Silica gel / NaHSO4: An efficient and recyclable heterogeneous catalyst for high yield synthesis of 1,5-benzodiazepine derivatives under microwave irradiation

Article abstract of DOI:10.1002/jhet.5570440431

(Chemical Equation Presented) Silica gel supported sodium hydrogen sulfate catalyzes efficiently the condensation of o-phenylene-diamines with ketones under microwaves in solvent free conditions to afford the corresponding 1,5-benzodiazepine derivatives i

Full text of DOI:10.1002/jhet.5570440431

Jul-Aug 2007
929
Silica gel / NaHSO4: An Efficient and Recyclable Heterogeneous
Catalyst for high yield Synthesis of 1, 5-Benzodiazepine Derivatives
under Microwave Irradiation
M. Adharvana Chari*, D. Shobha, and K. Syamasundar
Dept. of Chemistry, J.N.T. University, Kukatpally, Hyderabad –500072, India.
E-mail: drmacj@yahoo.co.uk, Fax: 0091-40-23060056
Received June 7, 2006
R''
R'
O
H
N
NH2
NH2
SiO2 -NaHSO4
+
R
R'-C-CH2R''
R
R''
N
R'
2
3
1
R = CH3 , R1 = Alkyl or Phenyl , R11 = Alkyl
Silica gel supported sodium hydrogen sulfate catalyzes efficiently the condensation of o-phenylene-
diamines with ketones under microwaves in solvent free conditions to afford the corresponding 1,5-benzo-
diazepine derivatives in high yields. Compared to conventional reaction conditions, this new approach
consistently has the advantage of excellent yields (90-98%) and short reaction times of 0.50 – 1.00 min.
J. Heterocyclic Chem., 44, 929 (2007).
nature, the catalyst can conveniently be separated by
simple filtration.
INTRODUCTION
Benzodiazepines and their derivatives are an important
class of bioactive molecules and are widely used as anti-
convulsant, ant anxiety, analgesic, sedative, anti depressant,
anti inflammatory, and hypnotic agents [1-3]. Some of the
benzodiazepine derivatives are used as dyes for acrylic
fibers [4] in photography. Particularly, 1,5-benzodiazepines
are useful precursors for the synthesis of some fused ring
benzodiazepine derivatives [5] such as triazolo-,
oxadiazolo-, oxazino-, or furanobenzodiazepines. Due to
their wide range of applications these compounds have
received a great deal of attention in connection with their
synthesis. Many reagents have been reported in the
literature [6] for this condensation including BF3-etherate,
NaBH4, polyphosphoric acid, Yb(OTf)3 and MgO/POCl3.
Recently these condensations have been reported even in an
ionic liquid medium [7,8]. However many of these
methodologies are associated with several short comings
such as long reaction times, expensive reagents, harsh
conditions, low product yields, occurance of several side
products and difficulty in recovery and reusability of the
catalysts. Generally 1,5-benzodiazopines are synthesised
by the condensation of o-phenylene diamines with ꢀ,ꢁ-
unsaturated carbonyl compounds or with ketones.
In view of the recent surge in the use of heterogeneous
catalysts [10,11] we wish to report a simple, convenient and
efficient method for the preparation of 1,5-benzodiazepine
derivatives using a solid supported reagent, SiO2-NaHSO4,
as an inexpensive and eco-friendly catalyst. The catalyst
was prepared by using known procedure [12]. This method
under Microwave irradiation not only affords the products
in excellent yields but also avoids the problems associated
with catalyst cost, handling, safety and pollution. This
catalyst can act as eco-friendly for a variety of organic
transformations, non-volatile, recyclable, non-explosive,
easy to handle, and thermally robust. In view of the
emerging importance of the heterogeneous catalyst, we
wish to explore the use of silica gel supported sodium
hydrogen sulfate as recyclable catalyst for the synthesis of
1,5-benzodiazepines (Scheme 1).
Scheme 1
R''
R'
O
H
NH2
NH2
N
SiO2 -NaHSO4
R
+
R'-C-CH2R''
R
R''
N
R'
3
2
1
Recently, the use of solid supported reagents [9] has
received considerable importance in organic synthesis
because of their ease of handling, enhanced reaction rates,
greater selectivity, simple workup, and recoverability of
catalysts. Among the various heterogeneous catalysts,
particularly, silica gel impregnated with sodium bisulfate
has advantages of low cost, ease of preparation, and
catalyst recycling. Since the reaction is heterogeneous in
R = CH3 , R1 = Alkyl or Phenyl , R11 = Alkyl
RESULTS AND DISCUSSION
The treatment of o-phenylenediamine with acetone in
the presence of silicagel supported sodium hydrogen
sulfate resulted in the formation of 2,3-dihydro-2,2,4-tri-

930
M. A. Chari, D. Shobha, and K. Syamasundar
Vol 44
methyl-1H-1,5-benzo[b][1,4]diazepine in 98%, 93%, 87%
and 88% yields over four cycles.
diamines in the presence of silica gel supported sodium
hydrogen sulfate are superior in terms of yields and
reaction rates and the results are presented in the Table 1
The rate enhancement under microwave irradiation may
be attributed to the effective absorption of microwaves by
the polar media. Thus microwaves have been applied to
accelerate reaction rates and to improve the yields of the
products. The classical synthesis of 1,5-benzodiazepine
derivatives [6d] requires long reaction time at reflux
temperature to moderate yields. In general microwave
assisted reactions are clean, rapid and afford higher yields
than those obtained by conventional methods. o-phenyl-
enediamine and ketone were mixed with dry catalyst and
subjected to microwave irradiation at 450 watts using
In a similar fashion, various ketones reacted smoothly
with o-phenylenediamines under these reaction conditions
to give the corresponding 1,5-benzodiazepine derivatives
in 85-98% yield under solvent free conditions. The crude
products were purified either by recrystallization from n-
hexane or by silica gel column chromatography. The
reaction of cyclic ketones with o-phenylenediamine in the
presence of this catalyst afforded fused ring 1,5-benzo-
diazepine derivatives in good yields. All the products
1
were characterized by IR, H NMR, and mass spectral
analysis and also by comparison with authentic samples.
The reactions of various ketones with o-phenylene-
Table1: Microwave assisted,SiO2-NaHSO4 catalysed efficient synthesis of 1,5-benzodiazepines .
Microwave
Conventional
Ketone
IrradiationC
Producta
Diamine
Entry
Time(m) Yield(%)b
Time(m) Yield(%)b
H
N
NH2
30
40
90
88
0.50
0.75
98
95
CH3COCH3
a
b
NH2
N
Ph
Me
H
N
NH2
NH2
PhCOCH3
N
Ph
H
N
NH2
NH2
c
40
88
0.75
95
95
90
CH3COCH2CH3
N
H
N
NH2
NH2
d
40
60
85
85
0.80
1.00
CH3CH2COCH2CH3
O
N
H
N
NH2
NH2
NH2
NH2
e
N
H
Me
Me
Me
N
Me
Me
CH3COCH3
0.75
30
90
96
f
N
NH2
NH2
H
N
g
hi
i
CH3COCH2CH3
87
85
88
87
40
40
45
50
0.75
0.70
1.00
1.00
92
90
95
95
N
NH2
NH2
H
N
CH3CH2COCH2CH3 Me
N
Me
NH2
NH2
Ph
Me
H
N
Me
PhCOCH3
N
Ph
NH2
NH2
Me
Me
H
N
Me
j
CH3COCH3
Me
N
a: All products were characterized by IR,1 HNMR, and mass spectra
b: Isolated and unoptimized yields
c:Pulsed irradiations (15 sec interval) at 450 watts using BPL-BMO 700T Domestic microwave oven.

Jul-Aug 2007
An Efficient and Recyclable Heterogeneous Catalyst for high yield
931
2-Methyl-2,4-diphenyl-2,3-dihydro-1H-1,5-benzodiazepine
(3b). Solid, m.p. 150-152 °C, 1H NMR (CDCl3): ꢀ 1.80 (s, 3H),
2.95 (d, 1H, J = 12.8 Hz), 3.15 (d, 1H, J = 12.8 Hz) 3.45 (brs,
NH), 6.55-7.0 (m, 3H), 7.15-7.35 (m, 7H), 7.55-7.65 (m, 4H).
13C NMR (Proton decoupled, CDCl3) ꢀ: 29.7, 42.9, 73.3, 121.2,
121.4, 125.2, 126.1, 126.8, 126.9, 127.8, 128.1, 128.5, 129.5,
137.9, 139.5, 139.9, 147.4, 167.3; EIMS: m/z: 312 [M+], 297,
235, 194, 103, 77, 40; IR (KBr): ꢁ 3320, 1631, 1597 cm-1.
BPL, BOM-700T microwave oven for an appropriate
time. The advantage of the use of heterogeneous catalyst
for this transformation is that ease of catalyst/substrate
separation provided by
a
heterogeneous catalyst.
However, the products were obtained of the same purity
as in the first run, and the yields were almost consistent
for a few cycles. The results of the reactions at microwave
irradiation conditions are compared with the reflux
conditions and short reaction times were observed, which
is more economical in terms of time. Compared to
conventional method, enhanced reaction rates, improved
yields and high selectivity are the features obtained in
microwave irradiation.
2,2,4-Triethyl-3-methyl-2,3-dihydro-1H-1,5-benzodiazepine
1
3d: Solid, m.p. 143-145 °C, H NMR (CDCl3:) ꢀ 0.70-1.0 (m,
10H), 1.20-1.38 (m, 4H), 1.50-1.65 (m, 2H), 2.40-2.60 (m, 2H),
2.87 (q, 1H, J = 6.8 Hz), 3.65 (brs, NH), 6.58 (d, 1H, J = 8.0
Hz), 6.65 (t, 1H, J = 8.0 Hz), 6.90 (t, 1H, J = 8.0 Hz), 7.38 (d,
1H, J = 8.0 Hz). 13C NMR (Proton decoupled, CDCl3) ꢀ: 7.4,
7.8, 11.4, 12.1, 28.0, 28.4, 35.6, 46.2, 68.8, 117.5, 118.0, 126.7,
132.8, 13.9, 142.4, 173.8; EIMS: m/z: 244 [M+], 229, 215, 194,
103, 77, 40; IR (KBr): ꢁ 3320, 1631, 1597cm-1.
CONCLUSION
2,2,4,8-Tetramethyl-2,3-dihydro-1H-1,5-benzodiazepine
(3f). Solid, m.p. 127-129 °C; H NMR (200 MHz, CDCl3): ꢀ
In summary, we have developed a simple, convenient
and effective method for facile synthesis of 2,3-dihydro-
1,5-benzodiazepines by the condensation of ketones with
o-phenylenediamines using NaHSO4-SiO2 catalyst in
solvent free conditions under microwave irradiation.
Present methodology offers very attractive features such
as reduced reaction times, higher yields and economic
viability of the catalyst, when compared with conven-
tional method as well as with other catalysts. The simple
procedure combined with easy of recovery and reuse of
this catalyst make this method economic, benign chemical
process for the synthesis of 1,5-benzodiazepines of
biological importance. The operational simplicity of the
procedure is also attractive. The catalyst can be prepared
from available inexpensive reagents and can be easy
recycled, which is heterogeneous and non-hazardous. The
reaction progress was monitored by TLC and NMR and
MS were used for analysis of the products. NMR spectra
were recorded on a 300 MHz and Mass spectra were
recorded on a LC-MS.
1
1.30 (s, 6H), 2.19 (s, 2H), 2.23 (s, 3H), 2.80 (s, 3H), 6.65-6.75
(s, 1H), 6.70-6.80 (1H), 7.05-7.10 (m, 1H); 13C NMR (Proton
decoupled, 75 MHz, CDCl3): ꢀ 20.9, 29.6, 30.4, 30.8, 45.8, 67.0,
122.6, 126.6, 127.0, 131.8, 136.7, 138.1, 174.3. EIMS: m/z(%):
202 (M+ 40), 187 (100), 146 (70), 77(15), 41 (20). IR (KBr): ꢁmax
3325, 1665, 1600 cm-1.
