A method for the synthesis of cyclopropanes by regiospecific and regioselective magnesium carbenoid 1, 3-CH insertion as the key reactions

Article abstract of DOI:10.1016/j.tet.2010.05.061

Addition reaction of two geometrical isomers of 1-chlorovinyl p-tolyl sulfoxides derived from unsymmetrical ketones and chloromethyl p-tolyl sulfoxide, with lithium enolate of tert-butyl acetate gave single diastereomers of the adduct, respectively. Treat

Full text of DOI:10.1016/j.tet.2010.05.061

Tetrahedron 66 (2010) 5675e5686
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Tetrahedron
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A method for the synthesis of cyclopropanes by regiospecific and regioselective
magnesium carbenoid 1,3-CH insertion as the key reactions
*
Hiroyuki Watanabe, Shingo Ogata, Tsuyoshi Satoh
Graduate School of Chemical Sciences and Technology, Tokyo University of Science, Ichigaya-funagawara-machi 12, Shinjuku-ku, Tokyo 162-0826, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Addition reaction of two geometrical isomers of 1-chlorovinyl p-tolyl sulfoxides, derived from
unsymmetrical ketones and chloromethyl p-tolyl sulfoxide, with lithium enolate of tert-butyl acetate
gave single diastereomers of the adduct, respectively. Treatment of each diastereomer with i-PrMgCl
resulted in the formation of magnesium carbenoid. Highly regiospecific 1,3-CH insertion reaction was
found to take place from each magnesium carbenoid to afford cyclopropanes. On the other hand, when
Received 24 March 2010
Received in revised form 14 May 2010
Accepted 14 May 2010
Available online 11 June 2010
the unsymmetrical ketones bearing an oxygen- or a nitrogen-functional group on the a-carbon were
Keywords:
Cyclopropane
1,3-CH insertion reaction
Magnesium carbenoid
Regiospecific reaction
Regioselective reaction
used in this procedure, the regioselective 1,3-CH insertion reaction proceeded mainly. Stereochemistry of
the adducts, reaction mechanism, and essence of the specificity and the selectivity are discussed.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
a-position, gave cyclopropanes 9 with high regioselectivity via the
regioselective 1,3-CH insertion reaction of magnesium carbenoid
intermediates 8. In this paper we would like to report, in detail, the
results described above.
Cyclopropanes are very important and interesting compounds
in organic and synthetic organic chemistry, and innumerable
studies have been reported concerning their chemistry, synthesis
and synthetic uses.1 Since the cyclopropane ring is highly strained,
ring-opening reactions of cyclopropanes occur under the influence
of a variety of chemical reagents under mild conditions with car-
bonecarbon or carbonehetero atom bond-formation.1 These
properties are one of the reasons why cyclopropanes are versatile
compounds in organic and synthetic organic chemistry.
2. Results and discussion
2.1. Synthesis of cyclopropanes by regiospecific magnesium
carbenoid 1,3-CH insertion as the key reaction
In our previous work, we investigated the synthesis of cyclo-
propanes based on the magnesium carbenoid 1,3-CH insertion
reaction by the use of 1-chlorovinyl p-tolyl sulfoxides derived
from symmetrical ketones.4b,c As we recognized that the 1,3-CH
insertion reaction of magnesium carbenoids is a new and very
useful reaction in the synthesis of cyclopropanes, we further
investigated this reaction with 1-chlorovinyl p-tolyl sulfoxides
derived from unsymmetrical ketones. The representative example
of this study is shown in Scheme 2.
At first, geometrical isomers E-11 and Z-11 were synthesized
from 4-phenyl-2-butanone and chloromethyl p-tolyl sulfoxide 10 in
three steps in high overall yields.6b Vinyl sulfoxide E-11 was treated
with lithium enolate of tert-butyl acetate in THF at ꢀ78 ꢁC to afford
adduct 12 in quantitative yield as a single product. The same
reaction starting from Z-11 again gave quantitative yield of adduct
15 as a single product. These products 12 and 15 were diaster-
eomers to each other. The configuration of the products, 12 and 15,
We also have been interested in the synthesis of cyclopropanes
by our original methods.2 Recently, we found that the treatment of
1-chloroalkyl p-tolyl sulfoxides bearing a quaternary carbon at the
2-position with i-PrMgCl resulted in the formation of cyclopropanes
in high yields via the 1,3-carbon hydrogen (1,3-CH) insertion
reaction3 of the generated magnesium carbenoid intermediates.4 In
continuation of our aforementioned chemistry, as shown in
Scheme 1, we recently found that the reaction of adducts 2, derived
from 1-chlorovinyl p-tolyl sulfoxides 1 with lithium enolate of tert-
butyl acetate, with i-PrMgCl gavecyclopropanes 4 or 5 via the 1,3-CH
insertionreaction ofgenerated magnesiumcarbenoidintermediates
3 with high regiospecificity.5 In contrast to this, the reaction of
adducts 7, which were derived from 1-chlorovinyl p-tolyl sulfoxides
6 derived from unsymmetrical ketones bearing a heteroatom at the
* Corresponding author. E-mail address: tsatoh@rs.kagu.tus.ac.jp (T. Satoh).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.061

5676
H. Watanabe et al. / Tetrahedron 66 (2010) 5675e5686
R1H2C CH2COOBu-t
R1H2C CH2COOBu-t
R1H2C
R2H2C
Cl
i-PrMgCl
LiCH2COOBu-t
R2H2C CH(Cl)S(O)Tol
R2H2C CH(Cl)MgCl
S(O)Tol
3
1
2
(two geometrical isomers)
(two diastereomers)
Regiospecific
1,3-CH insertion
R1H2C CH2COOBu-t
R1
CH2COOBu-t
or
CH2R2
R2
5
4
R1XH2C CH2COOBu-t
R1XH2C CH2COOBu-t
R1XH2C
R2H2C
Cl
i-PrMgCl
LiCH2COOBu-t
R2H2C CH(Cl)S(O)Tol
R2H2C CH(Cl)MgCl
S(O)Tol
6
8
7
X = O
(two diastereomers)
R1X = NPh2
Regioselective
1,3-CH insertion
R1XH2C CH2COOBu-t
R2
9
Scheme 1. Regiospecific and regioselective 1,3-CH insertion reactions.
TolS(O)CH2Cl
10
PhCH2CH2
PhCH2CH2
H3C
H3C
S(O)Tol
Cl
S(O)Tol
Cl
O
in 3 steps
PhCH2CH2
H3C
(E) - 11
(Z) - 11
PhCH2CH2 CH2COOBu-t
PhCH2CH2 CH2COOBu-t
CH3COOBu-t
i-PrMgCl / Et2O
(E) - 11
LDA / THF
-78 °C, 10 min
99 %
Toluene
-78 ~ 0 °C, 2 h
H3C
Cl
13
MgCl
S(O)Tol
H3C
Cl
12
PhCH2CH2
CH2COOBu-t
90 %
14
H3C CH2COOBu-t
PhCH2CH2 MgCl
H3C CH2COOBu-t
i-PrMgCl / Et2O
Toluene
-78 ~ 0 °C, 2 h
CH3COOBu-t
(Z) - 11
LDA / THF
-78 °C, 10 min
99 %
S(O)Tol
PhCH2CH2
Cl
15
Cl
16
H3C CH2COOBu-t
PhCH2
17
89 %
Scheme 2. Regiospecific 1,3-CH insertion reaction.
was determined by X-ray crystallographic analysis of the corre-
sponding carboxylic acids, as reported previously.5
generated magnesium carbenoid intermediate 13 took place
between the carbenoid and the methyl carbon to give cyclopro-
pane 14. The same reaction of adduct 15 with i-PrMgCl gave
again very clean reaction mixture and, somewhat surprisingly, we
obtained cyclopropane 17 as about 10:1 mixture of two
diastereomers in 89% yield. In this case, the 1,3-CH insertion
reaction of the generated magnesium carbenoid intermediate 16
took place between the carbenoid and the methylene carbon of
A solution of adduct 12 in THF was added to a solution of
i-PrMgCl (ether solution; 5 equiv) in toluene at ꢀ78 ꢁC and the
temperature of the reaction mixture was slowly allowed to warm
to 0 ꢁC for 2 h. The reaction mixture was found to be very clean
and cyclopropane 14 was obtained in 90% yield as a single
product. In this case, the 1,3-CH insertion reaction of the

H. Watanabe et al. / Tetrahedron 66 (2010) 5675e5686
5677
the 2-phenylethyl group to afford cyclopropanes 17. Namely, the 1,
3-CH insertion reaction of the magnesium carbenoid intermediates
13 and 16 gave cyclopropanes 14 and 17, respectively, with perfect
regiospecificity.
yields.6 Each geometrical isomer of 1-chlorovinyl p-tolyl sulfoxides
18, except 18c, was separated and reacted with lithium enolate of
tert-butyl acetate to give adduct 19 in up to 99% yield as a single
diastereomer. As shown in entry 3, the geometrical isomers 18c
could not be separated and were used as a mixture to give adduct
19c in 95% yield as a mixture of two diastereomers.
Each adduct 19 was treated with 5 equiv of i-PrMgCl (ether
solution) in toluene to give cyclopropane 20 in good to quantitative
yield with perfect regiospecificity. It is worth noting that the 1,3-CH
insertion reaction between the carbenoid and the methyl carbon
took place in the adducts derived from (E)-1-chlorovinyl p-tolyl
sulfoxides to give 1,1-disubstituted cyclopropanes 20 (entries 1, 3, 4,
6, 8, and 10). On the contrary, adducts 19 synthesized from (Z)-1-
chlorovinyl p-tolyl sulfoxides gave tri-substituted or tetra-
In order to investigate the generality, efficiency, and specificity
of these reactions, we further studied this procedure starting with
several unsymmetrical ketones and the results are summarized in
Table 1. 2-Heptanone (entries 1 and 2), 4-(4-methoxyphenyl)-2-
butanone (entry 3), 3-methyl-2-butanone (entries 4 and 5), cyclo-
hexyl methyl ketone (entries 6 and 7), cyclopropyl methyl ketone
(entries 8 and 9), and methyl vinyl ketone (entries 10 and 11) were
selected as the unsymmetrical ketones. 1-Chlorovinyl p-tolyl sulf-
oxides 18 were synthesized from the above-mentioned ketones
with chloromethyl p-tolyl sulfoxide 10 in three steps in good overall
Table 1
Synthesis of cyclopropanes 20 from 1-chlorovinyl p-tolyl sulfoxides 18 through adducts 19 by regiospecific 1,3-CH insertion of the magnesium carbenoid intermediates
R1
S(O)Tol
Cl
R1
COOBu-t
i-PrMgCl / Et2O
CH3COOBu-t
Cyclopropane 20
R2
R2
Cl
Toluene
LDA / THF
S(O)Tol
-78 ~ 0 °C, 2 h
-78 °C, 10 min
19
18
Entry
18
19
Yield (%)
Cyclopropane 20
R1
R2
Me
Configuration
Yield (%)
88
1
2
3
18a
18b
18c
Pentyl
E
19a
19b
19c
99a
20a
20b
COOBu-t
H3C
H3C
CH3
Me
Pentyl
Z
95a
91c
89d
COOBu-t
CH3
COOBu-t
ꢀ
ꢁ
ðCH2Þ2PMP
Me
ðCH2Þ2PMP
COOBu-t
( 4 : 3)
PMP
E, Z mixture (E/Z¼4:3)
95
20c
PMP
Me
H3C
COOBu-t
,
b
4
5
6
18d
18e
18f
Isopropyl
Me
E
Z
E
19d
19e
19f
70a
20d
20e
20f
99
77
73
CH3
CH3
H3C
COOBu-t
COOBu-t
Me
Isopropyl
Me
99a
97a
96a
99a
CH3
Cyclohexyl
Me
CH3
COOBu-t
COOBu-t
7
8
18g
18h
Cyclohexyl
Me
Z
E
19g
19h
20g
20h
77
99
Cyclopropyl
CH2COOBu-t
9
18i
18j
Me
Cyclopropyl
Me
Z
E
19i
19j
99a
99a
20i
20j
80
62
CH3
10
CH2¼CH
H2C
COOBu-t
CH2COOBu-t
11
18k
Me
CH2¼CH
Z
19k
97a
21
56
CH3
21
a
Obtained as a single diastereomer.
