FeCl3-Mediated One-Pot Cyclization–Aromatization of Anilines, Benzaldehydes, and Phenylacetylenes under Ball Milling: A New Alternative for the Synthesis of 2,4-Diphenylquinolines

Article abstract of DOI:10.1002/jccs.201700190

A straightforward and efficient method has been developed for the solvent-free synthesis of 2,4-diphenylquinolines via a one-pot reaction of anilines, benzaldehydes, and phenylacetylenes promoted by FeCl₃ under solvent-free mechanochemical ball

Full text of DOI:10.1002/jccs.201700190

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Special Issue Paper
FeCl3-Mediated One-Pot Cyclization–Aromatization of Anilines, Benzaldehydes,
and Phenylacetylenes under Ball Milling: A New Alternative for the Synthesis
of 2,4-Diphenylquinolines
a
Ya-Jun Tan,a Fang-Jian Wang,a Abdullah M. Asirib,b Hadi M. Marwanibb and Ze Zhang
*
aSchool of Biological and Chemical Engineering, Anhui Polytechnic University, Wuhu 241000, P. R. China
bChemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
(Received: May 31, 2017; Accepted: July 5, 2017; DOI: 10.1002/jccs.201700190)
A straightforward and efficient method has been developed for the solvent-free synthesis of
2,4-diphenylquinolines via a one-pot reaction of anilines, benzaldehydes, and phenylacetylenes
promoted by FeCl3 under solvent-free mechanochemical ball milling. Using this protocol,
a series of 2,4-diphenylquinolines were synthesized in good to excellent yield (74–95%) just by
washing the resulting reaction mixture with water and recrystallizing in EtOH/H2O without
any extraction or column chromatography work-up.
Keywords: Quinoline; Ball milling; Ferric trichloride; One-pot; Solvent free.
Ze Zhang obtained the Ph.D. degree from the University of Science & Technology of China in 2005, working
on mechanochemistry under the supervision of Prof. Guan-Wu Wang. He carried out postdoctoral work in Prof.
Tien-Yau Luh’s group at the National Taiwan University (2006–2007) and the Shanghai Institute of Organic
Chemistry (2007–2008). He has been a Full Professor at Anhui Polytechnic University since November of
2013. His current research interests include organic synthetic methodology and mechanochemistry.
INTRODUCTION
Quinoline is a common heterocyclic scaffold in
one employs the ortho-substituted anilines as the
C─C─C─N unit (b).4
many natural and synthetic compounds of medicinal
and biological significance. Consequently, there has
been growing attention and interest in the develop-
ment of synthetic methods for quinoline derivatives
bearing diverse substitution patterns.1 Since Skraup
reported the synthesis of quinoline in 1880 for the
first time,2 a large number of synthetic methods have
been extensively developed and well documented,
including the use of various new catalysts, reaction
media, physical conditions, multicomponent or cas-
cade synthetic strategy, and so on.3 Conceptually,
these methods can be classified into two approaches
(Figure 1): the first one relates to the use of the aro-
matic amine as the nucleophilic component providing
nitrogen as the C─C─N unit (a), and the second
Forthrightly, most of them are efficient enough,
but there are still some disadvantages such as harsh
reaction conditions, extended reaction times, limited
availability of the starting materials, tedious work-up
procedures, and the use of expensive catalysts or envi-
ronmentally harmful solvents. Keeping in view the
importance of the quinoline scaffold in pharmaceutical
and synthetic chemistry, it is necessary to circumvent
these problems by developing more convenient and effi-
cient methods. A powerful alternative is to perform
these reactions under ball milling, a novel solvent-free
technique that has been contributing more and more to
the efficient promotion of various organic transforma-
tions.5,6 This technique can provide high mechanical
energy and high local concentration of the reactants,
*Corresponding author. Email: zhangze@ustc.edu.cn
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1

Special Issue Paper
Tan et al.
of imine 5 with phenylacetylene very smoothly to gener-
ate dihydroquinoline 6 (entry 1–11) even in the presence
of a catalyst (entry 2, 4, 9, 11). In contrast, FeCl3 shows
the best efficiency. Although dihydroquinoline 6 can be
easily oxidized into the corresponding quinoline 4a in
the presence of air, the reaction system used here was
sealed and thus mostly suffered from inadequate oxi-
dant. Therefore, the generated dihydroquinoline 6 was
converted into quinoline 4a to a very poor extent with
the aid of the air in the reaction vessel. But when using
enough FeCl3, this conversion was almost completely
accomplished (entry 5–7) because of its strong oxidizing
ability.
C
N
C
C
C
C
+
C
+
C
N
(a)
(b)
C
C
N
N
C
C
C
+
C
C
C
N
N
Fig. 1. Common synthetic strategies towards quinolone.
These results, together with the effects to be
described later from different substituents in the ani-
lines, benzaldehydes, and phenylacetylene for formation
of various 2,4-diphenylquinolines, can be well under-
stood from the reaction mechanism (Scheme 1).
Although there are some minor controversies, it can
still be outlined as shown in Scheme 1 based on the cur-
rent experimental results and together with comprehen-
sive analysis and evaluation in various reports. Initially,
the intermediate A was formed by coordination of
Fe(III) with phenylacetylene 3 and imine 5, which was
in situ generated from aniline 1 and benzaldehyde 2.9
Then, the addition of the alkyne to the imine forms the
propargylamine intermediate B,10 in which the triple
bond is activated by Fe(III) to undergo an intramolecu-
lar hydroarylation through the aniline aromatic-ring
nitrogen,7a,11 resulting in the Fe(III) vinylate complex
and thus may be more suitable for multicomponent
reactions.
On the other hand, FeCl3 is a highly attractive
Lewis acid catalyst for construction of various hetero-
cycles from an environmental and economic point of
view.7 We therefore envisaged that synergies arising
from the combined use of ball milling and FeCl3 could
lead to an efficient method for the synthesis of quino-
lines. In continuation of our efforts to develop new
solvent-free methods for the synthesis of nitrogen-
containing compounds using the ball milling
technique,8 we report here a straightforward and practi-
cal one-pot synthesis of 2,4-diphenylquinolines via
cyclization–aromatization of anilines, benzaldehydes,
and phenylacetylenes catalyzed by FeCl3 under ball
milling.
C.12 The intermediate
C subsequently undergoes
RESULTS AND DISCUSSION
decomposition to regenerate Fe(III) for next catalytic
cycle and gives dihydroquinoline 6,13 which would be
further oxidized into quinoline 4 in the presence of
excessive Fe(III) and air. It should be pointed out that
we did not detect the propargylamine B in the reaction
mixture, which may imply that the formation of inter-
mediate B and the subsequent hydroarylation reaction
involve a cooperative process.
Considering its easy availability, low price, sus-
tainability, nontoxicity, and environmentally friendly
nature,14 we next selected FeCl3 to clarify the generality
of substrate scope by using various aldehydes, alkynes,
and amines for the synthesis of various 2,4-diphenylqui-
nolines. The results are summarized in Table 2.
Before the formal synthesis of 2,4-diphenylquino-
lines, we first selected the cyclization–aromatization of
phenylacetylene with in situ generated imine from 4-
methoxylaniline and 3-nitrobenaldehyde as the model
reaction to screen an optimal catalyst (Table 1).
As shown in Table 1, we attempted various Lewis
acids and Brønsted acids that have been widely
employed in the traditional synthesis of quinoline deri-
vatives. The experimental results demonstrated that rel-
atively weak Lewis acids and Brønsted acids work too
inefficiently or cannot work at all for the transforma-
tion of imine 5 into dihydroquinoline 6 even when a
large excess of them was employed (entry 12–20).
Strong Lewis acids such as ZnCl2, AlCl3, FeCl3, and
BF3ÁOEt2 promoted the addition–cyclization reaction
As shown in Table 2, a wide range of structurally
diverse benzaldehydes, phenylacetylenes, and anilines
2
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Mechanochemical synthesis of 2,4-diphenylquinoline
Table 1. Screening of optimal condition for the synthesis of 6-methoxy-2-(3-nitro-phenyl)-4-phenyl-quinoline (4a) under ball
millinga
OMe
OMe
N
OMe
N
OMe
N
NH2
+
[O]
ball milling
_
2H
catalyst
30 Hz, 40 min
CHO
ball milling
30 Hz, 75 min
NO2
NO2
NO2
NO2
4a
5
6
Entry
Catalyst (equiv.)
Conversion of 5 (%)b
Yield for 6 (%)c
Yield for 4a (%)c
1
2
3
4
5
6
7
8
ZnCl2 (2.5)
ZnCl2 (0.25)
AlCl3 (2.5)
AlCl3 (0.25)
FeCl3 (2.5)
FeCl3 (2.0)
94
90
96
73
70
74
72
18
18
19
18
93
92
87
64
27
18
17
Trace
Trace
12
94
>99
>99
>99
>99
94
97
93
<5
<5
21
Not detected
Trace
<5
FeCl3 (1.5)
FeCl3 (1.0)
30
63
73
70
9
FeCl3 (0.25)
BF3ÁEt2O (1.25)
BF3ÁEt2O (0.25)
Mn(OAc)3 (2.5)
Co(OAc)2 (2.5)
Cu(OTf )2 (2.5)
Cu(OAc)2 (2.5)
CuCl2 (2.5)
DDQ (2.5)
CuI (2.5)
TsOH (2.5)
CF3SO3H (2.5)
TFA (2.5)
10
11
12
13
14
15
10
16
17
18
19
20
Trace
Trace
Trace
Trace
Trace
Not detected
Trace
15
16
10
<5
<5
<5
35
38
39
Trace
Trace
Trace
17
18
16
17
18
a Reactions were carried out with 4-methoxylaniline (1.0 mmol), 3-nitrobenaldehyde (1.0 mmol), phenylacetylene (1.25 mmol)
and catalyst under ball milling at room temperature.
