Copper-Catalyzed C-S Cross-Coupling Reaction: S-Arylation of Arylthioureas

Article abstract of DOI:10.1055/s-0036-1590879

A simple and efficient copper-catalyzed S-arylation of aryl-thioureas was developed. Arylthioureas were smoothly converted into aryl-isothioureas with good yield by copper-catalyzed S-arylation. The features of this method include the use of a ligand-free catalyst, good yield, short reaction time, and broad substrate scope. The method provides a facile and convenient preparation of some potentially biologically active compounds.

Full text of DOI:10.1055/s-0036-1590879

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–F
paper
A
en
H. Zhu et al.
Paper
Synthesis
Copper-Catalyzed C–S Cross-Coupling Reaction: S-Arylation of
Arylthioureas
Hui Zhua
Xing Liua
Cai-Zhu Changa
Zhi-Bing Dong*a,b
S-arylation
Key block for potential
herbicidals and inhibitors of
streptococcus pyogenes
H
N
N
N
N
I
CuI, K2CO3
R2
R2
R1
S
+
S
DMSO, 100 °C
6–7.5 h
R1
a School of Chemistry and Environmental Engineering,
Wuhan Institute of Technology, Wuhan 430205,
P. R. of China
b Key Laboratory of Green Chemical Process, Ministry of
Education, Wuhan Institute of Technology, Wuhan 430205,
P. R. of China
63–88%, 13 examples
R1: Me, MeO, Br, Cl, F, tBu
R2: Me, H
dzb04982@wit.edu.cn
Received: 22.06.2017
Accepted after revision: 19.07.2017
Published online: 22.08.2017
We began our investigations by using iodobenzene (1a)
and arylthiourea 2a as substrates to carry out the model re-
action (Table 1). Optimization of the reaction conditions in-
cluded screening of solvents, bases, catalysts, temperature,
base loading, and catalyst loading. For the first trial, with no
addition of catalyst, aryl-isothiourea could not be detected
(entries 1–3), whereas the target compound was obtained
when catalyst (CuI) was added (entry 4). It was found that
the reaction was significantly affected by the nature of sol-
vent, and high yield (90%) was obtained when dimethyl
sulfoxide (DMSO) was used (entry 5). Subsequently, exam-
ination of base loading showed that increasing the amount
of base to 2.5 equiv led to almost no yield change, whereas
decreasing the base loading to 1.2 equiv led to a significant
decrease in yield (entries 5–10). Among these, 1.7 equiv
base loading was found to be optimal. Similarly, base
screening showed that K2CO3 was the most suitable (entries
9, 11–13). It was noted that the catalyst loading of copper
could be decreased to 0.05 equiv with almost no effect on
the yield of the reaction (entry 14). Among the copper spe-
cies surveyed, CuI was significantly superior to Cu2O, CuBr,
CuO, CuCl2, CoCl2·6H2O, NiCl2·6H2O, and CuSO4·5H2O (en-
tries 15–21). Finally, decreasing the reaction temperature
from 110 to 90 °C had a negative effect on the yield, where-
as increasing the temperature to 120 °C made almost no
difference (entries 22–24). The optimal reaction conditions
are thus summarized in Table 1, entry 23.
DOI: 10.1055/s-0036-1590879; Art ID: ss-2017-z0413-op
Abstract A simple and efficient copper-catalyzed S-arylation of aryl-
thioureas was developed. Arylthioureas were smoothly converted into
aryl-isothioureas with good yield by copper-catalyzed S-arylation. The
features of this method include the use of a ligand-free catalyst, good
yield, short reaction time, and broad substrate scope. The method pro-
vides a facile and convenient preparation of some potentially biological-
ly active compounds.
Key words copper, S-arylation, catalysis, thiourea, isothiourea
Aryl-isothiourea blocks are important functional groups
with a wide range of applications in agrochemicals and
drugs.1–6 In the past decades, research on the application
and synthesis of arylthioureas has attracted the attention of
many biologists and chemists. Several methods have been
reported for the synthesis of substituted aryl-isothioureas.
For example, the reaction of aromatic thiols with amines,7
isocyanates reacting with diazonium salts,8 and the most
widely used method is substituted arylthioureas reacting
with amines, alkyl halides or benzensulfonic acid.9–12 How-
ever, these methods suffer from restricted availability of
substrates8,9 and can produce mixtures of products.10 As
part of our longstanding interest in developing phenylth-
ioureas and relevant applications,13–17 herein we report a
facile synthesis of aryl-isothioureas by a copper-catalyzed
arylation reaction. In this work, substituted arylthioureas
were converted into aryl-isothioureas catalyzed by CuI with
good yields. The key grouping in the product (boxed in the
graphic abstract) is known to be biologically active,18,19
thus, the protocol might pave the way to the synthesis of a
number of potentially pharmaceutically and biologically
active molecules.
By using the optimized reaction conditions, we further
investigated the substrate scope of the C–S cross-coupling
reaction, the results are summarized in Table 2. A range of
substituted aryl iodides 1a–m reacted with aryl-iso-
thioureas 2a–b giving the corresponding products in good
yields. Aryl iodides bearing electron-withdrawing groups in
the aryl rings (1b, 1c, 1g, and 1h) were transformed into the
corresponding products with good yields (entries 2, 3, 7,
and 8), whereas electron-donating groups (1d, 1e, 1f, 1i,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

B
H. Zhu et al.
Paper
Synthesis
In conclusion, we have developed a simple and efficient
copper-catalyzed S-arylation of thioureas. A variety of aryl-
isothiourea derivatives are synthesized with good chemo-
selectivity and functional group tolerance. The protocol has
practical synthetic value for the preparation of a number of
biologically and pharmaceutically active compounds. Fur-
ther details on the mechanism and relevant studies on di-
methylphenylthioureas are under study in our laboratory.
Table 1 Screening Reaction Conditions for S-Arylation Starting from
Iodobenzene (1a) and Arylthiourea 2aa
H
N
N
conditions
N
N
I
+
S
S
1a
2a
Entry Catalyst (equiv)
Base (equiv) Solvent Temp (°C) Yield (%)b
1
2
–
NEt3 (2.0)
THF
0
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
90
N.R
N.R
N.R
51
90
57
69
82
90
91
23
89
32
90
83
20
75
84
N.R
N.R
42
58
87
91
All reactions were carried out under dried glassware fitted with sep-
tums. All starting materials were purchased from commercial suppli-
ers and used without further purification, unless otherwise stated.
DMSO was dried with molecular sieves. Yields refer to isolated com-
pounds estimated to be >95% pure as determined by 1H NMR spec-
troscopy and capillary GC analysis.
–
KOH (2.0)
DMSO
DMSO
DMF
3
–
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (1.0)
K2CO3 (1.2)
K2CO3 (1.5)
K2CO3 (1.7)
K2CO3 (2.5)
KOH (1.7)
4
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.05)
Cu2O (0.05)
CuO (0.05)
CuCl2 (0.05)
CuBr (0.05)
5
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
6
Preparation of S-Aryl Isothioureas in the Presence of CuI and K2CO3;
Typical Procedure (TP)
7
8
In a dried tube, equipped with a magnetic stirrer and a septum, iodo-
benzene (1.2 mmol) was dissolved in DMSO (1.5 mL), then arylth-
iourea (1.0 mmol), CuI (0.05 mmol), and K2CO3 (1.5 mmol) were add-
ed. The mixture was stirred and heated at 100 °C and the progress of
the reaction was monitored by TLC until the starting material was
consumed (ca. 6–7.5 h). The mixture was cooled to r.t. and the reac-
tion was quenched with sat. NH4Cl solution (5 mL). The mixture was
extracted with EtOAc (3 × 10 mL) and the organic extract was dried
over anhydrous Na2SO4 and evaporated under vacuum. The residue
was purified by flash column chromatography to afford the desired
product.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Cs2CO3 (1.7) DMSO
NEt3 (1.7)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
K2CO3 (1.7)
K2CO3 (1.7)
K2CO3 (1.7)
K2CO3 (1.7)
K2CO3 (1.7)
K2CO3 (1.7)
K2CO3 (1.7)
1,1-Dimethyl-2,3-diphenyl-isothiourea (3a)
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/EtOAc, 13:1) to give the target compound
3a.
CoCl2·6H2O (0.05)
NiCl2·6H2O (0.05)
Yield: 222.8 mg (87%); white solid; mp 65–67 °C.
1H NMR (400 MHz, CDCl3): δ = 7.10–7.13 (m, 7 H), 6.90 (t, J = 7.66 Hz,
1 H), 6.72 (d, J = 7.54 Hz, 2 H), 3.04 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 152.7, 150.7, 133.5, 130.3, 129.0,
128.4, 126.7, 122.3, 122.2, 39.8.
CuSO4·5H2O (0.05) K2CO3 (1.7)
CuI (0.05)
CuI (0.05)
CuI (0.05)
K2CO3 (1.7)
K2CO3 (1.7)
K2CO3 (1.7)
100
120
a Reaction conditions: 1a (1.2 mmol), 2a(1.0 mmol), solvent (1.5 mL) for 6 h.
HRMS (ESI): m/z calcd for C15H16N2S: 256.1034; found: 256.0954.
b Isolated yield.
2-(4-Bromophenyl)-1,1-dimethyl-3-phenyl-isothiourea (3b)
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/EtOAc, 13:1) to give the target compound
3b.
and 1j) attached to the aryl ring led to slightly reduced
yields (entries 4–6 and 9–10). Subsequently, another ar-
ylthiourea 2b was examined under the optimal conditions.
We were pleased to find that arylthiourea 2b was a good
coupling partner to react with substituted aryl iodides, af-
fording the corresponding products with reasonable yields
(entries 11–13).
A tentative reaction mechanism is proposed (Scheme 1).
Thiourea 2 could be transformed into isothiourea B in the
presence of base. Iodobenzene (1) undergoes oxidative ad-
dition with CuI to give intermediate A, then transmetala-
tion with isothiourea B gives intermediate C. Final reduc-
tive elimination from C furnishes the desired product D.
Yield: 293.9 mg (88%); light-yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 8.22 Hz, 2 H), 7.12 (t, J =
7.90 Hz, 2 H), 6.89–6.98 (m, 3 H), 6.66–6.69 (m, 2 H), 3.07 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 152.2, 150.3, 132.4, 132.1, 131.9,
128.4, 122.3, 122.2, 120.8, 39.8.
HRMS (ESI): m/z calcd for C15H15BrN2S: 334.0139; found: 334.0144.
2-(4-Fluorophenyl)-1,1-dimethyl-3-phenyl-isothiourea (3c)
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/EtOAc, 13:1) to give the target compound
3c.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

C
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Synthesis
Table 2 Copper-Catalyzed S-Arylation Starting from Iodobenzene (1) with Dimethylphenylthiourea (2)a
N
N
H
CuI (5%), K2CO3 (1.7 equiv)
DMSO, 100 °C, 6–7.5 h
I
N
N
R2
R1
R2
S
+
S
R1
1
2
3
Entry
1
Aryl iodides
Arylisothioureas
Product
Yield (%)b
N
H
I
N
N
N
S
87
S
1a
2a
3a
3b
3c
3d
3e
3f
N
S
H
N
N
N
N
N
N
N
N
N
N
N
N
Br
I
2
3
4
5
6
7
88
78
66
63
70
76
Br
S
S
S
S
S
1b
2a
2a
2a
2a
2a
N
S
H
N
F
I
F
1c
N
S
H
N
MeO
I
OMe
1d
N
S
H
N
I
1e
N
S
H
N
I
1f
N
S
H
N
I
N
S
Br
1g
2a
2a
Br
3g
3h
N
S
H
N
N
I
N
8
73
S
Cl
1h
Cl
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

D
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Synthesis
Table 2 (continued)
Entry
Aryl iodides
Arylisothioureas
Product
Yield (%)b
N
S
H
N
N
I
N
9
72
S
1i
1j
2a
2a
3i
3j
N
S
H
N
I
N
N
10
11
75
76
S
N
S
H
N
I
N
N
N
N
S
S
S
1k
2b
2b
2b
3k
N
S
H
N
N
Br
I
Br
12
13
78
70
1l
3l
N
S
H
N
N
I
Cl
Cl
1m
3m
a Reaction conditions: 1 (1.2 mmol), 2 (1.0 mmol), CuI (5 mol%), K2CO3 (1.7 mmol), and DMSO (1.5 mL), 100 °C, 6–7.5 h.
b Isolated yield.
Yield: 213.7 mg (78%); colorless oil.
2-(4-tert-Butylphenyl)-1,1-dimethyl-3-phenyl-isothiourea (3e)
1H NMR (400 MHz, CDCl3): δ = 7.03–7.12 (m, 4 H), 6.79–6.90 (m, 3 H),
6.66 (d, J = 7.80 Hz, 2 H), 3.07 (s, 6 H).
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/EtOAc, 13:1) to give the target compound
3e.
1
13CNMR (100 MHz, CDCl3): δ = 161.9 (d, JC–F=246 Hz), 153.4, 150.3,
3
4
Yield: 196.6 mg (63%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 6.87–7.13 (m, 7 H), 6.71 (d, J = 7.74 Hz,
133.2 (d, JC–F=8 Hz), 128.3, 128.0 (d, JC–F=2 Hz), 122.2, 122.1, 116.0
(d, 2JC–F=22 HZ), 39.87.
2 H), 3.06 (s, 6 H), 0.89–2.54 (m, 9 H).
HRMS (ESI): m/z calcd for C15H15FN2S: 274.0940; found: 274.0932.
13C NMR (100 MHz, CDCl3): δ = 153.6, 150.5, 141.4, 130.6, 129.7,
2-(4-Methoxyphenyl)-1,1-dimethyl-3-phenyl-isothiourea (3d)
129.0, 128.3, 122.3, 122.1, 39.8, 35.2, 33.5, 22.2, 14.0.
According to TP, the residue was purified by flash chromatography on
HRMS (ESI): m/z calcd for C19H24N2S: 312.1660; found: 312.1651.
silica gel (petroleum ether/EtOAc, 13:1) to give the target compound
3d.
2-(3,5-Dimethylphenyl)-1,1-dimethyl-3-phenyl-isothiourea (3f)
Yield: 188.8 mg (66%); colorless oil.
According to TP, the residue was purified by flash chromatography on
1H NMR (400 MHz, CDCl3): δ = 7.13 (t, J = 7.70 Hz, 2 H), 7.05 (d, J =
8.56 Hz,, 2 H), 6.91 (d, J = 7.42 Hz, 1 H), 6.68–6.72 (m, 4 H), 3.74 (s,
3 H), 3.06 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 158.9, 154.5, 150.5, 133.1, 128.3,
123.4, 122.2, 122.0, 114.5, 55.3, 39.9.
silica gel (petroleum ether/EtOAc, 13:1) to give the target compound
3f.
Yield: 198.8 mg (70%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.11 (t, J = 7.80 Hz, 2 H), 6.70–6.91 (m,
6 H), 3.09 (s, 6 H), 2.19 (s, 6 H).
HRMS (ESI): m/z calcd for C16H18N2OS: 286.1140; found: 286.1146.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

E
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Synthesis
N
N
S
Cu+1
D
I
1
oxidative addition
reductive elimination
I
Cu+2
N
Cu+2
S
N
A
C
transmetallation
N
base
N
KI + CO2 + H2O
HI
SH
B
base
H
N
N
S
2
Scheme 1 Proposed mechanism for copper-catalyzed S-arylation
13C NMR (100 MHz, CDCl3): δ = 153.4, 150.4, 138.5, 135.0, 132.5,
128.6, 128.2, 122.3, 122.0, 39.8, 21.2.
HRMS (ESI): m/z calcd for C15H15ClN2S: 290.0644; found: 290.0651.
1,1-Dimethyl-3-phenyl-2-o-tolyl-isothiourea (3i)
HRMS (ESI): m/z calcd for C17H20N2S: 284.1347; found: 284.1354.
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/EtOAc, 13:1) to give the target compound
2-(2-Bromophenyl)-1,1-dimethyl-3-phenyl-isothiourea (3g)
3i.
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/EtOAc, 13:1) to give the target compound
Yield: 194.5 mg (72%); colorless oil.
3g.
1H NMR (400 MHz, CDCl3): δ = 6.96–7.13 (m, 6 H), 6.86 (d, J = 7.16 Hz,
1 H), 6.68 (d, J = 7.38 Hz, 2 H), 3.04 (s, 6 H), 2.18 (s, 3 H).
Yield: 253.8 mg (76%); white solid; mp 70–72 °C.
1H NMR (400 MHz, CDCl3): δ = 7.40 (d, J = 8.24 Hz, 1 H), 7.03–7.14 (m,
4 H), 6.85–6.96 (m, 2 H), 6.70 (d, J = 7.80 Hz, 2 H), 3.08 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 153.2, 150.6, 138.4, 132.4, 131.7,
130.2, 128.3, 127.2, 126.5, 122.1, 122.0, 39.7, 20.8.
13C NMR (100 MHz, CDCl3): δ = 151.6, 150.2, 134.3, 132.9, 132.5,
HRMS (ESI): m/z calcd for C16H18N2S: 270.1191; found: 270.1199.
128.3, 128.1, 127.7, 124.9, 122.2, 122.0, 39.8.
1,1-Dimethyl-3-phenyl-2-p-tolyl-isothiourea (3j)
HRMS (ESI): m/z calcd for C15H15BrN2S: 334.0139; found: 334.0149.
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/EtOAc, 13:1) to give the target compound
2-(2-Chlorophenyl)-1,1-dimethyl-3-phenyl-isothiourea (3h)
3j.
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/EtOAc, 13:1) to give the target compound
Yield: 202.5 mg (75%); colorless oil.
3h.
1H NMR (400 MHz, CDCl3): δ = 7.14 (t, J = 8.02 Hz, 2 H), 6.98–7.05 (m,
4 H), 6.92 (t, J = 7.18 Hz, 1 H), 6.73 (d, J = 7.82 Hz, 2 H), 3.06 (s, 6 H),
2.28 (s, 3 H).
Yield: 211.7 mg (73%); white solid; mp 58–60 °C.
1H NMR (400 MHz, CDCl3): δ = 7.20–7.23 (m, 1 H), 6.95–7.10 (m, 5 H),
6.86 (t, J = 7.31 Hz, 1 H), 6.68 (d, J = 7.31 Hz, 2 H), 3.08 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 153.6, 150.5, 136.7, 130.5, 129.7,
129.7, 128.3, 122.3, 122.2, 39.8, 21.1.
13C NMR (100 MHz, CDCl3): δ = 151.6, 150.2, 134.8, 132.8, 132.1,
129.6, 128.3, 128.1, 127.0, 122.2, 121.9, 39.8.
HRMS (ESI): m/z calcd for C16H18N2S: 270.1191; found: 270.1199.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

F
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Synthesis
1,1-Dimethyl-2-phenyl-3-p-tolyl-isothiourea (3k)
Acknowledgment
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/EtOAc, 13:1) to give the target compound
3k.
We thank Prof. Aiwen Lei at Wuhan University for his generous NMR
analysis support.
Yield: 205.3 mg (76%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.15–7.21 (m, 5 H), 6.97 (d, J = 7.40 Hz,
2 H), 6.65 (d, J = 8.17 Hz, 2 H), 3.05 (s, 6 H), 2.26 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 152.8, 147.9, 133.7, 131.7, 130.0,
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590879.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
129.0, 128.9, 126.6, 122.0, 39.8, 20.9.
HRMS (ESI): m/z calcd for C16H18N2S: 270.1191; found: 270.1195.
References and Notes
2-(4-Bromophenyl)-1,1-dimethyl-3-p-tolyl-isothiourea (3l)
(1) Bean, G. J.; Flickinger, S. T.; Westler, W. M.; McCully, M. E.; Sept,
D.; Weibel, D. B.; Amann, K. J. Biochemistry 2009, 48, 4852.
(2) Perlovich, G. L.; Proshin, A. N.; Volkova, T. V.; Kurkov, S. V.;
Grigoriev, V. V.; Petrova, L. N.; Bachurin, S. O. J. Med. Chem.
2009, 52, 1845.
(3) Latosinska, J. N.; Latosinska, M.; Seliger, J.; Zagar, V.; Maurin, J.
K.; Kazimierczuk, Z. J. Phys. Chem. A 2012, 116, 1445.
(4) Polucci, P.; Magnaghi, P.; Angiolini, M.; Alessio, R. D. J. Med.
Chem. 2013, 56, 437.
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/EtOAc, 13:1) to give the target compound
3l.
Yield: 272.2 mg (78%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.29 (d, J = 8.32 Hz, 2 H), 6.95–7.01 (m,
4 H), 6.60 (d, J = 7.52 Hz, 2 H), 3.05 (s, 6 H), 2.26 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 152.0, 147.8, 132.7, 131.9, 131.7,
131.8, 129.0, 121.9, 120.7, 39.8, 20.9.
(5) Zhang, J.; McCarthy, T. J.; Moore, W. M.; Currie, M. G.; Welch, M.
J. J. Med. Chem. 1996, 39, 5110.
HRMS (ESI): m/z calcd for C16H17BrN2S: 348.0296; found: 348.0301.
(6) Shearer, B. G.; Lee, S.; Oplinger, J. A.; Frick, L. W.; Garvey, E. P.;
Furfine, E. S. J. Med. Chem. 1997, 40, 190.
2-(2-Chlorophenyl)-1,1-dimethyl-3-p-tolyl-isothiourea (3m)
(7) Katritzky, R.; Vvedensky, V.; Rogovoy, B. V.; Kovalenko, K.;
Torres, E.; Forood, B. J. Comb. Chem. 2002, 4, 285.
(8) Khalili, G. Monatsh. Chem. 2015, 146, 1891.
According to TP, the residue was purified by flash chromatography on
silica gel (petroleum ether/EtOAc, 13:1) to give the target compound
3m.
(9) Ley, K.; Eholzer, D. U. Angew. Chem. 1966, 78, 672.
(10) Biswas, K.; Greaney, M. F. Org. Lett. 2011, 13, 4946.
(11) Katritzky, R.; Cai, X. H.; Rogovoy, B. V.; Katritzky, A. R. J. Comb.
Chem. 2003, 5, 392.
(12) Katritzky, A. R.; Rogovoy, B.; Klein, C.; Insuasty, H.; Vvedensky,
V.; Insuasty, B. J. Org. Chem. 2001, 66, 2854.
Yield: 202.8 mg (70%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.24 (d, J = 7.48 Hz, 1 H), 7.00–7.13 (m,
3 H), 6.91 (d, J = 7.78 Hz, 2 H), 6.61 (d, J = 8.22 Hz, 2 H), 3.05 (s, 6 H),
2.23 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 151.5, 147.8, 134.6, 132.4, 131.5,
129.6, 129.0, 128.0, 127.0, 121.8, 39.7, 20.9.
(13) Liu, M.; Zeng, M. T.; Xu, W.; Chang, C. Z.; Liu, X.; Zhu, H.; Li, Y. S.;
Dong, Z. B. J. Chem. Res. 2017, 47, 165.
(14) Xu, W.; Zeng, M. T.; Liu, M.; Liu, X.; Chang, C. Z.; Zhu, H.; Dong,
Z. B. Chem. Lett. 2017, 46, 641.
HRMS (ESI): m/z calcd for C16H17ClN2S: 304.0801; found: 304.0809.
(15) Zeng, M. T.; Xu, W.; Liu, M.; Liu, X.; Chang, C. Z.; Zhu, H.; Dong,
Z. B. SynOpen 2017, 1, 1.
Funding Information
(16) Xu, W.; Zeng, M. T.; Liu, M.; Liu, X.; Chang, C. Z.; Zhu, H.; Dong,
Z. B. J. Sulfur Chem. 2017, DOI: 10.1080/17415993.2017.
1337771.
(17) Chang, C. Z.; Xu, W.; Zeng, M. T.; Liu, M.; Liu, X.; Zhu, H.; Dong,
Z. B. Synth. Commun. 2017, 47, 1262.
(18) Rogovoy, B.; Vvedenskiy, V.; Cai, X.; Chassaing, C.; Katritzky, A.
R.; Forood, B. Lion Bioscience A.-G.. WO 2003095396, 2003.
(19) Gross, M.; Held, P.; Vogel, R. VEB Fahlberg-List, Chemische und
Pharmazeutische Fabriken; DE 2035907, 1971.
We thank the National Natural Science Foundation of China
(21302150), Hubei Provincial Department of Education (D20131501),
Scientific Research Foundation for the Returned Overseas Chinese
Scholars, State Education Ministry [2012]1707, foundation of Chutian
distinguished fellow from Hubei Provincial Department of Education,
foundation of High-end Talent Cultivation Program from Wuhan In-
stitute of Technology.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F