A highly stereoselective preparation of CF3-substituted 1-aryl-1,2-diphenylethenes: Application to the synthesis of panomifene

Article abstract of DOI:10.1016/j.tetlet.2005.03.117

β-CF₃-α,β-diphenylvinyl sulfide 3a was prepared stereoselectively in 77% yield from the reaction of 2 with phenyllithium at room temperature for 5 h. Oxidation of 3a with MCPBA afforded the corresponding vinyl sulfone 4a, in which (E)-4a can be

Full text of DOI:10.1016/j.tetlet.2005.03.117

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3545–3548
A highly stereoselective preparation of CF3-substituted
1-aryl-1,2-diphenylethenes: application to the synthesis
of panomifene
Myong Sang Kim and In Howa Jeong*
Department of Chemistry, Yonsei University, Wonju 220-710, Republic of Korea
Received 7 February 2005; revised 7 March 2005; accepted 11 March 2005
Available online 5 April 2005
Abstract—b-CF3-a,b-diphenylvinyl sulfide 3a was prepared stereoselectively in 77% yield from the reaction of 2 with phenyllithium
at room temperature for 5 h. Oxidation of 3a with MCPBA afforded the corresponding vinyl sulfone 4a, in which (E)-4a can be
crystallized in a mixture of CH2Cl2 and hexane. The addition–elimination reaction of (E)-4a with phenyllithium having substituents
on the benzene ring provided 5a–j in 51–82% yields stereospecifically. Similarly, the treatment of (E)-4a with p-chloro-
ethoxyphenyllithium in the presence of 12-crown-4 (20 mol %) at ꢀ10 °C, followed by slowly warming to room temperature,
resulted in the formation of the corresponding panomifene precursor 6 in 82% yield.
Ó 2005 Elsevier Ltd. All rights reserved.
Triarylethene unit is a key framework in many nonste-
roidal antiestrogens, which exhibit mammary tumor
inhibiting properties.1 Tamoxifen, the most attractive
one among compounds having triarylethene framework,
is a drug in widespread clinical use for the treatment of
all stages of hormone dependent breast cancer.2 Only
the Z-isomer of tamoxifen has the antiestrogenic activity
required for clinical use, whereas the E-isomer has estro-
genic properties, which would oppose the action of
tamoxifen.3 Panomifene, a CF3-substituted tamoxifen-
like compound, exhibits antiestrogenic and tumor inhib-
iting activities superior to those of tamoxifen in the only
E isomer.4 Therefore, highly stereocontrolled synthesis
of the E-isomer of panomifene is a quite important
subject in recent years. Several methods for the stereo-
controlled preparation of panomifene have been docu-
mented in previous literatures since the first patent.4
Simig and co-workers, prepared panomifene via
the highly stereoselective dehydration5 of 3,3,3-triflu-
oro-1-{4-[2-(methoxymethoxy)ethoxy]phenyl}-1,2-diphen-
ylpropan-1-ol (diastereoisomer ratio = 7.9:1), which
was formed from the reaction of a-(trifluoromethyl)-
phenylacetic acid6,7 with 4-[2-(methoxymethoxy)eth-
oxy]phenylmagnesium bromide. Recently, a novel
method for the preparation of panomifene was accom-
plished via the Pd-catalyzed cross-coupling reaction of
aryl iodides with b-CF3-substituted alkenyl boronates,
generated high stereoselectively from the reaction of di-
chlorohydrines with 3 equiv of aryllithium,8,9 followed by
treatment with (Bpin)2.10 Konno also prepared panom-
ifene via the Suzuki–Miyaura cross-coupling reaction of
phenylboronic acid with a-CF3-substituted alkenyl
iodides formed from a highly regio- and stereoselective
carbocupration of trifluoromethylated internal alkynes,
followed by treatment with iodine.11 However, these
methods suffer from tedious procedure, low-yield prepa-
ration, and not easy availability of starting material. In
this communication, we wish to describe a simple and
highly stereoselective preparation of CF3-substituted
1-aryl-1,2-diphenylethenes from the b-CF3-a,b-diphen-
ylvinyl sulfone and apply this method to prepare anti-
estrogenic drug panomifene.
It has been reported that b-CF3-a,b-diphenylvinyl sul-
fone 4a (E:Z = 30:70) prepared via two steps from
1,1-bis(phenylthio)-2,2,3,3,3-pentafluoropropylbenzene12
was reacted with p-methoxyphenyllithium (1.1 equiv) in
ether at room temperature for 5 h to afford the corre-
sponding CF3-substituted 1-aryl-1,2-diphenylethene
derivative 5a (E:Z = 40:60).13 Although E-stereoselectiv-
ity for the formation of 5a was not accomplished in
this reaction, it was found that E-stereoselectivity was
Keywords: (E)-b-CF3-a,b-Diphenylvinyl sulfone; Highly stereoselec-
tive; CF3-Substituted 1-aryl-1,2-diphenylethenes; Panomifene.
*
Corresponding author. Tel.: +82 33 760 2240; fax: +82 33 760
2182; e-mail: jeongih@dragon.yonsei.ac.kr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.117

