A Novel Method for the Chlorolactonization of Alkenoic Acids Using Diphenyl Sulfoxide/Oxalyl Chloride

Article abstract of DOI:10.1055/s-0037-1609687

A facile chlorolactonization of alkenoic acids by treatment with diphenyl sulfoxide/oxalyl chloride has been developed. The reaction can generate various chlorolactones in moderate to good yields, wherein the chlorodiphenylsufonium salt derived from diphenyl sulfoxide/oxalyl chloride serves as the source of Cl ⁺.

Full text of DOI:10.1055/s-0037-1609687

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–L
paper
A
en
R. Ding et al.
Paper
Synthesis
A Novel Method for the Chlorolactonization of Alkenoic Acids
Using Diphenyl Sulfoxide/Oxalyl Chloride
Rui Ding
Cl
Liyuan Lan
n = 0
Shuhui Li
Ph2SO/(COCl)2
R
O
O
COOH
Yongguo Liu
Shaoxiang Yang
Hongyu Tian*
Baoguo Sun*
R
n
n
Cl
n = 1, 2
Ph
+
O
O
S
Cl
R
Ph
12 examples
up to 91% yield
stereospecific
Beijing Advanced Innovation Center for Food Nutrition
and Human Health, Beijing Key Laboratory of Flavor
Chemistry, Beijing Technology and Business University,
100048 Beijing, P. R. of China
tianhy@btbu.edu.cn
sunbg@btbu.edu.cn
Received: 28.02.2018
Accepted after revision: 22.03.2018
Published online: 24.04.2018
covery of the use of chloramine T in conjunction with
methanesulfonic acid.9
However, highly efficient electrophilic chlorine equiva-
lents for chlorolactonization are much less common than
those for iodo- or bromolactonization. The existing ap-
proaches for chlorolactonization generally suffer major or
minor drawbacks such as low yields,8a long reaction time,8b
poor regioselection,7 or generality.3e Although the chloro-
lactones are less useful for further manipulation than are
the iodo- or bromolactones in total syntheses, they are very
important structural motif occurring widely in natural
products. The simple and highly efficient methods for
chlorolactonization are still deficient and need to be devel-
oped urgently. Herein, we report a novel method of chloro-
lactonizaiton, which was found fortuitously in our study on
the sulfenyllactonization of alkenoic acids with diphenyl
sulfoxide/oxalyl chloride.
A simple approach has been developed for the sulfenyl-
lactonization of alkenoic acids using the combination of di-
methyl sulfoxide/oxalyl chloride in our previous work
(Scheme 1; from 1a to 4), in which methanesulfenyl chlo-
ride, generated via DMSO attack on the chlorodimethylsu-
fonium salt, acted as the real species for sulfenyllactoniza-
tion.10 In order to expand the application scope of this
sulfenyllactonization method, the combination of diphenyl
sulfoxide/oxalyl chloride was taken to carry out sulfenyllac-
tonization of alkenoic acids. We took it for granted that lac-
tones containing a phenylthio group instead of a methylthio
group would be obtained.
DOI: 10.1055/s-0037-1609687; Art ID: ss-2018-f0129-op
Abstract A facile chlorolactonization of alkenoic acids by treatment
with diphenyl sulfoxide/oxalyl chloride has been developed. The reac-
tion can generate various chlorolactones in moderate to good yields,
wherein the chlorodiphenylsufonium salt derived from diphenyl sulfox-
ide/oxalyl chloride serves as the source of Cl+.
Key words chlorolactonization, alkenoic acids, diphenyl sulfoxide,
oxalyl chloride, chlorodiphenylsulfonium salt
Halolactonization has received sustained attention and
became a very powerful synthetic transformation in organ-
ic synthesis since its discovery in the early 1900s.1 The most
common version of this reaction is known as iodolactoniza-
tion due to its subsequent flexible transformation, but
bromolactones and chlorolatones have also been prepared
although to a lesser extent. In contrast to iodolactonizaiton,
bromo- and chlorolactonization have usually been per-
formed by using alternative reagents instead of molecular
halogen in the traditional procedures.2 For bromolactoniza-
tion, N-bromosuccinimide (NBS) has been utilized most
commonly as the source of Br+,1d,3 and many asymmetric
versions involving NBS and its analogues (N-bromo-
phthalimide and N-bromohydantoins) have been explored
in order to obtain optically active bromolactones.1b,3b,4 In
addition, the combination of metal bromide salts with oxi-
dizing agents can generate the brominating agent in the
presence of substrate to undergo bromolactonization.5 The
reagents used for chlorolactonization are similar to those
for bromolactonization, such as N-chlorosuccinimide
(NCS),3d,e N-chlorohydantoins,6 and the combination of
metal chloride salts with oxidizing agents.7 In addition, it
has been reported that chlorolactonization was performed
with chloramine T catalyzed by Lewis acids8 since the dis-
In our preliminary experiment, 2,2-dimethylpent-4-
enoic acid (1a) was taken as the first substrate under inves-
tigation referring to the previous procedure10 as follows: to
a solution of diphenyl sulfoxide (3.0 equiv) in MeCN cooled
at 0 °C was added dropwise a solution of oxalyl chloride (1.5
equiv) in MeCN (Table 1, entry 1). After 10 minutes, a solu-
tion of the alkenoic acid (1.0 equiv) in MeCN was added.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

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R. Ding et al.
Paper
Synthesis
O
S
(COCl)2
S+ Cl
O
S
O
S
Cl–
MeSCl
Ph
Ph
PhS
MeS
Cl
COOH
O
O
O
(COCl)2
O
O
O
4
1a
3
2a
Scheme 1 Sulfenyllactonization of alkenoic acids and speculation on chlorolactonization
The reaction mixture was then stirred and allowed to warm
to room temperature over 2 hours. However, an unexpected
product, 3,3-dimethyl-5-chloromethyldihydrofuran-2(3H)-
one (2a) was obtained in about 42% yield after an usual
workup followed by purification. It was initially proposed
that the product of sulfenyllactonization, 3,3-dimethyl-5-
phenylthiomethyldihydrofuran-2(3H)-one (3) was prone to
be attacked by chloride ion in the reaction mixture, which
led to the generation of a nucleophilic substitution product
2a (Scheme 1).
hydrofuran-2(3H)-one (cis-2b), would be obtained by two
sequential reactions, namely sulfenyllactonization and a
subsequent SN2 nucleophilic substitution (Scheme 2). Con-
trary to our expectations, trans-4-chloro-5-phenyldihydro-
furan-2(3H)-one (trans-2b) was obtained in about 37%
yield, the relative configuration of which was determined
by NOE and confirmed by comparison of NMR data with the
reference.11 Three other by-products were formed in rela-
tively low yields accompanying the production of trans-2b
(Scheme 2). It was difficult to remove these by-products
from the major product by column chromatography due to
their similar polarities. These three by-products were de-
duced to be 4-phenylthio-5-phenyldihydrofuran-2(3H)-one
(5), 5-phenylfuran-2(5H)-one (6), and 5-phenylfuran-
In order to confirm the above speculation, the reaction
of (E)-4-phenylbut-3-enoic acid (1b) was then investigated
under the same conditions as above (Table 1, entry 2). It
was expected that the product, cis-4-chloro-5-phenyldi-
Table 1 Chlorolactonization of Alkenoic Acids with Diphenyl Sulfoxide/Oxalyl Chloride
Entry
1
Substrate and reaction conditions
Product(s)
Yield (%)a of 2
COOH
Cl
42
O
1a
O
Ph2SO/(COCl)2,b MeCN, 0 °C to r.t., 2 h
2a
Cl
PhS
Ph
O
Ph
O
O
O
O
O
O
Ph
COOH
2
37c
tans-2b
5
1b
Ph2SO/(COCl)2,b MeCN, 0 °C to r.t., 2 h
Ph
O
Ph
6
7
3
4
5
6
7
1b, Ph2SO/(COCl)2,d CH2Cl2, –78 °C, 24 h
1b, Ph2SO/(COCl)2,d CH2Cl2, –78 to 0 °C, 24 h
1b, Ph2SO/(COCl)2,d CH2Cl2, –78 °C to r.t., 1 h
1b, Ph2SO/(COCl)2,d CH2Cl2, 0 °C to r.t., 2 h
1a, Ph2SO/(COCl)2,d CH2Cl2, –78 °C to r.t., 1 h
trans-2b
trans-2b
trans-2b
trans-2b
2a
16
25
88
30
91
a Isolated yield.
