Synthesis of Alkynyl Sulfides by Copper-Catalyzed Thiolation of Terminal Alkynes Using Thiosulfonates

Article abstract of DOI:10.1021/acs.orglett.9b00875

A mild and odorless copper-catalyzed thiolation of terminal alkynes with thiosulfonates is described. The broad substrate scope provides convenient access to a wide variety of sulfur-containing heterocycles. In particular, divergent benzoheteroles are efficiently prepared in a simple manner by thiolation of ethynylbenzenes bearing ortho-nucleophilic functional groups followed by iodocyclization.

Full text of DOI:10.1021/acs.orglett.9b00875

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Alkynyl Sulfides by Copper-Catalyzed Thiolation of
Terminal Alkynes Using Thiosulfonates
Kazuya Kanemoto, 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: A mild and odorless copper-catalyzed thiolation of
terminal alkynes with thiosulfonates is described. The broad substrate
scope provides convenient access to a wide variety of sulfur-containing
heterocycles. In particular, divergent benzoheteroles are efficiently
prepared in a simple manner by thiolation of ethynylbenzenes bearing
ortho-nucleophilic functional groups followed by iodocyclization.
rganosulfur compounds have a broad range of
applications, particularly in the fields of medicinal
O
chemistry1 and materials science.2 Recent advances in the
transformations of thio groups have further enhanced the
synthetic utility of organosulfurs, enabling the preparation of a
wide variety of compounds via C−S bond cleavage including
cross-coupling reactions.3 In particular, alkynyl sulfides have
attracted attention as useful synthetic intermediates because
they are transformable into various organosulfur compounds
through diverse types of reactions including addition,4a,b,h
iodocyclization,4f,g cycloaddition,4d,e,i and cross-coupling re-
actions.4c In spite of their utility, C(sp)−S bond forming
reactions5 have been less studied than C(sp2)−S and C(sp3)−
S bond formations,6 and thus, an efficient method to prepare
alkynyl sulfides by thiolation of terminal alkynes is still
required.
In recent years, several facile methods to prepare alkynyl
sulfides from simple terminal alkynes employing thiols or
disulfides have been developed (Figure 1A and 1B).7 However,
during our work on drug discovery based on organosulfur
compounds,1c we found that these approaches suffer from a
series of practical limitations. For example, the copper-
catalyzed thiolation of terminal alkynes 1a and 1b bearing
amino or acetyl groups, respectively, with 2-phenethylthiol
(2a) under an oxygen atmosphere7e resulted in failure due to
the low conversion of 1a and undesired addition reaction of
the nucleophilic thiol 2a to the electron-deficient alkyne 1b
(Figure 1D). Another attempt to achieve the thiolation using
thiosulfonate 3a in the presence of t-BuOLi, which was
recently reported by Xu and co-workers as a part of their
mechanistic study of the interrupted click reaction (Figure
1C),7g was also unsuccessful, and the desired alkynyl sulfides
4a and 4b were obtained only in low yields (Figure 1E).
Moreover, using K2CO3 instead of t-BuOLi to avoid the
decomposition of the products resulted in lower yields.
To develop an efficient catalytic system for the synthesis of
alkynyl sulfides, we focused our attention on thiosulfonates,
Figure 1. Reported methods for catalytic formation of alkynyl sulfides
(A−C) and our attempts to synthesize alkynyl sulfides 4 by these
methods (D and E). a K2CO3 (2.0 equiv) was used instead of t-
BuOLi. Yields were determined by HPLC.
since they had been previously demonstrated to offer great
advantages in copper-8a,c and rhodium-catalyzed8b deborylth-
iolation reactions that proceed efficiently under mild and
odorless conditions and have a wide substrate scope.
Considering the good leaving ability of the sulfonyl group
and the lower nucleophilicity of the liberated sulfinic acids
compared with thiols, we conceived that the catalytic thiolation
Received: March 11, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00875
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
of terminal alkynes using thiosulfonates could enable the
efficient preparation of alkynyl sulfides even with substrates
bearing sensitive functional groups. Herein, we report an
efficient and odorless copper-catalyzed C−S bond forming
reaction between terminal alkynes and thiosulfonates that
exhibits a dramatically expanded substrate scope.
After an extensive screening using terminal alkyne 1b and
thiosulfonate 3a (1.5 equiv), we found the conditions suitable
for the desired thiolation at room temperature (Table 1).
Table 1. Optimization of the Reaction Conditions
a
entry catalyst/ligand (mol %)
base (equiv)
solvent yield (%)
1
2
3
4
5
6
7
8
CuSO4 (5)
CuCl (5)
CuI (5)
CuI (5)/bpy (6)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
K2CO3 (4.0)
NaHCO3 (4.0)
Cs2CO3 (4.0)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
10
18
22
14
18
9
CuI (5)/TMEDA (6)
CuI (5)/PPh3 (12)
CuI (5)/dppp (6)
CuI (5)/DPEphos (6)
CuI (5)/Xantphos (6)
CuI (5)/Xantphos (6)
CuI (5)/Xantphos (6)
CuI (5)/Xantphos (6)
CuI (5)/Xantphos (6)
CuI (5)/Xantphos (6)
43
21
74
25
trace
Figure 2. Thiolations of various terminal alkynes with S-methyl
thiosulfonate 3b. a CuI (10 mol %) and Xantphos (12 mol %) were
used. b The reaction was performed using 3.0 equiv of 3b at 100 °C
9
10
11
12
13
14
c
b
for 1 h. The reaction was performed using 3.0 equiv of 3b at 50 °C
90
for 12 h.
b
83
toluene
trace
a
Yields were determined by HPLC analysis, unless otherwise noted.
Isolated yield.
bearing a hydroxy group or acetal moiety also proceeded under
modified conditions to afford the corresponding alkynyl
sulfides 4n−q in moderate to good yields leaving these
functional groups untouched.
b
Although several copper salts catalyzed the phenethylthiolation
of 1b in the presence of K2CO3 (4.0 equiv) in DMSO, these
reactions resulted in low conversions (entries 1−3). A
screening of ligands (entries 4−9) revealed that the combined
use of Xantphos and CuI dramatically improved the efficiency
of the reaction (entry 9). Although the use of other bases such
as NaHCO3 and Cs2CO3 instead of K2CO3 proved ineffective
(entries 10 and 11), reducing the amount of K2CO3 to 1.5
equiv was found to further improve the yield of the desired
alkynyl sulfide 4b (entry 12). The thiolation also proceeded
efficiently in other polar solvents such as DMF (entry 13),
clearly ruling out the role of DMSO as an oxidant.
The optimized conditions (Table 1, entry 12) were
successfully applied to the thiolation of a wide range of
terminal alkynes with S-methyl thiosulfonate 3b (Figure 2).
Considering the utility of alkynyl methyl sulfides as synthetic
intermediates,4b,g,i our method using stable and odorless
thiosulfonate as the methylthio source presents an advantage
over conventional methods that require volatile methanethiol
with an unpleasant odor. Arylacetylenes bearing an electron-
donating or -withdrawing group on the benzene ring at the
ortho-, meta-, or para-position participated in this trans-
formation to afford alkynyl sulfides 4c−m. Notably,
arylacetylenes bearing an unprotected amino group or an
ester moiety and heteroarylacetylenes such as 3-pyridylacety-
lene, which were unfavorable substrates under the previously
reported conditions,9 were successfully thiolated using our
method, affording alkynyl sulfides 4e, 4f, and 4l, respectively,
in high yields. Furthermore, methylthiolation of alkylacetylenes
Various thiosulfonates including S-alkyl and S-(hetero)aryl
thiosulfonates were also applicable to this thiolation method, as
demonstrated in the reaction with 4-ethynylanisole (1q)
(Figure 3). Not only the methylthiolation of 1q with S-methyl
thiosulfonate (3b) but also arylthiolations using S-aryl
thiosulfonates bearing electron-donating or electron-with-
drawing groups on the benzene ring proceeded smoothly
under the standard conditions to afford alkynyl aryl sulfides
4t−y in high yields. Noteworthily, sulfides containing further
transformable groups such as chloro, bromo, and methox-
ycarbonyl groups were also obtained. Furthermore, alkyl
alkynyl sulfides were easily prepared from alkyl halides,
potassium thiosulfonate, and terminal alkynes following a
one-pot procedure. For example, substitution of alkyl bromide
5 with the readily available potassium thiosulfonate 6 in
DMSO, followed by direct addition of K2CO3, CuI, Xantphos,
and alkyne 1q to the reaction mixture, afforded 4s in moderate
yield (Scheme 1).
To gain insights into the mechanism of the copper-catalyzed
thiolation of terminal alkynes, we conducted several control
experiments (Figure 4). As shown in Figure 3, the thiolation of
alkyne 1q with thiosulfonate 3c proceeded smoothly under the
standard conditions using catalytic amounts of CuI and
Xantphos (redescribed in Figure 4A, top scheme). In contrast,
employment of disulfide 7 or thiol 2b instead of thiosulfonate
3c resulted in almost complete recovery of alkyne 1q (Figure
4A, middle and bottom schemes). These results indicate that
the catalytic cycle of the thiolation does not involve a C−S
B
DOI: 10.1021/acs.orglett.9b00875
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Figure 3. Thiolations of terminal alkyne 1q with various
thiosulfonates.
Scheme 1. One-Pot Synthesis of Alkynyl Sulfide 4s from
Phenethyl Bromide 5
bond formation with disulfide 7 or thiol 2b, which are potential
intermediates. In addition, conducting the reaction between 1q
and 3c in the presence of 2,2,6,6-tetramethylpiperidine 1-oxyl
free radical (TEMPO) did not affect significantly the formation
of alkynyl sulfide 4t, which suggests that the involvement of
radical intermediates can be ruled out (Figure 4B).
Furthermore, treatment of copper acetylide 8, which was
prepared in situ from the reaction between alkyne 1c, CuI, and
K2CO3 according to the reported method,10 with Xantphos
and a stoichiometric amount of thiosulfonate 3b afforded
alkynyl sulfide 4c with similar efficiency to that of the reaction
between alkyne 1c and 3b conducted using stoichiometric
amounts of CuI and Xantphos (Figure 4C). These results
indicate that the copper acetylide intermediate is likely
involved in the catalytic thiolation. On the basis of these
results, we propose the catalytic cycle depicted in Figure 4D,
which starts with the generation of copper acetylide
intermediate II by ligand exchange between terminal alkyne
and copper catalyst I coordinated with Xantphos with the
assistance of a base and the copper catalyst. Subsequently,
either σ-bond metathesis of copper acetylide II with
thiosulfonate (path a) or oxidative addition of thiosulfonate
to copper acetylide II followed by reductive elimination (path
b) would afford the alkynyl sulfide and regenerate the
catalyst.11
Figure 4. Mechanistic studies. (A) Thiolation of alkyne 1q using
different sulfur surrogates (thiosulfonate 3c, disulfide 7, and thiol 2b)
under the standard conditions; thiolation reagent (1.5 equiv), CuI (5
mol %), Xantphos (6 mol %), K2CO3 (1.5 equiv), DMSO, rt, 24 h.
(B) Thiolation of alkyne 1q in the presence of TEMPO. (C) Reaction
of copper acetylide 8 with thiosulfonate 3b and reaction of alkyne 1c
with 3b using stoichiometric amounts of CuI and Xantphos. (D)
Plausible reaction mechanisms. Yields were determined by HPLC
analysis.
methoxy-, o-methylthio-, and o-dimethylaminophenyl groups
proceeded efficiently to afford alkynyl sulfides 4z−af with
various substitutions including base-sensitive functional groups
(Table 2). Subsequent iodocyclization4f,g,12 of the resulting
alkynyl sulfides 4z−af successfully afforded benzo[b]furans
9a−e, benzo[b]thiophene 9f, and indole 9g having various
functional groups. Following this approach, we also achieved
the efficient synthesis of the tricyclic heteroaromatic
compound 12 from diyne 10 by a double-thiolation/
iodocyclization sequence (Figure 5A).13
The synthetic utility of the thiolation of terminal alkynes
developed in this study was further demonstrated by
performing derivatizations of the cyclized product containing
both iodo and methylthio groups. For example, tetracyclic 2-
chlorobenzofuro[2,3-b]benzofuran (15) was successfully pre-
pared from 5-chloro-3-iodo-2-methylthiobenzo[b]furan (9d)
The wide substrate scope of the alkynyl sulfide synthesis
provides easy access to a variety of sulfur-containing hetero-
cycles. For example, thiolation of terminal alkynes bearing o-
C
DOI: 10.1021/acs.orglett.9b00875
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Table 2. Thiolation and Subsequent Iodocyclization of
Terminal Alkynes
Figure 5. Synthesis of diverse benzoheterole derivatives. (A)
Synthesis of π-conjugated heteroacene 12 from diyne 10 via a
double-thiolation/iodocyclyzation sequence. (B) Derivatization of
benzofuran 9d via cross-coupling, oxidation, and cyclization. (C)
Sequential three-step coupling from 9d. See the Supporting
Information for details.
synthesis, which enables rapid access to privileged scaffolds
that are useful for developing new drugs and materials.18
Further studies including application toward the synthesis of
bioactive sulfur-containing molecules and detailed mechanistic
studies are currently underway.
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.9b00875.
Experimental procedures, characterization for new
compounds including NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
by selective Suzuki−Miyaura cross-coupling at the iodo group,
followed by oxidation of the methylthio group to methane-
sulfonyl and subsequent base-mediated cyclization14 (Figure
5B). Furthermore, benzofuran 9d was successfully subjected to
a sequential three-step selective arylation15 that involved a
palladium-catalyzed Suzuki−Miyaura cross-coupling at the
iodo group,16 a nickel-catalyzed Kumada−Tamao−Corriu
cross-coupling at the methylthio group,3e and a palladium-
catalyzed Suzuki−Miyaura cross-coupling at the remaining
chloro group (Figure 5C).17 These transformations took place
smoothly with high selectivity and efficiency, clearly showing
the utility of benzofuran 9d as a platform molecule for the
synthesis of diverse multifunctionalized benzofurans.
In summary, we have developed an odorless thiolation
reaction of terminal alkynes with thiosulfonates by a catalytic
CuI/Xantphos system. The method showed a wide substrate
scope owing to the mild conditions, providing ready access to
various alkynyl sulfides. We also achieved the facile synthesis of
a variety of sulfur-containing heterocycles by thiolation of
alkynes, followed by iodocyclization and further trans-
formations including sequential cross-coupling reactions.
These results highlight the utility of this alkynyl sulfide
*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) under Grant Numbers
JP18am0101098 (Platform Project for Supporting Drug
Discovery and Life Science Research, BINDS), JP18
cm0106109 (P-CREATE), and JP18gm0910007 (CREST);
JSPS KAKENHI Grant Numbers JP15H03118 and
JP18H02104 (B; T.H.), JP16H01133 and JP18H04386
(Middle Molecular Strategy; T.H.), JP26350971 (C; S.Y.);
the Cooperative Research Project of Research Center for
Biomedical Engineering; and the Naito Foundation (S.Y.).
D
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by Formal [2 + 2+2] Cycloaddition under Mild Conditions. Angew.
Chem., Int. Ed. 2016, 55, 12864.
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reported in ref 7e.
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Organic Letters
Letter
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