Facile and green synthesis of 1,4-dihydropyridine derivatives in n-butyl pyridinium tetrafluoroborate

Article abstract of DOI:10.1080/00397911.2010.525773

l,4-Dihydropyridine derivatives were synthesized from the one-pot condensation of aldehydes, acetoacetates, and ammonium acetate in room-temperature ionic liquid n-butyl pyridinium tetrafluoroborate ([BPy][BF4]). Compared with classical Hantzsch reaction conditions, this new method has the advantage of excellent yields, short reaction time, and easy workup. The recovered ionic liquid could be recycled for at least five runs without losing its activity. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.525773

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Facile and Green Synthesis of 1,4-
Dihydropyridine Derivatives in n-Butyl
Pyridinium Tetrafluoroborate
Xiao Yun Wu a
a School of Pharmaceutical Sciences , Southern Medical University ,
Guangzhou , China
Accepted author version posted online: 29 Jul 2011.Published
online: 06 Oct 2011.
To cite this article: Xiao Yun Wu (2012) Facile and Green Synthesis of 1,4-Dihydropyridine Derivatives
in n-Butyl Pyridinium Tetrafluoroborate, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:3, 454-459, DOI: 10.1080/00397911.2010.525773
To link to this article: http://dx.doi.org/10.1080/00397911.2010.525773
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Synthetic Communications1, 42: 454–459, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.525773
FACILE AND GREEN SYNTHESIS OF
1,4-DIHYDROPYRIDINE DERIVATIVES IN n-BUTYL
PYRIDINIUM TETRAFLUOROBORATE
Xiao Yun Wu
School of Pharmaceutical Sciences, Southern Medical University,
Guangzhou, China
GRAPHICAL ABSTRACT
Abstract l,4-Dihydropyridine derivatives were synthesized from the one-pot condensation of
aldehydes, acetoacetates, and ammonium acetate in room-temperature ionic liquid n-butyl
pyridinium tetrafluoroborate ([BPy][BF4]). Compared with classical Hantzsch reaction
conditions, this new method has the advantage of excellent yields, short reaction time,
and easy workup. The recovered ionic liquid could be recycled for at least five runs without
losing its activity.
Keywords 1,4-Dihydropyridine; ionic liquid; one-pot condensation
INTRODUCTION
Hantzsch l,4-dihydropyridines are a class of biologically, medicinally, and
synthetically important compounds in the field of drugs and pharmaceuticals. The
l,4-dihydropyridine heterocyclic ring is common to various bioactive compounds,
such as vasodilator, antihypertensive, bronchodilator, antiatherosclerotic, antitu-
mor, geroprotective, heptaprotective, and antidiabetic agents. l,4-Dihydropyridines
are also important calcium channel blockers for the treatment of cardiovascular
disease, as exemplified by therapeutic agents such as nifedipine, nitrendipine, and
nimodipine.[1–3]
The usefulness of 1,4-dihydropyridine derivatives has led to the development of
novel synthetic strategies to improve classical methods of preparation. Classical syn-
thesis of l,4-dihydropyridines consists of one-pot condensation of aldehydes, active
Received April 27, 2009.
Address correspondence to Xiao Yun Wu, School of Pharmaceutical Sciences, Southern Medical
University, Guangzhou 510515, China. E-mail: shmily80@163.com
454

SYNTHESIS OF 1,4-DIHYDROPYRIDINES
455
methylene carbonyl compounds (e.g., ethyl acetoacetate) and ammonia under reflux
for a long time in either acetic acid or ethanol. The yields are generally poor, in parti-
cular for sterically hindered aldehydes. Recently, several improved procedures have
been reported, but many of them still suffer from drawbacks such as unsatisfactory
yields, long reaction time, tedious workup, and pollution to the environment because
of the use of organic solvents.[4,5] Thus, the development of efficient and green meth-
ods for the Hantzsch reaction is still an active research area.
During recent decades, room-temperature ionic liquids have emerged as envir-
onmentally benign media with unique properties, such as tunable polarity, high ther-
mal stability, immiscibility with a number of organic solvents, negligible vapor
pressure, and recyclability. These properties offer an attractive alternative to conven-
tional organic solvents, and thus ionic liquids have been successfully employed in
several organic synthesis.[6] The use of room-temperature ionic liquids made it poss-
ible to decrease the reaction time and increase the yields. Among the room-
temperature ionic liquids, substituted pyridinium or imidazolium salts are currently
the focus of extensive investigation.
Given the advantage of pyridinum-based ionic liquids as novel reaction media,
we explore the use of n-butyl pyridinium tetrafluoroborate ([BPy][BF4]) as
environmentally friendly and recyclable solvent system for the synthesis of
l,4-dihydropyridines.
RESULTS AND DISCUSSION
First, the reaction of 3-nitrobenzaldehyde, methyl acetoacetate, and
ammonium acetate was selected as a model to optimize the reaction conditions.
The effect of temperature was discussed in this article, and the results are listed in
Table 1. As can be seen from Table 1, temperature had an important effect on the
reactions. At room temperature (25–30 ꢀC), the reaction was very slow and had
not completed for more than 48 h according to thin-layer chromatographic (TLC)
analysis. The target compound had poor solubility in [BPy][BF4] at room tempera-
ture and thus precipitated with a mixture of raw materials, which prevented the reac-
tion from proceeding to completion. The reaction was faster at 60–70 ꢀC. The target
compound had better solubility in [BPy][BF4], but there was still some crystal preci-
pitates during the reaction process. While at 100–110 ꢀC, the target compound was
Table 1. Effect of temperature on the synthesis of 1,4-dihy-
dropyridine 1aa
Entry
Temperature (ꢀC)
Time (h)
Yield (%)
1
2
3
25–30
60–70
100–110
48
18
3
30
58
97
aReactions were conducted with 3-nitrobenzaldehyde
(20 mmol), methyl acetoacetate (40 mmol), and ammonium
acetate (30 mmol) in [BPy][BF4] (10 mL).

456
X. Y. WU
Scheme 1. The synthesis of 1,4-dihydropyridines in ionic liquid.
readily soluble in ionic liquid, and the water produced in the reaction was evaporated
from the reaction system, which promoted the reaction to completion, thereby
increasing the yields. Thus the reaction was conducted in the following way: The
reaction mixture of l eq. of 3-nitrobenzaldehyde, 2 eq. of methyl acetoacetate, and
1.5 eq. of ammonium acetate in ionic liquid n-butyl pyridinium tetrafluoroborate
was heated at 100–110 ꢀC for 3 h (monitored by TLC). The reaction mixture was
cooled to room temperature. The target compound precipitated because of the very
poor solubility in ionic liquid at room temperature. The resulting precipitates were
isolated by filtration, washed with water to remove the water-soluble ionic liquid,
and dried to give the desired product in excellent yield of 97% (Scheme 1). A variety
of aldehydes have been reacted with ethyl acetoacetate or methyl acetoacetate and
ammonium acetate (Table 2). Compared to classical synthesis, using ionic liquid
as reaction media does not only provide a dramatic improvement of yields (87–
97%) over conventional method but also shortens the reaction time significantly
(Table 2). As shown, the products were easily separated by filtration because of
the poor solubility in hydrophilic [BPy][BF4] at room temperature. Therefore, the
reactions avoid many problems arising from the use of volatile organic solvents
(cost, handing, safety, and pollution).
Another advantage of the ionic liquid is that it is recyclable as reaction
medium. In view of environmentally friendly methodologies, recovery and reuse of
the ionic liquid is highly preferable. The ionic liquid could be recovered easily by
washing with ethyl acetate and dried over vacuum, and can be reused at least five
times with little decrease in the efficiency of the reaction (Table 3).
Table 2. Comparison of synthesis in ionic liquid and conventional method
In ionic liquid
Conventional methoda
Temperature Time Yielda
Time
(h)
Yieldb
(%)
Entry
Ar
R
Product
(ꢀC)
(h)
(%)
1
2
3
4
5
6
7
3-NO2C6H4
3-NO2C6H4
2-NO2C6H4
CH3
C2H5
CH3
1a
1b
1c
1d
1e
1f
100–110
100–110
100–110
100–110
100–110
100–110
100–110
3
3
3
2
3
3
3
97
95
87
96
96
93
92
12
12
15
18
18
24
24
73
70
60
61
58
40
36
2-Cl-5-NO2-C6H3 CH3
2-Cl-5-NO2-C6H3 C2H5
2,3-Cl2-C6H3
2,3-Cl2-C6H3
CH3
C2H5
1g
aReactions were conducted under reflux in ethanol.
bIsolated yields.

SYNTHESIS OF 1,4-DIHYDROPYRIDINES
457
Table 3. Recyclability of ionic liquid
Run
Isolated yield of 1a (%)
Recycle rate of ionic liquid (%)
1
2
3
4
5
97
94
96
97
94
93
92
92
90
91
CONCLUSION
This article described a method for the synthesis of Hantzsch l,4-dihydropyri-
dine derivatives from the one-pot condensation of aldehydes, acetoacetates, and
ammonium acetate in ionic liquid n-butyl pyridinium tetrafluoroborate. The pro-
cedure has the features of short reaction time, excellent yields, easy workup, and
recyclability of the ionic liquid. These advantages make it a convenient, economical
and green process for the synthesis of biologically and medicinally interesting
l,4-dihydropyridines.
EXPERIMENTAL
Melting points were uncorrected. 1H NMR spectra were recorded in CDCl3 on
a Unity 400-MHz instrument with tetramethylsilane (TMS) as an internal standard,
and mass spectra were measured on a Shimadzu GC-17-QP-5000 spectrometer.
n-Butyl pyridinium tetrafluoroborate was prepared according to the literature.[7]
All the other chemicals were obtained from commercial sources and were used
without further purification.
Typical Procedure and Data for the Synthesis of 2,6-Dimethyl-
3,5-dicarbomethoxy-4-(3-nitrophenyl)-1,4-dihydropyridine (1a)
A mixture of 3-nitrobenzaldehyde (20 mmol, 3.02 g), methyl acetoacetate
(40 mmol, 4.64 g), and ammonium acetate (30 mmol, 2.31 g) in [BPy][BF4] (10 mL)
was stirred at 100–110 ꢀC. After completion of the reaction (monitored by TLC),
the reaction mixture was cooled to room temperature. The solid precipitates were
isolated by filtration, washed with water, and dried to give the desired product 1a
in yield of 97%. The product was purified by recrystallization from ethanol. Mp:
210–212 ꢀC (lit.[8]: mp 210–212 ꢀC).1H NMR (400 MHz, CDCl3): d ¼ 2.37 (s, 6H, 2
CH3), 3.65 (s, 6H, 2 CH3), 5.11 (s, 1H, 4-CH), 5.96 (s, 1H, N-H), 7.38–8.10 (m,
4H, Ar-H) ppm. MS: m=z ¼ 346 (Mþ). The ionic liquid was recycled by thoroughly
washing it with ethyl acetate and drying in vacuum, and then was used without
further manipulation.
Data
2,6-Dimethyl-3,5-dicarboethoxy-4-(3-nitrophenyl)-1,4-dihydropyridine
(1b). Mp: 159–161 ꢀC (lit.[8]: mp 160–162 ꢀC). 1H NMR (400 MHz, CDCl3): d ¼ 1.24

458
X. Y. WU
(t, J ¼ 7.2 Hz, 6H, 2 CH3), 2.38 (s, 6H, 2 CH3), 4.12 (q, J ¼ 7.2 Hz, 4H, 2 CH2),
5.10 (s, 1H, 4-CH), 5.79 (s, 1H, N-H), 7.40–8.15 (m, 4H, Ar-H) ppm. MS:
m=z ¼ 374 (Mþ).
2,6-Dimethyl-3,5-dicarbomethoxy-4-(2-nitrophenyl)-1,4-dihydropyridine
(1c). Mp: 170–172 ꢀC (lit.[9]: mp 173–174 ꢀC).1H NMR (400 MHz, CDCl3): d ¼ 2.35
(s, 6H, 2 CH3), 3.60 (s, 6H, 2 CH3), 5.82 (s, 1H, 4-CH), 6.94 (s, 1H, N-H), 7.26–7.71
(m, 4H, Ar-H) ppm. MS: m=z ¼ 346 (Mþ).
2,6-Dimethyl-3,5-dicarbomethoxy-4-(2-chloro-5-nitrophenyl)-1,4-dihydro-
1
pyridine (1d). Mp: 220–222 ꢀC. H NMR (400 MHz, CDCl3): d ¼ 2.38 (s, 6H, 2
CH3), 3.58 (s, 6H, 2 CH3), 5.56 (s, 1H, 4-CH), 6.69 (s, 1H, N-H), 7.57–8.12 (m,
3H, Ar-H) ppm. MS: m=z ¼ 380 (Mþ).
2,6-Dimethyl-3,5-dicarboethoxy-4-(2-chloro-5-nitrophenyl)-1,4-dihydro-
pyridine (1e). Mp: 184–186 ꢀC. 1H NMR (400 MHz, CDCl3): d ¼ 1.22 (t,
J ¼ 7.2 Hz, 6H, 2 CH3), 2.37 (s, 6H, 2 CH3), 4.05 (q, J ¼ 7.2 Hz, 4H, 2 CH2), 5.56
(s, 1H, 4-CH), 6.67 (s, 1H, N-H), 7.58–8.12 (m, 3H, Ar-H) ppm. MS: m=z ¼ 408
(Mþ).
2,6-Dimethyl-3,5-dicarbomethoxy-4-(2,3-dichlorophenyl)-1,4-dihydropyri-
dine (1f). Mp: 170–171 ꢀC (lit.[10]: mp 172–174 ꢀC).1H NMR (400 MHz, CDCl3):
d ¼ 2.28 (s, 6H, 2 CH3), 3.56 (s, 6H, 2 CH3), 5.49 (s, 1H, 4-CH), 5.75 (s, 1H,
N-H), 7.08–7.46 (m, 3H, Ar-H) ppm. MS: m=z ¼ 369 (Mþ).
2,6-Dimethyl-3,5-dicarboethoxy-4-(2,3-dichlorophenyl)-1,4-dihydropyr-
idine (1g). Mp: 122–124 ꢀC (lit.[10]: mp 120–122 ꢀC).1H NMR (400 MHz, CDCl3):
d ¼ 1.14 (t, J ¼ 7.2 Hz, 6H, 2 CH3), 2.34 (s, 6H, 2 CH3), 4.08 (q, J ¼ 7.2 Hz, 4H, 2
CH2), 5.48 (s, 1H, 4-CH), 5.76 (s, 1H, N-H), 7.15–7.50 (m, 3H, Ar-H) ppm. MS:
m=z ¼ 397 (Mþ).
ACKNOWLEDGMENT
This work was financially supported by the Medical Scientific Research
Fundation of Guangdong Province (No. B2007112).
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