Enantiodivergent Synthesis of Chiral Tetrahydroquinoline Derivatives via Ir-Catalyzed Asymmetric Hydrogenation: Solvent-Dependent Enantioselective Control and Mechanistic Investigations

Article abstract of DOI:10.1021/acscatal.1c01353

Ir-catalyzed asymmetric hydrogenation of quinolines was developed, and both enantiomers of chiral tetrahydroquinoline derivatives could be easily obtained, respectively, in high yields with good enantioselectivities through the adjustment of reaction solvents (toluene/dioxane: up to 99% yield, 98% ee (R), TON = 680; EtOH: up to 99% yield, 94% ee (S), TON = 1680). It provided an efficient and simple synthetic strategy for the enantiodivergent synthesis of chiral tetrahydroquinolines, and gram-scale asymmetric hydrogenation proceeded well with low-catalyst loading in these two reaction systems. A series of deuterium-labeling experiments, control experiments, and 1H NMR and electrospray ionization-mass spectrometry experiments have been conducted, and a reasonable and possible reaction process was revealed on the basis of these useful observations.

Full text of DOI:10.1021/acscatal.1c01353

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Research Article
Enantiodivergent Synthesis of Chiral Tetrahydroquinoline
Derivatives via Ir-Catalyzed Asymmetric Hydrogenation: Solvent-
Dependent Enantioselective Control and Mechanistic Investigations
Zhengyu Han,∥ Gang Liu,∥ Xuanliang Yang, Xiu-Qin Dong,* and Xumu Zhang*
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ABSTRACT: Ir-catalyzed asymmetric hydrogenation of quinolines was developed, and both enantiomers of chiral
tetrahydroquinoline derivatives could be easily obtained, respectively, in high yields with good enantioselectivities through the
adjustment of reaction solvents (toluene/dioxane: up to 99% yield, 98% ee (R), TON = 680; EtOH: up to 99% yield, 94% ee (S),
TON = 1680). It provided an efficient and simple synthetic strategy for the enantiodivergent synthesis of chiral tetrahydroquinolines,
and gram-scale asymmetric hydrogenation proceeded well with low-catalyst loading in these two reaction systems. A series of
deuterium-labeling experiments, control experiments, and 1H NMR and electrospray ionization-mass spectrometry experiments have
been conducted, and a reasonable and possible reaction process was revealed on the basis of these useful observations.
KEYWORDS: enantiodivergent synthesis, asymmetric catalysis, chiral tetrahydroquinolines, hydrogenation, enantioselectivity
synthetic protocols. After immense effort has been devoted,
some catalytic synthetic methods have been well established,
INTRODUCTION
■
Asymmetric catalytic synthesis has been regarded as an
efficient and powerful method to access chiral molecules,
which is mainly based on the employment of chiral transition-
metal catalysis and organocatalysis.1 The synthesis of both
enantiomers of a target chiral molecule is usually in demand for
the preparation of chiral enantiomeric catalysts.2 However, a
great many chiral catalysts are only available in a single
configuration. To overcome this problem and realize
enantiodivergent synthesis, a remarkable protocol is that
adjusting other reaction parameters while using the same
catalyst, which can be easily implemented by altering the metal
precursor, introducing an additive, or modifying the reaction
conditions. Among these accessible alternatives, the reaction
solvent as an ideal condition parameter can be easily modified
to realize enantiodivergent synthesis. There are rare examples
of achieving dual well-controlled enantioselectivity by changing
the solvents.3
such as enantioselective α-N-arylation of tetrahydroquino-
5
̈
lines, asymmetric Friedlander condensation/transfer hydro-
genation,6a asymmetric cascade addition/cycloisomerization/
transfer hydrogenation,6b intramolecular hydroamination/
asymmetric transfer hydrogenation,7 and direct asymmetric
hydrogenation of prochiral quinolines8 (Scheme 1). Among
these available enantioselective approaches, the direct asym-
metric reduction of prochiral quinolines is a powerful and
convenient synthetic methodology to prepare chiral tetrahy-
droquinolines through transition-metal catalysis and organo-
catalysis.9−11 However, most of these transition-metal catalysts
failed to deliver satisfactory enantioselectivities in the
asymmetric hydrogenation of aryl-substituted quinolines,11
which were mainly due to their high aromatic stability,
coordinating ability, and intrinsic low reactivity. Therefore,
Enantioenriched 1,2,3,4-tetrahydroquinoline derivatives are
versatile chiral heterocycles, which not only worked as
favorable synthetic intermediates but also are represented as
privileged heterocyclic subunits in various natural products,
pharmaceuticals, and biologically active compounds (Figure
1).4 As a consequence, their great importance stimulated
considerable research interest for the development of efficient
Received: March 24, 2021
Revised: May 20, 2021
Published: June 4, 2021
https://doi.org/10.1021/acscatal.1c01353
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Figure 1. Examples of bioactive compounds featuring chiral tetrahydroquinoline motifs.
Scheme 1. Synthetic Strategy for Chiral 1,2,3,4-Tetrahydroquinoline Derivatives
there is a great demand to develop efficient transition-metal
catalytic systems to realize the challenging hydrogenation of
aryl-substituted quinolines. Moreover, until now, there is no
example involving the enantiodivergent synthesis of chiral
tetrahydroquinolines through the same transition-metal
complex catalysis. Considering the great importance of
noncovalent interactions12 and the continuous research on
the chiral bifunctional ferrocene-based bisphosphine−thiourea
system,9r,13 we envision that the noncovalent anion-binding
interaction between the chiral bisphosphine-thiourea ligand
and the aryl-substituted quinoline substrates could be achieved
by the introduction of Brønsted acid, which can activate the
quinoline ring, resulting in the great improvement of reactivity
and stereoselectivity control. Considering the solvent effect on
the noncovalent secondary interaction, we believe that the
solvent alternation could provide the possibility to realize
enantiodivergent synthesis, especially the variation from an
aprotic solvent to a protic solvent. Herein, we successfully
developed highly efficient Ir/N−Me-ZhaoPhos-catalyzed
asymmetric hydrogenation of challenging aryl-substituted
quinolines, and both enantiomers of chiral tetrahydroquino-
lines could be obtained through the reaction solvent
adjustment in good yields with excellent enantioselectivities
(Scheme 1).
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RESULTS AND DISCUSSION
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Research Article
with the preferred ligand N-methylated ZhaoPhos L2.
Reaction solvents always have a great influence on the
reactivity and stereoselectivity in asymmetric catalytic syn-
thesis. We found that the configuration of the hydrogenation
product was indeed strikingly dependent on the solvents.
Hydrogenation product (S)-2a could be obtained in strong
polar solvents, such as alcoholic solvents, acetonitrile, N,N-
dimethylformamide (DMF), and dimethyl sulfoxide (DMSO)
(Table 2, entries 1−8). Among these solvents, alcoholic
■
Optimization of Reaction Conditions. Initially, the
readily available 2-phenylquinoline 1a was selected as the
model substrate for the Ir-catalyzed asymmetric hydrogenation
of 2-aryl quinolines with 0.1 equiv HCl (0.2 M in dioxane) as
the additive in THF at room temperature to identify the
optimal reaction conditions. As listed in Table 1, a series of our
Table 1. Screening Ligands for Ir-Catalyzed Asymmetric
Hydrogenation of 2-Phenylquinoline (1a)
a
Table 2. Screening Solvents for Ir-Catalyzed Asymmetric
Hydrogenation of 2-Phenylquinoline (1a)
a
b
c
entry
solvent
MeOH
EtOH
iPrOH
conv. (%)
ee (%)
1
2
3
>99
>99
>99
90
10
16
20
6
47
64
87 (S)
89 (S)
83 (S)
80 (S)
65 (S)
10 (S)
70 (S)
82 (S)
82 (R)
77 (R)
93 (R)
91 (R)
84 (R)
86 (R)
4
5
6
7
8
9
10
11
12
13
14
CF3CH2OH
(CF3)2CHOH
CH3CN
DMF
DMSO
CH2Cl2
ClCH2CH2Cl
toluene
dioxane
THF
ethyl acetate
52
>99
>99
>99
a
All reactions were carried out with a substrate/catalyst ratio of 100:1
at room temperature under 30 atm H2 pressure for 13 h, 0.1 mmol 1a,
b
0.1 equiv HCl (0.2 M in dioxane), and 1.0 mL solvent. Determined
c
1
by H NMR analysis. Determined by chiral HPLC analysis.
a
Reaction conditions: 0.1 mmol substrate 1a, 1.0 mol % [Ir(COD)-
solvents provided better results, especially MeOH, EtOH,
iPrOH, and trifluoroethanol, which afforded high conversions
and good to excellent enantioselectivities (90−>99% con-
versions and 80−89% ee). As expected, the hydrogenation
product with reversed enantioselectivity can be achieved when
this reaction was performed in weak polar solvents, and most
of them provided good to excellent enantioselective control
(Table 2, entries 9−14). Although moderate conversion was
obtained in toluene, 93% ee can be achieved (52% conversion,
Table 2, entry 11). In addition, full conversion and 91% ee
were achieved in dioxane (Table 2, entry 12). The reaction
solvent may affect the anion-binding interaction between the
substrate and the ligand. These reaction results indicated that
this appealing asymmetric methodology afforded an efficient
method for the enantiodivergent synthesis just through the
change of reaction solvents.
Encouraged by the results presented above, our attention
then turned toward improving the enantioselectivity of this Ir-
catalyzed asymmetric hydrogenation in EtOH, toluene, and
dioxane to access both enantiomers, respectively. The additive
Brønsted acid may affect the formation of anion-binding
activation among the substrate, Brønsted acid, and ligand,
which should have a great impact on the reaction results. As
shown in Table 3, a variety of Brønsted acids with different
strengths were sequentially investigated. As to the access of
(S)-hydrogenation product 2a, TfOH, HCl, TFA, and AcOH
Cl]2/ligand, H2 (30 atm), 1.0 mL THF, room temperature, 13 h, and
HCl (0.2 M in dioxane, 0.1 equiv). Conversion was determined by 1H
NMR analysis. The ee value was determined by chiral HPLC analysis
using a chiral stationary phase.
chiral bisphosphine-(thio)urea ligands were employed in this
Ir-catalyzed asymmetric hydrogenation. The common priv-
ileged ligand ZhaoPhos L1 indeed promoted this trans-
formation with moderate enantioselectivity, albeit in poor
conversion (32% conversion, 64% ee). Encouraged by these
promising results, other related bisphosphine-(thio)urea
ligands were further evaluated. The N-methylated ZhaoPhos
L2 bearing one hydrogen-bonding donor provided good
conversion and enantioselectivity (84% conversion, 89% ee),
which could be conducive to the precise activation of the
substrates. Ligand L3 containing one trifluoromethyl group
and ligand L4 without a trifluoromethyl group on the phenyl
ring failed to give satisfactory results, and poor conversions and
enantioselectivities were obtained (8−26% conversions; 22−
36% ee). Ligand L5 containing a urea unit was also
investigated, and trace conversion was observed. In addition,
ligand L6 without a thiourea motif did not promote this
hydrogenation.
In an attempt to further improve the reactivity and
enantioselectivity, a variety of solvents were then screened
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a
Table 3. Screening Brønsted Acids for Ir-Catalyzed Asymmetric Hydrogenation of 2-Phenylquinoline (1a)
b
c
d
entry
solvent
acid
TfOH
HCl
CF3CO2H
CH3CO2H
CH3CO2H
TfOH
pKa
x M
y equiv
conv. (%)
ee (%)
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
EtOH
−14
−8
0.2
0.2
0.2
0.2
4.0
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.1
0.1
0.1
0.2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.2
0.2
0.2
96
89 (S)
89 (S)
89 (S)
90 (S)
90 (S)
23 (R)
91 (R)
62 (R)
NA
71 (R)
93 (R)
65 (R)
NA
>99
>99
97
>99
>99
>99
>99
Trace
72
43
51
trace
59
81
−0.25
4.76
4.76
EtOH
dioxane
dioxane
dioxane
dioxane
toluene
toluene
toluene
toluene
toluene
−14
−8
HCl
CF3CO2H
CH3CO2H
TfOH
−0.25
4.76
9
10
11
12
13
14
15
16
17
−14
−8
HCl
CF3CO2H
CH3CO2H
HCl
HCl
HCl
−0.25
4.76
−8
93 (R)
90 (R)
92 (R)
89 (R)
toluene/dioxane = 9:1
toluene/dioxane = 8:2
toluene/dioxane = 7:3
−8
−8
−8
>99
>99
HCl
a
All reactions were carried out with a substrate/catalyst ratio of 100:1 at room temperature under 30 atm H2 pressure for 13 h, 0.1 mmol 1a, 0.1
equiv HCl (0.2 M in dioxane), and 1.0 mL solvent; the configuration of product 2a was determined by comparing the optical data with those
b
c
d
reported in the literature.9d,10a,b,14 From Evans’ pKa table. Determined by H NMR analysis. Determined by chiral HPLC analysis.
1
were applied to this hydrogenation in EtOH, and the
reactivities and enantioselectivities almost remained at the
same level with 96−99% conversions and 89−90% ee (Table 3,
entries 1−4). When the AcOH concentration and amount
were increased, full conversion was observed (Table 3, entry
5). Meanwhile, these four acids were also investigated in
toluene and dioxane, individually. They exhibited similar
performances, and HCl provided the best enantioselectivities
with (R)-2a (Table 3, entries 7 and 11). In addition, there is
trace conversion in the presence of a weak acid, AcOH (Table
3, entries 9, 13). Better conversion can be obtained when more
HCl was added to the reaction system (59% conversion, 93%
ee, Table 3, entry 11 vs entry 14). In order to achieve both full
conversion and high enantioselectivity, mixed preferential
solvents of toluene and dioxane were investigated (Table 3,
entries 15−17). A mixture solvent of toluene/dioxane (v/v =
8:2) proved to be the best choice as a reaction solvent (>99%
conversion, 92% ee, Table 3, entry 16).
Substrate Scope Study. With the two optimized reaction
conditions in hand, we explored the substrate scope and
generality of the Ir/N−Me-Zhaophos-catalyzed asymmetric
hydrogenation in EtOH and in the mixed solvents of toluene
and dioxane, respectively, to access both enantiomers. This
asymmetric catalytic methodology provided an efficient way to
realize the synthesis of both enantiomers of chiral 1,2,3,4-
tetrahydroquinolines, promoted by the same catalyst in
different solvents. These reaction results are summarized in
Scheme 2. A series of 2-aryl-substituted quinolines could be
hydrogenated smoothly to give the desired products in high
yields, along with good to excellent enantioselectivities
(toluene and dioxane solvent system: 86−98% yields, 81−
98% ee; EtOH solvent system: 94−99% yields, 80−94% ee).
For most 2-aryl-substituted quinoline substrates, the introduc-
tion of substituents with different electronic properties and
positions on the phenyl ring had little effect on the reactivity
and ee value, which are compatible in these two reaction
systems. Interestingly, 2-(o-tolyl)quinoline 1b gave the product
2b in full conversion, 96% yield and 98% ee in the toluene and
dioxane mixed solvent, while only 80% ee was achieved in the
EtOH system. The 2-naphthyl-substituted substrate 1o also
worked well in both reaction solvent systems with 92% ee and
90% ee, respectively. The challenging heteroaromatic substrate
2-(thiophen-3-yl)quinoline 1p also displayed high reactivities
and good enantioselectivities. The alkyl substrate 2-methyl-
quinoline 1q was hydrogenated smoothly, resulting in
moderate enantioselectivity in the toluene and dioxane mixed
solvent (77% ee), unfortunately, with poor enantioselectivity in
EtOH (23% ee). Moreover, we further inspected the effect of
different substituted groups on the benzene ring; substituted 2-
phenylquinolines (1r−1u) were employed in this asymmetric
hydrogenation. They are generally suitable reaction partners in
both systems, affording the corresponding enantiomeric
hydrogenation products in high yields and good to excellent
enantioselectivities (toluene and dioxane solvent system: 91−
98% yield, 81−94% ee; EtOH solvent system: 92−97% yield,
91−93% ee). It is slightly strange that the substrate 2-(3,4-
dimethoxyphenyl)-6-fluoro-quinoline 1v nearly could not
undergo this transformation in the toluene and dioxane
mixed solvent, while it was hydrogenated well in EtOH to
access product 2v with full conversion, 98% yield and 94% ee.
In addition, several functionalized 2-substituted quinoline
substrates, such as ethyl quinoline-2-carboxylate (1w), 2-
(phenylethynyl)quinoline (1x), and (E)-2-styrylquinoline
(1y), were also investigated in this hydrogenation under
optimized reaction conditions. It is noteworthy that ethyl
quinoline-2-carboxylate (1w) was hydrogenated well in these
two reaction systems, affording the corresponding hydro-
genation product (2w) with the same configuration in full
conversion, high yields, and moderate enantioselectivities (95%
yield and 65% ee in the toluene and dioxane mixed solvent and
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a
Scheme 2. Substrate Scope Study for Ir-Catalyzed Asymmetric Hydrogenation of 2-Substituted Quinolines
a
Condition A: 0.1 mmol substrate 1, 1.0 mol % [Ir(COD)Cl]2/L2, H2 (50 atm), 1.0 mL toluene/dioxane = 8/2, room temperature, 24 h, HCl (0.2
M in dioxane, 0.2 equiv); condition B: 0.1 mmol substrate 1, 1.0 mol % [Ir(COD)Cl]2/L2, H2 (50 atm), 1.0 mL EtOH, room temperature, 12 h,
HOAc (4 M in EtOH, 0.2 equiv). Conversion was determined by 1H NMR analysis. Yield was isolated yield. Ee was determined by chiral HPLC
i
analysis. (b) 0.1 equiv HCl. (c) Dioxane instead of toluene/dioxane = 8:2. (d) 48 h. (e) 24 h. (f) PrOH instead of EtOH.
94% yield and 79% ee in EtOH). It is possible that the ester
group in ethyl quinoline-2-carboxylate as the hydrogen-
bonding acceptor group may interrupt the interaction between
the quinoline ring and the ligand. Unfortunately, 2-
(phenylethynyl)quinoline (1x) did not work, and no reaction
was observed. The alkenyl group of (E)-2-styrylquinoline (1y)
may be partly reduced, which led to mess reaction systems.
Promoted by the success in Ir-catalyzed enantioselective
hydrogenation of a variety of 2-substituted quinolines, we then
focused on the further exploration of the substrate scope with
more challenging 2,3-disubstituted quinolines (see the
optimized reaction conditions in Supporting Information).
As shown in Table 4, a range of different 2,3-disubstituted
quinolines were subjected to enantioselective hydrogenation in
our catalytic system, which led to the desired products chiral
cis-1,2,3,4-tetrahydroquinolines with full conversions, 95−98%
yields, >25:1 dr, and 89−92% ee. We found that the 3-methyl
(3a), ethyl (3b), or n-propyl (3c) 2-phenyl-substituted
quinoline substrates were well tolerated and proceeded
efficiently to obtain desired products (4a−4c) with high yields
and excellent stereoselectivities (95−98% yields, >25:1 dr, and
92% ee, Table 4, entries 1−3). Moreover, we also examined
the substituent on the phenyl ring (3d), which had a little
influence on the control of the enantioselectivities, and 97%
yield, >25:1 dr, and 89% ee were obtained (Table 4, entry 4).
Table 4. Substrate Scope Study for Ir-Catalyzed Asymmetric
Hydrogenation of 2,3-Disubstituted Quinolines
a
b
c
d
entry
R
R′
4
yield (%)
cis/trans (%)
ee (%)
1
2
3
4
Ph
Ph
Ph
Me
Et
4a
4b
4c
4d
98
97
95
97
>25:1
>25:1
>25:1
>25:1
92
92
92
89
nPr
4-Me-Ph
Me
a
Reaction conditions: 0.1 mmol substrate 3, 1.0 mol % [Ir(COD)-
Cl]2/L2, H2 (80 atm), 1.0 mL THF, 15 °C, HCl (0.1 M in dioxane,
b
c
0.1 equiv), and 24 h. Yield is isolated yield. The conversion and cis/
trans value were determined by H NMR analysis. Ee value was
d
1
determined by HPLC analysis using a chiral stationary phase.
Mechanism Investigation. As mentioned above, the cis-
hydrogenation products were obtained with 2,3-disubstituted
quinolines as the substrates. According to the high cis-
selectivity of hydrogenation products, we speculated that the
substrate 2,3-disubstituted quinolines may undergo 1,4-hydride
addition to give an enamine intermediate int-I. It should be
easily isomerized to form a chiral imine intermediate int-II/II′
similar to the process of dynamic kinetic resolution in a chiral
environment, which was then hydrogenated to generate cis-
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Scheme 3. Possible Hydrogenation Process of 2,3-Disubstituted Quinolines
Scheme 4. Possible Reaction Pathway of Sequential 1,2-Hydride Addition/3,4-Hydride Addition and Control Experiments
Scheme 5. Possible Reaction Pathway of Sequential 1,4-Hydride Addition/Isomerization/1,2-Hydride Addition and Control
Experiments
products (Scheme 3). Meanwhile, it also has the possibility
that the intermediate int-I could be hydrogenated directly to
give the cis-products.
line 2a with moderate enantioselectivity. In addition, we found
that compound 1,2-dihydroquinoline 5 seemed to go through a
similar disproportionation process without H2, resulting in the
formation of aromatic quinoline 1a and tetrahydroquinoline
2a. To avoid this transformation, the N-benzoyl compound 6
was prepared and then was employed in this reduction. It was
found as an inactive substrate under the same reaction
conditions, and the CC bond could not be reduced by
using this iridium catalyst. According to these results, this
hydrogenation pathway possessed much less possibility for our
catalytic system.
The reduction of quinoline has always been involved in the
sequential hydrogenation sequence of CC and CN bonds.
As shown in Scheme 4a, one possible pathway is 1,2-hydride
addition followed by 3,4-hydride addition. In order to verify
this pathway, we synthesized the 1,2-hydride addition
intermediate 1,2-dihydroquinoline 5, and it was applied to
these two catalytic systems, which provided both 2-phenyl-
quinoline 1a and the hydrogenation product tetrahydroquino-
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Scheme 6. Deuterium-Labeling Experiments
Scheme 7. Gram-Scale Ir-Catalyzed Asymmetric Hydrogenation of Quinolines
In addition, this hydrogenation may follow another pathway
with sequential 1,4-hydride addition to generate enamine first,
and then isomerized to an imine intermediate, which went
through a 1,2-hydride addition (Scheme 5). We prepared the
intermediate 3,4-dihydroquinoline 7, which was hydrogenated
well in the two solvent system to access both enantiomers of
the desired product 2a. Nearly same enantioselectivities and
reactivities were obtained with the above model quinoline
substrate 1a. All these observations indicated that compound 7
may be involved in this catalytic cycle, and this hydrogenation
pathway may be preferred through the sequential 1,4-hydride
addition/isomerization/1,2-hydride addition.
intermediate and the hydrogenation product were found in
spectra C and D, which demonstrated their existence in these
reaction systems. Moreover, the reaction mixture in toluene
and dioxane was further investigated by ESI-MS in the
positive-ion mode, and the signal peaks of substrate 1a·H+ (m/
z 206.0964), imine intermediate 7·H+ (m/z 208.1099), and
hydrogenation product 2a·H+ (m/z 210.1276) were observed.
These wonderful observations are in accordance with the
process of 1,4-hydride addition/isomerization/1,2-hydride
addition demonstrated in Scheme 5.
A series of isotope-labeling experiments were conducted to
further confirm the above possible hydrogenation pathway
(Scheme 6). The Ir-catalyzed asymmetric hydrogenation of
quinoline was first performed under 50 atm H2 in toluene/
dioxane in the presence of DCl/D2O solution, and the
hydrogenation product almost without deuterium atoms was
obtained (Scheme 6a). In addition, the hydrogenation reaction
was repeated under 15 atm D2 in these two reaction systems,
respectively. We found that the desired products were
To further verify the existence of imine intermediate 7 in the
1
hydrogenation process, H NMR spectroscopy and electro-
spray ionization-mass spectrometry (ESI-MS) were combined
1
to characterize it. H NMR spectra of hydrogenation product
2a, imine intermediate 7, and the reaction mixture of two
systems are successively listed as A−D (see Supporting
Information). As expected, the proton signals of the imine
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Authors
deuterium-incorporated at 2-, 3-, and 4-positions (Scheme
6b,c). In the toluene/dioxane system, hydrogenation product
(R)-2a-D with >95% deuterium incorporation at 2- and 3-
positions and part-deuterium incorporation at the 4-position
was obtained; meanwhile, the hydrogenation product (S)-2a-
D′ with >95% deuterium incorporation at 1- and 2-positions
and part-deuterium incorporation at 3- and 4-positions was
obtained in CH3OD, which demonstrated that they may go
through different reaction transition states.
Zhengyu Han − Engineering Research Center of Organosilicon
Compounds & Materials, Ministry of Education, College of
Chemistry and Molecular Sciences, Wuhan University,
Wuhan, Hubei 430072, P. R. China
Gang Liu − Engineering Research Center of Organosilicon
Compounds & Materials, Ministry of Education, College of
Chemistry and Molecular Sciences, Wuhan University,
Wuhan, Hubei 430072, P. R. China
Xuanliang Yang − Engineering Research Center of
Organosilicon Compounds & Materials, Ministry of
Education, College of Chemistry and Molecular Sciences,
Wuhan University, Wuhan, Hubei 430072, P. R. China
Synthetic Utility. In order to demonstrate the scalability
and utility of the present methodology, the gram-scale
synthesis of (R) or (S)-2-phenyl-1,2,3,4-tetrahydroquinoline
2a was efficiently realized in the presence of low-catalyst
loading with good reactivity and excellent enantioselectivity
(Scheme 7a,b, toluene and dioxane: 68% conversion, 64%
yield, 91% ee, TON = 680; EtOH: 84% conversion, 82% yield,
90% ee, TON = 1680). Meanwhile, 2 mmol-scale reduction of
2,3-disubstituted quinoline 3-methyl-2-phenylquinoline 3a was
also achieved in moderate conversion with excellent diaster-
eoselectivity and enantioselectivity (56% conversion, 55%
yield, 91% ee, TON = 1120, Scheme 7c).
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c01353
Author Contributions
∥Z.H. and G.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
CONCLUSIONS
■
We are grateful for financial support from the National Natural
Science Foundation (grant no. 22071187), the Natural Science
Foundation of Jiangsu Province (grant no. BK20190213), and
Guangdong Provincial Key Laboratory of Catalysis (grant no.
2020B121201002). The Program of Introducing Talents of
Discipline to Universities of China (111 Project) is also
appreciated. We are grateful to the High Performance
Computing Center of Southern University of Science and
Technology for doing the numerical calculations in this paper
on its blade cluster system.
In summary, a solvent-controlled highly enantioselective Ir-
catalyzed asymmetric hydrogenation of quinolines was
developed. The enantiodivergent synthesis of chiral tetrahy-
droquinolines could be more facilely realized by adjustment of
the solvents (toluene/dioxane: up to 99% yield, 98% ee (R),
TON = 680; EtOH: up to 99% yield, 94% ee (S), TON =
1680). This study would provide an efficient method for the
preparation of compounds of biological interest such as chiral
tetrahydroquinolines. Gram-scale asymmetric hydrogenation
easily proceeded in the presence of low-catalyst loading.
According to the results of deuterium-labeling experiments,
REFERENCES
1
■
control experiments, H NMR, and ESI-MS experiments, a
(1) (a) Noyori, R. Asymmetric Catalysis: Science and Opportunities
(Nobel Lecture) Copyright The Nobel Foundation 2002. We thank
the Nobel Foundation, Stockholm, for permission to print this lecture.
Angew. Chem., Int. Ed. 2002, 41, 2008−2022. (b) Berkessel, A.;
Gröger, H.. Cycloaddition Reactions. In Asymmetric Organocatalysis:
From Biomimetic Concepts to Applications in Asymmetric Synthesis;
Wiley-VCH: Weinheim, 2005; pp 256−268. (c) Kagan, H. B.
Organocatalytic Enantioselective Reduction of Olefins, Ketones, and
Imines. In Enantioselective Organocatalysis: Reactions and Experimental
Procedures; Dalko, P. I., Ed.; Wiley-VCH: New York, 2007; Chapter
11, pp 391−401. (d) Hartwig, J. F. Organotransition Metal Chemistry:
from Bonding to Catalysis; University Science Books, 2010; p xxxii-
1128. (e) Xu, L.; Wu, X.; Xiao, J. Stereoselective Reduction of Imino
Groups. In Science of Synthesis: Stereoselective Synthesis; de Vries, J. G.,
Evans, P. A., Molander, G. A., Eds.; Thieme Chemistry, 2011; Vol. 2,
pp 251−309. (f) Hiersemann, M.; Jaschinski, T. 2.21 Selected
Diastereoselective Reactions: Diastereoface-Differentiating Claisen,
Cope, and [2,3]-Wittig Rearrangements in Contemporary Natural
Product Synthesis. In Comprehensive Chirality; Carreira, E. M.,
Yamamoto, H., Eds.; Elsevier: Amsterdam, 2012; Vol. 2, pp 625−
647. (g) Mase, N. Enamine Catalysis of Michael Reactions. In Science
of Synthesis: Asymmetric Organocatalysis; List, B.; Maruoka, K., Ed.;
Thieme: Stuttgart, Germany, 2012; pp 135−216. (h) Jakab, G.;
Schreiner, P. R. Brønsted Acids: Chiral (Thio)urea Derivatives. In
Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions,
and Applications; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2013;
Chapter 12, pp 315−341.
reasonable and possible reaction pathway was provided for
illustration. The reaction results presented here clearly indicate
that the solvent is a very important parameter in asymmetric
synthesis.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c01353.
Experimental procedures and compound characteriza-
tion data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Xiu-Qin Dong − Engineering Research Center of Organosilicon
Compounds & Materials, Ministry of Education, College of
Chemistry and Molecular Sciences, Wuhan University,
Wuhan, Hubei 430072, P. R. China; Suzhou Institute of
Wuhan University, Suzhou, Jiangsu 215123, P. R. China;
orcid.org/0000-0002-5045-1198; Email: xiuqindong@
whu.edu.cn
Xumu Zhang − Guangdong Provincial Key Laboratory of
Catalysis and Department of Chemistry, Southern University
of Science and Technology, Shenzhen, Guangdong 518055, P.
R. China; orcid.org/0000-0001-5700-0608;
Email: zhangxm@sustech.edu.cn
(2) (a) Wang, B.; Wu, F.; Wang, Y.; Liu, X.; Deng, L. Control of
Diastereoselectivity in Tandem Asymmetric Reactions Generating
Nonadjacent Stereocenters with Bifunctional Catalysis by Cinchona
Alkaloids. J. Am. Chem. Soc. 2007, 129, 768−769. (b) Krautwald, S.;
7288
https://doi.org/10.1021/acscatal.1c01353
ACS Catal. 2021, 11, 7281−7291

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Enantio- and
Diastereodivergent Dual Catalysis: α-Allylation of Branched Alde-
hydes. Science 2013, 340, 1065−1068. (c) Schindler, C. S.; Jacobsen,
E. N. A New Twist on Cooperative Catalysis. Science 2013, 340,
1052−1053. (d) Shi, S.-L.; Wong, Z. L.; Buchwald, S. L. Copper-
catalysed enantioselective stereodivergent synthesis of amino alcohols.
Nature 2016, 532, 353−356. (e) Huo, X.; He, R.; Zhang, X.; Zhang,
W. An Ir/Zn Dual Catalysis for Enantio- and Diastereodivergent α-
Allylation of α-Hydroxyketones. J. Am. Chem. Soc. 2016, 138, 11093−
11096. (f) Krautwald, S.; Carreira, E. M. Stereodivergence in
Asymmetric Catalysis. J. Am. Chem. Soc. 2017, 139, 5627−5639.
(g) Jiang, X.; Beiger, J. J.; Hartwig, J. F. Stereodivergent Allylic
Substitutions with Aryl Acetic Acid Esters by Synergistic Iridium and
Lewis Base Catalysis. J. Am. Chem. Soc. 2017, 139, 87−90. (h) Cruz,
F. A.; Dong, V. M. Stereodivergent Coupling of Aldehydes and
Alkynes via Synergistic Catalysis Using Rh and Jacobsen’s Amine. J.
Am. Chem. Soc. 2017, 139, 1029−1032. (i) Vasilenko, V.; Blasius, C.
K.; Wadepohl, H.; Gade, L. H. Mechanism-Based Enantiodivergence
in Manganese Reduction Catalysis: A Chiral Pincer Complex for the
Highly Enantioselective Hydroboration of Ketones. Angew. Chem., Int.
Ed. 2017, 56, 8393−8397. (j) Wei, L.; Xu, S.-M.; Zhu, Q.; Che, C.;
Wang, C.-J. Synergistic Cu/Pd Catalysis for Enantioselective Allylic
Alkylation of Aldimine Esters: Access to α,α-Disubstituted α-Amino
Acids. Angew. Chem., Int. Ed. 2017, 56, 12312−12316. (k) Wei, L.;
Zhu, Q.; Xu, S.-M.; Chang, X.; Wang, C.-J. Stereodivergent Synthesis
of α,α-Disubstituted α-Amino Acids via Synergistic Cu/Ir Catalysis. J.
Am. Chem. Soc. 2018, 140, 1508−1513. (l) Wei, L.; Xiao, L.; Wang,
C.-J. Synergistic Cu/Pd Catalysis for Enantioselective Allylation of
Ketimine Esters: The Direct Synthesis of α-Substituted α-Amino
Acids and 2H-Pyrrols. Adv. Synth. Catal. 2018, 360, 4715−4719.
(m) Wei, L.; Zhu, Q.; Xiao, L.; Tao, H.-Y.; Wang, C.-J. Synergistic
Catalysis for Cascade Allylation and 2-Aza-cope Rearrangement of
Azomethine Ylides. Nat. Commun. 2019, 10, 1594−1605. (n) Gao,
T.-T.; Zhang, W.-W.; Sun, X.; Lu, H.-X.; Li, B.-J. Stereodivergent
Synthesis through Catalytic Asymmetric Reversed Hydroboration. J.
Am. Chem. Soc. 2019, 141, 4670−4677. (o) Liu, H.-C.; Hu, Y.-Z.;
Wang, Z.-F.; Tao, H.-Y.; Wang, C.-J. Synergistic Cu/Pd-Catalyzed
Asymmetric Allenylic Alkylation of Azomethine Ylides for the
Construction of α-Allene-Substituted Nonproteinogenic α-Amino
Acids. Chem.Eur. J. 2019, 25, 8681−8685. (p) Agarwal, R.; Liao, Y.;
Lin, D.-J.; Yang, Z.-X.; Lai, C.-F.; Chen, C.-T. Enantiodivergent
reduction of α-keto amides catalyzed by high valent, chiral oxido-
vanadium(v) complexes. Org. Chem. Front. 2020, 7, 2505−2510.
(q) Wu, H.-M.; Zhang, Z.; Xiao, F.; Wei, L.; Dong, X.-Q.; Wang, C.-J.
Stereodivergent Synthesis of α-Quaternary Serine and Cysteine
Derivatives Containing Two Contiguous Stereogenic Centers via
Synergistic Cu/Ir Catalysis. Org. Lett. 2020, 22, 4852−4857.
(3) (a) Seerden, J.-P. G.; Kuypers, M. M. M.; Scheeren, H. W.
Dramatic Solvents Effects on the Enantioselectivity of Chiral
Oxazaborolidine Catalyzed Asymmetric 1,3-Dipolar Cycloadditions
of Nitrones with Ketene Acetals. Tetrahedron: Asymmetry 1995, 6,
1441−1450. (b) Arseniyadis, S.; Valleix, A.; Wagner, A.; Mioskowski,
C. Kinetic Resolution of Amines: A Highly Enantioselective and
Chemoselective Acetylating Agent with a Unique Solvent-Induced
Reversal of Stereoselectivity. Angew. Chem., Int. Ed. 2004, 43, 3314−
3317. (c) Haddad, N.; Qu, B.; Rodriguez, S.; van der Veen, L.;
Reeves, D. C.; Gonnella, N. C.; Lee, H.; Grinberg, N.; Ma, S.;
Krishnamurthy, D.; Wunberg, T.; Senanayake, C. H. Catalytic
Asymmetric Hydrogenation of Heterocyclic Ketone-Derived Hydra-
zones, Pronounced Solvent Effect on the Inversion of Configuration.
Tetrahedron Lett. 2011, 52, 3718−3722. (d) Messerer, M.;
Wennemers, H. Reversing the Enantioselectivity of a Peptidic Catalyst
by Changing the Solvent. Synlett 2011, 4, 499−502. (e) Yu, H.; Xie,
F.; Ma, Z.; Liu, Y.; Zhang, W. The Effects of Solvent on Switchable
Stereoselectivity: Copper-Catalyzed Asymmetric Conjugate Additions
Using D2-Symmetric Biphenyl Phosphoramidite Ligands. Org. Biomol.
Chem. 2012, 10, 5137−5142. (f) Garzan, A.; Jaganathan, A.; Salehi
Marzijarani, N.; Yousefi, R.; Whitehead, D. C.; Jackson, J. E.; Borhan,
B. Solvent-Dependent Enantiodivergence in the Chlorocyclization of
Unsaturated Carbamates. Chem. - Eur. J. 2013, 19, 9015−9021.
(g) Kottala Vijaya, P.; Murugesan, S.; Siva, A. Unexpected Solvent/
Substitution-Dependent Inversion of the Enantioselectivity in Michael
Addition Reaction Using Chiral Phase Transfer Catalysts. Tetrahedron
Lett. 2015, 56, 5209−5212. (h) Flores-Ferrándiz, J.; Fiser, B.; Gómez-
Bengoa, E.; Chinchilla, R. Solvent-Induced Reversal of Enantiose-
lectivity in the Synthesis of Succinimides by the Addition of
Aldehydes to Maleimides Catalysed by Carbamate-Monoprotected
1,2-Diamines. Eur. J. Org. Chem. 2015, 2015, 1218−1225.
(i) Karasawa, T.; Saito, A.; Kumagai, N.; Shibasaki, M. Solvent-
Dependent Enantiodivergence in anti-Selective Catalytic Asymmetric
Nitroaldol Reactions. Org. Lett. 2019, 21, 3581−3583.
(4) (a) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Recent progress in
the synthesis of 1,2,3,4,-tetrahydroquinolines. Tetrahedron 1996, 52,
15031−15070. (b) Sridharan, V.; Suryavanshi, P. A.; Menéndez, J. C.
Advances in the Chemistry of Tetrahydroquinolines. Chem. Rev. 2011,
111, 7157−7259. (c) Nammalwar, B.; Bunce, R. A. Recent Syntheses
of 1,2,3,4-Tetrahydroquinolines, 2,3-Dihydro-4(1H)-quinolinones
and 4(1H)-Quinolinones using Domino Reactions. Molecules 2013,
19, 204−232. (d) Buhr, W.; Chiesa, V. M.; Zimmermann, P. J.;
Brehm, C.; Palmer, A.; Postius, S.; Kromer, W.; Simon, W.-A.; Senn-
Bilfinger, J. Preparation of Benzimidazole Derivatives as Gastric
Secretion Inhibitors. WO 2004087701 A1, 2004. (e) Rano, T.; Kuo,
G.-H.; Sieber-McMaster, E.; Demarest, K. T.; Pelton, P.; Wang, A.
1,2,3,4-Tetrahydro-quinoline Derivatives as CETP Inhibitors. U.S.
Patent 20,070,265,304 A1, 2007. (f) Schiemann, K.; Bruge, D.;
Buchstaller, H.-P.; Emde, U.; Finsinger, D.; Amendt, C.; Zenke, F.
Preparation of Tetrahydroquinolines for Use in the Treatment of
Tumors. DE 102005027168-A1, 2006. (g) Wang, G.; Beigelman, L.
Preparation of Isoxazolyl Compounds as FXR Modulators and
Methods of Their Use. WO 2017147047-A1, 2017. (h) Miller, M.;
Chobanian, H. R. Preparation of Antidiabetic Bicyclic Compounds.
WO 2017172505-A1, 2017.
(5) Greßies, S.; Klauck, F. J. R.; Kim, J. H.; Daniliuc, C. G.; Glorius,
F. Ligand-Enabled Enantioselective Csp3 -H Activation of Tetrahy-
droquinolines and Saturated Aza-Heterocycles by RhI. Angew. Chem.,
Int. Ed. 2018, 57, 9950−9954.
(6) (a) Ren, L.; Lei, T.; Ye, J.-X.; Gong, L.-Z. Step-Economical
Synthesis of Tetrahydroquinolines by Asymmetric Relay Catalytic
̈
Friedlander Condensation/Transfer Hydrogenation. Angew. Chem.,
Int. Ed. 2012, 51, 771−774. (b) Patil, N. T.; Raut, V. S.; Tella, R. B.
Enantioselective cooperative triple catalysis: unique roles of Au(i)/
amine/chiral Brønsted acid catalysts in the addition/cycloisomeriza-
tion/transfer hydrogenation cascade. Chem. Commun. 2013, 49, 570−
572.
(7) (a) Zhang, S.; Wei, F.; Song, C.; Jia, J.; Xu, Z. Recent Advances
of the Combination of Au/Acid Catalysis. Chin. J. Chem. 2014, 32,
937−956. (b) Du, Y.-L.; Hu, Y.; Zhu, Y.-F.; Tu, X.-F.; Han, Z.-Y.;
Gong, L.-Z. Chiral Gold Phosphate Catalyzed Tandem Hydro-
amination/Asymmetric Transfer Hydrogenation Enables Access to
Chiral Tetrahydroquinolines. J. Org. Chem. 2015, 80, 4754−4759.
(8) (a) Wang, D.-S.; Chen, Q.-A.; Lu, S.-M.; Zhou, Y.-G.
Asymmetric Hydrogenation of Heteroarenes and Arenes. Chem. Rev.
2012, 112, 2557−2590. (b) He, Y.-M.; Song, F.-T.; Fan, Q.-H.
Advances in Transition Metal-Catalyzed Asymmetric Hydrogenation
of Heteroaromatic Compounds. Top. Curr. Chem. 2013, 343, 145−
190. (c) Nagano, T.; Iimuro, A.; Yamaji, K.; Kita, Y.; Mashima, K.
Additive Effects on Asymmetric Hydrogenation of N-Heteroaro-
matics. Heterocycles 2014, 88, 103−127. (d) Luo, Y.-E.; He, Y.-M.;
Fan, Q.-H. Asymmetric Hydrogenation of Quinoline Derivatives
Catalyzed by Cationic Transition Metal Complexes of Chiral Diamine
Ligands: Scope, Mechanism and Catalyst Recycling. Chem. Rec. 2016,
16, 2697−2711. (e) Giustra, Z. X.; Ishibashi, J. S. A.; Liu, S.-Y.
Homogeneous Metal Catalysis for Conversion Between Aromatic and
Saturated Compounds. Coord. Chem. Rev. 2016, 314, 134−181.
(f) Wiesenfeldt, M. P.; Nairoukh, Z.; Dalton, T.; Glorius, F. Selective
Arene Hydrogenation for Direct Access to Saturated Carbo- and
Heterocycles. Angew. Chem., Int. Ed. 2019, 58, 10460−10476.
(g) Kim, A. N.; Stoltz, B. M. Recent Advances in Homogeneous
7289
https://doi.org/10.1021/acscatal.1c01353
ACS Catal. 2021, 11, 7281−7291

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
Catalysts for the Asymmetric Hydrogenation of Heteroarenes. ACS
Catal. 2020, 10, 13834−13851.
phine Modified Binaphthyl Palladium Nanoparticles. Catal. Sci.
Technol. 2017, 7, 5515−5520.
(9) Transition-metal catalytic system (a) Tang, J.; Jiang, G.-F.;
Zhou, Y.-G. Convenient Synthesis of Optically Pure 8-Methoxy-2-
Methyl-1,2,3,4-Tetrahydroquinoline and 2-Methyl-1,2,3,4-Tetrahy-
droquinoline. Heterocycles 2010, 82, 887−893. (b) Gou, F.-R.; Li,
W.; Zhang, X.; Liang, Y.-M. Iridium-Catalyzed Asymmetric Hydro-
genation of Quinoline Derivatives with C3*-TunePhos. Adv. Synth.
Catal. 2010, 352, 2441−2444. (c) Tang, W.; Sun, Y.; Lijin Xu, L.;
Wang, T.; Fan, Q.-H.; Lam, K.-H.; Chan, A. S. C. Highly Efficient and
Enantioselective Hydrogenation of Quinolines and Pyridines with Ir-
Difluorphos Catalyst. Org. Biomol. Chem. 2010, 8, 3464−3471.
(d) Wang, T.; Zhuo, L.-G.; Li, Z.; Chen, F.; Ding, Z.; He, Y.; Fan, Q.-
H.; Xiang, J.; Yu, Z.-X.; Chan, A. S. C. Highly Enantioselective
Hydrogenation of Quinolines Using Phosphine-Free Chiral Cationic
Ruthenium Catalysts: Scope, Mechanism, and Origin of Enantiose-
lectivity. J. Am. Chem. Soc. 2011, 133, 9878−9891. (e) Maj, A. M.;
Suisse, I.; Méliet, C.; Hardouin, C.; Agbossou-Niedercorn, F. Highly
Enantioselective Hydrogenation of New 2-Functionalized Quinoline
Derivatives. Tetrahedron Lett. 2012, 53, 4747−4750. (f) Tu, X.-F.;
Gong, L.-Z. Highly Enantioselective Transfer Hydrogenation of
Quinolines Catalyzed by Gold Phosphates: Achiral Ligand Tuning
and Chiral-Anion Control of Stereoselectivity. Angew. Chem., Int. Ed.
2012, 51, 11346−11349. (g) Maj, A. M.; Suisse, I.; Hardouin, C.;
Agbossou-Niedercorn, F. Synthesis of New Chiral 2-Functionalized-
1,2,3,4-Tetrahydroquinoline Derivatives via Asymmetric Hydrogena-
tion of Substituted Quinolines. Tetrahedron 2013, 69, 9322−9328.
(h) Ding, Z. Y.; Wang, T.; He, Y. M.; Chen, F.; Zhou, H. F.; Fan, Q.
H.; Guo, Q.; Chan, A. S. C. Highly Enantioselective Synthesis of
Chiral Tetrahydroquinolines and Tetrahydroisoquinolines by Ruthe-
nium-Catalyzed Asymmetric Hydrogenation in Ionic Liquid. Adv.
Synth. Catal. 2013, 355, 3727−3735. (i) Cai, X.-F.; Guo, R.-N.; Chen,
M.-W.; Shi, L.; Zhou, Y.-G. Synthesis of Chiral Exocyclic Amines by
Asymmetric Hydrogenation of Aromatic Quinolin-3-amines. Chem.
Eur. J. 2014, 20, 7245−7248. (j) Lyubimov, S. E.; Ozolin, D. V.;
Ivanov, P. Y.; Melman, A.; Velezheva, V. S.; Davankov, V. A. The Use
of Phosphite-Type Ligands in the Ir-Catalyzed Asymmetric Hydro-
genation of Heterocyclic Compounds. Chirality 2014, 26, 56−60.
(k) Yang, Z.; Chen, F.; He, Y.-M.; Yang, N.; Fan, Q.-H. Efficient
Asymmetric Hydrogenation of Quinolines in Neat Water Catalyzed
by Chiral Cationic Ru-Diamine Complexes. Catal. Sci. Technol. 2014,
4, 2887−2890. (l) Cai, X.-F.; Huang, W.-X.; Chen, Z.-P.; Zhou, Y.-G.
Palladium-catalyzed asymmetric hydrogenation of 3-phthalimido
substituted quinolines. Chem. Commun. 2014, 50, 9588−9590.
(m) Chen, F.; Ding, Z.-Y.; He, Y.-M.; Fan, Q.-H. Synthesis of
Optically Active 1,2,3,4-Tetrahydroquinolines via Asymmetric Hydro-
genation Using Iridium-Diamine Catalyst. Org. Synth. 2015, 92, 213−
(10) Organocatalytic system (a) Rueping, M.; Antonchick, A. P.;
Theissmann, T. A Highly Enantioselective Brønsted Acid Catalyzed
Cascade Reaction: Organocatalytic Transfer Hydrogenation of
Quinolines and their Application in the Synthesis of Alkaloids.
Angew. Chem., Int. Ed. 2006, 45, 3683−3686. (b) Guo, Q.-S.; Du, D.-
M.; Xu, J. The Development of Double Axially Chiral Phosphoric
Acids and Their Catalytic Transfer Hydrogenation of Quinolines.
Angew. Chem., Int. Ed. 2008, 47, 759−762. (c) Zheng, C.; You, S.-L.
Transfer Hydrogenation with Hantzsch Esters and Related Organic
Hydride Donors. Chem. Soc. Rev. 2012, 41, 2498−2518. (d) Guo, R.-
N.; Chen, Z.-P.; Cai, X.-F.; Zhou, Y.-G. Asymmetric Transfer
Hydrogenation of 3-(Trifluoromethyl)quinolines. Synthesis 2014, 46,
2751−2756. (e) Chen, M.-W.; Cai, X.-F.; Chen, Z.-P.; Shi, L.; Zhou,
Y.-G. Facile Construction of Three Contiguous Stereogenic Centers
via Dynamic Kinetic Resolution in Asymmetric Transfer Hydro-
genation of Quinolines. Chem. Commun. 2014, 50, 12526−12529.
(f) Isaac, K.; Stemper, J.; Servajean, V.; Retailleau, P.; Pastor, J.;
Frison, G.; Kaupmees, K.; Leito, I.; Betzer, J.-F.; Marinetti, A. Planar
Chiral Phosphoric Acids with Biphenylene-tethered Paracyclophane
Scaffolds: Synthesis, Characterization, and Catalytic Screening. J. Org.
Chem. 2014, 79, 9639−9646. (g) Kim, H.; Sugiono, E.; Nagata, Y.;
Wagner, M.; Bonn, M.; Rueping, M.; Hunger, J. Role of Ion-Pairs in
Brønsted Acid Catalysis. ACS Catal. 2015, 5, 6630−6633. (h) More,
G. V.; Bhanage, B. M. Chiral phosphoric acid catalyzed asymmetric
transfer hydrogenation of quinolines in a sustainable solvent.
Tetrahedron: Asymmetry 2015, 26, 1174−1179. (i) Li, G.; Liu, H.;
Lv, G.; Wang, Y.; Fu, Q.; Tang, Z. Enantioselective Organocatalytic
Transfer Hydrogenation of 1,2-Dihydroquinoline through Formation
of Aza-o-xylylene. Org. Lett. 2015, 17, 4125−4127. (j) Zhang, Y.;
Zhao, R.; Bao, R. L.-Y.; Shi, L. Highly Enantioselective SPINOL-
Derived Phosphoric Acid Catalyzed Transfer Hydrogenation of
Diverse C=N-Containing Heterocycles. Eur. J. Org. Chem. 2015,
2015, 3344−3351. (k) Zhou, J.; Zhang, Q.-F.; Zhao, W.-H.; Jiang, G.-
F. Chiral Phosphoric Acid-Catalyzed Asymmetric Transfer Hydro-
genation of 3-Trifluoromethylthioquinolines. Org. Biomol. Chem.
2016, 14, 6937−6941. (l) Zhao, X.; Xiao, J.; Tang, W.
Enantioselective Reduction of 3-Substituted Quinolines with a
Cyclopentadiene-Based Chiral Brønsted Acid. Synthesis 2017, 49,
3157−3164.
(11) (a) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-
G. Highly Enantioselective Iridium-Catalyzed Hydrogenation of
Heteroaromatic Compounds, Quinolines. J. Am. Chem. Soc. 2003,
125, 10536−10537. (b) Lam, K. H.; Xu, L.; Feng, L.; Fan, Q.-H.;
Lam, F. L.; Lo, W.-h.; Chan, A. S. C. Highly Enantioselective Iridium-
Catalyzed Hydrogenation of Quinoline Derivatives Using Chiral
Phosphinite H8-BINAPO. Adv. Synth. Catal. 2005, 347, 1755−1758.
(c) Reetz, M. T.; Li, X. Asymmetric Hydrogenation of Quinolines
Catalyzed by Iridium Complexes of BINOL-Derived Diphosphonites.
Chem. Commun. 2006, 2159−2160. (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.
Asymmetric Hydrogenation of Quinolines with High Substrate/
Catalyst ratio. Chem. Commun. 2007, 613−615. (e) Deport, C.;
Buchotte, M.; Abecassis, K.; Tadaoka, H.; Ayad, T.; Ohshima, T.;
Genet, J.-P.; Mashima, K.; Ratovelomanana-Vidal, V. Novel Ir-
SYNPHOS® and Ir-DIFLUORPHOS® Catalysts for Asymmetric
Hydrogenation of Quinolines. Synlett 2007, 17, 2743−2747.
́
̃
226. (n) Balakrishna, B.; Nunez-Rico, J. L.; Vidal-Ferran, A. Substrate
Activation in the Catalytic Asymmetric Hydrogenation of N-
Heteroarenes. Eur. J. Org. Chem. 2015, 2015, 5293−5303. (o) John,
J.; Wilson-Konderka, C.; Metallinos, C. Low Pressure Asymmetric
Hydrogenation of Quinolines using an Annulated Planar Chiral N-
Ferrocenyl NHC-Iridium Complex. Adv. Synth. Catal. 2015, 357,
2071−2081. (p) Kuwano, R.; Ikeda, R.; Hirasada, K. Catalytic
Asymmetric Hydrogenation of Quinoline Carbocycles: Unusual
Chemoselectivity in the Hydrogenation of Quinolines. Chem.
Commun. 2015, 51, 7558−7561. (q) Wang, T.; Chen, Y.; Ouyang,
G.; He, Y.-M.; Li, Z.; Fan, Q.-H. Solvent-Regulated Asymmetric
Hydrogenation of Quinoline Derivatives in Oligo(Ethylene Glycol)s
through Host-Guest Interactions. Chem.Asian J. 2016, 11, 2773−
2777. (r) Wen, J.; Tan, R.; Liu, S.; Zhao, Q.; Zhang, X. Strong
Brønsted acid promoted asymmetric hydrogenation of isoquinolines
and quinolines catalyzed by a Rh-thiourea chiral phosphine complex
via anion binding. Chem. Sci. 2016, 7, 3047−3051. (s) Kubota, K.;
Watanabe, Y.; Ito, H. Synthesis of Enantiomerically Enriched Chiral
Tetrahydroquinolines via Sequential Dearomatization/Enantioselec-
tive Borylation Reactions. Adv. Synth. Catal. 2016, 358, 2379−2384.
(t) Xia, Y.-T.; Ma, J.; Wang, X.-D.; Yang, L.; Wu, L. Enantioselective
Hydrogenation of N-Heteroaromatics Catalyzed by Chiral Diphos-
̌
́
(f) Mrsic, N.; Lefort, L.; Boogers, J. A. F.; Minnaard, A. J.; Feringa,
B. L.; de Vries, J. G. Asymmetric Hydrogenation of Quinolines
Catalyzed by Iridium Complexes of Monodentate BINOL-Derived
Phosphoramidites. Adv. Synth. Catal. 2008, 350, 1081−1089.
(g) Wang, X.-B.; Zhou, Y.-G. Synthesis of Tunable Bisphosphine
Ligands and Their Application in Asymmetric Hydrogenation of
Quinolines. J. Org. Chem. 2008, 73, 5640−5642. (h) Li, Z.-W.; Wang,
T.-L.; He, Y.-M.; Wang, Z.-J.; Fan, Q.-H.; Pan, J.; Xu, L.-J. Air-Stable
and Phosphine-Free Iridium Catalysts for Highly Enantioselective
Hydrogenation of Quinoline Derivatives. Org. Lett. 2008, 10, 5265−
5268. (i) Tadaoka, H.; Cartigny, D.; Nagano, T.; Gosavi, T.; Ayad, T.;
7290
https://doi.org/10.1021/acscatal.1c01353
ACS Catal. 2021, 11, 7281−7291

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
̂
Genet, J.-P.; Ohshima, T.; Ratovelomanana-Vidal, V.; Mashima, K.
2147. (k) Liu, G.; Li, A.; Qin, X.; Han, Z.; Dong, X. Q.; Zhang, X.
Efficient Access to Chiral β-Borylated Carboxylic Esters via Rh-
Catalyzed Hydrogenation. Adv. Synth. Catal. 2019, 361, 2844−2848.
(l) Liu, G.; Zhang, H.; Huang, Y.; Han, Z.; Liu, G.; Liu, Y.; Dong, X.-
Q.; Zhang, X. Efficient synthesis of chiral 2,3-dihydro-benzo[b]-
thiophene 1,1-dioxides via Rh-catalyzed hydrogenation. Chem. Sci.
2019, 10, 2507−2512. (m) Han, Z.; Liu, G.; Wang, R.; Dong, X.-Q.;
Zhang, X. Highly efficient Ir-catalyzed asymmetric hydrogenation of
benzoxazinones and derivatives with a Brønsted acid cocatalyst. Chem.
Sci. 2019, 10, 4328−4333. (n) Zhao, Q.; Chen, C.; Wen, J.; Dong, X.-
Q.; Zhang, X. Noncovalent Interaction-Assisted Ferrocenyl Phosphine
Ligands in Asymmetric Catalysis. Acc. Chem. Res. 2020, 53, 1905−
1921. (o) Yang, T.; Sun, Y.; Wang, H.; Lin, Z.; Wen, J.; Zhang, X.
Iridium-Catalyzed Enantioselective Hydrogenation of Oxocarbenium
Ions: A Case of Ionic Hydrogenation. Angew. Chem., Int. Ed. 2020, 59,
6108−6114.
Unprecedented Halide Dependence on Catalytic Asymmetric Hydro-
genation of 2-Aryl- and 2-Alkyl-Substituted Quinolinium Salts by
Using Ir Complexes with Difluorphos and Halide Ligands. Chem.
Eur. J. 2009, 15, 9990−9994. (j) Wang, D.-S.; Zhou, Y.-G.
Asymmetric hydrogenation of quinolines activated by Brønsted
acids. Tetrahedron Lett. 2010, 51, 3014−3017. (k) Tang, W.-J.; Tan,
J.; Xu, L.-J.; Lam, K.-H.; Fan, Q.-H.; Chan, A. S. C. Highly
Enantioselective Hydrogenation of Quinoline and Pyridine Deriva-
tives with Iridium-(P-Phos) Catalyst. Adv. Synth. Catal. 2010, 352,
1055−1062. (l) Zhang, D.-Y.; Yu, C.-B.; Wang, M.-C.; Gao, K.; Zhou,
Y.-G. A new electronically deficient atropisomeric diphosphine ligand
(S)-CF3O-BiPhep and its application in asymmetric hydrogenation.
Tetrahedron Lett. 2012, 53, 2556−2559. (m) Chen, Q.-A.; Gao, K.;
Duan, Y.; Ye, Z.-S.; Shi, L.; Yang, Y.; Zhou, Y.-G. Dihydrophenan-
thridine: A New and Easily Regenerable NAD(P)H Model for
Biomimetic Asymmetric Hydrogenation. J. Am. Chem. Soc. 2012, 134,
2442−2448. (n) Hu, X.-H.; Hu, X.-P. Highly Diastereo- and
Enantioselective Ir-Catalyzed Hydrogenation of 2,3-Disubstituted
Quinolines with Structurally Fine-Tuned Phosphine-Phosphoramidite
Ligands. Org. Lett. 2019, 21, 10003−10006. (o) Wang, J.; Zhao, Z.-B.;
Zhao, Y.; Luo, G.; Zhu, Z.-H.; Luo, Y.; Zhou, Y.-G. Chiral and
Regenerable NAD(P)H Models Enabled Biomimetic Asymmetric
Reduction: Design, Synthesis, Scope, and Mechanistic Studies. J. Org.
Chem. 2020, 85, 2355−2368. (p) Sun, S.; Nagorny, P. Exploration of
Chiral Diastereomeric Spiroketal (SPIROL)-Based Phosphinite
Ligands in Asymmetric Hydrogenation of Heterocycles. Chem.
Commun. 2020, 56, 8432−8435.
(14) Liao, H.-H.; Hsiao, C.-C.; Sugiono, E.; Rueping, M. Shedding
light on Brønsted acid catalysis - a photocyclization-reduction reaction
for the asymmetric synthesis of tetrahydroquinolines from amino-
chalcones in batch and flow. Chem. Commun. 2013, 49, 7953−7955.
(12) (a) Knowles, R. R.; Jacobsen, E. N. Attractive Noncovalent
Interactions in Asymmetric Catalysis: Links Between Enzymes and
Small Molecule Catalysts. Proc. Natl. Acad. Sci. U.S.A. 2010, 107,
20678−20685. (b) Wu, H.; He, Y. P.; Gong, L. Z. Cooperation of
Transition Metals and Chiral Brønsted Acids in Asymmetric Catalysis.
In Cooperative Catalysis: Designing Efficient Catalysts for Synthesis;
Peters, R., Ed.; Wiley-VCH: Weinheim, 2015; Chapter 6, pp 171−
196.
(13) Selected examples (a) Zhao, Q.; Li, S.; Huang, K.; Wang, R.;
Zhang, X. A Novel Chiral Bisphosphine-Thiourea Ligand for
Asymmetric Hydrogenation of β,β-Disubstituted Nitroalkenes. Org.
Lett. 2013, 15, 4014−4017. (b) Zhao, Q.; Wen, J.; Tan, R.; Huang,
K.; Metola, P.; Wang, R.; Anslyn, E. V.; Zhang, X. Rhodium-Catalyzed
Asymmetric Hydrogenation of Unprotected NH Imines Assisted by a
Thiourea. Angew. Chem., Int. Ed. 2014, 53, 8467−8470. (c) Li, P.;
Zhou, M.; Zhao, Q.; Wu, W.; Hu, X.; Dong, X.-Q.; Zhang, X.
Synthesis of Chiral β-Amino Nitroalkanes via Rhodium-Catalyzed
Asymmetric Hydrogenation. Org. Lett. 2016, 18, 40−43. (d) Wen, J.;
Jiang, J.; Zhang, X. Rhodium-Catalyzed Asymmetric Hydrogenation
of α,β-Unsaturated Carbonyl Compounds via Thiourea Hydrogen
Bonding. Org. Lett. 2016, 18, 4451−4453. (e) Han, Z.; Li, P.; Zhang,
Z.; Chen, C.; Wang, Q.; Dong, X.-Q.; Zhang, X. Highly
Enantioselective Synthesis of Chiral Succinimides via Rh/Bisphos-
phine-Thiourea-Catalyzed Asymmetric Hydrogenation. ACS Catal.
2016, 6, 6214−6218. (f) Li, P.; Huang, Y.; Hu, X.; Dong, X.-Q.;
Zhang, X. Access to Chiral Seven-Member Cyclic Amines via Rh-
Catalyzed Asymmetric Hydrogenation. Org. Lett. 2017, 19, 3855−
3858. (g) Liu, G.; Han, Z.; Dong, X.-Q.; Zhang, X. Rh-Catalyzed
Asymmetric Hydrogenation of β-Substituted-β-thio-α,β-unsaturated
Esters: Expeditious Access to Chiral Organic Sulfides. Org. Lett. 2018,
20, 5636−5639. (h) Huang, Y.; Li, P.; Dong, X.-Q.; Zhang, X.
Synthesis of chiral seven-membered β-substituted lactams via Rh-
catalyzed asymmetric hydrogenation. Org. Biomol. Chem. 2018, 16,
8819−8823. (i) Yin, X.; Huang, Y.; Chen, Z.; Hu, Y.; Tao, L.; Zhao,
Q.; Dong, X.-Q.; Zhang, X. Enantioselective Access to Chiral 2-
Substituted 2,3-Dihydrobenzo[1,4]dioxane Derivatives through Rh-
Catalyzed Asymmetric Hydrogenation. Org. Lett. 2018, 20, 4173−
4177. (j) Wen, J.; Fan, X.; Tan, R.; Chien, H.-C.; Zhou, Q.; Chung, L.
W.; Zhang, X. Brønsted-Acid-Promoted Rh-Catalyzed Asymmetric
Hydrogenation of N-Unprotected Indoles: A Cocatalysis of
Transition Metal and Anion Binding. Org. Lett. 2018, 20, 2143−
7291
https://doi.org/10.1021/acscatal.1c01353
ACS Catal. 2021, 11, 7281−7291