Starting material (29%) was recovered.
A 3:1 mixture of two diastereomers.
b
c
d
Minor cyclopropane was obtained as a 6:1 mixture of two diastereomers.

5678
H. Watanabe et al. / Tetrahedron 66 (2010) 5675e5686
substituted cyclopropanes 20 from the 1,3-CH insertion reaction
between the carbenoid and the methylene or methyne carbon
(entries 2, 3, 5, and 7). Special attention should be paid to the
reactions shown in entries 4e7. In these cases, the 1,3-CH insertion
reaction took place between the carbenoid and the methyl or
methyne carbon. As shown in Table 1, the specificity was still per-
fect in these cases. The result shown in entry 9 was quite
interesting. The reaction of 19i with i-PrMgCl did not give the
expected highly strained spiro[2.2]pentane derivative. Instead,
olefin 20i was obtained in 80% yield by the 1,2-carbonecarbon
(1,2-CC) insertion of the magnesium carbenoid intermediate. The
result in entry 11 shows that the 1,3-CH insertion reaction of
magnesium carbenoid does not take place between the carbenoid
and sp2 carbon. Only diene 21, which was produced by the 1,2-CC
insertion of the magnesium carbenoid intermediate, was obtained
in 56% yield as an isolable product.
Elucidation of the origin of the regiospecificity of the 1,3-CH
insertion reaction mentioned above is very important for
developing these reactions to a new method for the synthesis of
cyclopropanes. We proposed a plausible mechanism for these
regiospecific 1,3-CH insertion reactions of magnesium carbenoids
as shown in Scheme 3. Since the sulfoxideemagnesium exchange
reaction7 is known to take place with retention of the configuration
of the carbon bearing a sulfinyl group,8 treatment of adduct 12 with
interact to afford chair-like six-membered intermediate as shown
in Scheme 3. In this intermediate, CeH bond of the methyl group
attacks to the carbon bearing the chlorine atom from backside of
CeCl bond9 to give 1,1-disubstituted cyclopropane 14. On the other
hand, the reaction of 15 with i-PrMgCl gave magnesium carbenoid
intermediate 16. In the chair-like six-membered intermediate
(chair form 16), the CeH bond in the backside of the CeCl bond is
on the methylene carbon. From this intermediate tri-substituted
cyclopropane 17 must be obtained. As reported previously, this
specificity almost disappeared when the tert-butoxycarbonyl group
of adducts 12 and 15 was converted to trityloxymethyl group.5
2.2. Synthesis of cyclopropanes by regioselective magnesium
carbenoid 1,3-CH insertion reaction as the key reaction
Further development of the aforementioned chemistry was
carried out with the unsymmetrical ketones bearing a heteroatom
on the
a-position. The representative results are shown in
Scheme 4. At first, geometrical isomers of 1-chlorovinyl p-tolyl
sulfoxides E-23 and Z-23 were synthesized from 1-methoxy-2-
butanone 22 with chloromethyl p-tolyl sulfoxide 10 in three steps
in good overall yield. The addition reaction of each vinyl sulfoxide
with lithium enolate of tert-butyl acetate gave adduct 24 and 26,
respectively, in good yield as a single diastereomer.
i-PrMgCl gives magnesium carbenoid 13 having R -configuration.
*
Adduct 24 was treated with i-PrMgCl in the same way as
described above and from this reaction we obtained the expected
The magnesium and carbonyl oxygen atom of the ester group
H
H
PhCH2CH2 CH2COOBu-t
PhCH2CH2
CH2COOBu-t
OBu-t
i-PrMgCl
H
PhCH2
Mg
S(O)Tol
H3C
Cl
O
Cl
Cl
14
12
13 (chair form)
H
CH2Ph
Mg
H3C CH2COOBu-t
H3C CH2COOBu-t
PhCH2
OBu-t
i-PrMgCl
H
S(O)Tol
PhCH2CH2
Cl
15
O
Cl
Cl
17
16 (chair form)
Scheme 3. A plausible mechanism for the regiospecific 1,3-CH insertion reaction.
TolS(O)CH2Cl
10
CH3OCH2
CH3OCH2
CH3CH2
CH3CH2
S(O)Tol
Cl
S(O)Tol
Cl
O
in 3 steps
CH3CH2
CH3OCH2
22
(E) - 23
(Z) - 23
CH3OCH2
CH3CH2
CH3OCH2 CH2COOBu-t
CH2COOBu-t
i-PrMgCl / Et2O
CH3COOBu-t
(E) - 23
LDA / THF
-78 °C, 10 min
96 %
Toluene
-78 ~ 0 °C, 2 h
40%
H3C
S(O)Tol
25
Cl
24
dr = 1:5
CH3CH2
CH3COOBu-t
CH2COOBu-t
i-PrMgCl / Et2O
(Z) - 23
25
LDA / THF
-78 °C, 10 min
96 %
Toluene
-78 ~ 0 °C, 2 h
61%
CH3OCH2
S(O)Tol
dr = 5:1
Cl
26
CH3CH2 CH2COOBu-t
H3CO
OR
CH3
CH3
CH2OR
S(O)Tol
28
i-PrMgCl
CH3 CH2OR
27
H3C
H3C
Cl
29
30
R = THP, SiMe2Bu-t
Scheme 4. Regioselective 1,3-CH insertion reaction of 24 and 26 with i-PrMgCl.

H. Watanabe et al. / Tetrahedron 66 (2010) 5675e5686
5679
cyclopropane 25 as a mixture of two diastereomers (the ratio
about 1:5 with respect to the methyl group on the cyclopropane
ring) in 40% yield. In this case, as expected, the 1,3-CH insertion
reaction took place between the carbenoid and the methylene
carbon of the ethyl group. Next, adduct 26 was treated with
i-PrMgCl. This reaction gave a mixture of cyclopropanes in 61%
yield; however, the product was not the expected methoxy-
cyclopropane 27 but cyclopropane 25. In this case the ratio of the
diastereomers was found to be 5:1. Obviously, the 1,3-CH in-
sertion reaction of the magnesium carbenoid intermediate took
place between the carbenoid and the methylene carbon of the
ethyl group with high regioselectivity.
The real reason for this regioselectivity is not clear at present.
However, presence of the Lewis basic oxygen atom, as the ether
functional group, is thought to act as crucial role in the conformation
of the magnesium carbenoid intermediates. We previously reported
the 1,3-CH insertion reaction of sulfoxides bearing an alkoxymethyl
group 28. The 1,3-CH insertion reaction took place between the
carbenoid carbon and the methyl carbon to give 1,1-disubstituted
cyclopropane 29 in up to 97% yield without any trace of the
alkoxycyclopropane 30.4a The result in the presented study consis-
tent with that in the previous investigation.4a
Table 2. 1-Chlorovinyl p-tolyl sulfoxides bearing a phenoxymethyl
group 31 were synthesized from the corresponding ketones with
chloromethyl p-tolyl sulfoxide 10 in good overall yields. All the
addition reactions of 31 with lithium enolate of tert-butyl acetate
smoothly proceeded to give adducts 32 in quantitative yields as
single diastereomers.
Quite different reactivity was observed between the reaction of
the adducts 32a and 32b with i-PrMgCl. Thus, treatment of 32a
with i-PrMgCl was carried out under the same way as described
above to afford the expected 1,1-disubstituted cyclopropane 33a in
64% yield (entry 1). The same reaction of 32b only gave a very
complex mixture from which 33a was isolated in 6% yield as only
isolable product. Treatment of adducts 32c and 32d with i-PrMgCl
gave the expected tri-substituted cyclopropane 33b as a mixture of
two diastereomers with high regioselectivity; however, the yields
were low to moderate. The reaction of adduct 32e with i-PrMgCl
was found to be sluggish; however, this reaction cleanly gave the
expected tetra-substituted cyclopropane 33c. On the other hand,
the reaction with 32f gave the expected 33c (20% yield) and the
cyclopropane resulting from the 1,3-CH insertion reaction between
the carbenoid and the methylene carbon of the phenoxymethyl
group 34 as a main product (45%). Although the reason is not clear
at present the regioselectivity was found to be low in this case.
Finally, the l,3-CH insertion reaction of magnesium carbenoid
was investigated with the substrate bearing a nitrogen atom
Synthesis of cyclopropanes bearing a phenoxymethyl group on
the cyclopropane ring 33 starting from unsymmetrical ketones
having a phenoxy group on the
a-position was summarized in
Table 2
Synthesis of cyclopropanes bearing a phenoxymethyl group 33 from 1-chlorovinyl p-tolyl sulfoxides 31
PhOCH2
PhOCH2
CH2COOBu-t
S(O)Tol
Cl
i-PrMgCl / Et2O
CH3COOBu-t
Cyclopropane 33
Cyclopropane 33
LDA / THF
Toluene
-78 ~ 0 °C, 2 h
S(O)Tol
Cl
R
R
-78 °C, 10 min
31
Entry
31
32
Configuration
Yield (%)
95
Yield (%)
64
PhOCH2
S(O)Tol
Cl
1
2
3
4
31a
31b
31c
31d
E
Z
E
Z
32a
32b
32c
32d
PhOCH2
CH2COOBu-t
CH3
CH3
S(O)Tol
Cl
33a
96
96
97
6
PhOCH2
PhOCH2
S(O)Tol
Cl
,b
63a
PhOCH2 CH2COOBu-t
CH3CH2
CH3
H3C
S(O)Tol
33b
35a,c
PhOCH2
PhOCH2
Cl
S(O)Tol
5
6
31e
31f
E
Z
32e
32f
99
99
43d
H3C
Cl
PhOCH2 CH2COOBu-t
CH3
CH3
H3C
H3C
H3C
S(O)Tol
Cl
20a,e
33c
PhOCH2
CH3
CH2COOBu-t
H3C
PhO
34
a
The yield was determined by 1H NMR.
A 7:1 mixture of two diastereomers.
A 1:2 mixture of two diastereomers.
The starting material was recovered in 47% yield.
Cyclopropane 34 was obtained as a main product in 45% yield.
b
c
d
e

5680
H. Watanabe et al. / Tetrahedron 66 (2010) 5675e5686
(Scheme 5). 1-Chlorovinyl p-tolyl sulfoxide 35 was synthesized
from 1-diphenylamino-2-butanone with chloromethyl p-tolyl
sulfoxide 10 as an inseparable mixture of two geometrical isomers.
