An efficient one-pot three-component synthesis of fused 1,4-dihydropyridines using HY-zeolite

Article abstract of DOI:10.3390/molecules14041468

A facile and convenient protocol was developed for the fast (2.5-3.5 h) and high yielding (70-90 %) synthesis of fused 1,4-dihydropyridines from dimedone in the presence of HY-zeolite as an efficient recyclable heterogeneous catalyst.

Full text of DOI:10.3390/molecules14041468

Molecules 2009, 14, 1468-1474; doi:10.3390/molecules14041468
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
An Efficient One-Pot Three-Component Synthesis of Fused 1,4-
Dihydropyridines Using HY-Zeolite
Mohammad Nikpassand, Manouchehr Mamaghani * and Khalil Tabatabaeian
Department of Chemistry, Faculty of Sciences, University of Guilan, P. O. Box 41335-1914, Rasht,
Iran; E-mails: nikpassand@guilan.ac.ir (M.N.), taba@guilan.ac.ir (K.T.)
* Author to whom correspondence should be addressed; E-mail: m-chem41@guilan.ac.ir.
Received: 6 March 2009; in revised form: 19 March 2009 / Accepted: 30 March 2009 /
Published: 8 April 2009
Abstract: A facile and convenient protocol was developed for the fast (2.5-3.5 h) and high
yielding (70-90 %) synthesis of fused 1,4-dihydropyridines from dimedone in the presence
of HY-zeolite as an efficient recyclable heterogeneous catalyst.
Keywords: 1,4-Dihydropyridine; Dimedone; NH4OAc; One-Pot Conversion; HY-Zeolite.
1. Introduction
1,4-Dihydropyridines represent an important class of compounds which are found in many
biologically active products, such as vasodilator, bronchodilator, anti-atherosclerotic, antitumor,
geroprotective, hepatoprotective and antidiabetic agents [1]. Numerous synthetic methods have been
reported for the preparation of 1,4-dihydropyridine derivatives under classical or modified conditions
[2-10]. However, some of these methods suffer from long reaction times, low 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.
HY-zeolite is unique acid heterogeneous catalyst that has become popular over the last two
decades. It is used in various chemical transformations, such as liquid phase acylation of amines [11],
direct conversion of aldehydes into amines [12], selective removal of N-Boc protecting groups from
aromatic amines [13], one-pot synthesis of 2,3-dihydro-2,2-dimethylbenzofurans [14], and one-pot
syntheses of polyhydroquinolines [15].

Molecules 2009, 14
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This remarkable catalytic activity together with easy availability, operational simplicity and
recoverability of HY-zeolite encouraged us to utilize this catalyst for the synthesis of fused 1,4-
dihydropyridine derivatives.
2. Results and Discussion
Recent developments in 1,4-dihydropyridine chemistry and our continued interest in the
development of efficient and environmentally friendly procedures for the synthesis of heterocyclic
compounds [16-23], prompted us to study the conversion of dimedone into fused 1,4-dihydropyridines
in the presence of HY zeolite (Si/Al: 2.54). The reaction of dimedone (1, 2 eq.) with 1 equiv. of each
of various arylaldehydes 2a-i and NH4OAc in EtOH in the presence of HY-zeolite furnished the
desired fused 1,4-dihydropyridine derivatives 3a-i (Scheme 1) in reasonable reaction times (2.5-3.5 h)
and high yields (70-90%) (Table 1). Moreover, the catalyst was easily recovered and the high catalytic
activity was maintained even after third reuse of the catalyst.
Scheme 1. Synthesis of 1,4-dihydropyridines from dimedone in the presence of HY-zeolite.
O
Ar
O
O
O
HY-zeolite
+ ArCHO
NH4OAc
EtOH
reflux
N
H
3a-i
1
2a-i
Ar: 2-NO2C6H4, 3-NO2C6H4, 4-NO2C6H4, 2-ClC6H4, 4-ClC6H4, 3-BrC6H4, 4-FC6H4,
CHO
CHO
CHO
CHO
O(CH2)6O
O(CH2)4O
,
The reaction, using substrate 2a, was also performed in the presence of CH3CO2H (1 mL/mmol
substrate, 5 h, 67%), ZnCl2 (0.01 g/mmol substrate, 6 h, 65%) and RuCl3 (0.01 g/mmol substrate, 5.5
h, 70%) under optimized condition, which furnished the desired product after longer reaction times
and in lower yields. The control reaction was carried out on the substrates 2a and 2d in refluxing
ethanol without the zeolite catalyst. Under this classical condition the reaction proceeded smoothly
resulting in the expected 1,4-dihydropyridine products after longer reaction times and in lower yields
(2a: 6.5 h, 65%; 2d: 8.0 h, 63%). These results revealed that using HY-zeolite as catalyst appreciably
shortens the reaction times and increases the product yields. All of the products were fully
characterized by spectroscopic methods (IR, 1H-NMR, 13C-NMR) and elemental analysis.

