Highly enantioselective hydrogenation of quinolines using phosphine-free chiral cationic Ruthenium catalysts: Scope, mechanism, and origin of enantioselectivity

Article abstract of DOI:10.1021/ja2023042

Asymmetric hydrogenation of quinolines catalyzed by chiral cationic η⁶-arene-N-tosylethylenediamine-Ru(II) complexes have been investigated. A wide range of quinoline derivatives, including 2-alkylquinolines, 2-arylquinolines, and 2-functionalized and 2,3-disubstituted quinoline derivatives, were efficiently hydrogenated to give 1,2,3,4-tetrahydroquinolines with up to >99% ee and full conversions. This catalytic protocol is applicable to the gram-scale synthesis of some biologically active tetrahydroquinolines, such as (-)-angustureine, and 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline, a key intermediate for the preparation of the antibacterial agent (S)-flumequine. The catalytic pathway of this reaction has been investigated in detail using a combination of stoichiometric reaction, intermediate characterization, and isotope labeling patterns. The evidence obtained from these experiments revealed that quinoline is reduced via an ionic and cascade reaction pathway, including 1,4-hydride addition, isomerization, and 1,2-hydride addition, and hydrogen addition undergoes a stepwise H⁺/H^- transfer process outside the coordination sphere rather than a concerted mechanism. In addition, DFT calculations indicate that the enantioselectivity originates from the CH/π attraction between the η⁶-arene ligand in the Ru-complex and the fused phenyl ring of dihydroquinoline via a 10-membered ring transition state with the participation of TfO^- anion.

Full text of DOI:10.1021/ja2023042

ARTICLE
pubs.acs.org/JACS
Highly Enantioselective Hydrogenation of Quinolines Using
Phosphine-Free Chiral Cationic Ruthenium Catalysts: Scope,
Mechanism, and Origin of Enantioselectivity
Tianli Wang,† Lian-Gang Zhuo,‡ Zhiwei Li,† Fei Chen,† Ziyuan Ding,† Yanmei He,† Qing-Hua Fan,*,†
Junfeng Xiang,† Zhi-Xiang Yu,*,‡ and Albert S. C. Chan#
†Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry and Graduate School, Chinese Academy of Sciences (CAS), Beijing 100190, P. R. China
‡Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education, College of Chemistry,
Peking University, Beijing 100871, P. R. China
#Institute of Creativity, Hong Kong Baptist University, Hong Kong, China
S Supporting Information
b
ABSTRACT: Asymmetric hydrogenation of quinolines cata-
lyzed by chiral cationic η6-areneꢀN-tosylethylenediamineꢀ
Ru(II) complexes have been investigated. A wide range of
quinoline derivatives, including 2-alkylquinolines, 2-arylquino-
lines, and 2-functionalized and 2,3-disubstituted quinoline
derivatives, were efficiently hydrogenated to give 1,2,3,4-tetra-
hydroquinolines with up to >99% ee and full conversions. This
catalytic protocol is applicable to the gram-scale synthesis of some biologically active tetrahydroquinolines, such as (ꢀ)-
angustureine, and 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline, a key intermediate for the preparation of the antibacterial agent
(S)-flumequine. The catalytic pathway of this reaction has been investigated in detail using a combination of stoichiometric reaction,
intermediate characterization, and isotope labeling patterns. The evidence obtained from these experiments revealed that quinoline
is reduced via an ionic and cascade reaction pathway, including 1,4-hydride addition, isomerization, and 1,2-hydride addition, and
hydrogen addition undergoes a stepwise Hþ/Hꢀ transfer process outside the coordination sphere rather than a concerted
mechanism. In addition, DFT calculations indicate that the enantioselectivity originates from the CH/π attraction between the η6-
arene ligand in the Ru-complex and the fused phenyl ring of dihydroquinoline via a 10-membered ring transition state with the
participation of TfOꢀ anion.
’ INTRODUCTION
1,2,3,4-tetrahydroquinoline derivatives.7ꢀ12 However, most of
the reported chiral Rh, Ru, and Ir complexes, which have been
demonstrated to be highly efficient and enantioselective in the
hydrogenation of prochiral olefins, ketones, and imines,13 failed
to give satisfactory results in the asymmetric hydrogenation of
heteroaromatic compounds.14 In 2003, Zhou and co-workers
first reported the Ir-catalyzed highly effective asymmetric hydro-
genation of 2,6-substituted quinolines with (R)-MeO-BIPHEP
as the ligand in the presence of iodide to produce chiral
tetrahydroquinolines with up to 96% ee.8a Following this sig-
nificant lead, a variety of iridium complexes of chiral phosphorus
ligands, including diphosphines, diphosphites, monodentate
phosphorus ligands, and P,N-ligands, have been developed to
catalyze the enantioselective hydrogenation of a wide range of
2-alkyl-substituted quinoline derivatives, and good to excellent
enantioselectivities have been observed.8ꢀ10 Recently, we
have demonstrated that comparable or better results could
be achieved when employing recyclable iridium complexes of
Optically active tetrahydroquinoline derivatives are an impor-
tant class of building blocks for asymmetric synthesis in pharma-
ceutical and agrochemical industries and for the total synthesis
of natural products.1,2 For example (Figure 1), the (S)-enantio-
mer of flumequine3 is an antibacterial agent of the quinolone
family. Several tetrahydroquinoline derivatives, such as torcetrapib2d,4
and compound A,2g,5 have attracted much attention as potent
inhibitors of the cholesterol ester transfer protein, a target for
the treatment of low high-density lipoprotein cholesterol and
atherosclerosis. The chirality of these compounds was found to
play a pivotal role in their relevant bioactivities. In addition, many
naturally occurring alkaloids contain the tetrahydroquinoline
unit,6 including angustureine,6a galipinine,6b,c and cuspareine.6c
Therefore, it is highly desirable to develop efficient methods for
the preparation of optically pure tetrahydroquinoline derivatives
in both academia and industry.
The transition metal-catalyzed asymmetric hydrogenation of
quinoline derivatives, which are easily prepared from readily
available starting materials, represents one of the most atom-
economic and efficient methods for the synthesis of chiral
Received: March 14, 2011
Published: May 16, 2011
r
2011 American Chemical Society
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Figure 1. Selected bioactive compounds derived from chiral 1,2,3,4-tetrahydroquinoline derivatives.
P-Phos9a and dendrimeric BINAP9e in the asymmetric hydro-
Scheme 1
genation of 2,6-substituted quinolines. Despite this significant
progress, the catalytic efficiency was still far from being prac-
tical, as evidenced by the fact that good results could only be
obtained at a low substrate/catalyst (S/C) ratio of 100 in most
cases.8f,9dꢀ9g All these iridium catalysts had at least one phos-
phine ligand around the metal center and were often air sensitive.
Furthermore, most of these catalysts were highly enantioselective
only in the hydrogenation of 2-alkyl-substituted quinolines.8e,10f
From the viewpoints of both scientific interest and practical
applications, more efficient and stable catalyst systems for the
asymmetric hydrogenation of quinolines are desirable.
In comparison with chiral phosphorus ligands, chiral diamine
ligands are more readily available, easily tunable, and air-stable.15
Their Ru, Rh, and Ir complexes have been extensively studied in
the asymmetric transfer hydrogenation of aromatic ketones and
imines,16 although they were long neglected in the hydrogena-
tion of unsaturated compounds.17 Very recently, Noyori and
co-workers reported that chiral η6-areneꢀTsDpenꢀRu(II) com-
plex could be used for the asymmetric hydrogenation of ketones
under slightly acidic conditions.18a Later, we found that this Ru-
catalyst could catalyze the asymmetric hydrogenation of quino-
lines in ionic liquid or under solvent-free conditions with unpre-
cedented reactivity and enantioselectivity.19 Our preliminary result
alsosuggested that the hydrogenationof quinolines occurred by an
ionic catalytic pathway,20 which was different from the mechanism
of the asymmetric hydrogenation of ketones.21 At the same time,
Xiao et al. demonstrated that a cationic Cp*Rh(III)ꢀTsDpen
complex was an efficient catalyst for the asymmetric hydrogena-
tion of cyclic imines in the presence of AgSbF6.22a They further
found that a combination of the Irꢀdiamine complex together
with a chiral phosphate anion efficiently hydrogenate a variety of
acyclic N-aryl imines with excellent enantioselectivities.22b,c Ikariya
and Fan also reported that Ir- and Ru-complexes of N-sulfonylated
diamine efficiently catalyzed the asymmetric hydrogenation of
acyclic ketimines, respectively.22d,e These promising results de-
monstrated that Ru-, Rh-, and Ir-complexes of N-sulfonylated
diamines were excellent catalysts for the asymmetric hydrogena-
tion not only of ketones but also of quinolines and imines. Despite
this significant progress, the mechanism of imine reduction with
this type of catalyst remained to be elucidated,23 in contrast to the
better known asymmetric reduction of ketones.21 To extend the
scope of our practical hydrogenation of quinolines and to better
understand the reaction mechanism, in this article, we report a
systematic study on the asymmetric hydrogenation of a broad
range of quinoline derivatives using Ruꢀdiamine catalysts to-
gether with a detailed mechanistic study through experiments and
DFT calculations. It was found that various quinoline derivatives
including 2-alkyl- and 2-aryl-substituted quinolines, 2-functiona-
lized quinolines, and 2,3-disubstituted quinolines were successfully
hydrogenated with unprecedented enantioselectivities (up to
>99% ee) and high turnover numbers (TON up to 5000). To
the best of our knowledge, the levels of enantioselectivity and
substrate generality are the highest among all known systems.8ꢀ10
Moreover, mechanistic studies revealed that quinoline was re-
duced through a cascade reaction pathway, involving a 1,4-hydride
addition, isomerization, and 1,2-hydride addition. The hydrogen
addition underwent a stepwise Hþ/Hꢀ transfer process outside
the coordination sphere, supporting an ionic rather than a
concerted mechanism. This versatile catalytic protocol thus
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Journal of the American Chemical Society
ARTICLE
Table 1. Optimizing Conditions for Asymmetric
Hydrogenation of 2-Methylquinolinea
giving the corresponding cationic catalysts in quantitative yields
(Scheme 1),18a,21a which were used directly without further
purification.
Hydrogenation of 2-Alkyl-Substituted Quinolines. The
hydrogenation of 2-methylquinoline (2a) was chosen as the
standard reaction for the optimization of reaction conditions
and the screening of catalysts. We first examined the catalytic
activity of the RuCl complex (R,R)-1a at a substrate to
catalyst mole ratio (S/C) of 100 in methanol under 20 atm
of H2 for 6 h. Unlike the hydrogenation of ketones reported
by Noyori et al.,18a no conversion was observed at room
temperature, and only 21% conversion with moderate enan-
tioselectivity was obtained at elevated temperature (Table 1,
entry 1). The lack of reactivity was probably caused by the strong
coordination of the chloride anion to the cationic ruthenium
center.24 In sharp contrast to the RuꢀCl catalyst, the cationic
RuꢀOTf complex (R,R)-1b exhibited unprecedented reactivity
and enantioselectivity in a variety of solvents including water
(Table 1, entries 2ꢀ11).
temp H2 time conv
ee
(%)c
entry catalyst
solvent
MeOH
(°C) (atm) (h)
(%)b
1
2
3
4
5
6
7
8
9
(R,R)-1a
(R,R)-1b
(R,R)-1b
(R,R)-1b
(R,R)-1b
(R,R)-1b
(R,R)-1b
(R,R)-1b
(R,R)-1b
15
15
15
15
15
15
15
15
15
20
20
20
20
20
20
20
20
20
20
20
50
50
50
50
50
50
50
50
50
50
50
10
50
50
6
6
6
6
6
6
6
6
6
6
6
1
1
1
1
1
1
1
1
1
1
1
2
<5 (21)d Nd (83)d
MeOH
EtOH
100
100
84
40
37
38
78
54
43
31
33
40
23
74
17
19
22
15
48
27
74
12
96
96
97
92
93
92
96
98
98
94
96
>99
89
94
95
96
94
81
96
>99
>99
>99
99
99
i-PrOH
THF
Et2O
toluene
acetone
CH2Cl2
As shown in Table 1, the hydrogenation proceeded smoothly
in alcoholic solvent, giving 1,2,3,4-tetrahydroquinoline 3a with
excellent reactivities and enantioselectivities (entries 2ꢀ4). It
was found that the reactivity and enantioselectivity were reduced
when the reaction was carried out in aprotic solvents, such as
THF, ether, and toluene (entries 5ꢀ7). Interestingly, high
reactivity and enantioselectivity were obtained in acetone
(entry 8). Despite lower reactivity, the highest enantioselectivity
was achieved in both CH2Cl2 and [bmim]PF6 (entries 9 and 10).
It was worth noting that the reaction could be carried out in pure
water with very good enantioselectivity, albeit at a low conversion
(entry 11). Methanol was selected as the solvent of choice in
terms of both reactivity and enantioselectivity for the screening
of catalysts and reaction conditions.
Next, all catalysts described in Scheme 1 were tested and the
results are listed in Table 1. Generally, the catalytic performance
was significantly affected by both the substituents of the η6-arene
ligand and the N-sulfonate substituents (entries 12ꢀ18). Intro-
duction of alkyl substituents into the η6-arene of the Ru catalysts
led to significant increase in both conversion and enantioselec-
tivity (entries 12ꢀ14). The catalyst bearing hexamethylbenzene
ligand (R,R)-1c offered >99% ee and 40% conversion after 1 h
at 50 atm H2 and room temperature (entry 13). This result
suggested that the CH/π attractive interaction between the
η6-arene ligand and the aryl portion on quinoline, which was
proposed as the origin of enantioselectivity in the transfer
hydrogenation of aromatic ketones,21b might be also responsible
for the excellent enantioselectivity in the asymmetric hydrogena-
tion of 2-methylquinoline. The steric effect of N-sulfonate
substituent was also manifested. For example, the catalyst
(R,R)-1e having a methyl on the N-sulfonate group yielded
product 3a in high conversion (74%) with slightly lower ee value
(94%) (entry 15). In addition, introducing electron-withdrawing
N-sulfonate substituents into catalysts, such as (R,R)-1g and
(R,R)-1h, resulted in lower conversion although the enantio-
selectivity remained similar (entries 17 and 18). Replacement of
the diamine ligand TsDpen with TsCydn led to much lower
enantioselectivity and reactivity (entry 19). Notably, the Ir- and
Rh-complexes could also effectively catalyze the hydrogenation
of 2a with excellent enantioselectivity (entries 20 and 21). Thus,
the Ru-complex bearing hexamethylbenzene ligand (R,R)-1c was
chosen as the best catalyst due to its high enantioselectivity and
reactivity in the reduction (entry 13).
