Palladium-catalyzed tandem synthesis of 2-aminobenzothiazoles starting from unreactive 2-chloroanilines

Article abstract of DOI:10.1246/cl.170023

A simple and efficient protocol for the synthesis of 2-aminobenzothiazole derivatives is described. 2-Chloroanilines were treated with thiocarbamoyl chloride in the presence of Pd(dba)₂ and t-BuOK to afford the corresponding 2-amino-benzothiazoles in good to excellent yield via a tandem manner.

Full text of DOI:10.1246/cl.170023

Advance Publication Cover Page
Palladium-catalyzed tandem synthesis of 2-aminobenzothiazoles starting from unreactive
2-chloroanilines
Wan Xu, Meng-Tian Zeng, Min Liu, Xing Liu, Cai-Zhu Chang, Hui Zhu,
Yue-Sheng Li, and Zhi-Bing Dong*
Advance Publication on the web February 18, 2017
doi:10.1246/cl.170023
©
2017 The Chemical Society of Japan
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1
Palladium-catalyzed tandem synthesis of 2-aminobenzothiazoles starting from unreactive 2-
chloroanilines
a
a
a
a
a
a
c
a,b
Wan Xu , Meng-Tian Zeng , Min Liu , Xing Liu , Cai-Zhu Chang , Hui Zhu , Yue-Sheng Li and Zhi-Bing Dong*
a
School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430074, China
b
Key Laboratory of Green Chemical Process, Ministry of Education, Wuhan Institute of Technology, Wuhan 430074, China
c
Non-power Nuclear Technology Collaborative Innovation Center, Hubei University of Science & Technology, Xianning 437100, China
E-mail: zhibingdong80@aliyun.com
A simple and efficient protocol for the synthesis of 2-
aminobenzothiazole derivatives is described. 2-Chloroanilines
were treated with thiocarbamoyl chloride in the presence of
(entries 8-9). The effect of additive was further evaluated
entries 10-14), and the results indicated that t-BuOK is
(
superior than other bases. Solvents, temperature and the base
quantity were further investigated. The transform was conducted
in various solvents (DMAC, DMF, DMSO, toluene and
acetonitrile) but afforded the 2-aminobenzothiazole in poor to
moderate yield (entries 15-19). When the reaction was operated
Pd(dba)
2
and t-BuOK to afford the corresponding 2-
aminobenzothiazoles in good to excellent yield via a tandem
manner.
o
under 40 C or room temperature, it led to poor reactivity
Heterocycles, that most ubiqutious structural motifs, are
(entries 20-21). The excess of t-BuOK was proved crucial for
[1-3]
existing in natural products and therapeuticals . Benzothiazole
is an important constituent of various drugs and shows
fundamental potential application in the development of novel
full conversion. When one or two equivalent of base was used
giving lower yield or no product formation (entry 22-23).
[4-5]
therapeutics . For example, riluzole (a) is used as treatment of
Table 1. Screening reaction conditions for 2-chloroaniline and
[6]
armyotrophic lateral serotonin , R116010 (b) exhibits as an
a
dimethylthiocarbamoyl chloride .
[
7]
anticancer drug and 2-aminobenzothiazole (c) acts as anti-HIV
[
8]
agent (Fig. 1).
NH2
Cl
S
N
S
+
conditions
N
N
Cl
N
N
1
b
1
a
F3CO
S
Yieldb
(%)
-
-
-
-
-
-
-
83
91
62
54
31
73
67
19
25
53
65
-
NH2
S
N
N
Entry
Catalyst
Base (equiv)
Solvent
Temp
(°C)
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
40
rt
N
NH
b)
(
a)
1
2
3
4
5
6
7
8
9
1
11
12
1
1
1
1
1
1
1
Fe(OAc)
3
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
NaH (3.0)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DMAC
DMF
DMSO
(
NiCl
2
N
S
O
CuBr
Cu(OTf)
N
N
O
2
PdCl
Pd(OAc)
PdBr
Pd(PPh
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
2
N
OH
Me
2
(c)
2
Fig. 1 Examples of bioactive 2-aminobenzothiazoles
3
)
2
4
The development of efficient methods for the synthesis of
benzothiazoles has received considerable attention. Over the last
few decades, a wide range of synthetic methods have been
developed giving access to benzothiazoles bearing various
functionalities. Among the synthetic strategies, a series of
transition metal catalyzed reaction were explored to construct
benzothiazoles such as Pd , Cu , Fe and Ag . To the best
of our knowledge, there are few reports for the synthesis of
benzothiazoles using 2-chloroanilines as starting materials due
to the low reactivity of the C-Cl bond, and the reported methods
suffer from either long reaction time or low yield . Herein, we
present a facile and efficient protocol for the synthesis of 2-
aminobenzothiazoles utilizing functionalized 2-chloroanilines in
the presence of palladium catalyst.
For our initial studies, 2-chloroanilne (1a) and
dimethylthiocarbamoyl chloride (1b) were investigated under
various conditions (Table 1). For the catalyst screening,
0
2
2
K
2
CO
NEt
Cs CO
CH ONa (3.0)
3
(3.0)
(3.0)
(3.0)
2
3
3
4
5
6
7
8
9
2
2
3
2
3
2
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (2.0)
t-BuOK (1.0)
2
[10]
[11]
[12]
[13]
2
2
PhCH
CH CN
3
2
3
20
21
2
2
THF
THF
THF
THF
69
-
51
-
[14]
2
2
3
2
60
60
2
2
a
Reaction conditions: 1a (1.0 mmol), 2a (1.2 mmol), [Cat.] (5 mmol%)
solvent (3.0 mL) for 3.5 h; b Isolated yield.
Under optimal conditions, various functionalized 2-
chloroaniline derivatives and thiocarbamoyl chloride were
converted to desired benzothiazoles as shown in Table 2. 2-
Chloroanilines bearing a substitution at the 4-position tended to
cyclize well with dimethylthiocarbamoyl chloride (1b) in 71-
Fe(OAc)
were tested, but they let to no product formation (Table 1,
entries 1-7). Gratifyingly other catalysts, such as Pd(PPh and
Pd(dba) , provided the desired product in good yields
3 2 2 2 2 2
, NiCl , CuBr, Cu(OTf) , PdCl , Pd(OAc) , and PdBr
3 4
)
2

2
9
0%
yield
(entry
2-5).
When
5-substituted
2-
synthesis of various heterocyclic compounds is under research in
our laboratory.
chloroanilines were used, palladium mediated benzothiazole
formation providing desired product 6c-8c in 58-92% yield
(entry 6-8). Subsequently, the thiocarbamoyl chloride 2b was
Acknowledgement
examined under the same condition and afforded
corrsponding product 9c and 10c in 84% and 82% yield,
respectively.
We thank the foundation support from National Natural
Science Foundation of China (21302150, 11405050), Hubei
Provincial Department of Education (D20131501), Scientific
Research Foundation for the Returned Overseas Chinese
Scholars, State Education Ministry [2012]1707, President
foundation of Wuhan Institute of Technology (2014038),
foundation of Chutian distinguished fellow from Hubei
Provincial Department of Education, foundation of High-end
Talent Cultivation Program from Wuhan Institute of Technology.
We also thank Prof. Aiwen Lei at Wuhan University for his
generous NMR analysis support.
Table 2. Palladium-catalyzed synthesis of substituted 2-
a
aminobenzothiazoles .
S
NH2
Pd(dba)2, t-BuOK
N
S
R2
N
R2
R2
R1
+
R1
Cl
N
THF, 60 °C
Cl
R2
3
-3.5 h
Entry
2-Chloroaniline
Thiocarbamoyl
Product
Yieldb
chloride
S
(%)
NH2
N
N
1
2
3
4
5
6
7
8
9
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
N
N
N
N
N
N
N
S
91
Cl
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2
c
1
2
3
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a
a
a
a
a
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N
N
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80
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81
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