COMMUNICATIONS doi.org/10.1002/adsc.

202300325

Synthesis of (E)-α,β-Unsaturated Thioesters from Malonic Acid

Half Thioesters and Aldehydes
Shun Kawasaki,a Kengo Akagawa,a and Kazuaki Kudoa,*
a
Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153–8505, Japan
Fax: (+ 81)-3-5452-6359, phone: (+ 81)-3-5452-6357
E-mail: kkudo@iis.u-tokyo.ac.jp

Manuscript received: April 6, 2023; Revised manuscript received: May 15, 2023;
Version of record online: May 31, 2023

Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202300325

© 2023 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the
terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.

Abstract: A decarboxylative condensation of ma-
lonic acid half thioesters (MAHTs) with aldehydes
catalyzed by benzylammonium trifluoroacetate has
been developed for the synthesis of (E)-α,β-unsatu-
rated thioesters. The reaction of aromatic aldehydes
and sterically non-demanding aliphatic aldehydes
proceeded smoothly at room temperature in DMF in
a stereo- and regioselective manner. Besides the
unsubstituted malonate, 2-fluoro- and 2-meth-
ylmalonates could be employed as a nucleophile.
Use of the present catalyst could avoid nonproduc-
tive protiodecarboxylation of MAHTs.
Keywords: α,β-unsaturated thioesters; Malonic acid
half thioesters; Aldehydes; Amine salt catalyst;
Decarboxylative condensation
In the biological system, malonic acid half thioesters
(MAHTs) represented by malonyl-CoA possess unique
reactivity and play important roles in the synthesis of
fatty acid and polyketide.[1] Besides the electrophilic
reactivity as activated esters,[2] their high nucleophilic-
ity is noteworthy. They undergo decarboxylative
Claisen condensation under physiological conditions to
realize iterative carbon chain elongation.[3]
Inspired by the biochemical reaction, MAHTs have
been utilized in organic synthesis as thioester enolate
equivalents.[4] MAHT can be prepared in gram-scale[5]
and has been applied in various C C bond-forming
reactions, such as decarboxylative aldol reaction,[6]
Mannich reaction,[7] Michael addition,[8] and also
Claisen condensation[9] including biomimetic synthesis
of polyketides.[5b,10] The reactions proceed with high
atom economy because only a carbon dioxide molecule
is generated as a by-product from MAHT. Moreover,
the resulting thioesters can be transformed into various
functional groups based on their unique reactivities.[11]
On the other hand, α,β-unsaturated thioesters are
versatile building blocks in organic synthesis. They
exhibit higher reactivity as compared to the corre-
sponding oxyesters in Diels-Alder reaction,[12] Michael
addition,[13] and Morita-Baylis–Hilman reaction.[14] In
addition, decarbonylative reactions that are unique to
the thioesters have been developed.[15] Because of such
high level of utility, several methods have been
developed for the synthesis of α,β-unsaturated thio-
esters including thioesterification of carboxylic acids
or oxyesters,[16] Wittig and Horner-Wadsworth-Em-
mons (HWE) reaction of aldehydes,[17] and Ru-
catalyzed cross-metathesis reaction of terminal olefins
with thioacrylates.[18] Nevertheless, each of these
methods has a certain drawback: the thioesterification
and Wittig/HWE reaction requires stoichiometric
amounts of activator or reagent leading to low atom
economy. The cross-metathesis reaction requires sev-
eral steps to prepare thioacrylates which also includes
the Wittig reaction.
To overcome the above shortcomings for the syn-
thesis of α,β-unsaturated thioesters, the Doebner-
Knoevenagel reaction of MAHT and aldehydes might
be a possible method of choice, considering that the
corresponding decarboxylative condensation of ma-
lonic acid half oxyesters[19] or amides[20] with aldehydes
have already been reported. Thomas and coworkers
reported such a reaction promoted by a combination of
ytterbium triflate catalyst and a stoichiometric amount
of base.[21] However, this method suffered rather

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narrow substrate scope and low chemical yields (<
40%) for α,β-unsaturated thioesters. During the Alz-
heimer’s drug study, Rosini and co-workers made
efforts to carry out the Dobener-Knoevenagel reaction
of MAHTs with 3,4-hydroxy/alkoxy benzaldehydes.
However, the results were not very successful, as they
only achieved low to moderate yields, and the 4-
hydroxybenzaldehydes failed to react.[22] Furthermore,
there is no report of Doebner-Knoevenagel-type con-
densation between α–substituted MAHT and alde-
hydes. We herein report a widely applicable catalytic
decarboxylative condensation of MAHT with aldehyde
for the synthesis of α,β-unsaturated thioesters.
We selected a benzaldehyde 1 a and an S-dodecyl-
MAHT 2 a as model substrates. Dodecanethiol deriva-
tives have the advantage of eliminating the unpleasant
odor for the entire process.[23] The reaction was
performed in DMF at room temperature by the action
of an amine catalyst. Several amines that have been
utilized for catalytic decarboxylative C C bond for-
mation of malonate derivatives with aldehydes were
screened (Table 1).[6c,19,24] DMAP and triethylamine
brought about the protiodecarboxylation of 2 a to give
4 (entries 1, 2). Such a nonproductive reaction has also
been found to some extent in various kinds of MAHT-
based C C bond forming reactions under basic
conditions.[6d,8a,25] By contrast, secondary and primary
amines successfully afforded the target product,
although the acetate 4 was still generated (entries 3,4).
In order to suppress this side reaction, we tried amine
salts as catalyst instead of free amines.[26] While the
salt of weak carboxylic acids did not show notable
improvement (entries 5–7), use of strong acid salt
successfully gave the desired result (entries 8, 9). Not
only the monoalkylthio malonate, monophenylthio
ester was also viable (see Supporting Information).
Results revealed that higher concentration was advan-
tageous for this reaction (entry 9).[27]
With the optimized reaction conditions in hand, we
examined the substrate scope of various substituted
benzaldehydes. As shown in Table 2, those with
electron donating or withdrawing substituents on a
variety of positions were acceptable as substrates. It
has been independently claimed by two groups that 4-
nitrobenzaldehyde 1 c[21] and 4-hydroxy-3-methoxy-
benzaldehyde 3 e[22] are not reactive toward MAHTs.
By contrast, those aldehydes smoothly reacted under
the present conditions. In every case, the reaction of
the MAHT 2 a and aldehyde brought about exclusive
formation of (E)-isomers. α-fluorinated MAHT (F-
Table 2. Substrate scope for aromatic aldehydes.[a]

Table 1. Screening of catalyst.

Entry Catalyst Yield (%)[a] Yield (%)[a]

3a 4
1 DMAP Trace 90
2 Et3N 0 75
3 Morpholine 64 20
4 BnNH2 77 10
5 DL-proline 82 5 [a]
6 β-alanine 74 16 Isolated yields were shown in parentheses next to compound
7 BnNH2 · AcOH 79 11 number. The isomer depicted in the structural formula was
8 BnNH2 · HCl 80 0 the sole product obtained unless otherwise noted.
[b]
9 BnNH2 · TFA 88 (91)b,c 0 Reaction performed for 48 h.
[c]
F-MAHT 2 b was used.
[a] [d]
Yield was estimated by the NMR measurement of a crude The reaction was performed with 0.2 equiv. of catalyst at
mixture. 0.1 M. After the condensation, the reaction mixture was
[b]
Reaction was conducted at the concentration of 0.5 M for the stirred at 100 °C for 0.5 h in the presence of C12H25SH
substrates in the presence of 10 mol% of catalyst. (0.2 eq.) and iPrNEt2 (1.0 eq.). The crude product was a 94:6
[c]
Isolated yield. mixture of (2E,4E)- and (2Z,4E)-isomers.

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MAHT) 2 b[6f] can be employed as the donor substrate,
furnishing (Z)-α-fluoro-α,β-unsaturated thioester 3 g as
a single isomer.[28] For the case of the cinnamaldehyde
1 i, the present reaction conditions gave a mixture of 3 i
and 2-((dodecylthio)carbonyl)-5-phenylpenta-2,4-di-
enoic acid (5) in a 1:3 ratio. Treatment of this mixture
with catalytic amount of C12H25SH under basic
conditions transformed compound 5 into the desired
product 3 i. The decarboxylation is considered to
proceed in conjunction with 1,4-addition/retro addition
of the thiol.
Next, the reactions with aliphatic aldehydes were
investigated (Table 3). There are several reports that
not only α,β-unsaturated (thio)esters but also various
amounts of β,γ-isomers were generated in the reaction
with linear aliphatic aldehydes and malonate
derivatives.[19b,21,29] Gratifyingly, aldehydes 1 j–n re-
acted smoothly with MAHT and afforded the corre-
sponding products in moderate to good yields with
high α,β-regioselectively for the C=C bonds. In the
synthesis of 3 j and 3 k, formation of a trace amount of
(Z)-isomers accompanied, which could be separated by
silica gel chromatography. Meanwhile, the reaction
rate was quite low with pivalaldehyde 1 m, presumably
Table 3. Substrate scope for aliphatic aldehydes.[a]
[a]
Isolated yields were shown in parentheses next to compound
number. Distribution of the product isomer is that of the
crude reaction mixture unless otherwise noted.
[b]
Reaction performed for 48 h.
[c]
Me-MAHT 2 c was used at 60 °C with aldehyde (1.5 eq.) for
3 h.
[d]
Diastereomer ratio of the isolated product.
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due to the steric hindrance. The reaction between α-
methylated MAHT (Me-MAHT) 2 c and aldehyde 1 n
proceeded at elevated temperature (60 °C), to selec-
tively afford (E)-α-methyl α,β-unsaturated thioester
3 n.[30] We have attempted the low-yield reactions for a
longer time or higher temperatures. However, in every
case, the reaction resulted in either self condensation
of aldehydes or protiodecarboxylation from 2, and did
not lead to the increase in the product yield.
The proposed mechanism is shown in Scheme 1.[31]
At first, an iminium ion is formed from the catalyst
and the aldehyde. The iminium ion undergoes Man-
nich-type reaction with MAHT to give a β–amino acid
intermediate 6[32] which then converts to the α,β-
unsaturated thioester via concerted decarboxylation-
deamination. The intermediacy of imine/iminium ion
in the Doebner-Knoevenagel reaction is widely
accepted,[20,26b,c,31] and for the present case, it is
supported by the fact that the tertiary amines were not
viable as catalyst. For the formation of the final
product from the intermediate Mannich adduct, step-
wise mechanism for deamination and decarboxylation
can be ruled out by the two experimental facts: 1) in
the reaction of cinnamaldehyde 1 i, the ratio of the
dienoic acid 5 and the target product 3 i did not change
upon elongation of the reaction time, and 2) when
subjected to the present reaction condition, 3-benzyla-
mino-3-phenylpropanoyl dodecanethioate which is the
decarboxylation product of the Mannich adduct re-
mained intact even after 24 h.
This catalytic reaction has a characteristic that only
the strong acid salts of benzylamine gave the
Scheme 1. Proposed mechanism.
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successful result. In the cases of weak acid salts, the
acidity of MAHT is comparable with or even higher
than other carboxylic acids and consequently, the
deprotonation of MAHT leading to the protiodecarbox-
ylation might be unavoidable. By contrast, strong acids
could effectively inhibit the decarboxylation of
MAHT. Another important factor is that the highly
Lewis basic nature of DMF[33] can efficiently dissociate
the strong acid salt. In fact, BnNH2 · TFA catalyst
worked equally well in DMSO, while the reactions in
acetonitrile, tetrahydrofuran, or chloroform were slug-
gish.
To demonstrate the utility of the present method,
our protocol was applied to a gram-scale reaction of
Scheme 2. Gram-scale reaction.
Scheme 3. Derivatization of α,β-unsaturated thioesters. dppbz =
1,2-bis(diphenylphosphino)benzene, PMHS = poly(meth-
ylhydrosiloxane).
Scheme 4. One-pot synthesis of bioactive molecule analogue.
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aldehyde 1 a and MAHT 2 a to furnish the product 3 a
in 92% (Scheme 2). Next, derivatization of α,β-
unsaturated thioesters were performed (Scheme 3).
Sonogashira-type coupling of 3 e with 4-phenyl-1-
butyne delivered enynone 7 in 70% yield.[34] Moreover,
α,β-unsaturated thioester 3 j could be selectively
reduced into a saturated thioester 8.[35] Finally, the one-
pot synthesis of bioactive molecule analogue 10 was
conducted (Scheme 4).[36] Meldrum’s acid 9 was
converted to MAHT 2 a.[22] After evaporation of the
toluene solvent, decarboxylative condensation with
2,5-dihydroxybenzaldehyde and 2 a in DMF was
conducted to afford the unsaturated thioester 10 in
49% yield.
In conclusion, we have developed a method for the
synthesis of α,β-unsaturated thioesters by a catalytic
decarboxylative condensation of MAHTs and alde-
hydes. The reaction proceeded at room temperature
and exhibited tolerance for several functional groups.
The use of strong acid salt of amine as the catalyst
suppresses the generation of unwanted byproducts,
leading to 30–93% yield of the desired products. The
present method provides a strategy for the synthesis of
α,β-unsaturated thioesters, which complements existing
methods and expands the synthetic toolbox for the
construction of complex molecules.
Experimental Section
To a solution of the aldehyde 1 (0.18–1.46 mmol) in DMF (0.1–
0.5 M), were added MAHT 2 (1 equiv.) and BnNH2 · TFA (0.1–
0.2 equiv.) at room temperature and the mixture was stirred for
18–48 h. The mixture was extracted with diethyl ether, and the
organic layer was washed with water. After drying over
anhydrous magnesium sulfate, the solvent was removed under
reduced pressure. The residue was purified by preparative TLC
on silica gel plates to afford the α,β-unsaturated thioester 3.
Acknowledgements
This work was partially supported by a Grant-in-Aid for
Scientific Research (C) from Japan Society for the Promotion of
Science (20K05487 for K.K.). We thank Dr. Maria Carmelita Z.
Kasuya for carefully proofreading the manuscript, and Mr.
Kohsaku Okuyama for his experimental assistance. MS spectral
data were obtained at Komaba Analysis Core, Institute of
Industrial Science, The University of Tokyo.
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Supporting Information).
[28] α-Fluoro-α,β-unsaturated thioester has been synthesized
by HWE reaction as an E:Z = 9:1 mixture of isomers. M.
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coresponding product was obtained in 65% NMR yield,
however, this compound could not be chromatographi-
Adv. Synth. Catal. 2023, 365, 1811 – 1816
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cally separated from the protiodecarboxylated by-product
from 3 c.
[31] This mechanism follows the outlines proposed in ref. 20
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[32] There is accumulating evidence that decarboxylation
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