Highly enantioselective hydrogenation of quinolines under solvent-free or highly concentrated conditions

Article abstract of DOI:10.1039/b822822a

The phosphine-free chiral cationic Ru(OTf)(TsDPEN)(η⁶- cymene) complex was found to be an efficient catalyst for the enantioselective hydrogenation of quinolines under more environmentally friendly solvent-free or highly concentrated conditions

Full text of DOI:10.1039/b822822a

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Highly enantioselective hydrogenation of quinolines under solvent-free
or highly concentrated conditions†
Zhi-Jian Wang,‡ Hai-Feng Zhou,‡ Tian-Li Wang, Yan-Mei He and Qing-Hua Fan*
Received 19th December 2008, Accepted 10th March 2009
First published as an Advance Article on the web 18th March 2009
DOI: 10.1039/b822822a
6
The phosphine-free chiral cationic Ru(OTf)(TsDPEN)(g -
cymene) complex was found to be an efficient catalyst for the
enantioselective hydrogenation of quinolines under more
environmentally friendly solvent-free or highly concen-
trated conditions. Excellent yields and enantioselectivities
(up to 97% ee) were obtained at only 0.02–0.10 mol% catalyst
loading.
ligands7e,f have been found to be effective in the hydrogenation of
2-substituted quinolines. In most cases, however, good to excel-
lent enantioselectivity and activity could only be obtained by
using iodine as additive, and often at a low substrate-to-catalyst
ratio (S/C) of 100. From a practical application viewpoint, it
is highly desirable to develop air-stable phosphine-free catalysts
for such reactions.
In comparison with chiral diphosphines, chiral diamine
ligands are more readily available and air-stable.8 Their
Ru, Rh and Ir complexes have been widely used in the
asymmetric transfer hydrogenation of ketones.9 However, only
a few of them were found to be capable of activating molecular
hydrogen.10,11 Recently, Noyori and Ohkuma reported that chiral
The principles of green chemistry and green engineering dictate
that avoiding the use of solvents is an important way to prevent
the generation of waste.1 For practical synthesis, reactions under
solvent-free or highly concentrated conditions may have other
advantages, including reduced energy consumption, decreased
reaction times and considerable batch size reduction. Therefore,
much research effort has been devoted to the development of
solvent-free or highly concentrated reactions.2 Among them,
however, relatively few examples concerning solvent-free and
concentrated catalytic asymmetric reactions have been reported
so far.2c,3,4 This is not surprising because asymmetric catalytic
processes are usually highly sensitive to solvent and concen-
tration of substrates. For solvent-free catalytic reactions, the
reaction medium changes significantly as reagents and substrates
are converted to products. Therefore, it is still a big challenge
to develop highly enantioselective solvent-free and concentrated
catalytic reactions. In particular, asymmetric hydrogenation of
heteroaromatic compounds under solvent-free conditions is
expected to be more difficult due to the potential poisoning
of the catalysts by the substrates and/or the reduced products.
Transition metal-catalyzed asymmetric hydrogenations have
been extensively studied, and are considered a versatile method
for the preparation of optically active compounds.5 Although
a variety of chiral Rh, Ru, and Ir complexes have been
demonstrated to be highly efficient and enantioselective in the
hydrogenation of prochiral olefins, ketones, and imines, most of
these catalysts failed to give satisfactory results in the asym-
metric hydrogenation of heteroaromatic compounds.6 A few
successful examples of the asymmetric hydrogenation of quino-
lines have recently been reported.7 Iridium complexes containing
chiral diphosphine7a–c or diphosphinite ligands,7d and P, N
6
Ru(OTf)(TsDPEN)(h -cymene) and Cp*Ir(OTf)(MsDPEN)
[TsDPEN
=
N-(p-toluenesulfonyl)-1,2-diphenylethylenedi-
amine; TfO- = trifluoromethanesulfonate; Cp* = pentamethyl-
cyclopentadienyl; MsDPEN = N-(methanesulfonyl)-1,2-diphe-
nylethylenediamine] complexes could be used for the asymmetric
hydrogenation of prochiral ketones under slightly acidic
conditions.11 Later on, we found that ruthenium complex 1
is also an efficient catalyst for asymmetric hydrogenation of
quinolines in pure ionic liquid with high enantioselectivity
(Scheme 1).12 Herein, we report our continuing effort
on developing a more efficient process for this difficult
transformation. Unlike the reported asymmetric hydrogenation
of quinolines employing organic solvents, it was found that
reactions under solvent-free or highly concentrated conditions
provided the tetrahydroquinoline derivatives with much
higher reactivity and excellent enantioselectivity at only 0.10–
0.02 mol% catalyst loading.
