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.

  • Protocol
  • Published:

Synthesis and use of an asymmetric transfer hydrogenation catalyst based on iron(II) for the synthesis of enantioenriched alcohols and amines

Nature Protocols volume 10, pages 241–257 (2015)Cite this article

Subjects

Abstract

The catalytic hydrogenation of prochiral ketones and imines is an advantageous approach to the synthesis of enantioenriched alcohols and amines, respectively, which are two classes of compounds that are highly prized in pharmaceutical, fragrance and flavoring chemistry. This hydrogenation reaction is generally carried out using ruthenium-based catalysts. Our group has developed an alternative synthetic route that is based on the environmentally friendlier iron-based catalysis. This protocol describes the three-part synthesis of trans-[amine(imine)diphosphine]chlorocarbonyliron(II) tetrafluoroborate templated by iron salts and starting from commercially available chemicals, which provides the precatalyst for the efficient asymmetric transfer hydrogenation of ketones and imines. The use of the enantiopure (S,S) catalyst to reduce prochiral ketones to the (R)-alcohol in good to excellent yields and enantioenrichment is also detailed, as well as the reduction to the amine in very high yield and enantiopurity of imines substituted at the nitrogen with the N-(diphenylphosphinoyl) group (-P(O)Ph2). Although the best ruthenium catalysts provide alcohols in higher enantiomeric excess (ee) than the iron complex catalyst used in this protocol, they do so on much longer time scales or at higher catalyst loadings. This protocol can be completed in 2 weeks.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: The asymmetric transfer hydrogenation of prochiral ketones and imines by the title iron catalyst system at 0.02–1 mol% catalyst loading.
Figure 2: The structures of conventional and advanced ruthenium catalysts for asymmetric transfer hydrogenation.
Figure 3
Figure 4: Synthesis of the tridentate ligand (S,S)-PPh2CH2CH2NHCHPhCHPhNH2.
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Lin, G.Q., You, Q.D. & Cheng, J.F. Chiral Drugs: Chemistry and Biological Action (John Wiley & Sons, 2011).

  2. Busacca, C.A., Fandrick, D.R., Song, J.J. & Senanayake, C.H. The growing impact of catalysis in the pharmaceutical industry. Adv. Synth. Catal. 353, 1825–1864 (2011).

    Article  CAS  Google Scholar 

  3. Blaser, H.-U. et al. Selective hydrogenation for fine chemicals: recent trends and new developments. Adv. Synth. Catal. 345, 103–151 (2003).

    Article  CAS  Google Scholar 

  4. Rodriguez, S. et al. Amine-tunable ruthenium catalysts for asymmetric reduction of ketones. Adv. Synth. Catal. 356, 301–307 (2014).

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

  6. Magano, J. & Dunetz, J.R. Large-Scale carbonyl reductions in the pharmaceutical industry. Org. Process Res. Dev. 16, 1156–1184 (2012).

    Article  CAS  Google Scholar 

  7. Ager, D.J., de Vries, A.H.M. & de Vries, J.G. Asymmetric homogeneous hydrogenations at scale. Chem. Soc. Rev. 41, 3340–3380 (2012).

    Article  CAS  Google Scholar 

  8. Johnson, N.B., Lennon, I.C., Moran, P.H. & Ramsden, J.A. Industrial-scale synthesis and applications of asymmetric hydrogenation catalysts. Acc. Chem. Res. 40, 1291–1299 (2007).

    Article  CAS  Google Scholar 

  9. Patchett, R. et al. Asymmetric hydrogenation of ketones with H2 and ruthenium catalysts containing chiral tetradentate S2N2 ligands. Angew. Chem. Int. Ed. Engl. 52, 10352–10355 (2013).

    Article  CAS  Google Scholar 

  10. Noyori, R. Asymmetric catalysis: science and opportunities (Nobel lecture 2001). Adv. Synth. Catal. 345, 15–32 (2003).

    Article  CAS  Google Scholar 

  11. Ohkuma, T., Ishii, D., Takeno, H. & Noyori, R. Asymmetric hydrogenation of amino ketones using chiral RuCl2(diphosphine)(1,2-diamine) complexes. J. Am. Chem. Soc. 122, 6510–6511 (2000).

    Article  CAS  Google Scholar 

  12. Noyori, R. & Ohkuma, T. Asymmetric catalysis by architectural and functional molecular engineering: practical chemo- and stereoselective hydrogenation of ketones. Angew. Chem. Int. Ed. Engl. 40, 40–73 (2001).

    Article  CAS  Google Scholar 

  13. Klingler, F.D. Asymmetric hydrogenation of prochiral amino ketones to amino alcohols for pharmaceutical use. Acc. Chem. Res. 40, 1367–1376 (2007).

    Article  CAS  Google Scholar 

  14. Zuo, W., Lough, A.J., Li, Y. & Morris, R.H. Amino(imino)diphosphines activate iron catalysts in the asymmetric transfer hydrogenation of ketones and imines. Science 342, 1080–1083 (2013).

    Article  CAS  Google Scholar 

  15. Hashiguchi, S., Fujii, A., Takehara, J., Ikariya, T. & Noyori, R. Asymmetric transfer hydrogenation of aromatic ketones catalyzed by chiral ruthenium(II) complexes. J. Am. Chem. Soc. 117, 7562–7563 (1995).

    Article  CAS  Google Scholar 

  16. Yamada, I. & Noyori, R. Asymmetric transfer hydrogenation of benzaldehydes. Org. Lett. 2, 3425–3427 (2000).

    Article  CAS  Google Scholar 

  17. Baratta, W. et al. Chiral pincer ruthenium and osmium complexes for the fast and efficient hydrogen transfer reduction of ketones. Organometallics 29, 3563–3570 (2010).

    Article  CAS  Google Scholar 

  18. Baratta, W., Chelucci, G., Magnolia, S., Siega, K. & Rigo, P. Highly productive CNN pincer ruthenium catalysts for the asymmetric reduction of alkyl aryl ketones. Chem. Eur. J. 15, 726–732 (2009).

    Article  CAS  Google Scholar 

  19. Cheung, F.K. et al. An investigation into the tether length and substitution pattern of arene-substituted complexes for asymmetric transfer hydrogenation of ketones. Org. Lett. 9, 4659–4662 (2007).

    Article  CAS  Google Scholar 

  20. Hayes, A.M., Morris, D.J., Clarkson, G.J. & Wills, M. A class of ruthenium(II) catalyst for asymmetric transfer hydrogenations of ketones. J. Am. Chem. Soc. 127, 7318–7319 (2005).

    Article  CAS  Google Scholar 

  21. Morris, D.J., Hayes, A.M. & Wills, M. The 'reverse-tethered' ruthenium (II) catalyst for asymmetric transfer hydrogenation: further applications. J. Org. Chem. 71, 7035–7044 (2006).

    Article  CAS  Google Scholar 

  22. Mikhailine, A.A., Lagaditis, P.O., Sues, P., Lough, A.J. & Morris, R.H. New cyclic phosphonium salts derived from the reaction of phosphine-aldehydes with acid. J. Organometal. Chem. 695, 1824–1830 (2010).

    Article  CAS  Google Scholar 

  23. Lagaditis, P.O., Mikhailine, A.A., Lough, A.J. & Morris, R.H. Template synthesis of iron(II) complexes containing tridentate P-N-S, P-N-P, P-N-N and tetradentate P-N-N-P ligands. Inorg. Chem. 49, 1094–1102 (2010).

    Article  CAS  Google Scholar 

  24. Sues, P.E., Lough, A.J. & Morris, R.H. Stereoelectronic factors in iron catalysis: synthesis and characterization of aryl-substituted iron(II) carbonyl P-N-N-P complexes and their use in the asymmetric transfer hydrogenation of ketones. Organometallics 30, 4418–4431 (2011).

