Skip to main content

Thank you for visiting nature.com. 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.

  • Article
  • Published:

Highly enantioselective trapping of zwitterionic intermediates by imines

This article has been updated

Abstract

Reactions with the unstable and highly reactive zwitterionic intermediates generated in processes catalysed by transition metals are providing new opportunities for molecular constructions. Insertion reactions involve the collapse of zwitterionic intermediates, but trapping them would allow structural elaborations that are not currently available. To synthesize complex molecules in this manner, reactive electrophiles can be used to trap the zwitterionic intermediates. Here, we describe the use of imines, activated by chiral organocatalysts, and a highly efficient integrated rhodium and chiral Brønsted acid co-catalysed process to trap zwitterionic intermediates that have been proposed previously to undergo a formal C–H insertion reaction, allowing us to obtain polyfunctionalized indole and oxindole derivatives in a single step with excellent diastereoselectivity and enantioselectivity.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Concept for trapping zwitterionic intermediates with imines.
Figure 2
Figure 3: Rationalization for the stereoselective control of the reactions.

Similar content being viewed by others

Change history

  • 14 August 2012

    In the version of this Article previously published online, in Table 3, Entry 1, the structure of compound 6b was missing a Br atom label. This has now been corrected in all versions of this Article.

References

  1. Dorwald, F. Z. (eds) Metal Carbenes in Organic Synthesis (Wiley-VCH, 2007).

    Google Scholar 

  2. Zhu, S.-F., Cai, Y., Mao, H.-X., Xie, J.-H. & Zhou, Q.-L. Enantioselective iron-catalysed O–H bond insertions. Nature Chem. 2, 546–551 (2010).

    Article  CAS  Google Scholar 

  3. Zhu, S.-F., Xu, X., Perman, J. A. & Zhang, X. P. A general and efficient cobalt(II)-based catalytic system for highly stereoselective cyclopropanation of alkenes with α-cyanodiazoacetates. J. Am. Chem. Soc. 132, 12796–12799 (2010).

    Article  CAS  Google Scholar 

  4. Lian, Y.-J. & Davies, H. M. L. Rhodium-catalyzed [3+2] annulation of indoles. J. Am. Chem. Soc. 132, 440–441 (2010).

    Article  CAS  Google Scholar 

  5. Padwa, A. & Hornbuckle, S. F. Ylide formation from the reaction of carbenes and carbenoids with heteroatom lone pairs. Chem. Rev. 91, 263–309 (1991).

    Article  CAS  Google Scholar 

  6. Godula, K. & Sames, D. C–H bond functionalization in complex organic synthesis. Science 312, 67–72 (2006).

    Article  CAS  Google Scholar 

  7. Wang, D.-H., Engle, K. M., Shi, B.-F. & Yu, J.-Q. Ligand-enabled reactivity and selectivity in a synthetically versatile aryl C–H olefination. Science 327, 315–319 (2010).

    Article  CAS  Google Scholar 

  8. Davies, H. M. L. & Manning, J. R. Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion. Nature 451, 417–424 (2008).

    Article  CAS  Google Scholar 

  9. Nakamura, E., Yoshikai, N. & Yamanaka, M. Mechanism of C–H bond activation/C–C bond formation reaction between diazo compound and alkane catalyzed by dirhodium tetracarboxylate. J. Am. Chem. Soc. 124, 7181–7192 (2002).

    Article  CAS  Google Scholar 

  10. Doyle, M. P., Duffy, R., Ratnikov, M. & Zhou, L. Catalytic carbene insertion into C–H bonds. Chem. Rev. 110, 704–724 (2010).

    Article  CAS  Google Scholar 

  11. Doyle, M. P., Shanklin, M. S., Pho, H. Q. & Mahapatro, S. N. Rhodium(II) acetate and Nafion-H catalyzed decomposition of N-aryldiazoamides. Efficient synthesis of 2(3H)-indolinones. J. Org. Chem. 53, 1017–1022 (1988).

