REPORTS
8. H. U. Blaser, H.-J. Federsel, Eds., Asymmetric Catalysis on
26. Y. Ogho, S. Takeuchi, Y. Natori, J. Yoshimura, Bull. Chem.
Soc. Jpn. 54, 2124 (1981).
27. A. Corma, M. Iglesias, C. del Pino, F. Sánchez,
J. Organomet. Chem. 431, 233–246 (1992).
28. Q. Knijnenburg et al., J. Mol. Catal. A. 232, 151–159 (2005).
29. G. Zhang, B. L. Scott, S. K. Hanson, Angew. Chem. Int. Ed.
51, 12102–12106 (2012).
and (py)2Co(CH2SiMe3)2 without removal of the
volatiles, and hence in the presence of two equivalents
of pyridine, lowered the conversion and enantioselectivity
to 50 and 51%, respectively, indicating that incomplete
removal of the volatile byproducts in catalyst generation
could also be deleterious to overall performance.
Industrial Scale: Challenges, Approaches and Solutions
(Wiley-VCH, Weinheim, Germany, ed. 2, 2010).
9. C. S. Shultz, S. W. Krska, Acc. Chem. Res. 40, 1320–1326
(2007).
10. N. B. Johnson, I. C. Lennon, P. H. Moran, J. A. Ramsden,
Acc. Chem. Res. 40, 1291–1299 (2007).
30. G. Zhang, K. V. Vasudevan, B. L. Scott, S. K. Hanson,
J. Am. Chem. Soc. 135, 8668–8681 (2013).
31. S. Monfette, Z. R. Turner, S. P. Semproni, P. J. Chirik,
J. Am. Chem. Soc. 134, 4561–4564 (2012).
32. D. Zhu, F. F. B. J. Janssen, P. H. M. Budzelaar,
Organometallics 29, 1897–1908 (2010).
33. M. J. Burk, J. E. Feaster, W. A. Nugent, R. L. Harlow,
J. Am. Chem. Soc. 115, 10125–10138 (1993).
34. S. J. Roseblade, A. Pfaltz, Acc. Chem. Res. 40,
1402–1411 (2007).
35. P. G. Cozzi, N. Zimmermann, R. Hilgraf, S. Schaffner,
A. Pfaltz, Adv. Synth. Catal. 343, 450–454 (2001).
36. X. Cui, K. Burgess, Chem. Rev. 105, 3272–3296 (2005).
37. T. L. Church, P. G. Andersson, Coord. Chem. Rev. 252,
513–531 (2008).
38. The last number in the name indicates the enantiomer of
the ligand. SL-A109-1 corresponds to the (R) enantiomer,
whereas SL-A109-2 is the (S) antipode.
11. A. M. Rouhi, Chem. Eng. News 82, 47 (2004).
12. J. A. DiMasi, C. Paquette, Pharmacoeconomics 22,
(Suppl 2), 1–14 (2004).
13. A. M. Thayer, Chem. Eng. News 85, 11 (2007).
14. W. S. Knowles, M. J. Sabacky, J. Chem. Soc. Chem.
Commun. 1445 (1968).
Acknowledgments: We thank the U.S. National Science
Foundation for a Grant Opportunities for Academic Liaison
with Industry (GOALI) grant (CHE-1265988) between Princeton
and Merck. M.R.F. thanks the National Science Foundation
for a Graduate Research Fellowship (DGE-1148900). We also
thank Z. Turner, S. Semproni, and G. Margulieux (Princeton
University) for assistance with x-ray crystallography and
B. Chen, J. Cuff, L. Joyce, Z. Pirzada, W. Schafer, and H. Wang
(Merck) for assistance with chiral assays. Metrical parameters
for the solid-state structures are available free of charge
from the Cambridge Crystallographic Data Centre under the
reference numbers CCDC 958430, 958431, and 958432.
P.J.C., M.R.F., and J.M.H. along with Princeton University have
filed a U.S. patent application (13/838,835) for the
compounds disclosed in this work.
15. L. Horner, H. Siegel, H. Büthe, Angew. Chem. Int. Ed.
Engl. 7, 942 (1968).
16. R. R. Schrock, J. A. Osborn, J. Am. Chem. Soc. 93, 2397 (1971).
17. J. Halpern, Science 217, 401–407 (1982).
18. M. T. Ashby, J. Halpern, J. Am. Chem. Soc. 113, 589–594
(1991).
19. S. Bell et al., Science 311, 642–644 (2006).
20. J. Mazuela, P. O. Norrby, P. G. Andersson, O. Pàmies,
M. Diéguez, J. Am. Chem. Soc. 133, 13634–13645 (2011).
21. M. C. Perry et al., J. Am. Chem. Soc. 125, 113–123 (2003).
22. B. Plietker, Ed., Iron Catalysis in Organic Chemistry:
Reactions and Applications (Wiley-VCH, Weinheim,
Germany, 2008).
23. U. Leutenegger, A. Madin, A. Pfaltz, Angew. Chem.
Int. Ed. Engl. 28, 60–61 (1989).
24. L. O. Nindakova, F. M. Lebed, Z. Y. Zamazei, B. A. Shainyan,
Russ. J. Org. Chem. 43, 1322–1329 (2007).
