Magnetic Fe3O4 nanoparticles as efficient and reusable catalyst for the green synthesis of 2-Amino-4H-chromene in aqueous media

Article abstract of DOI:10.1246/bcsj.20120209

A simple and efficient protocol for one-pot three-component coupling of aldehyde, malononitrile, and resorcinol in water using magnetically recoverable Fe₃O₄ nanoparticles at room temperature is reported. The high yields of products and short reaction time were attributed to the nanosize of about 18nm in which the catalyst could act as a nanoreactor. This methodology is found to be fairly general and catalyst is easily separated by magnetic devices and can be reused without any apparent loss of activity for the reaction.

Full text of DOI:10.1246/bcsj.20120209

1332 Bull. Chem. Soc. Jpn. Vol. 85, No. 12, 1332-1338 (2012)
© 2012 The Chemical Society of Japan
Magnetic Fe3O4 Nanoparticles as Efficient and Reusable Catalyst for
the Green Synthesis of 2-Amino-4H-chromene in Aqueous Media
Javad Safari,* Zohre Zarnegar, and Marzieh Heydarian
Laboratory of Organic Chemistry Research, Department of Organic Chemistry, College of Chemistry,
University of Kashan, P. O. Box, Kashan 87317-51167, Iran
Received August 3, 2012; E-mail: Safari@kashanu.ac.ir
A simple and efficient protocol for one-pot three-component coupling of aldehyde, malononitrile, and resorcinol in
water using magnetically recoverable Fe3O4 nanoparticles at room temperature is reported. The high yields of products
and short reaction time were attributed to the nanosize of about 18 nm in which the catalyst could act as a nanoreactor.
This methodology is found to be fairly general and catalyst is easily separated by magnetic devices and can be reused
without any apparent loss of activity for the reaction.
In recent years, being focused on green chemistry using
environmentally benign reagents and conditions is one of the
most fascinating developments in synthesis of widely used
organic compounds. The use of water as a promising solvent
for organic reactions has received considerable attention in
the arena of organic synthesis owing to its green credentials,1-3
and organic synthesis in aqueous media offering key advan-
tages such as rate enhancement and insolubility of the final
products, which facilitates their isolation by simple filtration.
Because of increasing environmental concerns, the develop-
ment of clean synthetic procedures has become crucial and
demanding research. In this sense, heterogeneous organic
reactions have many advantages, such as ease of handling
separation, recycling, and environmentally safe disposal.4,5
On the other hand magnetic nanoparticles (MNPs) have
received a great deal of attention because of their potential
biomedical applications in fields such as drug delivery,6,7
magnetic resonance imaging,8 biomolecular sensors,9 biosepa-
ration,10 and magneto-thermal therapy.11 Additionally, recent
studies show that magnetic nanoparticles are excellent catalysts
for organic reactions.5,12-14 Additionally, the magnetic proper-
ties make possible the complete recovery of the catalyst by
means of an external magnetic field. These advantages become
even more attractive if such reactions can be conducted in
aqueous media.
Multicomponent coupling reaction (MCR) is a powerful
synthetic tool for the synthesis of biologically active com-
pounds.15-17 Heterocycles containing the chromene moiety
show interesting features that make them attractive targets for
MCRs. The 2-amino-chromenes are widely employed as pig-
ments, cosmetics, potential agrochemicals, and represent an
important class of chemical entities being the main constituents
of many natural products.18-20
Among different types of chromene systems, 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, spas-
molitic, and antianaphylactic activities.21-26 The current interest
in 2-amino-4H-chromene derivatives arises from their potential
application in the treatment of human inflammatory TNF¡-
mediated diseases, such as psoriatic arthritis and rheumatoid
and in cancer therapy.27-29 Many of the methods reported for
the synthesis of these compounds30-34 are associated with the
use of hazardous organic solvents, long reaction time, use of
toxic amine-based catalysts, and lack of general applicability.
Along with other reaction parameters, the nature of the catalyst
plays a significant role in determining yield, selectivity, and
general applicability. Thus, development of an inexpensive,
mild, general, and reusable catalyst for MCRs remains an issue
of interest.
In this paper, we report convenient and facile multicompo-
nent, one-pot synthesis of 2-amino-4H-chromene in water
using nanosized magnetic Fe3O4 as efficient and eco-friendly
heterogeneous catalyst (Scheme 1).
Experimental
Materials. Chemical reagents in high purity were pur-
chased from the Merck Chemical Co. All materials were of
commercial reagent grade.
Apparatus.
Melting points were determined in open
capillaries using an Electrothermal Mk3 apparatus and are
uncorrected. 1H NMR and 13C NMR spectra were recorded
with a Bruker DRX-400 spectrometer at 400 and 100 MHz
respectively. NMR spectra were obtained in DMSO-d6 solu-
tions and are 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
¹1
in the range 400-4000 cm with a Perkin-Elmer 550 spec-
trometer. A mass spectrum was recorded with a QP-1100EX
Shimadzu spectrometer. The elemental analyses (C, H, N) were
obtained from a Carlo ERBA Model EA 1108 analyzer carried
out on a Perkin-Elmer 240c analyzer. The UV-vis measure-
ments were obtained with a GBC cintra 6 UV-vis spectropho-
tometer. Nanostructures were characterized using a Holland
Philips Xpert, X-ray powder diffraction (XRD) diffractometer
Published on the web December 6, 2012; doi:10.1246/bcsj.20120209

J. Safari et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 12 (2012) 1333
R
OH
OH
CN
CN
CN
Fe3O4- MNPs
r.t, Water
+
+
RCHO
HO
O
NH2
1a-r
2
3
4a-r
Scheme 1. Magnetic Fe3O4 nanoparticle catalyzed MCRs leading to 2-amino-4H-chromenes.
(Cu K¡, radiation, - = 0.154056 nm), at a scanning speed of
2°/min from 10 to 100° (2ª). Scanning electron microscopy
(SEM) was performed on a 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. Transmission electron microscopy (TEM)
was performed with a Jeol JEM-2100UHR, operated at 200 kV.
Preparation of the Magnetic Fe3O4 Nanoparticles
(MNPs). Fe3O4-MNPs were prepared using simple chemical
coprecipitation described in the literature35 with little modifi-
cation. Typically, 20 mmol of FeCl3¢6H2O and 10 mmol of
FeCl2¢4H2O were dissolved in 75 mL of distilled water in a
three-necked bottom (250 mL) under Ar atmosphere for 1 h.
Thereafter, under rapid mechanical stirring, 10 mL of NaOH
(10 M) was added into the solution within 30 min with vigorous
mechanical stirring and ultrasound treatment under continuous
Ar atmosphere bubbling. After being rapidly stirred for 1 h,
the resultant black dispersion was heated to 85 °C for 1 h. The
black precipitate formed was isolated by magnetic decantation,
exhaustively washed with double-distilled water until neutral-
ity, and further washed twice with ethanol and dried at 60 °C
in vacuum.
2-Amino-3-cyano-7-hydroxy-4-(3-hydroxyphenyl)-4H-
chromene (4e): White solid; mp 215-217 °C; H NMR (400
1
MHz, DMSO-d6): ¤ 4.490 (s, 1H, H-4), 6.391 (d, 1H, J = 3 Hz,
H-Ar), 6.464 (dd, 1H, J = 3 Hz, J = 9 Hz, H-Ar), 6.521 (d, 1H,
J = 9 Hz, H-Ar), 6.849 (s, 2H, NH2), 6.539-7.085 (m, 4H,
H-Ar), 9.335 (s, 1H, OH), 9.688 (s, 1H, 7-OH); 13C NMR
(100 MHz, DMSO-d6): ¤ 57.04, 102.57, 112.79, 112.93,
114.38, 114.52, 121.19, 126.47, 128.89, 129.92, 130.39,
138.94, 149.22, 157.42, 158.42, 160.54; IR (KBr, cm¹1):
3415, 3336, 2188, 1651, 1586; Anal. Calcd for C16H12N2O3: C,
68.57; H, 4.32; N, 9.99%. Found: C, 68.52; H, 4.26; N, 9.94%.
2-Amino-3-cyano-4-(2-fluorophenyl)-7-hydroxy-4H-chro-
mene (4f): White solid; mp 218-221 °C; 1H NMR (400 MHz,
DMSO-d6): ¤ 4.875 (s, 1H, H-4), 6.394 (d, 1H, J = 3 Hz,
H-Ar), 6.464 (dd, 1H, J = 3 Hz, J = 9 Hz, H-Ar), 6.756 (d,
1H, J = 9 Hz, H-Ar), 6.918 (s, 2H, NH2), 7.099-7.252 (m,
4H, H-Ar); 13C NMR (100 MHz, DMSO-d6): ¤ 56.09, 102.59,
112.72, 112.97, 113.32, 114.64, 121.25, 125.87, 128.69,
130.93, 131.17, 138.74, 149.21, 158.02, 158.32, 160.44; IR
(KBr, cm¹1): 3425, 3223, 2192, 1652, 1564; Anal. Calcd for
C16H11FN2O2: C, 68.08; H, 3.93; N, 9.92%. Found: C, 68.02;
H, 3.98; N, 9.88%.
2-Amino-3-cyano-7-hydroxy-4-(2-methoxyphenyl)-4H-
chromene (4g):
White solid; mp 222-224 °C; 1H NMR
General Procedure for the Synthesis of 2-Amino-3-
cyano-7-hydroxy-4-substituted-4H-chromene Derivatives.
A mixture of resorcinol (1 mmol), aldehyde derivatives
(1 mmol), malononitrile (1 mmol), H2O (5 mL), and Fe3O4
nanoparticles (7 mol %) was stirred at room temperature for
the appropriate time, as shown in Table 3. After completion of
the reaction (TLC monitoring), the catalyst was separated by an
external magnet and reused as such for the next experiment
and the solvent was evaporated. The filtrate was concentrated
to dryness, and the crude solid product was crystallized from
EtOH to afford the pure 2-amino-3-cyano-7-hydroxy-4-sub-
stituted-4H-chromene derivatives (Table 3).
(400 MHz, DMSO-d6): ¤ 3.772 (s, 3H, OMe), 4.971 (s, 1H,
H-4), 6.370 (d, 1H, J = 3 Hz, H-Ar), 6.430 (dd, 1H, J = 3 Hz,
J = 10 Hz, H-Ar), 6.808 (d, 1H, J = 10 Hz, H-Ar), 6.814 (s,
2H, NH2), 6.816-7.171 (m, 4H, H-Ar); 13C NMR (100 MHz,
DMSO-d6): ¤ 55.42, 56.22, 102.41, 113.16, 113.32, 113.96,
121.12, 127.23, 128.34, 128.67, 130.43, 130.57, 138.68,
148.79, 157.39, 158.61, 160.42; IR (KBr, cm¹1): 3449, 3351,
2186, 1645, 1587; Anal. Calcd for C17H14N2O3: C, 69.38; H,
4.79; N, 9.52%. Found: C, 69.31; H, 4.70; N, 9.58%.
2-Amino-4-(2,4-dichlorophenyl)-3-cyano-7-hydroxy-4H-
1
chromene (4h): White solid; mp 256-258 °C; H NMR (400
MHz, DMSO-d6): ¤ 5.121 (s, 1H, H-4), 6.397 (d, 1H, J = 3 Hz,
H-Ar), 6.463 (dd, 1H, J = 9 Hz, J = 3 Hz, H-Ar), 6.696 (d, 1H,
J = 9 Hz, H-Ar), 6.986 (s, 2H, NH2), 7.193 (d, 1H, J = 8 Hz,
H-Ar), 7.380 (dd, 1H, J = 2 Hz, J = 8 Hz, H-Ar), 7.571 (d,
1H, J = 2 Hz, H-Ar), 9.779 (s, 1H, OH); 13C NMR (100 MHz,
DMSO-d6): ¤ 56.63, 102.72, 112.71, 112.91, 113.83, 113.97,
121.13, 121.63, 129.75, 129.95, 130.37, 142.04, 149.35,
155.62, 159.94, 160.69; IR (KBr, cm¹1): 3470, 3342, 2192,
1647, 1585; Anal. Calcd for C16H10Cl2N2O2: C, 57.68; H, 3.03;
N, 8.41%. Found: C, 57.79; H, 3.08; N, 8.47%.
Spectral Data for New Compounds.
chlorophenyl)-3-cyano-7-hydroxy-4H-chromene
2-Amino-4-(3-
(4d):
White solid; mp 106-108 °C; 1H NMR (400 MHz, DMSO-
d6): ¤ 4.739 (s, 1H, H-4), 6.382 (d, 1H, J = 3 Hz, H-Ar), 6.457
(dd, 1H, J = 3 Hz, J = 9 Hz, H-Ar), 6.591 (d, 1H, J = 9 Hz,
H-Ar), 6.94 (s, 2H, NH2), 7.04-7.305 (m, 4H, H-Ar), 9.731
(s, 1H, OH); 13C NMR (100 MHz, DMSO-d6): ¤ 56.32, 102.71,
112.96, 113.37, 113.66, 121.01, 128.23, 129.04, 129.75,
130.31, 130.38, 131.72, 145.79, 149.29, 157.69, 160.72; IR
(KBr, cm¹1): 3423, 3338, 2192, 1656, 1582; Anal. Calcd for
C16H11ClN2O2: C, 64.33; H, 3.71; N, 9.38%. Found: C, 64.27;
H, 3.65; N, 9.31%.
2-Amino-4-(2,6-dichlorophenyl)-3-cyano-7-hydroxy-4H-
1
chromene (4i): White solid; mp 217-220 °C; H NMR (400
MHz, DMSO-d6): ¤ 5.673 (s, 1H, H-4), 6.355 (d, 1H, J = 3 Hz,

1334 Bull. Chem. Soc. Jpn. Vol. 85, No. 12 (2012)
Magnetic Fe3O4 Nanoparticles as Efficient and Reusable Catalyst
H-Ar), 6.436 (dd, 1H, J = 10 Hz, J = 3 Hz, H-Ar), 6.555 (d,
1H, J = 10 Hz, H-Ar), 6.929 (s, 2H, NH2), 7.271-7.535 (m,
3H, H-Ar), 9.735 (s, 1H, OH); 13C NMR (100 MHz, DMSO-
d6): ¤ 55.42, 102.58, 112.91, 113.24, 113.54, 120.22, 120.93,
130.14, 130.25, 131.96, 146.32, 149.36, 157.79, 160.73; IR
(KBr, cm¹1): 3465, 3336, 2191, 1648, 1588; Anal. Calcd for
C16H10Cl2N2O2: C, 57.68; H, 3.03; N, 8.41%. Found: C, 57.64;
H, 3.12; N, 8.48%.
¤ 34.27, 53.86, 102.82, 106.74, 109.58, 110.32, 112.74,
120.96, 130.02, 146.79, 149.56, 151.40, 155.60, 157.82,
161.33; IR (KBr, cm¹1): 3437, 3333, 2189, 1649, 1586; Anal.
Calcd for C15H12N2O3: C, 67.16; H, 4.51; N, 10.44%. Found:
C, 67.19; H, 4.48; N, 10.41%.
2-Amino-3-cyano-4-ethyl-7-hydroxy-4H-chromene (4o):
Orange solid; mp 169-172 °C; 1H NMR (400 MHz, DMSO-
d6): ¤ 0.635 (t, 3H, J = 6 Hz, Me), 1.541 (qd, 2H, J = 6 Hz,
J = 8 Hz, CH2), 3.438 (t, 1H, J = 8 Hz, H-4), 6.326 (d, 1H,
J = 2 Hz, H-Ar), 6.527 (dd, 1H, J = 2 Hz, J = 10 Hz, H-Ar),
6.710 (s, 2H, NH2), 6.991 (d, 1H, J = 2 Hz, H-Ar), 9.607
(s, 1H, OH); 13C NMR (100 MHz, DMSO-d6): ¤ 26.62, 27.57,
43.76, 102.66, 107.94, 111.43, 112.26, 114.57, 121.69, 131.92,
156.58, 160.96; IR (KBr, cm¹1): 3460, 3332, 2193, 1650,
1625; Anal. Calcd for C12H12N2O2: C, 66.65; H, 5.59; N,
12.95%. Found: C, 66.61; H, 5.52; N, 12.89%.
2-Amino-3-cyano-7-hydroxy-4-(3,5-dimethoxyphenyl)-
1
4H-chromene (4j): White solid; mp 191-193 °C; H NMR
(400 MHz, DMSO-d6): ¤ 3.672 (s, 6H, OMe), 4.517 (s, 1H,
H-4), 6.282 (d, 1H, J = 3 Hz, H-Ar), 6.331 (dd, 1H, J = 3 Hz,
J = 9 Hz, H-Ar), 6.458 (d, 1H, J = 9 Hz, H-Ar), 6.848 (s, 2H,
NH2), 6.97-7.28 (m, 3H, H-Ar), 9.735 (s, 1H, OH); 13C NMR
(100 MHz, DMSO-d6): ¤ 55.62, 56.47, 102.77, 112.73, 113.82,
121.02, 128.64, 129.65, 130.22, 131.02, 143.06, 149.15,
156.63, 159.83, 160.72; IR (KBr, cm¹1): 3460, 3332, 2191,
1643, 1628; Anal. Calcd for C18H16N2O4: C, 66.66; H, 4.97; N,
8.64%. Found: C, 66.57; H, 4.93; N, 8.59%.
2-Amino-3-cyano-7-hydroxy-4-propyl-4H-chromene (4p):
1
White solid; mp 160-162 °C; H NMR (400 MHz, DMSO-d6):
¤ 0.778 (t, 3H, J = 6 Hz, Me), 1.011 (m, 2H, CH3CH2), 1.497
(m, 2H, CH2CH), 3.358 (t, J = 7 Hz, 1H, H-4), 6.307 (d, 1H,
J = 2 Hz, H-Ar), 6.503 (dd, 1H, J = 2 Hz, J = 10 Hz, H-Ar),
6.695 (s, 2H, NH2), 6.959 (d, 1H, J = 10 Hz, H-Ar), 9.590 (s,
1H, OH); 13C NMR (100 MHz, DMSO-d6): ¤ 26.42, 26.65,
27.59, 43.78, 102.73, 107.93, 111.39, 112.27, 114.56, 121.65,
131.86, 156.58, 160.92; IR (KBr, cm¹1): 3466, 3338, 2193,
1648, 1620; Anal. Calcd for C13H14N2O2: C, 67.81; H, 6.13; N,
12.17%. Found: C, 67.93; H, 6.18; N, 12.23%.
2-Amino-3-cyano-7-hydroxy-4-(2-naphthyl)-4H-chromene
(4k):
White solid; mp 230-232 °C; 1H NMR (400 MHz,
DMSO-d6): ¤ 4.793 (s, 1H, H-4), 6.429 (d, 1H, J = 3 Hz,
H-Ar), 6.444 (dd, 1H, J = 3 Hz, J = 9 Hz, H-Ar), 6.789 (d, 1H,
J = 9 Hz, H-Ar), 6.935 (s, 2H, NH2), 7.226-7.894 (m, 7H,
H-Ar), 9.723 (s, 1H, OH); 13C NMR (100 MHz, DMSO-d6): ¤
56.67, 102.59, 112.79, 113.27, 114.68, 114.95, 115.32, 116.21,
116.57, 121.14, 129.62, 129.83, 130.41, 131.36, 131.59,
143.11, 145.27, 146.79, 157.63, 160.67; IR (KBr, cm¹1):
3425, 3332, 2192, 1655, 1584; Anal. Calcd for C20H14N2O2: C,
76.42; H, 4.49; N, 8.91%. Found: C, 76.36; H, 4.43; N, 8.86%.
2-Amino-3-cyano-4-(2-furyl)-7-hydroxy-4H-chromene
2-Amino-3-cyano-4-heptyl-7-hydroxy-4H-chromene (4q):
1
White solid; mp 124-126 °C; H NMR (400 MHz, DMSO-d6):
¤ 0.783 (t, J = 6 Hz, 3H, Me), 2.36 (m, 12H, (CH2)6), 3.358 (t,
J = 7 Hz, 1H, H-4), 6.307 (d, 1H, J = 2 Hz, H-Ar), 6.503 (dd,
1H, J = 2 Hz, J = 10 Hz, H-Ar), 6.695 (s, 2H, NH2), 6.959 (d,
1H, J = 10 Hz, H-Ar), 9.590 (s, 1H, OH); 13C NMR (100 MHz,
DMSO-d6): ¤ 23.86, 24.69, 24.76, 26.42, 26.65, 26.88, 27.59,
43.78, 102.82, 107.94, 111.46, 112.23, 114.59, 121.67, 131.93,
156.69, 160.90; IR (KBr, cm¹1): 3482, 3328, 2197, 1647,
1589; Anal. Calcd for C17H22N2O2: C, 71.30; H, 7.74; N,
9.78%. Found: C, 71.37; H, 7.76; N, 9.83%.
1,4-Bis(2-amino-3-cyano-7-hydroxy-4H-chromen-4-yl)-
benzene (4r): Orange solid; mp >300 °C; 1H NMR (400
MHz, DMSO-d6): ¤ 4.554 (s, 2H, H-4), 6.380 (d, 2H, J = 3 Hz,
H-Ar), 6.455 (dd, 2H, J = 3 Hz, J = 9 Hz, H-Ar), 6.522 (d, 2H,
J = 9 Hz, H-Ar), 6.826 (s, 4H, NH2), 6.974-7.063 (m, 4H,
H-Ar), 9.683 (s, 2H, OH); 13C NMR (100 MHz, DMSO-d6): ¤
57.43, 102.62, 112.79, 112.82, 113.74, 113.92, 121.66, 128.85,
130.27, 144.02, 149.25, 159.93, 160.67; IR (KBr, cm¹1): 3427,
3330, 2191, 1650, 1588; Anal. Calcd for C26H18N4O4: C,
69.33; H, 4.02; N, 12.43%. Found: C, 69.39; H, 4.07; N,
12.49%.
(4l):
White solid; mp 208-210 °C; 1H NMR (400 MHz,
DMSO-d6): ¤ 4.753 (s, 1H, H-4), 6.125 (d, 1H, J = 2 Hz,
H-Ar), 6.332 (dd, 1H, J = 2 Hz, J = 8 Hz, H-Ar), 6.517 (d, 1H,
J = 8 Hz, H-Ar), 6.949 (s, 2H, NH2), 7.27-7.504 (m, 3H,
H-furyl), 9.752 (s, 1H, OH); 13C NMR (100 MHz, DMSO-d6):
¤ 53.83, 102.81, 106.78, 110.31, 112.34, 112.93, 116.33,
120.97, 130.36, 149.55, 151.43, 155.57, 157.62, 161.33; IR
(KBr, cm¹1): 3478, 3419, 2192, 1651, 1585; Anal. Calcd for
C14H10N2O3: C, 66.14; H, 3.96; N, 11.02%. Found: C, 66.07;
H, 4.03; N, 11.06%.
2-Amino-3-cyano-7-hydroxy-4-(2-thienyl)-4H-chromene
(4m):
White solid; mp 228-231 °C; 1H NMR (400 MHz,
DMSO-d6): ¤ 4.968 (s, 1H, H-4), 6.374 (d, 1H, J = 3 Hz,
H-Ar), 6.507 (d, 1H, J = 3 Hz, J = 10 Hz, H-Ar), 6.904 (d, 1H,
J = 10 Hz, H-Ar), 6.914 (s, 2H, NH2), 6.963-7.339 (m, 3H,
H-thienyl), 9.746 (s, 1H, OH); 13C NMR (100 MHz, DMSO-
d6): ¤ 53.87, 102.86, 106.94, 111.42, 112.39, 112.86, 116.53,
121.67, 130.97, 149.59, 153.49, 155.47, 157.69, 161.96; IR
(KBr, cm¹1): 3459, 3421, 2192, 1652, 1588; Anal. Calcd for
C14H10N2O2S: C, 62.21; H, 3.73; N, 10.36%. Found: C, 62.16;
H, 3.69; N, 10.42%.
Results and Discussion
In this paper, we describe a simple and high yielding
protocol for the synthesis of 2-amino-4H-chromenes involv-
ing the three-component, one-pot condensation of aldehyde,
malononitrile, and resorcinol using Fe3O4 nanoparticles as a
novel and eco-friendly heterogeneous catalyst.
2-Amino-3-cyano-7-hydroxy-4-(5-methyl-2-furyl)-4H-
1
chromene (4n): White solid; mp 179-181 °C; H NMR (400
MHz, DMSO-d6): ¤ 2.149 (s, 3H, Me), 4.660 (s, 1H, H-4),
5.923 (d, 1H, J = 2 Hz, H-Ar), 5.981 (dd, 1H, J = 2 Hz, J =
10 Hz, H-Ar), 6.375 (d, 1H, J = 10 Hz, H-Ar), 6.536 (d, 1H,
J = 6 Hz, H-furyl), 6.917 (s, 2H, NH2), 6.938 (d, 1H, J = 6 Hz,
H-furyl), 9.752 (s, 1H, OH); 13C NMR (100 MHz, DMSO-d6):
Characterization of the Prepared Fe3O4-MNPs.
The
magnetite nanoparticles of 18-20 nm were prepared by the
well-known Massart’s method36 which consists of Fe(III) and

J. Safari et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 12 (2012) 1335
80
60
40
20
0
-20
-40
-60
-80
-10000 -8000 -6000 -4000 -2000
0
2000 4000 6000 8000 10000
Applied Field/Oe
Figure 3. Magnetization curve for Fe3O4-MNPs at room
temperature.
(b)
(a)
Figure 1. FT-IR spectrum of Fe3O4-MNPs.
Figure 4. SEM (a) and TEM (b) images of MNPs.
0:94-
DðhklÞ ¼
ð1Þ
¢ cos ª
2θ/degree
where D(hkl) is the average crystalline diameter, 0.94 is the
Scherrer’s constant, - is the X-ray wavelength, ¢ is the half
width of the XRD lines, and ª is the Bragg’s angle in degrees.
Here, the (311) peak of the highest intensity was picked out
to evaluate the particle diameter of the nanoparticles. Size of
MNPs were calculated to be 18 nm.
The magnetization curve for Fe3O4 nanoparticles is shown
in Figure 3. Room-temperature specific magnetization (M)
versus applied magnetic field (H) curve measurements of
the sample indicate a saturation magnetization value (Ms) of
62.76 emu g¹1. We can also see that the magnetization curve
follows a Langevin behavior over the applied magnetic field
and the coercivity (HC) could be ignored, which can be con-
sidered superparamagnetism.39
SEM and TEM images are shown in Figures 4a and 4b.
The SEM image shows that magnetite nanoparticles have a
mean diameter of about 18 nm and a nearly spherical shape
in Figure 4a. The size and shape of synthesized nanoparticles
are deduced from the TEM images in Figure 4b. The mean
diameter of Fe3O4 nanoparticles is about 18-20 nm, which
is consistent with SEM and XRD. Both images show the
nanoparticles are well dispersed and uniform in shape and size.
Evaluation of the Catalytic Activity of MNPs through the
Figure 2. XRD pattern of Fe3O4-MNPs.
Fe(II) coprecipitation in alkaline solutions. Figure 1 shows
the Fourier transform infrared (FTIR) spectrum of magnetic
¹1
nanoparticles. The Fe-O stretching vibration near 580 cm
,
O-H stretching vibration near 3432 cm¹1, and O-H deformed
¹1
vibration near 1629 cm were observed.37
Figure 2 presents the XRD pattern of the prepared MNPs.
The position and relative intensities of all peaks confirm
well with standard XRD pattern of Fe3O4 (JCPDS card No.
85-1436) indicating retention of the crystalline cubic spinel
structure of MNPs. The XRD patterns of the particles show six
characteristic peaks reveal a cubic iron oxide phrase (2ª =
18.35, 30.27, 35.53, 42.95, 53.60, 57.18, 62.69, 71.31, and
74.14°). These are related to their corresponding indices
(110), (220), (311), (400), (331), (422), (511), (440), and
(531) respectively. It is implied that the resultant nanoparticles
are pure Fe3O4 with a spinel structure and that the grafting
process did not induced any phase change of Fe3O4.38
Synthesis of 2-Amino-4H-chromene.
In the preliminary
stage of investigation we focused on systematic evaluation
of different catalysts for the model reaction of benzaldehyde
1a, malononitrile 2, and resorcinol 3 at room temperature
The crystal size of MNPs can be determined from the XRD
pattern by using Debye-Scherrer’s equation.

1336 Bull. Chem. Soc. Jpn. Vol. 85, No. 12 (2012)
Magnetic Fe3O4 Nanoparticles as Efficient and Reusable Catalyst
in aqueous conditions. A wide variety of catalysts includ-
ing ZrCl4, VCl3, AlCl3, bulk Fe3O4, and Fe3O4-MNPs were
employed to improve the yield for the specific synthesis of 2-
amino-4H-chromene derivative. The results are presented in
Table 1. Interestingly, when the reaction was carried out in the
presence of 2 mol % Fe3O4-MNPs, it led to the desired prod-
uct in 80% yield in 25 min (Table 1, Entry 6). The catalytic
activity of Fe3O4-MNPs was evident when no product was
obtained in the absence of the catalyst (Table 1, Entry 1).
Subsequent efforts were focused on optimizing conditions
for formation of 2-amino-4H-chromene by using different
amounts of Fe3O4-MNPs to determine their effects on the
reaction (Table 2). As indicated, the best result was obtained
with 7 mol % Fe3O4-MNPs. The reaction yield with increasing
amount of Fe3O4-MNPs was not substantially increased.
The efficiency of water as solvent compared to various
organic solvents was also examined (Table 3). In this study, it
was found that water is a more efficient and superior solvent
(Table 3, Entry 6) over other organic solvents (Table 3, Entries
1-5) with respect to reaction time and yield of the desired
chromene.
Based on the above observations, we conducted the same
reactions using various aldehydes 1a-1r, malononitrile 2, and
resorcinol 3 in the presence of 7 mol % of Fe3O4-MNPs under
optimal conditions. As expected, satisfactory results were
observed, and the results are summarized in Table 4. Interest-
ingly, a variety of aldehydes including acyclic, aromatic, and
heteroaromatic aldehydes participated well in this reaction.
It is noteworthy that methodology worked well for spatially
hindered aldehydes (Table 4, Entries 6-11).
Table 1. Influence of Different Catalysts for the Reaction of
Benzaldehyde (1a), Malononitrile (2), and Resorcinol (3)
at Room Temperature in Aqueous Medium
Entry
Catalysta)
Time/min
Yieldb)/%
1
2
3
4
5
6
None
ZrCl4
VCl3
AlCl3
Fe3O4
Fe3O4-MNPs
150
70
50
60
50
25
®
55
68
50
60
80
Encouraged by this achievement, the versatility of the
reaction was explored further by extending the methodology to
the synthesis of bis-4H-chromene. When p-phthalaldehyde was
a) Catalyst amount (2 mol %). b) Isolated yield of the pure
compound.
Table 3. Solvent Screening for the Reaction between
Malononitrile, Benzaldehyde, and Resorcinola)
Entry
Solvent
Yieldb)/%
Table 2. Optimizing the Reaction Conditionsa)
1
2
3
4
5
6
7
Dichloromethane
Cyclohexane
Acetonitrile
EtOH
Acetone
Water
30
15
42
70
70
98
83
Entry
Catalysts/mol %
Time/min
Yieldb)/%
1
2
3
4
5
2
4
6
7
8
25
25
25
25
25
80
91
95
98
98
None
a) Malononitrile (1 mmol), benzaldehyde (1 mmol), and resor-
cinol (1 mmol) in H2O (5 mL) was stirred at room temperature.
b) Isolated yields.
a) Fe3O4-MNPs (7 mol %), malononitrile (1 mmol), benzalde-
hyde (1 mmol), and resorcinol (1 mmol) in various solvents
(5 mL) was stirred at room temperature. b) Isolated yields.
Table 4. Fe3O4-MNPs-Catalyzed Three-Component Condensations of Malononitrile, Aldehydes, and Resorcinol
to Form 2-Amino-4H-chromenes
Entry
R
Product
Time/min
Yielda)/%
Mp/°C
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
C6H5
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
25
28
30
23
30
98
95
93
96
97
234-237d)
183-186d)
110-112d)
1106-109
2215-217
2218-221
2222-224
2256-258
217-220
191-193
230-232
208-210
228-231
179-181
169-172
160-162
124-126
>300
4-MeC6H4
4-MeOC6H4
3-ClC6H4
3-HOC6H4
2-FC6H4
2-MeOC6H4
2,4-Cl2C6H3
2,6-Cl2C6H3
3,5-(MeO)2C6H3
2-Naphthyl
2-Furyl
2-Thienyl
5-Methyl-2-furyl
Ethyl
Propyl
Hepthyl
25 (180)b)
97 (40)c)
35 (180)b)
95 (43)c)
95 (30)c)
95 (26)c)
95 (25)c)
95 (43)c)
97
95
96
94
97
20 (180)b)
20 (180)b)
32 (180)b)
24 (180)b)
20
20
22
26
28
28
25
93
98
OHCC6H4
a) Isolated yields. b) Using commercial Fe3O4. c) Isolated yield using commercial Fe3O4. d) Ref. 40.

J. Safari et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 12 (2012) 1337
Fe3+
Ph
NC
N
OH
HO
O
3
NC
NC
H
NC
- H2O
CN
2
..
..
Ph
HO
OH
H
Micheal
addition
Ph
1a
4
5
+
+
Ph
O
Ph
O
Ph
H
NC
NC
Cyclization
NC
HN
d.+.
-
d
OH
H2N
OH
N
O
H
OH
TS
4a
6
Scheme 2. A plausible mechanism for one-pot synthesis of 2-amino-4H-chromenes.
98
95
treated with two equiv of malononitrile and resorcinol under
similar conditions, the reaction proceeded cleanly to give the
corresponding bis-4H-chromene (4r) in 98% yield. The order
of yield of aldehydes is aromatic > heteroaromatic > acyclic
aldehydes. The activity of aldehydes with electron-withdrawing
groups is higher than that with electron-donating groups. The
position of substituent in the benzene rings of aldehyde
influences this reaction. The activity of o-aldehyde is lower
than p- and m-benzaldehyde.
90
88
85
A plausible mechanism explaining the aforementioned
results and the selectivity is depicted in Scheme 2. The process
represents a typical cascade of Knoevenagel condensation,
Michael addition, and cyclization in the presence of Fe3O4-
MNPs (Scheme 2). As can be seen in Scheme 2, magnetic
Fe3O4 nanoparticles are Lewis acidic and so can activate
the carbonyl group of aldehydes 1a to decrease the energy of
transition state for the nucleophilic attack of malononitrile. The
reaction is thought to proceed through Knoevenagel condensa-
tion to form intermediate 4. Subsequently Michael addition
occurs to form intermediate 5. 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. Iron cations act as Lewis acid and
play a significant role in increasing the electrophilic character
of the aldehydes.
The reusability is one of the important properties of this
catalyst. After the reaction was complete ethyl acetate was
added, and the catalyst onto the magnetic stirring bar. The
catalyst was then washed with ethyl acetate, air-dried and used
directly with fresh substrates under identical conditions without
further purification. It was shown 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 five cycles
(Figure 5). As observed in Figure 6 the XRD of the recovered
1
2
3
4
Run
5
Figure 5. Recyclability of Fe3O4-MNPs (7 mol %) in the
reaction of malononitrile (1 mmol), benzaldehyde
(1 mmol), and resorcinol (1 mmol) in H2O (5 mL) at room
temperature.
nanocatalyst was indexed according to the magnetite phase
(JCPDS card No. 79-0417), and so there is no considerable
change in its magnetic phase. Thus, the magnetite nanocatalyst
is stable during synthesis of 2-amino-4H-chromene in aqueous
media.
In summary, we have been able to introduce an efficient
and environmentally friendly approach for the synthesis of
biologically active 2-amino-4H-chromenes by one-pot three-
component condensation of aldehyde, malononitrile, and res-
orcinol in water using Fe3O4 nanoparticles at room tem-
perature. This method offers several advantages including high
yield, short reaction time, simple work-up procedure, and ease
of separation by an external magnet.
Conclusion
In summary, we have developed an efficient method for
the synthesis of 2-amino-4H-chromene derivatives by means of

1338 Bull. Chem. Soc. Jpn. Vol. 85, No. 12 (2012)
Magnetic Fe3O4 Nanoparticles as Efficient and Reusable Catalyst
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Research Council of the University of Kashan for supporting
this work by Grant NO (159198/VII).
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