Aromatic Halogenation Using N-Halosuccinimide and PhSSiMe3 or PhSSPh

Article abstract of DOI:10.1021/acs.joc.9b00817

We developed a mild aromatic halogenation reaction using a combination of N-halosuccinimide and PhSSiMe₃ or PhSSPh. Less reactive aromatic compounds, such as methyl 4-methoxybenzoate, were brominated with PhSSiMe₃ or PhSSPh and N-bromosuccinimide in high yields. No reaction was observed in the absence of PhSSiMe₃ or PhSSPh. This method is also applicable to chlorination reactions using N-chlorosuccinimide and PhSSPh.

Full text of DOI:10.1021/acs.joc.9b00817

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Aromatic Halogenation Using N-Halosuccinimide and PhSSiMe or PhSSPh
Yuuka Hirose, Mirai Yamazaki, Misa Nogata, Akira Nakamura, and Tomohiro Maegawa
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00817 • Publication Date (Web): 25 Apr 2019
Downloaded from http://pubs.acs.org on April 26, 2019
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Aromatic Halogenation Using N-Halosuccinimide
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and PhSSiMe3 or PhSSPh
Yuuka Hirose, Mirai Yamazaki, Misa Nogata, Akira Nakamura, Tomohiro Maegawa*
School of Pharmaceutical Sciences, Kindai University, Higashi-Osaka, Osaka 577-8502, Japan
PhSTMS or PhSSPh
NXS
EWG
Efficient Halogenation
MeO
CH3CN, rt
Activation of NXS by PhSTMS
or PhSSPh
X
EWG
NXS
MeO
no reaction
CH3CN, rt
EWG: Electron Withdrawing Group
ABSTRACT: We developed a mild aromatic halogenation reaction using a combination of N-
halosuccinimide and PhSSiMe3 or PhSSPh. Less reactive aromatic compounds, such as methyl 4-
methoxybenzoate, were brominated with PhSSiMe3 or PhSSPh and N-bromosuccinimide in high
yields. No reaction was observed in the absence of PhSSiMe3 or PhSSPh. This method is also
applicable to chlorination reactions using N-chlorosuccinimide and PhSSPh.
Sulfur-containing compounds are important in living organisms and in a wide variety of fields
such as materials science and organic chemistry.1 In living organisms, sulfur compounds such as
cysteine act as redox substrates that can be reversibly oxidized to form disulfide (S-S) bonds.
These can then be easily reduced back to thiols by glutathione.2 Thiols are also well known as
easily oxidized compounds in organic syntheses, being converted to their corresponding
disulfides under oxidizing conditions.3 Reactions of thiols with brominating reagent, 1,3-
dibromo-5,5-dimethylhydantoin, naturally afford their corresponding disulfides.4 Conversely, we
have developed a novel series of reactions involving methylene acetals5 and reported mild
conversion method of methylene acetals using a combination of N-bromosuccinimide (NBS) and
phenylthiotrimethylsilane (PhSTMS)5d (Scheme 1).
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O
O
O
O
n
PhSTMS, NBS
CH3CN, rt
H
O
Br
n
Br
O
n
H
+
R1
R2
R1
R2
R1
R2
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Scheme 1. Conversion of Methylene Acetal to Bromoformate Under Mild Conditions
Methylene acetal is a robust protective group for diols and requires harsh reaction conditions for
deprotection. However, under mild conditions, a combination of NBS and PhSTMS is effective
in the transformation of methylene acetal to its corresponding bromoformates. This reaction
seems to involve the bromination of the methylene acetal moiety. We therefore hypothesized that
the combination of these reagents would effectively brominate aromatic compounds under mild
conditions. The combination of NBS and PhSTMS has not been previously reported but is
expected to yield PhSBr as an intermediate. Although reactions involving PhSBr have been
reported,4,6 the bromination of aromatic rings by PhSBr has not been demonstrated. This study
details the halogenation of aromatic compounds using a combination of N-halosuccinimide and
PhSTMS or PhSSPh. Aryl bromides are known as some of the most efficient substrates for
transition-metal catalyzed cross-coupling reaction.7 A number of methods for aromatic
bromination using NBS with activating reagents including Lewis acids and Lewis bases have
been reported.8 However, many of reported methods examined the bromination of reactive
(electron-rich) arenes such as phenol and aniline derivatives. We then investigated the
bromination of relatively less reactive arenes, anisole derivatives with electron-withdrawing
groups. Some methods can brominate such arenes but they used acids for activation,9 and only
NH4OAc was used for such a bromination of less reactive arenes as a mild activator.10
We first applied the optimized conditions from a previous method5d to the bromination of methyl
4-methoxybenzoate (1a) (Scheme 2). The reaction proceeded in CH3CN at room temperature and
afforded methyl 3-bromo-4-methoxybenzoate (2a) in 79% yield (Scheme 2, eq. 1). Surprisingly,
no reaction was observed in the absence of PhSTMS (Scheme 2, eq. 2). Note, however, that sulfur
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compounds activate NBS even under oxidative conditions. We then optimized the reagent ratios
for maximum yield (Table 1).
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Scheme 2. Activation of NBS with PhSTMS for Aromatic Bromination
O
O
PhSTMS (1.0 eq)
NBS (2.0 eq)
OMe
OMe
(eq. 1)
CH3CN, rt, 24 h
MeO
MeO
1a
2a (79%)
Br
O
NBS (2.0 eq)
OMe
(eq. 2)
no reaction
CH3CN, rt, 24 h
MeO
1a
Table 1. Equivalent of Reagents
O
O
PhSTMS (X eq)
NBS (Y eq)
OMe
OMe
CH3CN, rt
MeO
MeO
1a
2a
Br
Entry
PhSTMS
(equiv)
1.0
NBS (equiv)
Time
(h)
24
2
Yield (%)
1
2
3
4
5
2.0
3.0
3.0
3.0
3.0
79 (10)a
quant.
95
1.0
0.5
3
0.3
24
24
96
0.1
56 (28)a
a) The yield of the parenthesis indicated the remained starting material.
The use of one equivalent of PhSTMS and two equivalents of NBS afforded a 79% yield, but
returned starting material (entry 1). Increasing the equivalent of NBS led to the complete
consumption of starting material to give 2a in quantitative yield (entry 2). Decreasing the
equivalent of PhSTMS to 0.5 gave almost the same result as that of one equivalent (entry 3).
Further decreasing the amount of PhSTMS increased the reaction time (entries 4 and 5) and the
use of 0.1 equivalent of PhSTMS resulted in remaining starting material after 24 h (entry 5).
Given the above results, 0.5 equivalents of PhSTMS and 3.0 equivalents of NBS in CH3CN were
selected as optimized conditions for the bromination of aromatic compounds (Table 2). Reactions
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of anisole derivatives with electron-withdrawing groups such as esters, ketones, and carboxylic
acids (1a–1d) afforded corresponding mono-brominated compounds (2a–2d) in high yields,
whereas no reaction was observed in the absence of PhSTMS (entries 1–8). Electron-rich arenes
(1e–1h) underwent dibromination, giving the corresponding products (2e–2h) in good to high
yields (entries 9, 11, 13, and 15) except for 4-methylacetanilide (1i). In the absence of PhSTMS,
the reaction of mesitylene (1e), anisole (1f) and 1-methoxynaphthalene (1h) afforded sole mono-
brominated compounds (3e, 3f and 3h) (entries 10, 12, and 16). Similar result was obtained in the
case of more electron-rich dimethoxybenzene (1g) even in the absence of PhSTMS (entries 13
and 14). The reaction of 1i furnished the mono-brominated product 3i in 85% yield, which
decreased to 18% in the absence of PhSTMS with the same reaction time (entries 17 and 18).
More electron-deficient aromatic compounds, such as bromobenzene or nitrobenzene, did not
undergo bromination under these optimized reaction conditions (entries 19 and 20).
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Table 2. Aromatic Bromination with the Combination of PhSTMS and NBS
PhSTMS (0.5 equiv)
NBS (3.0 equiv)
Br
R
R
CH3CN, rt
1
2
Entry
Substrate
Time
Product
Yield
(%)
95
(h)
3
O
O
1
OMe
OMe
2a
1a 24
2a no
MeO
MeO
Br
reaction
92
O
Br
O
3
1
OMe
O
OMe
O
4a
1b 24
2b no
reaction
93
OMe
OMe
5
2
6a
1c 24
2c no
MeO
MeO
MeO
MeO
Br
reaction
82
O
O
7
24
OH
1d 24
OH
8a
2d no
Br
reaction
92
9
1
Br
10a
1e
1
2e 31 (3e)b
Br
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Br
11
2
2
96
OMe
OMe
12a
1f
2f 90 (3f)c
Br
Br
OMe
OMe
13
1
1
97
9
14a
1g
2g quant.
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OMe
OMe
OMe
Br
OMe
15
1
1
94
Br
16a
1h
2h 79 (3h)d
Br
NHAc
NHAc
17
18a
19
1
85
Br
1i
1
3i 18
12
no
Br
1j
reaction
no
NO2
20
12
1k
reaction
a) Without PhSTMS. b) The yield of 2-bromomesitylene (3e). c) The yield of 4-bromoanisole
(3f). d) The yield of 4-bromo-1-methoxynaphthalene (3h).
In these reactions, PhSSPh was observed as a byproduct and the reactions proceeded with only a
catalytic amount of PhSTMS (Table 1, entries 3–5). This suggests that PhSSPh also acts as an
activator for NBS. PhSSPh is less expensive than PhSTMS and, being a solid, is easier to handle.
PhSSPh also exhibits less of the malodor associated with sulfur. We next examined the
bromination of aromatic compounds using a combination of PhSSPh and NBS. With 0.5
equivalent of PhSSPh and 3.0 equivalents of NBS, 1a was successfully converted to the
corresponding brominated product 2a in quantitative yield. Note that a longer reaction time was
needed relative to that required for the combination of PhSTMS and NBS (Table 3, entry 1 vs.
Table 2, entry 1). Reactions of anisole derivatives bearing electron-withdrawing groups (1b–1d)
afforded the corresponding bromides (2b–2d) in high yields with similar or longer reaction time
than those with PhSTMS (entries 2 and 3). The activation of NBS with PhSSPh seems to be
weaker than that with PhSTMS. The bromination of electron-rich arenes 1g and 1i with PhSSPh
also yielded high yields, however 1f and 1h resulted in mono-brominated products as inseparable
mixture.
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Table 3. Aromatic Bromination with the Combination of PhSSPh and NBS
PhSSPh (0.5 equiv)
Br
NBS (3.0 equiv)
R
R
CH3CN, rt
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Entry Substrate
Time
(h)
Product
Yield
(%)
O
O
1
2
12
quant.
OMe
OMe
1a
2a
MeO
Br
MeO
Br
O
O
6.5
3
95
88
93
64
OMe
O
OMe
1b
2b
2c
OMe
OMe
O
3
4
5
1c
MeO
MeO
MeO
MeO
Br
O
O
24
2
OH
OH
1d
2d
Br
Br
1e
2e (35)a
Br
Br
OMe
b
6
7
3
1
-
OMe
1f
3f
Br
Br
OMe
OMe
quant.
1g
OMe 2g
OMe
Br
OMe
b
OMe
8
9
1
-
Br
1h
1i
3h
Br
NHAc
NHAc
2.5
quant.
Br
3i
a) The yield of 2-bromomesitylene (3e) was indicated in the parenthesis. b) Mono-brominated
product was obtained as inseparable mixture.
A plausible reaction mechanism is as follows (Scheme 3). First, PhSTMS reacts with NBS to
generate PhSBr as a reactive species. The resulting Br+ ion is then able to brominate the aromatic
compound, converting the sulfur moiety to a disulfide. The reaction of PhSSPh and NBS also
affords the same reactive species, PhSBr,6c which acts as a Br+ source for aromatic bromination6d
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(Scheme 3, path A). However, PhSBr is also reported as acting as a PhS+ ion,6c indicating that Br
should act as an anion. Another reaction mechanism involves the in situ conversion of PhSTMS
to PhSSPh, which then acts as a Lewis base to activate Br (Scheme 3, path B).11 However, the
reaction using PhSTMS is much faster than that using PhSSPh although PhSTMS should be
converted to PhSSPh (Scheme 4). Therefore, disulfide is unlikely to work as Lewis base for
activation. Another possible reactive intermediate is Br2, which may be generated from the
disproportionation of PhSBr (Scheme 3, path C).4,12 The reaction of olefin with a combination of
PhSTMS and NBS did not yield a dibrominated product, but bromothiophenylation was observed.
Although this result does not rule out the generation of Br2, the true active species has not been
elucidated. We also examined the addition of a radical scavenger, tert-dibutylhydroxytoluene
(BHT), to the reaction mixture. Surprisingly, this significantly suppressed the reaction (Scheme
5). Although the exact radical pathway remains unclear, disproportionation may occur via a
radical intermediate in the generation of Br2.
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Scheme 3. Plausible Reaction Mechanism
+
PhS- Br
+
(path A)
R
Br
NBS
NBS
PhSBr
PhSTMS
PhSSPh
Br2
R
(path B)
NBS
(path C)
Scheme 4. Differences of Reactivity between PhSTMS and PhSSPh
O
O
PhSTMS or PhSSPh (0.5 eq)
NBS (3.0 eq)
OMe
OMe
CH3CN
MeO
MeO
Br
PhSTMS (3 h, 95%)
PhSSPh (12 h, quant)
Scheme 5. Addition of Radical Scavenger
O
O
PhSTMS (0.5 eq)
NBS (3.0 eq)
OMe
OMe
BHT (1.0 eq)
MeO
MeO
Br
rt, CH3CN, 24 h
(BHT : tert-dibutylhydroxytoluene)
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Finally, we applied our method to the chlorination of aromatic compounds using PhSTMS-N-
chlorosuccinimide (NCS). Most general methods for the chlorination of aromatic rings with NCS
require activation with an acid.9d,13 We performed a chlorination of methyl 4-methoxybenzoate
(1a) using 0.3 equivalents of PhSSPh and 3.0 equivalents of NCS, affording methyl 3-chloro-4-
methoxybenzoate 4a in 88% yield after 24 h whereas no reaction proceeded without PhSSPh.
Other arenes (1b, 1g, and 1i) underwent the same chlorination reaction to give the corresponding
products 4b, 4g, and 4i in good to high yields (Scheme 6).
Scheme 6. Aromatic Chlorination with the Combination of PhSSPh and NCS
NCS (3.0 equiv)
no reaction
O
CH3CN, rt, 24 h
OMe
O
PhSSPh (0.3 equiv)
MeO
NCS (3.0 equiv)
OMe
4a (88%)
CH3CN, rt, 24 h
MeO
Cl
Cl
O
OMe
Cl
NHAc
Cl
OMe
MeO
4i (73%)
4b (83%)
4g (97%)
OMe
Cl
In conclusion, we have developed a novel halogenation method using a combination of N-
halosuccinimides and PhSTMS or PhSSPh under mild reaction conditions. This method was
shown to be applicable to less reactive aromatic compounds that do not react with N-
halosuccinimide alone. N-Halosuccinimides could be activated in the presence of sulfur-
containing compounds such as PhSTMS or PhSSPh through the generation of a reactive species,
PhSX, although the true reactive intermediate has not been fully elucidated. Furthermore, this
reaction proceeds under mild conditions and employs solid reagents that are relatively low-odor
and easy to handle. Further elucidation of the reaction mechanism and broadening of the
application space to similar reactions are currently underway.
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Experimental Section
General Information
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Column chromatography and TLC were performed on Merck Silica gel 60 (230‒400 mesh) and
Merck Silica gel F254 plates (0.25 mm), respectively. 1H and 13C NMR spectra were recorded on
the JEOL JMN-400 spectrometer in CDCl3 or DMSO-d6 with tetramethylsilane as an internal
standard. Data are reported as follows: chemical shift in ppm (δ), integration, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet), and coupling constant (Hz). High-
resolution mass spectra were obtained on the SHIMAZU IRAffinity-1 instrument with ionization
voltages of 70 eV.
General Procedure for bromination with PhSTMS and NBS (Table 2)
Typical procedure from 1a to 2a: PhSTMS (0.023 mL, 0.12 mmol) was added to a solution of
1a (40 mg, 0.24 mmol) in CH3CN (1.2 mL), then NBS (128 mg, 0.72 mmol) was added and stirred
for 3 h. Saturated NaHCO3 and Na2S2O3 (1:1) aqueous solution was added to the resultant solution
and the mixture was extracted with AcOEt. The organic layer was washed with brine and dried
over Na2SO4 and evaporated in vacuo. The residue was purified by column chromatography on a
silica gel (n-Hex/AcOEt = 10/1) to give 2a (56.1 mg, 95%).
Methyl 3-bromo-4-methoxybenzoate (2a)14
White solid, mp 95-96 ºC, 1H NMR (400 MHz, CDCl3)  : 8.21 (d, J = 2.0 Hz, 1H), 7.94 (d, J =
8.2 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H).
Methyl 2-bromo-5-methoxybenzoate (2b)15
According to the general procedure, the reaction of 1b (0.035 mL, 0.24 mmol) with PhSTMS
(0.023 mL, 0.12 mmol) and NBS (128 mg, 0.72 mmol) in CH3CN (1.2 mL) gave 2b (53.9 mg,
92%) after purification by SiO2 column chromatography (n-Hex/AcOEt = 10/1).
Yellow oil, 1H NMR (400 MHz, CDCl3)  : 7.50 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 3.0 Hz, 1H),
6.87 (dd, J = 3.0 Hz, 8.8 Hz, 1H), 3.91 (s, 3H), 3.80 (s, 3H)
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3-Bromo-4-methoxyacetophenone (2c)16
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According to the general procedure, the reaction of 1c (36 mg, 0.24 mmol) with PhSTMS (0.023
mL, 0.12 mmol) and NBS (128 mg, 0.72 mmol) in CH3CN (1.2 mL) gave 2c (51.1 mg, 93%) after
purification by SiO2 column chromatography (n-Hex/AcOEt = 5/1).
White solid, mp 87-88 ºC, 1H NMR (400 MHz, CDCl3)  : 8.16 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H),
6.93 (d, J = 8.8 Hz, 1H), 3.96 (s, 3H), 2.55 (s, 3H)
3-Bromo-4-methoxybenzoic acid (2d)17
According to the general procedure, the reaction of 1d (36 mg, 0.24 mmol) with PhSTMS (0.023
mL, 0.12 mmol) and NBS (128 mg, 0.72 mmol) in CH3CN (1.2 mL) gave 2d (43.5 mg, 82%)
after back extraction.
Yellow solid, mp 216-217 ºC, 1H NMR (400 MHz, DMSO-d6)  : 12.98 (brs, 1H), 8.06 (s, 1H),
7.94 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 3.93 (s, 3H), 3.34 (s, 3H)
2,4-Dibromo-1,3,5-trimethylbenzene (2e)18
According to the general procedure, the reaction of 1e (0.1 mL, 0.72 mmol) with PhSTMS (0.068
mL, 0.36 mmol) and NBS (384 mg, 2.16 mmol) in CH3CN (3.6 mL) gave 2e (184.1 mg, 92%)
after purification by SiO2 column chromatography (n-Hex only).
White solid, 1H NMR (400 MHz, CDCl3) δ : 6.87 (s, 1H), 2.35 (s, 6H), 2.22 (s, 3H)
2,4-Dibromo-1-methoxybenzene (2f)16
According to the general procedure, the reaction of 1f (0.1 mL, 0.93 mmol) with PhSTMS (0.088
mL, 0.47 mmol) and NBS (497 mg, 2.79 mmol) in CH3CN (4.7 mL) gave 2f (243.6 mg, 96%)
after purification by SiO2 column chromatography (n-Hex only).
Yellow oil, 1H NMR (400 MHz, CDCl3)  : 7.67 (d, J = 2.4 Hz, 1H), 7.38 (dd, J = 2.4 Hz, 8.8 Hz,
1H), 6.78 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H)
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1,5-Dibromo-2,4-dimethoxybenzene (2g)18
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According to the general procedure, the reaction of 1g (0.1 mL, 0.76 mmol) with PhSTMS (0.072
mL, 0.38 mmol) and NBS (408 mg, 2.29 mmol) in CH3CN (3.8 mL) gave 2g (218.4 mg, 97%)
after purification by SiO2 column chromatography (n-Hex only).
White solid, mp 144 ºC, 1H NMR (400 MHz, CDCl3)  : 7.59 (s, 1H), 6.42 (s, 1H), 3.84 (s, 6H)
2,4-Dibromo-1-methoxynaphthalene (2h)19
According to the general procedure, the reaction of 1h (0.035 mL, 0.24 mmol) with PhSTMS
(0.023 mL, 0.12 mmol) and NBS (128 mg, 0.72 mmol) in CH3CN (1.2 mL) gave 2h (71.4 mg,
94%) after purification by SiO2 column chromatography (n-Hex only).
Colorless oil, 1H NMR (400 MHz, CDCl3)  : 8.17-8.11 (m, 2H), 7.90 (s, 1H), 7.63-7.56 (m, 2H),
3.98 (s, 3H)
N-Acetyl-2-bromo-p-toluidine (3i)20
According to the general procedure, the reaction of 1i (36 mg, 0.24 mmol) with PhSTMS (0.023
mL, 0.12 mmol) and NBS (128 mg, 0.72 mmol) in CH3CN (1.2 mL) gave 3i (46.3 mg, 85%) after
purification by SiO2 column chromatography (n-Hex /AcOEt = 2/1).
White solid, mp 120-122 ºC, 1H NMR (400 MHz, CDCl3)  : 8.14 (d, J = 8.4 Hz, 1H), 7.49 (brs,
1H), 7.33 (s, 1H), 7.09 (d, J = 8.4 Hz, 1H), 2.27 (s, 3H), 2.20 (s, 3H)
2-Bromo-1,3,5-trimethylbenzene (3e)21
Colorless oil, 1H NMR (400 MHz, CDCl3)  : 6.87(s, 2H), 2.35(s, 6H), 2.22(s, 3H)
4-Bromo-1-methoxybenzene (3f)22
Colorless oil, 1H NMR (400 MHz, CDCl3)  : 7.36(dd, J = 2.4 Hz, 6.8 Hz, 2H), 6.76 (dd, J = 2.4
Hz, 6.8 Hz, 2H), 3.77(s, 3H)
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1-Bromo-4-methoxynaphthalene (3h)19
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Colorless oil, 1H NMR (400 MHz, CDCl3)  : 8.27 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H),
7.65-7.50 (m, 3H), 6.66 (d, J = 8.0 Hz, 1H), 3.97 (s, 3H)
General Procedure for chlorination with PhSSPh and NCS (Scheme 6)
Typical procedure from 1a to 4a: PhSSPh (16.4 mg, 0.075 mmol) was added to a solution of 1a
(41.5 mg, 0.25 mmol) in CH3CN (1.25 mL), then NCS (100 mg, 0.75 mmol) was added and stirred
for 3 h. Saturated NaHCO3 and Na2S2O3 (1:1) aqueous solution was added to the resultant solution
and the mixture was extracted with AcOEt. The organic layer was washed with brine and dried
over Na2SO4 and evaporated in vacuo. The residue was purified by column chromatography on a
silica gel (n-Hex only to n-Hex /AcOEt = 10/1 to 4/1) to give 4a (44.2, 88%).
Methyl 3-chloro-4-methoxybenzoate (4a)23
White solid, mp 90-92 ºC, 1H NMR (400 MHz, CDCl3)  : 8.04 (d, J = 1.8 Hz, 1H), 7.92 (dd, J =
1.8 Hz, 8.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H).
Methyl 2-chloro-5-methoxybenzoate (4b)24
According to the general procedure, the reaction of 1b (41.5 mg, 0.25 mmol) with PhSSPh (16.4
mg, 0.075 mmol) and NCS (100 mg, 0.75 mmol) in CH3CN (1.25 mL) gave 4b (41.4 mg, 83%)
after purification by SiO2 column chromatography (n-Hex only to n-Hex/AcOEt = 10/1 to 4/1).
Yellow oil, 1H NMR (400 MHz, CDCl3)  : 7.31 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 3.0 Hz, 1H),
6.93 (dd, J = 3.0 Hz, 8.8 Hz, 1H), 3.90 (s, 3H), 3.79 (s, 3H).
2,4-Dichloro-1,5-dimethoxybenzene (4g)25
According to the general procedure, the reaction of 1g (0.065 mL, 0.5 mmol) with PhSSPh (32.7
mg, 0.15 mmol) and NCS (200 mg, 1.50 mmol) in CH3CN (2.5 mL) gave 4g (100 mg, 97%) after
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purification by SiO2 column chromatography (n-Hex only).
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White solid, 1H NMR (400 MHz, CDCl3)  : 6.95 (s, 1H), 2.47 (s, 3H), 2.23 (s, 3H)
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N-Acetyl-2-chloro-p-toluidine (4i)26
According to the general procedure, the reaction of 1i (37.3 mg, 0.25 mmol) with PhSSPh (16.4
mg, 0.075 mmol) and NCS (100 mg, 0.75 mmol) in CH3CN (1.25 mL) gave 4i (33.7 mg, 73%)
after purification by SiO2 column chromatography (n-Hex/AcOEt = 2/1).
Yellow oil, 1H NMR (400 MHz, CDCl3)  : 8.18 (d, J = 7.8 Hz, 1H), 7.50 (brs, 1H), 7.16 (s, 1H),
7.05 (d, J = 7.8 Hz, 1H), 2.28 (s, 3H), 2.20 (s, 3H).
ASSOCIATED CONTENT
Supporting information
The Supporting Information is available free of charge on the ACS Publication website at DOI:
1H NMR spectra.
AUTHOR INFORMATION
Corresponding author
E-mail:maegawa@phar.kindai.ac.jp
ORCID
Tomohiro Maegawa: 0000-0003-1580-1110
Akira Nakamura: 0000-0002-4469-6519
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work was financially supported by JSPS KAKENHI Grant Number 18K05132 and MEXT
(Ministry of Education, Culture, Sports, Sciences, and Technology)-supported Program for the
Strategic Research Foundation at Private Universities, 2014-2018 (S1411037). We also thank
Kindai University Joint Research Center for use of facilities.
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