Air-stable and phosphine-free iridium catalysts for highly enantioselective hydrogenation of quinoline derivatives

Article abstract of DOI:10.1021/ol802016w

(Chemical Equation Presented) Enantioselective hydrogenation of quinoline derivatives catalyzed by phosphine-free chiral cationic Cp*Ir(OTf)(CF ₃T₈DPEN) complex (CF₃TsDPEN = N-(p-trifluoromethylbenzenesulfonyl)-1,2-diphenylethylene-diamine) afforded the 1,2,3,4-tetrahydroquinoline derivatives in up to 99% ee. The reaction could be carried out with a substrate-to-catalyst molar ratio as high as 1000 in undegassed methanol and with no need for inert gas protection.

Full text of DOI:10.1021/ol802016w

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5265-5268
Air-Stable and Phosphine-Free Iridium
Catalysts for Highly Enantioselective
Hydrogenation of Quinoline Derivatives†
Zhi-Wei Li,‡ Tian-Li Wang,‡ Yan-Mei He,‡ Zhi-Jian Wang,‡ Qing-Hua Fan,*,‡
Jie Pan,‡ and Li-Jin Xu*,§
Beijing National Laboratory for Molecular Sciences, Center for Chemical Biology,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China, and
Department of Chemistry, Renmin UniVersity of China, Beijing 100972, China
fanqh@iccas.ac.cn; xuchem@126.com
Received August 28, 2008
ABSTRACT
Enantioselective hydrogenation of quinoline derivatives catalyzed by phosphine-free chiral cationic Cp*Ir(OTf)(CF3TsDPEN) complex (CF3TsDPEN
) N-(p-trifluoromethylbenzenesulfonyl)-1,2-diphenylethylene-diamine) afforded the 1,2,3,4-tetrahydroquinoline derivatives in up to 99% ee. The
reaction could be carried out with a substrate-to-catalyst molar ratio as high as 1000 in undegassed methanol and with no need for inert gas
protection.
Homogeneous asymmetric hydrogenation has been estab-
lished as one of the most versatile and powerful tools for
the preparation of a wide range of enantiomerically pure
compounds in organic synthesis.1 Transition metal complexes
with chiral phosphorus ligands are the dominant choice of
catalysts for asymmetric hydrogenation. To date, a number
of efficient chiral phosphorus ligands with diverse structures
have been developed, and their applications in asymmetric
hydrogenation of prochiral olefins, ketones, and imines have
been extensively utilized in both academic research and
industry.2 In contrast, transition-metal-catalyzed asymmetric
hydrogenation of heteroaromatic compounds has achieved
few successes,3,4 probably due to the high resonance stability
of these substrates and/or the potential poisoning of the
catalysts by these heteroaromatic compounds. Recently, a
number of iridium complexes that are effective in the
asymmetric hydrogenation of quinolines have been reported
since the first example reported by Zhou and co-workers.4a
Although significant progress has been achieved in the area
of asymmetric hydrogenation of 2-substituted quinolines,4
several challenges still remain. For example, most of these
reported catalytic systems suffered from low catalyst ef-
(2) (a) Tang, W. J.; Zhang, X. M. Chem. ReV. 2003, 103, 3029. (b)
Blaser, H. U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer, M.
AdV. Synth. Catal. 2003, 345, 103.
† Dedicated to Professor Xi-Yan Lu in the occasion of his 80th birthday.
‡ Chinese Academy of Sciences.
(3) For recent reviews, see: (a) Glorius, F. Org. Biomol. Chem. 2005,
3, 4171. (b) Zhou, Y. G. Acc. Chem. Res. 2007, 40, 1357. For selected
examples, see: (c) Legault, C.; Charette, A. J. Am. Chem. Soc. 2005, 127,
8966. (d) Kuwano, R.; Kashiwabara, M. Org. Lett. 2006, 8, 2653. (e) Lu,
S. M.; Wan, Y. Q.; Han, X. W.; Zhou, Y. G. Angew. Chem., Int. Ed. 2006,
45, 2260. (f) Kaiser, S.; Smidt, S. P.; Pfaltz, A. Angew. Chem., Int. Ed.
2006, 45, 5194. (g) Kuwano, R.; Kashiwabara, M.; Ohsumi, M.; Kusano,
§ Renmin University of China.
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994. (b) Lin, G. Q.; Li, Y. M.; Chan, A. S. C. Principles and
Applications of Asymmetric Synthesis; Wiley-Interscience: New York, 2001.
(c) Zhang, W.; Chi, Y.; Zhang, X. Acc. Chem. Res. 2007, 40, 1278. (d)
Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res. 2007, 40, 1402. (e) Ikariya,
T.; Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300.
H. J. Am. Chem. Soc. 2008, 130, 808
.
10.1021/ol802016w CCC: $40.75
Published on Web 10/28/2008
2008 American Chemical Society

ficiency, as evidenced by the fact that good results could
only be obtained at a low substrate/catalyst ratio of 100.4d,e
Furthermore, all reported catalysts for such reactions have
at least one phosphine ligand around the iridium center and
are often air-sensitive.5 From the viewpoints of both scientific
interest and practical applications, it is highly desirable to
develop easily available and air-stable chiral catalysts for
the asymmetric hydrogenation of quinolines.
Scheme 1. Asymmetric Hydrogenation of 2-Methylquinoline
In comparison with the chiral phosphorus ligand-contain-
ing catalysts, the chiral diamine-based catalysts are more
easily available and are expected to be more air-stable.6
However, only a few of them were found to be capable of
activating molecular hydrogen.7,8 Recently, Noyori and
Ohkuma reported that the chiral cationic phosphine-free
Ru(OTf)(cymene)(TsDPEN) and Cp*Ir(OTf)(MsDPEN) com-
plexes,9 known as excellent catalysts for asymmetric transfer
hydrogenation, could be used for the asymmetric hydrogena-
tion of prochiral ketones in methanol.8 A neutral to slightly
acidic reaction condition fits the requirement of such reac-
tions. In our recent study, we extended the application of
this cationic Ru-catalyst to the enantioselective hydrogenation
of quinolines at a substrate/catalyst molar ratio of 100 in
neat ionic liquid, affording 1,2,3,4-tetrahydroquinolines with
excellent enantioselectivity.10 It was believed that the
hydrogenation of quinoline occurred through a stepwise H+/
H- transfer process, which was different from the concerted
mechanism proposed for the reduction of ketone.8b
known to be rapidly and irreversibly oxidized upon treatment
with oxygen.11 Therefore, asymmetric hydrogenation cata-
lyzed by such complexes must be performed under extremely
oxygen-free conditions. In contrast, Rauchfuss and co-
workers recently reported that the iridium hydride complex,
Cp*IrH(TsDPEN), could efficiently catalyze the hydrogena-
tion of oxygen in the presence of Brønsted acid.12 Similar
observation was independently made by Ikariya at almost
the same time.13 Based on this finding, they developed an
efficient protocol for the aerobic oxidative kinetic resolution
of racemic secondary alcohols by using oxygen as a hydrogen
acceptor.
Given the fact that the iridium hydride complexes could
not be deactivated by oxygen, we wish to report here our
continuing efforts on the investigation whether the chiral
diamine-containing Ir complexes could be used as efficient
and air-stable catalysts for the hydrogenation of quinolines
(Scheme 1). It was found that the hydrogenation proceeded
smoothly with a substrate-to-catalyst molar ratio as high as
1000 in undegassed methanol with no need for inert gas
protection throughout the entire operation, affording a series
of 2-substituted tetrahydroquinoline derivatives in up to 99%
ee.
We started with the hydrogenation of 2-methylquinoline
(2a) using Cp*Ir(OTf)(MsDPEN) (1a) as catalyst in unde-
gassed methanol. The precatalyst was prepared from com-
mercially available [Cp*IrCl2]2 and (S,S)-MsDPEN ligand
in two steps according to the published method with some
modifications.8d,14 With 1.0 mol % of 1a, the reaction was
carried out under 50 atm of hydrogen in undegassed methanol
without using a glovebox (Table 1). To our delight, 69%
conversion and 94% ee were obtained in 2 h (entry 1), which
are comparable to those obtained under anaerobic conditions
(with the use of degassed methanol and glovebox). Notably,
the reaction rate increased significantly upon the addition of
10 mol % CF3COOH as an additive (entry 2 vs entry 1).
To further test the stability of the catalyst to oxygen, the
catalyst solution was stirred under oxygen atmosphere for
1 h prior to the introduction of hydrogen. Almost identical
Many metal complexes that are reactive toward hydrogen,
for example, the chiral diphosphine-containing catalysts, are
(4) For selected recent examples, see: (a) Wang, W. B.; Lu, S. M.; Yang,
P. Y.; Han, X. W.; Zhou, Y. G. J. Am. Chem. Soc. 2003, 125, 10536. (b)
Xu, L. J.; Lam, K. H.; Ji, J.; Wu, J.; Fan, Q. H.; Lo, W. H.; Chan, A. S. C.
Chem. Commun. 2005, 1390. (c) Reetz, M. T.; Li, X. G. Chem.Commun.
2006, 2159. (d) Tang, W. J.; Zhu, S. F.; Xu, L. J.; Zhou, Q. L.; Fan, Q. H.;
Zhou, H. F.; Lam, K.; Chan, A. S. C. Chem. Commun. 2007, 613. (e) Wang,
Z. J.; Deng, G. J.; Li, Y.; He, Y. M.; Tang, W. J.; Fan, Q. H. Org. Lett.
2007, 9, 1243. (f) Chan, S. H.; Lam, K. H.; Li, Y. M.; Xu, L.; Tang, W.;
Lam, F. L.; Lo, W. H.; Yu, W. Y.; Fan, Q.; Chan, A. S. C. Tetrahedron:
Asymmetry 2007, 18, 2625. (g) Mrsˇic´, N.; Lefort, L.; Boogers, J. A. F.;
Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. AdV. Synth. Catal. 2008,
350, 1081. (h) Lu, S.-M.; Bolm, C. AdV. Synth. Catal. 2008, 350, 1101. (i)
Wang, X.-B.; Zhou, Y.-G. J. Org. Chem. 2008, 73, 5640.
(5) For asymmetric transfer hydrogenation of quinolines with organo-
catalysts, see: (a) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew.
Chem., Int. Ed. 2006, 45, 3683. (b) Guo, Q. S.; Du, D. M.; Xu, J. X. Angew.
Chem., Int. Ed. 2008, 47, 759. (c) Rueping, M.; Theissmann, T.; Raja, S.;
Bats, J. W. AdV. Synth. Catal. 2008, 350, 1001. For Ir-catalyzed asymmetric
transfer hydrogenation, see: (d) Wang, D.-W.; Zeng, W.; Zhou, Y.-G.
Tetrahedron: Asymmetry. 2007, 18, 1103.
(6) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. ReV.
2000, 100, 2159.
(7) (a) Ito, M.; Hirakawa, M.; Murata, K.; Ikariya, T. Organometallics
2001, 20, 379. (b) Guan, H.; Iimura, M.; Magee, M. P.; Norton, J. R.; Zhu,
G. J. Am. Chem. Soc. 2005, 127, 7805. (c) Hedberg, C.; Ka¨llstro¨m, K.;
Arvidsson, P. I.; Brandt, P.; Andersson, P. G. J. Am. Chem. Soc. 2005,
127, 15083. (d) Huang, H.; Okuno, T.; Tsuda, K.; Yoshimura, M.; Kitamura,
M. J. Am. Chem. Soc. 2006, 128, 8716
.
(8) (a) Ohkuma, T.; Utsumi, N.; Tsutsumi, K.; Murata, K.; Sandoval,
C.; Noyori, R. J. Am. Chem. Soc. 2006, 128, 8724. (b) Sandoval, C. A.;
Ohkuma, T.; Utsumi, N.; Tsutsumi, K.; Murata, K.; Noyori, R. Chem. Asian.
J. 2006, 1, 102. (c) Ohkuma, T.; Tsutsumi, K.; Utsumi, N.; Arai, N.; Noyori,
R.; Murata, K. Org. Lett. 2007, 9, 255. (d) Ohkuma, T.; Utsumi, N.;
Watanabe, M.; Tsutsumi, K.; Arai, N.; Murata, K. Org. Lett. 2007, 9, 2565
.
(11) Kubas, G. Metal Dihydrogen and s-Bond Complexes; Kluwer
Academic/Plenum Publishers: New York, 2001.
(12) Heiden, Z. M.; Rauchfuss, T. B. J. Am. Chem. Soc. 2007, 129,
14303.
(9) TsDPEN
) N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine;
TfO- ) trifluoromethanesulfonate; Cp* ) pentamethylcyclopentadienyl;
MsDPEN ) N-(methanesulfonyl)-1,2-diphenylethylenediamine.
(10) Zhou, H. F.; Li, Z. W.; Wang, Z. J.; Wang, T. L.; Xu, L. J.; He,
Y. M.; Fan, Q. H.; Pan, J.; Gu, L. Q.; Chan, A. S. Angew. Chem., Int. Ed.
2008, 47, 8464–8467.
(13) Arita, S.; Koike, T.; Kayaki, Y.; Ikariya, T. Angew. Chem., Int.
Ed. 2008, 47, 2447.
(14) For details, see Supporting Information.
5266
Org. Lett., Vol. 10, No. 22, 2008

Table 1. Asymmetric Hydrogenation of 2-Methylquinoline (2a)
Catalyzed by (S,S)-1a: Effects of the Oxygen and Acida
Table 3. Asymmetric Hydrogenation of 2-Substituted Quinoline
Derivatives Catalyzed by (S,S)-1ca
entry
time (h)
TFA (mol %)
conv (%)b
ee (%)c
1
2
2
1
1
1
24
1
69 (71)d
95
94 (94)d
96
10
10
10
10
2
3e
4f
5f,g
6
71
58
10
42
95
94
93
95
7
1
5
63
95
8
1
25
>95
94
a Reaction conditions: 28.6 mg of substrate 2a in 1 mL of undegassed
MeOH, 1.0 mol % catalyst (S,S)-1a, 50 atm H2, 25 °C. All manipulations
were conducted in air, and the autoclave was purged with H2 three times
before reaction. b Determined by 1H NMR analysis. c Determined by chiral
HPLC analysis. d Data in parentheses were obtained under nitrogen
atmosphere. e The catalyst solution was stirred under oxygen atmosphere
before hydrogenation. f Without purging the autoclave with H2 before
reaction. g Catalyst Ru(OTf)(cymene)(TsDPEN) was used.
enantioselectivity was observed, although the conversion
decreased slightly (entry 3). EVen when the hydrogenation
was carried out in undegassed solVent and in the presence
of air, similar enantioselectiVity was obserVed (entry 4).
These results indicated that both the Ir precatalyst and the
catalytically active species were air-stable. In contrast, the
reaction was found to be sluggish when Ru(OTf)(cymene)(Ts-
DPEN) was used as catalyst under otherwise identical
conditions, indicative of the decomposition and/or deactiva-
tion of the Ru-catalyst in the presence of air during the
hydrogenation (entry 5).
a Reaction conditions: 0.75 mmol substrate in 1 mL of undegassed
MeOH, 0.2 mol % (S,S)-1c, 10 mol % TFA, 50 atm H2, 15 °C, 24-48 h.
All manipulations were conducted in air, and the autoclave was purged
with H2 three times before reaction. b Isolated yield. c Determined by chiral
HPLC analysis.
Considering the important impact of acid additive on
reactivity, we then evaluated a number of organic and
inorganic acids, such as CF3SO3H, CF3COOH, CH3COOH,
p-toluenesulfonic acid, H2SO4, H3PO4, etc.15 CF3COOH
(TFA) was found to be the best choice. Low conversions
were observed by decreasing the amount of TFA (entries 6
and 7). In terms of both conversion and enantioselectivity,
10 mol % TFA was chosen for all following catalytic
reactions.
Next, the effects of chiral ligands, solvents, H2 pressure,
and reaction temperature on catalytic activity and enanti-
oselectivity were examined by using 2a as a standard
substrate. The results, in Table 2, showed the influence of
the sulfonyl group on the performance of catalysts (entries
1-3). Catalyst 1c, which gave the highest enantioselectivity
(97% ee, entry 3), was thus selected as the catalyst for the
optimization of other factors.
As shown in Table 2, a strong solvent-dependent effect
was observed (entries 3-10). The hydrogenation in alcoholic
solvent, such as methanol, ethanol, and isopropanol, pro-
ceeded well to give 2-methyl-1,2,3,4-tetrahydroquinoline (3a)
in good conversion and good to excellent enantioselectivity
(entries 3-5). Notably, the reaction could be carried out in
H2O and CH3CN, affording 3a with very good enantiose-
lectivity but low conversion (entries 6 and 7). In contrast,
aprotic solvents, such as CH2Cl2, toluene and THF gave
much lower conversions and enantioselectivities (entries
8-10). It was noted that the enantioselectivity is insensitive
Table 2. Optimization of Reaction Conditionsa
entry catalyst solvent H2 (atm); temp (°C) conv (%)b ee (%)c
1
2
3
4
5
6
7
8
(S,S)-1a MeOH
(S,S)-1b MeOH
(S,S)-1c MeOH
(S,S)-1c EtOH
(S,S)-1c IPA
50; 25
50; 25
50; 25
50; 25
50; 25
50; 25
50; 25
50; 25
50; 25
50; 25
80; 25
20; 25
1; 25
95
66
62
77
74
29
23
27
62
18
70
50
25
80
32
99
90
95
91
97
95
75
96
92
85
46
16
97
97
94
95
98
98
98
(S,S)-1c H2O
(S,S)-1c CH3CN
(S,S)-1c CH2Cl2
(S,S)-1c toluene
(S,S)-1c THF
(S,S)-1c MeOH
(S,S)-1c MeOH
(S,S)-1c MeOH
(S,S)-1c MeOH
(S,S)-1c MeOH
9
10
11
12
13
14
15
50; 50
50; 0
50; 15
50; 15
16d (S,S)-1c MeOH
17e (S,S)-1c MeOH
a Reaction conditions: 28.6 mg of substrate 2a in 1 mL of undegassed
solvent, 1.0 mol % Ir-catalyst, 10 mol % TFA, 1 h. All manipulations were
conducted in air, and the autoclave was purged with H2 three times before
reaction. b Determined by 1H NMR analysis. c Determined by chiral HPLC
analysis. d Substrate/catalyst ) 500 (143 mg substrate in 1 mL MeOH),
24 h. e Substrate/catalyst ) 1000 (286 mg substrate in 1 mL MeOH), 24 h.
Org. Lett., Vol. 10, No. 22, 2008
5267

to the hydrogen pressure in the range of 20-80 atm, while
much lower conversion and slightly low enantioselectivity
were observed under atmosphere hydrogenation pressure
(entries 11-13). Increasing reaction temperature led to higher
conversion but at a cost of slightly low enantioselectivity
(entries 14 and 15). Most importantly, the reaction proceeded
smoothly at low catalyst loading (0.1 mol %) in high
conVersion with excellent enantioselectiVity upon prolonged
reaction time (entries 16 and 17).
Under the optimized reaction conditions, a series of
2-substituted and 2,6-disubstituted quinoline derivatives were
then hydrogenated with catalyst 1c in undegassed methanol.16
The results are listed in Table 3. In general, all 2-alkyl-
substituted quinolines were hydrogenated with good reactiv-
ity and excellent enantioselectivity (96-98% ee). The
reaction was relatively insensitive to the length of the side
chain of 2-alkylated quinolines (entries 1-5). Excellent
results were also achieved with 2-phenethyl quinolines
(entries 6-8). Notably, the quinolines with a hydroxyl group
at the side chain provided the highest enantioselectivity of
99% ee (entries 9 and 10). The presence of a substituted
group on the 6-position had no obvious effect on either yield
or enantioselectivity (entries 11-13). The hydrogenation of
2-phenyl-substituted quinoline also proceeded smoothly but
gave a lower enantioselectivity than those of 2-alkylated
quinolines (entry 14).
In summary, we have developed a new kind of highly
effective phosphine-free Ir-catalysts for the asymmetric
hydrogenation of quinolines with up to 99% ee. The reaction
proceeded smoothly in undegassed solvent with no need for
inert gas protection throughout the entire operation. Thus,
this method provides an efficient and practical tool for the
synthesis of a variety of optically active 1,2,3,4-tetrahydro-
quinoline derivatives.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20532010 and
20772128) and Chinese Academy of Sciences is greatly
appreciated.
Supporting Information Available: Experimental pro-
cedures and characterization data for the Ir catalysts and the
reduced products. This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) For details, see Supporting Information.
(16) 3-Methylquinoline could also be completely hydrogenated with
catalyst 1c, but racemic product was obtained.
OL802016W
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Org. Lett., Vol. 10, No. 22, 2008