Ultrasound assisted the green synthesis of 2-amino-4H-chromene derivatives catalyzed by Fe3O4-functionalized nanoparticles with chitosan as a novel and reusable magnetic catalyst

Article abstract of DOI:10.1016/j.ultsonch.2014.02.002

Fe₃O₄ nanoparticles were prepared by chemical coprecipitation method. Subsequently immobilization of chitosan on Fe ₃O₄ nanoparticles was accomplished and afforded magnetic Fe₃O₄-chitosan nanoparticles. Synthesized nanoparticles was found to be a magnetic and heterogeneous catalyst for a one-pot and efficient synthesis of 2-amino-4H-chromenes by condensation of aldehydes with malononitrile and resorcinol under ultrasound irradiation as an ecofriendly method. This convenient procedure allowed us to achieve products under ultrasound irradiation in short time and excellent yield without using of harmful catalyst. The present method will permit a further increase of the diversity within the 2-amino-4H-chromene family.

Full text of DOI:10.1016/j.ultsonch.2014.02.002

Accepted Manuscript
Ultrasound assisted the green synthesis of 2-amino-4H-chromene derivatives
catalyzed by Fe3O4-functionalized nanoparticles with chitosan as a novel and
reusable magnetic catalyst
Javad safari, Leila javadian
PII:
S1350-4177(14)00050-9
DOI:
http://dx.doi.org/10.1016/j.ultsonch.2014.02.002
ULTSON 2512
Reference:
Ultrasonics Sonochemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 October 2013
1 February 2014
2 February 2014
Please cite this article as: J. safari, L. javadian, Ultrasound assisted the green synthesis of 2-amino-4H-chromene
derivatives catalyzed by Fe3O4-functionalized nanoparticles with chitosan as a novel and reusable magnetic catalyst,
Ultrasonics Sonochemistry (2014), doi: http://dx.doi.org/10.1016/j.ultsonch.2014.02.002
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Ultrasound assisted the green synthesis of 2-amino-4H-chromene derivatives
catalyzed by Fe3O4-functionalized nanoparticles with chitosan as a novel
and reusable magnetic catalyst
Javad safaria,* and Leila javadiana
aLaboratory of Organic Chemistry Research, Department of Organic Chemistry, College of
Chemistry, University of Kashan, P. O. Box: 87317-51167, Kashan, I.R.Iran
E-mail address: Safari@kashanu.ac.ir
Abstract. Fe3O4 nanoparticles were prepared by chemical coprecipitation method.
Subsequently immobilization of chitosan on Fe3O4 nanoparticles was accompllished and
afforted magnetic Fe3O4-chitosan nanoparticles. Synthesized nanoparticles was found to be a
magnetic and heterogenious catalyst for an one-pot and efficient synthesis of 2-amino-4H-
chromenes by condensation of aldehydes with malononitrile and resorcinol under ultrasound
irradiation as an ecofriendly method. This convenient procedure allowed us to achieve
products under ultrasound irradiation in short time and excellent yield without using of
harmful catalyst. The present method will permit a further increase of the diversity within the
2-amino-4H-chromene family.
Keywords: Ultrasound irradiation, Fe3O4 nanoparticles, Fe3O4-chitosan nanoparticles, 2-
Amino-4H-chromene, Magnetic catalyst, Green catalyst
1. Introduction
In recent decades, iron oxide nanoparticles have been received increasing attention due to
their fundamental properties and applications in the several fileds such as catalysts, sensors,
high density magnetic recording media and clinical uses [1]. Surface functionalized iron
oxide magnetic nanoparticles are a class of functional materials, which have been used in
catalysis and biotechnology [2-7]. These hybrid nanoparticles are composed of several
components and can exhibit the properties of different component in the same structure [8,9].
The modification of Fe3O4 nanoparticles have been carried out by various materials such as
precious metals, carbon, silica and biopolymers [10,11]. Biopolymers such as chitosan have
been applied as support in many heterogeneous catalytic systems [12]. Chitosan is a natural,
1

biodegradable and biocompatable polymer has shown extensive range of application.
Chitosan contains both primary and secondary hydroxyl groups and amino groups. Therefore,
it can activate the electrophilic and nucleophilic compounds by hydrogen bonding and lone
pairs [13] (Scheme 1). These requirement are exist in the reaction of aldehyde resorcinol and
malononitrile for the synthesis of 2-amino-4H-chromenes.
< Scheme1>
2-amino-4H-chromenes are of particular utility as they belong to privileged medicinal
scaffolds serving for generation of small-molecule ligands with highly pronounced
anticoagulant-, diuretic-, spasmolitic- and antianaphylactic activities [14-16]. The current
interest in 2-amino-4H-chromene derivatives arises from their potential application in the
treatment of human inflammatory TNFα-mediated diseases, such as psoriatic arthritis and
rheumatoid and in cancer therapy [17]. Many of the methods reported for the synthesis of
these compounds [18-21] are associated with the use of toxic catalyst and bases, long reaction
time, and lack of general applicability. Thus, development of an efficient, facile, and clean
method for the synthesis of chromene derivatives remains an issue of interest.
During the late several decades, Sonochemistry has gained increasing attention in chemistry
research fields. The use of Sonochemical method as a green and significant technique, has
many beneficial effects in synthetic organic chemistry and so organic chemists are focusing
on its use for the synthesis of organic compounds. [22-24].
Considering the basic green chemistry concepts, ultrasound technique is proving to be more
efficient and selectivity for improving the traditional reactions that require longer reaction
time, unsatisfactory yields, expensive reagents and high temperatures [25,26].
U.S. irradiation offers an alternative energy source which is ordinarily accomplished by
heating [27]. Ultrasound-assisted reactions proceed by acoustic cavitation phenomenon, that
is, the formation, growth, and collapse of bubbles in the liquid medium [27].
2

