Metal-free synthesis of biaryls from aryl sulfoxides and sulfonanilides via sigmatropic rearrangement

Article abstract of DOI:10.1016/j.tet.2020.131232

Treatment of aryl sulfoxides and sulfonanilides with trifluoroacetic anhydride resulted in the dehydrative metal-free construction of the corresponding unsymmetrical biaryls. The reaction would proceed via (1) the activation of aryl sulfoxide with the anhydride, (2) interrupted Pummerer reaction of the resulting arylsulfonium with sulfonanilide, (3) [3,3] sigmatropic rearrangement to cleave the transient S–N bond and to form the prospective biaryl C–C bond, and (4) global aromatization. The choice of the amino protecting group is crucial, and only N-sulfonylanilines, i.e., sulfonanilides, could participate in the formation of biaryls.

Full text of DOI:10.1016/j.tet.2020.131232

Journal Pre-proof
Metal-free synthesis of biaryls from aryl sulfoxides and sulfonanilides via sigmatropic
rearrangement
Akira Yoshida, Koichi Okamoto, Tomoyuki Yanagi, Keisuke Nogi, Hideki Yorimitsu
PII:
S0040-4020(20)30367-7
https://doi.org/10.1016/j.tet.2020.131232
TET 131232
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 March 2020
Revised Date: 18 April 2020
Accepted Date: 21 April 2020
Please cite this article as: Yoshida A, Okamoto K, Yanagi T, Nogi K, Yorimitsu H, Metal-free synthesis of
biaryls from aryl sulfoxides and sulfonanilides via sigmatropic rearrangement, Tetrahedron (2020), doi:
https://doi.org/10.1016/j.tet.2020.131232.
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Metal-free Synthesis of Biaryls from Aryl
Sulfoxides and Sulfonanilides via
Sigmatropic Rearrangement
Leave this area blank for abstract info.
Akira Yoshida, Koichi Okamoto, Tomoyuki Yanagi, Keisuke Nogi, and Hideki Yorimitsu*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan

1
Tetrahedron
journal homepage: www.elsevier.com
Metal-free Synthesis of Biaryls from Aryl Sulfoxides and Sulfonanilides via
Sigmatropic Rearrangement
Akira Yoshida, Koichi Okamoto, Tomoyuki Yanagi, Keisuke Nogi, and Hideki Yorimitsu*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Treatment of aryl sulfoxides and sulfonanilides with trifluoroacetic anhydride resulted in the
dehydrative metal-free construction of the corresponding unsymmetrical biaryls. The reaction
would proceed via (1) the activation of aryl sulfoxide with the anhydride, (2) interrupted
Pummerer reaction of the resulting arylsulfonium with sulfonanilide, (3) [3,3] sigmatropic
rearrangement to cleave the transient S–N bond and to form the prospective biaryl C–C bond,
and (4) global aromatization. The choice of the amino protecting group is crucial, and only N-
sulfonylanilines, i.e., sulfonanilides, could participate in the formation of biaryls.
Available online
Keywords:
Interrupted Pummerer reaction
Sigmatropic rearrangement
Aryl sulfoxide
2009 Elsevier Ltd. All rights reserved
.
N-sulfonylaniline
Biaryl
cascade (Y = S+R and Z = NH2 in Scheme 1a) to yield amino-
and sulfanyl-substituted biaryls.9 However, from a synthetic
viewpoint, the scope of this reaction is very limited: only 3,5-
dialkoxyphenyl sulfoxide was applicable as the sulfoxides. We
have thus endeavored to explore different reaction conditions to
achieve the use of anilines, which is disclosed herein.
+
1. Introduction
Biaryls often exist in bioactive molecules1 and functional
materials.2 Development of new methods for the synthesis of
biaryls has thus represented an important challenge in organic
synthesis for several decades. After the maturity of the
transition-metal-catalyzed approaches2c, 3 such as cross-coupling,
metal-free routes to biaryls have emerged as a new target to
explore4 because the use of heavy metals often poses problems of
contamination of products5 as well as supply risk.
2. Results/Discussion
According to the previous report about the use of phenols7a,
the reaction of benzothienyl sulfoxide (4a) with p-toluidine (5a)
was performed in the presence of trifluoroacetic anhydride
Among such metal-free routes to biaryls, sigmatropic
rearrangement of two-heteroatom-tethered intermediate 1 has
garnered increasing attention (Scheme 1a).6-10 Thanks to the
rather weak Y–Z bond, the sigmatropic rearrangement takes
place to connect the two ring systems with loss of the aromaticity
(TFAA) under various sets of conditions.
However,
trifluoroacetylation of 5a always took place predominantly (for
instance, Table 1, entry 1). We also examined the reaction of 4a
with 5a in the presence of triflic anhydride followed by treatment
with triflic acid under the previous conditions.9
Again,
of the two aromatic rings.
Global rearomatization of
intermediate 2 affords the corresponding disubstituted biaryls 3.
For about a century since the discovery of the benzidine
rearrangement,6a,b this synthetic trick has been investigated only
sporadically for exploring a new variant.7-9
trifluoromethanesulfonylation of 5a took place (entry 2). We thus
considered it important to lower the nucleophilicity of 5a by
protecting the amino group with an electron-withdrawing group
(Scheme 1c). Several protective groups were examined, and
sulfonyl protections were found to show positive effects (entries
3–8). Among them, p-anisylsulfonyl-protected 5b gave the best
result (entry 3). Methyl- and p-tolylsulfonyl groups are slightly
less effective (entries 4 and 5). More electron-donating and
sterically demanding 2,4-dimethoxyphenylsulfonyl protection led
to the formation of a complex mixture (entry 6). The uses of
In 2016, we discovered that the interrupted Pummerer reaction
of aryl sulfoxides with phenols is a good method to generate
intermediate 1 (Y = S+R and Z = O) and that the following
charge-accelerated sigmatropic rearrangement11 ends up with the
formation of 2-hydroxy-2’-sulfanylbiaryls.7a,d,e,12,13 Encouraged
by this, we envisioned that this cascade would be also applicable
to anilines instead of phenols. Very recently, we have discovered
such an extension (Scheme 1b): treatment of a mixture of 3,5-
dialkoxyphenyl sulfoxide and anilines with triflic anhydride
followed by further treatment with triflic acid promotes a similar
more
electron-withdrawing
p-cyanophenylsulfonyl
and
trifluoromethylsulfonyl groups gave complex mixtures (entries 7
and 8). Protections with acyl (entries 9–12) and phosphoryl
(entry 13) were completely unreactive, none of the corresponding
biaryls were formed at all.

2
Tetrahedron
to yield 7–13 in good yields. Carbonaceously aromatic 2-
Scheme 1. Sigmatropic Rearrangement of Two-heteroatom-
naphthyl sulfoxide and 3,5-dimethoxyphenyl sulfoxide reacted
with Ans-protected 2-naphthylamine to yield 14 and 15,
respectively. In the syntheses of 11, 12, 14, and 15,14 toluene was
the better solvent than dichloromethane while the reason for the
solvent effect remains unclear. Unfortunately, indolyl sulfoxides
were not suitable for this reaction, being converted to complex
mixtures.
tethered Intermediate Leading to Biaryls
Despite the success in using Ans-protected p-toluidine and 2-
naphthylamine, the reaction proved to be sensitive to substituents
on the benzene ring of anilides. For example, the use of p-
anisylsulfonylaniline instead of 5b, that is, simply replacing the
p-methyl group with a hydrogen, had a significantly negative
effect on the yield of the desired product 16 (cf. Table 1, entry 3).
To overcome the low yield, elevating temperature at the last stage
of the reaction from –20 ˚C to 0 ˚C was found to provide the
corresponding biaryl 16 in 75% yield.15 Ans-protected p-
chloroaniline was far less reactive and converted to 17 in only
22% yield albeit under the improved conditions.
Methylsulfonylaniline also reacted under similar temperature
control to yield 18 (eq 1). Further investigation is necessary to
improve the reaction scope.
Figure 1. Reaction Scope
Table 1. Exploring Suitable Protective Groupa
S
NHPG
SMe
NHPG
Me
S
1.5 equiv TFAA
S
O
+
CH2Cl2 (0.2 M)
–20 ˚C, 13 h
4a
5
6
1.2 equiv
entry
1
PG
6
NMR yield (%)
H (5a)
H (5a)
6a
6a
6b
6c
6d
0b,c
2
0d
3
SO2C6H4-p-OMe (5b)
SO2Me (5c)
86 (85e, 85e,f)
4
69 (72e)
68 (68e)
<20g
<26g
<22g
0h
5
SO2C6H4-p-Me (5d)
6
SO2C6H3-o,p-(OMe)2 (5e)
SO2C6H4-p-CN (5f)
SO2CF3 (5g)
6e
6f
6g
6h
6i
7
8
9
COCF3 (5h)
10
11
12
13
COMe (5i)
0c,h
CONMe2 (5j)
Fmoc (5k)
6j
6k
6l
0b,c
0h
PO(OEt)2 (5l)
0h
aStarting from 0.20 mmol of 4a. bN-trifluoroacetylation of 5 occurred.
cMost of 4a was recovered. dUnder the condtions in Reference 9. N-
e
f
trifluoromethanesulfonylation of 5a occurred. Isolated yield. Starting from
6.0 mmol (1.2 g) of 4a. gComplex product mixture. hMost of 5 was recovered.
S
NHMs
SMe
1.5 equiv TFAA
NHMs
4a
+
(1)
Employing the p-anisylsulfonyl group (Ans) as the best
protective group, we surveyed the scope of the reaction (Figure
1). Heteroaromatic sulfoxides underwent the reactions efficiently
CH2Cl2 (0.2 M)
–20 ˚C 19 h,
then 20 ˚C 1 h
1.2 equiv
18: 67%

3
4.2.1. General procedure for oxidation of aryl
sulfides to aryl sulfoxides (GP1)
Transformations of products 6b and 18 were explored
(Scheme 2). Catalytic removal of the methylsulfanyl group
proceeded cleanly under Nakada’s conditions16 to yield 19 and 20.
As another transformation, after oxidation of the sulfanyl moiety
of 6b and 18, the resulting sulfones 21 and 22 underwent base-
mediated SNAr cyclization to yield benzothienoindoles 23 and 24
with concomitant deprotection.
To a solution of an aryl sulfide (0.20 M in CH2Cl2), m-
chloroperbenzoic acid (contains ca. 30% H2O, 1.1 equiv) was
added portionwise at 0 °C. The resulting solution was allowed to
warm to room temperature and stirred. Progress of the oxidation
was checked by TLC. After completion of the reaction, saturated
aqueous NaHCO3 was added to the reaction mixture, and the
resulting solution was extracted with EtOAc (20 mL×3). The
combined organic layer was dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by
chromatography on silica gel to give the corresponding aryl
sulfoxide.
Scheme 2. Transformations of Products
S
S
3 mol% PdCl2
2.1 equiv Et3SiH
SMe
NHPG
NHPG
THF, r.t., 24 h
4.2.2. Typical procedure for preparation of aryl
sulfoxides
R
R
6b (R = Me, PG = Ans)
18 (R = H, PG = Ms)
19: 97% from 6b
20: 84% from 18
The synthesis of 7-methoxy-2-(methylsulfinyl)benzothiophene
is representative. A 50-mL round-bottom flask was charged with
7-methoxybenzothiophene (0.80 g, 4.9 mmol, prepared according
to the literature24) and THF (10 mL). A solution of BuLi (1.6 M
in hexane, 3.4 mL, 5.4 mmol) was added dropwise at 0 ºC. The
resulting solution was stirred at 0 ºC for 1 h before an addition of
dimethyl disulfide (0.45 mL, 5.1 mmol). After the mixture was
stirred for 1 h additionally, saturated aqueous NaHCO3 was
added. The resulting biphasic solution was extracted with EtOAc
(10 mL×3). The combined organic layer was washed with brine,
dried over Na2SO4, and concentrated under reduced pressure to
provide 7-methoxy-2-(methylsulfanyl)benzothiophene with some
impurities. Subsequent oxidation of the sulfide according to GP1
provided 7-methoxy-2-(methylsulfinyl)benzothiophene (0.89 g,
3.9 mmol, 80% over two steps) as a brown oil. 7-Methyl-2-
2.1 equiv mCPBA
CH2Cl2, 0 ˚C to r.t.
S
S
3.0 equiv Cs2CO3,
170 ˚C, 17 h for 21;
4.0 equiv Cs2CO3,
130 ˚C, 31 h for 22
SO2Me
NHPG
NH
DMSO
R
R
21: 74% from 6b, 20 h
22: 80% from 18, 70 h
23: 61% from 21
24: 68% from 22
3. Conclusion
We have developed metal-free, regioselective dehydrative C–
H/C–H coupling of aryl sulfoxides with sulfonanilides with the
aid of trifluoroacetic anhydride. Anilides have now become
available for the synthesis of biaryls by using a sequence of
interrupted Pummerer reaction and [3,3] sigmatropic
rearrangement, the scope of our strategy being significantly
expanded. Interestingly, the reaction was dominated by the
protective group of the amino unit, and sulfonyl groups such as
p-anisylsulfonyl proved to be promising. The products are useful
synthetic intermediates. Further expansion of the reaction scope
is now in progress in our laboratory.
(methylsulfinyl)benzothiophene
(methylsulfinyl)benzothiophene were prepared via the same
procedure from 7-methylbenzothiophene and 5-
methoxybenzothiophene, respectively.24
and
5-methoxy-2-
4.2.3. Preparation of 2-(methylsulfinyl)furan
A 100-mL two-necked flask was charged with furan (1.5 mL,
20 mmol) and THF (20 mL). BuLi (1.6 M in hexane, 12.9 mL, 20
mmol) was added dropwise at 0 ºC. The reaction mixture was
allowed to warm to room temperature and stirred for 4 h.
Dimethyl disulfide (1.8 mL, 20 mmol) was then added dropwise,
and the resulting solution was stirred for 12 h. The reaction was
quenched with 6 M aqueous KOH (50 mL), and the resulting
biphasic mixture was extracted with EtOAc (30 mL×3). The
combined organic layer was washed with brine, dried over
Na2SO4, and concentrated under reduced pressure to provide 2-
(methylsulfanyl)furan with some impurities. Subsequent
oxidation of the sulfide according to GP1 provided 2-
(methylsulfinyl)furan (1.1 g, 8.6 mmol, 43% over two steps) as a
brown oil.
4. Experimental Section
4.1. Instrumentation and Chemicals
1H NMR (600 MHz) and 13C NMR (151 MHz) spectra were
recorded on JEOL ECA-600 and JEOL ECZ-600 spectrometers.
Chemical shifts (δ) are reported in parts per million relative to
residual CHCl3 (1H: δ = 7.26 ppm) and relative to CDCl3 (13C: δ
= 77.16 ppm). Column chromatography was carried out on silica
gel (Wakosil® C-300), while preparative recycling gel
permeation chromatography (GPC) was performed on a JAI LC-
9260 II NEXT system using CHCl3 as the eluent. Mass spectra
were measured on a Bruker micrOTOF II spectrometer.
4.2.4. Preparation of 2-iodo-5-
(methylsulfinyl)thiophene
A modification of the procedure reported by Procter was
used.25 A 200-mL two-necked flask was charged with 2-
iodothiophene (1.0 mL, 10 mmol), DMSO (0.78 mL, 11 mmol),
and CH2Cl2 (50 mL). Tf2O (1.8 mL, 11 mmol) was slowly added
at –30 ºC. After the solution was stirred for 15 min at –30 ºC, the
solution was allowed to warm to room temperature and stirred for
an additional 1.5 h. Et2NH (4.3 mL, 41 mmol) was then added,
and the resulting solution was stirred for 6 h. After an addition of
H2O (30 mL), the biphasic solution was extracted with CH2Cl2
(30 mL × 3). The combined organic layer was dried over Na2SO4,
and concentrated under reduced pressure to provide 2-iodo-5-
(methylsulfanyl)thiophene with some impurities. Subsequent
oxidation of the sulfide according to GP1 provided 2-iodo-5-
Dehydrated THF, DMF, DMSO, CH2Cl2, and toluene were
purchased from common commercial suppliers and stored under
an atmosphere of nitrogen. Anilides 5g,17 5h,18 5i,19 5j,20 5k,21
and 5l22 were prepared from p-toluidine via similar procedures in
the
previous
reports.
Aryl
sulfoxides
2-
2-
(methylsulfinyl)benzothiophene
(4a),7a
(methylsulfinyl)naphthalene,7a 2-(methylsulfinyl)thiophene,7a and
1,3-dimethoxy-5-(methylsulfinyl)benzene23
according to the literature.
were
prepared
4.2. Preparation of Substrates

4
Tetrahedron
(methylsulfinyl)thiophene (1.25 g, 4.6 mmol, 46% over two
extracted with CH2Cl2 (2 mL×3). The combined organic layer
steps) as a brown solid.
was dried over Na2SO4 and concentrated under reduced pressure.
The residue was purified by chromatography on silica gel
(hexane/EtOAc = 3/1) to provide 6b (77.3 mg, 0.17 mmol, 85 %)
as a colorless oil.
4.2.5. Preparation of 3-(methylsulfinyl)thiophene
A
100-mL two-necked flask was charged with 3-
bromothiophene (1.9 mL, 20 mmol) and hexane (30 mL). BuLi
(1.6 M in hexane,13.8 mL, 22 mmol) was added to the mixture
dropwise at –40 ºC. After additions of THF (10 mL) and hexane
(10 mL), the resulting mixture was allowed to warm to room
temperature. After an addition of dimethyl disulfide (2.0 mL, 22
mmol), the resulting mixture was stirred for 12 h before an
addition of H2O (20 mL). The biphasic solution was extracted
with CH2Cl2 (20 mL×3). The combined organic layer was
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure to provide 3-(methylsulfanyl)thiophene with
some impurities. Subsequent oxidation of the sulfide according to
GP1 afforded 3-(methylsulfinyl)thiophene (1.0 g, 7.2 mmol, 36%
over two steps) as a colorless oil.
4.3.2. Desulfanylation of biaryls (Scheme 2)
A modification of the procedure reported by Nakada was
used.15 The reduction of 18 is representative. A Schlenk tube was
charged with biaryl 18 (69.8 mg, 0.20 mmol), PdCl2 (1.1 mg, 3
mol%), and THF (2 mL). After addition of triethylsilane (67 µL,
0.42 mmol), the resulting solution was stirred at room
temperature for 24 h. After addition of H2O (4 mL), the resulting
biphasic solution was extracted with CH2Cl2 (4 mL×2). The
combined organic layer was dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by
chromatography on silica gel (hexane/ EtOAc = 5/1) to provide
20 (51.0 mg, 0.17 mmol, 84%) as a colorless oil.
4.2.6. General procedure for preparation of
sulfonanilides
4.3.3. Cyclization of biaryls (Scheme 2)
The reaction of 18 is representative. To a solution of biaryl 18
(698.8 mg, 2.0 mmol) in CH2Cl2 (20 mL), m-chloroperbenzoic
acid (contains ca. 30% H2O, 1.0 g, 4.2 mmol) was added
portionwise at 0 ºC. The resulting solution was allowed to warm
to room temperature and stirred for 70 h. Saturated aqueous
NaHCO3 was then added, and the aqueous layer was extracted
with EtOAc (20 mL×3). The combined organic layer was
purified by chromatography on silica gel with CH2Cl2 as an
eluent to provide the corresponding aryl sulfone 22 (607.9 mg,
1.6 mmol, 80%) as a white solid.
A modification of the procedure reported by Nachtsheim was
used.26 The synthesis of 5c is representative. A Schlenk tube was
charged with p-toluidine (1.1 g, 10 mmol), pyridine (0.90 mL, 11
mmol), and CH2Cl2 (25 mL). Methanesulfonyl chloride (0.85
mL, 11 mmol) was then added portionwise at 0 ºC. The reaction
mixture was allowed to warm to room temperature and stirred.
After the completion of the reaction was checked by TLC, the
reaction was quenched with H2O (25 mL), and the biphasic
solution was extracted with CH2Cl2 (25 mL×3). The combined
organic layer was washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (hexane/EtOAc = 3/1) to
A Schlenk tube was charged with 22 (381.2 mg, 1.0 mmol),
Cs2CO3 (1.3 g, 4.0 mmol), and DMSO (10 mL). The resulting
mixture was stirred at 130 ºC for 31 h and then poured into H2O
(200 mL). The resulting solution was extracted with a mixture of
EtOAc/hexane (v/v = 1/1, 100 mL×5). The combined organic
layer was washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by
chromatography on silica gel (hexane/CH2Cl2 = 2/1) to provide
24 (151.9 mg, 0.68 mmol, 68%) as a white solid.
provide 5c (1.7 g, 8.9 mmol, 89%) as
Sulfonanilides 5b, 5d–f,
a
white solid.
4-methoxy-N-
phenylbenzenesulfonamide (for 16), and N-(4-chlorophenyl)-4-
methoxybenzenesulfonamide (for 17) were prepared via the same
procedure. 2,4-Dimethoxybenzenesulfonyl chloride for the
preparation of 5e was prepared according to the literature.27
4.2.7. Preparation of 2-(4-
methoxybenzenesulfonyl)aminonaphthalene
4.4. Characterization Data
A modification of the procedure reported by Guo was used.28
An oven-dried two-necked flask was charged with CuI (0.29 g,
1.5 mmol), 4-methoxybenzenesulfonamide (6.7 g, 36 mmol),
glycine (0.62 g, 6.0 mmol), K3PO4 (16 g, 75 mmol), 2-
iodonaphthalene (7.6 g, 30 mmol), and DMF (60 mL). The
resulting mixture was stirred at 100 ºC for 24 h. The reaction
mixture was poured into H2O (200 mL), and the resulting
biphasic solution was extracted with a mixture of EtOAc/hexane
(v/v = 1/1, 100 mL×3). The combined organic layer was dried
over Na2SO4 and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel
4.4.1. 7-methoxy-2-(methylsulfinyl)benzothiophene
1
Brown oil. H NMR: δ 7.71 (s, 1H), 7.44 (d, J = 7.9 Hz, 1H),
7.38 (t, J = 7.9 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 4.00 (s, 3H),
2.96 (s, 3H); 13C NMR: δ 154.63, 148.44, 139.90, 130.30, 126.71,
126.27, 117.37, 105.92, 55.92, 44.43; HRMS (APCI-MS,
positive) calcd for C10H11O2S2 [M+H]+: 227.0195, found:
227.0201.
4.4.2. 7-methyl-2-(methylsulfinyl)benzothiophene
1
Brown oil. H NMR: δ 7.74 (s, 1H), 7.69 (d, J = 7.5 Hz, 1H),
7.36 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 2.97 (s, 3H),
2.58 (s, 3H); 13C NMR: δ 147.55, 141.64, 138.19, 132.60, 126.74,
126.64, 125.80, 122.69, 44.46, 20.35; HRMS (APCI-MS,
positive) calcd for C10H11OS2 [M+H]+: 211.0246, found:
211.0243.
with
CH2Cl2
as
an
eluent
to
provide
2-(4-
methoxybenzenesulfonyl)aminonaphthalene (4.9 g, 16 mmol,
52%) as a white solid.
4.3. Experimental Procedure
4.4.3. 5-methoxy-2-(methylsulfinyl)benzothiophene
4.3.1. General Procedure for Coupling of Aryl
Sulfoxides with Sulfonanilides
Brown solid (m.p. = 106.5–107.9 ºC). 1H NMR: δ 7.74 (d, J =
8.2 Hz, 1H), 7.64 (s, 1H), 7.26 (s, 1H), 7.09 (d, J = 8.2 Hz, 1H),
3.88 (s, 3H), 2.96 (s, 3H); 13C NMR: δ 158.21, 149.12, 139.45,
133.73, 125.72, 123.69, 117.23, 106.61, 55.74, 44.49; HRMS
(APCI-MS, positive) calcd for C10H11O2S2 [M+H]+: 227.0195,
found: 227.0198.
The synthesis of 6b is representative. A Schlenk tube was
charged with 2-methylsulfinylbenzothiophene (39.1 mg, 0.20
mmol), sulfonanilide 5b (66.7 mg, 0.24 mmol), and CH2Cl2 (1.0
mL). Trifluoroacetic anhydride (42 μL, 0.30 mmol) was added to
the solution in one portion at –20 ºC, and the resulting solution
was stirred at the same temperature for 13 h before addition of
saturated aqueous NaHCO3. The resulting biphasic solution was
4.4.4. 2-(methylsulfinyl)furan

5
1
Brown oil. H NMR: δ 7.62 (s, 1H), 6.91 (d, J = 3.4 Hz, 1H),
Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 3.82 (s, 3H); 13C NMR: δ
6.49–6.49 (m, 1H), 2.92 (s, 3H); 13C NMR: δ 152.70, 146.83,
115.35, 111.52, 38.63; HRMS (APCI-MS, positive) calcd for
C5H7O2S [M+H]+: 131.0161, found: 131.0156.
163.40, 135.38, 130.89, 130.17, 129.57, 129.51, 122.95, 114.45,
55.73; HRMS (APCI-MS, positive) calcd for C13H1235ClNO3S
[M]: 297.0221, found: 297.0223.
4.4.5. 2-iodo-5-(methylsulfinyl)thiophene
4.4.13. 4-methoxy-N-(4-methyl-2-(2-
(methylsulfanyl)benzothiophen-3-
yl)phenyl)benzenesulfonamide (6b)
1
B Brown solid (m.p. = 82.4–86.8 ºC). H NMR (CDCl3): δ
7.25 (d, J = 3.4 Hz, 1H), 7.11 (d, J = 3.4 Hz, 1H), 2.89 (s, 3H);
13C NMR: δ 152.51, 137.29, 130.74, 80.26, 44.66; HRMS
(APCI-MS, positive) calcd for C5H6IOS2 [M+H]+: 272.8899,
found: 272.8909.
Colorless oil (77.3 mg, 0.17 mmol, 85%). 1H NMR: δ 7.73 (d,
J = 8.2 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.23–7.30 (m, 4H),
7.10 (t, J = 7.5 Hz, 1H), 6.96 (s, 1H), 6.77 (s, 1H), 6.73 (d, J =
7.9 Hz, 1H), 6.47 (d, J = 9.7 Hz, 2H), 3.69 (s, 3H), 2.48 (s, 3H),
2.33 (s, 3H); 13C NMR: δ 162.61, 139.74, 139.36, 136.57, 135.51,
131.90, 131.72, 131.65, 130.62, 130.29, 128.88, 126.95, 124.70,
124.35, 124.14, 122.18, 121.63, 113.78, 55.34, 20.97, 19.03;
HRMS (APCI-MS, positive) calcd for C23H22NO3S3 [M+H]+:
456.0756, found: 456.0751.
4.4.6. 3-(methylsulfinyl)thiophene
Brown oil. 1H NMR: δ 7.77–7.78 (m, 1H), 7.50–7.52 (m, 1H),
7.27–7.29 (m, 1H), 2.81 (s, 3H); 13C NMR: δ 144.89, 128.67,
125.60, 122.76, 43.06; HRMS (APCI-MS, positive) calcd for
C5H7OS2 [M+H]+: 146.9933, found: 146.9934.
4.4.7. 4-methoxy-N-(4-
methylphenyl)benzenesulfonamide (5b)
4.4.14. N-(4-methyl-2-(2-
(methylsulfanyl)benzothiophen-3-
yl)phenyl)methanesulfonamide (6c)
White solid (m.p. = 96.0–97.3 ºC). 1H NMR: δ 7.69 (d, J = 8.9
Hz, 2H), 7.02 (d, J = 8.2 Hz, 2H), 6.96 (d, J = 8.2 Hz, 2H), 6.88
(d, J = 8.9 Hz, 2H), 6.84 (br, 1H), 3.82 (s, 3H), 2.26 (s, 3H); 13C
NMR: δ 163.15, 135.42, 133.99, 130.77, 129.96, 129.57, 122.40,
114.25, 55.69, 20.97; HRMS (APCI-MS, positive) calcd for
C14H15NO3S [M]+: 277.0767 found: 277.0774.
White solid (52.5 mg, 0.15 mmol, 72%, m.p. = 114.0–115.3
1
ºC). H NMR: δ 7.82 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 8.2 Hz,
1H), 7.29–7.36 (m, 3H), 7.23 (d, J = 7.5 Hz, 1H), 7.12 (s, 1H),
6.28 (s, 1H), 2.69 (s, 3H), 2.55 (s, 3H), 2.39 (s, 3H); 13C NMR: δ
139.71, 139.61, 138.12, 135.63, 132.57, 132.15, 130.84, 130.71,
126.33, 125.39, 124.80, 122.30, 121.76 (one of these aromatic
signals contains overlapping), 39.23, 20.96, 18.96; HRMS
(APCI-MS, positive) calcd for C17H17NO2S3 [M]+: 363.0416,
found: 363.0426.
4.4.8. 2,4-dimethoxy-N-(4-
methylphenyl)benzenesulfonamide (5e)
1
White solid (m.p. = 130.2–131.6 ºC). H NMR: δ 7.70 (d, J =
8.9 Hz, 1H), 6.98 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 8.2 Hz, 2H),
6.81 (br, 1H), 6.47 (d, J = 2.7 Hz, 1H), 6.43 (dd, J = 8.9, 2.7 Hz,
1H), 4.00 (s, 3H), 3.80 (s, 3H), 2.23 (s, 3H); 13C NMR: δ 165.04,
157.73, 135.08, 134.40, 132.84, 129.83, 121.82, 118.75, 104.56,
99.50, 56.47, 55.78, 20.92; HRMS (APCI-MS, positive) calcd for
C15H17NO4S [M]+: 307.0873, found: 307.0869.
4.4.15. 4-methyl-N-(4-methyl-2-(2-
(methylsulfanyl)benzothiophen-3-
yl)phenyl)benzenesulfonamide (6d)
Colorless oil (59.8 mg, 0.14 mmol, 68%). 1H NMR: δ 7.74 (d,
J = 8.2 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.25–7.30 (m, 4H),
7.11 (t, J = 7.5 Hz, 1H), 6.97 (s, 1H), 6.83 (m, 3H), 6.73 (d, J =
8.2 Hz, 1H), 2.50 (s, 3H), 2.34 (s, 3H), 2.20 (s, 3H); 13C NMR: δ
143.20, 139.74, 139.43, 136.60, 136.11, 135.54, 131.86, 131.77,
131.70, 130.33, 129.31, 126.91, 126.85, 124.70, 124.34, 124.09,
122.27, 121.73, 21.60, 21.00, 19.08; HRMS (APCI-MS, positive)
calcd for C23H21NO2S3 [M]+: 439.0729, found: 439.0742.
4.4.9. 4-cyano-N-(4-
methylphenyl)benzenesulfonamide (5f)
Yellow solid (m.p. = 151.7–153.1 ºC). 1H NMR: δ 7.83 (d, J =
8.2 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H),
6.94 (d, J = 8.2 Hz, 2H), 6.79 (br, 1H), 2.29 (s, 3H); 13C NMR: δ
143.15, 136.57, 132.92, 132.76, 130.25, 128.00, 122.95, 117.38,
116.67, 20.99; HRMS (APCI-MS, positive) calcd for
C14H12N2O2S [M]+: 272.0614, found: 272.0627.
4.4.16. 4-methoxy-N-(2-(6-methoxy-2-
(methylsulfanyl)benzothiophen-3-yl)-4-
methylphenyl)benzenesulfonamide (7)
4.4.10. 4-methoxy-N-(naphthalen-2-
yl)benzenesulfonamide
White solid (64.1 mg, 0.13 mmol, 66%, m.p. = 155.0–160.7
1
ºC). H NMR: δ 7.68 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.9 Hz,
1
White solid (m.p. = 121.1–124.1 ºC). H NMR: δ 7.76 (d, J =
2H), 7.22 (dd, J = 8.2, 2.1 Hz, 1H), 7.07 (t, J = 7.9 Hz, 1H), 6.95
(d, J = 2.1 Hz, 1H), 6.71–6.73 (m, 2H), 6.51 (d, J = 8.9 Hz, 2H),
6.40 (d, J = 7.9 Hz, 1H), 4.03 (s, 3H), 3.72 (s, 3H), 2.49 (s, 3H),
2.32 (s, 3H); 13C NMR: δ 162.59, 153.74, 141.40, 137.27,
135.50, 131.93, 131.82, 130.83, 130.29, 128.95, 127.93, 127.15,
126.14, 124.17, 114.96, 113.83, 104.46 (one of these aromatic
signals contains overlapping), 55.95, 55.39, 21.02, 19.07; HRMS
(APCI-MS, positive) calcd for C24H23NO4S3 [M]+: 485.0784,
found: 485.0782.
7.5 Hz, 1H), 7.71–7.74 (m, 4H), 7.52 (d, J = 2.1 Hz, 1H), 7.45 (t,
J = 7.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.21 (dd, J = 8.9, 2.1 Hz,
1H), 6.85 (d, J = 9.6 Hz, 2H), 6.70 (br, 1H), 3.79 (s, 3H); 13C
NMR: δ 163.27, 134.35, 133.77, 131.14, 130.58, 129.58, 129.48,
127.75, 127.63, 126.78, 125.56, 121.11, 118.33, 114.38, 55.65;
HRMS (APCI-MS, positive) calcd for C17H16NO3S [M+H]+:
314.0845, found: 314.0838.
4.4.11. 4-methoxy-N-phenylbenzenesulfonamide
1
White solid (m.p. = 105.9–106.9 ºC). H NMR: δ 7.70 (d, J =
4.4.17. 4-methoxy-N-(4-methyl-2-(7-methyl-2-
(methylsulfanyl)benzothiophen-3-
yl)phenyl)benzenesulfonamide (8)
8.9 Hz, 2H), 7.23 (t, J = 7.5 Hz, 2H), 7.11 (t, J = 7.5 Hz, 1H),
7.06 (d, J = 7.5 Hz, 2H), 6.88 (d, J = 8.9 Hz, 2H), 6.69 (br, 1H),
3.82 (s, 3H); 13C NMR: δ 163.26, 136.70, 130.74, 129.57, 129.46,
125.50, 121.81, 114.31, 55.71; HRMS (APCI-MS, positive)
calcd for C13H14NO3S [M+H]+: 264.0689, found: 264.0686.
Colorless oil (65.7 mg, 0.14 mmol, 70%). 1H NMR: δ 7.68 (d,
J = 8.2 Hz, 1H), 7.29 (d, J = 9.6 Hz, 2H), 7.22 (dd, J = 8.2, 1.4
Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.95
(d, J = 1.4 Hz, 1H), 6.73 (s, 1H), 6.60 (d, J = 7.5 Hz, 1H), 6.48 (d,
J = 9.6 Hz, 2H), 3.70 (s, 3H), 2.55 (s, 3H), 2.49 (s, 3H), 2.32 (s,
3H); 13C NMR: δ 162.61, 139.61, 139.58, 136.25, 135.39, 132.45,
131.97, 131.79, 131.25, 130.74, 130.26, 128.95, 127.14, 125.23,
4.4.12. N-(4-chlorophenyl)-4-
methoxybenzenesulfonamide
White solid (m.p. = 94.6–95.9 ºC). 1H NMR: δ 7.72 (d, J = 8.9
Hz, 2H), 7.30 (s, 1H), 7.18 (d, J = 8.9 Hz, 2H), 7.03 (d, J = 8.9

6
Tetrahedron
124.77, 123.84, 119.96, 113.78, 55.37, 21.00, 20.22, 19.18;
129.60, 128.93, 128.69, 128.17, 128.15, 127.28, 125.47, 125.34,
119.11, 118.31, 114.28, 55.67, 17.47; HRMS (APCI-MS,
positive) calcd for C22H19NO3S3 [M]+: 441.0522, found:
441.0526.
HRMS (APCI-MS, positive) calcd for C24H23NO3S3 [M]+:
469.0835, found: 469.0838.
4.4.18. 4-methoxy-N-(2-(5-methoxy-2-
(methylsulfanyl)benzothiophen-3-yl)-4-
methylphenyl)benzenesulfonamide (9)
4.4.23. 4-methoxy-N-(2'-(methylsulfanyl)-[1,1'-
binaphthalen] -2-yl)benzenesulfonamide (14)
Colorless oil (60.2 mg, 0.12 mmol, 62%). 1H NMR: δ 7.68 (d,
J = 8.2 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.25 (d, J = 9.6 Hz,
2H), 7.22 (dd, J = 8.2, 1.4 Hz, 1H), 6.95 (d, J = 1.4 Hz, 1H), 6.89
(dd, J = 8.9, 2.1 Hz, 1H), 6.80 (s, 1H), 6.44 (d, J = 9.6 Hz, 2H),
6.15 (d, J = 2.1 Hz, 1H), 3.69 (s, 3H), 3.65 (s, 3H), 2.46 (s, 3H),
2.31 (s, 3H); 13C NMR: δ 162.61, 157.70, 141.01, 137.62,
135.72, 131.79, 131.54, 131.28, 130.65, 130.32, 128.95, 127.31,
124.67, 122.30, 113.87, 113.68, 104.92 (one of these aromatic
signals contains overlapping), 55.41, 55.31, 21.01, 18.95; HRMS
(APCI-MS, positive) calcd for C24H23NO4S3 [M]+: 485.0784,
found: 485.0781.
The reaction was performed in toluene. White solid (66.0 mg,
0.14 mmol, 68%, m.p. = 190.5–191.9 ºC, using toluene as
solvent). 1H NMR: δ 8.19 (d, J = 8.9 Hz, 1H), 7.98–8.01 (m, 2H),
7.86–7.88 (m, 2H), 7.53 (d, J = 8.9 Hz, 1H), 7.44 (d, J = 8.9 Hz,
2H), 7.35–7.38 (m, 2H), 7.19 (t, J = 7.5 Hz, 1H), 6.97 (t, J = 7.5
Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.64 (d, J = 8.9 Hz, 2H), 6.47
(d, J = 8.2 Hz, 1H), 6.41 (s, 1H), 3.78 (s, 3H), 2.38 (s, 3H); 13C
NMR: δ 163.09, 138.03, 133.05, 132.86, 132.66, 131.18, 131.05,
130.05, 129.94, 129.31, 128.24, 128.19, 127.47, 127.32, 127.13,
125.37, 125.28, 125.22, 124.34, 123.11, 122.36, 119.22, 114.03
(one of these aromatic signals contains overlapping), 55.54,
15.32; HRMS (APCI-MS, positive) calcd for C28H23NO3S2 [M]+:
485.1114, found: 485.1119.
4.4.19. 4-methoxy-N-(4-methyl-2-(2-
(methylsulfanyl)furan-3-
yl)phenyl)benzenesulfonamide (10)
4.4.24. N-(1-(2,4-dimethoxy-6-
(methylsulfanyl)phenyl)naphthalen-2-yl)-4-
methoxybenzenesulfonamide (15)
1
Brown oil (51.4 mg, 0.13 mmol, 66%). H NMR: δ 7.75 (d, J
= 8.2 Hz, 2H), 7.34 (d, J = 2.1 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H),
7.05–7.00 (br, 1H), 6.98 (dd, J = 8.2, 2.1 Hz, 1H), 6.88 (d, J =
8.2 Hz, 2H), 6.46–6.47 (m, 2H), 3.80 (s, 3H), 2.44 (s, 3H), 2.38
(s, 3H); 13C NMR: δ 163.21, 154.80, 147.11, 134.78, 132.27,
131.56, 130.73, 130.58, 129.64, 120.97, 120.07, 115.57, 114.32,
110.88, 55.67, 21.44, 18.71; HRMS (APCI-MS, positive) calcd
for C19H19NO4S2 [M]+: 389.0750, found: 389.0757.
Colorless oil (51.5 mg, 0.10 mmol, 52%, using toluene as
1
solvent). H NMR: δ 8.01 (d, J = 8.9 Hz, 1H), 7.84 (d, J = 8.9
Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.9 Hz, 2H), 7.34
(t, J = 7.5 Hz, 1H), 7.28 (t, J = 7.5 Hz, 1H), 7.12 (d, J = 8.9 Hz,
1H), 6.81 (d, J = 8.9 Hz, 2H), 6.54 (s, 1H), 6.43 (d, J = 2.1 Hz,
1H), 6.35 (d, J = 2.1 Hz, 1H), 3.94 (s, 3H), 3.77 (s, 3H), 3.44 (s,
3H), 2.18 (s, 3H); 13C NMR: δ 163.07, 161.85, 158.89, 142.90,
133.35, 133.00, 131.58, 130.88, 129.64, 129.43, 128.19, 126.71,
125.14, 124.90, 121.38, 118.56, 113.97, 111.87, 101.89, 94.81,
55.78, 55.61 (2C), 15.19; HRMS (APCI-MS, positive) calcd for
C26H25NO5S2 [M]+: 495.1169, found: 495.1172.
4.4.20. 4-methoxy-N-(1-(2-
(methylsulfanyl)thiophen-3-yl)naphthalen-2-
yl)benzenesulfonamide (11)
The reaction was performed in toluene. Colorless oil (62.7
mg, 0.14 mmol, 71%). 1H NMR: δ 7.98 (d, J = 8.9 Hz, 1H), 7.88
(d, J = 8.9 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 8.9 Hz,
2H), 7.41 (t, J = 8.2 Hz, 1H), 7.33–7.36 (m, 2H), 7.20 (d, J = 8.2
Hz, 1H), 6.81 (d, J = 8.9 Hz, 2H), 6.66 (s, 1H), 6.24 (d, J = 5.5
Hz, 1H), 3.79 (s, 3H), 2.22 (s, 3H); 13C NMR: δ 163.22, 136.71,
135.96, 132.96, 132.58, 131.17, 130.93, 130.42, 129.65, 129.43,
128.23, 127.35, 126.91, 125.60, 125.42, 123.01, 120.63, 114.23,
55.70, 20.56; HRMS (APCI-MS, positive) calcd for C22H19NO3S3
[M]+: 441.0522, found: 441.0516.
4.4.25. 4-methoxy-N-(2-(2-
(methylsulfanyl)benzothiophen-3-
yl)phenyl)benzenesulfonamide (16)
White solid (65.7 mg, 0.15 mmol, 75%, m.p. = 161.0–168.8
1
ºC). H NMR: δ 7.82 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 8.2 Hz,
1H), 7.43 (t, J = 7.9 Hz, 1H), 7.34 (d, J = 8.9 Hz, 2H), 7.28 (t, J =
7.5 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.15 (dd, J = 7.5, 1.4 Hz,
1H), 7.11 (t, J = 7.5 Hz, 1H), 6.77 (br, 1H), 6.73 (d, J = 7.5 Hz,
1H), 6.54 (d, J = 8.9 Hz, 2H), 3.72 (s, 3H), 2.48 (s, 3H); 13C
NMR: δ 162.79, 139.65, 139.45, 137.20, 134.69, 131.45, 131.38,
130.56, 129.59, 129.01, 126.51, 125.46, 124.82, 124.48, 123.15,
122.12, 121.75, 113.88, 55.42, 19.11; HRMS (APCI-MS,
positive) calcd for C22H19NO3S3 [M]: 441.0522, found: 441.0519.
4.4.21. N-(1-(5-iodo-2-(methylsulfanyl)thiophen-3-
yl)naphthalen-2-yl)-4-methoxybenzenesulfonamide
(12)
The reaction was performed in toluene. White solid (37.5 mg,
0.07 mmol, 33%, m.p. = 186.2–188.0 ºC). H NMR: δ 8.00 (d, J
1
4.4.26. N-(4-chloro-2-(2-
(methylsulfanyl)benzothiophen-3-yl)phenyl)-4-
methoxybenzenesulfonamide (17)
= 8.9 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H),
7.47 (d, J = 8.9 Hz, 2H), 7.43 (t, J = 8.2 Hz, 1H), 7.37 (t, J = 8.2
Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 8.9 Hz, 2H), 6.57
(s, 1H), 6.04 (s, 1H), 3.84 (s, 3H), 2.20 (s, 3H); 13C NMR: δ
163.21, 141.50, 139.75, 138.20, 132.68, 132.46, 131.46, 130.71,
130.00, 129.28, 128.33, 127.11, 125.73, 125.46, 122.74, 122.06,
114.42, 73.87, 55.76, 20.61; HRMS (APCI-MS, positive) calcd
for C22H18INO3S3 [M]+: 566.9488, found: 566.9474.
Colorless oil (21.0 mg, 0.04 mmol, 22%). 1H NMR: δ 7.77 (d,
J = 8.9 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.40 (dd, J = 8.9, 2.7
Hz, 1H), 7.32 (d, J = 8.9 Hz, 2H), 7.29 (t, J = 7.5 Hz, 1H), 7.15
(d, J = 2.7 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.72–6.73 (m, 2H),
6.54 (d, J = 8.9 Hz, 2H), 3.73 (s, 3H), 2.51 (s, 3H); 13C NMR: δ
163.01, 139.43, 139.33, 138.17, 133.52, 131.17, 130.88, 130.41,
129.80, 129.66, 129.07, 128.27, 125.08, 124.66, 124.59, 121.88,
121.86, 114.04, 55.48, 19.13; HRMS (APCI-MS, positive) calcd
for C22H1835ClNO3S3 [M]: 475.0132, found: 475.0134.
4.4.22. 4-methoxy-N-(1-(3-
(methylsulfanyl)thiophen-2-yl)naphthalen-2-
yl)benzenesulfonamide (13)
Colorless oil (63.6 mg, 0.14 mmol, 72%). 1H NMR: δ 8.01 (d,
J = 8.9 Hz, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.81 (d, J = 8.2 Hz,
1H), 7.67 (d, J = 9.4 Hz, 2H), 7.52 (d, J = 5.5 Hz, 1H), 7.36–7.41
(m, 2H), 7.30 (d, J = 8.2 Hz, 1H), 7.16 (d, J = 5.5 Hz, 1H), 6.84
(d, J = 9.4 Hz, 2H), 6.82 (s, 1H), 3.78 (s, 3H), 2.25 (s, 3H); 13C
NMR: δ 163.34, 135.49, 134.32, 133.79, 130.86, 130.75, 130.71,
4.4.27. N-(2-(2-(methylsulfanyl)benzothiophen-3-
yl)phenyl)methanesulfonamide (18)
The reaction was performed at –20 ˚C for 19 h and then at 20
˚C for 1 h. White solid (46.8 mg, 0.13 mmol, 67%, m.p. =
1
133.8–139.9 ºC). H NMR: δ 7.82 (d, J = 8.2 Hz, 1H), 7.79 (d, J

7
= 8.2 Hz, 1H), 7.48–7.51 (m, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.30–
7.33 (m, 3H), 7.22 (d, J = 7.5 Hz, 1H), 6.35 (s, 1H), 2.78 (s, 3H),
2.55 (s, 3H); 13C NMR: δ 139.71, 139.63, 138.49, 135.33,
131.88, 130.67, 130.07, 125.75, 125.43, 125.41, 124.88, 122.31,
121.78, 121.14, 39.43, 19.04; HRMS (APCI-MS, positive) calcd
for C16H15NO2S3 [M]+: 349.0259, found: 349.0267.
7.46 (m, 1H), 7.28–7.33 (m, 3H); 13C NMR: δ 141.37, 140.06,
138.59, 132.81, 125.19, 123.71, 122.85, 122.49, 122.18, 120.78,
120.69, 119.19, 118.85, 111.47; HRMS (APCI-MS, positive)
calcd for C14H10NS [M+H]+: 224.0528, found: 224.0533.
Acknowledgments
4.4.28. N-(2-(benzothiophen-3-yl)-4-methylphenyl)-
4-methoxybenzenesulfonamide (19)
This work was supported by JSPS KAKENHI Grant Numbers
JP16H04109, JP18H04254, JP18H04409, JP18K14212, and
JP19H00895 as well as JST CREST Grant Number
JPMJCR19R4, Japan. K.N. and H.Y. thank Toyota Physical and
Chemical Research Institute and The Mitsubishi Foundation,
respectively, for financial support. T.Y. thanks financial support
by JSPS Predoctoral Fellowship.
White solid (197.5 mg, 0.48 mmol, 97%, m.p. = 182.3–183.7
1
ºC). H NMR: δ 7.90 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.2 Hz,
1H), 7.35–7.39 (m, 3H), 7.21–7.26 (m, 2H), 7.09 (d, J = 7.5 Hz,
1H), 6.99 (s, 1H), 6.87 (s, 1H), 6.71 (d, J = 8.9 Hz, 2H), 6.43 (s,
1H), 3.80 (s, 3H), 2.33 (s, 3H); 13C NMR: δ 163.04, 140.24,
138.17, 135.10, 132.78, 132.39, 131.56, 130.64, 130.02, 129.26,
127.61, 125.11, 125.04, 124.84, 122.98, 122.66, 122.57, 114.03,
55.64, 20.93; HRMS (APCI-MS, positive) calcd for C22H19NO3S2
[M]+: 409.0801, found: 409.0804.
References and notes
1. (a) Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177. (b)
Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893. (c) Yamaguchi, J.; Itami, K.; Yamaguchi, A. D. Angew.
Chem. Int. Ed. 2012, 51, 8960. (d) Bringmann, G.; Günther, C.;
Ochse, M.; Schupp, O.; Tasler, S.; Prog. Chem. Org. Nat. Prod.
2001, 82, 1–249.
2. (a) Facchetti. A. Chem. Mater. 2011, 23, 733. (b) Wang, C.; Dong,
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2016, 57, 4334. (g) Dyker, G. Handbook of C–H Transformation;
Wiley-VCH: Weinheim, Germany, 2005. (h) Yamaguchi, J.;
Itami, K. In Metal-Catalyzed Cross-Coupling Reactions and
More, de Meijere, A., Bräse, S., Oestreich, M., Eds.; Wiley-VCH:
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M.; Manzini, C.; Perego, L. A. Synthesis 2014, 46, 2833.
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4.4.29. N-(2-(benzothiophen-3-
yl)phenyl)methanesulfonamide (20)
Colorless oil (51.0 mg, 0.17 mmol, 84%). 1H NMR: δ 7.95 (d,
J = 8.2 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.41–7.48 (m, 4H),
7.34–7.39 (m, 2H), 7.26 (t, J = 7.5 Hz, 1H), 6.39 (s, 1H), 2.81 (s,
3H); 13C NMR: δ 140.58, 138.10, 135.38, 132.61, 131.63, 129.74,
126.51, 126.03, 125.37, 125.10, 124.97, 123.29, 122.50, 120.08,
39.64; HRMS (APCI-MS, positive) calcd for C15H14NO2S2
[M+H]+: 304.0460, found: 304.0468.
4.4.30. N-(4-methyl-2-(2-(methylsulfonyl)benzothiophen-3-
yl)phenyl)-4-methoxybenzenesulfonamide (21)
Yellow solid (312.2 mg, 0.64 mmol, 74%, m.p. = 186.0–187.3
1
ºC). H NMR: δ 7.85 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 8.2 Hz,
1H), 7.46 (t, J = 7.5 Hz, 1H), 7.29–7.33 (m, 3H), 7.18 (t, J = 7.5
Hz, 1H), 6.93 (s, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.43 (d, J = 8.9
Hz, 2H), 3.70 (s, 3H), 2.88 (s, 3H), 2.35 (s, 3H); 13C NMR: δ
162.32, 140.07, 140.01, 138.42, 137.83, 136.34, 132.60, 131.75,
131.52, 131.04, 128.65, 127.84, 127.34, 127.00, 125.70, 125.47,
122.30, 113.74, 55.35, 44.40, 21.01; HRMS (APCI-MS, positive)
calcd for C23H21NO5S3 [M]+: 487.0576, found: 487.0582.
5. (a) Guideline on the specification limits for residues of metal
catalysts of metal reagents; EMEA: London, UK, February, 2008.
(b) Guideline for elemental impurities, Q3D (R1); Step 5 version;
ICH: March, 2019. (c) Krebs, F. C.; Nyberg, R. B.; Jørgensen, M.
Chem. Mater. 2004, 16, 1313.
4.4.31. N-(2-(2-(methylsulfonyl)benzothiophen-3-
yl)phenyl)methanesulfonamide (22)
White solid (607.9 mg, 1.59 mmol, 80%, m.p. = 233.7–234.9
1
ºC). H NMR: δ 7.99 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.9 Hz,
6. Reviews: N–N (a) Banthorpe, D. V.; Cooper, A.; Ingold, C. K.
Nature 1967, 216, 232. (b) Banthorpe, D. V.; Hughes, E. D.;
Ingold, C. J. Chem. Soc. 1964, 2864. N–O: (c) Tabolin, A. A.;
Ioffe, S. L. Chem. Rev. 2014, 114, 5426. S–O: (d) Yorimitsu, H.
Chem. Rec. 2017, 17, 1156. (e) Yanagi, T.; Nogi, K.; Yorimitsu,
H. Tetrahedron Lett. 2018, 59, 2951. (f) Kaiser, D.; Klose, I.;
Oost, R.; Neuhaus, J.; Maulide, N. Chem. Rev. 2019, 119, 8701.
(g) He, Z.; Pulis, A. P.; Perry, G. J. P.; Procter, D. J. Phosphorus
Sulfur Silicon Relat. Elem. 2019, 194, 669.
1H), 7.56–7.61 (m, 2H), 7.45 (t, J = 7.9 Hz, 1H), 7.32–7.36 (m,
2H), 7.25 (d, J = 7.5 Hz, 1H), 6.48 (s, 1H), 3.01 (s, 3H), 2.85 (s,
3H); 13C NMR: δ 140.59, 139.77, 139.70, 137.24, 136.42,
131.18, 130.69, 128.72, 126.40, 125.20, 125.08, 124.05, 123.12,
121.74, 45.00, 40.25; HRMS (APCI-MS, positive) calcd for
C16H16NO4S3 [M+H]+: 382.0236, found: 382.0233.
4.4.32. 9-methyl-6H-benzo[4,5]thieno[2,3]indole (23)
7. S–O: (a) Yanagi, T.; Otsuka, S.; Kasuga, Y.; Fujimoto, K.;
Murakami, K.; Nogi, K.; Yorimitsu, H.; Osuka, A. J. Am. Chem.
Soc. 2016, 138, 14582. (b) Shrives, H. J.; Fernández-Salas, J. A.;
Hedtke, C.; Pulis, A. P.; Procter, D. J. Nat. Commun. 2017, 8,
14801. (c) He, Z.; Shrives, H. J.; Fernández-Salas, J. A.;
Abengózar, A.; Neufeld, J.; Yang, K.; Pulis, A. P.; Procter, D. J.
Angew. Chem. Int. Ed. 2018, 57, 5759. (d) Yang, K.; Pulis, A. P.;
Perry, J. P.; Procter, D. J. Org. Lett. 2018, 20, 7498. (e) Yanagi,
T.; Nogi, K.; Yorimitsu, H. Synlett 2019, 31, 153.
Yellow solid (72.7 mg, 0.30 mmol, 61%, m.p. =151.3–154.7
ºC). 1H NMR: δ 8.11 (d, J = 8.2 Hz, 2H), 7.83 (s, 1H), 7.80 (d, J
= 8.2 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.28 (t, J = 7.5 Hz, 1H),
7.25 (d, J = 8.2 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 2.57 (s, 3H);
13C NMR: δ 140.21, 139.66, 138.57, 132.89, 130.04, 125.15,
123.69, 123.53, 123.01, 122.35, 120.73, 118.84, 118.77, 111.12,
21.71; HRMS (APCI-MS, positive) calcd for C15H11NS [M]+:
237.0607, found: 237.0608.
8. I–O: Hori, M.; Guo, J.-D.; Yanagi, T.; Nogi, K.; Sasamori, T.;
Yorimitsu, H. Angew. Chem. Int. Ed. 2018, 57, 4663.
4.4.33. 6H-benzo[4,5]thieno[2,3]indole (24)
9. S–N: Yanagi, T.; Nogi, K.; Yorimitsu, H. Chem. Eur. J. 2020, 26,
783.
10. Different modes of Y–Z bond formation: (a) Lim, Y.-K.; Jung, J.-
W.; Lee, H.; Cho, C.-G. J. Org. Chem. 2004, 69, 5778. (b) Kang,
White solid (151.9 mg, 0.68 mmol, 68%, m.p. = 152.1–152.9
ºC).1H NMR: δ 8.36 (br, 1H), 8.12 (d, J = 7.5 Hz, 1H), 8.03–8.05
(m, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.44–

8
Tetrahedron
H.-M.; Lim, Y.-K.; Shin, I.-J.; Kim, H.-Y.; Cho, C.-G. Org. Lett.
Supplementary Material
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Smith, L. H. S.; Coote, S. C.; Sneddon, H. F.; Procter, D. J.
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Supplementary data to this article can be found online at
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H.; Osuka, A. Angew. Chem. Int. Ed. 2014, 53, 7510. (b)
Okamoto, K.; Hori, M.; Yanagi, T.; Murakami, K.; Nogi, K.;
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Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: