Studies on synthesis of novel triazole tagged pyrazole fused naphthalene 5-thiazine-5,5-dioxide derivatives, their antimicrobial, and antioxidant activity

Article abstract of DOI:10.1002/jhet.2013

A series of novel triazole tagged pyrazole fused naphthalene-5-thiazine-5, 5-dioxide derivatives 8 and 9 were synthesized starting from sodium salt of saccharin 1. The structure of each intermediate and products was established on the basis of spectroscop

Full text of DOI:10.1002/jhet.2013

Month 2014
Studies on Synthesis of Novel Triazole Tagged Pyrazole Fused
Naphthalene 5-Thiazine-5,5-dioxide Derivatives, Their Antimicrobial,
and Antioxidant Activity
G. Malla Reddy,a P. Nagender,a R. Naresh Kumar,a J. H. Ahn,b K. Pranay Kumar,c A. K. R. Kanugula,d
e
d
a
*
K. V. S. Rama Krishna, S. Kotamraju, and B. Narsaiah
aFluoroorganic Division, Indian Institute of Chemical Technology, Hyderabad 500607, India
bDrug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, South Korea
cBiology Division, Indian Institute of Chemical Technology, Hyderabad 500607, India
dDepartment of Chemical Biology, Indian Institute of Chemical Technology, Hyderabad 500607, India
eNMR Division, Indian Institute of Chemical Technology, Hyderabad 500607, India
*
E-mail: narsaiah@iict.res.in or narsaiahbanda84@gmail.com
Received January 12, 2013
DOI 10.1002/jhet.2013
Published online in Wiley Online Library (wileyonlinelibrary.com).
A series of novel triazole tagged pyrazole fused naphthalene-5-thiazine-5,5-dioxide derivatives 8 and 9
were synthesized starting from sodium salt of saccharin 1. The structure of each intermediate and products
was established on the basis of spectroscopy data. All the synthesized compounds 8 and 9 were screened
against various bacterial and fungal strains but found to show no activity up to 150-mg/mL concentration.
Further screening for antioxidant property resulted promising compounds.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
CHEMISTRY
Pyrazole nucleus present in many biologically active
compounds are known to have antibacterial, antifungal
[1], antiviral [2], anti-arrhythmic [3], anti-inflammatory
[4], hypoglycemic [5], and herbicidal [6] activities. 1,2-
Benzothiazine-1,1-dioxides are also considered as another
class of potential molecules exemplified as piroxicam [7],
ampiroxicam [8], and meloxicam [9] and used all over
the world as nonsteroidal anti-inflammatory drugs. Some
of the 1,2-benzothiazine-3-ylquinazolin-4(3H)-ones pos-
sess 11b-HSD1 inhibitors [10] and antibacterial [11,12]
and antioxidant activities [13]. Similarly, the perfluoroalkyl
triazoles [14,15] and fluoroalkyl derivatives [16–18] also
show promising biological activity. Recently, pyrazole
fused [19] and benzylidene substituted [13] 1,2-
benzothiazine-1,1-dioxides were reported as promising
antibacterial/antioxidative agents. Keeping in view the
importance of all the above basic skeletons and in continu-
ation of our recent efforts on click chemistry [20–22],
we designed the synergism of three nuclei such as
pyrazole, 1,2-benzothiazine-1,1-dioxide, and triazole in
a single molecule to have a promising activity. Thus,
in the present paper, we have synthesized a novel series
of perfluoroalkyl triazole tagged pyrazole fused
naphthalene-5-thiazine-5,5-dioxide derivatives, screened
them for antimicrobial and antioxidant activities, and
reported them here for the first time.
The synthetic sequence involves reaction of sodium salt
of saccharin 1 with a–halo Ketones in DMF at 110ꢀC to
give N-alkylated product 2 followed by reaction with
sodium ethoxide in ethanol, which resulted in ring expan-
sion and formed 1,2-benzothiazine-1,1-dioxide derivatives
3. The compound 3 was N-alkylated with dimethyl sulfate
to give products 4 and was reacted with hydrazine hydrate
to form pyrazole fused benzene sulfonamide derivatives 5
[19]. The structure of product 5 is in two canonical forms,
and on reaction with propargyl bromide, product 5 resulted
N-propargylated regioisomers 6 and 7 in definite propor-
tions. When R = CH3, the ratio of 6:7 is 80:20, whereas
when R = C6H5, the ratio is 60:40. The polarity of both
the regioisomers 6 and 7 makes them very close, and they
could not be separated; however, the mixtures 6 and 7 were
further cyclized with alkyl/aryl azides by Click reaction
under Sharpless conditions [23,24] and obtained exclu-
sively triazole alkyl tagged pyrazole fused naphthalene-5-
thiazine- 5,5-dioxide derivatives 8 and 9, respectively.
Compounds 8 and 9 were separated and identified by
spectral data. The reaction steps are outlined in Schemes 1
and 2, and products are tabulated in Tables 1 and 2.
The structure of two sets of compounds 8 and 9 when
R = Me and R = ph were identified by 1H NMR (600MHz)
in CDCl3 with the help of 2D NMR double quantum
correlation spectroscopy (gDQCOSY), total correlation
© 2014 HeteroCorporation

G. M. Reddy, P. Nagender, R. N. Kumar, J. H. Ahn, K. P. Kumar, A. K. R. Kanugula,
K. V. S. R. Krishna S. Kotamraju, and B. Narsaiah
Vol 000
Scheme 1. Preparation of compounds 5.
spectroscopy (TOCSY), and nuclear overhauser enhance-
ment spectroscopy (NOESY) experiments. As a representa-
tive example, characteristic chemical shift difference
the strong NOE correlations between C16H/C1H (aromatic)
and C16H/C18H, and C18H/C22H support the energy mini-
mized structure as shown in Figure 2. In order to confirm
the structure of aryl substituted derivatives, compounds
1
between compound 8h and 9h in H NMR is identified.
