Enantioselective Reduction of 3-Substituted Quinolines with a Cyclopentadiene-Based Chiral Br?nsted Acid

Article abstract of DOI:10.1055/s-0036-1589012

Enantioselective reduction of 3-substituted quinolines has been achieved using a cyclopentadiene-based chiral Bronsted acid as catalyst and Hantzsch ester as hydrogen donor, affording the corresponding tetrahydroquinolines in good enantioselectivities.

Full text of DOI:10.1055/s-0036-1589012

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
paper
A
en
X. Zhao et al.
Paper
Synthesis
Enantioselective Reduction of 3-Substituted Quinolines with a
Cyclopentadiene-Based Chiral Brønsted Acid
Xiaofang Zhaoa
Jianliang Xiaoa,b
Weijun Tang*a
Me
iPr
Me
0
0
0
0
0-
0
0
3
3-
2
4
5
4-
7
6
3
O
EtO2C
R
CO2Et
O
OH
iPr
iPr
a Key Laboratory of Applied Surface and Colloid Chemistry
of Ministry of Education, and School of Chemistry &
Chemical Engineering, Shaanxi Normal University, Xi’an,
710119, P. R. of China
tangwj@snnu.edu.cn
b Department of Chemistry, University of Liverpool, Liver-
pool, L69 7ZD, UK
O
O
O
N
H
iPr
R
∗
O
(2.4 equiv)
O
cat. (5 mol%), toluene
O
Me
N
H
Me
N
O
25 °C, 8 h
iPr
22 examples
isolated yield: 57–88%
ee value: 16–75%
R = Me, Et, Pr, Bu, Bn,
cyclohexyl, Ph, Ar,
thiophenyl
Me
catalyst
Received: 04.02.2017
Accepted after revision: 29.03.2017
Published online: 08.05.2017
then 1,2-dihydride addition.9i Therefore, the asymmetric
reduction of 3-substituted quinolines has become a chal-
lenging task. The first example of asymmetric transfer hy-
drogenation of 3-substituted quinolines was reported by
Rueping in 2008, using a chiral phosphoric acid with a
Hantzsch ester as the hydrogen donor;11b moderate enanti-
oselectivities and yields were achieved. The chirality is like-
ly to be induced via a good chiral environment created by
the chiral phosphoric acid in the proton transfer process.
Very recently, an example of highly enantioselective trans-
fer hydrogenation of 3-tosylamide quinoline was report-
ed.11l Hydrogen bonding between the substrate and chiral
phosphoric acid may be responsible for the results. Consid-
ering the importance of chiral 3-substituted tetrahydro-
quinolines, pursuing the synthesis of such compounds is
still an interesting topic. Herein, we report our results on
the asymmetric reduction of 3-substituted quinolines via
transfer hydrogenation using chiral Brønsted acids.
DOI: 10.1055/s-0036-1589012; Art ID: ss-2017-h0073-op
Abstract Enantioselective reduction of 3-substituted quinolines has
been achieved using a cyclopentadiene-based chiral Brønsted acid as
catalyst and Hantzsch ester as hydrogen donor, affording the corre-
sponding tetrahydroquinolines in good enantioselectivities.
Key words tetrahydroquinolines, transfer hydrogenation, 3-substitut-
ed quinolones, enantioselectivity, chiral Brønsted acid
Chiral 3-substituted tetrahydroquinolines are important
structural units in a number of natural products and a wide
variety of biologically active compounds and pharmaceuti-
cals.1 For example, (21S)-argatroban is a synthetic peptido-
mimetic small molecule, serving as an antithrombotic
drug;2 API 1 is a peptide-like drug for treating diabetes;3
(–)-sumanirole is a potential drug for the treatment of
Parkinson’s disease and restless leg syndrome;4 JNJ-
26076713 is a αvβ3/αvβ5 integrin antagonist for the treat-
ment of eye disease (Figure 1).5 The chirality of these com-
pounds plays very important role in the relevant bioactivi-
ties. Therefore, it is highly desirable to develop efficient
methods to prepare these chiral heterocycles.
O
NH
Cl
HOOC
N
N
N
NH2
H
N
HN
O
O
S
O
H
N
N
NH HN
O
Since the pioneering work reported by Zhou in 2003,6
some exciting advances have been achieved in transition-
metal-catalyzed asymmetric hydrogenation and transfer
hydrogenation of quinoline derivatives.7–12 Using the re-
ported methods, excellent enantioselectivities have been
achieved for 2-substituted and 2,3-disubstituted quinoline
derivatives. However, in sharp contrast, asymmetric hydro-
genation of 3-substituted quinolines is not yet successful,
with one example giving a racemic mixture.9i This is not
unexpected, since the mechanism shows a reduction path-
way involving 1,4-dihydride addition, isomerization, and
21
N
O
(21S)-Argatroban
API 1
O
CO2H
N
O
H3C
N
NH
N
N
H
N
NH
H3C
(–)-Sumanirole
JNJ-26076713
Figure 1 Some examples of chiral 3-substituted tetrahydroquinolines
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
X. Zhao et al.
Paper
Synthesis
Very recently, a novel chiral Brønsted acid (Figure 2, A)
based on 1,2,3,4,5-pentacarboxycyclopentadiene was syn-
thesized by Lambert and co-workers.13 Compared to chiral
phosphoric acids, this kind of acid can be obtained easily
from some simple starting materials in three steps, and fur-
thermore, their acidity can be adjusted by combing differ-
ent chiral alcohols or amines. Given the excellent perfor-
mance of such Brønsted acids in the Mukaiyama–Mannich
reaction, their well-defined chiral environment and good
catalytic activity might afford an opportunity for the effi-
cient asymmetric reduction of 3-substituted quinolines.
With this hypothesis in mind, we synthesized the chiral
Brønsted acids A and B derived from (–)-menthol and (+)-
isopinocampheol, respectively.
tries 1–6), it was found that the reaction system was some-
what sensitive to steric effects. In particular, the presence of
the sterically much hindered cyclohexyl group led to a bet-
ter enantioselectivity, but a lower yield (Table 2, entry 5, cf.
entries 1–4 and 6). Interestingly, changing 3-substituted
quinolines to the analogous 2-substituted quinolines 1a′–
d′,k′,p′ gave some higher yields, but lower enantioselectivi-
ties under the conditions employed (Table 2, entries 1–4).
For quinolines containing aryl groups on the 3-position, the
substituents on the phenyl ring showed more significant ef-
fects on the enantioselectivities (Table 2, entries 7–21).
Thus, substrates containing electron-denoting groups
on the phenyl ring, at either the para- or meta- position, af-
forded similar enantioselectivities at ca. 50% ee (Table 2, en-
tries 8–12, except 2j), close to the non-substituted sub-
Me
iPr
Table 1 Optimization of Reaction Conditions for Transfer Hydrogena-
tion of 3-Methylquinoline (1a)a
Me
O
O
O
O
O
O
OH
OH
RO2C
CO2R
iPr
iPr
O
O
O
O
O
O
iPr
N
O
O
H
O
O
O
Me
Me
catalyst A or B, solvent
N
N
O
H
2a
1a
iPr
Me
Entry
R
Solvent
Cat.
(mol%)
T (°C)
Conv.