Molecules 2009, 14
Table 1. Synthesis of fused 1,4-dihydropyridine derivatives (3a-i) using HY-zeolite.
1470
Entry
Aldehyde
Time (h)
2.5 (6.5)3
Yield (%)1,2
a
b
c
d
e
f
2-NO2 C6H4CHO
3-NO2 C6H4CHO
4-NO2 C6H4CHO
2-ClC6H4CHO
4-ClC6H4CHO
3-BrC6H4CHO
4-FC6H4CHO
75 (65)3
2.5
83
3.0
3.5 (8.0)3
79
75 (63)3
3.5
77
3.0
90
g
3.5
70
CHO
CHO
O(CH2)6O
h
3.5
82
CHO
CHO
O(CH2)4O
i
3.5
78
2
1
1 Isolated yields; All the products were Identified by spectroscopic (IR, H-NMR, 13C-
NMR) and elemental analyses. 3A mixture of dimedone (20 mmol), aryl aldehydes (2a, 2d)
(10 mmol) and NH4OAc (10 mmol) in EtOH (10 mL) was refluxed for the required
reaction time, after which removal of the solvent produced the desired products 3a and 3d
in 65% and 63% yields, respectively.
Conclusions
In summary, we report a simple protocol for the synthesis of fused 1,4-dihydropyridines using HY
zeolite as an efficient catalyst. The simplicity, easy workup, together with the use of inexpensive,
environmentally friendly and reusabile catalyst, are the notable features of this catalytic procedure.
3. Experimental
3.1. General
Melting points were measured on an Electrothermal 9100 apparatus. IR spectra were determined on
a Shimadzo IR-470 spectrometer. 1H-NMR and 13C-NMR spectra were recorded on a 500 MHz Bruker
DRX-500 in CDCl3 as solvent and with TMS as internal standard. Chemicals were purchased from
Merck and Fluka. Elemental analyses were done on a Carlo-Erba EA1110CNNO-S analyzer and
agreed with the calculated values. All solvents used were dried and distilled according to standard
procedures.

Molecules 2009, 14
1471
3.2. General procedure for the synthesis of 3a-i in the presence of HY-zeolite
A mixture of dimedone (20 mmol), aryl aldehydes (10 mmol), NH4OAc (10 mmol), HY-zeolite (0.1
g) in EtOH (10 mL) was refluxed for the required reaction time (Table 1). The progress of the reaction
was monitored by TLC (EtOAc: petroleum ether 3:1). After completion of the reaction, the mixture
was cooled to room temperature and filtered. The filtrate was concentrated under vacuum and the
residue was recrystallized from ethanol to produce 1,4-dihydropyridine derivatives 3a-i as pure
crystalline products in 70-90% yields.
3,3,6,6-Tetramethyl-9-(2-nitrophenyl)-3,4,6,7-tetrahydroacridine-1,8(2H,5H,9H,10H)-dione
(3a):
Brown solid, mp 281-282 C; 1H-NMR δ 0.96 (s, 6H), 1.06 (s, 6H), 2.23- 2.46 (m, 8H), 5.80 (s, 1H),
7.21 (t, J = 6.99 Hz, 1H), 7.30- 7.35 (d, J = 6.81 Hz, 1H), 7.41- 7.48 (m, 2H); 13C-NMR δ 27.8, 29.5,
32.9, 41.2, 51.1, 112.9, 124.5, 127.0, 132.5, 134.2, 141.2, 149.6, 149.8, 195.9; IR (neat, cm-1) 3450,
3080, 2980,1650, 1520, 1480, 1360, 1220, 1140. Anal. Calcd. for C23H26N2O4: C, 70.03; H, 6.63; N,
7.10. Found: C, 70.25; H, 6.48; N, 7.02.
o
3,3,6,6-Tetramethyl-9-(3-nitrophenyl)-3,4,6,7-tetrahydroacridine-1,8(2H,5H,9H,10H)-dione (3b): Off
white solid, mp 273-275 oC; 1H-NMR δ 0.86 (s, 6H), 1.01 (s, 6H), 2.0 (d, J = 16.3 Hz , 2H ), 2.10 (d, J
= 16.3 Hz , 2H), 2.28 (d, J = 17.1 Hz, 2H), 2.35 (d, J = 17.1 Hz, 2H), 5.01 (s, 1H), 7.29 (t, J = 7.86 Hz,
1H), 7.65 (d, J= 6.9 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 8.02 (s, 1H), 8.90 (s, br., 1H) ; 13C-NMR δ 27.4,
29.9, 32.9, 34.4, 51.1, 112.2, 121.2, 123.1, 130.0, 135.2, 148.4, 149.6, 150.2, 195.6; IR (neat, cm-1)
3380, 3060, 2960, 1645, 1610, 1520, 1480, 1360, 1340, 1220, 1140. Anal. Calcd. for C23H26N2O4: C,
70.03; H, 6.63; N, 7.10. Found: C, 69.88; H, 6.52; N, 7.28.
3,3,6,6-Tetramethyl-9-(4-nitrophenyl)-3,4,6,7-tetrahydroacridine-1,8(2H,5H,9H,10H)-dione
(3c):
Yellow-orange solid, mp 282-283 oC; 1H-NMR δ 0.87 (s, 6H), 1.02 (s, 6H), 2.04 (d, J = 16.3 Hz, 2H),
2.15 (d, J = 16.3 Hz, 2H), 2.26 (d, J = 17.0 Hz, 2H), 2.34 (d, J = 17.0 Hz, 2H), 5.05 (s, 1H), 7.44 (d, J
13
= 8.5 Hz, 2H), 7.98 (d, J = 6.9 Hz, 2H), 8.49 (s, 1H); C-NMR δ 27.4, 29.9, 32.9, 34.9, 51.0, 112.3,
123.5, 129.4, 146.3, 149.8, 154.9, 195.6; IR (neat, cm-1) 3384, 3070, 2956,1643, 1515, 1479, 1342,
1218, 1166. Anal. Calcd. for C23H26N2O4: C, 70.03; H, 6.63; N, 7.10. (Found: C, 69.93; H, 6.75; N,
7.32.
9-(2-Chlorophenyl)-3,3,6,6-tetramethyl-3,4,6,7-tetrahydroacridine-1,8(2H,5H,9H,10H)-dione
(3d):
o
1
Off white solid, mp 217-219 C; H-NMR δ 1.05 (s, 6H), 1.14 (s, 6H), 2.10-2.30 (m, 4H), 2.45-2.62
(m, 4H), 5.04 (s, 1H), 7.09 (t, J = 7.2 Hz, 1H), 7.01-7.19 (m, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.47 (d, J =
6.4 Hz, 1H); 13C-NMR δ 27.8, 29.7, 32.5, 41.2, 51.2, 114.2, 126.8, 127.6, 128.2, 130.6, 133.9, 149.4,
163.5, 197.0; IR (neat, cm-1) 3400, 2980,1660, 1620, 1465, 1350, 1200. Anal. Calcd. for C23H26ClNO2:
C, 71.96; H, 6.82; N, 3.65. Found: C, 71.72; H, 6.55; N, 3.81.
9-(4-Chlorophenyl)-3,3,6,6-tetramethyl-3,4,6,7-tetrahydroacridine-1,8(2H,5H,9H,10H)-dione
(3e):
Off white solid, mp 228-229 oC; 1H-NMR δ 1.03 (s, 6H), 1.15 (s, 6H), 2.17- 3.33 (m, 8H), 5.51 (s, 1H),
7.20 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 8.06 (s, 1H); 13C-NMR δ 27.5, 30.0, 33.0, 41.1,

Molecules 2009, 14
1472
51.2, 113.3, 128.5, 129.9, 132.0, 145.6, 149.7, 196.8; IR (neat, cm-1) 3429, 3178, 3060,
2958,1641,1606, 1488, 1222, 1143. Anal. Calcd. for C23H26ClNO2 : C, 71.96; H, 6.82; N, 3.65. Found:
C, 71.83; H, 6.71; N, 3.55.
9-(3-Bromophenyl)-3,3,6,6-tetramethyl-3,4,6,7-tetrahydroacridine-1,8(2H,5H,9H,10H)-dione (3f): Off
1
white solid, mp 305-307 oC; H-NMR δ 1.01 (s, 6H), 1.12 (s, 6H), 2.18-2.35 (m, 8H), 5.05 (s, 1H),
7.11 (t, J = 7.74 Hz, 1H), 7.25 (d, J = 7.73 Hz, 1H), 7.35 (t, J = 7.59 Hz, 1H), 7.48 (s, 1H), 7.98 (s,
1H); 13C-NMR δ 27.5, 30.0, 33.1, 41.1, 51.3, 113.1, 122.6, 127.5, 129.5, 130.0, 131.4, 149.3, 149.8,
196.3; IR (neat, cm-1) 3280, 3080, 2970, 1640, 1555, 1250, 1220. Anal. Calcd. for C23H26BrNO2: C,
64.49; H, 6.11; N, 3.27. Found: C, 64.66; H, 6.32; N, 3.11.
9-(4-Fluorophenyl)-3,3,6,6-tetramethyl-3,4,6,7-tetrahydroacridine-1,8(2H,5H,9H,10H)-dione
(3g):
Yellow solid, mp 215-218 oC; H-NMR δ 0.98 (s, 6H), 1.10 (s, 6H), 2.04- 2.38 (m, 8H), 5.09 (s, 1H),
6.90 (m, 2H), 7.30 (m, 2H), 8.30 (s, 1H); 13C-NMR δ 27.4, 30.0, 33.0, 41.0, 51.3, 113.3, 115.2, 129.7,
143.0, 149.9, 162.5, 196.5 ; IR (neat, cm-1) 3355, 3047, 2958, 1618, 1498, 1362, 1220, 1147. Anal.
Calcd. for C23H26FNO2: C, 75.18; H, 7.12; N, 3.81. Found: C, 75.32; H, 7.23; N, 3.67.
1
3,3,6,6-tetramethyl-9-(2-(6-(2-(3,3,6,6-tetramethyl-3,4,6,7-tetrahydroacridine1,8(2H,5H,9H,10H)-
dione-9-yl)hexoxy)phenoxy)phenyl-3,4,6,7-tetrahydroacridine-1,8(2H,5H,9H,10H)-dione (3h): Off
white solid, mp 275-277 oC; 1H-NMR δ 0.90 (s, 12H), 0.97 (s, 12H), 1.01-1.06 (m, 4H), 1.96-2.29 (m,
20H), 3.97 (s, br., 4H), 5.30 (s, 2H), 6.71-7.26 (m, 8H), 8.83 (s, 2H); IR (neat, cm-1) 3290, 3065, 2960,
1645, 1490, 1365, 1225, 745. Anal. Calcd. for C52H64N2O6: C, 76.81; H, 7.93; N, 3.45. Found: C,
76.95; H, 7.82; N, 3.59.
3,3,6,6-tetramethyl-9-(2-(4-(2-(3,3,6,6-tetramethyl-3,4,6,7-tetrahydroacridine1,8(2H,5H,9H,10H)-
dione-9-yl)butoxy)phenoxy)phenyl-3,4,6,7-tetrahydroacridine-1,8(2H,5H,9H,10H)-dione (3i): Off
1
white solid, mp 269-271 oC; H-NMR δ 0.92 (s, 12H), 1.04 (s, 12H), 1.98-2.35 (m, 20H), 4.06 (s, br.,
4H), 5.22 (s, 2H), 6.80-7.06 (m, 8H), 8.67 (s, 2H); IR (neat, cm-1) 3290, 3060, 2960, 1660, 1480, 1360,
1235, 745. Anal. Calcd. for C50H60N2O6: C, 76.50; H, 7.70; N, 3.57. Found: C, 76.38; H, 7.78; N,
3.60.
Acknowledgements
Financial support from the Research Council of University of Guilan is sincerely acknowledged.
We also thank Prof. M.A. Zanjanchi for the HY-Zeolite and Dr. N.O. Mahmoodi for the aryl aldehydes
2h and 2i.
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Sample Availability: Samples of the compounds 3a-i are available from the authors.
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