Silica gel-supported sulfuric acid catalyzed synthesis of 1,5-benzodiazepine derivatives

Article abstract of DOI:10.1002/jhet.174

(Chemical Equation Presented) Silica gel-supported sulfuric acid has been found to be an efficient catalyst for the synthesis of 1,5-benzodiazepines from o-phenylenediamine and ketones in acetonitrile solvent. This method is simple, effective, and environ

Full text of DOI:10.1002/jhet.174

1028
Silica Gel-Supported Sulfuric Acid Catalyzed Synthesis of
1,5-Benzodiazepine Derivatives
Vol 46
D. Shobha,a,b M. Adharvana Chari,b* K. Mukkanti,a and K. H. Ahnb
aDepartment of Chemistry, Institute of Science and Technology, Jawaharlal Nehru Technological
University, Hyderabad, Andhra Pradesh 500072, India
bDepartment of Chemistry, Kyung Hee University, Seoul, South Korea
*E-mail: drmac_s@yahoo.com
Received January 16, 2009
DOI 10.1002/jhet.174
Published online 2 September 2009 in Wiley InterScience (www.interscience.wiley.com).
Silica gel-supported sulfuric acid has been found to be an efficient catalyst for the synthesis of 1,5-
benzodiazepines from o-phenylenediamine and ketones in acetonitrile solvent. This method is simple,
effective, and environmentally friendly and gives better yields. Compared to the classical reaction con-
ditions, this new method consistently has the advantage of excellent yields (80–97%) and short reaction
time (30–150 min) at room temperature.
J. Heterocyclic Chem., 46, 1028 (2009).
INTRODUCTION
[27] has advantages of low cost, ease of preparation,
and catalyst recycling. As the reaction is heterogeneous
in nature, the catalyst can conveniently be separated by
simple filtration. In view of recent surge in the use of
heterogeneous catalysts, we wish to report a simple,
convenient, and efficient method for the preparation of
1,5-benzodiazepines under acetonitrile solvent using
silica gel-supported sulfuric acid (10 mol %) as a cata-
lyst. This catalyst is easy to handle, thermally robust,
nonvolatile, nonexplosive, eco-friendly, and recyclable
for a variety of organic transformations.
Benzodiazepines are pharmacologically active com-
pounds having anti-inflammatory [1], antianxiety, anti-
convulsant, and hypnotic activity [2,3]. Because of the
broad biological significance, the syntheses of these
compounds have received a great deal of attention. Ben-
zodiazepines have been synthesized by the condensation
of o-phenylenediamines with b-unsaturated carbonyl
compounds, b-haloketones, or ketones. This condensa-
tion has been carried out using different reagents, such
as BF3-etherate [4], polyphosphoric acid [5], NaBH4 [6],
SiO2 [5], MgO/POCl3 [7], Yb(OTf)3 [8], Ga(OTf)3 [9],
lead nitrate [10], L-proline [11], acetic acid under micro-
wave conditions [12], molecular iodine [13], and in
ionic liquids [14]. Recently, this condensation is
reported using different acid catalysts [15–22]. Many of
these processes suffer from one or more limitations,
such as long reaction times, occurrence of several side
reactions, drastic reaction conditions, low yields, and
tedious workup procedure. Therefore, the search contin-
ues for a better catalyst for the synthesis of 1,5-benzo-
diazepines in terms of mild reaction conditions.
RESULTS AND DISCUSSION
Initially, we studied the catalytic properties of silica
gel-supported sulfuric acid for the synthesis of 1,5-ben-
zodiazepines at room temperature using o-phenylenedi-
amine (1) and the ketone (2) (Scheme 1) and varying
the mol % of silica gel-supported sulfuric acid (Table
1). Among the results obtained, use of 10 mol % silica
gel-supported sulfuric acid gave better yield (97%) in
30 min for the synthesis of 3a.We achieved good yield
when compared with our earlier report (90% in 30 min)
[16].
Recently, the use of heterogeneous catalysts [23–26]
has received considerable importance in organic synthe-
sis because of their ease of handling, enhanced reaction
rates, greater selectivity, simple workup, and recover-
ability of catalysts. Among the various heterogeneous
catalysts, particularly, silica gel-supported sulfuric acid
We investigated the reaction of a series of symmetri-
cal and unsymmetrical ketones with o-phenylenediamine
to get the corresponding 1,5-benzodiazepinederivatives
in 80–97% yield under acetonitrile conditions. All
C
V
2009 HeteroCorporation

September 2009
Silica Gel-Supported Sulfuric Acid Catalyzed Synthesis of
1,5-Benzodiazepine Derivatives
1029
Scheme 1
silica gel. After the removal of solvent in a rotary evaporator,
the solid powder was dried at 120ꢀC for 2–3 h under reduced
pressure.
General procedure for the synthesis of 1,5-
benzodiazepines. A mixture of o-phenylenediamine (1)
(1 mmol), ketone (2) (2.5 mmol), and silica gel-supported sul-
furic acid (0.1 mmol) was stirred in acetonitrile at room tem-
perature until thin layer chromatography indicated that the
reaction was complete. After the completion of reaction,
20 mL of ethyl acetate was added to the reaction mixture, and
the catalyst was recovered by filtration. The organic layer was
concentrated, and the crude product was purified by silica gel
column chromatography using ethyl acetate–n-hexane (1:9) as
eluent to afford the desired product (3). Entry 1–5 and 11
spectral data [20], entry 7, 8 spectral data [21], and entry 9,
10, and 13 spectral data [22] are in full agreement with the
reported literature, and the new compounds spectral data are
given later.
synthesized derivatives were characterized using IR,
1H NMR, and mass spectral analysis and also by com-
parison with authentic samples. The reactions of various
ketones with o-phenylenediamine in the presence of
silica gel-supported sulfuric acid are superior in terms of
yields and reaction times (Table 2) than the previously
reported methods. Especially, with p-chloroacetophe-
none (Table 2, entry 9), we have obtained 95% yield in
50 min, whereas previously reported was less than 95%
in 50 min [17,18].
Entry 6 (3f). Yellow solid, m.p. 140–142ꢀC, IR(KBr): mmax
1
3341, 1674, 1589 cmꢁ1. H NMR (300 MHz, CDCl3): d 0.92–
0.98 (m, 6H, 2CH3), 1.13 (s, 3H, CH3), 1.18–1.36 (m, 4H,
2CH2), 1.52–1.62 (m,1H, CHa), 2.10–2.20 (m, 1H, CHb),
2.51–2.59 (m, 4H, 2CH2), 3.05 (br s,1H, NH), 6.70–6.73 (m,
1H, ArAH), 6.95–6.98 (m, 2H, ArAH), 7.12–7.14 (m,
1H, ArAH). EIMS: m/z [Mþ] ¼ 244. Anal. Calcd for
C16H24N2: C, 78.64; H, 9.90; N, 11.46. Found: C, 78.50; H,
9.85; N, 11.36.
Chloro-substituted o-phenylenediamine and substi-
tuted ketones have been used with similar success to
provide the corresponding benzodiazepines in high
yields, which are also of much interest with regard to
biological activity. The efficiency of the recovered cata-
lyst was verified with the reaction of o-phenylenedi-
amine and ketone (entry 1). Using the fresh catalyst, the
yield of product (3a) was 97%, whereas using the recov-
ered catalyst in the three subsequent recyclization, the
yields were 94, 92, and 90, respectively.
Entry 12 (3l). Yellow solid, m.p. 94–96ꢀC, IR(KBr): mmax
1
3424, 1595, 1499 cmꢁ1. H NMR (300 MHz, CDCl3): d 0.93
(t, 3H, CH3), 1.24–1.25 (m, 6H, 2CH3), 1.60–1.65 (m, 2H,
CH2), 2.22 (m, 2H, CH2), 2.50–2.68 (q, 2H, J ¼ 3.23 Hz,
CH2), 3.00–3.20 (br s,1H, NH), 6.62–6.71 (m, 1H, ArAH),
6.88–6.93 (m, 1H, ArAH), 7.04–7.14 (m, 1H, ArAH). EIMS:
m/z [Mþ] ¼ 250, Anal. Calcd for C14H19ClN2: C, 67.05; H,
7.64; N, 11.17. Found: C, 67.00; H, 7.54; N, 11.10.
In summary, we have developed a new methodology
for the synthesis of various 1,5-benzodiazepines by
using substituted o-phenylenediamine and substituted
ketones in the presence of catalytic amount of silica gel-
supported sulfuric acid catalyst at room temperature.
Thus, this method is a simple, high yielding, time sav-
ing, and eco-friendly process. The catalyst can be pre-
pared from available inexpensive reagents and can be
easily recycled, which is heterogeneous and nonhazar-
dous. Hence, the utility of silica gel-supported sulfuric
acid catalyst for the synthesis of 1,5-benzodiazepines
would be a valuable addition to available methods.
Entry 14 (3n). Light yellow solid, m.p.140–142ꢀC, IR(KBr):
1
mmax 3197, 1623, 1590 cmꢁ1. H NMR (300 MHz, CDCl3): d
0.98–1.02 (m, 12H, 4CH3), 1.25 (m, 2H, 2CH), 1.30 (s, 3H,
CH3), 1.70–1.73 (m,2H, 2CH2), 2.15–2.20 (m, 2H, CH2), 2.40
(d, 2H, CH2), 3.50 (br s,1H, NH), 6.60–6.673 (m, 1H, ArAH),
6.86–6.94 (m, 1H, ArAH), 7.04–7.13 (m, 1H, ArAH). EIMS:
m/z [Mþ] ¼ 306. Anal. Calcd for C18H27ClN2: C, 70.45; H,
8.87; N, 9.13. Found: 70.35; H, 8.76; N, 9.09.
Entry 15 (3o). Yellow crystalline solid, m.p.156–158ꢀC,
IR(KBr): mmax 3344, 1647, 1603 cmꢁ1 1H NMR (300 MHz,
.
CDCl3): d 1.88–2.10 (m, 12H, 6CH2), 2.90–2.95 (d, 1H, CH),
3.90–4.25 (m, 2H, CH2), 3.05 (br s, 1H, NH), 6.63–6.64 (m,
1H, ArAH), 6.73–6.77 (m, 1H, ArAH), 7.87–7.90 (m, 1H,
EXPERIMENTAL
Table 1
All chemicals were AR grade obtained from Qualigens,
India. All the solvents were purified by standard techniques.
Column chromatographic separations were carried out on silica
gel 100–200 mesh size. IR spectra were scanned on FT/IR-
4200 Type A, spectrophotometer with potassium bromide
optics. NMR spectra were recorded on a 300 MHz and mass
spectra were recorded on a LC-MS.
Preparation of the catalyst. The catalyst was prepared by
mixing silica gel (10 g, 200–400 mesh) in dry diethyl ether
(50 mL), with sulfuric acid (3 mL). The resulting mixture was
stirred for 30 min to absorb sulfuric acid on the surface of
Optimization of reaction conditions and the concentration of silica
gel-supported sulfuric acid for the synthesis of 3a.
H2SO4/Silica
gel (mol %)
Reaction
time (min)
Yield (%)
2.5
5
110
80
30
85
89
97
97
97
10
15
20
30
30
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D. Shobha, M. A. Chari, K. Mukkanti, and K. H. Ahn
Vol 46
Table 2
Silica gel-supported sulfuric acid catalyzed synthesis of 2,3-dihydro-1H-1,5-benzodiazepines.
Entry
1
Diamine
Ketone
Product
Time (min)
30
Yield (%)
97
2
40
95
3
4
5
40
92
94
92
60
60
6
50
90
7
120
86
(Continued)
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Silica Gel-Supported Sulfuric Acid Catalyzed Synthesis of
1,5-Benzodiazepine Derivatives
1031
Table 2
(Continued)
Entry
8
Diamine
Ketone
Product
Time (min)
120
Yield (%)
82
9
50
95
10
50
96
11
50
94
12
60
92
13
120
90
14
90
88
(Continued)
Journal of Heterocyclic Chemistry
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D. Shobha, M. A. Chari, K. Mukkanti, and K. H. Ahn
Vol 46
Table 2
(Continued)
Entry
Diamine
Ketone
Product
Time (min)
90
Yield (%)
15
86
16
120
88
17
140
82
18
150
80
19
120
85
20
120
90
ArAH). EIMS: m/z [Mþ] ¼ 274. Anal. Calcd for C16H19ClN2:
C, 69.93; H, 6.97; N, 10.19. Found: C, 69.83; H, 6.87; N,
10.09.
6.60 (m, 1H, ArAH), 6.77–6.82 (m, 1H, ArAH), 6.93–7.02
(m, 1H, ArAH). EIMS: m/z [Mþ] ¼ 278. Anal. Calcd for
C16H23ClN2: C, 68.92; H, 8.31; N, 10.05. Found: C, 68.83; H,
8.21; N, 10.00.
Entry 16 (3p). Reddish yellow solid, m.p. 160–162ꢀC,
IR(KBr): mmax 3338, 1638, 1591 cmꢁ1
.
