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

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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.

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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

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Acknowledgements

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

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Authors and Affiliations

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

    Weiwei Zuo & Robert H Morris

Authors
  1. Weiwei Zuo
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  2. Robert H Morris
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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.

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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)

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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

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