Regio- And Stereoselective Photoredox-Catalyzed Atom Transfer Radical Addition of Thiosulfonates to Aryl Alkynes

Article abstract of DOI:10.1021/acs.orglett.0c01982

Despite extensive investigations, altering the regioselectivity of atom transfer radical addition (ATRA) to alkynes remains a highly desirable yet unachieved challenge. Guided by computational predictions, thiosulfonates were found herein as a tunable radical precursor for thiyl radicals instead of well-recognized sulfonyl radicals. Merging such a finding with ATRA to phenylacetylenes leads to a highly regio- and stereoselective approach to (E)-β-arylsulfonylvinyl sulfides. This protocol is feathered by mild conditions, low photocatalyst loading, no transition-metal catalyst required, and broad functional group compatibility. The successful application of our protocol in the late-stage functionalization of bioactive natural product derivatives demonstrates its synthetic utility. Mechanistic studies corroborate the photoredox-catalyzed ATRA pathway and reveal the pivotal role of thiyl radical, to which unprecedented regioselectivity was attributed.

Full text of DOI:10.1021/acs.orglett.0c01982

pubs.acs.org/OrgLett
Letter
Regio- and Stereoselective Photoredox-Catalyzed Atom Transfer
Radical Addition of Thiosulfonates to Aryl Alkynes
Zhiyuan Peng, Haolin Yin, Hui Zhang, and Tiezheng Jia*
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ABSTRACT: Despite extensive investigations, altering the
regioselectivity of atom transfer radical addition (ATRA) to
alkynes remains a highly desirable yet unachieved challenge.
Guided by computational predictions, thiosulfonates were found
herein as a tunable radical precursor for thiyl radicals instead of
well-recognized sulfonyl radicals. Merging such a finding with
ATRA to phenylacetylenes leads to a highly regio- and stereoselective approach to (E)-β-arylsulfonylvinyl sulfides. This protocol is
feathered by mild conditions, low photocatalyst loading, no transition-metal catalyst required, and broad functional group
compatibility. The successful application of our protocol in the late-stage functionalization of bioactive natural product derivatives
demonstrates its synthetic utility. Mechanistic studies corroborate the photoredox-catalyzed ATRA pathway and reveal the pivotal
role of thiyl radical, to which unprecedented regioselectivity was attributed.
To circumvent the issue of altering regioselectivity of ATRA
to alkynes, we envisioned utilizing a radical precursor, which
could produce one of the two possible radical intermediates
under suitable photoredox conditions, leading to the
corresponding regioisomeric addition products, respectively.
Under this conjecture, thiosulfonates (RSO2−SR′) have
attracted our attention for two major reasons: (1) Thiosulfo-
nates have been widely recognized as a common source of
sulfonyl radical.8 Xu and co-workers reported a gold- and
photoredox-co-catalyzed stereoselective ATRA to aryl alkynes
with thiosulfonates to deliver (E)-(β)-arylthiolvinyl sulfones
exclusively (Scheme 1b).7f,h In this elegant approach,
thiosulfonates have been proven as a reliable sulfonyl radical
precursor in the presence of Ru(bpy)3Cl2 as photocatalyst
under irradiation of blue LED. (2) Despite the lack of
precedence, the generation of thiyl radicals from thiosulfonates
is equally feasible from an energetic perspective based on our
prediction using density functional theory (see the Supporting
Information (SI) for details): single-electron reduction of S-(p-
tolyl)-4-methylbenzenesulfonothioate followed by S−S bond
heterolysis was found to favor the formation of thiyl radical
uilding on the pioneering work by Kharasch and co-
1
Bworkers,
atom transfer radical addition (ATRA) has
emerged as one of the most powerful and straightforward
methods to install two functional groups across an unsaturated
C−C bond in one step.2 Compared to ATRA of alkenes, the
studies on alkynes are overshadowed, probably due to the
related issues of stereoselectivity as well as regioselectivity.3
Vinyl sulfones, a class of scaffolds of great value in medicinal
chemistry4 and material science,5 are suitable synthetic targets
via a tactic of ATRA to alkynes. In particular, much synthetic
effort has been devoted to the development of visible-light
photoredox-catalyzed ATRA to alkynes.6 Nevertheless, chal-
lenge of regioselectivity persists, as evidenced by the fact that
only one type of regioisomeric styrene derivatives bearing a β-
tosyl group has been reported to date, to the best of our
knowledge (Scheme 1a),7 arising from the overwhelming
stability of α-aryl alkenyl radical intermediates.
Scheme 1. Representative Photoredox ATRA to Aryl
Alkynes
(RS•) and sulfinate (RSO2 ) slightly over the formation of
−
sulfonyl radical (RSO2 ) and thiolate (RS−) by 5.1 kcal mol−1
•
in free energy. This computational analysis suggests, under
certain conditions, that thiosulfonates could be switched from
Received: June 13, 2020
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© XXXX American Chemical Society
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Letter
a sulfonyl radical precursor to a thiyl radical precursor and
hence achieves the unmet regioselectivity (Scheme 1c)
complementary to those reported previously.7f,h Herein, we
report a highly regio- and stereoselective photoredox-catalyzed
ATRA to aryl alkynes with thiosulfonates to afford (E)-(β)-
arylsulfonylvinyl sulfides (Scheme 1c). Thiosulfonates were
found through mechanistic investigations to exclusively
generate thiyl radicals instead of sulfonyl radicals employing
Eosin Y as photocatalyst and white LED as light source.
The optimization of reaction conditions commenced by a
short survey of three common photocatalysts [Ru(bpy)3Cl2·
6H2O, Ir(ppy)3, and eosin Y] when NaOH served as base in
N,N-dimethylformamide (DMF) under irradiation of green
LED (Table 1, entries 1−3). Eosin Y9 was proven to be
with 2a (Scheme 2). The parent phenylacetylene 1a could
react with 2a to generate 3aa in 73% yield (1.0 mmol scale),
Scheme 2. Substrate Scope of Aryl Acetylenes in
a
Photoredox-Catalyzed ATRA with 2a
Table 1. Optimization of the Reaction Conditions of
Photoredox-Catalyzed ATRA of Phenylacetylene with 2a
a
isolated yield
entry
photocatalyst
base
NaOH
NaOH
NaOH
CsOH·H2O
KOH
KOH
KOH
KOH
KOH
solvent
(%)
1
2
3
4
5
6
7
Ru(bpy)3Cl2·6H2O
Ir(ppy)3
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
Eosin Y
DMF
DMF
DMF
DMF
DMF
DMSO
DMA
DMA
DMA
DMA
DMA
DMA
21
3
34
18
35
36
38
53
84
19
0
b
8
9
b,c
b
b
,
,
c
c
10
11
12
KOH
Eosin Y
Eosin Y
c,d
KOH
0
a
Unless otherwise stated, reactions were carried out with 1a (0.2
a
mmol), 2a (0.1 mmol), photocatalyst (1 mol %), base (0.1 mmol) in
Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), Eosin Y (1 mol
solvent (1.0 mL) at room temperature under green LED under an
%), KOH (0.1 mmol), DMA (1.0 mL), 12 h, white LED under argon.
b
c
b
argon atmosphere for 12 h. White LED. 1a (0.1 mmol), 2a (0.15
mmol). No light.
1 (1.0 mmol), 2a (1.5 mmol), Eosin Y (1 mol %), KOH (1.0 mmol),
d
c
d
e
DMA (10.0 mL). 14 h. Eosin Y (1 mol %), 36 h. 2a (0.2 mmol),
Eosin Y (2 mol %).
superior, affording the desired product 3aa in 34% yield (Table
1, entry 3). Then two other hydroxide bases (CsOH·H2O and
KOH) were investigated (Table 1, entries 4 and 5), and KOH
exhibited slightly better reactivity (Table 1, compare entry 5 to
entries 3 and 4). Forging ahead with KOH as base, the yield of
3aa could be elevated to 38% when N,N-dimethylacetamide
(DMA) served as solvent (Table 1, entry 7). The yield of 3aa
was improved to 53% using white LED instead of green LED
as the light source (Table 1, entry 8). Adjusting the limiting
agent to 1a while 2a was employed in 1.5 equiv resulted in
84% isolated yield of 3aa (Table 1, entry 9). Additionally, only
19% 3aa was obtained in the absence of eosin Y (Table 1,
entry 10), and no desired product was observed in the absence
of either light or base (Table 1, entries 11 and 12), which
demonstrated the essential roles of eosin Y, light, and base in
the catalytic transformation. Therefore, the optimal conditions
for photoredox-catalyzed difunctionalization of alkynes was: 1a
as limiting agent, 1.5 equiv of 2a as addition partner, 1 mol %
of Eosin Y as photocatalyst, 1.0 equiv of KOH as base, under
irradiation of white LED light at room temperature for 12 h.
