Green synthesis of polysubstituted quinoline and benzoquinoline derivatives in ionic liquid via a three-component reaction

Article abstract of DOI:10.1007/s11164-014-1819-y

A three-component reaction of aldehyde, (E)-3-aminobut-2-enenitrile and dimedone in ionic liquids, gave 1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxo-4-arylquinoline-3-carbonitrile derivatives at 50 °C. Using 2-hydroxynaphthalene-1,4-dione to replace dimedo

Full text of DOI:10.1007/s11164-014-1819-y

Res Chem Intermed
DOI 10.1007/s11164-014-1819-y
Green synthesis of polysubstituted quinoline
and benzoquinoline derivatives in ionic liquid
via a three-component reaction
•
Yong Sun Pei-Jun Cai Xiang-Shan Wang
•
Received: 30 March 2014 / Accepted: 20 September 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract A three-component reaction of aldehyde, (E)-3-aminobut-2-enenitrile and
dimedone in ionic liquids, gave 1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxo-4-arylqui-
noline-3-carbonitrile derivatives at 50 °C. Using 2-hydroxynaphthalene-1,4-dione to
replace dimedone at the same reaction conditions resulted in another series of poly-
substituted benzo[h]quinoline derivatives in high yields. This method involves the
advantages of mild conditions, high yields, one-pot synthesis, and an environmentally
benign procedure.
Keywords Quinoline Á Three-component reaction Á Ionic liquids Á Synthesis
Introduction
Quinolines are a very important class of alkaloids with a wide range of
pharmacological and biological activities, such as antimicrobial [1], antiprolifer-
ative [2], and antituberculosis activities [3]. It has been reported that some of them
were used as DNA methylation modulators for the treatment of cancer and
hematological disorders [4], and as antimalarial agents in the treatment of malarial
infections [5]. Quinidine is a well-known example of quinoline alkaloids (Fig. 1,
left) [6], a pharmaceutical agent that acts as a class I antiarrhythmic agent (Ia) in the
Y. Sun Á P.-J. Cai (&)
School of Chemical Engineering and Technology, China University of Mining and Technology,
Xuzhou 221116, Jiangsu, People’s Republic of China
e-mail: pjcai@cumt.edu.cn
X.-S. Wang (&)
School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green
Synthesis for Functional Materials, Jiangsu Normal University, Xuzhou 221116, Jiangsu,
People’s Republic of China
e-mail: xswang1974@yahoo.com
123

Y. Sun et al.
heart. It is widely used for treatment of life–threatening Plasmodium falciparum
malaria and ventricular arrhythmias. Another important drug is Chloroquine (Fig. 1,
right) [7]; it was discovered in 1934 by Hans Andersag and coworkers at the
laboratories of Bayer. The United States government-sponsored clinical trials for
antimalarial drug development showed unequivocally that chloroquine has a
significant therapeutic value as an antimalarial drug. Accordingly, novel strategies
for the synthesis of quinolines continued to receive considerable attention in the
field of organic synthetics chemistry [8–13].
Ionic liquids have attracted increasing interest in the context of green chemistry
in the past few years. They were initially introduced as alternative green reaction
media because of their unique chemical and physical properties of nonvolatility,
nonflammability, thermal stability, and controlled miscibility [14, 15]. The
possibility of recycling them also ensured their utility in organic synthesis as green
solvents for a large number of organic transformations [16].
As a continuation of our research devoted to the development of new methods for
the preparation of heterocycles in ionic liquids [17–21], we would like to report the
synthesis of 4-arylquinoline-3-carbonitrile and 4-arylbenzo[h]quinoline-3-carboni-
trile derivatives under catalyst-free conditions. The method involved a three-
component reaction of aldehyde, (E)-3-aminobut-2-enenitrile and dimedone or
2-hydroxynaphthalene-1,4-dione in ionic liquids.
Results and discussion
Treatment of aldehyde 1, (E)-3-aminobut-2-enenitrile 2, and 5,5-dimethyl-1,3-
cyclohex-2-ene (dimedone) 3 in ionic liquid [BMIm]Br at 50 °C, resulted in the
corresponding 1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxo-4-arylquinoline-3-car-
bonitrile derivatives 4a–k in high yields (Scheme 1).
Using the conversion of benzaldehyde 1a, (E)-3-aminobut-2-enenitrile 2 and 3 as
a model reaction, different temperatures and ionic liquids were explored to obtain an
optimal condition, as shown in Table 1. The product 4a was not detected in ionic
liquids at room temperature (Table 1, Entry 1), and was obtained successfully in
higher reaction temperature, reaching a maximum of 92 % yield at 50°C (Table 1,
entries 2-4). Different imidazolium ionic liquids were also tested, and [BMIm]Br
appeared to be the best solvent for this transformation (entry 3 vs. 5–9). Acidic ionic
liquids, such as [BMIm][HSO4], or acidic catalysts, for example, TsOH and AgOTf,
were used to further improve the yields of the product 4a, to our disappointed, the
results are not good (Table 1, entries 10–12).
After reaction completion as monitored by TLC, products were isolated by
simple filtration after the addition of a small amount of water to the cooled reaction
mixture. Water in the filtrate was removed by distillation under reduced pressure,
and the [BMIm]Br in the residue could be reused after being evaporated at 80°C for
4 h in vacuum. Successive reuse of the recycled ionic liquid of [BMIm]Br in the
model reaction gave high yields of 4a (90 %) even after the fourth cycle.
