Catalytic synthesis of fused 1,4-dihydropyridines and 1,4-dihydropyridine derivatives using preyssler heteropolyacids catalyst

Article abstract of DOI:10.1080/00397911.2011.581405

An efficient and convenient method for the synthesis of 1,4-dihydropyridines from β-dicarbonyl compounds, aldehydes, and ammonium acetate and the synthesis of fused 1,4-dihydropyridines from dimedone in the presence of Preyssler heteropolyacid catalyst ar

Full text of DOI:10.1080/00397911.2011.581405

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Catalytic Synthesis of Fused
1,4-Dihydropyridines and 1,4-
Dihydropyridine Derivatives Using
Preyssler Heteropolyacids Catalyst
Ali Gharib a b , Manouchehr Jahangir a , Mina Roshani a & J. (Hans)
W. Scheeren c
a Department of Chemistry , Islamic Azad University , Mashhad , Iran
b Agricultural Researches and Services Center , Mashhad , Iran
c Cluster for Molecular Chemistry, Department of Organic
Chemistry , Radboud University, Nijmegen , The Netherlands
Accepted author version posted online: 12 Jan 2012.Published
online: 18 Jul 2012.
To cite this article: Ali Gharib , Manouchehr Jahangir , Mina Roshani & J. (Hans) W. Scheeren
(2012) Catalytic Synthesis of Fused 1,4-Dihydropyridines and 1,4-Dihydropyridine Derivatives
Using Preyssler Heteropolyacids Catalyst, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:22, 3311-3320, DOI:
10.1080/00397911.2011.581405
To link to this article: http://dx.doi.org/10.1080/00397911.2011.581405
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Synthetic Communications1, 42: 3311–3320, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.581405
CATALYTIC SYNTHESIS OF FUSED
1,4-DIHYDROPYRIDINES AND 1,4-DIHYDROPYRIDINE
DERIVATIVES USING PREYSSLER
HETEROPOLYACIDS CATALYST
Ali Gharib,1,2 Manouchehr Jahangir,1 Mina Roshani,1 and
J. (Hans) W. Scheeren3
1Department of Chemistry, Islamic Azad University, Mashhad, Iran
2Agricultural Researches and Services Center, Mashhad, Iran
3Cluster for Molecular Chemistry, Department of Organic Chemistry,
Radboud University, Nijmegen, The Netherlands
GRAPHICAL ABSTRACT
Abstract An efficient and convenient method for the synthesis of 1,4-dihydropyridines from
b-dicarbonyl compounds, aldehydes, and ammonium acetate and the synthesis of fused
1,4-dihydropyridines from dimedone in the presence of Preyssler heteropolyacid catalyst
are reported under reflux conditions with good to excellent yields. Preyssler heteropolyacid
catalyst is easily prepared, stable (up to 300 ꢀC), reusable, efficient, green and inexpensive.
Keywords 1,4-Dihydropyridines; dimedone; Hantzsch reaction; heteropolyacid; Preyssler
INTRODUCTION
Hantzsch 1,4-dihydropyridines are well known as Ca2þ channel blockers and
have emerged as an important class of drugs for the treatment of cardiovascular
diseases, including hypertension.[1] 1,4-Dihydropyridines possess a wide range
of biological activities, being vasodilators, bronchodilators, geroprotectives,
hepatoprotectives, and antitumor, antiatherosclerotic, and antidiabetic agents.[2]
Recent studies have revealed that 1,4-dihydropyridines exhibit several other
medicinal applications, including neuroprotectant[3] and platelet antiaggregator
Received April 7, 2011.
Address correspondence to Ali Gharib, Agricultural Researches & Service Center and Department
of Chemistry, Islamic Azad University, Mashhad, Iran. E-mail: aligharib5@yahoo.com
3311

3312
A. GHARIB ET AL.
activity,[4] in addition to acting as cerebral anti-ischemic agents in the treatment of
Alzheimer’s disease[5] and as a chemosensitizer in tumor therapy.[6] Development
of drug resistance, both intrinsic drug resistance and acquired drug resistance,
remains a clinical obstacle in the chemotherapy of many cancers.[7] Numerous
synthetic methods have been reported for the preparation of 1,4-dihydropyridine
derivatives under classical or modified conditions.[8] However, some of these meth-
ods suffer from long reaction times, poor yields, use of large quantities of volatile
organic solvents, harsh reaction conditions, and tedious workups; therefore,
development of an efficient and versatile method is still required. The applications
of heteropolyacids (HPAs) in the field of catalysis are growing continuously. These
compounds possess unique properties such as Brønsted acidity, possibility of mod-
ifying their acid–base and redox properties by changing their chemical composition
(substituted HPAs), ability to accept and release electrons, high proton mobility,
easy workup procedures, easy filtration, and minimization of cost and waste gener-
ation due to reuse and recycling of these catalysts.[9] Because of their stronger acid-
ity, they generally exhibit better catalytic activity than conventional catalysts such as
mineral acids, ion exchange resins, mixed oxides, and zeolites.[10] In the context of
green chemistry, the substitution of harmful liquid acids by solid reusable HPAs
as catalysts in organic synthesis is the most promising application of these acids.[11,12]
RESULTS AND DISCUSSION
We report an easy and efficient procedure for the synthesis of fused 1,4-
dihydropyridine derivatives 3a–g in good yields from dimedone (1) with various
arylaldehydes 2a–g and NH4OAc in water (Scheme 1) and the synthesis of 1,4-
dihydropyridine from substituted benzaldehydes, ethyl acetoacetate, and ammonium
acetate in water under reflux conditions catalyzed by Preyssler heteropolyacid
(Scheme 2).