25. L. O. Nindakova, B. A. Shainyan, Russ. Chem. Bull.
Int. Ed. 54, 348–353 (2005).
Supplementary Materials
Materials and Methods
Figs. S1 to S27
Tables S1 to S6
cam.ac.uk/display_csd_search_results.php?
xml_temp_file=/temp/text_numeric_query_
041631900137230271451cbad7a67a84.
xml&identifier=NALPIA.
References (41–46)
40. Similarly, performing the hydrogenation of
trans-methylstilbene with 5 mol % each of SL-A109-2
22 July 2013; accepted 7 October 2013
10.1126/science.1243550
phenone at turnover frequencies up to 15 s−1 at
30°C; until the present work, this was an unrivaled
rate for the transfer hydrogenation of ketones under
these conditions (8). On this basis, we hypothesized
that the direct synthesis of complexes such as F
containing an unsymmetrical P-NH-N-P ligand
would lead to more active catalysts.
A key step toward this goal was the selective
synthesis of enantiopure tridentate ligands P-NH-
NH2 (1a and 1b) by an iron(II)-assisted method
(Fig. 2, reactions 7 and 8). The starting compounds
Amine(imine)diphosphine Iron
Catalysts for Asymmetric Transfer
Hydrogenation of Ketones and Imines
Weiwei Zuo, Alan J. Lough, Young Feng Li, Robert H. Morris*
A rational approach is needed to design hydrogenation catalysts that make use of Earth-abundant
elements to replace the rare elements such as ruthenium, rhodium, and palladium that are traditionally are air- and water-stable dimeric phosphonium
used. Here, we validate a prior mechanistic hypothesis that partially saturated amine(imine)diphosphine
ligands (P-NH-N-P) activate iron to catalyze the asymmetric reduction of the polar bonds of ketones
and imines to valuable enantiopure alcohols and amines, with isopropanol as the hydrogen donor, at
turnover frequencies as high as 200 per second at 28°C. We present a direct synthetic approach to
salts A that are readily prepared with a variety of
substituents at phosphorus (in green in Fig. 2); in
the present case, these are phenyl and meta-xylyl.
The latter group is often effective at increasing the
enantiopure ligands of this type that takes advantage of the iron(lI) ion as a template. The catalytic selectivity of catalysts (2, 9). These phosphonium
mechanism is elucidated by the spectroscopic detection of iron hydride and amide intermediates.
dimers release reactive a-phosphinoacetaldehyde
species when they are treated with base (NaOMe)
etal-based homogeneous catalysts are tionally efficient class of catalysts for the preparation and undergo Schiff-base condensation with an
used in the pharmaceutical, fragrance, of enantioenriched alcohols and amines.
enantiopure diamine at iron(II) to form com-
flavoring, and fine chemicals industries Our previous synthetic and mechanistic studies plexes with two tridentate ligands incorporat-
M
for the synthesis of enantiomerically pure organic of the iron(II)-based transfer hydrogenation pre- ing phosphine, imine, and amine donors (10). The
molecules such as alcohols, amines, and amino catalyst (S,S)-[Fe(CO)(Br)(PAr2CH2CH= optimum reaction conditions include the use of the
acids (1). Rare and expensive late transition metals NCHPhCHPhN=CHCH2PAr2)]BPh4 C (Fig. 1) enantiopure diamine (S,S)-NH2CHPhCHPhNH2
such as ruthenium and rhodium have typically been suggested that one imine linkage of the bis [(S,S)-dpen] and a slight excess of the phosphonium
used in this context (2–4). Iron is an element essen- (imine)diphosphine ligand (P-N-N-P) of C was dimer, 0.65 equiv.
tial to life and is abundant in mineral ores, in con- reduced by hydride addition from isopropoxide
These iron complexes are treated with lithium
trast to these precious metals, and thus its use is in a slow activation step (Fig. 1, reaction 3) to aluminum hydride to reduce the imine linkages
preferable for economic and health reasons. Recent produce complexes within the catalytic cycle. These and then hydrolyzed to release the enantiopure
research has shown that suitably designed ligands were postulated to be iron amide and iron hydride compounds 1a and 1b in high yields. This meth-
can activate iron complexes so that their catalytic complexes on the basis of computational chem- od is superior to other reductive amination meth-
turnover frequency rivals or surpasses that of in- istry and the trapping of these reactive interme- ods that either would require an excess of the
dustrial catalysts (5–7). We describe here an excep- diates by use of hydrogen chloride in ether to give expensive diamine or would result in a mixture of
complex F (reaction 6). Preliminary results showed amine products. The ligands are produced in ~90%
that complex F with an amine(imine)diphosphine purity and are used directly in the next step.
ligand (P-NH-N-P) was a more active catalyst pre-
These ligands enable the direct synthesis (via
Department of Chemistry, University of Toronto, 80 Saint
George Street, Toronto, Ontario M5S 3H6, Canada.
*Corresponding author. E-mail: rmorris@chem.utoronto.ca cursor than C (8, 9). This system reduced aceto- Fig. 2, reaction 9) of a range of catalyst precursors
1080