3-Thioaryne Intermediates for the Synthesis of Diverse Thioarenes

Article abstract of DOI:10.1021/acs.orglett.9b01862

The synthetic utility of 3-thioaryne intermediates has been demonstrated through an aryne relay approach. The efficient synthesis of o-silylaryl triflate-type 3-thioaryne precursors has been achieved by the regioselective silylthiolation of 3-(triflyloxy)

Full text of DOI:10.1021/acs.orglett.9b01862

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
3‑Thioaryne Intermediates for the Synthesis of Diverse Thioarenes
Yu Nakamura, Yoshihiro Miyata, Keisuke Uchida, Suguru Yoshida,* and Takamitsu Hosoya*
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
S
* Supporting Information
ABSTRACT: The synthetic utility of 3-thioaryne intermediates
has been demonstrated through an aryne relay approach. The
efficient synthesis of o-silylaryl triflate-type 3-thioaryne pre-
cursors has been achieved by the regioselective silylthiolation of
3-(triflyloxy)arynes with silyl sulfides. Various 3-thioarynes were
successfully generated from these precursors and reacted with
various arynophiles to afford diverse multisubstituted aryl
sulfides. Further derivatizations of the products enabled easy
access to the novel sulfur-containing π-extended heterocycles,
which demonstrates the utility of this method.
ulfur-containing aromatic compounds are widely used in
1
Svarious research fields, such as materials science
and
medicinal chemistry.2,3 Various efficient synthetic methods for
thioarenes such as aryl sulfides have been extensively
developed, which include the nucleophilic displacement of
disulfides with carbon nucleophiles, nucleophilic aromatic
substitution of electron-deficient aryl halides, and transition
metal-catalyzed coupling reactions of aryl halides or boronic
acids with disulfides or thiosulfonates.4,5 Nevertheless, steri-
cally congested multisubstituted aryl sulfides are often difficult
to synthesize because of the demanding reaction conditions
and catalyst poisoning caused by the sulfur atoms. To provide
an alternative means of synthesis for aryl sulfides, we conceived
a concept of using aryne intermediates substituted with a thio
group. However, despite the recent marked rise in synthetic
aryne chemistry that has enabled the convenient preparation of
a wide range of aromatic compounds via various aryne
intermediates,6,7 only a few transformations via sulfanylaryne
species have been studied.8 Therefore, their potential as
synthetic intermediates remains largely unexplored. This is
probably due to the time-consuming, linear, and multistep
routes required for the synthesis of 3-sulfanylaryne precursors.
Herein, we report a facile method for preparing various 3-
thioaryne precursors and demonstrate their utility for the
synthesis of multisubstituted aryl sulfides.
Figure 1. Background of this study. (A) Our previous study. (B)
Concept of the proposed study: synthesis of aryl sulfides via 3-
(triflyloxy)benzyne (I) and 3-sulfanylbenzyne II by an aryne relay
chemistry. (C) Attempts at silylthiolation of 3-methoxybenzyne with
As part of our previous study based on synthetic aryne
chemistry, we developed a facile method for synthesizing o-
silylaryl triflate-type 3-aminoaryne precursors via the regiose-
lective silylamination of 3-(triflyloxy)arynes (Figure 1A).9c It
silyl sulfide 2a.
was proven that it is possible to synthesize a diverse range of
aniline derivatives from these precursors via the generation of
silylamines.11,12 On the basis of the results of this previous
3-aminoarynes. The key to the success was the use of a
work, we anticipated that o-silylaryl triflate-type 3-thioaryne
silylmethyl Grignard reagent for generating 3-(triflyloxy)-
arynes9,10 from 1,3-bis(triflyloxy)-2-iodoarenes, which enabled
the iodine−magnesium exchange reaction without any
undesired cleavage of the weak N−Si bonds of the N-
Received: May 29, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01862
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
precursors would be obtained by regioselective silylthiola-
tion13,14 of 3-(triflyloxy)arynes I with silyl sulfides 2 (Figure
1B).
Although there was still some concern that the weak S−Si
bonds of the silyl sulfides would be cleaved, our initial study of
the silylthiolation of an aryne with a silyl sulfide provided an
encouraging result (Figure 1C). Unfortunately, our attempts to
achieve the silylthiolation of 3-methoxybenzyne generated
from o-silylaryl triflate 4a with phenyl trimethylsilyl sulfide
(2a) under the conditions reported for the thiostannylation of
arynes did not afford desired o-sulfanylarylsilane 5, and a
significant amount of starting material 4a remained unreacte-
d.12a This unfavorable result would be caused by the activation
of the silyl group of silyl sulfide 2a by the fluoride anion prior
to that of aryne precursor 4a. On the contrary, when the
reaction was performed using o-iodoaryl triflate-type 3-
methoxybenzyne precursor 4b by treatment with a
(trimethylsilyl)methyl Grignard reagent, desired product 5
was obtained, albeit in a low yield. These results indicate that
the soft reactivity of the (trimethylsilyl)methyl Grignard
reagent sufficiently triggered the iodine−magnesium exchange
reaction even in the presence of silyl sulfide 2a with a weak S−
Si bond.
On the basis of these preliminary results and our scenario,
we screened for the reaction conditions that efficiently
promoted the silylthiolation of 3-(triflyloxy)benzyne generated
from 1,3-bis(triflyloxy)-2-iodobenzene (1a) (Table 1). As
Table 1. Optimization of the Reaction Conditions
a
Figure 2. Synthesis of various 3-sulfanylaryne precursors. The yield
when the reaction was performed using 1a (10.0 mmol) and 2d (2.0
equiv) is shown in parentheses. bBis(trimethylsilyl) sulfide was used as
c
a silyl sulfide. See the Supporting Information for details.
a
entry
R-metal
solvent
yield (%)
1
2
3
4
5
6
7
Me3SiCH2MgCl
Me3SiCH2MgCl
Me3SiCH2MgCl
Me3SiCH2MgCl
n-BuLi
Et2O
THF
76
46
77
(trimethylsilyl)aryl triflates 3b−d in good yields. In addition,
sulfides having a dimethylsilyl or dimethylphenylsilyl group
participated in the reaction to afford 3-sulfanyl-2-silylaryl
triflate 3e or 3f, respectively. Notably, the reaction between 3-
(triflyloxy)benzyne and bis(trimethylsilyl) sulfide afforded 3-
mercapto-2-(trimethylsilyl)phenyl triflate (3g), wherein the
trimethylsilyl group on the sulfur was removed during the
reaction or workup procedures without further C−S bond
formation with 3-(triflyloxy)benzyne. Furthermore, the silylth-
iolation of 5-(4-anisyl)-3-(triflyloxy)benzyne proceeded to give
3-sulfanylaryne precursor 3h in a high yield. The reactions
using substrates bearing a bromo group at either the aryne
precursor or the sulfide also proceeded uneventfully to give
desired products such as 3i and 3j, leaving the bromo group
untouched. Additionally, treatment of 3-(triflyloxy)aryne
precursors bearing electron-withdrawing a chloro or methox-
ycarbonyl group with (trimethylsilyl)methylmagnesium chlor-
ide in the presence of methyl trimethylsilyl sulfide afforded 3-
sulfanylaryne precursor 3k or 3l, respectively, albeit in low to
moderate yields. The silylthiolation of 4,6-di(tert-butyl)-3-
(triflyloxy)benzyne also took place to provide desired o-
silylaryl triflate 3m despite the steric hindrance of the tert-butyl
groups. The reaction using 1,3-bis(triflyloxy)-4-(n-hexyl)-2-
iodobenzene afforded a mixture of 3-sulfanylaryne precursor
3n and its isomer 3n′ with moderate selectivity.9b The
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
b
81 (79)
35
47
61
i-PrMgCl·LiCl
PhMgBr
a
b
Yields based on 1H NMR analysis, unless otherwise noted. Isolated
yield.
expected, the reaction between 1a and silyl sulfide 2a under
conditions similar to those for silylamination, using
(trimethylsilyl)methylmagnesium chloride as an activator in
ether, afforded the desired 3-(phenylthio)-2-(trimethylsilyl)-
phenyl triflate (3a) in a high yield (entry 1). Among the
conditions tested, the use of dichloromethane as a solvent
yielded the best result (entry 4). Using more nucleophilic
activators instead of (trimethylsilyl)methylmagnesium chloride
decreased the yield of 3a (entries 5−7).
Various 3-sulfanylaryne precursors 3b−n were successfully
obtained by the regioselective silylthiolation of 3-(triflyloxy)-
arynes with silyl sulfides under the optimized conditions
(Figure 2). A wide range of trimethylsilyl sulfides, such as 4-
methoxyphenyl, methyl, and dodecyl trimethylsilyl sulfides
2b−d could be used for the silylthiolation of 3-(triflyloxy)-
benzyne, affording the corresponding 3-sulfanyl-2-
B
DOI: 10.1021/acs.orglett.9b01862
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
scalability of the reaction was demonstrated in the gram-scale
synthesis of 3d performed using 10 mmol of 1a.
We then examined the reactions of 3-(phenylthio)benzyne
with various arynophiles by generating the aryne intermediate
from precursor 3a under the typical conditions using a fluoride
anion source as an activator (Table 2).15 For example, treating
N,N-dimethylformamide (DMF) proceeded to provide 5-
thiocoumarin 15 as the sole product, which exhibited unique
fluorescence properties, including a large Stokes shift (entry
5).9c,16,17 Furthermore, the direct thioamination12k and
oxythiolation12t of 3-(phenylthio)benzyne with sulfilimine 16
and sulfoxide 18 proceeded smoothly, resulting in the selective
formation of 1,2-dithiophenyl aniline 17 and 1,2-dithiophenyl
ether 19, respectively.
We next examined the 3-sulfinyl- and 3-sulfonylbenzyne
species paying particular attention to the effect of electron-
withdrawing groups on their reactivity. Their precursors 20
and 22 were prepared by the oxidation of 3-(phenylthio)-
benzyne precursor 3a using equimolar and excess amounts of
mCPBA, respectively (Scheme 1). The generation of 3-
Table 2. Reactions of 3-(Phenylthio)benzyne with Various
Arynophiles
Scheme 1. Preparation and Transformation of 3-Sulfinyl-
and 3-Sulfonylbenzyne Precursors
(phenylsulfinyl)benzyne from 20 in the presence of benzyl
azide (12) under the same conditions for the reaction of 3-
(phenylthio)benzyne with 12 (Table 2, entry 4) selectively
afforded benzotriazole 21 along with a small amount of
regioisomer 21′. Similarly, 3-sulfonylbenzyne generated from
22 reacted with 12 to afford cycloadducts 23 and 23′ in good
yields with high selectivity.
To gain insight into the regioselectivity observed in the
cycloaddition of 3-sulfanyl-, 3-sulfinyl-, and 3-sulfonylbenzyne
with an azide, the optimized structures of 3-(phenylthio)-
benzyne (III), 3-(phenylsulfinyl)benzyne (IV), and 3-
(phenylsulfonyl)benzyne (V), respectively, were calculated
on the basis of density functional theory (DFT) at the B3LYP/
6-311+G(d,p) level of theory using the Spartan ‘16 program
(Figure 3).17,18 The order of the difference in the internal
a
1
Ratios of regioisomers determined on the basis of H NMR analysis
b
are shown in parentheses. The reaction was performed using 2.0
equiv of CsF as an activator in a MeCN solution. The reaction was
c
performed using 1.5 equiv of 14 and 3.0 equiv of Bu4NPh3SiF2 as an
d
activator in a DMF solution. The reaction was performed using 2.0
e
equiv of 16 at 60 °C for 21 h. The reaction was performed using 2.0
equiv of 18 at 110 °C for 20 h.
Figure 3. Optimized structures of 3-(phenylthio)benzyne (III), 3-
(phenylsulfinyl)benzyne (IV), and 3-(phenylsulfonyl)benzyne (V)
obtained using a DFT method [B3LYP/6-311+G(d,p)].
a mixture of 3a and aniline (6) in tetrahydrofuran (THF) with
potassium fluoride and 18-crown-6-ether at room temperature
for 24 h afforded diarylamine 7 as a single isomer in high yield
(entry 1). The Diels−Alder reaction of 3-(phenylthio)benzyne
with 2,5-dimethylfuran (8) took place uneventfully to afford
cycloadduct 9 in high yield (entry 2). Nitrone 10 and benzyl
azide (12) also reacted with 3-(phenylthio)benzyne to afford
cycloadducts 11 and 13 in good yields with moderate
selectivity (entries 3 and 4). The three-component coupling
reaction of 3-(phenylthio)benzyne, diethyl malonate (16), and
angles at the aryne carbons (Δθ1−2 = θ1 − θ2) in the optimized
structures was found to be III (6.1°) < V (8.5°) < IV (9.9°),
indicating that the structures of IV and V are more distorted
than that of III. This order was in good agreement with the
higher regioselectivity observed for the reaction of IV or V
with azide 12 (Scheme 1) than that of III (Table 2, entry 4).
For those benzynes bearing a sulfur atom, C1 of the benzyne
triple bond is more electron-deficient due to the increased p
C
DOI: 10.1021/acs.orglett.9b01862
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
character of the C−S bond, as in the cases of thiazolobenzy-
ne11e and thienobenzyne.11f
Experimental procedures and characterization of new
compounds, including NMR spectra (PDF)
The utility of 3-sulfanylbenzynes was showcased in the
synthesis of novel sulfur-containing π-extended heterocycles
(Figure 4).19 The Diels−Alder reaction of 3-(2-bromophenyl)-
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: s-yoshida.cb@tmd.ac.jp.
*E-mail: thosoya.cb@tmd.ac.jp.
ORCID
Suguru Yoshida: 0000-0001-5888-9330
Takamitsu Hosoya: 0000-0002-7270-351X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Japan Agency for Medical
Research and Development (AMED) via Grants
JP19am0101098 (Platform Project for Supporting Drug
Discovery and Life Science Research, BINDS), JP19
cm0106109 (P-CREATE), and JP19gm0910007 (CREST);
JSPS KAKENHI Grants JP15H03118 and JP18H02104 (B;
T.H.), JP15H05721 (S; T.H.), JP16H01133 and JP18H04386
(Middle Molecular Strategy; T.H.), JP26350971 (C; S.Y.), and
JP18J13702 (JSPS Research Fellow; Y.N.); the Cooperative
Research Project of the Research Center for Biomedical
Engineering; and the Naito Foundation (S.Y.).
Figure 4. Synthesis of sulfur-containing π-extended heterocycles via 3-
sulfanylbenzyne species. (A) Synthesis of dibenzothiophene derivative
25. (B) Synthesis of bisarene-fused 1,4-dithiin 28.
thiobenzyne, generated from 3i, with furan 8 and subsequent
deoxygenative aromatization using sodium iodide and chloro-
(trimethyl)silane20 furnished naphthalene 24 (Figure 4A). The
oxidation of 24 followed by the palladium-catalyzed cycliza-
tion21 afforded tetracyclic dibenzothiophene derivative 25.
Moreover, bisarene-fused 1,4-dithiin 28 was easily prepared by
the C−H sulfanylation of arylsulfoxide via the Pummerer-type
activation reported by Yorimitsu and co-workers22 and
subsequent cyclization through 3-sulfanylbenzyne. Indeed,
diaryl sulfide 27 was synthesized by treating 2-benzothienyl
methyl sulfoxide (26) and o-silylaryl triflate 3c with triflic
anhydride and trifluoroacetic anhydride (Figure 4B). The
subsequent intramolecular addition of the methylthio group to
3-sulfanylbenzyne generated from 27 proceeded efficiently to
afford tetracyclic compound 28 containing a 1,4-dithiin
structure.23
In summary, we demonstrated the synthetic utility of 3-
thioaryne species through aryne relay chemistry that consists of
the practical synthesis of aryne precursors by the regioselective
silylthiolation of 3-(triflyloxy)arynes and efficient generation/
transformation of 3-thioarynes. The key to the success of this
approach was the use of a silylmethyl Grignard reagent as an
activator to trigger the generation of 3-(triflyloxy)arynes from
o-iodoaryl triflate-type precursors. The low nucleophilic
characteristic of the silylmethyl Grignard reagent enabled the
iodine−magnesium exchange reaction without affecting the
weak S−Si bond of silyl sulfides. As demonstrated in this study,
3-thioarynes would serve as versatile intermediates for the
synthesis of diverse multisubstituted thioarenes. We are
currently undertaking further studies expanding the scope
and exploring the potential synthetic application of the
method.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01862.
D
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Letter
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