Pd-Catalyzed Intermolecular Transthiolation of Ar-OTf Using Methyl 3-(Methylthio) Propanoate as a Thiol Surrogate

Article abstract of DOI:10.1002/ejoc.202100822

A method for the odorless synthesis of unsymmetrical sulfides via Csp²?O and Csp³?S bond activation is presented. Using methyl 3-(methylthio) propanoate as a MeSH surrogate, a series of substituted aryl methyl sulfides have been obtained in moderate to good yields. This catalytic protocol can also tolerate methyl 3-(methylthio)propionate derivatives to afford the corresponding aryl sulfides.

Full text of DOI:10.1002/ejoc.202100822

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Pd–Catalyzed Intermolecular Transthiolation of Ar–OTf using
Methyl 3–(Methylthio) Propanoate as a Thiol Surrogate
Authors: Dandan Pan, Shasha Xu, Qingqiang Tian, and Yahui Li
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100822
Link to VoR: https://doi.org/10.1002/ejoc.202100822
0
1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202100822
COMMUNICATION
Pd–Catalyzed Intermolecular Transthiolation of Ar–OTf using
Methyl 3–(Methylthio) Propanoate as a Thiol Surrogate
[
a]
[a]
[a]
[a]
Dandan Pan, Shasha Xu, Qingqiang Tian and Yahui Li*
[
a]
Dr. Dandan Pan, Miss. Shasha Xu, Mr. Qingqiang Tian and Prof. Dr. Yahui Li, Department Key Laboratory of Agri–Food Safety of Anhui Province, School
of Resources and Environment, Anhui Agricultural University, Hefei 230036, China, E–mail: Yahui.Li@ahau.edu.cn
Supporting information for this article is given via a link at the end of the document.
Abstract: A method for odorless synthesis of unsymmetrical
sulfides via Csp2–O bond and Csp3–S activation is presented.
Using methyl 3–(methylthio) propanoate as a MeSH surrogate, a
series of substituted aryl methyl sulfides have been obtained in
moderate to good yields. This catalytic protocol can also tolerate
aryl iodides with thioethers.[9] Although these methods provided
alternative methods for the synthesis of aryl methyl sulfides,
substrates mainly focused on aryl iodides or bromides. Phenols
are one of the most common skeleton structures in natural
products and bioactive compounds.[ Using phenol derivatives in
the formation of aryl methyl sulfide can provide an efficient and
convenient way for the rapid late–stage modification approach.[
Also, methyl 3–(methylthio) propanoate is an odorless, easily
available, and stable substrate that has been used as a chemistry
additive. The direct use of methyl 3–(methylthio) propanoate
derivatives as a methylthio source are attractive from a practical
and environmental point of view.
10]
methyl
3–(methylthio)propionate
derivatives
to
afford
11]
corresponding aryl sulfides.
Organosulfur compounds represent an important class of
biological organic compounds that can be found in
[1]
pharmaceuticals, natural products, and agrochemicals. Aryl
methyl sulfide, sulfoxide, and sulfone molecular are of great
importance in modern pharmaceutical and agrochemical
science(Scheme 1). Thioridazine, a classical neurological drug, is
used for treating schizophrenia in adults and children.[2] Ametryn
is a triazine herbicide with selective uptake and conduction.[3]
Isoxaflutole, an isoxazole–containing compound, is a herbicide as
inhibitor of p–hydroxy–phenylpyruvate dioxygenase (HPPD).[4]
Considering the importance of these compounds, the
development of a novel process for the preparation of aryl methyl
sulfide is of great significance.[5] Transition–metal–catalyzed C–S
bond cross–coupling reactions between aryl (pseudo)halide and
mercaptans represent the most classical and important method
for the synthesis of aryl methyl sulfides.[6] However, methyl
mercaptan is a poisonous and fetid gas that not only cause
intractable problems, such as unpleasant odor, catalysts
poisoning, environmental pollution, and terrible risks during the
manufacturing process. Alternative sodium methyl mercaptide is
a concentration of 20% aqueous solution, which impedes its
application.
Scheme 2. Development of transfer catalysis
In all these backgrounds, we wish to report that the Pd–
catalyzed intermolecular transthiolation of aryl triflates using
methyl 3–(methylthio) propanoate and its derivatives as the
sulfurating reagent to afford a wide range of aryl sulfides. To begin
the study, we selected naphthalen–1–yl trifluoromethane–
sulfonate (1a) and methyl 3–(methylthio) propanoate (2a) as the
model substrate in the presence of PdCl
at 100 C for 17h, the desired product 3a was obtained in 20%
2
, xantphos, and Cs
2
CO
3
o
yield (Table 1, entry 1). Then different bases were tested and
Cs
2
CO
3
shown the best result. Moreover, more mild or strong
t
bases, such as K
3
PO
4
and KO Bu, were ineffective for this
Scheme 1. Methylsulfide–containing chemicals.
transformation (Table 1, entries 2 and 3). Different Pd salts was
also screened, such as Pd(OAc) Pd (dba) Pd(ally)Cl
Pd(CH CN) Cl and Pd(TFA) . Pd(TFA) was proved to be a
better choice affording the desired product in 47% yield (Table 1,
entry 8). After that, other ligands were tested and which, however,
2
,
2
2
,
2
,
In order to overcome this problem, developing new kinds of
sulfurating reagents is attractive(Scheme 2).[7] In 2018, Jiang and
co–worker developed a Pd–catalyzed thiomethylation of aryl
halides via a three–component cross–coupling strategy.[8] In 2020, did not exhibit any superior performance than xantphos (Table 1,
Our group reported an intermolecular transthioetherification of
entries 9, 10, and 11). In addition, Pd(TFA) is ineffective for this
3
2
2
2
2
2
1
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European Journal of Organic Chemistry
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COMMUNICATION
reaction in the absence of the ligand (Table 1, entry 12).
Interestingly, when the reaction temperature decreased to 80 C,
the yield of desired 3a increased to 68% yield (Table 1, entry 13).
A further study showed that argon atmosphere is more beneficial
for this transformation, and 83% yield could be achieved, although
this catalytic protocol was adapted to air atmosphere (Table 1,
o
entry 15). Finally, the optimal condition was established as 5
o
mol% Pd(TFA)
and 17 h.
2
/Xantohos Cs
2
CO
3
(3 equiv.), xylene (2 mL), 80 C,
Table 1. Optimization of Pd–catalyzed C–S bond formationa
o
b
entry
catalyst
ligand
base
T( C)
100
100
100
100
100
100
100
100
100
100
100
100
80
yield (%)
1
2
3
4
5
6
7
8
9
PdCl
PdCl
PdCl
2
2
2
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
dppe
Cs
2
CO
3
20
–
t
K OBu
K
3
PO
4
–
Pd(OAc)
Pd (dba)
Pd(ally)Cl
Pd(CH CN)
2
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
3
3
35
–
2
2
2
2
2
2
2
2
2
2
2
2
2
2
45
27
47
–
3
2 2
Cl
Pd(TFA)
Pd(TFA)
Pd(TFA)
Pd(TFA)
Pd(TFA)
Pd(TFA)
Pd(TFA)
Pd(TFA)
2
2
2
2
2
2
2
2
10
11
12
13
14
15
PPh
3
–
Brettphos
–
–
–
Xantphos
Xantphos
Xantphos
68
60
37
83c
80
a
b
o
Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), 2 (0.6 mmol, 3.0 equiv.), [Pd] (5 mol%), ligand (5 mol%), base (0.6 mmol, 3.0 equiv.), xylene (2 mL), 80 C , 17 h.
c
Yield was determined by GC using n–dodecane as internal standard. Under N
2
The reactivity of other thioether reagents, such as 2–
methylmercapto) ethanol and 4–(methylthio)–buta–2–one, also
been tested in the reaction with aryl triflates. But no better yield
was obtained (Table 2).
desired sulfide in 88% (3f) and 68% (3l) yield, respectively, which
provides the possibility for further transformation. In addition, aryl
triflates containing Ac and CN group can also be converted into
aryl sulfide smoothly, such as 1–(3–(methylthio)phenyl)ethan–1–
one and 3–(methylthio)benzonitrile, and give the desired products
3j and 3k in 57% and 67% yield. It is worth mentioning that
(
Table 2. Reactivity of differernt thiol donorsa
3
medicinally relevant CF S group can also be tolerated and gave
the desired product in 65% yield (3m).
To further make sure the synthetic value of this catalytic
protocol, we turned to test the scope of 4–methylthio–propionic
acid methyl ester derivatives. Substrates containing alkylthio-
instead of methylthio- could react smoothly and gave the desired
products in the range between 59–76% yield. Also, when the
reaction was performed benzylthio and phenylethylthio
derivatives, the sulfide product of benzyl(naphthalen–1–yl)–
sulfane and naphthalen–1–yl(phenethyl)sulfane could also be
obtained in 73% and 83% yield, respectively. It is noteworthy that
heterocycle thiophene was compatible in standard conditions and
furnish target product 3t in 67% yield. Methyl 3-
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), 2 (0.6 mmol, 3.0 equiv.), [Pd]
o
(5 mol%), ligand (5 mol%), base (0.6 mmol, 3.0 equiv.), xylene (2 mL), 80 C ,
b
1
7 h. Yield was determined by GC using n–dodecane as internal standard.
c
Under N
2
(
arylthio)propanoate can also be applied in this reaction. We have
With the optimized reaction conditions in hand, we
performed the reaction of Ar-OTf with methyl 3-(p-
tolylthio)propanoate, and the desired product could be obtained
in 70% yield (3u). We also compared the reactivity of 1-
iodonaphthalene, 1-bromonaphthalene and 1-naphthyl triflate.1-
Iodonaphthalene shown the best result (88% yield), and 1-
bromonaphthalene has the similar reactivity with 1-naphthyl
triflate.
investigated the substrate scope of this Pd–catalyzed
transthiolation of alkyl trifluoromethanesulfonate with thioether,
and
trifluoromethanesulfonate containing electron–donating groups,
such as CH O– or C O–, reacted smoothly and the led to
the
results
summarized
in
Table
3.
Alkyl
3
4 9
H
corresponding products in 67% (3b), 81% (3c), and 76% (3d)
respectively. Halogen atom Cl can also be tolerated and led to
2
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European Journal of Organic Chemistry
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Table 3. Pd–catalyzed thioetherification of aryl trifluoromethanesulfonatea
a
Reaction condition: 1a (0.2 mmol, 1.0 equiv.), 2 (0.6 mmol, 3.0 equiv.), Pd(TFA)
2
(5 mol%), Xantphos (5 mol%), Cs
2
CO
3
(0.6 mmol, 3.0 equiv.), xylene (2
o
b
c
d
mL), 80 C,17h, isolated yield. using1-iodonaphthalene instead of 1-naphthyl triflate. using 1-bromonaphthalene instead of 1-naphthyl triflate. 24h
and 2 equiv. Cs
consumed(Scheme 3, C). Furthermore, increasing the loading of
Pd(OAc) to 50 mol%, 27% of methyl 3–(methylthio)propanoate
2
CO3, 5% of methyl 3–(methylthio)propanoate was
2
was deposed(Scheme 3, D), and 23% of methyl acrylate was
detected. The results indicated that the palladium salt and base
play important roles in this C–S bond cleavage process.
Scheme 3. Control experiments
Scheme 4. Proposed Catalytic Cycle
To gain insight into the reaction mechanism, several control
experiments were conducted (see the Supporting Information).
The results implied that methyl 3–(methylthio)propanoate would
not depose at 80 C without catalyst and base (Scheme 3, A and
B), but when we performed the reaction with 5 mol% of catalyst
We hypothesized that precatalyst activation generates a Pd0
active species 1 (Scheme 4), which undergoes oxidative addition
with an Ar–OTf to form an organometallic Pd II halide complex 3.
Subsequently, a challenging sequence of C–SMe bond oxidative
addition followed by β–H elimination could be mediate by Pd–
o
3
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European Journal of Organic Chemistry
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catalyst and give the important intermediate H–Pd–SMe species
[11] a) X. Wang, F. Liu, Z. Yan, Q. Qiang, W. Huang, Z. Rong, ACS Catal.
2021, 11, 7319–7326; b) X. Yang, G. C. Tsui, Chem. Sci. 2018, 9, 8871–
1
0. The organometallic nucleophile (H–Pd–SMe) undergoes
8875.
transmetalation with Ar–M–L 3 to form the intermediate 4 that is
followed by reductive elimination to give the desired aryl methyl
sulfides. And the active Pd0 species 6 could be regenerated after
the reaction between H–Pd–X and a base.
In conclusion, we have described grenral and functional–
group–tolerant Pd–catalyzed transthiolation system to coupling of
aryl triflates with methyl 3–(methylthio) propanoate and its
derivatives. With methyl 3–(methylthio) propanoate as the low
toxicity, odorless, easily available, and stable methyl mercaptan
surrogates, the desired sulfide was produced in moderate to good
yields. The method exhibits a broad scope and a high tolerance
for functionality.
Acknowledgements
The authors are thankful for the financial support from the
Anhui Natural Science Foundation (19252004), Key R & D
projects in Anhui Province(202104a06020008), the Anhui
Leading Talent Project (03011002), Hefei Returned Students
Innovation and Entrepreneurship Support Program.
Keywords: Cleavage reactions • Cross-coupling • Csp3-S
activation • Elimination • MeSH Surrogate
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4
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Entry for the Table of Contents
Developing efficient strategies for the synthesis of organosulfur compounds is scientifically interesting and of high value, due to their
broad application in pharmaceuticals, nature products and agrochemicals. The work describes an intermolecular transthiolation of Ar–
OTf using methyl 3–(alkyllthio) propanoate as an odourless thiol surrogate.
5
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