RuCl3·xH2O: A novel and efficient catalyst for the facile synthesis of 1,5-benzodiazepines under solvent-free conditions

Article abstract of DOI:10.1080/00397910802109273

1,5-Benzodizepines are synthesized in excellent yields via condensation of o-phenylenediamine with ketones having a hydrogen at the α-position. The reaction is performed in solvent-free conditions and 5 mol% of RuCl ₃·xH₂O is enough

Full text of DOI:10.1080/00397910802109273

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RuCl ·xH O: A Novel and
3
2
Efficient Catalyst for the
Facile Synthesis of 1,5-
Benzodiazepines Under
Solvent-Free Conditions
a
a
a
Suresh , Anil Saini & Jagir S. Sandhu
a
Department of Chemistry, Punjabi University,
Patiala, Punjab, India
Published online: 09 Sep 2008.
To cite this article: Suresh , Anil Saini & Jagir S. Sandhu (2008) RuCl ·xH O: A Novel
3
2
and Efficient Catalyst for the Facile Synthesis of 1,5-Benzodiazepines Under Solvent-
Free Conditions, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:18, 3193-3200
To link to this article: http://dx.doi.org/10.1080/00397910802109273
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Synthetic Communications , 38: 3193–3200, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802109273
RuCl ꢀ xH O: A Novel and Efficient Catalyst
3
2
for the Facile Synthesis of 1,5-Benzodiazepines
Under Solvent-Free Conditions
Suresh, Anil Saini, and Jagir S. Sandhu
Department of Chemistry, Punjabi University, Patiala, Punjab, India
Abstract: 1,5-Benzodizepines are synthesized in excellent yields via condensation
of o-phenylenediamine with ketones having a hydrogen at the a-position. The
reaction is performed in solvent-free conditions and 5 mol% of RuCl
enough to direct the reaction to completion.
3
2
ꢀ xH O is
Keywords: 1,5-Benzodizepines, o-phenylenediamine, ketones, RuCl ꢀ xH O,
3
2
solvent-free
1
1
The discovery of chlordiazepoxide (Librium ) and diazepam (Valium )
[
1]
in the mid-fifties by Hoffman–LaRoche, which are highly effective cen-
tral nervous system (CNS) agents, led to very intensive research around
the world in benzodiazepine chemistry, and as a result of this research,
today nearly 24 molecules from this group are in clinical use with very
focused bioactivities. This 1,5-Benzodiazepines presently is identified as
one of the privileged molecules of organic chemistry. This scaffold has
shown a variety of promising biological activities such as antianxiety,
[
2]
anticonvulsant, hypnotic, sedative, and antidepressive activities. Also,
these molecules are good synthons for the production of fused-ring
[
3]
compounds such as oxazino-, triazolo-, or furano-benzodiazepines.
Benzodiazepines also find use in syntheses of commercially available dyes
[
4]
and acrylic fibers. As a consequences of their wide range of synthetic,
biological, and industrial applications, these compounds are of great
importance to chemists for assembling these molecules more efficiently
and do not have any environmental problems, making them readily
Received February 1, 2008.
Address correspondence to Jagir S. Sandhu, Department of Chemistry, Punjabi
University, Patiala 147 002, Punjab, India. E-mail: j_sandhu2002@yahoo.com
3
193

