Gold/photoredox-cocatalyzed atom transfer thiosulfonylation of alkynes: Stereoselective synthesis of vinylsulfones

Article abstract of DOI:10.1016/j.tetlet.2019.02.039

We report a gold and photoredox combined radical approach for the rapid synthesis of thio-functionalized vinylsulfones from alkynes. Key features of this method include very mild conditions, broad substrate scope, excellent regio- and stereoselectivties, and 100% atom economy.

Full text of DOI:10.1016/j.tetlet.2019.02.039

Accepted Manuscript
Gold/photoredox-cocatalyzed atom transfer thiosulfonylation of alkynes: Ster-
eoselective synthesis of vinylsulfones
Tingting Song, Haoyu Li, Fang Wei, Chen-Ho Tung, Zhenghu Xu
PII:
S0040-4039(19)30184-4
https://doi.org/10.1016/j.tetlet.2019.02.039
TETL 50633
DOI:
Reference:
Tetrahedron Letters
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Accepted Date:
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19 February 2019
22 February 2019
Please cite this article as: Song, T., Li, H., Wei, F., Tung, C-H., Xu, Z., Gold/photoredox-cocatalyzed atom transfer
thiosulfonylation of alkynes: Stereoselective synthesis of vinylsulfones, Tetrahedron Letters (2019), doi: https://
doi.org/10.1016/j.tetlet.2019.02.039
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Graphical Abstract
Gold/photoredox-cocatalyzed atom transfer
thiosulfonylation of alkynes: Stereoselective
synthesis of vinylsulfones
Leave this area blank for abstract info.
Tingting Song,a Haoyu Li,a Fang Wei,*a Chen-Ho Tunga and Zhenghu Xu*a,b

1
Tetrahedron Letters
Gold/photoredox-cocatalyzed atom transfer thiosulfonylation of alkynes:
Stereoselective synthesis of vinylsulfones
Tingting Songa , Haoyu Lia , Fang Weia,  Chen-Ho Tunga and Zhenghu Xua, b
a
School of chemistry and Chemical Engineering, Shandong University, Jinan 250100, People’s Republic of China.
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences Shanghai 200032, PR China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We report a gold and photoredox combined radical approach for the rapid synthesis of thio-
functionalized vinylsulfones from alkynes. Key features of this method include very mild
conditions, broad substrate scope, excellent regio- and stereoselectivties, and 100% atom
economy.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
sulfur chemistry
radical reaction
photocatalysis
Introduction
The construction of C-S bonds is one of the most important
and fundamental reactions in organic synthesis [1]. Sulfur
containing compounds are not only basic functional groups in
synthetic chemistry, but also widely exist in natural products and
bioactive molecules [2]. Sulfonyl group posses similar properties
in molecular size and charge distribution with carbonyl,
tetrazolium and phosphate group, so it was widely used as their
bioisosteres in drug discovery. Introducing sulfonyl group into
drug molecules can enhance the binding affinity of drug
molecules with target proteins through hydrogen bonding
interaction [3]. Vinylsulfones are
a particular type of
organosulfur compounds of interests in both organic synthesis
and also biological related research. They are excellent Michael
acceptors and have found widespread applications in
bioconjugation and also as covalent protease inhibitors [4].
Consequently, the development of efficient synthetic methods to
access functionalized vinylsulfones are highly desirable.
Alkynes are widely existed and easily available moieties in
organic synthesis [5]. Alkyne difunctionalization reactions are
one of the most straightforward approach to poly functionalized
olefins [6]. In this context, sulfonylation of alkynes with
synergistic formation of C-X [7], C-O [8], and C-C [9] bonds
have been recently developed to build various functionalized
vinylsulfones. For instance, the Nevado group reported an
elegant Ni-catalyed carbosulfonylation of alkynes with aryl
Scheme 1. Synthesis of functionalized vinylsulfones by alkyne difunctionalization
sulfonyl radical addition and cross coupling strategy (scheme 1A)
[10]. In 2017, Wu et al developed an efficient copper(I)-catalyzed
four-component reaction to synthesize β-halo vinylsulfones
(scheme 1B) [11]. Alkyne difunctionalization reactions with
simultaneous formation C-SO2 and another C-S bond in one pot
could give β-thio vinylsulfones. In this communication, we report
our preliminary results on this reaction.
boronic
acids
 Corresponding author. Tel.: +86-531-88364258; e-mail: xuzh@sdu.edu.cn
 Corresponding author. Tel.: +86-531-88364258; e-mail: weifang511@126.com
by
using
———

2
Tetrahedron
Atom transfer radical addition (ATRA) to alkynes is an
With the optimal conditions in hand, the alkyne scope of this
reaction was first tested. As illustrated in table 2, a variety of
alkynes including aaromatic alkynes and aliphatic alkynes all
could react with 2a to afford the difunctionalization products in
good to excellent yields. Aromatic alkynes bearing electron-
donating groups such as methyl and methoxyl groups at para
position favored this reaction, and the corresponding products
were isolated in very high yields (3b,3c). Alkynes with electron-
withdrawing groups such as F, Cl, Br, CN, and COOMe at
aromatic ring are also suitable substrates, albeit with slightly
lower yield (3d-3h). These results accord with the fact that the
para substituted electron-donating groups could stablize the in
situ formed vinyl radical. Methyl group at ortho or meta position,
or even free hydroxyl group at aromatic ring did not significantly
affect the reactivity and yielded the corresponding products in
excellent yields (3i-3k). Heterocycles such as thienyl alkyne was
also tolerated and was converted into the corresponding
thiosulfonylation product (3m) in 54% yield. Internal alkyne also
worked well under standard conditions, affording the (E)-isomer
of the tetrasubstituted alkene (3n) in 66% isolated yield with 5/1
E/Z selectivity. When cyclopropyl substituted alkyne was reacted
with 2a, only the addition product 3o was isolated in 62% yield
and no radical clock type allene product was observed. Aliphatic
enyne substrate was also amenable to this reaction and give
alkyne difunctionalization product 3p in 57% yield. All these
products were characterized by NMR, and Mass characterization,
and the structure of compound 3a was confirmed by single
crystal X-ray crystallography.
attractive but challenging synthetic method to provide vicinal
functionalized olefins in the most atom economic manner [12].
Only limited examples about ATRA of alkynes have been
reported and control of the E/Z selectivity of difunctionalization
product is difficult [13]. Recently, we developed
gold/photoredox mediated approach to realize atom transfer
trifluoromethylthio-sulfonylation and difluoromethylthio-
sulfonylation reaction of alkynes by using PhSO2SCF3 and
PhSO2SCF2H [14]. In this reaction, the gold(I) catalyst is crucial
to initiate the reaction and also deliver good stereoselectivity
with the possible interaction between gold catalyst and the situ
formed vinyl radical intermediate. Following this concept, we
wish to develop a more general thiosulfonylation of alkynes with
PhSO2SR (2, R = aryl or alkyl) as the reagent. However，such a
reaction might be more challenging because the oxidative
potential of 2 (− 1.64 V, vs SCE, R = C4H9) is lower than that of
PhSO2SCF3 (−1.11 V, vs SCE) [15].
a
Result and discussion
To validate our hypothesis, we tested the reaction of
phenylacetylene (1a) and PhSO2SPh (2a) under our previous
standard conditions. To our delight, the desired thiosulfonylation
product 3a was isolated in 92% as a single E isomer in the
presence of catalytic amount of Ph3PAuNTf2 and Ru(bpy)3Cl2
under blue LED light irradiation (Standard conditions, Table 1).
When the gold catalyst was removed or no LED light was
involved, much lower yields were observed (entries 2,3, Table 1),
which indicated that the transition metal and light irradiation are
all necessary for this reaction. Ph3PAuCl and (Me2S)AuCl were
used instead of Ph3PAuNTf2, very low NMR yields were
observed, indicating cationic gold catalyst is crucial for this
reaction (entries 4-5). Other catalysts such as IPrAuCl and
AgSbF6, AgOTf, CuI were all tested, but much inferior results
were obtained (entries 6-9). Use of other solvents such as CH3CN,
DCE, and THF led to decreased yields (entries 10-12). Replacing
photocatalyst Ru(bpy)3Cl2 with fac-Ir(ppy)3 or Ru(phen)3Cl2, only
63% and 14% yields were observed respectively.
Table 2. Substrate scope of alkynes.a
Table 1. Optimization of reaction conditionsa
Entry
1
2
3
4
5
6
7
8
Variation from the “standard” conditions
None
Yield (%)b
98 (92)
30
11
11
<5
18
52
16
14
0
No Ph3PAuNTf2
No light
aStandard conditions were employed. A mixture of 1a (0.2 mmol), 2a (0.4
mmol), PPh3PAuNTf2 (0.5 mol%), Ru(bpy)3Cl2 (0.1 mol%), in dioxane (1
mL) was stirred at rt under irradiation with blue LED strip for 6 hrs at N2
atmosphere. Isolated yields were reported.
Ph3PAuCl instead of Ph3PAuNTf2
(Me2S)AuCl instead of Ph3PAuNTf2
IPrAuCl and AgSbF6 instead of Ph3PAuNTf2
AgOTf instead of Ph3PAuNTf2
CuI instead of Ph3PAuNTf2
CuI/PPh3 instead of Ph3PAuNTf2
CH3CN instead of Dioxane
DCE instead of Dioxane
Then the scope of difunctionalization reagents were further
evaluated (Table 3). Compounds with various electron deficient
(3r,3s), or electron rich (3q,3t,3u,3v) substituents at different
positions did not significantly affect the reactivity and yielded the
corresponding products in good to excellent (81–92%) yields.
For the aliphatic thioreagent, the reaction is less efficient and
61% isolated yield was obtained with a methylthio reagent (3w).
Selenylation reaction was also important in organic synthesis. To
our delight, when PhSO2SePh (4) was subjected to standard
reaction conditions, the expected selensulfonylation reaction was
also very successful and gave corresponding products in over
90% yields (3x,3y).
9
10
11
12
13
14
6
9
63
14
THF instead of Dioxane
fac-Ir(ppy)3 instead of Ru(bpy)3Cl2
Ru(phen)3Cl2 instead of Ru(bpy)3Cl2
aReaction conditions:
a
mixture of 1a (0.2 mmol), 2a (0.4 mmol),
PPh3PAuNTf2 (0.5 mol%), Ru(bpy)3Cl2 (0.1 mol%), in dioxane (1 mL) was
stirred at rt under irradiation with blue LED strip for 6 hrs at N2 atmosphere.
1
b Determined by H NMR using trimethoxylbenzene as the internal standard.
The number in parentheses is the isolated yield. IPr = 1,3-bis(2,6-diisopropyl-
phenyl)imidazol-2-ylidene, ppy = 2-phenylpyridine, bpy =2,2’-bipyridine,
phen = phenanthroline.

3
Table 3. Substrate scope of alkynes.a
Conclusion
In conclusion, using combined gold catalysis and visible light
photoredox catalysis strategy, we have developed an efficient
atom transfer radical addition of alkynes. Prominent features of
this
reaction
include
excellent
regioselectivity and
stereoselectivity, 100% atom economy, broad scope, and very
low catalyst loading. This type of combined gold catalysis with
photoredox strategy provides helpful hints for further
development of metalloradical reactions in organic synthesis.
Acknowledgments
We are grateful for financial support from the National
Natural Science Foundation of China (no. 21572118
&
21750110444), and a Tang Scholar Award from Shandong
University.
aStandard conditions were employed. A mixture of 1a (0.2 mmol), 2a (0.4
mmol), PPh3PAuNTf2 (0.5 mol%), Ru(bpy)3Cl2 (0.1 mol%), in dioxane (1
mL) was stirred at rt under irradiation with blue LED strip for 6 hrs at N2
atmosphere. Isolated yields were reported.
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5
1) This strategy offers a new approach for the
radical dithiolation of alkynes.
2) Extremely low catalyst loading of both
catalysts was required.
3) Au catalyst helped to initiate the reaction
and deliver better stereoselectivity.
4) Features of this reaction include excellent
stereoselectivity and atom economy.