10 (R,R)-1b
11 (R,R)-1b
12 (R,R)-1b
13 (R,R)-1c
14 (R,R)-1d
15 (R,R)-1e
16 (R,R)-1f
17 (R,R)-1g
18 (R,R)-1h
19 (R,R)-1i
20 (R,R)-1j
21 (R,R)-1k
22 (R,R)-1c
23 (R,R)-1c
24e (R,R)-1c
25f (R,R)-1c
[Bmim]PF6 15
H2O
15
25
25
25
25
25
25
25
25
25
25
60
25
25
40
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
14 100
48 100
a Reaction conditions: 0.2 mmol of 2-methylquinoline (2a) in 1 mL of
solvent, 1.0 mol % catalyst. b Determined by 1H NMR. c Determined by
HPLC analysis with a chiral column. d Data in brackets were obtained at
60 °C. e 0.2 mol % (R,R)-1c. f 0.02 mol % (R,R)-1c and 2 mmol of 2a in
1 mL of MeOH.
provided a facile and practical access to a variety of optically
active 1,2,3,4-tetrahydroquinoline derivatives.
’ RESULTS AND DISCUSSION
Asymmetric Hydrogenation of Quinoline Derivatives Cat-
alyzed by Cationic Ruthenium Catalysts. Synthesis of Ruthe-
nium Catalysts. Since the pioneering work reported by Noyori
and co-workers,16 a number of Ru-, Rh-, and Ir-complexes of
N-monosulfonylated diamines have been synthesized and pro-
ven to be powerful catalysts for asymmetric transfer hydrogena-
tion of ketones and imines. In our study, chiral N-sulfonylated
1,2-diphenylethylenediamine (Dpen) and 1,2-cyclohexanedi-
amine (Cydn) were chosen as the ligands. According to the
well-established method and based on the modular nature of
such metal complexes, 10 metal complexes bearing chloride as
anions were prepared (see Supporting Information). The Clꢀ
anion was then replaced by TfOꢀ via the treatment with AgOTf,
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Table 2. Asymmetric Hydrogenation of 2-Alkyl-Substituted
Quinoline Derivativesa
Table 3. Asymmetric Hydrogenation of 2-Phenylquinoline:
Condition Optimizationa
entry catalyst solvent temp (°C) time (h) conv (%)b ee (%)c
1
1c
1b
1d
1e
1f
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
25
25
25
25
25
25
25
0
4
78
72
68
67
13
63
67
64
99
84
57
7
83
84
80
86
67
56
46
89
92
89
73
72
63
2
4
3
4
4
4
5
4
6
1h
1i
4
7
4
8
1e
1e
1e
1e
1e
1e
24
24
24
24
24
24
9
0
10
11
12
13
i-PrOH
THF
0
0
toluene
CH2Cl2
0
0
<5
a Reaction conditions: 0.15 mmol of 2-phenylquinoline in 1 mL of
1
solvent, 1.0 mol % catalyst, 50 atm H2. b Determination by H NMR.
c Determined by HPLC analysis with a chiral column (see Supporting
Information).
a Reaction conditions: 0.2 mmol of substrate in 1 mL of MeOH, 0.2 mol %
(R,R)-1c, 50 atm H2, 25 °C, 12ꢀ14 h. b Determined by 1H NMR, and
data in brackets are isolated yields. c Determined by HPLC analysis with
a chiral column (see Supporting Information); absolute configuration
was determined by comparison of optical rotation with literature data or
by analogy (see ref 19).
Figure 1, which has proven to be a potent inhibitor of the
cholesterol ester transfer protein,2g,5 the asymmetric hydroge-
nation of related quinoline derivatives remains undeveloped.
For almost all the reported Ir/phosphine/I2 catalytic systems,
low levels of enantiomeric enrichment (<80% ee) were often
observed, and only 2-phenylquinoline was examined as a unique
model substrate.25,26 Most recently, Mashima and co-workers
reported a highly enantioselective hydrogenation of 2-arylquino-
linium salts by using cationic dinuclear iridium halide complexes
with difluorophos.10f Good to excellent enantioselectivities
(up to 95% ee) were observed for a variety of 2-arylquinolinium salts.
We wanted to test whether the optimal catalyst selected for the
hydrogenation of 2-alkylquinoline could also work well in the
hydrogenation of 2-aryl-substituted substrates. To our delight,
the hydrogenation of the less basic 2-phenylquinoline proceeded
smoothly in methanol by using 1 mol % of complex 1c as the
catalyst, giving the corresponding product in 78% conversion and
83% ee in 4 h (entry 1 in Table 3). Prompted by this initial result,
we further screened the catalysts under the following conditions:
1.0 mol % catalyst, 50 atm H2, MeOH, and at room temperature.
As shown in Table 3, unlike in the hydrogenation of 2-alkylqui-
nolines, less effect of the substituents of η6-arene ligand on the
enantioselectivity was observed (entries 1ꢀ3). The catalyst 1f
having a bulk N-sulfonate substituent showed much lower
conversion and enantioselectivity (entry 5). The best enantio-
selectivity (86% ee) was obtained with complex (S,S)-1e as the
catalyst (entry 4). To further improve the enantioselectivity, we
then focused our attention on the effect of reaction temperature
and solvent. A slightly higher ee was obtained under lower
temperature (entry 8). After screening of methanol, ethanol,
2-propanol, THF, toluene, and dichloromethane as the hydro-
genation solvent, the enantioselectivity was further improved to
92% in ethanol at 0 °C (entry 9). Reactions carried out in toluene
and dichloromethane were almost retarded (entries 12 and 13).
In addition, increasing the reaction temperature resulted in a
remarkable increase in reactivity while maintaining of the en-
antioselectivity (entry 22). The hydrogenation of 2a could also
be carried out at 10 atm of hydrogen, giving the same ee value but
lower conversion (entry 23). The hydrogenation was completed
within 14 h with a S/C of 500, yielding the product 3a with 99%
ee (entry 24). Even with 0.02 mol % (R,R)-1c, the reaction still
proceeded smoothly and led to almost complete conversion and
the same high enantioselectivity (entry 25).
Having established the optimal catalyst and reaction condi-
tions (entry 24 in Table 1), we further explored the scope of the
Ru-catalyzed asymmetric hydrogenation of 2-alkyl-substituted
quinolines (Table 2). Generally, all 2-alkyl-substituted quino-
lines were hydrogenated with excellent reactivities and enantio-
selectivities (98% ∼ >99% ee). The reaction was found to be
insensitive to the length of the alkyl side chain (entries 1ꢀ7) as
well as the existence of phenyl groups on the side chain (entries
8ꢀ11). Substitution at the 6-position had no obvious effect on
either conversion or enantioselectivity (entries 12ꢀ14). Notably,
remarkable higher reactivities and comparable or better enan-
tioselectivities for the hydrogenation of all these substrates were
observed as compared with those obtained in ionic liquid.19a
Hydrogenation of 2-Aryl-Substituted Quinolines. Encour-
aged by the successful hydrogenation of 2-alkyl-substituted
quinolines 2, we then examined the hydrogenation of 2-aryl-
substituted quinolines. Although chiral 2-aryl-1,2,3,4-tetrahydro-
quinolines are important chiral building blocks in organic syn-
thesis and chiral drug production, for example, compound A in
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Journal of the American Chemical Society
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Table 4. Asymmetric Hydrogenation of 2-Aryl-Substituted
Quinoline Derivativesa
Hydrogenation of 2-Functionalized Quinolines. Chiral
2-functionalized 1,2,3,4-tetrahydroquinolines are important or-
ganic synthetic intermediates and structural units of alkaloids.
Practical and efficient methods for the preparation of these
compounds are still highly sought.8e On the basis of the excellent
results obtained in the hydrogenation of 2-alkyl quinolines, we
accepted the challenge of the hydrogenation of 2-functionalized
quinolines by using Ru-complex (R,R)-1c as the catalyst. Under
the optimized reaction conditions (entry 24 in Table 1), a variety
of 2-functionalized quinoline derivatives were successfully hy-
drogenated to afford the corresponding tetrahydroquinoline
derivatives with excellent enantioselectivities (97 to >99% ee).
As shown in Table 5, the quinoline substrates bearing free
hydroxyl group on the side chain could be efficiently hydro-
genated in full conversion with 99% ee (entries 1ꢀ4). In the
cases of 2-vinyl-substituted quinolines, hydrogenations pro-
ceeded smoothly to give the desired products with 99% ee
(entries 5ꢀ7). Interestingly, the conjugated double bond (6e)
was also hydrogenated, while the system could tolerate isolated
double bonds (6f and 6g). Quinolines having carboxyl acid and
ester substituents (6h and 6i) were inactive in this reaction
(entries 8 and 9).
Hydrogenation of 2,3-Disubstituted Quinolines. Although
a number of excellent examples of the asymmetric hydrogenation
of quinolines have been reported, the substrate scope mainly
focused on 2-substituted quinoline derivatives. Highly enantio-
selective hydrogenation of 2,3-disubstituted quinoline substrates
remains a challenging task. To date, only one example has been
reported by Zhou and co-workers.8e They successfully employed
their Ir/diphosphines/I2 system to the hydrogenation of a range
of 2,3-disubstituted quinolines at high temperature, giving tetra-
hydroquinolines with up to 86% ee.
entry
substrate (Ar)
phenyl (4a)
time (h)
yield (%)b
ee (%)c
1
24
36
36
36
36
24
36
24
36
24
24
48
24
24
24
30
36
94
91
95
95
96
96
97
95
91
92
92
90
95
90
97
93
90
92 (R)
95 (R)
85 (R)
88 (R)
95 (R)
89 (R)
90 (R)
89 (R)
87 (R)
92 (R)
91 (R)
97 (R)
86 (R)
85 (R)
90 (R)
86 (R)
92 (R)
2
2-methoxylphenyl (4b)
2-methylphenyl (4c)
2-naphthyl (4d)
3
4
5
2,4-dimethoxylphenyl (4e)
3-methoxylphenyl (4f)
3-hydroxyphenyl (4g)
3-chlorophenyl (4h)
3-CF3-phenyl (4i)
6
7
8
9
10
11
12d
13
14
15
16
17
4-methoxylphenyl (4j)
4-acetamidophenyl (4k)
4-aminophenyl (4l)
4-bromophenyl (4m)
4-chlorophenyl (4n)
4-fluorophenyl (4o)
2-furyl (4p)
2-thiozyl (4q)
a Reaction conditions: 0.15ꢀ0.20 mmol of substrate in 2 mL of EtOH,
1.0 mol % (S,S)-1e, 50 atm H2, 0 °C. b Isolated yield. c Determined by
HPLC analysis with a chiral column (see Supporting Information);
absolute configuration was determined by comparison of optical rota-
tion with literature data or by analogues (see refs 8c and 9). d 5.0 mol %
catalyst was used.
Considering that the cationic ruthenium catalysts have been
successfully applied to the asymmetric hydrogenation of 2-sub-
stituted quinolines, we thus performed the hydrogenation of
2-butyl-3-pentylquinoline 8a with 1.0 mol % (R,R)-1c in metha-
nol under 50 atm H2 at room temperature for 24 h. To our
delight, full conversion and good enantioselectivity for the syn-
product were observed (entry 1 in Table 6). After a survey of
other ruthenium catalysts bearing different substituents on the
sulfonyl group and the η6-arene ligand in the hydrogenation of
8a, catalyst (R,R)-1e was found to exhibit excellent enantioselec-
tivity for both syn- and anti-products although the diastereo-
selectivity was low (entry 4 in Table 6). With the optimized
catalyst in hand, different 2,3-disubstituted quinoline derivatives
were investigated, and the results are listed in Table 6. Notably,
all the 2,3-alkyl-disubstituted quinolines were hydrogenated
smoothly to give the corresponding 1,2,3,4-tetrahydroquinolines
with full conversions and 95ꢀ98% ee for syn-products, 68ꢀ86%
ee for anti-products (entries 4ꢀ7). Interestingly, for the cyclic
compounds 8eꢀg, excellent diastereoselectivities (up to >95:5)
were obtained, but the enantioselectivities dropped dramatically
from 95% ee to 17% ee when the cycle became smaller (entries
8ꢀ10). For 2-phenyl-3-methylquinoline 8h, low enantioselec-
tivity but high diastereoselectivity were obtained (entry 11).
Hydrogenation of 3-Substituted, 4-Substituted, and 2,4-
Disubstituted Quinolines. Encouraged by the excellent enan-
tioselectivity and reactivity observed in the hydrogenation
of 2-alkyl-substituted, 2-aryl-substituted, and 2,3-disubstituted
quinolines, we attempted to employ the cationic ruthenium
catalysts for the hydrogenation of other more difficult sub-
strates, including 3-substituted and 4-substituted quinolines,
Under the optimal reaction conditions (entry 9 in Table 3),
the hydrogenations of different 2-aryl-substituted quinolines
4aꢀq were examined, and good to excellent enantioselectivities
(85ꢀ97% ee) were obtained. It was found that both steric and
electronic properties of the substituents on 2-phenyl group of the
substrates have a great impact on enantioselectivity and reactivity
(Table 4). Introduction of a substituent into the ortho position of
the phenyl ring required longer reaction time (36 h) for achieving
complete conversions (entries 2ꢀ5 vs entry 1). Conversely, most
substrates having meta or para substituents on the phenyl ring
gave full conversions within 24 h. The substrates bearing hydro-
xyl and trifluoromethyl groups at the meta position of the phenyl
ring also exhibited low reactivity (entries 7 and 9). An exceptional
example was the substrate 4l having a p-amino group on the
phenyl ring (entry 12), which needed a higher catalyst loading (5
mol %) and longer reaction time, but giving the highest en-
antioselectivity (97%). To the best of our knowledge, this is the
highest ee value reported so far for the asymmetric hydrogena-
tion of 2-aryl-substituted quinoline derivatives. High enantio-
selectivities were also observed in the hydrogenation of
2-methoxylphenylquinoline 4b and 2,4-dimethoxylphenyl-
quinoline 4e (entries 2 and 5). For the former one, the
enantioselectivity was remarkably higher than that obtained from
Ir-difluorphos catalyst (95% ee vs 62% ee).10f Notably, the
hydrogenation of 2-furyl-substituted and 2-thiozyl-substituted
quinolines proceeded smoothly with very good enantioselectivity
(entries 16 and 17).
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Table 5. Asymmetric Hydrogenation of 2-Functionalized Quinoline Derivativesa
a Reaction conditions: 0.2 mmol of substrate in 1 mL of MeOH, 0.2 mol % (R,R)-1c, 50 atm H2, 25 °C, 12ꢀ14 h. b Determined by 1H NMR and data in
c
bracket was isolated yield. Determined by HPLC analysis with a chiral column; absolute configuration was determined by comparison of optical
rotation with literature data or by analogue (see ref 19). d dr = 1:1, determined by 1H NMR.
and 2,4-disubstituted quinolines. To date, successful hydrogena-
tion of these substrates catalyzed by chiral transition-metal
complexes has not been reported. As shown in Scheme 2, both
3-methylquinoline 8i and 3-phenylquinoline 8j were hydroge-
nated (under the following conditions: 1.0 mol % (R,R)-1b, 50
atm of H2 at rt for 24 h), giving the racemic products. (This is
consistent with the mechanistic interpretation described
below).27 For the 4-substituted and 2,4-disubstituted substrates
8k and 8l, hydrogenation could not take place.
Product Elaboration. The usefulness of the present work was
exemplified in the gram-scale synthesis of a biologically active
tetrahydroquinoline alkaloid, angustureine,6a and 6-fluoro-2-
methyl-1,2,3,4-tetrahydroquinoline 3n.3 Compound 3n is a key
intermediate for the synthesis of antibacterial agent of (S)-
flumequine, which was obtained via resolution.3 Asymmetric
hydrogenation of the easily available quinoline derivatives 2e and
2n was carried out ona gramscale ata catalyst loadingof0.2 mol %,
giving the tetrahydroquinolines in quantitative conversion with
excellent enantioselectivity. Subsequent N-methylation of 3e
gave (ꢀ)-angustureine in high overall yields with up to 99% ee
(Scheme 3).
of this reaction was unclear and some key issues were still debat-
able. First, there was still a lack of direct experimental evidence to
support the tandem CdC and CdN hydrogenation pathway.
Second, hydrogenation of the cyclic imine intermediate (1,2-
hydride addition to the dihydroquinoline) was the stereogenic
center forming step. The origin of enantioselectivity, however,
remained to be elucidated, which was also a big challenge in the
asymmetric reduction of imine with such type of catalysts.23 Here
we report the results of our detailed experimental and computa-
tional mechanistic studies.
Stoichiometric Reaction. In our initial study,19a activation of
quinoline substrate with Brønsted acid was found to be crucial for
the activity and enantioselectivity in the stoichiometric reaction.
Two equivalents of acid was required for achieving full conver-
sion in the reduction of 2-methylquinoline (2a) with a stoichio-
metric amount of hydride complex (R,R)-1l in ionic liquid. In
order to further investigate whether the acid was necessary for the
stoichiometric hydrogenation of quinolines in protonic metha-
nol, hydrogenation of substrates 2a and 4a with (R,R)-1l was
carried out either in the absence or in the presence of TfOH,
respectively. As shown in Table 7, similar results were observed
as those in ionic liquid. The hydrogenation reaction between
(R,R)-1l and 2a or 4a could not take place in the absence of acid,
even with an excess of (R,R)-1l (10 equiv) after 15 h (entries 1
and 2). Instead, the protonated quinolines of 2a and 4a could
react with (R,R)-1l to give the reduced product in 44% and 47%
Mechanistic Study. In our initial study with this ruthenium
catalyst in ionic liquid,19a we proposed an ionic and cascade
reaction pathway, including 1,4-hydride addition, isomerization,
and 1,2-hydride addition for the reduction of quinoline. Despite
such a general understanding, however, the detailed mechanism
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conversions with identical enantioselectivities to those of the
direct hydrogenation of 2a and 4a (entries 3 and 4). Further-
more, when another 1 equiv of tetrahydroquinoline salt was
added as the proton source, the reaction was found to proceed
smoothly, affording the product with up to 96% and 89%
conversions, respectively (entries 5 and 6). These results demon-
strated that, unlike the hydrogenation of aromatic ketones,21
quinoline should be activated by the Brønsted acid before
hydrogenation. A similar activation effect was also demonstrated
in the asymmetric hydrogenation of quinoline with the Ir/
diphosphine catalyst system.8g,10f On the basis of these observa-
tions, we speculated that the quinoline might be reduced through
a stepwise Hþ/Hꢀ transfer process outside the coordination
sphere (as shown in Scheme 4), which was different from the
concerted mechanism for the ketone hydrogenation.21, 28ꢀ30
Reaction Pathway of Hydrogen Transfer. In general, reduc-
tion of quinoline includes the hydrogenation sequence of CdC
and CdN bonds. Theoretically, in addition to the pathway as
described above (Scheme 4), another possible one is 1,2-hydride
addition followed by 3,4-hydride addition (Scheme 5). To
demonstrate which hydrogenation pathway is possible, the
synthesis of reaction intermediates is very important and some-
times can provide direct proof to support the mechanism.
First, the intermediate (11a) of 1,2-hydride addition was
synthesized by the reaction of quinoline with n-butyllithium.31
The freshly resulting 11a was immediately applied to hydro-
genation with (R,R)-1b under 50 atm H2. To our surprise, the
intermediate 11a could be smoothly reduced to give the product
Table 6. Asymmetric Hydrogenation of 2,3-Disubstituted
Quinoline Derivativesa
entry substrate catalyst time (h) conv (%)b syn/antib
ee (%)c
1
8a
8a
8a
8a
8b
8c
8d
8e
8f
(R,R)-1c
(R,R)-1b
24
24
100
100
100
70/30 77 (syn), 26 (anti)
40/60 94 (syn), 61 (anti)
39/61 92 (syn), 85 (anti)
2
Table 7. Stoichiometric Reaction between (R,R)-1l and
Quinoline 2a or 4a in MeOHa
3
(R,R)-1d 24
4
(R,R)-1e
(R,R)-1e
(R,R)-1e
(R,R)-1e
(R,R)-1e
(R,R)-1e
(R,R)-1e
(R,R)-1e
24
24
24
24
36
36
36
36
100 (95) 42/58 96 (syn), 80 (anti)
100 (94) 45/55 95 (syn), 68 (anti)
5
6
100
46/54 97 (syn), 77 (anti)
7
100 (96) 45/55 98 (syn), 86 (anti)
8
100
91
92/8 95 (syn)
90/10 79 (syn)
>95:5 17 (syn)
>95:5 21 (syn)
9
10
8g
100
11
8h
100
entry
quinoline
additive
conv (%)b
ee (%)c
a Reaction conditions: 0.2 mmol of substrate in 1 mL of MeOH, 1.0 mol
% catalyst, 50 atm H2, 25 °C, 24ꢀ36 h. b Determined by 1H NMR, and
data in brackets are isolated yields. c Determined by HPLC analysis with
a chiral column (see Supporting Information).
1
2
3
4
5
6
2a
none
none
none
none
0
ꢀ
4a
0
ꢀ
2a.TfOH
4a.TfOH
2a.TfOH
4a.TfOH
44 (48)d
96 (99)d
84
47
3e TfOH (1 equiv)
96 (95)d
89
96 (99)d
Scheme 2
3
3a TfOH (1 equiv)
84
3
a Reaction conditions: 0.2 mmol of substrate and 10 equiv of (R,R)-1l in
1.0ꢀ2.0 mL of MeOH, rt, 15 h. b Determined by 1H NMR. c Determined
by HPLC analysis with a chiral column. d Data in brackets were obtained
in ionic liquid.19a
Scheme 3
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Scheme 4. Possible Hydrogenation Pathway of Quinoline Based on the Study of the Stoichiometric Reaction
Scheme 5. The Second Plausible Hydrogenation Pathway of
Quinoline
Scheme 6. Hydrogenation of Intermediate with Catalyst (R,
R)-1b
3d in 100% conversion with the same enantioselectivity (94% ee)
as the direct hydrogenation of 2d (Scheme 6, eq 1). After careful
examination, it was found that the intermediate 11a was rapidly
dehydrogenated to form the aromatic 2d for no more than 5 min
at room temperature in the presence of the ruthenium catalyst.
Interestingly, some of the reduced tetrahydroquinoline 3d was
also observed with similar enantioselectivity to that of the direct
hydrogenation of 2d, suggesting the formation of the active
reducing species (R,R)-1l upon dehydrogenation. To overcome
this problem, the stable N-benzoyl compound 11b was synthe-
sized and found to be an inactive substrate for hydrogenation
under otherwise identical reaction conditions (Scheme 6, eq 2).
This result indicated that the unpolarized CdC bond could not
be reduced by using this ruthenium catalyst. On the other hand,
according to the recently published references,32 this kind of
diamine-derived metal complex was found to be effective only for
the asymmetric transfer hydrogenation of a polarized CdC
bond. Therefore, on the basis of these observations, the second
hydrogenation pathway might be less likely for our catalytic
system.
Next, we synthesized the intermediate (11c) of 1,4-hydride
addition in the hope of obtaining direct proof to support the first
hydrogenation pathway. Considering the easy decomposition of
the 2-alkyl-3,4-dihydroqinoline, we finally synthesized and fully
characterized the relatively more stable intermediate 2-phenyl-
3,4-dihydroqinoline (11c).33 Subsequently, hydrogenation of
11c was carried out in the presence of (R,R)-1b under 50 atm
H2, and the desired product 5a was obtained in 100% conversion
with 84% ee (Scheme 6, eq 3), which was the same enantio-
selectivity as that of the direct hydrogenation of 4a. Although
dehydrogenation of 11c was also observed in the presence of the
ruthenium catalyst (see Supporting Information), the deuterium
labeling experiment (as described below) indicated that direct
hydrogenation of 11c did occur.
(spectrum D) exhibited all the characteristic proton signals for all
these compounds (Figure 2). Importantly, the well-resolved
proton signal at δ 8.04ꢀ8.01 (multiplet), 7.16 (doublet), and
2.88 (singlet), which matched those of the independently
synthesized intermediate imine 11c, revealed the existence of
this imine in the reaction mixture. Furthermore, the ESI-HRMS
spectrum of the reaction mixture was collected in positive-ion
mode and shown in Figure 3. To our pleasure, in addition to the
presence of 4a Hþ (m/z 206.09609) and 5a Hþ (m/z
3
3
210.12727), the formation of the imine intermediate 11c Hþ
3
(m/z 208.11176) was observed. To the best of our knowledge,
this is the first time the imine intermediate in the hydrogenation
of quinolines was unequivocally identified, offering solid support
for the first pathway including 1,4-hydride addition, isomeriza-
tion, and then 1,2-hydride addition processes (Scheme 4).
Deuteration Study. To further confirm that the hydrogena-
tion occurred via the first pathway, in which the hydride was
transferred to the 2- and 4-positions of quinoline, and the proton
to the 1- and 3-positions of quinoline, isotope labeling experi-
ments using deuterated gas and solvents were carried out at room
temperature under the hydrogenation conditions as described
above and monitored by 1H NMR spectroscopy to identify the
concentration of deuterium in the various positions of the
hydrogenated product. First, the reaction was performed with
1.0 mol % (R,R)-1b under 50 atm D2 in MeOH for 24 h.
Remarkably, only the reduced product bearing 100% deuterium
at both the 2- and 4-positions were observed (Scheme 7, eq 1).
Instead, when hydrogenation was carried out in CD3OD under
50 atm H2, the deuterium atoms were found only at the 1- and
To further demonstrate the existence of this imine intermedi-
1
ate in the direct hydrogenation of 4a, we then employed H
NMR and ESI-MS techniques for characterization of this cata-
lytic system. ESI-MS allows the characterization of species that
are actually present in the reaction solution, which has been
successfully applied in the investigation of catalytic reaction
1
mechanism.34 In this study, the room-temperature H NMR
spectrum of the reaction mixture for hydrogenation of 4a was
taken after the reaction was carried out for 5 min. As compared
with the spectra of substrate 4a (spectrum A), product 5a
(spectrum B), and the preformed imine intermediate 11c
1
(spectrum C), the H NMR spectrum of the reaction mixture
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Figure 2. 1H NMR (300 MHz, CDCl3) spectra for characterization of the imine intermediate. (A) 2-phenylquinoline (4a), (B) 2-phenyl-1,2,3,4-
tetrahydroquinoline (5a), (C) 2-phenyl-3,4-dihydroquinoline (11c), (D) reaction mixture for the hydrogenation of 4a catalyzed by (R,R)-1b (5 min
after the start of the reaction).
Figure 3. ESI-HRMS spectrum (positive mode) of the reaction mixture for the hydrogenation of 4a catalyzed by (R,R)-1b (5 min after the start of the
reaction).
3-positions of the product 3a (Scheme 7, eq 2). Expectedly,
hydrogenation proceeded smoothly with both deuterated gas
and solvent, offering the reduced product with 100% deuterium
incorporation at all the 1-, 2-, 3-, and 4-positions (Scheme 7, eq 3).
Considering that methanol, ethanol, 2-propanol, and other
secondary alcohols were known to serve as hydrogen donors in
the asymmetric transfer hydrogenation of aromatic ketones, we
next conducted the hydrogenation of 2a in (CH3)2CDOH to test
if the reaction was partly associated with transfer hydrogenation.
It was found that full conversion was observed in the presence of
1.0 mol % (R,R)-1b under 50 atm H2 for 24 h, giving the reduced
product without any deuterium incorporation (Scheme 7, eq 4).
In addition, when the 16e Ru complex (R,R)-1m, which was
recognized as the active species in the transfer hydrogenation of
aromatic ketones,21d was used as the catalyst for the reduction of
2a, no reaction took place in the absence of H2 at room
temperature. Notably, even when the reaction was performed
under 50 atm H2 for 24 h, no more than 5% conversion was
observed, which was in agreement with the incapability of 1m to
activate H2.21a All these observations indicated that 1m was not
involved in this catalytic cycle, and the reaction was a net
hydrogenation using H2 as the hydrogen donor.
Reversibility of Hydrogenation. Although it has been de-
monstrated that the dehydrogenation of 1,2,3,4-tetrahydro-
quinoline could be carried out by using homogeneous iridium
catalysts,8e,35 this dehydrogenation reaction was not observed
at the temperature utilized in this study, suggesting that
1,2-hydrogen transfer is an irreversible step (Scheme 4). As
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Scheme 7. Deuterium-Labeling Studies
Scheme 8. Models for the Theoretical Study
characterization of the deuterated 4a, see Supporting Infor-
mation). Therefore, reversible hydrogen transfer in the first step
was conclusively demonstrated by deuterium scrambling into
recovered quinoline 4a at the 4-position, and 1,2,3,4-tetrahydro-
quinoline 5a at the 2- and 4-positions.
DFT Study of the Mechanism and Origins of Enantio-
selectivity. To gain further insights into the mechanism and the
origins of enantioselectivity, theoretical calculations were carried
out to study the hydrogenation process of the protonated imine
intermediate, which is generated by the 1,4-hydride addition and
isomerization (see this also in Scheme 9 later on).23a,36 There-
fore, dihydroquinoline/MsOH (12a) and the hydride ruthenium
catalyst (13a) were chosen for our computational investigation
(Scheme 8). All calculations were carried out with Gaussian 03
programs.37 Geometrical optimizations of all species were carried
out by using the B3LYP functional.38 The 6-31G (d) basis set was
used for all atoms, expect for Ru, which has been described by the
LANL2DZ basis set.39 This method has been successfully applied
by Noyori and co-workers to the study of mechanism of ketone
reduction by the Ru catalysts.21b,c The reported relative free
energies (ΔG) and enthalpies (ΔH) were obtained in the gas-
phase calculations. Topological analysis of electron densities at
bond critical points was performed with the AIM 2000
program.40a Unless otherwise specified, all the discussed energies
in this paper are the free energies in the gas phase (ΔG).
A direct concerted double-hydrogen transfer from the catalyst
(the hydrogen atoms from the RuꢀH and NꢀH bond in 13)
could not be located, even though this mechanism has been
found by Noyori in the ketone reduction by the Ru catalysts (see
this in the Supporting Information, Figure S7). DFT calculations
revealed that the hydrogenation of protonated imine started with
the formation of a series of complexes (14a, 14b, and 14c)
(Structures are shown in Figure S11 of the Supporting Infor-
mation) between the protonated imine and the RuꢀH catalyst.
Among these complexes, complex 14a, which used its sulfonate
to form a hydrogen bonding network with both the NꢀHeq
mentioned above, we found that the complex (R,R)-1b could
catalyze the dehydrogenation of imine 11c, suggesting the
possibility of reversible hydrogen transfer in the first step
(Scheme 4). To address this issue, 11c was first selected as the
substrate and hydrogenated with 1.0 mol % (R,R)-1b under 50
atm D2 in MeOH for 24 h. Notably, deuterium incorporation
into both 2-position (73% of D) and 4-position (21% of D) of the
reduced product was observed (Scheme 7, eq 5). This result
demonstrated the formation of quinoline 4a via dehydrogenation
of 11c, which was subsequently hydrogenated under deuterated
gas with deuterium incorporation into the 4-position. The
ruthenium hydride formed upon dehydrogenation was trapped
by 4a and 11c, which was responsible for the less deuterium
incorporation into the 2-position. Then, 4a was used as the
substrate for hydrogenation under identical conditions. Deuter-
ium incorporation into 2-position (93% of D) and 4-position
(103% of D) of the reduced product was observed (Scheme 7, eq
6). Unlike the hydrogenation of 2a (Scheme 7, eq 1), the
differences in deuterium incorporation into 2- and 4-positions
were attributed to the reversible hydrogen transfer to 4a, which
provided ruthenium hydride and subsequently trapped by 4a. In
addition, when the reaction was performed under 1 atm D2 for
48 h (about 50% conversion), deuterium incorporation into the
4-position of the recovered substrate 4a was observed (For full
(NꢀHeq O1) and the proton of the protonated imine,41 was
3 3 3
the most stable one and was in equilibrium with complexes 14b
and 14c, which were higher in energy than 14a by 0.9 and
5.7 kcal/mol, respectively (see Figure S10 in the Supporting
Information). In principle, all these complexes could undergo
hydride transfer reactions from their RuꢀH bonds to the carbon
atoms of the protonated imines. However, the preferred hydride
transfer could only take place from 14a via either transition state
TS1-re or TS1-si, owing to the energetic reasons that hydride
transfer transition states from 14b and 14c were higher in
energy than TS1-re and TS1-si (for details of TS2 and TS3,
see Supporting Information).
The hydride transfer from 14a preferred to give the
R-configuration product (via transition state TS1-si) since the
transition state TS1-re leading to the S-configuration product
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was higher in energy than TS1-si by 2.5 kcal/mol in the gas phase.
The calculated free energy barrier for 14a to reach TS1-si and
TS1-re were 12.8 and 15.3 kcal/mol, respectively (Figure 4).
This was consistent with the experimental observation, where
R-configuration product was the dominant product. The main
reason for the lower energy of TS1-si than TS1-re was the
existence of a favorable CH/π attraction between the phenyl
group of dihydroquinoline and the η6-benzene in TS1-si,
whereas this interaction was absent in TS1-re, where the phenyl
ring of the protonated imine pointed in the opposite direction
and there was no contact with the phenyl ring of the catalyst (see
below for detailed discussion). Such CH/π attraction was
realized by Noyori and co-workers in rationalizing the reduction
of ketone using RuꢀTs-dpen as the catalyst and many other
systems.21bꢀf,42
To better analyze the origins of enantioselectivity, we exam-
ined in detail the hydride transfer transition states from an
experimentally used reaction system.43,44 Therefore, we com-
puted TS4-si and TS4-re for the stoichiometric reaction de-
scribed in Table 7, where quinoline 2a (protonated by TfOH)
was reduced to give R-3a as the major product when the hydride
catalyst (R,R)-1l was used. Calculations showed that TS4-si,
which gave the experimentally observed major R-product, was
favored by 2.4 kcal/mol compared to TS4-re (Figure 5). Thus,
these calculations gave results agreeing with the experimental
observations, where the R-product was formed preferentially
Figure 4. DFT computed energy surface of the hydrogenation of
protonated imine by the ruthenium hydride catalyst. The reported
energies are the calculated relative free energies (ΔG) and enthalpies
(ΔH, in brackets) in the gas phase.
Figure 5. Calculated transition structures for the hydride transfer to imine. The calculated relative free energies ΔG and the enthalpies ΔH (in brackets)
are given.
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Scheme 9. Proposed Mechanism for the Asymmetric
Hydrogenation of Quinoline (ethylenediamine ligands
and OTfꢀ are omitted for clarity)
transfer, isomerization, and 1,2-hydride transfer. As illustrated
in Scheme 9, the ionized ruthenium complex Ruþ reversibly
accommodates a dihydrogen to form dihydrogen complex H2-
Ruþ. Deprotonation of the dihydrogen ligand by quinoline
generates both the active RuꢀH species and the activated
substrate. A subsequent 1,4-hydride transfer affords the enamine
intermediate and the regenerated Ruþ. Similarly, the enamine
serves as a base to deprotonate the dihydrogen ligand, resulting in
the RuꢀH and the iminium cation. Then 1,2-hydride transfer
gives the final product, 1,2,3,4-tetrahydroquinoline, enantio-
selectively and regenerates Ruþ. The dihydroquinoline intermedi-
ate can be reversibly dehydrogenated by Ru-catalyst to give the
quinoline, while the 1,2-hydride transfer step is irreversible under
the asymmetric hydrogenation conditions. As suggested by the
theoretical calculation, the activated iminium cation reacts with
RuꢀH via a cyclic 10-membered transition structure with the
participation of TfOꢀ anion. Similar to the ketone reduction,21c
the enantioselectivity originates from the CH/π attraction
between the η6-arene ligand in the Ru-complex and the fused
phenyl ring of the dihydroquinoline.
’ CONCLUSION
In summary, we have demonstrated that chiral cationic
η6-areneꢀN-tosylethylenediamineꢀRu(II) complexes are excel-
lent catalysts for the asymmetric hydrogenation of quinolines.
A wide range of quinoline derivatives, including 2-alkylquino-
lines, 2-arylquinolines, and 2-functionalized and 2,3-disubstitut-
ed quinolines, were efficiently hydrogenated under mild reaction
conditions with up to >99% ee and up to 5000 TON. A
mechanistic study by combining stoichiometric reaction, inter-
mediate characterization, and isotope labeling patterns revealed
that quinoline was reduced via an ionic and cascade reaction
pathway, including 1,4-hydride addition, isomerization, and 1,2-
hydride addition. The hydrogen addition underwent a stepwise
Hþ/Hꢀ transfer process outside the coordination sphere rather
than a concerted mechanism. Further theoretical calculations on
the transition states of the stereogenic step, 1,2-hydride addition
to dihydroquinoline, suggested that the enantioselectivity origi-
nated from the CH/π attraction between the η6-arene ligand in
the Ru-complex and the fused phenyl ring of dihydroquinoline
via a 10-membered ring transition state with the participation of
TfOꢀ anion. This versatile catalytic protocol provided a facile,
greener, and practical access to a variety of optically active 1,2,3,4-
tetrahydroquinoline derivatives. The mechanistic results pre-
sented in this work are expected to offer new insight into the
mechanism of other transition-metal-catalyzed hydrogenation of
quinoline and imines.22 Further kinetic study of this reaction and
exploration of this catalytic system for the hydrogenation of other
heteroaromatic compounds are in progress.
(96% in Table 8). It was found that the favored si addition
transition state was stabilized by the CH/π attraction: in TS4-si,
the shortest CꢀH (η6-benzene) C(sp2) distances are 2.743 Å
3 3 3
(H3 C2) and 2.971 Å (H3 C3), close to the sum of van der
3 3 3
3 3 3
Waals radii 2.9 Å for C and H. AIM analysis at the bond critical
point suggested a weak interaction between H3 and C2, where the
electron density (Fb) is 0.0062 au and the Laplacian values (Δ2Fb)
is 0.01903 au, indicating that a CH/π attraction is present. The
BCPs at the O1 Heq and O2 H1 have a Fb of 0.0152 and
’ ASSOCIATED CONTENT
S
3 3 3
3 3 3
Supporting Information. Synthetic and experimental
b
0.0320 au anda Δ2Fb of0.0508 and0.1013 au, within therange ofa
classic hydrogen bond,40b,c suggesting that these interactions are
the traditional hydrogen bonding interactions.
details, the characterizations of catalysts, substrates, and pro-
ducts, and the analysis of enantioselectivities of hydrogenation
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
Proposed Catalytic Cycle. On the basis of the results
obtained from the above experiments and calculations, as well
as relevant study on ketone reduction by Noyori,21b,d we pro-
posed a mechanism for the hydrogenation of quinoline. The
cascade hydrogenation of quinoline occurs via an ionic rather
than a concerted catalytic pathway, involving 1,4-hydride
’ AUTHOR INFORMATION
Corresponding Author
fanqh@iccas.ac.cn; yuzx@pku.edu.cn
9889
dx.doi.org/10.1021/ja2023042 |J. Am. Chem. Soc. 2011, 133, 9878–9891

Journal of the American Chemical Society
ARTICLE
’ ACKNOWLEDGMENT
(10) (a) Reetz, M.; Li, X. Chem. Commun. 2006, 2159. (b) Deport,
C.; Buchotte, M.; Abecassis, K.; Tadaoka, H.; Ayad, T.; Ohshima, T.;
Gen^et, J. P.; Mashima, K.; Ratovelomanana-Vidal, V. Synlett 2007,
17, 2743. (c) Mrꢁsiꢀc, N.; Lefort, L.; Boogers, J. A. F.; Minnaard, A. J.;
Feringa, B. L.; de Vries, J. G. Adv. Synth. Catal. 2008, 350, 1081. (d) Lu,
S. M.; Bolm, C. Adv. Synth. Catal. 2008, 350, 1101. (e) Eggenstein, M.;
Thomas, A.; Theuerkauf, J.; Franciꢂo, G.; Leitner, W. Adv. Synth. Catal.
2009, 351, 725. (f) Tadaoka, H.; Cartigny, D.; Nagano, T.; Gosavi, T.;
Ayad, T.; Gen^et, J. P.; Ohshima, T.; Ratovelomanana-Vidal, V.;
Mashima, K. Chem.—Eur. J. 2009, 15, 9990.
(11) For examples of organocatalyst catalyzed asymmetric transfer
hydrogenation of quinolines, see: (a) Rueping, M.; Antonchick, A. P.;
Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683. (b) Rueping, M.;
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2008, 47, 759.
This work is supported by the National Natural Science
Foundation of China (20973178 to Q.-H. Fan, and 20825205
to Z.-X. Yu), the National Basic Research Program of China (973
Programs, 2010CB833300 to Q.-H. Fan, and 2011CB808601 to
Z.-X. Yu), the Ministry of Health (grant no. 2009ZX09501-017),
and the Chinese Academy of Sciences.
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