Thiol Activation toward Selective Thiolation of Aromatic C-H Bond

Article abstract of DOI:10.1021/acs.orglett.0c01050

Direct C-S bond coupling is an attractive way to construct aryl sulfur ether, a building block for a variety of biological active molecules. Herein, we disclose an effective model for regioselective thiolation of the aromatic C-H bond by thiol activation instead of arene activation. Strikingly, this method has been applied into anisole derivatives that are not available in the arene activation approach to forge a single thioether isomer with high reactivity.

Full text of DOI:10.1021/acs.orglett.0c01050

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Letter
Thiol Activation toward Selective Thiolation of Aromatic C−H Bond
§
§
Jing-Hao Wang, Tao Lei, Hao-Lin Wu, Xiao-Lei Nan, Xu-Bing Li, Bin Chen, Chen-Ho Tung,
and Li-Zhu Wu*
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sı Supporting Information
ABSTRACT: Direct C−S bond coupling is an attractive way to
construct aryl sulfur ether, a building block for a variety of
biological active molecules. Herein, we disclose an effective model
for regioselective thiolation of the aromatic C−H bond by thiol
activation instead of arene activation. Strikingly, this method has
been applied into anisole derivatives that are not available in the
arene activation approach to forge a single thioether isomer with high reactivity.
ue to the wide applications of aryl sulfur ether in
natural products and pharmaceutical structures, site-
selective construction of this significant structure via direct
Scheme 1. Selective Thiolation of Aromatic C−H Bond
1
D
aryl C−S bond formation has received considerable attention
2
in organic chemistry. Over the past decades, arene activation
has been well established toward the thiolation of aromatic
C−H bond. Transition-metal-catalyzed activation of function-
3
−6
alized carbon−halogen (or pseudohalogen) bond
or
directing-group assistant carbon−hydrogen bond, followed
7
8
by S−H coupling, provide ortho-, meta-, and even para-
9
selective aryl C−H bond thiolation via one- or two-step
procedures. Alternatively, single electron oxidation of a highly
electron-rich arene substrate into the radical cation could be
followed by a thiol partner attack to realize its direct
activation of S−S bond. Compared to arene oxidation, this
model occurs under more favorable condition due to the
easier oxidation of thiol than that of arene, which renders its
excellent tolerance on functional group like OH, NH, and
consequent successful feasibility in late-stage decoration of
complex pharmaceuticals. We believe this thiol activation
strategy would offer great potential in selective C−S bond
formation in both substrate scope generality and practical
application.
10a
regioselective thiolation. However, the instinctive potential
difference between thiol substrates and common arenes
shows the preferable oxidative tendency of thiol and its
dimers, and we questioned whether one could realize the
thiolation of aromatic C−H bonds by thiol activation. In
contrast to arene activation for C−H/S−H coupling in the
literature, selective oxidation of thiol into a highly electro-
philic intermediate followed by arene nucleophilic attack, in
11
Our initial attempt was to choose anisole 1a (E1a = 1.62 V
vs Ag/AgCl) and 4-methylbenzenethiol 2a (E2a = 1.26 V vs
Ag/AgCl) as model substrates. When this reaction was
carried out in the mixture of 1,1,1,3,3,3-hexafluoro-2-propanol
and 1,2-dichloroethane (HFIP/DCE = 3:1) with 1.3 V vs
Ag/AgCl constant voltage electrolysis, in which two platinum
which eliminated protons reduced to hydrogen gas, would
offer a distinguishing but perfect model for site-selective C−S
bond formation with no requirement of strong electron-
donating profile (Scheme 1).
12−14
To execute our design, we selected electrochemistry
to precisely monitor the oxidation potential to guarantee
selective oxidation of thiol rather than arene and simulta-
neously avoid the use of external chemical oxidant. To our
delight, efficient and regioselective thiolation of aromatic C−
H bond has been achieved. By taking this simple system to
activate thiol to highly active disulfide radical cation, aromatic
substrates could be coupled to afford desired products in high
efficiency. Compared to reported S−I intermediate triggered
n
plates as electrode material and Bu NPF as electrolytes, an
4
6
exclusive para-thiolation product 3aa with 88% yield was
Received: March 23, 2020
9b
by stoichiometric hypervalent iodine, sustainable electricity
provides a clean and atom-economic environment for direct
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c01050
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a
Table 1. Optimization of the Reaction Conditions
b
entry
electrolysis conditions
yield (%)
n
1
2
3
4
5
6
7
8
9
1
1
1
Pt(+)/Pt(−), Bu NPF , HFIP/DCE = 3:1, rt, Ar, E = 1.3 V vs Ag/AgCl, 12 h
88
73
2
4
6
TFE as solvent
DCE as solvent
MeOH as solvent
MeCN as solvent
4
15
51
86
32
79
46
92
NR
n
Bu NOAc as electrolyte
4
n
n
Bu NBF as electrolyte
4
4
Bu NClO as electrolyte
4
4
RVC as anode
0
1
2
under air
A = 5 mA, 4.2 F/mol
no electric current
a
Reaction conditions: Pt plate anode (0.5 cm × 1.0 cm), Pt plate cathode (0.5 cm × 1.0 cm), Ag/AgCl reference electrode, 1a (0.2 mmol), 2a (0.4
n
b
mmol), Bu NPF (0.1 M), HFIP/DCE = 3:1 (4.0 mL), rt, Ar. Yield determined by GC analysis with tetradecane as the internal standard.
4
6
obtained in 12 h (Table 1, entry 1). Under this condition,
only 2a could be oxidized. Variations on other solvents
including 1,2-dichloroethane (DCE), methanol (MeOH),
acetonitrile (CH CN), and 2,2,2-trifluoroethanol (TFE)
3
showed that TFE could give 73% yield of product (Table
n
1
, entry 2−5). As for electrolytes, when Bu NPF was
4
6
n
replaced by Bu NBF , similar yield was obtained, while
Bu NOAc, Bu NClO led to inferior results (Table 1, entry
4
4
n
n
4
4
4
6
−8). Altering platinum plate into reticulated vitreous carbon
(
RVC) as electrode afforded 79% yield, suggesting the
independency of this reaction on electrode material (Table 1,
entry 9). It should be noted that this electrochemical system
worked smoothly in air albeit in 46% yield (Table 1, entry
1
0). Intriguingly, when this reaction was carried out under
constant current electrolysis, the highest yield was obtained in
.5 h (Table 1, entry 11). Control experiment showed that
no product was observed in the absence of electron input
4
(
Table 1, entry 12).
To clarify the reaction pathway and mechanism, several
control experiments were carried out. First, 2 equiv of
TEMPO as radical scavenger in this system resulted in no
products at all (Figure 1a). Instead, when 2 equiv of 1,1-
diphenylethylene was used, disulfide 4 and thiolated olefin 5
was obtained in 32% and 20% yields, which directly verified
the generation of thiyl radical (Figure 1b). Additionally, in
situ GC detection for the constant voltage period of
electrolysis (7 h) indicated that thiol 2a underwent
dimerization into disulfide 4 with 91% yield and a trace
amount of target product. Subsequently, a fast and complete
consumption of anisole 1a in next 5 h gave para-thiolation
product 3aa in 88% yield, along with 30% residue of disulfide
Figure 1. Radical capture and control experiments. Reaction
n
conditions: Pt plate anode, Pt plate cathode, Bu NPF (0.1 M),
4
6
HFIP/DCE = 3:1 (4.0 mL) 5 mA, 4.5 h, 1a (0.2 mmol), 2a (0.4
mmol) (a) TEMPO (0.4 mmol); (b) 1,1-diphenylethylene (0.4
mmol); (c) 4 (0.2 mmol), 1.0 V, 1.3 V, 1.7 V vs. Ag/AgCl for 3.0 h.
(d) 4 (0.2 mmol), 1.3 V vs. Ag/AgCl for 1.0 h.
substrate 2a and much lower than anisole 1a. Therefore, the
disulfide would be oxidized preferably to anisole. Indeed,
when the constant voltage electrolysis system containing
anisole 1a and disulfide 4 was carried out, a same trend in
the latter stage of Figure 2a,b was obtained via in situ GC
detection, providing 96% yield of product 3aa (Figure 2c).
When the electrolytic voltage was increased to 1.7 V vs Ag/
AgCl, which was enough to oxidize anisole 1a, 94% yield was
still obtained. As expected, no desired product was generated
with 1.0 V vs Ag/AgCl electrolysis (Figure 1c). More
4. As for constant current electrolysis, a similar phenomenon
was obtained in a shorter reaction time (Figure 2b). The
dimerization of thiol 2a achieved 78% yield in 2 h, and the
highest 82% yield of disulfide 4 was obtained in 2.5 h. In the
next 2 h, a dramatic conversion of anisole 1a into 3aa was
detected. When the reaction was complete after overall 4.5 h,
9
2% yield of 3aa and 33% disulfide 4 was confirmed in the
system and no substrates were left. Notably, the oxidant
potential of disulfide 4 was 1.23 V vs Ag/AgCl, similar to the
B
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n
Figure 2. In situ GC detection. Reaction conditions: Pt plate anode, Pt plate cathode, Bu NPF (0.1 M), HFIP/DCE = 3:1 (4.0 mL), GC
4
6
yields. (a) 1a (0.2 mmol), 2a (0.4 mmol), constant potential = 1.3 V; (b) 1a (0.2 mmol), 2a (0.4 mmol), constant current = 5 mA. (c) 1a (0.2
mmol), 4 (0.2 mmol), constant potential = 1.3 V.
interestingly, upon direct electrolysis of the disulfide 4 at a
constant potential (1.3 V vs Ag/AgCl) for 1 h the colorless
solution turned into purple. Immediately, anisole was added
without electrolysis, leading to the color disappearance, and
compatibility in this transformation (3ah−3am). Likewise,
multisubstituted substrates such as 2,6-dimethylbenzenethiol
and 2,4,6-trimethylthiophenol also worked well and afforded
the desired products in 99% and 58% yields, respectively
(3an and 3ao).
1
8% yield of product 3aa was detected (Figure 1d). From
these data, it was reasonable to infer that thiol 2a was
oxidized first and underwent rapid radical dimerization to
generate the disulfide 4, which was further oxidized into its
cation radical to provide a high electrophilic species.
From the above results and analysis, a plausible mechanism
is outlined in Scheme 2. Thiophenol was oxidized to the
Then anisole derivatives were explored to react with 4-
methoxybenzenethiol. Analyzing the reaction results led to
several conclusions as follows: (a) Most monosubstituted
anisole derivatives showed good reactivity in this trans-
formation (3ap−3ep). For example, methyl, ethyl, i-Pr, and
n-Bu groups displayed high tolerance and gave more than
92% yields of products. In addition, 1-methoxynaphthalene
Scheme 2. Plausible Mechanism
was also investigated and gave the corresponding para isomer
in 94% yield (3sp). (b) Para-selectivity products were also
obtained from disubstituted substrates. In detail, ortho-
substituted arenes like 2-methylanisole, 2,3-dihydrobenzofur-
an, and chromane were found to be active under the standard
conditions (3fp−3hp). In the cases of meta-substituted
arenes, electron-donating methyl- and methoxy-occupied
anisole produced single para-isomers in 99% yields (3ip
and 3jp). In addition, electron-withdrawing halogen groups at
the meta-position were also tolerated in this transformation
although with relatively low yields, highlighting the good
performance of this strategy in both chemo- and
regioselectivity (3kp−3np). (c) For multisubstituted arenes,
like 1-methoxy-3,5-dimethylbenzene, 1,3,5-trimethoxyben-
zene, and 1,2,3-trimethoxybenzene, single isomers with
specific regioselectivity were isolated after the reaction
(3op−3qp). Intriguingly, mesitylene was also tolerated to
afford the corresponding thiolation products in almost
quantitative yield (3ra). (d) Differently, 2-methoxynaphtha-
lene and 2-ethoxynaphthalene were found to give single
ortho-isomers with excellent yields (3tp−3up).
corresponding radical through single electron transfer on the
anode, which rapidly dimerized into disulfide. Further
oxidation of disulfide into its radical cation intermediate I
provided a highly electrophilic species. Subsequent selective
attack by anisole formed the intermediate II, which was
controlled by the electronics of the aromatic coupling
partner. The existence of HFIP was beneficial for keeping
the radical cation intermediate stable enough. Followed by
final deprotonation and release of a thiyl radical, the desired
para-thiolation product was obtained. In this process, the
overoxidation of disulfide to afford cationic species I′ could
More excitingly, our method could be successfully
exploited into late-stage decoration of pharmaceutical
1
0b
15
not be excluded,
which could also react with anisole to
molecules by sale in 2018. As listed in Scheme 3,
form the desired product. As for the released protons, they
were converted into hydrogen gas at the cathode.
To explore the generality of this new strategy, the scope of
thiophenol was investigated first. According to the results in
Scheme 3, thiophenols substituted by 4-methyl (3aa, 95%),
atomoxetine (treatment of attention-deficit hyperactivity
disorder (ADHD)) and ranolazine (antianginal) were
selectively thiolated in 67% and 42% yields, remaining the
alkyl amino and hydroxyl groups intact (3vp and 3wp).
Metaxalone (muscle relaxant and pain relief) and the even
more complicated tadalafil (treating erectile dysfunction (ED)
and the symptoms of benign prostatic hyperplasia (BPH))
gave target aryl sulfur ethers 3xp (92%) and 3yp (65%),
showing the great potential of this strategy in medicine
modification. What’s more, the scale-up reaction of template
(5 mmol) in 84% isolated yield proved the practicality of this
electrochemical cross-coupling strategy. Compared to the
2
9
-methyl (3ab, 92%), 4-ethyl (3ac, 90%), 4-isopropyl (3ad,
1%), and 4-tert-butyl (3ae, 93%) all gave para products with
excellent yields (3aa−3ae). Electron-donating methoxy even
methylthio substrates were compatible to provide correspond-
ing thioether in 98% and 82% yields (3af and 3ag).
