Metal-Free Cercosporin-Photocatalyzed C-S Coupling for the Selective Synthesis of Aryl Sulfides under Mild Conditions

Article abstract of DOI:10.1002/ejoc.201901444

Aryl sulfides are important motifs of bioactive molecules, which are generally synthesized by transition metal-based coupling reactions under harsh conditions. Herein, we developed a new method that visible light along with cercosporin, produced by liquid fermentation and functioned as a cost-effective and environmentally friendly photocatalyst, prompted the selective synthesis of aryl sulfides through C–S coupling of thiols and diazonium salts under mild conditions. Furthermore, this method can also be performed with a great conversion by the direct use of cercosporin-containing fermentation supernatant as catalytic system without organic solvent extraction.

Full text of DOI:10.1002/ejoc.201901444

A Journal of
Accepted Article
Title: Metal-free Cercosporin-photocatalyzed C-S Coupling for the
Selective Synthesis of Aryl Sulfides under Mild Conditions
Authors: Yijian Rao, Jia Li, Wenhao Bao, and Yan zhang
This manuscript has been accepted after peer review and appears as an
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901444
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901444
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201901444
COMMUNICATION
Metal-free Cercosporin-photocatalyzed C-S Coupling for the
Selective Synthesis of Aryl Sulfides under Mild Conditions
Jia Li, Wenhao Bao, Yan Zhang and Yijian Rao*[a]
[
a]
[a]
*[b]
Abstract: Aryl sulfides are important motifs of bioactive molecules,
which are generally synthesized by transition metal-based coupling
reactions under harsh conditions. Herein, we developed a new
C-S coupling reaction for the synthesis of aryl sulfide derivatives
(Scheme 1), which are significant motifs of various unnatural
bioactive molecules with anti-tumor, anti-HIV, anti-hepatitis C,
method that visible light along with cercosporin, produced by liquid
fermentation and functioned as a cost-effective and environmentally
friendly photocatalyst, prompted the selective synthesis of aryl
sulfides through C-S coupling of thiols and diazonium salts under
mild conditions. Furthermore, this method can also be performed
with a great conversion by the direct use of cercosporin-containing
fermentation supernatant as catalytic system without organic solvent
extraction.
anti-depression,
anti-inflammatory,
anti-histamine
and
8
antagonists bioactivities. Moreover, aryl sulfides have also been
widely used as precursors for the synthesis of higher-oxidation
state sulfoxide and sulfones, which are important skeletons of
9
10
bioactive molecules.
N
2
BF
4
R
1
O
OH
MeO
OH
Introduction
O
O
C-C coupling
C-S coupling
this work
Photocatalysis, driven by abundant, cheap and renewable light
sources, has expanded rapidly in the synthetic community to
promote various chemical reactions.1 During most of the
photocatalysis processes, highly reactive radical ions are
generated through the photo-induced electron transfer (PET)
process by using various photocatalysts, which facilitate
OH
our previous work
MeO
O
OH
R
2
R
3
.
SH
S
R
1
R2
H
R
1
R
3
R
1
2
reactions that are otherwise difficult to proceed. Among them,
Scheme 1. Cercosporin photo-catalyzed coupling reactions
metal-based photocatalysts, such as ruthenium and iridium
polypyridyl complexes, are most widely employed.3 However,
the metal-based photocatalysts have the limitation of high cost
and environmentally unfavourable outcomes. Thus, it is still
highly desired to develop green and cost-effective metal-free
photocatalysts.4
Traditionally, aryl sulfides were synthesized via Pd, Cu,12
1
1
Ni,13 Co, Fe, In -catalyzed coupling reactions, which were
achieved through (a) coupling of thiols with aryl halides, aryl
boronic acid or aryl triflates, (b) coupling of aryl halides with
thiocyanates, amines or aryltriazenes. However, these methods
suffered from utilizing toxic or expensive metal-based catalysts
and harsh reaction conditions including high temperatures and
addition of quantitative strong bases. In recent years,
photoredox catalysis has been expanded rapidly as an efficient
alternative method for the construction of various valuable aryl
sulfides through coupling reactions. However, most of them were
achieved with transition metal-based photocatalysts under mild
conditions.17 Thus, it is highly desired to develop a green and
metal-free photocatalytic system for the synthesis of aryl sulfide.
As aryl diazonium salts were idea candidates as precursors,
which could be easily prepared and transformed to aryl
radicals,17g herein, we developed a new method that cercosporin
employed as a metal-free photocatalyst to catalyze the synthesis
of aryl sulfides through reaction of thiols and aryl diazonium salts
under mild conditions (Scheme 1). Furthermore, a gram-scale
conversion of this C-S coupling reaction was achieved by using
cercosporin-containing fermentation supernatant with a small
amount of organic solvent, thus, showing the advantage of
cercosporin as a green and eco-friendly photocatalyst.
14
15
16
As one of the naturally-occurring perylenequinonoid
pigments, cercosporin (CP) has attracted considerable attention
owing to its excellent property of strong light absorption and the
ability of generating active oxygen species. Although its
photophysical and photobiological properties have been the
focus of great interests,5 its photoredox reactivity has been
rarely reported.7 Recently, our group has successfully
biosynthesized cercosporin through liquid fermentation method
-6
7
in a cheap and abundant manner. Then we have utilized it as a
metal-free photocatalyst to drive the C-C coupling reactions of
aryl diazonium salts and (het)arenes under mild conditions.7b
Here, we attempt to apply cercosporin as a photocatalyst in the
[
[
a]
Dr. Jia Li, Wenhao, Bao, Prof. Dr. Yijian Rao
Key Laboratory of Carbohydrate Chemistry and Biotechnology,
Ministry of Education, School of Biotechnology, Jiangnan University
Wuxi 214122, P. R. China
E-mail: raoyijian@jiangnan.edu.cn
Homepage: http://biotech.jiangnan.edu.cn/info/1014/5160.htm
Asso. Prof. Dr. Yan Zhang
b]
School of Pharmaceutical Science, Jiangnan University
Wuxi 214122, P. R. China
E-mail: zhangyan@jiangnan.edu.cn
Supporting information for this article is given via a link at the end of
the document
Results and Discussion
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European Journal of Organic Chemistry
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COMMUNICATION
We initiated our investigation by optimizing the reaction
the synthesis of aryl sulfide was proved to be suitable with
various thiols (Table 2). The aryl sulfide products could be
obtained with para-substitution of methyl- (3a-3k), tetrabutyl- (3l,
3m), bromo- (3n-3r) and chloro- (3s) groups on phenyl ring of
the thiols, with medium to excellent yields. Thiols with steric
hindrance at ortho- position also delivered excellent yields (3n,
3o, 3t, 3u). Additionally, a wide range of aryl diazonium salts
bearing electron donating (-OMe, -SMe) groups and electron-
conditions
using
4-methylbenzenethiol
1a
and
4-
methoxybenzenediazonium tetrafluoroborate 2a as the module
substrates. The reaction was first conducted at room
temperature with 15W CFL light irradiation under air atmosphere
in CH
entry 1). Next, various solvents, such as CH
THF, CH CN and DMSO (Table 1, entries 2-8), were tested.
3
OH, but giving the desired product with low yield (Table 1,
2
Cl , CHCl , EtOH,
2
3
3
Only, the condition in DMSO solvent selectively afforded the
2
accepting groups (-Cl, -Br, -NO , -EtOCO, -CN, -CHO) could
sulfide product 3a with a satisfactory yield of 87% (Table 1, entry
also tolerate well in this reaction, supplying the desired aryl
products with 52-96 % yields (Table 2).
8
). We then conducted this reaction under O
or N (Table 1, Entry 10) atmosphere, respectively, and found
that both of them gave slightly lower yields for the product 3a.
Since changing the atmosphere from air to O or N had
negligible effect on the reaction, it is reasonable to conclude that
was not involved in the reaction. Interestingly, the formation
of sulfoxide or sulfone was not observed even under O
2
(Table 1, Entry 9)
2
Considering cercosporin was biosynthesized through liquid
fermentation using glucose as a starting material,7 we next
performed the gram-scale reaction by the direct use of
cercosporin fermentation broth as the photocatalyst system,
which could avoid the purification process of cercosporin with
dichloromethane and methanol and use less DMSO in the
reaction condition. To our delight, with irradiation of 15W CFL,
treatment of 4-methylbenzenethiol (5 mmol) and 4-
nitrobenzenediazonium tetrafluoroborate (6 mmol) in 50 mL
fermentation broth together with only 2 mL DMSO delivered the
desired product 3a (0.71 g) with 61% yield (see SI), showing that
the advantage of cercosporin as a green, cost-effective and eco-
friendly photocatalyst in organic synthesis.
2
2
O
2
2
atmosphere. Control reactions were also conducted in the
absence of light source or cercosporin, respectively. As
expected, only trace amount of desired product was obtained
without irradiation, (Table 1, entry 11). Without the present of
cercosporin, the reaction could proceed in lower yield (Table 1,
entry 12). Combined with these results, we concluded both
irradiation and cercosporin were critical for this C-S coupling
reaction.
Table 2. Visible light mediated efficient synthesis of sulfidesa
Table 1. Optimization of reaction conditionsa
Entry
Photocatalyst
Solvent
CH OH
CH Cl
CHCl
Yield
1
2
Cercosporin
Cercosporin
Cercosporin
Cercosporin
Cercosporin
Cercosporin
Cercosporin
Cercosporin
Cercosporin
Cercosporin
Cercosporin
No
3
15%
trace
trace
10%
10%
15%
25%
87%
80%
83%
trace
18%
2
2
3
3
4
EtOH
THF
5
6
CH
3
CN
7
DMF
8
DMSO
DMSO
DMSO
DMSO
DMSO
9b
1
1
0c
1d
12
aReaction conditions: 4-methylbenzenethiol 1a (0.25 mmol), 4-
methoxybenzenediazonium tetrafluoroborate 2a (0.3 mmol) and cercosporin (1
mol %) in solvent (2.0 mL) at room temperature in air with 15W white CFL for
b
c
. d
a
Standard reaction conditions: aryl thiols 1 (0.25 mmol), aryl diazonium salts 2
0.3 mmol) and cercosporin (1 mmol%) in DMSO (2.0 mL) at room
temperature in air under 15W white CFL for 20 h.
2
2 2
0 h. Under O atmosphere. Under N atmosphere. Without light.
(
With the optimized reaction condition, we next started to
explore the scope of substrates for the reaction. This protocol for
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European Journal of Organic Chemistry
10.1002/ejoc.201901444
COMMUNICATION
Scheme 3. Proposed mechanism for cercosporin-catalyzed synthesis of
sulfides using aryl thiols and aryl diazonium salts.
Last, to unveil the mechanism of this photochemical
reaction, control experiments were performed using 4-
methylbenzenethiol
and
4-methoxybenzenediazonium
tetrafluoroborate as the model substrates. Owing to the ability of
generating active oxygen species by cercosporin as shown in
our previous studies,7c energy transfer pathway might participate
in this C-S coupling reaction. To verify our hypothesis, the well-
Conclusions
In summary, we have demonstrated that cercosporin can act as
a highly efficient metal-free photocatalyst for the selective
synthesis of sulfides through coupling of aryl thiols and aryl
diazonium salts in a sustainable and environmentally friendly
manner. Most importantly, the gram-scale reaction can efficiently
proceed using cercosporin-containing fermentation supernatant
without purification and only a small amount of organic solvent
was used.
known singlet oxygen inhibitors DABCO or NaN
the reaction, respectively. The reaction proceeded effectively
Scheme 2), suggeting that energy transfer pathway with the
involvement of singlet oxygen could be ruled out. Additionally, as
3
, was added to
(
shown in Table 1, the reaction can proceed effectively in N
2
(
Table 1, entry 10), thus we excluded the participation of active
.
-
oxygen specie O
2
from this reaction. However, when the radical
scavenger 1, 4-benzoquinone, butylated hydroxytoluene (BHT)
or 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) was added, this
reaction was obviously suppressed (Scheme 2), which suggest Experimental Section
that the reaction proceeded through radical transfer pathway.
Aryl thiol 1 (0.25 mmol, 1.0 equiv), aryl diazonium salt 2 (0.3 mmol, 1.2
equiv) and cercosporin (1 mol %) were dissolved in DMSO (2 mL). The
reaction mixture was stirred and irradiated by 15 W white CFL at room
temperature under air atmosphere for 20h. When the reaction was
completed, water (20 mL) was added, and the mixture was extracted by
CH
2
Cl
2
(3 x 10.0 mL). The combined organic layer was dried over
, filtered, and concentrated under reduced pressure.
anhydrous MgSO
4
Purification by flash chromatography with hexane or 3%
EtOAc/petroleum ether afforded the corresponding products.
Scheme 2. Mechanistic experiments
Based on the above results and pervious literature
reports,17d,17f
a
plausible mechanism is proposed for this Acknowledgments
photoreaction (Scheme 3). Initially, cercosporin CP is activated
to excited state CP* through irradiation of CFL. This CP* then
We thank for the National Key R&D Program of China
(2018YFA0901700), Natural Science Foundation of Jiangsu
Province (Grants No. BK20160167), the Thousand Talents Plan
(Young Professionals), the Fundamental Research Funds for the
Central Universities (JUSRP51712B), the National First-class
Discipline Program of Light Industry Technology and
Engineering (LITE2018-14), Postdoctoral Foundation in Jiangsu
Province (2018K153C) for the funding support.
.
+
can function as a strong reductant (E1/2(CP /CP*) = -0.77 V vs
SCE),7a to reduce benzenediazonium tetrafluoroborate 2 (E1/2
V vs SCE)18 to produce the aryl radical 5 and cercosporin
∼
0
.+
.+
.+
7a
radical cation CP . The CP (E1/2(CP /CP) = 1.56 V vs SCE),
a powerful oxidant, then oxidizes aryl thiol 1 (E1/2 = 0.83 V)
1
7d,19
to produce the thiol radical cation 4 and regenerates the
cercosporin CP at the same time. As a strong acidic radical
a
cation, the thiol radical cation 4 (pK = 2.4 for benzyl thiol radical
cation)1
7d,20
then undergoes deprotonation to produce the thiol
Keywords: Cercosporin • Photocatalyzed • Synthesis • Sulfides
radical 6, which then reacts with aryl radical 5, resulting in the
formation of aryl sulfide 3 as the final product.
•
C-S coupling
1
a) G. Ciamician, Science, 1912, 36, 385-394; b) C. K. Prier, D.
A. Rankic, D. W. C. MacMillan, Chem. Rev., 2013, 113, 5322-
5
9
6
363; c) D. M. Schultz, T. P. Yoon, Science., 2014, 343, 985-
93; d) J. Xuan, W. J. Xiao, Angew. Chem., Int. Ed., 2012, 51,
828-6838; e) N. Corrigan, S. Shanmugam, J. Xu, C. Boyer,
Chem. Soc. Rev., 2016, 45, 6165-6212; f) C. R. Stephenson,
T. P. Yoon and D. W. MacMillan, Visible Light Photocatalysis
in Organic Chemistry, John Wiley & Sons, 2018.
2
3
a) J. R. Chen, X. Q. Hu, L. Q. Lu, W. J. Xiao, Chem. Soc. Rev.,
2
016, 45, 2044-2056; b) S. Dadashi-Silab, S. Doran, Y. Yagci,
Chem. Rev., 2016, 116, 10212-10275.
a) T. P. Yoon, M. A. Ischay, J. Du, Nat. Chem., 2010, 2, 527-
5
32; b) C. K. Prier, D. A. Rankic, D. W. MacMillan, Chem.
Rev., 2013, 113, 5322-5363; c) T. Koike, M. Akita, Inorg.
Chem. Front., 2014, 1, 562-576.
4
a) N. A. Romero, D. A. Nicewicz, Chem. Rev., 2016, 116,
1
0075-10166; b) D. A. Nicewicz, T. M. Nguyen, ACS Catal.,
014, 4, 355-360; c) D. P. Hari, B. König, Chem. Commun.,
2
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201901444
COMMUNICATION
2
014, 50, 6688-6699; d) C. Liu, D. Liu, A. Lei, Acc. Chem.
10 J. Legros, J. R. Dehli, C. Bolm, Adv. Syn. Catal., 2005, 347,
19-31.
Res., 2014, 47, 3459-3470.
5
a) S. Yamazaki, A. Okubo, Y. Akiyama, K. Fuwa, Agric. Biol.
Chem., 1975, 39, 287-288; b) P. E. Hartman, W. J. Dixon, T.
A. Dahl, M. E. Daub, Photochem. Photobiol., 1988, 47, 699-
11 a) M. A. Fernández-Rodríguez, Q. Shen, J. F. Hartwig, J. Am.
Chem. Soc., 2006, 128, 2180-2181; b) T. Itoh, T. Mase, Org.
Lett., 2004, 6, 4587-4590; c) G. Y. Li, G. Zheng, A. F. Noonan,
J. Org. Chem., 2001, 66, 8677-8681.
7
2
03; c) F. Macri, A. Vianello, Plant Cell Environ., 1979, 2,
67-271; d) Daub, M. E.; Ehrenshaft, M. Annu. Rev.
12 a) C. G. Bates, R. K. Gujadhur, D. Venkataraman, Org. Lett.,
Phytopathol., 2000, 38, 461−490.
2002, 4, 2803-2806; b) X. Lv, W. Bao, J. Org. Chem., 2007,
6
7
a) S. Kuyama, T. Tamura, J. Am. Chem. Soc., 1957, 79,
5
72, 3863-3867; c) Y. J. Chen, H. H. Chen, Org. Lett., 2006, 8,
5609-5612; d) E. Sperotto, G. P. van Klink, J. G. de Vries, G.
van Koten, J. Org. Chem., 2008, 73, 5625-5628.
725−5726; b) Kuyama, S.; Tamura, T. J. Am. Chem. Soc.,
957, 79, 5726−5729.
1
a) S. W. Zhang, Z. C. Tang, W. H. Bao, J. Li, B. D. Guo, S. P.
13 a) Y. Zhang, K. C. Ngeow, J. Y. Ying, Org. Lett., 2007, 9,
3495-3498; b) S. Jammi, P. Barua, L. Rout, P. Saha, T.
Punniyamurthy, Tetra. Lett., 2008, 49, 1484-1487.
Huang, Y. Zhang, Y. J. Rao, Org. Biomol. Chem., 2019, 17,
4
364-4369; b) Y. Zhang, Y. Cao, L. S. Lu, S. W. Zhang, W. H.
Bao, S. P. Huang, Y. Rao, J. Org. Chem., 2019, 84, 7711-7721; 14 Y.-C. Wong, T. T. Jayanth, C.-H. Cheng, Org. Lett., 2006, 8,
c) J. Li, W. H. Bao, Z. C. Tang, B. D. Guo, S. W. Zhang, H. L. 5613-5616.
Liu, S. P. Huang, Y. Zhang, Y. J. Rao, Green Chem., 2019, DOI: 15 A. Correa, M. Carril, C. Bolm, Angew. Chem. Int. Ed., 2008
0.1039/C9GC02270H; d) J. Li, W. H. Bao, Y. Zhang, Y. J. Rao, 47, 2880-2883.
,
1
Org. Biomol. Chem., 2019, 17, 8958-8962; e) Z. C. Tang, J. Li,
F. L. Lin, W. H. Bao, S. W. Zhang, B. D. Guo, S. P. Huang, Y.
Zhang, Y. J. Rao, J. Catal., 2019, 380, 1-8.
a) P. Johannesson, G. Lindeberg, A. Johannesson, G. V.
Nikiforovich, A. Gogoli, B. Synergren, M. Le Greves, F.
Nyberg, A. Karlen, A. Hallberg, J. Med. Chem., 2002, 45,
16 a) V. P. Reddy, A. V. Kumar, K. Swapna, K. R. Rao, Org. Lett.,
2009, 11, 1697-1700; b) V. P. Reddy, K. Swapna, A. V.
Kumar, K. R. Rao, J. Org. Chem., 2009, 74, 3189-3191.
8
17 a) X. Wang, G. D. Cuny, T. Noël, Angew. Chem. Int. Ed.,
2013, 52, 7860-7864; b) C.-P. Zhang, D. A. Vicic, J. Am.
Chem. Soc., 2011, 134, 183-185; c) J. Santandrea, C. Minozzi,
1
767-1777; b) L. Llauger, H. Z. He, J. Kim, J. Aguirre, N.
Rosen, U. Peters, P. Davies, G. Chiosis, J. Med. Chem., 2005
8, 2892-2905; c) G. De Martino, M. C. Edler, G. La Regina,
C. Cruch
12255-12259; d) M. S. Oderinde, M. Frenette, D. W.
Robbins, B. Aquila, J. W. Johannes, J. Am. Chem. Soc., 2016
é, S. K. Collins, Angew. Chem. Int. Ed., 2017, 56,
,
4
,
A. Coluccia, M. C. Barbera, D. Barrow, R. I. Nicholson, G.
Chiosis, A. Brancale, E. Hamel, M. Artico, R. Silvestri, J. Med.
Chem., 2006, 49, 947-954; d) A. Gangjee, Y. B. Zheng, T.
Talreja, J. J. Mc Guire, R. L. Kisliuk, S. F. Queener, J. Med.
Chem., 2007, 50, 3046-3053.
a) M. C. Carreño, Chem. Rev., 1995, 95, 1717-1760; b) I.
Fernandez, N. Khiar, Chem. Rev., 2003, 103, 3651-3706; c)
D. A. Evans, G. C. Andrews, Acc. Chem. Res., 1974, 7, 147-
138, 1760-1763; e) M. W. Johnson, K. I. Hannoun, Y. Tan, G.
C. Fu, J. C. Peters, Chem. Sci., 2016, 7, 4091-4100; f) B. Hong,
J. Lee, A. Lee, Tetra. Lett., 2017, 58, 2809-2812; g) M. Majek,
A. J. von Wangelin, O Chem. Commun. 2013, 49, 5507-5509.
18 C. P. Andrieux, J. Pinson, J. Am. Chem. Soc., 2003, 125
,
9
14801-14806.
19 E. L. Tyson, M. S. Ament, T. P. Yoon, J. Org. Chem., 2013, 78,
2046-2050.
1
55; d) K. Kaczorowska, Z. Kolarska, K. Mitka, P. Kowalski, 20 a) F. G. Bordwell, X. M. Zhang, A. V. Satish, J. P. Cheng, J.
Tetrahedron, 2005, 35, 8315-8327; e) K. Jeyakumar, D. K.
Chand, Tetrahedron Lett., 2006, 47, 4573-4576; f) N. S.
Simpkins, Sulfones in Organic Synthesis; Pergamon Press:
Oxford, 1993; g) S. Patai, Z. Rappoprt, C. J. M. Stirling, The
Chemistry of Sulfones and Sulfoxides; Wiley: New York,
Am. Chem. Soc., 1994, 116, 6605-66010; b) V. V.
Pavlishchuk, A. W. Addison, Inorg. Chim. Acta, 2000, 298,
97-102.
1
988.
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European Journal of Organic Chemistry
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Key Topic*
Jia Li,[a] Wenhao Bao, Yan Zhang*[b]
[a]
*
[a]
and Yijian Rao
Page No. – Page No.
Cercosporin-photocatalyzed
C-S
Compared with extensive research of cercosporin at aspects of photophysic and
photobiology, its application in photocatalysis has been rarely reported. Herein we
report cercosporin-photocatalyzed selective synthesis of aryl sulfides under mild
and green conditions. The gram-scale reaction can proceed using cercosporin-
containing fermentation supernatant without purification.
Coupling for the Selective Synthesis
of Aryl Sulfides under Mild
Conditions
*
Photocatalysis, C-S coupling
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