A catalyst-free and additive-free method for the synthesis of benzothiazolethiones from: O -iodoanilines, DMSO and potassium sulfide

Article abstract of DOI:10.1039/c8gc00477c

Under catalyst-free and additive-free conditions, a novel, convenient, eco-friendly method for the synthesis of benzothiazolethiones has been developed. The three-component reaction of o-iodoanilines and K₂S with DMSO proceeded smoothly and the corresponding benzothiazolethiones were obtained with good isolated yields. Meanwhile, this method could be used for the synthesis of thioureas from primary diamines. Furthermore, mechanism research showed that DMSO not only functioned as a carbon source, but also as a mild oxidant in this reaction.

Full text of DOI:10.1039/c8gc00477c

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DOI: 10.1039/C8GC00477C
Catalyst-free and Additive-free Method for the Synthesis of
Benzothiazolethiones from o‑Iodoanilines, DMSO and Potassium
Sulfide
Xiaoming Zhu,a,b Wenguang Li,a Xiai Luo, a Guobo, Deng, a Yun Lianga* and Jianbin Liu a*
Under catalyst-free and additive-free conditions, a novel, convenient, environment-friendly method
for synthesis of benzothiazolethiones has been developed from o-iodoanilines, K2S and DMSO.

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Catalyst-free and Additive-free Method for the Synthesis of
Benzothiazolethiones from o‑Iodoanilines, DMSO and Potassium
Sulfide
Received 00th January 20xx,
Accepted 00th January 20xx
Xiaoming Zhu,a,b Wenguang Li,a Xiai Luo, a Guobo, Deng, a Yun Lianga* and Jianbin Liu a*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Under catalyst-free and additive-free conditions,
a
novel, as solvent. However, the complex sulphur source needed
of several steps to prepare. And on this basis, our group9 found
convenient, eco-friendly method for synthesis
benzothiazolethiones has been developed. The three-component that benzothiazolethiones could be synthesized via copper-
reaction of o-iodoanilines and K2S with DMSO proceeded catalyzed tandem multiple C-S bonds formation from 2-
smoothly and obtained the corresponding benzothiazolethiones iodoaniline, K2S and isocyanides. Although these methods
with good isolated yields. Meanwhile, this method could be used avoid the use of CS2 and complex sulphur source, and also has
for the synthesis of thioureas from primary diamines. Furthermore, good substrate suitability, it requires the addition of metal
mechanism research showed that DMSO not only functioned as a catalyst and ligand, which leads to not only high reaction cost
carbon source, but also as a mild oxidant in this reaction.
but also stoichiometric amounts of waste in the reaction.
Accordingly, it is highly desirable to develop a greener and
more environment-friendly approach to benzothiazolethiones
from cheap and easy to handle sulphur source under
transition-metal-free or additive-free reaction conditions.10
2-Mercaptobenzothiazole derivatives have frequently been
used as core structures for development of pharmaceutical
agents.1 They exist in numerous bioactive molecules (Figure 1),
such as protoporphyrinogen IX oxidase (PPO) inhibitors 1 1b
radiation protectant 21 c for protective normal tissue radiation
protective agents, antibacterial agents 31d against
,
s
taphylococcus aureus, heat shock protein-90 (HSP) inhibitors
41e and CCR3 antagonists 5 1f
.
Consequently, the research and
development of synthetic methods for benzothiazolethiones
continues to be one of the most active areas in synthetic
chemistry.2-5 The conventional methods involve the
condensation of carbon disulfide with o-aminothiopheols,3 o-
haloanilines,4 or o-halonitrobenzenes.5 Nevertheless, the toxic
and unpleasant odor of carbon disulfide impedes its
application. Alternatively, the nucleophilic aromatic
Figure 1. Examples of Some Biologically Active Compounds
substitution
reactions
of
o-haloanilines
with
potassium/sodium o-ethyl dithiocarbonate for synthesis of
benzothiazolethiones were developed by Yang6 and Zhu7
respectively. Recently, Dong8 reported a green and efficient
synthesis of benzothiazolethiones by cyclization of 2-
aminothiophenols with tetramethylthiuram disulfide using H2O
In synthetic chemistry, dimethyl sulfoxide (DMSO) is not
only utilized as a cheap, low-toxic and aprotic polar solvent but
also as an important and various synthon.11 Among them,
DMSO as a one-carbon synthon was widely used in organic
synthesis. In our previous work (Scheme 1, eq 1), the
isocyanides as a C1 building block could be used to synthesize
benzothiazolethiones.9 Therefore, we attempted to use DMSO
as C1 building block instead of isocyanides. Fortunately,
benzothiazolethiones were obtained in good yields (Scheme 1,
a.National & Local Joint Engineering Laboratory for New Petro-chemical Materials
