Effective synthesis of 1,5-disubstituted 2,1-benzisothiazol-3(1H)-ones

Article abstract of DOI:10.1080/00397911.2010.515343

A convenient and effective synthesis of novel 1,5-disubstituted 2,1-benzisothiazol-3(1H)-one derivatives is described. The approach involves nitration of inexpensive isatoic anhydride followed by its conversion to 5-nitro-2,1-benzisothiazol-3(1H)-ones in excellent yield and alkylation at the 1-position. The 5-amino group was further derivatized.

Full text of DOI:10.1080/00397911.2010.515343

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Effective Synthesis of 1,5-Disubstituted
2,1-Benzisothiazol-3(1H)-ones
Rajendra K. Kharul a , Pinkal N. Prajapati a , Amol A. Thorave a ,
Hardik A. Shah a , Arghya Dhar a , Darshan A. Joshi a , Mukul R. Jain a
, Pankaj R. Patel a & S. S. Pancholi b
a Zydus Research Centre , Ahmedabad , Gujarat , India
b Department of Pharmaceutical Chemistry, Ganpat University ,
Kherva , Gujarat , India
Published online: 26 Jul 2011.
To cite this article: Rajendra K. Kharul , Pinkal N. Prajapati , Amol A. Thorave , Hardik A. Shah ,
Arghya Dhar , Darshan A. Joshi , Mukul R. Jain , Pankaj R. Patel & S. S. Pancholi (2011) Effective
Synthesis of 1,5-Disubstituted 2,1-Benzisothiazol-3(1H)-ones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:22, 3265-3279,
DOI: 10.1080/00397911.2010.515343
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Synthetic Communications1, 41: 3265–3279, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515343
EFFECTIVE SYNTHESIS OF 1,5-DISUBSTITUTED
2,1-BENZISOTHIAZOL-3(1H)-ONES
Rajendra K. Kharul,1 Pinkal N. Prajapati,1 Amol A. Thorave,1
Hardik A. Shah,1 Arghya Dhar,1 Darshan A. Joshi,1
Mukul R. Jain,1 Pankaj R. Patel,1 and S. S. Pancholi2
1Zydus Research Centre, Ahmedabad, Gujarat, India
2Department of Pharmaceutical Chemistry, Ganpat University, Kherva,
Gujarat, India
GRAPHICAL ABSTRACT
Abstract A convenient and effective synthesis of novel 1,5-disubstituted 2,1-benzisothiazol-
3(1H)-one derivatives is described. The approach involves nitration of inexpensive isatoic
anhydride followed by its conversion to 5-nitro-2,1-benzisothiazol-3(1H)-ones in excellent
yield and alkylation at the 1-position. The 5-amino group was further derivatized.
Keywords 1,2-Benzisothiazol-3(2H)-one; 2,1-benzoisothiazolin-3(1H)-one; nitration;
sodium hydrogen sulfide
INTRODUCTION
1,2-Benzisothiazol-3(2H)-ones 1 are biologically important and exhibit
antifungal, antibacterial, and antipsychotic properties.[1] Thus, it is tempting and
logical to explore the biological potential of 2,1-benzisothiazol-3(1H)-ones 2, which
are structural isomers of 1. There are several reports for the synthesis of 1,2-
benzisothiazol-3(2H)-ones 1.[2] In contrast, there are few literature reports for the
synthesis of 2,1-benzisothiazol-3(1H)-ones 2.[3] To the best of our knowledge, there
is only one report for the synthesis of 1,5-disubstituted 2,1-benzisothiazol-
3(1H)-ones.[3e] The literature method involved conversion of isatoic anhydride with
Received April 1, 2010.
Address correspondence to Rajendra K. Kharul, Zydus Research Centre, Sarkhej-Bavala Highway
No. 8A, Moraiya, Ahmedabad 382 213, Gujarat, India. E-mail: rkharul@yahoo.co.in
3265

3266
R. K. KHARUL ET AL.
potassium hydrogen sulfide (KSH) followed by oxidation with hydrogen peroxide to
furnish 2,1-benzisothiazol-3(1H)-ones 2. An electrophilic substitution reaction was
utilized to introduce substitution at the 5-position, followed by alkylation at the
1-position. Although the approach furnished 1,5-disubstituted 2,1-benzisothiazol-
3(1H)-one, the poor yields for electophilic substitution and alkylation and inconsi-
stent reproducibility were the major drawbacks.
RESULTS AND DISCUSSION
In continuation of our interest in generating targeted chemical libraries,[4] we
were interested in the synthesis of 1,5-disubstituted 2,1-benzisothiazol-3(1H)-one.
Herein, we report a short and improved synthesis of novel 1,5-disubstituted
2,1-benzisothiazol-3(1H)-one derivatives.
We were particularly interested in 5-amino-2,1-benzisothiazol-3(1H)-ones
because the free amino group may give access to potentially biologically active
heterocycles and it could be further derivatized.
Because, literature report of introducing substituents at the 5-position of
2,1-benzisothiazol-3(1H)-one by electrophilic substitution reaction was unsuccessful
in our hands, we initiated synthesis by nitration of inexpensive isatoic anhydride 3
(Scheme 1). Isatoic anhydride on nitration furnished 6-nitroisatoic anhydride 4.[5]
Scheme 1. Synthesis of 5-amino 2,1-benzisothiazolin-3-one. Reagents and conditions: (a) NaNO3, H2SO4,
0–15 ꢀC, 20 min, 80%; (b) NaSH, MeOH, 26 ꢀC, 1 h; (c) H2O2, 30 min, 26 ꢀC, AcOH, 70%; (d) R1X,
K2CO3, acetone, reflux, 1 h, 63–90%; (e) Fe=HCl, H2O, EtOAc, reflux, 15 min, 80–95%.
Scheme 2. Reagents and conditions: (f) ArSO2Cl, pyridine, 26 ꢀC, 15 min, 65–93%.

1,5-DISUBSTITUTED 2,1-BENZISOTHIAZOL-3(1H)-ONES
3267
Table 1. 5-Arylsulfonamido 2,1-benzisothiazol-3-one derivatives 8a–p
Entry
1
Compound
R1
Ar
Mp (ꢀC)
Yield (%)
82
8a
-CH2Ph
180–182
2
3
8b
8c
-CH2Ph
-CH2Ph
168–170
180–182
80
77
4
5
8d
8e
-CH2Ph
-CH2Ph
154–156
160–162
65
74
6
7
8f
-CH2Ph
-CH2Ph
128–130
144–146
66
65
8g
8
9
8h
8i
-CH2Ph
-CH2Ph
128–130
144–146
79
93
10
11
12
13
14
15
16
8j
8k
8l
-CH2Ph
-CH2Ph
126–128
124–126
108–110
126–128
112–114
108–110
161–163
65
80
70
65
65
69
65
-CH2CH3
-CH2CH3
-CH2CH3
-CH2CH3
-CH2CH3
8m
8n
8o
8p

