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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.

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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.

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  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)

    Article  CAS  ADS  Google Scholar 

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

    Article  ADS  Google Scholar 

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

    Article  CAS  ADS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  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)

    Article  CAS  Google Scholar 

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

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  ADS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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. 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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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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.

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Authors and Affiliations



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.

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Correspondence to Peng Liu or Guangbin Dong.

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The authors declare no competing financial interests.

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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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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)

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

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