(%)b
ee
(%)c,d
A
B
1
2
3
4
5
Me
Et
Et2O
Et2O
Et2O
Et2O
Et2O
A (5)
B (5)
25
25
25
25
25
30
30
32
5
Figure 2 Chiral Brønsted acids A and B based on cyclopentadiene
A (5)
B (5)
95
95
36
4
With catalysts A and B in hand, we initially investigated
the transfer hydrogenation of 3-methylquinoline (1a) with
different Hantzsch esters (Table 1, entries 1–5) using dieth-
yl ether as the solvent. The results demonstrated that the
reaction proceeded with better enantioselectivity and yield
using A as the catalyst. To our surprise, catalyst B almost
gave a racemic product (cf. A and B in Table 1, entries 1–5).
Evaluation of the temperature revealed that a lower or
higher temperature gave a lower enantioselectivity (Table
1, entries 6 and 7). Considering the well-known effect of
solvent on hydrogen bonding, a series of solvents were next
investigated (Table 1, entries 8–13). Whilst most solvents
gave good product yields, the best enantioselectivity was
obtained in the nonpolar toluene. In addition, decreasing
the catalyst loading resulted in lower conversions and en-
antioselectivities (Table 1, entries 14 and 15). Increasing the
catalyst loading (10 mol%) resulted in an improved conver-
sion, but only a slightly higher enantioselectivity (Table 1,
entry 16).
allyl
t-Bu
Bn
A (5)
B (5)
75
49
32
4
A (5)
B (5)
58
63
17
2
A (5)
B (5)
90
95
21
4
6
7
8
Et
Et
Et
Et2O
A (5)
A (5)
50
10
25
99
30
27
26
Et2O
toluene
A (5)
B (5)
95
70
46
3
9
10
11
12
13
14
15
16
Et
Et
Et
Et
Et
Et
Et
Et
benzene
THF
A (5)
A (5)
A (5)
A (5)
A (5)
A (1)
A (3)
A (10)
25
25
25
25
25
25
25
25
95
84
71
95
87
37
70
99
41
36
31
26
41
32
45
48
MeCN
CH2Cl2
dioxane
toluene
toluene
toluene
Having established the best conditions for the transfer
hydrogenation of 3-methylquinoline (1a), we turned our at-
tention to exploring the scope of 3-substituted quinolines
1a–v. The results are listed in Table 2. As can be seen, all the
substrates were smoothly reduced under the optimized re-
action conditions, affording moderate to good isolated
yield. For alkyl substituents on the 3-position (Table 2, en-
a Reaction conditions: 1a (0.1 mmol), catalyst A or B, Hantzsch ester (2.4
equiv), solvent (2 mL), 8 h.
b The conversion was determined by 1H NMR spectroscopy.
c The ee values were determined by HPLC analysis using a chiral stationary
column.
d The absolute configuration was assigned as R by for A or S for B based on
the optical rotation and HPLC analysis.14
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
X. Zhao et al.
Paper
Synthesis
strate (Table 2, entry 7). However, enantioselectivities of
more than 60% ee were obtained when electron-withdraw-
ing groups were installed at these positions (Table 2, entries
15–19). On the other hand, depending on the substitution
position, the enantioselectivity varied considerably, rang-
ing from the lowest to the highest ees observed for the sub-
strates in Table 2. Thus, when the fluoro substituent was
placed at the ortho position, a dramatic decrease in the ee
was noted (Table 2, entries 14 and 20). The effect of the
substitution on the reaction rates appears less clear under
the conditions employed, however. For a comparison, we
also carried out the transfer hydrogenation of 2-aryl-sub-
stituted quinolones. The results demonstrated that the
yields and enantioselectivities decreased for both electron-
denoting and electron-withdrawing groups (Table 2, entries
11 and 16).
Table 2 Asymmetric Transfer Hydrogenation of 3-Substituted or 2-
Substituted Quinolinesa
EtO2C
CO2Et
R
R
*
N
H
N
N
H
1a–v
2a–v
(2.4 equiv)
catalyst A (5 mol%), toluene 5
∗
8 h
N
R
N
H
R
In summary, we have demonstrated a new method for
the asymmetric transfer hydrogenation of challenging 3-
substituted quinolines, using a cyclopentadiene-based chi-
ral Brønsted acid as catalyst. A series of chiral 3-substituted
tetrahydroquinolines were obtained with good isolated
yields and enantioselectivities.
1a'–d',k',p'
2a'–d',k',p'
Entry
1
Product
R
Yield (%)b ee (%)c
Config.d
R
S
2a
2a′
Me
Et
87
90
46
35
2
3
4
2b
2b′
74
93
55
5
R
R
2c
2c′
Pr
83
95
52
10
R
R
1H and 13C NMR spectra were recorded on Bruker 400 spectrometers
relative to TMS (δ = 0.00) using CDCl3 as solvent (1H) or to solvent car-
bon (δ = 77.0 for CDCl3) (13C). IR spectra were recorded on a Bruker
Tensor 27 FT-IR spectrophotometer. HRMS were recorded on Bruker
LC-MS spectrometer with ESI resource. Melting points were mea-
sured on RDY-1B micro melting point apparatus and are uncorrected.
Optical rotations were measured on an Autopol IV-T spectrometer at
the wavelength of the Na D-line (589 nm). TLC was performed on 10–
40 μm silica gel plates. Column chromatography was carried out with
silica gel (200–300 mesh) using mixtures of EtOAc and petroleum
ether (PE) as eluent. HPLC analysis was performed on Shimadzu
equipment using Daicel Chiralpak OJ-H or OD-H columns. GC analysis
was performed on Shimadzu G2014T equipment using a Supelco
Beta-DEX 225 chromatographic column.
2d
2d′
Bu
75
95
51
9
R
R
5
6
2e
2f
Cy
65f
81f
72
84
87
60
60
41
53
47
49
39
S
S
S
S
S
S
Bn
7
2g
2h
2i
Ph
8
3-MeC6H4
4-MeC6H4
3-MeOC6H4
4-MeOC6H4
9
10
11
2j
2k
2k′
87
84
53
23
S
S
12
13
14
15
16
2l
3,5-Me2C6H3
2-naphthyl
2-FC6H4
72
64
57
70
53
53
16
60
S
R
S
S
Unless otherwise specified, all reagents were commercially pur-
chased and used without further purification. Et2O and toluene were
distilled from Na/benzophenone. 3-Methylquinoline (1a) was com-
mercially available of analytical grade and used without purification.
All other substrates 1b–v were prepared according to the literature19
2m
2n
2o
3-FC6H4
2p
2p′
4-FC6H4
88
67
75
30
S
S
Data for 2-substituted products 2a′–d′,k′,p′ are given in the Support-
ing Information.
17
18
19
20
21
22
2q
2r
2s
2t
4-ClC6H4
4-BrC6H4
4-F3CC6H4
2,4-F2C6H4
3,5-F2C6H4
3-thienyl
87
71
82
82
71
77e
70
66
60
49
49
48
S
S
S
S
S
S
3-Aryl- or 3-Alkyltetrahydroquinolines 2a–v; General Procedure
Quinoline 1 (0.25 mmol), catalyst A (5 mol%), and Hantzsch dihydro-
pyridine (2.40 equiv) were suspended in toluene (5 mL) in a screw-
capped vial. The resulting yellow solution was stirred at 25 °C for 8 h.
The solvent was evaporated under vacuum and the residue was puri-
fied by column chromatography (silica gel, hexane/EtOAc, 15:1) to af-
ford the tetrahydroquinoline.
2u
2v
a Reaction conditions: 1a–v or 1a′–d′,k′,p′ (0.25 mmol), catalyst A (5
mol%), Hantzsch ethyl ester (2.4 equiv), toluene (5 mL), 8 h.
b Isolated yield.
(R)-3-Methyl-1,2,3,4-tetrahydroquinoline (2a)14
c The ee values were determined by HPLC analysis using a chiral stationary
column.
20
Yellow oil; yield: 32 mg (87%); 46% ee; Rf = 0.67 (PE/EtOAc, 5:1); [α]D
d The absolute configuration was assigned based on the optical rotation
(2a,14 2f,16b 2g,11b 2j,11b 2l–n11b) or HPLC in comparison with the literature
results.
–38 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OJ-H, λ = 210 nm, eluent:
i-PrOH/hexane (10:90), flow rate: 0.5 mL/min]: tR = 27.00 (major),
33.55 min (minor).
e The reaction time was 12 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
X. Zhao et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.00–6.95 (m, 2 H), 6.62 (t, J = 7.2 Hz, 1
H), 6.50 (d, J = 8.0 Hz, 1 H), 3.83 (br s, 1 H), 3.29–3.27 (m, 1 H), 2.91 (t,
J = 10.4 Hz, 1 H), 2.79 (dd, J = 15.6, 4.0 Hz, 1 H), 2.46–2.42 (m, 1 H),
2.09–2.06 (m, 1 H), 1.06 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 144.3, 129.5, 126.6, 121.1, 116.9,
113.8, 48.8, 35.4, 27.2, 19.0.
IR (KBr, film): 3469.75, 3408.03, 2920.07, 2852.56, 1506.32, 1373.24,
1269.09 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.96 (t, J = 6.8 Hz, 2 H), 6.60 (t, J = 7.2
Hz, 1 H), 6.48 (d, J = 8.0 Hz, 1 H), 3.83 (br s, 1 H), 3.37–3.35 (m, 1 H),
2.97 (t, J = 10.4 Hz, 1 H), 2.80 (dd, J = 16.0, 4.0 Hz, 1 H), 2.55 (dd, J =
15.6, 10.8 Hz, 1 H), 1.86–1.66 (m, 6 H), 1.30–1.16 (m, 4 H), 1.10–1.01
(m, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C10H14N: 148.1121; found:
148.1121.
13C NMR (100 MHz, CDCl3): δ = 144.7, 129.6, 126.6, 121.5, 116.9,
113.7, 45.2, 40.3, 37.8, 31.1, 30.4, 30.2, 26.6, 26.5.
(R)-3-Ethyl-1,2,3,4-tetrahydroquinoline (2b)15
HRMS (ESI): m/z [M + H]+ calcd for C15H22N: 216.1747; found:
216.1747.
20
Yellow oil; yield: 30 mg (74%); 55% ee; Rf = 0.67 (PE/EtOAc, 5:1); [α]D
–50 (c 0.1, CH2Cl2). GC (Beta-DEX 225, chromatographic column T =
80 °C, t = 100 min, heating rate 4 °C/min, T = 120 °C, t = 50 min]: tR =
136.68 (major), 138.16 min (minor).
1H NMR (400 MHz, CDCl3): δ = 6.97 (t, J = 7.2 Hz, 2 H), 6.61 (t, J = 7.2
Hz, 1 H), 6.49 (d, J = 7.6 Hz, 1 H), 3.84 (br s, 1 H), 3.35–3.32 (m, 1 H),
2.92 (t, J = 10.4 Hz, 1 H), 2.83 (dd, J = 16.0, 4.8 Hz, 1 H), 2.47–2.41 (m,
1 H), 1.86–1.81 (m, 1 H), 1.43–1.36 (m, 2 H), 1.00 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 144.6, 129.6, 126.7, 121.2, 117.0,
113.9, 47.1, 34.1, 33.5, 26.6, 11.6.
HRMS (ESI): m/z [M + H]+ calcd for C11H16N: 162.1283; found:
162.1278.
(S)-3-Benzyl-1,2,3,4-tetrahydroquinoline (2f)16
Yellow solid; yield: 45 mg (81%); 41% ee; mp 70–73 °C; Rf = 0.5
(PE/EtOAc, 5:1); [α]D20 –42 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OJ-
H, λ = 220 nm, eluent: i-PrOH/hexane (10:90), flow rate: 0.5 mL/min]:
tR = 48.25 (minor), 57.30 min (major).
1H NMR (400 MHz, CDCl3): δ = 7.31 (t, J = 7.2 Hz, 2 H), 7.24–7.20 (m, 3
H), 6.97 (t, J = 7.6 Hz, 1 H), 6.93 (d, J = 7.6 Hz, 1 H), 6.61 (t, J = 7.2 Hz, 1
H), 6.48 (d, J = 8.0 Hz, 1 H), 3.81 (br s, 1 H), 3.30–3.27 (m, 1 H), 3.01–
2.96 (m, 1 H), 2.80 (dd, J = 16.0, 4.8 Hz, 1 H), 2.67 (dd, J = 7.2, 2.8 Hz, 2
H), 2.56–2.50 (m, 1 H), 2.31–2.22 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 144.3, 140.1, 129.6, 129.0, 128.3,
(R)-3-Propyl-1,2,3,4-tetrahydroquinoline (2c)15
126.7, 126.0, 120.4, 116.9, 113.8, 46.5, 39.8, 34.0, 33.3.
HRMS (ESI): m/z [M + H]+ calcd for C16H18N: 224.1434; found:
224.1434.
Yellow oil; yield: 36.3 mg (83%); 52% ee; Rf = 0.67 (PE/EtOAc, 5:1);
20
[α]D –42 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OJ-H, λ = 210 nm,
eluent: i-PrOH/hexane (10:90), flow rate: 0.5 mL/min]: tR = 22.04 (mi-
nor), 24.51 min (major).
(S)-3-Phenyl-1,2,3,4-tetrahydroquinoline (2g)11b
1H NMR (400 MHz, CDCl3): δ = 6.97 (t, J = 7.6 Hz, 2 H), 6.61 (t, J = 7.2
Hz, 1 H), 6.48 (d, J = 8.0 Hz, 1 H), 3.82 (br s, 1 H), 3.32 (dd, J = 10.8, 1.6
Hz, 1 H), 2.92 (t, J = 10.4 Hz, 1 H), 2.81 (d, J =14.8 Hz, 1 H), 2.47–2.41
(m, 1 H), 1.94 (d, J = 0.8 Hz, 1 H), 1.47–1.40 (m, 2 H).1.36–1.31 (m, 2
H), 0.95 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 144.6, 129.5, 126.6, 121.1, 116.9,
113.8, 47.3, 36.0, 33.7, 31.9, 20.0, 14.2.
White solid; yield: 37.6 mg (72%); 53% ee; mp 55–61 °C; Rf = 0.50
(PE/EtOAc, 5:1); [α]D20 –24 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OD-
H, λ = 220 nm, eluent: i-PrOH/hexane (10:90), flow rate: 0.6 mL/min]:
tR = 19.68 (minor), 23.89 min (major).
1H NMR (400 MHz, CDCl3): δ = 7.33 (t, J = 7.2 Hz, 2 H), 7.25–7.23 (d, J =
8.0 Hz, 3 H), 7.01 (t, J = 7.2 Hz, 2 H), 6.64 (t, J = 7.2 Hz, 1 H), 6.54 (d, J =
8.0 Hz, 1 H), 4.01 (br s, 1 H), 3.47–3.43 (m, 1 H), 3.33 (t, J = 10.4 Hz, 1
H), 3.18–3.10 (m, 1 H), 3.05–2.97 (m, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C12H18N: 176.1439; found:
176.1432.
13C NMR (100 MHz, CDCl3): δ = 144.0, 143.8, 129.5, 128.6, 127.2,
126.9, 126.6, 121.3, 117.1, 114.0, 48.3, 38.7, 34.6.
(R)-3-Butyl-1,2,3,4-tetrahydroquinoline (2d)15
HRMS (ESI): m/z [M + H]+ calcd for C15H16N: 210.1277; found:
210.1273.
Yellow oil; yield: 35.4 mg; (75%); 51% ee; Rf = 0.67 (PE/EtOAc, 5:1);
[α]D –42 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OJ-H, λ = 210 nm,
20
eluent: i-PrOH/hexane (10:90), flow rate: 0.5 mL/min]: tR = 22.04 (mi-
(S)-3-(m-Tolyl)-1,2,3,4-tetrahydroquinoline (2h)
nor), 24.55 min (major).
White solid; yield: 47 mg (84%); 47% ee; mp 43–44 °C; Rf = 0.75
(PE/EtOAc, 5:1); [α]D20 –20 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OD-
H, λ = 220 nm, eluent: i-PrOH/hexane (10:90), flow rate: 0.6 mL/min]:
tR = 20.86 (minor), 24.26 min (major).
1H NMR (400 MHz, CDCl3): δ = 6.98 (t, J = 8.0 Hz, 2 H), 6.62 (td, J =7.2,
1.2 Hz, 1 H), 6.49 (d, J = 8.0 Hz, 1 H), 3.84 (br s, 1 H), 3.34–3.30 (m, 1
H), 2.92 (t, J = 10.2 Hz, 1 H), 2.85–2.80 (m, 1 H), 2.45 (dd, J = 16, 10.0
Hz, 1 H), 1.94–1.89 (m, 1 H), 1.41–1.33 (m, 6 H), 0.94 (t, J = 6.8 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ = 144.5, 129.5, 126.6, 121.1, 116.8,
113.8, 47.3, 33.7, 33.4, 32.1, 29.1, 22.8, 14.1.
IR (KBr, film): 3465.89, 3400.32, 1631.69, 1504.39, 1377.10 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.25 (t, J = 8.4 Hz, 1 H), 7.06 (t, J = 8.0
Hz, 3 H), 7.01 (d, J = 7.2 Hz, 2 H), 6.64 (t, J = 7.2 Hz, 1 H), 6.54 (d, J = 8.0
Hz, 1 H), 4.01 (br s, 1 H), 3.44 (dd, J = 10.8, 1.2 Hz, 1 H), 3.32 (t, J = 10.4
Hz, 1 H), 3.14–2.92 (m, 3 H), 2.36 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C13H20N: 190.1596; found:
190.1591.
13C NMR (100 MHz, CDCl3): δ = 144.0, 143.8, 138.1, 129.5, 128.5,
128.0, 127.4, 126.9, 124.1, 121.4, 117.0, 114.0, 48.3, 38.6, 34.7, 21.5.
HRMS (ESI): m/z [M + H]+ calcd for C16H18N: 224.1439; found:
(S)-3-Cyclohexyl-1,2,3,4-tetrahydroquinoline (2e)
White solid; yield: 35.1 mg (65%); 60% ee; mp 81–82 °C; Rf = 0.67
(PE/EtOAc, 5:1); [α]D20 –54 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OJ-
H, λ = 210 nm, eluent: i-PrOH/hexane (10:90), flow rate: 0.5 mL/min]:
tR = 25.45 (minor), 29.18 min (major).
224.1437.
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(S)-3-(p-Tolyl)-1,2,3,4-tetrahydroquinoline (2i)
HRMS (ESI): m/z [M + H]+ calcd for C17H20N: 238.1590; found:
238.1589.
White solid; yield: 48.3 mg (87%); 49% ee; mp 75–78 °C; Rf = 0.50
(PE/EtOAc, 5:1); [α]D20 –18 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OD-
H, λ = 220 nm, eluent: i-PrOH/hexane (10:90), flow rate: 0.6 mL/min]:
tR = 14.70 (minor), 18.42 min (major).
(R)-3-(Naphthalen-2-yl)-1,2,3,4-tetrahydroquinoline (2m)11b
White solid; yield: 41.5 mg (64%); 51% ee; mp 130–133 °C; Rf = 0.50
(PE/EtOAc, 5:1); [α]D20 –12 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OD-
H, λ = 220 nm, eluent: i-PrOH/hexane (10:90), flow rate: 0.6 mL/min]:
tR = 25.65 (minor), 31.01 min (major).
1H NMR (400 MHz, CDCl3): δ = 7.85–7.81 (m, 3 H), 7.69 (s, 1 H), 7.50–
7.44 (m, 2 H), 7.41 (d, J = 8.4 Hz, 1 H), 7.05 (t, J = 6.4 Hz, 2 H), 6.68 (t,
J = 7.6 Hz, 1 H), 6.59 (d, J = 8.4 Hz, 1 H), 4.08 (br s, 1 H), 3.55 (dd, J =
10.8, 1.2 Hz, 1 H), 3.45 (t, J = 10.4 Hz, 1 H), 3.36–3.29 (m, 1 H), 3.19–
3.04 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 144.0, 141.2, 133.5, 132.4, 129.5,
128.2, 127.6, 127.5, 127.0, 126.0, 125.9, 125.5, 125.3, 121.3, 117.1,
114.0, 48.3, 38.7, 34.6.
HRMS (ESI): m/z [M + H]+ calcd for C19H18N: 260.1434; found:
260.1432.
IR (KBr, film): 3512.18, 3388.74, 1647.12, 1506.32, 1365.52 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.18–7.14 (m, 4 H), 7.03 (t, J = 7.2 Hz, 2
H), 6.66 (t, J = 7.2 Hz, 1 H), 6.56 (d, J = 8.0 Hz, 1 H), 4.03 (br s, 1 H),
3.46–3.43 (m, 1 H), 3.33 (t, J = 10.4 Hz, 1 H), 3.17–3.09 (m, 1 H), 3.06–
2.94 (m, 2 H), 2.36 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 144.0, 140.8, 136.1, 129.5, 129.2,
127.0, 126.7, 121.3, 117.0, 114.0, 48.4, 38.2, 34.6, 21.0.
HRMS (ESI): m/z [M + H]+ calcd for C16H18N: 224.1434; found:
224.1433.
(S)-3-(3-Methoxyphenyl)-1,2,3,4-tetrahydroquinoline (2j)11b
White solid; yield: 35.9 mg (60%); 39% ee; mp 57–59 °C; Rf = 0.50
(PE/EtOAc, 5:1); [α]D20 –12 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OD-
H, λ = 220 nm, eluent: i-PrOH/hexane (10:90), flow rate: 0.6 mL/min]:
tR = 27.80 (minor), 36.00 min (major).
(S)-3-(2-Fluorophenyl)-1,2,3,4-tetrahydroquinoline (2n)11b
White solid; yield: 32.4 mg (57%); 16% ee; mp 70–72 °C; Rf = 0.50
(PE/EtOAc, 5:1); [α]D –8 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OD-
1H NMR (400 MHz, CDCl3): δ = 7.24–7.22 (m, 1 H), 6.99 (t, J = 7.2 Hz, 2
H), 6.82 (d, J = 7.6 Hz, 1 H), 6.78–6.77 (m, 2 H), 6.62 (t, J = 7.2 Hz, 1 H),
6.52 (d, J = 8.4 Hz, 1 H), 4.00 (br s, 1 H), 3.78 (s, 3 H), 3.45–3.42 (m, 1
H), 3.31 (t, J = 10.4 Hz, 1 H), 3.14–2.92 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.8, 145.5, 144.0, 129.5, 129.4,
126.9, 121.2, 119.6, 117.1, 114.0, 113.3, 111.5, 55.1, 48.2, 38.7, 34.6.
20
H, λ = 220 nm, eluent: i-PrOH/hexane (10:90), flow rate: 0.6 mL/min]:
tR = 18.84 (minor), 24.90 min (major).
1H NMR (400 MHz, CDCl3): δ = 7.23–7.19 (m, 2 H), 7.14–7.01 (m, 4 H),
6.67 (t, J = 7.6 Hz, 1 H), 6.56 (d, J = 8.4 Hz, 1 H), 4.01 (br s, 1 H), 3.57–
3.47 (m, 2 H), 3.38 (t, J = 10.4 Hz, 1 H), 3.09–2.97 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 162.0, 159.5, 144.0, 130.5 (d, JC-F = 14.3
Hz), 129.5, 127.5 (d, JC-F = 7.7 Hz), 127.0, 124.3 (d, JC-F = 3.4 Hz), 120.9,
117.2, 115.4 (d, JC-F = 22.5 Hz), 114.1, 46.9, 33.1, 31.5.
HRMS (ESI): m/z [M + H]+ calcd for C16H18NO: 240.1383; found:
240.1372.
(S)-3-(4-Methoxyphenyl)-1,2,3,4-tetrahydroquinoline (2k)
HRMS (ESI): m/z [M + H]+ calcd for C15H15FN: 228.1183; found:
228.1184.
White solid; yield: 52 mg (87%); 53% ee; mp 77–79 °C; Rf = 0.50
(PE/EtOAc, 5:1); [α]D20 –50 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OD-
H, λ = 220 nm, eluent: i-PrOH/hexane (10:90), flow rate: 0.6 mL/min]:
tR = 21.12 (minor), 26.11 min (major).
(S)-3-(3-Fluorophenyl)-1,2,3,4-tetrahydroquinoline (2o)
Colorless oil; yield: 39.7 mg (70%); 60% ee; Rf = 0.50 (PE/EtOAc, 5:1);
[α]D –20 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OD-H, λ = 220 nm,
eluent: i-PrOH/hexane (10:90), flow rate: 0.6 mL/min]: tR = 28.47 (mi-
nor), 36.63 min (major).
IR (KBr, film): 3487.11, 3408.03, 2964.43, 2862.20, 1612.40, 1257.52,
20
1103.22 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.17 (d, J = 8.4 Hz, 2 H), 7.02 (t, J = 7.2
Hz, 2 H), 6.89 (d, J = 8.4 Hz, 2 H), 6.65 (t, J = 7.6 Hz, 1 H), 6.55 (d, J = 8.0
Hz, 1 H), 4.03 (br s, 1 H), 3.81 (s, 3 H), 3.45–3.42 (m, 1 H), 3.30 (t, J =
10.8 Hz, 1 H), 3.15–3.03 (m, 1 H), 2.99–2.92 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 158.3, 144.0, 135.9, 129.5, 128.1,
126.9, 121.4, 117.1, 114.0, 55.3, 48.6, 37.8, 34.7.
IR (KBr, film): 3487.11, 3419.60, 1612.40, 1504.39, 1367.45 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.34–7.28 (m, 1 H), 7.04 (t, J = 8.0 Hz, 3
H), 6.98–6.94 (m, 2 H), 6.68 (t, J = 7.2 Hz, 1 H), 6.57 (d, J = 7.6 Hz, 1 H),
4.03 (br s, 1 H), 3.48 (dd, J = 11.2, 3.2 Hz, 1 H), 3.33 (t, J = 10.8 Hz, 1 H),
3.21–3.13 (m, 1 H), 3.00 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 164.2, 161.8, 146.4 (d, JC-F = 7.0 Hz),
143.9, 130.0 (d, JC-F = 8.3 Hz), 129.5, 127.1, 122.9 (d, JC-F = 2.8 Hz),
120.8, 117.2, 114.1 (t, JC-F = 9.7 Hz), 113.4 (d, JC-F = 20.9 Hz), 48.0, 38.4,
34.4.
HRMS (ESI): m/z [M + H]+ calcd for C16H18NO: 240.1383; found:
240.1385.
(S)-3-(3,5-Dimethylphenyl)-1,2,3,4-tetrahydroquinoline (2l)11b
White solid; yield: 42.8 mg (72%); 53% ee; mp 72–74 °C; Rf = 0.67
(PE/EtOAc, 5:1); [α]D20 –26 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OD-
H, λ = 220 nm, eluent: i-PrOH/hexane (10:90), flow rate: 0.6 mL/min]:
tR = 11.60 (minor), 12.99 min (major).
1H NMR (400 MHz, CDCl3): δ = 7.04 (t, J = 7.6 Hz, 2 H), 6.93 (s, 1 H),
6.89 (s, 2 H), 6.67 (t, J = 7.2 Hz, 1 H), 6.57 (d, J = 7.6 Hz, 1 H), 4.04 (br s,
1 H), 3.45 (d, J = 10.4 Hz, 1 H), 3.34 (t, J = 10.4 Hz, 1 H), 3.13–2.94 (m, 3
H), 2.35 (s, 6 H).
HRMS (ESI): m/z [M + H]+ calcd for C15H15FN: 228.1183; found:
228.1186.
(S)-3-(4-Fluorophenyl)-1,2,3,4-tetrahydroquinoline (2p)17
White crystal; 50 mg (88%); 75% ee; mp 82–84 °C; Rf = 0.67 (PE/EtOAc,
5:1); [α]D20 –24 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OD-H, λ = 220
nm, eluent: i-PrOH/hexane (10:90), flow rate: 0.6 mL/min]: tR = 20.13
(minor), 27.95 min (major).
13C NMR (100 MHz, CDCl3): δ = 144.0, 143.8, 138.0, 129.5, 128.3,
126.9, 125.0, 121.4, 116.9, 113.9, 48.4, 38.6, 34.7, 21.3.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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1H NMR (400 MHz, CDCl3): δ = 7.23–7.20 (m, 2 H), 7.04 (t, J = 8.8 Hz, 4
H), 6.67 (t, J = 7.2 Hz, 1 H), 6.56 (d, J = 7.6 Hz, 1 H), 4.03 (br s, 1 H), 3.45
(dd, J = 11.2, 3.6 Hz, 1 H), 3.31 (t, J = 10.4 Hz, 1 H), 3.19–3.12 (m, 1 H),
2.99 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 161.6 (d, JC-F = 243 Hz), 143.9, 139.5 (d,
JC-F = 3.1 Hz), 129.5, 128.5 (d, JC-F = 7.8 Hz), 127.0, 121.0, 117.2, 115.3
(d, JC-F = 21 Hz), 114.0, 48.4, 37.9, 34.7.
(S)-3-(2,4-Difluorophenyl)-1,2,3,4-tetrahydroquinoline (2t)
White solid; yield: 50.3 mg (82%); 49% ee; mp 89–93 °C; Rf = 0.50
20
(PE/EtOAc, 5:1); [α]D –4 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OD-
H, λ = 220 nm, eluent: i-PrOH/hexane (10:90), flow rate: 0.6 mL/min]:
tR = 22.12 (minor), 28.32 min (major).
IR (KBr, film): 3487.11, 3406.10, 1610.47, 1498.60, 1265.23 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.18–7.12 (m, 1 H), 7.06–7.00 (m, 2 H),
6.86–6.79 (m, 2 H), 6.66 (t, J = 7.2 Hz, 1 H), 6.55 (d, J = 8.0 Hz, 1 H),
4.00 (br s, 1 H), 3.51–3.45 (m, 2 H), 3.34 (t, J = 10.4 Hz, 1 H), 3.00 (d, J =
8.0 Hz, 2 H).
.
HRMS (ESI): m/z [M + H]+ calcd for C15H15FN: 228.1183; found:
228.1182.
(S)-3-(4-Chlorophenyl)-1,2,3,4-tetrahydroquinoline (2q)
13C NMR (100 MHz, CDCl3): δ = 143.9, 129.5, 128.6 (dd, JC-F = 9.4, 6.3
Hz), 127.1, 126.5, 126.3 (d, JC-F = 3.7 Hz), 120.6, 117.3, 114.2, 111.2
(dd, JC-F = 20.7, 3.7 Hz), 103.9 (t, JC-F =25.7 Hz), 46.8, 33.1, 31.1.
HRMS (ESI): m/z [M + H]+ calcd for C15H14F2N: 246.1089; found:
246.1088.
White solid; yield: 52.8 mg (87%); 70% ee; mp 99–103 °C; Rf = 0.50
(PE/EtOAc, 5:1); [α]D20 –16 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OD-
H, λ = 220 nm, eluent: i-PrOH/hexane (10:90), flow rate: 0.6 mL/min]:
tR = 23.11 (minor), 32.81 min (major).
IR (KBr, film): 3504.47, 3438.89, 3388.74, 1606.61, 1496.68, 1363.59,
750.26 cm–1
.
(S)-3-(3,5-Difluorophenyl)-1,2,3,4-tetrahydroquinoline (3u)
1H NMR (400 MHz, CDCl3): δ = 7.32 (d, J = 8.4 Hz, 2 H), 7.18 (d, J = 8.4
Hz, 2 H), 7.06–7.01 (m, 2 H), 6.67 (t, J = 7.2 Hz, 1 H), 6.56 (d, J = 8.0 Hz,
1 H), 4.03 (br s, 1 H), 3.45 (dd, J = 10.8, 3.2 Hz, 1 H), 3.31 (t, J = 10.4 Hz,
1 H), 3.18–3.11 (m, 1 H), 2.98 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 143.9, 142.3, 132.3, 129.5, 128.7,
128.5, 127.0, 120.9, 117.2, 114.1, 48.1, 38.1, 34.4.
White solid; yield: 43.5 mg (71%); 49% ee; mp 61–63 °C; Rf = 0.50
(PE/EtOAc, 5:1); [α]D20 –16 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OD-
H, λ = 220 nm, eluent: i-PrOH/hexane (10:90), flow rate: 0.6 mL/min]:
tR = 29.51 (minor), 37.83 min (major).
IR (KBr, film): 3525.68, 3386.81, 1600.83, 1504.39, 1361.67 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.06–7.01 (m, 2 H), 6.78 (d, J = 6.8 Hz, 2
H), 6.73–6.66 (m, 2 H), 6.57 (d, J = 8.0 Hz, 1 H), 4.02 (br s, 1 H), 3.47
(dd, J = 11.2, 2.0 Hz, 1 H), 3.31 (t, J = 10.4 Hz, 1 H), 3.19–3.12 (m, 1 H),
3.04–2.92 (m, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C15H15ClN: 244.0888; found:
244.0886.
(S)-3-(4-Bromophenyl)-1,2,3,4-tetrahydroquinoline (2r)
13C NMR (100 MHz, CDCl3): δ = 163.1 (dd, JC-F = 246.5, 12.9 Hz), 147.8,
143.7, 129.5, 127.2, 120.4, 117.4, 114.1, 110.0 (dd, JC-F = 18.2, 6.5 Hz),
102.0 (t, JC-F = 25.1 Hz), 47.7, 38.4, 34.2.
HRMS(ESI): m/z [M + H]+ calcd for C15H14F2N: 246.1089; found:
246.1091.
White solid; yield: 51.3 mg (71%); 66% ee; mp 107–109 °C; Rf = 0.50
(PE/EtOAc, 5:1); [α]D20 = +6 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OD-
H, λ = 220 nm, eluent: i-PrOH/hexane (10:90), flow rate: 0.6 mL/min]:
tR = 25.51 (minor), 36.48 min (major).
IR (KBr, film): 3487.11, 3417.67, 1620.11, 1485.10, 1257.52 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.47 (d, J = 8.0 Hz, 2 H), 7.13 (d, J = 8.0
Hz, 2 H), 7.06–7.02 (m, 2 H), 6.68 (t, J = 7.6 Hz, 1 H), 6.57 (d, J = 8.0 Hz,
1 H), 4.02 (br s, 1 H), 3.45 (dd, J = 10.8, 3.2 Hz, 1 H), 3.31 (t, J = 10.4 Hz,
1 H), 3.17–3.10 (m, 1 H), 2.98 (d, J = 7.6 Hz, 2 H).
(S)-3-(Thiophen-3-yl)-1,2,3,4-tetrahydroquinoline (2v)
White solid; yield: 41.1 mg (77%); 48% ee; mp 70–71 °C; Rf = 0.50
(PE/EtOAc, 5:1); [α]D20 –12 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OD-
H, λ = 220 nm, eluent: i-PrOH/hexane (10:90), flow rate: 0.6 mL/min]:
tR = 23.31 (minor), 29.67 min (major).
13C NMR (100 MHz, CDCl3): δ = 143.9, 142.8, 131.6, 129.5, 128.9,
127.0, 120.8, 120.4, 117.2, 114.1, 48.1, 38.1, 34.4.
HRMS (ESI): m/z [M + H]+ calcd for C15H15BrN: 288.0382; found:
IR (KBr, film): 3647.19, 3313.52, 1508.25, 1350.09, 1317.31, 742.55
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.32 (t, J = 3.6 Hz, 1 H), 7.06–7.01 (m, 4
H), 6.67 (t, J = 7.2 Hz, 1 H), 6.55 (d, J = 8.0 Hz, 1 H), 3.99 (br s, 1 H),
3.58–3.51 (m, 1 H), 3.36–3.28 (m, 2 H), 3.10–2.96 (m, 2 H).
288.0383.
(S)-3-[4-(Trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinoline
(2s)18
13C NMR (100 MHz, CDCl3): δ = 144.5, 144.0, 129.5, 127.0, 126.9,
White solid; yield: 56.5 mg (82%); 60% ee; mp 93–95 °C; Rf = 0.50
(PE/EtOAc, 5:1); [α]D20 –12 (c 0.1, CH2Cl2). HPLC [Daicel Chiralpak OD-
H, λ = 220 nm, eluent: i-PrOH/hexane (10:90), flow rate: 0.6 mL/min]:
tR = 25.12 (minor), 39.53 min (major).