The addition reaction of the mixture of 35 with lithium enolate of
tert-butyl acetate gave adduct 36 as an inseparable mixture of two
diastereomers in 78% yield. Treatment of 36 with i-PrMgCl under
the aforementioned conditions gave relatively clean reaction mix-
ture and cyclopropane 37 was obtained in 69% yield as a single
isomer. The structure of 37 was determined as shown in Scheme 5
by NOESY experiment; clear NOE was observed between hydrogen
of the methyl group and hydrogen on the methylene carbon of tert-
butyl acetate moiety.
unsymmetrical ketones, chloromethyl p-tolyl sulfoxide and tert-
butyl acetate, proceeded with complete regiospecificity when the
1-chloroalkyl p-tolyl sulfoxides have no heteroatom at the 3-posi-
tion. The essence of the regiospecificity was demonstrated on the
bases of the fixed conformation of the magnesium carbenoid
intermediate. On the other hand, the reaction of 1-chlorovinyl
p-tolyl sulfoxides prepared from unsymmetrical ketones bearing
oxygen- or nitrogen-functional group at the
a-position with
i-PrMgCl, the 1,3-CH insertion reaction usually takes place with
regioselectivity, though in some cases the yields were low to mod-
erate and the selectivity is not always high. In these cases, we still
find it very difficult to propose a rational transition model for
Ph2NCH2
S(O)Tol
Ph2NCH2
CH3CH2
CH2COOBu-t
CH3COOBu-t
LDA / THF
-78 °C, 10 min
78 %
CH3CH2
Cl
S(O)Tol
Cl
36
35
(two diastereomers)
CH2COOBu-t
Ph2NCH2
H3C
i-PrMgCl / Et2O
Toluene
-78 ~ 0 °C, 2 h
69%
37
Scheme 5. Synthesis of cyclopropane bearing a diphenylaminomethyl group 37 by regioselective 1,3-CH insertion reaction.
It is worth noting that since we obtained only 37 as the product,
explaining the selectivity. Coordination of the magnesium and the
oxygen of the carbonyl group and the ether group, or the nitrogen-
functional group at the same time were thought to be the reason for
this complexity. The results described in this paper contribute to the
regiospecific and regioselective synthesis of cyclopropanes from
various ketones and to further development of the chemistry of
magnesium carbenoids.
the 1,3-CH insertion reaction of the magnesium carbenoid
intermediate derived from the mixture of diastereomers 36 pro-
ceeded with high regio- and stereoselectivity. The real mechanism
of this region- and stereoselective reaction is still obscure; how-
ever, we could propose a plausible explanation of the selectivities
as shown in Scheme 6. Similar to the magnesium carbenoid
intermediate indicated in Scheme 3, the sulfoxideemagnesium
exchange reactionof36affordedmagnesiumcarbenoidintermediate
38. The magnesium and carbonyl oxygen atom of the ester group
interact to give chair-like six-membered intermediate in which very
bulky diphenylaminomethyl group occupies equatorial position.
Because of the steric repulsion of both the diphenylaminomethyl
group and the ethyl group, the methyl group in the ethyl group must
be moved away from the diphenylamino group, as shown in
Scheme 6. From this conformation, cyclopropane 37 was obtained
with high stereoselectivity.
3. Experimental
3.1. General
Melting points were measured on a Yanaco MP-S3 apparatus
and are uncorrected. 1H NMR spectra were measured in a CDCl3
solution with JEOL JNM-LA 500 and BRUKER UltraShield 400, 300
spectrometer. IR spectra were recorded on a PerkineElmer spec-
trum One FT-IR instrument. Electron-impact mass spectra (MS)
were obtained at 70 eV by direct insertion with JEOL JMS-SX102A.
Silica gel 60 N (KANTO CHEMICAL) containing 0.5% fluorescence
In conclusion, we found that the 1,3-CH insertion reaction of the
magnesium carbenoids generated from 1-chloroalkyl p-tolyl sulf-
oxides having an tert-butyl ester group, which were prepared from
reagent 254 and
a quartz column were used for column
H
CH3
Ph2NCH2 CH2COOBu-t
Ph2NCH2
H3C
CH2COOBu-t
i-PrMgCl
OBu-t
Ph2N
H
Mg
O
S(O)Tol
CH3CH2
Cl
Cl
Cl
37
36
38
one of the two
diastereomers
chair form of the generated
magnesium carbenoid
intermediate
Scheme 6. A plausible explanation for the regioselective and stereoselective formation of 37 from 36 through the 1,3-CH insertion reaction of magnesium carbenoid intermediate.

H. Watanabe et al. / Tetrahedron 66 (2010) 5675e5686
5681
chromatography and the products having UV absorption were
detected by UV irradiation. In experiments requiring a dry solvent
and reagent, diethyl ether, and THF were distilled from diphe-
nylketyl. Toluene, diisopropylamine, and triethylamine were dis-
tilled from CaH2, 1,2-epoxybutane and tert-butyl acetate from
anhydrous CaSO4. Compounds (E)-11,6b (Z)-11,6b 15,6b 18a,10 18b,10
18j,10 18k,10 and 2211 are known.
(41), 239 (3), 208 (6), 172 (11), 158 (7), 121 (100), 91 (14), 77 (10), 65
(6). Calcd for C19H21ClO2S: M, 348.0951. Found: m/z 348.0950.
3.1.5. (E)-1-Chloro-2,3-dimethylbut-1-enyl p-tolyl sulfoxide (18d).
Colorless crystals; mp 75e75.5 ꢁC (hexane); IR (KBr) 2966, 1595,
1490, 1464, 1366, 1231, 1088, 1055 (SO), 803 cmꢀ1 1H NMR
; d 1.16
(3H, d, J¼6.9 Hz),1.19 (3H, d, J¼6.8 Hz),1.90 (3H, s), 2.41 (3H, s), 3.83
(1H, septet, J¼6.8 Hz), 7.32 (2H, d, J¼8.2 Hz), 7.48 (2H, d, J¼8.2 Hz).
Anal. Calcd for C13H17ClOS: C, 60.80; H, 6.67; Cl, 13.81; S, 12.49.
Found: C, 60.75; H, 6.51; Cl, 13.70; S, 12.54.
3.1.1. tert-Butyl
3-[chloro(p-tolylsulfinyl)methyl]-3-methyl-5-phe-
nylpentanoate (12). tert-Butyl acetate (0.328 mL; 2.44 mmol) was
added to a solution of LDA (2.35 mmol) in 8 mL of dry THF at ꢀ78 ꢁC
under argon atmosphere with stirring. After the solution was stir-
red for 10 min, a solution of vinyl sulfoxide (E)-11 (150 mg;
0.47 mmol) in THF (1.4 mL) was added. The reaction mixture was
stirred for 10 min and the reaction was quenched by adding satd aq
NH4Cl. The product was purified by silica gel column chromatog-
raphy to afford adduct 12 (204.3 mg; 99%) as colorless oil; IR (neat)
2976, 2926, 1716 (CO), 1597, 1491, 1458, 1364, 1160, 1055 (SO),
3.1.6. (Z)-1-Chloro-2,3-dimethylbut-1-enyl p-tolyl sulfoxide (18e).
Colorless crystals; mp 122.5e124 ꢁC (hexane); IR (KBr) 2965, 1595,
1439, 1307, 1083, 1051 (SO), 811 cmꢀ1 1H NMR
; d 1.02 (3H, d,
J¼6.8 Hz), 1.08 (3H, d, J¼6.8 Hz), 2.22 (3H, s), 2.41 (3H, s), 3.18 (1H,
septet, J¼6.8 Hz), 7.31 (2H, d, J¼8.2 Hz), 7.46 (2H, d, J¼8.2 Hz). Anal.
Calcd for C13H17ClOS: C, 60.80; H, 6.67; Cl, 13.81; S, 12.49. Found: C,
60.90; H, 6.54; Cl, 13.70; S, 12.54.
812 cmꢀ1
;
1H NMR
d
1.42 (3H, s), 1.47 (9H, s), 2.19 (1H, dt, J¼9.6,
5.4 Hz), 2.29 (1H, dt, J¼9.6, 5.4 Hz), 2.42 (3H, s), 2.67 (1H, d,
J¼15.6 Hz), 2.68 (1H, dt, J¼12.6, 5.4 Hz), 2.75 (1H, dt, J¼12.6,
5.4 Hz), 3.07 (1H, d, J¼15.6 Hz), 5.21 (1H, s), 7.18 (1H, m), 7.23e7.26
(2H, m), 7.28e7.31 (4H, m), 7.72 (2H, d, J¼8.4 Hz). MS m/z (%) 434
(Mþ, 0.5), 361 (13), 203 (20), 140 (100), 91 (69). Calcd for
C24H31ClO3S: M, 434.1682. Found: m/z 434.1689.
3.1.7. (E)-1-Chloro-2-cyclohexylprop-1-enyl p-tolyl sulfoxide (18f).
Colorless crystals; mp 74e74.5 ꢁC (hexaneeAcOEt); IR (KBr) 2926,
2853, 1594, 1489, 1445, 1088, 1060 (SO), 806 cmꢀ1 1H NMR
;
d
1.13e1.31 (1H, m), 1.32e1.58 (5H, m), 1.70e1.90 (4H, m), 1.92 (3H,
s), 2.41 (3H, s), 3.43 (1H, tt, J¼11.3, 3.6 Hz), 7.31 (2H, d, J¼8.3 Hz),
7.47 (2H, d, J¼8.3 Hz). Anal. Calcd for C16H21ClOS: C, 64.74; H, 7.13;
Cl, 11.94; S, 10.80. Found: C, 64.88; H, 7.04; Cl, 11.79; S, 10.77.
3.1.2. tert-Butyl
[1-(2-phenylethyl)cyclopropyl]acetate
(14). To
a flame-dried flask was added dry toluene (2 mL) followed by i-
3.1.8. (Z)-1-Chloro-2-cyclohexylprop-1-enyl p-tolyl sulfoxide (18g).
Colorless crystals; mp 109.5e110.5 ꢁC (hexaneeAcOEt); IR (KBr)
PrMgCl (2.0 M solution in ether; 0.46 mmol; 5 equiv) at ꢀ78 ꢁC
under argon atmosphere.
A
solution of adduct 12 (40 mg;
2932, 2853, 1594, 1445, 1087, 1055 (SO), 879, 806 cmꢀ1 1H NMR
;
0.092 mmol) in toluene (1 mL) was added to a solution of the
Grignard reagent dropwise with stirring and the reaction mixture
was slowly allowed to warm to 0 ꢁC for 2 h. The reaction was
quenched with satd aq NH4Cl and the whole was extracted with
CHCl3. The product was purified over silica gel column chroma-
tography to afford cyclopropane 14 (21.5 mg; 90%) as colorless oil.
IR (neat) 2978, 2931, 1725 (CO), 1603, 1455, 1467, 1314, 1256, 1141,
d 1.10e1.25 (1H, m), 1.25e1.40 (4H, m), 1.47e1.57 (1H, m), 1.63e1.86
(4H, m), 2.23 (3H, s), 2.41 (3H, s), 2.74e2.88 (1H, m), 7.30 (2H, d,
J¼8.3 Hz), 7.45 (2H, d, J¼8.3 Hz). Anal. Calcd for C16H21ClOS: C,
64.74; H, 7.13; Cl, 11.94; S, 10.80. Found: C, 64.80; H, 7.01; Cl, 11.74; S,
10.78.
3.1.9. (E)-1-Chloro-2-cyclopropylprop-1-enyl
(18h). Colorless crystals; mp 120e120.5 ꢁC (hexaneeAcOEt); IR
(KBr) 3010, 2921, 1584, 1491, 1359, 1084, 1054 (SO), 930, 809 cmꢀ1
1H NMR
0.73e0.81 (1H, m), 0.87e1.03 (3H, m), 1.63 (3H, s), 2.42
p-tolyl
sulfoxide
1017, 966, 842, 746, 699 cmꢀ1; 1H NMR
d 0.38 (2H, m), 0.47 (2H, m),
1.47 (9H, s), 1.63 (2H, m), 2.21 (2H, s), 2.70 (2H, m), 7.14e7.20 (3H,
m), 7.24e7.28 (2H, m). MS m/z (%) 260 (Mþ, 3), 204 (51), 159 (12),
144 (82), 104 (37), 91 (100), 57 (78). Calcd for C17H24O2: M,
260.1777. Found: m/z 260.1772.
;
d
(3H, s), 2.67 (1H, m), 7.32 (2H, d, J¼8.0 Hz), 7.52 (2H, d, J¼8.0 Hz).
Anal. Calcd for C13H15ClOS: C, 61.29; H, 5.93; Cl, 13.92; S, 12.58.
Found: C, 61.34; H, 5.84; Cl, 13.80; S, 12.55.
3.1.3. tert-Butyl (2-benzyl-1-methylcyclopropyl)acetate (17). Color-
less oil (about 10:1 mixture of two diastereomers); IR (neat) 2978,
3.1.10. (Z)-1-Chloro-2-cyclopropylprop-1-enyl
(18i). Colorless crystals; mp 131.5e132 ꢁC (hexaneeAcOEt); IR
(KBr) 3013, 1581, 1447, 1266, 1083, 1050 (SO), 881, 808 cmꢀ1 1H
NMR 0.73e0.80 (1H, m), 0.81e0.95 (3H, m), 1.95 (3H, s), 2.18 (1H,
m), 2.42 (3H, s), 7.32 (2H, d, J¼8.0 Hz), 7.48 (2H, d, J¼8.0 Hz). Anal.
Calcd for C13H15ClOS: C, 61.29; H, 5.93; Cl, 13.92; S, 12.58. Found: C,
61.34; H, 5.80; Cl, 13.76; S, 12.52.
p-tolyl
sulfoxide
1732 (CO), 1455, 1368, 1253, 1150, 963, 698 cmꢀ1 1H NMR
; d 0.21
(0.1H, t, J¼4.9 Hz), 0.34 (0.9H, t, J¼5.1 Hz), 0.61 (0.9H, dd, J¼8.4,
4.7 Hz), 0.71 (0.1H, dd, J¼8.6, 4.9 Hz), 0.92 (1H, tt, J¼8.5, 5.9 Hz),1.14
(0.3H, s), 1.16 (2.7H, s), 1.46 (0.9H, s), 1.48 (8.1H, s), 2.13 (0.2H, d,
J¼3.9 Hz), 2.27 (1.8H, d, J¼4.2 Hz), 2.47 (0.9H, dd, J¼15.1, 8.5 Hz),
2.57 (0.1H, dd, J¼15.4, 8.0 Hz), 2.80 (0.1H, dd, J¼15.1, 6.6 Hz), 2.88
(0.9H, dd, J¼15.1, 6.3 Hz), 7.15e7.21 (1H, m), 7.21e7.31 (4H, m). MS
m/z (%) 260 (Mþ, 0.1), 222 (2), 204 (49), 187 (12), 159 (13), 144 (60),
117 (34), 104 (34), 91 (78), 57 (75). Calcd for C17H24O2: M, 260.1776.
Found: m/z 260.1768.
;
d
3.1.11. tert-Butyl 3-[chloro(p-tolylsulfinyl)methyl]-3-methyloctanoate
(19a). Colorless oil; IR (neat) 2932, 1724 (CO), 1597, 1456, 1368,
1218, 1161, 1056 (SO), 812 cmꢀ1
;
1H NMR
d
0.91 (3H, t, J¼6.6 Hz),
1.31 (3H, s), 1.31e1.41 (6H, m), 1.46 (9H, s), 1.79e1.88 (1H, m),
1.91e2.00 (1H, m), 2.42 (3H, s), 2.51 (1H, d, J¼15.5 Hz), 3.00 (1H, d,
J¼15.5 Hz), 5.16 (1H, s), 7.30 (2H, d, J¼8.2 Hz), 7.72 (2H, d, J¼8.2 Hz).
MS (FAB) m/z (%) 401 ([MþH]þ, 26), 345 (100), 327 (19), 205 (4), 169
(20), 140 (12), 123 (10), 109 (6), 57 (10). Calcd for C21H34ClO3S: M,
401.1917. Found: m/z 401.1915.
3.1.4. 1-Chloro-2-methyl-4-(4-methoxyphenyl)-but-1-enyl
p-tolyl
sulfoxide (18c). Colorless oil (about 4:3 mixture of two
diastereomers); IR (neat) 2998, 2933, 1612, 1515, 1456, 1302, 1249,
1178, 1088, 1058 (SO), 892, 810, 753 cmꢀ1; 1H NMR
d 2.05 (1.7H, s),
2.24 (1.3H, s), 2.39 (1.7H, s), 2.42 (1.3H, s), 2.49e2.57 (0.43H, m),
2.64e2.86 (2H, m), 2.89e2.96 (1.14H, m), 3.12e3.18 (0.43H, m), 3.78
(1.3H, s), 3.80 (1.7H, s), 6.79 (0.86H, d, J¼8.6 Hz), 6.87 (1.14H, d,
J¼8.6 Hz), 7.06 (0.86H, d, J¼8.6 Hz), 7.13 (1.14H, d, J¼8.6 Hz), 7.16
(1.14H, d, J¼8.3 Hz), 7.22 (1.14H, d, J¼7.9 Hz), 7.29 (0.86H, d,
J¼8.0 Hz), 7.37 (0.86H, d, J¼8.3 Hz). MS m/z (%) 348 (Mþ, 3), 331
3.1.12. tert-Butyl 3-[chloro(p-tolylsulfinyl)methyl]-3-methyloctanoate
(19b). Colorless oil; IR (neat) 2931, 1732 (CO), 1598, 1456, 1368,
1222, 1143, 1056 (SO), 812 cmꢀ1
1.23e1.38 (6H, m), 1.42 (3H, s), 1.45 (9H, s), 1.68 (2H, dd, J¼9.2,
;
1H NMR
d
0.89 (3H, t, J¼7.0 Hz),

5682
H. Watanabe et al. / Tetrahedron 66 (2010) 5675e5686
6.6 Hz), 2.42 (3H, s), 2.68 (1H, d, J¼15.6 Hz), 2.93 (1H, d, J¼15.6 Hz),
5.07 (1H, s), 7.31 (2H, d, J¼8.2 Hz), 7.72 (2H, d, J¼8.2 Hz). MS (FAB)
m/z (%) 401 ([MþH]þ, 25), 345 (100), 327 (20), 205 (4), 169 (15), 140
(11), 123 (8), 109 (6), 57 (9). Calcd for C21H34ClO3S: M, 401.1917.
Found: m/z 401.1916.
297 (19),164 (4),123 (18), 93 (12), 57 (12). Calcd for C19H28ClO3S: M,
371.1448. Found: m/z 371.1446.
3.1.19. tert-Butyl 3-[chloro(p-tolylsulfinyl)methyl]-3-cyclopropylbutanoate
(19i). Colorless oil; IR (neat) 2979, 1732 (CO), 1597, 1456, 1368, 1218,
1153, 1057 (SO), 812 cmꢀ1 1H NMR
; d 0.33 (1H, m), 0.45 (1H, m),
3.1.13. tert-Butyl 3-[chloro(p-tolylsulfinyl)methyl]-5-(4-methoxyphenyl)-
3-methylpentanoate (19c). Colorless oil; IR (neat) 2977, 2934, 1723
0.62 (1H, m), 0.76 (1H, m), 1.13 (3H, s), 1.19e1.33 (1H, m), 1.44 (9H,
s), 2.43 (3H, s), 2.63 (1H, d, J¼15.6 Hz), 2.73 (1H, d, J¼15.6 Hz), 5.26
(1H, s), 7.31 (2H, d, J¼8.1 Hz), 7.74 (2H, d, J¼8.1 Hz). MS (FAB) m/z
(%) 371 ([MþH]þ, 31), 315 (100), 297 (13), 139 (11), 123 (10), 93 (8),
57 (9). Calcd for C19H28ClO3S: M, 371.1448. Found: m/z 371.1445.
(CO), 1613, 1515, 1463, 1368, 1247, 1156, 1054 (SO), 813 cmꢀ1 1H
;
NMR
d 1.41 (1.3H, s), 1.47 (3.9H, s), 1.48 (5.1H, s), 1.50 (1.7H, s),
1.92e2.08 (1H, m), 2.11e2.35 (1H, m), 2.42 (1.3H, s), 2.43 (1.7H, s),
2.52e2.75 (2.43H, m), 2.82 (0.57H, d, J¼15.8 Hz), 3.06 (0.43H, d,
J¼15.3 Hz), 3.06 (0.57H, d, J¼15.5 Hz), 3.78 (1.3H, s), 3.79 (1.7H, s),
5.11 (0.43H, s), 5.20 (0.57H, s), 6.83 (2H, t, J¼8.0 Hz), 7.10 (0.86H, d,
J¼8.4 Hz), 7.15 (1.14H, d, J¼8.5 Hz), 7.31 (1.14H, d, J¼8.0 Hz), 7.32
(0.86H, d, J¼7.7 Hz), 7.72 (0.86H, d, J¼7.7 Hz), 7.74 (1.14H, d,
J¼8.0 Hz). MS (FAB) m/z (%) 465 ([MþH]þ, 26), 409 (100), 391 (17),
269 (5), 233 (58), 173 (37), 121 (80), 57 (16). Calcd for C25H34ClO4S:
M, 465.1866. Found: m/z 465.1864.
3.1.20. tert-Butyl 3-[chloro(p-tolylsulfinyl)methyl]-3-methylpent-4-
enoate (19j). Colorless oil; IR (neat) 2980, 1723 (CO), 1458, 1368,
1218, 1158, 1056 (SO), 813 cmꢀ1; 1H NMR
d 1.43 (3H, s), 1.46 (9H, s),
2.42 (3H, s), 2.64 (1H, d, J¼15.6 Hz), 3.20 (1H, d, J¼15.6 Hz), 5.24
(1H, s), 5.25e5.36 (2H, m), 6.27 (1H, dd, J¼17.5, 10.9 Hz), 7.31 (2H, d,
J¼8.1 Hz), 7.71 (2H, d, J¼8.1 Hz). MS m/z (%) 356 (Mþ, trace), 340
(0.1), 283 (17), 161 (13), 140 (100), 125 (16), 92 (12). Calcd for
C18H25ClO3S: M, 356.1213. Found: m/z 356.1211.
3.1.14. tert-Butyl 3-[chloro(p-tolylsulfinyl)methyl]-3,4-dimethylpenta-
noate (19d). Colorless oil; IR (neat) 2978, 1723 (CO), 1456, 1368,
3.1.21. tert-Butyl 3-[chloro(p-tolylsulfinyl)methyl]-3-methylpent-4-
enoate (19k). Colorless oil; IR (neat) 2979, 1728 (CO), 1455, 1368,
1220, 1159, 1056 (SO), 812 cmꢀ1
;
1H NMR
d
1.03 (3H, d, J¼6.9 Hz),
1.10 (3H, d, J¼6.9 Hz), 1.30 (3H, s), 1.47 (9H, s), 2.42 (3H, s), 2.51 (1H,
septet, J¼6.9 Hz), 2.52 (1H, d, J¼15.5 Hz), 2.90 (1H, d, J¼15.5 Hz),
5.25 (1H, s), 7.31 (2H, d, J¼8.1 Hz), 7.74 (2H, d, J¼8.1 Hz). MS (FAB)
m/z (%) 373 ([MþH]þ, 30), 317 (100), 299 (20), 177 (5), 141 (28), 123
(16), 91 (2), 57 (10). Calcd for C19H30ClO3S: M, 373.1605. Found: m/z
373.1601.
1220, 1152, 1057 (SO), 812 cmꢀ1; 1H NMR
d 1.44 (9H, s), 1.62 (3H, s),
2.42 (3H, s), 2.71 (1H, d, J¼15.8 Hz), 2.83 (1H, d, J¼15.8 Hz), 5.08
(1H, s), 5.24 (1H, d, J¼17.4 Hz), 5.28 (1H, d, J¼10.8 Hz), 6.11 (1H, dd,
J¼17.4, 10.8 Hz), 7.31 (2H, d, J¼8.0 Hz), 7.71 (2H, d, J¼8.0 Hz). MS m/
z (%) 356 (Mþ, trace), 340 (0.2), 283 (14), 161 (9), 140 (100), 125 (14),
92 (13). Calcd for C18H25ClO3S: M, 356.1213. Found: m/z 356.1212.
3.1.15. tert-Butyl 3-[chloro(p-tolylsulfinyl)methyl]-3,4-dimethylpenta-
noate (19e). Colorless oil; IR (neat) 2978, 1723 (CO), 1456, 1368,
3.1.22. tert-Butyl (1-pentylcyclopropyl)acetate (20a). Colorless oil;
IR (neat) 2960, 2930, 1732 (CO), 1459, 1368, 1256, 1144, 965,
1221, 1161, 1140, 1084 (SO), 1056, 812 cmꢀ1
;
1H NMR
d
0.97 (3H, d,
844 cmꢀ1 1H NMR
; d 0.33 (2H, m), 0.41 (2H, m), 0.88 (3H, t,
J¼6.9 Hz), 1.01 (3H, d, J¼6.9 Hz), 1.42 (3H, s), 1.46 (9H, s), 2.24 (1H,
septet, J¼6.9 Hz), 2.43 (3H, s), 2.60 (1H, d, J¼16.1 Hz), 2.93 (1H, d,
J¼16.1 Hz), 5.49 (1H, s), 7.32 (2H, d, J¼8.0 Hz), 7.79 (2H, d, J¼8.0 Hz).
MS (FAB) m/z (%) 373 ([MþH]þ, 31), 317 (100), 299 (22), 177 (4), 141
(20), 123 (14), 91 (2), 57 (10). Calcd for C19H30ClO3S: M, 373.1605.
Found: m/z 373.1604.
J¼7.3 Hz),1.18e1.41 (8H, m),1.45 (9H, s), 2.10 (2H, s). MS m/z (%) 226
(Mþ, trace), 170 (27), 153 (10), 141 (7), 110 (91), 99 (9), 83 (10), 69
(23), 57 (100). Calcd for C14H26O2: M, 226.1933. Found: m/z
226.1922.
3.1.23. tert-Butyl (2-butyl-1-methylcyclopropyl)acetate (20b). Col-
orless oil (about 3:1 mixture of two diastereomers); IR (neat) 2960,
3.1.16. tert-Butyl 3-[chloro(p-tolylsulfinyl)methyl]-3-cyclohexylbutanoate
(19f). Colorless crystals; mp 99e99.5 ꢁC (hexaneeAcOEt); IR (KBr)
2930, 1735 (CO), 1458, 1367, 1255, 1148, 965, 844 cmꢀ1 1H NMR
;
d
ꢀ0.03 (0.2H, t, J¼5.0 Hz), 0.09 (0.8H, t, J¼4.9 Hz), 0.47 (0.8H, dd,
2927, 1717 (CO), 1447, 1364, 1219, 1150, 1057 (SO), 814 cmꢀ1
;
1H
J¼8.6, 4.5 Hz), 0.51e0.60 (1H, m), 0.61e0.69 (0.2H, m), 0.84e0.93
(3H, m), 1.10 (3H, s), 1.20e1.41 (6H, m), 1.45 (1.8H, s), 1.46 (7.2H, s),
1.98 (0.2H, d, J¼14.2 Hz), 2.14 (0.2H, d, J¼14.2 Hz), 2.16 (0.8H, d,
J¼15.1 Hz), 2.21 (0.8H, d, J¼15.1 Hz). MS m/z (%) 226 (Mþ, 0.1), 170
(44), 152 (13), 141 (1), 125 (5),110 (100),100 (11), 83 (11), 69 (27), 57
(84). Calcd for C14H26O2: M, 226.1932. Found: m/z 226.1939.
NMR
d 1.06e1.23 (3H, m), 1.23e1.38 (2H, m), 1.31 (3H, s), 1.46 (9H,
s), 1.65e1.73 (1H, m), 1.75e1.90 (3H, m), 2.00e2.14 (2H, m), 2.42
(3H, s), 2.55 (1H, d, J¼15.4 Hz), 2.88 (1H, d, J¼15.4 Hz), 5.26 (1H, s),
7.31 (2H, d, J¼8.2 Hz), 7.74 (2H, d, J¼8.2 Hz). Anal. Calcd for
C22H33ClO3S: C, 63.98; H, 8.05; Cl, 8.58; S, 7.76. Found: C, 64.20; H,
8.00; Cl, 8.55; S, 7.75.
3.1.24. tert-Butyl {1-[2-(4-methoxyphenyl)ethyl]cyclopropyl}acetate
and tert-butyl [2-(4-methoxybenzyl)-1-methylcyclopropyl]acetate
(20c). Colorless oil (about 4:3 mixture of two diastereomers); IR
3.1.17. tert-Butyl 3-[chloro(p-tolylsulfinyl)methyl]-3-cyclohexylbutanoate
(19g). Colorless crystals; mp 109e109.5 ꢁC (hexaneeAcOEt); IR
(KBr) 2928, 1720 (CO), 1453, 1366, 1224, 1159, 1054 (SO),
(neat) 2977, 2932,1725 (CO),1512,1367,1245,1148,1038, 821 cmꢀ1
;
809 cmꢀ1
;
1H NMR
d
1.00e1.33 (6H, m), 1.42 (3H, s), 1.46 (9H, s),
1H NMR
d
0.32 (0.4H, t, J¼5.2 Hz), 0.34e0.39 (1.2H, m), 0.43e0.48
1.61e1.77 (2H, m), 1.77e1.88 (3H, m), 2.42 (3H, s), 2.58 (1H, d,
J¼16.1 Hz), 3.00 (1H, d, J¼16.1 Hz), 5.53 (1H, s), 7.31 (2H, d,
J¼8.2 Hz), 7.79 (2H, d, J¼8.2 Hz). Anal. Calcd for C22H33ClO3S: C,
63.98; H, 8.05; Cl, 8.58; S, 7.76. Found: C, 64.15; H, 7.94; Cl, 8.40;
S, 7.70.
(1.2H, m), 0.60 (0.4H, dd, J¼8.5, 4.8 Hz), 0.83e0.93 (0.4H, m), 1.16
(1.2H, s), 1.46 (5.1H, s), 1.47 (3.9H, s), 1.55e1.64 (1.2H, m), 2.20 (1.2H,
s), 2.26 (0.8H, d, J¼4.7 Hz), 2.42 (0.4H, dd, J¼15.1, 8.5 Hz), 2.60e2.67
(1.2H, m), 2.82 (0.4H, dd, J¼15.1, 5.9 Hz), 3.77 (1.7H, s), 3.78 (1.3H, s),
6.78e6.86 (2H, m), 7.04e7.12 (1.2H, m), 7.12e7.18 (0.8H, m). MS
(FAB) m/z (%) 290 ([MþH]þ, 20), 234 (43), 173 (19), 134 (29), 121
(100), 57 (15). Calcd for C18H26O3: M, 290.1882. Found: m/z
290.1881.
3.1.18. tert-Butyl 3-[chloro(p-tolylsulfinyl)methyl]-3-cyclopropylbutanoate
(19h). Colorless oil; IR (neat) 2979, 1728 (CO), 1598, 1456, 1372,
1219, 1159, 1055 (SO), 812 cmꢀ1; 1H NMR
d 0.47e0.61 (4H, m), 1.06
(3H, s), 1.32e1.44 (1H, m), 1.47 (9H, s), 2.27 (1H, d, J¼15.2 Hz), 2.43
(3H, s), 3.22 (1H, d, J¼15.2 Hz), 5.40 (1H, s), 7.32 (2H, d, J¼8.1 Hz),
7.75 (2H, d, J¼8.1 Hz). MS (FAB) m/z (%) 371 ([MþH]þ, 25), 315 (100),
3.1.25. tert-Butyl (1-isopropylcyclopropyl)acetate (20d). Colorless
oil; IR (neat) 2964, 1728 (CO), 1463, 1368, 1256, 1144, 968,
854 cmꢀ1; 1H NMR
d
0.36 (2H, dd, J¼6.3, 4.4 Hz), 0.45 (2H, dd, J¼6.3,

H. Watanabe et al. / Tetrahedron 66 (2010) 5675e5686
5683
4.4 Hz), 0.90 (6H, d, J¼6.9 Hz), 1.27 (1H, septet, J¼6.9 Hz), 1.44 (9H,
s), 2.17 (2H, s). MS m/z (%) 198 (Mþ, trace), 142 (69), 125 (15), 97
(34), 83 (32), 57 (100). Calcd for C12H22O2: M, 198.1620. Found: m/z
198.1627.
1088, 1061 (SO), 808 cmꢀ1
;
1H NMR
d
1.23 (3H, t, J¼7.5 Hz), 2.42
(3H, s), 2.84 (2H, m), 3.33 (3H, s), 4.19 (1H, d, J¼14.0 Hz), 4.22 (1H, d,
J¼14.0 Hz), 7.32 (2H, d, J¼8.2 Hz), 7.51 (2H, d, J¼8.2 Hz). MS m/z (%)
272 (Mþ, 38), 255 (76), 223 (78), 187 (18), 139 (24), 123 (15), 105
(22), 97 (7), 91 (24), 65 (22), 45 (100). Calcd for C13H17ClO2S: M,
272.0638. Found: m/z 272.0637.
3.1.26. tert-Butyl (1,2,2-trimethylcyclopropyl)acetate (20e). Color-
less oil; IR (neat) 2980, 1732 (CO), 1458, 1368, 1258, 1163, 963 cmꢀ1
;
1H NMR
d
0.17 (1H, d, J¼4.5 Hz), 0.26 (1H, d, J¼4.5 Hz), 1.10 (3H, s),
3.1.35. tert-Butyl
3-[chloro(p-tolylsulfinyl)methyl]-3-methoxy-
1.11 (3H, s), 1.15 (3H, s), 1.46 (9H, s), 2.18 (1H, d, J¼15.6 Hz), 2.36 (1H,
d, J¼15.6 Hz). MS m/z (%) 198 (Mþ, trace), 142 (85), 125 (11), 97 (40),
83 (100), 57 (78). Calcd for C12H22O2: M, 198.1620. Found: m/z
198.1615.
methylpentanoate (24). Colorless oil; IR (neat) 2980, 2929, 1720
(CO), 1456, 1392, 1367, 1216, 1151, 1113, 1083, 1050 (SO), 812,
755 cmꢀ1
;
1H NMR
d
0.98 (3H, t, J¼7.6 Hz), 1.45 (9H, s), 1.75e1.88
(2H, m), 2.42 (3H, s), 2.73 (1H, d, J¼15.6 Hz), 2.95 (1H, d,
J¼15.6 Hz), 3.40 (3H, s), 3.62 (1H, d, J¼9.5 Hz), 3.81 (1H, d,
J¼9.5 Hz), 5.08 (1H, s), 7.31 (2H, d, J¼8.2 Hz), 7.72 (2H, d, J¼8.2 Hz).
MS m/z (%) 388 (Mþ, 0.1), 315 (20), 193 (40), 157 (35), 140 (100),
125 (28), 91 (10), 57 (33), 45 (38). Calcd for C19H29ClO4S: M,
388.1475. Found: m/z 388.1480.
3.1.27. tert-Butyl (1-cyclohexylcyclopropyl)acetate (20f). Colorless
oil; IR (neat) 2927, 1728 (CO), 1451, 1368, 1257, 1146, 968 cmꢀ1 1H
;
NMR
d
0.34e0.39 (2H, m), 0.40e0.45 (2H, m), 0.84 (1H, tt, J¼11.8,
3.2 Hz), 0.97e1.23 (6H, m), 1.44 (9H, s), 1.63e1.78 (4H, m), 2.16 (2H,
s). MS m/z (%) 238 (Mþ, 0.1), 223 (1), 182 (47), 154 (11), 136 (18), 122
(100), 95 (15), 81 (26), 57 (65). Calcd for C15H26O2: M, 238.1933.
Found: m/z 238.1927.
3.1.36. tert-Butyl
(1-methoxymethyl-2-methylcyclopropyl)acetate
(25). Colorless oil (about 5:1 mixture of two diastereomers); IR
(neat) 2978, 2929, 1732 (CO), 1455, 1367, 1255, 1148, 1111, 951,
3.1.28. tert-Butyl (1-methylspiro[2.5]oct-1-yl)acetate (20g). Color-
850 cmꢀ1
;
1H NMR
d
0.13 (0.83H, t, J¼5.3 Hz), 0.20 (0.17H, t,
less oil; IR (neat) 2927, 1732 (CO), 1446, 1368, 1254, 1156, 960 cmꢀ1
;
J¼5.3 Hz), 0.64 (0.83H, dd, J¼8.5, 4.9 Hz), 0.67 (0.17H, dd, J¼8.5,
4.9 Hz), 0.76e0.92 (1H, m), 1.09 (2.5H, d, J¼6.3 Hz), 1.11 (0.5H, d,
J¼6.3 Hz),1.45 (1.5H, s), 1.46 (7.5H, s), 2.17 (0.17H, d, J¼15.0 Hz), 2.27
(0.83H, d, J¼16.0 Hz), 2.29 (0.17H, d, J¼15.0 Hz), 2.40 (0.83H, d,
J¼16.0 Hz), 3.19 (0.83H, d, J¼10.0 Hz), 3.30 (0.83H, d, J¼10.0 Hz),
3.31 (2.5H, s), 3.34 (0.5H, s), 3.34 (0.17H, d, J¼10.1 Hz), 3.46 (0.17H,
d, J¼10.1 Hz). MS m/z (%) 158 ([MꢀC4H9]þ, 62), 141 (22), 126 (38),
116 (73), 99 (29), 81 (33), 71 (57), 57 (100), 45 (22).
1H NMR
d
0.15 (1H, d, J¼4.5 Hz), 0.25 (1H, d, J¼4.5 Hz), 1.15 (3H, s),
1.23e1.62 (10H, m), 1.46 (9H, s), 2.23 (1H, d, J¼15.7 Hz), 2.32 (1H, d,
J¼15.7 Hz). MS m/z (%) 238 (Mþ, 0.1), 223 (1), 182 (65), 164 (22), 137
(14), 122 (100), 95 (17), 81 (35), 57 (33). Calcd for C15H26O2: M,
238.1932. Found: m/z 238.1940.
3.1.29. tert-(Butyl (1-cyclopropy)cyclopropyl)acetate (20h). Color-
less oil; IR (neat) 2979,1732 (CO),1458,1368,1257,1146,1018 cmꢀ1
;
1H NMR
d
ꢀ0.04e0.01 (2H, m), 0.23e0.29 (2H, m), 0.29e0.35 (4H,
3.1.37. tert-Butyl
3-[chloro(p-tolylsulfinyl)methyl]-3-methoxy-
m), 1.18 (1H, m), 1.47 (9H, s), 2.25 (2H, s). MS m/z (%) 196 (Mþ, 0.1),
181 (1), 140 (60), 125 (15), 95 (53), 79 (25), 57 (100). Calcd for
C12H20O2: M, 196.1463. Found: m/z 196.1462.
methylpentanoate (26). Colorless oil; IR (neat) 2978, 2927, 1722
(CO), 1458, 1392, 1367, 1254, 1218, 1153, 1115, 1083, 1054 (SO), 811,
755 cmꢀ1
;
1H NMR
d
1.03 (3H, t, J¼7.6 Hz), 1.46 (9H, s), 1.97 (1H,
dq, J¼14.8, 7.4 Hz), 2.03 (1H, dq, J¼14.8, 7.4 Hz), 2.42 (3H, s), 2.63
(1H, d, J¼15.0 Hz), 2.96 (1H, d, J¼15.0 Hz), 3.31 (3H, s), 3.56 (1H,
d, J¼9.3 Hz), 3.58 (1H, d, J¼9.3 Hz), 5.22 (1H, s), 7.31 (2H, d,
J¼8.3 Hz), 7.75 (2H, d, J¼8.3 Hz). MS m/z (%) 388 (Mþ, 0.3), 315
(22), 193 (32), 184 (16), 157 (36), 140 (100), 125 (29), 91 (11), 57
(36), 45 (50). Calcd for C19H29ClO4S: M, 388.1475. Found: m/z
388.1471.
3.1.30. tert-Butyl 4-cyclopropyl-3-methyl-3-butenoate (20i). Color-
less oil; IR (neat) 2978, 1732 (CO), 1459, 1368, 1295, 1151, 951 cmꢀ1
;
1H NMR
d
0.31 (2H, dt, J¼6.2, 4.4 Hz), 0.67e0.72 (2H, m), 1.41e1.49
(1H, m), 1.45 (9H, s), 1.75 (3H, d, J¼1.2 Hz), 3.07 (2H, d, J¼0.5 Hz),
4.74 (1H, br d, J¼9.1 Hz). MS m/z (%) 196 (Mþ, 0.4),140 (67),123 (12),
111 (28), 95 (69), 81 (17), 57 (100). Calcd for C12H20O2: M, 196.1464.
Found: m/z 196.1467.
The starting ketones for the synthesis of 31cef were synthesized
as follows.
3.1.31. tert-Butyl (1-vinylcyclopropyl)acetate (20j). Colorless oil; IR
(neat) 2979, 1732 (CO), 1638, 1458, 1368, 1357, 1146, 992, 901 cmꢀ1
;
3.1.38. 1-Phenoxy-2-butanone. To a solution of phenol (2.82 g;
30 mmol) and sodium hydroxide (1.20 g; 30 mmol) in 60 mL of
water at room temperature was added 1,2-epoxybutane
(7.75 mL; 90 mmol) dropwise with stirring. After 2 days, the
reaction was quenched with satd aq NH4Cl. The whole was
extracted with CHCl3. The organic layer was washed with satd
aq NH4Cl and dried over MgSO4. The solvent was evaporated to
afford crude alcohol. To a solution of the crude alcohol in
150 mL of DMSO in a flame-dried flask at room temperature
under argon atmosphere was added Et3N (20.9 mL; 150 mmol)
dropwise with stirring. After 10 min, sulfur trioxide pyridine
complex (98%, 14.6 g; 90.0 mmol) was added to the reaction
mixture with stirring. After 1 h, the reaction mixture was diluted
with ether and the reaction was quenched with satd aq NH4Cl.
The whole was extracted with benzene. The organic layer was
washed with satd aq NH4Cl and dried over MgSO4. The solvent
was evaporated and the residue was purified by silica gel col-
umn chromatography to afford 1-phenoxy-2-butanone (4.46 g;
90%) as colorless oil; IR (neat) 3064, 3043, 2979, 2939, 1732
(CO), 1599, 1495, 1457, 1434, 1293, 1246, 1161, 1084, 754,
1H NMR
d 0.68e0.72 (2H, m), 0.73e0.78 (2H, m), 1.44 (9H, s), 2.33
(2H, s), 4.91 (1H, dd, J¼10.7, 0.9 Hz), 4.96 (1H, dd, J¼17.4, 0.9 Hz), 5.53
(1H, dd, J¼17.4,10.7 Hz). MS m/z (%) 182 (Mþ, 2),126 (66),109 (21), 81
(45), 57 (100). Calcd for C11H18O2: M,182.1307. Found: m/z 182.1304.
3.1.32. tert-Butyl 3-methylhexa-3,5-dienoate (21). Colorless oil; IR
(neat) 2979, 1731 (CO), 1368, 1253, 1151 cmꢀ1 1H NMR
; d 1.44 (9H,
s), 1.86 (3H, s), 3.08 (2H, s), 5.04 (1H, d, J¼10.6 Hz), 5.14 (1H, d,
J¼16.9 Hz), 5.99 (1H, br d, J¼10.8 Hz), 6.54 (1H, dt, J¼16.7, 10.6 Hz).
3.1.33. (E)-1-Chloro-2-methoxymethylbut-1-enyl p-tolyl sulfoxide
((E)-23). Colorless oil; IR (neat) 2976, 2931, 2876, 1493, 1460, 1190,
1088, 1061 (SO), 811 cmꢀ1; 1H NMR
d
1.08 (3H, t, J¼7.6 Hz), 2.44 (2H,
m), 2.41 (3H, s), 3.44 (3H, s), 4.31 (1H, d, J¼11.3 Hz), 4.54 (1H, d,
J¼11.3 Hz), 7.31(2H, d,J¼8.2 Hz), 7.51(2H, d,J¼8.2 Hz).MSm/z(%) 272
(Mþ,1), 255 (100), 223 (32),139 (7),123 (5), 97 (12), 91 (8), 79 (10), 65
(7), 45 (19). Calcd for C13H17ClO2S: M, 272.0638. Found: m/z 272.0637.
3.1.34. (Z)-1-Chloro-2-methoxymethylbut-1-enyl p-tolyl sulfoxide
((Z)-23). Colorless oil; IR (neat) 2976, 2933, 2875, 1492, 1455, 1193,
691 cmꢀ1
;
1H NMR
d
1.11 (3H, t, J¼7.3 Hz), 2.64 (2H, q, J¼7.3 Hz),

5684
H. Watanabe et al. / Tetrahedron 66 (2010) 5675e5686
4.56 (2H, s), 6.85e6.93 (2H, m), 6.96e7.04 (1H, m), 7.24e7.35
(2H, m).
IR (KBr) 2969, 1598, 1498, 1230, 1084, 1058 (SO), 1014, 813, 757 cmꢀ1
1H NMR
3.24 (1H, septet, J¼6.9 Hz), 4.70 (1H, d, J¼10.1 Hz), 5.17 (1H, d,
J¼10.1 Hz), 6.94e7.09 (3H, m), 7.29e7.40 (4H, m), 7.58e7.66 (2H, m).
Anal. Calcd for C19H21ClO2S: C, 65.41; H, 6.07; Cl, 10.16; S, 9.19. Found:
C, 65.48; H, 5.91; Cl, 10.12; S, 9.26.
;
d
1.13 (3H, d, J¼6.9 Hz), 1.15 (3H, d, J¼6.9 Hz), 2.42 (3H, s),
3.1.39. 3-Methyl-1-phenoxy-2-butanone. To a solution of N,O-dime-
thylhydroxylamine hydrochloride (98%, 2.99 g; 30 mmol) and Et3N
(5 mL; 36 mmol) in 100 mL of THF was added phenoxyacetyl chloride
(98%, 4.97 mL; 36 mmol) dropwise with stirring at 0 ꢁC. The reaction
mixture was stirred at 0 ꢁC for 5 min and at room temperature for
overnight. The reactionwas quenched with satd aq NH4Cl. The whole
was extracted with CHCl3. The organic layer was washed with satd aq
NH4Cl and dried over MgSO4. The solvent was evaporated and the
residue was roughly purified by silica gel column chromatography to
afford the Weinreb amide. To a solution of the Weinreb amide in
100 mL dry THF in a flame-dried flask at0 ꢁC underargonatmosphere
was added a solution of i-PrMgCl (2.0 M solution in THF; 30 mL;
60 mmol) dropwise with stirring. The reaction mixture was stirred at
0 ꢁC for 5 min and at room temperature for 10 min. A solution of
i-PrMgCl(2.0 M solution inTHF; 7.5 mL;15 mmol)wasadded again to
the reaction mixture with stirring. After 20 min, the reaction was
quenched with satd aq NH4Cl. The whole was extracted with CHCl3.
The organic layer was washed with satd aq NH4Cl and dried over
MgSO4. The solvent was evaporated and the residue was purified by
silica gel column chromatography to afford 3-methyl-1-phenoxy-2-
butanone (4.46 g; 90%) as colorless oil; IR (neat) 2973,1731 (CO),1717,
3.1.45. (Z)-1-Chloro-3-methyl-2-phenoxymethylbut-1-enyl
p-tolyl
sulfoxide (31f). Colorless crystals; mp 88e89 ꢁC (hexaneeAcOEt);
IR (KBr) 2977, 2960, 1596, 1494, 1200, 1088, 1055 (SO), 1035, 800,
752 cmꢀ1
;
1H NMR
d
1.28 (3H, d, J¼6.9 Hz), 1.32 (3H, d, J¼6.9 Hz),
2.43 (3H, s), 3.83 (1H, septet, J¼6.9 Hz), 4.71 (1H, d, J¼11.4 Hz), 4.79
(1H, d, J¼11.4 Hz), 6.84e6.93 (2H, m), 6.93e7.02 (1H, m), 7.22e7.38
(4H, m), 7.49e7.57 (2H, m). Anal. Calcd for C19H21ClO2S: C, 65.41; H,
6.07; Cl, 10.16; S, 9.19. Found: C, 65.49; H, 5.84; Cl, 10.05; S, 9.12.
3.1.46. tert-Butyl
3-[chloro(p-tolylsulfinyl)methyl]-3-phenoxy-
methylbutanoate (32a). Colorless oil; IR (neat) 2978, 2932, 1723
(CO), 1599, 1496, 1470, 1366, 1244, 1149, 1081, 1054(SO), 812, 754,
691 cmꢀ1; 1H NMR
d 1.40 (9H, s), 1.50 (3H, s), 2.42 (3H, s), 2.69 (1H,
d, J¼15.8 Hz), 3.09 (1H, d, J¼15.8 Hz), 4.25 (1H, d, J¼9.2 Hz), 4.47
(1H, d, J¼9.2 Hz), 5.17 (1H, s), 6.91e7.02 (3H, m), 7.22e7.36 (4H, m),
7.68e7.75 (2H, m). MS m/z (%) 436 (Mþ, 0.3), 363 (21), 241 (24), 205
(30), 196 (9), 140 (100), 123 (10), 107 (54), 94 (12), 77 (14), 57 (31).
Calcd for C23H29ClO4S: M, 436.1475. Found: m/z 436.1470.
1600,1496,1245, 754 cmꢀ1; 1H NMR
septet, J¼6.9 Hz), 4.64 (2H, s), 6.85e6.93 (2H, m), 6.95e7.05 (1H, m),
7.24e7.35 (2H, m).
d
1.16 (6H, d, J¼6.9 Hz), 2.96 (1H,
3.1.47. tert-Butyl
3-[chloro(p-tolylsulfinyl)methyl]-3-phenoxy-
methylbutanoate (32b). Colorless oil; IR (neat) 2977, 2931, 1723
3.1.40. (E)-1-Chloro-2-phenoxymethyl-1-propenyl p-tolyl sulfoxide
(31a). Colorless crystals; mp 105.5e106.5 ꢁC (hexaneeAcOEt); IR
(KBr) 3055, 2947, 1599, 1498, 1241, 1085, 1055 (SO), 1016, 806,
(CO), 1599, 1496, 1471, 1392, 1367, 1302, 1243, 1138, 1081, 1055 (SO),
811, 754, 691 cmꢀ1; 1H NMR
d 1.39 (9H, s), 1.53 (3H, s), 2.43 (3H, s),
3.01 (1H, d, J¼15.5 Hz), 3.11 (1H, d, J¼15.5 Hz), 4.11 (1H, d,
J¼9.0 Hz), 4.22 (1H, d, J¼9.0 Hz), 5.18 (1H, s), 6.87e6.99 (3H, m),
7.22e7.36 (4H, m), 7.70e7.76 (2H, m). MS m/z (%) 436 (Mþ, 0.8), 363
(25), 241 (20), 205 (25),196 (11),140 (100),123 (8),107 (64), 94 (10),
77 (15), 57 (29). Calcd for C23H29ClO4S: M, 436.1475. Found: m/z
436.1469.
749 cmꢀ1; 1H NMR
d
2.15 (3H, s), 2.41 (3H, s), 4.89 (1H, d, J¼11.1 Hz),
5.20 (1H, d, J¼11.1 Hz), 6.95e7.08 (3H, m), 7.28e7.39 (4H, m),
7.46e7.53 (2H, m). MS m/z (%) 320 (Mþ, 4), 303 (100), 267 (22), 209
(26), 191 (11), 179 (30), 143 (34), 123 (20), 91 (11). Calcd for
C17H17ClO2S: M, 320.0638. Found: m/z 320.0641.
3.1.41. (Z)-1-Chloro-2-phenoxymethyl-1-propenyl p-tolyl sulfoxide
(31b). Colorless crystals; mp 93.0e93.5 ꢁC (hexaneeAcOEt); IR
(KBr) 2924, 1598, 1494, 1226, 1208, 1086, 1054 (SO), 1013, 804, 748,
3.1.48. tert-Butyl
methylpentanoate (32c). Colorless oil; IR (neat) 2976, 1723 (CO),
1599, 1496, 1367, 1243, 1146, 1081, 1056 (SO), 754 cmꢀ1 1H NMR
3-[chloro(p-tolylsulfinyl)methyl]-3-phenoxy-
;
687 cmꢀ1
;
1H NMR
d
2.36 (3H, s), 2.43 (3H, s), 4.75 (1H, d,
d
1.05 (3H, t, J¼7.6 Hz), 1.41 (9H, s), 1.95 (2H, q, J¼7.6 Hz), 2.42 (3H,
J¼14.2 Hz), 4.85 (1H, d, J¼14.2 Hz), 6.79e6.87 (2H, m), 6.94e7.03
(1H, m), 7.22e7.35 (4H, m), 7.42e7.49 (2H, m). MS m/z (%) 320 (Mþ,
21), 303 (61), 191 (43), 179 (97), 143 (100), 123 (83), 107 (33), 91
(21). Calcd for C17H17ClO2S: M, 320.0638. Found: m/z 320.0639.
s), 2.91 (1H, d, J¼16.2 Hz), 3.18 (1H, d, J¼16.2 Hz), 4.26 (1H, d,
J¼9.5 Hz), 4.39 (1H, d, J¼9.5 Hz), 5.14 (1H, s), 6.92e7.05 (3H, m),
7.23e7.36 (4H, m), 7.68e7.76 (2H, m). MS m/z (%) 450 (Mþ, 0.03),
377 (20), 255 (26), 237 (12), 219 (26), 195 (6), 159 (23), 140 (100),
125 (19),107 (58), 94 (15), 77 (18), 57 (41). Calcd for C24H31ClO4S: M,
450.1632. Found: m/z 450.1630.
3.1.42. (E)-1-Chloro-2-phenoxymethylbut-1-enyl p-tolyl sulfoxide
(31c). Colorless crystals; mp 94.5e95.0 ꢁC (hexaneeAcOEt); IR
(KBr) 2976, 2937, 1596, 1586, 1497, 1237, 1085, 1055 (SO), 1034, 807,
3.1.49. tert-Butyl
methylpentanoate (32d). Colorless oil; IR (neat) 2977, 1724 (CO),
1599, 1497, 1367, 1243, 1156, 1081, 1055 (SO), 754 cmꢀ1 1H NMR
3-[chloro(p-tolylsulfinyl)methyl]-3-phenoxy-
752 cmꢀ1; 1H NMR
d
1.14 (3H, t, J¼7.6 Hz), 2.41 (3H, s), 2.54 (2H, q,
J¼7.6 Hz), 4.85 (1H, d, J¼10.8 Hz), 5.21 (1H, d, J¼10.8 Hz), 6.95e7.08
(3H, m), 7.28e7.39 (4H, m), 7.48e7.56 (2H, m). Anal. Calcd for
C18H19ClO2S: C, 64.56; H, 5.72; Cl, 10.59; S, 9.58. Found: C, 64.55; H,
5.61; Cl, 10.56; S, 9.55.
;
d
1.11 (3H, t, J¼7.5 Hz), 1.40 (9H, s), 2.03e2.27 (2H, m), 2.43 (3H, s),
2.85 (1H, d, J¼15.6 Hz), 3.07 (1H, d, J¼15.6 Hz), 4.16 (1H, d,
J¼9.3 Hz), 4.25 (1H, d, J¼9.3 Hz), 5.32 (1H, s), 6.89e7.00 (3H, m),
7.22e7.37 (4H, m), 7.70e7.78 (2H, m). MS m/z (%) 450 (Mþ, 0.2), 377
(25), 255 (27), 237 (8), 219 (30), 196 (8), 159 (21), 140 (100), 125
(20), 107 (66), 94 (15), 77 (20), 57 (41). Calcd for C24H31ClO4S: M,
450.1632. Found: m/z 450.1632.
3.1.43. (Z)-1-Chloro-2-phenoxymethylbut-1-enyl p-tolyl sulfoxide
(31d). Colorless crystals; mp 90.0e90.5 ꢁC (hexaneeAcOEt); IR
(KBr) 2976, 2943, 1596, 1493, 1204, 1089, 1056 (SO), 1041, 802,
751 cmꢀ1
;
1H NMR
d
1.28 (3H, t, J¼7.5 Hz), 2.43 (3H, s), 2.75e3.00
(2H, m), 4.81 (1H, d, J¼14.1 Hz), 4.89 (1H, d, J¼14.1 Hz), 6.80e6.89
(2H, m), 6.94e7.03 (1H, m), 7.21e7.37 (4H, m), 7.45e7.53 (2H, m).
Anal. Calcd for C18H19ClO2S: C, 64.56; H, 5.72; Cl, 10.59; S, 9.58.
Found: C, 64.54; H, 5.60; Cl, 10.57; S, 9.60.
3.1.50. tert-Butyl
phenoxymethylpentanoate (32e). Colorless oil; IR (neat) 2976, 1725
(CO), 1242, 1144, 1057 (SO), 753 cmꢀ1 1H NMR
1.12 (3H, d,
3-[chloro(p-tolylsulfinyl)methyl]-4-methyl-3-
;
d
J¼6.9 Hz), 1.13 (3H, d, J¼6.9 Hz), 1.41 (9H, s), 2.48 (1H, septet,
J¼6.9 Hz), 2.42 (3H, s), 2.81 (1H, d, J¼16.3 Hz), 3.23 (1H, d,
J¼16.3 Hz), 4.34 (1H, d, J¼9.7 Hz), 4.40 (1H, d, J¼9.7 Hz), 5.50 (1H,
s), 6.92e7.03 (3H, m), 7.24e7.35 (4H, m), 7.77 (2H, d, J¼8.2 Hz). MS
3.1.44. (E)-1-Chloro-3-methyl-2-phenoxymethylbut-1-enyl p-tolyl sulf-
oxide (31e). Colorless crystals; mp 132.0e132.5 ꢁC (hexaneeAcOEt);

H. Watanabe et al. / Tetrahedron 66 (2010) 5675e5686
5685
m/z (%) 464 (Mþ, 0.3), 391 (19), 269 (43), 233 (28), 140 (100), 123
(10), 107 (54), 94 (19), 77 (15), 57 (42). Calcd for C25H33ClO4S: M,
464.1788. Found: m/z 464.1785.
the residue was purified by silica gel column chromatography to
afford an aminoalcohol (5.74 g; 79%). To a solution of the amino-
alcohol (2.41 g; 10 mmol) in 50 mL of DMSO in a flame-dried flask
at room temperature under argon atmosphere was added Et3N
(6.97 mL; 50 mmol) dropwise with stirring. After 10 min, sulfur
trioxide pyridine complex (98%, 4.87 g; 30 mmol) was added to the
reaction mixture with stirring. After 1 h, the reaction mixture was
diluted with ether and the reaction was quenched with satd aq
NH4Cl. The whole was extracted with benzene. The organic layer
was washed with satd aq NH4Cl and dried over MgSO4. The solvent
was evaporated and the residue was purified by silica gel column
chromatography to afford 1-diphenylamino-2-butanone (2.26 g;
94%) as colorless amorphous; IR (KBr) 2982, 1722 (CO), 1591, 1492,
3.1.51. tert-Butyl 3-[chloro(p-tolylsulfinyl)methyl]-4-methyl-3-phe-
noxymethylpentanoate (32f). Colorless oil; IR (neat) 2977, 1723
(CO), 1599, 1497, 1242, 1154, 1082, 1055 (SO), 754 cmꢀ1 1H NMR
;
d
1.15 (3H, d, J¼6.9 Hz), 1.21 (3H, d, J¼6.9 Hz), 1.41 (9H, s), 2.42 (3H,
s), 2.76 (1H, d, J¼15.7 Hz), 2.85 (1H, septet, J¼6.9 Hz), 2.98 (1H, d,
J¼15.7 Hz), 4.18 (1H, d, J¼9.6 Hz), 4.37 (1H, d, J¼9.6 Hz), 5.52 (1H, s),
6.91e7.00 (3H, m), 7.24e7.34 (4H, m), 7.73 (2H, d, J¼8.2 Hz). MS m/z
(%) 464 (Mþ, 0.4), 391 (21), 269 (48), 233 (30), 140 (100), 123 (11),
107 (54), 94 (19), 77 (16), 57 (46). Calcd for C25H33ClO4S: M,
464.1788. Found: m/z 464.1795.
1458, 1365, 1264, 1216, 1105, 752, 693 cmꢀ1 1H NMR
; d 1.05 (3H, t,
J¼7.3 Hz), 2.54 (1H, q, J¼7.3 Hz), 4.43 (2H, s), 6.90e7.04 (6H, m),
3.1.52. tert-Butyl (1-phenoxymethylcyclopropyl)acetate (33a). Col-
7.20e7.33 (4H, m).
orless oil; IR (neat) 2978, 2930, 1731 (CO), 1600, 1587, 1497, 1367,
1243, 1148, 1034, 753, 691 cmꢀ1; 1H NMR
d
0.58e0.69 (4H, m), 1.42
3.2.1. N-[3-Chloro-2-ethyl-3-(p-tolylsulfinyl)-2-propenyl]
N,N-di-
(9H, s), 2.41 (2H, s), 3.86 (2H, s), 6.86e6.96 (3H, m), 7.22e7.31 (2H,
m). MS m/z (%) 262 (Mþ, 6), 234 (5), 206 (10), 189 (16), 169 (3), 147
(10), 133 (8), 113 (24), 107 (4), 94 (100), 77 (9), 71 (10), 67 (10), 57
(36). Calcd for C16H22O3: M, 262.1569. Found: m/z 262.1571.
phenylamine (35). Yellow oil (about 1:1 mixture of two
diastereomers); IR (neat) 2975, 1589, 1495, 1244, 1087, 1058 (SO),
751, 966 cmꢀ1
;
1H NMR
d
1.07 (1.5H, t, J¼7.5 Hz), 1.13 (1.5H, t,
J¼7.5 Hz), 2.39 (1.5H, s), 2.44 (1.5H, s), 2.50 (1H, q, J¼7.5 Hz), 2.75
(0.5H, dq, J¼13.7, 7.5 Hz), 2.87 (0.5H, dq, J¼13.7, 7.5 Hz), 4.58 (0.5H,
d, J¼16.9 Hz), 4.72 (0.5H, d, J¼16.9 Hz), 4.90 (0.5H, d, J¼16.0 Hz),
5.08 (0.5H, d, J¼16.0 Hz), 6.88e7.10 (6H, m), 7.10e7.44 (8H, m). MS
m/z (%) 409 (Mþ, 16), 392 (100), 356 (23), 268 (66), 182 (81), 167
(25), 139 (11), 104 (16), 91 (10), 77 (28). Calcd for C24H24ClNOS: M,
409.1267. Found: m/z 409.1265.
3.1.53. tert-Butyl
(2-methyl-1-phenoxymethylcyclopropyl)acetate
(33b). Colorless oil (about 7:1 mixture of two diastereomers); IR
(neat) 2976, 2931, 1730 (CO),1600, 1497, 1367, 1243, 1149, 1032, 753,
691 cmꢀ1
;
1H NMR
d
0.23 (0.88H, t, J¼5.3 Hz), 0.34 (0.12H, t,
J¼5.4 Hz), 0.74e0.84 (1H, m), 0.85e1.04 (1H, m), 1.13 (2.63H, d,
J¼6.3 Hz), 1.15 (0.37H, d, J¼6.4 Hz), 1.42 (9H, s), 2.23 (0.12H, d,
J¼15.5 Hz), 2.34 (0.88H, d, J¼16.6 Hz), 2.51 (0.12H, d, J¼15.5 Hz),
2.61 (0.88H, d, J¼16.6 Hz), 3.68 (0.88H, d, J¼9.4 Hz), 3.83 (0.12H, d,
J¼9.8 Hz), 3.98 (0.88H, d, J¼9.4 Hz), 4.14 (0.12H, d, J¼9.8 Hz),
6.85e7.03 (3H, m), 7.21e7.32 (2H, m). MS m/z (%) 276 (Mþ, 5), 220
(14), 203 (13), 161 (10), 127 (74), 109 (15), 94 (100), 85 (37), 57 (29).
Calcd for C17H24O3: M, 276.1725. Found: m/z 276.1727.
3.2.2. tert-Butyl 3-[chloro(p-tolylsulfinyl)methyl]-3-[(diphenylamino)-
methyl]pentanoate (36). Yellow oil (about 2:1 mixture of two di-
astereomers); IR (neat) 2978, 1723 (CO), 1589, 1494, 1368, 1245, 1217,
1154, 1052 (SO), 753, 702 cmꢀ1; 1H NMR
d
0.99 (1H, t, J¼7.6 Hz), 1.07
(2H, t, J¼7.6 Hz), 1.24 (6H, s), 1.38 (3H, s), 1.97e2.14 (0.67H, m),
1.97e2.37 (1.33H, m), 2.42 (3H, s), 2.65 (0.67H, d, J¼17.9 Hz), 2.74
(0.33H, d, J¼17.3 Hz), 2.76 (0.67H, d, J¼17.9 Hz), 3.07 (0.33H, d,
J¼17.3 Hz), 4.18 (0.33H, d, J¼15.4 Hz), 4.44 (0.33H, d, J¼15.4 Hz),
4.55 (0.67H, d, J¼15.5 Hz), 4.74 (0.67H, d, J¼15.5 Hz), 5.18 (0.67H, s),
5.44 (0.33H, s), 6.93e7.15 (6H, m), 7.22e7.34 (6H, m), 7.63e7.73 (2H,
m). MS m/z (%) 525 (Mþ, 2), 452 (2), 294 (4), 182 (100), 139 (3), 104
(4), 77 (5). Calcd for C30H36ClNO3S: M, 525.2104. Found: m/z
525.2111.
3.1.54. tert-Butyl (2,2-dimethyl-1-phenoxymethylcyclopropyl)acetate
(33c). Colorless crystals, mp 54.5e55 ꢁC (pentane); IR (KBr) 2977,
1730 (CO), 1602, 1502, 1471, 1367, 1241, 1212, 1156, 1136, 1010,
754 cmꢀ1
;
1H NMR
d
0.46 (1H, d, J¼5.0 Hz), 0.58 (1H, d, J¼5.0 Hz),
1.18 (3H, s), 1.20 (3H, s), 1.42 (9H, s), 2.44 (1H, d, J¼16.6 Hz), 2.65
(1H, d, J¼16.6 Hz), 4.03 (2H, s), 6.86e6.96 (3H, m), 7.22e7.32 (2H,
m). MS m/z (%) 290 (Mþ, 1), 234 (8), 217 (7), 195 (5), 141 (100), 123
(57), 94 (72), 81 (12), 77 (7), 57 (32). Calcd for C18H26O3: M,
290.1882. Found: m/z 290.1881.
3.2.3. tert-Butyl {1-[(Diphenylamino)methyl]-2-methylcyclopropyl}
acetate (37). Yellow oil; IR (neat) 2978, 2930, 1728 (CO), 1590, 1498,
1367, 1239, 1211, 1147, 747, 698 cmꢀ1
;
1H NMR
d
ꢀ0.05 (1H, t,
3.1.55. tert-Butyl (1-isopropyl-2-phenoxycyclopropyl)acetate (34).
J¼5.4 Hz), 0.46 (1H, dd, J¼8.8, 4.9 Hz), 0.51e0.63 (1H, m), 0.91 (3H,
d, J¼6.2 Hz), 1.48 (9H, s), 2.38 (2H, s), 3.74 (1H, d, J¼14.8 Hz), 3.93
(1H, d, J¼14.8 Hz), 6.90e7.02 (6H, m), 7.19e7.30 (4H, m). MS m/z (%)
351 (Mþ, 68), 295 (16), 278 (15), 208 (13), 196 (20), 182 (65), 169
(100), 127 (11), 104 (12), 85 (15), 77 (14), 57 (13). Calcd for
C23H29NO2: M, 351.2198. Found: m/z 351.2199.
Colorless oil; IR (neat) 2966, 2932, 1728 (CO), 1600, 1494, 1367,
1239, 1147, 752 cmꢀ1; 1H NMR
d 0.91e1.04 (9H, m), 1.43 (9H, s), 2.27
(1H, d, J¼16.0 Hz), 2.47 (1H, dd, J¼16.0, 0.94 Hz), 3.49 (1H, dd, J¼6.1,
3.9 Hz), 6.90e7.07 (3H, m), 7.23e7.32 (2H, m). MS m/z (%) 290 (Mþ,
1), 234 (56), 217 (17), 191 (100), 141 (38), 131 (70), 123 (17), 94 (55),
57 (26). Calcd for C18H26O3: M, 290.1882. Found: m/z 290.1888.
Acknowledgements
3.2. 1-Diphenylamino-2-butanone, the starting material for
the synthesis of 35 was synthesized as follows
This work was supported by a Grant-in-Aid for Scientific Re-
search No. 19590018 from the Ministry of Education, Culture,
Sports, Science and Technology, Japan, and TUS Grant for Research
Promotion from Tokyo University of Science, which are gratefully
acknowledged.
To a solution of diphenylamine (11.8 g; 60 mmol) in 100 mL of
dry THF in a flame-dried flask at 0 ꢁC under argon atmosphere was
added a solution of n-BuLi (1.59 M solution in hexane, 38 mL;
60 mmol) dropwise with stirring. After 5 min, 1,2-epoxybutane
(2.58 mL; 30 mmol) was added to the reaction mixture dropwise at
0 ꢁC and the reaction mixture was stirred at room temperature for
30 min. The reaction was quenched with satd aq NH4Cl. The whole
was extracted with CHCl3. The organic layer was washed with satd
aq NH4Cl and dried over MgSO4. The solvent was evaporated and
References and notes
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