Facile synthesis of S-arylisothioureas via the S-arylation of arylthioureas with aryl iodides in water

Article abstract of DOI:10.1016/j.tetlet.2018.07.012

An environmentally benign, simple and highly efficient protocol for the synthesis of S-arylisothiourea derivatives has been achieved in good to excellent yields by reacting a series of aryl iodides with arylthioureas, using inexpensive CuSO₄·5H₂O as catalyst in water without PTC (phase transfer catalyst). The protocol features easy performance, good to excellent yields, good tolerance towards a variety of functional groups, which could be useful for the preparation of some biologically active compounds.

Full text of DOI:10.1016/j.tetlet.2018.07.012

Accepted Manuscript
Facile synthesis of S-arylisothioureas via the S-arylation of arylthioureas with
aryl iodides in water
Xing Liu, Hui Zhu, Shi-Bo Zhang, Yu Cheng, Han-Ying Peng, Zhi-Bing Dong
PII:
S0040-4039(18)30862-1
https://doi.org/10.1016/j.tetlet.2018.07.012
TETL 50121
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 May 2018
24 June 2018
2 July 2018
Please cite this article as: Liu, X., Zhu, H., Zhang, S-B., Cheng, Y., Peng, H-Y., Dong, Z-B., Facile synthesis of S-
arylisothioureas via the S-arylation of arylthioureas with aryl iodides in water, Tetrahedron Letters (2018), doi:
https://doi.org/10.1016/j.tetlet.2018.07.012
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Facile synthesis of S-arylisothioureas via the
S-arylation of arylthioureas with aryl iodides
in water
Leave this area blank for abstract info.
Xing Liua+, Hui Zhua+, Shi-Bo Zhanga, Yu Chenga, Han-Ying Penga, Zhi-Bing Donga,b*

1
Tetrahedron Letters
Facile synthesis of S-arylisothioureas via the S-arylation of arylthioureas with aryl
iodides in water
Xing Liua+, Hui Zhua+, Shi-Bo Zhanga, Yu Chenga, Han-Ying Penga, Zhi-Bing Donga,b*
aSchool of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430205, China.
bDepartment of Chemistry, Ludwig-Maximilians-Universität, Butenandtstrasse 5-13, 81377 München, Germany.
Email: dzb04982@wit.edu.cn
+These authors contribute equally to this work
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An environmentally benign, simple and highly efficient protocol for the synthesis of S-
arylisothiourea derivatives has been achieved in good to excellent yields by reacting a series of
.
aryl iodides with arylthioureas, using inexpensive CuSO4 5H2O as catalyst in water without PTC
(phase transfer catalyst). The protocol features easy performance, good to excellent yields, good
tolerance towards a variety of functional groups, which could be useful for the preparation of
some biologically active compounds.
Available online
Keywords:
S-arylisothiourea
arylthiourea
synthesis
2009 Elsevier Ltd. All rights reserved.
copper
water
1. Introduction
halides[8] or aryl boronic acids,[9] or the nucleophilic attack of
arylthiols.[10] Although these methods are suitable for certain
Isothioureas are an important class of bioactive and
industrially organic compounds with broad applications as
antivirals,[1] antihistamines,[2] insecticides,[3] acaricides,[4] and
herbicides.[5] S-arylisothioureas also show very interesting
biological effects, such as antiviral and antianginal[6] activities. In
recent years, increasing numbers of S-arylisothioureas have been
designed and synthesized for biological evaluation, including
HIV-1 inhibitors (A), anti-infective agent (B), central system
agents (C), and valosine containing protein inhibitor (D) (Figure
1).[7] Therefore the preparation of S-arylisothioureas has received
increased attention from synthetic organic chemists and
biologists.
synthesis, there somehow exist some drawbacks such as long
reaction time, expensive reagents, low yields of products, high
catalyst loading, and large amounts of solid supports, which
would eventually result in the generation of a large amount of
toxic waste. Several other methods are available for the synthesis
of S-arylisothioureas, including the S-arylation of N-
phenylthioureas with diazonium salts,[11] the reaction of
benzotriazolecarboximidamides with aromatic thiols,[12] and the
metathesis exchange reaction between isothioureas and aryl
isocyanates.[13] Although significant progress has been achieved
towards the synthesis of these compounds, development of
alternatively inexpensive, non-air sensitive catalytic systems for
the preparation of S-arylisothioureas is still highly desirable.
In recent decades, the development of environmentally
friendly reaction medium, especially water, has been paid much
attention because water is nontoxic, low price and widely
available.[14] On the other side, significant progress has been
made towards the development of copper-catalyzed C-S coupling
reactions in water recently.[15] However, PTC (phase transfer
catalyst) are normally added in most of the reported protocols. [15]
Lately, our group developed protocols for the synthesis of S-
arylisothioureas in organic phase, as well as the synthesis of the
substituted 2-mercaptobenzoheterocycles in water without
PTC.[16] For the continuous interest in the C-S coupling
reaction,[17] we present here the S-arylations of arylthioureas with
aryl iodides in water, furnishing the S-arylisothioureas by C-S
coupling.
Figure 1. Some biologically active S-arylisothioureas.
Conventionally, S-aryisothioureas have been synthesized via
the cross-coupling reactions of mercaptothioureas with aryl

