Efficient synthesis of cyclopropanecarboxylic acid esters starting from the conjugate addition of lithium ester enolates to 1-chlorovinyl p -Tolyl sulfoxides

Article abstract of DOI:10.1055/s-0032-1318168

An efficient synthesis of tert-butyl cyclopropanecarboxylates was achieved in three steps using 1-chlorovinyl p-tolyl sulfoxides as key materials. The conjugate addition of lithium ester enolates to the sulfoxides gave tert-butyl 4-chloro-4-(p-tolylsulfinyl)butanoates in high yield. The p-tolylsulfinyl group in the resultant adducts was then removed by the sulfoxide-magnesium exchange reaction with i-PrMgCl at -60 °C. Cyclization of the desulfinylated products, tert-butyl 4-chlorobutanoates, took place in the presence of NaHMDS in a THF-DMPU mixture to afford tert-butyl cyclopropanecarboxylates in good yield. The asymmetric synthesis of both enantiomers of tert-butyl cyclopropanecarboxylate was successfully achieved using optically active (E)- and (Z)-sulfoxides with high enantiomeric excesses. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318168

LETTER
▌483
letter
Efficient Synthesis of Cyclopropanecarboxylic Acid Esters Starting from the
Conjugate Addition of Lithium Ester Enolates to 1-Chlorovinyl p-Tolyl
Sulfoxides
Synthesis of tert-Butyl Cyclopropanecarboxylates
Tsutomu Kimura,a Yoshiaki Hattori,b Hitoshi Momochi,b Nobuhito Nakaya,b Tsuyoshi Satoh*a,b
a
Department of Chemistry, Faculty of Science, Tokyo University of Science, 12 Ichigaya-funagawara-machi, Shinjuku-ku, Tokyo 162-0826,
Japan
b
Graduate School of Chemical Sciences and Technology, Tokyo University of Science, 12 Ichigaya-funagawara-machi, Shinjuku-ku, Tokyo
162-0826, Japan
Fax +81(3)52614631; E-mail: tsatoh@rs.kagu.tus.ac.jp
Received: 20.12.2012; Accepted after revision: 15.01.2013
and magnesium carbenoid induced 1,3-C–H insertion af-
Abstract: An efficient synthesis of tert-butyl cyclopropanecarbox-
forded 2-cyclopropyl-substituted esters 5 (Scheme 1, eq.
ylates was achieved in three steps using 1-chlorovinyl p-tolyl sulf-
1). If magnesium carbenoids 4 can be protonated before
the 1,3-C–H insertion takes place, 4-chloro-substituted
oxides as key materials. The conjugate addition of lithium ester
enolates to the sulfoxides gave tert-butyl 4-chloro-4-(p-tolylsulfi-
nyl)butanoates in high yield. The p-tolylsulfinyl group in the resul- esters 6 can be obtained (Scheme 1, eq. 2). The treatment
tant adducts was then removed by the sulfoxide–magnesium
of esters 6 with a base is expected to result in the forma-
exchange reaction with i-PrMgCl at –60 °C. Cyclization of the de-
tion of cyclopropanecarboxylic acid esters 7, which are
sulfinylated products, tert-butyl 4-chlorobutanoates, took place in
structurally isomeric with esters 5, through an intramolec-
the presence of NaHMDS in a THF–DMPU mixture to afford tert-
ular substitution of the resultant enolates. Herein, we re-
butyl cyclopropanecarboxylates in good yield. The asymmetric syn-
port
an
efficient
synthesis
of
tert-butyl
thesis of both enantiomers of tert-butyl cyclopropanecarboxylate
was successfully achieved using optically active (E)- and (Z)-sulf-
oxides with high enantiomeric excesses.
cyclopropanecarboxylates 7 via the conjugate addition of
lithium enolates generated from tert-butyl carboxylates 2
to sulfoxides 1, the removal of the p-tolylsulfinyl group
from adducts 3, and the cyclization of 4-chloro-substitut-
ed esters 6.
Key words: conjugate addition, cyclization, chiral auxiliaries,
1-chlorovinyl p-tolyl sulfoxides, cyclopropanecarboxylates
Initially, the synthesis of tert-butyl 1-methylspiro[2.5]oc-
tane-1-carboxylate (7a) from 1-chlorovinyl p-tolyl sulf-
oxide (1a) and tert-butyl propionate (2a) was investigated
Cyclopropane derivatives are versatile compounds in or-
ganic synthesis and are often employed in the key steps of
natural product synthesis.1,2 Cyclopropane units are also
found in a wide variety of naturally occurring compounds
as optically active forms.3 Much effort has been devoted
to developing an efficient method for the construction of
cyclopropane rings, and a number of synthetic methods,
including the transition-metal-catalyzed decomposition of
diazoalkanes in the presence of alkenes, [2+1] cycloaddi-
tions of alkenes with metal carbenoids such as zinc car-
benoids and lithium carbenoids, and Michael-initiated
ring closure, have been established.4 Recently, we report-
ed various types of cyclopropane syntheses utilizing 1-
chlorovinyl p-tolyl sulfoxides and magnesium carbenoids
as key compounds.5,6 Among these syntheses, the 1,3-C–
H insertion of magnesium carbenoids 4 leading to the for-
mation of 2-cyclopropyl-substituted carboxylic acid es-
ters 5 is representative for our synthetic methods (Scheme
1).6c,d Specifically, the conjugate addition of lithium eno-
lates generated from carboxylic acid esters 2 to 1-chloro-
vinyl p-tolyl sulfoxides 1 gave adducts 3 in a highly
diastereoselective manner.7 The adducts 3 were good pre-
cursors for the generation of magnesium carbenoids 4,
O
O
R3
Cl
R3
, base
R2
O
S
t-BuO
O
S
t-BuO
i-PrMgCl
2
R2
R1
R1
Ar
Ar
Cl
1
3
O
O
R3
R3
(1)
1,3-C–H insertion
R1 = CH2R4
t-BuO
t-BuO
R2
MgCl
R2
R1
R4
Cl
5
4
H3O+
protonation
O
O–
O
R3
R3
R3
base
t-BuO
t-BuO
t-BuO
R2
(2)
R2
R1
R2
R1
R1
Cl
Cl
7
6
SYNLETT 2013, 24, 0483–0486
Advanced online publication: 29.01.2013
DOI: 10.1055/s-0032-1318168; Art ID: ST-2012-U1092-L
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Synthesis of 2-cyclopropyl-substituted carboxylic acid
esters 5 and cyclopropanecarboxylic acid esters 7 from 1-chlorovinyl
p-tolyl sulfoxides 1 and tert-butyl carboxylates 2.
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

484
T. Kimura et al.
LETTER
(Table 1, entry 1). As previously reported, the conjugate consumed at –60 °C within five minutes when treated
addition of the lithium enolate, generated from ester 2a with 3.5 equivalents of isopropylmagnesium chloride.
and lithium diisopropylamide (LDA), to sulfoxide 1a oc- The protonation of the resultant magnesium carbenoid
curred smoothly in THF at –78 °C for five minutes to give with aqueous NH4Cl gave a desulfinylated product 6a in
adduct 3a in a quantitative yield.7,8 The removal of the p- 93% yield.9 The cyclization of ester 6a was attempted in
tolylsulfinyl group from adduct 3a was then examined by the presence of sodium hexamethyldisilazide (NaHMDS)
the sulfoxide–magnesium exchange reaction and the sub- in THF.10 However, the reaction did not proceed at all. Af-
sequent protonation of the resultant magnesium carben- ter scrutiny of the reaction conditions, N,N′-dimethylpro-
oid. In our previous study, we found that the 1,3-C–H pyleneurea (DMPU) proved to be an effective cosolvent.11
insertion of magnesium carbenoids 4 proceeded at ap- The cyclization of ester 6a in a THF–DMPU mixture (1:1,
proximately –30 °C (Scheme 1, eq. 1).6g,k Therefore, the v/v) proceeded at room temperature for 28 hours to fur-
sulfoxide–magnesium exchange reaction had to be per- nish the desired spirocyclic compound 7a in a 96%
formed at a lower temperature. After some experimenta- yield.12
tion, we found that sulfoxide 3a was completely
Table 1 Synthesis of tert-Butyl Spiro[2.5]octane-1-carboxylates 7 from Sulfoxide 1a and tert-Butyl Carboxylates 2a–e
O
O
O
O
R
R
R
R
, LDA
O
S
t-BuO
t-BuO
O
S
t-BuO
t-BuO
i-PrMgCl
NaHMDS
2
Tol
Tol
THF
–60 °C, 5 min
THF–DMPU (1:1)
0 °C then r.t., 28 h
THF
–78 °C, 5 min
Cl
1a
Cl
Cl
3
6
7
Entry
2
R
Yield of 3 (%)
Yield of 6 (%)
Yield of 7 (%)
1
2a
2b
2c
2d
2e
Me
3a 99
3b 99
3c 94
3d 96
3e 97
6a 93
6b 92
6c 88
6d 90
6e 95
7a 96
7b 94
7c 92
7d 96
7e 99
2
BnCH2
BnO
Bn2N
H
3a,b
4a,b
5c
a The reaction of sulfoxide 1a with ester 2 was performed at –45 °C for 1 h.
