Copper-catalyzed intramolecular N-S bond formation by oxidative dehydrogenative cyclization

Article abstract of DOI:10.1021/jo401056g

Copper-catalyzed synthesis of benzo[d]isothiazol-3(2H)-ones and N-acyl-benzothiazetidine by intramolecular dehydrogenative cyclization is described. In this reaction, a new nitrogen-sulfur (N-S) bond is formed by N-H/S-H coupling. The present reaction has

Full text of DOI:10.1021/jo401056g

Note
pubs.acs.org/joc
Copper-Catalyzed Intramolecular N−S Bond Formation by Oxidative
Dehydrogenative Cyclization
Zhen Wang,†,‡ Yoichiro Kuninobu,*,†,‡ and Motomu Kanai*,†,‡
†Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
‡ERATO, Japan Science and Technology Agency (JST), Kanai Life Science Catalysis Project, 7-3-1 Hongo, Bunkyo-ku, Tokyo
113-0033, Japan
S
* Supporting Information
ABSTRACT: Copper-catalyzed synthesis of benzo[d]isothiazol-3(2H)-ones and N-
acyl-benzothiazetidine by intramolecular dehydrogenative cyclization is described. In
this reaction, a new nitrogen−sulfur (N−S) bond is formed by N−H/S−H coupling.
The present reaction has high functional group tolerance and gives products in gram
scale. This method promotes double cyclization, allowing for synthesis of a drug
intermediate.
rganic compounds bearing heteroatom−heteroatom
O
bond(s) are important as reagents, bioactive molecules,1
and functional materials.2 Among them, there are many natural
products and drugs that contain heteroatom-heteroatom
bond(s) between two different heteroatoms such as N−O,3
N−S,4 and S−O5 bonds. One bioactive compound with an N−
S bond is benzoisothiazolone which has effective antifungal,
antibacterial, and antipsychotic properties (Figure 1).6 As
Figure 1. Bioactive molecules that contain benzo[d]isothiazol-3(2H)-
one skeletons.
illustrated in Figure 2, several methods to construct
benzoisothiazolone skeletons have been reported: (a) con-
densation of 2-(chlorocarbamoyl)phenyl hypochlorothioites
with amines;7 (b) a CuI/1,10-phenanthroline-mediated reac-
tion using 2-halo-arylamides, sulfur powder, and potassium
carbonate as a substrate, S source, and base, respectively;8 and
(c) a dehydrogenative N−H/S−H coupling reaction via the
formation of an N-acylnitrenium ion using a hypervalent iodine
reagent as an oxidant.9 These synthetic methods require
multistep synthesis of the starting materials and/or highly
reactive reagents, however, and produce some waste from the
starting materials and reagents.10 We hypothesized that
catalytic dehydrogenative cross-coupling reactions between
N−H/S−H bonds might be the direct and efficient methods
to produce benzoisothiazolones (Figure 2d). Our findings
indicate that a small amount of a copper salt can promote an
intramolecular dehydrogenative coupling reaction between N−
H and S−H bonds to give N−S bonds using oxygen as an
oxidant.
Figure 2. Previous and present methods for the synthesis of
benzo[d]isothiazol-3(2H)-ones.
mamide (DMF) at 70 °C for 5 h under O2 conditions gave 2-
phenylbenzo[d]isothiazol-3(2H)-one (2a) in quantitative yield
(eq 1).11−18 This reaction did not proceed in the absence of O2.
Treatment of 2-mercapto-N-phenylbenzamide (1a) with a
catalytic amount of copper(I) iodide CuI in N,N-dimethylfor-
Received: May 15, 2013
© XXXX American Chemical Society
A
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The structure of 2a was determined by single-crystal X-ray
structure analysis (see the Supporting Information, Figure S1)
that revealed the formation of an N−S bond and construction
of a five-membered heterocyclic skeleton.
Next, the substrate scope was investigated (Table 1). N-aryl
2-mercaptobenzamides 1b−1l provided the corresponding 2-
afforded the corresponding benzoisothiazolones 2m−2o in
excellent yields (entries 12−14). The four-membered hetero-
cyclic product 2p was also obtained in 84% yield (entry 15). In
the case of 2-(((4-fluorophenyl)amino)methyl)benzenethiol
(2-(aminomethyl)benzenethiol instead of 2-(aminocarbonyl)-
benzenethiol), N−S bond formation proceeded; however, the
reaction did not stop at this step, and further oxidation of the
benzylic position also occurred to give 2d in 29% yield.
Table 1. Synthesis of Heterocyclic Compounds 2 via N−H
and S−H Bond Activation of 1
A double-cyclization reaction also proceeded, and product 4
was obtained in 87% yield (eq 2). In this reaction, the yield of
product 4 was comparable to that of single-cyclization products.
The present reaction was applied to the synthesis of a drug
precursor (eq 3). Piroxicam is a nonsteroidal anti-inflammatory
drug used to relieve the symptoms of rheumatoid and
osteoarthritis, primary dysmenorrhea, and postoperative
pain.19,20 Benzoisothiazolone 2q could be synthesized using
the present method. Oxidation of 2q21 would give a precursor
of piroxicam, 5, and several successive transformations would
lead to piroxicam following the reported method.18
a
Benzoisothiazolone 2a was not obtained from the corre-
sponding disulfide, which may be formed by dehydrogenative
homocoupling of 1a. This result indicated that cyclization did
not proceed via formation of the disulfide. The proposed
mechanism for the formation of benzoisothiazolone 2 is as
follows (Scheme 1): (1) coordination of 2-mercaptobenzamide
1 to a copper atom; (2) oxidative formation of a Cu−S bond
via the elimination of H2O, (3) oxidative formation of a Cu−N
bond via the elimination of H2O22 (or the order of steps 2 and
3 is reversed), and (4) reductive elimination23 to give
benzoisothiazolone 2 and regenerate the copper catalyst.
The reaction can be performed in gram scale. Treatment of
1.10 g of 1d with a catalytic amount of CuI produced 1.03 g of
2d in 95% yield (eq 4), which is comparable to the yield in eq 1
(46 mg scale).
a
Solvent: dimethylsulfoxide (DMSO).
arylbenzo[d]isothiazol-3(2H)-ones 2b−2l in excellent yields
(entries 1−11). The reaction was not affected by electron-
donating or -withdrawing groups (entries 1−4). In entries 5−7,
the reaction proceeded without loss of the halogen atoms. The
cyclization reaction was not inhibited by steric hindrance (entry
8). Pyridyl and quinolyl groups could be used as an aromatic
ring on a nitrogen atom of the substrates 1k and 1l (entries 10
and 11). Alkyl-substituted 2-mercaptobenzamides 1m−1o
B
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Note
added carefully. The solution was extracted with CH2Cl2 (3 × 150
mL), and the combined organic extracts were washed with a saturated
aq solution of NaHCO3 (150 mL) and brine (150 mL) consequently.
Then, the organic layer was dried over sodium sulfate. After filtration
and removal of the solvent under vacuum, the residue was purified by
crystallization from Et2O to afford 2-mercapto-N-phenylbenzamide
(1a) as a white solid (6.52 g, 95% yield). TLC (hexane/AcOEt = 3:1):
Rf = 0.14, 1H NMR (400 MHz, CDCl3) δ 7.83 (br s, 1H), 7.61 (d, J =
7.9 Hz, 2H), 7.57 (d, J = 7.7 Hz, 1H), 7.36 (dd, J = 11.0, 4.2 Hz, 3H),
7.33−7.24 (m, 1H), 7.23−7.12 (m, 2H), 4.55 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 166.8, 137.8, 133.7, 133.2, 131.6, 131.2, 129.3, 128.3,
125.7, 125.1, 120.5; IR (KBr, ν/cm−1) 3448, 1646, 1639, 1599, 1540,
1508, 1438, 1322, 1253, 1176, 1003, 889, 753, 690; HRMS (ESI+)
Calcd for C13H11NOS (M + Na+) 252.0454, Found 252.0454.
Scheme 1. Proposed Mechanism for the Formation of
Benzoisothiazolone 2
2-Mercapto-N-(4-methylphenyl)benzamide (1c). p-Toluidine
(3.82 g, 35.7 mmol), instead of aniline, was used following the general
procedure. Purification: crystallization from Et2O/hexane (1:1). 3.47 g,
1
96%, white solid. TLC (hexane/AcOEt = 3:1): Rf = 0.15, H NMR
(500 MHz, CDCl3) δ 7.81 (br s, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.49
(d, J = 7.5 Hz, 2H), 7.34 (d, J = 7.4 Hz, 1H), 7.28 (dd, J = 7.4, 7.4 Hz,
1H), 7.17 (m, 3H), 4.65 (br s, 1H), 2.34 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 166.8, 135.2, 134.8, 133.7, 133.2, 131.5, 131.1, 129.8,
128.2, 125.6, 120.6, 21.2; IR (KBr, ν/cm−1) 3435, 1644, 1514, 1403,
1321, 1300, 1253, 1113, 1060, 1038, 941, 894, 814, 785, 741, 652;
HRMS (ESI+) Calcd for C17H11NOS (M + Na+) 264.0454, Found
264.0456. HRMS (ESI+) Calcd for C14H13NOS (M + Na+) 266.0610,
Found 266.0610.
In summary, we successfully achieved a copper-catalyzed
synthesis of benzo[d]isothiazol-3(2H)-ones and N-acyl-benzo-
thiazetidine by intramolecular dehydrogenative cyclization. This
reaction proceeded using a small amount of the catalyst (0.3
mol %) and oxygen as an oxidant to form a new N−S bond by
N−H/S−H coupling. Many natural products and drugs contain
heteroatom−heteroatom bond(s) such as N−S bond(s), and it
is therefore important to develop novel and efficient methods
to construct N−S bonds. There have been several reports on
the construction of N−S bonds, but there is room for
improvement of the efficiency. On the other hand, the present
reaction is more efficient because N−S bond-containing
heterocyclic skeletons can be constructed catalytically by the
direct formation of N−S bonds from NH and SH bonds. The
present reaction affords products in gram scale. This method
promotes double cyclization, allowing for the synthesis of a
drug precursor. We believe that this reaction will be a useful
method for the synthesis of heterocyclic compounds with an
N−S bond.
N-(4-Fluorophenyl)-2-mercaptobenzamide (1d). 4-Fluoroani-
line (6.51 mL, 71.3 mmol), instead of aniline, was used following the
general procedure. Purification: crystallization from Et2O/hexane
(3:1). 6.01 g, 82%, white solid, TLC (hexane/AcOEt = 3:1): Rf =
1
0.39, H NMR (500 MHz, DMSO) δ 10.44 (br s, 1H), 7.75 (dd, J =
8.9, 8.9 Hz, 2H), 7.62 (d, J = 7.7 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H),
7.36 (td, J = 7.7, 1.2 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.24−7.14 (m,
2H), 5.28 (br s, 1H); 13C NMR (100 MHz, DMSO) δ 166.4, 158.3 (J
= 238 Hz), 135.4 (J = 2.4 Hz), 133.9, 133.2, 130.6, 128.6, 124.7, 121.7
(J = 8.4 Hz), 115.3 (J = 22.7 Hz); IR (KBr, ν/cm−1) 3333, 2955, 2928,
2856, 1634, 1540, 1457,1433, 1314, 1038, 742; HRMS (ESI+) Calcd
for C13H10FNOS (M + Na+) 270.0359, Found 270.0357.
N-(4-Cyanophenyl)-2-mercaptobenzamide (1e). 4-aminoben-
zonitrile (3.37 g, 11.9 mmol), instead of aniline, was used following the
general procedure. Purification: crystallization from Et2O/hexane
(3:1). 1.84 g, 61%, light-yellow solid, TLC (hexane/AcOEt = 2:1):
Rf = 0.31, 1H NMR (400 MHz, CDCL3) δ 7.81−7.74 (m, 2H), 7.67−
7.56 (m, 3H), 7.34 (m, 2H), 7.22 (t, J = 7.4 Hz, 1H), 4.35 (s, 1H). 13C
NMR (100 MHz, CDCL3) δ 166.8, 142.0, 133.54, 133.49, 132.8,
132.0, 131.8, 128.4, 125.9, 120.2, 119.0, 107.8; IR (KBr/cm−1) 3446,
2887, 2778, 2359, 2342, 1637, 1541, 1275, 1104, 749, 668, 648;
HRMS (ESI+) Calcd for C14H10N2OS (M + Na+) 277.0406, Found
277.0415.
EXPERIMENTAL SECTION
■
General. All reactions were carried out in dry solvents under argon
atmosphere unless otherwise noted. Methyl thiosalicylate was
purchased and was used without further purification. CuI (99.999%
purity) was purchased from a chemical supplier and used as received.
N,N-Dimethylformamide, methanol, dichloromethane, and dimethyl
sulfoxide were purchased and were dried and degassed before use.
1q24,25 was synthesized following the reported method. NMR spectra
were recorded on 500 MHz (500 MHz for 1H NMR and 125 MHz for
N-(2-Bromo-4-methylphenyl)-2-mercaptobenzamide (1h). 2-
Bromo-4-methylaniline (3.98 g, 21.4 mmol), instead of aniline, was
used following the general procedure. Purification: crystallization from
Et2O/hexane (2:1). 2.57 g, 90%, white solid, TLC (hexane/AcOEt =
13C NMR) and 400 MHz (400 MHz for H NMR and 100 MHz for
1
13C NMR) spectrometers. Proton chemical shifts are reported relative
1
3:1): Rf = 0.25, H NMR (500 MHz, CDCl3) δ 8.36 (s, 1H), 8.22 (s,
to residual solvent peak (CDCl3 at 7.26 ppm, CD3OD at 3.31 ppm,
and DMSO-d6 at 2.50 ppm). Carbon chemical shifts are reported
relative to solvent peaks (CDCl3 at 77.3 ppm, CD3OD at 49.1 ppm,
and DMSO-d6 at 39.5 ppm). IR spectra were recorded on Fourier
transform infrared spectrophotometer. High-resolution mass spectra
(HRMS) were measured on a TOF spectrometer (for HRMS). The
known starting materials, 1b, 1f, 1g, 1j, and 1o, were identified by
comparing their spectroscopic data with those of reported data.9
Typical Procedure for the Synthesis of 2-Mercapto-N-
phenylbenzamide (1a). To a cooled (0 °C) solution of aniline
(6.64 g, 71.3 mmol) in CH2Cl2 (150 mL) was added a solution of
AlMe3 in hexane (2.0 M, 35.7 mL, 71.3 mmol). The reaction mixture
was warmed to room temperature and continued to stir for 30 min
until the gas evolution ceased. Then, methyl thiosalicylate (5.00 g, 29.7
mmol) was added and the solution was refluxed for 12 h. The reaction
mixture was cooled in an ice bath, and aq HCl (10%, 60 mL) was
1H), 7.66 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0
Hz, 1H), 7.36−7.32 (m, 1H), 7.27−7.22 (m, 1H), 6.86 (d, J = 8.0 Hz,
1H), 4.59 (d, J = 0.8 Hz, 1H), 2.37 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 166.5, 139.0, 135.4, 134.6, 132.9, 132.1, 131.9, 131.5, 128.0,
126.8, 125.8, 122.8, 110.8, 21.6; IR (KBr, ν/cm−1) 3257, 1643, 1526,
1474, 1303, 1029, 797, 740; HRMS (ESI+) Calcd for C14H12BrNOS
(M + Na+) 343.9715, Found 343.9711.
N-(2,6-Dimethylphenyl)-2-mercaptobenzamide (1i). 2,6-Di-
methylaniline (2.59 g, 21.4 mmol), instead of aniline, was used
following the general procedure. Purification: crystallization from
Et2O/hexane (1:1). 2.08 g, 90%, yellow white solid, TLC (hexane/
1
AcOEt = 3:1): Rf = 0.11, H NMR (500 MHz, CDCl3) δ 7.63 (d, J =
7.7 Hz, 1H), 7.38 (d, J = 7.7 Hz, 2H), 7.32 (dd, J = 7.7, 7.7 Hz, 1H),
7.23−7.04 (m, 4H), 4.84 (s, 1H), 2.30 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 167.5, 135.8, 133.6, 133.5, 131.4, 131.1, 128.5, 128.2, 128.1,
C
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127.9, 125.5, 18.8; IR (KBr, ν/cm−1) 3433, 2956, 2928, 2856, 1634,
1540, 1457, 1433, 1313, 1263, 1038, 1009, 742, 649; HRMS (ESI+)
Calcd for C15H15NOS (M + Na+) 280.0767, Found 280.0770.
2-Mercapto-N-(3-pyridinyl)benzamide (1k). Pyridin-3-amine
(2.01 g, 21.4 mmol), instead of aniline, was used following the
general procedure. Purification: crystallization from Et2O. 1.78 g, 87%,
Typical procedure for copper-catalyzed intramolecular N−S
bond formation: Synthesis of 2-phenylbenzo[d]isothiazol-
3(2H)-one (2a). A mixture of 2-mercapto-N-phenylbenzamide (1a,
45.9 mg, 0.20 mmol), CuI (0.11 mg, 0.60 μmol), and DMF (2.0 mL)
was stirred at 70 °C for 5 h under oxygen. Then, the reaction mixture
was cooled to room temperature, diluted with water, and extracted
with ethyl acetate. The organic layer was dried over sodium sulfate.
After filtration and removal of the solvent in vacuo, the residue was
subjected to the flash column chromatography on silica gel with
hexane/AcOEt (3:1) as eluent to give 2-phenylbenzo[d]isothiazol-
3(2H)-one (2a, white solid, 45.6 mg, >99% yield). TLC (hexane/
1
white solid, TLC (hexane/AcOEt = 1:1): Rf = 0.42, H NMR (500
MHz, CD3OD) δ 8.86 (d, J = 2.3 Hz, 1H), 8.31 (dd, J = 4.5, 1.2 Hz,
1H), 8.25 (d, J = 7.9 Hz, 1H), 7.65 (dd, J = 7.9, 1.2 Hz, 1H), 7.46 (t, J
= 4.5 Hz, 1H), 7.45 (s, 1H), 7.35 (td, J = 7.9, 1.2 Hz, 1H), 7.25 (td, J =
7.9, 1.2 Hz, 1H); 13C NMR (125 MHz, CD3OD) δ 169.9, 145.5,
142.4, 137.7, 135.0, 134.8, 132.4, 132.2, 129.9, 129.7, 126.2, 125.5; IR
(KBr, ν/cm−1) 3442, 2721, 1637, 1558, 1540, 1456, 1419, 1330, 1302,
1129, 1005, 742, 630; HRMS (ESI+) Calcd for C12H10N2OS (M +
Na+) 253.0406, Found 253.0407.
1
AcOEt = 2:1): Rf = 0.43, H NMR (500 MHz, CDCl3) δ 8.09 (d, J =
7.7 Hz, 1H), 7.70 (d, J = 7.7 Hz, 2H), 7.63 (dd, J = 7.7, 7.7 Hz, 1H),
7.55 (d, J = 7.7 Hz, 1H), 7.50−7.39 (m, 3H), 7.30 (t, J = 7.7 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 164.2, 140.0, 137.4, 132.5, 129.5,
127.3, 127.2, 125.9, 125.0, 124.7, 120.3; IR (KBr, ν/cm−1) 3447, 1653,
1592, 1487, 1448, 1323, 1301, 1267, 1114, 1017, 753, 737, 688, 670,
609; HRMS (ESI+) Calcd for C13H9NOS (M + Na+) 250.0297, Found
250.0299.
2-Mercapto-N-(3-quinolinyl)benzamide (1l). Quinolin-3-amine
(3.08 g, 21.4 mmol), instead of aniline, was used following the general
procedure. Purification: crystallization from Et2O. 2.11 g, 84%, brown
1
white solid, TLC (hexane/AcOEt = 1:1): Rf = 0.45, H NMR (400
2-(4-Methoxyphenyl)benzo[d]isothiazol-3(2H)-one (2b): 48.6
MHz, CDCl3) δ 8.95 (d, J = 2.3 Hz, 1H), 8.85 (d, J = 2.3 Hz, 1H),
8.26 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.90−7.81 (m, 1H), 7.72−7.68
(m, 1H), 7.67−7.64 (m, 1H), 7.57 (ddd, J = 7.8, 7.8, 1.3 Hz, 1H), 7.41
(dd, J = 7.8, 1.3 Hz, 1H), 7.35 (td, J = 7.8, 1.3 Hz, 1H), 7.25 (td, J =
7.8, 1.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 167.3, 145.5, 144.1,
133.6, 132.9, 131.9, 131.7, 131.6, 129.1, 128.9, 128.43, 128.39, 128.1,
127.7, 125.9, 124.8; IR (KBr, ν/cm−1) 3438, 1637, 1542, 1508, 1489,
1466, 1420, 1366, 1300, 1144, 990, 782, 741; HRMS (ESI+) Calcd for
C16H12N2OS (M + Na+) 303.0563, Found 303.0562.
1
mg, 95%, white solid, TLC (hexane/AcOEt = 3:1): Rf = 0.29, H
NMR (500 MHz, CDCl3) δ 8.09 (d, J = 7.6 Hz, 1H), 7.64 (dd, J = 7.6,
7.6 Hz, 1H), 7.57−7.53 (m, 3H), 7.43 (dd, J = 7.6, 7.6 Hz, 1H), 7.02−
6.90 (m, 2H), 3.83 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 164.5,
158.9, 140.2, 132.3, 129.9, 127.3, 127.0, 125.9, 124.8, 120.3, 114.8,
55.8; IR (KBr, ν/cm−1) 3465, 2835, 1651, 1508, 1447, 1329, 1297,
1248, 1179, 1128, 1030, 972, 860, 826, 783, 738, 671; HRMS (ESI+)
Calcd for C14H11NO2S (M + Na+) 280.0403, Found 280.0402.
2-(p-Tolyl)benzo[d]isothiazol-3(2H)-one (2c): 45.8 mg, 95%,
N-Hexyl-2-mercaptobenzamide (1m). Hexan-1-amine (3.64 g,
35.7 mmol), instead of aniline, was used following the general
procedure. Purification: flash column chromatography with hexane/
EtOAc (5:1). 3.26 g, 92%, blue−white solid, TLC (hexane/AcOEt =
1
white solid, TLC (hexane/AcOEt = 3:1): Rf = 0.54, H NMR (500
MHz, CDCl3) δ 7.81 (dd, J = 8.0, 8.0 Hz, 1H), 7.40−7.32 (m, 1H),
7.27 (m, 3H), 7.18−7.10 (m, 1H), 6.98 (d, J = 8.0 Hz, 2H), 2.10 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 164.4, 140.2, 137.4, 134.8,
132.4, 130.1, 127.3, 125.9, 125.1, 124.9, 120.3, 21.3; IR (KBr, ν/cm−1)
3458, 1644, 1505, 1447, 1330, 1313, 1269, 1127, 928, 883, 814, 786,
749, 676, 636; HRMS (ESI+) Calcd for C14H11NOS (M + Na+)
264.0454, Found 264.0456.
1
3:1): Rf = 0.23, H NMR (500 MHz, CDCl3) δ 7.40 (dd, J = 7.6, 1.2
Hz, 1H), 7.30 (dd, J = 7.6, 1.2 Hz, 1H), 7.23 (td, J = 7.6, 1.2 Hz, 1H),
7.11 (dd, J = 7.6, 7.6 Hz, 1H), 6.14 (s, 1H), 4.75 (s, 1H), 3.41 (m, 6.9
Hz, 2H), 1.64−1.53 (m, 2H), 1.42−1.24 (m, 6H), 0.89 (t, J = 6.8 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 168.8, 133.7, 133.0, 131.1,
130.7, 128.0, 125.3, 40.3, 31.7, 29.7, 26.9, 22.8, 14.2; IR (KBr, ν/cm−1)
3433, 2955, 2928, 2855, 1634, 1620, 1540, 1457, 1433, 1313, 1263,
1162, 1038, 742; HRMS (ESI+) Calcd for C13H19NOS (M + Na+)
260.1080, Found 260.1080.
N-(tert-Butyl)-2-mercaptobenzamide (1n). 2-Methylpropan-2-
amine (2.27 mL, 21.4 mmol), instead of aniline, was used following
the general procedure. Purification: crystallization from Et2O/hexane
(3:1) 1.76 g, 95%, brown−white solid, TLC (hexane/AcOEt = 3:1): Rf
= 0.27, 1H NMR (500 MHz, CDCl3) δ 7.39 (dd, J = 7.7, 1.3 Hz, 1H),
7.32−7.28 (m, 1H), 7.26−7.22 (m, 1H), 7.13 (m, 1H), 5.80 (s, 1H),
4.62 (s, 1H), 1.48 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 168.4,
135.0, 132.3, 131.0, 130.4, 127.9, 125.4, 52.2, 29.0; IR (KBr, ν/cm−1)
3298, 2977, 2890, 1632, 1587, 1536, 1470, 1446, 1361, 1319, 1272,
1221, 1044, 878, 742, 676; HRMS (ESI+) Calcd for C11H15NOS (M +
Na+) 232.0767, Found 232.0764.
2-(4-Fluorophenyl)benzo[d]isothiazol-3(2H)-one (2d): 46.5
1
mg, 95%, white solid, TLC (hexane/AcOEt = 3:1): Rf = 0.32, H
NMR (500 MHz, CDCl3) δ 8.06 (d, J = 7.9 Hz, 1H), 7.69−7.59 (m,
3H), 7.55 (d, J = 7.9 Hz, 1H), 7.42 (dd, J = 7.9, 7.9 Hz, 1H), 7.13 (dd,
J = 7.9, 7.9 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 164.3, 161.3 (J =
246 Hz), 139.9, 133.2, 132.6, 127.3, 126.9 (J = 8.4 Hz), 126.0, 124.6,
120.3, 116.4 (J = 22.7 Hz); IR (KBr, ν/cm−1) 3450, 1657, 1599, 1505,
1460, 1447, 1417, 1333, 1310, 1298, 1233, 1159, 1127, 824, 802, 732,
669; HRMS (ESI+) Calcd for C13H8FNOS (M + Na+) 268.0203,
Found 268.0204.
4-(3-Oxobenzo[d]isothiazol-2(3H)-yl)benzonitrile (2e): 50.2
1
mg, 99%, white solid, TLC (hexane/AcOEt = 3:1): Rf = 0.30, H
NMR (500 MHz, CDCL3) δ 8.10 (d, J = 7.8 Hz, 1H), 7.99−7.92 (m,
2H), 7.78−7.68 (m, 3H), 7.60 (d, J = 7.8 Hz, 1H), 7.47 (dd, J = 11.3,
4.3 Hz, 1H). 13C NMR (125 MHz, CDCL3) δ 164.4, 141.8, 139.4,
133.5, 133.4, 127.7, 126.5, 124.8, 123.5, 120.4, 118.5, 109.7; IR (KBr/
cm−1) 3446, 2887, 2778, 2359, 2342, 1637, 1541, 1275, 1104, 749,
668, 648; HRMS (ESI+) Calcd for C14H8N2OS (M + Na+) 275.0255,
Found 275.0261.
N-(2-Mercaptophenyl)benzamide (1p): 0.75 g, 75%, white
1
solid, TLC (hexane/AcOEt = 1:2): Rf = 0.15, H NMR (500 MHz,
CDCl3) δ 8.94 (s, 1H), 8.50 (d, J = 7.8 Hz, 1H), 7.73−7.66 (m, 2H),
7.56 (dd, J = 7.8, 7.8 Hz, 1H), 7.50−7.41 (m, 3H), 7.31 (dd, J = 7.8,
7.8 Hz, 1H), 6.95 (td, J = 7.8, 1.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 165.2, 140.2, 136.9, 134.6, 132.6, 132.3, 129.1, 127.3, 124.6,
123.7, 120.8; IR (KBr, ν/cm−1) 3445, 3120, 2980, 2960, 1681, 1577,
1509, 1478, 1433, 1313, 1225, 963, 766, 729, 688, 623; HRMS (ESI+)
Calcd for C13H11NOS (M + Na+) 252.0454, Found 252.0451.
Methyl 2-(2-mercaptobenzamido)acetate (1q): 1.02 g, 76%,
2-(2-Bromophenyl)benzo[d]isothiazol-3(2H)-one (2f): 59.8
1
mg, 98%, brown solid, TLC (hexane/AcOEt = 3:1): Rf = 0.36, H
NMR (400 MHz, CDCl3) δ 8.16−8.12 (m, 1H), 7.74 (dd, J = 7.8, 1.6
Hz, 1H), 7.71−7.66 (m, 1H), 7.62−7.58 (m, 1H), 7.46 (m, 3H), 7.34
(ddd, J = 7.8, 7.8, 1.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 164.9,
141.5, 135.5, 134.1, 132.7, 131.5, 131.2, 128.7, 127.6, 126.0, 124.3,
123.6, 120.5; IR (KBr, ν/cm−1) 3446, 3063, 1667, 1595, 1471, 1445,
1328, 1309, 1250, 1131, 1047, 782, 755, 739, 671, 656, 613; HRMS
(ESI+) Calcd for C13H8BrNOS (M + Na+) 327.9402, Found 327.9398.
