A new synthetic route for the preparation of β-acyloxy mercaptans via the addition of thioacids to epoxides

Article abstract of DOI:10.1016/j.tetlet.2012.03.045

A new synthetic route for the preparation of S-benzylated β-acyloxy mercaptans starting from the one-pot reaction of thioacids and epoxides using a silica gel/Et₃N combined catalyst is described. The thiol functionality in the crude product is then protected via benzylation and the corresponding thioethers are isolated after chromatography.

Full text of DOI:10.1016/j.tetlet.2012.03.045

Tetrahedron Letters 53 (2012) 2608–2610
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A new synthetic route for the preparation of b-acyloxy mercaptans via the
addition of thioacids to epoxides
⇑
,
Mohammad Abbasi
Fisheries and Aquaculture Department, College of Agriculture and Natural Resources, Persian Gulf University, Bushehr 75169, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A new synthetic route for the preparation of S-benzylated b-acyloxy mercaptans starting from the one-pot
reaction of thioacids and epoxides using a silica gel/Et3N combined catalyst is described. The thiol func-
tionality in the crude product is then protected via benzylation and the corresponding thioethers are
isolated after chromatography.
Received 31 December 2011
Revised 16 February 2012
Accepted 13 March 2012
Available online 21 March 2012
Ó 2012 Published by Elsevier Ltd.
Keywords:
Thioacid
Epoxide
Silica gel
Et3N
b-Acyloxy mercaptan
O
OCOCH3
SH
The synthesis of sulfur-containing molecules has attracted
significant attention due to their application in industry, medicine,
and organic chemistry.1 Thiolic precursors are fundamental
substrates for the synthesis of many organosulfur compounds.2 Thi-
oesters are considered as masked thiols since they can be readily
transformed into the thiol functionality by hydrolysis or acyl group
transfer reactions under mild conditions.3 The addition of thioacids
to epoxides is a convenient method for the synthesis of b-hydroxy
thioesters and thus the corresponding thiols in organosulfur
synthesis. The synthesis of thiols starting from epoxides is synthet-
ically valuable since epoxides are readily available either commer-
cially, or by a variety of procedures. The addition of thioacids to
epoxides is not suitably developed and is limited to a few reports.4
Therefore, further studies on the addition of thioacids to epoxides
using easily available catalysts (to develop new efficient methods)
are important in organic synthesis.
Herein, we report a simple method for the one-pot generation of
b-acyloxy mercaptans from the reaction of thioacids with epoxides.
The reaction of thioacetic acid with 2-(phenoxymethyl)oxirane
under solvent-free conditions was chosen as a model reaction and
several attempts were made to find the best catalyst and optimize
the conditions. The corresponding b-acyloxy mercaptan was syn-
thesized in 89% yield at room temperature in the presence of an
Et3N/SiO2 combined catalyst after 10 h.
O
SiO2/Et3N
rt, 10 h
+
O
O
SH
Ph
Ph
In this study, silica gel (1 g) and Et3N (0.1 mmol) were added to a
stirred mixture of thioacetic acid (2 mmol) and 2-(phenoxy-
methyl)oxirane (2 mmol) at room temperature. According to TLC
and IR analysis of the reaction mixture, the reactants were com-
pletely converted into the corresponding b-hydroxy thioester dur-
ing the first 5 min. By continuing the stirring, b-hydroxy thioester
gradually rearranged into the corresponding b-acyloxy mercaptan
via acyl group transfer from oxygen to sulfur. It should be noted that
the presence of the Et3N/silica gel combined catalyst in this reaction
is crucial; similar reactions in the presence of only one of the cata-
lysts yielded the corresponding b-hydroxy thioester after 24 h. Also,
when b-hydroxy thioester was treated individually withEt3N or SiO2
δH
δ
= 4.02-4.04 (m, 2H); C = 71.0
δH
δ
= 5.13-5.22 (m, 1H); C = 67.4
δH
= 2.62 (dd, J = 14.1, 6.5 Hz, 1H), 2.70 (dd, J = 14.1, 6.6 Hz,
δ
1H); C = 31.3
O
S
OCOCH3
δH
δ
= 3.66 (s, 2H); C = 36.5
δH
δ
= 1.99 (s, 3H); C = 21.1
δC
= 170.4
⇑
Tel.: +98 7734221425; fax: +98 7734221462.
E-mail address: abbassi@pgu.ac.ir
Present address.
Figure 1. Selected NMR data for compound 2.
0040-4039/$ - see front matter Ó 2012 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2012.03.045