2
Tetrahedron Letters
2. Results and discussions
With the above mentioned optimized conditions in hand, we
made the investigation of S-arylation of arylthiourea by reacting
with different aryl iodides and the results are summarized in
Table 2. Different aryl iodides reacted with arylthiourea to give
the corresponding S-arylisothioureas. Electron-withdrawing
substituents resulted in good yields. Halide groups such as F, Cl,
and Br yielded the desired products in 86-93% yield (entries 2, 4,
8, 9), while strongly electron-withdrawing group (NO2) gave
lower yields (entry 3). For the electron-donating alkyl or
methoxy groups, general good yields were obtained. (entries 5-7,
10, 12, 13-14). Due to the possible steric hindrance reason,
compound 3k was obtained in a moderate yield (70%, entry 11).
Initially, we carried out a set of experiments using N-
phenylthioureas (1a) and iodobenzene (2a) as model substrates in
water under air using Cu(Ⅱ) salts as the catalyst for optimizing
the reaction conditions, and the results are summarized in Table
1. First, bases were screened by using 10 mol% of CuCl2 as the
catalyst, 20 mol% of 2,2'-Bipyridine (Bpy) as the ligand, and
H2O as the solvent (entries 1-5). Cs2CO3 as the base provided the
highest yield of the product at 91% (entry 1). Several copper
.
catalysts were then investigated (entries 6-10), and CuSO4 5H2O
was selected to be the most effective catalyst for the current
reaction (entry 10). No reaction could be detected with no
catalyst loading (entry 11). When copper salt is replaced by iron
salt, no product (3a) was obtained (entry 12). Among the ligands
tested, N,N′-dimethylethylenediamine (DMEDA) showed almost
no help for reaction, whereas other ligands, such as 1,10-
phenantroline, L-proline and pyridine all showed good effect
(entries 13-16). 10 mol% of the ligand loading did not affect the
yield of the product (entry 17), while the yield of the product was
Table 2. S-arylation of arylthiourea with various aryl iodides.a
Yield %b
91
.
Entry
1
Aryl iodide
Product
reduced to 81% when 5 mol% of CuSO4 5H2O was used (entry
18). The screening of the base loading showed that 2 equiv of
Cs2CO3 was optimal (entries 17, 19-20). In addition, the product
yield dropped to 62% when the temperature was reduced to 90 oC
(entries 17, 21-22). The later control experiments showed that the
Cu(I) was also suitable for the reaction, but less reactive (entry
23). Thus, the optimal reaction conditions were set and were
3a
2
3
89
33
3b
3c
.
summarized in entry 21 (10 mol% of CuSO4 5H2O, 10 mol% of
o
2,2’-bipyridine, 2 equiv. of Cs2CO3 in water, heating at 100 C
for 3 hours).
Table 1. Screening of the reaction conditions.a
4
5
86
81
3d
3e
Entry
Catalyst
Base
Ligand
T (oC)
Yield
(%)b
91
84
89
90
84
83
88
92
89
93
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17c
18d
19e
20f
21g
22
23
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
Cs2CO3
K2CO3
KOH
K3PO4
NaOH
Bpy
Bpy
Bpy
Bpy
Bpy
Bpy
Bpy
Bpy
Bpy
Bpy
--
Bpy
1,10-Phen
L-proline
Py
DMEDA
Bpy
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
90
Cu(OAc)2
Cu(OTf)2
CuBr2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
6
7
80
83
3f
.
CuCl2 2H2O
.
CuSO4 5H2O
--
.
3g
FeCl3 6H2O
0
.
CuSO4 5H2O
93
84
89
trace
93
81
85
80
91
62
82
.
CuSO4 5H2O
.
CuSO4 5H2O
.
CuSO4 5H2O
8
9
89
93
3h
3i
.
CuSO4 5H2O
.
CuSO4 5H2O
Bpy
Bpy
Bpy
Bpy
Bpy
Bpy
.
CuSO4 5H2O
.
CuSO4 5H2O
.
CuSO4.5H2O Cs2CO3
CuSO4 5H2O
CuI
Cs2CO3
Cs2CO3
100
aReaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), Catalyst (10 mol %),
ligand (20 mol %), base (2.0 equiv), and H2O (2 mL) in a sealed tube at 90-
b
c
.
120 C for 3 h. Isolated yield. In the presence of CuSO4 5H2O (10 mol %)
10
90
3j
d
.
and 1,10-phenanthroline (10 mol %). In the presence of CuSO4 5H2O (5 mol
%) and 1,10-phenanthroline (10 mol %). eIn the presence of Cs2CO3 (1.5
equiv). fIn the presence of Cs2CO3 (1.0 equiv). gThe optimal reaction
.
conditions: 10 mol% of CuSO4 5H2O, 10 mol% of 2,2’-bipyridine, 2 equiv. of
Cs2CO3 in water, heating at 100 oC for 3 hours.

