Magnetic Fe3O4 nanoparticles supported amine: a new, sustainable and environmentally benign catalyst for condensation reactions

Article abstract of DOI:10.1007/s11164-017-2914-7

Abstract: Diethylenetriamine immobilized on magnetic Fe₃O₄ nanoparticles (DETA-Fe₃O₄) was successfully prepared as a new and well dispersed magnetically separable amine catalyst. The structure of the resulting catalyst was well characterized by a series of analysis techniques such as FT-IR, SEM, EDX, VSM, TGA and XRD. The catalytic activity of DETA-Fe₃O₄ was evaluated with Knoevenagel condensation of active methylene compounds with aromatic aldehydes. Interestingly, the cyclocondensation of anthranilamide and aldehydes were effectively catalyzed by DETA-Fe₃O₄ in water, and the desired products (2,3-dihydroquinazoline-4(1H)-ones) were afforded in admirable yields. Catalysis research under aqueous medium (water) also makes this synthetic protocol ideal and fascinating from the environmental point of view. The amine catalyst can be magnetically recovered after the reaction and can be reused many times without appreciable decrease in activity.

Full text of DOI:10.1007/s11164-017-2914-7

Res Chem Intermed
DOI 10.1007/s11164-017-2914-7
Magnetic Fe O nanoparticles supported amine: a new,
3
4
sustainable and environmentally benign catalyst
for condensation reactions
1
1
Lotfi Shiri
•
Mosstafa Kazemi
Received: 27 November 2016 / Accepted: 16 February 2017
Ó Springer Science+Business Media Dordrecht 2017
Abstract Diethylenetriamine immobilized on magnetic Fe O nanoparticles (DETA-
3
4
Fe O ) was successfully prepared as a new and well dispersed magnetically separable
3 4
amine catalyst. The structure of the resulting catalyst was well characterized by a series
of analysis techniques such as FT-IR, SEM, EDX, VSM, TGA and XRD. The catalytic
activity of DETA-Fe O4 was evaluated with Knoevenagel condensation of active
3
methylene compounds with aromatic aldehydes. Interestingly, the cyclocondensation of
anthranilamide and aldehydes were effectively catalyzed by DETA-Fe O in water, and
3
4
the desired products (2,3-dihydroquinazoline-4(1H)-ones) were afforded in admirable
yields. Catalysis research under aqueous medium (water) also makes this synthetic
protocol ideal and fascinating from the environmental point of view. The amine catalyst
can be magnetically recovered after the reaction and can be reused many times without
appreciable decrease in activity.
&
Lotfi Shiri
Lshiri47@gmail.com
Mosstafa Kazemi
Mosstafakazemi@gmail.com
1
Department of Chemistry, Faculty of Basic Sciences, Ilam University,
P.O. Box 69315-516, Ilam, Iran
123

L. Shiri, M. Kazemi
Graphical Abstract
Keywords Magnetically separable catalyst Á DETA-Fe O Á Knoevenagel
3
4
condensation Á 2,3-dihydroquinazoline-4(1H)-ones Á Water Á Environmental
Introduction
The easy separation and reusability of catalysts is a key factor in the selection of
catalytic processes [1]. Catalysis chemical reactions by an acid or a base
immobilized on magnetic nanocatalysts (MNPs) have become a hot research topic
in modern catalysis research [2]. Among the various magnetic NPs employed as the
core magnetic support, Fe O NPs have received special attention due to their
3
4
simple preparation, low toxicity, abundance and unique activities, which allow the
use of mild reaction conditions in chemical transformations to achieve the
corresponding final products [3–6]. In addition, catalysis research under aqueous
media is an appropriate direction for the future of organic synthesis, in particular
from the point of view of green synthetic chemistry [7].
Knoevenagel condensation of aldehydes with active methylene compounds is a
well-known and extensively studied strategy for carbon–carbon bond formation in
organic synthesis [8], because Knoevenagel products (namely the a, b -unsaturated
1
23

