Highly regio- and stereo-selective carbometallation reaction of fluorine-containing internal acetylenes with organocopper reagents

Article abstract of DOI:10.1016/j.tet.2005.07.022

The carbometallation reactions of fluoroalkylated internal alkynes with various organocopper reagents derived from organolithium, Grignard, and organozinc reagents were examined. All carbocupration reactions proceeded smoothly in a highly regio- and stereo-selective manner to give the corresponding vinylcopper intermediates. The intermediates reacted with H ⁺ smoothly, leading to the trisubstituted alkenes in high to excellent yields, whereas they reacted only with strictly limited carbon electrophiles such as allyl-, crotyl-, methallyl bromide, etc, probably due to the low reactivity exerted by an electron-withdrawing fluoroalkyl group. Treatment of vinylcopper with iodine resulted in a high yield of the corresponding vinyl iodide, which was employed successfully for Suzuki-Miyaura and Sonogashira cross-coupling reactions. In addition, two key reactions, the carbocupration and the Suzuki-Miyaura cross-coupling reaction realized the first highly stereoselective total synthesis of anti-estrogen drug, panomifene.

Full text of DOI:10.1016/j.tet.2005.07.022

Tetrahedron 61 (2005) 9391–9404
Highly regio- and stereo-selective carbometallation reaction
of fluorine-containing internal acetylenes with
organocopper reagents
*
Tsutomu Konno, Takeshi Daitoh, Atsushi Noiri, Jungha Chae,
Takashi Ishihara and Hiroki Yamanaka
Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
Received 25 June 2005; revised 9 July 2005; accepted 11 July 2005
Available online 11 August 2005
Abstract—The carbometallation reactions of fluoroalkylated internal alkynes with various organocopper reagents derived from
organolithium, Grignard, and organozinc reagents were examined. All carbocupration reactions proceeded smoothly in a highly regio-
and stereo-selective manner to give the corresponding vinylcopper intermediates. The intermediates reacted with HC smoothly, leading to
the trisubstituted alkenes in high to excellent yields, whereas they reacted only with strictly limited carbon electrophiles such as allyl-,
crotyl-, methallyl bromide, etc, probably due to the low reactivity exerted by an electron-withdrawing fluoroalkyl group. Treatment of
vinylcopper with iodine resulted in a high yield of the corresponding vinyl iodide, which was employed successfully for Suzuki–Miyaura and
Sonogashira cross-coupling reactions. In addition, two key reactions, the carbocupration and the Suzuki–Miyaura cross-coupling reaction
realized the first highly stereoselective total synthesis of anti-estrogen drug, panomifene.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
provided with retention of configuration.5 Despite of
potentially great advantages, there have been quite limited
studies on the carbocupration of fluorine-containing
acetylene derivatives.6 Herein we wish to describe the
highly regio- and stereo-selective carbometallation of
fluoroalkylated internal alkynes with organocopper reagents
prepared from lithium,7 magnesium,8 and zinc reagents,9
which serves a novel synthetic approach for the preparation
of 1.
Much interest has been focused on fluorine-containing
materials due to their unique properties derived from
modified electron density, acidity, and hydrogen-bonding
patterns.1 Fluoroalkyl groups increase lipophilicity allowing
for easier drug transportation, cellular absorption, blood–
brain barrier penetration, and improved binding within
hydrophobic pockets of receptor. Consequently, the
development of novel synthetic methods for the preparation
of fluoroalkylated molecules has been becoming much more
important in the fluorine chemistry.2 Among a diversity of
fluoroalkylated molecules, alkenes having a fluoroalkyl
group (1) are well known as one of the most important
synthetic targets because they are found in the framework of
biologically active compounds such as panomifene
(Fig. 1).3 Though several synthetic methods for such
molecules have been reported thus far,4 carbocupration of
fluoroalkylated alkynes is very attractive because the C–C
and C–Cu bonds are simultaneously introduced across a
triple bond in a highly stereoselective fashion to give the
corresponding vinylcopper intermediates, which can react
with electrophiles, variously substituted ethenes being
Figure 1.
2. Results and discussion
2.1. The carbometallation reaction of fluorine-containing
alkynes with organocopper reagents prepared from
lithium reagents
Keywords: Fluorinated materials; Carbometallation; Fluorinated alkynes.
*
Corresponding author. Tel.: C81 75 724 7517; fax: C81 75 724 7580;
e-mail: konno@chem.kit.ac.jp
Initially, the reaction of trifluoromethylated acetylene
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.022

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T. Konno et al. / Tetrahedron 61 (2005) 9391–9404
Table 1. Investigation of the reaction conditions for the carbocupration
examined the reaction with cyanocuprates as shown in
entries 6–9. The reaction with n-BuCu(CN)Li or n-Bu2-
Cu(CN)Li2 proceeded at K45 8C more smoothly than at
K78 8C (entries 6 and 8 vs entries 7 and 9). In particular, the
use of n-Bu2Cu(CN)Li2 at K45 8C resulted in complete
consumption of the starting material, giving the correspond-
ing alkene in 96% yield (entry 9). The investigation of the
effect of the solvent, as shown in entries 10 and 11, revealed
that THF was the solvent of choice. In all cases, the isomers
such as trans-3a, cis-4a, and trans-4a were not detected at
all (Fig. 2).
Entry Copper reagenta
Temp./8C
Yieldb/%
of 3a
Recoveryb/%
of 2a
1
2
3
4
5
6
7
8
n-BuCu
n-BuCu
n-BuCu
n-Bu2CuLi
n-Bu2CuLi
n-BuCu(CN)Li
n-BuCu(CN)Li
n-Bu2Cu(CN)Li2
n-Bu2Cu(CN)Li2
n-Bu2Cu(CN)Li2
n-Bu2Cu(CN)Li2
K78
K45
K20
K78
K45
K78
K45
K78
K45
K45
K45
10
73
39
53
97 (81)
42
75
81
26
13
15
0
50
25
13
0
77
9
96 (87)
82
47
10c
11d
0
0
a Copper reagents were prepared from Grignard reagent and CuI or CuCN.
b Determined by 19F NMR. Values in parentheses are of isolated yields.
c DME was employed instead of THF.
Figure 2.
d Et2O was employed instead of THF.
With this optimised reaction conditions (Table 1, entry 9),
the carbocupration reaction of various fluorine-containing
acetylene derivatives was investigated in detail as listed in
Table 2. As can be seen in entries 2 and 4, the use of 1.2 eq.
of Me2Cu(CN)Li2 or Ph2Cu(CN)Li2 gave cis-3 in only 38 or
42% yield, 57 or 56% of the starting alkyne being recovered,
respectively. On the other hand, the use of 3.0 eq. of the
cyanocuprate and the prolonged reaction time led to the
complete consumption of the starting materials, affording
the desired alkenes in high yields (entries 3 and 5). No
influence of the substituents on the benzene ring in the
alkynes was observed. Thus, the alkynes having either an
electron-donating group (Me, MeO, entries 6 and 7) or an
electron-withdrawing group (EtO2C, entry 10) could
participate nicely in the carbocupration reaction. It should
be also noted that the position of the substituents on the
benzene ring (para-; entry 7, meta-; entry 8, ortho-: entry 9)
did not affect the yield. We also examined the effect of a
fluoroalkyl group on the reaction as shown in entries 11–13.
The alkynes bearing a difluoromethyl or hexafluoropropyl
group caused a partial decomposition of the intermediate,
derivative 2a10 (R1Zp-ClC6H4) with various organocopper
reagents, prepared from n-BuLi and copper salts, was
examined as shown in Table 1. Thus, to a solution of 1.2 eq.
of n-BuCu (prepared from 1.2 eq. each of n-BuLi and CuI at
K78 8C) in THF was added a THF solution of 2a at K78 8C
and the mixture was stirred for 4 h at that temperature. After
quenching the reaction with NH3 aq./MeOH, only cis-
addition product 3a was obtained in 10% yield, together
with 81% of the starting material (entry 1). Raising the
reaction temperature from K78 to K45 8C caused a
significant improvement of the yield, 3a being produced
in 73% yield with high regio- and stereo-selectivity, though
26% of 2a still remained unreacted (entry 2). However, the
reaction at K20 8C led to a partial decomposition of the
intermediate, affording the desired compound in only 39%
yield (entry 3). Switching the organocopper reagent from
n-BuCu to n-Bu2CuLi brought about a dramatic change, the
desired product being obtained quantitatively when the
reaction was performed at K45 8C (entry 5). We next
Table 2. The carbocupration reaction of fluoroalkylated alkynes with various organolithium reagents
Entry
Equiv of copper
reagent
R
Rf
R1
Product
Yielda/% of cis-
Recoverya/% of
3
2
1
1.2
1.2
3.0
1.2
3.0
1.2
2.4
2.4
2.4
2.4
1.2
1.2
2.4
n-Bu
Me
Me
Ph
Ph
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
HCF2
HCF2CF2CF2
HCF2CF2CF2
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-MeC6H4
p-MeOC6H4
m-MeOC6H4
o-MeOC6H4
p-EtO2CC6H4
p-ClC6H4
3a
3b
3b
3c
3c
3d
3e
3f
3g
3h
3i
3j
3j
96 (87)
38
79 (73)
42
91 (88)
91 (83)
96 (94)
99 (89)
94 (84)
quant. (98)
42 (27)
16
0
57
0
56
0
0
0
0
0
0
0
34
0
2
3b
4
5b
6
7
8
9
10
11
12
13
p-ClC6H4
p-ClC6H4
33 (33)
a Determined by 19F NMR. Values in parentheses are of isolated yields.
b Stirred for 8 h.

