A simple and new method for the synthesis of 1,5-benzodiazepine derivatives on a solid surface

Article abstract of DOI:10.1016/S0040-4039(00)02168-7

Magnesium oxide/phosphorus oxychloride (MOPO) was found to be an efficient reagent for the preparation of 1,5-benzodiazepine derivatives of o-phenylenediamine and ketones. This method is an easy, rapid, and high yielding reaction for the synthesis of 1,5-

Full text of DOI:10.1016/S0040-4039(00)02168-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1127–1129
A simple and new method for the synthesis of 1,5-benzodiazepine
derivatives on a solid surface
a,
b,
M. S. Balakrishna * and B. Kaboudin *
a
Department of Chemistry, Indian Institute of Technology (IIT), Powai, Mumbai 400 076, India
Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45195-159, Iran
b
Received 13 September 2000; revised 17 November 2000; accepted 22 November 2000
Abstract—Magnesium oxide/phosphorus oxychloride (MOPO) was found to be an efficient reagent for the preparation of
,5-benzodiazepine derivatives of o-phenylenediamine and ketones. This method is an easy, rapid, and high yielding reaction for
1
the synthesis of 1,5-benzodiazepine derivatives. © 2001 Elsevier Science Ltd. All rights reserved.
8
o-phenylenediamine, and (iii) the recently reported
Benzodiazepines are interesting compounds because of
their pharmacological properties. Many members of
1
condensation of methyl ketones with o-phenylenedi-
amines in the presence of PPA at high temperature.
9
this family are, in fact, nowadays widely used as tran-
quilizing and anticonvulsant agents. Although the first
benzodiazepine was introduced as a drug nearly 30
However, all of these methods have problems, including
drastic reaction conditions and also severe side-reac-
tions. Surface-mediated solid phase reactions are of
growing interest because of their ease of execution
and work-up, mild reaction conditions, rate of reaction,
selectivity, high yields, lack of solvent and low cost in
comparison with their homogeneous counterparts. As a
part of our efforts to explore the utility of surface-medi-
2
years ago, the research in this area is still very active
10
and is directed towards the synthesis of compounds of
enhanced pharmacological activity. Some benzodi-
azepine derivatives are also used in industry, such as in
3
photography (as dyes for acrylic fibers), and also as
4
anti-inflammatory agents. 1,5-Benzodiazepines are also
11–13
used as starting materials for the preparation of some
ated reactions,
we report here a new method for the
5
fused ring benzodiazepine derivatives, such as triaxol,
preparation of 1,5-benzodiazepine derivatives by con-
densation of o-p1henylenediamine with ketones. It was
found that a mixture of magnesia/phosphorus oxychlo-
ride under solvent-free conditions was capable of pro-
ducing high yields of 2,3-dihydro-2,2,4-trimethyl-1H-
1,5-benzodiazepine 3a by condensation of o-phenylene-
diamine with acetone under mild reaction conditions in
90% yield (Scheme 1; Table 1).
6
and oxadiazol. Despite their wide range of pharmaco-
logical activity, industrial and synthetic applications,
the synthesis of 1,5-benzodiazepines has received little
attention. The following methods, not generally appli-
cable, have been reported in the literature: (i) condensa-
tion of a,b-unsaturated compounds with o-phenyl-
7
enediamines, (ii) reaction of b-haloketones with
Scheme 1.
Keywords: benzodiazepine; magnesium oxide; phosphorus oxychloride; ketones.
*
Corresponding authors. Fax: (+91) 22 5723480 (M.S.B.); Fax: (+98) 241 449023 (B.K.); e-mail: krishna@chem.iitb.ernet.in; kaboudin@iasbs.ac.ir
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02168-7

1
128
M. S. Balakrishna, B. Kaboudin / Tetrahedron Letters 42 (2001) 1127–1129
The same process was successfully extended to other
was prepared in a mortar and pestle by grinding them
together until a fine, homogeneous mixture was
obtained (5–10 min). Phosphorus oxychloride (0.8 ml)
was added to this mixture. After 10 min of vigorous
stirring, the ketone (10 mmol) was added to this mix-
ture, which was stirred for 0.5 h. The reaction mixture
1
1
,5-benzodiazepine derivatives as summarized in Table
. As shown in Table 1, acetophenone in the presence
of a mixture of magnesia/phosphorus oxychloride with
o-phenylenediamine 1 afforded 2,3-dihydro-2-methyl-
2,4-diphenyl-1H-1,5-bezodiazepine 3b in 87% yield. The
reaction of cyclic ketones (2c and 2d) with o-phenylene-
diamine 1, in the presence of magnesia/phosphorus
oxychloride, gave fused ring 1,5-benzodiazepine deriva-
tives (3c and 3d) in good yields. The condensation of
was washed with n-hexane (200 mL), dried (CaCl ), and
2
the solvent evaporated to give the crude products. Pure
14
product was obtained by crystallization from n-hex-
ane in 65–90% yields.
2
-butanone 2e with o-phenylenediamine, in the pres-
ence of this reagent, gave two products (3e and 3e%).
In summary, a simple work-up, low consumption of
solvent, fast reaction rates, mild reaction condition,
good yields, and selectivity of the reaction make this
method an attractive and a useful contribution to
present methodologies.
This solvent-free method has an operationally simple
procedure. A mixture of the o-phenylenediamine (0.504
g, 5 mmol, finely ground) and magnesia (MgO, 1.5 g)
Table 1. The condensation of o-phenylenediamine with ketones in the presence of MgO/POCl3

M. S. Balakrishna, B. Kaboudin / Tetrahedron Letters 42 (2001) 1127–1129
1129
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DST), New Delhi for the financial support of this
work done at the Indian Institute of Technology, Bom-
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Basic Sciences (IASBS) for supporting this work.
701; (d) Kropp, P. J.; Daus, K. A.; Crawford, S. D.;
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