One-pot synthesis of allyl thioacetate from benzaldehydes and activated alkenes using the Morita-Baylis-Hillman reaction as a key step

Article abstract of DOI:10.1080/17415993.2015.1124275

An efficient, regioselective and steresoselecitive one-pot protocol for the synthesis of (Z)-S-2-alkoxycarbonyl-3-acylallyl ethanethioates and (E)-S-2-cyano-3-acylallyl ethanethioates from benzaldehydes and activated alkenes (methyl acrylate and acrylonit

Full text of DOI:10.1080/17415993.2015.1124275

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
One-pot synthesis of allyl thioacetate from
benzaldehydes and activated alkenes using the
Morita–Baylis–Hillman reaction as a key step
Hae-Won Yang, Ji-Su Choi, Sang-Jin Lee, Byung-Woo Yoo & Cheol Min Yoon
To cite this article: Hae-Won Yang, Ji-Su Choi, Sang-Jin Lee, Byung-Woo Yoo & Cheol Min Yoon
(2016) One-pot synthesis of allyl thioacetate from benzaldehydes and activated alkenes using
the Morita–Baylis–Hillman reaction as a key step, Journal of Sulfur Chemistry, 37:2, 134-140,
DOI: 10.1080/17415993.2015.1124275
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Date: 31 March 2016, At: 00:54

JOURNAL OF SULFUR CHEMISTRY, 2016
VOL. 37, NO. 2, 134–140
http://dx.doi.org/10.1080/17415993.2015.1124275
One-pot synthesis of allyl thioacetate from benzaldehydes
and activated alkenes using the Morita–Baylis–Hillman
reaction as a key step
Hae-Won Yang, Ji-Su Choi, Sang-Jin Lee, Byung-Woo Yoo and Cheol Min Yoon
Department of Advanced Material Chemistry, Korea University, Sejong-si, South Korea
ABSTRACT
ARTICLE HISTORY
Received 21 September 2015
Accepted 21 November 2015
An efficient, regioselective and steresoselecitive one-pot protocol
for the synthesis of (Z)-S-2-alkoxycarbonyl-3-acylallyl ethanethioates
and (E)-S-2-cyano-3-acylallyl ethanethioates from benzaldehydes
and activated alkenes (methyl acrylate and acrylonitrile) was devel-
oped. Our method consisted of Morita–Baylis–Hillman reaction of
benzaldehydes and activated alkenes using DABCO followed by
acetylation using acetic anhydride and a catalytic amount of DMAP,
and SN2ꢀ reaction with potassium thioacetate in DMF. The first two
reactions proceeded under solvent-free condition.
KEYWORDS
One-pot reaction;
benzaldehyde; activated
alkene;
Morita–Baylis–Hillman
reaction; allyl thioacetate
1. Introduction
One-pot reactions and solvent-free reactions have obtained significant attention in organic
synthesis. The development of one-pot reactions is therefore very important to minimize
the use of reagents, catalysts, and solvent, as well as to reduce the number of isolation steps
which generate waste.[1,2] Solvent-free reaction conditions are attractive from the point
of view of environmentally benign and clean technologies.[3,4]
The Morita–Baylis–Hillman (MBH) reaction is an important carbon–carbon bond-
forming reaction affording alkenes with several functional groups.[5–7] MBH adducts
and their acetates are valuable synthetic intermediates for the synthesis of a variety of
heterocycles.[8–15] They are also used as intermediates for the preparation of trisubsti-
tuted alkenes bearing various functional groups by nucleophilic substitution [16–18] or a
cross-coupling reaction with organometallics [19–22] using palladium and rhodium as a
catalyst or alkyl halides using zinc [23] and trialkylindium.[24] Organic compounds con-
taining the sulfur moiety are important for the construction of target molecules, such as
CONTACT Cheol Min Yoon
cmyoon@korea.ac.kr
© 2016 Taylor & Francis

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135
Scheme 1. One-pot synthesis of allyl thioacetate from benzaldehyde.
sulfur-containing drugs. The stereoselective and regioselective SN2ꢀ reaction of acetates
of MBH adducts have been reported to provide one of the important methods for the
preparation of bioactive organic compounds containing sulfur.[25,26]
Herein, we wish to report an efficient regioselective and stereoselective one-pot pro-
tocol for the synthesis of (Z)-S-2-alkoxycarbonyl-3-acylallyl ethanethioates and (E)-S-2-
cyano-3-acylallyl ethanethioates from benzaldehydes and activated alkenes via an MBH
reaction using DABCO followed by acetylation using acetic anhydride and a catalytic
amount of DMAP, and nucleophilic substitution using potassium thioacetate in DMF at
RT. (Scheme 1)
2. Results and discussion
For the success of our one-pot consecutive synthesis of (Z)-S-2-alkoxycarbonyl-3-acylallyl
ethanethioates and (E)-S-2-cyano-3-acylallyl ethanethioates from benzaldehydes and acti-
vated alkenes (methyl acrylate and acrylonitrile), we were faced with either finding the
proper reaction condition in the plethora of reported reaction conditions or the devel-
opment of new valid reaction conditions for each of the three-steps: MBH reaction,
acetylation, and nucleophilic substitution. Among the plethora of MBH reactions of aryl
aldehyde with activated alkene described in the literature, the neat conditions developed
by an Indian group [27] was found to be the best for our one-pot reaction on the basis of a
test study with benzaldehyde and acrylonitrile as a model system. However, excess methyl
acrylate (3 equiv.) and DABCO (1 equiv.) rather than a catalytic amount of DABCO and 1
equiv. of acrylate used in their report was identified as a requirement to achieve a reason-
able reaction time. The choice of acetylation protocols was the reaction of an MBH adduct
with acetic anhydride as acetylating agent and DMAP as a catalyst at room temperature in
the absence of a solvent.[28]
For the thioacetate substitution of the MBH acetate, thioacetic acid in methylene chlo-
ride [29] and potassium thioacetate in methanol [30] have been reported in literature.
When thioacetic acid protocol was applied to our one-pot method, the reaction was com-
plicated. In addition, thioacetic acid is nasty, foul-smelling, and toxic. When the reaction of
MBH acetate generated under one-pot conditions was conducted with potassium thioac-
etate in methanol, the reaction was clean, but the yield was relatively low due to the
formation of the side product. Therefore, substitution reaction of an MBH acetate gen-
erated using potassium thioacetate was tried in a variety of solvent systems such as THF,
THF/H2O, CH3CN, and DMF (route 1 of scheme 2). Finally, DMF was found as the
best choice for the solvent. The formation of isomer 3 [31] and DABCO salt 2 (The iso-
merization result of Baylis–Hillman acetate using a catalytic amount of DABCO will be
reported in a separate publication.) [32] in the middle of the substitution reaction was

136
H.-W. YANG ET AL.
Scheme 2. Mechanical study of nucleophilic substitution MBH acetate.
observed (The isomer 3 and DABCO salt 2 were characterized using TLC and 1H NMR
spectroscopy.). However, an independent study showed that isomer 3 and DABCO salt 2
prepared from MBH adduct acetate 1 undergoes nucleophilic substitution to give the tar-
get molecule thioacetate 4 in excellent yield in SN2 manner regioselectively (route 2 and
3 of Scheme 2). An interesting finding is that the substitution of acetate isomer 3 with
thioacetate proceeded in spite of the poor leaving ability of the acetate, which has not been
reported before. All reactions were monitored with TLC and 1H NMR spectroscopy.
One the basis of the optimized conditions for each of the three-steps, the reaction
was conducted as follows (entry 1). After benzaldehyde and methyl acrylate (3 equiv.) in
the presence of DABCO (1 equiv.) was stirred for 48 h, acetic anhydride (1.2 equiv.) and
DMAP (0.2 equiv.) were added to the reaction mixture. After the resulting solution was
stirred for 10 min, DMF and potassium thioacetate (2 equiv.) were added and the solution
was stirred for 30 min at RT to give (Z)-S-2-methoxycarbonyl-3-phenylallyl ethanethioate
regioselectively and stereoselectively in 92% yield.
This new one-pot reaction under our optimal conditions was conducted with a variety
of benzaldehydes with electron-withdrawing (Entries 2 and 4–9) and electron-donating
groups (Entry 10) attached to the aromatic rings and methyl acrylate to afford the cor-
responding allyl thioacetates 4 in excellent yields with (Z)-stereoselectivity as shown in
Table 1. The one-pot reaction of benzaldehyde and acrylonitrile gave a allyl thioacetate 4c
with (E)-stereoselectivity in 87% isolated yield. The stereochemistry of the products was
established by comparing 1H NMR parameters for the protons of the product with litera-
ture values.[29] The reaction times of the first step depend on the substrate and are listed
in Table 1.
3. Conclusion
In summary, a mild and efficient synthesis of (Z)-S-2-alkoxycarbonyl-3-acylallyl
ethanethioates and (E)-S-2-cyano-3-acylallyl ethanethioates from benzaldehydes and acti-
vated alkenes (acrylate and acrylonitrile) in one-pot reactions were developed. The method
consists of an MBH reaction using DABCO followed by acetylation using acetic anhydride
and a catalytic amount of DMAP and nucleophilic substitution using KSAc in DMF at RT.

JOURNAL OF SULFUR CHEMISTRY
137
Table 1. Synthesisa of allyl thioacetates from benzaldehydes and activated alkenes.
Entry
Aldehyde
Product
Yieldb (%)
92
1
2
98
3
4
87
87
5
6
90
97
7
8
95
95
9
96
85
10
aReaction conditions: 1st step: benzaldehydes (1 equiv.), activated alkenes (3 equiv.), and DABCO (1 equiv.). 2nd step: acetic
anhydride (1.2 equiv.) and DMAP (0.2 equiv.). 3rd step: KSAc (2 equiv.) and DMF (2 ml).
bIsolated yield.
cMBH reaction time.
dAll products are known and their spectroscopic data are consistent with reported one.[29]

138
H.-W. YANG ET AL.
4. Experimental
4.1. General procedure
A mixture composed of benzaldehyde (200 mg, 1.884 mmol), methyl acrylate (512.4 μL, 3
equiv.), and DABCO (211.4 mg, 1 equiv.) was stirred at room temperature for 48 h. After
the completion of the reaction (monitored by TLC), to the reaction mixture was added
acetic anhydride (213.4 μL, 1.2 equiv.) and DMAP (46.0 mg, 0.2 equiv.) and the resulting
solution was stirred for 10 min. Then potassium thioacetate (430.4 mg, 2 equiv.) and DMF
(2 ml) were added to the reaction and the resulting solution was stirred for 30 min at room
temperature. After the completion of the reaction, it was diluted with ethyl acetate (30 mL)
and washed with water (20 mL × 3) and brine (20 ml). The organic layer was dried with
anhydrous MgSO4, filtered, concentrated and chromatographed on silica gel using a solu-
tion of ethyl acetate and hexane (1:16) to afford a (Z)-S-2-methoxycarbonyl-3-phenylallyl
ethanethioate in 92% isolated yield. Selected data of products are given below.
4.2. Spectroscopic data of products
4a: oil, IR (KBr) 1715, 1693, 1630, 1435, 1267 cm−1; 1H NMR (300 MHz, CDCl3) δ = 2.36
(s, 3H, CH3), 3.84 (s, 3H, OCH3), 4.07 (s, 2H, CH2), 7.37–7.42 (m, 5H, Ar), 7.82 (s, 1H,
CH); 13C NMR (300 MHz, CDCl3) δ = 195.00, 167.55, 142.69, 142.66, 134.64, 129.62,
129.39, 128.86, 128.71, 126.94, 52.52, 52.47, 30.43, 30.40, 27.03.
4b: oil, IR (KBr) 1709, 1631, 1448, 1369, 1265 cm−1; 1H NMR (300 MHz, CDCl3) δ =
1.35 (t, J = 7.2 Hz, 3H, CH3), 2.35 (s, 3H, CH3), 4.08 (s, 2H, CH2), 4.29 (q, J = 7.2 Hz,
4H, OCH2), 7.36–7.43 (m, 5H, Ar), 7.81 (s, 1H, CH); 13C NMR (300 MHz, CDCl3) δ =
194.98, 167.04, 142.36, 142.33, 134.72, 129.58, 129.30, 128.83, 127.32, 61.43, 30.40, 26.98,
26.95, 14.37.
4c: oil, IR (KBr) 2214, 1698, 1620, 1576, 1496, 1448, 1408, 1356, 1215 cm−1; 1H NMR
(300 MHz, CDCl3) δ = 2.40 (s, 3H, CH3), 3.86 (s, 2H, CH3), 7.21 (s, 1H, CH), 7.40–7.43
(m, 3H, Ar), 7.73–7.78 (m, 2H, Ar); 13C NMR (300 MHz, CDCl3) δ = 194.98, 167.04,
142.36, 142.33, 134.72, 129.58, 129.30, 128.83, 127.32, 61.43, 30.40, 26.98, 26.95, 14.37.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by Korea University.
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