Flavin/I2 catalyzed aerobic oxidative C–H sulfenylation of anilines

Article abstract of DOI:10.1016/j.tetlet.2020.152141

A flavin/I₂ catalyzed aerobic oxidative C–H sulfenylation of anilines with thiols under mild reaction conditions is presented for the first time. This metal-free reaction provides an atom-economic pathway to prepare various aryl sulfides with outstanding functional group compatibility. Moreover, it consumes molecular oxygen as the only terminal oxidant and produces environmentally-friendly H₂O as the only byproduct.

Full text of DOI:10.1016/j.tetlet.2020.152141

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Flavin/I2 Catalyzed Aerobic Oxidative C-H Sulfenylation of Anilines
Xinpeng Jiang, Zhifeng Shen, Cong Zheng, Liyun Fang, Keda Chen,
Chuanming Yu
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S0040-4039(20)30600-6
DOI:
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https://doi.org/10.1016/j.tetlet.2020.152141
TETL 152141
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Tetrahedron Letters
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28 May 2020
8 June 2020
Please cite this article as: Jiang, X., Shen, Z., Zheng, C., Fang, L., Chen, K., Yu, C., Flavin/I2 Catalyzed Aerobic
Oxidative C-H Sulfenylation of Anilines, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
2020.152141
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Tetrahedron Letters
Flavin/I2 Catalyzed Aerobic Oxidative C-H Sulfenylation of Anilines
Xinpeng Jianga, Zhifeng Shena , Cong Zhenga , Liyun Fanga , Keda Chenb , and Chuanming Yua,b
a College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P.R. China.
b Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A flavin/I2 catalyzed aerobic oxidative C-H sulfenylation of anilines with thiols under mild
reaction conditions is presented for the first time. This metal-free reaction provides an atom-
economic pathway to prepare various aryl sulfides with outstanding functional group
compatibility. Moreover, it consumes molecular oxygen as the only terminal oxidant and
produces environmentally-friendly H2O as the only byproduct.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
aniline
sulfenylation
aerobic oxidation
flavin
o
of NaI at 120 C (Scheme 1c). In spite of such advantages, these
Introduction
protocols were still largely limited by excessive use of explosive
peroxides, harsh reaction conditions and limited substrate scopes,
such as amino group protected anilines. Hence, it is still a
challenging task to develop a versatile protocol which fits in all
the desired conditions for mild synthesis of diaryl sulfides via C-
H/S-H cross-coupling of arene and aryl thiols. Inspired by
Murahashi[21] and Iida’s[22] pioneering work on flavin catalysts
as well as our ongoing research on C-H functionalization and
heterocyclic chemistry,[23] herein, we report a flavin/I2 catalyzed
system for aerobic oxidative C-H bond sulfenylation of anilines
with thiols.
Aryl sulfides are crucial building blocks that exist in
pharmaceutical intermediates,[1] polymer materials,[2] and
semiconductor material.[3] Therefore, the research on efficient
construction of these valuable motifs has attracted extensive
attention.[4] Traditionally, aryl sulfides have been synthesized by
reacting stoichiometric organozinc[5] or Grignard reagents[6]
with aryl halides, or cross-coupling of thiols/disulfides with aryl
halides in the presence of catalysts of transition metals such as
Fe,[7] Pd,[8] Co,[9] Cu,[10] Ni,[11] and Rh.[12] In recent times,
direct C−H thiolation of arenes was also extensively explored to
synthesize diaryl sulfides.[13] Despite abundant advantages,
these methodologies still encounter certain limitations, including
the need for arranging sophisticated setup for handling
expensive/air-sensitive catalysts and harsh reaction conditions.
Besides, owing to the low threshold residual tolerance of metals
in the pharmaceutical industry and materials science,[14] there is
an increasing demand for metal-free reactions for C-S bond
formation.
Recently,
many
disulfides,[15]
sodium
arylsulfinates,[16] and sulfonylhydrazides[17] have been
developed for the sulfenylation of electron-rich arenes under
metal-free
conditions
(Scheme
1a).
Though
direct
dehydrogenative C-H/S-H cross-coupling is a more attractive
approach for constructing a C-S bond, it is hindered by the
vulnerable structure of sulfide which is prone to over-oxidization
to sulfoxides/sulfones.[18] In 2015, Wang group [19] reported
the formation of diaryl sulfides under the I2/peroxides system
(Scheme 1b). In 2017, Wang and co-workers[20] discovered that
oxygen could be used as a green oxidant to furnish cross-
coupling of N,N-dimethylanilines and aryl thiols with 20 mol%
Scheme 1. Different protocols for the synthesis of diaryl sulfides.
———
 Corresponding author. E-mail: ycm@zjut.edu.cn.

