CuI-catalyzed one-pot synthesis of benzothiazolones from 2-iodoanilines-derived carbamates and sodium sulfide

Article abstract of DOI:10.1016/j.tetlet.2012.03.006

A copper-catalyzed procedure was developed for assembling benzothiazolones from ethyl 2-iodophenylcarbamates and sodium sulfide. A number of functional groups, such as methoxy, acyl, amide, carboxylate, trifluoromethyl, fluoro, and chloro, were tolerated under these conditions, providing benzothiazolones in good yields.

Full text of DOI:10.1016/j.tetlet.2012.03.006

Tetrahedron Letters 53 (2012) 2511–2513
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
CuI-catalyzed one-pot synthesis of benzothiazolones from
2-iodoanilines-derived carbamates and sodium sulfide
Jiaojiao Li a, Yihua Zhang a, , Yongwen Jiang b, Dawei Ma b,
⇑
⇑
a Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
b State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A copper-catalyzed procedure was developed for assembling benzothiazolones from ethyl 2-iodophe-
nylcarbamates and sodium sulfide. A number of functional groups, such as methoxy, acyl, amide, carbox-
ylate, trifluoromethyl, fluoro, and chloro, were tolerated under these conditions, providing
benzothiazolones in good yields.
Received 15 January 2012
Revised 27 February 2012
Accepted 2 March 2012
Available online 14 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keyword:
Coupling
The skeleton of benzothiazolones has been frequently found in
medicines, pesticides, and dyestuffs. For example, tiaramide (1)
(Fig. 1) is a well-known antiinflammatory and analgesic drug;1
SN-56 (2) is a highly potent and selective sigma-1 receptor ligand;2
benazolin (3a) and chlobenthiazone (3b) are widely used in agri-
culture as herbicides and fungicides;3 compound 4 has shown
atypical antipsychotic property;4 sibenadet (5) is a promising drug
that is developed by AstraZeneca for the treatment of asthma,5
while compound 6 has been used in combination with steroi-
dal[3,2-C]pyrazole for the treatment of respiratory diseases.6
Traditionally, benzothiazolones were prepared by reacting
2-aminothiophenols with phosgene.7 To avoid the use of toxic
phosgene, several alternative reagents such as ClCO2Et,8 1,10-car-
bonyldimidazole (CDI),9 disuccinimido carbonate (DSC),10 and
urea11 were examined and they generally gave benzothiazolones
with satisfactory yields. Additionally, Pd(OAc)2-catalyzed cyclo-
carbonylation of 2-aminothiophenols could also be employed for
this transformation.12 However, for diverse synthesis, these
approaches suffer from the limitation of commercially available
substituted 2-aminothiophenols. To overcome this drawback,
Hirashima and coworkers attempted to use 2-halonitrobenzenes
as starting materials.13 They found that heating a mixture of
2-halonitrobenzenes, carbon monoxide, and sulfur under high
pressure could directly provide benzothiazolones. This transforma-
tion was believed to involve three consecutive reactions, namely,
nucleophilic displacement, reduction, and carbonylation. Herein,
we wish to report another alternative protocol for preparing ben-
zothiazolones, in which 2-haloanilines derived carbamates are
used as the starting materials.
Recently, we discovered that sodium sulfide could be used as a
partner for copper-catalyzed coupling reaction with aryl halides.14
In case of 2-haloanilides as substrates, coupling products
OH
R
N
Cl
N
O
N
S
N
3a
: R = CH2CO2H
N
O
O
3b: R = CH3
S
Cl
Me
N
2 (SN56)
O
N
O
S
S
1
(Tiaramide)
N
N
4
O
OMe
HN
HN
S
S
H
N
HO
S
O
O
O
O
5
(Sibenadet)
O
O
H
N
HO
N
Bu-n
6
⇑
Corresponding authors.
E-mail address: madw@mail.sioc.ac.cn (D. Ma).
Figure 1. Structures of bioactive benzothiazolones.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.006

2512
J. Li et al. / Tetrahedron Letters 53 (2012) 2511–2513
Table 2
Previous work
CuI-catalyzed synthesis of benzothiazolones from 2-iodophenylcarbamates 7a
X
Y
H
N
X
X
Y
NHCOR
I
R
N
S
+H+
-H2O
CuI, Na2S
R
O
1. 10 mol % CuI, Na2S.9H2O
X
Y
X
Y
H
N
Y
O
NHCO2Et
I
S-
DMF, 80 o
C
O
2. HOAc, 130 oC
This work
S
8
7
X
Y
H
N
X
X
Y
H
N
NHCO2R
I
OR
+H+
-ROH
CuI, Na2S
Entry
1
Productb (yield)
Entry
Productb (yield)
Y
O
S-
S
H
H
N
N
Scheme 1.
O
O
9
S
S
Me
Cl
8j (70%)
8b (72%)
Table 1
H
H
N
N
Reaction conditions screening for the synthesis of benzothiazolone from 2-iodophe-
nylcarbamates 7 and metal sulfidea
O
O
2
3c
4
10
11
12
13
S
S
n-Pr
F
H
8c (69%)
8k (65%)
NHCO2R
1. 10 mol % CuI, Na2S.9H2O, 80 oC
2. acid
N
Me
H
H
O
N
I
S
8a
N
O
O
7a: R = Et
S
F3C
7b: R = Me
S
Me
8l (66%)
8d (80%)
Entry
Aryl iodide
Solvent
Acid
Temp (°C)
Yieldb (%)
H
H
N
Me
Me
1
2
3
4
5
6
7
8
9
7a
7a
7a
7a
7a
7a
7b
7a
7a
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMA
HCl
HCl
15% H2SO4
TFA
HOAc
HOAc
HOAc
HOAc
HOAc
80
120
120
120
120
130
130
130
130
20
73
62
62
80
89
19
7
N
O
O
S
S
Ac
8m (64%)
8e (77%)
H
F
N
H
N
O
5
O
O
S
20
S
Cl
Cl
8f (61%)
a
Reaction conditions: Step 1: 2-iodophenylcarbamates (1 mmol), Na2Sꢀ9H2O
8n (68%)
(3 mmol), CuI (0.1 mmol), solvent (2 mL), 80 °C, 12 h. Step 2: Acid was added and
H
Cl
the reaction mixture was stirred at the indicated temperature.
N
H
b
Isolated yield.
N
O
O
6
7
8
14
15
16
S
MeO
MeO
S
8g (76%)
8o (72%)
H
N
H
underwent intramolecular condensation to afford substituted
benzothiazoles (Scheme 1). We envisioned that if 2-iodoanilines-
derived carbamates were used for coupling with sodium sulfide,
their products might go through another intramolecular condensa-
tion under suitable conditions, providing benzothiazolones after
elimination of the alkoxy group.
N
O
S
S
HO2C
Cl
8h (67%)
8p (84%)
H
N
H
N
O
With this idea in mind, we conducted a coupling reaction of
ethyl 2-iodophenylcarbamate 7a with Na2Sꢀ9H2O. It was found
that in the catalysis of CuI this reaction completed at 80 °C after
12 h. Upon treatment with HCl at the same temperature, 8a was
isolated with 20% yield (Table 1, entry 1). Since the coupling reac-
tion proceeded well, we assumed that low yield might result from
poor conversion or side-reactions in the cyclization step, and
therefore tried to improve this transformation. After some experi-
mentation, we were pleased to find that increasing the reaction
temperature to 120 °C could increase the yield to 73% (entry 2).
At this temperature, changing the acid from HCl to 15% H2SO4 or
TFA decreased the reaction yields (entries 3 and 4). However, a bet-
ter yield was obtained when acetic acid was used (entry 5). Further
attempts revealed that the best result could be observed when
cyclization reaction was carried out at 130 °C (entry 6). Interest-
ingly, under the same conditions, methyl 2-iodophenylcarbamate
7b only gave a 19% yield (entry 7), presumably because its carbonyl
group could be attacked more easily than that of 7a in a coupling
step. Additionally, solvent also played an important role for this
transformation, as evidenced by that poor yields were obtained
in the case of DMSO or DMA as the solvent (entries 8 and 9).
O
S
AcHN
S
8i (69%)
8q (61%)
a
Reaction conditions: ethyl 2-iodophenylcarbamates
(3 mmol), CuI (0.1 mmol), DMF (2 mL), 8 °C, 10–16 h; then HOAc was added and the
reaction was stirred at 130 °C for 36 h.
7
(1 mmol), Na2Sꢀ9H2O
b
Isolated yield.
c
The product was directly isolated at the coupling reaction step.
We next investigated the scope of this one-pot procedure by
varying 2-iodophenylcarbamates and the results were summarized
in Table 2. To our delight, the generality of this process is satisfac-
tory, as evident from the following characters: (1) both electron-
rich and electron-deficient 2-iodophenylcarbamates proceeded
smoothly under these conditions, providing the corresponding
benzothiazolones in 61–84% yields (entries 1–15); (2) a number
of functional groups, such as methoxy, acyl, amide, carboxylate,
trifluoromethyl, fluoro, and chloro, were tolerated under our condi-
tions; (3) besides 4,5- or 6-monosubstituted 2-iodophenylcarba-
mates, some 4,6- and 5,6-disubstituted 2-iodophenylcarbamates

J. Li et al. / Tetrahedron Letters 53 (2012) 2511–2513
2513
Bull. 1993, 41, 301; (c) Dog˘uer, D. S.; Ünlü, S.; Sahin, M. F.; Yegilada, E. II
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also worked well, delivering benzothiazolones 8e, f, n, and o with
good yields. Benzothiazolones 8c, q could be applied in the
synthesis of bioactive compound SN-56,2 benazolin 3a and
chlobenthiazone 3b,3 respectively. Interestingly, when ethyl
4,6-dimethyl-2-iodophenylcarbamate was employed, 8d could be
obtained directly after coupling reaction (entry 3), indicating that
the substituents and their orientations could alter the cyclization
process dramatically.
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As a conclusion, we have developed a concise procedure for
assembling substituted benzothiazolones, which relied on
a
copper-catalyzed coupling reaction between ethyl 2-iodophenylc-
arbamates and sodium sulfide.15 By using conveniently available
2-iodoanilines as starting materials, a series of substituents could
be introduced into the benzene ring of benzothiazolones at different
orientations. This advantage will make the present method applica-
ble in the synthesis of pharmaceutically important compounds.
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Acknowledgements
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The authors are grateful to the Ministry of Science and Technol-
ogy (Grant 2009ZX09501-00), Chinese Academy of Sciences and
National Natural Science Foundation of China (Grant 20632050 &
20921091) for their financial support.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
03.006.
References and notes
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