1H NMR (300 MHz,
Entry 17 (3q). Yellow solid, m.p. 130–132ꢀC, IR(KBr):
1
CDCl3): d 0.82–0.92 (m, 6H, 2CH3), 1.15 (s, 3H, CH3), 1.23–
1.49 (m, 4H, 2CH2), 1.58–1.68 (m, 2H, CH2), 2.02–2.10 (m,
2H, CH2), 2.39–2.45 (m, 2H, CH2), 3.10 (br s, 1H, NH), 6.51–
mmax 3303, 1599, 1471 cmꢁ1. H NMR (300 MHz, CDCl3): d
1.83 (s, 3H, CH3), 2.99 (d, 1H, J ¼ 13.20 Hz, CH2), 3.08 (d,
1H, J ¼ 13.20 Hz, CH2), 3.58 (br s, 1H, NH), 6.79–6.82 (m,
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Silica Gel-Supported Sulfuric Acid Catalyzed Synthesis of
1,5-Benzodiazepine Derivatives
1033
[5] Morales, H. R.; Bulbarela, A.; Contreras, R. Heterocycles
1986, 24, 135.
1H, ArAH), 6.90–6.93 (m, 2H, ArAH), 7.01–7.10 (m, 4H,
ArAH), 7.30–7.40 (m, 1H, ArAH), 7.63–7.69 (m, 1H, ArAH).
EIMS: m/z [Mþ] ¼ 358. Anal. Calcd for C18H15ClN2S2: C,
60.24; H, 4.21; N, 7.81. Found: C, 60.14; H, 4.15; N, 7.71.
Entry 18 (3r). Light yellow crystalline solid, m.p.120–
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M.; Lee, Y. G.; Jung, D. H. Synth Commun 1999, 29, 1941.
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42, 1127.
1
122ꢀC, IR(KBr): mmax 3320, 1602, 1490 cmꢁ1. H NMR (300
[8] Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.
Tetrahedron Lett 2001, 42, 3193.
MHz, CDCl3): d 1.73 (s, 3H, CH3), 2.86 (d, 1H, J ¼ 13.20
Hz, CH2), 2.93 (d, 1H, J ¼ 13.20 Hz, CH2), 3.43 (br s, 1H,
NH), 6.70–6.79 (m, 1H, ArAH), 6.99–7.01 (m, 2H, ArAH),
7.10–7.17 (m, 1H, ArAH), 7.20–7.30 (m, 5H, ArAH). EIMS:
m/z [Mþ] ¼ 358. Anal. Calcd for C18H15ClN2S2: C, 60.24; H,
4.21; N, 7.81. Found: 60.14; H, 4.15; N, 7.71.
[9] Pan, X.-Q.; Zou, J.-P.; Hauang, Z.-H.; Zhang, W.
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Chandra, R. Green Chem 2006, 8, 519.
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V. Synth Commun 2004, 34, 3833.
Entry 19 (3s). Yellow solid, m.p. 145–147ꢀC, IR(KBr):
1
mmax 3267, 1646, 1562 cmꢁ1. H NMR (300 MHz, CDCl3): d
[12] Minothora, P.; Julia, S. S.; Constantinos, A. T. Tetrahedron
Lett 2002, 43, 1755.
1.75 (s, 3H, CH3), 2.86 (d, 1H, J ¼ 12.80 Hz, CH2), 3.14 (d,
1H, J ¼ 12.80 Hz, CH2), 3.50 (br s, 1H, NH), 6.74–6.84 (m,
1H, ArAH), 6.98–7.06 (m, 1H, ArAH), 7.19–7.29 (m, 5H,
ArAH), 7.42–7.52 (m, 4H, ArAH). EIMS: m/z [Mþ] ¼ 415.
Anal. Calcd for C22H17Cl3N2: C, 63.56; H, 4.12; N, 6.74.
Found: C, 63.46; H, 4.06; N, 6.64.
[13] Chen, W. Y.; Lu, J. Synlett 2005, 1337.
[14] Jarikote, D. V.; Siddiqui, S. A.; Rajagopal, R.; Thomas, D.;
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Entry 20 (3t). Pale yellow solid, m.p. 138–140ꢀC, IR(KBr):
1
mmax 3320, 1602, 1567 cmꢁ1. H NMR (300 MHz, CDCl3): d
[16] Chari, M. A.; Shobha, D.; Syamasundar, K. J Heterocycl
Chem 2007, 44, 929.
1.72 (s, 3H, CH3), 2.17 (s, 2H, CH2), 2.33 (s, 6H, 2CH3) 3.00
(br s, 1H, NH), 6.80–6.81 (m, 1H, ArAH), 7.06–7.10 (m, 5H,
ArAH), 7.42–7.53 (m, 5H, ArAH). EIMS: m/z [Mþ] ¼ 374.
Anal. Calcd for C24H23ClN2: C, 76.89; H, 6.18; N, 7.47.
Found: C, 76.79; H, 6.08; N, 7.37.
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J.; Venkateswarlu, Y. Catal Commun 2007, 8, 1635.
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2006, 47, 8523.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet