An efficient synthesis of 1,5-benzodiazepine derivatives catalyzed by a solid superacid sulfated zirconia

Article abstract of DOI:10.1016/S0040-4039(03)01034-7

2,3-Dihydro-1H-1,5-benzodiazepines are synthesized by the condensation of o-phenylendiamine and various ketones in the presence of a versatile solid superacid catalyst 'sulfated zirconia' under solvent free conditions.

Full text of DOI:10.1016/S0040-4039(03)01034-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4447–4449
An efficient synthesis of 1,5-benzodiazepine derivatives catalyzed
by a solid superacid sulfated zirconia
Benjaram M. Reddy* and Pavani M. Sreekanth
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 10 March 2003; revised 17 April 2003; accepted 22 April 2003
Abstract—2,3-Dihydro-1H-1,5-benzodiazepines are synthesized by the condensation of o-phenylendiamine and various ketones in
the presence of a versatile solid superacid catalyst ‘sulfated zirconia’ under solvent free conditions. © 2003 Elsevier Science Ltd.
All rights reserved.
Benzodiazepines and their polycyclic derivatives are a
very important class of bioactive compounds. They are
finding numerous new applications and are widely
used as anticonvulsant, anti-inflammatory, analgesic,
hypnotic, sedative, and antidepressive agents.1,2 Benzo-
diazepines are also valuable intermediates for the syn-
thesis of fused ring compounds such as triazolo-,
oxadiazolo-, oxazino-, and furano-benzodiazepines.3–5
Due to their broad spectrum of biological activity,
these compounds have received a great deal of atten-
tion in connection with their synthesis. Generally, ben-
zodiazepines are synthesized by the condensation of
o-phenylenediamines with a,b-unsaturated carbonyl
compounds, b-haloketones or with ketones. Many
reagents have been reported in the literature for this
condensation including BF3–etherate,6 polyphosphoric
acid,7 NaBH4,8 SiO2, MgO/POCl3,9 Yb(OTf)3,10 and
acetic acid under microwave conditions.11 Recently,
these condensations have been reported even in an
ionic liquid medium.12,13 However, many of these
methodologies are associated with several shortcom-
ings such as long reaction times, harsh reaction condi-
tions, low product yields, occurrence of several side
products, and difficulty in recovery and reusability of
the catalysts. Moreover, some of the reagents
employed are very expensive.
Recently considerable attention has been devoted to
heterogeneous organic transformations utilizing inor-
ganic solid acids.14 Generally, heterogeneous catalysts
offer several advantages such as mild reaction condi-
tions, high selectivity, high throughput and ease of
work-up procedures. Among the various solid acid
catalysts investigated, sulfated zirconia has attracted
much attention recently because of its super-acidity,
non-toxicity and low cost.15–21 Sulfated zirconia cata-
lyzes many reactions under very mild conditions in the
vapor phase as well as in the liquid phase. It is finding
applications in the preparation of large volume chemi-
cals, especially in the petrochemical industry for light
alkane isomerization and alkylation reactions. Excel-
lent articles can be found in the literature on the
industrial applications of zirconia solid superacid cata-
lysts.15,18,21
Scheme 1.
Keywords: o-phenylenediamine; benzodiazepines; superacid; sulfated zirconia.
* Corresponding author. Fax: 91-40-27160921; e-mail: bmreddy@iict.ap.nic.in
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01034-7

4448
B. M. Reddy, P. M. Sreekanth / Tetrahedron Letters 44 (2003) 4447–4449
In this communication we report a facile method for
the synthesis of 2,3-dihydro-1H-1,5-benzodiazepines by
the condensation of o-phenylenediamine with ketones
under solvent free conditions catalyzed by a solid
superacid catalyst (Scheme 1).
filtration. The organic layer was concentrated and the
product was purified by silica gel chromatography (60–
120 mesh) being eluted by an ethyl acetate and n-hex-
ane (2:8 v/v) mixture. The wet catalyst was recycled and
no appreciable change in activity was noticed after a
few cycles. As is evident from Table 1, the sulfated
zirconia catalyzed condensation reactions give rise to
excellent yields under ambient conditions in relatively
short reaction times (2–3 h). We also tested the title
reaction with the acidic zeolite H-ZSM-5. Although this
catalyst was active for the condensation reactions, the
yields were insignificant when compared to those with
the sulfated zirconia catalyst, especially in the case of
cyclic ketones.
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 sulfated zirconia in a
round bottom flask with stirring at ambient conditions
for the appropriate time. The reaction proceeds
efficiently under ambient conditions giving good to
excellent yields of 1,5-benzodiazepines. Cyclic ketones
such as cyclohexanone also reacted effectively to pro-
duce the corresponding fused ring benzodiazepines. The
results are summarized in Table 1. Completion of the
reaction was monitored by TLC; NMR and GC–MS
were used for analysis of the products. After comple-
tion of the reaction, 10 ml of CH2Cl2 was added to the
reaction mixture and the catalyst was recovered by
In conclusion, the use of SO42−/ZrO2 solid superacid
catalyst for the synthesis of 2,3-dihydro-1H-1,5-benzo-
diazepines from o-phenylenediamine and ketones is an
environmentally benign and atom economic process.
The easy work-up procedure and recyclable catalyst
Table 1. Condensation of o-phenylenediamine with various ketones under solvent free conditions catalyzed by sulfated
zirconia. All the reactions were completed in 2–3 h

B. M. Reddy, P. M. Sreekanth / Tetrahedron Letters 44 (2003) 4447–4449
4449
makes this methodology attractive for large-scale
operations.
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Preparation of the catalyst. Zirconium hydroxide was
prepared from an aqueous solution of zirconium oxy-
chloride by the addition of dilute NH4OH. About 25 g
of ZrOCl2·8H2O (Aldrich, GR Grade) was dissolved in
doubly distilled water; the pH of the resulting solution
was 2. To this solution, dilute aqueous ammonia was
added drop-wise from a burette with vigorous stirring
until the pH of the solution reached 8. The precipitate
obtained was washed with distilled water several times
until free from chloride ions and then dried at 393 K
for 24 h. The sample thus obtained was ground to a
fine powder and immersed in an 0.5 M H2SO4 solution
(30 ml) for 30 min. Excess water was evaporated on a
water bath and the resulting sample was oven dried at
393 K for 12 h and calcined at 873 K for 4 h. The
X-ray powder diffraction analysis of the sample
revealed the presence of tetragonal zirconia and XPS
measurements confirmed a highly stabilized zirconia
sulfate species.22,23
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Acknowledgements
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muir 1998, 14, 3019.
P.M.S. thanks CSIR, New Delhi, for the award of
senior research fellowship.
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