Letter | Published:

Catalytic activation of carbon–carbon bonds in cyclopentanones

Nature volume 539, pages 546550 (24 November 2016) | Download Citation

Abstract

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.

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References

  1. 1.

    , , & Activation of a carbon–carbon bond in solution by transition-metal-insertion. Nature 364, 699–701 (1993)

  2. 2.

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

  3. 3.

    , & Selective activation of carbon−carbon bonds next to a carbonyl group. Nature 370, 540–541 (1994)

  4. 4.

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

  5. 5.

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

  6. 6.

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

  7. 7.

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

  8. 8.

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

  9. 9.

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

  10. 10.

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

  11. 11.

    , , & Cyclobutanes in catalysis. Angew. Chem. Int. Ed. 50, 7740–7752 (2011)

  12. 12.

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

  13. 13.

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

  14. 14.

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

  15. 15.

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

  16. 16.

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

  17. 17.

    , , , & Csp3–Csp3 and Csp3–H bond activation of 1,1-disubstituted cyclopentane. J. Am. Chem. Soc. 134, 19580–19583 (2012)

  18. 18.

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

  19. 19.

    , , & 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)

  20. 20.

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

  21. 21.

    , , & Total synthesis of (+)-erogorgiaene using lithiationborylation methodology, and stereoselective synthesis of each of its diastereoisomers. J. Am. Chem. Soc. 133, 16798–16801 (2011)

  22. 22.

    & 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)

  23. 23.

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

  24. 24.

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

  25. 25.

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

  26. 26.

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

  27. 27.

    , & 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)

  28. 28.

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

  29. 29.

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

  30. 30.

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

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Acknowledgements

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

Affiliations

  1. Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, USA

    • Ying Xia
    •  & Guangbin Dong
  2. Department of Chemistry, University of Chicago, Chicago, Illinois 60637, USA

    • Ying Xia
    •  & Guangbin Dong
  3. Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA

    • Gang Lu
    •  & Peng Liu

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Peng Liu or Guangbin Dong.

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

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    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).

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DOI

https://doi.org/10.1038/nature19849

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