125.5, 120.7, 119.8, 117.2, 114.0, 48.0, 34.4, 34.1.
HRMS (ESI): m/z [M + H]+ calcd for C13H14NS: 216.0847; found:
216.0842.
1H NMR (400 MHz, CDCl3): δ = 7.60 (d, J = 8.0 Hz, 2 H), 7.36 (d, J = 8.0
Hz, 2 H), 7.04 (t, J = 8.8 Hz, 2 H), 6.67 (t, J = 7.2 Hz, 1 H), 6.57 (d, J = 8.0
Hz, 1 H), 4.04 (br s, 1 H), 3.48 (dd, J = 11.2, 3.6 Hz, 1 H), 3.36 (t, J = 11.2
Hz, 1 H), 3.27–3.20 (m, 1 H), 3.02 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 147.9, 143.8, 129.5, 128.9 (d, JC-F = 32
Hz), 127.6, 127.1, 125.5 (q, JC-F = 3.7 Hz), 122.9, 120.7, 117.3, 114.1,
47.9, 38.6, 34.3.
Funding Information
National Science Foundation of China 21302116
Fundamental Research Funds for the Central Universities GK201703018
We are grateful for the financial support of the National Science Foun-
dation of China (21302116), the Fundamental Research Funds for the
Central Universities (GK201703018), and Shaanxi Normal University.
HRMS (ESI): m/z [M + H]+ calcd for C16H15F3N: 278.1151; found:
278.1155.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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X. Zhao et al.
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Synthesis
Supporting Information
Z. Y.; Fan, Q. H. Chem. Asian J. 2016, 11, 2773. (n) Ma, W. P.;
Zhang, J. W.; Xu, C.; Chen, F.; He, Y. M.; Fan, Q. H. Angew. Chem.
Int. Ed. 2016, 55, 12891.
Supporting information for this article is available online at
https://doi.org /10.1055/s-0036-1589012.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(10) (a) Reetz, M.; Li, X. Chem. Commun. 2006, 2159. (b) Deport, C.;
Buchotte, M.; Abecassis, K.; Tadaoka, H.; Ayad, T.; Ohshima, T.;
Genêt, J. P.; Mashima, K.; Ratovelomanana-Vidal, V. Synlett
2007, 2743. (c) Mršić, 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.; Franció, G.;
Leitner, W. Adv. Synth. Catal. 2009, 351, 725. (f) Tadaoka, H.;
Cartigny, D.; Nagano, T.; Gosavi, T.; Ayad, T.; Genêt, J. P.;
Ohshima, T.; Ratovelomanana-Vidal, V.; Mashima, K. Chem. Eur.
J. 2009, 15, 9990. (g) Maj, A. M.; Suisse, I.; Meliet, C.; Hardouin,
C.; Agbossou-Niedercorn, F. Tetrahedron Lett. 2012, 53, 4747.
(h) Maj, A. M.; Suisse, I.; Hardouin, C.; Agbossou-Niedercorn, F.
Tetrahedron 2013, 69, 9322. (i) John, J.; Wilson-Konderka, C.;
Metallinos, C. Adv. Synth. Catal. 2015, 357, 2071. (j) Kuwano, R.;
Ikeda, R.; Hirasada, K. Chem. Commun. 2015, 51, 7558. (k) Wang,
X.; Li, J.; Lu, S. M.; Liu, Y.; Li, C. Chin. J. Catal. 2015, 36, 1170.
(l) Wen, J. L.; Tan, R. C.; Liu, S. D.; Zhao, Q. Y.; Zhang, X. M. Chem.
Sci. 2016, 7, 3047.
(11) For examples of 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.; Theissmann, T.; Raja, S.; Bats, J. W. P. Adv. Synth.
Catal. 2008, 350, 1001. (c) Guo, Q.-S.; Du, D.-M.; Xu, J. Angew.
Chem. Int. Ed. 2008, 47, 759. (d) Wang, C.; Li, C.; Wu, X.;
Pettman, A.; Xiao, J. Angew. Chem. Int. Ed. 2009, 48, 6524.
(e) Rueping, M.; Theissmann, T.; Stoeckel, M.; Antonchick, A. P.
Org. Biomol. Chem. 2011, 9, 6844. (f) Tu, X. F.; Gong, L. Z. Angew.
Chem. Int. Ed. 2012, 51, 11346. (g) Qiao, X.; Zhang, Z. G.; Bao, Z.
B.; Su, B. G.; Xing, H. B.; Yang, Q. W.; Ren, Q. L. RSC Adv. 2014, 4,
42566. (h) More, G. V.; Bhanage, B. M. Tetrahedron: Asymmetry
2015, 26, 1174. (i) Shugrue, C. R.; Miller, S. J. Angew. Chem. Int.
Ed. 2015, 54, 11173. (j) Wang, P.; Jia, Y. E.; Zhao, J. Z.; Zhao, D.;
Yuan, R.; Da C, S. Asian J. Org. Chem. 2015, 4, 430. (k) Wang, J.;
Chen, M. W.; Ji, Y.; Hu, S. B.; Zhou, Y. G. J. Am. Chem. Soc. 2016,
138, 10413. (l) Aillerie, A.; de Talencé, V. L.; Dumont, C.;
Pellegrini, S.; Capet, F.; Bousquet, T.; Pélinski, L. New J. Chem.
2016, 40, 9034.
References
(1) For selected reviews, see: (a) Katritzky, A. R.; Rachwal, S.;
Rachwal, B. Tetrahedron 1996, 52, 15031. (b) Sridharan, V.;
Suryavanshi, P. A.; Menendez, J. C. Chem. Rev. 2011, 111, 7157.
(2) Yeh, R. W.; Jang, I.-K. Am. Heart J. 2006, 151, 1131.
(3) (a) Abe, H. MedChem News 2007, 17, 18. (b) Kato, K.; Terauchi, J.;
Suzuki, N.; Takekawa, S. WO 2001025228, 2001. (c) Sawai, Y.;
Yamane, T.; Ikeuchi, M.; Kawaguchi, S.; Yamada, M.; Yamano, M.
Org. Process Res. Dev. 2010, 14, 1110.
(4) Heier, R. F.; Dolak, L. A.; Duncan, J. N.; Hyslop, D. K.; Lipton, M.
F.; Martin, I. J.; Mauragis, M. A.; Piercey, M. F.; Nichols, N. F.;
Schreur, P. J. K. D.; Smith, M. W.; Moon, M. W. J. Med. Chem.
1997, 40, 639.
(5) Ghosh, S.; Santulli, R. J.; Kinney, W. A.; DeCorte, B. L.; Liu, L.;
Lewis, J. M.; Proost, J. C.; Leo, G. C.; Masucci, J.; Hageman, W. E.;
Thompson, A. S.; Chen, I.; Kawahama, R.; Tuman, W. E.;
Galemmo, R. A. Jr.; Johnson, D. A.; Damiano, B. P.; Maryanoff, B.
E. Bioorg. Med. Chem. Lett. 2004, 14, 5937.
(6) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am.
Chem. Soc. 2003, 125, 10536.
