Copper-Catalyzed Three-Component Synthesis of Benzothiazolethiones from o-Iodoanilines, Isocyanide, and Potassium Sulfide

Article abstract of DOI:10.1021/ol503186w

An efficient copper catalyzed strategy for the synthesis of a variety of benzothiazolethione derivatives has been developed. In the presence of CuCl, the three-component reaction of o-iodoanilines and K₂S with p-toluenesulfonylmethyl isocyanide proceeded smoothly to obtain the corresponding benzothiazolethiones in good to excellent isolated yields. Notably, isocyanide functioned as a carbon source and K₂S functioned as a sulfur source in this reaction.

Full text of DOI:10.1021/ol503186w

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Three-Component Synthesis of
Benzothiazolethiones from o‑Iodoanilines, Isocyanide, and
Potassium Sulfide
Pan Dang,† Weilan Zeng,† and Yun Liang*,†,‡
†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, Hunan Normal University, Changsha,
Hunan 410081, China
‡Beijing National Laboratory for Molecular Sciences, Beijing, 100871, China
S
* Supporting Information
ABSTRACT: An efficient copper catalyzed strategy for the synthesis of a
variety of benzothiazolethione derivatives has been developed. In the
presence of CuCl, the three-component reaction of o-iodoanilines and K2S
with p-toluenesulfonylmethyl isocyanide proceeded smoothly to obtain the
corresponding benzothiazolethiones in good to excellent isolated yields.
Notably, isocyanide functioned as a carbon source and K2S functioned as a
sulfur source in this reaction.
opper-catalyzed tandem C−S bond formations are
of 2-thio-substituted benzothiazoles.13 Nevertheless, the
toxicity and unpleasant odor of carbon disulfide still impedes
its application. To overcome this drawback, Zhang and Yang
reported a new method for the synthesis of benzothiazole-
thiones via the nucleophilic aromatic substitution reaction of o-
haloanilines with potassium/sodium o-ethyl dithiocarbonate in
good yields.14 These reported synthetic methods are useful and
interesting for the synthesis of benzothiazolethiones. However,
for the synthesis of N-substituted benzothiazolethiones, they
are limited. For these reasons, general and efficient methods for
the synthesis of benzothiazolethiones and N-substituted
benzothiazolethiones from simple and readily available
precursors are of great value.
Isocyanides, which readily undergo similar transformations as
carbon monoxide, are a class of powerful and versatile C1
building blocks. Moreover, isocyanides are more easily handled
than carbon monoxide and contain a diversity point.15 In our
previous work, we found a copper-catalyzed three-component
reaction to synthesize benzothiazolones from o-iodoanilines,
DMF, and potassium sulfide (Scheme 1, eq 1).5 In this reaction,
DMF functioned both as the carbon monoxide source and as
the reaction medium. We envisioned the DMF could be
replaced by isocyanides as a C1 building block to synthesize 2-
amino benzothiazoles (Scheme 1, eq 2). Unexpectedly,
benzothiazolethiones were obtained in good yields, and no 2-
amino benzothiazoles were observed (Scheme 1, eq 3). Herein,
we wish to detail our results.
C
powerful methods for the synthesis of sulfur-containing
heterocyclic compounds from relatively simple starting
materials in a convergent manner.1 In particular, the usage of
metal sulfides as a sulfur source for the efficient construction of
sulfur-containing heterocycles is an important strategy in
synthetic chemistry from the viewpoints of operational
simplicity, economic raw material, and assembly efficiency.2
Recently, we successfully synthesized benzo[b]thiophene,3
benzo[d]thiazole,4 benzo[d]thiazol-2(3H)-one,5 and 2-amino-
benzothiazole6 using metal sulfides as a sulfur source for
tandem C−S bond formations. However, three or greater
tandem C−S bond formations for the synthesis of sulfur-
containing compounds have been seldom reported. Therefore,
tandem multiple C−S bond formations in a step reaction
represent a significantly bigger challenge.
Benzothiazolethiones (2-mercapto benzothiazoles) are an
important class of heterocycles that not only are encountered in
a number of natural and non-natural biologically active
compounds but also are versatile synthons toward antimicro-
bial, anti-inflammatory, anthelmintic, antitubercular, antihyper-
tensive, and antihyperlipidemic drugs.7 Consequently, the
research and development of synthetic methods for benzothia-
zolethiones continues to be one of the most active areas in
synthetic chemistry.8−14 Classical methods involve the reaction
of carbon disulfide with o-aminothiopheols,9 o-halonitroben-
zenes,10 or o-haloaniline.11 Due to required harsh conditions
and poor tolerance of functional groups, the synthetic
application of these approaches is limited. Recently, Xi and
co-workers reported a DBU-promoted tandem reaction of the
o-haloanilines with carbon disulfide toward 2-mercaptobenzo-
thiazoles under relatively mild conditions.12 Ma and co-workers
developed a domino condensation/S-arylation reaction of the
o-iodoanilines and carbon disulfide with thiols for the synthesis
As shown in Table 1, o-iodoaniline 1a, p-toluenesulfonyl-
methyl isocyanide (TosMIC), and potassium sulfide were
selected as substrates to optimize the reaction conditions.
