Highly enantioselective synthesis of chiral tetrahydroquinolines and tetrahydroisoquinolines by ruthenium-catalyzed asymmetric hydrogenation in ionic liquid

Article abstract of DOI:10.1002/adsc.201300698

Asymmetric hydrogenation reactions of quinolines and 3,4- dihydroisoquinolines using the chiral cationic ruthenium complex Ru(TsDPEN) [TsDPEN=N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine] as catalyst in neat imidazolium ionic liquids have been investigated. The catalytic performance was influenced by the anion of the ionic liquids for both substrate classes. A range of 2-alkyl-substituted 1,2,3,4-tetrahydroquinolines and 1-alkyl-substituted 1,2,3,4-tetrahydroisoquinolines was obtained in high yields with up to >99% ee. Interestingly, the hydrogenation of quinoline derivatives bearing a carbonyl group was selective for the C-N (quinoline) over the C-O (ketone) bonds, while such a unique chemoselectivity was not observed in methanol. Furthermore, the ruthenium catalysts could be easily recycled at least 5 times in the asymmetric hydrogenation of 3,4-dihydroisoquinoline by solvent extraction. To further facilitate the recovery of catalyst and reduce the use of organic solvent, a thin film of ionic liquid containing Ru(TsDPEN) was supported on silica gels. This supported ionic liquid-phase catalyst was effective in the asymmetric hydrogenation of quinoline, and could be recycled at least 6 times by simple filtration. Copyright

Full text of DOI:10.1002/adsc.201300698

UPDATES
DOI: 10.1002/adsc.201300698
Highly Enantioselective Synthesis of Chiral Tetrahydroquinolines
and Tetrahydroisoquinolines by Ruthenium-Catalyzed
Asymmetric Hydrogenation in Ionic Liquid
Zi-Yuan Ding,a,b Tianli Wang,b Yan-Mei He,b Fei Chen,b Hai-Feng Zhou,b
Qing-Hua Fan,b,* Qingxiang Guo,a,* and Albert S. C. Chanc
a
Anhui Province Key Laboratory of Biomass Clean Energy, Department of Chemistry, University of Science and
Technology of China, Hefei 230026, Peopleꢀs Republic of China
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function,
b
Institute of Chemistry and Graduate School, Chinese Academy of Sciences (CAS), Beijing 100190, Peopleꢀs Republic of
China
E-mail: fanqh@iccas.ac.cn or qxguo@ustc.edu.cn
Institute of Creativity, Hong Kong Baptist University, Hong Kong, Peopleꢀs Republic of China
c
Received: August 2, 2013; Revised: September 10, 2013; Published online: December 6, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300698.
Abstract: Asymmetric hydrogenation reactions of
quinolines and 3,4-dihydroisoquinolines using the
Introduction
chiral cationic ruthenium complex Ru
(TsDPEN)
Optically active tetrahydroquinolines and tetrahydroi-
soquinolines are two kinds of important structural
units in a large number of natural and synthetic prod-
ucts with a wide variety of biological activities.[1] For
example (Figure 1), (S)-flumequine,[1b] which belongs
to the quinoline family, is an important antibacterial
agent. Solifenacin is a prescription drug for the treat-
ment of overactive bladder.[1c] Chiral torcetrapib[1d]
has recently attracted much attention for the treat-
ment of low high-density lipoprotein cholesterol and
atherosclerosis. In addition, many naturally occurring
alkaloids contain tetrahydroquinoline or tetrahydro-
[TsDPEN=N-(p-toluenesulfonyl)-1,2-diphenylethy-
lenediamine] as catalyst in neat imidazolium ionic
liquids have been investigated. The catalytic perfor-
mance was influenced by the anion of the ionic liq-
uids for both substrate classes. A range of 2-alkyl-
substituted 1,2,3,4-tetrahydroquinolines and 1-alkyl-
substituted 1,2,3,4-tetrahydroisoquinolines was ob-
tained in high yields with up to >99% ee. Interest-
ingly, the hydrogenation of quinoline derivatives
bearing a carbonyl group was selective for the C=N
(quinoline) over the C=O (ketone) bonds, while
such a unique chemoselectivity was not observed in
methanol. Furthermore, the ruthenium catalysts
could be easily recycled at least 5 times in the asym-
metric hydrogenation of 3,4-dihydroisoquinoline by
solvent extraction. To further facilitate the recovery
of catalyst and reduce the use of organic solvent,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
is not surprising that the development of efficient
methods for the preparation of such enantiomerically
enriched heterocycles has been an appealing goal in
both academia and industry for many years.