3268
R. K. KHARUL ET AL.
Scheme 3. Reagents and conditions: (g) R2COCl, CH2Cl2, 0 to 26 ꢀC, 15 min, 65–85%.
Table 2. 5-Alkyl=arylcarboxamido 2,1-benzisothiazol-3-one derivatives 9a–n
Entry
Compound
R1
R2
Mp (ꢀC)
Yield (%)
1
2
3
4
9a
9b
9c
9d
-CH2Ph
-CH2Ph
-CH2Ph
-CH2Ph
-CH3
-C6H5
166–168
222–224
154–156
146–148
77
74
75
73
-CH2CH3
-C(CH3)
5
9e
-CH2Ph
198–200
78
6
7
9f
-CH2Ph
-CH2Ph
188–190
186–188
79
74
9g
8
9
9h
9i
-CH2Ph
-CH2Ph
172–174
152–154
74
84
10
11
12
13
14
9j
9k
9l
-CH2CH3
-CH2CH3
-CH2CH3
-CH2CH3
-CH2CH3
140–142
156–158
142–144
188–190
141–143
80
85
65
79
65
9m
9n

1,5-DISUBSTITUTED 2,1-BENZISOTHIAZOL-3(1H)-ONES
3269
Compound 4 was subjected to ring opening with sodium hydrogensulfide[6] to give
sodium salt of the corresponding thioanthranilic acid 5, which was not isolated
but oxidized in situ with hydrogen peroxide to the desired 5-nitro-2,1-
benzisothiazol-3(1H)-one 6. Substitution at the 1-position was achieved by alky-
lation. Alkylation was attempted with different bases and various solvents; optimum
yield was obtained by employing potassium carbonate as a base and acetone as
solvent. Alkylation followed by reduction with Fe=HCl[7] furnished 5-amino-2,1-
benzisothiazol-3(1H)-one 7.
As mentioned earlier, the free amino group at the 5-position may give a proper
handle for further transformations. For example, 5-amino-2,1-benzisothiazol-
3(1H)-one was reacted either with different sulfonyl chlorides to give differentially
substituted sulfonamide derivatives (Scheme 2; Table 1) or with acyl chlorides to give
corresponding acetamide derivatives (Scheme 3; Table 2) of 7.[8]
CONCLUSION
In summary, we have achieved an effective and improved synthesis of 1,5-
disubstituted 2,1-benzisothiazol-3(1H)-ones using simple organic transformations
and inexpensive chemicals. The synthetic sequence described is short and provides
a free amino group at the 5-position, which is further derivatized. Presently, we
are working on insertion of different substituents at the 5-position as well as conver-
sion of the free amino group to potential biologically active heterocycles.
EXPERIMENTAL
1H NMR was recorded on an NMR spectrometer at either 300 MHz or
400 MHz in CDCl3 or dimethylsulfoxide (DMSO-d6) as solvent. Chemical shifts
were reported as parts per million (ppm) downfield from an internal tetramethyl-
1
silane (TMS) standard (d ¼ 0.00 for H NMR). Mass spectra were recorded on a
Perkin-Elmer Sciex API 3000. 13C NMR was recorded on the NMR spectrometer
at either 75 MHz or 100 MHz in CDCl3 or DMSO-d6 solvent. Infrared (IR) spectra
were recorded on a Fourier transform (FT)–IR 8300 Shimadzu instrument in KBr
pellets or CHCl3 or CCl4 as solvent. Target compounds were analyzed for purity
by analytical high-performance liquid chromatography (HPLC) at kmax 220 nm
using column ODS C-18, 150 mm ꢁ 4.6 mm ꢁ 4 mm on an Agilent 100 series instru-
ment. Melting points were taken on a Scientific melting-point apparatus and
are uncorrected. Thin-layer chromatography (TLC) was performed using 25
DC-Alufolien 20 ꢁ 20 cm Kieselgel 60 F254 Merck plates.
Glassware was oven or flame dried prior to use. Reactions were performed
under an argon or nitrogen inert atmosphere whenever needed. Crude products were
purified by flash chromatography using silica gel (100–200 mesh, 230–400 mesh) or
neutral aluminum oxide.
Preparation of 5-Nitroisatoic Anhydride (4)
Isatoic anhydride (0.6 mol) was dissolved carefully in concentrated H2SO4 (1 L)
in a round-bottomed flask equipped with calcium chloride guard tube at 0–5 ꢀC.

3270
R. K. KHARUL ET AL.
Sodium nitrate (0.7 mol) was slowly added in portions over 20 min while maintaining
the temperature below 10 ꢀC and stirring vigorously. Nitration was complete within
a few minutes after complete addition of sodium nitrate. TLC using EtOAc=
petroleum ether (1:1) as mobile phase showed conversion to polar, nonfluorescent
spot, absence of starting material, and formation of nonfluorescent material. The
reaction mixture was carefully and slowly poured on ice (1 kg) in a glass beaker at
0 ꢀC. The yellow solid was separated, filtered, washed with water, suspended in acet-
onitrile (1 L), filtered, and air dried to yield a pale yellow solid. Yield 80%; mp 220 ꢀC
(dec); IR (KBr) cmꢂ1: 3199 (N-H) 1762 and 1697 (C O), 1608, 1508, 1336 (NO2),
=
1035 (C N), 767, 659; 1H NMR (400 MHz DMSO-d6) d (ppm) 7.30 (d, 1H,
=
J ¼ 9.2 Hz, aromatic), 8.52 (dd, 1H, J ¼ 2.4, 9.2 Hz, aromatic), 8.56 (d, 1H,
J ¼ 2.4 Hz, aromatic), 12.33 (bs, 1H NH, D2O exchangeable); MS (m=z) 208.9
(M þ H)þ; % purity by HPLC 99.5, ret. time 13.06 min. Anal. calcd. for
C8H4N2O5: C, 46.17; H, 1.94; N, 13.46; O, 38.44. Found: C, 45.85; H, 2.16; N,
13.23; O, 38.67.
Preparation of 5-Nitro-2,1-benzisothiazol-3(1H)-one (6)
A solution of sodium hydrogen sulfide in methanol was generated in situ by
bubbling hydrogen sulfide gas into a solution of sodium hydroxide (0.0274 mol) in
methanol (70 mL) for 30 min followed by purging with nitrogen gas for 15 min. This
solution was added over 30 min to a stirred suspension of 5-nitroisatoic anhydride 4
(0.027 mol) in methanol (70 mL) at 26 ꢀC. The resulting red solution was filtered
through a sintered glass funnel, and the solvent was removed under vacuum yielding
a yellow-orange solid. The solid obtained was suspended in sodium hydroxide (1 N,
70 mL), slowly treated with hydrogen peroxide (16.2 mL, 30%) at 0–5 ꢀC, and stirred
for 15 min at 26 ꢀC. The resulting dark red solution was filtered, and the filtrate was
made strongly acidic with concentrated hydrochloric acid. The yellow solid obtained
was collected, washed with water, and again dissolved in sodium hydroxide solution
(1 N, 100 mL). The resulting red solution was filtered and adjusted to exactly pH 5.8
with acetic acid using a pH meter. The yellow solid was collected, washed with watꢂer1,
and air dried to get a yellow-green solid. Yield 70%; mp 190 ꢀC (dec); IR (KBr) cm
:
1
=
3483 (N-H), 1683 C O), 1519, 1328 (NO2), 1429, 849, 748; H NMR (300 MHz,
DMSO-d6) d (ppm) 6.85 (d, 1H, J ¼ 9.3 Hz, aromatic), 8.05 (dd, 1H, J ¼ 2.67,
9.27 Hz aromatic), 8.55 (d, 1H, J ¼ 2.7 Hz, aromatic), 13.28 (bs, 1H, NH, D2O
exchangeable); MS (m=z) 196.9 (M þ H)þ; % purity by HLPC 99.62, ret. time
12.42 min. Anal. calcd. for C7H4N2O3S: C, 42.86; H, 2.06; N, 14.28; O, 24.47; S,
16.34. Found: C, 42.98; H, 2.26; N, 14.47; O, 24.32.
General Procedure for Preparation of N-Substituted-
5-nitro-2,1-benzisothiazol-3(1H)-ones
5-Nitro-2,1-benzisothiazol-3(1H)-one 6, (0.1 mol) was suspended in acetone
(500 mL) in a round-bottomed flask equipped with reflux condenser and N2(g) bal-
loon. Potassium carbonate (0.12 mol) was added to the reaction mixture, which
turned red after addition. Alkyl halide or aryl alkyl halide (0.11 mol) was added to
the reaction mixture, and it was then refluxed. The reaction was monitored by