3 4
Magnetic Fe O nanoparticles supported amine…
products or synthesized alkene) play a vital role in the synthesis of fine chemicals
9], therapeutic drugs [10], natural products [11], functional polymers [12],
[
cosmetics [13], perfumes [14], hetero Diels–Alder reactions [15] and in the
synthesis of carbocyclic as well as heterocyclic compounds of biological
significance [16]. In general, this type of condensation is catalyzed by organic
bases and their salts, such as ethylene diamine, dimethyl amino pyridine and
guanidine in an organic solvent or a liquid-phase system [17]. In these cases, the
recovery of the catalyst is very difficult and their utilization isn’t ideal from the
economical point of view. For this reason, synthetic chemists’ thoughts have shifted
toward applying heterogeneous reagents and catalysts for this condensation.
Recently, for the Knoevenagel condensation, a series of heterogeneous reagents and
catalysts such as Lewis acids [18, 19], sulfate-ion promoted Zirconia [20],
surfactants [21], ionic liquids [22, 23], Si-MCM-41 supported basic materials [24],
amine functionalized polyacrylonitrile fiber [25], Ni supported on SiO [26] and Tin
2
oxide (SnO ) nanoparticles [27] have been reported in the literature. However, most
2
of these suffer from notable drawbacks, such as unsatisfactory yields, formation of
undesirable di-substituted product, long reaction times, high temperatures, difficult
recovery of catalyst, and use of hazardous and carcinogenic solvents as reaction
media. Therefore, the development of new and efficient green synthetic strategies
(
using reusable heterogeneous catalysts under aqueous media) for the performance
of Knoevenagel condensation is an important challenge in organic synthesis.
In this respect, in this paper, we report the simple synthesis of diethylenetriamine
immobilized on Fe O nanoparticles (DETA-Fe O ) as a highly active and reusable
3
4
3 4
amine catalyst for the Knoevenagel condensation of active methylene compounds
with aromatic aldehydes.
Experimental
Materials
Chemicals were purchased from Fisher and Merck. The reagents and solvents used
in this work were obtained from Sigma-Aldrich, Fluka or Merck and used without
further purification. Nanostructures were characterized using a Holland Philips X,
pert X-ray powder diffraction (XRD) diffractometer (Co Ka, radia-
-
1
tion = 0.154056 nm), at a scanning speed of 2° min from 10° to 100°. The
particle size and morphology were investigated by means of a JEOL JEM-2010
scanning electron microscope (SEM) using an accelerating voltage of 200 kV. The
infrared spectra (IR) of samples were recorded in KBr disks using a NICOLET
impact 410 spectrometer. The thermogravimetric analysis (TGA) curves were
recorded using a PL-STA 1500 device manufactured by Thermal Sciences.
Supermagnetic properties of the catalyst were measured on a vibrating sample
magnetometer (VSM) MDKFD.
123

L. Shiri, M. Kazemi
Preparation of the magnetic Fe O -nanoparticles
3
4
To prepare the mixture, FeCl Á6H O (5.838 g, 0.0216 mol) and FeCl Á4H O
3
2
2
2
(2.147 g, 0.0108 mol) were dissolved in 100 mL of deionized water in a three-
necked flask (250 mL) under N atmosphere. After that, under rapid mechanical
2
stirring, 10 mL of NH was added into the solution within 30 min with vigorous
3
mechanical stirring. After being rapidly stirred for 30 min, the resultant black
dispersion was heated to 80 °C for 30 min. The black precipitate formed was
isolated by magnetic decantation, washed with double-distilled water until neutral,
and further washed twice with ethanol and dried at room temperature [28].
Preparation of CPTMS-Fe O
3
4
The obtained Fe O nanoparticles (1.5 g) were dispersed in 250 mL ethanol/water
3
4
(
volume ratio, 1:1) by sonication for 30 min, and then 3-chloropropyltrimethoxysi-
lane (CPTMS) (2.5 mL) was added to the mixture. The reaction mixture was stirred
using mechanical stirring under N2 atmosphere at 40 °C for 8 h. Then, the
nanoparticles were redispersed in ethanol by sonication five times and separated
through magnetic decantation. The nanoparticles product (CPTMS-Fe O ) was
3
4
dried at room temperature.
Preparation of DETA-Fe O
3
4
The CPTMS-Fe O (1.5 g) was dispersed in toluene (50 mL) by ultrasonic bath for
3
4
1
3
0 min. Diethylenetriamine (DETA) (2 mL) was added and stirred at 100 °C for
0 h under N atmosphere. Then, the prepared functionalized magnetic nanopar-
2
ticles were separated by magnetic decantation and washed three times with ethanol
to remove the unattached substrates. The resulting product was dried at room
temperature.
General procedure for DETA-Fe O -catalyzed Knoevenagel condensation
4
3
A mixture of aldehyde (1 mmol), activated methylene compounds (1.05 mmol) and
DETA-Fe O (10 mg) in water (2 mL) was stirred at 70 °C. Reaction progress was
3
4
monitored by TLC (acetone: n-hexane, 3:7). After the times specified in Tables 2
and 3, the reaction mass was allowed to cool down to room temperature. Ethyl
acetate (3 9 5 mL) was added to the reaction mixture and the catalyst was
separated by an external magnet. Ethyl acetate was evaporated under reduced
pressure to yield the crude products. The obtained crude products were further
recrystallized from ethanol to get the pure final products.
General procedure for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones
A mixture of anthranilamide (1.05 mmol, 142 mg), aldehyde or ketone (1 mmol)
and DETA-Fe O (20 mg) in water (2 mL) was stirred at 70 °C. Reaction progress
was monitored by TLC (acetone: n-hexane, 2:8). After the times specified in
3
4
1
23

3 4
Magnetic Fe O nanoparticles supported amine…
Table 5, the reaction mass was allowed to cool down to room temperature. CH Cl
2
2
(
external magnet. CH Cl was evaporated under reduced pressure to yield the crude
3 9 5 mL) was added to the reaction mixture and the catalyst was separated by an
2
2
products. The obtained crude products were further recrystallized from ethanol to
get the pure 2,3-dihydroquinazolin-4(1H)-ones (70–97%).
Spectroscopic data
All the products reported here are known compounds and the spectroscopic data
matched literature values. Data for the some of the compounds are given below.
2
-(4-Chlorobenzylidene)malononitrile (2a)
1
H NMR (400 MHz, DMSO-d6): d = 7.74 (d, J = 8.8 Hz, 2H), 7.97 (d,
H
1
3
J = 8.8 Hz, 2H), 8.73 (s, 1H). C-NMR (100 MHz, DMSO-d6): d = 82.7,
C
1
13.5 (CN), 114.5 (CN), 115.7 (2C), 130.5, 132.6 (2C), 139.5, 160.6.
2
-(4-Methoxybenzylidene)malononitrile (2b)
1
H NMR (400 MHz, DMSO-d6): d = 7.21 (d, J = 7.2 Hz, 2H), 7.99 (d,
H
1
3
J = 7.2 Hz, 2H), 8.41 (s, 1H). C-NMR (100 MHz, DMSO-d6): d = 56.4,
C
1
14.4 (CN), 115.3 (CN), 115.7 (2C), 124.6, 133.8 (2C), 160.9, 164.8.
2
-(4-Nitrobenzylidene)malononitrile (2e)
1
H NMR (400 MHz, DMSO-d6): d = 8.15 (d, J = 8.8 Hz, 2H), 8.44 (d,
H
1
3
J = 8.8 Hz, 2H), 8.57 (s, 1H). C-NMR (100 MHz, DMSO-d6): d = 86.3,
C
1
12.9 (CN), 114.1 (CN), 124.8 (2C), 131.9 (2C), 137.1, 150.1, 159.7.
2
-(4-Ethoxybenzylidene)malononitrile (2g)
1
H NMR (400 MHz, DMSO-d6): d = 1.37 (t, J = 7.2 Hz, 3H), 4.19 (q,
H
J = 7.2 Hz, 2H), 7.19 (d, J = 9.2 Hz, 2H), 7.98 (d, J = 9.2 Hz, 2H), 8.41 (s,
1
3
1
H). C-NMR (100 MHz, DMSO-d6): d = 14.8, 64.5, 77.1, 114.4 (CN), 115.3
C
(
CN), 116 (2C), 124.5, 133.9 (2C), 160.9, 164.2.
Ethyl (E)-2-cyano-3-(4-methylphenyl)-2-propenoate (4c)
1
H NMR (400 MHz, DMSO-d6): 1.26 (t, J = 7.2 Hz, 3H), 2.4 (S, 3H), 3.54 (q,
J = 7.2 Hz, 2H) 7.1 (d, J = 8 Hz, 2H), 7.45-7.47 (d, J = 8 Hz, 2H), 8.03 (s, 1H).
1
3
C-NMR (100 MHz, DMSO-d6): d = 15.24 (CH ), 55.31 (CH O), 65.39 (O–CH ),
3
3
2
1
02.33 (C–CN), 113.77 (CN), 121.36, 126.51, 132.22, 139.33, 152.57, 162.26
C = O).
(
123

L. Shiri, M. Kazemi
2
-(4-Chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (6a)
1
H NMR (400 MHz, DMSO-d6): d = 5.79 (s, 1H), 6.70 (t, J = 7.6 Hz, 1H, Ar–H),
H
6
.76 (d, J = 8 Hz, 1H, Ar–H), 7.16 (brs, 1H, N–H), 7.24–7.29 (td, J = 7.6, 1.6 Hz,
H, Ar–H), 7.46–7.49 (dt, J = 8.8, 2 Hz, 2H, Ar–H), 7.51–7.53 (dt, J = 8.4, 2 Hz,
1
2
1
H, Ar–H), 7.62 (dd, J = 7.6, 1.6 Hz, 1H, Ar–H), 8.35 (brs, 1H, N–H). C NMR
3
(
100 MHz, DMSO-d6): d = 66.3, 114.9, 115.4, 117.8, 127.9, 128.8, 129.2, 133.5,
C
1
33.9, 141.1, 148.1, 164.
2
-(4-Methylphenyl)-2,3-dihydroquinazolin-4(1H)-one (6c)
1
H NMR (400 MHz, DMSO-d6): d = 2.31 (s, 3H, CH ), 5.73 (s, 1H), 6.68 (t,
H
3
J = 7.6 Hz, 1H, Ar–H), 6.75 (d, J = 8.4 Hz, 1H, Ar–H), 7.07 (brs, 1H, N–H),
7
1
1
.20–7.27 (m, 3H, Ar–H), 7.39 (d, J = 8 Hz, 2H, Ar–H), 7.62 (dd, J = 7.6, 1.2 Hz,
1
3
H, Ar–H), 8.25 (brs, 1H, N–H). C NMR (100 MHz, DMSO-d6): d = 21.2, 66.9,
C
14.9, 115.5, 117.5, 127.3, 127.8, 129.3, 133.7, 138.2, 139.1, 148.4, 164.1.
2
-(4-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (6e)
1
H NMR (400 MHz, DMSO-d6): d = 5.94 (t, J = 2 Hz, 1H, CH), 6.71 (t,
H
J = 7.6 Hz, 1H, Ar–H), 6.79 (d, J = 7.6 Hz, 1H, Ar–H), 7.26-7.30 (td, J = 7.6,
1
7
8
1
.6 Hz, 1H, Ar–H), 7.35 (brs, 1H, N–H), 7.62–7.65 (dd, J = 8, 1.6 Hz, 1H, Ar–H),
.75–7.79 (dt, J = 8.8, 2 Hz, 2H, Ar–H), 8.26–8.30 (dt, J = 9.2, 2 Hz, 2H, Ar–H),
1
3
.55 (brs, 1H, N–H). C NMR (100 MHz, DMSO-d6): d = 66.8, 115, 115.4, 118,
C
24.1, 127.9, 128.5, 134.1, 147.7, 147.9, 149.8, 163.8.
2
-phenyl-2,3-dihydroquinazolin-4(1H)-one (6i)
1
H NMR (400 MHz, DMSO-d6): d = 5.77 (s, 1H), 6.69 (t, J = 8 Hz, 1H, Ar–H),
H
6
Ar–H), 7.34–7.43 (m, 3H, Ar–H), 7.51 (dd, J = 6.8, 1.2 Hz, 2H, Ar–H), 7.63 (dd,
.77 (d, J = 7.6 Hz, 1H, Ar–H), 7.13 (brs, 1H, N–H), 7.26 (td, J = 8, 1.6 Hz, 1H,
1
3
J = 7.6, 1.2 Hz, 1H, Ar–H), 8.31 (brs, 1H, N–H). C NMR (100 MHz, DMSO-d6):
dC = 67.1, 114.9, 115.4, 117.6, 127.4, 127.9, 128.8, 129, 133.8, 142.1, 148.4, 164.1.
2
-(3-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (6j)
1
H NMR (400 MHz, DMSO-d6): d = 5.98 (s, 1H), 6.72 (t, J = 8 Hz, 1H, Ar–H),
H
6
.82 (d, J = 8 Hz, 1H, Ar–H), 7.29 (td, J = 6.8, 1.6 Hz, 1H, Ar–H), 7.38 (brs, 1H,
N–H), 7.65 (dd, J = 8, 1.6 Hz, 1H, Ar–H), 7.71 (t, J = 8 Hz, 1H, Ar–H), 7.97 (d,
J = 7.6 Hz, 1H, Ar–H), 8.23 (dq, J = 8, 1.6 Hz, 1H, Ar–H), 8.39 (t, J = 2 Hz, 1H,
1
3
Ar–H), 8.57 ((brs, 1H, N–H). C NMR (100 MHz, DMSO-d6): d = 65.7, 115.1,
C
1
15.4, 118, 122.1, 123.8, 127.9, 130.5, 133.8, 134.1, 144.7, 147.8, 148.2, 163.9.
1
23

3 4
Magnetic Fe O nanoparticles supported amine…
Result and discussion
Preparation and characterization of DETA-Fe O4
3
Immobilized diethylenetriamine on Fe O4 nanoparticles (DETA-Fe O ) was
3
3 4
successfully synthesized by using the surface modification strategy as depicted in
Scheme 1. The Fe O nanoparticles were prepared by a chemical co-precipitation
3
4
method [28] and coated with 3-chloropropyltrimethoxysilane (CPTMS) by covalent
bonds [1]. The reaction of the supported CPTMS with diethylenetriamine (DETA)
in toluene under reflux conditions for 42 h produced the DETA functionalized
Fe O nanoparticles (DETA-Fe O ).
3
4
3 4
The prepared magnetic nanocatalyst was comprehensively characterized by FT-
IR, TGA, XRD, SEM, EDX and VSM analysis techniques.
To certify the successful immobilization of DETA on the surface of magnetic
Fe O nanoparticles, the FT-IR spectra (Fig. 1) for the Fe O MNPs (a), CPTMS-
Fe O (b) and DETA-Fe O (c) were investigated. As seen on Fig. 1, the bands at
3
4
3 4
3
4
3 4
-
1
5
72 cm and 625 are attributed to vibration of the Fe–O bonds, which confirm the
existence of the Fe O ingredients in three samples. As seen on Fig. 1, the Fe O
3 4
3
4
-
1
MNPs has a broad peak at nearly 3420 cm , which is the characteristic of both
symmetrical and unsymmetrical modes of O–H bonds linked to the surface iron
-
1
atoms. Also, the existence of a stretch peak at 1624 cm is attributed to an
adsorbed water layer. In the curve of CPTMS-Fe O , bond formation between
Fe O and CPTMS is confirmed by an Fe–O–Si absorption band whose peak
3
4
3
4
-
1
appears at 996 cm . Also, in the spectra of CPTMS-Fe O , there is a weak peak at
4
3
-
1
2926 cm , which is attributed to the C–H stretching vibration of an alky chain of
chlorine. In the curve of DETA-Fe O , three obvious peaks at 1041, 1119 and
3
4
-
204 cm prove the existence of C–N bonds and their vibration. Also the broad
1
1
Scheme 1 General route for the synthesis of immobilized diethylenetriamine on Fe
DETA-Fe
3 4
O nanoparticles
(
3 4
O )
123

L. Shiri, M. Kazemi
3 4 3 4 3 4
Fig. 1 FT-IR spectra of Fe O MNPs (a), CPTMS-Fe O (b) and DETA-Fe O (c)
-
peak at nearly 3200–3400 cm in the curve of DETA-Fe O is attributed to N–H
1
3
4
groups. Accordingly, good grafting of diethylenetriamine on the surface of Fe O4
3
nanoparticles is verified.
The morphology of the catalyst nanostructures was studied by scanning electron
microscope (SEM). The surface morphology of the DETA-Fe O catalyst is shown
3
4
in Fig. 2. The SEM images put their stamp of approval on the idea that the catalyst
was made up of uniform nanometer-sized particles with an average size of
1
7–21 nm.
The components of DETA-Fe O were analyzed by using energy-dispersive
3
4
X-ray spectroscopy (EDX) (Fig. 3). As shown in Fig. 3, characteristic peaks of Fe,
O, C, N and Si demonstrate clearly that the EDTA successfully immobilized on
MNPs nanoparticles. As the result of this analysis, the DETA-Fe O catalyst has
3
4
been successfully synthesized.
The magnetic property of the catalyst was investigated by vibrating sample
magnetometer (VSM) at ambient temperature. The curves of magnetization for the
Fe O nanoparticles (red line) and DETA-Fe O (green line) are depicted in Fig. 4.
3
4
3 4
1
23

3 4
Magnetic Fe O nanoparticles supported amine…
3 4
Fig. 2 SEM images of the DETA-Fe O
As seen in Fig. 4, the field-dependent magnetization curves at ambient temperature
exhibit that the Fe O nanoparticles and DETA-Fe O are both super-paramagnetic
3
4
3 4
with saturation magnetizations of 55 and 50 emu/g, respectively. The decrease of
the saturation magnetization can be related to the presence of amine groups on the
surface of the Fe O nanoparticles supports.
3
4
Thermogravimetric analysis (TGA) is an efficient spectra technique to study both
the thermal stability of the catalyst and the bond formation between MNPs and the
catalyst. The overlaid thermal curves of Fe O MNPs (red line), CPTMS-Fe O
3 4
3
4
(
green line) and DETA-Fe O (blue line) are shown in Fig. 5. As seen in Fig. 5, in
3 4
all TGA curves a minute amount of weight loss at temperatures below 200 °C is
observed. This can be attributed to the removal of physically adsorbed solvent and
123

L. Shiri, M. Kazemi
3 4
Fig. 3 EDX spectrum of the DETA-Fe O
80
60
40
20
0
5
5.00697
50.45823
-
10000
-5000
0
5000
10000
-
-
-
-
20
40
60
80
Applied field (Oe)
3 4
MNPs (red line) and DETA-Fe O (green line) at room
Fig. 4 Magnetization curves for Fe
temperature. (Color figure online)
3
O
4
surface hydroxyl groups. Organic groups have been reported to desorb at
temperatures above 260 °C. In the curve of CPTMS-Fe O (green line), a weight
3
4
loss about 5% is observed for CPTMS-Fe O in the temperature range between 230
3
4
1
23

3 4
Magnetic Fe O nanoparticles supported amine…
1
10
05
00
1
1
9
8.92970195
9
5.01883918 5%
0.98203876
95
90
85
80
9
9%
2
5
125
225
325
425
525
625
725
o
Temperature ( C)
Fig. 5 TGA curves of Fe
Color figure online)
3
O
4
NPs (red line), CPTMS-Fe
3
O
4
3 4
(green line) and DETA-Fe O (blue line).
(
5
4
4
3
3
2
2
1
1
00
50
00
50
00
50
00
50
00
(
311)
(220)
(440)
(400)
(
511)
(
422)
50
0
1
9
29
39
49
59
69
79
2θ / degree
3 4
Fig. 6 The XRD pattern of the DETA-Fe O
and 450 °C, which is attributed to the thermal decomposition of the 3-chloropropyl
silane groups. Also, a mass percentage loss of about 9% is observed for DETA-
Fe O (blue line) at 320–480 °C, which is presumably attributed to decomposition
3
4
of the catalyst or the breakdown of the DETA moieties.
The structure of prepared DETA-Fe O4 was analyzed by X-ray diffraction
3
(
XRD) spectroscopy. The XRD pattern of Fe O -DETA is displayed in Fig. 6. The
3 4
123

L. Shiri, M. Kazemi
XRD pattern of DETA-Fe O exhibit several characteristic peaks at 2h = 34.7°,
3
4
4
1.3°, 50.7°, 63.4°, 67.5° and 74.7°, which are assigned to the (220), (311), (400),
422), (511) and (440) lattice planes of magnetite.These agree well with the standard
(
Fe O XRD spectrum reported in literature [6]. This analysis clearly affirmed the
3
4
idea that the surface modification and conjugation of the Fe O nanoparticles did
3
4
not lead to phase change.
Catalytic studies
Knoevenagel condensation
To establish the feasibility of the strategy, the reaction condition was optimized with
respect to the quantity of catalyst and solvent, as well as the temperature, by
studying the condensation of malononitrile and 4-chlorobenzaldehyde as a model
reaction (Table 1). First, to study the effect of catalyst loading, the model reaction
was studied by varying the amount of DETA-Fe O in water at 70 °C (Table 1,
3
4
Entries 1–5). As shown in Table 1, a sharp increase in the yield from 80 to 98% and
Table 1 Optimization of the reaction conditions
a
Entry
Amount of catalyst (mg)
Solvent (Temp.°C)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
3
H
H
H
H
H
2
2
2
2
2
O (70 °C)
O (70 °C)
O (70 °C)
O (70 °C)
O (70 °C)
50
35
80
5
86
10
15
20
15
15
15
15
15
15
–
20
98*
98
20
20
97
CH
3
CN (reflux)
85
92
EtOH (reflux)
THF (reflux)
PhMe (reflux)
70
94
120
150
20
75
65
10
11
12
13
H
H
H
2
2
2
O (reflux)
O (60 °C)
O (70 °C)
98
35
90
120
120
Trace
N.R
–
Solvent-free (70 °C)
Reaction conditions: malononitrile (1.05 mmol) and 4-chlorobenzaldehyde (1 mmol) in the presence of
catalyst and solvent (2 mL)
Bold represents the optimal conditions
a
Isolated yield
1
23