Moreover, it should be noted that the insertion of halogen
groups on different position of thiophenol showed good
C
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Letter
Scheme 3. Substrate Scope of Thiophenol and Anisole
a
n
Reaction conditions: Pt plate anode (0.5 cm × 1.0 cm), Pt plate cathode (0.5 cm × 1.0 cm), 1 (0.2 mmol), 2 (0.4 mmol), 5 mA/4.5 h, Bu NPF
4
6
b
n
c
n
(
0.1 M), HFIP/DCE = 3:1 (4.0 mL), rt, Ar. HFIP as solvent and Bu NOAc as electrolyte. HFIP as solvent and Bu NBF as electrolyte. Isolated
4
4
4
yields are shown.
outstanding performance in our system, the electrochemical
ASSOCIATED CONTENT
■
10a
arene activated method showed no product formation for
the simple anisole with different thiols (Scheme S5),
highlighting this new mechanistic approach.
*
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01050.
In summary, we have developed a new approach to realize
the regioselective thiolation of simple aromatic rings via the
activation of thiols other than arene. Via electrocatalysis, this
model enabled common arenes like anisole derivatives,
without strong electron-donating profile or directing groups,
to react with diverse thiols without any metal or external
chemical oxidants. The released electron and proton were
converted into hydrogen gas at the cathode. The good
efficiency of large-scale conversion, successful decoration of
drug molecules, as well as external metal- and chemical
oxidant-free characters illustrate its great promise in practical
applications.
Preparative procedures and analytical data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Li-Zhu Wu − Key Laboratory of Photochemical Conversion
and Optoelectronic Materials, Technical Institute of Physics
and Chemistry, Chinese Academy of Sciences, Beijing 100190,
P.R. China; School of Future Technology, University of
Chinese Academy of Sciences, Beijing 100049, P.R. China;
orcid.org/0000-0002-5561-9922; Email: lzwu@
mail.ipc.ac.cn
D
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Organic Letters
Authors
pubs.acs.org/OrgLett
Letter
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00190, P.R. China; School of Future Technology, University
of Chinese Academy of Sciences, Beijing 100049, P.R. China
Tao Lei − Key Laboratory of Photochemical Conversion and
Optoelectronic Materials, Technical Institute of Physics and
Chemistry, Chinese Academy of Sciences, Beijing 100190, P.R.
China; School of Future Technology, University of Chinese
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Chinese Academy of Sciences, Beijing 100049, P.R. China
Xiao-Lei Nan − Key Laboratory of Photochemical Conversion
and Optoelectronic Materials, Technical Institute of Physics
and Chemistry, Chinese Academy of Sciences, Beijing 100190,
P.R. China; School of Future Technology, University of
Chinese Academy of Sciences, Beijing 100049, P.R. China
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and Optoelectronic Materials, Technical Institute of Physics
and Chemistry, Chinese Academy of Sciences, Beijing 100190,
P.R. China; School of Future Technology, University of
Chinese Academy of Sciences, Beijing 100049, P.R. China
Bin Chen − Key Laboratory of Photochemical Conversion and
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Chemistry, Chinese Academy of Sciences, Beijing 100190, P.R.
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Complete contact information is available at:
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9
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(
Author Contributions
§J.-H.W. and T.L. contributed equally to this work.
via transition-metal-catalyzed arene activation: (a) Saidi, O.; Marafie,
J.; Ledger, A. E.; Liu, P. M.; Mahon, M. F.; Kociok-Kohn, G.;
Whittlesey, M. K.; Frost, C. G. J. Am. Chem. Soc. 2011, 133, 19298−
Notes
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The authors declare no competing financial interest.
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Tsuchiya, Y.; Nakajima, K.; Nishihara, Y. J. Org. Chem. 2014, 79,
1
(
1330−11338.
ACKNOWLEDGMENTS
■
9) Selected examples for para-selective aryl C−H bond thiolation
We are grateful for financial support from the Ministry of
Science and Technology of China (2017YFA0206903), the
National Natural Science Foundation of China
via transition-metal-catalyzed arene activation: (a) Hsu, W. C.; Li,
C. E.; Lee, C. F. Asian J. Org. Chem. 2017, 6, 1667−1673.
(b) Choudhuri, K.; Maiti, S.; Mal, P. Adv. Synth. Catal. 2019, 361,
1092−1101.
(
21861132004), the Strategic Priority Research Program of
the Chinese Academy of Science (XDB17000000), Key
Research Program of Frontier Sciences of the Chinese
Academy of Science (QYZDY-SSW-JSC029) and K. C.
Wong Education Foundation.
(10) (a) Wang, P.; Tang, S.; Huang, P.; Lei, A. Angew. Chem., Int.
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the existence of HFIP which could act as an nucleophile, the
overoxidized cation species seems to be less possible.
(
11) (a) Meng, Q.-Y.; Zhong, J.-J.; Liu, Q.; Gao, X.-W.; Zhang, H.-
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