2-Methyl-2,4-diethyl-8-methyl-2,3-dihydro-1H-1,5-benzo-
1
diazepine (3g). Light yellow solid; m.p. 116-118 °C; H NMR
(300 MHz, CDCl3): ꢀ 0.95 (t, 3H, J = 7.0 Hz), 1.15-1.30 (m,
6H), 1.50–1.70 (m, 1H), 2.05-2.10 (d, 1H, J = 12.8 Hz), 2.15-
2.20 (d, 1H, J = 12.8 Hz), 2.30 (s, 3H), 2.50-2.65 (m, 2H), 2.90
(brs, 1H, NH), 6.55-7.00 (m, 3H); EIMS: m/z (relative intensity
%): 230 (M+, 15), 201 (20), 172 (40), 132 (100), 90 (50), 56
(25); IR (KBr): ꢁmax 3500, 3220, 1620 cm-1
2,2,4-Triethyl-3,8-dimethyl-2,3-dihydro-1H-1,5-benzodiaze-
pine (3h). Solid, m.p. 153-155 °C, 1H NMR (CDCl3) ꢀ: 0.71-1.0
(m, 10H), 1.20-1.38 (m, 4H), 1.51-1.65 (m, 2H), 2.25(s,3H),
2.40-2.62 (m, 2H), 2.87 (q, 1H, J = 6.8 Hz), 3.65 (brs, NH),
6.58-7.35 (m,3H).EIMS: m/z: 258 [M+], 244, 229, 215, 194,
103, 77, 40. IR (KBr) ꢁ: 3320, 1631, 1597cm-1.
2-Methyl-2,4-diphenyl-2,3-dihydro-8-methyl-1H-1,5-benzo-
diazepine (3i). Yellow color solid; m.p 91-93 °C; 1H NMR (200
MHz, CDCl3): ꢀ 1.80 (s, 3H), 2.41 (s, 3H), 2.98 (d, 1H, J = 12.7
Hz), 3.15 (d, 1H, J = 12.7 Hz), 3.50 (brs, 1H, NH), 6.70-7.69
(m, 13H). 13C NMR (Proton decoupled, 50 MHz, CDCl3 ): ꢀ
20.6, 28.5, 45.8, 51.2, 113.5, 125.5, 126.4, 127.3, 128.1, 128.3,
128.6, 128.8, 129.1, 130.9, 131.2, 134.0, 136.8, 164.8; EIMS:
m/z(%): 326 (M+ 10), 261 (100), 246 (90), 206 (40), 145 (50),
102 (35), 76 (30). IR (KBr): ꢁmax 3315, 1657, 1600 cm-1.
EXPERIMENTAL
General procedure for the synthesis of 2,3-dihydro-1, 5-benzo-
diazepines. (a) A mixture of o-phenylenediamine (1 mmol),
ketone (2.5 mmol), and Silicagel supported sodium hydrogen
sulfate, (5 mole%) was stirred at reflux temperature for an
appropriate time (Table1). (b) A mixture of o-phenylenediamine
(1 mmol), ketone (2.5 mmol), and Silicagel supported sodium
hydrogen sulfate (5mole%) were mixed in a pyrex test tube and
subjected to microwave irradiation for an appropriate time
(Table 1). After completion of the reaction, 10 ml of CH2Cl2 was
added to the reaction mixture and the catalyst was recovered by
filtration. The organic layer was concentrated and the products
were purified by silicagel column (100-200 mesh) and eluted
with ethyl acetate - n-hexane (2:8) to afford pure compounds in
90-98% yield. The wet catalyst was recycled and no appreciable
change in activity was noticed after a few cycles. Spectral data
for compounds 3a-3j are given in Table 1. For compounds 3a,
3c and 3e the spectroscopic data is in full agreement with the
literature data [7].
2,2,4,7,8-Pentamethyl-2,3-dihydro-1H-1,5-benzodiazepine
(3j). Yellow solid, m.p. 112-114 °C; 1H NMR (300 MHz,
CDCl3): ꢀ1.35 (s, 6H), 2.19 (s, 3H), 2.20 (s, 3H) 2.22 (s, 2H),
2.34 (s, 3H), 2.80 (brs, NH, 1H), 6.52 (s, 1H), 6.39 (s, 1H); 13C
NMR (Proton decoupled, 75 MHz, CDCl3): ꢀ 18.9, 19.1, 29.8,
30.3, 30.4, 45.3, 67.7, 122.8, 127.8, 129.9, 133.6, 135.5, 138.4,
171.3; EIMS: m/z(%): 216 (M+ 20), 201 (60), 161 (30), 145 (15),
97 (17), 71 (50), 43 (100); IR (KBr): ꢁmax 3290, 1635, 1605 cm-1.
REFERENCE AND NOTES
[1] (a) Schutz, H. Benzodiazepines; Springer: Heidelberg 1982.
(b) Landquist, J. K. “In Comprehensive Heterocyclic Chemistry”;

932
M. A. Chari, D. Shobha, and K. Syamasundar
Vol 44
Katritzky, A. R.; Rees, C. W. Eds. Pergamon: Oxford 1984, 1, 166.
[2] Randall, L. O.; Kappel, B. in Benzodiazepines; (Garattini,
Mussini, Randal Eds.) Raven Press: New York 1973, 27.
[3] De Baun, J. R.; Pallos, F. M.; Baker, D. R. U. S. Patent 3,
978, 227, 1976; Chem. Abstr. 1977, 86, 5498d.
Ber. 1994, 127, 2249; (h) Pazarentsi, M., Stephanidou-Stephanatou, J.;
Tsoleridis, C. A. Tetrahedron. Lett. 2002, 43, 1755; (i) Sivamurugan, V.;
Deepa, K.; Palanichamy, M.; Murugesan, V. Synthetic Communications,
2004, 34, 3833; (j) Giri, Y.; Prabavathi Devi, B. L. A.; Vijaya Lakshmi,
K.; Prasad, R. B. N.; Lingaiah, N.; Sai Prasad, P. S. Synthetic
Communications, 2006, 36, 3797; (k) Wu; Jianting; Xu; Fan; Zhou;
Zhuqing; Shen; Qi; Synthetic Communications, 2006, 36, 457; (l)
Rupesh Kumar; Preeti Chaudhary; Surendra Nimesh; Akhilesh K.
Verma; Ramesh Chandra Green Chem. 2006, 8, 519.
[7] Yadav, J. S.; Reddy, B. V. S.; Eshwaraiah, B.; Anuradha, K.
Green Chem. 2002, 6, 592.
[8] Jarikote, D. V.; Siddiqui, S.; Rajagopal, R.; Daniel, T.;
Lahoti, R. J.; Srinivasan, K. V. Tetrahedron Lett. 2003, 44, 1835.
[9] Ramesh, C.; Mahender, G.; Ravindranath, N.; Das, B.
Tetrahedron Lett. 2003, 44, 1465.
[4] Haris, R. C.; Straley, J. M. U. S. Patent 1, 537, 757, 1968;
Chem. Abstr. 1970, 73, 100054w.
[5] (a) Essaber, M.; Baouid, A.; Hasnaoui, A.; Benharref, A.;
Lavergne, J. P. Synth. Commun. 1998, 28, 4097; (b) El-Sayed, A. M.;
Abdel-Ghany, H.; El-Saghier, A. M. M. Synth. Commun. 1999, 29,
3561; (c) Reddy, K. V. V.; Rao, P. S.; Ashok, D. Synth. Commun. 2000,
30,1825.
[6] (a) Herbert, J. A.; Suschitzky, H. J. Chem. Soc., Perkin
Trans. 1 1974, 2657; (b) Morales, H. R.; Bulbarela, A.; Contreras, R.
R. Heterocycles 1986, 24, 135; (c) Jung, D. I.; Choi, D. W.; Kim, I. S.;
Park, Y. M.; Lee, Y. G.; Jung, D. H. Synth. Commun. 1999, 29, 1941;
(d) Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O. Tetrahedron
Lett. 2001, 42, 3193; (e) Balakrishna, M. S.; Kaboudin, B. Tetrahedron
Lett. 2001, 42, 1127; (f) Zhong, W.; Zhang, Y.; Chen, X. Tetrahedron
Lett. 2001, 42, 73; (g). Kaupp, G.; Pogodda U.; Schmeyers, J. Chem.
[10] Nishiguchi, T.; Kamio, C. J. J. Chem. Soc. Perkin. Trans 1
1989, 707.
[11] Yadav, J. S.; Subba Reddy, B. V.; Srinivas, R.; Ramalingam,
T. Synlett. 2000, 5, 701.
[12] Breton, G. W. J. Org. Chem. 1997, 62, 8952.