Synthesis of 1,2-benzisothiazolin-3-ones by ring transformation of 1,3-benzoxathiin-4-one 1-oxides

Article abstract of DOI:10.1016/j.tet.2012.03.094

1,2-Benzisothiazolin-3-ones were synthesized from 1,3-benzoxathiin-4-one 1-oxides by means of a nonhazardous and inexpensive method. The 1,3-benzoxathiin-4-one 1-oxides were prepared by oxidation of 1,3-benzoxathiin-4-ones with hydrogen peroxide in the presence of a catalyst. Attack of amines on the carbonyl groups of the 1,3-benzoxathiin-4-one 1-oxides and subsequent elimination of carbonyl compounds likely produced sulfenic acids, which then underwent ring closure to afford the 1,2-benzisothiazolin-3-ones.

Full text of DOI:10.1016/j.tet.2012.03.094

Tetrahedron 68 (2012) 3932e3936
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Synthesis of 1,2-benzisothiazolin-3-ones by ring transformation of
1,3-benzoxathiin-4-one 1-oxides
,
b
b
a
b
Masao Shimizu a , Teruaki Shimazaki , Tetsuya Yoshida , Wataru Ando , Takeo Konakahara
*
a National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan
b Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
1,2-Benzisothiazolin-3-ones were synthesized from 1,3-benzoxathiin-4-one 1-oxides by means of a non-
hazardous and inexpensive method. The 1,3-benzoxathiin-4-one 1-oxides were prepared by oxidation of 1,3-
benzoxathiin-4-ones with hydrogen peroxide in the presence of a catalyst. Attack of amines on the carbonyl
groups of the 1,3-benzoxathiin-4-one 1-oxides and subsequent elimination of carbonyl compounds likely
produced sulfenic acids, which then underwent ring closure to afford the 1,2-benzisothiazolin-3-ones.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 20 February 2012
Received in revised form 22 March 2012
Accepted 24 March 2012
Available online 29 March 2012
Keywords:
Heterocycles
1,2-Benzisothiazolin-3-one
Sulfoxide
Sulfenic acid
Hydrogen peroxide
1. Introduction
Meanwhile, 1,3-benzoxathiin-4-ones can be regarded as O,S-ace-
tals and can be easily synthesized by reactions of thiosalicylic acids
1,2-Benzisothiazolin-3-one and its derivatives show fungistatic,
antimicrobial, and antipsychotic activities;1 for example, 1,2-
benzisothiazolin-3-one and 2-butyl-1,2-benzisothiazolin-3-one are
well-known industrial biocides. Compounds with nitrogenesulfur
bonds are generally synthesized by reactions of amines with sulfenyl
chlorides prepared from thiols or disulfides and chlorine gas;2 and
1,2-benzisothiazolin-3-ones have also been synthesized by the re-
action of dithiodibenzoic acids3 or their esters4 with chlorine gas in
the same manner. Because there is a trend toward minimizing the
use of hazardous reagents in synthetic chemistry, a chlorine gas-free
method for the synthesis of 1,2-benzisothiazolin-3-ones is desirable.
We previously reported a convenient, chlorine gas-free synthesis
of 1,2-benzisothiazolin-3-ones by cyclization of 2-sulfenamoyl-
benzoates, which are easily prepared by S-amination of thio-
salicylates with hydroxylamine-O-sulfonic acid.5 In addition, various
syntheses of 1,2-benzisothiazolin-3-one derivatives have been
reported in the last decade, including reactions of thiosalicylamides
with hypervalent iodine reagents6 or O-methylhydroxylamine,7 re-
action of thiosalicylic acid with diphenylphospholyl azide,8 and re-
actionsof 2,20-dithiodibenzoates withacetamideor ureafollowed by
oxidation with hydrogen peroxide.9
with carbonyl compounds or their acetals in the presence of acids.10,11
However, the reactivity of 1,3-benzoxathiin-4-ones has not yet been
extensively studied. Reactions with nucleophiles11,12 and oxi-
dants11,13,14 to afford ring-opened products and sulfoxides, re-
spectively, have been reported. Although most of these reactions are
not particularly useful for synthetic chemistry, Krische reported an
interesting ring transformation of 8-carbamoyl-substituted
1,3-benzoxathiin-4-one 1-oxides to 7-carboxy-substituted 1,2-
benzisothiazolin-3-ones but did not discuss the precise reaction
mechanism.13b
Because 1,3-benzoxathiin-4-ones react with primary amines at
the carbonyl groups to give ring-opened products (thiosalicylamide
derivatives12), we expected that 1,3-benzoxathiin-4-one 1-oxides
would undergo similar reactions to form the corresponding sulfe-
nobenzamides. Sulfeno group formation is known for sulfoxides
with active protons at the b
-positions.15,16 We expected the resulting
2-sulfenobenzamides to cyclize easily to 1,2-benzisothiazolin-3-
ones, as reported previously.15,17 In this paper, we report the re-
actions of 1,3-benzoxathiin-4-one 1-oxides with primary amines
and the use of the reactions for the synthesis of 1,2-benzisothiazolin-
3-ones (Scheme 1).
2. Results and discussion
First we prepared 1,3-benzoxathiin-4-one 1-oxides
2 by
* Corresponding author. Tel.: þ81 29 861 6266; fax: þ81 29 861 4511; e-mail
address: m.shimizu@aist.go.jp (M. Shimizu).
oxidation of 1,3-benzoxathiin-4-ones with 1.5 equiv of
1
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.094

M. Shimizu et al. / Tetrahedron 68 (2012) 3932e3936
3933
acid or phosphomolybdic acid, accelerated the oxidation, affording
the sulfoxide product in a good yield after only 1 h. Interestingly,
when the solvent was changed to a mixture of acetic acid and
formic acid, the yield improved to 90% even in the absence of
a catalyst (entry 2). Methyltrioxorhenium(VII) also effectively cat-
alyzed the oxidation, and the sulfoxides were obtained in excellent
yields (entries 6e8). In summary, the use of an oxidative catalyst or
formic acid as a solvent allowed us to oxidize 1,3-benzoxathiin-4-
ones rapidly in good yields.
Next, we investigated the reactions of 1,3-benzoxathiin-4-one
1-oxides 2 with primary amines in various solvents (Table 3).
(Note that the reactions were carried out on the mixtures of the 2-
monosubstituted 1,3-benzoxathiin-4-one 1-oxide diastereomers.)
When 2c was treated with benzylamine in toluene for 2 h at 50 ꢀC, 2-
benzyl-1,2-benzisothiazolin-3-one (3a) was isolated in 91% yield;
the identity of the product was confirmed by comparison of its
spectral data with spectral data20 for 3a prepared by a literature
method. No reaction intermediates were observed. The ring trans-
formations also proceeded in good yields in all the other solvents,
except alcohols. Reaction of the 1,3-benzoxathiin-4-one 1-oxides
with various amines in toluene afforded the desired 1,2-
benzisothiazolin-3-ones (Table 4). No steric effects were observed
in the reactions between benzylamine and the 2-substituted ben-
zoxathiin-4-ones (entries 1e3, 17, 18). However, the yields of re-
actionwith anilines or sterically hindered amines were low, and high
reaction temperatures were required to improve the yields of 3.
O
O
S
O
S
R1NH2
NHR1
O
N
R1
R2
R3
S
O
OH
2
3
Scheme 1. Proposed strategy for the synthesis of 1,2-benzisothiazolin-3-ones 3.
m-chloroperoxybenzoic acid (mCPBA) according to literature
methods11,13 (Table 1). Oxidation of 2-monosubstituted 1,3-
benzoxathiin-4-ones afforded two products after isolation by
means of silica gel column chromatography (entries 2e6); the two
products were deduced to be diastereomers with referring to lit-
erature.14 Note that although mCPBA oxidation of 1f has been
reported to afford trans-2f with high stereoselectivity,14 we
obtained 2f as a 1.43:1 mixture of two diastereomers (entry 6).
Table 1
Oxidation of 1,3-benzoxathiin-4-ones 1 with mCPBAa
O
O
O
O
mCPBA
CH2Cl2, rt
R1
R2
R1
R3
S
R3
S
R2
O
1
2
Table 3
Entry
1
R1
R2
R3
Time
Product Yield (%) Ratio of isomers
Effect of solvent on the synthesis of 1,2-benzisothiazolin-3-one 3aa
1
2
3
4
5
6
1a Me Me
H
H
H
2 h
2 h
2 h
2a
2b
2c
2d
91
30
80
79
82
88
d
O
O
1b
H
H
H
H
H
H
d
1c Et
1d Et
1e i-Pr
1f Ph
1.27:1
1.07:1
1.32:1
1.43:1
MeO 3 h
H
H
O
PhCH2NH2
solvent
N CH2Ph
40 min 2e
2 h 2f
S
S
Et
a
Compound 1 (2 mmol); 3 mmol mCPBA; 20 mL CH2Cl2.
3a
2c
O
mCPBA is expensive, and oxidation reactions with mCPBA afford
Entry
Solvent
Temp (ꢀC)
Time (h)
Yield (%)
m-chlorobenzoic acid as a waste product, while hydrogen peroxide
is a superior oxidation reagent because water is the only theoretical
product18 after oxidation. Therefore, oxidation with hydrogen
peroxide is regarded as environmentally benign and economi-
cal.18,19 However, it was reported that the oxidation of 1,3-
benzoxathiin-4-one proceeds with mCPBA or NaIO4,13b but the
other standard oxidants11 do not afford oxidation products. Con-
sidering these points, we next investigated the oxidation of 1,3-
benzoxathiin-4-ones with hydrogen peroxide (Table 2). First, we
oxidized 1,3-benzoxathiin-4-one with hydrogen peroxide in acetic
acid according to the literature procedure,13b but none of the de-
sired sulfoxide product was obtained even after 6 h (entry 1).
However, the addition of an oxidative or acidic catalyst activated
the hydrogen peroxide. For example, in the presence of sodium
tungstate, 1a was oxidized to 2a in 72% yield after 6 h (entry 3). A
heteropoly acid, such as commercially available phosphotungstic
1
2
3
4
5
6
7
Toluene
CH2Cl2
MeCN
Cyclopentyl methyl ether
THF
50
Reflux
50
50
50
2
4
2.5
3
2
91
89
80
90
96
5
MeOH
EtOH
50
50
0.5
1.5
43
a
Compound 2c (1 mmol); 3 mmol benzylamine; 10 mL solvent.
We propose the reaction mechanism outlined in Scheme 2 for
the formation of compounds 3. 1,3-Benzoxathiin-4-ones 1 can be
regarded as O,S-acetals formed by reaction of carbonyl compounds
with thiosalicylic acid. In the same manner, 1,3-benzoxathiin-4-one
1-oxides can be regarded as O,S-acetals formed by reaction of car-
bonyl compounds with 2-hydrosulfinobenzoic acid, which is
a tautomer of 2-sulfenobenzoic acid.21 Attack of an amine on the
carbonyl group of a 1,3-benzoxathiin-4-one resulted in elimination
of the carbonyl compound and production of a thiol com-
pound.11,12b We propose that similar ring-opening reactions of 1,3-
benzoxathiin-4-one 1-oxides resulted in the formation of 2-
carbonylbenzenesulfenic acids by elimination of carbonyl com-
pounds. An eliminated carbonyl compound, benzaldehyde, was in
fact isolated in 63% yield from the reaction of 2f with butylamine.
The amide nitrogen atoms of the intermediates attacked the sulfur
atoms, and subsequent dehydration resulted in the formation of
the 1,2-benzisothiazolin-3-one. Note that the formation of 2-
sulfenobenzamide intermediates and subsequent formation of
1,2-benzisothiazolin-3-one have been reported previously,15,17 and
these previous reports support our proposed reaction mechanism.
