Heterogeneous Cu(II)/l-His@Fe3O4 nanocatalyst: A novel, efficient and magnetically-recoverable catalyst for organic transformations in green solvents

Article abstract of DOI:10.1039/c6ra19776k

A novel, efficient and green Cu(ii)/l-His@Fe₃O₄ catalyst has been applied successfully in the synthesis of heterocyclic compounds. The resulting catalyst was used in the synthesis of 2,3-dihydroquinazolin-4(1H)-ones, polyhydroquinolines and 2-amino-6-(arylthio)pyridine-3,5-dicarbonitriles as biologically interesting compounds. The present research is focused on investigation of recycling, reusability and stability of the catalyst in phase reactions. The Cu(ii)/l-His@Fe₃O₄ catalyst was used at least six times with comparable activities to that of fresh catalyst. The chemical composition and the structure of the catalyst were analysed by TGA/DTG, EDS, XRD, VSM, FT-IR and SEM.

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gReceived 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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Heterogeneous Cu(II)/L-His@Fe3O4 nanocatalyst: a novel, efficient and magnetically-
recoverable catalysts for organic transformations in green solvents
Masoomeh Norouzi , Arash Ghorbani-Choghamarani ,* Mohsen Nikoorazm
A novel, efficient and green Cu(II)/L-His@Fe3O4 catalyst has been applied successfully in the synthesis of heterocyclic compounds. The resulted catalyst were
used in the synthesis of 2,3-dihydroquinazolin-4(1H)-ones, polyhydroquinolines and 2-amino-6-(arylthio) pyridine-3,5-dicarbonitriles as biologically
interesting compounds. The present research is focused on investigation of recycling, reusability and stability of the catalyst in the phase reaction. The Cu
(II)/L-His@Fe3O4 catalyst was used at least six times with comparable activities to that of fresh catalyst. The chemical composition and the structure of the
catalyst were analysed by TGA/DTG, EDS, XRD, VSM, FT-IR and SEM.
Introduction
Scheme 1. A potential tridentate ligand, L-histidine.
Copper is an essential metal element for all living organisms [6-7].
Since the discovery of Copper (II)–L-Histidine species in human
blood (Sarkar et al., 1966), extensive research has been carried out
to determine its role in copper uptake into cells [8-11].
The solid state monocrystal X-ray structural analysis of this complex
shows four coordinate square-planar arrangement around copper
ion with nitrogen and oxygen atoms in trans coordination (Scheme
2) [12].
Metal−organic interfaces with biologically active molecules are
important issues in biocatalysts, biocompatibility, and biosensors.
Histidine and its peptides are interesting for possible applications,
and one example is the electrochemical detection of metal ions [1].
It is well-known that histidine (2-amino-3-(4-imidazolyl) - propanoic
acid, His) is an essential amino acid for human growth and repair of
tissues and acts as a neurotransmitter in the central nervous of
mammals [2-3]. The imidazole side chain of histidine can serve as a
coordinating ligand in the metal ions transmission in biological
bases [4] and was detected in the active sites of certain enzymes
(Scheme 1) [5].
A. Ghorbani-Choghamarani, Department of Chemistry, Faculty of Science,
Ilam University, P.O. Box 69315516, Ilam, Iran; Tel/Fax: +98 841 2227022; E-
mail address: arashghch58@yahoo.com or a.ghorbani@mail.ilam.ac.ir
Scheme 2. The structure of the Cu(L-His)2 complex.
Immobilization of Copper (II)–L-Histidine onto solid surface is the
key step for creating a recoverable and reusable catalyst or reagent
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In this context, magnetic nanoparticles (MNPs) materials have been
efficiently used as environmentally friendly solid supports for
immobilizing homogeneous catalysts
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DOI: 10.1039/C6RA19776K
The main advantage of this catalytic system is high surface area and
low toxicity, potential towards applications in various fields such as
uses in disciplines including physics, biomedicine, biotechnology,
material science and catalyst support. In addition the magnetic
nanoparticles can be efficiently isolated from the reaction medium
by magnetic separation [13-15].
2,3-Dihydroquinazolin-4(1H)-ones and polyhydroquinolines are an
important group of nitrogen containing heterocyclic that have
attracted much attention because of their diverse therapeutic and
pharmacological properties, such as vasodilator, hepatoprotective,
antiatherosclerotic, antidefibrillatory, antipyretic, analgesic [16-23].
