catalyzed cross-coupling of aryltrimethylammonium triflates and amines. Org. Biomol. Chem. 12, 1448–1453 (2014)

    Article  CAS  PubMed  Google Scholar 

  22. Tobisu, M., Nakamura, K. & Chatani, N. Nickel-catalyzed reductive and borylative cleavage of aromatic carbon–nitrogen bonds in N-aryl amides and carbamates. J. Am. Chem. Soc. 136, 5587–5590 (2014)

    Article  CAS  PubMed  Google Scholar 

  23. Shiba, T., Kurahashi, T. & Matsubara, S. Nickel-catalyzed decarbonylative alkylidenation of phthalimides with trimethylsilyl-substituted alkynes. J. Am. Chem. Soc. 135, 13636–13639 (2013)

    Article  CAS  PubMed  Google Scholar 

  24. Quasdorf, K. W. et al. Suzuki–Miyaura cross-coupling of aryl carbamates and sulfamates: experimental and computational studies. J. Am. Chem. Soc. 133, 6352–6363 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mesganaw, T. et al. Nickel-catalyzed amination of aryl carbamates and sequential site-selective cross-couplings. Chem. Sci. 2, 1766–1771 (2011)

    Article  CAS  PubMed  Google Scholar 

  26. Hong, X., Liang, Y. & Houk, K. N. Mechanisms and origins of switchable chemoselectivity of Ni-catalyzed C(aryl)–O and C(acyl)–O activation of aryl esters with phosphine ligands. J. Am. Chem. Soc. 136, 2017–2025 (2014)

    Article  CAS  PubMed  Google Scholar 

  27. Lu, Q., Yu, H. & Fu, Y. Mechanistic study of chemoselectivity in Ni-catalyzed coupling reactions between azoles and aryl carboxylates. J. Am. Chem. Soc. 136, 8252–8260 (2014)

    Article  CAS  PubMed  Google Scholar 

  28. Xu, H. et al. Key mechanistic features of Ni-catalyzed C–H/C–O biaryl coupling of azoles and naphthalene-2-yl pivalates. J. Am. Chem. Soc. 136, 14834–14844 (2014)

    Article  CAS  PubMed  Google Scholar 

  29. Yamamoto, T., Ishizu, J., Kohara, T., Komiya, S. & Yamamoto, A. Oxidative addition of aryl carboxylates to nickel(0) complexes involving cleavage of the acyl–oxygen bond. J. Am. Chem. Soc. 102, 3758–3764 (1980)

    Article  CAS  Google Scholar 

  30. Amaike, K., Muto, K., Yamaguchi, J. & Itami, K. Decarbonylative C–H coupling of azoles and aryl esters: unprecedented nickel catalysis and application to the synthesis of muscoride A. J. Am. Chem. Soc. 134, 13573–13576 (2012)

    Article  CAS  PubMed  Google Scholar 

Download references


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).

Author information

Authors and Affiliations



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.

Corresponding authors

Correspondence to K. N. Houk or Neil K. Garg.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data – see Table of Contents for details. (PDF 15394 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing