HSO3-pmim][CH3SO3] as an efficient catalyst for the synthesis of 1,5-benzodiazepine derivatives under ultrasound irradiation

Article abstract of DOI:10.14233/ajchem.2013.14340

1,5-Benzodiazepine derivatives were synthesized in moderate to excellent isolated yields by the condensation reactions of o-phenylenediamine and ketones catalyzed by [1-methyl-3-(3-sulphopropyl)imidazolium methyl sulphate] under ultrasound irradiation usi

Full text of DOI:10.14233/ajchem.2013.14340

Asian Journal of Chemistry; Vol. 25, No. 11 (2013), 6243-6246
http://dx.doi.org/10.14233/ajchem.2013.14340
[
HSO -pmim][CH SO ] as an Efficient Catalyst for the Synthesis of
3 3 3
1
,5-Benzodiazepine Derivatives under Ultrasound Irradiation
1
,2
3
1
1
1,*
1
CHENG LI , QING-HONG HAO , HAI-YAN LIU , CHUN WANG , JING-JUN MA and WEN-GANG ZHU
1
2
3
Hebei Key Laboratory of Bioinorganic Chemistry, College of Sciences, Agricultural University of Hebei, Baoding 071001, P.R. China
Department of Science and Technology Management, Agricultural University of Hebei, Baoding 071001, P.R. China
College of Life Sciences, Agricultural University of Hebei, Baoding 071001, P.R. China
*
Corresponding author: Fax: +86 312 7528292; Tel: +86 312 7528291; E-mail: mjjwjpmartin@sina.com
Received: 19 July 2012; Accepted: 2 May 2013)
(
AJC-13446
1,5-Benzodiazepine derivatives were synthesized in moderate to excellent isolated yields by the condensation reactions of o-phenylenedi-
amine and ketones catalyzed by [1-methyl-3-(3-sulphopropyl)imidazolium methyl sulphate] under ultrasound irradiation using n-hexane as
solvent. This method is simple, effective and gives better yields.
Key Words: 1-Methyl-3-(3-sulphopropyl)imidazolium methyl sulphate, 1,5-Benzodiazepines, o-Phenylenediamines, Ultrasound.
3c
methods, this method is more convenient and easily controlled .
A large number of organic reactions can be carried out with a
higher yield, shorter reaction time and environmentally benign
INTRODUCTION
Benzodiazepines and their derivatives are very important
compounds because of their easy functionalization and
3d-3g
approach under ultrasonic irradiation
.
1
potential pharmacological properties . They are widely used
a
Room temperature ionic liquids (RTILs) have received
increasingly attention as potential "greener" alternatives to
volatile organic solvent and they have been investigated
extensively as a solvent or catalyst for many important organic
reactions because of their special properties such as their
negligible vapour pressure, tunable polarity, high thermal
stability, good solvating ability, ease of recyclability and their
1
as anticonvulsant , analgesic , hypnotic , sedative and
a
1a
1b
1b
1
antidepressive agents . Besides their biological properties,
c
benzodiazepine derivatives are also used as dyes for acrylic
1
c
fibers . In addition, 1,5-benzodiazepines are valuable synthons
used for the synthesis of other fused ring compounds such as
1d-1h
triazolo-, oxazino-, oxadiazolo- or furano-benzodiazepines
.
So the preparation of 1,5-benzodiazepines has received incre-
asingly attention in recent years. But until now, comparatively
few methods for their preparation had been reported in the
4
potential to enhance reaction rates and selectivity . They have
also been referred as "designer solvents," as their properties
can be altered by the fine-tuning of parameters such as the
choice of organic cation, inorganic anion and alkyl chain
attached to the organic cation. These structural variations offer
flexibility to the chemist to devise the most idealized solvent
2
a
literature . These include condensation reactions of o-
phenylenediamine derivatives with α,β-unsaturated carbonyl
2
compounds , β-haloketones or ketones promoted by
b
2
c
2d
2e
BF
ammonium nitrate (CAN) , MgO/POCl
or AcOH under microwave conditions , Amberlyst-15
3
·OEt
2
, NaBH
4
, polyphosphoric acid or SiO
2
, ceric
5
and catalyst, catering for the needs of a particular process .
In continuing our endeavor in green synthesis and using
ionic liquids as a recyclable reaction medium to enhance rates
2f
2g
2h
3
3 2 3
,Yb(OTf) ,Al O /
2i,2j
2 5
P O
2k
2l
in ionic liquid , CeCl
2a
3
·7H
2
O/NaI supported on silica gel ,
and Sc(OTf) . However, many of these methodologies
6
and selectivity , we report herein a mild and efficient protocol
2m
InBr
3
3
for the preparation of 1,5-benzodiazepine and their deri-
vatives under ultrasound using acidic ionic liquids (1-methyl-
have shortcomings, such as long reaction times, low yields of
the products, drastic reaction conditions, co-occurrence of
several side products and expensive reagents.
3
3
-(3-sulpho-propyl)imidazolium methyl sulphate ([HSO -
pmim][CH SO
3
3
])) as an efficient catalyst (Scheme-I).
In recent years, ultrasound has increasingly been used in
3
organic synthesis . As it is known, it can accelerate diverse
a
EXPERIMENTAL
types of organic reactions and it is established as an important
Melting points were recorded on an Electrothermal
1
(Shanghai XRC-1) apparatus and are uncorrected. H NMR
3b
technique in organic synthesis . Compared with traditional