1,5-DISUBSTITUTED 2,1-BENZISOTHIAZOL-3(1H)-ONES
3271
TLC using EtOAc–petroleum ether (1:9) as mobile phase, which showed formation
of a nonpolar spot. The reaction mixture was concentrated under vacuum to furnish
a yellow-orange solid, which was suspended in EtOAc (50 mL). Diluted HCl (1 N,
300 mL) was added at 0 ꢀC very slowly. The solution was filtered, layers were sepa-
rated, and the organic layer was washed with water (2 ꢁ 250 mL) and brine (250 mL),
dried over anhydrous sodium sulfate, filtered, and concentrated to get the crude pro-
duct. The crude material was purified by column chromatography using silica gel
(100–200) as stationary phase and EtOAc–Petroleum ether gradient as mobile phase.
The desired product was eluted at 6–8% of EtOAc in petroleum ether to yield the
solid.
Selected Data
1-Benzyl-5-nitro-2,1-beꢂn1zisothiazol-3(1H)-one. Yellow solid. Yield 90%;
mp 183–185 ꢀC; IR (KBr) cm : 3062, 1681 (C O), 1662, 1502 and 1323 (NO2),
=
1078, 723; 1H NMR (300 MHz, DMSO-d6) d (ppm) 5.08 (s, 2H, -CH2-Ph),
7.27–7.28 (m, 3H, aromatic), 7.37–7.42 (m, 3H, aromatic), 8.37 (dd, 1H, J ¼ 2.8,
9.6 Hz, aromatic), 8.75 (d, 1H, J ¼ 2 Hz, aromatic); 13C NMR (75 MHz, CDCl3) d
(ppm) 192.0 (s), 154.3 (s), 129.4 (s), 127.9 (d), 117.0 (d), 33.6 (t); MS (m=z) 286.9
(M þ H)þ, 308.7 (M þ Na)þ; % purity by HPLC 98.5, ret. time 12.76 min. Anal.
calcd. for C14H10N2O3S: C, 58.73; H, 3.52; N, 9.78; O, 16.76; S, 11.20. Found: C,
58.93; H, 3.35; N, 9.65; O, 16.92.
1-Ethyl-5-nitro-2,1-benzisothiazol-3(1H)-one. Greenish yellow solid. Yield
1
83%; mp 150–152 ꢀC; IR: 2923, 1577 and 1438 (NO2), 1228, 1159, 1093, H NMR
(400 MHz, CDCl3) d (ppm): 1.45 (t, 3H, J ¼ 7.2 Hz, -CH2-CH3), 4.02 (q, 2H,
J ¼ 7.2 Hz, -CH2-CH3), 7.22 (d, 1H, J ¼ 5.6 Hz, aromatic), 8.40 (dd, 1H, J ¼ 2.4,
9.6 Hz, aromatic), 8.72–8.73 (m, 1H, aromatic); MS (m=z) 225 (M þ H)þ; % purity
by HPLC 95. Ret. time 17.47 min.
1-Methyl-5-nitro-2,1-benzisothiazol-3(1H)-one. Yellow solid. Yield 56%;
mp 148–150 ꢀC; IR: 2823, 1577 and 1438 (NO2), 1228, 1155, 1083; 1H NMR
(400 MHz, CDCl3) d (ppm): 2.7 (s, 3H, ꢂCH3), 7.25 (d, 1H, J ¼ 5.8 Hz, aromatic),
8.35 (dd, 1H, J ¼ 2.4, 9.6 Hz, aromatic), 8.70–8.72 (m, 1H, aromatic); MS (m=z)
210 (M þ H)þ, 209.1 (Mꢂ1)ꢂ; % purity by HPLC 85. Ret. time 16.97 min.
1-Isopropyl-5-nitro-2,1-benzisothiazol-3(1H)-one. Yellow solid. Yield
1
43%; mp 174–176 ꢀC; IR: 2897, 1560 and 1420 (NO2), 1245, 1112, 1050; H NMR
(400 MHz, CDCl3) d (ppm): 1.24 (d, 6H, J ¼ 3.4 Hz, ꢂ2 ꢁ CH3), 4.02 (m, -CH-),
7.26 (m, 1H, aromatic), 8.38 (m, 1H, aromatic), 8.69–8.71 (m, 1H, aromatic); MS
(m=z) 237.1 (M ꢂ 1)ꢂ; % purity by HPLC 86. Ret. time 19.55 min.
General Procedure for Preparation of 5-Amino-1-substituted-
2,1-benzisothiazol-3(1H)-ones (7a–d)
A solution of 1-substituted-5-nitro-2,1-benzisothiazol-3(1H)-one (1.4 mol) in
EtOAc (23 mL) was treated with iron powder (0.025 mol) and concentrated hydro-
chloric acid (0.3 mL) in a round-bottomed flask equipped with reflux condenser
and anhydrous CaCl2 guard tube. The reaction mixture, was heated to reflux. Water

3272
R. K. KHARUL ET AL.
(13 mL) was added to the reaction mixture, and again reflux was continued for
10–30 min at 60 ꢀC. The reaction was monitored constantly by TLC using EtOAc–
petroleum ether (1:1) as mobile phase. When TLC showed completion of reaction
and formation of a polar spot, it was cooled to 26 ꢀC and diluted with ethyl acetate.
The reaction mixture was filtered through celite placed on a sintered glass funnel.
The filtrate was washed with water (20 mL) and brine (20 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated to get crude solid. The crude solid was pur-
ified by column chromatography using neutral alumina (100–200) as stationary
phase and EtOAc–petroleum ether gradient as mobile phase.
Selected Data
5-Amino-1-benzyl-2,1-benzisothiazol-3(1H)-one (7a). Yellow solid. Yield
ꢂ1
81%; mp 146–148 ꢀC; IR (KBr) cm : 3357 (N-H), 2962 (C-H), 1631 (C O), 1404,
=
1
1215, 1074, 758; H NMR (300 MHz, DMSO-d6) d (ppm) 3.64 (s, 2H, NH2, D2O
exchangeable), 4.87 (s, 2H, -CH2-Ph), 6.98 (d, 1H, J ¼ 2.8 Hz, aromatic), 7.00 (m,
1H, aromatic), 7.1 (d, 1H, J ¼ 8.8 Hz), 7.27–7.36 (m, 5H, aromatic); 13C NMR
(100 MHz, CDCl3) d (ppm) 188.6 (s), 148.1 (s), 143.1 (s), 136.3 (s), 124.0 (d), 123.1
(d), 115.5 (d), 52.9 (t); MS (m=z) 256.8 (M þ H)þ, 278.8 (M þ Na)þ; % purity by
HPLC 96.83. Ret. time 12.58 min.
5-Amino-1-ethyl-2,1-benzisothiazol-3(1H)-one (7b). Brown liquid. Yield
89%; IR (KBr) cmꢂ1: 3421 and 3018 (N-H) 1215, 780; 1H NMR (400 MHz, CDCl3)
d (ppm): 1.27 (t, 3H, J ¼ 7.2, -CH2-CH3), 3.6 (bs, 2H, NH, D2O exchangeable), 3.80
(q, 2H, J ¼ 7.2 Hz, -CH2-CH3), 7–7.02 (m, 2H, aromatic), 7.06–7.10 (m, 1H, aro-
matic); MS (m=z) 194 (M þ H)þ, 216.8 (M þ Na)þ; % purity by HPLC 89. Ret. time
8.12 min.
5-Amino-1-methyl-2,1-benzisothiazol-3(1H)-one (7c). Brown liquid.
Yield 95%; IR (KBr) cmꢂ1: 3460 and 3020 (N-H); 2920, 1215, 1150, 780; 1H
NMR (400 MHz, CDCl3) d (ppm): 2.72 (s, 3H, CH3), 5.6 (bs, 2H, N-H, D2O
-
exchangeable), 7.1–7.08 (m, 2H, aromatic), 7.21–7.25 (m, 1H, aromatic); MS (m=z)
180.8 (M þ H)þ, 203 (M þ Na)þ; % purity by HPLC 96. Ret. time 7.56min.
5-Amino-1-isopropyl-2,1-benzisoꢂth1iazol-3(1H)-one (7d). Brown solid.
Yield 75%; mp 126–128 ꢀC; IR (KBr) cm : 3360 (N-H), 2922 (C-H), 1651 (C O),
=
1414, 1218, 1074, 758; 1H NMR (300 MHz, DMSO-d6) d (ppm) 1.27 (d, 6H,
J ¼ 6.5 Hz, 2 ꢁ CH3), 4.02 (m, 1H), 5.27 (bs, 2H, NH2, D2O exchangeable) 6.75 (d,
1H, J ¼ 2.66 Hz, aromatic), 7.55 (m, 1H, aromatic), 7.49 (d, 1H, J ¼ 8.96 Hz, aro-
matic); MS (m=z) 209.1 (M þ H)þ, 231.1 (M þ Na)þ; % purity by HPLC 96.53.
Ret. time 11.02 min.
General Procedure for Synthesis of 5-Arylsulfonamido
2,1-Benzisothiazol-3(1H)-one Derivatives (8a–p)
Substituted anilines 7a–d (0.01 mol) were dissolved in pyridine (3 mL) in a
round-bottomed flask equipped with air condenser and N2(g) balloon. Sulfonyl chlor-
ide (0.01 mol) was added to the reaction mixture and heated to 60 ꢀC. Progress of the

1,5-DISUBSTITUTED 2,1-BENZISOTHIAZOL-3(1H)-ONES
3273
reaction was monitored by TLC using in EtOAc–petroleum ether (1:1) as mobile
phase. After completion, the reaction was diluted with EtOAc (20 mL); washed with
diluted HCl (1 N, 2 ꢁ 10 mL), water (10 mL), and brine (10 mL); dried over anhy-
drous sodium sulfate; filtered; and concentrated to get a dark brown crude residue.
This crude product was purified by column chromatography using silica gel (100–
200) as stationary phase and EtOAc–petroleum ether gradient as mobile phase.
Selected Data
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-benzenesulfonamide (8a).
Light yellow solid. Yield 82%; mp 180–182 ꢀC. IR (KBr) cmꢂ1: 3436 and 3232
1
=
(N-H), 2864, 1629 (C O), 1483, 1352, 758, 742; H NMR (300 MHz, DMSO-d6) d
(ppm) 5.09 (s, 2H, -CH2-Ph), 7.23–7.33 (m, 5H, aromatic), 7.34–7.37 (m, 2H, aro-
matic), 7.32–7.50 (m, 6H, aromatic), 10.26 (s, 1H, NH, D2O exchangeable); MS
(m=z) 397 (M þ H)þ, 418.9 (M þ Na)þ; % purity by HPLC 99.79, Ret. time
19.35 min. Anal. calcd. for C20H16N2O3S2: C, 60.59; H, 4.07; N, 7.07; O, 12.11; S,
16.17. Found: C, 60.72; H, 3.95; N, 7.29; O, 12.34; S, 16.34.
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-3-chloro-4-fluoroben-
zenesulfonamide (8b). Light yellow solid. Yield 80%; mp 168–170 ꢀC; IR (KBr)
1
cmꢂ1: 3433 and 3292 (N-H), 2929, 1631 (C O), 1487 and 1357 (S O), 823; H
NMR (300 MHz, DMSO-d6) d (ppm) 4.97 (s, 2H, -CH2-Ph), 6.57 (s, 1H, NH,
D2O exchangable), 7.26–7.46 (m, 6H, aromatic), 7.35–7.37 (m, 1H, aromatic),
7.45–7.55 (m, 1H, aromatic), 7.78–7.81, (m, 1H, aromatic); MS (m=z) 449 (M þ H)þ,
470.9 (Mþ Na)þ; % purity by HPLC 96.69. Ret. time 21min.
=
=
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-3-chloro-2-methyl ben-
zenesulfonamide (8c). Light yellow solid. Yield 77%; mp 180–182 ꢀC; IR (KBr)
1
cmꢂ1: 3257 and 3080 (N-H), 2923, 1622 (C O), 1477 and 1149 (S O), 617; H
NMR (300 MHz, DMSO-d6) d (ppm) 2.68, (s, 3H, -CH3), 5.09 (s, 2H, -CH2-Ph),
7.22–7.28 (m, 3H, aromatic), 7.33–7.37 (m, 2H, aromatic), 7.37–7.39 (m, 3H, aro-
matic), 7.63, (d, 1H, J ¼ 9.12 Hz, aromatic), 7.72 (d, 1H, J ¼ 7.83 Hz, aromatic),
7.79 (d, 1H, J ¼ 7.83 Hz, aromatic), 10.59 (s, 1H, NH, D2O exchangeable); MS
(m=z) 444.8 (M þ H)þ, 466.8 (M þ Na)þ; % purity by HPLC 98.38. Ret. time
21.44 min.
=
=
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-4-methylbenzenesulfo-
namide (8d). Yellow solid. Yield 65%; mp 154–156 ꢀC, IR (KBr) cmꢂ1: 3448 and
3230 (N-H), 2856, 1618 (C O), 1490 and 1321 (S O), 1159, 812. 1H NMR
(300 MHz, DMSO-d6,) d (ppm) 2.39 (s, 3H, -CH3), 4.95 (s, 2H, -CH2-Ph), 6.36 (s,
1H, NH, D2O exchangeable), 7.17–7.26 (m, 6H, aromatic), 7.35–7.36 (m, 3H, aro-
matic), 7.50–7.58 (m, 3H, aromatic); MS (m=z) 410.9 (M þ H)þ, 433.2 (M þ Na)þ;
% purity by HPLC 98.22. Ret. time 20.19 min.
=
=
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-2,4,6-trimethyl-ben-
zenesulfonamide (8e). Light yellow solid. Yield 74%; mp 160–162 ꢀC; IR (KBr)
cmꢂ1: 3448 and 3274 (N-H), 2914, 1643 (C O), 1489, 1317 and 1157 (S O), 854,
=
=
1
663; H NMR (300 MHz, DMSO-d6) d (ppm) 2.20 (s, 3H, -CH3), 2.49 (s, 6H, 2 ꢁ
-CH3), 5.09 (s, 2H, -CH2-Ph), 6.98 (s, 2H, aromatic), 7.13–7.16 (d, 1H, J ¼ 2.04 Hz,

3274
R. K. KHARUL ET AL.
aromatic), 7.23–7.30 (m, 6H, aromatic), 7.61–7.62 (d, 1H, J ¼ 9.1 Hz, aromatic),
10.10 (s, 1H, NH, D2O exchangeable); MS (m=z) 438.9 (M þ H)þ, 460.9 (M þ Na)þ;
% purity by HPLC 98.6. Ret. time 21.73 min. Anal. calcd. for C23H22N2O3S2: C,
62.99; H, 5.06; N, 6.39; O, 10.94; S, 14.62. Found: C, 63.13; H, 5.23; N, 6.59; O,
10.63; S, 14.39.
N (1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-4-methoxy-benzenesul-
fonamide (8f). Light yellow solid. Yield 66%; mp 128–130 ꢀC; IR (KBr) cmꢂ1: 3438
1
=
=
and 3246 (N-H), 2927, 1595 (C O), 1492, 1261 and 1155 (S O), 833, 559; H NMR
(300 MHz, DMSO-d6) d (ppm) 3.77 (s, 3H, OCH3), 5.09 (s, 2H, -CH2-Ph), 7.02 (d,
2H, J ¼ 8.85 Hz, aromatic), 7.24–7.37 (m, 7H, aromatic), 7.60–7.64 (m, 3H, aro-
matic), 10.13 (s, 1H, NH, D2O exchangeable); MS (m=z) 426.9 (M þ H)þ, 449.2
(M þ Na)þ; % purity by HPLC 97.1. Ret. time 19.50 min.
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-4-chlorobenzenesulfo-
namide (8g). Light yellow solid. Yield 65%; mp 144–146 ꢀC; IR (KBr) cmꢂ1: 3234
1
=
=
and 3060 (N-H), 2918, 1768 (C O), 1604, 1498 and 1161 (S O), 756; H NMR
(300 MHz, DMSO-d6) d (ppm) 5.11 (s, 2H, -CH2-Ph), 7.23–7.28 (m, 3H, aromatic),
7.29–7.33 (m, 4H, aromatic), 7.33–7.36 (m, 1H, aromatic), 7.60–7.63 (m, 2H, aro-
matic), 7.65–7.67, (m, 2H, aromatic), 10.34 (s, 1H, NH, D2O exchangeable); MS
(m=z) 430.9 (M þ H)þ, 453 (M þ Na)þ; % purity by HPLC 99.28. Ret. time
20.80 min. Anal. calcd. for C20H15ClN2O3S2: C, 55.74; H, 3.51; Cl, 8.23; N, 6.50;
O, 11.14; S, 14.88. Found: C, 55.85; H, 3.39; Cl, 8.48; N, 6.68; O, 11.23; S, 14.69.
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-3-chlorobenzenesulfo-
namide (8h). Light yellow solid. Yield 79%; mp 128–130 ꢀC; IR (KBr) cmꢂ1 3255
1
=
=
and 3028 (N-H), 2922, 1604 (C O), 1496, 1321 and 1163 (S O), 773; H NMR
(400 MHz, CDCl3) d (ppm): 4.90 (s, 2H, -CH2-Ph). 6.99 (s, 1H, NH, D2O exchange-
able), 7.05–7.08 (m, 1H, aromatic), 7.27–7.31 (m, 2H, aromatic), 7.37–7.41 (m, 5H,
aromatic), 7.46–7.51 (m, 2H, aromatic), 7.53–7.55 (m, 1H, aromatic), 7.90–7.92 (m,
1H, aromatic); MS (m=z) 431.1 (M þ H)þ, 453 (M þ Na)þ; % purity by HPLC 97.52.
Ret. time 20.03 min.
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-2-chloro-benzenesulfo-
namide (8i). Light yellow solid. Yield 93%; mp 144–146 ꢀC; IR (KBr) cmꢂ1: 3423
1
=
=
and 3276 (N-H), 3030, 2924, 1633 (C O), 1487, 1321 and 1172 (S O), 673; H NMR
(400 MHz, CDCl3) d (ppm) 4.98 (s, 2H, -CH2-Ph), 6.46 (s, 1H, NH, D2O exchange-
able), 7.18–7.20 (m, 2H, aromatic), 7.31–7.40 (m, 5H, aromatic), 7.47–7.56 (m, 4H,
aromatic), 7.70–7.71 (m, 1H, aromatic); MS (m=z) 430.8 (M þ H)þ, 452.9
(M þ Na)þ; % purity by HPLC 95.7. Ret. time 20.74 min.
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-4-fluoro-benzenesulfo-
namide (8j). Light yellow solid. Yield 65%; mp 126–128 ꢀC, IR (KBr) cmꢂ1: 3441
1
and 3230 (N-H), 2862, 1591, 1493, 1321 and 1167 (S O), 837; H NMR (300 MHz,
=
DMSO-d6) d (ppm) 4.95 (s, 2H, -CH2-Ph), 6.53 (s, 1H, NH, D2O exchangeable),
7.02–7.08 (m, 2H, aromatic), 7.28–7.32 (m, 4H, aromatic), 7.35–7.37 (m, 3H, aro-
matic), 7.46–7.50 (m, 1H, aromatic), 7.69–7.72, (m, 2H, aromatic); MS (m=z)
414.9 (M þ H)þ, 436.8 (M þ Na)þ; % purity by HPLC 98.54%. Ret. time 19.85 min.

1,5-DISUBSTITUTED 2,1-BENZISOTHIAZOL-3(1H)-ONES
3275
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-2,4-difluoro-benzene-
sulfonamide (8k). Light yellow solid. Yield 80%; mp 124–126 ꢀC; IR (KBr) cmꢂ1
:
1
=
=
3246 and 3033 (N-H), 2918 (S O), 1639 (C O), 1598, 1456, 1317, 1124, 698; H
NMR (400 MHz, CDCl3) d (ppm) 4.92 (s, 2H, -CH2-Ph), 6.75 (s, 1H, NH, D2O
exchangeable), 6.89–6.99 (m, 2H, aromatic), 7.14–7.17 (m, 1H, aromatic),
7.34–7.38 (m, 4H, aromatic), 7.47–7.52 (m, 2H, aromatic), 7.74–7.79 (m, 2H, aro-
matic); MS (m=z) 432.8 (M þ H)þ, 454.8 (M þ Na)þ; % purity by HPLC 99.20.
Ret. time 19.99 min.
N-(1-Ethyl-2,1-benzisothiazol-3(1H)-one-5-yl)-benzenesulfonamide (8l).
Light yellow solid. Yield 70%; mp 108–110 ꢀC; IR (KBr) cmꢂ1: 3448 (N-H), 2941,
1
=
=
1647 (C O), 1444, 1340 and 1282 (S O), 1091, 754; H NMR (400 MHz, CDCl3)
d (ppm) 1.35 (t, 3H, J ¼ 7.2 Hz, -CH2-CH3), 3.87 (q, 2H, J ¼ 7.2 Hz, -CH2-CH3),
6.5 (s, 1H, NH, D2O exchangeable), 7.21–7.22 (m, 1H, aromatic), 7.42–7.46 (m,
2H, aromatic), 7.12–7.15 (m, 1H, aromatic), 7.52–7.57 (m, 2H, aromatic),
7.69–7.71 (m, 2H, aromatic); MS (m=z) 335 (M þ H)þ 356.9 (M þ Na)þ; % purity
by HPLC 99.19. Ret. time 17.34 min.
2-Chloro-N-(1-ethyl-2,1-benzisothiazol-3(1H)-one-5-yl)-benzenesulfo-
namide (8m). Yellow solid. Yield 65%; mp 126–128 ꢀC; IR (KBr) cmꢂ1: 3450
1
=
=
(N-H), 2974, 1616, (C O), 1452, 1336 and 1161 (S O), 762; H NMR (400 MHz,
CDCl3) d (ppm) 1.29 (t, 3H, J ¼ 7.2 Hz, -CH2-CH3), 3.83 (q, 2H, J ¼ 7.2 Hz,
-CH2-CH3), 7.30 (m, 1H, aromatic), 7.1 (s, 1H, NH, D2O exchangeable),
7.32–7.35 (m, 1H, aromatic), 7.45–7.48 (m, 1H, aromatic), 7.49–7.51 (m, 1H, aro-
matic), 7.53–7.56 (m, 2H, aromatic), 7.89–7.92 (m, 1H, aromatic); MS (m=z) 369.1
(M þ H)þ, 390.8 (M þ Na)þ; % purity by HPLC 99.21. Ret. time 18.02 min. Anal.
calcd. for C15H13ClN2O3S2: C, 48.84; H, 3.55; Cl, 9.61; N, 7.59; O, 13.01; S,
17.39. Found: C, 49.12; H, 3.32; Cl, 9.95; N, 7.43; O, 12.91; S, 17.21.
N-(1-Ethyl-2,1-benzisothiazol-3(1H)-one-5-yl)-2,4-difluorobenzenesulfo-
namide (8n). Yellow solid. Yield 65%; mp 112–114 ꢀC; IR (KBr) cmꢂ1: 3101
(N-H), 2925, 1601 (C O), 1491, 1334 and 1171 (S O), 816, 546; 1H NMR
(400 MHz, CDCl3) d (ppm) 1.33 (t, 3H, J ¼ 14.2 Hz, -CH2-CH3), 3.85 (q, 2H,
J ¼ 7.2 Hz, -CH2-CH3), 6.85 (s, 1H, NH, D2O exchangeable), 6.88–6.94 (m, 1H, aro-
matic), 6.96–6.99 (m, 1H, aromatic), 7.11–7.13 (m,1H, aromatic), 7.37 (d, 1H,
J ¼ 2 Hz, aromatic), 7.50–7.53 (m, 1H, aromatic), 7.73–7.79 (m, 1H, aromatic);
MS (m=z) 370.9 (M þ H)þ, 392 (M þ Na)þ; % purity by HPLC 96.68. Ret. time
18.01 min.
=
=
N-(1-Ethyl-2,1-benzisothiazol-3(1H)-one-5-yl)-4-fluorobenzenesulfona-
mide (8o). Yellow solid. Yield 69%; mp 108–110 ꢀC; IR (KBr) cmꢂ1: 3107 (N-H),
1
=
=
2926, 1608 (C O), 1491, 1331 and 1171 (S O), 818; H NMR (400 MHz, CDCl3) d
(ppm) 1.35 (t, 3H, J ¼ 7.2 Hz, -CH2-CH3), 3.89 (q, 2H, J ¼ 7.2 Hz, -CH2-CH3), 6.73
(s, 1H, NH, D2O exchangeable), 7.08–7.15 (m, 3H, aromatic), 7.26–7.28 (m, 1H, aro-
matic), 7.50–7.53 (m, 1H, aromatic), 7.70–7.75 (m, 2H, aromatic); MS (m=z) 352.9
(M þ H)þ, 374.9 (M þ Na)þ; % purity by HPLC 94.47. Ret. time 17.89 min.
N-(1-Ethyl-2,1-benzisothiazol-3(1H)-one-5-yl)-2,4,6-trimethylbenzene-
sulfonamide (8p). Yellow solid. Yield 65%; mp 161–163 ꢀC; IR (KBr) cmꢂ1: 3435

