Highly enantioselective iridium-catalyzed hydrogenation of quinoline derivatives using chiral phosphinite H8-BINAPO

Article abstract of DOI:10.1002/adsc.200505130

The chiral diphosphinite H8-BINAPO derived from H8-BINOL has been used in the Ir-catalyzed asymmetric hydrogenation of quinolines, and high enantioselectivity (up to 97% ee) was obtained. Immobilization of the iridium catalyst in poly(ethylene glycol) dimethyl ether (DMPEG) is also discussed. With DMPEG/hexane biphasic system, better enantioselectivities were obtained as compared to those observed in aprotic organic solvents.

Full text of DOI:10.1002/adsc.200505130

COMMUNICATIONS
DOI: 10.1002/adsc.200505130
Highly Enantioselective Iridium-Catalyzed Hydrogenation of
Quinoline Derivatives Using Chiral Phosphinite H8-BINAPO
Kim Hung Lam,a Lijin Xu,a,* Lichun Feng,a Qing-Hua Fan,b,* Fuk Loi Lam,a
Wai-hung Lo,a Albert S. C. Chana,*
a
Open 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
Fax: (þ852)-2364-9932, e-mail:bcachan@polyu.edu.hk
b
Institute of Chemistry, The Chinese Academy of Sciences, Beijing 100080, Peopleꢀs Republic of China
Received: March 29, 2005; Accepted: June 9, 2005
Abstract: The chiral diphosphinite H8-BINAPO de-
rived from H8-BINOL has been used in the Ir-cata-
lyzed asymmetric hydrogenation of quinolines, and
high enantioselectivity (upto 97% ee) was obtained.
Immobilization of the iridium catalyst in poly(ethy-
lene glycol) dimethyl ether (DMPEG) is also dis-
cussed. With DMPEG/hexane biphasic system, bet-
ter enantioselectivities were obtained as compared
to those observed in aprotic organic solvents.
hols with chlorophosphines in the presence of an organic
base. Given the general utility of these phosphinite li-
gands in asymmetric hydrogenation reactions, it is very
attractive to develop effective chiral phosphinite ligands
for the asymmetric hydrogenation of heteroaromatics.
In our pursuit of effective chiral phosphinite ligands
for asymmetric hydrogenation,[6] we demonstrated that
the easily accessible H8-BINAPO ligand provided bet-
ter enantioselectivities in the Rh-catalyzed asymmetric
hydrogenation of enamides and a-dehydroamino acid
derivatives than their unmodified BINAPO ligand.[6c, d]
Compared with the BINAPO ligand, the better per-
formance of the H8-BINAPO ligand resulted from its
more rigid structure, which made it possible to compen-
Keywords: asymmetric hydrogenation; immobiliza-
tion; iridium; phosphinite ligands; poly(ethylene
glycol) dimethyl ether; quinoline
sate for the conformational flexibility caused by the in-
[6e]
À À
troduction of C O P bond. Herein we report the
use of the (S)-H8-BINAPO (L1) ligand in the Ir-cata-
The catalytic asymmetric hydrogenation of heteroaro- lyzed asymmetric hydrogenation of quinoline deriva-
matic compounds as a means to prepare optically pure tives in THF giving the desired products in up to 96%
heterocycles is an interesting, yet challenging task in or- ee. Even higher enantioselectivities (upto 97%) were
ganic synthesis.[1] Although considerable effort has been obtained when the reaction was carried out in
made in this area, the reports on the development of DMPEG/hexane.
highly effective catalysts are rare.[2–4] Among the report-
ed examples, the use of chiral bidentate diphosphine li-
gands seems to be an important factor for high enantio-
selectivity.