a thin film of ionic liquid containing Ru
(TsDPEN)
Among various methods available for the synthesis
of chiral 1,2,3,4-tetrahydroquinolines[1a,2a] and 1,2,3,4-
tetrahydroisoquinolines,[2b] asymmetric homogeneous
hydrogenation of the corresponding unsaturated com-
pounds using inexpensive molecular hydrogen and
a small amount of chiral transition metal catalyst is
perhaps the most straightforward, efficient and atom-
economic method. Indeed, considerable progress has
been made in this field over the past decade.[3] A vari-
ety of chiral metal catalysts, including Ir, Ru, Ti, Rh
and Pd complexes, has been successfully employed in
the asymmetric hydrogenation of readily available
quinolines,[4] isoquinolines[5] as well as isoquinoline-
type imines,[6] affording the chiral 1,2,3,4-tetrahydro-
was supported on silica gels. This supported ionic
liquid-phase catalyst was effective in the asymmet-
ric hydrogenation of quinoline, and could be recy-
cled at least 6 times by simple filtration.
Keywords: asymmetric hydrogenation; catalyst re-
cycling; ionic liquids; tetrahydroisoquinolines; tet-
rahydroquinolines
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Zi-Yuan Ding et al.
UPDATES
Figure 1. Structures of selected bioactive compounds and alkaloids derived from chiral 1,2,3,4-tetrahydroquinoline or 1,2,3,4-
tetrahydroisoquinoline derivatives.
quinolines and 1,2,3,4-tetrahydroisoquinolines with droisoquinolines in imidazolium ionic liquids. It was
good to excellent enantioselectivities. However, in found that a range of 2-substituted quinoline and 1-
comparison with the relative maturity of asymmetric alkyl-3,4-dihydroisoquinoline derivatives could be ef-
hydrogenation of prochiral olefins and ketones, enan- ficiently hydrogenated to give the chiral 1,2,3,4-tetra-
tioselective hydrogenation of nitrogen-containing het- hydroquinolines and 1,2,3,4-tetrahydroisoquinolines
erocyclic compounds, including heteroaromatic com- with unprecedented reactivity, chemoselectivity and
pounds and cyclic imines, is still suffering from some excellent enantioselectivity. In addition, the rutheni-
drawbacks. First, asymmetric hydrogenation of um catalysts in ionic liquid are more stable and could
heteroACHTUNGTRENNUNGaromatic compounds under mild conditions be recycled by simple solvent extraction. The hydro-
might be difficult due to their high resonance stability. genation and catalyst recycling were also realized by
Second, the nitrogen-containing substrates and/or using the ruthenium catalyst immobilized in a support-
products may poison and/or deactivate the metallic ed ionic liquid-phase.
catalysts, and thus high catalyst loading (1.0 mol% in
most cases) is often required.[7] In addition, recycling
of the homogeneous catalysts is still a big challenge. Results and Discussion
From the viewpoints of both fundamental research
and industrial applications, more efficient, stable and Asymmetric Hydrogenation of Quinoline Derivatives
recyclable catalyst systems are desirable.
Catalyzed by Cationic Ruthenium Catalysts in Ionic
On the other hand, room-temperature ionic liquids Liquids
(RTILs), especially those based on 1,3-dialkylimida-
zolium cations have emerged as environmentally The pioneer works on asymmetric hydrogenation of
benign alternative reaction media for a number of quinolines were started by Zhou and co-workers.[4a]
catalytic reactions.[8] Many catalytic reactions dis- They first reported that an Ir/MeO-BIPHEP/I2 system
played enhanced reactivities and selectivities in could produce chiral tetrahydroquinolines with up to
RTILs, even the ones which could not occur in 96% ee. After that, numerous Ir complexes containing
common organic solvents.[9] Furthermore, the widely chiral phosphorus ligands have been developed for
tunable features of RTILs can be adapted to a specific the hydrogenation of a wide range of quinoline deriv-
catalytic reaction and their advantages as reusable ho- atives with good to excellent enantioselectivities.[3b] In
mogeneous supports offer an opportunity to reuse the most cases, good results could only be obtained at
catalyst. Most recently, we demonstrated that the a low substrate/catalyst ratio of 100. Additionally,
phosphine-free chiral cationic Ru
[TsDPEN=N-(p-toluenesulfonyl)-1,2-diphenylethy-
lenediamine] was an efficient catalyst for the enantio- genation of 2-methylquinoline in ionic liquid resulted
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
selective hydrogenation of quinoline derivatives in in poor ees and conversions.[4c] In contrast, the Ru
neat [Bmim]PF6 (Bmim=1-n-butyl-3-methylimidazo- complexes containing chiral diamines[10] were found
lium).[4d] It was found that the use of ionic liquid not to be highly effective catalysts for the asymmetric hy-
only facilitated the recycling of catalyst, but also en- drogenation of quinolines in neat ionic liquid.[4d] In
hanced the stability and selectivity of the catalyst. En- addition, such transformation could also be carried
couraged by these preliminary observations, we then out under solvent-free conditions by using the same
performed a systematic and detailed study on the Ru-TsDPEN catalyst.[4e] Both catalytic systems cata-
asymmetric hydrogenation of quinolines and 3,4-dihy- lyzed the reaction under homogeneous conditions
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Highly Enantioselective Synthesis of Chiral Tetrahydroquinolines and Tetrahydroisoquinolines
Table 1. Anion effect of ionic liquids on the asymmetric hy-
drogenation of 2a.[a]
Entry Solvent
Time [h] Conv. [%][b,c] ee [%][d]
1
2
3
4
5
6
N
1.5
3
>99 (56)
>99 (52)
>99 (94)
>99 (25)
>99 (26)
>99 (51)
99
96
>99
98
95
24
24
>99
[a]
Reaction conditions: 0.2 mmol 2a in 1 mL solvent,
1.0 mol% (R,R)-1a, 50 atm H2, 258C.