1
The protons in compound 8h show upfield shift of C1H to
C16H and downfield shift of C11H to C23H, whereas in
compound 9h the chemical shift is reversed. Similarly, the
change in chemical shift of compounds 8a and 9a are com-
pared and found to be different. The comparative proton
chemical shift (ppm) and coupling constant (J = Hz) for both
the compounds are outlined in Table 3.
Thus, compound 8h show the strong NOE correlations
between C16H/C12H3, C16H/C18H, and C18H/C22H, which
provide compelling evidence for energy minimized
structure shown in Figure 1. Similarly, compound 9h show
8a and 9a are also analyzed by H NMR followed by
NOE correlations, and the structures are established. The
comparative proton chemical shift (ppm) and coupling
constant (J = Hz) data for both the compounds and their
NOE correlations are presented in the Experimental
section. The strong NOE correlations of compound 8a
between protons of C21H/C16H, C21H/C23H, C23H/C28H,
and C20H/C11H3 (methyl) provide an emphatic support
for the energy minimized structure shown in Figure 3.
Similarly, in compound 9a the strong NOE correlations
between protons of C21H/C6H, C21H/C26H, and C20H/
Scheme 2. Preparation of compounds 8 and 9.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Studies on Synthesis of Novel Triazole Tagged Pyrazole Fused Naphthalene 5-Thiazine-
5,5-dioxide Derivatives, Their Antimicrobial, and Antioxidant Activity
Month 2014
Table 1
Table 3
Physical properties of compounds 5–7.
Chemical shift of protons in compounds 8h and 9h.
S. no
Compounds
R
mp (ꢀC)
Yield (%)
89
Chemical shift (ppm) of compounds
1
2
3
4
5a
5b
6a + 7a
6b + 7b
CH3
C6H5
CH3
229–230
246–247
154–155
169–170
S. no
Protons
C1H
8h
9h
93
84 (67 + 17)
80 (48 + 32)
1
2
3
4
7.98 (d, 1H,
J = 7.8 Hz)
8.15 (d, 1H,
J = 7.8 Hz)
C6H5
C2H
7.52 (t, 1H,
J = 7.8 Hz)
7.59 (m, 1H)
C12H3 (methyl) provide the clear-cut evidence for the
structure outlined in Figure 4.
C3H
7.65 (t, 1H,
J = 7.8 Hz)
7.74 (t, 1H,
J = 7.8 Hz)
C4H
7.92 (d, 1H,
J = 7.8 Hz)
7.99 (d, 1H,
J = 7.8 Hz)
5
6
7
8
9
10
C11H3
C12H3
3.02 (s, 3H)
2.44 (s, 3H)
5.45 (s, 2H)
7.59 (s, 1H)
4.64 (m, 2H)
2.82 (m, 2H)
2.38 (s, 3H)
3.03 (s, 3H)
5.68 (s, 2H)
7.59 (m, 1H)
4.63 (m, 2H)
2.78 (m, 2H)
RESULTS AND DISCUSSION
C16
C18
C22
C23
H
H
H
H
In vitro antibacterial activity.
Compounds 8a–h and
9a–h were dissolved in DMSO and screened for in vitro
antibacterial activity against Gram-positive (Bacillus subtilis,
Staphylococcus aureus, Staphylococcus epidermidis) and
gram-negative (Pseudomonas aeruginosa, Escherichia coli)
bacteria. The MIC values of the compounds were compared
with those obtained with penicillin and streptomycin.
However, none of the compounds showed significant
activity against all species of Gram-positive and Gram-
negative bacteria at 150-mg/mL concentration except
compounds 9a and 9g, which showed response at 75-mg/mL
concentration against B. subtilis. The details of the
compounds and their activity profiles are tabulated in Table 4.
method. All the compounds were found to be inactive against
all the strains except compounds 9a and 9g, which showed
response at 75 mg/mL against B. subtilis.
Antioxidant activity. The compounds 6a +7a, 6b +7b,
8a–h, and 9a–h were screened in vitro for inhibition of
pyrogallol auto-oxidation in alkaline solution as per reported
procedure of S. Marklund and G. Marklund [25]. Compounds
8e, 8g, and 9f showed good antioxidant activity at 50-mM
concentration and increased with increase in concentration.
Compounds 9b and 9c showed high activity at 50-mM
concentration but decreased activity with increase in
concentration. All other compounds promote pyrogallol auto-
oxidation rather than inhibition and increase with increase in
concentration. The mixture of compounds 6b +7b show
maximum pyrogallol auto-oxidation inhibition activity at
100-mM concentration. The structure activity relation reveals
In vitro antifungal activity.
The fungal strains were
obtained from the Institute of Microbial Technology,
Chandigarh, India. The compounds 8a–h and 9a–h were
screened in vitro against the fungal strains, viz. Candida
albicans (MTCC 227), Saccharomyces cerevisiae (MTCC
36), Aspergillus niger (MTCC 1344), Aspergillus flavus
(MTCC 277), and Candida rugosa (NCIM 3462) at 100-
and 150-mg/mL concentrations by agar cup diffusion
Table 2
Physical properties of compounds 8a–h and 9a–h.
S. no
Compounds
R
R1
Yield (%)
mp (ꢀC)
1
2
3
4
5
6
7
8
8a
9a
8b
9b
8c
9c
8d
9d
8e
9e
8f
C6H5
3-CF3C6H4
3-CF3C6H4
C6H5
53
35
54
36
50
34
40
26
38
25
70
18
61
15
59
14
114–115
134–135
192–193
132–133
176–177
145–146
173–174
128–129
84–85
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
C6H5
─(CH2)2─C8F17
─(CH2)2─C8F17
─(CH2)2─C6F13
─(CH2)2─C6F13
─(CH2)2─C6H13
─(CH2)2─C6H13
C6H5
C6H5
3-CF3C6H4
3-CF3C6H4
─(CH2)2─C8F17
─(CH2)2─C8F17
9
10
11
12
13
14
15
16
82–83
158–159
196–197
212–213
90–91
173–174
110–111
9f
CH3
CH3
CH3
CH3
8g
9g
8h
9h
CH3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G. M. Reddy, P. Nagender, R. N. Kumar, J. H. Ahn, K. P. Kumar, A. K. R. Kanugula,
K. V. S. R. Krishna S. Kotamraju, and B. Narsaiah
Vol 000
Figure 3. Compound 8a.
Figure 1. Compound 8h.
that the activity of compounds is independent of triazole
ring and the substituents therein. The details are
tabulated in Table 5.
Preparation of 3,4-disubstituted-2,4-dihydropyrazolo[4,3-c]
[1,2]benzothiazine-5,5-dioxide (5a–b): General procedure.
A mixture of 1-(4-hydroxy-2-methyl-1,1-dioxido-2H-1,2-
benzothiazin-3-yl) ethanone/phenyl methanone (19.8 mmol)
and hydrazine monohydrate (99.0 mmol) was added to
ethanol (20 mL). The reaction mixture was refluxed for 2 h
while stirring; unreacted hydrazine and ethanol were
removed under vacuum. The residue obtained was poured
into ice cold hydrochloric acid (20 mL, 10%); the precipitate
obtained was filtered, washed with excess water and later
CONCLUSION
A series of novel triazole tagged pyrazole fused naphtha-
lene 5-thiazine-5,5-dioxide derivatives 8 and 9 were
prepared and screened for antimicrobial and antioxidant
activities. Compounds 8e, 8g, and 9f have been identified
to show promising auto-oxidant activity.
with cold ethanol, and dried.
3,4-Dimethyl-2,4-dihydropyrazolo[4,3-c][1,2]benzothiazine-5,5-
dioxide (5a). Light yellow powder, yield 89%, mp 229–230ꢀC;
EXPERIMENTAL
IR (KBr) cmÀ1: 3362, 1600, 1324, 1140; 1H NMR (300 MHz,
DMSO-d6): d 2.37 (s, 3H, CH3), 3.00 (s, 3H, NCH3), 7.49–
7.58 (m, 1H, ArH), 7.63–7.72 (m, 1H, ArH), 7.83 (d,
J = 7.7 Hz, 1H, ArH), 7.97 (d, J= 7.7 Hz, 1H, ArH), 10.09
Melting points were recorded on Cassia-Siamia (VMP-AM) melt-
ing point apparatus and are uncorrected. All chemicals and reagents
were purchased from Aldrich (Sigma-Aldrich, St. Louis, MO) and
Merck (Darmstadt, Germany). IR spectra were recorded on a
Perkin-Elmer FT-IR 240-C spectrophotometer using KBr optics. 1H
NMR spectra were recorded on Bruker AV (Karlsruhe, Germany)
300 and 600MHz in CDCl3 and DMSO-d6 using TMS as internal
standard. 13C NMR spectra were recorded on Bruker AV 75MHz in
CDCl3 and DMSO-d6. Electron impact and chemical ionization mass
spectra were recorded on a VG 7070H instrument at 70 eV. All the
reactions were monitored by thin layer chromatography on precoated
silica gel 60F254 (mesh); spots were visualized with UV light. Merck
silica gel (60-120 mesh) was used for column chromatography.
1,1-Dioxo-2-(2-oxo-propyl)-1,2-dihydro-1l6-benzo[d]isothiazol-
3-one (2a). See Ahmad et al. [19].
(brs, 1H, NH); MS m/z: 249.0 (M+).
4-Methyl-3-phenyl-2,4-dihydropyrazolo[4,3-c][1,2]benzothiazine-
5,5-dioxide (5b). White powder, yield 93%, mp 246–247ꢀC ; IR
1
(KBr) cmÀ1: 3365, 1603, 1330, 1145; H NMR (300MHz,
DMSO-d6): d 2.94 (s, 3H, NCH3), 7.33–7.41 (m, 1H, ArH),
7.44–7.53 (m, 2H, ArH), 7.55–7.63 (m, 1H, ArH), 7.69–
7.77 (m, 1H, ArH), 7.86–7.91 (m, 1H, ArH), 7.93–8.00 (m,
2H, ArH), 8.03–8.08 (m, 1H, ArH); MS m/z: 311.0 (M+).
Preparation of 3,4-dimethyl-1-prop-2-ynyl-1,4-dihydro-5-
thia-1,2,4-triazocyclopenta[a]naphthalene-5,5-dioxide (6a) and
3,4-dimethyl-2-prop-2-ynyl-2,4-dihydro-5-thia-1,2,4-triazacy-
clopenta[a]naphthalene-5,5-dioxide (7a)
1,1-Dioxo-2-(2-oxo-2-phenyl-ethyl)-1,2-dihydro-1l6-benzo
[d]isothiazol-3-one (2b). See Kim et al. [10,26].
Procedure.
