Synthesis of Polyhydroquinoline, 2,3-Dihydroquinazolin-4(1H)-one, Sulfide and Sulfoxide Derivatives Catalyzed by New Copper Complex Supported on MCM-41

Article abstract of DOI:10.1007/s10562-018-2311-x

Abstract: A simple, efficient and less expensive protocol for the synthesis of Cu(II) immobilized on MCM-41@Serine has been reported. This nanohybrid material was carefully characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy, inductively coupled plasma optical emission spectroscopy, X-ray diffraction, TEM, thermal gravimetric analysis, and N₂ adsorption and desorption. The obtained nanostructured compound were also employed as a green, efficient, heterogeneous and reusable catalytic system for the synthesis of polyhydroquinoline, 2,3-dihydroquinazolin-4(1H)-one, sulfide and sulfoxide derivatives. High surface area, convenient recovery and reusability for several times without any significant loss of activity, the use of a commercially available, eco-friendly, cheap and chemically stable reagents, good reaction times, simple practical methodology and ease of use all make Cu(II) immobilized on MCM-41@Serine a promising candidate for potential applications in some organic reactions; makes this protocol both attractive and economically viable. Graphical Abstract: MCM-41 nanostructured was prepared via simple and versatile procedure and directly immobilized with a new type of Cu–serine complex. After characterization of this catalyst, the catalytic activity of this nanostructure compound has been investigated for the synthesis of polyhydroquinoline, 2,3-dihydroquinazolin-4(1H)-one, sulfide and sulfoxide derivatives. [Figure not available: see fulltext.].

Full text of DOI:10.1007/s10562-018-2311-x

Catalysis Letters
https://doi.org/10.1007/s10562-018-2311-x
Synthesis of Polyhydroquinoline, 2,3-Dihydroquinazolin-4(1H)-one,
Sulfide and Sulfoxide Derivatives Catalyzed by New Copper Complex
Supported on MCM-41
Taiebeh Tamoradi1 · Mohammad Ghadermazi1 · Arash Ghorbani‑Choghamarani2
Received: 8 December 2017 / Accepted: 12 January 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
A simple, efficient and less expensive protocol for the synthesis of Cu(II) immobilized on MCM-41@Serine has been
reported. This nanohybrid material was carefully characterized by Fourier transform infrared spectroscopy, scanning elec-
tron microscopy, energy-dispersive X-ray spectroscopy, inductively coupled plasma optical emission spectroscopy, X-ray
diffraction, TEM, thermal gravimetric analysis, and N2 adsorption and desorption. The obtained nanostructured compound
were also employed as a green, efficient, heterogeneous and reusable catalytic system for the synthesis of polyhydroquino-
line, 2,3-dihydroquinazolin-4(1H)-one, sulfide and sulfoxide derivatives. High surface area, convenient recovery and reus-
ability for several times without any significant loss of activity, the use of a commercially available, eco-friendly, cheap and
chemically stable reagents, good reaction times, simple practical methodology and ease of use all make Cu(II) immobilized
on MCM-41@Serine a promising candidate for potential applications in some organic reactions; makes this protocol both
attractive and economically viable.
Graphical Abstract
MCM-41 nanostructured was prepared via simple and versatile procedure and directly immobilized with a new type of
Cu–serine complex. After characterization of this catalyst, the catalytic activity of this nanostructure compound has been
investigated for the synthesis of polyhydroquinoline, 2,3-dihydroquinazolin-4(1H)-one, sulfide and sulfoxide derivatives.
* Mohammad Ghadermazi
mghadermazi@yahoo.com
* Arash Ghorbani-Choghamarani
arashghch58@yahoo.com; a.ghorbani@ilam.ac.ir
1
Department of Chemistry, Faculty of Science, University
of Kurdistan, Sanandaj, Iran
2
Department of Chemistry, Faculty of Science, Ilam
University, P.O. Box 69315516, Ilam, Iran
Vol.:(0123456789)
1 3

T. Tamoradi et al.
Keyword MCM-41 · Copper · Polyhydroquinoline · 2,3-Dihydroquinazolin-4(1H)-one · Sulfide · Sulfoxide
ring molecules-containing organic molecules are very well-
known; particularly, polyhydroquinoline (PHQ) derivatives
have been employed as imperative molecules in biological
and pharmaceutical such as vasodilator, hepatoprotective,
antiatherosclerotic, bronchodilator, antitumor, geroprotec-
tive, antidiabetic activity and also their ability to modulate
calcium channels [20–25]. As reported in several well-
documented reviews, 2,3-dihydroquinazolin-4(1H)-one
derivatives can seek the opportunities in an important class
of heterocyclic compounds in the production of industrially
important chemicals and biological products such as antitu-
mor, antibiotic, antidefibrillatory, antipyretic, antihistamine,
vasodilating behavior, analgesic, antihypertonic, diuretic and
antidepressant [26, 27]. Since then, various catalytic systems
have emerged for the reactions mentioned above. Some of
these procedures have various disadvantages including haz-
ardous reaction conditions, difficulty in preparation and/or
storage of reagents or catalysts, toxic chemicals and tedious
workup, operational costs and product purity, use of strong
acids, difficulty in separation of catalyst from the products,
poor yields and long reaction times [28–33]. Furthermore,
1 Introduction
Diaryl sulfides and their derivatives have been intensively
investigated in recent years. They have been attracting much
attention, due to their wide applications in areas such as
biological and pharmaceutical systems and organic synthe-
sis. More importantly, they have found widespread applica-
tion as precursors or synthetic intermediates in numerous
drugs such as those against diabetes, Alzheimer’s disease,
inflammation, cancer, Parkinson’s disease and HIV [1–9].
It should be noted that sulfides were important substrate
source for the synthesis of sulfoxides. Recently, consider-
able interest in sulfoxide compounds was occurred because
they are versatile reagents for organic synthesis. Indeed, sul-
foxide derivatives have a wide range of important potential
applications as precursors or intermediates in the synthesis
of natural products and valuable physiologically and phar-
macologically active molecules and as well as important
integral and supplementary parts in many pharmaceutical
and biological active molecules such as omeprazole and
fipronil [10–19]. In addition, six membered heterocyclic
1 3