    Article  CAS  Google Scholar 

  12. Davies, H. M. L. & Hedley, S. J. Intermolecular reactions of electron-rich heterocycles with copper and rhodium carbenoids. Chem. Soc. Rev. 36, 1109–1119 (2007).

    Article  CAS  Google Scholar 

  13. DeAngelis, A., Shurtleff, V. W., Dmitrenko, O. & Fox, J. M. Rhodium(II)-catalyzed enantioselective C–H functionalization of indoles. J. Am. Chem. Soc. 133, 1650–1653 (2011).

    Article  CAS  Google Scholar 

  14. Cai, Y., Zhu, S.-F., Wang, G.-P. & Zhou, Q.-L. Iron-catalyzed C–H fuctionalization of indoles. Adv. Synth. Catal. 353, 2939–2944 (2011).

    Article  CAS  Google Scholar 

  15. Hansen, J. & Davies, H. M. L. High symmetry dirhodium(II) paddlewheel complexes as chiral catalysts. Coord. Chem. Rev. 252, 545–555 (2008).

    Article  CAS  Google Scholar 

  16. Doyle, M. P. & Forbes, D. C. Recent advances in asymmetric catalytic metal carbene transformations. Chem. Rev. 98, 911–935 (1998).

    Article  CAS  Google Scholar 

  17. Li, Z.-J. & Davies, H. M. L. Enantioselective C–C bond formation by rhodium-catalyzed tandem ylide formation/[2,3]-sigmatropic rearrangement between donor/acceptor carbenoids and allylic alcohols. J. Am. Chem. Soc. 132, 396–401 (2010).

    Article  CAS  Google Scholar 

  18. Ji, J.-J. et al. Diastereoselectivity switch in cooperatively catalyzed three-component reactions of an aryldiazoacetate, an alcohol, and a β,γ-unsaturated α-keto ester. J. Org. Chem. 76, 5821–5824 (2011).

    Article  CAS  Google Scholar 

  19. Shao, Z.-H. & Zhang, H.-B. Combining transition metal catalysis and organocatalysis: a broad new concept for catalysis. Chem. Soc. Rev. 38, 2745–2755 (2009).

    Article  CAS  Google Scholar 

  20. Hu, W.-H. et al. Cooperative catalysis with chiral Brønsted acid–Rh2(OAc)4: highly enantioselective three-component reactions of diazo compounds with alcohols and imines. J. Am. Chem. Soc. 130, 7782–7783 (2008).

    Article  CAS  Google Scholar 

  21. Jiang, J. et al. Diastereoselectively switchable enantioselective trapping of carbamate ammonium ylides with imines. J. Am. Chem. Soc. 133, 8428–8431 (2011).

    Article  CAS  Google Scholar 

  22. Williams, A. L. & Johnston, J. N. The Brønsted acid-catalyzed direct Aza-Darzens synthesis of N-alkyl cis-aziridines. J. Am. Chem. Soc. 126, 1612–1613 (2004).

    Article  CAS  Google Scholar 

  23. Johnston, J. N., Muchalski, H. & Troyer T. L. To protonate or alkylate? Stereoselective Brønsted acid catalysis of C–C bond formation using diazoalkanes. Angew. Chem. Int. Ed. 49, 2290–2298 (2010).

    Article  CAS  Google Scholar 

  24. Zhong, C. & Shi, X.-D. When organocatalysis meets transition-metal catalysis. Eur. J. Org. Chem. 2999–3025 (2010).

  25. Uraguchi, D., Sorimachi, K. & Terada, M. Organocatalytic asymmetric aza-Friedel–Crafts alkylation of furan. J. Am. Chem. Soc. 126, 11804–11805 (2004).