b The cyclization of 6 was carried out under reflux for 28 h.
c The cyclization of 6 was performed at r.t. for 4 h.
Table 2 Synthesis of tert-Butyl Cyclopropanecarboxylates 7 from Sulfoxides 1b–f and tert-Butyl Acetate (2e)
O
O
O
O
R2
O
S
t-BuO
O
S
t-BuO
t-BuO
R2
t-BuO
, LDA
i-PrMgCl
NaHMDS
2e
R2
R1
R2
R1
R1
Tol
Tol
R1
THF
THF
–60 °C, 5 min
THF–DMPU (1:1)
0 °C then r.t., 4 h
–78 °C, 5 min
Cl
Cl
Cl
1
3
6
7
Entry
1
1
R1
R2
Yield of 3 (%)
3f 98
Yield of 6 (%)
Yield of 7 (%)
1b
6f 88
7f 96
2
3
1c
3g 97
3h 98
6g 86
7g 95
1d
6h 90
6i 93
7h 99
7i 93
4
1e
BnCH2
BnCH2
3i 96
Synlett 2013, 24, 483–486
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of tert-Butyl Cyclopropanecarboxylates
485
The scope of this three-step procedure for the synthesis of
tert-butyl cyclopropanecarboxylates was explored with a
series of tert-butyl carboxylates 2b–e (Table 1, entries 2–
5). Ester 2b, which bears a 2-phenylethyl group at the α
position, could be converted into spirocyclic ester 7b in an
86% yield over three steps (Table 1, entry 2). The cycliza-
tion of desulfinylated esters 6c and 6d, which were de-
rived from α-heteroatom-substituted esters 2c and 2d, was
sluggish at room temperature, and the cyclization of esters
6c and 6d under reflux afforded α-benzyloxy-substituted
ester 7c and cyclopropane amino acid derivative 7d in 92
and 96% yields, respectively (Table 1, entries 3 and 4).13
By contrast, the cyclization of ester 6e, which was pre-
pared from tert-butyl acetate (2e), proceeded smoothly at
room temperature within four hours to give the desired
product 7e (Table 1, entry 5).
O
R2
O
S
t-BuO
O
S
2e/LDA
R1
R2
R1
Tol
Tol
THF
–78 °C, 5 min
Cl
Cl
(RS)-(E)-1f, R1 = H, R2 = BnCH2
(RS)-(Z)-1f, R1 = BnCH2, R2 = H
(3S,RS)-3j 99% yield, 99% ee
(3R,RS)-3j' 98% yield, 99% ee
O
t-BuO
i-PrMgCl
R1
R2
THF
–60 °C, 5 min
Cl
(3S)-6j
99% yield, 97% ee
(3R)-6j 97% yield, 99% ee
O
Ph
NaHMDS
THF–DMPU (1:1)
t-BuO
(3S)-6j
(3R)-6j
This three-step synthetic method was also applicable to a
range of 1-chlorovinyl p-tolyl sulfoxides 1b–e (Table 2).
tert-Butyl spiro[2.n]alkane-1-carboxylates 7f–h (n = 4, 7,
14) were obtained from ester 2e and sulfoxides 1b–d bear-
ing a 5-, 8-, or 15-membered ring at the β position in good
overall yields. Acyclic sulfoxide 1e could also be used as
a substrate (Table 2, entry 4).
(1R,2R)-7j 99% yield, 97% ee
0 °C then r.t., 4 h
O
Ph
NaHMDS
t-BuO
(1S,2S)-7j
THF–DMPU (1:1)
0 °C then r.t., 4 h
99% yield, 99% ee
Scheme 2 Asymmetric synthesis of tert-butyl cyclopropanecarbox-
ylates (1R,2R)-7j and (1S,2S)-7j.
The asymmetric syntheses of tert-butyl cyclopropanecar-
boxylates (1R,2R)-7j and (1S,2S)-7j were examined uti-
lizing an optically active S-chiral p-tolylsulfinyl group as
a chiral auxiliary (Scheme 2). The reaction of lithium ester
enolate, generated from ester 2e and LDA, with optically
active S-chiral sulfoxide (RS)-(E)-1f, which has two dif-
ferent substituents at the β position, gave adducts (3S,RS)-
3j as a single diastereomer, and the reaction with the Z iso-
mer (RS)-(Z)-1f afforded another diastereomer (3R,RS)-
3j′.7b The p-tolylsulfinyl group was removed from ad-
ducts (3S,RS)-3j and (3R,RS)-3j′ without significant loss
of enantiomeric excess to give both enantiomers of tert-
butyl 3-(chloromethyl)-5-phenylpentanoate, (3S)-6j and
(3R)-6j. The cyclization of 4-chloro-substituted esters
(3S)-6j and (3R)-6j in the presence of NaHMDS provided
optically active tert-butyl cyclopropanecarboxylates
(1R,2R)-7j and (1S,2S)-7j as a 1:20 mixture of the cis and
trans isomers with high enantiomeric excesses.14
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
No. 22590021 from the Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan, and TUS Grant for Research Promoti-
on from Tokyo University of Science, which are gratefully
acknowledged.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SupInpfioomgrattr
o
nSupprigI
o
tnnofrmat
References and Notes
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In summary, we established a highly efficient method for
the synthesis of tert-butyl cyclopropanecarboxylates uti-
lizing 1-chlorovinyl p-tolyl sulfoxides as key materials.
The conjugate addition of lithium ester enolates to sulfox-
ides led to the formation of adducts having chloro and p-
tolylsulfinyl groups on the same carbon atom. The remov-
al of the p-tolylsulfinyl group from the adducts resulted in
umpolung of the carbon atom, allowing the second nu-
cleophilic attack of the enolates. Further applications of
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 483–486

486
T. Kimura et al.
LETTER
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silica gel [Rf = 0.54 (hexane–EtOAc = 10:1] to give 6a as a
colorless oil; yield 594 mg (2.28 mmol, 93%).
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(12) Synthesis of tert-Butyl Cyclopropanecarboxylates 7 –
Typical Procedure
(8) Synthesis of tert-Butyl 4-Chloro-4-(p-
tolylsulfinyl)butanoates 3 – Typical Procedure
A 1.65 M solution of BuLi in hexane (9.09 mL, 15.0 mmol)
was added to a solution of i-Pr2NH (1.52 g, 15.0 mmol) in
THF (55 mL) at 0 °C, and the mixture was stirred at that
temperature for 10 min. tert-Butyl propionate (2a, 1.95 g,
15.0 mmol) was added dropwise to the solution at –78 °C,
and the mixture was stirred at that temperature for 10 min. A
solution of sulfoxide 1a (806 mg, 3.00 mmol) in THF (5 mL)
was added to the resulting solution at –78 °C, and the
reaction mixture was stirred at that temperature for 5 min.
The reaction was quenched with sat. aq NH4Cl (5 mL), and
the mixture was extracted with CHCl3 (3 × 80 mL). The
organic layer was dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by column
chromatography on silica gel [Rf = 0.51 (hexane–EtOAc =
2:1)] to give 3a as a colorless oil; yield 1.18 g (2.97 mmol,
99%).
A 1.9 M solution of NaHMDS in THF (0.082 mL, 0.16
mmol) was added dropwise to a solution of 6a (27.2 mg,
0.104 mmol) in a THF–DMPU mixture (0.52 mL/0.52 mL)
at 0 °C, and the reaction mixture was stirred at r.t. for 28 h.
The reaction was quenched with sat. aq NH4Cl (0.5 mL), and
the mixture was extracted with toluene (3 × 8 mL). The
organic layer was dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by column
chromatography on silica gel [Rf = 0.51 (hexane–EtOAc =
10:1] to give 7a as a colorless oil; yield 22.5 mg (0.100
mmol, 96%).
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(9) Synthesis of tert-Butyl 4-Chlorobutanoates 6 – Typical
Procedure
A solution of 3a (978 mg, 2.45 mmol) in THF (10 mL) was
added dropwise to a 75.9 mM solution of i-PrMgCl in THF
(113 mL, 8.58 mmol) at –60 °C, and the reaction mixture
Synlett 2013, 24, 483–486
© Georg Thieme Verlag Stuttgart · New York

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