Visible-Light-Mediated Thiol-Ene Reactions through Organic Photoredox Catalysis

Article abstract of DOI:10.1021/acs.orglett.7b01441

Synthetically useful radical thiol-ene reactions can be initiated by visible-light irradiation in the presence of an organic photocatalyst, 9-mesityl-10-methylacridinum tetrafluoroborate. The key thiyl radical intermediates are generated upon quenching of

Full text of DOI:10.1021/acs.orglett.7b01441

Letter
pubs.acs.org/OrgLett
Visible-Light-Mediated Thiol−Ene Reactions through Organic
Photoredox Catalysis
Gaoyuan Zhao, Sarbjeet Kaur, and Ting Wang*
Department of Chemistry, University at Albany, State University of New York, 1400 Washington Avenue, Albany, New York 12222,
United States
S
* Supporting Information
ABSTRACT: Synthetically useful radical thiol−ene reactions can be initiated by visible-light irradiation in the presence of an
organic photocatalyst, 9-mesityl-10-methylacridinum tetrafluoroborate. The key thiyl radical intermediates are generated upon
quenching of the photoexcited catalyst with a variety of thiols. The success of this method requires only the use of near-
stoichiometric levels of alkene coupling partners. Using these highly efficient metal-free conditions, thiol−ene reactions between
carbohydrates and peptides can be accomplished in excellent yields.
Scheme 1. Radical Thiol−Ene Reactions
arbon−sulfur bond-forming reactions are synthetically
Cimportant because organosulfur moieties are widely
represented within natural products, pharmaceuticals, and
modern materials.1,2 Among various carbon−sulfur bond
formations, the thiol−ene reaction, a radical addition of thiols
to olefins, is arguably one of the most powerful current methods
because of its widespread employment in areas of bioconjugate
chemistry, polymer science, and pharmaceutical chemistry.3,4
This atom-economical process provides efficient and selective
access to anti-Markovnikov thioethers, fulfilling the “click”
chemistry concept.5 Traditionally, the radical thiol−ene reaction
is promoted by UV light or a radical initiator (Scheme 1).4d
However, it either needs stoichiometric reagents or requires
expensive specialized UV photochemical equipment. Recently,
Yoon6 and Stephenson7 reported the transition-metal-mediated
photoredox catalysis of thiol−ene reactions driven by household
visible-light sources as a convenient alternative to UV irradiation
(Scheme 1). In addition, other catalyst types, such as TiO2,8 have
shown the ability to promote thiol−ene reactions when
combined with visible-light irradiation.9 The visible-light photo-
redox catalysis approach to thiol−ene chemistry provides a
significantly milder reaction medium that could be potentially
useful in bioconjugation and polymer synthesis.10
radical initiator) and transition-metal-mediated approaches. In
particular, a metal-free process could potentially benefit peptide
and glycoprotein chemistry, since certain polypeptide sequences
and proteins have been shown to interfere with transition-metal-
mediated processes.15
To test the idea, we started our investigations by examining the
thiol−ene reaction between benzyl mercaptan (1) (Er1e/d2 = +0.45
V vs SCE)16 and allyl alcohol (2) (Table 1). After a survey of
2+
In the works by Yoon and Stephenson, both Ru(bpy)32+
(E [*RuII/RuI] = +0.77 V vs SCE) and Ru(bpz)3
red
1/2
11
red
(E [*RuII/RuI] = +1.35 V vs SCE) were extensively studied.
1/2
Interested in seeking a metal-free opportunity,12 we report herein
that a more powerful oxidizing organic catalyst, 9-mesityl-10-
red
1/2
methylacridinum tetrafluoroborate (E = +2.06 V vs SCE in
MeCN), can serve as an effective visible-light photoinitiator of
the thiol−ene reaction (Scheme 1).13,14 This photoredox process
driven by an organic photocatalyst is synthetically complemen-
tary to both traditional (using UV irradiation or thermolysis of a
Received: May 11, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01441
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization Studies for the Thiol−Ene Reaction of
Table 3. Scope of Alkenes
a
Benzyl Mercaptan with Allyl Alcohol
b
entry
catalyst
yield (%)
1
2
3
4
5
6
7
8
9
A
B
C
90
83
69
80
0
rhodamine 6G
riboflavin
eosin Y
30
33
0
rose bengal
methylene blue
none
0
c
10
A
0
a
Reactions were conducted by irradiating 1 (0.5 mmol), 2 (0.6 mmol),
and the photocatalyst (1 mol %) in MeCN (1 mL) with two 12 W,
b
c
450 nm LED floodlamps for 6 h. Isolated yields. The reaction was
conducted in the dark.
a
Table 2. Scope of Thiols
a
Reactions were conducted by irradiating benzyl mercaptan (0.5
mmol), the alkene (0.6 mmol), and photocatalyst A (1 mol %) in
MeCN (1 mL) with two 12 W, 450 nm LED floodlamps for 6 h.
b
Isolated yields.
organic photocatalysts (entries 1−8), we were pleased to observe
that 9-mesityl-10-methylacridinum tetrafluoroborate (A) suc-
cessfully initiated the photocatalytic thiol−ene reaction under
blue light-emitting diode (LED) irradiation, providing the thiol−
ene adduct 3 in 90% isolated yield. It is worth noting that only a
minimal excess of alkene (1.2 equiv) is required for full
conversion of thiol to product. In addition, MeCN was found
to be the optimal solvent after careful screening of various
solvents (CH2Cl2, DMF, DMSO, THF, 1,4-dioxane, MeOH, and
toluene). Control experiments (entries 9 and 10) verified that
both the catalyst and the LED irradiation are necessary.
Encouraged by these results, we next focused our attention on
exploring the scope of the photocatalytic thiol−ene reaction.
Table 2 summarizes experiments probing a variety of thiols that
can be activated using the optimized conditions. Primary thiols
such as benzyl mercaptan (entry 1), p-methoxybenzyl mercaptan
(entry 2), methyl thioglycolate (entry 3), and a protected
cysteine derivative (entry 4) reacted with allyl alcohol efficiently
to generate hydrothiolated products in high yields. Secondary
thiols such as cyclohexyl mercaptan (entry 5) and 1-phenylethyl
mercaptan (entry 6) also produced thiol−ene adducts
successfully. Happily, even sterically encumbered tert-butyl
mercaptan (entry 7) and 1-adamantylthiol (entry 8) afforded
good yields. In addition, aromatic thiols such as thiophenol
(entry 9) were converted into the corresponding aryl thioethers
in high yield under these conditions.
a
Reactions were conducted by irradiating the thiol (0.5 mmol), allyl
alcohol (0.6 mmol), and photocatalyst A (1 mol %) in MeCN (1 mL)
with two 12 W, 450 nm LED floodlamps for 6 h. Isolated yields.
b
B
DOI: 10.1021/acs.orglett.7b01441
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Next, we evaluated the scope of alkenes that can participate in
this coupling process (Table 3). Both styrene and aliphatic
alkenes reacted smoothly under these reaction conditions
(entries 1 and 2). We were pleased to find that both 1,1-
disubstituted (entry 3) and 1,2-disubstituted (entries 4 and 5)
alkene substrates underwent successful thiol−ene reaction with
benzyl mercaptan. In all cases, high anti-Markovnikov
regioselectivity was observed, which is consistent with the
proposed radical reaction process. Moreover, this radical thiol−
ene process is compatible with a variety of functional groups, as
ester (entry 6), formyl amide (entry 7), alcohol (entry 8), and
silane (entry 9) are tolerated under these conditions.
Scheme 2. Visible-Light-Mediated Thiol−Ene Conjugations
Having demonstrated the high efficiency of the visible-light-
mediated thiol−ene reaction, we next investigated the
applicability of this chemistry to enable the synthesis of
glycoconjugates between glycosyl thiols and amino acid
derivatives (Scheme 2). Glycoconjugates have become impor-
tant tools for the exploration of many biological processes,17,18
and more recently, S-linked glycoconjugates have become
promising analogues of glycopeptides and glycoproteins because
of their enhanced chemical stability and enzymatic resist-
ance.19,20 Happily, the thiol−ene reaction between an aspartic
acid derivative and a variety of glycosyl thiols occurred smoothly
(Scheme 2a), giving the corresponding S-linked glycoconjugates
4−7 in good yields. More complex examples serve to
demonstrate the potential utility of this method for bioconju-
gation. We observed efficient coupling of glucose thiol with a
nucleoside derivative and an N-terminus-functionalized dipep-
tide, affording S-linked glyconucleoside 8 and glycopeptide 9 in
yields of 78% and 79%, respectively. The reverse fashion of
coupling between a protected cysteine derivative and a variety of
alkenes also provided excellent yields of the conjugated products
10−13 (Scheme 2b).
A reasonable mechanism for the reaction is outlined in Scheme
3. Photoexcitation of catalyst A provides a strongly oxidizing state
(A*) that can oxidize a thiol to generate the thiyl radical cation
and one-electron-reduced acridinium 14. The proposed
preference for oxidation of the thiol over the alkene relies on
the difference in their reduction potentials.14o,16 Deprotonation
of the radical cation generates a thiyl radical, which couples to the
alkene with anti-Markovnikov selectivity. The resulting alkyl
radical then abstracts a hydrogen atom from an unreacted thiol to
afford the thiol−ene product and generate another equivalent of
thiyl radical. However, the light irradiation is necessary for the
reaction to reach completion on the basis of our experimental
results (Scheme S1 in the Supporting Information). It is likely
that the catalyst is reoxidized by a molecule of oxygen,
regenerating the photoactive catalyst A.
Scheme 3. Proposed Mechanism
In summary, we have reported a visible-light-promoted radical
thiol−ene reaction using catalytic amounts of 9-mesityl-10-
methylacridinum tetrafluoroborate. This highly efficient reaction
shows scope generality, as demonstrated by the use of a variety of
thiols and alkenes to provide thioethers in excellent yields.
Moreover, this method demonstrates promise for future
glycoprotein studies through the successful generation of
model glycoconjugates. Applications of this thiol−ene reaction
in more complicated bioconjugate settings are ongoing in our
laboratory.
C
DOI: 10.1021/acs.orglett.7b01441
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Organic Letters
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01441.
A.; Nguyen, T. M. ACS Catal. 2014, 4, 355. (b) Fukuzumi, S.; Ohkubo,
K. Org. Biomol. Chem. 2014, 12, 6059. (c) Hari, D. P.; Konig, B. Chem.
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A. C.; Elliott, K. J.; Harrington, R. W.; Clegg, W. Eur. J. Org. Chem. 2009,
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: twang3@albany.edu.
ORCID
́
2009, 253. (c) Joshi-Pangu, A.; Levesque, F.; Roth, H. G.; Oliver, S. F.;
Campeau, L.; Nicewicz, D. A.; DiRocco, D. A. J. Org. Chem. 2016, 81,
7244.
Ting Wang: 0000-0001-7630-4148
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the University at Albany, State University of
New York, for financial support. We thank Prof. Alexander
Shekhtman (SUNY-Albany) and Prof. Zhang Wang (SUNY-
Albany) for NMR assistance. We also thank Dr. Andrew Roberts
(Memorial Sloan-Kettering Cancer Center) for helpful dis-
cussion and proofreading of the manuscript. The other Dr. Ting
Wang is acknowledged for help in preparing this article.
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