Received: November 3, 2014
© XXXX American Chemical Society
A
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Letter
were found when the reaction was carried out at 100 or 140 °C
(entries 14 and 15) and when CuCl (10 mol %) and TEMED
(20 mol %) were used as the catalyst (entry 16). Finally, under
these optimized reaction conditions, a similar result was
achieved when the NMP solvent was replaced by DMF
(entry 17).
Scheme 1. Synthesis of Benzothiazolethiones
With the optimized conditions in hand, a series of substituted
o-iodoanilines were examined in NMP or DMF respectively,
and the results are summarized in Table 2. First, o-iodoanilines
bearing an electron-withdrawing group such as fluoro, chloro,
bromo, and trifluoromethyl were screened under the standard
conditions, and these tandem thiolation reactions were
observed to be more efficient in DMF than in NMP. The
corresponding products all were afforded in moderate to good
yields. Unfortunately, 4-amino-3-iodobenzonitrile could not
produce the given product. The cyano group could not be
tolerated under the optimized reaction conditions, and low
yields of 2-thioxo-2,3-dihydrobenzo[d]thiazole-6-carbothio-
amide (2g) were obtained.14 Both in NMP and in DMF, 2-
iodoanilines bearing an electron-donating group such as methyl,
methoxyl, and N,N-dimethyl performed with similar reactive
activity and obtained higher yields than those bearing electron-
withdrawing groups. These results indicated the electron-
donating group favored the copper-catalyzed insertion of
isocyanide to 2-iodoaniline due to increasing the electrophilicity
of the amino group. Finally, we investigated the reactivity of o-
bromoaniline. Unfortunately, the o-bromoaniline could not
efficiently react with TosMIC and potassium sulfide, and a low
yield of benzothiazolethione was afforded in DMF or in NMP.
We next explored the possibility of employing N-substituted-
2-iodoanilines as the substrate to react with K2S and TosMIC,
and the results are summarized in Scheme 2. The
corresponding N-substituted benzothiazolethiones were ob-
tained in good to perfect yields. First, the substituent of the
nitrogen moiety was screened. As shown in type I (R = alkyl),
the N-alkyl benzothiazolethiones with Me, Oct, and cyclohexyl
groups were obtained in 93%, 74%, and 53% yield respectively
when NMP was used as the reaction medium. The results
showed the steric hindrance seemed to have a negative effect on
the yields of final products. As shown in type II, the R could be
substituted phenyl or naphthyl. Interestingly, the yield of 3-(4-
methylbenzyl)benzo[d]thiazole-2(3H)-thione (4f) afforded in
NMP was higher than that in DMF, and the yield of 3-(3,4-
dichlorobenzyl)benzo[d]thiazole-2(3H)-thione (4g) obtained
in DMF was higher than that in NMP. When the reaction was
performed in NMP or in DMF, the yields of the products
bearing benzyl and naphthal were not remarkably affected.
Nevertheless, it was found that when type III (N-phenyl 2-
iodoaniline) was used as the starting substrate, 3-phenylbenzo-
[d]thiazole-2(3H)-thione (4j) was obtained in a low yield
(37%) under optimized conditions. The most likely reason is
that the decreased nucleophilicity of N-aryl 2-iodoaniline and
the bigger steric hindrance effect of the benzene group result in
low reactivity. Finally, the substituted N-methyl 2-iodoanilines
(type IV) were examined, and the results showed that the
presence of an electron-donating group (methyl) or electron-
withdrawing group (fluoro, chloro) on the aromatic ring
afforded good yields of the corresponding products under the
optimized reaction conditions.
a
Table 1. Optimization of Reaction Conditions
b
b
entry catalyst
ligand
solvent
yield 2a (%)
yield 5 (%)
1
CuI
−
−
−
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NMP
DMSO
CH3CN
NMP
NMP
NMP
NMP
NMP
NMP
DMF
44
44
47
57
28
51
52
53
38
47
64
78
78
76
61
67
77
9
11
9
2
CuBr
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
3
4
TEMED
DEMED
1,10-Phen
L-Proline
TEMED
TEMED
TEMED
TEMED
TEMED
TEMED
TEMED
TEMED
TEMED
TEMED
13
36
27
20
6
5
6
7
8
9
21
12
0
10
11
12
13
c
d
e
0
0
fd
14 ,
0
gd
,
15
16
17
0
hd
,
0
d
0
a
Reaction conditions: 1a (0.3 mmol), K2S (0.9 mmol), TosMIC (0.3
mmol), Cu salt (20 mol %), ligand (40 mol %), solvent (2 mL), under
a N2 atmosphere in a sealed Schlenk tube, at 120 °C for 4 h. Isolated
yields. K2S (1.2 mmol). K2S (1.5 mmol). K2S (1.8 mmol). 140 °C.
b
c
d
e
f
g
h
100 °C. CuCl (10 mol %), TEMED (20 mol %).