b Oxalyl chloride was added to the solution of diphenyl sulfoxide and the ratio of Ph2SO/(COCl)2 was 3.0 equiv:1.5 equiv.
c Determined based on the 1H NMR data.
d Diphenyl sulfoxide was added to the solution of oxalyl chloride and the ratio of Ph2SO/(COCl)2 was 1.5 equiv:1.5 equiv.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

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Synthesis
Cl–
O
Cl
PhS
Ph
S
Ph
Ph
Ph
Ph
COOH
(COCl)2
Ph
O
O
O
O
1b
1b
trans-5
cis-2b
O
S
Cl
PhS
Ph
Ph
+
+
+
COOH
Ph
O
Ph
Ph
O
O
Ph
O
(COCl)2
O
O
O
O
5
trans-2b
6
7
:
:
:
0.02
1
0.15
0.04
Scheme 2 The reaction of (E)-4-phenyl-3-butenoic acid with Ph2SO/(COCl)2
2(3H)-one (7), respectively, according to 1H NMR spectrum
combined with GC/MS analysis. The 1H NMR data of 5-
phenylfuran-2(5H)-one (6)12 and 5-phenylfuran-2(3H)-one
(7)13 were consistent with those in the literature. The ratio
of the major product to these three by-products was deter-
mined to be 1:0.15:0.04:0.02 based on the 1H NMR data.
The production of 4-chloro-5-phenyldihydrofuran-
2(3H)-one with trans configuration indicated that it was
impossible to be generated via an SN2 attack of chloride ion
selective ene-type allylic chlorination of electron-rich
alkenes, in which the salt was produced by the reaction of
chlorotrimethylsilane with dimethyl sulfoxide.14 However,
it was noteworthy that chlorodimethylsulfonium salt would
convert alkenoic acids into the corresponding (meth-
ylthio)methyl esters instead acting as a electrophilic Cl+ to-
wards double bonds, which was observed in our previous
work10 and the literature.15 trans-2b underwent elimina-
tion to generate two by-products, 5-phenylfuran-2(5H)-
one (6) and 5-phenylfuran-2(3H)-one (7). Another by-
on
trans-4-phenylthio-5-phenyldihydrofuran-2(3H)-one
(trans-5) produced from sulfenyllactonization. It was sup-
posed to be formed by the electrophilic addition of the
chlorodiphenylsulfonium salt to the double bond of the
substrate followed by a ring closure (Scheme 3), in which
the intervention of the cyclic chloronium ion 8 led to the
stereospecific production of trans-2b. The role of chlorodi-
phenylsulfonium salt acting as the source of Cl+ was very
similar to that of chlorodimethylsulfonium salt in the regio-
product,
4-phenylthio-5-phenyldihydrofuran-2(3H)-one
(5) was supposed to be formed with trans-configuration via
an episulfide intermediate 9 undertaking a ring closure as
we proposed previously (Scheme 3). The sulfenyllactoniza-
tion did not occur as the predominant reaction as expected,
which might be due to the key intermediate, phenylsulfenyl
chloride more difficult to be formed than methanesulfenyl
chloride generated in our previous work.10 The formation of
Ph
Ph
O
O
O
Cl–
Cl
O
Ph
Ph
(COCl)2
6
elimination
S+ Cl
O
S
Ph
Ph
Ph
+Cl
Ph
O
O
OH
trans-2b
8
O
Ph
COOH
7
1b
PhS
O
PhS Cl
Ph
S+
Ph
O
O
OH
Ph
9
trans-5
Ph
COOH
Ph
Cl
Ph +S
Ph
Ph
O–
S+
S+ Cl
O
S+
Ph
(COCl)2
PhO S+
PhSCl
+
Ph
Ph
Ph
O–
S+
Ph
Ph
10
O–
S+
Me
Me
Me
Me
S+ Cl
MeO +S
Me
Me
MeSCl
+
Scheme 3 Proposed mechanisms for chlorolactonization and sulfenyllactonizaiton
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

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Synthesis
phenylsulfenyl chloride involved an aromatic substitution
on one of the phenyl rings of the chlorodiphenylsulfonium
salt via a nucleophilic adduct 10 taking place elimination.
The low electrophilic activity of phenyl rings of the chlo-
rodiphenylsulfonium salt led to the difficulty of the forma-
tion of phenylsulfenyl chloride, which limited the genera-
tion of the sulfenyllactonization product trans-5. In con-
trast, it is much easier to produce methanesulfenyl chloride
via the attack of DMSO on the chlorodimethylsulfonium salt
by an SN2 mechanism as in our previous work (Scheme 3).10
Obviously, the above chlorolactonization occurred by a
different pathway from that of sulfenyllactonization we re-
ported previously, which implies that it should proceed un-
der different conditions from those of sulfenyllactonization.
Four more experiments were carried out in order to opti-
mize the reaction conditions for chlorolactonization (Table
1, entries 3–6). In the following experiments, the ratio of di-
phenyl sulfoxide with oxalyl chloride was decreased from
2:1 to 1:1 and the order of addition was inversed by adding
diphenyl sulfoxide to the solution of oxalyl chloride in con-
trast to those conditions for sulfenyllactonization, which
could avoid the attack of excess diphenyl sulfoxide in the
reaction mixture on the chlorodiphenylsulfonium salt so as
to prevent the formation of the key intermediate PhSCl for
sulfenyllactonization. In addition, the reactions were car-
ried out at –78 °C in CH2Cl2 since the chlorodiphenylsulfo-
nium salt was supposed to be the key intermediate, which
should present similar behavior to the intermediate chloro-
dimethylsulfonium salt unstable above –65 °C in the Swern
oxidation. After the addition of the substrate to the solution
of Ph2SO/(COCl)2 at –78 °C, the reaction mixture was treat-
ed in three different manners, remaining at –78 °C, or
warming up to 0 °C, or room temperature. The results indi-
cated that the reactions did not proceed completely to give
the product in poor yields (entries 3 and 4) with most of the
substrate recovered if the reaction mixture was kept below
0 °C, even stirring for 24 hours. However, the product was
obtained in a high yield of 88% when the reaction mixture
was stirred at room temperature for 1 hour after the addi-
tion of substrate at –78 °C (entry 5). For comparison, a reac-
tion was also carried out under the same temperature con-
ditions as entry 2 in Table 1, but the ratio of Ph2SO/(COCl)2,
addition order, and solvent were different (entry 6). The
product was obtained only in 30% yield close to that of en-
try 2 in Table 1. These results indicated that the reaction
temperature made important impact on yield. The addition
at a low temperature was necessary for the formation of the
key intermediate chlorodiphenylsulfonium salt and the
temperature rising to room temperature after addition fa-
vored the occurrence of chlorolactonization.
As we expected, the results showed that the sulfenyl-
lactonization product, 4-phenylthio-5-phenyldihydrofu-
ran-2(3H)-one (5), was not observed, which indicated that
the formation of PhSCl was prevented completely by avoid-
ing the presence of excess diphenyl sulfoxide in the reac-
tion mixture. The chlorolactonization of 2,2-dimethylpent-
4-enoic acid (1a) was carried out again to give the product
in 91% yield under the above optimized conditions (Table 1,
entry 7), which was much higher than that of entry 1 in Ta-
ble 1.
The combination of Ph2SO/(COCl)2 was supposed to be
an efficient reagent for chlorolactonization of alkenoic acids
based on the above results. More alkenoic acids were inves-
tigated further under the above optimized conditions in or-
der to investigate the application scope of this chlorolacton-
ization method, including four alk-3-enoic acids, five alk-4-
enoic acids, and one alk-5-enoic acid (Table 2).
Table 2 Investigation on the Application Scope of the Chlorolactonization Method
Entry
1
Substrate and reaction conditionsa
Product
Yield (%)b
28
Cl
COOH
1c
O
O
O
Ph2SO/(COCl)2, CH2Cl2, –78 °C to r.t., 1 h
trans-2c
2
3
1c, Ph2SO/(COCl)2, K2CO3 (5.0 equiv), 18-crown-6 (0.05 equiv), CH2Cl2, –78 °C to r.t., 5 h
85
40
O
11
Cl
R
COOH
R = n-C5H11
O
R
O
1d
R = n-C5H11
Ph2SO/(COCl)2, CH2Cl2, –78 °C to r.t., 1 h
trans-2d
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

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Synthesis
Table 2 (continued)
Entry
Substrate and reaction conditionsa
Product
Yield (%)b
O
R
O
4
1d, Ph2SO/(COCl)2, K2CO3 (5.0 equiv), 18-crown-6 (0.05 equiv), CH2Cl2, –78 °C to r.t., 5 h
83
R = n-C5H11
12
Cl
COOH
5
6
82
77
O
1e
O
Ph2SO/(COCl)2, CH2Cl2, –78 °C to r.t., 1 h; K2CO3 (5.0 equiv), MeCN, r.t., 2 h
2e
2e
1e, Ph2SO/(COCl)2, K2CO3 (5.0 equiv), 18-crown-6 (0.05 equiv), CH2Cl2, –78 °C to r.t., 5 h
H
H
O
36
23
O
Cl
7
COOH
cis-2f
1f
Ph2SO/(COCl)2, K2CO3 (5.0 equiv), 18-crown-6 (0.05 equiv), CH2Cl2, –78 °C to r.t., 5 h
O
Cl
O
2f
Cl
8
88
O
COOH
O
O
1g
Ph2SO/(COCl)2, CH2Cl2, –78 °C to r.t., 1 h
2g
COOH
9
51
50
Cl
1h
O
Ph2SO/(COCl)2, K2CO3 (5.0 equiv), 18-crown-6 (0.05 equiv), CH2Cl2, –78 °C to r.t., 5 h
2h
COOH
O
10
Cl
O
1i
2i
Ph2SO/(COCl)2, CH2Cl2, –78 °C to r.t., 1 h
O
Cl
Ph
OH
11
12
13
75
75
71c
Ph
O
O
1j
2j
Ph2SO/(COCl)2, CH2Cl2, –78 °C to r.t., 1 h
Cl
Br
O
O
O
OH
1k
Br
Ph2SO/(COCl)2, CH2Cl2, –78 °C to r.t., 1 h
trans-2k
O
OH
Cl
O
O
1l
2l
Ph2SO/(COCl)2, CH2Cl2, –78 °C to r.t., 1 h
a Diphenyl sulfoxide was added to the solution of oxalyl chloride and the ratio of Ph2SO/(COCl)2 was 1.5 equiv:1.5 equiv.
b Isolated yield.
c A mixture of trans- and cis-isomers in a ratio of 1:2.
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Four alk-3-enoic acids were (E)-pent-3-enoic acid (1c),
(E)-non-3-enoic acid (1d), (E)-4-phenylpent-3-enoic acid
(1j), and (E)-4-(4-bromophenyl)but-3-enoic acid (1k), re-
spectively. (E)-Pent-3-enoic acid (1c) was first treated with
Ph2SO/(COCl)2 under the same conditions as those in entry
5 in Table 1. Unexpectedly, a mixture of trans-4-chloro-5-
methyldihydrofuran-2(3H)-one (trans-2c) and 3,4-dichlo-
ropentanoic acid was obtained in a ratio of 1:1.7 (deter-
mined by 1H NMR analysis), which was washed with aque-
ous 5% NaHCO3 solution at 0 °C to give pure trans-4-chloro-
5-methyldihydrofuran-2(3H)-one (trans-2c) in 28% yield
(Table 2, entry 1). If the mixture was treated with saturated
aqueous NaHCO3 solution at room temperature, an elimina-
tion product, 5-methylfuran-2(5H)-one (11) was obtained.
This enlightened us that K2CO3 could be introduced to the
reaction system to produce 5-methylfuran-2(5H)-one (11).
As we expected, 5-methylfuran-2(5H)-one (11) was ob-
tained in an ideal yield of 85% (entry 2). Likewise, the situa-
tion of (E)-3-nonenoic acid (1d) was similar, which also
first produced a mixture of trans-4-chloro-5-pentyldihy-
drofuran-2(3H)-one (trans-2d) and 3,4-dichlorononanoic
chloro-2-oxabicyclo[3.2.1]octan-3-one (2f′) were obtained
in 36% and 23% yield, respectively, when the reaction was
carried out in the presence of K2CO3 (entry 7). 5-Nor-
bornene-2-carboxylic acid (1g) was purchased as a mixture
of endo- and exo-isomers in a ratio of 1:0.2. In contrast to
the other two alk-4-enoic acids 1e and 1f, a single chloro-
lactone 2g was obtained in 88% yield based on the content
of endo-1g in the substrate in the absence of K2CO3 (entry
8). The chlorolactonization of cyclohex-3-ene-1-carboxylic
acid (1i) also gave a mixture of a chlorolactone and a dichlo-
ride in a ratio of 1.3:1 in the absence of K2CO3 and gave the
pure chlorolactone 2i in 50% yield (entry 10). The addition
of K2CO3 did not promote the production of the chlorolac-
tone. The last alk-4-enoic acid substrate 1l gave 5-chloro-
methyl-3-methyldihydrofuran-2(3H)-one (2l) in 71% yield
in the absence of K2CO3. The product 2l was obtained as a
mixture of trans- and cis-isomers in a ratio of 1:2 (entry
13).
The only one alk-5-enoic acid (1h), hex-5-enoic acid
also gave a mixture of 6-(chloromethyl)tetrahydropyran-2-
one (2h) and 5,6-dichlorohexanoic acid in ratio of 1:6 (de-
1
1
acid in a ratio of 1:1 (determined by H NMR analysis) and
termined by H NMR analysis) if the reaction was carried
gave pure trans-4-chloro-5-pentyldihydrofuran-2(3H)-one
(trans-2d) in 40% yield (entry 3) after treatment with aque-
ous 5% NaHCO3 solution at 0 °C. An unsaturated lactone, 5-
pentylfuran-2(5H)-one (12) was obtained in 83% yield
when the reaction was carried out in the presence of K2CO3
(entry 4). In contrast, the chlorolactonization of (E)-4-
phenylpent-3-enoic acid (1j) and (E)-4-(4-bromophe-
nyl)but-3-enoic acid (1k) underwent smoothly under the
above optimized conditions to give (4R*,5S*)-4-chloro-5-
methyl-5-phenyldihydrofuran-2(3H)-one (2j) and trans-4-
chloro-5-(4-bromophenyl)dihydrofuran-2(3H)-one (trans-
2k) both in 75% yield, and the dichloride was not observed
(entries 11 and 12).
out in the absence of a base. In contrast, 6-(chlorometh-
yl)tetrahydropyran-2-one (2h) was produced exclusively in
51% yield in the presence of K2CO3 (Table 2, entry 9).
The formation of dichlorides interfered with the chloro-
lactonization of most substrates when the reactions were
carried out with Ph2SO/(COCl)2 only. This problem was
solved to obtain the chlorolactones only by the addition of
K2CO3. However, it failed for two alk-3-enoic acids 1c and
1d, which produced the α,β-unsaturated lactones due to the
occurrence of β-elimination of the β-chloro-γ-butanolides
under basic conditions (Table 2, entries 2 and 4). In order to
avoid the occurrence of β-elimination during the reactions
of these alk-3-enoic acids, the addition of Ag2O was ex-
plored instead of K2CO3 to prevent the formation of the di-
chlorides. All the substrates involving the formation of the
dichlorides in Table 2 were investigated further and the re-
sults are shown in Table 3. All these substrates except 1f un-
derwent chlorolactonization very smoothly in the presence
of Ag2O to afford the corresponding chlorolactones in more
than 80% yield. No dichlorides were observed in the present
conditions. These results indicated that Ag2O was able to
scavenge the chloride ion in most cases and prevented it
from attacking the cyclic chloronium ion intermediates to
produce the dichlorides. For cyclopent-2-ene-1-acetic acid
(1f), the addition of Ag2O had no effect on the reaction and
only dichloride was obtained.
Five alk-4-enoic acids were also investigated, including
pent-4-enoic acid (1e) cyclopent-2-ene-1-acetic acid (1f),
5-norbornene-2-carboxylic acid (1g), cyclohex-3-ene-1-
carboxylic acid (1i), and 2-methylpent-4-enoic acid (1l). A
mixture of 5-chloromethyldihydrofuran-2(3H)-one (2e)
and 4,5-dichloropentanoic acid with a ratio of 1:0.9 (deter-
1
mined by H NMR analysis) was obtained first when pent-
4-enoic acid (1e) reacted with Ph2SO/(COCl)2 under the op-
timized conditions in Table 1, which was then treated with
K2CO3 in MeCN at room temperature to afford 5-chloro-
methyldihydrofuran-2(3H)-one (2e) in 82% yield (Table 2,
entry 5). We also tried to add K2CO3 directly to the reaction
mixture in order to simplify the procedure, and 5-chloro-
methyldihydrofuran-2(3H)-one (2e) was produced exclu-
sively in 77% yield without the by-product 4,5-dichloropen-
tanoic acid (entry 6). Cyclopent-2-ene-1-acetic acid (1f) al-
most gave 2,3-dichlorocyclopentyl-1-acetic acid exclusively
if the reaction was carried out in the absence of base. How-
ever, two chlorolactones, (3aS*,6S*,6aR*)-6-chlorohexahy-
drocyclopenta[b]furan-2-one (cis-2f) and (1S*,5S*,8R*)-8-
In comparison, of all the substrates under investigation,
six substrates, including three alk-4-enoic acids 1a, 1g, and
1l, and three alk-3-enoic acids 1b, 1j, and 1k could give the
corresponding chlorolactones in good yields without the
aid of an extra reagent, K2CO3 or Ag2O (entries 5 and 7 in
Table 1, entries 8 and 11–13 in Table 2). These results were
understandable in view of the structural features of these
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Table 3 The Effect of Ag2O on the Formation of Dichlorides in the Present Chlorolactonization Method
Entry
1
Substrate and reaction conditionsa
Product
Yield (%)b
Cl
1c, Ph2SO/(COCl)2/Ag2O (1.5 equiv), CH2Cl2, –78 °C to r.t., 1 h
83
84
O
O
trans-2c
Cl
O
2
1d, Ph2SO/(COCl)2/Ag2O (1.5 equiv), CH2Cl2, –78 °C to r.t., 3 h
R
O
R = n-C5H11
trans-2d
Cl
3
4
1e, Ph2SO/(COCl)2/Ag2O (1.5 equiv), CH2Cl2, –78 °C to r.t., 30 min
1h, Ph2SO/(COCl)2/Ag2O (3.0 equiv), CH2Cl2, –78 °C to r.t., 3 h
87
80
O
O
O
2e
Cl
O
O
2h
5
1i, Ph2SO/(COCl)2/Ag2O (1.5 equiv), CH2Cl2, –78 °C to r.t., 1 h
80
Cl
O
2i
a Diphenyl sulfoxide was added to the solution of oxalyl chloride and the ratio of Ph2SO/(COCl)2 was 1.5 equiv:1.5 equiv.
b Isolated yield.
three substrates 1a, 1g, and 1l. It has been reported earlier
that the presence of substituents on a saturated carbon
atom α to the carbonyl function appears to promote halo-
lactonization.1e There is a so-called ‘buttressing effect’,
which brings the cationic intermediate and carboxyl func-
tion into a sufficiently close proximity for them to enter
into a transition state for lactonization, and prevent scav-
enging of the cation by halogen. So this is the reason that
1a, 1g, and 1l were observed to react very smoothly to give
the corresponding chlorolactones. Moreover, for 1g, its bi-
cyclic structure also favored the formation of lactone be-
cause the reacting groups were locked in the proper orien-
tation for reaction. For three alk-3-enoic acids 1b, 1j, and
1k, all of them contained a phenyl group conjugating with
the double bond, which could stabilize the cationic inter-
mediate and favored lactonization via an intramolecular at-
tack of carboxyl function on the cation. The chlorolactones
derived from 1a, 1g, and 1l were obtained in comparable
yields with those produced by other chlorolactonization
methods.7,8a Meanwhile, the chlorolactonization of 1b in
the present work afforded 4-chloro-5-phenyldihydrofuran-
2(3H)-one (trans-2b) in a much higher yield than other re-
agents, such as chloramine T,8a NaOCl,8b or chlorine.11
Ag2O could prevent the formation of dichlorides to promote
chlorolactonizaiton. Two alk-3-enoic acids 1c and 1d gave
the α,β-unsaturated lactones via β-elimination under the
basic conditions (Table 2, entries 2 and 4), whereas the β-
chloro-γ-butanolides were obtained in good yields in the
presence of Ag2O (Table 3, entries 1 and 2). The regioselec-
tion was a common issue in the chlorolactonization of alk-
3-enoic acids, which usually gave a mixture of β- and γ-lac-
tones.7 In contrast, the by-products β-lactones were not
formed and only γ-lactones were produced selectively in
the presence of Ag2O in the present method.
In contrast to alk-3-enoic acids, those dichlorides pro-
duced in the reactions of alk-4-enoic and alk-5-enoic acids
could be converted to the corresponding chlorolactones in
acceptable yields under basic conditions (Table 2, entries 5,
7, and 9). The addition of Ag2O could also promote the
chlorolactonization of these substrates to avoid the forma-
tion of dichlorides except 1f (Table 3, entries 3–5). More-
over, for the substrates 1h and 1i with lower yields under
basic conditions (Table 2, entries 9 and 10), the presence of
Ag2O promoted the reactions more efficiently to produce
the corresponding chlorolactones in much higher yields (Ta-
ble 3, entries 4 and 5). Meanwhile, for the alk-4-enoic acid
1e and the alk-5-enoic acid 1h, the corresponding chloro-
lactones were obtained in much better yields than the liter-
ature methods.7a,8,9
The other six substrates under investigation gave di-
chlorides more or less when the reactions were carried out
without K2CO3 or Ag2O, which was also observed for other
chlorolactonization method.16 The addition of K2CO3 or
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

H
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Synthesis
H
H
O
O
OH
OH
a
Cl
Cl
O
O
O
Cl
14
Cl
a
cis-2f
COOH
COOH
b
Ph
Ph
Cl+
S+ Cl
Cl–
1f
Cl–
13
Cl
O
b
Cl
2f'
15
Scheme 4 Proposed mechanism of chlorolactonization of 1f
Among all the substrates under investigation, 1f was the
only one that gave the corresponding chlorolactones in rela-
tively low yields (Table 2, entry 7). The reaction underwent
in two different ways to give two chlorolactones,
(3aS*,6S*,6aR*)-6-chlorohexahydrocyclopenta[b]furan-2-one
(cis-2f) and (1S*,5S*,8R*)-8-chloro-2-oxabicyclo[3.2.1]octan-
3-one (2f′) under basic conditions, which were supposed to
be produced in the following pathway as shown in Scheme
4. First, the electrophilic addition of the chlorodiphenylsul-
fonium salt to cyclopent-2-ene-1-acetic acid (1f) produced
the cyclic chloronium ion intermediate 13, which took
place stereoselectively on the face of the double bond oppo-
site the acetic acid substituent. Then the cyclic chloronium
ion intermediate 13 was attacked by chloride ion via two
different ways a or b to give (1S*,2S*,3S*)-2,3-dichlorocyclo-
pentyl-1-acetic acid (14) or (1S*,2R*,3R*)-2,3-dichlorocyclo-
pentyl-1-acetic acid (15), respectively, which undertook an
intramolecular SN2 nucleophilic substitution to afford the
corresponding chlorolactone cis-2f or 2f′. The relative con-
figuration of the chlorolactone cis-2f was determined by
the NOE experiments. In contrast with the other substrates,
the addition of Ag2O did not improve the chlorolactoniza-
tion. The addition of other silver salts, such as AgClO4 and
AgOAc to the reaction system was also tried to improve the
yields. In addition, the combination of Ag2O and K2CO3 was
also examined. Unfortunately, these measures did not make
any positive effect on the yields and regioselectivity in-
volved in the reaction of this substrate.
In conclusion, we have developed a novel method of
chlorolactonization of alkenoic acids using diphenyl sulfox-
ide and oxalyl chloride as the reagents. The real species for
chlorolactonization was proposed to be the chlorodiphenyl-
sulfonium salt derived from the reaction of diphenyl sulfox-
ide with oxalyl chloride, which served as the source of Cl+. A
variety of chlorolactones could be obtained in moderate to
good yields from alk-3-enoic, alk-4-enoic, and alk-5-enoic
acids by treatment with Ph2SO/(COCl)2. In some cases, the
addition of K2CO3 or Ag2O was needed to promote the for-
mation of the desired chlorolactones. For most cases, the
chlorolactones were obtained in comparable or much high-
er yields than those in literature. This chlorolactonization
method presented has notable advantages, such as easy op-
eration, short reaction time, high yields, and good generali-
ty, and is thus a good supplement for the existing methods.
NMR spectra were obtained on a Bruker AV 300 or 600 spectrometer
(1H NMR at 300 MHz, or 600 MHz, 13C NMR at 75 MHz, or 150 MHz)
in CDCl3 using TMS as an internal standard. Chemical shifts (δ) were
given in ppm and coupling constants (J) in hertz (Hz). HRMS data
were obtained on a SolariX mass spectrometer. GC-MS data were ob-
tained on an Agilent 7890B-5977A under the following conditions:
capillary column HP-5MS 5% Phenyl Methyl Silox (30 m × 0.25 mm ×
0.25 um); the oven temperature was programed from 50 to 150 °C at
a rate of 20 °C/min, then to 280 °C at a rate of 10 °C/min; carrier gas,
He; flow rate, 1.2 mL/min; electron ionization, 70 eV; ion source tem-
perature, 230 °C. TLC was performed with precoated TLC plates, silica
gel 60F-254, layer thickness 0.25 mm. Flash chromatography separa-
tions were performed on 200–400 mesh silica gel. Reagents and sol-
vents are commercial grade and were used as supplied. Substrates
1a–i and 1l are commercially available and were purchased from Sig-
ma-Aldrich; the other 3-alkenoic acids 1j and 1k were synthesized in
our lab.
(E)-4-Phenylpent-3-enoic Acid (1j)
[CAS Reg. No. 223243-86-5]
To a stirred solution of 2-phenylpropanal (2.68 g, 20 mmol, 1.0 equiv)
in Et3N (20 mL) was added malonic acid (3.12 g, 30 mmol, 1.5 equiv).
The mixture was heated at 90 °C for 15 h and then cooled to r.t. The
mixture was diluted with Et2O (100 mL) and acidified with aq 2 M
HCl. The organic phase was collected and the aqueous solution was
extracted with Et2O (3 × 30 mL). The combined extracts were basified
with aq 1 M NaOH. The aqueous phase was collected, acidified with
aq 2 M HCl, and extracted with Et2O (3 × 30 mL). The combined ex-
tracts were washed with brine (2 × 30 mL), dried (Na2SO4), filtered,
and concentrated under reduced pressure. The residue was purified
by recrystallization from PE/EtOAc (10:1) to afford 1j; yield: 1.62 g
(46%); white solid; mp 78–79 °C.
1H NMR (300 MHz, CDCl3): δ = 7.42–7.38 (m, 2 H, H-C2-phenyl and H-
C6-phenyl), 7.35–7.29 (m, 2 H, H-C3-phenyl and H-C5-phenyl), 7.28–
7.22 (m, 1 H, H-C4-phenyl), 5.93 (tq, J = 7.2, 1.2 Hz, 1 H, H-3), 3.31 (dq,
J = 7.2, 0.9 Hz, 2 H, H-2), 2.07 (dt, J = 1.2, 0.9 Hz, 3 H, H-5).
13C NMR (75 MHz, CDCl3): δ = 178.21 (C-1), 143.04 (C1-phenyl),
138.84 (C-4), 128.38 (C3 and C5-phenyl), 127.32 (C4-phenyl), 125.94
(C2- and C6-phenyl), 118.51 (C-3), 34.27 (C-2), 16.39 (C-5).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

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Synthesis
(E)-4-(4-Bromophenyl)but-3-enoic Acid (1k)
13C NMR (75 MHz, CDCl3): δ = 172.85 (C-2), 135.86 (C1-phenyl),
129.33 (C4-phenyl), 129.10 (C3- and C5-phenyl), 125.30 (C2- and C6-
phenyl), 87.53 (C-5), 57.82 (C-4), 38.16 (C-3).
[CAS Reg. No. 184360-96-1]
To a suspension of (2-carboxylethyl)triphenylphosphonium bromide
(6.83 g, 16.5 mmol, 1.1 equiv) in THF (45 mL) and DMSO (15 mL) was
added NaH (60% dispersion in mineral oil, 1.32 g, 33 mmol, 2.2 equiv)
at 0 °C. After the evolution of H2 gas, 4-bromobenzaldehyde (2.76 g,
15 mmol, 1.0 equiv) was added slowly at r.t. The mixture was stirred
at r.t. overnight, acidified with aq 1 M HCl, and extracted with EtOAc
(3 × 30 mL). The combined extracts were washed with brine (2 × 30
mL), dried (Na2SO4), filtered, and concentrated under reduced pres-
sure. The residue was purified by flash chromatography (silica gel,
PE/EtOAc 5:1) to afford 1k; yield: 1.80 g (50%); white solid; mp 110–
111 °C.
HRMS (ESI): m/z [M + Na+] calcd for C10H9ClO2Na: 219.01888; found:
219.01842.
trans-4-Chloro-5-methyldihydrofuran-2(3H)-one (trans-2c)
[CAS Reg. No. 22373-87-1]
Colorless oil; yield: 187 mg (28%).
1H NMR (600 MHz, CDCl3): δ = 4.62 (dq, J = 6.0, 6.6 Hz, 1 H, H-5), 4.15
(ddd, J = 7.8, 6.6, 6.0 Hz, 1 H, H-4), 3.10 (dd, J = 18.0, 7.8 Hz, 1 H, H-3),
2.79 (dd, J = 18.0, 6.6 Hz, 1 H, H′-3), 1.46 (d, J = 6.6 Hz, 3 H, CH3).
13C NMR (150 MHz, CDCl3): δ = 172.74 (C-2), 83.78 (C-5), 56.51 (C-4),
38.65 (C-3), 18.64 (CH3).
1H NMR (600 MHz, CDCl3): δ = 7.43 (d, J = 7.8 Hz, 2 H, H-C3 and C5-
phenyl), 7.24 (d, J = 7.8 Hz, 2 H, H-C2 and C6-phenyl), 6.46 (d, J = 15.9
Hz, 1 H, H-4), 6.28 (dt, J = 15.0, 7.2 Hz, 1 H, H-3), 3.29 (d, J = 7.2 Hz, 2
H, H-2).
HRMS (ESI): m/z [M + Na+] calcd for C5H7ClO2Na: 157.00323; found:
157.00271.
13C NMR (150 MHz, CDCl3): δ = 177.53 (C-1), 135.66 (C1-phenyl),
133.00 (C-4), 131.82 (C3 and C5-phenyl), 127.99 (C2 and C6-phenyl),
121.75 (C-3), 121.65 (C4-phenyl), 38.03 (C-2).
trans-4-Chloro-5-pentyldihydrofuran-2(3H)-one (trans-2d)
Colorless oil; yield: 380 mg (40%).
1H NMR (600 MHz, CDCl3): δ = 4.47 (dt, J = 9.0, 4.8 Hz, 1 H, H-5), 4.20
(ddd, J = 9.0, 7.8, 6.0 Hz, 1 H, H-4), 3.06 (dd, J = 18.0, 7.8 Hz, 1 H, H-3),
2.74 (dd, J = 18.0, 6.0 Hz, 1 H, H′-3), 1.74–1.69 (m, 1 H, H-C1-pentyl),
1.64–1.58 (m, 1 H, H′-C1-pentyl), 1.51–1.46 (m, 1 H, H-C2-pentyl),
1.43–1.37 (m, 1 H, H′-C2-pentyl), 1.34–1.25 (m, 4 H, H-C3-pentyl and
H-C4-pentyl), 0.88–0.83 (m, 3 H, CH3).
13C NMR (150 MHz, CDCl3): δ = 172.96 (C-2), 87.63 (C-5), 55.22 (C-4),
38.69 (C-3), 33.17 (C1-pentyl), 31.32 (C3-pentyl), 24.89 (C2-pentyl),
22.42 (C4-pentyl), 13.95 (CH3).
Chlorolactones 2a–l; General Procedure
To a solution of oxalyl chloride (0.65 mL, 7.5 mmol, 1.5 equiv) in
CH2Cl2 (10 mL) cooled at –78 °C was added dropwise a solution of di-
phenyl sulfoxide (1.52 g, 7.5 mmol, 1.5 equiv) in CH2Cl2 (10 mL) under
N2 atmosphere. After 10 min, a solution of alkenoic acid 1 (5 mmol,
1.0 equiv) in CH2Cl2 (10 mL) was added. The mixture was then al-
lowed to warm up to r.t. and stirred for 1 h. Distilled H2O (30 mL) was
added dropwise at 0 °C. After stirring for 10 min, the organic layer
was separated and successively washed with brine (2 × 30 mL). The
combined organic extracts were dried (Na2SO4), filtered, and concen-
trated under reduced pressure. Purification by flash chromatography
(silica gel, PE/EtOAc 10:1) afforded the corresponding chlorolactones.
HRMS (ESI): m/z [M + Na+] calcd for C9H15ClO2Na: 213.06583; found:
213.06539.
5-(Chloromethyl)dihydrofuran-2(3H)-one (2e)
[CAS Reg. No. 39928-72-8]
In an optimized procedure for chlorolactones 2e, 2f, and 2h, K2CO3
(3.45 g, 25 mmol, 5.0 equiv) and 18-crown-6 (66 mg, 0.025 mmol,
0.05 equiv) were added after the addition of substrate, then the mix-
ture was allowed to warm up to r.t. and stirred for 5 h. For cyclopent-
2-ene-1-acetic acid (1f), two chlorolactones cis-2f and 2f′ were ob-
tained.
Colorless oil; yield: 516 mg (77%).
1H NMR (600 MHz, CDCl3): δ = 4.78–4.74 (m, 1 H, H-5), 3.72 (dd, J =
11.4, 4.8 Hz, 1 H, H-CH2Cl, A part of ABX), 3.68 (dd, J = 11.4, 4.2 Hz, 1
H, H′-CH2Cl, B part of ABX), 2.64 (ddd, J = 18.0, 10.2, 6.0 Hz, 1 H, H-3),
2.55 (ddd, J = 18.0, 10.2, 7.8 Hz, 1 H, H′-3), 2.41–2.39 (m, 1 H, H-4),
2.15 (dddd, J = 13.2, 10.2, 7.2, 6.6 Hz, 1 H, H′-4).
5-(Chloromethyl)-3,3-dimethyldihydrofuran-2(3H)-one (2a)
[CAS Reg. No. 205528-10-5]
13C NMR (150 MHz, CDCl3): δ = 176.37 (C-2), 78.21 (C-5), 46.13
Colorless oil; yield: 740 mg (91%).
(CH2Cl), 28.28 (C-3), 25.02 (C-4).
1H NMR (300 MHz, CDCl3): δ = 4.67–4.58 (m, 1 H, H-5), 3.66 (dd, J =
11.7, 5.4 Hz, 1 H, H-CH2Cl, A part of ABX), 3.65 (dd, J = 11.7, 4.8 Hz, 1
H, H′-CH2Cl, B part of ABX), 2.19 (dd, J = 12.9, 6.3 Hz, 1 H, H-4), 1.95
(dd, J = 12.9, 9.6 Hz, 1 H, H′-4), 1.26 (s, 3 H, CH3), 1.24 (s, 3 H, CH3).
HRMS (ESI): m/z [M + Na+] calcd for C5H7ClO2Na: 157.00323; found:
157.00268.
(3aS*,6S*,6aR*)-6-Chlorohexahydrocyclopenta[b]furan-2-one (cis-
2f)
13C NMR (75 MHz, CDCl3): δ = 180.98 (C-2), 75.02 (C-5), 45.64 (CH2Cl),
40.38 (C-4), 40.30 (C-3), 24.91 (CH3), 24.85 (CH3).
Colorless oil; yield: 360 mg (36%; purity: 80% by GC).
HRMS (ESI): m/z [M + Na+] calcd for C7H11ClO2Na: 185.03453; found:
185.03404.
1H NMR (300 MHz, CDCl3): δ = 4.86 (dd, J = 6.9, 4.5 Hz, 1 H, H-6a),
4.20–4.14 (m, 1 H, H-6), 3.00–2.89 (m, 1 H, H-3a), 2.84 (dd, J = 18.0,
10.5 Hz, 1 H, H-3), 2.33 (dd, J = 17.7, 3.3 Hz, 1 H, H′-3), 2.12–1.94 (m, 3
H, H-4, H-5, H′-5), 1.76–1.62 (m, 1 H, H′-4).
trans-4-Chloro-5-phenyldihydrofuran-2(3H)-one (trans-2b)
[CAS Reg. No. 819795-96-5]
13C NMR (75 MHz, CDCl3): δ = 176.89 (C-2), 84.43 (C-6a), 59.92 (C-6),
36.92 (C-3), 35.81 (C-3a), 32.70 (C-5), 30.39 (C-4).
HRMS (ESI): m/z [M + Na+] calcd for C7H9ClO2Na: 183.01888; found:
183.01839.
Colorless oil; yield: 862 mg (88%).
1H NMR (300 MHz, CDCl3): δ = 7.43–7.32 (m, 5 H, C6H5), 5.54 (d, J = 4.5
Hz, 1 H, H-5), 4.42 (ddd, J = 7.2, 5.7, 4.5 Hz, 1 H, H-4), 3.13 (dd, J = 18.0,
7.2 Hz, 1 H, H-3), 2.84 (dd, J = 18.0, 5.7 Hz, 1 H, H′-3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

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(1S*,5S*,8R*)-8-Chloro-2-oxabicyclo[3.2.1]octan-3-one (2f′)
1H NMR (300 MHz, CDCl3): δ = 7.43–7.32 (m, 5 H, C6H5), 4.69 (dd, J =
6.3, 3.6 Hz, 1 H, H-4), 2.97 (dd, J = 18.0, 6.3 Hz, 1 H, H-3), 2.79 (dd, J =
18.0, 3.6 Hz, 1 H, H′-3), 1.83 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 172.90 (C-2), 142.06 (C1-phenyl),
129.14 (C3- and C5-phenyl), 128.60 (C4-phenyl), 124.23 (C2- and C6-
phenyl), 88.99 (C-5), 62.37 (C-4), 39.56 (C-3), 25.60 (CH3).
Colorless oil; yield: 184 mg (23%).
1H NMR (300 MHz, CDCl3): δ = 4.67–4.64 (m, 1 H, H-1), 4.12–4.07 (m,
1 H, H-8), 3.11 (ddd, J = 18.6, 5.1, 2.1 Hz, 1 H, H-4), 2.62–2.54 (m, 1 H,
H-5), 2.46 (ddd, J = 18.6, 1.2, 1.2 Hz, 1 H, H′-4), 2.31–2.18 (m, 1 H, H-
7), 2.12–1.96 (m, 2 H, H-6 and H′-7), 1.95–1.82 (m, 1 H, H′-6).
13C NMR (75 MHz, CDCl3): δ = 169.07 (C-3), 81.40 (C-1), 58.19 (C-8),
37.00 (C-5), 36.00 (C-4), 30.00 (C-7), 27.48 (C-6).
HRMS (ESI): m/z [M + Na+] calcd for C11H11ClO2Na: 233.03453; found:
233.03404.
HRMS (ESI): m/z [M + Na+] calcd for C7H9ClO2Na: 183.01888; found:
183.01845.
trans-4-Chloro-5-(4-bromophenyl)dihydrofuran-2(3H)-one
(trans-2k)
Yellow oil; yield: 1.03 g (75%).
6-Chlorohexahydro-2H-3,5-methanocyclopenta[b]furan-2-one
(2g)
1H NMR (300 MHz, CDCl3): δ = 7.57 (dm, J = 8.4 Hz, 2 H, H-C3-phenyl),
7.26 (dm, J = 8.4 Hz, 2 H, H-C2-phenyl), 5.48 (d, J = 5.1 Hz, 1 H, H-5),
4.35 (ddd, J = 7.5, 6.3, 5.1 Hz, 1 H, H-4), 3.14 (dd, J = 18.0, 7.5 Hz, 1 H,
H-3), 2.88 (dd, J = 18.0, 6.3 Hz, 1 H, H′-3).
13C NMR (75 MHz, CDCl3): δ = 172.33 (C-2), 134.95 (C1-phenyl),
132.41 (C3- and C5-phenyl), 127.08 (C2- and C6-phenyl), 123.63 (C4-
phenyl), 86.86 (C-5), 57.50 (C-4), 38.31 (C-3).
[CAS Reg. No. 35242-26-3]
Colorless oil; yield: 756 mg (88%).
1H NMR (300 MHz, CDCl3): δ = 4.72 (d, J = 5.1 Hz, 1 H, H-CHO), 3.80
(dd, J = 2.4, 6.0 Hz, 1 H, H-CHCl), 3.24 (tq, J = 4.8, 1.5 Hz, 1 H, H-CHCH-
Cl), 2.61–2.60 (m, 1 H, H-CHCO), 2.56 (ddm, J = 11.4, 4.8 Hz, 1 H, H-
CHCHO), 2.26 (dq, J = 11.4, 1.8 Hz, 1 H, H-CH2CHCO), 2.12 (ddd, J =
13.8, 11.4, 4.2 Hz, 1 H, H-CH2CHCHCl), 1.75 (ddt, J = 13.8, 0.6, 2.4 Hz, 1
H, H′-CH2CHCHCl), 1.68 (ddq, J = 11.4, 0.6, 1.8 Hz, 1 H, H′-CH2CHCO).
HRMS (ESI): m/z [M + Na+] calcd for C10H8BrClO2Na: 296.92939;
found: 296.92892.
13C NMR (75 MHz, CDCl3): δ = 179.40 (C=O), 87.66 (CHO), 63.21 (CH-
Cl), 45.62 (CHCHCl), 45.27 (CHCO), 37.81 (CHCHO), 34.94 (CH2CHCO),
33.42 (CH2CHCHCl).
5-(Chloromethyl)-3-methyldihydrofuran-2(3H)-one (2l)
Colorless oil; yield: 525 mg (71%); trans/cis = 1:2.
HRMS (ESI): m/z [M + Na+] calcd for C8H9ClO2Na: 195.01888; found:
195.01832.
trans-Isomer
[CAS Reg. No. 88431-09-8]
1H NMR (300 MHz, CDCl3): δ = 4.74 (ddt, J = 8.4, 4.5, 4.5 Hz, 1 H, H-5),
3.70–3.63 (m, 2 H, CH2Cl), 2.89–2.75 (m, 1 H, H-3), 2.43 (ddd, J = 13.2,
9.3, 3.6 Hz, 1 H, H-4), 2.07 (dt, J = 13.2, 8.4 Hz, 1 H, H′-4), 1.30 (d, J =
7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 179.35 (C-2), 76.06 (C-5), 46.05 (CH2Cl),
33.89 (C-3), 33.01 (C-4), 16.35 (CH3).
6-(Chloromethyl)tetrahydropyran-2-one (2h)
[CAS Reg. No. 77944-06-0]
Colorless oil; yield: 378 mg (51%).
1H NMR (600 MHz, CDCl3): δ = 4.55–4.50 (m, 1 H, H-6), 3.67 (dd, J =
11.4, 4.8 Hz, 1 H, H-CH2Cl, A part of ABX), 3.63 (dd, J = 11.4, 6.0 Hz, 1
H, H′-CH2Cl, B part of ABX), 2.62 (dddd, J = 18.0, 6.6, 4.8, 1.2 Hz, 1 H,
H-3), 2.48 (ddd, J = 18.0, 9.6, 7.2 Hz, 1 H, H′-3), 2.10–2.05 (m, 1 H, H-
5), 1.99 (ddq, J = 13.8, 7.2, 4.8 Hz, 1 H, H-4), 1.92–1.83 (m, 1 H, H′-4),
1.73 (dtd, J = 13.8, 10.8, 4.8 Hz, 1 H, H′-5).
HRMS (ESI): m/z [M + Na+] calcd for C6H9ClO2Na: 171.01888; found:
171.01839.
13C NMR (150 MHz, CDCl3): δ = 170.45 (C-2), 79.06 (C-6), 45.89 (CH2-
cis-Isomer
Cl), 29.63 (C-3), 25.43 (C-5), 18.30 (C-4).
[CAS Reg. No. 88431-19-0]
HRMS (ESI): m/z [M + Na+] calcd for C6H9ClO2Na: 171.01888; found:
171.01833.
1H NMR (300 MHz, CDCl3): δ = 4.60 (ddt, J = 10.2, 5.4, 5.4 Hz, 1 H, H-
5), 3.73 (dd, J = 11.4, 4.8 Hz, 1 H, H-CH2Cl, A part of ABX), 3.67 (dd, J =
11.4, 5.4 Hz, 1 H, H′-CH2Cl, B part of ABX), 2.81–2.67 (m, 1 H, H-3),
2.58 (ddd, J = 12.3, 9.0, 5.7 Hz, 1 H, H-4), 1.77 (td, J = 12.0, 9.9 Hz, 1 H,
H′-4), 1.32 (d, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 178.52 (C-2), 76.32 (C-5), 45.49 (CH2Cl),
35.57 (C-3), 34.43 (C-4), 15.30 (CH3).
(1R*,4R*,5R*)-4-Chloro-6-oxabicyclo[3.2.1]octan-7-one (2i)
[CAS Reg. No. 76644-31-0]
White solid; yield: 400 mg (50%).
1H NMR (300 MHz, CDCl3): δ = 4.76 (t, J = 5.1 Hz, 1 H, H-5), 4.33 (t, J =
4.6 Hz, 1 H, H-4), 2.68–2.65 (m, 1 H, H-1), 2.53 (d, J = 12.3 Hz, 1 H, H-
8), 2.30–2.22 (m, 2 H, H′-8 and H-3), 2.07 (dd, J = 15.9, 5.4 Hz, 1 H, H′-
3), 2.01–1.80 (m, 2 H, H-2).
HRMS (ESI): m/z [M + Na+] calcd for C6H9ClO2Na: 171.01888; found:
171.01839.
α,β-Unsaturated γ-Lactones 11 and 12; General Procedure
13C NMR (75 MHz, CDCl3): δ = 177.66 (C-7), 79.00 (C-5), 53.55 (C-4),
To a solution of oxalyl chloride (0.65 mL, 7.5 mmol, 1.5 equiv) in
CH2Cl2 (10 mL) cooled at –78 °C was added dropwise a solution of di-
phenyl sulfoxide (1.52 g, 7.5 mmol, 1.5 equiv) in CH2Cl2 (10 mL) under
N2 atmosphere. After 10 min, a solution of the corresponding alkenoic
acid 1c, d (5 mmol, 1.0 equiv) in CH2Cl2 (10 mL) was added. The mix-
ture was then allowed to warm up to r.t. and stirred for 1 h. K2CO3
(3.45 g, 25 mmol, 5.0 equiv) and 18-crown-6 (66 mg, 0.025 mmol,
0.05 equiv) were added and stirred for 5 h. The mixture was filtered
38.25 (C-1), 31.92 (C-8), 27.90 (C-3), 22.43 (C-2).
HRMS (ESI): m/z [M + Na+] calcd for C7H9ClO2Na: 183.01888; found:
183.01841.
(4R*,5S*)-4-Chloro-5-methyl-5-phenyldihydrofuran-2(3H)-one (2j)
Colorless oil; yield: 788 mg (75%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

K
R. Ding et al.
Paper
Synthesis
and the filtrate was diluted with distilled H2O (30 mL). The organic
layer was separated and successively washed with brine (2 × 30 mL).
The combined organic extracts were dried (Na2SO4), filtered, and con-
centrated under reduced pressure. Purification by flash chromatogra-
phy (silica gel, PE/EtOAc 10:1) afforded the corresponding α,β-unsat-
urated-γ-lactones.
Funding Information
Financial support from the National Key Research and Development
Program (2016YFD0400801), Beijing Postdoctoral Research Founda-
tion (2017-22-011), and the Importation and Development of High-
Caliber Talents Project of Beijing Municipal Institutions
(CIT&TCD20140306) is gratefully acknowledged.
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5-Methylfuran-2(5H)-one (11)
[CAS Reg. No. 591-11-7]
Supporting Information
Colorless oil; yield: 420 mg (85%).
Supporting information for this article is available online at
1H NMR (300 MHz, CDCl3): δ = 7.44 (dd, J = 5.7, 1.5 Hz, 1 H, H-4), 6.02
(dd, J = 5.7, 2.1 Hz, 1 H, H-3), 5.09 (qdd, J = 6.9, 1.8, 1.5 Hz, 1 H, H-5),
1.39 (d, J = 6.9 Hz, 3 H, CH3).
https://doi.org/10.1055/s-0037-1609687.
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13C NMR (75 MHz, CDCl3): δ = 173.12 (C-2), 157.65 (C-4), 121.07 (C-
3), 79.67 (C-5), 18.75 (CH3).
References
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5-Pentylfuran-2(5H)-one (12)
[CAS Reg. No. 21963-26-8]
Colorless oil; yield: 640 mg (83%).
1H NMR (300 MHz, CDCl3): δ = 7.44 (dd, J = 5.7, 1.5 Hz, 1 H, H-4), 6.09
(dd, J = 5.7, 2.1 Hz, 1 H, H-3), 5.03 (ddt, J = 7.2, 5.4, 1.8 Hz, 1 H, H-5),
1.77–1.64 (m, 2 H, H-C1-pentyl), 1.47–1.40 (m, 2 H, H-C2-pentyl),
1.35–1.28 (m, 4 H, H-C3-pentyl and H-C4-pentyl), 0.91–0.86 (m, 3 H,
CH3).
13C NMR (75 MHz, CDCl3): δ = 173.28 (C-2), 156.42 (C-4), 121.64 (C-
3), 83.57 (C-5), 33.28 (C1-pentyl), 31.58 (C3-pentyl), 24.76 (C2-pen-
tyl), 22.53 (C4-pentyl), 14.04 (CH3).
By-Products Obtained from the Reaction of 1b with Diphenyl Sulf-
oxide and Oxalyl Chloride (Scheme 2)
4-Phenylthio-5-phenyldihydrofuran-2(3H)-one (5)
1H NMR (600 MHz, CDCl3): δ = 7.45–7.32 (m, 10 H, 2 × C6Η5), 5.34 (d,
J = 6.0 Hz, 1 H, H-5), 3.81 (ddd, J = 8.4, 7.2, 6.0 Hz, 1 H, H-4), 3.02 (dd,
J = 18.0, 8.4 Hz, 1 H, H-3), 2.65 (dd, J = 18.0, 7.2 Hz, 1 H, H′-3).
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corn, F.; Michon, C.; Deniau, E. Tetrahedron: Asymmetry 2016,
27, 980.
GC/MS (EI): m/z (%) = 77 (17), 91 (26), 109 (12), 115 (13), 135 (59),
136 (100), 137 (13), 270 (16).
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5-Phenylfuran-2(5H)-one (6)
[CAS Reg. No. 53138-45-7]
1H NMR (600 MHz, CDCl3): δ = 7.53 (dd, J = 5.4, 1.8 Hz, 1 H, H-4), 7.45–
7.32 (m, 5 H, C6H5), 6.23 (dd, J = 5.4, 1.8 Hz, 1 H, H-3), 6.02 (dd, J = 1.8,
1.8 Hz, 1 H, H-5).
GC/MS (EI): m/z (%) = 51 (29), 55 (11), 77 (60), 103 (10), 105 (100),
115 (12), 131 (49), 132 (16), 160 (86).
5-Phenylfuran-2(3H)-one (7)
[CAS Reg. No. 1955-39-1]
1H NMR (600 MHz, CDCl3): δ = 7.45–7.32 (m, 5 H, C6H5), 5.79 (t, J = 3.0
Hz, 1 H, H-4), 3.43 (d, J = 3.0 Hz, 2 H, H-3).
GC/MS (EI): m/z (%) = 50 (17), 51 (34), 54 (22), 55 (10), 63 (14), 77
(68), 78 (11), 82 (61), 89 (11), 103 (34), 105 (91), 115 (42), 131 (100),
132 (13), 160 (60).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

L
R. Ding et al.
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L