Cu-Mediated C-H Thioetherification of Arenes at Room Temperature

Article abstract of DOI:10.1021/acs.orglett.9b02120

Cu-mediated C-H thioetherification of arenes with ethylene sulfide has been developed using a readily removable directing group. The reaction proceeded at room temperature, and a variety of sensitive functional groups including chloro, bromo, and vinyl were well tolerated. The thiolated products could be converted to the seven-membered benzoxathiepinones derivatives by a sequence of hydrolysis-lactonization reactions.

Full text of DOI:10.1021/acs.orglett.9b02120

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cu-Mediated C−H Thioetherification of Arenes at Room
Temperature
Xing Wang,†,§ Xing Yi,∥ Hui Xu,†,§ and Hui-Xiong Dai*,†,‡,§
†Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai 201203,
China
‡State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
§University of Chinese Academy of Sciences, Beijing 100049, China
∥School of Pharmaceutical Science, Shanxi Medical University, 56 Xinjian South Road, Taiyuan 030001, China
S
* Supporting Information
ABSTRACT: Cu-mediated C−H thioetherification of arenes with ethylene sulfide has been developed using a readily
removable directing group. The reaction proceeded at room temperature, and a variety of sensitive functional groups including
chloro, bromo, and vinyl were well tolerated. The thiolated products could be converted to the seven-membered
benzoxathiepinones derivatives by a sequence of hydrolysis−lactonization reactions.
ryl thioethers are an important structural motif ubiquity
in numerous biologically active compounds and pharma-
as Pd,8 Rh,9 Ru,10 Ni,11 and Co12 have been developed for C−
H thioetherification. Since Yu and co-workers reported the first
example of Cu-mediated thioetherification of 2-phenylpyridine
with PhSH and MeSSMe in 2006 (eq 1, Scheme 1), copper-
catalyzed or -mediated direct C−H thioetherification has
attracted considerable attention owing to the abundance,
inexpensiveness, and versatile reactivity of copper cata-
lysts.7d,f,g,13 Subsequently, Qing and co-workers disclosed an
A
ceuticals (Figure 1).1−5 For instance, craniformin is a natural
Scheme 1. Cu-Mediated Directed Ortho C−H
Thioetherification of Arenes
Figure 1. Bioactive aryl thioethers and pharmaceuticals.
product isolated from Calvatia craniformis.2 Axitinib as a
tyrosine kinase inhibitor is used as a treatment for renal cell
carcinoma.3 Moreover, aryl thioethers are also important
intermediates for the synthesis of aryl sulfones and sulfoxides.6
Therefore, the development of efficient and facile protocols for
the construction of sulfur-containing compounds is highly
desirable.
In recent years, transition-metal-catalyzed C−H activation
has provided a direct and powerful tool for the synthesis of
thioethers compounds.7 Various transition-metal catalysts such
Received: June 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02120
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
interesting example of Cu-mediated C−H bonds methylthio-
lation of 2-phenylpyridine using DMSO as the methylthiola-
tion reagent.13b Both the Yu and Qing groups have
demonstrated Cu-mediated thioetherification of 2-phenyl-
pyridine at temperatures above 125 °C. In 2012, Daugulis
made a great breakthrough in Cu-promoted C−H bond
sulfenylation by adopting a removable 8-aminoquinoline
directing group in which the reaction temperature could be
lowered to 90−110 °C (eq 2, Scheme 1).13c Subsequently,
similar work was reported by Liu’s group.13d Recently, Song
reported a copper-promoted thiolation of benzamides using
the 2-aminoalkylbenzimidazole (MBIP) directing group at 135
°C.13e Assisted by the 2-(pyridin-2-yl)isopropylamine (PIP)
directing group, Shi’s group developed a Cu-mediated C−H
thiolation of various arenes with disulfides and S8 at 100−130
°C.13f,j Copper-catalyzed regioselective C−H thiolation of
indolines (C7 position) and indoles (C2 position) was
reported by Ackermann.13i
Despite significant advances in this research field, a high
reaction temperature is commonly required in copper-
catalyzed C−H thioetherification. Previously, our group
developed the first copper-mediated diastereoselective C−H
thiolation of ferrocenes with the bidentate chiral oxazoline
directing group.13g In this work, we detail a facile Cu(II)-
promoted room-temperature ortho C−H thioetherification of
arenes using ethylene sulfide as the thiolation reagent (eq 3,
Scheme 1). Under the mild reaction conditions, substrates
bearing chloro, bromo, and vinyl could be well tolerated. The
products are useful synthons and could be converted to the
seven-membered benzoxathiepinone derivatives by a sequence
of hydrolysis−lactonization reactions.
Table 1. Optimization of the Reaction Conditions
entry
[Cu] (equiv)
base
temp (°C) yield (%) [mono/di]
1
2
3
4
5
6
7
8
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
CuOAc (1.0)
CuI (1.0)
CuCl2 (1.0)
CuBr2 (1.0)
Cu(OTf)2 (1.0)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
KOAc
KOAc
KOAc
KOAc
80
60
40
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
24[0:24]
23[0:23]
51[34:17]
39[34:5]
41[35:6]
56[43:13]
25[13:12]
0
22[19:3]
14[9:5]
0
12[12:0]
26[22:4]
10[10:0]
65[47:18]
25[22:3]
LiOAc
NaOAc
CsOAc
NH4OAc
Na2CO3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
9
10
11
12
13
14
c
15
16
d
a
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), [Cu], base (0.2
b
mmol), DMSO (1.0 mL), temperature, air, 12 h. Yield was
determined by 1H NMR analysis of crude reaction mixture using
c
d
CH2Br2 as the internal standard. 18 h, DMSO (2.0 mL). The
reaction was carried out under N2 atmosphere.
Based on the successful application of the amide−oxazoline
directing group in copper-mediated C−H functionalization,14
we initially treated substrate 1a with 1 equiv of Cu(OAc)2, 2
equiv of ethylene sulfide 2a, and 2 equiv of KOAc at 80 °C.
Only the dithiolated benzamide 3a′ was obtained in 24% yield
(Table 1, entry 1). The substrate 1a was completely converted,
which implied that the substrate was partially decomposed.
Next, we screened the reaction temperature (Table 1, entries
1−4) and were delighted to find that the thiolated product
could be obtained at room temperature with a total yield of
39% (entry 4). The structure of product 3a was confirmed by
X-ray crystallography. The influence of base was examined, and
NaOAc showed the best results (entries 4−9). Other copper
catalysts, including CuI, CuCl2, CuBr2, and Cu(OTf)2, were
also investigated, and Cu(OAc)2 gave the highest yields
(entries 10−14). Lowering the concentration and increasing
the reaction time could improve the yield to 65% with a 47/18
mono- to dithiolation ratio (entry 15). Moreover, we found
that the lower yield was achieved under N2 (entry 16).
Substrates bearing other bidentate directing groups, such as 8-
aminoquinoline, gave the thiolated products with lower yields
(see the Supporting Information).
With the optimized reaction conditions in hand, we turned
our attention to investigate the substrate scope. As shown in
Scheme 2, a variety of benzamide derivatives with electron-rich
methyl, methoxy, and tert-butyl substituents could be thiolated
smoothly, providing the thiolated products in moderate to
good yields (3a−3f). When the meta-positions of the
benzamides were substituted with a methoxyl group, two
regioisomeric products were formed, with the less sterically
hindered 6-position-thiolated product as the major one (3c).
Notably, the halogen (F, Cl, Br) and vinyl groups in the
substrates could be tolerated well, providing a useful handle for
further structural elaborations (3g−3m). Intestinally, the meta-
fluoro substrate 1h was regioselectively thiolated to give
product 3h with trace formation of the other regioisomer,
perhaps due to the small size and electronic properties of the
fluorine atom.15 Thiolation of arenes containing electron-
withdrawing acetyl and trifluoromethyl groups also gave
moderate to good yields (3n−3p). For 2-naphthalene-derived
substrates, thiolation occurred at both the 1- and 3-positions,
affording the mono- and diproducts 3q1‑mono, 3q3‑mono, and
3q1,3‑di in isolated yields of 34%, 13%, and 7%, respectively.
The protocol could be extended to heterocycle-containing
compounds (1r), giving the corresponding products in 48%
yields.
Removal of the amide-oxazoline directing group was
demonstrated by treating product 3a with 2 N KOH/EtOH
at 80 °C, releasing the deacetylated carboxylic acid 4a and the
directing group 6a in good yields (Scheme 3).
Seven-membered ring compounds containing two heter-
oatoms have drawn more and more attention due to their
important pharmacological properties.16 To our delight, the
monothiolated product 3 could be converted to the seven-
membered benzoxathiepinones derivatives 5 by a sequence of
hydrolysis−lactonization reactions (Scheme 4).
To gain insight into the reaction mechanism of the C−H
thiolation, several control experiments have been carried out.