3546
M. S. Kim, I. H. Jeong / Tetrahedron Letters 46 (2005) 3545–3548
increased in the formation of 5a from the addition–elim-
ination reaction of 4a with p-methoxyphenyllithium.
This result prompted us to attempt another approach
to prepare 4a in high E-stereoselectivity. We started with
1,1,3,3,3-pentafluoro-2-phenylpropene 1.14,15 Although
1 undergoes direct addition–elimination reaction twice
with substituted phenyllithium to provide CF3-substi-
tuted 1-aryl-1,2-diphenylethene derivatives, this ap-
proach is not highly stereoselective.15 Treatment of 1
with sodium phenylthiolate in THF at room tempera-
ture for 12 h resulted in the formation of vinyl sulfide
2 (E:Z = 85:15) in 71% yield. The high E-stereoselectiv-
ity for the formation of 2 can be rationalized by thermo-
dynamic stabilities of two carbanion intermediates [A]
and [B] arising from the addition of 1 with sodium
phenylthiolate, in which intermediate [A] is thermody-
namically more stable than intermediate [B] because of
larger electrostatic repulsion between CF3 and phenyl-
thio groups in [B] than that between CF3 and fluorine
groups in [A].16,17 When 2 was reacted with 2 equiv of
phenyllithium in THF at room temperature for 5 h,
b-CF3-a,b-diphenylvinyl sulfide 3a (E:Z = 89:11) was
obtained in 77% yield. Subsequent oxidation of 3a with
MCPBA provided the corresponding vinyl sulfone 4a
(E:Z = 89:11) in 87% yield. The formation of 3a from
2 is a crucial stepto give E-isomer of 4a high stereoselec-
tively. The reaction of 4a with p-methoxyphenyllithium
(1.1 equiv) in ether at room temperature for 5 h to afford
the corresponding CF3-substituted 1-aryl-1,2-diphenyl-
ethene derivative 5a (E:Z = 93:7) in 78% yield. Pure
E-isomer of 4a can be obtained in 92% yield by recrys-
tallization of 4a (E:Z = 89:11) in a mixture of CH2Cl2
and hexane. However, we could not have a X-ray crys-
tallographic data for pure E-isomer of 4a because of
crystal problem of 4a.
ene ring are more shielded than those arranged to the
other side.18 Therefore, the methoxy protons in E-iso-
mer appears at d = 3.83 ppm in H NMR, whereas the
1
methoxy protons in Z-isomer appears at d = 3.64 ppm.
As a result of the chemical shift of methoxy group,
CF3 fluorine in E-isomer was observed at
d = ꢀ58.47 ppm, whereas the peak of CF3 fluorine in
Z-isomer appears at ꢀ53.87 ppm. The reaction of pure
(E)-4a with phenyllithium substituted by bromo, chloro,
fluoro, ethyl, methyl, and methoxy on the benzene ring
provided stereospecifically the corresponding E-isomer
of 1-aryl-1,2-diphenylethenes 5a–j in 51–82% yields.
The results of these reactions are summarized in Table
1. Stereoisomers of 5 were assigned in a similar manner
as shown in the determination of stereoisomer 4a.
Table 1. Preparation of (E)-CF3-substituted 1-aryl-1,2-diphenyleth-
enes 5
CF3
CF3
X
Li
ether, t(oC), 5 h
X
SO2Ph
(E)-4a
5
Compound no
X
t (°C)
Yield (%)a
E/Zb
5a
5b
5c
5d
5e
5f
p-OCH3
p-CH3
p-C2H5
p-Cl
25
25
78
74
75
79
77
82
78
51
69
56
99/1
99/1
99/1
99/1
99/1
99/1
99/1
99/1
99/1
99/1
25
25
p-Br
0!25
ꢀ5!25
25
p-CF3
p-SCH3
m-F
5g
5h
5i
ꢀ50!25
25
m-Cl
m-CF3
5j
0!25
Assignment of (E)-b-CF3-a,b-diphenylvinyl sulfone 4a
was established by assigning the isomers of b-CF3-a-
methoxyphenyl-b-phenylvinyl sulfone 4b, in which the
methoxy protons arranged to the same side with benz-
a Isolated yield.
b E/Z ratio was determined by 1H and 19F NMR spectroscopic
analysis.
X
CF3
CF3
CF3
Li
X
MCPBA
CH2Cl2, reflux, 24 h
PhSNa
THF, rt, 12 h
F
F
THF, rt, 5 h
F
SPh
2 (E : Z = 85 : 15)
SPh
71%
1
3a (X = H , 77%, E : Z = 89 : 11)
3b (X = p-OCH3, 73%, E : Z = 88 : 12)
CF3
CF3
H3CO
Li
X
X
ether, rt, 5 h
78%
SO2Ph
4a (X = H , 87%, E : Z = 89 : 11)
OCH3
4b (X = p-OCH3, 81%, E : Z = 88 : 12)
5a (X = H, E : Z = 93 : 7)
F
F
Ph
CF3
F
Ph
CF3
SPh
_
_
PhS
F
[A]
[B]

M. S. Kim, I. H. Jeong / Tetrahedron Letters 46 (2005) 3545–3548
3547
X
_
CF3
X
Ph
60o rotation
top attack
Ph
Ph
CF3
Ph
Ph
CF3
Ph
_
PhO2S
SO2Ph
(E)-4a
SO2Ph
[D]
[C]
bottom attack
-SO2Ph
_
SO2Ph
CF3
PhO2S
Ph
Ph
60o rotation
-SO2Ph
Ph
X
CF3
Ph
CF3
Ph
Ph
_
X
X
[F]
(E)-5
[E]
The stereospecificity for the formation of 5 can be
explained by the formation of stable carbanion inter-
mediate followed by elimination of sulfonyl group.
The conformational intermediates [C] and [E] could
be formed from topand bottom attack of the
substituted phenyllithium on (E)-4a, respectively. Rota-
tion of these two intermediates by 60° would result
in two reasonably stable conformational intermediates
[D] and [F], which quickly undergo the elimination
of sulfonyl groupto give ( E)-5. The high E-stereoselec-
tivity for the formation of 3 can also be explained
in a similar manner as shown in the formation of
(E)-5.
A typical reaction procedure for the preparation of 6 is as
follows. A 25 mL two-neck round bottom flask equipped
with a magnetic stirrer bar, a septum, and nitrogen tee
connected to an argon source was charged with p-chloro-
ethoxyiodobenzene (0.169 g, 6.0 mmol) and ether (5 mL)
and then cooled to ꢀ10 °C. n-BuLi (4.0 mmol, 2.5 M
solution in hexane) was slowly added into flask and then
the mixture was stirred at ꢀ10 °C for 1 h. (E)-4a (0.388 g,
1.0 mmol) dissolved in 1 mL of THF and 12-crown-4
(20 mol %) were added at ꢀ10 °C and then the reaction
mixture was stirred at ꢀ10 °C for 1 h, followed by slowly
warming to room temperature. After the reaction mix-
ture was allowed to stir at room temperature for 12 h
and then quenched with 1 N HCl, the reaction mixture
was extracted with ether twice. The ether solution was
dried over anhydrous MgSO4 and chromatographed on
SiO2 column. Elution with a mixture of hexane and ethyl
acetate (10:1) provided 0.330 g of 6 (E:Z = 99:1) in 82%
Since the preparation of panomifene via demethylation
of 5a, followed by chloroethylation and amination is te-
dious procedure,10 direct addition–elimination reaction
of (E)-4a with p-chloroethoxyphenyllithium should pro-
vide a simple and efficient method for the preparation of
panomifene precursor 6. Therefore, the reaction of (E)-
4a with p-chloroethoxyphenyllithium was carried out
under the similar reaction condition, but the reaction
was not proceeded at all and starting material was
recovered quantitatively. Addition of TMEDA (2 equiv)
in this reaction did not make any difference, but the use
of HMPA (2 equiv) resulted in the formation of 6 in
58% yield based on 70% conversion of 4a. When 4a
was reacted with p-chloroethoxyphenyllithium in ether
in the presence of catalytic amount of 12-crown-4
(20 mol %) at ꢀ10 °C for 1 h, followed by slowly warm-
ing to room temperature and then stirring for 12 h, de-
sired product 6 was obtained in 82% yield. Subsequent
amination of 6 with 2-aminoethanol in 2-methoxyetha-
nol at reflux temperature for 2 h afforded panomifene
7 in 82% yield.
1
yield. (E)-6: mp108–109 °C: H NMR (CDCl3) d 7.34–
7.24 (m, 10H), 6.82 (d, J = 8.8 Hz, 2H), 6.56 (d,
J = 8.8 Hz, 2H), 4.08 (t, J = 5.8 Hz, 2H), 3.71 (t,
J = 5.8 Hz, 2H); 19F NMR (CDCl3, internal standard
CFCl3) d ꢀ55.98 (s, 3F); MS, m/z (relative intensity)
404 (M++2, 33), 402 (M+, 100), 270 (16), 253 (9), 239
(14), 215 (6), 183 (6), 165 (6); IR (KBr) 3057, 2929,
1604, 1508, 1328, 1246, 1171, 1140, 1110, 826, 761,
705 cmꢀ1. Anal. Calcd for C23H18ClF3O: C, 68.64; H,
4.51. Found: C, 68.51; H, 4.47.
Acknowledgements
This work was supported by grant No (R05-2001-000-
00211-0) from the Basic Research Program of the Korea
Science and Engineering Foundation.
CF3
CF3
CF3
Li
OCH2CH2Cl/ether
NH2(CH2)2OH
12-crown-4, -10oC rt, 12 h
82%
CH3O(CH2)2OH, reflux, 2 h
SO2Ph
(E)-4a
82%
OCH2CH2NH(CH2)2OH
OCH2CH2Cl
6 (E : Z = 99 : 1)
7 (Panomifene)

3548
M. S. Kim, I. H. Jeong / Tetrahedron Letters 46 (2005) 3545–3548
9. Shimizu, M.; Fujimoto, T.; Liu, X.; Minezaki, H.;
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