Sonochemical synthesis of library benzodiazepines using highly efficient molecular ionic liquid supported on Fe-MCM-41 nanocomposites as a recyclable catalyst

Article abstract of DOI:10.1002/aoc.5072

In this study, library substituted benzodiazepines was synthesized using molecular ionic liquid supported on Fe-MCM-41 nanocomposites (Fe-MCM-41-IL). This protocol using ultrasound provided advantages such as rapid, clean conversion and simplicity in expe

Full text of DOI:10.1002/aoc.5072

Received: 18 November 2018
DOI: 10.1002/aoc.5072
Revised: 30 April 2019
Accepted: 25 May 2019
F U L L P A P E R
Sonochemical synthesis of library benzodiazepines using
highly efficient molecular ionic liquid supported on
Fe‐MCM‐41 nanocomposites as a recyclable catalyst
Vajihe Nejadshafiee1,2
| Hossein Naeimi1
| Mohammad Reza Islami2
1 Department of Organic Chemistry,
Faculty of Chemistry, University of
Kashan, Kashan 87317, I.R., Iran
2 Chemistry Department, Shahid Bahonar
University of Kerman, Kerman 76169,
I.R., Iran
In this study, library substituted benzodiazepines was synthesized using molec-
ular ionic liquid supported on Fe‐MCM‐41 nanocomposites (Fe‐MCM‐41‐IL).
This protocol using ultrasound provided advantages such as rapid, clean con-
version and simplicity in experimental setup that led to rapid generation of
benzodiazepines under mild condition. The catalyst can be easily isolated by
using an external magnetic field and reused in the next reaction up to six cycles
without obvious activity decreasing.
Correspondence
Hossein Naeimi, Department of Organic
Chemistry, Faculty of Chemistry,
University of Kashan, Kashan, 87317, I.R.
Iran.
KEYWORDS
Email: naeimi@kashanu.ac.ir
benzodiazepines, catalyst, Fe‐MCM‐41‐IL nanocomposites, synthesis, ultrasound
Funding information
University of Kashan, Grant/Award
Number: grant no. 159148/73 159148/73
1 | INTRODUCTION
MCRs combine from three up to eight reactants to
furnish products containing structure or substructure of
MCM‐41 structures have hexagonal arrays of uniform
channels, high surface area and pore volume and hydro-
thermal stability that make them as potential heteroge-
neous nanocatalysts to a larger variety of organic
reactions.[1–7] Also, the introduction of metal ingredient
to MCM‐41 leads to catalyst properties enhancement,
which is beneficial to organic reaction. In comparison to
other metals, impregnation of iron species into MCM‐41
is significant benefits for the use of this metal in cataly-
sis because of Lewis acidity, cheap, low in toxicity,
easily accessible, and stability of Fe (III) metal (Fe‐
MCM‐41).[8–12] On the other hands, various organic
groups of functionalizing the surfaces of MCM‐41 have
been investigated recently because surface modification
provides rising of the surface properties for many poten-
tial applications including catalysis.[13–16] The latest
developments in supported ionic liquid systems have
mainly focused on catalytic applications by functional-
ized ionic liquid onto the surface of MCM‐41 framework
(MCM‐41‐IL).[17–19]
all starting materials in one pot, that offers significant
advantages in normal linear synthesis because of its
convergent, flexible, atom efficient nature and reducing
the number of purification steps.[20–23] Over the past
decade, considerable attention has been focused on the
development of new methodologies to MCRs, especially
applicability of nanocatalysts in MCRs.[24–27] Among the
wide varieties of MCRs, the synthesis of benzodiazepine
is a reaction of three component that is considered a pri-
vileged scaffold in medicinal chemistry, bioactive natural
products and many biologically active compounds bear
this core.[28–31]
Benzodiazepine molecules are important substruc-
tures in a number of molecules which exhibit an array
of both pharmaceutical and biological activities.[32] The
various members of the benzodiazepine family have been
used as commercially available in clinical practice for the
management of panxiolytic,[33] antianxiety,[34] anticon-
vulsant,[35] antidepressive sedative, antileishmanial,[36]
and antitumor activity[37,38] as well as inhibitor of
Appl Organometal Chem. 2019;e5072.
wileyonlinelibrary.com/journal/aoc
© 2019 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.5072

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NEJADSHAFIEE ET AL.
mitochondrial F1F0 ATP hydrolase.[39] In recent years,
three‐component synthesis of benzodiazepines have been
developed under different condition such as; thermal,[40]
electroactive[41] and microwave[42] in the presence of
variety heterogeneous catalysts e.g., Pd2(dba)3,[43] CsF cat-
apparatus and are uncorrected. The purity determination
of the substrates and reaction monitoring were accom-
plished by TLC on silica‐gel poly gram SILG/UV 254 plates
(from Merck Company).
alyst,[44] PdCl2(MeCN)2.
[45]
The ultrasound‐synthesized has been increasingly
applied as an efficient tool in promoting chemical trans-
formations and for the rapid generation of combinatorial
chemicals.[46] The reactions carried out under ultrasonic
procedure have been attained with short reaction times,
higher yields, cleaner conversion, improved selectivity,
and mild reaction conditions as compared to the con-
ventional methods.[47–57] It should be noted that although
a number of methods have been reported for the synthe-
sis of benzodiazepines most of the procedures involve
thermal condensation that require high temperature, long
reaction times, and purification steps and tedious workups
such as column chromatography.
2.2 | Preparation of Fe‐MCM‐41
The Fe‐MCM‐41 was prepared through in situ
coprecipitation of Fe (III) on MCM‐41. The experimen-
tal details were as follows: 2.24 g of FeCl3.6H2O was
added to a mixture of 1.0 g of CTAB, 3.5 ml of 2 M
NaOH aqueous solution and 480 ml of deionized water.
Then 5 ml of tetraethyl orthosilicate (TEOS) was subse-
quently dropped into the homogeneous solution under
stirring. After stirring for 2 hr at ambient temperature,
the product was separated by filtration, washed with
deionized water, and dried at 100 °C for 6 hr. The solid
product was calcined at 550 °C for 6 hr to obtain Fe‐
MCM‐41 structure.
The present study has been developed the Fe‐MCM‐
41‐IL as a nanocatalyst and recyclable catalyst for synthe-
sis of benzodiazepine products in higher yields under
mild conditions and ultrasound irradiation.
2.3 | Preparation of ionic liquid
To prepare the ionic liquid, the β‐hydroxy‐1,2,3‐triazole
was prepared according to the literature procedures.[58]
Briefly, 3‐chloropropyltrimethoxysilane (12.0ml, 50mmol)
was added to a solution of β‐hydroxy‐1,2,3‐triazole (3.4 g,
50 mmol) in dry toluene (50 ml), and the mixture was
refluxed overnight under a nitrogen atmosphere. Then,
the 1,4‐butanesultone was added to the reaction mixture
and stirred at room temperature for 8 hr to produce the
zwitter ionic triazolene ammonium salt. Conc. H2SO4
(0.54 ml, 10 mmol) was added drop wise into the solution
of the above residue in ethanol (30 ml) over 30 min and the
final mixture was stirred at 50 °C for another 8 hr. The
final mixture was evaporated under reduced pressure to
give the ionic liquid as a viscous yellow liquid.
2 | EXPERIMENTAL
2.1 | Materials and apparatus
All chemicals were purchased from Fluka, Merck and
Aldrich chemical companies. FT‐IR spectra were obtained
as KBr pellets on a Perkin‐Elmer 781 spectrophotometer
and on an impact 400 Nicolet FT‐IR spectrophotometer.
1H NMR and 13C NMR were recorded in CDCl3 and
DMSO‐d6 solvents on a Bruker DRX‐400 spectrometer
with tetramethylsilane as internal reference. The XRD
patterns were recorded on an X‐ray diffractometer (Bruker,
D8 ADV ANCE, Germany) using a Cu‐Ka radiation
(λ = 0.154056 nm) in the range 2θ = 0.5–5°. The N2
adsorption/desorption analysis (BET) was performed at
−196 °C using an automated gas adsorption analyzer
(Tristar 3000, Micromeritics). The surface morphology of
the supported catalyst was studied by transmission
electron microscopy (TEM), with an accelerating voltage
of 300 kV (CM30 300 kV). Elemental analysis were carried
out using a Joel SEM instrument (model‐ VEGA/TESCAN)
combined with an INCA instrument for energy dis-
persive X‐ray spectroscopy scanning electron microscopy
(EDS), with scanning electron electrode at 15 kV. The
magnetic property of the catalyst was studied by vibrat-
ing sample magnetometer (VSM, Meghnatis Daghigh
Kavir Company, Kashan, Iran). Melting points are deter-
mined in open capillaries using an Electrothermal Mk3
2.4 | Modification of Fe‐MCM‐41 with
ionic liquid
For immobilization of IL onto Fe‐MCM‐41 nanoparticles,
the solution IL (0.3 g) was diluted with dry CHCl3 and
was then added slowly to a suspension of 1 g hydrated
Fe‐MCM‐41 nanoparticles in dry CHCl3 (180 mL), under
argon atmosphere. The resulting mixture was refluxed for
24 hr. After cooling, the solid materials were filtered off
and the residue was washed with CHCl3 and then dried
in oven at 90 °C overnight to give IL matrix immobilized
on Fe‐MCM‐41 named as Fe‐MCM‐41‐IL.

NEJADSHAFIEE ET AL.
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2.5 | Typical procedure for synthesis of
benzodiazepines
The o‐phenylenediamine (1 mmol), tetronic acid (1 mmol),
aldehydes (1 mmol) and 15 mg of Fe‐MCM‐41‐IL in H2O
(5 ml) were irradiated at 40 W in an ultrasonic probe. After
sonication at ambient temperature until completion of the
reaction (5–10 min), the catalyst was separated mag-
netically from the product solution and used for subse-
quent cycles after washing and drying under vacuum.
Then the products were further recrystallized by 50%
EtOH to give pure product (FT‐IR, 1H NMR and 13C
NMR of products see the Supporting Information).
2.6 | 4‐(1‐Oxo‐3,4,9,10‐tetrahydro‐1H‐2‐oxa‐
4,9‐diazabenzo[f]azulen‐10‐yl)‐benzonitrile
(4a)
SCHEME 1 Different steps for synthesis of Fe‐MCM‐41‐IL.
Pale white solid, mp: 280–282 °C; IR (KBr): 3419, 3060,
2926, 1730, 1626, 1530, 1394, 1334, 1280, 1161, 1039,
745 cm−1,1H NMR(400 MHz, DMSO‐d6) (σ, ppm): 9.84
(s, 1H, NH),7.28–7.09 (m, 5H, ArH), 6.72 (d, J¼ 8.0 Hz,
1H, ArH), 6.70–6.68 (m, 2H, ArH), 6.57 (d, J¼ 7.9 Hz,
1H, ArH), 6.07 (d, 1H, NH), 5.06 (d, J¼ 4 Hz, 1H, CH),
5.01 (dd, J¼ 5.2 Hz, 2H, CH2); 13C NMR (100 MHz,
DMSO‐d6) (σ, ppm): 172.7, 158.6, 143.7, 137.2, 127.8,
127.0, 126.4, 122.7, 120.5, 120.2, 119.4, 96.6, 65.9, 57.2.
As shown in Figure 2, from the TEM images, the well‐
ordered pore arrangements and the incorporation of iron
in the mesoporous silicate framework were visible. Mean-
while the long‐rang order and mesoporous structure
arrays were not disturbed significantly after Fe doping.
The Fe and Si contents in Fe‐MCM‐41 were deter-
mined using X‐ray fluorescence analysis (XRF) and their
results was shown that the weight percentages of Si and
Fe were 33.63 wt.%, 9.03 wt.%, respectively. The sup-
ported ionic liquid Fe‐MCM‐41‐IL was further confirmed
by energy dispersive spectrometer (EDS) (Figure 3). The
obtained results by EDS were as follows (%): C, 5.40; N,
5.25; Si, 17.38; O, 61.32; S, 6.92; Fe, 3.72.
3 | RESULTS AND DISCUSSION
3.1 | Synthesis and characterization
The preparation procedures adopted for obtaining Fe‐
MCM‐41‐IL with its structural formulation is given in
Scheme 1.
The N2 adsorption–desorption isotherms are necessary
to ascertain the manner in which the pore parameters
(namely, diameter, pore volume, surface area, etc.) change
in Fe‐MCM‐41 matrixes containing loadings of the Fe‐
MCM‐41‐IL. The N2 adsorption and desorption isotherms
are given in Figure 1.
From Figure 1, it could be seen that the N2 sorption
isotherms exhibited a type‐II‐like behavior and capillary
condensation at relative pressures of 0.3 < P/P0 < 0.5,
which was the characteristic of mesoporous materials.[59]
The total pore volumes, sizes and surface areas of Fe‐
MCM‐41 and Fe‐MCM‐41‐IL are given in Table 1.
It could be concluded from Table 1, that introduction
of ionic liquid significantly affected the surface area and
pore volume of the support and there was a negligible
change in pore size and volume after grafting process.
FIGURE 1 N2 adsorption–desorption isotherms of Fe‐MCM‐41
and Fe‐MCM‐41‐IL

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NEJADSHAFIEE ET AL.
TABLE 1 Pore volume, surface area, and average pore diameter
of Fe‐MCM‐41 and Fe‐MCM‐41‐IL
3.2 | Optimization of the reaction
Initially, we studied the optimization of the reaction con-
ditions using o‐phenyldiamine (1 mmol), tetronic acid
(1 mmol), and aldehydes (1 mmol) as model substrates.
However different set of reaction conditions were screened
under ultrasonic irradiation, amount of Fe‐MCM‐41‐IL
catalyst and different catalysts in various solvents, accord-
ing to Table 2.
When changing the amount of catalyst, the reaction
proceeded rapidly (within 5 min) to give the desired prod-
uct in 93% under neat conditions.
Surface areaa Pore Sizeb Pore Volumec
Sample
(m2 g−1
)
(nm)
(cm3 g−1
)
Fe‐MCM‐41
307.98
8.42
8.25
0.42
0.38
Fe‐MCM‐41‐IL 225
aCalculated by the BET model.
bCalculated by the BJH model from the desorption isotherm.
cTotal pore volume at P/P0 = 0.99.
In order to evaluate the efficiency of sonochemical
synthetic method and also catalytic activity of Fe‐MCM‐
41‐IL, the model reaction was checked in the presence
of different amounts of Fe‐MCM‐41‐IL at various ultra-
sound times and solvents (Table 1, entries 2–8). Also, in
a control experiment where a similar model reaction
was carried out under ultrasound irradiation without
catalyst (entry 1) and stirring at room temperature (entry
9), the desired product was isolated in lower yield and
higher reaction time and this study confirmed that the
reaction was accelerated significantly under ultrasonic
The thermal stability of the Fe‐MCM‐41‐IL was inves-
tigated through TGA, shown in Figure 4a. The TGA ther-
mogram of Fe‐MCM‐41‐IL show two peaks, namely, (i)
25–130 °C corresponding to adsorbed water (1.6%), (ii)
neat IL started to decompose at 140 °C and completely
decomposed at 550 °C (7.5%) (iii). The results obtained
from TGA analysis confirmed presence of IL supporting
onto MCM‐41‐IL.
The FT‐IR spectra, XRD and VSM curve of Fe‐MCM‐
41 matrix and IL were provided and reported in
Supporting Information.
FIGURE 2 Typical TEM images of a)
Fe‐MCM‐41 and b) Fe‐MCM‐41‐IL
FIGURE 3 EDS pattern of Fe‐MCM‐41‐
IL

NEJADSHAFIEE ET AL.
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FIGURE 4 TGA curves of the Fe‐
MCM‐41‐IL and recycled Fe‐MCM‐41‐IL
TABLE 2 Effect of catalyst amount on the reactiona
improving in the synthesis of benzodiazepines using Fe‐
MCM‐41 to MCM‐41 catalyst. On the other hand, the
incorporation of iron in the MCM‐41 provided magnetic
properties for the catalyst. Therefore, the Fe‐MCM‐41 cat-
alyst was able to be recycled simply via attaching an
external magnet after completion of the reaction.
These results demonstrated a significant improvement
of the reaction outcome through the effect of ultrasound
and catalyst. Thus the best yields were observed when
the reaction was carried out using 15 mg of the catalyst
in H2O under ultrasonic irradiation. However, the combi-
nation of the prepared Fe‐MCM‐41‐IL nanocomposite
with an ultrasonic probe was supportive for enhancing
the sonocatalytic synthesis efficiency.
With the obtained optimal conditions, a synthesis of
a small library of substituted benzodiazepines was then
carried out using 1:1:1 molar ratio of o‐phenyldiamine
tetronic acid and aldehyde derivatives containing
electron‐donating as well as electron‐withdrawing groups,
Fe‐MCM‐41‐IL catalyst under ultrasound irradiation
(Table 3).
Catalyst
Method
Entry (amount, mg)
Solvent (time, min)
yield
1
‐
H2O
H2O
sonication (30) 50
sonication (10) 68
2
Fe‐MCM‐41‐IL (5)
3
Fe‐MCM‐41‐IL (10) H2O
Fe‐MCM‐41‐IL (15) H2O
Fe‐MCM‐41‐IL (20) H2O
Fe‐MCM‐41‐IL (15) THF
Fe‐MCM‐41‐IL (15) CH3N
Fe‐MCM‐41‐IL (15) EtOH
Fe‐MCM‐41‐IL (15) H2O
sonication (7)
sonication (5)
sonication (5)
sonication (5)
sonication (5)
sonication (5)
stirring (60)
82
93
93
55
75
80
45
61
40
4
5
6
7
8
9
10
11
Fe‐MCM‐41 (15)
MCM‐41 (15)
H2O
H2O
sonication (5)
sonication (5)
The electron‐deficient aldehydes were found to be
more effective substrate relative to the electron‐rich alde-
hydes. The reaction times of aldehydes with electron‐rich
groups were longer than those of with electron withdraw-
ing groups, thus these groups gave the benzodiazepine
products in lower yields.
aReaction condition: o‐phenyldiamine (1 mmol), tetronic acid (1 mmol),
benzaldehyde (1 mmol), catalyst (Fe‐MCM‐41‐IL), solvent (5 ml).
method. This can be due to an increase the dispersion of
nanocomposite (catalyst) into the bulk of sample that
cause increasing mass transfer between the immiscible
reactants during ultrasound irradiation.
The proposed mechanism of benzodiazepines synthe-
sis by Fe‐MCM‐41‐IL is depicted in Scheme 2.
Also for more understanding the catalytic performance
of Fe‐MCM‐41‐IL, the Fe‐MCM‐41 and MCM‐41 were
tested as catalyst in this reaction model (entries 10 and
11). These results confirmed that the IL supported onto
Fe‐MCM‐41 provided a proton source in all steps of the
synthesis of benzodiazepines. Also, the incorporation of
iron into MCM‐41 generated acid sites[60] that led to
After the protonation of tetronic acid by Fe‐MCM‐41‐
IL catalyst, an amino group of o‐phenylenediamine would
be added and affording enaminone intermediate (I). In a
subsequent step, the condensation of aldehyde and
intermediate (I) would give intermediate (II), which
after condensation would obtain main product through
intramolecular cyclization.

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NEJADSHAFIEE ET AL.
TABLE 3 Sonosynthesis of benzodiazepinesa
Time
(min)
Entry
Aldehydes
Products
Yield b
1
5
93
(4a)
(4b)
2
3
10
91
89
10
10
(4c)
4
90
(4d)
5
6
7
8
5
5
5
5
89
90
92
(4e)
(4f)
(4 g)
97
(Continues)

NEJADSHAFIEE ET AL.
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TABLE 3 (Continued)
Time
(min)
Entry
Aldehydes
Products
Yield b
(4 h)
9
5
5
95
90
(4i)
10
(4j)
11
10
90
(4 k)
aReaction condition: o‐phenyldiamine (1 mmol) tetronic acid (1 mmol), aldehydes (1 mmol), catalyst (Fe‐MCM‐41‐IL, 15 mg), water (5 ml), 5–10 min
sonication.
bIsolated yields.
Nevertheless, these yields with the improvement
induced by ultrasound were greater than those obtained
using other reported methods where the reactions were
performed at high temperatures using significantly longer
times.[41,42]
filtrate was allowed to react up to 5 min in absence of
catalyst. After up to 5 min, the solid product was
obtained with low yield (20%) that can be due to exis-
tence ultrasound irradiation. Also, to confirm stability
of Fe‐MCM‐41‐IL catalyst, the IL leaching was studied.
The IL content after catalyst recycling was determined
by TGA and FT‐IR analysis. In TGA analysis, the IL
amount of recyclable catalyst was with negligible
decrease approximately 0.34% to fresh catalyst (7.5%
reducing to 7.16%, Figure 4b). On the basis of these
results, it can be concluded that there is slight leaching
of IL species from the support MCM‐41. The FT‐IR
spectrum of recycled Fe‐MCM‐41‐IL catalyst is shown
in the Figure S1c. The FT‐IR spectrum of recycled Fe‐
MCM‐41‐IL is similar to Fe‐MCM‐41‐IL. So the presence
of IL in the framework after reuse of the catalyst and
stability of catalyst was confirmed.
3.2.1 | Heterogeneity test
Any leaching of the active species from the support
makes the catalyst unattractive, and hence, it is
worthwhile to understand the stability of the Fe‐MCM‐
41‐IL, the leaching of IL from the MCM‐41 surface
was studied. Heterogeneity experiment was carried out
by filtering the catalyst and the reaction mixture under
ultrasound irradiation after 2.5 min the solid product
was obtained as product 4a in 47% yield. Then, the

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NEJADSHAFIEE ET AL.
SCHEME 2 Proposed mechanism for
sono‐synthesis of benzodiazepines using
Fe‐MCM‐41‐IL catalyst.
the affinity between reactants and catalyst compared to
conventional synthetic techniques.
3.2.2 | Comparative with other reported
methods
A
comparative study for the reaction of o‐
3.2.3 | Recycling of catalyst
phenylendiamine, tetronic acid and aldehydes with
other reported methods was summarized in Table 4.
The results exhibited the significant improvements in
the reaction condition of present work with previous
studies. It was noteworthy that higher yield of benzodi-
azepines using Fe‐MCM‐41‐IL catalyst along with other
parameters such as short reaction time, lower catalyst
dosage and usage recyclable and heterogeneous catalyst
made it more suitable method than the other reported
methods for synthesis of benzodiazepines. In addition to,
ultrasound‐assisted is a highly efficient tool for modifying
Due to the additional advantage of solid catalyst, the
recovering of catalyst Fe‐MCM‐41‐IL was explored.
Therefore, the catalyst could be magnetically recovered
by employing an external magnet after completion the
reaction and washed with water, dried under vacuum
and reused in a subsequent reaction. The reaction scale
was amplified 6 cycles to ensure that the catalyst of good
quality was available for us to perform several recycling
reactions. The recycling results of Fe‐MCM‐41‐IL are re-
flected in Figure 5.
TABLE 4 Synthesis of benzodiazepines under different conditionsa
Entry
Catalyst
Catalyst amount
Solvent
t (°C)
T (min)
Yield (%)
Ref.
1
2
3
4
HOAc
0.1
H2O
150/MW
78/Reflux
r.t
15
360
35
85
73
95
97
42
CF3COOH
Fe‐MCM‐41‐IL
Fe‐MCM‐41‐IL
2 Drops
60 mg
15 mg
EtOH
EtOH
H2O
41
61
r.t/U.S
5
this work
aReaction condition: o‐phenyldiamine, tetronic acid, aldehydes.

NEJADSHAFIEE ET AL.
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Fe‐MCM‐41‐IL as nanocatalyst. The use of this method
compared to heating method was found to extremely
simplify and green both the experimental setup and the
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Vajihe Nejadshafiee
8967
Hossein Naeimi https://orcid.org/0000-0002-9627-596X
https://orcid.org/0000-0002-2722-
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How to cite this article: Nejadshafiee V, Naeimi
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