b Rapidly determined by GC-MS analysis on the sample solution from prompt extraction of the reaction mixture.
c Rapidly determined by GC-MS analysis on the sample solution from prompt extraction of the reaction mixture and calculated
according to 4-methoxylaniline.
gave the corresponding quinolines in good to excellent
yields. The structure of all the synthesized compounds
was confirmed by 1H NMR, 13C NMR, and high-
resolution mass spectrometry. In general, different func-
tional groups such as Me, OMe, F, Cl and NO2 are tol-
erated, and the reactions get completed within 2–3 h.
The role and high efficiency of ball milling is expected
from the high mechanical energy causing local high
pressure, friction, shear strain, and so on.5c,15 In
contrast, reactions in which anilines bearing strong
electron-donating substituents and phenylacetylenes/
benzaldehydes containing strong electron-withdrawing
substituents proceeded more smoothly, thus resulting in
relatively higher yields. This result can be reasonably
interpreted according to the mechanism in Scheme 1, in
which the electron-donating group in aniline and the
electron-withdrawing group in phenylacetylene or benz-
aldehyde may facilitate the intramolecular nucleophilic
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Tan et al.
Table 2. Synthesis of 2,4-diphenyl-quinolines 4 via imino Diels–Alder and aromatization of in situ generated imine (from
anilines 1 and benzaldehydes 2) with phenylacetylene 3 under ball millinga
R3
R1
O
R3
NH2
R2
3
1
+
R1
ball milling
Time 1
R1
N
FeCl3
R2
N
R2
ball milling
Time 2
4
2
Reaction time (min)
Time 1b Time 2c
40 75
Entry
R1
R2
R3
Product 4
Yield (%)a
1
2
3
4
5
6
7
8
4-OMe
4-Me
4-OMe
4-Me
4-OMe
4-OMe
4-Me
3-NO2
3-NO2
4-Cl
3-NO2
3-NO2
4-NO2
3-NO2
4-Cl
H
H
H
4-F
4-F
4-F
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
81
78
83
83
92
86
78
85
86
84
71
77
75
78
77
70
75
50
40
50
40
45
45
50
50
40
55
45
50
45
50
55
50
75
75
60
60
60
80
80
80
80
80
80
90
90
90
90
90
4-Me
9
4-OMe
4-OMe
4-Cl
4-Me
4-OMe
4-Me
4-Me
4-Cl
3-Me
4-Cl
10
11
12
13
14
15
16
17
3-NO2
4-NO2
4-NO2
4-Cl
3-NO2
4-Cl
4-NO2
4-NO2
a Reactions were carried out with aniline 1 (1.0 mmol) and benzaldehyde 2 (1.0 mmol), and afterward added phenylacetylene
3 (1.25 mmol) and FeCl3 (2.0 mmol) under ball milling (vibration frequency: 30 Hz) at room temperature.
b Optimized time for complete conversion of aniline 1 or benzaldehyde 2 by TLC analysis.
c Optimized time for complete conversion of in situ generated imine by TLC analysis.
d Isolated yield combined from two parallel runs by washing the resulting reaction mixture with water and recrystallization from
EtOH/H2O.
attack to the triple bond of propargylamine B. Further-
more, all the desired products 4a–q were obtained
through a very simple work-up, just involving washing
the resulting reaction mixture with water and recrystal-
lization from EtOH–H2O.
Inspired by widely reported multicomponent strat-
egy toward the synthesis of quinolines, we further
explored the three-component reaction of anilines 1,
benzaldehydes 2, and phenylacetylene 3 mediated by
FeCl3 under ball milling for the synthesis of 2,4-
diphenylquinolines 4. Gratifyingly and as expected, the
desired products 4a–q could also be obtained as effi-
ciently as that from above stepwise work. The crude
R2
R1
R3
+
NH2
OHC
R3
1
2
FeIII
R2
R2
R1
R1
N
N
A
N
R2
R1
R3
6
5
FeIII
FeII + H+
O2 (air)
H2O
FeIII
R3
FeIII
R3
R3
3
R1
..
N
R2
H
B
FeIII
R1
R1
N
H
C
N
R2
R2
4
Scheme 1. Proposed mechanism.
4
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Mechanochemical synthesis of 2,4-diphenylquinoline
Table 3. Three-component synthesis of 2,4-diphenyl-quinolines 4 from anilines 1, benzaldehydes 2, and phenylacetylene
3 mediated by FeCl3 under ball millinga
R3
R3
3
R1
+
FeCl3
NH2
R1
ball milling
120 min
1
N
O
R2
R2
4
2
Entry
R1
R2
R3
Product 4
Yield (%)b
1
2
3
4
5
6
7
8
4-OMe
4-Me
4-OMe
4-Me
4-OMe
4-OMe
4-Me
3-NO2
3-NO2
4-Cl
3-NO2
3-NO2
4-NO2
3-NO2
4-Cl
H
H
H
4-F
4-F
4-F
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
84
79
86
85
95
90
82
87
90
87
75
82
78
82
80
74
79
4-Me
9
4-OMe
4-OMe
4-Cl
4-Me
4-OMe
4-Me
4-Me
4-Cl
3-Me
4-Cl
10
11
12
13
14
15
16
17
3-NO2
4-NO2
4-NO2
4-Cl
3-NO2
4-Cl
4-NO2
4-NO2
a Reactions were carried out with aniline 1 (1.0 mmol) and benzaldehyde 2 (1.0 mmol), and afterward added phenylacetylene
3 (1.25 mmol) and FeCl3 (2.0 mmol) under ball milling (vibration frequency: 30 Hz) at room temperature for 120 min.
b Yield combined from two parallel runs by washing the resulting reaction mixture with 3% HCl and water.
products were collected just by washing the reaction
mixture with dilute hydrochloric acid and water with-
out further recrystallization, with the purity of most
products being >95%; thus the yields are somewhat
higher than the stepwise results (Table 3).
ID, film thickness 0.25 μm df ) with column flow rate of
2 mL/min and heating rate of 10ꢀC/min rising from
70ꢀC to 250ꢀC. A mixer mill (MM 400; Retsch GmbH,
Germany) was used for ball milling. Phenylacetylenes,
all liquid benzaldehydes, and anilines were further puri-
fied using standard methods before use. All solid ben-
zaldehydes and anilines were purchased from Acros or
Aldrich Chemical Co., and used without further purifi-
cation. All solvents were obtained from SCRC
(Sinopharm Chemical Reagent Co., Ltd) in AR grade
and used without further purification.
EXPERIMENTAL
General
NMR spectra were recorded on a Bruker AV300
or AV500 NMR spectrometer in CDCl3. TMS was
used as the internal standard. Chemical shifts (δ) and
J values are reported in ppm and Hz, respectively. All
melting points were determined on a XT-4 binocular
microscope (Beijing Tech Instrument Co., China) and
are not corrected. Analytical TLC and column chroma-
tography were performed on silica gel GF254, and sil-
ica gel H60, respectively. GC-MS was conducted on a
GC-MS-QP 2010 instrument (Rtx-17, 30 m × 25 mm
Typical procedure
Aniline
1
(1.0 mmol) and benzaldehyde
2 (1.0 mmol), together with a stainless ball of 7.0 mm
in diameter, were introduced into a stainless jar
(25 mL). The same mixture was also introduced into a
second similar jar. The two reaction vessels were sealed
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Tan et al.
with screw caps, fixed on the vibration arms of the ball
milling apparatus, and were vibrated vigorously at a
rate of 1800 rounds per minute (30 Hz) at room tem-
perature for the designated time (Time 1). After the ves-
sels were opened, phenylacetylene 3 (1.25 mmol) and
FeCl3 (2.0 mmol) were added into the in situ generated
imine, and the sealed vessels were continued to vibrate
for the designated time (Time 2). The combined reac-
tion mixtures were immersed in 30 mL water under
ultrasonic irradiation. After Büchner filtration and
washing with water several times until the filtrate
became colorless, the solid was collected and recrystal-
lized from EtOH/H2O (v/v = 5/1) to afford 2,4-
diphenylquinoline 4.
138.1, 135.1, 131.6, 129.4, 128.9, 128.8, 128.5, 128.5,
126.8, 122.0, 119.1, 103.7, 55.4; HRMS (ESI) m/z calcd
for C22H17ClNO (M + H)+: 346.0999, found: 346.0992.
4-(4-Fluoro-phenyl)-6-methyl-2-(3-nitro-phenyl)-quinoline
(4d)
1
Gray solid; yield: 83%; m.p. 169–171ꢀC; H NMR
(CDCl3, 500 MHz) δ (ppm) 9.00 (s, 1H, ArH), 8.54 (d,
J = 7.5 Hz, 1H, ArH), 8.27 (d, J = 8.5 Hz, 1H, ArH),
8.15 (d, J = 6.5 Hz, 1H, ArH), 7.75 (s, 1H, ArH), 7.66
(t, J = 8.0 Hz, 1H, ArH), 7.58–7.60 (m, 2H, ArH),
7.49–7.52 (m, 2H, ArH), 7.22–7.26 (m, 2H, ArH), 2.47
(s, 3H, CH3); 13C NMR (CDCl3, 125 MHz) δ (ppm)
164.0, 162.0, 153.0, 148.8, 148.1, 147.3, 141.2, 137.4,
134.1, 133.2, 132.4, 131.3, 130.0, 129.7, 126.1, 124.2,
123.8, 122.3, 118.7, 116.0, 115.7, 21.9; HRMS (ESI) m/
z calcd for C22H16FN2O2 (M + H)+: 359.1196, found:
359.1187.
6-Methoxy-2-(3-nitro-phenyl)-4-phenyl-quinoline (4a)
Yellow solid; yield: 81%; m.p. 129–131ꢀC; 1H
NMR (CDCl3, 500 MHz) δ (ppm) 9.03 (s, 1H, ArH),
8.56 (d, J = 7.5 Hz, 1H, ArH), 8.29 (d, J = 8.0 Hz,
1H, ArH), 8.16 (d, J = 9.0 Hz, 1H, ArH), 7.81 (s, 1H,
ArH), 7.69 (t, J = 7.5 Hz, 1H, ArH), 7.54–7.59 (m, 5H,
ArH), 7.44 (d, J = 9.0 Hz, 1H, ArH), 7.21 (s, 1H,
ArH), 3.82 (s, 3H, OCH3); 13C NMR (CDCl3,
125 MHz) δ (ppm) 158.3, 151.4, 148.8, 148.3, 144.8,
141.2, 138.3, 132.9, 131.7, 129.7, 129.3, 128.8, 128.7,
127.1, 123.5, 122.4, 122.0, 118.9, 103.6, 55.5; HRMS
(ESI) m/z calcd for C22H17N2O3 (M + H)+: 357.1239,
found: 357.1233.
4-(4-Fluoro-phenyl)-6-methoxy-2-(3-nitro-phenyl)-quinoline
(4e)
Brown solid; yield: 92%; m.p. 193–196ꢀC; 1H
NMR (CDCl3, 500 MHz) δ (ppm) 8.97 (s, 1H, ArH),
8.53 (d, J = 7.5 Hz, 1H, ArH), 8.26 (d, J = 8.0 Hz,
1H, ArH), 8.19 (d, J = 8.0 Hz, 1H, ArH), 7.75 (s, 1H,
ArH), 7.66 (t, J = 8.0 Hz, 1H, ArH), 7.51–7.54 (m, 2H,
ArH), 7.40–7.42 (m, 1H, ArH), 7.22–7.16 (m, 2H,
ArH), 7.10 (d, J = 2.5 Hz, 1H, ArH), 3.79 (s, 3H,
OCH3); 13C NMR (CDCl3, 125 MHz) δ (ppm) 164.0,
162.0, 158.5, 151.6, 148.8, 147.4, 144.9, 141.2, 134.2,
133.0, 131.8, 131.1, 129.8, 127.2, 123.6, 122.6, 122.1,
119.0, 116.0, 115.9, 103.4, 55.5; HRMS (ESI) m/z calcd
for C22H16FN2O3 (M + H)+: 375.1145, found:
375.1151.
6-Methyl-2-(3-nitro-phenyl)-4-phenyl-quinoline (4b)
Slightly yellow solid; yield: 78%; m.p. 146–149ꢀC;
1H NMR (CDCl3, 300 MHz) δ (ppm) 9.06 (s, 1H,
ArH), 8.59 (d, J = 7.5 Hz, 1H, ArH), 8.32 (d,
J = 7.8 Hz, 1H, ArH), 8.19 (d, J = 7.7 Hz, 1H, ArH),
7.83 (s, 1H, ArH), 7.58–7.74(m, 8H, ArH), 2.51 (s, 3H,
CH3); 13C NMR (CDCl3, 125 MHz) δ (ppm) 153.0,
149.2, 148.8, 147.4, 141.3, 138.2, 137.2, 133.2, 132.3,
130.0, 129.7, 129.5 (2C), 128.7 (2C), 128.6, 126.1,
124.5, 123.7, 122.3, 118.7, 21.9; HRMS (ESI) m/z calcd
for C22H17N2O2 (M + H)+: 341.1290, found: 341.1296.
