DBU-catalyzed expeditious and facile multicomponent synthesis of N-arylquinolines under microwave irradiation

Article abstract of DOI:10.1007/s00706-011-0651-y

N-Arylquinoline derivatives are obtained in excellent yields by a rapid, easy, and efficient one-pot multicomponent reaction of aromatic aldehydes, 3-arylamino-5,5-dimethylcyclohex-2-enone, and active methylene compounds utilizing 1,8-diazabicyclo[5.4.0]u

Full text of DOI:10.1007/s00706-011-0651-y

Monatsh Chem (2012) 143:805–808
DOI 10.1007/s00706-011-0651-y
ORIGINAL PAPER
DBU-catalyzed expeditious and facile multicomponent synthesis
of N-arylquinolines under microwave irradiation
•
Satish Kumar Singh Krishna Nand Singh
Received: 29 December 2010 / Accepted: 2 September 2011 / Published online: 5 October 2011
Ó Springer-Verlag 2011
Abstract N-Arylquinoline derivatives are obtained in
excellent yields by a rapid, easy, and efficient one-pot
multicomponent reaction of aromatic aldehydes, 3-aryla-
mino-5,5-dimethylcyclohex-2-enone, and active methylene
compounds utilizing 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) as a catalyst in ethanol under microwave irradiation.
such as long reaction times, poor product yields, harsh
conditions, high costs, and use of hazardous catalysts.
Further, there are few examples of syntheses of N-substi-
tuted quinoline derivatives in the literature [20–22].
Microwave (MW) irradiation has evolved as a powerful
method to perform organic synthesis with great success,
particularly in the light of the current paradigm shift to
green chemistry [23, 24]. The environmental acceptability
of the process is further improved if a multicomponent
approach is adopted under microwave irradiation [25, 26].
The multicomponent syntheses of such N-arylquinoline
derivatives has been recently effected by employing cata-
lysts such as [Bmim]BF4 (1-butyl-3-methylimidazolium
tetrafluoroborate) [27] and TBAF (tetrabutylammonium
fluoride) [28].
Keywords Microwave-assisted synthesis ꢀ
Multicomponent reaction ꢀ One-pot synthesis ꢀ
Quinoline ꢀ DBU
Introduction
Heteroaromatic rings containing nitrogen atoms often play
an important role as the scaffolds of bioactive substances.
Quinoline is one of the most popular N-heteroaromatic
frameworks present in many pharmaceuticals and exhibits
a wide spectrum of pharmacological effects, such as anti-
plasmodial [1], intrinsic [2], cytotoxic [3], functional [4],
antibacterial [5], antiproliferative [6], antimalarial [7], and
anticancer activities [8]. Therefore, the synthesis of quin-
olines has attracted much attention in organic synthesis.
The classical methods for the preparation of quinoline
derivatives include the Skraup, Doebner–Von Miller,
Conrad–Limbach, Combes, and Pfitzinger syntheses
[9–13]. Owing to the remarkable potential of these com-
pounds as a source of valuable drugs, various synthetic
methods have also been reported [14–19]. Most of these
processes, however, suffer from one or other drawbacks
Results and discussion
In view of the above, we have investigated a 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU; 5 mol%) catalyzed, one-
pot, simple, and efficient procedure for the rapid con-
struction of N-substituted quinolines via a three-component
reaction of 3-arylamino-5,5-dimethylcyclohex-2-enones,
aromatic aldehydes, and active methylene compounds such
as malononitrile or ethyl cyanoacetate in ethanol under
controlled microwave irradiation (Scheme 1).
In order to optimize the effect of catalyst, MW power,
and temperature, we investigated the model reaction
of 3-phenylamino-5,5-dimethylcyclohex-2-enone (1a),
p-anisaldehyde (2c), and malononitrile (3a). The reaction
was carried out in the presence of different organic bases
such as DBU, Et3N, piperidine, and pyridine under
microwave irradiation at different power, temperature, and
time in ethanol. It is evident from the results presented in
S. K. Singh ꢀ K. N. Singh (&)
Department of Chemistry, Faculty of Science,
Banaras Hindu University, Varanasi 221 005, India
e-mail: knsinghbhu@yahoo.co.in
123

