Asymmetric hydrogenation of quinolines with recyclable and air-stable iridium catalyst systems

Article abstract of DOI:10.1016/j.tetasy.2007.10.034

The iridium complex-catalyzed asymmetric hydrogenation of quinolines in a DMPEG/hexane biphasic system was studied. Catalysts with C₂-symmetric ligands such as Xyl-P-Phos, Cl-MeO-BIPHEP, SYNPHOS, and DifluorPhos are highly effective for this type of reaction. Most of the catalysts tested can be retained in DMPEG (M_n = 500), and the asymmetric hydrogenation of various quinoline substrates can be carried out in DMPEG/hexane biphasic system with up to 92% ee. The catalysts and the products can be separated via simple phase separation, and the reactivity/stereoselectivity of the catalysts can be retained for at least three reaction cycles.

Full text of DOI:10.1016/j.tetasy.2007.10.034

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2625–2631
Asymmetric hydrogenation of quinolines with recyclable and
air-stable iridium catalyst systems
Sau Hing Chan,a Kim Hung Lam,a,* Yue-Ming Li,a Lijin Xu,a Weijun Tang,a Fuk Loi Lam,a
Wai Hung Lo,a Wing Yiu Yu,a Qinghua Fanb,* and Albert S. C. Chana,*
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 SAR, PR China
bInstitute of Chemistry, The Chinese Academy of Sciences, Beijing 100080, PR China
Received 23 July 2007; accepted 16 October 2007
Abstract—The iridium complex-catalyzed asymmetric hydrogenation of quinolines in a DMPEG/hexane biphasic system was studied.
Catalysts with C2-symmetric ligands such as Xyl-P-Phos, Cl–MeO–BIPHEP, SYNPHOS, and DifluorPhos are highly effective for this
type of reaction. Most of the catalysts tested can be retained in DMPEG (Mn = 500), and the asymmetric hydrogenation of various
quinoline substrates can be carried out in DMPEG/hexane biphasic system with up to 92% ee. The catalysts and the products can be
separated via simple phase separation, and the reactivity/stereoselectivity of the catalysts can be retained for at least three reaction cycles.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
would provide an effective route to this type of compounds.
Prior to the works by Zhou,4 ourselves,5 and Reetz,6 only
limited systems were known for the successful asymmetric
hydrogenation of heteroaromatic compounds such as quin-
olines under homogeneous conditions.7 Chiral ligands,
which have been tested in the iridium-catalyzed asymmetric
hydrogenation of quinolines, include MeO–BIPHEP,4a
ferrocenyl-oxazoline derived ligand,4b P-Phos,5a H8-
BINAPO,5b a BINOL-derived diphosphonite6a and BIN-
AP-cored dendrimers.6b We have reported an air-stable
Ir/(R)-P-Phos/DMPEG/hexane catalyst system for the
asymmetric hydrogenation of quinolines with up to 89%
ee and nearly quantitative conversion.5 As part of our
continuing effort in this area, we sought to improve both
the enantioselectivity and catalyst recyclability for this
reaction.
Despite the fact that transition metal-catalyzed asymmetric
hydrogenation has been extensively studied and over a
thousand new ligands have been developed, examples of
successful industrial application of this type of important
reaction are still very much limited. This is partially due
to the difficulties in separation and reusability of the gener-
ally very expensive chiral catalysts. For these reasons, reac-
tions under conditions, which would facilitate the
separation of products from the reaction media are of high
interest. Moreover, environmental problems are calling for
greener and more environmentally friendly reaction media
for chemical processes.1 Among the various approaches
studied, liquid biphasic systems have been proven to be
effective by providing easy catalyst-product separation.2
Herein, we report our recent progress in the asymmetric
hydrogenation in liquid biphasic systems, and the recycle
and re-use of the air-stable iridium catalyst systems.
2. Results and discussion
Chiral tetrahydroquinolines are important structural units
of alkaloids,3 and asymmetric hydrogenation of quinolines
At first, some readily available chiral ligands were exam-
ined in the asymmetric hydrogenation of 2-methylquinoline
1a (Scheme 1). All catalysts were prepared via in situ reac-
tion of [Ir(COD)Cl]2 with a chiral ligand in THF (unless
otherwise specified) with I2 as an additive, and the reac-
tions were carried out for 20 h at room temperature.
*
Corresponding authors. Tel.: +852 2766 5222; fax: +852 2303 1590
(A.S.C.C.); e-mail addresses: scachan@polyu.edu.hk; bcjoelam@inet.
polyu.edu.hk
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.034

2626
S. H. Chan et al. / Tetrahedron: Asymmetry 18 (2007) 2625–2631
Table 1. Ligand screening for Ir-catalyzed asymmetric hydrogenation of
2-methylquinoline (1a)a
From Table 1, classical ligands, such as BINAP 7, DIOP 8
and CHIRAPHOS 13 exhibited high conversions; however,
only moderate enantioselectivities were obtained. The ferro-
cenyl N–P/S ligand 109f showed nearly zero enantioselec-
tivity. Ligands with special structural features 11 and12
did not offer any special advantages in improving the
enantioselectivities also. The O–P 9 and 16, N–P 17,
and P/N 14 and 15 ligands only showed poor enantioselec-
tivities here. After screening, we found that some axially
chiral bidendate phosphines, especially those with elec-
tron-donating groups attached to the backbones (Fig. 1)
showed good enantioselectivity and conversion. P-Phos 3a,
Xyl-P-Phos 3b, and Cl–MeO–BIPHEP 4a exhibited an
additional advantage of air-stability under the reaction
conditions and were chosen for further studies.
Entry
Ligand
eeb (%)
Conv.c (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
7a
7b
7c
8
52
69
77
31
1
1
2
1
51
15
13
14
9
>99
>99
99
>99
>99
>99
84
>99
>99
3
>99
>99
35
9
10
11
12
13
14
15
16
17
a Reaction conditions: 0.15 mmol 1a, [Ir(COD)Cl]2 (0.0015 mmol), ligand
(0.0032 mmol), I2 (0.015 mmol), 1.5 ml THF, 700 psi H2 pressure at rt
for 20 h.
b The ee values were determined by HPLC using Chiralpak OJ-H column
with mobile phase of IPA/hexane (5:95) at 0.5 ml/min.
c The conversions were determined by 1H NMR spectroscopy of the crude
product.
As can be seen from Table 2, the solvent had a significant
effect on both the enantioselectivities and conversions. The
use of protic solvents led to poor conversion and enantio-
selectivities (entries 3–4, 8–9 and 15–16). The best results
were obtained when mixed THF and DCM (dichlorometh-
ane) (v/v = 1:1) was used as the reaction solvent with 89%
enantioselectivity and 99% conversion for both SYNPHOS
OMe
R
O
O
N
F
F
MeO
MeO
PAr2
PAr2
O
O
MeO
MeO
PPh2
PPh2
O
O
PPh2
PPh2
PPh2
PPh2
F
F
N
O
R
O
OMe
(i) Ar = Ph; (R)-P-Phos 3a
(ii) Ar = 3,5-(Me)2Ph; (R)-Xyl-P-Phos 3b
(i) R = Cl; (R)-CL-MeO-Biphep 4a
(ii) R = H; (R)-MeO-Biphep 4b
(R)-DifluorPhos 6
(R)-SYNPHOS 5
PPh2
O
H
N
O
O
PPh2
PPh2
PAr2
PAr2
PPh2
Fe
H
O
Ph2P
(i) Ar = 3,5(Me)2Ph 7a
(ii) Ar = 4-MePh 7b
(iii) Ar = Ph 7c
10
(S,S)-DIOP 8
PPh2
(R)-SpiroP 9
PPh2
PPh2
H
H
PPh2
PPh2
PPh2
(S)-PHANEPHOS 11
(R,R)-NORPHOS 12
(S,S)-CHIRAPHOS 13
PAr2
O
O
Ph2P
N
BzO
O
NHPPh2
NHPPh2
PAr2
N
O
PPh2
MeO
OBz
(S)-QUINAP 14
15
Ar = 3,5-(Me)2Ph
CARBOPHOS 16
(R)-BINAM 17
Figure 1. Structures of chiral ligands8 3–17.

S. H. Chan et al. / Tetrahedron: Asymmetry 18 (2007) 2625–2631
2627
Table 2. Ir Complex-catalyzed asymmetric hydrogenation of 2-methyl-
quinoline 1aa
5 and DifluorPhos 6. For Cl–MeO–BIPHEP 4a the best
solvent was THF with 91% enantioselectivity and 99% con-
version. For the purpose of comparison, we carried out the
asymmetric hydrogenation of 1a with the optimal solvent
systems of the respective ligands: that is, THF for ligands
3a, 3b, and 4a, DCM (dichloromethane)/THF mixture
for ligands SYNPHOS 5 and DifluorPhos 6.
