A Facile Method for the Sulfenyllactonization of Alkenoic Acids Using Dimethyl Sulfoxide Activated by Oxalyl Chloride

Article abstract of DOI:10.1055/s-0036-1588378

A simple approach has been developed for the sulfenyllactonization of alkenoic acids using dimethyl sulfoxide activated with oxalyl chloride, in which methanesulfenyl chloride is proposed as the intermediate.

Full text of DOI:10.1055/s-0036-1588378

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
T. Zhang et al.
Paper
Synthesis
A Facile Method for the Sulfenyllactonization of Alkenoic Acids
Using Dimethyl Sulfoxide Activated by Oxalyl Chloride
S
Ting Zhang1
Yifeng Dai1
n = 0
R
O
O
Siwei Cheng
Yongguo Liu
Shaoxiang Yang
Baoguo Sun
DMSO/(COCl)2
COOH
R
S
S
n
n = 1
n = 2
O
O
R
R
MeSCl
Hongyu Tian*
MeCN, 0 °C to reflux
Beijing Advanced Innovation Center for Food Nutrition and Human
Health, Beijing Key Laboratory of Flavor Chemistry, Beijing Technology
and Business University, Beijing, 100048, P. R. of China
tianhy@btbu.edu.cn
O
O
10 examples
up to 95% yield
stereospecific
Received: 07.10.2016
Accepted after revision: 28.11.2016
Published online: 19.12.2016
pent-3-enoic acid, which was obtained by the Knoevenagel
condensation of propanal with malonic acid in the presence
of piperidinium acetate in DMSO.6 It is well known that
DMSO activated by various reagents, such as trifluoroacetic
anhydride, sulfur trioxide/pyridine, thionyl chloride, and
oxalyl chloride (especially known as the Swern oxidation),
has been used extensively in the oxidation of primary and
secondary alcohols, which is a very important and useful
tool in synthetic chemistry.7 It occurred to us that it should
be a convenient approach to the sulfenyllactonization of
alkenoic acids using DMSO/oxalyl chloride.
DOI: 10.1055/s-0036-1588378; Art ID: ss-2016-h0710-op
Abstract A simple approach has been developed for the sulfenyllac-
tonization of alkenoic acids using dimethyl sulfoxide activated with ox-
alyl chloride, in which methanesulfenyl chloride is proposed as the in-
termediate.
Key words sulfenyllactonization, alkenoic acids, dimethyl sulfoxide,
oxalyl chloride, methanesulfenyl chloride
Halolactonization of alkenoic acids has been well devel-
oped due to its importance and wide application in organic
syntheses.2 In contrast, sulfenyllactonization has been
known to a much lesser extent with only a few examples of
sulfenyllactonization having been reported so far. It was
found that unsaturated acids were converted into sulfenyl-
lactones by treatment with lead tetraacetate and disulfide
in the presence of trifluoroacetic acid when Trost’s group
studied the hydroxysulfenylation of olefins.3 Young et al. re-
ported that sulfenyllactonization of alkenoic acids could be
accomplished using sulfenyl chlorides derived from disul-
fides with complex multifunctional groups and chlorine.4
Commercially available dimethyl(methylthio)sulfonium
fluoroborate (DMTSF) was also reported to execute the
sulfenyllactonization of unsaturated acids in moderate to
high yields,5 which was very straightforward, however, suf-
fered from two major disadvantages: relatively long reac-
tion times (1 day to 3 days) and the high price of DMTSF.
An unexpected product, 4-(methylthio)-5-methyldihy-
drofuran-2(3H)-one (a γ-butanolide) was generated when
(E)-pent-3-enoic acid, synthesized in our laboratory, was
transformed into its methyl ester by treatment with thionyl
chloride in methanol. This was found to be the result of the
reaction of (E)-pent-3-enoic acid with thionyl chloride and
entrained dimethyl sulfoxide from the synthesis of (E)-
The use of three types of alkenoic acids was examined
with the DMSO/(COCl)2 reagent, including alk-3-enoic, alk-
4-enoic, and alk-5-enoic acids (Scheme 1). The results are
listed in Table 1.
S
Ph
COOH
COOH
Ph
S
O
O
2a
1a
DMSO/(COCl)2
CH2Cl2
O
O
O
O
2b
2c
1b
1c
COOH
S
Scheme 1 Sulfenyllactonization of alkenoic acids with DMSO/(COCl)2
Initially, we thought that the sulfenyllactonization we
observed accidently might follow the mechanism similar to
that in the Swern oxidation. Therefore, a typical procedure
for the Swern oxidation was initially adopted as follows: a
solution of (COCl)2 (1.5 equiv) in CH2Cl2 was added drop-
wise to a solution of DMSO (3.0 equiv) in CH2Cl2 at –65 °C
and about 15 minutes after the addition, a solution of (E)-4-
phenylbut-3-enoic acid (1a, 1 equiv) in CH2Cl2 was added,
and the mixture stirred at –65 °C. The reaction was moni-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
T. Zhang et al.
Paper
Synthesis
1
tored by H NMR. Unfortunately, none of the desired prod-
uct, 4-(methylthio)-5-phenyldihydrofuran-2(3H)-one (2a)
was obtained, as expected, even after stirring for 24 hours,
whereas the (methylthio)methyl ester 3a was produced in
high yield (90%) (entry 1). Then a reaction was tried at 0 °C.
After stirring at 0 °C for 24 hours, the desired product 2a
was detected by 1H NMR and the yield was about 11% based
Table 1 Sulfenyllactonization of Alkenoic Acids with DMSO/(COCl)2 in
CH2Cl2
Entry
1
Substrate (temp, time) Product
Yield (%)a
90
O
S
Ph
1a (–65 °C, 24 h)
O
O
O
3a
1
on the ratio of the product to the substrate in the H NMR
S
spectrum (entry 2). In contrast, no (methylthio)methyl es-
ter 3a was produced at 0 °C. Obviously, these results indi-
cate that the reaction temperature has an important impact
on sulfenyllactonization. Therefore, the reaction tempera-
ture was raised further to room temperature (about 26 °C),
but with the addition temperature at 0 °C since oxalyl chlo-
ride reacts vigorously with DMSO at room temperature. The
reaction was complete after about 15 hours and the desired
product 2a was obtained in 90% isolated yield (entry 3).
In our experiments, the effect of different ratios of sub-
strate to reagent on the reaction was also investigated.
Three molar ratios of 1:4:2, 1:3:1.5, and 1:2.4:1.2 (sub-
strate/DMSO/oxalyl chloride) were examined. It was found
that the former two levels gave similar results and the last
level gave a relatively low yield. Hence the middle level, i.e.
1:3:1.5 (substrate/DMSO/oxalyl chloride) was adopted in
the following experiments.
Based on these results from 1a, an alk-4-enoic acid [2,2-
dimethylpent-4-enoic acid (1b)] and an alk-5-enoic acid
[hex-5-enoic acid (1c)] were examined. Both of them gave
the corresponding (methylthio)methyl esters 3b and 3c in
high yields by treatment with DMSO/oxalyl chloride at
–65 °C (entries 4 and 6), whereas sulfenyllactones 2b and
2c were produced when the reactions were performed at
room temperature (entry 5 and 7). The reaction with hex-
5-enoic acid (1c) took longer (about 24 h) to go to comple-
tion, which might be attributed to the formation of the
δ-lactone, 6-[(methylthio)methyl]tetrahydro-2H-pyran-
2-one (2c), instead of γ-lactones 2a and 2b for substrates 1a
and 1b.
In view of the relative long reaction times for the pro-
duction of these sulfenyllactones, the procedure for the
sulfenyllactonization was optimized further using 1b as a
model substrate. The results are listed in Table 2. Since we
have observed that the reaction temperature had a signifi-
cant effect on the formation of the sulfenyllactone, the reac-
tion was attempted under reflux using CH2Cl2 as the solvent
in order to shorten the reaction time. The result indicates
that the reaction was faster under reflux than at room tem-
perature (entries 1 and 2). Potassium carbonate was also
added using acetonitrile as the solvent and 18-crown-6 as a
phase-transfer catalyst in order to speed up reaction. How-
ever, the reaction time did not change much when the reac-
tion was carried out at room temperature (entry 3). Howev-
er, the reaction was found to be complete in 5 hours when
the reaction mixture was heated to reflux without obvious
2
1a (0 °C, 24 h)
11
Ph
2a
O
O
S
3
4
5
1a (0 °C to r.t., 15 h)
90
94
95
Ph
2a
O
S
1b (–65 °C, 24 h)
O
3b
1b (0 °C to r.t., 18 h)
S
O
O
2b
3c
O
S
6
7
1c (–65 °C, 24 h)
91
91
O
1c (0 °C to r.t., 24 h)
S
O
O
2c
a Isolated yields, except entry 2 (1H NMR yield).
loss of yield (entry 4). In order to identify the crucial factor
affecting the reaction speed, high temperature, or potassi-
um carbonate, or the combined action of both, one further
reaction was carried out under reflux but without potassi-
um carbonate, which gave similar results (entry 4 vs. 5).
This indicates that the presence of potassium carbonate has
a negligible effect on sulfenyllactonization, whereas high
temperature is the crucial factor to guarantee a smooth re-
action.
Sulfenyllactonizations of substrates 1a and 1c were also
performed in acetonitrile under reflux without K2CO3. The
reaction time for 1a was shortened to about 3 hours, and
the latter about 7 hours, whereas the yields were close to
those at room temperature.
More alkenoic acids were examined in the sulfenyllac-
tonization under the optimized reaction conditions (Table
3). Three alk-3-enoic acids, (E)-pent-3-enoic acid (1d), (E)-
non-3-enoic acid (1e), and (E)-dodec-3-enoic acid (1f),
were treated with the DMSO/(COCl)2 reagent in acetonitrile
under reflux to afford 5-alkyl-4-(methylthio)dihydrofuran-
2(3H)-ones 2d–f (entries 1–3). Four more alk-4-enoic acids
1g–j were examined, which also produced γ-butanolides
2g–j (entries 4–7). It usually took 3–4 hours to complete
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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T. Zhang et al.
Paper
Synthesis
Table 2 The Procedure Optimization for Sulfenyllactonization
Most sulfenyllactones obtained contain at least two chi-
ral carbons except 2b, 2c, and 2g. The NMR spectra and GC
analysis indicated that single diastereomers were obtained
for those sulfenyllactones with at least two chiral carbons.
In order to determine the relative configuration of the prod-
ucts, a series of NOE experiments were carried out. For 5-
methyl-4-(methylthio)dihydrofuran-2(3H)-one (2d), irradi-
ation of the signal at δ = 4.40 (CHCH3) gave a small en-
hancement of the signal at δ = 2.14 (SCH3), and irradiation
of the signal at δ = 3.06 (CHSCH3) gave a small enhancement
of the signal at δ = 1.46 (CHCH3). These results indicate that
H-C5 was cis to the methylthio group (SCH3) attached to C4
and H-C4 cis to the methyl group attached to C5, i.e. the
methylthio group (SCH3) attached to C4 was trans to the
methyl group attached to C5. Similarly, for all other prod-
ucts, irradiation of the signal of CH attached to ester group
gave a small enhancement of the signal of the methyl of the
methylthio group without exception. These results indicate
that methylthio group and ester group introduced to double
bond of alkenoic acids through sulfenyllactonization were
located trans.
Possible reaction pathways for sulfenyllactonization of
alkenoic acids with DMSO/oxalyl chloride are depicted in
Scheme 2. At first, DMSO reacted with oxalyl chloride to
produce the chlorodimethylsulfonium salt, which is the
same intermediate as the Swern oxidation. Methanesulfenyl
chloride, the real species for sulfenyllactonization of alke-
noic acids, is formed via DMSO attack on the chlorosulfo-
nium intermediate. The electrophilic additions of methane-
sulfenyl chloride to the double bonds of alkenoic acids pro-
duced thiiranium ions, which were then attacked by the
carboxyl group via an intramolecular nucleophilic substitu-
tion to afford the corresponding sulfenyllactones.
The speculation of the intervention of methanesulfenyl
chloride was originally based on the reactions of (E)-4-
phenylbut-3-enoic acids (1a) with DMSO/oxalyl chloride,
which produced trans-4-(methylthio)-5-phenyldihydrofu-
ran-2(3H)-one (2a) exclusively (Table 1, entry 1). In addi-
tion, all the sulfenyllactones with multiple chiral centers
were produced as a single diastereomer. These results im-
plied that sulfenyllactonization occurred in a stereospecific
way. The intermediates thiiranium ions derived from the
electrophilic additions of methanesulfenyl chloride to the
double bonds of alkenoic acids gives a perfect explanation
for the observed stereospecific phenomena.
In order to prove the intervention of methanesulfenyl
chloride generated in situ, cyclohexene was treated follow-
ing the same protocol as the above alkenoic acids (Scheme
3). trans-1-Chloro-2-(methylthio)cyclohexane (4) was ob-
tained as expected in 89% yield, the spectroscopic data of
which were consistent with those of the product prepared
by the reaction of trans-2-(methylthio)cyclohexanol with
thionyl chloride in the reference.8 This product was also
found to be prepared by the reaction of cyclohexene with
Me2S/SO2Cl2/DMSO reported by Bellesia et al.9 In their work,
DMSO/(COCl)2
COOH
S
O
O
2b
1b
Entry
Conditions
Time (h)
Yield (%)a
1
2
3
4
5
CH2Cl2, r.t.
18
12
15
5
95
90
93
88
91
CH2Cl2, reflux
MeCN, K2CO3, 18-crown-6, r.t.
MeCN, K2CO3, 18-crown-6, reflux
MeCN, reflux
5
a Isolated yield.
the reactions and produced sulfenyllactones in more than
83% yield except substrates 1h and 1i with slightly lower
yields.
Table 3 Sulfenyllactonization of Alkenoic Acids with DMSO/(COCl)2 in
MeCN
En- Substrate
try
Product
Yield (%)a (time)
85 (3 h)
S
R
COOH
1
1d, R = Me
R
O
O
O
2d, R = Me
S
R
COOH
COOH
2
84 (3 h)
1e, R = n-C5H11
R
O
2e, R = n-C5H11
S
R
3
4
5
88 (3 h)
89 (3 h)
78 (3.5 h)
1f, R = n-C8H17
R
O
O
2f, R = n-C8H17
COOH
S
O
O
1g
2g
COOH
O
S
O
1h
2h
O
COOH
6
O
76 (4 h)
S
1i
1j
2i
H
COOH
O
7
83 (3.5 h)
O
H
S
2j
a Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
T. Zhang et al.
Paper
Synthesis
O
O
O
O
O
O
Cl
Cl
S
O
Cl
S
CO
+
2
Cl–
S
O
+
CO
+
S
O
Cl
Cl
Cl
Cl–
O
S
CH3
Cl
S
CH3SCl
+
H2C
H
O
S
Cl–
CH3
Cl–
– CH3Cl
HCHO + CH3SCH3 + HCl
O
S
n = 0
R
OH
n
S
– H+
R
O
O
H3CS Cl
COOH
COOH
R
S
R
S
n
n
n = 1
n = 2
O
O
O
Cl
R
R
R
OH
n
S
– H+
S
O
O
Scheme 2 Proposed reaction mechanism for sulfenyllactonization of alkenoic acids with DMSO/oxalyl chloride
a series of β-chloroalkyl sulfides were obtained from
alkenes by treatment with Me2S/SO2Cl2/DMSO, in which
methanesulfenyl chloride was considered as the key inter-
mediate. The pathway of the formation of methanesulfenyl
chloride was deduced to be via DMSO attack on the chlo-
rodimethylsulfonium salt derived from the reaction Me2S
with SO2Cl2. As shown by Bellesia et al., the crucial role of
DMSO in the formation of methanesulfenyl chloride was
also observed in our experiments. At first, reaction of
DMSO and oxalyl chloride in different molar ratios was at-
tempted. Almost no reaction occurred when the molar ratio
of DMSO to oxalyl chloride was less than 1. This result indi-
cates that the excess of DMSO against (COCl)2 was necessary
for the reaction to occur. Therefore, it could be concluded
that methanesulfenyl chloride did exist as a crucial inter-
mediate in the process of the reaction and two equivalents
of DMSO were required for the formation of this intermedi-
ate, among which one was for the production of the chlo-
rodimethylsulfonium salt and the other was needed to con-
vert this salt into the active species.
tio of DMSO to oxalyl chloride was less than 2, which
should be produced by the chlorodimethylsulfonium salt
via Pummerer’s rearrangement. After the role of DMSO was
recognized in the formation of methanesulfenyl chloride in-
termediate, the order of addition was inverted, i.e. (COCl)2
was added to the solution of DMSO in CH2Cl2 with the mo-
lar ratio of 2:1 (DMSO/oxalyl chloride), which avoided the
formation of chloromethyl methyl sulfide.
A possible pathway to these (methylthio)methyl esters
(Table 1, entries 1, 4, and 6) is shown in Scheme 4. The nuc-
leophilic attack of the carboxyl group of the substrates on
the chlorodimethylsulfonium salt produced the intermedi-
ate of acyloxysulfonium salt, which underwent Pummerer
rearrangement to afford the corresponding esters. The for-
mation of (methylthio)methyl esters indicated that no
methanesulfenyl chloride was produced via DMSO attack
on the chlorodimethylsulfonium salt at –65 °C. During re-
trieval of the literature, we found in Ghosh’s work that they
reported the synthesis of (methylthio)methyl esters under
Swern oxidation conditions.10 It was found that the yields of
S
DMSO/(COCl)2
CH2Cl2, 0 °C to r.t.
Cl
H
Cl
S
R
4
R
O
O
S
Scheme 3 The reaction of cyclohexene with DMSO/oxalyl chloride
HO
OH
– H+
Initially, the reactions were carried out followed the or-
der of addition as that of the Swern oxidation, i.e. DMSO
was added to the solution of (COCl)2 in CH2Cl2 before the
above mechanism was proposed. A byproduct, chlorometh-
yl methyl sulfide was usually detected when the molar ra-
R
R
O
S
+
O
CH2SCH3
O
OH
Scheme 4 The pathway of the formation of (methylthio)methyl alke-
noate
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

E
T. Zhang et al.
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Synthesis
(methylthio)methyl esters were not affected when the reac-
tion time was shortened from 24 hours to 30 minutes after
the addition of alkenoic acids to the DMSO/(COCl)2 reagent.
Obviously, the results we obtained at –65 °C were in agree-
ment with Ghosh’s work.
In conclusion, alkenoic acids can be converted into
sulfenyllactonates via thiiranium ions by methanesulfenyl
chloride generated in situ by the reaction of DMSO and ox-
alyl chloride. The reaction temperature makes significant
impact on this reaction. It presents very good generality for
various unsaturated acids, such as alk-3-enoic, alk-4-enoic,
and alk-5-enoic acids and affords the corresponding
sulfenyllactones in good yields under mild conditions.
Methylthio-Substituted Lactones 2a–j; General Procedure
To a solution of DMSO (2.3 mL, 30 mmol, 3.0 equiv) in CH2Cl2 (30 mL)
cooled at –0 °C was added dropwise a solution of oxalyl chloride (1.3
mL, 15 mmol, 1.5 equiv) in CH2Cl2 (20 mL). After 10 min, a solution of
alkenoic acid (10 mmol, 1.0 equiv) in CH2Cl2 (20 mL) was added. The
mixture was then allowed to warm up to r.t. and stirred overnight.
Et3N (7.0 mL, 50 mmol, 5.0 equiv) was added in one portion. After
stirring for 20 min, the mixture was diluted with CH2Cl2 (60 mL). The
organic layer was successively washed with sat. aq NH4Cl solution (50
mL) and brine (2 × 50 mL). The combined organic extracts were dried
(MgSO4), filtered, and concentrated under reduced pressure. Purifica-
tion by flash chromatography (silica gel, petroleum ether/EtOAc 10:1)
afforded the corresponding sulfenyllactone.
In an optimized procedure, CH2Cl2 was replaced by MeCN and the re-
action mixture was heated to reflux after addition of substrate.
trans-4-(Methylthio)-5-phenyldihydrofuran-2(3H)-one (2a)
1H NMR spectra were recorded on a Bruker AV300 or AV600 spec-
trometer. 13C NMR spectra were recorded at 100 MHz. The residual
solvent peak was used as an internal reference. HRMS data were ob-
tained on a Solarix XR or Autoflex III Mass Spectrometer. Analytical
TLC was performed with precoated TLC plates, silica gel 60F-254, lay-
er thickness 0.25 mm. Flash chromatography separations were per-
formed on 230–400 mesh silica gel. Reagents and solvents are com-
mercial grade and were used as supplied. Compounds 1a–c are com-
mercially available and were purchased from Sigma-Aldrich.
Light yellow oil; yield: 1.87 g (90%).
1H NMR (300 MHz, CDCl3): δ = 7.39 (m, 5 H), 5.28 (d, J = 6.9 Hz, 1 H),
3.38 (td, J = 8.4, 6.9 Hz, 1 H), 3.03 (dd, J = 18.0, 8.4 Hz, 1 H), 2.64 (dd,
J = 18.0, 8.4 Hz, 1 H), 2.06 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 174.23, 137.52, 128.94, 128.78, 125.69,
86.11, 48.26, 35.77, 14.24.
HRMS (EI): m/z [M]+• calcd for C11H12O2S: 208.05525; found:
208.05517.
(E)-Alken-3-enoic Acids 1d–f; General Procedure
3,3-Dimethyl-5-[(methylthio)methyl]dihydrofuran-2(3H)-one
To a 250-mL round-bottomed flask equipped with a condenser and a
bubbler connected to the exit of the condenser was added a solution
of malonic acid (26 g, 0.25 mol), piperidinium acetate [from piperi-
dine (0.22 g) and AcOH (0.15 g, 2.5 mmol)], and aliphatic aldehyde
(0.125 mol) in DMSO (100 mL). The mixture was stirred at 40 °C for 2
h. Then, the solution was heated in an oil bath at 100 °C. A rapid evo-
lution of CO2 was observed. Heating was maintained until the evolu-
tion of CO2 ceased. The solution was cooled to r.t., poured into cold
water (200 mL) and extracted with Et2O. The combined extracts were
washed with water and brine, dried (anhyd MgSO4), and evaporated
under reduced pressure. The residue was distilled under vacuum to
give the (E)-alk-3-enoic acid.
(2b)
Colorless oil; yield: 1.65 g (95%).
1H NMR (300 MHz, CDCl3): δ = 4.61 (dq, J = 9.6, 6.0 Hz, 1 H), 2.83 (dd,
J = 14.1, 5.7 Hz, 1 H), 2.72 (dd, J = 14.1, 6.3 Hz, 1 H), 2.23 (dd, J = 12.9,
6.0 Hz, 1 H), 2.20 (s, 3 H), 1.90 (dd, J = 12.9, 9.6 Hz, 1 H), 1.29 (s, 3 H),
1.27 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 181.27, 76.28, 42.32, 40.20, 38.48,
24.74, 24.45, 16.56.
HRMS (EI): m/z [M]+• calcd for C8H14O2S: 174.0715; found: 174.0716.
6-[(Methylthio)methyl]tetrahydro-2H-pyran-2-one (2c)
Colorless oil; yield: 1.45 g (91%).
(E)-Pent-3-enoic Acid (1d)
1H NMR (300 MHz, CDCl3): δ = 4.40 (dddd, J = 10.5, 6.9, 5.1, 3.3 Hz, 1
H), 2.73 (dd, J = 14.1, 5.4 Hz, 1 H), 2.63 (dd, J = 14.1, 6.6 Hz, 1 H), 2.53
(dt, J =17.7, 5.7 Hz, 1 H), 2.39 (ddd, J = 17.7, 9.0, 7.2 Hz, 1 H), 2.11 (s, 3
H), 2.01 (m, 1 H), 1.71–1.94 (m, 2 H), 1.59 (m, 1 H).
[CAS Reg. No.: 1617-32-9]
Colorless oil; yield: 8.5 g (68%); bp 60–65 °C/0.4 kPa.
All measured values were identical to those in the literature.6
13C NMR (75 MHz, CDCl3): δ = 170.89, 79.79, 38.83, 29.23, 26.58,
18.08, 16.67.
(E)-Non-3-enoic Acid (1e)
[CAS Reg. No.: 4124-88-3]
HRMS (EI): m/z [M]+• calcd for C7H12O2S: 160.0558; found: 160.0555.
Colorless oil; yield: 15.6 g (80%); bp 94–95 °C/0.4 kPa.
All measured values were identical to those in the literature.11
trans-5-Methyl-4-(methylthio)-5-dihydrofuran-2(3H)-one (2d)
Light yellow oil; yield: 1.24 g (85%).
1H NMR (300 MHz, CDCl3): δ = 4.40 (m, 1 H), 3.06 (q, J = 8.4 Hz, 1 H),
2.92 (dd, J = 17.7, 8.4 Hz, 1 H), 2.54 (dd, J = 17.7, 8.4 Hz, 1 H), 2.14 (s, 3
H), 1.46 (d, J = 6.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 174.39, 81.56, 46.67, 35.93, 19.79,
13.92.
(E)-Dodec-3-enoic Acid (1f)
[CAS Reg. No.: 4998-72-5]
Colorless oil; yield: 18.8 g (76%); bp 113–119 °C/0.014 kPa.
All measured values were identical to those in the literature.12
HRMS (EI): m/z [M]+• calcd for C6H10O2S: 146.03960; found:
146.03944.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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trans-4-(Methylthio)-5-pentyldihydrofuran-2(3H)-one (2e)
13C NMR (75 MHz, CDCl3): δ = 176.86, 90.08, 51.18, 37.15, 35.38,
31.82, 30.14, 14.89.
Light yellow oil; yield: 1.70 g (84%).
HRMS (EI): m/z [M]+• calcd for C8H12O2S: 172.0558; found: 172.0560.
1H NMR (300 MHz, CDCl3): δ = 4.27 (ddd, J = 8.1, 6.3, 4.2 Hz, 1 H), 3.11
(td, J = 8.1, 6.3 Hz, 1 H), 2.92 (dd, J = 17.7, 8.1 Hz, 1 H), 2.53 (dd, J =
17.7, 8.1 Hz, 1 H), 2.13 (s, 3 H), 1.56–1.82 (m, 2 H), 1.20–1.56 (m, 6 H),
0.87 (t, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 174.57, 85.26, 44.74, 35.87, 34.34,
31.32, 25.02, 22.34, 13.85 (CH3S and CH3CH2).
(Methylthio)methyl Alkenoates 3a–c; General Procedure
To a solution of DMSO (2.3 mL, 30 mmol, 3.0 equiv) in CH2Cl2 (30 mL)
cooled at –0 °C was added dropwise a solution of oxalyl chloride (1.3
mL, 15 mmol, 1.5 equiv) in CH2Cl2 (20 mL). After 10 min, a solution of
alkenoic acid (10 mmol, 1.0 equiv) in CH2Cl2 (20 mL) was added. The
mixture was then stirred for 30 min at –65 °C and Et3N (7.0 mL, 50
mmol, 5.0 equiv) was added in 1 portion. After 20 min at –65 °C, the
mixture was allowed to warm up to r.t. and diluted with CH2Cl2 (60
mL). The organic layer was successively washed with sat. aq NH4Cl
solution (50 mL) and brine (2 × 50 mL). The combined organic ex-
tracts were dried (MgSO4), filtered, and concentrated under reduced
pressure. Purification by flash chromatography (silica gel, petroleum
ether/EtOAc 10:1) afforded the corresponding (methylthio)methyl es-
ter.
HRMS (EI): m/z [M]+• calcd for C10H18O2S: 202.10220; found:
202.10215.
trans-4-(Methylthio)-5-octyldihydrofuran-2(3H)-one (2f)
Light yellow oil; yield: 2.14 g (88%).
1H NMR (300 MHz, CDCl3): δ = 4.27 (ddd, J = 8.1, 6.6, 4.2 Hz, 1 H), 3.11
(td, J = 8.1, 6.6 Hz, 1 H), 2.92 (dd, J = 18.0, 8.1 Hz, 1 H), 2.53 (dd, J =
18.0, 8.1 Hz, 1 H), 2.13 (s, 3 H), 1.56–1.82 (m, 2 H), 1.16–1.56 (m, 12
H), 0.86 (t, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 174.58, 85.28, 44.76, 35.89, 34.40,
31.73, 29.28, 29.18, 29.08, 25.36, 22.55, 14.01, 13.87.
(Methylthio)methyl (E)-4-Phenylbut-3-enoate (3a)
Colorless oil; yield: 2.01 g (90%).
HRMS (EI): m/z [M]+• calcd for C13H24O2S: 244.14915; found:
244.14915.
1H NMR (300 MHz, CDCl3): δ = 7.22–7.43 (m, 5 H), 6.53 (d, J = 15.9 Hz,
1 H), 6.31 (dt, J = 15.9, 6.9 Hz, 1 H), 5.19 (s, 2 H), 3.31 (dd, J = 6.9, 1.2
Hz, 2 H), 2.27 (s, 3 H).
5-[(Methylthio)methyl]dihydrofuran-2(3H)-one (2g)
13C NMR (75 MHz, CDCl3): δ = 171.23, 136.69, 133.76, 128.53, 127.62,
Colorless oil; yield: 1.30 g (89%).
126.27, 121.14, 68.54, 38.37, 15.44.
HRMS (EI): m/z [M]+• calcd for C12H14O2S: 222.0715; found: 222.0713.
1H NMR (300 MHz, CDCl3): δ = 4.71 (qd, J = 7.2, 5.4 Hz, 1 H), 2.84 (dd,
J = 14.1, 5.1 Hz, 1 H), 2.74 (dd, J = 14.1, 6.3 Hz, 1 H), 2.52–2.65 (m, 2 H),
2.34–2.47 (m, 1 H), 2.20 (s, 3 H), 2.02–2.12 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 176.78, 79.80, 38.68, 28.56, 26.89,
(Methylthio)methyl 2,2-Dimethylpent-4-enoate (3b)
16.80.
Colorless oil; yield: 1.76 g (94%).
HRMS (EI): m/z [M]+• calcd for C6H10O2S: 146.0402; found: 146.0403.
1H NMR (300 MHz, CDCl3): δ = 5.75 (m, 1 H), 5.13 (s, 2 H), 5.06 (m, 2
H), 2.30 (d, J = 7.5 Hz, 2 H), 2.23 (s, 3 H), 1.19 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 176.94, 133.89, 118.08, 68.04, 44.56,
(1R*,4R*,5R*)-4-(Methylthio)-6-oxabicyclo[3.2.1]octan-7-one (2h)
42.36, 24.64, 15.26.
Colorless oil; yield: 1.34 g (78%).
HRMS (EI): m/z [M]+• calcd for C9H16O2S: 188.0871; found: 188.0871.
1H NMR (300 MHz, CDCl3): δ = 4.78 (t, J = 4.5 Hz, 1 H), 3.08 (t, J = 4.5
Hz, 1 H), 2.59 (m, 1 H), 2.25 (m, 2 H), 2.04–2.20 (m, 1 H), 2.14 (s, 3 H),
1.76–1.93 (m, 3 H).
(Methylthio)methyl Hex-5-enoate (3c)
13C NMR (75 MHz, CDCl3): δ = 178.40, 79.16, 43.83, 38.59, 32.63,
Colorless oil; yield: 1.58 g (91%).
24.78, 23.14, 15.64.
HRMS (EI): m/z [M]+• calcd for C8H12O2S: 172.0558; found: 172.0559.
1H NMR (300 MHz, CDCl3): δ = 5.76 (m, 1 H), 5.12 (s, 2 H), 5.00 (m, 2
H), 2.35 (t, J = 7.5 Hz, 2 H), 2.23 (s, 3 H), 2.09 (q, J = 6.9 Hz, 2 H), 1.74
(m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 172.95, 137.35, 115.27, 67.78, 33.33,
(1R*,4S*,6R*)-6-(Methylthio)-2-oxabicyclo[2.2.1]heptan-3-one (2i)
32.75, 23.74, 15.18.
Colorless oil; yield: 1.20 g (76%).
HRMS (EI): m/z [M]+• calcd for C8H14O2S: 174.0715; found: 174.0715.
1H NMR (300 MHz, CDCl3): δ = 4.74 (br s, 1 H), 3.07 (m, 1 H), 2.85 (m,
1 H), 2.12–2.31 (m, 5 H), 2.04 (d, J = 10.8 Hz, 1 H), 1.55 (dt, J = 13.5, 4.5
Hz, 1 H).
trans-1-Chloro-2-(methylthio)cyclohexane (4)
13C NMR (75 MHz, CDCl3): δ = 177.31, 82.01, 45.27, 41.14, 37.01,
[CAS Reg. No.: 41578-06-7]
31.16, 16.21.
To a solution of DMSO (8.5 mL, 120 mmol, 2.4 equiv) in CH2Cl2 (100
mL) cooled at –0 °C was added dropwise a solution of oxalyl chloride
(5.2 mL, 60 mmol, 1.2 equiv) in CH2Cl2 (50 mL). After 10 min, a solu-
tion of cyclohexene (4.1 g, 50 mmol, 1.0 equiv) in CH2Cl2 (50 mL) was
added. The mixture was then allowed to warm up to r.t. and stirred
for 1 h. Et3N (34.8 mL, 250 mmol, 5.0 equiv) was added in 1 portion.
After stirring for 10 min, the mixture was successively washed with
sat. aq NH4Cl solution (100 mL) and brine (2 × 80 mL). The combined
HRMS (EI): m/z [M]+• calcd for C7H10O2S: 158.0402; found: 158.0401.
(1R*,5S*,8R*)-8-(Methylthio)-2-oxabicyclo[3.3.0]octan-3-one (2j)
Colorless oil; yield: 1.43 g (83%).
1H NMR (300 MHz, CDCl3): δ = 4.82 (dd, J = 6.6, 1.2 Hz, 1 H), 3.23 (m, 1
H), 3.04 (m, 1 H), 2.81 (dd, J = 18.3, 9.9 Hz, 1 H), 2.32 (dd, J = 18.3, 2.4
Hz, 1 H), 2.05–2.26 (m, 5 H), 1.66 (m, 1 H), 1.51 (m, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

G
T. Zhang et al.
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Synthesis
organic extracts were dried (MgSO4), filtered, and concentrated under
reduced pressure. The residue was distilled under reduced pressure to
give 4 (7.3 g, 89%) as a light yellow oil; bp 65–68 °C/0.067 kPa.
All measured values were identical to those in the literature.9
(2) (a) Balkrishna, S. J.; Prasad, C. D.; Panini, P.; Detty, M. R.;
Chopra, D.; Kumar, S. J. Org. Chem. 2012, 77, 9541. (b) Nolsøe, J.
M. J.; Hansen, T. V. Eur. J. Org. Chem. 2014, 3051. (c) Alvarado-
Beltran, I.; Maerten, E.; Toscano, R. A.; Lopez-Cortes, J. G.;
Baceiredo, A.; Alvarez-Toledano, C. Tetrahedron: Asymmetry
2015, 26, 802. (d) Gladkowski, W.; Skrobiszewski, A.; Mazur, M.;
Siepka, M.; Bialonska, A. Eur. J. Org. Chem. 2015, 605.
(3) Trost, B. M.; Ochiai, M.; McDougal, P. G. J. Am. Chem. Soc. 1978,
100, 7103.
(4) Young, R. N.; Coombs, W.; Guindon, Y.; Rokach, J.; Ethier, D.;
Hall, R. Tetrahedron Lett. 1981, 22, 4933.
(5) O’Malley, G. J.; Cava, M. P. Tetrahedron Lett. 1985, 26, 6159.
(6) Dai, Y.; Shao, J.; Yang, S.; Sun, B.; Liu, Y.; Ning, T.; Tian, H. J. Agric.
Food Chem. 2015, 63, 464.
Acknowledgment
Financial support from the National Natural Science Foundation of
China (No. 31271932 and 31571886), the National key research and
development program (2016YFD0400801), and the Importation and
Development of High-Caliber Talents Project of Beijing Municipal In-
stitutions (CIT&TCD20140306) is gratefully acknowledged.
(7) Lee, T. B. In Comprehensive Organic Synthesis; Vol. 7; Trost, B. M.,
Ed.; Pergamon: Oxford, 1991, 291.
(8) Carreño, M. C.; Carretero, J. C.; Garcia Ruano, J. L.; Rodriguez, J.
H. Tetrahedron 1990, 46, 5649.
Supporting Information
Supporting information for this article is available online at
(9) Bellesia, F.; Boni, M.; Ghelfi, F.; Pagnoni, U. M.; Pinetti, A. Synth.
Commun. 1992, 22, 1101.
http://dx.doi.org/10.1055/s-0036-1588378.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(10) Jadhav, S. B.; Ghosh, U. Tetrahedron Lett. 2007, 48, 2485.
(11) Dai, Y.; Tian, H.; Sun, B.; Sun, Y.; Chen, H.; Liu, X. J. Chem. Res.
2012, 36, 495.
(12) Rao, B. V. S. K.; Vijayalakshmi, P.; Subbarao, R. J. Am. Oil Chem.
Soc. 1993, 70, 297.
References
(1) These two authors contributed equally to this paper.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G