Synthesis and antimicrobial activity of structurally flexible heterocycles with the 1,4-thiazine heterosystem

Article abstract of DOI:10.1007/s11164-011-0320-0

In this work, 4H-1,4-benzothiazines were synthesized by an efficient synthetic method in a single step involving heterocyclization of substituted 2-aminobenzenethiols with β-ketoester. The structures of the synthesized compounds were confirmed by their analytical and spectral data. The synthesized compounds were evaluated for their antimicrobial activity against bacterial species; E. coli and Bacillus cereus. The synthesized compounds showed significant activity against microorganisms, which can be correlated with the privileged heterocyclic structural scaffolds.

Full text of DOI:10.1007/s11164-011-0320-0

Res Chem Intermed (2011) 37:1103–1111
DOI 10.1007/s11164-011-0320-0
Synthesis and antimicrobial activity of structurally
flexible heterocycles with the 1,4-thiazine heterosystem
•
Praveen Kumar Sharma Ankur Fogla
•
•
B. S. Rathore M. Kumar
Received: 2 January 2011 / Accepted: 29 April 2011 / Published online: 18 May 2011
Ó Springer Science+Business Media B.V. 2011
Abstract In this work, 4H-1,4-benzothiazines were synthesized by an efficient
synthetic method in a single step involving heterocyclization of substituted 2-am-
inobenzenethiols with b-ketoester. The structures of the synthesized compounds
were confirmed by their analytical and spectral data. The synthesized compounds
were evaluated for their antimicrobial activity against bacterial species; E. coli and
Bacillus cereus. The synthesized compounds showed significant activity against
microorganisms, which can be correlated with the privileged heterocyclic structural
scaffolds.
Keywords 2-aminobenzenethiols Á 4H-1,4-benzothiazines Á
Antimicrobial activities
Introduction
Nitrogen- and sulphur-containing heterocycles are undoubtedly the most important
targets in the pharmaceutical chemistry because most of the natural products of
pharmaceutical interest incorporate N- and S- heterocycles in their structures [1, 2].
The 1,4-thiazine ring system is an important heterosystem in heterocyclic chemistry
because it constitutes the skeleton of natural products, such as the two cytotoxic
terpene, quinones, conicaquinones A and B, xanthizone, and xnthiside. The 1,4-
thiazine ring system is known to also play an important role in pigments and
dyestuffs [3–7]. In addition, 4H-1,4-benzothiazine derivatives have been shown to
exhibit wide-ranging biological activities, such as anticancer, antifungal, antago-
nistic, antioxidant, antihypertensive, analgesic, cardiovascular, antibacterial, anti-
malarial, and antimicrobial, etc. [8–21]. 1,4-Benzothiazines have also been reported
P. K. Sharma Á A. Fogla Á B. S. Rathore Á M. Kumar (&)
Department of Chemistry, University of Rajasthan, Jaipur 302055, India
e-mail: mahendrakpathak@yahoo.com
123

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P. K. Sharma et al.
as new antiallergic and antirheumatic agents. 1,4-Benzothiazines annelated with
benzopyrene have shown a very interesting cytoprotective effect against t-BHP-
induced cytotoxicity. The diverse range of biological activities of 1,4- benzothi-
azines has been attributed to the structural specificity, i.e., structural flexibility due
to folding along the N–S axis. The folding angle is affected to a larger extent by the
nature and arrangement of the substituents which in turn influence the activity. The
structural features present in the 1,4-benzothiazine heterosystem are also present in
10H-phenothiazine and are responsible for their wide-ranging activities, which
makes them therapeutically as well as industrially interesting [22–24].
Encouraged by promising diverse biological activities of 1,4-benzothiazines,
and as a part of our ongoing research program on the synthesis of nitrogen- and
sulphur-containing novel heterocycles [25–29], we have designed and synthesized
structurally diverse 1,4-benzothiazines and evaluated their activity against
microorganisms.
Results and discussion
2-Aminobenzenethiols Va–g were prepared by the heterolytic cleavage of
substituted 2-aminobenzothiazoles IVa–g, which were prepared by brominative
cyclization of the corresponding phenylthioureas IIa–g obtained by thiocyanogen-
ation of substituted anilines Ia–g (Scheme 1) [30–34].
Substituted 4H-1,4-benzothiazines Xa–g have been synthesized by heterocycli-
zation of 2-aminobenzenethiols with b-ketoester in the presence of dimethyl
sulphoxide (Scheme 2).
R
R
R
R1
R2
R1
R2
NH4SCN
H2O
R1
R2
Br2
S
C NH2.HBr
CHCl3
N
NH2
NH C NH2
S
R3
R3
R3
IIIa-g
Ia-g
IIa-g
liq. NH3
R
R
R1
R2
SH
R1
R2
S
(i) KOH
(ii) gl. acetic acid
C NH2
N
NH2
R3
R3
IVa-g
Va-g
Scheme 1 Mechanistic presentation of synthesis of substituted 2-aminobenzenethiols
123

