Ultrasound-mediated synthesis of 4-substituted 1,4-dihydropyridine-3,5- dicarboxylates catalyzed by 1-carboxymethyl-3-methylimidazolium tetrafluoroborate under solvent free condition

Article abstract of DOI:10.1016/j.ultsonch.2014.05.026

4-Substituted 1,4-dihydropyridine-3,5-dicarboxylates (4) have been synthesized by the solvent-free reaction of aldehyde, methyl propiolate and ammonium carbonate catalyzed by ionic liquid 1-carboxymethyl-3-methylimidazolium tetrafluoroborate under ultraso

Full text of DOI:10.1016/j.ultsonch.2014.05.026

Accepted Manuscript
Ultrasound-mediated synthesis of 4-substituted 1,4-dihydropyridine-3,5-dicar-
boxylates catalyzed by 1-carboxymethyl-3-methylimidazolium tetrafluorobo-
rate under solvent free condition
Jing-Yu He, Hui-Zhen Jia, Qing-Guo Yao, Si-Jie Liu, Hong-Kun Yue, Hong-
Wei Yu, Rui-Sheng Hu
PII:
S1350-4177(14)00185-0
DOI:
http://dx.doi.org/10.1016/j.ultsonch.2014.05.026
ULTSON 2622
Reference:
Ultrasonics Sonochemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 November 2013
25 January 2014
30 May 2014
Please cite this article as: J-Y. He, H-Z. Jia, Q-G. Yao, S-J. Liu, H-K. Yue, H-W. Yu, R-S. Hu, Ultrasound-mediated
synthesis of 4-substituted 1,4-dihydropyridine-3,5-dicarboxylates catalyzed by 1-carboxymethyl-3-
methylimidazolium tetrafluoroborate under solvent free condition, Ultrasonics Sonochemistry (2014), doi: http://
dx.doi.org/10.1016/j.ultsonch.2014.05.026
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Ultrasound-mediated
synthesis
of
4-substituted
1,4-dihydropyridine-3,5-dicarboxylates
1-carboxymethyl-3-methylimidazolium
under solvent free condition
catalyzed
by
tetrafluoroborate
Jing-Yu He∗, Hui-Zhen Jia, Qing-Guo Yao, Si-Jie Liu, Hong-Kun Yue, Hong-Wei Yu,
Rui-Sheng Hu
College of Chemical Engineering, Shijiazhuang University, Shijiazhuang 050035,
China
Abstract: 4-Substituted 1,4-dihydropyridine-3,5-dicarboxylates (4) have been
synthesized by the solvent-free reaction of aldehyde, methyl propiolate and
ammonium
carbonate
catalyzed
by
ionic
liquid
1-carboxymethyl-3-methylimidazolium tetrafluoroborate under ultrasonic irradiation.
The effects of changes in the ultrasonic power, temperature, catalysts and reactants on
the synthesis of 4-substituted 1,4-dihydropyridine-3,5-dicarboxylates (4) are
discussed. With the optimized reaction conditions, various aldehydes were used to
synthesize 1,4-dihydropyridines (4) under the influence of ultrasound irradiation.
Compared with the conventional thermal methods, the remarkable advantages of this
method are the simple experimental procedure, shorter reaction time (2-10 min) and
high yield of product (76–95 %). Furthermore, the green catalytic system can be
recycled specific times without significantly decreasing the yields and reaction rates.
∗ Corresponding author. Tel.: +86 0311 66617321.
E-mail address: jyhe@emails.bjut.edu.cn (J.Y. He).
1

Keywords:
Ultrasound;
Ionic
liquid;
Synthesis;
4-Substituted
1,4-dihydropyridine-3,5-dicarboxylates.
1. Introduction
1,4-Dihydropyridines (1,4-DHPs) are a class of highly important molecular
skeletons abundant in natural products. They are are key intermediates of
nitrogen-containing polycyclic hydrocarbons and widely used in pharmaceutical
agents [1,2]. In view of their high significance, great effort has been made to develop
new methods to synthesize 1,4-DHPs, among which, the Hantzsch reaction utilizing
an amine, an aldehyde, and two 1,3-dicarbonyl compounds to synthesize 1,4-DHPs is
the most classic approach. However, this approach has some obvious disadvantages
such as harsh reaction conditions, excessive use of volatile organic solvents and high
reaction temperature [3]. Later, chemists developed several alternate and efficient
methods for the synthesis of 1,4-DHPs, which include the promotion of microwave
[4], polymer [5], TMSCl [6], Lewis acid [7], Brønsted acid [8], solid acid [9], base
[10], biocatalysts [11] and organocatalysts [12]. Although the known methodologies
have convenient protocols with good to high yields, the reported methods still
suffered from drawbacks, such as prolonged reaction times, high temperature and the
use of non-recyclable catalysts. Thus, it is essential to develope a simple, efficient and
green method for the synthesis of 1,4-DHPs.
In the recent years, green chemistry using environment-friend reagents and conditions
is one of the most fascinating developments in synthesis of widely used organic
compounds. Ultrasound has been used to accelerate the chemical reactions proceed
2

via the formation and adiabatic collapse of transient cavitation bubbles. The ultrasonic
effect induces very high local pressure and temperatures inside the bubbles and
enhances mass transfer and turbulent flow in the liquid [13]. Ultrasound has been
utilized to accelerate a number of synthetically useful reactions, especially in
heterocyclic chemistry [13].
Ionic liquids (ILs) technology has been widely used as another new and
environment-friend approach toward modern synthetic chemistry and has attracting
advantages such as extremely low vapor pressure, excellent thermal stability,
reusability, and talent to dissolve many organic and inorganic substrates [14].
1-Carboxymethyl-3-methylimidazolium tetrafluoroborate ([CMMIM]BF4) is
a
Brønsted acidic ionic liquid and has been proofed to be excellent catalysts to some
organic synthesis, which clearly indicate its advantages such as benign to environment,
easy to be recycled and homogeneous to reaction, such as synthesis of Fischer indole
[15], synthesis of 3,4-dihydropyrimidin-2-(1H)-ones [16], Mannich reaction [17].
Besides, solvent-free organic synthesis as a green synthetic approach has received
considerable attention because they are operationally simple, often involve nontoxic
materials, and proceed in excellent yield with high selectivity [18]. Toward the
development of clean chemical processes [19], we report a novel and
environment-friend procedure for the solvent-free preparation of 4-substituted
1,4-dihydropiridine-3,5-dicarboxylates in the presence of [CMMIM]BF4 as an
efficient and versatile catalyst under ultrasonic irradiation (Scheme 1).
Scheme 1
3

2. Experimental
2.1. Chemicals and apparatus
The chemical used in this work were purchased from commercial sources without
further purification. [CMMIM]BF4, [BMIM]Cl, [BMIM]BF4, [EMIM]Cl and
[EMIM]BF4 were synthesized according to the literature [20]. Melting points
(uncorrected) were determined by X-5 instrument. IR spectra were performed as KBr
pellets on a Bruker VERTEX 70 spectrometer. NMR spectra were measured on a
Bruker AVANCE 400 spectrometer. MS spectra were recorded on a ZAB-HS and
ESQUIRE 6000 mass spectrometer. Elemental analyses were carried out on a CARLO
ERBA 1106 elemental analysis instrument. Ultrasonication was performed in a
GEX750-5C ultrasonic processor equipped with a 3 mm wide and 140 mm long probe
that was immersed directly into the reaction mixture. The operating frequency was 24
KHz and the output power was 0–750 W through manual adjustment. The temperature
was controlled by a Buchi B-491 water bath at 60 0C.
2.2. General procedure for synthesis of 4-substituted 1,4-dihydropyridines
A mixture of the aldehyde (1.0 mmol ), methyl propiolate (2.0 mmol), ammonium
carbonate (1.0 mmol), and [CMMIM]BF4 (0.1 mmol, 10 mmol%) was irradiated
o
under an ultrasonic processor at 60 C and 300 W. After the indicated time (Table 5),
the mixture was poured into water, and the crude product was obtained by filtration.
The product was recrystallized with ethanol. The aqueous layer containing IL was
subjected to vacuum distillation to remove water, leaving the IL [CMMIM]BF4. The
residual ionic liquid was washed with small amount of ethyl acetate, dried under
4

o
vacuum at 80 C for 4 h and recycled. Structure of new derivatives of 4-substituted
1
1,4-dihydropyridines (4d, 4f, 4i, 4l, 4m and 4o) properly characterized by their IR, H
NMR, elemental analyses and mass spectra, while the known compounds were
identified by comparison of their melting points with those reported in the literature
[3a,24,25].
2.2.1. Dimethyl 4-(3-methylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate (4d)
o
Pale yellow powder; m.p. 175.3-177.1 C. IR (KBr, cm-1): 3336, 2983, 2926, 1595,
1
1485, 1369, 878, 830, 754. H NMR (400 MHz, CDCl3) δ (ppm): 2.16 (s, 3H,
Ar-CH3), 3.56 (s, 6H, OCH3), 4.91 (s, 1H, CH), 6.35 (brs, 1H, NH), 6.76-7.21 (m, 4H,
Ar-H), 7.33 (s, 1H, CH), 7.35 (s, 1H, CH). MS: 288 (M+H+). Anal. calcd for
C16H17NO4 : C, 66.89; H, 5.96; N, 4.88. Found C, 66.83; H, 5.97; N, 4.87.
2.2.2.
Dimethyl
4-(3-methoxyl-4-hydroxylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate (4f)
o
Pale yellow powder; m.p. 247.4-249.9 C. IR (KBr, cm-1): 3348, 2981, 2924, 1605,
1487, 1191, 881, 835, 764. 1H NMR (400 MHz, CDCl3) δ (ppm): 3.58 (s, 3H, -OCH3),
3.76 (s, 3H, Ar-OCH3), 5.13 (s, 1H, C-H), 6.27 (brs, 1H, N-H), 6.38-7.18 (m, 3H,
Ar-H), 7.23 (s, 1H, CH), 7.25 (s, 1H, CH). MS: 342 (M+Na+). Anal. calcd for
C16H17NO6: C, 60.18; H, 5.37; N, 4.39. Found C, 60.14; H, 5.35; N, 4.38.
2.2.3. Dimethyl 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (4i)
o
Pale yellow powder; m.p. 175.3-177.1 C. IR (KBr, cm-1): 3334, 2981, 2928, 1598,
1
1483, 1365, 873, 835, 751. H NMR (400 MHz, CDCl3) δ (ppm): 3.58 (s, 3H,
COOCH3), 5.41 (s, 1H, CH), 6.42 (brs, 1H, N-H), 7.41 (s, H, CH), 7.43 (s, H, CH),
5

7.45-8.19 (m, 4H, Ar-H). MS: 318 (M+). Anal. calcd for C15H14N2O6: C, 56.60; H,
4.43; N, 8.80. Found C, 56.63; H, 4.42; N, 8.83.
2.2.4. Dimethyl 4-(pyridin-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate (4l)
o
Brown powder; m.p. 146.2-148.9 C. IR (KBr, cm-1): 3341, 2989, 2924, 1601, 1483,
1
1368, 868, 832, 745. H NMR (400 MHz, CDCl3) δ (ppm): 3.58 (s, 3H, COOCH3),
5.11 (s, 1H, CH), 6.12 (brs, 1H, N-H), 7.14-7.20 (m, 1H, Py-H), 7.46 (s, 1H, CH),
7.48 (s, 1H, CH), 7.59-8.53 (m, 3H, Py-H). MS: 297 (M+Na+). Anal. calcd for
C14H14N2O4: C, 61.31; H, 5.14; N, 10.21. Found C, 61.38; H, 5.13; N, 10.20.
2.2.5. Dimethyl 4-(pyridin-4-yl)-1,4-dihydropyridine-3,5-dicarboxylate (4m)
o
Brown powder; m.p. 210.0-212.7 C. IR (KBr, cm-1): 3337, 2994, 2926, 1598, 1489,
1
1363, 871, 832, 740. H NMR (400 MHz, CDCl3) δ (ppm): 3.58 (s, 3H, COOCH3),
5.13 (s, 1H, CH), 6.15 (brs, 1H, N-H), 7.49 (s, 1H, CH), 7.52 (s, 1H, CH), 7.58-7.60
(d, 2H, J = 8.0 Hz, Py-H), 8.46-8.48 (d, 2H, J = 8.0 Hz, Py-H). MS: 297 (M+Na+).
Anal. calcd for C14H14N2O4: C, 61.31; H, 5.14; N, 10.21. Found C, 61.35; H, 5.13; N,
10.22.
2.2.6. Dimethyl 4-hexyl-1,4-dihydropyridine-3,5-dicarboxylate (4o)
o
Yellow powder; m.p. 127.5-128.8 C. IR (KBr, cm-1): 3332, 2987, 2922, 1602, 1504,
1
1365, 882, 835. H NMR (400 MHz, CDCl3) δ (ppm): 0.87-0.91 (m, 3H, CH3),
1.27-1.31 (m, 10H, CH2), 3.23 (s, 1H, CH), 3.65 (s, 3H, COOCH3), 6.08 (brs, 1H,
N-H), 7.21 (s, 1H, CH), 7.26 (s, 1H, CH). MS: 282 (M+H+). Anal. calcd for
C15H23NO4: C, 64.03; H, 8.24; N, 4.98. Found C, 64.28; H, 8.25; N, 4.98.
6

3. Results and discussion
For
the
solvent-free
synthesis
of
the
dimethyl
4-phenyl-1,4-dihydropiridine-3,5-dicarboxylate (4a), ultrasound promotion, ionic
liquid catalyzation are the two most important parameters. To optimize, the
o
preliminary reaction was sonicated under various sets of conditions at 25 - 30 C
catalyzed by benzaldehyde (1a, 1mmol), methyl propiolate (2, 2 mmol), ammonium
carbonate (1 mmol) and 5 mol% [CMMIM]BF4 as catalyst (Table 1). The effect of the
ultrasound power intensity on the product yield was also investigated by increasing
the irradiation power from 150 to 350 W. It can be seen from Table 1 that increase of
ultrasonic power led to relatively higher yield and shorter reaction time，which peaked
at 300 W. Then the yield decreased slightly with increasing ultrasound power
intensity >300 W. Therefore, 300 W of ultrasonic irradiation was sufficient to push the
reaction forward. The best yield for 4a was obtained at 15 min at room temperature
with 300 W ultrasonic irradiation. The possible explanation for the positive
association of between yield and irradiation power is that the increase in the
acoustic power could increase the number of active cavitation bubbles and the size of
the individual bubbles, both of which are expected to result in higher maximum
collapse temperature and accelerated respective reaction. However, when ultrasonic
intensity exceeded the optimal value (>300 W), excessive number of gas bubbles exist
in the solution, which adversely exhibits scattering effect on the sound waves and
lowers the level of energy focused on the reaction vessel. Additionally, the
coalescence of the cavities in the presence of large number of cavities may promote
7

the formation of a large cavity which collapses less violently. Consistent with
previous studies, increase in the operating intensity beyond the optimum will lead to
the decrease of the utilization efficiency of ultrasound and the reaction yield [21,22].
Table 1
To determine the optimal sonication temperature, we also investigated the reaction of
benzaldehyde (1a, 1mmol), methyl propiolate (2, 2 mmol), ammonium carbonate (1
o
mmol) and 5 mol% [CMMIM]BF4 at various temperatures (30, 40, 50, 60, 70 C) as
o
the model (Table 2). With the increase of temperature from 30 to 60 C, the yield of
product 4a increased from 80 % to 85 %, and the reaction time decreased from 15 min
o
to 10 min. When the reaction was at 60 C, the higher yield (85 %) and the shorter
reaction time (10 min) of the product could be reached. At the higher temperature (70
o
oC) tested, accelerated reaction rate was not observed. So, 60 C was used as the
optimal reaction temperature for the ultrasonic synthsis of 4a.
Table 2
Based on the results mentioned above, the catalytic activity of HOAc, trifluoroacetic
acid (TFA), [CMMIM]BF4 and other ionic liquids containing alkyl imidazolium salts
such as [BMIM]Cl, [BMIM]BF4, [EMIM]Cl, and [EMIM]BF4 were further examined.
In the absence of catalyst, a blank reaction was conducted with benzaldehyde (1a,
o
1mmol), methyl propiolate (2, 2mmol), and ammonium carbonate (1mmol) at 60 C
with 300
W
ultrasound irradiation and the yield of dimethyl
4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (4a) was 42 % at 25 min. In contrast,
4a was gained in 68 % yield in the presence of 5 mol % of HOAc at 15 min, and in
8

75 % yield in the presence of 5 mol % of TFA at 10 min. This indicates that Brønsted
acids can accelerate the reaction and the catalytic effect of ILs [CMMIM]BF4 and
other alkyl imidazolium salts including [BMIM]Cl, [BMIM]BF4, [EMIM]Cl and
[EMIM]BF4 are summarized in Table 3. Although Brønsted acids and alkyl
imidazolium salts can also accelerate the formation of 4a, [CMMIM]BF4 shows a
more effective catalytic activity than HOAc, TFA and other ILs in terms of reaction
time and yield. Moreover, table 3 shown that the increase in amounts of
[CMMIM]BF4 (0, 5, 10, 15 mol%) resulted in increasing yield from 42 % to 89 % and
shortening reaction time from 25 min to 5 min. 10 mol% of [CMMIM]BF4 was
sufficient to push the reaction at maximum rate, more catalyst did not improve the
results greatly. For example, in comparison with the catalytic effect of 10 mol% of
[CMMIM]BF4 on the reaction, product 4a was obtained in 71 % and 80 % yields
using the same catalytic amount of HOAc and TFA within 15 and 10 min, respectively
(Table 3, entries 11, 12). Therefore, 10 mol% of [CMMIM]BF4 was chosen as the
optimal catalyst for the following syntheses of 4.
Table 3
Besides the effect of the ultrasonic power intensity, the sonication temperature and the
activity of catalyst on the above solvent-free reaction, the reactants themselves might
also be an important factor for the future application of a green procedure on a large
scale. Therefore, the effect of the nitrogen source (ammonium salts) on the synthesis
of 4a was subsequently studied in the fixed combination of benzaldehyde (1a), methyl
propiolate (2), and ammonium salt (mole ratio = 1:2:1) in the presence of 10 mol%
9

o
[CMMIM]BF4 at 60 C and 300 W sonication. Table 4 showed that thermal stable
o
ammonium salts such as NH4Cl ( M.p. 277.8 C [23] ) and NH4SO4 ( M.p.
decomposes > 280 oC [23]) did not participate in synthesizing 4a, while unstable ones
o
such as (NH4)2CO3 ( M.p. volatilizes 60 C [23]), NH4HCO3 ( M.p. 107 C [23]),
o
o
o
HCOONH4 ( M.p. 116 C [23]), and CH3OONH4 ( M.p. 114 C [23]) underwent
feasibly and gained the corresponding 83-89 % yields within 5-15 min. This
phenomenon may suggest that the decomposition of ammonium salts played an
important role accelerating this procedure. A possible explanation is that the unstable
ammonium salts having lower decomposition temperature brings ammonia more
easily than stable ammonium salts for the condensation of ammonia with methyl
propiolate to form intermediate ester enamines in the synthesizing 4a (Scheme 2).
Although CH3COONH4, HCO2NH4, (NH4)2CO3 and NH4HCO3 have the similar
yields (83-89 %), HCO2NH4 and CH3COONH4 have relative lower atom economy
and are more expensive than inorganic ammonium salts. Among them, the reaction
time of (NH4)2CO3 is the shortest (5 min). Considering safety, efficiency, and price,
ammonium carbonate is the best nitrogen source in this procedure.
Table 4
To assess the scope and generality of the optimized reaction condition, various
aldehydes (aliphatic and aromatic) 1, methyl propiolate 2 and ammonium carbonate 3
were
used
to
synthesize
a
series
of
4-substituted
1,4-dihydropiridine-3,5-dicarboxylates 4. Under the optimized conditions, the
corresponding 4 were formed in 76–95 % yields within 2–10 min at 60 oC and 300 W
10

(Table 5).
Tabel 5.
As is shown in the Table 5, in all cases, aliphatic and aromatic aldehydes were
compatible with each other under the optimized reaction condition. Heteroaromatic
aldehydes such as 3-pyridinecarboxaldehyde and 4-pyridinecarboxaldehyde were
equally amenable to these conditions (Table 5, entries 12 and 13). It is evident that our
methodology is reasonably general and appliable to several aldehydes. Moreover, it
seemed that there was little difference between yields of aromatic aldehydes and alkyl
aldehydes (Table 5, entries 1-13 vs. entries 14, 15). This may be attributed to the
reactivity similarity of aldehyde carbonyls activated by ultrasonic irradiation under
solvent-free
conditions.
In
the
preparation
of
4-aryl-1,4-dihydropiridine-3,5-dicarboxylates (4), various aromatic aldehydes were
used for the synthesis of 1,4-DHPs (4) with substituents such as –Me, –OMe, –
Cl, – OH and – NO2. Under the optimized conditions previously described,
electronrich aromatic aldehydes afford fairly high yields of the desired products than
electron-deficient ones (Table 5, entries 2-6 vs. entries 7-9). For example, 4b was
obtained in 92 % yield in the condensation of 4-methylbenzaldehyde, methyl
propiolate and ammonium carbonate in the presence of 10 mol% [CMMIM]BF4
within 5 min under ultrasound irradiation, but only in 76 % yield in warm acetic acid
for 10-15 min [3a]. Even more drastically, 4i was obtained in 76 % yield in the
condensation of 3-nitrophenylaldehyde (1i), methyl propiolate and ammonium
carbonate within 10 min under ultrasound irradiation, whereas no product but
11

bis-imine was formed in warm acetic acid through the classical Hantzsch reaction [3a].
Furthermore, we also examined the reaction of aliphatic amines, methyl propiolate
and ammonium carbonate in the presence of 10 mol% [CMMIM]BF4 under
ultrasound irradiation (Table 5, entries 14, 15). Similarly, the corresponding aliphatic
aldehydes such as paraformaldhyde (or hexamethenetetramine) and heptanal were
found to give high yields (86-89 %) in the shortest reaction time (2-3 min). These
observations suggest that the ultrasonic irradiation can significantly assist the process,
even accelerate to form some products hardly obtained in conventional thermal
methods.
To check the reusability of catalyst, when the ultrasonic reaction of benzaldehyde,
methyl propiolate and ammonium carbonate was completed, the mixture was poured
into water, and the crude product was obtained by filtration. The product was
recrystallized from alcohol. The aqueous layer containing IL was subjected to vacuum
distillation to remove water, leaving the IL [CMMIM]BF4. The residual ionic liquid
o
was washed with small amount of ethyl acetate, dried under vacuum at 80 C for 4 h
and recycled. It was found that catalyst [CMMIM]BF4 can be recycled for at least five
times with no significant decrease but some loss of yields of products (Fig. 1).
Fig. 1.
A possible mechanism for this reaction is shown in Scheme 2. Ammonium was
produced from the thermal decomposition of (NH4)2CO3. Subsequently, methyl
propiolate reacts with ammonium to form enamine A and B. Catalyst [CMMIM]BF4
interacts with carbonyl groups of the aldehyde to form the activated carbonyls of
12

complex C. Eventually, nucleophilic attack of the enamine B on the activated
carbonyls in complex C leads to the detachment of protons to reproduce the catalyst
[CMMIM]BF4
and
the
formation
of
the
dimethyl
4-substituted
1,4-didydropyridine-3,5-dicarboxylate.
Scheme 2.
4. Conclusion
In summary, we have designed a novel, clean, and efficient procedure for
ultrasound-assisted synthesis of 4-substituted 1,4-didydropyridine-3,5-dicarboxylates
using a catalytic amount of [CMMIM]BF4 with satisfactory yields of 76 – 95 %.
Compared with classical methods, the ultrasound promoted reaction using a Brønsted
acid functionalized imidazolium salt IL as catalyst under solvent free condition at 60
oC has exhibited simple product isolation procedure, high yields, exclusive selectivity,
short reaction times, mild conditions and avoidance of excess use of an organic
solvent. Recovery and reuse of ionic liquids are also satisfactory, which demonstrates
the cost efficiency and green aspect of our methodology.
Acknowledgement
The project was supported by the Shijiazhuang National Natural Science Foundation
(No. 12120453).
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18

1 0 0
8 0
6 0
4 0
2 0
0
8 9
8 9
8 9
8 8
8 6
1
2
3
4
5
R un
Fig. 1. Reusabilities of the catalysis. Reaction conditions: benzaldehyde (1 mmol), methyl
propiolate (2 mmol), (NH4)2CO3 (1 mmol), [CMMIM]BF4 (10 mol%), 300 W ultrasonic
irradiation, 60 oC.
19

COOH
BF4
R
N
N
MeOOC
COOMe
+
RCHO
Ammonium salt
+
N
H
U. S., r.t.
COOMe
2
1
3
4
R = a: C6H5; b: 4-CH3C6H4; c: 4-OCH3C6H4; d: 3-CH3C6H4; e: 4-OHC6H4;
f: 3-OCH3,4-OHC6H3;g: 4-ClC6H4; h: 2-ClC6H4; i: 3-NO2C6H4;
j: 2,4-(OCH3)2C6H3; k: 3,4,5-(OCH3)3C6H2; l: pyridin-3-yl; m: pyridin-4-yl;
n: H; o: n-Hexyl
Scheme 1.
20

(NH4)2CO3
H2O, CO2
NH3
COOMe
MeOOC
COOMe
NH2
A
R
MeOOC
COOMe
MeOOC
COOMe
N
H
N
H
B
R
O
COOH
BF4
C
from
H
H
N
N
COOH
C
N
N
BF4
Scheme 2. Possible mechanism for the synthesis of dimethyl 4-substituted
1,4-dihydropyridine-3,5-dicarboxylate.
21

Table 1.
The effect of ultrasonic power on the synthesis of 4a.
Power (W)
Time (min)/Yield (%)a
a Isolated yields.
150
200
250
300
350
50/53
30/65
20/71
15/80
15/76
22

Table 2.
The effect of sonication temperature on the synthesis of 4a.
Temperature (oC)
30
40
50
60
70
Time (min)/Yield (%)a
15/80
15/82
10/82
10/85
10/84
a Isolated yields.
23

Table 3.
Effects of catalysts on the synthesis of 4a.
Catalyst loading
Time
(min)
25
15
10
10
10
10
10
10
5
Entry
Catalyst
Yield (%)a
(mol%)
1
2
-
0
5
42
68
75
85
60
75
64
71
89
89
71
80
HOAc
3
TFA
5
4
[CMMIM]BF4
[BMIM]Cl
[BMIM]BF4
[EMIM]Cl
[EMIM]BF4
[CMMIM]BF4
[CMMIM]BF4
HOAc
5
5
5
6
5
7
5
8
5
9
10
15
10
10
10
11
12
5
15
10
TFA
a Isolated yields.
24

Table 4.
Effect of different ammonium salts on the synthesis of 4a.
Entry
Ammonium salts
NH4Cl
Time (min)
Yielda (%)
1
2
3
4
5
6
60
60
15
10
5
0
(NH4)2SO4
CH3COONH4
HCOONH4
(NH4)2CO3
NH4HCO3
0
85
85
89
83
10
a Isolated yields.
25

Tabel 5.
The yields of 4-substituted 1,4-dihydropyridines under ultrasonic irradiation.
Entry
1
Producta
4a
R
C6H5
Time (min)
Yieldb (Lit.)(%)
89 (72) [3a]
92 (76) [3a]
89 (68) [3a]
90c
5
5
4-CH3C6H4
4-OCH3C6H4
3-CH3C6H4
4-OHC6H4
3-OCH3,4-OHC6H3
4-ClC6H4
2
4b
4c
5
3
5
4
4d
4e
5
93 (52) [3a]
95c
5
3
6
4f
10
10
10
5
84 (72) [3a]
81 (56) [3a]
76 (0) [3a]
95 (58) [24]
93 (60.5) [24]
78c
7
4g
2-ClC6H4
8
4h
4i
3-NO2C6H4
2,4-(OCH3)2C6H3
3,4,5-(OCH3)3C6H2
Pyridin-3-yl
Pyridin-4-yl
H
9
10
11
12
13
14
15
4j
5
4k
4l
5
5
82c
4m
4n
4o
2
89 (74) [25]
86c
n-hexyl
3
a Reaction condition: aldehyde (1 mmol), methyl propiolate (2 mmol), (NH4)2CO3
(1 mmol) and [CMMIM]BF4 (10 mol%) at 60 oC under 300W sonication.
b Isolated yields.
c Novel compound.
26

Highlights
► Brønsted acid ionic liquid [CMMIM]BF4 was used as catalyst.
►Ultrasound-assisted preparation of 1,4-dihydropiridine was finished under solvent
free condition.
►The procedure showed high yields, exclusive selectivity, short reaction times, and
mild conditions.
►The catalyst could be recycled and reused.
Acknowledgements
The project was supported by the Shijiazhuang National Natural Science Foundation
(No. 12120453) and the Hebei National Natural Science Foundation (B2014106034).
27