One-pot synthesis of thia-Michael products from thio acids, epoxides, and electron-deficient alkenes promoted by a silica gel/Et3N combined catalyst

Article abstract of DOI:10.1016/j.tetlet.2012.05.042

An efficient method for the one-pot production of thia-Michael adducts using thio acids, epoxides, and electron-deficient alkenes is described. Epoxides quickly underwent nucleophilic ring-opening with thio acids on the silica gel surface at room temperat

Full text of DOI:10.1016/j.tetlet.2012.05.042

Tetrahedron Letters 53 (2012) 3683–3685
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Tetrahedron Letters
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One-pot synthesis of thia-Michael products from thio acids, epoxides, and
electron-deficient alkenes promoted by a silica gel/Et3N combined catalyst
⇑
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:
An efficient method for the one-pot production of thia-Michael adducts using thio acids, epoxides, and
electron-deficient alkenes is described. Epoxides quickly underwent nucleophilic ring-opening with thio
acids on the silica gel surface at room temperature under solvent-free conditions to yield b-hydroxy
thioester intermediates. After addition of an electron-deficient alkene and a catalytic amount of Et3N
to the reaction mixture, the b-acyloxy mercaptans were generated in situ and subsequently underwent
thia-Michael addition reactions to produce the corresponding adducts in good to excellent yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 27 March 2012
Revised 27 April 2012
Accepted 10 May 2012
Available online 16 May 2012
This article is dedicated to my dear teacher,
Professor Habib Firouzabadi
Keywords:
Michael addition
Conjugate addition
Thiol
Silica gel
Epoxide
Organosulfur compounds are important materials in chemistry,
biochemistry, and industry.1 They are prepared by diverse synthetic
methods using different starting materials. Thiols are versatile sub-
strates for the synthesis of various organosulfur molecules in many
chemical transformations.2 For instance, thia-Michael adducts, as
key intermediates in the synthesis of some bioactive compounds,3
are prepared through the addition of thiols to electron-deficient
olefins. Studies on thia-Michael addition reactions are mainly
restricted to modification of the catalysts and conditions for addi-
tion of simple, commercially available thiols to the conjugated
alkenes.2,4 For the preparation of structurally diverse thia-Michael
adducts, the corresponding thiols must be synthesized initially.
One-pot, multi-stage, and multi-component reactions are
important since they represent efficient synthetic routes for the
preparation of target molecules. The one-pot synthesis of thia-
Michael adducts via addition of in situ generated thiols to elec-
tron-deficient olefins using alkyl halides and thiourea has been
previously reported.5 In this Letter, a new procedure for the one-
pot synthesis of thia-Michael products using thio acids, epoxides,
and Michael acceptors is introduced.
silica gel/Et3N combined catalyst.7 Accordingly, we were interested
in exploring a procedure for the one-pot synthesis of thia-Michael
adducts using thio acids, epoxides, and electron-deficient alkenes.
For this purpose, 2-(phenoxymethyl)oxirane, thioacetic acid, and
n-butyl acrylate were chosen as model substrates. Thus, silica gel
60 (Merck, 70–230 mesh) (1 g) was added to a mixture of 2-(phen-
oxymethyl)oxirane (2.1 mmol) and thioacetic acid (2.1 mmol) at
room temperature under solvent-free conditions. After 5 min, the
addition of thioacetic acid to the epoxide was complete and the
corresponding b-hydroxy thioester was obtained. Next, n-butyl
acrylate (2 mmol) and Et3N (0.1 mmol) were added to the stirred
mixture at 50–60 °C and the stirring was continued for 3 h. During
this period, n-butyl acrylate was completely consumed and the
corresponding thia-Michael adduct was isolated in 92% yield. A
similar reaction in the absence of Et3N proceeded more slowly
and produced the desired thia-Michael adduct in only 30% yield
after 24 h. Unreacted n-butyl acrylate and b-hydroxy thioester
were also detected in this reaction mixture, whereas the free thiol
was not found. Further experiments showed that the presence of
silica gel for in situ generation of thiol from the b-hydroxy thioes-
ter was also important; in its absence the reaction failed and both
substrates were isolated intact after 24 h. To establish the scope of
the method, various Michael acceptors, epoxides, and thioacetic
and thiobenzoic acids were examined under the optimized condi-
tions8 (Table 1).
The nucleophilic addition of thio acids to epoxides to produce
the corresponding b-hydroxy thioesters is a well-known process.6
Our recent studies have shown that a b-hydroxy thioester can rear-
range to the corresponding b-acyloxy mercaptan isomer using a
In accordance with the experiments, a feasible pathway is illus-
trated in Scheme 1.
⇑
Tel.: +98 7734221425; fax: +98 7734221462.
E-mail address: abbassi@pgu.ac.ir
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.042

3684
M. Abbasi / Tetrahedron Letters 53 (2012) 3683–3685
Table 1
One-pot thia-Michael product synthesis using electron-deficient alkenes, thio acids, and epoxides
OCOR1
S
R2
1) SiO2, 5 min
R1COSH
+
R2
EWG
O
2) Et3N,
EWG
thio acid
epoxide
product
Entry
1
R1
Epoxide
EWG
Product
PhOH2C
PhOH2C
PhOH2C
PhOH2C
PhOH2C
PhOH2C
Yielda
92
O
OCOCH3
S
CH3
CO2Bu-n
COCH3
CN
1
2
3
4
5
6
7
CH2OPh
CO2Bu-n
COCH3
CN
O
O
O
O
O
O
O
OCOCH3
S
2
3
4
5
6
7
CH3
CH3
Ph
90
94
90
84
93
87
CH2OPh
CH2OPh
CH2OPh
CH2OPh
CH2OPh
OCOCH3
S
OCOPh
S
CO2Bu-n
COCH3
CN
CO2Bu-n
COCH3
CN
OCOPh
S
Ph
OCOPh
S
Ph
OCOCH3
S
CH3
CO2Bu-n
CH3
CO2Bu-n
OCOCH3
S
8
CH3
CH3
Ph
COCH3
CN
8
84
87
86
85
82
89
87
CH3
COCH3
O
O
OCOCH3
S
9
9
CH3
CH3
CN
OCOPh
S
10
11
12
13
14
CO2Bu-n
COCH3
CN
10
11
12
13
14
CO2Bu-n
O
OCOPh
S
Ph
CH3
CH3
COCH3
O
O
OCOPh
S
Ph
CN
OCOCH3
S
CH3
Ph
CO2Bu-n
CO2Bu-n
CH2OCH(CH3)2
(CH3)2CHOCH2
CO2Bu-n
CO2Bu-n
O
O
O
O
O
OCOPh
S
CH2OCH(CH3)2
O
(CH3)2CHOCH2
OCOCH3
S
15
16
17
18
CH3
CH3
Ph
CO2Bu-n
CN
15
16
17
18
90
85
91
90
CH2=CHCH2OCH2
CH2=CHCH2OCH2
CH2=CHCH2OCH2
CH2=CHCH2OCH2
CO2Bu-n
OCOCH3
S
O
O
CN
OCOPh
S
CO2Bu-n
CN
CO2Bu-n
CN
OCOPh
S
O
O
Ph
OCOPh
O
19
20
21
Ph
Ph
Ph
CO2Bu
COCH3
CN
19
20
21
87
83
83
S
OBu-n
OCOPh
O
O
O
S
OCOPh
CN
S
a
Yield refers to isolated product.
Regioselective addition of thio acid to the non-substituted car-
oxygen atom; this immediately undergoes Michael addition reac-
tion with the electron-deficient alkene. This stage is promoted by
the SiO2/Et3N combination.
In conclusion, an efficient, straightforward, and high yielding
procedure for the one-pot preparation of thia-Michael adducts of
bon atom of the terminal epoxide is facilitated by silica gel produc-
ing the corresponding b-hydroxy thioester. The b-acyloxy
mercaptan intermediate is then produced gradually from b-hydro-
xy thioester due to the acyl group transfer from sulfur to the

M. Abbasi / Tetrahedron Letters 53 (2012) 3683–3685
3685
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R1
H
R1
O
O
OH
O
O
SiO2
+
SiO2/Et3N
O
R1
SH
R2
S
S
R2
R2
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R1
HS
O
R1
O
EWG
S
SiO2/Et3N
R2
EWG
R2
Scheme 1. A possible pathway for the one-pot generation of thia-Michael products
using thio acids, epoxides, and Michael acceptors.
b-acyloxy mercaptans using thio acids, epoxides, and electron-
deficient alkenes under solvent-free conditions has been devel-
oped. In this method, the b-acyloxy mercaptans are generated
in situ utilizing thio acid and epoxide substrates and a silica gel/
Et3N combined catalyst. This method is important because it
provides a short synthetic route to achieve the corresponding
thia-Michael adducts of non-commercial mercaptans using readily
available substrates.
Acknowledgement
7. Abbasi, M. Tetrahedron Lett. 2012, 53, 2608–2610.
8. General procedure: silica gel 60 (1 g) was added to a stirred mixture of a thio acid
(2.1 mmol) and an epoxide (2.1 mmol) at room temperature under solvent-free
conditions. After consumption of the starting materials (less than 5 min), an
electron-deficient alkene (2 mmol) and Et3N (0.1 mmol) were added to the
mixture and stirring was continued at 50–60 °C. The reaction progress was
monitored by GC or TLC. After complete consumption of the alkene (3 h for
reactions using thioacetic acid and 7 h for reactions using thiobenzoic acid), the
mixture was extracted with EtOAc, and then concentrated. The crude product was
purified by silica gel column chromatography (EtOAc:n-hexane = 1:15 v/v) and
the corresponding thia-Michael product was isolated in 82–94% yield. Physical,
spectral, and analytical data for butyl 3-{[2-(acetyloxy)-3-phenoxypropyl]sulfanyl}
propanoate (1): Colorless oil; 1H NMR (250 MHz, CDCl3) d: 7.21–7.13 (m, 2H),
6.88–6.71 (m, 3H), 5.22–5.12 (m, 1H), 4.11–4.50 (m, 2H), 3.99 (t, J = 6.6 Hz, 2H),
2.88–2.69 (m, 4H), 2.54–2.48 (m, 2H), 1.98 (s, 3H), 1.56–1.45 (m, 2H), 1.34–1.17
(m, 2H), 0.83 (t, J = 7.3 Hz, 3H); 13C NMR (62.9 MHz, CDCl3) d: 171.7, 170.3, 158.4,
129.5, 121.3, 114.6, 71.4, 67.2, 64.5, 34.7, 32.2, 30.6, 27.6, 21.0, 19.1, 13.7; IR
We gratefully acknowledge financial support of this study by
the Persian Gulf University Research Council.
Supplementary data
Supplementary data (1H and 13C NMR spectra of all products)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.05.042.
References and notes
1. (a) Frausto da Silva, J. R.; Williams, R. J. P. The Biological Chemistry of the Elements;
Oxford University Press: New York, 2001; (b)The Chemistry of Sulfur-containing
Functional Groups; Patai, S., Rappoport, Z., Eds.; Wiley-Interscience: New York,
1993; (c) Oae, S. Organic Sulfur Chemistry; CRC: Boca Raton, 1991; (d) Parry, R. J.
(neat):
(C18H26O5S): C, 60.99; H, 7.39; S, 9.05. Found: C, 60.76; H, 7.51; S, 8.90.
m
(cmÀ1) = 1735 (C@O ester), 1597 (C@C aromatic); Anal. Calcd for