3276
R. K. KHARUL ET AL.
1
=
=
(N-H), 2972, 1602 (C O), 1494, 1446, 1319 and 1159 (S O), 872, 697; H NMR
(400 MHz, CDCl3) d (ppm) 1.32 (t, 3H, J ¼ 7.2 Hz, -CH2-CH3-), 1.55 (s. 9H, 3 ꢁ
CH3), 3.85 (q, 2H, J ¼ 11.2, 7.2 Hz, -CH2-CH3), 6.4 (s, 1H, NH, D2O exchangeable),
6.91 (s, 2H, aromatic), 7.09–7.12 (m, 1H, aromatic), 7.17 (d, 1H, J ¼ 2.4, aromatic),
7.45–7.48 (m, 1H, aromatic); MS m=z 376.9.1 (M þ H)þ, % purity by HPLC 97.75.
Ret. time 20.06 min.
General Procedure for Synthesis of 5-Aryl/Alkylcarboxamido
2,1-Benzisothiazol-3(1H)-one Derivatives (9)
The substituted anilines (7) (0.01 mol) was dissolved in DCM (3 mL) in a
round-bottomed flask equipped with air condenser and N2(g) balloon. Triethylamine
(0.012 mol) was added at 26 ꢀC, the mixture was cooled to 0 ꢀC, corresponding acid
chloride (0.01 mol) was added to the reaction mixture, and it was stirred for 10 min.
After completion of the reaction, it was diluted with EtOAc (20 mL); washed with
diluted HCl (1 N, 2 ꢁ 10 mL), water (10 mL), and brine (10 mL); dried over
anhydrous sodium sulphate; filtered; and concentrated to get the crude residue.
The residue was purified by column chromatography using silica gel (100–200) as
the stationary phase and EtOAc–petroleum ether gradient as the mobile phase.
Selected Data
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-acetamide
(9a). Light
yellow solid. Yield 77%; mp 166–168 ꢀC; IR (KBr) cmꢂ1: 3342 and 3097 (N-H),
1
=
2958, 1726 and 1682 (C O), 1489, 1307; H NMR (400 MHz, DMSO-d6) d (ppm)
2.03 (s, 3H, -CH3) 5.11 (s, 2H, -CH2-Ph), 7.28–7.33 (m, 5H, aromatic), 7.68 (s,
2H, aromatic), 8.02 (s, 1H, aromatic), 10.06 (s, 1H, NH, D2O exchangeable); MS
m=z 298.9 (M þ H)þ, 320.8 (M þ Na)þ; % purity by HPLC 98.77. Ret. time
16.11 min. Anal. calcd. for C16H14N2O2S: C, 64.41; H, 4.73; N, 9.39; O, 10.72; S,
10.75. Found: C, 64.59; H, 4.51; N, 9.18; O, 10.96; S, 10.56.
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-benzamide (9b). Light
yellow solid. Yield 74%; mp 222–224 ꢀC; IR (KBr) cmꢂ1: 3367 and 3057 (N-H),
1
=
1637 and 1587 (C O), 1497, 1307. H NMR (400 MHz, DMSO-d6) d (ppm) 5.17
(s, 2H, -CH2-Ph). 7.30–7.37 (m, 5H, aromatic), 7.51–7.59 (m, 3H, aromatic), 7.73
(d, 1H, J ¼ 9.2 Hz, aromatic), 7.94–7.98, (m, 3H, aromatic), 8.19 (m, 1H, aromatic),
10.37 (s, 1H, NH, D2O exchangeable); MS m=z 361 (M þ H)þ, 382.9 (M þ Na)þ, %
purity by HPLC 99.12. Ret. time 19.11 min. Anal. calcd. for C21H16N2O2S: C, 69.98;
H, 4.47; N, 7.77; O, 8.88; S, 8.90. Found: C, 69.81; H, 4.62; N, 7.59; O, 9.12; S, 8.71.
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-propionamide
(9c).
Light yellow solid. Yield 75%; mp 156–158 ꢀC; IR (KBr) cmꢂ1: 3384 and 3096
1
(N-H), 2950, 1720 and 1645 (C O), 1487, 1352; H NMR (400 MHz, DMSO-d6)
=
d (ppm) 1.11 (t, 2H, J ¼ 4.5 Hz -CH2- CH3), 2.58 (q, 1H, J ¼ 4.8 Hz), 5.10 (s, 2H,
-CH2-Ph), 7.37–7.43 (m, 5H, aromatic), 7.77 (m, 2H, aromatic), 8.05 (m, 1H, aro-
matic), 8.88 (s, 1H, NH, D2O exchangeable); MS m=z 313.1 (M þ H)þ, 335.9
(M þ Na)þ; % purity by HPLC 91.25. Ret. time 14.66 min.

1,5-DISUBSTITUTED 2,1-BENZISOTHIAZOL-3(1H)-ONES
3277
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-isobutyramide
(9d).
Light yellow solid. Yield 73%; mp 146–148 ꢀC; IR (KBr) cmꢂ1: 3430 and 3110
1
(N-H), 2928, 1754 and 1641 (C O), 1400, 1357; H NMR (400 MHz, DMSO-d6)
=
d (ppm) 1.19 (s, 6H, 2 ꢁ -CH3), 2.68 (m, 1H), 5.11 (s, 2H, -CH2-Ph), 7.27–7.32 (m,
5H, aromatic), 7.67 (s, 2H, aromatic), 8.01 (s, 1H, aromatic), 8.89 (s, 1H, NH,
D2O exchangeable); MS m=z 326.8 (M þ H)þ, 348.9 (M þ Na)þ; % purity by HPLC
99.66. Ret. time 18.11 min. Anal. calcd. for C18H18N2O2S: C, 66.23; H, 5.56; N, 8.58;
O, 9.80; S, 9.82. Found: C, 66.59; H, 5.20; N, 8.18; O, 9.96; S, 8.56.
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-2,4,6-trimethylbenzamide
(9e). Light yellow solid. Yield 78%; mp 198–200 ꢀC; IR (KBr) cmꢂ1: 3410 and 3256
1
(N-H), 2922, 1641 (C O), 1477, 1324, 1191, 855, 670; H NMR (300 MHz, DMSO-
=
d6) d (ppm) 2.19 (s, 3H, -CH3), 2.54 (s, 6H, 2 ꢁ -CH3), 5.11 (s, 2H, -CH2-Ph), 7.01 (s,
2H, aromatic), 7.23 (d, 1H, J ¼ 2.04 Hz, aromatic), 7.33–7.40 (m, 6H, aromatic),
7.65–7.69 (d, 1H J ¼ 9.1 Hz, aromatic), 9.56 (s, 1H, NH, D2O exchangeable); MS
(m=z) 402.9 (M þ H)þ, 425.9 (M þ Na)þ; % purity by HPLC 95.6. Ret. time
12.73 min.
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-4-methoxy-benzamide
(9f). Light brown solid. Yield 79%; mp 188–190 ꢀC; IR (KBr) cmꢂ1: 3421 and 3266
1
(N-H), 2912, 1584 (C O), 1492, 1261,1155, 833, 559; H NMR (300 MHz, DMSO-
=
d6) d (ppm) 3.55 (s, 3H, OCH3), 5.12 (s, 2H, -CH2-Ph), 7.12 (d, 2H, J ¼ 8.85 Hz, aro-
matic), 7.26–7.34 (m, 7H, aromatic), 7.62–7.68 (m, 3H, aromatic), 09.11 (s, 1H, NH,
D2O exchangeable); MS (m=z) 390.9 (M þ H)þ, 411.9 (M þ Na)þ; % purity by HPLC
98.2. Ret. time 11.45 min.
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-4-chlorobenzamide (9g).
Light yellow solid. Yield 74%; mp 186–188 ꢀC; IR (KBr) cmꢂ1 3315 and 3090 (N-H),
1
=
2920, 1612, 1711, (C O), 1487, 756; H NMR (300 MHz, DMSO-d6) d (ppm) 5.09 (s,
2H, -CH2-Ph), 7.20–7.25 (m, 3H, aromatic), 7.28–7.31 (m, 4H, aromatic), 7.32–7.33
(m, 1H, aromatic), 7.59–7.61 (m, 2H, aromatic), 7.64–7.69, (m, 2H, aromatic), 9.22
(s, 1H, NH, D2O exchangeable). MS (m=z) 394.9 (M þ H)þ, 418 (M þ Na)þ; %
purity by HPLC 99.28. Ret. time 12.80 min. Anal. calcd. for C21H15ClN2O2S2: C,
63.87; H, 3.83; Cl, 8.98; N, 7.09; O, 8.10; S, 8.12. Found: C, 63.27; H, 3.58; N,
6.99; O, 8.22; S, 8.55.
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-3-chlorobenzamide (9h).
Light yellow solid. Yield 74%; mp 186–188 ꢀC; IR (KBr) cmꢂ1 3325 and 3080 (N-H),
1
=
2930, 1610, 1705, (C O), 1496, 773; H NMR (400 MHz, CDCl3) d (ppm): 4.90 (s,
2H, -CH2-Ph), 6.99 (s, 1H, NH, D2O exchangeable), 7.05–7.08 (m, 1H, aromatic),
7.27–7.31 (m, 2H, aromatic), 7.37–7.41 (m, 5H, aromatic), 7.46–7.51 (m, 2H, aro-
matic), 7.53–7.55 (m, 1H, aromatic), 7.90–7.92 (m, 2H, aromatic); MS (m=z) 431.1
(M þ H)þ, 453 (M þ Na)þ; % purity by HPLC 97.52. Ret. time 20.03 min.
N-(1-Benzyl-2,1-benzisothiazol-3(1H)-one-5-yl)-2-chloro-benzenamide
(9i). Light yellow solid. Yield 84%; mp 152–154 ꢀC; IR (KBr) cmꢂ1: 3400 and 3254
1
(N-H), 3029, 2922, 1633, 1712 (C O), 1487, 1321, 673; H NMR (400 MHz, CDCl3)
=
d (ppm) 5.05 (s, 2H, -CH2-Ph), 6.55 (s, 1H, NH, D2O exchangeable), 7.11–7.18 (m,
2H, aromatic), 7.25–7.46 (m, 5H, aromatic), 7.47–7.56 (m, 4H, aromatic), 7.71–7.78

3278
R. K. KHARUL ET AL.
(m, 2H, aromatic); MS (m=z) 395.5 (M þ H)þ, 317.2 (M þ Na)þ; % purity by HPLC
94.1. Ret. time 14.74 min.
N-(1-Ethyl-2,1-benzisothiazol-3(1H)-one-5-yl)-benzamide (9j). Light yel-
low solid. Yield 80%; mp 140–142 ꢀC; IR (KBr) cmꢂ1: 3455 (N-H), 2930, 1630,
1
=
1705 (C O), 1455, 1366, 1085, 754; H NMR (400 MHz, CDCl3) d (ppm) 1.25 (t,
3H, J ¼ 7.2 Hz, -CH2-CH3), 3.67 (q, 2H, J ¼ 7.2 Hz, -CH2-CH3), 6.45 (s, 1H, NH,
D2O exchangeable), 7.25–7.20 (m, 1H, aromatic), 7.13–7.17 (m, 1H, aromatic),
7.41–7.49 (m, 2H, aromatic), 7.42–7.47 (m, 2H, aromatic), 7.59–7.61 (m, 2H, aro-
matic); MS (m=z) 298.8 (M þ H)þ, % purity by HPLC 89.22. Ret. time 11.34 min.
2-Chloro-N-(1-ethyl-2,1-benzisothiazol-3(1H)-one-5-yl)-benzamide (9k).
Yellow solid. Yield 85%; mp 156–158 ꢀC; IR (KBr) cmꢂ1: 3481 (N-H), 2950, 1620,
1
=
1750, (C O), 1426, 1336, 750; H NMR (400 MHz, CDCl3) d (ppm) 1.25 (t, 3H,
J ¼ 7.2 Hz, -CH2-CH3), 3.55 (q, 2H, J ¼ 7.2 Hz, -CH2-CH3), 7.45 (m, 1H, aromatic),
7.3 (s, 1H, NH, D2O exchangeable), 7.35–7.36 (m, 1H, aromatic), 7.55–7.58 (m, 1H,
aromatic), 7.79–7.80 (m, 1H, aromatic), 7.83–7.86 (m, 2H, aromatic), 7.89–7.92 (m,
1H, aromatic); MS (m=z) 333.9 (M þ H)þ 356.8 (M þ Na)þ; % purity by HPLC
88.51. Ret. time 14.02 min.
N-(1-Ethyl-2,1-benzisothiazol-3(1H)-one-5yl)-2,4-difluorobenzamide (9l).
Yellow solid. Yield 65%; mp 142–144 ꢀC; IR (KBr) cmꢂ1: 3122 (N-H), 2957, 1601,
1
=
1710, (C O), 1491, 1010, 816, 546; H NMR (400 MHz, CDCl3) d (ppm) 1.3 (t,
3H, J ¼ 6.2 Hz, -CH2-CH3), 3.95 (q, 2H, J ¼ 7.2 Hz, -CH2-CH3), 5.95 (s, 1H, NH,
D2O exchangeable), 6.88–6.94 (m, 1H, aromatic), 6.96–6.99 (m, 1H, aromatic),
7.11–7.13 (m,1H, aromatic), 7.37 (d, 1H, J ¼ 2 Hz, aromatic), 7.50–7.53 (m, 1H, aro-
matic), 7.73–7.79 (m, 1H, aromatic); MS (m=z) 370.9 (M þ H)þ, 392 (M þ Na)þ; %
purity by HPLC 96.68, ret. time 18.01 min.
N-(1-Ethyl-2,1-benzisothiazol-3(1H)-one-5-yl)-4-fluoro-benzenesulfona-
mide (9m). Yellow solid. Yield 79%; mp 188–190 ꢀC; IR (KBr) cmꢂ1: 3110 (N-H),
1
=
2925, 1608 (C O), 1458, 1171, 818; H NMR (400 MHz, CDCl3) d (ppm) 1.25 (t, 3H,
J ¼ 7.2 Hz, -CH2-CH3), 3.75 (q, 2H, J ¼ 7.2 Hz, -CH2-CH3), 6.58 (s, 1H, NH, D2O
exchangeable), 7.15–7.20 (m, 3H, aromatic), 7.23–7.30 (m, 1H, aromatic),
7.45–7.50 (m, 1H, aromatic), 7.60–7.65 (m, 2H, aromatic); MS (m=z) 317.1 (M þ H)þ
339.9 (M þ Na)þ; % purity by HPLC 84.20. Ret. time 12.7 min.
N-(1-Ethyl-2,1-benzisothiazol-3(1H)-one-5-yl)-2,4,6-trimethylbenznamide
(9n). Yellow solid. Yield 65%; mp 141–143 ꢀC; IR (KBr) cmꢂ1: 3420 (N-H), 2970,
1
=
1601 (C O), 1458, 1159, 870; H NMR (400 MHz, CDCl3) d (ppm) 1.32 (t, 3H,
J ¼ 7.2 Hz, -CH2-CH3-), 1.58 (s. 9H, 3 ꢁ CH3), 3.75 (q, 2H, J ¼ 7.2 Hz, -CH2-CH3),
6.35 (s, 1H, NH, D2O exchangeable), 7.02 (s, 2H, aromatic), 7.11–7.20 (m, 1H, aro-
matic), 7.27 (d, 1H, J ¼ 2.4, aromatic), 7.49–7.55 (m, 1H, aromatic); MS m=z 340.1
(M þ H)þ, % purity by HPLC 91.11. Ret. time 14.06 min.
ACKNOWLEDGMENT
We are thankful to the Zydus management and analytical department for the
support.

1,5-DISUBSTITUTED 2,1-BENZISOTHIAZOL-3(1H)-ONES
3279
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