The first example of γ-chloromagnesio γ-lactones: their generation from γ-tolylsulfinyl γ-lactones with isopropylmagnesium chloride, stability, and reaction with electrophiles

Article abstract of DOI:10.1016/j.tetlet.2006.09.165

The treatment of γ-lactones having a sulfinyl group at the γ-position, which were synthesized from 1-chlorovinyl p-tolyl sulfoxides with lithium enolate of carboxylic esters, with isopropyl magnesium chloride in THF at -78 °C gave γ-chloromagnesio γ-lacto

Full text of DOI:10.1016/j.tetlet.2006.09.165

Tetrahedron Letters 47 (2006) 8771–8775
The first example of c-chloromagnesio c-lactones:
their generation from c-tolylsulfinyl c-lactones
with isopropylmagnesium chloride, stability,
and reaction with electrophiles
Shimpei Sugiyama, Hitomi Shimizu and Tsuyoshi Satoh*
Department of Chemistry, Faculty of Science, Tokyo University of Science, Ichigaya-funagawara-machi,
Shinjuku-ku, Tokyo 162-0826, Japan
Received 12 September 2006; revised 28 September 2006; accepted 29 September 2006
Available online 20 October 2006
Abstract—The treatment of c-lactones having a sulfinyl group at the c-position, which were synthesized from 1-chlorovinyl p-tolyl
sulfoxides with lithium enolate of carboxylic esters, with isopropyl magnesium chloride in THF at À78 °C gave c-chloromagnesio
c-lactones by the sulfoxide–magnesium exchange reaction in high yields. The generated c-chloromagnesio c-lactones were found to
be stable at below À50 °C for at least 2 h. The reaction of these c-chloromagnesio c-lactones with electrophiles and the stereochem-
istry of the reactions were investigated.
Ó 2006 Elsevier Ltd. All rights reserved.
Organomagnesium compounds, the Grignard reagents,
are one of the most important reagents for the forma-
tion of a carbon–carbon bond with carbonyl com-
pounds or alkyl halides.1 As the carbon–magnesium
bond is highly reactive, it has long been generally recog-
nized that the presence of electrophilic functional
groups, such as esters, nitriles, and ketones, cannot be
compatible in the Grignard reagents. However, recently,
the preparation of functionalized Grignard reagents and
their properties have been studied and reported by Kno-
chel2 and some other chemists.
In previous studies, we have found that various ester
lithium enolates reacted with 1-chlorovinyl p-tolyl sulf-
oxides 1 to give adducts 2 in high yields. Furthermore,
we also reported a novel method for the synthesis of
lactones having a sulfinyl group at c-position 3 from
adducts 2 in two steps in high overall yields.7 We
thought that if Grignard reagents react with the sulfi-
nyl group in lactones 3, c-chloromagnesio c-lactone 4
could be generated via sulfoxide–magnesium exchange
reaction.8 We also anticipated that the continuous
reaction of 4 with various electrophiles would afford
lactones 5 having a carbon–carbon bond at the c-posi-
tion. Herein, we report the generation of the first
example of c-chloromagnesio c-lactones and investiga-
tion of their property and the reaction with electro-
philes (Scheme 1).
The functionalized Grignard reagents are those for
functionalized arylmagnesium reagents,3 polyfunctional
heteroaryl-magnesium reagents,4 functionalized alkenyl-
magnesium reagents.5 These functionalized magnesium
reagents have ester, nitrile, halogen, and amide as the
functional groups. However, those 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 exceptions are also reported.6
First, 1-chlorovinyl p-tolyl sulfoxide 6 was selected as a
representative example of the 1-chlorovinyl p-tolyl sulf-
oxide in this study and was synthesized from ethylene
glycol in five steps in a 54% overall yield (Scheme 2).
Lithium ester enolate of tert-butyl 4-phenylbutyrate
was generated in THF at À78 °C and to this solution
was added 1-chlorovinyl p-tolyl sulfoxide 6. The desired
addition reaction took place within 5 min to afford
adduct 7 in a quantitative yield. Adduct 7 has three chiral
centers and theoretically four diastereomers would be
Keywords: Sulfoxide; Sulfoxide–magnesium exchange; Grignard reag-
ents; c-Chloromagnesio c-lactone; c-Lactone.
*
Corresponding author. Tel.: +81 3 5228 8272; fax: +81 3 3235
2214; e-mail: tsatoh@ch.kagu.tus.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.165

8772
S. Sugiyama et al. / Tetrahedron Letters 47 (2006) 8771–8775
R3
R3
O
R1 CHCOOC(CH3)3
R1
R2
R3CH2COOC(CH3)3
R1
R2
Cl
R2
S(O)Tol
O
LDA / THF
S(O)Tol
Cl
S(O)Tol
1
2
3
R3
R3
O
O
R1
R2
R1
E+
i-PrMgCl
O
O
R2
E
MgCl
5
4
Scheme 1.
O
1) TolSSTol
1) Ac2O, Py, 98%
2) NCS / CCl4, 80%
PPh3, 97%
STol
OH
HO
HO
2) mCPBA / CH2Cl2,
74%
O
N
Li
O
H
Cl
STol
AcO
H
STol
O
THF, 96%
Cl
6
Scheme 2.
produced; however, adduct 7 was obtained as a single
sium exchange reaction without a trace of the starting
sulfoxide 9b. Quenching this reaction with CH3OD gave
c-lactone deuterated at c-position 11b with 99% deute-
rium incorporation. This result showed that the inter-
mediate of this reaction was c-chloromagnesio c-lactone
10b (see Scheme 3).
diastereomer.9
Next, trifluoroacetic anhydride (TFAA) was added to a
solution of adduct 7 in the presence of NaI in acetone to
give c-lactone 8 having a tolylsulfanyl group at the c-po-
sition (Scheme 3).7 c-Lactone 8 has two chiral centers
and, theoretically, two diastereomers are possible. On
silica gel TLC, two products could be observed and they
could be separated by silica gel column chromatography
as a less polar (expressed as 8a; 31%) and a more polar
product (expressed as 8b; 52%).
At this stage, we were worried about an intermolecular
or an intramolecular proton abstraction, because 10b
has a relatively acidic hydrogen on the a-position.
However, no deuterium incorporation at the a-position
1
of c-lactone 11b was observed on its H NMR.
In order to determine the configuration of 8a and 8b, the
NOESY spectrum of both lactones was measured. From
the detailed inspection of the spectra, we were able to
determine unambiguously the cis-structure of 8b as
shown in Scheme 3. The main isomer 8b was used in
the following studies. Sulfide 8b was oxidized with
m-chloroperbenzoic acid (m-CPBA) at À50 °C to give
sulfoxide 9b as a mixture of two diastereomers in a good
yield.
Next, we investigated the stability of c-chloromagnesio
c-lactone 10b by the chemical yield and the rate of deu-
terium incorporation and the results are summarized in
Table 1. The c-sulfinylated lactone 9b was treated with
1.6 equiv of i-PrMgCl and the reaction mixture was stir-
red at À78 °C for 1 h, and the reaction was quenched
with CH3OD (Table 1, entry 1). The result was almost
the same as the result in Scheme 3. Next, the reaction
mixture was stirred at À78 °C for 2 h and the reaction
was quenched with CH3OD (entry 2). The result was
almost the same compared with that in entry 1. These
results show that c-chloromagnesio c-lactone 10b is stable
at À78 °C for at least 2 h. Next, the reaction mixture was
slowly allowed to warm to À50 °C for over 50 min and
Finally, 9b was treated with 1.6 equiv of i-PrMgCl at
À78 °C for 10 min (a solution of 9b in THF was added
to a solution of i-PrMgCl in THF) to give the desulfiny-
lated product 11b in a 91% yield via sulfoxide–magne-

S. Sugiyama et al. / Tetrahedron Letters 47 (2006) 8771–8775
8773
4.5 eq.
(CH2)2Ph
TFAA (5 eq)
NaI (5 eq)
H
H
Cl
Ph
COOC(CH3)3
H
H
COOC(CH3)3
S(O)Tol
oC
LDA / THF, -78 o
acetone, -50
S
Tol
C
99%
Cl
O
6
7
H
H
CH2CH2Ph
O
CH2CH2Ph
O
NOE
+
O
STol
O
H
TolS
H
8a : 31%
8b : 52 %
(CH2)2Ph
O
(CH2)2Ph
(CH2)2Ph
O
O
H
H
H
H
H
H
i-PrMgCl (1.6 eq)
mCPBA (2.3 eq)
CH3OD
91%
8b
O
S(O)Tol
9b
O
O
CHCl3, -50 ˚C
94%
THF, -78 oC
MgCl
D (D=99%)
11b
10b
Scheme 3.
Table 1. Generation of c-chloromagnesio c-lactone 10b form 9b and quenching with deuterio methanol
(CH2)2Ph
O
(CH2)2Ph
O
(CH2)2Ph
O
i-PrMgCl (1.6 eq)
H
H
H
H
H
H
CH3OD
O
O
MgCl
10b
O
THF
Conditions
S(O)Tol
D
11b
9b
Entry
Conditions
11b Yield (%)/D-content (%)
1
2
3
4
5
6
À78 °C, 60 min
À78 °C, 120 min
91/94
85/91
80/91
80/88
63/93
54/53
À78 to À50 °C, 50 min, then À50 °C for 60 min
À78 to À50 °C, 50 min, then À50 °C for 120 min
À78 to À30 °C, 90 min, then À30 °C for 10 min
À78 to 0 °C, 150 min, then 0 °C for 10 min
the reaction mixture was further stirred at À50 °C for 1 h
(entry 3). In addition, the reaction was further left to
stand at À50 °C for 2 h (entry 4). Both reactions showed
the chemical yield and deuterium content were the same
within an experimental error. Furthermore, the reaction
temperature was slowly allowed to rise to À30 °C over
1.5 h and the reaction mixture was further stirred at
À30 °C for 10 min (entry 5). Marked decomposition of
c-chloromagnesio c-lactone 10b was observed. The yield
of 11b was markedly diminished when this reaction was
carried out at 0 °C (entry 6). From these studies, the c-
chloromagnesio c-lactone has been found to be stable
at below À50 °C for at least 2 h.
eral electrophiles. As a preliminary result, the reaction
of 10a and 10b with ethyl chloroformate at À78 °C for
1 h gave a good yield of ester 12a and12b (Scheme 4).
Interestingly, both products, 12a and 12b, were obtained
as a single diastereomer. Configuration of the products
was again confirmed by NOESY experiment and this
reaction was found to be highly stereospecific as shown
in Scheme 4. Namely, the stereochemistry of the anionic
carbon was retained throughout the sequence. The reac-
tion of 10a and 10b with benzoyl chloride at À78 °C for
1 h gave the products 13a and 13b in 65% and 54%
yields, respectively, as a single diastereomer. Unfortu-
nately, propanal did not react at all with c-chloromag-
nesio c-lactone 10.
In order to extend this unprecedented Grignard reagent
to a new synthetic method for c-substituted c-lactones,
we tried to trap c-chloromagnesio c-lactone 10 with sev-
In order to investigate the generality of these reactions,
14a and 14b were used in the following studies. The

8774
S. Sugiyama et al. / Tetrahedron Letters 47 (2006) 8771–8775
H
H
H
CH2CH2Ph
CH2CH2Ph
O
CH2CH2Ph
O
O
i-PrMgCl (1.6 eq)
ClCOOC2H5
O
O
O
THF, -78 °C
–78 °C, 1 h
ClMg
C2H5OOC
Tol(O)S
H
H
H
70%
10a
12a
9a
H
CH2CH2Ph
PhCOCl
O
–78˚C, 1 h
O
65%
PhC
O
H
13a
H
NOE
H
H
CH2CH2Ph
O
CH2CH2Ph
O
CH2CH2Ph
O
i-PrMgCl (1.6 eq)
THF, –78 °C
ClCOOC2H5
O
MgCl
O
O
–78 °C, 1 h
H
H
H
S(O)Tol
COOC2H5
63%
10b
9b
12b
H
CH2CH2Ph
O
PhCOCl
-78 °C, 1 h
O
CPh
54%
H
O
13b
Scheme 4.
same treatment of 14a and 14b with i-PrMgCl followed
by benzoyl chloride resulted in the formation of c-lac-
tones 15a and 15b via c-chloromagnesio c-lactones,
again highly stereospecifically (Scheme 5).
4). In the same manner, the reaction of the c-chloromag-
nesio c-lactones derived from 16a and 16b with benzoyl
chloride gave c-lactones having a benzoyl group at the
c-position up to 61% yield (entries 3 and 5). The yields
of both reactions were not satisfactory and steric hin-
drance was thought to be the reason for the low yield.
Interestingly, the products were obtained as a single dia-
stereomer, respectively, and again the reaction pro-
ceeded in a highly stereospecific manner.
We further investigated this reaction with b-monosubsti-
tuted c-lactones 16a10 and 16b, and b,b-disubstituted
c-lactones, 16c and 16d (Table 2). The c-sulfinylated
c-lactones 16 were treated with 1.6 equiv of i-PrMgCl at
À78 °C to give c-chloromagnesio c-lactone 17 in quanti-
tative yields, which was confirmed by quenching the
reactions with deuterated methanol. The reaction gave
c-deuterated c-lactones 18 in quantitative yields with
95–99% deuterium incorporation (entries 1, 6 and 10).
The reaction of 17a and 17b with ethyl chloroformate
at À78 °C for 1 h gave the products having an ethoxy-
carbonyl group in 36% and 46% yields (entries 2 and
Entries 6–11 show the results concerning the c-chloro-
magnesio c-lactones generated from b,b-disubstituted
c-lactones, 16c and 16d. As shown in the results in
entries 6–8, the c-chloromagnesio c-lactones generated
from b,b-disubstituted c-lactones 16c were found to be
stable at below À50 °C. The reactivity of the c-chloro-
magnesio c-lactones generated from 16c and16d was
investigated; however, both ethyl chloroformate and
benzoyl chloride, and propanal did not react at all with
the alkylmagnesiums. Steric hindrance (neopentyl posi-
tion) was thought to be the reason for the low reactivity
with the electrophiles.
H
H
CH3
CH3
O
O
i-PrMgCl (1.6 eq)
THF, -78 °C
PhCOCl
O
O
-78 °C, 1 h
PhC
O
Tol(O)S
In conclusion, we were able to generate, for the first
time, the c-chloromagnesio c-lactones from c-lactones
having a tolylsulfinyl group at the c-position by sulfox-
ide–magnesium exchange reaction. The c-chloromagne-
sio c-lactones were found to be stable at below À50 °C
for several hours and were reactive with some electro-
philes to give c-lactones having multi-substituents. We
are continuing to investigate the scope and limitation
of this reaction and development for the asymmetric
synthesis of highly substituted c-lactones.
H
H
43%
15a
14a
H
H
CH3
CH3
O
O
i-PrMgCl (1.6 eq)
THF, -78 °C
PhCOCl
O
O
CPh
-78 °C, 1 h
H
H
S(O)Tol
45%
O
14b
15b
Scheme 5.

S. Sugiyama et al. / Tetrahedron Letters 47 (2006) 8771–8775
8775
Table 2. Generation of c-chloromagnesio c-lactone 17 form 16 and quenching with electrophiles
O
O
O
R1
R2
R1
R2
R1
R2
i-PrMgCl (1.6 eq)
Electrophile
O
O
O
THF
Conditions
S(O)Tol
MgCl
E
16
R1
18
17
Entry
R2
Electrophile
Conditions
18
Yield (%)
1
2
3
4
5
6
7
8
9
16aa
16aa
16aa
16ba
16ba
16c
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
CH3(CH2)5
CH3(CH2)5
H
H
H
H
H
CH3OD
ClCOOEt
PhCOCl
ClCOOEt
PhCOCl
CH3OD
CH3OD
CH3OD
ClCOOEt
CH3OD
ClCOOEt
À78 °C, 10 min
À78 °C, 60 min
À78 °C, 60 min
À78 °C, 60 min
À78 °C, 60 min
À78 °C, 10 min
À78 °C, 60 min
95
36b
36b
46b
61b
99
90
85
0
(D-content, 98%)
–(CH2)14
–(CH2)14
–(CH2)14
–(CH2)14
–
–
–
–
(D-content, 95%)
(D-content, 91%)
(D-content, 94%)
16c
16c
À78 to À50 °C, 60 min
À78 °C, 60 min
16c
10
11
16da
16da
4-CH3C6H4(CH2)2
4-CH3C6H4(CH2)2
CH3
CH3
À78 °C, 10 min
99
0
(D-content, 99%)
À78 °C, 60 min
a The main isomer of the c-lactone having a tolylsulfanyl group at the c-position was used in this study.
b Some amount of protonated lactone was contaminated and the yield was determined from its 1H NMR.
Synthesis 2002, 565; (i) Sugimoto, O.; Aoki, K.; Tanji, K.
Tetrahedron Lett. 2004, 45, 1915.
Acknowledgments
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This work was supported by Tokyo University of Sci-
ence, Joint Study Program in Graduate Course, which
is gratefully acknowledged.
5. (a) Tucker, C. E.; Majid, T. N.; Knochel, P. J. Am. Chem.
Soc. 1992, 114, 3983; (b) Rottlander, M.; Boymond, L.;
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