2-(2-Iodophenyl)benzo[d]isothiazol-3(2H)-one (2g): reaction
conditions: DMSO (2 mL), 100 °C, 5 h. Purification: silica gel column
chromatography (hexane/AcOEt = 1:1) 58.6 mg, 83%, brown solid,
TLC (hexane/AcOEt = 3:1): Rf = 0.28, 1H NMR (500 MHz, CDCl3)
δ 8.14 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.71−7.66 (m,
1
yellow oil, TLC (hexane/AcOEt = 1:2): Rf = 0.35, H NMR (400
MHz, CDCl3) δ 7.78 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H),
7.45−7.35 (m, 1H), 7.29−7.19 (m, 1H), 6.64 (s, 1H), 4.23 (d, J = 5.1
Hz, 2H), 3.81 (s, 3H); 13C NMR (125 MHz, CDCL3) δ 170.5, 167.9,
137.7, 133.4, 131.9, 128.2, 127.9, 126.6, 52.8, 42.0; IR (KBr, ν/cm−1)
3420, 2924, 2851, 1748, 1734, 1646, 1636, 1541, 1212, 1173, 1092,
801, 745, 635; HRMS (ESI+) Calcd for C10H11NO3S (M + Na+)
248.0352, Found 248.0350.
D
dx.doi.org/10.1021/jo401056g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1H), 7.62−7.58 (m, 1H), 7.50−7.41 (m, 3H), 7.19−7.15 (m, 1H); 13
C
1H), 7.48 (d, J = 7.7 Hz, 1H), 7.34 (dd, J = 7.7, 7.7 Hz, 1H), 1.69 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 165.8, 139.6, 131.5, 127.1,
126.3, 125.3, 119.9, 58.9, 28.6; IR (KBr, ν/cm−1) 3479, 3065, 2970,
2929, 1644, 1594, 1540, 1394, 1365, 1324, 1303, 1204, 1155, 786, 741,
675; HRMS (ESI+) Calcd for C11H13NOS (M + Na+) 230.0616,
Found 230.0608.
NMR (125 MHz, CDCl3) δ 164.7, 141.4, 140.4, 139.1, 132.7, 131.3,
130.9, 129.7, 127.7, 126.0, 123.9, 120.6, 99.7; IR (KBr, ν/cm−1) 3447,
2921, 1660, 1596, 1464, 1447, 1328, 1308, 1250, 1131, 1019, 908, 781,
755, 738, 670, 613; HRMS (ESI+) Calcd for C13H8INOS (M + Na+)
375.9263, Found 375.9258.
2-Allylbenzo[d]isothiazol-3(2H)-one (2o): 36.2 mg, 95%,
yellow−white solid, TLC (hexane/AcOEt = 3:1): Rf = 0.35, 1H
NMR (500 MHz, CDCl3) δ 8.03 (d, J = 8.2 Hz, 1H), 7.59 (m, 1H),
7.54 (d, J = 8.0 Hz, 1H), 7.39 (dd, J = 7.6, 7.6 Hz, 1H), 5.93 (ddt, J =
17.8, 12.0, 7.4 Hz, 1H), 5.33 (ddt, J = 17.8, 1.1, 1.0 Hz, 1H), 5.30 (ddt,
J = 12.0, 1.3, 1.1 Hz, 1H), 4.56 (ddd, J = 7.4, 1.3, 1.0 Hz, 2H); 13C
NMR (125 MHz, CDCl3) δ 165.3, 140.6, 132.6, 132.0, 126.9, 125.7,
124.9, 120.6, 119.5, 46.4; IR (KBr, ν/cm−1) 3447, 2918, 1644, 1447,
1334, 1314, 1284, 1240, 1192, 990, 932, 785, 740, 673; HRMS (ESI+)
Calcd for C10H9NOS (M + Na+) 214.0297, Found 214.0293.
7-Thia-8-azabicyclo[4.2.0]octa-1,3,5-trien-8-yl(phenyl)-
methanone (2p): reaction conditions: DMSO (2.0 mL), 100 °C, 5 h.
Purification: silica gel column chromatography (hexane/AcOEt = 3:1).
38.0 mg, 84%, white solid, TLC (hexane/AcOEt = 3:1): Rf = 0.63, 1H
NMR (500 MHz, CDCl3) δ 8.09 (m, 3H), 7.91 (d, J = 7.6 Hz, 1H),
7.50 (m, 4H), 7.39 (dd, J = 7.6, 7.6 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 168.3, 154.4, 135.3, 133.9, 131.2, 129.3, 127.8, 126.6, 125.4,
123.5, 121.9; IR (KBr, ν/cm−1) 3065, 3019, 1509, 1478, 1455, 1314,
1225, 1159, 1071, 963, 908, 764, 730, 688, 666, 622; HRMS (ESI+)
Calcd for C13H9NOS (M + Na+) 250.0297, Found 250.0298.
Methyl 2-(3-oxobenzo[d]isothiazol-2(3H)-yl)acetate (2q):
43.0 mg, 96%, yellow oil, TLC (hexane/AcOEt = 1:2): Rf = 0.34,
1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 7.8 Hz, 1H), 7.63 (d, J =
2-(2-Bromo-4-methylphenyl)benzo[d]isothiazol-3(2H)-one
(2h): 62.0 mg, 97%, white solid, TLC (hexane/AcOEt = 3:1): Rf =
1
0.33, H NMR (500 MHz, CDCl3) δ 8.12 (d, J = 8.0 Hz, 1H), 7.67
(td, J = 8.0, 1.5 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.45 (dd, J = 8.0, 8.0
Hz, 1H), 7.30 (d, J = 1.5 Hz, 1H), 7.14 (dd, J = 8.0, 1.5 Hz, 1H), 2.35
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 165.0, 141.5, 139.1, 135.1,
133.6, 132.6, 132.1, 132.0, 127.6, 125.9, 123.7, 120.7, 120.5, 21.0; IR
(KBr, ν/cm−1) 3446, 1645, 1474, 1444, 1400, 1324, 1308, 1249, 1113,
1038, 1017, 810, 785, 737, 670, 623; HRMS (ESI+) Calcd for
C14H10BrNOS (M + Na+) 341.9559, Found 341.9557.
2-(2,6-Dimethylphenyl)benzo[d]isothiazol-3(2H)-one (2i):
50.1 mg, 98%, white solid, TLC (hexane/AcOEt = 3:1): Rf = 0.38,
1H NMR (500 MHz, CDCl3) δ 8.14 (d, J = 7.8 Hz, 1H), 7.72−7.64
(m, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.45 (m, 1H), 7.29−7.24 (m, 1H),
7.17 (d, J = 7.8 Hz, 2H), 2.20 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
164.6, 141.6, 138.4, 133.6, 132.3, 129.9, 128.8, 127.6, 125.7, 124.4,
120.7, 18.2; IR (KBr, ν/cm−1) 3444, 2951, 2919, 2854, 1653, 1598,
1471, 1445, 1325, 1307, 1245, 1129, 775, 740; HRMS (ESI+) Calcd
for C15H13NOS (M + Na+) 278.0610, Found 278.0607.
2-(1-Naphthalenyl)benzo[d]isothiazol-3(2H)-one (2j): 52.8
1
mg, 95%, white solid, TLC (hexane/AcOEt = 3:1): Rf = 0.30, H
NMR (500 MHz, CDCl3) δ 8.19 (d, J = 7.8 Hz, 1H), 7.99−7.92 (m,
2H), 7.73 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.8
Hz, 2H), 7.59−7.47 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 165.6,
141.7, 134.7, 132.8, 132.6, 130.9, 130.3, 128.7, 127.9, 127.6, 127.5,
127.0, 126.0, 125.6, 123.9, 123.2, 120.5; IR (KBr, ν/cm−1) 3444, 1659,
1596, 1507, 1446, 1394, 1305, 1272, 1139, 908, 798, 770, 739, 672,
645, 613; HRMS (ESI+) Calcd for C17H11NOS (M + Na+) 300.0454,
Found 300.0449.
7.8 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.42 (dd, J = 7.8, 7.8 Hz, 1H),
4.62 (s, 2H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.3,
166.1, 141.0, 132.6, 127.1, 125.9, 123.5, 120.6, 52.9, 44.8; IR (KBr, ν/
cm−1) 3446, 1749, 1647, 1636, 1339, 1316, 1213, 1088, 742; HRMS
(ESI+) Calcd for C10H9NO3S (M + Na+) 246.0195, Found 246.0186.
N,N′-(Hexane-1,6-diyl)bis(2-mercaptobenzamide) (3): 3.43 g,
1
93%, light green solid, TLC (hexane/AcOEt = 1:2): Rf = 0.18; H
2-(3-Pyridinyl)benzo[d]isothiazol-3(2H)-one (2k): 43.8 mg,
1
NMR (400 MHz, DMSO) δ 8.51 (s, 2H), 7.47 (d, J = 7.5 Hz, 2H),
7.40 (d, J = 7.5 Hz, 2H), 7.27 (dd, J = 7.5, 7.5 Hz, 2H), 7.15 (dd, J =
7.5, 7.5 Hz, 2H), 5.36 (s, 2H), 3.29−3.11 (m, 4H), 1.52 (m, 4H), 1.36
(m, 4H); 13C NMR (125 MHz, CDCl3) δ 168.9, 133.7, 133.1, 131.2,
130.8, 128.1, 125.5, 39.8, 29.7, 26.4; IR (KBr, ν/cm−1) 3455, 3010,
2920, 1702, 1637, 1540, 1424, 1368, 1317, 1236, 1093, 744; HRMS
(ESI+) Calcd for C20H24N2O2S2 (M + Na+) 411.1171, Found
411.1156.
2,2′-(Hexane-1,6-diyl)bis(benzo[d]isothiazol-3(2H)-one) (4):
66.0 mg, 87%, white solid, TLC (hexane/AcOEt = 1:2): Rf = 0.34;
1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.5 Hz, 2H), 7.59 (dd, J =
7.5, 7.5 Hz, 2H), 7.54 (d, J = 7.5 Hz, 2H), 7.40 (dd, J = 7.5, 7.5 Hz,
2H), 3.89 (t, J = 7.1 Hz, 4H), 1.81−1.73 (m, 4H), 1.50−1.41 (m, 4H);
13C NMR (125 MHz, CDCl3) δ 165.6, 140.3, 131.9, 126.9, 125.7,
125.0, 120.6, 44.0, 30.0, 26.4; IR (KBr, ν/cm−1) 3453.9, 2929.3,
2856.1, 2799.2, 1638.2, 1459.9, 1446.4, 1187.9, 1160.0, 1100.2, 786.8,
741.5, 674.0; HRMS (ESI+) Calcd for C20H20N2O2S2 (M + Na+)
407.0858, Found 407.0840.
95%, brown solid, TLC (hexane/AcOEt = 2:1): Rf = 0.43, H NMR
(500 MHz, CDCl3) δ 8.93 (d, J = 2.2 Hz, 1H), 8.53 (d, J = 3.9 Hz,
1H), 8.16 (m, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.69−7.64 (m, 1H), 7.59
(d, J = 8.0 Hz, 1H), 7.44 (dd, J = 8.0, 8.0 Hz, 1H), 7.40 (dd, J = 8.0,
8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 164.6, 147.7, 145.1,
139.9, 134.7, 133.1, 131.7, 127.5, 126.3, 124.3, 124.0, 120.5; IR (KBr,
ν/cm−1) 3688, 3647, 3472, 3098, 1670, 1652, 1574, 1481, 1446, 1424,
1322, 1301, 1133, 801, 781, 734, 699, 670, 633; HRMS (ESI+) Calcd
for C12H8N2OS (M + Na+) 251.0250, Found 251.0240.
2-(3-Quinolinyl)benzo[d]isothiazol-3(2H)-one (2l): reaction
conditions: DMSO (2.0 mL), 100 °C, 5 h. Purification: silica gel
column chromatography (hexane/AcOEt = 1:1) 50.2 mg, 90%, brown
1
solid, TLC (hexane/AcOEt = 3:1): Rf = 0.25, H NMR (500 MHz,
CDCl3) δ 9.28 (d, J = 2.6 Hz, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.15 (d, J
= 7.8 Hz, 2H), 7.88 (d, J = 7.8 Hz, 1H), 7.77−7.69 (m, 2H), 7.66−
7.59 (m, 2H), 7.49 (dd, J = 7.8, 7.8 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 164.8, 146.8, 146.6, 140.1, 133.1, 131.4, 130.3, 130.1, 129.6,
128.1, 127.93, 127.87, 127.6, 126.4, 124.4, 120.6; IR (KBr, ν/cm−1)
3442, 1664, 1630, 1597, 1426, 1344, 1320, 1296, 1423, 1107, 974, 781,
733, 670; HRMS (ESI+) Calcd for C16H10N2OS (M + Na+) 301.0406,
Found 301.0409.
ASSOCIATED CONTENT
■
S
* Supporting Information
2-Hexylbenzo[d]isothiazol-3(2H)-one (2m): 46.8 mg, >99%,
1
pale-yellow solid, TLC (hexane/AcOEt = 3:1): Rf = 0.52, H NMR
Copies of NMR spectra for all compounds; crystallographic
information file. This material is available free of charge via the
Internet at http://pubs.acs.org.
(500 MHz, CDCl3) δ 8.03 (d, J = 7.5 Hz, 1H), 7.62−7.57 (m, 1H),
7.57−7.52 (m, 1H), 7.39 (ddd, J = 7.5, 7.5, 1.3 Hz, 1H), 3.89 (td, J =
7.4, 2.6 Hz, 2H), 1.82−1.68 (m, 2H), 1.42−1.24 (m, 6H), 0.88 (t, J =
5.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 165.5, 140.3, 131.8,
126.8, 125.6, 125.1, 120.5, 44.2, 31.6, 29.7, 26.5, 22.7, 14.2; IR (KBr,
ν/cm−1) 3457, 2955, 2928, 2857, 1649, 1598, 1447, 1339, 1303, 1248,
1189, 740, 673; HRMS (ESI+) Calcd for C13H17NOS (M + Na+)
258.0923, Found 258.0918.
AUTHOR INFORMATION
■
Corresponding Author
*kuninobu@mol.f.u-tokyo.ac.jp (Y.K.); kanai@mol.f.u-tokyo.
ac.jp (M.K.).
2-(tert-Butyl)benzo[d]isothiazol-3(2H)-one (2n): 38.2 mg, 92%,
1
Notes
white solid, TLC (hexane/AcOEt = 3:1): Rf = 0.55, H NMR (500
MHz, CDCl3) δ 7.94 (d, J = 7.7 Hz, 1H), 7.55 (dd, J = 7.7, 7.7 Hz,
The authors declare no competing financial interest.
E
dx.doi.org/10.1021/jo401056g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(14) Investigation of several concentrations (CuI, 1.0 mol %; O2, 1.0
atm; DMF; 70 °C; 6 h): 0.01 M, 77%; 0.05 M, 84%; 0.20 M, 90%; 0.50
M, 86%; 1.0 M, 73%.
ACKNOWLEDGMENTS
■
This work was supported in part by ERATO from JST.
(15) Investigation of several temperatures (CuI, 1.0 mol %; O2, 1.0
atm; DMSO; 6 h): 25 °C, 11%; 40 °C, 37%; 60 °C, 66%; 80 °C, 90%.
In the case of DMF as a solvent: (CuI, 1.0 mol %; O2, 1.0 atm; DMF;
6 h): 25 °C, 9%; 60 °C, 92%; 70 °C, >99%; 80 °C, >99%.
(16) Investigation of several reaction times (CuI, 0.3 mol %; O2, 1.0
atm; DMF; 70 °C): 3 h, 74%; 4.5 h, 97%; 5 h, >99%.
(17) The product 2a was obtained in 62% yield when the reaction
was carried out under air conditions.
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(11) Investigation of several catalysts (catalyst, 1.0 mol %; O2, 1.0
atm; DMSO; 100 °C; 6 h): none, 31%; KBr, 84%; FeBr3, 35%; CuI,
>99%. In other conditions (catalyst, 0.3 mol %; O2, 1.0 atm; DMF; 70
°C; 5 h): none, 11%; KBr, 0%; MnBr2, 27%; FeBr3, 38%; CoI2, 24%;
NiI2, 26%; CuCl, 63%; CuBr, 83%; CuBr2, 69%; Cu(OAc)2, 80%;
Cu2O, 13%; CuO, 11%.
(12) Investigation of the amount of catalyst loading (CuI, O2, 1.0
atm; DMF; 70 °C; 6 h): 0.10 mol %, 87%; 0.30 mol%, 99%; 0.50 mol
%, 99%.
(13) Investigation of several solvents (CuI, 1.0 mol %; O2, 1.0 atm;
60 °C; 6 h): 1,4-dioxane, 17%; toluene, 9%; 1,2-dichloroethane, 7%;
isopropanol, 15%; methanol, 11%; NMP, 18%; DMA, 18%; DMF,
97%; acetonitrile, 22%; water, 11%.
F
dx.doi.org/10.1021/jo401056g | J. Org. Chem. XXXX, XXX, XXX−XXX