Synthesis of bioactive substituted pyrazolylbenzothiazinones

Article abstract of DOI:10.1007/s11164-014-1727-1

Abstract Pyrazolylbenzothiazinones have been synthesized in good yields by the reaction of 2-hydrazinocarbonymethyl-3,4-dihydro-2H-1,4-benzothiazin-3-ones with β-diketone in the presence of ethanol. The structures of synthesized pyrazolylbenzothiazinones were confirmed on the basis of their analytical and spectral data. The antimicrobial activities of the synthesized compounds have also been included.

Full text of DOI:10.1007/s11164-014-1727-1

Res Chem Intermed
DOI 10.1007/s11164-014-1727-1
Synthesis of bioactive substituted
pyrazolylbenzothiazinones
•
Praveen Kumar Sharma M. Kumar
Received: 10 December 2013 / Accepted: 26 May 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract Pyrazolylbenzothiazinones have been synthesized in good yields by the
reaction of 2-hydrazinocarbonymethyl-3,4-dihydro-2H-1,4-benzothiazin-3-ones
with b-diketone in the presence of ethanol. The structures of synthesized pyr-
azolylbenzothiazinones were confirmed on the basis of their analytical and spectral
data. The antimicrobial activities of the synthesized compounds have also been
included.
Keywords Pyrazolylbenzothiazinones ꢀ Benzothiazinones ꢀ 2-aminobenzenethiol ꢀ
Antibacterial activities
Introduction
Heterocyclic ring systems have played an important role in medicinal chemistry, as
most of the heterosystems have served as key templates in the development of
numerous important therapeutic agents [1–3]. The design and synthesis of
biologically active molecules is one of the main challenges in medicinal chemistry.
Potential efforts have been focused on the synthesis of small heterocyclic molecules
because of their structural diversity and extensive utility as therapeutic agents.
Nitrogen and sulfur-containing heterocycles; thiazine and its derivatives are of
synthetic interest because they constitute an important class of natural and synthetic
heterocycles, many of which exhibit useful biological and pharmacological
activities, and are used as antifungal agents, anticancer, Na/H exchange inhibitors,
P. K. Sharma (&)
Department of Chemistry, Lovely Professional University, Phagwara 144402, Punjab, India
e-mail: pk_pandit1982@yahoo.com
M. Kumar
Department of Chemistry, University of Rajasthan, Jaipur 302055, India
123

P. K. Sharma, M. Kumar
Ca2? channel opener, antagonists, antioxidants, antimicrobial agents, and bacteri-
cides [4–15], etc.
2H-1,4-Benzothiazin-3-one derivatives especially attracted the attention of
synthetic chemists due to their wide-ranging biological activities [16, 17]. The
structural modification in 1,4-benzothiazin-3-ones will lead to the development of a
new class of therapeutic agents. Similarly, pyrazole and its derivatives have been
identified as active core structures in anti-bacterial, hypotensive, and anti-
inflammatory agents, as well as neurotoxicity inhibitors. They have also been
reported to exhibit antimicrobial, antifungal, anticancer, and herbicidal activities
[18–25]. In addition, pyrazole-fused derivatives have shown a broad spectrum of
pharmacological and biological activities. In particular, pyrazole-fused benzothia-
zines have been reported to exhibit antimalarial activities [26]. The pyrazole
derivatives are also used in supramolecular and polymer chemistry, agrochemicals,
cosmetic colorings, complexing agents for the synthesis of hydrogenation catalysts,
and UV stabilizers [27, 28]. Pyrazole derivatives have also shown liquid crystal
properties.
As a consequence of the wide-ranging pharmacological and industrial applica-
tions of pyrazoles and benzothiazines and our continuing interest in the synthesis of
therapeutically interesting heterocycles, we have designed and synthesized
pyrazolylbenzothiazinones, incorporating to medicinally privileged heterosystems
attached by ethanone functionality, on the basis of combinatorial synthesis, being
practiced in most drug discoveries, with a view to develop multi-target drugs with
promising bioactivities.
Results and discussion
The starting 2-aminothiophenols 1a–g were prepared by the alkaline hydrolysis of
2-aminobenzothiazole, which were synthesized by the brominative cyclization of
corresponding phenylthioureas by bromine and chloroform [29–31]. The required
intermediates 3,4-dihydro-2-(ethoxycarbonyl)methyl-2H-1,4-benzothiazinones 3a–
g were prepared by the reaction of 2-aminothiophenols 1a–g with maleic anhydride
2 according to literature [32, 33]. Treatment of 3a–g with hydrazine hydrate in the
presence of ethanol provided 2-hydrazinocarbonylmethyl-3,4-dihydro-3-oxo-2H-
1,4-benzothiazine 4a–g, which were further reacted with acetyl acetone in ethanol
giving pyrazolylbenzothiazine 5a–g (Scheme 1).
The structures of the synthesized heterocycles have been confirmed by their
spectral characteristics. The IR spectra of pyrazolylbenzothiazinones 5a–g exhibit
characteristic absorption bands at 3,375–3,320 cm-1(–NH), 1,730–1,705 cm-1
(C=O) and 3,065–3,010 cm-1 (Ar, C–H). In compounds 5c, 5e, and 5f, the
absorption at 810–805 cm-1 is assigned to the C–Cl stretching vibrations. The
absorption band at 670 cm-1 in compound 5d is attributed to the C–Br stretching
vibrations. In compound 5e, the absorption at 1,050 cm-1 is observed due to C–F
1
stretching vibrations. HNMR spectra of all the synthesized pyrazolylbenzothiazi-
nones show a singlet at d 8.59–8.25 ppm due to NH proton and a multiplet is
observed at d 7.71–6.92 ppm due to the aromatic protons. In all the synthesized
123