Synthesis of Polyhydroquinoline, 2,3-Dihydroquinazolin-4(1H)-one, Sulfide and Sulfoxide…
a versatile and environmentally friendly procedure has
been reported to overcome these drawbacks. In this regard,
mesoporous silica materials with nano-sized pores and con-
trollable porous structure and pore volume were offered as
suitable operation procedure for the synthesis of organic
molecules because of their large specific surface areas, high
dispersion of metal nanoparticles, facility in the access of
substrates to active sites and facility in the separation of the
catalyst upon reaction completion [34–39]. In recent years,
the copper heterogeneous catalysts have been widely uti-
lized for the organic synthesis because of their chemical,
economic, and environmental aspects [40–42]. Therefore,
in the development of greener and sustainable processes for
organic synthesis and nanocatalyst, we report the prepara-
tion and characterization of recoverable and efficient MCM-
41@Serine@Cu(II) nanoparticles. Interestingly, the results
of these studies were indicated a highly catalytic nature, easy
to handle procedure, short reaction time, recycle exploita-
tion and excellent isolated yields for the synthesis of PHQ,
2,3-dihydroquinazolin-4(1H)-one, sulfide and sulfoxide
derivatives.
template agent, to a solution containing 3.5 mL of NaOH
solution (2 M) and deionized water (480 mL) and then
stirred at 80 °C followed by a dropwise addition of 5 mL of
tetraethylorthosilicate as the silica source under vigorous
stirring. Upon stirring for 2 h under the nearly same con-
dition, the resulting precipitate was filtered, washed with
deionized water and dried in an oven at 60 °C. Finally, the
resultant white powder was calcinated at 823 K for 5 h at a
rate of 2 °C min−1 to remove the residual surfactants. The
final product is designated as pure silica MCM-41. Sub-
sequently, MCM-41@Serine was synthesized by adding
1.5 g of serine to a suspension of MCM-41 (1 g) in 30 mL
distilled water under reflux conditions for 48 h. Finally, the
resulting mixture was filtered, washed with ethanol/water
and dried in vacuum at 70 °C to give pure MCM-41@
Serine. In the last step, for the synthesis of MCM-41@
Serine@Cu(II) nanoparticles, 1 g MCM-41@Serine and
0.604 g Cu(NO3)2·3H2O were mixed in ethanol (30 mL)
under reflux conditions for 16 h, filtered, washed thor-
oughly with ethanol and dried in vacuum to obtain a novel
nanocatalyst.
2.3 General Procedure for the Synthesis of Sulfides
2 Experimental
In the next study, MCM-41@Serine@Cu(II) catalyst
(0.08 g) was added to a mixture of thiourea (1 mmol), aryl
halide (1 mmol), KOH (0.7 g) in DMSO (2 mL) as solvent
and the mixture kept under stirring at 130 °C for the appro-
priate time. The progress of the reaction was monitored by
TLC. After reaction completion, the catalyst was collected
by magnetic separation and the product was extracted with
ethyl acetate. The organic extract was washed twice with
water and dried with anhydrous Na2SO4. Finally, the solvent
of the organic layers was evaporated to obtain correspond-
ing sulfide.
2.1 Materials and Instrumentation
All commercially available chemicals in this study were
purchased from Aldrich, Merck or Fluka and used without
further purification. The thermo-gravimetric analysis (TGA)
curve of the MCM-41@Serine@Cu(II) nanocatalyst was
recorded using Shimadzu DTG-60 instrument in the tem-
perature range of 50–800 °C. X-ray diffraction (XRD) pat-
terns of samples were taken to obtain the crystallographic
structure of catalyst by XRD patterns using Co radiation
source with a wavelength l=1.78897 Å, 40 kV. Measuring
the Amount of copper in the synthesized nanohybrid was
investigated by inductively coupled plasma optical emission
spectrometry (ICP-OES).The particle size and external mor-
phology of the nanoparticles were characterized by TEM
and SEM techniques using Zeiss-EM10C TEM and FESEM-
TESCAN MIRA3, respectively. Fourier transform infrared
(FT-IR) spectra of samples were also recorded on a Bruker
VERTEX 80 v model using the KBr pellets in the range
of 400–4000 cm−1. The elemental analysis of the samples
was done by energy-dispersive X-ray spectroscopy (EDAX,
TSCAN).
2.4 General Procedure for the Synthesis of Sulfox‑
ides
In order to examine the catalytic activity of the catalyst, a
solution of sulfide (1 mmol) and MCM-41@Serine@Cu(II)
(3 mg) was added to the round-bottomed flask containing
hydrogen peroxide solution (0.5 mL) under solvent-free con-
dition. The mixed reaction was stirred at room temperature
for a time period. After completion of the reaction (monitor-
ing by TLC), MCM-41@Serine@Cu(II) catalyst was easily
separated by filtration, and then the product extracted with
ethyl acetate and dried over anhydrous Na2SO4 to give the
pure sulfoxide.
2.2 Preparation of Mesoporous Silica‑Anchored
MCM‑41@Serine@Cu(II)
Initially, mesoporous MCM-41 was prepared by adding 1 g
of cetyltrimethylammonium bromide, as structure directing
1 3

T. Tamoradi et al.
2.7.5 Diphenyl Sulfide
2.5 General Procedure for the Synthesis of Polyhyd‑
roquinolines
1H NMR (400 MHz, DMSO): δH = 6.30–7.34 (m, 6H),
7.37–7.46 (m, 4H) ppm.
In a typical procedure, a mixture of dimedone (1 mmol),
aldehyde (1 mmol), ethyl acetoacetate (1 mmol), ammo-
nium acetate (1.2 mmol) and MCM-41@Serine@Cu(II)
catalyst (0.05 g) in ethanol (2 mL) was magnetically
stirred in the reaction flask at 80 °C. After completion
of the reaction, the catalyst was separated by an external
magnet and solvent was evaporated at 50 °C for reuse.
Finally, a crude solid was obtained followed by crystalli-
zation from ethanol which prepared the pure product with
excellent yield.
2.7.6 Ethyl-4-(3,4-dimethoxyphenyl)-2,7,7-trime-
thyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carbox-
ylate
1H NMR (400 MHz, DMSO): δH =9.05 (s, 1H), 6.79–6.76
(m, 2H), 6.65–6.63 (d, J =8, 1H), 4.80 (s, 1H), 4.04–3.99
(q, J = 7.2, 2H), 3.69–3.68 (d, J = 4.4, 5H), 2.47–2.42 (d,
J=17.2, 2H), 2.35–2.27 (m, 4H), 2.22–2.18 (d, J=16, 1H),
2.03–1.99 (d, J=16, 1H), 1.20–1.16 (t, J=6.8, 3H), 1.03 (s,
3H), 0.90 (s, 3H) ppm.
2.6 General Procedure for the Synthesis of 2,3‑Dihy‑
droquinazolin‑4(1H)‑ones
2.7.7 Ethyl-4-(4-methoxyphenyl)-2,7,7-trime-
thyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carbox-
ylate
In order to illustrate the catalytic activity of MCM-41@
Serine@Cu(II) in the synthesis of 2,3-dihydroquinazolin-
4(1H)-ones, a mixture of aldehyde (1 mmol), 2-aminoben-
zamide (1 mmol) and catalyst (0.009 g) in ethanol (2 mL)
was magnetically stirred in the reaction flask at room tem-
perature. After the completion of the reaction indicated
by TLC, the catalyst was separated by an external magnet
and solvent was evaporated at 70 °C for reuse. Finally, a
crude solid was obtained followed by crystallization from
hot ethanol which prepared the pure product with excel-
lent yield.
1H NMR (400 MHz, DMSO): δH =9.04 (s, 1H), 7.08–7.06
(d, J = 8.4, 2H), 6.77–6.75 (d, J = 8.4, 2H), 4.80 (s, 1H),
4.02–3.96 (q, J = 7.2, 2H), 3.69 (s, 3H), 2.52–2.45 (d,
J=29.2, 1H), 2.31–2.29 (m, 4H), 2.20–2.16 (d, J=16, 1H),
2.01–1.97 (d, J=16.4, 1H), 1.17–1.14 (t, J=7.2, 3H), 1.02
(s, 3H), 0.87 (s, 3H).
3 Result and Discussion
2.7 Selected Spectral Data
3.1 Catalyst Preparation
2.7.1 Methyl Phenyl Sulfoxide
Immobilized serine ligand on mesostructured MCM-
41(MCM-41@Serine) was successfully synthesized by using
the surface modification strategy as depicted in Scheme 1.
The MCM-41 nanoparticles are initially prepared according
to a previous report by Hajjami et al. [43] and coated with
serine ligand by using stable interaction between the car-
boxylic groups of serine ligand and the hydroxyl groups on
MCM-41 surface. Finally, the reaction of MCM-41@Serine
with Cu(NO3)2·3H2O in ethanol under reflux for 16 h led
to generation of immobilized serine copper(II) complex on
MCM-41 nanoparticles (MCM-41@Serine@Cu(II)).
1H NMR (400 MHz, CDCl3): δH =2.75 (s, 3H), 7.52–7.62
(m, 2H), 7.66–7.69 (m, 3H) ppm.
2.7.2 Dodecyl Methyl Sulfoxide
1H NMR (400 MHz, DMSO):δH = 0.87 (t, J = 6.8, 3H),
1.26–1.71 (m, 20H), 2.58(s, 3H), 3.09 (t, J=8, 2H) ppm.
2.7.3 Dibenzyl Sulfoxide
1H NMR (400 MHz, CDCl3): δH =3.90 (d, 2H, J=12.8 Hz),
3.2 Catalyst Characterization
3.95 (d, 2H, J=12.8 Hz), 7.29–7.43 (m, 10H) ppm.
After successful synthesis of a new highly efficient cata-
lyst system by the immobilization of copper complex on the
surface of MCM-41 mesoporous via coordination bonding
through hydroxyl group interaction (Scheme 1), the prepared
catalyst has been characterized by FT-IR, XRD, TEM, SEM,
TGA, EDX, ICP and BET techniques.
2.7.4 2,20-Dimethoxy Diphenyl Sulfide
1H NMR (400 MHz, DMSO): δH =6.96–7.36 (m, 8H), 3.82
(s, 6H) ppm.
1 3

Synthesis of Polyhydroquinoline, 2,3-Dihydroquinazolin-4(1H)-one, Sulfide and Sulfoxide…
Scheme 1 Synthesis of MCM-41@Serine@Cu(II)
Fig. 1 SEM images of a cal-
cined MCM-41and b MCM-
41@Serine@Cu(II) catalyst
Figure 1a, b show the FESEM images of the MCM-41
and MCM-41@Serine@Cu(II) catalyst for investigation
of the surface morphology of the obtained nanostructure.
According to the SEM image, nanoparticles were made
up of quite homogeneous and uniform spherical particles
and no significant changes in the morphology occurred
after anchoring of copper complex onto the surface of
mesoporous MCM-41 silica.
XRD patterns of MCM-41@Serine and MCM-41@Serine@
Cu(II), the absence of (110) and (200) reflections was also
noticed that similar type of behavior was observed by Joseph
et al. [45].
Figure 3 shows the quantitative determination of the
organic groups supported on the surface of MCM-41
nanostructure by TGA. According to the TGA results, all
samples indicated the small amount of weight loss below
200 °C that is due to removal of the adsorbed water as well
as dehydration of the surface OH groups. The 60% mass
loss at temperatures in the range of 200–500 °C is chiefly
due to the decomposition of the organic layers on the sur-
face of the synthesized mesoporous silica MCM-41 nano-
particles [46]. It should be noted that the good grafting of
nanocatalyst onto the surface of magnetic nanoparticles is
verified on the basis of the results obtained from the TGA
curves.
As seen in Fig. 2, the XRD analysis patterns of the MCM-
41, MCM-41@Serine and MCM-41@Serine@Cu(II) were
recorded by powder XRD. According to the XRD pattern of
MCM-41, a single intense peak and two weak peaks indi-
cated which can be corresponds to (1 0 0), (1 1 0) and (2 0
0) reflections, respectively. These spectra reflect hexagonal
mesoporous structure of MCM-41. More importantly, after
post-synthetic grafting, an overall decrease in diffraction
(100) in all samples is indicated which is due to the differ-
ence in the scattering contrast of the pores and the walls
of nano-channels of MCM-41 [44]. As shown in powder
Figure 4 shows the FT-IR spectra of MCM-41, MCM-
41@Serine and MCM-41@Serine@Cu(II). According
1 3

T. Tamoradi et al.
Fig. 2 The XRD patterns of
MCM-41, MCM-41@Serine,
and MCM-41@Serine@Cu(II)
Fig. 3 The TGA diagrams of MCM-41 (red) and MCM-41@Serine@
Cu(II) (blue)
to the FT-IR results, the spectrum of MCM-41 shows a
band at 476 cm−1 which is attributed to the Si–O bend-
ing vibration. Furthermore, absorption peaks appear-
ing at around 1100–1200 and 3000–3600 cm−1 are due
to Si–O–Si asymmetric stretching and the silanol OH
groups, respectively. Also, the absorption peaks at approx-
imately 2890–3000 cm−1 (C–H stretching vibration) and
1394 cm−1 (C–N stretching vibration) in the MCM-41@
Serine spectra are due to the existence of serine ligand
on the surface of nanoparticles. The FT-IR spectrum of
MCM-41@Serine@Cu(II) shows absorption bands at
approximately around 1100–1200 cm−1 (Si–O–Si asym-
metric stretching), 3000–3600 cm−1 (silanol OH groups)
and 475 cm−1 (Si–O bending vibration). Therefore, the
Fig. 4 FT-IR spectra for bare MCM-41 (a), MCM-41@Serine (b) and
MCM-41@Serine@Cu(II) (c)
FT-IR spectra of MCM-41@Serine@Cu(II) was indicated
that the MCM-41 phase has not been destroyed during the
modifications.
1 3

