Fe3O4@ZrO2/SO4 2-: A recyclable magnetic heterogeneous nanocatalyst for synthesis of β-amino carbonyl derivatives and synthesis of benzylamino coumarin derivatives through Mannich reaction

Article abstract of DOI:10.1002/aoc.4147

In the present work, we developed an effective protocol for the synthesis of β-amino carbonyl compounds and synthesis of benzylamino coumarin derivatives through Mannich type reaction in high yields. Fe₃O₄@ZrO₂/SO₄ ^2- was employed as an effective heterogeneous nanocatalyst for the Mannich reaction. This research consists of two sections. In first section, β-amino carbonyl derivatives were synthesized under solvent-free condition. In the other section, benzylamino coumarin compounds were synthesized at room temperature. The present approach offers several advantages such as short reaction times, low cost, easy work-up, mild reaction conditions, high yields and ease of recovery and reusability of the catalyst without significant loss of activity.

Full text of DOI:10.1002/aoc.4147

Received: 19 July 2017
DOI: 10.1002/aoc.4147
Revised: 18 September 2017
Accepted: 23 September 2017
F U L L P A P E R
2‐
Fe3O4@ZrO2/SO4 : A recyclable magnetic heterogeneous
nanocatalyst for synthesis of β‐amino carbonyl derivatives
and synthesis of benzylamino coumarin derivatives through
Mannich reaction
Hossein Ghafuri
| Behnaz Ghorbani | Afsaneh Rashidizadeh | Majid Talebi | Mahdi Roshani
Catalysts and Organic Synthesis Research
Laboratory, Department of Chemistry,
Iran University of Science and
Technology, P.O. Box 16846‐13114,
Tehran, I. R., Iran
In the present work, we developed an effective protocol for the synthesis of β‐
amino carbonyl compounds and synthesis of benzylamino coumarin deriva-
2‐
tives through Mannich type reaction in high yields. Fe3O4@ZrO2/SO4 was
employed as an effective heterogeneous nanocatalyst for the Mannich reaction.
This research consists of two sections. In first section, β‐amino carbonyl deriv-
atives were synthesized under solvent‐free condition. In the other section,
benzylamino coumarin compounds were synthesized at room temperature.
The present approach offers several advantages such as short reaction times,
low cost, easy work‐up, mild reaction conditions, high yields and ease of recov-
ery and reusability of the catalyst without significant loss of activity.
Correspondence
Hossein Ghafuri, Catalysts and Organic
Synthesis Research Laboratory,
Department of Chemistry, Iran University
of Science and Technology, P.O. Box
16846‐13114 Tehran, I. R. Iran.
Email: ghafuri@iust.ac.ir
Funding information
Research Council of the Iran University of
Science and Technology
KEYWORDS
Mannich reaction, Fe3O4@ZrO2/SO42‐, heterogeneous nanocatalyst, recyclable catalyst, β‐amino
carbonyl derivatives
1 | INTRODUCTION
leading to β‐amino carbonyl compounds and their deriva-
tives including benzylamino coumarin have become cen-
The synthesis of pharmaceuticals, natural molecules and
other nitrogenous biologically active compounds is an
important field in organic synthesis. The Mannich reac-
tion provides significant protocols for the synthesis of
such compounds.[1] Usually in this reaction, an amine,
two carbonyl compounds and acid (or base) catalysts are
used to afford various β‐amino carbonyl compounds.[2]
β‐amino carbonyl compounds forming from Mannich
reaction are significant synthetic intermediates for
various pharmaceuticals and natural products.[3]
Benzylamino coumarin and its derivatives are formed
through Mannich type reactions. They are important
members of heterocyclic compounds family. These com-
pounds are biologically active and have many properties
such as: anti‐HIV,[4] anticoagulant[5] and antioxidants.[6]
Hence, the devolvement of novel synthetic methods
ter of attentions. From these methods, one‐pot three‐
component reaction strategy is reliable and promising
which allows for a wide range of structural variations.
Various catalyst systems were examined for the catalytic
three‐component Mannich reaction including NbCl5,[7]
H3PW12O40,[8] Zn(OTf)2,[9] PS‐SO3H,[10] HClO4‐SiO2,[11]
DBSA,[12] silica sulfuric acid,[13] ZrOCl2.8H2O[14] and
organic catalysts.[15–18] To the best of our knowledge only
a few remarkable researches on synthesis of benzylamino
coumarin derivatives have been reported.[19–21] It is note-
worthy that the most of reported methods for the synthe-
sis of β‐amino carbonyl compounds and benzylamino
coumarin derivatives have some drawbacks such as: lon-
ger reaction time, inadequate yields, use of expensive cat-
alyst and limited success in term of stereoselectivity.
Therefore, development of an effective and affordable
Appl Organometal Chem. 2017;e4147.
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https://doi.org/10.1002/aoc.4147

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GHAFURI ET AL.
protocol for the synthesis of them is really important.
Furthermore, the preparation of an efficient and reus-
able catalyst is significant for both environmental and
chemical points of view. In the past decade, functional-
ized magnetic nanoparticles have attracted remarkable
interest due to their specific advantages such as:
reusability, high surface area, high chemical stability,
availability, easy separation with an external magnet
and so on. In summary, nanocatalysts are reliable and
green option for researchers to apply in organic reac-
tions.[22] We have recently reported the synthesis of
2‐
nano magnetic sulfated zirconia Fe3O4@ZrO2/SO4
and its application in multicomponent reactions and
protection of hydroxyl groups that has all mentioned
advantages.[23–26] Regarding these facts and in connec-
tion with our previous researches on the one‐pot multi-
component reactions,[27–30] herein, we wish to report a
superior, green, and facile synthesis of β‐amino
carbonyl compounds and benzylamino coumarin
derivatives by using nano‐magnetic sulfated zirconia
as a catalyst, through Mannich reaction (Scheme 1).
FIGURE
Fe3O4@ZrO2/SO4
1
The X‐ray diffraction patterns of Fe3O4 and
2‐
be seen for the synthesized Fe3O4@ZrO2/SO42‐. The peak
positions of Fe3O4 are unchanged through the production
of Fe3O4@ZrO2/SO42‐, representing that the crystalline
structure of the magnetite is essentially conserved. Stan-
dard XRD patterns confirmed the diffraction signals and
relative intensities of all peaks. Peaks at 2θ = 35.62 are
indexed as Fe3O4. Additional diffraction peaks around
2θ = 30.6, 51.1, and 60.1 are attributed to ZrO2 and reveal
that after calcination, the major form is tetragonal phase.
We investigated the morphology, size and struc-
2 | RESULTS AND DISCUSSIONS
2.1 | Catalyst identification
2‐
ture of Fe3O4@ZrO2/SO4 using scanning electron
Nano magnetic sulfated zirconia was prepared through
the method that we have reported recently (for more
details please see support information). X‐ray diffraction
(XRD) patterns of the prepared Fe3O4 and Fe3O4@ZrO2/
SO42‐ are shown in Figure 1 respectively. It has been used
to determine the structure of nanocatalyst. Six character-
istic peaks of Fe3O4 (2θ = 30.1, 35.4, 43.0, 53.5, 57.0 and
62.5) are observed. Similarly the peaks of the Fe3O4 could
microscopy (SEM) and transmission electron micros-
copy (TEM) (Figure 2). SEM micrograph showed that
the synthetic Fe3O4@ZrO2/SO4 presented uniform
2‐
nanoparticles. To illustrate the particle size and its
distribution, 200 particles were chosen randomly.
The particle size distribution was narrow and the
sizes of most of the particles were about 30–40 nm
2‐
(Figure 2d). The TEM image of Fe3O4@ZrO2/SO4
SCHEME 1 Synthesis of β‐amino
carbonyl compounds (A, B) and benzyl
amino coumarinderivatives (C) through
Mannich type reaction

GHAFURI ET AL.
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FIGURE 2 TEM (a) and SEM (b) micrographs of Fe3O4@ZrO2/SO42‐ (c) The particle size distribution diagram of the Fe3O4@ZrO2/SO42‐ (d)
demonstrated the successful coating of ZrO2 on
2‐
Fe3O4. The EDX spectrum of Fe3O4@ZrO2/SO4
reveals the presence of Fe, Zr, O and S elements,
further confirming the formation of zirconia on the
Fe3O4 nanoparticle (Figure 3). Additionally, induc-
tively coupled plasma atomic spectroscopy (ICP) indi-
cated that the weight content of the loading amount
2‐
of Zr in the 1.0 g of Fe3O4@ZrO2/SO4 was about
22.11 wt%. All the results suggest that Fe3O4@ZrO2/
SO4 has been successfully synthesized.
FIGURE
Fe3O4@ZrO2/SO4
3
Energy dispersive X‐ray spectroscopy of
2‐
2‐

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GHAFURI ET AL.
TABLE 1 Screening of Fe3O4@ZrO2/SO42‐ amount, solvent and temperature effect on Mannich reaction of 4‐nitrobenzaldehyde, aniline
and acetophenonea
Entry
Solvent
Catalyst (mg)
Temperature (°C)
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
9
CH3CN (2.0 ml)
50
50
50
50
‐
60
60
60
60
60
60
60
25
100
60
60
60
60
420
60
60
60
60
55
EtOH (2.0 ml)
60
H2O (2.0 ml)
40
‐
‐
‐
‐
‐
‐
90
Trace
65
40
60
50
50
90
60
80
aReaction conditions: 4‐nitrobenzaldehyde (1.0 mmol), aniline (1.0 mmol), acetophenone (1.0 mmol). b Isolated yields.
both electron‐withdrawing and electron‐donating groups.
The results show that being electron‐withdrawing or
electron‐donating does effect the general trend of the
reactivity. In general, aromatic aldehydes which contain
electron‐withdrawing groups require shorter reaction time
in comparison to those with electron‐donating groups.
It is expected that amines with electron‐donating
groups act as more effective nucleophile in comparison
to amines with electron‐withdrawing groups, but a reverse
fact was seen in practice. Amines with electron‐donating
groups have more electron density on their nitrogen. In
other words, they have more basic property which causes
more interaction with acidic catalyst and finally reduction
of nucleophilicity. Therefore, in order to achieve high
yield, we chose solvent‐free condition. The reaction mech-
anism possibly involves activation of carbonyl functional
2.2 | Investigation of the catalytic activity
of Fe3O4@ZrO2/SO42‐ in the synthesis of β‐
amino carbonyl compounds and
benzylamino coumarin derivatives
2.2.1 | Synthesis of β‐amino carbonyl
compounds by using Fe3O4@ZrO2/SO42‐ as
catalyst
In order to optimize the reaction conditions, we consid-
ered the reaction of 4‐nitrobenzaldehyde, aniline and
ketones in (A and B) Scheme 1 (mole ratio 1: 1: 1) as a
model reaction. The results are shown in Table 1. The
progress of the reaction was monitored by TLC. The
results indicated that we have not desired yield in the
2‐
absence of Fe3O4@ZrO2/SO4 even after 7 h (entry 5,
Table 1), so the use of catalyst is necessary for the reaction
progress. The addition of iron oxide to sulfated zirconia
increased catalytic activity, it was found that iron oxide
(Fe3O4) modifies the sulfated zirconia surface by generat-
ing acidic sites of medium strength. Sufficiently doping
the sulfated zirconia with iron oxide can increase the total
number acidic sites with lower strength. These changes,
especially the simultaneous presence of two acidic type
sites with different strengths, are interesting for catalytic
activity. The ionic nature of S = O imparts the Bronsted
acid site to the catalyst which enhances the acidity of
the material thereby reinforcing the catalytic activity.
Regarding the results that showed in Table 1, the effi-
ciency and the yield of the model reaction under solvent
free condition and 60 °C was higher than those obtained
in presence of solvent. These results inspired us to develop
this optimized condition to other aromatic aldehydes, ani-
lines and ketones for the synthesis of β‐amino carbonyl
compounds (Table 2). This reaction has the advantages of
easy separation of catalyst by an external magnet and easy
work‐up. We investigated aldehydes and amines containing
2‐
group by using Fe3O4@ZrO2/SO4 as the catalyst, hence
it increases the carbonyl activity. Subsequent the attack
of amine to the carbonyl group of aldehyde gives the corre-
sponding imine intermediate. Afterward, the in‐situ gener-
ated enolate reacts with imine intermediate to afford the
desired β‐amino carbonyl compounds (Scheme 2).
For determination of anti/syn ratio (Table 3), two
methods have been reported.[30,31] Method (1): with
technical chromatography, HPLC can illustrates two dia-
stereoisomers syn and anti (in support information data).
1
Method (2): with technical H‐NMR, to notice of product
structure two protons were diastereotopic, so two peaks
were appearance in two difference chemical shift, there
for Hsyn with smaller constant coupling than Hanti was
splitting, and ratio of anti/syn% is equal to the integration
of area under the peaks. The results of these two methods
are the same (Jsyn < Janti). The anti/syn ratio was deter-
1
mined by H‐NMR. Coupling constant of the anti‐isomer
is higher than that of the syn‐isomer (Scheme 3). For
example, in the 1H NMR spectra of 2‐((3‐hydroxy

GHAFURI ET AL.
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TABLE 2 Synthesis of β‐amino carbonyl derivatives through Mannich reaction of various aldehydes with aniline and acetophenone cata-
2‐a
lyzed by Fe3O4@ZrO2/SO4
ref
Entry
1
Aldehyde
Product
Time(min)
Yield(%)b
M.p. (°C)
[32]
50
90
162‐164
2
3
30
40
90
85
85 [33]
[34]
129‐130
[35]
4
5
35
50
96
85
111‐114
144‐147
[36]
[37]
6
45
87
189‐190
[35]
7
8
30
45
95
90
127‐130
135‐137
[34]
(Continues)

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GHAFURI ET AL.
TABLE 2 (Continued)
ref
Entry
9
Aldehyde
Product
Time(min)
Yield(%)b
M.p. (°C)
[32]
40
85
112‐115
[38]
10
35
85
123‐125
11
12
N.R
N.R
─
*
*
─
─
─
13
N.R
─
*
─
aReaction condition: aniline (1.0 mmol), aldehyde (1.0 mmol), acetophenone (1.0 mmol) and 50 mg Fe3O4@ZrO2/SO42‐ were used under solvent‐free condition at
60 °C.
bIsolated yields.
*No Reaction.
SCHEME 2 The plausible mechanism
for synthesis of β‐amino carbonyl
compounds throughMannich reaction
2‐
catalysed by Fe3O4@ZrO2/SO4

GHAFURI ET AL.
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TABLE 3 Synthesis of β‐amino carbonyl derivatives through Mannich reaction using various aldehydes, anilines and cyclic ketones cata-
2a
lyzed by Fe3O4@ZrO2/SO4
Entry
Aldehyde
Ketone
Amine
Products
Yield (%)b
(anti)/ (syn)
1
85
74:26
2
3
96
88
93:7
80:20
4
95
84:16
aReaction condition: amine (1.0 mmol), aldehyde (1.0 mmol), cyclohexanone (1.0 mmol) and 50 mg Fe3O4@ZrO2/SO42‐ were used under solvent‐free condition
and ball‐milling at room temperature.
bIsolated yields.
phenyl)(phenylamino)methyl)cylohexanone (2a), the sig-
nal at δ = 4.61‐4.64 ppm (J = 8.5 Hz) is contributed by
the anti isomer, while the one at 4.73‐4.75 ppm (J = 4.7
Hz) is contributed by the syn isomer.
In order to examine reusability of the Fe3O4@ZrO2/
SO42‐, the reaction of 4‐nitrobenzaldehyde, aniline and
acetophenone (mole ratio 1: 1: 1) as the model reaction
was carried out. After completion of the reaction, the cata-
lyst was separated by an external magnet, washed with eth-
anol and dried at room temperature and used directly for
the next reaction. The Fe3O4@ZrO2/SO42‐ was recycled five
times without significant loss of catalytic activity (Figure 4).
To show the efficiency of Fe3O4@ZrO2/SO42‐ as a conve-
1
SCHEME 3 Determination of syn and anti isomer by H‐NMR
nient catalyst for Mannich reaction, catalytic activity of the
Fe3O4@ZrO2/SO42‐ was compared with other catalytic sys-
tem which has been reported for the synthesis of β‐amino
carbonyl compounds. As it can be observed in Table 4, this
method has some advantages containing shorter reaction
time, high yield under solvent free conditions, easy separa-
tion the catalyst via an external magnet and recyclable.
2.2.2 | Synthesis of benzylamino coumarin
derivatives by using Fe3O4@ZrO2/SO42‐ as
catalyst
2‐
FIGURE 4 Examination of Fe3O4@ZrO2/SO4 reusability in the
We also extended our study to the synthesis of
benzylamino coumain derivatives. To optimize the
synthesis of β‐amino carbonyl compounds in five consecutive
reaction

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GHAFURI ET AL.
TABLE 4 Comparison of the catalytic efficiency of Fe3O4@ZrO2/SO42‐ with other catalysts for the synthesis of β‐amino carbonyl com-
pounds through Mannich reactiona
Entry
Catalyst
γ‐Al2O3/CH3SO3H
CaCl2
Solvent, temperature(°C)
Ethanol, 20
Time (min)
Yield (%)b
Ref
[39]
1
2
3
4
5
6
7
8
9
600
120
180
60
89
72
90
92
56
82
90
91
96
[35]
[40]
[41]
[42]
[43]
[44]
[45]
Ethanol, 60
GuHCl
Solvent‐free, 20
Solvent‐free, r.t.
Solvent‐free, r.t.
Ethanol, reflux
Ethanol, r.t.
SiCl4
I2
60
Sulfated MCM‐41
K3PO4
8 h
40
Tin(ll) chloride
Ethanol, 20
6 h
30
2‐
Fe3O4@ZrO2/SO4
Solvent‐free, 60
This work
aReaction condition: 4‐cholorobenzaldehyde (1.0 mmol), aniline (1.0 mmol), acetophenone (1.0 mmol).
bIsolated yields.
2‐
TABLE 5 Screening of Fe3O4@ZrO2/SO4 amount and solvent effect on Mannich type reaction of 4‐nitrobenzaldehyde, pyrolidine and
4‐hydroxycoumarin (each one 1.0 mmol)
Entry
Solvent
Catalyst amount(mg)
Time(min)
Yield (%)a
1
2
3
4
5
6
7
Acetonitrile
Ethanol
70
70
70
70
0
30
30
30
30
30
30
30
97
60
H2O
30
Solvent‐free
Acetonitrile
Acetonitrile
Acetonitrile
Trace
Trace
65
60
80
90
aIsolated yields.
reaction conditions for the one‐pot synthesis of
benzylamino coumain compounds, the reaction of 4‐
nitrobenzaldehyde, pyrolidine and 4‐hydroxycoumarin
(mole ratio 1: 1: 1) was used as a model reaction (Table 5).
When the reaction was carried out in the absence of cata-
lyst, the desired product was obtained in low yield (entry
5, Table 5). Thus, the catalyst is an essential factor for
the synthesis of benzylamino coumain derivatives. Subse-
quent different solvents such as acetonitrile, ethanol and
water were evaluated. As indicated in Table 5, acetonitrile
was found much better than other solvents under room
temperature. These results encouraged us to develop these
optimized conditions to other aromatic aldehydes and
amines for the synthesis of benzylamino coumarin com-
pounds. (Table 6). We investigated aldehydes and amines
containing both electron‐withdrawing and electron‐
donating groups. The results show that being electron‐
withdrawing or electron‐donating does effect the general
trend of the reactivity. In general, aromatic aldehydes
which contain electron‐withdrawing groups require
shorter reaction time in comparison to those with
electron‐donating groups. A plausible mechanism for the
synthesis of benzylamino coumarin derivatives by using
2‐
Fe3O4@ZrO2/SO4 is shown in Scheme 4. First, the
2‐
Fe3O4@ZrO2/SO4 binds with oxygen of carbonyl group
of aldehyde, therefore it increases the carbonyl activity
to facilitate formation of imine intermediate from second-
ary amine and aldehyde. Afterward, nucleophilic addition
of 4‐hydroxycoumarin to carbon of iminium, leads to the
desired product (Scheme 4).
To investigate the reusability of the Fe3O4@ZrO2/
SO42‐, the model reaction was done in the presence of
the recycled catalyst in subsequent runs without notice-
able loss of activity (Figure 5).
When the reaction was complete, the catalyst was
removed by an external magnet, after washing the catalyst
with ethanol; No remarkable change was seen in its struc-
ture. The presence of sulfate ion in the catalyst was con-
firmed by FT‐IR spectra of Fe3O4@ZrO2/SO42‐ (Figure 6).
Figure
6
(b) shows the Infrared spectra of
2‐
Fe3O4@ZrO2/SO4 in comparison to Fe3O4 spectra. A
broad peak about 3400 cm‐1 was observed which is

GHAFURI ET AL.
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GHAFURI ET AL.

GHAFURI ET AL.
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attributed to σ O‐H stretching mode of water that
adsorbed from air on the surface of catalyst. Hydrogen
bonding causes the broadness of this peak. The peak
about 1630 cm‐1 is attributed to δ O‐H bending mode of
water. A strong band that emerged at 1126 cm‐1 is attrib-
uted to the stretching vibration of S = O and another peak
which emerged at approximately 1400 cm‐1 is attributed
to asymmetric stretching vibration of covalent S = O
band. The peak emerged at 600 cm‐1 is attributed to Zr
= O band and finally, the vibration peak of Fe‐O was
emerged at about 500 cm‐1. In order to show the efficiency
of the Fe3O4@ZrO2/SO42‐ in comparison with other cata-
lysts used for the synthesis of benzylamino coumarin
derivatives, the results are summarized in Table 7. As
seen in Table 7, that present procedure is superior to some
of the other methods in terms of yields, reaction time, and
reaction temperature and recyclable.
3 | EXPERIMENTAL
3.1 | Materials and methods
All chemicals were purchased from Merck or Aldrich and
used as received. Melting points were determined using
an Electro thermal 9100 apparatus. FT‐IR spectra were
recorded as KBr pellets on a Shimadzu FT IR‐8400S
spectrometer. Analytical TLC was carried out using Merck
1
0.2 mm silica gel 60 F‐254 Al‐plates. H NMR (500 MHz)
spectra were obtained using Bruker DRX‐500 Avance
spectrometers at ambient temperature. The powder X‐ray
diffraction pattern was recorded using a X‐PERT‐ PRO dif-
fractometer with Cu Kα, (λ = 1.54 Å) irradiation, in the
range of 5 to 80 (2θ) with a scan Step of 0.026. The morphol-
ogy of catalyst was studied with scanning electron micros-
copy using SEM (KYKY, EM 3200) on gold coated
2‐
samples. The magnetic properties of Fe3O4@ZrO2/SO4
nanoparticles were measured with a vibrating magnetome-
ter/ Alternating Gradient Force Magnetometer (VSM/,
MDKFD). Inductively coupled plasma atomic (ICP)
measurement was performed on Shimadzu 7000 Ver.2.
3.2 | General procedure for the synthesis of
β‐amino carbonyl derivatives (Scheme 1, A)
A mixture of aldehyde 1 (1.0 mmol), aniline 2 (1.0
mmol), acetophenone
3 (1.0 mmol) and 50 mg
2‐
Fe3O4@ZrO2/SO4 was stirred vigorously in a 5 ml
round bottom flask equipped with a magnetic bar at 60
°C under solvent free condition. Reaction progress was
monitored by TLC. After completion of the reaction,
the catalyst was separated by a magnet. Then the catalyst
was washed by hot ethanol for further use in other reac-
tions. Purification of products was performed by using

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GHAFURI ET AL.
SCHEME 4 The plausible mechanism for the synthesis of benzylamino coumarin derivatives through Mannich reaction
2‐
FIGURE 5 Examination of Fe3O4@ZrO2/SO4 reusability in the
synthesis of benzylamino coumarin derivatives in five consecutive
reaction
ethanol or normal hexane and in some cases by using
solvent‐antisolvent method.
3.3 | General procedure for the synthesis of
β‐amino carbonyl derivatives (Scheme 1, B)
A mixture of aldehyde 1 (1.0 mmol), aniline 2 (1.0 mmol),
2‐
FIGURE 6 a) comparison the FT‐IR of Fe3O4@ZrO2/SO4
,
cyclohexanone 5 (1.0 mmol) and 50 mg Fe3O4@ZrO2/
Fe3O4@ZrO2 and Fe3O4. b) The FT‐IR spectra of the Fe3O4@ZrO2/
2‐
SO42‐ just prepared and after 5 runs
SO4 was ballmilled for the appropriate time (Table 3).
Reaction progress was monitored by TLC. After comple-
tion of the reaction, the catalyst was separated by a mag-
net. Then the catalyst was washed by hot ethanol for
further use in other reactions. Purification of products
was performed by using ethanol or normal hexane and
in some cases by using solvent‐antisolvent method.
3.4 | General procedure for the synthesis
of benzylamino coumarin (Scheme 1, C)
A mixture of aldehyde 1 (1.0 mmol), pyrolidine or piperidine
7 (1.0 mmol), 4‐hydroxy coumarin 8 (1.0 mmol), 2 ml

GHAFURI ET AL.
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TABLE 7 Comparison of the catalytic efficiency of Fe3O4@ZrO2/SO42‐ with other catalysts for the synthesis of benzylamino coumarin
derivatives through Mannich reactiona
Entry
Catalyst
Solvent, temperature (°C)
Toluene, 20
Time (h)
Yield (%)b
Ref.
1
2
3
InCl3
3
5
1
89
91
96
19
Triton X‐100
Fe3O4@ZrO2/SO4
H2O, 20
21
2‐
CH3CN, r.t.
Present work
aReaction condition: aldehyde (1.0 mmol), amine (1.0 mmol), 4‐hydroxycumarin (1.0 mmol).
bIsolated yields.
2‐
[3] R. Müller, H. Goesmann, H. Waldmann, Angew. Chem. Int. Ed.
1999, 38, 18.
acetonitrile as solvent and 50 mg Fe3O4@ZrO2/SO4 was
stirred vigorously in a 5 ml round bottom flask equipped
with a magnetic bar at room temperature. Reaction progress
was monitored by TLC. After completion of the reaction, the
catalyst was separated by a magnet. Then the catalyst was
washed by hot ethanol for further use in other reactions.
Purification of products was performed by using ethanol or
normal hexane and in some cases by using dichloromethane.
[4] S. Hesse, G. Kirsch, Tetrahedron Lett. 2002, 43, 1213.
[5] J. C. Jung, Y. J. Jung, O. S. Park, Synth. Commun. 2001, 31,
1195.
[6] A. D. Patil, A. J. Freyer, D. S. Eggleston, R. C. Haltiwanger, M.
F. Bean, P. B. Taylor, M. J. Caranfa, A. L. Breen, H. R. Bartus, J.
Med. Chem. 1993, 36, 4131.
[7] R. Wang, B. G. Li, T. K. Huang, L. Shi, X. X. Lu, Tetrahedron
Lett. 2007, 48, 2071.
4 | CONCLUSION
[8] N. Azizi, L. Torkiyan, M. R. Saidi, Org. Lett. 2006, 8, 2079.
This research consist of three sections. In first section, β‐
amino carbonyl derivatives were synthesized in solvent‐
free condition. In second section, β‐amino carbonyl deriv-
atives were synthesized by milling mixture of reagent in
ball‐mill and finally in third section, benzylamino couma-
rin derivatives were synthesized in room temperature. As
regards to our earlier researches on the one‐pot multicom-
ponent reactions, we report a facile stereoselective synthe-
sis of β‐amino carbonyl compounds and benzylamino
coumarin derivatives by using Fe3O4@ZrO2/SO42‐ as cata-
lyst. This heterogeneous nanocatalyst was employed for
Mannich reaction and can be easily recovered by an exter-
nal magnet and used several times with no significant loss
of activity. These procedures in Mannich reaction resulted
in the short reaction time, low cost, easy work‐up, mild
reaction condition and high yields.
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