Determined by H NMR analysis.
Data in brackets were obtained when the reaction time
was 40 min.
Determined by chiral HPLC analysis.
Scheme 1. Chiral diamine-containing ruthenium catalysts
used in this study.
[b]
[c]
1
[d]
with high reactivity. However, in the latter case, the
ruthenium catalyst could not be recycled. To develop
a more efficient and recyclable catalytic system for as the best choice of reaction media for the asymmet-
the asymmetric hydrogenation of quinolines, we thus ric hydrogenation of quinolines.
started to investigate the effects of IL anions and cat-
Next, we screened all the ruthenium catalysts de-
alyst structures on catalytic performance. Two series scribed in Scheme 1, and the results are listed in
of ruthenium complexes containing chiral N-sulfony- Table 2. Generally, the catalytic performance was sig-
lated 1,2-diphenylethylenediamine (DPEN) and 1,2- nificantly affected by both the substituents of the h6-
cyclohexanediamine (CYDN) were prepared accord- arene ligand and the N-monosulfonylated diamine
ingly (Scheme 1).
ligand (entries 1–7). The steric effects of the N-sulfo-
In our initial study, we investigated the asymmetric nate substituents were also manifest. It was found
hydrogenation of 2-methylquinoline (2a) with Ru-di- that catalyst (R,R)-1a having a p-tolyl group as the N-
ACHTUNGTRENNUNGamine catalyst (R,R)-1a in neat [Bmim]PF6. To our sulfonate substituent gave the highest ee value and
great delight, the reaction proceeded smoothly with conversion (entry 1), while the catalysts bearing the
high reactivity and excellent enantioselectivity, even less steric methyl group or the more steric 2,4,6-(i-
better than those obtained with common organic sol- Pr)3C6H2 group gave much lower reactivities and
vents under the same reaction conditions (Table 1, slightly lower enantioselectivities (entries 2 and 3).
entry 1 vs. entry 2). Encouraged by this result and Catalyst (R,R)-1d with an electron-withdrawing N-sul-
based on our previous finding about the significant fonate substituent resulted in much lower conversion
anion effect of this catalytic system,[11] we further ex- and ee value (entry 4). In addition, introducing
amined a series of imidazolium ionic liquids with dif- a methyl group to the other N atom of the diamine
ferent weakly coordinating anions ([Bmim]X, X= ligand or replacement of the p-cymene ligand with
SbF6, BF4, NTf2, OTf). The results are summarized in the sterically demanding h6-arene gave much lower
Table 1. It was found that all of these ionic liquids conversion without any loss of enantioselectivity (en-
gave complete conversions with excellent enantiose- tries 5 and 6). Catalyst (R,R)-1g bearing the diamine
lectivities. Notably, both the reactivity and enantiose- ligand TsCYDN [TsCYDN=N-(p-toluenesulfonyl)-
lectivity were influenced by the nature of the anion. 1,2-cyclohexanediamine] showed much lower enantio-
When [Bmim]PF6, [Bmim]SbF6 and [Bmim]NTf2 were selectivity and reactivity (entry 7). Having the opti-
used, almost optically pure product 3a (99% ee) was mized catalyst structure in hand (entry 1), we further
obtained, and [Bmim]SbF6 gave the highest reactivity. examined the effects of hydrogen pressure and tem-
However, the use of more coordinating anions, such perature on the catalytic performance. It was found
as OTf and BF4, significantly reduced the reactivity that the enantioselectivity was insensitive to hydrogen
and slightly lowered the enantioselectivity (95% and pressure and temperature (entries 8–13). Notably,
98% ee, respectively). Thus, [Bmim]SbF6 was selected when the catalyst loading of (R,R)-1a was decreased
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Zi-Yuan Ding et al.
UPDATES
Table 2. Optimization of the reaction conditions for the
asymmetric hydrogenation of 2a.[a]
Table 3. Asymmetric hydrogenation of 2-alkyl-quinoline de-
rivatives catalyzed by (R,R)-1a in [Bmim]SbF6.[a]
Entry
Catalyst
H2 [atm];
Time
[h]
Conv.
