Synthesis of phenoxathiins and phenothiazines by aryne reactions with thiosulfonates

Article abstract of DOI:10.1246/cl.200132

Novel synthetic methods for phenoxathiins and phenothiazines by aryne reactions are disclosed. We found that phenoxathiins were efficiently prepared by the reaction between aryne intermediates and S-(2-hydroxyaryl) 4-toluenethiosulfo-nates. A synthetic method for phenothiazines was also developed by the reaction of arynes with S-(2-aminoaryl) 4-toluenethiosulfonates.

Full text of DOI:10.1246/cl.200132

Received: February 18, 2020 | Accepted: March 6, 2020 | Web Released: March 12, 2020
CL-200132
Synthesis of Phenoxathiins and Phenothiazines by Aryne Reactions with Thiosulfonates
Kazuya Kanemoto, Yuki Sakata, Takamitsu Hosoya, and Suguru Yoshida*
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU),
2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
E-mail: s-yoshida.cb@tmd.ac.jp
Novel synthetic methods for phenoxathiins and pheno-
thiazines by aryne reactions are disclosed. We found that
phenoxathiins were efficiently prepared by the reaction between
aryne intermediates and S-(2-hydroxyaryl) 4-toluenethiosulfo-
nates. A synthetic method for phenothiazines was also
developed by the reaction of arynes with S-(2-aminoaryl) 4-
toluenethiosulfonates.
A
B
Conventional methods
S
8
S
X
AlCl
3
(X = O)
or
X
X = O, NH
I2 (X = NH)
heat
Design of the phenoxathiin synthesis
O
O
S
O
O
p-Tol
p-Tol
Keywords: Phenoxathiin | Phenothiazine
| Aryne
S
S
S
S
Organosulfur heterocycles such as phenoxathiins and phe-
nothiazines are attractive molecules in a broad range of research
fields including pharmaceutical sciences and materials chemis-
O
H
O
H
O
Ts
H
S
1
try. However, accessible phenoxathiins and phenothiazines by
protonation
O
the conventional methods from diaryl ethers and diarylamines,
respectively, with elemental sulfur are quite limited due to the
harsh conditions and poor selectivity (Figure 1A).2 Therefore,
novel methods to prepare phenoxathiins and phenothiazines
are sought after. Herein, we report aryne reactions5 to provide
phenoxathiins and phenothiazines using thiosulfonates.
Figure 1. Synthesis of phenoxathiins and phenothiazines. (A)
­4
Conventional methods. (B) Design of this work. Ts = SO ­p-
2
Tol.
,6
Table 1. Optimization of the reaction conditions
On the basis of our previous studies on synthetic aryne
O
7
8
O
p-Tol
chemistry and organosulfur chemistry using thiosulfonates, we
designed the phenoxathiin synthesis from aryne intermediates
with S-(2-hydroxyphenyl) 4-toluenethiosulfonate (Figure 1B).
Owing to the sulfonyl group lowering the nucleophilicity of
the neighboring sulfur(II) atom, the nucleophilic addition of
S
activator
(3.5 equiv)
SiMe3
OTf
S
S
+
solvent
rt, 24 h
HO
2a
(1.0 equiv)
O
1
a
3a
(3.0 equiv)
9
the hydroxy group to aryne intermediates would take place.
Entry
Activator
Solvent
Yield/%
We expected that the electrophilicity of thiosulfonates could
facilitate cyclization without protonation.10
1
2
3
4
5
6
7
8
KF, 18-crown-6
CsF
THF
THF
THF
THF
toluene
DME
64
36
33
45
34
67
71
84
After a vigorous screening of the reaction conditions, an
efficient synthesis of phenoxathiin (3a) was accomplished from
o-(trimethylsilyl)phenyl triflate (1a) and S-(2-hydroxyphenyl)
Bu4NF¢3H2O
Cs CO
2
3
KF, 18-crown-6
KF, 18-crown-6
KF, 18-crown-6
KF, 18-crown-6
4-toluenethiosulfonate (2a) (Table 1). Indeed, treatment of 1a
and 2a dissolved in tetrahydrofuran with several activators
provided the desired product 3a in low to good yields (Entries
diglyme
triglyme
1
­4). Among activators examined, potassium fluoride with 18-
crown-6 facilitated the phenoxathiin ring formation efficiently
Entry 1). Further improvement of the yield was achieved by
DME = 1,2-dimethoxyethane; diglyme = bis(2-methoxyethyl)
ether; triglyme = 1,2-bis(2-methoxyethoxy)ethane.
(
changing the solvent (Entries 5­8). In particular, when triglyme
was used as a solvent, phenoxathiin (3a) was obtained in high
yield (Entry 8).
synthesis using 3-methylbenzyne intermediate furnished a
mixture between 3f and 3f¤ in a high combined yield (Entry 5),
1-morpholinophenoxathiin (3g) was selectively prepared via 3-
A wide range of phenoxathiins were successfully prepared
from various o-silylaryl triflates with thiosulfonate 2a (Table 2).
Reactions of 3-methoxyaryne precursors 1b and 1c with 2a
afforded phenoxathiins 3b and 3c, respectively, as single
isomers due to the inductive electron-withdrawing effect of
11
morpholinobenzyne intermediate (Entry 6). Electron-deficient
difluorinated phenoxathiin 3h was also synthesized albeit in low
yield (Entry 7). This phenoxathiin synthesis enabled π-extended
benzene- and naphthalene-fused phenoxathiins 3i and 3j in good
yields (Entries 8 and 9). In particular, a selective reaction of
3,4-didehydrophenanthrene intermediate took place to afford
naphthophenoxathiin 3j presumably owing to the steric effect
(Entry 9).
5
the methoxy group (Entries 1 and 2). Dimethoxy-substituted
phenoxathiin 3d was also synthesized through 4,5-dimethoxy-
benzyne intermediate (Entry 3). A regioisomeric mixture of
phenoxathiins 3e and 3e¤ was obtained by the reactions of 4-
methylbenzyne intermediate (Entry 4). While the phenoxathiin
Chem. Lett. 2020, 49, 593–596 | doi:10.1246/cl.200132
© 2020 The Chemical Society of Japan | 593

Table 2. Phenoxathiin synthesis using various aryne precursors
1
Table 3. Phenoxathiin synthesis using o-silylaryl triflates 1 and
thiosulfonates 2
KF (3.5 equiv)
KF (3.5 equiv)
SiMe
OTf
3
TsS
HO
18-crown-6 (3.5 equiv)
S
SiMe3
OTf
TsS
HO
18-crown-6 (3.5 equiv)
S
+
+
triglyme
rt, 24 h
triglyme
rt, 24 h
O
3
O
3
R
R
R1
R2
R1
R2
1
2a
1
2
(
3.0 equiv)
(1.0 equiv)
(
3.0 equiv)
(1.0 equiv)
a
Entry
1
3
Yield/%
62
a
Entry
1
1
2
3
Yield/%
55
OMe
OMe
TsS
HO
S
SiMe
OTf
3
S
1
1b
3b
1a
2b
3k
OMe
O
S
OMe
O
OMe
OMe
OMe
SiMe
OTf
3
S
b
2
1b
1d
2b
2b
3l
45
56
2
3
1c
3c
55
55
Br
Br
O
O
OMe
MeO
MeO
S
MeO
SiMe
3
MeO
S
c
3
3m
1d
1e
3d
MeO
OTf
MeO
Me
O
O
OMe
Me
S
OMe
TsS
HO
Me
S
1
b
2c
3n
3o
56
39
Me
SiMe
OTf
3
O
+
O
3e
+
3e’
4
7
3
4
5
6
O
Me
(3e:3e’ = 56:44)
S
Me
5
1i
2c
S
O
S
a
b
Isolated yield. KF (2.4 equiv) and 18-crown-6 (2.4 equiv) were
c
SiMe
OTf
3
O
used. KF (3.0 equiv) and 18-crown-6 (3.0 equiv) were used.
3
f
Me
+
80
1f
+
O
(
3f:3f’ = 46:54)
3
f’
Me
S
A
B
Me
O
HO
OMe
OMe
KF (2.4 equiv)
18-crown-6 (2.4 equiv)
O
N
S
SiMe
3
S
S
+
N
triglyme
rt, 24 h
OTf
O
1g
3g
42
SiMe3
S
1b
3b
trace
HO
(
3.0 equiv)
OTf
O
4
(
1.0 equiv)
F
F
SiMe
3
F
F
S
7
8
1h
1i
3h
3i
26
67
OTf
O
KF (2.4 equiv)
18-crown-6 (2.4 equiv)
OMe
OMe
O
O
N
SiMe
3
S
S
SiMe
3
+
S
triglyme
rt, 24 h
OTf
O
O
OTf
HO
3
b
1b
5
22%
(
3.0 equiv)
(1.0 equiv)
9
1j
3j
78
SiMe
OTf
3
S
Figure 2. Reactions of 3-methoxybenzyne with disulfide 4 (A)
and N-(arylthio)succinimide 5 (B).
O
a
Isolated yield.
synthesis (Figure 2). Although disulfides frequently serve in
the electrophilic thiolations, the phenoxathiin synthesis using
disulfide by the reaction with aryne resulted in failure
(Figure 2A). Phenoxathiin 3b was obtained only in low yield
Thiosulfonates 2b and 2c uneventfully participated in the
phenoxathiin synthesis (Table 3). Indeed, 3-methoxyphenox-
athiin 3k was selectively prepared through the reaction of
benzyne generated from o-silylphenyl triflate 1a and thiosulfo-
nate 2b (Entry 1). Di- and trimethoxyphenoxathiin 3l and 3m
were also synthesized by the reaction using aryne precursors 1b
and 1d, respectively, with thiosulfonate 2b (Entries 2 and 3).
The phenoxathiin synthesis using S-(2-hydroxy-5-methylphenyl)
-toluenethiosulfonate (2c) provided the corresponding methyl-
substituted phenoxathiins 3n and 3o in moderate yields (Entries
and 5).
when using N-(arylthio)succinimide
(Figure 2B).
5 as an arynophile
We then attempted the phenothiazine synthesis using amino-
substituted thiosulfonates 6a and 6b instead of hydroxy-sub-
stituted thiosulfonates 2 (Figure 3). While phenothiazine 7 was
not obtained by treatment of a mixture of S-(2-(tert-butoxycar-
bonylamino)phenyl) 4-toluenethiosulfonate (6a) and o-silylaryl
triflate 1a with potassium fluoride and 18-crown-6 (Figure 3A),
the aryne reaction using S-(2-aminophenyl) 4-toluenethiosulfo-
nate (6b) successfully furnished phenothiazine 8a in high yield
(Figure 3B). Methoxy- and morpholino-substituted phenothi-
4
4
Aryne reactions using disulfide 4 and N-(arylthio)succini-
mide 51 instead of thiosulfonates 2 clarified that the sulfonyl
0f
group in the sulfur surrogate promoted the phenoxathiin
594 | Chem. Lett. 2020, 49, 593–596 | doi:10.1246/cl.200132
© 2020 The Chemical Society of Japan

A
B
491.
KF (2.4 equiv)
SiMe
OTf
3
TsS
18-crown-6 (2.4 equiv)
S
3
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triglyme
rt, 24 h
BocHN
N
Boc
1
a
6a
7
(
2.4 equiv)
(1.0 equiv)
not detected
R
R
KF (2.4 equiv)
18-crown-6 (2.4 equiv)
SiMe
OTf
3
TsS
S
+
triglyme
rt, 24 h
H
2
N
N
H
1
6b
8
(
2.4 equiv)
(1.0 equiv)
4
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N
N
N
H
H
H
8
a
8b
66%
8c
60%
7
5%
Figure 3. Phenothiazine synthesis through aryne intermedi-
ates. (A) Reaction using t-butoxycarbonylamino-substituted
thiosulfonate 6a. (B) Reactions using amino-substituted thio-
sulfonate 6b.
5
azines 8b and 8c were also synthesized by the reactions of
o-silylaryl triflates 1b and 1g in moderate yields.
In summary, we developed facile synthetic methods for
phenoxathiins and phenothiazines by aryne reactions. The
sulfonyl group facilitated these ring formations. A wide range
of phenoxathiins and phenothiazines were prepared using
various o-silylaryl triflates and thiosulfonates. Further synthetic
applications and mechanistic study are now underway.
This work was supported by JSPS KAKENHI Grant
Numbers JP19K05451 (C; S.Y.), JP18H02104 (B; T.H.), and
JP18H04386 (Middle Molecular Strategy; T.H.); the Naito
Foundation (S.Y.); the Japan Agency for Medical Research and
Development (AMED) under Grant Number JP19am0101098
Platform Project for Supporting Drug Discovery and Life
Science Research, BINDS); and the Cooperative Research
Project of Research Center for Biomedical Engineering.
6
(
Supporting Information is available on https://doi.org/
0.1246/cl.200132.
1
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596 | Chem. Lett. 2020, 49, 593–596 | doi:10.1246/cl.200132
© 2020 The Chemical Society of Japan