A new and efficient procedure for synthesis of 1,5-benzodiazepine derivatives in solution and under solvent-free conditions

Article abstract of DOI:10.1002/cjoc.201190239

Borax/phosphorous oxychloride (BPO) efficiently catalyzes the preparation of 1,5-benzodiazepine derivatives of o-phenylenediamines and ketones in solvent-free and solution conditions. The reaction proceeds efficiently under ambient conditions giving excel

Full text of DOI:10.1002/cjoc.201190239

NOTE
A New and Efficient Procedure for Synthesis of
1,5-Benzodiazepine Derivatives in Solution
and under Solvent-Free Conditions
Gholivand, Khodayar*,a
Zare, Karima
Jafari, Hadia
Adibi, Hadib
a Department of Chemistry, Science and Research Branch, Islamic Azad University, Tehran, Iran
b Department of Medicinal Chemistry, Faculty of Pharmacy, Kermanshah University of Medical
Sciences, Kermanshah 67145-1673, Iran
Borax/phosphorous oxychloride (BPO) efficiently catalyzes the preparation of 1,5-benzodiazepine derivatives
of o-phenylenediamines and ketones in solvent-free and solution conditions. The reaction proceeds efficiently under
ambient conditions giving excellent yields of the products. This new protocol allows the recycling of catalyst with
no loss in its potency.
Keywords 1,5-benzodiazepine, o-phenylenediamine, borax, phosphorus oxychloride
Introduction
(Scheme 1).
The preparation of benzodiazepines and their poly-
cyclic derivatives is important due to their pharmacol-
ogical and industrial properties.1,2 1,5-Benzodiazepines
are useful precursors for the preparation of some fused
ring compounds such as triazolo-,3 oxadiazolo-,4
oxazino-,5 furano,5,6 or tricyclic derivatives.7 Several
methods have been reported in the literature for the
synthesis of benzodiazepines. These include condensa-
tion reactions of o-phenylenediamines (OPD) with
α,β-unsaturated carbonyl compounds,8 β-haloketones,9
or ketones in the presence of BF3-etherate,10 NaBH4,11
polyphosphoric acid or SiO2,12 MgO and POCl3,13
Yb(OTf)3,14 Al2O3/P2O5 or CH3COOH under MW,15,16
Sc(OTf)3,17 clay-supported polyoxometalates,18 polymer
supported ferric chloride,19 and tetranitrile-silver com-
plex.20 Many of these processes suffer from one or other
limitations such as requiring harsh condition, expensive
reagents, long reaction times, low yields and occurrence
of several side products. Moreover, the main disadvan-
tages of almost all existing methods are that the used
catalysts are expensive or destroyed in the work-up
procedure and cannot be recovered or reused. Surface-
mediated solid phase reactions are of growing inter-
est,21-24 because of their ease of set-up and work-up,
mild reaction conditions, rate of the reaction, selectivity,
high yields, lack of solvent and the low cost of the reac-
tions in comparison with their homogeneous counter-
parts.
Scheme 1 BPO catalyzed synthesis of 2,3-dihydro-1H-1,5-
benzodiazepines from ketones and o-phenylenediamines under
both solvent-free and in solution conditions
Results and discussion
To find the optimal conditions, a mixture of 1,2-
phenylenediamine and acetone was stirred under various
reaction conditions (Table 1). The reaction did not occur
in the absence of catalyst after 5 h (Table 1, Entry 1).
Best results were obtained using 0.1 g of BPO, 2 mmol
o-phenylenediamine and 5 mmol acetone, and any ex-
cess of BPO did not lead to an increase in the conver-
sion and yield. It is interesting to note that no reaction
was observed in the presence of POCl3 or borax (Table
1, Entries 2— 5).
As shown in Table 2, both acyclic and cyclic ketones
react without any significant difference to give the cor-
responding 2,4-dihydro-1H-1,5-benzodiazepines under
optimal conditions. The benzodiazepines 3 were the
This paper describes a facile synthesis of benzodi-
azepines by condensation of ketones with o-phenylene-
diamines in the presence of Na2B4O7/POCl3 (BPO)
*
E-mail: gholi_kh@modares.ac.ir; Tel.: 0098-21-82883443; Fax: 0098-21-82883455
Received August 26, 2010; revised November 30, 2010; accepted February 16, 2011.
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Chin. J. Chem. 2011, 29, 1290— 1293