A mixture of 3,4-dimethyl-2,4-dihydro
1-(4-Hydroxy-1,1-dioxo-1,2-dihydro-1l6-benzo[e][1,2]thiazin-
3-yl)-ethanone (3a). See Ahmad et al. [19].
pyrazolo[4,3-c][1,2]benzothiazine-5,5-dioxide 5a (5.0 g,
20.0 mmol), anhydrous potassium carbonate (3.31 g,
24.0 mmol), and dry DMF (30 mL) was stirred for a period
of 30 min at room temperature followed by the addition of
propargyl bromide (3.55mL, 40.0 mmol). The total
reaction mixture was stirred for a period of 12h at room
temperature and then poured over ice water, and precipitate
(4-Hydroxy-1,1-dioxo-1,2-dihydro-1l6-benzo[e][1,2]thiazin-3-
yl)-phenyl-methanone (3b). See Kim et al. [10,26].
1-(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1l6-benzo[e]
[1,2]thiazin-3-yl)-ethanone (4a). See Ahmad et al. [19].
(4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1l6-benzo[e]
[1,2]thiazin-3-yl)-phenyl-methanone (4b). See Ahmad et al. [19].
Figure 4. Compound 9a.
Figure 2. Compound 9h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Studies on Synthesis of Novel Triazole Tagged Pyrazole Fused Naphthalene 5-Thiazine-
5,5-dioxide Derivatives, Their Antimicrobial, and Antioxidant Activity
Month 2014
Table 4
Antibacterial activity of compounds 6a + 7a, 6b + 7b, 8a–h, and 9a–h.
MIC (mg/mL)
Compound
B. subtilis
S. aureus
S. epidermidis
E. coli
P. aeroginosa
6a + 7a
6b + 7b
8a
8b
8c
8d
8e
8f
8g
8h
9a
9b
9c
9d
9e
9f
9 g
>150
150
>150
>150
75
150
>150
150
>150
>150
75
150
150
>150
>150
>150
75
>150
1.562
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
1.562
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
3.125
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
12.5
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
150
>150
>150
12.5
9 h
Penicillin
2-Ethynyl-4-methyl-3-phenyl-2,4-dihydro-5-thia-1,2,4-triaza-
thus obtained was washed with excess water and dried. Light
cyclopenta[a]naphthalene-5,5-dioxide (6b). IR (KBr) cmÀ1
2114 (─CꢁC), 1594 (CN), 1343 (SO2asym), 1175
:
yellowish powder, yield 84%; mp 154–156ꢀC.
3,4-Dimethyl-1-prop-2-ynyl-1,4-dihydro-5-thia-1,2,4-triazacy-
clopenta[a]naphthalene-5,5-dioxide (6a). IR (KBr) cmÀ1
:
(SO2sym); 1H NMR (300 MHz, CDCl3):
d 2.48
2117 (─CꢁC), 1594 (CN), 1342 (SO2asym), 1171
(t, Ј = 2.2 Hz, 1H, ─CꢁCH), 2.82 (s, 3H, NCH3), 4.89
(d, Ј = 2.2 Hz, 1H, NCH2), 7.32–7.51 (m, 4H, ArH),
7.63–7.72 (m, 3H, ArH), 7.99–8.06 (m, 2H, ArH);
ESI–MS (m/z): 349.0 (M+).
1
(SO2sym); H NMR (300 MHz, CDCl3): d 2.41–2.44 (m,
1H, ─CꢁCH), 2.46 (s, 3H, CH3), 3.03 (s, 3H, NCH3),
4.92 (d, J = 2.6 Hz, 2H, NCH2), 7.47–7.55 (m, 1H, ArH),
7.61–7.68 (m, 1H, ArH), 7.89 (d, J = 7.7 Hz, 1H, ArH,),
7.98 (d, J = 7.7 Hz, 1H, ArH); MS m/z: 287.0 (M+).
3,4-Dimethyl-2-prop-2-ynyl-2,4-dihydro-5-thia-1,2,4-triaza-
Table 5
cyclopenta[a]naphthalene-5,5-dioxide (7a). IR (KBr) cmÀ1
:
Percent of pyrogallol auto-oxidation inhibition.
2115 (─CꢁC), 1594 (─CN), 1314 (SO2asym), 1170
1
(SO2sym); H NMR (300 MHz, CDCl3): d 2.37 (s, 3H,
% of pyrogallol auto-oxidation inhibition
CH3), 2.53 (m, 1H, ─CꢁCH), 3.07 (s, 3H, NCH3), 5.09
(d, J = 2.4 Hz, 2H, NCH2), 7.56–7.60 (m, 1H, ArH), 7.70–
7.77 (m, 1H, ArH), 7.94 (d, J = 7.7 Hz, 1H, ArH), 8.01
S. no
Compound
50 mM
100 mM
1
2
3
4
5
6
7
8
6a + 7a
6b + 7b
8a
8b
8c
8d
8e
8f
8g
8h
9a
9b
9c
9d
9e
9f
9g
7.17
11.01
À8.09
À7.63
6.04
5.57
7.20
8.24
10.68
À2.31
À33.91
18.53
9.30
À14.44
À5.11
10.99
À40.63
À6.94
6.51
51.76
À10.79
À17.55
6.43
(d, J = 7.7 Hz, 1H, ArH); ESI–MS (m/z): 287.0 (M+).
Preparation of 2-ethynyl-4-methyl-3-phenyl-2,4-dihydro-5-
thia-1,2,4-triazocyclopenta[a]naphthalene-5,5-dioxide (6b) and
1-ethynyl-4-methyl-3-phenyl-1,4-dihydro-5-thia-1,2,4-triaza-
cyclopenta[a]naphthalene-5,5-dioxide (7b).
1.25
36.32
Procedure.
