Ionic liquid [EMIM]OAc under ultrasonic irradiation towards synthesis of 1,4-DHP's

Article abstract of DOI:10.1002/jccs.201190041

The ionic liquid 1-ethyl-3-methylimidazole acetate ([EMIM]OAc) was found to be a mild and effective catalyst for the efficient, one-pot, three-component synthesis of 1,4-dihydropyridines from arylalde-hydes, ethylacetoacetate/ acetylacetone and ammonium acetate at room temperature under sonication. The developed method has many advantages, including devoid of harmful catalysts, reacting at room temperature, higher yields in a simple methodology or operational convenience.

Full text of DOI:10.1002/jccs.201190041

384
Journal of the Chinese Chemical Society, 2011, 58, 384-388
Ionic Liquid [EMIM]OAc under Ultrasonic Irradiation towards Synthesis of
1,4-DHP’s
B. Palakshi Reddy, K. Rajesh and V. Vijayakumar*
Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore-632014, India
Received December 8, 2010; Accepted February 19, 2011; Published Online February 25, 2011
The ionic liquid 1-ethyl-3-methylimidazole acetate ([EMIM]OAc) was found to be a mild and effec-
tive catalyst for the efficient, one-pot, three-component synthesis of 1,4-dihydropyridines from arylalde-
hydes, ethylacetoacetate/acetylacetone and ammonium acetate at room temperature under sonication. The
developed method has many advantages, including devoid of harmful catalysts, reacting at room tempera-
ture, higher yields in a simple methodology or operational convenience.
Keywords: Hantzsch reaction; 1,4-Dihydropyridines; [EMIM]OAc; Ultrasound irradiation.
INTRODUCTION
1,4-Dihydropyridines (1,4-DHP’s)1,2 are among the
harmful to the environment; the long reaction times and
high temperature conditions limits the use of these meth-
ods. Thus, the development of a simple and efficient method
for the synthesis of 1,4-DHP’s is an active area of research
and hence having the scope for further improvement with
milder reaction conditions and higher product yields.
Ionic liquids have been initially introduced as alter-
native green reaction media due to their unique chemical
and physical properties of non-volatility, non-flamma-
bility, thermal stability, and controlled miscibility20,21 but
nowadays they have proved beyond this, showing their im-
portance in controlling the reactions as catalysts in green
synthesis.19,22,23
most widely used drugs for the management of cardiovas-
cular disease, have a broad range of pharmacological activ-
ities3-8 and also proven to be very important synthetic inter-
mediates, finding application in the preparation of a large
number of nitrogen alkaloids.9,10 The 1,4-DHP’s heterocy-
clic ring is a common feature of various bioactive com-
pounds such as vasodilator, bronchodilator, antiathero-
sclerotic, antitumor, geroprotective, hepatoprotective and
antidiabetic agents.11,12 The studies revealed that the 1,4-
DHP’s exhibit several other medicinal applications which
include neuroprotectant13a and platelet anti-aggregatory
activity,13b in addition to cerebral antiischemic agent in the
treatment of Alzheimer’s13c disease and as a chemosensi-
tizer in tumor therapy.13d
During the last three decades, in organic synthesis ul-
trasound irradiation24 has been considered as a clean, con-
venient and useful protocol compared with traditional
methods and hence, a large number of organic reactions can
be carried out with higher yields in shorter reaction time
under mild conditions.25-28 In continuation of our earlier in-
terest in 1,4-DHP’s29-35 as well as considering its signifi-
cance herein we report an efficient and simple procedure
for preparation of 1,4-DHP’s at room temperature under
ultrasonication using ionic liquid [EMIM]OAc as catalyst
(see Scheme I).
The synthesis of 1,4-DHP’s by classical method in-
volves the three-component coupling of an aldehyde with
ethylacetoacetate, and ammonia in acetic acid or in reflux-
ing alcohol. However, these methods suffer by several
drawbacks such as long reaction time, excess use of an or-
ganic solvent, less yield and harsh refluxing conditions.
Thus, chemists developed several alternate and efficient
methods for the synthesis of 1,4-DHP’s, which include mi-
crowave assisted synthesis14 refluxing at high temperature,
usage of TMSCl–NaI,15 metal triflates,16 and I2.17,18 How-
ever, the use of expensive metal precursors, catalysts are
RESULTS AND DISCUSSION
The present work describes a mild and convenient
* Corresponding author. Tel: +91-9443916746; Fax: +91-4162202243091; E-mail: kvpsvijayakumar@gmail.com

Ionic Liquid [EMIM]OAc Promoted Synthesis of 1,4-DHP’s
J. Chin. Chem. Soc., Vol. 58, No. 3, 2011 385
Scheme I
Ph
O
O
N
C2H5
O
O
CH3COO
(10%)
N
R
R
H3C
NH4OAc
+
+ PhCHO
EtOH, ))), rt
N
H
1
2
3
R
4a-u
R = CH3, OC2H5.
method for the synthesis of 1,4-DHP’s at room temperature
and the [EMIM]OAc was found to be an efficient catalyst
for the synthesis of 1,4-DHP’s with better yields. The com-
pound 4b has been considered as representative example
and synthesized by subjecting a mixture of 4-chlorobenz-
aldehyde 1 equi, ethylacetoacetate 2 equi, ammonium ace-
tate 1 equi, 20 mol% of [EMIM]OAc in ethanol under ul-
trasonic irradiation at 25-30 oC temperature afforded 95%
yield of the desired product. The reaction conditions have
been optimized by varying the temp, solvent as well as the
concentration of the catalyst under the ultrasonic irradia-
tion and the results were summarized in Table 1.
for the completion of the reaction. The results in Table 1 re-
vealed that the entry 2 is having the optimized conditions.
To prove the generality of the reaction the three-component
coupling reactions of various arylaldehydes, ethylacetoac-
etate/acetylacetone and ammonium acetate in the presence
of 10 mol% of [EMIM]OAc in ethanol at room temperature
has been carried out under the ultrasound irradiation; the
results were tabulated in Table 2. The products 4(a-u) were
characterized by IR, 1H NMR and mass spectral data and
are found to be in accord with the literature data. The re-
sults revealed that the reactions proceeded smoothly to af-
ford corresponding 1,4-DHP’s in good to excellent yields
(87-97%). To explore the scope and limitations of this reac-
tion, it has been extended to various arylaldehydes with
electron releasing or electron withdrawing substituents at
ortho, para, meta positions and found to be proceeded very
efficiently in all cases. Higher yield has been observed with
electron withdrawing substituents. In general higher yields
have been observed with ethylacetoacetate compared to
The catalyst load of 10 mol% has been observed as
the optimized concentration. Similarly ethanol has been
found as suitable solvent than methanol, chloroform and
acetonitrile for the reaction. The EtOH/H2O (8:2) co-sol-
vent system also worked well but with less yield. The reac-
tion carried out at room temperature with stirring as well as
refluxing conditions required 5 hrs and 3 hrs respectively
Table 1. Optimization conditions for the synthesis of 1,4-DHP’s
Amount of
catalyst
Type of Temp Time
Yield
(%)
Entry
Catalyst
Solvent
reaction
(°C)
(min)
(mol %)
1
[EMIM]OAc
[EMIM]OAc
[EMIM]OAc
[EMIM]OAc
[EMIM]OAc
[EMIM]OAc
[EMIM]OAc
[EMIM]OAc
[EMIM]OAc
[EMIM]OAc
20
10
5
EtOH
EtOH
US
US
25-30
25-30
25-30
25-30
25-30
25-30
25-30
25-30
25-30
40
40
95
97
89
70
80
60
71
66
80
84
2
3
EtOH
US
40
4
0
EtOH
US
40
5
10
10
10
10
0
EtOH/H2O2 (8:2)
CHCl3
US
40
6
US
40
7
CH3CN
MeOH
US
40
8
US
40
9
EtOH
stirring
reflux
5 hrs
3 hrs
10
0
EtOH
Reaction conditions: 4-chlorobenzaldehyde (1.0 mmol), ethylacetoacetate (2.0 mmol),
ammonium acetate (1.0 mmol), ionic liquid (10%).

386 J. Chin. Chem. Soc., Vol. 58, No. 3, 2011
Reddy et al.
maximum energy area in the water bath, where the surface
of reactants (reaction vessel) is slightly lower than the level
of the water, and the addition or removal of water con-
trolled the temperature of the water bath. The temperature
of the water bath was controlled at 25-30 oC.
Table 2. Synthesis of various substituted 1,4-dihydropyridines
using ionic liquid [EMIM]OAca
Ultrasound Yieldc
Entry
Ph
R
Productsb
(min)
(%)
1
C6H5
OC2H5
OC2H5
4a
4b
4c
4d
4e
4f
35
40
45
30
40
40
40
45
45
40
40
35
35
40
45
45
35
40
45
45
35
96
97
94
96
92
91
93
90
89
90
87
94
93
92
90
91
92
89
88
89
93
2
4-Cl.C6H4
General procedure for the synthesis of 1,4-DHP’s
To a mixture of arylaldehyde (1.0 mmol), ethylaceto-
acetate/acetylacetone (2.0 mmol) and ammonium acetate
(1.0 mmol) in ethanol, [EMIM]OAc (0.0170 g, 0.1 mmol)
was added in a 100 mL flask. The reaction mixture was
sonicated at room temperature for required time. The prog-
ress of the reaction has been monitored by TLC. After com-
pletion of the reaction, the solvent has been removed under
reduced pressure. The resulting solution was extracted us-
ing ethyl acetate (20 mL) and the extract has been dried
over Na2SO4 and then concentrated. The obtained products
4(a-u) were purified by recrystallisation in ethylacetate
and their yield have been tabulated in Table 2. The authen-
ticity of the known products was established by comparing
their melting points and spectral data with the literature.
Spectral data of representative compounds
3
4-OCH3.C6H4 OC2H5
3-NO2.C6H4 OC2H5
4
5
4-Pyridyl
3-Pyridyl
4-Br.C6H4
2-Thienyl
OC2H5
OC2H5
OC2H5
OC2H5
6
7
4g
4h
4i
8
9
4-CH3.C6H4 OC2H5
4-HO.C6H4 OC2H5
3-HO.C6H4 OC2H5
10
11
12
13
14
15
16
17
18
19
20
21
4j
4k
4l
3-NO2.C6H4
2-NO2.C6H4
2-Furyl
CH3
CH3
CH3
CH3
CH3
CH3
4m
4n
4o
4p
4q
4r
4s
2-Thienyl
3-Pyridyl
3-Cl.C6H4
3-OCH3.C6H4 CH3
4-C2H5.C6H4
4-Pyridyl
CH3
CH3
CH3
4t
4-Br.C6H4
4u
o
(4a) Mp 158-160 C; IR (KBr): 3348 (NH), 1692
a Reaction conditions: aldehyde (1.0 mmol), ethylacetoacetate/
acetylacetone (2.0 mmol), ammonium acetate (1.0 mmol), ionic
liquid (10%).
(C=O), cm-1; 1H NMR (400 MHz, CDCl3, ppm): d 1.26 (t,
6H, J = 8.0 Hz), 2.35 (s, 6H), 4.1 (m, 4H, J = 8.0 Hz), 5.93
(s, 1H), 5.76 (s, 1H), 7.38-7.54 (m, 5H, Ar-H); MS (ESI)
m/z 329 (M+).
b Ultrasound irradiation.
c Isolated yields.
o
(4b) Mp 145-146 C; IR (KBr): 3345 (NH), 1705
acetylacetone. Moreover, the [EMIM]OAc was success-
fully reused for three cycles without significant loss of ac-
tivity. It is thus a rapid, convenient and environmentally
benign method for the synthesis of compounds of type
4(a-u).
(C=O), cm-1; 1H NMR (400 MHz, CDCl3, ppm): d 1.22 (t,
6H, J = 6.0 Hz), 2.33 (s, 6H), 4.09 (m, 4H, J = 6.0 Hz), 4.96
(s, 1H), 5.70 (s, 1H), 7.17-7.25 (m, 4H, Ar-H); MS (ESI)
m/z 363 (M+).
o
(4c) Mp 153-155 C; IR (KBr): 3342 (NH), 1689
(C=O), cm-1; 1H NMR (400 MHz, CDCl3, ppm): d 1.23 (t,
6H, J = 8.0 Hz), 2.34 (s, 6H), 3.72 (s, 3H), 4.09 (m, 4H, J =
8.1 Hz), 4.94 (s, 1H), 5.58 (s, 1H), 6.76 (d, 2H, J = 4 Hz),
7.21 (d, 2H, J = 4 Hz); MS (ESI) m/z 360 (M+).
EXPERIMENTAL
IR spectra were recorded using AVATAR 330 equipped
with DTGS detector. NMR spectra were measured on a
Bruker AMX-400 instrument at room temperature in CDCl3
using TMS as the internal reference. The coupling con-
stants J are in Hz. Mass spectra were taken on a macro mass
spectrometer (Waters) by electro-spray method (ES). Melt-
ing points were determined in open capillaries and uncor-
rected. [EMIM]OAc was synthesized based on the litera-
ture.36 Sonication was performed in Kunshan KQ-250B ul-
trasonic reactor with a frequency of 40 KHz and a nominal
power of 250 W. The reaction flasks were located in the
o
(4d) Mp 165-167 C; IR (KBr): 3357 (NH), 1692
(C=O) cm-1; 1H NMR (400 MHz, CDCl3, ppm): d 1.23 (t,
6H, J = 8.1 Hz), 2.33 (s, 6H), 4.09 (m, 4H, J = 8.1 Hz), 5.90
(s, 1H), 5.73 (s, 1H), 7.38 (t, 1H, J = 8 Hz), 7.65 (d, 1H, J =
8 Hz), 8.02 (d, 1H, J = 4 Hz), 8.14 (s, 1H); MS (ESI) m/z:
374 (M+).
o
(4e) Mp 181-182 C; IR (KBr): 3378 (NH), 1698
(C=O), cm-1; 1H NMR (400 MHz, CDCl3, ppm): d 1.19 (t,
6H, J = 7.2 Hz), 2.32 (s, 6H), 4.08 (m, 4H, J = 7.2 Hz), 4.98

Ionic Liquid [EMIM]OAc Promoted Synthesis of 1,4-DHP’s
J. Chin. Chem. Soc., Vol. 58, No. 3, 2011 387
(s, 1H), 6.09 (s, 1H), 7.2 (d, 2H, J = 6 Hz), 8.40 (d, 2H, J = 6
Hz); MS (ESI) m/z 330 (M+).
use of sonication and ionic liquid leads to the efficient and
environmental friendly method under mild conditions with
good yields and simple work-up procedures.
o
(4f) Mp 188-190 C; IR (KBr): 3378 (NH), 1698
(C=O), cm-1; 1H NMR (400 MHz, CDCl3, ppm): d 1.84 (t,
6H, J = 7.2 Hz), 2.30 (s, 6H), 4.05 (m, 4H, J = 7.2 Hz), d
4.95 (s, 1H), 6.3 (s, 1H), 7.14 (t, 1H, J = 2.0 Hz), 7.59 (d,
1H, J = 2.0 Hz), 8.32 (d, 1H, J = 2.0 Hz), 8.49 (s, 1H); MS
(ESI) m/z 330 (M+).
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