Scheme 1 Asymmetric hydrogenation of quinolines catalyzed by
Ru-catalyst (S,S)-1 in [BMIM]PF6 (BMIM=1-n-butyl-3-methylimida-
zolium).
Beijing National Laboratory for Molecular Sciences, CAS Key
Laboratory of Molecular Recognition and Function, Institute of
Chemistry and Graduate School, Chinese Academy of Sciences, Beijing,
100190, China. E-mail: fanqh@iccas.ac.cn
† Electronic supplementary information (ESI) available: Procedures for
the catalytic asymmetric hydrogenation and enantioselective synthesis
of (-)-angustureine. See DOI: 10.1039/b822822a
We initially focused on the evaluation of the substrate
concentration effects in the asymmetric hydrogenation by using
2-methylquinoline (2a) as a model substrate and methanol as
the solvent.8a As shown in Table 1, when the reaction was run at
0.2 mol L-1 substrate concentration in methanol, decreasing the
‡ These authors contributed equally to this work.
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Table 1 Comparison of the asymmetric hydrogenation of 2-methyl-
quinoline 2a catalyzed by (S,S)-1 in MeOH and under solvent-free
conditionsa
Table 3 Asymmetric hydrogenation of quinolines catalyzed by (S,S)-1
under solvent-free or highly concentrated conditionsa
Entry
S/C
Solvent
Time/h
Conv. (%)b
ee (%)c
1
2
3
4
5
6
7
200
500
1000
1000
1000
200
MeOH (0.2 M)
MeOH (0.2 M)
MeOH (0.2 M)
MeOH (2.0 M)
MeOH (2.0 M)
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
4
12
24
24
48
4
12
24
24
20
29
12
<5
38
95
94
N. D.
95
95
97
96
96
93
H2/atm;
76
Entry R1/R2
Temp./◦C Yield (%)b ee (%)c
>95
>95
95
57
50
500
1
2
3
4
H/Me (2a)
50; 25
50; 25
50; 25
80; 25
99
98
97
99
97
95
94
94
8
1000
5000
100
H/Et (2b)
9d
10e
H/n-Pr (2c)
H/n-Pentyl (2d)
77
a Reaction conditions: 0.2–2.0 mmol 2a in 1 ml MeOH or under solvent-
free conditions, 50 atm H2, rt. b Determined by 1H NMR. c Determined
by HPLC analysis with Chiralpak OJ-H Column, the product was in the
S-configuration. d 0.1 mol% TfOH was used as an additive. e Ir-catalyst
generated in situ from [Ir(COD)Cl]2 and P-Phos in combination with
5 mol% I2 used as additive.
5d
6d
7d
(2e)
50; 50
95
99
98
92
87
85
(2f) 80; 80
(2g)
80; 80
80; 50
80; 80
Table 2 Temperature and hydrogen pressure effect on the asymmetric
hydrogenation of 2a under solvent-free conditionsa
8d
9d
(2h)
92
98
97
97
Entry
Temp./◦C
H2/atm
Time/h
Conv. (%)b
ee (%)c
1
2
3
4
5
6
7
8
0
25
50
80
25
25
25
25
50
50
50
50
80
50
20
1
24
24
8
23
>95
>95
60
100
86
97
96
94
90
96
96
96
96
(2i)
4
12
12
12
24
10d
11d
MeO/Me (2j)
F/Me (2k)
80; 80
80; 80
99
96
93
90
46
6
a Reaction conditions: 1.0–2.0 mmol substrate, 0.1 mol% (S,S)-1, 24–
60 h. b Isolated yield. c Determined by HPLC analysis with Chiralpak
OJ-H (or OD-H and AS-H) Column. d 0.1 mL 2-propanol and 0.1 mol%
TfOH were added.
a Reaction conditions: 2.0 mmol 2a, 0.1 mol% (S,S)-1. b Determination
by 1H NMR. c Determined by chiral HPLC analysis.
catalyst loading resulted in a significant decrease in reactivity
(entries 1–3). It was noted that a higher conversion was ob-
tained when increasing the substrate concentration from 0.2 to
2.0 mol L-1 at 0.1 mol% catalyst loading (entries 4 and 5). Thus,
we speculated that the employment of solvent-free conditions
would further increase the reactivity and allow a reduction in
catalyst loading. To our delight, the reaction proceeded effi-
ciently under solvent-free conditions in quantitative conversion
with a slightly higher enantioselectivity as compared to those
obtained in methanol under otherwise the same conditions
(entries 6–8). Remarkably, even when the catalyst loading was
further reduced to 0.02 mol%, the reaction still gave the product in
57% conversion with 93% ee in the presence of 0.1 mol% TfOH.