806
S. K. Singh, K. N. Singh
Scheme 1
Table 1 that DBU (5 mol%) as catalyst accomplishes the
reaction successfully and the use of the microwave irradi-
ation further enhances the yield of the product considerably
with dramatic reduction in the reaction time, the best result
being obtained using 140 W at 80 °C in 3 min (entry 6).
Under the optimized reaction conditions (entry 6), a
number of 3-arylamino-5,5-dimethylcyclohex-2-enones 1
undergo multicomponent reaction with different aromatic
aldehydes 2 and malononitrile in a molar ratio of 1:1:1 in
ethanol under microwave heating (140 W, 80 °C). When
malononitrile was replaced by ethyl cyanoacetate, another
series of 4-arylquinoline derivatives 4s–4w were obtained
in excellent yields (92–95%) under similar reaction con-
ditions at 120 W microwave power and 80 °C in ethanol.
All the reactions were completed in 3–5 min (TLC moni-
toring) and the results are given in Table 2. Both electron-
rich and electron-deficient aldehydes afforded excellent
yields of the products 4a–4w (92–99%). All products were
crystalline and fully characterized on the basis of their
melting points, elemental analyses, and spectral data (IR,
1H NMR, and 13C NMR).
Conclusion
We have developed a new, facile, and efficient methodology
for the DBU-catalyzed rapid preparation of N-substituted
quinoline derivatives via one-pot three-component con-
densation of 3-arylamino-5,5-dimethylcyclohex-2-enone,
aromatic aldehyde, and active methylene compounds
including malononitrile and ethyl cyanoacetate in ethanol.
The mildness of the conversion, its experimental simplicity,
compatibility with various functional groups, excellent
product yields, short reaction times, and the easy workup
procedure make this approach attractive for synthesizing a
variety of such derivatives.
Experimental
Table 1 Optimization of reaction conditions for the synthesis of 4d
All chemicals were procured from Aldrich, USA, and
E. Merck, Germany, and were purified prior to their use. IR
spectra were recorded on a JASCO FT-IR-5300 spectro-
photometer. NMR spectra were run on a JEOL AL300
FT-NMR spectrometer; chemical shifts are given as d
(ppm) relative to TMS as internal standard. Elemental
microanalysis was performed on an Exeter Analytical Inc
model CE-440 CHN analyzer. Melting points were mea-
sured in open capillaries. The microwave irradiation was
effected using CEM’s Discover BenchMate single-mode
microwave synthesis system using safe pressure regulation
10-cm3 pressurized vials with ‘‘snap-on’’ caps. 3-Aryl-
amino-5,5-dimethylcyclohex-2-enones 1 were synthesized
according to the procedure described in Ref. [29].
Entry Base/mol%
Microwave
Yield/%
MW/W Temp/°C Time/min
1
–
180
120
120
140
120
140
180
140
140
140
140
140
80
80
100
80
80
80
80
80
80
80
80
80
80
80
80
10
5
–
2
DBU (3)
DBU (3)
DBU (3)
DBU (5)
DBU (5)
DBU (5)
DBU (7)
DBU (10)
Et3N (5)
Et3N (10)
Piperidine (5)
67
71
73
92
98
98
97
95
56
70
45
58
20
28
3
5
4
5
5
3
6
3
7
3
8
3
9
3
10
11
12
13
14
15
5
5
7
Piperidine (10) 140
5
General procedure for the synthesis of N-substituted
quinolines 4a–4w
Pyridine (5)
180
180
10
10
Pyridine (10)
A mixture of 3-arylamino-5,5-dimethylcyclohex-2-enone 1
(1 mmol), aromatic aldehyde 2 (1 mmol), 0.066 g malono-
The bold entry signifies the best result obtained during the
optimization
123

Synthesis of N-arylquinolines under microwave irradiation
807
Table 2 DBU-catalyzed synthesis of N-substituted quinolines under MW
Entry
Ar
Ar0
X
Product
Time/min
Yield/%a
M.p./°C
Observed
Refs. [21, 27, 28]
1
C6H5
C6H5
CN
4a
4b
4c
4d
4e
4f
3
3
3
3
3
4
4
4
4
4
5
4
3
5
5
4
5
3
5
5
5
5
5
97
98
99
98
99
97
96
94
95
94
93
95
95
93
93
94
92
96
94
93
95
94
92
223–225
231–232
252
246–247
–
2
C6H5
4-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
4-CH3OC6H4
4-ClC6H4
4-ClC6H4
3-ClC6H4
3-ClC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-FC6H4
CN
3
4-CH3C6H4
C6H5
CN
252–254
244–245
239–241
260–262
268–269
–
4
CN
245–246
240–241
258–260
268–269
230–232
232–234
254–256
276–277
259–261
259–260
276–277
267–268
280
5
4-CH3C6H4
4-CH3C6H4
C6H5
CN
6
CN
7
CN
4g
4h
4i
8
C6H5
CN
9
4-CH3C6H4
C6H5
CN
233–234
275–277
276–278
261–263
260–261
275–276
268–269
281–283
271–274
267–268
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CN
4j
4-BrC6H4
4-CH3C6H4
C6H5
CN
4k
4l
CN
CN
4m
4n
4o
4p
4q
4r
4s
C6H5
4-NO2C6H4
3-NO2C6H4
3-NO2C6H4
3-NO2C6H4
4-OHC6H4
4-CH3C6H4
4-ClC6H4
4-ClC6H4
3-ClC6H4
3-NO2C6H4
CN
C6H5
CN
4-CH3C6H4
4-BrC6H4
C6H5
CN
CN
272–274
266–268
176–178
204–205
201–203
220–222
236–237
CN
C6H5
COOEt
COOEt
COOEt
COOEt
COOEt
C6H5
4t
204–206
198–200
219–221
236–237
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4u
4v
4w
Microwave heating using 140 W (120 W for entries 19–23) at 80 °C
a
Isolated yield
1,488, 1,411, 1,371, 1,256, 1,147, 1,043, 848, 793,
670 cm-1
nitrile 3a (1 mmol) or 0.113 g ethyl cyanoacetate 3b
(1 mmol), 0.0076 g DBU (5 mol%), and 1.5 cm3 ethanol
was placed in a sealed pressure regulation 10-cm3 pres-
surized vial with ‘‘snap-on’’ cap and was irradiated in the
single-mode microwave synthesis system at 140 W/120 W
at 80 °C for 3–5 min. After completion of reaction (TLC),
the mixture was cooled and the resulting product was fil-
tered, dried, and recrystallized from ethanol to afford the
pure products 4a–4w.
.
2-Amino-4-(3-chlorophenyl)-1,4,5,6,7,8-hexahydro-7,7-
dimethyl-5-oxo-1-phenylquinoline-3-carbonitrile
(4h, C24H22ClN3O)
1H NMR (300 MHz, CDCl3): d = 0.85 (s, 3H, CH3), 0.97
(s, 3H, CH3), 1.82 (d, J = 17.4 Hz, 1H, CH), 2.05 (d,
J = 17.4 Hz, 1H, CH), 2.17–2.19 (m, 2H, CH2), 4.07 (s,
2H, NH2), 4.74 (s, 1H, CH), 7.16–7.29 (m, 6H, ArH), 7.59–
7.61 (m, 3H, ArH) ppm; 13C NMR (75 MHz, CDCl3):
d = 195.6, 149.8, 149.3, 144.7, 136.1, 133.5, 130.1, 129.3,
128.4, 127.2, 126.2, 120.4, 112.8, 62.7, 49.5, 41.3, 36.1,
32.3, 29.1, 26.5 ppm; IR (KBr): vꢀ = 3,461, 3,329, 3,218,
3,065, 2,959, 2,180, 1,653, 1,592, 1,566, 1,494, 1,416,
2-Amino-1,4,5,6,7,8-hexahydro-7,7-dimethyl-4-(4-methyl-
phenyl)-5-oxo-1-phenylquinoline-3-carbonitrile
(4b, C25H25N3O)
1H NMR (300 MHz, CDCl3): d = 0.85 (s, 3H, CH3), 0.96
(s, 3H, CH3), 1.80 (d, J = 17.4 Hz, 1H, CH), 2.04 (d,
J = 17.1 Hz, 1H, CH), 2.16–2.18 (m, 2H, CH2), 2.31 (s,
3H, CH3), 3.99 (s, 2H, NH2), 4.72 (s, 1H, CH), 7.12 (d,
J = 7.8 Hz, 2H, ArH), 7.23–7.58 (m, 7H, ArH) ppm; 13C
NMR (75 MHz, CDCl3): d = 195.2, 150.1, 149.2, 145.4,
136.2, 130.6, 130.2, 129.8, 128.7, 127.2, 126.4, 120.7,
113.2, 62.8, 49.7, 41.2, 35.9, 32.4, 29.3, 26.7, 21.2 ppm; IR
(KBr): vꢀ = 3,458, 3,334, 3,038, 2,954, 2,178, 1,653, 1,575,
1,372, 1,257, 1,148, 1,044, 879, 758, 699 cm-1
.
Ethyl 2-amino-1,4,5,6,7,8-hexahydro-7,7-dimethyl-4-
(4-methylphenyl)-5-oxo-1-phenylquinoline-3-carboxylate
(4s, C27H30N2O3)
1H NMR (300 MHz, CDCl3): d = 0.78 (s, 3H, CH3), 0.94
(s, 3H, CH3), 1.22 (t, J = 6.9 Hz, 3H, CH3), 1.65–1.77
123

808
S. K. Singh, K. N. Singh
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(m, 2H, CH2), 2.02–2.18 (m, 2H, CH2), 2.28 (s, 3H, CH3),
4.04 (q, J = 7.2 Hz, 2H, CH2), 5.10 (s, 1H, CH), 6.18
(s, 2H, NH2), 7.05 (d, J = 7.8 Hz, 2H, ArH), 7.26–7.34
(m, 4H, ArH), 7.56–7.59 (m, 3H, ArH) ppm; 13C NMR
(75 MHz, CDCl3): d = 195.2, 167.4, 149.8, 145.2, 136.1,
130.7, 130.0, 129.6, 128.6, 127.2, 126.5, 113.1, 105.9,
59.8, 50.7, 40.8, 36.5, 32.6, 29.4, 27.1, 19.8, 14.2 ppm; IR
(KBr): vꢀ = 3,464, 3,329, 3,063, 2,963, 1,656, 1,596, 1,505,
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Acknowledgments The authors are thankful to the Department of
Biotechnology, New Delhi for financial assistance.
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