Perchloric acid supported on silica catalyzed efficient synthesis of 1,5-benzodiazepines

Article abstract of DOI:10.1080/00397910701572936

Perchloric acid adsorbed on silica gel efficiently catalyzed the condensation of o-phenylenediamines (OPDA) with cyclic and acyclic ketones at ambient temperature to afford 1,5-benzodiazepines in good yields under solvent-free conditions. Copyright Taylor

Full text of DOI:10.1080/00397910701572936

Synthetic Communicationsw, 37: 4117–4122, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701572936
Perchloric Acid Supported on Silica
Catalyzed Efficient Synthesis of
1,5-Benzodiazepines
H. M. Meshram, P. N. Reddy, P. Vishnu Murthy, and
J. S. Yadav
Organic Chemistry Division I, Indian Institute of Chemical Technology,
Hyderabad, India
Abstract: Perchloric acid adsorbed on silica gel efficiently catalyzed the condensation
of o-phenylenediamines (OPDA) with cyclic and acyclic ketones at ambient tempera-
ture to afford 1,5-benzodiazepines in good yields under solvent-free conditions.
Keywords: HClO4-SiO2, ketones, o-phenylenediamines
INTRODUCTION
Benzodiazepin and its derivatives constitute an important class of biologically
active compounds showing remarkable therapeutic and pharmacological proper-
ties. They are extensively used as anticonvulsant, antianxiety, analgesic, sedative,
antidepressive, and hypnotic agents.[1,2] In addition, 1,5-benzodiazepines also
serve as key intermediates en route to a wide array of fused ring compounds
such as triazolo-, oxadiazolo-, oxazino-, or furano-benzdiazepines.[3] 1,5-Benzo-
diazepines are usually obtained through the condensation of o-phenylenediamines
with ketones in the presence of BF3-etherate,[4] polyphosphoric acid,[5] NaBH4,[6]
MgO/POCl3,[7] metal triflates,[8] InBr3,[9] and ionic liquid[10] and under
microwave conditions.[11] However, many of these methods suffer from one or
more disadvantages such as harsh reaction conditions, extreme temperatures,
Received April 30, 2007
Address correspondence to H. M. Meshram, Organic Chemistry Division I, Indian
Institute of Chemical Technology, Hyderabad 500 007, India. E-mail: hmmeshram@
yahoo.com
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H. M. Meshram et al.
relatively long reaction times, use of toxic or expensive reagents, and occurrence
of side reactions, which limit their use, especially in large-scale synthesis. As a
consequence, there is need to find a simple, efficient, economical protocol for
the synthesis of 1,5-benzodiazepines.
In recent years, heterogeneous catalysts have gained prominence because
of environmental and economical considerations.[12] Recently, an interesting
reagent, HClO4 supported on silica gel, has been used as a stable and highly
efficient catalyst in organic transformations.[13] This reagent is nontoxic, inex-
pensive, and environmentally acceptable. It also has excellent activity even on
an industrial scale and in most cases can be recovered from reaction mixtures
and reused. Because of its moisture insensitivity, ease of handling, and
environmental friendliness, we disclose here the catalytic efficiency of
HClO4–silica for the synthesis of 1,5-benzodiazepines.
RESULTS AND DISCUSSION
The reaction of o-phenylenediamine (1) and acetone was carried out at
ambient temperature in the presence of a catalytic amount of HClO4-SiO2
under solvent-free conditions. Complete conversion was achieved within 1 h
to furnish 1,5-benzodiazepine 3a in 92% yield (Scheme 1).
In a similar manner, electron-rich and electron-deficient o-phenylene-
diamines such as 4-methyl, 4,5-dimethyl, and 4-chloro reacted with
various ketones to give the corresponding benzodiazepines in good yields
under similar conditions. Our results are summarized in Table 1. After com-
pletion of reactions, it does not require any workup, as mere filtration of the
catalyst is sufficient. The recovered catalyst can be reused at least four to five
times with gradual decrease in activity. For instance, o-phenylenediamine
with acetone gave 92, 88, 82, and 79% yields over four cycles. The crude
products were purified either by recrystallization from n-hexane or by
silica-gel column chromatography. However, the synthesis could not be
achieved in the absence of catalyst.
The reactions are completed within 1.0–2.0 h and yields ranging from 78 to
95% depending upon the nature of the substrate. Cyclic ketones such as cyclo-
hexanone and cyclopentanone also reacted well to produce the corresponding
Scheme 1.

