A facile stereocontrolled approach to CF3-substituted triarylethenes: Synthesis of panomifene

Article abstract of DOI:10.1002/anie.200353032

The stereoselective preparation and Pd-catalyzed cross-coupling reaction of boronates 2 provides a new general and convenient route to CF ₃-substituted triaryl ethenes 3, in which the CF₃ and Ar³ groups are cis to each other. The synthetic potential was demonstrated by the total synthesis of panomifene (Ar¹ = Ar ³ = Ph, Ar² = 4-(OHCH₂CH₂NHCH ₂CH₂O)-C₆H₄). Bpin = (pinacolato)boryl.

Full text of DOI:10.1002/anie.200353032

Angewandte
Chemie
Organofluorine Compounds
A Facile Stereocontrolled Approach to CF3-
Substituted Triarylethenes: Synthesis of
Panomifene**
Xinyu Liu, Masaki Shimizu,* and Tamejiro Hiyama
Triaryl ethenes is a key structure in nonsteroidal antiestro-
gens.[1] In particular, tamoxifen (1) has been widely used for
clinical treatment of breast cancer.[2] The antiestrogenic
activity is known to depend on the olefin geometry of the
triaryl ethene component.[3] On the other hand, selective
À
À
replacement of C H bonds with C F bonds in biologically
active compounds has been proved to be the most effective
and powerful strategy in the optimization of parent com-
pounds.[4] This strategy, when applied to the exploration of
highly potent triaryl ethenes,[5,6] led to discovery of panomi-
fene (2),[6] which exhibits antiestrogenic and tumor-inhibiting
activities superior to those of 1. In viewof this history, a
general, convenient, and stereoselective synthetic method for
the preparation of CF3-substituted triaryl ethenes should
definitely open a newentry to highly potent nonsteroidal
antiestrogens.
We recently found that treatment of CF3-substituted
1
ꢀ
dichlorohydrin
3
(Ar = PhC C) with BuLi or PhLi
(3 equiv) in THF at À988C generated the corresponding
1
2
ꢀ
CF3-substituted lithio-oxirane 4 (Ar = PhC C, Ar = Bu or
Ph), which reacted with bis(pinacolato)diboron, (Bpin)2, to
1
2
ꢀ
afford 5 (Ar = PhC C, Ar = Bu or Ph) in high yields with
excellent diastereoselectivity (Scheme 1).[7] We envisioned
that the stereospecific cross-coupling reaction of b-CF3-
substituted alkenyl boronates 5 with Ar3X, if feasible, would
give rise to a series of compounds 6 conveniently and
stereoselectively. Herein we describe the success of this
[*] X. Liu, Dr. M. Shimizu, Prof. Dr. T. Hiyama
Department of Material Chemistry
Graduate School of Engineering, Kyoto University
Katsura Campus, Nishikyo-ku, Kyoto 615-8510 (Japan)
Fax: (+81)75-383-2445
E-mail: shimizu@npc05.kuic.kyoto-u.ac.jp
[**] This work was supportedby a Grant-in-Aidfor COE Research on
Elements Science, no. 12CE2005, from the Ministry of Education,
Culture, Sports, Science, andTechnology, Japan. 1,1-Difluoro-3,3,3-
trifluoropropan-2-one was kindly donated by Central Glass Co. Ltd.
We are grateful to Dr. Yi-Chou Tsai for a helpful literature survey.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 879 –879
DOI: 10.1002/anie.200353032
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
879

Communications
Table 2: Coupling reaction of 5a with iodobenzene.[a]
Scheme 1. Novel approach to CF3-substitutedtriarylethenes 6.
Bpin=(pinacolato)boryl.
Entry
Catalyst
H2O [equiv]
t [h]
Conv. [%][b]
6a/7[c]
1
2
3
[Pd(PPh3)4]
–
–
–
–
3
3
6
12
12
12
2
4
1.5
2
100
25
37
100
100
100
100
100
100(94)[f]
0:100
84:16
70:30
22:78
77:23
82:18
91:9
approach and demonstrate the versatility of the sequence
through the total synthesis of panomifene (2).
[PdCl2(PPh3)2]
[Pd(tBu3P)2]
[Pd(tBu3P)2]
[PdCl2(PPh3)2]
[Pd(tBu3P)2]
[Pd(tBu3P)2]
[Pd(tBu3P)2]
[Pd(tBu3P)2]
4[d]
5
Following our original protocol, we first treated a solution
of 3[8] in THF with Ar2Li (3 equiv) at lowtemperatures and
soon found that the corresponding lithio-oxiranes 4 could be
generated at À788C. The 3-aryl derivatives 4 (Ar2 = aryl) are
stable at À788C, in sharp contrast to 3-alkyl-substituted lithio-
oxiranes 4 (Ar2 = alkyl) whose reactions had to be conducted
at À988C. The enhanced stability of lithio-oxiranes 4 may be
ascribed to the anion-stabilizing effect of an Ar2 group in 4,[9]
which smoothly reacted with (Bpin)2 at À788C to room
temperature to give the corresponding compounds 5 in
moderate to good yields with high E selectivity (Table 1).
Fluorine, chlorine, methoxy, and methoxymethoxy (MOMO)
substituents on Ar1 and Ar2 were tolerated under these
conditions. The E configuration of 4 was confirmed by
conversion of 5a into a deborylated product (see below).
6
7
8
9
15
5
6
93:7
98:2
[e]
[a] Reaction conditions: 5a (0.5 mmol), iodobenzene (0.75 mmol),
palladium catalyst (0.05 mmol), Cs2CO3 (1.5 mmol), H2O (indicated
amount), dioxane (0.1 mL), 508C. [b] For entries 1–3, reaction was
terminatedafter 12 h. For entries 4–9, reaction was monitoredby TLC
andterminatedwhen 5a was completely consumed. [c] The ratio was
determined by 19F NMR analysis of crude product. [d] TlOEt was used
insteadof Cs 2CO3. [e] A 5m aqueous solution of Cs2CO3 was employed.
[f] The value in parentheses is the yieldof isolated 6a.
accelerated the reaction remarkably, but led to preferential
formation of 7 (Table 2, entry 4).[15] After several attempts, we
found that the addition of water also accelerated the coupling
reaction and was quite effective for the selective production
of 6a (Table 2, entries 5–9).[16] In particular, aqueous solution
of Cs2CO3 (5m) in combination with [Pd(tBu3P)2] allowed the
reaction to go to completion in 6 h, and 6a was isolated as a
single stereoisomer in 94% yield (6a/7 = 98:2; Table 2,
entry 9). The minor stereoisomer of 5a (Z isomer) did not
undergo the coupling reaction under these conditions,
although the reason is not clear at present.
Table 1: Stereoselective preparation of 5 from 3 with Ar2Li.[a]
Entry
3
Ar1
Ar2
5
Yield[%] [b] E/Z[c]
1
2
3
4
5
6
7
a
a
a
a
b
c
d
Ph
Ph
Ph
Ph
Ph
a
b
c
d
e
f
63
73
78
75
65
80
63
98:2
97:3
94:6
92:8
99:1
p-Cl-C6H4
p-MeO-C6H4
p-MOMO-C6H4
Ph
[d]
p-F-C6H4
p-Cl-C6H4
p-MeO-C6H4 Ph
Ph
99:1
>99:<1
g
The optimized conditions were applied to the synthesis of
several CF3-substituted triaryl ethenes 6 (Table 3). The yields
and selectivity of 6 were uniformly high. Both electron-
withdrawing and -donating group at para-position of any of
the aryl groups did not affect the performance of the coupling
reaction. Notably, the coupling reaction cleanly discriminates
Cl from I in 5 and Ar3-I (Table 3, entries 3, 6, 7, 11, 12). The
remaining Cl substituent can be elaborated for further
transformation (see below). In all cases, the Z isomer of 5
did not undergo reaction, as determined by 19F NMR
spectroscopic and GC-MS analysis of the crude products, so
that 6 was always obtained as a single diastereomer.
2
[a] A THF solution of 3 (5 mmol) was treatedwith Ar Li (15 mmol) at
À788C for 0.5–2 h, andthen with (Bpin) (5.25 mmol) at À788C. The
2
mixture was gradually warmed to room temperature before quenching
with saturatedaqueous NH Cl solution. [b] Yields of isolated products.
4
[c] E/Z ratio was determined by 19F NMR spectroscopic analysis.
[d] MOM=methoxymethyl.
With 5 in hand, we next examined the Pd-catalyzed cross-
coupling reaction with aryl iodide Ar3I.[10] To the best of our
knowledge, no examples of cross-coupling reactions of b-CF3-
substituted alkenyl boron reagents is available.[11,12] The
reaction conditions were first optimized with iodobenzene
as a typical coupling partner. The results are summarized in
Table 2. When a dioxane solution of 5a (E/Z = 98:2) and
iodobenzene was heated in the presence of [Pd(PPh3)4]
(10 mol%) and Cs2CO3 (3 equiv) at 508C for 12 h, only
protodeborylation took place to give (E)-1,2-diphenyl-3,3,3-
trifluoropropene (7)[13] as the sole product (Table 2,
entry 1).[14] The formation of 7 indicated that the Bpin
group in 5a was positioned cis to the CF3 group.
[PdCl2(PPh3)2] or [Pd(tBu3P)2] catalyst produced 6a as the
major product though very slowly; fair amounts of 7 were still
obtained (Table 2, entries 2 and 3). The use of TlOEt as base
Synthetic transformations of chlorine-substituted 6 are
illustrated in Scheme 2. The remaining Cl functionality in 6l
À
À
and 6g was subjected to palladium-catalyzed C N or C O
coupling reactions[17,18] to introduce nitrogen or oxygen
functionality. Thus, aniline 8 and phenyl ether 9 were isolated
in 83% and 52% yields, respectively.
Finally, we demonstrated the synthetic potential of the
methodology described herein by conversion of 6i into
panomifene (2). Demethylation of 6i with NaSEt proceeded
without any isomerization of the double bond in 6i to give
10,[19] which was treated with Cl(CH2)2OTs and then with
ethanolamine to give rise to 2 as shown in Scheme 3.
880
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Angewandte
Chemie
Table 3: Synthesis of CF3-substitutedtriarylethenes 6.[a]
Entry
5
Ar1
Ar2
Ar3
6
Yield[%] [b]
1
2
3
4
5
a
a
a
a
a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-EtO2C-C6H4
p-F-C6H4
p-Cl-C6H4
p-MeO-C6H4
p-Me2N(CH2)2O-
C6H4
b
c
d
e
f
92
91
96
95
95
Scheme 3. Application to the synthesis of panomifene (2). Conditions:
a) NaSEt, DMF, 1508C, 10 h, 78% yield; b) Cl(CH2)2OTs, K2CO3,
MeCN, reflux, 12 h; c) H2N(CH2)2OH, 2-methoxyethanol, reflux, 2 h,
66% (two steps from 10). DMF=N,N-dimethylformamide, Ts=p-tol-
uenesulfonyl.
6
7
8
9
b
b
c
Ph
Ph
Ph
Ph
p-Cl-C6H4
p-Cl-C6H4
p-MeO-C6H4 Ph
p-MOMO-
C6H4
Ph
Ph
g
h
i
92
89
90
92
Keywords: alkenes · boron · cross-coupling · fluorine · synthetic
methods
p-MeO-C6H4
.
d
Ph
j
10
11
12
13
e
f
f
p-F-C6H4
p-Cl-C6H4 Ph
p-Cl-C6H4 Ph
p-MeO-
C6H4
p-F-C6H4
p-MeO-C6H4
p-F-C6H4
k
l
m
n
91
91
90
94
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g
Ph
p-F-C6H4
[a] Reaction conditions: 5 (0.2 mmol), Ar3I (0.22 mmol), [Pd(tBu3P)2]
(0.01 mmol), aqueous Cs2CO3 (5m; 120 mL), dioxane (0.4 mL), 508C.
[b] Yields of isolated products based on E isomer of 5.
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porting Information).
Scheme 2. