Synthesis of 2,4-Diarylquinoline Derivatives via Chloranil-Promoted Oxidative Annulation and One-Pot Reaction

Article abstract of DOI:10.1055/s-0039-1691740

An oxidative annulation for the synthesis of 2,4-diarylquinolines from o -allylanilines is disclosed that uses recyclable reagent Chloranil as the oxidant. The corresponding products are obtained in moderate to excellent yields. Furthermore, a one-pot access to 2,4-di aryl quinolines from easily available anilines and 1,3-diarylpropenes is described as a highly atom-efficient protocol that involves oxidative coupling, rearrangement, and oxidative annulation.

Full text of DOI:10.1055/s-0039-1691740

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–H
paper
A
en
D. Cheng et al.
Paper
Synthesis
Synthesis of 2,4-Diarylquinoline Derivatives via Chloranil-Promoted
Oxidative Annulation and One-Pot Reaction
Dongping Cheng*a
Xianhang Yana
Jing Shena
Yueqi Pua
Xiaoliang Xu*b
Jizhong Yan*a
1) DDQ, r.t.
2) FeCl3, 80 °C
3) Chloranil, 80 °C
N
Ar
R
Ar
R
Ar
Chloranil
R
NH2
Ar
+
one pot
DCE
80 °C
Ar
NH2
Ar
R: F, Cl, Br, NO2 18 examples
10 examples
36–89% yields
R: F, Cl, Br
CH3, OCH3
CH3, OCH3
50–95% yields
- simple operation
- cheap and recyclable oxidant
- high atom-economy
a College of Pharmaceutical Science, Zhejiang University of
Technology, Hangzhou 310014, P. R. of China
b College of Chemical Engineering, Zhejiang University of
Technology, Hangzhou 310014, P. R. of China
chengdp@zjut.edu.cn
Received: 24.12.2019
F
Accepted after revision: 06.02.2020
Published online: 24.02.2020
DOI: 10.1055/s-0039-1691740; Art ID: ss-2019-f0706-op
Abstract An oxidative annulation for the synthesis of 2,4-diarylquino-
lines from o-allylanilines is disclosed that uses recyclable reagent
Chloranil as the oxidant. The corresponding products are obtained in
moderate to excellent yields. Furthermore, a one-pot access to 2,4-di-
arylquinolines from easily available anilines and 1,3-diarylpropenes is
described as a highly atom-efficient protocol that involves oxidative
coupling, rearrangement, and oxidative annulation.
N
Br
N
P
Ph
Ph
F
S
(topoisomerase I inhibitors)
anticancer
(against E. coli and S. aureus)
antibacterial
Key words oxidative annulation, one-pot reaction, chloranil, 2,4-di-
arylqunoline
N
N
S
S
Br
N
N
The quinoline nucleus is an important structure unit
that exists widely in natural products and pharmaceuticals
such as antibacterial,1 antimalarial,2 antioxidant,3 anti-
inflammatory,4 and insecticidal agents.5 Quinolines are also
applied as crucial ligands in the synthesis of phosphores-
cent materials, fluorsensors, and asymmetric catalysts.6
Given their outstanding characteristics, various quinoline
derivatives containing different substituents at specific po-
sitions have been designed and synthesized.7 Among them,
2,4-diarylquinolines have been proven to be especially im-
portant because of their potential biological activities, as
shown in Figure 1.3,8 As a result, a large number of synthetic
protocols have been developed for the preparation of 2,4-
diarylquinolines.9
The traditional routes for synthesizing 2,4-diarylquino-
lines include the Combes reaction of anilines and 1,3-di-
aryl-1,3-diketones,10 the Friedländer reaction of 2-amino-
benzophenone and acetophenones/benzylalcohols,11 the
Povarov reaction of anilines, arylaldehydes, and arylacetyl-
enes/arylethylenes,12 and the transition-metal- or acid-
catalyzed cyclization of N-benzylanilines and arylacetyl-
enes/arylethylenes.13 However, these methods usually
Br
(against C. albicans and C. neoformans)
(against M. tuberculosis)
antifungal
antimycobacterial
Figure 1 Bioactive 2,4-diarylquinoline skeleton
suffer from the drawbacks of prolonged reaction time and
undesired self-condensation of the starting materials. Re-
cently, a strategy based on the cyclization of o-functional-
ized anilines has emerged as an efficient alternative for
constructing 2,4-diarylquinolines.14 For example, the
Ghorai group developed the KOtBu-mediated oxidative cy-
cloisomerization of o-cinnamylanilines with DMSO as an
oxidant (Scheme 1, a).15 The Alabugin group reported the
DDQ/FeCl3-mediated intramolecular oxidative amination of
o-substituted anilines (Scheme 1, b).16 Considering the im-
portance of 2,4-diarylquinolines, it is still desirable to de-
velop new, concise and efficient routes for the preparation
of such structures under mild conditions. Recently, our
group has explored the use of metal-free tandem annula-
tions for constructing heterocycles with potential biological
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
D. Cheng et al.
Paper
Synthesis
activities.17 With our ongoing interest in this research area,
herein, we disclose an oxidative annulation for the synthe-
sis of 2,4-diarylquinolines from o-allylanilines mediated by
Chloranil. Quinones as good oxidants have been widely ap-
plied in organic synthesis.18 Although Chloranil is a cheap
and recyclable reagent, an extensive review of the literature
revealed that the application of Chloranil in oxidative cou-
pling/annulation reactions is not common.19 Based on our
previous report,20 a one-pot access to 2,4-diarylquinolines
from easily available anilines and 1,3-diarylpropenes is also
developed in this paper. The approach affords a highly
atom-efficient protocol, with the loss of only six hydrogen
atoms, which involves oxidative coupling, rearrangement,
and oxidative annulation.
Chloranil was best suited for the reaction (entries 12–14).
After the reaction, the tetrachlorohydroquinone formed
could be recycled to Chloranil by aerobic oxidation (see the
Supporting Information for recyclability experiments).22
The reaction proceeded well and the product was obtained
in 88% yield when recycled Chloranil was used.
Table 1 Screening of the Optimal Conditionsa
NH2
N
Ph
oxidant
Ph
solvent, 80 °C
Ph
Ph
1a
2a
Entry
Oxidant
Solvent
Temp (°C)
Yield (%)b
a) Prasanta Ghorai 's work:
R
1c
2c
3c
4
DDQ/FeCl3
BQ/FeCl3
Chloranil/FeCl3
Chloranil
DDQ
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1,4-dioxane
CH3NO2
DCE
80
80
80
80
80
80
80
80
80
80
60
80
80
80
80
39
–
KOtBu
NH2
DMSO, rt
60
66
48
73
76
88
41
64
76
93
81
82
88
N
Ar
R
Ar
b) Igor V. Alabugin 's work:
5
R
DDQ/FeCl3
6
Chloranil
Chloranil
Chloranil
Chloranil
Chloranil
Chloranil
Chloranil
Chloranil
Chloranil
Chloranilg
R
NH2
R'
CH3CN, 80 °C
N
R'
7
c) This work:
8
Ar
9
DMSO
DMF
Chloranil
R
(1)
NH2
Ar
10
11
12d
13e
14f
15
DCE, 80 °C
R
N
Ar
Ar
DCE
oxidative annulation
NH2
DCE
Ar
1) DDQ, r.t.
(2)
DCE
2) FeCl3, 80 °C
3) Chloranil, 80 °C
R
R
+
DCE
N
Ar
Ar
Ar
one-pot reaction
DCE
a Reaction conditions: 1a (0.2 mmol), oxidant (2.2 equiv), solvent (3 mL), 2
Scheme 1 Previous and present strategies via oxidative annulation
h.
b Isolated yield.
c FeCl3 (20 mol%).
d Chloranil (2.1 equiv).
e Chloranil (2.0 equiv).
f Chloranil (2.3 equiv).
g Recycled Chloranil was used.
Considering the similarity of o-allylaniline 1a to Alabugin’s
substrate, the standard reaction conditions of Alabugin’s
method were tried (Table 1, entry 1).16 That is, the cycliza-
tion of 1a was performed in CH3CN at 80 °C in the presence
of DDQ/FeCl3. Unfortunately, the desired product 2,4-di-
phenylquinoline could be isolated in only 39% yield. To opti-
mize the reaction conditions, other quinones such as ben-
zoquinone (BQ, Ered = –0.50 V vs. SCE) and Chloranil (CA, Ered
= 0.01 V vs. SCE) were used instead of DDQ (Ered = 0.51 V vs.
SCE) (entries 2 and 3).21 The reaction did not proceed when
benzoquinone was used as an oxidant. It was found that
FeCl3 did not promote the reaction and the product was ob-
tained in 66% yield only in the presence of Chloranil (entries
3 and 4). Encouraged by the result, several solvents, such as
1,4-dioxane, CH3NO2, 1,2-ClCH2CH2Cl (DCE), DMSO, and
DMF were screened (entries 6–10). The reaction was found
to proceed in all the examined solvents, but DCE was opti-
mal. Decreasing the temperature to 60 °C reduced the yield
(entry 11). Furthermore, the amount of Chloranil was ex-
amined and the results indicated that 2.1 equivalents
With the optimized conditions in hand, o-allylanilines
with different substituents on the aniline moiety were first
investigated. Aniline moieties containing electron-donating
or electron-withdrawing substituents were good candi-
dates for the reaction and afforded the corresponding prod-
ucts 2b–i in 68–93% yields (Table 2, entries 2–9). Notably, o-
allylaniline, with a nitro group on the aniline moiety, react-
ed smoothly and provided the product 2f in 76% yield (en-
try 6). The desired products 2g–h were obtained in 86–93%
yield when the ortho-position of the aniline moiety was
substituted with a methyl or methoxyl group, regardless of
their steric hindrance effect (entries 7 and 8). Secondly, var-
ious symmetrical 1′,3′-diarylallyl groups of o-allylanilines
were examined (entries 10–16). The products were
obtained in 90–91% yields when methyl group was
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

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D. Cheng et al.
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Synthesis
attached at the para- and meta- position of 1′,3′-diarylallyls
(entries 10 and 11). Only 61% yield was obtained when a
methyl group was attached to the ortho-position, likely due
to its steric bulk (entry 12). The yields were slightly lower
when the para- and meta-position of 1′,3′-diarylallyls con-
tained electron-withdrawing substituents such as F, Cl, or
Br (entries 13–16). Finally, isomerized o-allylanilines with
an unsymmetrical 1′,3′-diarylallyl group were examined,
giving the isomerized products with excellent yields (en-
tries 17 and 18).
Screening other Lewis acids such as FeCl3, FeCl3·6H2O,
CuCl2, CuCl, CuBr, and FeSO4 indicated that FeCl3 was the
best catalyst.