(7) For recent reviews, see: (a) Glorius, F. Org. Biomol. Chem. 2005,
3, 4171. (b) Zhou, Y. G. Acc. Chem. Res. 2007, 40, 1357.
(c) Kuwano, R. Heterocycles 2008, 76, 909. (d) Wang, D. S.; Chen,
Q. A.; Lu, S. M.; Zhou, Y. G. Chem. Rev. 2012, 112, 2557.
(8) (a) Lu, S.-M.; Han, X.-W.; Zhou, Y.-G. Adv. Synth. Catal. 2004,
346, 909. (b) Wang, D.-W.; Zeng, W.; Zhou, Y.-G. Tetrahedron:
Asymmetry 2007, 18, 1103. (c) Wang, X.-B.; Zhou, Y.-G. J. Org.
Chem. 2008, 73, 5640. (d) Wang, D.-S.; Zhou, J.; Wang, D.-W.;
Guo, Y.-L.; Zhou, Y.-G. Tetrahedron Lett. 2010, 51, 525. (e) Wang,
D.-S.; Zhou, Y.-G. Tetrahedron Lett. 2010, 51, 3014. (f) Zhang, D.
Y.; Wang, D. S.; Wang, M. C.; Yu, C. B.; Gao, K.; Zhou, Y. G. Syn-
thesis 2011, 2796.
(9) (a) Xu, L. J.; Lam, K. H.; Ji, J. X.; Fan, Q. H.; Lo, W. H.; Chan, A. S. C.
Chem. Commun. 2005, 1390. (b) Lam, K. H.; Xu, L. J.; Feng, L. C.;
Fan, Q. H.; Lam, F. L.; Lo, W. H.; Chan, A. S. C. Adv. Synth. Catal.
2005, 347, 1755. (c) Chan, S. H.; Lam, K. H.; Li, Y. M.; Xu, L. J.;
Tang, W. J.; Lam, F. L.; Lo, W. H.; Yu, W. Y.; Fan, Q. H.; Chan, A. S.
C. Tetrahedron: Asymmetry 2007, 18, 2625. (d) Tang, W. J.; Zhu,
S.-F.; Xu, L. J.; Zhou, Q. L.; Fan, Q. H.; Zhou, H. F.; Lam, K.; Chan,
A. S. C. Chem. Commun. 2007, 613. (e) Wang, Z. J.; Deng, G. J.; Li,
Y.; He, Y. M.; Tang, W. J.; Fan, Q. H. Org. Lett. 2007, 9, 1243.
(f) Tang, W. J.; Sun, Y. W.; Xu, L. J.; Wang, T. L.; Fan, Q. H.; Lam, K.
H.; Chan, A. S. C. Org. Biomol. Chem. 2010, 8, 3464. (g) Tang, W.
J.; Tan, J.; Xu, L. J.; Lam, K. H.; Fan, Q. H.; Chan, A. S. C. Adv. Synth.
Catal. 2010, 352, 1055. (h) Wang, T. L.; Ouyang, G. H.; He, Y. M.;
Fan, Q. H. Synlett 2011, 939. (i) Wang, T. L.; Zhuo, L. G.; Li, Z. W.;
Chen, F.; Ding, Z. Y.; He, Y. M.; Fan, Q. H.; Xiang, J. F.; Yu, Z. X.;
Chan, A. S. C. J. Am. Chem. Soc. 2011, 133, 9878. (j) Ding, Z. Y.;
Wang, T. L.; He, Y. M.; Chen, F.; Zhou, H. F.; Fan, Q. H.; Guo, Q. X.;
Chan, A. S. C. Adv. Synth. Catal. 2013, 355, 3727. (k) Yang, Z. S.;
Chen, F.; He, Y. M.; Yang, N. F.; Fan, Q. H. Catal. Sci. Technol.
2014, 4, 2887. (l) Luo, Y. E.; He, Y. M.; Fan, Q. H. Chem. Rec. 2016,
16, 2697. (m) Wang, T. L.; Chen, Y.; Ouyang, G. H.; He, Y. M.; Li,
(12) For examples of reduction of 2,3-disubstituted quinolines, see:
(a) Wang, D.-W.; Wang, X.-B.; Wang, D.-S.; Lu, S.-M.; Zhou, Y.-
G.; Li, Y.-X. J. Org. Chem. 2009, 74, 2780. (b) Chen, Z. P.; Ye, Z. S.;
Chen, M. W.; Zhou, Y. G. Synthesis 2013, 45, 3239. (c) Cai, X. F.;
Chen, M. W.; Ye, Z. S.; Guo, R. N.; Shi, L.; Li, Y. Q.; Zhou, Y. G.
Chem. Asian J. 2013, 8, 1381. (d) Cai, X. F.; Huang, W. X.; Chen, Z.
P.; Zhou, Y. G. Chem. Commun. 2014, 50, 9588. (e) Chen, M. W.;
Cai, X. F.; Chen, Z. P.; Shi, L.; Zhou, Y. G. Chem. Commun. 2014,
50, 12526. (f) Guo, R. N.; Chen, Z. P.; Cai, X. F.; Zhou, Y. G. Syn-
thesis 2014, 46, 2751. (g) Cai, X. F.; Guo, R. N.; Feng, G. S.; Wu, B.;
Zhou, Y. G. Org. Lett. 2014, 16, 2680. (h) Zhang, Z. H.; Du, H. F.
Org. Lett. 2015, 17, 2816. (i) Zhang, Z. H.; Du, H. F. Org. Lett.
2015, 17, 6266. (j) Zhou, J.; Zhang, Q. F.; Zhao, W. H.; Jiang, G. F.
Org. Biomol. Chem. 2016, 14, 6937.
(13) (a) Gheewala, C. D.; Collins, B. E.; Lambert, T. H. Science (Wash-
ington, D. C.) 2016, 351, 961. (b) Fleischer, I. Angew. Chem. Int.
Ed. 2016, 55, 7582.
(14) Ferraboschi, P.; Ciceri, S.; Grisenti, P. Tetrahedron: Asymmetry
2013, 24, 1142.
(15) Zhang, L. J.; Qiu, R. Y.; Xue, X.; Pan, Y. X.; Xu, C. H.; Li, H. R.; Xu, L.
J. Adv. Synth. Catal. 2015, 357, 3529.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

H
X. Zhao et al.
Paper
Synthesis
(16) (a) Lee, A.; Younai, A.; Price, C. K.; Izquierdo, J.; Mishra, R. K.;
Scheidt, K. A. J. Am. Chem. Soc. 2014, 136, 10589. (b) Long, Y.;
Shi, J. L.; Liang, H. Q.; Zeng, Y. L.; Cai, Q. Synthesis 2015, 47, 2844.
(17) Chakravarty, S.; Hart, B. P.; Jain, R. P. WO 2011103460, 2011.
(18) Cai, J.; Crespo, A.; Du, X.; Dubois, B. G.; Guiadeen, D.;
Kothandaraman, S.; Liu, P.; Liu, R.; Quan, W.; Sinz, C.; Wang, L.
WO 2016045127, 2016.
(19) (a) Dumouchel, S.; Mongin, F.; Trecourt, F.; Queguiner, G. Tetra-
hedron 2003, 59, 8629. (b) Liu, H. Y.; Li, X. S.; Liu, F.; Tan, Y.;
Jiang, Y. Y. J. Organomet. Chem. 2015, 794, 27.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H