A practical synthesis of N-substituted 1,2-benzisothiazolin-3-ones from N,N′-disubstituted 2,2′-dithiodibenzamides

Article abstract of DOI:10.1055/s-2004-829101

A variety of N-substituted 1,2-benzisothiazolin-3-ones were easily synthesized from N,N′-disubstituted 2,2′-dithiodibenzamides in the presence of O-methylhydroxylamine hydrochloride. Derivatives with a primary, secondary, or tertiary alkyl group or an aryl group on the N-1 nitrogen of the 1,2-benzisothiazolin-3-one were obtained.

Full text of DOI:10.1055/s-2004-829101

PAPER
1585
A Practical Synthesis of N-Substituted 1,2-Benzisothiazolin-3-ones from
N,N¢-Disubstituted 2,2¢-Dithiodibenzamides
Synthesis of
N-
o
Substituted 1
m
, 2-Benzisothiazolin
o
-3-one
s
humi Sano, Toshiyuki Takagi, Yasuo Gama, Isao Shibuya, Masao Shimizu*
National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565,
Japan
Fax +81(29)8614487; E-mail: m.shimizu@aist.go.jp
Received 16 December 2003; revised 14 April 2004
sized by reacting N,N¢-disubstituted 2,2¢-dithiodibenz-
Abstract: A variety of N-substituted 1,2-benzisothiazolin-3-ones
amides with O-methylhydroxylamine hydrochloride.
were easily synthesized from N,N¢-disubstituted 2,2¢-dithiodibenz-
amides in the presence of O-methylhydroxylamine hydrochloride.
We examined the reaction of N,N¢-bis(2-phenylethyl)-
Derivatives with a primary, secondary, or tertiary alkyl group or an
aryl group on the N-1 nitrogen of the 1,2-benzisothiazolin-3-one
were obtained.
2,2¢-dithiodibenzamide (1a) with O-methylhydroxyl-
amine hydrochloride (4 equiv) in the presence of pyridine
(8 equiv) under reflux in propionitrile. After 3 hours, the
Key words: benzisothiazoles, disulfides, amides, hydroxylamines,
oximes
reaction mixture was purified to give 2-(2-phenylethyl)-
1,2-benzisothiazolin-3-one (2a) in 95% yield10 (Table 1,
entry 1). When acetonitrile was used as a solvent, the yield
of 2a lowered to 79% (entry 2). The reaction was carried
out for various N,N¢-disubstituted 2,2¢-dithiodibenz-
The synthesis of 1,2-benzisothiazolin-3-ones and their de-
rivatives is of widespread interest owing to their effective
antifungal, antibacterial, and antipsychotic properties.1 In
general, 1,2-benzisothiazolin-3-ones are synthesized by
reacting the appropriate amines with arylsulfenyl chlo-
rides that have been previously prepared by reacting
dithiosalicylic acids or their esters with chlorine gas.1a
However, chlorine is hazardous and poisonous, and its use
in the laboratory is sometimes restricted to prevent acci-
dents. Thus, the chlorine gas-free synthesis of 1,2-benz-
isothiazolin-3-ones has emerged.2 Recently, we
demonstrated that 1,2-benzisothiazolin-3-ones can be
conveniently synthesized by S-amination of thiosalicy-
lates with hydroxylamine-O-sulfonic acid (HOSA) fol-
lowed by treatment with base.3 N,N¢-Disubstituted 2,2¢-
dithiodibenzamides have also been used as starting mate-
rials for N-substituted 1,2-benzisothiazolin-3-ones. When
the 2,2¢-dithiodibenzamides were treated with bromine,4,5
iodide,6 or N-bromosuccinimide (NBS),7 the correspond-
ing 1,2-benzisothiazolin-3-ones were obtained. 1,2-Benz-
isothiazolin-3-ones were also prepared from 2,2¢-
dithiodibenzamides in the presence of base or acid,4 but
the yields were low because the produced 2-mercapto-
benzamides was unavoidably oxidized to 2,2¢-dithio-
dibenzamides by atmospheric oxygen.8 While we were
attempting to develop a new method for the synthesis of
1,2-benzisothiazolin-3-ones, we found that the reaction of
2,2¢-dithiodibenzamides with O-methylhydroxylamine
gave 1,2-benzisothiazolin-3-ones in good yield. It was re-
ported that O-alkylhydroxylamines behaved as an aminat-
ing agent.9 In this paper, we report that various N-
substituted 1,2-benzisothiazolin-3-ones can be synthe-
amides 1 and the results are summarized in Table 1. When
the N-substituent of amide 1 was a primary alkyl (entries
1, 3, and 4) or secondary alkyl (entries 5 and 6), the corre-
sponding N-substituted 1,2-benzisothiazolin-3-ones 2
were obtained in excellent yields; good yields were ob-
tained in the case of a tertiary alkyl (entries 7 and 8). N-
Arylamides gave moderate yields of N-arylbenzisothiazo-
Table 1 Synthesis of N-Substituted 1,2-Benzisothiazolin-3-ones 2a
O
O
MeONH2·HCl, Pyridine
EtCN, reflux, 3 h
R
N
N R
H
S
S
)
2
2
1
Entry
1
1
R
2
Yield (%)
1a
1a
1b
1c
1d
1e
1f
PhCH2CH2
PhCH2CH2
Bu
2a
2a
2b
2c
2d
2e
2f
95
79
97
91
87
93
80
67
72
63
63
2b
3
4
HOCH2CH2CH2
i-Pr
5
6
c-C3H7
7
tert-Bu
8
1g
1h
1i
PhMe2C
p-MeC6H4
p-MeOC6H4
MeO2CCH2
2g
2h
2i
9
10c
11
1j
2j
a 2,2¢-Dithiodibenzamide: 0.5 mmol; O-methylhydroxylamine hydro-
chloride: 2 mmol; pyridine: 4 mmol; propionitrile: 5 mL.
b In MeCN as solvent.
SYNTHESIS 2004, No. 10, pp 1585–1588
Advanced online publication: 16.06.2004
DOI: 10.1055/s-2004-829101; Art ID: F12703SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
4
c Pyridine: 12.5 mmol.

1586
T. Sano et al.
PAPER
lin-3-ones 2 (entries 9 and 10). A 1,2-benzisothiazolin-3- the formed thiosalicylamides are oxidized to the 2,2¢-
one 1j derived from glycine methyl ester was also synthe- dithiodibenzamides, which, in turn, continue to dispropor-
sized (entry 11).
tionate.8 Since O-methylhydroxylamine existed in the re-
action mixture in our method, the sulfur atoms of the 2-
mercaptobenzamides 3 were aminated to give sulfen-
amide derivatives 4. As we previously reported, 2-sulfen-
amoylbenzamides easily cyclize to 1,2-benzisothiazolin-
3-ones.11 Consequently, 1,2-benzisothiazolin-3-ones 2
were obtained in good yields from 2,2¢-dithiodibenz-
amides (Scheme 1).
Next, the effect of additives in acetonitrile was investigat-
ed, and the results are listed in Table 2. When hydroxyl-
amine hydrochloride was used instead of O-
methylhydroxylamine hydrochloride, the yield of 2a was
only 14% due to low solubility of the additive (entry 2).
O-Benzylhydroxylamine hydrochloride gave 2a in 67%,
with benzyl alcohol as a by-product (entry 3). Triethyl-
amine was an ineffective base in this reaction (entry 4). In conclusion, the present synthesis of N-substituted 1,2-
Because oximes hydrolyze to carbonyl compounds and benzisothiazolin-3-ones has the following advantages: (1)
hydroxylamines, oxime additives were also evaluated (en- good to excellent yields are obtained; (2) the synthesis can
tries 5 and 6). The oximes have good solubility in the sol- be performed with a wide variety of substrate amides (the
vent, and the yields of 2a improved in comparison with N-substituent group can be a primary, secondary, or tertia-
the result of entry 2.
ry alkyl group or an aryl group); and (3) reactions are car-
ried out under halogen-free reaction conditions.
Table 2 Effect of Additives in the Synthesis of 2-(2-Phenylethyl)-
1,2-benzisothiazolin-3-one (2a)a
Melting points were determined on a Mettler FP90 microscopic
plate and are uncorrected. IR spectra were recorded on a JASCO
FTIR–5300 spectrophotometer. 1H and 13C NMR spectra were ob-
tained with a JEOL LA-500 spectrometer, and chemical shifts (d)
are reported in ppm relative to internal tetramethylsilane (1H NMR)
or CDCl3 (13C NMR). Mass spectra were obtained with a Shimadzu
QP-5000 mass spectrometer. N,N¢-Disubstituted 2,2¢-dithiodibenz-
amides 1 were prepared from 2,2¢-dithiodibenzoyl chloride and ap-
propriate amines.
O
O
Ph
Ph
additive
reflux, 3 h
N
N
H
S
S
)
2
2a
1a
Entry
Additive
Yield (%)
1
2
3
4
5
6c
MeONH2·HCl, pyridine
HONH2·HCl, pyridine
PhCH2ONH2·HCl, pyridine
MeONH2·HCl, Et3N
Me2C=NOH
79
14
67b
5
2-(2-Phenylethyl)-1,2-benzisothiazolin-3-one (2a); Typical Pro-
cedure
A mixture of N,N¢-bis(2-phenylethyl)-2,2¢-dithiodibenzamide (1a;
255 mg, 0.5 mmol), O-methylhydroxylamine hydrochloride (167
mg, 2.0 mmol), and pyridine (316 mg, 4.0 mmol) in propionitrile (5
mL) was stirred for 3 h under reflux. The reaction mixture was con-
centrated in vacuo. The crude product was purified by column chro-
matography on silica gel with EtOAc–hexane (1:1) as an eluent to
yield N-(2-phenylethyl)-1,2-benzisothiazolin-3-one (2a);11 yield:
242 mg (95%); white crystals; mp 92.5–93.5 °C (hexane) (Lit.11 mp
92.5–93.5 °C).
59
62
EtMeC=NOH
a Entries 1–4: 1a: 0.5 mmol; hydroxylamine hydrochloride: 2 mmol;
pyridine: 4 mmol; MeCN: 5 mL. Entries 5 and 6: 1a: 0.5 mmol;
oxime: 4 mmol; solvent: 5 mL.
IR (KBr): 1645 (C=O), 1449, 1341, 1252, 1184, 735 cm–1.
b Benzyl alcohol was obtained as a by-product.
c In propionitrile as solvent.
1H NMR (500 MHz, CDCl3): d = 3.07 (t, 2 H, J = 7.5 Hz), 4.13 (t,
2 H, J = 7.5 Hz), 7.22–7.26 (m, 3 H), 7.29–7.32 (m, 2 H), 7.39 (ddd,
1 H, J = 7.9, 7.6, 0.9 Hz), 7.51 (d, 1 H, J = 8.2 Hz), 7.59 (ddd, 1 H,
J = 8.2, 7.6, 1.2 Hz), 8.03 (d, 1 H, J = 7.9 Hz).
The mechanism for the formation of 1,2-benzisothiazolin-
3-ones in these reactions is not certain. However, Ranga-
nathan et al. reported that 2,2¢-dithiodibenzamide deriva-
tives disproportionate to 1,2-benzisothiazolin-3-ones and
2-mercaptobenzamides in the presence of acid, and that
MS: m/z (%) = 255 (M+), 164, 151 (100), 136, 108, 91.
2-Butyl-1,2-benzisothiazolin-3-one (2b)
Colorless oil.12
O
O
N R
NHR
NHR
S
2
S
S
+
S
NH2
SH
H2N OMe
2
NHR
NHR
O
O
O
1
3
4
Scheme 1 A plausible mechanism for the formation of 1,2-benzisothiazolin-3-ones
Synthesis 2004, No. 10, 1585–1588 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Substituted 1,2-Benzisothiazolin-3-ones
1587
IR (neat): 2959, 2930, 1659 (C=O), 1447, 1339, 741, 673 cm–1.
2-(p-Methylphenyl)-1,2-benzisothiazolin-3-one (2h)
White crystals; mp 136.7–137.1 °C (benzene–hexane) (Lit.13 mp
136.7–137.1 °C).
1H NMR (500 MHz, CDCl3): d = 0.94 (t, 3 H, J = 7.3 Hz), 1.39
(sext, 2 H, J = 7.3 Hz), 1.73 (quint, 2 H, J = 7.3 Hz), 3.88 (t, 2 H,
J = 7.3 Hz), 7.38 (ddd, 1 H, J = 7.7, 7.0, 0.9 Hz), 7.53 (dd, 1 H,
J = 7.9, 0.9 Hz), 7.58 (ddd, 1 H, J = 7.9, 7.0, 1.3 Hz), 8.01 (dd, 1 H,
J = 7.7, 1.3 Hz).
13C NMR (125 MHz, CDCl3): d = 13.6, 19.8, 31.6, 43.7, 120.3,
124.9, 235.4, 126.6, 131.6, 140.1, 165.3.
IR (KBr): 1642 (C=O), 1505, 1447, 1331, 1127, 750 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.39 (s, 3 H), 7.28 (d, 2 H, J = 8.2
Hz), 7.45 (ddd, 1 H, J = 8.0, 6.9, 1.1 Hz), 7.55–7.60 (m, 3 H), 7.66
(ddd, 1 H, J = 8.0, 6.9, 1.1 Hz), 8.11 (dt, 1 H, J = 8.0, 1.1 Hz).
MS: m/z (%) = 241 (M+, 100), 226, 208, 198, 136, 120, 108, 91, 69.
MS: m/z (%) = 207 (M+), 190, 164, 151 (100), 136, 108.
2-(p-Methoxyphenyl)-1,2-benzisothiazolin-3-one (2i)
2-(3-Hydroxypropyl)-1,2-benzisothiazoline-3-one (2c)
Chromatography on silica gel with CH2Cl2–acetone–MeOH
(100:20:4) mixture as eluent; white crystals; mp 76.6–77.4 °C
(EtOAc) (Lit.13 mp 76.6–77.4 °C).
White crystals; mp 147–148 °C (EtOH) (Lit.13 mp 147–148 °C).
IR (KBr): 1659 (C=O), 1507, 1443, 1242, 1019, 839, 749 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.84 (s, 3 H), 6.98 (d, 2 H, J = 9.2
Hz), 7.44 (td, 1 H, J = 7.6, 1.2 Hz), 7.54 (d, 2 H, J = 9.2 Hz), 7.57
(d, 1 H, J = 8.3 Hz), 7.65 (ddd, 1 H, J = 8.3, 7.6, 1.1 Hz), 8.09 (dd,
1 H, J = 7.6, 1.1 Hz).
IR (KBr): 3364, 2944, 1632 (C=O), 1445, 1350, 1192, 1065, 937,
743 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.92 (tt, 2 H, J = 6.2, 5.6 Hz), 3.58
(t, 2 H, J = 5.6 Hz), 3.65 (br s, 1 H), 4.08 (t, 2 H, J = 6.2 Hz), 7.44
(ddd, 1 H, J = 8.0, 7.0, 1.1 Hz), 7.58 (dt, 1 H, J = 8.0, 1.1 Hz), 7.65
(td, 1 H, J = 7.8, 1.1 Hz), 8.05 (dt, 1 H, J = 7.8, 1.1 Hz).
MS: m/z (%) = 257 (M+, 100), 242, 214, 186, 136, 108, 69.
Methyl (3-Oxo-1,2-benzisothiazol-2-yl)acetate (2j)
Chromatographed with CH2Cl2–acetone–MeOH (100:5:1) mixture
as an eluent; white crystals; mp 92.2–93.2 °C (EtOAc–hexane).
MS: m/z (%) = 209 (M+), 166, 165, 151, 136 (100), 108, 82, 69.
IR (KBr): 2980, 2361, 1742 (C=O), 1667 (C=O), 1449, 1431, 1399,
1370, 1345, 1290, 1223, 1069, 970, 747 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.79 (s, 3 H), 4.63 (s, 2 H), 7.42
(td, 1 H, J = 7.0, 0.9 Hz), 7.57 (d, 1 H, J = 7.9 Hz), 7.64 (ddd, 1 H,
J = 8.2, 7.0, 1.2 Hz), 8.06 (dd, 1 H, J = 7.9, 0.9 Hz).
13C NMR (125 MHz, CDCl3): d = 44.5, 52.7, 120.4, 123.4, 125.7,
127.0, 132.3, 140.9, 165.8, 168.2.
2-Isopropyl-1,2-benzisothiazolin-3-one (2d)
Colorless oil.14
IR (neat): 2973, 1649 (C=O), 1449, 1308, 1155, 741, 675 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.42 (d, 6 H, J = 6.7 Hz), 5.00
(sept, 1 H, J = 6.7 Hz), 7.39 (ddd, 1 H, J = 7.9, 6.7, 1.2 Hz), 7.56 (d,
1 H, J = 7.9 Hz), 7.59 (ddd, 1 H, J = 7.9, 6.7, 1.2 Hz), 8.03 (d, 1 H,
J = 7.9 Hz).
13C NMR (125 MHz, CDCl3): d = 22.2, 46.0, 120.4, 125.3, 125.5,
126.5, 131.5, 140.1, 164.8.
MS: m/z (%) = 223 (M+), 164 (100), 136, 108, 82, 69.
Anal. Calcd for C10H9NO3S: C, 53.80; H, 4.06; N, 6.27. Found: C,
53.96; H, 3.83; N, 6.08.
MS: m/z (%) = 193 (M+), 178, 151 (100), 123, 96, 69.
2-Cyclopropyl-1,2-benzisothiazolin-3-one (2e)
References
Colorless oil.13
(1) (a) Davis, M. Adv. Heterocycl. Chem. 1972, 14, 43.
(b) Pain, D. L.; Peart, B. J.; Wooldridge, K. R. H.
Comprehensive Heterocyclic Chemistry, Vol. 6; Katritzky,
A. R.; Rees, C. W.; Potts, K. T., Eds.; Pergamon: Oxford,
1984, 175.
(2) (a) Kim, W.; Dannaldson, J.; Gates, K. S. Tetrahedron Lett.
1996, 37, 5337. (b) Etsuzan, T.; Kitagawa, S.; Kamioka, C.;
Miki, S. Japan Pat. Appl. JP 20007667, 2000; Chem. Abstr.
2000, 132, 78550. (c) Chiyoda, T.; Iida, K.; Takatori, K.;
Kajiwara, M. Synlett 2000, 1427. (d) Jin, C. K.; Moon, J.-
K.; Lee, W. S.; Nam, K. S. Synlett 2003, 1967.
(3) Shimizu, M.; Kikumoto, H.; Konakahara, T.; Gama, Y.;
Shibuya, I. Heterocycles 1999, 51, 3005.
IR (neat): 1657 (C=O), 1449, 1333, 741, 673 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.05–1.12 (m, 4 H), 3.10–3.17 (m,
1 H), 7.38 (ddd, 1 H, J = 8.0, 6.9, 1.1 Hz), 7.50 (dt, 1 H, J = 8.0, 0.8
Hz), 7.60 (ddd, 1 H, J = 8.0, 6.9, 1.4 Hz), 8.01 (ddd, 1 H, J = 8.0,
1.4, 0.8 Hz).
MS: m/z (%) = 191 (M+), 137, 136 (100), 108, 82, 69.
2-(tert-Butyl)-1,2-benzisothiazolin-3-one (2f)
Chromatographed with CH2Cl2–acetone–MeOH (100:5:1) mixture
as an eluent; colorless oil.11
IR (neat): 1651 (C=O), 1451, 1302, 1206, 741, 675 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.71 (s, 9 H), 7.37(ddd, 1 H,
J = 8.0, 6.9, 1.1 Hz), 7.50 (ddd, 1 H, J = 8.0, 1.1, 0.8 Hz), 7.57 (ddd,
1 H, J = 8.0, 6.9, 1.3 Hz), 7.97 (ddd, 1 H, J = 8.0, 1.3, 0.8 Hz).
(4) Reissert, A.; Manns, E. Ber. Dtsch. Chem. Ges. 1928, 61,
1308.
(5) (a) Bartlett, R. G.; McClelland, E. W. J. Chem. Soc. 1934,
818. (b) Kamigata, N.; Hashimoto, S.; Kobayashi, M.;
Nakanishi, H. Bull. Chem. Soc. Jpn. 1985, 58, 3131.
(c) Okachi, R.; Niino, H.; Kitaura, K.; Mineura, K.;
Nakamizo, Y.; Murayama, Y.; Ono, T.; Nakamizo, A. J.
Med. Chem. 1985, 28, 1772. (d) Loo, J. A.; Holler, T. P.;
Sanchez, J.; Gogliotti, R.; Maloney, L.; Reily, M. D. J. Med.
Chem. 1996, 39, 4313.
MS: m/z (%) = 207 (M+), 152, 151 (100), 123, 108, 96.
2-(2-Phenyl-2-propyl)-1,2-benzisothiazolin-3-one (2g)
Chromatographed with CH2Cl2 as an eluent; white crystals; mp
131–132 °C (EtOAc–hexane) (Lit.11 mp 131–132 °C).
IR (KBr): 1638 (C=O), 1445, 1327, 1179, 745, 698 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.06 (s, 6 H), 7.29–7.43 (m, 6 H),
7.48 (ddd, 1 H, J = 8.0, 1.1, 0.8 Hz), 7.58 (ddd, 1 H, J = 8.0, 7.1, 1.1
Hz), 7.92 (ddd, 1 H, J = 8.0, 1.3, 0.8 Hz).
(6) Katz, L.; Schroeder, W. J. Org. Chem. 1954, 19, 103.
(7) Turpin, J. A.; Song, Y.; Inman, J. K.; Huang, M.; Wallqvist,
A.; Maynard, A.; Covell, D. G.; Rice, W. G.; Appella, E. J.
Med. Chem. 1999, 42, 67.
(8) Ranganathan, S.; Muraleedharan, K. M.; Bharadwaj, P.;
Chatterji, D.; Karle, I. Tetrahedron 2002, 58, 2861.
MS: m/z (%) = 269 (M+), 151 (100), 119, 118, 103, 91, 77.
Synthesis 2004, No. 10, 1585–1588 © Thieme Stuttgart · New York

1588
T. Sano et al.
PAPER
(9) (a) Seko, S.; Kawamura, N. J. Org. Chem. 1996, 61, 442.
(b) Seko, S.; Miyake, K.; Kawamura, N. J. Chem. Soc.,
Perkin Trans. 1 1999, 1437.
(10) The stoichiometry of the reaction means that 100% yield
corresponds to 2 equiv of 2 produced for 1 equiv of 1.
(11) Shimizu, M.; Takeda, A.; Fukazawa, H.; Abe, Y.; Shibuya,
I. Heterocycles 2003, 60, 1855.
(12) Vitali, T.; Amoretti, L.; Plazzi, V. Farmaco 1968, 23, 1075;
Chem. Abstr. 1969, 70, 37701.
(13) Shimizu, M.; Sugano, Y.; Konakahara, T.; Gama, Y.;
Shibuya, I. Tetrahedron 2002, 58, 3779.
(14) Uchida, Y.; Kozuka, S. Bull. Chem. Soc. Jpn. 1982, 55,
1183.
Synthesis 2004, No. 10, 1585–1588 © Thieme Stuttgart · New York