Ultrasound-Accelerated Synthesis of Asymmetrical Thiosulfonate S-Esters by Base-Promoted Reaction of Sulfonyl Chlorides with Thiols

Article abstract of DOI:10.1080/10426507.2015.1034313

Amberlyst A-26, Mg-Al hydrotalcite, potassium fluoride absorbed on alumina, triethylamine and pyridine have been tested as base catalysts and reagents for the reaction of sulfonyl chlorides with thiols to prepare thiosulfonate S-esters. The reactions were performed under solvent-free conditions or with a minimum amount of solvent assisted by magnetic stirring, ultrasound irradiation and microwave irradiation. Ultrasound irradiation has good effects on the synthesis of sterically hindered thiosulfonate S-esters in solvent-free media as well as in a minimum amount of anhydrous diethyl ether.

Full text of DOI:10.1080/10426507.2015.1034313

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Phosphorus, Sulfur, and Silicon and the Related
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Ultrasound accelerated synthesis of asymmetrical
thiosulfonate s-esters by base-promoted reaction of
sulfonyl chlorides with thiols
Hien Thi Phama, Ngoc-Lan Thi Nguyenb, Fritz Duusa & Thi Xuan Thi Luuab
a Department of Science, Systems and Models, Roskilde University, POB 260, Roskilde
DK-4000, Denmark
b Department of Organic Chemistry, University of Science, Hochiminh city, Vietnam
Accepted author version posted online: 13 May 2015.
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To cite this article: Hien Thi Pham, Ngoc-Lan Thi Nguyen, Fritz Duus & Thi Xuan Thi Luu (2015): Ultrasound accelerated
synthesis of asymmetrical thiosulfonate s-esters by base-promoted reaction of sulfonyl chlorides with thiols, Phosphorus,
Sulfur, and Silicon and the Related Elements
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ULTRASOUND
ACCELERATED
SYNTHESIS
OF
ASYMMETRICAL
THIOSULFONATE S-ESTERS BY BASE-PROMOTED REACTION OF SULFONYL
CHLORIDES WITH THIOLS
Hien Thi Phama, Ngoc-Lan Thi Nguyenb, Fritz Duusa and Thi Xuan Thi Luua,b*
aDepartment of Science, Systems and Models, Roskilde University, POB 260, Roskilde DK-
4000, Denmark
bDepartment of Organic Chemistry, University of Science, Hochiminh city, Vietnam
* Corresponding author: Email: ltxthi@hcmus.edu.vn; Tel.: +84-838-353-659; Fax: +84-838-
350-096.
Abstract
Amberlyst A-26, Mg-Al hydrotalcite, potassium fluoride absorbed on alumina, triethyl
amine and pyridine have been tested as base catalysts and reagents for the reaction of
sulfonyl chlorides with thiols to prepare thiosulfonate S-esters. The reactions were
performed under solvent-free conditions or with a minimum amount of solvent assisted
by magnetic stirring, ultrasound irradiation and microwave irradiation. Ultrasound
irradiation has good effects on the synthesis of sterically hindered thiosulfonate S-esters
in solvent-free media as well as in a minimum amount of anhydrous diethyl ether.
O
O
R1 S Cl
O
Base
, )
R1 S S R2
R2 SH
+
)
)
O
1
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Keywords
Thiosulfonates, thiols, sulfonyl chlorides, triethyl amine, ultrasound irradiation
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INTRODUCTION
Thiosulfonate S-esters (general formula: R1SO2-SR2) have been known as existing
compounds since the early years of the 20th century. They have been recognized as powerful
sulfenylating reagents in general and industrial organic chemistry,[1] as blocking reagents in
protein chemistry,[2] and as bioactive compounds in medicinal chemistry.[3-6]
Symmetrical thiosulfonates (R1SO2-SR2, R1 = R2) have been prepared by the oxidation of
thiols,[7-8] of disulfides,[9-11] and of thiosulfinates,[12-13] as well as by reduction of sulfinyl
chlorides or sulfonyl chlorides,[14-15] and by chlorosolvolysis.[16-19] On the other hand, the direct
oxidation of asymmetrical disulfides to produce the corresponding thiosulfonate S-esters
appeared not to be successful owing to the poor selectivity with respect to the potential
products.[20-22]. The synthesis of asymmetrical thiosulfonates (R1SO2-SR2, R1 ≠ R2) by reaction
of sulfonyl chlorides with thiols in the presence of the base pyridine were investigated over
eighty years ago and demonstrated that the formation of disulfides (R2-S-S-R2) influenced on the
yield of thiosulfonates.[23-24]. Based on this achievement, many sulfonyl halides were used to
react with the other thiols or thiolates.[6,24-26]. Similarly, asymmetrical thiosulfonates have also
been obtained by the reaction of sulfinic acids with thionitrites in situ (activated thiols),[27-28]
,
with thiosulfinates in aniline as solvent,[29] and by the reaction of sulfonates with thiols.[30] The
alkylation of salts of thiosulfonic acid at low temperature,[31-33] as well as the sulfenylation of
several metal sulfinates by using sulfenyl halides,[34-35] disulfides,[35-37] or N-
(alkylthio/arylthio)succinimides were developed.[38] In some cases of synthesis of asymmetrical
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thiosulfonates, the addition of heterocyclic thiosulfonic acids to carbonyl compounds,[39] or the
oxidation of asymmetrical thiosulfinic S-ester were studied.[13,21]
Good stability and commercial availability of sulfonyl chlorides and thiols have made S-
sulfonylation become an interesting method for many decades to produce symmetrical and
asymmetrical thiosulfonates.[23-24] Due to the toxicity of pyridine, its presence as base catalyst
has no longer been favorite in organic synthesis.[40]. In 2006, S. R. El-Zemity et al. replaced
pyridine with triethyl amine to produce asymmetrical benzenethiosulfonates by the overnight
reaction of sulfonyl chlorides and thiols.[6]
With some reasons of green chemistry on benign and fast procedures as well as energy
saving way,[41-42] the reaction of sulfonyl chlorides with thiols catalyzed by several bases under
homogeneous or heterogeneous conditions was investigated in detail (Scheme 1). Moreover, the
nature of sulfonyl chlorides as well as thiols was tested to illustrate the scope and generality of
this process.
RESULTS AND DISCUSSION
On the way to find a good base catalyst, the reaction of 1-propanesulfonyl chloride (1a, R1
= CH3CH2CH2) and 2-methyl-2-propanethiol [2a, R2 = (CH3)3C] was initially carried out at
room temperature under different reaction activations such as magnetic stirring, ultrasound
irradiation and microwave irradiation (Table 1). The primary results demonstrated that potassium
fluoride adsorbed on alumina gave low yields, especially under microwave irradiation. Some
experiments on testing the stability of tert-butyl propane-1-thiosulfonate in the presence of
w
potassium fluoride adsorbed on alumina (40%, /w) under microwave irradiation displayed that
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the remaining thiosulfonate S-ester occupied 5%, and some products were formed from
disaggregation of thiosulfonates including symmetrical/asymmetrical disulfides (31%), and
trisulfides (45%). This led us to select magnetic stirring and ultrasound irradiation as two
methods for reaction activation. A series of experiments on categories of catalysts was performed
in order to find out good conditions to get high yields. The results of Table 1 were evidences for
selection of triethyl amine as a good base catalyst for the preparation of thiosulfonate from
sulfonyl chloride and thiol under magnetic stirring and ultrasound irradiation (Entry 3, Table 1).
This is logical because triethyl amine is not only a base catalyst but also a reagent to form
sulfene from alkanesulfonyl chloride to produce alkanethiosulfonates.[43-44]
Following the current aim of green chemistry, the solvent-free experiments of propane-1-
sulfonyl chloride and 2-methyl-2-propanethiol with triethyl amine were preferred to carry out in
the beginning of research. Ultrasound irradiation made the reaction become milder, less disulfide
formation occurred and a higher yield of thiosulfonate S-ester (86%) compared with magnetic
stirring (Entry 3, Table 1) was obtained. Obviously, ultrasound irradiation has good effects on
the liquid/liquid interface as well as the solid/liquid phase to increase the interfacial contact area
more than conventional rotational mixing techniques.[45] However, due to triethylammonium
chloride appeared under solvent-free condition as obstacles on the interaction of reagents,
reaction conversions were not converted completely even if they were assisted by ultrasound
irradiation. It turned our mind to use a minimum amount of organic solvent to support the
reaction mixing. A series of experiments was carried out under one-hour stirring, in which the
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amount of solvent was varied. Finally, the most appropriate amount of anhydrous diethyl ether (2
mL) used for the reaction was selected.
A complete reaction conversion was not obtained by prolongation of the reaction time at
equivalent molar of propane-1-sulfonyl chloride, 2-methyl-2-propanethiol and triethyl amine.
Therefore, varying the molar ratio of sulfonyl chloride, thiol and triethyl amine was necessary for
further investigations to increase the reaction conversion and the yield of thiosulfonate S-ester.
Consequently, using an excessive triethyl amine amount was regarded as the better way to
increase the reaction conversion than using an excessive amount of sulfonyl chloride as well as
thiol. In comparison of the efficiency of two activation methods, the reaction conditions were
optimized under magnetic stirring or ultrasound irradiation independently. A maximum yield of
thiosulfonate S-esters obtained under magnetic stirring (97%) are comparable to or a little bit less
than it was under ultrasound irradiation (98%) after a short reaction time (Entry 3, Table 1).
In order to master the formation of thiosulfonate S-esters and disulfides, eight alkane/arene
thiols and nine sulfonyl chlorides were investigated (cf. Table 2). The results displayed that the
formation of symmetrical disulfides happened very fast with thiols containing primary aliphatic
alkyl groups (ethanethiol, n-butanethiol, phenylmethanethiol, and 2-furylmethanethiol in entry 5-
8 of Table 2), as well as with thiophenol (entry 9, Table 2). Based on the previous literature, the
formation of disulfides has been occurred due to i) the self-coupling of thiols in strong base
media under microwave irradiation,[46] or ii) the further reaction of thiosulfonate S-esters and
thiols in the base medium.[24,47-48] A series of experiments on two categories of the above
reaction was tested under the same conditions of the synthetic procedure of tert-butyl propane-1-
thiosulfonate. For self-coupling of thiols by using triethyl amine as base catalyst (weaker base
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than potassium fluoride absorbed on alumina), the corresponding disulfides were not obtained
from branched alkanethiols (2-methyl-2-propanethiol, and cyclohexanethiol), or obtained a low
yield (2 %) from simple aliphatic alkanethiol (n-butanethiol). In contrary, aromatic disulfide was
produced easily from benzenethiol with 45% yield. It was explained that thiophenol had higher
acidity and formed thiolate anions easier than the aliphatic alkanethiols in base medium due to
the resonance of the aromatic ring on sulfide atom. In the other way to account for the formation
of disulfide, tert-butyl benzenethiosulfonate was easily converted into the corresponding
asymmetrical disulfides by reacting of thiols (n-butanethiol, thiophenol, n-octanethiol and
cyclohexanethiol).[49] Evidently, the nucleophilic substitution of thiols into new-born
thiosulfonate S-esters was affected by factor of steric hindrance. Therefore, it is difficult for
thiols with bulky alkyl groups to form disulfides in the next stage (entry 1-4, Table 2).
On the other hand, 2-methyl-2-propanethiol was selected for surveying the effects of
alkyl/aryl groups linked to nine sulfonyl chlorides (entry 10-18, Table 2). The results showed
that the chlorine replacement of arenesulfonyl chlorides with thiol by using triethyl amine
happened following the slow nucleophilic substitution. It is compatible to the previous literature
explanation of the formation of highly reactive sulfene intermediates from alkanesulfonyl
chlorides in the presence of trimethylamine.[43-44]
CONCLUSION
Comprehensive experiments on the synthesis of thiosulfonate S-esters from sulfonyl
chlorides and thiols have demonstrated that triethylamine is still a better base reagent than
pyridine, Mg-Al hydrotalcite, amberlyst A-26 or potassium fluoride on alumina. The sterically
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hindered asymmetrical thiosulfonate S-esters are produced with high yields in shorter reaction
times. Ultrasound irradiation affects efficiently the reaction conversion and the yield of
thiosulfonate under the solvent-free or solvent conditions.
EXPERIMENTAL
General
All commercially available chemicals used were from Sigma Aldrich. Ultrasound
irradiation was performed by means of a BRANSON 1210E-MT ultrasonic bath, operating at a
frequency 47 kHz. GC/MS analyses were performed on a Hewlett Packard 5890 GC 5971A MS
apparatus equipped with a J&W DB-5MS capillary column (30 m, 0.25 mm i.d., 0.25 µm film
thickness) and a Hewlett Packard 7673A autosampler. NMR spectra were recorded on a Varian
Mercury 300 NMR spectrometer at 300 MHz (1H) and 75 MHz (13C) in CDCl3.
tert-Butyl propane-1-thiosulfonate by using triethyl amine under ultrasound
irradiation.
Triethyl amine (5.2 mmol) was added to a 10 mL two-neck flask containing 2-methyl-2-
propanethiol (5 mmol) dissolved in anhydrous diethyl ether (2 mL). Then propane-1-sulfonyl
chloride (5 mmol) was added drop-wise at room temperature. The flask was fitted with a
condenser jointed an anhydrous calcium chloride tube and was placed in an ultrasound bath,
where the mixture of reactants was exposed to ultrasound irradiation for a specified period of
time (20 min). After the reaction was completed, the mixture was poured into a separatory funnel
and washed with de-ionized water until a neutral pH. The organic layer was dried over Na2SO4.
After removal of the solvent by rotational evaporation, the remaining crude product was
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analyzed by GC/MS. The desired product was purified by silica gel column chromatography and
eluted by hexane and dichloromethane, and then was analyzed by NMR spectroscopy.
Spectroscopic data
The identity and purity of all thiosulfonates synthesized were ensured by 1H and 13C NMR
1
spectroscopy as well as by GC/MS. The observed H and 13C NMR spectroscopic data are listed
below, and all of them were found compatible with those reported in the literature.[50-53]
tert-Butyl propane-1-thiosulfonate 3a: 1H NMR: δ = 3.30 (t, J = 7.8 Hz, 2H), 1.89-2.20 (m,
2H), 1.59 (s, 9H), 1.08 (t, J = 7.5 Hz, 3H); 13C NMR: δ = 66.25, 55.15, 31.10 (3C), 17.31, 12.74.
MS: m/z = 196[M]⋅+, 89, 75, 57, 41.
1
s-Butyl propane-1-thiosulfonate 3b: H NMR: δ = 3.44-3.55 (m, 1H), 3.29 (t, J = 7.8 Hz, 2H),
1.90-2.03 (m, 2H), 1.70-1.80 (m, 2H), 1.48 (d, J = 7.2 Hz, 3H), 1.09 (t, J = 7.8 Hz, 3H), 1.04 (t, J
= 7.5 Hz, 3H); 13C NMR: δ = 64.94, 49.53, 30.14, 21.95, 17.39, 12.71, 11.25. MS: m/z =
196[M]⋅+, 167, 141, 131, 99, 88, 75, 57, 41.
Isopropyl propane-1-thiosulfonate 3c: 1H NMR: δ = 3.68 (sept, J = 6.9 Hz, 1H), 3.29 (t, J
= 7.8 Hz, 2H), 2.02-1.90 (m, 2H), 1.47 (d, J = 6.9 Hz, 6H), 1.09 (t, J = 7.5 Hz, 3H); 13C NMR: δ
= 65.00, 42.92, 24.07 (2C), 17.35, 12.71. MS: m/z = 182[M]⋅+, 167, 141, 118, 99, 76, 61, 43.
1
Cyclohexyl propane-1-thiosulfonate 3d: H NMR: δ = 3.45-3.54 (m, 1H), 3.28 (t, J = 7.8
Hz, 2H), 2.08-2.14 (m, 2H), 1.89-2.02 (m, 2H), 1.72-1.80 (m, 2H), 1.22-1.64 (m, 6H), 1.08 (t, J
= 7.5 Hz, 3H); 13C NMR: δ = 65.23, 50.55, 34.02 (2C), 25.86 (2C), 25.14, 17.39, 12.71. MS: m/z
= 222[M]⋅+, 158, 141, 114, 83, 55, 41.
tert-Butyl methanethiosulfonate 3j: 1H NMR: δ = 3.35 (s, 3H), 1.61 (s, 9H); 13C NMR: δ =
55.19, 52.83, 30.89 (3C). MS: m/z = 168[M]⋅+, 91, 73, 57, 41.
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tert-Butyl ethanethiosulfonate 3k: 1H NMR: δ = 3.34 (q, J = 7.5 Hz, 2H), 1.59 (s, 9H), 1.46
13
(t, J = 7.3 Hz, 3H); C NMR: δ = 58.85, 55.14, 31.08 (3C), 8.34. MS: m/z = 182[M]⋅+, 89, 75,
57, 41.
1
tert-Butyl 2-propanethiosulfonate 3l: H NMR: δ = 3.36 (sept, J = 6.9 Hz, 1H), 1.59 (s,
13
9H), 1.46 (d, J = 6.9 Hz, 6H); C NMR: δ = 64.12, 55.43, 31.29 (3C), 16.28 (2C). MS: m/z =
196[M]⋅+, 89, 75, 57, 41.
1
tert-Butylbutane-1-thiosulfonate 3m: H NMR: δ = 3.32 (t, J = 7.8 Hz, 2H), 1.85-1.96 (m,
2H), 1.59 (s, 9H), 1.42-1.54 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H); 13C NMR: δ = 64.34, 55.14, 31.09
(3C), 25.45, 21.31, 13.56. MS: m/z = 210[M]⋅+, 89, 75, 57, 41.
tert-Butyl 2-methylpropanethiosulfonate 3n: 1H NMR: δ = 3.26 (d, J = 6.3 Hz, 2H), 2.38-
13
2.51 (m, 1H), 1.59 (s, 9H), 1.12 (d, J = 6.9 Hz, 6H); C NMR: δ = 72.67, 55.12, 31.08 (3C),
25.16, 22.58 (2C). MS: m/z = 211[M]⋅+, 146, 113, 90, 57, 41.
1
tert-Butyl octane-1-thiosulfonate 3o: H NMR: δ = 3.31 (t, J = 7.9 Hz, 2H), 1.86-1.96 (m,
13
2H), 1.59 (s, 9H), 1.26-1.48 (m, 10H), 0.88 (t, J = 6.9 Hz, 3H); C NMR: δ = 64.62, 55.13,
31.69, 31.10 (3C), 29.00, 28.92, 28.03, 23.45, 22.59, 14.06. MS: m/z = 266[M]⋅+, 89, 71, 57, 41.
tert-Butyl phenylmethanethiosulfonate 3p: 1H NMR: δ = 7.38-7.45 (m, 5H), 4.51 (s, 2H),
1.53 (s, 9H); 13C NMR: δ = 131.46 (2C), 129.21, 128.71 (2C), 127.89, 70.21, 55.95, 31.02 (3C).
MS: m/z = 244[M]⋅+, 180, 124, 91, 57, 41.
1
tert-Butyl cyclohexanethiosulfonate 3q: H NMR: δ = 3.07 (tt, J = 12.0 Hz, J = 3.3 Hz,
13
1H), 2.30-2.36 (m, 2H), 1.92-1.97 (m, 2H), 1.13-1.74 (m, 15H); C NMR: δ = 72.04, 55.37,
31.34 (3C), 26.14 (2C), 25.33 (2C), 25.12. MS: m/z = 236[M]⋅+, 149, 115, 83, 57, 41.
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1
tert-Butyl benzenethiosulfonate 3r: H NMR: δ = 7.94-7.98 (m, 2H), 7.50-7.64 (m, 3H),
13
1.45 (s, 9H); C NMR: δ = 146.80, 133.30, 129.08 (2C), 126.93 (2C), 55.36, 30.81 (3C). MS:
m/z = 230[M]⋅+, 141, 109, 77, 57.
ACKNOWLEDGEMENTS
The authors are grateful to the Vietnamese National Foundation for Science and
Technology Development (NAFOSTED) for financial support under grant number [104.01-
2011.40]. The authors are also indebted to the Danish International Development Agency
(DANIDA) for financial support via the Enhancement of Research Capacity (ENRECA)
program.
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Table 1: Base catalysts on the yield of t-butyl 1-propanethiosulfonate.a
CH3
H3C C SH
CH3
O
CH3
O
H3CH2CH2C S Cl
O
CH3
H3C C S S C CH3
CH3 CH3
CH3
Base catalyst
H3CH2CH2C S S C CH3
+
+
O
CH3
(2a)
(1a)
(3a)
(4a)
Entry
Catalyst
Et2O
Time
3a,
Yielde
(Conv.e) (Conv.e)
4a,
Yielde
(mL)
(min)
60b
60c
5d
-
-
16 (28)
11 (21)
9 (26)
18 (28)
8 (14)
KF/Al2O3 40%
(3 g)
1
2
-
15 (38)
0.5 (1)
Mg-Al HT (3 g)
Mg-Al HT (30
g)
2
60c
9 (13)
10
240c
31 (52)
0.7 (1)
-
60b
30c
30b
20c
30b
30c
30b
65 (85)
86 (95)
97 (99)
98 (99)
15 (30)
19 (34)
0.6 (1)
8 (9)
2 (2)
-
Et3N (5.2
mmol)
3
2
2
2
2
2
Trace
Trace
17 (31)
16 (25)
0.9 (1.3)
Amberlyst A-26
(2 g)
4
5
Pyridin (5.2
mmol)
a The molar ratio of thiol : sulfonyl chloride = 5 : 5.
b Stirring method; c Ultrasound irradiation; d Microwave
irradiation.
e Yield and Conv. (Conversion yield) were based on GC/MS
analyses.
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Table 2: Yields of thiosulfonate S-esters under ultrasound irradiation.a
3, Yieldb
4, Yieldb
Entry
1
R1
R2
(Conv.b)
(Conv.b)
n-Propyl
t-Butyl
3a, 98 (99)
4a, trace
2
3
4
5
6
7
8
n-Propyl
n-Propyl
n-Propyl
n-Propyl
n-Propyl
s-Butyl
i-Propyl
Cyclohexyl
n-Butyl
3b, 65 (74)
3c, 61 (71)
3d, 60 (70)
3e, 23 (29)
3f, 13 (23)
3g, 9 (11)
3h, 2 (3)
4b, 17 (17)
4c, 16 (16)
4d, 20 (23)
4e, 50 (57)
4f, 34 (34)
4g, 48 (61)
4h, 53 (70)
Ethyl
n-Propyl 2-Furanemethyl
n-Propyl
n-Propyl
Benzyl
Phenyl
9
-
4i, 71 (90 )
4a, 2 (2)
4a, 1 (1)
4a, 1 (1)
4a, trace
4a, trace
4a, trace
4a, trace
10
11
12
13
14
15
16
t-Butyl
t-Butyl
t-Butyl
t-Butyl
t-Butyl
t-Butyl
t-Butyl
Methyl
Ethyl
3j, 81 (96)
3k, 87 (99)
3l, 79 (97)
3m, 92 (96)
3n, 86 (97)
3o, 89 (96)
3p, 90 (98)
i-Propyl
n-Butyl
i-Butyl
n-Octyl
Benzyl
Cyclohex
yl
17
t-Butyl
3q, 84 (86)
3r, 74 (82)
4a, trace
4a, 1 (1)
18
t-Butyl
Phenyl
a. The reaction of sulfonyl chlorides (5 mmol), thiols (5 mmol),
triethylamine (5.2 mmol) in anhydrous diethyl ether (2 mL) was irradiated
by ultrasound within twenty minutes.
b. Yield and Conv. (conversion yield) were based on GC/MS analysis.
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O
S
O
Base
R2
S
R1
S
R2
+
R2
R1
S
Cl
+
R2 SH
S
, )
)
)
O
O
(1)
MW
(4)
(2)
(3)
R1: Me, Et, n-Pr, n-Bu, n-Oc, i-Pr, i-Bu, Benzyl, Ph, c-C6H11
.
R2: Et, n-Bu, i-Pr, sec-Bu, t-Bu, c-C6H11, Benzyl, 2-Furanemethyl.
Scheme 1. Synthesis of thiosulfonate S-esters from sulfonyl chlorides and thiols in base medium.
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