Table 2
Oxidation of 1,3-benzoxathiin-4-ones 1 with hydrogen peroxidea
Entry
1
Catalyst (mol %)
Solvent
Time Product Yield
(h)
(%)
1
2
3
4
5
6
7
8
1a
1a
d
d
AcOH
6
1
6
1
1
4
1
0.5
d
2a
2a
2a
2a
2a
2c
2f
d
AcOH, HCO2Hb
AcOH
90
72
79
82
97
78
91
1a Na2WO4 (1)
1a H3PW12 40$nH2O (2)
1a H3PMo12
1a MeReO3 (4)
1c MeReO3 (4)
1f MeReO3 (4)
O
O
AcOH
40$nH2O (4) AcOH
CH2Cl2
CH2Cl2
CH2Cl2
a
Compound 1 (1 mmol); 1.5 mmol 30% H2O2; 20 mL solvent; rt.
1:1 mixture.
b

3934
M. Shimizu et al. / Tetrahedron 68 (2012) 3932e3936
Table 4
Chromatographic separation of products was performed on silica gel
Synthesis of 1,2-benzisothiazolin-3-ones 3a
60 (Merck, 70e230 mesh). Thin layerchromatography wasperformed
on plates precoated with silica gel 60 (Merck). 1,3-Benzoxathiin-4-
ones 1 were prepared according to literature procedures.10a,11
O
S
O
R4NH2
toluene
O
N
R4
R1
R2
3.1.1. 2,2-Dimethylbenzo[d]-1,3-oxathiin-4-one (1a).11 Bp 157 ꢀC
(1.1ꢁ102 Pa); nmax (liquid film) 1724, 1593, 1441, 1287, 1247, 1172,
R3
R3
S
1093, 1051, 960, 744 cmꢂ1
; dH (500 MHz, CDCl3) 1.84 (6H, s), 7.28
3
2
O
(1H, d, J 7.3 Hz), 7.29 (1H, d, J 7.3 Hz), 7.49 (1H, d, J 7.3 Hz), 8.18 (1H,
d, J 7.3 Hz); dC (125 MHz, CDCl3) 29.1, 86.2, 123.5, 126.3, 127.9, 132.1,
133.9, 136.9, 163.5.
Entry
2
R1
R2
R3
R4
Temp
(ꢀC)
Time Product Yield
(h)
(%)
1
2
3
4
5
6
7
8
2a Me Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
PhCH2
PhCH2
PhCH2
PhCH2CH2
Bu
HO(CH2)2
HO(CH2)3
Cyclohexyl
p-MeOC6H4 Reflux
p-MeC6H4
Ph
50
50
50
50
50
50
50
Reflux
6
5
2
2
3
3
2
2
4
6
7
8
7
6
6
3
6
3
3
3a
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
84
3.1.2. Benzo[d]-1,3-oxathiin-4-one (1b).11 Bp 175 ꢀC (1.3ꢁ102 Pa); dH
(500 MHz, CDCl3) 5.43 (2H, s), 7.34 (2H, t, J 7.3 Hz), 7.36 (1H, d,
J 7.3 Hz), 7.49 (1H, t, J 7.3 Hz), 8.19 (1H, d, J 7.3 Hz); dC (125 MHz,
CDCl3) 68.8, 124.5, 126.9, 127.7, 132.8, 133.5, 138.8, 163.3.
2b
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
92
91
84
89
68
83
70
74
76
75
75
59
45
43
100
82
93
84
2c Et
2c Et
2c Et
2c Et
2c Et
2c Et
2c Et
2c Et
2c Et
2c Et
2c Et
2c Et
2c Et
2d Et
2e i-Pr
2f Ph
2f Ph
3.1.3. 2-Ethylbenzo[d]-1,3-oxathiin-4-one
(1c). Bp
173
ꢀC
(1.7ꢁ102 Pa); [Found: C, 62.25; H, 5.14. C10H10O2S requires C, 61.83;
H, 5.19%]; nmax (liquid film) 2973, 1729, 1593, 1461, 1442, 1296, 1275,
9
10
11
12
13
14
15
16
17
18
19
Reflux
Reflux
Reflux
110b
Reflux
50b
50
50
50
50
1247, 1224, 1125, 1095, 1051, 1032, 973, 942 cmꢂ1
; dH (500 MHz,
p-ClC6H4
Me3C
CDCl3) 1.16 (3H, t, J 7.6 Hz), 2.04e2.21 (2H, m), 5.54 (1H, t, J 6.1 Hz),
7.29e7.34 (2H, m), 7.48 (1H, ddd, J 7.9, 7.3, 1.5 Hz), 8.17 (1H, dd, J 7.9,
1.2 Hz); dC (125 MHz, CDCl3) 9.6, 27.7, 84.3, 124.3, 126.6, 127.7, 132.6,
133.5, 138.5, 164.3.
2-Pyridyl
Hc
3m
3n
3a
3a
3c
MeO PhCH2
H
H
H
PhCH2
PhCH2
Bu
3.1.4. 2-Ethyl-7-methoxybenzo[d]-1,3-oxathiin-4-one (1d). Bp 235 ꢀC
(1.1ꢁ102 Pa); [Found: C, 58.97; H, 5.17. C11H12O3S: C, 58.91; H,
5.39%]: nmax (liquid film) 2973, 1720, 1596, 1488, 1256, 1089, 1043,
a
Compound 2 (1 mmol); 3 mmol amine; 10 mL solvent.
In a sealed tube.
As a 1,4-dioxane solution.
b
c
975, 768 cmꢂ1
;
dH (500 MHz, CDCl3) 1.15 (3H, t, J 7.3 Hz), 2.03e2.19
O
O
R3NH2
O
NHR3
R1
R2
- R1R2C=O
S
S H
1
mCPBA
or
H2O2 / cat.
O
O
O
O
R3NH2
NHR3
NHR3
O
N R3
R1
R2
- R1R2C=O
S
S
H
- H2O
S
S
3
OH
2
O
O
Scheme 2. Mechanism of formation of 1,2-benzisothiazolin-3-ones 3 from 1,3-benzoxathiin-4-ones 1.
