Atom transfer radical addition to styrenes with thiosulfonates enabled by synergetic copper/photoredox catalysis

Article abstract of DOI:10.1021/acs.orglett.0c04254

A synergetic copper/photoredox catalyzed ATRA of styrenes and thiosulfonates is developed. Besides aryl ethylenes, the challenging α-substituted styrenes were employed to construct the benzylic quaternary carbon centers. Owing to the mild conditions as well as the high level of substrate compability, this ATRA could be applied to derivatize bioactive natural products in late stage, and to install fluorophores across alkenes. The mechanistic studies reveal sulfonyl radicals as the key intermediate in the transformation.

Full text of DOI:10.1021/acs.orglett.0c04254

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Letter
Atom Transfer Radical Addition to Styrenes with Thiosulfonates
Enabled by Synergetic Copper/Photoredox Catalysis
Xin Zhou, Zhiyuan Peng, Peng George Wang, Qingchao Liu,* and Tiezheng Jia*
Cite This: Org. Lett. 2021, 23, 1054−1059
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ABSTRACT: A synergetic copper/photoredox catalyzed ATRA of
styrenes and thiosulfonates is developed. Besides aryl ethylenes, the
challenging α-substituted styrenes were employed to construct the
benzylic quaternary carbon centers. Owing to the mild conditions as well
as the high level of substrate compability, this ATRA could be applied to
derivatize bioactive natural products in late stage, and to install
fluorophores across alkenes. The mechanistic studies reveal sulfonyl
radicals as the key intermediate in the transformation.
Scheme 1. Difunctionalization of Alkenes with
Thiosulfonates
ver since the pioneering works by Kharasch and co-
workers,1 atom transfer radical addition (ATRA) has
E
provided a facile and straightforward tool to install two
functional groups across an unsaturated CC bond in a single
step, and thus has found widespread applications in organic
synthesis2 and polymer science.3 Traditionally initiated by
radical initiators4 or transition-metal catalysts,5 ATRA enables
the rapid difunctionalization of alkenes or alkynes with
increasing the molecular complexity. Since photoredox
catalysis is considered to be mild, efficient, and environ-
mentally benign,2,6 much effort has been devoted to the
development of visible-light photoredox catalyzed ATRA
reactions in recent years.7
Sulfones and sulfides are prevailing scaffolds in natural
products,8 bioactive synthetic molecules,9 and marketed
therapeutics.10 Consequently, methods for the construction
of sulfones and sulfides have been intensively studied. In this
regard, ATRA reactions of thiosulfonates11 with alkenes or
alkynes are particularly attractive, primarily due to the
incorporation of sulfonyl group (RSO2−) and thiyl group
(RS−) into vicinal carbons of unsaturated CC bonds
simultaneously. In 2007, Xu’s group disclosed a seminal
photoredox ATRA protocol of thiosulfonates with styrenes
enabled by dual gold and ruthenium-based photocatalyst in the
presence of AgSbF6 (Scheme 1a).12 Though representing the
breakthrough of thiosulfonates in ATRA reactions, Xu’s
protocol required the employment of three precious metal
salts. Later on, the same group succeeded in reversing the
regioselectivity of additions between thiosulfonates and
styrenes in the assistance of a Lewis acid catalyst (Scheme
1b).13 Of note, the method was demonstrated to operate in an
ionic pathway rather than a radical process. The first ATRA of
thiosulfonates with unactivated alkenes catalyzed by silver
nitrate employing stoichiometric potassium persulfate as
oxidant was developed by Shen’s group (Scheme 1c).14
Unfortunately, only monofluoromethyl and difluoromethyl-
Received: December 24, 2020
Published: January 11, 2021
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Org. Lett. 2021, 23, 1054−1059
© 2021 American Chemical Society
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benzenethiosulfonate (PhSO2SCH2F and PhSO2SCHF2) were
utilized as coupling partners, which jeopardized its further
application. Very recently, Maes and co-workers described an
efficient and environmentally benign photocatalyzed ATRA
protocol of thiosulfonates with unactivated alkenes, employing
9-mesityl-10-methylacridinium perchlorate as photocatalyst
under the irradiation of visible light (Scheme 1d).15 A vast
array of unactivated alkenes could be successfully utilized as
coupling partners, whereas styrenes were not tolerated by their
protocol due to their low oxidation potentials. Therefore, a
general and practical ATRA of thiosulfonates and styrenes with
broad functional group compability, especially tolerating α-
and/or β-substituted styrenes as well as alkylthiosulfonates, is
still a highly desirable but unmet task.
Following our continuous interests regarding the develop-
ment of sulfones’ synthetic methods via difunctionalization of
alkenes16 and alkynes17 employing thiosulfonates, herein we
report a highly regioselective ATRA procedure of styrenes with
thiosulfonates enabled by synergetic photoredox and copper
catalysts (Scheme 1e).
the catalytic reaction. No or only a trace amount of desired
product was observed in the absence of any of these
components (Table 1, entries 2−4). Furthermore, when the
reactions were performed in the absence of Cu(CH3CN)4PF6
or L4, the yields of 3aa dramatically dropped to 56% and 65%,
respectively (Table 1, entries 5 and 6), with emphasis on the
synergetic catalysis of copper and photoredox. Ligand L4
outperformed other three structurally similar ligands (L1−L3)
screened in the transformation (Table 1, compare entry 1 vs
entries 7−9). The structure, especially the regioselectivity, of
3aa was unambiguously assigned by X-ray crystallography
(Table 1).
With the optimal conditions established, the substrate
generality of styrenes was evaluated in synergetic copper/
photoredox catalyzed ATRA with 2a (Scheme 2). The parent
styrene (1a) reacted with 2a to produce 3aa in 93% yield.
Styrenes possessing electron-donating groups, such as 4-Me
Scheme 2. Substrate Scope of Styrenes in Synergetic
a
Copper/Photoredox Catalyzed ATRA with 2a
We chose styrene (1a) and S-(p-tolyl)-4-methyl-benzene-
sulfonothioate (2a) as the model reactants (Table 1). After
Table 1. Optimization of ATRA of Styrene 1a with 2a
a
Enabled by Synergetic Copper/Photoredox Catalysis
b
entry
derivation from standard conditions
assay yield /%
c
1
2
3
4
5
6
7
8
9
none
without light
97(93 )
0
0
trace
56
65
87
85
56
without Ru(phen)3(PF6)2
without DIPEA
without Cu(CH3CN)4PF6
without L4
L1 instead of L4
L2 instead of L4
L3 instead of L4
a
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), Ru-
(phen)3(PF6)2, DIPEA (0.1 mmol), Cu(CH3CN)4PF6 (5 mol %),
L4 (7.5 mol %), DMF (3.0 mL) at room temperature under the
irradiation of 11 W blue LED under an argon atmosphere for 12 h.
b
Assay yield determined by 1H NMR using 0.1 mmol of CH2Br2 (7.0
c
μL) as internal standard. Isolated yield.
intensive optimization studies, the synergetic conditions were
as follows: styrene (1a) as the limiting reagent, 2.0 equiv of
thiosulfonate (2a) as addition partner, 5 mol % Cu-
(CH3CN)4PF6 and 7.5 mol % L4 as the copper catalyst, 1
mol % Ru(phen)3(PF6)2 as the photocatalyst, 1.0 equiv DIPEA
as base, under the irradiation of 11 W blue LED in DMF at
room temperature for 12 h (for complete screening results, see
Supporting Information). The assay yield of the desired
product 3aa was 97%, with 93% isolated yield (Table 1, entry
1). In a series of control experiments, the light source, DIPEA,
and Ru(phen)3(PF6)2 were demonstrated to be essential for
a
Reaction conditions: 1 (0.1 mmol), 2a (0.2 mmol), Ru-
(phen)3(PF6)2 (1 mol %), DIPEA (0.1 mmol), Cu(CH3CN)4PF6
(5 mol %), L4 (7.5 mol %), DMF (3.0 mL) at room temperature
under the irradiation of 11 W blue LED under an argon atmosphere
for 12 h. 1u (1.0 mmol), 2a (2.0 mmol), Ru(phen)3(PF6)2 (1 mol
%), DIPEA (1.0 mmol), Cu(CH3CN)4PF6 (5 mol %), L4 (7.5 mol
b
%), DMF (30.0 mL).
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(1b) or 4-OMe (1c), were suitable substrates, giving 3ba and
3ca in 90% and 84% yield, respectively. Electron-withdrawing
groups on styrenes exert a negligible effect on the outcome of
the catalysis, affording 3da−3fa in 83−90% yields. Sterically
demanding 2-methylstyrene could be well tolerated by our
method, providing 3ga in 85% yield. Various functional groups,
including hydroxyl (1j), amide (1k), ketone (1l), and aldehyde
(1m), could be well tolerated by our ATRA strategy, owing to
the mild reaction conditions, furnishing 3ja−3ma in 58−91%
yields. Heterocycles are a class of structural motifs of great
value in medicinal chemistry and marketed drugs. Our ATRA
strategy was proven to be applicable to a variety of heteroaryl
alkenes, and pyridyl (1n, 1o), indolyl (1p), benzofuranyl (1q),
and benzothiophenyl (1r) alkenes reacted smoothly with 2a to
deliver the desired products (3na−3ra) in good to excellent
yields. The internal styrene derivatives, exemplified by linear β-
methylstyrene (cis-/trans- mixtures, 1s) and cyclic indene (1t),
were compatible with the optimal catalytical conditions,
providing 3sa and 3ta as a single diastereomer, albeit in
modest yields. Though representing a facile and atom-
economical access to benzylic quaternary carbon center,
ATRA of α-substituted styrenes remains underexplored,
presumably due to the related steric hindrance as well as the
competitive elimination pathway of benzylic cation intermedi-
ates.18 Remarkably, the chemistry is well accommodated with
the α-substituted styrenes, independent of the electronic or
steric effects of the substituents. Styrenes bearing an aromatic
α-substituent, exemplified by 1,1-diphenylethylene (1u),
proceeded smoothly under the optimal conditions to deliver
3ua in near-quantitative yield. Styrenes with α-alkyl sub-
stituents, either linear (1v, 1w) or cyclic (1x), were amenable
for the newly devised method, providing the desired products
(3va−3xa) in good yields. Of note, the substrates feathered
with exocyclic alkene, such as 1y, were also tolerated by our
catalytical conditions, giving 3ya in 82% yield. However, our
protocol finds its limitation, as unactivated aliphatic alkenes,
such as 1-hexene, cannot be tolerated. Encouraged by the
broad functional group tolerance as well as the mild reaction
conditions, our synergetic ATRA strategy was applied to the
late-stage functionalization of bioactive natural products
derivatives. Aryl ethylenes derived from the prevalent
pharmacores, such as flavone (1z), estrone (1aa), estradiol
(1ba), and tocol (1ca), reacted effectively with 2a to generate
3za-caa in modest to good yields, which displays the synthetic
utility of our protocol. The synergetic ATRA proceeded
smoothly with 1u and 2a to generate 3ua in 98% yield (1.0
mmol scale), demonstrating the synthetic utility of our
protocol.
Scheme 3. Substrate Scope of S-Aryl-4-
Methylbenzenesulfonothioates in Synergetic Copper/
a
Photoredox Catalyzed ATRA with 1a
a
Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol), Ru-
(phen)3(PF6)2 (1 mol %), DIPEA (0.1 mmol), Cu(CH3CN)4PF6
(5 mol %), L4 (7.5 mol %), DMF (3.0 mL) at room temperature
under the irradiation of 11 W blue LED under an argon atmosphere
for 12 h.
groups bearing electron-withdrawing groups could be
efficiently installed on styrene via our ATRA strategy to
prepare 3aj−l in the yields ranging from 75% to 80%. Electron-
donating para-OMe group on S-(p-tolyl)-arylsulfonothioate
exhibited little effect on the outcome of the catalytical
transformation, giving 3am in 85% yield. We were delighted
to observe that our synergetic ATRA protocol could even be
applied to label styrene with l-dimethylaminonaphthalene-5-
sulfonyl group, a powerful and widely used fluorescent probe
named dansyl,19 as evidenced by the generation of 3an, albeit
in slightly diminished yield. In sharp contrast to aryl-
sulfonothioates, alkyl-sulfonothioates are a category of
challenging addition partners primarily due to the inferior
stability of alkyl sulfonyl radicals to their aryl counterparts. To
date, only a single substrate of this class (S-phenyl-
methylsulfonothioate) has been employed in ATRA reac-
tions.15 Nevertheless, the tested alkylsulfonothioates (2o−q)
with varied substitution patterns could undergo effective
Next, we turned our attention to the substrate scope of S-
aryl-4-methylbenzenesulfonothioates in synergetic copper/
photoredox catalyzed ATRA with 1a (Scheme 3). The parent
S-phenyl-4-methylbenzenesulfonothioate (2b) reacted with 1a
to afford 3ab in 86% yield. Substrates possessing electron-
withdrawing substituents, such as para-F (2c) or Cl (2d) were
well-suited under the optimal conditions, generating 3ac and
3ad in 84% and 72% yield, respectively. S-Aryl thiosulfonates
with electron-donating groups were compatible substrates, as
evidenced by 3ae obtained in 95% yield. The sterically
demanding 2-tolylthiosulfonate (2f) underwent ATRA with 1a
smoothly to provide 3af in 75% yield. It is noteworthy that S-
heteroaryl thiosulfonates (2g−i) could be utilized as addition
partners with 1a under the optimal conditions to prepare the
corresponding products (3ag−i) in good yields. Arylsulfonyl
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Letter
transformation under the standard conditions to deliver the
desired products (3ao−q) in synthetic useful yields, high-
lighting the expediency and breadth of the newly devised
method. Unfortunately, S-alkyl-arylthiosulfonates are not
compatible by our protocol.
To shed light on the mechanism of the synergetic ATRA, a
light “on−off” experiment was carried out (Figure S1). It is
revealed that occurrence of the ATRA reaction between 1a and
2a required the continuous irradiation of the blue LED light. In
addition, the photochemical quantum yield (Φ) (λex = 457
nm) of the reaction between 1u and 2a was determined to be
Φ = 0.1 (see SI for details), implying the reaction more likely
performed through a photoredox-catalysis pathway rather than
a radical chain process.
Furthermore, when 1i and 2a were subjected to the
otherwise standard catalytical conditions along with 1,4-
dinitrobezene (2 equiv), a commonly used radical scavenger
(Scheme 4a), the formation of 3ia was completely inhibited,
Figure 1. Proposed mechanism of synergetic copper/photoredox
catalyzed ATRA.
elimination to afford the final product 3aa, and regenerates D
to close the overall catalytical cycle. Another possible
mechanism without the copper catalyst is also provided in SI
as Figure S5.
Scheme 4. Synergetic Copper/Photoredox Catalyzed ATRA
Interfered with Radical Scavengers
In summary, a general and practical synergetic copper/
photoredox catalyzed ATRA of styrenes with thiosulfonates is
reported. A vast array of functional groups, especially medically
relevant heteroaryl scaffolds, could be well tolerated by the
newly devised method. By leveraging the high level of substrate
compability as well as the mild reaction conditions, our
protocol can be used to introduce fluorophores across the
olefin moieties, and to derivatize bioactive natural products in
late stage. The mechanistic studies support the pivotal role of
sulfonyl radicals in the transformation, and corroborate a
synergetic copper/photoredox catalysis process.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04254.
and the reactant 1i could be quantitatively recovered based on
the analysis of H NMR. As we expected, introduction of 1
1
Detailed experimental procedures, characterization data,
and NMR spectra of new compounds (PDF)
equiv of 5,5-dimethyl-1-pyrroline N-oxide (DMPO) led to the
generation of tosyl radical trapped product 4 (Scheme 4b),
which was characterized by electron paramagnetic resonance
spectroscopy (EPR) (Figure S2)20 and HRMS analysis (Figure
S3). These results coincidentally supported the key role of tosyl
radical in the transformation. Subsequently, we performed the
fluorescence quenching experiments of Ru(phen)3(PF6)2 by
styrene 1a, thiosulfonates 2a and DIPEA (Figure S4). The
Stern−Volmer plots indicate that the excited state of
Ru(phen)3(PF6)2 was quenched by DIPEA, whereas 1a and
2a exhibited no quenching effect at all.
Accession Codes
CCDC 2023810 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Based on the aforementioned observations, a plausible
mechanism is proposed in Figure 1. The photocatalytic cycle
commences with the reductive quenching of the excited state
Ru(phen)3(PF6)2 ([RuII]*) with DIPEA to yield the radical
cation of DIPEA and [RuI] species. A single electron transfer
(SET) from the latter species to 2a yields the tosyl radical A
and the thiyl anion B. The CuI species D is oxidized by radical
cation of DIPEA to provide CuII species E, initiating the
copper catalysis cycle. Thiyl anion B binds to E to generate the
intermediate F. Simultaneously, A undergoes addition to 1a to
afford the benzylic radical intermediate C, which subsequently
reacts with F in a single-electron oxidation manner to provide
G. The copper(III) species G undergoes rapidly reductive
AUTHOR INFORMATION
■
Corresponding Authors
Qingchao Liu − Department of Pharmaceutical Engineering,
College of Chemical Engineering, Northwest University, Xi’an,
Shanxi 710069, P. R. China; Email: liuqc21@nwu.edu.cn
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; State Key
Laboratory of Elemento-Organic Chemistry, Nankai
University, 300071 Tianjin, China; orcid.org/0000-
0002-9106-2842; Email: jiatz@sustech.edu.cn
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Authors
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Letter
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DOI: 10.1016/j.cclet.2020.06.003.
Xin Zhou − Department of Pharmaceutical Engineering,
College of Chemical Engineering, Northwest University, Xi’an,
Shanxi 710069, P. R. China; 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
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
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Peng George Wang − School of Medicine, Southern University
of Science and Technology, Shenzhen 518055, P. R. China;
orcid.org/0000-0003-3335-6794
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04254
(6) (a) Hopkinson, M. N.; Tlahuext-Aca, A.; Glorius, F. Merging
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Author Contributions
T.J. designed and supervised the project. X.Z. and Z.P.
performed the experiments. T.J., P.G.W., and Q.L. analyzed the
results. T.J. wrote the paper.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
3950. (b) Lipp, B.; Kammer, L. M.; Ku
̈
cu
̈
kdisli, M.; Luque, A.;
̌
We thank the Science and Technology Innovation Commis-
sion of Shenzhen Municipality (JCYJ20180302180256215),
Shenzhen Nobel Prize Scientists Laboratory Project
(C17783101), Guang-dong Provincial Key Laboratory of
Catalysis (2020B121201002), and the National Natural
Science Foundation of China (22078263) for financial
support. SUSTech is greatly acknowledged for providing
startup funds to T.J. (Y01216129). We are also very grateful
to Dr. Yang Yu and Dr. Xiaoyong Chang (SUSTech) for
HRMS and X-ray crystallography analysis. Prof. Wei Lu and
Prof. Feng He (SUSTech) are acknowledged for helpful
discussions on quantum yield test.
̌
̌
̇
Ku
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hlborn, J.; Pusch, S.; Matuleviciute, G.; Schollmeyer, D.; Sackus,
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O. M.; Terentev, A. O.; Opatz, T. Photoredox-Catalyzed Four-
Component Reaction for the Synthesis of Complex Secondary
Amines. Org. Lett. 2020, 22, 3318.
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