Silica-supported NiO nanocomposites prepared: Via a sol-gel technique and their excellent catalytic performance for one-pot multicomponent synthesis of benzodiazepine derivatives under microwave irradiation

Article abstract of DOI:10.1039/c6nj04013f

Heterogeneous and versatile NiO-SiO₂ NCs were synthesized by a sol-gel technique and used as a catalyst for the one-pot multicomponent synthesis of benzodiazepine derivatives (4a-u) from a mixture of o-phenylenediamine, aromatic aldehydes and d

Full text of DOI:10.1039/c6nj04013f

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PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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Silica supported NiO nanocomposite prepared via sol-gel
technique and its excellent catalytic performance for one-pot
multicomponent synthesis of benzodiazepine derivatives under
microwave irradiation
Zeba Nasira†**, Abad Alia†, Mohammad Shakira, Rizwan Wahabb, Shamsuzzamana,
Lutfullaha*
aDepartment of Chemistry, Aligarh Muslim University, Aligarh 202 002, UP, India
bDepartment of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi
Arabia
Abstract
A heterogeneous versatile NiOꢀSiO2 NCs were synthesized by a solꢀgel technique and used
as a catalyst for the synthesis of oneꢀpot multicomponent benzodiazepine derivatives (4a-u)
from a mixture of oꢀphenylenediamine, aromatic aldehydes and dimedone under microwave
irradiation. Tetraethyl orthosilicate (TEOS) was used as a source of SiO2 for the creation of
NiOꢀSiO2 NCs. This catalytic protocol has many advantages such as simple work up,
inexpensive precursors, short reaction time, high yield and high surface area. The structure
and morphology of the prepared nanocatalyst was characterized by using elemental analysis,
scanning electron microscopy (SEM), transmission electron microscopy (TEM), Xꢀray
diffraction (XRD), energyꢀdispersive Xꢀray spectroscopy (EDAX) and Fourier transform
1
infrared (FTIR). H NMR, 13C NMR and MS analyses were performed for the confirmation
of the synthesized compounds (4a-u). Moreover, the remarkable catalytic properties of NiOꢀ
SiO2 NCs permit easy separation of the catalyst from the reaction mixture without significant
loss of catalytic activity.
Keywords: NiOꢀSiO2 NCs, Benzodiazepine, Microwave, Heterogenous catalyst, TEOS.
*Corresponding author, **Corresponding author, Eꢀmail address: lutfullah786@gmail.com; phone no
+919319084391, zeba.nasir1@gmail.com; phone no +919458470894.
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†These authors contributed equally; Eꢀmail address: zeba.nasir1@gail.com; abadchem12@gmail.com; phone
no +919456063243.
1. Introduction
Metal oxide based nanocatalyst have attracted much attention in the fields of catalysis,
separation, optoelectronics, active adsorbents for gases, magnetism, and microelectronics
owing to their unique physical and chemical properties.1–5 Catalysis is becoming a strategic
field of science because it represents a new way to meet the challenges of energy and
sustainability. These challenges are becoming the main concerns of the global vision of
societal challenges and world economy. The societal pressure has been at the origin of the
concept of nanoscience, which is an exponentially growing research field in modern science
that involves the synthesis and application of nanoparticles of different sizes and shapes.6–9
The exciting prospect of nanoscience is its potential use in almost any conceivable domain.
Every field from medicine and electronics to manufacturing and fashion stand to be
benefitted from advances in nanotechnology.10,11 Though nanoscale technology is
multifaceted in its application, the use of nanomaterial as catalyst is perhaps the most
intriguing. Further, the nanomaterial catalyzed reactions provide the advantages of high atom
efficiency, simplified isolation of product, easy recovery and recyclability of the catalyst.12–16
Benzodiazepines and their polycyclic derivatives are a very important class of bioactive
compounds. They are finding numerous new applications and are widely used as
anticonvulsant, antiꢀinflammatory, analgesic, hypnotic, sedative, and antidepressive agents.17–
19 Benzodiazepines are also valuable intermediates for the synthesis of fused ring compounds
such as triazoloꢀ, oxadiazoloꢀ, oxazinoꢀ, and furanoꢀbenzodiazepines.20–22 Due to their wide
range of pharmacological activity and industrial applications, the development of mild and
efficient protocols for their preparation continues to be a challenging endeavour in the
synthetic organic chemistry.19,23–36
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However, a large number of the modified methods reported in the literature, suffer from
several drawbacks such as the use of a large amount of catalysts, unsatisfactory product
yields and critical product isolation procedures. These disadvantages require a development
of an efficient and practically useful process of preparation.37 Generally, benzodiazepines are
synthesized by the condensation of oꢀphenylenediamines with α,βꢀunsaturated carbonyl
compounds, βꢀhaloketones or ketones. Many reagents have been reported in the literature for
this condensation including Fe(ClO4)3.XH2O,38 Er(OTf)3,39 PPA,40 NaBH4,24 MgO/POCl3,25
Yb (OTf)3,26, InBr3,30 and CH3COOH under microwave conditions.27 Silica composite
materials containing different metal oxide particles like ZrO2,41 ZnO,42,43 TiO2,44,45 Fe3O4,46
NiO,47,48 and CuO,49–54 present a variety of interesting magnetic, electric, and catalytic
properties, and have attracted considerable attention.
As a part of our research program in the field of nanomaterial’s,55–61 herein, we report first
time to the best of our knowledge silica supported NiO nanocomposites (NiOꢀSiO2 NCs)
used as a nanocatalyst for the synthesis of benzodiazepines. The NiOꢀSiO2 NCs has emerged
as a promising heterogeneous solid catalyst for various organic transformations.62,63 The
catalyst possesses inherent environmentally benevolent properties such as nonꢀtoxicity,
biocompatibility, physiological inertness, recyclability, inexpensiveness and thermal stability.
The catalyst was prepared by employing solꢀgel technique and the formation of NiOꢀSiO2
NCs was evaluated by FTꢀIR, HRTEM, XRD and SEMꢀEDX analysis.
2. Experimental
2.1. Materials and methods
All the chemicals and reagents were purchased from Merck and SigmaꢀAldrich (India) as
‘synthesis grade’ and used without further purification. The microwave synthesis was
performed in Anton Paar, Monowave 300 microwave synthesizer. Melting points were
determined on a Biogen digital auto melting point apparatus. The IR spectra were recorded
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on KBr pellets with Perkin Elmer FTꢀIR Spectrometer spectrum Two and values are given in
1
cmꢀ1. H and 13C NMR spectra were run in DMSOꢀd
6
/CDCl
3
on a Bruker AvanceꢀII 400
1
13
NMR Spectrometer (operating at 400 MHz for H and at 100 MHz for C NMR) with TMS
as an internal standard and values are given in parts per million (ppm) (δ). Mass spectra were
recorded on a Waters, Micromass QꢀTOF micro YB361, UK. Elemental analysis of all the
new compounds were recorded on Perkin Elmer 2400 CHN Elemental Analyzer. XRD of the
catalyst were recorded in the 2θ range of 20ꢀ80o with a scan rate of 4.0o minꢀ1 on a Shimadzuꢀ
6100 Xꢀray diffractometer with Niꢀfiltered Cu Kα radiation at a wavelength of 1.54060 Å.
The SEMꢀEDX analysis was obtained using a JEOL (JSMꢀ6510) instrument. HRTEM
micrographs were recorded by JEOL TEM (JEM 2100F) instrument. Thin layer
chromatography (TLC) glass plates (20×5 cm) were coated with silica gel G (Merck) using
benzeneꢀacetone (8:2) mixture as mobile phase and exposed to iodine vapors to check the
homogeneity as well as the progress of the reaction. Sodium sulfate (anhydrous) was used as
a drying agent.
2.2. Preparation of silica supported nickel oxide nanocomposites (NiO-SiO2 NCs)
NiOꢀSiO2 NCs were synthesized via a solꢀgel technique. For the synthesis of NiOꢀSiO2 NCs,
Ni(NO3)2.6H2O is used as a precursor. 20 mL TEOS was mixed with ethyl alcohol
(C2H5OH), ultrapure water (H2O) and nitric acid (HNO3) under vigorous stirring for 1 h to
form a homogeneous solution. The overall molar ratio of TEOS: C2H5OH: H2O: HNO3 was
1: 4: 8: 0.02. An aqueous solution of Ni(NO3)2.6H2O (0.2 M in 20 mL of H2O) was added
into the above solution under vigorous stirring for 60 min. The prepared samples were aged
for 24 h. Finally, the samples were evaporated and dried at 80°C, followed by calcination at
400 °C for 3 h in air.
2.3. General procedure for the synthesis of benzodiazepine derivatives (4a-u) under
microwave irradiation
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A mixture of oꢀphenylenediamine 1 (1 mmol, 0.108 g), dimedone 2 (1 mmol, 0.140 g),
aromatic aldehydes 3a-u (1 mmol) and NiOꢀSiO2 NCs (0.05 g) in EtOH (5 mL) was taken in
a G30 vial and irradiated using microwaves with continuous stirring at 70 °C for 20ꢀ25 min.
After completion of reaction (monitored by TLC for the purity), the reaction mixture was
allowed to cool at room temperature and the catalyst was separated from the reaction mixture
by filtration, and the residue was washed with ethanol to give benzodiazepine derivatives 4a-
u.64 The recovered catalyst was reused for subsequent cycles without a significant loss in
yield.
3. Results and discussion
3.1. Characterization of catalyst (NiO-SiO2 NCs)
To obtain a better understanding of the formation and evolution of nanoparticles (NPs) in
silica matrix, FTIR analysis of SiO2 and NiOꢀSiO2 NCs are carried out. For silica (SiO2), the
major characteristic peaks were broad asymmetric SiꢀOꢀSi stretching from 1200 to 1000 cmꢀ1
and symmetric SiꢀOꢀSi stretching and bending modes lie near 809 and 468 cmꢀ1, respectively
(Fig. 1b). The broad band at 3450 cmꢀ1 was assigned to OH stretching of free silanol groups
of silica moiety. For FTIR spectra of NiOꢀSiO2 NCs, the dominant peak at around the 1090
cmꢀ1 together with less pronounced bands at 801cmꢀ1, conforming to the vibration absorption
of SiꢀOꢀSi groups, implying that the sample is mainly composed of silica network (Fig. 1a).
In addition, band at 466 cmꢀ1 is assigned to the stretching vibration of NiꢀO bond65
overlapping with the SiꢀO band at 468 cmꢀ1. NiꢀOꢀNi stretching mode is observed at 667 cmꢀ
1.66 A weak band at 1637 and 3436 cmꢀ1 is assigned to the bending and stretching absorption
of OH groups, respectively.52 Peaks at 2854 and 2925 cmꢀ1 are ascribed to stretching
vibration of CꢀH bond. The absorption band at 973 cmꢀ1 in SiO2 reveals the presence of nonꢀ
bonded oxygen Si–Oꢀ or SiꢀOH67 stretching vibration is shifted to 968 cmꢀ1 in NiOꢀSiO2 NCs
that argues for formation of the NiꢀOꢀSi bond.68 However, some researchers47,69 also
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attribute this band to vibration of the SiꢀOH bond. Considerably, the band in the range 1240ꢀ
1480 cmꢀ1 assigned to the nitrate vibration which are sorely decreased at higher temperature
showing the evolution of nitrogen compounds possibly in the form of nitrogen oxide.70 Thus,
it is assumed that the NiO NPs in silica matrix are prepared by the pyrogenic decomposition
of nitrate.
Figure 1. FTIR spectra of (a) NiOꢀSiO2 NCs and (b) SiO2.
Formation of the catalytic system (NiOꢀSiO2 NCs) was further confirmed by the powder
XRD analysis (Fig. 2). XRD patterns showed reflection planes: (111), (200), (220), (311) and
(222) comparably close with the reflection planes of NiO. The XRD pattern also show a broad
hump and tailing centered at around 23.1° which is characteristic of nonꢀcrystalline
(amorphous) silica. The patterns of NiOꢀSiO2 NCs display characteristic NiO peaks centred
at 2θ = 37.17, 43.27 and 62.90.71,72 All the peaks in the diffraction pattern have been indexed
and refinement of their lattice parameter was done by using Powder X software. The
variation in FWHM is in agreement with the crystallite size reckoned by DebyeꢀSherrer’s
Formula:
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0.9 ꢂ
ꢀ ꢁ
ꢃꢄꢅꢆꢇ
Where, λ is the wavelength of Cu Kα radiation, D is the particle size, β is the full width half
maximum intensity and θ is the position of the peak.
Figure 2. XRD patterns of NiOꢀSiO2 NCs.
The SEM images of catalyst (NiOꢀSiO2 NCs) before and after catalytic reaction were taken
in Fig. 3(a) and 3(b). The SEM images revealed that the particles polydisperse in nature and
show relatively diffused patterns. The successful incorporation of nickel oxide was also
confirmed by EDX analysis (Fig. 4). EDX spectrum showed the presence of Ni in addition to
O and Si elements.
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Figure 3. SEM images of (a) freshly synthesized NiOꢀSiO2 NCs and (b) NiOꢀSiO2 NCs after
seven catalytic cycles.
Figure 4. EDX spectrum of NiOꢀSiO2 NCs.
o
Fig. 5(a) and 5(b), shows HRTEM images of catalyst (NiOꢀSiO2 NCs) calcined at 400 C.
The HRTEM images indicates clearly that the particle size is homogeneous and moderately
small. From these images, it can be seen remarkably that the darker NiO NPs are surrounded
by the lighter amorphous silica layer. The average particle size is around 20 nm in diameter
which are in good agreement with the calculated results of XRD. Fig. S1 and S2
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(Supplementary information), presents the particle size distribution histogram of Fig. 5(a)
and 5(b), respectively.
Figure 5. HRTEM images of NiOꢀSiO2 NCs (a, b).
Furthermore, SAED (selected area electron diffraction) pattern in Fig. S3 (see supplementary
file), clearly shown the concentric circles composed of bright dots in NiOꢀSiO2 NCs reveal
the polycrystalline structure of the NiO NPs and the continuous rings shows amorphous
nature of silica. The diffraction rings in Fig. S3 (Supplementary information), correspond
well with the (111), (200), (220) and (311) planes of NiO NPs. Thus, SAED pattern supports
the presence of both phases, NiO and SiO2, within the prepared sample.
3.2. Optimization of reaction conditions
In order to explore the optimum conditions, we investigate the solvent effect, catalyst
loading, effect of temperature, reaction time and recyclability of the catalyst on the model
reaction 4e. Initially, we optimized the catalytic efficiency of different catalysts such as
FeCl3, ZnO, NiO NPs, Fe3O4, ZnS, ZnCl2, MgO, CuCl2, NiCl2 and NiOꢀSiO2 NCs (Table 1,
entry 1-10) applied for oneꢀpot three component reaction of oꢀphenylenediamine 1 (1 mmol,
0.108 g), dimedone 2 (1 mmol, 0.140 g) and 4ꢀ(dimethylamino)benzaldehyde 3e (1 mmol) in
o
EtOH at 70 C as a model reaction (Table 1). Among them NiOꢀSiO2 NCs showed best
catalytic activity when compared to other catalysts. Further, to improve the catalytic efficacy
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of NiOꢀSiO2 NCs, the model reaction 4e was examined at different concentrations (0.01ꢀ0.06
g) (Table1, entries 11-16) of the NiOꢀSiO2 nanocatalyst under the microwave. Firstly, we
have tested the model reaction 4e with 0.01 g weight of the NiOꢀSiO2 NCs to obtain 65 %
yield of the product in 40 min (Table 1, entry 11). By increasing the loading of the NiOꢀSiO2
NCs from 0.02 to 0.05 g, improved in yield and reaction rate increased up to 70 % to 98 %
with prominent fall in reaction time from 35 to 10 min (Table 1, entry 12-15), respectively. It
is significant to note that no progress was observed in the case of reaction rate and yield by
increasing the amount of NiOꢀSiO2 NCs beyond 0.05 g (Table 1, entry 16). Based on these
outcomes, 0.05 g of the NiOꢀSiO2 NCs is sufficient for the reaction (Scheme 1) (Fig. 6).
Furthermore, we also investigate the catalytic efficiency of pure NiO NPs on the model
reaction 4e under microwave irradiation in the same time and catalyst loading as used in
NiOꢀSiO2 NCs (Table 1, entries 17-22), but the yield of the reaction is very low (46ꢀ63 %)
while in the presence of NiOꢀSiO2 NCs yield is improved because the incorporation of silica
in NiOꢀSiO2 NCs not only increased the specific surface area and providing more
catalytically active sites, but also decreasing the deactivation over time of the catalysts, which
led to a remarkable improvement of the catalytic activity. Thus, the results showed that the
efficiency and the yield of the model reaction in the presence of NiOꢀSiO2 NCs was higher
than those obtained in other catalyst.
