Asymmetric transfer hydrogenation of ketones with a polymer-supported chiral diamine

Article abstract of DOI:10.1016/j.tetlet.2003.11.104

A new supported chiral diamine has been developed and shown to be highly effective in ruthenium-catalysed asymmetric transfer hydrogenation of simple aromatic ketones.

Full text of DOI:10.1016/j.tetlet.2003.11.104

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 951–953
Asymmetric transfer hydrogenation of ketones with a
polymer-supported chiral diamine
Xiaoguang Li,a Weiping Chen,a William Hems,b Frank Kingb and Jianliang Xiaoa,*
aDepartment of Chemistry, Liverpool Centre for Materials and Catalysis, University of Liverpool, Liverpool L69 7ZD, UK
bJohnson Matthey Synetix, Billingham, Cleveland TS23 1LB, UK
Received 10 October 2003; revised 11 November 2003; accepted 21 November 2003
Abstract—A new supported chiral diamine has been developed and shown to be highly effective in ruthenium-catalysed asymmetric
transfer hydrogenation of simple aromatic ketones.
Ó 2003 Elsevier Ltd. All rights reserved.
Asymmetric transfer hydrogenation of prochiral ketones
to provide chiral alcohols has received a great deal of
attention in the last decade or so.1 Of the various chiral
catalysts reported, the most notable is TsDPEN 1
(TsDPEN ¼ N-(p-toluenesulfonyl)-1,2-diphenylethylene-
diamine) coordinated Ru(II) complexes developed by
Noyori and co-workers.2;3 Good to excellent results
have been achieved with TsDPEN and related ligands
using propan-2-ol or HCOOH-Et3N as hydrogen sour-
ces. As with other homogeneous catalysts, however,
these catalysts cannot be easily separated from products
and hence present a serious obstacle for synthetic
applications. Prompted by this, immobilised DPEN and
derivatives have been developed and shown to be effi-
cient in the asymmetric transfer hydrogenation of
ketones.4;5 So far all the immobilisation methods rely on
functionalisation of the nitrogen atom, and hence are
limited to reactions where the coordinating amino group
–NH2 can be modified.5 Herein we present a new form
of immobilised 1, where 1 is attached to a support via
the phenyl rings. This attachment minimises the effects
of the support on enantioface selection and makes it
easy to modify the amino functionality when necessary.
Specifically, we report that the polyethylene glycol-
supported (R,R)-2 (PEG-2) is an efficient ligand for the
asymmetric transfer hydrogenation of unfunctionalised
ketones, furnishing excellent enantioselectivities and
enabling easy catalyst separation. To the best of our
knowledge, polymer-supported TsDPEN or, more gen-
erally, DPEN (DPEN ¼ 1,2-diphenylethylenediamine),
in which the polymer is linked to the phenyl rings, had
not been reported before this research was launched.6
O
O
H2N
NHTs
H2N
NHTs
1
PEG-2
PEG-2 was conveniently synthesised from the
functionalised, enantiomerically pure 1,2-diphenylethyl-
enediamine (R,R)-3, which was prepared from 3-
benzyloxybenzaldehyde (Scheme 1).7 The diamine
(R,R)-3 was first monosulfonylated with TsCl to provide
(R,R)-4 in 75% yield. Boc protection of the diamine
(R,R)-4, followed by the reduction of 5 with hydrogen in
the presence of 10% Pd/C, afforded (R,R)-6 in an almost
quantitative yield. The diphenol (R,R)-6 was then con-
verted via 7 into PEG-2 by a nucleophilic reaction with
polyethylene glycol 2000 monomethyl ether mesylate
(MeO-PEG-OMs) followed by removal of the Boc
protecting group. As with other PEG-supported ligands/
catalyts,8 PEG-2 is soluble in polar solvents such as
lower alcohols, water and DMF, but insoluble in sol-
vents of low polarity such as diethyl ether.