A New and Efficient Procedure for Synthesis of 1,5-Benzodiazepine Derivatives
Table 1 Reaction of o-phenylenediamine with acetone in vari-
only products obtained. The reactions were carried out
ous conditions
in solution and we found that solvent-free conditions
were more suitable in term of reaction rate. It is note-
worthy to mention that by starting from an unsymmet-
rical ketone, such as 2-butanone (Table 2, Entry f), the
ring closure occurs selectively only from one side of
carbonyl group yielding a single product.
The recovery and reusability of the catalyst have
been investigated. The condensation of OPD and ace-
tone with BPO afforded the corresponding 1,5-benzo-
diazepine in 90%, 81%, 65% and 43% yields over four
cycles in dichloromethane at room temperature. But in
the reaction of 1,2-phenylenediamine and acetone with
BPO under solvent-free conditions, the recovered cata-
lyst has been charged to the reaction mixture for four
runs without any observable loss of its catalytic activity
(Table 3).
Entry
Catalyst (g)
—
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
—
Time/h
Yielda/%
1
2
5
5
0
0
POCl3 (0.2)
Borax (0.2)
POCl3 (0.2)
Borax (0.2)
BPO (0.2)
BPO (0.2)
BPO (0.2)
BPO (0.05)
BPO (0.1)
BPO (0.1)
3
5
0
4
5
0
5
—
5
0
6
CH3CN
CH2Cl2
MeOH
CH2Cl2
CH2Cl2
—
1
85
93
90
65
90
92
7
1
8
1
9
1
10
1
11
0.5
a Isolated yields.
Table 2 Na2B4O7/POCl3 catalyzed formation of 2,3-dihydro-1H-1,5-benzodiazepines
m.p.
Reported (Ref.)
Entry
a
Reactant
Product 3
Yielda,b/%
Found
OPD
92 (90)
136—139
137—13910
150—15219
138—13910
143—14519
137—13914
137—13918
136—13714
Acetone
OPD
b
c
d
e
f
95 (91)
93 (90)
94 (93)
92 (88)
91 (92)
87 (84)
150—151
138—140
142—144
139—140
135—136
136—138
Acetophenone
OPD
Cyclopentanone
OPD
3-Pentanone
OPD
Cyclohexanone
OPD
2-Butanone
OPD
g
Cycloheptanone
Chin. J. Chem. 2011, 29, 1290— 1293
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Gholivand et al.
NOTE
Continued
m.p.
Entry
h
Reactant
Product 3
Yielda,b/%
92 (90)
Found
Reported (Ref.)
4-Methyl-o-phenylenediamine
90—91
9225
Acetophenone
4-Methyl-o-phenylenediamine
i
91 (89)
136—138
137—13925
Cyclohexanone
a Isolated yields. b The data in parenthesis are yields in solution.
Table 3 Recycling of BPO in reaction of o-phenylenediamine and acetone with BPO
Yielda,b/%
Run
Solvent-freec
Solutiond
1
2
3
4
92
90
88
89
90
81
65
43
a Isolated yields. b The recovered catalyst was washed with diethyl ether and dried. c Reaction conditions: o-phenylenediamine (2 mmol),
d
acetone (5 mmol), BPO (0.1 g), room temperature, 0.5 h. Reaction conditions: o-phenylenediamine (2 mmol), acetone (5 mmol), BPO
(0.1 g), CH2Cl2 (5 mL), room temperature, 1 h.
Experimental
1.78 (s, 3H), 2.40 (s, 3H), 2.98 (s, 1H), 3.13 (s, 1H), 3.4
(br s, 1H), 6.63—7.68 (m, 13H); 13C NMR (CDCl3, 50
MHz) δ: 164.6, 136.5, 133.4, 131.3, 130.5, 128.7, 128.5,
128.3, 128.2, 128.0, 127.5, 126.0, 125.5, 123.5, 113.4,
50.9, 45.8, 28.5, 20.6; IR ν: 3295, 1665 cm .
The other products were characterized by spectral
(IR, 1H and 13C NMR) data and also by the mixed melt-
ing points with the authentic samples.
Preparation of BPO
A mixture of POCl3 (1.5 g) and anhydrous borax (2
g) were combined in a mortar and pestle by grinding
them together until a fine, homogeneous powder was
obtained (15—20 min).
－
1
General procedure for the synthesis of 1,5-benzo-
diazepine derivatives under solvent-free conditions
General procedure for the synthesis of 1,5-benzo-
diazepine derivatives in solution
A mixture of o-phenylenediamine or 4-methyl-1,2-
phenylenediamine (2 mmol), ketone (5 mmol) and BPO
(0.1 g) was well stirred at room temperature. After 0.5 h
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 were purified
by silica gel column chromatography (100—200 mesh)
and eluted with V(EtOAc)∶V(n-hexane)＝2∶8 to af-
ford the pure compounds in 87%—95% yields. The wet
catalyst was recycled and no appreciable change in its
activity was achieved after four runs. The spectral data
of some of the compounds are given below.
A mixture of o-phenylenediamine or 4-methyl-1,2-
phenylenediamine (2 mmol), ketone (5 mmol) and BPO
(0.1 g) was well stirred at room temperature in 5 mL of
CH2Cl2. After 1 h catalyst was recovered by filtration.
The filtrate was concentrated and the products were pu-
rified by silica gel column chromatography (100—200
mesh) and eluted with V(EtOAc)∶V(n-hexane)＝2∶8
to afford the pure compounds in 84%—93% yields.
Conclusion
3b: m.p. 150—151 ℃; 1H NMR (CDCl3, 200 MHz)
δ: 1.78 (s, 3H), 2.90 (d, J＝13 Hz, 1H), 3.15 (d, J＝13
Hz, 1H), 3.4 (br s, 1H), 6.63—7.05 (m, 3H), 7.10—7.32
(m, 7H), 7.50—7.63 (m, 4H); 13C NMR (CDCl3, 50
MHz) δ: 167.0, 145.5, 140.4, 140.0, 138.5, 129.7, 128.5,
128.4, 127.9, 127.0, 126.8, 126.2, 125.5, 121.5, 121.2,
We have developed a simple, convenient and effec-
tive method for easy synthesis of 2,3-dihydro-1,5-
benzodiazepines by the condensation of ketones with
o-phenylenediamines using borax-supported POCl3 as
catalyst in both solvent-free and solution conditions.
The catalyst can be prepared easily with available inex-
pensive reagents and works under heterogeneous condi-
tions. The simple procedure combined with ease of
－
1
73.7, 42.8, 30.0; IR ν: 3330, 1650 cm .
1
3i: m.p. 90—91 ℃; H NMR (CDCl3, 200 MHz) δ:
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1290— 1293

A New and Efficient Procedure for Synthesis of 1,5-Benzodiazepine Derivatives
recovery and reuse of the catalyst make this method
economical, benign and is a waste-free chemical process
for the synthesis of 1,5-benzodiazepines. Studies for the
application of the catalyst for several reactions are under
investigation in our laboratory.
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