Moreover, the catalyst was easily recovered and the high catalytic activity was
maintained even after the third reuse of the catalyst. The control reaction was carried
out on the aldehydes 2a and 2d in refluxing water without the Preyssler heteropolyacid
catalyst. Under these conditions the reaction proceeded smoothly, resulting in the
expected 1,4-dihydropyridine products after longer reactions times and in lower yields
(Table 1, entry a: 7 h, 59%; entry d: 8.5 h, 53%).
Scheme 1. Synthesis of fused 1,4-dihydropyridines (3a–g) from dimedone in the presence of Preyssler
heteropolyacid catalyst.

FUSED 1,4-DIHYDROPYRIDINES
3313
Scheme 2. Synthesis of 1,4-dihydropyridines (6a–g) from ethyl acetoacetate in the presence of Preyssler
heteropolyacid catalyst.
These results revealed that using Preyssler heteropolyacid as catalyst appreci-
ably shortens the reaction times and increases the product yields. All of the products
were fully characterized by spectroscopic methods (infrared [IR], 1H NMR, and 13
C
NMR). We performed the reactions of various aldehydes with ethyl acetoacetate and
ammonium acetate in water at reflux over Preyssler heteropolyacid catalyst. The
desired 1,4-dihydropyridine derivatives were obtained in good yields (Table 2, 6a–
g). It was evident that different aromatic aldehydes with ethyl acetoacetate and
ammonium acetate could be converted to the corresponding products in good yields
over the Preyssler heteropolyacid catalyst (Table 2).
The control reaction was carried out on the aldehydes 4a and 4 g in refluxing
water without the Preyssler heteropolyacid catalyst. Under these conditions the reac-
tion proceeded smoothly, resulting in the expected 1,4-dihydropyridine products after
longer reaction times and in lower yields (Table 2, entry a: 9 h, 59%; entry g: 8.0 h,
53%). Various substituents on the aromatic aldehydes including electron-donating
groups (such as hydroxyl and alkoxyl groups) and electron-withdrawing groups (such
as nitro or chloro groups) did not detrimentally affect the yields.
Table 1. Synthesis of fused 1,4-dihydropyridine derivatives (3a–g) using Preyssler heteropolyacid catalyst
in water under reflux conditions
Mp (ꢀC)
Time
(min)
Yield
(%)a,b
Entry
Aldehyde
Yield (%)c
Reported
Found
a
b
c
d
e
f
4-FC6H4CHO
180 (7 h)d
190
185
180 (8.5 h)d
130
135
85 (59)d
94
82
80 (53)d
84
87
85, 84, 82, 80
94, 92, 92, 91
81, 81, 80, 78
80, 79, 77, 75
83, 83, 81, 80
87, 85, 83, 82
85, 84, 82, 79
215–218[13]
305–307[13]
228–229[13]
217–219[13]
281–282[13]
273–275[13]
282–283[13]
216–217
303–305
228–230
218–220
280–283
274–276
281–282
3-BrC6H4CHO
4-ClC6H4CHO
2-ClC6H4CHO
2-NO2C6H4CHO
3-NO2C6H4CHO
4-NO2C6H4CHO
g
170
85
aIsolated yields.[13]
bAll the products were identified by spectroscopic analysis (IR, 1H NMR, 13C NMR).
cYields obtained in the first, second, and third use of the catalyst.
dThe control reaction was carried out on the aldehydes 2a and 2d in refluxing water without the
Preyssler heteropolyacid catalyst.

3314
A. GHARIB ET AL.
Table 2. Synthesis of 1,4-dihydropyridine derivatives (6a–g) using Preyssler heteropolyacid catalyst in
water under reflux conditions
Mp (ꢀC)
Time
(min)
Yield
(%)a,b
Yield
(%)c
Entry
Aldehyde
Reported
Found
a
195 (9.0 h)d
83 (59)d
83, 82, 81, 80
78, 78, 77, 74
130–131.5[14]
131–132
b
c
d
e
180
79
164–165.5[14]
124–125[14]
185–185.5[14]
169–171[14]
164–166
123–125
185–186.5
169–172
175
170
165
70
74
80
70, 69, 69, 67
73, 72, 72, 71
80, 79, 78, 77
f
175
75
75, 74, 72, 70
75, 74, 72, 71
121–122[14]
121–123
g
166 (8.0 h)d
76 (53)d
155–157[14]
154–156.5
aIsolated yields.[14]
bAll the products were Identified by spectroscopic analysis (IR, 1H NMR, 13C NMR).
cYields obtained in the first, second, and third use of the catalyst.
dThe control reaction was carried out on the aldehydes 4a and 4g in refluxing water without the
Preyssler heteropolyacid catalyst.
CONCLUSION
In conclusion, we have successfully developed an easy and efficient method to
prepare a variety of fused 1,4-dihydropyridine and 1,4-dihydropyridine derivatives
from the reaction of different aryl aldehydes, dimedone, ethyl acetoacetate,

FUSED 1,4-DIHYDROPYRIDINES
3315
ammonium acetate, and water in the presence of a catalytic amount of heteropolya-
cid under reflux conditions. Relatively short reaction times, very simple performance
and workup procedure, and good yields are some of advantages of this procedure.
The catalyst is recyclable and could be reused three times. Preyssler heteropolyacid
catalyst is also noncorrosive and environmentally benign and presents fewer disposal
problems. The use of this solid acid catalyst allows replacement of the usual soluble
inorganic acids, contributing in this way to the reduction of wastes.
EXPERIMENTAL
All chemicals were obtained from Merck and used as received. 1H NMR spectra
were recorded on a Fourier transform (FT) NMR Bruker 400-MHz spectrometer at
298 K. Melting points were recorded on an Electrothermal type 9100 melting-point
apparatus and were uncorrected. Chemical shifts were reported in parts per million
(ppm, d scale) relative to internal standard tetramethylsilane (TMS) (0.00 ppm); the
solvent was used as a reference. IR spectra were obtained with a Buck 500 scientific
spectrometer (KBr pellets). The products were identified by comparison of their
melting points (mp), IR, and NMR spectra with those of authentic samples.
Catalyst Preparation
Preyssler catalyst, H14[NaP5W30O110], was prepared by passage of a solution of
the potassium salt (30 mL) in water (30 mL) through a column (50 cmꢁ 1 cm) of Dowex
50w ꢁ 8 in the Hþ form. The eluent was evaporated to dryness under vacuum.[15–18]
Synthesis of Fused 1,4-Dihydropyridines
A mixture of dimedone (20 mmol), aryl aldehyde (10 mmol), NH4OAc
(10 mmol), and Preyssler heteropolyacid catalyst (0.01 g) in water (10 mL) was heated
at reflux for the required reaction time (Table 1). The progress of the reaction was
monitored by thin-layer chromatography (TLC; EtOAc–petroleum ether 3:1). After
completion of the reaction, the catalyst was filtered, following by washing with ethyl
acetate (3 ꢁ 30 mL). Then the reaction mixture was cooled to room temperature,
extracted with EtOAc, followed by a water and brine solution, dried with anhydrous
Na2SO4, and filtered. The filtrate was concentrated under vacuum, and the residue
was recrystallized from ethanol to produce the fused 1,4-dihydropyridine derivatives
(3a–g) as pure crystalline products in 80–94% yields.
9-(4-Fluorophenyl)-3,3,6,6-tetramethyl-3,4,6,7-tetrahydroacridine-1,8(2H,
5H,9H,10H)-dione (3a)[13]. Yellow solid, yield: 85%, mp 216–217 ꢀC; IR (KBr)
1
n
max=cmꢂ1: 3353, 3045, 2955, 1618, 1499, 1364, 1223, 1146. H NMR (400 MHz,
CDCl3): d 0.97 (s, 6H), 1.10 (s, 6H), 2.38 (m, 8H), 5.10 (s, 1H), 6.92 (m, 2H), 7.30
(m, 2H), 8.32 (s, 1H); 13C NMR (100 MHz, CDCl3): d 27.3 (CH3, aliphatic), 30.0
(CH, aliphatic), 33.1 (C, aliphatic), 41.2 (CH, aliphatic), 51.3 (CH2, aliphatic),
113.3 (CH, benzene), 115.3 (CH, benzene), 129.8 (CH, benzene), 143.0 (C, benzene),
149.7 (C, 1-ethylene), 162.6 (C-F, benzene), 196.5 (C, carbonyl); MS m=z (rel. int.%):

3316
A. GHARIB ET AL.
367.19 [Mþ] (89), 272.17 (18.3), 28(100). Anal. calcd. for C23H26FNO2: C, 75.18; H,
7.12; N, 3.81. Found: C, 75.36; H, 7.20; N, 3.65.
9-(3-Bromophenyl)-3,3,6,6-tetramethyl-3,4,6,7-tetrahydroacridine-1,8(2H,
5H,9H,10H)-dione (3b)[13]. White solid, yield: 94%, mp 303–305 ꢀC; IR (KBr) nmax
=
cmꢂ1: 3282, 3080, 2970, 1644, 1555, 1255, 1220. 1H NMR (400 MHz, CDCl3): d 1.03
(s, 6H), 1.14 (s, 6H), 2.35 (m, 8H), 5.07 (s, 1H), 7.14 (1 ꢁ t, J ¼ 7.7 Hz, 1H), 7.27 (2 ꢁ
d, J ¼ 7.7 Hz, 1H), 7.35 (1 ꢁ t, J ¼ 7.5 Hz, 1H), 7.45 (1 ꢁ s, 1H), 7.96 (1 x s, 1H); 13
C
NMR (100 MHz, CDCl3): d 27.4, 30.3, 33.1, 41.2, 51.3, 113.2, 122.8, 127.6, 129.5,
130.0, 131.5, 149.3, 149.9, 196.5; MS m=z (rel. int.%): 427.11 [Mþ] (86), 272.11
(15.3), 274.15 (7.1). Anal. calcd. for C23H26BrNO2: C, 64.49; H, 6.11; N, 3.27.
Found: C, 64.62; H, 6.30; N, 3.09.
9-(4-Chlorophenyl)-3,3,6,6-tetramethyl-3,4,6,7-tetrahydroacridine-1,8(2H,
5H,9H,10H)-dione (3c)[13]. White solid, yield: 82%, mp 228–230 ꢀC; IR (KBr) nmax
=
cmꢂ1: 3428, 3178, 3064, 2958, 1642, 1605, 1489, 1224, 1143. H NMR (400 MHz,
CDCl3): d 1.04 (s, 6H), 1.17 (s, 6H), 3.30 (m, 8H), 5.53 (s, 1H), 7.20 (d, J ¼ 8.3 Hz,
Hz, 2H), 7.34 (d, J ¼ 8.3 Hz, 2H), 8.05 (s, 1H); 13C NMR (100 MHz, CDCl3): d 27.5,
30.0, 33.0, 41.1, 51.2, 113.3, 128.5, 129.9, 132.0, 145.6, 149.7, 196.8; MS m=z (rel.
int.%): 383.17 [Mþ] (88), 272.17 (18.8). Anal. calcd. for C23H26ClNO2: C, 71.96;
H, 6.82; N, 3.65. Found: C, 71.80; H, 6.73; N, 3.50.
1
9-(2-Chlorophenyl)-3,3,6,6-tetramethyl-3,4,6,7-tetrahydroacridine-1,8(2H,
5H,9H,10H)-dione (3d)[13]. White solid, yield: 80%, mp 218–220 ꢀC; IR (KBr) nmax
=
cmꢂ1: 3400, 2983, 1662, 1620, 1465, 1354, 1200. 1H NMR (400 MHz, CDCl3): d 1.06
(s, 6H), 1.15 (s, 6H), 2.33 (m, 4H), 2.60 (m, 4H), 5.05 (s, 1H), 7.08 (t, J ¼ 7.2 Hz, 1H),
7.15 (m, 1H), 7.24 (d, J ¼ 7.5 Hz, 1H), 7.45 (d, J ¼ 6.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d 27.7, 29.6, 32.5, 41.4, 51.3, 114.2, 126.7, 127.6, 128.3, 130.5, 133.9, 149.3,
163.5, 197.5; MS m=z (rel. int.%): 383.17 [Mþ] (80), 272.17 (18.7). Anal. calcd. for
C23H26ClNO2: C, 71.96; H, 6.82; N, 3.65. Found: C, 71.70; H, 6.58; N, 3.83.
3,3,6,6-Tetramethyl-9-(2-nitrophenyl)-3,4,6,7-tetrahydroacridine-1,8(2H,
5H,9H,10H)-dione (3e)[13]. Brown solid, yield: 84%, mp 280–283 ꢀC, IR (KBr)
n
max=cmꢂ1: 3450, 3082, 2981,1650, 1525, 1483, 1364, 1220, 1145. 1H NMR
(400 MHz, CDCl3): d 0.95 (s, 6H), 1.05 (s, 6H), 2.45 (m, 8H), 5.80 (s, 1H), 7.23 (t,
J ¼ 6.9 Hz, 1H), 7.37 (d, J ¼ 6.8 Hz, 1H), 7.46 (m, 2H); 13C NMR (100 MHz, CDCl3):
d 27.7, 29.5, 32.8, 41.4, 51.3, 112.9, 124.6, 127.0, 132.5, 134.4, 141.3, 149.5, 149.6,
195.9; MS m=z (rel. int.%): 394.19 [Mþ] (89), 272.17 (18.9). Anal. calcd. for
C23H26N2O4: C, 70.03; H, 6.63; N, 7.10. Found: C, 69.90; H, 6.77; N, 7.38.
