PEG1000-Based Dicationic Acidic Ionic Liquid Catalyzed One-pot Synthesis of 1,4-Dihydropyridines via the Hantzsch Reaction

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PEG1000-Based Dicationic Acidic Ionic
Liquid Catalyzed One-pot Synthesis of
1,4-Dihydropyridines via the Hantzsch
Reaction
Yi-Ming Rena, Juan-Juan Shaoa, Zhi-Chuan Wua & Mao-Dong Xua
a Department of Biochemical Engineering, Anhui Polytechnic
University, Wuhu, Anhui, P. R. China
Published online: 19 Nov 2014.
To cite this article: Yi-Ming Ren, Juan-Juan Shao, Zhi-Chuan Wu & Mao-Dong Xu (2014) PEG1000-Based
Dicationic Acidic Ionic Liquid Catalyzed One-pot Synthesis of 1,4-Dihydropyridines via the Hantzsch
Reaction, Organic Preparations and Procedures International: The New Journal for Organic Synthesis,
46:6, 545-550, DOI: 10.1080/00304948.2014.963455
To link to this article: http://dx.doi.org/10.1080/00304948.2014.963455
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Organic Preparations and Procedures International, 46:545–550, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2014.963455
PEG1000-Based Dicationic Acidic Ionic Liquid
Catalyzed One-pot Synthesis of
1,4-Dihydropyridines via the Hantzsch Reaction
Yi-Ming Ren, Juan-Juan Shao, Zhi-Chuan Wu, and Mao-Dong Xu
Department of Biochemical Engineering, Anhui Polytechnic University, Wuhu,
Anhui, P. R. China
Devising reactions that achieve multiple-bond formation in one operation has become one
of the major challenges in the search for efficient syntheses. Multi-component reactions
(MCRs) allow the creation of several bonds in a single operation and are attracting in-
creasing attention as one of the most powerful emerging synthetic tools for the creation
of molecular diversity and complexity.1–5 1,4-Dihydropyridines display a variety of bio-
logical properties such as vasodilator, anti-tumour, broncho-dilator, anti-atherosclerotic,
gero-protective and hepato-protective activity.6 Due to their wide range of pharmacological
activity and applications, a number of methods have been reported for their synthesis. The
most straightforward preparation of these compounds involves multi-component consid-
erations such as four-component condensation of aldehyde, 1,3-cyclohexanedione, active
methylene compounds, and ammonium acetate;7–11 the condensation of aromatic aldehy-
des, ethyl acetoacetate, and ammonium acetate12–15 (or ethanolammonium acetate,16 urea,17
ammonium hydroxide solution,18 ammonium formate,19 etc.) and three-component reac-
tion of ethyl acetoacetate, chalcones and ammonium acetate20 etc. However, most of these
methods require prolonged reaction times, drastic reaction conditions, tedious work-up
procedures, and generate only moderate yields of the product. Therefore, it is desirable to
develop improved conditions for the Hantzsch reaction.
Ionic liquids (ILs) have attracted extensive interest in recent years as environmentally
benign solvents due to their favorable properties such as non-flammability, negligible
vapor pressure, re-usability and high thermal stability.21–23 Among the numerous ILs
developed, poly(ethylene glycol)-linked dicationic neutral ionic liquids (PEG-DILs)24,25
and poly(ethylene glycol)-linked dicationic acidic ionic liquids (PEG-DAILs)26–30 have
been explored as a powerful catalysts for various transformations. The PEG-DAILs (or
PEG-DILs) were found to have the temperature-dependent biphasic behavior with toluene
in a certain temperature (biphasic conditions at lower temperatures and monophasic at
Received April 4, 2014; in final form July 21, 2014.
Address correspondence to Yi-Ming Ren, Department of Biochemical Engineering, Anhui Poly-
technic University, Wuhu, Anhui, 241000, P. R. China. E-mail: yimingren@ahpu.edu.cn
545

546
Ren et al.
O
Ar
O
1
CO2Et
Me
i
+ ArCHO + NH4OAc + MeCOCH2CO2Et
O
R
N
H
R
R
R
2
3
4
5a-5o
R = H or CH3
Ar
EtO2C
Me
CO2Et
Me
ii
ArCHO + NH4OAc + 2 MeCOCH2CO2Et
N
2
3
4
H
6a-6h
+
+
N
N
2 HSO4
(CH2)3SO3H
N
N
CH2CH2(OCH2CH2)nOCH2CH2
HO3S(CH2)3
PEG1000-DAIL:
(i) PEG1000-DAIL, toluene, 80°C, 15-30 min (ii) PEG1000-DAIL, toluene, 80°C, 30-45 min
Scheme 1
higher temperatures).24,26 The temperature-dependent feature of ILs provide a novel route
for the separating and recycling of the catalysts.
To the best of our knowledge, there is no report on the application of PEG1000-DAIL as
acid catalysts for the preparation of 1,4-dihydropyridines. As part of our ongoing interest in
ILs24,25 and MCRs,1,31–34 we now report a simple and efficient procedure for the Hantzsch
reaction using PEG1000-DAIL as an effective and reusable catalyst (Scheme 1).
Model exploratory experiments indicated that PEG1000-DAIL efficiently catalyzed the
reaction of benzaldehyde, 1,3-cyclohexanedione, ethyl acetoacetate and ammonium acetate
to give the corresponding dihydropyridine. Although the yield rose with increasing temper-
atures (Table 1, Entries 1–6), the results showed the optimal temperature to be 80◦C. The
yields did not increase when higher temperature was employed (Table 1, Entries 7 and 8).
The performance of recycled PEG1000-DAIL was investigated in the reaction of ben-
zaldehyde, 1,3-cyclohexanedione, ethyl acetoacetate, and ammonium acetate. The data
listed in Table 1 showed that PEG1000-DAIL could be re-used nine times with excellent
results (Table 1, Entry 6). The bottom layer of PEG1000-DAIL was recycled without any
treatment and the work-up procedure of recycling is accomplished by simple phase sepa-
ration.
In order to evaluate the efficiency of PEG1000-DAIL as a catalyst, a range of aromatic
aldehydes were similarly treated with 1,3-cyclohexanedione, ethyl acetoacetate, and am-
monium acetate in the presence of PEG1000-DAIL; the 1,4-dihydropyridines (5a–5h) were
formed in excellent yields (Table 2, Entries 1–8). The position and/or nature of substituent
on the aromatic ring had a negligible effect on the yields of the final products. Similarly,

One-Pot Synthesis of 1,4-Dihydropyridines via the Hantzsch Reaction
547
Table 1
Optimizing the Reaction Conditions
Entry
T (◦C)
t (min)
Yield (%)
1
2
3
4
5
6a
7
8
r.t.
40
50
60
70
80
90
100
100
100
100
100
60
25
25
25
15
45
61
75
93
93, 93, 93, 93, 91, 91, 91, 90, 90
93
93
aThe PEG1000-DAIL was run for nine consecutive cycles.
the corresponding products (5i–5o) were obtained in excellent yields when dimedone was
employed under the same conditions (Table 2, Entries 9–15).
Table 2
PEG1000-DAIL Catalyzed the Synthesis of 1,4-Dihydroquinolines 5a–5o at 80◦C
Entry
Ar
R
t (min) Product Yield (%)
mp. (lit.) (◦C)
1
2
3
4
5
6
7
8
C6H5
4-ClC6H4
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
25
20
30
30
15
20
20
25
25
20
30
30
25
20
20
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
93
94
95
92
94
93
91
93
94
92
92
94
95
93
92
240–241 (240–2417)
234–235 (234–2357)
241–242 (241–2427)
192–194 (193–1957)
204–205 (204–2057)
198–200 (198–2007)
190–192 (190–1917)
220–222 (220–2227)
209–210 (209–2107)
229–231 (230–2327)
236–238 (237–2387)
262–264 (262–2648)
242–244 (243–2457)
242–243 (242–2448)
175–177 (176–1788)
4-CH3C6H4
4-CH3OC6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-HOC6H4
C6H5
4-ClC6H4
4-HOC6H4
4-CH3C6H4
9
10
11
12
13
14
15
4-CH3OC6H4 CH3
4-NO2C6H4
3-NO2C6H4
CH3
CH3
This success led us to extend the Hantzsch reaction to the use of aromatic aldehydes
with ethyl acetoacetate, and ammonium acetate under the same conditions. Table 3 shows
that different aromatic aldehydes reacted successfully within 45 min to give the expected
products 6a–6h in high yields. The nature of aldehyde has no significant effect on the
reaction; both electron-rich and electron-deficient aldehydes reacted to give high yields of
products.

548
Ren et al.
Table 3
PEG1000-DAIL Catalyzed the Synthesis of 1,4-Dihydropyridines 6a–6h at 80◦C
Entry
Ar
t (min)
Product
Yield (%)
mp. (mp. lit.) (◦C)
1
2
3
4
5
6
7
8
C6H5
4-ClC6H4
40
30
45
45
30
45
30
40
6a
6b
6c
6d
6e
6f
91
93
96
87
93
95
92
86
156–158 (155–15714)
145–147 (146–14914)
136–138 (136–13814)
159–161 (160–16114)
131–133 (131–13414)
162–164 (161–16314)
162–163 (162–16314)
230–232 (230–23314)
4-CH3C6H4
4-CH3OC6H4
4-NO2C6H4
3-NO2C6H4
4-BrC6H4
6g
6h
4-HOC6H4
Comparison of the results of the condensation of benzaldehyde with ethyl acetoacetate,
and ammonium acetate in Table 4 shows that PEG1000-DAIL is a more efficient catalyst
with respect to times and yields than other catalysts.
Table 4
Different Catalytic Systems for the Condensation of Benzaldehyde with Ethyl
Acetoacetate, and Ammonium Acetate
Entry
Catalysts
Solvents
T (◦C)
t (min)
Yield (%)
1
2
3
4
5
6
PEG1000-DAIL
PPh3
MgO nanoparticles
MgAl2-HT
TMSCl/NaI
Cellulose sulfuric acid
toluene
EtOH
EtOH
CH3CN
CH3CN
None
80
reflux
reflux
r.t.
r.t.
80
40
91
300
110
390
360
300
7213
8514
7335
8036
9037
In conclusion, we have developed an efficient and facile method to prepare a variety of
1,4-dihydropyridines in the presence of PEG1000-DAIL. The advantages of our procedure
include the elimination of the use of metals, short reaction times, operational simplicity and
excellent yields of products. Simple reaction conditions, good thermo-regulated biphasic
behavior of PEG1000-DAIL and easy isolation of the product are additional features of this
methodology, besides the excellent recyclability of the PEG1000-DAIL.
Experimental Section
The PEG1000-DAIL was prepared by the procedure given in the literature.26 All the other
chemicals and reagents were obtained from commercial sources and were used without
1
further purification. H NMR spectra were recorded on Bruker Avance DMX500. All
products were known compounds and were identified by their mp and 1H NMR.

One-Pot Synthesis of 1,4-Dihydropyridines via the Hantzsch Reaction
549
General Procedure for the Synthesis of 1,4-Dihydroquinolines 5a–5o
To a solution of aromatic aldehyde (1 mmol), 1,3-cyclohexanediones (or dimedone)
(1 mmol), ethyl acetoacetate (0.13g, 1 mmol) and ammonium acetate (0.077g, 1 mmol)
in toluene (1.5 ml) was added PEG1000-DAIL (1 ml) in tube reactor at room temperature.
Then the mixture was stirred at 80◦C for the specified time and monitored by TLC. After
the reaction, the mixture was cooled to room temperature, the upper toluene layer was
separated by decantation. The toluene was evaporated to give products 5a–5o purified by
recrystallization from ethanol. The bottom layer of PEG1000-DAIL was reused without any
treatment.
General Procedure for the Synthesis of 1,4-Dihydropyridines 6a–6h
To a solution of aromatic aldehyde (1 mmol), ethyl acetoacetate (0.26 g, 2 mmol) and
ammonium acetate (0.077 g, 1 mmol) in toluene (1.5 ml) was added PEG1000-DAIL (1 ml)
in tube reactor at room temperature. Then the mixture was stirred at 80◦C for the specified
time and the reaction mixture was treated as above to afford the products 6a–6h. The bottom
layer of PEG1000-DAIL was reused without any treatment.
Acknowledgments
The project sponsored by the Anhui Polytechnic University for Young Elite Talents (No.
2013RZR002ZD) and the National Innovation Program for University Students (No.
201210363036 and 201310363065).
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