Synthesis and anti-bacterial activities of some novel pyrazolobenzothiazine-based chalcones and their pyrimidine derivatives

Article abstract of DOI:10.1007/s00044-011-9820-0

A novel series of fifteen pyrimidine derivatives was prepared from pyrazolobenzothiazine-based chalcones by refluxing with guanidine hydrochloride. The starting materials 4-(3,4-dimethyl-5,5-dioxidobenzo[4,3-c][1,2]thiazin- 2(4-H)yl)phenyl)ethanone (2) or 4-(3,4-dimethyl-5,5-dioxidobenzo[ 4,3-c][1,2]thiazin-2(4-H)yl)benzaldehyde (3) were obtained by N-arylation of 3,4-dimethyl-2,4-dihydrobenzo[ e]pyrazolo[4,3-c][1,2]thiazine 5,5-dioxide (1) with 4-fluoroacetophenone or 4-fluorobenzaldehyde, respectively, using phase transfer catalyst, hexadecyl-tri-n-butylphsophonium bromide. The N-arylated product (2) or (3) was reacted in MeONa/MeOH with diversified aromatic aldehydes or ketones to furnish two series of newchalcones 4 and 5. Refluxing of 4 or 5 with guanidine hydrochloride in KOH_(aq) and H₂O ₂/EtOH yielded the 2-(4-(2-amino-6-arylpyrimidin- 4-yl)phenyl)3,4-dimethyl-2,4-dihydrobenzo[e] pyrazolo[4,3-c][1,2]thiazine-5,5- dioxide (6). The structures of chalcones (4 or 5) and corresponding pyrimidines (6) were confirmed with spectral data and elemental analysis. Several chalcones as well as pyrimidines showed marked activity against E. coli and S. aureus. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9820-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:2885–2895
DOI 10.1007/s00044-011-9820-0
ORIGINAL RESEARCH
Synthesis and anti-bacterial activities of some novel
pyrazolobenzothiazine-based chalcones and their pyrimidine
derivatives
•
Mujahid Hussain Bukhari Hamid Latif Siddiqui
•
•
Matloob Ahmad Tanvir Hussain Mark G. Moloney
•
Received: 29 July 2011 / Accepted: 11 October 2011 / Published online: 30 October 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A novel series of fifteen pyrimidine derivatives
was prepared from pyrazolobenzothiazine-based chalcones
by refluxing with guanidine hydrochloride. The starting
materials 4-(3,4-dimethyl-5,5-dioxidobenzo[4,3-c][1,2]thia-
zin-2(4-H)yl)phenyl)ethanone (2) or 4-(3,4-dimethyl-5,5-di-
oxidobenzo[4,3-c][1,2]thiazin-2(4-H)yl)benzaldehyde (3)
were obtained by N-arylation of 3,4-dimethyl-2,4-dihydro-
benzo[e]pyrazolo[4,3-c][1,2]thiazine 5,5-dioxide (1) with
4-fluoroacetophenone or 4-fluorobenzaldehyde, respec-
tively, using phase transfer catalyst, hexadecyl-tri-n-buty-
lphsophonium bromide. The N-arylated product (2) or (3)
was reacted in MeONa/MeOH with diversified aromatic
aldehydes or ketones to furnish two series of new chalcones 4
and 5. Refluxing of 4 or 5 with guanidine hydrochloride in
KOH(aq) and H2O2/EtOH yielded the 2-(4-(2-amino-6-aryl-
pyrimidin-4-yl)phenyl)3,4-dimethyl-2,4-dihydrobenzo[e]
pyrazolo[4,3-c][1,2]thiazine-5,5-dioxide (6). The structures
of chalcones (4 or 5) and corresponding pyrimidines (6) were
confirmed with spectral data and elemental analysis. Several
chalcones as well as pyrimidines showed marked activity
against E. coli and S. aureus.
Introduction
Pyrimidine and its derivatives are most important nitrogen
based heterocycles which play a vital role in many life pro-
cesses. The ring system is present in nucleic acids and their
derivatives (willardiine, tingitanine) (Bell and Foster, 1962),
several vitamins (vitamin B1) (Jansen and Donath, 1926),
antibiotics (bacimethrin, sparsomycin, bleomycin) (Tanaka
et al., 1961), alkaloids (heteromines, crambescins, manzac-
idins, variolins, meridianins, psammopemmins) (Berlinck
et al., 1993; Lin et al., 1997), toxins (Banker et al., 2000;
Ohtani et al., 1992), coenzymes, uric acid, and purines. Many
synthetic members of the group are also important as drugs
including barbituric acid derivatives and chemotherapeutic
agents including sulfadiazine (Petersen and Schmidt 2003),
Gleevec (imatinib mesilate) (Nadal and Olavarria, 2004),
and Xeloda (capecitabine) (Blum, 2001). Trimethoprim,
Iclaprim, and metronidazole are well known synthetic anti-
bacterial remedies based on pyrimidine scaffold (Joffe et al.,
1989). Some pyrimidine derivatives are recently reported as
inhibitors of CDK (Chu et al., 2006; Moravec et al., 2003),
MK2 (Argiriadi et al., 2010), CB2 (Sullivan et al., 1998),
VEGFR (Munchhof et al., 2004), and Adenosine A1/A2a/A3
(Baraldi et al., 2001; Chang et al., 2004) (Fig. 1).
Keywords Pyrazolobenzothiazine ꢀ Chalcones ꢀ
Pyrimidines ꢀ Anti-bacterial
The current investigations reveal that pyrimidine analogs
exhibit potential biological activities such as anticancer
(Baraldi et al., 2002), antiviral (Chern et al., 2004), anti-
mycobacterial (Ballell et al., 2007), anti-inflammatory and
analgesic (Sondhi et al., 2005), antiallergic (Ban et al.,
1998), and anti-HIV (Malik et al., 2006). Pyrrolo-pyrimidine
nucleoside derivatives act as potential anti-HCV (Hepatitis C
Virus) agents (Chamakura et al., 2007; Coelmont et al.,
2006).
M. H. Bukhari ꢀ H. L. Siddiqui (&) ꢀ M. Ahmad ꢀ T. Hussain
Institute of Chemistry, University of the Punjab, Lahore 54590,
Pakistan
e-mail: drhamidlatif@yahoo.com
M. G. Moloney
Department of Chemistry, University of Oxford,
12 Mansfield Road, Oxford OX1 3TA, UK
On the other hand, 1,2-benzothiazine-1,1-dioxides are
also known as potentially biologically active molecules
123

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Med Chem Res (2012) 21:2885–2895
Fig. 1 Structures of well
known bioactive molecules
containing pyrimidine scaffold
N
N
N
H2N
N
N
H
H
N
N
HN
N
S
O2
N
.HO3SMe
O
Sulfadiazine
Gleevec
O
NH2
N
O
F
OMe
F
O
N
O
S
N
O
O
O
N
N
NH
N
HO
H
F
OH
CDK Inhibitor
Xeloda
e.g., 1,2-benzothiazine-3-carboxamide-1,1-dioxide deriva-
tives belonging to oxicams, i.e., piroxicam, meloxicam,
ampiroxicam, and isoxicam are well known as analgesic
and anti-inflammatory compounds (Lee et al., 2008)
(Fig. 2).
corresponding aromatic aldehyde or acetophenone
(Scheme 1) gave two series of chalcones i.e., 4a–k and 5a–
f, respectively (Table 1). For this reaction, stronger base
NaOMe, in MeOH instead of NaOH was used.
Each chalcone was treated with guanidine hydrochloride
in the presence of 50% aqueous KOH solution in absolute
ethanol followed by portion wise addition of 30% H2O2
solution at reflux temperature (Varga et al., 2003). This
crucial step resulted in a novel series of pyrimidines (6a–o)
by ring closure (Table 1). Spectral data IR, 1H- and
13C-NMR, and MS of all the synthesized compounds were
recorded and found in full agreement with the proposed
structures. The elemental analysis results were within
0.4% of the theoretical values.
Moreover, benzothiazine derivatives are known as potent
calpain I inhibitors (Xu, 2007) while its 3-aryl-quinazolin-
4-one derivatives showed marked antimicrobial (Ahmad
et al., 2011) activity. We have already reported N0-aryl-
methylidene-2-(3,4-dimethyl-5,5-dioxidopyrazolo[4,3-c]
[1,2]benzothiazin-2(4H)-yl)acetohydrazides as potent anti-
oxidant and anti-bacterial agents (Ahmad et al., 2010).
Keeping in view the long-lasting interest of the synthetic
community in pyrimidines as well as 1,2-benzothiazine-
1,1-dioxides as potential drugs, we planned to synthesize
both the heterocyclic moieties in a single nucleus and study
their synergic effect which may result some biologically
more potent molecules.
Antibacterial studies
Bioassay of synthesized compounds summarized in
Table 2 indicated that bioactivity of pyrimidines was
somewhat greater than their corresponding chalcones. It
seems that pyrimidine ring may have enhanced the activity
against pathogens. Moreover, it was observed that all the
compounds were active against E. coli (gram negative) but
only two compounds, i.e., pyrimidines 6e and 6h showed
activity against both pathogens. The results indicated that
compound 6h showed high activity against both pathogens
which may be attributed by 2-MeO-phenyl group of the
compound which was also higher than its corresponding
chalcone 4g. However, interestingly, compound 6j show-
ing highest activity against E. coli was inactive against
S. aureus. It may be considered that two methoxy func-
tionalities at 3 and 4 positions of 6-phenyl group enhanced
its activity against E. coli but these groups inactivated the
compound against S. aureus. Bromo-chalcones 4c, 4f, and
Results and discussion
Chemistry
3,4-Dimethyl-2,4-dihydropyrazolo[4,3-c][1,2]benzothiazine-
5,5-dioxide 1 was synthesized by our own method (Ahmad
et al., 2010) starting from commercially available sodium
saccharin. N-arylation of 1 was carried out with 4-fluoro-
acetophenone or 4-fluorobenzaldehyde in the presence of
phase transfer catalyst hexadecyl-tri-n-butylphosphonium
bromide yielding 4-(3,4-dimethyl-5,5-dioxidobenzo[4,3-c]
[1,2]thiazin-2(4-H)yl)phenyl)ethanone 2 or 4-(3,4-dime-
thyl-5,5-dioxidobenzo[4,3-c][1,2]thiazin-2(4-H)yl)benzalde-
hyde 3, respectively. Further reaction of 2 or 3 with
123

Med Chem Res (2012) 21:2885–2895
2887
O
O
O
O
O
OH
O
OH
O
N
OH
O
O
N
N
N
S
N
N
N
N
H
H
H
H
N
N
N
N
S
S
S
S
O2
O2
O2
O2
(Ampiroxicam)
(Isoxicam)
(Meloxicam)
(Piroxicam)
Fig. 2 Structures of well known oxicam drugs
Scheme 1 Synthetic route to
2-(4-(2-amino-6-arylpyrimidin-
4-yl)phenyl)-3,4-dimethyl-2,4-
dihydrobenzo[e]pyrazolo[4,3-
c][1,2]thiazine-5,5-dioxides
(6a–o)
O
Ar
CHO
CHO
N
S
N
N
S
N
N
NH
F
ArCOCH3
(ii)
(i)
N
N
N
S
O
O
O
O
O
O
H2N
N
(5a-f)
(1)
(3)
N
O
O
O
(iii)
Ar
Ar
(i)
F
N
N
N
N
N
S
N
(iii)
ArCHO
(ii)
N
N
N
S
S
O
O
O
O
O
O
(6a-o)
(2)
(4a-k)
R1
R2
Where;
Ar =
R5
R3
R4
(i) K2CO3 (anhydrous); Hexadecyl-tri-n-butylphosphonium bromide; DMF, 120°C (ii) NaOMe/MeOH, RT
(iii) (NH2)2 C=NH.HCl; 50% KOH/EtOH, reflux; 30%H2O2 , reflux
5b showed marked activity against E. coli, while bromo-
pyrimidine 6e exhibited significant activity against both
pathogens. The results are summarized in Table 2.
group at position 6 exhibited highest activity against both
pathogens. Bromo derivatives showed more activity against
the pathogens, in general. Moreover, pyrimidines showed
more activity than chalcones and could be a suitable tem-
plate for further manipulation leading to novel anti-bacterial
agents. The new moieties may also possess other biological
activities of the parent ring systems.
Conclusion
We have synthesized series of pyrazolobenzothiazine based
chalcones and their pyrimidine derivatives which were
found to possess anti-bacterial activity. It was observed that
all the chalcones as well as pyrimidines except 4j and 5d
showed activity against gram negative bacteria i.e., E. coli.
On the other hand, no activity was observed against gram
positive bacteria i.e., S. aureus except two pyrimidines i.e.,
6e and 6h. Compound 6h containing 2-methoxyphenyl
Experimental
General
All the chemicals were purchased from E. Merck, Sigma
Aldrich or Wako and used without purification. However,
123

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Med Chem Res (2012) 21:2885–2895
Analysis% calculated (found)
Table 1 Characterization of the synthesized compounds
Compounds R1
R2
R3
R4
R5
Molecular formula Yield % mp °C
C
H
N
4a
4b
4c
4d
4e
4f
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C26H20FN3O3S
78
68
72
62
58
59
66
59
81
72
69
70
63
76
58
65
79
80
69
58
60
65
60
57
76
69
72
66
70
61
57
79
188–190 65.95 (65.94) 4.26 (4.27)
235–236 63.73 (63.72) 4.11 (4.12)
235–236 63.73 (63.72) 4.11 (4.12)
210–212 59.55 (59.56) 3.65 (3.64)
205–206 58.43 (58.42) 3.77 (3.78)
261–262 58.43 (58.42) 3.77 (3.78)
178–179 66.79 (66.79) 4.77 (4.77)
261–262 65.23 (65.22) 4.89 (4.88)
185–186 63.84 (63.85) 4.99 (4.97)
211–213 63.84 (63.85) 4.99 (4.97)
8.87 (8.88)
H
H
Cl
H
C
C
C
C
C
C
C
C
C
26H20ClN3O3S
26H20ClN3O3S
26H19Cl2N3O3S
26H20BrN3O3S
26H20BrN3O3S
27H23N3O4S
8.58 (8.57)
8.58 (8.57)
8.08 (8.00)
7.86 (7.85)
7.86 (7.85)
8.65 (8.64)
8.15 (8.16)
7.70 (7.69)
7.70 (7.69)
H
Cl
H
Cl
H
Cl
Br
H
H
H
Br
H
4g
4h
4i
MeO
H
H
MeO MeO
28H25N3O5S
MeO MeO MeO
29H27N3O6S
4j
H
MeO MeO MeO
29H27N3O6S
4k
5a
5b
5c
5d
5e
5f
H
H
H
H
H
H
H
H
H
H
Cl
H
H
Br
H
H
NO2
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C26H20N4O5S
186–187 62.39 (62.38) 4.03 (4.03) 11.19 (11.20)
H
C
C
C
C
26H20ClN3O3S
26H20BrN3O3S
27H23N3O4S
26H21N3O4S
178–179 63.73 (63.74) 4.11 (4.10)
216–217 58.43 (58.44) 3.77 (3.76)
207–209 66.79 (66.79) 4.77 (4.77)
8.58 (8.57)
7.86 (7.86)
8.65 (8.65)
9.22 (9.21)
8.95 (8.94)
8.95 (8.97)
H
Br
H
MeO
H
H
231–232 68.55 (58.57
4.65 (4.65)
H
CH3
CH3
F
C27H23N3O3S
CH3 C29H27N3O3S
172–174 69.06 (69.07) 4.94 (4.93)
244–246 70.00 (70.02) 5.47 (5.46)
CH3
H
6a
6b
6c
6d
6e
6f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C
C
C
C
C
C
C
C
C
C
C
27H21FN6O2S
27H21ClN6O2S
27H21ClN6O2S
27H20Cl2N6O2S
27H21BrN6O2S
27H21BrN6O2S
29H26N6O4S
238–240 63.27 (63.9)
4.13 (4.12) 16.40 (16.41)
H
Cl
233–234 61.30 (61.30) 4.00 (4.01) 15.89 (15.88)
220–221 61.30 (61.29) 4.00 (4.02) 15.89 (15.87)
265–267 57.55 (57.54) 3.58 (3.57) 14.92 (14.95)
179–180 56.55 (56.56) 3.69 (3.71) 14.65 (14.63)
245–246 56.55 (56.53) 3.69 (3.68) 14.65 (14.68)
187–188 64.11 (64.13) 4.61 (4.59) 16.02 (16.00)
180–182 64.11 (64.12) 4.61 (4.58) 16.02 (16.03)
241–242 62.80 (62.78) 4.73 (4.73) 15.15 (15.16)
203–204 61.63 (61.62) 4.83 (4.84) 14.37 (14.36)
172–174 61.63 (61.61) 4.83 (4.85) 14.37 (14.37)
185–187 60.10 (60.12) 3.92 (3.92) 18.17 (18.16)
211–212 65.57 (65.60) 4.48 (4.45) 16.99 (16.97)
173–175 66.12 (66.13) 4.76 (4.76) 16.52 (16.50)
209–210 67.14 (67.12) 5.26 (5.25) 15.66 (15.67)
H
H
Cl
H
Cl
Br
H
H
6g
6h
6i
H
MeO
H
MeO
H
28H24N6O3S
MeO MeO
29H26N6O4S
6j
MeO MeO MeO
30H28N6O5S
6k
6l
H
MeO MeO MeO
30H28N6O5S
H
H
H
H
H
NO3
H
H
H
H
H
C27H21N7O4S;
27H22N6O2S
C28H24N6O2S
CH3 C30H28N6O2S
6m
6n
6o
H
C
H
CH3
CH3
CH3
solvents were purified through distillation. 1H NMR spectra
were recorded on a Bruker DPX-400 instrument at
400 MHz. Chemical shifts are reported in ppm referenced
to the residual solvent signal. Mass spectra were recorded
on Agilent 5973N instrument using EI mode. Melting
points were recorded on a Gallenkamp melting point
apparatus and are uncorrected. Elemental analysis was
carried out using a Perkin Elmer 2400-CHN Analyser.
X-ray crystallography was carried out on Bruker Nonius
Kappa CCD diffractometer with graphite monochromated
Mo-Ka radiation and the data were corrected for Lorentz
and polarization effects and for absorption using multi-scan
method [25, 26].
Synthesis of 4-(3,4-dimethyl-5,5-
dioxidobenzo[e]pyrazolo[4,3-c][1,2]thiazin-2(4H)-
yl)ethanone (2)
A
mixture of 3,4-dimethyl-2,4-dihydropyrazolo[4,3-c]
[1,2]benzothiazine 5,5-dioxide (1) (6.25 g; 25.0 mmol),
4-fluoroacetophenone (4.14 g; 30.0 mmol), anhydrous
K2CO3 (4.15 g; 30.0 mmol), and hexadecyl-n-tributyl-
phosphonium bromide (1.27 g; 2.5 mmol) was refluxed in
DMF (100 mL) for a period of 2 h under nitrogen atmo-
sphere. The precipitates formed after adding ice cold water
were collected, dried, and recrystallized from EtOH. Pale
1
yellow crystals. Yield: 6.88 g; (75%). mp 230–232 °C. H
123

Med Chem Res (2012) 21:2885–2895
2889
General procedure for the synthesis of 3-aryl-1-(4-(3,4-
dimethyl-5,5-dioxidobenzo[e]pyrazolo[4,3-c][1,2]thiazin-
2(4H) yl)phenyl)prop-2-en-1-ones (4a–k)
Table 2 Bioactivities of the synthesized compounds
Compounds Inhibition
zone (mm)
E. coli X580
Bioactivity Inhibition zone Bioactivity
(mm)
S. aureus
N.C.T.C. 6571
All chalcones were prepared according to the literature
procedure (Furniss et al., 1989). A mixture of 4-(3,4-
dimethyl-5,5-dioxidobenzo[e]pyrazolo[4,3-c][1,2]thiazin-
2(4H)-yl)acetophenone (2) (20.0 mmol), corresponding
aromatic aldehyde (20.0 mmol), MeONa (20.0 mmol) in
MeOH (100 mL) was stirred at room temperature for a
period of 2–4 h. The resulted precipitates were collected
and washed with MeOH followed by cold water. The
products were purified by flash chromatography by eluting
with MeOH/CHCl3 (1:4).
4a
4b
4c
4d
4e
4f
14
13
15
16
15
17
16
15
14
–
4.13
3.55
4.81
5.61
4.81
6.53
5.61
4.81
4.13
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
17
–
–
22
–
–
–
–
–
–
–
–
–
–
–
–
–
4g
4h
4i
–
–
–
4j
–
1-(4-(3,4-dimethyl-5,5-dioxidobenzo[e]pyrazolo[4,3-c]
[1,2]thiazin-2(4H)-yl)phenyl)-3-(4-fluorophenyl)prop-2-
en-1-one (4a) Yellowish white powder; 1H NMR
(400 MHz, CDCl3) d: 2.51 (3H, s, CH3), 3.13 (3H, s, NCH3),
7.14 (2H, t, J = 8.5 Hz, ArH), 7.49 (1H, d, J = 15.7 Hz,
Ha), 7.54–7.62 (2H, m, ArH), 7.66 (1H, d, J = 8.0 Hz.
ArH), 7.70 (4H, d, J = 8.5 Hz, ArH), 7.83 (1H, d,
J = 15.7 Hz, Hb), 7.97 (1H, d, J = 7.8 Hz, ArH), 8.12 (1H,
d, J = 7.4 Hz, ArH), 8.19 (1H, d, J = 8.5 Hz, ArH). 13C
NMR: 10.9, 40.0, 116.2, 116.4, 121.3, 124.2, 124.5, 124.9,
125.2, 127.9, 129.3, 129.6, 129.7, 130.5, 130.6, 130.9, 132.5,
133.0, 133.6, 137.5, 139.5, 142.7, 144.3, 162.9, 165.4, 189.0.
MS m/z: 496.11 (M ? Na)?.
4k
5a
5b
5c
5d
5e
5f
15
14
16
15
–
4.81
4.13
5.61
4.81
–
–
–
–
–
–
13
15
15
16
16
–
3.55
4.81
4.81
5.61
5.61
–
–
–
6a
6b
6c
6d
6e
6f
–
–
–
–
19
14
–
8.87
4.13
–
508
–
6g
6h
6i
–
3-(4-chlorophenyl)-1-(4-(3,4-dimethyl-5,5-dioxidobenzo[e]
pyrazolo[4,3-c] [1,2]thiazine-2(4H)-yl)phenyl)prop-2-en-
1-one (4b) Pale yellow powder; 1H NMR (400 MHz,
CDCl3) d: 2.52 (3H, s, CH3), 3.14 (3H, s, NCH3), 7.43 (2H, m,
ArH), 7.54 (1H, d, J = 15.8 Hz,Ha), 7.60–7.63 (3H, m, ArH),
7.71(3H,d,J = 8.6 Hz, ArH),7.82(1H,d,J = 15.8 Hz,Hb),
7.98 (1H, d, J = 7.8 Hz, ArH), 8.12 (1H, d, J = 7.7 Hz, ArH),
8.19 (2H, m, J = 8.6 Hz, ArH). 13C NMR: 10.9, 40.0, 121.9,
124.2, 124.5, 127.9, 129.2, 129.4, 129.6, 129.8, 130.1, 130.5,
131.0, 131.6, 132.1, 132.5, 132.9, 133.1, 133.5, 135.5, 136.8,
137.4, 139.5, 142.7, 144.1, 188.9. MS m/z: 512.08 (M ? Na)?.
20
14
24
13
14
14
14
15
10.34
4.13
19.06
3.55
4.13
4.13
4.13
4.81
1390
–
6j
–
6k
6l
–
–
6m
6n
6o
–
–
–
2 mg/mL solution in DMSO
Equivalent inhibition to that of nmoles Cephalosporin C in well
volume of 100 lL
3-(3-chlorophenyl)-1-(4-(3,4-dimethyl-5,5-dioxidobenzo[e]
pyrazolo[4,3-c][1,2]thiazin-2(4H)-yl)phenyl)prop-2-en-1-
one (4c) Yellow powder; 1H NMR (400 MHz, CDCl3) d:
2.53 (3H, s, CH3), 3.15 (3H, s, NCH3), 7.42 (1H, m, ArH),
7.52 (1H, d, J = 15.8 Hz, Ha), 7.57–7.60 (2H, m, ArH),
7.64 (1H, d, J = 15.8 Hz, Hb), 7.69–7.73 (3H, m, ArH),
7.76 (2H, d, J = 5.1 Hz, ArH), 7.99 (1H, d, J = 6.7 Hz,
ArH), 8.13 (1H, d, J = 7.0 Hz, ArH), 8.20–8.23 (2H, m,
ArH). 13C NMR: 10.6, 40.2, 121.7, 124.0, 124.5, 127.4,
128.8, 129.4, 129.7, 129.9, 130.2, 130.5, 131.4, 131.7,
132.3, 132.6, 133.1, 133.4, 133.7, 135.3, 136.1, 138.4,
139.8, 141.6, 143.2, 188.6. MS m/z: 512.08 (M ? Na)?.
NMR (400 MHz, CDCl3) d: 2.50 (3H, s, CH3), 2.68 (3H, s,
COCH3), 3.13 (3H, s, NCH3), 7.57–7.61 (1H, m, ArH),
7.64–7.67 (2H, m, ArH), 7.69–7.73 (1H, m, ArH), 7.97
(2H, d, J = 7.7 Hz, ArH), 8.10 (1H, m., ArH), 8.11–8.13
(1H, m, ArH). 13C NMR: 10.9, 26.7, 40.0, 124.2, 124.4,
124.7, 124.9, 125.2 (2C), 127.9, 129.2, 129.6, 132.5, 132.9,
133.5, 136.4, 139.5, 142.9, 196.9. MS m/z: 390.09
(M ? Na)?. Anal. calc. for C19H17N3O3S; C, 62.11; H,
4.66; N, 11.44; Found: C, 62.10; H, 4.67; N, 11.43.
123

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3-(2,4-dichlorophenyl)-1-(4-(3,4-dimethyl-5,5-dioxidobenzo
[e]pyrazolo[4,3-c][1,2]thiazin-2(4H)-yl)phenyl)prop-2-en-1-
1
one (4d) Yellow amorphous solid; H NMR (400 MHz,
132.3, 132.6, 132.9, 133.2, 133.9, 135.5, 136.2, 138.4, 139.3,
141.9, 142.9, 189.7. MS m/z: 508.13 (M ? Na)?.
CDCl3) d: 2.52 (3H, s, CH3), 3.15 (3H, s, NCH3), 7.51 (1H,
m, ArH), 7.57 (1H, d, J = 15.6 Hz, Ha), 7.58 (2H, m, ArH),
7.64 (1H, d, J = 15.6 Hz, Hb), 7.70 (3H, t, J = 8.0 Hz,
ArH), 7.76–7.80 (1H, m, ArH), 7.95–8.01 (1H, m, ArH),
8.10–8.15 (1H, m, ArH), 8.18 (1H, J = 5.1 Hz, ArH). 13C
NMR: 10.8, 40.2, 121.9, 124.2, 124.5, 127.9, 129.2, 129.4,
129.6, 129.8, 130.1, 130.5, 131.0, 131.6, 132.1, 132.5, 132.9,
133.1, 133.5, 135.5, 136.8, 137.4, 140.5, 143.7, 144.9, 187.6.
MS m/z: 546.04 (M ? Na)?.
3-(3,4-dimethoxyphenyl)-1-(4-(3,4-dimethyl-5,5-diox-
idobenzo[e]pyrazolo[4,3-c][1,2]thiazin-2(4H)-yl)phenyl)
prop-2-en-1-one (4h) Yellow solid; Yield; 59%; mp
1
261–262 °C. H NMR (400 MHz, CDCl3) d: 2.52 (3H, s,
CH3), 3.14 (3H, s, NCH3), 3.93 (3H, s, OCH3), 3.95 (3H, s,
OCH3), 6.87–6.91 (2H, m, ArH), 7.40 (1H, d, J = 5.5 Hz,
ArH), 7.44 (1H, d, J = 15.6 Hz, Ha), 7.58–7.62 (1H, m,
ArH), 7.71 (3H, d, J = 5.6 Hz, ArH), 7.78 (1H, d,
J = 15.6 Hz, Hb), 7.99 (1H, d, J = 7.8 Hz, ArH), 8.12 (1H,
d, J = 7.7 Hz, ArH), 8.19 (2H, d, J = 8.5 Hz, ArH). 13C
NMR: 10.9, 40.0, 56.2, 61.0, 105.8, 120.9, 121.6, 124.6,
124.8, 124.8, 125.2, 127.9, 129.2, 129.8, 130.1, 132.4, 132.9,
133.5, 133.9, 135.5, 136.2, 137.6, 139.3, 140.6, 142.5, 145.8,
153.5 189.4. MS m/z: 538.14 (M ? Na)?.
3-(4-bromophenyl)-1-(4-(3,4-dimethyl-5,5-dioxidobenzo[e]
pyrazolo[4,3-c][1,2]thiazin-2(4H)-yl)phenyl)prop-2-en-1-
one (4e) Yellow powder; Yield: 1H NMR (400 MHz,
CDCl3) d: 2.53 (3H, s, CH3), 3.15 (3H, s, NCH3), 7.32 (1H,
d, J = 15.7 Hz, Ha,), 7.36 (1H, d, J = 1.9 Hz, ArH), 7.49
(1H, m, ArH), 7.55 (1H, d, J = 3.5 Hz, ArH), 7.62 (1H, d,
J = 15.7 Hz, Hb), 7.68–7.73 (4H, m, ArH), 7.79 (1H, m,
ArH), 7.99 (1H, d, J = 6.5 Hz, ArH), 8.12–8.17 (2H, m,
ArH), 8.22 (1H, m, ArH). 13C NMR: 10.8, 40.1, 121.7,
124.0, 124.5, 127.4, 128.8, 129.4, 129.7, 129.9, 130.2, 130.5,
131.4, 131.7, 132.3, 132.6, 132.9, 133.2, 133.9, 135.5, 136.5,
138.4, 139.2, 142.3, 144.0, 187.6. MS m/z: 556.03
(M ? Na)?.
1-(4-(3,4-dimethyl-5,5-dioxidobenzo[e]pyrazolo[4,3-c][1,2]
thiazin-2(4H)-yl)phenyl)-3-(2,3,4-trimethoxyphenyl)prop-2-
1
en-1-one (4i) Pale yellow powder; H NMR (400 MHz,
CDCl3) d: 2.67 (3H, s, CH3), 3.13 (3H, s, NCH3), 3.91 (3H, s,
OCH3), 3.93 (3H, s, OCH3), 3.98 (3H, s, OCH3), 6.75 (1H, d,
J = 15.8 Hz, Ha), 7.42 (1H, d, J = 15.8 Hz, Hb), 7.58 (2H,
d, J = 7.2 Hz, ArH), 7.65–7.69 (2H, m, ArH), 7.96–7.99
(1H, m, ArH), 8.13 (3H, d, J = 8.7 Hz, ArH), 8.18 (2H, d,
J = 8.5 Hz, ArH). 13C NMR: 10.9, 40.0, 56.1, 60.9, 61.4,
107.6, 120.8, 121.7, 124.1, 124.5, 127.9, 129.2, 129.4, 129.6,
129.7, 131.5, 131.9, 132.5, 132.9, 133.5, 136.3, 138.0, 139.4,
141.0, 142.3, 142.5, 152.9, 156.1, 189.7. MS m/z: 568.15
(M ? Na)?.
3-(3-bromophenyl)-1-(4-(3,4-dimethyl-5,5-dioxidobenzo[e]
pyrazolo[4,3-c][1,2]thiazin-2(4H)-yl)phenyl)prop-2-en-1-
one (4f) Yellow crystals; 1H NMR (400 MHz, CDCl3) d:
2.53 (3H, s, CH3), 3.15 (3H, s, NCH3), 7.31–7.33 (1H, m,
ArH), 7.36–7.39 (1H, m, ArH), 7.49 (1H, d, J = 16.9 Hz,
Ha), 7.55–7.58 (1H, m, ArH), 7.62 (1H, d, J = 16.9 Hz,
Hb), 7.69–7.72 (4H, m, ArH), 7.79 (1H, m., ArH), 7.99
(1H, d, J = 6.5 Hz, ArH), 8.12–8.14 (1H, m, ArH), 8.18
(1H, d, J = 6.3 Hz, ArH), 8.22 (1H, d, J = 5.5 Hz, ArH).
13C NMR: 10.8, 40.1, 121.7, 124.0, 124.5, 127.4, 128.8,
129.4, 129.7, 129.9, 130.2, 130.5, 131.4, 131.7, 132.3,
132.6, 132.9, 133.2, 133.9, 135.5, 136.5, 138.4, 139.2,
142.3, 144.0, 187.6. MS m/z: 556.03 (M ? Na)?.
1-(4-(3,4-dimethyl-5,5-dioxidobenzo[e]pyrazolo[4,3-c][1,2]
thiazin-2(4H)-yl)phenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-
en-1-one (4j) Yellow amorphous solid; 1H NMR
(400 MHz, CDCl3) d: 2.47 (3H, s, CH3), 3.13 (3H, s, NCH3),
3.91 (3H, s, OCH3), 3.94 (6H, s, 2xOCH3), 6.75 (2H, d,
J = 8.8 Hz, ArH), 7.42 (1H, d, J = 15.8 Hz, Ha), 7.58 (1H,
d, J = 15.8 Hz, Hb), 7.65–7.68 (2H, m, ArH), 7.94–7.98
(1H, m, ArH), 8.13 (3H, d, J = 8.7 Hz, ArH), 8.18 (2H, d,
J = 8.5 Hz, ArH). 13C NMR: 10.9, 40.0, 56.1, 60.9, 61.4,
107.6, 120.8, 121.7, 124.1, 124.5, 127.9, 129.2, 129.4, 129.6,
129.7, 132.5, 132.9, 133.5, 133.9, 134.5, 136.3, 138.0, 139.4,
141.0, 142.4, 142.5, 152.9, 156.1, 189.7. MS m/z: 568.15
(M ? Na)?.
1-(4-(3,4-dimethyl-5,5-dioxidobenzo[e]pyrazolo[4,3-c][1,2]
thiazin-2(4H)-yl)phenyl)-3-(2-methoxyphenyl)prop-2-en-1-
one (4g) Yellow powder; 1H NMR (400 MHz, CDCl3) d:
2.49 (3H, s, CH3), 3.03 (3H, s, NCH3), 3.90 (3H, s, OCH3),
6.91 (1H, d, J = 16.7 Hz, Ha), 7.37 (2H, m, ArH), 7.61 (1H,
d, J = 16.7 Hz, Hb), 7.65 (1H, m, ArH), 7.70–7.73 (1H, m,
ArH), 7.78 (1H, d, J = 6.1 Hz, ArH), 7.82 (2H, d,
J = 2.7 Hz, ArH), 7.89 (1H, m, ArH), 7.97 (1H, d,
J = 5.8 Hz, ArH), 8.03–8.06 (1H, m, ArH), 8.10–8.14 (2H,
m, ArH). 13C NMR: 10.8, 40.1, 60.8 121.2, 121.8, 124.6,
124.8, 126.8, 128.4, 129.7, 130.5, 130.8, 131.1, 131.4, 131.7,
1-(4-(3,4-dimethyl-5,5-dioxidobenzo[e]pyrazolo[4,3-c][1,2]
thiazin-2(4H)-yl)phenyl)-3-(4-nitrophenyl)prop-2-en-1-one
(4k) Yellow powder; 1H NMR (400 MHz, CDCl3) d: 2.53
(3H, s, CH3), 3.14 (3H, s, NCH3), 7.59 (1H, d, J = 15.6 Hz,
Ha), 7.66 (1H, d, J = 15.6 Hz, Hb), 7.72 (2H, d,
J = 1.7 Hz, ArH), 7.76–7.79 (1H, m, ArH), 7.81 (1H, d,
123

Med Chem Res (2012) 21:2885–2895
2891
J = 5.2 Hz, ArH), 7.85-7.88 (1H, m, ArH), 7.98 (1H, d,
J = 7.7 Hz, ArH), 8.12 (2H, d, J = 6.8 Hz, ArH), 8.20 (2H,
m, ArH), 8.24 (1H, m, ArH), 8.31 (1H, d, J = 8.7 Hz, ArH).
13C NMR: 10.9, 40.0, 121.9, 124.1, 124.6, 127.6, 128.7,
129.3, 129.6, 129.9, 130.2, 130.4, 131.5, 131.8, 132.3, 132.6,
132.9, 133.2, 133.9, 135.5, 136.5, 138.4, 139.2, 143.3, 145.4,
188.5. MS m/z: 523.1 (M ? Na)?.
131.6, 132.4, 132.9, 133.1, 133.4, 133.5, 134.5, 136.2, 137.4,
139.2, 140.8, 143.6, 188.7. MS m/z: 512.08 (M ? Na)?.
1-(4-bromophenyl)-3-(4-(3,4-dimethyl-5,5-dioxidobenzo[e]
pyrazolo[4,3-c][1,2]thiazin-2(4H)-yl)phenyl)prop-2-en-1-
one (5b) Pale yellow crystals; 1H NMR (400 MHz,
CDCl3) d: 2.50 (3H, s, CH3), 3.14 (3H, s, NCH3),
7.48–7.59 (4H, m, ArH), 7.62 (1H, d, J = 14.4 Hz, Ha),
7.68–7.73 (3H, m, ArH), 7.82 (1H, d, J = 14.5 Hz, Hb),
7.87 (1H, d, J = 7.1 Hz, ArH), 7.96–8.03 (3H, m, ArH),
8.11 (1H, d, J = 7.7 Hz, ArH). 13C NMR: 10.8, 40.0, 122.8,
124.1, 124.7, 125.0, 128.0, 128.7, 129.1, 129.3, 130.5, 130.8,
132.4, 132.9, 133.0, 133.4, 134.8, 137.9, 138.4, 139.0, 139.2,
140.6, 142.3, 143.1, 144.0, 190.1. MS m/z: 556.03
(M ? Na)?.
Synthesis of 4-(3,4-dimethyl-5,5-
dioxidobenzo[e]pyrazolo[4,3-c][1,2]thiazin-2(4H)-
yl)benzaldehyde (3)
A mixture of 3,4-dimethyl-2,4-dihydropyrazolo[4,3-c][1,2]
benzothiazine 5,5-dioxide (1) (6.25 g, 25.0 mmol), 4-fluoro-
benzaldehyde (3.72 g, 30.0 mmol), anhydrous K2CO3
(4.15 g, 30.0 mmol), and hexadecyl-n-tributylphosphonium
bromide (1.27 g, 2.5 mmol) was refluxed in DMF (100 mL)
for a period of 2 h under nitrogen atmosphere. The precipi-
tates formed after adding ice cold water were collected, dried,
and recrystallized from EtOH. Yellow crystals. Yield: 7.15 g,
(81%); mp 230–232 °C. 1H NMR (400 MHz, CDCl3) d: 2.52
(3H, s, CH3), 3.13 (3H, s, NCH3), 7.57–7.60 (1H, m, ArH),
7.68–7.72 (1H, m, ArH), 7.73–7.76 (2H, m, ArH), 7.97(1H, d,
J = 7.7 Hz, ArH), 8.06–8.09 (2H, m, ArH), 8.11 (1H, d,
J = 7.7 Hz, ArH), 10.10 (1H, s, CHO). 13C NMR: 11.0, 40.0,
124.2, 124.7, 124.9(2C), 125.5, 127.8, 129.3(2C), 130.8,
132.6, 133.0, 133.6, 135.4, 139.7, 143.9, 190.9;MSm/z: 376.1
(M ? Na) ?. Anal. calc. for C18H15N3O3S; C, 61.18; H, 4.28;
N, 11.89; Found: C, 61.18; H, 4.28; N, 11.88.
3-(4-(3,4-dimethyl-5,5-dioxidobenzo[e]pyrazolo[4,3-c][1,2]
thiazin-2(4H)-yl)phenyl)-1-(4-methoxyphenyl)prop-2-en-1-
1
one (5c) Yellow amorphous solid; H NMR (400 MHz,
CDCl3) d: 2.48 (3H, s, CH3), 3.13 (3H, s, NCH3), 3.90 (3H, s,
OCH3), 7.01 (1H, d, J = 15.2 Hz, Ha), 7.57–7.61 (2H, m,
ArH), 7.64–7.67 (2H, m, ArH), 7.74 (1H, d, J = 15.2 Hz,
Hb), 7.75–7.79 (1H, m, ArH), 7.82 (2H, d, J = 2.7 Hz,
ArH), 7.86–7.89 (1H, m, ArH), 7.97 (1H, d, J = 6.8 Hz,
ArH), 8.05–8.14 (3H, m, ArH). 13C NMR: 10.8, 40.1, 57.8,
121.2, 121.8, 124.6, 124.8, 126.8, 128.4, 129.7, 130.5, 130.8,
131.1, 131.4, 131.7, 132.3, 132.6, 132.9, 133.2, 133.9, 135.5,
136.2, 138.4, 139.3, 141.9, 142.9, 189.7. MS m/z: 508.13
(M ? Na)?.
General procedure for the synthesis of 1-aryl-3-(4-(3,4-
dimethyl-5,5-dioxidobenzo[e]pyrazolo[4,3-c][1,2]thiazin-
2(4H) yl)phenyl)prop-2-en-1-ones (5a–f)
3-(4-(3,4-dimethyl-5,5-dioxidobenzo[e]pyrazolo[4,3-c][1,2]
thiazin-2(4H)-yl)phenyl)-1-phenylprop-2-en-1-one (5d) Yel-
lowish white solid; 1H NMR (400 MHz, CDCl3) d: 2.49 (3H,
s, CH3), 3.13 (3H, s, NCH3), 7.52-7.57 (2H, m, ArH),
7.59–7.62 (4H, m, ArH), 7.65 (1H, d, J = 15. 7 Hz, Ha),
7.70 (1H, t, J = 8.2 Hz, ArH), 7.81 (2H, d, J = 8.5 Hz,
ArH), 7.86 (1H, d, J = 15.7 Hz, Hb), 7.97 (1H, d,
J = 7.7 Hz, ArH), 8.06 (2H, d, J = 7.2 Hz, ArH), 8.11 (1H,
d, J = 7.7 Hz, ArH). 13C NMR: 10.8, 40.0, 123.1, 124.2,
124.7, 124.9, 125.1, 125.2, 128.8, 128.5, 128.7(2C), 129.1,
130.5, 130.8, 132.4(2C), 132.9, 133.1, 133.4, 134.8, 138.0,
139.2, 140.6, 143.1, 190.1. MS m/z: 478.12 (M ? Na)?.
A mixture of 1-(4-(3,4-dimethyl-5,5-dioxidobenzo[e]pyr-
azolo[4,3-c][1,2]thiazin-2(4H)-yl)phenyl)benzaldehyde (3)
(20.0 mmol), corresponding acetophenone (20.0 mmol),
MeONa (20.0 mmol) in MeOH (100 mL) was stirred at
room temperature for a period of 2–4 h. The resulted ppt
were collected and washed with MeOH followed by cold
water. The products were purified by flash chromatography
by eluting with CHCl3/MeOH (4:1).
1-(4-chlorophenyl)-3-(4-(3,4-dimethyl-5,5-dioxidobenzo[e]
pyrazolo[4,3-c][1,2]thiazin-2(4H)-yl)phenyl)prop-2-en-1-
1
one (5a) Yellow amorphous solid; H NMR (400 MHz,
3-(4-(3,4-dimethyl-5,5-dioxidobenzo[e]pyrazolo[4,3-c]
[1,2]thiazin-2(4H)-yl)phenyl)-1-(p-tolyl)prop-2-en-1-one
1
(5e) Pale yellow crystalline solid; H NMR (400 MHz,
CDCl3) d: 2.48 (3H, s, CH3), 3.12 (3H, s, NCH3), 7.50 (2H, d,
J = 8.6 Hz, ArH), 7.52 (1H, d, J = 14.2 Hz, Ha), 7.60 (2H,
d, J = 8.3 Hz, ArH), 7.64 (1H, d, J = 14.2 Hz, Hb),
7.74–7.89 (4H, m, ArH), 7.94–8.02 (3H, m, ArH), 8.10 (1H,
d, J = 7.7 Hz, ArH). 13C NMR: 10.8, 40.0, 122.5, 124.2,
124.8, 125.0, 127.9, 129.0, 129.4, 129.9, 130.1, 130.5, 131.0,
CDCl3) d: 2.46 (3H, s, CH3), 2.49 (3H, s, CH3), 3.14 (3H,
s, NCH3), 7.34 (1H, d, J = 14.8 Hz, Ha), 7.60 (1H,
J = 14.8 Hz, Hb), 7.63 (2H, d, J = 5.4 Hz, ArH), 7.70
(2H, t, ArH), 7.79–7.84 (4H, m, ArH), 7.98 (3H, d,
J = 8.0 Hz, ArH), 8.11 (1H, d, J = 7.7 Hz, ArH). 13C
NMR: 10.8, 21.7, 40.1, 121.2, 121.8, 124.6, 124.8, 126.8,
123

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Med Chem Res (2012) 21:2885–2895
128.4, 129.7, 130.5, 130.8, 131.1, 131.4, 131.7, 132.3,
132.6, 132.9, 133.2, 133.9, 135.5, 136.2, 138.4, 139.3,
141.9, 142.9, 189.7. MS m/z: 492.14 (M ? Na)?.
104.5, 105.4, 124.2, 124.4, 124.8, 125.0, 127.8, 128.2, 129.2,
129.6, 130.4, 132.4, 132.9, 133.0, 133.3, 134.3, 136.4, 138.8,
137.6, 139.1, 143.9, 163.5, 163.9, 165.7. MS m/z: 551.10
(M ? Na)?.
3-(4-(3,4-dimethyl-5,5-dioxidobenzo[e]pyrazolo[4,3-c][1,2]
thiazin-2(4H)-yl)phenyl)-1-mesitylprop-2-en-1-one (5f) Yel-
2-(4-(2-amino-6-(3-chlorophenyl)pyrimidin-4-yl)phenyl)-
3,4-dimethyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c][1,2]thia-
zine 5,5-dioxide (6c) Light brown amorphous powder; 1H
NMR (400 MHz, CDCl3) d: 2.50 (3H, s, CH3), 3.14 (3H, s,
N CH3), 5.27 (2H, br. s, NH2), 7.04 (1H, m, ArH),
7.29–7.40 (4H, m, ArH), 7.48 (1H, s, ArH), 7.67 (3H, d,
J = 7.3 Hz, ArH), 7.98 (2H, d, J = 7.3 Hz, ArH), 8.11
(1H, d, J = 2.4 Hz, ArH), 8.24 (1H, d, J = 8.5 Hz, ArH).
13C NMR: 10.8, 39.9, 48.8, 49.0, 49.2, 49.4, 49.7, 121.9,
124.2, 124.6, 124.8, 125.5, 127.7, 129.3, 129.7, 129.8,
130.2, 130.6, 132.4, 133.1, 133.8, 135.8, 136.4, 137.5,
163.3, 163.9, 165.5. MS m/z: 551.10 (M ? Na)?.
1
low crystals; H NMR (400 MHz, CDCl3) d: 2.22 (6H, s,
2xCH3), 2.34 (3H, s, CH3), 2.47 (3H, s, CH3), 3.12 (3H, s,
NCH3), 6.94 (2H, d, J = 6.2 Hz, ArH), 6.98 (1H, d,
J = 16.2 Hz, Ha), 7.19–7.22 (1H, m, ArH), 7.56 (1H, d,
J = 16.2 Hz, Hb), 7.58–7.61 (2H, m, ArH), 7.65–7.70 (3H,
m, ArH), 7.96 (1H, d, J = 7.8 Hz, ArH), 8.08 (1H, m, ArH).
13C NMR: 10.8, 19.4, 21.2, 40.0, 56.1, 107.6, 120.8, 121.7,
124.1, 124.8, 125.0, 128.5, 129.4, 129.6, 129.7, 131.4, 131.9,
132.5, 132.9, 133.5, 134.1, 138.0, 139.4, 141.0, 142.4, 144.8,
152.9, 156.1, 188.9. MS m/z: 520.17 (M ? Na)?.
General procedure for the synthesis of 2-(4-(2-amino-6-
arylpyrimidin-4-yl)phenyl)-3,4-dimethyl-2,4-dihydrobenzo
[e]pyrazolo[4,3-c][1,2]thiazine-5,5-dioxides (6a–o)
2-(4-(2-amino-6-(2,4-dichlorophenyl)pyrimidin-4-yl)phe-
nyl)-3,4-dimethyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c][1,2]
thiazine 5,5-dioxide (6d) Yellow powder; 1H NMR
(400 MHz, CDCl3) d: 2.47 (3H, s, CH3), 3.09 (3H, s,
NCH3), 5.25 (2H, br. s, NH2), 7.35–7.38 (2H, m, ArH),
7.56–7.60 (2H, m, ArH), 7.67 (3H, d, J = 8.7 Hz,,ArH),
7.77 (1H, d, J = 7.7 Hz, ArH), 7.93 (1H, d, J = 8.0 Hz,
ArH), 8.07 (1H, d, J = 9.0 Hz, ArH), 8.15–8.18 (2H, m,
J = 8.7 Hz, ArH). 13C NMR: 10.8, 40.0, 104.0, 104.5,
105.4, 124.2, 124.4, 124.8, 125.0, 127.8, 128.2, 129.2,
129.6, 130.4, 132.4, 132.9, 133.0, 133.3, 134.3, 136.4,
138.8, 137.6, 139.1, 143.9, 163.5, 163.9, 165.7. MS m/z:
585.06 (M ? Na)?.
All compounds were prepared according to the literature
procedure (Varga et al., 2003). A mixture of corresponding
chalcone (9.1 mmol), guanidine hydrochloride (13.6 mmol)
and 50% aqueous KOH solution (4.0 mL) was stirred at
reflux temperature for a period of 1 h in EtOH (20.0 mL)
followed by portion wise addition of 30% H2O2 (30.3 mmol,
3.1 mL) over 1 h under the same conditions. The precipitates
thus formed were thoroughly washed with EtOH and then
with pure water. Recrystallization from a suitable solvent
resulted pure compounds.
2-(4-(2-amino-6-(4-fluorophenyl)pyrimidin-4-yl)phenyl)-
3,4-dimethyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c][1,2]thia-
2-(4-(2-amino-6-(4-bromophenyl)pyrimidin-4-yl)phenyl)-3,
4-dimethyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c][1,2]thia-
zine 5,5-dioxide (6e) Dirty white crystals; 1H NMR
(400 MHz, CDCl3) d: 2.50 (3H, s, CH3), 3.14 (3H, s,
NCH3), 5.29 (2H, br. s, NH2), 7.49 (1H, s, ArH), 7.54–7.64
(3H, m, ArH), 7.69 (4H, d, J = 5.6 Hz, ArH), 7.99 (3H, d,
J = 8.2 Hz, ArH), 8.13 (1H, d, J = 7.7 Hz, ArH), 8.25
(1H, d, J = 8.4 Hz, ArH). 13C NMR: 10.9, 40.0, 124.2,
124.4, 124.9, 125.2, 127.9, 129.2, 129.6, 132.5, 132.9,
133.5, 136.4(2C), 136.7, 136.9, 137.2, 137.5, 137.7(2C),
137.9, 139.5, 142.9(2C), 162.3, 162.5, 164.3. MS m/z:
595.05 (M ? Na)?.
1
zine 5,5-dioxide (6a) Yellowish white powder; H NMR
(400 MHz, CDCl3) d: 2.50 (3H, s, CH3), 3.15 (3H, s,
NCH3), 5.21 (2H, br. s, NH2), 7.21 (2H, t, J = 8.5 Hz,
ArH), 7.45–7.48 (1H, m, ArH), 7.57–7.61 (1H, m, ArH),
7.66–7.75 (3H, m, ArH), 7.99 (1H, d, J = 7.8 Hz, ArH),
8.07–8.16 (3H, m, ArH), 8.25 (2H, d, J = 8.3 Hz, ArH).
13C NMR: 10.8, 40.0, 103.8, 115.7, 124.2, 124.8 (2C),
125.0, 128.2 (2C), 129.1, 129.4, 132.4, 132.9, 133.0, 133.5,
136.4, 137.5, 137.6, 139.1, 143.2, 153.5, 162.0, 162.9,
163.8, 164.6, 165.5. MS m/z: 535.14 (M ? Na)?.
2-(4-(2-amino-6-(3-bromophenyl)pyrimidin-4-yl)phenyl)-3,
4-dimethyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c][1,2]thia-
zine 5,5-dioxide (6f) White amorphous powder; 1H NMR
(400 MHz, CDCl3) d: 2.50 (3H, s, CH3), 3.15 (3H, s,
NCH3), 5.32 (2H, br. s, NH2), 7.42 (2H, d, J = 7.8 Hz,
ArH), 7.49 (1H, s, ArH), 7.65 (3H, d, J = 7.5 Hz, ArH),
8.00 (3H, t, J = 7.2 Hz, ArH), 8.10–8.13 (1H, m, ArH),
8.24–8.27 (2H, m, ArH). 13C NMR: 10.9, 40.0, 124.2,
2-(4-(2-amino-6-(4-chlorophenyl)pyrimidin-4-yl)phenyl)-3,
4-dimethyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c][1,2]thiazine
5,5-dioxide (6b) Pale yellow powder; 1H NMR (400 MHz,
CDCl3) d: 2.48 (3H, s, CH3), 3.09 (3H, s, NCH3), 5.25 (2H,
br. s, NH2), 7.38 (2H, m, ArH), 7.56–7.60 (3H, m, ArH), 7.67
(2H, d, J = 8.7 Hz, ArH), 7.87 (2H, d, J = 7.6 Hz, ArH),
7.93 (1H, d, J = 8.0 Hz, ArH), 8.07 (2H, d, J = 8.0 Hz,
ArH), 8.12–8.16 (1H, m, ArH). 13C NMR: 10.8, 40.0, 104.0,
123

Med Chem Res (2012) 21:2885–2895
2893
124.4, 124.9, 125.4, 127.8, 129.3, 129.8, 132.5, 132.9,
133.5, 134.4(2C), 136.7, 136.9, 137.2, 137.5, 137.4(2C),
137.9, 139.5, 142.2(2C), 162.3, 162.5, 164.3. MS m/z:
571.06 (M-H)?.
s, OCH3), 5.24 (2H, br. s, NH2), 6.82 (1H, d, J = 8.8 Hz,
ArH), 7.55–7.60 (1H, m, ArH), 7.64–7.72 (4H, m, ArH),
7.74 (1H, s, ArH), 7.97 (1H, d, J = 7.8 Hz, ArH), 8.12
(1H, d, J = 7.7 Hz, ArH), 8.22 (2H, d, J = 8.2 Hz, ArH).
13C NMR: 10.8, 40.0, 56.1, 56.4, 61.0, 104.0, 104.5, 105.4,
124.2, 124.4, 124.8, 125.0, 127.8, 128.2, 129.2, 129.6, 130.4,
132.4, 132.9, 133.0, 133.5, 136.4, 136.8, 137.6, 139.1, 140.9,
153.5, 163.5, 163.8, 167.0. MS m/z: 585.19 (M ? H)?.
2-(4-(2-amino-6-(4-methoxyphenyl)pyrimidin-4-yl)phenyl)-
3,4-dimethyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c][1,2]thia-
zine 5,5-dioxide (6g) Yellow powder; 1H NMR
(400 MHz, CDCl3) d: 2.48 (3H, s, CH3), 3.13 (3H, s,
NCH3), 3.63 (3H, s, OCH3), 5.24 (2H, br. s, NH2), 6.82
(1H, d, J = 8.8 Hz, ArH), 7.55–7.60 (2H, m, ArH),
7.64–7.72 (4H, m, ArH), 7.74 (1H, s, ArH), 7.97 (1H, d,
J = 7.8 Hz, ArH), 8.02 (1H, d, J = 7.7 Hz, ArH), 8.14
(2H, d, J = 8.2 Hz, ArH), 8.27(1H, d, J = 8.1 Hz, ArH).
13C NMR: 10.8, 40.0, 60.0, 104.0, 104.5, 105.4, 118.2,
120.7, 124.8, 125.0, 126.9, 128.2, 129.2, 129.6, 130.4,
132.4, 132.9, 133.0, 133.5, 136.4, 138.8, 137.6, 139.1,
140.9, 153.6, 157.8, 163.2, 164.5. MS m/z: 525.17
(M ? H)?.
2-(4-(2-amino-6-(3,4,5-trimethoxyphenyl)pyrimidin-4-yl)
phenyl)-3,4-dimethyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c]
1
[1,2]thiazine 5,5-dioxide (6k) Light brown powder; H
NMR (400 MHz, CDCl3) d: 2.49 (3H, s, CH3), 3.14 (3H, s,
NCH3), 3.87 (3H, s, OCH3), 3.94 (3H, s, OCH3), 4.00 (3H,
s, OCH3), 5.24 (2H, s, NH2), 6.49 (1H, m, ArH), 7.33 (1H,
d, J = 7.0 Hz, ArH), 7.44 (1H, d, J = 7.0 Hz, ArH),
7.56–7.59 (2H, m, ArH), 7.65–7.74 (3H, m, ArH), 7.98
(1H, d, J = 7.7 Hz, ArH), 8.13 (2H, d, J = 7.4 Hz, ArH).
13C NMR: 10.8, 40.0, 56.1, 56.4, 61.0, 104.0, 104.5, 105.4,
124.2, 124.4, 124.8, 125.0, 127.8, 128.2, 129.2, 129.6,
130.4, 132.4, 132.9, 133.0, 133.5, 136.4, 138.8, 137.6,
139.1, 140.9, 153.5, 163.5, 164.8, 166.2. MS m/z: 607.17
((M ? Na)?.
2-(4-(2-amino-6-(2-methoxyphenyl)pyrimidin-4-yl)phenyl)-
3,4-dimethyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c][1,2]thia-
zine 5,5-dioxide (6h) Dark yellow powder; 1H NMR
(400 MHz, CDCl3) d: 2.49 (3H, s, CH3), 3.18 (3H, s,
NCH3), 3.93 (3H, s, OCH3), 5.24 (2H, br. s, NH2), 6.87
(1H, d, J = 8.6 Hz, ArH), 7.35–7.40 (2H, m, ArH),
7.64–7.68 (4H, m, ArH), 7.72 (1H, s, ArH), 7.95 (1H, d,
J = 6.8 Hz, ArH), 8.10 (1H, d, J = 8.0 Hz, ArH), 8.22
(2H, d, J = 8.1 Hz, ArH), 8.29(1H, d, J = 7.7 Hz, ArH).
13C NMR: 10.8, 40.0, 60.0, 104.0, 104.5, 105.4, 118.2,
120.7, 124.8, 125.0, 127.8, 128.2, 129.2, 129.6, 130.4, 132.4,
132.9, 133.0, 133.5, 136.4, 138.8, 137.6, 139.1, 140.9, 153.5,
158.2, 163.5, 164.8. MS m/z: 526.17 (M ? H)?.
2-(4-(2-amino-6-(4-nitrophenyl)pyrimidin-4-yl)phenyl)-3,4-
dimethyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c][1,2]thiazine
5,5-dioxide (6l) Yellow powder; 1H NMR (400 MHz,
CDCl3) d: 2.51 (3H, s, CH3), 3.15 (3H, s, NCH3), 5.49 (2H,
br. s, NH2), 7.57 (1H, m, ArH), 7.64 (1H, s, ArH),
7.69–7.75 (3H, m, ArH), 7.91–8.03 (4H, m, ArH), 8.13
(2H, d, J = 7.2 Hz, ArH), 8.27–8.37 (2H, m, ArH). 13C
NMR: 10.8, 40.0, 104.0, 104.5, 105.4, 121.9, 124.2, 124.6,
124.8, 125.5, 127.7, 129.3, 129.7, 129.8, 130.2, 130.6,
132.4, 133.1, 133.8, 134.8, 135.4, 136.5, 141.9, 147.8,
163.3, 163.8, 165,6. MS m/z: 562.14 ((M ? Na)?.
2-(4-(2-amino-6-(3,4-dimethoxyphenyl)pyrimidin-4-yl)phe-
nyl)-3,4-dimethyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c][1,2]
1
thiazine 5,5-dioxide (6i) Pale yellow crystals; H NMR
2-(4-(2-amino-6-phenylpyrimidin-4-yl)phenyl)-3,4-dime-
thyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c][1,2]thiazine 5,5-
dioxide (6m) Yellow powder; 1H NMR (400 MHz,
CDCl3) d: 2.49 (3H, s, CH3), 3.14 (3H, s, NCH3), 5.22 (2H,
br. s,, NH2), 7.51–7.56 (4H, m, ArH), 7.58 (1H, t,
J = 7.6 Hz, ArH), 7.66–7.72 (3H, m, ArH), 7.98 (1H, d,
J = 7.7 Hz, ArH), 8.08–8.10 (2H, m, ArH), 8.13 (1H, d,
J = 7.7 Hz, ArH), 8.25 (2H, d, J = 8.5 Hz, ArH). 13C
NMR: 10.5, 40.0, 104.2, 124.2, 124.8, 124.9, 125.2, 127.1,
128.0, 128.2, 128.7, 129.02, 129.4, 130.6, 130.9 132.4,
132.9, 133.2, 133.5, 134.0, 137.5, 137.6, 139.1, 140.8,
163.6, 164.7, 166.6. MS m/z: 517.14 (M ? Na)?.
(400 MHz, CDCl3) d: 2.49 (3H, s, CH3), 3.14 (3H, s,
NCH3), 3.97 (3H, s, OCH3), 4.03 (3H, s, OCH3), 5.25 (2H,
br. s, NH2), 6.99 (1H, d, J = 8.4 Hz, ArH), 7.47 (1H, s,
ArH), 7.64–7.74 (6H, m, ArH), 7.98 (1H, d, J = 7.7 Hz,
ArH), 8.13 (1H, d, J = 7.5 Hz, ArH), 8.23 (2H, d,
J = 8.5 Hz, ArH). 13C NMR: 10.2, 40.1, 56.1, 56.4, 101.5,
109.0, 111.5, 124.2, 124.4, 124.8, 125.0, 127.8, 128.2,
129.2, 129.6, 130.4, 132.4, 132.9, 133.0, 133.5, 136.4,
136.8, 137.6, 139.1, 143.9, 153.5, 163.5, 164.8, 166.2. MS
m/z: 555.18 (M ? H)?.
2-(4-(2-amino-6-(2,3,4-trimethoxyphenyl)pyrimidin-4-yl)
phenyl)-3,4-dimethyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c]
2-(4-(2-amino-6-(p-tolyl)pyrimidin-4-yl)phenyl)-3,4-dime-
thyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c][1,2]thiazine 5,5-
dioxide (6n) Yellow powder; 1H NMR (400 MHz,
CDCl3) d: 2.46 (3H, s, CH3), 2.49 (3H, s, CH3), 3.14 (3H,
1
[1,2]thiazine 5,5-dioxide (6j) Yellow powder; H NMR
(400 MHz, CDCl3) d: 2.48 (3H, s, CH3), 3.13 (3H, s,
NCH3), 3.87 (3H,s, OCH3), 3.93 (3H, s, OCH3), 3.95 (3H,
123

2894
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s, CH3), 5.25 (2H, br. s, NH2), 7.34 (2H, d, J = 8.0 Hz,
ArH), 7.56–7.61 (2H, m, ArH), 7.64 (2H, d, J = 3.8 Hz,
ArH), 7.79 (1H, s, ArH), 7.83 (2H, d, J = 3.8 Hz, ArH),
7.98 (3H, d, J = 7.9 Hz, ArH), 8.12 (1H, d, J = 7.6 Hz,
ArH). 13C NMR: 10.7, 20.4, 40.0, 104.0, 104.5, 105.4,
124.2, 124.4, 124.8, 125.0, 127.8, 128.2, 129.2, 129.6,
130.4, 132.4, 132.9, 133.2, 133.5, 136.4, 138.8, 137.6,
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dioxide (6o) Yellow powder; 1H NMR (400 MHz, CDCl3)
d: 2.20 (6 H, s, 2xCH3), 2.37 (3H, s, CH3), 2.45 (3H, s, CH3),
3.12 (3H, s, NCH3), 6.12 (2H, br. s, NH2), 7.07–7.26 (3H, m,
ArH), 7.53 (2H, d, J = 8.3 Hz, ArH), 7.69 (2H, t, J =
7.6 Hz, ArH), 7.94–7.99 (2H, m, ArH), 8.10 (2H, d, J =
7.7 Hz, ArH). 13C NMR: 10.7, 19.3 (3C), 40.0, 104.0, 104.5,
105.4, 124.2, 124.4, 124.8, 125.0, 127.8, 128.2, 129.2, 129.6,
130.4, 132.4, 132.9, 133.0, 133.5, 136.4, 138.8, 137.6, 139.1,
140.9, 153.5, 163.5, 164.8, 166.2. MS m/z: 536.20 (M?).
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Acknowledgments The authors are thankful to the Higher Educa-
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Wendy Sobey of the Department of Chemistry Research Laboratories,
University of Oxford, UK for antibacterial testing and valuable
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