Synthesis and antimicrobial activity of structurally flexible heterocycles
1105
CH3
R3
O
CH
CH3
(CH3)2SO
R2
R1
NH2
SH
C
+
H2C
OEt
C
O
R
VI
V
R3
R3
R2
NH2
R2
R1
NH2
R1
S
S
R
R
R
O
C
O
C
R
R1
S
OEt
R1
S
N
OEt
CH3
HC
C
H2C
C
CH3
N
H
CH
R2
CH
R2
R3
CH3
R3
CH3
VIII
VII
R3
R
O
C
H
N
H
R2
R1
CH(CH3)2
R1
R2
S
- H
OEt
CH3
O
C
S
N
H
CH
OEt
R
R3
CH3
X
IX
(Xa) R = H, R = CH ,
R = H, R = H
2 3
1
3
(Xb) R = Cl, R = H,
R = H, R = CH
2 3 3
1
(Xc) R = H, R = OCH , R = H, R = H
1
3
2
3
(Xd) R = H, R = H,
R = H, R = Cl
2 3
1
(Xe) R = H, R = H,
R = H, R = H
2 3
1
(Xf) R = H, R = OC H , R = H, R = H
1
6
5
2
3
(Xg) R = H, R = Cl,
R = H, R = H
2 3
1
Scheme 2 Mechanistic presentation of synthesis of substituted 4H-1,4-benzothiazines
123

1106
P. K. Sharma et al.
The reaction is considered to proceed via in situ formation of an enaminoketone
intermediate VIII, which is simultaneously cyclized to 4H-1,4-benzothiazine with
the cleavage of S–S bond involving intramolecular nucleophilic attack. Thus, the
reaction is regioselective and occurs through the predominately keto form of
b-ketoester (Scheme 2). Although different methods have been reported in the
literature [35–50], the present method has been considered as one of the best
methods as far as its operational simplicity and the yields of the products are
concerned.
The structures of the newly synthesized 4H-1,4-benzothiazines have been
assigned by their elemental analyses and IR, 1H NMR, 13C NMR, and mass spectral
studies. The absence of the absorption bands corresponding to –NH2 and –SH
groups and the appearance of the absorption bands corresponding to the N–H and
C=O stretching vibrations in the regions, 3,325–3,450 and 1,625–1,740 cm-1
,
respectively, in IR spectra revealed that heterocyclization has occurred under the
reaction conditions and provided substituted 4H-1,4-benzothiazines (Xa–g) involv-
ing the proposed reaction mechanism (Scheme 2). An absorption band in the region
790–820 cm-1 is observed due to C–Cl stretching vibrations in the compounds Xb,
Xd, and Xg.
1H NMR spectra of all the synthesized 4H-1,4-benzothiazines exhibit a singlet in
the region d 8.10–8.24 ppm due to N–H proton. All 4H-1,4-benzothiazines show
multiplet in the region d 7.00–7.75 ppm due to aromatic protons. In compound (Xf)
a multiplet is observed in the region d 6.87–6.98 ppm due to aromatic protons of
–OC6H5. In compound (Xc) a singlet is observed at d 3.93 ppm due to CH3 protons
of OCH3. All 4H-1,4-benzothiazines show a triplet in the region d 1.21–1.33 ppm
due to CH3 protons of OC2H5 and a quartet in the region d 3.72–4.79 ppm due to CH2
protons of OC2H5. All 4H-1,4-benzothiazines show a heptate (appears as multiplet) in
the region d 2.33–2.92 ppm due to CH of isopropyl group and a doublet in the region d
1.29–1.13 ppm due to (CH3)2 protons of isopropyl group. 13C NMR spectrum of the
synthesized 1,4-benzothiazine Xg showed distinct resonance signals including for
aromatic carbons and other carbons in agreement with the assigned structure. 13C
NMR spectra of the synthesized compounds (Xa–f) are similar to that of Xg except for
the substituents CH3, OCH3, and OC6H5, which exhibit characteristics resonance
signals with appropriate chemical shifts. In the mass spectrum of compound Xg, the
molecular ion peak observed at 297 (M?) is in accordance with the molecular weight
of the synthesized compound. The base peak at m/z 136 (100%) and other peaks (m/z,
I [ 5%) 91, 109, 124, 147, 176, 190, 218, 234, 235, 269 are according to the structural
fragments of the compound Xg.
Pharmacological activity
All the synthesized compounds were screened for their antibacterial activity against
Bacillus cereus (Gram-positive bacteria) and E. coli (Gram-negative bacteria) at a
concentration of 30 lg/mL using ethanol as a solvent by well-diffusion method
[51–54]. After 24 h of incubation at 37°C, the zone of inhibition was measured in
millimeters (Table 1).
123

Synthesis and antimicrobial activity of structurally flexible heterocycles
1107
Table 1 Pharmacological activity substituted 4H-1,4-benzothiazines (Xa–g)
Compounds (30 lg/mL)
Antimicrobial (zone of inhibition in mm)
R
R1
R2
R3
E. Coli (A)
Bacillus cereus (B)
I
II
H
Cl
H
H
H
H
H
III
IV
H
H
H
H
H
H
H
V
VI
11
12
12
11
12
13
9
VII
10
13
12
10
9
Xa
Xb
Xc
Xd
Xe
Xf
Xg
CH3
H
H
CH3
H
OCH3
H
Cl
H
H
OC6H5
Cl
H
12
12
11
H
Chloramphenicol
10
Conclusions
It has been observed that all the synthesized benzothiazines Xa–g show activity
against microbes. Compounds Xb, Xc, and Xf show excellent activity against both
bacteria, whereas compounds Xa and Xd show moderate activity against E. coli.
However, weak activity was shown by the compounds Xa and Xd against B. cereus.
Compound Xe shows moderate activity against E. coli while weak activity is shown
against B. cereus. Compound Xg shows weak activity against E. coli, whereas
moderate activity was shown against B. cereus. Chloramphenicol (30 lg/mL) was
used as reference drug for the activity (Fig. 1) .
Experimental
Melting points of the synthesized compounds were determined on an electric
melting apparatus and the values are uncorrected. The IR spectra were recorded on a
Shimadzu 470 spectrometer in KBr discs. The 1H NMR and 13C NMR spectra were
Antimicrobial activity of synthesized compound Xa-g compared with reference
(Chloramphenicol) at the concentration of 30 µg/ml in ethanol as control
14
12
10
8
6
4
E.Coli
Bacillus
Cereus
2
0
Compounds
Fig. 1 Graphical representation of in vitro antibacterial activity of the synthesized compounds (Xa–g)
123

1108
P. K. Sharma et al.
recorded on a JEOL 300-MHz spectrophotometer using TMS as an internal standard
in CDCl3/DMSO as solvent. The chemical shifts are expressed as d ppm. Mass
spectrum data was recorded on a JEOL SX-102/Da-600 using Argon/Xenon (6 kV,
10 mA0 as the FAB gas) mass spectrometer.
General method of preparation
Preparation of substituted 2-aminobenzenethiols (Va–g)
Substituted 2-aminobenzenthiols have been prepared from substituted anilines in the
three steps shown below:
1. Preparation of substituted phenylthioureas
A mixture of substituted aniline (0.1 mol) conc. HCl (9 mL) and water (25 mL)
was formed in an R.B. flask and refluxed for 30 min. The solution of aniline
hydrochloride obtained was then allowed to cool to room temperature and then
ammonium thiocyanate (0.1 mol) was added. The reaction mixture was then
refluxed for 4 h until two layers were separated out. The solution was poured into
crushed ice and was then filtered, dried, and crystallized from ethanol.
2. Preparation of substituted 2-aminobenzothiazoles
Substituted phenylthiourea (0.1 mol) and chloroform (100 mL) were taken in
two-necked R.B. flask (500 mL) equipped with a mechanical stirrer. A solution of
bromine (0.1 mol) in chloroform (100 mL) was added dropwise with stirring to the
reaction mixture by maintaining the temperature below 5°C. After the complete
addition of bromine, the stirring was continued for a period of 4 h and the contents
of the flask were refluxed on water bath until the evolution of HBr ceased.
Chloroform was removed by filtration and the resulting solid material was treated
with aqueous sulphur dioxide solution and then filtered. The filtrate was neutralized
by aqueous ammonia solution and the precipitate obtained was filtered, washed with
water, and crystallized from ethanol.
3. Preparation of substituted 2-aminobenzenethiols
In a round-bottomed flask, substituted 2-aminobenzothiazole, KOH (five times
by weight of thiazole) and water (ten times by weight of thiazole) were placed and
refluxed until evolution of ammonia ceased. The contents were filtered and diluted
by ice-cold water. Adding 5 N acetic acid with vigorous stirring neutralized the
filtrate. The temperature of the solution was not allowed to rise above room
temperature (controlled by adding ice) otherwise a decomposed greenish mass is
obtained. The semisolid yellowish precipitate was extracted 2–3 times with ether.
Ether was evaporated and the product was crystallized from ethanol.
b-ketoester(active methylene compound) (VI)
b–ketoester used for the synthesis of 4H-1,4-benzothiaines was purchased from
Sigma-Aldrich.
123

Synthesis and antimicrobial activity of structurally flexible heterocycles
1109
Preparation of substituted 4H-1,4-benzothiazines (Xa–g)
2-aminobenzenethiol (Va–g; 0.01 mol) was added to the stirred suspension of
b-ketoester (VI; 0.01 mol) in DMSO (5 mL) and then the reaction mixture was
refluxed for 25 min. The reaction mixture was cooled to room temperature and the
solid obtained was filtered and washed with petroleum ether. The synthesized
4H-1,4-benzothiazines were crystallized from methanol.
Xa. Ethyl 3-isopropyl-7-methyl-4H-1,4-benzothiazine-2-carboxylate
1
Yield 81% M.P. °C 192; IR (KBr, cm-1): 3,325(–NH), 1,625(C=O); H NMR
(CDCl3, d ppm); 2.92 (s, 3H, CH3 proton at C7), 8.14 (s, 1H,–NH proton), 2.39–2.54
(m, 1H, Isopropyl CH proton at C3), 1.18 (d, J = 6.9 Hz, 6H, Isopropyl (CH3)2
proton at C3), 3.86 (q, 2H, Ester CH2 protons), 1.25 (t, J = 7.1 Hz, 3H, Ester CH3
proton), 7.20–7.75 (m, 3H, Aromatic protons); Anal. Calcd. for C15H19NO2S : C,
64.95, H, 6.90, N, 5.05. Found: C, 64.88, H, 6.83, N, 5.01.
Xb. Ethyl 8-chloro-3-isopropyl-5-methyl-4H-1,4-benzothiazine-2-carboxylate
1
Yield 72% M.P. °C 206; IR (KBr, cm-1): 3,450(–NH), 1,730(C=O); H NMR
(CDCl3, d ppm); 2.71(s, 3H, CH3 proton at C5), 8.18 (s, 1H,-NH proton), 2.33–2.50
(m, 1H, Isopropyl CH proton at C3), 1.14–1.16 (d, J = 6.9 Hz, 6H, Isopropyl
(CH3)2 proton at C3), 3.92 (q, 2H, Ester CH2 protons), 1.25 (t, J = 7.1 Hz, 3H, Ester
CH3 proton), 7.00–7.42 (dd, J = 8.1 Hz, 2H, Aromatic protons); Anal. Calcd. for
C15H18ClNO2S: C, 57.78, H, 5.82, N, 4.49. Found: C, 57.71, H, 5.77, N, 4.41.
Xc. Ethyl 3-isopropyl-7-methoxy-4H-1,4-benzothiazine-2-carboxylate
1
Yield 65% M.P. °C 202; IR (KBr, cm-1): 3,360(–NH), 1,680(C=O); H NMR
(CDCl3, d ppm); 3.93(s, 3H, OCH3 proton at C7), 8.22 (s, 1H,–NH proton), 2.59(m,
1H, Isopropyl CH proton at C3), 1.17–1.19 (d, J = 6.9 Hz, 6H, Isopropyl (CH3)2
proton at C3), 3.78–3.84 (q, 2H, Ester CH2 protons), 1.21–1.29 (t, J = 7.1 Hz, 3H,
Ester CH3 proton), 7.46–7.50 (m, 3H, Aromatic protons); Anal. Calcd. for
C15H19NO3S: C, 61.41, H, 6.53, N, 4.77. Found: C, 61.39, H, 6.49, N, 4.71.
Xd. Ethyl 5-chloro-3-isopropyl-4H-1,4-benzothiazine-2-carboxylate
1
Yield 60% M.P. °C 198; IR (KBr, cm-1): 3,340(–NH), 1,740(C=O); H NMR
(CDCl3, d ppm); 8.21 (s, 1H, –NH proton), 2.58 (m, 1H, Isopropyl CH proton at C3),
1.26–1.29 (d, J = 6.9 Hz, 6H, Isopropyl (CH3)2 proton at C3), 3.72–3.80 (q, 2H,
Ester CH2 protons), 1.33 (t, J = 7.1 Hz, 3H, Ester CH3 proton), 7.19–7.31 (m, 3H,
Aromatic protons); Anal. Calcd. for C14H16ClNO2S: C, 56.46, H, 5.42, N, 4.70.
Found: C, 56.41, H, 5.39, N, 4.65.
Xe. Ethyl 3-isopropyl-4H-1,4-benzothiazine-2-carboxylate.
1
Yield 85% M.P. °C 190; IR (KBr, cm-1): 3,425(–NH), 1,680(C=O); H NMR
(CDCl3, d ppm); 8.24 (s, 1H, –NH proton), 2.61 (m, 1H, Isopropyl CH proton at C3),
123