The pyridine ring systems represent the major class of heterocycles
and their analogues show diverse biological and physiological
activities [24]. Among the pyridine derivatives, 2-amino-6-(arylthio)
pyridine-3, 5-dicarbonitrile is a privileged scaffold for developing
pharmaceutical agents because various compounds with this
structural motif display significant and diverse biological activities.
Compounds with 2-amino-3,5-dicarbonitrile-6-thio-pyridines ring
system exhibit diverse pharmacological activities and are useful as
anti-prion, anti-hepatitis B virus, anti-bacterial, and anticancer
agents and as potassium channel openers for treatment of urinary
incontinence [25-29].
Scheme 3. Synthesis of Cu(II)/L-His@Fe3O4.
Characterization of the Cu(II)/L-His@Fe3O4
The catalyst has been characterised using a number of different
complementary techniques.
FTIR spectra of Fe3O4 nanoparticles (a), functionalized Fe3O4 (b-e)
and recovered catalyst (f) are shown in Fig. 1. Typical peaks at 573 cm-
In this communication, we report preparation and characterization
of a novel, efficient and green Cu(II)/L-His@Fe3O4 catalyst for the
synthesis of 2,3-dihydroquinazolin-4(1H)-ones, polyhydroquinolines
and 2-amino-6-(arylthio) pyridine-3,5-dicarbonitrile through MCRs.
Furthermore, the catalyst can be easily separated with an external
magnet without using extra organic solvents or more filtration
steps. Thus, the technology is green and solves the problems
associated with mass transfer and recycling in multi-component
reactions.
1
and 3500-2800 cm−1 originated from stretching vibration of the
Fe–O and O-H (Fe3O4 nanoparticles Fig. 1. a). The C–H and N–H
vibration bands in the 2922–2852 cm-1 and 1650–1500 cm-1 region
were found in the FTIR spectra of Fig.1b, indicating the successful
attachment of APTES on the surface of Fe3O4 nanoparticles matrix.
The bands observed at 1710 cm−1 and 1642 cm−1 in Fig. 1c could be
attributed to the stretching frequency of C=O and C=C respectively
(amide 1 band).
The L-Histidine-Fe3O4 absorption bands at 3411 cm-1 corresponding
to the stretching vibration of O–H were recorded together with the
N–H absorption bands. The absorption bands in the range of 3030-
3130 cm-1 are due to asymmetric valence vibrations of the
Results and discussion
The process of Cu(II)/L-His@Fe3O4 synthesis is schematically described
in Scheme 3.
+)
ammonium (NH3 group. The symmetric absorption vibrations in
2080-2140 cm-1 or 2530-2760 cm-1, depend on amino acid chemical
structures. The peak of bending absorption of carboxylate (COO-)
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group appears at 1610-1641 cm-1. The bands appeared at 1144 and are assigned to decomposition of iron oxide phase VtierawnAsrtiitciloenOsnlitnoe
DOI: 10.1039/C6RA19776K
1622 cm−1 can be assigned to the vibration of C-N and C=N in thermodynamically more stable Fe2O3 phase (the DTA patterns are
imidazolium rings, respectively.
the signature of the recrystallization and phase transformation from
The infrared spectrum of the Cu(II)/L-His@Fe3O4 complex has Fe3O4 to γ-Fe2O3).
shown changes in the position and profiles of some bands as The TGA curve of Cu(II)/L-His@Fe3O4 showed the first weight loss
compared to those of the free L-Histidine@Fe3O4, suggesting below 100 °C due to desorption of physisorbed water. This was
participation of the groups that produce these bands in the followed by a gradual decrease in the weight after 250 °C. The
coordination with copper atoms. Major changes are related to the metal-organic structure grafting to the Fe3O4 surface were
carboxylate and amine bands. The infrared spectrum of the Cu(II)/L- decomposed in the temperature range of 250 to 450°C. The
His@Fe3O4 complex exhibits (Cu-O) and (Cu -N) stretching bands at exothermic peak at about 402°C indicated the beginning of
973 cm-1 and 448 cm-1, respectively. These results confirm the decomposition of the organic surfactant, the amount of loading
introduction of carboxylate and amino nitrogen groups of L- organic groups is estimated to be 26.87% (w/w).
100
90
80
70
60
50
Histidine to Cu (II) ions through coordination mode.
The infrared spectrum of recovered catalyst (Fig. 1f) indicates that
the catalyst can be recycled six times without any significant change
in its structure.
MNP
Cu(II)/L-His@MNP
0
200
400
600
800
1000
Temperature (°C)
80
60
40
20
0
MNP
Cu(II)/L-His@MNP
0
200
400
600
800
-20
-40
Temperature (°C)
Fig. 2. TGA/DTA curves of Fe3O4 and Cu(II)/L-His@Fe3O4.
Fig. 3 shows the magnetic curve for Fe3O4 nanoparticles and
Cu(II)/L-His@Fe3O4 catalyst. Ms value for Cu(II)/L-His@Fe3O4
nanoparticle was found to be 34.7 emug−1, which is lower than the
saturation magnetization of the Fe3O4 bulk materials (77 emug−1).
This decrease in Ms could mainly be attributed to the small particle
Fig. 1. FT-IR spectra of (a) Fe3O4 nanoparticles, (b) amino-
functionalized (c) MNP-acryloxyl, (d) L-His@Fe3O4, (e) Cu(II)/L-
His@Fe3O4 and (f) recovered catalyst
TGA/DTA analysis of the samples is presented in Fig. 2. We assign
the first weight loss to water leaving the sample. The latter losses
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surface effect that becomes more prominent as the particle size
decreases.
View Article Online
DOI: 10.1039/C6RA19776K
b
90
Fe3O4
70
50
30
Cu(II)/L-His@Fe3O4
10
-10
-30
-50
-70
-90
-10000
-5000
0
5000
10000
Applied Field (Oe)
c
Fig. 3. Magnetization curves for Fe3O4 and Cu(II)/L-His@Fe3O4
SEM images of Cu (II)/L-His@Fe3O4 at different magnification (a-b)
and EDS pattern of Cu (II)/L-His@Fe3O4(c) are shown in Fig. 4.
The Scanning electron microscopy (SEM) of Cu(II)/L-His@Fe3O4
materials shows that they consist of spherical particles and have a
relatively uniform diameter of 8-15 nm (Fig. 4a-b). The shape of the
support is retained after immobilization of the metal complexes.
The electron dispersive spectroscopy (EDS) spectra of the Cu(II)/L-
His@Fe3O4 was taken at random points on the surface.
The EDS results of the core–shell structure confirms the presence of
Si, C, O, N, Fe, and Cu elements, indicating the successful
attachment of the Copper(II)–L-Histidine on the surface Fe3O4 MNPs
(Fig. 4c).
Fig.4. SEM images of Cu(II)/L-His@Fe3O4 at different
magnification (a-b). EDS pattern of Cu(II)/L-His@Fe3O4 (c).
Powder XRD diffraction patterns (Fig. 5) obtained for the
Copper(II)–L-Histidine exhibited very broad peaks indicating the
ultrafine nature and small crystallite size of the particles. The
diffraction peaks located at 20.94°, 35.25°, 41.48°, 50.72°, 63.02°,
67.50°, and 74.72° have been keenly indexed as a cubic spinel
structure. The average particle size of the sample was found to be
14.28 nm which is derived from the FWHM of more intense peak
corresponding to 311 planes located at 41.48° using Scherrer’s
formula.
a
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400
300
200
100
0
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DOI: 10.1039/C6RA19776K
b
10
30
50
70
90
2 Theta (degree)
Fig. 5. XRD patterns of Cu(II)/L-His@Fe3O4 .
Fig.6. TEM images of (a) Cu (II)/L-His@Fe3O4 and (b) recovered
The Cu loading of the prepared catalyst, measured by coupled plasma (ICP-
AES) analysis, showed a value of about 0.96 mmol/g of catalyst.
ICP-AES analysis of catalysts recycled showed minor changes of Cu
contents (0.92 mmol/g). These phenomena indicate that the multi
component reactions indeed go through a heterogeneous catalytic
reaction process. In addition, the very low metal leached during the
reaction.
catalyst.
Catalytic studies
In continuation of our interest on environmentally benign chemical
processes for synthesis of biologically molecules [30–35], we
developed a new method for preparation of a stable, cheap and
efficient heterogeneous Cu(II)/L-His@Fe3O4 nanocatalyst which has
been used with excellent activity in multi component reactions
(Scheme 4 and 5).
The transmission electron microscopy (TEM) image of Cu (II)/L-
His@Fe3O4 and recovered catalyst are illustrated in Fig. 6a and b.
Particles are observed to have spherical morphology from Fig. 6a
and b. Average particle size is estimated at 5-15 nm which show a
close agreement with the values calculated by XRD analysis. TEM
image of recycled catalyst was showed that the morphology of
Cu(II)/L-His@Fe3O4 remained after recovery (Fig. 6b).
Scheme 4. Synthesis of 2,3-dihydroquinazolin-4(1H)-ones.
In the first part of our program, the catalytic activity of Cu(II)/L-
a
His@Fe3O4 was evaluated
in the synthesis of 2,3-
dihydroquinazolin-4(1H)-ones (DHQ) derivatives. In order to
optimize the reaction conditions, the reaction of 4-
chlorobenzaldehyde with 2-aminobenzamide was chosen as a
model reaction. As shown in Table 1, different amounts of catalyst
between 2-6 mg were used for this reaction, and 4 mg of Cu(II)/L-
His@Fe3O4 nanocatalyst was found to be optimal. For higher
amounts of the catalyst, the desired product was obtained in a
nearly quantitative yield (Table 1, entries 5).
In the second part of our investigation, we demonstrated that
Cu(II)/L-His@Fe3O4 can also be used in the synthesis of
polyhydroquinolines (PHQ) derivatives (Scheme 5).
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3
4
5
3
4
6
70
99
99
80
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DOI: 10.1039/C6RA19776K
98
98
Scheme 5. Synthesis of polyhydroquinolines.
a Reaction conditions for the synthesis DHQ: 4‐chlorobenzaldehyde (1
mmol), 2 aminobenzamide (1 mmol) and ethanol solvent (10 mL) at
reflux temperature.
bReaction conditions for the synthesis PHQ: 4‐chlorobenzaldehyde (1
mmol ), dimedone (1 mmol) , ethyl acetoacetate (1 mmol), ammonium
acetate (1.2 mmol).
During our initial studies, 4-chlorobenzaldehyde was selected as
substrates for the model reaction. Various conditions were
screened and the results are summarized in Table 1.
The reactions was carried out in the absence and presence of
Cu(II)/L-His@Fe3O4 catalyst. It was found that in the absence of the
catalyst the reaction was slightly sluggish and only trace amount of
product was obtained after 24 h. But when the reaction was
conducted in the presence of Cu(II)/L-His@Fe3O4 (4 mg), the
reaction was completed yielding (98%) in 120 min (entry 4).
Finally, the outset, the model reaction was carried out in the
presence of 4 mg catalyst in ethanol at 50 °C temperature.
Under the optimized reaction conditions, the generality of
substrates was checked next. Different aldehydes were used for the
synthesis of 2, 3-dihydroquinazolin-4(1H)-ones (Table 2) and
polyhydroquinolines derivatives (Table 3). As shown in Table 2 and
3 most of the aromatic and aliphatic aldehydes would give the
prouducts in good yields. A variety of functional groups of
aldehydes are known to tolerate this reaction condition, which
include alkoxyl, methyl, nitro, Cl, F, and OH groups. However, the
substituents on the phenyl ring of aromatic aldehydes had same
influence on the yields.
Table 1: Optimization of the amount of the Cu(II)/L-His@Fe3O4
Entry Catalyst (mg)
Yield of DHQa
Yield of PHQb
(%)
Tracec
(%)
32
1
2
-
2
55
62
Table 2
Synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives
Time
Entry
Aldehyde
Product
Yieldb (%)
Mp (°C) [Ref.]
202-203[30]
(min)
1
25
99
2
3
10
40
98
97
225-226[30]
197-200[30]
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4
5
10
23
98
94
182-183[30]
211-212[30]
6
7
15
35
96
98
223-224[30]
167-168[30]
8
9
25
32
98
96
192-193[30]
184-185[30]
10
11
60
80
94
86
244-245[30]
272-273[30]
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12
13
14
23
15
50
98
98
96
280-282[21]
220-222[21]
191–192[21]
15
100
84
202–204[21]
16
17
17
45
98
96
157-159[30]
160-164[31]
a Reaction conditions: aldehyde (1 mmol), 2-aminobenzamide (1 mmol), catalyst (4 m g) and ethanol solvent (5mL) at reflux temperature.
b Isolated yields
Table 3
Synthesis of polyhydroquinolines derivatnives
Entry
Aldehyde
Product
Time (min)
Yieldb (%)
Mp (°C) [Ref.]
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1
2
3
4
90
98
96
96
94
95
239-241[17]
120
110
100
252-254[17]
249-252[32]
247-249[17]
5
90
201-202[17]
6
95
92
207-209[17]
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7
110
98
176-178[32]
8
100
90
96
96
93
183-185[17]
234-236[19]
230-232[17]
9
90
11
90
11
12
13
100
150
120
217-219[17]
92
162-164[17]
92
170-172[17]
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14
90
91
146-147[17]
a Reaction conditions: arylaldehyde (1mmol), dimedone (1 mmol),ethyl acetoacetate (1 mmol), NH4OAc (1.2 mmol), catalyst (4 m g) and ethanol
solvent (5mL) at 50 °C.
b Isolated yields
Table 4
During the course of one of our drug discovery programs, we
became interested in the synthesis of 2-amino-6-(arylthio) pyridine-
3,5-dicarbonitrile (Scheme 6). These pyridine derivatives are a
privileged scaffold for developing pharmaceutical agents because
various compounds with this structural motif display significant and
diverse biological activities.
Optimization of reaction conditions for the one-pot synthesis of pyridines
Entry
Solvent
H2O
Catalyst (mg)
Time (min)
Yieldb (%)
Treac
23
1
No catalyst
24h
60
60
60
60
60
60
2
H2O
2
3
5
7
5
5
3
H2O
61
4
H2O
91
5
H2O
90
6
7
Acetonitrile
EtOH
30
trace
mmol),
bReaction
conditions:
4-methoxybenzaldehyde
(1
4-
Scheme 6. Synthesis of 2-amino-6-(arylthio) pyridine-3,5-
dicarbonitrile.
bromobenzenethiol (1 mmol), malononitrile (2 mmol) in water (5 mL) at 80
°C for 60 min.
We initiated our study with the reaction between 4-
methoxybenzaldehyde, 4-bromobenzenethiol and malononitrile as
a model reaction (Table 4).
With the optimal reaction conditions in hand (Table 4, entry 4), the
scope and generality of this protocol was investigated next. A wide
variety of aromatic aldehydes and thiols were used for synthesis of
2-amino-3,5-dicarbonitrile-6-thio-pyridines. The results are
summarized in Table 5. Meanwhile, the electronic properties and
different positions of the substituents have no obvious effect on the
reaction yields.
Subsequently, we agreeably found out that the presence of 5 mg of
Cu(II)/L-His@Fe3O4, promoted the reaction efficiently and improved
the yield to 91% (entry 4). The nature of solvent was then screened.
In water, the reaction also proceeded smoothly and gave a good
yield. In acetonitrile, however, only
a low yield of (30%
) was obtained (entry 6). When the reaction was carried out in,
ethanol, almost no desired product was found (entries 7). Based on
the above mentioned reasons, it was found that the water is the
best solvent. The effect of temperature on reaction was
examined.With increasing the temperature the yield of product also
increases and It was found that optimal reaction temperature is 80
°C
Table 5 Synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridinesa
Entry
Aldehyde
Thiophenol
Product
Yieldb (%)
Mp (°C) [Ref.]
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1
2
3
92
90
86
238-240[29]
220-222[28]
238-239[25]
4
91
233-235[26]
5
89
230-232[26]
6
95
217-218[27]
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7
8
9
94
221-223[27]
245-250[26]
223-225[27]
315-317[27]
211-212[27]
87
97
94
92
11
11
12
89
225-227[27]
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a
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13
90
288-290[27]
14
93
240-242[27]
Reaction conditions: arylaldehyde (1mmol), thiol (1 mmol), malononitrile (2 mmol), catalyst (5 mg) and in water (5 mL) at 80 °C for 60 min.
b Isolated yields.
metal-chelating monomer via metal coordination interactions and
Based on industrial green chemistry principles, the reusability of the histidine template. Copper (II) bound to L-histidine is in equilibrium
catalyst is important for the large scale operation. Therefore, with human serum albumin and may undergo mutual exchange
reusability of described catalyst was examined for the synthesis which modulates the bioavailability of copper to the cell. A range of
DHQ (Table 2, entry 1) and PHQ (Table 3, entry 1). After the first corresponding products were synthesized by this strategy with
run, the catalyst was easily and rapidly separated from the reaction moderate to good yields under mild and green conditions in a
mixture using an external magnet and subsequently was used for heterogeneous system with short reaction times. These
the next run. As it can be seen from Fig. 7, the catalyst can be nanocatalysts have emerged as powerful tools for the efficient
recycled at lease for six runs without any significant loss of its conversion of raw materials into useful chemicals of both industrial
catalytic activity and efficient.
and pharmaceutical significance.
Furthermore, the Cu(II)/L-His@Fe3O4 nanocatalyst can be easily
separated from the reaction mixture and the catalytic activity
remained unchanged even after 6 successive recycling experiments.
DHQ
PHQ
100
80
60
40
20
0
Experimental
Materials
All the reagents and solvents were purchased from Sigma-Aldrich,
Fluka or Merck and utilized without further purification.
The particle morphology was examined by measuring SEM using
FESEM-TESCAN MIRA3. The products component measurement was
carried out by the energy dispersive spectroscopy (EDS) using
FESEM-TESCAN MIRA3 scanning electron microscopes. The
thermogravimetric analysis (TGA) curves are recorded using a
Shimadzu DTG-60 instrument. VSM measurements were performed
using a Vibrating Sample Magnetometer (VSM) MDKFD. The
magnetization measurements were carried out in an external field
up to 15 kOe at several temperatures.
1
2
3
4
5
6
Run
Fig. 7. Recycling of Cu(II)/L-His@Fe3O4 for the model reaction under
optimized conditions
In summary, we have successfully developed an efficient and novel
catalyst for several synthetic organic transformations. Cu(II)-L-
Histidine was grafted onto magnetic Fe3O4 nanoparticles, as a
14 | J. Name., 2012, 00, 1-3
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Nanostructures were characterized using a Holland Philips X,pert X- DMSO-d6): δ 163.9, 148.1, 141.1, 133.8, 133.4, 129.2, 128.7, 127.8,
View Article Online
DOI: 10.1039/C6RA19776K
ray powder diffraction (XRD) diffractometer (Co Ka, radiation= 117.7, 115.4, 114.9, 66.2 ppm.
0.154056 nm). IR spectra were recorded as KBr pellets on a VRTEX 2-(4-methylphenyl)-2,3-dihydroquinazolin-4(1H)-one (Table 2, entry
1
70 model BRUKER FTIR spectrophotometer. NMR spectra were 2): White solid, Mp: 225-226 °C. H NMR (250 MHz, DMSO-d6): δ
recorded on a Bruker Avance III 400MHz. Chemical shifts are given 8.21 (s, 1H), 7.62-7.59 (d, 1H), 7.38-7.35 (d, 2H), 7.26-7.16 (m, 3H),
in ppm (δ) relative to internal TMS and coupling constants J are 7.03 (s, 1H), 6.75-6.63 (m, 2H), 5.71 (s, 1H), 2.49-2.42 (s, 3H)
reported in Hz. Melting points were measured with an ppm.13C NMR (62 MHz, DMSO-d6): δ 164.1, 148.4, 139.1, 138.2,
Electrothermal 9100 apparatus. The Cu amount of catalyst was 133.7, 129.3, 127.8, 127.2, 117.5, 115.4, 114.9, 66.8, 21.2 ppm.
measure by Inductively Coupled Plasma Atomic Emission
2-(4-ethoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (Table 2, entry
7): White solid, m.p. 167–168 °C, 1H NMR (400 MHz, CDCl3): δ (ppm)
Spectrometer (ICP-OES). The particle size and morphology were
investigated by a Zeiss-EM10C transmission electron microscope
7.98 (brs, 1H), 7.6 (d, J = 6 Hz, 2H) 7.34 (s, 1H), 7.26 (d, J = 2 Hz, 1H),
(TEM) on an accelerating voltage of 80 kV.
6.87–7.03 (m, 3H), 6.65 (d, J = 5.6 Hz, 1H), 5.87 (s, 1H), 5.75 (s, 1H),
4.12 (t, J= 4 Hz, 2H) 1.45 (q, J= 6.4 Hz, 3H). 13C NMR (100MHz,
Preparation of Cu(II)/L-His@Fe3O4 catalyst
Acryloyl chloride-coated magnetic nanoparticles (MNP-acryloxyl)
CDCl3): δ 161.4, 148.9, 147.5, 131.52, 129.89, 120.7, 116.79, 116.01,
were prepared according to the literature method [29]. The
115.68, 69.82, 64.78, 15.9; IR (KBr): mmax 3300, 3060, 3000, 2930,
resulting materials were dispersed in ethanol (10.0 mL), and then L-
1666, 1650, 1610, 1487, 1387, 70.
Histidine (3.2 mmol) was added to it and stirred continuously for 1
2,2'-(1,2-phenylene)bis(2,3-dihydroquinazolin-4(1H)-one) (Table 2,
week at room temperature. The L-His@Fe3O4 particleswere
1
entry 11): White solid, m.p. 272-273 °C, H NMR (400 MHz, DMSO):
separated by a magnetic field, washed with ethanol and dried
δ (ppm) 7.87 (d, J = 8.4 Hz, 4H), 7.64 (s, 2H), 7.46 (s, 2H), 7.32 (d, J =
under vacuum for 12 h.
6 Hz, 2H), 7.15 (s, 2H), 6.69 (s, 3H), 6.63 (s, 2H), 5.75 (s, 2H). IR
The L-His@Fe3O4 (0.5 g), was added to the round-bottom flask
(KBr): mmax 3299, 3248, 3181, 2961, 2831, 1698, 1639, 1808, 1515,
containing a solution of Copper (II) chloride (0.25 g) in ethanol (20
1481, 1297, 1151, 742.
mL). The mixture was then stirred vigorously under reflux conditions
2-isopropyl-2,3-dihydroquinazolin-4(1H)-one (Table 2, entry 17):
White solid, m.p. 160–164°C,1H NMR (400 MHz, CDCl3): δ = 7.88 (d,
for 8 h. The solid was separated by magnetic decantation. The
magnetic catalyst was washed with copious amounts of ethanol and
J = 7.6 Hz, 1H), 7.31 (t, J = 7.2 Hz, 1H), 6.84 (t, J = 7.2 Hz, 1H), 6.74
dried under vacuum at room temperature.
(s,1), 6.69 (d, J = 8 Hz, 1H), 4.72 (d, J= 4.4, 1H), 2.00 (m, 6H), 1.05 (d,
J = 6.8 Hz, 6H). 13C NMR (100 MHz,CDCl3): δ =, 165.52, 147.55,
General synthesis for the preparation of 2,3-dihydroquinazolin-
4(1H)-ones
133.87, 128.46, 118.97, 115.52, 114.51, 70.16, 32.82, 148.9, 16.94.
A mixture of aldehyde (1 mmol), 2-aminobenzamide (1mmol),
Cu(II)/L-His@Fe3O4 (4 mg) and ethanol (4 mL) was stirred at 80 °C.
General method for the synthesis of polyhydroquinolines
Upon completion, the progress of the reaction was monitored by
4 mg of Cu(II)/L-His@Fe3O4 catalyst was ultrasonically dispersed in
TLC. After the TLC indicates the disappearance of starting materials,
freshly distilled ethanol (5 mL). Then, a mixture of aldehydes (1
the reaction was cooled to room temperature. The catalyst was
mmol), dimedone (1 mmol), ethyl acetoacetate (1 mmol) and
separated by an external magnet and reused as such for the next
ammonium acetate (1.2 mmol) was added. The resulting mixture
experiment. The filtrate was evaporated to remove solvent, the
was stirred at 50°C for the appropriate time, as shown in Table 3.
resultant solid was then washed with ethanol to obtain pure 2,3-
After completion of the reaction the catalyst was separated from
dihydroquinazolin-4(1H)-ones in 89-99% yields.
the reaction mixture using an external magnet. Subsequently, the
2-(4-chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (Table 2, entry
solvent was evaporated and the residue was purified by further
1
1): White solid, Mp: 202-203 °C. H NMR (250 MHz, DMSO-d6): δ
recrystallisation in ethanol. A wide range of products were obtained
8.29 (s, 1H), 7.61-7.41 (m, 5H), 7.26-7.2 (t, 1H), 6.75-6.63 (m, 2H),
7.12 (s, 1H), 6.75-6.63 (m, 2H), 5.75 (s, 1H) ppm. 13C NMR (62 MHz,
in good to excellent yields (91−98%).
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2,7,7-trimethyl-5-oxo-4-(p-tolyl)-1,4,5,6,7,8- external magnet and reused as such for the next experiment. The
Ethyl
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hexahydroquinoline-3-carboxylate (Table 2, entry 3):White solid, mixture was diluted with ethyl acetate and DwOaIt:e1r0.s1o0l3u9t/iCo6nRaAn19d77th6Ke
M.p. 252-254°C, 1H NMR (400 MHz, CDCl3) δ: 9.05 (s, 1H, NH), 7.01- extracted organic layer was dried over Na2SO4 (1.5 g) and the
7.29 (m, 4H), 5.03 (s, 1H), 4.04 (q, j= 8.2HZ, 2H), 2.21 (m,3H), 2.28 solvent was evaporated. The crude product was recrystallized from
(s, 3H), 1.96 (s, 1H), 1.25 (t, J =7.2 Hz, 3H), 1.11 (s, 3H), 0.98 (s, 3H) ethanol to obtain pure product.
ppm. IR (KBr, cm_1): 3274, 2956, 1699, 1603, 1488, 1378, 1233,
2-amino-4-(4-fluorophenyl)-6-(phenylthio)pyridine-3,5
dicarbonitrile (Table 5, entry 9): Yellow solid, Mp 223-225°C, 1H
NMR (300 MHz, DMSO-d6) δ: 7.81 (d, J = 8.1 Hz, 2H), 7.60–7.59 (m,
2H), 7.55–7.51 (m, 5H), 5.51 (s, 2H).
1139, 1030, 748, 743.
Ethyl
4-(3,4-dimethoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (Table 3, entry 5): White solid,
M.p. 201-202°C, IR (kbr, cm_1): 3203, 2958, 1692, 1601, 1485, 1378,
1216, 1139, 1029, 758, 730. 1H NMR (400 mhz, DMSO-d6) δ: 9.06
(s, NH) 6.74 (d, J=16 H, 2H), 6.65 (d, J =8 Hz, 1H), 4.80 (s, 1H), 4.02
(d, J=8 Hz, 2H), 3.67 (s, 6H), 2.42 (d, J=8 Hz, 1H), 2.28-2.32 (m, 4H),
2.21 (d, J=16 Hz, 1H), 2.02 (d, J=14 Hz, 1H), 1.17 (s, 3H), 1.03 (s, 3H),
0.90 (s, 3H) ppm. 13CNMR (100 mhz, DMSO-d6) δ: 194.8, 161.4,
149.9, 148.3, 147.4, 145.1, 144.9, 140.9, 119.6, 112.1, 111.9, 110.5,
104.3, 59.5, 55.8, 50.7, 35.6, 32.6, 29.7, 26.9, 18.7, 18.6, 14.7 ppm.
2-Amino-4-(4-methoxy-phenyl)-6-phenylsulfanyl-pyridine-3,5-
dicarbonitrile (Table 5, entry 14): Yellow solid, Mp 240-242°C, 1H
NMR (300 MHz, CDCl3) δ: 7.43–7.59 (m, 7H), 7.08 (d, J = 8.8 Hz, 2H),
5.46 (s, 2H), 3.91 (3H, s).
Complete experimental procedures and relevant spectra (1H NMR
and 13C NMR) for several prepared compounds, and the catalyst
characterization data are available in the Supporting information.
Acknowledgements
Ethyl
4-(4-ethoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (Table 2, entry 7): White solid,
Authors thank Ilam University for financial support of this research
project.
1
M.p. 176-178 °C, H NMR (400 MHz, CDCl3): δ= 7.19 (d, J = 6.4 Hz,
2H) , 6.73 (d, J = 6.4 Hz, 2H), 5.80 (s, 1H), 4.99 (s, 1H), 4.06 (t, 2H),
3.96 (t, 2H), 2.15-2.38 (m, 7H), 1.37-1.38 (m, 3H), 1.20-1.21 (m, 3H),
1.07 (s, 3H), 0.95 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ= 198,
169, 158.3, 150.2, 144.7, 140.7, 130.1, 114.9, 113.1107.3, 64.3,
60.9, 51.9, 41.8, 36.8, 33.7, 30.6, 28.2, 20.3, 16.05, 15.4 ppm.
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DOI: 10.1039/C6RA19776K
Graphical abstract
Heterogeneous Cu(II)/L-His@Fe3O4 nanocatalyst: a novel, efficient and
magnetically-recoverable catalysts for organic transformations in green
solvents
Masoomeh Norouzi, Arash Ghorbani-Choghamarani,* Mohsen Nikoorazm