Cellulose sulfuric acid catalyzed multicomponent reaction for efficient synthesis of 1,4-dihydropyridines via unsymmetrical Hantzsch reaction in aqueous media

Article abstract of DOI:10.1016/j.molcata.2010.11.012

C₅-unsubstituted 1,4-dihydropyridines were obtained in good to excellent yields by proceeding through a simple, mild and efficient procedure utilizing cellulose sulfuric acid (CSA) as a catalyst. The reaction work-up is very simple and catalyst

Full text of DOI:10.1016/j.molcata.2010.11.012

Journal of Molecular Catalysis A: Chemical 335 (2011) 46–50
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Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Cellulose sulfuric acid catalyzed multicomponent reaction for efficient synthesis
of 1,4-dihydropyridines via unsymmetrical Hantzsch reaction in aqueous media
Javad Safari∗, Sayed Hossein Banitaba, Shiva D. Khalili
Laboratory of Organic Chemistry Research, Department of Organic Chemistry, College of Chemistry, University of Kashan, 87317-51167 Kashan, Islamic Republic of Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
C5-unsubstituted 1,4-dihydropyridines were obtained in good to excellent yields by proceeding through
a simple, mild and efficient procedure utilizing cellulose sulfuric acid (CSA) as a catalyst. The reaction
work-up is very simple and catalyst can be easily separated from reaction mixture and reused several
times in subsequent reactions.
Received 1 September 2010
Received in revised form
10 November 2010
Accepted 11 November 2010
Available online 19 November 2010
© 2010 Elsevier B.V. All rights reserved.
Keywords:
Cellulose sulfuric acid
Biodegradable catalysts
Hantzsch reaction
One-step condensation
Aqueous media
1. Introduction
method have been reported for the facile and efficient synthesis of
important dihydropyridine derivatives [17–22]. Other procedures
The developing of new multicomponent reactions (MCRs) and
improving the known MCRs are an area of considerable current
interest [1–3]. As opposed to the classical way to synthesize com-
plex molecules by sequential synthesis, MCRs allow the assembly
of complex molecules in one-pot and show a facile execution, high
atom-economy and high selectivity [4–7]. As a one-pot reaction,
MCRs generally afford good yields and are fundamentally different
from two-component and stepwise reactions in several aspects [8]
and permitted a rapid access to combinatorial libraries of complex
organic molecules for an efficient lead structure identification and
optimization in drug discovery.
1,4-Dihydropyridines (1,4-DHPs) are important class of com-
pounds in the field of drugs and pharmaceuticals [9]. The DHP
moiety is common to numerous bioactive compounds which
include various antihypertensive, vasodilator, antimutagenic, anti-
tumor and antidiabetic agents [10–13]. 1,4-DHPs are generally
synthesised by classical Hantzsch method, which involves cyclo-
condensation of an aldehyde, ␤-ketoesters and ammonia either in
acetic acid or in refluxing ethanol for long reaction times which
typically leads to low yields [14–16]. However, this method cannot
be applied for the synthesis of different substitiuted biologically
active 1,4-DHPs. Recently, several modifications for this classical
comprise the use of microwave [23], ionic liquids [24], CAN [25],
tetrabutylammonium hydrogen sulfate [26], I2 [27] and metal tri-
flate [28].
In recent years, the direction of science and technology has
been shifting more towards eco-friendly, natural product resources
and reusable catalysts. Thus, natural biopolymers are attrac-
tive candidates in the search for such solid support catalysts
[29,30]. Recently, cellulose sulfuric acid (CSA) has emerged as a
promising biopolymeric recyclable solid support acid catalysts for
acid-catalyzed reactions, such as the synthesis of ␣-aminonitriles
[31], imidazoazines [32], xanthenes [33] and quinolines [34]. We
now report an efficient catalyzed method for the synthesis of
C5-unsubstitiuted 1,4-dihydropyridines via the three-component
reaction of ethyl acetoacetate, chalcone derivatives and ammonium
acetate in aqueous media (Scheme 1). To the best of our knowl-
edge, the use of cellulose sulfuric acid as a catalyst for the synthesis
of C5-unsubstitiuted 1,4-dihydropyridines previously has not been
reported.
2. Experimental
2.1. General
Melting points were determined in open capillaries using an
Electrothermal Mk3 apparatus and are uncorrected. Infrared (IR)
spectra were recorded using a Perkin-Elmer FT-IR 550 spectrom-
∗
Corresponding author. Fax: +98 361 5912397.