    Article  CAS  Google Scholar 

  25. Zuo, W., Tauer, S., Prokopchuk, D.E. & Morris, R.H. Iron catalysts containing amine(imine)diphosphine P-NH-N-P ligands catalyze both asymmetric hydrogenation and asymmetric transfer hydrogenation of ketones. Organometallics 33, 5791–5801 (2014).

    Article  CAS  Google Scholar 

  26. Mikhailine, A.A., Kim, E., Dingels, C., Lough, A.J. & Morris, R.H. Template syntheses of iron(II) complexes containing chiral P-N-N-P and P-N-N ligands. Inorg. Chem. 47, 6587–6589 (2008).

    Article  CAS  Google Scholar 

  27. Sues, P.E., Demmans, K.Z. & Morris, R.H. Rational development of iron catalysts for asymmetric transfer hydrogenation. Dalton Trans. 43, 7650–7667 (2014).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the Natural Sciences and Engineering Research Council of Canada for a discovery grant to R.H.M.

Author information

Authors and Affiliations

  1. Department of Chemistry, University of Toronto, Toronto, Ontario, Canada

    Weiwei Zuo & Robert H Morris

Authors
  1. Weiwei Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert H Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

W.Z. performed all the experiments. R.H.M. directed the research and both authors wrote the manuscript.

Corresponding author

Correspondence to Robert H Morris.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 1H NMR (CDCl3 +4 drops CD3OD, 600 MHz) (top) and 31P{1H} NMR (bottom) spectra of (PPh2CH2CHOH-)2Cl2.

Supplementary Figure 2 The reaction of diphenylphosphine (HPPh2) with potassium hydride (KH) in THF in the glovebox.

Supplementary Figure 3 The formation of the phosphonium dimer [(PPh2CH2CHOH-)2Cl2] after the addition of the hydrochloric acid in THF in the air.

Supplementary Figure 4 The reaction of iron chloride with the diamine and phosphine-aldehyde.

The reaction of iron chloride (FeCl2), (S,S)-1,2-diphenyl-1,2-diaminoethane (S,S-dpen), sodium methoxide (NaOMe) and the phosphonium dimer [(PPh2CH2CHOH-)2Cl2] in methanol in the glovebox.

Supplementary Figure 5 Isolation of (S,S)-PPh2CH2CH2NHCH(Ph)CH(Ph)NH2.

Using dichloromethane to extract the PPh2-NH-NH2 ligand [(S,S)-PPh2CH2CH2NHCH(Ph)CH(Ph)NH2] using a separatory funnel in the air.

Supplementary Figure 6 The solid trans-[Fe(MeCN)2(PPh2CH2CH=NCH(Ph)CH(Ph)NHCH2CH2PPh2)](BF4)2.

Supplementary Figure 7 Precipitating of trans-[Fe(CO)(Cl)(PPh2CH2CH=NCH(Ph)CH(Ph)NHCH2CH2PPh2)]BF4 by adding methanol.

Supplementary Figure 8 The reaction solution during the asymmetric transfer hydrogenation of acetophenone catalyzed by the iron complex.

Supplementary Figure 9 1H NMR (CD2Cl2, 400 MHz) (top) and 31P{1H} NMR spectra of (S,S)-PPh2CH2CH2NHCH(Ph)CH(Ph)NH2.

Supplementary Figure 10 1H NMR (CD2Cl2, 400 MHz) (top) and 31P{1H} NMR spectra of trans-[Fe(CO)(Cl)(PPh2CH2CH=NCH(Ph)CH(Ph)NHCH2CH2PPh2)]BF4.

Supplementary information

Supplementary Figures

Supplementary Figures 1–10, Supplementary Notes 1–9 (PDF 4378 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zuo, W., Morris, R. Synthesis and use of an asymmetric transfer hydrogenation catalyst based on iron(II) for the synthesis of enantioenriched alcohols and amines. Nat Protoc 10, 241–257 (2015). https://doi.org/10.1038/nprot.2015.012

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nprot.2015.012

This article is cited by

Comments

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.

Search

Advanced 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