Asymmetric transfer hydrogenation in water with a supported Noyori-Ikariya catalyst

Article abstract of DOI:10.1021/ol0487175

(Chemical Equation Presented) The poly(ethylene glycol)-supported ruthenium precatalyst shown above is highly effective for asymmetric transfer hydrogenation of unfunctionalized aromatic ketones by HCOONa in neat water, affording fast rates, good to excellent enantioselectivities, and outstanding reusability.

Full text of DOI:10.1021/ol0487175

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3321-3324
Asymmetric Transfer Hydrogenation in
Water with a Supported Noyori−Ikariya
Catalyst
Xiaoguang Li,† Xiaofeng Wu,† Weiping Chen,† Fred E. Hancock,‡ Frank King,‡ and
,†
Jianliang Xiao*
Department of Chemistry, LiVerpool Center for Materials and Catalysis,
UniVersity of LiVerpool, LiVerpool L69 7ZD, UK, and Johnson Matthey,
Billingham, CleVeland TS23 1LB, UK
j.xiao@liV.ac.uk
Received July 6, 2004
ABSTRACT
The poly(ethylene glycol)-supported ruthenium precatalyst shown above is highly effective for asymmetric transfer hydrogenation of
unfunctionalized aromatic ketones by HCOONa in neat water, affording fast rates, good to excellent enantioselectivities, and outstanding
reusability.
Asymmetric transfer hydrogenation of ketones has recently
emerged as an alternative method to asymmetric hydrogena-
tion for the production of chiral alcohols due to its operational
simplicity and the easy availability of reductants.1 Among
the various chiral catalysts reported, the most notable is the
ruthenium catalyst Ru-TsDPEN (TsDPEN) N-(p-toluene-
sulfonyl)-1,2-diphenylethylenediamine) developed by Noyori,
Ikariya, Hashiguchi, and co-workers.2 This catalyst and
related variants have since been applied by Noyori, Ikariya,
and others to a wide range of prochiral ketones and imines,
leading to good to excellent ees in 2-propanol and the
HCOOH-NEt3 azeotropic mixture, which have been used
almost exclusively as hydrogen donor as well as solvent for
the ruthenium catalyst.3-6 In terms of catalyst activity and
reusability, there is still room for improvement, however.
(3) ) (a) Hamada, T.; Torri, T.; Izawa, K.; Ikariya, T. Tetrahedron 2004,
60, 7411-7417. (b) Watanabe, M.; Murata, K.; Ikariya, T. J. Org. Chem.
2002, 67, 1712-1715. (c) Okano, K.; Murata, K.; Ikariya, T. Tetrahedron
Lett. 2000, 41, 9277-9280. (d) Murata, K.; Okano, K.; Miyagi, M.; Iwane,
H.; Noyori, R.; Ikariya, T. Org. Lett. 1999, 1, 1119-1121. (e) Matsumura,
K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119,
8738-8739. (f) Hashiguchi, S.; Fujii, A.; Haack, K.-J.; Matsumura, K.;
Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 288-290.
(g) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T. Noyori, R. J. Am.
Chem. Soc. 1996, 118, 4916-4917. (h) Fujii, A.; Hashiguchi, S.; Uematsu,
N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521-2522.
(4) For some recent examples, see: (a) Hannedouche, J.; Clarkson, G.
J.; Wills, M. J. Am. Chem. Soc. 2004, 126, 986-987. (b) Geldbach, T. J.;
Dyson, P. J. J. Am. Chem. Soc. 2004, 126, 8114-8115. (c) Sterk, D.;
Stephan, M. S.; Mohar, B. Tetrahedron Lett. 2004, 45, 535-537. (d) Pasto,
M.; Riera, A.; Pericas, M. A. Eur. J. Org. Chem. 2002, 2337-2341. (e)
Maj, A. M.; Pietrusiewicz, K. M.; Suisse, I.; Agbossou, F.; Mortreux, A. J.
Organomet. Chem. 2001, 626, 157-160. (f) Petra, D. G. I.; Kamer, P. C.
J.; Spek, A. L.; Schoemaker, H. E.; van Leeuwen, P. W. N. M. J. Org.
Chem. 2000, 65, 3010-3017. (g) Mizugaki, T.; Kanayama, Y.; Ebitani,
K.; Kaneda, K. J. Org. Chem. 1998, 63, 2378-2381. (h) Palmer, M.;
Walsgrove, T.; Wills, M. J. Org. Chem. 1997, 62, 5226-5228.
† University of Liverpool.
‡ Johnson Matthey.
(1) For recent reviews, see: (a) Blaser, H.-U.; Malan, C.; Pugin, B.;
Spindler, F.; Steiner, H.; Studer, M. AdV. Synth. Catal. 2003, 345, 103-
151. (b) Everaere, K.; Mortreux, A.; Carpentier, J.-F. AdV. Synth. Catal.
2003, 345, 67-77. (c) Saluzzo, C.; Lemaire, M. AdV. Synth. Catal. 2002,
344, 915-928. (d) Fan, Q. H.; Li, Y. M.; Chan, A. S. C. Chem. ReV. 2002,
102, 3385-3466. (e) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry
1999, 10, 2045-2061. (f) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997,
30, 97-102.
(2) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1995, 117, 7562-7563.
10.1021/ol0487175 CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/20/2004

Herein we report that, when carried out in water, the ketone
reduction can be drastically accelerated with the additional
benefit of very easy catalyst recycle.
h with no need for additional base.9,10 The transfer hydro-
genation started with the introduction of 5 equiv of HCOONa
(2.5 M) and acetophenone (0.5 M). To our delight, the
reaction proceeded to give a 99% conversion at a substrate/
catalyst (S/C) ratio of 100 and 40 °C in 1 h, furnishing (R)-
1-phenylethanol in 92% ee (entry 1, Table 1). In comparison
Table 1. Asymmetric Transfer Hydrogenation of
Acetophenone under Various Conditionsa
[HCOONa] temp time conversionb eeb
As with most other homogeneous catalysts, the Noyori-
Ikariya Ru-TsDPEN catalyst cannot be easily separated from
products. To address the challenge, various immobilized
TsDPEN and related ligands have been reported. However,
few have been demonstrated to be both effective and
recyclable, and none appears to be more active than TsDPEN
itself.5,6 As part of a program aimed at developing supported
chiral diamines,7 we recently reported that the poly(ethylene
glycol)-supported TsDPEN, PTsDPEN, is effective in the
Ru(II)-catalyzed asymmetric reduction of unfunctionalized
aromatic ketones by HCOOH-NEt3; however, catalyst
recycle appears to be possible only when some water is
present as a cosolvent.7a In its absence, much reduced
conversions and ees were observed. We now disclose that
water is in fact an excellent solvent for the Ru-PTsDPEN-
catalyzed reaction with HCOONa as a reductant. Very
recently, we have shown that the unmodified Ru-TsDPEN
is also highly effective for ketone reduction by HCOONa in
water;8 however, recycle of the catalyst proved to be difficult
due to the catalyst being soluble in common solvents, which
renders catalyst separation by extraction impossible.
entry
S/C
(M)
(°C)
(h)
(%)
(%)
1
2
3
4
5c
6
7d
8e
9f
100
100
100
100
100
1000
1000
1000
1000
2.5
2.5
1.0
5.0
2.5
5.0
5.0
5.0
40
22
40
40
22
40
40
40
40
1
8
4
1
8
12
44
44
12
99
>99
>99
>99
>99
>99
>99
36
92
93
89
93
94
89
89
75
89g
34
a For detailed procedures, see ref 9. b Determined by GC. The alcohol
configuration was R and was determined by comparison of GC retention
time or sign of optical rotation with literature data. c Sodium dodecyl sulfate
(4 mol %) was added. d Performed in CH2Cl2-H2O (1:1). e Performed in
toluene-H2O (1:1). f According to Wills’s procedure, in iPrOH with (1R,2S)-
(+)-amino-2-indanol as a ligand.4h g (S)-Isomer formed.
with the HCOOH-Et3N azeotrope solvent using similarly
prepared catalyst11 or using the Ru-TsDPEN catalyst,10 the
current system affords a reduced ee, but a much faster rate.
This is evident from the time-conversion diagram shown
in Figure 1. With the azeotrope as both reductant and solvent,
the Ru-PTsDPEN catalyst produced an ee of 93% and a
conversion of 96% in 22 h, while the Ru-TsDPEN catalyst
furnished a 97% ee and a 98% conversion in 16 h. There
appears to be an induction period for both catalysts in the
azeotrope, and it is longer for the PEG-supported one.
We set out by examining the asymmetric transfer hydro-
genation of acetophenone to 1-phenylethanol. The precatalyst
was generated by reacting the polymer-supported ligand
PTsDPEN with [RuCl2(p-cymene)]2 in water at 40 °C for 1
(5) For examples of supported TsDPEN and related diamines, see: (a)
Liu, P. N.; Gu, P. M.; Wang, F.; Tu, Y. Q. Org. Lett. 2004, 6, 169-172.
(b) Itsuno, S.; Tsuji, A.; Takahashi, M. Tetrahedron Lett. 2003, 44, 3825-
3828. (c) 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, 1488-1489. (d) Touchard,
F.; Fache, F.; Lemaire, M. Eur. J. Org. Chem. 2000, 3787-3792. (e)
Bayston, D. J.; Travers, C. B.; Polywka, M. E. C. Tetrahedron: Asymmetry
1998, 9, 2015-2018. (f) ter Halle, R.; Schulz, E.; Lemaire, M. Synlett 1997,
1257-1258.
(8) Wu, X. F.; Li, X. G.; Hems, W.; King, F.; Xiao, J. L. Org. Biomol.
Chem. 2004, 2, 1818-1821.
(9) General Procedure. [RuCl2(p-cymene)]2 (3.1 mg, 0.005 mmol) and
PTsDPEN7a (50 mg, 0.012 mmol) were dissolved in 2 mL of water. After
the solution was stirred at 40 °C for 1 h, HCO2Na (340 mg, 5 mmol) and
acetophenone (120 mg, 1.0 mmol) were added to the solution. Following
degassing three times, the solution was allowed to react at 40 °C for a
certain period of time. After the solution was cooled to room temperature,
the organic compounds were extracted with Et2O (6 mL). The conversion
and enantioselectivity were determined by GC analysis (Chrompack Chirasil-
Dex CB (25 m × 0.25 mm) column). In the case of recycle (10 equiv of
HCO2Na was used in the first run), following each reduction the aqueous
phase was extracted with ether (2 × 3 mL) by using a syringe, and the new
reduction was started by introducing another portion of acetophenone (120
mg) along with 1 equiv of HCOOH (0.1 mL, 10 M). There was no
significant decrease in the reaction rates in the first 11 runs; however, the
14th run gave a 87% conversion in 48 h.
(6) For literature about aqueous-phase asymmetric transfer hydrogenation
of ketones, see: (a) Ma, Y. P.; Liu, H.; Chen, L.; Cui, X.; Zhu, J.; Deng,
J. G. Org. Lett. 2003, 5, 2103-2106. (b) Himeda, Y.; Onozawa-
Komatsuzaki, N.; Sugihara, H.; Arakawa, H.; Kasuga, K. J. Mol. Catal. A:
Chem. 2003, 195, 95-100. (c) Rhyoo, H. Y.; Park, H. J.; Suh, W. H.;
Chung, Y. K. Tetrahedron Lett. 2002, 43, 269-272. (d) Rhyoo, H. Y.;
Park, H. J.; Chung, Y. K. Chem. Commun. 2001, 2064-2065. (e) Thorpe,
T.; Blacker, J.; Brown, S. M.; Bubert, C.; Crosby, J.; Fitzjohn, S.;
Muxworthy, J. P.; Williams, J. M. J. Tetrahedron Lett. 2001, 42, 4041-
4043. (f) Bubert, C.; Blacker, J.; Brown, S. M.; Crosby, J.; Fitsjohn, S.;
Muxworthy, J. P.; Thorpe, T.; Williams, J. M. Tetrahedron Lett. 2001, 42,
4037-4039. (g) Ogo, S.; Makihara, N.; and Watanabe, Y. Organometallics
1999, 18, 5470-5474.
(10) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R.
Angew. Chem., Int. Ed. Engl. 1997, 36, 285-288.
(11) Catalyst was prepared in a way similar to that given in ref 9 except
CH2Cl2 instead of water was used as solvent at rt for 30 min. The reduction
was started following removal of CH2Cl2 and then introduction of the
azeotrope.
(7) (a) Li, X. G.; Chen, W. P.; Hems, W.; King, F.; Xiao, J. L.