6
244 Li et al.
Asian J. Chem.
1
H R
N
R2
fully characterized by IR and H NMR spectroscopy and
melting points, which were consistent with the literature data.
1
NH2
O
[HSO -pmim][CH SO ]
3 3 3
+
2
Ultrasound Irradiation
R2
R1
R2
NH2
Spectroscopic data for compounds
N
R1
1
Entry 3a: H NMR (300 MHz, CDCl
2
3
3
H
) δ : 1.35 (s, 6H),
1
Scheme-I
2.22 (s, 2H ), 2.38 (s, 3H), 3.45 (br, 1H), 6.65-7.21 (m, 4H);
1
C NMR ( H-decoupled, 50 MHz, CDCl
13
3 c
) δ : 29.8, 30.3, 45.0,
1
3
(
300 MHz) and C NMR (50 MHz) spectra were determined
with BrukerAVANCE 300 spectrometer (CDCl -d ) using TMS
as internal standard. Mass spectra were recorded on a Finnigan
68.0, 121.5, 122.0, 125.3, 126.1, 137.8, 140.6, 171.8; EIMS:
+
m/z (% relative intensity) = 187(100) [M ], 170(50), 130(15),
3
6
-1
105(15), 80(32), 65(20); IR (KBr, νmax, cm ): 3280, 1650, 1590.
1
Entry 3b: H NMR (300 MHz, CDCl
-
1
Mat 8230MSr operating 70 eV. IR spectra (cm ) were measured
with a Braic WQF-510 spectrometer. Sonication was performed
in a Shanghai Kudos CQX ultrasonic cleaner with a frequency
3
H
) δ : 1.72 (s, 3H),
2.95 (d, 2H, J = 0.17 Hz), 3.12 (d, 2H, J = 0.17 Hz), 3.38 (br,
1
13
1H), 6.80-7.72 (m, 14H); C NMR ( H-decoupled, 50 MHz,
CDCl ) δ : 29.8, 43.3, 73.0, 121.4, 121.5, 125.3, 126.1, 126.8,
127.1, 127.6, 127.9, 128.5, 129.6, 137.8, 138.8, 140.1, 170.1;
of 59 kHz and a nominal power of 200W. [HSO
3
-pmim][CH SO
3
3
]
3
c
7
was synthesized according to the literature .
General procedure: A mixture of o-phenylenediamine
5 mmol), ketone (12 mmol) and [HSO -pmim][CH SO
10 mmol %) in n-hexane (5 mL) was stirred rapidly under
+
EIMS: m/z (% relative intensity) = 313(10) [M ], 300(100),
-
1
(
(
3
3
3
]
235(25), 195(30), 105(15), 80(60), 45(80); IR (KBr, νmax, cm ):
3350, 1645, 1592.
1
Entry 3c: H NMR (300 MHz, CDCl
ultrasound irradiation for a certain period of time (Table-1) to
complete the reaction (monitored by TLC). After completion,
the reaction mixture was diluted with water (10 mL) and
extracted with EtOAc (3 mL × 5 mL). The extract was dried
3 H
) δ : 0.99 (t, 3H,
J = 7.0 Hz), 1.25 (t, 3H, J = 7.1 Hz), 1.68 (q, 2H, J = 7.0 Hz),
2.14 (m, 2H), 2.32 (s, 3H), 2.70 (q, 2H, J = 7.1 Hz), 3.29 (br,
13
1
1H), 6.80-7.30 (m, 4H); C NMR ( H-decoupled, 50 MHz,
CDCl ) δ : 8.8, 10.7, 27.1, 35.3, 35.7, 43.0, 69.0, 121.5, 125.3,
126.1, 127.8, 137.8, 140.6, 175.8; EIMS: m/z (% relative
over anhydrous MgSO
4
and evaporated under reduced
3
c
pressure. Then, the crude product was subjected to column
chromatography over silica gel using EtOAc:hexane (1:4) as
eluent to afford pure 1,5-benzodiazepine.All the products were
+
intensity) = 215(15) [M ], 141(5), 108(100), 80(35), 45(75);
-1
IR (KBr, νmax, cm ): 3348, 1647, 1590.
TABLE-1
HSO -pmim][CH SO ] CATALYZED SYNTHESIS OF 1,5-BENZODIAZEPINES
[
3
3
3
lit
m.p. (ºC)
Entry
a
Ketone
Product
Time (min)
Yield (%)
m.p. (ºC)
H
N
[
2c,2h]
CH COCH
3
30
95
139-141
137-139
3
N
H
N
Ph
Me
[
2c,2h]
2c,2h]
b
PhCOCH3
60
90
150-151
151-152
N
Ph
H
N
[
c
d
e
CH COCH CH
3
45
50
50
90
95
85
138-139
138-140
142-144
137-138
3
2
N
H
N
[
8]
CH COCH CH CH
3
139-140
3
2
2
N
H
N
[
2c,2h]
CH CH COCH CH
3
144-145
3
2
2
N
H
CH COCH CH
3
N
[9]
2
f
50
45
50
88
83
81
118-119
137-139
137-138
118-120
(
CH3)2
N
H
N
[
2c,2d,2g]
g
h
O
138-139
N
H
N
[
2c]
O
137-139
N

Vol. 25, No. 11 (2013)
3 3 3
[HSO -pmim][CH SO ] as an Efficient Catalyst for the Synthesis of 1,5-Benzodiazepine Derivatives 6245
1
Entry 3d: H NMR (300 MHz, CDCl
TABLE-2
YIELD OF REACTIONS ON DIFFERENT
3
) δ
H
: 0.78-1.48 (m,
3H), 2.40 (s, 3H), 2.89 (q, 1H, J = 7.0 Hz), 3.72 (br, 1H),
1
6
δ
1
a
QUANTITIES OF CATALYST
13
1
.68-7.41 (m, 4H); C NMR ( H-decoupled, 50 MHz, CDCl
: 7.0, 8.1, 12.1, 13.0, 28.3, 29.6, 30.1, 46.0, 69.0, 117.2,
19.0, 128.1, 132.0, 139.8, 142.6, 175.5; EIMS: m/z (% rela-
3
)
0
2
5
7
10
(mmol (mmol (mmol (mmol (mmol (mmol
15
c
Catalyst
%)
–
%)
12
%)
47
%)
72
%)
95
%)
95
+
tive intensity) = 244(30) [M ], 230(25), 160(15), 215(100);
Yield (%)
-1
a
IR (KBr, νmax, cm ): 3348, 1655, 1592.
The reaction time was 0.5 h.
1
Entry 3e: H NMR (300 MHz, CDCl
3
H
) δ : 0.83-1.52 (m,
1
6
δ
1
4H), 2.33 (m, 2H), 2.93 (q, 1H, J = 7.0 Hz), 3.69 (br, 1H),
13
1
.67-7.41 (m, 4H); C NMR ( H-decoupled, 50 MHz, CDCl
: 8.0, 9.1, 12.0, 13.5, 29.3, 35.1, 46.0, 69.2, 118.2, 119.0,
27.1, 131.0, 137.8, 142.6, 175.1; EIMS: m/z (% relative
3
)
after stirring for 36 h, thus highlighting the role of the [HSO
pmim][CH
pmim][CH
3
-
c
3
3 3
SO ] as a promoter. Any excess of [HSO
-
3
3
SO ] beyond this loading did not show any further
+
intensity) = 245(30) [M ], 230(25), 160(15), 215(100); IR
increase in conversion and yield. Use of less than the required
catalyst loading resulted in poor yields.
-1
(KBr, νmax, cm ): 3340, 1649, 1588.
1
Entry 3f: H NMR (300 MHz, CDCl
) δ
H
: 0.96-1.05 (m,
2H), 1.30 (s, 3 H), 1.49-1.50 (m, 2 H), 1.67-1.75 (m, 1H),
Under the optimal reaction conditions, we investigated
the reaction of a series of symmetrical and unsymmetrical
ketones with o-phenylenediamine to get the corresponding 1,5-
benzodiazepines (Table-1). In all cases, the reaction could
proceed efficiently and complete in 30-60 min with yields
ranged in 81-95 %.
3
1
2
1
.04-2.25 (m, 3 H), 2.24 (d, J = 12.7 Hz, 2 H), 6.62-6.65 (m,
13
1
H), 6.85-6.90 (m, 2 H), 7.05-7.13 (m, 1H); C NMR ( H-
) δ : 22.5, 22.9, 24.6, 24.8, 25.1,
6.3, 30.1, 44.0, 50.9, 69.2, 121.5, 121.8, 125.3, 127.1, 137.8,
decoupled, 50 MHz, CDCl
3
c
2
1
1
ν
+
40.6, 174.8; EIMS: m/z (% relative intensity) = 272(10) [M ],
Since the recovery and reuse of catalyst and solvent are
highly preferable for a green process, so we investigated the
reusability and recycling of the ionic liquid. After completion
of the reaction, water was added into the reaction mixture and
the solid was collected by filtration to give the product. The
70(50), 160(15), 140(25), 105(100), 80(50), 55(15); IR (KBr,
-1
max, cm ): 3330, 1655, 1589.
1
Entry 3g: H NMR (300 MHz, CDCl
3
H
) δ : 1.02-2.23 (m,
13
1
3H), 3.24 (m, 2H), 3.72 (br, 1H), 6.58-7.21 (m, 4H); C NMR
1
(
H-decoupled, 50 MHz, CDCl ) δ
3
c
: 23.5, 24.2, 24.6, 28.8,
3.5, 38.1, 40.0, 54.9, 67.2, 120.5, 120.8, 126.3, 131.5, 137.8,
filtrate containing [HSO
under reduced pressure to recover the ionic liquid. The recycled
[HSO -pmim][CH SO ] was reused in the model reaction of 1
and 2a. The catalytic activity of [HSO -pmim][CH SO ] did
3 3 3
-pmim][CH SO ] was concentrated
3
1
+
43.6, 177.8; EIMS: m/z (% relative intensity) = 240(30) [M ];
3
3
3
-1
IR (KBr, νmax, cm ): 3344, 1659, 1600.
3
3
3
1
Entry 3h: H NMR (300 MHz, CDCl
) δ
3 H
: 0.92-2.32 (m,
not show any significant decrease even after five runs. The
results are shown in Table-3. The results also indicate that the
ionic liquid employed was stable under the reaction temperature.
13
1
7H), 3.21 (m, 2H), 3.70 (br, 1H), 6.5-7.16 (m, 4H); C NMR
1
(
3 c
H-decoupled, 50 MHz, CDCl ) δ : 21.5, 21.8, 23.5, 24.6,
2
1
=
6.7, 33.5, 35.2, 38.8, 40.5, 52.9, 64.2, 120.9, 121.8, 126.3,
31.0, 137.0, 142.6, 180.1; EIMS: m/z (% relative intensity)
+
-1
270 (25) [M ]; IR (KBr, νmax, cm ): 3340, 1648, 1600.
TABLE-3
STUDIES ON THE REUSE OF THE
[
HSO -pmim][CH SO ]FOR THE PREPARATION OF 3a
3 3 3
RESULTS AND DISCUSSION
Round
Yield (%)
1
2
3
4
5
In our initial research, we studied the catalytic properties
95
93
91
90
87
of [HSO
diazepine using o-phenylenediamine and acetone as substrates.
The reaction was carried out using 10 mmol % [HSO
pmim][CH SO ] in CH Cl as solvent under ultrasound irra-
3 3 3
-pmim][CH SO ] for the synthesis of 1,5-benzo-
3
-
Conclusion
3
3
2
2
diation for 6 h to afford the corresponding 1,5-benzodiazepine
in 56 % yield. Encouraged by this result, we studied different
reaction parameters to optimize the reaction conditions. The
We have demonstrated here a new and efficient procedure
for the synthesis of 1,5-benzodiazepine derivatives catalyzed
3 3 3
by [HSO -pmim][CH SO ]. The advantages of our protocol
reaction was performed in different solvents such as CH
CH Cl , C OH and n-hexane. n-Hexane was found to be
3
CN,
are easy work-up, short reaction times, mild reaction condition,
good yields which make the method an attractive and a useful
contribution to present methodologies. The application studies
of the task-specific ionic liquids for other reactions are in
progress.
2
2
2 5
H
the best solvent in terms of yields and reaction time. The
reaction was also conducted in solvent-free conditions but the
yields were poorer compared to the yields obtained in n-
hexane as solvent. Next, the loading amount of [HSO
pmim][CH SO ] was also optimized (Table-2). The results
indicated that 10 mmol % of [HSO -pmim][CH SO ] is suffi-
3
-
3
3
ACKNOWLEDGEMENTS
3
3
3
cient to promote reaction. The optimum yields of the product
were obtained when a 1:2.4 ratio of o-phenylenediamine
to ketones was used. No products were obtained when o-
phenylenediamine was reacted with acetone under similar
This project was sponsored by the Nature Development
Foundation of Hebei Province (B2011204051), the Develop-
ment Foundation of the Department of Education of Hebei
Province (2010137) and the Research Development Founda-
tion of the Agricultural University of Hebei.
3 3 3
conditions in the absence of the [HSO -pmim][CH SO ] even

6
246 Li et al.
Asian J. Chem.
1
8, 466 (2011); (c) S.H. Gou, H.C. Chen, Z.P. Fang, J. Luo and Y.L.
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