An efficient one-pot synthesis of 1,5-benzodiazepine derivatives catalyzed by TBAB under mild conditions

Article abstract of DOI:10.1155/2012/657439

2,3-Dihydro-1H-1,5-benzodiazepines were synthesized by reaction of o-phenylenediamine with ketones (acyclic / cyclic) under solvent free conditions in the presence of tetra butyl ammonium bromide (TBAB) in short reaction time with excellent yield.

Full text of DOI:10.1155/2012/657439

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2012, 9(1), 407-414
http://www.e-journals.net
An Efficient One-Pot Synthesis of
1, 5-Benzodiazepine Derivatives Catalyzed by
TBAB under Mild Conditions
MOHAMMAD A BASEER and ASGAR JAFAR KHAN*
Organic Chemistry Research Laboratory
Yeshwant Mahavidyalaya, Nanded-431602, India
*Laboratory of Organic Synthesis
Milliya College, Beed-431122, India
khan_asgar@yahoo.com
Received 18 June 2010; Accepted 1 March 2011
Abstract: 2,3-Dihydro-1H-1,5-benzodiazepines were synthesized by reaction of
o-phenylenediamine with ketones (acyclic / cyclic) under solvent free conditions
in the presence of tetra butyl ammonium bromide (TBAB) in short reaction time
with excellent yield.
Keywords: Tetra butyl ammonium bromide, 1, 5-Benzodiazepine, o-Phenylenediamine, Ketones,
Short reaction time
Introduction
Benzodiazepines and their derivatives are important class of nitrogen containing
heterocyclic compounds because of their pharmacological properties1. So many members of
this family are nowadays mostly used as anti-anxiety, anti-inflammatory, tranquilizing, anti-
convulsant, anti-depressive, anti-bacterial, analgesic, sedative and hypnotic agents2. The first
benzodiazepine was introduced as a drug nearly thirty years before3. They are also used
against viral disease and cardiovascular disorder4. Some benzodiazepine derivatives are used
in fine chemical industries such as photographical dyes for acrylic fiber5 they are used as a
valuable synthons for the synthesis of fused ring benzodiazepines class of compounds like
triazolo, oxadiazolo, oxazino and furano-benzodiazepines6 due to their wide demand they
have received a great attention of different chemist. According to the literature survey
several synthetic methodology have been introduced for the synthesis of benzodiazepines,
these include condensation of o-phenylenediamine with α-β unsaturated carbonyl
compounds7, β haloketones8 or ketones in the presence various catalyst such as BF3OEt9,
NaBH410, PPA- SiO211, MgO-POCl312, Yb(OTf)313, amberlyst-1514, Ag3PW12O4015, solid

408
M. A. BASEER et al.
super acid sulphated zirconia16, acetic acid – under MWI17, AgNO318, zinc montmorilonite
as catalyst at r.t19 and ionic liquid20,21. However these methodologies have several
disadvantages such as harsh reaction condition, long reaction time, expensive reagents, low
yield, tedious workup and formation of side products. Keeping in mind in the present study
we have develop a one pot synthesis of 1, 5-benzodiazepines by condensation of
o-phenylenediamine with ketones under mild conditions catalyzed by tetrabutylammonium
bromide (Scheme 1).
Experimental
A mixture of o-phenylenediamine (10 mmole), ketones (20 mmole) and phase transfer
o
catalyst TBAB (catalytic amount) was reflux for 50 min in ethyl alcohol (10 mL) at 60 C,
after completion of reaction (monitored by TLC) the reaction mixture was cooled and
poured on crushed ice, extracted from ethyl acetate (30 mL) and washed with water and
brine (20 mL each). The solvent was removed by distillation under reduced pressure. The
crude product was purified by column chromatography (eluent, ethyl acetate – pet-ether).
The corresponding 1, 5 benzodiazepines and fused ring benzodiazepine derivatives were
obtained in 85-95% yield.
R
O
N
N H 2
T B A B ,E tO H
C
2
oC
60
50 m in ,
,
C H 3
R
N H 2
N
H
Me
R
2
3
1
O
N
N H 2
N H 2
T B A B ,E tO H
,
2
oC
,
6 0
50m in
N
H
2
3
1
Scheme 1
Characterizations
All H1 NMR spectra were recorded in CDCl3 on a Brucker AC 200 and Brucker MSL 300
spectrometers and chemical shift were reported in ppm downfield from tetra methyl silane.
Infrared spectra were recorded on a PerkinElmer infra red spectrophotometer using KBr
discs, TLC was performed on silica gel coated aluminum plates using ethyl acetate and pet
ether (3:7 v/v) as eluent, melting points were determined on an electronic melting point
apparatus and were uncorrected.
Results and Discussion
Tetrabutylammonium bromide (TBAB) is a cheap and readily available reagent it efficiently
catalyze the condensation of ketones with o-phenylenediamine at 60 oC, under mild
conditions, in short reaction time (50 min) with excellent yield of the product. In the present
study, o-phenylenediamine, cyclic /acyclic ketones and catalytic amount of TBAB were
reflux at 60 oC in 10 mL ethyl alcohol after completion of the reaction (monitored by TLC)
the series of corresponding1,5 benzodiazepines and fused ring benzodiazepine derivatives were

An Efficient One-Pot Synthesis of 1, 5-Benzodiazepine
409
obtained in 85-95% yield. Whereas the yield is comparatively lower in presence of other
PTC such as tricaprilmethylammonium chloride (Aliquat-336) and triethylbenzyl-
ammonium chloride (TEBA) etc. The results are summarized in Table 1. The structures of
the synthesized compounds were established by their mp, IR and H1 NMR spectroscopy. The
1H NMR and IR spectrum of selected compounds (3a, 3d, 3f, 3g and 3i) obtained are shown
in the Figures 1 -7 respectively.
Table 1. TBAB-catalyzed synthesis of 1, 5-benzodiazepines under mild conditions
_______________________________________________________________
o
0
Entry
Ketone{2}
Products{3}
Yield(%)
Yield, %
M.P( C)
mp, C
________________________________________________________________
Me
N
Me
Me
85
86
144 -145
a
O
N
H
Me
Me
N
138 -139
b
c
N
H
O
N
88
136 -138
138 -140
O
N
H
N
O
85
85
95
d
e
N
H
N
138 -140
O
N
H
O
N
150 -152
f
N
H
O
N
Me
Me
88
g
140 -142
N
H
Me
N
92
142 -144
h
N
H
O
O
OH
OH
N
88
145 -147
i
HO
N
H

410
M. A. BASEER et al.
Me
Me
N
N
H
Me
Figure 1. 1H NMR spectra of (3a)
Me
Me
N
N
H
Me
Figure 2. IR spectra of (3a)

An Efficient One-Pot Synthesis of 1, 5-Benzodiazepine
411
N
N
H
Figure 3. 1H NMR spectra of (3d)
N
N
H
Figure 4. IR spectra of (3d)

412
M. A. BASEER et al.
N
Me
Me
N
H
Figure 5. 1H NMR spectra of (3g)
N
Me
Me
N
H
Figure 6. IR spectra of (3g)

An Efficient One-Pot Synthesis of 1, 5-Benzodiazepine
413
OH
OH
N
N
H
Figure7. 1H NMR spectra of (3i)
Spectral data for selected compounds
3a. IR (KBr): 3389, 2970, 1631,1591,1470,1100,744 cm-1; H1 NMR (CDCl3): δ= 1.1 (s, 6H),
1.4 (s, 2H), 1.90 (s, 3H), 3.6 (brs, 1H), 5.9-7.0 (m, 4H); MS (m/z):188 (M+) 3d. IR (KBr):
3377,1664,1599,1440,750 cm-1; H1 NMR (CDCl3): δ= 0.7-1.5 (m, 16H), 1.7-2.2 (m, 3H),
3.56 (brs, 1H), 6.1-7.0 (m, 4H). 3f. IR (KBr): 3377, 1631 cm-1; H1 NMR (CDCl3): δ= 1.34
(s, 3H), 2.2 (d, 1H, J=12.8 Hz), 2.4 (d, 1H, J=12.8Hz), 3.6 (brs, 1H), 7.7 - 7.1 (m, 14H). 3g.
IR (KBr): 2922, 1600, 1356,746 cm-1; H1 NMR (CDCl3): δ= 2.13 (s, 6H), 1.24 (s, 3H), 2.4
(d, 1H, J=6.9 Hz), 2.5 (d, 1H J= 6.9 Hz), 3.67 (brs, 1H), 6.0-6.66 (m, 4H), 6.72-7.2 (m, 8H);
3i. IR (KBr): 3377, 1631, 1440 cm-1; H1 NMR (CDCl3): δ= 1.3 (s, 3H), 2.2 (d, 1H), 2.49
(d, 1H), 3.6 (brs, 1H), 8.4 (s,1H), 8.87 (s,1H), 6.3- 6.7 (m, 4H), 6.8 -7.2 (m, 8H)
Conclusion
We have developed a new, mild and efficient method for the synthesis of 1, 5-benzodiazepines.
The workout procedure is easy, environmental friendly and inexpensive catalyst, short
reaction time, reaction mild reaction conditions and in excellent yield.
Acknowledgment
The present study was sponsored by the University Grants Commission, New Delhi for
which our gratitude is expressed. Authors also thankful to the Principal, Milliya College,
Beed and Principal Yeshwant College, Nanded for providing all research facilities.
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