Synthetic methodology, spectral elucidation, and antioxidative properties of benzothianes and their sulfones

Article abstract of DOI:10.1080/10426500802704225

This article reflects the synthetic strategies and spectral investigation of 4H-1,4-benzothiazines. 4H-1,4-benzothiazines have been prepared by the condensation and oxidative cyclization of substituted 2-aminobenzenethiol with β-diketones/β-ketoesters in

Full text of DOI:10.1080/10426500802704225

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Synthetic Methodology,
Spectral Elucidation, and
Antioxidative Properties
of Benzothianes and Their
Sulfones
Vibha Gautam a , Meenakshi Sharma a , Meenakshi
Panwar b , Naveen Gautam c , Ashok Kumar b , I. K.
Sharma a & D. C. Gautam a
a Department of Chemistry , University of
Rajasthan , Jaipur, India
b Department of Zoology , University of Rajasthan ,
Jaipur, India
c Department of Chemistry , L.B.S. Govt. P.G.
College , Kotputli, Jaipur, India
Published online: 03 Nov 2009.
To cite this article: Vibha Gautam , Meenakshi Sharma , Meenakshi Panwar , Naveen
Gautam , Ashok Kumar , I. K. Sharma & D. C. Gautam (2009) Synthetic Methodology,
Spectral Elucidation, and Antioxidative Properties of Benzothianes and Their Sulfones,
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:11, 3090-3109, DOI:
10.1080/10426500802704225
To link to this article: http://dx.doi.org/10.1080/10426500802704225
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Phosphorus, Sulfur, and Silicon, 184:3090–3109, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802704225
Synthetic Methodology, Spectral Elucidation, and
Antioxidative Properties of Benzothianes and Their
Sulfones
Vibha Gautam,1 Meenakshi Sharma,1
Meenakshi Panwar,2 Naveen Gautam,3 Ashok Kumar,2
I. K. Sharma,1 and D. C. Gautam1
1Department of Chemistry, University of Rajasthan, Jaipur, India
2Department of Zoology, University of Rajasthan, Jaipur, India
3Department of Chemistry, L.B.S. Govt. P.G. College, Kotputli, Jaipur,
India
This article reflects the synthetic strategies and spectral investigation of 4H-1,4-
benzothiazines. 4H-1,4-benzothiazines have been prepared by the condensation
and oxidative cyclization of substituted 2-aminobenzenethiol with β-diketones/β-
ketoesters in dimethyl sulfoxide and with the oxidation of 4H-1,4-benzothiazines
by 30% hydrogen peroxide in glacial acetic acid, which results in the formation
of 4H-1,4-benzothiazine sulfones. The compounds were evaluated for their antiox-
idative properties through in vitro and in vivo studies in Swiss albino mice. The
structural assignments of compounds were made on the basis of spectroscopic data
and elemental analysis.
Keywords Antioxidant activities; benzothiazines; sulfones; Swiss albino mice
INTRODUCTION
Benzothiazines possess a bend along the nitrogen–sulfur axis, which
is one of the structural specificities responsible for similar pharmaco-
logical activities. As part of an ongoing program in the development of
novel synthetic methodologies for the preparation of biologically active
substances, we have been interested in the synthesis of various hetero-
cyclic structures because they are an integral part of many naturally
Received 14 July 2008; accepted 18 December 2008.
Authors are thankful to the Head, Chemistry and Zoology Department, University
of Rajasthan, Jaipur, India for laboratory facilities. Thanks are due to CSIR and UGC
(Bhopal) for financial support. Thanks are also due to CDRI, Lucknow for providing the
IR, proton NMR, and mass facilities.
Address correspondence to D. C. Gautam, Department of Chemistry, University of
Rajasthan, Jaipur- 302004, India. E-mail: drdcgautam@yahoo.co.in
3090

Benzothianes and Their Sulfones
3091
occurring and biologically active compounds.1–5 This review also reflects
up-to-date, comprehensive coverage of chemical and biomedical aspects
of sulfones of 4H-1,4-benzothiazines. Such heterocyclic compounds are
interesting because of their theoretical and structural implications; the
diversity of synthetic methods used in their preparation; and their bio-
logical, pharmacological, and industrial significance. This provides an
exhaustive coverage of their basic and applied aspects. The compounds
were evaluated for their antioxidative properties through in vitro and
in vivo studies in Swiss albino mice.6–11
RESULTS
Various substituted 2-aminobenzenethiols (I) were condensed with
β-diketones/β-ketoesters (IIa) in the presence of dimethyl sulfoxide,
which results in oxidative cyclization. The mechanism of the reac-
tion reports an intermediate, i.e., bis-(2-aminophenyl) disulfide (Ia),
obtained by the ready oxidation of substituted, 2-aminobenzenethiol
(I), which cyclizes to substituted 4H-1,4-benzothiazine (IV) by the scis-
sion of the sulfur–sulfur bond due to the high reactivity of α-position of
the enaminoketone system (III) towards nucleophilic attack. Oxidation
of 1,4-benzothiazine IVa–c by hydrogen peroxide in glacial acetic acid
yielded sulfones VIIa–i in high yield.2–5
The structures of all the synthesized compounds are characterized
by correct spectroscopic data and elemental analysis (Tables I to VII).
The synthesized compounds showed mixed radical scavenging activity.
The compounds were further treated for evaluation of antioxidative
properties on Swiss albino mice. Results showed that there was signifi-
cant decrease in lipid peroxidation (LPO) level and elevation in reduced
glutathione (GSH) in Swiss albino mice.8,10
DISCUSSION
The structural assignment of these compounds was made on basis of
spectroscopic data and elemental analysis; Table I for benzothiazines
1
and Table IV for their sulfones. The characteristic IR bands and H
NMR data of compounds IVa–i are presented in Tables II and III, respec-
tively, and for compounds VIIa–i the IR and NMR spectra are presented
in Tables V and VI, respectively. A single sharp peak in the region
3390–3240 cm−1 is observed due to N–H stretching vibrations in ben-
zothiazines IVa–i (Table II, column A). The series of synthesized 4H-1,4-
benzothiazines exhibits a single sharp peak in the region δ 8.95–7.89
ppm due to N-H proton in 1H NMR spectra (Table III). In the spectra of

3092

3093

3094

3095

3096

Benzothianes and Their Sulfones
3097
TABLE V Infrared Spectral Data of Substituted 4H-1,4-Benzothiaz-
ine Sulfones (VIIa–i) (in KBr∗) in cm−1
Compound
Compd.
VII
A
N-H
B
C=O
C
C-S
R1 R2 R3
R4
R5
a
b
c
d
e
f
g
h
i
Cl
Cl
Cl
Cl
Br
F
F
F
F
H
H
H
H
H
Br
Br
Br
Br
CF3 CH3 C6H4–Cl(p)
CF3 CH3 C6H4–F(p)
3340(3400) 1620(1650) 1048(1085)
3240(3500) 1590(1620) 1050(1070)
CF3 CH3 C6H4–OCH3(o) 3380(3440) 1600(1620) 1050(1080)
CF3 CH3 C6H4–Cl(o) 3260(3550) 1610(1660) 1042(1090)
CH3 C6H4–(CH3)(p) 3350(3420) 1600(1680) 1060(1080)
Br
H
H
H
H
C6H5 C6H5
CH3 C6H5
CH3 CF3
3340(3410) 1580(1620) 1040(1085)
3260(3420) 1610(1630) 1050(1090)
3390(3430) 1620(1650) 1040(1070)
3370(3400) 1610(1640) 1060(1080)
CH3 C6H4-Br(p)
benzothiazine sulfones, the absorption band due to NH stretching vi-
brations is shifted to higher frequency region (3550–3400 cm–1) (Table
V, column A). The series of synthesized 4H-1,4-benzothiazine sulfones
(VIIa–i) exhibits a single sharp peak in the region δ 8.86–7.86 ppm due
to N-H proton in 1H NMR spectra (Table VI).
EXPERIMENTAL
All the melting points were determined in open capillary tubes and
are uncorrected. IR spectra were recorded in KBr on a Nicolet-Megna
1
FT-IR 550 spectrometer, and the H NMR spectra on a JEOL AL-300
spectrometer (300 MHz) in CDCl3/DMSO-d6 using TMS as an inter-
nal standard (chemical shifts are measured in δ ppm). The purity of
the compounds was checked by TLC using silica gel “G” as adsorbent,
visualizing these by UV light or iodine.

3098

3099

3100
V. Gautam et al.
TABLE VII Antioxidant Activity of Synthesized Benzothiazines
(DPPH Assay)
Compound
Compd.
IV
DPPH% inhibition of
1 mg/mL of the compound
R1
R2
R3
R4
R5
a
Cl
Cl
Cl
Cl
Br
F
F
F
F
H
H
H
H
H
Br
Br
Br
Br
CF3
CF3
CF3
CF3
Br
H
H
H
H
CH3 C6H4–Cl(p)
CH3 C6H4–F(p)
CH3 C6H4–OCH3(o)
CH3 C6H4–Cl(o)
CH3 C6H4–CH3(p)
C6H5 C6H5
CH3 C6H5
CH3 CF3
CH3 C6H4-Br(p)
53.84 1.5
46.92 1.3
30.91 0.9
52.89 1.6
42.62 1.3
48.72 1.4
32.63 0.8
20.41 1.1
19.21 0.6
B
C
D
E
F
G
H
I
Preparation of 4H-1,4-Benzothiazine (IVa–i
)
Substituted 2-aminobenzenethiol (I; 0.01 mol) was added to a stirred
suspension of β-diketone (IIa; 0.01 mol) in DMSO (5 mL), and the
resulting mixture was refluxed for 20–40 min. The mixture was
cooled down to room temperature. The solid separated out was fil-
tered, washed with petroleum ether, and crystallized from methanol
(Scheme 1). The physical data of 4H-1,4-benzothiazines are reported in
Table I.
Preparation of 4H-1,4-Benzothiazine Sulfones VIIa–i
The 4H-1,4-benzothiazine (0.01 mol), glacial acetic acid (20 mL), and
30% hydrogen peroxide (5 mL) were added together in a 50◦mL R.B.
flask and the mixture was refluxed for 15–20 min at 50–60 C. After
this, a second portion of hydrogen peroxide (5 mL) was added. The
reaction was further refluxed for 4 h. The mixture was poured into a
beaker containing crushed ice. The obtained precipitate was filtered,
washed with water, and crystallized from ethanol1–5 (Scheme 1). The
physical data of 4H-1,4-benzothiazine sulfones are reported in Table
IV.

Benzothianes and Their Sulfones
3101
SCHEME 1

3102
V. Gautam et al.
TABLE VIII Antioxidant Activity of Synthesized Benzothiazine
Sulfones (DPPH Assay)
Compound
Compd.
IV
DPPH% inhibition of
1 mg/mL of the compound
R1
R2
R3
R4
R5
a
Cl
Cl
Cl
Cl
Br
F
F
F
F
H
H
H
H
H
Br
Br
Br
Br
CF3
CF3
CF3
CF3
Br
H
H
H
H
CH3 C6H4–Cl(p)
CH3 C6H4–F(p)
CH3 C6H4–OCH3(o)
CH3 C6H4–Cl(o)
CH3 C6H4–CH3(p)
C6H5 C6H5
CH3 C6H5
CH3 CF3
CH3 C6H4-Br(p)
40.91 0.2
34.62 1.3
10.11 0.4
50.73 1.2
33.61 0.8
50.22 0.9
44.28 1.1
25.17 0.3
36.78 0.3
B
C
D
E
F
G
H
I
Mechanism for the Synthesis of 4H-1,4-Benzothiazines and
Their Sulfones
ANTIOXIDANT ACTIVITY
All the synthesized compounds IVa–i and their sulfones VIIa–i
were screened for their antioxidant activity by the 1,1-diphenyl-2-
picryl hydrazyl (DPPH) radial scavenging assay and 2,2-azinobis(3-
ethylbenzothiazoline-6-sulfonic acid) (ABTS+) radical cation decol-
orization assay.
The present study demonstrated that the synthesized compounds
showed mixed radical scavenging activity in both DPPH for benzoth-
iazine (Table VII) and their sulfones (Table VIII) in and ABTS + assays
(Tables IX and X).
1. Compounds showed strong radical scavenging activity in DPPH
assays that have DPPH% inhibition ≥ 50.
2. Compounds showed moderate radical scavenging activity in DPPH
assays that have DPPH% inhibition ≥ 30.

Benzothianes and Their Sulfones
3103
TABLE IX Antioxidant Activity of Synthesized Benzothiazines
(ABTS Assay)
ABTS Activity at different time
Compound
R4 R5
intervals (min)
Compd.
IV
R1 R2 R3
0
1
2
4
6
a
b
c
d
e
f
g
h
i
Cl
Cl
Cl
Cl
Br
F
F
F
F
H
H
H
H
H
Br
Br
Br
Br
CF3 CH3 C6H4–Cl(p)
CF3 CH3 C6H4–F(p)
CF3 CH3 C6H4–OCH3(o) 0.722 0.106 0.105 0.104 0.103
CF3 CH3 C6H4–Cl(o)
Br CH3 C6H4–CH3(p)
0.731 0.190 0.189 0.189 0.189
0.732 0.231 0.231 0.231 0.231
0.732 0.690 0.689 0.688 0.688
0.731 0.308 0.308 0.308 0.308
0.731 0.431 0.430 0.430 0.429
0.733 0.051 0.051 0.051 0.051
0.721 0.659 0.655 0.654 0.653
0.738 0.238 0.238 0.236 0.236
H
H
H
H
C6H5 C6H5
CH3 C6H5
CH3 CF3
CH3 C6H4-Br(p)
3. Compounds showed mild radical scavenging activity in DPPH as-
says that have DPPH% inhibition < 30.
+
4. Compounds were found to be more active in ABTS assays that
showed much decline in graph (Figures 1 and 2).
DPPH RADICAL SCAVENGING ASSAY
Radical scavenging activity of compounds IVa–i and VIIa–i against sta-
ble 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical was determined spec-
trophotometrically as described by Cuendet et al.6 A stock solution 1
mg/mL of the compound was prepared in methanol. 50 µl of the com-
pounds were added to 5 mL of a 0.004% methanol solution of DPPH.
After 30 min incubation in a dark at room temperature, the absorbance
was read against a blank at 517 nm.
The assay was carried out in triplicate, and the percentage of inhi-
bition was calculated using the following formula:
(AB − AA)
% Inhibition =
× 100
AB

3104
V. Gautam et al.
TABLE X Antioxidant Activity of Synthesized Benzothiazine
Sulfones (ABTS Assay)
ABTS Activity at different time
intervals (min)
Compd. No.
R1 R2 R3 R4 R5
Compd.
IV
0
1
2
4
6
a
b
c
d
e
f
g
h
I
Cl
Cl
Cl
Cl
Br
F
F
F
F
H
H
H
H
H
Br
Br
Br
Br
CF3 CH3 C6H4–Cl(p)
CF3 CH3 C6H4–F(p)
CF3 CH3 C6H4–OCH3(o) 0.732 0.181 0.181 0.181 0.181
CF3 CH3 C6H4–Cl(o)
Br CH3 C6H4–CH3(p)
0.732 0.692 0.692 0.692 0.692
0.731 0.301 0.300 0.300 0.300
0.738 0.219 2.16
0.215 0.214
0.725 0.114 0.114 0.113 0.113
0.722 0.212 0.212 0.211 0.210
0.733 0.414 0.414 0.414 0.414
0.731 0.068 0.068 0.068 0.066
0.722 0.109 0.108 0.106 0.106
H
H
H
H
C6H5 C6H5
CH3 C6H5
CH3 CF3
CH3 C6H4-Br(p)
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 min.
a
1 min.
2 min.
Time (minutes)
4 min.
6 min.
h
b
c
d
e
f
g
i
FIGURE 1 After addition of 1 mL of diluted ABTS solution (A 734 nm = 0.700
0.020) to 10 µL of the compound, the absorbance reading was taken at 30
◦C exactly 1 min after initial mixing and up to 6 min. All determinations were
carried out in triplicate.

Benzothianes and Their Sulfones
3105
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 min.
a
1 min.
c
2 min.
4 min.
6 min.
h
Time (minutes)
b
d
e
f
g
i
FIGURE 2 After addition of 1 mL of diluted ABTS solution (A 734 nm = 0.700
0.020) to 10 µL of the compound, the absorbance reading was taken at 30
◦C exactly 1 min after initial mixing and up to 6 min. All determinations were
carried out in triplicate.
Where
AB = Absorption of blank
AA = Absorption of test
ABTS RADICAL CATION DECOLORIZATION ASSAY
The 2,2-azinobis(3-ethybenzothiazoline-6-sulphonic acid) radical
cation (ABTS) decolorization test was also used to assess the an-
tioxidant activity of compounds IVa–i and VIIa–i. The ABTS assay
was carried out using the improved assay of Re.7 In brief, ABTS was
generated by oxidation of ABTS with potassium persulfate. For this
purpose, ABTS was dissolved in deinoized water at a concentration of
7 mM, and potassium was persulfate added to a concentration of 2.45
mM. The reaction mixture was left at room temperature overnight
(12–16 h) in the dark before use; the ABTS solution then was diluted
with ethanol to an absorbance of 0.700
0.020 at 734 nm. After
addition of 1 mL of the diluted ABTS solution to 10 µ◦l of the compound
and mixing, absorbance readings were taken at 30 C at intervals of
exactly 1–6 min later. All determinations were carried out in triplicate.

3106
V. Gautam et al.
IN VIVO STUDIES IN SWISS ALBINO MICE
The compound was further treated for evaluation of antioxidative prop-
erties in Swiss albino mice. Results showed that there was significant
decrease in lipid peroxidation (LPO) level and elevation in reduced
glutathione (GSH) in Swiss albino mice.
Material and Methods
Animals
Swiss albino mice were obtained from, Jawaharlal Nehru University,
New Delhi, India. Random-bred, male Swiss albino mice (8 weeks old),
weighing 24
2 g were used for experiments. These animals were
maintained in the animal house at temperature of 24◦C 3◦C. They
were housed in polypropylene cages and fed standard mice feed from
Hindustan Lever Ltd., India. Tap water was provided to the animals.
Chemicals
Compound synthesized: sodium chloride, tris potassium chloride,
trichloro acetic acid, 5-dithiobis-2-nitrobenzoic acid (DTNB), acetic
acid, thiobarbituric acid, n-butanol, and pyridine.
BIOCHEMICAL STUDIES
1. Lipid peroxidation assay. The LPO level in liver was measured in
terms of thiobarbitituric and reactive substance (TBARS) using the
method of Ohkhawa et al.9 Absorbance in the assay was read at 532
nm (Tables XI and XII).
2. Sulfhydral group assay (GSH): The level of acid-soluble sulfhydral
groups was estimated in liver as total non-protein sulfhydral groups
using the method described by Moron et al.10 Reduced glutathione
(GSH; obtained from Sisco Research Laboratories, Bombay, India)
was used as a standard to calculate the micromoles of SH/g of tis-
sue. Absorbance in the assay was read at 412 nm using a systronic
spectrophotometer (Systronics Type 108; Naroda, Ahmedabad, In-
dia) (Tables XIII and XIV).
STATISTICAL ANALYSIS
Results of the biochemical studies were evaluated using student’s t test.
The above value shows there was significant increase in GSH content
of liver in animals treated with compounds IVa–i and VIIa–i. Also in

Benzothianes and Their Sulfones
3107
TABLE XI Antioxidative Properties of Benzothiazine in the Liver in
Swiss Albino Mice (LPO n mol/ mg tissue)
Treatment Compound No.
Compd.
IV
LPO (n mol/mg
tissue)
R1
R2
R3
R4
R5
a
Cl
Cl
Cl
Cl
Br
F
H
H
H
H
H
Br
Br
Br
CF3
CF3
CF3
CF3
Br
H
H
H
CH3
CH3
CH3
CH3
CH3
C6H5 C6H5
CH3
CH3
C6H4–Cl(p)
C6H4–F(p)
C6H4–OCH3(o) 6.42 0.16, p < 0.05
C6H4–Cl(o) 6.81 0.16
C6H4–(CH3)(p) 6.02 0.17, p < 0.025
6.69 0.5
6.7 0.18, p < 0.05
B
C
D
E
F
G
H
6.53 0.5
6.72 0.16
6.51 0.17, p < 0.05
F
F
C6H5
C6H4-Br(p)
TABLE XII Antioxidative Properties of Benzothiazine Sulfones in
the Liver in Swiss Albino Mice (LPO n mol/mg tissue)
Treatment Compound No.
Compd.
IV
LPO (n mol/mg
tissue)
R1
R2
R3
R4
R5
a
Cl
Cl
Cl
Br
F
F
F
F
H
H
H
CF3
CF3
CF3
Br
H
H
H
H
CH3
CH3
CH3
CH3
C6H4–F(p)
6.81 0.16
B
C
D
E
F
G
h
C6H4–OCH3(o) 6.79 0.17, p < 0.05
C6H4–Cl(o) 6.20 0.22, p < 0.005
C6H4–(CH3)(p) 6.68 0.17, p < 0.05
H
Br
Br
Br
Br
C6H5 C6H5
6.5 0.5
6.81 0.17
6.70 0.18, p < 0.05
6.51 0.17, p < 0.05
CH3
CH3
CH3
C6H5
CF3
C6H4-Br(p)

3108
V. Gautam et al.
TABLE XIII Antioxidative Properties of Benzothiazine in the Liver
in Swiss Albino Mice (GSH n mol/100 g tissue)
Treatment Compound No.
Compd.
IV
GSH (n mol/100 g
tissue)
R1
R2
R3
R4
R5
a
Cl
Cl
Cl
Cl
Br
F
H
H
H
H
H
Br
Br
Br
CF3
CF3
CF3
CF3
Br
H
H
H
CH3
CH3
CH3
CH3
CH3
C6H5 C6H5
CH3
CH3
C6H4–Cl(p)
C6H4–F(p)
C6H4–OCH3(o) 4.20 0.19
C6H4–Cl(o) 4.16 0.26
C6H4–(CH3)(p) 5.01 0.12, p < 0.005
5.00 0.11, p < 0.005
4.80 0.15, p < 0.05
B
C
D
e
F
G
H
4.90 0.12, p < 0.005
4.21 0.19
4.15 0.16
F
F
C6H5
C6H4-Br(p)
TABLE XIV Antioxidative Properties of Benzothiazine Sulfones in
the Liver in Swiss Albino Mice (GSH n mol/100 g tissue)
Treatment Compound No.
Compd.
IV
GSH (n mol/100 g
tissue)
R1
R2
R3
R4
R5
a
Cl
Cl
Cl
Br
F
F
F
F
H
H
H
CF3
CF3
CF3
Br
H
H
H
H
CH3
CH3
CH3
CH3
C6H4–F(p)
C6H4–OCH3(o)
C6H4–Cl(o)
5.01 0.11, p < 0.005
4.17 0.20
4.80 0.15, p < 0.05
4.80 0.15, p < 0.05
4.21 0.19
4.69 0.15, p < 0.025
4.7 0.13, p < 0.05
4.19 0.19
B
C
D
E
F
G
H
H
C6H4–(CH3)(p)
Br
Br
Br
Br
C6H5 C6H5
CH3
CH3
CH3
C6H5
CF3
C6H4-Br(p)

Benzothianes and Their Sulfones
3109
these animals, the value of LPO was significantly decreased, showing
potent antioxidant activities in Swiss albino mice.
CONCLUSION
Synthesized compounds showed mixed radical scavenging and antiox-
idant activity in Swiss albino mice.
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