Microwave-Assisted, solvent free preparation of 1,5-benzodiazepine derivatives using nanomagnetic-supported sulfonic acid as a recyclable and heterogeneous catalyst

Article abstract of DOI:10.3184/174751915X14473291357176

A new preparation of 1,5-benzodiazepine derivatives has been achieved in good to excellent yields by the condensation of o-phenylenediamine with a variety of ketones employing nano-Fe2O3-SO3H as catalyst under microwave irradiation and solvent-free condit

Full text of DOI:10.3184/174751915X14473291357176

694 RESEARCH PAPER
VOL. 39 DECEMBER, 694–697
JOURNAL OF CHEMICAL RESEARCH 2015
Microwave-assisted, solvent free preparation of 1,5-benzodiazepine
derivatives using nanomagnetic-supported sulfonic acid as a recyclable and
heterogeneous catalyst
Ali Amoozadeh*, Masoumeh Malmir, Nadia Koukabi and Somayeh Otokesh
Department of Chemistry, Semnan University, Semnan 3535119111, Iran
A new preparation of 1,5-benzodiazepine derivatives has been achieved in good to excellent yields by the condensation of
o-phenylenediamine with a variety of ketones employing nano-γ-Fe2O –SO H as catalyst under microwave irradiation and solvent-free
conditions. Recyclable nano-γ-Fe O3–SO H provided high reactivity a3nd w3as easily separated from the reaction mixture by using an
external magnet. The advantages2offered3by this method are based on the principles of ‘green chemistry’: a facile and rapid reaction, no
solvent, easy separation of products and good to excellent yields..
Keywords: nanomagnetic-supported sulfonic acid, 1,5-benzodiazepine, solvent-free condition, microwave irradiation
the synthesis of benzodiazepines. Recent developments in organic
The benzodiazepine skeleton represents a significant class of
reactions lead to new eco-benign reaction procedures that save
heterocyclic compounds containing nitrogen which exhibit a
energy and uphold green reaction procedures. Microwave-assisted
number of important therapeutic and pharmacological properties.
solvent free organic reactions show various advantages over
traditional reactions in organic solvents, such reactions are reducing
the load of hazardous organic solvent disposal and improve the rate
and yield of organic reactions.14
Indeed, derivatives of benzodiazepines are one of the best known
classes of drugs, due to the effect upon the neurotransmitter gamma-
aminobutyric acid (GABA), which results in sedative, hypnotic,
anti-anxiety, anticonvulsant and muscle-relaxant action.1 Clobazam
(A) which has been marketed across the world as an anxiolytic
since 1975 and as an anti-covulsant2 since 1984 has also proved
useful in the treatment of epilepsy and anxiety and has also been
approved as a short term adjunctive agent in psychotic disorders
such schizophrenia. Arfendazam (B) has sedative and anxiolytic
effects similar to other benzodiazepine derivatives (Fig. 1).
Diazepines and their derivatives have been used as starting
materials for the preparation of a number of fused ring compounds
such as triazole and oxadiazole derivatives.3 Derivatives of
benzodiazepines are also used as dyes for acrylic fibres in
photography, their distinct electron mobility have been exploited in
layer materials for electron transformation.4 Thus, due to the wide
applications of benzodiazepine derivatives in medicine and industry,
and in organic reactions, there is an imperative need to develop
new methodology for the synthesis of these compounds. Various
methods for the preparation of benzodiazepines are reported in the
literature nine of which5-13 are listed in Table 2. However, many of
these methods have some limitations such as low to poor yields,
tedious work-up procedures, hazardous and expensive reagents and
solvents, and relatively long reaction times. Furthermore, the major
drawback of most of the existing methods is that, the catalysts are
destroyed in work-up procedures and could not be recovered nor
reused. Therefore, there is an essential need for the development of
clean processes and utilisation of eco-friendly and heterogeneous
catalysts which can be simply recycled at the end of reactions for
Magnetic nanoparticles (MNP) have emerged as an alternative to
porous materials and have potential applications in various fields.15,16
These materials have attracted interest owing to their properties as
magnetically recoverable, low toxicity, heterogeneous supports with
a large ratio of surface area to volume. This environmentally benign
and impressive process for catalyst separation has become an
important tool from an economic, safety and environmental point
of view.17-20 Also, surface functionalisation of magnetic particles
is an elegant way to bridge the gap between heterogeneous and
homogeneous catalysis.