3
6
61
3t
11
12
70
93
3k
3l
7
8
50
45
95
82
3u
3v
3w
3x
13
14
94
94
3m
3n
9
10
a
Cs2CO3
oC Isolated yield.
Studies on the scope of the coupling reactions with respect to
11
12
85
3y
3z
a wide array of electronically and structurally diverse thioureas
were summarized in Table 3. As expected, the reaction showed
good functional compatibility. Substrates bearing ortho Br or Cl
group resulted in moderate yield (entries 7-8). To further
illustrate our protocol in the organic synthesis, we explored the
benzo-heterocycle substrate (entry 12). It is a pity that the
benzo[d]thiazole-2(3H)-thione could not be converted to the
desired product 3z under the standard conditions. While the
reaction could be proceeded smoothly when TBAB
(tetrabutylammonium bromide, 5 mol %) was added.
87c
traced
aReaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), CuSO4 5H2O (10 mol %),
.
2,2’-bipyridine (10 mol %), Cs2CO3 (2.0 equiv), H2O (2 mL), 100 oC.
bIsolated yield. In the presence of TBAB (tetrabutylammonium bromide, 5
c
mol %). dWithout TBAB.
A control experiment was conducted in a N2 atmosphere, and
the model reaction gave only trace of the product, indicating that
the oxygen in the air serves as oxidant in the reaction. Although
the reaction mechanism is not clear so far, we speculate that the
reaction proceeds through an oxidative addition−reductive
elimination mechanism via an unstable CuIII intermediate,[18]
which is energetically more feasible than other possible
mechanisms. The further details and the related applications are
still under research in our lab.
Table 3. S-Arylation of aryl iodide with various
arylthioureas.a
Entry
1
Arylthiourea
Product
Yield %b
94
3o
3. Conclusion
In summary, we have developed a simple and effective
method for the synthesis of a series of S-arylisothiourea
.
derivatives by using CuSO4 5H2O as a catalyst, the reaction was
2
3
4
96
94
96
3p
3q
3r
conducted under PTC-free (PTC: phase transfer catalyst)
conditions in an aqueous medium. The experimental simplicity,
good to excellent yields and environmental friendliness of this
protocol, is expected to be useful for the preparation of some
biologically active compounds.
Acknowledgments
We thank the foundation support from National Natural
Science Foundation of China (21302150), foundation of Chen-
Guang program from Hubei Association for Science and
Technology, foundation of Chutian distinguished fellow from
Hubei Provincial Department of Education, foundation of High-
end Talent Cultivation Program from Wuhan Institute of
Technology. Z.-B. D. acknowledges the Humboldt Foundation
and China Scholarship Council for a fellowship. X. L. thanks the
support of Postgraduate Innovation Foundation (CX2017088)
from Wuhan Institute of Technology.
5
96
3s

4
Tetrahedron Letters
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All starting materials were purchased from commercial
suppliers and used without further purification unless otherwise
stated. Yields refer to isolated compounds estimated to be >95%
pure as determined by 1H NMR and capillary GC analysis. NMR
spectra were recorded on a Bruker AM400 NMR instrument in
CDCl3 using TMS as an internal standard. Chemical shifts are
given in ppm and coupling constants (J) are given in Hz. All
melting points were determined on a RY-1G melting point
instrument without correction. High-resolution mass spectra
(HRMS) were recorded on a Finnigan MAT 95Q or Finnigan 90
mass instrument (ESI). TLC was performed using aluminum
plates coated with SiO2 (Merck 60, F-254) and visualized with
UV light at 254 nm. Column chromatography was performed on
silica gel (200-300 mesh) with PE-EtOAc as eluent.
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Typical procedure for the preparation of aryl-isothioureas (3a)
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B. J. Org. Chem. 2001; 66: 2854-2857.
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Aryl thiourea (1, 0.5 mmol), aryl iodide (2, 0.6 mmol),
.
CuSO4 5H2O (0.05 mmol), Cs2CO3 (2.0 equiv), 2,2’-bypyridine
(0.05 mmol) were added in sealed tube equipped with a septum
and magnetic stirring bar, H2O (2.0 mL) was then added. The
o
mixture was stirred at 100 C and checked by TLC until the
starting material was finished (about 3h). The reaction was
terminated with sat. NH4Cl solution (3 mL) and then extracted
with ethyl acetate. The crude solution was dried over anhydrous
Na2SO4 and evaporated under vacuum. The residue was purified
by flash column chromatography to afford the desired product
3a.
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49: 3084-3090. (b) Xu W, Zeng MT, Liu M, Liu X, Chang CZ, Zhu H, Li
YS, Dong ZB. Chem. Lett. 2017; 46: 641-643. (c) Dong ZB, Wang M,
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Eur. J. Org. Chem. 2017; 6060-6066. (h) Liu X, Cao Q, Xu W, Zeng
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5
Highlights:
●25 S-arylisothiourea derivatives are synthesized in
good to excellent yields.
●Inexpensive CuSO4.5H2O serve as catalyst, and water
serve as solvent.
●No PTC (phase transfer catalyst) is needed.
●The protocol features easy performance, good
tolerance towards a variety of functional groups.