Directing-group-assisted markovnikov-selective hydrothiolation of styrenes with thiols by photoredox/cobalt catalysis

Article abstract of DOI:10.1021/acs.orglett.1c00999

In contrast with the well-developed radical thiol-ene reaction to access anti-Markovnikov-type products, the research on the catalytic Markovnikov-selective hydrothiolation of alkenes is very restricted. Because of the catalyst poisoning of metal catalysts by organosulfur compounds, limited examples of transition-metal-catalyzed thiol-ene reactions have been reported. However, in this work, a directing-group-assisted hydrothiolation of styrenes with thiols by photoredox/cobalt catalysis is found to proceed smoothly to afford Markovnikov-type sulfides with excellent regioselectivity.

Full text of DOI:10.1021/acs.orglett.1c00999

pubs.acs.org/OrgLett
Letter
Directing-Group-Assisted Markovnikov-Selective Hydrothiolation of
Styrenes with Thiols by Photoredox/Cobalt Catalysis
Qian Xiao, Hong Zhang, Jing-Hong Li, Jing-Xin Jian, Qing-Xiao Tong,* and Jian-Ji Zhong*
Cite This: Org. Lett. 2021, 23, 3604−3609
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ABSTRACT: In contrast with the well-developed radical thiol-ene
reaction to access anti-Markovnikov-type products, the research on
the catalytic Markovnikov-selective hydrothiolation of alkenes is
very restricted. Because of the catalyst poisoning of metal catalysts
by organosulfur compounds, limited examples of transition-metal-
catalyzed thiol-ene reactions have been reported. However, in this
work, a directing-group-assisted hydrothiolation of styrenes with
thiols by photoredox/cobalt catalysis is found to proceed smoothly
to afford Markovnikov-type sulfides with excellent regioselectivity.
Scheme 1. Thiol-Ene Reactions
he incorporation of sulfur into organic molecules is of
great importance owing to the fact that organosulfur
T
moieties are widespread in natural products,1 pharmaceuticals,2
and polymer materials.3 In this context, the direct hydro-
thiolation of alkenes with thiols, well known as the thiol-ene
reaction,4 represents one of the simplest and most atom-
economical approaches for C−S bond construction.5 This
reaction can proceed by way of an electrophilic pathway or a
radical pathway, leading to the formation of a branched
product via Markovnikov addition or a linear product via anti-
Markovnikov addition, respectively. Owing to the high
reactivity of sulfur, the reaction tends to proceed via a radical
pathway. Consequently, the radical thiol-ene reactions6
affording anti-Markovnikov products have been well re-
searched by the thermal or UV-light activation of a radical
initiator or direct UV-light irradiation or visible-light photo-
redox catalysis (Scheme 1a).
knowledge, all of the reported catalytic systems afforded the
anti-Markovnikov-type adducts,19 and the photoredox-cata-
lyzed Markovnikov-selective thiol-ene reaction has not yet
been reported. With our continuous interest in photoredox
catalysis, designing a specific and active photocatalytic system
to overcome the previously described issues will be appealing
and desirable. In this work, we report a directing-group-
assisted strategy for the addition of thiols to styrenes with
excellent Markovnikov regioselectivity in good yields by
photoredox/cobalt catalysis20 (Scheme 1c).
In contrast, the Markovnikov-selective thiol-ene reaction is
far less developed. Traditional methods focus on using
stoichiometric Brønsted acids or Lewis acids7 to suppress the
thiyl radicals and promote the electrophilic pathway for
Markovnikov-type adducts (Scheme 1b). However, the
research on the catalytic Markovnikov-selective thiol-ene
reaction is very restricted.8 Transition-metal catalysis offers
potential for this transformation; however, because of the
inherent challenge of catalyst poisoning of metal catalysts by
organosulfur compounds, to date, very limited examples of
transition-metal catalytic systems,9 including In(OTf)3,10
Ph3PAuOTf,11 AuBr3,12 FeCl3/AgNTf2,13 Pd(OAc)2,14 Cu-
Received: March 23, 2021
Published: April 12, 2021
15
(OAc)2
and ZnI2/TsOH,16 have been reported for
Markovnikov thiol-ene reactions.
Visible-light photoredox catalysis17 as an alternative for a
greener and more sustainable thiol-ene reation has attracted
much attention in recent years;18 however, to the best of our
https://doi.org/10.1021/acs.orglett.1c00999
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3604−3609
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Letter
One reason for the difficulty of the transition-metal-
catalyzed thiol-ene reaction is the poor coordination ability
of alkenes to the transition-metal catalyst. Introducing a
directing group to the alkenes is a potential solution to address
this problem. Thus 2-vinyl aniline a1 was designed as the
model substrate. To our delight, the presence of just a catalytic
amount of 9-mesityl-2,7,10-trimethylacridinium perchlorate
(PC, 5 mol %) as a photocatalyst and Co(dmgH)2PyCl (20
mol %) as a cocatalyst and the irradiation of 4-chlorothiophe-
nol b1 with a slight excess a1 (1.1 equiv) in degassed CH2Cl2
by blue light-emitting diodes (LEDs) (λ = 450 nm) at room
temperature resulted in the sole Markovnikov-type adduct c1
in 88% yield with excellent regioselectivity (Table 1, entry 1).
of this highly selective and atom-economical thiol-ene reaction
(Table 1, entries 13−15).
To investigate the functional group tolerance of the
photoredox/cobalt-catalyzed Markovnikov-selective thiol-ene
reaction, we first examined a variety of different substituted 2-
vinyl anilines under standard conditions, and some representa-
tive results are shown in Scheme 2. For various substituents on
a
Scheme 2. Scope of 2-Vinyl Anilines
a
Table 1. Optimization of Reaction Conditions
b
entry variation from the “standard reaction conditions” yield (%) c1
1
2
3
4
5
6
none
88
67
47
55
70
0
Mes-Acr-Me+ClO4 as photocatalyst
4CzIPN as photocatalyst
Ru(bpy)3Cl2 as photocatalyst
Co(dmgBF2)2(H2O)2 as cocatalyst
CoCl2 as cocatalyst
−
7
8
Co(OAc)2 as cocatalyst
DMF as solvent
0
trace
63
42
78
89
0
9
CH3CN as solvent
THF as solvent
DCE as solvent
toluene as solvent
no photocatalyst
no cobaloxime catalyst
no light
10
11
12
13
14
15
0
0
a
a
Reaction conditions: a (0.22 mmol), b1 (0.20 mmol), PC (5 mol
Reaction conditions: a1 (0.22 mmol), b1 (0.20 mmol), PC (5 mol
%), Co(dmgH)2PyCl (20 mol %), CH2Cl2 (3.0 mL), under N2, room
temperature, 450 nm LED irradiation for 24 h. Isolated yields.
%), Co(dmgH)2PyCl (20 mol %), CH2Cl2 (3.0 mL), under N2, room
temperature, 450 nm LED irradiation for 24 h. Isolated yields.
b
b
the phenyl ring of 2-vinyl anilines, regardless of the position of
the electron-withdrawing group or the electron-donating
group, the desired Markovnikov-type adducts were obtained
in good to excellent yields (Scheme 2, c1−c12). Notably, to
demonstrate the scalability of this protocol, a gram-scale
reaction of a1 and b1 was conducted and proceeded smoothly
to give the desired Markovnikov-type product c1 in 70% yield
(Scheme 2, c1). Unfortunately, when the unactivated alkene
a13 was attempted, no desired product was observed (Scheme
2, a13). As previously stated, the transition-metal-catalyzed
thiol-ene reaction of alkenes is a challenging task owing to its
poor coordination ability to the metal center. Indeed, when the
directing group of the tosyl-protected amine group was
removed, the reaction could not happen (Scheme 2, a14),
and the unprotected 2-vinyl aniline was also proved to be
ineffective in the reaction (Scheme 2, a15). Therefore, we next
investigated the N-substituents of 2-vinyl anilines, Various
−
Other photocatalysts such as Mes-Acr-Me+ClO4 , 4CzIPN,
and Ru(bpy)3Cl2 were also investigated, but just moderate
yields were provided (Table 1, entries 2−4). The reaction yield
decreased to 70% when Co(dmgBF2)2(H2O)2 instead of
Co(dmgH)2PyCl was used (Table 1, entry 5). No reaction was
observed when CoCl2 or Co(OAc)2 acted as the cocatalyst
(Table 1, entries 6 and 7), indicating that the ligand around
the cobalt center plays an important role in the catalytic
activity. Furthermore, the solvent examination revealed that
besides CH2Cl2, toluene also proved to be a good choice, with
an 89% yield (Table 1, entries 8−12). When diphenyl disulfide
d1 replaced thiol b1 in the optimized reaction, only the
disulfidation product e1 rather than the hydrothiolation
product c1 was obtained (Scheme S1). Further control
experiments indicated that a photocatalyst, cobaloxime
catalyst, and light were essential parameters for the success
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Letter
functional groups such as methyl, methoxyl, fluoride, chloride,
and bromide were introduced to the phenyl ring of the
arylsulfone moiety in 2-vinyl anilines, and the desired products
were obtained in good to excellent yields (Scheme 2, c16−
c21). Further experiments found that, besides arylsulfone
moieties, the substrates equipped with quinoline sulfonyl,
naphthalene sulfonyl, and trifluoroacetyl as the N-protected
group were also compatible with the reaction to give yields of
86, 71, and 73%, respectively (Scheme 2, c22−c24).
Regrettably, when N-Boc 2-vinyl aniline was used, no desired
product was observed (Scheme 2, c25). It is noteworthy that
the structure of c23 has been confirmed by single-crystal X-ray
diffraction analysis.21
detected by high-resolution mass spectrometry (HRMS),
revealing that a thiyl radical is involved in the reaction
(Scheme 4a). It is commonly known that once a sulfur radical
Scheme 4. Reaction Mechanism Investigations
We further explored the variety of thiols. It is known that the
formation of thiyl radicals from aryl thiols is faster than that of
alkyl thiols, leading to the addition of aryl thiols to styrene
preferentially affording anti-Markovnikov-type adducts via a
radical pathway. Notably, in this photoredox/cobalt-catalytic
system, the anti-Markovnikov-type adducts were completely
suppressed, and the Markovnikov-type adducts were exclu-
sively obtained with excellent regioselectivity, no matter
whether the phenyl ring of the aryl thiols was substituted
with electron-withdrawing groups or electron-donating groups
(Scheme 3, c26−c30). Moreover, various commercially
is generated, it is preferential to access the anti-Markovnikov-
type product via a radical pathway. However, in this catalytic
system, Markovnikov-type products were exclusively obtained.
We assume that this is attributed to the fact that the rate of the
addition of the thiyl radical to the cobaloxime catalyst is faster
than that of alkene, which could suppress the generation of an
anti-Markovnikov-type adduct. The deuterium labeling experi-
ment indicated that the hydrogen source in the product c1
mainly originated from the thiol substrate b1 (Scheme 4b).
Recently, Chen, Xiao, and coworkers22 reported a nitrogen-
radical-mediated difunctionalization of 2-vinyl anilines. To
confirm the possibility of a nitrogen radical’s involvement in
this reaction, we designed several control experiments. 3-Vinyl
aniline a40 and 4-vinyl aniline a41 were exposed to the
standard conditions, and no reaction occurred (Scheme 4c,d).
Furthermore, when the N−H moiety of a1 was methylated, the
reaction still proceeded smoothly in 70% yield (Scheme 4e).
These results suggest that a nitrogen-radical-mediated pathway
could be excluded in this reaction. Nevertheless, when the N−
H moiety was protected by bulky groups such as benzyl (a43),
isopropyl (a44), and tert-butyl (a45), the reaction could not
happen (Scheme S2). We speculate that the steric hindrance
would affect the coordination ability of nitrogen.
a
Scheme 3. Scope of Thiols
a
Reaction conditions: a1 (0.22 mmol), b (0.20 mmol), PC (5 mol
%), Co(dmgH)2PyCl (20 mol %), CH2Cl2 (3.0 mL), under N2, room
b
temperature, 450 nm LED irradiation for 24 h. Isolated yields.
available alkyl thiols were examined. The results revealed
that primary thiols such as 2-phenyl ethyl mercaptan (b31),
ethyl thioglycolate (b32), 2-methy butyl mercaptan (b33), n-
octyl mercaptan (b34), and furan-2-yl methanethiol (b35)
reacted well with a1 to generate the corresponding
Markovnikov-type products in good yields (Scheme 3, c31−
c35). Regrettably, secondary and tertiary thiols were ineffective
in this transformation, probably due to the steric hindrance
effect (Scheme 3, c36−c39).
On the basis of the above observations, a reasonable
mechanism is proposed in Scheme 5. The protected amine
group as a directing group for activating the alkene is
coordinated to a cobalt catalyst to generate the species I-1.
Scheme 5. Proposed Reaction Pathway
To gain more insights into the reaction mechanism, a series
of control experiments were carried out. Quenching experi-
ments showed that the excited photocatalyst *PC could be
effectively quenched by thiol b1, indicating an electron-transfer
process between b1 and *PC (Figure S1). Furthermore, when
a radical inhibitor (2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO)) was added, the desired product was completely
inhibited, and the TEMPO-trapped thiyl radical adduct was
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A thiol is oxidized by the excited photocatalyst *PC to
generate the thiyl radical cation and the one-electron-reduced
photocatalyst PC•−. Then, single-electron transfer from PC•−
to I-1 regenerates the photoredox cycle and leads to the
formation of Co(II) species I-2. Deprotonation of the thiyl
radical cation generates a thiyl radical, which is added to I-2 to
form the cobalt sulfide intermediates I-3. The subsequent
migration insertion of cobalt sulfide to the alkene produces
intermediate I-4 with exclusive Markovnikov selectivity. The
final protonation of I-4 furnishes the desired product and
regenerates the cobalt-catalyzed cycle.
In summary, we have described a photoredox/cobalt-
catalyzed strategy for the challenging catalytic Markovnikov-
type thiol-ene reaction with excellent regioselectivity. The
protected amine group as the directing group plays an
important role in this reaction. This catalytic system shows
mild reaction conditions, good functional group tolerance, and
excellent atom economy. The gram-scale synthesis demon-
strates the practicability of the strategy. Applications of this
strategy to the hydrothiolation of more challenging alkenes are
ongoing in our laboratory.
Hanshan Normal University, Chaozhou, Guangdong
521041, P. R. China
Hong Zhang − Department of Chemistry, Key Laboratory for
Preparation and Application of Ordered Structural Materials
of Guangdong Province, and Chemistry and Chemical
Engineering Laboratory of Guangdong Province, Shantou
University, Shantou, Guangdong 515063, P. R. China
Jing-Hong Li − Department of Chemistry, Key Laboratory for
Preparation and Application of Ordered Structural Materials
of Guangdong Province, and Chemistry and Chemical
Engineering Laboratory of Guangdong Province, Shantou
University, Shantou, Guangdong 515063, P. R. China
Jing-Xin Jian − Department of Chemistry, Key Laboratory for
Preparation and Application of Ordered Structural Materials
of Guangdong Province, and Chemistry and Chemical
Engineering Laboratory of Guangdong Province, Shantou
University, Shantou, Guangdong 515063, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00999
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00999.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (21801163,
51973107), the STU Scientific Research Foundation for
Talents (NTF18003), the Chemistry and Chemical Engineer-
ing Guangdong Laboratory (1922003), the 2020 Li Ka Shing
Foundation Cross-Disciplinary Research Grant
(2020LKSFG05A), and the Guangdong Province Universities
and Colleges Pearl River Scholar Funded Scheme 2019
(GDUPS2019).
Experimental procedures, methods, characterization
data, and copies of the NMR spectra (PDF)
Accession Codes
CCDC 2041016 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.
REFERENCES
■
(1) (a) Jacob, C. A. Scent of Therapy: Pharmacological Implications
of Natural Products Containing Redox-Active Sulfur Atoms. Nat.
Prod. Rep. 2006, 23, 851. (b) Clayden, J.; MacLellan, P. Asymmetric
Synthesis of Tertiary Thiols and Thioethers. Beilstein J. Org. Chem.
2011, 7, 582.
AUTHOR INFORMATION
■
Corresponding Authors
(2) (a) Secrist, J. A.; Tiwari, K. N.; Riordan, J. M.; Montgomery, J.
A. Synthesis and Biological Activity of 2’-Deoxy-4’-Thio Pyrimidine
Nucleosides. J. Med. Chem. 1991, 34, 2361. (b) Ilardi, E. A.; Vitaku,
E.; Njardarson, J. T. Data-Mining for Sulfur and Fluorine: An
Evaluation of Pharmaceuticals To Reveal Opportunities for Drug
Design and Discovery. J. Med. Chem. 2014, 57, 2832. (c) Feng, M.;
Tang, B.; Liang, S. H.; Jiang, X. Sulfur Containing Scaffolds in Drugs:
Synthesis and Application in Medicinal Chemistry. Curr. Top. Med.
Chem. 2016, 16, 1200.
(3) (a) Mishra, A.; Ma, C.-Q.; Bäuerle, P. Functional Oligothio-
phenes: Molecular Design for Multidimensional Nanoarchitectures
and Their Applications. Chem. Rev. 2009, 109, 1141. (b) Hoyle, C. E.;
Lowe, A. B.; Bowman, C. N. Thiol-Click Chemistry: A Multifaceted
Toolbox for Small Molecule and Polymer Synthesis. Chem. Soc. Rev.
2010, 39, 1355. (c) Cinar, M. E.; Ozturk, T. Thienothiophenes,
Dithienothiophenes, and Thienoacenes: Syntheses, Oligomers,
Polymers, and Properties. Chem. Rev. 2015, 115, 3036.
Jian-Ji Zhong − Department of Chemistry, Key Laboratory for
Preparation and Application of Ordered Structural Materials
of Guangdong Province, and Chemistry and Chemical
Engineering Laboratory of Guangdong Province, Shantou
University, Shantou, Guangdong 515063, P. R. China;
orcid.org/0000-0001-5248-5538; Email: jjzhong@
stu.edu.cn
Qing-Xiao Tong − Department of Chemistry, Key Laboratory
for Preparation and Application of Ordered Structural
Materials of Guangdong Province, and Chemistry and
Chemical Engineering Laboratory of Guangdong Province,
Shantou University, Shantou, Guangdong 515063, P. R.
China; orcid.org/0000-0002-8125-9684;
Email: qxtong@stu.edu.cn
(4) (a) Hoyle, C. E.; Bowman, C. N. Thiol-Ene Click Chemistry.
Angew. Chem., Int. Ed. 2010, 49, 1540. (b) Sinha, A. K.; Equbal, D.
Thiol-Ene Reaction: Synthetic Aspects and Mechanistic Studies of an
Anti-Markovnikov-Selective Hydrothiolation of Olefins. Asian J. Org.
Chem. 2019, 8, 32.
(5) (a) Kondo, T.; Mitsudo, T.-a. Metal-Catalyzed Carbon-Sulfur
Bond Formation. Chem. Rev. 2000, 100, 3205. (b) Beletskaya, I. P.;
Ananikov, V. P. Transition-Metal-Catalyzed C-S, C-Se, and C-Te
Authors
Qian Xiao − Department of Chemistry, Key Laboratory for
Preparation and Application of Ordered Structural Materials
of Guangdong Province, and Chemistry and Chemical
Engineering Laboratory of Guangdong Province, Shantou
University, Shantou, Guangdong 515063, P. R. China;
School of Chemistry and Environmental Engineering,
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pubs.acs.org/OrgLett
Letter
Bond Formation via Cross-Coupling and Atom-Economic Addition
Reactions. Chem. Rev. 2011, 111, 1596. (c) Chauhan, P.; Mahajan, S.;
Enders, D. Organocatalytic Carbon-Sulfur Bond-Forming Reactions.
Chem. Rev. 2014, 114, 8807. (d) Wang, M.; Jiang, X. Sulfur-Sulfur
Bond Construction. Top. Curr. Chem. 2018, 376, 14.
(6) (a) ten Brummelhuis, N.; Diehl, C.; Schlaad, H. Thiol-Ene
Modification of 1,2-Polybutadiene Using UV Light or Sunlight.
Macromolecules 2008, 41, 9946. (b) Rissing, C.; Son, D. Y. Thiol-Ene
Reaction for the Synthesis of Multifunctional Branched Organo-
silanes. Organometallics 2008, 27, 5394.
(7) (a) Ipatieff, V. N.; Pines, H.; Friedman, B. S. Reaction of
Aliphatic Olefins with Thiophenol. J. Am. Chem. Soc. 1938, 60, 2731.
(b) Screttas, C. G.; Micha-Screttas, M. Markownikoff Two-Step
Hydrolithiation of α-Olefins. Transformation of Secondary and
Tertiary Alkyl Phenyl Sulfides to the Relevant Alkyllithium Reagents.
J. Org. Chem. 1979, 44, 713. (c) Belley, M.; Zamboni, R. Addition of
Thiols to Styrenes: Formation of Benzylic Thioethers. J. Org. Chem.
1989, 54, 1230.
(8) (a) Kanagasabapathy, S.; Sudalai, A.; Benicewicz, B. C.
Montmorillonite K 10-Catalyzed Regioselective Addition of Thiols
and Thiobenzoic Acids Onto Olefins: An Efficient Synthesis of
Dithiocarboxylic Esters. Tetrahedron Lett. 2001, 42, 3791. (b) Mosa-
feri, E.; Ripsman, D.; Stephan, D. W. The Air-Stable Carbocation Salt
[(MeOC6H4)CPh2][BF4] in Lewis Acid Catalyzed Hydrothiolation of
Alkenes. Chem. Commun. 2016, 52, 8291. (c) Taniguchi, N. Brønsted
Acid-Assisted Zinc-Catalyzed Markovnikov-Type Hydrothiolation of
Alkenes Using Thiols. J. Org. Chem. 2020, 85, 6528. (d) Wang, H.;
Lu, Q.; Chiang, C. W.; Luo, Y.; Zhou, J.; Wang, G.; Lei, A.
Markovnikov-Selective Radical Addition of S-Nucleophiles to
Terminal Alkynes through a Photoredox Process. Angew. Chem., Int.
Ed. 2017, 56, 595.
Chemistry Enabled by Visible Light-Induced Electron Transfer. Acc.
Chem. Res. 2016, 49, 2295. (g) Liu, Q.; Wu, L.-Z. Recent Advances in
Visible-Light-Driven Organic Reactions. Natl. Sci. Rev. 2017, 4, 359.
(h) Cai, B.-G.; Xuan, J.; Xiao, W.-J. Visible Light-Mediated C-P Bond
Formation Reactions. Sci. Bull. 2019, 64, 337. (i) Qi, X.-K.; Zhang,
H.; Pan, Z.-T.; Liang, R.-B.; Zhu, C.-M.; Li, J.-H.; Tong, Q.-X.; Gao,
X.-W.; Wu, L.-Z.; Zhong, J.-J. Photoinduced Synthesis of Fluorinated
Dibenz[b,e]azepines via Radical Triggered Cyclization. Chem.
Commun. 2019, 55, 10848. (j) Zhong, J.-J.; To, W.-P.; Liu, Y.; Lu,
W.; Che, C.-M. Efficient Acceptorless Photo-Dehydrogenation of
Alcohols and N-Heterocycles with Binuclear Platinum(II) Diphos-
phite Complexes. Chem. Sci. 2019, 10, 4883.
(18) (a) Li, Y.; Miyazawa, K.; Koike, T.; Akita, M. Alkyl- and Aryl-
Thioalkylation of Olefins with Organotrifluoroborates by Photoredox
Catalysis. Org. Chem. Front. 2015, 2, 319. (b) Timpa, S. D.; Pell, C. J.;
Ozerov, O. V. A Well-Defined (POCOP)Rh Catalyst for the Coupling
of Aryl Halides with Thiols. J. Am. Chem. Soc. 2014, 136, 14772.
(c) Li, Y.; Xie, W.; Jiang, X. Mechanistic Study of a Photocatalyzed C-
S Bond Formation Involving Alkyl/Aryl Thiosulfate. Chem. - Eur. J.
2015, 21, 16059. (d) Xu, J.; Boyer, C. Visible Light Photocatalytic
Thiol-Ene Reaction: An Elegant Approach for Fast Polymer
Postfunctionalization and Step-Growth Polymerization. Macromole-
cules 2015, 48, 520. (e) Healy, J.; Rasmussen, T.; Miller, S.; Booth, I.
R.; Conway, S. J. The Photochemical Thiol-Ene Reaction as a
Versatile Method for the Synthesis of Glutathione S-Conjugates
Targeting the Bacterial Potassium Efflux System Kef. Org. Chem.
Front. 2016, 3, 439. (f) Zalesskiy, S. S.; Shlapakov, N. S.; Ananikov, V.
P. Visible Light Mediated Metal-Free Thiol-Yne Click Reaction.
Chem. Sci. 2016, 7, 6740. (g) Wimmer, A.; König, B. Photocatalytic
Formation of Carbon-Sulfur Bonds. Beilstein J. Org. Chem. 2018, 14,
54. (h) Zhu, J.; Yang, W.-C.; Wang, X.-D.; Wu, L. Photoredox
Catalysis in C-S Bond Construction: Recent Progress in Photo-
Catalyzed Formation of Sulfones and Sulfoxides. Adv. Synth. Catal.
2018, 360, 386. (i) Li, Y.; Cai, J.; Hao, M.; Li, Z. Visible Light
Initiated Hydrothiolation of Alkenes and Alkynes Over ZnIn2S4.
Green Chem. 2019, 21, 2345.
(9) Castarlenas, R.; Di Giuseppe, A.; Pérez-Torrente, J. J.; Oro, L. A.
The Emergence of Transition-Metal-Mediated Hydrothiolation of
Unsaturated Carbon-Carbon Bonds: A Mechanistic Outlook. Angew.
Chem., Int. Ed. 2013, 52, 211.
(10) Weïwer, M.; Coulombel, L.; Dunach, E. Regioselective
̃
(19) (a) Tyson, E. L.; Ament, M. S.; Yoon, T. P. Transition Metal
Photoredox Catalysis of Radical Thiol-Ene Reactions. J. Org. Chem.
2013, 78, 2046. (b) Tyson, E. L.; Niemeyer, Z. L.; Yoon, T. P. Redox
Mediators in Visible Light Photocatalysis: Photocatalytic Radical
Thiol-Ene Additions. J. Org. Chem. 2014, 79, 1427. (c) Keylor, M. H.;
Park, J. E.; Wallentin, C.-J.; Stephenson, C. R. J. Photocatalytic
Initiation of Thiol-Ene Reactions: Synthesis of Thiomorpholin-3-
Ones. Tetrahedron 2014, 70, 4264. (d) Bhat, V. T.; Duspara, P. A.;
Seo, S.; Abu Bakar, N. S. B.; Greaney, M. F. Visible Light Promoted
Thiol-Ene Reactions Using Titanium Dioxide. Chem. Commun. 2015,
51, 4383. (e) Fadeyi, O. O.; Mousseau, J. J.; Feng, Y.; Allais, C.;
Nuhant, P.; Chen, M. Z.; Pierce, B.; Robinson, R. Visible-Light-
Driven Photocatalytic Initiation of Radical Thiol-Ene Reactions Using
Bismuth Oxide. Org. Lett. 2015, 17, 5756. (f) Zhao, G.; Kaur, S.;
Wang, T. Visible-Light-Mediated Thiol-Ene Reactions through
Organic Photoredox Catalysis. Org. Lett. 2017, 19, 3291. (g) Kaur,
S.; Zhao, G.; Busch, E.; Wang, T. Metal-Free Photocatalytic Thiol-
Ene/Thiol-Yne Reactions. Org. Biomol. Chem. 2019, 17, 1955.
(h) Limnios, D.; Kokotos, C. G. Photoinitiated Thiol-Ene ″Click″
Reaction: An Organocatalytic Alternative. Adv. Synth. Catal. 2017,
359, 323.
(20) (a) Chen, B.; Wu, L.-Z.; Tung, C.-H. Photocatalytic Activation
of Less Reactive Bonds and Their Functionalization via Hydrogen-
Evolution Cross-Couplings. Acc. Chem. Res. 2018, 51, 2512.
(b) Zhong, J.-J.; Meng, Q.-Y.; Chen, B.; Tung, C.-H.; Wu, L.-Z.
Visible Light Induced Cross-Coupling Hydrogen Evolution Reactions.
Huaxue Xuebao 2017, 75, 34. (c) Zhong, J.-J.; Meng, Q.-Y.; Liu, B.;
Li, X.-B.; Gao, X.-W.; Lei, T.; Wu, C.-J.; Li, Z.-J.; Tung, C.-H.; Wu, L.-
Z. Cross-Coupling Hydrogen Evolution Reaction in Homogeneous
Solution without Noble Metals. Org. Lett. 2014, 16, 1988. (d) Meng,
Q.-Y.; Zhong, J.-J.; Liu, Q.; Gao, X.-W.; Zhang, H.-H.; Lei, T.; Li, Z.-
J.; Feng, K.; Chen, B.; Tung, C.-H.; Wu, L.-Z. A Cascade Cross-
Coupling Hydrogen Evolution Reaction by Visible Light Catalysis. J.
Indium(III) Trifluoromethanesulfonate-Catalyzed Hydrothiolation
of Non-Activated Olefins. Chem. Commun. 2006, 42, 332.
(11) Brouwer, C.; Rahaman, R.; He, C. Gold(I)-Mediated
Hydrothiolation of Conjugated Olefins. Synlett 2007, 2007, 1785.
(12) Menggenbateer; Narsireddy, M.; Ferrara, G.; Nishina, N.; Jin,
T.; Yamamoto, Y. Gold-Catalyzed Regiospecific Intermolecular
Hydrothiolation of Allenes. Tetrahedron Lett. 2010, 51, 4627.
(13) Cabrero-Antonino, J. R.; Leyva-Pérez, A.; Corma, A. Iron-
Catalysed Markovnikov Hydrothiolation of Styrenes. Adv. Synth.
Catal. 2012, 354, 678.
(14) (a) Tamai, T.; Ogawa, A. Regioselective Hydrothiolation of
Alkenes Bearing Heteroatoms with Thiols Catalyzed by Palladium
Diacetate. J. Org. Chem. 2014, 79, 5028. (b) Tamai, T.; Fujiwara, K.;
Higashimae, S.; Nomoto, A.; Ogawa, A. Gold-Catalyzed Anti-
Markovnikov Selective Hydrothiolation of Unactivated Alkenes. Org.
Lett. 2016, 18, 2114.
(15) Xi, H.; Ma, E.; Li, Z. Copper-Catalyzed Selective Syntheses of
Markovnikov-Type Hydrothiolation Products and Thioacetals by the
Reactions of Thiols with Alkenes Bearing Heteroatoms. Tetrahedron
2016, 72, 4111.
(16) Taniguchi, N. Brønsted Acid-Assisted Zinc-Catalyzed Markov-
nikov-Type Hydrothiolation of Alkenes Using Thiols. J. Org. Chem.
2020, 85, 6528.
(17) (a) Zeitler, K. Photoredox Catalysis with Visible Light. Angew.
Chem., Int. Ed. 2009, 48, 9785. (b) Yoon, T. P.; Ischay, M. A.; Du, J.
Visible Light Photocatalysis as a Greener Approach to Photochemical
Synthesis. Nat. Chem. 2010, 2, 527. (c) Xuan, J.; Xiao, W. J. Visible-
Light Photoredox Catalysis. Angew. Chem., Int. Ed. 2012, 51, 6828.
(d) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light
Photoredox Catalysis with Transition Metal Complexes: Applications
in Organic Synthesis. Chem. Rev. 2013, 113, 5322. (e) Romero, N. A.;
Nicewicz, D. A. Organic Photoredox Catalysis. Chem. Rev. 2016, 116,
10075. (f) Staveness, D.; Bosque, I.; Stephenson, C. R. J. Free Radical
3608
https://doi.org/10.1021/acs.orglett.1c00999
Org. Lett. 2021, 23, 3604−3609

Organic Letters
pubs.acs.org/OrgLett
Letter
Am. Chem. Soc. 2013, 135, 19052. (e) He, K. H.; Li, Y. Oxidant-Free
Dehydrogenative Coupling Reactions via Hydrogen Evolution.
ChemSusChem 2014, 7, 2788. (f) Wang, H.; Gao, X.; Lv, Z.;
Abdelilah, T.; Lei, A. Recent Advances in Oxidative R1-H/R2-H
Cross-Coupling with Hydrogen Evolution via Photo-/Electrochemis-
try. Chem. Rev. 2019, 119, 6769. (g) Zhang, H.; Xiao, Q.; Qi, X.-K.;
Gao, X.-W.; Tong, Q.-X.; Zhong, J.-J. Selective Photoredox
Decarboxylation of α-Ketoacids to Allylic Ketones and 1,4-Dicarbonyl
Compounds Dependent on Cobaloxime Catalysis. Chem. Commun.
2020, 56, 12530.
(21) For detailed information, see the SI and CCDC no. 2041016.
(22) (a) Zhao, Q.-Q.; Chen, J.; Zhou, X.-S.; Yu, X.-Y.; Chen, J.-R.;
Xiao, W.-J. Photogenerated Neutral Nitrogen Radical Catalyzed
Bifunctionalization of Alkenes. Chem. - Eur. J. 2019, 25, 8024.
(b) Zhao, Q.-Q.; Li, M.; Xue, X.-S.; Chen, J.-R.; Xiao, W.-J. Visible-
Light-Driven Neutral Nitrogen Radical Mediated Intermolecular
Styrene Difunctionalization. Org. Lett. 2019, 21, 3861. (c) Yu, X.-
Y.; Zhao, Q.-Q.; Chen, J.; Xiao, W.-J.; Chen, J.-R. Visible-Light-
Driven Neutral Nitrogen Radical Mediated Intermolecular Styrene
Difunctionalization. Acc. Chem. Res. 2020, 53, 1066.
3609
https://doi.org/10.1021/acs.orglett.1c00999
Org. Lett. 2021, 23, 3604−3609