To the best of our knowledge, this is the first example of highly
enantioselective hydrogenation of heteroaromatic compounds
under solvent-free conditions. In contrast, the same reaction
catalyzed by the reported Ir(P-Phos)/I2 catalytic system7b under
solvent-free conditions at high catalyst loading (1.0 mol%) gave
only 50% yield with 77% ee (entry 10).
pressures although a low conversion was observed by decreasing
the hydrogen pressure (entries 5–8).
Next, a variety of 2-substituted quinoline derivatives (2a–2k)
were hydrogenated in the presence of 0.1 mol% of catalyst
(S,S)-1 under solvent-free or highly concentrated conditions.
Nearly quantitative yields and high enantioselectivities (up
to 97% ee) were obtained in all cases (Table 3). In the
case of liquid substrates, 2-alkyl substituted quinolines, the
reactions proceeded smoothly under solvent-free conditions.
It was found that the length of side chain slightly influenced
the enantioselectivity and reactivity (entries 1–4). For the
solid substrates, hydrogenation was carried out under highly
concentrated conditions (10 mol L-1) in the presence of 0.1 mol%
of TfOH. As compared with 2-alkyl substituted quinolines,
2-phenethyl substituted quinolines also gave high yield, albeit
with slightly lower enantioselectivities (entries 5–7). It was noted
that quinolines with a free hydroxyl group on the side chain
could be hydrogenated smoothly in high yield with excellent
enantioselectivities (entries 8–9). However, the presence of
substituted groups at C-6 led to slightly lower enantioselectivities
(entries 10 and 11).
We then examined the effects of the reaction temperature and
hydrogen pressure on the solvent-free asymmetric hydrogenation
of 2a, and the results are listed in Table 2. It was found that
increasing the temperature led to a high conversion rate but at a
cost of slightly lower enantioselectivity (entries 1–4). Notably, a
similar high enantioselectivity was achieved at various hydrogen
Finally, we applied this attractive new protocol to the
synthesis of a biologically active tetrahydroquinoline alka-
loid, angustureine.13 Asymmetric hydrogenation of 2-pentyl
768 | Green Chem., 2009, 11, 767–769
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substituted quinoline was carried out on a gram scale at a
catalyst loading of 0.1 mol%, giving the tetrahydroquinoline
derivative in quantitative conversion with 94% ee. Subsequent
N-methylation of the hydrogenated product afforded the desired
natural product in 96% overall yield (Scheme 2).
4 To our knowledge, only two examples of asymmetric hydrogenation
under solvent-free or highly concentrated conditions have been
reported, see: (a) S. E. Clapham, R. Guo, M. Zimmer-De Iuliis,
N. Rasool, A. Lough and R. H. Morris, Organometallics, 2006, 25,
5477; (b) X. Wan, Y. Sun, Y. Luo, D. Li and Z. Zhang, J. Org. Chem.,
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Spindler, H. Steiner and M. Studer, Adv. Synth. Catal., 2003, 345,
103; (b) W. Tang and X. Zhang, Chem. Rev., 2003, 103, 3029;
(c) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley,
New York, 1994; (d) G. Q. Lin, Y. M. Li, A. S. C. Chan, Principles
and Applications of Asymmetric Synthesis, Wiley-Interscience, New
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6 For recent reviews, see: (a) F. Glorius, Org. Biomol. Chem., 2005, 3,
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Scheme 2 Synthesis of naturally occurring tetrahydroquinoline alka-
loid, (-)-angustureine.
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Yang, X. W. Han and Y. G. Zhou, J. Am. Chem. Soc., 2003, 125,
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In conclusion, the first highly enantioselective hydrogenation
of quinolines catalyzed by phosphine-free chiral cationic Ru-
TsDPEN catalyst has been achieved under more environmen-
tally friendly solvent-free or highly concentrated conditions at
low catalyst loading (low to 0.02 mol%). This new method
provides a practical synthetic approach to optically active
tetrahydroquinoline derivatives.
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Acknowledgements
Financial support from the National Natural Science Founda-
tion of China (20532010) and Chinese Academy of Sciences
(project no. KJCX2.YW.H16) is greatly acknowledged.
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This journal is
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Green Chem., 2009, 11, 767–769 | 769
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