M. Abbasi / Tetrahedron Letters 53 (2012) 2608–2610
2609
Table 1
One-pot synthesis of b-acyloxy mercaptans from the reaction of epoxides with thioacids in the presence of SiO2/Et3N combined catalyst followed by –SH protection
O
O
R
O
R1
O
O
PhCH2Cl, Et3N
H2O
+
Et3N/SiO2, 10 h
R1
O
R1
SH
S
Ph
R
R
SH
Entry
1a
Epoxide
R1
Product
Yield (%)
O
O
O
O
O
O
CH2OC4H9-n
CH3
1
2
3
4
5
85
87
84
80
81
SCH2Ph
CH2OC4H9-n
O
O
O
O
O
O
O
O
O
O
CH2OPh
SCH2Ph
2a
3a
4a
5a
CH3
CH3
CH3
CH3
CH2OPh
CH2OCH(CH3)2
SCH2Ph
CH2OCH(CH3)2
CH2CH3
CH2CH3
SCH2Ph
CH3
SCH2Ph
CH3
O
SCH2Ph
O
O
6a
7a
CH3
CH3
6
7
88
O
O
O
SCH2Ph
O
O
73c
O
O
O
O
O
O
SCH2Ph
8a
CH3
8
79
O
O
O
O
O
O
O
CH2OC4H9-n
9b
10b
11b
12b
13b
Ph
Ph
Ph
Ph
Ph
9
10
11
12
13
79
78
85
85
80
SCH2Ph
CH2OC4H9-n
CH2CH3
Ph
Ph
Ph
O
O
O
O
O
CH2CH3
SCH2Ph
O
O
O
O
CH2OPh
SCH2Ph
CH2OPh
CH2OCH(CH3)2
SCH2Ph
CH2OCH(CH3)2
Ph
Ph
CH3
SCH2Ph
CH3
O
SCH2Ph
O
O
14b
15b
Ph
Ph
14
15
80
76
Ph
O
O
O
O
SCH2Ph
Ph
a
b
c
The reactions were conducted at room temperature.
The reactions were conducted at 50–60 °C.
The corresponding Michael product was not obtained.
at room temperature and at 60 °C, it was recovered intact from the
reaction mixture after 24 h. The crude product was extracted using
EtOAc, concentrated and before purification by chromatography
on silica gel, the –SH functionality was protected. The crude product
was added to a mixture of benzyl chloride (2 mmol) and Et3N
(2 mmol) in water (2 mL). The mixture was then stirred at
50–60 °C until the mercaptan was completely consumed (1.5–2 h).
The product was extracted and subjected to column chromatogra-
phy (silica gel 70–230 mesh) using EtOAc/hexane (1:20) as eluent
to afford 2-(benzylsulfanyl)-1-(phenoxymethyl)ethyl acetate (2) in
87% yield. This compound was obtained as colorless oil and its struc-
ture was established by spectroscopic and analytical techniques.
The IR spectrum of the product showed the characteristic signal of
an ester (1742 cmÀ1). The 1H NMR spectrum of this compound
consisted of two singlets at 1.99 and 3.66 ppm which correlated to
the resonances of CH3 and benzylic CH2 protons, respectively. The
multiple resonances between 4.02–4.04 and 5.13–5.22 ppm were
due to CH2O and CH hydrogens, and the two doublets of doublet
resonances at 2.62 and 2.70 ppm were assigned to the diastereotop-
ic hydrogens on CH2S linked to methine carbon. Also, 10 aromatic

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M. Abbasi / Tetrahedron Letters 53 (2012) 2608–2610
hydrogen atoms were appeared as multiplet resonances between
6.78 and 7.23 ppm. The 13C NMR spectrum contained 14 resonances,
which were assigned to methyl (d = 21.1), methylenes (d = 31.3,
36.5, 71.0), methine (d = 67.4), aromatic (d = 114.7, 121.3, 127.2,
128.6, 129.0, 129.5, 137.9, 158.4), and carbonyl (d = 170.4) carbons
(Fig. 1).
This protocol was applied for the synthesis of structurally
diverse S-benzylated b-acyloxy mercaptans.5 The results are sum-
marized in Table 1.
These results clearly prove that the reaction of thioacids with
epoxides in the presence of SiO2/Et3N combined catalyst can be
used for the one-pot synthesis of valuable bifunctional b-acyloxy
mercaptans in high yields. It can be concluded from the results that
the less-hindered carbon atom of epoxides is attacked by thioacids.
In conclusion, we have developed an efficient one-pot proce-
dure for the synthesis of b-acyloxyl mercaptans via the addition
of thioacids to epoxides in the presence of silica gel/Et3N combined
catalyst. This method is particularly important because it provides
a short route to obtain derivatives of non-commercially available
thiols. It is also noteworthy given its experimental simplicity, high
generality, and the low cost of the catalyst system.
References and notes
1. (a) Metzner, P.; Thuillier, A. Sulfur Reagents in Organic Synthesis; Academic Press:
New York, 1994; (b) Fujita, E.; Nagao, Y. Bioorg. Chem. 1977, 6, 287–309; (c)
Nudelman, A. The Chemistry of Optically Active Sulfur Compounds; Gordon and
Breach: New York, 1984; (d) Chatgilialoglu, C.; Asmus, K. D. Sulfur-Centered
Reactive Intermediates in Chemistry and Biology; Springer: New York, 1991.
2. (a) Koval, I. V. Russ. J. Org. Chem. 2007, 43, 319–346; (b) Procter, D. J. J. Chem. Soc.,
Perkin Trans. 1 1999, 641–667; (c) Patai, S. The Chemistry of the Thiol Group;
Wiley: New York, 1974.
3. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; John
Wiley and Sons: New York, 2007; (b) Patai, S. The Chemistry of Thiol Group;
Wiley: New York, 1974; (c) Koval, I. V. Russ. Chem. Rev. 1994, 63, 147–168; (d)
Mukaiyama, T.; Araki, M.; Takei, H. J. Am. Chem. Soc. 1973, 95, 4763–4765; (e)
McGarvey, G. J.; Williams, J. M.; Hiner, R. N.; Matsubara, Y.; Oh, T. J. Am. Chem.
Soc. 1986, 108, 4943–4952; (f) Conrow, R.; Portoghese, P. S. J. Org. Chem. 1986,
51, 938–940.
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Org. Chem. 2005, 41, 631–648; (c) Lesuisse, D.; Gourvest, J. F.; Hartmann, C.; Tric,
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5. General procedure: Silica gel 60 (70–230 mesh) (1 g) and Et3N (0.1 mmol) were
added to a stirred mixture of an epoxide and a thioacid at room temperature
under solvent-free conditions. The progress of the reaction was monitored by
TLC and IR spectroscopy. After 5 min, the starting epoxide had been completely
converted into the corresponding b-hydroxy thioester. However, stirring was
continued for another 10 h at rt (for reactions using thioacetic acid) or at 50–
60 °C (for thiobenzoic acid including reactions). During this time, b-hydroxy
thioester was mainly converted into the corresponding b-acyloxy mercaptan.
Next, the crude b-acyloxy mercaptan product was extracted using EtOAc
(3 Â 3 mL) and after concentration was directly subjected to –SH benzylation in
H2O (2 mL) using benzyl chloride (2 mmol) and Et3N (2 mmol). This mixture
was stirred at 50–60 °C until the mercaptan had been completely consumed
(1.5–2 h). The product was extracted with EtOAc (3 Â 2 mL). The organic layers
were combined, washed with HCl (1 M, 3 mL), dried over Na2SO4, filtered, and
concentrated to yield the crude product. This product was then further purified
by chromatography on silica gel using n-hexane/EtOAc (20:1) as eluent to
provide the desired pure product in good to excellent yield (Table 1).
Acknowledgement
We gratefully acknowledge the support of this study by the
Persian Gulf University Research Council.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.03.
045.