3,3,6,6-Tetramethyl-9-(3-nitrophenyl)-3,4,6,7-tetrahydroacridine-1,8(2H,
5H,9H,10H)-dione (3f)[13]. White solid, yield: 87%, mp 274–276 ꢀC; IR (KBr) nmax
=
cmꢂ1: 3380, 3062, 2960, 1646, 1610, 1520, 1484, 1360, 1344, 1225, 1145. H NMR
(400 MHz, CDCl3): d 0.85 (s, 6H), 1.02 (s, 6H), 2.0 (d, J ¼ 16.3 Hz, 2H), 2.14 (d,
J ¼ 16.3 Hz, 2H), 2.27 (d, J ¼ 17.1 Hz, 2H), 2.35 (d, J ¼ 17.1 Hz, 2H), 5.04 (s, 1H),
7.31 (t, J ¼ 7.86 Hz, 1H), 7.65 (d, J ¼ 6.9 Hz, 1H), 7.84 (d, J ¼ 8.1 Hz, 1H), 8.01
(s, 1H), 8.91 (s, br., 1H); 13C NMR (100 MHz, CDCl3): d 27.5, 29.7, 32.9, 34.5,
51.2, 112.3, 121.2, 123.4, 130.1, 135.3, 148.4, 149.5, 150.2, 195.7; MS m=z
1

FUSED 1,4-DIHYDROPYRIDINES
3317
(rel. int.%): 394.19 [Mþ] (78), 272.17 (18.8). Anal. calcd. for C23H26N2O4: C, 70.03;
H, 6.63; N, 7.10. Found: C, 69.84; H, 6.50; N, 7.31.
3,3,6,6-Tetramethyl-9-(4-nitrophenyl)-3,4,6,7-tetrahydroacridine-1,8(2H,
5H,9H,10H)-dione (3g)[13]. Orange solid, yield: 85%, mp 281–282 ꢀC; IR (KBr)
n
max=cmꢂ1: 3385, 3072, 2955, 1643, 1517, 1478, 1342, 1219, 1165. 1H NMR
(400 MHz, CDCl3): d 0.85 (s, 6H), 1.01 (s, 6H), 2.03 (d, J ¼ 16.3 Hz, 2H), 2.16 (d,
J ¼ 16.3 Hz, 2H), 2.25 (d, J ¼ 17.0 Hz, 2H), 2.34 (d, J ¼ 17.0 Hz, 2H), 5.06 (s, 1H),
7.43 (d, J ¼ 8.5 Hz, 2H), 7.96 (d, J ¼ 6.9 Hz, 2H), 8.50 (s, 1H); 13C NMR
(100 MHz, CDCl3): d 27.5, 29.8, 32.9, 34.9, 51.2, 112.4, 123.5, 129.4, 146.2, 149.7,
154.9, 195.5; MS m=z (rel. int.%): 394.19 [Mþ] (89), 272.17 (18.7). Anal. calcd. for
C23H26N2O4: C, 70.03; H, 6.63; N, 7.10. Found: C, 69.90; H, 6.79; N, 7.30.
Synthesis of 1,4-Dihydropyridines
A mixture of aldehyde (10 mmol), ethyl acetoacetate (20 mmol), NH4OAc
(10 mmol), and Preyssler heteropolyacid catalyst (0.01 g) in water (20 mL) was heated
under reflux conditions with stirring for the required reaction time. After completion
of the reaction (as indicated by TLC), the catalyst was filtered and washed with ethyl
acetate (3 ꢁ 30 mL). Then the reaction mixture was washed with ice-cold water,
cooled, extracted with EtOAc, followed by a water and brine solution, dried with
anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum, and
the residue was recrystallized from ethanol to produce fused 1,4-dihydropyridine
derivatives (6a–g) as pure crystalline products in 70–83% yields.
2,6-Dimethyl-3,5-dicarboethoxy-4-(2-chlorophenyl)-1,4-dihydropyridine
(6a)[14]. White solid, yield: 83%, mp 131–132 ꢀC, IR (KBr) nmax=cmꢂ1: 3351, 3105,
2985, 2850, 1705, 1699, 1300, 1486, 1214, 1100; 1H NMR (400 MHz, CDCl3): d 1.28
(t, J ¼ 8.02 Hz, 6H, CH3), 2.25 (s, 6H, CH3), 4.06 (m, 4H, CH2), 5.45 (s, 1H, CH),
6.00 (br, s, NH), 7.05 (dt, J ¼ 7.2 Hz, J ¼ 1.6 Hz, 1H, Ar-H), 7.14 (dt, J ¼ 7.2 Hz,
J ¼ 1.6 Hz, 1H, Ar-H), 7.24 (dd, J ¼ 8.0 Hz, J ¼ 1.6 Hz, 1H, Ar-H), 7.38 (dd,
J ¼ 8.0 Hz, J ¼ 1.6 Hz, 1H, Ar-H). 13C NMR (100 MHz, CDCl3): d 19.9, 39.0,
62.2, 127.3,126.9, 132.0, 144.0, 150.7, 167.2. MS m=z (rel. int.%): 364.90 (Mþ þ 1,
21.2), 275.57, 219.70, 185.26, 171.23, 157.21, 144.21. Anal. calcd. for C19H22ClNO4:
C, 62.72; H, 6.09; N, 3.85. Found C, 61.59; H, 5.37; N, 3.02.
2,6-Dimethyl-3,5-dicarboethoxy-4-(2-methoxyphenyl)-1,4-dihydropyr-
idine (6b)[14]. White solid, yield: 79%, mp 164–166 ꢀC; IR (KBr) nmax=cmꢂ1: 3329,
3095, 2870, 1689, 1675, 1644, 1619, 1492, 1284, 1385, 1304, 1283, 1210, 1120, 745; 1H
NMR (400 MHz, CDCl3): d 1.19 (t, J ¼ 7.1 Hz, 6H, CH3), 2.25 (s, 6H, CH3), 3.75
(s, 3H, O-CH3), 4.05 (q, J ¼ 7.1 Hz, 4H, CH2), 5.29 (s, 1H, CH), 5.72 (br, s, NH),
6.80 (m, 2H, Ar-H,), 7.07 (dt, J ¼ 7.7 Hz, J ¼ 1.4 Hz, 1H, Ar-H), 7.22 (dd, J ¼ 7.4 Hz,
J ¼ 1.5 Hz, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): d 14.1, 19.3, 35.3, 55.2, 59.4,
103.1, 110.6, 119.9, 127.2, 130.6, 135.6, 143.6, 157.1, 168.5. MS m=z (rel. int.%):
360.44 (Mþ þ 1, 41.2), 331.81, 287.31, 243.25, 187.23, 157.21. Anal. calcd. for
C20H25NO5: C, 66.83; H, 7.01; N, 3.90. Found C, 66.00; H, 7.30; N, 3.45.
2,6-Dimethyl-3,5-dicarboethoxy-4-(3-methoxyphenyl)-1,4-dihydropyr-
idine (6c)[14]. White solid, yield: 70%, mp 123–125 ꢀC; IR (KBr) nmax=cmꢂ1: 3315,

3318
A. GHARIB ET AL.
1
3087, 2985, 1680, 1643, 1605, 1484, 1303, 1277, 1208, 1120, 1017, 805; H NMR
(400 MHz, CDCl3): d 1.24 (t, J ¼ 7.20 Hz, 6H, CH3), 2.33 (s, 6H, CH3), 3.75 (s,
3H, O-CH3), 4.09 (m, 4H, CH2), 4.97 (s, 1H, CH), 5.88 (br, s, NH), 6.68 (dd,
J ¼ 8.1 Hz, J2 ¼ 2.4 Hz, 1H, Ar-H), 6.86 (m, 2H, Ar-H), 7.14 (t, J ¼ 8.1 Hz, 1H,
Ar-H). 13C NMR (100 MHz, CDCl3): d 19.8, 44.5, 112.0, 130.0, 120.3, 144.5,
151.0, 160.8. MS m=z (rel. int.%): 360.44 (Mþ þ 1, 41.2), 331.81, 287.31, 243.25,
187.23, 157.21. Anal. calcd. for C20H25NO5: C, 66.83; H, 7.01; N, 3.92. Found C,
66.04; H, 7.30; N, 3.43.
2,6-Dimethyl-3,5-dicarboethoxy-4-(3-hydroxyphenyl)-1,4-dihydropyri-
dine (6d)[14]. White solid, yield: 74%, mp 185–186.5 ꢀC; IR (KBr) nmax=cmꢂ1: 3450,
1
3350, 2978, 1653, 1596, 1215, 1129, 1017; H NMR (400 MHz, CDCl3): d 1.27 (t,
J ¼ 7.20 Hz, 6H, CH3), 2.35 (s, 6H, CH3), 4.12 (m, 4H, CH2), 4.65 (s, 1H, OH),
4.96 (s, 1H, CH), 5.55 (br, s, NH), 6.63 (dd, J ¼ 8.1 Hz, J ¼ 2.4 Hz, 1H, Ar-H),
6.75 (s, 1H, Ar-H), 6.88 (d, J ¼ 8.1 Hz, 1H, Ar-H), 7.26 (t, J ¼ 8.1 Hz, 1H, Ar-H).
13C NMR (100 MHz, CDCl3): d 15.5, 20.2, 44.5, 103.2, 115.5, 122.0, 130.2, 144.3,
151.1, 158.4, 168.3. MS m=z (rel. int.%): 346.81 (Mþ þ 1, 12.3), 310.45, 257.81,
201.48, 187.22, 173.28, 157.21. Anal. calcd. for C19H23NO5: C, 66.08; H, 6.72; N,
4.06, Found: C, 65.03; H, 7.10; N, 3.97.
2,6-Dimethyl-3,5-dicarboethoxy-4-(3-nitrophenyl)-1,4-dihydropyridine
(6e)[14]. Brown solid, yield: 80%, mp 169-172 ꢀC, IR (KBr) nmax=cmꢂ1: 3350, 3083,
2980, 1705, 1640, 1525, 1486, 1344, 1300, 1212, 1114; 1H NMR (400 MHz, CDCl3): d
1.20 (t, J ¼ 7.0 Hz, 6H, CH3), 2.36 (s, 6H, CH3), 4.14 (q, J ¼ 7.0 Hz, 4H, CH2), 5.09
(s, 1H, CH), 6.14 (br, s, NH), 7.37 (t, J ¼ 8.0 Hz, 1H, Ar-H,), 7.64 (d, J ¼ 8.0 Hz, 1H,
Ar-H), 8.03 (d, J ¼ 8.0 Hz, 1H, Ar-H), 8.14 (s, 1H, Ar-H). 13C NMR (100 MHz,
CDCl3): d 20.2, 43.3, 62.1, 122.2, 135.2, 148.0, 145.4, 151.3, 168.2. MS m=z (rel.
int.%): 375.22 (Mþ þ 1, 21.2), 286.26, 185.26, 171.23, 157.21. Anal. calcd. for
C20H25NO5: C, 60.95; H, 5.92; N, 7.48. Found: C, 59.34; H, 5.12; N, 7.01.
2,6-Dimethyl-3,5-dicarboethoxy-4-(4-methylphenyl)-1,4-dihydropyri-
dine (6f)[14]. White solid, yield: 75%, mp 121–123 ꢀC, IR (KBr) nmax=cmꢂ1: 3365,
3094, 2979, 1696, 1653, 1487, 1332, 1211, 1117, 1096; H NMR (400 MHz, CDCl3):
1
d 1.24 (t, J ¼ 7.2 Hz, 6H, CH3), 2.25 (s, 3H, Ar-CH3), 2.32 (s, 6H, CH3), 4.07 (q,
J ¼ 7.2 Hz, 4H, CH2), 4.95 (s, 1H, CH), 5.65 (br, s, NH), 7.16 (d, J ¼ 8.0 Hz, 2H,
Ar-H,), 7.15 (d, J ¼ 8.0 Hz, 2H, Ar-H). 13C NMR (100 MHz, CDCl3): d 20.2, 44.1,
62.2, 103.0, 129.4, 135.5, 142.2, 151.3, 168.4. MS m=z (rel. int.%): 343.18 (Mþ þ 1,
59.9), 252.12, 257.14, 253.13, 185.12, 167.09, 153.08. Anal. calcd. for C20H25NO4:
C, 69.95; H, 5.92; N, 7.34. Found: C, 59.89; H, 5.39; N, 7.38.
2,6-Dimethyl-3,5-dicarboethoxy-4-phenyl-1,4-dihydropyridine (6g)[14]
.
White solid, yield: 76%, mp 154–156.5 ꢀC, IR (KBr) nmax=cmꢂ1: 3345, 3063, 2982,
1687, 1686, 1650, 1489, 1455,1372, 1321, 1213, 1121, 1090, 705; 1H NMR (400 MHz,
CDCl3): d 1.22 (t, J ¼ 7.1 Hz, 6H, CH3), 2.35 (s, 6H, CH3), 4.10 (m, 4H, CH2), 4.96
(s, 1H, CH), 5.63 (br, s, NH), 7.20 (m, 5H, Ar-H).13C NMR (100 MHz, CDCl3): d
19.5, 44.4, 62.2, 103.0, 127.6, 145.5, 151.5, 168.3. MS m=z (rel. int.%): 330.39
(Mþ þ 1, 38.9), 285.33, 253.39, 241.28, 185.26, 171.23, 157.21, 81.11, 68.11. Anal.
calcd. for C19H23NO4: C, 69.28; H, 7.04; N, 4.25. Found: C, 69.01; H, 6.94; N, 4.35.

FUSED 1,4-DIHYDROPYRIDINES
3319
Catalyst Reusability
At the end of the reaction, the catalysts could be recovered by a simple
filtration. It is noteworthy that the catalyst may be reused without significant loss
of activity. To know whether the catalyst would succumb to poisoning and lose its
catalytic activity during the reaction, we investigated the reusability of the catalyst.
For this purpose, we first carried out the reaction in the presence of the catalyst.
After completion of the reaction, the catalyst was removed, washed with diethyl
ether (10 mL), and subjected to second, third, and fourth runs of the reaction process
with the same substrates.
ACKNOWLEDGMENTS
The authors are thankful to the Agricultural Researches and Services Center,
Mashhad, Feyzabad, Iran; Mashhad Islamic Azad University; Chemistry Department,
University of Oslo, Norway; and National Research Council Canada for support of
this work. Special thanks go to J. (Hans) W. Scheeren from the Organic Chemistry
Department, Radboud University, Nijmegen, the Netherlands.
REFERENCES
1. Bossert, F.; Meyer, H.; Wehinger, E. Aryldihydropyridines, a new class of highly active
calcium antagonists. Angew. Chem., Int. Ed. Engl. 1981, 20, 762–769.
2. Godfraid, T.; Miller, R.; Wibo, M. Calcium antagonism and calcium entry blockade.
Pharmocol. Rev. 1986, 38, 321–416.
3. Goldmann, S.; Stoltefuss, J. 1,4-Dihydropyridines: Effects of chirality and conformation
on the calcium antagonist and calcium agonist activities. Angew. Chem., Int. Ed. Engl.
1991, 30, 1559–1578.
4. Bretzel, R. G.; Bollen, C. C.; Maeser, E.; Federlin, K. F. Nephroprotective effects of
nitrendipine in hypertensive type I and type II diabetic patients. Am. J. Kidney. Dis.
1993, 21, S53–S64.
5. Sulzbach, R. A.; Iqbal, A. F. M. Addition of acrylonitrile to derivatives of 1,4-dihydropyr-
idine. Angew. Chem., Int. Ed. Engl. 1971, 10, 733.
6. Kvita, V.; Hans-Peter, S. Substituted a-pyrones as starting compounds for the synthesis of
4,4-disubstituted 1,4-dihydropyridines. Angew. Chem., Int. Ed. Engl. 2003, 26, 790–791.
7. Davis, H. L.; Davis, T. E. Daunorubicin and adriamycin in cancer treatment: An analysis
of their roles and limitations. Cancer Treat. Rep. 1979, 63, 809–815.
8. Ohberg, L.; Wesman, J. An efficient and fast procedure for the Hantzsch dihydropyridine
synthesis under microwave conditions. Synlett 2001, 1296–1298.
9. Heravi, M. M.; Rajabzadeh, G.; Bamoharram, F. F.; Seifi, N. An eco-friendly catalytic
route for synthesis of 4-amino-pyrazolo[3,4-d]pyrimidine derivatives by Keggin heteropo-
lyacids under classical heating and microwave irradiation. J. Mol. Catal. A: Chem. 2006,
256, 238–241.
10. Bamoharram, F. F.; Heravi, M. M.; Roshani, M.; Gharib, A.; Jahangir, M. A catalytic
method for synthesis of c-butyrolactone, e-caprolactone, and 2-cumaranone in the presence
of Preyssler’s anion, [NaP5W30O110]
14ꢂ, as a green and reusable catalyst. J. Mol. Catal. A:
Chem. 2006, 252, 90–95.
11. Heravi, M. M.; Motamedi, R.; Seifi, N.; Bamoharram, F. F. Catalytic synthesis of 6-aryl-
1H-pyrazolo[3,4-d]pyrimidin-4[5H]-ones by heteropolyacid: H14[NaP5W30O110] and
H3PW12O40. J. Mol. Catal. A: Chem. 2006, 249, 1–3.

3320
A. GHARIB ET AL.
12. Bamoharram, F. F.; Heravi, M. M.; Roshani, M.; Akbarpour, M. Catalytic performance
of Preyssler heteropolyacid as a green and recyclable catalyst in oxidation of primary
aromatic amines. J. Mol. Catal. A: Chem. 2006, 255, 193–198.
13. Nikpassand, N.; Mamaghani, M.; Tabatabaeian, K. An efficient one-pot three-component
synthesis of fused 1,4-dihydropyridines using HY-zeolite. Molecules 2009, 14, 1468–1474.
14. Zonouz, A. M.; Sahranavard, N. Synthesis of 1,4-dihydropyridine derivatives under
aqueous media. E-J. Chem. 2010, 7 (S1), S372–S376.
15. Misono, M.; Ono, L.; Koyano, G.; Aoshima, A. Heteropolyacids: Versatile green catalysts
usable in a variety of reaction media. Pure Appl. Chem. 2000, 72, 1305–1311.
16. Pope, M. T.; Muller, A. Polyoxometalates: From Platonic Solids to Anti-Retroviral
Activity; Kluwer Academic Publishers: Dordrecht, the Netherlands, 1994.
17. Hekmatshoar, R.; Sajadi, S.; Heravi, M. M.; Bamoharram, F. F. H14[NaP5W30O110] as a
heterogeneous recyclable catalyst for the air oxidation of thiols under solvent-free
conditions. Molecules. 2007, 12, 2223–2228.
18. Alizadeh, M. H.; Harmalker, S. P.; Jeannin, Y.; Martin-Frere, J.; Pope, M. T. A hetero-
polyanion with fivefold molecular symmetry that contains a nonlabile encapsulated
sodium ion: The structure and chemistry of [NaP5W30O110]
14-. J. Am. Chem. Soc. 1985,
107, 2662–2669.