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.

Catalytic activation of carbon–carbon bonds in cyclopentanones


In the chemical industry, molecules of interest are based primarily on carbon skeletons. When synthesizing such molecules, the activation of carbon–carbon single bonds (C–C bonds) in simple substrates is strategically important: it offers a way of disconnecting such inert bonds, forming more active linkages (for example, between carbon and a transition metal) and eventually producing more versatile scaffolds1,2,3,4,5,6,7,8,9,10,11,12,13. The challenge in achieving such activation is the kinetic inertness of C–C bonds and the relative weakness of newly formed carbon–metal bonds6,14. The most common tactic starts with a three- or four-membered carbon-ring system9,10,11,12,13, in which strain release provides a crucial thermodynamic driving force. However, broadly useful methods that are based on catalytic activation of unstrained C–C bonds have proven elusive, because the cleavage process is much less energetically favourable. Here we report a general approach to the catalytic activation of C–C bonds in simple cyclopentanones and some cyclohexanones. The key to our success is the combination of a rhodium pre-catalyst, an N-heterocyclic carbene ligand and an amino-pyridine co-catalyst. When an aryl group is present in the C3 position of cyclopentanone, the less strained C–C bond can be activated; this is followed by activation of a carbon–hydrogen bond in the aryl group, leading to efficient synthesis of functionalized α-tetralones—a common structural motif and versatile building block in organic synthesis. Furthermore, this method can substantially enhance the efficiency of the enantioselective synthesis of some natural products of terpenoids. Density functional theory calculations reveal a mechanism involving an intriguing rhodium-bridged bicyclic intermediate.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Activation of C–C bonds in ring systems.
Figure 2: Substrate scope.
Figure 3: Gram-scale synthesis and synthetic applications.
Figure 4: DFT-computed pathways for the activation of C–C bonds in cyclopentanones.


  1. 1

    Gozin, M., Weisman, A., Ben-David, Y. & Milstein, D. Activation of a carbon–carbon bond in solution by transition-metal-insertion. Nature 364, 699–701 (1993)

    CAS  ADS  Article  Google Scholar 

  2. 2

    Jones, W. D. The fall of the C–C bond. Nature 364, 676–677 (1993)

    ADS  Article  Google Scholar 

  3. 3

    Murakami, M., Amii, H. & Ito, Y. Selective activation of carbon−carbon bonds next to a carbonyl group. Nature 370, 540–541 (1994)

    CAS  ADS  Article  Google Scholar 

  4. 4

    Rybtchinski, B. & Milstein, D. Metal insertion into C–C bonds in solution. Angew. Chem. Int. Ed. 38, 870–883 (1999)

    Article  Google Scholar 

  5. 5

    Murakami, M. & Ito, Y. Cleavage of carbon−carbon single bonds by transition metals. Top. Organomet. Chem. 3, 97–129 (1999)

    CAS  Article  Google Scholar 

  6. 6

    Jun, C.-H. Transition metal-catalyzed carbon–carbon bond activation. Chem. Soc. Rev. 33, 610–618 (2004)

    CAS  Article  Google Scholar 

  7. 7

    Miura, M. & Satoh, T. Catalytic processes involving β-carbon elimination. Top. Organomet. Chem. 14, 1–20 (2005)

    Article  Google Scholar 

  8. 8

    Park, Y. J., Park, J.-W. & Jun, C.-H. Metal–organic cooperative catalysis in C–H and C–C bond activation and its concurrent recovery. Acc. Chem. Res. 41, 222–234 (2008)

    CAS  Article  Google Scholar 

  9. 9

    Dong, G. (ed.) C–C bond activation Vol. 346 of Topics in Current Chemistry (Springer, 2014)

  10. 10

    Souillart, L. & Cramer, N. Catalytic C–C bond activations via oxidative addition to transition metals. Chem. Rev. 115, 9410–9464 (2015)

    CAS  Article  Google Scholar 

  11. 11

    Seiser, T., Saget, T., Tran, D. N. & Cramer, N. Cyclobutanes in catalysis. Angew. Chem. Int. Ed. 50, 7740–7752 (2011)

    CAS  Article  Google Scholar 

  12. 12

    Mack, D. J. & Njardarson, J. T. Recent advances in the metal-catalyzed ring expansions of three- and four-membered rings. ACS Catal. 3, 272–286 (2013)

    CAS  Article  Google Scholar 

  13. 13

    Masarwa, A. et al. Merging allylic carbon–hydrogen and selective carbon–carbon bond activation. Nature 505, 199–203 (2014)

    CAS  ADS  Article  Google Scholar 

  14. 14

    Halpern, J. Determination and significance of transition-metal-alkyl bond dissociation energies. Acc. Chem. Res. 15, 238–244 (1982)

    CAS  Article  Google Scholar 

  15. 15

    Jun, C.-H., Lee, H. & Lim, S.-G. The C–C bond activation and skeletal rearrangement of cycloalkanone imine by Rh(I) catalysts. J. Am. Chem. Soc. 123, 751–752 (2001)

    CAS  Article  Google Scholar 

  16. 16

    Zeng, R. & Dong, G. Rh-catalyzed decarbonylative coupling with alkynes via C–C activation of isatins. J. Am. Chem. Soc. 137, 1408–1411 (2015)

    CAS  Article  Google Scholar 

  17. 17

    Mukai, C., Ohta, Y., Oura, Y., Kawaguchi, Y. & Inagaki, F. Csp3–Csp3 and Csp3–H bond activation of 1,1-disubstituted cyclopentane. J. Am. Chem. Soc. 134, 19580–19583 (2012)

    CAS  Article  Google Scholar 

  18. 18

    Li, G., Arisawa, M. & Yamaguchi, M. Rhodium-catalyzed synthesis of unsymmetrical di(aryl/heteroaryl)methanes using aryl/heteroarylmethyl ketones via CO–C bond cleavage. Chem. Commun. 50, 4328–4330 (2014)

    CAS  Article  Google Scholar 

  19. 19

    Albrecht, M., Gossage, R. A., Spek, A. L. & van Koten, G. Metal-mediated C–C bond making and breaking: first direct evidence for a reversible migration of a benzyl group along a metal-carbon bond. J. Am. Chem. Soc. 121, 11898–11899 (1999)

    CAS  Article  Google Scholar 

  20. 20

    Davies, H. M. L. & Walji, A. M. Direct synthesis of (+)-erogorgiaene through a kinetic enantiodifferentiating step. Angew. Chem. Int. Ed. 44, 1733–1735 (2005)

    CAS  Article  Google Scholar 

  21. 21

    Elford, T. G., Nave, S., Sonawane, R. P. & Aggarwal, V. K. Total synthesis of (+)-erogorgiaene using lithiationborylation methodology, and stereoselective synthesis of each of its diastereoisomers. J. Am. Chem. Soc. 133, 16798–16801 (2011)

    CAS  Article  Google Scholar 

  22. 22

    Chavan, S. P. & Khatod, H. S. Enantioselective synthesis of the essential oil and pheromonal component ar-himachalene by a chiral pool and chirality induction approach. Tetrahedron Asymmetry 23, 1410–1415 (2012)

    CAS  Article  Google Scholar 

  23. 23

    Mukherjee, P. & Sarkar, T. K. Heteroatom-directed Wacker oxidations. A protection-free synthesis of (−)-heliophenanthrone. Org. Biomol. Chem. 10, 3060–3065 (2012)

    CAS  Article  Google Scholar 

  24. 24

    Hayashi, T. & Yamasaki, K. Rhodium-catalyzed asymmetric 1,4-addition and its related asymmetric reactions. Chem. Rev. 103, 2829–2844 (2003)

    CAS  Article  Google Scholar 

  25. 25

    Lapointe, D. & Fagnou, K. Overview of the mechanistic work on the concerted metallation deprotonation pathway. Chem. Lett. 39, 1118–1126 (2010)

    Article  Google Scholar 

  26. 26

    Matsuda, T., Shigeno, M. & Murakami, M. Asymmetric synthesis of 3,4-dihydrocoumarins by rhodium-catalyzed reaction of 3-(2-hydroxyphenyl)cyclobutenones. J. Am. Chem. Soc. 129, 12086–12087 (2007)

    CAS  Article  Google Scholar 

  27. 27

    Seiser, T., Roth, O. A. & Cramer, N. Enantioselective synthesis of indanols from tert-cyclobutanols using a rhodium-catalyzed C–C/C–H activation sequence. Angew. Chem. Int. Ed. 48, 6320–6323 (2009)

    CAS  Article  Google Scholar 

  28. 28

    Shigeno, M., Yamamoto, T. & Murakami, M. Stereoselective restructuring of 3-arylcyclobutanols into 1-indanols by sequential breaking and formation of carbon–carbon bonds. Chem. Eur. J. 15, 12929–12931 (2009)

    CAS  Article  Google Scholar 

  29. 29

    Matsuda, T., Suda, Y. & Takahashi, A. Double 1,4-rhodium migration cascade in rhodium-catalysed arylative ring-opening/spirocyclisation of (3-arylcyclobutylidene)acetates. Chem. Commun. 48, 2988–2990 (2012)

    CAS  Article  Google Scholar 

  30. 30

    Matsuda, T. & Yuihara, I. A rhodium(I)-catalysed formal intramolecular C–C/C–H bond metathesis. Chem. Commun. 51, 7393–7396 (2015)

    CAS  Article  Google Scholar 

Download references


This project was supported by the Cancer Prevention Research Institute of Texas (grant R1118), the National Institute of General Medical Science (grant R01GM109054) and the Welch Foundation (grant F1781). G.D. is a Searle Scholar and Sloan fellow. Y.X. acknowledges the International Postdoctoral Exchange Fellowship Program 2015 from the Office of China Postdoctoral Council (OCPC, document 38, 2015). We thank Johnson Matthey for a donation of Rh salts, and Chiral Technologies for donation of chiral high-performance liquid-chromatography columns. We are grateful to Y. Xu for providing 1,4-dioxane, F. Mo for providing some 3-aryl cyclopentanones, and H. Lim for checking the experimental procedures. DFT calculations were performed using supercomputer resources at the Center for Simulation and Modeling at the University of Pittsburgh, and the Extreme Science and Engineering Discovery Environment supported by the National Science Foundation.

Author information




Y.X. and G.D. conceived and designed the experiments. Y.X. performed the experiments. G.L. performed the DFT calculations. Y.X., G.L., P.L. and G.D. co-wrote the manuscript.

Corresponding authors

Correspondence to Peng Liu or Guangbin Dong.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Reviewer Information Nature thanks J. Harvey, M. Lautens and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data, Supplementary Tables 1-9, Supplementary Figures 1-18 and additional references (see Contents for more details). (PDF 35980 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Xia, Y., Lu, G., Liu, P. et al. Catalytic activation of carbon–carbon bonds in cyclopentanones. Nature 539, 546–550 (2016).

Download citation

Further reading


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