In summary, we prepared 1,2-benzisothiazolin-3-ones in good
(2H, m), 3.86 (3H, s), 5.54 (1H, t, J 6.1 Hz), 6.79 (1H, d, J 2.4 Hz),
6.82 (1H, dd, J 8.5, 2.4 Hz), 8.12 (1H, d, J 8.5 Hz); dC (125 MHz,
CDCl3) 9.5, 27.7, 55.7, 89.9, 111.7, 113.4, 116.6, 134.6, 140.7, 163.4,
164.3.
yields by means of reactions of amines with 1,3-benzoxathiin-4-one
1-oxides formed by oxidation of 1,3-benzoxathiin-4-ones with hy-
drogen peroxide. Thus, 1,2-benzisothiazolin-3-ones were synthe-
sized by means of a convenient and environmentally benign method.
3.1.5. 2-Isopropylbenzo[d]-1,3-oxathiin-4-one (1e).10a,22 Bp 171 ꢀC
(1.8ꢁ102 Pa); nmax (liquid film) 2966, 1729, 1442, 1279, 1099, 1033,
3. Experimental section
3.1. General
741 cmꢂ1
; dH (500 MHz, CDCl3) 1.17 (3H, d, J 7.3 Hz), 1.18 (3H, d, J
7.3 Hz), 2.34 (1H, deseptet, J 7.3, 6.1 Hz), 5.43 (1H, d, J 6.1 Hz), 7.30
(1H, t, J 7.3 Hz), 7.35 (1H, d, J 7.3 Hz), 7.47 (1H, t, J 7.3 Hz), 8.17 (1H, d,
J 7.3 Hz); dC (125 MHz, CDCl3) 18.2, 18.4, 32.6, 88.7, 124.3, 126.4,
127.9, 132.5, 133.4, 138.6, 164.4.
Melting points were determined on a Mettler FP90 microscopic
plate and are uncorrected. 1H and 13C NMR spectra were obtained
with a JEOL LA-500 spectrometer, and chemical shifts are given rel-
ative to internal tetramethylsilane (1H NMR) or CDCl3 (13C NMR). IR
spectra were recorded on a JASCO FTIR-4100 spectrophotometer.
3.1.6. 2-Phenylbenzo[d]-1,3-oxathiin-4-one (1f). Mp 90.7e91.6 ꢀC
(hexane) [lit.23 90 ꢀC]; dH (500 MHz, CDCl3) 6.57 (1H, s), 7.34e7.38

M. Shimizu et al. / Tetrahedron 68 (2012) 3932e3936
3935
(2H, m), 7.43e7.45 (3H, m), 7.52 (1H, td, J 7.9, 1.5 Hz), 7.60 (2H, dd, J
7.9, 2.1 Hz), 8.23 (1H, ddd, J 7.9,1.5, 0.6 Hz); dC (125 MHz, CDCl3) 83.7,
124.3,126.8,126.9,127.4,128.8,129.9,132.8,133.8,134.7,138.7,164.0.
(3H, d, J 7.3 Hz), 1.31 (3H, d, J 7.3 Hz), 2.66 (1H, septetedoublet, J 7.3,
2.4 Hz), 5.04 (1H, d, J 2.4 Hz), 7.68 (1H, t, J 7.3 Hz), 7.86 (1H, t, J
7.3 Hz), 7.93 (1H, d, J 7.3 Hz), 8.14 (1H, d, J 7.3 Hz); dC (125 MHz,
CDCl3) 15.8, 18.3, 28.0, 98.7, 121.2, 125.4, 131.3, 132.0, 135.2, 145.6,
161.5.
3.2. General procedure for the synthesis of 1,3-benzoxathiin-
4-one 1-oxides 2 with mCPBA
(Isomer 2): mp 139.3e140.4 ꢀC (AcOEt/hexane); [Found: C,
58.95; H, 5.37. C11H12O3S requires C, 58.91; H, 5.39%]; Rf (CH2Cl2/
AcOEt¼20:1) 0.3; nmax (KBr) 2970, 1738, 1297, 1267, 1242, 1092,
1,3-Benzoxathiin-4-one (1, 2.0 mmol) was dissolved in
dichloromethane (20 mL), and mCPBA (518 mg, 3.0 mmol) was
added. The solution was stirred at room temperature for 40 min to
3 h. Then saturated aqueous sodium sulfite was added until no
peroxide compound was observed with peroxide test paper, and
products were extracted with dichloromethane. The organic layer
was washed with water and dried over magnesium sulfate. Evap-
oration of the solvent with a rotary evaporator afforded the crude
product, which was purified by chromatography on silica gel with
an appropriate eluent.
1053, 1029, 751, 687, 527 cmꢂ1
; dH (500 MHz, CDCl3) 1.30 (3H, d, J
7.3 Hz), 1.33 (3H, d, J 7.3 Hz), 2.65 (1H, doubleteseptet, J 8.5, 7.3 Hz),
4.65 (1H, d, J 8.5 Hz), 7.80e7.87 (3H, m), 8.35 (1H, t, J 4.9 Hz); dC
(125 MHz, CDCl3) 17.9, 18.4, 29.2, 95.4, 123.0, 130.0, 134.2, 134.7,
139.6, 161.8.
3 . 2 . 6 . 2 - P h e nyl b e n z o [ d ] - 1, 3 - o x a t h i i n - 4 - o n e 1 - o x i d e
(2f).13a,14 (Isomer 1): mp 129.9e131.8 ꢀC (AcOEt/hexane) [lit.13a
142 ꢀC, lit.14 130e132 ꢀC]; [Found: C, 65.06; H, 3.75. C14H10O3S re-
quires C, 65.10; H, 3.90%]; Rf (CH2Cl2/AcOEt¼10:1) 0.5; nmax (KBr)
3.2.1. 2,2-Dimethylbenzo[d]-1,3-oxathiin-4-one 1-oxide (2a).11 Rf
(CH2Cl2/AcOEt¼10:1) 0.4; dH (500 MHz, CDCl3) 1.70 (3H, s),1.74 (3H,
s), 7.72 (1H, td, J 7.5, 1.8 Hz), 7.82e7.89 (2H, m), 8.22 (1H, dd, J 7.5,
0.9 Hz); dC (125 MHz, CDCl3) 20.5, 24.6, 94.0, 122.3, 128.6, 131.8,
132.5, 135.2, 140.7, 160.5.