During the collapse of a cavity, high local temperatures and pressures arise which lead to
increase in the rate of reactions [28, 29].
In this study, we report magnetic Fe3O4-chitosan nanoparticles as a new magnetic
nanocatalyst for the three-component synthesis of 2-amino-4H-chromenes under ultrasound
irradiation (scheme 2). This green method is a rapid ultrasonic assisted route for the synthesis
of wide variety of 2-amino-4H-chromenes.
< Scheme2>
2. Experimental
2.1. Chemical and apparatus
Chitosan (Medium molecular weight) was purchased from Aldrich company and used
without any post-modification. Ferric chloride hexahydrate (FeCl3.6H2O, Merck), ferrous
chloride tetrahydrate (FeCl2.4H2O, Merck), and chitosan (CS, Aldrich) were used as iron and
polymer sources, respectively. All other chemical reagents in high purity were purchased
from the Merck Chemical Company and used as received except for benzaldehyde which a
fresh distilled sample was used. Melting points are determined in open capillaries using an
1
Electrothermal Mk3 apparatus and are uncorrected. H NMR and 13C NMR spectra were
recorded with a Bruker DRX-400 spectrometer at 400 and 100 MHz respectively. NMR
spectra were reported as parts per million (ppm) downfield from tetramethylsilane as internal
standard. The abbreviations used are: singlet (s), doublet (d), triplet (t) and multiplet (m). FT-
IR spectra were obtained with potassium bromide pellets in the range 400–4000 cm-1 with a
Perkin–Elmer 550 spectrometer. The elemental analysis (C, H, N) were obtained from a
Carlo ERBA Model EA 1108 analyzer carried out on Perkin–Elmer 240c analyzer. The UV–
vis measurements were obtained with a GBC cintra 6 UV–vis spectrophotometer.
Nanostructures were characterized using a Holland Philips Xpert X-ray powder diffraction
(XRD) diffractometer (CuK, radiation, k = 0.154056 nm), at a scanning speed of 2°/min from
10° to 100° (2ө). Scanning electron microscope characterization (SEM) was performed on a
3

FEI Quanta 200 SEM operated at a 20 kV accelerating voltage. The samples for SEM were
prepared by spreading a small drop containing nanoparticles onto a silicon wafer and being
dried almost completely in air at room temperature for 2 h, and then were transferred onto
SEM conductive tapes. For conventional imaging in the SEM, specimens must be electrically
conductive, at least at the surface, and electrically grounded to prevent the accumulation of
electrostatic charge at the surface. So, the transferred sample was coated with a thin layer of
gold before measurement. Sonication was performed in Shanghai Branson-BUG40-06
ultrasonic cleaner (with a frequency of 35 kHz and a nominal power 200 W) estimated
calorimetrically. A circulating water bath (DC2006, Shanghai Hengping Apparatus Factory)
with an accuracy of 0.1 K was adopted to keep the reaction temperature constant.
2.2 preparation of magnetic heterogeneous catalyst
Fe3O4 nanoparticles were prepared by chemical co-precipitation as described in the literature
[30] and subsequently were functionalized with chitosan [31]. In short, 0.02 mol of
FeCl3.6H2O and 0.01 mol of FeCl2.4H2O were dissolved in 80 mL of deionized water. Then,
10 mL of NH4OH solution was added into the mixture at 80 ˚C under N2 atmosphere and the
black magnetic Fe3O4 nanoparticles were formed. Next, the reaction mixture was cooled and
the catalyst was isolated in the magnetic field and washed three times with distilled water.
Subsequently, In order prepare Fe3O4-chitosan nanoparticles, 1 g of the Fe3O4 nanoparticles
was dispersed in 120 mL distilled water under ultrasound irradiation and 0.5 g of chitosan in
120 mL of 2.0 wt% acetic acid solution was slowly added under vigorous stirring at 50 ◦C for
1 h. The modified Fe3O4-chitosan nanoparticles were recovered by magnetic decantation and
washed with CH2Cl2.finally, Fe3O4-chitosan nanoparticles were dried at 60 ◦C (Scheme 3).
< Scheme3>
2.3. General procedure for the synthesis of 2-amino-4H-chromenes in water under silent
condition
4

A mixture of aldehyde (1 mmol), malononitrile (1 mmol), resorcinol (1 mmol) and Fe3O4-
chitosan (0.15 g, 30 mol%) in water (5 mL) was taken in a 25 mL flask and the mixture
was stirred under reflux conditions. After the completion of the reaction (monitored by
TLC), the reaction was allowed to cool and the magnetic catalyst was removed by an
external magnet. Then, the solvent was evaporated and the solid residue was recrystallized
from ethanol to produce the product 4a in 89% yield.
2.4. General procedure for the synthesis of 2-amino-4H-chromenes in water under
ultrasound irradiation
A 50 mL Erlenmeyer flask was charged with benzaldehyde (1 mmol), malononitrile (1
mmol), resorcinol (1 mmol) and Fe3O4-chitosan (0.15 g, 30 mol%) in water (5 mL). The
reaction flask was taken in the ultrasonic bath, where the level of the reaction mixture is
lower than the surface of the water. Then, the mixture was sonicated under 20, 40, 60, 80,
and 100% of power of the ultrasonic bath at 50 °C for the appropriate time, as shown in
Table 1. After the completion of the reaction (monitored by TLC), the reaction was
allowed to cool and the magnetic catalyst was removed by an external magnet. Then, the
solvent was evaporated and the solid residue was recrystallized from ethanol to afford the
pure 2-amino-4H-chromene derivatives as white solid (Table 1).
< Table 1>
2.5. Spectral data for selected compounds
2-5-1. 2-Amino-3-cyano-7-hydroxy-4-(3-hydroxyphenyl)-4H-chromene (4e)
IR (KBr) ( νmax cm−1): 3413 (OH), 3332 (NH2), 2190 (CN), 1653 (C=C vinyl nitrile), 1587
(C=C aromatic); 1H NMR (400 MHz, DMSO-d6) δ: 4.51 (s, 1H, H-4), 6.42 (d, 1H, J=3 , H-
Ar), 6.49 (dd, 1H, J=3, J=9, H-Ar), 6.54 (d, 1H, J=9, H-Ar), 6.86 (s, 2H, NH2), 6.52-7.10 (m,
5

4H, H-Ar), 9.35 (s,1H, OH), 9.69 (s, 1H, 7-OH) ppm; 13C NMR (100 MHz, DMSO-d6) δ:
57.10, 102.56, 112.76, 112.99, 114.35, 114.50, 121.29, 126.48, 128.91, 129.96, 130.48,
138.93, 149.21, 157.43, 158.47, 160.59 ppm. Anal. Calcd. for. C16H12N2O3: C, 68.57; H,
4.32; N, 9.99%. Found: C, 68.53; H, 4.27; N, 9.92%.
2-5-2. 2-Amino-3-cyano-7-hydroxy-4-(2,4-dichlorophenyl)-4H-chromene (4h)
IR (KBr) ( νmax cm−1): 3473 (OH), 3344 (NH2), 2195 (CN), 1641 (C=C vinyl nitrile), 1594
1
(C=C aromatic); H NMR (400 MHz, DMSO-d6) δ: 5.15 (s, 1H, H-4), 6.41 (d, 1H, J=3, H-
Ar), 6.47 (dd, 1H, J=9, J=3 , H-Ar), 6.72 (d, 1H, J=9 , H-Ar), 6.93 (s, 2H, NH2), 7.23 (d, 1H,
J=8 , H-Ar), 7.39 (dd, 1H, J=2, J=8, H-Ar), 7.62 (d, 1H, J=2 , H-Ar), 9.81 (s, 1H, OH) ppm;
13C NMR (100 MHz, DMSO-d6) δ: 56.64, 102.73, 112.72, 112.95, 113.87, 113.99, 121.12,
121.67, 129.79, 129.99, 130.34, 142.06, 149.38, 155.65, 159.96, 160.66 ppm. Anal. Calcd.
for. C16H10Cl2N2O2: C, 57.68; H, 3.03; N, 8.41%. Found: C, 57.8; H, 3.09; N, 8.45%.
2-5-3. 2-Amino-3-cyano-7-hydroxy-4-(3,5-dimethoxyphenyl)-4H-chromene (4j)
IR (KBr) ( νmax cm−1): 3465 (OH), 3332 (NH2 ), 2195 (CN), 1644 (C=C vinyl nitrile), 1629
1
(C=C aromatic); H NMR (400 MHz, DMSO-d6) δ: 3.68 (s, 6H, OMe), 4.56 ( s, 1H, H-4),
6.29 (d, 1H, J=3 , H-Ar), 6.38 (dd, 1H, J=3, J=9, H-Ar), 6.49 (d, 1H, J=9 , H-Ar), 6.86 (s, 2H,
NH2), 6.99-7.29 (m, 3H, H-Ar), 9.76 (s, 1H, OH) ppm; 13C NMR (100 MHz, DMSO-d6) δ:
55.67, 56.49, 102.79, 112.75, 113.84, 121.08, 128.65, 129.66, 130.28, 131.10, 143.17,
149.18, 156.67, 159.81, 160.73 ppm. Anal. Calcd. for. C18H16N2O4: C, 66.66; H, 4.97; N,
8.64%. Found: C, 66.59; H, 4.94; N, 8.57%.
2-5-4. 2-Amino-3-cyano-7-hydroxy-4-(2-furyl)-4H-chromene (4l)
IR (KBr) ( νmax cm−1): 3479 (OH), 3419 (NH2 ), 2198 (CN), 1655 (C=C vinyl nitrile), 1586
(C=C aromatic); 1H NMR (400 MHz, DMSO-d6) δ: 4.77(s, 1H, H-4), ), 6.18 (d, 1H, J=2 , H-
Ar), 6.36 (dd, 1H, J=2, J= 8, H-Ar), 6.55 (d, 1H, J=8, H-Ar), 6.98 (s, 2H, NH2), 7.28-7.55 (m,
3H, H-furyl), 9.77 (s, 1H, OH) ppm; 13C NMR (100 MHz, DMSO-d6) δ: 53.87, 102.87,
6

106.79, 110.33, 112.36, 112.98, 116.36, 120.93, 130.34, 149.57, 151.44, 155.58, 157.63,
161.37 ppm. Anal. Calcd. for. C14H10N2O3: C, 66.14; H, 3.96; N, 11.02%. Found: C, 66.09;
H, 4.02; N, 11.05%.
2-5-5. 2-Amino-3-cyano-7-hydroxy-4-(propyl)-4H-chromene (4p)
IR (KBr) ( νmax cm−1): 3467 (OH), 3333 (NH2 ), 2196 (CN), 1644 (C=C vinyl nitrile), 1627
(C=C aromatic); 1H NMR (400 MHz, DMSO-d6) δ: 0.74 (t, 3H, Me), 1.07 (m, 2H, CH3CH2),
1.50 (m, 2H, CH2CH), 3.36 (t, 1H, H-4), 6.34 (d, 1H, J=2, H-Ar), 6.53 (dd, 1H, J=2, J=10, H-
Ar), 6.67 (s, 2H, NH2), 6.90 (d, 1H, J=10, H-Ar), 9.58 (s, 1H, OH) ppm; 13C NMR (100
MHz, DMSO-d6) δ: 26.44, 26.67, 27.62, 43.81, 102.74, 107.99, 111.45, 112.24, 114.61,
121.61, 131.81, 156.62, 160.99 ppm. Anal. Calcd. for. C13H14N2O2: C, 67.81; H, 6.13; N,
12.17%. Found: C, 67.94; H, 6.17; N, 12.23%.
3. Results and discussion
3.1. Characterization of magnetic Fe3O4-chitosan nanoparticles as heterogeneous catalyst
Magnetic nanoparticles were synthesized by co-precipitation. Fig. 1a and 2a demonstrates
crystal structures of Fe3O4 and Fe3O4-chitosan. The XRD patterns of Fe3O4 and Fe3O4-
chitosan nanoparticles indicates iron oxide cubic structure and six peaks that related to the
(220), (311), (400), (331), (422), (333), (440) and (531) planes. The weaker diffraction lines
of magnetic Fe3O4-chitosan nanoparticles exhibite that the Fe3O4 nanoparticles were coated
by amorphous chitosan polymer. But, chitosan did not destroy the crystal structure of iron
oxide nanoparticles. The average crystal size of pure Fe3O4 and chitosan-coated Fe3O4
nanoparticles are 15 and 19, respectively.
< Fig. 1>
7

The SEM image (Fig. 2a) shows that magnetite Fe3O4 nanoparticles have a mean diameter of
about 18 nm and Fig. 2(b) shows that magnetic Fe3O4-chitosan nanoparticles with nanometer
size were successfully prepared and still keep the morphological properties of Fe3O4 except
for a slightly larger particle size, which chitosan molecule is uniform coated on the Fe3O4
particles to form chitosan shell. Therefore, magnetic Fe3O4-chitosan nanoparticles have larger
particle size than Fe3O4 nanoparticles. The SEM image shown in Fig. 2(b) demonstrates that
the structure of Fe3O4-chitosan nanoparticles is looser, leading to the bigger size, the diameter
of such a structure is more than 20 nm in size. So, it revealed the coating process and change
in size of the particles.
< Fig. 2>
The elemental compositions are calculated from the energy dispersive X-ray (EDX). The
elemental compositions of Fe3O4-chitosan nanoparticles are 74.6, 21.94, 2.94 and 0.52% for
Fe, O, C, and N, respectively. This meant the chitosan was coated onto the surface of the
Fe3O4 nanoparticles (Fig. 3).
< Fig. 3>
Fig 4 shows the fourier transform infrared (FT-IR) spectra of pure Fe3O4 nanoparticles (a),
chitosan (b) and Fe3O4-chitosan (c). The characteristic peaks of Fe3O4 at 570 and 580 cm−1
could be observed in both (a) and (c). Also, the O-H streching vibration near 3423 cm−1 and
3430 cm−1 were observed in Fig. 4(a) and (c), which identifies these nanoparticles as Fe3O4
nanoparticles. The IR spectrum of chitosan was characterized by the following absorption
bands: the (C-H) of backbone polymer appearing at 2874 and 2940 cm−1; (C-O) of primary
alcoholic group at 1424 cm−1; and (N-H) at 3435 and 1653 cm−1. Compared with the IR
spectra of three samples (a, b, c), the presence of chitosan shifted the vibration of Fe3O4. The
band shift of Fe-O stretching (from 570 to 580 cm−1) and of N-H bending vibration from
1623 to 1630 cm−1 are the most significant, indicating that iron ions bind to the NH2 group of
8

chitosan. Electrostatic interaction between the negatively charged Fe3O4 nanoparticles surface
and the positively protonated chitosan also donates to the IR change. The peak at 3430 cm−1in
was probably attributed to the amino group of chitosan, which is overlapped by the O-H
stretching vibration of Fe3O4 nanoparticles.
Thus, the magnetite nanocatalyst is stable during synthesis of 2-amino-4H-chromene in
aqueous media.
< Fig. 4>
The magnetization curve for Fe3O4 nanoparticles and Fe3O4-chitosan nanoparticles is shown
in Fig 5. Room temperature specific magnetization (M) versus applied magnetic field (H)
curve measurements of the Fe3O4-chitosan nanoparticles indicate a saturation magnetization
value (Ms) of 50.27 emu g -1, lower than of pristine Fe3O4 nanoparticles (55.69 emu g-1) due
to the coated shell.
3.2. Evaluation of the catalytic activity of magnetic Fe3O4-chitosan nanoparticles through the
synthesis of 2-amino-4H-chromenes.
To obtain appropriate conditions for the synthesis of 2-amino-4H-chromenes, different
reaction conditions have been examined in the reaction of benzaldehyde 1a, resorcinol and
malononitrile as a model reaction (Scheme 4).
< Scheme 4>
We investigated the effect of various solvents such as H2O, EtOH, DMSO, DMF, CH3CN,
◦
and CH3Cl on a model reaction under ultrasound irradiation (power intensity: 80%) at 50 C.
The results were summarized in Table 2. Also, we tried the selected solvents under different
power intensities. Although, the enhancement in the acoustic power could enhance the
number of active cavitation bubbles and also the size of the individual bubbles, the model
reaction showed the best yield in the presence of H2O. It indicated that the role of solvent is
more important than power intensity for this reaction.
9

< Table 2>
The best results were obtained using of 0.15 g (30 mol%) of Fe3O4-chitosan nanoparticles in
H2O (Table 2, Entry 1) of the corresponding product. Therefore H2O was chosen as solvent
of reaction. After this, the reaction was carried out in the presence of 0.05, 0.10, 0.15 and
0.20 g of Fe3O4-chitosan nanoparticles (Table 3) with and without sonication for the synthesis
of 4a product.
< Table 3>
In all cases, the results shows that the reaction times are shorter and the yields of the products
are higher under ultrasound irradiation. The reason may be the phenomenon of cavitation
produced by ultrasound irradiation. Cavitation is the origin of sonochemistry, a physical
process that creates, enlarges, and implodes gaseous and vaporous cavities in an irradiated
liquid, therefore increasing the mass transfer and allowing chemical reactions to take place.
Ultrasound wave propagates via an alternating adiabatic compression and rarefaction cycle
waves induced in the molecules of the medium. In some cases, the rarefaction cycle may
exceed the attractive forces of the molecules of the liquid at a sufficiently high power, which
would involve a negative net pressure applied to the medium and consequently causing
cavitation bubbles formation. This negative pressure can lead to rupture of the fluid and is
accompanied by the generation of cavities. The varying pressure makes the bubbles oscillate
in size. These oscillations are low energetic. Above a certain negative pressure threshold, this
will lead to inertial cavitation, which is the high energetic fast growth and collapse of bubbles
[33]. The bubbles are small can be seen as microreactors that offer the opportunity of
speeding up certain reactions. Also, they allow mechanistically novel reactions to occur in an
absolutely safe manner [23, 27, 34]. The use of 0.15 g of catalyst afforded the best yields
under both conditions (Table 3, Entry 4). As shown in Table 3, in the absence of catalyst the
yield of the 4a product was found to be low. In order to investigate the effect of intensity
10

power of ultrasonic on reaction, the reaction was carried out at 20%, 40%, 60%, 80% and
100% of the rate power of the ultrasonic bath (40, 80, 120, 160 and 200 W). The results are
shown in Table 1. The intensity of sonication is proportional to the amplitude of vibration of
the ultrasonic source and, as such, an increment in the amplitude of vibration will direct to an
enhance in the intensity of vibration and to an enhance in the sonochemical effects. Increase
of ultrasonic power led to higher yield and shorter reaction time before the ultrasound power
intensity reached 80%, and then the yield decreased slightly with increasing ultrasound power
intensity. Commonly, the enhance in the acoustic power could enhance the number of active
cavitation bubbles and also the size of the individual bubbles. Both increases can be supposed
to result in an increase in the maximum collapse temperature and the respective reaction
could be did faster [35].
Different catalysts such as Fe3O4, chitosan and Fe3O4-chitosan nanoparticles were tested
under ultrasound irradiation (Table 4). The reaction in the presence of Fe3O4-chitosan
afforded the product in higher yield and shorter reaction time under ultrasound irradiation.
<Table 4>
2-amino-4H-chromenes was prepared by the wide range of substituted aldehydes under
optimized reaction conditions in high to excellent yields (Table 5, method A).
< Table 5 >
Aldehydes bearing either electron-withdrawing or electron-donating groups showed equally
well in the reaction and all 2-amino-4H-chromenes were prepared in high yields. For more
examination of the effect of ultrasound irradiation in this reaction, comparison of the reaction
under two methods, ultrasound irradiation at 50 ◦C (method A) and reflux conditions (method
B) was carried out. As shown in Table 4, method A in comparison with method B is better in
both yields and the reaction times.
11

A plausible mechanism explaining the aforementioned results and the selectivity is depicted
in Scheme 5. The process represents a typical cascade of Knoevenagel condensation, Michael
addition, and cyclization in the presence of Fe3O4-chitosan nanoparticles. As can be seen in
Scheme 5, Fe3O4 as a lewis acid and the free hydroxyl groups on the surface of chitosan play
a significant role in increasing the electrophilic character of the aldehyde and so can activate
the carbonyl group of aldehyde 1a to decrease the energy of transition state for the
nucleophilic attack of malononitrile. Also, lone pairs of amino group on surface of chitosan
activate the nucleophilic property of the malononitrile. The reaction is thought to proceed
through Knoevenagel condensation to form intermediate 5. Subsequently Michael addition
occurs to form intermediate 6. The dipolar transition states (TS) occur resulting in generation
intermediate of 6 in aqueous media as dipolar solvent that is converted to product 4a via an
intramolecular cyclization. The mechanism of this reaction involves a polar transition state
starting from a neutral ground state. ionic reactions are accelerated by physical effects better
mass transport under ultrasonic irradiation. Generally, when ultrasound is passed through a
liquid–solid system, bubble cavitation causes a series of unique physical phenomena that can
affect the solid. Microjets and high energetic shockwaves are produced by inertial cavitation.
Shockwaves are formed when cavities rapidly expand or collapse. Spherical particles can be
accelerated significantly by the shockwave that occurs during the explosive growth of a
cavity on the particle surface. During the collapse of a cavity, high local temperatures and
pressures arise which result in a pressure shockwave. Shockwaves may cause mechanical
damage to close objects and are known to cause material erosion. The collapse of bubbles
close to a large rigid boundary will be asymmetric and leads to microjet formation in the
direction of the surface. Microjets have an estimated speed of 100 m/s [aqueous solution;
Suslick et al. (1990)] and lead to pitting and erosion of solid surface and the overall particle
size reduction in heterogeneous systems. In fact, asymmetric collapse of the bubbles in
heterogeneous system produce micro-jet with high velocity enhancing mass and heat transfer
through stationary film surrounding adsorbent and also within the pores [36-40]. This effect
is equivalent to high-pressure/high-velocity liquid jets. The jets activate the solid catalyst and
enhance the mass transfer to the surface by the disruption of the interfacial boundary layers as
well as dislodging the material occupying the inactive sites. Also, ultrasound irradiation can
increase the surface area between the two phases for the reaction and provide additional
activation through efficient mixing and improved mass transport, thus increasing the rate of
the reaction. In addition, ultrasound irradiation activates the reaction mixture via inducing
high local temperatures and pressure generated inside the cavitation bubble when it collapses
12

and increase the speed of the reaction rate [24]. Therefore, it is reasonable to assume that
these effects should accelerate this reaction.
< Scheme 5>
The reusability is one of the important properties of this catalyst. After the completion of the
reaction, ethyl acetate was added and the catalyst was separated by an external magnet. The
catalyst was then washed with ethyl acetate, air-dried and used directly with fresh substrates
under identical conditions without further purification. It was found that the catalyst could be
reused for the next cycle without any appreciable loss of its activity. Similarly, reusability for
sequential reaction was also carried out and catalyst was found to be reusable for four cycles
(Table 5).
<Table 5>
The XRD of the recovered magnetic nanocatalyst was indexed according to the magnetite
phase (Fig. 6), and so there is no considerable change in its magnetic phase. Therfore, the
nanocatalyst is stable during synthesis of 2-amino-4H-chromenes under ultrasound
irradiation.
<Fig. 6>
4. Conclusions
We have reported a green, efficient and environmentally procedure for the synthesis of 2-
amino-4H-chromenes via condensation of various aldehydes with malononitrile and
resorcinol using Fe3O4-chitosan nanoparticles as a magnetic heterogenous catalyst under
ultrasound irradiation. This novel method offers several advantages including ease of
separation and recovery, higher yields, safety, mild reaction conditions, short reaction time,
simple workup procedure and recyclability of the magnetic nanocatalyst, as well as the ability
to tolerate a large range of substitutions in the reagents.
Acknowledgements
We gratefully acknowledge the financial support from the Research Council of the
University of Kashan for supporting this work by Grant NO. 256722/ XIII.
13

References
[1] N. D. Cuong, T. T. Hoa, D. Q. Khieu, T. D. Lam, N. D. Hoa, N. V. Hieu, J. Alloys
Compd. 523 (2012) 120–126.
[2] A. H. Lu, E.L. Salabas, F. Schuth, Angew. Chem. Int. Ed. 46 (2007) 1222-1244.
[3] B. Hu, J. Pan, H.L.Yu, J.W.Liu, J.H. Xu, Process Biochem. 44 (2009)1019-1024.
[4]C.S. Gill, B.A. Price, C.W. Jones,J.Catal.251 (2007)145-152.
[5] Ataher, J.B. Kim, J.Y. Jung, W.S. Ahn, M.J. Jin, Synlett. (2009) 2477-2482.
[6] O.C. Dalaigh, a.S. Corr, Y. Gun Ko, J.S. Connon, Angew. Chem. Int. Ed. 46 (2007)4329-
4332.
[7] Y. Zhang, Y. Zhao, C. Xia, J. Mol. Catal. A: Chem. 306 (2009) 107-112.
[8] A. Dong, Sh. Lan, J. Huang, T. Wang, T. Zhao, L. Xiao, W. Wang, X. Zheng, F. Liu, G.
Gao,Y. Chen, ACS Appl. Mater. Interfaces, 3 (2011), 4228-4235.
[9] Lek, J.Y.,Xi, L., Kardynal, B.E., Wong, L.H., Lam, Y.M. ACS Appl. Mter. Interfaces 3
(2011) 287-292.
[10] H.V. Tran, L.D. Tran, T.N. Nguyen, Mater. Sci. Eng. C 30 (2010) 304–310.
[11] L.D. Tran, B.H. Nguyen, N.V. Hieu, H.V. Tran, H.L. Nguyen, P.X. Nguyen, Mater.
Sci. Eng. C 31 (2011) 477–485.
[12] A. Shaabani and A. Maleki, Appl. Catal.: A., 331 (2007) 149-151.
[13] M. G. Dekamin, M. Azimoshan and L. Ramezani, Green Chem., 15 (2013) 811-820.
[14] M. S. Singh, S. Chowdhury, RSC Adv. 2012, 2, 4547-4592.
[15] G. Zhang, Y. Zhang, J. Yan, R. Chen, S. Wang, Y. Ma, R. Wang, J. Org. Chem. 77
(2012) 878-888.
[16] N. M. Sabry, H. M. Mohamed, E. S. A. E. H. Khattab, S. S. Motlaq, A. M. El-Agrody,
Eur. J. Med. Chem. 46 (2011) 765-772.
[17] D. Wlodkowic, J. Skommer, M. Mättö, M. Eray, J. Pelkonen, Leuk. Res. 30 (2006) 322-
331.
[18] G. Yang, C. Luo, X. Mu, T. Wang, X.-Y. Liu, Chem. Commun. 48 (2012) 5880-5882.
[19] S. Makarem, A. A. Mohammadi, A. R. Fakhari, Tetrahedron Lett. 49 (2008) 7194-7196.
[20] A. Shaabani, R. Ghadari, S. Ghasemi, M. Pedarpour, A. H. Rezayan, A. Sarvary, S. W.
Ng, J. Comb. Chem. 11 (2009) 956-959.
[21] J. M. Khurana, B. Nand, P. Saluja, Tetrahedron 66 (2010) 5637-5641.
[22] J. Safari, M.N, Arani, Ultrason Sonochem. 18 (2011) 640-643.
[23] J. Safari, S.H. Banitaba, Sh. Dehghan Khalili, Ultrason Sonochem. 19 (2012) 1061–
1069.
[24] J. Safari, S.H. Banitaba, S. D. Khalili, Ultrason. Sonochem. (2012), Ultrason. Sonochem.
20 (2013) 401–407.
[25] N.G. Khaligh, F. Shirini, Ultrason. Sonochem. 20 (2013) 19-25.
[26] N.G. Khaligh, F. Shirini, Ultrason. Sonochem. 20 (2013) 26–31.
[27] D. Nagargoje, P. Mandhane, S. Shingote, P. Badadhe, C. Gill, Ultrason. Sonochem. 19
(2012) 94–96.
[28] P. V. Shinde, B. B. Shingate, M. S. Shingare, Bull. Korean Chem. Soc. 32 (2011) 1179-
1182.
[29] F. Dang, N.Y. Enomoto, J.C. Hojo, K.J. Enpuku, Ultrason Sonochem. 16 (2009) 649-
654.
[30] J. Safari, L. Javadian, C. R. Chimie, 16 (2013), 1165-1171.
[31] N. D. Cuong, T. T. Hoa, D. Q. Khieu, T. D. Lam, N. D. Hoa, N. V. Hieu, J. Alloys
Compd. 523 (2012) 120–126.
[32] J. Safari, Z. Zarnegar, M. Heydarian, Bull. Chem. Soc. Jpn. 85 (2012) 1332-1338.
14

[33] R.M. Wagterveld, L. Boels, M.J. Mayer , G.J. Witkamp Ultrason. Sonochem. 18 (2011)
216–225.
[34] D. Nagargoje, P. Mandhane, S. Shingote, P. Badadhe, C. Gill, Ultrason. Sonochem. 19
(2012) 94–96.
[35] X. Wang, Y. Wei, J. Wang, W. Guo, C. Wang, Ultrason. Sonochem. 19 (2012) 32–37.
[36]. R.M. Wagterveld ,L. Boels, M.J. Mayer a, G.J. Witkamp Ultrason. Sonochem. 18
(2011) 216–225.
[37] J. S. Markovski, V. Dokic´, M. Milosavljevic´, M. Mitric´, Aleksandra, A. Peric´-
Grujic´, A. E. Onjia a, A. D. Marinkovic, Ultrason. Sonochem. 21 (2014) 790–801.
[38] L. H. Thompson, L. K. Doraiswamy Ind. Eng. Chem. Res. 38 (1999) 1215-1249.
[39] P. R. Gogate, V. S. Sutkar, A. B. Pandit, Chem. Eng. J. 166 (2011) 1066–1082.
[40] A. Ziarati, J. Safaei-Ghomi, S. Rohani, Ultrason. Sonochem. 20 (2013) 1069-1075.
Figures and captions
Scheme1. Chemical structure of chitosan
Scheme2. One-pot synthesis of 2-amino-4H-chromenes catalyzed by Fe3O4-chitosan
nanoparticles.
under ultrasound irradiation at 50 ◦C.
Scheme 3. Synthesis of Fe3O4-chitosan nanoparticles.
Scheme 4. Standard model reaction.
Scheme 5. The plasuable mechanism for one-pot synthesis of 2-amino-4H-chromenes
Fig. 1. XRD pattern of Fe3O4 (a) and chitosan-coated Fe3O4 (b)
.
Fig. 2. SEM images of PureFe3O4 (a) and chitosan-coated Fe3O4(b).
Fig. 3. The energy dispersive X-ray (EDX) of Fe3O4-chitosan nanoparticles.
Fig. 4. FT-IR of spectra of pure Fe3O4 nanoparticles (a), chitosan (b) and Fe3O4-chitosan (c).
Fig. 5. Magnetization versus applied field (H) isotherms for Fe3O4 nanoparticles and
chitosan-coated Fe3O4.
Fig. 6. XRD patterns of recovered Fe3O4-chitosan nanoparticles after five recovery.
Table 1. The effect of intensity power of ultrasonic on the synthesis of 4a.a
Table 2. Optimization of reaction conditions for synthesis of 4a under ultrasound irradiation.a
Table 3. Comparison of yield and reaction time with or without ultrasound irradiation for the
synthesis of 4a product.
Table 4. Screening of type of catalyst for the synthesis of 2-amino-4H-chromenes a.
Table 5. Fe3O4-chitosan nanoparticles catalyzed three component condensations of
malononitrile
aldehydes and resorcinol to form 2-amino-4H-chromenes under ultrasound irradiation.
Table 6. The effect of reusability of Fe3O4-chitosan nanoparticles on the product 4a yeilda.
15

Table 1. The effect of intensity power of ultrasonic on the synthesis of 4a.a
Yield (%) Time (min) Max power/intensity (W) Entry
72
75
76
99
86
29
25
22
20
21
20% (40 W)
40% (80 W)
60% (120 W)
80% (160 W)
100% (200 W)
1
2
3
4
5
aReaction conditions: aldehyde 1a (1 mmol), malononitrile 2 (1 mmol), resorcinol 3 (1 mmol), Fe3O4-chitosan nanoparticles
(0.15 g, 30 mol%) and 5 ml water
16

Table 2. Optimization of reaction conditions for synthesis of 4a under ultrasound irradiation.a
Yieldb (%)
Time (min)
Method
Solvent
None
Entry
trace
73
35
35
35
35
35
25
20
31
Ultrasound
Ultrasound
Ultrasound
Ultrasound
Ultrasound
Ultrasound
Ultrasound
High speed stirring
1
2
3
4
5
6
7
8
Chloroform
DMSO
Acetonitrile
DMF
77
86
83
92
EtOH
99
Water
90
Water
a
Reaction conditions: aldehyde 1a (1 mmol), malononitrile 2 (1 mmol), and resorcinol 3 (1 mmol), catalyst (0.15 g, 30
mol%), 5 ml solvent under ultrasound irradiation at 50°C.
b Isolated yield.
17

Table 3 Comparison of yield and reaction time with or without ultrasound irradiation for the
synthesis of 4a product.
With sonication
Yield (%) / Time (min)
Without sonication
Yield (%) / Time (min)
Catalyst (g)
Entry
82/30
87/25
88/23
99/20
71/65
78/47
85/49
90/31
90/31
0
1
2
3
4
5
0.05
0.10
0.15
0.20
99/20
a Reflux condition.
b Under ultrasonic waves (power intensity: 80%) at 50°C.
18

Table 4.
Screening of type of catalyst for the synthesis of 2-amino-4H-chromenes a.
Yield (%)
Time (min)
Catalyst
None
Fe3O4
Chitosan
Fe3O4-chitosan
Entry
82
98
97
99
30
24
21
20
1
2
3
4
a Reaction conditions: aldehyde 1a (1 mmol), malononitrile 2 (1 mmol), and resorcinol 3 (1 mmol), catalyst (0.15 g, 30 mol%),
5 ml solvent under ultrasound irradiation at 50°C.
19

Table 5. Fe3O4-chitosan nanoparticles catalyzed three component condensations of
malononitrile aldehydes and resorcinol to form 2-amino-4H-chromenes under ultrasound
irradiation.
m.p.rep./m.p.lit. (ºC)b
Time (min)/ Yield (%)a
Product
4a
R
Entry
235-238/234-237 20/99
180-183/183-186 23/97
108-111/110-11112 25/94
1103-106/106-109 15/96
2216-218/215-217 25/95
2219-222/218-221 20/97
2224-227/222-224 27/95
2257-259/256-258 15/96
219-221/217-220 15/95
189-190/191-193 25/95
230-232/230-232 20/95
209-211/208-210 15/97
230-232/228-231 15/96
180-183/179-181 18/96
167-170/169-172 22/95
163-166/160-162 23/97
125-128/124-126 23/95
C6H5
1
2
3
4
5
6
7
8
9
4-MeC6H4
4-MeOC6H4
3-ClC6H4
3-HOC6H4
2-FC6H4
4b
4c
4d
4e
4f
2-MeOC6H4
2,4-Cl2C6H3
2,6-Cl2C6H3
4g
4h
4i
3,5-(MeO)2C6H3 10
4j
4k
4l
2-Naphthyl
2-Furyl
11
12
13
14
15
16
17
18
2-Thienyl
5-Mefuryl
Ethyl
4m
4n
4o
propyl
4p
4q
4r
Hepthyl
OHCC6H4
>300/>300
20/98
a Isolated yields.
b ref [32]
20

Table 6. The effect of reusability of Fe3O4-chitosan nanoparticles on the product 4a yeilda.
Yield (%)b
Cycle
Entry
99
99
98
97
97
0
1
2
3
4
5
1
2
3
4
5
6
92
a
Reaction conditions: malononitrile (1 mmol), aldehyde 1a (1 mmol) and resorcinol (1 mmol), Fe3O4-chitosan
nanoparticles (0.15 g, 30 mol%) under U.S. irradiation.
b
Isolated yields.
21

Scheme 1. Chemical structure of chitosan.
22

R
O
OH
OH
CN
CN
Fe3O4-Chitosan MNPs
+
+
RCHO
(1 a-r)
Water/ u. s.
HO
CN
(2)
NH2
(4 a-r)
(3)
Scheme2. One-pot synthesis of 2-amino-4H-chromenes catalyzed by Fe3O4-chitosan
nanoparticles under ultrasound irradiation at 50 ◦C.
23

Scheme 3. Synthesis of Fe3O4-chitosan nanoparticles.
24

Ph
O
OH
Ultrasound irradiation
CN
CN
CN
+
+
PhCHO
Condition
HO
NH2
OH
Scheme 4. Standard model reaction.
25

Fe3O4 MNPs
N
OH
HO
OH
n
O
O
H
Ph
O
3+
CN
NC
Ph
Fe
H
(3)
NC
O
O
NC
CN
+
or
-H2O
Ph
Ph
H
H
H
N
O
H
OH
(1a)
(1a)
(5)
(6)
H2N
O
OH
n
O
O
Fe3O4 MNPs
Ph
CN
Ph
Ph
O
+
CN
NH
CN
Cyclization
N
-
O
HO
H
HO
NH2
O
HO
TS(7)
(4a)
(8)
Scheme 5. The plasuable mechanism for one-pot synthesis of 2-amino-4H-chromenes
26

Fig. 1. XRD pattern of Fe3O4 (a) and chitosan-coated Fe3O4 (b)
.
27

Fig. 2. SEM images of PureFe3O4 (a) and chitosan-coated Fe3O4(b).
28

Fig. 3. The energy dispersive X-ray (EDX) of Fe3O4-chitosan
cps/eV
60
N
Fe
O
40
20
0
C
Fe
5
10
keV
15
20
nanoparticles.
29