A new, efficient and environmentally benign protocol for the synthesis of 1,5-benzodiazepines using cerium(III) chloride/sodium iodide supported on silica gel

Article abstract of DOI:10.1002/adsc.200303196

A novel and green approach has been described for the synthesis of 2,3-dihydro-1H-1,5-benzodiazepines from o-phenylenediamines and ketones using cerium(III) chloride/sodium iodide supported on silica gel under mild and heterogeneous conditions. The reacti

Full text of DOI:10.1002/adsc.200303196

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A New, Efficient and Environmentally Benign Protocol for the
Synthesis of 1,5-Benzodiazepines using Cerium(III)
≤
Chloride/Sodium Iodide Supported on Silica Gel
Gowravaram Sabitha,* G. S. Kiran Kumar Reddy, K. Bhaskar Reddy,
N. Mallikarjuna Reddy, J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax: (þ91)-40-27160512, e-mail: sabitha@ins.iictnet.com
Received: November 2, 2003; Revised: May 6, 2004; Accepted: May 13, 2004
Abstract: A novel and green approach has been de-
scribed for the synthesis of 2,3-dihydro-1H-1,5-ben-
zodiazepines from o-phenylenediamines and ketones
using cerium(III) chloride/sodium iodide supported
on silica gel under mild and heterogeneous condi-
tions. The reactions are carried out at room temper-
ature without using any organic solvent.
ide (CeCl ¥7 H O) has gained much popularity, owing
3 2
to its unique reactivity, ease of handling, low toxicity,
[
14]
moisture and air tolerance. Although the use of the
CeCl ¥7 H Oand NaI system without solvent satisfies
3
2
the demands of environmentally benign ™green∫ chem-
[
15]
istry, in some cases the reactions are sluggish and give
low yields. Therefore cerium(III) chloride/NaI support-
ed on silica gel has been developed by Bartoli and Mar-
[
16]
Keywords: benzodiazepines; cerium(III) chloride;
ketones; Lewis acids; o-phenylenediamines; silica
gel, supported catalysts
cantoni, to improve its utility in organic synthesis.
In the course of our research on applications of CeCl ¥
3
[
17]
7 H Oin various organic transformations, we describe
2
in this report a new, efficient and environmentally be-
nign protocol for the synthesis of 1,5-benzodiazepines
using cerium(III) chloride/NaI supported on silica gel
under solvent-free conditions (Scheme 1). The reaction
Benzodiazepines are an important class of compounds of o-phenylenediamine (1 mmol) with acetone
and find many applications as anticonvulsant, anti-in- (2.2 mmol) was carried out in the presence of
flammatory, anti-anxiety, hypnotic, and anti-depressive 30 mol % of CeCl ¥7 H Oand 30 mol % of NaI sup-
3
2
[1,2]
[16]
agents.
These derivatives are also used as dyes for ported on silica gel (0.5 g/mmol of diamine) under sol-
[3]
acrylic fibres in photography. In addition, benzodiaze- vent-free conditions at room temperature. The reaction
pines are used as synthons for the preparation of other proceeded smoothly to give the corresponding 1,5-ben-
fused ring systems such as triazolo-, oxadiazolo-, oxazi- zodiazepine in 95% yield within 45 minutes. Diethyl
[
4]
no- or furanobenzodiazepines. Due to their wide range ether was added to the reaction mixture and the product
of pharmacological activity, industrial, and synthetic ap- was isolated simply by filtering the mixture and evapo-
plications, the synthesis of 1,5-benzodiazepines has re- rating the solvent from the filtrate and it was further pu-
ceived more attention and recently many methods rified by silica gel column chromatography. In a similar
have been reported for their synthesis. Generally these fashion, o-phenylenediamine and substituted o-phenyl-
compounds are prepared by condensation of o-phenyle- enediamines reacted well with ketones and gave the cor-
nediamines with a,b-unsaturated carbonyl compounds, responding 1,5-benzodiazepines in good to excellent
b-halo ketones or ketones. Many reagents have been re- yields. Cyclic ketones such as cyclopentanone and cyclo-
ported for this condensation reaction in the literature hexanone (entries f and g) also reacted efficiently to af-
[
5]
[6]
which include the use of BF -etherate, NaBH , poly- ford the fused ring benzodiazepines. In all cases the re-
3
4
[
7]
[8]
[9]
phosphoric acid or SiO , MgO/POCl3, Yb(OTf) ,
sulfated zirconia and Al O /P O or AcOH under tained within 40±90 minutes leading to the correspond-
action works well and complete conversion was ob-
2
3
[10]
[12]
2
3
2
5
microwave conditions. Recently these condensations
have also been reported even in an ionic liquid me-
[12]
dium. However, a milder, selective, non-hazardous
and inexpensive reagent is still in demand. [
13]
In recent years, solid supported catalysts have at-
tracted much interest in organic synthesis because of
their high reactivity, stability and selectivity. In particu-
lar, among the lanthanide Lewis acids, cerium(III) chlor- Scheme 1.
Adv. Synth. Catal. 2004, 346, 921±923
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Gowravaram Sabitha et al.
ing 1,5-benzodiazepines in high yields. The scope and ef- Table 1. CeCl
¥7 H O/NaI supported on silica gel catalyzed
2
synthesis of 1,5-benzodiazepines.
3
ficiency of our method are summarized in Table 1. The
products were characterized by spectroscopic methods
1
13
such as IR, H NMR, C NMR and mass spectroscopy
and have also been identified by comparison of spectral
data and mp with those reported. Although these reac-
tions can be accomplished using cerium(III) chloride/
NaI without silica gel support, long reaction times, low
yields of products were observed when compared to
those with the cerium(III) chloride/NaI supported cata-
lyst and moreover, the work-up procedures were not
clean. Other remarkable features of the procedure are
its simplicity, together with the easy and inexpensive
preparation, air stability of the catalyst, and the use of
cerium(III) compounds as environmentally friendly re-
[18]
agents. The catalyst can be easily recovered by filtra-
tion and reused for 4±5 cycles with little decrease in ac-
tivity.
In conclusion, we have developed a novel and envi-
ronmentally friendly method for the synthesis of 2,3-di-
hydro-1H-1,5-benzodiazepines at room temperature us-
ing a cerium(III) chloride/NaI combination adsorbed on
silica gel under solvent free conditions. The advantages
of the present protocol are mild, heterogeneous condi-
tions, shorter reaction times, easy work-up, and low tox-
icity, inexpensive, ready availability, recoverability, re-
cyclability of the catalyst that make the procedure an at-
tractive alternative to the existing methods for the syn-
thesis of 1,5-benzodiazepines.
Experimental Section
Preparation of Solid Supported Catalyst
Silica gel (Merck 60±120 mesh, 0.5 g) was added to a mixture
of cerium(III) chloride (0.113 g, 0.3 equivs.), NaI (0.046 g, 0.3
equivs.) in acetonitrile (8 mL), and the mixture was stirred
overnight at room temperature. The acetonitrile was removed
by rotary evaporation to leave a solid catalyst.
[
[
a]
b]
1
All products were characterized by H NMR, IR, mass
spectral data and mps compared with the literature values.
Yield of isolated products.
1
3
C NMR (75 MHz, CDCl ): d¼20.78, 21.18, 29.80, 42.74,
3
7
1
1
3.09, 121.30, 121.45, 125.13, 125.99, 127.08, 128.49, 128.69,
28.87, 129.13, 136.47, 136.98, 138.16, 139.76, 140.23, 144.95,
67.21; MS: m/z¼340 (M ).
Typical Procedure
o-Phenylenediamine 1e (1 mmol), p-methylacetophenone (2e,
þ
2.2 mmol) and the above solid support catalyst were mixed and
the heterogeneous mixture was stirred rapidly at room temper-
ature for the specified time (see Table 1). After the TLC indi-
cated the disappearance of starting material, diethyl ether was
added and the reaction mixture was filtered to separate the cat-
alyst. The filtrate was concentrated under vacuum and the
product was purified on a small silica gel column eluting with
EtOAc:n-hexane (2:8) to afford a pure product 3e in 84% yield
Acknowledgements
GSKK and NMK thank CSIR, and KBR thanks UGC, New
Delhi for the award of fellowships.
(
isolated yields after each cycle 76%, 63%, 58%). The catalyst
References and Notes
could be recovered and reused for further reactions. Viscous
ꢀ
1
1
liquid; IR (KBr): n¼3325, 1636, 1594 cm
;
H NMR
≥
(
2
200 MHz, CDCl ): d¼1.72 (s, 3H), 2.26 (s, 3H), 2.32 (s, 3H),
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3
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¹ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 921±923

Synthesis of 1,5-Benzodiazepines using Cerium(III) Chloride/Sodium Iodide
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