Air-stable Ir-(P-Phos) complex for highly enantioselective hydrogenation of quinolines and their immobilization in poly(ethylene glycol) dimethyl ether (DMPEG)

Article abstract of DOI:10.1039/b416397d

An air-stable catalyst system Ir-(P-Phos) catalyst was found to be highly effective in the asymmetric hydrogenation of quinoline derivatives. The catalyst immobilized in DMPEG was efficiently recovered and reused eight times, retaining reactivity and enan

Full text of DOI:10.1039/b416397d

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Air-stable Ir-(P-Phos) complex for highly enantioselective
hydrogenation of quinolines and their immobilization in poly(ethylene
glycol) dimethyl ether (DMPEG)
Lijin Xu,a Kim Hung Lam,a Jianxin Ji,a Jing Wu,a Qing-Hua Fan,*b Wai-Hung Loa and Albert S. C. Chan*a
Received (in Cambridge, UK) 28th October 2004, Accepted 4th January 2005
First published as an Advance Article on the web 24th January 2005
DOI: 10.1039/b416397d
be effectively immobilized and reused in polyethylene glycol
dimethyl ether (DMPEG), a low-cost and environmentally benign
liquid polymer. To the best of our knowledge, immobilized catalyst
for asymmetric hydrogenation of heteroaromatic compounds has
not been previously reported. This also represents the first example
of the immobilization of the new family of chiral dipyridylphos-
phane ligands and their organometallic complexes.
An air-stable catalyst system Ir-(P-Phos) catalyst was found to
be highly effective in the asymmetric hydrogenation of quino-
line derivatives. The catalyst immobilized in DMPEG was
efficiently recovered and reused eight times, retaining reactivity
and enantioselectivity.
Asymmetric hydrogenation of heteroaromatic compounds pro-
vides an attractive and convenient approach to optically pure
heterocycloalkanes and their derivatives.1 However, a variety of
chiral Rh, Ru and Ir complexes, which have been demonstrated to
be highly efficient and enantioselective in the hydrogenation of
prochiral olefins, ketones, and imines, often failed to give good
results.2 So far only limited examples of the homogeneous
asymmetric hydrogenation of heteroaromatic compounds have
been reported.2–4
To assess the effectiveness and the air-stability of the Ir-(P-Phos)
catalyst in asymmetric hydrogenation of quinolines, we chose
2-methyl quinoline 1a as the model substrate. The catalyst was
generated in situ from [Ir(COD)Cl]2 and P-Phos in combination
with I2 as an additive and the hydrogenation was carried out for
20 h at room temperature under the conditions previously reported
by Zhou and coworkers (Scheme 1).4 Initially 84% ee and 84%
yield were achieved. A series of organic solvents were tested for the
reaction and the corresponding results on the product ee and yield
(in parenthesis) were found to be as follows: CH2Cl2, 88% (47%);
1, 2-dichloroethane, 89% (76%); THF, 91% (97%); benzene, 91%
(55%); methanol, 48% (33%); and ethanol 18% (83%). THF
was found to give the best results, and the use of alcoholic
solvents resulted in lower enantioselectivity or catalytic activity.
Most importantly, the Ir-(P-Phos) catalyst was found to be air-
stable even after exposing the catalyst solution to air for 24 h. A
31P-NMR study of the solution showed no change of the spectrum
even after two weeks in air. However, using MeO-BIPHEP as
ligand under the same conditions, the enantioselectivity and the
conversion of 2a obtained dropped to 21% and 28%, respectively.
A series of 2-substituted quinoline derivatives were hydroge-
nated using Ir/P-Phos/I2 catalyst in THF without degassing. The
results are listed in Table 1. In general, all substituted quinolines
studied were hydrogenated with high enantioselectivity (¢90% ee)
and very good yields. The reaction is relatively insensitive to the
length of side chain of 2-alkylated substituted quinolines, and good
yields and enantioselectivities have been consistently obtained
(entries 1–3). Good result was also achieved with 2-phenethyl
quinoline (entry 4). The presence of substituted group on position
7 has no effect on either yield or enantioselectivity (entry 5). The
tolerance of hydroxyl group is also demonstrated by the successful
hydrogenation of substrates 1f–g with excellent yields and high
enantioselectivities (entries 6–7).
Optically pure tetrahydroquinoline derivatives are important
organic synthetic intermediates and building blocks for the
preparation of biologically active compounds.5 However, methods
for the enantioselective formation of these chiral compounds are
scarce. Recently, Zhou and co-workers found that the iridium
complex generated in situ from [Ir(COD)Cl]2 and (R)-MeO-Biphep
or ferrocenyloxazoline-derived P,N-ligand worked efficiently in the
enantioselective hydrogenation of quinoline derivatives at room
temperature, providing optically active tetrahydroquinolines bear-
ing a chiral carbon at 2-position with high enantioselectivities and
yields.4
A frequently encountered problem associated with the use of
transition metal phosphine catalyst is the air-sensitivity of the
active catalyst. The existence of trace amount of air in the reaction
system can lead to deactivation of the catalyst and irreproducible
results. Therefore it is highly desirable to develop catalyst with high
activity and good air-stability. We have recently prepared a new
family of chiral dipyridylphosphane ligands and have shown their
effectiveness in asymmetric hydrogenations of prochiral olefins
and ketones.6 It is notable that the ruthenium complexes,
[Ru(C6H6)(P-Phos)Cl2] and [RuCl2(P-Phos)(DPEN)] display good
air-stability even in solution. Herein we report a highly effective
and air-stable iridium catalyst generated in situ from P-Phos and
[Ir(COD)Cl]2, and its application in the enantioselective hydro-
genation of a series of 2-substituted quinolines. The air-stability of
the catalyst makes the experimental operations very convenient
and shows good potential for industrial applications. Following
our interest in the immobilization and recycling of chiral catalysts
in asymmetric hydrogenation,7 we find this Ir-(P-Phos) catalyst to
Having established the high efficiency and the air-stability of our
Ir-(P-Phos) catalyst system, we started exploring the recyclability
of this catalyst in the hydrogenation reaction. Since ionic liquids
and polyethylene glycol (PEG) have attracted a great deal of recent
interest because of their potential as displacements for conven-
tional solvents and as a means to immobilize and recycle
*bcachan@polyu.edu.hk (Albert S. C. Chan)
1390 | Chem. Commun., 2005, 1390–1392
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Scheme 1
Table 1 Asymmetric hydrogenation of quinolines catalyzed by
Ir-(P-Phos)a
importantly, the product could be easily separated by simple
extraction with hexane while the catalyst was retained in the
DMPEG phase (Scheme 2). In order to facilitate the separation of
the product and the recycling of the catalyst, we also examined the
DMPEG/hexane two-phase catalytic system for this reaction.
Interestingly, higher enantioselectivity (up to 89% ee) and nearly
quantitative yield (up to 98%) were achieved. A variety of
substituted quinoline derivatives were also hydrogenated in
DMPEG-500/hexane, and the results summarized in Table 1
(entries 1, 2, 5 and 6, data in parentheses) were comparable to
those obtained in THF.
Entry
R1/R2
Yield (%)
eeb (%)
Config.c
1
2
3
4
5
6
Me/H (1a)
Et/H (1b)
n-Pentyl/H (1c)
Phenethyl/H (1d)
Me/F (1e)
97(98)d (2a)
99(99)d (2b)
97 (2c)
99 (2d)
90(90)d (2e)
99(99)d (2f)
91(89)d
92(90)d
91
90
90(88)d
91(88)d
R
R
R
R
S
The recyclability of the Ir-catalyst in DMPEG was examined
using 1a as the model substrate. Upon completion of the reaction,
the product was easily separated via simple decantation and the
DMPEG layer was further extracted twice with hexane in air. The
DMPEG phase was recharged with 1a and hexane, and then
subjected to hydrogenation again under the same conditions. The
Ir-(P-Phos) catalyst was reused for eight times with the retention of
reactivity and enantioselectivity (Table 2). These results further
demonstrated the air-stability of the Ir-(P-Phos) catalyst system.
ICP-AES analysis of the hexane extract showed leaching of less
than 0.4% of the iridium complex during the extraction of the
products.
S
(1f)
7
98 (2g)
90
S
(1g)
a
Reaction conditions: 1 mmol quinoline, [Ir(COD)Cl]2 (0.005 mmol),
(R)-P-Phos (0.011 mmol), I2 (0.05 mmol), 5 mL THF, 700 psi H2, rt,
b
20 h. The enantioselectivities of products were determined by
HPLC analysis with Chiralpak OJ–H (2a–c), As–H (2d) and OD–H
c
(2e–g) columns.
comparison of the HPLC retention time with these reported in the
literature data.
The absolute configuration is assigned by
d
Data in parenthesis were obtained by using
DMPEG/hexane (1/1) as solvent under otherwise the same reaction
conditions.
transition-metal catalyst,8,9 we attempted the hydrogenation in the
two kinds of reaction media with 1a as model compound.
However, ionic liquids and PEG all proved to be ineffective
reaction media, giving either poor conversions and/or poor ees.
For example, using ionic liquid 1-butyl 3-methyl imidazolium
hexafluorophosphate as reaction medium only led to 5%
conversion and 52% ee. When PEG-400 was used as solvent,
complete conversion and 77% ee were obtained. It was quite likely
that the Ir-(P-Phos) catalytic system favored a less polar reaction
medium, and the hydrogenation reaction was retarded by the
highly polar ionic liquids and alcoholic PEG. Similar observation
has been reported by Burgess and coworkers in their Ir-catalyzed
asymmetric hydrogenation of unfunctionalized aryl alkenes in
ionic liquid.10 Considering the detrimental effect of the OH groups
on PEG on the enantioselectivity, we switched to the less polar
DMPEG. To our delight, hydrogenation of 1a in pure DMPEG
(M 5 500) gave complete conversion and 85% ee. Most
Scheme 2 Immobilized Ir-(P-Phos) catalyst in hexane/DMPEG biphasic
system (lower DMPEG phase).
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Table 2 Recycling and reuse of Ir-(P-Phos) catalyst in asymmetric
hydrogenation of 1aa
Run
1
2
3
4
5
6
7
8
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Conv. (%)
ee (%)
98
89
98
88
99
87
98
88
99
86
98
87
99
87
99
88
a
Reaction conditions: 0.5 mmol 1a, [Ir(COD)Cl]2 (0.0025 mmol),
(R)-P-Phos (0.0055 mmol), I2 (0.025 mmol), 5 mL DMPEG/hexane
(1/1), 700 psi H2, rt, 20 h.
In summary, we have developed a highly effective and air-stable
Ir-(P-Phos) catalyst for the asymmetric hydrogenation of quino-
lines. The catalyst has been effectively immobilized in DMPEG for
the first time with retained reactivity and enantioselectivity in the
eight catalytic runs. It is noteworthy that DMPEG has shown
great potential as a low-cost, benign and recyclable solvent for
catalytic reactions.
We thank the University Grants Committee Areas of Excellence
Science (AoE P/10-01) in Hong Kong, the Hong Kong Polytechnic
University Area of Strategic Development Fund, and National
Natural Science Foundation of China (No 203900507 and
20325209) for financial support of this study.
Lijin Xu,a Kim Hung Lam,a Jianxin Ji,a Jing Wu,a Qing-Hua Fan,*b
Wai-Hung Loa and Albert S. C. Chan*a
aOpen Laboratory of Chirotechnology of the Institute of Molecular
Technology for Drug Discovery and Synthesis and Department of
Applied Biology and Chemical Technology, the Hong Kong Polytechnic
University, Hong Kong, P. R. China. E-mail: bcachan@polyu.edu.hk
bInstitute of Chemistry, Chinese Academy of Sciences, Beijing, 100080,
P. R. China
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1392 | Chem. Commun., 2005, 1390–1392
This journal is ß The Royal Society of Chemistry 2005