Copper-Catalyzed S-Arylation of Arylthioureas by Using Diaryliodonium Salts

Article abstract of DOI:10.1055/s-0036-1591569

A convenient and efficient copper-catalyzed S-arylation of arylthioureas using diaryliodonium salts is reported. The desired arylisothioureas were synthesized in good yields in the presence of CuCl as catalyst and K ₂ CO ₃ as base, and a wide variety of functional groups on the arylthioureas and diaryliodonium salts were tolerated. The protocol affords an alternative synthesis of some potentially useful biological and pharmaceutical compounds.

Full text of DOI:10.1055/s-0036-1591569

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–H
paper
A
en
H. Zhu et al.
Paper
Synthesis
Copper-Catalyzed S-Arylation of Arylthioureas by Using Diaryl-
iodonium Salts
Hui Zhua
Xing Liua
Yu Chenga
Han-Ying Penga
Yue-Sheng Li*b
Zhi-Bing Dong*a
S-arylation
N
N
R2
H
I+
CuCl (6.25% equiv)
K2CO3 (2.5 equiv)
N
N
S
R1
R2
R1
R1
+
S
DMSO, 100 °C, 2 h
short reaction time
X–
22 examples
yield: 74–88%
a School of Chemistry and Environmental Engineering,
Wuhan Institute of Technology, Wuhan 430205,
P. R. of China
R
2 = F, Cl, Br, NO2, OMe, H
wide substrate scope
dzb04982@wit.edu.cn
b Nonpower Nuclear Technology Collaborative Innovation
Center, Hubei University of Science & Technology,
Xianning 437100, P. R. of China
frank78929@163.com
Received: 15.02.2018
Accepted after revision: 19.03.2018
Published online: 25.04.2018
veloping arylthioureas and relevant applications,9 herein
we report an alternative synthesis of the important aryliso-
thiourea building block starting from arylthioureas and dia-
ryliodonium salts in the presence of copper catalyst.
DOI: 10.1055/s-0036-1591569; Art ID: ss-2018-z0094-op
Abstract A convenient and efficient copper-catalyzed S-arylation of
arylthioureas using diaryliodonium salts is reported. The desired aryli-
sothioureas were synthesized in good yields in the presence of CuCl as
catalyst and K2CO3 as base, and a wide variety of functional groups on
the arylthioureas and diaryliodonium salts were tolerated. The protocol
affords an alternative synthesis of some potentially useful biological and
pharmaceutical compounds.
At the outset of the study, diphenyliodonium nitrate
(1a) and phenylthiourea 2a were chosen as model sub-
strates to establish the best reaction conditions (Table 1).
The initial effort to select a green solvent for the reaction
was not successful (entries 1 and 2). To our delight, the de-
sired product 3a could be obtained in good yield when 1a
was reacted with 2a in the presence of Cs2CO3 and DMSO
catalyzed by CuI at 100 °C (entry 3). In efforts to improve
the yield, a variety of bases including Et3N, KOH, K2CO3, and
KOt-Bu were screened (entries 4–7), and K2CO3 was found
to be the most suitable. Subsequently, screening of metal
catalysts was performed (entries 8–17) which revealed that
CuCl was the most efficient (entry 12). We next checked the
effects of various solvents, such as DMF, THF, and toluene,
which were less effective than DMSO (entries 18–20 vs 12).
Moreover, decreasing the reaction temperature from 100 °C
to room temperature had a negative effect on the yield,
Key words copper, S-arylation, arylthioureas, diaryliodonium salts,
synthesis
Arylisothioureas are important structural motifs in syn-
thetic chemistry owing to their biological activities; exam-
ples include nitric oxide synthase (NOS) inhibitors, anti-in-
fective agents, and central nervous system agents (Figure
1).1 As a result, research on the applications and synthesis
of aryisothioureas has attracted the attention of many biol-
ogists and chemists. Traditional synthetic routes to aryliso-
thioureas have often relied on the reaction of aromatic thi-
ols with amines,2 reaction with sodium sulfide as a sulfur
source,3 and the reaction of isocyanates with diazonium
salts,4 as well as the reaction of aryisothioureas with prima-
ry amines or alkyl halides.5 In general, these reactions are
efficient; however, they suffer from the formation of unde-
sired products or the restricted availability of substrates.4,5
Hypervalent iodine chemistry is currently a field of in-
tense development.6 Thanks to the variety of possible de-
rivatives, diaryliodonium salts have been widely used in or-
ganic synthesis because of their low toxicity, stability, high
reactivity, and availability.7 Recently, we described the cop-
per-catalyzed synthesis of arylisothioureas starting from
iodobenzenes.8 As part of our long-standing interest in de-
N
N
S
NOS inhibitor
S
N
N
O
S
N
N
anti-infective agent
central nervous system agent
Figure 1 Isothioureas with biological activity
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

B
H. Zhu et al.
Paper
Synthesis
whereas increasing the temperature to 120 °C made almost
no difference (entries 21–23). To further optimize the reac-
tion parameters, we optimized the catalyst and base load-
ing: 0.0625 equivalents of CuCl and 2.5 equivalents of K2CO3
were found optimal for this reaction (entries 24–26). We
also found the best reaction time was 2 hours (entries 24,
27, and 28). The best reaction conditions are summarized in
entry 24.
Table 1 Optimization of the Reaction Conditionsa
N
S
H
I+
N
N
N
+
S
–
NO3
1a
3a
2a
With the optimized conditions in hand, we were ready
to prepare a series of arylisothioureas (Table 2). Thus, a va-
riety of substituted diaryliodonium salts 1 were treated
with substituted arylthioureas 2 under the optimized reac-
tion conditions. In general, substituted diaryliodonium
salts with various counteranions reacted with arylthioureas
well, furnishing the desired C–S coupling products in good
yields, although diaryliodonium salts 1 with electron-do-
nating groups gave the corresponding products in slightly
lower yields (entries 4, 5, 9, and 10). Examination of the
substrate scope of different substituted arylthioureas 2 re-
vealed that electron-withdrawing or electron-donating
groups on the phenyl ring (such as methoxy, fluoro, chloro,
bromo, or nitro) have almost no or little effect on the yield,
demonstrating the broad substrate compatibility.
Thereafter, the unsymmetrical salts 1f and 1g were also
used to investigate the regioselectivity of diaryliodonium
salts (Scheme 1). The reactions of 2a with unsymmetrical
salts 1f and 1g were performed under the standard condi-
tions, and revealed that the less sterically hindered C–S
coupling products 3a and 3b were favored (68% and 65%
yield, respectively), showing the regioselectivity.
A possible reaction mechanism is proposed (Scheme 2)
according to the reaction results and the related literature.10
Firstly, oxidation of Cu(I) salt A with iodonium nitrate
would give active aryl–Cu(III) species B. Secondly, the
phenylthiourea would isomerize to the corresponding
phenylisothiourea C in the presence of base, which is then
ready for coordination with B to give intermediate D. Final-
ly, reductive elimination of D would yield the coupling
product E and regenerated Cu(I) catalyst A allowing the cat-
alytic cycle to continue.
In conclusion, we have developed an alternative proto-
col for the synthesis of arylisothioureas using diaryliodoni-
um salts as the electrophilic coupling partner. In the pres-
ence of copper catalyst, the diaryliodonium salts reacted
smoothly with arylthioureas to give the desired aryliso-
thioureas. The protocol, which features easy performance,
broad substrate scope, and good yields, affords an alterna-
tive way for the synthesis of a number of potentially useful
biological and pharmaceutical compounds. Further details
on the reaction mechanism and related applications are un-
der study in our laboratory.
Entry
Catalyst
Base
Solvent
Temp (°C) Yieldg
(%)
1
2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
–
–
H2O
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
r.t.
15
37
71
25
43
29
80
19
77
67
65
84
41
30
39
33
42
50
62
65
65
67
78
86
84
66
51
83
Cs2CO3
Cs2CO3
KOt-Bu
Et3N
H2O
3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
toluene
THF
4
5
6
KOH
7
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
8
9
CuBr
Cu2O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24b
25c
26d
27e
28f
Cu(OAc)2
CuCl
CuCl2
FeBr3
Pd(OAc)2
NiBr2
CuSO4·5 H2O
CuCl
CuCl
CuCl
DMF
CuCl
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CuCl
60
CuCl
120
100
100
100
100
100
CuCl
CuCl
CuCl
CuCl
CuCl
a Reaction conditions: 1a (0.5 mmol), 2a (0.4 mmol), [metal] (0.1 mmol,
0.25 equiv), base (1.0 mmol, 2.5 equiv), solvent (2 mL), 2 h.
b CuCl (0.025 mmol, 6.25% equiv) was used.
c CuCl (0.125 equiv) was used.
d K2CO3 (1.25 equiv) was used.
e Reaction time: 1 h.
f Reaction time: 2.5 h.
g Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

C
H. Zhu et al.
Paper
Synthesis
I+
–OTf
N
S
N
S
N
N
1f
+
3l: 12%
3a: 68%
H
N
N
CuCl (6.25% equiv)
K2CO3 (2.5 equiv)
DMSO, 100 °C, 2 h
S
2a
N
N
N
N
S
S
+
I+
3b: 65%
3l: 15%
–OTf
1g
Scheme 1 Control experiments for investigation of the regioselectivity
Table 2 Reaction of Diaryliodonium Salts with Arylthioureasa
I+
R1
R1
X–
1
N
N
CuCl, K2CO3
R2
+
S
DMSO, 100 °C, 2 h
R1
H
N
N
3
R2
S
2
Entry
1
Diaryliodonium salt
Arylthiourea
Arylisothiourea product
Yieldb (%)
I+
N
N
N
N
N
N
H
N
N
N
N
S
S
S
85
S
S
S
–
NO3
2a
1a
3a
3a
3a
I+
H
N
2
3
84
82
Cl–
2a
1b
I+
H
N
–OTf
1c
2a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

D
H. Zhu et al.
Paper
Synthesis
Table 2 (continued)
Entry
4
Diaryliodonium salt
Arylthiourea
Arylisothiourea product
Yieldb (%)
I+
N
N
H
N
N
S
78
S
–OTf
1d
2a
3b
3c
I+
N
N
H
N
N
S
5
6
77
82
83
85
75
79
80
82
S
–OTf
2a
1e
1a
I+
N
N
N
N
N
N
H
N
N
N
N
N
N
S
F
S
S
S
S
S
–
NO3
F
2b
3d
I+
N
N
N
N
H
N
S
S
S
S
7
F
Cl–
F
2b
1b
1c
3d
I+
H
N
8
F
–OTf
F
2b
3d
I+
H
N
9
F
–OTf
F
1d
2b
3e
I+
H
N
10
11
12
F
F
–OTf
2b
1e
1a
3f
I+
N
N
H
N
N
S
Br
S
–
NO3
Br
2c
3g
I+
N
N
H
N
N
S
Br
S
Cl–
Br
2c
1b
3g
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

E
H. Zhu et al.
Paper
Synthesis
Table 2 (continued)
Entry
13
Diaryliodonium salt
Arylthiourea
Arylisothiourea product
Yieldb (%)
I+
N
N
H
N
N
S
88
O2N
S
–
NO3
O2N
1a
1b
1a
1b
1a
1b
1a
1b
2d
3h
I+
N
N
H
N
N
S
14
15
16
17
18
19
20
86
86
82
74
78
82
80
O2N
S
Cl–
O2N
2d
3h
I+
Br
N
N
H
N
Br
N
S
S
–
NO3
2e
3i
I+
Br
N
N
H
N
Br
N
S
S
Cl–
2e
3i
I+
N
N
N
N
H
N
N
S
Cl
S
–
NO3
Cl
2f
3j
I+
N
H
N
N
S
Cl
S
Cl–
Cl
2f
3j
I+
N
H
N
N
S
O
S
–
NO3
O
2g
3k
I+
N
N
H
N
N
S
O
S
Cl–
O
2g
3k
a Reaction conditions: 1 (0.5 mmol), 2 (0.4 mmol), CuCl (0.025 mmol), K2CO3 (1.0 mmol), DMSO (2.0 mL), 100 °C, stirred for 2 h.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

F
H. Zhu et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 152.7, 150.6, 133.5, 130.2, 128.9,
128.3, 126.6, 122.2, 122.2, 39.7.
HRMS (ESI): m/z [M + H]+ calcd for C15H17N2S: 257.1107; found:
257.1111.
N
S
N
CuICl
Ph2INO3
A
E
1,1-Dimethyl-3-phenyl-2-p-tolylisothiourea (3b)
The residue was purified by silica gel flash chromatography (PE/EtOAc,
7:1) to give 3b as a yellow oil (85 mg, 78%).
PhI
1H NMR (400 MHz, CDCl3): δ = 7.17 (m, 2 H), 7.01 (m, 5 H), 6.77 (t, J =
8.0 Hz, 2 H), 3.12 (s, 6 H), 2.31 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 153.6, 150.5, 136.7, 130.4, 129.8,
NO3
Ph CuIII
129.7, 128.3, 122.3, 122.2, 39.8, 21.1.
HRMS (ESI): m/z [M + H]+ calcd for C16H19N2S: 271.1263; found:
271.1267.
Ph
CuIII
Cl
S
N
Cl
N
H
B
N
N
2-(2,5-Dimethylphenyl)-1,1-dimethyl-3-phenylisothiourea (3c)
S
The residue was purified by silica gel flash chromatography (PE/EtOAc,
D
7:1) to give 3c as a yellow oil (88 mg, 77%).
1H NMR (400 MHz, CDCl3): δ = 7.11 (t, J = 16.0 Hz, 2 H), 6.92 (m, 4 H),
6.71 (d, J = 8.0 Hz, 2 H), 3.14 (s, 6 H), 2.23 (s, 3H), 2.21 (s, 3H).
13C NMR (100 MHz, CDCl3): δ = 153.6, 150.3, 135.9, 135.6, 132.8,
base
SH
N
N
131.5, 129.9, 128.2, 128.1, 121.9, 121.9, 39.7, 20.8, 20.1.
HRMS (ESI): m/z [M + H]+ calcd for C17H21N2S: 285.1420; found:
285.1428.
C
Scheme 2 Proposed reaction mechanism
3-(4-Fluorophenyl)-1,1-dimethyl-2-phenylisothiourea (3d)
The residue was purified by silica gel flash chromatography (PE/EtOAc,
7:1) to give 3d as a white solid (93 mg, 85%); mp 165–170 °C.
1H NMR (400 MHz, CDCl3): δ = 7.18 (m, 5 H), 6.83 (m, 2 H), 6.67 (m, 2
H), 3.14 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 158.7 (d, J = 238.0 Hz, 1 C), 153.5,
146.6, 133.0, 130.4, 128.9, 126.8, 123.2 (d, J = 8.0 Hz, 1 C), 114.8 (d, J =
22.0 Hz, 1 C), 39.8.
All starting materials were purchased from commercial suppliers and
used without further purification unless otherwise stated. Yields re-
fer to isolated compounds, estimated to be >95% pure as determined
by 1H NMR spectroscopy and capillary GC analysis. NMR spectra were
recorded in CDCl3 using TMS as an internal standard on a Bruker
AM400 instrument. Chemical shifts are given in ppm and coupling
constants (J) are given in Hz. Melting points were determined on an
RY-1G melting point instrument without correction. High-resolution
mass spectra were recorded on a Finnigan MAT 95Q or Finnigan 90
mass spectrometer (ESI). TLC was performed using aluminum plates
coated with silica gel (Merck 60, F-254) and visualized with UV light
at 254 nm. Column chromatography was performed on silica gel
(200–300 mesh) with petroleum ether (PE)/EtOAc as eluent.
HRMS (ESI): m/z [M + H]+ calcd for C15H16FN2S: 275.1013; found:
275.1019.
3-(4-Fluorophenyl)-1,1-dimethyl-2-p-tolylisothiourea (3e)
The residue was purified by silica gel flash chromatography (PE/EtOAc,
7:1) to give 3e as a yellow oil (86 mg, 75%).
1H NMR (400 MHz, CDCl3): δ = 7.03 (m, 4 H), 6.84 (t, J = 16.0 Hz, 2 H),
6.67 (m, 2 H), 3.13 (s, 6 H), 2.13 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.9 (d, J = 238.0 Hz, 1 C), 154.2,
146.5, 136.9, 130.6, 129.7, 129.3, 123.2 (d, J = 8.0 Hz, 1 C), 114.7 (d, J =
22.0 Hz, 1 C), 39.8, 21.0.
HRMS (ESI): m/z [M + H]+ calcd for C16H18FN2S: 289.1169; found:
289.1164.
1,1-Dimethyl-2,3-diphenylisothiourea (3a); Typical Procedure for
the Preparation of Phenylisothioureas 3a–l
Diphenyliodonium nitrate (1a; 172 mg, 0.5 mmol), phenylthiourea 2a
(72 mg, 0.4 mmol), CuCl (2.5 mg, 6.25% equiv), and K2CO3 (138 mg, 2.5
equiv) were added to a dried tube sealed with a septum and equipped
with a magnetic stirring bar; DMSO (2.0 mL) was then added. The
mixture was stirred at 100 °C until the starting material was con-
sumed (about 2 h), as monitored by TLC. The reaction was quenched
with sat. NH4Cl solution (3 mL) and the resulting mixture extracted
with EtOAc. The crude solution was dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was purified by sil-
ica gel flash column chromatography (PE/EtOAc, 3:1) to afford the de-
sired product 3a as a yellow oil (87 mg, 85%).
2-(2,5-Dimethylphenyl)-3-(4-fluorophenyl)-1,1-dimethyliso-
thiourea (3f)
The residue was purified by silica gel flash chromatography (PE/EtOAc,
7:1) to give 3f as a yellow oil (96 mg, 79%).
1H NMR (400 MHz, CDCl3): δ = 6.89 (m, 3 H), 6.76 (t, J = 8.0 Hz, 2 H),
6.58 (m, 2 H), 3.16 (s, 6 H), 2.22 (s, 3 H), 2.20 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.6 (d, J = 238.0 Hz, 1 C), 154.0,
146.4, 135.9, 135.7, 133.0, 131.4, 129.9, 128.3, 122.8 (d, J = 8.0 Hz, 1
C), 114.5 (d, J = 22.0 Hz, 1 C), 39.8, 20.6, 20.1.
1H NMR (400 MHz, CDCl3): δ = 7.21 (m, 7 H), 6.97 (s, 1 H), 6.78 (m, 2
H), 3.13 (s, 6 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

G
H. Zhu et al.
Paper
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C17H20FN2S: 303.1326; found:
303.1329.
1H NMR (400 MHz, CDCl3): δ = 7.11 (t, J = 8.0 Hz, 2 H), 6.89 (t, J = 8.0
Hz, 1 H), 6.71 (t, J = 16.0 Hz, 4 H), 3.05 (s, 3 H), 3.04 (s, 3 H), 2.29 (s, 6
H), 2.23 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 154.3, 150.2, 140.8, 137.8, 128.9,
3-(4-Bromophenyl)-1,1-dimethyl-2-phenylisothiourea (3g)
128.0, 127.4, 121.8, 121.3, 39.7, 22.4, 20.8.
The residue was purified by silica gel flash chromatography (PE/EtO-
HRMS (ESI): m/z [M + H]+ calcd for C18H23N2S: 299.1576; found:
299.1582.
Ac, 7:1) to give 3g as a yellow oil (109 mg, 82%).
1H NMR (400 MHz, CDCl3): δ = 7.21 (m, 5 H), 7.14 (m, 2 H), 6.60 (d, J =
8.0 Hz, 2 H), 3.15 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 153.6, 149.4, 132.7, 131.1, 130.6,
129.0, 126.9, 124.0, 114.9, 39.8.
Funding Information
HRMS (ESI): m/z [M + H]+ calcd for C15H16BrN2S: 335.0212; found:
335.0217.
We are thankful for support from the National Natural Science Foun-
dation of China (21302150, 11405050), Foundation of Chen-Guang
Program from Hubei Association for Science and Technology, Founda-
tion of Chutian Distinguished Fellow from Hubei Provincial Depart-
ment of Education, and Foundation of High-end Talent Cultivation
1,1-Dimethyl-3-(4-nitrophenyl)-2-phenylisothiourea (3h)
The residue was purified by silica gel flash chromatography (PE/EtOAc,
Program from Wuhan Institute of Technology.
N
oaitn
a
l
N
a
utra
l
Secince
F
o
u
n
d
oaitn
of
C
h
n
i
a
2(
1
3
0
2
1
5
0
N)oaitn
a
l
Natuarl
Secince
F
o
u
n
d
oaitn
of
C
h
n
i
a
1(
1
4
0
5
0
5
0)
3:1) to give 3h as a yellow oil (106 mg, 88%).
1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 8.0 Hz, 2 H), 7.12 (m, 5 H),
6.69 (m, 2 H), 3.23 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 156.4, 154.9, 141.9, 131.7, 131.3,
Acknowledgment
129.0, 127.5, 124.2, 122.2, 40.0.
HRMS (ESI): m/z [M + H]+ calcd for C15H16N3SO2: 302.0958; found:
302.0954.
We thank Dr. Georg Manolikakes at Johann Wolfgang Goethe-Univer-
sität (Germany) for generous chemical donations, and thank Prof. Dr.
Aiwen Lei at Wuhan University (China) for kind NMR analysis sup-
port. Z.-B.D. acknowledges the Humboldt Foundation and China
Scholarship Council for a fellowship. H. Z. thanks the support of Post-
graduate Innovation Foundation (CX2017106) from Wuhan Institute
of Technology.
3-(3-Bromophenyl)-1,1-dimethyl-2-phenylisothiourea (3i)
The residue was purified by silica gel flash chromatography (PE/EtOAc,
7:1) to give 3i as a yellow oil (115 mg, 86%).
1H NMR (400 MHz, CDCl3): δ = 7.17 (m, 5 H), 6.98 (m, 2 H), 6.86 (t, J =
4.0 Hz, 1 H), 6.63 (m, 1 H), 3.16 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 154.1, 151.6, 132.3, 131.1, 129.4,
128.9, 127.1, 125.3, 124.7, 121.8, 121.0, 39.9.
HRMS (ESI): m/z [M + H]+ calcd for C15H16BrN2S: 335.0212; found:
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591569.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
335.0219.
References
3-(2-Chlorophenyl)-1,1-dimethyl-2-phenylisothiourea (3j)
(1) (a) Bean, G. J.; Flickinger, S. T.; Westler, W. M.; McCully, M. E.;
Sept, D.; Weibel, D. B.; Amann, K. J. Biochemistry 2009, 48, 4852.
(b) Paesano, N.; Marzocco, S.; Vicidomini, C.; Saturnino, C.;
Autore, G.; Sbardella, G. Bioorg. Med. Chem. Lett. 2005, 15, 539.
(c) Rogovoy, B.; Vvedenskiy, V.; Cai, X.; Chassaing, C.; Katritzky,
A. R.; Forood, B.(Lion Bioscience AG) WO 2003095396, 2003.
(d) Gross, M.; Held, P.; Vogel, R.(VEB Fahlberg-List, Chemische
und Pharmazeutische Fabriken) DE 2035907, 1971. (e) Zhang,
J.; McCarthy, T. J.; Moore, W. M.; Currie, M. G.; Welch, M. J.
J. Med. Chem. 1996, 39, 5110.
The residue was purified by silica gel flash chromatography (PE/EtOAc,
7:1) to give 3j as a yellow oil (91 mg, 78%).
1H NMR (400 MHz, CDCl3): δ = 7.24 (m, 6 H), 7.07 (t, J = 4.0 Hz, 1 H),
6.90 (m, 1 H), 6.81 (m, 1 H), 3.16 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 154.4, 147.4, 132.6, 130.7, 129.1,
129.0, 127.0, 126.7, 126.7, 123.9, 123.2, 39.9.
HRMS (ESI): m/z [M + H]+ calcd for C15H16ClN2S: 291.0717; found:
291.0722.
(2) Katritzky, A. R.; Cai, X. H.; Vvedensky, V. Y.; Rogovoy, B. V.;
Forood, B.; Hebert, N. Heterocycles 2002, 57, 1799.
(3) Dang, Q.; Brown, B. S.; Liu, Y.; Rydzewski, R. M.; Robinson, E. D.;
Poelje, P. D.; Reddy, M. R.; Eroin, M. D. J. Med. Chem. 2009, 52,
2880.
3-(4-Methoxyphenyl)-1,1-dimethyl-2-phenylisothiourea (3k)
The residue was purified by silica gel flash chromatography (PE/EtOAc,
3:1) to give 3k as a yellow oil (94 mg, 82%).
1H NMR (400 MHz, CDCl3): δ = 7.20 (m, 5 H), 6.73 (m, 4 H), 3.78 (d, J =
4.0 Hz, 3 H), 3.11 (s, 6 H).
(4) Khalili, G. Monatsh. Chem. 2015, 146, 1891.
(5) (a) Biswas, K.; Greaney, M. F. Org. Lett. 2011, 13, 4946. (b) Ley,
K.; Eholzer, D. U. Angew. Chem. 1966, 78, 672. (c) Dawra, N.;
Ram, R. N. Synthesis 2016, 48, 4199. (d) Yavari, I.; Nematpour,
M.; Damghani, T. Tetrahedron Lett. 2014, 55, 1323.
(6) (a) Martin, F. M. Synthesis 2017, 49, 1905. (b) Yang, M. N.; Yan,
D. M.; Zhao, Q. Q.; Chen, J. R.; Xiao, W. J. Org. Lett. 2017, 19,
5208. (c) Duan, Y. N.; Jiang, S.; Han, Y. C.; Sun, B.; Zhang, C. Chin.
13C NMR (100 MHz, CDCl3): δ = 155.2, 153.1, 143.9, 133.5, 130.1,
128.9, 126.6, 123.0, 113.7, 55.4, 39.8.
HRMS (ESI): m/z [M + H]+ calcd for C16H19N2SO: 287.1213; found:
287.1210.
1,1-Dimethyl-3-phenyl-2-(2,4,6-trimethylphenyl)isothiourea (3l)
The residue was purified by silica gel flash chromatography (PE/EtOAc,
3:1) to give 3l as a yellow oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

H
H. Zhu et al.
Paper
Synthesis
J. Org. Chem. 2016, 36, 1973. (d) Christopher, J. T.; Shariar, M. A.
S.; Danielle, L. B.; Sachin, G. M.; Michael, F. G. Angew. Chem. Int.
Ed. 2017, 56, 5263.
M.-T.; Liu, S.-S.; Li, Y.-S.; Dong, Z.-B. Tetrahedron Lett. 2017, 58,
4289. (f) Liu, X.; Liu, M.; Xu, W.; Zeng, M.-T.; Zhu, H.; Chang, C.-
Z.; Dong, Z.-B. Green Chem. 2017, 19, 5591. (g) Dong, Z.-B.; Liu,
X.; Bolm, C. Org. Lett. 2017, 19, 5916. (h) Zeng, M.-T.; Xu, W.;
Liu, X.; Chang, C.-Z.; Zhu, H.; Dong, Z.-B. Eur. J. Org. Chem. 2017,
6060. (i) Liu, X.; Cao, Q.; Xu, W.; Zeng, M.-T.; Dong, Z.-B. Eur. J.
Org. Chem. 2017, 5795. (j) Zeng, M.-T.; Wang, M.; Peng, H.-Y.;
Cheng, Y.; Dong, Z.-B. Synthesis 2018, 50, 644. (k) Cheng, Y.; Liu,
X.; Dong, Z.-B. Eur. J. Org. Chem. 2018, 815. (l) Xu, W.; Gao, F.;
Dong, Z.-B. Eur. J. Org. Chem. 2018, 821. (m) Cao, Q.; Peng, H.-Y.;
Cheng, Y.; Dong, Z.-B. Synthesis 2018, 50, 1527.
(7) (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
(b) Silva, L. F.; Olofsson, B. Nat. Prod. Rep. 2011, 28, 1722.
(c) Merritt, E. A.; Olofsson, B. Angew. Chem. Int. Ed. 2009, 48,
9052. (d) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116,
3328.
(8) Zhu, H.; Liu, X.; Chang, C.-Z.; Dong, Z.-B. Synthesis 2017, 49,
5211.
(9) (a) Xu, W.; Zeng, M.-T.; Liu, M.; Liu, S.-S.; Li, Y.-S.; Dong, Z.-B.
Synthesis 2017, 49, 3084. (b) Xu, W.; Zeng, M.-T.; Liu, M.; Liu, X.;
Chang, C.-Z.; Zhu, H.; Li, Y.-S.; Dong, Z.-B. Chem. Lett. 2017, 46,
641. (c) Dong, Z.-B.; Wang, M.; Zhu, H.; Liu, X.; Chang, C.-Z. Syn-
thesis 2017, 49, 5258. (d) Liu, M.; Zeng, M.-T.; Xu, W.; Wu, L.;
Dong, Z.-B. Tetrahedron Lett. 2017, 58, 4352. (e) Xu, W.; Zeng,
(10) (a) Hickman, A. J.; Sanford, M. S. Nature 2012, 484, 177.
(b) Casitas, A.; Ribas, X. Chem. Sci. 2013, 4, 2301. (c) Bhong, B. Y.;
Shelke, A. V.; Karade, N. N. Tetrahedron Lett. 2013, 54, 739.
(d) Lee, O. S.; Lee, H. K.; Kim, H.; Shin, H.; Sohn, J.-H. Tetrahedron
2015, 71, 2936.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H