Recently, chiral phosphinite ligands have been suc-
cessfully used in the asymmetric hydrogenation of pro-
chiral olefins.[1,5] For example, O-BINAPO ligands
have been prepared to provide good to excellent enan-
tioselectivities in the asymmetric hydrogenation of a-
dehydroamino acids and b-aryl-b-(acylamino) acryl-
ates.[5a] The use of carbohydrate-derived phosphinite li-
gands also gave good to excellent results in the enantio-
We first examined the catalytic performance of L1 li-
selective hydrogenation of a-dehydroamino acids.[5b–d] gand in the Ir-catalyzed hydrogenation of quinaldine
Compared with phosphine ligands, phosphinites offer (1a). For comparison, the performance of (R)-BINAPO
the advantages of easy preparation and derivatization. (L2) ligand was also examined under otherwise identical
In general, the phosphinites can be conveniently synthe- conditions. The catalysts were prepared in situ from the
sized in good yields by reacting the corresponding alco- phosphinites and [Ir(COD)Cl]2 with I2 as additive. Un-
Adv. Synth. Catal. 2005, 347, 1755 – 1758
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1755

Kim Hung Lam et al.
COMMUNICATIONS
Table 1. Asymmetric hydrogenation of quinoline 1a under
Table 2. Catalytic asymmetric hydrogenation of quinoline
derivatives in THF with L1 ligand.[a]
various conditions.[a]
Conversion [%][b]
ee [%][b]
Entry
R1/R2
Yield [%]
ee [%][b]
Entry
Ligand
Solvent
1
2
3
4
5
6
7
8
Me/H (1a)
Et/H (1b)
n-Pr/H (1c)
n-Bu/H (1d)
Ph/H (1e)
Me/Me (1f)
Me/MeO (1g)
Me/F (1h)
98 (2a)
97 (2b)
98 (2c)
99 (2d)
96 (2e)
97 (2f)
90 (2g)
99 (2h)
95 (R)
92 (R)
88 (R)
90 (R)
84 (S)
92 (R)
94 (R)
83 (R)
1
2
3
4
5
6
7
8
9
L1
L2
L1
L2
L1
L1
L1
L2
L1
L2
L1
L1
toluene
toluene
CH2Cl2
CH2Cl2
MeOH
EtOH
Et2O
Et2O
THF
THF
THF
>99
92
79
75
13
89
79
93
91
68
41
94
80
95
81
78
90
11
>99
>99
>99
>99
9
9
10
11[c]
12[d]
98 (2i)
98 (2j)
95 (S)
/H (1i)
THF
74
10
[a]
96 (S)
All reactions were carried out at room temperature using
1 mol % of Ir complex generated in situ from [Ir(COD)Cl]2
and ligand, and I2 (10 mol%) under 700 psi H2 for 20 h.
The conversion was determined by H NMR, and the en-
antioselectivity was determined by HPLC analysis with a
Chiralpak OJ-H column.
/H (1j)
[a]
[b]
1
All reactions were carried out in THF at room tempera-
ture using 1 mol % of Ir complex generated in situ from
[Ir(COD)Cl]2 and L1, and I2 (10 mol %) under 700 psi
H2 for 20 h.
The enantioselectivities of products was determined by
HPLC analysis with Chiralpak OJ-H (2a–e), AS-H (2f
and g), and OD-H(2h–j) columns. The absolute config-
urations were assigned by comparison of the HPLC reten-
tion times with the reported data.
[c]
[d]
[Ir(COD)]BF4 was used as the precursor
[Ir(COD)]PF6 was used as the precursor.
[b]
der the conditions previously optimized by Zhou and
coworkers,[3] using L1 gave promising enantioselectivity
(89%), furnishing the product in more than 99% conver- a marked decrease of yield and enantioselectivity (en-
sion. L2 gave rise to a comparatively lower enantioselec- tries 11 and 12). We also examined a series of additives
tivity (79%) with 92% conversion. Encouraged by these including KI, NaI, BiI3, LiCl, tetrabutylammonium io-
results, we then investigated the effect of solvent on the dide, phthalimide, and I2 was found to be the only effec-
reaction with the objective of achieving an improvement tive additive.
of the enantioselectivity. The results are summarized in
The asymmetric hydrogenation of other 2-substituted
Table 1. It was obvious that the enantioselectivity of the quinoline derivatives using Ir-L1 catalyst was also car-
reaction was sensitive to the solvents used. A higher ee ried out and the results are summarized in Table 2.
value of 2a was achieved in aprotic solvents whereas in Good to excellent enantioselectivities were achieved
an alcohol solvent the enantioselectivity was lower. in the hydrogenation of 2-alkyl-substituted quinolines.
