An efficient approach to construct benzisothiazol-3(2: H)-ones via copper-catalyzed consecutive reaction of 2-halobenzamides and carbon disulfide

Article abstract of DOI:10.1039/c6ob00819d

An efficient copper-catalyzed reaction for the synthesis of benzisothiazol-3(2H)-ones has been developed, starting from easily available 2-halobenzamides and carbon disulfide, which gave the corresponding target products in 30-89% yield for 25 examples. The reaction proceeds via a consecutive process with S-C bond and S-N bond formation.

Full text of DOI:10.1039/c6ob00819d

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Organic & Biomolecular Chemistry
PAPER
An efficient approach to construct benzisothiazol-3(2H)-ones via
copper-catalyzed consecutive reaction of 2-halobenzamides and
carbon disulfide
Received 00th January 20xx,
Accepted 00th January 20xx
Ting Li, Lei Yang, Kaidong Ni, Zhenyu Shi, Fei Li and Dongyin Chen*
DOI: 10.1039/x0xx00000x
An efficient copper-catalyzed reaction for the synthesis of benzisothiazol-3(2H)-ones has been developed, starting from
the easily available 2-halobenzamides and carbon disulfide, which gave the corresponding target products in 30-89% yield
www.rsc.org/
for 25 examples. The reaction proceeds via
a consecutive process with S−C bond and S−N bond formaꢀon.
3(2H)-ones are summarized. Among these, a classical approach
converged on the successive reactions of halogenation by the
treatment of thionyl chloride and chlorine gas, amidation with
primary amines, and intramolecular cyclization successively,
Introduction
Benzisothiazol-3(2H)-ones are one of the most important
sulfur- and nitrogen-containing heterocycles that are
ubiquitous in medicine, agriculture and food industry.1 Various
benzisothiazol-3(2H)-one derivatives represent a wide range of
biological activities, such as antibacterial2, antipsychotic3,
antivirus4, antithrombotic5 and analgesic6. For example,
Lurasidone and Ziprasidone are well-known atypical
antipsychotic for the treatment of schizophrenia7; 1,2-
Benzisothiazolin-3-one (BIT) and 2-butyl-1,2-benzisothiazolin-
3-one (BBIT) are widely used as biocide or cosmetics
preservative8; Saccharin, an oxidized form of a benzisothiazol-
3(2H)-one, is one of the most common artificial sweeteners9.
(Fig. 1)
starting from 2,2′-dithiosalicylic acids10 and their esters11
.
However, the highly toxic and corrosive reagents restricted its
application in synthetic chemistry. Therefore, various chlorine-
free synthetic methods have been developed, including
reactions of 2-sulfenamoylbenzoates12, 3H-1,2-benzodithiol-3-
one 1-oxide13 or 1,3-benzoxathiin-4-one 1-oxides14 with
various primary amines, reaction of 2-mercaptobenzoic acid
with diphenyl phosphoryl azide (DPPA)15 or hydroxylamine
hydrochloride16
in
one
pot,
reactions
of
2-
mercaptobenzamides
hydroxylamine-O-sulfonic acid12c
with
oxidation
reagents17
or
,
reactions of 2,2’-
dithiodibenzoates with acetamide or urea via one-pot
process18,
amidation-cyclization
dithiodibenzamides
reactions
of
2,2’-
with
O-methylhydroxylamine
hydrochloride (OMAH)19, and intramolecular cyclization of 2-(t-
butyl
sulfoxide)benzamides
or
2-(benzyl
sulfoxide)benzamides20. Recently, several copper-catalyzed
tandem reactions have been applied to synthesis
benzisothiazol-3(2H)-ones, starting from 2-halobenzamides
and sulfur21 (or potassium thiocyanate22) with 1,10-
21
phenanthroline as the ligand and K2CO3
(or 1,4-
diazabicyclo[2.2.2]octane22) as the base. Furthermore, Shi et
al. has reported copper-mediated C−S/N−S bonds formaꢀon
via C−H acꢀvaꢀon to construct benzisothiazol-3(2H)-ones using
N-(2-(pyridin-2-yl)propan-2-yl)benzamides and sulfur in the
presence of tetrabutylammonium iodide (TBAI), Cu(OAc)2 and
Ag2O.23 Although these above reactions provided powerful
access to various substituted benzisothiazol-3(2H)-ones, their
applications are limited due to certain disadvantages, including
the use of highly toxic and corrosive reagents10,11, addition of
excess base21 and strong acid17, difficult-to-prepare starting
materials12-14,18-20, narrow substrate scope15,16, high reaction
temperature22, and complex reaction conditions23. Therefore,
the development of a simple, effective, mild and economic
Fig. 1 Structures of some selected benzisothiazol-3(2H)-one
derivatives.
In view of the great value of benzisothiazol-3(2H)-ones and
their derivatives,
a number of methodologies for their
synthesis have been reported in the last decade.10-23 As shown
in Scheme 1, the main synthetic methods on benzisothiazol-
Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical
University, 101 Longmian Avenue, Nanjing 211166, China.
E-mail: chendongyin321@163.com; Tel: +86-025-86868485.
† Electronic Supplementary Informaꢀon (ESI) available: copies of 1H and 13C NMR
spectra for products. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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method for the preparation of benzisothiazol-3(2H)-ones is still In the absence of CuBr or L-proline, the desired product was
highly desirable.
observed in lower yields (Table 1, entries 10 and 11), and the
result showed significant effect of a suitable catalyst and ligand
to the reaction system. We then investigated various solvent
effects on this transformation in the presence of CuBr and L-
Previous work
O
O
R2
R2
NHR1
SH
OH
O
O
S
R2
SH
R2
o
proline at 80 C, and DMSO proved to be the optimal solvent
OR3
OR3
_
S)2
NHR4
R1 NH2
base
ref 15, 16
(Table 1, compare entries 3 and 12-15). Changed the reaction
temperature did not lead to any further improvements in the
o
yield, and 80 C gave the best result (Table 1, compare entries
R1 NH2
ref 17, 12c
ref 12
ref 10, 11, 18
O
X
O
O
3 and 16-17). In addition, increasing amount of CuBr and L-
proline, and adding a base such as K2CO3, the reactions did not
give higher yields (Table 1, compare entries 3 and 18-20). After
further screening, the optimized reaction condition was
determined that 1a (2.0 mmol) and CS2 (1.1 equiv) were
smoothly converted into benzisothiazol-3(2H)-one (2a) in 77%
yield with CuBr (0.1 equiv) as the catalyst, L-proline (0.2 equiv)
as the ligand, and DMSO as the solvent under an air
atmosphere at 80 oC over 6 h (Table 1, entry 3).
R2
R2
R2
S8 or KSCN
Cu, base
R1 NH2
ref 14
NHR1
O
R1
R3
R4
N
ref 21, 22
S
S
X = Cl, Br, I
O
S8, Cu, Ag2O
R1 NH2
ref 13
TBAI
O
ref 23
OMAH
O
(Cl3CCO)2O
O
ref 19
O
ref 20
R2
S
N
S
R2
H
NHR1
N
O
NHR1
_
S
Ph
S)2
O
Table
1 Investigation of conditions for copper-catalyzed
This work
synthesis of 2a using 1a and CS2 as the substratesa
O
X
O
R2
R2
R1
CuBr, L-proline
DMSO, 80oC
N
C
H
N
R1
+
CS
+
S
S
S
X = I, Br, Cl
Simpler operation
Base-free condition
Lower reaction temperature
Higher reaction rate
Scheme 1 Synthetic Routes to benzisothiazol-3(2H)-ones and
their derivatives.
T
Yield
Carbon disulfide (CS2) is a well-known building block for the
efficient construction of sulfur-containing heterocycles in
synthetic chemistry from the viewpoints of operational
simplicity, economic raw material, and assembly efficiency.24
However, it is of interest to note that CS2 used as a sulfur
source in the reaction involving C-S and S−N bond formation is
rare in the construction of heterocyclic compounds. As part of
an ongoing research in our laboratory to systematically
construct various heterocyclic compounds based on copper-
catalyzed consecutive reaction25, herein we first report the
example of copper-catalyzed C-S and S−N bond formation to
construct benzisothiazol-3(2H)-ones from readily available 2-
halobenzamides with CS2 as sulfur source.
Entry
Catalyst
Ligand Solvent
(oC) (%)b
1
CuI
L-1
L-1
L-1
L-1
L-1
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
80
80
80
80
80
80
80
80
80
80
80
80
47
2
CuCl
CuBr
CuBr2
CuCl2
23
3
77
4
Trace
Trace
Trace
27
5
6
Cu(OAc)2 L-1
7
CuBr
CuBr
CuBr
-
L-2
L-3
L-4
L-1
-
8
20
9
23
10
11
12
13
14
15
16
17
18c
19d
13
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
46
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-1
40
1,4-dioxane 80
Trace
Trace
Trace
27
Results and discussion
toluene
DCE
80
80
70
90
80
80
80
To optimize the reaction conditions, an initial experiment was
carried out using 2-iodobenzamide (1a) and CS2 as model
substrates and L-proline as a ligand in DMSO at 80 °C.
Gratifyingly, the desired product 2a was obtained in 47% yield
with CuI as catalyst (Table 1, entry 1). Then, a series of copper
catalysts were screened for this reaction under the same
reaction conditions (Table 1, entries 1-6), and CuBr showed the
highest efficiency (Table 1, entry 3). Unsatisfactorily, Copper
(II) salt such as CuBr2, CuCl2, and Cu(OAc)2 were ineffective for
this reaction (entries 4−6). Next, other three ligands including
1,10-phenanthroline, picolinic acid and piperazine were tested
using 0.1 equiv CuBr (relative to amount of 1a) as the catalyst
in DMSO, and they provided lower yields (Table 1, entries 7-9).
DMSO
DMSO
DMSO
DMSO
DMSO
63
70
72
20e
a
43
Reactions conditions: 1a (2.0 mmol), CS2 (2.2 mmol),
catalyst (0.2 mmol), ligand (0.4 mmol), solvent (3 mL),
c
under air for 6 h. b Isolated yield. Extra CuBr (0.1 mmol)
was added. d Extra L-proline (0.2 mmol) was added. e K2CO3
(2.0 mmol) was added.
2 | J. Name., 2012, 00, 1-3
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Under the optimized conditions, a study on the substrate iodobenzamide used as substrate under the optimized
scope of this transformation was carried out, and the results condition, gave 2s in 68% yield, which indicating that the steric
were summarized in Scheme 2. We first used 2-iodo-, 2- effect from methyl group had no significant difference on the
bromo-, 2-chlorobenzamide as substrates to react with CS2 in yield of corresponding product. Therefore, this approach
this consecutive copper-catalyzed C-S and S−N coupling showed high functional group tolerance and proved to be a
reaction. As predicted, 2-iodobenzamide 1a showed higher quite general methodology for the preparation of multifarious
reactivity to provide the desirable product 2a in 77% yield at benzisothiazol-3(2H)-one derivatives.
80 °C, than the corresponding 2-bromobenzamide (give 2a in
48% yield at 100 °C) and 2-chlorobenzamide (give 2a in 35%
yield at 110 °C). Then,
a variety of N-substituted 2-
iodobenzamides reacted with CS2 to give the corresponding
products 2a−2p in moderate to good yields (31%−89%).
Notably, our current work provides an easy-access procedure
for the N-substituted benzisothiazol-3(2H)-ones, which
exhibited antibacterial2 and antipsychotic3 bioactivities.
Compared with the reported methods21-23, simpler operation,
lower temperature (80 °C) and higher reaction rate were
required for this transformation. Generally, when 2-
iodobenzamides with N-substituted alkyl groups such as
methyl, ethyl, isopropyl, n-butyl, and cyclohexyl successfully
underwent this coupling reaction and gave respective
benzisothiazol-3(2H)-ones 2b-2f in 63-83% yields. Other
substrates such as N-benzyl-, 2-bromobenzyl- and pyridin-2-
ylmethyl substituted 2-iodobenzamides with CS2 also
proceeded in good yields, and provided the corresponding
benzisothiazol-3(2H)-ones 2g-2i (62-89%). On the other hand,
when N-aryl 2-iodobenzamides were treated with CS2 under
the optimized conditions, the desirable N-aryl benzisothiazol-
3(2H)-ones 2j-2p could be obtained in 31-63% yield.
Furthermore, substrates bearing electron-neutral groups (H,
2j) and electron-donating groups (4-Et, 2k; 2-OMe, 2l) on N-
aryl groups gave higher yields than those bearing electron-
withdrawing groups (3−Br, 2n; 4−Cl, 2o; and 4−NO2, 2p). This
qualitative trend may be attributed to the nucleophilicity of
nitrogen from amide groups in different N-aryl 2-
O
O
O
O
NH
N
N
N
S
S
S
S
2b (81%)a
2c (83%)a
2d (65%)a
2a (77%)a,
(48%)b, (35%)c
O
O
O
N
S
2e (72%)a
N
N
S
2g (89%)a
S
2f (63%)a
O
O
O
N
N
S
2h (67%)a
Br
N
S
2i (62%)a
N
S
2j (63%)a
O
O
O
O
N
S
2m (31%)a
N
S
2k (48%)a
N
S
2l (53%)a
O
O
Br
O
N
S
2n (41%)a
N
NO2
N
S
Cl
S
2p (39%)a
2o (42%)a
Cl
O
O
O
Cl
NH
NH
NH
S
S
Cl
Br
S
iodobenzamides.
Additionally,
when
using
N-(2,6-
2q (67%)a
2r (51%)b
2s (32%)c
dimethylphenyl)-2-iodobenzamide as substrate under the
optimized condition, the desired product 2m was afforded in a
lower yield (31%), possibly due to the large steric hindrance.
Then, the scope of substituents on the aromatic ring of the
2-halobenzamides was thoroughly investigated. As shown in
Scheme 2, both electron-rich and -deficient benzamides
F
O
O
O
O2N
NH
NH
NH
S
S
S
2t (58%)a
2u (55%)b
2v (30%)b
O
O
O
underwent smoothly to afford
benzisothiazol-3(2H)-ones. To our delight, the reaction for
synthesis of 2q 2r 2t and 2u containing bromine, chlorine,
a variety of substituted
O
NH
S
NH
NH
S
S
2y (72%)a, (50%)b
2x (56%)b
,
,
2w (68%)a
and fluoride atom proceeded well in moderate yields (51-
67%), which allowed further modifications on the aromatic
rings. However, when using 2-chlorobenzamide and 2,6-
dichlorobenzamide as substrates under the standard reaction
condition, gave the desired products 2a and 2s in low yields.
This result showed that 2-chlorobenzamides exhibited weaker
reactivity than 2-iodo- and 2-bromobenzamides. In addition,
the strong electron-withdrawing group (−NO2, 2v) on aromatic
ring was a possible negative factor for this transformation. In
contrast, substrates bearing electron-donating groups (−Me,
2w and 2x; −OMe, 2y) gave the desired products in moderate
yields (50-72%). It is worth noting that 3-methyl-2-
Scheme 2 Scope of 2-halobenzamides. Reaction conditions: 2-
halobenzamide (2.0 mmol), CS2 (2.2 mmol), CuBr (0.2 mmol),
and L-proline (0.4 mmol) in DMSO (3 mL) at 80 oC under air for
a
b
6 h. Product was obtained from 2-iodobenzamide. Product
c
was obtained from 2-bromobenzamide.
obtained from 2-chlorobenzamide.
Product was
On the basis of the above results and reported
literatures,22,26,27 we proposed a possible reaction mechanism
for this copper-catalyzed consecutive process. As depicted in
Scheme 3, oxidative addition of CuBr into the 2-halobenzamide
1
with the aid of L-proline26, gave the aromatic organocopper
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(II) compound22. Then, ligand exchange between X- and CS2, over anhydrous Na2SO4 and concentrated under reduced
led to the formation of intermediate (II). Reductive elimination pressure. The residue was purified by column chromatography
of II along with insertion reaction of CS2 into copper-carbon on silica gel using petroleum ether/ethyl acetate (20:1 to 5:1)
bond of II 27
underwent an intramolecularly nucleophilic substitution
reaction22 to give the target product . The generating red mp 140−141 oC. 1H NMR (300 MHz, DMSO-d6) δ 11.46 (brs, 1H),
,
afforded the unstable intermediate (III), which as the eluent to give the desired products
2.