3194
Suresh, A. Saini, and J. S. Sandhu
available for further biological screenings. The simplest process for their
production seems to be catalyzed condensation of 1,2-diamines with
ketones having a proton at a-carbon. To achieve this, a variety of cata-
[
5]
lysts have been employed such as BF ꢀ OEt , polyphosphoric acid–
3
2
[
6]
[7]
[8]
[9]
[10]
SiO , NaBH , MgO–POCl , Al O –P O , YbCl3, Yb(OPf)3,
[11]
2
4
3
2
3
2
5
[12]
and ionic liquids.
In spite of some good procedures available to che-
mists, many of these suffer from disadvantages such as requirements
for anhydrous conditions, use of strong acid or organic solvents, elevated
temperature, and prolonged reaction time. Evidently, several of these
catalysts break up to even more hazardous and nondegradable toxic
compounds during aqueous workup. Therefore, the search for a safe
and mild method for synthesis of these important molecules is a conti-
[13]
nuing subject of investigations.
Applications of RuCl ꢀ xH O in organic synthesis are of current
3
2
interest because of its various attractive properties such as mildness,
selectivity, and solubility in organic solvents. RuCl ꢀ xH O has been
3
2
[
successfully used for the deoxygenation of organic N-oxides, cleavage
14]
[
15]
[16]
of epoxides to yield trans diols, and selective protection of aldehydes
as acylals. The utility of RuCl ꢀ xH O has also been extended to other
3
2
important named reactions of organic chemistry such as the Biginelli
reaction,
[
17]
[18]
[19]
Prins reaction,
aldol reaction,
and Strecker synthesis
[20]
of a-amino nitriles. In addition to this, when employed with oxidants
such as H O and NaIO , it facilitates oxidative transformations such as
2
2
4
N-alkyl pyrrolidines to pyrrolidin-2-ones and Hantzsch 1,4-dihydropyri-
dines to pyridines (interestingly, in the latter case, only aerial oxygen is
used). Because of these promising applications and other attractive fea-
tures of this mild Lewis acid, and also in continuation of our own interest
[
14,16]
in the applications of this mild Lewis acid,
we were prompted to
use RuCl ꢀ xH O in the synthesis of 1,5-benzodizepines (Scheme 1).
3
2
We initiated our investigation with preliminary experiments using
o-phenylenediamine, acetone, and RuCl ꢀ xH O (1:2.5:0.05) by thoroughly
3
2
mixing=stirring the contents at room temperature under solvent-free con-
ditions for 30 min to obtain 1,5-benzodiazepine in 92% yields. In further
investigations, we could achieve excellent results even with 5 mol% of
Scheme 1. Synthesis of 1,5-benzodiazepines.

RuCl
3
2
ꢀ xH O in 1,5-Benzodiazepines Synthesis
3195
RuCl ꢀ xH O. Using a lesser amount of catalyst (2 mol%) resulted in the
3
2
decrease of yield. Increasing the amount of catalyst beyond 5 mol%
10 mol%) did not show any significant influence on the reaction rate or
(
yields. However, this reaction did not yield desirable results in the absence
of catalyst even after mixing of reactants for 20h. To check the efficacy and
applicability of this catalyst, we used several other differently substituted
ketones and could successfully obtain desired products in 79–94% yields
(
Table 1).
Regarding the scope of the reaction variously substituted diamines
with electron-releasing substitutents such as the methyl group at the
-position also reacted with various ketones to afford products in excel-
4
lent yields. Both aromatic and aliphatic ketones (acyclic and cyclic)
reacted well with diamine to furnish corresponding 1,5-benzodizepines
in excellent yields. In the case of unsymmetrical ketones (Table 1, entries
4
, 5, 9), cyclization occurred selectively from one side of the carbon skel-
eton. Only less the sterically hindered primary carbon with an a-hydrogen
involved in the cyclization reaction gave the product. The reaction of
cyclic ketones (Table 1, entries 10, 11) with diamines gave fused-ring
1
,5-benzodizepines.
The reaction is presumed to proceed via the initial formation of
diimine 4 from the reaction of o-phenylenediamine with 2 equivalents
of ketone and the assistance of RuCl ꢀ xH O (Scheme 2). Diimine thus
3
2
formed undergoes a 1,3-hydrogen shift to produce enamine 5, which
cyclizes to form a seven-membered ring.
In summary, the present method employing RuCl ꢀ xH O is a mild,
3
2
efficient, and environmentally benign protocol for the synthesis of 1,5-
benzodizepines. Products are obtained in excellent yields in a short reac-
tion time. Operational simplicity, avoidance of organic solvents, and
anhydrous reaction conditions are the other attractive features that place
this procedure at a superior position over the already existing procedures.
Needless to say, during workup no hazardous or unsafe products were
formed in this new method.
EXPERIMENTAL
Melting points were determined in open capillaries and are uncorrected.
Reagent-grade chemicals were purchased from commercial sources and
used without further purification. IR spectra were recorded in KBr discs
1
on a Perkin-Elmer 240 C analyzer. H NMR spectra were recorded on a
Varian Gemini 300 (300-MHz) spectrometer using TMS as the internal
standard. The progress of the reaction was monitored by thin-layer chro-
matography (TLC) using silica gel G (Merck).

3196
Suresh, A. Saini, and J. S. Sandhu
Table 1. RuCl
3
2
ꢀ xH O-mediated synthesis of 1,5-benzodiazepines
Time
(min)
Yield
b
(%)
a
Entry Substrate
Ketones
Benzodiazepines
c
30 92 , 62 , 93
d
e
1
2
3
35
40
88
79
4
5
30
30
84
85
6
7
8
35
25
35
87
94
90
(
Continued)

RuCl
3
2
ꢀ xH O in 1,5-Benzodiazepines Synthesis
3197
Table 1. Continued
Time
(min)
Yield
b
(%)
a
Entry Substrate
Ketones
Benzodiazepines
9
30
25
30
89
85
82
1
1
0
1
a
All the products were characterized by comparison of their spectral and
physical data with those of authentic samples.
b
Isolated yields.
c
Using 5 mol% of RuCl ꢀ xH O.
3
2
d
e
Using 2mol% of RuCl
3
ꢀ xH
2
O.
O.
Using 10 mol% of RuCl
3
ꢀ xH
2
Scheme 2. Probable reaction path.

3198
Suresh, A. Saini, and J. S. Sandhu
General Procedure for Preparation of 1,5-Benzodizepines
To a stirred mixture of o-phenylenediamine (1 mmol) and ketone
(
2.5 mmol) at room temperature, RuCl ꢀ xH O (0.05 mmol) was
3
2
added. The reaction mixture was stirred for time given in Table 1.
After completion of the reaction (monitored via thin-layer chromato-
graphy, TLC), it was diluted with ethyl acetate (20 mL). The organic
layer was washed with saturated NaHCO3 solution (3 ꢁ 15 mL) and
then with brine. Dying the organic layer over anhydrous Na SO
2
4
and concentrating it under reduced pressure gave the crude product,
which was purified by recrystallization from an ethyl acetate–hexane
mixture.
Representative Spectral Data
2
,2,4-Trimethyl-2,3-dihydro-1H-1,5-benzodiazepine (3a)
ꢂ
ꢃ1
Mp 122–124 C; IR (KBr): 3317, 2970, 1640 cm H NMR (300 MHz,
CDCl ) d ¼ 7.32–7.09 (m, 4H), 3.08 (br s, 1H), 2.40 (s, 3H), 2.27 (s,
3
1
3
2
H), 1.29 (s, 6H); C NMR (75 MHz, CDCl ) d ¼ 174.2, 142.5,
3
138.2, 128.8, 127.1, 126.4, 123.3, 122.5, 70.2, 46.3, 32.8, 30.6; EIMS:
m=z 188.
2
-Methyl-2,4-diphenyl-2,3-dihydro-1H-1,5-benzodiazepine (3b)
ꢂ
ꢃ1
Mp 151–153 C; IR (KBr): 3308, 2962, 1632 cm H NMR (300 MHz,
CDCl ) d ¼ 7.56–7.40 (m, 4H), 7.36–7.09 (m, 7H), 7.01–6.85 (m, 3H),
3
3
1
1
3
.39 (br s, 1H), 3.19 (d, J ¼ 12.5 Hz, 1H), 2.88 (d, J ¼ 12.5 Hz, 1H),
1
3
.78 (s, 3H); C NMR (75 MHz, CDCl ) d ¼ 173.3, 168.5, 147.3,
3
40.1, 139.7, 130.1, 128.4, 127.9, 126.7, 126.1, 125.3, 119.5, 72.4, 45.7,
0.6, 29.5; EIMS: m=z 312.
2
,2,4-Triethyl-3-methyl-2,3-dihydro-1H-1,5-benzodiazepine (3f)
ꢂ
ꢃ1
Mp 143–145 C; IR (KBr): 3306, 2951, 1643 cm H NMR (300 MHz,
CDCl ) d ¼ 7.39–6.82 (m, 4H), 3.53 (br s, 1H), 2.91 (q, J ¼ 6.7 Hz, 1H),
3
2
1
1
.68–2.51 (m, 2H), 1.70–1.48 (m, 2H), 1.40–1.19 (m, 4H), 1.10–0.83 (m,
1
3
0H); C NMR (75 MHz, CDCl ) d ¼ 173.3, 143.8, 139.4, 132.7,
3
28.3, 127.1, 126.3, 126.1, 120.1, 118.8, 70.5, 46.8, 35.3, 29.4; EIMS:
m=z 244.

RuCl
3
2
ꢀ xH O in 1,5-Benzodiazepines Synthesis
3199
ACKNOWLEDGMENT
The authors are thankful to the Council of Scientific and Industrial
Research, New Delhi, India, for financial assistance and to the Indian
National Science Academy, New Delhi, India, for additional financial
support for this research project.
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catalyses aldol condensations of aldehydes
3