A
mixture of 4-methyl-3-phenyl-1,4-
À9.66
dihydro-5-thia-1,2,4-triaza-cyclopenta[a]naphthalene 5b
9
25.51
(5.0 g, 16.07 mmol), anhydrous potassium carbonate
(3.31 g, 24.0 mmol), and dry DMF (30 mL) was stirred for a
period of 30 min at room temperature followed by the
addition of propargyl bromide (2.84 mL, 32 mmol). Then,
this total reaction mixture was stirred for a period of 12 h at
room temperature and then poured over ice water, and
precipitate thus obtained was washed with excess water and
dried. Light yellowish powder, yield 84%; mp 169–170ꢀC.
10
11
12
13
14
15
16
17
18
À5.99
À47.30
À12.95
2.25
À38.39
16.43
19.08
À89.84
9h
À19.75
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G. M. Reddy, P. Nagender, R. N. Kumar, J. H. Ahn, K. P. Kumar, A. K. R. Kanugula,
K. V. S. R. Krishna S. Kotamraju, and B. Narsaiah
Vol 000
1-Ethynyl-4-methyl-3-phenyl-1,4-dihydro-5-thia-1,2,4-triaza-
cyclopenta[a]naphthalene-5,5-dioxide (7b). IR (KBr) cmÀ1: 2117
(─CꢁC), 1594 (CN), 1343 (SO2asym), 1175 (SO2sym); H
ArH), 8.09 (s, 1H, triazol H); HRMS m/z Calcd for
C26H20N6SO2 ([M + Na]+): 491.1266, found 491.1268.
2-[1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadeca-fluoro-
decyl)-1H-[1,2,3]triazol-4-ylmethyl]-4-methyl-3-phenyl-2,4-dihydro-
5-thia-1,2,4-triaza-cyclopenta[a]naphthalene-5,5-dioxide (8c).
1
NMR (300 MHz, CDCl3): d 2.59 (t, Ј = 2.2 Hz, 1H,
─CꢁCH), 2.96 (s, 3H, NCH3), 5.21 (d, Ј = 2.2 Hz, 1H,
NCH2), 7.41–7.60 (m, 4H, ArH), 7.69–7.80 (m, 2H,
ArH), 8.00–8.12 (m, 3H, ArH); MS m/z: 349.0 (M+).
Preparation of triazole tagged pyrazole fused naphthalene-
5,5-dioxide derivatives 8a–h and 9a–h: General procedure.
A mixture of propargylated products 6 and 7 (0.2 g) and
catalytic amount of CuI was taken into a 50-mL two-
necked RB flask, and then dry THF was added under inert
condition. The reaction mixture was stirred for 30 min at
room temperature, and then alkyl azide was added to the
reaction mixture and further stirred at room temperature
till the reaction was completed (12–18 h). Then, the crude
product was purified by passing through a column packed
White powder; mp 176–177ꢀC; IR (KBr) cmÀ1: 1604
(─CN), 1342 (SO2asym), 1149 (SO2sym); 1H NMR
(300MHz, CDCl3): d 2.68–2.87 (m, 2H, CH2CF2), 2.93
(s, 3H, NCH3), 4.62 (t, J = 7.5 Hz, 2H, NCH2CH2), 5.78
(s, 2H, NCH2), 7.33–7.41 (m, 1H, ArH), 7.43–7.48 (m, 2H,
ArH), 7.57–7.63 (m, 2H, ArH), 7.75–7.80 (m, 1H, ArH),
7.98–8.03 (m, 3H, ArH), 8.20 (d, J = 8.3 Hz, 1H, ArH);
HRMS m/z Calcd for C29H19F17N6SO2 ([M + Na]+):
861.0916, found 861.0874.
1-[1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadeca-fluoro-
decyl)-1H-[1,2,3]triazol-4-ylmethyl]-4-methyl-3-phenyl-1,4-dihydro-
5-thia-1,2,4-triaza-cyclopenta[a]naphthalene-5,5-dioxide (9c).
White powder; mp 145–146ꢀC; IR (KBr) cmÀ1: 1602
(─CN), 1343 (SO2asym), 1154 (SO2sym); 1HNMR
(300 MHz, CDCl3): d 2.70–2.95 (m, 5H, CH2CF2 and
NCH3), 4.64 (t, J = 6.9 Hz, 2H, NCH2CH2), 5.43 (s, 2H,
NCH2), 7.43–7.78 (m, 8H, ArH), 7.91 (d, J = 7.3 Hz, 1H,
ArH), 8.01 (d, J = 7.3 Hz, 1H, ArH); HRMS m/z Calcd
for C29H19F17N6SO2 ([M + Na]+): 861.0916, found
with silica gel and n-hexane:ethylacetate (4:1) as eluents.
4-Methyl-3-phenyl-2-[1-(3-trifluoromethyl-phenyl)-1H-[1,2,3]
triazol-4-ylmethyl]-2,4-dihydro-5-thia-1,2,4-triaza-cyclopenta[a]
naphthalene-5,5-dioxide (8.a) Light yellow powder; mp 114–
115ꢀC; IR (KBr) cmÀ1: 1599 (─CN), 1349 (SO2asym),
1
1182 (SO2sym); H NMR (600 MHz, CDCl3): d 2.95 (s,
3H, NCH3), 5.89 (s, 2H, NCH2), 7.41 (t, J= 7.6Hz, 1H,
ArH), 7.48 (t, J= 7.6 Hz, 2H, ArH,), 7.64–7.66 (m, 2H,
ArH), 7.71 (s, 1H, ArH), 7.81 (t, J= 7.8 Hz, 1H, ArH), 7.90
(d, J= 7.8 Hz, 1H, ArH), 8.01–8.05 (m, 4H, ArH), 8.06 (s,
1H, ArH), 8.27 (d, J= 7.6 Hz, 1H, ArH); HRMS m/z Calcd
861.0912.
4-Methyl-3-phenyl-2-[1-(3,3,4,4,5,5,6,6,7,7,8,8,8-trideca-fluoro-
octyl)-1H-[1,2,3]triazol-4-ylmethyl]-2,4-dihydro-5-thia-1,2,4-
triaza-cyclopenta[a]naphthalene-5,5-dioxide (8d). White
powder; mp 173–174ꢀC; IR (KBr) cmÀ1: 1602 (─CN),
1341 (SO2asym), 1187 (SO2sym); 1H NMR (300 MHz,
CDCl3): d 2.68–2.87 (m, 2H, CH2CF2), 2.92 (s, 3H, NCH3),
4.62 (t, J = 7.5 Hz, 2H, NCH2CH2), 5.77 (s, 2H,
NCH2), 7.33–7.40 (m, 1H, ArH), 7.41–7.49 (m, 2H,
ArH), 7.57–7.64 (m, 2H, ArH), 7.74–7.81 (m, 1H, ArH),
7.97–8.05 (m, 3H, ArH), 8.20 (d, J = 8.3 Hz, 1H, ArH);
HRMS m/z Calcd for C27H19F13N6SO2 ([M + H]+):
for C26H19F3N6SO2 ([M + Na]+): 559.1140, found 559.1161.
4-Methyl-3-phenyl-1-[1-(3-trifluoromethyl-phenyl)-1H-[1,2,3]
triazol-4-ylmethyl]-1,4-dihydro-5-thia-1,2,4-triaza-cyclopenta[a]
naphthalene-5,5-dioxide (9a)Y. ellowish powder; mp 134–135ꢀC;
IR (KBr) cmÀ1: 1600 (─CN), 1323 (SO2asym), 1165
1
(SO2sym); H NMR (600 MHz, CDCl3): d 2.82 (s, 3H,
NCH3), 5.56 (s, 2H, NCH2), 7.51–7.59 (m, 4H, ArH), 7.69
(t, J = 7.8 Hz, 2H, ArH), 7.73–7.76 (m, 3H, ArH),
7.94–7.96 (m, 2H, ArH), 8.04 (s, 1H, ArH), 8.08
(d, J = 7.8 Hz, 1H, ArH), 8.12 (s, 1H, triazole H); HRMS
m/z Calcd for C26H19F3N6SO2 ([M + Na]+): 559.1140,
739.1160, found 739.1173.
4-Methyl-3-phenyl-1-[1-(3,3,4,4,5,5,6,6,7,7,8,8,8-trideca-fluoro-
octyl)-1H-[1,2,3]triazol-4-ylmethyl]--1,4-dihydro-5-thia-1,2,4-
triaza-cyclopenta[a]naphthalene-5,5-dioxide (9d). Yellowish
found 559.1147.
powder; mp 128–129ꢀC; IR (KBr) cmÀ 1: 1603 (─CN),
4-Methyl-3-phenyl-2-(1-phenyl-1H-[1,2,3]triazol-4-ylmethyl)-
2,4-dihydro-5-thia-1,2,4-triaza-cyclopenta[a]naphthalene-5,5-
1
1346 (SO2asym), 1146 (SO2sym); H NMR (300 MHz,
dioxide (8b). White powder; mp 192–193ꢀC; IR (KBr) cmÀ1
:
CDCl3): d 2.70–2.94 (m, 5H, CH2CF2 and NCH3),
4.66 (t, J = 7.5 Hz, 2H, NCH2CH2), 5.43 (s, 2H,
NCH2), 7.46–7.78 (m, 8H, ArH), 7.92 (d, J = 7.5 Hz,
1H, ArH), 8.02 (d, J = 7.5 Hz, 1H, ArH); HRMS m/z
Calcd for C27H19F13N6SO2 ([M + Na]+): 761.0980,
1
1594 (─CN), 1342 (SO2asym), 1181 (SO2sym); H NMR
(300 MHz, CDCl3): d 2.94 (s, 3H, NCH3), 5.85 (s, 2H,
NCH2), 7.34–7.53 (m, 6H, ArH), 7.59–7.66 (m, 1H, ArH),
7.70–7.74 (m, 2H, ArH), 7.78–7.85 (m, 1H, ArH), 7.99–8.06
(m, 4H, ArH), 8.32–8.36 (m, 1H, ArH); HRMS m/z Calcd
found 761.1009.
for C26H20N6SO2 ([M + H]+): 469.1446, found 469.1444.
4-Methyl-3-phenyl-1-(1-phenyl-1H-[1,2,3]triazol-4-ylmethyl)-
1,4-dihydro-5-thia-1,2,4-triaza-cyclopenta[a]naphthalene-5,5-
dioxide (9b). Light yellow powder; mp 132–133ꢀC; IR
4-Methyl-2-(1-octyl-1H-[1,2,3]triazol-4-ylmethyl)-3-phenyl-
2,4-dihydro-5-thia-1,2,4-triaza-cyclopenta[a]naphthalene-5,5-
dioxide (8e). Brown solid; mp 84–85ꢀC; IR (KBr) cmÀ1
:
1
1600 (─CN), 1343 (SO2asym), 1186 (SO2sym); H NMR
(300 MHz, CDCl3): d 0.8–0.94 (m, 3H, CH2CH3), 1.1–1.36
(m, 10H, C5H10), 1.78–1.93 (m, 2H, NCH2CH2), 2.93 (s,
3H, NCH3), 4.3 (t, J = 6.7 Hz, 2H, NCH2CH2), 5.77 (s, 2H,
NCH2), 7.32–7.41 (m, 1H, ArH), 7.96–8.07 (m, 3H, ArH),
(KBr) cmÀ1: 1598 (─CN), 1341 (SO2asym), 1147
1
(SO2sym); H NMR (300 MHz, CDCl3): d 2.80 (s, 3H,
ArH), 7.47–7.68 (m, 7H, ArH), 7.72–7.83 (m, 4H, ArH),
7.91 (d, J = 7.7 Hz, 1H, ArH), 8.04 (d, J = 7.7 Hz, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Studies on Synthesis of Novel Triazole Tagged Pyrazole Fused Naphthalene 5-Thiazine-
5,5-dioxide Derivatives, Their Antimicrobial, and Antioxidant Activity
Month 2014
2-[1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadeca-fluoro-
decyl)-1H-[1,2,3]triazol-4-yl methyl]-3,4-dimethyl-2,4-dihydro-5-
thia-1,2,4-triaza-cyclopenta[a]naphthalene-5,5-dioxide (8h).
8.28 (d, J = 8.3 Hz, 1H, ArH); HRMS m/z Calcd for
C27H32N6SO2 ([M + H]+): 505.0759, found 505.0773.
4-Methyl-1-(1-octyl-1H-[1,2,3]triazol-4-ylmethyl)-3-phenyl-1,4-
dihydro-5-thia-1,2,4-triaza-cyclopenta[a]naphthalene-5,5-dioxide
(9e). Brown solid; mp 82–83ꢀC; IR (KBr) cmÀ1: 1603
White powder mp 173–174ꢀC; IR (KBr) cmÀ1: 1598
(─CN), 1341 (SO2asym), 1149 (SO2sym); 1H NMR
(600 MHz, CDCl3): d 2.44 (s, 3H, CH3), 2.74–2.90 (m,
2H, CH2CF2), 3.02 (s, 3H, NCH3), 4.64 (m, 2H,
NCH2CH2), 5.45 (s, 2H, NCH2), 7.52 (t, J = 7.8 Hz, 1H,
ArH), 7.59 (s, 1H, ArH), 7.65 (t, J = 7.8 Hz, 1H, ArH),
7.92 (d, J = 7.8 Hz, 1H, ArH), 7.98 (d, J = 7.8 Hz, 1H,
ArH); HRMS m/z Calcd for C24H17F17N6SO2
(─CN), 1340 (SO2asym), 1140 (SO2sym); 1H NMR
(300 MHz, CDCl3): d 0.79–0.95 (m, 3H, CH2CH3),
1.15–1.41 (m, 10H, C5H10), 1.82–1.97 (m, 2H,
NCH2CH2), 2.79 (s, 3H, NCH3), 4.25–4.40 (t, 2H,
NCH2CH2), 5.42 (s, 2H, NCH2), 7.42–7.67 (m, 6H,
ArH), 7.70–7.82 (m, 2H, ArH), 7.86–7.96 (m, 1H,
ArH). 7.97–8.07 (m, 1H, ArH); HRMS m/z Calcd for
([M + Na]+): 799.0759, found 799.0773.
1-[1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluoro-decyl)-
1H-[1,2,3]triazol-4-ylmethyl]-3,4-dimethyl-1,4-dihydro-5-thia-
1,2,4-triaza-cyclopenta[a]naphthalene-5,5-dioxide (9h). Yellowish
C27H32N6SO2 ([M + H]+): 505.0759, found 505.0782.
3,4-Dimethyl-2-(1-phenyl-1H-[1,2,3]triazol-4-ylmethyl)-2,4-
dihydro-5-thia-1,2,4-triaza-cyclo
penta[a]naphthalene-5,5-
dioxide (8f). Yellowish powder; mp 158–159ꢀC; IR (KBr)
cmÀ1: 1603 (─CN), 1348 (SO2asym), 1170 (SO2sym);
1H NMR (300 MHz, CDCl3): d 2.5 (s, 3H, CH3), 3.01
(s, 3H, NCH3), 5.50 (s, 2H, NCH2), 7.36–7.43 (m,
1H, ArH), 7.45–7.55 (m, 3H, ArH), 7.60–7.67 (m, 1H,
ArH), 7.68–7.74 (d, J = 7.5 Hz, 2H, ArH,), 7.87–7.92
(d, J = 7.5 Hz, 1H, ArH), 7.94–8.00 (m, 2H, ArH);
HRMS m/z Calcd for C20H18N6SO2 ([M + Na]+):
powder; mp 110–111ꢀC; IR (KBr) cmÀ1: 1599 (─CN),
1346 (SO2asym), 1149 (SO2sym); 1H NMR (600 MHz,
CDCl3): d 2.38 (s, 3H, CH3), 2.70–2.86 (m, 2H,
CH2CF2), 3.03 (s, 3H, NCH3), 4.62–4.64 (m, 2H,
NCH2CH2), 5.68 (s, 2H, NCH2), 7.52–7.61 (m, 2H,
ArH), 7.74 (t, J = 7.8 Hz, 1H, ArH), 7.99 (d,
J = 7.8 Hz, 1H, ArH), 8.15 (d, J = 7.8 Hz, 1H, ArH);
HRMS m/z Calcd for C24H17F17N6SO2 ([M + Na]+):
429.1109, found 429.1111.
799.0759, found 799.0780.
3,4-Dimethyl-1-(1-phenyl-1H-[1,2,3]triazol-4-ylmethyl)-1,4-
Antibacterial activity: Procedure. Five bacterial test
dihydro-5-thia-1,2,4-triaza-cyclo
penta[a]naphthalene-5,5-
organisms such as B. subtilis (MTCC 441), S. aureus
(MTCC 96), S. epidermidis (MTCC 435), E. coli (MTCC
443), and P. aeruginosa (MTCC 741) were selected and
obtained from the Institute of Microbial Technology,
Chandigarh, India. Cultures of test organisms were
maintained on Nutrient agar slants and were subcultured in
Petri dishes prior to testing. The media used was Nutrient
agar, Nutrient broth procured from Himedia Laboratories,
Mumbai, India. The minimum inhibitory concentration was
determined by broth dilution method.
dioxide (9f). Light yellow powder; mp 196–197ꢀC; IR
(KBr) cmÀ1: 1594 (─CN), 1343 (SO2asym), 1171
1
(SO2sym); H NMR (300 MHz, CDCl3): d 2.38 (s, 3H,
CH3), 3.02 (s, 3H, NCH3), 5.72 (s, 2H, NCH2), 7.36–7.55
(m, 3H, ArH), 7.60 (t, J = 7.5 Hz, 1H, ArH), 7.71 (d,
J = 7.7 Hz, 2H, ArH,), 7.80 (t, J = 7.7 Hz, 1H, ArH), 7.94–
8.01 (m, 2H, ArH), 8.29 (d, J = 7.7 Hz, 1H, ArH); HRMS
m/z Calcd for C20H18N6SO2 ([M + Na]+): 429.1109, found
429.1118.
3,4-Dimethyl-2-[1-(3-trifluoromethyl-phenyl)-1H-[1,2,3]triazol-
4-ylmethyl]-2,4-dihydro-5-thia-1,2,4-triaza-cyclo-penta[a]
naphthalene-5,5-dioxide (8g). White powder; mp
Antifungal activity: Procedure.
Antifungal activity
was studied by agar cup diffusion method. The
readymade potato dextrose agar medium (Himedia, 39 g)
was suspended in distilled water (1000 mL) and heated to
boiling until it dissolved completely. The medium and
Petri dishes were autoclaved at a pressure of 15 lb/inch
for 20 min. Agar cup bioassay was employed for testing
antifungal activity. The medium was poured into sterile
Petri dishes under aseptic conditions in a laminar flow
chamber. When the medium in the plates solidified,
0.5 mL of (week old) culture of test organism was
inoculated and uniformly spread over the agar surface
with a sterile L-shaped rod. Solutions were prepared by
dissolving the compound in acetone, and different
concentrations (30 and 100 mg/mL) were made. After
inoculation, cups were scooped out with a 6-mm sterile
cork borer, and the lids of the dishes were replaced. To
each cup, different concentrations (30 and 100 mg/mL) of
test solutions were added. Controls were maintained with
acetone and amphotericin-B (50 mg/mL). The treated and
212–213ꢀC; IR (KBr) cmÀ1
: 1594 (─CN), 1328
(SO2asym), 1166 (SO2sym); 1H NMR (300 MHz,
CDCl3): d 2.51 (s, 3H, CH3), 3.02 (s, 3H, NCH3),
5.51 (s, 2H, NCH2), 7.48–7.51 (m, 1H, ArH), 7.60–
7.74 (m, 3H, ArH), 7.87–8.07 (m, 5H, ArH); HRMS
m/z Calcd for C21H17F3N6SO2 ([M + Na]+): 497.0983,
found 497.0992.
3,4-Dimethyl-1-[1-(3-trifluoromethyl-phenyl)-1H-[1,2,3]triazol-
4-ylmethyl]-1,4-dihydro-5-thia-1,2,4-triaza-cyclopenta[a]
naphthalene-5,5-dioxide (9g). Light yellow powder; mp
90–91ꢀC; IR (KBr) cmÀ1: 1599 (─CN), 1334 (SO2asym),
1175 (SO2sym); 1H NMR (300 MHz, CDCl3): d 2.39
(s, 3H, CH3), 3.04 (s, 3H, NCH3), 5.75 (s, 2H,
NCH2), 7.56–7.72 (m, 3H, ArH), 7.74–7.83 (m, 1H,
ArH), 7.74–7.83 (m, 1H, ArH), 7.89–8.05 (m, 4H,
ArH), 8.22 (d, J = 8.31 Hz, 1H, ArH); HRMS m/z
Calcd for C21H17F3N6SO2 ([M + Na]+): 497.0983,
found 497.0999.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

G. M. Reddy, P. Nagender, R. N. Kumar, J. H. Ahn, K. P. Kumar, A. K. R. Kanugula,
K. V. S. R. Krishna S. Kotamraju, and B. Narsaiah
Vol 000
the controls were kept at 28ꢀC for 48 h. Inhibition zones were
measured, and the diameter was calculated in millimeter.
Antioxidant activity: Procedure. Compounds 8a–h,
9a–h, 6a + 7a, and 6b + 7b were dissolved in DMSO
solution to prepare 100 mM stock solutions. Potassium
phosphate buffer (50 mM; pH 8.0) containing 1 mM
EDTA was used as assay buffer. Total reaction volume
of the assay was 200 mL, which contained various
concentrations of the test compounds (0–100 mM), and
was studied for their ability to inhibit the pyrogallol
auto-oxidation at 420 nm for using TECAN M-200
multimode reader. The readings were taken at 1-min
interval up to 5 min. DMSO solution was used as a
reagent blank. All the experiments were carried out in
triplicates, and average value is taken for consideration.
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Acknowledgments. Authors are thankful to the Director of IICT
for his constant encouragement, and authors (G. Malla Reddy, P.
Nagender, R. Naresh Kumar, and A. K. Kanugula) are thankful to
the Council of Scientific and Industrial Research (CSIR), India,
for providing financial assistance in the form of Junior Research
Fellowship and contingency grant. Part of this work was also
supported by utilizing CSIR funds (SMILE).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet