Chitosan: a sustainable, reusable and biodegradable organocatalyst for green synthesis of 1,4-dihydropyridine derivatives under solvent-free condition

Article abstract of DOI:10.1007/s11164-016-2579-7

Abstract: Chitosan, a biodegradable green catalyst, was found to be an impressive system for one-pot four-component reaction of different aldehydes, dimedone, β‐ketoesters or acetoacetanilide, and ammonium acetate leading to 1,4-dihydropyridine derivatives via Hantzsch-type condensation under solvent-free condition. This methodology produces diverse superiorities such as operational simplicity, short reaction time, satisfied yield and recyclable catalyst. In this work, we attempted to develop several modifications for the classical Hantzsch conversion to report a novel eco-friendly method that is free from previously reported disadvantages. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11164-016-2579-7

Res Chem Intermed
DOI 10.1007/s11164-016-2579-7
Chitosan: a sustainable, reusable and biodegradable
organocatalyst for green synthesis of 1,4-dihydro-
pyridine derivatives under solvent-free condition
Sara Zhaleh1 Nourallah Hazeri1 Mohammad Reza Faghihi1
Malek Taher Maghsoodlou1
•
•
•
Received: 2 March 2016 / Accepted: 10 May 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract Chitosan, a biodegradable green catalyst, was found to be an impressive
system for one-pot four-component reaction of different aldehydes, dimedone, b-ke-
toesters or acetoacetanilide, and ammonium acetate leading to 1,4-dihydropyridine
derivatives via Hantzsch-type condensation under solvent-free condition. This method-
ology produces diverse superiorities such as operational simplicity, short reaction time,
satisfied yield and recyclable catalyst. In this work, we attempted to develop several
modifications for the classical Hantzsch conversion to report a novel eco-friendly
method that is free from previously reported disadvantages.
Graphical Abstract
&
Nourallah Hazeri
nhazeri@chem.usb.ac.ir
1
Department of Chemistry, University of Sistan and Baluchestan,
P. O. Box 98135-674, Zahedan, Iran
123

S. Zhaleh et al.
Keywords Chitosan Á 1,4-Dihydropyridine Á Green synthesis Á Solvent-free
condition Á Reusability
Introduction
Recently, multicomponent reactions (MCRs) have been found to be a powerful and
versatile tool in the synthesis of many chemical compounds in biological and
pharmacological scopes. The great capability of these reactions is to combine two or
more components in a single step, without the isolation of any intermediates, to
synthesize complex and substantial substances with high efficiency, simplicity, time
saving and atom economy [1–5].
Nowadays, all over the world, green chemistry has become a concern for organic
chemists in order to provide important biological and pharmaceutical compounds in
a safe and eco-friendly manner to minimize environmentally pollutants as well as
destructive consequences on the human body [6, 7]. Hence, in response to anxieties
about environmental threats, organic chemists merge multicomponent reactions into
green chemistry [8–11]. From this viewpoint, those reactions are more suit-
able which are operated without solvents or with non-hazardous solvents. Now,
solvent-free multicomponent reactions have modernized conventional procedures
via increasing yield, operational simplicity, cost saving and decreasing reaction
times, energy consumption and reactor size. In regard to the aforementioned, the
optimal option is a solvent-free reaction [12–15].
Chitosan is a bifunctional hetero bio-polymer catalyst possessing both glu-
cosamine and acetyl glucosamine units prepared from alkali hydrolysis of chitin—
obtained from the exoskeletons of crustaceans such as crabs, lobsters and shrimps,
the radulas of mollusks as well as the beaks of cephalopods—the most plentiful
available polysaccharide after cellulose in nature (Fig. 1) [16–18].
The presence of several –NH2 and –OH groups in chitosan disposes it either to
directly catalyse miscellaneous sets of organic reactions such as transamidation
[19], Strecker reaction [20], Biginelli reaction [21], Michael addition [22], and
Aldol and Knoevenagel reactions [23–26], or to catalyse through metals supported
on chitosan such as Suzuki–Miyaura and Heck cross-coupling reactions [27], metal-
catalyzed reaction [28], oxidation [29], and [3 ? 2] Huisgen cycloaddition [30].
