New green, recyclable magnetic nanoparticles supported amino acids as simple heterogeneous catalysts for knoevenagel condensation

Article abstract of DOI:10.2174/15701786113109990002

Coumarin derivatives were synthesized using magnetically recoverable iron oxide nanoparticles supported amino acids as heterogeneous catalysts via one-pot multi component reaction using MW irradiation. Easy recovery of the catalyst using an external magne

Full text of DOI:10.2174/15701786113109990002

Send Orders for Reprints to reprints@benthamscience.net
68 Letters in Organic Chemistry, 2013, 10, 468-477
4
New Green, Recyclable Magnetic Nanoparticles Supported Amino Acids as
Simple Heterogeneous Catalysts for Knoevenagel Condensation
D. Girija, H.S. Bhojya Naik*, B. Vinay Kumar, C.N. Sudhamani and K.N. Harish
Department of Studies and Research in Industrial Chemistry, School of Chemical Sciences, Kuvempu University,
Shankaraghatta 577 451, India
Received November 26, 2012: Revised March 15, 2013: Accepted May 03, 2013
Abstract: Coumarin derivatives were synthesized using magnetically recoverable iron oxide nanoparticles supported
amino acids as heterogeneous catalysts via one-pot multi component reaction using MW irradiation. Easy recovery of the
catalyst using an external magnet, efficient recycling, and reusable without significant loss of their catalytic efficiency
makes the protocol greener and sustainable.
Keywords: Knoevenagel condensation, Fe
3
O
4
-DA-Phe, nanocatalyst, green chemistry.
INTRODUCTION
Coumarin and their derivatives have attracted significant
interest in recent times because of their potential biological
activities such as antibacterial, anticoagulant, pesticidal, fun-
gicidal and antimicrobial [18-22]. A notable achievement has
been made by Philip Kisanga and co-workers [23] for the
preparation of some substituted coumarins by Knoevenagel
condensation under solvent-free conditions. Following these
pioneering works, a number of other groups have reported
similar approaches for these reactions under mild conditions,
with different kinds of catalysts [24]. More recently nano
metal oxides have been used in the synthesis of coumarin
derivatives through Knoevenagel condensation [25] however,
these nano metal oxides feature difficulty in separation of
catalyst from reaction mixture. As a consequence, novel
catalysts that can be magnetically separated are still urgently
required.
Primary amines as catalysts in organic reactions are un-
doubtedly very commonly used. The first primary amine-
promoted process was credibly the Knoevenagel condensa-
tion [1], which was reported more than a century ago. Sev-
eral ventures in the field of amino acid catalysis are pre-
sented in the literature [2-6]. Following these significant
discoveries, asymmetric amino catalysis has sophisticated
amazingly in the past few years, and immense new catalysts
and novel reactions appeared in the literature at an increased
rate [7, 8]. The fact that chemists frequently aim to mimic
nature and prepare biomimetic catalysts, whose role in
asymmetric catalysis is even more surprising, as primary
amino acid catalysis is of vast significance in enzyme cataly-
sis. There has been intensive research trepidation on the ex-
pansion of surface adaption of superparamagnetic nanoparti-
cles for their imminent applications in catalysis [9, 10].
As part of our ongoing research focused on the develop-
ment of reusable catalysts for various organic transforma-
tions [26-29]. Here we report the preparation and characteri-
Magnetic nanomaterials are envisaged to have a major
impact in many areas, including biotechnology/ biomedicine,
environmental remediation and particularly catalysis [11].
Few numbers of methods have been developed for the syn-
3 4
zation of a magnetically separable Fe O functionalized with
dopamine conjugated amino acid catalyst and its application
for the catalytic activity of Knoevenagel condensation via
the enamine mechanism that has an alternative in asymmet-
ric organocatalysis. The objective is not only to easily sepa-
rate the catalyst from the reactant by means of the simple
application of an external magnetic field, but at the same
time also, to demonstrate advances in primary amine-
catalyzed enantioselective reactions.
thesis of high-quality Fe
acid based surface modifiers such as L-Arginine-Capped
Fe [12], Fe –cysteine [13], functionalization of ferrite
3 4
O nanoparticles of various amino
3
O
4
3 4
O
MNPs by the glutathione [14] and magnetic nanoparticle-
supported proline [15] are used in catalytic reactivity. Vari-
ous types of MNPs-supported dopamine with amino acid
have emerged recently which include N-acetyl histidine [16]
2 3
and biomimetic nanocatalyst Fe O -Asp-His [17]. Since eas-
ily recoverable and reuseable heterogenous catalyst is still in
high demand, an impressive feature of supported magnetic
nanoparticle catalyst is the ready separation using an external
magnet, which achieves a simple separation of catalyst with-
out filtration.
RESULT AND DISCUSSION
The catalysts (Fe O -DA-Phe), (Fe O -DA-Val) and
3
4
3
4
(Fe O -DA-Ile) were prepared by the concise route outlined
3
4
in (Scheme 1). Dopamine (DOPA) was first linked with car-
boxylic group of Fmoc protected amino acids via the DCC/
NHS chemistry. The dopamine moiety proved to have high
*
Address correspondence to this author at the Department of Studies and
3 4
affinity to the Fe O surface. Through DOPA, the amino
Research in Industrial Chemistry, School of Chemical Sciences, Kuvempu
University, Shankaraghatta 577 451, India; Tel: +91 9448438281;
Fax: +91 8282 257302; E-mail: hsb_naik@rediffmail.com
acids were covalently anchored on the surface of the Fe
particles.
3 4
O
1
875-6255/13 $58.00+.00
© 2013 Bentham Science Publishers

New Green, Recyclable Magnetic Nanoparticles Supported Amino Acids
Letters in Organic Chemistry, 2013, Vol. 10, No. 7
469
Scheme 1. Synthesis of functionalized iron oxide nanoparticle supported-amino acids ((Fe
3
O
4
-DA-Phe), (Fe
3
O
4
-DA-Val) and (Fe
3
O
4
-DA-
Ile)).
ite which conforms well to the reported value [30] The aver-
age crystallite size D was calculated using the Debye–
Sherrer formula D= K ꢀ /(ꢁ Cos ꢂ) where K is Sherrer con-
stant, ꢀ the X ray wavelength, ꢁ the peak width of half-
maximum, and ꢂ is the Bragg diffraction angle [31]. The 2ꢂ
value to be 35.9. The crystallite size of the powder particles
is calculated as about 28 nm.
The morphology of the sample was investigated with
scanning electron microscopy SEM (Fig. 2) which shows a)
(
3 4 3 4 3 4
Fe O -DA-Phe), b) (Fe O -DA-Val) and c) (Fe O -DA-Ile)
Catalyst to be in nanostructure. These nanoparticles are gen-
erally random and not uniform.
The FTIR spectrum for the Fe
pamine conjugated amino acid catalysts is shown in (Fig. 3).
In the FT-IR spectrum of Fe -DA-Phe (1), the disappear-
ance of the C=O stretching peak of the carboxylic groups of
3 4
O functionalized with do-
3
O
4
-
1
phenylalanine at 1680 cm and the appearance of the amide
-
1
peaks at 1647 and 1552 cm clearly indicate the formation
of the conjugated product. The N–H stretching bonds of the
amide and OH-groups of the dopamine anchors are at around
-
1
3
438 cm . The aromatic CH stretching peaks of the
dopamine and phenyl units of phenylalanine appeared at
Fig. (1). XRD pattern of the a) (Fe
Val) and c) (Fe -DA-Ile)).
3
O
4
-DA-Phe), b) (Fe
3
O
4
-DA-
-1
-1
3
008 cm . The absorption band at 764.4cm is attributed to
-1
3
O
4
the Fe-O bonds and 574 cm for Fe
of dopamine conjugated amino acid are observed for
functionalized Fe by the presence of vibration bands at
3 4
O . The spectral features
Catalyst Characterization
3
O
4
-
1
The obtained particles were analyzed by XRD to identify
the crystallographic structure. The XRD pattern of nano
1096, 1552, 1647, 3008 and 3438 cm , respectively. These
bands are absent in the spectrum of uncoated magnetite
particles and confirm the presence of dopamine conjugated
amine on magnetite. Similarly for Fe O -DA-Val (2) Bands
sized catalysts ((Fe
3 4 3 4
O -DA-Phe), (Fe O -DA-Val) and
(
Fe O -DA-Ile)) is shown in (Fig. 1). The diffraction patterns
3 4
3
4
-
1
and relative intensities of all the peaks matched well with
those of magnetite (JCPDS No.19-0629). Broad XRD peaks
clearly indicate the nanocrystalline nature of the material
which is indicative of a cubic spinel structure of the magnet-
at 1640 cm (C=O stretching of a secondary amide),
-
1
-
1
3432cm N–H stretching bands of the amide, 3020 cm
attributes for aromatic CH stretching and band at 2961 cm
-
1
contribute for C-H stretching. A strong absorption band at
5
91.8 cm-1 was due to the vibration of the Fe–O bond of

4
70 Letters in Organic Chemistry, 2013, Vol. 10, No. 7
Girija et al.
3 4 3 4 3 4
Fig (2). SEM images of synthesized a) (Fe O -DA-Phe), b) (Fe O -DA-Val) and c) (Fe O -DA-Ile).
3 4 3 4 3 4
Fig. (3). IR spectra of synthesized a) (Fe O -DA-Phe), b) (Fe O -DA-Val) and c) (Fe O -DA-Ile).
to the vibration of the Fe–O bond of ferrite and the weak
NMR resolved spectra of ligands bound to a paramagnetic
nanocrystal are difficult to perform due to large broadening
effects caused by paramagnetic properties.
-
1
wide absorption at about 1029 cm in the spectra and the
vibration of C–O bond of Fe
In IR spectrum for Fe
3
O
4
modified by dopamine.
-
1
3
O
4
-DA-Ile (3) bands at 1645 cm
-
1
(
C=O stretching of a secondary amide), 3425 cm N–H
Catalytic Reactivity of Fe O -DA-Phe Catalyst Through
3
4
-
1
stretching bonds of the amide, 3062 cm attributes to aro-
Knoevenagel Condensation
-
1
matic CH stretching and band at 2930 cm contributes for C-
-
1
Although numerous methods in preparing coumarins by
Knoevenagel condensation are known, newer methods con-
tinue to attract attention for their experimental simplicity and
effectiveness. To demonstrate the reactivity of amino acids
found at the surface of Fe O -DA-Phe catalyst, we decided
H stretching. A strong absorption band at 592 cm was due
to the vibration of the Fe–O bond of ferrite.
To study the surface group on magnetic nanoparticles,
1
1
very dilute samples were examined by H NMR [32]. H
3
4

New Green, Recyclable Magnetic Nanoparticles Supported Amino Acids
Letters in Organic Chemistry, 2013, Vol. 10, No. 7
471
to evaluate the catalytic reactivity through Knoevenagel con-
densation for the synthesis of coumarin derivatives. This
system was successfully applied to our previous research
(Table 2). In order to select the appropriate microwave
power, the model reaction was examined at different micro-
wave powers (100–400W) with controlled temperature (max.
[
25]. Thus, we have been interested in the development of
3 4
140 ꢀC) in the presence of Fe O -DA-Phe catalyst. The reac-
method for Knoevenagel condensation that would avoid the
use of added acids and bases, is easy to perform and eco-
nomical for application to large scale preparations. The ex-
perimental reaction is presented in (scheme 2).
tion was also examined at 60–140 °C under thermal condi-
tions. Higher yield and shorter reaction time were attained at
120 °C.
3 4
Table 2. Optimization of the Fe O -DA-Phe Catalyzed Model
To obtain the optimal reaction conditions, the synthesis
of ethyl 2-oxo-2H-chromene-3-carboxylate (3a) was used as
a model reaction. A mixture of o-hydroxy benzaldehyde (2
mmol), nano catalyst (15mg) and diethyl malonate (2.5
mmol) was irradiated in a microwave oven. The effect of
Reaction for Synthesis of Ethyl 3-carboxylate (3a).
a
Entry
Catalysts (mg)
Yields(%)
1
2
3
4
5
No catalyst
-
3 4 3 4 3 4
catalysts Fe O -DA-Phe, Fe O -DA-Val and Fe O -DA-Ile
was examined under microwave and thermal conditions to
evaluate their capabilities. The results are summarized in
Fe
Fe
Fe
Fe
Fe
3
3
3
3
3
O
O
O
O
O
4
4
4
4
4
-DA-Phe (10 mg)
-DA-Phe (15 mg)
-DA-Phe (20 mg)
-DA-Phe (15 mg)
-DA-Phe (15 mg)
65
b
94
(
Table 1). A control experiment was conducted in the ab-
sence of the nano catalyst; for ethyl 2-oxo- 2H-chromene-3-
carboxylate (3a) the reaction did not proceed and the sub-
strate remained unchanged, while good results were obtained
in the presence of nanocatalyst.
75
c
80
d
6
75
a Isolated yield
On the optimized amount of catalyst, we found that 15mg
b Reaction was carried out at 120 °C
c Reaction was carried out at 100 °C
d Reaction was carried out at 140 °C
3 4
of Fe O -DA-Phe catalyst could effectively catalyze the re-
action for formation of the desired product. With the inclu-
sion of 10 mg of Fe -DA-Phe catalyst the reaction took
3
O
4
To compare the efficiency of the solvent-free versus so-
lution conditions, the reaction was examined in several sol-
vents under microwave and thermal conditions. Thus, a mix-
3 4
longer time. Using more than 20 mg of Fe O -DA-Phe cata-
lyst has less effect on the yield and time of the reaction
3 4
Scheme 2. Synthesis of coumarins by Knoevenagel condensation using Fe O -DA-Phe.
Table 1. The effect of different catalysts (15 mg) on reaction of o-hydroxy benzaldehyde (2 mmol), and diethyl malonate (2.5 mmol)
under microwave (MW, 300W, max.120 °C) and thermal (ꢀ, 100 °C) conditions.
a
Time (min)
Yield (%)
Entry
Catalysts
MW
ꢀ
MW
ꢀ
1
2
3
4
5
No catalyst
--
15
6
--
---
88
94
89
89
---
79
90
80
90
Fe
3
O
4
80
35
60
75
Fe
3
O
4
-DA-Phe
Fe
3
O
4
-DA-Val
8
Fe
3
O
4
-DA-Ile
12

4
72 Letters in Organic Chemistry, 2013, Vol. 10, No. 7
Girija et al.
Table 3. Comparative synthesis of compound 3a using solution versus the solvent-free conditions under microwave (MW, 300W,
o
max.120 C’).
a
Time (min)
MW
Yield (%)
MW
Entry
Solvents
1
2
3
4
5
6
No solvent
DMF
6
94
25
20
30
75
80
10
18
16
12
10
Acetonitrile
Dioxane
Methanol
Ethanol
a
isolated yield
ture of 2-hydroxy benzaldehyde (2 mmol), Fe
3
O
4
-DA-Phe
tion (Table 4, entries 1–12). A variety of substituted o-
hydroxy benzaldehydes possessing a wide range of electron-
donating and electron-withdrawing functional groups af-
forded the corresponding products in good yields. Structure
of all the synthesized compounds was confirmed by IR
(
15mg) and ꢀ-dicarbonyl compound (2.5 mmol) was irradi-
ated in microwave oven (300 W, max. 120 °C). The results
are depicted in (Table 3). As it is clear from (Table 3), lower
yields and longer reaction times were observed in solution
conditions. Therefore, the solvent-free method is more effi-
cient.
1
and H NMR and data for these compounds are shown in
experimental procedure section. These spectral data matched
well with those of reported samples [22-33].
To investigate the versatility and capability of our
method, the reactions of o-hydroxy benzaldehyde were ex-
amined with diethyl malonate compounds under both mi-
crowave conditions. As (Table 3) indicates, the reactions
proceeded efficiently and the desired products were obtained
in good to excellent yields.
The structure of ethyl 2-oxo-2H-chromene-3-carboxylate
(3a). It showed strong IR absorption bands at 1744,
-
1
1656,1614 cm due to coumarin carbonyl, C=O (ketone) and
1
alkene aromatic groups respectively. In its H NMR spec-
trum one singlet at ꢀ 8.7, 6.31 and 6.94 was assigned to a
methyl group, olefinic proton and an aromatic proton respec-
tively. Two aromatic protons of coumarin moiety appeared
as doublets at 6.92, 7.57.
In order to investigate the scope of this reaction, a variety
of different substituted o-hydroxybenzaldehydes and differ-
ent 1,3-dicarbonyl compounds were subjected to this reac-
3 4
Table 4. Knoevenagel condensation of 2-hydroxy aldehydes with various ꢁ-dicarbonyl compounds in the presence of Fe O -DA-Phe
catalyst under microwave (MW, 300 W, max. 130 °C) and thermal (ꢀ, 100 °C) conditions.
a
Time (min) Yield (%)
Observed
M.P. (°C)
Literature
M.P. (°C)
1
Entry
R
R
Product
MW
MW
O
OEt
1
H
CO
2
Et
6
94
92
93-94 [23]
O
O
O
3
a
CH3
2
3
H
COMe
5
5
93
82
122
121-123 [23]
O
O
3
b
O
OEt
3
-OH, 4-
OH
CO
2
Et
232
233-234 [33]
HO
O
O
OH
3
c

New Green, Recyclable Magnetic Nanoparticles Supported Amino Acids
Letters in Organic Chemistry, 2013, Vol. 10, No. 7 473
Table 4. contd….
a
Time (min) Yield (%)
Observed
M.P. (°C)
Literature
MW
1
Entry
R
R
Product
MW
MW
O
O
OEt
4
3-OMe
CO
2
Et
8
85
89
88-90 [23]
O
OMe
3
d
O
O
CH3
5
3-OMe
COMe
8
92
175
173-174 [23]
O
OMe
3
e
O
OEt
6
7
4-OMe
4-OMe
CO
2
Et
8
6
90
86
121-124
115-116
120-125 [23]
115-116 [23]
MeO
O
O
O
3
f
CH3
COMe
MeO
O
O
O
3
3
g
OEt
Et
8
9
Et
2
N
CO
2
Et
8
89
77
77-78 [23]
N
O
O
Et
h
O
O
CH3
Et
Et
2
N
COMe
5
6
94
92
152
227
151-154 [23]
228-229 [23]
N
O
Et
3
3
i
CN
O
Et
N
O
1
0
Et
2
N
CN
Et
j

4
74 Letters in Organic Chemistry, 2013, Vol. 10, No. 7
Girija et al.
Table 4. contd….
Entry
a
Time (min) Yield (%)
Observed
M.P. (°C)
Literature
1
R
R
Product
MW
MW
MW
O
O
OEt
1
1
1
2
3-OH
CO
CO
2
Et
6
65
172
167
174-175 [33]
O
OH
3
k
O
OEt
4-OH
2
Et
7
88
166-167 [33]
HO
O
O
3
l
Recovery of Catalyst
chromatography was performed using commercially pre-
pared 60-mesh silica gel plates and visualization was ef-
fected with short wavelength UV light (254 nm). The IR
spectra were recorded on a Shimadzu model impact 400D
To examine applications of heterogeneous systems, since
the lifetime of the catalyst and its level of reusability are
significant factors, the catalyst recovered by magnetic sepa-
ration from the reaction mixture of o-hydroxy benzaldehyde
and diethyl malonate after dilution with ethyl acetate was
reused as such for subsequent experiments (up to five cycles)
under similar reaction conditions. The catalyst was washed
with distilled water repeatedly and dried for 2–3 h under
vacuum before re-use. The observed fact that yields of the
product remained comparable in these experiments (Table
1
FT-IR Spectrophotometer using KBr pellets. H NMR was
recorded on a Bruckner AC-300F 300 MHz spectrometer in
1
DMSO using TMS as an internal standard with H resonance
frequency of 300 MHz. The microwave oven (2.45 GHz,
maximum power 300 W) used for sample preparation was a
single mode microwave synthesis system (Discover, CEM,
USA). Temperature was controlled by automatic adjusting of
microwave power. X-ray powder diffraction (XRD) patterns
were recorded using a Rigaku D/max 2550 V X-ray diffrac-
tometer with high-intensity Cu Ka radiation (k=1.54178 Å)
and a graphite monochromator. A JEOL JEM 6700F field
emission scanning electron microscope was used for the de-
termination of the morphology of the particles.
5
), established the recyclability and reusability of the Fe
3 4
O -
DA-Phe catalyst without significant loss of activity.
Table 5. Reuse of Fe
3
O
4
-DA-Phe catalyst.
Yield (%)
No. of Uses
Recovery of Catalyst
General Procedure for the Synthesis of Magnetic
Nanoparticles
1
2
3
4
5
94
92
88
85
84
96
92
90
90
85
A mixed solution of iron(II) chloride heptahydrate (0.546
g, 2.16 mmol) and iron(III) chloride hexahydrate (1.169 g,
4
.32 mmol) in deionized water (5 mL) was added dropwise
to sodium hydroxide solution (20 mL, 1 M) with vigorous
stirring and continuous bubbling of nitrogen through the so-
lution. The solution became blue-black in color and was left
to stir for further 30 minutes. The nanoparticles were mag-
netically separated with an external magnet, the supernatant
solution decanted, and the particles washed with deionized
water until the pH of the supernatant stabilized at pH 7. Fur-
ther magnetic separation, replacement of the aqueous super-
natant with methanol and removal of the solvent under re-
EXPERIMENTAL
Chemicals and Instruments
All chemicals (AR grade) were commercially available
and used without further purification. o-hydroxybenz-
aldehydes and 1,3-dicarbonyl compounds were commer-
cially, procured from HiMedia Laboratories Pvt. Ltd., and
used without any further purification, Dopamine hydrochlo-
dicyclohexylcarbodiimide
succinimide (NHS) and Fmoc Protected Amino Acids were
purchased from Sigma–Aldrich.
duced pressure gave the Fe
powder [34].
3 4
O nanoparticles as a fine black
ride,
(DCC)
N-hydroxy-
Synthesis of 2-amino-N-[2-(3,4-dihydroxyphenyl)ethyl]-3-
phenylpropanamide 1
The melting points of the products were determined by a
Mel-Temp apparatus and were uncorrected. Thin-layer
2-Amino-N-[2-(3,4-dihydroxyphenyl)ethyl]-3-phenylpro
panamide was prepared in accordance with the reported pro-

New Green, Recyclable Magnetic Nanoparticles Supported Amino Acids
Letters in Organic Chemistry, 2013, Vol. 10, No. 7 475
cedure [17] with slight modification. Fmoc protected pheny-
General Experimental Procedure for the Synthesis of
Coumarins
3
lalanine (0.387mg, 1.0 eq.) was dissolved in CHCl (3 mL)
at 0 ºC under N
and the solution stirred for 15 minutes at 0 ºC. NHS (4 mg,
3 ꢃmol, 1.1 eq.) and 12.7 mg of dopamine hydro
chloride (DOPA) were dissolved in a mixture solvent con-
taining 20 mL of CHCl , 10 mL of DMF, was added and the
solution stirred for 1 hour at 0 ºC and for 14 hours at RT
2
. DCC (7 mg, 33 ꢃmol, 1.1 eq.) was added
A mixture of o-hydroxy benzaldehyde (2 mmol), 1,3-
dicarbonyl compound (2 mmol) and Fe O -DA-Phe (30mg)
3 4
3
was mixed in a 50 mL flask and irradiated under microwave
for the time indicated in (Table 6.1). The reaction progress
was monitored by TLC. After completion of the reaction, the
reaction mixture was cooled to room temperature which then
solidified within an hour. The resulting solidified mixture
was diluted with ethyl acetate (5 mL) and the catalyst was
separated by using external magnet and dried for reuse. The
reaction mixture was washed twice with water and solvent
was evaporated under reduced pressure which yielded the
crude product, which was further purified by recrystalliza-
tion. The same procedure was used for synthesis of deriva-
tives. All synthesized coumarin derivatives were character-
3
2
under N . Solvent was removed under reduced pressure,
leaving a pale brown residue. Added 50 mL aq NaOH were
added to remove the Fmoc group. Swirled mixture for 30
min.
Synthesis of 2-amino-N-[2-(3,4-dihydroxyphenyl)ethyl]-2-
methylpropanamide 2
Fmoc-protected valine (0.325mg, 1.0 eq.) was dissolved
1
in CHCl
3
(3 mL) at 0 ºC under N
2
. DCC (7 mg, 33 ꢃmol, 1.1
ized using analytical techniques such as IR and H NMR.
eq.) was added and the solution was stirred for 15 minutes at
ºC. NHS (4 mg, 33 ꢃmol, 1.1 eq.) and 12.7 mg of dopa-
mine hydrochloride (DOPA) were dissolved in a mixture
solvent containing 20 mL of CHCl , 10 mL of DMF, was
added and the solution stirred for 1 hour at 0 ºC and for 14
hours at RT under N . Solvent was removed under reduced
The identity of these compounds was established by com-
1
0
parison of IR, H NMR spectral data and their melting points
with those of reported samples (Table 4) [23-33]. Spectral
data for all compounds are listed.
3
Ethyl 2-oxo-2H-chromene-3-carboxylate (3a); IR (KBr)
2
-1
ꢀ1
cm : 1744, 1656, 1614, 1543, 1431, 1291, 960, 775 cm
;
pressure, leaving a brown residue, 50 mL aq NaOH were
added to remove the Fmoc group. Swirled mixture for 30
min.
1
H NMR (DMSO, 300 MHz) ꢁ (ppm): 8.7 (s, 1H, CH), 7.63-
7
.66 (m, 2H, Ar-H), 7.43-7.48 (m, 2H, Ar-H), 4.4 (q, 2H,
CH ), 1.4 (t, 3H, CH ).
2
3
Synthesis of 2-amino-N-[2-(3,4-dihydroxyphenyl)ethyl]-
-1
3
-Acetyl-2H-chromen-2-one (3b); IR (KBr) cm : 1732,
ꢀ1 1
3
-methylpentanamide 3
1
677, 1613, 1557, 1455, 1233, 1210, 979, 756 cm ; H
NMR (DMSO, 300 MHz) ꢁ (ppm): 8.51 (s, 1H, CH), 7.64-
.67 (m, 2H, Ar-H), 7.33-7.39 (m, 2H, Ar-H), .2.73 (s, 3H,
CH ).
Fmoc protected isolucine (0.353 mg, 1.0 eq.) was dis-
solved in CHCl (3 mL) at 0 ºC under N . DCC (7 mg, 33
3 2
7
ꢃmol, 1.1 eq.) was added and the solution stirred for 15 min-
utes at 0 ºC. NHS (4 mg, 33 ꢃmol, 1.1 eq.) and 12.7 mg of
dopamine hydrochloride (DOPA) were dissolved in a mix-
3
Ethyl 7,8-dihydroxy-2-oxo-2H-chromene-3-carboxylate
-
1
(3c); IR (KBr) cm : 3476, 3214, 2973, 1738, 1693, 1618,
ꢀ1 1
ture solvent containing 20 mL of CHCl
was added and the solution stirred for 1 hour at 0 ºC and for
4 hours at RT under N . Solvent was removed under re-
3
, 10 mL of DMF,
1588 cm ; H NMR (DMSO, 300 MHz) ꢁ (ppm): 8.90 (b,
2H, OH), 8.75 (s, 1H, CH), 7.27 (d, 1H, Ar-H), 6.87 (d, 1H),
1
2
2 3
4.19 (q, 2H, CH ),1.30 (t,3H, CH ).
duced pressure, leaving a pale brown residue. Added 50 mL
aq NaOH were added to remove the Fmoc group. Swirled
mixture for 30 min.
Ethyl 8-methoxy-2-oxo-2H-chromene-3-carboxylate(3d);
-1
IR (KBr) cm :1732, 1685, 1598, 1548, 1282, 1201, 954,
ꢀ1
1
8
12, 765 cm ; H NMR (DMSO, 300 MHz) ꢁ (ppm): 8.44
(
(
s, 1H, CH),7.22~7.38 (m, 3H, Ar-H), 4.4 (q, 2H, CH
s, 3H, OCH ), 1.4 (t, 3H, CH ).
2
), 3.99
Synthesis of amino acid fuctionalized Fe
Fe -DA-Phe)/ (Fe -DA-Val)/ (Fe
3
O
4
nanoparticles
-DA-Ile)
3
3
(
3
O
4
3
O
4
3
O
4
3-acetyl-8-methoxy-2H-chromen-2-one (3e); IR (KBr)
-
1
cm : 1735, 1686, 1602, 1568, 1282, 1201, 950, 801, 766
Magnetite nanoparticles (50 mg, 216 ꢃmol) were sus-
ꢀ1
1
cm ; H NMR (DMSO, 300 MHz) ꢁ (ppm): 8.48 (s, 1H,
CH), 7.18~7.29 (m, 3H, Ar-H) 3.99 (s, 3H, OCH ), 2.73 (s,
H, CH ).
pended in a solution of 1 (10.8 mg, 36 ꢃmol) in methanol (3
mL) under nitrogen and sonicated for 6 hours. The dispersed
particles were magnetically separated and the supernatant
solution decanted and collected. The residue was washed
with methanol (3 ꢁ 10 mL) to remove any unreacted 1; each
time the particles were re-dispersed by sonication and iso-
lated by external magnet, followed by decantation and col-
lection of the supernatant solution. After this, the particles
were resuspended in methanol (10 mL) and the solvent re-
moved under reduced pressure. Drying under high vacuum
3
3
3
Ethyl 7-methoxy-2-oxo-2H-chromene-3-carboxylate (3f);
-
1
ꢀ1 1
IR (KBr) cm : 3052, 2986, 1619, 1381, 1216 cm ; H NMR
(DMSO, 300 MHz) ꢁ (ppm): 8.51 (s, 1H,CH), 7.50 (d,1H,
Ar-H), 6.93 (d, 1H, Ar-H), 6.80 (d, 1H,Ar-H), 4.40 (q,
2
H,CH
2
), 3.90 (s,3H, OCH
3-acetyl-7-methoxy-2H-chromen-2-one(3g); IR (KBr)
1
3 3
), 1.40 (t, 3H,CH )
-
cm : 1736, 1672, 1616, 1504, 1366, 1210, 989, 837, 767
ꢀ1
1
gave the coated nanoparticles (Fe
powder. Similar procedure was followed for the synthesis of
Fe -DA-Val) and (Fe -DA-Ile).
3
O
4
-DA-Phe) as a black
cm ; H NMR (DMSO, 300 MHz) ꢁ (ppm): 8.50 (s, 1H,
CH), 7.55 (d, 1H, Ar-H), 6.91 (q, 1H, Ar-H), 6.84 (d, 1H,
Ar-H), 3.92 (s, 3H, OCH ), 2.71 (s, 3H, CH ).
(
3
O
4
3 4
O
3
3

4
76 Letters in Organic Chemistry, 2013, Vol. 10, No. 7
Girija et al.
Ethyl 7-(diethylamino)-2-oxo-2H-chromene-3-carboxy-
Stork, G.; Landesman, H. A new alkylanon of carbonyl com-
pounds. J. Am. Chem. Soc. 1956, 78, 5128-5129; (c) Stork, G.;
Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell,R.The
enamine alkylation and acylation of carbonyl compounds J. Am.
Chem. Soc. 1963, 85, 207-222.
-
1
late (3h); IR (KBr) cm : 3465, 3008, 1716, 1676, 1206, 960,
ꢀ1 1
8
34, 787 cm ; H NMR (DMSO, 300 MHz) ꢂ (ppm): 8.81
s, 1H,CH), 7.62-7.66 (d, 1H, Ar-H), 6.77 (d, 1H, Ar-H),
.54 (s, 1H,Ar-H), 4.25-4.28(q, 2H,CH ), 3.3-3.5(q, 4H,
CH ), 1.23-1.32(t, 3H,CH ), 1.14-1.18 (t, 6H,CH ).
(
6
[3]
[4]
Eder, U.; Sauer, G.; Wiechert, R. New Type of Asymmetric Cycli-
zation to Optically Active Steroid CD Partial Structures. Angew.
Chem., Int. Ed. Engl. 1971, 10, 496-497; (b) Hajos, Z.G.; Parrish,
D.R. Asymmetric synthesis of bicyclic intermediates of natural
product chemistry. J. Org. Chem. 1974, 39, 1615-1621.
2
2
3
3
3
-acetyl-7-(diethylamino)-2H-chromen-2-one (3i); IR
-1
(
KBr) cm :3356., 2966, 1723, 1661, 1560, 1472, 1214, 1186
ꢀ1 1
Buchschacher, P.; Cassal, J.-M.; Furst, A.; Meier,W. Contribution
to the asymmetric synthesis of bicyclic compounds catalysed by
cm ; H NMR (DMSO, 300 MHz) ꢂ (ppm): 8.70 (s, 1H,
CH),7.46 (d, 1H, Ar-H), 6.60 (d, 1H, Ar-H), 6.53(d, 1H,Ar-
optically
active
amino
acids.
Synthesis
of
(S)-2-
H), 3.37 (q, 4H, CH
2
), 2.65 (s,3H, CH
3
), 1.20 (t, 6H, CH
3
);
pyrrolidinepropionic acid and (R)-4-amino-5-phenylvaleric acid.
Helv. Chim. Acta. 1977, 60, 2747-2755.
7
-(diethylamino)-2-oxo-2H-chromene-3-carbonitrile (3j);
[
5]
Danishefsky, S.; Cain, P. Pyridine route to optically active estrone
and 19 norsteroids. J. Am. Chem. Soc. 1975, 97, 5282-5284; (b)
Shimizu, I.; Naito, Y.; Tsuji, J. Synthesis of optically active (+)-19-
nortestosterone by asymmetric bis-annulation reaction Tetrahedron
Lett. 1980, 21, 487-490; (c) Hagiwara, H.; Uda, H. Optically pure
-1
IR (KBr) cm : 3305, 2998, 2230, 1715, 1645, 1297, 958,
ꢀ1 1
7
60 cm ; H NMR (DMSO, 300 MHz) ꢂ (ppm): 8.50 (s, 1H,
CH), 7.80 (s, 1H, Ar-H), 7.73-7.76 (d, 1H, Ar-H), 7.03-7.06
(
d, 1H,Ar-H), 4.13- 4.20 (m, 4H,CH
Ethyl
2 3
), 1.17(t, 6H, CH ).
(
4aS)-(+)-
or
(4aR)-(-)-1,4a-dimethyl-4,4a,7,8-
tetrahydronaphthalene 2,5(3H,6H)-dione and its use in the synthe-
8-hydroxy-2-oxo-2H-chromene-3-carboxylate
ꢀ1
sis of an inhibitor of steroid biosynthesis. J. Org. Chem. 1988, 53,
(
3k); IR (KBr): 3303, 3045, 2984, 1746, 1696, 1611 cm ;
H NMR (DMSO, 300 MHz) ꢂ (ppm): 10.8 (s, 1H .OH),
2
308-2311; (d) Corey, E.J.; Virgil, S.C. Enantioselective total syn-
1
thesis of a protosterol, 3.beta.,20-dihydroxyprotost-24-ene. J. Am.
Chem. Soc. 1990, 112, 6429-6431.
8
.69 (s, 1H,CH), 7.28 (m, 1H, Ar-H), 7.10- 7.19 (m, 2H, Ar-
[
6]
7]
Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. New Strategies
for Organic Catalysis:ꢀ The First Highly Enantioselective Organo-
catalytic DielsꢀAlder Reaction J. Am. Chem. Soc. 2000, 122, 4243-
H), 4.30 (q, 2H, CH
2 3
), 1.32 (t, 3H, CH ),
Ethyl 7-hydroxy-2-oxo-2H-chromene-3-carboxylate(3l);
ꢀ1 1
4
244.
IR (KBr): 3550, 3470, 1739, 1617 cm ; H NMR (DMSO,
00 MHz) ꢂ (ppm): 9.60(s, 1H, OH), 8.67 (s,1H ,CH) 7.75
d, 1H, Ar-H), 6.84 (d, 1H,Ar-H), 6.73 (s, 1H,Ar-H), 4.20 (q,
H, CH ),1.30 (t, 3H, CH ).
[
List, B.; Lerner, R.A.; Barbas, C.F. Proline-Catalyzed Direct
3
Asymmetric Aldol Reactions. J. Am. Chem. Soc. 2000, 122, 2395-
(
2
396.
2
2
3
[8]
Mukherjee, S.; Yang, J.W.; Hoffmann, S.; List. B. Asymmetric
Enamine Catalysis. Chem. Rev. 2007, 107, 5471-5569; (b) Erkkila,
A.; Majander, I.; Pihko, P.M. Iminium catalysis Chem. Rev. 2007,
1
07, 5416-5470.
CONCLUSION
[9]
Machajewski, T.D.; Wong, C.-H. The Catalytic Asymmetric Aldol
Reaction. Angew. Chem., Int. Ed. 2000, 39, 1352-1375; (b) Mar-
tynowski, D.; Eyobo, Y.; Li, T.F.; Yang, K.; Liu, A.; Zhang, H.
Crystal structure of alpha-amino-beta carboxymuconate-epsilon-
semialdehyde decarboxylase: insight into the active site and cata-
lytic mechanism of a novel decarboxylation reaction. Biochem,
2006, 45, 10412-10421; (c) Jordan, P.M. Highlights in haem bio-
synthesis. Curr. Opin. Struct. Biol. 1994, 4, 902-911.
In conclusion we have developed the iron oxide nanopar-
ticles functionalized with dopamine conjugated amino acids
as alternative in asymmetric organocatalysis and examined
their catalytic activity for synthesis of coumarins. We have
developed an efficient, facile and environmentally-
acceptable synthetic methodology for the synthesis of cou-
marin derivatives using magnetically supported Aminocata-
lysis via the enamine mechanism under solvent-free condi-
tion. The advantages of this environmentally benign and safe
protocol include a simple reaction setup, very mild reaction
conditions, high product yields, short reaction times, and the
possibility for reusing the catalyst, chemoselectivity and sol-
vent-free conditions.
[
10]
11]
Xu, L.-W.; Lu, Y. Primary amino acids: privileged catalysts in
enantioselective organocatalysis. Org. Biomol. Chem. 2008, 6,
2
047-2053; (b) Peng, F.; Shao, Z. Advances In Asymmetric Or-
ganocatalytic Reactions Catalyzed By Chiral Primary Amines J.
Mol. Catal. A: Chem. 2008, 285, 1-13; (c) Chen, Y-C. The Devel-
opment of Asymmetric Primary Aminocatalysts Based on Cin-
chona Alkaloids, Synlett, 2008, 1919.
[
Lu, A.H.; Salabas, E.L.; Schuth, F. Magnetic Nanoparticles: Syn-
thesis, Protection, Functionalization, and Application. Angew.
Chem., Int. Ed. 2007, 46, 1222-1244; (b) Perez,J. M. Iron oxide
nanoparticles: hidden talent. Nat. Nanotechnol. 2007, 2, 535-536.
Lai, Y.; Yin, W.; Liu, J.; Xi, R.; Zhan, J. One-Pot Green Synthesis
CONFLICT OF INTEREST
[12]
[13]
and Bioapplication ofl-Arginine-Capped Superparamagnetic Fe
3
O .
4
The authors confirm that this article content has no con-
flicts of interest.
Nanoparticles.Nanoscale Res Lett. 2009, 5,302-307.
Gawande, M.B.; Velhinho, A;. Nogueira, I.D.; Ghumman, C.A.A.;
Teodoro, O.M.N.D.; Branco,P.S. A facile synthesis of cysteine–
ferrite magnetic nanoparticles for application in multicomponent
reactions—a sustainable protocol. RSC Adv. 2012, 2, 6144-6149.
Polshettiwar, V.; Baruwati, B.; Varma, R.S. Magnetic nanoparticle-
supported glutathione: a conceptually sustainable organocatalyst.
Chem. Commun., 2009, 1837-1839.
ACKNOWLEDGEMENTS
[
14]
15]
Declared none.
[
Chouhan, G.; Wang, D.; Alper, H. Magnetic nanoparticle-
supported proline as a recyclable and recoverable ligand for the CuI
catalyzed arylation of nitrogen nucleophiles. Chem. commum.
2007, 4809-4811.
Liem, K.P.; Mart, R.J.; Webb, S.J. Magnetic assembly and pattern-
ing of vesicle/nanoparticle aggregates. J. Am. Chem. Soc. 2007,
129, 12080-12081.
Zheng, Y.; Duanmu, C.; Gao, Y. A magnetic biomimetic nanocata-
lyst for cleaving phosphoester and carboxylic ester bonds under
mild conditions. Org. Lett. 2006, 8, 3215-3217.
REFERENCES
[
1]
Knoevenagel. E. Ueber eine Darstellungsweise der Glutarsäure
Ber. Dtsch. Chem. Ges., 1894, 27, 2345-2346. (b) Tietze, L.F.; Bei-
fuss, U., in Comprehensive Organic Synthsis, ed. B.M. Trost, I.
Fleming, Pergamon, Oxford, UK, 1991, pp. 341-394.
Stork, G.; Terrell, R.; Szmuszkovicz, J. A new synthesis of 2- alkyl
and 2-acyl ketones. J. Am. Chem. Soc. 1954, 76, 2029-2030; (b)
[16]
[17]
[
2]

New Green, Recyclable Magnetic Nanoparticles Supported Amino Acids
Letters in Organic Chemistry, 2013, Vol. 10, No. 7 477
[
18]
Modranka, J.N.; Nawrot, E.; Graczyk, J. In vivo antitumor, in vitro
antibacterial activity and alkylating properties of phosphorohydra-
zine derivatives of coumarin and chromone. Eur. J. Med. Chem.
Pyridine Moiety and Studies on their Catalytic Behavior.
Am.Chem. Sci. J. 2011, 1, 97-108.
[27]
[28]
[29]
[30]
Girija, D.; Bhojya Naik, H.S.; Sudhamani, C.N.; Vinay Kumar, B.
Cerium oxide nanoparticles - a green, reusable, and highly efficient
heterogeneous catalyst for the synthesis of Polyhydroquinolines
under solvent-free conditions Arch. Appl.Sci.Res, 2011, 3, 373-382.
Prakash Naik, H.R.; Bhojya Naik, H.S.; Aravinda, T. Nano-
Titanium dioxide (TiO2) mediated simple and efficient modifica-
tion to Biginelli reaction. Afr. J. Pure Appl. Chem. 2009, 3, 202-
207.
2
006, 41, 1301-1309.
[19]
Rosselli, S.; Maggio, A.; Bellone, G.; Formisano, C.; Basile, A.;
Cicala, C.; Alfieri, A.; Mascolo, N.; Bruno, M. Antibacterial and
anticoagulant activities of coumarins isolated from the flowers of
Magydaris tomentosa. Planta Med. 2007, 72, 116-120..
[20]
[21]
[22]
Deng, Y.; Nicholson,R.A. Block of electron transport by surangin
B in bo- vine heart mitochondria. Pestic. Biochem. Physiol.2005.
8
1, 39-50.
Ramesha, S.: Bhojya Naik, H.S.; Harish Kumar, H.N. Titanium
trichloride-catalysed cyclocondensation: synthesis of 2-
mercaptoquinoline substituted 1,2,3,4-tetrahydropyrimidinones. J.
Sul. Chem. 2007, 28. 573-579.
Patel, H.S.; Patel, S R. Coumarin Polymers Derived from Salicy-
laldehyde-Formaldehyde Polymer, J. Macromol. Sci. Part A: Pure
Appl. Chem. 1984. 21, 343-352.
Yagodinets, P.I; Skripskaya, O.V.; Chernyuk, I.N.; Bezverkhnii,
V.D; Vasikand,L.I.; Sinchenko,V.G. Synthesis And Antimicrobial
Activity Of Coumarin-Containing Imidazoles. Pharm. Chem. J.
Yang, T.Z.; Shen, C.M.; Gao, H.J. Highly Ordered Self-Assembly
with Large Area of Fe3O4 Nanoparticles and the MagneticProper-
ties. J. Phys. Chem. B. 2005, 109, 23233-23236.
1
996, 30, 335-336.
[31]
[32]
Cullity, B.D. Elements of X-ray Diffraction, Addision Wesely,
London, 1959, 261.
[
[
[
23]
24]
25]
Kisanga, P.; Fei, X.; Verkade, J. An efficient promoter for the
synthesis of 3-substistuted coumarins. Synth. Commun. 2002, 32,
Willis, A.L.; Turro, N.J.; O'Brien, S. Spectroscopic Characteriza-
tion of the Surface of Iron Oxide Nanocrystals. Chem. mater. 2005,
17, 5970-5975.
1
135-1144.
Prajapati, D.; Gohain, M. Iodine a simple, effective and inexpen-
sive catalyst for the synthesis of substituted coumarins. Catal. Lett.
[33]
[34]
Alvim, J.; Dias, R. L. A.; Castilho, M. S.; Oliva, G.; Corrêa, A. G.
Preparation and evaluation of a coumarin library towards the in-
hibitory activity of the enzyme GAPDH fromTrypanosoma cruzi. J.
Braz. Chem. Soc. 2005, 16, 763-773.
2
007, 119, 59-63.
Vinay Kumar, B.; Bhojya naik, H.S.; Girija, D.; Vijaya kumar, B.
ZnO nanoparticle as catalyst for efficient green one-pot synthesis of
coumarins through Knoevenagel condensation. J. Chem. Sci. 2011,
Mart, R.J.; Liem, K.P.; Wang, X.; Webb, S.J. The effect of receptor
clustering on vesicle-vesicle adhesion. J. Am. Chem. Soc. 2006,
128, 14462-14463.
1
23, 615-621.
[
26]
Girija, D.; Bhojya Naik, H.S.; Vinay Kumar, B.; Sudhamani, C.N.
Synthesis of Functionalized Iron OxideNanoparticle with Amino