Synthesis of Polyhydroquinoline, 2,3-Dihydroquinazolin-4(1H)-one, Sulfide and Sulfoxide…
silica is found to be 0.51 mmol g−1 using the ICP atomic
emission spectroscopy technique.
3.3 Catalytic Studies
After synthesis and characterization of the catalyst, we
were interested in investigation of catalytic activity in the
synthesis of sulfide (Scheme 2), sulfoxide (Scheme 3),
PHQ (Scheme 4) and 2,3-dihydroquinazolin-4(1H)-one
(Scheme 5) derivatives using MCM-41@Serine@Cu(II)
as a highly efficient and recoverable heterogeneous nano-
catalyst. In order to investigate the possibility of the syn-
thesis of sulfides using the obtained catalyst, the reaction
of iodobenzene (1 mmol), KOH and thiourea (1 mmol)
was selected as a model reaction. Then, influence of
solvent, temperature, amount of catalyst and the type of
base on the outcome of reaction has been investigated
(Table 2). As shown in Table 2, the type of base, the
nature of the solvent and temperature have a profound
effect on both the activity of the catalyst and the yield of
product. These results indicate that the best conditions
were obtained in DMSO at 130 °C in the presence of
0.08 g of catalyst.
Fig. 5 Nitrogen adsorption/desorption isotherms of MCM-41 and
MCM-41@Serine@Cu(II)
Table 1 Texture parameters obtained from nitrogen adsorption stud-
ies
Sample
SBET (m2 g−1
)
Pore diameter by
BJH method (nm)
Pore volume
(cm3 g−1
)
After optimization of the reaction parameters, a variety
of aromatic halides were employed as substrates for the
synthesis of sulfides derivatives in the presence of MCM-
41@Serine@Cu(II) for the appropriate time in moderate
to good yields. The results of this study are summarized
in Table 3.
MCM-41
1113.7
216.74
2.39
1.21
1.39
0.354
MCM-41@
Serine@
Cu(II)
After successful synthesis of sulfides derivatives, a plau-
sible reaction mechanism for the synthesis of this product is
proposed in Scheme 6 [50].
As shown in Fig. 5, the structural and textural properties
of MCM-41 and MCM-41@Serine@Cu(II) were investi-
gated through the N2-adsorption and desorption isotherms
results. The BET analysis (Table 1) shows the surface area
of 1113.7 and 216.74 for MCM-41 and MCM-41@Ser-
ine@Cu(II), respectively. According to these results, pore
volume and pore size distributions of MCM-41@Serine@
Cu(II) are lower than MCM-41. We can conclude that cop-
per serine complex was successfully supported on MCM-41
mesoporous silica.
In continuation of this research work, the catalytic activ-
ity of MCM-41@Serine@Cu(II) was also investigated in
the oxidation of sulfides. In search of the optimized reac-
tion conditions for the synthesis of sulfoxides, the reaction
of methylphenylsulfide (1 mmol) with H2O2 in presence of
MCM-41@Serine@Cu(II) as catalyst was used as a model
reaction. As shown in Table 4, the solvent-free condition
in the presence of MCM-41@Serine@Cu(II) (0.005 g) and
H2O2 (0.5 mL) at room temperature was found to be ideal
reaction conditions for the conversion of methyl phenyl
sulfide to the methyl phenyl sulfoxide.
TEM image of the MCM-41@Serine@Cu(II) cata-
lyst at different magnifications is depicted in Fig. 6. As
shown in Fig. 6, MCM-41@Serine@Cu(II) was made
up of quite homogeneous and uniform spherical par-
ticles and no significant changes in the morphology
occurred upon the insertion of copper complex group
onto MCM-41.
Then, under the optimized reaction conditions, a variety
of sulfides with different functional groups were successfully
tested to prepare the corresponding sulfoxides. As shown
in Table 5, the products were obtained in high to excellent
yields in a short reaction time.
Immobilization of Cu complex on mesoporous MCM-41
was confirmed through presence of Cu, N, O, C, Si species
in the energy-dispersive X-ray spectroscopy (EDX) analy-
sis of this synthesized nanocatalyst (Fig. 7). Also, the exact
amount of Cu loaded on surface of modified mesoporous
A plausible reaction mechanism for the oxidation
of sulfides is shown in Scheme 7. The intermediate A is
obtained by reaction of H2O2 with MCM-41@Serine@
Cu(II), which is converted to active oxidant B. Then,
1 3

T. Tamoradi et al.
Fig. 6 TEM images of MCM-
41@Serine@Cu(II) catalyst
nucleophilic attack of the sulfide on this intermediate (C)
produces corresponding sulfoxide [52].
We finally investigated the possibility of the synthesis
of PHQ derivatives using the obtained catalyst. Initially, in
order to optimize the reaction conditions, we investigated
the reaction of 4-chlorobenzaldehyde (1 mmol), dimedone
(1 mmol), ethyl acetoacetate (1 mmol) and ammonium ace-
tate (1.2 mmol) in the presence of the MCM-41@Serine@
Cu(II) under the effect of various parameters such as solvent,
catalyst concentration and temperature. The results of this
study can be seen in Table 6. As shown in Table 1, the best
conditions were obtained in EtOH at 120 °C with in the
presence of 0.05 g of catalyst.
In order to generalize the scope of the reaction under the
optimized conditions, a series of substituted benzaldehydes
were chosen for the synthesis of PHQ, with the results pre-
sented in Table 7.
Fig. 7 EDX spectrum of MCM-41@Serine@Cu(II)
On the basis of the literatures, a plausible reac-
tion mechanism for the synthesis of PHQ derivatives in
the presence of MCM-41@Serine@Cu(II) as catalyst
1 3

Synthesis of Polyhydroquinoline, 2,3-Dihydroquinazolin-4(1H)-one, Sulfide and Sulfoxide…
Scheme 2 MCM-41@Serine@
Cu(II) catalyzed the synthesis
of sulfides
X
S
S
MCM-41@Serine@Cu(II)
+
H2N
NH2
130ºC
DMSO,
R
KOH
R
R
Cl
X=I, Br,
2a-j
1a-j
Serine@Cu(II) as catalyst was used as a model reaction.
In order to optimize the reaction conditions, the effects of
solvent and catalyst concentration were investigated for the
model reaction. It can be seen that the best results were
obtained in EtOH in the presence of 0.008 g of catalyst
at room temperature. Our observations are summarized in
Table 8.
O
MCM-41@Serine@Cu(II)
rt
S
S
H
O
,
2
Solvent-Free,
2
R1
R2
R1
3a-i
R2
4a-i
It can be seen that a variety of aromatic aldehydes bear-
ing electron-donating and electron-withdrawing substituents
were successfully employed to prepare the corresponding
2,3-dihydroquinazolin-4(1H)-ones derivatives and it was
observed that good to excellent yields of desired products
were obtained (Table 9).
Scheme 3 SBA-15@Serine@Cu(II) catalyzed the oxidation of
sulfides to sulfoxides
is shown in Scheme 8. It should be noted that the role
of catalyst comes in the Knoevenagel coupling of alde-
hydes with active methylene compounds to produce an α,
β-unsaturated compound and in the Michael addition of
intermediates to obtain the PHQ [52].
It can be seen that the following mechanism (Scheme 9)
has been suggested for described catalytic system. Initially,
anhydride is activated and then, an intermediate (A) is
formed by the N-nucleophilic attacks of amine on the car-
bonyl. As shown in this scheme, the imine intermediate B
is obtained. Subsequently, after activation of imine in this
intermediate by metal, intermediate C could be generated by
intramolecular nucleophilic attack of the amide nitrogen on
activated imine group. Finally, 1,5-proton transfer occurred
to yield the final product [54].
Finally, in view of the importance of 2,3-dihydroquina-
zolin-4(1H)-ones, we turned our attention towards the
synthesis of 2,3-dihydroquinazolin-4(1H)-ones derivatives
in high efficiency in the presence of MCM-41@Serine@
Cu(II) as catalyst. In search of the optimized reaction con-
ditions for the synthesis of 2,3-dihydroquinazolin-4(1H)-
ones, the condensation of 4-chlorobenzaldehyde (1 mmol)
with 2-aminobenzamide in presence of MCM-41@
R
O
O
O
O
O
OEt
OEt
MCM-41@Serine@Cu(II)
+
+
NH4OAc
+
Reflux
EtOH,
H
R
N
H
O
O
6a-i
5a-i
Scheme 4 MCM-41@Serine@Cu(II) catalyzed the one-pot synthesis of PHQ derivatives
Scheme 5 MCM-41@Serine@
O
C
Cu(II) catalyzed the synthesis of
CONH2
O
2,3-dihydroquinazolin-4(1H)-
ones
MCM-41@Serine@Cu(II)
r.t
NH
+
R
H
EtOH,
NH2
R
N
H
8a-i
7a-i
1 3

T. Tamoradi et al.
Table 2 Optimization of the
reaction conditions for the C–S
coupling using MCM-41@
Serine@Cu(II) catalyst
Entry
Solvent
Base
Temp. (°C)
Catalyst (mg)
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
DMSO
DMF
PEG
CH3CN
EtOH
H2O
Toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
NaOH
Et3N
130
130
130
130
130
130
130
80
100
130
130
130
130
130
130
0
80
80
80
80
80
80
80
80
80
40
60
100
80
80
210
210
210
210
210
210
210
210
210
210
210
210
210
210
210
N.R
N.R
N.R
N.R
N.R
N.R
17
15
29
65
21
9
10
11
12
13
14
15
49
68
22
26
aIsolated yields
methyl phenyl sulfoxide (a), 2-(4-chlorophenyl)-2,3-dihyd-
roquinazolin-4(1H)-one (b), ethyl-4-(4-chlorophenyl)-2,7,7-
trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3 carboxy-
late (c) and diphenyl sulfide (d).
3.4 Reusability of the Catalyst
Notably, according to the green chemistry viewpoint, the
recovery and reusability of catalyst is an outstanding issue in
modern catalysis researches. After the completion of the reac-
tion, the catalyst was recycled by filtration and washed with
ethyl acetate, and then dried for the next run without consider-
able decrease of its catalytic activity (Fig. 8). This observation
can describe the practical recyclability of this catalyst.
Then, the remaining catalyst was also used under the
same experimental reaction conditions. Figure 9 shows the
yield of several consecutive cycles for the preparation of
3.5 Catalyst Leaching Study
In this research, we also report amounts of copper leaching
in the synthesis of methylphenyl sulfoxide by checking the
copper loading amount before and after recycling of the cata-
lyst by ICP-OEIS technique. It can be seen that the amount
of copper in fresh catalyst and the recycled catalyst after
11 times recycling is 0.51 and 0.45 mmol g−1, respectively,
which indicated that copper leaching of this catalyst is very
low. In order to perform hot filtration experiment, two reac-
tions for the synthesis of methylphenyl sulfoxide has been
investigated under optimized reaction conditions. In the first
reaction, we found the yield of product under optimized con-
ditions in half time of the reaction that it was 67%. Simulta-
neously in second reaction, the same reaction was repeated,
but in the half time of the reaction, the catalyst was separated
from the reaction mixture by filtration process and allowed to
react further under identical reaction conditions. It is worth
noting that the yield of reaction in this stage was 69% that
confirmed the leaching of copper hasn’t been occurred.
Table 3 Synthesis of symmetrical sulfides via reaction of sulfur and
aryl halides using DMSO in the presence of MCM-41@Serine@
Cu(II)
Entry Substrate
Product Time Yield (%)a M.p. (°C)
1
2-Methoxyiodo- 2a
180 63
Oil [29]
benzene
2
3
Iodobenzene
2b
2c
210 65
95 58
Oil [47]
159–161 [48]
4-Bromoni-
trobenzene
4
5
6
7
Bromobenzene
Benzylbromide
4-Iodotoluene
2d
2e
2f
380 49
220 67
430 61
150 52
Oil [47]
44–46 [49]
Oil [48]
4-Chloroni-
2g
161–164 [48]
3.6 Comparison of the Catalyst
trobenzene
8
9
10
4-Bromotoluene 2h
590 42
690 32
70 62
Oil [48]
Oil [48]
156 [48]
In order to examine the efficiency of these procedures, we
compared the results for the oxidation of sulfides in the pres-
ence of our catalyst with previously reported catalysts in the
literature. It can be seen in Table 10 that the present cata-
lyst showed shorter reaction times and better yields than the
Chlorobenzene
2i
2j
4-Iodonitroben-
zene
aIsolated yields
1 3

Synthesis of Polyhydroquinoline, 2,3-Dihydroquinazolin-4(1H)-one, Sulfide and Sulfoxide…
Ph
Ph
S
Ph
S
S
Ph
X
HO
Cu
HO
NH2
NH2
_
Cu
_
MCM-41
H2N
Ph
OH
NH2
@Serine@Cu(II)
+
HX
NH
S
MCM-41
+NH2X
@Serine@Cu(II)
Ph
+
_
S
H2N
H2N
S
NH2
Cu
OH
OH
Cu
_
Ph
XH2N+
Ph
Ph
X
Cu
Ph
NH2
S
NH2
Ph
OH
OH
HN
H2N
_
X
H2N
NH2
O
NH2
Cu
_
S
HO
H2
N
S
H2N
NH2
Scheme 6 Proposed mechanism for synthesis of sulfides in the presence of MCM-41@Serine@Cu(II)
Table 4 Optimization of
oxidation of sulfides to the
corresponding sulfoxides using
MCM-41@Serine@Cu(II)
nanoparticles under various
conditions
Entry
Solvent
H2O2
Catalyst (mg)
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
Solvent-Free
Acetonitrile
Ethanol
Ethyl acetate
Solvent-free
Solvent-free
Solvent-free
Solvent-free
0.5
0.5
0.5
0.5
0.5
0.4
0.5
0.5
0
5
5
5
5
5
3
7
5 h
95
80
110
35
45
55
30
Trace
91
86
92
96
91
84
98
aIsolated yields
Table 5 Oxidation of sulfides to
the sulfoxides in the presence of
MCM-41@Serine@Cu(II)
Entry
Substrate
Product
Time
Yield (%)a
M.p. (°C)
1
2
3
4
5
6
7
8
9
Dipropylsulfide
Diethylsulfide
Dibenzylsulfide
Benzylphenylsulfide
Tetrahydrothiophene
Dimethylsulfide
Dodecylmethylsulfide
Methylphenylsulfide
2-(Phenylthio)ethanol
4a
4b
4c
4d
4e
4f
4g
4h
4i
55
45
25
40
5
60
55
35
65
98
96
95
89
93
93
97
96
89
Oil [51]
Oil [52]
130–133 [51]
122 [52]
Oil [51]
Oil [51]
63–65 [51]
30–32 [52]
Oil [52]
aIsolated yields
1 3

T. Tamoradi et al.
other catalysts. Noticeably, this new catalyst is comparable
in terms of price, non-toxicity, ease of operation, commer-
cially available materials, stability, and easy separation.
O
S
R1 R2
NH2
Cu
C
4 Conclusions
OH
Cu
HO
R2
O
S+
In conclusion, a novel and efficient heterogeneous catalyst
(MCM-41@Serine@Cu(II)) was synthesized by anchor-
ing copper on the surface of organically modified MCM-41
mesoporous nanoparticles. In the next step, this nanohybrid
was carefully characterized by FT-IR, XRD, TGA, TEM,
BET, SEM, EDX and ICP-OES techniques. More impor-
tantly, high surface area, the use of a commercially avail-
able, eco-friendly, low cost, chemically stable reagents, easy
separation of the catalyst by simple filtration, good reac-
tion times, high efficiency, operational simplicity, conveni-
ent recovery and ease of use all make Cu(II) immobilized
on MCM-41@Serine a promising candidate for potential
applications in the synthesis of PHQ, 2,3-dihydroquinazolin-
4(1H)-one, sulfide and sulfoxide derivatives.
NH2
R1
MCM-41@Serine@Cu(II)
R2
S
H
2O2
R1
H
O
O
H2N
O
Cu
OH
OH
Cu
O
H2N
Cu
H2N
OH
R1
B
S
A
R2
Scheme 7 Proposed mechanism for oxidation of sulfides in presence
of MCM-41@Serine@Cu(II) as catalyst
Table 6 Optimization of
Entry
Solvent
Catalyst (mg)
Temperature
(°C)
Time (min)
Yield (%)a
amount of catalyst, solvent and
temperature for the synthesis of
PHQs in the presence of MCM-
41@Serine@Cu(II)
1
2
3
4
5
6
7
8
9
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
PEG
0
30
40
50
70
50
50
50
50
80
80
80
80
80
60
40
80
80
170
170
170
170
170
170
170
170
170
Trace
78
85
92
94
86
81
75
68
H2O
aIsolated yields
Table 7 Synthesis of various
PHQs in the presence of MCM-
41@Serine@Cu(II) under the
standard reaction conditions
Entry
Aldehyde
Product
Time (min)
Yield (%)a
M.p. (°C)
1
2
3
4
5
6
7
8
9
Benzaldehyde
6a
6b
6c
6d
6e
6f
6g
6h
6i
210
195
210
170
110
215
130
180
190
91
95
97
96
97
96
91
93
93
220 [52]
255 [52]
252–255 [52]
153 [52]
186–188 [52]
251 [52]
223–225 [52]
174–177 [52]
207 [52]
4-Bromobenzaldehyde
4-Methylbenzaldehyde
4-Chlorobenzaldehyde
4-Fluorobenzaldehyde
4-Methoxybenzaldehyde
4-Hydroxybenzaldehyde
4-Nitrobenzaldehydel
3,4-Di(methoxy)benzaldehyde
aIsolated yields
1 3

Synthesis of Polyhydroquinoline, 2,3-Dihydroquinazolin-4(1H)-one, Sulfide and Sulfoxide…
Scheme 8 The proposed
O
O
mechanism of synthesis of
R
+
PHQ derivatives in presence of
MCM-41@Serine@Cu(II) as
catalyst
OEt
Me
Me
O
H2N
Me
HO
HO
NH2
NH2
H
NH4OAc
Cu
Cu
MCM-41@Serine@Cu(II)
O
R
O
O
O
O
R
OEt
O
OEt
Me
Me
Me
Me
N
H
O
O
Me
NH4OAc
Me
O
R
OEt
Me
+
NH2
HO
NH2
HO
O
NH2
Me
Cu
Cu
O
R
H
Table 8 Optimization of various
parameters for the synthesis of
2,3-dihydroquinazolin-4(1H)-
ones by MCM-41@Serine@
Cu(II)
Entry
Solvent
Catalyst (mg)
Time (min)
Yield (%)a
1
2
3
4
5
7
8
9
H2O
H2O
H2O
H2O
H2O
EtOH
PEG
DMF
0
10
8
6
4
8
8
8
45
45
45
45
45
45
45
45
Trace
98
97
88
72
91
88
85
aIsolated yields
Table 9 Synthesis of various
PHQs in the presence of MCM-
41@Serine@Cu(II) under the
standard reaction conditions
Entry
Aldehyde
4-Nitrobenzaldehydel
4-Hydroxybenzaldehyde
4-Fluorobenzaldehyde
4-Methoxybenzaldehyde
3-Nitrobenzaldehydel
Benzaldehyde
4-Bromobenzaldehyde
4-Methylbenzaldehyde
4-Chlorobenzaldehyde
Product
Time (min)
Yield (%)a
M.p. (°C)
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8f
8g
8h
6i
40
60
30
75
50
65
55
70
45
93
91
97
96
93
91
95
97
97
174–177 [53]
223–225 [53]
186–188 [53]
251 [54]
169 [54]
220 [54]
255 [53]
252–255 [54]
153 [54]
aIsolated yields
1 3

T. Tamoradi et al.
Scheme 9 Proposed mechanism
for the synthesis of quina-
zolinones
O
C
OH+
C
O
NH
1,5- proton transfer
NH
R
H
O
-
R
N
H
R
N
H
C
HO NH2
Cu
MCM-41
@Serine@Cu(II)
OH
Cu
NH2
R
CONH2
NH2
H
OH
Cu
O
NH2
C
NH
N
H2N
Cu
HO
HO
Cu
NH2
NH
R
-H
2
OH
C
O
B
OH
R
N
Cu
H2N
OH
A
Fig. 8 Recovery of MCM-41@
Serine@Cu(II) by simple filtra-
tion
1 3

Synthesis of Polyhydroquinoline, 2,3-Dihydroquinazolin-4(1H)-one, Sulfide and Sulfoxide…
Fig. 9 Reusability of
MCM-41@Serine@
Cu(II) in the synthesis of
methyl phenyl sulfoxide (a),
2-(4-chlorophenyl)-2,3-dihy-
droquinazolin-4(1H)-one (b),
ethyl-4-(4-chlorophenyl)-2,7,7-
trimethyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3 carboxy-
late (c) and diphenyl sulfide (d)
Table 10 Comparison
Entry
Substrate
Catalyst
Time (min)
Yield (%)a
of MCM-41@Serine@
Cu(II) for the oxidation of
methylphenylsulfide with
previously reported procedure
1
2
3
4
5
6
7
8
Methylphenylsulfide
Methylphenylsulfide
Methylphenylsulfide
Methylphenylsulfide
Methylphenylsulfide
Methylphenylsulfide
Methylphenylsulfide
Methylphenylsulfide
Fe3O4–adenine–Ni
O(IV)–MCM-41
VO2F(dmpz)2
Ni–salen–MCM-41
NBS
Mn–ZSM-5
MCM-41@Serine
MCM-41@Serine@Cu(II)
55
240
300
156
270
360
480
35
98 [52]
95 [55]
95 [56]
90 [57]
93 [58]
83 [59]
35 [this work]
96 [this work]
aIsolated yields
9. Okamoto T, Mitsui C, Yamagishi M, Nakahara K, Soeda J, Hirose
Y, Miva K, Sato H, Yamano A, Matsushita T, Uemura T, Takeye
j (2013) Adv Mater 25:6392
Acknowledgements We gratefully acknowledge the support of this
work by University of Kurdistan and University of Ilam.
10. Gao J, Lu L, Zhou W, Gao G, He M (2008) J Porous Mater 15:127
11. Fernandez I, Khiar N (2003) Chem Rev 103:3651
12. Darabi M, Tamoradi T, Ghadermazi M, Ghorbani-Choghamarani
A (2017) Transit Met Chem 42:703
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