Synthesis of bioactive substituted pyrazolylbenzothiazinones
O
OEt
R
R
O
R1
R2
S
R1
R2
SH
C2H5OH
H2SO4
O
N
H
O
NH2
O
R3
R3
3
1
2
NH2NH2.H2O
CH3
..
O
NHNH2
..
O
R
N
O
O
O
R
N
CH3
R1
S
H
H3C
C2H5OH
CH3
R1
S
R2
N
H
O
R2
N
H
O
R3
R3
4
4a
-H2O
CH3
(5a) R =H, R1=CH3, R2=H, R3=H
N
N
(5b) R =H, R1=H,
(5c) R =H, R1=Cl,
(5d) R =H, R1=Br,
(5e) R =H, R1=Cl,
(5f) R =Cl, R1=H,
R2=H, R3=CH3
R2=H, R3=H
R2=H, R3= H
R2=H, R3=CF3
R2=H, R3=Cl
O
R
CH3
R1
R2
S
(5g) R =H, R1=OCH3, R2=H, R3=H
N
H
O
R3
5
Scheme 1 Synthesis of substituted pyrazolybenzothiazinones 5a–g
pyrazolylbenzothiazinones, a double doublet is observed at d 4.83–3.90 ppm due to
C2–H proton. In all the synthesized pyrazolylbenzothiazinones, two doublets are
observed at d 3.54–2.83 ppm and at d 2.85–2.73 ppm due to CHa and CHb protons
0
of CH2 at C1 . The formation of pyrazole ring has been confirmed by the fact that all
the synthesized pyrazolylbenzothiazine show two singlets at d 2.58–2.43 ppm and d
2.46–2.27 ppm due to CH3 protons at C3 and C5 position of pyrazole ring. The
formation of pyrazole ring has also been supported by one proton singlet at d
6.21–5.90 ppm due to pyrazole C4–H. Compounds 5a and 5b show a singlet at d
2.47 ppm and d 2.44 ppm due to CH3 protons at C7 and C5, respectively. 13C NMR
spectra of the synthesized pyrazolylbenzothiazinone 5e showed distinct resonance
signals in agreement with the structures assigned to the synthesized compounds. In
the mass spectrum of compound 5e, the molecular ion peak at 403 (M?),
123

P. K. Sharma, M. Kumar
Table 1 Antimicrobial activity of substituted 2-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-3,4-
dihydro -2H-1,4-benzothiazin-3-ones (5a–g)
Compounds
Antibacterial activity (zone of inhibition in mm)
R
R1
R2
R3
E. coli (A)
Bacillus cereus (B)
5a
5b
5c
5d
5e
5f
H
H
H
H
H
Cl
H
CH3
H
H
H
H
H
H
H
H
H
8
13
11
12
11
11
10
11
8
12
9
CH3
H
Cl
Br
H
11
11
12
9
Cl
CF3
Cl
H
H
5g
OCH3
Chloramphenicol
10
corresponds to the molecular weight of the compound. The base peak at 95 (100 %)
(pyrazole ring fragment) supports the formation of pyrazole ring as a result of the
reaction of 2-hydrazinocarbonylmethyl-3,4-dihydro-3-oxo-2H-1,4-benzothiazine
with acetylacetone. The mass fragmentation of the compound 5e with peaks at
(m/z, I [ 5 %) 91, 107, 136, 147, 175, 191, 267, 281, 341, 371, and 401 is also in
accordance with structural fragments of the molecular structure.
All the synthesized compounds were screened for their antimicrobial activity.
The data presented in Table 1 indicate that the synthesized compounds are active
against two bacterial species; Escherichia coli and Bacillus cereus. It has been
observed that all the synthesized pyrazolylbenzothiazinones 5a–g show activity
against microbes. Compounds 5b, 5d, 5e, and 5f show better activity against both
bacteria, whereas compounds 5c and 5 g show moderate activity against E. coli, but
weak activity was shown by the compound 5c and 5 g against B. cereus. Compound
5a shows weak activity against E. coli and B. cereus as compared to the reference
compound. Therefore, it can be concluded that antimicrobial activities of the
synthesized compounds are comparable or in some cases more than that of
chloramphenicol (Fig. 1). The antimicrobial activity of these compounds may be
attributed to the presence of combined structural effect of two privileged
heterosystems: pyrazole and 1,4-thiazine. Along with the presence of substituents,
especially electron-releasing groups, its orientation also contributes considerably to
the activity.
Experimental
Melting points of the synthesized compounds were determined on an electric
melting point apparatus and are uncorrected. The IR spectra were recorded on a
SHIMADZU 8400 s spectrometer in KBr discs. The 1H NMR and 13CNMR spectra
were recorded on a JEOL-300 MHz spectrometer using TMS as an internal
standard. The chemical shifts are expressed as d ppm. Mass spectrum was recorded
123

Synthesis of bioactive substituted pyrazolylbenzothiazinones
Fig. 1 Antimicrobial activity of synthesized pyrazolylbenzothiazinones 5a–g
on a JEOL SX-102/Da-600 mass spectrometer using Argon/Xenon (6 kV, 10 mA)
as the FAB gas.
Preparation of substituted 2-aminobenzenethiols (1)
Substituted 2-aminobenzenethiols(1), required for the synthesis of pyrazolylben-
zothiazinones, have been synthesized from substituted anilines by the method
described in the literature [34–37].
Synthesis of 3,4-dihydro-2-(ethoxycarbonyl)methyl-2H-1,4-benzothiazin-3-ones
(3a–g)
A mixture of substituted 2-aminobenzenethiol (0.01 mol), maleic anhydride
(0.01 mol), and H2SO4 (one or two drops) in ethanol (50 ml) was refluxed for
4–5 h. The excess solvent was distilled off and the residue was poured into cold
water and then extracted with CHCl3. The CHCl3 extract was washed with NaHCO3
solution, water, and then dried over anhydrous Na2SO4. The solvent was then
removed to give a crude solid, which was recrystallized from CHCl3 to hexane to
give 3 [38].
Synthesis of 2-hydrazinocarbonylmethyl-3,4-dihydro-2H-1,4-benzothiazin-3-
ones (4a–g)
A mixture of compound 3 (0.01 mol) and hydrazine hydrate (0.01 mol) was taken in
a round-bottomed flask and then refluxed for 15 min. The sufficient quantity of
absolute ethanol was added through the condenser to produce a clear solution and
refluxed for 2–3 h and then cooled. The resulting solid was dried and crystallized
from ethanol [39].
123

P. K. Sharma, M. Kumar
Synthesis of pyrazolylbenzothiazinones (5a–g)
A solution of compound 4 (0.01 mol) and acetylacetone (0.02 mol) in absolute
ethanol (50 ml) was refluxed on a boiling water bath for approximately 2 h. After
completion of the reaction, the mixture was allowed to stand overnight. The solid
residue was filtered and then washed with ethanol to obtain pure sample of
pyrazolylbenzothiazine 5. The following 2-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-
oxoethyl]-3,4-dihydro-2H-1,4-benzothiazin-3-ones have been synthesized:
(a) 7-methyl-2-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-3,4-dihydro-2H-1,4-
benzothiazin-3-one Yield 61 % M.P. °C 190; IR (KBr, cm-1): 3,330 (–NH), 1,730
1
(C=O), 3,015 (Ar, C–H) H NMR (CDCl3, d ppm); 5.90 (s, 1H, pyrazole C4–H),
8.29 (s,1H,–NH proton), 4.08 (dd, 1H, C2–H proton), 2.95 (d, 1H, CHa proton of
0
0
CH2 at C1 ), 2.81 (d, 1H, CHb proton of CH2 at C1 ), 2.47 (s, 3H, CH3 proton at C7),
2.52 (s, 3H, CH3 proton at pyrazole C3), 2.37 (s, 3H, CH3 proton at pyrazole C5),
7.30–7.22 (m, 3H, aromatic protons); Anal. Calcd. for C16H17N3O2S : C, 60.90, H,
5.43, N, 13.32,. Found: C, 60.86, H, 5.40, N, 13.29.
(b) 5-methyl-2-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-3,4-dihydro-2H-1,4-
benzothiazin-3-one Yield 58 % M.P. °C 185; IR (KBr): 3,340 (–NH), 1,710
1
(C=O), 3m010 (Ar, C–H) H NMR (CDCl3, d ppm) 5.95 (s, 1H, pyrazole C4–H),
8.50 (s,1H,–NH proton), 4.08 (dd, 1H, C2–H proton), 3.54 (d, 1H, CHa proton of
0
0
CH2 at C1 ), 2.85 (d, 1H, CHb proton of CH2 at C1 ), 2.44 (s, 3H, CH3 proton at C5),
2.54 (s, 3H, CH3 proton at pyrazole C3), 2.27 (s, 3H, CH3 proton at pyrazole
C5),7.32–7.23 (m, 3H, aromatic protons); Anal. Calcd. for C16H17N3O2S : C, 60.90,
H, 5.43, N, 13.32,. Found: C, 60.86, H, 5.40, N, 13.28.
(c) 7-chloro-2-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-3, 4-dihydro-2H-1,
4-benzothiazin-3-one Yield 53 % M.P. °C 200; IR (KBr): 3,320 (–NH), 1,720
1
(C=O), 3,018 (Ar, C–H), 810 (C–Cl);, H NMR (CDCl3, d ppm); 6.01 (s, 1H,
pyrazole C4–H), 8.59 (s,1H,–NH proton), 3.90 (dd, 1H, C2–H proton), 2.83 (d, 1H,
0
0
CHa proton of CH2 at C1 ), 2.68 (d, 1H, CHb proton of CH2 at C1 ), 2.56 (s, 3H, CH3
proton at pyrazole C3), 2.31 (s, 3H, CH3 proton at pyrazole C5), 7.35–7.21 (m, 3H,
aromatic protons); Anal. Calcd. for C15H14ClN3O2S : C, 53.65, H, 4.20, N, 12.51,.
Found: C, 53.61, H, 4.19, N, 12.49.
(d) 7-bromo-2-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-3,4-dihydro-2H-1,4-
benzothiazin-3-one Yield 63 % M.P. °C 204; IR (KBr): 3,350 (–NH), 1,725
1
(C=O), 3,055 (Ar, C–H) H NMR (CDCl3, d ppm); 6.21 (s, 1H, pyrazole C4–H),
8.29 (s,1H,–NH proton), 4.12 (dd, 1H, C2–H proton), 2.88 (d, 1H, CHa proton of
0
0
CH2 at C1 ), 2.73 (d, 1H, CHb proton of CH2 at C1 ), 2.48 (s, 3H, CH3 proton at
pyrazole C3), 2.31 (s, 3H, CH3 proton at pyrazole C5), 7.30–6.92 (m, 3H, aromatic
protons); Anal. Calcd. for C15H14BrN3O2S: C, 47.38, H, 3.71, N, 11.05,. Found: C,
47.32, H, 3.65, N, 11.01.
(e) 7-chloro-5-trifluromethyl-2-[2-(3, 5-dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-3,4-
dihydro-2H-1,4-benzothiazin-3-one Yield 58 % M.P. °C 210; IR (KBr): 3,375 (–
NH), 1,705 (C=O), 3,065 (Ar, C–H), 810 (C–Cl), 1,050 (C–F); 1H NMR (CDCl3, d
123

Synthesis of bioactive substituted pyrazolylbenzothiazinones
ppm); 5.92 (s, 1H, pyrazole C4–H), 8.25 (s,1H,–NH proton), 4.83 (dd, 1H, C2–H
0
proton), 2.94 (d, 1H, CHa proton of CH2 at C1 ), 2.77 (d, 1H, CHb proton of CH2 at
0
C1 ), 2.58 (s, 3H, CH3 proton at pyrazole C3), 2.46 (s, 3H, CH3 proton at pyrazole
C5), 7.77–7.51 (m, 3H, aromatic protons); 13C NMR (CDCl3, d ppm); 13.76, 29.91,
64.21, 107.97, 112.21 119.45, 121.76, 122.73, 129.67, 132.81, 143.10, 164.32,
190.11; MS: m/z: 403 (M?), BP: m/z: 95; Anal. Calcd. for C16H13ClF3N3O2S : C,
47.59, H, 3.24, N, 10.41,. Found: C, 47.54, H, 3.21, N, 10.38.
(f) 5,8-dichloro-2-[2-(3, 5-dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-3,4-dihydro-2H-
1,4-benzothiazin-3-one Yield 64 % M.P. °C 199; IR (KBr): 3,360 (–NH), 1,710
1
(C=O), 3,020 (Ar, C–H), 805 (C–Cl); H NMR (CDCl3, d ppm); 6.21 (s, 1H,
pyrazole C4–H), 8.52 (s,1H,–NH proton), 4.18 (dd, 1H, C2–H proton), 2.92 (d, 1H,
0
0
CHa proton of CH2 at C1 ), 2.81 (d, 1H, CHb proton of CH2 at C1 ), 2.51 (s, 3H, CH3
proton at pyrazole C3), 2.29 (s, 3H, CH3 proton at pyrazole C5), 7.28–7.02 (m, 3H,
aromatic protons); Anal. Calcd. for C15H13Cl2N3O2S : C, 48.66, H, 3.54, N, 11.35,.
Found: C, 48.61, H, 3.50, N, 11.31.
(g) 7-methoxy-2-[2-(3, 5-dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-3, 4-dihydro-2H-
1,4-benzothiazin-3-one Yield 69 % M.P. °C 202; IR (KBr): 3,345 (–NH), 1,710
1
(C=O), 3,012 (Ar, C–H); H NMR (CDCl3, d ppm); 6.21(s, 1H, pyrazole C4–H),
8.59 (s,1H,–NH proton), 4.03 (dd, 1H, C2–H proton), 2.91 (d, 1H, CHa proton of
0
0
CH2 at C1 ), 2.78 (d, 1H, CHb proton of CH2 at C1 ), 3.12 (s, 3H, OCH3 proton at
C7), 2.43 (s, 3H, CH3 proton at pyrazole C3), 2.36 (s, 3H, CH3 proton at pyrazole
C5), 7.42–7.18 (m, 3H, aromatic protons); Anal. Calcd. for C16H17N3O3S : C, 57.99,
H, 5.17, N, 12.68,. Found: C, 57.95, H, 5.15, N, 12.63.
Antimicrobial activity
All the synthesized compounds were screened for 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 [40–
44]. After 24 h of incubation at 37 °C, the zone of inhibitions was measured in
millimeters. The standard drug chloramphenicol (30 lg/ml) was also screened for
antimicrobial activities, which are presented in Table 1.
Acknowledgments The authors are thankful to the Head, Department of Chemistry, University of
Rajasthan, Jaipur (India) for providing necessary laboratory facilities as well as instrumentation facilities
(IR, and 1HNMR). The Director RSIC, CDRI, Lucknow (India) is acknowledged for providing mass
spectra of the synthesized compounds. We express our thanks to University Grant Commission, New
Delhi, for providing meritorious student fellowship to one of us (P.K.S.).
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