With the optimized conditions in hand, we first investigated
the substrate scope of alkynes in photoredox-catalyzed ATRA
demonstrating the synthetic utility of our protocol. Aryl
alkynes bearing electron-withdrawing groups, such as p-F, -Cl,
-Br, and -CF3, were well tolerated by our protocol, affording
3ba−3ea in 59−83% yields. Electron-donating substituents on
aryl alkynes (1f−h) exerted negligible influence on the
outcome of the catalysis, providing 3fa−3ha in good yields.
m-Tolylacetylene was also suitable for the reaction, giving 3ia
in 73% yield. Sterically hindered 1-naphthylacetylene 1j could
be employed as substrate as well, and 3ja was successfully
afforded in slightly diminished yield. The benzoyl group was
compatible with the catalytic conditions, furnishing 3ka in
modest yield. Remarkably, this chemistry was also well
accommodated by heteroaryl alkynes to generate 3la−3qa
with good results, highlighting the expediency and breadth of
this protocol. The configuration of 3ma was unambiguously
determined by X-ray crystallography analysis (see the SI for
details). Aryl acetylenes derived from commercially available
pharmacores, such as estrone (1r), coumarin (1s), and flavone
(1t), could be easily introduced with arylsulfonyl and arylthiyl
groups under the standard conditions in synthetically useful
yields (42−60%). This approach provides a practical tool for
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the late-stage modification of bioactive natural products and
drugs.
We next turned our attention to the substrate generality of
S-aryl thiosulfonates 2 in photocatalyzed ATRA with 1a
(Scheme 3). Substrates possessing the electron-withdrawing
Scheme 4. Substrate Scope of S-p-Tolylarylsulfonothioates
in Photoredox-Catalyzed ATRA with 1a and Synthetic
Application of Trisubstituted Alkenes with Three
a
Heteroaryl Moieties
Scheme 3. Substrate Scope of S-Aryl-4-
Methylbenzenesulfonothioates in Photoredox-Catalyzed
a
ATRA with 1a
a
Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), Eosin Y (1 mol
%), KOH (0.1 mmol), DMA (1.0 mL), 12 h, white LED under argon.
b
2j (0.2 mmol), Eosin Y (2 mol %).
a
Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), eosin Y (1 mol
groups, such as 4-F (2c) and 4-Cl (2d), furnished 3ac and 3ad
in 76% and 69% yield, respectively. S-Aryl thiosulfonates with
electron-donating groups, exemplified by 2e, were well
tolerated, giving 3ae in 81% yield. The sterically demanding
2-tolylthiosulfonates 2f reacted with 1a smoothly under the
optimal conditions to afford 3af in 67% yield. It is noteworthy
that S-heteroaryl thiosulfonates bearing 2-pyridinyl (2g), 4-
pyridinyl (2h), 2-thienyl (2i), 2-methyl-3-furanyl (2j), and 2-
benzoxazole (2k) moieties could be successfully employed as
addition substrates to prepare the corresponding products in
yields ranging from 44% to 86%.
Furthermore, the substrate scope of a variety of arylsulfonyl
methyl thiosulfonates 2 in ATRA with phenylacetylene (1a)
was examined (Scheme 4). The parent phenylsulfonyl
thiosulfonates (2l) reacted smoothly with 1a to provide 3al
in 76% yield. Substrates bearing the electron-withdrawing 4-F
(2m), 4-Cl (2n), 4-Br (2o), or 4-CF3(2p) groups furnished
the corresponding products (3am−3ap) in 52−61% yields.
Electron-donating 4-OMe on arylsulfonyl thiosulfonate was
well suited for the catalytic transformation, giving 3aq in 80%
yield. Sterically hindered 2-tolylsulfonyl thiosulfonates (1r)
underwent addition reaction with 1a to give 3ar in 63% yield.
S-(p-Tolyl)-4-acetylbenzenesulfonothioate (2s) could also be
successfully utilized under our standard conditions. To our
delight, heteroarylsulfonyl thiosulfonate 3t bearing a 2-thienyl
moiety could afford 3at via this route, albeit in lower yield
(41%). Our photoredox-catalyzed addition protocol could be
successfully applied to the synthesis of trisubstituted alkenes
bearing heteroaryl, heteroaryl thiyl and heteroaryl sulfonyl
groups (3lu, 3qv, and 3nw), a class of compounds which are
%), KOH (0.1 mmol), DMA (1.0 mL), 12 h, white LED under argon.
2t (0.2 mmol), Eosin Y (2 mol %). 2u or 2v (0.2 mmol). Eosin Y
(2 mol %).
b
c
d
challenging to prepare previously as evidenced by lack of
precedence in literature.
To probe the rationale of the unexpected regioselectivity, a
series of mechanistic experiments have been performed. First,
we observed that this addition process required continuous
visible-light irradiation based on the results of light “on−off”
experiment (see the SI for details), which indicates that the
present reaction proceeds likely through a photoredox catalytic
process rather than a radical-chain pathway.10
When sodium benzensulfinate (8) was subjected to the
standard reactions with 1a and 2a, both the desired products
3aa derived from 1a and 2a and the crossover product 3al
from 1a, 2a, and 8 were obtained in similar yields (Scheme
5a), indicating the character of sulfonyl group is indeed an
anion instead of a radical. Following this hypothesis, disulfides
Scheme 5. Crossover Experiments
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7 and 9 were utilized together as addition partners in place of
2a, and the desired product 3aa was successfully afforded in
58% yield (Scheme 5b). To gain more insight into the catalytic
mechanism, 2,2,6,6-tetramethylpiperidinooxy (TEMPO) as a
radical scavenger was subjected to our standard conditions. As
we expected, the reaction was significantly inhibited; in
addition, thiyl radical was trapped by TEMPO to yield the
products 10 (see the SI for details).11 Moreover, introduction
of 1 equiv of 5,5-dimethyl-1-pyrroline N-oxide (DMPO) into
the standard catalytic reaction between 1a and 2a resulted in
the isolation of radical trapped complex 11, which was
identified by electron paramagnetic resonance spectroscopy
(EPR)12 and HRMS analysis (see the SI for details). These
results collectively led to the conclusion that thiyl radicals
generated from thiosulfonates are indeed the key intermediate
in our photoredox-catalyzed addition reactions. The Stern−
Volmer experiment of eosin Y by 1a and 2a (see the SI for
details) clearly indicates that the excited state of eosin Y was
quenched by 2a, whereas 1a exhibited no quenching effect at
all.
thiyl radicals instead of well-recognized sulfonyl radicals,
leading to the unprecedented regioselectivity of our protocol.
This work not only offers a facile access to (E)-(β)-
sulfonylvinyl sulfides but also provides a basis for the
photoswitchable radical formation in other contexts.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01982.
Detailed experimental procedures, characterization data,
and NMR spectra of new compounds (PDF)
Accession Codes
CCDC 1948420 contains the supplementary crystallographic
data (3ma) for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Based on the aforementioned results, a plausible mechanism
is illustrated (Figure 1). Photocatalytic cycle begins with
AUTHOR INFORMATION
Corresponding Author
■
Tiezheng Jia − Shenzhen Grubbs Institute, Department of
Chemistry and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen, Guangdong 518055, P.R. China; orcid.org/
0000-0002-9106-2842; Email: jiatz@sustech.edu.cn
Authors
Zhiyuan Peng − Shenzhen Grubbs Institute, Department of
Chemistry and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen, Guangdong 518055, P.R. China
Haolin Yin − Roy and Diana Vagelos Laboratories, Department
of Chemistry, University of Pennsylvania, Philadelphia,
Pennsylvania 19104-6323, United States; orcid.org/0000-
0002-2063-8605
Hui Zhang − Shenzhen Grubbs Institute, Department of
Chemistry and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen, Guangdong 518055, P.R. China
Figure 1. Proposed mechanism of photoredox-catalyzed ATRA
reactions of alkynes with thiosulfonates.
oxidative quenching of the excited-state eosin Y*13 by
thiosulfonates 2a to yield the thiyl radical I and Ts anion II.
The thiyl radical I14 is added to phenylacetylene to afford the
α-alkenyl carbon radical (III), which is then single-electron
oxidized by eosin Y•+ to deliver the benzyl alkenyl cation IV,
and regenerate the ground-state Eosin Y to close up the
photocatalytic cycle at the same time. Finally, the target
product 3aa was produced from the nucleophilic attack of Ts
anion (II) to alkenyl cation III. The role of base in our
protocol is believed to enhance the absorbance of eosin Y via
an acid−base interaction.15
In conclusion, we have developed a photoredox-catalyzed
ATRA reaction to aryl alkynes with thiosulfonates to prepare
(E)-(β)-arylsulfonylvinyl sulfides in excellent regio- and
stereoselectivity. Our protocol features mild reaction con-
ditions, various functional groups, low catalyst loading, and no
transition-metal catalyst. To demonstrate its synthetic utility,
this ATRA method was successfully applied in the late-stage
functionalization of bioactive natural product derivatives. The
mechanistic studies support a photoredox-catalyzed pathway.
In the presence of eosin Y under irradiation of white LED,
thiosulfonates were developed to be a competent precursor for
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01982
Author Contributions
T.J. designed and supervised the project. Z.P. and H.Z.
performed the experiments. H.Y. conducted the computational
studies. T.J. and Z.P. analyzed the results and wrote the paper.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Science and Technology Innovation Commis-
sion of Shenzhen Municipality (JCYJ20180302180256215),
Shenzhen Nobel Prize Scientists Laboratory Project
(C17783101), and Guangdong Provincial Key Laboratory of
Catalysis (2020B121201002) for financial support. SUSTech is
greatly acknowledged for providing startup funds to T.J.
(Y01216129). We are also very grateful to Dr. Yang Yu, Dr.
Xiaoyong Chang, and Dr. Zhou Tang (SUSTech) for HRMS,
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