4-(4-Fluoro-phenyl)-6-methoxy-2-(4-nitro-phenyl)-quinoline
(4f)
Brown solid; yield: 86%; m.p. 180–181ꢀC; 1H
NMR (CDCl3, 500 MHz) δ (ppm) 8.28–8.33 (m, 4H,
ArH), 7.75 (s, 1H, ArH), 7.51–7.53 (m, 2H, ArH),
7.42–7.45 (m, 1H, ArH), 7.11–7.26 (m, 3H, ArH), 7.10
(s, 1H, ArH), 3.79 (s, 3H, OCH3); 13C NMR (CDCl3,
125 MHz) δ (ppm) 164.0, 162.0, 158.7, 151.6, 148.1,
147.3, 145.4, 144.9, 134.2, 134.2, 131.9, 131.1, 131.0,
128.0, 127.3, 124.0, 122.7, 119.5, 116.1, 115.9, 103.4,
55.6; HRMS (ESI) m/z calcd for C22H16FN2O3
(M + H)+: 375.1145, found: 375.1155.
2-(4-Chloro-phenyl)-6-methoxy-4-phenyl-quinoline (4c)
1
Pale solid; yield: 83%; m.p. 118–121ꢀC; H NMR
(CDCl3, 500 MHz) δ (ppm) 8.07–8.08 (m, 3H, ArH),
7.69 (s, 1H, ArH), 7.42–7.52 (m, 6H, ArH), 7.36 (d,
J = 9.0 Hz, 1H, ArH), 7.22 (s, 1H, ArH), 7.14 (s, 1H,
ArH), 3.76 (s, 3H, OCH3); 13C NMR (CDCl3,
125 MHz) δ (ppm) 158.0, 153.1, 147.9, 144.9, 138.6,
6
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Mechanochemical synthesis of 2,4-diphenylquinoline
6-Methyl-2-(3-nitro-phenyl)-4-p-tolyl-quinoline (4g)
Slightly yellow solid; yield: 78%; m.p. 177–179ꢀC;
1H NMR (CDCl3, 500 MHz) δ (ppm) 9.06 (s, 1H,
ArH), 8.57 (d, J = 8.0 Hz, 1H, ArH), 8.31 (d,
J = 8.0 Hz, 1H, ArH), 8.16 (d, J = 9.0 Hz, 1H, ArH),
7.81 (s, 1H, ArH), 7.68–7.72 (m, 2H, ArH), 7.62 (d,
J = 9.0 Hz, 1H, ArH), 7.48 (d, J = 8.0 Hz, 2H, ArH),
7.40 (d, J = 8.0 Hz, 2H, ArH), 2.52 (s, 3H, CH3), 2.51
(s, 3H, CH3); 13C NMR (CDCl3, 125 MHz) δ (ppm)
152.8, 149.2, 148.7, 147.3, 141.3, 138.6, 137.1, 135.2,
133.1, 132.2, 129.9, 129.7, 129.4 (overlapped), 126.1,
124.6, 123.6, 122.2, 118.6, 21.9, 21.4; HRMS (ESI) m/z
calcd for C23H19N2O2 (M + H)+: 355.1447, found:
355.1440.
122.8, 122.4, 119.3, 104.0, 55.9, 21.8; HRMS (ESI) m/z
calcd for C23H19N2O3 (M + H)+: 371.1396, found:
371.1387.
6-Chloro-2-(4-nitro-phenyl)-4-p-tolyl-quinoline (4k)
Slightly yellow solid; yield: 71%; m.p. 188–189ꢀC;
1H NMR (CDCl3, 300 MHz) δ (ppm) 8.37 (s, 4H,
ArH), 8.19 (d, J = 9.0 Hz, 1H, ArH), 7.93 (s, 1H,
ArH), 7.86 (s, 1H, ArH), 7.69–7.72 (m, 1H, ArH),
7.38–7.46 (m, 4H, ArH), 2.50 (s, 3H, CH3); 13C NMR
(CDCl3, 125 MHz) δ (ppm) 154.6, 149.6, 148.8, 147.6,
145.4, 139.5, 134.7, 133.6, 132.3, 131.3, 130.1, 129.7,
128.7, 127.4, 125.1, 124.4, 120.1, 21.8; HRMS (ESI) m/
z calcd for C22H16ClN2O2 (M + H)+: 375.0900, found:
375.0911.