Initially, the CuI-catalyzed tandem thiolation reaction of
substrate 1a and TosMIC with K2S was investigated in DMF
at 120 °C, and the desired product 2a could be isolated in 44%
yield (entry 1). Simultaneously, 9% of benzothiazole was gained
as a byproduct. Other copper salts, such as CuBr and CuCl,
were examined (entries 2 and 3). The results showed that CuCl
displayed high catalytic activity for this reaction. Then, a
screening of ligands such as 1,10-phenanthroline, TEMED, L-
proline, and DMEDA was also carried out, and the results
indicated that TEMED gave the best yield of the product
(entries 4−7). While investigating the effect of solvents, DMF
and NMP gave high yields compared to DMSO and CH3CN
(entries 8−10). In the following studies, the metal sulfides such
as Na2S and Li2S were not efficient sulfur sources for this
reaction, and no corresponding benzothiazolethione was
obtained in DMF. To our satisfaction, when the amount of
K2S increased to 5 equiv, the yield of benzothiazolethione
increased to 78% and no benzothiazole was observed (entries
11−13). Our further studies indicated that relatively low yields
In order to probe the C1 source, the reaction of o-
iodoaniline, K2S, and tert-butyl isocyanide was performed, and
25% of benzothiazolethione and 37% of 2-amino benzothiazole
were afforded (Scheme 3, eq 1). This result indicated that the
B
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a b
,
Table 2. Synthesis of Benzothiazolethiones
Scheme 2. Synthesis of N-Substituted
a
,b
Benzothiazolethiones
a
Reaction conditions: 1 (0.3 mmol), K2S (1.5 mmol), TosMIC (0.3
mmol), CuCl (20 mol %), TEMED (40 mol %), DMF or NMP (2
mL), under a N2 atmosphere in a sealed Schlenk tube, at 120 °C for 4
b
h. Isolated yields, the former in NMP, the latter in DMF.
Scheme 3. Possible Mechanism
carbon of isocyanide as the C1 source was provided to the
product. Meanwhile, this result also indicated that the 2-amino-
2-thiol-benzothiazoline F should be a key intermediate, which
would deliver benzothiazolethione or 2-amino benzothiazole
upon elimination of an amine or hydrogen sulfide, respectively.
According to the results of this transformation and previous
reports,2−6,13 a proposed catalytic cycle for the formation of
benzothiazolethione from 2-iodoaniline, TosMIC, and potas-
sium sulfide is given in Scheme 3. First, a cross-coupling
reaction of o-iodoaniline and K2S under copper-catalyzed
conditions provides the intermediate A. Second, intermediate A
undergoes a copper assisted insertion with isocyanide to
produce the intermediate C. Subsequently, intermediate C via
an intramolecular nucleophilic addition produced intermediate
D. Intermediate D undergoes protonation and subsequently
a
Reaction conditions: 1 (0.3 mmol), K2S (1.5 mmol), TosMIC (0.3
mmol), CuCl (20 mol %), TEMED (40 mol %), DMF or NMP (2
mL), under a N2 atmosphere in a sealed Schlenk tube, at 120 °C for 4
b
h. Isolated yields, the former in NMP, the latter in DMF.
C
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Organic Letters
Letter
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Intermediate D also undergoes a coupling reaction with K2S
to achieve the intermediate F. Finally, two pathways may take
place from intermediate F: elimination of an amine or hydrogen
sulfide from intermediate F affords benzothiazolethione 2a or
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In conclusion, we have disclosed an efficient copper-catalyzed
three-component reaction of o-iodoaniline, isocyanide, and
potassium sulfide for the synthesis of benzothiazolethiones.
Notably, this method could provide a general approach to N-
substituted benzothiazolethiones from simple and readily
available starting material. In this reaction, isocyanide acts as
a C1 source for constructing complex benzothiazolethiones.
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ASSOCIATED CONTENT
■
S
* Supporting Information
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Supporting Information for this letter is available (Experimental
details, and scanned NMR spectra of all new products). This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yliang@hunnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Natural Science Foundation of
China (21072054), Ministry of Education of China
(20094306120003, 213027A), Training Program Foundation
for the Young Talents by Hunan Normal University
(ET21003), Hunan Provincial Natural Science Foundation
(12JJ2009), Scientific Research Fund of Hunan Provincial
Education Department (12A095), and Aid Program for Science
and Technology Innovative Research Team in Higher Educa-
tional Institutions of Hunan Province for financial support.
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