and Fine Utilization of Resources, Key Laboratory of Chemical Biology and
Traditional Chinese Medicine Research, Ministry of Education, Key Laboratory of
the Assembly and Application of Organic Functional Molecules, Hunan Normal
University, Changsha, Hunan 410081, China. Email: yliang@hunnu.edu.cn; eq 2). To the best of our knowledge, this was the first
1485192973@qq.com
successful example for construction of two C−S bonds and a
b.Key Laboratory of Functional Metal-Organic Compounds of Hunan Province,
C=S double bond from o-iodoaniline, K2S and DMSO. Herein,
Hunan Province Universities Key Laboratory of Functional Organometallic
Materials, College of Chemistry and Material Science, Hengyang Normal
University, Hengyang, Hunan 421008, China.
we wished to detail our results.
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reaction and the results were shown in Scheme 2. Firstly, the
substitutents of the amino moiety (R1) were investigated,
which could be alkyl (type I), benzyl (type II) and aryl (type III),
Scheme 1. Synthesis of Benzothiazolethiones
and various N-substituted benzothiazolethiones (2b-2n) were
obtained in moderate to perfect yields. For type I, the amino
moiety with short-chain alkyls such as methyl and ethyl were
converted into the corresponding product 2b and 2c in 92%
and 97% yield. In contrast, long-chain alkyl (1d and 1e) and
cycloalkyl (1f) substituted o-iodoanilines only give the desired
product
in
good
yields.
Remarkably,
could
3-(3-
be
hydroxypropyl)benzo[d]thiazole-2(3H)-thione
afforded in 86% yield. Moreover, N-(thiophen-2-yl)ethyl and
phenethyl substituted benzothiazolethiones were obtained in
moderate yields only.
Scheme 2. Synthesis of Benzothiazolethionesa,b
As shown in Table 1, the three-component reaction of o-iodoaniline
with K2S and DMSO were chosen as substrates to optimize the
reaction conditions. Treatment of 1a with 6 equivalents of K2S, and
o
2 mL DMSO at 140 C for 12 hours afforded the desired product 2a
in 70% yield (entry 1). Inspired by this result, the amount of K2S was
subsequently examined (entries 1-3), 6 equivalents of K2S was
found to give the best result. Notably, the reaction could not occur
without K2S (entries 4), or K2CO3 instead of K2S (entries 5). These
results indicated that the K2S played an important role for the
reaction. In the following studies, various additives such as
(CH3CO)2O, KOH, I2 and KI were tested, and they did not lead to a
significant difference in the yield of 2a (entries 6-9). Furthermore,
lower temperature resulted in lower yields, and only 15% yield was
obtained at 120 oC (entry 10). Finally, appling the conditions we
developed previous in the related studies9 (CuCl as catalyst, TMED
as ligand), the desired product was isolated in 72% yield. Compare
with catalyst-free conditions, no obvious change was observed.
Therefore, we still selected the catalyst-free conditions as the
optimized reaction conditions.
Table 1. Optimization of Reaction Conditionsa
Entry
Variation from the standard conditions Yield (%)b
1
none
70
2
K2S (3 equiv.)
57%
61%
N.D.
N.D.
30%
43%
61%
50%
15%
72%
3
K2S (5 equiv.)
4
without K2S
5
K2CO3 instead of K2S
(CH3CO)2O(1 equiv.)
KOH (1 equiv.)
I2(0.5 equiv.)
6
a
Reaction conditions:
1 (0.2 mmol), K2S (1.2 bmmol), DMSO (2 mL), under N2
atmosphere in sealed Schlenk tube, at 140 oC. Isolated yields. c o-bromoaniline
instead of o-iodoaniline.
7
8
Similarly, N-benzyl substituted benzothiazolethiones (type II,
9
10c
KI (1 equiv.)
2j-2m) could be achieved in moderate yields. These results
none
showed the substituents did not remarkably affect the
reaction. For type III, aryl substituted 3-phenylbenzo-
[d]thiazole-2(3H)-thione was obtained in 76% yield (2n).
Finally, the substituted groups on the benzene ring of o-
iodoaniline were evaluated (type IV). Under the standard
reaction conditions, the benzene rings bearing electron-
11
CuI (10 mol%), TMED (20 mol%)
a
Reaction conditions: 1a (0.2 mmol), K2S (1.2 mmol), DMSO (2 mL), under N2
atmosphere in sealed Schlenk tube, at 140 oC for 12 h. b Isolated yields. c120 oC.
Having the optimized reaction conditions in hand, we next
surveyed the substrate (1) scope of the three-component
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donating groups such as methyl and methoxyl or electron-
withdrawing groups such as fluoro, chloro and trifluoromethyl
were well tolerated and given the corresponding products in
moderate to good yields. Generally, the activity of o-
iodoanilines bearing electron-donating groups is higher than
the activity of o-iodoanilines bearing electron-withdrawing
groups. In addition, polycyclic 2-amino-1-iodonaphthalene
could give the desired products 2v in 66% yield. Unfortunately,
the o-bromoaniline was not a proper substrate, and only
obtained the benzothiazolethione (2a) in 26% yield.
88
(12 h)
7
3g
4g
