Room temperature ionic liquid promoted synthesis of 1,5-benzodiazepine derivatives under ambient conditions

Article abstract of DOI:10.1016/S0040-4039(03)00096-0

The reaction of o-phenylenediamines with both acyclic and cyclic ketones in the ionic liquid 1,3-di-n-butylimidazolium bromide afforded 1,5-benzodiazepines in excellent isolated yields in the absence of a catalyst at ambient temperature.

Full text of DOI:10.1016/S0040-4039(03)00096-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1835–1838
Room temperature ionic liquid promoted synthesis of
1,5-benzodiazepine derivatives under ambient conditions
D. V. Jarikote, S. A. Siddiqui, R. Rajagopal, Thomas Daniel, R. J. Lahoti and K. V. Srinivasan*
Division of Organic Chemistry; Technology, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
Received 12 November 2002; revised 24 December 2002; accepted 10 January 2003
Abstract—The reaction of o-phenylenediamines with both acyclic and cyclic ketones in the ionic liquid 1,3-di-n-butylimidazolium
bromide afforded 1,5-benzodiazepines in excellent isolated yields in the absence of a catalyst at ambient temperature. © 2003
Elsevier Science Ltd. All rights reserved.
presence of BF3–etherate,11 NaBH4,12 polyphosphoric
Benzodiazepines are an important class of pharmaco-
acid or SiO2,13 MgO/POCl3,14 Yb(OTf)3,15
logically active compounds finding application as anti-
convulsant, antianxiety and hypnotic agents.1,2
Al2O3/P2O5 or AcOH under microwave irradiation
(MW).16,17 Many of these processes suffer from one or
other limitations such as requiring harsh conditions,
expensive reagents, low to moderate yields, relatively
long reaction times and occurrence of several side reac-
tions. Almost all of them make use of an acid catalyst
giving rise to tedious work-up procedures for their
separation and recycling or disposal problems.
Benzodiazepine derivatives also find commercial use as
dyes for acrylic fibers3 and as anti-inflammatory
agents.4 Moreover, they are key intermediates for the
preparation of other fused ring compounds such as
triazolo-,5 oxazino-,6 oxadiazolo-,7 or furano-benzodi-
azepines.8 The literature methods for the synthesis of
1,5-benzodiazepines many of which have been reported
recently, include condensation reactions of o-
phenylenediamines with a,b-unsaturated carbonyl com-
pounds,9 b-haloketones,10 or with ketones in the
In recent years, the use of room temperature ionic
Scheme 1.
Keywords: benzodiazepines; ionic liquid; o-phenylenediamines; green solvent.
* Corresponding author. E-mail: kvsri@dalton.ncl.res.in
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00096-0

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D. V. Jarikote et al. / Tetrahedron Letters 44 (2003) 1835–1838
The results are summarized in Table 1. As is evident,
the reactions in I.L. gave rise to excellent isolated yields
of the 1,5-benzodiazepines in a relatively short reaction
time (50 min). The isolated benzodiazepines 3 were
completely characterized by IR, 1H and 13C NMR
analyses, and their melting points.21 The elemental
analyses were in agreement with their structures. The
benzodiazepines 3 were the only products obtained and
the rest of the material was essentially starting material.
The I.L. could be recovered and recycled at least three
times for the reaction of the OPD with acetone without
incurring any loss in yield of the benzodiazepine 3a.
liquids (I.L.s) as ‘green’ solvents in organic synthetic
processes has gained considerable importance due to
their solvating ability, negligible vapor pressure, easy
recyclability and reusability.18 Very recently, we have
reported the use of 1,3-di-n-butylimidazolium salts as
newer I.L.s as solvents for promoting the sonochemical
Heck and Suzuki reactions under ambient conditions.19
In continuation of our investigations of organic trans-
formations in ionic liquids acting both as media and
promoters, this communication reports for the first time
a regioselective synthesis of 1,5-benzodiazepine deriva-
tives in excellent isolated yields and in relatively short
reaction times using the I.L., 1,3-n-dibutylimidazolium
bromide ([bbim]Br), at ambient temperature in the
absence of any added catalyst.
No reaction was observed when OPD was reacted with
acetone under similar conditions in the absence of the
I.L., thus highlighting the role of the I.L. as a pro-
moter. It was also ascertained that a minimum of an
equimolar proportion of the I.L. with respect to the
OPD is needed to achieve optimum conversion. Any
excess of I.L. beyond this proportion did not show any
further increase in conversion and yield.
ortho-Phenylenediamine (OPD) and substituted OPD’s
were reacted with both acyclic and cyclic ketones in the
I.L. [bbim]Br at 28°C in the absence of any added
catalyst (Scheme 1).20
Table 1. Synthesis of benzodiazepines 3 in [bbim]Br