3 4
Magnetic Fe O nanoparticles supported amine…
a significant decrease in time of reaction from 50 to 20 min were observed when the
amount of DETA-Fe O increased from 3 to 10 mg (Table 1, Entries 1–3). Further
3
4
increase in catalyst concentration (from 10 to 20 mg) did not show any significant
effect on reaction time and product yield (Table 1, Entries 4–5). Therefore, 10 mg
of DETA-Fe O was selected for all subsequent condensations (Table 1, Entry 3).
3
4
Next, to choose the best solvent for Knoevenagel condensation, the effects of
several classical solvents at reflux temperature on the model reaction catalyzed by
DETA-Fe O (10 mg) were studied (Table 2, Entries 6–10). The results of Table 2
3
4
demonstrate clearly that solvents have a strong effect on the time of reaction and the
product yield. The results could be interpreted with the much better solubility of the
catalyst and the reagents in the polar solvents. The results obtained by ethanol and
acetonitrile were satisfactory, but, considering reaction time, product yield, reaction
temperature and environmental effects, water was selected as the best solvent for the
Knoevenagel condensation. The effect of reaction temperature on the model
reaction, under obtained optimal reaction conditions (10 mg DETA-Fe O in
3
4
water), was also studied. However, when the reaction was carried out at 70 °C, the
Table 2 DETA-Fe
in H
O at 70 °C
3
O
4
catalyzed the one-pot Knoevenagel condensation of malononitrile with aldehydes
2
a
Entry
Substrate
Product
Time (min)
Yield (%)
Mp (°C) [Ref.]
1
2
3
4
5
6
7
8
9
4-ClC
4-OMeC
4-MeC
4-FC
4-NO
4-BrC
4-OEtC
4-(Me )NC
CHO
3-NO
3-OMeC
3-OHC
2-NO
2-OHC
2-ClC
CH=CH
6
H
5
CHO
2a
2b
2c
2d
2e
2f
20
30
25
10
15
25
40
35
15
35
30
40
45
35
25
30
98
94
93
96
95
99
98
95
95
93
93
94
92
91
94
93
160–162 [29]
111–112 [29]
128–130 [5]
122–123 [5]
159–161 [29]
157–158 [30]
170–172 [30]
176–178 [29]
80–81 [27]
6
H
5
CHO
CHO
CHO
CHO
CHO
CHO
CHO
6 5
H
6 5
H
2 6 5
C H
6 5
H
6
H
5
2g
2h
2i
2
6 5
H
6 5
C H
10
11
12
13
14
15
16
a
2
C
6
H
5
CHO
CHO
CHO
CHO
CHO
CHO
2j
103–105 [30]
108–110 [31]
158–159 [32]
140–142 [32]
157–159 [32]
95–97 [33]
6
H
5
2k
2l
6 5
H
2
C
6
H
5
2m
2n
2o
2p
6 5
H
6 5
H
C
6
H
5
126–128 [32]
Isolated yield
123

L. Shiri, M. Kazemi
progress of the reaction was higher in comparison with 60 °C and reflux
temperature. To understand the role of DETA-Fe O in this process, the same
3
4
condensation was carried out without catalyst (Table 1, Entry 12), and only a trace
amount of the product was observed after 120 min. Finally, no reaction was
observed when the reaction was performed under catalyst-free and solvent-free
conditions at 70 °C for 120 min (Table 1, Entry 13). Therefore, 10 mg DETA-
Fe O in water at 70 °C were considered to be the optimal reaction conditions
3
4
(
Table 1, Entry 3).
Next, the Knoevenagel condensations of two types of active methylene
compounds with a diverse range of aldehydes were investigated under the
optimized reaction conditions (Scheme 2). tThe results of this study are listed in
Tables 2 and 3. As can be seen from the results in Tables 2 and 3, aromatic
aldehydes containing both electron withdrawing and electron donating groups
reacted smoothly with malononitrile and ethyl cynoacetate to produce excellent
product yields (90–98%). These results demonstrated well that malononitrile
(
Table 2) was more reactive than ethyl cyanoacetate (Table 3), because the
reactions are carried out faster and the products achieved higher yields when
malononitrile is used as an active methylene compound.
2
,3-dihydroquinazoline-4(1H)-ones
2
,3-dihydroquinazoline-4(1H)-one derivatives are very fascinating research targets
for medicinal synthesis, as they constitute an important scaffold of a wide category
of biologically and pharmacologically nitrogen-containing heterocyclic molecules
[
37, 38]. Recent studies clearly show that the 2,3-dihydroquinazoline-4(1H)-ones
and their analogues have many notable biological and medicinal activities such as
antitumor, anticancer, antibiotic, antibacterial, antidefibrillatory, antipyretic, and
anticonvulsant [39–42]. In general, the condensation of aryl, alkyl and hetroaryl
aldehydes or ketones with anthranilamide in the presence of acids as catalysts is the
most straightforward synthetic strategy for the synthesis of 2,3-dihydroquinazoline-
4(1H)-ones [41]. In recent times, for the synthesis of 2,3-dihydroquinazoline-4(1H)-
ones frameworks, a variety of catalysts such as copper [6], sulfamic acid
Scheme 2 Knoevenagel condensation (KC) of active methylene compounds with aromatic aldehydes
catalyzed by DETA-Fe O
3 4
1
23

3 4
Magnetic Fe O nanoparticles supported amine…
Table 3 DETA-Fe
aldehydes in H
3 4
O catalyzed the one-pot Knoevenagel condensation of ethyl cynoacetate with
2
O at 70 °C
a
o
Mp ( C) [Ref.]
Entry
Substrate
Product
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
4-ClC
4-OMeC
4-MeC
4-FC
6
H
5
CHO
CHO
CHO
CHO
CHO
CHO
CHO
)NC CHO
CHO
4a
4b
4c
4d
4e
4f
45
70
60
30
35
65
70
75
40
50
55
95
55
95
91
90
92
93
96
93
94
93
88
89
87
90
92–94 [30]
6
H
5
80–82 [34]
6
H
5
91–92 [30]
6
H
5
89–91 [35]
4-NO
2
C
6
H
5
169–171 [30]
88–90 [30]
6 5
4-BrC H
6
4-OHC H
5
4g
4h
4i
171–172 [30]
122–123 [30]
49–51 [27]
4-(Me
2
6 5
H
6 5
C H
10
11
12
13
a
3-NO
2
2
C
C
6
H
H
5
CHO
CHO
4j
129–131 [30]
101–103 [36]
132–134 [34]
116–117 [34]
2-NO
6
5
4k
4l
6 5
2-OHC H CHO
C
6
H
5
CH=CH
4m
Isolated yield
[
28, 38, 41, 42], b-cyclodextrin-SO H [43], Ga(OTf) [44], iodine [45, 46] and silica
3
3
sulfuric acid [47] have been reported in the literature. Despite satisfactory results
obtain in most of the reported methodologies; catalysis research (search for
designing recoverable catalysts under green mediums) for the synthesis of 2,3-
dihydroquinazoline-4(1H)-one scaffolds is still an important challenge in organic
synthetic chemistry.
Considering the valuable activities of 2,3-dihydroquinazoline-4(1H)-one deriva-
tives in various fields, especially medicinal chemistry, we decided to study the
catalytic activity of DETA-Fe O in the synthesis of these compounds. To establish
3
4
the feasibility of the strategy and evaluate the effects of various parameters on the
system, the reaction conditions were optimized with respect to the quantity of
catalyst and the solvent as well as the reaction temperature by studying the
cyclocondensation of 4-chlorobenzaldehyde and anthranilamide as a model
reaction. The collected results are listed in Table 4. As the result of these
experiments, 20 mg of DETA-Fe O in water (2 mL) at 70 °C were selected as the
3
4
optimal reaction conditions for the synthesis of 2,3-dihydroquinazoline-4(1H)-ones.
To determine the scope and limitations of this catalytic system, the cyclocon-
densation of anthranilamide with a diverse range of aldehydes or ketones was then
studied under the optimized reaction conditions (Scheme 3). The results obtained in
123

L. Shiri, M. Kazemi
Table 4 Optimization of the reaction conditions
°
a
Entry
The amount of catalyst (mg)
Solvent (Temp. C)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
5
H
H
H
H
H
2
2
2
2
2
O (70 °C)
O (70 °C)
O (70 °C)
O (70 °C)
O (70 °C)
215
165
120
100
100
170
135
230
295
100
120
120
120
91
93
95
10
15
20
25
15
15
15
15
15
15
–
*
96
96
CH CN (reflux)
3
93
EtOH (reflux)
THF (reflux)
PhMe (reflux)
95
87
81
10
11
12
13
H
2
H
2
H
2
O (reflux)
O (60 °C)
O (70 °C)
96
92
Trace
N.R
–
Solvent-free (70 °C)
Reaction conditions: anthranilamide (1.05 mmol) and 4-chlorobenzaldehyde (1 mmol) in the presence of
catalyst and solvent (2 mL)
Bold represents the optimal conditions
a
Isolated yield
3 4
Scheme 3 Cyclocondensation of anthranilamide with aldehydes/ketones catalyzed by DETA-Fe O
the current protocol are summarized in Table 5. In general, the condensation
reactions proceeded smoothly in all cases to give the desired products in good to
excellent yields. The achieved results in Table 5 demonstrated well that the reaction
time and product yields of the cyclocondensation reactions depend on the
substituents’ relative positions on the aldehyde ring, because 4-substituted-2,3-
dihydroquinazo-lin-4(1H)-ones (Table 5, Entries 1–8) were obtained in shorter
1
23

3 4
Magnetic Fe O nanoparticles supported amine…
3 4 2
Table 5 DETA-Fe O catalyzed the one-pot synthesis of 2,3-dihydroquinazolin-4(1H)-ones in H O at
70 °C
0
a
°
Entry
R
R
Product
Time (min)
Yield (%)
Mp ( C) [Ref.]
1
2
3
4
5
6
7
8
9
4-ClC
6
H
5
CHO
CHO
CHO
CHO
CHO
CHO
CHO
)NC CHO
CHO
3-NO
3-BrC
3-OMeC
2-NO
2-ClC
3,4-(OMe)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
–
6a
6b
6c
6d
6e
6f
100
105
100
90
96
93
92
94
92
97
90
95
90
85
88
87
81
82
86
76
70
199–201 [38]
184–185 [41]
223–224 [41]
197–199 [41]
200–202 [48]
201–203 [41]
169–170 [38]
208–209 [48]
218–220 [41]
193–194 [49]
185–187 [49]
146–147 [50]
190–191 [41]
204–206 [48]
210–212 [41]
220–221 [41]
222–224 [49]
4-OMeC
4-MeC
4-FC
4-NO
4-BrC
4-EtOC
4-(Me
6 5
H
6 5
H
6 5
H
2
C
6
H
5
185
135
105
105
125
270
195
135
345
185
145
405
655
6 5
H
6
H
5
6g
6h
6i
2
6 5
H
6 5
C H
10
11
12
13
14
15
16
17
a
2
C
6
H
5
CHO
CHO
CHO
CHO
CHO
6j
6
H
5
6k
6l
6 5
H
2
C
6
H
5
6m
6n
6o
6p
6q
6 5
H
2 6 5
C H CHO
Cyclohexanone
Ph
Me
Isolated yield
reaction times and higher yields, in comparison with 3 or 2-substituted-2,3-
dihydroquinazo-lin-4(1H)-ones (Table 5, Entries 10–14). Ketones such as cyclo-
hexanone and acetophenone also afforded the desired product with satisfactory
yields, however longer reaction times were required (Table 5, Entries 16–17).
To show the high potential of presented synthetic protocol in compression with
methodologies that previously reported in literature, we compared the achieved
results for the synthesis of products 2a and 6a (as typical examples) with those of
other methodologies (Table 6). As shown in Table 6, this synthetic protocol is
superior to some of the previously reported procedures in terms of product yield,
reaction time and reaction conditions.
Reusability of the amine catalyst
Recovery and reusability of the catalyst is a valuable advantage in catalysis
research, in which makes recoverable catalysts very desirable from the commercial
and economical points of view. In this respect, the reusability of DETA-Fe O in the
3
4
synthesis of products 2a and 6a was studied under optimized reaction conditions.
After completion of the reaction, the catalyst was readily separated from the
reaction mixture by an external magnet field, washed several times with ethyl
acetate and dried to remove residual product. Then, the recovered catalyst was
reused for a subsequent fresh batch of the reaction. The catalytic activity was
studied at least seven successive times and it showed similar results (Fig. 7).
123

L. Shiri, M. Kazemi
Table 6 Comparison of the activity of various catalysts in the synthesis of products 2a and 6a
Entry Catalyst
Condition
Time (min) Yield (%) [Ref.]
1
2
3
4
5
6
7
8
9
1
1
1
PVC-TEPA
EtOH, reflux
60
120
60
90
88
100
94
87
98
80
97
81
87
85
96
[51]
-
4
2
SO
/ZrO
2
Solvent-free, reflux
Toluene, r.t
[52]
Mn salen complex
Lipase
[31]
DMSO, 35 °C
Solvent-free, 80 °C 180
720
[53]
Triphenylphosphane (TPP)
[34]
DETA-Fe
KAl(SO
3
O
4
H
2
O, 70 °C
20
300
360
180
150
120
100
This work
[54]
4
)
2
.E12
H
2
O
EtOH, reflux
Glycerosulfonic acid
Silica sulfuric acid
SBNPSA
Glycerol, 80 °C
[55]
H
2
O,80 °C
EtOH, reflux
[56]
0
1
2
[41]
b
Dodecylbenzenesulfonic acid EtOH, US , 40 °C
[42]
3
DETA-Fe O
4
H
2
O, 70 °C
This work
1
9
9
8
8
7
7
6
6
00
5
0
5
2
6
a
a
0
5
0
5
0
7
6
5
4
3
2
1
Run
Fig. 7 Reusability of DETA-Fe
3
O
4
in the synthesis of products 2a and 6a
Furthermore, one of the fascinating advantages of this new catalytic system is the
simple, rapid and efficient separation of the catalyst by using a suitable external
magnet, which minimizes the loss of catalyst during separation.
The SEM image of the recovered catalyst is shown in Fig. 8. Comparing Fig. 8
with Fig. 2, it can be concluded that there aren’t any significance differences in the
morphologies of freshly prepared catalyst and the recovered catalyst after operation
for seven consecutive reaction cycles.
Conclusion
In summary, the obtained results of this study demonstrated that diethylenetriamine
heterogenized on Fe O nanoparticles (DETA-Fe O ) is a novel, versatile and
highly efficient reusable heterogeneous catalyst for the Knoevenagel condensation
3
4
3 4
1
23

3 4
Magnetic Fe O nanoparticles supported amine…
3 4
Fig. 8 SEM image of the recovered catalyst (DETA-Fe O ) after seven cycles
and synthesis of 2,3-dihydroquinazoline-4(1H)-ones. Catalysis research under water
also makes this synthetic protocol ideal and fascinating from the environmental
point of view. This is the first report on the use of amine functionalized Fe O
3
4
nanoparticles as a magnetically separable amine catalyst for the synthesis of 2,3-
dihydroquinazoline-4(1H)-ones. Good to excellent yields, water as the reaction
medium, simplicity of operation, high catalytic activity, easy magnetic separation
and reusability of the solid catalyst are notable advantages of this protocol. As a
result of this study, this protocol can act as an efficient strategy for the synthesis of
biologically and pharmaceutically active molecules.
Acknowledgements This work was supported by the research facilities of Ilam University, Ilam, Iran.
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