Expeditious synthesis of thiadiazolo benzodiazepines under conventional method and microwave irradiation

Article abstract of DOI:10.1080/10426500802049670

This article explores the use of sulfamic acid as an efficient catalyst for the one-pot synthesis of thiadiazolo 1, 5 benzodiazepines by using benzo[c][1,2,5]thiadiazole-4,5-diamine and various types of ketones in the presence of chloroform as a solvent under conventional methods and microwave irradiation. Our method is more advantageous than current methods. The catalyst (sulfamic acid) is cost effective, readily available and gives excellent yields with high purity. In comparison, the microwave irradiation method is equally as effective with a shorter reaction time and still maintaining high yields. Copyright Taylor & Francis Group, LLC.

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Phosphorus, Sulfur, and Silicon
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Expeditious Synthesis of
Thiadiazolo Benzodiazepines
Under Conventional Method
and Microwave Irradiation
J. Venu Madhav a & B. Rajitha a
a Department of Chemistry , National Institute of
Technology , Warangal, India
Published online: 03 Nov 2008.
To cite this article: J. Venu Madhav & B. Rajitha (2008) Expeditious Synthesis of
Thiadiazolo Benzodiazepines Under Conventional Method and Microwave Irradiation,
Phosphorus, Sulfur, and Silicon and the Related Elements, 183:12, 2984-2989, DOI:
10.1080/10426500802049670
To link to this article: http://dx.doi.org/10.1080/10426500802049670
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Phosphorus, Sulfur, and Silicon, 183:2984–2989, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802049670
Expeditious Synthesis of Thiadiazolo Benzodiazepines
Under Conventional Method and Microwave Irradiation
J. Venu Madhav and B. Rajitha
Department of Chemistry, National Institute of Technology,
Warangal, India
This article explores the use of sulfamic acid as an efficient catalyst for the one-pot
synthesis of thiadiazolo 1, 5 benzodiazepines by using benzo[c][1,2,5]thiadiazole-
4,5-diamine and various types of ketones in the presence of chloroform as a solvent
under conventional methods and microwave irradiation. Our method is more ad-
vantageous than current methods. The catalyst (sulfamic acid) is cost effective,
readily available and gives excellent yields with high purity. In comparison, the
microwave irradiation method is equally as effective with a shorter reaction time
and still maintaining high yields.
Keywords Benzodiazepine; benzo[c][1,2,5]thiadiazole-4,5-diamine; ketone; sulfamic
acid
INTRODUCTION
Anthramycin, tomaymycin, and sibiromycin are found to be antitumor
agents and antibiotics, which contain the benzodiazepine moiety.1,2
In the literature, this moiety is extensively exploited as anti-HIV
agents,3 anti-inflammatory, analgesic, hypnotic and anti-depressive
agent.4 1, 5 benzodiazepines are used as starting materials for the
preparation of some fused ring benzodiazepine derivatives.5−7 Due
to their broad spectrum of biological activity, these compounds have
received a great deal of attention in connection with their synthe-
sis. Thiadiazolo benzodiazepines were not reported in the litera-
ture. In continuation of our studies on thiadiazolo heterocycles,8 we
have expedited synthesis of these new systems. Generally, benzo-
diazepines are synthesized by the condensation of o-phenylene di-
amines with α, β-unsaturated carbonyl compounds,9β-haloketones,10
Received 30 January 2008; accepted 12 March 2008.
Financial assistance from U.G.C (RGNF) Grant No: F.16-158/2006(SA-II) New Delhi
is gratefully acknowledged.
Address correspondence to B. Rajitha, Department of Chemistry, National Institute
of Technology, Warangal 506004, India. E-mail: rajitabhargavi@yahoo.com
2984

Synthesis of Thiadiazolo Benzodiazepines
2985
or ketones.11 Several methodologies have been reported in the litera-
ture for this condensation by using various types of reagents, including
BF3-etherate,11 polyphosphoric acid-SiO2,12NaBH4, 13 Yb(OTf)3, 14and
17
acetic acid under microwave conditions,15 ionic liquids,16 SbCl3-Al2O
3,
YbCl3, 18Zn[L-proline]19Ag3PW12O40,20 and MgO/POCl3.21Many of
these methodologies, h2o,wever, are associated with several shortcom-
ings such as long-reaction conditions, low product yields and occurrence
of several side products. Moreover, some of the reagents employed are
expensive.
Recently, sulfamic acid has emerged as a good solid acid catalyst
for some important organic transformations such as the synthesis of
benzoxanthenes,22 and oxazoles.23 In continuation of our work on sul-
famic acid, we wish to report here the synthesis of thiadiazolo benzo-
diazepines. Sulfamic acid is recyclable and easy to handle as a catalyst
owing to its immiscibility with common organic solvents and it is a very
stable crystalline solid, it is commercially available and is an inexpen-
sive catalyst. The microwave irradiation accelerated synthesis is also
emerging as a powerful tool in organic synthesis24 due to short reaction
times and increase of yields with high purity, and allow precise control
of reaction parameters.
RESULTS AND DISCUSSION
We portray here a new method for the synthesis of thiadiazolo ben-
zodiazepines by the condensation of benzo[c][1,2,5]thiadiazole-4,5-
diamine25 with cyclic and acyclic ketones in the presence of sulfamic
acid in chloroform, irradiated in a domestic microwave oven at 300 W
level for 4–6 min at an interval of 30s. This furnished the expected
products in good yields. Correspondingly, the reaction was carried out
through a conventional method by stirring at 55◦C for 2–5 h and af-
forded identical products. The results are summarized in Table I. A
comparison of these two methods suggests that the microwave method
is highly advantageous over the conventional method. The spectro-
scopic characterization and elemental analyses are shown in Tables II
and III.
EXPERIMENTAL
All the melting points were uncorrected. The progress of the reaction
was monitored by TLC. IR spectra (KBr) were recorded on Shimadzu
FTIR model 8010 spectrometer and the 1H NMR spectra on Varian
Gemini 200 MHz spectrometer using TMS as internal standard. The

2986
J. V. Madhav and B. Rajitha
TABLE I Sulfamic Acid Catalyzed Synthesis of Thiadiazolo
1,5-Benzodiazepine Derivatives
Method A
Method B
Time Yield Time Yield Mp
(min) (%) (h) (%) (◦C)
Entry
Ketone
Product
1
2
CH3COCH3
4
86
81
2
81 110
78 125
CH3COCH2CH3
4.5
3.5
3
5
80
3
75 80
4
5
4.5
5.5
85
77
4
4
78 150
CH3COPh
75 82
6
7
p-C!PhCH3COPh
p-CH3OCH3COPh
4.5
85
72
3.5
80 178
6
5
70 85

Synthesis of Thiadiazolo Benzodiazepines
2987
TABLE II IR (Cm−1), 1H NMR (δ ppm) and Mass of the Compounds
Compd.
NH-str C=N-str
1H NMR (CDCl3)
MS (EI): m/z (M+)
3a
3345
1610
δ 1.85(s, 6H), 2.65(s, 2H), 2.91(s,
3H), 5.30(br s, 1H), 7.45(d,
1H), 7.63(d, 1H)
246
3b
3379
1610
δ 1.34(t, 3H), 1.51(t, 3H), 1.75(q,
2H), 2.35(m, 2H), 2.55(s, 3H),
2.95(q, 2H), 5.10(br s, 1H),
7.60(d, 1H), 7.75(d, 1H)
δ 2.12 − 2.81(m, 12H), 3.03(m,
2H), 3.15(t, 1H), 5.10(s, 1H),
7.65(d, 1H), 7.71(d, 1H)
δ 1.50 − 2.35(m, 16H), 2.70(t,
1H), 2.91(t, 2H), 5.31(s, 1H),
7.60-7.80(m, 2H)
δ 1.91(s, 3H), 3.29(d, 1H), 3.45
(d, 1H), 5.45 (s, 1H), 7.15–7.71
(m, 12H)
δ 1.87(s, 3H), 3.07(d, 1H), 3.50
(d, 1H), 5.85 (s, 1H), 7.15–7.65
(m, 10H)
274
3c
3d
3e
3f
3380
3370
3365
3388
3380
1630
1635
1630
1637
1610
298
326
370
439
430
3g
δ 1.85(s, 3H), 3.10–3.25(m, 2H),
3.91(s, 3H), 4.05(s, 3H), 5.31(s,
1H), 6.90–7.75(m, 10H)
elemental (C, H, N) microanalyses were performed on a Carlo Erba
model EA1108. Mass spectra were recorded on a JEOL JMS D-300
Spectrometer.
General Procedure
Method-A (Microwave Irradiation)
To a mixture of benzo[c][1,2,5]thiadiazole-4,5-diamine (0.6 m mol),
ketone (1.2m mol) in chloroform (3 ml) was added sulfamic acid (0.02
m mol) and the reaction was irradiated in microwave oven (BPL, 800
model) at 300 W power level for the appropriate time (Table I). Com-
pletion of the reaction was monitored by TLC. The reaction mixture
was cooled to room temperature, and the solvent was evaporated under
vacuum on a rotary evaporator. Water (5 ml) was added to reaction mix-
ture and extracted with EtOAc (4 ml). The organic layer was dried over
anhydrous sodium sulfate and evaporated under reduced pressure. The
crude product was purified by chromatography on silica gel using ethyl
acetate-hexane (1:7) as eluent to afford the thiadiazolo benzodiazepine.

2988
J. V. Madhav and B. Rajitha
TABLE III C, H, N, S Analysis of the Compounds
Cal (found) (%)
Molecular
Formula
Compd.
C
H
N
S
C12H14N4S
58.51 (58.47)
61.28 (61.24)
64.40 (64.42)
66.22 (66.25)
71.32 (71.27)
60.14 (60.11)
66.96 (66.97)
5.73 (5.77)
6.61 (6.64)
6.08 (6.06)
6.79 (6.82)
4.90 (4.94)
3.67 (3.62)
5.15 (5.11)
22.74 (22.70)
20.42 (20.38)
18.78 (18.74)
17.16 (17.19)
15.12 (15.17)
12.75 (12.72)
13.01 (13.05)
13.02 (13.07)
11.69 (11.65)
10.75 (10.71)
9.82 (9.80)
8.66 (8.62)
7.30 (7.32)
7.45 (7.49)
3b
3c
3d
3e
3f
C14H18N4S
C16H18N4S
C18H22N4S
C22H18N4S
C
22H16Cl2N4S
C24H22N4O2S
3g
Method-B (Conventional Method)
To a mixture of benzo[c][1,2,5]thiadiazole-4,5-diamine (0.6 m mol),
ketone (1.2m mol) in chloroform (10 ml) in a round-bottomed flask (50
ml) was added sulfamic acid (0.02 m mol) and the mixture was stirred
at 55◦C for appropriate time (Table I). After completion of the reac-
tion (TLC), contents were cooled to room temperature, the solvent was
evaporated under vacuum on a rotary evaporator. Water (5 ml) was
added to the reaction mixture and extracted with EtOAc (4 ml). The
organic layer was dried over anhydrous sodium sulfate and evaporated
under reduced pressure. The crude product was purified by chromatog-
raphy on silica gel using ethyl acetate-hexane (1:7) as eluent to give
the thiadiazolo benzodiazepine.
S
N
S
N
R
N
H
N
NH2
NH2
O
N
CH3
Sulfamic acid/MW/300W
Sulfamic acid/55oC
2
R
CH3
2 a-g
N
R
3 a-g
1
SCHEME 1
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