γ-chloromagnesio γ-lactones and δ-chloromagnesio γ-lactones: Generation, properties, and synthetic uses

Article abstract of DOI:10.1055/s-0028-1088019

Treatment of γ- and δ-lactones having a sulfinyl group at the γ- and δ-positions with isopropylmagnesium chloride in THF at -78°C gave γ-chloromagnesio γ-lactones and δ- chloromagnesio δ-lactones, respectively, by the sulfoxide-magnesium exchange reaction

Full text of DOI:10.1055/s-0028-1088019

PAPER
1323
g-Chloromagnesio g-Lactones and d-Chloromagnesio d-Lactones: Generation,
Properties, and Synthetic Uses
g
-Chloromagnesio
i
g
-Lact
t
one
s
an
o
d
d
-Chlorom
m
agnesio
d
-Lactonesi Shimizu, Shigehiko Fukuda, Shimpei Sugiyama,* Tsuyoshi Satoh
Department of Chemistry, Faculty of Science, Tokyo University of Science, Ichigaya-Funagawara-machi, Shinjuku-ku, Tokyo 162-0826,
Japan
Fax +81(565)52614631; E-mail: ssugi@rs.kagu.tus.ac.jp
Received 26 November 2008; revised 25 December 2008
In our previous studies, it was found that the reaction of
Abstract: Treatment of g- and d-lactones having a sulfinyl group at
alkyl aryl sulfoxides having a heteroatom at the carbon
bearing the sulfinyl group, such as sufinyloxiranes 1
(X = O) and sulfinylaziridines 1 (X = NAr), with alkyl-
the g- and d-positions with isopropylmagnesium chloride in THF at
–78 °C gave g-chloromagnesio g-lactones and d-chloromagnesio d-
lactones, respectively, by the sulfoxide–magnesium exchange reac-
tion in high yields. Comparing the stability of the g-chloromagnesio metals (alkyllithiums and Grignard reagents) resulted in
the formation of oxiranyl anions 2 (X = O)8,9 and aziridi-
g-lactones with that of the d-chloromagnesio d-lactones, the former
nyl anions 2 (X = NAr) (Scheme 1).8,10 Namely, the bond
was found to be much more stable. The reaction of these g-chloro-
magnesio g-lactones and d-chloromagnesio d-lactones with electro-
between the sulfur and the carbon bearing a heteroatom is
philes and the stereochemistry of the reactions are discussed.
cleaved by the reaction with alkylmetals through the sulf-
oxide–metal exchange reaction.11 Furthermore, we found
Key words: g-chloromagnesio g-lactone, d-chloromagnesio d-lac-
tone, sulfoxide–magnesium exchange reaction, organomagnesium
that the oxiranyl anions and aziridinyl anions 2 reacted
compound, Grignard reagent
with several electrophiles to give epoxides and aziridines
3 in good yields.
In continuation of this chemistry, we envisaged that if
Organomagnesium compounds, generally called as Grig-
Grignard reagents react with the sulfinyl group in lactones
nard reagents, were discovered by V. Grignard over 100
years ago.1 Grignard reagents are easily prepared from
alkyl- or aryl halides with magnesium metal in an ethereal
solvent and are usually stable at room temperature and
storable for a long period of time. In addition, Grignard re-
agent can act as a base and a nucleophile as well. These
are the reasons why Grignard regents have been one of the
most important reagents for the formation of a carbon–
carbon bond on reaction with carbonyl compounds or
alkyl halides.2
4, g-chloromagnesio g-lactones 5 (n = 1) and d-chloro-
magnesio d-lactones 5 (n = 2) could be generated via
sulfoxide–magnesium exchange reaction.11 We also anti-
cipated that the further reaction of 5 with various electro-
philes would afford lactones 6 having a carbon–carbon
bond at the g- and d-position, respectively. We report
here, in detail, the first example for the generation of
g-chloromagnesio g-lactones and d-chloromagnesio d-
lactones and the investigation of their properties and the
reaction with electrophiles (Scheme 1).12
Although Grignard reagents are less basic and less nucleo-
philic than the corresponding organolithium reagents, the
carbon–magnesium bond is still highly reactive and it has
long been generally recognized that the presence of elec-
trophilic functional groups, such as esters, nitriles, and ke-
tones, cannot be compatible with the Grignard reagents.
However, recently, the preparation of functionalized
Grignard reagents and their properties have been studied
and reported by Knochel3 and others. The functionalized
Grignard reagents are those of functionalized arylmagne-
sium reagents,4 polyfunctional heteroarylmagnesium re-
agents,5 and functionalized alkenylmagnesium reagents.6
These functionalized magnesium reagents have ester, ni-
trile, halogen, and amide as the functional groups. How-
ever, these functional groups are usually present directly
on the aromatic ring or on the sp2-carbon, which means
that there is no acidic a-hydrogen, although some excep-
tion is also reported.7
R2
R3
R2
R3
R1
R2
R3
R1
E
R1
X
X
E+
X
R-Metal
Metal = Li, MgX
Ar(O)S
Metal
1
3
2
X = O, NAr
R
O
R
O
R
O
E+
i-PrMgCl
n
E
6
n
n
O
O
O
S(O)Tol
MgCl
4
(n = 1, 2)
5
Scheme 1
Synthesis of g-p-Tolylsulfanyl g-Lactones and
d-p-Tolylsulfanyl d-Lactones
SYNTHESIS 2009, No. 8, pp 1323–1335
Advanced online publication: 16.03.2009
DOI: 10.1055/s-0028-1088019; Art ID: F23808SS
x
x
.
x
x
.2
0
0
9
At first, g-(p-tolylsulfinyl) g-lactones and d-(p-tolylsulfi-
nyl) d-lactones 4 were synthesized as follows. Thus, 1-
© Georg Thieme Verlag Stuttgart · New York

1324
H. Shimizu et al.
PAPER
chlorovinyl p-tolyl sulfoxide (7) was synthesized starting intermediate of this addition reaction was trapped with io-
from methyl formate and chloromethyl p-tolyl sulfoxide domethane to give adduct 10 in 99% yield as a single iso-
in three steps in 75% overall yield (Scheme 2).13 Lithium mer (Scheme 3).
enolate of tert-butyl 4-phenylbutyrate (4.5 equiv) was
generated from tert-butyl 4-phenylbutyrate with LDA in
Ph(CH2)3CO2t-Bu
(4.5 equiv)
1)
(CH2)2Ph
CO2t-Bu
THF at –78 °C and to this reaction mixture was added a
solution of 7 in THF. The addition reaction was found to
be instantaneous and the adduct 8 was obtained within one
minute in 99% yield. When less amount of the lithium
enolate of tert-butyl 4-phenylbutyrate was used, the reac-
tion was not completed.
H
H
Cl
S
H
H
LDA, THF, –78 °C
Tol
S(O)Tol
2) MeI
99%
Me
Cl
O
7
10
(CH2)2Ph
CO2H
TFAA (10 equiv)
NaI (10 equiv)
4.5 equiv
Ph(CH2)3CO2t-Bu
H
H
TolS(O)CH2Cl
TFA, CH2Cl2
91%
H
H
Cl
S
HCO2Me
S(O)Tol
acetone, –50 °C
LDA, THF, –78 °C
99%
Tol
Me
Cl
O
11
7
(CH2)2Ph
(CH2)2Ph
H
H
(CH2)2Ph
(CH2)2Ph
O
TFAA (5 equiv)
NaI (5 equiv)
O
H
H
CO2t-Bu
S(O)Tol
H
CO2H
NOE
+
O
O
H
I–
STol
acetone, –50 °C
TolS
Me
Cl
Me
12b 37%
STol
Cl
OCOCF3
8
12a 36%
I
Ph(CH2)3CO2t-Bu
(4.5 equiv)
1)
(CH2)2Ph
O
(CH2)2Ph
H
(CH2)2Ph
H
NOE
H
(CH2)2Ph
CO2t-Bu
O
H
H
COOH
STol
1) TFA, CH2Cl2
LDA, THF, –78 °C
H
H
+
O
O
7
2) TFAA (10 equiv)
NaI (10 equiv)
acetone, –50 °C
S(O)Tol
2) allyl iodide
TolS
STol
H
85%
Cl
II
9a: 52%
9b: 31%
13
Scheme 2
(CH2)2Ph
(CH2)2Ph
H
H
O
O
Although adduct 8 has three chiral centers, only one iso-
mer was obtained judging from its H NMR spectrum.
+
1
O
O
TolS
Next, the adduct 8 was treated with trifluoroacetic anhy-
dride (TFAA) in the presence of NaI in acetone at –50 °C
to give g-lactone 9 having a tolylsulfanyl group at the g-
position.14 The presumed mechanism of this reaction is
shown in Scheme 2. First, the reaction of the sulfoxide 8
with TFAA gives an acyloxysulfonium ion. At the same
time, the tert-butyl ester is eliminated by trifluoroacetic
acid to carboxylic acid I. The iodine anion then attacks the
chlorine atom to give thionium ion II. The oxygen of the
carboxylic acid attacks intramolecularly the thionium ion
to afford the g-lactone 9. Two diastereomers were ob-
served on silica gel TLC and they could be separated by
silica gel column chromatography. In order to determine
the stereochemistry of these two products 9a and 9b,
NOESY spectra of the lactones were measured. From de-
tailed inspection of the spectra, we were able to determine
that the main lactone 9a has cis-stereochemistry as shown
in Scheme 2.
STol
14a 24% (from 13)
14b 27% (from 13)
Scheme 3
As the treatment of 10 with TFAA and NaI did not give
the desired g-lactone but a complex mixture, tert-butyl es-
ter group was converted to the carboxylic acid with triflu-
oroacetic acid (TFA) in dichloromethane to give 11 in
91% yield. Carboxylic acid 11 was treated with TFAA
and NaI in the same way as described above to afford a
mixture of g-lactones 12a (36%) and 12b (37%). The ste-
reochemistry of 12a and 12b was again determined by
NOESY spectra of both lactones. In a similar way, the in-
termediate of the addition reaction of 7 with lithium eno-
late of tert-butyl 4-phenylbutyrate was trapped with allyl
iodide to give 13 in 85% yield. Removal of the tert-butyl
ester group of 13 with TFA followed by the treatment with
In a similar way, the addition reaction of tert-butyl 4-phe-
nylbutyrate with vinyl sulfoxide 7 was carried out and the
Synthesis 2009, No. 8, 1323–1335 © Thieme Stuttgart · New York

PAPER
g-Chloromagnesio g-Lactones and d-Chloromagnesio d-Lactones
1325
TFAA-NaI gave a mixture of g-lactones 14a and 14b hav- product 18b showed a double-double-doublet at d = 5.55.
ing an allyl group at the g-carbon in moderate yield.
The small coupling constant (J = 0.6 Hz) indicated that
the hydrogen has long-range coupling (long-range W cou-
pling)15 between the equatorial hydrogen on the b-carbon
(depicted in Scheme 4).
Next, the synthesis of d-sulfanyl d-lactones 18 was inves-
tigated (Scheme 4). Lithium enolate of tert-butyl 4-phe-
nylbutyrate was generated from tert-butyl 4-phenyl-
butyrate with LDA in THF in the presence of HMPA and
to this reaction mixture was added a solution of (3-io-
do)propyl tolyl sulfide (15) in THF to afford the alkylated
ester 16 in 82% yield. The sulfanyl group of 16 was oxi-
dized with m-chloroperbenzoic acid (MCPBA) to a sulfi-
nyl group, and the resulting sulfinyl ester was chlorinated
with N-chlorosuccinimide (NCS). Finally, the tert-butyl
ester was converted to the carboxylic acid 17 with TFA in
78% overall yield from 16. Carboxylic acid 17 was treated
with TFAA in the presence of NaI in propionitrile at
–50 °C to afford the desired d-sulfanyl d-lactone 18 in
moderate yield.
Generation of g-Chloromagnesio g-Lactones and
d-Chloromagnesio d-Lactones from g-p-Tolylsulfinyl
g-Lactones and d-p-Tolylsulfinyl d-Lactones, Respec-
tively, with i-PrMgCl
Generation of g-chloromagnesio g-lactones and d-chloro-
magnesio d-lactones was investigated next. At first, 9a
and 18a were used in the following studies. Sulfide 9a
was oxidized with MCPBA at –50 °C to afford sulfoxide
19a as a mixture of two diastereomers in high yield. Next,
the mixture of the sulfoxides 19a was treated with 1.6
equivalents of i-PrMgCl at –78 °C for 10 minutes (a solu-
tion of 19a in THF was added to a solution of i-PrMgCl in
THF) to give the desulfinylated product 21 in 94% yield
via sulfoxide–magnesium exchange reaction without a
trace of the starting sulfoxide 19a. Quenching this reac-
tion with MeOD gave deuterated product (deuterated at g-
position) 21 with 99% deuterium incorporation. This re-
sult showed that the intermediate of this reaction was g-
chloromagnesio g-lactone 20 (see Scheme 5).
O
Ph(CH2)3CO2t-Bu
I
STol
t-BuO
STol
LDA-HMPA / THF
82%
(CH2)2Ph
16
15
TFAA (5 equiv)
NaI (5 equiv)
O
Cl
1) MCPBA, CH2Cl2
HO
S(O)Tol
propionitrile
–50 °C
2) NCS, CCl4
(CH2)2Ph
3) TFA, CH2Cl2
In a similar way, sulfoxide–magnesium exchange reaction
of d-tolylsulfinyl d-lactone 22a, which was synthesized
from d-tolylsulfanyl d-lactone 18a with MCPBA in a
quantitative yield, was carried out with three equivalents
of i-PrMgCl and the reaction was quenched with MeOD
to give d-lactone 24 deuterated at d-position in 87% yield
(D-content 99%). When less than three equivalents of
i-PrMgCl was used in this reaction, the sulfoxide-magne-
sium exchange reaction did not go to completion. Obvi-
ously, the intermediate of this reaction was the d-
chloromagnesio d-lactone 23. At this stage, we were wor-
ried about an intermolecular or an intramolecular proton
abstraction of these magnesiated lactones; because, both
20 and 23 have relatively acidic hydrogen on the a-posi-
tion. However, no deuterium incorporation at the a-posi-
78%; 3 steps
17
Ph(CH2)2
H
Ph(CH2)2 H
O
O
+
O
O
H
STol
TolS
H
18a 45%
18b 22%
O
O
STol
Ph
H
1
18a
tion of 21 and 24 were observed as revealed by their H
δ 5.58
(dd, J = 8.4, 4.2 Hz)
NMR spectra.
O
Next, the stability of g-chloromagnesio g-lactone 20 and
d-chloromagnesio d-lactone 23 was investigated. The sta-
bility of 20 and 23 was evaluated by the chemical yield
and the rate of deuterium incorporation of the reaction of
19a and 22a with i-PrMgCl followed by MeOD and the
results are summarized in Table 1. The result of the reac-
tion of 19a already mentioned in Scheme 5 is described in
entry 1. The result of the reaction of 19a with i-PrMgCl at
–78 °C for 1 hour is shown in entry 2. Comparing the re-
sults shown in entries 1 and 2, it is expected that the gen-
erated g-chloromagnesio g-lactone 20 is stable at –78 °C
for over one hour. Other reaction conditions for the reac-
tion of 19a with i-PrMgCl are shown in entries 3 to 6.
O
δ 5.55
H
Ph
H
(ddd, J = 7.2, 5.1, 0.6 Hz)
STol
18b
Scheme 4
On a silica gel TLC, two products could be observed and
they were separated by silica gel column chromatography
as a less polar main product 18a (45%) and a more polar
minor product 18b (22%). The stereochemistry of the two
products was easily determined from the coupling pattern
of the hydrogen at the carbon bearing the sulfanyl group
as depicted in Scheme 4. Thus, the hydrogen of the minor
Synthesis 2009, No. 8, 1323–1335 © Thieme Stuttgart · New York

1326
H. Shimizu et al.
PAPER
(CH2)2Ph
O
(CH2)2Ph
O
(CH2)2Ph
O
MeOH
i-PrMgCl (1.6 equiv)
THF, –78 °C, 10 min
MCPBA
(MeOD)
9a
O
S(O)Tol
19a
O
MgCl
20
O
94%
CHCl3, –50 °C
94%
H (D)
21
(D-content = 99%)
(CH2)2Ph
O
(CH2)2Ph
O
(CH2)2Ph
O
MeOH
(MeOD)
MCPBA
i-PrMgCl (3 equiv)
18a
O
O
O
87%
CHCl3, 0 °C
99%
THF, –78 °C, 10 min
S(O)Tol
H (D)
MgCl
22a
24
23
(D-content = 99%)
Scheme 5
These data indicate that g-chloromagnesio g-lactone 20 is When the reaction was quenched with MeOD, the rate of
rather stable even about –50 °C.
deuterium incorporation at the g-position was 99%. Next,
g-sulfanyl g-lactone 14a was converted to g-lactone bear-
ing an allyl group 28 with 99% deuterium in corporation
via g-chloromagnesio g-lactone 27 in 82% overall yield.
Interestingly, although both g-lactones 26 and 28 have
two stereogenic centers, only a single product was ob-
tained. No isomer was observed from detailed inspection
of their 1H NMR spectra. From these results, it was found
that the stereochemistry of the carbon bearing the sulfinyl
group of 12a or 14a at the g-position was retained
throughout the whole sequence (see Scheme 6).10,16
Contrary to the results described above, d-chloromagne-
sio d-lactone 23 generated from d-p-tolylsulfanyl d-lac-
tone 22a with i-PrMgCl was found to be fairly unstable.
Thus, the reaction of 22a carried out even at –78 °C for 10
minutes produced 24 in only 87% yield with several un-
known by-products (entry 1). When the reaction mixture
was stirred at –78 °C for one hour, the yield of 24 was
markedly diminished (entry 2). When the temperature of
the reaction mixture was allowed to warm to –50 °C, we
obtained only a complex mixture (entry 4). We still find it
difficult to propose a rational reason for the instability of In order to extend this unprecedented Grignard reagent as
d-chloromagnesio d-lactone 23 compared to 20 – the size a new synthetic method for g-substituted g-lactones, trap-
of the ring is one possibility.
ping of g-chloromagnesio g-lactones 20 and 31 with sev-
eral electrophiles was investigated (Scheme 7). Thus, the
reaction of 19a and 19b with i-PrMgCl followed by ethyl
chloroformate at –78 °C for one hour gave good yields of
esters 29 and 32. Interestingly, both products, 29 and 32,
were obtained each as a single diastereomer.
In a similar way, the sulfanyl group of 12a was oxidized
with MCPBA to a sulfinyl group, and the resultant sulfi-
nyl lactone was treated with 1.6 equivalents of i-PrMgCl
to give lactone 26 bearing a methyl group at the g-position
via g-chloromagnesio g-lactone 25 in 71% overall yield.
(CH2)2Ph
(CH2)2Ph
O
(CH2)2Ph
O
1) MCPBA
O
CHCl3, –50 °C, 94%
MeOD
71%
O
O
O
2) i-PrMgCl (1.6 equiv)
Me
Me
Me
THF, –78 °C, 10 min
STol
MgCl
D
(D-content = 99%)
12a
26
25
(CH2)2Ph
O
(CH2)2Ph
O
(CH2)2Ph
O
1) MCPBA
CHCl3, –50 °C, 94%
MeOD
82%
O
O
O
2) i-PrMgCl (1.6 equiv)
THF, –78 °C, 10 min
MgCl
D
(D-content = 99%)
STol
27
28
14a
Scheme 6
Synthesis 2009, No. 8, 1323–1335 © Thieme Stuttgart · New York

PAPER
g-Chloromagnesio g-Lactones and d-Chloromagnesio d-Lactones
1327
Configuration of the products was again confirmed by
NOESY experiments and the reactions were found to be
highly stereospecific as shown in Scheme 7. Namely, the
stereochemistry of the anionic carbon was retained
throughout the sequence. The reactions of 20 and 31 with
benzoyl chloride at –78 °C for one hour gave products 30
and 33 in 54 and 65% yield, respectively, as a single prod-
uct. When this reaction mixture was slowly allowed to
warm to –50 °C and further stirred at –50 °C for one hour,
the result was almost the same compared with the condi-
tion described above. No isomer was observed from de-
tailed inspection of their 1H NMR spectra.
Table 1 Formation of Lactones 21 and 24 via Chloromagnesio Lac-
tones 20 and 23 (Scheme 5)
(CH2)2Ph
O
(CH2)2Ph
O
(CH2)2Ph
O
MeOD
i-PrMgCl
n
n
n
O
O
O
THF
conditions
S(O)Tol
D
MgCl
19a (n = 1)
22a (n = 2)
20 (n = 1)
23 (n = 2)
21 (n = 1)
24 (n = 2)
Entry Conditions
21
24
Yield (%)/
D-content (%)a D-content (%)b
Yield (%)/
In order to investigate the generality of these reactions,
34a and 34b were used in the following studies (Scheme
8). Treatment of g-tolylsulfinyl g-lactones 34a and 34b
with i-PrMgCl followed by benzoyl chloride in the same
way as described above resulted in the formation of g-lac-
tones 35 and 36, respectively, via g-chloromagnesio g-lac-
tones, again highly stereospecifically in moderate yields.
1c
2
–78 °C, 10 min
94/99
91/94
85/91
80/91
87/99
–78 °C, 1 h
–78 °C, 2 h
62/99
3
55/99
4
–78 to –50 °C, 50 min,
then –50 °C for 1 h
complex mixture
In order to compare the reactivity of d-chloromagnesio
d-lactones with g-chlolomagnesio g-lactones, we tried to
trap d-chloromagnesio d-lactones generated from 22a and
22b with ethyl chloroformate as an electrophile. In the
same way described above, the reaction of 22a and 22b
with i-PrMgCl followed by ethyl chloroformate at –78 °C
for one hour gave the desired d-lactones 37and 38, respec-
tively, however, the yields were miserably low (Scheme
5
6
–78 to –50 °C, 50 min,
then –50 °C for 2 h
80/88
63/93
–
–
–78 to –30 °C, 90 min,
then –30 °C for 10 min
a Amount of i-PrMgCl used = 1.6 equiv.
b Amount of i-PrMgCl = 3.0 equiv.
c The results are described in Scheme 5.
(CH2)2Ph
O
(CH2)2Ph
(CH2)2Ph
O
NOE
H
H
O
i-PrMgCl (1.6 equiv)
ClCO2Et
O
O
O
CO2Et
29
–78 °C, 1 h
63%
THF, –78 °C
H
H
S(O)Tol
MgCl
19a
20
(CH2)2Ph
H
H
O
PhCOCl
O
–78 °C, 1 h
54%
CPh
O
30
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
O
O
O
i-PrMgCl (1.6 equiv)
THF, –78 °C
ClCO2Et
O
O
O
–78 °C, 1 h
70%
Tol(O)S
ClMg
EtO2C
H
H
H
32
31
19b
(CH2)2Ph
O
PhCOCl
O
–78 °C, 1 h
65%
PhC
O
H
33
Scheme 7
Synthesis 2009, No. 8, 1323–1335 © Thieme Stuttgart · New York

1328
H. Shimizu et al.
PAPER
Me
least 10 minutes. Entries 6 to 8 show that g-chloromagne-
sio g-lactone 40c is fairly stable even at –50 °C for at least
one hour.
Me
H
1) i-PrMgCl (1.6 equiv)
O
H
O
THF, –78 °C
O
O
2) PhCOCl
The reaction of g-chloromagnesio g-lactones 40a and 40b
with ethyl chloroformate at –78 °C for one hour gave the
products 41b and 41d having an ethoxycarbonyl group in
36 and 46% yield, respectively (entries 2 and 4). In the
same manner, the reaction of g-chloromagnesio g-lac-
tones 40a and 40b, derived from 39a and 39b, with ben-
zoyl chloride gave g-lactones having a benzoyl group at
the g-position, 41c and 41e, in up to 61% yield (entries 3
and 5). The yields of both reactions were not satisfactory
and steric hindrance was thought to be the reason for the
low yield. Interestingly, the products were obtained as a
single diastereomer, and again the reaction proceeded in a
highly stereospecific manner.
Tol(O)S
PhC
O
–78 °C, 1 h, 43%
H
H
35
34a
Me
Me
1) i-PrMgCl (1.6 equiv)
THF, –78 °C
H
H
H
H
O
O
O
O
2) PhCOCl
–78 °C, 1 h, 45%
CPh
O
S(O)Tol
34b
36
Scheme 8
Entries 6–11 show the results concerning the g-chloro-
magnesio g-lactones, 40c and 40d, generated from b,b-
disubstituted g-lactones 39c and 39d, respectively. As
shown in the results in entries 6–8, and as already men-
tioned above, the g-chloromagnesio g-lactones 40c gener-
ated from b,b-disubstituted g-lactone 39c were found to
be stable at below –50 °C. The reactivity of the g-chloro-
magnesio g-lactone generated from 39c and 39d was in-
vestigated; however, both ethyl chloroformate and
benzoyl chloride did not react at all with the generated g-
chloromagnesio g-lactones 40c and 40d. Steric hindrance
(neopentyl position) was thought to be the reason for the
low reactivity with the electrophiles.
9) while, about 50% of protonated lactone at the d-posi-
tion was observed from 1H NMR spectrum. From these re-
sults, g-chloromagnesio g-lactones were found to be more
reactive at the low temperature. Instability of d-chloro-
magnesio d-lactones is one explanation for the low yields
of the products 37 and 38.
1) i-PrMgCl (3 equiv)
THF, –78 °C
Ph(CH2)2
H
Ph(CH2)2
H
O
O
2) ClCO2Et
O
O
–78 °C, 1 h, 10%
H
CO2Et
H
S(O)Tol
22a
In conclusion, we were able to generate, for the first time,
g-chloromagnesio g-lactones and d-chloromagnesio d-
lactones from g-lactones and d-lactones having a tolyl-
sulfinyl group at the g- or d-position by the sulfoxide–
magnesium exchange reaction. Comparing the stability of
g-chlolomagnesio g-lactones with d-chloromagnesio d-
lactones, the former was found to be much more stable at
low temperature and more reactive with some electro-
philes. The presented procedure contributes to the synthe-
sis of g- or d-lactones having multi-substituents.
37
1) i-PrMgCl (3 equiv)
THF, –78 °C
Ph(CH2)2
Ph(CH2)2
Tol(O)S
H
H
O
O
O
2) ClCO2Et
O
H
–78 °C, 1 h, 18%
H
EtO2C
22b
38
Scheme 9
All melting points were measured on Yanaco MP-S3 apparatus and
1
are uncorrected. H NMR spectra were measured in CDCl3 using
b-Monosubstituted g-Chloromagnesio g-Lactones
and b,b-Disubstituted g-Chloromagnesio g-Lactones
Jeol JNMLA 500 and Burker XWIN-600 spectrometers. Electron-
impact mass spectra (MS) were obtained at 70 eV by direct insertion
on a HITACHI M-80B mass spectrometer. IR spectra were record-
ed on a Perkin-Elmer Spectrum One FT-IR instrument. Silica gel
60N (Kanto Chemical) containing 0.5% fluorescence reagent 254
and a quartz column were used for column chromatography and the
products having UV absorption were detected by UV irradiation. In
experiments requiring an anhydrous reagent, CH2Cl2, DIPA, Et3N,
and pyridine were distilled from CaH2. THF was distilled from
diphenylketyl and acetone was dried over CaSO4 and distilled be-
fore use. Benzoyl chloride and ethyl chloroformate were distilled
prior to use.
Finally, we investigated this reaction with b-monosubsti-
tuted g-lactones 39a and 39b, and b,b-disubstituted g-lac-
tones, 39c and 39d, and the results are summarized in
Table 2. g-Sulfinylated g-lactones 39 were treated with
1.6 equivalents of i-PrMgCl at –78 °C to give g-chloro-
magnesio g-lactones 40 in quantitative yields, which was
confirmed by quenching the reaction with MeOD. The re-
action gave g-deuterated g-lactones 41 in almost quantita-
tive yields with 95–99% deuterium incorporation (entries
1, 6, and 10). These results indicates that g-chloromagne-
sio g-lactones 40a, 40c, and 40d were generated from the
corresponding sulfoxides by the sulfoxide–magnesium
exchange reaction, and these are stable at –78 °C for at
tert-Butyl 4-Chloro-2-(2-phenylethyl)-4-(p-tolylsulfinyl)bu-
tyrate (8)
tert-Butyl 4-phenylbutyrate (440 mg, 2.0 mmol) was added to a so-
lution of LDA [2.0 mmol, prepared from i-Pr2NH (0.28 mL) and
n-BuLi (1.25 mL, 1.6 M in hexane)] in anhyd THF (11.5 mL) at
Synthesis 2009, No. 8, 1323–1335 © Thieme Stuttgart · New York

PAPER
g-Chloromagnesio g-Lactones and d-Chloromagnesio d-Lactones
1329
Table 2 Generation of g-Chloromagnesio g-Lactone 40 from 39 and Quenching with Electrophiles
O
O
O
R1
R2
R1
R2
R1
R2
i-PrMgCl (1.6 equiv)
electrophile
O
O
O
THF
conditions
S(O)Tol
MgCl
E
39
40
41
Entry
1
39
R1
R2
H
Electrophile
MeOD
Conditions
41
Yield (%)
39aa
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Me(CH2)5
Me(CH2)5
-(CH2)14-
-(CH2)14-
-(CH2)14-
–78 °C,
10 min
41a
95
(D-content, 98%)
2
3
4
5
6
7
8
39aa
39aa
39ba
39ba
39c
H
H
H
H
ClCO2Et
PhCOCl
ClCO2Et
PhCOCl
MeOD
–78 °C,
1 h
41b
41c
41d
41e
41f
41f
41f
36b
36b
46b
61b
99
–78 °C,
1 h
–78 °C,
1 h
–78 °C,
1 h
–78 °C,
10 min
(D-content, 95%)
(D-content, 91%)
(D-content, 94%)
39c
MeOD
–78 °C,
1 h
90
39c
MeOD
–78 to
–50 °C,
1 h
85
9
10
11
39c
-(CH2)14-
ClCO2Et
Me
–78 °C,
1 h
0
99
0
39da
39da
4-MeOC6H4(CH2)2
4-MeOC6H4(CH2)2
MeOD
–78 °C,
10 min
41g
(D-content, 99%)
Me
ClCO2Et
–78 °C,
1 h
a The main isomer of the g-lactone having a p-tolylsulfinyl group at the g-position was used.
b Some amount of lactone was contaminated and the yield was determined from its 1H NMR spectrum.
–78 °C with stirring and the solution was stirred for 15 min. A solu-
tion of 7 (100 mg, 0.5 mmol) in THF (1 mL) was added to the solu-
tion dropwise with stirring. The reaction mixture was stirred for 5
min at –78 °C, and the reaction was quenched by adding sat. aq
NH4Cl (30 mL). The mixture was extracted with CHCl3 (3 × 30 mL)
and the combined organic layers were dried (MgSO4). Filtration and
evaporation of the solvent gave a residue which was purified by sil-
ica gel column chromatography (hexane–EtOAc, 5:1) to afford 8
(208 mg, 99%) as colorless crystals.
g-Sulfanyl g-Lactones; 3-(2-Phenylethyl)-5-(p-tolylsulfanyl)di-
hydrofuran-2-ones (9a,b); Typical Procedure
A solution of NaI (356 mg, 2.4 mmol) in anhyd acetone (14 mL)
was stirred for 15 min at –55 °C. TFAA (0.34 mL, 2.4 mmol) was
added dropwise to the solution of NaI with stirring at –55 °C and the
mixture was stirred for 15 min. A solution of the adduct 8 (200 mg,
0.48 mmol) in anhyd acetone (2 mL) was added dropwise to the so-
lution of NaI and TFAA at –55 °C with stirring and the reaction
mixture was stirred for 10 min. The reaction was quenched by add-
ing sat. aq NaHCO3 (20 mL) followed by sat. aq Na2SO3 (5 mL) and
the mixture was extracted with CHCl3 (3 × 30 mL). The organic lay-
er was washed with sat. aq NaHCO3 (30 mL) and dried (MgSO4).
Filtration and evaporation of the solvent gave a residue which was
purified by silica gel column chromatography (hexane–EtOAc,
10:1) to give 9a (78 mg, 52%) and 9b (46.5 mg, 31%) as colorless
crystals.
Mp 84–85 °C (EtOAc–hexane).
IR (KBr): 2975, 1723 (C=O), 1273, 1143, 1045 (S=O) cm–1.
1H NMR: d = 1.42 (s, 9 H), 1.72–1.83 (m, 1 H), 1.85–2.01 (m, 2 H),
2.43 (s, 3 H), 2.41–2.45 (m, 1 H), 2.62 (t, J = 8.0 Hz, 2 H), 2.65–
2.74 (m, 1 H), 4.54 (dd, J = 11.0, 2.7 Hz, 1 H), 7.13–7.22 (m, 3 H),
7.24–7.30 (m, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.59 (d, J = 8.0 Hz, 2
H).
9a
Anal. Calcd for C23H29ClO3S: C, 65.62; H, 6.94; Cl, 8.42; S, 7.62.
Found: C, 65.32; H, 6.50; Cl, 8.54, S, 7.66.
Mp 70–71 °C (hexane).
IR (KBr): 2919, 1772 (C=O), 1758, 1492, 1455, 1170, 923 cm–1.
1H NMR: d = 1.62–1.71 (m, 1 H), 1.84 (dt, J = 13.2, 9.3 Hz, 1 H),
2.14–2.23 (m, 1 H), 2.32 (s, 3 H), 2.51–2.75 (m, 4 H), 5.56 (dd,
Synthesis 2009, No. 8, 1323–1335 © Thieme Stuttgart · New York

1330
H. Shimizu et al.
PAPER
J = 9.3, 6.6 Hz, 1 H), 7.12–7.20 (m, 5 H), 7.25–7.29 (m, 2 H), 7.40–
7.43 (m, 2 H).
Anal. Calcd for C20H23ClO3S: C, 63.40; H, 6.12; Cl, 9.36; S, 8.46.
Found: C, 63.33; H, 6.08; Cl, 9.20; S, 8.32.
MS: m/z (%) = 312 (M+, 28), 189 (63), 171 (23), 143 (13), 129 (21),
117 (36), 91 (100), 77 (9), 65 (12).
HRMS: m/z calcd for C19H20O2S (M+): 312.1183; found: 312.1189.
5-Methyl-3-(2-phenylethyl)-5-(p-tolylsulfanyl)dihydrofuran-2-
ones (12a,b)
12a
Colorless crystals; mp 58–59 °C (hexane).
IR (KBr): 2939, 1774 (C=O), 1762 (C=O), 1232, 1143, 817 cm–1.
Anal. Calcd for C19H20O2S: C, 73.04; H, 6.45; S, 10.26. Found: C,
72.92; H, 6.28; S, 10.09.
1H NMR: d = 1.65–1.71 (m, 1 H), 1.67 (s, 3 H), 2.00 (dd, J = 13.2,
11.4 Hz, 1 H), 2.18–2.24 (m, 1 H), 2.42–2.48 (m, 1 H), 2.60–2.65
(m, 1 H), 2.61 (dd, J = 13.2, 9 Hz, 1 H), 2.68–2.74 (m, 1 H), 7.12
(d, J = 7.8 Hz, 2 H), 7.15 (d, J = 7.8 Hz, 2 H), 7.20–7.23 (m, 1 H),
7.28–7.30 (m, 2 H), 7.41 (d, J = 8.4 Hz, 2 H).
9b
Mp 86–87 °C (hexane).
IR (KBr): 2920, 1781 (C=O), 1496, 1452, 1346, 1236, 1203, 1164,
1133, 1062 cm–1.
1H NMR: d = 1.66–1.75 (m, 1 H), 2.12–2.21 (m, 1 H), 2.33 (s, 3 H),
2.28–2.49 (m, 3 H), 2.61–2.75 (m, 2 H), 5.72 (dd, J = 7.6, 3.4 Hz, 1
H), 7.10–7.21 (m, 5 H), 7.25–7.29 (m, 2 H), 7.37–7.41 (m, 2 H).
Anal. Calcd for C20H22O2S: C, 73.58; H, 6.79; S, 9.82. Found: C,
73.53; H, 6.67; S, 9.85.
MS: m/z (%) = 312 (M+, 29), 189 (67), 171 (24), 143 (14), 129 (22),
12b
Colorless crystals; mp 69–70 °C (hexane).
117 (37), 91 (100), 77 (9).
HRMS: m/z calcd for C19H20O2S (M+): 312.1162; found: 312.1172.
IR (KBr): 2942, 2927, 1760 (C=O), 1494, 1453, 1237, 1081, 920,
811 cm–1.
1H NMR: d = 1.48–1.59 (m, 1 H), 1.61 (s, 3 H), 2.02–2.08 (m, 2 H),
2.33 (s, 3 H), 2.42 (dd, J = 13.2, 9.6 Hz, 1 H), 2.49–2.54 (m, 1 H),
2.58–2.71 (m, 2 H), 7.12, 7.16 (d, J = 7.8 Hz, 2 H each), 7.18–7.20
(m, 1 H), 7.27, 7.45 (d, J = 7.8 Hz, 2 H each).
Anal. Calcd for C19H20O2S: C, 73.04; H, 6.45; S, 10.26. Found: C,
72.13; H, 6.36; S, 10.30.
Adduct of an Ester Having Functional Groups at the g-Position;
tert-Butyl 4-Chloro-2-(2-phenylethyl)-4-(p-tolylsulfinyl)penta-
noate (10); Typical Procedure
Anal. Calcd for C20H22ClO2S: C, 73.58; H, 6.79; S, 9.82. Found: C,
73.62, H, 6.70, S, 9.81.
tert-Butyl 4-phenylbutyrate (440 mg, 2 mmol) was added to a solu-
tion of LDA [2.0 mmol; prepared from i-Pr2NH (0.28 mL) and n-
BuLi (1.25 mL, 1.6 M in hexane)] in anhyd THF (12 mL) at –78 °C
with stirring. The mixture was stirred for 15 min, then a solution of
7 (100 mg, 0.5 mmol) in anhyd THF (1 mL) was added. The mixture
was stirred for 5 min at –78 °C, MeI (354 mg, 2.5 mmol) was added
and the mixture was stirred for 5 min. The reaction was quenched
by adding sat. aq NH4Cl (30 mL) and the mixture was extracted
with CHCl3 (3 × 30 mL). The combined organic layers were dried
(MgSO4), filtered, and the filtrate was evaporated to give a residue
which was purified by silica gel column chromatography (hexane–
EtOAc, 10:1) to afford 10 (208 mg, 99%) as colorless crystals.
tert-Butyl 4-Chloro-2-(2-phenylethyl)-4-(p-tolylsulfinyl)hept-6-
enoate (13)
Colorless crystals; mp 98–100 °C (hexane).
IR (KBr): 2977, 2931, 1727 (C=O), 1367, 1143, 1050 (S=O), 937,
811 cm–1.
1H NMR: d = 1.49 (s, 9 H), 1.82–2.01 (m, 2 H), 2.11–2.19 (m, 2 H),
2.43 (s, 3 H), 2.66–2.78 (m, 4 H), 2.86–2.92 (m, 1 H), 5.14 (dd,
J = 16.8, 1.2 Hz, 1 H), 5.22 (d, J = 10.0 Hz, 1 H), 5.73–5.81 (m, 1
H), 7.19–7.30 (m, 5 H), 7.32 (d, J = 8.2 Hz, 2 H), 7.64 (d, J = 8.2
Hz, 2 H).
Mp 85–86 °C (hexane).
Anal. Calcd for C26H33ClO3S: C, 67.73; H, 7.21; Cl, 7.69; S, 6.95.
Found: C, 67.63; H, 7.18; Cl, 7.61; S, 6.91.
IR (KBr): 2973, 2927, 1722 (C=O), 1494, 1457, 1391, 1366, 1144,
1051 (S=O) cm–1.
1H NMR: d = 1.45 (d, J = 9.0 Hz, 3 H), 1.48 (s, 9 H), 1.58 (m, 1 H),
1.79–2.18 (m, 4 H), 2.43 (s, 3 H), 2.55–2.68 (m, 3 H), 2.77–2.84 (m,
1 H), 7.15–7.33 (m, 7 H), 7.59–7.63 (m, 2 H).
5-Allyl-3-(2-phenylethyl)-5-(p-tolylsulfanyl)dihydrofuran-2-
ones (14a,b)
14a
Colorless crystals; mp 111–112 °C (hexane).
Anal Calcd for C24H31ClO3S: C, 66.26; H, 7.18; Cl, 8.15; S, 7.37.
Found: C, 66.14; H, 7.09; Cl, 8.09; S, 7.42.
IR (KBr): 2934, 1775 (C=O), 1495, 1452, 1257, 1216, 1139, 1022
cm–1.
1H NMR: d = 1.63–1.72 (m, 1 H), 2.06–2.22 (m, 2 H), 2.34 (s, 3 H),
2.37–2.49 (m, 2 H), 2.55–2.74 (m, 4 H), 5.15 (dd, J = 10.1, 1.8 Hz,
1 H), 5.21 (dd, J = 10.1, 1.7 Hz, 1 H), 5.77 (m, 1 H), 7.12–7.22 (m,
5 H), 7.27–7.30 (m, 2 H), 7.42 (d, J = 8.1 Hz, 2 H).
4-Chloro-2-(2-phenylethyl)-4-(p-tolylsulfinyl)pentanoic Acid
(11)
Trifluoroacetic acid (TFA, 0.56 mL, 7.5 mmol) was added to a so-
lution of 10 (208 mg, 0.5 mmol) in CH2Cl2 (10 mL) at r.t. The reac-
tion mixture was stirred for 1 d and the reaction was quenched by
adding sat. aq NaHCO3 (20 mL). The mixture was extracted with
CH2Cl2 (3 × 20 mL) and the aqueous separted. The aqueous layer
was acidified with aq 10% HCl and extracted with CH2Cl2 (3 × 20
mL). The combined organic layers were evaporated to give 11 (172
mg, 91%) as colorless crystals.
Anal. Calcd for C22H24O2S: C, 74.96; H, 6.86; S, 9.10. Found: C,
74.82; H, 6.76; S, 9.10.
14b
Colorless crystals; mp 105–106 °C (hexane).
Mp 93–94 °C (EtOAc–hexane).
IR (neat): 2926, 1772 (C=O), 1493, 1262, 1190, 936, 812 cm–1.
IR (KBr): 2923, 1732 (C=O), 1454, 1032 (S=O), 811 cm–1.
1H NMR: d = 1.38–1.47 (m, 1 H), 1.92–2.04 (m, 2 H), 2.32 (s, 3 H),
2.45–2.61 (m, 6 H), 5.13–5.20 (m, 2 H), 5.71–5.81 (m, 1 H), 7.09–
7.20 (m, 5 H), 7.25–7.29 (m, 2 H), 7.46 (d, J = 8.0 Hz, 2 H).
1H NMR: d = 1.45 (s, 3 H), 1.90–1.99 (m, 1 H), 2.02–2.12 (m, 1 H),
2.31 (dd, J = 15.0, 2.1 Hz, 1 H), 2.43 (s, 3 H), 2.93–2.99 (m, 1 H),
2.69–2.75 (m, 3 H), 7.17–7.29 (m, 5 H), 7.31 (d, J = 8.2 Hz, 2 H),
7.62 (d, J = 8.2 Hz, 2 H).
Anal. Calcd for C22H24O2S: C, 74.96; H, 6.86; S, 9.10. Found: C,
74.85; H, 6.79; S, 9.08.
Synthesis 2009, No. 8, 1323–1335 © Thieme Stuttgart · New York

PAPER
g-Chloromagnesio g-Lactones and d-Chloromagnesio d-Lactones
1331
tert-Butyl 2-(2-Phenylethyl)-5-(p-tolylsulfanyl)pentanoate (16)
tert-Butyl 4-phenylbutyrate (754 mg, 3.42 mmol) was added to a
solution of LDA [3.42 mmol, prepared from i-Pr2NH (0.48 mL and
n-BuLi (2.14 mL), 1.6 M in hexane)] in the presence of HMPA (0.6
mL, 3.42 mmol) in anhyd THF (4.8 mL) at –78 °C with stirring. The
mixture was stirred for 10 min, then a solution of 3-(p-tolylsulfa-
nyl)propyl iodide (200 mg, 0.68 mmol) in THF (2 mL) was added
The reaction mixture was stirred at –78 °C for 10 min. The reaction
was quenched by adding sat. aq NH4Cl (30 mL) and the mixture was
extracted with CHCl3 (3 × 30 mL). The combined organic layers
were washed with sat. aq NH4Cl (30 mL) and dried (MgSO4). Fil-
tration and evaporation of the solvent gave a residue which was pu-
rified by silica gel column chromatography (hexane–EtOAc, 10:1)
to afford 16 (217 mg, 82%) as colorless oil.
3-(2-Phenylethyl)-6-(p-tolylsulfanyl)tetrahydropyran-2-ones
(18a,b)
A solution of NaI (1.76 g, 11.7 mmol) in EtCN (55 mL) was stirred
for 10 min at –50 °C. TFAA (1.62 mL, 11.7 mmol) was added drop-
wise with stirring at –50 °C and the reaction mixture was stirred for
15 min. A solution of carboxylic acid 17 (744 mg, 1.96 mmol) in
EtCN (10 mL) was added dropwise –50 °C with stirring and the
mixture was stirred for 10 min. The reaction was quenched by add-
ing sat. aq NaHCO3 (50 mL) followed by sat. aq Na2SO3 (10 mL).
The mixture was extracted with CHCl3 (3 × 50 mL) and the com-
bined organic layers were washed with sat. aq NaHCO3 (60 mL) and
dried (MgSO4). Filtration and evaporation of the solvent gave a res-
idue which was purified by silica gel column chromatography (hex-
ane–EtOAc, 20:1) to give 18a (288 mg, 45%) and 18b (144 mg,
22%) as colorless crystals.
IR (neat): 2930, 1724 (C=O), 1499, 1366, 1145 cm–1.
1H NMR: d = 1.43 (s, 9 H), 1.57–1.63 (m, 3 H), 1.64–1.72 (m, 2 H),
1.85–1.93 (m, 1 H), 2.25 (sept. 1 H), 2.54–2.64 (m, 2 H), 2.84 (t,
J = 6.7 Hz, 2 H), 7.08 (d, J = 7.9 Hz, 2 H), 7.14–7.19 (m, 3 H), 7.23
(d, J = 8.1 Hz, 2 H), 7.28 (d, J = 7.4 Hz, 2 H).
MS: m/z (%) = 218 (M+, 65), 328 (100), 311 (15), 280 (14), 219 (7),
205 (23), 187 (15), 163 (25), 137 (28), 124 (44), 91 (60), 57 (28).
18a
Mp 35–36 °C (EtOAc–hexane).
IR (KBr): 3027, 2954, 2926, 2869, 1713 (C=O), 1492, 1454, 1374,
1169, 1070, 1017, 814 cm–1.
1H NMR: d = 1.59–1.66 (m, 1 H), 1.75–1.82 (m, 1 H), 1.85–1.92 (m,
1 H), 2.09–2.20 (m, 1 H), 2.23–2.38 (m, 3 H), 2.64–2.77 (m, 2 H),
5.58 (dd, J = 8.4, 4.2 Hz, 1 H), 7.13 (d, J = 7.8 Hz, 2 H), 7.18 (m, 3
H), 7.27 (t, J = 7.8 Hz, 2 H), 7.41 (d, J = 8.4 Hz, 2 H).
HRMS: m/z calcd for C24H32O2S (M+): 384.2123; found: 384.2132.
5-Chloro-2-(2-phenylethyl)-5-(p-tolylsulfinyl)pentanoic Acid
(17)
Anal. Calcd for C20H22O2S: C, 73.58; H, 6.79; S, 9.82. Found: C,
73.54; H, 6.71; S, 9.73.
MCPBA (206 mg) was added to a solution of 16 (218 mg, 0.776
mmol) in CH2Cl2 (11 mL) at 0 °C with stirring. The solution was
stirred for 10 min, and the reaction was quenched by adding sat. aq
Na2SO3 (5 mL) followed by NaHCO3 (30 mL). The mixture was ex-
tracted with CH2Cl2 (3 × 20 mL) and the combined organic layers
were washed with sat. aq NaHCO3 (30 mL) and dried (MgSO4). Fil-
tration and evaporation of the solvent gave a residue. The residue
was purified by silica gel column chromatography to give the sulf-
oxide as a mixture of two diastereomers (colorless oil). N-Chloro-
succinimide (NCS, 112 mg, 0.833 mmol) was added to a solution of
the sulfoxide (224 mg, 0.757 mmol) in CCl4 (2.5 mL) and the sus-
pension was stirred at r.t. for 12 h. The precipitate (succinimide)
was filtered off and the solvent evaporated. The residue was puri-
fied by silica gel column chromatography to give 222 mg (89%) of
tert-butyl 5-chloro-2-(2-phenylethyl)-5-(p-tolylsulfinyl)pentanoate
(a mixture of two diastereomers) as a colorless oil. To a solution of
the product (386 mg, 0.887mmol) in CH2Cl2 (12.6 mL) was added
trifluoroacetic acid (1.36 mL, 17.7 mmol). The reaction mixture
was stirred for 12 h and the reaction was quenched by adding sat. aq
NaHCO3 (20 mL). The mixture was extracted with CH2Cl2 (3 × 20
mL) and the organic layer was washed and dried (MgSO4). Filtra-
tion and evaporation of the solvent gave a residue which was puri-
fied by silica gel column chromatography (hexane–EtOAc, 10:1) to
afford carboxylic acid 17 (308 mg, 92%) as a colorless oil.
18b
Mp 75–76 °C (EtOAc–hexane).
IR (KBr): 2918, 1713 (C=O), 1493, 1454, 1192, 1170, 1143, 1074,
980, 858 cm–1.
1H NMR: d = 1.75–1.82 (m, 2 H), 2.02–2.10 (m, 2 H), 2.19–2.25 (m,
2 H), 2.33 (s, 3 H), 2.41–2.46 (m, 1 H), 2.67–2.77 (m, 2 H), 5.55
(ddd, J = 7.2, 5.1, 0.6 Hz, 1 H), 7.13 (d, J = 7.8 Hz, 2 H), 7.19 (d,
J = 7.2 Hz, 2 H), 7.27 (m, 3 H), 7.44 (d, J = 8.4 Hz, 2 H).
Anal. Calcd for C20H22O2S: C, 73.58; H, 6.79; S, 9.82. Found: C,
73.76; H, 6.74; S, 9.73.
3-(2-Phenylethyl)-5-(p-tolylsulfinyl)dihydrofuran-2-ones
(19a,b)
MCPBA (42.3 mg; 0.18 mmol) was added to a solution of 9a (50
mg, 0.16 mmol) in CHCl3 (5 mL) at 0 °C with stirring. The mixture
was stirred for 30 min and the reaction was quenched by adding sat.
aq Na2SO3 (5 mL) and NaHCO3 (30 mL). The mixture was extract-
ed with CHCl3 (3 × 20 mL) and the combined organic layers were
dried (MgSO4). Filtration and evaporation of the solvent gave a res-
idue which was purified by silica gel column chromatography (hex-
ane–EtOAc, 10:1) to afford 19a (49.4 mg, 94%) as a 9:1 mixture of
two diastereomers.
IR (neat): 3026, 2930, 1724 (C=O), 1495, 1454, 1216, 1085, 1040
(S=O), 811 cm–1.
19a
1H NMR: d = 1.69–1.81 (m, 2 H), 1.83–1.87 (m, 1 H), 1.96–2.02 (m,
2 H), 2.24–2.36 (m, 1 H), 2.42 (s, 3 H), 2.38–2.47 (m, 1 H), 2.57–
2.63 (m, 2 H), 2.64–2.71 (m, 1 H) 4.51–4.55 (m, 1 H), 7.15–7.20 (m,
3 H), 7.27–7.29 (m, 2 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.54 (d, J = 7.9
Hz, 2 H).
MS: m/z (%) = 378 (M+, trace), 241 (3), 239 (10), 238 (10), 203
(15), 202 (13), 157 (19), 140 (62), 105 (30), 91 (100), 65 (20).
Colorless crystals; mp 117–120 °C (EtOAc).
IR (KBr): 2950, 2919, 1784 (C=O), 1770 (C=O), 1494, 1455, 1303,
1208, 1156, 1089, 1059 (S=O), 1034, 805 cm–1.
1H NMR: d = 1.24–1.37 (m, 1 H), 1.94–2.01 (m, 1 H), 2.09–2.18 (m,
1 H), 2.39 (s, 3 H), 2.48–2.90 (m, 4 H), 4.92 (t, J = 9.5 Hz, 0.9 H),
5.18 (t, J = 10.0 Hz, 0.1 H), 7.11–7.36 (m, 5 H), 7.35, 7.40 (d,
J = 8.0 Hz, 2 H each).
HRMS: m/z calcd for C20H23ClO3S (M+): 378.1056; found:
378.1057.
MS: m/z (%) = 329 ([M + 1]+, trace), 312 (5), 189 (68), 171 (23),
140 (25), 117 (26), 91 (100), 84 (15).
HRMS: m/z calcd for C19H20O3S (M+): 329.1201; found: 329.1209.
Anal. Calcd for C19H20O3S: C, 69.48; H, 6.14; S, 9.76. Found: C,
69.26; H, 6.10; S, 9.74.
Synthesis 2009, No. 8, 1323–1335 © Thieme Stuttgart · New York

1332
19b
H. Shimizu et al.
PAPER
5-Deuterio-3-(2-phenylethyl)dihydrofuran-2-one (24)
Colorless oil.
Prepared from 9b; colorless crystals; mp 79–80 °C (EtOAc–hex-
ane).
IR (neat): 2934, 1732 (C=O), 1454, 1375, 1250, 1144, 1094, 751
cm–1.
1H NMR: d = 1.55–1.63 (m, 1 H), 1.74–1.81 (m, 1 H), 1.83–1.96 (m,
2 H), 2.13 (sext, J = 7.3 Hz, 1 H), 2.24–2.29 (m, 1 H), 2.43–2.47 (m,
1 H), 2.69–2.79 (m, 2 H), 4.26–4.30 (m, 1 H), 7.18–7.21 (m, 3 H),
7.26–7.30 (m, 2 H).
MS: m/z (%) = 205 (M+, 4), 101 (100), 91 (42), 65 (11).
HRMS: m/z calcd for C13H15DO2 (M+): 205.1212; found: 205.1210.
IR (KBr): 2873, 1789 (C=O), 1493, 1129, 1045, 812 cm–1.
1H NMR: d = 1.68–1.77 (m, 1 H), 1.92–1.99 (m, 1 H), 2.16–2.25 (m,
1 H), 2.44 (s, 3 H), 2.73 (t, J = 7.8 Hz, 2 H), 2.80–2.89 (m, 2 H),
5.18 (dd, J = 8.7, 1.5 Hz, 1 H), 7.16–7.31 (m, 5 H), 7.37 (d, J = 8.3
Hz, 2 H), 7.51 (d, J = 8.3 Hz, 2 H).
Anal. Calcd for C19H20O3S: C, 69.48; H, 6.14; S, 9.76. Found: C,
69.39; H, 6.11; S, 9.71.
Generation of g-Chloromagnesio g-Lactones and d-Chloromag-
nesio d-Lactones; 5-Deuterio-3-(2-phenylethyl)dihydrofuran-2-
one (21); Typical Procedure
5-Deuterio-5-methyl-3-(2-phenylethyl)dihydrofuran-2-one (26)
Colorless oil.
IR (neat): 2973, 2930, 1763 (C=O), 1496, 1454, 1244, 1143, 1108,
976 cm–1.
1H NMR: d = 1.34 (s, 3 H), 1.71–1.83 (m, 1 H), 1.97–2.24 (m, 3 H),
2.57–2.83 (m, 3 H), 7.19–7.32 (m, 5 H).
MS: m/z (%) = 204 (M+, 10), 100 (100), 91 (35), 65 (8), 41 (8).
HRMS: m/z calcd for C15H16O2 (M+): 204.1150; found: 204.1155.
A solution of i-PrMgCl (2.0 mol/L, 0.07 mL) in THF was added to
a solution of 19a (30 mg, 0.09 mmol) in THF (6 mL) in a flame-
dried flask at –78 °C under argon. The reaction mixture was stirred
for 10 min, quenched with MeOD (3 mL), and extracted with CHCl3
(3 × 20 mL). The combined organic layers were dried (MgSO4), fil-
tered, and the solvent was evaporated to give a residue which was
purified by silica gel column chromatography (hexane–EtOAc, 5:1)
to afford 21 (16.1 mg, 94%) as a colorless oil.
5-Allyl-5-deuterio-3-(2-phenylethyl)dihydrofuran-2-one (28)
Colorless oil.
IR (neat): 2925, 1770 (C=O), 1643, 1454, 1206, 975 cm–1.
1H NMR: d = 1.53–1.62 (m, 1 H), 1.68–1.80 (m, 1 H), 2.27 (dddd,
J = 13.7, 9.2, 7.2, 4.9 Hz, 1 H), 2.36–2.83 (m, 6 H), 5.13–5.20 (m,
2 H), 5.71–5.85 (m, 1 H), 7.18–7.32 (m, 5 H).
MS: m/z (%) = 231 (M+, 15), 190 (26), 172 (8), 144 (8), 127 (33),
109 (35), 91 (100), 77 (9).
IR (neat): 2927, 1766 (C=O), 1496, 1454, 1350, 1330, 1163, 1045
cm–1.
1H NMR: d = 1.76–1.81 (m, 1 H), 1.91–2.01 (m, 2 H), 2.20–2.29 (m,
1 H), 2.37 (ddd, J = 12.4, 8.8, 6.7 Hz, 1 H), 2.46–2.54 (m, 1 H),
2.68–2.84 (m, 2 H), 4.13–4.20 (m, 1 H), 7.19–7.22 (m, 3 H), 7.28–
7.32 (m, 2 H).
MS: m/z (%) = 191 (M+, 19), 105 (17), 91 (38), 87 (100).
HRMS: m/z calcd for C12H13DO2 (M+): 191.1055; found: 191.1056.
HRMS: m/z calcd for C15H17DO2 (M+): 231.1369; found: 231.1370.
3-(2-Phenylethyl)-6-(p-tolylsulfinyl)tetrahydropyran-2-ones
(22a,b)
5-Ethoxycarbonyl-3-(2-phenylethyl)dihydrofuran-2-ones (29
and 32)
22a
A solution of i-PrMgCl (2.0 mol/L, 0.11 mL) in THF was added to
a solution of 19a (45.4 mg, 0.14 mmol) in THF (5 mL) in a flame-
dried flask at –78 °C under argon. After stirring the reaction mixture
for 10 min, ethyl chloroformate (0.05 mL, 0.56 mmol) was added.
The mixture was stirred for 1 h at –78 °C and the reaction was
quenched by adding sat. aq NH4Cl (20 mL). The mixture was ex-
tracted with CHCl3 (3 × 20 mL) and the combined organic layers
were dried (MgSO4). Filtration and evaporation of the solvent gave
a residue which was purified by silica gel column chromatography
(hexane–EtOAc, 5:1) to afford 29 (23.1 mg, 63%) as a colorless oil.
Colorless crystals (mixture of two diastereomers).
Major product; mp 110–118 °C (EtOAc–hexane).
IR (KBr): 2960, 2922, 1736 (C=O), 1495, 1454, 1162, 1097, 1054
(S=O), 813 cm–1.
1H NMR: d = 1.59–1.68 (m, 1 H), 1.75–1.87 (m, 1 H), 1.97–2.06 (m,
1 H), 2.16–2.33 (m, 3 H), 2.42 (s, 3 H), 2.49–2.59 (m, 1 H), 2.65–
2.80 (m, 2 H), 4.88 (dd, J = 8.4, 5.5 Hz, 1 H), 7.20 (t, J = 6.8 Hz, 3
H), 7.29 (t, J = 6.8 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.54 (d,
J = 8.0 Hz, 2 H).
IR (neat): 3029, 2939, 1782 (C=O), 1753 (C=O), 1497, 1454, 1378,
1217, 1155, 1070, 956 cm–1.
Anal. Calcd for C20H22O3S: C, 70.15; H, 6.48; S, 9.36. Found: C,
70.07; H, 6.42; S, 9.27.
1H NMR: d = 1.32 (t, J = 7.1 Hz, 3 H), 1.77–1.83 (m, 1 H), 2.00 (dt,
J = 12.8, 9.2 Hz, 1 H), 2.24–2.31 (m, 1 H), 2.54–2.61 (m, 1 H),
2.67–2.73 (m, 2 H), 2.79–2.84 (m, 1 H), 4.27 (q, J = 7.3 Hz, 2 H),
4.77 (dd, J = 9.2, 7.3 Hz, 1 H), 7.18–7.23 (m, 3 H), 7.28–7.31 (m, 2
H).
22b
Colorless crystals (about 9:1 mixture of two diastereomers).
Major product; mp 108–113 °C (EtOAc–hexane).
IR (KBr): 2926, 1763 (C=O), 1496, 1453, 1093, 1047 (S=O), 939,
813 cm–1.
MS: m/z (%) = 262 (M+, 17), 189 (31), 171 (7), 158 (58), 140 (10),
129 (8), 112 (100), 105 (26), 91 (85), 77 (7).
1H NMR: d = 1.80–1.93 (m, 1 H), 1.99–2.14 (m, 3 H), 2.24–2.35 (m,
1 H), 2.42 (s, 3 H), 2.40–2.49 (m, 1 H), 2.53–2.62 (m, 1 H), 2.67–
2.84 (m, 2 H), 4.82 (t, J = 4.9 Hz, 0.9 H), 5.02 (t, J = 5.1 Hz, 0.1 H),
7.18–7.23 (m, 3 H), 7.27–7.33 (m, 2 H), 7.36 (d, J = 8.2 Hz, 2 H),
7.58 (d, J = 8.2 Hz, 2 H).
HRMS: m/z calcd for C15H18O4 (M+): 262.1204; found: 262.1208.
32
Colorless oil.
IR (neat): 2983, 2939, 1779 (C=O), 1746 (C=O), 1497, 1455, 1377,
1195, 1164, 1136, 1061, 1025, 937 cm–1.
1H NMR: d = 1.29 (t, J = 7.2 Hz, 3 H), 1.70–1.80 (m, 1 H), 2.19–
2.29 (m, 2 H), 2.44–2.50 (m, 1 H), 2.62–2.77 (m, 3 H), 4.24 (q,
J = 3.2 Hz, 2 H), 4.88 (dd, J = 9.2, 2.4 Hz, 1 H), 7.18–7.31 (m, 5 H).
Anal. Calcd for C20H22O3S: C, 70.15; H, 6.48; S, 9.36. Found: C,
69.98; H, 6.50; S, 9.25.
Synthesis 2009, No. 8, 1323–1335 © Thieme Stuttgart · New York

PAPER
g-Chloromagnesio g-Lactones and d-Chloromagnesio d-Lactones
1333
MS: m/z (%) = 262 (M+, 15), 190 (24), 189 (23), 158 (40), 112 (65),
91 (91), 86 (100), 84 (21). HRMS: m/z calcd for C15H18O4 (M+):
262.1205; found: 262.1203.
J = 7.7 Hz, 0.8 H), 5.16 (t, J = 7.7 Hz, 0.2 H), 7.36 (d, J = 8.3 Hz, 2
H), 7.51 (d, J = 8.3 Hz, 1.6 H), 7.55 (d, J = 8.3 Hz, 0.4 H).
MS: m/z (%) = 239 ([M + H]+, 63), 221 (8), 154 (40), 123 (55), 123
(55), 99 (100).
5-Benzoyl-3-(2-phenylethyl)dihydrofuran-2-ones (30 and 33)
A solution of i-PrMgCl (2.0 mol/L, 0.11 mL) in THF (5 mL) was
added to a solution of 19a (45.4 mg, 0.14 mmol) in THF (1 mL) in
a flame-dried flask at –78 °C under argon. After stirring the reaction
mixture for 10 min, benzoyl chloride (0.06 mL, 0.56 mmol) was
added. The mixture was stirred for 1 h at –78 °C and the reaction
was quenched by adding sat. aq NH4Cl (20 mL). The mixture was
extracted with CHCl3 (3 × 20 mL) and the combined organic layers
were dried (MgSO4). Filtration and evaporation of the solvent gave
a residue which was purified by silica gel column chromatography
(hexane–EtOAc, 5:1) to afford 30 (22.3 mg, 54%) as colorless crys-
tals.
HRMS: m/z calcd for C12H15O3S (M+): 239.0742; found: 239.0738.
5-Benzoyl-3-methyldihydrofuran-2-ones (35 and 36)
35
Colorless crystals; mp 63–64 °C (hexane).
IR (KBr): 2976, 1785 (C=O), 1695 (C=O), 1595, 1451, 1222, 1167,
1007, 908 cm–1.
1H NMR: d = 1.31 (d, J = 6.8 Hz, 3 H), 2.22–2.32 (m, 1 H), 2.61–
2.77 (m, 2 H), 5.77 (dd, J = 9.5, 1.5 Hz, 1 H), 7.52 (dd, J = 9.3, 7.5
Hz, 1 H), 7.59–7.64 (m, 1 H), 7.98 (dd, J = 8.3, 1.2 Hz, 2 H).
MS: m/z (%) = 204 (M+, trace), 105 (100), 99 (14), 77 (30), 71 (10).
HRMS: m/z calcd for C12H12O3 (M+): 204.0785; found: 204.0784.
30
Mp 87–88 °C (hexane).
Anal. Calcd for C12H12O3: C, 70.57; H, 5.92. Found: C, 70.65; H,
5.81.
IR (KBr): 2926, 1778 (C=O), 1694 (C=O), 1597, 1450, 1233, 1159
cm–1.
1H NMR: d = 1.75–1.85 (m, 1 H), 2.16–2.31 (m, 2 H), 2.64–2.86 (m,
4 H), 5.56 (dd, J = 8.9, 7.0 Hz, 1 H), 7.16–7.32 (m, 5 H), 7.51 (t,
J = 7.8 Hz, 2 H), 7.64 (t, J = 7.8 Hz, 1 H), 7.99 (d, J = 7.8 Hz, 2 H).
36
Colorless crystals; mp 54–55 °C (hexane).
IR (KBr): 2990, 2941, 2888, 1775 (C=O), 1697 (C=O), 1597, 1449,
1231, 1198, 1186, 1013, 933 cm–1.
MS: m/z (%) = 294 (M+, 9), 190 (25), 171 (12), 162 (9), 145 (24),
133 (15), 117 (22), 105 (100), 91 (66), 77 (41), 65 (11).
HRMS: m/z calcd for C19H18O3 (M+): 294.1255; found: 294.1257.
1H NMR: d = 1.32 (d, J = 6.8 Hz, 3 H), 2.13–2.16 (m, 1 H), 2.75–
2.83 (m, 2 H), 5.60 (dd, J = 9.2, 9.0 Hz, 1 H), 7.51 (t, J = 7.6 Hz, 2
H), 7.63 (tt, J = 7.4, 1.3 Hz, 1 H), 8.00 (dd, J = 8.5, 1.3 Hz, 2 H).
Anal. Calcd for C19H18O3: C, 77.53; H, 6.16. Found: C, 77.45; H,
6.05.
MS: m/z (%) = 204 (M+, trace), 105 (100), 77 (27).
HRMS: m/z calcd for C12H12O3: (M+): 204.0786; found: 204.0788.
33
Anal. Calcd for C12H12O3: C, 70.57; H, 5.92. Found: C, 70.68; H,
5.79.
Colorless crystals; mp 93–94 °C (hexane).
IR (KBr): 2943, 2924, 1768 (C=O), 1699, 1595, 1448, 1224, 1174,
1057, 1008 cm–1.
1H NMR: d = 1.76–1.82 (m, 1 H), 2.22–2.35 (m, 2 H), 2.60–2.68 (m,
2 H), 2.74 (t, J = 8.2 Hz, 2 H), 5.77 (dd, J = 9.4, 2.1 Hz, 1 H), 7.17–
7.30 (m, 5 H), 7.62–7.65 (m, 1 H), 7.97 (d, J = 8.3 Hz, 2 H).
6-Ethoxycarbonyl-3-(2-phenylethyl)tetrahydropyran-2-ones
(37 and 38)
37
Colorless oil.
IR (neat): 2932, 1740 (C=O), 1377, 1203, 1108, 1030, 752 cm–1.
Anal. Calcd for C19H18O3: C, 77.53; H, 6.16. Found: C, 77.34; H,
6.07.
1H NMR: d = 1.28 (t, J = 7.2 Hz, 3 H), 1.60–1.72 (m, 1 H), 1.75–
1.87 (m, 1 H), 1.94–2.15 (m, 2 H), 2.21–2.34 (m, 2 H), 2.42–2.52
(m, 1 H), 2.65–2.82 (m, 2 H), 4.24 (q, J = 7.2 Hz, 2 H), 4.87 (dd,
J = 7.4, 5.4 Hz, 1 H), 7.17–7.22 (m, 3 H).
MS: m/z (%) = 276 (M+, 2), 203 (20), 172 (69), 154 (30), 126 (40),
108 (54), 104 (21), 91 (100), 77 (8).
3-Methyl-5-(p-tolylsulfinyl)dihydrofuran-2-ones (34a and 34b)
34a
Colorless oil (ca. 7:3 mixture of two diastereomers).
IR (neat): 2976, 2937, 1788 (C=O), 1494, 1455, 1188, 1148, 1090
(S=O), 1018, 970, 813 cm–1.
HRMS: m/z calcd for C16H20O4 (M+): 276.1360; found: 276.1366.
1H NMR: d = 1.19 (d, J = 7.2 Hz, 0.9 H), 1.28 (d, J = 6.8 Hz, 2.1 H),
1.88–1.98 (m, 0.7 H), 2.19–2.22 (m, 0.3 H), 2.43 (s, 0.9 H), 2.44 (s,
2.1 H), 2.87–2.99 (m, 2 H), 4.95 (dd, J = 8.3, 1.4 Hz, 0.7 H), 5.13
(dd, J = 8.3, 1.4 Hz, 0.3 H), 7.35–7.39 (m, 2 H), 7.53 (d, J = 8.2 Hz,
2 H).
38
Colorless oil.
IR (neat): 2932, 1748 (C=O), 1379, 1196, 1114, 1029, 751 cm–1.
1H NMR: d = 1.30 (t, J = 7.2 Hz, 3 H), 1.55–1.68 (m, 1 H), 1.84
(dddd, J = 13.5, 9.1, 7.4, 5.8 Hz, 1 H), 1.98–2.09 (m, 1 H), 2.10–
2.23 (m, 2 H), 2.25–2.37 (m, 1 H), 2.40–2.50 (m, 1 H), 4.19–4.35
(m, 2 H), 4.90 (t, J = 4.9 Hz, 1 H), 7.17–7.23 (m, 3 H), 7.26–7.31
(m, 2 H).
MS: m/z (%) = 276 (M+, 3), 203 (30), 172 (94), 154 (42), 126 (54),
108 (66), 104 (22), 91 (100), 77 (8), 65 (11).
MS: m/z (%) = 238 (M+, trace), 222 (6), 140 (56), 139 (15), 123 (6),
99 (100), 92 (31), 91 (27), 71 (49).
HRMS: m/z calcd for C12H14O3S (M+): 238.0664; found: 238.0665.
34b
Colorless oil (ca. 4:1 mixture of two diastereomers).
IR (neat): 2978, 2929, 1789 (C=O), 1494, 1455, 1308, 1187, 1145,
1088, 1054, 1022, 924 cm–1.
HRMS: m/z calcd for C16H20O4 (M+): 276.1360; found: 276.1354.
1H NMR: d = 1.10 (d, J = 7.0 Hz, 0.6 H), 1.36 (d, J = 7.0 Hz, 2.4 H),
2.11 (dd, J = 8.0, 6.9 Hz, 0.2 H), 2.20 (dd, J = 8.0, 6.9 Hz, 0.8 H),
2.38–2.45 (m, 1 H), 2.43 (s, 3 H), 2.57–2.75 (m, 1 H), 4.93 (t,
4-Phenethyl-5-(toluene-4-sulfinyl)dihydrofuran-2-one (39a)
Colorless crystals (ca. 9:1 mixture of two diastereomers); mp 94–
108 °C (EtOAc–hexane).
Synthesis 2009, No. 8, 1323–1335 © Thieme Stuttgart · New York

1334
H. Shimizu et al.
PAPER
IR (neat): 2929, 1788 (C=O), 1455, 1170, 1073, 1024, 840 cm–1.
IR (KBr): 2924, 1792 (C=O), 1494, 1146, 1039, 813 cm–1.
1H NMR: d = 1.40–1.69 (m, 1.8 H), 1.78–1.96 (m, 0.2 H), 2.09, 2.13
(d, J = 3.3 Hz, 0.05 H each), 2.25, 2.29 (d, J = 3.3 Hz, 0.45 H each),
2.32–2.40 (m, 2 H), 2.42 (s, 0.3 H), 2.44 (s, 2.7 H), 2.86–2.99 (m, 2
H), 4.72 (d, J = 2.5 Hz, 0.9 H), 4.82 (d, J = 2.3 Hz, 0.1 H), 6.94–
7.27 (m, 5 H), 7.33 (d, J = 8.2 Hz, 2 H), 7.47 (d, J = 8.2 Hz, 2 H).
MS: m/z (%) = 329 ([M + H]+, 21), 311 (39), 263 (20), 190 (10), 129
(100), 91 (25).
1H NMR: d = 1.30 (t, J = 7.3 Hz, 3 H), 1.78–1.84 (m, 2 H), 2.05
(sext, J = 6.8 Hz, 1 H), 2.51–2.79 (m, 4 H), 4.25 (q, J = 7.0 Hz, 2
H), 4.61 (d, J = 4.3 Hz, 1 H), 7.14–7.31 (m, 5 H).
MS: m/z (%) = 262 (M+, 15), 244 (5), 189 (33), 158 (58), 171 (9),
158 (59), 140 (9), 117 (20), 112 (95), 91 (100), 86 (60).
HRMS: m/z calcd for C15H18O4 (M+): 262.1205; found: 262.1208.
HRMS: m/z calcd for C19H21O3S (M+): 329.1185; found: 329.1210.
5-Benzoyl-4-(2-phenylethyl)dihydrofuran-2-one (41c)
Colorless oil.
4-Hexyl-5-(p-tolylsulfinyl)dihydrofuran-2-one (39b)
Colorless crystals (ca. 4:1 mixture of two diastereomers); mp 76–
88 °C (EtOAc–hexane).
IR (neat): 2927, 1781 (C=O), 1693, 1452, 1170, 1022, 840 cm–1.
1H NMR: d = 1.79–1.81 (m, 2 H), 2.00–2.02 (m, 1 H), 2.54–2.79 (m,
4 H), 5.43 (d, J = 3.4 Hz, 1 H), 7.14–7.32 (m, 5 H), 7.45–7.52 (m, 2
H), 7.59–7.66 (m, 1 H), 7.92–7.95 (m, 1 H), 8.09–8.12 (m, 1 H).
MS: m/z (%) = 294 (M+, 10), 276 (6), 266 (3), 190 (30), 189 (20),
145 (25), 144 (22), 105 (100), 91 (70), 77 (35).
IR (KBr): 2927, 1800 (C=O), 1458, 1155, 1048 (S=O), 1022, 843,
812 cm–1.
1H NMR: d = 0.84 (t, J = 7.5 Hz, 3 H), 0.87–1.36 (m, 10 H), 2.82–
2.90 (m, 1 H), 2.22, 2.90 (d, J = 15.0 Hz, 0.8 H each), 2.08, 2.92
(J = 15.0 Hz, 0.4 H each), 4.69 (d, J = 2.1 Hz, 0.8 H), 4.84 (d,
J = 2.5 Hz, 0.2 H), 7.38 (d, J = 8.0 Hz, 2 H), 7.52 (d, J = 8.0 Hz, 2
H).
HRMS: m/z calcd for C19H18O3 (M+): 294.1256; found: 294.1261.
5-Ethoxycarbonyl-4-hexyldihydrofuran-2-one (41d)
Colorless oil.
Anal. Calcd for C17H24O3S: C, 66.20; H, 7.84; S, 10.40. Found: C,
66.23; H, 7.88; S, 10.45.
IR (neat): 2928, 1790 (C=O), 1747 (C=O), 1466, 1378, 1169, 1022,
839 cm–1.
1H NMR: d = 0.81–0.96 (m, 6 H), 1.21–1.40 (m, 8 H), 1.64–1.76 (m,
2 H), 2.22–2.36 (m, 1 H), 4.26 (q, J = 6.9 Hz, 2 H), 4.56 (d, J = 4.3
Hz, 1 H).
1-(p-Tolylsulfinyl)-2-oxaspiro[4.14]nonadecan-3-one (39c)
Colorless oil (ca. 4:1 mixture of two diastereomers).
IR (neat): 2930, 1800 (C=O), 1459, 1140, 1055 (S=O), 1031, 811
cm–1.
MS: m/z (%) = 242 (M+, 2), 169 (51), 151 (10), 139 (6), 123 (10),
1H NMR: d = 1.23–1.54 (m, 28 H), 2.26, 2.89 (d, J = 17.4 Hz, 0.8 H
each), 2.40, 2.64 (d, J = 17.7 Hz, 0.2 H each), 2.42 (s, 2.4 H), 2.43
(s, 0.6 H), 4.49 (s, 1 H), 7.34, 7.52 (d, J = 8.0 Hz, 1.6 H each), 7.35,
7.58 (d, J = 8.0 Hz, 0.4 H).
MS: m/z (%) = 418 (M+, trace), 279 (100), 249 (12), 219 (8), 124
(25), 91 (33), 55 (27).
109 (100), 92 (17), 83 (26), 69 (35).
HRMS: m/z calcd for C13H22O4 (M+): 242.1518; found: 242.1520.
5-Benzoyl-4-hexyldihydrofuran-2-one (41e)
Colorless oil.
IR (neat): 2923, 1785 (C=O), 1459, 1380, 1144, 1089, 1021 cm–1.
1H NMR: d = 0.86–0.89 (m, 6 H), 1.26–1.70 (m, 10 H), 1.84–1.90
(m, 1 H), 2.17–2.30 (m, 2 H), 5.44 (d, J = 3.2 Hz, 1 H), 7.50–7.54
(m, 2 H), 7.60–7.68 (m, 1 H), 7.96–7.98 (m, 2 H).
MS: m/z (%) = 274 (M+, 2), 170 (2), 154 (4), 139 (9), 114 (32), 105
(61), 83 (47), 69 (54), 56 (100).
HRMS: m/z calcd for C25H38O3S (M+): 418.2542; found: 418.2540.
4-[2-(4-Methoxyphenyl)ethyl]-4-methyl-5-(p-tolylsulfinyl)dihy-
drofuran-2-one (39d)
Colorless crystals; mp 160–161 °C (EtOAc–hexane).
IR (KBr): 2934, 1784 (C=O), 1610, 1513, 1246, 1051 (S=O), 811
cm–1.
HRMS: m/z calcd for C17H22O3 (M+): 274.1569; found: 274.1573.
1H NMR: d = 1.33 (s, 3 H), 1.57 (d, J = 3.3 Hz, 1 H), 2.17 (d,
J = 17.0 Hz, 1 H), 2.32–2.37 (m, 2 H), 2.42 (s, 3 H), 2.65–2.72 (m,
1 H), 2.81–2.88 (m, 1 H), 2.97 (d, J = 17.0 Hz, 1 H), 3.81 (s, 3 H),
4.46 (s, 1 H), 6.87 (d, J = 8.7 Hz, 2 H), 7.20 (d, J = 8.6 Hz, 2 H),
7.33 (d, J = 8.2 Hz, 2 H), 7.49 (d, J = 8.2 Hz, 2 H).
2-Oxaspiro[4.14]nonadecan-3-one (41f, E = H)
Colorless crystals; mp 53–54 °C (EtOH–H2O).
IR (KBr): 2929, 1787 (C=O), 1459, 1170, 1025 cm–1.
1H NMR: d = 1.31–1.52 (m, 28 H), 2.32 (s, 2 H), 4.01 (s, 2 H).
MS: m/z = 280 (M+, 22), 249 (100), 222 (29), 55 (47), 41 (45).
HRMS: m/z calcd for C18H32O2 (M+): 280.2401; found: 280.2412.
Anal. Calcd C, 77.09; H, 11.50. Found: C, 77.32; H, 11.21.
Anal. Calcd for C21H24O4S: C, 67.72; H, 6.49; S, 8.61. Found: C,
67.55; H, 6.34; S, 8.63.
4-(2-Phenylethyl)dihydrofuran-2-one (41a, E = H)
Colorless oil.
4-[2-(4-Methoxyphenyl)ethyl]-4-methyltetrahydrofuran-2-one
(41g, E = H)
Colorless oil.
IR (neat): 2933, 1722 (C=O), 1611, 1512, 1245, 1032, 822 cm–1.
1H NMR: d = 1.25 (m, 3 H), 1.77 (t, J = 8.5 Hz, 2 H), 2.29 (d,
J = 17.3 Hz, 1 H), 2.41 (d, J = 17.3 Hz, 1 H), 2.57 (t, J = 8.6 Hz, 2
H), 3.78 (s, 3 H), 3.97 (d, J = 8.7 Hz, 1 H), 4.05 (d, J = 8.7 Hz, 1 H),
6.83 (d, J = 8.9 Hz, 2 H), 7.08 (d, J = 8.9 Hz, 2 H).
IR (neat): 2924, 1770 (C=O), 1454, 1171, 1022, 840, 751 cm–1.
1H NMR: d = 1.75–1.87 (m, 2 H), 2.19 (dd, J = 16.6, 7.7 Hz, 1 H),
2.48–2.70 (m, 4 H), 3.92 (dd, J = 9.1, 7.2 Hz, 1 H), 4.38 (dd, J = 9.1,
7.2 Hz, 1 H), 7.14–7.31 (m, 5 H).
MS: m/z (%) = 190 (M+, 38), 159 (17), 130 (12), 104 (45), 91 (100),
77 (8).
HRMS: m/z calcd for C12H14O2 (M+): 190.0980; found: 190.0986.
MS: m/z = 234 (M+, 28), 134 (13), 121 (100), 78 (7).
HRMS: m/z calcd for C14H18O3 (M+): 234.1254; found: 234.1255.
5-Ethoxycarbonyl-4-(2-phenylethyl)dihydrofuran-2-one (41b)
Colorless oil.
Synthesis 2009, No. 8, 1323–1335 © Thieme Stuttgart · New York

PAPER
g-Chloromagnesio g-Lactones and d-Chloromagnesio d-Lactones
1335
(6) (a) Tucker, C. E.; Majid, T. N.; Knochel, P. J. Am. Chem.
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2001, 2068. (d) Thibonnet, J.; Knochel, P. Tetrahedron Lett.
2000, 41, 3319. (e) Vu, V. A.; Berillon, L.; Knochel, P.
Tetrahedron Lett. 2001, 42, 6847. (f) Thibonnet, J.; Vu,
V. A.; Berillon, L.; Knochel, P. Tetrahedron 2002, 58, 4787.
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1999, 1820. (b) Vu, V. A.; Marek, I.; Polborn, K.; Knochel,
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Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
No. 19590018 from the Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan, which is gratefully acknowledged.
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Synthesis 2009, No. 8, 1323–1335 © Thieme Stuttgart · New York