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P. K. Sharma et al.
1.13–1.15 (d, J = 6.9 Hz, 6H, Isopropyl (CH3)2 proton at C3), 4.79 (q, 2H, Ester
CH2 protons), 1.24–1.27 (t, J = 7.1 Hz, 3H, Ester CH3 proton), 7.09–7.56 (m, 4H,
Aromatic protons); Anal. Calcd. for C14H17NO2S: C, 63.85, H, 6.51, N, 5.32 Found:
C, 63.80, H, 6.49, N, 5.29.
Xf. Ethyl 3-isopropyl-7-phenoxy-4H-1,4-benzothiazine-2-carboxylate
1
Yield 78% M.P. °C 210; IR (KBr, cm-1): 3,400(–NH), 1,740 (C=O); H NMR
(CDCl3, d ppm); 6.87–6.98 (m, 5H, OC6H5 at C7) 8.10 (s, 1H, –NH proton), 2.92
(m, 1H, Isopropyl CH proton at C3), 1.27–1.28 (d, J = 6.9 Hz, 6H, Isopropyl
(CH3)2 proton at C3), 4.08 (q, 2H, Ester CH2 protons), 1.25 (t, J = 7.1 Hz, 3H, Ester
CH3 proton), 7.28–7.46 (m, 3H, Aromatic protons); Anal. Calcd. for C20H21NO3S:
C, 67.58, H, 5.95, N, 3.94 Found: C, 67.51, H, 5.91, N, 3.90.
Xg. Ethyl 7-chloro-3-isopropyl-4H-1,4-benzothiazine-2-carboxylate
1
Yield 64% M.P. °C 195; IR (KBr, cm-1): 3,390(–NH), 1,690(C=O); H NMR
(CDCl3, d ppm); 8.24 (s, 1H, –NH proton), 2.55(m, 1H, Isopropyl CH proton at C3),
1.17–1.18 (d, J = 6.9 Hz, 6H, Isopropyl (CH3)2 proton at C3), 4.30–4.37 (q, 2H,
Ester CH2 protons), 1.25–1.30 (t, J = 7.1 Hz, 3H, Ester CH3 proton), 7.12–7.54 (m,
4H, Aromatic protons); 13C NMR (CDCl3, d ppm); 158.24, 147.92, 146.51, 129.65,
128.15, 127.05, 124.75, 118.47, 117.63, 64.44, 35.45, 18.24,19.52 MS: m/z: 297
(M?), BP: m/z: 136; Anal. Calcd. for C14H16ClNO2S: C, 63.85, H, 6.51, N, 5.32
Found: C, 63.80, H, 6.49, N, 5.29.
Acknowledgments The authors are thankful to the head of the Department of Chemistry, University of
Rajasthan, Jaipur (India) for providing the necessary laboratory facilities as well as instrumentation
facilities (IR, and 1HNMR). The director of the RSIC, CDRI, Lucknow (India) is acknowledged for
providing mass spectra of the synthesized compounds. We express our thanks to UGC, New Delhi,
for providing a meritorious student fellowship to one of the authors (P.K.S.).
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