Catalyst-free, Knoevenagel-Michael addition reaction of dimedone under microwave irradiation: An efficient one-pot synthesis of polyhydroquinoline derivatives

Article abstract of DOI:10.1002/jhet.1541

Present investigation reports a concise and efficient protocol for the synthesis of polyhydroquinoline derivatives through coupling of four different components viz. aromatic aldehydes, dimedone, ethyl acetoacetate or ethyl cyanoacetate, and ammonium acetate. The same phenomenon can be observed using arylmethylene bis(3-hydroxy-2-cyclohexene-1-ones), ethyl acetoacetate, and ammonium acetate in one pot under microwave irradiation. The key advantages of the given protocol include short reaction time, high yields, and simple work-up and purification procedure. The present method also allows us to synthesize highly functionalized title compounds from simple and readily available starting materials.

Full text of DOI:10.1002/jhet.1541

July 2013
Catalyst-free, Knoevenagel–Michael Addition Reaction of Dimedone
under Microwave Irradiation: An Efficient One-pot Synthesis of
Polyhydroquinoline Derivatives
941
M. Saha, T. S. Luireingam, T. Merry, and A. K. Pal*
Department of Chemistry, North Eastern Hill University, Mawlai Campus, Shillong 793022, India
*
E-mail: amartya_pal22@yahoo.com
Supporting information can be found in on line version of this article.
Received June 15, 2011
DOI 10.1002/jhet.1541
Published online 24 June 2013 in Wiley Online Library (wileyonlinelibrary.com).
R
R
O
CHO
O
O
O
O
O
O
Y
X
X
O
O
6
O
6
+
NH
4
4
OAc
NH
4
OAc
O
N
R
4
OH
OH
H
7
1
2
X =CN,
X = CH CO, Y= CH
3
Y= NH
2
3
X =CH CO, Y = CH
8
3
3
Present investigation reports a concise and efficient protocol for the synthesis of polyhydroquinoline
derivatives through coupling of four different components viz. aromatic aldehydes, dimedone, ethyl acetoacetate
or ethyl cyanoacetate, and ammonium acetate. The same phenomenon can be observed using arylmethylene
bis(3-hydroxy-2-cyclohexene-1-ones), ethyl acetoacetate, and ammonium acetate in one pot under microwave
irradiation. The key advantages of the given protocol include short reaction time, high yields, and simple
work-up and purification procedure. The present method also allows us to synthesize highly functionalized
title compounds from simple and readily available starting materials.
J Heterocyclic Chem., 50, 941 (2013).
INTRODUCTION
have revealed several other medicinal applications that
include neuroprotectant and platelet anti-aggregratory activity,
cerebral anti-ischemic activity in the treatment of Alzheimer’s
disease, and as a chemosensitizer in tumor therapy [9].
Therefore, several methods have been developed for
the preparation of polyhydroquinoline derivatives by using
various catalysts, including molecular iodine [10], ionic liquid
Design of highly efficient chemical reaction sequence
that provide structurally complex molecules and diversity
with a minimum number of synthetic steps to assemble
compounds with increasing properties is a major challenge
of modern drug discovery [1]. Recently, multicomponent
reactions have emerged as a highly valuable synthetic tool
in modern drug discovery. The atom economy and conver-
gent character, the simplicity of one-pot procedure, the
possible structural variation, and the very large number of
accessible compounds are among the described advantages
of multicomponent reaction [2]. Thus, they are perfectly
amenable to automation for combinatorial synthesis [3].
Many chemical processes require a large amount of energy
from heating, which can have considerable adverse effects
on the environment. Therefore, microwave technology
is becoming increasingly attractive as an alternative
energy source to assist organic reactions under milder
conditions [4]. Microwave irradiation is a powerful tool for
reducing reaction time and increasing desire product yields,
thus producing many efficient organic reactions [5,6].
[
11], rare earth metal triflates [12], HClO –SiO [13],
4 2
HY-zeolites [14], TMSCl–NaI [15], ceric ammonium nitrate
16], grinding technique [17], ultrasound [18], montmorillon-
ite K 10 [19], p-TSA [20], polymer [21,22], hetrapolyacid
23], heterogeneous catalyst [24], L-proline [25], nickel
[
[
nanoparticles [26], and ZrCl [27] . Although most of these
4
processes offer distinct advantages, they suffer from certain
drawbacks such as longer reaction time, unsatisfactory yields,
high cost, harsh reaction conditions, the use of volatile
organic solvents, stoichiometric amounts of catalyst, and also
environmentally toxic catalysts. Moreover, there are relatively
limited number of reports on the synthesis of polyhydroquino-
line derivatives as compared with simple 4-substituted 1,
4
-dihydropyridine molecules. Herein, for the first time, we
report the synthesis of polyhydroquinoline derivatives without
using any catalyst or base under microwave irradiation.
Polydroquinolines are an important group of nitrogen
heterocycles that have attracted much attention because of
their diverse therapeutic and pharmacological properties, such
as calcium channel blockers, vasodilator, antiatherosclerotic,
bronchodilator, antitumor, geroprotective, antidiabetic activ-
ity, and hepatoprotective [7,8]. Furthermore, recent studies
RESULT AND DISCUSSION
In continuation of our research work in the development
of highly expedient methodologies for the synthesis of
©
2013 HeteroCorporation

9
42
M. Saha, T. S. Luireingam, T. Merry, and A. K. Pal
Vol 50
biologically important heterocyclic compounds [28], we
report here the synthesis of polyhydroquinoline from the
Knoevenagel condensation of various aromatic aldehydes,
b-keto/cyano esters, ammonium acetate, and dimedone in
a protic solvent under microwave irradiation in the absence
of any added catalyst. In fact, we concentrated our study on
the effect of solvents, on this condensation process. The
reaction was carried out in various aprotic, protic, polar,
and nonpolar solvents. Impressive result was achieved in
polar protic solvent such as ethanol.
In the literature, Atul Kumar et al. [29] have reported
the synthesis of polyhydroquinolines from arylmethylene bis
(3-hydroxy-2-cyclohexene-1-ones) 8. Compounds 8a–j were
prepared by the condensation of dimedone 1 and aryl alde-
hydes (2a–j) in presence of EDDA (30 mol%) in THF under
refluxing condition [30]. Encouraged by our initial results,
we extended the scope of our present protocol for the conden-
sation of arylmethylene bis(3-hydroxy-2-cyclohexene-1-ones)
8a–j (Scheme 3) with ethyl acetoacetate and ammonium ace-
tate in ethanol under microwave irradiation, and it was
afforded polyhydroquinolines 5a–j in good to excellent yields
(Table 3). The mechanism for the formation of polyhydroqui-
nolines 5a–j from arylmethylene bis(3-hydroxy-2-cyclohex-
ene-1-ones) 8a–j is still uncertain. All the products were
analytically pure, and structures were determined by the spec-
tral methods (IR, NMR, mass) and the physical data (mp) with
those in literature [25–27,31].
The reaction of dimedone 1 (1.42 mmol), benzaldehyde
2
a (1.42 mmol), ethyl acetoacetate 3 (1.42mmol), and
ammonium acetate 4 (2.85mmol) in ethanol (2mL) under
microwave irradiation has been considered as a model
reaction. We have also studied the effect of different
microwave power setting and temperature variation on this
conversion. It was observed that the best result was obtained
ꢀ
at 80W and 50 C. After optimizing the condition, the gener-
ality of this method was examined by the reaction of several
substituted aromatic aldehydes, ammonium acetate, ethyl
acetoacetate or ethyl cyanoacetate, and dimedone in ethanol
under microwave irradiation; (Schemes 1, 2) the results are
shown in Tables 1 and 2. It is noteworthy to mention that var-
ious aromatic aldehydes containing electron-donating to elec-
tron-withdrawing functional groups at the different position
in the aromatic ring did not show any remarkable effect on
this conversion because desired products were obtained in
high yields in relatively short reaction time (Tables 1 and 2).
CONCLUSION
In conclusion, we hereby propose a simple and efficient
method for the synthesis of polyhydrquinoline derivatives
with excellent yields via microwave-assisted one-pot reac-
tion. Reaction time was considerably reduced, and product
yields were increased under microwave irradiation. The
proposed methodology does not require any expensive
catalyst or base, thus proved to be economically efficient.
Scheme 1. Synthesis of polyhydroquinoline derivatives using ethyl acetoacetate.
R
O
CHO
O
O
O
O
O
EtOH
+
+
+
4
NH OAC
O
MWI, 5-8 min
O
N
R
2 a-j
1
3
4
H
5
a-j
Table 1
Synthesis of polyhydroqunoline derivatives 5a–j.
a
Entry
2a–j
Aryl aldehydes
Time (min)
Product
Yield (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
Benzaldehyde
6
5
5
5
7
5
8
6
6
6
5a
5b
5c
5d
5e
5f
5g
5h
5i
88
92
91
89
86
90
87
88
86
89
4-Nitrobenzaldehyde
4-Flurobenzaldehyde
4-Chlorobenzaldehyde
4-Methylbenzaldehyde
4-Bromobenzaldehyde
Para aminodimethylabenzaldehyde
3-Chlorobenzaldehyde
3-Flurobenzaldehyde
4-Methoxybenzaldehyde
1
0
2j
5j
a
Isolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2013
Catalyst-free, Knoevenagel–Michael Addition Reaction of Dimedone under Microwave Irradiation 943
Scheme 2. Synthesis of polyhydroquinoline derivatives using ethyl cyanoacetate.
R
O
CHO
O
O
O
N
O
+
+
EtOH
MWI, 5-8 min
+
4
NH OAc
O
O
N
NH2
R
2a-e
H
7a-e
1
6
4
Table 2
Synthesis of polyhydroquinoline derivatives 7a-e.
a
Entry
2a–e
Aryl aldehyde
Time (min)
Product
Yield (%)
1
2
3
4
5
2a
2b
2c
2d
2e
Benzaldehyde
5
7
5
5
5
7a
7b
7c
7d
7e
91
89
92
91
90
4-Methylbenzaldehyde
4-Nitrobenzaldehyde
4-Chlorobenzaldehyde
4-Bromobenzaldehyde
a
Isolated yields.
Scheme 3. Synthesis of polyhydroquinoline derivatives from arylmethylene bis(3-hydroxy-2-cyclohexene-1-ones).
R
R
O
O
O
O
O
O
+
O
+
NH
4
OAc
EtOH
MWI, 4-6 min
O
N
OH OH
a-j
H
5 a-j
8
3
4
Table 3
Synthesis of polyhydroquinoline derivatives 5a–j from 8a–j.
a
Entry
8a–j
Aryl aldehydes
Time (min)
Product
Yield (%)
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8f
8g
8h
8i
Benzaldehyde
4-Nitrobenzaldehyde
4-Flurobenzaldehyde
4-Chlorobenzaldehyde
4-Methylbenzaldehyde
4-Bromobenzaldehyde
Para aminodimethylabenzaldehyde
3-Chlorobenzaldehyde
3-Flurobenzaldehyde
4
5
4
6
4
4
5
4
4
4
5a
5b
5c
5d
5e
5f
5g
5h
5i
90
91
89
90
88
90
86
89
90
90
1
0
8j
4-Methoxybenzaldehyde
5j
a
Isolated yields.
À1
EXPERIMENTAL
All the experiments were carried out in MATTHEWS, NC-MADE
cm ) on KBr disks [1]. H NMR and [13] C NMR (400 MHz
and 100 MHz, respectively) spectra were recorded on Bruker Avance
3
II-400 spectrometer in CDCl (chemical shifts in d with TMS as inter-
IN USA, MODEL-DISCOVER-S, MODEL NO-NP-1009, micro-
wave digester in closed vessel. Melting points were determined in
open capillaries and are uncorrected. IR spectra were recorded on
Spectrum BX FTIR, Perkin Elmer (Rodgau, Germany) (υmax in
nal standard). Mass spectra were recorded on Waters ZQ-4000
(Milford, USA). CHN were recorded on CHN-OS analyzer (Perkin
Elmer 2400, Series II). Silica gel G (E-mark, India) was used for
ο
TLC. Hexane refers to the fraction boiling between 60 and 80 C.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

9
44
M. Saha, T. S. Luireingam, T. Merry, and A. K. Pal
Vol 50
General procedure for the synthesis of polyhydroquinoline
derivatives (5a–j) and (7a–e) from dimedone. A mixture of
dimedone (1) 200 mg (1.42 mmol), aromatic aldehydes (2)
1.42 mmol), ethyl acetoacetate (3) 0.17 mL (1.42 mmol) or
ethyl cyanoacetate (6) 0.15 mL (1.42 mmol), ammonium acetate
4) 219 mg (2.85 mmol), and ethanol (2 mL) was subjected to
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ꢀ
and 2 at 80 W and 50 C. The reaction was monitored by TLC.
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General procedure for the synthesis of polyhydroquinoline
[12] Wang, L.; Sheng, J.; Zhang, L.; Han, J.; Fan, Z.; Tian, H.;
Qian, C. Tetrahedron 2005, 61, 1539.
derivatives (5a–j) from arylmethylene bis(3-hydroxy-2-
[13] Maheswara, M.; Siddaiah, V.; Damu, G. L. V.; Rao, C. V.
Arcivok 2006, 201.
cyclohexene-1-ones) (8a–j).
3-hydroxy-2-cyclohexene-1-ones) (8a–j) (0.12 mmol) ethyl
acetoacetae (3) 0.01 mL (0.12 mmol), and ammonium acetate
A mixture of arylmethylene bis
[
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(
[
(
4) 19.0 mg (0.24 mmol) in ethanol (2 mL) was subjected to
ꢀ
microwave irradiation for 4–6 min at 80 W and temp 50 C.
After complete conversion, as shown by TLC, the reaction mass
was cooled to room temperature. Then, it was poured into
crushed ice and filtered. The crude products were purified by
silica gel (60–120 mesh) column chromatography by using
hexane and ethyl acetate as an eluent,(7:3), which were further
recrystallized from ethanol.
[
[
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Acknowledgments. We thank the Chemistry Department and
SAIF of North Eastern Hill University for analytical support.
The financial support from Department of Biotechnology
4
2
[
(
TT/DBT/TPI/2011) is gratefully acknowledged.
[
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DOI 10.1002/jhet