Chitosan based heterogeneous catalyses: Chitosan-grafted-poly(4- Vinylpyridne) as an efficient catalyst for michael additions and alkylpyridazinyl carbonitrile oxidation

Article abstract of DOI:10.3390/molecules18055288

Chitosan-grafted-poly(4-vinylpyridine) (Cs-PVP) copolymers could be synthesized under heterogeneous conditions in presence of a potassium persulfate and sodium sulfite redox system. The synthesized graft copolymer could be utilized effectively, in the form of beads, as an efficient catalyst for Michael additions of active methylenes to functionally substituted alkenes. Moreover, methyl moiety oxidation in methyl pyridazinyl carbonitriles by H ₂O₂ in the presence of chitosan-g-polyvinyl pyridine-supported iron (III) complex, Cs-PVP/Fe, could be affected. A variety of pyrans, naphthopyrans, and thiopyrans could be synthesized efficiently in the presence of these graft copolymer beads by novel catalytic routes. These polymeric catalysts could be used instead of the old toxic commercial organic basic catalysts, piperidine or pyridine, and could be readily isolated from the reaction mixture and recycled several times without significant loss of catalytic activity.

Full text of DOI:10.3390/molecules18055288

Molecules 2013, 18, 5288-5305; doi:10.3390/molecules18055288
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Chitosan Based Heterogeneous Catalyses:
Chitosan-Grafted-Poly(4-Vinylpyridne) as an
Efficient Catalyst for Michael Additions and
Alkylpyridazinyl Carbonitrile Oxidation
Khaled D. Khalil 1,2 and Hamad M. Al-Matar 1,*
1
Chemistry Department, Faculty of Science, University of Kuwait, P.O. Box 5969, Safat 13060,
Kuwait
2
Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt
* Author to whom correspondence should be addressed; E-Mail: h.almatar@ku.edu.kw;
Tel.: +965-2498-7559; Fax: +965-2481-6482.
Received: 10 April 2013; in revised form: 28 April 2013 / Accepted: 28 April 2013 /
Published: 8 May 2013
Abstract: Chitosan-grafted-poly(4-vinylpyridine) (Cs-PVP) copolymers could be
synthesized under heterogeneous conditions in presence of a potassium persulfate and
sodium sulfite redox system. The synthesized graft copolymer could be utilized effectively,
in the form of beads, as an efficient catalyst for Michael additions of active methylenes to
functionally substituted alkenes. Moreover, methyl moiety oxidation in methyl pyridazinyl
carbonitriles by H2O2 in the presence of chitosan-g-polyvinyl pyridine–supported iron (III)
complex, Cs-PVP/Fe, could be affected. A variety of pyrans, naphthopyrans, and
thiopyrans could be synthesized efficiently in the presence of these graft copolymer beads
by novel catalytic routes. These polymeric catalysts could be used instead of the old
toxic commercial organic basic catalysts, piperidine or pyridine, and could be readily
isolated from the reaction mixture and recycled several times without significant loss of
catalytic activity.
Keywords:
chitosan;
chitosan-g-poly(4-vinylpyridine);
graft
copolymer;
[chitosan-g-PVP]-supported iron (III) complex; Michael additions

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1. Introduction
Recently, biocatalysis and sustainable chemistry researchers are directed to develop new green
methodologies that aim to reduce and prevent pollution at its source [1–3]. Biocatalysis is a promising
technique based on the use of natural renewable biological materials, such as enzymes and polymers,
that provide cleaner methodologies with high selectivity and energy-efficient operation under mild
conditions in contrast to the traditional chemical catalysts [4,5]. Chitosan (2-acetamido-2-deoxy-β-D-
glucose-(N-acetylglucosamine) is a partially deacetylated polymer of chitin and is usually prepared
from chitin by reflux with a strong alkaline solution [6–8]. Some time ago, the utility of chitosan
as an efficient eco-friendly basic biocatalyst for Michael additions was reported and it could
already be shown that chitosan can catalyze the addition of bi-functional active methylenes to
arylidenemalononitriles and enaminones [9–12]. This type of reaction, involving simple addition of
active methylenes, phenols and naphthols to electron poor functionally substituted alkenes, is an
efficient C-C bond forming reaction. Classically these additions have been effected in the presence of
homogeneous basic catalysis [13–17]. Recently emphasis has been placed on adopting instead
heterogeneous recyclable catalyses [12,18]. So far a diversity of such catalyses were employed [19,20].
Moreover, chitosan, a chiral polysaccharide, has been used as an efficient catalyst for enantioselective
syntheses that result in the creation of asymmetric products with chiral center(s) [21–25]. Previously,
while using chitosan [9,11], we suffered from some disadvantages of this catalyst namely, that it
afforded low yields of products in many of the investigated reactions and it could not easily be
recycled because of its high hygroscopicity, leading it to form gels. Herein, we successfully overcome
the drawbacks of chitosan and enhance its catalytic activity via heterogeneous grafting
with 4-vinyl-pyridine (VP) [26] (Scheme 1), thereby producing a basic, recyclable, eco-friendly
biocatalyst that could be used efficiently in Michael additions, especially when a stronger basic
catalyst than chitosan, is required. Also, the use of the chitosan-g-polyvinyl pyridine, Cs-PVP in the
form of beads is usually required to increase the catalytic activity of the catalyst [18,27,28].
Scheme 1. Preparation of chitosan-g-PVP catalyst.
NH2
HOH2C
HO
HO
NH2
O
O
O
O
O
O
O
HOH2C
NHCOCH3
HO
H2C
OH
Chitosan
Heterogeneous Grafting
4-VP
N
H2
C
C
H
HN
O
HOH2C
HO
n
HO
NH2
O
O
O
O
O
O
HOH2C
NHCOCH3
HO
H2C
O
H
C
Chitosan-g-PVP
Graft Copolymer
C
H2
n
N