Synthesis of 1,5-Benzodiazepnes
4119
Table 1. Synthesis of 1,5-benzodiazepinesa using HCLO4-SiO2
Time Yieldb
Entry
a
Diamine 1
Ketone 2
Producta 3
(h)
(%)
CH3COCH3
1.0
92
b
PhCOCH3
1.5
90
c
CH3CH2COCH2CH3
1.5
1.0
86
93
d
e
f
PhCOCH3
2.0
1.5
2.0
79
95
87
g
PhCOCH3
h
i
CH3COCH3
1.0
2.0
94
78
CH3CH2COCH3
aAll the products were characterized by 1H NMR, mass, and IR spectra data.
bIsolated yields.
fused-ring benzodiazepines (entries d and f). In case of an unsymmetrical ketone
such as 2-butanone, the ring closure occurs regioselectively from only one side
of the carbon skeleton, giving a single product. The catalyst can be easily
prepared[13a] and can be handled safely. The reaction conditions are mild so

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H. M. Meshram et al.
that no side products or decomposition of the products are observed. All
1
products were characterized by H NMR, IR, and mass spectra and also
confirmed by direct comparison with known compounds.[4–11] The reaction
presumably proceeds via an intramolecular imine–enamine cyclization
promoted by catalyst.
In summary, HClO4-SiO2 is found to be a new and highly efficient
catalyst for the synthesis of 1,5-benzodiazepines. The notable advantages of
this protocol, such as simplicity in operation, the low-cost catalyst, ease of
handling, solvent-free conditions, high yields of products in short reaction
times, and reusability of the catalyst make it a valuable alternative to the
existing catalysts reported in the literature.
EXPERIMENTAL
IR spectra were recorded on either a Perkin-Elmer spectrophotometer or on
1
the IR Nicole 740 FT-IR. H NMR was recorded in Gemini at 200 MHz
using TMS as an internal standard. M/s was recorded on a Micromass
7070 h or Finnigan Mat 1020 B mass spectrometer operating at 70 eV.
Thin-layer chromatography (TLC) was done on precoated silica-gel-60f 254
(0.5-mm) glass plates.
General Procedure
To a stirred mixture of o-phenylenediamine (1 mmol) and ketone (2.5 mmol),
HClO4-SiO2 (50 mg) was added at ambient temperature. After completion of
the reaction, as indicated by TLC, the mixture was diluted with dichloro-
methane, and the catalyst was allowed settle down. Then reaction mixture
was filtered, the catalyst was washed with dichloromethane, and the
combined organic extract was dried over Na2SO4, concentrated in vacuo,
and purified by column chromatography on silica gel (Merck, 100–200
mesh) ethyl acetate–hexane (1:9) to afford pure 1,5-benzodiazepine. The
recovered catalyst was activated by heating at 808C under vacuum for 2 h
and reused.
SPECTRAL DATA FOR SELECTED COMPOUNDS
Spiro[cyclohexane-1,110-(20,30,40,100,110,11a0-hexahydro-10H-
bibenzo[b,e][1,4]diazepine)] (3d)
1H NMR (300 MHz, CDCl3) d: 1.22–1.94 (m, 16H), 2.18 (s, 6H), 2.45–2.58
(m, 3H), 6.40 (s, 1H), 7.00 (s, 1H). IR (KBr): v 3443, 2925, 1634, 1452 cm21
EIMS: m/z: 228 Mþ.
.

Synthesis of 1,5-Benzodiazepnes
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2,2,4-Trimethyl-2,3-dihydro-1H-benzo[b][1,4]diazepin-8-yl
Chloride (3h)
1H NMR (300 MHz, CDCl3) d: 1.31 (m, 6H), 2.18 (s, 1H), 2.22 (s, 1H), 2.31
(s, 3H), 2.96 (brs, NH), 6.55–7.06 (m, 3H). IR (KBr): v 3422, 2961, 1640,
1472 cm21. EIMS: m/z: 222 Mþ.
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