2-(4-Chloro-phenyl)-6-methyl-4-p-tolyl-quinoline (4h)
1
Pale solid; yield: 85%; m.p. 154–155ꢀC; H NMR
6-Methyl-2-(4-nitro-phenyl)-4-p-tolyl-quinoline (4l)
Slightly yellow solid; yield: 77%; m.p. 180–182ꢀC;1H
NMR (CDCl3, 300 MHz) δ (ppm) 8.36 (s, 4H, ArH),
8.14 (d, J = 8.4 Hz, 1H, ArH), 7.79 (s, 1H, ArH), 7.71 (s,
1H, ArH), 7.61 (d, J = 8.7 Hz, 1H, ArH), 7.46 (d,
J = 7.8 Hz, 2H, ArH), 7.38 (d, J = 7.8 Hz, 2H, ArH),
2.50 (s, 6H, CH3, CH3); 13C NMR (CDCl3, 125 MHz) δ
(ppm) 153.4, 149.5, 148.5, 147.8, 145.9, 139.0, 137.8,
135.6, 132.7, 130.5, 129.8 (overlapped), 128.4, 126.6,
125.0, 124.3, 119.4, 22.3, 21.8; HRMS (ESI) m/z calcd for
C23H19N2O2 (M + H)+: 355.1447, found: 355.1441.
(CDCl3, 300 MHz) δ (ppm) 8.10–8.14 (m, 3H, ArH),
7.72 (s, 1H, ArH), 7.68 (s, 1H, ArH), 7.58–7.59 (m, 1H,
ArH), 7.44–7.50 (m, 4H, ArH), 7.26–7.36 (m, 2H,
ArH), 2.50 (s, 3H, CH3), 2.48 (s, 3H, CH3); 13C NMR
(CDCl3, 75 MHz) δ (ppm) 154.6, 148.7, 147.4, 138.3,
138.2, 136.4, 135.6, 135.3, 131.9, 129.9, 129.5, 129.4,
129.0, 128.7, 125.9, 124.6, 118.9, 21.9, 21.4; HRMS
(ESI) m/z calcd for C23H19ClN (M + H)+: 344.1206,
found: 344.1217.
2-(4-Chloro-phenyl)-6-methoxy-4-p-tolyl-quinoline (4i)
1
Pale solid; yield: 86%; m.p. 132–134ꢀC; H NMR
2-(4-Chloro-phenyl)-6-methoxy-4-(4-methoxy-phenyl)-
quinoline (4m)
(CDCl3, 300 MHz) δ (ppm) 8.09–8.15 (m, 3H, ArH),
7.71 (s, 1H, ArH), 7.35–7.49 (m, 6H, ArH), 7.21–7.26
(m, 2H, ArH), 3.81 (s, 3H, OCH3), 2.48 (s, 3H, CH3);
13C NMR (CDCl3, 125 MHz) δ (ppm) 158.3, 153.6,
148.4, 145.3, 138.7, 138.6, 136.1, 135.5, 132.0, 129.9,
129.6, 129.3, 128.9, 127.3, 122.4, 119.6, 104.1, 55.9,
21.7; HRMS (ESI) m/z calcd for C23H19ClNO
(M + H)+: 360.1155, found: 360.1164.
Brown solid; yield: 75%; m.p. 144–146ꢀC; 1H
NMR (CDCl3, 300 MHz) δ (ppm) 8.10–8.14 (m, 3H,
ArH), 7.71 (s, 1H, ArH), 7.46–7.53 (m, 4H, ArH),
7.38–7.42 (m, 1H, ArH), 7.22–7.26 (m, 1H, ArH),
7.08–7.10 (m, 2H, ArH), 3.92 (s, 3H, OCH3), 3.82 (s,
3H, OCH3); 13C NMR (CDCl3, 125 MHz) δ (ppm)
160.2, 158.3, 153.6, 148.1, 145.3, 138.6, 135.4, 131.9,
131.2, 131.0, 129.3, 128.9, 127.3, 122.4, 119.5, 114.6,
104.1, 55.9, 55.8; HRMS (ESI) m/z calcd for
C23H19ClNO2 (M + H)+: 376.1104, found: 376.1108.
6-Methoxy-2-(3-nitro-phenyl)-4-p-tolyl-quinoline (4j)
Brown solid; yield: 84%; m.p. 176–177ꢀC; 1H
NMR (CDCl3, 300 MHz) δ (ppm) 9.03 (s, 1H, ArH),
8.55 (d, J = 7.8 Hz, 1H, ArH), 8.27–8.30 (m, 1H,
ArH), 8.15 (d, J = 9.2 Hz, 1H, ArH), 7.80 (s, 1H,
ArH), 7.68 (t, J = 8.0 Hz, 1H, ArH), 7.37–7.50 (m, 5H,
ArH), 7.24–7.26 (m, 1H, ArH), 3.83 (s, 3H, OCH3),
2.50 (s, 3H, CH3); 13C NMR (CDCl3, 125 MHz) δ
(ppm) 158.7, 151.9, 149.2, 148.8, 145.2, 141.8, 139.0,
135.7, 133.4, 132.1, 130.1, 129.9, 129.6, 127.6, 123.8,
4-(4-Methoxy-phenyl)-6-methyl-2-(3-nitro-phenyl)-quino-
line (4n)
Yellow solid; yield: 78%; m.p. 156–157ꢀC; 1H
NMR (CDCl3, 300 MHz) δ (ppm) 9.04 (s, 1H, ArH),
8.57 (d, J = 7.8 Hz, 1H, ArH), 8.30 (d, J = 8.0 Hz,
1H, ArH), 8.16 (d, J = 8.6 Hz, 1H, ArH), 7.80 (s, 1H,
ArH), 7.67–7.72 (m, 2H, ArH), 7.61 (d, J = 8.6 Hz,
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7

Special Issue Paper
Tan et al.
1H, ArH), 7.52 (d, J = 8.5 Hz, 2H, ArH), 7.11 (d,
J = 8.5 Hz, 2H, ArH), 3.94 (s, 3H, OCH3), 2.51 (s, 3H,
CH3); 13C NMR (CDCl3, 125 MHz) δ (ppm) 160.4,
153.3, 149.2, 149.1, 147.8, 141.7, 137.4, 133.5, 132.5,
131.2 (2C), 130.8, 130.3, 130.0, 126.6, 124.9, 124.0,
122.6, 119.0, 114.6 (2C), 55.8, 22.3; HRMS (ESI) m/z
calcd for C23H19N2O3 (M + H)+: 371.1396, found:
371.1387.
55.8, 22.1; HRMS (ESI) m/z calcd for C23H19N2O3
(M + H)+: 371.1396, found: 371.1385.
CONCLUSION
In summary, we have developed a straightforward
and efficient method for the synthesis of 2,4-
diphenylquinolines by employing a time-saving ball milling
technique at room temperature. Through the solvent-free
and one-pot cyclization–aromatization of anilines, benzal-
dehydes, and phenylacetylenes promoted by easily availa-
ble and environmentally friendly FeCl3, a series of
quinoline derivatives with broad molecular diversity were
rapidly obtained in good to excellent yields. This protocol
has the advantages of short reaction time, use of no
organic solvent, low cost, employment of cheap, easily
available, and nontoxic catalyst, and simple work-up pro-
cedure. These merits make it a new and green alternative
to the synthesis of substituted quinolines over existing
methods.
2-(4-Chloro-phenyl)-4-(4-methoxy-phenyl)-6-methyl-quin-
oline (4o)
Slightly yellow solid; yield: 77%; m.p. 136–139ꢀC;
1H NMR (CDCl3, 300 MHz) δ (ppm) 8.09–8.14 (m,
3H, ArH), 7.71 (s, 1H, ArH), 7.69 (s, 1H, ArH), 7.56
(d, J = 8.7 Hz, 1H, ArH), 7.46–7.50 (m, 4H, ArH),
7.09 (d, J = 8.4 Hz, 2H, ArH), 3.92 (s, 3H, OCH3),
2.48 (s, 3H, CH3); 13C NMR (CDCl3, 125 MHz) δ
(ppm) 160.3, 154.9, 148.8, 147.8, 138.6, 136.8, 135.7,
132.3, 131.2, 131.1, 130.2, 129.3, 129.1, 126.4, 124.9,
119.2, 114.5, 55.8, 22.3; HRMS (ESI) m/z calcd for
C23H19ClNO (M + H)+: 360.1155, found: 360.1162.
ACKNOWLEDGMENT
We gratefully acknowledge the National Natural
Science Foundation of China (No. 21242013) for finan-
cial support.
6-Chloro-4-(4-methoxy-phenyl)-2-(4-nitro-phenyl)-quinol-
ine (4p)
Slightly yellow solid; yield: 70%; m.p. 216–217ꢀC;
1H NMR (CDCl3, 300 MHz) δ (ppm) 8.37 (s, 4H,
ArH), 8.19 (d, J = 9.0 Hz, 1H, ArH), 7.94 (s, 1H,
ArH), 7.85 (s, 1H, ArH), 7.69–7.72 (m, 1H, ArH), 7.49
(d, J = 8.7 Hz, 2H, ArH), 7.11 (d, J = 8.7 Hz, 2H,
ArH), 3.93 (s, 3H, OCH3); 13C NMR (CDCl3,
125 MHz) δ (ppm) 160.7, 154.7, 149.3, 148.9, 147.7,
145.5, 133.6, 132.3, 131.3, 131.1, 129.9, 128.7, 127.5,
125.1, 124.5, 120.1, 114.9, 55.9; HRMS (ESI) m/z calcd
for C22H16ClN2O3 (M + H)+: 391.0849, found:
391.0842.
Supporting information
Additional supporting information is available in
the online version of this article.
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