[%][b]
ee
Entry
R1/R2
Conv. [%][b]
ee [%][c]
Temp. [oC]
[%][c]
1
2
3
4
H/Me (2a)
H/Et (2b)
H/n-Pr (2c)
H/n-pentyl (2d)
>99
>99
>99
>99
99
99
99
98
1
2
3
4
5
6
7
8
A
E
R
E
N
N
R
E
G
N
G
G
G
ACHTUNGTRENNUNG
R
A
50; 25
50; 25
50; 25
50; 25
50; 25
50; 25
50; 25
50; 0
50; 50
50; 80
1; 25
20; 25
80; 25
50; 25
50; 25
50; 25
1
1
1
1
1
1
1
7
>99
76
9
17
14
5
70
>99
>99
>99
60
>99
98
98
78
5
>99
98
>99
>99
90
>99
99
6
>99
99
9
40 min
40 min
18
40 min
40 min
24
10
11
12
13
14[d]
15[e]
16[f]
98
7
8
>99
>99
99
99
>99
>99
>99
99
99
96
88
>99
>99
>99
32
9
MeO/Me (2i)
Me/Me (2j)
F/Me (2k)
H/Ph (2l)
>99
>99
>99
>99
99
98
99
50
24
24
10
11
12
[a]
Reaction conditions: 0.2 mmol 2a in 1 mL [Bmim]SbF6,
1.0 mol% (R,R)-1, 258C.
Determined by H NMR analysis.
Determined by chiral HPLC analysis.
Substrate/catalyst=500.
Substrate/catalyst=1000.
[a]
[b]
[c]
[d]
[e]
[f]
1
Reaction conditions: 0.2 mmol substrate in 1 mL
[Bmim]SbF6, 0.2 mol% (R,R)-1a, 50 atm H2, 258C, 24–
60 h.
Determined by H NMR analysis.
Determined by chiral HPLC analysis.
[b]
[c]
1
Substrate/catalyst=2000.
to 0.2 mol% and 0.1 mol%, full conversions and ex- smoothly, albeit only with medium enantioselectivity
cellent enantioselectivities (99% ee) were still ob- (51% ee, entry 12).
served within 24 h (entries 14 and 15). Even with
To further extend the substrate scope, we investi-
0.05 mol% catalyst, the reaction still led to excellent gated the asymmetric hydrogenation of some quino-
enantioselectivity, albeit with quite lower conversion line derivatives bearing a carbonyl group. In previous
(entry 16).
studies, we have found that substrate 4a bearing an
Under the optimized conditions (entry 1 in acetyl group at the 6-position could be selectively hy-
Table 2), we further explored the substrate scope of drogenated to tetrahydroquinoline 5a in good yield
the Ru-catalyzed asymmetric hydrogenation of 2- with 96% ee (Scheme 2).[4d] This result indicated that
alkyl-substituted quinolines in [Bmim]SbF6. As shown the hydrogenation with Ru-diamine catalyst in ionic
in Table 3, all reactions proceeded smoothly to give liquid was more selective for C=N (quinoline) over
full conversions and excellent enantioselectivities C=O (ketone) bonds. We futher found that the hydro-
(94% to 99% ee) with 0.2 mol% catalyst loading. The genations of substrates 4b and 4c bearing the C=O
reaction was found to be insensitive to the length of group at different positions on the phenyl ring of the
the alkyl side chain (entries 1–4) as well as the exis- side chain afforded the corresponding 1,2,3,4-tetrahy-
tence of phenyl groups or free hydroxy groups on the droquinoline derivatives in high yields and excellent
side chain (entries 5–8). Substitution at the 6-position enantioselectivities with the C=O bonds being re-
had no obvious effect on either conversion or enan- tained. In contrast, both unsaturated bonds were re-
tioselectivity (entries 9–11). Notably, remarkably duced in MeOH under otherwise the same reaction
higher reactivities and comparable or better enantio- conditions. This solvent-induced different chemoselec-
selectivities for the hydrogenation of all these sub- tivity of the ruthenium catalyst probably results from
strates were observed as compared with those ob- different mechanisms for the hydrogenation of
tained in [Bmim]PF6 and under solvent-free condi- ketones[10c] and imines.[4f] On the basis of this unique
tions.[4d,e] Also, we studied the asymmetric hydrogena- chemoselectivity in different solvents, all four enan-
tion of 2-phenylquinoline. The reaction proceeded tiomers of the fully reduced product of 4b could be
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Highly Enantioselective Synthesis of Chiral Tetrahydroquinolines and Tetrahydroisoquinolines
Asymmetric Hydrogenation of 3,4-
Dihydroisoquinoline Derivatives Catalyzed by
Cationic Ruthenium Catalysts in Ionic Liquids
The first asymmetric hydrogenation of isoquinoline-
type imines was reported by Buchwald and co-work-
ers in 1993.[6a] They used a chiral titanocene catalyst
for the hydrogenation of 6,7-dimethoxy-1-methyl-3,4-
dihydroisoquinoline with 98% ee. Since then,
a number of chiral transition metal catalysts was ap-
plied to such types of transformation.[3a,6] More re-
cently, Xiao and co-workers found that a cationic
Cp*RhACTHNURGTNE(UNG TsDPEN) complex was an efficient catalyst
Scheme 2. Asymmetric hydrogenation of quinoline deriva-
tives bearing a C=O functional group in [Bmim]PF6 (4a)
and [Bmim]SbF6 (4b and 4c). Reaction conditions: 0.2 mmol
substrate in 1 mL ionic liquid, 1 mol% (R,R)-1a, 50 atm H2,
258C, 15 h.