Tetrahedron Lett. 2004, 45, 951-953. (b) Li, X. G.; Chen, W. P.; Hems,
W.; King, F.; Xiao, J. L. Org. Lett. 2003, 5, 4559-4561.
3322
Org. Lett., Vol. 6, No. 19, 2004

Encouraged by the results, the reduction was extended to
other nonfunctionalized aromatic ketones. Table 2 sum-
Table 2. Asymmetric Transfer Hydrogenation of Ketones with
Ru-PTsDPEN by HCOONa in Watera
temp
(°C)
time
(h)
conversionc
(%)
eec
ketoneb
(%)
Acp
Acp
2′-chloro-acp
2′-chloro-acp
4′-chloro-acp
4′-trifluoromethyl-acp
3′-methoxy-acp
4′-methyl-acp
1′-acetonaphthone
2′-acetonaphthone
2′-acetonaphthone
2-acetylfuran
1-indanone
22
40
22
40
22
22
22
22
22
22
40
22
22
40
22
40
8
1
>99
99 (98)
>99
93
92
91
85
90
85
90
86
88
94
92
91
93
92
94
92
13
1.5
13
12
18
18
36
36
8
18
18
3
18
3
Figure 1. Conversion-time diagram for the reduction of acetophe-
none (0.5 M) in HCOONa-water with Ru-PTsDPEN9 and in
HCOOH-NEt3 with Ru-TsDPEN10 and Ru-PTsDPEN11 at 40
°C.
100 (99)
>99 (98)
>99 (91)
98 (97)
>99 (99)
85 (91)
>99
88 (87)
98 (87)
>99
Table 1 also shows the effect of other variables on the
reaction. Thus, lowering the temperature to 22 °C yielded a
slightly higher ee at a longer time. The reaction is also
affected by the concentration of the formate, with a lower
concentration yielding a slower reduction and a lower ee
(entries 1, 3, and 4), but it does not appear to be much
affected by adding a surfactant (entry 5). Similar observations
have been made with the ruthenium catalysts containing
proline amides6c and a water-soluble, sulfonated TsDPEN.6a
However, surfactants have proved to be important with these
catalysts, particularly in the case of the latter. In our case,
PEG itself can serve as a phase-transfer catalyst,12,15 facilitat-
ing the transfer of ketones to water. The reaction was also
feasible at a higher S/C ratio of 1000, though a prolonged
reaction time was necessary (entry 6). The benefit of using
neat water as the solvent is further seen in entries 7 and 8,
where dichloromethane and toluene were introduced into the
aqueous solution, respectively, creating a biphasic system
in both cases. The presence of the organic solvents brought
about a much slower reaction and, unexpectedly, resulted in
a significant reduction in ee in the case of toluene. Although
the decrease in rates may be ascribed to substrate diffusion
control, a homogeneous mixture of H2O-CH3CN led to a
similar, slow reaction. The advantage of the current system
over one of the most active asymmetric transfer catalysts, a
complex similar to Ru-TsDPEN but containing a â-amino
alcohol ligand, is seen by comparing entries 9 and 6.4h
1-indanone
1-tetralone
1-tetralone
100 (98)
>99
98 (97)
a Reactions were performed at the temperatures indicated, using 1 mmol
of ketone, 5 equiv of HCOONa, and a S/C ratio of 100 in 2 mL of water.
b Acp ) acetophenone. c Determined by GC equipped with a chiral column.
Numbers in brackets refer to isolated yields for reactions performed at 40
°C (for details, see Supporting Information). The alcohol configuration was
R.
marizes the results obtained. As can be seen, various ketones,
including 2-substituted, electron-rich, and electron-deficient
variants, were reduced with good to excellent ee values using
HCOONa as the reductant and neat water as the solvent. At
the room temperature of 22 °C, the reactions took longer
times to complete than at 40 °C but gave slightly higher
ees. As in the case of acetophenone, a most notable feature
of these reactions is their rates, which are much faster than
those observed with the same Ru-PTsDPEN catalyst in the
HCOOH-NEt3 azeotrope. Thus, for example, when carried
out in the azeotrope at 50 °C at S/C ) 100 (1 M substrate),
the reduction of 4′-methylacetophenone with Ru-PTsDPEN
led to a conversion of 75% in 30 h and an ee value of 88%.7a
In sharp contrast, when switched to aqueous HCOONa, the
same catalyst afforded a conversion of 99% and an ee of
86% in 18 h at a lower temperature of 22 °C. Another
remarkable example is seen in the reduction of 1-indanone
with Ru-PTsDPEN, which led to a 71% conversion and
88% ee in 25 h at 50 °C in HCOOH-NEt3,7a but a complete
reaction with an increased ee of 92% in 3 h at 40 °C in
water.
(12) Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. ReV. 2002, 102,
3325-3344.
(13) (a) Kobayashi, S. AdV. Synth. Catal. 2002, 344, 219. (b) Joo, F.
Aqueous Organometallic Catalysis; Kluwer: Dordrecht, 2001. (c) Li, C.
J.; Chan, T. H. Organic Reactions in Aqueous Media; Wiley: New York,
1997.
(14) For recent mechanistic studies, see: (a) Koike, T.; Ikariya, T. AdV.
Synth. Catal. 2004, 346, 37-41. (b) Brandt, P.; Roth. P.; Andersson, P. G.
J. Org. Chem. 2004, 69, 4885-4890 and references therein. (c) Casey, C.
P.; Johnson, J. B. J. Org. Chem. 2003, 68, 1998-2001. (d) Noyori, R.;
Yamakawa, M.; Hashiguchi, S. J. Org. Chem. 2001, 66, 7931-7944.
(15) Starks, C. M.; Liotta, C. L.; Halpern, M. Phase-Transfer Catalysis;
Chapman & Hall: London, 1994; Chapter 4.
The PEG-supported TsDPEN was designed to facilitate
catalyst/product separation. However, as indicated above,
when the reduction was carried out in the HCOOH-NEt3
azeotrope, catalyst recycle led quickly to loss of catalyst
Org. Lett., Vol. 6, No. 19, 2004
3323

activity and enantioselectivity, presumably due to the
decomposition of active Ru-PTsDEPEN complexes.7a In the
aqueous-phase reaction, the ruthenium catalyst is certainly
more stable. In fact, the reduction with Ru-PTsDEPEN can
be run in water in the open air without much compromise
in conversion and ee (95% conversion and 91% ee in 1.5 h
with S/C ) 100 and 5 equiv of HCOONa).
With a stable catalyst system in hand, separation and
recycle of the catalyst becomes much easier to perform. Thus,
in the end of a reduction, a solvent of low polarity such as
diethyl ether can be added to precipitate the Ru(II)-
PTsDPEN catalyst.12 In the particular case of acetophenone
reduction, we measured the leached ruthenium; ICP analysis
showed that 0.4 mol % ruthenium had leached into the
organic phase (diethyl ether).
A demonstration of the excellent recyclability of the
catalyst is shown in Figure 2. As can be seen, the im-
mobilized catalyst can be reused more than 10 times with
no loss in enantioselectivity. Toward the end of the recycle
(runs 12-14), longer reaction times were necessary to deliver
the observed conversions. This decrease in catalytic activity
is most likely due to catalyst loss during solvent extraction
rather than its decomposition, as the ees remained literally
unchanged even at the 14th run. To the best of our
knowledge, this represents the most efficient catalyst system
in transfer hydrogenation in terms of catalyst recyclability
and activity5,6 and a novel example of water-accelerated
reactions in aqueous catalysis.13
In conclusion, this work demonstrates that the Ru-
PTsDPEN catalyst is highly effective for the asymmetric
transfer hydrogenation of ketones by formate in water, in
which it is stable, recyclable, and capable of delivering good
to excellent enantioselectivities. A most interesting question
arising from the work is how water stabilizes the ruthenium
catalyst and accelerates the reaction.14 This and the possible
Figure 2. Conversions (grey bar) and ees (black bar) (%) against
number of runs in the reduction of acetophenone by HCOONa with
Ru-PTsDPEN in water at 40 °C.9
application of the catalytic system to other reactions are being
explored in our lab.
Acknowledgment. We thank Johnson Matthey for fi-
nancial support and Dr. William Hems and Dr. Antonio
Zanotti-Gerosa for helpful discussions. We also thank
Johnson Matthey for the loan of ruthenium.
Supporting Information Available: Experimental pro-
cedures for the hydrogenation of aromatic ketones and
1
catalyst recycle and H and 13C NMR data, GC retention
times, and isolated yields for the alcohol products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0487175
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