E-mail addresses: Safari jav@yahoo.com, Safari@kashanu.ac.ir (J. Safari).
1381-1169/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcata.2010.11.012

J. Safari et al. / Journal of Molecular Catalysis A: Chemical 335 (2011) 46–50
47
OSO H
3
R1
OSO H
3
O
O
H OSO
3
O
O
O
O
O
H3C
H OSO
3
OSO H
3
O
O
OSO H
3
n
H5C2O
H3C
R2
NH4OAc
R1
+
+
Reflux, water
N
H
R2
H5C2O
1
2
3
4
Scheme 1. Cellulose sulfuric acid-catalyzed unsymmetrical one-pot three-component Hantzsch reaction.
eter. 1H NMR and 13C NMR spectra were recorded with a Bruker
DRX-400 spectrometer at 400 and 100 MHz respectively. NMR
spectra were obtained in DMSO-d6 solutions. The element analyses
(C, H, N) were obtained from a Carlo ERBA Model EA 1108 analyzer
carried out on Perkin-Elmer 240c analyzer.
2H) ppm; 13C NMR (100 MHz, DMSO-d6): ı 14.2, 18.2, 37.9, 61.1,
103.7, 105.8, 122.8, 124.7, 128.3, 130.3, 131.4, 141.4, 142.5, 143.9,
147.5, 148.1, 169.6 ppm; Anal. Calcd. for C21H20N2O4 (%): C, 69.22;
H, 5.53; N, 7.69. Found: C, 69.15; H, 5.49; N, 7.67.
2.4.3. Ethyl 6-(4-bromophenyl)-2-methyl-4-phenyl-1,4-dihydro-
3-pyridinecarboxilate
2.2. Preparation of cellulose sulfuric acid
(4c)
IR (KBr): ꢀ (cm−1) 3344, 1679, 1731; 1H NMR (400 MHz, DMSO-
d6): ı 1.16 (t, J = 6.9 Hz, 3H), 2.17 (s, 3H), 3.78 (q, J = 6.9 Hz, 2H), 5.70
(d, J = 6.7 Hz, 1H), 6.64 (d, J = 6.7 Hz, 1H), 6.89 (s, 1H, NH), 7.0–7.25
(m, 5H), 7.36 (d, J = 7.9 Hz, 2H), 7.45 (d, J = 7.9 Hz, 2H) ppm; 13C
NMR (100 MHz, DMSO-d6): ı 14.2, 18.2, 35.7, 60.9, 104.1, 106.1,
120.8, 123.9, 127.5, 128.2, 129.7, 130.2, 134.90, 141.3, 143.7, 146.8,
169.1 ppm; Anal. Calcd. for C21H20BrNO2 (%): C, 63.33; H, 5.06; N,
3.52. Found: C, 63.25; H, 5.03; N, 3.51.
To a magnetically stirred mixture of 5.0 g of cellulose in 20 ml
of n-hexane, 1.0 g of chlorosulfonic acid (9 mmol) was added drop
wise at 0 ◦C during 2 h. HCl gas was removed from the reaction
vessel immediately. After the addition was complete, the mixture
was stirred for 2 h. Then the mixture was filtered and washed with
30 ml of acetonitrile and dried at room temperature to afford 5.25 g
of cellulose sulfuric acid as a white powder. Sulfur content of the
samples by conventional elemental analysis, was 0.55 for cellulose
sulfuric acid. The number of H+ sites on the cellulose-SO3H was
determined by acid–base titration was 0.50 mequiv./g [31].
2.4.4. Ethyl 2-methyl-4-(4-methylphenyl)-6-phenyl-1,4-dihydro-
3-pyridinecarboxilate
(4d)
2.3. General procedure for the synthesis of
2-methyl-4,6-diphenyl-1,4-dihydro-3-pyridinecarboxilate
derivatives
IR (KBr): ꢀ (cm−1) 3344, 1679, 1731; 1H NMR (400 MHz, DMSO-
d6): ı 1.19 (t, J = 6.8 Hz, 3H), 1.98 (s, 3H), 2.20 (s, 3H), 3.87 (q,
J = 6.8 Hz, 2H), 5.73 (d, J = 7.1 Hz, 1H), 6.69 (d, J = 7.1 Hz, 1H), 6.79 (s,
1H, NH), 7.0–7.50 (m, 5H), 7.66 (d, J = 8.1 Hz, 2H), 7.98 (d, J = 8.1 Hz,
2H) ppm; 13C NMR (100 MHz, DMSO-d6): ı 14.2, 18.2, 22.5, 35.6,
60.9, 104.1, 106.2, 120.7, 123.8, 127.5, 128.1, 130.2, 130.4, 134.8,
141.2, 143.7, 146.7, 170.1 ppm; Anal. Calcd. for C22H23NO2 (%): C,
79.25; H, 6.95; N, 4.20. Found: C, 79.17; H, 6.92; N, 4.18.
A mixture of ethyl acetoacetate (1 mmol), 1,3-diphenyl-2-
propen-1-one derivatives (1 mmol), ammonium acetate (1 mmol)
and cellulose sulfuric acid (0.05 g) was stirred in H2O (5 ml) at
100 ◦C for the appropriate time, as shown in Table 2. After com-
pletion of the reaction (TLC monitoring), the reaction mixture was
cooled to ambient temperature, CH2Cl2 was added, and the cel-
lulose sulfuric acid was filtered off. The filtrate was concentrated
to dryness, and the crude solid product was crystallized from
EtOH to afford the pure ethyl 2-methyl-4,6-diphenyl-1,4-dihydro-
3-pyridinecarboxilate derivatives (Table 2).
2.4.5. Ethyl 4-(4-chlorophenyl)-2-methyl-6-(4-nitrophenyl)-1,4-
dihydro-3-pyridinecarboxilate
(4e)
IR (KBr): ꢀ (cm−1) 3347, 1674, 1736; 1H NMR (400 MHz, DMSO-
d6): ı 1.19 (t, J = 6.8 Hz, 3H), 2.14 (s, 3H), 3.87 (q, J = 6.8 Hz, 2H),
5.74 (d, J = 6.6 Hz, 1H), 6.62 (d, J = 6.6 Hz, 1H), 7.12 (s, 1H, NH),
7.19 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 7.8 Hz, 2H), 7.45 (d, J = 7.9 Hz,
2H), 7.65 (d, J = 7.9 Hz, 2H), ppm; 13C NMR (100 MHz, DMSO-d6):
ı 14.1, 19.1, 33.3, 61.4, 103.7, 105.8, 124.8, 128.1, 128.9, 131.6,
132.6, 140.9, 141.2, 141.3, 146.3, 147.6, 167.8 ppm; Anal. Calcd. for
2.4. Spectral data for new compounds
2.4.1. Ethyl
2-methyl-4,6-diphenyl-1,4-dihydro-3-pyridinecarboxilate (4a)
IR (KBr): ꢀ (cm−1) 3341, 1688, 1726; 1H NMR (400 MHz, DMSO-
d6): ı 1.09 (t, J = 7.2 Hz, 3H), 2.23 (s, 3H), 3.91 (q, J = 7.2 Hz, 2H), 5.25
(d, J = 5.7 Hz, 1H), 5.94 (d, J = 5.7 Hz, 1H), 6.57 (s, 1H, NH), 7.0–7.50
(m, 5H), 7.60–8.0 (m, 5H) ppm; 13C NMR (100 MHz, DMSO-d6):
ı 14.2, 18.2, 38.4, 61.2, 102.1, 105.7, 123.8, 126.7, 127.6, 128.37,
128.7, 129.8, 134.5, 140.9, 143.9, 147.2, 171.3 ppm; Anal. Calcd. for
C21H21NO2 (%): C, 78.97; H, 6.63; N, 4.39. Found: C, 78.79; H, 6.60;
N, 4.35.
C21H19ClN2O4 (%): C, 63.24; H, 4.80; N, 7.02. Found: C, 63.14; H,
4.78; N, 7.01.
2.4.6. Ethyl 6-(4-chlorophenyl)-2-methyl-4-(3-nitrophenyl)-1,4-
dihydro-3-pyridinecarboxilate
(4f)
IR (KBr): ꢀ (cm−1) 3344, 1675, 1721; 1H NMR (400 MHz, DMSO-
d6): ı 1.16 (t, J = 7.1 Hz, 3H), 2.11 (s, 3H), 3.82 (q, J = 7.1 Hz, 2H), 5.62
(d, J = 6.9 Hz, 1H), 6.32 (d, J = 6.9 Hz, 1H), 7.25 (s, 1H, NH), 7.34 (d,
J = 7.3 Hz, 2H), 7.43 (d, J = 7.3 Hz, 2H), 7.48 (dd, J = 8.1 Hz, J = 7.8 Hz,
1H), 7.53 (d, J = 7.8 Hz, 1H), 8.13 (dd, J = 8.1 Hz, J = 2 Hz, 1H), 8.32
(d, J = 2 Hz, 1H), ppm; 13C NMR (100 MHz, DMSO-d6): ı 14.1, 20.2,
33.9, 61.1, 104.2, 105.8, 122.4, 123.4, 124.9, 127.7, 132.5, 133.3,
134.4, 136.2, 140.1, 141.3, 143.5, 149.6, 168.3 ppm; Anal. Calcd. for
2.4.2. Ethyl 2-methyl-6-(4-nitrophenyl)-4-phenyl-1,4-dihydro-
3-pyridinecarboxilate
(4b)
IR (KBr): ꢀ (cm−1) 3342, 1687, 1728, 1436, 1354; 1H NMR
(400 MHz, DMSO-d6): ı 1.18 (t, J = 7.1 Hz, 3H), 2.19 (s, 3H), 3.56 (q,
J = 7.1 Hz, 2H), 5.42 (d, J = 6.1 Hz, 1H), 6.23 (d, J = 6.1 Hz, 1H), 6.65 (s,
1H, NH), 7.0–7.40 (m, 5H), 7.52 (d, J = 8.1 Hz, 2H), 7.87 (d, J = 8.1 Hz,

48
J. Safari et al. / Journal of Molecular Catalysis A: Chemical 335 (2011) 46–50
Table 1
Optimizing the reaction conditions.a
OSO
H
O
OSO
O
H
O
H
OSO
O
O
OSO
O
O
H3C
H
OSO
H
O
OSO
H
n
H5C2O
H3C
AcONH4
+
+
Water, reflux
O
N
H
H5C2O
.
Entry
Cellulose sulfuric acid (g)
Time (h)
Yield (%)b
1
2
3
4
5
0
6
3
1.5
1
1.0
35
90
98
75
74
0.02
0.05
0.1
0.12
a
Ethyl acetoacetate/1,3-diphenyl-2-propen-1-one/ammonium acetate = 1:1:1.
Isolated yields.
b
C21H19ClN2O4 (%): C, 63.24; H, 4.80; N, 7.02. Found: C, 63.14; H,
4.78; N, 7.01.
119.4, 122.4, 126.5, 129.4, 130.6, 133.3, 135.6, 140.5, 143.7, 144.5,
145.8, 148.5, 169.5 ppm; Anal. Calcd. for C21H19N3O6 (%): C, 60.76;
H, 4.33; N, 10.63. Found: C, 60.65; H, 4.26; N, 10.59.
2.4.7. Ethyl 4-(4-methoxyphenyl)-2-methyl-6-phenyl-1,4-
dihydro-3-pyridinecarboxilate
(4g)
2.4.11. Ethyl 6-(4-hydroxyphenyl)-2-methyl-4-(4-nitrophenyl)-
1,4-dihydro-3-pyridinecarboxilate
IR (KBr): ꢀ (cm−1) 3342, 1679, 1729; 1H NMR (400 MHz, DMSO-
d6): ı 1.19 (t, J = 6.9 Hz, 3H), 2.20 (s, 3H), 3.53 (s, 3H, OMe), 3.77 (q,
J = 6.9 Hz, 2H), 6.04 (d, J = 7.4 Hz, 1H), 6.54 (d, J = 7.4 Hz, 1H), 6.88 (s,
1H, NH), 6.99 (d, J = 7.7 Hz, 2H), 7.10–7.30 (m, 5H), 7.56 (d, J = 7.7 Hz,
2H) ppm; 13C NMR (100 MHz, DMSO-d6): ı 14.1, 17.9, 36.3, 55.4,
62.3, 98.2, 106.3, 113.6, 126.4, 127.2, 128.5, 130.2, 134.5, 139.6,
(4k)
IR (KBr): ꢀ (cm−1) 3338, 1671, 1731, 1342; 1H NMR (400 MHz,
DMSO-d6): ı 1.21 (t, J = 6.5 Hz, 3H), 2.16 (s, 3H), 3.81 (q, J = 6.5 Hz,
2H), 5.61 (d, J = 6.4 Hz, 1H), 5.84 (d, J = 6.4 Hz, 1H), 6.22 (s, 1H, NH),
6.93 (bs, 1H, OH), 7.21 (d, J = 7.4 Hz, 2H), 7.29 (d, J = 7.4 Hz, 2H), 7.36
(d, J = 7.8 Hz, 2H), 7.65 (d, J = 7.8 Hz, 2H), ppm; 13C NMR (100 MHz,
DMSO-d6): ı 14.4, 20.3, 33.8, 62.1, 104.5, 106.1, 124.7, 128.9, 130.6,
131.9, 132.7, 141.6, 141.9, 142.6, 147.4, 148.6, 168.3 ppm; Anal.
Calcd. for C21H20N2O5 (%): C, 63.31; H, 5.30; N, 7.36. Found: C, 63.21;
H, 5.28; N, 7.34.
140.4, 141.7, 155.8, 169.8 ppm; Anal. Calcd. for C22H23NO3 (%): C,
75.62; H, 6.63; N, 4.01. Found: C, 75.58; H, 6.60; N, 4.00.
2.4.8. Ethyl 4-(4-chlorophenyl)-2-methyl-6-phenyl-1,4-dihydro-
3-pyridinecarboxilate
(4 h)
2.4.12. Ethyl 4-(4-hydroxyphenyl)-2-methyl-6-(4-nitrophenyl)-
1,4-dihydro-3-pyridinecarboxilate
(4l)
IR (KBr): ꢀ (cm−1) 3346, 1673, 1722; 1H NMR (400 MHz, DMSO-
d6): ı 1.17 (t, J = 6.8 Hz, 3H), 2.14 (s, 3H), 3.52 (q, J = 6.8 Hz, 2H),
6.37 (d, J = 7.1 Hz, 1H), 6.98 (d, J = 7.1 Hz, 1H), 7.21 (s, 1H, NH), 7.32
(d, J = 7.2 Hz, 2H), 7.30–7.50 (m, 5H), 7.71 (d, J = 7.2 Hz, 2H) ppm;
13C NMR (100 MHz, DMSO-d6): ı 14.3, 18.7, 36.9, 63.1, 99.3, 107.8,
125.4, 127.7, 128.3, 129.3, 130.2, 132.7, 134.5, 139.6, 141.3, 141.7,
170.1 ppm; Anal. Calcd. for C21H20ClNO2 (%): C, 71.28; H, 5.70; N,
3.96. Found: C, 71.20; H, 5.65; N, 3.93.
IR (KBr): ꢀ (cm−1) 3336, 1670, 1731, 1339; 1H NMR (400 MHz,
DMSO-d6): ı 1.22 (t, J = 6.6 Hz, 3H), 2.15 (s, 3H), 3.83 (q, J = 6.6 Hz,
2H), 5.64 (d, J = 6.3 Hz, 1H), 5.81 (d, J = 6.3 Hz, 1H), 6.20 (s, 1H, NH),
6.85 (bs, 1H, OH), 7.10 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.42
(d, J = 7.1 Hz, 2H), 7.68 (d, J = 7.1 Hz, 2H), ppm; 13C NMR (100 MHz,
DMSO-d6): ı 13.8, 21.4, 33.8, 63.5, 105.7, 106.8, 123.2, 126.9, 131.5,
131.8, 133.4, 141.5, 141.9, 143.8, 147.8, 148.7, 165.2 ppm; Anal.
Calcd. for C21H20N2O5 (%): C, 63.31; H, 5.30; N, 7.36. Found: C, 63.21;
H, 5.28; N, 7.34.
2.4.9. Ethyl 6-(4-chlorophenyl)-2-methyl-4-phenyl-1,4-dihydro-
3-pyridinecarboxilate
(4i)
IR (KBr): ꢀ (cm−1) 3348, 1669, 1745; 1H NMR (400 MHz, DMSO-
d6): ı 1.22 (t, J = 7.4 Hz, 3H), 2.11 (s, 3H), 3.44 (q, J = 7.4 Hz, 2H), 6.76
(d, J = 6.1 Hz, 1H), 7.10 (d, J = 6.1 Hz, 1H), 7.29 (s, 1H, NH), 7.0–7.3
(m, 5H), 7.34 (d, J = 7.4 Hz, 2H), 7.55 (d, J = 7.4 Hz, 2H) ppm; 13C
NMR (100 MHz, DMSO-d6): ı 14.5, 19.1, 36.1, 62.3, 100.1, 106.9,
122.3, 124.2, 127.2, 130.2, 130.9, 132.2, 133.5, 140.6, 141.4, 143.2,
170.3 ppm; Anal. Calcd. for C21H20ClNO2 (%): C, 70.69; H, 5.35; N,
4.12. Found: C, 70.61; H, 5.32; N, 4.09.
3. Results and discussion
We had the opportunity to further explore the catalytic activity
of cellulose sulfuric acid in the synthesis of 1,4-dihydropyridines.
Herein, we wish to report on a novel synthesis of 1,4-DHP pro-
moted by a catalytic amount of cellulose sulfuric acid (CSA) in
water under reflux conditions to excellent yields. In an initial
endeavor, 1 mmol each of ethyl acetoacetate 1, 1,3-diphenyl-2-
propen-1-one 2a, and ammonium acetate were stirred at 100 ◦C
in water. After 6 h, only 35% of the expected product 4a was
obtained when after workup and recrystallization of the crude
product from ethanol (Table 1, Entry 1). To improve the yield and
optimize the reaction conditions, the same reaction was carried
out in the presence of a catalytic amount of 0.02 g of CSA under
similar conditions. Surprisingly, a significant improvement was
observed and the yield of 4a was dramatically increased to 90%
after stirring; the mixture was stirred for only 3 h (Entry 2). With
this optimistic result in hand, we further investigated the best
2.4.10. Ethyl 2-methyl-6-(3-nitrophenyl)-4-(4-nitrophenyl)-1,4-
dihydro-3-pyridinecarboxilate
(4j)
IR (KBr): ꢀ (cm−1) 3347, 1671, 1712; 1H NMR (400 MHz, DMSO-
d6): ı 1.17 (t, J = 6.9 Hz, 3H), 2.15 (s, 3H), 3.65 (q, J = 6.9 Hz, 2H), 5.80
(d, J = 7.4 Hz, 1H), 6.64 (d, J = 7.4 Hz, 1H), 7.15 (s, 1H, NH), 7.44 (d,
J = 7.7 Hz, 1H), 7.53 (s, 1H), 7.89 (dd, J = 8.2 Hz, J = 7.7 Hz, 1H), 8.12 (d,
J = 7.1 Hz, 2H), 8.34 (d, J = 7.2 Hz, 2H); 8,57 (d, J = 8.2 Hz, 1H); ppm;
13C NMR (100 MHz, DMSO-d6): ı 14.1, 21.1, 32.3, 60.5, 100.3, 105.8,

J. Safari et al. / Journal of Molecular Catalysis A: Chemical 335 (2011) 46–50
49
Table 2
Solvent screening for the reaction between ethyl acetoacetate 1, chalcone 2a and ammonium acetate.a
O
O
H3C
O
O
H5C2O
H3C
n
AcONH4
+
+
Solvent, reflux
N
H
H5C2O
.
Entry
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
EtOH
MeOH
6.0
6.0
6.0
24.0
24.0
24.0
6.0
3.0
1.5
3.0
60
50
30
25
Trace
Trace
80
92
98
Isopropanol
t-BuOH
THF
Acetonitrile
Water
Water
Water
None
85
a
CSA (0.05 g), ethyl acetoacetate/1,3-diphenyl-2-propen-1-one/ammonium acetate = 1:1:1.
Isolated yields.
b
reaction conditions using different amounts of CSA. An increase
in the quantity of CSA from 0.02 g to 0.05 g not only decreased
the reaction time from 3 h to 1.5 h, but also increased the prod-
uct yield slightly from 90% to 98% (Entry 3). Although the use of
0.10 g of CSA permitted the reaction time to be decreased to 1 h, the
yield unexpectedly decreased to 75% (Entry 4). A possible explana-
tion for the low product yield is that the starting material or the
product may have been destroyed during the reaction when an
excess amount (0.10 g) of CSA was used in the exothermic reac-
tion and that 0.05 g CSA was sufficient to catalyze the reaction
effectively.
The efficiency of water as solvent compared to various organic
solvents was also examined (Table 2). In this study, it was found
that water is a more efficient and superior solvent (Entries 7–9)
over other organic solvents (Entries 1–6) with respect to reaction
time and yield of the desired dihydropyridine.
It is shown that in general a wide range of chalcones could
react with ethyl acetoacetate and ammonium acetate smoothly and
give 4a–l in good to excellent yields (Table 3, Entries 1–12). It is
also notable that the electronic property of the aromatic ring of
chalcones has some effects on the rate of the condensation pro-
cess. Generally speaking, shorter reaction time was needed for
the substrates bearing electron-withdrawing groups on the aro-
matic rings (Table 3, Entries 2, 3, 5, 6, 8, 9, 10 and 12). On the
other hand, while substrates bearing electron-donating groups can
afford the corresponding products with almost equally satisfac-
tory yields. A little bit longer reaction period was necessary to
complete the reaction (Table 3, Entries 1, 4, 7 and 11). A possible
mechanism for the formation of title compounds 4a–l is shown in
Scheme 2.
The reusability of the catalyst was checked by separating the
cellulose sulfuric acid from the reaction mixture by simple fil-
tration, washing with CH2Cl2, and drying in a vacuum oven at
60 ◦C for 5 h prior to reuse in subsequent reactions. The recov-
ered catalyst can be reused at least three additional times in
subsequent reactions without significant loss in product yield
(Table 4).
Based on above observations, we conducted the same reac-
tions using ethyl acetoacetate 1, variety of different substituted
1,3-diphenyl-2-propen-1-one 2a–j and 3 in the presence of 0.05 g
of CSA under similar conditions. As expected, satisfactory results
were observed, and the results are summarized in Table 3.
Table 3
Cellulose sulfuric acid catalyzed synthesis of C5-unsubstitiuted 1,4-dihydropyridines.
R1
OSO H
O
OSO H
O
H OSO
O
O
O
H3C
O
O
H OSO
OSO H
O
O
OSO H
H5C2O
H3C
n
R2
AcONH4
R1
+
+
Water, reflux
N
H
R2
H5C2O
.
Entry
R1
R2
Product
Time (h)
Yield (%)a
Mp (◦C)
1
2
3
4
5
6
7
8
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
1.5
1.1
1.2
1.5
1.0
1.0
1.5
1.4
1.3
1.1
1.5
1.0
98
95
93
87
96
85
85
92
90
92
93
98
245–247
232–235
257–259
235–238
211–213
218–220
223–225
252–255
264–266
203–205
271–274
265–269
p-NO2
p-Br
H
p-NO2
p-Cl
H
p-CH3
p-Cl
m-NO2
p-OCH3
p-Cl
H
p-NO2
p-NO2
p-OH
H
9
p-Cl
m-NO2
p-OH
p-NO2
10
11
12
4j
4k
4l
a
Isolated yields.

50
J. Safari et al. / Journal of Molecular Catalysis A: Chemical 335 (2011) 46–50
O
Ar
O
Ar
Ar
O
O
EtO
H
Micheal
addition
EtO
EtO
NH4OAc
O
H
Ar'
O
+
O
O
Ar'
Ar
O
N
Ar'
H
Ar
O
H
Intramolecular
condensation
EtO
EtO
H2O
N
H
Ar'
N
H
Ar'
HO
Scheme 2. Plausible mechanism of C5-unsubstitiuted 1,4-dihydropyridine derivatives.
Table 4
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The effect of reusability of cellulose sulfuric acid catalyst on the product 4a yield.a
Entry
Cycle
Yield (%)b
1
2
3
4
0
1
2
3
98
92
91
91
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a
Reaction conditions: ethyl acetoacetate (1 mmol), chalcone 2a (1 mmol) and
ammonium acetate (1 mmol), CSA (0.05 g), water (5 ml), 100 ◦C.
b
Isolated yields.
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4. Conclusion
Cellulose sulfuric acid, an efficient, non-toxic, reusable, and solid
support biodegradable acid catalyst, has been prepared and utilized
for the synthesis of C5-unsubstitiuted 1,4-dihydropyridines via the
three-component reaction of ethyl acetoacetate with a wide range
of chalcone derivatives and ammonium acetate in aqueous media.
Prominent of this modified methodology is superior to existing
methodologies for the synthesis of 1,4-dihydropyridines.
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Acknowledgment
We acknowleged the research council of University of Kashan.
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