T. Konno et al. / Tetrahedron 61 (2005) 9391–9404
9393
the desired product being obtained in low yields. Next, we
investigated the coupling reaction of the carbometallated
adduct with a variety of electrophiles instead of H2O. The
results are collected in Table 3.
coupling product 6g almost quantitatively.11 Furthermore,
the reaction of 5g with trimethylsilylacetylene and Et3N in
the presence of a catalytic amount of CuI and Pd(PPh3)4
took place smoothly to give the fluorine-containing enyne
compound 7g in 95% yield.12
Table 3. The cross-coupling reaction of the carbocuprated adduct with
various electrophiles
2.2. The carbometallation reaction of fluorine-containing
alkynes with organocopper reagents prepared from
Grignard reagents
As an extension of the studies on the carbocupration
reaction, our interest was next directed toward the reaction
of fluoroalkylated alkynes with organocopper reagents
derived from Grignard reagents in place of lithium reagents.
Initially, the reaction was carried out under the optimised
reaction conditions in the case of lithium reagents (n-
Bu2Cu(CN)(MgBr)2, THF, K45 8C, 4 h), but the desired
compound was given in only 43% yield together with 12%
of the dimer 8 and 20% of 2a recovered (Scheme 2).
Therefore, we reexamined the feasibility of the carbome-
tallation reaction with a series of organocopper reagents by
using trifluoromethylated alkyne 2a in order to determine
the optimum linchpin (Table 4). Treatment of 2a with n-
BuCu at K45 8C for 4 h furnished cis-3a in only 5% yield,
together with 48% of the starting material, after quenching
the reaction with NH3 aq./MeOH at K45 8C. The product
was proved to be a cis-adduct as a single isomer. Using a
lower ordered dibutylcuprate, generated from butyl-
magnesium bromide and CuBr, significantly improved the
yield of cis-3a from 5 to 58% (entry 2). Furthermore, the
reaction at K78 8C was found to give the desired product
Entry
Electrophile (EC
)
Product
Yielda/%
of 5
1
2
5a
5b
91 (86)
97 (88)
3
4
5c
85 (81)
88 (84)
5d
5
5e
quant. (76)
6
7
5f
84 (63)
90 (88)
I2
5g
a Determined by 19F NMR. Values in parentheses are of isolated yields.
As can be seen in entries 1–5, variously-substituted allyl
bromide such as allyl- methallyl-, crotyl-, prenyl-bromide,
and b-(methoxycarbonyl)allyl bromide, could undergo the
coupling reaction nicely to give the corresponding fluorine-
containing tetrasubstituted alkenes 5a–e in excellent yields.
The propargyl bromide was also a good electrophile (entry
6), but other carbon electrophiles such as benzyl bromide,
ethyl bromoacetate, iodomethane, and ethyl chloroformate
were not subjected to the coupling reaction at all, the
protonated cis-3a being obtained in moderate yield after
quenching the reaction with NH3 aq./MeOH. Additionally,
trimethylsilyl chloride and tributylstannyl chloride were
also found to be poor electrophiles, the desired tetra-
substituted alkenes being obtained in low yields. On the
other hand, the reaction with iodine took place smoothly to
give the corresponding vinyl iodide 5g in 90% yield (entry
7). Hereupon, we attempted the cross-coupling reaction of
5g with organometallic reagents in the presence of a
transition metal catalyst (Scheme 1). Thus, treatment of 5g
with phenylboronic acid and sodium carbonate in the
presence of a catalytic amount of Pd(PPh3)4 in benzene at
the reflux temperature for 12 h gave the corresponding
Scheme 2. The carbocupration using cyanocuprate.
Table 4. Investigation of the reaction conditions for the carbocupration
Entry Copper reagenta
Temp./8C Time/h Yieldb/%
of 3a
Recoveryb/%
of 2a
1
n-BuCu
K45
K45
K78
K78
K78
K78
4
4
2
2
2
2
5
58
48
0
2
n-Bu2CuMgBr
n-Bu2CuMgBr
n-Bu2CuMgBr
n-BuCu(CN)MgBr
n-Bu2Cu(CN)(MgBr)2
3
4c
94 (85)
31
0
68
76
28
5
24
6
69
a
Copper reagents were prepared from Grignard reagent and CuBr or CuCN, unless
otherwise noted.
b
c
Determined by 19F NMR. Value in parentheses is of isolated yield.
CuI was employed instead of CuBr.
Scheme 1. Suzuki–Miyaura and Sonogashira cross-coupling reactions.

9394
T. Konno et al. / Tetrahedron 61 (2005) 9391–9404
Table 5. The carbocupration reaction of fluoroalkylated alkynes with various Grignard reagents
Entry
Equiv of copper
reagent
R
Rf
R1
Product
Yielda/% of cis-3
1
2
3
1.2
2.4
1.2
1.2
1.2
2.4
2.4
2.4
2.4
1.2
1.2
1.2
1.2
1.2
1.2
n-Bu
s-Bu
c-Hex
Bn
Allyl
Vinyl
Ph
p-MeOC6H4
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
HCF2
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
3a
3k
3l
93 (83)
84 (69)
74
4b
5c
6
3m
3n
3o
3c
3p
3q
3r
3e
3d
3h
3s
quant. (69)
98 (86)
53 (41)
93
7
8
9
10
11
12
13
14
15
61d
m-ClC6H4
o-ClC6H4
90 (70)
89 (83)
97 (93)
96 (90)
84 (80)
quant. (99)
65 (55)
p-MeOC6H4
p-MeC6H4
p-EtO2CC6H4
p-(MeOC6H4)-CH2
p-ClC6H4
3i
a Determined by 19F NMR. Values in parentheses are of isolated yields.
b Benzylmagnesium chloride was used for the preparation of copper reagent.
c Allylmagnesium chloride was used for the preparation of copper reagent.
d CuCN was employed instead of CuBr because the copper reagents prepared from Grignard reagent and CuBr did not give a reproducible result.
cis-3a in 94% yield. Additional studies focused on a copper
salt such as CuI and CuCN, both of which had proven to be
good copper salts in the carbocupration reaction using
organolithium reagents. Thus, changing a copper salt from
CuBr to CuI appreciably affected the yield (entry 4). Higher
ordered cyanocuprate realized the satisfactory reaction at
K78 8C, resulting in the formation of cis-3a in 69% yield
(entry 6), whereas lower ordered cyanocuprate did not lead
to the good results (entry 5). In order to examine the scope
and limitation of this carbocupration, the optimised reaction
conditions were applied for various types of fluoroalkylated
alkynes 2 as shown in Table 5. Primary and secondary
Grignard reagents such as n-BuMgBr and s-BuMgBr
(entries 1 and 2), cyclohexyl, benzyl, and allyl Grignard
reagents (entries 3–5) could participate well in the
carbocupration reaction to give the corresponding adducts
cis-3 in good to excellent yields (69–86% isolated yields).
However, the yield was somewhat eroded with vinyl
Grignard reagent employed (entry 6). Switching R in
Grignard reagent from aliphatic to aromatic groups had no
discernible effect on the yield, though 2.4 eq. of copper
reagents or CuCN were required for the smooth reaction
(entries 7 and 8). Changing the aromatic substituent (R1) of
the alkynes 2 from p-chlorophenyl to m-chloro- or
o-chlorophenyl also did not significantly affect the yield
(entries 1, 9 and 10). In addition, no influence of the yield on
the substituents in R1, such as the electron-donating (MeO,
Me, entries 11 and 12) or the electron-withdrawing group
(EtO2C, entry 13), was observed. It is worthwhile to note
that the internal alkynes having an alkyl side chain as R1
(entry 14) or a difluoromethyl moiety as Rf (entry 15) could
also undergo the smooth carbocupration reaction to afford
the corresponding adducts in good to high yields.
was directed toward the cross-coupling reaction using the
carbometallated adduct 9 (Scheme 3).
Scheme 3. The cross-coupling reaction.
Treatment of 9 with 4.0 eq. of allyl-, methallyl-, crotyl-,
propargyl bromide or iodine at K78 8C resulted in the
smooth coupling reaction, affording the tetrasubstituted
alkenes 5a–c,f,g in high yields. Similar to the results on the
lithium reagents, other electrophiles such as benzyl
bromide, ethyl chloroformate, ethyl bromoacetate, etc.
were all unreacted, leading to the formation of trisubstituted
alkene cis-3a after quenching the reaction with NH3 aq./
MeOH. The coupling reaction of 9 with iodobenzene under
the influence of palladium catalyst at 0 8C–rt did not give
any desired product due to the decomposition of 9.
2.3. The carbometallation reaction of fluorine-containing
alkynes with organocopper reagents prepared from
organozinc reagents
Organozinc reagents are well known as useful inter-
mediates, and their chemistry has been actively investigated
in the recent years. They tolerate a broad range of
functionalities and undergo various reactions such as
Michael addition, SN2 reaction, and so on, in the presence
Based on the above-described results on the regio- and
stereo-selective carbometallation of the fluoroalkylated
internal alkynes 2 with organocopper reagents, our interest

T. Konno et al. / Tetrahedron 61 (2005) 9391–9404
9395
of a copper salt like CuBr, CuCN, etc.13 Therefore, we next
attempted the carbometallation reaction of various fluorine-
containing alkynes with copper reagents derived from
organozinc reagents (Table 6). In initial experiments, 2a
was treated with 1.2 eq. of copper reagent (prepared from
1.2 eq. each of copper bromide and Et2Zn) at K45 8C for
2 h to give a mixture of cis-3t, cis-4t, and trans-4t in 78%
yield. The 19F NMR analysis showed that the ratio of cis-3t:
(cis-4tCtrans-4t) was 94:6 (entry 1). Interestingly, the
reaction at K78 8C led to a decrease in the regioselectivity
(entry 2). The use of 2.4 eq. of Et2Zn caused a smooth
carbocupration, cis-3t being produced with high regio- and
stereo-selectivity (entry 3). It should be noted that the
present reaction proceeded smoothly even in the presence of
a catalytic amount of CuBr, 73% of the desired compounds
being obtained, though the regioselectivity decreased
slightly (entry 5). With the optimised reaction conditions
(Table 6, entry 3), the scope of the carbocupration reaction
with various organozinc reagents was examined. The results
are summarized in Table 7. In the case of diorganozinc
reagents, the reaction took place smoothly to afford cis-3
with high regio- and stereoselectivity in high yields (entries
1–3). As can be seen in entries 5 and 6, an ester or a nitrile
group in the organozinc reagents did not influence on the
yield and the regioselectivity, whereas the zinc reagent
derived from ethyl bromoacetate did not react with 2a at all,
the starting material being recovered quantitatively (entry
4). It is noteworthy that the carbometallation reaction with
n-butylzinc iodide at K78 8C gave the desired molecule in a
higher regioselective manner than the reaction at K45 8C
(entry 7 vs 8). We also investigated the cross-coupling
reaction of the carbometallated adduct 9 with various
electrophiles (Scheme 4). Initially, treatment of the in situ
generated carbometallated adduct with an excess amount of
iodine at K78 8C did not give the corresponding vinyl
iodide at all, the starting alkyne 2a being recovered
quantitatively. After several trials, we have found that the
addition of DMF to the reaction mixture promoted the cross-
coupling reaction significantly. Thus, to a solution of the
in situ generated carbometallated adduct in THF was added
the same volume of DMF as THF at K78 8C. After stirring
of the reaction mixture for 10 min, then 4.8 eq. of iodine
was added to the reaction mixture, and the whole was stirred
for 1 h at room temperature before the reaction was
quenched with NH3 aq./MeOH. As a result, the vinyl iodide
5g was obtained in high yield as a single isomer. The same
reaction procedure could be applied for the reaction of the
carbometallated adduct with allyl bromide, tetrasubstituted
alkene 5a being afforded in high yields with high
regioselectivity. However, the reaction with methallyl-
and crotylbromide gave the coupling products in moderate
yields, 37 and 43% of 2a being recovered, respectively.
Table 6. Investigation of the reaction conditions
Entry
Eq. of
CuBr
Eq. of
Et2Zn
Temp./8C Yielda/%
of 3C4
Ratioa,b Recoverya/%
(3:4)
of 2a
1
2
3
4
5
6
1.2
1.2
1.2
2.4
2.4
2.4
2.4
K45
K78
K45
K78
K45
K45
78
86
94:6
85:15
98:2
96:4
89:11
—
0
0
1.2
1.2
92 (84)
92
0
1.2
0
0.2
73
20
99
None
0
a
Determined by 19F NMR. Value in parentheses is of isolated yield.
b
A ratio of cis-4t:trans-4t was not determined.
Table 7. The carbocupration reaction of fluoroalkylated alkynes with
various organozinc reagents
Scheme 4. The cross-coupling reaction.
2.4. Determination of the stereochemistry of the
carbocupration products
Entry
Zinc reagent
Product
Yielda/% of 3C4
Ratioa,b (3:4)
The stereochemistry in the carbocupration was determined
1
as follows. Thus, the H and 19F NMR spectra of cis-3a
showed a quartet signal due to the vinylic proton Ha and a
1
2
3
4
5
6
7
8c
Et2Zn
3t
3a
3c
—
3u
3v
3a
3a
92(84)
80(80)
80
98:2
100:0
100:0
—
n-Bu2Zn
Ph2Zn
BrZnCH2CO2Et
IZnCH2CH2CO2Me
IZnCH2CH2CH2CN
n-BuZnI
0
80(79)
95(90)
80
95:5
100:0
78:22
100:0
n-BuZnI
96(96)
a
Determined by 19F NMR. Values in parentheses are of isolated yields.
A ratio of cis-4:trans-4 was not determined.
Carried out at K78 8C.
b
c
Figure 3.

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T. Konno et al. / Tetrahedron 61 (2005) 9391–9404
doublet signal due to the CF3 group, respectively (Fig. 3).
Additionally, the NOE between Hb and Hc in 5f was
observed in the NOESY, strongly indicating that the
propargyl and the butyl groups were situated in the cis
configuration (Fig. 4). These spectral data suggest that the
present carbocupration reaction occurred in a highly cis
addition manner, in which the copper metal was attached
with a carbon bearing a fluoroalkyl group.
Scheme 5. Mechanism.
2.6. The synthetic application of the carbocupration
reaction of fluorine-containing alkynes—total synthesis
of anti-estrogenic drug, panomifene
As a synthetic application of the carbocupration reaction of
fluorine-containing internal acetylenes, the total synthesis of
panomifene 103 (EGIS-5656, GYKI-13504), which is a
follow-up molecule of tamoxifen 1115 (Nolvadex), the well-
known triarylethylene type anti-estrogenic drug in the
therapy of breast cancer and for the treatment of menstrual
disorders (Fig. 5), was executed as follows (Scheme 6).
Thus, alkyne 2x10 was exposed to the carbocupration
reaction with (4-MeOC6H4)2Cu(CN)(MgBr)2 (1.2 eq.) at
K45 8C for 2 h, followed by addition of 2.4 eq. of iodine at
K78 8C, to afford vinyl iodide 5x in 51% yield. The 1H, 13C,
19F NMR, and GLC analyses were indicative of no other
stereoisomers being formed. The stereochemically pure 5x
was treated with 4.0 eq. of phenylboronic acid under the
Suzuki–Miyaura cross-coupling reaction conditions, produ-
cing the triarylethylene derivative 12x almost quantitatively
with complete retention of the stereochemistry. Surpris-
ingly, treatment of 12x with BBr3 gave 13x in low yield.16
All attempts for improving this demethylation were
unsuccessful. On the other hand, the demethylation of 5x
with BBr3 proceeded readily to give the corresponding
phenol derivative. The following nucleophilic substitution
Figure 4. NOESY spectrum of 5f.
2.5. Mechanism
Based on the results of the stereochemical assignment, the
proposed mechanism for the present carbocupration
reaction is outlined in Scheme 5. Thus, when copper
reagent coordinates on the triple bond, oxidative addition of
the alkyne to Cu(I) takes place to form the intermediate
Int-A. Due to the strong electron-withdrawing effect
exerted by a fluoroalkyl group (Rf), (Rf)C–Cu(III) bond
may be stronger than (R1)C–Cu(III). Accordingly, R on
Cu(III) may transfer to the olefinic carbon distal to a
fluoroalkyl group, vinylcopper intermediate Int-B being
produced preferentially. Low nucleophilicity exerted by a
fluoroalkyl group results in the coupling reaction of Int-A
with only active electrophiles such as HC, IC, and
variously-substituted allyl bromide. In the reaction of
Int-B with variously-substituted allyl bromide, d-p*
complexation between Cu(I) and the double bond may
promote the generation of p-allylcopper intermediate,
leading to the formation of tetrasubstituted alkenes via
reductive elimination at the less hindered carbon.14
Figure 5. Panomifene and tamoxifen.

T. Konno et al. / Tetrahedron 61 (2005) 9391–9404
9397
reactivity exerted by an electron-withdrawing fluoroalkyl
group. Treatment of vinylcopper with iodine resulted in the
high yield of the corresponding vinyl iodide, which was
employed successfully for the Suzuki–Miyaura and
Sonogashira cross-coupling reactions. Two key reactions,
the carbocupration and the Suzuki–Miyaura cross-coupling
reaction realized the first highly stereoselective total
synthesis of anti-estrogenic drug, panomifene 10 (total
yield for five steps: 28%).17
4. Experimental
4.1. General
1H NMR spectra were measured with a Bruker DRX
(500.13 MHz) spectrometer in a chloroform-d (CDCl3)
solution with tetramethylsilane (Me4Si) as an internal
reference. 13C NMR spectra were recorded on a Bruker
DRX (125.77 MHz). A JEOL JNM-EX90F (54.21 MHz,
FT) spectrometer was used for determining 19F NMR yield
with internal C6F6. It was used for determining regio-
selectivity and stereoselectivity and was used for taking 19F
NMR spectra in a CDCl3 solution with internal CFCl3.
CFCl3 was used (dFZ0) as an internal standard for 19F
NMR. Infrared spectra (IR) were recorded on a Shimadzu
FTIR-8200A (PC) spectrophotometer. Mass spectra (MS)
were taken on a JEOL JMS-700.
4.2. Materials
All chemicals were of reagent grade and, if necessary, were
purified in the usual manner prior to use. Thin-layer
chromatography (TLC) was done with Merck silica gel 60
F254 plates. Preparative thin layer chromatography (TLC)
was done with Merck silica gel 60 F254, 1 mm.
Scheme 6. A short total synthesis of panomifene.
4.3. Typical procedure for the reaction of fluoroalkylated
acetylene derivatives with cuprate derived from lithium
reagents
reaction between phenoxide and 2-chloroethyl tosylate in
DMF at the reflux temperature gave rise to the desired ether
14x in 67% yield. The Suzuki–Miyaura cross-coupling
reaction of 14x with phenylboronic acid afforded the
corresponding alkene 15x quantitatively. Finally, on
treating 15x with ethanolamine in 2-methoxy-
ethyleneglycol, the desired panomifene 10 was obtained in
83% yield (28% overall yield from 2x).
To a solution of copper cyanide (53 mg, 0.6 mmol) in THF
(2.0 mL) was added 0.76 mL (1.2 mmol) of n-BuLi (1.6 M
hexane solution) at K78 8C and the whole was stirred for
10 min, then allowed to warm to K20 8C and stirred for
30 min. To this solution was added dropwise 1-(4-
chlorophenyl)-3,3,3-trifluoropropyne (102 mg, 0.5 mmol).
The reaction was stirred for 4 h at K78 8C, and was then
quenched with NH3 aq./MeOH (1 mL/5 mL), extracted with
Et2O three times. The combined organic layers were dried
over anhydrous Na2SO4 and concentrated in vacuo. The
residue was chromatographed on silica gel (hexane only) to
afford (Z)-3-(4-chlorophenyl)-1,1,1-trifluoro-2-heptene
(0.114 g, 0.44 mmol, 87% yield).
3. Conclusion
In summary, we have investigated the carbocupration
reaction of fluoroalkylated internal acetylene derivatives
with various copper reagents derived from organolithium,
Grignard, and organozinc reagents. The carbocupration
reaction of fluoroalkylated internal alkynes proceeded in a
highly regio- and stereo-selective manner to give the
corresponding trisubstituted alkenes in high yields. Zinc
reagents possessing a functional group such as an ester or a
nitrile moiety were also applied for the reaction of the
alkynes in a similar manner. The vinylcopper intermediate
reacted only with a few carbon electrophiles such as allyl-,
methally-, crotyl-bromide, etc, probably due to low
4.3.1. (Z)-3-(4-Chlorophenyl)-1,1,1-trifluoro-2-heptene
1
(3a). H NMR (CDCl3) d 0.88 (3H, t, JZ7.0 Hz), 1.31–
1.34 (4H, m), 2.35–2.40 (2H, m), 5.67 (1H, q, JZ8.2 Hz),
7.08 (2H, d, JZ8.3 Hz), 7.33 (2H, d, JZ8.3 Hz); 19F NMR
(CDCl3) d K56.70 (3F, d, JZ8.2 Hz); 13C NMR (CDCl3) d
13.7, 22.1, 29.2, 39.7, 115.7 (q, JZ33.4 Hz), 122.7 (q, JZ
271.0 Hz), 128.3, 128.6, 133.9, 136.8, 153.2 (q, JZ5.9 Hz);
IR (neat) n 2962, 2873, 1666, 1492, 1280 cmK1; HRMS

9398
T. Konno et al. / Tetrahedron 61 (2005) 9391–9404
(FAB) calcd for C13H1435ClF3 (MC) 262.0736, found
262.0751. Anal. Calcd: C, 59.44; H, 5.37. Found: C,
59.03; H, 5.15.
7.4 Hz), 7.01 (1H, dd, JZ1.3, 7.4 Hz), 7.29 (1H, td, JZ7.9,
1.8 Hz); 19F NMR (CDCl3) d K62.78 (3F, d, JZ8.0 Hz);
13C NMR (CDCl3) d 13.8, 22.2, 29.3, 38.3, 55.4, 110.7,
115.6 (q, JZ32.9 Hz), 120.0, 122.9 (q, JZ270.6 Hz),
127.5, 129.0, 129.1, 152.1 (q, JZ5.6 Hz), 155.79; IR
(neat) n 2935, 2873, 1672, 1492 cmK1; HRMS (FAB) calcd
for C14H17F3 (MC) 258.1231, found 258.1237.
4.3.2. (Z)-3-(4-Chlorophenyl)-1,1,1-trifluoro-2-butene
1
(3b). H NMR (CDCl3) d 2.13 (3H, q, JZ2.0 Hz), 5.71
(1H, qq, JZ1.5, 8.2 Hz), 7.16 (2H, d, JZ8.5 Hz), 7.33 (2H,
d, JZ8.5 Hz); 19F NMR (CDCl3) d K59.94 (3F, d, JZ
8.2 Hz); 13C NMR (CDCl3) d 26.7, 116.2 (q, JZ33.6 Hz),
122.4 (q, JZ271.3 Hz), 128.2, 128.4, 134.1, 137.5, 148.9
(q, JZ5.9 Hz); IR (neat) n 1670, 1492 cmK1; HRMS (FAB)
calcd for C10H835ClF3 (MC) 220.0267, found 220.0260.
4.3.8. (Z)-Ethyl 4-(1-butyl-3,3,3-trifluoro-1-propenyl)
benzoate (3h). 1H NMR (CDCl3) d 0.80 (3H, t, JZ
7.0 Hz), 1.23–1.28 (4H, m), 1.32 (3H, t, JZ7.0 Hz), 2.31–
2.35 (2H, m), 4.31 (2H, q, JZ7.0 Hz), 5.63 (1H, q, JZ
8.3 Hz), 7.16 (2H, d, JZ8.3 Hz), 7.96 (2H, d, JZ8.3 Hz);
19F NMR (CDCl3) d K57.97 (3F, d, JZ8.3 Hz); 13C NMR
(CDCl3) d 13.7, 14.3, 22.1, 29.1, 39.6, 61.0, 115.8 (q, JZ
33.6 Hz), 122.6 (q, JZ271.4 Hz), 127.2, 129.3, 130.0,
143.1, 153.4 (q, JZ5.3 Hz), 166.2; IR (neat) n 2935, 2873,
1720, 1666 cmK1; HRMS (FAB) calcd for C16H20F3O2
(MCH) 301.1416, found 301.1409. Anal. Calcd: C, 63.99;
H, 6.38. Found: C, 64.01; H, 6.78.
4.3.3. (1Z)-1-(4-Chlorophenyl)-3,3,3-trifluoro-1-phenyl-
prop-1-ene (3c). 1H NMR (CDCl3) d 6.14 (1H, q, JZ
8.2 Hz), 7.18 (2H, d, JZ7.8 Hz), 7.23 (2H, d, JZ7.8 Hz)
7.32–7.40 (5H, m); 19F NMR (CDCl3) d K56.36 (3F, d, JZ
8.2 Hz); 13C NMR (CDCl3) d 115.9 (q, JZ34.0 Hz), 122.7
(q, JZ264.8 Hz), 127.9, 128.4, 128.6, 129.6, 130.5, 134.7,
135.7, 139.7, 151.3 (q, JZ5.8 Hz); IR (neat) n 1643, 1492,
1361 cmK1; HRMS (FAB) calcd for C15H1035ClF3 (MC)
282.0423, found 282.0446.
4.3.9. (Z)-3-(4-Chlorophenyl)-1,1-difluoro-2-heptene
1
(3i). H NMR (CDCl3) d 0.87 (3H, t, JZ7.0 Hz), 1.28–
4.3.4. (Z)-1,1,1-Trifluoro-3-(4-methylphenyl)-2-heptene
1.36 (4H, m), 2.38–3.42 (2H, m), 5.69 (1H, q, JZ7.7 Hz),
5.86 (1H, td, JZ55.5, 7.7 Hz), 7.12 (2H, d, JZ8.5 Hz), 7.35
(2H, d, JZ8.5 Hz); 19F NMR (CDCl3) d K109.23 to
K109.55 (1F, m), K109.93 to K101.18 (1F, m); 13C NMR
(CDCl3) d 13.8, 22.1, 29.4, 38.4, 113.5 (t, JZ229.6 Hz),
120.3 (t, JZ26.4 Hz), 128.7, 129.3, 134.2, 136.6, 151.1 (t,
1
(3d). H NMR (CDCl3) d 0.88 (3H, t, JZ7.0 Hz), 1.30–
1.37 (4H, m), 2.37 (3H, s), 2.38–2.42 (2H, m), 5.66 (1H, q,
JZ8.3 Hz), 7.07 (2H, d, JZ8.0 Hz), 7.16 (2H, d, JZ
8.0 Hz); 19F NMR (CDCl3) d K57.99 (3F, d, JZ8.3 Hz);
13C NMR (CDCl3) d 13.8, 21.2, 22.1, 29.3, 39.9, 114.8 (q,
JZ33.1 Hz), 123.0 (q, JZ270.3 Hz), 127.1, 128.7, 135.5,
137.6, 154.5 (q, JZ5.6 Hz); IR (neat) n 2931, 2873,
1662 cmK1. HRMS (CI) calcd for C14H18F3 (MCH)
243.1361, found 243.1362. Anal. Calcd: C, 69.40; H,
7.07. Found: C, 69.13; H, 7.15.
JZ1.3 Hz); IR (neat) n 2958, 2862, 1662, 1492 cmK1
;
HRMS (EI) calcd for C13H1535ClF2 (MC) 244.0830, found
244.0831.
4.3.10. (Z)-5-(4-Chlorophenyl)-1,1,2,2,3,3-hexafluoro-4-
1
nonene (3j). H NMR (CDCl3) d 0.88 (3H, t, JZ7.0 Hz),
4.3.5. (Z)-1,1,1-Trifluoro-3-(4-methoxyphenyl)-2-hep-
1
1.28–1.37 (4H, m), 2.44–2.48 (2H, m), 5.92 (1H, m), 6.02–
6.29 (1H, m), 7.11 (2H, d, JZ8.5 Hz), 7.33 (2H, d, JZ
8.5 Hz); 19F NMR (CDCl3) d K127.10 to K127.50 (6F, m);
13C NMR (CDCl3) d 13.7, 22.1, 29.7, 39.6, 105–109 (3C,
m), 110.5 (dt, JZ15.9, 7.8 Hz), 128.6, 128.7, 134.1, 137.5,
152.8 (d, JZ8.3 Hz); IR (neat) n 2958, 2873, 1631,
1492 cmK1; m/z (EI) 306 (93) 271 (100) 215 (86) 177
(90) 164 (60) 137 (30).
tene (3e). H NMR (CDCl3) d 0.88 (3H, t, JZ7.0 Hz),
1.28–1.36 (4H, m), 2.36–2.42 (2H, m), 3.82 (3H, s), 5.62
(1H, q, JZ8.3 Hz), 6.88 (2H, d, JZ8.8 Hz), 7.12 (2H, d,
JZ8.8 Hz); 19F NMR (CDCl3) d K56.62 (3F, d, JZ
8.3 Hz); 13C NMR (CDCl3) d 13.8, 22.1, 29.4, 39.8, 55.2,
113.4, 114.7 (q, JZ33.1 Hz), 124.3 (q, JZ270.6 Hz),
128.5, 130.6, 154.1 (q, JZ5.6 Hz), 159.3; IR (neat) n
2935, 2873, 1662, 1612 cmK1. HRMS (FAB) calcd for
C14H17F3O (MC) 258.1231, found 258.1220. Anal. Calcd:
C, 65.10; H, 6.63. Found: C, 65.20; H, 6.78.
4.4. Typical procedure for the synthesis of tetra-
substituted alkenes
4.3.6. (Z)-1,1,1-Trifluoro-3-(3-methoxyphenyl)-2-hep-
1
tene (3f). H NMR (CDCl3) d 0.81 (3H, t, JZ7.0 Hz),
To a solution of copper cyanide (53 mg, 0.6 mmol) in THF
(2 mL) was added 0.76 mL (1.2 mmol) of n-BuLi (1.6 M
hexane solution) at K45 8C, and the whole was stirred for
10 min, then allowed to warm to K20 8C and stirred for
30 min. To this solution was added dropwise 1-(4-
chlorophenyl)-3,3-3-trifluoropropyne (102 mg, 0.5 mmol).
The reaction was stirred for 4 h at K45 8C, and then was
added dropwise allyl bromide (290 mg, 2.4 mmol). The
reaction was stirred for 4 h at K45 8C, and then was
quenched with NH4Cl aq. (3 mL), extracted with Et2O three
times. The combined layers were dried over anhydrous
Na2SO4 and concentrated in vacuo. The residue was
chromatographed on silica gel (hexane only) to afford
(Z)-5-(4-chlorophenyl)-4-trifluoromethyl-1,4-nonadiene
(129 mg, 0.43 mmol, 86% yield).
1.22–1.31 (4H, m), 2.29–2.34 (2H, m), 3.74 (3H, s), 5.56
(1H, q, JZ8.0 Hz), 6.64 (1H, s), 6.68 (1H, d, JZ7.3 Hz),
6.78 (1H, dd, JZ2.3, 8.4 Hz), 7.19 (1H, dd, JZ7.3, 8.4 Hz);
19F NMR (CDCl3) d K60.95 (3F, d, JZ8.0 Hz); 13C NMR
(CDCl3) d 13.8, 22.1, 29.3, 39.7, 55.20, 113.1, 113.1, 115.0
(q, JZ33.4 Hz), 119.6, 122.8 (q, JZ270.4 Hz), 129.0,
139.8, 154.2 (q, JZ5.6 Hz), 159.1; IR (neat) n 2935, 2873,
1666, 1581 cmK1; HRMS (FAB) calcd for C14H17F3 (MC)
258.1231, found 258.1220.
4.3.7. (Z)-1,1,1-Trifluoro-3-(2-methoxyphenyl)-2-hep-
1
tene (3g). H NMR (CDCl3) d 0.88 (3H, t, JZ7.0 Hz),
1.30–1.39 (4H, m), 2.37–2.41 (2H, m), 33.80 (3H, s), 5.69
(1H, q, JZ8.0 Hz), 6.90 (1H, d, JZ7.9 Hz), 6.93 (1H, t, JZ

