Asymmetric Hydrogenation of Ketones with Polymer-Supported Chiral 1,2-Diphenylethylenediamine

Article abstract of DOI:10.1021/ol0355837

(Equation presented) A poly(ethylene glycol)-supported chiral diamine (PEG-2), in which the polymer is attached to the phenyl rings, has been synthesized and shown to be highly effective in asymmetric hydrogenation of unfunctionalized aromatic ketones with the possibility of reuse. PEG-2 can also serve as a chiral scaffold on which various immobilized chiral catalysts could be easily built.

Full text of DOI:10.1021/ol0355837

ORGANIC
LETTERS
2003
Vol. 5, No. 24
4559-4561
Asymmetric Hydrogenation of Ketones
with Polymer-Supported Chiral
1,2-Diphenylethylenediamine
,†
Xiaoguang Li,† Weiping Chen,† William Hems,‡ Frank King,‡ and Jianliang Xiao*
LeVerhulme Centre for InnoVatiVe Catalysis, Department of Chemistry, UniVersity of
LiVerpool, LiVerpool L69 7ZD, U.K., and Johnson Matthey Synetix,
Billingham, CleVeland TS23 1LB, U.K.
j.xiao@liV.ac.uk
Received August 22, 2003
ABSTRACT
A poly(ethylene glycol)-supported chiral diamine (PEG-2), in which the polymer is attached to the phenyl rings, has been synthesized and
shown to be highly effective in asymmetric hydrogenation of unfunctionalized aromatic ketones with the possibility of reuse. PEG-2 can also
serve as a chiral scaffold on which various immobilized chiral catalysts could be easily built.
Asymmetric catalysis with polymer-supported transition
metal complexes has attracted a great deal of recent interest.1
A prominent advantage of immobilized chiral catalysts lies
in easy catalyst separation and recycle. This is important
considering in particular that such catalysts are usually
expensive and toxic. When the supporting polymer is soluble
and can be separated by various chemical and physical
means, an additional advantage is offered: the reaction is
performed homogeneously, leading to higher rates and better
enantioselectivities than catalysts immobilized on solids.1a,b
Optically active 1,2-diphenylethylenediamine [DPEN,
(R,R)-1] is one of the most important chiral ligands. DPEN
and its derivatives have been used as ligands for metals such
as Ru(II), Co(II), Al(III), Mn(III), and Os(VIII) to generate
highly enantioselective catalysts for many asymmetric or-
ganic transformations, such as asymmetric reduction of
ketones,2 Aldol reaction,3 Diels-Alder reaction,4 epoxida-
tion,5 and dihydroxylation.6 Polymer-supported DPEN and
derivatives have recently been reported and shown to be
efficient in the asymmetric hydrogenation and transfer
hydrogenation of ketones.7,8 So far all of the immobilization
methods hinge on the functionalization of the nitrogen atom
and thus render further derivatization difficult and are limited
to reactions where the coordinating amino group NH2 can
be modified. To the best of our knowledge, polymer-
(2) (a) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1995, 117, 2675. For a review, see: (b) Noyori, R.;
Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40.
(3) Corey, E. J.; Kim, S. S. J. Am. Chem. Soc. 1990, 112, 4976.
(4) (a) Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J. Am.
Chem. Soc. 1989, 111, 5493. (b) Corey, E. J.; Sarshar, S.; Bordner, J. J.
Am. Chem. Soc. 1992, 114, 7938. (c) Corey, E. J.; Letavic, M. A. J. Am.
Chem. Soc. 1995, 117, 9616.
(5) (a) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am.
Chem. Soc. 1990, 112, 2801. (b) Jacobsen, E. N.; Zhang, W.; Muci, A. R.;
Ecker, J. R.; Deng, L. J. Am. Chem. Soc. 1991, 113, 7063. (c) Irie, R.;
Noda, K.; Ito, Y.; Katsuki, T. Tetrahedron Lett. 1991, 32, 1055. (d) Irie,
R.; Ito, Y.; Katsuki, T. Synlett 1991, 265.
(6) (a) Corey, E. J.; Jardine, P. D.; Virgil, S.; Yuen, P. W.; Connell, R.
D. J. Am. Chem. Soc. 1989, 111, 9243. (b) Corey, E. J.; Sarshar, S.;
Azimioara, M. D.; Newbold, R. C.; Noe, M. C. J. Am. Chem. Soc. 1996,
118, 7851.
† University of Liverpool.
‡ Johnson Matthey.
(1) For recent reviews, see: (a) Dickerson, T. J.; Reed, N. N.; Janda, K.
D. Chem. ReV. 2002, 102, 3325. (b) Bergbreiter, D. E. Chem. ReV. 2002,
102, 3345. (c) Fan, Q. H.; Li, Y. M.; Chan, A. S. C. Chem. ReV. 2002,
102, 3385. (d) Leadbeater, N. E.; Marco, M. Chem. ReV. 2002, 102, 3217.
(e) Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer,
M. AdV. Synth. Catal. 2003, 345, 103.
10.1021/ol0355837 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/29/2003

