Synthesis of polysubstituted quinolines using cyanuric chloride as a catalyst under aqueous conditions

Article abstract of DOI:10.1002/jccs.200800141

A mild, eco-friendly and efficient route for the synthesis of quinolines and polycyclic quinolines via Friedlaender annulation using cyanuric chloride as a catalyst under aqueous conditions is described.

Full text of DOI:10.1002/jccs.200800141

Journal of the Chinese Chemical Society, 2008, 55, 947-951
947
Communication
Synthesis of Polysubstituted Quinolines Using Cyanuric Chloride as a
Catalyst under Aqueous Conditions
Babasaheb P. Bandgar,* Parmeshwar. E. More and Vinod T. Kamble
Organic Chemistry Research Laboratory, School of Chemical Sciences,
Swami Ramanand Teerth Marathwada University, Nanded-431606, India
A mild, eco-friendly and efficient route for the synthesis of quinolines and polycyclic quinolines via
Friedländer annulation using cyanuric chloride as a catalyst under aqueous conditions is described.
Keywords: Quinolines; Polycyclic quinolines; Friedländer annulation; Cyanuric chloride.
INTRODUCTION
The chemical industry is a major contributor to envi-
luene sulphonic acid, phosphoric acids are widely used as
catalysts for this conversion.6 However, many of these
classical methods require high temperatures, longer reac-
tion times, drastic conditions, and low yields. Therefore,
new catalytic systems are continuously explored. As a re-
sult, recently Lewis acids such as Ag3PW12O40, Y(OTf)3,
FeCl3 or Mg(ClO4)2, NaAuCl4.2H2O, SnCl2 or ZnCl2,
Bi(OTf)3, NaF, SnCl2.2H2O, CeCl3.7H2O, ZnCl2, and I2
have been used in presence of organic solvent for the syn-
thesis of quinolines.7a-k Also, microwave irradiations have
been used for the synthesis of these compounds.8a-c How-
ever, there have been no reports on the use of cyanuric
chloride for Friedländer quinoline synthesis.
ronmental pollution due to the ubiquitous use of several
hazardous organic solvents, flammables, carcinogens, ex-
plosives, etc. The development of non-hazardous alterna-
tives is not only due to the increased regulatory pressure fo-
cusing on organic solvents but the great importance with
respect to green chemistry.1 Organic reactions in water as
solvent have many advantages from both economic and en-
vironmental point of view.2 Although water is inexpensive,
non-toxic and non-flammable, it is frequently overlooked
as a solvent for organic reactions. Most of catalysts and re-
agents are either deactivated or decomposed in water and in
general organic compounds are insoluble in water. There-
fore, carrying out organic reactions in water poses one of
the fundamental challenges to organic chemists.
RESULTS AND DISCUSSION
In earlier reports we showed the efficacy of cyanuric
chloride (2,4,6-trichloro-1,3,5-triazine, TCT) for various
transformations.9 In continuation of our research work in
the development of synthetic methods using cyanuric chlo-
ride, we report herein, the efficient application of this re-
agent for Friedländer annulation followed by cyclodehy-
dration of ketones under aqueous conditions.
The synthesis of quinoline derivatives has been con-
sidered of great interest to organic chemists owning to its
wide range of biological and pharmaceutical properties
such as anti-malarial, anti-inflammatory, anti-asthmatic,
anti-bacterial, anti-hypertensive and tyrosine kinase inhib-
iting agents.3 In addition, quinolines are valuable synthones
used for the preparation of nano- and meso-structures with
enhanced electronic and photonic properties.4 Conse-
quently, various methods were developed for the synthesis
of quinoline derivatives. The Friedländer annulation has
been catalyzed by both acids and bases. Under base cata-
lyzed conditions 2-aminobenzophenone fails to react with
simple ketones such as cyclohexanone or b-ketoesters.5
Brønsted acids like hydrochloric acid, sulphuric acid, p-to-
Initially, we optimized the amount of cyanuric chlo-
ride as a catalyst required for the reaction of 2-aminoben-
zophenone (1 mmol) and dimedone (1 mmole). When this
reaction is carried out without catalyst (Table 1, entry 1)
even trace mount of the product did not formed. When the
amount of catalyst used is less than 16 mol%, low to moder-
ate yield of quinoline is obtained (Table 1, entries 2-5).
With 16 mol% of the catalyst, the corresponding quinoline
* Corresponding author. Fax: +0091-2462-229245; E-mail: bandgar_bp@yahoo.com

948 J. Chin. Chem. Soc., Vol. 55, No. 5, 2008
Bandgar et al.
Scheme I
used in this protocol. In some methods7d,7f,7i costly heavy
metal ions with low catalyst loading are used. However,
these methods suffer from disadvantages like use of haz-
ardous and toxic organic solvents and poor yields of the
products.
Table 1. Catalytic study of cyanuric chloride for the synthesis of
quinoline 3c under aqueous medium at room
temperature
Entry Cyanuric chloride (mol %)
Time (h)
Yielda (%)
1
--
02
04
08
12
16
20
20
24
30
50
50
48
40
40
30
20
22
19
18
--
05
15
30
45
78
96
-88b
96
96
2
The advantages of the present protocol are: (i) use of
inexpensive catalyst (ii) use of water as a green solvent (iii)
mild reaction conditions (iv) method works well on 100
mmol scale therefore, this protocol may be applicable on
large scale synthesis of these bioactive molecules (Table 1,
entry 8) (v) purification of the product using column chro-
matography is not required.
3
4
5
6
7
8
9
10
In conclusion, we believe that the present methodol-
ogy compared to many of the reported methods offers a
simple and efficient route for the synthesis of poly-substi-
tuted quinolines under aqueous medium at room tempera-
ture. Mild conditions, simple work-up procedure, pure
products and excellent yields make an alternative contribu-
tion to the existing methodologies.
a Isolated yields.
b The reaction was carried out with 2-aminobenzophenol (100
mmol), dimidone (100 mmol) by using 20 mol% cyanuric
chloride and 100 mL water.
was obtained in good yield (Table 1, entry 6). While the use
of 20 mol% catalyst leads to the excellent yield of the prod-
uct (Table 1, entry 7) whereas the yield of the product did
not improve even after using excess amount of the catalyst
(Table 1, entries 9, 10).
EXPERIMENTAL SECTION
All Chemicals were of analytical grade and pur-
chased from Aldrich and Fluka companies. 1H NMR spec-
tra were recorded on 300 MHz (Varian Mercury) instru-
ment using CDCl3 as a solvent and TMS as an internal stan-
dard. IR spectra were recorded on Bomem MB 104 IR
spectrometer. Melting points are not corrected. Chemical
shifts are given in ppm and J values are quoted in Hz.
General experimental procedure
Using the best conditions reported in Table 1, we then
continued to study the reaction by using variety of 2-ami-
noaryl and a-methylene ketones respectively. The results
were summarized in Table 2 indicating that both cyclic and
acyclic ketones underwent smooth reaction with 2-amino-
aryl ketones to give high yields of products. The present
protocol is highly effective for substituted 2-aminoaryl ke-
tones such as 2-aminobenzophenone and 2-amino-5-chlo-
robenzophenone. In general, the yields of the quinoline
dervetives were high. It is noteworthy to mention that the
method is clean and free form side reactions which nor-
mally observed under basic conditions.
A mixture of 2-aminoaryl ketone (1.0 mmol), a-meth-
ylene ketone (1 mmol) cyanuric chloride (20 mol%) and
water (1.0 mL) was stirred at room temperature for the
specified time (Table 2). After completion of the reaction
(TLC), the resulting suspension was neutralized with 2N
NaOH. The crude solid was separated by filtration under
suction and washed with water to get practically pure white
or slightly yellow powder.
Comparison of effect of cyanuric chloride catalyst
with reported catalysts is shown in Table 3. As compared to
recently reported method,10 involving the use of heavy
metal ion and stringent conditions under aqueous medium
the present protocol is superior as no heavy metal ion is
Spectral data of the compounds
3a: Yellow solid; m.p. 112 °C; IR (KBr): 3029, 2962,

Synthesis of Polysubstituted Quinolines
J. Chin. Chem. Soc., Vol. 55, No. 5, 2008 949
Table 2. Synthesis of poly-substituted quinolines using cyanuric chloride as a catalyst under
aqueous conditions
Substrate
(1)
Substrate
(2)
Product
(3)
Time
(h)
Yielda
(%)
Entry
a
18
16
93
95
96
90
88
93
b
c
d
e
f
20
17
17.30
16
g
h
i
12.30
14.30
16
95
94
91
j
17
85
a Yields pure isolated products
1707, 1615, 1572, 1480, 703 cm-1; 1H NMR (CDCl3, 300
MHz): d = 1.81 (s, 3H), 2.01 (s, 3H), 7.10-7.15 (m, 2H),
7.20 (t, J = 8.4 Hz, 1H), 7.25-7.29 (m, 3H), 7.31 (d, J = 8.6
Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H);
13C NMR (75 MHz, CDCl3): d = 23.3, 29.2, 31.4, 124.5,
125.6, 126.0, 128.1, 128.4, 129.5, 134.7, 147.0, 153.0,
205.6; Anal. Calcd for C18H15NO: C, 82.73; H, 5.78; N,
5.36. Found: C, 82.70; H, 5.81; N, 5.32.
3b: Yellow solid; m.p. 97 °C; IR (KBr): 3028, 2960,
1701, 1610, 1563, 1482, 907 cm-1; 1H NMR (CDCl3, 300
MHz): d = 1.10 (t, J = 7.4 Hz, 3H), 2.91 (s, 3H), 4.11 (q, J =
7.4 Hz, 2H), 7.42-7.47 (m, 6H), 7.53 (d, J = 8.6 Hz, 1H),
7.70 (t, J = 8.1 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d = 14.1, 15.4, 23.6, 61.4, 123.8, 125.7,

950 J. Chin. Chem. Soc., Vol. 55, No. 5, 2008
Bandgar et al.
Table 3. Comparison of cyanuric chloride catalyst against reported catalysts
Loading
(mol %)
Reaction
Yield
(%)
Entry
1
Catalyst
p-TsOH
Time
Ref.
[8a]
Conditions
100
M.W./Oil bath
100 °C
3-10 min
86-96
2
3
4
5
6
7
8
NaAuCl4.2H2O
CeCl3.7H2O
2.5
25
EtOH/40-60 °C
CH3CN/r.t.
Neat/110 °C
EtOH/70 °C
100 °C
6 h
54-93
65-95
53-78
70-94
88-96
50-98
85-96
[7d]
[7i]
1.5-5 h
4 min
Diphenyl Phosphate
ZnCl2, SnCl2
Ionic liquid
150
150
100
10
[8c]
[7e]
[11]
[10]
3 h
3.3-6.0 h
3.15 h
12.30-20 h
Zr(DS)4
H2O-EtOH/Reflux
H2O/r.t.
Cyanuric chloride
20
126.1, 127.9, 129.2, 29.8, 141.2, 147, 154.2, 168.9; Anal.
Calcd for C19H17NO2: C, 78.32; H, 5.88; N, 4.80. Found: C,
78.30; H, 5.89; N, 4.78.
129.1, 129.8, 130.8, 132.3, 134.5, 135.4, 142.9, 145.8,
153.8, 204.9; Anal. Calcd for C18H14ClNO: C, 73.09; H,
4.77; N, 4.73. Found: C, 73.07; H, 4.75; N, 4.75.
3c: Yellow solid; m.p. 193 °C; IR (KBr): 3054, 1712,
1603, 1575, 1209, 740 cm-1; 1H NMR (CDCl3, 300 MHz): d
= 1.21 (s, 6H), 2.26 (s, 2H), 2.39 (s, 2H), 7.22 (d, J = 8.7,
2H), 7.47-7.49 (m, 2H), 7.5 (t, J = 7.2 Hz, 1H), 7.74-7.76
(m, 4H); 13C NMR (22.5 MHz, CDCl3): d = 28.18, 31.99,
48.25, 54.02, 126.24, 127.26, 127.91, 127.98, 128.44,
131.27, 137.46, 148.91, 150.71, 160.94, 197.48; Anal.
Calcd for C21H19NO: C, 83.69; H, 6.35; N, 5.30. Found: C,
83.66; H, 6.37; N, 5.27.
3g: Yellow solid; m.p. 125-127 °C; IR (KBr): 3060,
2980, 1720, 1600, 1221, 909, 732 cm-1; 1H NMR (CDCl3,
300 MHz): d = 1.21 (t, J = 7.4 Hz, 3H), 2.83 (s, 3H), 4.13-
4.17 (q, J = 7.1 Hz, 2H), 7.31-7.62 (m, 7H), 8.01 (d, J = 8.8
Hz, 1H); 13C NMR (200 MHz, DMSO, d6): d = 13.31,
23.21, 61.14, 124.41, 125.21, 127.66, 128.47, 128.89,
128.99, 130.84, 130.97, 131.33, 134.13, 144.67, 145.46,
154.53, 167.06; Anal. Calcd for C19H16ClNO2: C, 70.04; H,
4.94; N, 4.29. Found: C, 70.03; H, 4.91; N, 4.30.
3d: Yellow solid; m.p. 143 °C; IR (KBr): 3057, 2935,
1608, 1577, 1480, 1212, 708 cm-1; 1H NMR (CDCl3, 300
MHz): d = 1.81-1.90 (m, 2H), 1.97-2.12 (m, 2H), 2.70 (t, J
= 7.0 Hz, 2H), 3.23 (t, J = 7.2 Hz, 2H), 7.30-7.39 (m, 3H),
7.52-7.68 (m, 5H), 8.10 (d, J = 8.6 Hz, 1H); 13C NMR (22.5
MHz, CDCl3): d = 22.64, 22.76, 27.74, 33.99, 125.09,
125.47, 126.40, 127.44, 128.01, 128.32, 128.85, 136.88,
146.13, 158.71; Anal. Calcd for C19H17N: C, 87.99; H,
6.60; N, 5.40. Found: C, 87.96; H, 6.61; N, 5.41.
3h: Yellow solid; m.p. 238-240 °C; IR (KBr): 3062,
2985, 1712, 1603, 1578, 1210, 735 cm-1; 1H NMR (CDCl3,
300 MHz): d = 1.22 (s, 6H), 2.28 (s, 2H), 2.41 (s, 2H),
7.35-7.38 (m, 2H), 7.55-7.65 (m, 5H), 8.01 (d, J = 8.6 Hz,
1H); 13C NMR (22.5 MHz, CDCl3): d = 28.19, 31.99,
48.27, 54.04, 124.8, 125.8, 128.8, 129.1, 129.8, 130.8,
132.3, 134.5, 135.4, 142.9, 145.8, 153.8, 204.9; Anal.
Calcd for C21H18ClNO: C, 75.10; H, 5.40; N, 4.17. Found:
C, 75.07; H, 5.42; N, 4.18.
3e: White solid; m.p. 136 °C; IR (KBr): 3060, 2958,
1606, 1487, 826, 716 cm-1; 1H NMR (CDCl3, 300 MHz): d
= 2.12 (m, 2H), 2.87 (t, J = 7.2 Hz, 2H), 3.19 (t, J = 7.0 Hz,
2H), 7.27-7.35 (m, 3H), 7.49-7.67 (m, 5H), 8.01 (d, J = 8.5
Hz, 1H); 13C NMR (22.5 MHz, CDCl3): d = 14.6, 22.7,
29.4, 34.8, 123.1, 125, 126.9, 127.8, 128.9, 133.7, 137.8,
147.2, 166.7; Anal. Calcd for C18H15N: C, 88.12; H, 6.16;
N, 5.70. Found: C, 88.10; H, 6.18; N, 5.67.
3i: Yellow solid; m.p. 158-160 °C; IR (KBr): 3060,
2945, 1606, 1575, 1480, 1215, 704 cm-1; 1H NMR (CDCl3,
300 MHz): d = 1.49 (m, 2H), 1.57 (m, 2H), 2.54 (t, J = 6.5
Hz, 2H), 3.30 (t, J = 7.1 Hz, 2H), 7.32-7.34 (m, 2H),
7.59-7.70 (m, 5H), 7.98 (d, J = 8.8 Hz, 1H); 13C NMR (75
MHz, CDCl3): d = 23, 28.2, 34.3, 124.6, 127.5, 128.2,
128.9, 129.1, 129.3, 129.5, 130.2, 131.3, 136.5, 144.8,
145.8, 159.6; Anal. Calcd for C19H16ClN: C, 77.67; H,
5.48; N, 4.76. Found: C, 77.64; H, 5.50; N, 4.73.
3f: Yellow solid; m.p. 153 °C; IR (KBr): 3032, 2961,
1702, 1608, 1569, 1483, 909, 694 cm-1; 1H NMR (CDCl3,
300 MHz): d = 1.90 (s, 3H), 2.61 (s, 3H), 7.30-7.33 (m,
2H), 7.50-7.60 (m, 5H), 7.91 (d, J = 8.7 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d = 23.6, 31.6, 124.7, 125.8, 128.8,
3j: White solid; m.p. 150-152 °C; IR (KBr): 3060,
2958, 1606, 1486, 715 cm-1; 1H NMR (CDCl3, 300 MHz): d
= 2.12 (m, 2H), 2.90 (t, J = 7.4 Hz, 2H), 3.20 (t, J = 7.2 Hz,
2H), 7.30-7.36 (m, 2H), 7.55-7.59 (m, 5H), 8.01 (d, J = 8.6

Synthesis of Polysubstituted Quinolines
J. Chin. Chem. Soc., Vol. 55, No. 5, 2008 951
Hz, 1H); 13C NMR (75 MHz, CDCl3): d = 23.3, 30.2, 35,
124.4, 126.9, 128.2, 128.6, 129, 130.3, 131.2, 134.3, 135.9,
141.8, 146.3, 167.7; Anal. Calcd for C18H14NCl: C, 77.27;
H, 5.04; N, 5.00. Found: C, 77.23; H, 5.05; N, 4.97.
104, 281.
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ACKNOWLEDGEMENT
More P. E. thanks UGC, New Delhi and Chairman,
Agricultural Development Trust, Baramati for sanctioning
Study leave.
Received June 19, 2008.
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