Synthesis of conjugated enynes from ketones and aldehydes by 1,2-CC insertion and 1,2-CH insertion of carbenoids as the key reactions

Article abstract of DOI:10.1016/j.tet.2011.02.079

The addition reactions of 1-chlorovinyl p-tolyl sulfoxides, which were derived from ketones and chloromethyl p-tolyl sulfoxide, with lithium acetylides gave adducts in moderate to good yields. Treatment of the adducts with Grignard reagents resulted in th

Full text of DOI:10.1016/j.tet.2011.02.079

Tetrahedron 67 (2011) 3081e3090
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Synthesis of conjugated enynes from ketones and aldehydes by 1,2-CC insertion
and 1,2-CH insertion of carbenoids as the key reactions
*
Naoyuki Ishida, Hideki Saitoh, Simpei Sugiyama, 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:
Received 11 January 2011
Received in revised form 25 February 2011
Accepted 28 February 2011
Available online 5 March 2011
The addition reactions of 1-chlorovinyl p-tolyl sulfoxides, which were derived from ketones and chlor-
omethyl p-tolyl sulfoxide, with lithium acetylides gave adducts in moderate to good yields. Treatment of
the adducts with Grignard reagents resulted in the formation of conjugated enynes in good to high yields
via the 1,2-carbonecarbon insertion (1,2-CC insertion) reaction of the generated magnesium carbenoid
intermediates. On the other hand, the addition reactions of 1-chlorovinyl p-tolyl sulfoxides derived from
aldehydes with lithium acetylides directly gave conjugated enynes bearing a p-tolyl sulfinyl group at the
1-position through the 1,2-carbonehydrogen insertion (1,2-CH insertion) reaction of the generated
lithium carbenoid intermediates. These procedures provide a good way for the synthesis of multi-
substituted conjugated enynes from ketones and aldehydes.
Keywords:
Magnesium carbenoid
Lithium carbenoid
Sulfoxideemagnesium exchange reaction
Conjugated enyne
Ó 2011 Elsevier Ltd. All rights reserved.
1,2-Carbonecarbon insertion
1. Introduction
methods.9 In continuation of our studies for the chemistry and
synthetic uses of magnesium carbenoids, we recently found a ver-
Recently, conjugated enynes are of great interest in organic,
synthetic organic, and bioorganic chemistry. The enediyne anti-
cancer antibiotics, such as calicheamicine, dynemicin, and esper-
amicin, have conjugated enyne moiety as the essential structure
for their biological activities.1 Conjugated enynes are also very
important compounds in synthetic organic chemistry.2
The synthesis of conjugated enynes has received considerable
attention in these days and some methods have already been
published. The cross-coupling of vinyl halides with terminal acet-
ylenes in the presence of Pd(0) or Pd(II)/Cu is known as Sonogashira
coupling.3 Oxidative Pd(II)-catalyzed Heck-type coupling of alkynes
satile method for the synthesis of conjugated enynes starting from
ketones and aldehydes as shown in Scheme 1.
R3
TolS(O)CH2Cl
2
R1
R2
R1
R2
Cl
Li
S(O)Tol
R3 R1
R2
S(O)Tol
Cl
O
2 or 3 steps
1
4
3
R3
R3
1,2-CC
insertion
R1
R1
R2
RMgCl (in Et2O)
with a,b-unsaturated carbonyl compounds is also the method for
MgCl
Cl
the coupling of acetylenes with olefins.4 Rhodium- or palladium-
catalyzed hydroalkynylation of internal alkynes with silylacety-
lenes,5 and dimerization of terminal alkynes6 are the methods for
the synthesis of conjugated enynes from two acetylenes. Some
other methods for the synthesis of conjugated enynes have been
reported.7 We also reported a synthesis of conjugated enynes based
on the reaction of magnesium alkylidene carbenoids with lithium
acetylides.8
R2
Toluene, -78 ~ 0 °C
H
5
6
R3
R3
1,2-CH
insertion
R1
H
S(O)Tol
H
Li
(R2 = H)
R3
S(O)Tol
Cl
3
R1
Li
8
7
We have been interested in the chemistry of carbenoids, espe-
cially magnesium carbenoids, in the development of new synthetic
Scheme 1.
Thus, the addition reactions of 1-chlorovinyl p-tolyl sulfoxides 3,
synthesized from ketones 1 and chloromethyl p-tolyl sulfoxide 2,
with lithium acetylides gave adducts 4 in moderate to good yields.
* Corresponding author. Tel.: þ81 3 5228 8272; fax: þ81 3 5261 4631; e-mail
address: tsatoh@rs.kagu.tus.ac.jp (T. Satoh).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.079

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N. Ishida et al. / Tetrahedron 67 (2011) 3081e3090
Treatment of the adducts 4 with Grignard reagents resulted in the
formation of conjugated enynes 6 via the 1,2-CC insertion reaction
of the generated magnesium carbenoid intermediates 5. On the
other hand, the addition reactions of 1-chlorovinyl p-tolyl sulfox-
ides 3 (R2¼H) derived from aldehydes 1 (R2¼H) and chloromethyl
p-tolyl sulfoxide 2 with lithium acetylides directly gave conjugated
enynes bearing a p-tolyl sulfinyl group at the 1-position 8 through
the 1,2-CH insertion reaction of the generated lithium carbenoid
intermediates 7. In this paper we would like to report, in detail, the
results described above.10
(derived from phenylacetylene with n-BuLi) to give adduct 13 in
73% yield as an easily separable mixture of two diastereomers (less
polar adduct 13L and more polar adduct 13P on silica gel TLC; the
ratio 3:1, respectively). Main diastereomer 13L was treated with
5 equiv of i-PrMgCl (in ether) in toluene at ꢀ78 ꢁC to result in the
formation of magnesium carbenoid intermediate 14. The reaction
mixture was slowly allowed to warm to 0 ꢁC to give a clean reaction
mixture from which a single product was obtained. Initially, as
described above, bicyclo[4.1.0]heptane 15 was expected to be
formed by the 1,3-CH insertion reaction of magnesium carbenoid
14.12 However, very interestingly, the product had an olefinic
hydrogen and was confirmed to be conjugated enyne 16 (97% yield)
and no bicyclo[4.1.0]heptane 15 was observed. The same reaction of
the minor diastereomer 13P gave the same conjugated enyne 16;
however, the yield was moderate (46%). Significant difference
about the yields of 16 from diastereomers 13P and 13L was
observed; however, the real reason for this difference is still not
clear at present.10
Although the expected bicyclo[4.1.0]heptane 15 could not be
obtained, we recognized that this reaction is unprecedented and
would become quite interesting way for preparing conjugated
enynes. At first, we investigated to obtain better yield of 16 from the
minor diastereomer 13P and cyclopentylmagnesium chloride
(c-PentMgCl; in ether solution) was found to be the Grignard re-
agent of choice and 71% yield of 16 was obtained.10 We use i-PrMgCl
and c-PentMgCl for the reaction of the less polar adduct (L) and the
more polar adduct (P), respectively, throughout in this study.
Next, an investigation to find the best conditions for the addition
reaction of 3a with lithium phenylacetylide was carried out and the
results are summarized inTable 1. The conditions inentry 1 have been
mentioned already in the text. As shown in entries 2e7, the addition
reaction could be started at ꢀ30 ꢁC and somewhat better yield was
obtained (entry 2). Starting the reaction at 0 ꢁC gave diminished yield
(entry 3). Using LDA, instead of n-BuLi, as the base gave much better
yield of 13 (entry 4). Toluene and diethyl ether were proved to be
unsuitable solvents in this reaction (entries 6 and 7). As a result, we
decided that the conditions inentry 4 were the conditionsof choice in
this study.
2. Results and discussion
2.1. Synthesis of conjugated enynes from ketones with
chloromethyl p-tolyl sulfoxide and acetylenes
In our previous study, we reported the synthesis of bicyclo[n.1.0]
alkanes from ketones by 1,3-CH insertion reaction of magnesium
carbenoids as the key reaction. For example, as shown in Scheme 2,
addition reaction of 1-chlorovinyl p-tolyl sulfoxide 3a, which was
synthesized from ketone 9 with chloromethyl p-tolyl sulfoxide in
high overall yield,11 with lithium enolate of tert-butyl acetate to
give adduct 10 in quantitative yield. Treatment of adduct 10 with
i-PrMgCl resulted in the formation of magnesium carbenoid
intermediate 11, from which 1,3-CH insertion reaction took place to
afford bicyclo[4.1.0]heptane bearing a tert-butyl acetate moiety on
the bridgehead carbon 12 in quantitative yield.12
Cl
O
O
O
O
2
LiCH2COOBu-t
O
Lit. 11
S(O)Tol
3a
9
1,3-CH
insertion
i-PrMgCl
CH2COOBu-t
CH2COOBu-t
MgCl
S(O)Tol
Lit. 12
Cl
Cl
H
H
11
10
CH2COOBu-t
O
O
Table 1
Investigation for the addition reaction of lithium acetylide derived from phenyl-
acetylene to 1-chlorovinyl p-tolyl sulfoxide 3a
12
Li
Ph
H
Ph
Ph
Ph
Cl
O
O
O
O
base (5 eq)
(5 eq)
i-PrMgCl (in Et2O)
Toluene, -78 ~ 0 °C
3a
S(O)Tol
Conditions
S(O)Tol
THF, -78 °C to r.t.
73%
S(O)Tol
Cl
3a
Cl
13
13 (13L : 13P = 3:1)
Ph
Entry
Conditions
13
Ph
Temp/ꢁC
Time/h
Solvent
Base
Yield/%
1,3-CH insertion
O
O
1
2
3
4
5
6
7
ꢀ78 to rt
ꢀ30 to rt
0 to rt
ꢀ30 to rt
ꢀ30 to rt
ꢀ30 to rt
ꢀ30 to rt
3
2
1
2
2
2
2
THF
THF
THF
THF
THF
Toluene
Et2O
n-BuLi
n-BuLi
n-BuLi
LDA
LHMDS
LDA
73
75
60
MgCl
Cl
Ph
15
80
14
O
O
48
1,2-CC insertion
20a
19b
H
LDA
16
a
Starting material 3a was recovered in 69% yield.
Starting material 3a was recovered in 64% yield.
b
from 13L 97%
from 13P 46%
(71% by using c-PentMgCl)
Next, the substrate scope of this procedure was investigated
Scheme 2.
with some 1-chlorovinyl p-tolyl sulfoxides derived from symmet-
rical ketones (3bee) by using above-mentioned best conditions
and the results are summarized in Table 2. Thus, 1-chlorovinyl
p-tolyl sulfoxides 3 derived from cyclohexanone, cyclododecanone,
cyclopentadecanone, and 4-heptanone, were used as the repre-
sentative examples for the substrates and phenylacetylene was
As an application of this chemistry into the synthesis of bicyclo
[n.1.0]alkanes bearing an alkyne moiety on the bridgehead carbon,
we planned the procedure shown in Scheme 2. Thus, 1-chlorovinyl
p-tolyl sulfoxide 3a11 was treated with 5 equiv of lithium acetylide

N. Ishida et al. / Tetrahedron 67 (2011) 3081e3090
3083
Table 3
used as the representative example for the alkyne. The addition
reaction of 1-chlorovinyl p-tolyl sulfoxides derived from large
membered cyclic ketones and an acyclic ketone was not completed;
however, about 30% yield of adducts 17bed were obtained (entries
3e8). In these cases, significant amount of the staring materials
were recovered and the yields calculated based on the consumed
starting material were moderate.
Addition reaction of 3a with lithium acetylide generated from acetylenes with LDA and
the reaction of the adducts 19 with Grignard reagents to give conjugated enynes 20
R'
Acetylene
R'
RMgCl
(5 eq)
H
R'
O
O
3a
Toluene,
-78 ~ 0 °C
2 h
LDA, THF,
-30 °C ~ r.t.
2 h
S(O)Tol
H
Cl
Table 2
20
19
Addition reaction of 3 with lithium acetylide generated from phenylacetylene with
LDA followed by the treatment with Grignard reagents to give conjugated enynes 18
Entry
Acetylene
19
RMgCl
20
Ph
Ph
R’
Yield/%
Yield/%
RMgCl
(5 eq)
(diastereomeric
R1
R1
Cl
R1
R1
R1
R1
ratio)a
Li
Ph
S(O)Tol
Cl
S(O)Tol
THF, -30 °C to
r.t., then at r.t.
for 30 min
Toluene,
-78 to 0 °C,
2 h
H
20a 93
(from 19aL)
3
17
18
1
2
19a 69b
i-PrMgCl
CH3
Entry
3
R1
17
RMgCl
18
(2:1)
c-PentMgCl
20a 54
Yield/%
Yield/%
(from 19aP)
(diastereomeric
ratio)a
20b 93
(from 19bL)
1
2
3
4
5
6
7
8
3b e(CH2)5ꢀ
17a 73 (2:1)
17b 36 (3:2)b
i-PrMgCl
18a 98 (from 17aL)
3
4
19b 55c
i-PrMgCl
c-PentMgCl 18a 42 (from 17aP)
i-PrMgCl 18b 93 (from 17bL)
c-PentMgCl 18b 96 (from 17bP)
i-PrMgCl 18c 91 (from 17cL)
c-PentMgCl 18c 99 (from 17cP)
i-PrMgCl 18d 98 (from 17dL)
c-PentMgCl 18d 99 (from 17dP)
3c e(CH2)11
ꢀ
OCH3
(2:1)
c-PentMgCl
20b 80
(from 19bP)
3d e(CH2)14e 17c 33 (3:2)c
17d 29 (9:2)d,e
3e CH3(CH2)2
20c 95
(from 19cL)
5
19c 66
i-PrMgCl
a
The ratio for less polar product (L) and more polar product (P) on silica gel TLC.
Starting material was recovered in 27% yield.
Starting material was recovered in 42% yield.
Starting material was recovered in 59% yield.
The reaction mixture was slowly allowed to warm from ꢀ30 ꢁC to room tem-
b
c
F
d
e
6
7
8
(2:1)
19d 77
(5:2)
dd
c-PentMgCl
i-PrMgCl
20c 56
(from 19cP)
20d 99
(from 19dL)
20d 52
(from 19dP)
eSi(CH3)3
perature for 2 h, then stirred at room temperature for 2 h.
c-PentMgCl
Treatment of adducts 17aed with Grignard reagents was con-
ducted in the same way as described above. The reaction of 17a,
which has six-membered cyclic carbon chain, showed again sig-
nificant difference in the reactivity with respect to the two
diastereomers (entries 1 and 2). Quite interestingly, in the reaction
with the adducts bearing a large cyclic carbon chain (17b,c) or
acyclic carbon chain (17d), both diastereomers gave almost quan-
titative yields of the desired conjugated enynes 18 (entries 3e8). In
other words, the differences in the reactivity appear only when the
reaction is carried out with adducts 17 derived from medium-sized
cyclic ketones. From the results shown in Table 2, the generality of
this procedure was verified.
Further, substrate scope about the alkynes was investigated with
1-chlorovinyl p-tolyl sulfoxide 3a and the results are summarized in
Table 3. The addition reaction of lithium acetylides derived from
arylacetylenes and (trimethylsilyl)acetylene with 1-chlorovinyl
p-tolyl sulfoxide 3a proceeded smoothly to afford moderate to good
yields of adducts 19aed (entries 1e8). However, quite interestingly,
addition reaction of lithium acetylide derived from an alkylacety-
lene, 4-phenyl-1-butyne, with 3a did not proceed at all (entry 9).
Generation of the magnesium carbenoids from the adducts was
conducted with i-PrMgCl or c-PentMgCl, and similar results (less
polar adducts gave almost quantitative yields of conjugated enynes
20 and more polar adducts gave somewhat lower yields) were ob-
served (compare the results inTable 3 with those shown in Scheme 2
and Table 2, entries 1 and 2).
9
eCH2CH2Ph
a
The ratio for less polar product (L) and more polar product (P) on silica gel TLC.
The reaction mixture was slowly allowed to warm from ꢀ30 ꢁC to room tem-
b
perature for 2 h and then stirred for 30 min at the temperature.
c
Starting material was recovered in 15% yield.
No addition reaction was observed.
d
Representative procedure from 19d is reported as shown in
Scheme 3. Thus, trimethylsilyl groups of adduct 19dL and 19dP were
cleaved with potassium carbonate in methanol to give terminal
acetylene 21L and 21P, respectively, in almost quantitative yields. At
first, alkynes 21 were treated with 1.2 equiv of LDA (to remove the
acidic hydrogen on the terminal acetylene) to give lithium acety-
lides. The lithium acetylide derived from 21L was treated with
5 equiv of i-PrMgCl to give smoothly the desired conjugated enyne
23 in 97% yield by the 1,2-CC insertion of the generated magnesium
carbenoid intermediate 22L. In the same way, the treatment of 21P
with LDA followed by c-PentMgCl gave 23 in 77% yield.
As mentioned in Table 3 entry 9, the addition reaction of lithium
acetylide derived from an alkylacetylene to 1-chlorovinyl p-tolyl
sulfoxide 3a did not proceed. This result implied that by the pre-
sented procedure conjugated enynes bearing an alkyl group on the
acetylenic carbon could not be obtained. To overcome this problem,
we tried to alkylate the aforementioned conjugated enyne bearing
a terminal acetylenic group 23. The results for the treatment of 23
with n-BuLi followed by electrophiles including iodoalkanes are
summarized in Table 4.
As the addition reaction of 1-chlorovinyl p-tolyl sulfoxides with
lithium acetylide itself did not give the desired adducts, the conju-
gated enynes without a substituent on the acetylenic carbon was
synthesized from the adducts with (trimethylsilyl)acetylene.
Thus, at first, conjugated enyne 23 was treated with 2 equiv of n-
BuLi followed by 5 equiv of iodomethane in THF at 0 ꢁC and the

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N. Ishida et al. / Tetrahedron 67 (2011) 3081e3090
Table 5
TMS
H
Synthesis of conjugated enynes 27 from 1-chlorovinyl p-tolyl sulfoxides 25 derived
from unsymmetrical ketone, 3-methylcyclohexanone
LDA (1.2 eq), then
RMgCl (5 eq)
O
O
K2CO3
MeOH
95%
Ph
Toluene
-78 ~ 0 °C
H
Ph
Cl
19d
S(O)Tol
Cl
21
S(O)Tol
Cl
(5 eq)
H
Li
S(O)Tol
S(O)Tol
LDA, THF, -30 °C
to r.t., 2 h
Me
Me
Me
1,2-CC insertion
O
O
Cl
25
26
Ph
97% (from 21L)
77% (from 21P)
H
MgCl
Cl
23
RMgCl
H
22
+
Toluene
-78 to 0 °C, 2 h
Scheme 3.
H
Me H H
NOESY
27Z
Table 4
Ph
H-H COSY
27E
Synthesis of conjugated enynes 24 by treatment of 23 with n-BuLi followed by
electrophiles
H
E
Entry
25
26 Yield/%
(diastereomeric
ratio)a
RMgCl
27
Yield % (E:Z)b
1) n-BuLi (2 eq)
2) Electrophile (5 eq)
O
O
O
O
THF
Conditions
H
H
(1:14)c
(9:1)d
Cl
1
2
3
i-PrMgCl
92
24
23
26a 70 (3:2)
S(O)Tol
Entry Electrophile Additive
Conditions
Temp ꢁC Time
24
c-PentMgCl 88
Me
Me
25E
E
Yield/%
1
2
3
4
5
6
7
CH3I
CH3CH2I
non
0
30 min CH3
24a 69
24b 52
CH3(CH2)5 24c 82
24d 64
(20:1)c
(1:16)d
S(O)Tol
Cl
i-PrMgCl
98
HMPA (6 equiv) rt
12 h
12 h
CH3CH2
CH3(CH2)5I HMPA (6 equiv) rt
26b 76 (3:2)
PhCOCl
non
0
0
0
0
30 min PhCO
4
c-PentMgCl 85
25Z
ClCOOC2H5 non
30 min COOC2H5 24e 57
30 min PhCH(OH) 24f 65
a
PhCHO
I2
non
non
The ratio for less polar product (L) and more polar product (P) on silica gel TLC.
The ratio of E/Z was determined by 1H NMR.
The yield from less polar adduct.
b
c
30 min
I
24g 79
d
The yield from more polar adduct.
reaction mixture was stirred at 0 ꢁC for 30 min to give conjugated
enyne bearing a methyl group on the acetylenic carbon 24a in 69%
yield (entry 1). The alkylation with iodoethane and 1-iodohexane
required somewhat forcing conditions. In these cases, HMPA was
found to be an effective additive and the desired conjugated enynes
having ethyl (24b) or n-hexyl group (24c) were obtained in mod-
erate to good yields (entries 2 and 3). The reaction with benzoyl
chloride and ethyl chloroformate gave the desired products 24d
and 24e, respectively, in up to 64% yield (entries 4 and 5). Benzal-
dehyde reacted with the lithium acetylide to give adduct 24f in 65%
yield (entry 6). Iodoacetylene 24g could be obtained in 79% yield by
adding iodine in the reaction mixture (entry 7).
Next, we investigated this procedure starting with an un-
symmetrical ketone, 3-methylcyclohexanone, and the results are
summarized inTable 5. Thus, geometrical isomers 25E and 25Z were
synthesized from 3-methylcyclohexanone in the same way as de-
scribed above11 in high overall yield. The structure of both isomers
was easily determined by 1H NMR (HeH COSY spectra and chemical
shift of the allylic hydrogen11a). 1-Chlorovinyl p-tolyl sulfoxide 25E
was treated with lithium acetylide of phenylacetylene to afford ad-
ducts 26aL and 26aP (26aL/26aP¼3:2) in 70% yield. In the same
manner, treatment of 25Z with lithium acetylide of phenylacetylene
afforded adducts 26bL and 26bP (26aL/26aP¼3:2) in 76% yield.
The sulfoxideemagnesium exchange reaction of 26aL with
5 equiv of i-PrMgCl in toluene smoothly afforded the desired con-
jugated enyne 27 in 92% yield (entry 1). Somewhat surprisingly, the
product was a mixture of two geometrical isomers and the ratio of
27E to 27Z was found to be 1:14, respectively. Treatment of 26aP
with c-PentMgCl gave conjugated enyne 27 in 88% yield as a mixture
of two geometrical isomers, 27E and 27Z. In this case, the ratio of 27E
to 27Z was found to be 9:1, respectively (entry 2). Obviously, rela-
tively high stereospecificity was obtained. Higher stereospecificity
was observed in the reaction of 26bL and 26bP with Grignard
reagents as shown in entries 3 and 4 in Table 5. The specificity of the
reactions is very interesting; however, we still find it very difficult to
propose a rational mechanism for explaining this specificity.
Finally, this procedure was carried out starting with
unsymmetrical ketone, 4-phenyl-3-butyn-2-one, and the results
are summarized in Scheme 4. Thus, 1-chlorovinyl p-tolyl sulfoxide
28 was synthesized from 4-phenyl-3-butyn-2-one in three steps in
92% overall yield as an equal mixture of two diastereomers. The
geometrical isomers (28E and 28Z) were easily separated by silica
gel column chromatography. Addition reaction of 28E with lithium
enolate of tert-butyl acetate gave adduct 29a in quantitative yield as
a single product. In the same way 28E gave adduct 29b in quanti-
tative yield as a single product. The products 29a and 29b are
diastereomers to each other. The configuration of the products, 29a
and 29b, was confirmed to be as shown in Scheme 4 based on the
study reported previously.12b
These two diastereomers 29a and 29b showed quite interesting
specificity in the reaction with Grignard reagent. Thus, the sulfox-
ideemagnesium exchange reaction of 29a was conducted with
5 equiv of i-PrMgCl in toluene to afford cyclopropane 30 (63%) and
the desired conjugated enyne 31 (25%) as a mixture of two geo-
metrical isomers (E/Z¼4.5:1). Obviously, cyclopropane 30 was
formed by the 1,3-CH insertion reaction of the generated magne-
sium carbenoid intermediate (between the magnesium carbenoid
and the hydrogen at the methyl group).12 In the same way, 29b was
treated with i-PrMgCl to give the desired conjugated enyne 31 in
83% yield as a mixture of two geometrical isomers (E/Z¼1:4.5) and
no cyclopropane 30 was observed.
This specificityof thereactions can be explainedas follows. Asthe
sulfoxideemagnesium exchange reaction is proved to take place

N. Ishida et al. / Tetrahedron 67 (2011) 3081e3090
3085
Ph
representative example is reported by using pivalaldehyde 32 as an
aldehyde (Scheme 5). Thus, 1-chlorovinyl p-tolyl sulfoxide 33 was
synthesized from 32 in two steps in 85% overall yield as a mixture of
easily separable two geometrical isomers (33E and 33Z).14 Main
product 33E was treated with 5 equiv of lithium acetylide, derived
from phenylacetylene with LDA, in THF and the temperature of the
reaction mixture was allowed to warm to 0 ꢁC. The reaction mixture
was very clean and a single product was obtained. Initially, we an-
ticipated that the product was adduct 36; however, the product had
an olefinic hydrogen and the structure was confirmed to be conju-
gated enyne bearing a sulfinyl group at the 1-position 35 (yield was
found to be 95%). Obviously, product 35 was produced by the 1,2-CH
insertion reaction of lithium carbenoid intermediate 34 that gen-
erated from the addition reaction of 33 with lithium acetylide.
The configuration of 35 was confirmed to be Z by NOESY spec-
trum. Neither anticipated adduct 36 nor the corresponding E iso-
mer were observed as the product. The same treatment of 33Z gave
the same product 35 in somewhat lower yield. Again, neither
anticipated adduct 36 nor the E isomer were observed. Very in-
terestingly, these reactions were found to be highly stereoselective.
The presumed mechanism of this stereoselectivity is shown in
Scheme 5. Thus, addition reaction of 33E with a carbanion is
expected to give lithium carbenoid intermediate A.12b As the
chlorine and the hydrogen atoms are trans to each other, 1,2-CH
insertion reaction (rearrangement of the hydrogen atom) would
smoothly take place to give 35 in high yield. In this event, the
acetylenic group and the sulfinyl group must be placed cis to each
other. On the other hand, the reaction of 33Z gave lithium carbe-
noid intermediate B. As the chlorine and the hydrogen atoms are cis
to each other, the 1,2-CH insertion is though to be difficult. In this
case, the configuration of the carbenoid carbon must be inverted to
give intermediate C. From this intermediate the 1,2-CH insertion
would take place to give the same product 35.
Ph
S(O)Tol
O
H3C
H3C
Cl
92%
28 (E : Z = 1 : 1)
Ph
CH3COOBu-t
S(O)Tol
Cl
H3C
COOBu-t
(5 eq.)
LDA / THF
-78 °C , 10 min.
99%
S(O)Tol
H3C
Cl
28E
Ph
Ph
29a
H
CH2
t-BuOOC
OBu-t
Mg
Ph
Ph
H
O
i-PrMgCl
(5 eq)
Cl
Cl
30 (63%)
Ph
A
Toluene
-78 to 0 °C,
2 h
CH3
Cl
H3C
t-BuOOC
OBu-t
ClMg
O
H
H
31 (25%)
B
Ph
E : Z = 4.5 : 1
Ph
CH3COOBu-t
Cl
COOBu-t
(5 eq.)
S(O)Tol
LDA / THF
-78 °C , 10 min.
98%
H3C
S(O)Tol
H3C
Cl
29b
28Z
Ph
Ph
i-PrMgCl
(5 eq.)
t-BuOOC
H3C
H3C
H
OBu-t
Mg
H
O
Toluene
Cl
Cl
Generality of this reaction was investigated and the results are
summarized in Table 6. As shown in the table, 1-chlorovinyl p-tolyl
sulfoxides 37 could be synthesized from aldehydes in good yields.
The reaction of 37 with some lithium acetylides was carried out and
again it was found that E isomer of 37 gave much better yields of
conjugated enynes 38 (entries 1e8).
-78 to 0 °C,
2 h
31 (83%)
C
E : Z = 1 : 4.5
Scheme 4. Synthesis of conjugated enynes bearing a tert-butyl acetate moiety 31 from
4-phynyl-3-butyn-2-one.
with retention of the configuration of the carbon bearing the sulfinyl
group,13 treatmentof 29awith i-PrMgCl gives magnesium carbenoid
having R -configuration. The magnesium and carbonyl oxygen atom
In conclusion, we have found that the magnesium carbenoids
bearing an acetylenic group on the b-position, which were derived
*
from ketones, gave conjugated enynes via 1,2-CC insertion reaction in
good to highyields. A highlystereospecific reactions were observed in
this case. Both conjugated enynes bearing an aromatic group and an
alkyl grouponthe acetylenic carbon can beobtained by the presented
procedure. On the other hand, the addition reactions of 1-chlorovinyl
p-tolyl sulfoxides derived from aldehydes with lithium acetylides
directly gave conjugated enynes bearing a p-tolyl sulfinyl group at the
1-position through the 1,2-CH insertion reaction of the generated
lithium carbenoid intermediates. In this case, high stereoselectivity
was observed. These procedures provide a good way for the synthesis
of multi-substituted conjugated enynes from ketones and aldehydes.
The chemistry presented here is unprecedented and would contrib-
ute to the synthesis of conjugated enynes.
of the ester group must make six-membered intermediate A, in
which the bulkiest tert-butoxy group would occupy equatorial-like
position. In this intermediate, the chlorine atom was attacked by the
CeH bond of the methyl group from back side (1,3-CH insertion
reaction) to afford cyclopropane 30. On the other hand, rearrange-
ment of the acetylenic group (1,2-CC insertion) would occur simul-
taneously via the conformation B to give conjugated enyne 31 in low
yield.
The sulfoxideemagnesium exchange reaction of 29b again gives
magnesium carbenoid having R -configuration. The magnesium
*
and carbonyl oxygen atom of the ester group must make six-
membered intermediate C, in which the acetylenic group occupies
axial position. In this case, the rearrangement of the acetylenic
group (1,2-CC insertion) is expected to be easily taken place from
back side of the carbonechlorine bond to afford conjugated enyne
31 in good yield. However, the E/Z ratio of the produced enyne 31 is
still very difficult to be rationalized.
3. Experimental
3.1. General
All melting points were measured on a Yanaco MP-S3 apparatus
and are uncorrected. 1H NMR spectra were measured in a CDCl3 so-
lution with JEOL JNM-LA 300, 500, Bruker DPX 400, and AV 600
spectrometer. Electron-impact mass spectra (MS) were obtained at
70 eV by direct insertion by HITACHI M-80B mass spectrometer. IR
spectra were recorded on a PerkineElmer Spectrum One FTIR in-
strument. Silica gel 60N (KANTO CHEMICAL) containing 0.5%
2.2. Synthesis of conjugated enynes bearing a sulfinyl group
at the 1-position from aldehydes with chloromethyl p-tolyl
sulfoxide and acetylenes
Finally, the procedure described above was developed with al-
dehydes and quite interesting results were obtained. The

3086
N. Ishida et al. / Tetrahedron 67 (2011) 3081e3090
Ph
H
TolS(O)CH2Cl
2
Cl
H
H
Cl
Ph
H
O
Li
S(O)Tol
S(O)Tol
LDA / THF
-78 to 0 °C / 3 h
2 steps, 85%
Ph
32
33 (E : Z = 14 : 3)
34
Ph
1,2-CH insertion
S(O)Tol
H
S(O)Tol
Cl
H3C
H3C CH3
95% (from 33E)
49% (from 33Z)a
NOE
36
not observed
35
a Starting material was recoverd in 51% yieid.
Ph
Ph
S(O)Tol
S(O)Tol
H
S(O)Tol
Li
H
H
Cl
H
Cl
33E
35
A
Ph
H
Ph
H
S(O)Tol
S(O)Tol
Cl
inversion
S(O)Tol
Li
Cl
33Z
Li
Cl
B
C
Scheme 5. Synthesis of conjugated enyne bearing a sulfinyl group at the 1-position 35 by the reaction of 33 with lithium phenylacetylide and the presumed mechanism for the
stereoselectivity.
3.1.1. 8-[Chloro-(p-tolylsulfinyl)methyl]-8-phenylethynyl-1,4-dioxas-
piro[4.5]decane (13). Phenylacetylene (0.055 mL; 0.5 mmol) was
added to a solution of LDA (0.5 mmol) in 1 mL of dry THF in a flame-
dried flask under argon atmosphere dropwise at 0 ꢁC with stirring.
The reaction mixture was stirred for 10 min at 0 ꢁC and cooled to
ꢀ30 ꢁC. A solution of 3a (33 mg; 0.1 mmol) in 1 mL of THF was
added to the solution and the reaction mixture was slowly allowed
to warm to room temperature for 2 h. The reaction was quenched
with satd aq NH4Cl and the whole mixture was extracted three
times with CHCl3. The organic layer was dried over MgSO4 and
concentrated in vacuo. The product was purified by flash column
chromatography (hexane/AcOEt) to give 13L (25.7 mg; 60%) as
colorless crystals and 13P (8.5 mg; 20%) as colorless oil. Compound
13L: mp 137.5e138 ꢁC (hexane/AcOEt); IR (KBr) 2957, 2884, 1152,
Table 6
Synthesis of conjugated enynes bearing a sulfinyl group at the 1-position 38 from
aldehydes and acetylenes
R2
R2
H
2 steps
H
R1
S(O)Tol
H
(5 eq)
H
R1
S(O)Tol
Cl
O
R1
LDA / THF
-78 to 0 °C / 3 h
37
38
Entry
37
R1
38
R2
Yield/%a
Yield/%
1
2
3
Ph(CH2)2
Ph(CH2)2
37aE 53
37aZ 35
37bE 32
Ph
Ph
Ph
38a 55
38a 27
38b 78
1110, 1087, 1054, 809, 758, 693 cmꢀ1; 1H NMR
d 1.75e1.93 (3H, m),
2.07e2.25 (5H, m), 2.41 (3H, s), 3.92e4.02 (4H, m), 4.40 (1H, s),
7.29e7.37 (5H, m), 7.46e7.55 (4H, m). Anal. Calcd for C24H25ClO3S:
C, 67.20; H, 5.87; Cl, 8.26; S, 7.48. Found: C, 67.06; H, 6.02; Cl, 8.14; S,
7.39. Compound 13P: IR (neat) 2954, 2883, 2232, 1164, 1107, 1083,
4
5
6
7
8
37bZ 41
33E 70
33Z 15
33E 70
33Z 15
Ph
Ph(CH2)2
Ph(CH2)2
H
H
38b 38
38c 69
db
(CH3)3C
(CH3)3C
(CH3)3C
(CH3)3C
38dc 82
1052, 809, 757, 692 cmꢀ1 1H NMR
; d 1.70e1.90 (3H, m), 1.94e2.25
38dc 9b
(4H, m), 2.40 (3H, s), 2.72e2.80 (1H, m), 3.90e4.02 (4H, m), 4.40
(1H, s), 7.27e7.34 (5H, m), 7.44e7.48 (2H, m), 7.70e7.75 (2H, m). MS
m/z (%) 428 (Mþ, 2), 289 (38), 253 (100), 167 (61), 139 (33), 99 (40).
Calcd for C24H25ClO3S: M, 428.1213. Found: m/z 428.1219.
a
Two-step overall yield from aldehydes.
Starting material was mainly recovered.
Trimethylsilylacetylene was used as the acetylene.
b
c
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 dry solvents and
reagents, THF and diethyl ether were distilled from diphenylketyl.
Diisopropylamine, toluene, and HMPA were distilled from CaH2. All
reactions involving air- or water-sensitive compounds were routinely
conducted in glassware, which was flame-dried under a positive
pressure of argon. Compounds 18a7b and 18c8 are known.
3.1.2. 8-(3-Phenylprop-2-ynylidene)-1,4-dioxaspiro[4.5]decane
(16). To a flame-dried flask under argon atmosphere was added dry
toluene (3 mL) followed by i-PrMgCl (2.0 M solution in diethyl
ether; 0.195 mL, 0.39 mmol) at ꢀ78 ꢁC. A solution of 13L (33.6 mg;
0.078 mmol) in toluene (1 mL) was added dropwise to the solution
of the Grignard reagent 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 mixture was extracted three

N. Ishida et al. / Tetrahedron 67 (2011) 3081e3090
3087
times with CHCl3. The organic layer was dried over MgSO4 and
concentrated in vacuo. The product was purified by flash column
chromatography (hexane/AcOEt) to give 16 (19.2 mg; 97%) as col-
orless oil. IR (neat) 2951, 2882, 2197, 1120, 1087, 1034, 906, 756,
7.45e7.55 (4H, m). MS m/z (%) 386 (Mþ, 11), 247 (78), 211 (49), 169
(100), 155 (56), 141 (50), 139 (58), 129 (41), 115 (78). Calcd for
C23H27ClOS: M, 386.1471. Found: m/z 386.1462.
690 cmꢀ1
;
1H NMR
d
1.72e1.79 (4H, m), 2.36e2.42 (2H, m),
3.1.7. (3-Phenylprop-2-ynylidene)cyclododecane (18b). Colorless oil;
2.63e2.68 (2H, m), 3.97e4.00 (4H, m), 5.50 (1H, s), 7.27e7.32 (3H,
m), 7.41e7.44 (2H, m). MS m/z (%) 254 (Mþ, 100), 209 (20), 192 (20),
167 (57), 153 (20), 115 (19). Calcd for C17H18O2: M, 254.1307. Found:
m/z 254.1303.
IR (neat) 2939, 2862, 2198, 1489,1469,1443, 754, 690 cmꢀ1; 1H NMR
d
1.24e1.44 (14H, m), 1.52e1.66 (4H, m), 2.18e2.24 (2H, m),
2.43e2.49 (2H, m), 5.59 (1H, s), 7.24e7.32 (3H, m), 7.40e7.43 (2H,
m). MS m/z (%) 280 (Mþ, 100), 181 (10), 167, (25), 155 (22), 128 (18),
115 (17). Calcd for C21H28: M, 280.2191. Found: m/z 280.2191.
3.1.3. 1-[Chloro(p-tolylsulfinyl)methyl]-1-phenylethynylcyclohexane
(17a). Compound 17aL; colorless crystal; mp 112.5e113 ꢁC (hex-
ane/AcOEt); IR (KBr) 2941, 2855, 1491, 1087, 1058, 813, 755, 613,
3.1.8. 1-Phenyl-4-propylhept-3-en-1-yne (18d). Colorless oil; IR
(neat) 2960, 2932, 2872, 2199, 1595, 1489, 755, 690 cmꢀ1; 1H NMR
516 cmꢀ1; 1H NMR
d
1.70e1.90 (9H, m), 2.14e2.21 (1H, m), 2.41 (3H,
d
0.92 (3H, t, J¼7.4 Hz), 0.97 (3H, t, J¼7.4 Hz), 1.41e1.61 (4H, m),
s), 4.37 (1H, s), 7.29e7.36 (5H, m), 7.48e7.54 (4H, m). Anal. Calcd for
C22H23ClOS: C, 71.24; H, 6.25; Cl, 9.56; S, 8.64. Found: C, 71.07; H,
6.21; Cl, 9.43; S, 8.54. Compound 17aP; colorless crystal; mp
85e85.5 ꢁC (hexane/AcOEt); IR (KBr) 2942, 2863, 2079, 1490, 1084,
2.07e2.15 (2H, m), 2.33e2.42 (2H, m), 5.49 (1H, s), 7.25e7.34 (3H,
m), 7.39e7.44 (2H, m). MS m/z (%) 212 (Mþ, 100), 183 (57), 169 (30),
155 (71), 141 (35), 128 (25), 115 (35). Calcd for C16H20: M, 212.1565.
Found: m/z 212.1566.
1047, 812, 755, 691, 508 cmꢀ1 1H NMR
; d 1.54e1.62 (2H, m),
1.66e1.85 (6H, m), 2.10e2.15 (1H, m), 2.40 (3H, s), 2.58e2.64 (1H,
m), 4.42 (1H, s), 7.28e7.32 (5H, m), 7.43e7.47 (2H, m), 7.71e7.75
(2H, m). Anal. Calcd for C22H23ClOS: C, 71.24; H, 6.25; Cl, 9.56; S,
8.64. Found: C, 71.21; H, 6.09; Cl, 9.45; S, 8.52.
3.1.9. 8-[Chloro(p-tolylsulfinyl)methyl]-8-(p-tolylethynyl)-1,4-diox-
aspiro[4.5]decane (19a). Compound 19aL; colorless crystal; mp
167.5e168 ꢁC (hexane/AcOEt); IR (KBr) 2954, 2880, 2101, 1509, 1151,
1112, 1055, 947, 893, 819, 704 cmꢀ1 1H NMR
; d 1.74e1.89 (3H, m),
2.08e2.22 (5H, m), 2.36 (3H, s), 2.41 (3H, s), 3.94e3.98 (4H, m), 4.40
(1H, s), 7.14 (2H, d, J¼7.9 Hz), 7.32 (2H, d, J¼7.9 Hz), 7.36e7.40 (2H,
m), 7.50e7.54 (2H, m). Anal. Calcd for C25H27ClO3S: C, 67.78; H, 6.14;
Cl, 8.00; S, 7.24. Found: C, 67.62; H, 6.28; Cl, 7.78; S, 7.15. Compound
19aP; colorless oil; IR (neat) 2954, 2883, 2231,1510,1163,1107,1082,
3.1.4. 1-[Chloro(p-tolylsulfinyl)methyl]-1-phenylethynylcyclododecane
(17b). Compound 17bL; colorless crystal; mp 119.5e120 ꢁC (hexane/
AcOEt); IR (KBr) 2926, 2861, 2113, 1596, 1490, 1468, 1443, 1079, 1060,
815, 753, 689 cmꢀ1; 1H NMR
d 1.23e1.54 (16H, m), 1.65e1.74 (2H, m),
1.78e1.86 (1H, m),1.95e2.08 (2H, m), 2.37 (3H, s), 2.39e2.47 (1H, m),
4.45 (1H, s), 7.24e7.34 (5H, m), 7.39e7.43 (2H, m), 7.71e7.75 (2H, m).
Anal. Calcd for C29H37ClOS: C, 73.90; H, 7.75; Cl, 7.79; S, 7.05. Found:
C, 73.45; H, 7.69; Cl, 8.08; S, 6.99. Compound 17bP; colorless crystal;
mp 177.5e178 ꢁC (hexane/AcOEt); IR (KBr) 2850, 1597, 1490, 1467,
1052, 816, 757 cmꢀ1 1H NMR
; d 1.68e1.88 (3H, m), 1.92e2.23 (4H,
m), 2.35 (3H, s), 2.40 (3H, s), 2.70e2.79 (1H, m), 3.93e3.98 (4H, m),
4.39 (1H, s), 7.08e7.14 (2H, m), 7.27e7.32 (2H, m), 7.32e7.37 (2H, m),
7.69e7.75 (2H, m). MS m/z (%) 442 (Mþ, 4), 379 (52), 303 (38), 276
(50), 267(100), 254 (71), 223 (30),181(79),135(47),119(36), 99(58).
Calcd for C25H27ClO3S: M, 442.1369. Found: m/z 442.1367.
1446, 1088, 1063, 811, 765, 695 cmꢀ1; 1H NMR
d 1.24e1.76 (18H, m),
1.89e2.04 (4H, m), 2.41 (3H, s), 4.31 (1H, s), 7.27e7.34 (5H, m),
7.48e7.55 (4H, m). Anal. Calcd for C29H37ClOS: C, 73.90; H, 7.75; Cl,
7.79; S, 7.05. Found: C, 73.79; H, 7.72; Cl, 7.66; S, 7.03.
3.1.10. 8-[Chloro(p-tolylsulfinyl)methyl]-8-[(4-methoxyphenyl)ethy-
nyl]-1,4-dioxaspiro[4.5]decane (19b). Compound 19bL; colorless
crystal; mp 136.5e137 ꢁC (hexane/AcOEt); IR (KBr) 2964, 2883,
3.1.5. 1-[Chloro(p-tolylsulfinyl)methyl]-1-phenylethynylcyclopenta-
decane (17c). Compound 17cL; colorless crystal; mp 107e108 ꢁC
(hexane/AcOEt); IR (KBr) 2929, 2857, 1491, 1460, 1083, 1060, 811,
2222, 1605, 1508, 1246, 1087, 1053, 830, 807 cmꢀ1 1H NMR
;
d
1.75e1.82 (2H, m), 1.84e1.88 (1H, m), 2.07e2.21 (5H, m), 2.41 (3H,
s), 3.83 (3H, s), 3.94e4.00 (4H, m), 4.39 (1H, s), 6.84e6.87 (2H, m),
7.30e7.34 (2H, m), 7.41e7.45 (2H, m), 7.50e7.53 (2H, m). Anal. Calcd
for C25H27ClO5S H2O: C, 62.95; H, 6.13; Cl, 7.43; S, 6.72. Found: C,
62.74; H, 5.69; Cl, 7.59; S, 6.87. Compound 19bP; colorless oil; IR
(neat) 2955, 2933, 2885, 1606, 1509, 1249, 1084, 1052, 733 cmꢀ1; 1H
756, 691 cmꢀ1 1H NMR
; d 1.15e1.62 (24H, m), 1.80e1.95 (2H, m),
2.03e2.11 (1H, m), 2.25e2.33 (1H, m), 2.38 (3H, s), 4.51 (1H, s),
7.25e7.31 (5H, m), 7.39e7.43 (2H, m), 7.74 (2H, d, J¼8.1 Hz). MS m/z
(%) 496 (Mþ, 8), 357 (38), 321 (95), 309 (37), 167 (59), 141 (64), 91
(100). Calcd for C31H41ClOS: M, 496.2567. Found: m/z 496.2564.
Anal. Calcd for C31H41ClOS: C, 74.89; H, 8.31; Cl, 7.13; S, 6.45. Found:
C, 74.68; H, 8.28; Cl, 7.03; S, 6.41. Compound 17cP; colorless oil; IR
NMR d 1.66e1.94 (4H, m), 1.96e2.22 (3H, m), 2.41 (3H, s), 2.68e2.78
(1H, m), 3.81 (3H, s), 3.90e4.00 (4H, m), 4.39 (1H, s), 6.80e6.87 (2H,
m), 7.27e7.33 (2H, m), 7.37e7.42 (2H, m), 7.70e7.75 (2H, m). MS m/
z (%) 458 (Mþ, 2), 395 (53), 283 (58), 307 (25), 270 (54), 242 (49),
209 (47), 197 (61), 151 (100), 139 (28), 99 (70). Calcd for
C25H27ClO4S: M, 458.1319. Found: m/z 458.1315.
(neat) 2929, 2857,2330, 1491, 1459, 1091, 1065, 809, 756, 691 cmꢀ1
1H NMR
1.25e1.60 (24H, m), 1.81e1.96 (3H, m),2.03e2.12 (1H, m)
;
d
2.40 (3H, s), 4.40 (1H, s), 7.29e7.34 (5H, m), 7.43e7.53 (4H, m). MS
m/z (%) 496 (Mþ, 17), 357 (58), 321 (100), 309 (26), 167 (59), 139
(67), 115 (46), 91(92). Calcd for C31H41ClOS: M, 496.2567. Found: m/
z 496.2559.
3.1.11. 8-[Chloro(p-tolylsulfinyl)methyl]-8-[(4-fluorophenyl)ethynyl]-
1,4-dioxaspiro[4.5]decane (19c). Compound 19cL; colorless crystal;
mp 116e116.5 ꢁC (hexane/AcOEt); IR (KBr) 2965, 2884, 1506, 1234,
3.1.6. 1-Chloro-2-phenylethynyl-2-propyl-1-(p-tolylsulfinyl)pentane
(17d). Compound 17dL; colorless oil; IR (neat) 2961, 2932, 2873,
1116, 1087, 1054, 838, 812 cmꢀ1 1H NMR
; d 1.73e1.86 (2H, m),
1.91e1.97 (1H, m), 2.04e2.23 (5H, m), 2.42 (3H, s), 3.93e4.01 (4H,
m), 4.37 (1H, s), 6.99e7.06 (2H, m), 7.33 (2H, d, J¼8.2 Hz), 7.45e7.53
(2H, m). Anal. Calcd for C24H24ClFO3S: C, 64.49; H, 5.41; Cl, 7.93; F,
4.25; S, 7.17. Found: C, 64.38; H, 5.56; Cl, 7.82; F, 4.04; S, 7.11.
Compound 19cP; colorless crystal; mp 109.5e110 ꢁC (hexane/
AcOEt); IR (KBr) 2954, 2932, 2884, 2244, 1506, 1234, 1107, 1083,
1598, 1491, 1083, 1059, 756, 691 cmꢀ1 1H NMR
; d 0.96 (3H, t,
J¼7.2 Hz), 1.02 (3H, t, J¼7.2 Hz), 1.38e1.66 (4H, m), 1.72e2.18 (4H,
m), 2.41 (3H, s), 4.64 (1H, s), 7.27e7.33 (5H, m), 7.40e7.46 (2H, m),
7.70e7.76 (2H, m). MS m/z (%) 386 (Mþ, 8), 247 (44), 211 (52), 169
(100), 155 (55), 141 (52), 139 (59), 115 (75). Calcd for C23H27ClOS: M,
386.1471. Found: m/z 386.1480. Compound 17dP; colorless oil; IR
(neat) 2960, 2932, 2873, 1492, 1090, 1065, 756, 691 cmꢀ1; 1H NMR
1052, 838, 733 cmꢀ1 1H NMR
; d 1.72e1.88 (3H, m), 1.95e2.13 (3H,
m), 2.17e2.24 (1H, m), 2.41 (3H, s), 2.71e2.79 (1H, m), 3.93e4.01
(4H, m), 4.38 (1H, s), 7.01 (2H, t, 8.6 Hz), 7.30 (2H, d, J¼8.1 Hz),
7.40e7.48 (2H, m) 7.73 (2H, d, J¼8.1 Hz). Anal. Calcd for
d
0.96 (3H, t, J¼7.2 Hz), 1.02 (3H, t, J¼7.2 Hz), 1.32e1.86 (7H, m),
2.01e2.12 (1H, m) 2.41 (3H, s), 4.48 (1H, s), 7.28e7.37 (5H, m),

3088
N. Ishida et al. / Tetrahedron 67 (2011) 3081e3090
C24H24ClFO3S: C, 64.49; H, 5.41; Cl, 7.93; F, 4.25; S, 7.17. Found: C,
64.53; H, 5.26; Cl, 7.82; F, 4.06; S, 6.89.
NMR d 1.67e1.79 (4H, m), 2.30e2.38 (2H, m), 2.55e2.63 (2H, m), 2.98
(1H, d, J¼2.2 Hz), 3.98 (4H, s), 5.27 (1H, t, J¼1.0 Hz). MS m/z (%) 178
(Mþ, 88), 163 (63), 149 (100), 119 (19), 105 (30), 99 (15), 91 (60), 86
(19). Calcd for C11H14O2: M, 178.0994. Found: m/z 178.0996.
3.1.12. 8-[Chloro(p-tolylsulfinyl)methyl]-8-[(2-trimethylsilyl)ethy-
nyl]-1,4-dioxaspiro[4.5]decane (19d). Compound 19dL; colorless
crystal; mp 164e164.5 ꢁC (hexane/AcOEt); IR (KBr) 2961, 2931,
3.1.19. 8-(But-2-ynylidene)-1,4-dioxaspiro[4.5]decane (24a). Colorless
2884, 2167, 1250, 1091, 1061, 861, 846 cmꢀ1; 1H NMR
d
0.22 (9H, s),
oil; IR (neat) 2952, 2880, 2236, 1120, 1083, 1035, 908 cmꢀ1; 1H NMR
1.65e1.80 (3H, m), 1.98e2.12 (5H, m), 2.42 (3H, s), 3.90e4.01 (4H,
m), 4.32 (1H, s), 7.33 (2H, d, J¼8.2 Hz), 7.50 (2H, d, J¼8.2 Hz). Anal.
Calcd for C21H29ClO3SSi: C, 59.34; H, 6.88; Cl, 8.34; S, 7.54; Si, 6.61.
Found: C, 59.53; H, 6.90; Cl, 8.03; S, 7.22. Compound 19dP; colorless
oil; IR (neat) 2957, 2932, 2884, 2166, 1251, 1109, 1084, 1055, 845,
d
1.66e1.75 (4H, m), 1.97 (3H, d, J¼2.3 Hz), 2.26e2.35 (2H, m),
2.50e2.58 (2H, m), 3.97 (4H, s), 5.23 (1H, t, J¼1.0 Hz). MS m/z (%) 192
(Mþ, 100), 177 (18), 163 (42), 133 (20), 119 (22), 105 (51), 91 (50). Calcd
for C12H16O2: M, 192.1150. Found: m/z 192.1149.
761 cmꢀ1
;
1H NMR
d
0.20 (9H, s), 1.64e2.10 (7H, m), 2.43 (3H, s),
3.1.20. 8-(Pent-2-ynylidene)-1,4-dioxaspiro[4.5]decane (24b). Color-
2.60e2.68 (1H, m), 3.89e4.01 (4H, m), 4.27 (1H, s), 7.28e7.34 (2H,
m), 7.67e7.73 (2H, m). MS m/z (%) 424 (Mþ, 3), 408 (11), 285 (39),
257 (25), 249 (100), 177 (17), 99 (48), 73 (77). Calcd for
C21H29ClO3SSi: M, 424.1295. Found: m/z 424.1291.
less oil; IR (neat) 2951, 2880, 1120, 1084, 1035, 907 cmꢀ1 1H NMR
;
d
1.17 (3H, t, J¼7.6 Hz), 1.67e1.74 (4H, m), 2.28e2.37 (4H, m), 2.55
(2H, dt, J¼0.8, 6.6 Hz), 3.95e3.99 (4H, m), 5.26 (1H, t, J¼1.1 Hz). MS
m/z (%) 206 (Mþ, 100), 177 (39), 133 (18), 119 (29), 105 (44), 91 (39),
77 (18). Calcd for C13H18O2: M, 206.1307. Found: m/z 206.1308.
3.1.13. 8-[3-(p-Tolyl)prop-2-ynylidene]-1,4-dioxaspiro[4.5]decane
(20a). Colorless crystal; mp 57e58 ꢁC (hexane/AcOEt); IR (KBr)
3.1.21. 8-(Non-2-ynylidene)-1,4-dioxaspiro[4.5]decane (24c). A so-
lution of 23 (20.6 mg; 0.12 mmol) in 1 mL of THF and HMPA
(0.12 mL; 0.72 mmol) was added to a solution of n-BuLi (1.57 M
solution in hexane, 0.15 mL; 0.24 mmol) in 1.3 mL of dry THF in
a flame-dried flask under argon atmosphere at 0 ꢁC and the re-
action mixture was stirred for 10 min to generate lithium acetylide.
Iodohexane (0.09 mL; 0.6 mmol) was added to the reaction mixture
dropwise with stirring and the whole mixture was stirred at room
temperature overnight. The reaction was quenched with satd aq
NH4Cl and the whole mixture was extracted three times with
CHCl3. The organic layer was dried over MgSO4 and concentrated in
vacuo. The product was purified by flash column chromatography
(hexane/AcOEt) to give 24c (25.7 mg; 82%) as light yellow oil; IR
2951, 2881, 2196, 1120, 1087, 1034, 906, 817 cmꢀ1
;
1H NMR
d
1.70e1.80 (4H, m), 2.34 (3H, s), 2.35e2.42 (2H, m), 2.61e2.68 (2H,
m), 3.96e4.01 (4H, m), 5.49 (1H, s), 7.07e7.13 (2H, m), 7.29e7.34 (2H,
m). MS m/z (%) 268 (Mþ, 100), 223 (24), 206 (16), 181 (38), 167 (33),
152 (17). Calcd for C18H20O2: M, 268.1463. Found: m/z 268.1461. Anal.
Calcd for C18H20O2: C, 80.28; H, 7.13. Found: C, 80.20; H, 7.60.
3.1.14. 8-[3-(4-Methoxyphenyl)-2-ynylidene]-1,4-dioxaspiro[4.5]dec-
ane (20b). Light yellow oil; IR (neat) 2950, 2883, 2839, 2197, 1508,
1247, 1034, 831 cmꢀ1 1H NMR
; d 1.70e1.79 (4H, m), 2.38 (2H, dt,
J¼1.1, 6.5 Hz), 2.60e2.68 (2H, m), 3.81 (3H, s), 3.98 (4H, s), 5.48 (1H,
t, J¼1.1 Hz), 6.80e6.86 (2H, m), 7.33e7.39 (2H, m). MS m/z (%) 284
(Mþ, 100), 239 (30), 222 (11), 197 (28), 183 (13), 165 (11). Calcd for
C18H20O3: M, 284.1412. Found: m/z 284.1410.
(neat) 2931, 2858, 1120, 1083, 1035, 908, 684 cmꢀ1; 1H NMR
d 0.89
(3H, t, J¼6.8 Hz), 1.24e1.59 (8H, m), 1.66e1.78 (4H, m), 2.27e2.36
(4H, m), 2.50e2.58 (2H, m), 3.97 (4H, s), 5.26 (1H, s). MS m/z (%) 262
(Mþ, 100), 233 (14), 191 (12), 147 (13), 119 (14), 105 (19), 91 (24), 80
(14). Calcd for C17H26O2: M, 262.1933. Found: m/z 262.1941.
3.1.15. 8-[3-(4-Fluorophenyl)-2-ynylidene]-1,4-dioxaspiro[4.5]dec-
ane (20c). Colorless oil; IR (neat) 2952, 2883, 2198, 1506, 1228,
1120, 1087, 853 cmꢀ1; 1H NMR
d 1.70e1.80 (4H, m), 2.35e2.42 (2H,
m), 2.80e2.87 (2H, m), 3.99 (4H, s), 5.48 (1H, s), 6.96e7.03 (2H, m),
7.37e7.43 (2H, m). MS m/z (%) 272 (Mþ, 100), 227 (19), 210 (18), 185
(59), 171 (19), 157 (11) 133 (20). Calcd for C17H17FO2: M, 272.1213.
Found: m/z 272.1211.
3.1.22. 4-(1,4-Dioxaspiro[4.5]dec-8-ylidene)-1-phenylbut-2-yn-1-
one (24d). Colorless oil; IR (neat) 2953, 2884, 2404, 2177,1640,1266,
1120, 1083, 701 cmꢀ1 1H NMR
; d 1.75e1.84 (4H, m), 2.47 (2H, dt,
J¼1.0, 6.5 Hz), 2.70e2.78 (2H, m), 4.00 (4H, s), 5.57 (1H, t, J¼1.0 Hz),
7.45e7.53 (2H, m), 7.57e7.64 (1H, m), 8.12e8.18 (2H, m). MS m/z (%)
282 (Mþ, 54), 239 (58),196 (57),181 (100),167 (87),105 (80), 86 (55),
77 (58). Calcd for C18H18O3: M, 282.1256. Found: m/z 282.1247.
3.1.16. 8-[3-(Trimethylsilyl)prop-2-ynyliden]-1,4-dioxaspiro[4.5]dec-
ane (20d). Colorless oil; IR (neat) 2955, 2883, 2144, 2124,1249,1098,
843 cmꢀ1 1H NMR
; d 0.19 (9H, s), 1.67e1.77 (4H, m), 2.32 (2H, dt,
J¼1.1, 6.5 Hz), 2.54e2.61 (2H, m), 3.97 (4H, s), 5.31 (1H, t, J¼1.1 Hz).
MS m/z (%) 250 (Mþ, 100), 235 (11), 221 (42), 191 (18), 163 (18), 73
(23). Calcd for C14H22O2Si: M, 250.1389. Found: m/z 250.1389.
3.1.23. Ethyl
(24e). Colorless oil; IR (neat) 2955, 2203, 1705, 1256, 1122, 1077,
1034 cmꢀ1; 1H NMR
(2H, dt, J¼0.9, 6.5 Hz), 2.59e2.68 (2H, m), 3.98 (4H, s), 4.24 (2H, q,
J¼7.2 Hz), 5.38 (1H, t, J¼0.9 Hz). MS m/z (%) 250 (Mþ, 18), 205 (35),
178 (16), 134 (28), 120 (100), 105 (12), 91(22), 86 (20). Calcd for
C14H18O4: M, 250.1205. Found: m/z 250.1204.
4-(1,4-dioxaspiro[4.5]dec-8-ylidene)but-2-ynoate
d
1.32 (3H, t, J¼7.2 Hz), 1.69e1.79 (4H, m), 2.40
3.1.17. 8-[Chloro(p-tolylsulfinyl)methyl]-8-ethynyl-1,4-dioxaspiro
[4.5]decane (21). Compound 21L; colorless crystal; mp 141.5e142 ꢁC
(hexane/AcOEt); IR (KBr) 3253, 2956, 2939, 2893, 2113, 1437, 1277,
1088, 1058, 808, 692 cmꢀ1; 1H NMR
d 1.72e1.80 (2H, m), 1.87e2.17
(6H, m), 2.42 (3H, s), 2.56 (1H, s) 3.90e4.01 (4H, m), 4.28 (1H, s),
7.29e7.37 (2H, m), 7.48e7.54 (2H, m). Anal. Calcd for C18H21ClO3S: C,
61.27; H, 6.00; Cl, 10.05; S, 9.09. Found: C, 61.31; H, 5.96; Cl, 9.96; S,
8.98. Compound 21P; colorless oil; IR (neat) 3294, 2955, 2931, 2886,
3.1.24. 4-(1,4-Dioxa-spiro[4.5]dec-8-ylidene)-1-phenylbut-2-yn-1-ol
(24f). Colorless oil; IR (neat) 3420, 2952, 2885, 2208, 1119, 1082,
1033, 908, 699 cmꢀ1; 1H NMR
d
1.66e1.76 (4H, m), 2.34 (2H, dt, J¼0.8,
6.4 Hz), 2.30e2.40 (1H, m), 2.52e2.62 (2H, m), 3.96 (4H, s), 5.35 (1H,
t, J¼0.8 Hz), 5.60(1H, s), 7.29e7.42(3H, m), 7.53e7.59 (2H, m). MSm/z
(%) 284 (Mþ, 84), 267 (58), 198 (74), 181 (51), 165 (60), 105 (100), 91
(46), 77 (57). Calcd for C18H20O3: M, 284.1412. Found: m/z 284.1409.
2107,1107,1036 cmꢀ1; 1H NMR
d 1.67e2.19 (7H, m), 2.43 (3H, s), 2.47
(1H, s), 2.66e2.75 (1H, m), 3.89e4.00 (4H, m), 4.29 (1H, s), 7.29e7.35
(2H, m), 7.69e7.75 (2H, m). MS m/z (%) 352 (Mþ, 9), 213 (100), 185
(60), 177 (81), 169 (24), 139 (38), 105 (60), 99 (80) 91 (58). Calcd for
C18H21ClO3S: M, 352.0900. Found: m/z 352.0886.
3.1.25. 8-(3-Iodoprop-2-ynylidene)-1,4-dioxapiro[4.5]decane
(24g). Light yellow oil; IR (neat) 2949, 2879, 1646, 1120, 1089, 1030,
3.1.18. 8-(Prop-2-ynylidene)-1,4-dioxaspiro[4.5]decane (23). Colorless
904 cmꢀ1 1H NMR
; d 1.72e1.81 (4H, m), 2.23e2.32 (4H, m), 4.00
oil; IR (neat) 3289, 2953, 2883, 2577, 2097, 1121, 1088, 686 cmꢀ1; 1H
(4H, s), 5.60 (1H, t, J¼1.0 Hz). MS m/z (%) 304 (Mþ, 25), 260 (17), 105

N. Ishida et al. / Tetrahedron 67 (2011) 3081e3090
3089
(21), 99(19), 91 (22), 71 (13). Calcd for C11H13O2I: M, 303.9960.
Found: m/z 303.9960.
(1H, tq, J¼4.2, 12.6 Hz), 1.53e1.62 (1H, m), 1.69 (1H, t, J¼12.6 Hz),
1.71e1.78 (1H, m), 1.79e1.88 (1H, m), 2.06 (1H, dt, J¼4.2, 13.2 Hz),
2.25e2.30 (1H,m), 2.96 (1H, dt, J¼13.2, 1.8 Hz), 5.44 (1H, s),
7.24e7.31 (3H, m), 7.41e7.44 (2H, m). MS m/z (%) 210 (Mþ, 100), 195
(19), 167 (36), 154 (30), 141 (18), 128 (43), 115 (31), 95 (26). Calcd for
C16H18: M, 210.1409. Found: m/z 210.1406.
3.1.26. (E)-[Chloro(p-tolylsulfinyl)methylidene]-3-methylcyclohexane
(25E). Colorless crystal; mp 153.5e154 ꢁC (hexane/AcOEt); IR (KBr)
2947, 2918, 2860, 1600, 1492, 1086, 1056, 807 cmꢀ1; 1H NMR
d 1.08
(3H, d, J¼6.6 Hz), 1.17e1.25 (1H, m), 1.36 (1H, tq, J¼4.2, 12.0 Hz),
1.57e1.67 (1H, m), 1.78e1.85 (1H, m), 1.89 (1H, dt, J¼13.8, 4.2 Hz),
1.97e2.05 (2H, m), 2.41 (3H, s), 2.82e2.88 (1H, m), 3.36 (1H, dquint,
J¼13.8,1.8 Hz), 7.28e7.35 (2H, m), 7.44e7.50 (2H, m). Anal. Calcd for
C15H19ClOS: C, 63.70; H, 6.77; Cl, 12.53; S, 11.34. Found: C, 63.69; H,
6.77; Cl, 12.54; S, 11.33.
3.1.31. (E)-1-Chloro-2-methyl-4-phenyl-1-(p-tolylsulfinyl)but-1-en-
3-yne (28E). Colorless crystal; mp 102.5e103.5 ꢁC (hexane/AcOEt);
IR (KBr) 3056, 3019, 2921, 2207, 2184, 1492, 1083, 1064, 760,
687 cmꢀ1 1H NMR
; d 2.16 (3H, s), 2.39 (3H, s), 7.27e7.32 (2H, m),
7.34e7.40 (3H, m) 7.49e7.54 (2H, m), 7.58e7.63 (2H, m). Anal. Calcd
for C18H15ClOS: C, 68.67; H, 4.80; Cl, 11.26; S, 10.18. Found: C, 68.50;
H, 4.74; Cl, 11.33; S, 10.14.
3.1.27. (Z)-[Chloro(p-tolylsulfinyl)methylidene]-3-methylcyclohexane
(25Z). Colorless crystal; mp 122.5e123.0 ꢁC (hexane/AcOEt); IR
(KBr) 2950, 2919, 2864, 1600, 1491, 1084, 1054, 805 cmꢀ1; 1H NMR
3.1.32. (Z)-1-Chloro-2-methyl-4-phenyl-1-(p-tolylsulfinyl)but-1-en-
3-yne (28Z). Colorless crystal; mp 94.0e95.0 ꢁC (hexane/AcOEt); IR
d
0.98 (3H, d, J¼6.6 Hz), 1.17e1.25 (1H, m), 1.43 (1H, tq, J¼4.2,
13.2 Hz), 1.51e1.60 (1H, m), 1.76 (1H, dd, J¼11.4, 13.2 Hz), 1.78e1.84
(1H, m), 2.03e2.08 (1H, m), 2.27 (1H, dt, J¼4.2,13.2 Hz), 2.41 (3H, s),
2.86 (1H, dt, J¼13.2, 1.8), 3.36e3.42 (1H, m), 7.29e7.35 (2H, m),
7.44e7.51 (2H, m). Anal. Calcd for C15H19ClOS: C, 63.70; H, 6.77; Cl,
12.53; S, 11.34. Found: C, 63.68; H, 6.78; Cl, 12.48; S, 11.32.
(KBr) 3079, 3000, 2223, 2180, 1489, 1087, 1060, 758, 687 cmꢀ1 1H
;
NMR
d 2.40 (3H, s), 2.47 (3H, s), 7.28e7.36 (5H, m), 7.43e7.48 (2H,
m), 7.49e7.54 (2H, m). Anal. Calcd for C18H15ClOS: C, 68.67; H, 4.80;
Cl, 11.26; S, 10.18. Found: C, 68.53; H, 4.81; Cl, 11.09; S, 10.04.
3.1.33. (3S
5-phenylpent-4-ynoate (29a). Colorless oil; IR (neat) 2980, 2936, 2234,
1722, 1368, 1159, 1083, 1056, 757 cmꢀ1; 1H NMR
1.49 (9H, s),1.64 (3H,
*
,4R
*
,S
*
)-tert-Butyl 3-[chloro(p-tolylsulfinyl)methyl]-3-methyl-
3.1.28. 1-[Chloro(p-tolylsulfinyl)methyl]-3-methyl-1-phenyl-
ethynylcyclohexane (26). Compound 26aL; colorless oil; IR (neat)
d
2927, 2866,1597,1492,1090,1063, 756, 692 cmꢀ1; 1H NMR
d
0.91 (3H,
s), 2.41 (3H, s), 2.91 (1H, d, J¼15.8 Hz) 3.50 (1H, d, J¼15.8 Hz), 5.32 (1H,
s), 7.28e7.34 (5H, m), 7.43e7.52 (2H, m), 7.72e7.79 (2H, m). MS m/z (%)
430 (Mþ, 4), 414 (5), 357 (28), 207 (19), 199 (16), 187 (65), 171 (20), 140
(80), 115 (19), 105 (30), 57 (100). Calcd for C24H21ClOS: M, 430.1369.
Found: m/z 430.1367.
d, J¼6.1 Hz), 0.92e1.08 (1H, m),1.35e1.94 (6H, m), 2.29e2.39 (1H, m),
2.39 (3H, s), 2.97e3.08 (1H, m), 4.78 (1H, s), 7.26e7.33 (5H, m),
7.40e7.46 (2H, m), 7.71e7.77 (2H, m). MS m/z (%) 384 (Mþ, 2), 349 (5),
266 (10), 230 (24), 209 (100),181 (32),167 (51),151 (52),139 (40),115
(77), 105 (41), 91 (58). Calcd for C23H25ClOS: M, 384.1315. Found: m/z
384.1313. Compound 26aP; colorless oil; IR (neat) 2929, 2867, 1598,
3.1.34. (3R
thyl-5-phenyl-pent-4-ynoate (29b). Colorless oil; IR (neat) 2979,
2935, 2238,1726, 1160, 1084, 1055, 757 cmꢀ1; 1H NMR
1.46 (9H, s),
*
,4R
*
,S
*
)-tert-Butyl 3-[chloro(p-tolylsulfinyl)methyl]-3-me
1492, 1093, 1067, 757, 692 cmꢀ1
;
1H NMR
d
1.10 (3H, d, J¼6.1 Hz),
1.28e1.44 (1H, m),1.53e1.86 (6H, m), 2.18e2.30 (1H, m), 2.42 (3H, s),
2.44e2.52 (1H, m), 4.59 (1H, s), 7.25e7.32 (3H, m), 7.34 (2H, d,
J¼8.1 Hz), 7.47e7.55 (4H, m). MS m/z (%) 384 (Mþ, 2), 232 (62), 209
(97), 181 (36), 167 (61), 151 (60), 139 (65), 115 (100), 91 (78). Calcd for
C23H25ClOS: M, 384.1315. Found: m/z 384.1315. Compound 26bL;
colorless oil; IR (neat) 2928, 2866, 1598, 1491, 1082, 1059, 756,
d
1.89 (3H, s), 2.42 (3H, s), 2.91 (1H, d, J¼15.7 Hz), 3.16 (1H, d,
J¼15.7 Hz), 5.25 (1H, s), 7.25e7.35 (5H, m), 7.38e7.44 (2H, m),
7.73e7.79 (2H, m). MS m/z (%) 430 (Mþ, 2), 357 (20), 235 (20), 207
(18), 199 (19), 187 (20), 171 (19), 140 (100), 105 (20), 57 (90). Calcd
for C24H21ClOS: M, 430.1369. Found: m/z 430.1372.
692 cmꢀ1
;
1H NMR
d
1.01 (3H, d, J¼6.3 Hz), 1.24e1.45 (1H, m),
1.57e1.89 (6H, m), 2.30e2.44 (1H, m), 2.39 (3H, s), 2.93e3.04 (1H, m),
4.81 (1H, s), 7.25e7.32 (5H, m), 7.38e7.45 (2H, m), 7.74 (2H, d,
J¼8.1 Hz). MSm/z (%) 384 (Mþ, 6), 349 (8), 321 (7), 232 (60), 209 (100),
181 (34), 167 (56), 151 (53), 139 (43), 115 (79), 91 (60). Calcd for
C23H25ClOS: M, 384.1315. Found: m/z 384.1308. Compound 26bP;
colorless oil; IR (neat) 2927, 2866, 1598, 1492, 1093, 1067, 757,
3.1.35. tert-Butyl2-(1-phenylethynylcyclopropyl)acetate(30). Colorless
1
oil; IR (neat) 2978, 2930, 2220, 1726, 1368, 1147, 756 cmꢀ1; H NMR
d
0.86 (1H, d, J¼7.2 Hz), 0.87 (1H, d, J¼6.6 Hz), 1.10 (1H, d, J¼6.6 Hz),
1.11 (1H, d, J¼7.2 Hz), 1.49 (9H, s), 2.36 (2H, s), 7.22e7.28 (3H, m),
7.32e7.39 (2H, m). MS m/z (%) 256 (Mþ, 8), 200 (48), 183 (12), 155
(100), 127 (22) 57 (31). Calcd for C17H20O2: M, 256.1463. Found: m/z
256.1459.
692 cmꢀ1
;
1H NMR
d
1.03 (3H, d, J¼6.0 Hz), 1.08e1.20 (1H, m),
1.33e1.73 (3H, m), 1.79e2.09 (3H, m), 2.24e2.32 (1H, m), 2.37e2.46
(1H, m),2.42(3H,s), 4.57(1H, s), 7.26e7.36(5H, m),7.49e7.55(4H,m).
MSm/z (%) 384 (Mþ, 2), 349(10), 321 (8), 245(27), 232 (64), 209 (100),
181 (38), 167 (59), 151 (58), 139 (50), 115 (89), 91 (63). Calcd for
C23H25ClOS: M, 384.1315. Found: m/z 384.1316.
3.1.36. (E)-tert-Butyl 3-methyl-6-phenylhex-3-en-5-ynoate (31E).
Colorless oil; IR (neat) 2979, 2932, 2199, 1732, 1368, 1145, 756,
691 cmꢀ1; 1H NMR
J¼0.9 Hz), 5.59e6.62 (1H, m), 7.27e7.33 (3H, m), 7.40e7.47 (2H, m).
MS m/z (%) 256 (Mþ, 23), 200 (62), 155 (78), 115 (19) 57 (100), 41
(11). Calcd for C17H20O2: M, 256.1463. Found: m/z 256.1463.
d
1.46 (9H, s), 2.05 (3H, d, J¼1.1 Hz), 3.05 (2H, d,
3.1.29. (E)-1-(3-Phenylprop-2-ynylidene)-3-ethycyclohexane
(27E). Colorless oil; IR (neat) 2924, 2197, 1596, 1489, 1442, 754,
690 cmꢀ1; 1H NMR
d
0.94 (3H, d, J¼6.4 Hz), 1.07e1.16 (1H, m), 1.40
3.1.37. (Z)-tert-Butyl 3-methyl-6-phenylhex-3-en-5-ynoate (31Z).
(1H, tq, J¼3.6, 12.6 Hz), 1.50e1.60 (1H, m), 1.72e1.78 (1H, m), 1.79
(1H, t, J¼12.6 Hz), 1.83e1.89 (1H, m), 1.92e2.00 (1H, m), 2.31 (1H,
dt, J¼13.2, 1.8 Hz), 2.94 (1H, dt, J¼13.8, 3.6 Hz), 5.42 (1H, s),
7.25e7.31 (3H, m), 7.41e7.44 (2H, m). MS m/z (%) 210 (Mþ, 100), 195
(18), 167 (31), 154 (25), 141 (13), 128 (38), 115 (22), 95 (20). Calcd for
C16H18: M, 210.1409. Found: m/z 210.1410.
Colorless oil; IR (neat) 2978, 2933, 2199, 1732, 1368, 1145, 757,
691 cmꢀ1; 1H NMR
5.64 (1H, d, J¼1.5 Hz), 7.26e7.33 (3H, m), 7.40e7.46 (2H, m). MS m/z
(%) 256 (Mþ, 36), 200 (97), 183 (30), 155 (89), 115 (24) 57 (100).
Calcd for C17H20O2: M, 256.1463. Found: m/z 256.1464.
d
1.46 (9H, s), 1.94 (3H, d, J¼1.5 Hz), 3.35 (2H, s),
3.1.38. (Z)-2-tert-Butyl-4-phenyl-1-(p-tolylsulfinyl)but-1-en-3-yne
(35). Phenylacetylene (0.38 mL; 1.3 mmol)wasadded toa solutionof
LDA (1.3 mmol) in 3 mL of dry THF in a flame-dried flask under argon
atmosphere dropwise at 0 ꢁC with stirring. The reaction mixture was
3.1.30. (Z)-1-(3-Phenylprop-2-ynylidene)-3-ethycyclohexane
(27Z). Colorless oil; IR (neat) 2926, 2198, 1595, 1489, 1443, 754,
690 cmꢀ1; 1H NMR
d
0.99 (3H, d, J¼6.6 Hz), 1.07e1.15 (1H, m), 1.37

3090
N. Ishida et al. / Tetrahedron 67 (2011) 3081e3090
stirred for 10 min at 0 ꢁC and cooled to ꢀ78 ꢁC. A solution of 35
(69 mg; 0.27 mmol) in 3 mL of THF was added to the solution and the
reaction mixture was slowly allowed to warm to 0 ꢁC for 3 h. The
reaction was quenched with satd aq NH4Cl and the whole mixture
was extracted three times with CHCl3. The organic layer was dried
over MgSO4 and concentrated in vacuo. The product was purified by
flash column chromatography (hexane/AcOEt) to give 35 (83.2 mg;
95%)ascolorlessoil;IR(neat)2968, 2870,2210,1490,1082,1060,1041,
Education, Culture, Sports, Science and Technology, Japan, and TUS
Grant for Research Promotion from Tokyo University of Science,
which are gratefully acknowledged.
References and notes
1. Reviews on the chemistry, synthesis, and biology of enediyne anticancer anti-
biotics: (a) Nicolaou, K. C.; Dai, W.-M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1387;
(b) Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; Wiley-VCH:
Weinheim, 1996, pp 523e564; (c) Nicolaou, K. C.; Snyder, S. A. Classics in Total
Synthesis II; Wiley-VCH: Weinheim, 2003, pp 75e108; (d) Sato, I.; Hirama, M. J.
Syn. Org. Chem. Jpn. 2010, 68, 1123.
2. (a) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901; (b) Saito, S.; Yamamoto,
Y. J. Syn. Org. Chem. Jpn. 2001, 59, 346; (c) Tykwinski, R. R.; Zhao, Y. Synlett 2002,
1393; (d) Saito, S.; Yamamoto, Y. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York, NY, 2002; Vol.
1, pp 1635e1646; (e) Kong, J.-R.; Cho, C.-W.; Krische, M. J. J. Am. Chem. Soc.
2005, 127, 11269.
1016, 757 cmꢀ1 1H NMR
; d 1.22 (9H, s), 2.41 (3H, s), 6.42 (1H, s),
7.28e7.41 (5H, m), 7.51e7.63 (4H, m). MS m/z (%) 322 (Mþ, 10), 306
(21), 291 (13), 229 (12), 199 (100), 115 (12) 105 (79), 91 (18), 77 (11).
Calcd for C21H22OS: M, 322.1391. Found: m/z 322.1392.
3.1.39. (Z)-2-(2-Phenylethyl)-4-phenyl-1-(p-tolylsulfinyl)but-1-en-
3-yne (38a). Colorless oil; IR (neat) 3027, 2922, 2858, 2196, 1490,
1080, 1042, 757 cmꢀ1 1H NMR
; d 2.41 (3H, s), 2.56e2.71 (2H, m),
2.94 (2H, t, J¼6.3 Hz), 6.33 (1H, t, J¼1.2 Hz), 7.13e7.20 (3H, m),
7.22e7.29 (4H, m), 7.36e7.41 (3H, m), 7.46e7.50 (2H, m), 7.53e7.56
(2H, m). MS m/z (%) 370 (Mþ, 26), 265 (18), 247 (80), 229 (40), 215
(50), 141 (19) 115 (21), 105 (50), 91 (100). Calcd for C25H22OS: M,
370.1391. Found: m/z 370.1397.
3. (a) Pal, M.; Parasuraman, K.; Subramanian, V.; Dakarapu, R.; Yeleswarapu, K. R.
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Name Reactions and Reagents in Organic Synthesis, 2nd ed.; John Wiley: Hobo-
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Chem. Soc. 2003, 125, 1184; (b) Katayama, H.; Yari, H.; Tanaka, M.; Ozawa,
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therein.
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3.1.40. (Z)-2-Cyclohexyl-4-phenyl-1-(p-tolylsulfinyl)but-1-en-3-yne
(38b). Colorless oil; IR (neat) 2928, 2853, 2194,1490,1449.1080,1044,
808, 757 cmꢀ1 1H NMR
; d 1.10e1.44 (5H, m), 1.63e1.74 (1H, m),
1.74e1.94 (4H, m), 2.14e2.27(1H, m), 2.41(3H, s), 6.39(1H, d, J¼1.0 Hz),
7.28e7.33 (2H, m), 7.36e7.41 (3H, m), 7.51e7.61 (4H, m). MS m/z (%)
348 (Mþ, 9), 332 (28), 225 (100),141 (18),129 (18) 115 (25),105 (81), 91
(40), 81 (22). Calcd for C23H24OS: M, 348.1548. Found: m/z 348.1550.
3.1.41. (Z)-2-tert-Butyl-6-phenyl-1-(p-tolylsulfinyl)hex-1-en-3-yne
(38c). Colorless oil; IR (neat) 2967, 2930, 2214, 1493, 1455, 1080,
1043, 810, 700 cmꢀ1; 1H NMR
d 1.07 (9H, s), 2.40 (3H, s), 2.75e2.82
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1013.
(2H, m), 2.89e2.97 (2H, m), 6.27 (1H, s), 7.17e7.33 (7H, m), 7.47 (2H,
d, J¼8.2 Hz). MS m/z (%) 350 (Mþ, 7), 302 (15), 259 (75), 246 (23),
231 (26), 211 (20), 155 (18), 135 (32), 105 (21), 91 (100), 57 (29).
Calcd for C23H26OS: M, 350.1704. Found: m/z 350.1705.
10. Preliminary results of this study were reported as a letter: Saitoh, H.; Ishida, N.;
Satoh, T. Tetrahedron Lett. 2010, 51, 633.
3.1.42. (Z)-2-tert-Butyl-1-(p-tolylsulfinyl)but-1-en-3-yne
(38d). Colorless oil; IR (neat) 3202, 2969, 2901, 1493, 1082, 1040,
11. (a) Satoh, T.; Takano, K.; Ota, H.; Someya, H.; Matsuda, K.; Koyama, M. Tetra-
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Tetrahedron 2003, 59, 9599.
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S.; Masaoka, S.; Sakai, K.; Satoh, T. Tetrahedron Lett. 2007, 48, 5017; (c) Ogata, S.;
Saitoh, H.; Wakasugi, D.; Satoh, T. Tetrahedron 2008, 64, 5711.
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1999, 55, 2515; (b) Hoffmann, R. W.; Holzer, B.; Knopff, O.; Harms, K. Angew.
Chem., Int. Ed. 2000, 39, 3072; (c) Satoh, T.; Matsue, R.; Fujii, T.; Morikawa, S.
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(e) Mitsunaga, S.; Ohbayashi, T.; Sugiyama, S.; Saitou, T.; Tadokoro, M.; Satoh, T.
Tetrahedron: Asymmetry 2009, 20, 1697.
812, 787 cmꢀ1; 1H NMR
d 1.13 (9H, s), 2.39 (3H, s), 3.55 (1H, s), 6.41
(1H, s), 7.29 (2H, d, J¼8.1 Hz), 7.54 (2H, d, J¼8.1 Hz). MS m/z (%) 246
(Mþ, 5), 231 (21), 215 (24), 198 (53), 183 (100), 141 (56), 91 (60), 41
(30). Calcd for C15H18OS: M, 246.1078. Found: m/z 246.1078.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research No. 19590018 and 22590021 from the Ministry of
14. (a) Satoh, T.; Hayashi, Y.; Yamakawa, K. Bull. Chem. Soc. Jpn. 1993, 66, 1866; (b)
Sugiyama, S.; Satoh, T. Tetrahedron: Asymmetry 2005, 16, 665.