2
Br) at the para-, ortho-, and meta- positions of the benzene ring,
reacted smoothly with aniline 1a to afford 3a−3m in 79−93%
yields. Notably, the brominated thiophenol gave the
corresponding product 3d in 91% yield, offering possibilities for
further functionalization. Moreover, this reaction was not only
limited to phenyl substrates, but heterocycles such as 2-
thiophenethiol gave 3n in 52% yield. The versatility of this
reaction also displayed good functional group compatibility for
2-naphthalenethiol, furnishing 3o in 72% yield.
In the next stage, the substituents on nitrogen were examined
(4a-4h and 4s, Table 3). When one of the hydrogens of the amino
group was substituted by a single methyl group, the desired
products 4a-4d were obtained in good yields, disregarding the
electronic property of the substituents on thiophenols. Besides, 2-
thiophenethiol and 2-naphthalenethiol were also well-tolerated,
giving the corresponding coupling products 4e and 4f in 67% and
85% yields respectively. In sharp contrast, acetyl aniline was
ineffective in this reaction. The N,N-disubstituted anilines,
however, gave the desired products 4g and 4s in slightly lower
than expected yields. It is worth noting that the arythiation could
occur at the ortho site of an amino group when the para position
was occupied by a substituent, thereby giving the corresponding
product in low yield (44%). This might be due to the steric
hindrance effect at the ortho position. As for ortho-substituted
anilines, the substrates containing electron-donating groups (Me,
Et, and MeO) (4j-4m) showed higher reactivity than those with
electron-withdrawing groups (4n and 4o). To our delight,
substrates with bulky substituents at ortho-site of an amino group
(1p and 1s) could also afford the corresponding products 4p and
4s in 80% and 64% yields, respectively. Moreover, CONH2 and
CO2Et substituted anilines require longer reaction time owing to
deactivated substrates caused by the substitution of electron
withdrawing groups and gave the corresponding products 4t and
4u in 40% and 36% yields, respectively. Furthermore, NO2 and
CN substituted anilines were also tested, but did not afford the
desired products.
Fig 1. Structures of flavins and flavinium salts.
Results and discussion
Initially, aniline 1a and 4-methylbenzenethiol 2a were
selected as the model substrates for optimizing the reaction
conditions (Table 1). Action of different flavin catalysts were
o
investigated under the oxygen atmosphere at 60 C for 24 h with
5 mol % of iodine as cocatalyst and acetonitrile (0.5 mL) as the
solvent (entries 1-5). Flavin II catalyzed the formation of 4-(p-
tolylthio)aniline 3a in 85% yield, with 9% of the corresponding
ortho-substituted product 3a’ (entry 5). In the next phase of
optimization of reaction conditions, different solvents such as
DMSO, DMF, and TFE were screened, but all of those gave 3a
in lower yields (entries 6–8). Decreasing or elevating the reaction
temperature did not enhance the yield (entries 9 and 10). Finally,
iodide sources such as KI or NIS were also tested, but both gave
inferior results (Table 1, entries 12 and 13). Thus, the optimized
reaction conditions were established as: 1a (1.0 mmol), 2a (0.5
mmol), flavin II (5 mol %), and I2 (5 mol %) in CH3CN (0.5 mL)
under O2 atmosphere at 60 °C for 24 h.
With the optimized reaction conditions in hand, a range of
thiophenols were employed for coupling with aniline, which
yielded the corresponding products in moderate to excellent
yields (Table 2). Thiophenols containing electron-donating (Me,
MeO, Ph, and NH2) and electron-withdrawing groups (F, Cl, and
To gain insight into the reaction mechanism, a series of
Table 2.
Substrate scope of thiolsa.
Table 1.
Optimization of reaction conditions.
Entrya
1
catalyst solvent
yield of 3a (%)b
yield of 3a’ (%)b
I
II
III
IV
V
II
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
DMF
NR
84 (85)c
50
NR
9 (9)c
6
2
3
4
35
9
5
NR
15
NR
4
6
7
II
51
7
8
II
TFE
37
8
9d
10e
11f
12g
13h
II
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
36
3
II
88
10
8
II
80
II
49
11
9
II
83
a Reaction conditions: 1a (1.0 mmol), 2a (0.5 mmol), solvent (0.5 mL) at 60
oC for 24 h with O2 atmosphere. b Yield determined by NMR with mesitylene
as internal standard. c Isolated yield. d 40 oC. e 80 oC. f Under air. g KI instead
of I2. h NIS instead of I2. NR = no reaction.
a Reaction conditions: 1a (1.0 mmol), 2 (0.5 mmol), flavin II (5 mol%), I2 (5
b
mol%), and MeCN (0.5 mL) at 60 oC for 24 h under O2 atmosphere
Reaction time (30 h).
.

3
Table 3.
Substrate scope of thiols and anilinesa.
Scheme 3. Proposed mechanism for flavin/I2 catalyzed aerobic
oxidative C-H sulfenylation of anilines.
a
Reaction conditions: 1 (1.0 mmol), 2 (0.5 mmol), flavin II (5 mol%), I2 (5
standard conditions, the reaction yield significantly decreased in
the absence of either iodine, flavin catalyst, or oxygen. In
addition, 38% of 3a formed by using 1 equivalent of iodine
without flavin and oxygen. When HI was used instead of iodine,
the yield of 3a slightly decreased to 80%. These results indicated
that flavin/I2 catalyst system played a significant role in this
reaction (Scheme 2C). Moreover, addition of a radical scavenger
butylated hydroxytoluene (BHT) to the reaction, gave the ideal
product 3a in 84% yield under standard conditions, which ruled
out the likelihood of a radical mechanism (Scheme 2D). Thus, we
concluded that an in situ generated sulfenyl iodide is the crucial
intermediate in this reaction, and in the presence of flavin II
catalyst, oxygen can continuously oxidize I- to I2 to complete the
catalytic cycle. Last but not the least, sulfenyl iodide might first
form arenesulfenanilides, which then underwent rearrangement
to generate desired products according to theoretical
calculation.[24] Arenesulfenanilide 4x was then synthesized[25]
and reacted under standard conditions to gave arrangement
product 4x in 25% yield, which is much lower than the 72% yield
of reaction of aniline 1a and thiophenol (Scheme 2E and 2F). In
addition, N,N-disubstituted anilines could also produce the
desired products (4g and 4s) in moderate yields (Table 3).
Therefore, we excluded the likelihood of arenesulfenanilide to be
an intermediate of this reaction.
mol%), and MeCN (0.5 mL), at 60 oC for 24 h under O2 atmosphere.
b
Reaction time (30 h). NR = no reaction.
control experiments were conducted (Scheme 2). Firstly, 4-
methylbenzenethiol 2a could be easily oxidized by oxygen to
diphenyl disulfide 7a in the absence of aniline (Scheme 2A).
Secondly, the reaction of 7a and aniline 1a forms the desired
product 3a in 89% yield under standard conditions (Scheme 2B).
These results indicated that diphenyl disulfide might be the
intermediate of this transformation. Thirdly, compared to the
Based on the previous reports [26, 24]and the control
experiments performed herein, a plausible mechanism for this
reaction is proposed (Scheme 3). Initially, the thiophenol 2 is
converted to diphenyl disulfide 7 by flavin-catalyzed oxidation
reaction.[22b-d] Then, the aryl disulfide 7 reacts with I2 to form
aryl sulfenyl iodide 6, which then undergoes attack by aniline 1a
to produce the desired product 3 and HI as the byproduct. The
latter is subsequently oxidized by the flavin-catalyzed system
when it enters the next catalytic cycle. In the flavin-catalyzed
Scheme 2. Control experiments

4
[13](a) M. Zhang, S. Zhang, C. Pan and F. Chen. Synth. Commun. 42
system (green circle), flavin II oxidizes the thiol and HI under
aerobic conditions to produce the disulfide and I2 along with
simultaneous generation of flavin IIred. Next, the reductive flavin
IIred is oxidized to hydroperoxyflavin IIOOH by oxygen. Finally,
IIOOH could also promote the oxidation of thiol and HI, and at the
same time, itself got reduced to flavin II to complete the
cycle.[21] Therefore, the overall reaction consumes oxygen and
produces H2O as the only byproduct.
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Conclusions
In conclusion, we report an aerobic oxidative C-H
sulfenylation of anilines with thiols catalyzed by flavin/I2 for the
first time. This metal-free reaction uses molecular oxygen as the
only terminal oxidant and produces environmentally-friendly
H2O as the only byproduct. Furthermore, the reaction was
performed successfully under mild conditions with high atom-
economy and excellent functional group compatibility. Further
research on the practical applications of this method is in
progress in our lab.
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Conflicts of interest
[21](a) S. Murahashi, T. Oda and Y. Masui. J. Am. Chem. Soc. 111 (1989)
5002-5003;
There are no conflicts to declare.
Acknowledgements
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[22](a) T. Ishikawa, M. Kimura, T. Kumoi and H. Iida. ACS Catal. 7 (2017)
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We gratefully acknowledge the National Natural Science
Foundation of China (grant number 21506191 and 21676252)
for financial support.
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☒ The authors declare that they have no known
competing financial interests or personal

5
relationships that could have appeared to influence
the work reported in this paper.
sulfenylation of anilines under mild
conditions.
2. It consumes oxygen as the terminal
oxidant and produces H2O as the
byproduct.
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
3. It features broad functional group
tolerance and good to excellent yields.
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Flavin/I2 Catalyzed Aerobic Oxidative C-H
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Xinpeng Jiang, Zhifeng Shen, Cong Zheng, Liyun Fang, Keda Chen, and Chuanming Yu