Entry Ligand Solvent
eeb (%) Conv.c (%) Config.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
3a
3b
4a
4a
4a
4a
4a
5
THF
THF
91
92
5
14
92
79
91
26
7
77
81
66
45
97
>99
65
51
68
20
99
14
17
72
15
39
53
99
50
64
73
54
99
63
99
(R)
(R)
(S)
(S)
(R)
(R)
(R)
(S)
(R)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(R)
(R)
(R)
(R)
(R)
MeOH
EtOH
Toluene
DCM
THF
MeOH
EtOH
Toluene
DCM
Ether
With the best reaction medium, the effect of pressure and
temperature on the hydrogenation was then investigated.
Table 3 shows that the conversion was relatively insensitive
to changes in hydrogen pressure, but the enantioselectivity
slightly decreased at higher pressure for Ir/4a and Ir/6 (en-
tries 3–6). The reaction with Ir/4a and Ir/5 is favored at low
temperature (entry 1). The effect of the substrate-to-cata-
lyst (S/C) ratio on the hydrogenation reaction of quinoline
was also examined and the results are listed in Table 4.
From the table, it can be seen that a change in S/C ratio
had a slight effect on enantioselectivities (entries 1–6).
Remarkably, this reaction could even be performed at a
substrate-to-catalyst (S/C) ratio of 5000:1 without any loss
in enantioselectivities for ligands 5 and 6.
5
5
5
5
5
THF
5
DCM/THF (1:1) 89
6
MeOH
EtOH
Toluene
DCM
Ether
33
45
81
91
77
84
6
6
6
6
6
THF
6
DCM/THF (1:1) 89
a Reaction conditions: 0.15 mmol 1a, [Ir(COD)Cl]2 (0.0015 mmol), ligand
(0.0032 mmol), I2 (0.015 mmol), 1.5 ml solvent, 700 psi H2 pressure at rt
for 20 h.
b The ee values were determined by HPLC using Chiralpak OJ-H column
with mobile phase of IPA/hexane (5:95) at 0.5 ml/min.
c The conversions were determined by 1H NMR spectroscopy of the crude
product.
To verify the effectiveness of these catalyst systems in the
asymmetric hydrogenation of quinoline substrates, the
asymmetric hydrogenation of a series of 2-alkylated
quinolines 1b–1k were also carried out under the opti-
mized conditions (Scheme 1), and the results are listed in
Table 5.
Table 3. Effect of temperature/pressure on the asymmetric hydrogenation of 1aa
Entry
Temperature (ꢁC)/pressure (psi)
Ligand
(R)-4a
Conv.c (%)
(R)-5
Conv.c (%)
(R)-6
Conv.c (%)
eeb (%)
eeb (%)
eeb (%)
1
2
3
4
5
6
0/700
À30/700
rt/100
rt/200
rt/500
95
94
92
—
92
91
99
99
99
—
99
99
93
93
87
92
91
89
>99
42
99
>99
>99
>99
87
80
93
90
87
85
99
50
99
99
99
99
rt/700
a Reaction conditions: 0.15 mmol quinoline, [Ir(COD)Cl]2 (0.0015 mmol), ligand (0.0032 mmol), I2 (0.015 mmol), 1.5 ml solvent at rt for 20 h.
b The ee values were determined by HPLC analysis with Chiralpak OJ-H column with mobile phase of IPA/hexane (5:95) at 0.5 ml/min.
c The conversion was determined by 1H NMR spectroscopy of the crude product.
Table 4. Effect of substrate-to-catalyst (S/C) ratio on the asymmetric hydrogenation of 1aa
Entry
S/C ratio
Ligand
(R)-4a
(R)-5
(R)-6
eeb (%)
Conv.c (%)
eeb (%)
Conv.c (%)
eeb (%)
Conv.c (%)
1
2
3
4
5
6
100:1
200:1
500:1
1000:1
2000:1
5000:1
92
92
91
92
93
—
99
99
99
96
93
—
87
90
91
92
92
90
99
99
96
83
73
47
93
93
95
94
95
95
99
99
98
77
69
37
a Reaction conditions: 0.15 mmol quinoline, [Ir(COD)Cl]2 (0.0015 mmol), ligand (0.0032 mmol), I2 (0.015 mmol), 1.5 ml solvent at rt for 20 h.
b The ee values were determined by HPLC analysis with Chiralpak OJ-H column with mobile phase of IPA/hexane (5:95) at 0.5 ml/min.
c The conversion was determined by 1H NMR spectroscopy of the crude product.

2628
S. H. Chan et al. / Tetrahedron: Asymmetry 18 (2007) 2625–2631
Table 5. Ir complex-catalyzed asymmetric hydrogenation of quinolines 1a–1ka
R2
R2
Ir(COD)Cl2, H2
*
R1
L*, I2, solvent, rt
N
H
N
R1
1
2
Scheme 1
HO
1a R1 = Me, R2 = H;
1e R1 = n-Pentyl, R2 = H;
1i
R1 =
, R2 = H;
1b R1 = Et, R2 = H;
1f R1 = Me, R2 = Me;
1j R1 = Me, R2 = F;
1c R1 = n-Pr, R2 = H;
1g R1 = Me, R2 = OMe;
HO
R1 =
, R2 = H.
1k
1d R1 = n-Bu, R2 = H; 1h R1 = Phenylethyl, R2 = H;
Entry Substrate
Ligand
(R)-3ae eeb (conv.)c (%) (R)-3be eeb (conv.)c (%) (R)-4ae eeb (conv.)c (%) (R)-5 eeb (conv.)c (%) (R)-6 eeb (conv.)c (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
91 (97)d
92 (99)d
88 (98)
88 (99)
91 (97)d
87 (97)
87 (97)
90 (99)d
85 (99)
90 (99)d
91 (99)d
92 (99)
92 (99)
92 (99)
89 (99)
89 (99)
90 (99)
95 (99)
84 (99)
92 (99)
86 (99)
94 (99)
92 (99)
90 (99)
88 (99)
87 (99)
88 (99)
83 (87)
89 (94)
88 (73)
89 (89)
88 (89)
85 (93)
92 (99)
92 (99)
90 (99)
89 (99)
88 (99)
86 (99)
87 (99)
92 (99)
92 (86)
89 (99)
91 (91)
93 (99)
94 (99)
92 (99)
90 (99)
92 (99)
88 (99)
86 (67)
93 (99)
92 (99)
92 (94)
90 (99)
1g
1h
1i
10
11
1j
1k
a Reaction conditions: 0.15 mmol 1a, [Ir(COD)Cl]2 (0.0015 mmol), ligand (0.0032 mmol), I2 (0.015 mmol), 1.5 ml THF or THF/DCM (1:1, v/v) as solvent
at rt for 20 h.
b The ee values were determined by HPLC with a Chiralpak OJ-H 2a–g, OJ (2h,i), or OD-H 2j,k column. The chiral products 2a–h and 2j are (R)-
configuration, while 2i and 2k are (S)-configuration.
c The conversion was determined by 1H NMR spectroscopy of the crude product.
d Data were taken from Ref. 5a for comparison.
e Operation under air without the use of glovebox and degassed solvent.
Table 6. Asymmetric hydrogenation of 1a in ionic liquidsa
The Ir-catalyzed hydrogenation of the quinolines bearing a
C1–C5 side chain at the 2-position of quinoline ring gave
Entry
Ligand
[bmim][BF4]
eeb (%) Conv.c (%)
[bmim][PF6]
products in 87–95% ee (Table 5, entries 1–5). A substituent
at the 6-position did not show significant effect on the con-
version and enantioselectivity of the reaction (entries 6–7
and 10). Good results were also obtained with 2-phenethyl
substituted quinoline (entry 8). The tolerance of the hydro-
xyl group was well demonstrated by the successful hydro-
genation of substrates 1i and 1k with 99% conversion
and 94% ee (entries 9 and 11).
eeb (%)
Conv.c (%)
1
2
3
4
5
(R)-3a
(R)-3b
(R)-4a
(R)-5
17
55
33
59
24
5
4
3
8
67
23
11
16
13
10
34
54
27
99
42
(R)-6
a Reaction conditions: 0.15 mmol quinoline, [Ir(COD)Cl]2 (0.0015 mmol),
ligand (0.0032 mmol), I2 (0.015 mmol), 0.5 ml [bmim][BF4] or
[bmim][PF6] as solvent; 1000 psi H2 pressure at rt for 20 h.
b The ee values were determined by HPLC analysis with Chiralpak OJ-H
column.
c The conversion was determined by 1H NMR spectroscopy of the crude
product.
After establishing a general method for the asymmetric
hydrogenation of quinolines, and having a better under-
standing of the catalyst stability, we examined the effective-
ness of these iridium complexes in other solvent systems,
namely room temperature ionic liquids or poly(ethyl gly-
col) dimethyl ether (DMPEG).9,10 To facilitate the separa-
tion of a product from the reaction system, it is generally
recognized that there should be distinct solubility differ-
ences of the catalysts and products in the solvent systems.
In this regard, two common imidazole ionic liquids 1-but-
yl-3-methylimidazolium tetrafluoroborate ([bmim][BF4])
and 1-butyl-3-methylimidazolium hexafluorophosphate
([bmim][PF6]) were first chosen as solvents for the catalysts.
The hydrogenation of 2-methylquinoline 1a in these two
imidazole ionic liquid resulted in poor ee’s (ca 3%) and
conversions (ca 5%), irrespective of the Ir catalyst systems
used (Table 6).
