An Efficient Chan–Lam S-Arylation of Arylthioureas with Arylboronic Acids

Article abstract of DOI:10.1002/ejoc.201800892

A convenient and efficient protocol has been developed for the preparation of aryl-isothioureas based on the Chan–Lam C–S coupling reaction. The desired aryl-isothioureas were synthesized in good yields (up to 95 %) in the presence of Cu(OAc)₂·H₂O as catalyst and bipyridine as ligand. A variety of functional groups on the aryl-thiourea and arylboronic acid reagents are tolerated. The method features mild reaction conditions and good yields, thereby illustrating its practical synthetic value in organic synthesis.

Full text of DOI:10.1002/ejoc.201800892

A Journal of
Accepted Article
Title: An Efficient Chan-Lam S-Arylation of Arylthioureas with Aryl
Boronic Acids
Authors: Zhi-Bing Dong, Xing Liu, Shi-Bo Zhang, Hui Zhu, Yu Cheng,
and Han-Ying Peng
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800892
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10.1002/ejoc.201800892
European Journal of Organic Chemistry
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An Efficient Chan-Lam S-Arylation of Arylthioureas with Aryl
Boronic Acids
Xing Liua, Shi-Bo Zhanga, Hui, Zhua, Yu Chenga, Han-Ying Penga, Zhi-Bing Donga, b *
Dedication ((optional))
Abstract: A convenient and efficient protocol has been developed
for the preparation of aryl-isothioureas based on a Chan-Lam C-S
coupling reaction. The desired aryl-isothioureas were synthesized in
reaction.[10] For the continuous efforts on the study of C-S
coupling,[11] we wish to report here an efficient and practical
approach for the synthesis of isothioureas starting from aryl
thioureas and aryl boronic acids (Scheme 1C).
.
good yields (up to 95%) in the presence of Cu(OAc)2 H2O as catalyst
and bipyridine as ligand, a variety of functional groups on aryl-
thioureas and aryl boronic acids could be tolerated. The method
features mild reaction conditions and good yields, illustrating its
practical synthetic value in organic synthesis.
Introduction
Establishing efficient methods for constructing the isothiourea
block is currently an active area in organic synthesis. Isothiourea
derivatives are not only important structures in biological
systems but also common moieties in pharmaceutical
research.[1] A significant number of isothiourea derivatives have
been reported to have biomedical applications (Scheme 1A).[2]
Several methods have been reported for the synthesis of
substituted isothioureas. For example, the reaction of aromatic
thiols with amines,[3] isocyanates reacting with diazonium salts,[4]
and the most widely used method is substituted arylthioureas
reacting with aryl halides.[5] However, these methods suffer from
restricted substrates, high temperature, environmental issues
and the mixture of the products. Thus, the development of milder,
cheaper and more efficient method is still desirable.
Although Chan-Lam reaction is emerging as an efficient and
valuable alternative way in the construction of carbon-
heteroatom bond,[6] the formation of carbon-sulfur bond has
received less attention. Difficulties in C-S bond formation can be
attributed to the sulfur species rapidly and irreversibly
deactivating the catalyst.[7] Recently, the sulfidation using
organoboronic acids have been reported,[8] and the direct
Chan-Lam C-S coupling of arylboronic acid with cyclic thioureas
was also explored (Scheme 1B).[9] However, these reactions
Scheme 1. Synthesis and application of isothioureas.
often require harsh conditions such as moderate/low yields, Results and Discussion
sensitive to water or air, great amount of boronic acids, which on
Previous work in the Chan,[12] Cundy,[13] and Evans[14]
scale-up leads to problem of waste disposal. It is thus desirable
to develop a milder (room temperature and open to air), eco-
friendly, efficient and practical protocol for the C-S bond
formation reactions. Lately, our group described that aryl-
laboratories has revealed the efficiency of copper(II) acetate in
mediation of the cross-coupling of aryl boronic acids and
phenols or amines to give biaryl ethers and aryl alkylethers. We
sought to further develop this procedure for the formation of aryl
alkyl sulfides and report herein the success of this approach.
Initially, we explored the model reaction condition shown in
Table 1. In our early attempts to aryl thiourea (1a) with
phenylboronic acid (2a) under the conditions (1.0 equiv. of
copper(II) acetate and 1.0 equiv. of bipyridine), we found that the
yield of 3a was 86% based on 1 (Table 1, entry 1). Encouraged
by this result, various solvents were investigated, and THF gave
the best yield compared with other solvents (Table 1, entries 2-
isothioureas could be prepared via
a
copper-catalyzed
[a]
[b]
School of Chemistry and Environmental Engineering, Wuhan
Institute of Technology, Wuhan 430205, China.
