Organic reactions in ionic liquids: An efficient method for selective S-alkylation of 2-mercaptobenzothia(xa)zole with alkyl halides

Article abstract of DOI:10.1081/SCC-120037917

Ionic liquids based on 1-butyl-3-methylimidazolium hexafluorophosphate (BmimPF₆) and 1-butyl-3-methylimidazolium tetrafluoroborate (BmimBF₄) are used as reusable reaction medium in the selective S-alkylation of 2-mercaptobenzothia(xa)zole with alkyl halides in the presence of potassium carbonate. This procedure is convenient, efficient, and generally gives rise to the S-alkylated product exclusively.

Full text of DOI:10.1081/SCC-120037917

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Organic Reactions in Ionic Liquids: An
Efficient Method for Selective S‐Alkylation of
2‐Mercaptobenzothia(xa)zole with Alkyl Halides
Yi Hu a b , Zhen‐Chu Chen a b , Zhang‐Gao Le b & Qin‐Guo Zheng c
a Ningbo Institute of Technology, Zhejiang University, Ningbo, 315100, P.R. China
b Department of Chemistry, Zhejiang University (Xi‐Xi Campus), Hangzhou, P.R. China
c Pharmaceutical Science Research Institute, Aston University, Aston Triangle,
Birmingham, UK
Version of record first published: 20 Aug 2006.
To cite this article: Yi Hu, Zhen‐Chu Chen, Zhang‐Gao Le & Qin‐Guo Zheng (2004): Organic Reactions in Ionic Liquids: An
Efficient Method for Selective S‐Alkylation of 2‐Mercaptobenzothia(xa)zole with Alkyl Halides, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:11, 2039-2046
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 11, pp. 2039–2046, 2004
Organic Reactions in Ionic Liquids: An
Efficient Method for Selective S-Alkylation
of 2-Mercaptobenzothia(xa)zole
with Alkyl Halides
2
Yi Hu,1,2 Zhen-Chu Chen,1,2, Zhang-Gao Le, and
*
Qin-Guo Zheng3
1Ningbo Institute of Technology, Zhejiang University,
Ningbo, P.R. China
2Department of Chemistry, Zhejiang University (Xi-Xi Campus),
Hangzhou, P.R. China
3Pharmaceutical Science Research Institute, Aston University,
Aston Triangle, Birmingham, UK
ABSTRACT
Ionic liquids based on 1-butyl-3-methylimidazolium hexafluorophos-
phate (BmimPF6) and 1-butyl-3-methylimidazolium tetrafluoroborate
(BmimBF4) are used as reusable reaction medium in the selective
S-alkylation of 2-mercaptobenzothia(xa)zole with alkyl halides in
*
Correspondence: Zhen-Chu Chen, Ningbo Institute of Technology, Zhejiang Univer-
sity, Ningbo 315100, P.R. China; E-mail: zhenchuc@mail.hz.zj.cn.
2039
DOI: 10.1081/SCC-120037917
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Hu et al.
the presence of potassium carbonate. This procedure is convenient, effi-
cient, and generally gives rise to the S-alkylated product exclusively.
Key Words: 2-Mercaptobenzothia(xa)zole; Ionic liquids; S-Alkylation;
Alkyl halides; Organic reaction.
INTRODUCTION
2-Substituted derivatives of 2-mercaptobenzothia(xa)zole constitute an
important class of chemically, biologically, and pharmaceutically significant
compounds.[1] Despite their wide applicability, available convenient and effi-
cient route for their synthesis are some limited. The most important method to
prepare these derivatives is the direct alkylation of 2-mercaptobenzothia(xa)-
zole with alkyl halides. Generally, this reaction needs to use strong base such
as NaOMe,[2] NaOEt,[3] KOH,[4] Et3N,[5] etc. and volatile organic compounds
(VOCs), for example, CH3OH,[2] EtOH,[3] DMSO,[4] CH2Cl2,[5] xylene,[6]
acetonitrile,[7] DMF,[8] and acetone[1b,9] as solvents. Usually, the traditional
method is restricted by harsh reaction conditions, long reaction times, low
yields, low selectivity, and the use of unamiable solvents. The reaction also
can be accomplished via phase transfer catalysts (PTCs) process[1g,10] in
which the toxic and odorous solvent is used and catalyst separation and reco-
very are considerable challenges. In the most recently, Voelter et al.[11]
performed this reaction using CsF-Celite in acetonitrile, however, this method
need expensive reagent, toxic and volatile solvent and sometimes gave unsa-
tisfactory yields. Therefore, S-alkylation of 2-mercaptobenzothia(xa)zole
using facile and efficient methods with environmental benign technologies
is still full of significance in organic synthesis.
In recent years, room temperature ionic liquids (RTILs) are attracting
increasing interest as green reaction medium for synthetic organic chemistry,
there are many reports of great improvements in the reaction yields and
rates.[12] Seddon et al. reported ionic liquids were an attractive clean synthetic
alternative to classical solvents for solvent dependant selective alkylation
at the heteroatom of ambident nucleophiles.[13] However, to our knowledge,
there is no report on the preparation of thioether by reaction of thiol with
alkyl halide in ionic liquids to date, as prompted us to investigate the
S-alkylation of 2-mercaptobenzothia(xa)zole in ionic liquids.
Here, we examined the S-alkylation of 2-mercaptobenzothia(xa)zole with
alkyl halides in ionic liquids 1-butyl-3-methylimidazolium hexafluorophos-
phate (BmimPF6) and 1-butyl-3-methylimidazolium tetrafluoroborate
(BmimBF4) (Sch. 1). For this study BmimPF6 and BmimBF4 were synthesized
according to the procedures reported in literature.[14] In fact, simple stirring of

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S-Alkylation of 2-Mercaptobenzothia(xa)zole with Alkyl Halides
2041
Scheme 1.
a mixture of 2-mercaptobenzothia(xa)zole 1, alkyl halide 2, and K2CO3 in
ionic liquid BmimPF6 or BmimBF4 for about 2–7 hr gave, after extraction
with diethyl ether, the desired product S-substituted mercaptobenzothia(xa)-
zole 3 in high yield. The results are summarized in Table 1. The products
1
were characterized by H-NMR, IR and melting points that were consistent
with the literature data.
As can be seen from Table 1, the reaction was found to be general appli-
cable to primary alkyl chloride, bromide, iodide, activated chloride, activated
bromide, and even to secondary alkyl halide. Furthermore, all reactions exhi-
bited very high selectivity, only the S-alkylation products were obtained and
TLC showed no detectable amount of N-alkylated products, which were
usually obtained under the other reaction conditions.[6,9b] Additionally, we
found the tested ionic liquids BmimPF6 and BmimBF4 were all efficient and
both gave excellent results.
Further investigation was the recyclability of ionic liquid as a solvent.
Upon completion of the reaction, the product was extracted with diethyl
ether first and the ionic liquid was dried for 2 hr under vacuum followed filter-
ing the suspension to remove residual potassium carbonate and formed potass-
ium halide. As a result, the recovered ionic liquid could be reused with no
appreciable decrease in yield and in reaction rate. The representative results
are summarized in Table 2.
In order to compare with traditional procedure, some literature data[1b,5,9a,11]
are summarized in Table 3.
In conclusion, we have demonstrated that the S-alkylation of 2-mercapto-
benzothia(xa)zole could be effectively performed with alkyl halides in ionic
liquids BmimPF6 and BmimBF4. The present method has many obvious
advantages compared to those reported in the literature, including being envi-
ronmentally more benign, the generality, the simplicity of the methodology,
the ease of product isolation, the higher yield, the shorter reaction times, the
avoidance of using strong base, the higher selectivity, and the potential for
recycling of ionic liquids, which play a dual role as solvent and promoter in
this reaction.

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Hu et al.

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S-Alkylation of 2-Mercaptobenzothia(xa)zole with Alkyl Halides
2043
Table 2. Recycling of BmimPF6 and BmimBF4 for the S-benzylation of
2-mercaptobenzothia(xa)zole with BzCl.
Time
(hr)
Yieldc
(%)
Time
(hr)
Yieldc
(%)
Cyclea
Product
Cycleb
Product
1
2
3
2
2
2
3a
3a
3a
96
94
95
1
2
3
2
2
2
3h
3h
3h
97
95
96
aBmimPF6 was used as solvent in the S-benzylation of 2-mercaptobenzothiazole.
bBmimBF4 was used as solvent in the S-benzylation of 2-mercaptobenzoxazole.
cIsolated yields based on 2-mercaptobenzothia(xa)zole.
EXPERIMENTAL
Melting points were determined on digital melting point apparatus and
were not corrected. Infrared spectra were recorded on a VECTOR-22 Infrared
Spectrophotometer. 1H-NMR spectra were recorded on a BRUKER-400 MHz
spectrometer using CDCl3 as the solvent with TMS as an internal standard.
All materials are commercially available and were used without further
purification.
General Procedure for the S-Alkylation of
2-Mercaptobenzothia(xa)zole with Alkyl Halides
2-Mercaptobenzothia(xa)zole (2 mmol), alkyl halide (3 mmol), and
K2CO3 (2 mmol) were added in ionic liquid BmimPF6 or BmimBF4 (3 mL).
Table 3. S-alkylation of 2-mercaptobenzothia(xa)zole under different reaction
conditions.
Yields (%)
Yields (%)
Product
This work
Literature
Product
This work
Literature
3a
3b
95/96
93
74[11]
80[1b]
3h
3i
96/97
92
ꢀ70[5,9a]
69[1b]
Note: Yield for reaction with K2CO3 (1.5 eq.) as base, reflux 40 hr in acetone.[1b] Yield
for reaction with Et3N (2.0 eq.) as base at 458C for 2 hr in CH2Cl2.[5] Yield for reaction
with NaOH as base, reflux 4 hr in acetone.[9a] Yield for reaction with KF–Celite as base
at r.t. for 1–8 hr in acetonitrile.[11]

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Hu et al.
The reaction mixture was stirred for 2.0–7.0 hr at 508C. After TLC indicated
the starting material of 2-mercaptobenzothia(xa)zole had disappeared, the
resulting mixture was extracted with Et2O (3 Â 10 mL). The combined
ether solution was evaporated under reduced pressure to give crude product.
The crude product was purified by recrystallization or preparative thin-layer
chromatography (silica gel). After isolation of the product, the remainder of
the ionic liquids can be typically recovered by during at vacuum first and
filtering the suspension to remove the residual potassium carbonate and the
formed potassium halide.
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