for this type of cyclic imines in the presence of
AgSbF6.[6d]
Encouraged by the excellent results obtained in the
asymmetric hydrogenation of quinolines in ionic liq-
uids, and based on our recent reports on the asym-
metric hydrogenation of other acyclic and cyclic N-al-
kylimines with this catalytic system,[11] we thus expand
the imine substrate range to 3,4-dihydroisoquinoline
derivatives.
We first chose the hydrogenation of 6,7-dimethoxy-
1-methyl-3,4-dihydroisoquinoline (7a) in the presence
of 2.0 mol% (R,R)-1a in [Bmim]PF6 as a standard re-
action. To our great delight, the reaction proceeded
smoothly to afford the 1,2,3,4-tetrahydroisoquinoline
in full conversion with 96% ee (Table 4, entry 1).
Then we investigated the anion effect of ionic liquids
in this reaction. Generally, all the ionic liquids tested
gave full conversions with excellent enantioselectivi-
ties. Similar to the asymmetric hydrogenation of qui-
nolines, the catalytic performance was also affected
by the anions. It was found that hydrogenation of 7a
Table 4. Anion effect of ionic liquids on the asymmetric hy-
drogenation of 6,7-dimethoxy-1-methyl-3,4-dihydroisoquino-
line 7a.[a]
Scheme 3. Synthesis of all four enantiomers of 6b through
asymmetric hydrogenation of 4b. Reaction conditions:
0.2 mmol substrate in 1 mL solvent, 1.0 mol% catalyst,
50 atm H2, 258C, 12 h.
Entry
Solvent
Conv. [%][b,c]
ee [%][d]
1
2
3
4
5
6
A
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
>99 (38)
>99 (98)
>99 (48)
>99 (30)
>99 (60)
>99 (60)
96
95
97
96
98
96
easily obtained through two-step or one-pot asymmet-
ric hydrogenation catalyzed by (S,S)- and/or (R,R)-1a,
respectively (Scheme 3). Some of these optically pure
compounds are difficult to access with other methods.
AHCTUNGTRENNUNG
[a]
Reaction conditions: 0.2 mmol substrate in 1 mL solvent,
1.0 mol% (R,R)-1a, 50 atm H2, 258C, 24 h.
Determined by H NMR analysis.
Data in brackets were obtained when the reaction time
was 2.5 h.
Determined by chiral HPLC analysis.
[b]
[c]
1
[d]
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Zi-Yuan Ding et al.
UPDATES
Table 5. Optimization of the reaction conditions for the
asymmetric hydrogenation of 7a.[a]
Table 6. Asymmetric hydrogenation of 3,4-dihydroisoquino-
line derivatives catalyzed by catalyst (R,R)- or (S,S)-1f in
[Bmim]NTf2.[a]
Entry
Catalyst
H2 [atm];
Time
[h]
Conv.
[%][b]
ee
Entry
R1/R2
Yield [%][b]
ee [%][c]
Temp. [oC]
[%][c]
1
2
MeO/Me (7a)
MeO/Et (7b)
MeO/i-Pr (7c)
MeO/n-pentyl (7d)
MeO/cyclohexyl (7e)
H/Me (7f)
H/Et (7g)
H/n-pentyl (7h)
H/cyclohexyl (7i)
92
93
94
95
91
91
92
93
93
99
97
93
98
97
99
96
98
94
1
2
3
4
5
6
7
8
N
50; 25
50; 25
50; 25
50; 25
50; 25
50; 25
50; 25
50; 0
50; 50
20; 25
80; 25
50; 25
3.5
3.5
44
44
44
3.5
3.5
10
3.5
3.5
3.5
14
84
64
28
15
38
>99
78
70
>99
83
98
96
73
49
86
99
75
>99
98
99
98
97
3[d]
4[d]
5
6[d]
7
8
9[d]
9
[a]
10
11
12[d]
Reaction conditions: 0.2 mmol substrate in 1 mL
[Bmim]NTf2, 2.0 mol% (R,R)-1f, 50 atm H2, 258C, 10–
20 h.
Isolated yield (complete conversion in all cases).
Determined by chiral HPLC analysis.
>99
75
[b]
[c]
[d]
[a]
With 2.0 mol% (S,S)-1 f, and the corresponding products
have the R configuration.
[b]
[c]
[d]
1
Under the optimized reaction conditions (entry 6 in
Table 5), a variety of 1-alkyl-substituted 3,4-dihydro-
ACHTUNGTRENNiUNG soquinolines was hydrogenated in [Bmim]NTf2. As
in [Bmim]SbF6 showed the highest reactivity with
95% ee (entry 2). The highest enantioselectivity was shown in Table 6, all substrates were completely re-
observed in [Bmim]NTf2 (98% ee, entry 5), which was duced to afford 1,2,3,4-tetrahydroisoquinolines with
better than that in methanol (96% ee, entry 6). In excellent enantioselectivities (93–99% ee), which are
terms of both reactivity and enantioselectivity, better than those obtained with the rhodium catalytic
[Bmim]NTf2 was selected as the best choice of media system in organic solvent.[6d] In comparison with 7a,
for the asymmetric hydrogenation of dihydroisoquino- substrates bearing longer (ethyl, pentyl) or more
lines.
steric (isopropyl, cyclohexyl) alkyl side chains gave
Next, all catalysts described in Scheme 1 were only slightly lower enantioselectivities (entries 2–5).
screened and the results are listed in Table 5. It was Notably, hydrogenation of substrates without methoxy
found that steric and electronic effects of the diamine substitutions at the 6,7-positions also gave very good
ligand were manifested (entries 1–7), and the yields with excellent enantioselectivities (entries 6–9).
TsDPEN ligand gave the best catalytic performance Unfortunately, the hydrogenation of the 1-phenyl-sub-
(entries 1 and 6). Catalyst bearing TsCYDN showed stituted substrate did not occur in neat ionic liquid or
much lower enantioselectivity and reactivity (entry 7). methanol.
Gratefully, replacement of the p-cymene ligand with
the sterically demanding hexamethylbenzene ligand
led to an increase in both enantioselectivity and reac- Stabilization of Catalyst in Ionic Liquid
tivity (entry 6). Thus, the ruthenium complex (R,R)-1f
was the best choice of catalyst for such transforma- Immobilization of a transition metal catalyst in ionic
tions. In addition, it was found that the enantioselec- liquids often gives enhanced catalyst stability.[9] To in-
tivity was insensitive to the hydrogen pressure and re- vestigate the stabilization of catalyst (S,S)-1a in
action temperature (entries 8–11); and lower conver- [Bmim]PF6, we chose the hydrogenation of 2a as the
sions were observed when the reactions were carried model reaction, and all manipulations were conducted
out under low temperature or low hydrogen pressure in air. The catalyst solutions in organic solvents
(entries 8 and 10). Decreasing catalyst loading (MeOH, CH2Cl2) or ionic liquid ([Bmim]PF6) were
(1.0 mol%) resulted in lower conversion and enantio- stirred under an air atmosphere for 20 h before use.
selectivity (entry 12).
Then, substrate 2a was added for hydrogenation after
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Highly Enantioselective Synthesis of Chiral Tetrahydroquinolines and Tetrahydroisoquinolines
Table 7. Asymmetric hydrogenation of 2a with (S,S)-1a: cat-
Table 8. Reuse of (S,S)-1f in the asymmetric hydrogenation
of 7g in ionic liquid.[a]
alyst stability.[a]
Entry
Solvent
[Bmim]PF6
MeOH
CH2Cl2
Conv. [%][b]
ee [%][c,d]
Run
Conv. [%][b]
Yield [%][c]
ee [%][d]
1
2
N
98
6
16
>99
98 (99)
85 (94)
92 (97)
99 (99)
1
2
3
4
5
6
>99
91
>99
>99
>99
94
84
88
96
93
95
90
99
99
98
96
96
90
3
4[e]
ACHTUNGTRENNUNG[Bmim]PF6
[a]
Reaction conditions: (S,S)-1a (1.0 mol%) in 1 mL solvent,
which was stirred in air for 20 h before 2a (0.2 mmol)
was added, 50 atm H2, 258C, 24 h.
[a]
[b]
[c]
[d]
1
Reaction conditions: 7g (0.2 mmol) in 1 mL [Bmim]NTf2,
2.0 mol% (S,S)-1f, 50 atm H2, 258C, 10 h (entries 1 and
2) and 24 h (entries 3–6).
Determined by H NMR spectroscopy.
Isolated yields.
Determined by H NMR analysis.
Determined by chiral HPLC analysis.
Data in brackets were obtained in degassed solvents
under an N2 atmosphere.
The catalyst in [Bmim]PF6 was stored in air for a month
before use.
[b]
[c]
[d]
1
[e]
Determined by HPLC analysis.
purging the autoclave with hydrogen gas several obviously decreased enantioselectivity was also ob-
times. As shown in Table 7, almost identical enantio- served.
selectivity was observed with 98% conversion in
To further facilitate the recovery of catalyst and
[Bmim]PF6 (entry 1), while a significant decrease in reduce the use of organic solvents, we next attempted
conversions and enantioselectivities was observed in to immobilize the catalyst (R,R)-1a in a thin film of
MeOH and CH2Cl2 (entries 2 and 3). Notably, it was ionic liquid which was supported on 200–300M silca
found that the catalyst in [Bmim]PF6 could catalyze gels. This supported ionic liquid-phase (SILP) catalyt-
the hydrogenation smoothly in full conversion with ic system[12] was applied to the asymmetric hydrogena-
99% ee, even after air exposure for a month (entry 4). tion of 2a in hexane. It was found that the reaction
These results indicated that the ruthenium catalyst in could proceed smoothly in full conversion with 99%
the ionic liquid medium was highly stable.
ee (Table 9, entry 1). Furthermore, this heterogenized
Catalyst Recycling
Table 9. Reuse of the heterogenized (R,R)-1a in the asym-
metric hydrogenation of 2a.[a]
Another advantage of ionic liquids as environmental-
ly friendly reaction media is the facile catalyst recy-
cling via solvent extraction. In our study, the cationic
RuACHTUNGTRENNUNG(diamine) complexes, which have a strong affinity
to the highly polar ionic liquids, hardly dissolved in
non-polar solvents like hexane. In contrast, the less
polar products show good solubility in hexane. Such
distinct solubility differences between the catalyst and
the product can facilitate catalyst separation and
product isolation.
In our previous work, we have demonstrated that
the ruthenium catalyst (S,S)-1a could be easily recy-
cled at least 7 times for quinoline hydrogenation in
[Bmim]PF6 by solvent extraction.[4d] Then, we also in-
vestigated the recyclability of catalyst (S,S)-1f in the
asymmetric hydrogenation of 7g (Table 8). In a similar
way, the catalyst immobilized in [Bmim]NTf2 could be
recycled no less than five times, maintaining excellent
enantioselectivity (96% ee) but at the expense of
gradually decreasing reactivity. In the sixth run, an
Run
Conv. [%][b]
Yield [%][c]
ee [%][d]
1
2
3
4
>99
>99
>99
>99
>99
>99
84
94
92
96
96
94
93
64
20
99
98
98
97
98
98
99
98
5
6
7[e]
8[e]
37
[a]
Reaction conditions: 0.2 mmol 2a in 1 mL hexane, 50 atm
H2, 258C, 1.0 mol% SILP-(R,R)-1a, 24 h.
Determined by H NMR spectroscopy.
Isolated yields.
Determined by HPLC analysis.
For 48 h.
[b]
[c]
[d]
[e]
1
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Zi-Yuan Ding et al.
UPDATES
after purging the autoclave with hydrogen gas several times.
The reaction mixture was stirred at room temperature for
12 h. After the autoclave was depressurized, the reduced
product was extracted with n-hexane (6ꢂ1 mL). The com-
bined hexane layer was concentrated under vacuum to give
the partially hydrogenated product (S)-5b. In the second
step, (S)-5b was further hydrogenated with (R,R)-1a
(1.5 mg, 0.002 mmol) in 1 mL MeOH, affording the fully re-
duced product (S,R)-6b. The conversion was determined by
1H NMR, and the diastereoselectivity (94/6 dr) and enantio-
selectivity (99% ee) were determined by HPLC on a chiral
stationary phase.
ruthenium catalyst could be easily separated by
simple filtration and reused five times without obvi-
ous loss of reactivity and enantioselectivity (entries 2–
6). Notably, a decrease of reactivity was observed in
the seventh and eighth runs, even though identical ee
values were retained.
Conclusions
In conclusion, we have demonstrated that chiral cat-
ionic phosphine-free RuACTHNUTRGNE(NUG diamine) complexes exhibit-
ed unprecedented reactivity and excellent enantiose-
lectivity (up to >99% ee) in the hydrogenation of
quinolines and 3,4-dihydroisoquinolines in neat ionic
liquids. It was found that the catalytic performance
was influenced by the anion of the ionic liquids in
both cases. Interestingly, the hydrogenation of quino-
line derivatives bearing a carbonyl group was selec-
tive for C=N (quinoline) over C=O (ketone) bonds,
while such a chemoselectivity was not observed in
methanol. Importantly, the use of ionic liquid could
stabilize the ruthenium catalyst and thus facilitate its
recycling. This catalytic protocol thus provides
a greener and practical access to a variety of optically
active 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahy-
droisoquinoline derivatives.
General Procedure for the Asymmetric Hydrogena-
tion of 3,4-Dihydroisoquinolines in Ionic Liquids and
Catalyst Recycling
A 50-mL glass-lined stainless-steel reactor equipped with
a magnetic stirrer bar was charged with Ru catalyst [(S,S)-1f
or (R,R)-1f, 1.6 mg, 0.002 mmol] and 1-alkyl-3,4-dihydroiso-
quinoline (0.20 mmol) in [Bmim]X (1.0 mL, X=BF4, PF6,
SbF6, OTf or NTf2) under a nitrogen atmosphere in a glove
box. The autoclave was closed, and the final pressure of the
hydrogen gas was adjusted to 50 atm after purging the auto-
clave with hydrogen gas several times. The reaction mixture
was stirred at room temperature for a predetermined period
of time. After the autoclave had been depressurized, the re-
duced product was extracted with n-hexane (6ꢂ2 mL).
After vacuum drying, the ionic liquid phase containing the
catalyst was reused for the next run by recharging of sub-
strate under the same reaction conditions. The combined
hexane layer was concentrated under vacuum to give the
tetrahydroisoquinoline product. The conversions were deter-
Experimental Section
1
mined by H NMR, and the ee values were determined by
General Procedure for the Asymmetric Hydrogena-
tion of Quinolines in Ionic Liquids
HPLC on a chiral stationary phase.
A 50-mL glass-lined stainless-steel reactor equipped with
a magnetic stirrer bar was charged with Ru catalyst [(S,S)-1a
or (R,R)-1a] and 2-substituted quinoline in [Bmim]X
(1.0 mL, X=BF4, PF6, SbF6, OTf or NTf2) under a nitrogen
atmosphere in a glove box. The autoclave was closed, and
the final pressure of the hydrogen gas was adjusted to
50 atm after purging the autoclave with hydrogen gas sever-
al times. The reaction mixture was stirred at room tempera-
ture for a predetermined period of time. After the autoclave
had been carefully depressurized, the reduced product was
extracted with n-hexane (6ꢂ1 mL). The combined hexane
layer was concentrated under vacuum to give the tetrahy-
droquinoline product. The conversions were determined by
1H NMR, and the ee values were determined by HPLC on
a chiral stationary phase.
General Procedure for the Preparation and Reuse of
the Supported Ionic Liquid-Phase Catalyst
The preparation of the immobilized Ru catalyst was carried
out under an inert gas atmosphere. First, the ruthenium
complex (R,R)-1a (150 mg, 0.2 mmol, 3 wt%) and the ionic
liquid [Bmim]PF6 (1.25 g, 4.4 mmol, 25 wt%) were dissolved
in 25 mL acetone to give a clear orange solution. After the
addition of silica gel (200–300M, 3.75 g, 75 wt%), the vola-
tile component of the mixture was removed under reduced
pressure. The resulting material was dried under vacuum at
room temperature for 12 h to give the supported ionic
liquid-phase catalyst as an orange solid.
Then, a 50-mL glass-lined stainless-steel reactor equipped
with a magnetic stirrer bar was charged with the above
formed immobilized catalyst [1.0 mol% SILP-(R,R)-1a], and
2-methylquinoline 2a (50 mg, 0.20 mmol) in 1.0 mL hexane
under a nitrogen atmosphere in a glove box. The autoclave
was closed, and the final pressure of the hydrogen gas was
adjusted to 50 atm after purging the autoclave with hydro-
gen gas several times. The reaction mixture was stirred at
room temperature for a predetermined period of time.
After the autoclave had been depressurized, the heterogen-
ized catalyst was separated by simple filtration, and then
reused in the next run under the same reaction conditions.
The hexane layer was concentrated under vacuum to give
Typical Procedure for the Two-Step Asymmetric
Hydrogenation of 4b
In the first step, a 50-mL glass-lined stainless-steel reactor
equipped with a magnetic stirrer bar was charged with Ru
catalyst [(S,S)-1a, 1.5 mg, 0.002 mmol] and substrate 4b
(0.20 mmol) in 1 mL [Bmim]SbF6 under a nitrogen atmos-
phere in a glove box. The autoclave was closed, and the
final pressure of the hydrogen gas was adjusted to 50 atm
3734
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Adv. Synth. Catal. 2013, 355, 3727 – 3735

Highly Enantioselective Synthesis of Chiral Tetrahydroquinolines and Tetrahydroisoquinolines
the tetrahydroquinoline product. The conversions were de-
termined by H NMR, and the ee values were determined
by HPLC on a chiral stationary phase.
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and Institute of Chemistry, Chinese Academy of Sciences
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