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R
H
N
O
O
NH2
NH2
O
O
NiOꢀSiO2 NCs
EtOH,MW
R
N
H
1
2
3a-u
4a-u
F
R
=
N
N
N
F
N
H3C
a
b
c
d
CH3
NO2
e
S
O
S
OH
O2N
Cl
f
g
OCH3
h
i
j
H3CO
H3CO
H3C
Cl
H3CO
Cl
Cl
k
l
m
n
o
Cl
HO
Cl
Cl
OH
HO
p
q
r
s
t
u
Scheme 1. NiOꢀSiO2 NCs catalyzed benzodiazepine reaction.
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Figure 6. Effects of catalyst (NiOꢀSiO2 NCs) dose (0.01ꢀ0.06 g) on the production yield of
benzodiazepine 4e under microwave irradiation.
Table 1. Comparison of the catalytic efficiency of NiOꢀSiO2 NCs with other catalysts 4ea.
Entry
1.
2.
Catalyst
FeCl3
ZnO
Catalyst loading (g) Time (h) b
Yieldc (%)
45
0.05
0.05
21
19
57
NiO NPs
Fe3O4
0.05
0.05
15
17
43
61
3.
4.
ZnS
0.05
12
59
5.
ZnCl2
0.05
13
52
6.
MgO
0.05
10
48
7.
CuCl2
0.05
9
35
8.
NiCl2
0.05
14
26
9.
NiOꢀSiO2 NCs
NiOꢀSiO2 NCs
NiOꢀSiO2 NCs
NiOꢀSiO2 NCs
NiOꢀSiO2 NCs
NiOꢀSiO2 NCs
NiOꢀSiO2 NCs
NiO NPs
NiO NPs
NiO NPs
NiO NPs
NiO NPs
NiO NPs
0.05
4
85
65
70
80
85
98
98
46
51
54
61
63
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
0.01, MW
0.02, MW
0.03, MW
0.04, MW
0.05, MW
0.06, MW
0.01, MW
0.02, MW
0.03, MW
0.04, MW
0.05, MW
0.06, MW
40 min
35 min
30 min
20 min
10 min
10 min
40 min
35 min
30 min
20 min
10 min
10 min
63
aReaction condition: oꢀphenylenediamine 1 (1 mmol, 0.108 g), dimedone 2 (1 mmol, 0.140
g), and 4ꢀ(dimethylamino)benzaldehyde 3e (1 mmol) in the presence of different catalyst in
EtOH at 70 oC. Reaction progress monitored by TLC. cIsolated yield of products.
b
Further, we also screened the model reaction 4e by retaining oꢀphenylenediamine 1 (1 mmol,
0.108 g), dimedone 2 (1 mmol, 0.140 g), and 4ꢀ(dimethylamino)benzaldehyde 3e (1 mmol) in
various solvents and NiOꢀSiO2 NCs used as a catalyst at different temperatures were
displayed in the Table 2. First we accomplished the reaction in EtOH (5 mL) by loading
o
NiOꢀSiO2 NCs (0.05 g) at 50 C for 24 h to obtain the 70 % yield of benzodiazepine 4e
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(Table 2, entry 1). To reduce the reaction time, we executed the reaction at various
o
temperatures such as 60, 65 and 70 C with equal amount of catalyst yielding the
benzodiazepine in 75 %, 80 % and 85% (Table 2, entry 2-4) for 15 h, 10 h and 4 h,
respectively. However, no further enhancement in the yield of product 4e was observed when
the reaction temperature was raised from 70 oC to 80 oC (Table 2, entry 5). Therefore, 70 oC
was chosen as the optimum temperature for the reaction. When the same reaction was carried
out in nꢀHexane, CH2Cl2, CHCl3 and CH3CN as solvents at 70 oC for a period of 15 h, 9 h, 7
h and 6 h, we obtained 75 %, 78 %, 73 % and 79 % yields (Table 2, entry 6, 8-10),
respectively. A moderate yield of 51 % (Table 2, entry 7) was observed with CH3COOH as
o
solvent at 70 C for 19 h. Low yields of 33 %, 35 % and 24% (Table 2, entry 11-13) were
o
obtained when we used DMF, DMSO and MeOH at 70 C for 13 h. In order to further
improve the protocol to make it more energy efficient we introduced microwaves (Anton
Paar, Monowave 300). The use of microwaves enhanced the protocol extraordinarily with
high yield of the product 4e in very short time period in EtOH as solvent (Table 2, entry 14-
17) and no further increment observed from 70 oC to 80 oC under microwave (Table 2, entry
18) same as in conventional methods (Table 2, entry 5). Based on the above results we
suggested that EtOH is the most excellent solvent in comparison with other polar, nonꢀpolar,
o
protic, and aprotic solvents and 70 C as the optimum temperature in the case of NiOꢀSiO2
NCs catalyzed reaction (Scheme 1) (Fig. 7).
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Figure 7. Effects of temperature with 0.05 g of the catalyst (NiOꢀSiO2 NCs) on the
production yield of benzodiazepine 4e under microwave irradiation.
Table 2. Effect of solvent and temperature on the model reaction 4ea.
H3C
N
CH3
CHO
H
N
O
O
NH2
NH2
O
NiOꢀSiO2 NCs
EtOH, MW
N
N
H
H3C
CH3
1
2
3e
4e
Entry
Catalyst
loading (g)
0.05
Solvent
Time (h)
Temp. (oC)
Yieldb (%)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
EtOH
EtOH
EtOH
EtOH
EtOH
24
15
10
4
4
15
19
9
7
6
13
13
13
50
60
65
70
80
70
70
70
70
70
70
70
70
50
60
65
70
80
70
75
80
85
85
75
51
78
73
79
33
35
24
90
91
94
98
98
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
nꢀHexane
CH3COOH
CH2Cl2
CHCl3
CH3CN
DMF
DMSO
MeOH
EtOH, MW
EtOH, MW
EtOH, MW
EtOH, MW
EtOH, MW
55 min
35 min
20 min
10 min
10 min
0.05
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aReaction condition: oꢀphenylenediamine 1 (1 mmol, 0.108 g), dimedone 2 (1 mmol, 0.140
g), and 4ꢀ(dimethylamino)benzaldehyde 3e (1 mmol) in the presence of NiOꢀSiO2 NCs (0.05
b
g) in different solvents (5 mL) at various temperatures. Isolated yield of products.
Having identified the optimal reaction conditions, we required to evaluate the scope and
efficiency of the reaction. For this purpose, oꢀphenylenediamine, aromatic aldehydes and
dimedone were chosen to perform the reaction to yield the corresponding benzodiazepines
(4a-u) and the results were displayed in Table 3. With regard to the aromatic aldehydes
containing both electron donating and withdrawing substituents, they can be efficiently
converted into benzodiazepines (4a-u) in high yields as shown in Table 3.
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Table 3. Synthesis of benzodiazepine derivatives (4a-u) in the presence of NiOꢀSiO2 NCs.
Conventional
Method
Microwave
irradiation
Entry
Product
M.p (oC)
Time
(h)
5
Yield Time
Yield
(%)
Observed
Reported
(%)
(min)
81
10
94 245ꢀ247
247ꢀ24873
4a
4.5
4
79
80
15
20
91 232ꢀ235
90 212ꢀ214
230ꢀ23373
216ꢀ21873
4b
4c
5.5
4
77 10
97 255ꢀ257
98 226ꢀ228
260ꢀ26373
228ꢀ23074
4d
4e
85 10
6
5
78 10
96 220ꢀ221
94 226ꢀ227
216ꢀ21874
227ꢀ22974
4f
80 10
4g
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Table 3. (Continued)
Entry
Product
Conventional
Method
Microwave
irradiation
M.p (oC)
Time
(h)
4
Yield Time
Yield
(%)
Observed
Reported
(%)
(min)
76
15
91 273ꢀ275
94 240ꢀ242
92 190ꢀ191
269ꢀ27074
4h
6.5
80
15
243ꢀ24574
196ꢀ19775
4i
4j
5
82 20
5.5
4.5
81 15
96 227ꢀ229
97 224ꢀ226
224ꢀ22675
229ꢀ23176
4k
4l
78 10
5
6
80 10
98 215ꢀ217
95 221ꢀ223
217ꢀ21876
225ꢀ22776
4m
4n
72 15
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Table 3. (Continued)
Entry
Product
Conventional
Method
Microwave
irradiation
M.p (oC)
Observed
Time
Yield Time
Yield
(%)
Reported
235ꢀ23776
(h)
(%)
(min)
6
74
10
98 230ꢀ231
4o
4
79
10
96 241ꢀ243
98 237ꢀ239
239ꢀ24076
230ꢀ23276
4p
4q
4.5
81 15
5
6
77
15
94 255ꢀ257
97 229ꢀ230
256ꢀ25876
4r
4s
75 10
22577
4
82 10
95 197ꢀ199
96 290ꢀ292
201ꢀ20276
287ꢀ28976
4t
5.5
81 10
4u
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1
The structural elucidation of the desired products (4a-u) was confirmed using FTꢀIR, H
NMR, 13C NMR, MS and analytical data (see Supplementary file). The selected diagnostic
bands in the IR spectra of synthesized compounds provide useful information for determining
their structures. The analytical results for C, H and N were within ±0.4% of the theoretical
values. The FTꢀIR spectrum of the synthesized compounds (4a-u) exhibits a broad band at
3302ꢀ3351 and 3210ꢀ3268 cmꢀ1 which were related to the stretching vibrations of amine
protons (2 NH groups). The bands at 1058ꢀ1061, 742ꢀ749, 1612ꢀ1630, 715ꢀ718, and 1159ꢀ
1168 cmꢀ1 confirm the presence of CꢀO, CꢀCl, C=C, CꢀS, CꢀF groups, whereas the strong
bands at 1624ꢀ1642 cmꢀ1 were attributed to the stretching vibrations of carbonyl groups (C=O
stretching). Moreover, the absorption bands at 3071ꢀ3098, 1550–1572, 1372ꢀ1390 cmꢀ1 are
attributed to the aromatic ring in the products 4a-u and the bands in the range 1633ꢀ1636 cmꢀ1
confirm the presence of C=N in compounds 4b-d. Characteristic peaks for the different
functional groups such as methoxy, nitro and hydroxyl etc. have been deliberated in
1
Supplementary file. In their H NMR spectrum, each compound displayed the downfield
singlet at around δ 6.32ꢀ7.99 was credited to aromatic protons, a broad singlet at around δ
5.01ꢀ6.30 and δ 6.98ꢀ8.87 has been ascribed to –NH proton (D2O exchangeable) of
benzodiazepine ring. Similarly, each compound exhibited two singlet bands for the gemꢀ
dimethyl groups at δ 0.94ꢀ1.12 and δ 1.01ꢀ1.26, as well as an AB quartet for the CH2 protons
1
at δ 2.07ꢀ2.24. Moreover, H NMR spectrum of the compounds 4a-u also contained a signal
at δ 2.32ꢀ2.63 for CH2–C=O protons, as well as a signal at δ 5.25ꢀ6.01 for CH proton of
benzodiazepine ring. 13C NMR spectra, displayed a series of signals resonating at around δ
110.8–168.7 which have been assigned to aromatic carbons, peaks resonating at around δ
52.3ꢀ66.1
and δ 133.2ꢀ145.8 corresponds to CꢀCHꢀNH and C=CꢀNH moiety of
benzodiazepine ring, respectively. Similarly signals at δ 193.1ꢀ197.9 have been attributed to
carbonyl group (C=Odimethylcyclohexꢀ2ꢀenone) of compounds 4a-u. Finally, the mass spectral
19

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analysis of the synthesized compounds 4a-u (Fig. L1-L12, Supplementary information)
displayed a molecular ion peak at the appropriate m/z value (Scheme Q1-Q5, Supplementary
information).74,77
Based on the results of the current study, we herein suggest a plausible mechanism in
Scheme 2, for oneꢀpot threeꢀcomponent reaction of aromatic aldehydes, oꢀphenylenediamine
and dimedone catalyzed by NiOꢀSiO2 NCs in EtOH. The proposed mechanism is based on
sequential Michael addition and Knoevenagel cyclization reactions. Initially, NiOꢀSiO2 NCs
activated carbonyl group of dimedone 2 undergo Michael addition reaction with oꢀ
phenylenediamine 1 to form imine intermediate 4. The oxygen atoms of dimedone interact
via lone pairs of electrons with the active sites of the catalyst surface, and the amino groups
of oꢀphenylenediamine attack the carbonyl group of dimedone with elimination of H2O
leading to imine intermediate 4. A 1,3ꢀhydrogen shift then results in the formation of
tautomeric enamine 5.64,76 The NH2 group of enamine intermediate 5 would then react with
the activated carbonyl group of aromatic aldehyde 6 to form the corresponding imine 7,
which would undergo an intramolecular cyclization to give the desired sevenꢀmembered
benzodiazepine ring 4a-u.
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Scheme 2. The plausible reaction mechanism for the synthesis of benzodiazepines 4a-u.
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3.3. Reusability of the catalyst
To establish the heterogeneous character of the catalyst, recycling experiments were carried
out under microwave irradiation using selected model reaction 4e in order to explore the
extent of recyclability of our catalytic system (NiOꢀSiO2 NCs) and reduce the cost of the
process (Scheme 3).
Scheme 3. Schematic representation of reusability of NiOꢀSiO2 NCs for the model reaction
4e.
After the first fresh run with 98% yield, the catalyst was recovered by simple filtration,
o
washed with ethanol/ethylacetate and dried at 155 C for 18 h and reused up to six more run
with a minor loss in catalytic activity. The XRF analysis of the catalyst before (4.32 % w/w
Ni) and after recycling experiments (4.25 % w/w Ni) revealed that the metal concentration
remained unchanged with a very marginal reduction (within the experimental error of XRF
analysis) (Table 4). This indicates that metal is tightly bound to the support and leaching of
Ni(II) does not takes place during the course of reaction. The SEM image (Fig. 3b) of the
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catalyst after 7 runs showed no significant changes in the morphology indicating substantial
retention of the catalytic activity throughout the recycling processes.
Table 4. Composition of NiOꢀSiO2 NCs determined by XRF analysis.
Concentration (% w/w)
Entry
Compound/element
Fresh catalyst
Recycled catalyst
(after 7 runs)
83.22
8.19
SiO2
C
Si
Ni
O
82.51
8.47
3.46
4.32
0.81
0.07
0.13
1.
2.
3.
4.
5.
6.
7.
3.21
4.25
0.68
0.04
Na
others
0.09
4. Conclusion
In summary, a series of benzodiazepine derivatives (4a-u) in excellent yields were
synthesized by using oꢀphenylendiamine (1), dimedone (2), and aromatic aldehydes (3a-u) in
the presence of recyclable and reusable NiOꢀSiO2 NCs under microwave irradiation. The
catalyst does not need special precautions for preparation and can be stored at an ambient
temperature without losing its catalytic activity. This new and efficient one pot threeꢀ
component protocol not only offers use of microwave at low temperature and substantial
yield of products but also affords mild reaction conditions, shorter reaction times, high purity,
operational simplicity, reusability of heterogeneous nanocatalyst, high atom economy and
easy workup. The protocol has several advantages over previously reported methods for the
synthesis of benzodiazepines. The combination of heterogeneous catalysis and microwave
irradiation has made possible development of efficient, rapid, and environmentally friendly
synthetic methodologies in the future. The reusability of this catalyst was high and it can be
reused seven times without any significant decrease from its initial activity. We hope that this
synthetic approach provides a better scope for the synthesis of benzodiazepine analogues and
will be a more practical substitute to the other existing methods.
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Author information
The authors declare no competing financial interest.
Acknowledgments
Zeba Nasir thanks the Chairman, Department of Chemistry, A.M.U., Aligarh, for providing
necessary research facilities. Facilities provided by SAP (DRSꢀII), FIST & PURSE for their
generous research support are gratefully acknowledged. University Sophisticated
Instrumentation Facility (USIF), A.M.U., Aligarh is acknowledged for SEMꢀEDX, HRTEM
analysis and SAIF Chandigarh, for XRD, NMR and MASS analysis. UGC is also gratefully
acknowledged for research fellowship to Zeba Nasir.
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