Aluminum dodecatungstophosphate promoted synthesis of 1,5-benzodiazepine derivatives under solvent-free conditions

Article abstract of DOI:10.3987/COM-06-10948

Solid heteropoly acids (AITP and AIMP) are easily used as efficient catalyst for conversion of o-phenylenediamines and ketones to their corresponding 2,3-dihydro-1H-1,5-benzodiazepines at room temperature under solvent-free conditions. The method is an ea

Full text of DOI:10.3987/COM-06-10948

HETEROCYCLES, Vol. 71, No. 4, 2007
805
HETEROCYCLES, Vol. 71, No. 4, 2007, pp. 805 - 814. © The Japan Institute of Heterocyclic Chemistry
Received, 16th November, 2006, Accepted, 13th February, 2007, Published online, 13th February, 2007. COM-06-10948
ALUMINUM DODECATUNGSTOPHOSPHATE PROMOTED
SYNTHESIS OF 1,5-BENZODIAZEPINE DERIVATIVES UNDER
SOLVENT-FREE CONDITIONS
Razieh Fazaeli,a* Hamid Aliyan,a* and Shahram Tangestaninejadb
aDepartment of Chemistry, Islamic Azad University, Shahreza branch, 86145-311,
Iran
E-mail: fazaeli@iaush.ac.ir
bDepartment of Chemistry, Isfahan University, Isfahan , 81746-73441, Iran
Abstract – Solid heteropoly acids (AlTP and AlMP) are easily used as efficient
catalyst for conversion of o-phenylenediamines and ketones to their
corresponding 2,3-dihydro-1H-1,5-benzodiazepines at room temperature under
solvent-free conditions. The method is an easy, rapid, and high yielding reaction
for the synthesis of 1,5-benzodiazepine derivatives and is applicable to both
cyclic or acyclic ketones without significant difference.
INTRODUCTION
Benzodiazepines and their derivatives are important class of bioactive molecules. Many members of this
family, infact, nowadays widely used as tranquilizing, anticonvulsant, antianxiety, analgesic, sedative,
antidepressive and hypnotic agents,1-3 and also nevirapine analogues.4 Some benzodiazepine derivatives
are also used in industry, such as in photography (as dyes for acrylic fibers),5 and also as antiinflamatory
6,7
agent. In addition, 1,5-benzodiazepines are valuable synthons used for the preparation of some fused
ring benzodiazepine derivatives for the preparation of other fused ring compounds such as triaxolo-,
triazolo-, oxadiazolo-, oxazino- or furano-benzodiazepines. 8
Many reagents have been reported in the literature for this condensation including Yb(OTf)3, Sc(OTf)3,
2-
MgO/POCl3, acetic acid under microwave conditions, SO4 /ZrO2, polymer-supported FeCl3, BF3-etherate,
NaBH4, SiO2, polyphosphoric acid, Al2O3/P2O5, TiCl4/Sm or zeolite.9 Recently these condensations have
been reported even in an ionic liquid medium.10,11
Unfortunately, many of these processes suffer from one or other limitation such as harsh reaction
conditions, low product yields, tedious work-up procedures, relatively long reaction times, and

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HETEROCYCLES, Vol. 71, No. 4, 2007
co-occurrence of several side products, and difficulty in recovery and reusability of the catalysts.
Moreover, some of the reagents employed are very expensive. Therefore, the search continues for a better
catalyst for the synthesis of 1,5-benzodiazepines in term of operational simplicity, reusability, economic
viability, and greater selectivity.
Preparation of aluminum dodecatungstophosphate (AlPW12O40) was reported in 1982 by Ono by the
reaction of aluminum nitrate and dodecatungstophosphoric acid in a quantitative yield. We have also
prepared aluminum dodecatungstophosphate (AlPW12O40, denoted as AlTP hereafter) and aluminum
dodecamolybdophosphate (AlPMo12O40, denoted as AlMP hereafter) by the addition of aluminum nitrate
or by aluminum carbonate to the aqueous solution of tungstophosphoric acid and molybdophosphoric
acid, respectively, which on complete evaporation of water gave the desired compound as a white (AlTP)
and yellow (AlMP) powders in quantitative yield. AlTP prepared by both protocols gave satisfactory
analytical results within the range of the experimental errors. This salt is a water stable and a
nonhygroscopic compound.12-14
15
In continuation of our work on the catalytic properties of heteropoly acids , herein, we have utilized
AlTP and AlMP as Bronsted acid and efficient catalysts for synthesis of
2,3-dihydro-1H-1,5-benzodiazepines by condensation of ketones with o-phenylenediamines (Scheme 1)
under solvent-free conditions.
R1
H
R2
R
N
NH2
NH2
O
AlTP or AlMP
solvent-free, rt
R
R
+
R2
R1
N
R1
Scheme 1
RESULTS AND DISCUSSION
The reactions were carried out by taking a 1:2.5 mole ratio mixture of o-phenylenediamine and the ketone
along with a catalytic amount of polyoxometalates (POMs), and the mixture were ground together in
mortar with a pestle at room temperature for several minutes (Table 1). Cyclic ketones such as
cyclohexanone also reacted effectively to produce the corresponding fused ring benzodiazepines. The
results are summarized in Table 1.
Best results were obtained using 0.05 and 0.06 equivalents of AlTP and AlMP, respectively, lower
loading resulted in lower yields, while upper loading did not increase reaction times significantly. The
synthesis of 1,5-benzodiazepine derivatives was also conducted in different solvents in the presence of
catalytic amount of AlTP. The results show that the efficiency and the yield of the reaction in solutions
were much less than that observed under solvent-free conditions (Table 2).

HETEROCYCLES, Vol. 71, No. 4, 2007
807
Table 1. POM catalyzed formation of 2,3-dihydro-1H-1,5-benzodiazepines
Time (min) :
Yield (%)
25: 90
mp (oC)
Entry
Ketone
acetone
Diamine
1,2-phenylenediamine
POM
AlTP
AlMP
Product
Found
141
Reported
Me
Me
1
H
N
28 : 98
137-139
[9a-9f]
N
Me
1a
Me
Me
4-methyl-1,2-phenylenediamine
AlTP
35 : 90
20 : 90
H
N
Me
AlMP
138
131
-
[9d,9f]
N
1b
Me
Me
Me
4,5-dimethyl-1,2-phenylenediamine
AlTP
20 : 86
45 : 95
H
N
Me
AlMP
-
Me
N
[9d-9f]
Me
1c
H
Me
Me
4-benzoyl-1,2-phenylenediamine
2,3-naphthalenediamine
AlTP
32 : 86
35 : 90
N
PhCO
AlMP
136
141
-
N
Me
[9d,9f]
1d
H
Me
Me
AlTP
55 : 92
N
AlMP
120 : 87
-
N
Me
[9d,9e]
1e
Me
Me
4-chloro-1,2-phenylenediamine
1,2-phenylenediamine
AlTP
65 : 92
H
N
Cl
AlMP
100 : 95
139
151
-
N
[8]
Me
1f
Me
Ph
2
acetophenone
AlTP
18 : 92
55 : 90
H
N
AlMP
151-152
[9a-9f]
N
Ph
2a
Me
Ph
4-methyl-1,2-phenylenediamine
AlTP
28 : 90
64 : 90
H
N
Me
AlMP
129
115
-
[9f]
N
Ph
2b
4,5-dimethyl-1,2-phenylenediamine
AlTP
Me
Ph
35: 90
H
N
Me
114-116
[9d,9e]
AlMP
110: 90
Me
N
Ph
2c

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HETEROCYCLES, Vol. 71, No. 4, 2007
Table 1 (continued)
Time (min) :
Yield (%)
40 : 90
mp (oC)
Reported
Entry
Ketone
Diamine
POM
AlTP
AlMP
Product
Found
128
H
N
Me
Ph
2
acetophenone
4-benzoyl-1,2-phenylenediamine
PhCO
-
N
Ph
2d
[9f]
Et
Et
Me
3
3-pentanone
1,2-phenylenediamine
AlTP
60 : 89
55 : 82
H
N
AlMP
138
143
144-145
[9a-9f]
N
Et
3a
Me
Et
4-methyl-1,2-phenylenediamine
AlTP
35 : 90
20 : 87
H
Et
Me
N
AlMP
143-145
[9f]
N
3b
Et
Me
Et
4
2-butanone
1,2-phenylenediamine
AlTP
15 : 78
55 : 93
H
N
AlMP
139
141
137-138
[9a-9f]
N
Et
4a
Me
Et
4-methyl-1,2-phenylenediamine
AlTP
25 : 95
95 : 90
H
N
Me
AlMP
-
N
4b
[9f]
Et
4,5-dimethyl-1,2-phenylenediamine
AlTP
Me
Et
40 : 90
H
N
Me
AlMP
140 : 95
-
Me
141
138
[9d,9e]
N
Et
4c
2,3-naphthalenediamine
AlTP
H
N
Me
Et
120 : 95
80 : 95
AlMP
-
N
[9d]
Et
4d
5
6
cyclopentanone
cycloheptanone
1,2-phenylenediamine
AlTP
50 : 90
50 : 88
H
N
AlMP
139
131
138-139
[9a-9f]
N
5a
4-methyl-1,2-phenylenediamine
AlTP
65 : 86
H
N
Me
AlMP
135 : 85
136-137
[9a]
N
6a

HETEROCYCLES, Vol. 71, No. 4, 2007
809
Table 1 (continued)
Time (min) :
Yield (%)
20 : 87
mp (oC)
Entry
Ketone
Diamine
1,2-phenylenediamine
POM
AlTP
AlMP
Product
Found
139
Reported
7
cyclohexanone
H
N
25 : 87
137-139
[9a,9c,9f]
N
7a
aReaction condition: diamine (1 mmol), ketone (2.5 mmol), POM (5 mol %), rt, solvent-free conditions.
bIsolated yields after column chromatography.
Table 2. Synthesis of some 1,5-benzodiazepine derivatives with o-phenylenediamine in the presence of
AlTP in various solvents.
Temperature (oC)
Time (h) : Yield (%)
CHCl3
5:45
CH3CN
6:60
CH2Cl2
CCl4
7:35
7:55
EtOH
9:50
rt
11:45
8:45
60
3:60
5:70
7:65
aReaction conditions: o-phenylenediamine (1 mmol), acetone (2.5 mmol), AlTP (5 mol %), solvent.
We also tested the title reaction with Al(NO3)3. 9H2O, Al2(CO3)3, Al2O3, AlPO4 and AlCl3. Although
these catalysts were active for the synthesis of 1,5-benzodiazepine derivatives, the yields were
insignificant when compared to those with the AlTP and AlMP (Table 3 ).
Table 3. Reaction of o-phenylenediamine with acetone in the presence of different catalysts After 20 h.
Entry Ketone
Yield (%)
Al2(NO3)3. 9H2O Al2(CO3)3 Al2O3
Al(PO4)
43
AlCl3
15
1
2
3
acetone
55
28
19
35
23
17
15
21
11
acetophenone
2-butanone
56
21
31
41
aReaction condition: o-phenylenediamine (1 mmol), acetone (2.5 mmol), catalyst (5 mol %), rt, solvent-
free conditions.
A reasonable pathway for the reaction of diamine with ketone in the presence of AlPW12O40 is presented
by Scheme 2. In order to show the merit of the present work in comparison with recently reported
protocols, we compared the results of the 1,5-benzodiazepine derivative synthesis from various ketones

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HETEROCYCLES, Vol. 71, No. 4, 2007
2-
and diamines in the presence of Yb(OTf)3, MgO/POCl3, SO4 /ZrO2, Sc(OTf)3, and AlTP with respect to
the amounts of the catalysts used, reaction times and yields of the products (Table 4). Comparison of
Keggin type POM with these catalysts for this reaction show that activity of AlTP and AlMP seems to
be higher than or equal with other known catalysts (Table 4).
In this study, we have introduced aluminium dodecatungstophosphate (AlTP) and aluminum
dodecamolybdophosphate (AlMP) as new highly effective non-hygroscopic, non-corrosive,
heterogeneous and environmentally benign catalysts for the efficient synthesis of a variety of
1,5-benzodiazepine derivatives in high yields.
_
O
C
AlPW12O40
NH2
NH2
NH2
O
R
CH3
+
+
NH2
CH3
C
R
H
+
O
NH2
N
_
NH2
NH2
AlPW12O40
+
NH
R
C
R
C
NH
CH3
C
R
_
CH3
CH3
+ H-OAlPW12O40
+ H2O + AlPW12O40
_
_
H-OAlPW12O40
H-OAlPW12O40
CH3
C
CH3
+
NH
+
NH
R
C
R
R
C
N
CH2
C
N
H
CH3
R
_
H-OAlPW12O40
R
H
N
CH3
CH2
R
H
N
CH3
CH2
N
+
N
R
R
H
+ H2O + AlPW12O40
_
H-OAlPW12O40
Scheme 2

HETEROCYCLES, Vol. 71, No. 4, 2007
811
Table 4. Comparision of AlTP with several catalysts for synthesis of 1,5-benzodiazepine
derivatives with o-phenylenediamine.
Time (h) : Yield (%)
2-
Entry
Ketone
acetone
AlTP
Yb(OTf)3
4 : 96
4 : 99
MgO/POCl3
0.8 : 90
0.8 : 87
0.8 : 80
-
SO4 /ZrO2
2-3 : 94
2-3 : 96
2-3 : 91
2-3 : 84
2-3 : 80
2-3 : -
Sc(OTf)3
3 : 96
3 : 93
3 : 90
3 : 89
-
Zeolite
1
2
3
4
6
7
0.4 : 90
0.3 : 92
0.2 : 78
1 : 89
4 : 98
acetophenone
2-butanone
4 : 95
4 : 93
4 : 95
4 : 89
4 : 87
3-pentanone
cyclohexanone
cyclopentanone
-
-
-
0.3 : 87
0.8 : 90
0.8 : 80
0.8 : 65
4 : 99
3 : 87
EXPERIMENTAL
Tungstophosphoric acid and molybdophosphoric acid (HTP and HMP), which are cheap, reusable,
heterogeneous and easily available catalysts, were purchased from Merck and were purified by extraction
o
with Et2O from aqueous solution of the acid. After evacuation at 150-300 C for 1-2 h under reduced
pressure, pure HTP and HMP were obtained.16
AlTP can be prepared from cheap and commercially available chemicals in a quantitative yield in
aqueous media. In contrast to many other Lewis acids, storage of this compound does not need special
precautions, e.g. it can be stored on a bench top for months without losing its catalytic activity. In
addition, as a non-hygroscopic, non-corrosive and a water stable compound, the handling of AlTP is easy
which makes this catalyst suitable for the large-scale operations.
All solvents were reagent grade. All reaction mixtures were stirred magnetically and were monitored by
1
GC or TLC. IR spectra were recorded on a Perkin-Elmer FT/IR-Impact 400D spectrophotometer. H
NMR spectra were recorded on a Bruker A W 200 MHz specrometer in CDCl3-d6 using TMS as an
internal standard.
Typical procedure: A mixture of diamine (1 mmol), ketone (2.5 mmol) and POM (0.05 mmol) were
ground together in mortar with a pestle at rt for several minutes (Table 1). In cases when the mixture
stuck to the walls of the mortar, it was taken off the walls with a spatula and grounding was redone. The
reaction was monitored by TLC, NMR and mass were used for analysis of the products. After completion
of the reaction, 10 mL of CH2Cl2 was added to the reaction mixture and the catalyst was recovered by
filtration. The organic layer was concentrated and the products was purified by silica gel column

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HETEROCYCLES, Vol. 71, No. 4, 2007
(100-200 mesh) and eluted with EtOAc:n-hexane (2:8) to afford pure compound in 80-98% yield. The
wet catalyst was recycled and no appreciable change in activity was noticed after few cycles. The spectral
data of the some of the compounds are given below. The catalyst was removed and the residue was
purified by SiO2 gel column chromatography using CH2Cl2/MeOH 95:5 as eluent.
Selected spectroscopic data:
1
2,2,4-Trimethyl-2,3-dihydro-1H-1,5-benzodiazepine (1a): yellow solid; mp 137–139 °C; IR; H
NMR;9a,c 13C NMR;9a,h GC/MS: M+=188.
2-Methyl-2,4-diphenyl-2,3-dihydro-1H-1,5-benzodiazepine (2a): yellow solid; mp 151–152 °C; IR
1
3330 (s br), 1635 (s) cm-1; H NMR;9a,i 13C NMR (50 MHz, CDCl3) δ 167.5, 146.6, 140.1, 139.5, 138.2,
129.8, 128.6, 128.4, 128.1, 127.1, 127.1, 126.4, 125.5, 121.7, 121.5, 73.9, 43.0, 29.9; GC/MS: M+=312.
2,2,4-Triethyl-3-methyl-2,3-dihydro-1H-1,5-benzodiazepine (3a): yellow solid; mp 144–145 °C; IR
3330 (s br), 1638 (s) cm-1; 1H NMR (200 MHz, CDCl3) δ 0.76–1.48 (m, 13H), 1.61 (s, 3H), 2.87 (q, 1H,
J=7.0 Hz), 3.75 (s br, 1H), 6.65–7.40 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 173.8, 142.4, 139.0, 132.7,
126.7, 118.0, 117.5, 68.7, 46.2, 35.6, 28.4, 28.0, 12.2, 11.5, 7.8, 7.3; GC/MS: M+=244.
ACKNOWLEDGEMENTS
We gratefully thank Islamic Azad University, Shahreza branch and the Isfahan University for financial
support.
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