Ionic liquids - Promoted S-methylation of thiols utilizing dimethyl carbonate

Article abstract of DOI:10.1080/10426501003776939

Convenient and efficient S-methylation of mercaptans or thiophenols occurs with dimethyl carbonate (DMC) in room temperature ionic liquids (RTILs) [Bmim]Cl. [Bmim]Cl can be recycled in four subsequent runs with only a gradual decrease in activity. A possible mechanism of this transformation is also discussed. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. Copyright Taylor & Francis Group, LLC.

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Ionic Liquids—Promoted S-Methylation of
Thiols Utilizing Dimethyl Carbonate
a b
a
c
Jiangang Xie
, Chengyao Wu , Branford White Christopher ,
a
a
Jing Quan & Limin Zhu
a
College of Chemistry, Chemical Engineering and Biotechnology ,
Donghua University , Shanghai, P.R. China
b
Department of Chemistry , Zhengzhou Teachers College ,
Zhengzhou, P.R. China
c
Institute for Health Research and Policy , London Metropolitan
University , London, UK
Published online: 13 Jan 2011.
To cite this article: Jiangang Xie , Chengyao Wu , Branford White Christopher , Jing Quan & Limin
Zhu (2010) Ionic Liquids—Promoted S-Methylation of Thiols Utilizing Dimethyl Carbonate, Phosphorus,
Sulfur, and Silicon and the Related Elements, 186:1, 31-37, DOI: 10.1080/10426501003776939
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Phosphorus, Sulfur, and Silicon, 186:31–37, 2011
Copyright ꢀ
Taylor & Francis Group, LLC
C
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426501003776939
IONIC LIQUIDS—PROMOTED S-METHYLATION
OF THIOLS UTILIZING DIMETHYL CARBONATE
1
,2
1
3
Jiangang Xie, Chengyao Wu, Branford White Christopher,
1
1
Jing Quan, and Limin Zhu
College of Chemistry, Chemical Engineering and Biotechnology, Donghua
University, Shanghai, P.R. China
Department of Chemistry, Zhengzhou Teachers College, Zhengzhou, P.R. China
Institute for Health Research and Policy, London Metropolitan University,
1
2
3
London, UK
GRAPHICAL ABSTRACT
DMC
R
SH
RSCH3
o
[
Bmim]Cl, 110 C
R = alkyl, aryl or heteroaryl
Abstract Convenient and efficient S-methylation of mercaptans or thiophenols occurs with
dimethyl carbonate (DMC) in room temperature ionic liquids (RTILs) [Bmim]Cl. [Bmim]Cl
can be recycled in four subsequent runs with only a gradual decrease in activity. A possible
mechanism of this transformation is also discussed.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Dimethyl carbonate; ionic liquids; methyl thioether; thiol
INTRODUCTION
As organic sulfur compounds have become increasingly important in organic synthe-
sis, the development of convenient and practical methods for preparing methyl thioethers,
especially those that carry heterocyclic functional groups, is desirable. At present, the usual
1
2
route involves the methylation of thiol groups using methylic halides or dimethyl sulfate.
However, substrate factors and operational issues have restricted the synthesis of methyl
thioethers due to the toxicity of reagents and generation of a stoichiometric amount of
salt. For these reasons, dimethyl carbonate (DMC) is currently considered to be a genuine
Received 8 January 2010; accepted 15 March 2010.
The present investigation was supported by Natural Science Foundation of China (No. 50773009), Esquel
Group, Science and Technology Commission of Shanghai Municipality (08JC1400600), and “111 Project” from
Ministry of Education of China (B07024).
Address correspondence to Limin Zhu and Jing Quan, College of Chemistry, Chemical Engineering
and Biotechnology, Donghua University, 2999 North Renmin Road, Shanghai 201620, P.R. China. E-mail:
lzhu@dhu.edu.cn; jquan@dhu.edu.cn
3
1

3
2
J. XIE ET AL.
example of a green and versatile methylating reagent. It has also been widely used as
3
an alternative methylating reagent to replace hazardous compounds in organic synthesis.
4
The most common examples involve using some catalysts, such as K2CO3-crown ether,
5
6
7
K2CO3-Bu4NBr, DBU, or 2,4-diaminotoluene. In such cases, separation of the catalysts
and reutilization can be problematic. Hence, the development of recycling catalytic systems
is of importance for the methylation reaction. In this respect, room temperature ionic liquids
(RTILs) are attracting a growing interest as alternative reaction media for various chem-
ical and biotransformations. RTILs have emerged as a set of green solvents with unique
properties such as tunable polarity, high thermal stability, immiscibility with a number of
8
organic solvents, negligible vapor pressure, and recyclability. Since 2004, there have been
9
extensive studies on the S-alkylation reactions in [Bmim][PF6] or [Bmim][BF4]. Shen et al.
10
performed the reactions of phenols with DMC using RTILs as a catalyst. However, there
are no examples on the use of RTILs for the conversion of thiols to methyl thioethers in the
open literature. In conjunction with our interest in readily accessing diversified sulfoxide
and sulfone, we are keen to develop a convenient and efficient method for the construction
of methyl thioethers.
In this article, we report on the methylation reaction of thiols with DMC promoted
by RTILs in the absence base and organic solvents (Scheme 1). Simple stirring of a mixture
of various thiols and DMC in [Bmim]Cl gave the desired methyl thioethers in high yields.
Because [Bmim]Cl and DMC are green reagents and [Bmim]Cl can be recycled and reused,
the reaction has notable advantages and remarkable environmentally benign features. The
possible mechanism relating to this transformation is also discussed.
DMC
R
SH
RSCH
3
o
[
Bmim]Cl, 110 C
R = alkyl, aryl or heteroaryl
Scheme 1 The route of S-methylation of thiols with DMC promoted [Bmim]C1.
RESULTS AND DISCUSSION
Initially, we carried out the experiment with 2-mercaptobenzothiazole (1a) and DMC
in different reaction media. The product was obtained after a simple extraction stage with
ethyl acetate. The results are shown in Table 1. When the mixture of 1a and DMC was
◦
heated to 90 C in the absence of catalyst, no products were detected (Table 1, entry 1).
Similarly, the reaction was sluggish when using [Bmim]PF6 or [Bmim]BF4 as catalyst (Ta-
ble 1, entries 2 and 3). In the presence of RTILs, such as [Bmim]Br, [Emim]Br, [BmPy]Br,
[EmPy]Br, [Emim]Ac, or [Bmim]Cl, products were obtained in 45–77% yields (Table 1,
entries 4–9), indicating that these ionic liquids are moderately effective for the methy-
lation reaction. [Bmim]Cl was the most efficient catalyst and gave the highest yield of
◦
2
-methylthiobenzothiazole (2a) at 90 C (77%). It was noteworthy that ionic liquids with
different anions showed varying catalytic activities (Table 1, entries 2–4 and 9). The results
suggested that the anion had a strong impact on the catalytic activity of the ionic liquid in
the reaction. Similar yields of 2a were obtained when [Bmim]Br, [Emim]Br, [BmPy]Br, or
[EmPy]Br were employed in the reaction of 1a with DMC. This suggested that the chain
length of the substituted group of imidazole or pyridine was not a crucial factor in the

S-METHYLATION OF THIOLS WITH DIMETHYL CARBONATE
33
Table 1 Reaction of 1a with DMC in the presence of different catalystsa
Reaction
time (h)
Temperature
Isolated
yield (%)
◦
b
Entry
Catalyst
None
( C)
1
2
3
4
5
6
7
8
9
20
20
20
3
3
3
3
3
3
12
3
90
90
90
90
90
90
90
90
90
70
110
90
—
<5
<5
46
45
65
62
77
77
—
82
<5
[Bmim]PF6
[Bmim]BF4
[Bmim]Br
[Emim]Br
[BmPy]Br
[EmPy]Br
[Emim]Ac
[Bmim]Clc
[Bmim]Cl
[Bmim]Cl
1
1
1
0
1
2
d
Bu4NCl
20
a
b
c
Reaction conditions: 1a = 10 mmol, DMC = 20 mmol, ionic liquid = 20 mmol.
Isolated yield of S-methylated product based on 1a after column chromatography.
N-methylated byproduct (3a) was 6%.
Reaction conditions: 1a = 10 mmol, DMC = 200 mmol, Bu4NCl = 2 mmol.
d
catalytic activity of the ionic liquid (Table 1, entries 4–7). Compared with the ionic liquids,
Bu4NCl showed poor catalytic activity (Table 1, entry 12). This was also applied to the
selectivity of 2a as well. The main byproduct was N-methylated byproduct (Table 1, entry
9). This suggested that the imidazolium moiety of the ionic liquids has a significant function
in catalytic S-methylation of 1a with DMC. This is similar for O-methylation of phenol
10
with DMC. The reactivity of DMC at moderate temperatures can be significantly lower
7
than that of methyl iodide or dimethyl sulfate. We found that no products were obtained
◦
when using [Bmim]Cl as catalyst in DMC at 70 C after 12 h (Table 1, entry 10). However
◦
when the reaction was carried out at 110 C for 3 h, the yield was further enhanced to 82%
yield (Table 1, entry 11).
The results given in Table 2 outline the reactions of thiols with DMC in [Bmim]Cl.
The Supplemental Materials (available online) include the characterization data for the
compounds. Clearly alkyl, aryl, and heterocyclic thiols reacted well with DMC to producing
corresponding thioethers. Interestingly, the alkyl thiols were found to lower the reactivity
(Table 2, entries 1 and 2). Higher yields of aryl methyl thioethers were obtained compared
to alkyl methyl thioethers (Table 2, entries 3–5). Heterocyclic thiols such as 1e, 1f, and 1g
were converted into the corresponding heteroaryl methyl thioethers giving high yields and
good regioselectivity (Table 2, entries 10–12). This is probably due to the higher stability of
−
nucleophilic anions (RS ) in the reaction. Heterocyclic thiols such as 1a, 1b, and 1c were
converted into the corresponding heteroaryl methyl thioethers giving a bit of N-methylated
byproduct at the same time. This is probably the result of proton migration between thiol
form and thione form (Table 2, entries 6–8).1 Moreover, for reactions of thiophenol, an
electron-donating substituent such as methyl group was found to increase the reactivity,
while electron-withdrawing substituent on the thiophenol such as chloro was found to lower
1
◦
the reactivity at 90 C (Table 2, entries 3–5). Heterocyclic thiols such as 1f and 1g gave
similar results (Table 2, entries 11–12).
We performed reactions at 90 C and 110 C to compare the influence of temperature
on the catalytic process (Table 2). Although, the reactions did occur at 90 C, longer
◦
◦
◦

3
4

S-METHYLATION OF THIOLS WITH DIMETHYL CARBONATE
35
Table 3 Reuse of [Bmim]Cl for the reaction of 1d with DMCa
HS
S
N
N
[Bmim]Cl
N
N
N
+ DMC
N
o
110 C , 1.5h
N
N
Cycle
1
2
3
4
Isolated yield (%)
76
75
73
71
a
◦
Reaction conditions: 1d = 10 mmol, DMC = 20 mmol, [Bmim]Cl = 20 mmol, 110 C, 1.5 h.
incubation times were required to produce methyl thioethers, and the yields were low.
◦
When the reactions did occur at 110 C, methyl thioethers were produced in a short time,
and the yields were higher. Clearly temperature is an influencing factor on the yields and
reaction times.
We further investigated the recyclability of ionic liquid. The recovery potential of
[Bmim]Cl in the reaction of 1d and DMC was investigated. As shown in Table 3, the
ionic liquid was further recycled in four subsequent runs with little decrease in activity. For
example, in the fourth run, the yield was still 71%. Even though yields gradually decreased
in runs carried out using recovered ionic liquid, the products obtained were of the same
purity (∼97.2% base on GC) as in the first run.
To study the possible mechanism relating to this transformation, [Bmim]Br was used
◦
as a promoter to the reaction of 1a with DMC, and 2a was obtained in 46% yield at 90 C
after 3 h. When [Bmim]Cl was used as the promoter, a 77% yield was recorded (Table 1,
entries 4 and 9). This implied that the chloride ion may play a key role in this process.
Moreover, when Bu4NCl was used as the promoter, the reaction was slow and gave a low
yield (Table 1, entry 12). This implied that the imidazolium cation may also influence
this transformation. The change of proton chemical shift of the mercapto group of the
1
pyrimidine was investigated using H NMR. It was found that the mercapto group proton
of the pyrimidine was shifted downfield from 13.84 ppm to 14.30 ppm in the presence of
[
Bmim]Cl. The proposed key intermediate relating to this reaction is proposed (Scheme 2).
Due to the chloride ion and the imidazolium cation, the hydrogen bond interaction of
Bmim]Cl with the mercapto group may enhance the formation of a complex containing
[
−
7
−
nucleophilic anion (ArS ). If this occurs, then the nucleophile anion (ArS ) may attack
DMC through the BAl2 mechanism to generate the product (Scheme 3).
12
O
O
H C
CH
3
3
n-Bu
O
N
N
S
N
N
Cl
H
Scheme 2 Proposed key intermediate for the methylation reaction promoted by [Bmim]Cl.

3
6
J. XIE ET AL.
N
HS
N
n-Bu
n-Bu
N
N
N
N
N
N
S
H
Cl
Cl
CH OH + CO
3
2
DMC
O
Bu-n
H C
O
N
3
CH3
O
n-Bu
O
CH3
N
N
O
O
S
N
N
N
Cl
H
Cl
H
N
N
S
Scheme 3 Plausible catalytic cycle.
In this study, [Bmim]Cl was shown to be a useful and alternative reaction medium
for the synthesis of methyl thioethers from thiols by playing a dual role as both solvent and
catalyst. Additional factors make the reaction have notable advantages: (i) [Bmim]Cl and
DMC are non toxic; (ii) [Bmim]Cl can be easy recovered and reused; (iii) for heterocyclic
thiols, the high yields and good regioselectivity are very attractive. This method indeed
provides a less toxic system for the preparation of thioethers from thiols.
EXRERIMENTAL
The General Procedure of S-Methylation of Thiols in Ionic Liquid
Thiols (10 mmol), DMC (20 mmol), and ionic liquid [Bmim]Cl (20 mmol) were
added in a 25 mL reaction flask equipped with a magnetic stirrer. The mixture was stirred at
◦ ◦
0 C or at 110 C for the time indicated in Table 1 or Table 2. The reaction was monitored by
9
thin-layer chromatography (TLC). After the reaction was completed, the resulting mixture
was extracted with diethyl ether (entries 1–5) or ethyl aceate (entries 6–12) (3 × 15 mL). The
organic layers were washed with water (10 mL) and were dried over anhydrous Na2SO4.
The solvent was evaporated under reduced pressure to give the crude product, which was
purified by preparative column chromatography (silica gel).
Recovery of the Ionic Liquid
After extraction of the products, the ionic liquid was washed with diethyl ether
◦
(
10 mL) and was evaporated under reduced pressure at 60 C. Then the residue was dried

S-METHYLATION OF THIOLS WITH DIMETHYL CARBONATE
37
◦
under vacuum at 90 C for 4 h, and 96% of the ionic liquid was recovered and reused for
subsequent reactions (Table 3).
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