Direct Thioamination of Arynes via Reaction with Sulfilimines and Migratory N-Arylation

Article abstract of DOI:10.1021/jacs.5b10557

A novel method for preparing a diverse range of o-sulfanylanilines is described. Direct thioamination of arynes with sulfilimines gives o-sulfanylanilines, involving C-N and C-S bond formations and migratory N-arylation.

Full text of DOI:10.1021/jacs.5b10557

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Communication
Direct Thioamination of Arynes via Reaction
with Sulfilimines and Migratory N-Arylation
Suguru Yoshida, Takahisa Yano, Yoshihiro Misawa, Yasuyuki Sugimura,
Kazunobu Igawa, Shigeomi Shimizu, Katsuhiko Tomooka, and Takamitsu Hosoya
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b10557 • Publication Date (Web): 01 Nov 2015
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Direct Thioamination of Arynes via Reaction with Sulfilimines and
Migratory N-Arylation
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Suguru Yoshida,† Takahisa Yano,† Yoshihiro Misawa,† Yasuyuki Sugimura,‡ Kazunobu Igawa,§ Shigeomi
Shimizu,‡ Katsuhiko Tomooka,§ Takamitsu Hosoya*,†
†Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-
3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
‡Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45
Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
§Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasuga-koen, Kasuga, Fukuoka 816-8580, Japan
Supporting Information Placeholder
A
ABSTRACT: A novel method for preparing a diverse
H
H
hydrolysis
range of o-sulfanylanilines is described. Direct thioami-
nation of arynes with sulfilimines gives o-
sulfanylanilines, involving C–N and C–S bond for-
mations and migratory N-arylation.
H
H
N
S
N
S
NH2
N
S
R
R
R
R
R'
R'
R'
R'
R'
R'
B
C
OMe
O
OMe
S
SiMe3
OTf
3
not
detected
N
S
CsF
Arenes with sulfur and nitrogen substituents at ortho-
positions with respect to each other, play important roles
in a broad range of fields, including materials science
and medicinal chemistry.1,2 In particular, o-
sulfanylaniline is a core structure of a variety of het-
eroaromatics, such as benzothiazoles, phenothiazines,
and benzothiazepines, which are frequently found in
pharmaceuticals and drug candidates.2,3 Despite the im-
portance of o-sulfanylanilines, only a limited number of
synthetic methods have been reported, and the need to
develop more efficient approaches remains. Herein we
report a straightforward synthetic method for o-
sulfanylanilines through direct thioamination of aryne
species with sulfilimines.
Ph
Ph
1a
N
(2.0 equiv)
+
+
H
OMe
CH3CN
rt, 15 h
N
S
SPh
4a
26%
Ph
Ph
2a
(2.0 equiv)
NHPh
Figure 1. Unexpected reaction between an aryne and a sul-
filimine. (A) An initial plan: synthesis of anilines via amina-
tion of arynes with sulfilimines. (B) The reaction between 3-
methoxybenzyne generated from precursor 1a with sulfilimine
2a. (C) X-ray crystal structure of 4a. Hydrogen atoms are
omitted for clarity.
anticipated C–N bond formation between the electro-
philic aryne carbon and the nucleophilic nitrogen.8 Fur-
thermore, one of the phenyl groups of the sulfilimine
seemed likely to have migrated from sulfur to nitrogen
during the reaction. Owing to the limited number of re-
ports on thioamination of arynes,10–12 we embarked on a
study to optimize this promising and mechanistically
interesting synthetic transformation.
Vigorous screening of reaction conditions for the gen-
eration of an aryne species from 1a greatly improved the
yield of 4a (Table 1). Treatment of aryne precursor 1a
with potassium fluoride and 18-crown-6-ether in the
presence of sulfilimine 2a (2.0 equiv) in tetrahydrofuran
at 60 °C afforded the desired product 4a in high yield
and as a single regioisomer (entry 1). Performing the
reaction at room temperature or in the absence of crown
ether considerably decreased the yield of 4a (entries 2
and 3). An alternative method for generating aryne
During the course of our studies on aryne chemistry,4
we unexpectedly found that an o-sulfanylaniline was
produced from the reaction of an aryne5,6 with a sul-
filimine7 (Figure 1). Initially, we intended to achieve a
simple amination of arynes8 via the formation of a C–N
bond using a sulfilimine as an amino source, followed
by hydrolysis of the adduct (Figure 1A). However, for
example, the reaction of S,S-diphenylsulfilimine (2a)
with 3-methoxybenzyne, which was generated by the
treatment of o-silylaryl triflate 1a9 with cesium fluoride,
did not afford the desired N-arylsulfilimine 3 (Figure
1B). Instead, o-sulfanylaniline 4a was obtained in low
yield. The structure of 4a bearing a phenylthio and phe-
nylamino group was confirmed by X-ray crystallograph-
ic analysis (Figure 1C). This result indicated that C–S
bond formation simultaneously proceeded with the
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Table 1. Optimization of the Reaction Conditions Table 2. Reactions of Various Arynes with Sulfilimine 2a
Page 2 of 5
1
2
3
4
5
6
7
8
KF (2.0 equiv)
18-crown-6 (2.0 equiv)
OMe
OMe
SiMe3
OTf
SPh
H
SiMe3
OTf
SPh
N
S
H
conditions
+
N
S
+
THF
60 °C, 15 h
NHPh
Ph
Ph
R
R
NHPh
Ph
Ph
1
2a
(2.0 equiv)
4
1a
2a
(2.0 equiv)
4a
SPh
entry
conditionsa
yield (%)b
SPh
SPh
77c
17
Me
NHPh
NHPh
NHPh
1
2
3
4
5
6
KF, 18-crown-6, THF, 60 °C, 15 h
KF, 18-crown-6, THF, rt, 15 h
KF, THF, 60 °C, 15 h
+ isomer
+ isomer
69%, 4b
Me
82%, 4c:4c' (63:37)
60%, 4d:4d' (55:45)
OMe
9
OMe
2
10
11
12
13
14
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16
17
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SPh
SPh
Cs2CO3, 18-crown-6, THF, rt, 15 h
n-Bu4NF, THF, 0 °C, 1 h
69c
trace
41
Br
NHPh
NHPh
66%, 4e
75%, 4f
MeO
n-Bu4N[Ph3SiF2], THF, rt, 24 h
Cl
Cl
b
1
aSee Supporting Information for details. Yields based on H
NMR analysis by using 1,1,2,2-tetrachloroethane as an inter-
nal standard, unless otherwise noted. cIsolated yield.
SPh
MeO
SPh
SPh
NHPh
SiMe3
62%, 4g
NHPh
SiMe3 + isomer
81%, 4h:4h' (90:10)a
NHPh
53%, 4ia SiMe3
efficiently from o-silylaryl triflate using cesium car-
bonate4i and 18-crown-6 also afforded 4a in good yield
(entry 4). Other conventional methods that use tetrabu-
tylammonium fluoride or tetrabutylammonium difluo-
ro(triphenyl)silicate as an activator were less effective
(entries 5 and 6).
MeN
SPh
SPh
NHPh + isomer
80%, 4j:4j' (52:48)
NHPh + isomer
47%, 4k:4k' (85:15)a
a
Isolated yields are shown. Conditions: Cs2CO3 (2.0 equiv),
18-crown-6 (2.0 equiv), THF, rt, 15 h.
Using either of the two optimized conditions, various
o-sulfanylaniline derivatives 4b–k were prepared from
reactions of sulfilimine 2a with a variety of arynes, which
were generated from o-silylaryl triflates 1 (Table 2). Un-
substituted benzyne reacted with 2a to yield N-phenyl-o-
(phenylthio)aniline (4b) in good yield. 3-Methylbenzyne
and 4-methylbenzyne also participated in the reactions to
2c (entries 1 and 2) but also those with electron-deficient
aryl groups such as 2d or 2e (entries 3 and 4) participated
in the reaction. Remarkably, the reaction of unsymmetri-
cal sulfilimine 2f having both an electron-rich p-tolyl and
an electron-deficient p-benzoylphenyl group with 3-
methoxybenzyne selectively afforded benzoylphenyl-
migrated product 4p and the tolyl-migrated isomer was
not detected (entry 5, Figure 2). A similar trend was ob-
served for S-(o-nitrophenyl)-S-phenylsulfilimine (2g) that
afforded nitrophenyl-migrated product 41 exclusively
(entry 6). These results indicate that more electron-
deficient aryl group attached to the sulfur atom is prone to
migrated to the nitrogen atom, which proceeds at the ipso-
position of the aryl group. Besides diaryl sulfilimines, S-
alkyl-S-arylsulfilimines also participated in the reaction,
expanding the reaction’s scope. For example, the reaction
of S-cyclopropyl-S-phenylsulfilimine (2h) afforded 2-
cyclopropylthio-3-(phenylamino)anisole (4r) via a selec-
tive rearrangement of the phenyl group (entry 7). Intri-
guingly, the reaction of S-methyl-S-p-tolylsulfilimine (2i)
furnished 2-(4-tolylthio)-m-anisidine (4s) wherein the
methyl group was lost during the reaction (entry 8). Nota-
bly, the reaction using cyclic sulfilimine 2j afforded a
unique eight-membered thiazocine derivative 4t in high
yield via a ring expansion (entry 9, Figure 2).
afford regioisomeric mixtures 4c/4c and 4d/4d , respec-
' '
tively, with low regioselectivities. Conversely, the reac-
tion of 3-methoxybenzyne afforded 3-phenylamino-2-
(phenylthio)anisole (4a) in a regioselective manner (Table
1). A similar selectivity was observed for the reactions of
5-substituted 3-methoxyarynes that were generated from
the corresponding precursors, which were easily prepared
from 3-methoxybenzyne precursor 1a via the C–H
borylation.4j,13 For example, thioaminated products 4e and
4f with bromo or p-anisyl groups, respectively, were se-
lectively obtained in good yields. Reactions of 3-
(trimethylsilyl)arynes resulted in the opposite regioselec-
tivity to that of 3-methoxyarynes, which were similar to
those of reported reactions with other arynophiles.14 Thus,
thioaminated arylsilanes 4g–i were prepared in good
yields with high to exclusive regioselectivities. The regi-
oselectivities observed in the reactions between sul-
filimines and 3-methoxyarynes or 3-silylarynes can be
rationalized by their distorted structures.14c Furthermore,
while 1,2-naphthalyne reacted with 2a to afford regioiso-
To gain more insight into the reaction mechanism, we
conducted a crossover experiment using a mixture that
contained an equimolar amount of sulfilimines 2a and 2b
in the reaction with 3-methoxybenzyne (Scheme 1). The
products obtained were o-sulfanylanilines 4a and 4b, and
crossover products 4u or 4v were not detected. This result
suggests that rearrangement of the aryl group from the
arylthio group proceeded in an intramolecular manner.
mers 4j and 4j in almost equal proportions, a moderate
'
selectivity was observed for the reaction of the more dis-
torted 4,5-indolyne, which agrees with previous reports.15
A variety of sulfilimines such as 2b–j also reacted ef-
ficiently with 3-methoxybenzyne to afford an array of o-
sulfanylaniline derivatives 4l–t (Table 3). Not only sul-
filimines with electron-rich aryl groups such as 2b and
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Table 3. Reactions of 3-Methoxybenzyne with Various Sulfilimines Scheme 1. Crossover Experiment
1
2
3
4
5
6
7
8
OMe
OMe
OMe
OMe
H
KF (2.0 equiv)
18-crown-6 (2.0 equiv)
1a
(1.0 equiv)
KF
(2.0 equiv)
18-crown-6
(2.0 equiv)
N
S
SiMe3
OTf
SR
S
Ph
Ph
S
Ph
H
N
S
+
Ph
Ph
THF
60 °C, 15 h
NHR'
N
H
4a
N
p-tol
R
R'
2a
(1.0 equiv)
H
4u
1a
2
(2.0 equiv)
4
+
37% (1H NMR)
not detected
H
THF
60 °C, 15 h
yield
(%)a
N
OMe
OMe
entry
1
sulfilimine
2
product
4
S
S
p-tol
p-tol
S
p-tol
p-tol
p-tol
OMe
2b
(1.0 equiv)
H
N
H
N
H
Ph
S
p-tol
p-tol
N
9
2b
4l 69
S
4l
4v
not detected
p-tol
p-tol
N
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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42
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
35% (1H NMR)
OMe
H
N
S
S
OMe
OMe
2b
3
2c
2d
2e
4m 54
4n 67
4o 71
Scheme 2. Plausible Reaction Mechanisms
N
H
Me
MeO
OMe
OMe
H
N
S
Cl
Cl
MeO
S
MeO
p-tol
S
N
H
Cl
Cl
S
Ph
O
N
H
Ar
OMe
H
N
H
N
S
S
Br
Br
MeO p-tol
4
MeO
MeO
B
D
S–N bond
cleavage & SNAr
p-tol
S
N
H
S
addition &
cyclization
Br
Br
Ar
Ar
N
H
OMe
N
N
S
p-tol
H
4p
A
C
S
p-tol
H
[2+2]
Ar
cycloaddition
ligand
coupling
S
p-tol
N
5
6
2f
O
4p 66
4q 60
O
N
H
2f
H
Ph
Ph
Ar = C6H4-p-COPh
OMe
H
S
Ph
N
NO2
deficient aryl group provided the N-arylated product.
However, the possibility of a pathway involving direct
ligand coupling on the sulfur of C cannot be excluded.16
The synthetic utility of this method was further
demonstrated in combination with other methods for
preparing diverse multisubstituted o-silylaryl triflates4j
and sulfides via copper-catalyzed thiolation of organo-
borons17 that we recently developed. This method al-
lowed for modular synthesis of multisubstituted o-
sulfanylanilines. As an example, four readily available
components, namely aryne precursor 1a, aryl iodide 5,
arylboronic acid 6, and thiosulfonate 7 were easily as-
sembled in high efficiency to afford multi-arylated o-
sulfanylaniline 4w (Scheme 3). A wide variety of multi-
substituted o-sulfanylanilines can be easily synthesized
by replacing each component with another compound.18
S
2g
Ph
N
H
O2N
OMe
H
N
S
S
7
8
2h
2i
4r 50
4s 43
Ph
N
H
Ph
OMe
H
N
S
S
p-tol
p-tol
Me
NH2
OMe
H
N
S
S
9
2j
4t 73
HN
aIsolated yields. Conditions: Cs2CO3 (2.0 equiv), 18-crown-6
b
(2.0 equiv), THF, rt, 16 h.
O
O
Scheme 3. Modular Synthesis of Multi-arylated o-Sulfanylaniline
S
N
S
1. (Bpin)2
cat. Ir
97%
OMe
OMe
SiMe3
SiMe3
OTf
Me
N
I
OTf 2.
S
1a
KF
O
S
8
5
4p
4t
(2.0 equiv)
18-crown-6
(2.0 equiv)
MeO
cat. Pd
87%
S
Figure 2. X-ray crystal structures of 4p and 4t. Hydrogen
atoms and solvent molecules are omitted for clarity.
Ts
1.
NH
THF
60 °C
15 h
S
Me
S
7
B(OH)2
Me
Based on the experimental results, we currently con-
sider the reaction to proceed through a four-membered
ring intermediate C, which is produced either via nucle-
ophilic addition of sulfilimine to the aryne followed by
cyclization or via a direct [2+2] cycloaddition (Scheme
2).6k,m Cleavage of the S–N bond of C and subsequent
intramolecular ipso-substitution at the more electron-
cat. Cu
83%
4w
68%
CF3
HN
S
2. H2NCOCF3
cat. Rh
PhI(OAc)2
82%
CF3
6
CF3
2k
3. KOH
91%
Isolated yields are shown.
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M. Chem. Rev. 2012, 112, 3550. (e) Pérez, D.; Peña, D.; Guitián, E.
In summary, we have developed a novel method for
preparing a diverse range of o-sulfanylanilines via direct
thioamination of arynes with sulfilimines. Further appli-
cations of the method to the synthesis of diverse sulfur
and nitrogen containing aromatics are currently under-
way in our laboratory.
1
2
3
4
5
6
7
8
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ASSOCIATED CONTENT
Supporting Information
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Experimental procedures and characterization for new
compounds including copies of NMR spectra and the X-ray
crystallographic data for 4a (CCDC 1428754), 4p (CCDC
1428753), and 4t (CCDC 1428752). This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
thosoya.cb@tmd.ac.jp
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
The authors thank Central Glass Co., Ltd. for their gener-
ous gift of Tf2O. This work was supported by JSPS KA-
KENHI Grant Numbers 15H03118 (T.H.) and 26350971
(S.Y.); the Uehara Memorial Foundation (S.Y.); the Plat-
form for Drug Discovery, Informatics, and Structural Life
Science of MEXT and AMED, Japan; and the Cooperative
Research Program of the Network Joint Research Center
for Materials and Devices (IMCE, Kyushu University).
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