Alumina supported 12-tungstophosphoric acid as an efficient and reusable catalyst for synthesis of 1,5-benzodiazepines

Article abstract of DOI:10.1002/jccs.200800001

Alumina supported 12-tungstophosphoric acid catalyzes efficiently the reaction of o-phenylenediamine with ketones under solvent-free condition to afford the corresponding 1,5-benzodiazepines in good to excellent yields. The catalyst can be recovered and r

Full text of DOI:10.1002/jccs.200800001

Journal of the Chinese Chemical Society, 2008, 55, 1-4
1
Communication
Alumina Supported 12-Tungstophosphoric Acid as an Efficient and
Reusable Catalyst for Synthesis of 1,5-Benzodiazepines
a
Mohammad Abdollahi-Alibeik, * Zahra Zaghaghi and Iraj Mohammadpoor-Baltork
a
b
a
Department of Chemistry, Yazd University, Yazd 89195-741, Iran
b
Department of Chemistry, Isfahan University, Isfahan 81746-73441, Iran
Alumina supported 12-tungstophosphoric acid catalyzes efficiently the reaction of o-phenylene-
diamine with ketones under solvent-free condition to afford the corresponding 1,5-benzodiazepines in
good to excellent yields. The catalyst can be recovered and reused.
Keywords: 1,5-Benzodiazepine; o-Phenylenediamine; Alumina supported; Heteropoly acid;
1
2-Tungstophosphoric acid; Catalyst reusability.
INTRODUCTION
rosiveness, less expensive, ease of handling, recovery and
1
7
reusability. Among the various types of solid acids, het-
eropoly acids such as 12-tungstophosphoric acid (TPA) are
well known to passes purely Brønsted acidity and have
Benzodiazepines are an important class of biologi-
cally active compounds, widely used as analgesic, anti-
anxiety, anticonvulsant, hypnotic, sedative and antidepres-
1
8
been widely used in some acid-catalyzed reactions. How-
ever, pure heteropoly acids generally show very low cata-
lytic reactivity owning to their very poor surface area.
Therefore, immobilization of heteropoly acids on the sur-
face of porous solids, are more effective for catalytic reac-
1
sive agents. In addition, some benzodiazepine derivatives
2
are used as anti-inflammatory agents and also as dyes for
3
acrylic fibers. Particularly, 1,5-benzodiazepines are valu-
able synthons for the preparation of some fused ring benzo-
4
,5
19
diazepine derivatives. Due to their wide range of phar-
maceutical, industrial and synthetic applications, these
compounds have received a great deal of attention. The
simple and general method for the synthesis of 1,5-benzo-
diazepines involves the acid catalyzed condensation of
o-phenylendiamines with ketones. A variety of catalysts
tions. In this regards, deposition of heteropoly acids on
basic solids like MgO and Al
2 3
O prevents its dissolution in
polar solvents and reagents due to strong chemical bond-
2
0
ing. In spite of their advantages, comparatively few re-
ports for the application of alumina supported heteropoly
acid are reported in the literature.
6
7
8
9
such as BF
1
3
0
.OEt
2
, NaBH
11
4
, MgO-POCl
12
3
, PPA-SiO
-2
2
,
13
In this communication, we wish to report efficient
synthesis of 1,5-benzodiazepines by the reaction of o-phen-
ylenediamines with ketones in the presence of catalytic
amounts of alumina supported 12-tungstophosphoric acid
(Scheme I).
Yb(OTf)
Ag
3
,
Al
1
2
O
3
-P
2
O
5
,
4 2
HOAc-MW, SO /ZrO ,
16
HClO
4
15
3
PW12
O
40
,
Fe(ClO
4
)
3
,
4
/SiO
2
are utilized for
this condensation reaction. However, the use of many of
these catalysts are associated with several shortcomings
such as application of expensive materials, drastic reaction
conditions, extended reaction times, side products forma-
tion, low product yields and difficulty in recovery and reus-
ability of the catalysts. Hence, there is a need to develop a
convenient, efficient and practically useful protocol for the
synthesis of 1,5-benzodiazopines. In recent years, the use
of solid acid catalyst has received considerable attention in
organic transformations. This is mainly due to the advan-
tages of solid acid catalysts such as non-toxicity, non-cor-
Scheme I
*
Corresponding author. E-mail: abdollahi@yazduni.ac.ir

2
J. Chin. Chem. Soc., Vol. 55, No. 1, 2008
Abdollahi-Alibeik et al.
RESULTS AND DISCUSSION
The reaction of cyclopentanone with o-phenylene-
diamines also afforded corresponding fused ring 1,5-ben-
zodiazepines in good yields (3e, 3f), whereas cyclohex-
anone was treated under similar conditions, gave only 2,3-
dihydrobenzimidazole-2-spirocyclohexane (3g) (Scheme
II). To the best of our knowledge there is only one report
about different reaction products of cyclohexanone and
Initially, the supported 12-tungstophosphoric acid
catalysts were prepared by impregnation method with con-
centration depending upon the loading required to the sup-
port. The reaction of o-phenylenediamine with acetophe-
none was performed using different TPA loaded (20-60
wt.%) catalysts and the results are presented in Table 1. It is
seen that 1,5-benzodiazepine formation increased with in-
crease in TPA loading up to 40 wt.% and decreased further
with increase in loading. However, the 30 wt.% catalyst
was chosen because of less leaching of heteropoly acid.
The effect of catalyst concentration was also investi-
gated in the same reaction. It was found that 1.5 mol% of
heteropoly acid relation to o-phenylenediamine shows the
most activity, better reusability and less leaching of hetero-
poly acid. To show efficiency of the support, the reaction in
the presence of pure heteropoly acid was performed and
low yield of product was achieved. As shown in Table 1 the
reaction in the presence of pure alumina and neat condition
was performed and no reaction was observed.
6
cyclopentanone with o-phenylenediamine. In this report
3 2
BF -Et O has been used as catalyst for the reaction of ke-
tones with o-phenylenediamines and in the case of cyclo-
hexanone the corresponding spiro compounds has been
achieved. However in our hands, the reaction of cyclohex-
anone with various o-phenylenediamines in the presence of
2 3
TPA/Al O was provided corresponding spiro compounds
(3g-3i).
Scheme II
Along this line, the reaction of acetone and o-phenyl-
enediamine was performed in the presence of catalytic
Torsional strain plays a major role in different treat-
ment of cyclic ketones with o-phenylenediamine. The
products of the first step in these reactions are correspond-
ing imines with different torsional strain and stability. It is
2 3
amount of TPA/Al O (1.5 mol% of 30 wt.% catalyst per 1
mol o-phenylenediamine) at 60-70 °C under solvent-free
condition which afforded 2,4,4-trimethyl-2,3-dihydro-
1
H-1,5-benzodiazepine (3a) in 92% yield. Accordingly,
2
observed that the reactions which convert a sp carbon to
3
sp carbon in a six-membered ring are more favorable than
other types of ketones and o-phenylenediamines were re-
acted in the same reaction conditions and corresponding
2
1
the corresponding reaction in a five-membered ring. This
change in hybridization in a six-membered ring leads to a
completely staggered arrangement and reduced torsional
strain in the corresponding spiro compounds. Conversely,
1
,5-benzodiazepines were achieved in high yields (Table 2).
Table 1. Reaction of acetophenone with o-phenylenediamine in
the presence of various catalysts
2
3
conversion of an sp atom in a five-membered ring to sp ,
increases in the number of eclipsing interactions in the cor-
responding spiro compounds. Thus, after formation of the
first imine intermediate from cyclohexanone and o-phenyl-
enediamine, second amino group of diamine prefer to at-
b
c
Entry
Catalyst
TPA
Time (min) Yield (%)
1
2
3
4
5
6
7
8
9
20% TPA/Al O3
1
1
100
100
100
100
090
150
090
080
070
120
100
70
85
86
75
70
80
88
82
60
05
00
2
30% TPA/Al O3
2
40% TPA/Al
2
O
3
1
50% TPA/Al O3
2
1
2
60% TPA/Al O3
2
1
tack at sp carbon of cyclic imine to produce spiro com-
30% TPA/Al
30% TPA/Al
2
2
O
O
3
0.5
1.5
2
pounds, whereas, the corresponding imine of cyclopen-
tanone is more stable and second amino group can attack to
second cyclopentanone for production of diimine as
intermediate of corresponding benzodiazepine.
3
30% TPA/Al O3
2
TPA
1
a
1
0
1
Al O3
2
-
1
None
-
The progress of the reactions was monitored by TLC
(eluant; EtOAc:n-hexane, 2-4:8-6). After completion of
the reaction, the catalyst was easily separated by addition
of ethyl acetate and simple filtration. All products were
a
9
7 mg Al O for 1 mmol o-phenylenediamine was used.
2 3
b
c
Mole ratio relative to o-phenylenediamine.
Isolated yield.

Alumina Supported 12-Tungstophosphoric Acid
J. Chin. Chem. Soc., Vol. 55, No. 1, 2008
3
Table 2. Alumina-supported TPA catalyzed reaction of o-phenylenediamines with ketones
a
Entry
Diamine (1)
Ketone (2)
Product (3)
Time (min) Yield (%)
NH2
N
O
a
30
91
NH2
N
H
NH2
NH2
NH2
NH2
NH2
N
O
b
c
30
50
55
88
88
90
H C
H C
N
H
3
3
O
Ph
N
Ph
Ph
N
H
O
N
d
H C
N
H
Ph
H C
NH2
NH2
NH2
3
3
O
N
e
f
40
40
40
45
90
89
93
88
N
H
O
O
NH2
N
H C
N
H
H C
NH2
3
3
NH2
H
N
g
h
N
H
NH2
O
O
NH2
H
N
N
H
H C
NH2
H C
3
3
H
N
NH2
i
50
95
N
H
O N
NH2
O N
2
2
a
Isolated yields
identified by comparing their spectral and physical data
with authentic samples.
EXPERIMENTAL SECTION
To show reusability of the catalyst, the recovered cat-
alyst from the reaction of cyclopentanone with o-phenyl-
enediamine was used for the same reaction for three times.
After each run the catalyst was washed thoroughly with ac-
etone and dried in an oven at 120 °C for 1 h. For any reac-
tion, no appreciable change in activity was noticed.
In summary, we introduced a mild, convenient and ef-
ficient method for the synthesis of 1,5-benzodiazepines by
the reaction of o-pheneylenediamines with ketones using
All chemicals were commercial products. All melting
points were obtained by Buchi B-540 apparatus and are un-
corrected. TLC monitored all reactions and all yields refer
1
to isolated products. H NMR spectra were recorded in
3
CDCl on a Bruker (DRX-500 Avance) 500 MHz spec-
trometer. Infrared spectra were recorded on a Bruker FT-IR
Equinax-55 spectrophotometer in KBr with absorption in
-
1
cm . Microwave irradiation was carried out in a Kenwood
microwave oven, model MW303, operating at 800 W.
2 3
TPA/Al O as recyclable solid catalyst. The simple experi-
mental procedure, mild reaction conditions, ease of recov-
ery and reuse of catalyst are advantages of this method.
Catalyst preparation
Alumina-supported 12-tungstophosphoric acid (TPA)

4
J. Chin. Chem. Soc., Vol. 55, No. 1, 2008
Abdollahi-Alibeik et al.
containing 30 wt. % H
3
PW12
O
40/Al
2
O
3
(TPA/Al
2
O
3
) was
Received August 8, 2007.
prepared by impregnating alumina with an aqueous solu-
tion of TPA using 10 mL solution per gram of alumina. The
suspension was stirred overnight. The mixture was evapo-
rated at 80 °C until dryness. The catalyst was then calcined
by irradiation in microwave oven (800 W) for 20 minutes.
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