D. V. Jarikote et al. / Tetrahedron Letters 44 (2003) 1835–1838
1837
The reaction of OPD with acetone when performed
under similar conditions in the I.L. n-Butyl pyridinium
tetrafluoroborate showed no conversion whereas the
I.L. ethyl ammonium nitrate showed only 53% conver-
sion. The use of [bbim]BF4 and [bmim]Br gave similar
results as for [bbim]Br.
84–91; (b) Zhang, X. Y.; Xu, J. X.; Jin, S. Chin. J. Chem.
1999, 17, 404–410.
8. Reddy, K. V. V.; Rao, P. S.; Ashok, D. Synth. Commun.
2000, 30, 1825–1836.
9. Stahlofen, P.; Ried, W. Chem. Ber. 1957, 90, 815–824.
10. Ried, W.; Torinus, E. Chem. Ber. 1959, 92, 2902–2916.
11. Herbert, J. A. L.; Suschitzky, H. J. Chem. Soc., Perkin
Trans. 1 1974, 2657–2661.
The enhanced reactivity for the synthesis of the benzo-
diazepines in the imidazolium I.L. even in the absence
of a catalyst may be attributed to the inherent Brønsted
and Lewis acidities of the ring hydrogens H2, H4 and
H5 of the imidazolium cation in [bbim]Br. Previous
studies involving multi-nuclear NMR spectroscopy and
conductivity measurements for the imidazolium ions
correlating their acidity characteristics support the
above observations.22–24 Further work is in progress to
enhance the acidities of such I.L.s by incorporating
weakly coordinating anions and to study their efficacy
in promoting similar reactions.
12. Morales, H. R.; Bulbarela, A.; Contreras, R. Heterocy-
cles 1986, 24, 135–139.
13. Jung, D. I.; Choi, T. W.; Kim, Y. Y.; Kim, I. S.; Park, Y.
M.; Lee, Y. G.; Jung, D. H. Synth. Commun. 1999, 29,
1941–1951.
14. Balakrishna, M. S.; Kaboudin, B. Tetrahedron Lett. 2001,
42, 1127–1129.
15. Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.
Tetrahedron Lett. 2001, 42, 3193–3195.
16. Kaboudin, B.; Navace, K. Heterocycles 2001, 55, 1443–
1446.
17. Minothora, P.; Julia, S.-S.; Constantinos, A. Tetrahedron
In conclusion, we have developed a new and efficient
method for the regioselective synthesis of 1,5-benzodi-
azepines in excellent isolated yields in short reaction
times using a room temperature ionic liquid viz.
[bbim]Br as a reaction medium for the first time.
Importantly, the I.L. not only acts as a solvating
medium but also as a promoter for the reaction giving
rise to twin advantages of ambient temperature condi-
tions and the non-requirement of a catalyst. The easy
work-up procedures, the absence of a catalyst and
recyclability of the non-volatile I.L. used as the reaction
medium makes the method amenable for scale-up
operations.
Lett. 2002, 43, 1755–1758.
18. (a) Welton, T. Chem. Rev. 1999, 99, 2071–2083; (b)
Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. Engl.
2000, 39, 3772–3789; (c) Earle, M. J.; Seddon, K. R. Pure
Appl. Chem. 2000, 72, 1391–1398; (d) Gordon, C. M.
Appl. Catal. A: General 2001, 222, 101–117; (e) Sheldon,
R. Chem. Commun. 2001, 2399–2407.
19. (a) Deshmukh, R. R.; Rajagopal, R.; Srinivasan, K. V.
Chem. Commun. 2001, 1544–1545; (b) Rajagopal, R.;
Jarikote, A.; Dilip, V.; Srinivasan, K. V. Chem. Commun.
2002, 616–617.
20. Typical procedure:
The I.L. [bbim]Br was prepared as per the reported
procedure.19
A solution of OPD/substituted OPD 1 (4.62 mmol) and
the ketone 2 (9.72 mmol) in [bbim]Br (4.62 mmol) was
stirred at 28°C for 50 min. The completion of reaction
was followed by TLC using 30% EtOAc in petroleum
ether as eluent. After completion, the reaction mixture
was diluted with water (25 ml) and extracted with EtOAc
(2×15 ml). The combined organic layer was separated,
dried over anhydrous sodium sulphate and the solvent
evaporated under reduced pressure to afford the 1,5-ben-
zodiazepines. The products, thus isolated, were pure (sin-
gle spot on TLC). They were subjected to further
purification by chromatography through a column of
silica-gel using 20% EtOAc in petroleum ether as eluent
and fully characterized. The aqueous layer consisting of
the I.L. was subjected to distillation (80°C at 10 mmHg)
for 2 h to remove water, leaving behind the I.L. [bbim] Br
(recovery 98%), which could be recycled.
Acknowledgements
Financial assistance from DST, New Delhi (Project,
SR¯S5¯OC-23¯2002) is gratefully acknowledged.
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3d. Mp 92°C (found C, 84.53; H, 6.85; N, 8.62. C23H22N2
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1
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a
b
CH2 ), 3.13–3.17 (d, 1H, J=13, CH2 ), 3.5 (br s, 1H,
NH), 6.70–7.69 (m, 13H, Ar-H); 13C NMR (50 MHz,
CDCl3) l 164.6, 136.9, 134.0, 131.2, 130.8, 129.0, 128.6,
128.5, 128.3, 128.2, 127.4, 126.3, 125.7, 123.5, 113.5, 51.0,
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1838
D. V. Jarikote et al. / Tetrahedron Letters 44 (2003) 1835–1838
(cm−1) 3268 (NH), 1665 (CꢀN); 1H NMR (200 MHz,
and NꢀC-CH2), 4.99 (br s, 1H, NH), 7.00–7.50 (m, 3H,
Ar-H); 13C NMR (50 MHz, CDCl3) l 164.6, 134.0, 132.7,
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3H, CH3), 1.42 (d, 6H, J=7.2, NꢀC-CH (CH3)2),
1.85 (m, 1H, CH (CH3)2), 2.1 (m, 1H, CH (CH3)2),
a
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19H, 8×CH2 and Ar-CH3), 2.95–3.29 (m, 3H, NꢀC-CH