Synthesis of Methylthiomethyl Esters by the Reaction of Carboxylic Acid with Dimethylsulfoxide

Full text of DOI:10.1002/bkcs.11498

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DOI: 10.1002/bkcs.11498
BULLETIN OF THE
S. Yu et al.
KOREAN CHEMICAL SOCIETY
Synthesis of Methylthiomethyl Esters by the Reaction of Carboxylic
Acid with Dimethylsulfoxide
*
*
Subeen Yu, Kye Chun Nam, and Sunwoo Lee
Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea.
*E-mail: kcnam@chonnam.ac.kr; sunwoo@chonnam.ac.kr
Received May 9, 2018, Accepted May 25, 2018
Keywords: Methylthiomethyl esters, Dimethylsulfoxide, Cinnamic acid, Benzoic acid
Methylthiomethyl (MTM) esters are frequently used as pro-
reaction between carboxylic acid derivatives (cinnamic acid
and benzoic acid) and DMSO in the presence of a base.
To find the optimal reaction conditions, cinnamic acid
(1a) was allowed to react with DMSO in the presence of a
variety of bases. The results are summarized in Table 1.
When Et3N and i-Pr2EtN were employed as bases, the
desired product, methylthiomethyl cinnamate (2a), was
formed at yields of 87% and 86%, respectively (Table 1,
entries 1 and 2). Reactions with pyridine, 1,4-diazabicyclo
[2.2.2]octane (DABCO), and 1,5-diazabicyclo(4.3.0)non-
5-ene (DBN) led to the desired product with slightly lesser
tecting groups for carboxylic acids and as activating groups
for the amidation of acids.1 In addition, they exhibit a unique
chemical property of electron transfer under photochemical
conditions.2 Furthermore, they are often used in bio-active
reagents due to their good absorbability and as flavor addi-
tives in some dairy and oil products.3 Therefore, the synthe-
sis of MTM esters has received much attention in the
organic synthesis, materials, and pharmaceutical domains.
Many preparation methodologies have been reported for
MTM esters. One typical method to synthesize MTM esters
is the reaction of methylthiomethyl chloride with carboxylic
acid in the presence of a base and 18-crown-6.4 Although
this method is frequently employed in organic synthesis,
methylthiomethyl chloride is known to be toxic. To address
this issue, dimethylsulfoxide (DMSO) was used and allowed
to react with carboxylate salt in the presence of activating
reagents, such as tert-butyl bromide,5 N-chlorosuccinimide,6
dicyclohexylcarbodiimide,7 and sulfuryl chloride,8 to syn-
thesize MTM esters according to the Pummerer
rearrangement.9
MTM esters were prepared by Swern oxidation using
DMSO, oxalyl chloride, and triethylamine by Ghosh et al.
(Scheme 1(a)).10 Using oxalyl chloride has some draw-
backs owing to its moisture sensitivity. Zimmerman
reported the synthesis of MTM esters using the Pummerer
rearrangement with microwave radiation (Scheme 1(b)).11
Very recently, Yang et al. reported iron-catalyzed Pum-
merer rearrangement of acyl chlorides and DMSO for the
synthesis of alkylthiomethyl esters (Scheme 1(c)).12 How-
ever, these processes also have their own sets of limitations.
The former method requires special equipment, such as a
microwave instrument. On the other hand, the handling of
moisture-sensitive acyl chloride is a major drawback in the
latter method. Therefore, more convenient methods are
desired. To meet this requirement, we attempted to develop
a simple method for the synthesis of MTM esters.
A variety of carboxylic acid derivatives have been evalu-
ated in the past for the formation of the corresponding
MTM esters. However, there is not much information avail-
able on cinnamic acid derivatives for MTM ester synthesis.
Herein, we report the synthesis of MTM esters by the
Scheme 1. Synthesis of methylthiomethyl groups.
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Table 1. Optimized conditions for the synthesis of the MTM
ester, 2a, from cinnamic acid.a
Entry
Base
Temperature (ꢀC)
Yield (%)b
1
2
3
4
5
6
7
8
Et3N
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
140
120
150
150
87
86
32
40
22
0
0
0
0
15
0
0
0
0
0
73
44
77
62
i-Pr2EtN
Pyridine
DABCO
DBN
DBU
KOAc
NaOAc
K2CO3
Na2CO3
Cs2CO3
K3PO4
Na3PO4
KOMe
NaOMe
Et3N
9
10
11
12
13
14
15
16
17
18
19
a
Et3N
Et3Nc
Et3Nd
Reaction conditions: 1a (0.3 mmol), DMSO (1.0 mL), and base
(0.36 mmol).
Determined by gas chromatography with internal standard.
0.18 mmol was used.
b
c
d
Scheme 2. Synthesis of methylthiomethyl esters from cinnamic
acid and benzoic acid derivatives.aaReaction conditions:
1 (2.0 mmol), Et3N (2.4 mmol), DMSO (8.0 mL), 150ꢀC,
and 16 h.
0.6 mmol was used.
yields (Table 1, entries 3–5). However, no product was
formed with all other tested bases, except for Na2CO3
(entries 6–15). As the reaction temperature decreased, the
product yield decreased (entries 16 and 17). When the
amount of base was decreased to 0.6 equiv. or increased to
2.0 equiv., the product yields decreased to 77 and 62%,
respectively (Table 1, entries 18 and 19). On the basis of
these results, we optimized the reaction conditions to be
2 mmol of carboxylic acid, 2.4 mmol of Et3N, and 8 mL of
DMSO at 150ꢀC for 16 h.
At these optimized conditions, a variety of substituted
cinnamic acids were evaluated for the formation of the cor-
responding MTM esters (see Supporting Information). As
expected, 2a could be isolated at a yield of 87%. 4-Methyl
substituted cinnamic acid (2b) was formed at a yield of
89%. Alkoxy-substituted cinnamic acids were successfully
converted into the corresponding methylthiomethyl esters
2c, 2d, 2e, and 2f (as shown in Scheme 2) with good
yields. However, hydroxyl- and nitro-substituted cinnamic
acids did not yield the desired product. The optimized con-
ditions were also employed for the protection of benzoic
acid derivatives. Benzoic acid led to the synthesis of 2i
with 92% yield. 4-Fluoro and 4-acetyl substituted benzoic
acids were transformed into the corresponding methylthio-
methyl esters 2j and 2k with 77 and 67% yield, respec-
tively. Alkoxy-substituted benzoic acids showed good
yields in the formation of 2l and 2m.
We studied the reactivity of cinnamic acid and benzoic
acid at the optimized conditions. When cinnamic acid (1a)
and benzoic acid (1i) were allowed to react in the same
reaction vessel at the optimized conditions, 2a and 2i were
formed at yields of 40 and 53%, respectively (Scheme 3).
This result proves that benzoic acid exhibits a slightly
higher reactivity than cinnamic acid at the optimized reac-
tion conditions.
Based on our observations and previous studies, we sug-
gest a possible mechanism for the formation of MTM esters
(Scheme 4). When heated, carboxylic acid reacted with
DMSO to yield an acylated DMSO adduct, A; this was fol-
lowed by thermal elimination resulting in the thionium
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with water and dried over magnesium sulfate. Evaporation
of the solvent under reduced pressure yielded the crude
product, which was purified by column chromatography on
silica gel (eluent: hexane/ethyl acetate = 10/1).
Acknowledgment. This research was supported by the
National Research Foundation of Korea (NRF) grant
funded by the Korea government (MSIP) (NRF-
2017R1D1A3B03035736, NRF-2015R1A4A1041036). The
spectral data were obtained at the Korea Basic Science Insti-
tute, Gwangju Branch.
Scheme 3. Competitive reaction of cinnamic acid and
benzoic acid.
Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
References
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Scheme 4. Proposed mechanism for the formation of MTM esters.
intermediate, B. The carboxylate formed during the reaction
between carboxylic acid and the base reacts with the inter-
mediate product, B, to yield the final product.
In summary, we developed a simple method for the prep-
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acid derivatives and benzoic acid derivatives, reacted with
DMSO in the presence of Et3N to result in the correspond-
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Bull. Korean Chem. Soc. 2018
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