E-mail: dzb04982@wit.edu.cn
http://cee.wit.edu.cn/info/1052/1538.htm
Department of Chemistry, Ludwig-Maximilians-Universität,
Butenandtstrasse 5-13, 81377 München, Germany.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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5). Subsequently, we checked the loading of catalysts and
ligands. The use of 0.8 equiv. of Cu(OAc)2 and 0.8 equiv. of Bpy
was optimal (Table 1, entries 6-8). In order to estimate the
superiority of Bpy compared to other ligands, a number of other
ligands were tested for this reaction (Table 1, entries 9-11), and
the results showed that other ligands displayed less activity.
afforded a higher yield of 3u (75%) than the o-chloro group of 3v
(57%). Diverse electron-donating substituents also showed
excellent results. The p-methyl and p-methoxy yielded the
desired products 3w (93%) and 3x (95%), respectively.
Table 2. Thiolation of substituted arylboronic acids with arylthioureaa
.
Interestingly, when Cu(OAc)2 H2O was used as a catalyst, the
yield kept the same value (92%). Thus, the relatively cheap
.
Cu(OAc)2 H2O was selected as the optimal catalyst (Table 1,
entry 12).
Table 1. Optimization of the reaction conditionsa
Entry
Catalyst
Ligand
Solvent
CH2Cl2
EtOH
DMF
MeCN
THF
THF
THF
THF
THF
Yield (%)b
1
2
3
4
5
6
7
8
9
Cu(OAc)2 (1.0 eq)
Cu(OAc)2 (1.0 eq)
Cu(OAc)2 (1.0 eq)
Cu(OAc)2 (1.0 eq)
Cu(OAc)2 (1.0 eq)
Cu(OAc)2 (0.8 eq)
Cu(OAc)2 (0.5 eq)
Cu(OAc)2 (0.1 eq)
Cu(OAc)2 (0.8 eq)
Bpy (1.0 eq)
Bpy (1.0 eq)
Bpy (1.0 eq)
Bpy (1.0 eq)
Bpy (1.0 eq)
Bpy (0.8 eq)
Bpy (0.5 eq)
Bpy (0.1 eq)
1,10-phen
86
86
81
87
92
92
66
0
87
(0.8 eq)
10
11
12
Cu(OAc)2 (0.8 eq)
Cu(OAc)2 (0.8 eq)
Cu(OAc)2 H2O (0.8 eq)
Py (0.8 eq)
Et3N (0.8 eq)
Bpy (0.8 eq)
THF
THF
THF
83
85
92
.
[a] Reaction conditions: [Cu], ligand, 1a (0.5 mmol) and 2a (0.75 mmol) in 2
mL of THF at room temperature for 4 h, open air; [b] isolated yield.
[a] Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), Cu(OAc)2 (0.8 equiv.),
Bpy (0.8 equiv.), THF (2.0 mL), room temperature, open air; Isolated yield
based on 1.
To show the generality and substrate scope of this protocol,
structurally diverse aryl boronic acids were treated with aryl
thiourea. The results are summarized in Table 2. It was
gratifying to find that a variety of substituted aryl boronic acids
could couple with aryl thiourea in moderate to excellent yields.
Generally, reactions with arylboronic acids having both electron-
withdrawing and electron-donating groups in the para, meta, or
ortho position gave products 3b-3k in moderate to excellent
yields (45-95%). In addition, the reaction was investigated with
1-naphthylboronic acid, and products 3l was afforded in decent
Table 3. Thiolation of substituted arylthioureas with phenylboronic acida
yield (76%).
The coupling of
aryl thiourea and
phenylethenylboronic acids was also successfully achieved to
give 3m and 3n in good yields (85%, 88%), which showed its
good substrate compatibility.
Studies on the scope of the coupling reactions with respect to a
wide array of electronically and structurally diverse aryl thioureas
were summarized in Table 3. As expected, the tolerance of the
catalytic system on aryl thiourea counterpart was remarkable.
The reaction showed no distinct preference toward either
electron-withdrawing or electron-donating effects of the
substituents of aryl thioureas. Diverse electron-withdrawing
substituents showed good results. Halide groups, such as F, Cl,
and Br yielded the desired products in 86-94% yield (3o, 3p, 3q),
and other electron-withdrawing groups such as NO2 and CN also
showed good results (3r, 3s). For the m-bromo group, no
significant effect of steric hindrance was observed in the
production of 3t (85%), while the less hindered o-methyl group
[a] Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), Cu(OAc)2 (0.8 equiv.),
Bpy (0.8 equiv.), THF (2.0 mL), room temperature, open air; Isolated yield
based on 1.
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10.1002/ejoc.201800892
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Motivated by the positive results above, we proceeded to
explore the electronic effects-either in the arylthiourea
component or in the arylboronic acid. The results are
summarized in Table 4. As could be seen, in general, the
process was highly tolerant for a variety of common functional
groups and the aryl-isothioureas were formed in 68-92% yields.
For aryl thioureas contain electron-withdrawing groups such as
NO2, the p-methyl arylboronic acid afforded higher yields than
the p-bromo arylboronic acid (3za, 3zb). When 3-(4-
methoxyphenyl)-1,1-dimethylthiourea was used as substrate, no
significant effect of electronic effect on the arylboronic acid was
observed (3zc, 3zd). In addition, stereo hindered (2-
bromophenyl)boronic acid and styrylboronic acid were also
suitable for the C-S coupling, furnishing the desired products
3ze and 3zf smoothly.
A possible mechanism for the reaction is outlined in Scheme 2.
Firstly, aryl boronic acid reacts with complex A to form complex
B. Secondly, aryl thiourea is transformed to aryl isothiourea by
the isomerization, which is ready for the coordination with B to
give the transmetallated product C. Complex C easily provides
the desired C-S coupling product D along with E species by
reductive elimination, E is then oxidized by oxygen to regenerate
Cu(Ⅱ) catalyst A.
Conclusions
In summary, we have demonstrated a practical method for the
synthesis of a variety of aryl-isothioureas by Chan-Lam C-S
Coupling under mild conditions. In light of its operational
simplicity, nice yields, good tolerance of functional groups and
mild conditions (room temperature, open to air), the protocol
showed potential synthetic value in the convenient preparation
of some potentially biologically active compounds.
Table 4. Thiolation of substituted arylthioureas and phenylboronic acidsa
Experimental Section
General remarks: 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.
[a] Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), Cu(OAc)2 (0.8 equiv.),
Bpy (0.8 equiv.), THF (2.0 mL), room temperature, open air; Isolated yield
based on 1.
Typical procedure for the preparation of aryl-isothioureas (TP):
Phenyl thiourea (1, 0.5 mmol), phenyl boronic acid (2, 0.75 mmol),
Cu(OAc)2 (0.4 mmol), bipyridine (0.4 mmol) were added in a dried tube
(open to air) equipped with a magnetic stirring bar, THF (2.0 mL) was
then added. The mixture was stirred at room temperature and checked
by TLC until the starting material was finished (about 4 h). The reaction
was quenched 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.
Phenyl-N,N-dimethyl-N'-phenylcarbamimidothioate (3a): According to
TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 4:1) to give the target compound 3a as a
1
yellow oil (yield = 92%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.15
(m, 7H), 6.94 (m, 1H), 6.76 (d, 2H, J = 8.0 Hz), 3.09 (s, 6H). 13C NMR
(100 MHz, CDCl3, TMS): δ (ppm) 153.0, 150.5, 133.4, 130.2, 128.9,
128.3, 126.6, 122.3, 122.2, 39.8. HRMS (ESI) m/z [M+H]+ Calcd for
C15H17N2S (257.1107), found: 257.1112.
4-Fluorophenyl-N,N-dimethyl-N'-phenylcarbamimidothioate
(3b):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3b as a colorless oil (yield = 85%). 1H NMR (400 MHz, CDCl3,
Scheme 2. Proposed reaction mechanism
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10.1002/ejoc.201800892
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TMS): δ (ppm) 7.05-6.97 (m, 4H), 6.84-6.73 (m, 3H), 6.59 (d, 2H, J = 8.0
Hz), 3.02 (s, 6H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 161.9 (d, J
= 246.0 Hz), 153.5, 150.2, 133.2 (d, J = 9.0 Hz), 128.3, 127.9 (d, J = 3.0
Hz), 122.2, 122.1, 115.9 (d, J = 22.0 Hz), 39.8. HRMS (ESI) m/z [M+H]+
Calcd for C15H16FN2S (275.1013), found: 275.1007.
154.8, 150.3, 133.1, 128.3, 123.1, 122.3, 122.0, 115.1, 63.5, 39.9, 14.7.
HRMS (ESI) m/z [M+H]+ Calcd for C17H21N2OS (301.1369), found:
301.1359.
2-Bromophenyl-N,N-dimethyl-N'-phenylcarbamimidothioate
(3i):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3i as a colorless oil (yield = 45%). 1H NMR (400 MHz, CDCl3,
TMS): δ (ppm) 7.35 (d, 2H, J = 8.0 Hz), 7.08-6.99 (m, 4H), 6.90 (t, 1H, J
= 8.0 Hz), 6.81 (t, 1H, J = 8.0 Hz), 6.64 (d, 2H, J = 8.0 Hz), 3.05 (s, 6H).
13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 150.9, 148.8, 133.1, 131.9,
131.5, 127.2, 127.0, 126.6, 123.8, 121.2, 120.9, 38.8. HRMS (ESI) m/z
[M+H]+ Calcd for C15H16BrN2S (335.0212), found: 335.0206.
