Visible-light-promoted synthesis of diaryl sulfides under air

Article abstract of DOI:10.1016/j.tetlet.2017.06.006

A convergent, organocatalytic visible-light-mediated process for the synthesis of diaryl sulfides has been developed. A broad range of aryl thiols reacted with various aryl diazonium salts in the presence of eosin Y under air atmosphere to afford the desired diaryl sulfides in high yields. This novel and environmentally friendly method provides an alternative route to established synthetic approaches.

Full text of DOI:10.1016/j.tetlet.2017.06.006

Tetrahedron Letters xxx (2017) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Visible-light-promoted synthesis of diaryl sulfides under air
Boseok Hong a, Juyoung Lee a, Anna Lee a,b,
⇑
a Department of Chemistry, Myongji University, Yongin 17058, Republic of Korea
b Department of Energy Science and Technology, Myongji University, Yongin 17058, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A convergent, organocatalytic visible-light-mediated process for the synthesis of diaryl sulfides has been
developed. A broad range of aryl thiols reacted with various aryl diazonium salts in the presence of eosin
Y under air atmosphere to afford the desired diaryl sulfides in high yields. This novel and environmentally
friendly method provides an alternative route to established synthetic approaches.
Ó 2017 Elsevier Ltd. All rights reserved.
Received 29 April 2017
Revised 27 May 2017
Accepted 2 June 2017
Available online xxxx
Keywords:
Organo-photocatalysis
Diaryl sulfides
Thiols
Introduction
diazonium salts and thiolates.13 In these studies, the reactions
were performed carefully under nitrogen since the intermediate
Sulfur-containing compounds are found in numerous natural
products and pharmaceuticals.1 In particular, diaryl sulfides and
their derivatives are important structural motifs in natural and
synthetic molecules and have shown interesting biological activi-
ties such as HIV protease inhibition, anti-hepatitis C activity,
anti-depression activity, anti-inflammatory and anti-histamine
properties (Scheme 1).1e,2 Moreover, diaryl sulfides have been
employed as organic materials in the field of materials science.3
Furthermore, they are precursors to other sulfur-containing com-
pounds comprising higher-oxidation state-sulfur, which have sim-
ilar important bioactive properties.2f,4
Given the significance of these compounds as important struc-
tural scaffolds in natural products and drug candidates, it is very
important to develop an efficient process for synthesizing diaryl
sulfides. Previous approaches for the synthesis of diaryl sulfides
utilized various transition metals such as Pd,5 Cu,1d,6 Fe,7 Ni,8
Rh,9 Co10 and In.11 These methods provide powerful tools for the
synthesis of diaryl sulfides. However, metal-catalyzed reactions
have some limitations such as using expensive and/or toxic metal
catalysts and sensitive or harsh reaction conditions. A number of
metal-free processes were also investigated; for example, conden-
sation of arenethiols with aryl halides, and nucleophilic substitu-
tion of activated aryl halides with thiols.12 Early studies for the
synthesis of diaryl sulfides reported by the Petrillo group used
metal-free processes that included the use of various aryl
diazosulfide is a potent explosive.
Recently, metal-free CAH thioarylation of electron rich arenes
and heteroarenes using electrophilic sulfur reagents such as sul-
fonyl chlorides,14 sulfonyl hydrazines,15 N-(thio)succinimides,16
sodium sulfinates,17 thiols,18 disulfides,19 sulfoxides2f and
others20 has been developed. Despite these recent advances, a
direct process for the synthesis of diaryl sulfides via photocatalysis
would offer a complementary strategy to the existing synthesizing
methods.
Recently, visible-light-mediated photoredox catalysis has
emerged as a powerful tool in organic synthesis. Ruthenium and
iridium polypyridyl complexes are widely employed in visible light
photocatalysis with great reported success.21 However, based on
the limitations of utilizing transition metals, the development of
green activation modes in photoredox system is very important.
Organic dyes have been used as an attractive alternative to transi-
tion metal photoredox catalysts;22 especially, eosin Y was widely
employed as an organocatalyst in various photoredox processes.23
Herein, we report a mild convergent approach for the synthesis of
diaryl sulfides in the presence of eosin Y via visible light photo-
catalysis (Scheme 2).
Results and discussion
To develop a metal-free protocol, we designed a reaction model
with thiophenol 1a and 4-methoxybenzenediazonium tetrafluo-
roborate 2a in the presence of organo-photocatalysts at room tem-
perature under air atmosphere (Table 1). Various organic dyes
⇑
Corresponding author at: Department of Chemistry, Department of Energy
Science and Technology, Myongji University, Yongin 17058, Republic of Korea.
E-mail address: annalee@mju.ac.kr (A. Lee).
http://dx.doi.org/10.1016/j.tetlet.2017.06.006
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Hong B., et al. Tetrahedron Lett. (2017), http://dx.doi.org/10.1016/j.tetlet.2017.06.006

2
B. Hong et al. / Tetrahedron Letters xxx (2017) xxx–xxx
reaction yield; other solvents such as acetonitrile, dimethylfor-
mamide, methanol and tetrahydrofuran resulted in lower yields
(entries 6–9). Poor conversion was observed when the reaction
was performed in the absence of either the photocatalyst or light
(entries 13 and 14). Furthermore, we carried out the reaction under
nitrogen atmosphere where low yield was observed (entry 15).
These results indicated that photocatalyst, visible light, and air
are necessary for this transformation process.
Scheme 1. The diaryl sulfide moiety in bioactive compounds.
After determining the optimized reaction conditions, the scope
of this transformation was explored (Table 2). The reaction was
found to tolerate a wide range of aromatic thiols and aryl diazonium
salts to afford the desired diaryl sulfides in good to high yields.
Both electron-rich and electron-deficient aryl thiols provided
the products in high yields (82–91%, 3d–3k, 3m–3n, 3p–3q, 3s–
3t). Ortho and meta-substituted aryl diazonium salts were well-
tolerated as well (82–88%, 3b–3c, 3e–3f, 3h–3i). Electron-deficient
Table 2
Substrate scope.a
Scheme 2. Strategies for the synthesis of diaryl sulfides.
Table 1
Optimization of reaction conditions.a
Entry
Catalyst (mol%)
Solvent
Yield (%)b
1c
2c
3
4
5
Rose Bengal (5)
Rose Bengal (5)
Rose Bengal (5)
Rhodamin B (5)
Rhodamin B (5)
Eosin Y (5)
CH3CN
DMF
DMF
CH3CN
DMF
CH3CN
DMF
10
30
31
Trace
Trace
37
6
7
Eosin Y (5)
51
8
Eosin Y (5)
THF
35
9
Eosin Y (5)
Eosin Y (5)
Eosin Y (2)
Eosin Y (4)
Eosin Y (5)
None
Eosin Y (5)
MeOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
33
90
68
84
10
11
13
10
11
12
13d
14
15e
a
Conditions: 1a (0.5 mmol, 1.0 equiv), 2a (1.2 equiv), catalyst, solvent (0.2 M) at
23 °C for 5 h.
b
Yields are of isolated product after column chromatography.
The reaction was conducted under blue LED light irradiation.
The reaction was performed in the dark.
c
d
e
The reaction was conducted under N2 atmosphere.
including rose bengal, eosin Y, and rhodamine B were examined.
The reaction yield was low in the case of rose bengal (entries 1–
3). Eosin Y was found to be more effective for this transformation,
with a 90% yield for the desired product 3a (entry 10). In the case of
solvents, dimethyl sulfoxide provided the best results in terms of
a
Reactions conducted on 0.5 mmol scale. Yields are of isolated product after
column chromatography. For details, see the Supporting Information.
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B. Hong et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
aryl diazonium salts also afforded the products in high yields (83–
92%, 3n–3p). Similarly, a heteroaromatic thiol starting compound
was employed successfully, even though the reaction yield was
slightly decreased (68%, 3r). Naphthyl diazonium salts were also
suitable substrates for this reaction, the desired products were
obtained in high yields (82–85%, 3s–3t).
Next, a scale-up synthesis of diaryl sulfide 3a was carried out
(Scheme 3). The reaction turned out to be scalable and practical
as the gram-scale reaction was equally efficient. The reaction of
thiophenol 1a (10.0 mmol, 1.0 equiv, 1.1 g) and 4-methoxyben-
zenediazonium tetrafluoroborate 2a (12.0 mmol, 1.2 equiv) pro-
vided the desired product 3a in 84% yield under optimized
reaction conditions.
To gain mechanistic insights, some control experiments were
carried out (Scheme 4). First, TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy) and BHT (butylated hydroxytoluene) were
employed in the reaction as radical inhibitors. These conditions
did not provide the desired product (Scheme 4). A similar reaction
yield was obtained when we carried out the reaction under oxygen
atmosphere (88% yield). On the other hand, when the reaction was
carried out under nitrogen atmosphere, the reaction was sup-
pressed severely and the yield of 3a decreased from 90% to 13%
(Scheme 4). Thus, these results suggest that radical intermediates
and oxygen would be involved during the reaction.
Scheme 6. Synthetic transformations. Reagents: (a) BBr3, CH2Cl2; (b) Oxone,
MeOH/H2O; (c) BBr3, CH2Cl2.
excited state species EY⁄, which interacts with O2 to generate sin-
glet oxygen (1O2) via energy transfer.24b,g Subsequently, the singlet
oxygen abstracts a hydrogen atom from thiol to produce thiyl
radical II,24e which reacts with aryl radical IV generated from aryl
diazonium salt III to produce the desired diaryl sulfide V (Path
A). On the other hand, the thiyl radical II could also be generated
through a one-electron oxidation process of thiol (Path B). The
oxidized species I by the eosin Y radical cation could react with
O2ꢀ–, which is generated from HOÅ2 to provide thiyl radical II for
further reaction with aryl radical IV to produce the desired
product V.
To demonstrate the importance of this transformation, the dia-
ryl sulfide product 3s was converted into 4-(naphthalen-1-ylthio)
phenol 4 and sulfone 5, which are analogues of amyloid aggrega-
tion inhibitors (Scheme 6).25 Aryl sulfones have also been known
as important scaffolds due to their bioactive properties.4,25,26 By
oxidation of 3s followed by demethylation, the desired sulfone 5
was easily obtained in high yields.
The proposed reaction mechanisms based on our results and
previous reports24 are shown in Scheme 5.
Two plausible reaction pathways are hypothesized. First, eosin
Y (EY) is excited under visible light irradiation to generate its
Conclusion
We have developed a highly efficient and environment-friendly
method for the synthesis of diaryl sulfides via organic photocatal-
ysis. This new method is operationally simple and allows a rapid
access to diaryl sulfides. The reaction is easy to perform and pro-
vides a convenient process for the synthesis of bioactive compound
scaffolds. Further studies on synthetic applications of this transfor-
mation are ongoing in our laboratories and the results will be dis-
closed in the near future.
Scheme 3. Scalability of the reaction of thiophenol 1a with 4-methoxybenzenedi-
azonium tetrafluoroborate 2a.
Acknowledgments
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education (2016R1D1A1B03931335) and the
Korea Institute of Energy Technology Evaluation and Planning
(KETEP) and the Ministry of Trade, Industry & Energy (MOTIE) of
the Republic of Korea (No. 20174010201160).
A. Supplementary data
Scheme 4. Control experiments.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.06.006.
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