Moreover, chitosan can be applied in medicine, drug delivery, agriculture, water
treatment, fuel cells and so on [31].
Fig. 1 Chemical structure of
chitosan
123

Chitosan: a sustainable, reusable and biodegradable…
One of the unique properties of chitosan is insolubility in both water and some
organic solvents. This characteristic introduces it as a reusable catalyst that can be
employed many times without any excess modification in organic synthetic designs.
1,4-Dihydropyridines are a valuable group of nitrogen-containing, six-member
heterocyclic compounds that have attracted much attention because of numerous
biological activities such as anti-HIV agents [32], anti-inflammatory and anti-
diabetes [33], antitumor [34], analgesic [35] and the treatment of Alzheimer’s
disease [36, 37]. Additionally, usage of them as a calcium channel blocker has
enhanced their value among other heterocycles [38–41]. The structures of some
biologically active 1,4-DHPs are illustrated in Fig. 2 [42, 43].
For the first time, the synthesis of 1,4-DHPs was by the famous, three-component
condensation of aldehyde, ethylacetoacetate and ammonia carried out by Hantzsch
Fig. 2 Representative 1,4-DHPs with biological properties
123

S. Zhaleh et al.
in 1882 [44]. Since then, various changes have been made in the reactants,
conditions and catalysts. The use of dimedone as C–H acid and amines or
ammonium acetate as nitrogen sources have been performed. In addition,
widespread catalysts and conditions have been used, such as phosphoric acid
[45], L-proline [46], heteropolyacids [47], magnetite/chitosan [48], magnetic Fe3O4
nanoparticles [49], La2O3 [50], Yb(OTf)3 [51], ionic liquid(BMImSac) [52], solar
thermal energy [53], I2 [54], q-toluenesulfonic acid [55], glycine [56], nano ZnO
[57], FeF3 [58], Baker’s yeast [59] and hafnium(IV) bis(perfluorooctanesulfonyl)
imide complex in fluorous media [60]. But most of these suffer from some
drawbacks such as the use of a toxic solvent and catalyst, high cost, harsh reaction
conditions and severe work-up procedures.
As part of our research on employing green catalysts to carry out MCRs in these
reports [61, 62], chitosan has been assisted as a sustainable, reusable and
biodegradable organocatalyst for the synthesis of 1,4-DHPs.
Experimental
General
All chemicals and reagents were purchased from Merck, Fluka and Aldrich and used
as received without any purification. Melting points were measured using
Electrothermal 9100 apparatus (UK). 1H NMR and 13C NMR spectra were recorded
on a BRUKER DRX at 300 or 400 and 100 MHz in DMSO-d6, respectively. The
mass spectra were recorded on an Agilent Technology (HP) mass spectrometer,
operating at an ionization potential of 70 eV. Elemental analyses were performed
using a Elementar, Vario EL III instrument. Chitosan of high molecular weight
(from shrimp shells, MW: 310–375 kDa, degree of deacetylation [75 %) was
provided from by Sigma-Aldrich and used as received.
General procedure for the synthesis of 1,4-dihidropyridine derivatives
Substituted aldehyde (0.5 mmol), ammonium acetate (1 mmol, 0.077 g), dimedone
(0.5 mmol, 0.071 g), ethyl or methyl acetoacetate (0.6 mmol, 0.065 or 0.059 g) or
acetoacetanilide (0.6 mmol, 0.106 g) in the presence of a catalytic amount of
chitosan (0.015 g, more than 0.011 g deacetylated) were magnetically stirred
without solvent at 60 °C for appropriate times as specified in Tables 3 and 4. The
progress of the reaction was monitored by TLC 30 % EA: Hex. After completion of
the reaction, the resulting solid products was dissolved in hot ethanol, filtered for
removing the unsolvable catalyst and then the filtrate was concentrated and the
crude was purified by recrystallization from ethanol to afford the pure 1,4-
dihidropyridine drivatives (5a–5x). The catalyst was subsequently washed with
5 ml ethanol.
The structures of the synthesized products were confirmed by comparison of their
melting points with reliable data reported in the literature and spectral techniques
1H, 13C NMR spectra, CHNS analysis and mass spectroscopy.
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Chitosan: a sustainable, reusable and biodegradable…
Ethyl 4-(4-methoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-
carboxylate (5b) 1H NMR (300 MHz, DMSO-d6): d 0.86 (3H, s, CH3), 1.01 (3H,
s, CH3), 1.14 (3H, t, J = 7.2 Hz, CH2–CH3), 1.95-2.39 (4H, m, CH2–CMe2–CH2),
2.25 (3H, s, CH3–C=), 3.68 (3H, s, OCH3), 3.98 (2H, q, J = 7.2 Hz, OCH2CH3),
4.75 (1H, s, C–CH(R)-C), 6.75 (2H, d, J = 8.7 Hz, CH(Ar)), 7.05 (2H, d,
J = 8.7 Hz, CH(Ar)), 9.01 (1H, br, D2O-exchange).
Ethyl 4-(3-fluorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-
carboxylate (5c) 1H NMR (400 MHz, CDCl3): d 1.00 (3H, s, CH3), 1.10 (3H, s,
CH3), 1.22 (3H, t, J = 7.2 Hz, CH2–CH3), 2.11-2.36 (4H, m, CH2–CMe2–CH2),
2.41 (3H, s, CH3–C=), 4.07-4.12 (2H, m, OCH2CH3), 5.09 (1H, s, C–CH(R)-C),
6.04 (1H, br, D2O-exchange), 6.81 (1H, t, J = 6.0 Hz), 7.00 (1H, d, J = 10 Hz),
7.12-7.20 (2H, m). 13C NMR (400 MHz, DMSO-d6): d 14.6, 18.7, 26.8, 29.5, 32.6,
36.3, 50.6, 59.8, 103.5, 110.0, 112.9, 114.4, 123.9, 130.1, 146.1, 150.4, 162.5 (d,
JCF = 243.5 Hz), 195.0. MS (EI, 70 eV): m/z (%) M? 353 (12), 262 (100), 234
(23), 178 (6), 122 (3), 95 (1), 91 (6), 41 (5). Anal. Calcd. for C21H24FNO3: C
(70.57), H (6.77), N (3.92); Found: C (70.27), H (7.40), N (3.80).
Ethyl 4-(4-hydroxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-
carboxylate (5g) 1H NMR (300 MHz, DMSO-d6): d 0.87 (3H, s, CH3), 1.01 (3H,
s, CH3), 1.14 (3H, t, J = 7.2 Hz, CH2–CH3), 1.95-2.44 (4H, m, CH2–CMe2–CH2),
2.30 (3H, s, CH3–C=), 3.98 (2H, q, J = 7.2 Hz, OCH2CH3), 4.80 (1H, s, C–CH(R)-
C), 6.57 (2H, d, J = 8.4 Hz, CH(Ar)), 6.94 (2H, d, J = 8.4 Hz, CH(Ar)), 9.00 (1H,
br, D2O-exchange), 9.08 (1H, br, D2O-exchange).
Ethyl 4-(3-methylphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-
carboxylate (5i) 1H NMR (400 MHz, CDCl3): d 0.98 (s, 3H, CH3), 1.08 (s, 3H,
CH3), 1.24 (3H, t, J = 7.2 Hz, CH2–CH3), 2.15-2.26 (4H, m, CH2–CMe2–CH2),
2.29 (3H, s, CH3–C=), 2.37 (3H, s, CH3–Ar), 4.04-4.12 (2H, m, OCH2CH3), 5.04
(1H, s, C–CH(R)-C), 6.72 (1H, br, D2O-exchange), 6.93-6.96 (1H, m), 7.10–7.11
(2H, m), 7.13 (1H, m). 13C NMR (400 MHz, DMSO-d6): d 14.6, 18.7, 21.6, 26.9,
29.6, 32.6, 36.2, 50.7, 59.5, 61.6, 104.3, 110.4, 125.1, 126.9, 128.2, 130.0, 137.0,
145.3, 148.1, 150.2, 167.3, 195.0. MS (EI, 70 eV): m/z (%) M ? 353 (37), 262
(100), 234 (45), 178 (12), 122 (5), 91 (10), 65 (9), 41 (7). Anal. Calcd. for
C22H27NO3: C (74.76), H (7.70), N (3.96); Found: C (74.77), H (7.10), N (4.06).
Ethyl 4-(4-cyanophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-
carboxylate (5k) 1H NMR (400 MHz, CDCl3): d 0.94 (3H, s, CH3), 1.11 (3H, s,
CH3), 1.19 (3H, t, J = 7.2 Hz, CH2–CH3), 2.15–2.38 (4H, m, CH2–CMe2–CH2),
2.44 (3H, s, CH3–C=), 4.07 (2H, q, J = 7.2 Hz, OCH2CH3), 5.12 (1H, s, C–CH(R)-
C), 6.06 (1H, br, D2O-exchange), 7.45 (2H, d, J = 8.4 Hz, CH(Ar)), 7.53 (2H, d,
J = 8.4, CH(Ar) Hz).
Ethyl 4-(2-naphthyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-car-
boxylate (5l) 1H NMR (400 MHz, CDCl3): d 0.93 (3H, s, CH3), 1.04 (3H, s,
CH3), 1.21 (3H, t, J = 7.2 Hz, CH2–CH3), 2.14-2.40 (4H, m, CH2–CMe2–CH2),
2.47 (3H, s, CH3–C=), 4.03–4.10 (2H, m, OCH2CH3), 5.26 (1H, s, C–CH(R)-C),
123

S. Zhaleh et al.
6.41 (1H, br, D2O-exchange), 7.38–7.44 (2H, m), 7.52 (1H, d, J = 7.2 Hz), 7.70
(1H, s), 7.72 (1H, s), 7.75–7.78 (2H, m).
Ethyl
2,7,7-trimethyl-5-oxo-4-(1-phenylprop-1-en-2-yl)-1,4,5,6,7,8-hexahydro-
quinoline-3-carboxylate (5m) 1H NMR (400 MHz, CDCl3): d 1.10 (3H, s,
CH3), 1.13 (3H, s, CH3), 1.31 (3H, t, J = 7.2 Hz, CH2–CH3), 1.90 (3H, s, CH3–C=),
2.19–2.38 (4H, m, CH2–CMe2–CH2), 2.40 (3H, s, CH3–C=), 4.07 (2H, q,
J = 7.2 Hz, OCH2CH3), 4.68 (1H, s, C–CH(R)-C), 5.90 (1H, br, D2O-exchange),
6.43 (1H, s, Ph-CH=C), 7.15–7.22 (3H, m), 7.27–7.31 (2H, m). 13C NMR
(400 MHz, DMSO-d6): d 14.8, 16.2, 18.7, 27.0, 29.7, 32.4, 46.8, 50.9, 59.5, 61.8,
102.8, 108.6, 125.3, 126.4, 128.6, 129.0, 145.6, 150.8, 167.7, 195.2. MS (EI,
70 eV): m/z (%) M? 380 (3), 262 (100), 234 (24), 178 (6), 122 (2), 117 (4), 91 (6),
41 (2). Anal. Calcd. for C24H29FNO3: C (75.96), H (7.70), N (3.69); Found: C
(76.20), H (7.36), N (3.79).
Ethyl
2,7,7-trimethyl-5-oxo-4-(thiophen-2-yl)-1,4,5,6,7,8-hexahydroquinoline-3-
carboxylate (5n) 1H NMR (300 MHz, DMSO-d6): d 0.95 (3H, s, CH3), 1.04
(3H, s, CH3), 1.20 (3H, t, J = 7.2 Hz, CH2–CH3), 2.05-2.47 (4H, m, CH2–CMe2–
CH2), 2.28 (3H, s, CH3–C=), 4.08 (2H, q, J = 7.2 Hz, OCH2CH3), 5.18 (1H, s, C–
CH(R)-C), 6.67 (1H, d, J = 3.3 Hz), 6.83 (1H, t, J = 5.1 Hz), 7.19 (1H, dd,
J1 = 1.2 Hz, J2 = 5.2 Hz) 9.26 (1H, br, D2O-exchange).
Ethyl 2,7,7-trimethyl-5-oxo-4-propyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate
(5o) 1H NMR (400 MHz, CDCl3): d 0.85 (3H, t, J = 7.2 Hz, CH3CH2–), 1.11
(3H, s), 1.13 (3H, s), 1.20-1.36 (4H, m, –CH2–CH2–), 1.30 (3H, t, J = 7.2 Hz),
2.19-2.37 (4H, m, CH2–CMe2–CH2), 2.33 (3H, s, CH3–C=), 4.04 (1H, t,
J = 10.0 Hz, C–CH(Pr)-C), 4.11-4.26 (2H, m, OCH2CH3), 6.21 (1H, br, D2O-
exchange).
Methyl 4-(4-nitrophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-
carboxylate (5r) 1H NMR (300 MHz, DMSO-d6): d 0.82 (3H, s, CH3), 1.01
(3H, s, CH3), 1.96–2.42 (4H, m, CH2–CMe2–CH2), 2.33 (3H, s, CH3–C=), 3.53 (3H,
s, OCH3), 4.96 (1H, s, C–CH(R)-C), 7.42 (2H, d, J = 9.0 Hz), 6.96 (2H, d,
J = 9.0 Hz), 9.29 (1H, br, D2O-exchange).
Methyl 4-(4-(dimethylamino)phenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydro-
quinoline-3-carboxylate (5s) 1H NMR (300 MHz, CDCl3): d 0.88 (3H, s, CH3),
1.02 (3H, s, CH3), 2.01–2.45 (4H, m, CH2–CMe2–CH2), 2.28 (3H, s, CH3–C=), 2.81
(6H, s, N–(CH3)2), 3.54 (3H, s, OCH3), 4.75 (1H, s, C–CH(R)-C), 6.56 (2H, d,
J = 11.6, CH(Ar)), 6.96 (2H, d, J = 11.6, CH(Ar)), 9.01 (1H, br, D2O-exchange).
2,7,7-trimethyl-5-oxo-N,4-diphenyl-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide
(5t) 1H NMR (300 MHz, CDCl3): d 0.90 (3H, s, CH3), 1.09 (3H, s, CH3),
2.15–2.38 (4H, m, CH2–C(CH3)2–CH2), 2.42 (3H, s, CH–CH3), 4.96 (1H, s, C–
CH(Ar)–C), 5.91 (1H, br, D2O-exchange), (1H,), (5H, d, J = 8.7 Hz, CH(Ar)), 7.36
(2H, t, J = 8.7 Hz, CH(Ar)), (2H, d,).
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Chitosan: a sustainable, reusable and biodegradable…
4-(4-methoxyphenyl)-2,7,7-trimethyl-5-oxo-N-phenyl-1,4,5,6,7,8-hexahydroquino-
line-3-carboxamide (5x) 1H NMR (300 MHz, CDCl3): d 0.86 (s, 3H, CH3), 1.04
(s, 3H, CH3), 2.11–2.30 (4H, m, CH2–C(CH3)2–CH2), 2.36 (3H, s, CH3–CH), 2.38
(3H, s, CH3–Ar), 4.90 (1H, s, C–CH(Ar)–C), 6.76 (1H, br, D2O-exchange), 6.88
(2H, d, J=), 7.03-7.08 (1H, m), 7.23-7.30 (4H, m), 7.40 (2H,). 13C NMR (300 MHz,
CDCl3): d 18.7, 27.0, 29.3, 32.6, 36.2, 37.1, 40.9, 50.6, 55.2, 108.3, 111.0, 119.9,
124.0, 128.9, 129.0, 137.7, 138.1, 141.1, 148.6, 158.7, 166.6, 195.4.
Result and discussion
In our work, we applied chitosan without any further modification for the Hantzch
synthesis of 1,4-DHP derivatives. Fortunately, short reaction times and good to
excellent yields were found; in addition, as in previous literature, recyclability and
reusability of the catalyst were observed.
Catalytic studies
At the beginning of our ongoing research, we evaluated the reaction between
benzaldehyde (1a), dimedone (2), ethyl acetoacetate (3a) and ammonium acetate (4)
at different catalyst loading at room temperature. The results are presented in
Table 1.
In the absence of the catalyst, only 45 % of corresponding product was obtained
after 24 h (entry 1). To improve output of the reaction, chitosan was utilized in
various loadings. Surprisingly, using just 0.010 g chitosan not only diminished the
reaction time to one-third but also considerably enhanced the yield (entry 2). In the
following, the reaction product was studied by catalyst loading variations (entries
2–4), and finally, due to the observed negligible difference between two last entries,
we chose to apply 0.015 g chitosan as the optimum quantity of catalyst.
Table 1 Optimizing the amount of chitosan
Entry
Chitosan (g)
Time (h)
Yield (%)a
1
2
3
4
-
24
8
45
80
91
91
0.010
0.015
0.020
5.5
5
Benzaldehyde:1,3-cyclohexanedione:ethyl acetoacetate:ammonium acetate = 1:1:1.2:2
a
Isolated yields
123

S. Zhaleh et al.
Effect of temperature and solvent
Next, considering the selected amount of catalyst (0.015 g), appropriate conditions
of temperature and solvent were assessed (Table 2). As illustrated in Table 2, the
reaction time in the solvent-free condition had a decreasing trend, when the
temperature increased from room temperature up to 70 °C (entries 1–6). Consid-
ering green chemistry, we chose only safe solvents including H2O and EtOH. The
reaction was carried out in both solvents at room temperature and reflux and no
better results were found (entries 7–10).
A notable result was observed when H2O was utilized as the solvent as the
desired corresponding product was not observed; instead, the reaction promoted to
afford product 6 according as below (Scheme 1).
The formation of product 6 was confirmed by 1H and 13C NMR spectra.
Additionally, the melting point for product 6 was found to be 191–193 °C which
was in accordance with the literature [45]. It is suggested that water-soluble
ammonium acetate could not be treated with lipophilic other reactants dispersed in
water, and so the reaction proceeded without involvement of ammonium acetate. On
the other hand, regarding the higher activity of dimedone compared with ethyl
acetoacetate, the latter did not participate in the reaction leading to the
corresponding product 6.
Table 2 The screening of
various conditions for the
Entry Solvent Temperatures (°C) Time (min) Yielda (%)
reaction of benzaldehyde
(0.5 mmol), dimedone
(0.5 mmol), ethyl acetoacetate
(0.6 mmol), ammonium acetate
(1 mmol) and chitosan (0.015 g)
1
–
r.t
240
180
90
70
2
–
30
75
3
–
40
75
4
–
50
20
78
5
–
60
8
82
6
–
70
8
85
7
EtOH
EtOH
H2O
H2O
r.t.
15b
70
8
Reflux
r.t.
35
30
9
24b
120
Trace
Trace
a
Isolated yield
10
Reflux
b
Time in hours
Scheme 1 Unwanted reaction in water
123

Chitosan: a sustainable, reusable and biodegradable…
Versatility of procedure
To demonstrate the repeatability of this strategy, a broad variety of aromatic
aldehydes possessing electron-withdrawing and electron-releasing substitutions,
heterocyclic and aliphatic, were employed and the results are summarized in
Table 3, from which it can be seen than all the utilized aldehydes supplied the
desired products with great yields in short reaction times.
To show the generality of our green protocol, in addition to the derivatives of b-
ketoester (ethyl and methylacetoacetate), acetoacetanilide as a b-ketoeamide was
selected to participate in this reaction and the results are shown in Table 4.
Table 3 Chitosan-catalysed one-pot synthesis of 1,4-dihydropyridines
R1
R2
Product
Time (min)
m.p. (l)
Yield (%)a
Ph
Et
5a
5b
5c
5d
5e
5f
8
8
205–207 (204–205)65
258 (258–259)66
91
91
88
90
89
90
82
91
88
86
80
87
83
84
75
45
80
91
91
4-MeO-Ph
3-F-Ph
Et
Et
9
206–208
3-Cl-Ph
4-Cl-Ph
4-Br-Ph
4-HO-Ph
4-Me-Ph
3-Me-Ph
2-NO2-Ph
4-CN-Ph
2-Naph
Et
8
188–190 (192–193)56
242–244 (244–246)66
257–259 (255–257)64
237–239 (234–236)66
259–261 (261–262)65
228–230
Et
6
Et
6
Et
5g
5h
5i
6
Et
7
Et
8
Et
5j
10
10
8
207–209 (205–207)63
176–179 (140–142)58
237 (235–237)66
Et
5k
5l
Et
a-Me-Cinn
2-Thienyl
CH3CH2CH2
Ph
Et
5m
5n
5o
5p
5q
5r
5s
11
5
230–232
Et
237–239 (238–240)63
147–149 (150–152)66
259–261 (260–262)64
232–235 (235–236)64
252–254 (254–256)48
255 (256–258)48
Et
19
11
9
Me
Me
Me
Me
3-Br-Ph
4-NO2-Ph
4-NMe2-Ph
7
10
Reaction conditions: aldehyde (0.5 mmol), dimedone (0.5 mmol), ethylacetoacetate (0.6 mmol),
ammonium acetate (1 mmol) and catalyst (0.015 g)
a
Isolated yields
123

S. Zhaleh et al.
Table 4 Chitosan-catalysed one-pot synthesis of 1,4-dihydropyridines
R
Product
Time (min)
m.p. (l)
Yield (%)a
Ph
5t
35
50
60
55
40
243–245 (245–247)
233–235 (238–240)
305–307 ([300)
259–261 (255–257)
244–246
87
80
72
68
88
3-Cl-Ph
4-OH-Ph
2-NO2-Ph
4-OMe-Ph
5u
5v
5w
5x
Reaction conditions: aldehyde (0.5 mmol), dimedone (0.5 mmol), acetoacetanilide (0.6 mmol), ammo-
nium acetate (1 mmol) and catalyst (0.015 g)
a
Isolated yields
Fig. 3 Reusability of chitosan for the preparation of 1,4-DHPs
Reusability of chitosan
In terms of green chemistry, we investigated the reusability of chitosan as a
heterogeneous catalyst. Hence, after completion of the reaction, 5 ml ethanol was
added to the reaction mixture and the chitosan was separated by simple filtration,
washed with ethanol and dried and was then reused up to nine times without any
reduction in catalytic performance (Fig. 3). Ease of separation, recyclability and
reusability of the catalyst are promising plus points of our protocol.
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Chitosan: a sustainable, reusable and biodegradable…
Mechanistic evaluation
Here, a plausible mechanism for the Hantzsch synthesis of 1,4-dihydropyridine
derivatives is depicted (Scheme 2). As obvious from the catalyst structure, each
chitosan unit containing one amine group and two hydroxyl groups can activate both
nucleophilic and electrophilic species participating in the pathway leading to 1,4-
DHPs preparation. Mechanistically, H–H bonds between the hydroxyl and carbonyl
groups in three steps including knoevenagel product formation (I), 1,4-addition (II)
and cyclization (III) are key factors in this reaction. In addition, amine groups can
Scheme 2 A plausible reaction pathway
123

S. Zhaleh et al.
also behave as a base, enabling enol and enamine to act powerfully (I,II). In addition
to that, amine groups may speed up the dehydration reaction via proton abstraction
(IV).
Conclusion
In brief, we have introduced a new strategy for the preparation of a diversity of
known and unknown 1,4-dihydropyridines via Hantzsch-type condensation using
chitosan as an inexpensive green catalyst under solvent-free conditions. The
structure of the synthesized products were confirmed by NMR, CHNS analysis and
mass spectroscopy.
The promising aspects of this methodology are its efficiency, simplicity, clean
reaction profile, compatibility with different functional groups, quick reaction, high
yields of the reaction product and non-chromatographic purification. Moreover,
from the green point of view, recyclability of the catalyst without loss of its activity,
easy catalyst separation from the reaction mixture, low cost, small catalyst loading
and eco-compatibility of the catalyst are other significant features of this green
procedure.
Acknowledgment The University of Sistan and Baluchestan is thanked for financial supporting of this
work.
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