Subsequently, the optimized conditions were applied for the conversion of
various kinds of aldehydes into the corresponding 4-arylquinoline-3-carbonitrile
123

Polysubstituted quinoline and benzoquinoline derivatives in ionic liquid
Fig. 1 The interesting drugs
containing quinoline analogues
H
Me
(CH2)3NEt2
H
H
N
HO
N
N
O
Cl
N
Chloroquine
Quinidine
O
O
Ar
CN
CN
IL
ArCHO
+
+
50 oC
H2N
O
N
H
1
2
3
4
Scheme 1 The reaction of 1, 2, and 3
Table 1 Synthetic results of 4a
Entry
Temp./°C
Ionic liquida
Yield/%b
under different reaction
conditions
1
r.t.
50
80
100
50
50
50
50
50
50
50
50
[BMIm]Br
trace
92
87
85
84
82
86
86
88
72
68
82
2
3
[BMIm]Br
[BMIm]Br
4
[BMIm]Br
Reaction condition: 2 ml
solvent, 1a (102 mg, 1.0 mmol),
2 (84 mg, 1.0 mmol) and 3
(144 mg, 1.0 mmol)
5
[EMIm]Br
6
[PMIm]Br
7
[EMIm][BF4]
[PMIm][BF4]
[BMIm][BF4]
[BMIm][HSO4]
[BMIm]Br/TsOHc
[BMIm]Br/AgOTfc
a
BMIm = 1-butyl-3-
8
methylimidazolium; EMIm = 1-
ethyl-3-methylimidazolium;
PMIm = 1-propyl-3-
9
10
11
12
methylimidazolium
b
Isolated yields
c
TsOH or AgOTf 0.05 mmol
analogues 4a–k in high yields (Table 2, entries 1–11). The results are summarized
in Table 2. It is observed that the process can tolerate both electron-donating (alkyl
and alkoxy) and electron-withdrawing (halogen) substituents in the benzaldehydes.
In all cases, the reactions proceeded efficiently at 50°C under mild conditions to
afford the corresponding products in high yields.
In our continued study, it was found that 2-hydroxynaphthalene-1,4-dione 5 also
gave the satisfied results, if it was used as an 1,3-dicarbonyl compound to react with
1 and 2 under the same reaction conditions (Scheme 2), and resulted another series
123

Y. Sun et al.
Yields (%)a
Table 2 Synthetic results of
4a–k in ionic liquids
Entry
Ar
Time (h)
Products
1
C6H5
8
6
4a
4b
4c
4d
4e
4f
92
90
89
89
93
87
86
90
90
86
88
2
2-ClC6H4
3
4-ClC6H4
8
4
4-BrC6H4
9
5
4-CNC6H4
4-MeC6H4
2-MeOC6H4
2,3-Cl2C6H3
2,4-Cl2C6H3
3,4-Cl2C6H3
3,5-(MeO)2C6H3
6
6
10
12
6
7
4g
4h
4i
8
Reaction condition: 2 ml
[BMIm]Br, 1 (1.0 mmol), 2
(82 mg, 1.0 mmol), 3 (144 mg,
1.0 mmol) and 50 °C
9
8
10
11
8
4j
10
4k
a
Isolated yields
of novel 1,4,5,6-tetrahydro-2-methyl-5,6-dioxo-4-arylbenzo[h]quinoline-3-carboni-
triles 6 in high yields (Table 3). All the products of 4a–k and 6a–k were
1
characterized by H NMR, IR and HRMS, and the data were in good agreement
with the preconceived structures.
According to the product structures of 4 and 6, we think that subsequent
Knoevenagel condensation, Michael addition, intra-molecular cyclization, and
dehydration reaction may take place; the possible reaction mechanism is outlined in
Scheme 3.
Experimental
Melting points were determined in open capillaries and are uncorrected. IR spectra
were recorded on a Tensor 27 spectrometer in KBr pellet. NMR spectra were
obtained from a solution in DMSO-d6 or CDCl3 with Me4Si as internal standard
using a Bruker-400 spectrometer. HRMS analyses were carried out using a Bruker-
micro-TOF-Q-MS analyzer.
General procedure for the synthesis of quinoline and benzo[h]quinoline
derivatives 4 and 6
A dry 50-ml flask was charged with aldehyde 1 (1.0 mmol), (E)-3-aminobut-2-
enenitrile 2 (82 mg, 1.0 mmol), dimedone (144 mg, 1.0 mmol) 3 or 2-hydroxy-
naphthalene-1,4-dione 5 (174 mg, 1.0 mmol) and ionic liquid [BMIm]Br (2 ml).
