Uncatalyzed and solvent-free process for the synthesis of 1,4-diarylquinoline derivatives

Article abstract of DOI:10.1080/00397910801916397

The uncatalyzed and three-component reaction of arylaldehyde, malonodinitrile, and 3-arylamino-5,5-dimethylcyclohex-2-enone at 160°C under solvent-free conditions gave 1,4-diarylquinoline derivatives in high yields. Copyright Taylor & Francis Group, LLC.

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Uncatalyzed and Solvent‐Free Process for the
Synthesis of 1,4‐Diarylquinoline Derivatives
Xiang‐Shan Wang a b , Mei‐Mei Zhang b , Hong Jiang b , Chang‐Sheng Yao a
Shu‐Jiang Tu a b
&
a School of Chemistry and Chemical Engineering , Xuzhou Normal
University , Xuzhou, Jiangsu, China
b Key Laboratory of Biotechnology on Medical Plant , Xuzhou, Jiangsu, China
Published online: 25 Apr 2008.
To cite this article: Xiang‐Shan Wang , Mei‐Mei Zhang , Hong Jiang , Chang‐Sheng Yao & Shu‐Jiang Tu
(2008) Uncatalyzed and Solvent‐Free Process for the Synthesis of 1,4‐Diarylquinoline Derivatives, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:9,
1355-1364, DOI: 10.1080/00397910801916397
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Synthetic Communicationsw, 38: 1355–1364, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801916397
Uncatalyzed and Solvent-Free Process
for the Synthesis of 1,4-Diarylquinoline
Derivatives
Xiang-Shan Wang,1,2 Mei-Mei Zhang,2 Hong Jiang,2
Chang-Sheng Yao,1 and Shu-Jiang Tu1,2
1School of Chemistry and Chemical Engineering, Xuzhou Normal
University, Xuzhou, Jiangsu, China
2Key Laboratory of Biotechnology on Medical Plant, Xuzhou, Jiangsu,
China
Abstract: The uncatalyzed and three-component reaction of arylaldehyde, malonodi-
nitrile, and 3-arylamino-5,5-dimethylcyclohex-2-enone at 160 8C under solvent-free
conditions gave 1,4-diarylquinoline derivatives in high yields.
Keywords: 1,4-Diarylquinoline, malononitrile, solvent-free, synthesis
1
INTRODUCTION
Organic reactions under solvent-free conditions have gained in popularity in
recent years.[1] This is because no-solvent reactions usually need shorter
reaction times and simpler reactors and result in simple and efficient workup
procedures. They have recently attracted considerable interest for a large
number of organic transformation because of the concern with green
chemistry.[2] Quinoline is one of the most popular N-heteroaromatic compounds
incorporated into the structures of many pharmaceuticals. Many quinoline-con-
taining compounds exhibit a wide spectrum of pharmacological activities, such
as antiplasmodial,[3] intrinsic,[4] cytotoxic,[5] functional,[6] antibacterial,[7]
Received in Poland September 6, 2007
Address correspondence to Xiang-Shan Wang, School of Chemistry and Chemical
Engineering, Xuzhou Normal University, Xuzhou 221116, Jiangsu, China. E-mail:
xswang1974@yahoo.com
1355

1356
X.-S. Wang et al.
antiproliferative,[8] antimalarial,[9] and anticancer activity.[10] Therefore, the
synthesis of quinolines has attracted much attention in organic synthesis. As a
part of our ongoing program to synthesize these active quinoline derivatives
using a green method,[11] herein we report an uncatalyzed and solvent-free multi-
component procedure for the synthesis of 1,4-arylquinoline derivatives.
2
RESULTS AND DISCUSSION
When the reaction of arylaldehyde 1, malonodinitrile 2, and 3-arylamino-5,5-
dimethylcyclohex-2-enone 3 were performed under solvent-free conditions at
160 8C (Scheme 1), the desired 2-amino-1,4-diaryl-5-oxo-7,7-dimethyl-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile 4 were obtained successfully
in high yields in a few minutes.
To apply this reaction (Scheme 1) to a library synthesis, various kinds of ary-
laldehydes 1 and 3-arylamino-5,5-dimethylcyclohex-2-enone3 were subjected to
reaction with malonodinitrile 2, all giving the corresponding 1,4-diarylquinolines
4, and representative examples are shown in Table 1. All of 1 and 3 gave
expected products in high yields, either bearing electron-withdrawing groups
(such as halide or nitro) or electron-donating groups (such as alkyl group or
alkoxyl group) under the same reaction conditions. The isolated quinolines4
1
were characterized by IR, H NMR, and elemental analyses. The analyses are
in agreement with their structures. The IR spectra for 4a exhibit sharp bands at
3464 and 3390 cm21 for amino group (NH2), sharp band at 2183 cm21 for
cyano group (CN), and strong band at 1657 cm21 for carbonyl group (C55O),
respectively. The 1H NMR spectrum of 4a exhibits a singlet identified methine
(5.00 ppm), along with multiplets (7.18–7.85 ppm) for aromatic protons. The
NH2 proton resonance at 5.62 ppm as a broad singlet disappeared after
addition of D2O to the DMSO-d6 solution of 4a. It is interesting that the
positions of the two methyl groups are different because of the conformation
of the hexagonal ring: one methyl is in the pseudoaxial site while the other is
in the pseudoequatorial site, so they exhibit two singlets at 0.81 and 0.92 ppm,
respectively, due to the different shielding degree. Furthermore the four
protons of the two methylenes also form four double peaks at 1.80 (17.2 Hz),
Scheme 1.

Synthesis of 1,4-Diarylquinoline Derivatives
1357
Table 1. Uncatalyzed and solvent-free synthesis of 1,4-diarylquinoline derivativesa
Entry
Ar
2-ClC6H4
R
Products
Time (min)
Yields (%)b
1
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
4a
4b
4c
4d
4e
4f
10
20
20
15
20
10
20
15
20
15
10
20
15
20
10
10
95
94
96
92
93
98
95
92
94
98
94
93
90
95
95
96
4-CH3OC6H4
4-CH3C6H4
C6H5
3
4
5
2-CH3OC6H4
3-NO2C6H4
2,3-(CH3O)2C6H4
3-ClC6H4
6
7
4g
4h
4i
8
9
2,3-(CH3O)2C6H4
3-ClC6H4
10
11
12
13
14
15
16
H
4j
3-NO2C6H4
2-CH3OC6H4
C6H5
H
4k
4l
H
H
4m
4n
4o
4p
4-CH3OC6H4
2-ClC6H4
4-CH3C6H4
H
H
H
aReaction conditions: 2 mmol of arylaldehyde, 2 mmol of malonodinitrile, and
2 mmol of 3-arylamino-5,5-dimethylcyclohex-2-enone, 160 8C.
bIsolated yields.
1.96 (16.0 Hz), 2.16 (16.0 Hz), and 2.23 (17.2 Hz), respectively, because of the
conformation of the hexagonal ring.
Although the detailed mechanism of this reaction has not been clarified
yet, the formation of 4 can be tentatively explained by the pathway
presented in Scheme 2. A sequential reaction of the Knoevenagel conden-
sation and Michael addition reaction may take place, followed by cyclization
to give the final product 4.
Scheme 2.

1358
X.-S. Wang et al.
Scheme 3.
To verify the mechanism, we individually performed each separate step.
The Knoevenagel condensation product, 2-chlorophenylidenemalonodinitrile
5, was obtained in 92% yield, subsequently, product 5 was treated with
3-arylamino-5,5-dimethylcyclohex-2-enone at 160 8C under solvent-free con-
ditions (Scheme 3). As expected, intermediate products 5 smoothly reacted
with 3a to give the corresponding 2-amino-4-(2-chlorophenyl)-1-(3-chloro-
4-fluorophenyl)-5-oxo-7,7-dimethyl-1,4,5,6,7,8-hexahydroquinoline-3-carbo-
nitrile 4a in 93%. This result suggested that a Knoevenagel condensation took
place during the reaction.
3
CONCLUSION
In conclusion, we found a green method for the synthesis of 2-amino-1,4-diaryl-
5-oxo-7,7-dimethyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile derivatives
by uncatalyzed three-component reaction of arylaldehyde, malonodinitrile,
and 3-arylamino-5,5-dimethylcyclohex-2-enone under solvent-free conditions.
The features of this procedure are mild reaction conditions, high yields, oper-
ational simplicity, and environmentally friendly procedure.
4
EXPERIMENTAL
Melting points were determined in open capillaries and are uncorrected. IR
1
spectra were recorded on a Tensor 27 spectrometer in KBr pellets. H NMR
spectra were obtained from solution in DMSO-d6 with Me4Si as internal
standard using an Inova-400 spectrometer. Elemental analyses were carried
out using Perkin-Elmer 2400 II analyzer.
4.1 General Procedure for the Syntheses of 2-Amino-1,4-diaryl-7,7-
dimethyl-1,4,5,6,7,8-hexahydro-5-oxo-quinoline-3-carbonitrile 4
A dry 50-mL flask was charged with arylaldehyde (2.0 mmol), malononitrile
(0.132 g, 2 mmol), and 3-arylamino-5,5-dimethylcyclohex-2-enone (2.0 mmol).
The reaction mixture was stirred at 160 8C for 10–20 min and then cooled to
room temperature. The solid was purified by recrystallization from DMF and
water, followed by drying at 80 8C for several hours in vacuo to give 4.

Synthesis of 1,4-Diarylquinoline Derivatives
4.2 Data
1359
2-Amino-4-(2-chlorophenyl)-1-(3-chloro-4-fluorophenyl)-7,7-
dimethyl-1,4,5,6,7,8-hexahydro-5-oxo-quinoline-3-carbonitrile 4a
1
Mp 277–279 8C. H NMR (DMSO-d6, d, ppm): 0.81 (s, 3H, CH3), 0.92
(s, 3H, CH3), 1.80 (d, J ¼ 17.2 Hz, 1H, CH), 1.96 (d, J ¼ 16.0 Hz, 1H,
CH), 2.16 (d, J ¼ 16.0 Hz, 1H, CH), 2.23 (d, J ¼ 17.2 Hz, 1H, CH), 5.00
(s, 1H, CH), 5.62 (s, 2H, NH2), 7.18–7.22 (m, 1H, ArH), 7.30–7.41
(m, 3H, ArH), 7.50 (s, 1H, ArH), 7.59–7.64 (m, 1H, ArH), 7.84 (d, J ¼ 6.0
Hz, 1H, ArH). IR (KBr, n, cm21): 3464, 3339, 3047, 2960, 2870, 2183,
1657, 1574, 1499, 1412, 1373, 1259, 1227, 1149, 1126, 1066, 1046, 890,
834, 796, 759, 704. Anal. calcd. for C24H20Cl2FN3O: C, 63.17; H, 4.42; N,
9.21; found C, 63.03; H, 4.58; N, 9.33.
2-Amino-1-(3-chloro-4-fluorophenyl)-7,7-dimethyl-1,4,5,6,7,8-
hexahydro-4-(4-methoxylphenyl)-5-oxo-quinoline-3-carbonitrile 4b
1
Mp 252–255 8C. H NMR (DMSO-d6, d, ppm): 0.75 (s, 3H, CH3), 0.91
(s, 3H, CH3), 1.74 (d, J ¼ 17.6 Hz, 1H, CH), 1.98 (d, J ¼ 16.0 Hz, 1H,
CH), 2.17 (d, J ¼ 16.0 Hz, 1H, CH), 2.24 (d, J ¼ 17.6 Hz, 1H, CH), 3.73
(s, 3H, CH3O), 4.39 (s, 1H, CH), 5.58 (s, 2H, NH2), 6.87 (d, J ¼ 8.4 Hz,
2H, ArH), 7.19 (d, J ¼ 8.4 Hz, 2H, ArH), 7.43 (s, 1H, ArH), 7.58–7.64
(m, 1H, ArH), 7.78 (d, J ¼ 4.8 Hz, 1H, ArH). IR (KBr, n, cm21): 3424,
3337, 3041, 3003, 2956, 2839, 2182, 1661, 1576, 1520, 1411, 1372, 1329,
1300, 1258, 1171, 1151, 1127, 1070, 1041, 1003, 891, 851, 804, 705. Anal.
calcd. for C25H23ClFN3O2: C, 66.44; H, 5.13; N, 9.30; found C, 66.59; H,
5.10; N, 9.45.
2-Amino-1-(3-chloro-4-fluorophenyl)-7,7-dimethyl-1,4,5,6,7,8-
hexahydro-4-(4-methylphenyl)-5-oxo-quinoline-3-carbonitrile 4c
1
Mp 273–275 8C. H NMR (DMSO-d6, d, ppm): 0.75 (s, 3H, CH3), 0.91
(s, 3H, CH3), 1.75 (d, J ¼ 17.6 Hz, 1H, CH), 1.98 (d, J ¼ 16.0 Hz, 1H,
CH), 2.17 (d, J ¼ 16.0 Hz, 1H, CH), 2.23 (d, J ¼ 17.6 Hz, 1H, CH), 2.27
(s, 3H, CH3), 4.39 (s, 1H, CH), 5.57 (s, 2H, NH2), 7.11 (d, J ¼ 8.0 Hz, 2H,
ArH), 7.16 (d, J ¼ 8.0 Hz, 2H, NH2), 7.40–7.42 (m, 1H, ArH), 7.58–7.62
(m, 1H, ArH), 7.59 (d, J ¼ 4.8 Hz, 1H, ArH). IR (KBr, n, cm21): 3458,
3333, 2954, 2181, 1656, 1575, 1498, 1412, 1372, 1256, 1148, 1126, 1044,
848, 797, 704. Anal. calcd. for C25H23ClFN3O: C, 68.88; H, 5.32; N, 9.64;
found C, 68.94; H, 5.23; N, 9.43.

1360
X.-S. Wang et al.
2-Amino-1-(3-chloro-4-fluorophenyl)-7,7-dimethyl-1,4,5,6,7,8-
hexahydro-5-oxo-4-phenyl-quinoline-3-carbonitrile 4d
1
Mp 259–261 8C. H NMR (DMSO-d6, d, ppm): 0.75 (s, 3H, CH3), 0.91
(s, 3H, CH3), 1.76 (d, J ¼ 17.6 Hz, 1H, CH), 2.01 (d, J ¼ 16.0 Hz, 1H,
CH), 2.18 (d, J ¼ 16.0 Hz, 1H, CH), 2.25 (d, J ¼ 17.6 Hz, 1H, CH), 4.44
(s, 1H, CH), 5.62 (s, 2H, NH2), 7.18–7.21 (m, 1H, ArH), 7.28–7.34
(m, 4H, ArH), 7.44 (s, 1H, ArH), 7.58–7.62 (m, 1H, ArH), 7.79 (d, J ¼ 4.4
Hz, 1H, ArH). IR (KBr, n, cm21): 3461, 3334, 2958, 2180, 1655, 1573,
1498, 1451, 1413, 1374, 1335, 1256, 1227, 1176, 1148, 1126, 1044, 832,
759, 701. Anal. calcd. for C24H21ClFN3O: C, 68.32; H, 5.02; N, 9.96; found
C, 68.50; H, 4.91; N, 9.83.
2-Amino-1-(3-chloro-4-fluorophenyl)-7,7-dimethyl-1,4,5,6,7,8-
hexahydro-5-oxo-4-(2-methoxylphenyl)-quinoline-3-carbonitrile 4e
1
Mp 286–288 8C. H NMR (DMSO-d6, d, ppm): 0.84 (s, 3H, CH3), 0.93
(s, 3H, CH3), 1.82 (d, J ¼ 17.6 Hz, 1H, CH), 1.98 (d, J ¼ 16.0 Hz, 1H,
CH), 2.17 (d, J ¼ 16.0 Hz, 1H, CH), 2.26 (d, J ¼ 17.0 Hz, 1H, CH), 3.82
(s, 3H, CH3O), 4.87 (s, 1H, CH), 5.40 (s, 2H, NH2), 6.88–6.92 (m, 1H,
ArH), 6.99 (d, J ¼ 8.0 Hz, 1H, ArH), 7.12–7.18 (m, 2H, ArH), 7.50 (s, 1H,
ArH), 7.58–7.63 (m, 1H, ArH), 7.73 (d, J ¼ 4.4 Hz, 1H, ArH). IR (KBr,
n, cm21): 3364, 3142, 3035, 2963, 2178, 1642, 1567, 1503, 1417, 1375,
1257, 1511, 1101, 1041, 1013, 838, 748, 707. Anal. calcd. for
C25H23ClFN3O2: C, 66.44; H, 5.13; N, 9.30; found C, 66.59; H, 5.10; N, 9.45.
2-Amino-1-(3-chloro-4-fluorophenyl)-7,7-dimethyl-1,4,5,6,7,8-
hexahydro-4-(3-nitrophenyl)-5-oxo-quinoline-3-carbonitrile 4f
1
Mp 262–264 8C. H NMR (DMSO-d6, d, ppm): 0.74 (s, 3H, CH3), 0.91
(s, 3H, CH3), 1.79 (d, J ¼ 17.6 Hz, 1H, CH), 2.00 (d, J ¼ 16.0 Hz, 1H,
CH), 2.20 (d, J ¼ 16.0 Hz, 1H, CH), 2.27 (d, J ¼ 17.6 Hz, 1H, CH), 4.62
(s, 1H, CH), 5.82 (s, 2H, NH2), 7.43 (s, 1H, ArH), 7.61–7.67 (m, 2H, ArH),
7.81 (d, J ¼ 7.2 Hz, 2H, ArH), 8.07 (s, 1H, ArH), 8.08 (d, J ¼ 8.0 Hz, 1H,
ArH). IR (KBr, n, cm21): 3335, 3148, 2961, 2182, 1654, 1570, 1525, 1498,
1419, 1376, 1349, 1260, 1148, 1094, 825, 745, 710. Anal. calcd. for
C24H20ClFN4O2: C, 61.74; H, 4.32; N, 12.00; found C, 61.55; H, 4.54; N,
11.89.
2-Amino-1-(3-chloro-4-fluorophenyl)-4-(2,3-dimethoxylphenyl)-7,7-
dimethyl-1,4,5,6,7,8-hexahydro-5-oxo-quinoline-3-carbonitrile 4g
1
Mp 274–275 8C. H NMR (DMSO-d6, d, ppm): 0.81 (s, 3H, CH3), 0.91
(s, 3H, CH3), 1.79 (d, J ¼ 17.6 Hz, 1H, CH), 1.96 (d, J ¼ 16.0 Hz, 1H,
CH), 2.16 (d, J ¼ 16.0 Hz, 1H, CH), 2.23 (d, J ¼ 17.6 Hz, 1H, CH), 3.80

Synthesis of 1,4-Diarylquinoline Derivatives
1361
(s, 3H, CH3O), 3.88 (s, 3H, CH3O), 4.88 (s, 1H, CH), 5.47 (s, 2H, NH2), 6.81–
6.86 (m, 2H, ArH), 7.00–7.03 (m, 1H, ArH), 7.46 (s, 1H, ArH), 7.59–7.63
(m, 1H, ArH), 7.78 (d, J ¼ 4.4 Hz, 1H, ArH). IR (KBr, n, cm21): 3443,
3333, 2956, 2185, 1656, 1575, 1502, 1490, 1414, 1371, 1257, 1226, 1150,
1066, 1004, 891, 810, 743, 704. Anal. calcd. for C26H25ClFN3O3: C, 64.80;
H, 5.23; N, 8.72; found C, 64.94; H, 5.10; N, 8.70.
2-Amino-4-(3-chlorophenyl)-1-(3-chloro-4-fluorophenyl)-7,7-
dimethyl-1,4,5,6,7,8-hexahydro-5-oxo-quinoline-3-carbonitrile 4h
1
Mp 269–271 8C. H NMR (DMSO-d6, d, ppm): 0.76 (s, 3H, CH3), 0.91
(s, 3H, CH3), 1.78 (d, J ¼ 17.6 Hz, 1H, CH), 2.01 (d, J ¼ 16.0 Hz, 1H,
CH), 2.16–2.25 (m, 2H, ArH), 4.45 (s, 1H, CH), 5.72 (s, 2H, NH2), 7.26–
7.28 (m, 3H, ArH), 7.36–7.43 (m, 2H, ArH), 7.59–7.61 (m, 1H, ArH),
7.79 (d, J ¼ 5.2 Hz, 1H, ArH). IR (KBr, n, cm21): 3464, 3332, 2964,
2181, 1655, 1572, 1499, 1416, 1372, 1256, 1148, 1044, 884, 786, 711.
Anal. calcd. for C24H20Cl2FN3O: C, 63.17; H, 4.42; N, 9.21; found C,
63.03; H, 4.58; N, 9.33.
2-Amino-4-(2,3-dimethoxylphenyl)-7,7-dimethyl-1-(4-fluorophenyl)-
1,4,5,6,7,8-hexahydro-5-oxo-quinoline-3-carbonitrile 4i
1
Mp 273–275 8C. H NMR (DMSO-d6, d, ppm): 0.80 (s, 3H, CH3), 0.90
(s, 3H, CH3), 1.75 (d, J ¼ 17.2 Hz, 1H, CH), 1.97 (d, J ¼ 17.2 Hz, 1H,
CH), 2.15–2.22 (m, 2H, ArH), 3.82 (s, 3H, CH3O), 3.88 (s, 3H, CH3O),
4.89 (s, 1H, CH), 5.30 (s, 2H, NH2), 6.81 (d, J ¼ 8.0 Hz, 1H, ArH), 6.86
(d, J ¼ 8.0 Hz, 1H, ArH), 7.00–7.04 (m, 1H, ArH), 7.40–7.48 (m, 4H,
ArH); IR (KBr, n, cm21): 3437, 3331, 2958, 2183, 1653, 1572, 1509,
1478, 1416, 1372, 1284, 1257, 1223, 1181, 1157, 1053, 1005, 861, 742.
Anal. calcd. for C26H26FN3O3: C, 69.78; H, 5.86; N, 9.39; found C, 69.88;
H, 5.78; N, 9.49.
2-Amino-4-(3-chlorophenyl)-7,7-dimethyl-1-(4-fluorophenyl)-
1,4,5,6,7,8-hexahydro-5-oxo-quinoline-3-carbonitrile 4j
1
Mp 283–285 8C. H NMR (DMSO-d6, d, ppm): 0.75 (s, 3H, CH3), 0.90
(s, 3H, CH3), 1.74 (d, J ¼ 17.2 Hz, 1H, CH), 2.02 (d, J ¼ 16.0 Hz, 1H,
CH), 2.20 (d, J ¼ 16.0 Hz, 1H, CH), 2.21 (d, J ¼ 17.2 Hz, 1H, CH), 4.48
(s, 1H, CH), 5.57 (s, 2H, NH2), 7.26–7.28 (m, 3H, ArH), 7.38–7.44
(m, 5H, ArH). IR (KBr, n, cm21): 3464, 3331, 2966, 2873, 2180, 1654,
1620, 1590, 1569, 1507, 1470, 1416, 1373, 1256, 1225, 1180, 1150, 1045,
786, 711, 698. Anal. calcd. for C24H21ClFN3O: C, 68.32; H, 5.02; N, 9.96;
found C, 68.50; H, 5.06; N, 9.69.

1362
X.-S. Wang et al.
2-Amino-7,7-dimethyl-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4-
(3-nitrophenyl)-5-oxo-quinoline-3-carbonitrile 4k
1
Mp 286–288 8C. H NMR (DMSO-d6, d, ppm): 0.73 (s, 3H, CH3), 0.90
(s, 3H, CH3), 1.75 (d, J ¼ 17.2 Hz, 1H, CH), 2.01 (d, J ¼ 16.0 Hz, 1H,
CH), 2.21 (d, J ¼ 16.0 Hz, 1H, CH), 2.24 (d, J ¼ 17.2 Hz, 1H, CH), 4.64
(s, 1H, CH), 5.67 (s, 2H, NH2), 7.42–7.46 (m, 4H, ArH), 7.64–7.68
(m, 1H, ArH), 7.79 (d, J ¼ 8.0 Hz, 1H, ArH), 8.08 (s, 1H, ArH), 8.09
(d, J ¼ 7.2 Hz, 1H, ArH). IR (KBr, n, cm21): 3468, 3332, 2965, 2180,
1650, 1619, 1567, 1526, 1507, 1417, 1374, 1349, 1256, 1223, 1153, 1092,
1046, 749, 694. Anal. calcd. for C24H21FN4O3: C, 66.66; H, 4.89; N, 12.96;
found C, 66.50; H, 5.03; N, 12.79.
2-Amino-7,7-dimethyl-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4-
(2-methoxylphenyl)-5-oxo-quinoline-3-carbonitrile 4l
1
Mp 266–268 8C. H NMR (DMSO-d6, d, ppm): 0.84 (s, 3H, CH3), 0.92
(s, 3H, CH3), 1.78 (d, J ¼ 17.6 Hz, 1H, CH), 1.99 (d, J ¼ 16.0 Hz, 1H,
CH), 2.18 (d, J ¼ 16.0 Hz, 1H, CH), 2.23 (d, J ¼ 17.6 Hz, 1H, CH), 3.82
(s, 3H, CH3O), 4.87 (s, 1H, CH), 5.23 (s, 2H, NH2), 6.89–6.92 (m, 1H,
ArH), 6.98 (d, J ¼ 8.0 Hz, 1H, ArH), 7.11–7.19 (m, 2H, ArH), 7.40–7.44
(m, 4H, ArH). IR (KBr, n, cm21): 3475, 3382, 3063, 2951, 2176, 1651,
1631, 1563, 1509, 1466, 1401, 1377, 1258, 1227, 1159, 1119, 1031, 857,
749. Anal. calcd. for C25H24FN3O2: C, 71.92; H, 5.79; N, 10.07; found C,
71.80; H, 5.66; N, 9.99.
2-Amino-7,7-dimethyl-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-5-oxo-
4-phenyl-quinoline-3-carbonitrile 4m
1
Mp 257–259 8C. H NMR (DMSO-d6, d, ppm): 0.75 (s, 3H, CH3), 0.90
(s, 3H, CH3), 1.73 (d, J ¼ 17.6 Hz, 1H, CH), 2.01 (d, J ¼ 16.0 Hz, 1H,
CH), 2.20 (d, J ¼ 16.0 Hz, 1H, CH), 2.22 (d, J ¼ 17.6 Hz, 1H, CH), 4.46
(s, 1H, CH), 5.47 (s, 2H, NH2), 7.18–7.21 (m, 1H, ArH), 7.27–7.35
(m, 4H, ArH), 7.40–7.44 (m, 4H, ArH). IR (KBr, n, cm21): 3464, 3339,
3051, 3023, 2957, 2867, 2179, 1655, 1571, 1508, 1452, 1414, 1374, 1335,
1259, 1223, 1177, 1150, 1045, 853, 836, 760, 700. Anal. calcd. for
C24H22FN3O: C, 74.40; H, 5.72; N, 10.85; found C, 74.50; H, 5.76; N, 10.79.
2-Amino-7,7-dimethyl-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4-
(4-methoxylphenyl)-5-oxo-quinoline-3-carbonitrile 4n
1
Mp 278–280 8C. H NMR (DMSO-d6, d, ppm): 0.74 (s, 3H, CH3), 0.89
(s, 3H, CH3), 1.70 (d, J ¼ 17.2 Hz, 1H, CH), 1.99 (d, J ¼ 16.0 Hz, 1H,
CH), 2.18 (d, J ¼ 16.0 Hz, 1H, CH), 2.20 (d, J ¼ 17.2 Hz, 1H, CH), 3.73
(s, 3H, CH3O), 4.40 (s, 1H, CH), 5.40 (s, 2H, NH2), 6.88 (d, J ¼ 8.0 Hz,

Synthesis of 1,4-Diarylquinoline Derivatives
1363
2H, ArH), 7.19 (d, J ¼ 8.0 Hz, 2H, ArH), 7.39–7.43 (m, 4H, ArH). IR (KBr,
n, cm21): 3461, 3338, 3074, 2957, 2178, 1651, 1571, 1509, 1444, 1413, 1373,
1302, 1258, 1176, 1156, 1037, 849, 798. Anal. calcd. for C25H24FN3O2: C,
71.92; H, 5.79; N, 10.07; found C, 71.90; H, 5.88; N, 9.96.
2-Amino-4-(2-chlorophenyl)-7,7-dimethyl-1-(4-fluorophenyl)-1,4,5,6,7,8-
hexahydro-5-oxo-quinoline-3-carbonitrile 4o
1
Mp 256–258 8C. H NMR (DMSO-d6, d, ppm): 0.81 (s, 3H, CH3), 0.90
(s, 3H, CH3), 1.77 (d, J ¼ 17.2 Hz, 1H, CH), 1.97 (d, J ¼ 16.0 Hz, 1H,
CH), 2.17 (d, J ¼ 16.0 Hz, 1H, CH), 2.21 (d, J ¼ 17.2 Hz, 1H, CH), 5.01
(s, 1H, CH), 5.44 (s, 2H, NH2), 7.19–7.22 (m, 1H, ArH), 7.33–7.45
(m, 5H, ArH), 7.49–7.51 (m, 2H, ArH). IR (KBr, n, cm21): 3438, 3293,
3073, 2959, 2870, 2181, 1655, 1625, 1562, 1509, 1471, 1444, 1407, 1258,
1223, 1155, 1035, 862, 822, 762, 708. Anal. calcd. for C24H21ClFN3O: C,
68.32; H, 5.02; N, 9.96; found C, 68.45; H, 4.98; N, 9.77.
2-Amino-7,7-dimethyl-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4-
(4-methylphenyl)-5-oxo-quinoline-3-carbonitrile 4p
1
Mp 279–281 8C. H NMR (DMSO-d6, d, ppm): 0.74 (s, 3H, CH3), 0.89
(s, 3H, CH3), 1.71 (d, J ¼ 17.2 Hz, 1H, CH), 1.99 (d, J ¼ 16.0 Hz, 1H,
CH), 2.19 (d, J ¼ 16.0 Hz, 1H, CH), 2.21 (d, J ¼ 17.2 Hz, 1H, CH), 2.23
(s, 3H, CH3), 4.41 (s, 1H, CH), 5.43 (s, 2H, NH2), 7.12 (d, J ¼ 8.0 Hz, 2H,
ArH), 7.16 (d, J ¼ 8.0 Hz, 2H, ArH), 7.41–7.43 (m, 4H, ArH). IR (KBr,
n, cm21): 3461, 3335, 2961, 2178, 1654, 1572, 1508, 1414, 1372, 1258,
1224, 1179, 1152, 1045, 855, 795. Anal. calcd. for C25H24FN3O: C, 74.79;
H, 6.03; N, 10.47; found C, 74.88; H, 5.89; N, 10.52.
REFERENCES
1. (a) Metzger, J. O. Solvent-free organic syntheses. Angew. Chem. Int. Ed. 1998, 37,
2975–2978; (b) Li, C.-J.; Chan, T.-H. Organic syntheses using indium-mediated
and catalyzed reactions in aqueous media. Tetrahedron 1999, 55, 11149–11176.
2. (a) Loh, T.-P.; Huang, J.-M.; Goh, S.-H.; Vittal, J. J. Aldol reaction under solvent-
free conditions: Highly stereoselective synthesis of 1,3-amino alcohols. Org. Lett.
2000, 2, 1291–1294; (b) He, T.; Zha, Z.; Pan, C.; Wang, Z. Microwave-promoted,
solvent-free, three-component coupling of aldehyde, alkyne, and amine catalyzed
by AgNO3. Synth. Commun. 2007, 37, 849–858; (c) Lamiri, M.; Bougrin, K.;
Daou, B.; Soufiaoui, M.; Nicolas, E.; Giralt, E. Microwave-assisted solvent-free
regiospecific synthesis of 5-alkylidene and 5-arylidenehydantoins. Synth.
Commun. 2006, 36, 1575–1584; (d) Koshkin, A. V.; Fedorova, O. A.;
Lokshin, V.; Guglielmetti, R.; Hamelin, J.; Texier-Boullet, F.; Gromov, S. P.
Microwave-assisted solvent-free synthesis of the substituted spiroindolino
naphth[2,1-b][1,4]oxazines. Synth. Commun. 2004, 34, 315–322; (e) Sharifi, A.;

1364
X.-S. Wang et al.
Mirzaei, M.; Reza Naimi-Jamal, M. Mild and solvent-free alkynylation of ketones
on the KF/alumina. Synth. Commun. 2005, 35, 1039–1044.
3. Beagley, P.; Blackie, M. A. L.; Chibale, K.; Clarkson, C.; Meijboom, R.;
Moss, J. R.; Smith, P.; Su, H. Synthesis and antiplasmodial activity in vitro of
new ferrocene-chloroquine analogues. Dalton Trans. 2003, 3046–3051.
4. Sawada, Y.; Kayakiri, H.; Abe, Y.; Mizutani, T.; Inamura, N.; Asano, M.;
Hatori, C.; Aramori, I.; Oku, T.; Tanaka, H. Discovery of the first non-peptide
full agonists for the human bradykinin B2 receptor incorporating 4-(2-picolyloxy)-
quinoline and 1-(2-picolyl)benzimidazole frameworks. J. Med. Chem. 2004, 47,
2853–2863.
5. Ma, Z.; Hano, Y.; Nomura, T.; Chen, Y. Novel quinazoline-quinoline alkaloids
with cytotoxic and DNA topoisomerase II inhibitory activities. Bioorg. Med.
Chem. Lett. 2004, 14, 1193–1196.
6. Denton, T. T.; Zhang, X.; Cashman, J. R. 5-Substituted, 6-substituted, and unsub-
stituted 3-heteroaromatic pyridine analogues of nicotine as selective inhibitors of
cytochrome P-450 2A6. J. Med. Chem. 2005, 48, 224–239.
7. Fokialakis, N.; Magiatis, P.; Chinou, L.; Mitaku, S.; Tillequin, F. Megistoquinones
I and II, two quinoline alkaloids with antibacterial activity from the bark of Sarco-
melicope megistophylla. Chem. Pharm. Bull. 2002, 50, 413–414.
8. Fossa, P.; Mosti, L.; Menozzi, G.; Marzano, C.; Baccichetti, F.; Bordin, F. Novel
angular furo and thieno-quinolinones: Synthesis and preliminary photobiological
studies. Bioorg. Med. Chem. 2002, 10, 743–751.
9. Ryckebusch, A.; Derprez-Poulain, R.; Maes, L.; Debreu-Fontaine, M. A.;
Mouray, E.; Grellier, P.; Sergheraert, C. Synthesis and in vitro and in vivo antima-
larial activity of N1-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine
derivatives. J. Med. Chem. 2003, 46, 542–557.
10. Morgan, L. R.; Jursic, B. S.; Hooper, C. L.; Neumann, D. M.; Thangaraj, K.;
Leblanc, B. Anticancer activity for 4,40-dihydroxybenzophenone-2,4-dinitrophe-
nylhydrazone (A-007) analogues and their abilities to interact with lymphoen-
dothelial cell surface markers. Bioorg. Med. Chem. Lett. 2002, 12, 3407–3411.
11. (a) Wang, X. S.; Zhang, M. M.; Shi, D. Q.; Tu, S. J.; Wei, X. Y.; Zong, Z. M. A
simple and clean procedure for the synthesis of polyhydro acridine and quinoline
derivatives: Reaction of Schiff base with 1,3-dicarbonyl compounds in aqueous
medium. Tetrahedron Lett. 2005, 46, 7169–7173; (b) Wang, X. S.;
Zhang, M. M.; Jiang, H.; Shi, D. Q.; Tu, S. J.; Wei, X. Y.; Zong, Z. M. An
improved and benign synthesis of 9,10-diarylacridin-1,8-dione and indenoquino-
line derivatives from 3-arylamino-5,5-dimethylcyclohex-2-enone, arylaldehyde
and 1,3-dicarbonyl compound in ionic liquid medium. Synthesis 2006,
4187–4199; (c) Wang, X. S.; Zhang, M. M.; Jiang, H.; Yao, C. S.; Tu, S. J.
Three-component green synthesis of N-arylquinoline derivatives in ionic liquid
[Bmim][BF4]: Reactions of arylaldehyde, 3-arylamino-5,5-dimethyl cyclohex-2-
enone, and active methylene compounds. Tetrahedron 2007, 63, 4439–4449.