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In addition, chitosan has been reported to have high affinity for adsorption of metal ions [29–32].
The adsorption capacity of Fe(III) ions for chitosan/4-vinylpyridine copolymer is higher than that of
the original non-grafted chitosan owing to the presence of pyridine moieties in the PVP side chains [33].
Herein, chitosan-g-poly(4-vinylpyridine)-supported iron(III) complex, [Cs-PVP/Fe(III)], could be
prepared in the form of beads (Scheme 2) [34] of higher catalytic activity, and effectively used as a
powerful recyclable catalyst to oxidize methylpyridazinone in the presence of hydrogen peroxide to
afford the corresponding furopyridazinone derivative. The surface adsorption of Fe3+ ions on the
surface of chitosan involves nitrogen and oxygen atoms of the repeating units of chitosan as shown
below [34]:
Cs–NH2 + Fe3+ ↔ [Cs – NH2 --- Fe --- ]+3
Scheme 2. Probable structure of chelated complexes of chitosan with iron (III) ions.
HOH2C
O
O
HO
NH2
Fe
H2O
OH2
HO
NH2
O
O
HOH2C
2. Results and Discussion
2.1. Preparation of Cs-PVP Catalyst Beads
The investigated basic catalyst, (Cs-PVP), was prepared through heterogeneous grafting of
4-vinylpyridine onto chitosan powder as previously reported by Khalil et al. [26]. The structure of
1
13
grafted chitosan copolymer was confirmed by FT-IR, H-NMR, C-NMR and elemental analysis as
reported in our previous work [26]. Elemental analysis showed that the nitrogen content of chitosan,
N% = 7.1, was increased upon grafting with 4-vinylpyridine to N% = 8.0, which is an evidence for the
presence of pyridine moieties. The structure of the grafted copolymer was confirmed by FTIR, that
showed a characteristic C=N groups band at 2,197 cm−1 from the poly 4-vinylpyridine chains (Figure 1).
Also, the presence of pyridine rings is confirmed in the 1H-NMR spectrum (Figure 2) by the presence
of the peaks at 7.1 and 8.5 ppm in the aromatic range (Figure 2).

Molecules 2013, 18
Figure 1. FTIR of (a) Chitosan, (b) chitosan-g-poly(4-vinylpyridine) copolymer 80% G.
5291
Figure 2. 1H-NMR spectrum of 80% VP grafted chitosan.
The prepared Cs-PVP beads exhibited more basic character (pka = 5.9), as compared to chitosan
(pka = 6.4), owing to the presence of pyridine moieties along the chitosan backbone. The cross-linked
chitosan graft copolymer is characterized by higher thermal stability as compared to chitosan [26] so it
could then be used effectively in higher temperature reactions (TGA was reported previously [26]).
2.2. Applying Cs-PVP Beads as Efficient Basic Heterogeneous Catalyst in Michael Additions
Benzylidene-malononitrile 1 reacted with dimedone to yield the chromene-3-carbonitrile derivative
2 in an excellent yield (>95%), more than that was obtained in presence of the original chitosan (75%),
(Scheme 3). The product structure was assigned by using X-ray crystallographic analysis (Figure 3) [35].
These derivatives could be previously prepared in the presence of homogeneous basic catalysts [9–17].
As a result of the cross-linking nature of the invented Cs-PVP catalyst, it could be readily isolated by
simple filtration and reused again for more than five times without loss of its catalytic activity, after
extensive washing with hot ethanol and drying in an oven at 100 °C for 4 h. Similarly, reaction of 1
with cyclohexanone was conducted successfully in the presence of Cs-PVP beads to give a similar

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product 3 to that was obtained previously [9] in the presence of chitosan (55%) but in much higher
yield (~90%). While the reaction of 1 with ethyl acetoacetate has been reported earlier [36] to produce
the 2-aminopyran 4 together with the benzene derivative 5, only 4 was formed in a higher yield ~90%
when 1 was reacted with ethyl acetoacetate in ethanol in presence of Cs-PVP beads. Again, the
produced structure was confirmed by X-ray crystal structure determination (Figure 4). The catalyst
could be easily isolated from the reaction media and recycled several times after being washed with
ethanol and dried in an oven. α-Naphthol 6 also reacted with 1 to yield 7 in 86% yield.
Scheme 3. Heterogeneous basic catalyzed Michael additions using Cs-PVP beads.
Ar
CN
EtOOC
Me
Ph
O
O
NH2
O
CN
4a-c
Me
O
O
Me
Ar = C6H5, 4-Cl-C6H4-,
4-Meo-C6H4-
OMe
OMe
O
OEt
O
NH2
13
Me
12
Ph
Ph
CN
CN
O
COOEt
EtOOC
1
O
Me
CH3
NC
CN
CN
OH
NH2
5
CN
NC
CN
Ph
O
Ph
O
6
NH2
CN
NH2
3
O
2
Ph
7
Ph
CN
NC
CN
CN
CN
H2C
H2N
+
H2C
S
+
Ph CHO
H2N
NH2
S
10
8
9
11
Figure 3. X-ray crystal structure of chromene-3-carbonitrile derivative 2.

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Figure 4. X-ray crystal structure of 2-aminopyran derivative 4.
In order to estimate the appropriate catalyst loading, a model reaction of benzylidene-malononitrile
1 (1.54 g, 10 mmol) and dimedone (1.40 g, 10 mmol) was carried out in 25 mL absolute ethanol using
1, 5, 10, 15, and 20% wt. of catalyst under the same conditions. The 10%wt catalyst loading was found
to be the optimal quantity (Figure 5). Catalyst was reused four times and the results showed that the
chitosan graft copolymer can be reused as such without significant loss in its catalytic activity (Table 1).
Figure 5. Optimization of the chitosan graft copolymer as basic catalyst.
120
100
80
60
40
20
0
320
300
280
260
240
220
200
180
160
Loading Catalyst %wt vs %Yield
Loading Catalyst %wt vs Time (min.)
0
5
10
15
20
25
30
Loading Catalyst %wt
Table 1. Recyclability of the chitosan graft copolymer as basic catalyst.
Product
2
Fresh Catalyst
Recycled (1)
Recycled (2)
Recycled (3)
Recycled (4)
95
93
93
92
92
All these products were previously [9,11] obtained in presence of chitosan but in lower yields, and
furthermore, with the latter, removal of the product from the catalyst could not be easily accomplished
as in each case the catalyst adsorbed part of the reaction media forming a gel mass. The cross-linked
graft copolymer beads did not behave similarly and its use in the form of beads has enhanced its
catalytic activity to a great extent. The thiopyran 11 could be obtained in a one pot reaction of 8, 9, and 10,
(yields: Cs = 80%; Cs-PVP = 95%; cf. Scheme 3). This product has been obtained earlier via addition
of cyanothioacetamide to 1. While 1 failed to add to 12 in the presence of chitosan or even piperidine,
it reacted smoothly with 12 in the presence of Cs-PVP beads affording the 5-acetyl-2-aminopyran
derivative 13 in 80% yield.

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Some time ago the formation of dieneamide 15a via reaction of enaminone 14a with malononitrile
has been reported from our laboratories [37,38]. We have recently shown that this product can be
obtained in better yields by utilizing chitosan as catalyst [11]. Now we report that the dieneamide 15a is
also obtainable in higher yield in the presence of grafted chitosan Cs-PVP beads (yields: Cs = 80;
Cs-PVP = 90). Moreover, the furanyl derivative 15b could be obtained from 14b (yields: Cs = 78;
Cs-PVP = 95). The postulated mechanism of this remarkable transformation is shown below (Scheme 4).
Scheme 4. Synthesis of dieneamides by using Cs-PVP basic catalyst.
CN
CN
O
NC
H2C
O
CN
R
R
NMe2
Cs-PVP
NMe2
14a,b
R, a = phenyl-,
b = 2-furyl-
NH2
CONH2
CN
CN
Me2N
R
O
R
NMe2
15a,b
2.3. Preparation of Cs-PVP/Fe(III) Catalyst Beads
The second goal of our study was the formation of chitosan-PVP/Fe(III) complex, Cs-PVP/Fe(III),
using same methodology that published by Ngah et al. [33] and Burke et al. [34]. It is of value to
mention that the previously prepared basic catalyst Cs-PVP exhibited higher metal-binding capacity, as
compared to the original chitosan, owing to the presence of extra binding nitrogen-atoms with free
lone pairs like in NH2 groups and pyridine moieties. When 50 mg of chitosan or graft chitosan were
placed in a 10 nM Fe3+ solution at pH = 1.8, for a period of time 5 h, it was found that the adsorption
capacity of the graft copolymer, Cs-PVP, was higher than that of the original chitosan, since the
amount of adsorbed iron on the graft copolymer was 0.086 mmol Fe3+/g while it was 0.077 is for
original chitosan. Elemental analysis of Fe(III)-supported chitosan graft copolymer by EDS (Table 2,
Figure 6) showed that 32% of Fe(III) wascon the surface as result of the metal complexation with the
N-atoms of glucosamine units and pyridine moieties and C-6 hydroxyl group binding sites over the
chitosan graft surface.
Table 2 EDS of chitosan-g-poly(4-vinylpyridine)/Fe3+ chelate.
Element
C K
Weight%
17.24
Atomic%
38.89
N K
4.25
8.22
O K
12.25
20.74
Fe K
66.27
32.15
Totals
100.00

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Figure 6. EDS of Fe(III) supported chitosan-poly(4-vinylpyridine) graft, Cs-PVP/Fe3+ complex.
The produced Cs-PVP/F(III) complex could be used successfully as an efficient catalyst for
oxidation of methyl pyridazinones as shown in the last part of our study. Scanning electron microscopy
exhibited great differences in the surface morphology upon grafting and complexation with Fe3+ ions
(Figure 7). From the SEM the fibrous nature of chitosan is lost upon grafting and regular geometric
shapes appeared that were attributed to the coordination with Fe3+ ions. The suggested structure of
chitosan Fe(III) chelates is supposed [39] to occur as follows (Scheme 4).
Figure 7 Scanning electron microscope for (a) Chitosan Cs, (b) Cs-PVP 80%G,
(c) Cs-PVP/Fe3+ complex.
(a)
(b)

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Figure 7. Cont.
(c)
2.4. Utility of Cs-PVP/Fe(III) beads as an Efficient Catalyst for Oxidation of Methyl Pyridazinones
One of the major challenges for organic synthesis is how to effect controlled oxidation of non-
activated alkyl functions. Several approaches exist among which Fe (III) Chitosan-PVP copolymer
catalysts are of utility. We would like here to report first successful controlled oxidation of the methyl
function in 16 utilizing Cs-PVP/Fe (III) chelates. Thus refluxing 16a,b with Cs-PVP/Fe (III) complex
in the presence of excess hydrogen peroxide afforded 17a,b. The potential utility of 17a,b as
precursors to phthalazines via addition of electron poor alkenes, thus replacing thienopyridazines
classically utilized by Elnagdi et al. for this purpose will be subject of further communication (Scheme 5).
Scheme 5. Selective oxidation of methylpyridazinones in presence of chitosan-based iron
(III) catalyst, Cs-PVP/Fe(III).
O
CH3
NH2
CN
O
H2O2 / AcOH
Cs-PVP-Fe
N
N
O
N
N
Ar
Ar
17a,b
16a,b
Ar = phenyl, p-Chlorophenyl
3. Experimental
3.1. General
Melting points were recorded on Gallenkamp apparatus and are reported uncorrected. The Fourier
Transform infrared (FTIR) spectra were recorded in KBr pellets on a JASCO FT-IR-6300 system at a
resolution of 4 cm−1 in the 400–4000 cm−1 range. 1H-NMR measurements were determined on a Bruker
1
DPX spectrometer, at 400 MHz for H-NMR and 100 MHz for 13C-NMR, in DMSO-d6 as solvent
using TMS as internal standard. Solid NMR spectra were recorded on a 600MHz Bruker Avance II

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spectrometer, operating at 150 MHz for 13C-NMR. Mass spectra were measured on a GC-MS
DFS-Thermo spectrometer, using 70 eV EI. Elemental analyses were measured by means of an
Elementar-Vario Microcube Elemental Analyzer. The scanning electron microscopy (SEM) was
conducted using a JEOL JSM-630 J scanning electron microscope operated at 20 kV. (TGA data was
reported previously [26]) Single crystal X-ray crystallographic analysis was performed using a Rigaku
Rapid II instrument. Copies of original data can be provided upon request.
3.2. Samples
Chitosan, with degree of deacetylation (DDA) = 77.8%, was kindly supplied by Professor Furuhata
of Tokyo Institute of Technology (T. I. Tech.). 4-Vinylpyridine, initiators (K2S2O7 and NaHSO3),
and all solvents were purchased from Sigma-Aldrich Chemicals (Germany) and used without any
further purification.
3.3. Materials
3.3.1. Preparation of Chitosan Beads Cs
Chitosan beads were prepared according to the published procedure of Ngah et al. [30]. Chitosan
solution was prepared by dissolving chitosan powder (2.00 g) in 5% (v/v) acetic acid solution (60 mL).
The chitosan solution was sprayed into 0.50 M NaOH solution (500 mL) as a precipitation bath, which
neutralized the acetic acid within the chitosan gel and thereby coagulated the chitosan gel as uniform
spherical chitosan gel beads. A magnetic stirrer was used to stir the aqueous NaOH solution. The wet
chitosan gel beads (hereafter called chitosan beads) were extensively rinsed with distilled water to
remove any NaOH, filtered and finally air-dried to remove the water from the pores of the structure.
The beads were then stored in distilled water and ready for use.
3.3.2. Preparation of Basic Catalyst Chitosan-g-poly(vinylpyridine)(Cs-PVP) Beads
3.3.2.1. Heterogeneous Grafting of 4-Vinylpyridine onto Chitosan
The grafting of 4-vinylpyridine onto chitosan was conducted using the same procedure reported in
the literature [21], a typical heterogeneous method in which chitosan powder (1.00 g) was suspended
in distilled water (50 mL) and mixed with 3 × 10−3 M of redox initiator mixture (1:0.75) K2S2O7 and
NaHSO3, respectively. 4-Vinylpyridine monomer (1.05 g, 10 mmol) was added and the reaction was
conducted at 55 °C for 3 h. At the end of reaction time, the graft copolymer was filtered off and
washed with water and was then extensively purified with hot ethanol using the Soxhlet extraction
technique to get rid of the unreacted monomer. Finally the graft copolymer (Cs-PVP), was dried. An
80% graft was obtained. The used amount in all reaction was 10% wt of the Cs-PVP catalyst.
3.3.2.2. Preparation of Chitosan/PVP Copolymer Beads
Applying the same reported methodology [30], freshly prepared Cs-PVP copolymer was converted
into spherical beads by dissolving graft copolymer (1.00 g) in 5% (v/v) acetic acid solution (50 mL).

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The graft copolymer solution was treated as usual and thereby the gel beads were coagulated. The wet
grafted chitosan beads were extensively washed with distilled water to be ready for use.
3.3.3. Preparation of Cs-PVP—Supported Iron(III) Complex by Adsorption of Fe3+ Ions on Cs-PVP
Grafted Chitosan Beads Using Fe(NO3)3 [34]
The degree of adsorption was calculated based on the difference of Fe3+ concentration in aqueous
solution before and after adsorption at a wavelength of 248 nm using an atomic absorption
spectrophotometer (Perkin-Elmer 3100 Model). For Fe(III) adsorption onto Cs-PVP, a contact time of
5 h at pH 1.8 was used for stirred mixture of Cs-PVP beads (0.05 g) and Fe(III) solution (100 mL,
10 mM) in a 250 mL beaker. The amount adsorbed on the beads was calculated according to the
following equation:
( C0 - Ce ) V
Adsorption Capacity (qe) =
W
where C0 is the initial Fe(III) concentration (ppm), Ce is the final concentration of Fe(III) after the
adsorption time, V is the volume of Fe(III) solution (mL) and W is the used weight of graft copolymer
Cs-PVP beads (g). The yellowish-colored beads adsorbed Fe3+ were washed thoroughly with distilled
water and stored in distilled water for further use. Under the previous conditions, the maximum
adsorption capacity was obtained as 0.089 mmol Fe3+/g chitosan.
3.3.4. Reaction of Benzylidene-Malononitrile 1 with Dimedone and Cyclohexanone
A mixture of benzylidene-malononitrile 1 (1.54 g, 10.0 mmol) with either dimedone or
cyclohexanone (10.0 mmol) in absolute ethanol (50 mL) was refluxed for 3 h in the presence of a
catalytic amount (10%wt.) of the catalyst (Method A using Cs beads and Method B using Cs-PVP
beads). The solid product, so formed, was filtered of and recrystallized from ethanol.
2-Amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (2). Colorless
crystals; % Yields: Method A (Cs beads = 75%), Method B (Cs-PVP beads = 95%); Mp 234 °C, lit.
1
233–235 °C [40]; IR (KBr): υ = 1708 (C=O), 2198 (CN), 3341, 3420 (NH2) cm−1; H-NMR
(DMSO-d6): δ = 0.96 (s, 3H, CH3), 1.05 (s, 3H, CH3), 2.09–2.24 (s, 2H, CH2), 2.47 (s, 2H, CH2), 4.20
(s, 1H, CH, C-4 pyran), 7.01 (s, 2H, NH2), 7.15–7.28 (m, 5H, phenyl-H); 13C-NMR (DMSO-d6):
δ = 26.9 (CH3), 28.5 (CH3), 31.9 (C(CH3)2), 35.7 (C-4, pyran), 50.1 (CH2), 58.5 (CH2), 119.8 (CN),
112.9, 126.7, 127.3, 128.5, 144.8, 158.6, 162.7 (aromatic carbons); MS, m/z (%), 294.1 (M+, 29), 217.1
(66), 55.1 (100). Anal. Calcd. for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found: C, 73.36; H, 6.10;
N, 16.43.
2-Amino-4-phenyl-4a,5,6,7-tetrahydronaphthalene-1,3,3(4H)-tricarbonitrile (3). Yellow crystals; %
Yields: Method A (Cs beads = 55%), Method B (Cs-PVP beads = 90%); Mp 252 °C; Lit. Mp 253 °C [9];
1
IR (KBr): υ = 1650 (olefinic C=C), 2211 (CN), 2254 (CN) 3341, 3420 (NH2) cm−1; H-NMR
(DMSO-d6): δ = 0.84 (m, 1H, 5-H), 1.44 (m, 2H, 5-H, 6-H), 1.66 (m, 1H, 6-H), 2.04 (m, 1H, 7-H),
2.17 (m, 1H, 7-H), 2.80 (m, 1H, 4a-H), 3.52 (d, 3J = 12.3 Hz, 1H, 4-H), 5.72 ("s", 1H, 8-H), 7.37

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(s, 2H, NH2), 7.41 (m, 3H, m-H, p-H, Phenyl), 7.48 (m, 1H, o-H, Phenyl), 7.59 (m, 1H, o-H, Phenyl);
13C-NMR (DMSO-d6): δ = 21.0 (C-6), 24.9 (C-7), 27.0 (C-5), 33.8 (C-4a), 42.9 (C-3), 50.5 (C-4), 81.5
(C-1), 112.4 (3-CN), 112.6 (3-CN), 116.2 (1-CN), 120.3 (C-8), 126.9 (o-C, Phenyl), 128.6 (m-C,
Phenyl), 128.8 (C-8a), 128.9 (p-C, Phenyl), 132.4 (o-C, Phenyl), 134.6 (i-C, Phenyl), 143.6 (C-2); MS,
m/z (%), 300.2 (M+, 100), 209.1 (43), 91.1 (54).
3.3.5. Reaction of Arylidene-Malononitrile with Ethyl Acetoacetate
A mixture of the arylidenemalononitrile derivative (phenyl, p-chlorophenyl or p-methoxyphenyl)
(10.0 mmol) with ethyl acetoacetate (10.0 mmol) in absolute ethanol (50 mL) was refluxed for 3 h in
the presence of catalytic amount (10%wt.) of the catalyst (Method A using Cs beads and Method B
using Cs-PVP beads). The solid product, so formed, was filtered off and recrystallized from ethanol.
Ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate (4a). Colorless crystals; % Yields:
Method A (Cs beads = 59%), Method B (Cs-PVP = 90%); Mp 194 °C; Lit. Mp 194–195 °C [41];
1
IR (KBr): υ = 1691 (C=O), 2190 (CN), 3329, 3385 (NH2) cm−1; H-NMR (DMSO-d6): δ = 1.03
(t, J = 7.0 Hz, 3H, ester CH3), 2.32 (s, 3H, pyran-CH3), 3.98 (AB of ABX3, J = 7.0 Hz, 2H, OCH2),
13
4.32 (s, 1H, H-4), 6.93 (br. s, 2H, NH2), 7.16–7.34 (m, 5H, Phenyl); C-NMR (DMSO-d6): δ = 13.7
(CH3, ester), 18.1 (CH3), 38.8 (C-4), 57.3 (C-3), 60.1 (CH2, ester), 107.3 (C-5), 119.6 (CN), 126.8
(C-4', Phenyl), 127.1 (C-2', Phenyl), 128.4 (C-3', Phenyl), 144.8 (C-1', Phenyl), 156.5 (C-6), 158.5
(C-2), 165.4 (C=O); MS, m/z (%), 284.1 (M+, 70), 207.1 (100). Anal. Calcd. for C16H16N2O3: C, 67.59;
H, 5.67; N, 9.85. Found: C, 67.44; H, 5.61; N, 9.70.
Ethyl 6-amino-4-(4-chlorophenyl)-5-cyano-2-methyl-4H-pyran-3-carboxylate (4b). Pale yellow
crystals; % Yields: Method A (Cs beads = 68%), Method B (Cs-PVP = 87%); Mp 162 °C; IR (KBr):
1
υ = 1695 (C=O), 2210 (CN), 3330, 3400 (NH2) cm−1; H-NMR (DMSO-d6): δ = 1.10 (t, J = 7.1 Hz),
3H, ester CH3), 2.39 (s, 3H, pyran-CH3), 4.14 (AB of ABX3, J = 7.1 Hz), 2H, OCH2), 4.34 (s, 1H,
4-H), 7.01 (br. s, 2H, NH2), 7.08 (d, 2H, o-H, J = 8 Hz, aryl), 7.37 (d, 2H, m-H, J = 8 Hz, aryl);
13C-NMR (DMSO-d6): δ = 14.1 (CH3 of CO2C2H5), 19.2 (CH3), 37.0 (C-4), 56.1 (C-5), 61.3 (O-CH2),
106.5 (C-3), 118.6 (CN), 125.8, 128.7, 129.6, 146.4, 154.2, 156.8 (C-2, C-6), 167.0 (C=O); MS, m/z
(%), 318.1 (M+, 37), 207.1 (100). Anal. Calcd. for C16H15ClN2O3: C, 60.29; H, 4.74; Cl, 11.12; N,
8.79. Found: C, 60.13; H, 4.66; Cl, 10.94; N, 8.57.
Ethyl 6-amino-5-cyano-4-(4-methoxyphenyl)-2-methyl-4H-pyran-3-carboxylate (4c). Colorless
crystals; % Yields: Method A (Cs beads = 70%), Method B (Cs-PVP = 90%); Mp. 145 °C; Mp
1
144–145 °C [41]; IR (KBr): υ = 1684 (C=O), 2188 (CN), 3325, 3395 (NH2) cm-1; H-NMR
(DMSO-d6): δ = 1.12 (t, J = 7.1 Hz, 3H, ester CH3), 2.36 (s, 3H, pyran-CH3), 3.79 (s, 3H, O-CH3),
3.99 (AB of ABX3, J = 7.1 Hz, 2H, ester CH2), 4.38 (s, 1H, H-4), 4.54 (br. s, 2H, NH2), 6.85 (d, 2H,
H-3', J = 8 Hz, aryl), 7.16 (d, 2H, H-2', J = 8 Hz, aryl); 13C-NMR (DMSO-d6): δ = 18.1 (CH3 of ester),
37.7 (C-4), 55.0 (O-CH3), 60.3 (CH2 of ester), 62.4 (C-3), 108.1 (C-5), 114.1 (C-3'), 118.8 (CN), 128.7
(C-2'), 136.0 (C-1'), 156.4 (C-4'), 157.4 (C-6), 158.5 (C-2), 160.3 (C=O); MS, m/z (%), 314.1 (M+, 9),
184.1 (100). Anal. Calcd. for C17H18N2O4: C, 64.96; H, 5.77; N, 8.91. Found: C, 64.58; H, 5.62;
N, 8.78.

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3.3.6. Reaction of 1 with α-Naphthol
A mixture of benzylidene-malononitrile 1 (1.54 g, 10.0 mmol) with α-naphthol (10.0 mmol) in
absolute ethanol (50 mL) was refluxed for 4 h in the presence of a catalytic amount (10% wt.) of the
catalyst (Method A using Cs beads and Method B using Cs-PVP beads). The solid product, so formed,
was filtered off and recrystallized from ethanol.
2-Amino-4-phenyl-4H-benzo[h]chromene-3-carbonitrile (7). This compound was obtained as yellow
crystals [42]; % Yields: Method A (Cs beads = 71%), Method B (Cs-PVP = 86%); Mp 210 °C; IR
1
(KBr): υ = 1605 (Ar C=C), 1656 (olefinic C=C), 2205 (CN), 3303, 3448 (NH2) cm−1; H-NMR
(DMSO-d6): δ = 4.90 (s, 1H, 4-H), 7.11 (d, 3J = 8.5 Hz, 1H, 5-H), 7.56 m, 2H/7.64, t, 1H/7.88, d,
1H/8.27, d, 1H (6-H, 7-H, 8-H, 9-H, 10-H), 7.18 (s, 2H, NH2), 7.24 (m, 1H, p-H, Phenyl), 7.25 (m, 2H,
13
o-H, Phenyl), 7.32 (m, 2H, m-H, Phenyl); C-NMR (DMSO-d6): δ = 40.9 (C-4), 56.3 (C-3), 117.9,
120.7, 122.7, 123.9, 126.2, 126.6, 126.7, 126.9, 127.6, 132.7 (C-4a, C-5, C-6, C-6a, C-7, C-8, C-9,
C-10, C-10a, p-C, Phenyl), 120.4 (CN), 127.6 (o-C, Phenyl), 128.7 (m-C, Phenyl), 142.7, 145.6
(C-10b, i-C, Phenyl), 160.1 (C-2); MS, m/z (%), 298.1 (M+, 75), 221.1 (100), 77 (10). Anal. Calcd. for
C20H14N2O: C, 80.52; H, 4.73; N, 9.39. Found: C, 80.19; H, 4.64; N, 8.17.
3.3.7. One Pot Reaction of benzaldehyde and malononitrile with 2-cyanothioacetamide (11)
A mixture of benzaldehyde (1.06 g, 10.0 mmol), malononitrile (0.66 g, 10.0 mmol) and
2-cyanothioacetamide (1.00 g, 10.0 mmol) in absolute ethanol (50 mL) was refluxed for 4 h in the
presence of a catalytic amount (10% wt.) of both catalysts (Method A using Cs beads and Method B
using Cs-PVP beads). The solid product was filtered off and recrystallized from ethanol.
2,6-Diamino-4-phenyl-4H-thiopyran-3,5-dicarbonitrile (11). Yellow crystals; % Yields: Method A (Cs
beads = 80%), Method B (Cs-PVP = 95%); Mp 191–192 °C [36]; IR(KBr): υ = 2192 (broad band, two
1
CN groups), 3300–3450 (two NH2 groups) cm−1; H-NMR (DMSO-d6): δ = 4.24 (s, 1H,4-H),
6.86–6.89 (s, 4H, two NH2 groups), 7.22–7.34 (m, 5H, Phenyl); 13C-NMR (DMSO-d6): δ = 43.4 (C-4),
72.0 (C-3), 118.6 (two CN), 126.7, 127.2, 128.9, 143.2 (Phenyl), 151.0 (C-2, thiopyran); MS, m/z (%),
254.1 (M+, 12), 228.1 (41), 77.1 (100). Anal. Calcd. for C13H10N4S: C, 61.40; H, 3.96; N, 22.03; S,
12.61. Found: C, 61.13; H, 3.88; N, 21.87; S, 12.52.
3.3.8. Reaction of 1 with 4,4-Dimethoxybutan-2-one
A mixture of benzylidene-malononitrile 1 (1.54 g, 10.0 mmol) with acetylacetaldehyde, dimethyl
acetal (AADMA, 10.0 mmol) in absolute ethanol (50 mL) was refluxed for 4 h in the presence of a
catalytic amount (10%wt.) of the catalyst (Method A using Cs beads and Method B using Cs-PVP
beads). The solid product, so formed, was filtered off and recrystallized from ethanol.
5-Acetyl-2-amino-4-phenyl-4H-pyran-3-carbonitrile (13). Yellow powder; % Yields: Method A (Cs
beads = 0%), Method B (Cs-PVP = 70%); 198 °C; IR (KBr): υ = 1701 (C=O), 2205 (CN), 3320–3400
(NH2 groups) cm−1; 1H-NMR (DMSO-d6): δ = 2.32 (s, 3H, CH3), 4.29 (s, 1H, C-2 pyran), 6.94 (s, 2H,
NH2), 7.14–7.33 (m, 5H, Phenyl); 13C-NMR (DMSO-d6): δ = 19.4 (CH3), 38.6 (C-4, pyran), 60.9 (C-3,

Molecules 2013, 18
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pyran), 114.2 (C-5, pyran), 116.8 (CN), 122.1, 128.4, 129.0, 138.6, (phenyl), 152.9, 157.3 (C-2, C-6
pyran), 183.9 (C=O); MS, m/z (%), 240.1 (M+, 24), 197.1 (92), 163.1 (100). Anal. Calcd. for
C14H12N2O2: C, 69.99; H, 5.03; N, 11.66. Found: C, 69.78; H, 4.92; N, 11.49.
3.3.9. Reaction of Enaminones 14a,b with Malononitrile
A mixture of (10.0 mmol) of enaminone 14a,b with malononitrile (0.66 g, 10.0 mmol), in absolute
ethanol (50 mL) was refluxed for 3 h in the presence of catalytic amounts (10%wt.) of the catalyst
(Method A using Cs beads and Method B using Cs-PVP beads). The solid product, so formed, was
filtered off and recrystallized from ethanol.
2-Cyano-5-(dimethylamine)-5-phenylpenta-2,4-dienamide (15a). Yellow crystals; % Yields: Method A
(Cs beads = 80%), Method B (Cs-PVP = 90%); Mp: 257 °C; IR (KBr, cm1): ν = 1667 (CO), 2191
1
(CN), 3330 and 3395 (NH2); H-NMR (400 MHz, DMSOd6) δ = 2.77 (s, 3H, CH3), 3.16 (s, 3H,
CH3), 5.63 (d, 1H, J = 12.6 Hz, H-4), 6.84 (s, 2H, NH2), 6.98 (d, 1H, J = 12.6 Hz, H-3), 7.26–7.29 (m,
13
2H, phenyl-H), 7.38–7.41 (m, 3H, phenyl-H). C-NMR (125 MHz, DMSO-d6), δ = 39.8 (N(CH3)2),
87.6, 96.9, 118.8 (CN), 128.6, 129.6, 134.0 (aromatic carbons), 153.3 (C-3), 164.6 (C-5), 165.11
(C=O). MS (m/z (%)): 241.1 (M+, 100), 179.1(76). Anal. Calcd. for C14H15N3O: C, 69.69; H, 6.27; N,
17.41. Found: C, 69.56; H, 6.27; N, 17.29.
2-Cyano-5-(dimethylamino)-5-(furan-2-yl)penta-2,4-dienamide (15b). Reddish brown crystals;
% Yields: Method A (Cs beads = 78%), Method B (Cs-PVP = 95%); M.p. 245 °C; IR (KBr, cm−1):
1
ν = 1669 (CO), 2189 (CN), 3340 and 3305 (NH2); H-NMR (400 MHz, DMSO-d6), δ = 2.97 (s, 6H,
N(CH3)2), 5.59 (d, 1H, J = 12.5 Hz, H-4), 6.72 (d, 1H, J = 5.0 Hz, furyl H-3), 6.78 (d, 1H, J = 5.0 Hz,
furyl H-5), 7.02 (s, 2H, NH2), 7.56 (d, 1H, J = 12.5 Hz, H-3), 7.99 (t, 1H, J = 5.0 Hz, furyl H-4);
13C-NMR (125 MHz, DMSO-d6): δ = 40.77, 90.40, 98.31, 111.53, 115.75, 118.38, 144.80, 145.37,
151.73, 153.40 (C-5), 164.49 (CONH2). MS (m/z (%)): 231.1 (M+, 21), 179.1(100). Anal. Calcd. for
C12H13N3O2: C, 62.33; H, 5.67; N, 18.17. Found: C, 62.19; H, 5.57; N, 17.58.
3.3.10. Oxidation of Methyl Pyridazinone with Cs-PVP-Fe(III) Complex
Hydrogen peroxide solution (10 mmol, 30%) was added carefully to a preheated solution of
methylpyridazinones 16a,b (2 mmol) in glacial acetic acid (5 mL). The reaction mixture was then
refluxed in the presence of 10%wt of Cs-PVP/Fe catalyst until thin layer chromatography indicated
that the reaction was completed. The solid crude product, so formed, was poured into ice/water
mixture (20 mL) and stirred for 30 min. The product so formed was extracted using CH2Cl2. The
organic layer was dried over anhydrous Na2SO4 and then concentrated under reduced pressure to yield
analytically pure products 17a,b. The used Cs-PVP/Fe(III) catalyst could be regenerated and used for 5
times without appreciable loss of activity.
7-Amino-2-phenylfuro[3,4-d]pyridazin-1(2H)-one (17a). Yellow powder; M.p. 198 °C; IR (KBr, cm1):
1
ν = 1660 (CO), 3330 and 3390 (NH2); H-NMR (400 MHz, DMSO-d6), δ = 6.07 (s, 2H, NH2), 7.46
(s, 1H, pyridazinone), 7.51 (m, 5H, phenyl), 8.14 (s, 1H, furan); 13C-NMR (125 MHz, DMSO-d6),
δ = 114.1, 121.6, 126.8, 130.7, 131.2, 139.9, 140.8, 144.0, 147.2 (aromatic carbons), 168.2 (C=O). MS

Molecules 2013, 18
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(m/z (%)): 227.1 (M+, 12), 77.1 (100). Anal. Calcd. for C12H9N3O2: C, 63.43; H, 3.99; N, 18.49.
Found: C, 63.28; H, 3.78; N, 18.29.
7-Amino-2-(4-chlorophenyl)furo[3,4-d]pyridazin-1(2H)-one (17b). Pale yellow powder. (M.p. 216 °C);
1
IR (KBr, cm−1): ν = 1668 (CO), 3360 and 3330 (NH2); H-NMR (400 MHz, DMSO-d6), δ = 6.29
(s, 2H, NH2), 7.25 (d, 2H, o-H, J = 8 Hz, aryl), 7.69 (d, 2H, m-H, J = 8 Hz, aryl), 8.26 (s, 1H, furan);
13C-NMR (125 MHz, DMSO-d6) δ = 113.1, 124.4, 126.9, 128.6, 129.0, 133.1, 139.1, 151.7, 155.9
(aromatic carbons), 171.9 (C=O). MS (m/z (%): 261.1 (M+, 4), 111.1 (100). HRMS; 261.0298
(C12H8O2N3Cl1).
4. Conclusions
We could clearly show that chitosan-g-PVP beads can be used as an efficient basic, recyclable,
environmentally friendly biocatalyst for Michael additions while its supported iron (III) complex is a
promising catalyst for controlled oxidation of alkyl functions. The novel catalysts, Cs-PVP and
Cs-PVP/Fe(III) beads, could be regenerated and reactivated at least five times, without appreciable loss
of activity.
Acknowledgments
The authors are grateful to the Kuwait University Research Administration for financial support of
project SC 01/08, Analytical facilities provided by SAF projects No. GS 01/01, GS 01/03, GS 03/08 &
GS 01/05 are greatly appreciated.
Conflict of Interest
The authors declare no conflict of interest.
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© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).