NH2
+
Ph
Ph
4a
3a
DDQ/1,4-dioxane
LA catalyst Yield (%)
Cu(OTf)2
CuCl
CuBr
CuCl2
FeCl3
60
46
48
70
83
LA catalyst
80°C
NH2
NH
Table 2 Substrate Scopea
FeCl3•6H2O 66
FeSO4 32
Ph
Ph
Ph
Ph
R2
R3
5a
1a
R3
R1
R2
R1
N
Ar1
Scheme 2 The conversion of N-allylaniline 5a into o-allylaniline 1a
Chloranil
NH2
DCE, 80 °C
Ar2
Ar1
Ar2
Based on the above experiments, a one-pot cascade ap-
proach to 2,4-diarylquinolines from easily available anilines
and 1,3-diarylpropenes was explored (Table 3). The tandem
reaction of 4-methylaniline 3a and 1,3-diphenylpropene 4a
was carried out in 1,4-dioxane, which gave the final prod-
uct 2,4-diphenylquinoline in 77% yield (entry 1). Examining
a selection of solvents revealed that the yield could be
increased to 87% when DCE was used (entry 2). Several
corresponding products 2 were obtained from anilines 4
and symmetrical 1,3-arylpropenes 3 in moderate to good
yields (entries 3–11).
1
2
Entry R1
R2
R3
Ar1
Ar2
Product Yield (%)b
1
2
CH3
H
H
H
H
H
H
H
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
2a
2b
2c
2d
2e
2f
93
80
88
76
90
76
86
93
68
90
91
61
80
56
50
70
95
90
CH3O
F
H
3
H
4
Cl
H
5
Br
H
6
NO2
CH3
CH3O
H
7
CH3
2g
2h
2i
Table 3 One-Pot Synthesis of 2,4-Diarylquinolinesa
8
CH3O C6H5
9
CH3O CH3O
H
H
H
H
H
H
H
H
H
H
C6H5
R
Ar
R
Ar
10
11
12
13
14
15
16
17
18
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
4-CH3C6H4 4-CH3C6H4 2j
3-CH3C6H4 3-CH3C6H4 2k
2-CH3C6H4 2-CH3C6H4 2l
4
+
1) DDQ, r.t.
3) Chloranil
80 °C
2
NH2
Ar
2) FeCl3, 80 °C
NH2
Ar
1
4-FC6H4
4-ClC6H4
4-BrC6H4
3-ClC6H4
C6H5
4-FC6H4
4-ClC6H4
4-BrC6H4
3-ClC6H4
4-ClC6H4
2m
2n
2o
2p
2q
3
Entry
Ar
R
Product
Yield (%)b
1
2
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-CH3
4-CH3
4-CH3O
4-F
2a
2a
2b
2c
2d
2e
2g
2j
77c
87
61
74
65
70
89
67
66
36
67
3
C6H5
4-CH3C6H4 2r
a Reaction conditions: 1 (0.5 mmol), Chloranil (1.05 mmol), DCE (3 mL),
4
80 °C, 1–2 h.
5
4-Cl
b Isolated yield.
6
4-Br
In 2012, our group reported the DDQ-mediated oxida-
tive coupling of anilines and 1,3-diarylpropenes, which pro-
vided an efficient and convenient method for preparing N-
allylanilines.20 To obtain o-allylaniline 1a, the rearrange-
ment of the coupling product N-allylaniline 5a was tried.
Lewis acid Cu(OTf)2 (5 mol%) was subsequently added to
the reaction mixture after the oxidative coupling of 4-
methylaniline 3a and 1,3-diphenylpropene 4a (Scheme 2).
To our delight, the desired 2-allylaniline 1a was isolated in
60% yield when the reaction was stirred at 80 °C for 1 h.
7
2,4-(CH3)2
4-CH3
8
4-CH3C6H4
3-CH3C6H4
2-CH3C6H4
4-FC6H4
9
4-CH3
2k
2l
10
11
4-CH3
4-CH3
2m
a Reaction conditions: 3 (0.55 mmol), 4 (0.5 mmol), DDQ (0.55 mmol),
DCE (3 mL), r.t., 10 min; FeCl3 (0.025 mmol), 80 °C, 1 h; Chloranil (1.05
mmol), 80 °C, 1–2 h.
b Isolated yield.
c 1,4-Dioxane (3 mL) as solvent.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

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D. Cheng et al.
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Synthesis
Further, gram-scale oxidative annulation of 1a under
similar reaction conditions provided the desired product 2a
in good yield (80% isolated yield) (Scheme 3).
In summary, an efficient method for the synthesis of
2,4-diarylquinolines from o-allylanilines that uses recycla-
ble Chloranil as the oxidant has been developed. The corre-
sponding products are obtained in moderate to excellent
yields. Additionally, a one-pot protocol is extended to the
synthesis of 2,4-diarylquinolines from easily available ani-
lines and 1,3-diarylpropenes through a three-step tandem
reaction, which involves oxidative coupling, rearrangement,
and oxidative annulation.
N
Ph
Chloranil (2.1 equiv)
DCE, 80 °C, 2 h
NH2
Ph
Ph
Ph
1 gram scale, 80%
1a
2a
Scheme 3 Gram-scale synthesis
To establish the mechanism of reaction, a series of con-
trol experiments were conducted (Scheme 4). The desired
product 2a was obtained in good yield when 2.1 equiva-
lents of radical scavenger 2,2,6,6-tetramethylpiperidine-1-
oxyl (TEMPO), butylated hydroxytoluene (BHT), or 1,1-di-
phenylethene (DPE) was added to the reaction mixture,
which indicated that a radical process was disfavored in the
oxidative annulation. Based on our previous work and on
the above results, a plausible mechanism is proposed in
Scheme 5. Firstly, 4-methylaniline 3a reacts with 1,3-di-
phenylpropene 4a in the presence of DDQ to give 5a, which
then rearranges to give o-allylaniline 1a. The latter reacts
with Chloranil to afford the ion pair II via charge-transfer
complex I and subsequent hydride transfer.23 Finally, attack
of the amino group on the allylic cation occurs, followed by
oxidative dehydro-aromatization to generate the product
2a.
Column chromatography was carried out on silica gel (200–300
mesh). 1H NMR spectra were recorded with a 500 MHz spectrometer
(Bruker AVANCE III 500MHz NMR spectrometer) or 600 MHz spec-
trometer (Bruker Ascend™ 600MHz superconducting NMR spectrom-
eter). 13C NMR spectra were recorded with a 125 MHz spectrometer
(Bruker AVANCE III 500MHz NMR spectrometer) or 150 MHz spec-
trometer (Bruker AscendTM 600MHz superconducting NMR spec-
trometer). Chemical shifts are reported in parts per million () rela-
tive to the internal standard TMS (0 ppm) for CDCl3 or DMSO. The
coupling constants, J, are reported in hertz (Hz). High-resolution mass
spectra (HRMS) were recorded with a ESI-TOF (Agilent 6210 TOF
LC/MS). Melting points were measured with a SGW X-4. The reagents
were purchased from commercial chemical reagent companies and
used without further purification unless otherwise stated. o-Allyl-
aniline 1 was prepared according to reported procedures.24
Synthesis of 2 through Oxidative Annulation; General Procedure
In a 10 mL round-bottomed flask o-allylaniline 1 (0.5 mmol) was dis-
solved in DCE (3 mL), then Chloranil (1.05 mmol, 0.2582 g) was added.
The reaction mixture was stirred at 80 °C for 2 h. After the reaction,
chloroform (10 mL) was added and the organic layer was washed with
2 N NaOH solution to remove tetrachlorohydroquinone completely,
then with brine, dried over Na2SO4, and filtered. The solution was
concentrated to dryness under reduced pressure and the crude prod-
uct was purified by column chromatography on silica gel (200–300
mesh) with petroleum ether and EtOAc (10:1–80:1) as eluent to give
the pure product 2.
N
Ph
Chloranil (2.1 equiv)
radical scavenger (2.1 equiv)
NH2
DCE, 80 °C
Ph
Ph
Ph
1a
2a
TEMPO: 60%
BHT: 59%
DPE: 77%
Synthesis of 2 through One-Pot Reaction; General Procedure
Scheme 4 Control experiments
A solution of 1,3-diarylpropene 4 (0.5 mmol) and DDQ (0.55 mmol,
0.1249 g) in DCE (3 mL) was stirred at r.t. for 5 minutes. Aniline 3
(0.55 mmol) was added and the solution was stirred for 10 minutes,
then FeCl3 (0.025 mmol, 0.0041 g) was added and the reaction mix-
ture was stirred at 80 °C for 1 h. Finally, Chloranil (1.05 mmol, 0.2582
g) was added and the mixture was stirred at 80 °C for another 2 h. Af-
ter completion of the reaction, the solution was concentrated under
reduced pressure and the product was purified by column chroma-
tography on silica gel (200–300 mesh) with petroleum ether and
EtOAc (10:1–60:1) as eluent to give the pure product 2.
FeCl3
DDQ
Ph
Ph
NH
3a
+
rearrangement
4a
Ph
Ph
5a
O
Cl
Cl
Cl
Ph
CA
NH2
Ph
Cl
Ph
O
For the recyclability of Chloranil and its use in the one-pot synthesis
of 2,4-diarylquinones, see the Supporting Information.
NH2 Ph
1a
I
H
N
O
Ph
Ph
Cl
Cl
Cl
6-Methyl-2,4-diphenylquinoline (2a)
CA
2a
Reaction time: 1 h; purification by column chromatography on silica
gel (200–300 mesh) with petroleum ether and EtOAc (15:1) as eluent.
Yield: 0.1374 g (93%); yellow solid; mp 127–129 °C (lit.25 130–
131 °C).
Cl
Ph
NH2
Ph
OH
II
Scheme 5 Proposed mechanism
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

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D. Cheng et al.
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Synthesis
1H NMR (500 MHz, CDCl3):  = 8.23–8.18 (m, 3 H), 7.82 (s, 1 H), 7.69
(s, 1 H), 7.61–7.53 (m, 8 H), 7.50–7.47 (m, 1 H), 2.51 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 156.0, 148.5, 147.4, 139.8, 138.7,
136.2, 131.7, 129.9, 129.5, 129.1, 128.8, 128.6, 128.3, 127.5, 125.7,
124.4, 119.4, 21.8.
13C NMR (126 MHz, CDCl3):  = 157.2, 148.5, 147.4, 139.1, 137.7,
133.1, 131.8, 129.7, 129.5, 128.9, 128.84, 128.75, 127.8, 127.6, 127.0,
120.5, 120.0.
HRMS (ESI): m/z [M + H]+ calcd for C21H15BrN: 360.0382; found:
360.0379.
HRMS (ESI): m/z [M + H]+ calcd for C22H18N: 296.1434; found:
296.1435.
6-Nitro-2,4-diphenylquinoline (2f)
Reaction time: 2 h; purification by column chromatography on silica
gel (200–300 mesh) with petroleum ether and EtOAc (10:1) as eluent.
6-Methoxy-2,4-diphenylquinoline (2b)
Reaction time: 2 h; purification by column chromatography on silica
gel (200–300 mesh) with petroleum ether and EtOAc (10:1) as eluent.
Yield: 0.1240 g (76%); white solid; mp 204–206 °C (lit.15 197–200 °C).
1H NMR (500 MHz, DMSO-d6):  = 8.71 (d, J = 2.4 Hz, 1 H), 8.53 (dd, J =
9.2, 2.5 Hz, 1 H), 8.44–8.42 (m, 2 H), 8.36 (d, J = 9.2 Hz, 1 H), 8.29 (s,
1 H), 7.76–7.59 (m, 8 H).
HRMS (ESI): m/z [M + H]+ calcd for C21H15N2O2: 327.1128; found:
327.1141.
Yield: 0.1246 g (80%); yellow solid; mp 296–298 °C.
1H NMR (500 MHz, CDCl3):  = 8.20–8.18 (m, 3 H), 7.80 (s, 1 H), 7.62–
7.52 (m, 7 H), 7.48–7.45 (m, 1 H), 7.43 (dd, J = 9.2, 2.8 Hz, 1 H), 7.22
(d, J = 2.8 Hz, 1 H), 3.82 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 157.8, 154.6, 147.8, 144.9, 139.7,
138.8, 131.6, 129.4, 129.0, 128.8, 128.7, 128.4, 127.3, 126.7, 121.8,
119.7, 103.7, 55.5.
6,8-Dimethyl-2,4-diphenylquinoline (2g)
Reaction time: 2 h; purification by column chromatography on silica
gel (200–300 mesh) with petroleum ether and EtOAc (40:1) as eluent.
HRMS (ESI): m/z [M + H]+ calcd for C22H18NO: 312.1383; found:
312.1378.
Yield: 0.1330 g (86%); white solid; mp 124–126 °C.
1H NMR (500 MHz, CDCl3):  = 8.35–8.33 (m, 2 H), 7.86 (s, 1 H), 7.60–
7.55 (m, 8 H), 7.51–7.49 (m, 2 H), 2.99 (s, 3 H), 2.48 (s, 3 H).
6-Fluoro-2,4-diphenylquinoline (2c)
Reaction time: 2 h; purification by column chromatography on silica
gel (200–300 mesh) with petroleum ether and EtOAc (40:1) as eluent.
13C NMR (126 MHz, CDCl3):  = 154.0, 148.6, 146.3, 139.9, 139.2,
137.6, 135.7, 131.9, 129.6, 129.1, 128.7, 128.5, 128.1, 127.4, 125.7,
122.3, 118.7, 21.8, 18.3.
Yield: 0.1317 g (88%); light-yellow solid; mp 98–100 °C.
1H NMR (500 MHz, CDCl3):  = 8.27 (dd, J = 9.1, 5.6 Hz, 1 H), 8.21–8.20
HRMS (ESI): m/z [M + H]+ calcd for C23H20N: 310.159; found:
(m, 2 H), 7.86 (s, 1 H), 7.60–7.48 (m, 10 H).
310.1582.
13C NMR (126 MHz, CDCl3):  = 161.8 (d, J = 245.8 Hz), 156.3 (d, J =
2.7 Hz), 148.8, 148.7, 145.9, 139.3, 138.0, 132.5 (d, J = 9.0 Hz), 129.43,
129.36, 128.9, 128.8, 128.7, 127.5, 126.5 (d, J = 9.6 Hz), 119.9, 119.7
(d, J = 25.6 Hz), 109.1 (d, J = 23.0 Hz).
6,8-Dimethoxy-2,4-diphenylquinoline (2h)
Reaction time: 2 h; purification by column chromatography on silica
gel (200–300 mesh) with petroleum ether and EtOAc (15:1) as eluent.
HRMS (ESI): m/z [M + H]+ calcd for C21H15FN: 300.1183; found:
Yield: 0.1588 g (93%); white solid; mp 147–149 °C (lit.25 145–148 °C).
300.1174.
1H NMR (500 MHz, CDCl3):  = 8.16–8.15 (m, 2 H), 7.69 (s, 1 H), 7.62–
7.55 (m, 5 H), 7.54–7.51 (m, 3 H), 7.46–7.43 (m, 1 H), 7.19 (s, 1 H),
4.10 (s, 3 H), 3.87 (s, 3 H).
6-Chloro-2,4-diphenylquinoline (2d)
Reaction time: 2 h; purification by column chromatography on silica
gel (200–300 mesh) with petroleum ether and EtOAc (60:1) as eluent.
Yield: 0.1200 g (76%); white solid; mp 97–99 °C (lit.15 92–95 °C).
13C NMR (126 MHz, CDCl3):  = 155.1, 152.5, 149.8, 147.5, 146.0,
139.9, 139.0, 129.3, 128.9, 128.8, 128.7, 128.3, 127.3, 121.1, 117.9,
108.7, 103.4, 56.2, 55.9.
1H NMR (500 MHz, CDCl3):  = 8.22–8.19 (m, 3 H), 7.89 (d, J = 2.1 Hz,
1 H), 7.86 (s, 1 H), 7.69 (dd, J = 9.0, 2.2 Hz, 1 H), 7.61–7.54 (m, 7 H),
7.51–7.48 (m, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C23H20NO2: 342.1489; found:
342.1489.
13C NMR (126 MHz, CDCl3):  = 157.0, 148.5, 147.2, 139.2, 137.8,
132.2, 131.7, 130.5, 129.6, 129.4, 128.9, 128.8, 128.7, 127.5, 126.5,
124.5, 120.0.
6,7-Dimethoxy-2,4-diphenylquinoline (2i)
Reaction time: 2 h; purification by column chromatography on silica
gel (200–300 mesh) with petroleum ether and EtOAc (20:1) as eluent.
HRMS (ESI): m/z [M + H]+ calcd for C21H15ClN: 316.0888; found:
Yield: 0.1161 g (68%); white solid; mp 164–165 °C (lit.15 160–162 °C).
316.0885.
1H NMR (500 MHz, CDCl3):  = 8.21–8.20 (m, 2 H), 7.81 (s, 1 H), 7.60–
7.55 (m, 4 H), 7.53–7.49 (m, 3 H), 7.44–7.41 (m, 1 H), 6.77 (s, 2 H),
4.11 (s, 3 H), 3.79 (s, 3 H).
6-Bromo-2,4-diphenylquinoline (2e)
Reaction time: 2 h; purification by column chromatography on silica
gel (200–300 mesh) with petroleum ether and EtOAc (60:1) as eluent.
Yield: 0.1621 g (90%); pale-yellow solid; mp 150–152 °C (lit.26 152–
154 °C).
1H NMR (500 MHz, CDCl3):  = 8.21 (d, J = 8.2 Hz, 2 H), 8.14 (d, J =
8.9 Hz, 1 H), 8.06 (d, J = 1.8 Hz, 1 H), 7.85 (s, 1 H), 7.82 (dd, J = 9.0,
2.1 Hz, 1 H), 7.61–7.53 (m, 7 H), 7.51–7.48 (m, 1 H).
13C NMR (126 MHz, CDCl3):  = 158.1, 156.8, 153.4, 147.8, 139.8,
139.1, 137.4, 129.3, 128.8, 128.7, 128.6, 128.3, 127.5, 127.4, 120.4,
101.2, 95.3, 56.3, 55.4.
HRMS (ESI): m/z [M + H]+ calcd for C23H20NO2: 342.1489; found:
342.1486.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

F
D. Cheng et al.
Paper
Synthesis
6-Methyl-2,4-di-p-tolylquinoline (2j)
2,4-Bis(4-chlorophenyl)-6-methylquinoline (2n)
Reaction time: 2 h; purification by column chromatography on silica
gel (200–300 mesh) with petroleum ether and EtOAc (30:1) as eluent.
Reaction time: 5 h; purification by column chromatography on silica
gel (200–300 mesh) with petroleum ether and EtOAc (80:1) as eluent.
Yield: 0.1455 g (90%); light-yellow solid; mp 105–107 °C (lit.25 105–
106 °C).
1H NMR (500 MHz, CDCl3):  = 8.17 (d, J = 8.6 Hz, 1 H), 8.13 (d, J =
8.2 Hz, 2 H), 7.79 (s, 1 H), 7.71 (s, 1 H), 7.58 (dd, J = 8.6, 1.8 Hz, 1 H),
7.49 (d, J = 8.0 Hz, 2 H), 7.40 (d, J = 7.8 Hz, 2 H), 7.36 (d, J = 8.0 Hz,
2 H), 2.51 (2 s, 2 × CH3, 6 H), 2.47 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 156.0, 148.4, 147.4, 139.1, 138.1,
137.0, 135.9, 135.8, 131.6, 129.8, 129.51, 129.46, 129.26, 127.33,
125.7, 124.4, 119.2, 21.8, 21.3.
Yield: 0.1020 g (56%); white solid; mp 183–184 °C (lit.15 182–185 °C).
1H NMR (500 MHz, CDCl3):  = 8.16–8.12 (m, 3 H), 7.70 (s, 1 H), 7.60
(d, J = 7.0 Hz, 2 H), 7.55 (d, J = 8.4 Hz, 2 H), 7.49 (d, J = 8.4 Hz, 4 H),
2.50 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 154.6, 147.5, 147.2, 137.8, 136.9,
136.8, 135.5, 134.6, 132.2, 130.8, 129.8, 129.0, 128.9, 128.7, 125.5,
124.1, 118.8, 21.9.
HRMS (ESI): m/z [M + H]+ calcd. for C22H16Cl2N: 364.0654; found:
364.0643.
HRMS (ESI): m/z [M + H]+ calcd for C24H22N: 324.1747; found:
324.1757.
2,4-Bis(4-bromophenyl)-6-methylquinoline (2o)
Reaction time: 2 h; purification by column chromatography on silica
gel (200–300 mesh) with petroleum ether and EtOAc (80:1) as eluent.
6-Methyl-2,4-di-m-tolylquinoline (2k)
Reaction time: 2 h; purification by column chromatography on silica
gel (200–300 mesh) with petroleum ether and EtOAc (40:1) as eluent.
Yield: 0.1133 g (50%); yellow solid; mp 182–184 °C (lit.15 188–190 °C).
1H NMR (500 MHz, CDCl3):  = 8.15 (d, J = 8.4 Hz, 1 H), 8.08–8.06 (m,
2 H), 7.73–7.70 (m, 3 H), 7.67–7.64 (m, 2 H), 7.61–7.59 (m, 2 H), 7.45–
7.42 (m, 2 H), 2.50 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 154.7, 147.6, 147.3, 138.3, 137.3,
136.9, 132.2, 132.0, 131.9, 131.1, 129.8, 129.0, 125.5, 124.1, 123.9,
122.8, 118.7, 21.9.
Yield: 0.1472 g (91%); light-yellow solid; mp 93–95 °C.
1H NMR (500 MHz, CDCl3):  = 8.21 (d, J = 10.0 Hz, 1 H), 8.09 (s, 1 H),
8.01 (d, J = 7.8 Hz, 1 H), 7.82 (s, 1 H), 7.72 (s, 1 H), 7.61 (dd, J = 8.6,
1.9 Hz, 1 H), 7.50–7.36 (m, 5 H), 7.31 (d, J = 5.0 Hz, 1 H), 2.52 (2 s, 3 × CH3,
9 H).
13C NMR (126 MHz, CDCl3):  = 156.2, 148.7, 147.2, 139.6, 138.6,
138.5, 138.4, 136.2, 131.8, 130.2, 120.0, 129.7, 129.0, 128.7, 128.4,
128.2, 126.7, 125.8, 124.7, 124.5, 119.5, 21.8, 21.6, 21.5.
HRMS (ESI): m/z [M + H]+ calcd for C22H16Br2N: 451.9644; found:
451.9651.
HRMS (ESI): m/z [M + H]+ calcd for C24H22N: 324.1747; found:
324.1751.
2,4-Bis(3-chlorophenyl)-6-methylquinoline (2p)
Reaction time: 2 h; purification by column chromatography on silica
gel (200–300 mesh) with petroleum ether and EtOAc (40:1) as eluent.
6-Methyl-2,4-di-o-tolylquinoline (2l)
Yield: 0.1275 g (70%); white solid; mp 124–125 °C.
Reaction time: 2 h; purification by column chromatography on silica
gel (200–300 mesh) with petroleum ether and EtOAc (20:1) as eluent.
1H NMR (500 MHz, CDCl3):  = 8.22 (d, J = 1.9 Hz, 1 H), 8.16 (d, J =
8.4 Hz, 1 H), 8.07–8.05 (m, 1 H), 7.72 (s, 1 H), 7.62–7.43 (m, 8 H), 2.51
(s, 3 H).
13C NMR (126 MHz, CDCl3):  = 154.3, 140.7, 140.2, 137.2, 135.0,
134.7, 132.3, 130.1, 129.9, 129.5, 129.3, 128.6, 127.8, 127.6, 125.61,
125.55, 124.1, 119.0, 21.9.
Yield: 0.0986 g (61%); light-yellow oil.
1H NMR (500 MHz, CDCl3):  = 8.17 (d, J = 8.6 Hz, 1 H), 7.61–7.58 (m,
2 H), 7.43–7.41 (m, 3 H), 7.36–7.30 (m, 6 H), 2.48 (2 s, 2 × CH3, 6 H),
2.15 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 158.8, 147.7, 146.7, 140.7, 137.9,
136.4, 136.1, 136.0, 131.8, 130.8, 130.2, 129.8, 129.7, 129.6, 128.4,
128.3, 126.0, 125.79, 125.76, 124.5, 122.8, 21.7, 20.4, 20.1.
HRMS (ESI): m/z [M + H]+ calcd for C22H16Cl2N: 364.0654; found:
364.0661.
HRMS (ESI): m/z [M + H]+ calcd for C24H22N: 324.1747; found:
324.1736.
Mixture of 4-(4-Chlorophenyl)-6-methyl-2-phenylquinoline and
2-(4-Chlorophenyl)-6-methyl-4-phenylquinoline as 3:4 (2q)
Reaction time: 1 h; purification by column chromatography on silica
gel (200–300 mesh) with petroleum ether and EtOAc (80:1) as eluent.
2,4-Bis(4-fluorophenyl)-6-methylquinoline (2m)
Reaction time: 2 h; purification by column chromatography on silica
gel (200–300 mesh) with petroleum ether and EtOAc (60:1) as eluent.
Yield: 0.1567 g (95%); white solid.
1H NMR (500 MHz, CDCl3):  = 8.20–8.18 (m, 1 H), 8.16–8.14 (m,
3/7×5 H), 7.75 (d, J = 4.2 Hz, 1 H), 7.67 (s, 1 H), 7.60–7.48 (m,
5+4/7×5 H), 2.50 (s, 3/7×3 H), 2.50 (s, 4/7×3 H).
13C NMR (126 MHz, CDCl3):  = 156.0, 154.6, 148.7, 147.3, 139.5,
138.5, 138.1, 137.0, 136.6, 135.4, 134.5, 131.98, 131.96, 130.9, 129.9,
129.8, 129.5, 129.3, 129.0, 128.87, 128.85, 128.7, 128.6, 128.4, 127.5,
125.8, 125.5, 124.4, 124.1, 119.3, 119.0, 21.8.
Yield: 0.1325 g (80%); white solid; mp 138–140 °C.
1H NMR (500 MHz, CDCl3):  = 8.20–8.14 (m, 3 H), 7.70 (s, 1 H), 7.62
(s, 1 H), 7.58 (dd, J = 8.6, 1.8 Hz, 1 H), 7.54–7.52 (m, 2 H), 7.29–7.25
(m, 2 H), 7.22–7.18 (m, 2 H), 2.50 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 164.7, 163.8, 162.7, 161.9, 154.8,
147.5, 147.3, 136.5, 135.69, 135.66, 134.44, 134.42, 131.9, 131.2,
131.1, 129.8, 129.3, 129.2, 125.6, 124.1, 118.9, 115.74, 115.70, 115.6,
115.5, 21.8.
HRMS (ESI): m/z [M + H]+ calcd for C22H17ClN: 330.1044; found:
330.1054.
HRMS (ESI): m/z [M + H]+ calcd for C22H16F2N: 332.1245; found:
332.1249.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

G
D. Cheng et al.
Paper
Synthesis
Mixture of 6-Methyl-4-phenyl-2-(p-tolyl)quinoline and 6-Methyl-
2-phenyl-4-(p-tolyl)quinoline as 3:1 (2r)
Zuñiga, O. M. P.; Romanelli, G. P.; Fernandes, S. A. Bioorg. Med.
Chem. 2017, 25, 1153. (c) Alonso, C.; Fuertes, M.; Martín-Encinas,
E.; Selas, A.; Rubiales, G.; Tesauro, C.; Knudssen, B. K.; Palacios, F.
Eur. J. Med. Chem. 2018, 149, 225.
Reaction time: 2 h; purification by column chromatography on silica
gel (200–300 mesh) with petroleum ether and EtOAc (25:1) as eluent.
(9) (a) Tokunaga, M.; Eckert, M.; Wakatsuki, Y. Angew. Chem. Int. Ed.
1999, 38, 3222. (b) Korivi, R. P.; Cheng, C.-H. J. Org. Chem. 2006,
71, 7079. (c) Horn, J.; Marsden, S. P.; Nelson, A.; House, D.;
Weingarten, G. G. Org. Lett. 2008, 10, 4117. (d) Wang, Y.; Chen,
C.; Peng, J.; Li, M. Angew. Chem. Int. Ed. 2013, 52, 5323. (e) Zhou,
W.; Lei, J. Chem. Commun. 2014, 50, 5583. (f) Trillo, P.; Pastor, I.
M. Adv. Synth. Catal. 2016, 358, 2929. (g) Zheng, W.; Yang, W.;
Luo, D.; Min, L.; Wang, X.; Hu, Y. Adv. Synth. Catal. 2019, 361,
1995. (h) Kundal, S.; Chakraborty, B.; Paul, K.; Jana, U. Org.
Biomol. Chem. 2019, 17, 2321.
Yield: 0.1392 g (90%); white solid.
1H NMR (500 MHz, CDCl3):  = 8.24–8.19 (m, 1+3/4×2 H), 8.14 (d, J =
8.2 Hz, 1/4×2 H), 7.81 (d, 1 H), 7.74 (s, 3/4×1 H), 7.69 (s, 1/4×1 H),
7.61–7.55 (m, 4 H), 7.51–7.49 (m, 2 H), 7.40 (d, J = 7.9 Hz, 3/4×2 H),
7.37 (d, J = 8.0 Hz, 1/4×2 H), 2.53–2.47 (m, 6 H).
13C NMR (126 MHz, CDCl3):  = 156.0, 148.5, 147.4, 139.8, 139.2,
138.7, 138.2, 136.9, 136.1, 136.0, 135.7, 131.7, 129.8, 129.7, 129.52,
129.49, 129.4, 129.3, 129.1, 128.8, 128.5, 128.2, 127.5, 127.3, 125.8,
125.6, 124.44, 124.35, 119.3, 119.2, 21.8, 21.3.
(10) (a) Johnson, W. S.; Mathews, F. J. J. Am. Chem. Soc. 1944, 66, 210.
(b) Born, J. L. J. Org. Chem. 1972, 37, 3952.
HRMS (ESI): m/z [M + H]+ calcd for C23H20N: 310.159; found:
310.1577.
(11) (a) Martínez, R.; Ramón, D. J.; Yus, M. Eur. J. Org. Chem. 2007,
1599. (b) Martínez, R.; Ramón, D. J.; Yus, M. J. Org. Chem. 2008,
73, 9778. (c) Marco-Contelles, J.; Pérez-Mayoral, E.; Samadi, A.;
Carreiras, M. D. C.; Soriano, E. Chem. Rev. 2009, 109, 2652.
(d) Anand, N.; Koley, S.; Ramulu, B. J.; Singh, M. S. Org. Biomol.
Chem. 2015, 13, 9570. (e) Das, K.; Mondal, A.; Srimani, D. Chem.
Commun. 2018, 54, 10582. (f) Das, S.; Maiti, D.; De Sarkar, S.
J. Org. Chem. 2018, 83, 2309.
Funding Information
The authors are grateful to the Natural Science Foundation of China
(21602197) and the Natural Science Foundation of Zhejiang Province
(LY18B020018).
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Eur. J. 2009, 15, 6332. (b) Kulkarni, A.; Török, B. Green Chem.
2010, 12, 875. (c) Rotzoll, S.; Willy, B.; Schönhaber, J.; Rominger,
F.; Müller, T. J. J. Eur. J. Org. Chem. 2010, 3516. (d) Zhang, X.; Liu,
B.; Shu, X.; Gao, Y.; Lv, H.; Zhu, J. J. Org. Chem. 2012, 77, 501.
(e) Meyet, C. E.; Larsen, C. H. J. Org. Chem. 2014, 79, 9835.
(f) Deshidi, R.; Devari, S.; Shah, B. A. Org. Chem. Front. 2015, 2,
515. (g) Jiang, K.-M.; Kang, J.-A.; Jin, Y.; Lin, J. Org. Chem. Front.
2018, 5, 434.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691740.
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