Methylthiolation for Electron-Rich Heteroarenes with DMSO-TsCl

Article abstract of DOI:10.1002/ejoc.202100001

DMSO-TsCl has been developed for direct methylthiolation of various electron-rich heteroarenes (more than 40 examples) with high regioselectivity in moderate to excellent yields (up to 96 %). Especially, pyrroles, furans, and thiophenes can be efficiently mono-methylthiolated. This practical method features scalable, metal-free, mild conditions and is compatible with air and moisture. Several applications of methylthiolated products were demonstrated for the first time. Based on controlled experimental results, a plausible mechanism was proposed with two key intermediates involved in the mechanism being detected by HRMS.

Full text of DOI:10.1002/ejoc.202100001

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doi.org/10.1002/ejoc.202100001
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Methylthiolation for Electron-Rich Heteroarenes with
DMSO-TsCl
Lei-Yang Zhang,[a] Yue-Hua Wu,[a] Nai-Xing Wang,*[a] Xue-Wang Gao,[a] Zhan Yan,[a]
Bao-Cai Xu,*[b] Ning Liu,[c] Bo-Zhou Wang,*[c] and Yalan Xing*[d]
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DMSO-TsCl has been developed for direct methylthiolation of
various electron-rich heteroarenes (more than 40 examples)
with high regioselectivity in moderate to excellent yields (up to
96%). Especially, pyrroles, furans, and thiophenes can be
efficiently mono-methylthiolated. This practical method features
scalable, metal-free, mild conditions and is compatible with air
and moisture. Several applications of methylthiolated products
were demonstrated for the first time. Based on controlled
experimental results, a plausible mechanism was proposed with
two key intermediates involved in the mechanism being
detected by HRMS.
Introduction
Sulfides and their derivatives which are commonly found in
many pharmaceuticals and agrochemicals exhibit important
biological activities.[1] Especially heteroaromatic sulfides and
their derivatives play significant roles in medicinal chemistry
and drug development (Figure 1).[2] Additionally, heteroaro-
matic sulfides can be further transformed into thiols,[3]
sulfoxides,[4] sulfones,[5] and applied to cross-coupling reaction.[6]
The formation of CÀ S bond has attracted extensive
attention from chemists in recent ten years.[7] RSH,[8] RSSR,[9]
sulfonates and derivatives,[10] and even sulfur-containing in-
organic salts[11] have been extensively used as thioetherification
reagents. Metal-catalyzed coupling of aryl halides with thiols
has emerged as a popular synthetic methodology for CÀ S bond
formation.[12] Fu’s group in 2017 reported a visible-light photo-
redox arylation of thiols with aryl halides and heteroaromatic
halides at room temperature (Scheme 1a).[13] However, thiols
with smelly odors are not environmentally friendly. In addition,
the Ir photocatalyst used for this reaction is expensive. Luo’s
group developed a catalytic synthesis of 3-thioindoles using
Figure 1. Bioactive Aryl Sulfides and Heteroaromatic Sulfides.
Bunte salts (RÀ SÀ SO3Na) as sulfur sources.[14] Nevertheless,
Bunte salts are not commercially available. More importantly,
they could decompose into toxic gas such as SO2 under
heating. Therefore, it is highly desirable to develop more
versatile and environmentally friendly reagents for CÀ S bond
formation.
Dimethyl sulfoxide (DMSO) is a readily available and less
toxic polar solvent.[15] During the past decades, it was reported
as important precursors for many organic motifs such as
À CH3,[16] À CHO,[17] À CN,[18] À SMe,[19] À SOMe,[20] and À SO2Me.[21]
Cheng’s group reported a Cu(I)-mediated methylthiolation of
[a] L.-Y. Zhang, Y.-H. Wu, Prof. N.-X. Wang, X.-W. Gao, Z. Yan
Technical Institute of Physics and Chemistry
& University of Chinese
Academy of Sciences, Chinese Academy of Sciences,
Beijing, 100190, China
E-mail: nxwang@mail.ipc.ac.cn
[b] Prof. B.-C. Xu
School of Food and Chemical Engineering, Beijing Technology and Business
University,
Beijing, 100048, China
°
aryl iodides and aryl bromides with DMSO using ZnF2 at 150 C
E-mail: xubac@163.com
(Scheme 1b).[22] Magolan’s group developed a metal-free meth-
[c] Prof. N. Liu, Prof. B.-Z. Wang
State Key Laboratory of Fluorine & Nitrogen Chemicals, Xi’an Modern
Chemistry Research Institute,
Xi’an, 710065, China
E-mail: wbz600@163.com
[d] Prof. Y. Xing
ylthiolation of activated arenes using DMSO/Hunig’s base
[23]
°
system at 189 C (Scheme 1c). The use of excessive metal
catalysts and harsh reaction temperatures limited the potential
applications. Adimurthy and coworkers[24] reported a meth-
ylthiolation of imidazo[1,2-a]pyridines in the presence of p-Tosyl
Chloride (TsCl) in the combination solvents of dichloroethane
Department of Chemistry, William Paterson University of New Jersey,
New Jersey, 07470, United States
E-mail: xingy@wpunj.edu
°
and DMSO at 100 C. However, only 2-phenylimidazo[1,2-a]
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100001
pyridine derivatives were discussed in this study. Also, the yields
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heteroarenes and arenes with excellent regioselectivity. Signifi-
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cantly, this method was successfully applied to the meth-
ylthiolation of five-membered heteroarenes such as pyrroles,
furans, and thiophenes. To the best of our knowledge, this is
the first report of DMSO-TsCl for the methylthiolation of
pyrroles, furans and thiophenes. Compared to previous studies,
this protocol features scalable conditions, general applicability
of substrates, a broad functional group tolerance, and moderate
to excellent yields. Moreover, a plausible mechanism was
proposed. Notably, two of the key intermediates involved in the
mechanism were detected by HRMS, confirming the validity of
the proposed mechanism.
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Results and Discussion
We initially began our investigations by using 2,4-dimethyl-1H-
pyrrole (1a) with DMSO (2a) as model substrates for the
optimization studies. The yield of 3aa was only optimized to
75% (Table S1). The yield was higher when using a more
reactive 1-H-indole (1u) with DMSO (2a) as model substrates
for the further optimization studies (Table 1).
According to our previous work,[28] DMSO/I2 system worked
well as a methylthiolation reagent. Unfortunately, there was no
desired product observed when DMSO/I2 was used (entry 1). To
our delight, 22% yield of the desired product was obtained in
the presence of 1.0 equiv. of NH4I (entry 4). A series of acidic
Table 1. Optimization of the Reaction Conditions of Methylthiolation of
Indole.[a]
Scheme 1. Strategies for CÀ S Bond Coupling Reactions.
of the corresponding methylthiolated products were relatively
low (23–67%) except 2-phenylimidazo[1,2-a]pyridine (91%).
Additionally, Roychowdhury and co-workers[25] reported a meth-
ylthiolation of imidazo[1,2-a] pyridines and other imidazo-fused
heterocycles using POCl3 as the activator. Very recently, Zhao
and Cao disclosed a methylthiolation of electron-rich aromatic/
heteroaromatic compounds using KSCN and methanol under
electrochemical redox conditions.[26] However, the meth-
ylthiolated or bismethylthiolated products of heteroaromatic
compounds were obtained with low yields.
Despite the recent development of these methods for
methylthiolation of heteroarenes with DMSO,[23–27] there are still
challenges: 1) High catalyst loadings and harsh conditions were
utilized. 2) The scope of the heteroarenes is relatively limited. 3)
Direct methylthiolation of five-membered heteroarenes with
low activity are less explored. Consequently, developing more
general synthetic methods for methylthiolation are highly
desirable.
Temp. [ C] Yield[b][%]
°
Entry Activator [equiv] Base
Solvent
1
2
I2(1.0)
KI(1.0)
–
–
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CH3CN
toluene
cyclohexane 60
dioxane 60
cyclohexane 60
cyclohexane 60
cyclohexane 60
cyclohexane 60
60
60
60
60
60
60
60
60
60
60
0
0
0
22
0
0
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
TBAI(1.0)
NH4I(1.0)
H2SO4(1.0)
TsOH(1.0)
TFAA(1.0)
TsCl(1.0)
TsCl(1.0)
TsCl(1.0)
TsCl(1.0)
TsCl(1.0)
TsCl(0.75)
TsCl(1.25)
TsCl(1.5)
TsCl(1.5)
TsCl(1.5)
TsCl(1.5)
TsCl(1.5)
TsCl(1.5)
TsCl(1.5)
–
–
–
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
K2CO3
26
64
34
59
74
47
54
82
89
41
53
81
56
92
82
0
t-BuOK cyclohexane 60
DBU
Et3N
Et3N
Et3N
Et3N
–
cyclohexane 60
cyclohexane 50
cyclohexane 70
cyclohexane 80
cyclohexane 70
cyclohexane 70
Our group has dedicated to the development of high-value
transformations of bulk chemicals. We previously reported a
metal-free catalytic synthesis of methylthio-substituted cate-
chols with DMSO in one pot (Scheme 1d).[28] In order to
establish a general synthetic methodology for CÀ S bond
coupling reaction, we would like to report a methylthiolation of
TsCl(1.5)
0
[a] Reaction conditions: indole (1u, 0.4 mmol 1.0 equiv), base (2.5 equiv),
DMSO (2a, 0.5 mL) and 0.5 mL solvent in sealed tube for 24 h, unless
otherwise noted. [b] Isolated yield.
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substances in the presence of Et3N were then screened. It was
products of phenyl ethers, phenols, and electron-deficient
heteroarenes such as pyridines and pyrimidines were failed to
obtain.
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found that 64% yield of the product was achieved when
1.0 equiv. of TsCl was utilized (entries 5–8). The effects of
different solvents in the reaction were then investigated and
cyclohexane was selected as the most suitable solvent for this
transformation (entries 9–12). Subsequently, the amount of TsCl
was screened. 89% yield was achieved when the amount of
TsCl was increased to 1.5 equiv. (entries 13–15). To further
improve the yield, several bases were also examined and Et3N
was found to give the best result (entries 16–18). The
investigation of the effect of reaction temperature revealed that
To gain insights into the mechanism, several experiments
were designed and performed (Scheme 3a). First, 2,2,6,6-
tetramethylpiperidine 1-oxyl (TEMPO) and 2,6-di-t-butylphenol
(BHT) as two kinds of radical scavengers were added into the
reaction of methylthiolation of indole under standard condi-
tions. We found that the yield of 3au was not decreased, which
excluded the free-radical reaction pathway [Eq. (1), Eq. (2)].
Subsequently, a deuterium-labeling experiment was carried out
with DMSO-d6 to explore the potential role of DMSO in the
reaction of methylthiolation [Eq. (3)]. The deuterated product
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°
70 C was the optimal temperature (entries 19–21). Notably,
there was no product formed in the absence of TsCl or Et3N
(entries 22–23), which indicated that DMSO-TsCl and Et3N were
crucial for this methylthiolation reaction.
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3au was obtained with yield of 91%, (The data of H NMR, 13C
NMR, and HRMS could be seen in Supporting Information
Figure S1–S3), indicating that DMSO-TsCl was generated and
reacted in situ. The deuterated experiment not only verified the
source of methylthiolation but also provided an efficient
synthetic method for introducing deuterated groups into the
drug intermediates.
With the optimal conditions in hand, a wide range of
substrates were converted to the corresponding products
(Scheme 2). First, various five-membered heteroarenes were
investigated, including pyrroles, furans, and thiophenes. Numer-
ous pyrrole derivatives participated in this coupling reaction,
affording the desired sulfides in moderate to good yields (3aa–
3ai). We found that pyrroles bearing electron-withdrawing
groups (Ac, COOMe and COOH) were unfavorable for this
reaction (3ag–3ai). In addition, disubstituted and monosubsti-
tuted furan and thiophene derivatives gave the corresponding
sulfides with lower yields (3aj–3at). Unfortunately, there were
no desired products obtained with furan derivatives bearing
strong electron-withdrawing groups (3am–3an). It is note-
worthy that thiophene and furan derivatives with strong
electron-donating groups are advantageous to this transforma-
tion (3at Vs 3ao).
Due to indoles and its derivatives commonly exist in
bioactive natural molecules and pharmaceutical agents.[29] We
next directed our attention to examine the scope of indoles.
Gratifyingly, unprotected indoles and an array of monosubsti-
tuted indoles at N-position (such as Me, Ph, and Bn) were found
to provide the desired products in excellent yields (3au–3ax).
When there were different substituted groups (Me and COOMe)
at the C2-position of indoles, the yields of the products
decreased dramatically. Especially with the strong electron-
withdrawing group (3ay Vs 3ba). Owing to the steric hindrance
at the C2-position of indoles, 3az was not observed under the
standard conditions. When the methyl group was at the
different positions of indoles, the products were obtained in
good yields (3ba–3be). Furthermore, various electron-with-
drawing (CN, F, and Cl) and electron-donating groups (Me, OH,
and OMe) at the C4-position of indoles were fully tolerated,
giving the desired products in moderate to good yields (3bf–
3bj). Different halogen functionalities, in particular, Cl and Br,
survived the reaction conditions and provided synthetic handles
for further structural elaboration through metal-catalyzed
coupling reactions (3bk–3bn). Moreover, the yields of the
target products were decreased as the electronegativity of the
halogen atom increased. (3bk Vs 3bl, 3bm Vs 3bn). It was
exciting to find that our method was also successfully applied
to electron-rich benzene derivatives with moderate yields
(3bo–3bp). Unfortunately, the corresponding methylthiolated
In order to further verify the mechanism, a series of control
experiments were also conducted (Scheme 3b). According to
the previous reports,[30] sulfur-containing organic compounds
such as dimethyldisulfide, methanethiol, and methyl sulfide can
be generated by thermal decomposition of DMSO. To confirm
whether one of these compounds acted as the intermediate of
this newly-developed transformation, we investigated the
reaction with dimethyl disulfide, methyl sulfide, and n-propylth-
iol instead of DMSO, no related products were found [Eq. (1),
Eq. (2), Eq. (3)]. Fortunately, intermediate A was detected by
HRMS when only TsCl was added into DMSO under the
standard condition, indicating that DMSO-TsCl was generated
in situ and acted as the methylthiolation reagent. Also, inter-
mediate C was detected by HRMS in the absence of Et3N at the
methylthiolation of indole [Eq. (4), Eq. (5)]. These detected
intermediates provided important evidence of the mechanistic
pathways.
Based on the experimental results, a plausible mechanism
was proposed for the reaction (Scheme 3c). DMSO was
originally activated by TsCl to form intermediate A (detected by
HRMS, Figure S4). Then intermediate B was obtained when the
sulfonium was attacked by C3-position of indole. Intermediate
B was converted into a more stable intermediate C through
deprotonation. (detected by HRMS, Figure S5). Finally, desired
product P was formed by eliminating a methyl cation under
heating.
To demonstrate further applications of the methylthiolation
of heteroarenes, a gram scale reaction was carried out to form
3au under open-air conditions. To our delight, the desired
product was obtained in a yield of 88% (Scheme 4a). Because
sulfoxides and sulfones are important precursors of numerous
chemically and biologically active molecules.[31] We converted
3au to 4a and 5a in the yield of 72% and 65% respectively
under the different conditions with H2O2 (30% in water).
Moreover, methylthiolation of C2 position of indole (6a) and
cross-coupling product (7a) were also obtained with the yield
of 42% and 47% respectively (Scheme 4b).
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Scheme 2. Substrates Scope for the Methylthiolation of Heteroarenes with DMSO-TsCl.[a] [a] Reaction conditions: for five-membered heteroarenes, 1 (1.0 mmol
°
1.0 equiv), TsCl (1.25 equiv), Et3N (2.5 equiv), DMSO (2a, 1.5 mL) and cyclohexane (1.5 mL) in sealed tube under 60 C for 24 h; for indoles, 1 (1.0 mmol
°
1.0 equiv), TsCl (1.5 equiv), Et3N (2.5 equiv), DMSO (2a, 1.5 mL) and cyclohexane (1.5 mL) in sealed tube under 70 C for 24 h, unless otherwise noted. [b] TsCl
°
(1.0 equiv). [c] under 120 C.
Conclusion
excellent yields with excellent functional group tolerance.
Several further applications of methylthiolated products were
also conducted, providing a powerful methodology for the
synthesis of thioethers compounds. The DMSO-TsCl reagent
provides a practical methodology for the synthesis of useful
heteroaromatic sulfides and aryl sulfides. Further studies and
synthetic applications are currently ongoing in our laboratory.
In summary, we have developed a general and efficient
methylthiolation methodology. The DMSO-TsCl reagent exhibits
excellent activity for methylthiolation of heteroarenes and
arenes under facile conditions. Various heteroarenes including
pyrroles, furans, thiophenes, indoles, and arenes are smoothly
converted to the corresponding products in moderate to
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Scheme 4. Gram Scale Reaction and Further Applications.
°
at 60 C for 24 h. After completion of the reaction, the mixture was
quenched with 10 mL water, then extracted with ethyl acetate
(15 mL) 3 times. The combined organic phase was concentrated by
a rotary evaporator. The residue was purified by column chroma-
tography on silica gel (200–300 mesh) using petroleum ether and
ethyl acetate as eluent to provide the desired products.
General Procedure of 4a
Sc(OTf)3 (49 mg, 0.1 mmol, 20 mol%) was suspended in CH2Cl2/10%
EtOH (2.0 mL) and 30% H2O2 ( 227 mg, 4 equiv) was added under
stirring. 3au (0.5 mmol, 1.0 equiv) dissolved in CH2Cl2/10%EtOH
(1.5 mL) was added (17.8 mg, 0.1 mmol, 1 equiv) as follow. The vial
in which 3au was weighed was further washed with CH2Cl2/10%
EtOH (1.5 mL) and added to the reaction mixture. Then the mixture
was stirring at room temperature for 3 h. After completion of the
reaction, the mixture was quenched with 15 mL water, then
extracted with ethyl acetate (10 mL) 3 times. The combined organic
phase was concentrated by a rotary evaporator. The residue was
purified by column chromatography on silica gel (200–300 mesh)
using dichloromethane and methanol as eluent to provide 4a with
the yield of 72%.
General Procedure of 5a
In a sealed tube with magnetic stir bar was charged with 3au
(0.5 mmol, 1.0 equiv), CH2Cl2/10%EtOH (2.5 mL), and 30% H2O2
(340 mg, 6 equiv). Then the tube was sealed with Tefloncape and
°
heated at 70 C for 10 h. After completion of the reaction, the
mixture was quenched with 15 mL water, then extracted with ethyl
acetate (10 mL) 3 times. The combined organic phase was concen-
trated by a rotary evaporator. The residue was purified by column
chromatography on silica gel (200–300 mesh) using petroleum
ether and ethyl acetate as eluent to provide 5a with a yield of 65%.
Scheme 3. Mechanism Studies.
Experimental Section
General Procedure of Heteroaromatic Sulfides.
General Procedure of 6a
3au (0.5 mmol, 1.0 eqviv) dissolved in CF3COOH (2.5 mL), the
mixture was stirring at room temperature for 3 h. After completion
of the reaction, the mixture was quenched with 15 mL water, then
extracted with ethyl acetate (10 mL) 3 times. The combined organic
In a sealed tube with magnetic stir bar was charged with
heteroarenes (1.0 mmol, 1.0 equiv), TsCl (1.25 mmol, 1.25 equiv),
DMSO (1.5 mL), cyclohexane (1.5 mL) and Et3N (2.5 mmol,
2.5 equiv). Then the tube was sealed with Teflon cape and heated
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14090–14094; b) J. Xu, R. Y. Liu, C. S. Yeung, S. L. Buchwald, ACS Catal.
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phase was concentrated by a rotary evaporator. The residue was
purified by column chromatography on silica gel (200–300 mesh)
using dichloromethane and methanol as eluent to provide the
desired product 6a with a yield of 42%.
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3
4
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5
6
7
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General Procedure of 7a
In a sealed tube with magnetic stir bar was charged with
Cu(OAc)2 ·H2O (0.25 mmol, 0.5 equiv. ), 3au (0.5 mmol, 1.0 eqviv)
and dioxane (2.5 mL). Then the tube was sealed with Teflon cape
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°
and heated at 80 C for 10 h. After completion of the reaction, the
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mixture was quenched with 15 mL water, then extracted with ethyl
acetate (10 mL) 3 times. The combined organic phase was concen-
trated by a rotary evaporator. The residue was purified by column
chromatography on silica gel (200–300 mesh) using petroleum
ether and ethyl acetate as eluent to provide the desired product 7a
with a yield of 47%.
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Acknowledgements
Financial support for this research was provided by National Key
R&D Program of China (2017YFB0308700) and Natural Science
Foundation of China (21676003).
Conflict of Interest
The authors declare no conflict of interest.
Keywords: CÀ S bond coupling
Heterocycles · Synthetic methods
·
Methylthiolation
·
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Manuscript received: January 1, 2021
Revised manuscript received: January 25, 2021
Accepted manuscript online: February 4, 2021
Eur. J. Org. Chem. 2021, 1446–1451
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