    Article  CAS  Google Scholar 

  26. Akiyama, T., Itoh, J., Yokota, K. & Fuchibe, K. Enantioselective Mannich-type reaction catalyzed by a chiral Brøsted acid. Angew. Chem. Int. Ed. 43, 1566–1568 (2004).

    Article  CAS  Google Scholar 

  27. Tian, X., Jiang, K., Peng, J., Du, W. & Chen Y.-C. Organocatalytic stereoselective Mannich reaction of 3-substituted oxindoles. Org. Lett. 10, 3583–3586 (2008).

    Article  CAS  Google Scholar 

  28. Galliford, C. V. & Scheidt, K. A. Pyrrolidinyl-spirooxindole natural products as inspirations for the development of potential therapeutic agents. Angew. Chem. Int. Ed. 46, 8748–8758 (2007).

    Article  CAS  Google Scholar 

  29. Zhang, D., Song, H. & Qin, Y. Total synthesis of indoline alkaloids: a cyclopropanation strategy. Acc. Chem. Res. 44, 447–457 (2011).

    Article  CAS  Google Scholar 

  30. Simon, L. & Goodman, J. M. A model for the enantioselectivity of imine reactions catalyzed by BINOL-phosphoric acid catalysts. J. Org. Chem. 76, 1775–1788 (2011).

    Article  CAS  Google Scholar 

  31. Liu, H., Dagousset, G., Masson, G., Retailleau, P. & Zhu, J.-P. Chiral Brønsted acid-catalyzed enantioselective three-component Povarov reaction. J. Am. Chem. Soc. 131, 4598–4599 (2009).

    Article  CAS  Google Scholar 

  32. Jia, Y.-X., Zhong, J., Zhu, S.-F., Zhang, C.-M. & Zhou, Q.-L. Chiral Brøsted acid catalyzed enantioselective Friedel–Crafts reaction of indoles and α-aryl enamides: construction of quaternary carbon atoms. Angew. Chem. Int. Ed. 46, 5565–5567 (2007).

    Article  CAS  Google Scholar 

  33. Xu, B., Zhu S.-F., Xie X.-L., Shen J.-J. & Zhou Q.-L. Asymmetric N–H insertion reaction cooperatively catalyzed by rhodium and chiral spiro phosphoric acids. Angew. Chem. Int. Ed. 50, 11483–11486 (2011).

    Article  CAS  Google Scholar 

  34. Liang Y., Zhou H.-L. & Yu Z.-X. Why is copper (I) complex more competent than dirhodium (II) complex in catalytic asymmetric O–H insertion reactions? A computational study of the metal carbenoid O–H insertion into water. J. Am. Chem. Soc. 131, 17783–17785 (2009).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors acknowledge support from the National Science Foundation of China (nos 20932003 and 21125209 to W.-H.H.), the MOST of China (2011CB808600) and from Shanghai (10XD1401700). M.P.D. thanks the National Institutes of Health (GM 46503) and National Science Foundation (CHE-0748121) for financial support.

Author information

Authors and Affiliations

Authors

Contributions

H.Q. and M.L. contributed equally to the work. H.Q. designed and performed experiments for the three-component reaction, and M.L. designed and performed experiments for oxindole formation. L.-Q.J. took part in the development of the initial reaction. F.-P.L. made the organocatalysts. L.Z. and C.-W.Z. performed experiments. M.P.D. discussed, commented on and revised the manuscript. W.-H.H. conceived and directed the project. W.-H.H., M.L. and H.Q. wrote the paper.

Corresponding author

Correspondence to Wen-Hao Hu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 6249 kb)

Supplementary information

Crystallographic data for compound 5ba (CIF 28 kb)

Supplementary information

Crystallographic data for compound 6b (CIF 20 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Qiu, H., Li, M., Jiang, LQ. et al. Highly enantioselective trapping of zwitterionic intermediates by imines. Nature Chem 4, 733–738 (2012). https://doi.org/10.1038/nchem.1406

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.1406

This article is cited by

Search

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