1730, 1589, 1444, 1273, 1246, 1100, 1063, 1014, 746, 700 cmꢂ1
; dH
(500 MHz, CDCl3) 6.03 (1H, s), 7.50e7.52 (3H, m), 7.62e7.64 (2H,
m), 7.73 (1H, t, J 7.3 Hz), 7.90 (1H, t, J 7.3 Hz), 7.96 (1H, d, J 7.3 Hz),
8.21 (1H, d, J 7.3 Hz); dC (125 MHz, CDCl3) 95.6, 121.4, 125.7, 127.6,
129.1, 130.3, 130.9, 131.7, 132.3, 135.5, 145.6, 161.4.
(Isomer 2): mp 143.2e144.2 ꢀC (AcOEt/hexane) [lit.13a 146 ꢀC,
lit.14 134e135 ꢀC]; [Found: C, 65.24; H, 3.71. C14H10O3S requires C,
65.10; H, 3.90%]; Rf (CH2Cl2/AcOEt¼10:1) 0.4; nmax (KBr) 1746, 1589,
1496, 1449, 1279, 1248, 1102, 1050, 792, 774, 751, 699, 526, 475,
3.2.2. Benzo[d]-1,3-oxathiin-4-one 1-oxide (2b).13a Rf (CH2Cl2/ace-
tone/MeOH¼100:10:2) 0.4; dH (500 MHz, CDCl3) 5.31 (1H, d, J
11.0 Hz), 5.41 (1H, d, J 11.0 Hz), 7.79 (1H, td, J 7.3, 2.4 Hz), 7.87 (2H, q,
J 7.3 Hz), 8.29 (1H, d, J 7.3 Hz); dC (125 MHz, CDCl3) 80.3, 122.1,128.0,
132.6, 133.3, 135.1, 142.1, 160.6.
427 cmꢂ1
; dH (500 MHz, CDCl3) 6.15 (1H, s), 7.47e7.54 (3H, m),
7.63e7.65 (2H, m), 7.84e7.90 (3H, m), 8.40e8.43 (1H, m); dC
(125 MHz, CDCl3) 91.0, 122.8, 127.2, 129.2, 130.5, 131.2, 132.8, 134.2,
134.9, 140.5, 161.9.
3.2.3. 2-Ethylbenzo[d]-1,3-oxathiin-4-one 1-oxide (2c). (Isomer 1):
mp 79.7e80.4 ꢀC (AcOEt/hexane); [Found: C, 57.18; H, 4.71.
C10H10O3S requires C, 57.13; H, 4.79%]; Rf (CH2Cl2/AcOEt¼10:1) 0.4;
dH (500 MHz CDCl3) 1.27 (3H, t, J 7.3 Hz), 2.23 (1H, septet, J 7.3 Hz),
2.36 (1H, dqd, J 14.6, 7.3, 3.7 Hz), 5.11 (1H, dd, J 7.3, 3.7 Hz), 7.69 (1H,
t, J 7.3 Hz), 7.86 (1H, t, J 7.3 Hz), 7.92 (1H, d, J 7.3 Hz), 8.15 (1H, d, J
7.3 Hz); dC (125 MHz, CDCl3) 8.7, 23.1, 95.4, 121.3, 125.5, 131.5, 132.1,
135.3, 145.5, 161.4.
3.3. General procedure for the synthesis of 1,3-benzoxathiin-
4-one 1-oxides (2) with hydrogen peroxide
To a solution (20 mL) of 1,3-benzoxathiin-4-one (1, 1.0 mmol)
and catalyst in appropriate solvent, 30% aqueous hydrogen perox-
ide (1.5 mmol) was added dropwise. The solution was stirred at
room temperature for 0.5e6 h. Then saturated sodium sulfite
aqueous solution was added until no peroxide compound was ob-
served with peroxide test paper, and the products were extracted
with dichloromethane. The organic layer was washed with water
and dried over magnesium sulfate. Evaporation of the solvent
afforded the crude product, which was purified by chromatography
on silica gel with an appropriate eluent.
(Isomer 2): mp 87.1e88.1 ꢀC (AcOEt/hexane); [Found: C, 57.28;
H, 4.63. C10H10O3S requires C, 57.13; H, 4.79%]; Rf (CH2Cl2/
AcOEt¼10:1) 0.25; dH (500 MHz, CDCl3) 1.27 (3H, t, J 7.3 Hz), 2.31
(2H, quintet, J 7.3 Hz), 4.99 (1H, t, J 7.3 Hz), 7.81e7.88 (3H, m), 8.36
(1H, d, J 7.3 Hz); dC (125 MHz, CDCl3) 8.9, 23.4, 91.5, 122.9, 130.1,
132.6, 134.1, 134.8, 139.6, 161.5.
3.2.4. 2-Ethyl-7-methoxybenzo[d]-1,3-oxathiin-4-one 1-oxide
(2d). (Isomer 1): mp 123.3e124.1 ꢀC (AcOEt/hexane); [Found: C,
55.01; H, 4.93. C11H12O4S requires C, 54.99; H, 5.03%]; Rf (CH2Cl2/
AcOEt¼10:1) 0.5; dH (500 MHz, CDCl3) 1.27 (3H, t, J 7.3 Hz), 2.23 (1H,
ddq, J 14.6, 8.5, 7.3 Hz), 2.37 (1H, dqd, J 14.6, 7.3, 3.7 Hz), 3.97 (3H, s),
5.09 (1H, dd, J 7.3, 3.7 Hz), 7.10 (1H, dd, J 8.5, 2.4 Hz), 7.36 (1H, d, J
2.4 Hz), 8.07 (1H, d, J 8.5 Hz); dC (125 MHz, CDCl3) 8.6, 23.1, 56.2,
95.2, 109.6, 113.0, 117.8, 134.4, 148.0, 161.4, 165.1.
3.4. General procedure for the synthesis of 1,2-benzisothazolin-
3-ones (3)
1,3-Benzoxathiin-4-one 1-oxide (2, 1.0 mmol) and the appro-
priate amine or aniline (3 mmol) were stirred in toluene (10 mL) at
50e100 ꢀC until 2 was consumed (2e8 h). After the solvent was
removed by evaporation, the products were purified by silica gel
chromatography with an appropriate eluent. In the case of 3m,
a 1,4-dioxane solution of ammonia (0.5 M) was used.
(Isomer 2): mp 111.5e112.2 ꢀC (AcOEt/hexane); [Found: C,
55.06; H, 4.94. C11H12O4S requires C, 54.99; H, 5.03%]; Rf (CH2Cl2/
AcOEt¼10:1) 0.3; dH (500 MHz, CDCl3) 1.25 (3H, t, J 7.3 Hz), 2.28
(2H, ddq, J 14.6, 9.7, 7.3 Hz), 3.97 (3H, s), 4.98 (1H, t, J 7.3 Hz), 7.23
(1H, dd, J 8.5, 2.4 Hz), 7.32 (1H, d, J 2.4 Hz), 8.28 (1H, d, J 8.5 Hz); dC
(125 MHz, CDCl3) 8.9, 23.2, 56.2, 91.3, 114.7, 115.0, 119.2, 134.8, 141.5,
161.4, 164.3.
3.4.1. 2-Benzyl-1,2-benzisothiazolin-3-one (3a). Mp 87.0e87.7 ꢀC
(AcOEt/hexane) [lit.20 85.5e87 ꢀC (i-PrOH)]; Rf (CH2Cl2/
AcOEt¼20:1) 0.4; dH (500 MHz, CDCl3) 5.06 (2H, s), 7.31e7.36 (5H,
m), 7.41 (1H, t, J 7.3 Hz), 7.49 (1H, d, J 7.3 Hz), 7.59 (1H, t, J 7.3 Hz),
8.07 (1H, d, J 7.3 Hz); dC (125 MHz, CDCl3) 47.5, 120.4, 124.5, 125.5,
126.8, 128.3, 128.4, 128.8, 131.8, 136.2, 140.4, 165.3.
3.2.5. 2-Isopropylbenzo[d]-1,3-oxathiin-4-one 1-oxide (2e). (Isomer
1): mp 79.3e80.5 ꢀC (AcOEt/hexane); [Found: C, 58.84; H, 5.37.
C11H12O3S requires C, 58.91; H, 5.39%]; Rf (CH2Cl2/AcOEt¼20:1) 0.5;
nmax (KBr) 2968, 1750, 1590, 1464, 1444, 1271, 1246, 1227, 1053,
3.4.2. 2-(2-Phenylethyl)-1,2-benzisothiazolin-3-one (3b). Mp 92.8e
93.4 ꢀC (hexane) [lit.24 92.5e93.5 ꢀC (hexane)]; Rf (CH2Cl2/
AcOEt¼10:1) 0.67; dH (500 MHz, CDCl3) 3.07 (2H, t, J 7.3 Hz), 4.13
1029, 1008, 975, 746, 698, 680, 532 cmꢂ1
; dH (500 MHz, CDCl3) 1.27

3936
M. Shimizu et al. / Tetrahedron 68 (2012) 3932e3936
(2H, t, J 7.3 Hz), 7.22e7.26 (3H, m), 7.30 (2H, t, J 7.3 Hz), 7.39 (1H, t, J
7.3 Hz), 7.51 (1H, d, J 7.3 Hz), 7.59 (1H, t, J 7.3 Hz), 8.03 (1H, d, J
7.3 Hz); dC (125 MHz, CDCl3) 35.6, 45.4, 120.3, 124.6, 125.4, 126.6,
126.8, 128.7, 128.9, 131.7, 137.7, 140.2, 165.3.
(500 MHz, CDCl3) 1.71 (9H, s), 7.36 (1H, t, J 7.3 Hz), 7.50 (1H, d, J
8.5 Hz), 7.57 (1H, t, J 7.3 Hz), 7.96 (1H, d, J 8.5 Hz).
3.4.12. 2-(2-Pyridyl)-1,2-benzisothiazolin-3-one (3l). Mp 197.4e
197.9 ꢀC (AcOEt/hexane) [lit.25 194.5e195.5 ꢀC (CHCl3)]; Rf
(CH2Cl2/AcOEt¼20:1) 0.67; dH (500 MHz, CDCl3) 7.15 (1H, ddd, J
7.3, 4.9, 0.9 Hz), 7.41 (1H, ddd, J 7.9, 7.0, 0.9 Hz), 7.59 (1H, dt, J 7.9,
0.9 Hz), 7.66 (1H, ddd, J 7.9, 7.3, 1.2 Hz), 7.81 (1H, ddd, J 8.2, 7.3,
1.8 Hz), 8.07 (1H, dt, J 7.9, 0.9 Hz), 8.42 (1H, ddd, J 4.9, 1.8,
0.9 Hz), 8.75 (1H, dt, J 8.2, 0.9 Hz); dC (125 MHz, CDCl3) 114.5,
120.3, 120.7, 125.5, 126.6, 126.8, 132.8, 138.4, 141.0, 147.6, 150.4,
164.0.
3.4.3. 2-Butyl-1,2-benzoisothiazoline-3-one (3c).7 Bp 180 ꢀC
(1.1ꢁ102 Pa); Rf (CH2Cl2/AcOEt¼20:1) 0.4; dH (500 MHz, CDCl3)
0.97 (3H, t, J 7.3 Hz), 1.42 (2H, sextet, J 7.3 Hz), 1.75 (2H, quintet, J
7.3 Hz), 3.90 (2H, t, J 7.3 Hz), 7.40 (1H, t, J 7.3 Hz), 7.55 (1H, d, J
8.5 Hz), 7.60 (1H, t, J 7.3 Hz), 8.04 (1H, d, J 7.3 Hz); dC (125 MHz,
CDCl3) 13.7, 19.8, 31.6, 43.7, 120.3, 124.9, 125.4, 126.7, 131.6, 140.1,
165.3.
3.4.4. 2-(2-Hydroxyethyl)-1,2-benzisothiazolin-3-one (3d). Mp 110.6e
112.0 ꢀC (AcOEt/hexane) [lit.4 112e114 ꢀC (acetone)]; Rf (CH2Cl2/ace-
tone/MeOH¼100:40:8) 0.4; dH (500 MHz, CDCl3) 3.48 (1H, br s), 3.95
(2H, q, J 4.9 Hz), 4.03 (2H, t, J 4.9 Hz), 7.38 (1H, t, J 7.3 Hz), 7.53 (1H, d, J
7.3 Hz), 7.60 (1H, t, J 7.3 Hz), 8.00 (1H, d, J 7.3 Hz); dC (125 MHz, CDCl3)
47.5, 62.0, 120.2, 124.2, 125.6, 126.6, 131.9, 140.7, 166.4.
3.4.13. 1,2-Benzisothiazolin-3-one (3m). Mp 153.3e155.9 ꢀC (AcOEt/
hexane) [lit.5 158 ꢀC (EtOH)]; Rf (CH2Cl2/acetone/MeOH¼100:10:2)
0.3; dH (500 MHz, CDCl3) 7.45 (1H, ddd, J 7.8, 5.0, 3.2 Hz), 7.65e7.66
(2H, m), 8.08 (1H, dt, J 7.8, 1.0 Hz).
3.4.14. 2-Benzyl-6-methoxy-1,2-benzisothiazolin-3-one (3n). Mp
114.4e115.0 ꢀC (AcOEt/hexane); [Found: C, 65.22; H, 4.64;
N, 5.00. C15H13NO2S requires C, 66.40; H, 4.83; N, 5.16%]; Rf
(CH2Cl2/AcOEt¼10:1) 0.4; dH (500 MHz, CDCl3) 3.86 (3H, s), 5.02
(2H, s), 6.90 (1H, d, J 2.1 Hz), 6.96 (1H, dd, J 8.7, 2.1 Hz), 7.30e7.37
(5H, m), 7.95 (1H, d, J 8.7 Hz); dC (125 MHz, CDCl3) 47.5, 55.8,
103.1, 114.6, 117.7, 127.9, 128.2, 128.4, 128.8, 136.4, 142.6, 162.9,
165.2.
3.4.5. 2-(3-Hydroxypropyl)-1,2-benzisothiazolin-3-one (3e). Mp 75.3e
76.6 ꢀC (AcOEt/hexane) [lit.20 76.6e77.4 ꢀC (AcOEt)]; Rf (CH2Cl2/ace-
tone/MeOH¼100:40:8) 0.5; dH (500 MHz, CDCl3) 1.92 (2H, quintet, J
6.1 Hz), 3.57 (2H, q, J 6.1 Hz), 3.62e3.65 (1H, m), 4.08 (2H, t, J 6.1 Hz),
7.44 (1H, t, J 7.3 Hz), 7.58 (1H, d, J 7.3 Hz), 7.64 (1H, d, J 7.3 Hz), 8.05
(1H, d, J 7.3 Hz); dC (125 MHz, CDCl3) 31.9, 40.4, 57.8,120.4,124.1,125.7,
126.8, 132.0, 140.3, 166.4.
References and notes
3.4.6. 2-Cyclohexyl-1,2-benzisothiazolin-3-one
(3f). Mp
87.2e88.0 ꢀC (hexane) [lit.4 86e88 ꢀC (diethylether/hexane)]; Rf
(CH2Cl2/AcOEt¼20:1) 0.4; dH (500 MHz, CDCl3) 1.17e1.27 (1H, m),
1.43e1.60 (4H, m), 1.74 (1H, d, J 12.2 Hz), 1.85e1.90 (2H, m), 2.05
(2H, dd, J 11.6, 3.7 Hz), 4.60 (1H, tt, J 11.6, 3.7 Hz), 7.39 (1H, t, J
7.3 Hz), 7.55e7.60 (2H, m), 8.04 (1H, d, J 7.3 Hz); dC (125 MHz,
CDCl3) 25.2, 25.6, 32.9, 53.2, 120.3, 125.3, 125.5, 126.5, 131.4, 140.3,
164.8.
1. For examples: (a) Pain, D. L.; Peart, B. J.; Wooldridge, K. R. H.; Potts, K. T., Eds.
Comprehensive Heterocyclic Chemistry; Pergamon: Oxford, 1984; Vol. 6, p 175;
(b) Chapman, R. F.; Peart, B. J.; Shinkai, I., Eds. Comprehensive Heterocyclic
Chemistry II; Pergamon: Oxford, 1996; Vol. 3, p 371.
ꢀ
2. (a) Drabowicz, J.; Kie1basinski, P.; Miko1ajczyk, M. In The Chemistry of Sulphenoic
Acids and Their Derivatives; Patai, S., Eds.; John Wiley: Chichester, UK, 1990;
pp 221e292; (b) Craine, L.; Raban, M. Chem. Rev. 1989, 89, 689e712; (c) Davis,
F. A.; Nadir, U. K. Org. Prep. Proced. Int. 1979, 11, 35e51; (d) Kharasch, N.;
Potempa, S. J.; Wehrmeister, H. L. Chem. Rev. 1946, 39, 269e332.
3. McClelland, E. W.; Gait, A. J. J. Chem. Soc. 1926, 921e925.
4. Grivas, J. C. J. Org. Chem. 1975, 40, 2029e2032.
5. Shimizu, M.; Kikumoto, H.; Konakahara, T.; Gama, Y.; Shibuya, I. Heterocycles
1999, 51, 3005e3012.
6. Correa, A.; Tellitu, I.; Domínguez, E.; SanMartin, R. Org. Lett. 2006, 8,
4811e4813.
7. Sano, T.; Takagi, T.; Gama, Y.; Shibuya, I.; Shimizu, M. Synthesis 2004,
1585e1588.
3.4.7. 2-(p-Methoxyphenyl)-1,2-benzisothiazolin-3-one (3g). Mp
146.2e147.5 ꢀC (AcOEt/hexane) [lit.4 147e149 ꢀC (EtOH)]; Rf
(CH2Cl2/hexane¼2:1 on alumina) 0.33; dH (500 MHz, CDCl3) 3.85
(3H, s), 6.99 (2H, dd, J 7.3, 2.4 Hz), 7.45 (1H, t, J 7.3 Hz), 7.54e7.56
(2H, m), 7.58 (1H, d, J 7.3 Hz), 7.66 (1H, t, J 7.3 Hz), 8.10 (1H, d, J
7.3 Hz); dC (125 MHz, CDCl3) 55.6, 114.6, 120.1, 124.6, 125.7, 126.9,
127.2, 129.7, 132.2, 140.0, 158.7, 164.3.
8. Chiyoda, T.; Iida, K.; Takatori, K.; Kajiwara, M. Synlett 2000, 1427e1428.
9. Jin, C. K.; Moon, J.-K.; Lee, W. S.; Nam, K. S. Synlett 2003, 1967e1968.
10. (a) Senning, A.; Lawesson, S.-O. Ark. Kemi 1961, 17, 261e264, 387e391,
489e495; Chem. Abstr. 1963, 59, 6388; (b) Senning, A.; Lawesson, S.-O. Acta
Chem. Scand. 1962, 16, 1175e1182.
3.4.8. 2-(p-Methylphenyl)-1,2-benzisothiazolin-3-one(3h). Mp 136.1e
136.7 ꢀC (AcOEt/hexane) [lit.20 136.7e137.1 ꢀC (benzene/hexane)]; Rf
(CH2Cl2/AcOEt¼20:1) 0.5; dH (500 MHz, CDCl3) 2.40 (3H, s), 7.27 (2H,
d, J 8.2 Hz), 7.44 (1H, ddd, J 8.2, 6.9, 0.9 Hz), 7.55e7.59 (3H, m), 7.66
(1H, ddd, J 8.2, 6.9, 0.9 Hz), 8.10 (1H, dt, J 8.2, 0.9 Hz).
_
11. Siedlecka, R.; Skarzewski, J. Pol. J. Chem. 2000, 74, 1369e1374.
12. (a) Nandi, B.; Kundu, N. G. J. Chem. Soc., Perkin Trans. 1 2001, 1649e1655; (b)
El-Barbary, A. A.; Clausen, K.; Lawesson, S.-O. Tetrahedron 1980, 36, 3309e3315;
(c) Dittmer, D. C.; Whitman, E. S. J. Org. Chem. 1969, 34, 2004e2006.
13. (a) Krische, B.; Walter, W. Chem. Ber. 1983, 116, 1708e1727; (b) Krische, B.;
Walter, W.; Adiwidjaja, G. Chem. Ber. 1982, 115, 3842e3850.
14. Larsen, B. S.; Kolc, J.; Lawesson, S.-O. Tetrahedron 1971, 27, 5163e5176.
15. Sivaramakrishnan, S.; Keerthi, K.; Gates, K. S. J. Am. Chem. Soc. 2005, 127,
10830e10831.
16. Jones, D. N.; Cottam, P. D.; Davies, J. Tetrahedron Lett. 1979, 20, 4977e4980.
17. Kim, W.; Dannaldson, J.; Gates, K. S. Tetrahedron Lett. 1996, 37, 5337e5340.
18. (a) Strukul, G. In Catalytic Oxidations with Hydrogen Peroxide as Oxidant; Kluwer
Academic: Netherland, 1992; (b) Jones, C. W. In Applications of Hydrogen Per-
oxide and Derivatives; Royal Society of Chemistry: Cambridge, 1999.
19. (a) Trost, B. M. Science 1991, 254, 1471e1477; (b) Sheldon, R. A. Chem. Ind. 1992,
903e906.
3.4.9. 2-Phenyl-1,2-benzisothiazolin-3-one (3i). Mp 138.5e140.3 ꢀC
(AcOEt/hexane) [lit.20 138e140 ꢀC (EtOH)]; Rf (CH2Cl2/AcOEt¼20:1)
0.5; dH (500 MHz, CDCl3) 7.33 (1H, t, J 7.3 Hz), 7.44e7.49 (3H, m),
7.59 (1H, d, J 7.3 Hz), 7.67 (1H, t, J 7.3 Hz), 7.71 (2H, d, J 7.3 Hz), 8.11
(1H, d, J 7.3 Hz); dC (125 MHz, CDCl3) 120.1, 124.6,124.8, 125.8, 127.0,
127.2, 129.3, 132.3, 137.2, 139.9, 164.1.
3.4.10. 2-(p-Chlorophenyl)-1,2-benzisothiazolin-3-one(3j). Mp 122.6e
124.0 ꢀC (AcOEt) [lit.4 129e130 ꢀC (EtOH)]; Rf (CH2Cl2) 0.4; dH
(500 MHz, CDCl3) 7.43e7.49 (3H, m), 7.59 (1H, d, J 8.5 Hz), 7.67 (3H, d, J
8.5 Hz), 8.10 (1H, d, J 8.5 Hz); dC (125 MHz, CDCl3) 120.1, 124.6, 125.6,
126.0, 127.3, 129.5, 132.5, 132.6, 135.8, 139.6, 164.1.
20. Shimizu, M.; Sugano, Y.; Konakahara, T.; Gama, Y.; Shibuya, I. Tetrahedron 2002,
58, 3779e3783.
21. For examples: (a) Heckel, A.; Pfleiderer, W. Tetrahedron Lett. 1983, 24,
5047e5050; (b) Shelton, J. R.; Davis, K. E. J. Am. Chem. Soc. 1969, 89, 718e719.
22. Chaminade, X.; Coulombel, L.; Olivero, S.; Dunach, E. Eur. J. Org. Chem. 2006,
3554e3557.
23. Mowry, D. T. J. Am. Chem. 1947, 69, 2362e2363.
24. Shimizu, M.; Takeda, A.; Abe, Y.; Shibuya, I. Heterocycles 2003, 60, 1855e1864.
25. Kamigata, N.; Iizuka, H.; Kobayashi, M. Bull. Chem. Soc. Jpn. 1986, 59,
1601e1602.
3.4.11. 2-tert-Butyl-1,2-benzisothiazolin-3-one (3k).24 Bp 150 ꢀC
(1.8ꢁ102 Pa); Rf (CH2Cl2/acetone/MeOH¼100:5:1) 0.6; dH