In recent years, solid acid catalysts have opened new avenues
and introduced an amazing and efficient system in the field of
green catalysis of organic synthesis due to their environmental
friendliness, ease of handling, non-toxic nature and their
reusability.21-24 Among these, sulfuric acid functionalised magnetite
nanoparticles (nano-γ-Fe2O3–SO3H) has been found to be a
heterogeneous and effective solid acid catalyst for different organic
reactions under environmentally friendly conditions with magnetic
separation techniques.25-27
Following our interest in the catalytic application of solid acid
catalysts,25 we now report an efficient and simple method for
the preparation of 1,5-benzodiazepine derivatives through the
cyclocondensation of o-phenylenediamine or its 4-methyl derivative
with a variety of ketones under solvent free conditions in the
presence of a catalytic amount of nano-γ-Fe2O3–SO3H.
Results and discussion
O
O
O
We describe a simple and efficient preparation of variously
N
N
ʹ
ʹʹ
substituted 1,5-benzodiazepines (3a–o; R, R =alkyl, aryl) from
o-phenylenediamine 1a (1mmol) (or its 4-methyl derivative 1b) and
various α-methylene ketones (2a–o; Rʹ, Rʹʹ =alkyl, aryl) (2.1mmol)
using nano-γ-Fe2O3–SO3H catalyst under solvent-free conditions
(Scheme 1). Two techniques, conventional heating (method A) and
microwave (MW) irradiation (method B) were compared. In order
to find out the optimal thermal conditions, the condensation reaction
between o-phenylenediamine 1a (1 mmol) and acetophenone (2a;
Rʹ= Ph, Rʹʹ=H) (2.1 mmol) to form 1,5-benzodiazepine (3a; Rʹ=
Ph, Rʹʹ =H) (Scheme 1) was chosen as a model reaction. A diverse
l
C
N
l
C
O
O
B
A
Fig.
1 Biologically and pharmaceutically active benzodiazepine
derivatives.
* Correspondent. E-mail: aamozadeh@semnan.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2015 695
'
R
H
NH2
NH2
"
N
O
R
Nano- -Fe O -SO H
γ
2
3
3
"
"
R
R
'
R
R
MW or 90 oC
solvent-free
R
N
'
R
1a, R = H, 1b, R = Me
2a-n (R' , R" = alkyl, aryl)
3a-n (R',R" = alkyl, aryl)
Scheme 1
range of solvent systems, loading of catalysts and temperature were
evaluated. The results are summarised in Table 1. We first used
0.0125 g of catalyst in 1,5-benzodiazepine synthesis and obtained
a yield of 35% (entry 1). When the amount of nano-γ-Fe2O3–SO3H
catalyst was increased from 0.0125 to 0.025 and then to 0.05 g, the
yield of 3a increased to some extent (entries 1–3). Since the yield
of 3a did not show any significant improvement with a further
increment of nano-γ-Fe2O3–SO3H catalyst to 0.07g (entry 4), 0.05
g of catalyst was optimal.
The above experiment was also performed in various solvents
including water, acetonitrile, methanol, ethanol, chloroform and
dimethylsulfoxide (DMSO), but the yields were lower (entries
10–15). Therefore, solvent-free conditions appear to give the best
results.
Finally, in order to study the effect of temperature on the
synthesis of 1,5-benzodiazepines, we carried out the synthesis of 3a
at various temperature and results are summarised in Table 1. When
the reaction was performed at room temperature, only a trace of the
desired product was formed during 2h (entry 6). On the other hand,
at 100 and 110 oC, (entries 8 and 9), the product yield decreased. As
a results, the reaction temperature 90 oC was chosen for subsequent
experiments.
We also carried out synthesis of 3a using various other iron
oxide catalysts to compare the catalytic activity of prepared nano-
γ-Fe2O3–SO3H as catalyst under solvent-free conditions. The results
are shown in Table 2. FeCl2.4H2O, FeCl3.6H2O and bulk-Fe2O3 as
homogeneous catalysts showed very poor yields compared with
nano-γ-Fe2O3–SO3H and all other heterogeneous catalyst (nano-
γ-Fe2O3) used in this study under solvent free reaction condition
(entries 11–14). However, we used 0.05g of bulk-Fe2O3–SO3H to
investigate effect of –SO3H group in synthesis of benzodiazepine,
this reaction showed good performance of respective diazepine
during 2h (entry 15). Also, in order to compare the catalytic
activity of nano-γ-Fe2O3–SO3H, the yields of 1,5-benzodiazepine
using other catalysts recently reported are included in Table 2,
entries 1–9).
From the above observations, it is clear that nano-γ-Fe2O3–SO3H
plays a specific role compared to other catalysts, due to its nano-
active surface and acidic sites
Thus, employing 0.05 g of nano-γ-Fe2O3–SO3H as catalyst
under solvent free condition at 90 °C for the synthesis of
1,5-benzodiazepine derivatives was considered as optimal. Having
optimised the reaction conditions, we applied them to the synthesis
of other 1,5-benzodiazepines. The reaction of o-phenylenediamine
and various substituted ketones, which afforded the corresponding
products 3a–o under two different sets of conditions and the yields
are listed in Table 3. All the products 3a–o are known compounds
and the literature melting points of each are listed in Table 3.
As shown in Table 3 (entries 1–8), in the reaction of
o-phenylenediamines with acetophenones 2a–h the desired
products 3a–h were obtained in good to excellent yields. Note
that, when using cyclic ketones such as cyclopentanone and
Table 2 Comparison of nano-γ-Fe O3–SO3H with other recently reported
acid catalysts in the preparatio2n of 1,5-benzodiazepine (3a; Rʹ=Ph,
Rʹʹ=H) from o-phenylenediamine 1a (1equiv.) and acetophenone (2a; Rʹ=
Ph, Rʹʹ=H) (2.1 equiv.) (Scheme 1)a
Entry Catalyst/g
Conditions
Time/h Yield/%b Ref.
1
2
Hg(OTf)2 (0.5 mol%) EtOH/RT
6.5
12
90
89
5
6
Silver substituted
silicotungstic acid
(10 mol %)
CH3CN/Reflux
Table 1 Effects of amount of catalyst, duration of reaction and solvent
on the yield of 1,5-benzodiazepine (3a; Rʹ=Ph, Rʹʹ=H) prepared from
o-phenylenediamine 1a and acetophenone (2a; Rʹ=Ph, Rʹ=H) (Scheme 1)a
3
4
PhB(OH)2 (20 mol %) CH3CN/Reflux
p-nitrobenzoic acid CH3CN/RT
(0.5 equiv)
12
7
93
90
7
8
Entry
Conditions
Time/h:min Yield/%b
Nano-γ-Fe2O3–SO3H/g
1
2
3
4
5
6
7
8
0.0125
0.025
0.05
0.07
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
Solvent free/90oC
Solvent free/90oC
Solvent free/90oC
Solvent free/90oC
2
2
2
2
35
63
90
85
92
Trace
70
85
80
20
30
40
35
40
65
5
Zinc montmorillonite Solvent free/RT 12
(0.05g)
81
9
6
7
NaClO4 (2 mol%)
2,4.6-trichloro-1,3,5- MeOH/RT
triazine (4 mol%)
Water/RT
3
12
85
99
10
11
Solvent freec/90oC 00:06
8
9
H-MCM-22 Zeolite CH3CN/RT
(0.1 g)
1
86
12
Solvent free/25oC
Solvent free/80oC
Solvent free/100oC
Solvent free/110oC
Reflux /H2O
2
2
2
2
2
2
2
2
2
2
NbCl5 (10 mol %)
n-Hexane/50oC
6
91
13
10 None
Solvent free/90oC 5
Trace This work
Trace This work
Trace This work
Trace This work
11 FeCl2.4H2O (0.05g) Solvent free/90oC 2
12 FeCl3.6H2O (0.05g) Solvent free/90oC 2
13 Bulk-Fe2O3 (0.05g) Solvent free/90oC 2
9
10
11
12
13
14
15
Reflux /EtOH
15
Solvent free/90oC 2
Solvent free/90oC 2
40
This work
Reflux /MeOH
Reflux /CH3CN
Reflux /CHCl3
Nano-γ-Fe2O3 (0.05g)
14 Bulk-Fe O3–SO3H
60
This work
(0.05g)2
16
Solvent free/90oC 2
90
This work
Reflux /DMSO
Nano-γ-Fe2O3–SO3H
aReaction conditions: a mixture of o-phenylenediamine 1a (1equiv.) and acetophenone
(2a; Rʹ=Ph, Rʹʹ=H) (2.1 equiv.) was reacted with nano-γ-Fe2O3–SO3H.
bIsolated yield.
(0.05 g)
aReaction condition: a mixture of o-phenylenediamine 1a (1equiv.) and acetophenone (2a; Rʹ=Ph,
Rʹʹ=H) (2.1 equiv.) was reacted under various sets of conditions with various acid catalysts.
bIsolated yield.
cMicrowave condition.

696 JOURNAL OF CHEMICAL RESEARCH 2015
Table 3 Preparation of 1,5-benzodiazepines (3a–o; Rʹ, Rʹʹ=alkyl, aryl) from o-phenylene-diamines (1a, R=H or 1b, R=Me) and various ketones (2a–o;
Rʹ, Rʹʹ=alkyl, aryl) catalysed by nano-γ-Fe2O3–SO3H
Method A
Yield/%b
Method B
Yield/%b
Product
R
Rʹ
R”
M.p./oCRef.
Time/min
120
180
110
120
75
85
90
90
90
80
105
60
90
75
Time/min
6
6
6
7
6
7
8
10
10
9
8
6
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
H
H
H
H
H
H
H
H
90
85
88
87
90
90
89
90
88
85
89
90
89
85
93
95
90
93
90
91
90
90
95
90
87
95
90
85
150–151(lit. 150–152)12
142–144 (lit. 143–145)9
146–148 (lit. 145–146)7
154–156 (lit. 157)7
218–220 (lit. 219–220)7
116–117 (lit. 114–116)7
98–100 (lit. 98–99)7
86–88 (lit. 86–88)5
p-ClC6H4
p-BrC6H4
p-O2NC6H4
p-HOC6H4
p-CH3OC6H4
p-CH3C6H4
m-O2NC6H4
-
-
–(CH2)4
–(CH2)3
136–138 (lit. 137–139)7
138–140 (lit. 137–138)7
136–138 (lit. 137–139)12
137–139 (lit. 137–139)12
90–92 (lit. 92)9
CH3
CH3
CH3
H
H
Me C6H5
Me CH3
7
9
H
125–127 (lit. 127–129)9
a Reaction conditions: a mixture of o-phenylenediamine 1a (1equiv.) (or its 4-methyl derivative 1b), acetophenone (2a–o; Rʹ, Rʹʹ=alkyl, aryl) (2.1 equiv.) and nano-γ-Fe2O3–SO3H (0.05 g)
was heated (Method A) or subjected to microwave irradiation (360 W) (Method B) under solvent-free conditions at 90 oC.
b Isolated yield.
cyclohexanone, the corresponding 1,5-benzodiazepine products
3i,j were achieved in excellent yields (entries 9 and 10). 2-Butanone
as an unsymmetrical ketones was also able to give a single
product 3k due to the ring closure occurring selectively only
from one side of the carbon skeleton. We also studied a different
o-phenylenediamine, 4-methyl-benzene-1,2-diamine 1b with an
aromatic and aliphatic ketone and excellent yields of the respective
products 3m and 3n under the optimised reaction conditions were
obtained. Additionally, to develop the generality of the reaction and
to embrace green chemistry, the cyclocondensation reactions were
carried out under the optimised conditions but under microwave
irradiation. Using microwave irradiation gave high yields in very
short reaction times (6–12 min) and the products were obtained
in good to excellent yields. Thus, this methodology becomes an
efficient strategy for the quick synthesis of 1,5-benzodiazepine
derivatives.
This is a substantial finding: due to the magnetic property of nano-
γ-Fe2O3–SO3H, recovery of the catalyst is very simple and efficient
from the reaction mixture during workup procedure. Hence, the
catalyst was separated easily from the reaction mixture by using
an external magnet. The isolated catalyst was washed with acetone,
dried in air and re-used for five runs without any significant loss
of activity. In each run, the desired pure product (3a) was obtained
after separation and products were purified by recrystallisation to
afford the pure product in good to excellent yield without the need
for flash or column chromatography for purification of products.
The isolated yields of the product for five successive runs were: 90,
90, 89, 88 and 87% which demonstrates the excellent recyclability
of this catalyst.
Based on reports in the literature12 a plausible mechanism for
the formation of 1,5-benzodiazepine is proposed in Scheme 2.
The amino groups of o-phenylenediamine attack the protonated
NH2
H2O
NH2
NH2
R
H
H
O
O
S
H
C
NH2
N
3
O
S
H
O
O
N
H3C
3
R
H
C
3
H
C
H
H
O
O
R
O
R
O
R
R
H
3
C
R
H
N
C
CH3
CH3
Nano- -Fe O
γ
=
H
2
3
H
C
N
3
N
C
R
C
R
H
N
R
N
H
H
C
3
R
H
R
H
C
N
3
N
C CH3
H+
H2O
N
C
R
CH3
N
H
N
H
C
C
R
H
2
R
1,3-H Shift
R
N
C
H
H
N
C
R
H
H
Scheme 2

JOURNAL OF CHEMICAL RESEARCH 2015 697
2-Methyl-2,4-bis(3-nitrophenyl)-2,3-dihydro-1H-1,5-benzodiazepine
carbonyl groups of the molecules of ketone in the presence of
nano-γ-Fe2O3–SO3H giving the intermediate diimine. Then, a
tautomeric 1,3-hydrogen shift of the methyl group occurs to form an
intermediate bicylcic enamine B, which cyclises to afford the seven
membered ring of 1,5-benzodiazepine 3.
1
(3h): Light brown crystals; m.p. 86–88 oC (EtOH); H NMR: δ 1.90 (s, 3H,
CH3), 3.00 (d, 1H, CHa), 3.25 (d, 1H, CHb), 3.55 (br s, 1H, NH), 6.81–7.08
(m, 1H, C6H4), 7.10–7.13 (m, 2H, C6H4), 7.18–7.36 (m, 3H, C6H4), 7.83–7.99
(m, 3H, C6H4), 8.02–8.07 (t, 2H, C6H4), 8.30 (s, 1H, C6H4).
2,2,4-Trimethyl-2,3-dihydro-1H-1,5-benzodiazepine (3l): Yellow solid;
Experimental
o
m.p. 137-139 C (EtOH); IR (KBr) νmax/cm–1: 3297 (NH), 2962 (C–H
All chemicals were obtained from Merck and used without any further
purification. Melting points were recorded on an electro thermal 9100
apparatus and are uncorrected. A microwave LG oven MG 555f model
was used. UV-Vis spectra were obtained on a Shimadzu UV-1650PC
spectrophotometer. The IR spectra were recorded on a PerkinElmer model
783 spectrophotometer (Waltham, MA, USA). NMR spectra were obtained
on a Bruker Avance 300 spectrometer (1H NMR at 400 Hz, 13C NMR at 100
Hz) in CDCl3 using TMS as an internal standard. Chemical shifts (δ) are
given in ppm and coupling constants (J) in Hz.
Nano-γ-Fe2O3–SO3H was prepared according to the literature25 and
characterised by XRD, TG, SEM, TEM, XPS and FTIR. Its acidity
function, H0=1.65 was determined spectroscopically, as described in one
of our recent articles.27
aromatic), 2955 and 2925 (C–H aliphatic), 1634 (C=N), 1594 and 1475
(C=C); 1H NMR: δ 1.27 (s, 6H, CH3), 2.16 (s, 2H, CH2), 2.31 (s, 3H, CH3),
4.47 (br s, 1H, NH), 7.22–7.28 (m, 2H, C6H4), 7.38–7.40 (q, 2H, C6H4).
Conclusions
In conclusion, we have successfully achieved a simple and efficient
method for the synthesis of 1,5-benzodiazepine derivatives from
various aromatic, aliphatic and cyclic ketones, in good to excellent
yields using nano-γ-Fe2O3–SO3Hasaheterogeneousandrecoverable
catalyst under solvent-free conditions. This catalyst could be easily
separated and reused up to five times with no significant loss of
activity and selectivity. This new method has several advantages:
it is rapid, gave good yields under mild reaction conditions and the
products were easily purified without the need for column nor flash
chromatography.
Synthesis 1,5-benzodiazepine under conventional thermal method
(method A)
A mixture of o-phenylenediamine (1 mmol), ketone (2.1 mmol) and nano-
γ-Fe2O3–SO3H (0.05g) was mixed and heated at 90oC. After completion
of the reaction (monitored by TLC), the mixture was cooled to room
temperature and the catalyst removed by external magnet. The products
were purified by recrystallisation to afford the pure product in good to
excellent yield. All products were characterised by melting point, IR,
1H NMR and 13C NMR spectroscopy (Table 3, entry 1).
We gratefully acknowledge Semnan University for financial
support of this work.
Received 11 October 2015; accepted 15 October 2015
Paper 1503650 doi: 10.3184/174751915X14473291357176
Published online: 1 December 2015
Synthesis 1,5-benzodiazepine under microwave irradiation method
(method B)
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The reaction substances of method A were heated in a microwave oven at
360 W for 6 minutes. The reaction mixture was then worked-up a similar
way to method A.
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2-Methyl-2,4-bis (4-methoxyphenyl) -2,3-dihydro-1H-1,5-
benzodiazepine (3f): Yellowish solid; m.p. 119–120 oC (EtOH); IR
(KBr) νmax/cm–1: 3295 (NH), 3019 (C–H aromatic), 2964 and 2911 (C–H
1
aliphatic), 1633 (C=N), 1594 and 1476 (C=C); H NMR: δ 1.71 (s, 3H,
CH3), 2.90 (d, 1H, CHa), 3.03 (d, 1H, CHb), 3.06 (br s, 1H, NH), 3.52 (d,
3H, OCH3), 3.79 (t, 3H, OCH3), 6.74–6.94 (m, 5H, C6H4), 7.02–7.05 (t,
2H, C6H4), 7.24–7.30 (q, 1H, C6H4), 7.51–7.60 (q, 4H, C6H4); 13C NMR: δ
29.9 (CH3), 43.05 (C-3), 55.5 (OCH3), 55.5 (OCH3), 73.5 (C-2), 113.6 (C-
9), 113.7 (C-3”, 5”), 121.7 (C-3’, 5’), 121.9 (C-7), 126.0 (C-6), 126.7 (C-1’),
128.3 (C-2’, 6’), 129.0 (C-8), 132.3 (C-2’, 6’), 138.3 (C-1”), 140.3 (C-5a),
140.8 (C-9a), 158.8 (C-4”), 161.2 (C-4’), 167.3 (C-4).
2-Methyl-2,4-bis(4-methylphenyl)-2,3-dihydro-1H-1,5-benzodiazepine
(3g): Pale yellow crystalline solid; m.p. 98–100 oC (EtOH); 1H NMR: δ
1.66 (s, 3H, CH3), 2.24 (s, 3H, CH3), 2.26 (s, 3H, CH3), 2.91 (d, 1H, CHa),
3.08 (d, 1H, CHb), 3.44 (br s, 1H, NH), 6.83 (t, 1H, C6H4), 7.08–7.12 (m, 3H,
C6H4), 7.28–7.32 (q, 3H, C6H4), 7.49 (d, 2H, C6H4), 7.57 (d, 2H, C6H4).
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