Benzisothiazol-3(2H)-one (2a).22 White solid, 77% yield (235 mg),
2
carbon monosulfide (CS) was observed during the purification 7.98 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.62 (t, J = 7.4 Hz,
process, which could be trapped by some nucleophilic amines 1H), 7.43 (t, J = 7.7 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 164.8,
due to its weak electrophilicity28 (see Supporting information).
147.4, 130.0, 124.8, 124.1, 121.4. MS (ESI): m/z 150.0 [M - H]-.
2-Methylbenzisothiazol-3(2H)-one (2b).22 White solid, 81% yield
o
1
(268 mg), mp 125-126 C. H NMR (300 MHz, DMSO-d6) δ 7.97 (d, J
= 8.0 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.44 (t,
J = 7.6 Hz, 1H), 3.36 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 164.2,
140.2, 131.6, 125.4, 123.9, 121.7, 29.9. MS (ESI): m/z 166.0 [M +
H]+.
2-Ethylbenzisothiazol-3(2H)-one (2c).22 Light yellow liquid, 83%
1
yield (298 mg). H NMR (300 MHz, DMSO-d6) δ 7.98 (d, J = 8.1 Hz,
1H), 7.86 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 8.1 Hz, 1H), 7.44 (t, J = 7.7
Hz, 1H), 3.85 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H); 13C NMR (75
MHz, DMSO-d6) δ 164.3, 140.8, 132.2, 126.0, 125.9, 124.8, 122.3,
38.6, 15.0. MS (ESI): m/z 180.0 [M + H]+.
2-Isopropylbenzisothiazol-3(2H)-one (2d).19 Light brown liquid,
Scheme 3 A possible reaction mechanism.
1
65% yield (251 mg). H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 8.0
Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.67-7.70 (m, 1H), 7.43-7.46 (m,
1H), 4.77-4.81 (m, 1H), 1.27-1.36 (m, 6H); 13C NMR (125 MHz,
DMSO-d6) δ 163.8, 140.3, 131.6, 125.4, 125.4, 121.8, 45.3, 21.7. MS
(ESI): m/z 216.0 [M + Na]+.
2-n-Butylbenzisothiazol-3(2H)-one (2e).22 Light brown liquid, 72%
yield (298 mg). 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J = 7.8 Hz, 1H),
7.67-7.49 (m, 2H), 7.39 (t, J = 7.3 Hz, 1H), 3.90 (t, J = 7.2 Hz, 2H),
1.74 (dd, J = 14.9, 7.5 Hz, 2H), 1.42 (dd, J = 15.0, 7.4 Hz, 2H), 0.97 (t,
J = 7.3 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 164.8, 140.8, 132.1,
126.0, 126.0, 124.7, 122.3, 43.1, 31.5, 19.6, 13.9. MS (ESI): m/z
230.1 [M + Na]+.
Conclusions
In summary, we have developed an efficient and practical
approach to construct benzisothiazol-3(2H)-ones via copper-
catalyzed reaction of easily available 2-halobenzamides with
CS2 as sulfur source under mild reaction condition. The
reaction underwent a consecutive process with S−C bond and
S−N bond formaꢀon. Further uꢀlizaꢀons of this method are
underway to prepare more complex sulfur- and nitrogen-
containing heterocycles in our laboratory.
2-Cyclohexylbenzisothiazol-3(2H)-one (2f).14 White solid, 63%
yield (294 mg), mp 65-66 oC. 1H NMR (300 MHz, DMSO-d6) δ 7.96 (d,
J = 8.1 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.44
(t, J = 7.3 Hz, 1H), 1.90-1.94 (m, 2H), 1.80-1.84 (m, 2H), 1.34-1.68
(m, 5H), 1.11-1.30 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 163.8,
140.2, 131.5, 125.4, 125.4, 124.7, 121.7, 52.4, 32.2, 25.1, 24.7. MS
(ESI): m/z 256.1 [M + Na]+.
2-Benzylbenzisothiazol-3(2H)-one (2g).14 Light yellow liquid, 89%
yield (429 mg). 1H NMR (300 MHz, DMSO-d6) δ 7.93 (t, J =7.5 Hz,
2H), 7.65-7.70 (m, 1H), 7.45 (t, J = 7.3 Hz, 1H), 7.28-7.39 (m, 5H),
5.03 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 164.3, 140.5, 136.8,
131.9, 128.6, 127.9, 127.8, 125.7, 125.5, 123.9, 121.9, 46.3. MS
(ESI): m/z 242.1 [M + H]+.
Experimental section
General methods
1H and 13C NMR spectra were measured on a 300 or 500 MHz
spectrometer using DMSO-d6 as the solvent with
tetramethylsilane (TMS) as the internal standard. Low- and
high-resolution mass spectra (LRMS and HRMS) were recorded
in electron impact mode. Melting points were determined on a
melting point apparatus and were uncorrected. Reactions
were monitored by TLC on silica gel 60 F254 plates (Qingdao
Ocean Chemical Company, China). Column chromatography
was carried out on silica gel (200−300 mesh, Qingdao Ocean
Chemical Company, China). All commercial materials and
solvents were used directly without further purification.
2-(2-Bromobenzyl)benzisothiazol-3(2H)-one (2h). Light yellow
o
1
solid, 67% yield (429 mg), mp 90-92 C. H NMR (300 MHz, DMSO-
d6) δ 7.92-7.97 (m, 2H), 7.68-7.69 (m, 2H), 7.45-7.47 (m, 1H), 7.38-
7.40 (m, 1H), 7.29-7.34 (m, 2H), 5.09 (s, 2H); 13C NMR (75 MHz,
DMSO-d6) δ 164.5, 149.1, 148.9, 140.5, 135.9, 132.0, 125.7, 125.6,
123.7, 122.0, 43.9. MS (ESI): m/z 342.0 [M + Na]+; HRMS calcd for
C14H10BrNOSNa [M + Na]+ 341.9564, found 341.9569.
General procedure for preparation of benzisothiazol-3(2H)-ones (2)
To a solution of 2-halobenzamide (1) (2.0 mmol) in dried
DMSO (3 mL), was carbon disulfide (2.2 mmol), CuBr (0.2
mmol), and L-proline (0.4 mmol). The reaction mixture was
stirred at 80 °C under air. After disappearance of the reactant
(monitored by TLC), water (30 mL) was added to the mixture,
and then extracted with ethyl acetate (10 mL) for three times.
The extract was washed with saturated NaCl solution, dried
2-(Pyridin-2-ylmethyl)benzisothiazol-3(2H)-one (2i). Brown solid,
62% yield (300 mg), mp 118-119 oC. 1H NMR (300 MHz, DMSO-d6) δ
8.70 (s, 1H), 8.62 (s, 1H), 8.00-8.08 (m, 2H), 7.77-7.82 (m, 2H), 7.49-
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7.59 (m, 2H), 5.19 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 164.4, 11.81 (brs, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.87 (s, 1H), 7.68 (d, J = 8.7
149.0, 148.9, 140.5, 135.9, 132.7, 132.0, 125.7, 125.6, 123.8, 123.7, Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 163.3, 132.5, 126.6, 126.2,
122.0, 43.9. MS (ESI): m/z 243.1 [M + H]+; HRMS calcd for 123.6, 117.8. MS (ESI): m/z 186.0 [M + H]+.
C13H11N2OS [M + H]+ 243.0592, found 243.0598.
4-Chlorobenzisothiazol-3(2H)-one (2s). Light yellow solid, 32%
2-Phenylbenzisothiazol-3(2H)-one (2j).17b White solid, 63% yield yield (119 mg), mp 200-202 oC. 1H NMR (300 MHz, DMSO-d6) δ 9.36
1
(286 mg), mp 132-133 oC. H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J (brs, 1H), 7.42-7.55 (m, 3H); 13C NMR (75 MHz, DMSO-d6) δ 165.8,
= 8.1 Hz, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.70-7.79 (m, 3H), 7.48-7.56 136.7, 131.8, 128.6, 119.9. MS (ESI): m/z 184.0 [M - H]-; HRMS calcd
(m, 3H), 7.37 (t, J = 7.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ for C7H3ClNOS [M - H]- 183.9624, found 183.9629.
163.2, 140.0, 137.1, 132.5, 129.4, 126.9, 126.1, 125.9, 124.4, 124.3,
121.8. MS (ESI): m/z 250.0 [M + Na]+.
5-Bromobenzisothiazol-3(2H)-one (2t). White solid, 58% yield
o
(267 mg), mp 219-221 C. 1H NMR (300 MHz, DMSO-d6) δ 8.10 (d, J
2-(4-Ethylphenyl)benzisothiazol-3(2H)-one (2k).17a White solid, = 8.7 Hz, 2H), 7.86-7.89 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ
48% yield (245 mg), mp 122-124 oC. 1H NMR (300 MHz, DMSO-d6) δ 163.3, 132.5, 126.6, 126.2, 123.6, 117.7. MS (ESI): m/z 227.9 [M -
8.04 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.75 (t, J = 7.3 Hz, H]-; HRMS calcd for C7H3BrNOS [M - H]- 227.9119, found 227.9122.
1H), 7.59 (d, J = 8.2 Hz, 2H), 7.50 (t, J = 7.5 Hz, 1H), 7.36 (d, J = 8.2
4-Fluorobenzisothiazol-3(2H)-one (2u). White solid, 55% yield
Hz, 2H), 2.66 (q, J = 7.8 Hz, 2H), 1.21(t, J = 7.5 Hz, 3H); 13C NMR (75 (186 mg), mp 260-262 oC. 1H NMR (300 MHz, DMSO-d6) δ 11.75
MHz, DMSO-d6) δ 163.72, 143.3, 140.5, 135.2, 132.9, 129.1, 126.6, (brs, 1H), 8.03-8.08 (m, 2H), 7.51-7.64 (m, 2H); 13C NMR (75 MHz,
126.4, 126.2, 125.1, 124.8, 122.3, 28.2, 15.9. MS (ESI): m/z 278.1 [M DMSO-d6) δ 163.8, 161.3, 159.3, 126.1, 123.4, 118.7, 109.2. MS
+ Na]+.
(ESI): m/z 168.0 [M - H]-; HRMS calcd for C7H3FNOS [M - H]-
2-(2-Methoxyphenyl)benzisothiazol-3(2H)-one
yellow solid, 53% yield (273 mg), mp 153-154 oC. 1H NMR (300 MHz,
(2l).21a
Light 167.9919, found 167.9923.
5-Nitrobenzisothiazol-3(2H)-one (2v). Yellow solid, 30% yield (118
DMSO-d6) δ 8.10 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.85 (t, J mg), mp 173-174 oC. H NMR (300 MHz, DMSO-d6) δ 9.44 (brs, 1H),
= 7.5 Hz, 1H), 7.53-7.59 (m, 3H), 7.34 (d, J = 8.4 Hz, 1H), 7.18 (t, J = 8.47 (s, 1H), 8.07 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 163.4,
7.5 Hz, 1H), 3.90 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 164.4, 149.2, 135.1, 132.1, 124.2, 116.4. MS (ESI): m/z 194.9 [M - H]-;
156.2, 142.0, 132.7, 131.1, 130.8, 126.5, 126.1, 124.9, 123.9, 122.2, HRMS calcd for C7H3N2O3S [M - H]- 194.9907, found 194.9913.
1
121.2, 113.3, 56.3. MS (ESI): m/z 256.3 [M - H]-.
7-Methylbenzisothiazol-3(2H)-one (2w). White solid, 68% yield
2-(2,6-Dimethylphenyl)benzisothiazol-3(2H)-one (2m).17b White (225 mg), mp 178-179 C. H NMR (500 MHz, DMSO-d6) δ 7.73 (d, J
solid, 31% yield (158 mg), mp 122-124 oC. 1H NMR (300 MHz, = 7.8 Hz, 1H), 7.45 (d, J = 7.0 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 2.40 (s,
DMSO-d6) δ 8.08 (s, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.53 (s, 1H), 7.35 3H); 13C NMR (125 MHz, DMSO-d6) δ 165.8, 130.7, 130.5, 126.0
(s, 1H), 7.28 (s, 2H), 2.25 (s, 6H); 13C NMR (75 MHz, DMSO-d6) δ 124.9, 122.1, 18.9. MS (ESI): m/z 166.0 [M + H]+; HRMS calcd for
163.4, 141.4, 137.4, 135.5, 132.3, 129.3, 128.4, 127.7, 126.4, 125.7, C8H8NOS [M + H]+ 166.0327, found 166.0330.
o
1
123.5, 122.1, 17.3. MS (ESI): m/z 256.1 [M + H]+.
6-Methylbenzisothiazol-3(2H)-one (2x).22 White solid, 56% yield
2-(3-Bromophenyl)benzisothiazol-3(2H)-one (2n).29 Light yellow (185 mg), mp 176-177 oC. 1H NMR (300 MHz, DMSO-d6) δ 8.98 (brs,
solid, 41% yield (251 mg), mp 180-182 oC. 1H NMR (300 MHz, 1H), 7.49 (s, 1H), 7.22-7.32 (m, 2H), 2.33 (s, 3H); 13C NMR (75 MHz,
DMSO-d6) δ 8.04-8.08 (m, 2H), 7.96 (d, J = 8.1 Hz, 1H), 7.75-7.80 (m, DMSO-d6) δ 166.9, 140.6, 135.1, 134.9, 132.5, 128.3, 127.4, 19.8.
1H), 7.67 (d, J = 8.1 Hz, 1H), 7.47-7.58 (m, 3H); 13C NMR (75 MHz, MS (ESI): m/z 164.0 [M - H]-.
DMSO-d6) δ 164.2, 140.5, 139.1, 133.3, 131.8, 130.1, 127.1,
126.6, 126.6, 124.6, 123.4, 122.5, 122.3. MS (ESI): m/z 308.0 [M (261 mg), mp 184-186 C. H NMR (300 MHz, DMSO-d6) δ 7.86 (d, J
+ H]+. = 8.7 Hz, 1H), 7.25-7.36 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ
5-Methoxybenzisothiazol-3(2H)-one (2y). White solid, 72% yield
o
1
2-(4-Chlorophenyl)benzisothiazol-3(2H)-one (2o).14 White solid, 157.7, 125.7, 122.9, 121.0, 105.8, 56.0. MS (ESI): m/z 180.0 [M -
42% yield (220 mg), mp 107-108 oC. 1H NMR (300 MHz, DMSO-d6) δ H]-; HRMS calcd for C8H6NO2S [M - H]- 180.0119, found 180.0123.
8.06 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.74-7.79 (m, 3H),
7.60 (d, J = 7.7 Hz, 2H), 7.51 (t, J = 7.5 Hz, 1H); 13C NMR (75 MHz,
Acknowledgements
DMSO-d6) δ 163.5, 139.7, 136.2, 132.7, 129.3, 126.1, 126.0, 125.8,
123.7, 121.9. MS (ESI): m/z 262.0 [M - H]-.
This work was supported by the Universities Natural Science
Research Project of Jiangsu Province (No. 15KJB350002), and
Nanjing Medical University Education Development
Foundation (No. 2014NJMUZD019).
2-(4-Nitrophenyl)benzisothiazol-3(2H)-one (2p).30 White solid,
39% yield (212 mg), mp 126-130 oC. 1H NMR (300 MHz, DMSO-d6) δ
8.05-8.09 (m, 2H), 7.97 (d, J = 7.8 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H),
7.68 (d, J = 7.8 Hz, 1H), 7.48-7.60 (m, 3H); 13C NMR (75 MHz, DMSO-
d6) δ 163.3, 140.0, 138.6, 132.8, 131.3, 129.5, 126.6, 126.2, 126.0,
124.0, 122.9, 121.9, 121.8. MS (ESI): m/z 273.0 [M + H]+.
Notes and references
6-Chlorobenzisothiazol-3(2H)-one (2q).12a Light yellow solid, 67%
yield, (248 mg), mp 201-202 oC. 1H NMR (300 MHz, DMSO-d6) δ
11.86 (brs, 1H), 8.72 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.4
Hz , 1H); 13C NMR (75 MHz, DMSO-d6) δ 164.3, 135.6, 125.9, 125.8,
124.1, 121.6. MS (ESI): m/z 184.0 [M - H]-.
5-Chlorobenzisothiazol-3(2H)-one (2r).12a Light yellow solid, 51%
yield (189 mg), mp 198-200 oC. 1H NMR (300 MHz, DMSO-d6) δ
1
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