The efficacy of PEG-2 in asymmetric catalysis was
assessed in the ruthenium-catalysed asymmetric transfer
hydrogenation of simple ketones using a protocol simi-
lar to that developed for 1.2f The chiral ruthenium
* Corresponding author. Tel.: +44-151-794-2937; fax: +44-151-794-
3589; e-mail: j.xiao@liv.ac.uk
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.104

952
X. Li et al. / Tetrahedron Letters 45 (2004) 951–953
O
O
t-Bu
t-Bu
O
O
O
NH2
NH2
TsCl, Et3N
THF, rt
EtN(i-Pr)2
BnO
BnO
BnO
OBn
OBn
OBn
CH2Cl2, rt
NHTs
(R,R)-4
NH2
(R,R)-3
MeO PEG OMs
Cs2CO3
BocHN
BocHN
H2, Pd/C
EtOH
HO
OH
DMF, 50 o
C
NHTs
(R,R)-5
NHTs
(R,R)-6
NH2
NHTs
BocHN
F3CCO2H
CH2Cl2, rt
O
MeO
O
PEG
O
PEG
O
OMe
NHTs
7
2
Scheme 1. Synthesis of polyethylene glycol-supported chiral diamine PEG-2.
catalyst was prepared by stirring [RuCl2(p-cymene)]2
with the polymer-supported ligand in dichloromethane
at room temperature for 30 min followed by removal of
the solvent. Acetophenone 8a was chosen as substrate
for initial testing, and the reaction was carried out by
adding the substrate and an azeotropic mixture of
HCOOH–Et3N to the catalyst.9 With a substrate/cata-
lyst (S/C) ratio of 100 at 40 °C, (R)-1-phenylethanol was
obtained in 90% yield and 95% ee in a 20 h reaction time
(Table 1, entry 1). In comparison, the molecular cata-
lyst, [RuCl2(p-cymene)((R,R)-TsDPEN)], produced an
ee of 98% at 28 °C.2f Increasing the reaction temperature
to 50 °C resulted in a higher conversion and only a slight
loss of enantioselectivity (entry 2). At a higher S/C ratio
of 250, the conversion decreased considerably, although
a higher turnover number was delivered; no change in
the ee value was observed (entry 3).
O
O
O
O
X
8a: X = H
9
10
11
8b: X = o-Cl
8c: X = p-Cl
8d: X = o-Me
8e: X = p-Me
8f: X = m-OMe
8g: X = m-Br
8h: X = p-CF3
O
Table 1. Asymmetric transfer hydrogenation of ketones with Ru(II)-
PEG-2 in formic acid–triethylamine azeotropea
O
O
O
OH
O
Ru(II)-PEG-2
12
14
13
Ar
Ar
HCOOH-Et3N
With these results in hand, the asymmetric transfer
hydrogenation was then extended to other ketone sub-
strates under the conditions of S/C ¼ 100 and 50 °C. As
shown in Table 1, the immobilised chiral Ru(II)-PEG-2
complex exhibited good to excellent enantioselectivities
for various aromatic ketones, including acetonaph-
thones, substituted acetophenones, propiophenone,
1-indanone and 1-tetralone. Results with the substituted
acetophenones 8a–h suggest that electron-withdrawing
groups show higher reaction activities and o-substitution
with bulky and electron-donating groups tends to afford
both low conversion and low ee. These observations are
reminiscent of those made with the parent molecular
analogue, [RuCl2(p-cymene)((R,R)-TsDPEN)] and are
in line with the six-membered transition state proposed
by Noyori, where a hydride at Ru(II) interacts with the
positively-charged carbonyl carbon atom.2a In the case
of 2-acetonaphthone 9, the reaction could be run at a
higher S/C ratio of 250 without notable loss of conver-
sion and enantioselectivity (entries 11 and 12). The
enantioselectivities shown in Table 1 are in general
slightly lower than those obtained with the molecular
catalyst 1. A notable exception is seen in the case of
1-acetonaphthone (entry 13), in which PEG-2 furnished
a significantly higher ee value than 1, the latter giving
Entry
Ketone
Time (h)
Conv. (%)b Ee (%)b
1c
2
3d
8a
8a
8a
8b
8c
8d
8e
8f
20
20
20
20
20
20
30
20
20
10
20
20
30
30
25
20
18
90
95
95 (R)
94 (R)
94 (R)
90 (R)
90 (R)
80 (R)
88 (R)
90 (R)
88 (R)
87 (R)
94 (R)
94 (R)
90 (R)
88 (R)
88 (R)
94 (R)
93 (R)
74
4
100
100
28
5
6
7
75
98
8
9
8g
8h
9
100
100
99
10
11
12d
13
14
15
16
17
9
98
71
10
11
12
13
14
66
71
99
100
a Reactions were performed at 50 °C with ketone (1.0 mmol) in a for-
mic acid–triethylamine azeotropic mixture (1.0 mL) at S/C ¼ 100.
b Determined by chiral GC. The alcohol configuration was determined
by comparison of the GC retention time or the sign of the optical
rotation with literature data.
c The reaction temperature was 40 °C.
d S/C ¼ 250.

X. Li et al. / Tetrahedron Letters 45 (2004) 951–953
953
rise to an ee of 83%.2f 1-Indanone 12 and 1-tetralone 13
could also be reduced to 1-indanol and 1-tetralol with
good chiral induction. Furthermore, 2-acetylfuran was
cleanly reduced to (R)-1-(2-furyl)ethanol in 93% ee
without saturating the furan ring (entry 17).
Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori,
R. Angew. Chem., Int. Ed. 1997, 36, 285–288; (e) Matsum-
ura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738–8739; (f) Fujii, A.; Hashiguchi,
S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
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hara, J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995,
117, 7562–7563.
An attractive feature of the present catalytic system lies
in the fact that the catalyst can be readily removed from
the product by addition of a low polarity solvent. Thus,
when the reduction reaction is complete, diethyl ether is
added to precipitate the Ru(II)-PEG-2 catalyst. In the
reduction of acetophenone 8a, ICP analysis of the
solution phase showed that less than 0.7 mol % of
ruthenium had leached into the solution. Attempts have
been made to recycle the catalyst. The experiment was
conducted with 8a using the HCO2H–Et3N azeotrope in
the presence of an equal volume of water (1 mL); the
catalyst was precipitated by introducing diethyl ether
and the product removed by syringe. In three consecu-
tive runs, the following conversions (eeÕs in parenthesis)
were observed: 99% (91%), 95% (92%) and 56% (82%).
These data suggest that whilst it is possible to recycle the
PEG-2 based catalyst, its stability remains to be
addressed.
3. For recent examples of similar ligands, see: (a) Handgraaf,
J.-W.; Reek, J. N. H.; Meijer, E. J. Organomet. 2003, 22,
€
€
3150–3157; (b) Pastor, I. M.; Vastila, P.; Adolfsson, H.
Chem. Commun. 2002, 2046–2047; (c) Sterk, D.; Stephan,
M. S.; Mohar, B. Tetrahedron: Asymmetry 2002, 13, 2605–
2608; (d) Rhyoo, H. Y.; Park, H.-J.; Chung, Y. K. Chem.
Commun. 2001, 2064–2065; (e) Cross, D. J.; Kenny, J. A.;
Houson, I.; Campbell, L.; Walsgrove, T.; Wills, M. Tetra-
hedron: Asymmetry 2001, 12, 1801–1806; (f) Nordin, S. J.
M.; Roth, P.; Tarnai, T.; Alonso, D. A.; Brandt, P.;
Andersson, P. G. Chem. Eur. J. 2001, 7, 1431–1436; (g)
Bubert, C.; Blacker, J.; Brown, S. M.; Fitzjohn, J. S.;
Muxworthy, J. P.; Thorpe, T.; Williams, J. M. J. Tetrahe-
dron Lett. 2001, 42, 4037–4039; (h) Petra, D. G. I.; Reek, J.
N. H.; Handgraaf, J.-W.; Meijer, E. J.; Dierkes, P.; Kamer,
P. C. J.; Brussee, J.; Schoemaker, H. E.; van Leeuwen, P. W.
N. M. Chem. Eur. J. 2000, 6, 2818–2829; (i) Alonso, D. A.;
Brandt, P.; Nordin, S. J. M.; Andersson, P. G. J. Am. Chem.
Soc. 1999, 121, 9580–9588; (j) Murata, K.; Ikariya, T.;
Noyori, R. J. Org. Chem. 1999, 64, 2186–2187; (k) Jiang,
Y.-T.; Jiang, Q.-Z.; Zhang, X.-M. J. Am. Chem. Soc. 1998,
120, 3817–3818; (l) Schwink, L.; Ireland, T.; Puntener, K.;
Knochel, P. Tetrahedron: Asymmetry 1998, 9, 1143–1163.
4. For recent reviews on polymer-immobilised ligands, see: (a)
Leadbeater, N. E.; Marco, M. Chem. Rev. 2002, 102, 3217–
3274; (b) Fan, Q.-H.; Li, Y.-M.; Chan, A. S. C. Chem. Rev.
2002, 102, 3385–3466; (c) van Heerbeek, R.; Kamer, P. C.
J.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Chem. Rev.
2002, 102, 3717–3756; (d) Clapham, B.; Reger, T. S.; Janda,
K. D. Tetrahedron 2001, 57, 4637–4662.
In summary, we have developed a new polymer sup-
ported, soluble chiral diamine ligand and shown its
ruthenium complex to be a highly efficient and easily
separable catalyst in asymmetric transfer hydrogenation
of simple ketones with HCOOH–Et3N as the hydrogen
source. Work is in progress on further applications of
this and related diamine ligands and improvement of the
recyclability of the catalyst.
5. (a) ter Halle, R.; Schulz, E.; Lemaire, M. Synlett 1997,
1257–1258; (b) Bayston, D. J.; Travers, C. B.; Polywka, M.
E. C. Tetrahedron: Asymmetry 1998, 9, 2015–2018; (c)
Touchard, F.; Fache, F.; Lemaire, M. Eur. J. Org. Chem.
2000, 3787–3792; (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, 1488–1489.
Acknowledgements
We thank Johnson Matthey Synetix for financial sup-
port and Dr. Robert Tooze for helpful discussions at the
beginning of the project.
6. While our work was in progress, which was first commu-
nicated at the 11th ICI Symposium in May 2002, two
publications appeared where DPEN was functionalised at
the phenyl rings: (a) Itsuno, S.; Tsuji, A.; Takahashi, M.
Tetrahedron Lett. 2003, 44, 3825–3828; (b) Ma, Y.-P.; Liu,
H.; Chen, L.; Cui, X.; Zhu, J.; Deng, J.-G. Org. Lett. 2003,
5, 2103–2106.
7. The synthetic route for 3 will be published elsewhere.
8. Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. Rev.
2002, 102, 3325–3344.
References and notes
1. For reviews on asymmetric transfer hydrogenation, 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) Saluzzo, C.; ter Halle,
R.; Touchard, F.; Fache, F.; Schulz, E.; Lemaire, M. J.
Organomet. Chem. 2000, 603, 30–39; (e) Palmer, M. J.;
Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045–2061; (f)
Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97–
102; (g) Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem.
Rev. 1992, 92, 1051–1069.
9. General procedure:
A solution of [RuCl2(p-cymene)]2
(3.1 mg, 0.005 mmol) and PEG-2 (50 mg, 0.012 mmol) in
CH2Cl2 (1 mL) was stirred for 30 min at room temperature.
After removal of CH2Cl2 under reduced pressure, ketone
(1.0 mmol) and HCOOH–Et3N azeotrope (1.0 mL) were
added. The mixture was degassed three times and then
stirred for the appropriate period of time (see Table 1) at
50 °C. The solvent was removed under reduced pressure and
Et2O (10 mL) was added to extract the organic compounds.
The conversion and enantioselectivity were determined by
GC analysis.
2. (a) Noyori, R.; Yamakawa, M.; Hashiguchi, S. J. Org.
Chem. 2001, 66, 7931–7944; (b) Yamakawa, M.; Ito, H.;
Noyori, R. J. Am. Chem. Soc. 2000, 122, 1466–1478; (c)
Yamada, I.; Noyori, R. Org. Lett. 2000, 2, 3425–3427; (d)