4-Chlorophenyl-N,N-dimethyl-N'-phenylcarbamimidothioate
(3c):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3c as a colorless oil (yield = 85%). 1H NMR (400 MHz, CDCl3,
TMS): δ (ppm) 7.07-7.03 (m, 4H), 6.97 (d, 2H, J = 8.0 Hz), 6.85 (t, 1H, J
= 8.0 Hz), 6.62 (d, 2H, J = 8.0 Hz), 3.04 (s, 6H). 13C NMR (100 MHz,
CDCl3, TMS): δ (ppm) 151.8, 148.7, 131.8, 130.8, 130.3, 127.9, 127.2,
121.2, 121.1, 38.8. HRMS (ESI) m/z [M+H]+ Calcd for C15H16ClN2S
(291.0717), found: 291.0725.
o-Tolyl-N,N-dimethyl-N'-phenylcarbamimidothioate (3j): According to
TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 3:1) to give the target compound 3j as a
4-Bromophenyl-N,N-dimethyl-N'-phenylcarbamimidothioate
(3d):
1
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3d as a colorless oil (yield = 83%). 1H NMR (400 MHz, CDCl3,
TMS): δ (ppm) 7.21-7.18 (m, 2H), 7.06 (t, 2H, J = 8.0 Hz), 6.93-6.84 (m,
3H), 6.62 (d, 2H, J = 8.0 Hz), 3.04 (s, 6H). 13C NMR (100 MHz, CDCl3,
TMS): δ (ppm) 151.6, 148.8, 131.0, 131.0, 130.8, 127.2, 121.3, 121.1,
119.7, 38.8. HRMS (ESI) m/z [M+H]+ Calcd for C15H16BrN2S (335.0212),
found: 335.0205.
brown oil (yield = 75%). H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.07-
6.93 (m, 6H), 6.81 (t, 1H, J = 8.0 Hz), 6.62 (d, 2H, J = 8.0 Hz), 3.00 (s,
6H), 2.12 (s, 3H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 152.3,
149.3, 137.3, 131.3, 130.6, 129.1, 127.2, 126.1, 125.4, 121.0, 120.9,
38.7, 19.5. HRMS (ESI) m/z [M+H]+ Calcd for C16H19N2S (271.1264),
found: 271.1257.
3-Bromophenyl-N,N-dimethyl-N'-phenylcarbamimidothioate
(3k):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3k as a colorless oil (yield = 75%). 1H NMR (400 MHz, CDCl3,
TMS): δ (ppm) 7.26-7.24 (m, 2H), 7.12 (t, 2H, J = 8.0 Hz), 7.06-6.99 (m,
2H), 6.92 (t, 1H, J = 8.0 Hz), 6.69 (d, 2H, J = 8.0 Hz), 3.12 (s, 6H). 13C
NMR (100 MHz, CDCl3, TMS): δ (ppm) 150.8, 149.0, 134.2, 131.9, 129.0,
128.7, 127.9, 127.2, 121.5, 121.3, 121.1, 38.8. HRMS (ESI) m/z [M+H]+
Calcd for C15H16BrN2OS (335.0212), found: 335.0207.
4-Cyanophenyl-N,N-dimethyl-N'-phenylcarbamimidothioate
(3e):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3e as a colorless oil (yield = 82%). 1H NMR (400 MHz, CDCl3,
TMS): δ (ppm) 7.35 (d, 2H, J = 8.0 Hz), 7.12 (d, 2H, J = 8.0 Hz), 7.02 (d,
2H, J = 8.0 Hz), 6.84 (t, 1H, J = 8.0 Hz), 6.59 (d, 2H, J = 8.0 Hz), 3.07 (s,
6H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 149.0, 148.8, 139.3,
131.2, 128.7, 127.3, 121.5, 121.0, 117.4, 108.7, 38.7. HRMS (ESI) m/z
[M+H]+ Calcd for C16H16N3S (282.1060), found: 282.1068.
Naphthalen-1-yl-N,N-dimethyl-N'-phenylcarbamimidothioate
(3l):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3l as a brown oil (yield = 76%). 1H NMR (400 MHz, CDCl3,
TMS): δ (ppm) 7.98 (d, 1H, J = 8.0 Hz), 7.67 (d, 1H, J = 8.0 Hz), 7.57 (d,
1H, J = 8.0 Hz), 7.40-7.29 (m, 3H), 7.19-7.12 (m, 1H), 6.95 (t, 2H, J = 8.0
Hz), 6.72 (t, 1H, J = 8.0 Hz), 6.60 (d, 2H, J = 8.0 Hz), 2.97 (s, 6H). 13C
NMR (100 MHz, CDCl3, TMS): δ (ppm) 152.3, 149.1, 132.8, 131.3, 129.2,
129.2, 127.5, 127.2, 127.0, 126.4, 125.5, 125.2, 124.5, 123.6, 121.2,
121.0, 107.4, 38.8. HRMS (ESI) m/z [M+H]+ Calcd for C19H19N2S
(307.1264), found: 307.1269.
Mesityl-N,N-dimethyl-N'-phenylcarbamimidothioate (3f): According to
TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 4:1) to give the target compound 3f as a
yellow oil (yield = 73%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 6.97 (t,
2H, J = 8.0 Hz), 6.76 (t, 1H, J = 8.0 Hz), 6.62 (s, 2H), 6.55 (d, 2H, J = 8.0
Hz), 2.93 (s, 6H), 2.17 (s, 6H), 2.10 (s, 3H). 13C NMR (100 MHz, CDCl3,
TMS): δ (ppm) 153.4, 148.8, 139.8, 136.8, 127.9, 126.9, 126.2, 120.8,
120.3, 38.7, 20.6, 19.8. HRMS (ESI) m/z [M+H]+ Calcd for C18H23N2S
(299.1577), found: 299.1569.
p-Tolyl-N,N-dimethyl-N'-phenylcarbamimidothioate (3g): According to
TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 4:1) to give the target compound 3g as a
colorless oil (yield = 92%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm)
7.06 (t, 2H, J = 8.0 Hz), 6.96 (d, 2H, J = 8.0 Hz), 6.90 (d, 2H, J = 8.0 Hz),
6.84 (t, 1H, J = 8.0 Hz), 6.66 (d, 2H, J = 8.0 Hz), 2.98 (s, 6H), 2.19 (s,
3H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 153.6, 150.5, 136.7,
130.5, 129.7, 128.3, 123.1, 122.3, 122.2, 39.8, 21.1. HRMS (ESI) m/z
[M+H]+ Calcd for C16H19N2S (271.1264), found: 271.1269.
Styryl-N,N-dimethyl-N'-phenylcarbamimidothioate (3m): According to
TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 4:1) to give the target compound 3m as
a yellow oil (yield = 88%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm)
7.28-7.19 (m, 5H), 7.14 (d, 2H, J = 4.0 Hz), 6.95 (m, 1H), 6.87 (d, 2H, J =
8.0 Hz), 6.55-6.45 (m, 2H), 3.15 (s, 6H). 13C NMR (100 MHz, CDCl3,
TMS): δ (ppm) 153.3, 149.8, 136.2, 131.7, 128.6, 128.6, 127.6, 126.0,
122.5, 122.3, 120.3, 40.1. HRMS (ESI) m/z [M+H]+ Calcd for C17H19N2S
(283.1264), found: 283.1256.
4-Ethoxyphenyl-N,N-dimethyl-N'-phenylcarbamimidothioate
(3h):
4-Chlorostyryl-N,N-dimethyl-N'-phenylcarbamimidothioate
(3n):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3h as a colorless oil (yield = 95%). 1H NMR (400 MHz, CDCl3,
TMS): δ (ppm) 7.05 (t, 2H, J = 8.0 Hz), 6.96 (d, 2H, J = 8.0 Hz), 6.83 (t,
1H, J = 8.0 Hz), 6.64-6.59 (m, 4H), 3.91-3.86 (m, 2H), 3.00 (s, 6H), 1.31
(t, 3H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 158.3,
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3n as a yellow oil (yield = 85%). 1H NMR (400 MHz, CDCl3,
TMS): δ (ppm) 7.23 (m, 4H), 7.04 (d, 2H, J = 8.0 Hz), 6.97-6.88 (m, 1H),
6.53-6.39 (m, 2H), 3.16 (s, 6H). 13C NMR (100 MHz, CDCl3, TMS): δ
(ppm) 152.7, 149.8, 134.8, 133.2, 130.0, 128.7, 128.6, 127.1, 122.5,
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10.1002/ejoc.201800892
European Journal of Organic Chemistry
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122.2, 121.3, 40.1. HRMS (ESI) m/z [M+H]+ Calcd for C17H18ClN2S
(317.0874), found: 317.0878.
yellow oil (yield = 75%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.12-
7.06 (m, 5H), 6.94 (t, 2H, J = 8.0 Hz), 6.80 (t, 1H, J = 8.0 Hz), 6.60 (d, 1H,
J = 8.0 Hz), 3.02 (s, 6H), 1.99 (s, 3H). 13C NMR (100 MHz, CDCl3, TMS):
δ (ppm) 151.7, 147.5, 132.0, 129.5, 128.7, 128.7, 127.8, 125.8, 124.8,
121.6, 120.9, 38.9, 17.1. HRMS (ESI) m/z [M+H]+ Calcd for C16H19N2S
(271.1264), found: 271.1257.
Phenyl-N'-(4-fluorophenyl)-N,N-dimethylcarbamimidothioate
(3o):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3o as a colorless oil (yield = 90%). 1H NMR (400 MHz, CDCl3,
TMS): δ (ppm) 7.10-7.02 (m, 5H), 6.71 (t, 2H, J = 8.0 Hz), 6.56-6.53 (m,
2H), 3.01 (s, 6H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 157.7 (d, J
= 238.0 Hz), 152.4, 145.6, 132.0, 129.3, 127.9, 125.7, 122.2 (d, J = 8.0
Hz), 113.7 (d, J = 22.0 Hz), 38.7. HRMS (ESI) m/z [M+H]+ Calcd for
C15H16FN2S (275.1013), found: 275.1006.
Phenyl-N'-(2-chlorophenyl)-N,N-dimethylcarbamimidothioate
(3v):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3v as a colorless oil (yield = 57%). 1H NMR (400 MHz, CDCl3,
TMS): δ (ppm) 7.16-7.06 (m, 6H), 6.95 (t, 1H, J = 8.0 Hz), 6.76 (t, 1H, J =
8.0 Hz), 6.69 (d, 1H, J = 8.0 Hz), 3.03 (s, 6H). 13C NMR (100 MHz, CDCl3,
TMS): δ (ppm) 153.2, 146.5, 131.6, 129.6, 128.1, 127.9, 125.9, 125.6,
125.6, 122.8, 122.0, 38.8. HRMS (ESI) m/z [M+H]+ Calcd for
C15H16ClN2S (291.0717), found: 291.0712.
Phenyl-N'-(4-chlorophenyl)-N,N-dimethylcarbamimidothioate
(3p):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3p as a white solid (yield = 86%), mp: 81-83 oC. 1H NMR (400
MHz, CDCl3, TMS): δ (ppm) 7.09-6.94 (m, 7H), 6.52 (d, 2H, J = 8.0 Hz),
3.00 (s, 6H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 152.3, 148.0,
131.8, 129.5, 127.9, 127.2, 126.1, 125.8, 122.5, 38.7. HRMS (ESI) m/z
[M+H]+ Calcd for C15H16ClN2S (291.0717), found: 291.0723.
Phenyl-N,N-dimethyl-N'-(p-tolyl)carbamimidothioate (3w): According
to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 4:1) to give the target compound 3w as
a white solide (yield = 93%), mp: 78-80 oC. 1H NMR (400 MHz, CDCl3,
TMS): δ (ppm) 7.12-7.04 (m, 5H), 6.88 (d, 2H, J = 8.0 Hz), 6.57 (d, 2H, J
= 8.0 Hz), 2.96 (s, 6H), 2.17 (s, 3H). 13C NMR (100 MHz, CDCl3, TMS): δ
(ppm) 151.6, 147.0, 132.7, 130.5, 129.0, 128.0, 127.9, 125.5, 121.0, 38.7,
19.8. HRMS (ESI) m/z [M+H]+ Calcd for C16H19N2S (271.1264), found:
271.1269.
Phenyl-N'-(4-bromophenyl)-N,N-dimethylcarbamimidothioate
(3q):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3q as a yellow oil (yield = 94%). 1H NMR (400 MHz, CDCl3,
TMS): δ (ppm) 7.12-7.02 (m, 7H), 6.49 (d, 2H, J = 8.0 Hz), 3.14 (s, 6H).
13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 153.5, 149.4, 132.7, 131.1,
130.6, 129.0, 126.9, 124.0, 114.9, 39.8. HRMS (ESI) m/z [M+H]+ Calcd
for C15H16BrN2S (335.0212), found: 335.0218.
Phenyl-N'-(4-methoxyphenyl)-N,N-dimethylcarbamimidothioate (3x):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3x as a yellow solid (yield = 95%), mp: 77-79 oC. 1H NMR
(400 MHz, CDCl3, TMS): δ (ppm) 7.12-7.02 (m, 4H), 6.63-6.57 (m, 4H),
3.63 (s, 3H), 2.98 (s, 6H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm)
154.2, 151.8, 143.0, 132.6, 129.0, 127.9, 125.5, 121.9, 112.7, 54.4, 38.7.
HRMS (ESI) m/z [M+H]+ Calcd for C16H19N2OS (287.1213), found:
287.1208.
Phenyl-N'-(4-cyanophenyl)-N,N-dimethylcarbamimidothioate
(3r):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3r as a white solid (yield = 81%), mp: 73-75 oC. 1H NMR (400
MHz, CDCl3, TMS): δ (ppm) 7.21 (t, 2H, J = 8.0 Hz), 7.06-6.97 (m, 5H),
6.60 (d, 2H, J = 8.0 Hz), 3.10 (s, 6H). 13C NMR (100 MHz, CDCl3, TMS):
δ (ppm) 153.4, 153.3, 131.2, 130.6, 130.3, 127.9, 126.3, 121.8, 119.0,
103.0, 38.9. HRMS (ESI) m/z [M+H]+ Calcd for C16H16N3S (282.1060),
found: 282.1067.
p-Tolyl-N'-(4-fluorophenyl)-N,N-dimethylcarbamimidothioate
(3y):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3y as a yellow oil (yield = 90%). 1H NMR (400 MHz, CDCl3,
TMS): δ (ppm) 6.94-6.89 (m, 4H), 6.72 (t, 2H, J = 8.0 Hz), 6.57-6.54 (m,
2H), 3.00 (s, 6H), 2.19 (s, 3H). 13C NMR (100 MHz, CDCl3, TMS): δ
(ppm) 157.7 (d, J = 238.0 Hz), 153.1, 145.5, 135.8, 129.6, 128.6, 128.2,
122.2 (d, J = 7.0 Hz), 113.7 (d, J = 22.0 Hz), 38.7, 20.0. HRMS (ESI) m/z
[M+H]+ Calcd for C16H18FN2S (289.1169), found: 289.1163.
Phenyl-N,N-dimethyl-N'-(4-nitrophenyl)carbamimidothioate
(3s):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3s as a green oil (yield = 81%). 1H NMR (400 MHz, CDCl3,
TMS): δ (ppm) 7.82 (d, 2H, J = 8.0 Hz), 7.05-6.97 (m, 5H), 6.59 (d, 2H, J
= 8.0 Hz), 3.11 (s, 6H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 156.6,
154.7, 141.8, 131.6, 131.4, 128.9, 127.5, 124.2, 122.2, 39.9. HRMS (ESI)
m/z [M+H]+ Calcd for C15H16N3O2S (302.0968), found: 302.0957.
p-Tolyl-N'-(4-bromophenyl)-N,N-dimethylcarbamimidothioate
(3z):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3z as a colorless oil (yield = 89%). 1H NMR (400 MHz, CDCl3,
TMS): δ (ppm) 7.12 (d, 2H, J = 8.0 Hz), 6.91 (s, 4H), 6.49 (d, 2H, J = 8.0
Hz), 3.01 (s, 6H), 2.21 (s, 3H). 13C NMR (100 MHz, CDCl3, TMS): δ
(ppm) 153.2, 148.7, 136.3, 130.3, 130.0, 128.9, 128.2, 123.2, 114.0, 39.0,
20.2. HRMS (ESI) m/z [M+H]+ Calcd for C16H18BrN2S (349.0369), found:
349.0375.
Phenyl-N'-(3-bromophenyl)-N,N-dimethylcarbamimidothioate
(3t):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3t as a colorless oil (yield = 85%). 1H NMR (400 MHz, CDCl3,
TMS): δ (ppm) 7.09-7.02 (m, 5H), 6.90 (d, 1H, J = 8.0 Hz), 6.84 (t, 1H, J
= 8.0 Hz), 6.75 (t, 1H, J = 4.0 Hz), 6.51 (d, 1H, J = 8.0 Hz), 3.04 (s, 6H).
13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 152.8, 150.7, 131.3, 130.0,
128.3, 127.8, 126.0, 124.2, 123.6, 120.7, 120.0, 38.8. HRMS (ESI) m/z
[M+H]+ Calcd for C15H16BrN2S (335.0212), found: 335.0218.
p-Tolyl-N,N-dimethyl-N'-(4-nitrophenyl)carbamimidothioate
(3za):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
1
compound 3za as a yellow oil (yield = 92%). H NMR (400 MHz, CDCl3,
Phenyl-N,N-dimethyl-N'-(o-tolyl)carbamimidothioate (3u): According
to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 4:1) to give the target compound 3u as a
TMS): δ (ppm) 7.83 (d, 2H, J = 8.0 Hz), 6.85 (q, 4H, J = 8.0 Hz), 6.60 (d,
2H, J = 12.0 Hz), 3.12 (s, 6H), 2.18 (s, 3H). 13C NMR (100 MHz, CDCl3,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800892
European Journal of Organic Chemistry
FULL PAPER
TMS): δ (ppm) 155.4, 154.5, 140.8, 136.9, 130.9, 128.6, 126.4, 123.1,
121.2, 39.0, 20.0. HRMS (ESI) m/z [M+H]+ Calcd for C16H18N3O2S
(316.1114), found: 316.1107.
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
4-Bromophenyl-N,N-dimethyl-N'-(4-nitrophenyl)carbamimidothioate
(3zb): According to TP, the residue was purified by flash chromatography
on silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
Council for
a fellowship. X. L. thanks the support of
Postgraduate Innovation Foundation (CX2017088) from Wuhan
Institute of Technology.
1
compound 3zb as a green oil (yield = 68%). H NMR (400 MHz, CDCl3,
TMS): δ (ppm) 7.88 (d, 2H, J = 12.0 Hz), 7.18 (t, 2H, J = 8.0 Hz), 6.87 (d,
2H, J = 8.0 Hz), 6.63 (d, 2H, J = 8.0 Hz), 3.15 (s, 6H). 13C NMR (100
MHz, CDCl3, TMS): δ (ppm) 154.3, 153.9, 141.2, 132.1, 131.1, 129.0,
123.3, 121.3, 121.0, 39.3. HRMS (ESI) m/z [M+H]+ Calcd for
C15H15BrN3O2S (380.0063), found: 380.0071.
Keywords: aryl-isothioureas • Chan-Lam reaction • aryl-thiourea
• aryl boronic acid • synthesis
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4852-4857.
p-Tolyl-N'-(4-methoxyphenyl)-N,N-dimethylcarbamimidothioate
(3zc): According to TP, the residue was purified by flash chromatography
on silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
1
compound 3zd as a yellow oil (yield = 86%). H NMR (400 MHz, CDCl3,
TMS): δ (ppm) 7.06-6.99 (m, 4H), 6.73-6.65 (m, 4H), 3.75 (s, 3H), 3.05 (s,
6H). 2.29 (s, 3H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 155.2,
153.5, 144.2, 136.6, 130.3, 130.0, 129.7, 123.0, 113.7, 55.4, 39.7, 29.7,
21.0. HRMS (ESI) m/z [M+H]+ Calcd for C17H21N2OS (301.1369), found:
301.1376.
4-Bromophenyl-N'-(4-methoxyphenyl)-N,N-
[2]
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a) V. K. Srivastava, P. Kumar, J. C. Agarwal, S. Vrat, K. N. Dhawan, K.
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Ren, M. Cheng, Arch. Pharm. 2013, 346, 891-900.
dimethylcarbamimidothioate (3zd): According to TP, the residue was
purified by flash chromatography on silica gel (petroleum ether/ethyl
acetate = 4:1) to give the target compound 3zd as a colorless oil (yield =
87%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm) 7.21 (d, 2H, J = 8.0 Hz),
6.92 (d, 2H, J = 12.0 Hz), 6.63 (d, 2H, J = 12.0 Hz), 6.55 (d, 2H, J = 8.0
Hz), 3.67 (s, 6H), 3.02 (s, 3H). 13C NMR (100 MHz, CDCl3, TMS): δ
(ppm) 155.3, 152.7, 143.5, 132.4, 131.9, 131.9, 123.0, 120.7, 113.7, 55.4,
39.9. HRMS (ESI) m/z [M+H]+ Calcd for C16H18BrN2OS (365.0318),
found: 365.0324.
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1236.
[6]
2-Bromophenyl-N,N-dimethyl-N'-(p-tolyl)carbamimidothioate (3ze):
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate = 4:1) to give the target
compound 3ze as a colorless oil (yield = 87%). 1H NMR (400 MHz,
CDCl3, TMS): δ (ppm) 7.33 (d, 1H, J = 8.0 Hz), 7.07 (d, 1H, J = 8.0 Hz),
7.00 (t, 1H, J = 8.0 Hz), 6.89-6.83 (m, 3H), 6.54 (d, 2H, J = 8.0 Hz), 2.96
(s, 6H), 2.15 (s, 3H). 13C NMR (100 MHz, CDCl3, TMS): δ (ppm) 151.5,
147.8, 134.7, 132.9, 132.1, 131.6, 129.0, 128.0, 127.7, 124.6, 121.8,
39.7, 20.9. HRMS (ESI) m/z [M+H]+ Calcd for C16H18BrN2S (349.0369),
found: 349.0376.
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Angewandte Chemie. 2008, 47, 2880-2883.
Styryl-N,N-dimethyl-N'-(p-tolyl)carbamimidothioate (3zf): According
to TP, the residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 4:1) to give the target compound 3zf as
a yellow oil (yield = 88%). 1H NMR (400 MHz, CDCl3, TMS): δ (ppm)
7.19-7.06 (m, 5H), 6.94 (d, 2H, J = 8.0 Hz), 6.68 (d, 2H, J = 8.0 Hz),
6.48-6.37 (m, 2H), 3.04 (s, 6H), 2.15 (s, 3H). 13C NMR (100 MHz, CDCl3,
TMS): δ (ppm) 153.1, 147.5, 136.4, 131.9, 131.4, 129.3, 128.6, 127.6,
126.0, 122.1, 120.6, 40.1, 20.9. HRMS (ESI) m/z [M+H]+ Calcd for
C18H21N2S (297.1420), found: 297.1429.
[8]
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Acknowledgements
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2018, 50, 2247-2254; b) H. Zhu, X. Liu, C.-Z. Chang, Z.-B. Dong,
Synthesis 2017, 49, 5211-5216.
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,
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800892
European Journal of Organic Chemistry
FULL PAPER
S. S. Liu, Y. S. Li, Z. B. Dong, Tetrahedron Lett. 2017, 58, 4289-4292;
d) W. Xu, M. T. Zeng, M. Liu, X. Liu, C. Z. Chang, H. Zhu, Y. S. Li,Z. B.
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Gao, Z. B. Dong, Eur. J. Org. Chem. 2018, 821-828; g) X. Liu, M. Liu,
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2940.
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Entry for the Table of Contents (Please choose one layout)
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Author(s), Corresponding Author(s)*
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Title
((Insert TOC Graphic here: max.
width: 5.5 cm; max. height: 5.0 cm;
NOTE: the final letter height should
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Chan-Lam Coupling*
Xing Liu, Shi-Bo Zhang, Hui, Zhu, Yu
Cheng, Han-Ying Peng, Zhi-Bing Dong *
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Text for Table of Contents
An Efficient Chan-Lam S-Arylation of
Arylthioureas with Aryl Boronic Acids
*one or two words that highlight the emphasis of the paper or the field of the study
A convenient and efficient protocol has been developed for the preparation of aryl-isothioureas based on a Chan-Lam C-S
.
coupling reaction. The desired aryl-isothioureas were synthesized in good yields (up to 95%) in the presence of Cu(OAc)2 H2O
as catalyst and bipyridine as ligand.
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