Development of heterogeneous catalyst systems for the continuous synthesis of chiral amines via asymmetric hydrogenation


Continuous-flow synthesis of fine chemicals has several advantages over batch synthesis in terms of environmental compatibility, efficiency and safety. Nevertheless, most preparative methods still rely on conventional batch systems. For instance, chiral amines are ubiquitous functionalities in pharmaceutical compounds, but methods for their continuous synthesis with broad substrate generality remain very challenging. Here we show the development of heterogeneous iridium complexes combined with chiral phosphoric acids for the asymmetric hydrogenation of imines towards the continuous synthesis of chiral amines. Direct asymmetric reductive amination of ketones under a hydrogen atmosphere also proceeded smoothly using the same catalyst systems. Various chiral aromatic and aliphatic amines including pharmaceutical intermediates could be prepared in high yields with high enantioselectivities. It was found that continuous-flow reactions that use columns packed with the heterogeneous iridium complexes afforded chiral amines continuously for more than two days even at pressures lower than those in the corresponding batch reactions.

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Fig. 1: The substrate scope for asymmetric hydrogenation of aromatic imines.
Fig. 2: The substrate scope for DARA.
Fig. 3: The formal synthesis of tamsulosin.
Fig. 4: Asymmetric hydrogenation of an imine with a continuous-flow system.
Fig. 5: Direct asymmetric reductive amination of a ketone with a continuous-flow system.

Data availability

Other reaction procedures and characterization data of compounds are available in the Supplementary Information. All data is available from the authors on reasonable request.


  1. 1.

    Nugent, T. C. & El-Shazly, M. Chiral amine synthesis—recent developments and trends for enamide reduction, reductive amination, and imine reduction. Adv. Synth. Catal. 352, 753–819 (2010).

    CAS  Article  Google Scholar 

  2. 2.

    Kobayashi, S. Flow “Fine” synthesis: high yielding and selective organic synthesis by flow methods. Chem. Asian J. 11, 425–436 (2016).

    CAS  Article  Google Scholar 

  3. 3.

    Masuda, K., Ichitsuka, T., Koumura, N., Sato, K. & Kobayashi, S. Flow fine synthesis with heterogeneous catalysts. Tetrahedron 74, 1705–1730 (2018).

    CAS  Article  Google Scholar 

  4. 4.

    Geier, D., Schmitz, P., Walkowiak, J., Leitner, W. & Franciò, G. Continuous flow asymmetric hydrogenation with supported ionic liquid phase catalysts using modified CO2 as the mobile phase: from model substrate to an active pharmaceutical ingredient. ACS Catal. 8, 3297–3303 (2018).

    CAS  Article  Google Scholar 

  5. 5.

    Amara, Z. et al. Enabling the scale-up of a key asymmetric hydrogenation step in the synthesis of an API using continuous flow solid-supported catalysis. Org. Process Res. Dev. 20, 1321–1327 (2016).

    CAS  Article  Google Scholar 

  6. 6.

    Madarász, J. et al. A continuous-flow system for asymmetric hydrogenation using supported chiral catalysts. J. Flow. Chem. 1, 62–67 (2011).

    Article  Google Scholar 

  7. 7.

    Shi, L. et al. Development of a continuous-flow system for asymmetric hydrogenation using self-supported chiral. Catalysts. Chem. Eur. J. 15, 9855–9867 (2009).

    CAS  Article  Google Scholar 

  8. 8.

    Hopmann, K. H. & Bayer, A. Enantioselective imine hydrogenation with iridium-catalysts: reactions, mechanisms and stereocontrol. Coord. Chem. Rev. 268, 59–82 (2014).

    CAS  Article  Google Scholar 

  9. 9.

    Xie, J.-H., Zhu, S.-F. & Zhou, Q.-L. Transition metal-catalyzed enantioselective hydrogenation of enamines and imines. Chem. Rev. 111, 1713–1760 (2011).

    CAS  Article  Google Scholar 

  10. 10.

    Fleury-Brégeot, N., de la Fuente, V., Castillón, S. & Claver, C. Highlights of transition metal-catalyzed asymmetric hydrogenation of imines. ChemCatChem 2, 1346–1371 (2010).

    Article  Google Scholar 

  11. 11.

    Li, Q. et al. Chiral phosphine–phosphoramidite ligands for highly enantioselective hydrogenation of N-arylimines. RSC Adv. 5, 13702–13708 (2015).

    CAS  Article  Google Scholar 

  12. 12.

    Lindqvist, M. et al. Chiral molecular tweezers: synthesis and reactivity in asymmetric hydrogenation. J. Am. Chem. Soc. 137, 4038–4041 (2015).

    CAS  Article  Google Scholar 

  13. 13.

    Schramm, Y., Barrios-Landeros, F. & Pfaltz, A. Discovery of an iridacycle catalyst with improved reactivity and enantioselectivity in the hydrogenation of dialkyl ketimines. Chem. Sci. 4, 2760–2766 (2013).

    CAS  Article  Google Scholar 

  14. 14.

    Hou, C.-J., Wang, Y.-H., Zheng, Z., Xu, J. & Hu, X.-P. Chiral phosphine–phosphoramidite ligands for highly efficient Ir-catalyzed asymmetric hydrogenation of sterically hindered N-aryl imines. Org. Lett. 14, 3554–3557 (2012).

    CAS  Article  Google Scholar 

  15. 15.

    Zhou, S., Fleischer, S., Junge, K. & Beller, M. Cooperative transition-metal and chiral Brønsted acid catalysis: enantioselective hydrogenation of imines to form amines. Angew. Chem. Int. Ed. 50, 5120–5124 (2011).

    CAS  Article  Google Scholar 

  16. 16.

    Mršić, N., Minnaard, A. J., Feringa, B. L. & Vries, J. Gd Iridium/monodentate phosphoramidite catalyzed asymmetric hydrogenation of N-aryl imines. J. Am. Chem. Soc. 131, 8358–8359 (2009).

    Article  Google Scholar 

  17. 17.

    Tang, W. J. & Xiao, J. L. Asymmetric hydrogenation of imines via metal–organo cooperative catalysis. Synthesis 46, 1297–1302 (2014).

    Article  Google Scholar 

  18. 18.

    Tang, W. J. et al. Cooperative catalysis: combining an achiral metal catalyst with a chiral bronsted acid enables highly enantioselective hydrogenation of Imines. Chem. Eur. J. 19, 14187–14193 (2013).

    CAS  Article  Google Scholar 

  19. 19.

    Li, C. Q., Wang, C., Villa-Marcos, B. & Xiao, J. L. Chiral counteranion-aided asymmetric hydrogenation of acyclic imines. J. Am. Chem. Soc. 130, 14450–14451 (2008).

    CAS  Article  Google Scholar 

  20. 20.

    Huang, H., Zhao, Y., Yang, Y., Zhou, L. & Chang, M. Direct catalytic asymmetric reductive amination of aliphatic ketones utilizing diphenylmethanamine as coupling partner. Org. Lett. 19, 1942–1945 (2017).

    CAS  Article  Google Scholar 

  21. 21.

    Zhou, S. L., Fleischer, S., Jiao, H. J., Junge, K. & Beller, M. Cooperative catalysis with iron and a chiral bronsted acid for asymmetric reductive amination of ketones. Adv. Synth. Catal. 356, 3451–3455 (2014).

    CAS  Article  Google Scholar 

  22. 22.

    Villa-Marcos, B., Li, C. Q., Mulholland, K. R., Hogan, P. J. & Xiao, J. L. Bifunctional catalysis: direct reductive amination of aliphatic ketones with an iridium–phosphate catalyst. Molecules 15, 2453–2472 (2010).

    CAS  Article  Google Scholar 

  23. 23.

    Rubio-Pérez, L., Pérez-Flores, F. J., Sharma, P., Velasco, L. & Cabrera, A. Stable preformed chiral palladium catalysts for the one-pot asymmetric reductive amination of ketones. Org. Lett. 11, 265–268 (2009).

    Article  Google Scholar 

  24. 24.

    Li, C. Q., Villa-Marcos, B. & Xiao, J. L. Metal-bronsted acid cooperative catalysis for asymmetric reductive amination. J. Am. Chem. Soc. 131, 6967–6969 (2009).

    CAS  Article  Google Scholar 

  25. 25.

    Rueping, M., Bootwicha, T. & Sugiono, E. Continuous-flow catalytic asymmetric hydrogenations: reaction optimization using FTIR inline analysis. Beilstein J. Org. Chem. 8, 300–307 (2012).

    CAS  Article  Google Scholar 

  26. 26.

    Brenna, D., Pirola, M., Raimondi, L., Burke, A. J. & Benaglia, M. A stereoselective, catalytic strategy for the in-flow synthesis of advanced precursors of rasagiline and tamsulosin. Bioorg. Med. Chem. 25, 6242–6247 (2017).

    CAS  Article  Google Scholar 

  27. 27.

    Brenna, D., Porta, R., Massolo, E., Raimondi, L. & Benaglia, M. A new class of low-loading catalysts for highly enantioselective, metal-free imine reduction of wide general applicability. ChemCatChem 9, 941–945 (2017).

    CAS  Article  Google Scholar 

  28. 28.

    Altava, B., Burguete, M. I., Garcia-Verdugo, E. & Luis, S. V. Chiral catalysts immobilized on achiral polymers: effect of the polymer support on the performance of the catalyst. Chem. Soc. Rev. 47, 2722–2771 (2018).

    CAS  Article  Google Scholar 

  29. 29.

    Trindade, A. F., Gois, P. M. P. & Afonso, C. A. M. Recyclable stereoselective catalysts. Chem. Rev. 109, 418–514 (2009).

    CAS  Article  Google Scholar 

  30. 30.

    Tang, W. et al. Cooperative catalysis through noncovalent interactions. Angew. Chem. Int. Ed. 52, 1668–1672 (2013).

    CAS  Article  Google Scholar 

  31. 31.

    Waldeck, B. “The β1-selective adrenoceptor agonist dobutamine”: a fallacy being perpetuated. Chirality 23, 63–64 (2011).

    CAS  Article  Google Scholar 

  32. 32.

    Tuttle, R. R. & Mills, J. Method for increasing cardiac contractility. US patent 3987200 (1976).

  33. 33.

    Sagratini, G. et al. Synthesis and α1-adrenoceptor antagonist activity of tamsulosin analogues. Eur. J. Med. Chem. 45, 5800–5807 (2010).

    CAS  Article  Google Scholar 

  34. 34.

    Kim, Y. G., Kang, L. S., Ha, H. J., Ko, S. W. & Lee, W. K. Asymmetric formal synthesis of (–)-formoterol and (–)tamsulosin. Heterocycles 71, 2243–2248 (2007).

    CAS  Article  Google Scholar 

  35. 35.

    Niigata, K. & Fujikura, T. Sulfamoyl-substituted phenethylaminederivatives, their preparation, and pharmaceutical compositions, containing them. US patent 4731478 (1988).

  36. 36.

    Verkade, J. M. M. et al. Mild and efficient deprotection of the amine protecting p-methoxyphenyl (PMP) group. Tetrahedron Lett. 47, 8109–8113 (2006).

    CAS  Article  Google Scholar 

  37. 37.

    Miyamura, H., Suzuki, A., Yasukawa, T. & Kobayashi, S. Polysilane-immobilized Rh–Pt bimetallic nanoparticles as powerful arene hydrogenation catalysts: synthesis, reactions under batch and flow conditions and reaction mechanism. J. Am. Chem. Soc. 140, 11325–11334 (2018).

    CAS  Article  Google Scholar 

  38. 38.

    Zhao, D. B. & Ding, K. L. Recent advances in asymmetric catalysis in flow. ACS Catal. 3, 928–944 (2013).

    CAS  Article  Google Scholar 

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This work was supported in part by a Grant-in-Aid for Scientific Research from JSPS, the University of Tokyo, MEXT (Japan), AMED and JST. We thank T. Maki (The University of Tokyo) for scanning transmission electron microscopy and energy dispersive X-ray spectrometry analyses.

Author information




T.Y. and R.M. designed and performed the experiments. T.Y. conceived and designed the study. S.K. conceived, designed and directed the investigations and wrote the manuscript with revisions provided by T.Y and R.M.

Corresponding author

Correspondence to Shū Kobayashi.

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Supplementary Information

Supplementary Figs. 1–11, Tables 1–11, methods and references.

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Yasukawa, T., Masuda, R. & Kobayashi, S. Development of heterogeneous catalyst systems for the continuous synthesis of chiral amines via asymmetric hydrogenation. Nat Catal 2, 1088–1092 (2019).

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