The reaction mixture was stirred at 50°C for 6–14 h, and then a small amount of
water (5 ml) was added to the mixture, and the generated yellow solid was filtered
off. The water in the filtrate was removed by distillation under reduced pressure, and
the ionic liquid in the residue could be reusable by being evaporated at 80 °C for 4 h
at vacuum. The crude yellow products were washed with water and purified by
123

Polysubstituted quinoline and benzoquinoline derivatives in ionic liquid
O
Ar
O
O
CN
CN
HO
IL
ArCHO
+
+
N
H
50 oC
H2N
O
1
2
5
6
Scheme 2 Reaction of 1, 3, and 5
Table 3 Synthetic results of
6a–k in ionic liquids
Entry
Ar
Time (h)
Products
Yields (%)a
1
C6H5
10
12
10
14
8
6a
6b
6c
6d
6e
6f
86
90
84
89
86
90
85
86
82
85
90
2
4-ClC6H4
3
4-FC6H4
4
4-BrC6H4
5
4-CNC6H4
4-MeC6H4
4-MeOC6H4
2,3-Cl2C6H3
2,4-Cl2C6H3
3,4-Cl2C6H3
3,5-(MeO)2C6H3
6
9
7
9
6g
6h
6i
8
8
Reaction condition: 2 ml
[BMIm]Br, 1 (1.0 mmol), 2
(82 mg, 1.0 mmol), 5 (174 mg,
1.0 mmol) and 50 °C
9
8
10
11
8
6j
12
6k
a
Isolated yields
r
A
r
A
r
A
r
A
O
O
O
O
N
C
N
C
N
C
N
C
O
O
O
O
-
H
2O
N
N
H
NH
NH
2 O
O
H OH
6
2
O
O
O
O
N
C
r
A
H
O
r
A
H2N
O
O
5
O
r
A
H
O
1
C
O
O
2
3
O
r
A
r
A
O
r
A
O
r
A
O
N
C
N
C
N
C
N
C
-
H
2O
O
N
H
O
N
H
H2N
HN
H
O
4
Scheme 3 The possible reaction mechanism
123

Y. Sun et al.
recrystallization from 95 % EtOH, then dried at 80 °C for 2 h under vacuum to give
4 or 6.
1,4,5,6,7,8-Hexahydro-2,7,7-trimethyl-5-oxo-4-phenylquinoline-3-carbonitrile
4a: M. p. 236–238 °C, (Lit [22].: 232–234 °C); 1H NMR (DMSO-d6, 400 MHz): dH
0.92 (s, 3H, CH3), 1.02 (s, 3H, CH3), 1.99 (d, J = 16.4 Hz, 1H, CH), 2.06 (s, 3H,
CH3), 2.18 (d, J = 16.4 Hz, 1H, CH), 2.34 (d, J = 17.2 Hz, 1H, CH), 2.43 (d,
J = 17.2 Hz, 1H, CH), 4.41 (s, 1H, CH), 7.17–7.20 (m, 3H, ArH), 7.27–7.31 (m,
2H, ArH), 9.44 (s, 1H, NH). 13C NMR (CDCl3, 100 MHz): dC 18.4, 27.5, 29.3, 32.6,
38.4, 41.1, 50.6, 89.0, 109.7, 119.2, 127.1, 127.5, 128.6, 144.4, 144.7, 148.4, 195.4.
IR (KBr): m 3,288, 3,072, 2,962, 2,930, 2,885, 2,811, 2,751, 2,204, 1,659, 1,608,
1,490, 1,469, 1,382, 1,341, 1,319, 1,260, 1,148 cm-1. HRMS (ESI, m/z): Calcd for
C19H19N2O [M–H]- 291.1498, found 291.1499.
4-(2-chlorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-car-
1
bonitrile 4b: M. p. 245–247 °C; H NMR (DMSO-d6, 400 MHz): dH 0.94 (s, 3H,
CH3), 1.03 (s, 3H, CH3), 1.99 (d, J = 16.0 Hz, 1H, CH), 2.03 (s, 3H, CH3), 2.17 (d,
J = 16.0 Hz, 1H, CH), 2.33 (d, J = 17.2 Hz, 1H, CH), 2.44 (d, J = 17.2 Hz, 1H,
CH), 4.74 (s, 1H, CH), 7.09–7.24 (m, 4H, ArH), 9.50 (s, 1H, NH). IR (KBr):
m 3,240, 3,189, 3,077, 2,962, 2,931, 2,895, 2,880, 2,203, 1,660, 1,607, 1,489, 1,471,
1,457, 1,435, 1,383, 1,261, 1,222, 1,149, 751 cm-1. HRMS (ESI, m/z): Calcd for
C19H18ClN2O [M - H]- 325.1108, found 325.1098.
4-(4-Chlorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-car-
1
bonitrile 4c: M. p. 253–255 °C; H NMR (DMSO-d6, 400 MHz): dH 0.91 (s, 3H,
CH3), 1.02 (s, 3H, CH3), 2.01 (d, J = 16.4 Hz, 1H, CH), 2.07 (s, 3H, CH3), 2.18 (d,
J = 16.4 Hz, 1H, CH), 2.33 (d, J = 17.2 Hz, 1H, CH), 2.42 (d, J = 17.2 Hz, 1H,
CH), 4.44 (s, 1H, CH), 7.20 (d, J = 8.4 Hz, 2H, ArH), 7.36 (d, J = 8.4 Hz, 2H,
ArH), 9.50 (s, 1H, NH). 13C NMR (CDCl3, 100 MHz): dC 18.5, 27.4, 29.2, 32.6,
38.0, 41.2, 50.5, 88.7, 109.6, 118.9, 128.7, 129.0, 132.8, 143.2, 144.5, 147.9, 195.1.
IR (KBr): m 3,242, 3,190, 3,078, 2,961, 2,881, 2,810, 2,749, 2,360, 2,200, 1,658,
1,610, 1,491, 1,435, 1,391, 1,317, 1,258, 1,147, 1,126, 1,089, 1,015, 972, 847 cm-1
.
HRMS (ESI, m/z): Calcd for C19H18ClN2O [M–H]- 325.1108, found 325.1095.
4-(4-Bromophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-car-
1
bonitrile 4d: M. p. 204–206 °C; H NMR (DMSO-d6, 400 MHz): dH 0.91 (s, 3H,
CH3), 1.02 (s, 3H, CH3), 2.01 (d, J = 16.4 Hz, 1H, CH), 2.06 (s, 3H, CH3), 2.18 (d,
J = 16.4 Hz, 1H, CH), 2.33 (d, J = 17.2 Hz, 1H, CH), 2.42 (d, J = 17.2 Hz, 1H,
CH), 4.42 (s, 1H, CH), 7.14 (d, J = 8.4 Hz, 2H, ArH), 7.49 (d, J = 8.4 Hz, 2H,
ArH), 9.50 (s, 1H, NH). 13C NMR (CDCl3, 100 MHz): dC 18.3, 27.4, 29.2, 32.6,
38.1, 40.8, 50.6, 88.2, 109.1, 119.2, 121.0, 129.3, 131.7, 143.9, 145.2, 149.1, 195.7.
IR (KBr): m 3,306, 3,226, 3,096, 2,960, 2,880, 2,811, 2,197, 1,657, 1,638, 1,496,
1,434, 1,394, 1,365, 1,316, 1,258, 1,198, 1,166, 1,144, 1,129, 1,067, 1,010, 975,
843 cm-1. HRMS (ESI, m/z): Calcd for C19H20BrN2O [M ? H]? 371.0759, found
371.0593.
4-(4-Cyanophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-car-
1
bonitrile 4e: M. p. 251–253 °C; H NMR (DMSO-d6, 400 MHz): dH 0.91 (s, 3H,
CH3), 1.02 (s, 3H, CH3), 2.02 (d, J = 16.4 Hz, 1H, CH), 2.08 (s, 3H, CH3), 2.18 (d,
J = 16.4 Hz, 1H, CH), 2.35 (d, J = 17.2 Hz, 1H, CH), 2.43 (d, J = 17.2 Hz, 1H,
CH), 4.55 (s, 1H, CH), 7.39 (d, J = 8.0 Hz, 2H, ArH), 7.78 (d, J = 8.0 Hz, 2H,
123

Polysubstituted quinoline and benzoquinoline derivatives in ionic liquid
ArH), 9.57 (s, 1H, NH). IR (KBr): m 3,249, 3,158, 3,073, 2,959, 2,931, 2,884, 2,809,
2,749, 2,229, 2,198, 1,656, 1,617, 1,492, 1,433, 1,422, 1,394, 1,380, 1,317, 1,260,
1,146, 1,124, 1,019, 854 cm-1. HRMS (ESI, m/z): Calcd for C20H18N3O [M–H]-
316.145, found 316.1457.
1,4,5,6,7,8-Hexahydro-2,7,7-trimethyl-5-oxo-4-p-tolylquinoline-3-carbonitrile
4f: M. p. 234–236 °C; 1H NMR (DMSO-d6, 400 MHz): dH 0.91 (s, 3H, CH3), 1.02
(s, 3H, CH3), 1.99 (d, J = 16.0 Hz, 1H, CH), 2.05 (s, 3H, CH3), 2.17 (d,
J = 16.0 Hz, 1H, CH), 2.25 (s, 3H, CH3), 2.32 (d, J = 16.8 Hz, 1H, CH), 2.42
(d, J = 16.8 Hz, 1H, CH), 4.36 (s, 1H, CH), 7.05 (d, J = 8.0 Hz, 2H, ArH), 7.08 (d,
J = 8.0 Hz, 2H, ArH), 9.42 (s, 1H, NH). 13C NMR (CDCl3, 100 MHz): dC 18.2,
21.1, 27.4, 29.3, 32.6, 38.0, 40.8, 50.7, 88.8, 109.4, 119.5, 127.3, 129.3, 136.6,
142.0, 144.7, 149.1, 195.8. IR (KBr): m 3,241, 3,193, 3,079, 2,963, 2,930, 2,881,
2,199, 1,660, 1,607, 1,491, 1,470, 1,435, 1,381, 1,316, 1,258, 1,147, 1,020, 839,
731 cm-1. HRMS (ESI, m/z): Calcd for C20H21N2O [M–H]- 305.1654, found
305.1654.
1,4,5,6,7,8-Hexahydro-4-(2-methoxyphenyl)-2,7,7-trimethyl-5-oxoquinoline-3-
carbonitrile 4g: M. p. 255–257 °C; 1H NMR (DMSO-d6, 400 MHz): dH 0.98 (s, 3H,
CH3), 1.03 (s, 3H, CH3), 1.99 (s, 3H, CH3), 1.98 (d, J = 16.0 Hz, 1H, CH), 2.17 (d,
J = 16.0 Hz, 1H, CH), 2.34 (d, J = 17.2 Hz, 1H, CH), 2.44 (d, J = 17.2 Hz, 1H,
CH), 3.78 (s, 3H, CH3O), 4.84 (s, 1H, CH), 6.84–6.87 (m, 1H, ArH), 6.96 (d,
J = 8.0 Hz, 1H, ArH), 7.00 (dd, J = 8.0 Hz, J’ = 1.6 Hz, 1H, ArH), 7.13–7.17 (m,
1H, ArH), 9.33 (s, 1H, NH). IR (KBr): m 3,299, 3,262, 3,230, 3,097, 2,970, 2,955,
2,938, 2,899, 2,198, 1,657, 1,609, 1,499, 1,460, 1,434, 1,382, 1,316, 1,257, 1,163,
1,147, 1,138, 1,100, 1,014, 764 cm-1. HRMS (ESI, m/z): Calcd for C20H21N2O2
[M–H]- 321.1602, found 321.1614.
4-(2,3-Dichlorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-
1
carbonitrile 4g: M. p. [300 °C; H NMR (DMSO-d6, 400 MHz): dH 0.95 (s, 3H,
CH3), 1.03 (s, 3H, CH3), 1.98 (d, J = 16.0 Hz, 1H, CH), 2.04 (s, 3H, CH3), 2.17 (d,
J = 16.0 Hz, 1H, CH), 2.35 (d, J = 16.8 Hz, 1H, CH), 2.44 (d, J = 16.8 Hz, 1H,
CH), 5.05 (s, 1H, CH), 7.22 (dd, J = 8.0 Hz, J’ = 1.2 Hz, 1H, ArH), 7.32 (t,
J = 8.0 Hz, 1H, ArH), 7.48 (dd, J = 8.0 Hz, J’ = 1.2 Hz, 1H, ArH), 9.87 (s, 1H,
NH). IR (KBr): m 3,284, 3,236, 3,104, 2,962, 2,957, 2,914, 2,868, 2,193, 1,650,
1,502, 1,447, 1,421, 1,377, 1,321, 1,305, 1,258, 1,153, 1,137, 1,041, 766, 713 cm-1
.
HRMS (ESI, m/z): Calcd for C19H17Cl2N2O [M - H]- 359.0718, found 359.0718.
4-(2,4-Dichlorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-
carbonitrile 4i: M. p. 253–255 °C; 1H NMR (DMSO-d6, 400 MHz): dH 0.95 (s, 3H,
CH3), 1.02 (s, 3H, CH3), 1.98 (d, J = 16.4 Hz, 1H, CH), 2.03 (s, 3H, CH3), 2.17 (d,
J = 16.4 Hz, 1H, CH), 2.34 (d, J = 17.2 Hz, 1H, CH), 2.44 (d, J = 17.2 Hz, 1H,
CH), 4.95 (s, 1H, CH), 7.25 (d, J = 8.4 Hz, 1H, ArH), 7.39 (dd, J = 8.4 Hz,
J’ = 2.0 Hz, 1H, ArH), 7.53 (d, J = 2.0 Hz, 1H, ArH), 9.55 (s, 1H, NH). 13C NMR
(CDCl3, 100 MHz): dC 18.4, 27.5, 29.2, 32.5, 36.4, 41.0, 50.4, 87.3, 108.8, 118.6,
127.4, 129.8, 131.6, 133.3, 133.7, 140.3, 145.1, 149.0, 195.1. IR (KBr): m 3,185,
3,075, 2,960, 2,936, 2,888, 2,870, 2,810, 2,204, 1,658, 1,604, 1,501, 1,470, 1,435,
1,381, 1,316, 1,259, 1,148, 1,131, 1,100, 1,045, 848, 839 cm-1. HRMS (ESI, m/z):
Calcd for C19H17Cl2N2O [M–H]- 359.0718, found 359.0716.
123

Y. Sun et al.
4-(3,4-Dichlorophenyl)-1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxoquinoline-3-
carbonitrile 4j: M. p. 231–233 °C; 1H NMR (DMSO-d6, 400 MHz): dH 0.92 (s, 3H,
CH3), 1.02 (s, 3H, CH3), 2.03 (d, J = 16.0 Hz, 1H, CH), 2.08 (s, 3H, CH3), 2.18 (d,
J = 16.0 Hz, 1H, CH), 2.35 (d, J = 16.8 Hz, 1H, CH), 2.42 (d, J = 16.8 Hz, 1H,
CH), 4.49 (s, 1H, CH), 7.19 (dd, J = 8.4 Hz, J’ = 2.0 Hz, 1H, CH), 7.39 (d,
J = 2.0 Hz, 1H, ArH), 7.58 (d, J = 8.4 Hz, 1H, ArH), 9.56 (s, 1H, NH). 13C NMR
(CDCl3, 100 MHz): dC 18.6, 27.5, 29.1, 32.7, 38.0, 41.2, 50.5, 88.3, 109.3, 118.7,
127.2, 129.5, 130.5, 131.1, 132.7, 144.7, 144.8, 148.1, 195.1. IR (KBr): m 3,190,
3,079, 2,963, 2,936, 2,885, 2,810, 2,750, 2,360, 2,341, 2,207, 1,659, 1,609, 1,490,
1,437, 1,392, 1,351, 1,319, 1,259, 1,147, 1,129, 1,032, 876, 829 cm-1. HRMS (ESI,
m/z): Calcd for C19H17Cl2N2O [M–H]? 359.0718, found 359.0704.
1,4,5,6,7,8-Hexahydro-4-(3,5-dimethoxyphenyl)-2,7,7-trimethyl-5-oxoquinoline-
1
3-carbonitrile 4k: M. p. 241–243 °C; H NMR (DMSO-d6, 400 MHz): dH 0.96 (s,
3H, CH3), 1.03 (s, 3H, CH3), 2.02–2.06 (m, 4H, CH ? CH3), 2.19 (d, J = 16.4 Hz,
1H, CH), 2.34 (d, J = 16.8 Hz, 1H, CH), 2.44 (d, J = 16.8 Hz, 1H, CH), 3.70 (s,
6H, 2CH3O), 4.34 (s, 1H, CH), 6.29 (d, J = 2.0 Hz, 2H, ArH), 6.35 (d, J = 2.0 Hz,
1H, ArH), 9.43 (s, 1H, NH). IR (KBr): m 3,291, 3,265, 3,233, 3,097, 2,954, 2,840,
2,196, 1,657, 1,610, 1,496, 1,469, 1,431, 1,379, 1,315, 1,257, 1,199, 1,157, 1,065,
858, 709 cm-1. HRMS (ESI, m/z): Calcd for C21H23N2O3 [M - H]? 351.1709,
found 351.1712.
1,4,5,6-Tetrahydro-2-methyl-5,6-dioxo-4-phenylbenzo[h]quinoline-3-carboni-
trile 6a: M. p. 256–258 °C; 1H NMR (DMSO-d6, 400 MHz): dH 2.21 (s, 3H, CH3),
4.81 (s, 1H, CH), 7.21–7.25 (m, 1H, ArH), 7.30–7.35 (m, 4H, ArH), 7.78–7.88
(m, 3H, ArH), 8.03–8.05 (m, 1H, ArH), 10.00 (s, 1H, NH). IR (KBr): m 3,127, 3,043,
2,928, 2,839, 2,360, 2,341, 2,197, 1,678, 1,653, 1,637, 1,592, 1,493, 1,367, 1,344,
1,299, 1,244, 1,206, 1,103, 953, 727, 714 cm-1. HRMS (ESI, m/z): Calcd for
C21H13N2O2 [M–H]- 325.0976, found 325.0969.
4-(4-Chlorophenyl)-1,4,5,6-tetrahydro-2-methyl-5,6-dioxobenzo[h]quinoline-3-
carbonitrile 6b: M. p. 263–265 °C; 1H NMR (DMSO-d6, 400 MHz): dH 2.21 (s, 3H,
CH3), 4.84 (s, 1H, CH), 7.35 (d, J = 8.4 Hz, 2H, ArH), 7.37 (d, J = 8.4 Hz, 2H,
ArH), 7.79–7.88 (m, 3H, ArH), 8.03–8.05 (m, 1H, ArH), 10.03 (s, 1H, NH). 13C
NMR (DMSO-d6, 100 MHz): dC 18.3, 38.5, 86.2, 115.1, 119.7, 126.0, 126.5, 129.0,
130.1, 130.8, 132.2, 132.3, 133.8, 135.3, 139.0, 144.0, 147.5, 179.6, 182.4. IR
(KBr): m 3,286, 3,047, 2,985, 2,875, 2,360, 2,341, 2,202, 1,684, 1,650, 1,612, 1,592,
1,490, 1,434, 1,393, 1,364, 1,340, 1,298, 1,252, 1,163, 1,100, 1,087, 1,012,
951 cm-1. HRMS (ESI, m/z): Calcd for C21H12ClN2O2 [M–H]- 359.0588, found
359.0586.
4-(4-Fluorophenyl)-1,4,5,6-tetrahydro-2-methyl-5,6-dioxobenzo[h]quinoline-3-
carbonitrile 6c: M. p. 273–275 °C; 1H NMR (DMSO-d6, 400 MHz): dH 2.21 (s, 3H,
CH3), 4.82 (s, 1H, CH), 7.14 (t, J = 8.8 Hz, 2H, ArH), 7.34–7.38 (m, 2H, ArH),
7.79–7.88 (m, 3H, ArH), 8.03–8.05 (m, 1H, ArH), 10.01 (s, 1H, NH). 13C
NMR(DMSO-d6, 100 MHz): dC 18.3, 38.3, 86.4, 115.3, 115.8 (d, JF–C = 21.2 Hz),
119.7, 126.0, 126.4, 130.1 (d, JF–C = 8.2 Hz), 130.8, 132.2, 133.8, 135.3, 138.8,
141.3 (d, JF–C = 2.9 Hz), 147.3, 161.7 (d, JF–C = 241.8 Hz), 179.7, 182.4. IR
(KBr): m 3,128, 3,043, 2,929, 2,882, 2,799, 2,357, 2,204, 1,675, 1,652, 1,614, 1,595,
123

Polysubstituted quinoline and benzoquinoline derivatives in ionic liquid
1,504, 1,434, 1,368, 1,344, 1,298, 1,251, 1,219, 1,157, 1,097, 955, 842, 722 cm-1
HRMS (ESI, m/z): Calcd for C21H12FN2O2 [M–H]- 343.0883, found 343.0885.
4-(4-Bromophenyl)-1,4,5,6-tetrahydro-2-methyl-5,6-dioxobenzo[h]quinoline-3-
.
carbonitrile 6d: M. p. 267–269 °C; 1H NMR (DMSO-d6, 400 MHz): dH 2.20 (s, 3H,
CH3), 4.82 (s, 1H, CH), 7.29 (d, J = 8.4 Hz, 2H, ArH), 7.51 (d, J = 8.4 Hz, 2H,
ArH), 7.79–7.87 (m, 3H, ArH), 8.02–8.04 (m, 1H, ArH), 10.03 (s, 1H, NH). 13C
NMR (DMSO-d6, 100 MHz): dC 18.3, 38.6, 86.1, 115.0, 119.7, 120.9, 126.0, 126.4,
130.5, 130.8, 132.0, 132.2, 133.8, 135.3, 139.0, 144.4, 147.5, 179.6, 182.3. IR
(KBr): m 3,234, 3,213, 3,093, 3,062, 2,983, 2,750, 2,359, 2,340, 2,208, 1,678, 1,650,
1,610, 1,595, 1,488, 1,428, 1,339, 1,298, 1,252, 1,069, 1,009, 952, 938, 722 cm-1
.
HRMS (ESI, m/z): Calcd for C21H12BrN2O2 [M–H]- 403.0081, found 403.0097.
4-(4-Cyanophenyl)-1,4,5,6-tetrahydro-2-methyl-5,6-dioxobenzo[h]quinoline-3-
1
carbonitrile 6e: M. p. 267–269 °C; H NMR (DMSO-d6, 400 MHz): dH 2.21 (s,
3H, CH3), 4.96 (s, 1H, CH), 7.56 (d, J = 8.4 Hz, 2H, ArH), 7.80–7.86 (m, 5H,
ArH), 8.04–8.06 (m, 1H, ArH), 10.09 (s, 1H, NH). 13C NMR(DMSO-d6,
100 MHz): dC 18.3, 39.2, 85.7, 110.5, 114.5, 119.1, 119.5, 126.0, 126.5, 129.3,
130.8, 132.1, 133.1, 133.8, 135.3, 139.4, 148.0, 150.0, 179.5, 182.3. IR (KBr): m
3,300, 3,140, 3,035, 2,910, 2,870, 2,798, 2,420, 2,360, 2,224, 2,201, 1,674, 1,650,
1,614, 1,503, 1,435, 1,344, 1,301, 1,252, 1,159, 1,101, 949, 833, 751, 723 cm-1
.
HRMS (ESI, m/z): Calcd for C22H12N3O2 [M–H]- 350.093, found 350.0938.
1,4,5,6-Tetrahydro-2-methyl-5,6-dioxo-4-p-tolylbenzo[h]quinoline-3-carboni-
1
trile 6f: M. p. 263–265 °C; H NMR (DMSO-d6, 400 MHz): dH 2.20 (s, 3H,
CH3), 2.24 (s, 3H, CH3), 4.76 (s, 1H, CH), 7.12 (d, J = 8.0 Hz, 2H, ArH), 7.19
(d, J = 8.0 Hz, 2H, ArH), 7.79–7.87 (m, 3H, ArH), 8.02–8.05 (m, 1H, ArH), 9.97
(s, 1H, NH). 13C NMR (DMSO-d6, 100 MHz): dC 18.3, 21.1, 38.5, 86.7, 115.7,
119.8, 125.9, 126.4, 128.0, 129.6, 130.7, 132.2, 133.8, 135.3, 136.8, 138.6, 142.2,
147.0, 179.7, 182.4. IR (KBr): m 3,245, 3,120, 3,031, 2,925, 2,881, 2,359, 2,310,
2,209, 1,678, 1,666, 1,612, 1,487, 1,430, 1,364, 1,339, 1,297, 1,251, 1,208, 1,161,
1,092, 1,050, 950, 721 cm-1. HRMS (ESI, m/z): Calcd for C22H15N2O2 [M–H]-
339.1134, found 339.1141.
1,4,5,6-Tetrahydro-4-(4-methoxyphenyl)-2-methyl-5,6-dioxobenzo[h]quinoline-
1
3-carbonitrile 6g: M. p. 260–262 °C; H NMR (DMSO-d6, 400 MHz): dH 2.21 (s,
3H, CH3), 3.71 (s, 3H, CH3O), 4.75 (s, 1H, CH), 6.87 (d, J = 8.4 Hz, 2H, ArH),
7.22 (d, J = 8.4 Hz, 2H, ArH), 7.79–7.88 (m, 3H, ArH), 8.03 (d, J = 7.2 Hz, 1H,
ArH), 9.96 (s, 1H, NH). IR (KBr): m 3,350, 3,085, 2,901, 2,810, 2,359, 2,339, 2,205,
1,675, 1,650, 1,611, 1,595, 1,489, 1,434, 1,343, 1,298, 1,253, 1,176, 1,098, 1,033,
951 cm-1. HRMS (ESI, m/z): Calcd for C22H15N2O3 [M–H]- 355.1083, found
355.1089.
4-(2,3-Dichlorophenyl)-1,4,5,6-tetrahydro-2-methyl-5,6-dioxobenzo[h]quino
line-3-carbonitrile 6h: M. p. 280–282 °C; 1H NMR (DMSO-d6, 400 MHz): dH 2.18
(s, 3H, CH3), 5.46 (s, 1H, CH), 7.29–7.33 (m, 1H, ArH), 7.46 (dd, J = 7.6 Hz,
J’ = 1.2 Hz, 1H, ArH), 7.52 (dd, J = 7.6 Hz, J’ = 1.2 Hz, 1H, ArH), 7.80–7.84
(m, 3H, ArH), 8.04–8.07 (m, 1H, ArH), 10.07 (s, 1H, NH). IR (KBr): m 3,131, 3,042,
2,929, 2,881, 2,800, 2,360, 2,341, 2,205, 1,669, 1,640, 1,614, 1,593, 1,503, 1,474,
1,420, 1,367, 1,346, 1,304, 1,254, 1,158, 1,095, 955, 745 cm-1. HRMS (ESI, m/z):
Calcd for C21H11Cl2N2O2 [M - H]- 393.0198, found 393.0196.
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Y. Sun et al.
4-(2,4-Dichlorophenyl)-1,4,5,6-tetrahydro-2-methyl-5,6-dioxobenzo[h] quino-
line-3-carbonitrile 6i: M. p. 257–259 °C; 1H NMR (DMSO-d6, 400 MHz): dH
2.18 (s, 3H, CH3), 5.35 (s, 1H, CH), 7.36 (dd, J = 8.4 Hz, J’ = 2.0 Hz, 1H, ArH),
7.49 (d, J = 8.4 Hz, 1H, ArH), 7.60 (d, J = 2.0 Hz, 1H, ArH), 7.81–7.84 (m, 3H,
ArH), 8.06 (dd, J = 6.4 Hz, J’ = 1.6 Hz, 1H, ArH), 10.04 (s, 1H, NH). 13C NMR
(DMSO-d6, 100 MHz): dC 18.2, 35.8, 85.3, 114.9, 119.2, 126.0, 126.5, 128.6, 129.0,
130.7, 132.1, 132.7, 132.87, 132.88, 133.9, 135.4, 139.7, 142.0, 147.7, 179.6, 182.2.
IR (KBr): m 3,250, 3,066, 2,927, 2,850, 2,359, 2,340, 2,204, 1,671, 1,650, 1,614,
1,592, 1,497, 1,473, 1,434, 1,344, 1,296, 1,253, 1,158, 1,096, 1,046, 951 846,
723 cm-1. HRMS (ESI, m/z): Calcd for C21H11Cl2N2O2 [M–H]- 393.0198, found
393.0198.
4-(3,4-Dichlorophenyl)-1,4,5,6-tetrahydro-2-methyl-5,6-dioxobenzo[h] quino-
line-3-carbonitrile 6j: M. p. 231–233 °C; 1H NMR (DMSO-d6, 400 MHz): dH
2.21 (s, 3H, CH3), 4.90 (s, 1H, CH), 7.35 (dd, J = 8.0 Hz, J’ = 2.0 Hz, 1H, ArH),
7.59 (d, J = 8.0 Hz, 1H, ArH), 7.62 (d, J = 2.0 Hz, 1H, ArH), 7.79–7.86 (m, 3H,
ArH), 8.03–8.05 (m, 1H, ArH), 10.05 (s, 1H, NH). IR (KBr): m 3,140, 3,061, 2,928,
2,796, 2,359, 2,340, 2,203, 1,668, 1,650, 1,614, 1,593, 1,496, 1,474, 1,344, 1,300,
1,252, 1,156, 1,130, 1,096, 1,030, 953 cm-1. HRMS (ESI, m/z): Calcd for
C21H11Cl2N2O2 [M–H]- 393.0198, found 393.0199.
1,4,5,6-Tetrahydro-4-(3,5-dimethoxyphenyl)-2-methyl-5,6-dioxobenzo[h] quino-
line-3-carbonitrile 6k: M. p. 260–262 °C; 1H NMR (DMSO-d6, 400 MHz): dH 2.21
(s, 3H, CH3), 3.71 (s, 6H, 2CH3O), 4.74 (s, 1H, CH), 6.40 (d, J = 2.0 Hz, 1H, ArH),
6.42 (d, J = 2.0 Hz, 2H, ArH), 7.78–7.90 (m, 3H, ArH), 8.03–8.05 (m, 1H, ArH),
9.96 (s, 1H, NH). IR (KBr): m 3,210, 3,094, 2,927, 2,839, 2,810, 2,420, 2,390, 2,201,
1,667, 1,610, 1,595, 1,500, 1,475, 1,431, 1,346, 1,318, 1,256, 1,198, 1,157, 1,097,
1,058, 923, 817, 743, 720 cm-1. HRMS (ESI, m/z): Calcd for C23H17N2O4 [M–H]-
385.1189, found 385.1181.
Conclusions
In summary, a mild, facile, and environmentally benign method was developed for
the synthesis of polysubstituted quinoline and benzo[h]quinoline derivatives in high
yields in ionic liquids. The advantages of this procedure include mild reaction
conditions, good to high yields, one-pot synthesis, operational simplicity, and being
environmentally benign.
Acknowledgments We are grateful to the National Natural Science Foundation of China (No.51174201),
the Open Foundation of Southwest University of Science and Technology (No.11zxjk10), a Project Funded
by the Priority Academic Program Development of Jiangsu Higher Education Institutions, and College
Industrialization Project (JHB2012-31) of Jiangsu Province for financial support.
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