The much lower conversion in alcohol solvent was prob- The length of the alkyl chain did not seem to have very
ably due to decomposition of the Ir catalyst (entries 5 large effect on the ee values (entries 1–4). When the al-
and 6). Ether solvents were more effective than other kyl group at the 2-position was replaced by a phenyl
aprotic solvents (entries 7 and 9 vs. entries 1 and 3), group, a lower enantioselectivity was observed (en-
and the highest enantioselectivity (95%) was obtained try 5). The introduction of electron-donating groups
in THF using L1 ligand (entry 9). It was clearly observed on the 6-position had no clear effect on the ee (entries 6
that Ir-L1 performed better than Ir-L2 in this reaction, and 7). However, a 6-substituted quinoline with an elec-
although Ir-L2 also displayed good catalytic perform- tron-withdrawing groupgave low enantioselectivity
ance. Therefore, we focused on the use of L1 ligand in (entry 8). The asymmetric hydrogenation of quinolines
the subsequent study of this reaction. It should be point- bearing hydroxy groups proceeded smoothly, affording
ed out that in all cases only the tetrahydroquinoline excellent results (entries 9 and 10). It is noted that
product was obtained and the fused aromatic ring re- most of these results are comparable to or better than
mained intact. Furthermore, the change of Ir source to those obtained by using Ir/MeO-BIPHEP[3] or Ir/P-
a cationic [Ir(COD)]BF4 or [Ir(COD)]PF6 form caused Phos.[4]
1756
asc.wiley-vch.de
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2005, 347, 1755 – 1758

Enantioselective Iridium-Catalyzed Hydrogenation of Quinoline Derivatives
COMMUNICATIONS
Table 3. Catalytic asymmetric hydrogenation of quinoline
derivatives in DMPEG-hexane with L1 ligand.[a]
Since the immobilization and recycle of chiral catalyst
is of high interest,[4,7] we have also studied the immobili-
zation of the Ir-L1. Room temperature ionic liquids and
poly(ethylene glycol) (PEG) have recently received
much attention as alternative reaction media.[7,8] We car-
ried out the hydrogenation in these two reaction media,
and found a significant reduction in both conversion and
ee. For example, the reaction in ionic liquid 1-butyl-3-
methylimidazolium tetrafluoroborate gave much low
conversion (<10%) and poor enantioselectivity (40%
ee). The use of PEG (MW¼400) brought about only
70% conversion and a lower ee of 60%. Considering
the fact that this reaction worked better in less polar sol-
vents, it was possible that the decrease in conversion and
enantioselectivity was due to the high polarity of ionic
liquids and PEG. A similar observation has been made
in the Ir-catalyzed asymmetric hydrogenation of un-
functionalized olefins using ionic liquid as solvent.[10]
On the other hand, we have recently demonstrated
that the less polar biphasic system poly(ethylene glycol)
dimethyl ether (DMPEG, MW¼500)/hexane is a good
alternative reaction medium to THF in the Ir-catalyzed
asymmetric hydrogenation of quinolines, and can be
used as a new option for catalyst immobilization.[4] We
thus carried out the Ir-catalyzed hydrogenation in
DMPEG/hexane biphasic system. The preliminary re-
sults are shown in Table 3. To our surprise, a significant
increase of enantioselectivity (upto 11%) was observed
compared with those obtained in THF solvent. For ex-
Entry
R1/R2
Yield [%]
ee [%][b]
1
2
3
4
5
6
7
Me/H (1a)
Et/H (1b)
n-Pr/H (1c)
n-Bu/H (1d)
Ph/H (1e)
Me/Me (1f)
Me/F (1h)
98 (2a)
97 (2b)
99 (2c)
99 (2d)
98 (2e)
98 (2f)
96 (2h)
97 (R)
94 (R)
95 (R)
94 (R)
87 (S)
95 (R)
94 (R)
8
98 (2i)
97 (S)
/H (1i)
[a]
All reactions were carried out in THF at room tempera-
ture using 1 mmol % of Ir complex generated in situ
from [Ir(COD)Cl]2 and L1, and I2 (10 mol %) under
700 psi H2 for 20 h.
The enantioselectivities of products was determined by
HPLC analysis with Chiralpak OJ-H (2a–e), AS-H (2f
and g), and OD-H (2h–j) columns. The absolute config-
urations were assigned by comparison of the HPLC reten-
tion times with the reported data.
[b]
ample, hydrogenation of 1h in THF only led to 83% ee conversion dropped to 42% after two runs. ICP-AES
(Table 2, entry 8). However, when switched to analysis of the hexane layer in each recycle experiment
DMPEG/hexane, the same catalyst afforded the corre- showed a 0.2 ppm loss of iridium (0.21% of the total Ir
sponding products in 94% ee (Table 3, entry 7). It was content), indicating that no appreciable leaching of iridi-
noteworthy that the hydrogenation of both substrates um occurred during the extraction of the products. It is
1a and 1i gave 97% ee, which was the highest value ach- possible that the drop in enantioselectivity and conver-
ieved for this reaction so far (Table 3, entries 1 and 8). sion was due to deactivation of the iridium catalyst. A
After the reaction, the chiral catalyst was totally soluble further study to understand and eventually to resolve
in the DMPEG phase, and the products were easily re- this problem is in progress.
covered in the upper hexane phase. It was evident that
In summary, we have demonstrated that the Ir-H8-BI-
the DMPEG/hexane system had beneficial effects on NAPO catalyst was highly effective in the asymmetric
enantioselectivity. A similar effect was reported by hydrogenation of quinoline derivatives. By using
Bolm and co-workers who found that the addition of DMPEG/hexane as reaction medium, better enantiose-
simple methoxypoly(ethylene glycol)s improved the lectivities were obtained than in THF. The investiga-
asymmetric addition of aryl and alkyl groups to alde- tions on the effective recycling of the catalyst in
hydes.[11]
DMPEG/hexane are still in progress.
The recycle of the catalyst proved to be difficult. We
carried out the recycling study using 1a as a model sub-
strate. At the end ofeach experiment the product was re-
covered via simple decantation of the upper hexane
phase and three additional extractions with degassed
hexane. The DMPEG phase was recharged with 1a, I2
and hexane, and was subjected to the hydrogenation
conditions. Unfortunately, after two runs, the conver-
sion and enantioselectivity were found to decrease to
65% and 72%, respectively. The replenishment of
1 mol % ligand in each run only maintained the high
Experimental Section
Typical Procedure for the Asymmetric Hydrogenation
of Quinolines in THF and Other Solvents
A mixture of [Ir(COD)Cl]2 (1.0 mg, 0.0015 mmol) and the li-
gand (0.003 mmol) in THF (1.0 mL) was stirred at room tem-
perature for 30 minutes in a glovebox, and the mixture was
transferred by a syringe to a stainless steel autoclave, in which
enantioselectivities (over 90% ee) for 3 runs, while the I2 (4 mg, 0.015 mmol) and substrate (0.3 mmol) in 0.5 mLTHF
Adv. Synth. Catal. 2005, 347, 1755 – 1758
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1757

Kim Hung Lam et al.
COMMUNICATIONS
were placed beforehand. The hydrogenation was performed at
room temperature under H2 (700 psi) for 20 h. After carefully
releasing the hydrogen, the reaction mixture was diluted with
dichloromethane (5 mL), saturated sodium carbonate aqueous
solution (2.0 mL) was added and stirred for 15 minutes. The
aqueous layer was extracted with CH2Cl2 (3ꢀ3 mL). The com-
bined organic layers were dried with sodium sulfate and con-
centrated under vacuum to give the crude product. Purification
on a silica gel column gave the pure product. The enantiomeric
excesses were determined by HPLC with chiral columns (OJ-
H, OD-H, or AS-H).
[4] L. Xu, K. H. Lam, J. Ji, J. Wu, Q. Fan, W. Lo, A. S. C.
Chan, Chem. Commun. 2005, 1390.
[5] a) Y. Zhou, W. Tang, W. Wang, W. Li, X. Zhang, J. Am.
Chem. Soc. 2002, 124, 4952; b) T. V. RajanBabu, T. A.
Ayers, A. L. Casalnuovo, J. Am. Chem. Soc. 1996,
#118#116, 4101; c) T. V. RajanBabu, T. A. Ayers, G. A.
Halliday, K. K. You, J. C. Calabrese, J. Org. Chem.
1997, 62, 6012; d) K. Yonehara, T. Hashizume, K. Mori,
K. Ohe, S. Uemura, J. Org. Chem. 1999, 64, 5593.
[6] a) A. S. C. Chan, W. Hu, C. Pai, C. Lau, Y. Jiang, A. Mi,
M. Yan, J. Sun, R. Lou, J. Deng, J. Am. Chem. Soc. 1997,
#119#117, 9570; b) Y. Chen, X. Li, S. Tong, M. Choi,
A. S. C. Chan, Tetrahedron Lett. 1999, 40, 957; c) F.
Zhang, W. Kwok, A. S. C. Chan, Tetrahedron: Asymme-
try 2001, 12, 2337; d) R. Guo, T. T. L. Au-Yeung, J. Wu,
M. C. K. Choi, A. S. C. Chan, Tetrahedron: Asymmetry
2002, 13, 2519; e) T. T. L. Au-Yeung, S. Chan, A. S. C.
Chan, Adv. Synth. Catal. 2003, 345, 537.
[7] a) Q. Fan, Y. Li, A. S. C. Chan, Chem. Rev. 2002, 102,
3667; b) G. Deng, Q. Fan, X. Chen, D. Liu, A. S. C.
Chan, Chem. Commun. 2002, 1570; c) Q. Fan, Y. Chen,
X. Chen, D. Zhang, F. Xi, A. S. C. Chan, Chem. Com-
mun. 2000, 789; d) Q. Fan, C. Ren, C. Yeung, W. Hu,
A. S. C. Chan, J. Am. Chem. Soc. 1999, 121, 7407; e) B.
Yi, Q. Fan, G. Deng, Y. Li, A. S. C. Chan, Org. Lett.
2004, 6, 1361.
[8] For some recent reviews, see: a) C. E. Song, Chem. Com-
mun. 2004, 1033; b) C. Baudequin, J. Baudoux, J. Levil-
lain, D. Cahard, A. Gaumon, J.-C. Plaquevent, Tetrahe-
dron: Asymmetry 2003, 14, 3081; for recent examples,
see c) A. Hu, H. L. Ngo, W. Lin, Angew. Chem. Int.
Ed. 2004, 43, 2501; d) B. Pugin, M. Studer, E. Kuesters,
G. Sedelmeier, X. Feng, Adv. Synth. Catal. 2004, 346,
1481; e) M. Berthod, J.-M. Joerger, G. Mignani, M.
Vaultier, M. Lemaire, Tetrahedron: Asymmetry 2004,
15, 2219; f) M. Solinas, A. Pfaltz, P. Giorgio, W. Leitner,
J. Am. Chem. Soc. 2004, 126, 16142.
[9] For some recent publications, see a) R. G. da Rosa, L.
Martinelli, L. H. M. da Silva, W. Loh, Chem. Commun.
2000, 33; b) D. J. Heldebrant, P. G. Jessop, J. Am.
Chem. Soc. 2003, 125, 5600; c) W. Leitner, Nature,
2003, 423, 930; d) A. Haimov, R. Neumann, Chem. Com-
mun. 2002, 876; e) S. Chandrasekhar, C. Narsihmulu, S. S.
Sultana, N. R. Reddy, Org. Lett. 2002, 4, 4399; f) S. Chan-
drasekhar, C. Narsihmulu, S. S. Sultana, N. R. Reddy,
Chem. Commun. 2003, 1716; g) S. Chandrasekhar, C.
Narsihmulu, G. Chandrasekhar, T. Shyamsunder, Tetra-
hedron Lett. 2004, 45, 2421; h) P. C. Andrew, A. C. Peatt,
C. L. Raston, Green Chem. 2004, 6, 119; i) R. Jiang, Y.
Kuang, X. Sun, S. Zhang, Tetrahedron: Asymmetry
2004, 15, 743; j) S. Chandrasekhar, C. Narsihmulu, B. Sar-
itha, S. S. Sultana, Tetrahedron Lett. 2004, 45, 5865.
[10] D. Hou, J. Reibenspies, T. J. Colacot, K. Burgess, Chem.
Eur. J. 2001, 7, 5391.
Typical Procedure for the Asymmetric Hydrogenation
of Quinoline in MPEG/Hexane
A mixture of [Ir(COD)Cl]2 (1.7 mg, 0.003 mmol) and (S)-H8-
BINAPO (4.0 mg, 0.006 mmol) in DMPEG (2.0 mL) was stir-
red at room temperature for 30 minutes in a stainless steel au-
toclave inside a glovebox, then I2 (7 mg, 0.03 mmol) and sub-
strate (0.6 mmol) together with 2 mL hexane were added and
stirred for another 5 minutes. The hydrogenation was then per-
formed at room temperature under H2 (700 psi) for 20 h. After
carefully releasing the hydrogen, the hexane layer was de-
canted and the product in the DMPEG phase was then further
extracted with hexane (3ꢀ2 mL). The combined hexane solu-
tion was then washed with saturated sodium carbonate aque-
ous solution (2.0 mL) and concentrated under vacuum to
give the crude product. Purification on a silica gel column led
to pure product. The enantiomeric excesses were determined
on an HPLC equipped with chiral columns.
Acknowledgements
We thank the University Grants Committee Area of Excellence
Scheme in Hong Kong (Project No. AoE/P-10/01), the Hong
Kong Polytechnic University Area of Strategic Development
Fund for financial support and National Natural Science Foun-
dation of China for financial support.
References and Notes
[1] a) H.-U. Blaser, C. Malan, B. Pugin, F. Splindler, H.
Steiner, M. Studer, Adv. Synth. Catal. 2003, 345, 103;
b) W. Tang, X. Zhang, Chem. Rev. 2003, 103, 3029;
c) G. Lin, Y. Li, A. S. C. Chan, Principles and Applica-
tions of AsymmetricSynthesis , Wiley-Interscience, New
York, 2001.
[2] For some recent publications, see: a) R. Kuwano, K. Ka-
neda, T. Ito, K. Sato, T. Kurokawa, D. Karube, Y. Ito,
Org. Lett. 2004, 6, 2213; b) J. P. Henschke, M. J. Burk,
C. G. Malan, D. Herzberg, J. A. Peterson, A. J. Wild-
smith, C. J. Cobley, G. Casy, Adv. Synth. Catal. 2003,
345, 300.
[11] J. Rudolph, N. Hermanns, C. Bolm, J. Org. Chem. 2004,
69, 3997.
[3] a) W. Wang, S. Lu, P. Yang, X. Han, Y. Zhou, J. Am.
Chem. Soc. 2003, 125, 10536; b) P. Yang, Y. Zhou, Tetra-
hedron: Asymmetry 2004, 15, 1145; c) S. Lu, X. Han, Y.
Zhou, Adv. Synth. Catal. 2004, 346, 909.
1758
asc.wiley-vch.de
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2005, 347, 1755 – 1758