Copper-catalyzed thiolation of terminal aromatic alkynes to access alkynyl disulfides

Article abstract of DOI:10.1016/j.tetlet.2020.152256

A copper-catalyzed thiolation of terminal aromatic alkynes by disulfur transfer to access alkynyl disulfides was developed. Different types of products were afforded due to the steric hindrance of dithiolsulfonates. Some important compounds, such as fully substituted triazoles and pyrene-gemcitabine conjugate were prepared by this new approach.

Full text of DOI:10.1016/j.tetlet.2020.152256

Journal Pre-proofs
Copper-catalyzed thiolation of terminal aromatic alkynes to access alkynyl di‐
sulfides
Junhao Li, Ming Li, Xuelun Duan, Wangze Song
PII:
S0040-4039(20)30723-1
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152256
TETL 152256
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Tetrahedron Letters
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Accepted Date:
10 May 2020
11 July 2020
13 July 2020
Please cite this article as: Li, J., Li, M., Duan, X., Song, W., Copper-catalyzed thiolation of terminal aromatic
alkynes to access alkynyl disulfides, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152256
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Tetrahedron Letters
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Communication
Copper-Catalyzed Thiolation of Terminal Aromatic Alkynes to Access Alkynyl
Disulfides
Junhao Lia, Ming Lia, Xuelun Duana, Wangze Songa,b,

a
State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian, 116024, P. R. China.
Zhongli Science and Technology Group Co., Ltd., Changshu, 215542, P. R. China.
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Type your Abstract text here
A copper-catalyzed thiolation of terminal aromatic alkynes by disulfur transfer to access alkynyl
disulfides was developed. Different types of products were afforded due to the steric hindrance of
dithiolsulfonates. Some important compounds, such as fully substituted triazoles and pyrene-
gemcitabine conjugate were prepared by this new approach.
Available online
Keywords:
Alkynyl disulfides
Disulfur transfer
Thiolation
Copper-catalyzed
Steric hindrance
Organosulfur compounds widely exist in drugs and natural
products, and play significant roles in medicinal chemistry and
materials science [1-2]. Particularly, disulfides containing sulfur-
sulfur bonds have received considerable attentions due to the
widely applications in various areas [3-5]. For instance, the
three-dimensional structures of proteins are stabilized by
disulfide bridges. The S-S bonds are designed to mediate
glutathione (GSH)-responsive drugs release. Disulfides are
utilized as vulcanizing agents for rubbers and elastomers in
material science. Disulfide bond is very important linker in
amino-acid, bio-active natural products and medicinal chemistry,
therefore, a variety of strategies have been developed to
construct symmetric disulfides and asymmetric disulfides. The
symmetric disulfides could be easily accessible by the oxidation
of thiols [6-7]. The asymmetric disulfides could be prepared by
substitution reactions of S-H bonds [8-9], thio-disulfide
interchange [10-11], oxidative cross-couplings [12-13] and other
methods [14-16]. Although numerous methods have been
developed to control C-S bonds formation, it is still limited and
challenge to form C-S-S bonds in one step, especially for alkynyl
disulfides. C(sp)-S-S bond are less disclosed than C(sp2)-S-S and
C(sp3)-S-S [17-19]. Therefore, it is very urgent and important to
develop method to prepare alkynyl disulfides by direct thiolation
of terminal alkynes.
methanethiolsulfonate (MsSMe) or tert-butylsulfenyl thiocyanate
(t-BuSSCN) in two steps under -30℃ (Scheme 1a) [20]. After
two decades, Senning’s group further modified this method to
one step using alkynyl lithium and chlorodisulfane under -78℃
(Scheme 1b) [21]. However, both approaches suffer low
temperature to afford prefunctionalization of lithium reagents
and undesired rearrangement byproducts either by the [3,3]-
sigmatropic (hetero-Cope, thio-Claisen) route or by the [1,3]-
sigmatropic manner. There are no any literatures reported to
prepare alkynyl disulfides since 1993. Recently, Dong’s group
disclosed a protocol for the synthesis of tBuSSTs [22], which was
further applied to prepare only one example of alkynyl disulfide
by Xu’s group [23]. Inspired by Dong and Xu’s pioneering
works and as
a continuation of our studies on the
functionalization of terminal alkynes [24-25], herein, we report a
In 1972, Brandsma’s group first reported the synthesis of 1-
alkynyl disulfides from lithium alkynethiolate and methyl
———
 Corresponding author.
E-mail address: wzsong@dlut.edu.cn

Scheme 1. Approaches for the synthesis of alkynyl disulfides.
deficient terminal alkynes (Table 2, entries 1-10). The p-ethyl
phenylacetylene (1d) could give highest yield (up to 75%) (Table
2, entry 4). The yield for phenylacetylene (1c) was slightly lower
than other electron-donating alkynes (Table 2, entry 3), which
was similar for more bulky tert-butyl substituted phenylacetylene
(1e) (Table 2, entry 5). If the para-substituted groups were
electron-donating groups, the yields for 3a, 3b and 3d were
much higher than 3f, 3g and 3h which substituted by electron-
copper-catalyzed thiolation of terminal alkynes by disulfur
transfer to access alkynyl disulfides. Remarkably, different types
of products were afforded due to the steric hindrance of
dithiolsulfonates (Scheme 1c).
Initially, 4-methoxyphenylacetylene 1a and SS-tert-butyl p-
toluenesulfono (dithioperoxoate) 2a were selected as model
substrates for optimizing reaction conditions (Table 1). The Cu(I)
catalysts were first screened (Table 1, entries 1-5). Among CuI,
CuBr, CuCl, CuTc and CuOTf, highest yield of 3a was acquired
using CuI as catalyst (Table 1, entry 1). Several ligands were
employed in order to further improve the yield (Table 1, entries
6-9). Unfortunately, most of the N-containing ligands could not
efficiently promote this transformation. Therefore, the reaction
was set up in a ligand-free manner. Inorganic and organic bases
were next investigated (Table 1, entries 10-14). LitOBu could
provide higher yield than NatOBu or KtOBu (Table 1, entries 10,
11). Trace product was obtained using K2CO3 or LiOH as base
(Table 1, entries 12, 13). The yield decreased dramatically using
triethylamine as organic base (Table 1, entry 14). The reaction
could proceed smoothly in other solvents such as THF, DMSO,
DCM and chloroform, except for MeOH, which may due to the
easy protonation of intermediates (Table 1, entries 15-19). The
reaction failed to occur when the temperature was dropped to
room temperature (Table 1, entry 20).
Table 2
Substrate scope of terminal alkynes with p-toluenesulfono (dithioperoxoate)a.
Table 1
Optimization of reaction conditionsa.
Entry Cu(I)
Ligand
-
-
-
-
-
1,10-phenathroline
TMEDA
PMDETA
pyridine
-
-
-
-
-
-
-
-
-
-
-
Base
Solvent Yield (%)b
1
CuI
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
NaOtBu
KOtBu
K2CO3
LiOH
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
MeOH
72
66
52
31
50
52
45
61
48
64
60
trace
trace
38
55
trace
2
3
4
5
CuBr
CuCl
CuTc
CuOTf
CuI
6
7
CuI
8
CuI
9
CuI
10
11
12
13
14
15
16
17
18c
19c
20d
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
NEt3
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
DMSO 45
CuI
CuI
CuI
DCM
CHCl3
DCE
61
68
trace
a Reaction conditions: 1a (1 equiv), 2a (2 equiv), Cu(I) (20 mol%), ligand (40
mol%), base (2 equiv) in solvent (0.2 M) at 70℃ for 12 h.
b Determined by 1H-NMR of the crude mixture with an internal standard.
c The reaction was set up in sealed tube.
d The reaction was set up at room temperature.
With the optimized conditions in hand, we explored the
substrate scope of the copper-catalyzed reactions. Various
terminal alkynes and p-toluenesulfono (dithioperoxoates) were
used as substrates to afford alkynyl disulfides or alkynyl sulfides
at 70℃ in good yields (Table 2). Using SS-tert-butyl p-
toluenesulfono (dithioperoxoate) 2a as electrophile, alkynyl
disulfides were acquired from both electron-rich and electron-
a Reaction conditions: 1 (1 equiv), 2 (2 equiv), CuI (20 mol%), LitOBu (2
equiv) in DCE (0.2 M) at 70℃ for 8-12 h.

b Isolated yield.
alkynyl disulfides. Some important compounds, such as fully
substituted triazoles and pyrene-gemcitabine conjugate could be
prepared by this methodology.
c The combined yield for inseparable mixture (3n and 3n’) in 1:1 ratio.
withdrawing group (Table 2, entries 6-8). Thus, an obvious
electronic effect was observed. The p-nitro group could be
tolerated in this transformation albeit in low yield (3h). Besides
para-substituted alkynes, meta- and ortho-substituted alkynes
could also achieve this reaction (Table 2, entries 9, 10). The yield
for ortho-substituted phenylacetylene (1j) was slightly lower
than the para- and meta-substituted alkynes (Table 2, entry 10).
When less bulky SS-methyl or SS-ethyl p-toluenesulfono
(dithioperoxoates) were used as electrophiles instead of SS-tert-
butyl one, surprisingly, alkyne sulfides (3’k and 3’l) were
obtained as major products with moderate yields (Table 2, entries
11, 12) [26]. Alkyne sulfide (3’m) was also afforded using SS-n-
butyl substrate (Table 2, entry 13). However, the mixture of
alkyne disulfide (3n) and alkyne sulfide (3’n) were observed
when SS-isopropyl substrate was used (Table 2, entry 14). The
heterocyclic alkyne sulfide (3’o) was isolated as major product
(Table 2, entry 15). Hence, this transformation was controlled by
the steric hindrance of electrophiles.
Acknowledgments
We are grateful for financial supports form the National
Natural Science Foundation of China (21978039, 21702025),
Science and Technology Innovation Foundation of Dalian City
(2019J12GX029) and the Fundamental Research Funds for the
Central Universities (DUT20YG120).
Appendix A. Supplementary data
Supplementary material related to this article can be found, in
the online version,
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In summary, we have developed a copper-catalyzed thiolation
of terminal aromatic alkynes by disulfur transfer to access

Graphical Abstract
Copper-Catalyzed Thiolation of Terminal Aromatic
Alkynes to Access Alkynyl Disulfides
Leave this area blank for abstract info.
Junhao Li, Ming Li, Xuelun Duan, Wangze Song*

Highlights:
1. A copper-catalyzed thiolation by disulfur
transfer to access alkynyl disulfides was developed.
2. Alkynyl disulfides and alkynyl sulfides were
afforded due to the steric hindrance of
dithiolsulfonates.
3. Fully substituted triazoles and pyrene-
gemcitabine conjugate were prepared by this new
approach.