An efficient copper-catalyzed synthesis of 2-mercaptobenzothiazole through S-arylation/heterocyclization of 2-haloaniline with potassium xanthate

Article abstract of DOI:10.1080/10426507.2015.1067208

A mild and efficient methodology to produce 2-mercaptobenzothiazoles in DMF via ortho-haloaniline coupling with potassium O-ethyl dithiocarbonate catalyzed by copper without a ligand has been developed.

Full text of DOI:10.1080/10426507.2015.1067208

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
An efficient copper-catalyzed synthesis of 2-
mercaptobenzothiazole through S-arylation/
heterocyclization of 2-haloaniline with potassium
xanthate
Lei Liu, Ning Zhu, Min Gao, Xiaole Zhao, Limin Han & Hailong Hong
To cite this article: Lei Liu, Ning Zhu, Min Gao, Xiaole Zhao, Limin Han & Hailong Hong (2015):
An efficient copper-catalyzed synthesis of 2-mercaptobenzothiazole through S-arylation/
heterocyclization of 2-haloaniline with potassium xanthate, Phosphorus, Sulfur, and Silicon
and the Related Elements, DOI: 10.1080/10426507.2015.1067208
To link to this article: http://dx.doi.org/10.1080/10426507.2015.1067208
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Oct 2015.
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Date: 24 January 2016, At: 01:57

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An efficient copper-catalyzed synthesis of 2-mercaptobenzothiazole through
S-arylation/heterocyclization of 2-haloaniline with potassium xanthate
1
1,
1
1
1
1
Lei Liu , Ning Zhu , Min Gao , Xiaole Zhao , Limin Han , Hailong Hong
1
Chemical Engineering College, Inner Mongolia University of Technology, Hohhot, 010051, P.
R. China
*
Corresponding author Email: Zhuning2622@yahoo.com
Abstract
A mild and efficient methodology to produce 2-mercaptobenzothiazoles in DMF via
ortho-haloaniline coupling with potassium O-ethyl dithiocarbonate catalyzed by copper without
a ligand has been developed.
Keyword
2
-mercaptobenzothiazole, ortho-iodoaniline, potassium O-ethyl dithiocarbonate,
copper-catalyzed synthesis
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INTRODUCTION
2
-Mercaptobenzothiazole (MBT) also named 1,3-benzothiazole-2(3H)-thione was prepared
1
for the first time by Hofmann in 1887 .2-Mercaptobenzothiazole is an important
2
-5
6-10
heterocyclic compound and broadly applied in industrial production , organic chemistry
and
1
1-13
biology medical industry
. For example, MBT 1 can be used as a rubber vulcanization
2
6
accelerator , and an important intermediate in organic synthesis . Additionally, 1, as a ligand, can
4
be used to prepare organolanthanide luminescent complexes .
1
1
6
-(Trifluoromethyl)benzothiazole-2-thiol 2 shows antimicrobial activity . Transition metal
complexes 3 have an excellent inhibitory effect on fungi, which are good at controlling diseases
1
2
of crops . Furthermore, Au/MBT complexes, as biosensors, are applied to a variety of
agricultural products such as vegetables and fruits for carbamate and organophosphate pesticide
5
13
detection . The substituted MBT 4 exhibits an antioxidant effect , which could be used as
potential radioprotective agent (Figure 1).
1
4
There are many different methods to prepare 2-mercaptobenzothiazole (Scheme 1).
1
5
Sebrell reported that aniline reacted with sulfur and carbon disulfide at high temperature (200 -
o
4
00 C) and high pressures (2MPa-9MPa) to form 2-mercaptobenzothiazole in 1923 (route a).
1
6-18
This method was mainly used to produce 2-mercaptobenzothiazoles in industry
. It should be
noticed that these protocols from aniline require drastic reaction conditions, and odorous,
1
9
flammable carbon disulfide. Kumar gave a protocol in which 2-aminobenzenethiol reacted with
2
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potassium O-ethyl dithiocarbonate, assisted by microwaves, for the synthesis of
2
-mercaptobenzothiazole (route b). This strategy avoids the usage of carbon disulfide. However,
20
the starting material 2-aminobenzenethiol was readily oxidized. Thus, our research group
developed the idea that 2,2'-disulfanediyldianiline was used as the staring material reacted with
carbon disulfide to prepare 2-mercaptobenzothiazole in the presence of DBU/EtSH (route c).
2
-Mercaptobenzothiazoles can also be afforded from the reaction of ortho-haloanilines with
2
1-24
25
carbon disulfide
. Moreover, Scott prepared 2-mercaptobenzothiazole from the interaction
of 2-chlorobenzothiazole and thiourea. Thiocarbanilide could react with sulfur under high
1
5
pressure at 265°C to give 2-mercaptobenzothiazole . But those staring materials
2
6
(
2-chlorobenzothiazole and thiocarbanilide) were not easily obtained. In addition, Singh et al.
o
reported 2-bromoanilines reacted with potassium ethyl xanthate at 160 -170 C for 7h to afford
2
7-31
2
-mercaptobenzothiazoles (route d). Other workers
used nucleophilic aromatic substitution
reaction of ortho-haloanilines (2-F, 2-Br, 2-Cl) with potassium O-ethyl dithiocarbonate to
synthesize 2-mercaptobenzothiazoles at high temprature in DMF giving good yields. To
overcome the drawback of high temperature and increase the productivity, the reaction of
ortho-haloanilines with potassium O-ethyl dithiocarbonate was improved by microwave
3
2
irradiation . In recent years, a three-component reaction has been applied in the synthesis of
3
3, 34
33
2
-mercaptobenzothiazole
. For example, Dang et al. gave an efficient copper-catalyzed
three-component reaction of ortho-iodoaniline, isocyanide, and potassium sulfide for the
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synthesis of 2-mercaptobenzothiazole. However, 2-mercaptobenzothiazole could not be obtained
effectively from the reaction of 2-iodoaniline with potassium/sodium O-ethyl dithiocarbonate
under the present reaction conditions.
Despite those interesting examples, it is still meaningful to develop a mild method to
synthesize 2-mercaptobenzothiazoles. To our knowledge, there is few report about utilizing the
reaction of ortho-iodoaniline with potassium/sodium O-ethyl dithiocarbonate to prepare the
2
-mercaptobenzothiazole. Therefore, we initially examined the model reaction of
ortho-iodoaniline with potassium O-ethyl dithiocarbonate in DMF under various conditions to
optimize the reaction conditions. In this model reaction, excessive amount of potassium O-ethyl
dithiocarbonate was used to guarantee the reaction completed.
RESULTS AND DISCUSSION
As shown in Table 1, the liquid chromatographic (LC) yield of the desired product was
2
1.3%, when ortho-iodoaniline 1a reacted with 2 at 90 C for 24h without any catalyst (Entry 1).
However, when CuCl was added into the reaction mixture, the yield of the target product was
remarkably improved (91.7%) (Entry 2). Moreover, it only took 6h to complete the reaction
determined by TLC, which showed that CuCl could catalyze the reaction of 1a and 2. When we
raised the reaction temperature from 90 C to 110 C (Entry 3), the yield of the target product
was increased correspondingly from 91.7% to 98.8%. Furthermore, CuI, CuCl
2
and Cu(OAc)
2
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


could also been utilized to catalyze the reaction of 1a with 2, and the anion of I , Cl , OAc have
negligible influence on the reaction (Entries 4-6). As shown in the experimental results, the
product 3a could be obtained in a slightly higher yield catalyzed by CuCl than other copper
o
catalysts (Entries 3-6). It turned out that 0.1 equivalent CuCl at 110 C in DMF under the
atmosphere of argon gave the best results.
To explore the scope and limitations of this methodology, a variety of substituted
ortho-haloanilines were used to react with potassium O-ethyl dithiocarbonate under the
optimized reaction conditions to synthesize the derivatives of 2-mercaptobenzothiazole (Table
2
). Potassium O-ethyl dithiocarbonate reacted with ortho-iodoaniline, ortho-chloroanilines and
ortho-bromoanilines to produce 2-mercaptobenzothiazoles in high yields (Entries 1-3). We got
the same result that the relative reactivity of ortho-chloroanilines was lower than that of
3
0
ortho-bromoanilines during the preparation of 2-mercaptobenzothiazoles (Entries 2 - 3).
Different 4-halogenated ortho-iodoanilines (4-F, 4-Cl, 4-Br) were utilized to react with
potassium O-ethyl dithiocarbonate, and the corresponding products were also obtained in high
yields (Entries 4-6). Electron-withdrawing group (4-F, 4-CF
ortho-iodoanilines also gave the corresponding products in high yields (entries 4, 7-8). However,
electron-donating group (4-CH3, 4-OCH ) substituted ortho-iodoanilines only produced the target
3
, 4-CN) substituted
3
product in 44.2% and 63.6% yield (Entries 9-10). Furthermore, we examined the reaction of
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5
-CF and 4-Br substituted ortho-bromoanilines with potassium o-ethyl dithiocarbonate, it could
3
be seen, which also gave a high yield of the target products (Entries 10 - 11).
CONCLUSIONS
In conclusion, we established a facile method for the synthesis of 2-mercaptobenzothiazoles
via ortho-iodoaniline coupling with potassium O-ethyl dithiocarbonate catalyzed by cooper in
good yields. It also proved that copper play an important role in the coupling of C-S bond. This
methodology could produce 2-mercaptobenzothiazoles in short time at relative low reaction
temperature.
EXPERIMENTAL
All experiments were carried out under an atmosphere of argon in a Wattecs Parallel Reactor. All
materials were obtained from commercial sources and used as received. Flash column
chromatography was performed over 200-300 mesh size silica gel. Reaction was monitored by
1
13
TLC on silica gel. H NMR and C NMR spectra were recorded on Agilent 500 MHz DD2
instrument and referenced to SiMe or non-deuterated solvent signals. MS analyses were
performed on PloarisQ MS instrument (EI). All the structure of the compounds were
4
1
13
characterized by H NMR, C NMR and MS and compared with those of literature.
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General experimental procedure
A 25 mL Wattecs reaction tube was charged with 2-haloaniline 1 (0.6 mmol), potassium O-ethyl
dithiocarbonate 2 (1.8 mmol), CuCl(0.06 mmol), and DMF (2 mL). The reaction vessel was
flushed with argon three times and sealed. Then the mixture was stirred electromagnetically in an
oil bath at 110℃ for 6h. The reaction process was monitored by TLC on silica gel. After the
reaction was completed, the reaction mixture was cooled to room temperature, and then HCl (3
mL, 3mol/L) was added and stirred for another 30 min. The reaction mixture solution was
extracted by ethyl acetate (3×20 mL). Subsequently, the combined organic solutions were dried
by anhydrous sodium sulfate and the target product was purified by chromatography on a silica
gel column (eluent: petroleum ether / ethyl acetate) to give the corresponding pure product 3.
Complete characterization of the products (all known) is found in the Supplemental Materials
(
Figures S1--S13).
FUNDING
This work was supported by the National Natural Science Foundation of China (21362019) and
the Inner Mongolia Natural Science Foundation of China (2012MS0204).
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a
Table 1 Optimization of the reaction conditions
b
Entry Catalyst Solvent T (°C) Time(h) Yields (%)
1
2
3
4
5
6
-
DMF
DMF
DMF
DMF
DMF
DMF
90
90
24
6
21.3
CuCl
CuCl
CuI
91.7
110
110
110
110
6
98.8 (82.3)
86.3 (80.3)
96.3 (86.5)
96.0 (85.6)
6
CuCl
2
6
Cu(OAc)
2
6
a
Conditions: 1a (0.60 mmol), 2 (1.8 mmol), catalyst (0.06 mmol) 2 mL DMF, under the
atmosphere of argon.
b
Liquid Chromatographic yield, (Isolated yield).
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Table 2 2-Mercaptobenzothiazoles prepared by the reaction of 2-haloanilines with
a
potassium O-ethyl dithiocarbonate
b
Yield
Entry
1
1
Product
(
%)
I
3a
82.3
91.2
78.4
95.5
92.3
78.7
87.8
NH2
1
a
Br
2
3
4
5
6
7
3a
3a
3b
3c
3d
3e
NH2
1
b
Cl
NH2
1c
F
Cl
I
NH2
1
d
I
NH2
1
e
Br
I
NH2
1
f
F3C
I
NH2
1g
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NC
I
8
9
3f
82.1
NH2
1
h
H C
I
3
3g
3h
3i
44.2
63.6
98.1
97.3
NH2
1i
1
0
1
2
1
j
Br
1
1
F3C
NH2
1
k
3d
1
l
a
Conditions: 1 (0.6 mmol), 2 (1.8 mmol), CuCl (0.06 mmol) 2 mL DMF, under the atmosphere
of argon.
b
Isolated yield.
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Figure 1 Examples of 2-mercaptobenzothiazole derivatives
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Scheme 1 Literature methodologies for the synthesis of 2-mercaptobenzothiazoles
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