supported DPEN, in which the polymer is linked to the
phenyl rings, had not been reported before this research was
launched.9 We report herein that the poly(ethylene glycol)-
supported (R,R)-2 (PEG-2) is an efficient ligand for the
asymmetric hydrogenation of simple ketones, furnishing
excellent enantioselectivities and enabling easy catalyst
separation and recycle. We also demonstrate that PEG-2 can
provide a versatile chiral platform on which various im-
mobilized chiral catalysts can be readily built.
in almost quantitative yield. The diphenol (R,R)-5 was then
converted into PEG-2 by reaction with poly(ethylene glycol)
2000 monomethyl ether mesylate and removal of Boc at 6.
As with other PEG-supported ligands/catalysts,1a,b PEG-2 is
soluble in polar solvents such as lower alcohols, water and
DMF, but insoluble in solvents of low polarity such as diethyl
ether.
To investigate the efficiency of PEG-2 in asymmetric
catalysis, the ruthenium-catalyzed asymmetric hydrogenation
of simple ketones developed by Noyori and co-workers was
chosen as a model reaction (Scheme 2).2 The Noyori catalyst
Scheme 2. Asymmetric Hydrogenation of Ketones with 8
PEG-2 was synthesized from the functionalized, enantio-
merically pure 1,2-diphenylethylenediamine (R,R)-3, which
was prepared from 3-benzyloxylbenzaldehyde (Scheme 1).10
Scheme 1. Synthesis of Poly(ethylene glycol)-Supported
PEG-2
operates on a dual ligand system composed of a chiral
primary diamine and a chiral bisphosphine, e.g., DPEN and
BINAP, and successful attempts have been made in its
immobilization through the BINAP naphthyl rings.7 We first
prepared the catalyst 8 by reacting the PhanePhos ligand (S)-7
with [(benzene)RuCl2]2 at 100 °C in DMF for 3 h, followed
by treatment with 1 equiv of PEG-2 at room temperature
for 12 h.11,12 Our initial effort was directed at probing the
asymmetric induction of the catalyst using acetonaphthone
9 as substrate. In the presence of 8 under 10 bar H2, the
asymmetric hydrogenation of 9 in 2-propanol using t-BuOK
as base provided (S)-1-naphthylethanol in 98% yield and 97%
ee over 2 h at S/C ) 2000 at room temperature. The ee is
comparable to that obtained with the parent, molecular
catalyst, [((S)-PhanePhos)RuCl2((R,R)-DPEN)].11a
Protection with Boc of (R,R)-3, followed by the reduction
of 4 with hydrogen in the presence of Pd/C, afforded (R,R)-5
(7) References for supported BINAP: (a) Bayston, D. J.; Fraser, J. L.;
Ashton, M. R.; Baxter, A. D.; Polywka, M. E. C.; Moses, E. J. Org. Chem.
1998, 63, 3137. (b) ter Halle, R.; Schulz, E.; Spagnol, M.; Lemaire, M.
Synlett 2000, 680. (c) Yu, H. B.; Hu, Q. S.; Pu, L. Tetrahedron Lett. 2000,
41, 1681. (d) Yu, H. B.; Hu, Q. S.; Pu, L. J. Am. Chem. Soc. 2000, 122,
6500. (e) Fan, Q.-H.; Chen, Y.-M.; Chen, X.-M.; Jiang, D.-Z.; Xi, F.; Chan,
A. S. C. Chem. Commun. 2000, 789. (f) Ohkuma, T.; Takeno, H.; Honda,
Y.; Noyori, R. AdV. Synth. Catal. 2001, 343, 369. (g) Deng, G.-J.; Fan,
Q.-H.; Chen, X.-M.; Liu, D.-S.; Chan, A. S. C. Chem. Commun. 2002, 1570.
(8) References for supported DPEN: (a) ter Halle, R.; Schulz, E.;
Lemaire, M. Synlett 1997, 1257. (b) Bayston, D. J.; Travers, C. B.; Polywka,
M. E. C. Tetrahedron: Asymmetry 1998, 9, 2015. (c) Bubert, C.; Blacker,
J.; Brown, S. M.; Crosby, J.; Fitzjohn, S.; Muxworthy, J. P.; Thorpe, T.;
Williams, J. M. J. Tetrahedron Lett. 2001, 42, 4037. (d) Chen, Y.-C.; Wu,
T.-F.; Deng, J.-G.; Liu, H.; Jiang, Y.-Z.; Choi, M. C. K.; Chan, A. S. C.
Chem. Commun. 2001, 1488.
(11) PhanePhos:
4,12-bis(diphenylphospino)-[2,2]paracyclophane.
(9) While our work was in progress, which was first communicated at
the 11th ICI Symposium in May 2002, two publications appeared where
DPEN was immobilized through functionalization at the phenyl ring: (a)
Itsuno, S.; Tsuji, A.; Takahashi, M. Tetrahedron Lett. 2003, 44, 3825. (b)
Ma, Y.-P.; Liu, H.; Chen, L.; Cui, X.; Zhu, J.; Deng, J.-G. Org. Lett. 2003,
5, 2103.
See: (a) Burk, M. J.; Hems, W.; Herzberg, D.; Malan, C.; Zanotti-Gerosa,
A. Org. Lett. 2000, 2, 4173. (b) Pye, P. J.; Rossen, K.; Reamer, R. A.;
Tsou, N. N.; Volante, R. P.; Reider, P. J. J. Am. Chem. Soc. 1997, 119,
6207. (c) Pye, P. J.; Rossen, K.; Reamer, R. A.; Volante, R. P.; Reider, P.
J. Tetrahedron Lett. 1998, 39, 4441.
(12) The nitrogen content of PEG-2 is 0.61% (or 92% of theoretical
loading), which leads to a Ru/7/diamine ratio of 1/1/1.1 in 8.
(10) The details of the synthesis will be published elsewhere.
4560
Org. Lett., Vol. 5, No. 24, 2003

first step toward this direction, four ruthenium complexes
of (R)-BINAP, (R)-tolBINAP, (R)-MeO-BIPEHP, and DPPF
were individually complexed with PEG-2 to give four
catalysts, each containing an amino functionality necessary
for the ketone hydrogenation. As shown in Table 2, the
Table 1. Results of Asymmetric Hydrogenation of Ketones
with 8a
ketone
time (h)
conversion (%)b
ee (%)b
9
2
10
2
2
4
4
4
4
2
98
100
100
99
100
100
100
99
97 (S)
97 (S)
96 (S)
94 (S)
93 (S)
97 (S)
90 (S)
90 (S)
94 (S)
92 (S)
9c
10
Table 2. Asymmetric Hydrogenation of Ketones by Combining
PEG-2 with Different Bisphosphinesa
11a
11b
11c
11d
11e
12a
12b
100
100
3
a Reactions were performed at room temperature under 10 bar H2 with
1.0-2.0 M solution of ketone in i-PrOH at S/C ) 2000 with t-BuOK as
base (base/Ru ) 12) unless otherwise noted. b Determined by chiral GC.
The alcohol configuration was determined by comparison of GC retention
time or sign of optical rotation with literature data. c S/C ) 10000, initial
H2 pressure 50 bar.
phosphine
time (h)
conversion (%)
ee (%)
13a b
13b
14b
4
12
12
4
99
100
99
98 (S)
91 (S)
92 (S)
61 (S)
15b
99
The asymmetric hydrogenation was then extended to other
ketone substrates. As shown in Table 1, the immobilized 8
exhibited excellent enantioselectivities and activities for the
hydrogenation of various aromatic ketones, including 2-ac-
etonaphthone, substituted acetophenones, and propiophenone.
The acetophenones 11a-e, regardless of being activated or
deactivated, all furnished high ee’s. Of particular note is that
the reaction can be run at a much higher S/C ratio without
affecting the ee, as exemplified by the hydrogenation of 9
at S/C ) 10 000.
A most important feature of polymer-supported catalysts
is their easy separation and reuse. This is the case with the
catalyst 8. A recycling experiment was carried out with
ketone 9 at 9 bar H2 and S/C ) 1000 over 3 h. The catalyst
was then precipitated by Et2O, and the product was removed
by syringe. In three consecutive reactions, the catalyst
afforded conversions of 98%, >99%, and 96%, with the
corresponding ee’s being 96.1%, 96.1%, and 96.0%, showing
only slightly decreased activity and no loss in enantioselec-
tivity. The leached ruthenium in the Et2O solution upon
precipitation of the catalyst was shown, without any opti-
mization, to be low at 2.7 ppm, a feature that is particularly
appealing to the manufacture of pharmaceutical intermedi-
ates.
a See Table 1 for conditions. b The catalysts were prepared in situ by
reacting the ruthenium-phosphine complex with PEG-2 in i-PrOH.
catalysts derived from the three chiral phosphines all resulted
in excellent ee values, and with the (R)-BINAP ligand, an
ee of 98% was observed. DPPF produced an active catalyst
but did not yield a high enantioselectivity, although it could
be asymmetrically activated by PEG-2 upon coordination to
ruthenium.13
In conclusion, a supported chiral diamine has been
developed and shown to be highly effective in asymmetric
hydrogenation of simple aromatic ketones. A further interest-
ing aspect of this study is that ligands such as this could
serve as a chiral platform on which to build catalysts of
designer properties.
Acknowledgment. We thank Johnson Matthey Synetix
for financial support and Dr. Robert Tooze for helpful
discussions at the beginning of the project.
Supporting Information Available: Experimental pro-
cedures for the synthesis of chiral PEG-2, procedures for
the hydrogenation of aromatic ketones and catalyst recycle,
and analytical data for chiral aromatic alcohols. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0355837
Unlike many other immobilized ligands, PEG-2 can readily
be used as a scaffold to build tailor-made chiral catalysts by
combining with desired ligands or by derivatization. As the
(13) (a) Mikami, K.; Aikawa, K. Org. Lett. 2002, 4, 99. (b) Subongkoj,
S.; Lange, S.; Chen, W.; Xiao, J. J. Mol. Catal. 2003, 196, 125.
Org. Lett., Vol. 5, No. 24, 2003
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