T. Konno et al. / Tetrahedron 61 (2005) 9391–9404
9399
4.4.1. (Z)-5-(4-Chlorophenyl)-4-trifluoromethyl-1,4-non-
adiene (5a). H NMR (CDCl3) d 0.85 (3H, t, JZ7.0 Hz),
6.8 Hz), 1.24–1.35 (4H, m), 2.08 (1H, t, JZ2.5 Hz), 2.44–
2.48 (2H, m), 3.21 (2H, d, JZ2.5 Hz), 7.05 (2H, d, JZ
8.3 Hz), 7.31 (2H, d, JZ8.3 Hz); 19F NMR (CDCl3) d
K59.53 (3F, s); 13C NMR (CDCl3) d 13.8, 17.6, 22.6, 28.9,
36.1, 68.9, 80.1, 121.4 (q, JZ275.1 Hz), 121.9 (q, JZ
28.1 Hz), 128.1, 128.7, 133.4, 138.3, 149.4 (q, JZ3.4 Hz);
IR (neat) n 3309, 2962, 2873, 1654 cmK1; HRMS (FAB)
calcd for C16H1635ClF3 (MC) 300.0893, found 300.0896.
1
1.20–1.30 (4H, m), 2.33–2.37 (2H, m), 3.09 (2H, d, JZ
6.0 Hz), 5.11–5.20 (2H, m), 5.83–5.92 (1H, m), 7.04 (2H, d,
JZ8.3 Hz), 7.30 (2H, d, JZ8.3 Hz); 19F NMR (CDCl3) d
K59.33 (3F, s); 13C NMR (CDCl3) d 13.8, 22.6, 29.2, 32.0,
35.7, 116.1, 124.2 (q, JZ276.0 Hz), 124.3 (q, JZ26.7 Hz),
128.0, 128.9, 133.1, 134.5, 139.1, 148.5 (q, JZ3.6 Hz); IR
(neat) n 2962, 2866, 1651 cmK1; HRMS (FAB) calcd for
C16H1835ClF3 (MC) 302.1049, found 302.1050.
4.4.7. (E)-3-(4-Chlorophenyl)-1,1,1-trifluoro-2-iodo-2-
1
heptene (5g). H NMR (CDCl3) d 0.89 (3H, t, JZ7.0 Hz),
4.4.2. (Z)-5-(4-Chlorophenyl)-2-methyl-4-trifluoro-
methyl-1,4-nonadiene (5b). 1H NMR (CDCl3) d 0.83
(3H, t, JZ7.0 Hz), 1.17–1.28 (4H, m), 1.83 (3H, s), 2.28–
2.32 (2H, m), 3.00 (2H, s), 4.79 (1H, s), 4.89 (1H, s), 7.06
(2H, d, JZ8.5 Hz), 7.31 (2H, d, JZ8.5 Hz); 19F NMR
(CDCl3) d K59.13 (3F, s); 13C NMR (CDCl3) d 13.8, 22.6,
23.0, 29.1, 35.5 (d, JZ2.0 Hz), 35.9, 111.0, 124.1 (q, JZ
274.9 Hz), 124.4 (q, JZ28.1 Hz), 128.0, 129.0, 133.1,
139.0, 141.8, 149.2 (q, JZ3.4 Hz); IR (neat) n 2962, 2862,
1651, 1488 cmK1; HRMS (FAB) calcd for C17H2035ClF3
(MC) 316.1206, found 316.1202. Anal. Calcd: C, 64.45; H,
6.36. Found: C, 64.65; H, 6.48.
1.30–1.36 (4H, m), 2.62–2.67 (2H, m), 7.02 (2H, d, JZ
8.5 Hz), 7.32 (2H, d, JZ8.5 Hz); 19F NMR (CDCl3) d
K55.23 (3F, s); 13C NMR (CDCl3) d 13.8, 22.4, 28.2, 46.3,
86.6 (q, JZ34.2 Hz), 120.8 (q, JZ273.7 Hz), 128.3, 128.4,
134.0, 137.3, 157.2 (q, JZ2.9 Hz); IR (neat) n 2958, 2862,
1593 cmK1; HRMS (FAB) calcd for C13H1335ClF3I (MC)
387.9703, found 387.9694. Anal. Calcd: C, 40.18; H, 3.37.
Found: C, 40.55; H, 3.23.
4.5. The Suzuki–Miyaura cross-coupling of 5g with
phenyl iodide in the presence of palladium catalyst
To a solution of (E)-3-(4-chlorophenyl)-1,1,1-trifluoro-2-
iodo-2-heptene (109 mg, 0.273 mmol), Pd(PPh3)4 (34 mg,
0.024 mmol), in benzene (6 mL) was added Na2CO3
(72 mg, 0.68 mmol), PhB(OH)2 (133 mg, 1.092 mmol),
H2O (0.35 mL), and EtOH (0.3 mL). The reaction mixture
was refluxed for 12 h, then quenched with saturated NH4Cl
aq. The whole was extracted with EtOAc three times. The
combined organic layers were washed with NaCl aq., dried
over Na2SO4, and then concentrated in vacuo. The residue
was purified by silica gel column chromatography to give
the corresponding (Z)-3-(4-chlorophenyl)-1,1,1-trifluoro-2-
phenyl-2-heptene (91 mg, 0.269 mmol, 98% yield).
4.4.3. (2E,5Z)-6-(4-Chlorophenyl)-5-trifluoromethyl-2,5-
decadiene (5c). 1H NMR (CDCl3) d 0.84 (3H, t, JZ7.0 Hz),
1.19–1.30 (4H, m), 1.70 (3H, dd, JZ1.3, 6.8 Hz), 2.31–2.36
(2H, m), 3.00 (2H, d, JZ6.3 Hz), 5.43–5.49 (1H, m), 5.52–
5.60 (1H, m), 7.03 (2H, d, JZ8.3 Hz), 7.29 (2H, d, JZ
8.3 Hz); 19F NMR (CDCl3) d K56.00 (3F, s); 13C NMR
(CDCl3) d 13.8, 17.9, 22.6, 29.2, 31.0, 35.6, 124.3 (q, JZ
276.0 Hz), 125.1 (q, JZ22.5 Hz), 126.8, 127.1, 128.9,
133.0, 139.3, 147.7 (q, JZ3.8 Hz); IR (neat) n 2962, 2873,
1630 cmK1; HRMS (EI) calcd for C17H2035ClF3 (MC)
316.1256, found 316.1187. Anal. Calcd: C, 64.45; H, 6.36.
Found: C, 64.35; H, 6.11.
4.5.1. (Z)-3-(4-Chlorophenyl)-1,1,1-trifluoro-2-phenyl-2-
heptene (6g). H NMR (CDCl3) d 0.66 (3H, t, JZ7.1 Hz),
4.4.4. (Z)-6-(4-Chlorophenyl)-2-methyl-5-trifluoro-
methyl-2,5-decadiene (5d). H NMR (CDCl3) d 0.85 (3H,
1
1
1.03–1.13 (4H, m), 2.13 (2H, d, JZ7.2 Hz), 7.18 (2H, d, JZ
8.3 Hz), 7.29 (2H, d, JZ8.3 Hz), 7.35–7.46 (5H, m); 19F
NMR (CDCl3) d K56.43 (3F, s); 13C NMR (CDCl3) d 13.6,
22.2, 29.3, 36.7, 123.2 (q, JZ274.9 Hz), 125.3, 127.2,
127.2, 128.2, 128.4, 128.8, 129.8, 133.4, 134.6, 138.2, 149.3
(q, JZ2.4 Hz); IR (neat) n 2929, 2862, 1643 cmK1; HRMS
(FAB) calcd for C19H1835ClF3 (MC) 338.1049, found
338.1051.
t, JZ6.8 Hz), 1.21–1.29 (4H, m), 1.70 (3H, s), 1.74 (3H, s),
2.31–2.35 (2H, m), 3.01 (2H, d, JZ6.8 Hz), 5.10 (1H, t, JZ
6.8 Hz), 7.03 (2H, d, JZ8.5 Hz), 7.29 (2H, d, JZ8.5 Hz);
19F NMR (CDCl3) d K62.10 (3F, s); 13C NMR (CDCl3)
d 13.9, 17.8, 22.7, 25.7, 27.1, 29.3, 35.8, 121.1, 124.9 (q,
JZ276.0 Hz), 126.0 (q, JZ27.3 Hz), 128.0, 128.9 (d,
JZ2.0 Hz), 132.8, 133.0, 139.40, 147.0 (q, JZ3.6 Hz);
IR (neat) n 2962, 2862, 1651, 1488 cmK1; HRMS (FAB)
calcd for C18H2235ClF3 (MC) 329.1283, found 329.1285.
4.6. The Sonogashira cross-coupling reaction of 8b with
trimethylsilyl acetylene
4.4.5. (Z)-Methyl 5-(4-chlorophenyl)-2-methylene-4-tri-
fluoromethyl-4-nonenate (5e). H NMR (CDCl3) d 0.81
1
(3H, t, JZ7.0 Hz), 1.17–1.27 (4H, m), 2.24–2.29 (2H, m),
3.35 (2H, s), 3.81 (3H, s), 5.62 (1H, s), 6.33 (1H, s), 7.06
(2H, d, JZ8.5 Hz), 7.32 (2H, d, JZ8.5 Hz); 19F NMR
(CDCl3) d K61.83 (3F, s); 13C NMR (CDCl3) d 13.8, 22.5,
29.1, 29.6, 36.0, 52.1, 123.9 (q, JZ275.8 Hz), 123.0 (q, JZ
28.0 Hz), 125.1, 128.1, 128.9, 133.3, 136.8, 138.5, 150.5 (q,
To a solution of 3-(4-chlorophenyl)-2-iodo-1,1,1-trifluoro-
2-heptene (100 mg, 0.260 mmol), trimethylsilylacetylene
(50 mg, 0.52 mmol) and copper (I) iodide (5 mg,
0.026 mmol) in THF (2.0 mL) was added Pd(PPh3)4
(13 mg, 0.02 mmol), Et3N (1.5 mL) and the whole was
stirred for 24 h at 50 8C. The reaction mixture was quenched
with NH4Cl aq. and extracted with Et2O three times. The
combined organic layers were dried over Na2SO4 and
concentrated in vacuo. The residue was chromatographed
on silica gel to afford (Z)-4-(4-chlorophenyl)-3-trifluoro-
methyl-1-trimethylsilyl-3-heptene-1-yne (90 mg, 0.247 mmol,
95% yield).
JZ3.1 Hz); IR (neat) n 2958, 2837, 1724, 1635, 1488 cmK1
;
HRMS (FAB) calcd for C18H2135ClF3O2 (MC) 361.1183,
found 361.1180.
4.4.6.
(Z)-5-(4-Chlorophenyl)-4-trifluoromethyl-4-
1
nonen-1-yne (5f). H NMR (CDCl3) d 0.86 (3H, t, JZ

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T. Konno et al. / Tetrahedron 61 (2005) 9391–9404
4.6.1. (Z)-4-(4-Chlorophenyl)-3-trifluoromethy-1-tri-
methylsilyl-3-hepten-1-yne (7g). 1H NMR (CDCl3) d
0.25 (9H, s), 0.89 (3H, t, JZ7.0 Hz), 1.33 (4H, m), 2.70
(2H, t, JZ6.7 Hz), 7.05 (2H, d, JZ8.5 Hz), 7.32 (2H, d, JZ
8.5 Hz); 19F NMR (CDCl3) d K57.42 (3F, s); 13C NMR
(CDCl3) d 0.3, 13.8, 22.4, 29.0, 38.8, 97.3, 102.8, 112.9 (q,
JZ33.2 Hz), 121.5 (q, JZ274.7 Hz), 128.3, 128.4, 134.1,
137.0, 158.7 (q, JZ2.6 Hz); IR (neat) n 2862, 2152,
1488 cmK1; HRMS (EI) calcd for C18H2235ClF3Si (MC)
358.1131, found 358.1137. Anal. Calcd: C, 60.24; H, 6.18.
Found: C, 60.06; H, 6.18.
3062, 3031, 1666, 1596 cmK1; HRMS (EI) calcd for
C16H1235ClF3 (MC) 296.0580, found 296.0579. Anal.
Calcd: C, 64.77; H, 4.08. Found: C, 65.20; H, 4.03.
4.7.4. (4Z)-4-(4-Chlorophenyl)-6,6,6-trifluoro-1,4-hexa-
1
diene (3n). H NMR (CDCl3) d 3.11 (2H, d, JZ5.5 Hz),
5.11 (1H, d, JZ17.0 Hz), 5.16 (1H, d, JZ10.0 Hz), 5.72
(2H, m), 7.13 (2H, d, JZ8.0 Hz), 7.33 (2H, d, JZ8.0 Hz);
19F NMR (CDCl3) d K56.68 (3F, d, JZ8.0 Hz); 13C NMR
(CDCl3) d 43.8, 116.6 (q, JZ34.0 Hz), 119.0, 124.8 (q, JZ
270.4 Hz), 128.4, 128.6, 132.9, 134.1, 136.7, 151.2 (q, JZ
5.0 Hz); IR (neat) n 3082, 1670, 1639, 1596 cmK1; HRMS
(FAB) calcd for C12H1035ClF3 (MC) 246.0423, found
246.0420. Anal. Calcd: C, 58.43; H, 4.08. Found: C,
58.15; H, 3.98.
4.7. Typical procedure for the carbocupration of
fluorine-containing acetylene derivatives with Grignard
reagents
To a solution of CuBr (47 mg, 0.328 mmol) in THF (2 mL)
was added a THF solution of n-butylmagnesium bromide
(0.66 mmol, prepared by magnesium and 1-bromobutane) at
K78 8C. After stirring for 10 min, the reaction mixture was
allowed to warm to K15 8C, then stirred for 5 min. The
reaction mixture was again cooled to K78 8C, and to this
mixture was added a solution of 1-(4-chlorophenyl)-3,3,3-
trifluoropropyne (49 mg, 0.240 mmol) in THF (2 mL). After
stirring at that temperature for 2 h, the reaction was
quenched with NH3 aq./MeOH, and the whole was extracted
with EtOAc three times. The combined organic layers were
washed with NaCl aq., dried over anhydrous Na2SO4, then
concentrated in vacuo. The residue was purified by silica gel
column chromatography to give the corresponding (Z)-3-(4-
chlorophenyl)-1,1,1-trifluoro-2-heptene (52 mg, 0.198 mmol,
83% yield).
4.7.5. (3Z)-3-(4-Chlorophenyl)-5,5,5-trifluoro-1,3-penta-
diene (3o). H NMR (CDCl3) d 5.01 (1H, d, JZ17.2 Hz),
1
5.43 (1H, d, JZ10.4 Hz), 5.82 (1H, q, JZ8.1 Hz), 6.56 (2H,
dd, JZ10.4, 17.2 Hz), 7.11 (2H, d, JZ8.4 Hz), 7.37 (2H, d,
JZ8.4 Hz); 19F NMR (CDCl3) d K56.56 (3F, d, JZ
8.1 Hz); 13C NMR (CDCl3) d 118.8 (q, JZ33.6 Hz), 122.8
(q, JZ270.5 Hz), 123.4, 128.3, 128.6, 130.0, 132.8, 134.2,
149.1 (q, JZ5.5 Hz); IR (neat) n 2360, 1643, 1610,
1596 cmK1; HRMS (EI) calcd for C11H835ClF3 (MC)
262.0736, found 262.0735.
4.7.6. (Z)-1-(4-Chlorophenyl)-3,3,3-trifluoro-1-(4-meth-
oxyphenyl)-propene (3p). H NMR (CDCl3) d 3.81 (3H,
1
s), 6.06 (1H, q, JZ8.3 Hz), 6.85 (2H, d, JZ8.9 Hz), 7.1d 6
(2H, d, JZ8.3 Hz), 7.17 (2H, d, JZ8.9 Hz), 7.37 (2H, d,
JZ8.3 Hz); 19F NMR (CDCl3) d K57.23 (3F, d, JZ
8.3 Hz); 13C NMR (CDCl3) d 55.4, 113.9 (q, JZ34.1 Hz),
113.9, 123.1 (q, JZ270.5 Hz), 128.3, 129.3, 131.9, 134.5,
135.9, 150.6 (q, JZ5.8 Hz), 160.8; IR (neat) n 1604, 1512,
1490 cmK1; HRMS (FAB) calcd for C16H1235ClF3O (MC)
312.0529, found 312.0526.
4.7.1. (Z)-3-(4-Chlorophenyl)-1,1,1-trifluoro-4-methyl-2-
1
hexene (3k). H NMR (CDCl3) d 0.92 (3H, t, JZ7.5 Hz),
1.05 (3H, d, JZ6.5 Hz), 1.26 (1H, dq, JZ7.5, 21.0 Hz),
1.46 (1H, m), 2.34 (1H, q, JZ6.5 Hz), 5.65 (1H, q, JZ
7.8 Hz), 7.05 (2H, d, JZ8.5 Hz), 7.32 (2H, d, JZ8.5 Hz);
19F NMR (CDCl3) d K56.25 (3F, d, JZ7.8 Hz); 13C NMR
(CDCl3) d 11.5, 18.4, 27.1, 44.1, 115.7 (q, JZ33.3 Hz),
122.9 (q, JZ271.2 Hz), 128.0, 129.0, 133.7, 136.1, 157.3
4.7.7. (Z)-3-(3-Chlorophenyl)-1,1,1-trifluoro-2-heptene
1
(3q). H NMR (CDCl3) d 0.89 (3H, t, JZ7.0 Hz), 1.33
(q, JZ5.2 Hz); IR (neat) n 2966, 2935, 2877, 1662 cmK1
;
(4H, m), 2.37 (2H, m), 5.67 (1H, q, JZ8.0 Hz), 7.05 (1H, d,
JZ7.0 Hz), 7.16 (1H, s), 7.24–7.32 (2H, m); 19F NMR
(CDCl3) d K56.62 (3F, d, JZ8.0 Hz); 13C NMR (CDCl3) d
13.8, 22.1, 29.1, 39.6, 115.8 (q, JZ33.4 Hz), 122.6 (q, JZ
271.2 Hz), 125.5, 127.1, 128.0, 129.3, 133.9, 140.2, 152.8
(q, JZ5.7 Hz); IR (neat) n 2963, 2936, 2874, 2500, 1666,
1600 cmK1; HRMS (CI) calcd for C13H1435ClF3 (MC)
262.0736, found 262.0739. Anal. Calcd: C, 59.44; H, 5.17.
Found: C, 59.67; H, 5.17.
HRMS (FAB) calcd for C13H1435ClF3 (MC) 262.0736,
found 262.0735.
4.7.2. (Z)-1-(4-Chlorophenyl)-1-cyclohexyl-3,3,3-tri-
fluoropropene (3l). H NMR (CDCl3) d 1.08–1.40 (5H,
1
m), 1.66–1.98 (5H, m), 2.16 (1H, t, JZ11.7 Hz), 5.62 (1H,
q, JZ8.0 Hz), 7.04 (2H, d, JZ8.4 Hz), 7.31 (2H, d, JZ
8.4 Hz); 19F NMR (CDCl3) d K56.17 (3F, d, JZ8.0 Hz);
13C NMR (CDCl3) d 25.9, 26.3, 31.3, 46.8, 114.7 (q, JZ
33.3 Hz), 123.1 (q, JZ271.2 Hz), 128.0, 128.9, 133.6,
136.6, 158.0 (q, JZ5.4 Hz); IR (neat) n 2931, 2856, 1664,
1595 cmK1; HRMS (EI) calcd for C15H1635ClF3 (MC)
288.0893, found 288.0897.
4.7.8. (Z)-3-(2-Chlorophenyl)-1,1,1-trifluoro-2-heptene
1
(3r). H NMR (CDCl3) d 0.83 (3H, t, JZ6.5 Hz), 1.25–
1.37 (4H, m), 2.32 (2H, t, JZ7.0 Hz), 5.69 (1H, q, JZ
7.5 Hz), 7.01 (1H, d, JZ9.0 Hz), 7.16–7.21 (2H, m), 7.32
(1H, d, JZ9.0 Hz); 19F NMR (CDCl3) d K58.72 (3F, d, JZ
7.5 Hz); 13C NMR (CDCl3) d 13.8, 22.2, 29.0, 38.0, 116.5
(q, JZ33.8 Hz), 122.6 (q, JZ271.1 Hz), 126.2, 129.0,
129.3, 129.3, 129.4, 131.4, 151.7 (q, JZ5.8 Hz); IR (neat) n
3066, 2960, 2933, 2864, 1672, 1593 cmK1; HRMS
(CI) calcd for C13H1435ClF3 (MC) 262.0736, found
262.0744. Anal. Calcd: C, 59.44; H, 5.17. Found: C,
59.79; H, 5.01.
4.7.3. (Z)-2-(4-Chlorophenyl)-4,4,4-trifluoro-1-phenyl-2-
butene (3m). 1H NMR (CDCl3) d 3.65 (2H, s), 5.59 (1H, q,
JZ8.0 Hz), 7.01 (2H, d, JZ8.0 Hz), 7.08 (2H, d, JZ
8.0 Hz), 7.22–7.30 (5H, m); 19F NMR (CDCl3) d K56.72
(3F, d, JZ8.0 Hz); 13C NMR (CDCl3) d 46.2, 117.4 (q, JZ
33.6 Hz), 121.6 (q, JZ271.3 Hz), 127.1, 128.3, 128.7,
129.3, 134.0, 136.1, 136.4, 152.3 (q, JZ5.5 Hz); IR (neat) n

T. Konno et al. / Tetrahedron 61 (2005) 9391–9404
9401
4.7.9. (Z)-1,1,1-Trifluoro-3-[(4-methoxyphenyl)methyl]-
2-heptene (3s). 1H NMR (CDCl3) d 0.86 (3H, t, JZ
7.4 Hz), 1.24 (2H, tq, JZ7.4, 7.5 Hz), 1.38 (2H, tt, JZ7.5,
7.6 Hz), 3.54 (2H, s), 3.79 (3H, s), 5.54 (1H, q, JZ8.5 Hz),
6.83 (2H, d, JZ8.4 Hz), 7.09 (2H, d, JZ8.4 Hz); 19F NMR
(CDCl3) d K56.01 (3F, d, JZ8.5 Hz); 13C NMR (CDCl3) d
13.8, 22.2, 29.4, 35.2, 36.4, 55.2, 113.9, 114.8 (q, JZ
32.9 Hz), 123.5 (q, JZ274.9 Hz), 129.7, 129.8, 129.9, 154.2
(q, JZ5.2 Hz), 158.3; IR (neat) n 2933, 2861, 2837, 1668,
1612 cmK1; HRMS (FAB) calcd for C15H1935ClF3 (MC)
272.1388, found 272.1387.
washed with NaCl aq., dried over anhydrous Na2SO4, then
concentrated in vacuo. The residue was purified by silica gel
column chromatography to give the corresponding (E)-3-(4-
chlorophenyl)-1,1,1-trifluoro-2-iodo-2-heptene (152 mg,
0.392 mmol, 85% yield).
4.10. Typical procedure for the carbocupration of
fluorine-containing acetylene derivatives with organo-
zinc reagents
To a suspension of CuBr (50 mg, 0.349 mmol) in THF
(4 mL) was added a THF solution of n-BuZnI (0.73 M,
0.95 mL, 0.697 mmol) at K78 8C for 20 min. To this
solution was added dropwise a solution of 1-(4-chloro-
phenyl)-3,3,3-trifluoropropyne (57 mg, 0.279 mmol) in
THF (2 mL). After stirring at that temperature for 2 h,
DMF (6 mL) was added as a co-solvent. The whole was
allowed to warm to room temperature, and then to this
solution was added a solution of iodine (355 mg,
1.40 mmol) in THF (2 mL). After stirring of the reaction
mixture for 1 h, the reaction was quenched with NH3 aq./
MeOH, and a few drops of Na2SO3 were added until the
color of the reaction mixture changed. The whole was
extracted with Et2O three times. The combined organic
layers were washed with NaCl aq., dried over anhydrous
Na2SO4, then concentrated in vacuo. The residue was
purified by silica gel column chromatography to give the
corresponding (E)-3-(4-chlorophenyl)-1,1,1-trifluoro-2-
iodo-2-heptene (98 mg, 0.252 mmol, 90% yield).
4.7.10. (5Z,7Z)-5,8-Bis(4-chlorophenyl)-6,7-bis(trifluoro-
methyl)-5,7-dodecadiene (8). 1H NMR (CDCl3) d 0.85
(6H, t, JZ7.3 Hz), 1.15–1.25 (4H, m), 1.26–1.33 (4H, m),
2.34–2.42 (2H, m), 2.48–2.60 (2H, m), 7.12 (4H, d, JZ
8.5 Hz), 7.37 (4H, d, JZ8.5 Hz); 19F NMR (CDCl3) d
K55.58 (6F, s); 13C NMR (CDCl3) d 13.7, 22.8, 28.6, 37.2,
122.1 (q, JZ31.8 Hz), 122.5 (q, JZ275.9 Hz), 128.3,
128.7, 133.9, 136.7, 154.4; IR (neat) n 2962, 2873, 1631,
1488 cmK1; HRMS (FAB) calcd for C26H2635Cl2F6 (MC)
522.1316, found 522.1309.
4.8. Typical procedure for the carbocupration of the
fluorine-containing acetylene derivatives and the
following coupling reaction of various carbon
electrophiles
To a solution of CuBr (96 mg, 0.669 mmol) in THF (4 mL)
was added a THF solution of n-butylmagnesium chloride
(1.34 mmol, purchased from Aldrich) at K78 8C. After
stirring for 10 min, the reaction mixture was allowed to
warm to K15 8C, then stirred for 5 min. The reaction
mixture was again cooled to K78 8C, and to this mixture
was added a solution of 1-(4-chlorophenyl)-3,3,3-trifluoro-
propyne (114 mg, 0.56 mmol) in THF (2 mL). After stirring
at that temperature for 2 h, allyl bromide (324 mg,
2.68 mmol) was added slowly to the reaction mixture.
After stirring of the solution for 1 h, the reaction was
quenched with NH3 aq./MeOH, and the whole was extracted
with EtOAc three times. The combined organic layers were
washed with NaCl aq., dried over anhydrous Na2SO4, then
concentrated in vacuo. The residue was purified by silica gel
column chromatography to give the corresponding (4Z)-5-
(4-chlorophenyl)-4,4,4-trifluoro-1,3-nonadiene (110 mg,
0.364 mmol, 77% yield).
4.10.1. (Z)-3-(4-Chlorophenyl)-1,1,1-trifluoro-2-pentene
(3t). 1H NMR (CDCl3) d 1.03 (3H, t, JZ7.4 Hz), 2.40 (2H,
q, JZ7.4 Hz), 5.66 (1H, q, JZ8.0 Hz), 7.11 (2H, d, JZ
8.4 Hz), 7.33 (2H, d, JZ8.4 Hz); 19F NMR (CDCl3) d
K56.50 (3F, d, JZ8.0 Hz); 13C NMR (CDCl3) d 11.8, 32.9,
114.9 (q, JZ33.6 Hz), 122.8 (q, JZ270.9 Hz), 128.3,
128.5, 133.9, 136.9, 154.4 (q, JZ5.5 Hz); IR (neat) n
2976, 2943, 1492, 1465 cmK1; HRMS (FAB) calcd
for C11H1035ClF3 (MC) 234.0423, found 234.0421.
4.10.2. Methyl (Z)-4-(4-chlorophenyl)-6,6,6-trifluoro-4-
hexenoate (3u). 1H NMR (CDCl3) d 2.36 (2H, t, JZ
7.5 Hz), 2.71 (2H, t, JZ7.5 Hz), 3.65 (3H, s), 5.72 (1H, q,
JZ7.9 Hz), 7.11 (2H, d, JZ8.4 Hz), 7.33 (2H, d, JZ
8.4 Hz); 19F NMR (CDCl3) d K56.87 (3F, d, JZ7.9 Hz);
13C NMR (CDCl3) d 31.6, 34.8, 51.8, 116.8 (q, JZ33.7 Hz),
122.4 (q, JZ271.1 Hz), 128.5, 128.7, 134.3, 135.6, 151.0
4.9. Preparation of fluorine-containing vinyl iodide
(q, JZ5.5 Hz), 172.3; IR (neat) n 2955, 1740, 1668 cmK1
;
To a solution of CuBr (91 mg, 0.634 mmol) in THF (4 mL)
was added a THF solution of n-butylmagnesium chloride
(1.260 mmol, purchased from Aldrich) at K78 8C. After
stirring for 10 min, the reaction mixture was allowed to
warm to K15 8C, then stirred for 5 min. The reaction
mixture was again cooled to K78 8C, and to this mixture
was added a solution of 1-(4-chlorophenyl)-3,3,3-trifluoro-
propyne (94 mg, 0.459 mmol) in THF (2 mL). After stirring
at that temperature for 2 h, iodine (644 mg, 2.54 mmol) in
THF (2 mL) was added to the reaction mixture slowly. After
1 h, the reaction was quenched with NH3 aq./MeOH, and a
few drops of Na2SO3 were added until the color of the
reaction mixture changed. The whole was extracted with
EtOAc three times. The combined organic layers were
HRMS (FAB) calcd for C13H1335ClF3O2 (MC) 293.0556,
found 293.0563.
4.10.3. (Z)-4-(4-Chlorophenyl)-6,6,6-trifluoro-4-hexene-
nitrile (3v). 1H NMR (CDCl3) d 1.70 (2H, tt, JZ7.0,
7.6 Hz), 2.34 (2H, t, JZ7.0 Hz), 2.57 (2H, t, JZ7.6 Hz),
5.76 (1H, q, JZ7.9 Hz), 7.11 (2H, d, JZ8.3 Hz), 7.36 (2H,
d, JZ8.3 Hz); 19F NMR (CDCl3) d K56.82 (3F, d, JZ
7.9 Hz); 13C NMR (CDCl3) d 16.4, 22.8, 38.3, 117.4 (q, JZ
34.0 Hz), 118.7, 122.2 (q, JZ271.3 Hz), 128.5, 128.7,
134.6, 135.3, 150.5 (q, JZ5.4 Hz); IR (neat) n 2943, 2248,
1668 cmK1; HRMS (FAB) calcd for C13H1135ClF3N (MC)
273.0532, found 273.0528.

