(NH4)2.5H0.5PW12O 40-catalyzed rapid and efficient one-pot synthesis of dihydropyridines via the Hantzsch reaction under solvent-free conditions

Article abstract of DOI:10.1007/s11164-012-0962-6

A heterogeneous reaction with the ammonium salt of 12-tungstophosphoric acid as catalyst has been designed for synthesis of 1,4-dihydropyridine and polyhydroquinoline via the Hantzsch condensation. Molten tetrabutylammonium bromide ionic liquid was used a

Full text of DOI:10.1007/s11164-012-0962-6

Res Chem Intermed
DOI 10.1007/s11164-012-0962-6
(NH4)2.5H0.5PW12O40-catalyzed rapid and efficient
one-pot synthesis of dihydropyridines via
the Hantzsch reaction under solvent-free conditions
•
Seyyed Naeim Ghattali Kazem Saidi
Hojatollah Khabazzadeh
•
Received: 2 October 2012 / Accepted: 29 November 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract A heterogeneous reaction with the ammonium salt of 12-tungstophos-
phoric acid as catalyst has been designed for synthesis of 1,4-dihydropyridine and
polyhydroquinoline via the Hantzsch condensation. Molten tetrabutylammonium
bromide ionic liquid was used as reaction medium.
Keywords Hantzsch Á 1,4-Dihydropyridine Á Polyhydroquinoline Á
12-Tungstophosphoric Á Heterogeneous Á Tetrabutylammonium bromide
Introduction
Use of heterogeneous, rather than homogeneous, acid catalysts in organic synthesis
is an attractive area of research in the laboratory and in industry. The main
advantage of heterogeneous catalysts over homogeneous catalysts are their high
stability toward air and moisture, lack of corrosion, and ease of handling, recovery,
and regeneration [1]. Keggin-type heteropoly acids and their salts are a class of
highly acidic solid acid catalysts containing metal heteropolyanions coordinated by
octahedral oxygen as the basic structural unit [2]. Salts of 12-tungstophosphoric acid
are very important catalysts in several organic conversions, for example hydrocar-
bon cracking [3], conversion of methanol to hydrocarbons, cracking of alkenes [4],
esterification [5], benzylation, and benzoylation [6].
Multi-component reactions (MCRs) are efficient and powerful methods in
modern synthetic organic chemistry. They enable facile creation of several new
Dedicated with respect and admiration to Professor Issa Yavari, a leading pioneer in the development of
multicomponent reactions.
S. N. Ghattali Á K. Saidi (&) Á H. Khabazzadeh
Department of Chemistry, Shahid Bahonar University of Kerman, 76169 Kerman, Iran
e-mail: saidik@uk.ac.ir
123

S. N. Ghattali et al.
bonds in a one-pot reaction [7, 8]. Clearly, for efficient multi-step synthetic
procedures, the number of reactions and purification steps are among the most
important criteria, and should be as low as possible.
1,4-Dihydropyridyl compounds are well known as calcium-channel modulators
and are among the most important drugs used for treatment of cardiovascular
diseases [9]. Cardiovascular agents, for example nifedipine, nicardipine, amlodip-
ine, and related derivatives are dihydropyridyl compounds effective in the treatment
of hypertension. 1,4-Dihydropyridine (DHP) derivatives have a variety of biological
activity for example vasodilator, bronchodilator, antiatherosclerotic, antitumor,
geroprotective, hepatoprotective, and antidiabetic [10]. Extensive studies have
revealed that 1,4-DHP derivatives also have such medicinal functions as neuropro-
tectant, platelet anti-aggregatory activity, cerebral antischemic activity in the
treatment of Alzheimer’s disease, and chemosensitizers in tumor therapy [11].
These examples clearly indicate the remarkable potential of novel DHP derivatives
as a source of valuable drug candidates. Oxidation of these compounds to pyridines
has also been extensively studied [12]. Thus, there is much current interest in the
synthesis of this heterocyclic nucleus, because six-membered nitrogen heterocycles
are contained in many biologically interesting compounds.
Experimental
All chemicals used in the syntheses were purchased from Merck and were used
without further purification. All products are known and were identified by
comparing their spectral data and physical properties with those of the authentic
samples. NMR spectra were recorded on a Bruker DRX-500 Avance NMR
spectrometer using CDCl3 or DMSO-d6 as solvents.
General procedure for synthesis of 1,4-DHPs
Aldehyde (1 mmol), b-ketoester (2 mmol), NH4OAc (1 mmol) (NH4)2.5H0.5PW12O40
(0.02 mmol), and TBAB (1 mmol) were mixed and stirred at 110 °C. After completion
of the reaction, as indicated by TLC, 10 ml ethanol was added. After isolation of the
catalystbyfiltrationthe mixture waspouredintoice coldwater. Theresultingprecipitate
was purified by recrystallization from ethanol to afford 1,4-DHPs. The same procedure
was used for synthesis of polyhydroquinolines with b-ketoester (1 mmol), cyclic
diketone (1 mmol), and TBAB (2 mmol). The catalyst was dried at 120 °C and reused.
Spectroscopic data for selected examples are shown below.
Dimethyl 1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylate
(Table 1, entry 4)
1H NMR (500 MHz, CDCl3): d (ppm) 2.36 (s, 6H, 2 CH3), 3.68 (s, 6H, 2 CH3), 5.04
(s, 1H, CH), 5.81 (s, 1H, NH), 7.16-7.30 (m, 5H, arom). 13C NMR (125 MHz,
CDCl3): d (ppm) 19.9, 39.7, 51.4, 104.3, 126.6, 128.0, 128.4, 144.7, 147.8, 168.5.
123

(NH4)2.5H0.5PW12O40-catalyzed rapid and efficient one-pot synthesis
Table 1 (NH4)2.5H0.5PW12O40-catalyzed synthesis of 1,4-DHP derivatives via the Hantzsch reaction
Entry R1
R2 Product
Time
(min)
Yield
(%)
mp (°C)
Observed Reported
[Ref.]
1
4-Cl–C6H4
Et
10
89
140–143 144–145
[17]
Cl
O
O
EtO
OEt
N
H
2
4-CH3–
C6H4
Et
18
81
131–134 135–138
[15]
Me
O
O
EtO
OEt
N
H
3
3-NO2–
C6H4
Et
4
96
158–161 162–164
[15]
NO2
O
O
O
O
EtO
OEt
N
H
4
4-Br–C6H4
Et
8
73
162–165 160–162
[18]
Br
O
EtO
OEt
N
H
5
4-OCH3–
C6H4
Et
14
64
162–164 157–159
[15]
OMe
O
EtO
OEt
N
H
123

S. N. Ghattali et al.
Table 1 continued
Entry R1
R2 Product
Time
(min)
Yield
(%)
mp (°C)
Observed Reported
[Ref.]
6
2-OCH3–
C6H4
Et
14
65
135–137 139–141[15]
OMe
O
O
EtO
MeO
MeO
OEt
N
H
7
4–Br–C6H4 Me
8
88
195–198 200–201
[16]
Br
O
O
OMe
N
H
8
4-NO2–
C6H4
Me
4
93
190–193 195–196
[16]
NO2
O
O
OMe
N
H
Dimethyl 4-(4-bromophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
(Table 1, entry 9)
1H NMR (500 MHz, CDCl3): d (ppm) 2.36 (s, 6H, 2 CH3), 3.67 (s, 6H, 2 OCH3),
4.99 (s, 1H, CH), 5.77 (s, 1H, NH), 7.17 (d, J = 8.4 Hz, 2H, arom), 7.36 (d,
J = 8.4 Hz, 2H, arom). 13C NMR (125 MHz, CDCl3): d (ppm) 20.0, 39.5, 51.5,
104.0, 120.4, 129.9, 131.5, 144.7, 146.9, 168.2.
Ethyl 1,4,5,6,7,8-hexahydro-4-(4-methoxyphenyl)-2-methyl-5-oxoquinoline-3-
carboxylate (Table 2, entry 12)
1H NMR (500 MHz, CDCl3): d (ppm) 1.13 (t, J = 7.0 Hz, 3H, CH3), 1.74 (m, 1H),
1.88 (m, 1H), 2.16–2.24 (m, 2H), 2.27 (s, 3H, CH3), 2.46 (m, 2H), 3.67 (s, 3H,
OCH3), 3.97 (q, J = 7.0 Hz, 2H, CH2), 4.83 (s, 1H, CH), 6.73 (d, J = 8.4 Hz, 2H,
arom), 7.04 (d, J = 8.4 Hz, 2H, arom), 9.07 (s, 1H, NH).
123

(NH4)2.5H0.5PW12O40-catalyzed rapid and efficient one-pot synthesis
Table 2 (NH4)2.5H0.5PW12O40-catalyzed synthesis of polyhydroquinoline derivatives via the Hantzsch
Reaction
Entry R1
R2 R3 Product
Time
(min)
Yield
(%)
mp (°C)
Observed Reported
[Ref.]
1
C6H5
Et
Me
8
70
198–200 203–205
[19]
O
O
OEt
OEt
OEt
OEt
N
H
2
4-CH3–
C6H4
Et
Me
4
73
255–257 261–263
[19]
Me
O
O
O
O
N
H
3
4
5
4-Cl–
C6H4
Et
Et
Et
Me
Me
Me
4
4
4
76
68
92
235–238 242–244
[19]
Cl
O
N
H
3-NO2–
C6H4
236–239 242–244
[19]
NO2
O
N
H
4-NO2–
C6H4
172–175 178–180
[19]
NO2
O
O
OEt
N
H
123

S. N. Ghattali et al.
Table 2 continued
Entry R1
R2 R3 Product
Time
(min)
Yield
(%)
mp (°C)
Observed Reported
[Ref.]
6
7
8
9
4-OCH3– Et
C6H4
Me
4
4
8
6
68
86
90
85
245–249 252–255
[19]
OMe
O
O
O
O
O
O
OEt
OEt
OEt
N
H
4-Br–
Et
Me
248–250 253–255
[19]
Br
C6H4
N
H
4-OH–
C6H4
Et
Me
229–232 231–233
[19]
OH
N
H
4-CH3–
C6H4
Me Me
260–264 270 [18]
Me
O
O
OMe
N
H
10
C6H5
Et
H
6
74
236–239 243–245
[19]
O
O
OEt
N
H
123

(NH4)2.5H0.5PW12O40-catalyzed rapid and efficient one-pot synthesis
Table 2 continued
Entry R1
R2 R3 Product
Time
(min)
Yield
(%)
mp (°C)
Observed Reported
[Ref.]
11
4-CH3–
C6H4
Et
H
10
89
238–240 242–243
[19]
Me
O
O
OEt
OEt
OEt
OEt
N
H
12
13
14
15
4-OCH3– Et
C6H4
H
H
H
H
4
6
8
4
70
92
71
82
248–253 252–255
[19]
OMe
O
O
O
O
N
H
4-Cl–
C6H4
Et
Et
Et
230–232 234–236
[19]
Cl
O
N
H
4-OH–
C6H4
222–225 220–222
[20]
OH
O
N
H
3-NO2–
C6H4
195–196 200–201
[20]
NO2
O
O
OEt
N
H
123

S. N. Ghattali et al.
Table 2 continued
Entry R1
R2 R3 Product
Time
(min)
Yield
(%)
mp (°C)
Observed Reported
[Ref.]
16
4-NO2–
C6H4
Et
H
4
76
210–212 204–205
[20]
NO2
O
O
OEt
N
H
Results and discussion
Because of the significant effect of heteropoly acid catalysts in many organic
transformations [13, 14] and our interest in their catalytic activity in the synthesis of
six membered nitrogen heterocycles, for example 1,4-dihydropyridines (DHPs), we
have undertaken the synthesis of 1,4-DHPs and related polyhydroquinolines
promoted by a catalytic amount of (NH4)2.5H0.5PW12O40 in molten tetrabutylam-
monium bromide (TBAB).
To pursue this approach the conditions were optimized by examining the reaction
involving p-chlorobenzaldehyde, ethyl acetoacetate, and ammonium acetate to
afford the appropriate DHP. The best results were obtained at 110 °C with 2 mol%
of (NH4)2.5H0.5PW12O40.
Several types of aldehyde with electron-donating or electron-withdrawing
substituents were reacted under the optimized conditions to establish the scope
and generality of the process (Scheme 1).
In all cases good yields of the expected 1,4-DHP derivatives were obtained. The
results are summarized in Table 1.
After successful synthesis of a series of Hantzsch DHPs, we turned our attention
to the synthesis of polyhydroquinoline derivatives via unsymmetrical Hantzsch
reaction. A procedure analogous to that used to prepare compounds (1–14), the four-
component coupling reaction of cyclic 1,3-diketone, aldehyde, acetoacetic ester, and
ammonium acetate, was conducted under similar reaction conditions (Scheme 2).
All products were obtained in high yields under the same reaction conditions as
shown in Table 2.
This method not only affords the products in excellent yields but also avoids the
disadvantages associated with catalyst cost, handling, safety, and pollution. Shorter
reaction times and improved selectivity were obtained in the presence of this
heterogeneous catalyst.
The reusability of the catalyst was also examined by treating ethyl acetoacetate
with 3-nitrobenzaldehyde in the presence of 2 mol % catalyst for four consecutive
123

(NH4)2.5H0.5PW12O40-catalyzed rapid and efficient one-pot synthesis
1
O
R
O
O
O
2
RO
2
1
R
molten TBAB, NH4OAc
(NH4)2.5H0.5PW12O40
2 mol%
OR
2
2
CHO
+
OR
N
H
Scheme 1 (NH4)2.5H0.5PW12O40-catalyzed synthesis of DHP derivatives in molten tetrabutylammonium
bromide
1
O
R
O
2
O
O
CO2R
1
R
molten TBAB, NH4OAc
(NH4)2.5H0.5PW12O40
2
OR
+
CHO
3
R
3
R
+
N
H
O
3
3
2 mol%
R
R
Scheme 2 (NH4)2.5H0.5PW12O40-catalyzed synthesis of polyhydroquinoline derivatives in molten
tetrabutylammonium bromide
Table 3 Reusability of (NH4)2.5H0.5PW12O40 for Hantzsch reaction of 3-nitrobenzaldehyde with ethyl
acetoacetate
NO2
O
O
CHO
O
O
molten TBAB, NH4OAc
(NH4)2.5H0.5 PW12O40
2 mol%
EtO
OEt
2
+
OEt
N
NO2
H
Number of recycles
Time (min)
Yield (%)
Fresh
4
96
93
92
92
2
3
4
6
10
14
reactions. The reactions proceeded smoothly with little increase in reaction time and
furnished yields between 92 and 96 %, indicating the catalyst can be reused without
significant loss of activity (Table 3).
To show the merit of (NH4)2.5H0.5PW12O40 in comparison with the other
catalysts used for similar reactions, we have listed some results in Table 4. As it is
evident from the results, the required ratio for most of the catalysts used for this
purpose is higher and also the required reaction times are much longer.
Conclusions
We have developed a novel and highly efficient method for synthesis of 1,4-DHP
and polyhydroquinoline derivatives by treatment of aromatic aldehydes with a 1,
123

S. N. Ghattali et al.
Table 4 Comparison of the Hantzsch reaction in the presence of different catalysts
Product
Catalyst
Catalyst molar Solvent
ratio
Time Yield (%)
(min) [Ref.]
(NH4)2.5H0.5PW12O40
PPh3
2
Molten TBAB 10
89
Cl
20
EtOH
120
60
81 [21]
90 [22]
89 [23]
SiO2 –RSO3H
HClO4–SiO2
0.1 g
0.05 g
Solvent-free
Solvent-free
O
O
20
EtO
OEt
N
H
3-dicarbonyl compound in the presence of (NH4)2.5H0.5PW12O40 as heterogeneous
catalyst. The novelty of this method is the use of molten (tetrabutylammonium
bromide) as reaction medium; it has a very low vapor pressure and is very stable. In
this medium (NH4)2.5H0.5PW12O40 acts as a heterogeneous catalyst. Many other
catalysts are soluble in this type of medium and cannot act as heterogeneous
catalysts and cannot be recovered. This method has such attractive features as
reduced reaction times, higher yields, using of a molten salt instead of organic
solvents, and economic reusability of the catalyst compared with conventional
methods and with other catalysts. The simple procedure combined with ease of
recovery and reuse of the catalyst makes this an economic and benign chemical
process for synthesis of 1,4-DHPs. The catalyst can be recovered by filtration
several times without significant loss of activity. In addition no cumbersome
apparatus is needed to perform this reaction.
Acknowledgments We gratefully acknowledge financial support from the Research Council of Shahid
Bahonar University of Kerman.
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