Sc(OTf)3-catalyzed synthesis of thiosulfonates in ionic liquid-water

Article abstract of DOI:10.1016/j.tetlet.2012.09.132

The first example of Sc(OTf)₃-catalyzed sulfenylation of sodium sulfinates with N-(organothio)succinimides in ionic liquids (ILs) and water cosolvent system was developed, achieving thiosulfonates in moderate to excellent yields. Additionally, Sc(OTf)₃/ILs could be recovered easily after the reactions and reused without a significant loss in the catalytic activity. Thus, the present protocol represents an interesting complement to known methods for thiosulfonates synthesis.

Full text of DOI:10.1016/j.tetlet.2012.09.132

Tetrahedron Letters 53 (2012) 6768–6770
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sc(OTf)3-catalyzed synthesis of thiosulfonates in ionic liquid-water
Gaigai Liang a, Jing Chen a, Jiali Chen a, Wanmei Li a,b, Jiuxi Chen a, , Huayue Wu a
⇑
a College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
b College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 June 2012
Revised 18 September 2012
Accepted 29 September 2012
Available online 12 October 2012
The first example of Sc(OTf)3-catalyzed sulfenylation of sodium sulfinates with N-(organothio)succini-
mides in ionic liquids (ILs) and water cosolvent system was developed, achieving thiosulfonates in
moderate to excellent yields. Additionally, Sc(OTf)3/ILs could be recovered easily after the reactions
and reused without a significant loss in the catalytic activity. Thus, the present protocol represents an
interesting complement to known methods for thiosulfonates synthesis.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Thiosulfonates
Sc(OTf)3
Ionic liquid
Sulfinate
N-(Organothio)succinimide
O
S
O
O
S
O
Thiosulfonate derivatives have been widely used as sulfenylat-
ing reagents in the field of organic synthesis.1 In addition, these
compounds have also shown a broad spectrum of biological activ-
ities.2 Consequently, a variety of efficient methods have been
developed for the synthesis of thiosulfonates.3–13 The vast majority
of these transformations have focused on the direct oxidation of
disulfides and thiols leading to the synthesis of symmetrical thio-
sulfonates.3 In 2010, we developed new methods for the synthesis
of symmetrical thiosulfonates by the direct oxidation of disulfides
or thiols in the presence of CAN/I2 or TCCA.4 However, these meth-
ods cannot be suitable for the synthesis of unsymmetrical thiosul-
fonates, which may lead to a mixture of isomeric products5 with
low regioselectivity when R1 and R2 have similar skeletons
(Scheme 1).
oxidation
R1 ¡Ù R2
R1
S
R2
R1
S
R2
R1
S S
R2
+
Scheme 1. Direct oxidation of unsymmetrical disulfides.
O
O
S
O
S
5 mol% Sc(OTf)3
ILs/H2O
R1
S
R2
N
R1
+
S
R2
ONa
O
O
Scheme 2. New strategy for the synthesis of thiosulfonates.
In general, unsymmetrical thiosulfonates are generated by the
sulfur–sulfur bond formation. One of the most common ap-
proaches is the direct sulfenylations of sulfinic acid or its deriva-
tives with different sulfenylating reagents,6–8 which is restricted
with poor functional groups compatibility and the use of foul
smelling/harmful sulfenylating reagents. An alternative approach
for the synthesis of unsymmetrical thiosulfonates involves thiosul-
fonates exchange reaction with sulfenamides,9 oxidation of thio-
sulfinates,10 spontaneous desulfurization of sulfenic sulfonic
thioanhydrides,11 reduction of sulfonyl chlorides,12 and reaction
of potassium thiosulfonates with diaryliodonium salts.13 However,
these methods were limited to the use of toxic and unstable sulfe-
nylating reagents, and/or the unavailable starting materials. Thus,
the development of a simple and general procedure for the synthe-
sis of thiosulfonates is in demand.
Recently, N-(arylthio)phthalimides14 and N-(organothio)succin-
imides15 have been widely used as new alternative sulfenylating
reagents. Inspired by this impressive developments and our inter-
est in the organosulfur chemistry,4,16 herein we report a new strat-
egy for the synthesis of thiosulfonates by the sulfenylation of
sodium sulfinates with N-(organothio)succinimides in ionic liquids
(ILs) and water cosolvent system (Scheme 2).
We initiated our investigations by examining the reaction of N-
(phenylthio)succinimide (1a) with sodium p-tolylsulfinate (2a) in
water in the absence of catalyst at 30 °C, but no target product
was observed (Table 1, entry 1). We next investigated a variety
of conditions with the reaction using various metal triflates in
aqueous media (Table 1, entries 2–7). We were delighted to find
that the yield of the target product 3aa could be improved to
⇑
Corresponding author. Tel./fax: +86 577 8836 8280.
E-mail address: jiuxichen@wzu.edu.cn (J. Chen).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.132

G. Liang et al. / Tetrahedron Letters 53 (2012) 6768–6770
6769
Table 1
Table 2
Screening for the optimal reaction conditionsa
Sc(OTf)3-catalyzed synthesis of unsymmetrical thiosulfonatesa
O
O
O
S
O
S
5 mol% Sc(OTf)3
[BMIM]PF6/H2O, 30 o
catalyst
SR1
R1
S
R2
SO2Na
S
R2SO2Na
+
+
N
SPh
N
solvent
C
O
O
O
O
1
2
3
1a
2a
3aa
Yieldb (%)
Entry
R1 (1)
R2 (2)
Product
Yieldb (%)
Entry
Solvent
Catalyst
Temp (°C)
1
2
3
4
5
6
7
8
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
p-(Me)C6H4 (2a)
o-(Me)C6H4 (2b)
p-(OMe)C6H4 (2c)
p-(F)C6H4 (2d)
p-(Cl)C6H4 (2e)
p-(Br)C6H4 (2f)
Me (2g)
o-(Me)C6H4 (2b)
p-(F)C6H4 (2d)
p-(Cl)C6H4 (2e)
p-(Br)C6H4 (2f)
p-(NO2)C6H4 (2h)
p-(CF3)C6H4 (2i)
Ph (2j)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3bb
3bd
3be
3bf
3bh
3bi
3bj
3bg
3ca
3cb
3 cd
3cf
91
1
2
3
4
5
6
7
8
H2O
H2O
H2O
H2O
H2O
H2O
H2O
EtOH
none
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
50
80
NR
65
70
68
63
64
72
73
36
41
56
39
71
42
37
23
77
85
81
80
86
91
88
63
83
67
56
80
Cu(OTf)2
Mg(OTf)2
Zn(OTf)2
Eu(OTf)3
Yb(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
90c
73
72
76c
84c
84
p-MeC6H4 (1b)
p-MeC6H4 (1b)
p-MeC6H4 (1b)
p-MeC6H4 (1b)
p-MeC6H4 (1b)
p-MeC6H4 (1b)
p-MeC6H4 (1b)
p-MeC6H4 (1b)
p-ClC6H4 (1c)
p-ClC6H4 (1c)
p-ClC6H4 (1c)
p-ClC6H4 (1c)
p-ClC6H4 (1c)
p-ClC6H4 (1c)
p-BrC6H4 (1d)
p-BrC6H4 (1d)
p-BrC6H4 (1d)
p-BrC6H4 (1d)
p-BrC6H4 (1d)
p-(OMe)C6H4 (1e)
p-(NO2)C6H4 (1f)
PhCH2 (1g)
9
85c
80c
79c
77
9
DMF
DMSO
THF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
PEG-400
[BPy]BF4
[BMIM]BF4
[BMIM]ClO4
[BMIM]NO3
[BMIM]HSO4
[BMIM]PF6
[HMIM]PF6
[OMIM]PF6
76c
92
Me (2g)
88c
82
p-(Me)C6H4 (2a)
o-(Me)C6H4 (2b)
p-(F)C6H4 (2d)
p-(Br)C6H4 (2f)
Ph (2j)
78
71c
69c
78
3cj
74c
81c
73c
72c
71c
79c
84c
75c
82c
79c
73c
68c
79c
[BMIM]PF6/H2Oc
[BMIM]PF6/H2Od
[BMIM]PF6/H2Oe
[BMIM]BF4/H2Od
[HMIM]PF6/H2Od
[BMIM]PF6/H2Od
[BMIM]PF6/H2Od
Me (2g)
3cg
3da
3dd
3de
3dj
3dg
3ea
3fa
3ga
3gd
3ge
3gf
3gj
p-(Me)C6H4 (2a)
p-(F)C6H4 (2d)
p-(Cl)C6H4 (2e)
Ph (2j)
Me (2g)
p-(Me)C6H4 (2a)
p-(Me)C6H4 (2a)
p-(Me)C6H4 (2a)
p-(F)C6H4 (2d)
p-(Cl)C6H4 (2e)
p-(Br)C6H4 (2f)
Ph (2j)
NR = no reaction.
a
Reaction conditions: 1a (0.3 mmol), 2a (0.36 mmol), and catalyst (5 mol %) in
solvent (4 mL) for 6 h.
PhCH2 (1g)
PhCH2 (1g)
PhCH2 (1g)
PhCH2 (1g)
b
Isolated yield.
Volume ratio of [BMIM]PF6 to H2O is 2:1.
Volume ratio of [BMIM]PF6 to H2O is 3:1.
Volume ratio of [BMIM]PF6 to H2O is 1:1.
c
d
a
e
Reaction conditions: 1 (0.3 mmol), 2 (0.36 mmol), and Sc(OTf)3 (5 mol %) in
[BMIM]PF6/H2O (4 mL, volume ratio is 3:1) for 6 h, see Ref. 19.
b
Isolated yield.
For 2 h.
c
72% using 5 mol % Sc(OTf)3 at 30 °C (Table 1, entry 7). These results
also further proved that metal triflates do play an important role in
this reaction. Encouraged by these promising results, we further
adjusted the reaction parameters including solvent, reaction tem-
perature, and molar ratio of 1a to 2a (Table 1, entries 8–20). First,
the solvent effect was tested using Sc(OTf)3 as catalyst. Among all
the solvents screened, low or moderate yields of 3aa were detected
in organic solvents, such as CH3CH2OH, DMSO, DMF, THF, and PEG-
400 (Table 1, entries 8–12). Next, we have examined the model
reaction using different ionic liquids as reaction media in the pres-
ence of 5 mol % Sc(OTf)3 (Table 1, entries 13–20). After a series of
trial experiments, we were pleased to discover that the yield of
3aa was improved to 85% when the combination of Sc(OTf)3 and
[BMIM]PF6 was employed (Table 1, entry 18).
Recently, we have reported an eco-friendly synthesis of 2,3-
dihydroquinazolin-4(1H)-ones in ionic liquid/water cosolvent sys-
tem.17 Enlightened by the work, we made an attempt to examine
the model reaction in ionic liquid/water cosolvent system (Table 1,
entries 21–27). Using an ionic liquid/water cosolvent system in-
stead of ionic liquid alone, 91% yield of the desired product 3aa
was detected in [BMIM]PF6/H2O with a ratio of 3:1 (v/v) (Table 1,
entry 21). The water presumably plays an important role in the
reaction due to the good water solubility of sodium sulfinates.
The yield was decreased to some extent when the reaction was car-
ried out at the elevated temperature (Table 1, entries 26–27).
With the optimized reaction conditions in hand, we next inves-
tigated the scope and generality of the sulfenylation using various
sulfinates and N-(organothio)succinimides (Table 2).
Initially, we examined the reactions of N-(phenylthio)succini-
mide (1a) with different sodium sulfinates (2a–2j). Arylsulfinates
with a methyl group at the para position proved to be a good sub-
strate for this transformation, affording the corresponding prod-
ucts in higher yields than those bearing ortho position analogues,
which indicated that the steric effects of substituent affected the
yields of the reaction to some extent (Table 2, entries 1–2 and
16–17). The electronic properties of the substitution groups on
the aromatic ring associated with arylsulfinates had some effects
on the yields. Generally, the arylsulfinates possessing an elec-
tron-donating substituent gave a slightly higher yield of sulfenyla-
tion products. For example, electron-rich sulfinates, such as p-
methoxyphenylsulfinate (2c), afforded the desired product 3ce in
90% yield (Table 2, entry 3). In contrast, having an electron-with-
drawing substituent (e.g., NO2 and CF3) at the para position affor-
ded slightly lower yields of sulfenylation products 3bh and 3bi
(Table 2, entries 12–13). It is worth noting that aliphatic sulfinates,
such as sodium methylsulfinate (2f) was still a good partner for the
sulfenylation reaction, affording the corresponding products 3ag,
3bg, 3cg, and 3dg in good yields (Table 2, entries 7, 15, 21, and 26).

6770
G. Liang et al. / Tetrahedron Letters 53 (2012) 6768–6770
moderate to good yields. Efforts to explore the applications of
the present system in other transformations using N-(organo-
thio)succinimides as sulfur sources are ongoing in our group.
O
O
S
5 mol% Sc(OTf)3
[BMIM]PF6/H2O, 30 o
SAr1
1c
Ar2SO2Na
Ar1
S
Ar2
+
N
C
O
O
Ar1 = Ar2
= p-ClC6H4
2e
3ce, 82% yield
Acknowledgment
Scheme 3. Synthesis of symmetrical thiosulfonate.
We thank the National Natural Science Foundation of China
(No. 21102105), Natural Science Foundation of Zhejiang Province
(No. LY12B02011), the Technology Innovation Foundation of Zhe-
jiang Province (No. 2012R424015), and the Opening Foundation
of Zhejiang Provincial Top Key Discipline (No. 100061200114) for
financial support.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
09.132.
References and notes
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O
O
Sc(OTf)3/ILs
SO2Na
S
S
+
SPh
N
H2O
O
O
1a
2a
3aa
Run 1: 88%; Run 2: 85%; Run 3: 81%; Run 4: 81%; Run 5: 79%
Scheme 4. Reuse of the catalyst.
8. (a) Bentley, M. D.; Douglass, J. B.; Lacadie, J. A. J. Org. Chem. 1972, 37, 333; (b)
Fujiki, K.; Tanifuji, N.; Sasaki, Y.; Yokoyama, T. Synthesis 2002, 343; (c) Billard,
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On the other hand, other N-(organothio)succinimides (1b–1f)
were also investigated. First, N-(arylthio)succinimides bearing var-
ious groups, such as methyl, chloro, bromo, methoxy, and nitro
groups, were tolerated in this procedure, achieving the correspond-
ing desired products in acceptable yields (Table 2, entries 8–28).
The moderate to good yields of the desired products were obtained
when N-(alkylthio)succinimides, such as N-(benzylthio)succini-
mide (1g) was used as substrate (Table 2, entries 29–33).
It would be specially mentioned that the fluoro, chloro, and bro-
mo moieties in arylsulfinates were all tolerated in our catalytic sys-
tem and provided a novel route to the corresponding products in
moderate to good yields, making further elaborations of the corre-
sponding biaryl products possible.
Furthermore, we explored the synthesis of symmetrical thiosul-
fonates under our standard conditions. The reaction between N-(4-
chlorophenylthio)succinimide (1c) and sodium p-chlorobenzene-
sulfinate (2e) as a representative example is shown in Scheme 3.
It was observed that S-4-chlorophenyl 4-chlorobenzenesulfono-
thioate (3ce) was isolated in 82% yield. The structure of 3ce was
unambiguously confirmed by X-ray single-crystal diffraction anal-
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18. CCDC-851468 contains the supplementary crystallographic data for 3ce, which
are available free of charge via www.ccdc.cam.ac.uk.
Finally, we investigated the recycling of the Sc(OTf)3/ILs in subse-
quent sulfenylation, for example, the reaction of N-(phenylthio)suc-
cinimide (1a) and sodium p-tolylsulfinate (2a) (Scheme 4). The
catalytic system (Sc(OTf)3/[BMIM]PF6) was reused for five runs
without a significant loss in the catalytic activity.
In summary, we have developed Sc(OTf)3-catalyzed sulfenyla-
tion of sodium sulfinates with N-(organothio)succinimides in ionic
liquids and water cosolvent system, affording thiosulfonates in
19. General procedure for the synthesis of thiosulfonates: To
a solution of 1
(0.3 mmol) and 2 (0.36 mmol) in [BMIM]PF6 (3 mL) and H2O (1 mL), Sc(OTf)3
was added at 30 °C. The mixture solution was stirred at 30 °C for respective
time. After the completion of the reaction, as monitored by TLC and GC–MS
analysis, the mixture was washed with water and extracted with diethyl ether.
The organic phase was concentrated and the resulting residue was purified by
column chromatography on silica gel (300–400 mesh) with petroleum ether-
EtOAc as eluent to provide the desired thiosulfonates 3.