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T. Konno et al. / Tetrahedron 61 (2005) 9391–9404
4.11. Typical procedure for the carbocupration of the
fluorine-containing acetylene derivatives with organo-
zinc reagents and the following coupling reaction of
various electrophiles
then concentrated in vacuo. Without purification, the
reaction mixture was used for next reaction.
To a solution of NaH (12 mg, 0.494 mmol) in DMF (4 mL)
was added a solution of the above-obtained crude product in
DMF (2 mL) at 0 8C, and the resulting mixture was stirred at
this temperature for 30 min. Then 2-chloroethyl tosylate
(116 mg, 0.494 mmol) was added to this mixture. The
reaction mixture was allowed to 80 8C. After 2 h, the
reaction was quenched with saturated NH4Cl aq., and
the whole was extracted with EtOAc three times. The
combined organic layers were washed with NaCl aq., dried
over Na2SO4, and then concentrated in vacuo. The residue
was purified by silica gel column chromatography to give
the corresponding (Z)-1-[4-(2-chloroethoxy)phenyl]-3,3,3-
trifluoro-2-iodo-1-phenylpropene (74 mg, 0.163 mmol,
67% yield).
To a suspension of CuBr (50 mg, 0.349 mmol) in THF
(4 mL) was added Et2Zn (0.70 ml, 0.700 mmol) at K45 8C
for 20 min. To this solution was added dropwise a solution
of 1-(4-chlorophenyl)-3,3,3-trifluoropropyne (63 mg,
0.308 mmol) in THF (2 mL). After stirring at that
temperature for 2 h, DMF (6 mL) was added as additive.
The whole was stirred for 10 min, then to this solution was
added a solution of iodine (355 mg, 1.40 mmol) in THF
(2 mL). After 1 h later, the reaction was quenched with NH3
aq./MeOH, and a few drops of Na2SO3 were added until
color of the reaction mixture was changed. And the whole
was extracted with Et2O three times. The combined organic
layers were washed with NaCl aq., dried over anhydrous
Na2SO4, then concentrated in vacuo. The residue was
purified by silica gel column chromatography to give the
corresponding (E)-3-(4-chlorophenyl)-1,1,1-trifluoro-2-
iodo-2-pentene (81 mg, 0.225 mmol, 73%).
4.12.2. (Z)-3,3,3-Trifluoro-2-iodo-1-[4-(2-chloroethoxy)
phenyl]-1-phenylpropene (14x). H NMR (CDCl3) d 3.82
1
(2H, t, JZ5.8 Hz), 4.23 (2H, t, JZ5.8 Hz), 6.89 (2H, d, JZ
8.7 Hz), 7.15–7.32 (7H, m); 19F NMR (CDCl3) d K54.26
(3F, s); 13C NMR (CDCl3) d 44.7, 67.9, 85.8 (q, JZ
34.3 Hz), 114.3, 121.3 (q, JZ274.0 Hz), 128.1, 128.4,
129.9, 138.4, 139.5, 158.3 (q, JZ6.4 Hz); IR (KBr) n 1606,
1510, 1454, 1296, 1249 cmK1; HRMS (FAB) calcd for
C17H1335ClF3IO (MC) 451.9652, found 451.9656. Anal.
Calcd: C, 45.11; H, 2.89. Found: C, 45.18; H, 2.80.
4.12. Total synthesis of panomifene
To a solution of CuCN (56 mg, 0.625 mmol) and 3,3,3-
trifluoro-1-phenylpropyne (81 mg, 0.476 mmol) in THF
(4 mL) was added p-methoxyphenylmagnesium bromide
(1.25 mmol, purchased from Aldrich) at K45 8C. After
stirring for 10 min, the reaction mixture was allowed to
warm to K5 8C, then stirred for 30 min. The reaction
mixture was again cooled to K45 8C. After stirring at that
temperature for 2 h, iodine (635 mg, 2.50 mmol) in THF
(2 mL) was added slowly. After 1 h, the reaction was
quenched with NH3 aq./MeOH, and a few drops of Na2SO4
were added until the color of the reaction mixture changed.
The whole was extracted with EtOAc three times. The
combined organic layers were washed with NaCl aq., dried
over anhydrous Na2SO4, then concentrated in vacuo. The
residue was purified by silica gel column chromatography to
give the corresponding (Z)-3,3,3-trifluoro-2-iodo-1-(4-
methoxyphenyl)-1-phenylpropene (99 mg, 0.245 mmol,
51% yield).
A solution of (Z)-1-[4-(2-chloroethoxy)phenyl]-3,3,3-tri-
fluoro-2-iodo-1-phenylpropene (59 mg, 0.130 mmol) and
Pd(PPh3)4 (16 mg, 0.013 mmol) in benzene (5 mL) was
added Na2CO3 (34 mg, 0.325 mmol), PhB(OH)2 (63 mg,
0.517 mmol), H2O (0.15 mL) and EtOH (0.15 mL). The
whole was refluxed for 12 h, then the reaction was quenched
with saturated NH4Cl aq., and the whole was extracted with
EtOAc three times. The combined organic layers were
washed with NaCl aq., dried over Na2SO4, and then
concentrated in vacuo. The residue was purified by silica
gel column chromatography to give the corresponding (E)-
1-[4-(2-chloroethoxy)phenyl]-3,3,3-trifluoro-1,2-diphenyl-
propene (52 mg, 0.130 mmol, 100% yield).
4.12.3. (E)-3,3,3-Trifluoro-1-[4-(2-chloroethoxy)phenyl]-
1,2-diphenylpropene (15x). Mp 108–109 8C; 1H NMR
(CDCl3) d 3.63 (3H, t, JZ5.8 Hz), 3.99 (3H, t, JZ5.8 Hz),
6.48 (2H, d, JZ8.8 Hz), 6.48 (2H, d, JZ8.8 Hz), 6.74 (2H,
d, JZ8.8 Hz), 7.14–7.31 (10H, m); 19F NMR (CDCl3) d
K57.05 (3F, s); 13C NMR (CDCl3) d 41.7, 67.7, 113.7,
123.7 (q, JZ275.5 Hz), 127.8, 127.8, 127.9, 128.0, 128.6,
128.6 (q, JZ28.8 Hz), 131.4, 131.5, 134.0, 135.3, 140.2,
149.6 (q, JZ3.4 Hz), 157.3; IR (KBr) n 1606, 1510,
1326 cmK1; HRMS (FAB) calcd for C23H1835ClF3O (MC)
402.0998, found 402.0995. Anal. Calcd: C, 68.58; H, 4.50.
Found: C, 68.23; H, 4.18.
4.12.1. (Z)-3,3,3-Trifluoro-2-iodo-1-(4-methoxyphenyl)-
1-phenylpropene (5x). H NMR (CDCl3) d 3.81 (3H, s),
1
6.87 (2H, d, JZ8.2 Hz), 7.13–7.17 (4H, m), 7.30–7.31 (3H,
m); 19F NMR (CDCl3) d K54.21 (3F, s); 13C NMR (CDCl3)
d 55.2, 85.2 (q, JZ34.2 Hz), 113.7, 121.4 (q, JZ270.5 Hz),
128.1, 128.1, 129.8, 137.7, 139.7, 158.6 (q, JZ3.2 Hz),
160.8; IR (neat) n 1604, 1508, 1461 cmK1; HRMS (FAB)
calcd for C16H12F3IO (MC) 403.9885, found 403.9889.
Anal. Calcd: C, 47.55; H, 2.99. Found: C, 47.54; H, 2.71.
To a solution of (Z)-3,3,3-trifluoro-2-iodo-1-(4-methoxy-
phenyl)-1-phenylpropene (100 mg, 0.247 mmol) in CH2Cl2
(5 mL) was added a CH2Cl2 solution of boron tribromide
(0.5 mmol, purchased from Aldrich) at room temperature.
After stirring at that temperature for 1 h, the reaction was
quenched with saturated NH4Cl aq., and the whole was
extracted with EtOAc three times. The combined organic
layers were washed with NaCl aq., dried over Na2SO4, and
A mixture of (E)-1-[4-(2-chloroethoxy)phenyl]-3,3,3-tri-
fluoro-1,2-diphenylpropene (84 mg, 0.201 mmol) and
2-methoxyethanol (3 mL) was refluxed for 10 h. It was
diluted with dichloromethane and washed with 4% aqueous
NaOH solution and water, dried (Na2SO4) and evaporated.
The residue was purified by silica gel column

T. Konno et al. / Tetrahedron 61 (2005) 9391–9404
9403
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chromatography to give the target compound, panomifene
(71 mg, 0.167 mmol, 83% yield).
4.12.4. (E)-3,3,3-Trifluoro-1-{4-[2-(2-hydroxyethyl-
amino)ethoxy]phenyl}-1,2-diphenylpropene (Pano-
1
mifene, 10). Mp 96–98 8C; H NMR (CDCl3) d 2.02 (2H,
br s), 2.73 (2H, t, JZ5.1 Hz), 2.86 (2H, t, JZ5.1 Hz), 3.55
(2H, t, JZ5.1 Hz), 3.85 (2H, t, JZ5.1 Hz), 6.48 (2H, d, JZ
8.7 Hz), 6.74 (2H, d, JZ8.7 Hz), 7.14–7.31 (10H, m); 19F
NMR (CDCl3) d K55.94 (3F, s); 13C NMR (CDCl3) d 48.1,
50.7, 60.8, 67.1, 113.5, 123.7 (q, JZ274.9 Hz), 127.7,
129.8, 127.9, 128.0, 128.3 (q, JZ28.4 Hz), 128.6, 131.40,
131.50, 133.50, 135.34, 140.79, 149.70 (q, JZ2.8 Hz),
157.87; IR (KBr) n 3348, 3032, 2925, 1735, 1606, 1573,
1510, 1445, 1415, 1363, 1249, 1074, 981, 952, 918, 821,
762, 707, 630, 588 cmK1; HRMS (FAB) calcd for
C25H25F3NO2 (MCH) 428.1837, found 428.1839. Anal.
Calcd: for C25H25F3NO2: C, 70.24; H, 5.66; N, 3.28. Found:
C, 69.44; H, 5.84; N, 3.18.
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Posner, G. H. Org. React. 1975, 22, 253–400. (g) Posner, G. H.
Org. React. 1972, 19, 1–113.
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Toldy, L.; Borvendeg, J.; Csanyi, E.; Kiss, E.; Hermann-
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