24
(12 h)
8
4h
3h
a
Reaction conditions:
3 (0.4 mmol), K2S (1.2 mmol), DMSO (2 mL), under N2
atmosphere in sealed Schlenk tube, at 140 oC.b Isolated yields.
Considering thioureas with widespread application in
biological chemistry, natural products synthesis and material
science,12 we were curious about the possibility to apply this
method to synthesis thiocarbamides. As expected, when the
1,2-diamines (0.4 mmol) was treated with three equivalent of
K2S under the similar reaction conditions, the corresponding
In order to reveal the reaction mechanism, a series of
controlled experiments were performed (scheme3). Firstly,
45% of 2a were afforded when the reaction of 2-
aminobenzenethiol, K2S and DMSO was performed under
standard conditions (eq 1). No desired product 2a was
observed and 5% of benzothiazole (G) were isolated in the
products
4 were obtained in 24% to 88% yields (Tabe 2). To
absence of K2S under same reaction conditions (eq 2). These
results indicated the sulfur source impossibly derived from
DMSO. However, benzothiazole could not react with K2S to
benzothiazolethione (eq 3), but benzothiazolethione could be
benzene-1,2-diamines, whether the substituent on the
benzene ring or on the amino, the benzo[d]imidazole-2-
thionesall were given in moderate yields. Importantly, cyclic
cyclohexane-1,2-diamine 3g was employed as a substrate, and
the corresponding thiocarbamides were obtained in 88%
isolated yield. Unfortunately, the linear N,N’-dimethylethane-
1,2-diamine 3h only transformed to the desired products1,3-
dimethylimidazolidine-2-thione 4h in 24% yield.
synthesized from 2-(methylthio)benzo[d]thiazole (
These results indicate that this reaction probably involved the
2-(methylthio)benzo[d]thiazole as the intermediate.
H) (eq 4).
Moreover, by replacing DMSO with methyl phenyl sulfoxide
under the standard reaction conditions, benzothiazolethione
2a was obtained in 60% isolated yields, along with compounds
Table 2. Synthesis of Thiocarbamidesa
of benzenethiol
(2aa), methyl(phenyl)sulfide (2ab) and
diphenyl disulfide (2ac) (eq 5) was detected from the reaction
mixture via GC-MS analysis (see the ESI for details). This result
proved the DMSO not only was the C1 source of
benzothiazolethione and but also performed as an oxidant in
this reaction. Finally, dimethyl sulfide was obviously observed
via GC analysis of the model reaction of 1a, K2S and DMSO (see
the ESI for details). This result proved DMSO acted as an
oxidant to promote this reaction again.
Yield
Entry
1
Substrate 3
Product 4
(%)b
Scheme3. Controlled Experiments
65
(24 h)
3a
4a
55
(30 h)
2
3
4
3b
4b
75
(24 h)
3c
4c
50
(12 h)
3d
3e
4d
50
(12 h)
5
6
4e
4f
46
(12 h)
According to the experimental results and previous
reports,9,11,13
3f
a
proposed reaction mechanism for the
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formation of 2a from o-iodoaniline, DMSO and potassium
sulfide is given in Scheme 4. Firstly, the intermediate
obtained via nucleophilic addition reaction of the DMSO with
intermediate , which is formed by the SNAr-type reaction of
o-iodoaniline with K2S. Subsequently, the intermediate is
afforded via the oxidation of intermediate and sequentially
undergoes the process of intramolecular nucleophilic addition.
Intermediate can transform into benzothiazole or 2-
D is
C
F
D
F
(methylthio)benzo[d]thiazolevia aromatization. However, the
desired product 2a was only obtained via the nucleophilic
addition/elimination from 2-(methylthio)benzo[d]thiazole with
K2S.
Scheme 4. Possible Mechanism for the Formation of 2a
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In summary, we have disclosed a novel, convenient, eco-
friendly method for synthesis of benzothiazolethiones from o-
iodoanilines and K2S with DMSO under catalyst-free and
additive-free conditions. In this reaction, DMSO served as a C
source and an oxidant. Notably, this method could also
provide a general approach to construction of a thiocarbonyl
group from simple, low-toxic, low-odor and readily available
starting material. Further studies of this method will focus on
the detailed mechanism and applications in organic synthesis.
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This work was supported by the National Natural Science
Foundation of China (21572051
， 21602057), Ministry of
Education of the People's Republic of China (213027A),
Education Department of Hunan Province (15A109), Aid
Programs for Technology Innovative Team and Key Discipline
in Education Department of Hunan Province for financial
support. Opening Fund of Key Laboratory of Chemical Biology
and Traditional Chinese Medicine Research (Ministry of
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Conflicts of interest
There are no conflicts to declare.
Notes and references
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