First, significant intra- and intermolecular kinetic isotope
effects (KIE) indicate that the cleavage of C−H bond could be
involved in the rate-determining step (Scheme 5). In addition,
the addition of 2 equiv of radical scavenger 2,2,6,6-
tetramethylpiperidine-N-oxyl (TEMPO) has a negligible effect
on the yield, which indicates that a radical pathway is unlikely
B
DOI: 10.1021/acs.orglett.9b02120
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
a
Scheme 2. Scope of Thioetherification Reaction
Scheme 4. Transformation of Thiolated Product
a
Key: (1) 3 (0.25 mmol), KOH (10 mmol), EtOH (4.0 mL), air, 80
°C, 12 h; (2) TsOH (20 mol %), PhMe (1.0 mL), air, 120 °C, 2 h.
Scheme 5. (a) Intramolecular KIE; (b) Intermolecular KIE
a
Reaction conditions: 1a−1r (0.1 mmol), 2 (0.2 mmol), Cu(OAc)2
b
(1 equiv), NaOAc (2 equiv), DMSO (2.0 mL), air, rt, 18 h. Isolated
yield. 8 h. 12 h. 5 h.
Scheme 6. Effect of TEMPO
c
d
e
Scheme 3. Removal of the Directing Group
Scheme 7. Plausible Pathway
to be involved in the reaction (Scheme 6). We used 2-
acetoxyethanethiol as the thiolated reagent under the standard
reaction conditions, and only <5% of the desired product 3e
could be formed (see the Supporting Information). By
combining these results, we proposed a copper(II)-mediated
C−H thiolation pathway (Scheme 7). Compound 1a
coordinated with Cu(OAc)2 with the bidentate amide−
oxazoline directing group. Subsequently, C−H activation of
benzamide took place, giving the intermediate A. The Cu(II)
in A was disproportioned to give Cu(III) complex B.17
Ethylene sulfide coordinated with Cu(III) complex B to form
intermediate C. OAc− attacked the coordinated ethylene
sulfide via a six-membered-ring transition state, leading to the
formation of the intermediated D, which then underwent
reductive elimination to release the desired product 3a and
Cu(I) species.
C
DOI: 10.1021/acs.orglett.9b02120
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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In summary, we have developed a copper(II)-mediated ortho
C−H thioetherification of arenes at room temperature. The
reaction is compatible with a wide variety of functional groups.
The resulting thiolated products can be easily converted to
seven-membered benzoxathiepinone derivatives by a sequence
of hydrolysis−lactonization reactions.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02120.
Experimental procedures, characterizations of new
compounds, NMR spectra data (PDF)
Accession Codes
CCDC 1918024 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hxdai@simm.ac.cn.
ORCID
Hui-Xiong Dai: 0000-0002-2937-6146
Notes
The authors declare no competing financial interest.
(8) (a) Zhao, X.-D.; Dong, V. M. Carbon−Sulfur Reductive
Elimination from Palladium(IV) Sulfinate Complexes. Angew.
Chem., Int. Ed. 2011, 50, 932−934. (b) Iwasaki, M.; Lyanaga, M.;
Tsuchiya, Y.; Nishimura, Y.; Li, W.-J.; Li, Z.-P.; Nishihara, Y.
Palladium-Catalyzed Direct Thiolation of Aryl C−H Bonds with
Disulfides. Chem.−Eur. J. 2014, 20, 2459−2462. (c) Iwasaki, M.;
Kaneshika, W.; Tsuchiya, Y.; Nakajima, K.; Nishihara, Y. Palladium-
Catalyzed peri-Selective Chalcogenation of Naphthylamines with
Diaryl Disulfides and Diselenides via C−H Bond Cleavage. J. Org.
Chem. 2014, 79, 11330−11338. (d) Iwasaki, M.; Nishihara, Y.
Palladium-catalysed direct thiolation and selenation of aryl C−H
bonds assisted by directing groups. Dalton Trans 2016, 45, 15278−
15284. (e) Jiang, Y.-J.; Liang, G.-H.; Zhang, C.; Loh, T.-P. Palladium-
Catalyzed C−S Bond Formation of Stable Enamines with Arene/
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ACKNOWLEDGMENTS
■
We gratefully acknowledge Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, NSFC (21772211),
Youth Innovation Promotion Association CAS (NO. 2014229
and 2018293), Institutes for Drug Discovery and Develop-
ment, Chinese Academy of Sciences (NO.CA-
SIMM0120163006), Science and Technology Commission of
Shanghai Municipality (17JC1405000), Program of Shanghai
Academic Research Leader (19XD1424600), National Science
& Technology Major Project “Key New Drug Creation and
Manufacturing Program”, China (2018ZX09711002-006), and
the State Key Laboratory of Natural and Biomimetic Drugs for
financial support.
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Wang, B.-Q. Rh(III)-Catalyzed C7-Thiolation and Selenation of
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DOI: 10.1021/acs.orglett.9b02120
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