Catalytic asymmetric umpolung reactions of imines


The carbon–nitrogen double bonds in imines are fundamentally important functional groups in organic chemistry. This is largely due to the fact that imines act as electrophiles towards carbon nucleophiles in reactions that form carbon–carbon bonds, thereby serving as one of the most widely used precursors for the formation of amines in both synthetic and biosynthetic settings1,2,3,4,5. If the carbon atom of the imine could be rendered electron-rich, the imine could react as a nucleophile instead of as an electrophile. Such a reversal in the electronic characteristics of the imine functionality would facilitate the development of new chemical transformations that convert imines into amines via carbon–carbon bond-forming reactions with carbon electrophiles, thereby creating new opportunities for the efficient synthesis of amines. The development of asymmetric umpolung reactions of imines (in which the imines act as nucleophiles) remains uncharted territory, in spite of the far-reaching impact such reactions would have in organic synthesis. Here we report the discovery and development of new chiral phase-transfer catalysts that promote the highly efficient asymmetric umpolung reactions of imines with the carbon electrophile enals. These catalysts mediate the deprotonation of imines and direct the 2-azaallyl anions thus formed to react with enals in a highly chemoselective, regioselective, diastereoselective and enantioselective fashion. The reaction tolerates a broad range of imines and enals, and can be carried out in high yield with as little as 0.01 mole per cent catalyst with a moisture- and air-tolerant operational protocol. These umpolung reactions provide a conceptually new and practical approach to chiral amino compounds.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Design of a catalytic C–C bond-forming umpolung reaction of imines.
Figure 2: Gram-scale reaction and synthetic applications.
Figure 3: Asymmetric umpolung reactions of aryl and unsaturated aldimines.


  1. 1

    Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and Applications (Wiley-VCH, 2010)

    Google Scholar 

  2. 2

    Robak, M. T., Herbage, M. A. & Ellman, J. A. Synthesis and applications of tert-butanesulfinamide. Chem. Rev. 110, 3600–3740 (2010)

    CAS  Article  Google Scholar 

  3. 3

    Kobayashi, S., Mori, Y., Fossey, J. S. & Salter, M. M. Catalytic enantioselective formation of C−C bonds by addition to imines and hydrazones: a ten-year update. Chem. Rev. 111, 2626–2704 (2011)

    CAS  Article  Google Scholar 

  4. 4

    Silverio, D. L. et al. Simple organic molecules as catalysts for enantioselective synthesis of amines and alcohols. Nature 494, 216–221 (2013)

    CAS  ADS  Article  Google Scholar 

  5. 5

    Dewick, P. M. Medicinal Natural Products: A Biosynthetic Approach 3rd edn (Wiley & Sons, 2009)

    Google Scholar 

  6. 6

    Seebach, D. Methods of reactivity umpolung. Angew. Chem. Int. Ed. Engl. 18, 239–258 (1979)

    Article  Google Scholar 

  7. 7

    Seebach, D. & Corey, E. J. Generation and synthetic applications of 2-lithio-1,3-dithianes. J. Org. Chem. 40, 231–237 (1975)

    CAS  Article  Google Scholar 

  8. 8

    Smith, A. B. & Adams, C. M. Evolution of dithiane-based strategies for the construction of architecturally complex natural products. Acc. Chem. Res. 37, 365–377 (2004)

    CAS  Article  Google Scholar 

  9. 9

    Brehme, R., Enders, D., Fernandez, R. & Lassaletta, J. M. Aldehyde N-dialkylhydrazones as neutral acyl anion equivalents: umpolung of the imine reactivity. Eur. J. Org. Chem. 5629–5660 (2007)

  10. 10

    Vora, H. U. & Rovis, T. Asymmetric N-heterocyclic carbene (NHC) catalyzed acyl anion reactions. Aldrichim. Acta 44, 3–11 (2011)

    CAS  Google Scholar 

  11. 11

    Reich, B. J. E., Justice, A. K., Beckstead, B. T., Reibenspies, J. H. & Miller, S. A. Cyanide-catalyzed cyclizations via aldimine coupling. J. Org. Chem. 69, 1357–1359 (2004)

    CAS  Article  Google Scholar 

  12. 12

    Ogle, J. W., Zhang, J., Reibenspies, J. H., Abboud, K. A. & Miller, S. A. Synthesis of electronically diverse tetraarylimidazolylidene carbenes via catalytic aldimine coupling. Org. Lett. 10, 3677–3680 (2008)

    CAS  Article  Google Scholar 

  13. 13

    Liu, X., Gao, A., Ding, L., Xu, J. & Zhao, B. Aminative umpolung synthesis of aryl vicinal diamines from aromatic aldehydes. Org. Lett. 16, 2118–2121 (2014)

    CAS  Article  Google Scholar 

  14. 14

    Matsumoto, M., Harada, M., Yamashita, Y. & Kobayashi, S. Catalytic imine-imine cross-coupling reactions. Chem. Commun. 50, 13041–13044 (2014)

    CAS  Article  Google Scholar 

  15. 15

    Wu, Y. & Deng, L. Asymmetric synthesis of trifluoromethylated amines via catalytic enantioselective isomerization of imines. J. Am. Chem. Soc. 134, 14334–14337 (2012)

    CAS  Article  Google Scholar 

  16. 16

    Liu, M., Li, J., Xiao, X., Xie, Y. & Shi, Y. An efficient synthesis of optically active trifluoromethyl aldimines via asymmetric biomimetic transamination. Chem. Commun. 49, 1404–1406 (2013)

    CAS  Article  Google Scholar 

  17. 17

    Jakubowska, A. & Kulig, K. Progress in the glycine equivalent based α-amino acids synthesis. Curr. Org. Synth. 10, 547–563 (2013)

    CAS  Article  Google Scholar 

  18. 18

    Zhu, Y. & Buchwald, S. L. Ligand-controlled asymmetric arylation of aliphatic α-amino anion equivalents. J. Am. Chem. Soc. 136, 4500–4503 (2014)

    CAS  Article  Google Scholar 

  19. 19

    Qian, X. et al. Palladium-catalyzed decarboxylative generation and asymmetric allylation of α-imino anions. Org. Lett. 16, 5228–5231 (2014)

    CAS  Article  Google Scholar 

  20. 20

    Shirakawa, S. & Maruoka, K. Recent developments in asymmetric phase-transfer reactions. Angew. Chem. Int. Ed. Engl. 52, 4312–4348 (2013)

    CAS  Article  Google Scholar 

  21. 21

    Ooi, T., Ohara, D., Tamura, M. & Maruoka, K. Design of new chiral phase-transfer catalysts with dual functions for highly enantioselective epoxidation of α,β-unsaturated ketones. J. Am. Chem. Soc. 126, 6844–6845 (2004)

    CAS  Article  Google Scholar 

  22. 22

    Dolling, U. H., Davis, P. & Grabowski, E. J. J. Efficient catalytic asymmetric alkylations. 1. Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysis. J. Am. Chem. Soc. 106, 446–447 (1984)

    CAS  Article  Google Scholar 

  23. 23

    Bandini, M., Bottoni, A., Eichholzer, A., Miscione, G. P. & Stenta, M. Asymmetric phase-transfer-catalyzed intramolecular N-alkylation of indoles and pyrroles: a combined experimental and theoretical investigation. Chem. Eur. J. 16, 12462–12473 (2010)

    CAS  Article  Google Scholar 

  24. 24

    Knowles, R. R., Lin, S. & Jacobsen, E. N. Enantioselective thiourea-catalyzed cationic polycyclizations. J. Am. Chem. Soc. 132, 5030–5032 (2010)

    CAS  Article  Google Scholar 

  25. 25

    Fu, P., Snapper, M. L. & Hoveyda, A. H. Catalytic asymmetric alkylations of ketoimines. Enantioselective synthesis of N-substituted quaternary carbon stereogenic centers by Zr-catalyzed additions of dialkylzinc reagents to aryl-, alkyl-, and trifluoroalkyl-substituted ketoimines. J. Am. Chem. Soc. 130, 5530–5541 (2008)

    CAS  Article  Google Scholar 

  26. 26

    Nie, J., Guo, H.-C., Cahard, D. & Ma, J.-A. Asymmetric construction of stereogenic carbon centers featuring a trifluoromethyl group from prochiral trifluoromethylated substrates. Chem. Rev. 111, 455–529 (2011)

    CAS  Article  Google Scholar 

  27. 27

    Giacalone, F., Gruttadauria, M., Agrigento, P. & Noto, R. Low-loading asymmetric organocatalysis. Chem. Soc. Rev. 41, 2406–2447 (2012)

    CAS  Article  Google Scholar 

  28. 28

    Bordwell, F. G., Algrim, D. & Vanier, N. R. Acidities of anilines and toluenes. J. Org. Chem. 42, 1817–1819 (1977)

    CAS  Article  Google Scholar 

  29. 29

    Hartwig, J. F. & Stanley, L. M. Mechanistically driven development of iridium catalysts for asymmetric allylic substitution. Acc. Chem. Res. 43, 1461–1475 (2010)

    CAS  Article  Google Scholar 

  30. 30

    Jaun, B., Schwarz, J. & Breslow, R. Determination of the basicities of benzyl, allyl, and tert-butylpropargyl anions by anodic oxidation of organolithium compounds. J. Am. Chem. Soc. 102, 5741–5748 (1980)

    CAS  Article  Google Scholar 

Download references


We are grateful for financial support from the National Institute of General Medical Science (NIH, GM-61591). We thank M. Bezpalko and B. Foxman for X-ray crystallographic characterizations of structures. C. Fei and B. Hu are acknowledged for the help in substrate preparation.

Author information




Y.W., L.H. and Z.L. performed the experiments and analysed data. Y.W. and L.D. conceived the idea and prepared this manuscript with feedback from L.H. and Z.L.

Corresponding author

Correspondence to Li Deng.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Methods, NMR Spectra for new compounds, HPLC Spectra for chiral products and additional references (see Table of Contents for more details). (PDF 24203 kb)

Supplementary Data

This zipped file contains the 'cif' files for the X-ray crystallographic data for compounds 24Aa and 24Ge. (ZIP 10 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wu, Y., Hu, L., Li, Z. et al. Catalytic asymmetric umpolung reactions of imines. Nature 523, 445–450 (2015).

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.