Given that using DMPEG as a reaction medium for
Ir-P-Phos and Ir-H8-BINAPO-catalyzed asymmetric
hydrogenation of quinoline proceeded readily with good
stereoselectivity,5 we examined the activity of the Ir-cata-
lyst systems for the asymmetric hydrogenation of quinoline
in a DMPEG/hexane biphasic system. After balancing the
catalyst/product solubility and the medium viscosity,
DMPEG (Mn = 500) was chosen to be the reaction me-
dium. As shown in Table 7, the catalysts tested provided
good conversions (up to 99%) and moderate to high
enantioselectivities for the asymmetric hydrogenation of

S. H. Chan et al. / Tetrahedron: Asymmetry 18 (2007) 2625–2631
2629
Table 7. Iridium complex-catalyzed asymmetric hydrogenation of substituted quinolines in DMPEG/hexane biphasic systema
Entry
Substrate
Ligand
3ae eeb (conv.)c (%)
3be eeb (conv.)c (%)
4ae eeb (conv.)c (%)
4b eeb (conv.)c (%)
5 eeb (conv.)c (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
89 (98)d
90 (99)d
80 (99)
80 (99)
80 (99)
73 (97)
51 (73)
86 (99)
79 (91)
88 (90)d
88 (99)d
86 (99)
82 (97)
78 (98)
71 (99)
72 (97)
79 (99)
88 (99)
64 (99)
53 (97)
68 (97)
80 (95)
86 (99)
92 (99)
90 (99)
85 (99)
87 (99)
82 (99)
67 (72)
91 (99)
79 (96)
79 (99)
82 (89)
84 (99)
79 (99)
76 (99)
75 (99)
78 (99)
77 (99)
73 (99)
71 (99)
65 (99)
75 (99)
79 (99)
83 (99)
85 (98)
82 (99)
77 (99)
80 (98)
78 (99)
80 (98)
78 (98)
92 (97)
77 (99)
75 (98)
1g
1h
1i
10
11
1j
1k
a Reaction conditions: 0.15 mmol 1a, [Ir(COD)Cl]2 (0.0015 mmol), ligand (0.0032 mmol), I2 (0.015 mmol), DMPEG–hexane (1:1, v/v) as solvent, 1000 psi
H2 pressure at rt for 20 h.
b The ee values were determined by HPLC with a Chiralpak OJ-H (2a–g), OJ (2h,i), or OD-H (2j,k) column. Chiral products 2a–h and 2j are (R)-
configuration while 2i and 2k are (S)-configuration.
c The conversion was determined by 1H NMR spectroscopy of the crude product.
d Data were taken from Ref. 5a for comparison.
e Operation under air without the use of glovebox and degassed solvent.
substituted quinolines (up to 92%). Ir-4a was found to give
the best results in a DMPEG/hexane biphasic system (up
to 92% ee). Ir-3a, 3b, and 4a were found to be air-stable
and all the reactions were performed in air without using
a glovebox. In contrast, Ir-4b and Ir-5 were rather unstable
in air.
Table 8. Recycling and reuse of Ir-4a, Ir-4b and Ir-5 for the asymmetric
hydrogenation of 2-methylquinolinea
Run
1
2
3
4
(R)-4ae
eeb (%)
Conv.c (%)
86
99 (70)
84
99 (61)
82
99 (56)
81
93
(R)-4b
(R)-5
eeb (%)
84
84
84
84
99
Conv.c (%)
99 (53d)
99 (43d)
99 (37d)
The air-stability of these iridium catalyst systems was then
tested by comparing the results under dried and anaerobic
conditions (with the use of degassed solvents and glovebox)
with those under conditions of using unpurified reagent-
grade solvents unaffected by air.
eeb (%)
Conv.c (%)
83
99 (36)
84
99 (34)
84
99 (32)
83
99
a Reaction conditions: 0.5 mmol 1a, [Ir(COD)Cl]2 (0.0026 mmol), ligand
(0.005 mmol), I2 (0.055 mmol), 2 ml DMPEG and 2 ml hexane as sol-
vent, 1000 psi H2 pressure at rt for 20 h.
b The ee values were determined by HPLC analysis with Chiralpak OJ-H
column.
The reactions performed in untreated solvents and under
open atmosphere catalyzed with Ir-3a, Ir-3b, and Ir-4a
gave good conversions and high enantioselectivities. For
ligands 3a, 3b, and 4a, the results (91% ee and 97% conver-
sion for ligand 3a; 92% ee and 99% conversion for ligand
3b and 92% ee and 99% conversion for ligand 4a) were
comparable to those obtained using glovebox and degassed
solvents. Ir-5 and Ir-6 were less effective under those reac-
tions and lower ee’s were observed: Ir-5, 92% ee (glovebox)
versus 84% ee (open atmosphere); Ir-6, 93% ee (glovebox)
versus 90% ee (open atmosphere). These results indicated
that the Ir-3a, Ir-3b, and Ir-4a systems were more air-stable
than Ir-5 and Ir-6, and therefore were used for further
study.
c The conversion was determined by 1H NMR spectroscopy of the crude
product.
d Reaction time 3 h.
e Operation under air without the use of glovebox and degassed solvent.
3. Conclusion
In conclusion, iridium complexes with C2-symmetric
ligands such as Xyl-P-Phos, Cl–MeO–BIPHEP, SYN-
PHOS, and DifluorPhos are effective catalysts for the
asymmetric hydrogenation of quinolines. These catalysts
can be retained in low molecular weight poly(ethylene
glycol) dimethyl ether (DMPEG, Mn = 500), and the asym-
metric hydrogenation of 2-methyl quinoline can be carried
out in a DMPEG/hexane biphasic system with up to 92%
ee. The catalysts and products can be separated via simple
phase separation, and the reactivity/stereoselectivity of the
catalysts can be retained for at least three reaction cycles.
By employing 1a as a model substrate, we tested the cata-
lyst recyclability in a DMPEG/hexane biphasic system.
Results in Table 8 indicate that Ir-4a, Ir-4b, and Ir-5 might
be suitable for catalyst recovery and reuse. Experiments
were carried out to monitor the course of the reaction in
DMPEG/hexane biphasic system, and the conversions of
1
1a after 1 h of reaction was measured via H NMR analy-
4. Experimental
ses of the reaction mixture (Table 8, data in parentheses).
The results indicated that the activity decreased slightly
after each cycle. The loss of activity might be due to either
(i) catalyst loss during the extraction process or (ii) loss of
catalyst activity after the recycling process.
4.1. General methods
Reagents were purchased from either Acros or Aldrich and
used without further purification. NMR spectra were

2630
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G.; Armstrong, A.; Coombe, V.; Wells, A. Angew. Chem., Int.
Ed. 2007, 46, 3798.
recorded on a Varian 500 spectrometer. Chiralpak OJ-H,
OD-H and OJ columns were purchased from Daicel.
HPLC analyses were performed using HP1100 equipped
with UV–visible detector and chiral column using IPA/hex-
ane as eluent.
2. For the most recent examples on biphasic catalytic systems,
see: (a) Ladnak, V.; Hofmann, N.; Brausch, N.; Wasserscheid,
P. Adv. Synth. Catal. 2007, 349, 719; (b) Sieffert, N.; Wipff, G.
Chem. Eur. J. 2007, 13, 1978; (c) Hernandez, F. J.; de los Rios,
A. P.; Gomez, D.; Rubio, M.; Villora, G. Appl. Catal. Environ.
2006, 67, 121; (d) Vallee, C.; Chauvin, Y.; Basset, J. M.;
Santini, C. C.; Galland, J. C. Adv. Synth. Catal. 2005, 347,
1835; (e) Fujita, S.; Akihara, S.; Zhao, F. Y.; Liu, R. X.;
Hasegawa, M.; Arai, M. J. Catal. 2005, 236, 101; (f) Solinas,
M.; Pfaltz, A.; Cozzi, P. G.; Leitner, W. J. Am. Chem.
Soc. 2004, 126, 16142; For a recent review, see: (g) Behr, A.;
Henze, G.; Schomacker, R. Adv. Synth. Catal. 2006, 348,
1485.
3. (a) Comprehensive Organic Synthesis; Keay, J. G., Trost, B.
M., Pergamon, I. F., Eds.; Oxford, 1991; Vol. 8, pp 579–601;
(b) Products Chemistry; Katritzky, A. R. S., Barton, D. H.,
Nakanishi, K., Eds.; Oxford, 1999; Vols. 1–9, (c) Catalytic
Asymmetric Synthesis; Ojima, I., Ed., 2nd ed.; John Wiley &
Sons: New York, 2000.
4. (a) Wang, W. B.; Lu, S. M.; Yang, P. Y.; Han, X. W.; Zhou,
Y. G. J. Am. Chem. Soc. 2003, 125, 10536; (b) Lu, S. M.;
Han, X. W.; Zhou, Y. G. Adv. Synth. Catal. 2004, 346, 909;
(c) Yang, P. Y.; Zhou, Y. G. Tetrahedron: Asymmetry 2004,
15, 1145; (d) Lu, S. M.; Wang, Y. Q.; Han, X. W.; Zhou, Y.
G. Angew. Chem., Int. Ed. 2006, 45, 2260.
5. (a) Xu, L. J.; Lam, K. H.; Ji, J. X.; Wu, J.; Fan, Q. H.; Lo, W.
H.; Chan, A. S. C. Chem. Commun. 2005, 11, 1390; (b) Lam,
K. H.; Xu, L. J.; Feng, L. C.; Fan, Q. H.; Lam, F. L.; Lo, W.
H.; Chan, A. S. C. Adv. Synth. Catal. 2005, 347, 1755; (c)
Tang, W. J.; Zhu, S. F.; Xu, L. J.; Zhou, Q. L.; Fan, Q. H.;
Zhou, H. F.; Lam, K. H.; Chan, A. S. C. Chem. Commun.
2007, 613.
4.2. General procedure for the asymmetric hydrogenation of
quinoline in organic solvents and DMPEG/hexane
For the asymmetric hydrogenation in organic solvent, a
mixture of [Ir(COD)Cl]2 (0.0015 mmol) and ligands
(0.0032 mmol) in 1.0 ml dried solvent was stirred at room
temperature for 30 min in a glovebox. The mixture was
transferred with a gas-tight syringe to a stainless steel auto-
clave, which contains a mixture of I2 (4 mg, 0.015 mmol)
and quinoline (0.15 mmol) in 0.5 ml solvent. The hydroge-
nation reaction was performed at room temperature under
H2 (700 psi/200 psi/100 psi) for 20 h unless otherwise spec-
ified. After careful release of the hydrogen gas, an aqueous
sodium carbonate solution (2 ml) was added, and the
mixture was stirred for 15 min. The aqueous layer was then
extracted with ethyl acetate (3 · 2 ml). The combined
organic extracts were dried over sodium sulfate and con-
centrated under reduced pressure in a rotary evaporator
to afford the crude product. The substrate conversion
1
was determined by H NMR spectroscopy. The enantio-
meric excesses were determined by HPLC after purification
on silica gel (n-hexane/EA = 5:1) with a chiral column
(OJ-H, OD-H or OJ).
For asymmetric hydrogenation in DMPEG (Mn = 500)/
hexane solvent system, the procedures were the same as
above except that the catalyst was generated in situ in
1.0 ml DMPEG; the same amount of substrate (0.15 mmol)
with I2 in 1 ml hexane was added before charging H2
(1000 psi) at room temperature. After 20 h of reaction,
the hexane layer was decanted and the products in
DMPEG layer were extracted further with hexane
(3 · 2 ml). The combined hexane layer was concentrated
in vacuo to give the crude product, which was analyzed
with the same method as described above. All the tetra-
hydroquinoline products, 2a–2k, are known compounds.4a
6. (a) Reetz, M. T.; Li, X. Chem. Commum. 2006, 2159; (b)
Wang, Z. J.; Deng, G. J.; Li, Y.; He, Y. M.; Tang, W. J.; Fan,
Q. H. Org. Lett. 2007, 9, 1213.
7. Reviews of asymmetric hydrogenation of heteroaromatic
compounds (a) Kuwan, R.; Sato, K.; Kurokawa, T.;
Karube, D.; Ito, Y. J. Am. Chem. Soc. 2000, 122, 7614;
(b) Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.;
Steiner, H.; Studer, M. Adv. Synth. Catal. 2003, 345, 103;
(c) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029; (d)
Principles and Applications of Asymmetric Synthesis; Lin, G.
Q., Li, Y. M., Chan, A. S. C., Eds.; Wiley-Interscience: New
York, 2001; For some recent publications, see: (e) Henschke,
J. P.; Burk, M. J.; Malan, C. G.; Herzberg, D.; Peterson, J.
A.; Wildsmith, A. J.; Cobley, C. J.; Casy, G. Adv. Synth.
Catal. 2003, 345, 300; (f) Kuwano, R.; Kaneda, K.; Ito, T.;
Sato, K.; Kurokawa, T.; Ito, Y. Org. Lett. 2004, 6, 2213; (g)
Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005, 127,
8966; (h) Glorius, F.; Spielkamp, N.; Holle, S.; Goddard,
R.; Lehmann, C. W. Angew. Chem. 2004, 116, 2910;
(i) Yamagata, T.; Tadaoka, H.; Nagata, M.; Hirao, T.;
Kataoka, Y.; Ratovelomanana-Vidal, V.; Genet, J. P.;
Mashima, K. Organometallics 2006, 25, 2505; (j) Kaiser,
S.; Smidt, S. P.; Pfaltz, A. Angew. Chem., Int. Ed. 2006, 45,
5194; (k) Feiertag, P.; Albert, M.; Nettekoven, U.; Spindler,
F. Org. Lett. 2006, 8, 4133; (l) Rueping, M.; Antonchick, A.
P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683;
(m) Rueping, M.; Antonchick, A. P. Angew. Chem., Int. Ed.
2007, 46, 4562.
Acknowledgments
We thank the Hong Kong Research Grants Council (Pro-
ject Number N_PolyU 506/04), the University Grants
Committee Areas of Excellence Scheme in Hong Kong
(AoE P/10-01), the Hong Kong Polytechnic University
Areas of Strategic Development Fund, and the National
Natural Science Foundation of China for financial support
of this study.
References
8. (a) Pai, C. C.; Lin, C. W.; Lin, C. C.; Chen, C. C.; Chan, A. S.
C. J. Am. Chem. Soc. 2000, 122, 11513; (b) Duprat de Paule,
S.; Champion, N.; Vidal, V.; Geneˆt, J.-P.; Dellis, P. FR
2830254, 2001; Chem. Abstr. 2001, 1138, 280367; (c) Duprat
de Paule, S.; Champion, N.; Vidal, V.; Geneˆt, J.-P.; Dellis, P.
WO 2003029259, 2002; Chem. Abstr. 2001, 1138, 280367; (d)
1. While many consider that the reaction in aqueous phase is
more environmentally friendly, some scientists argue that a
fundamental mechanistic understanding of the role of water
in a reaction is necessary before water can be used in
organocatalytic reactions. See for example: Blackmond, D.

S. H. Chan et al. / Tetrahedron: Asymmetry 18 (2007) 2625–2631
2631
Pai, C. C.; Li, Y. M.; Zhou, Z. Y.; Chan, A. S. C. Tetrahedron
Lett. 2002, 43, 2789; (e) Wu, J.; Chen, H.; Kwok, W. H.; Lam,
K. H.; Zhou, Z. Y.; Yeung, C. H.; Chan, A. S. C. Tetrahedron
Lett. 2002, 43, 1539; (f) Duprat de Paule, S.; Jeulin, S.;
Ratovelomanana-Vidal, V.; Genet, J.-P.; Champion, N.;
Dellis, P. Tetrahedron Lett. 2003, 44, 823; (g) Jeulin, S.;
Paule, S.; Vidal, V.; Genet, J.-P.; Champion, N.; Dellis, P.
Angew. Chem., Int. Ed. 2004, 43, 320; (h) Patents (Bayer) EP
0749973, DE 10027154.
Deng, G.; Li, Y.; Chan, A. S. C. Org. Lett. 2004, 6, 1361; (f)
Lam, F. L.; Au-Yeung, T. L.; Cheung, H. Y.; Kok, H. L.;
Lam, W. S.; Wong, K. Y.; Chan, A. S. C. Tetrahedron:
Asymmetry 2006, 17, 497.
10. For some recent reviews, see: (a) Song, C. E. Chem. Commun.
2004, 1033; (b) Baudequin, C.; Baudoux, J.; Levillain, J.;
Cahard, D.; Gaumon, A.; Plaquevent, J. C. Tetrahedron:
Asymmetry 2003, 14, 3081; for recent examples, see: (c) Hu,
A.; Ngo, H. L.; Lin, W. Angew. Chem., Int. Ed. 2004, 43,
2501; (d) Pugin, B.; Studer, M.; Kuesters, E.; Sedelmeier, G.;
Feng, X. Adv. Synth. Catal. 2004, 346, 1481; (e) Berthod, M.;
Joerger, J.-M.; Mignani, G.; Vaultier, M.; Lemaire, M.
Tetrahedron: Asymmetry 2004, 15, 2219; (f) Solinas, M.;
Pfaltz, A.; Giorgio, P.; Leitner, W. J. Am. Chem. Soc. 2004,
126, 16142.
9. (a) Fan, Q.; Li, Y.; Chan, A. S. C. Chem. Rev. 2002, 102,
3667; (b) Deng, G.; Fan, Q.; Chen, X.; Liu, D.; Chan, A. S.
C. Chem. Commun. 2002, 1570; (c) Fan, Q.; Chen, Y.; Chen,
X.; Zhang, D.; Xi, F.; Chan, A. S. C. Chem. Commun. 2000,
789; (d) Fan, Q.; Ren, C.; Yeung, C. H.; Hu, W.; Chan, A. S.
C. J. Am. Chem. Soc. 1999, 121, 7407; (e) Yi, B.; Fan, Q.;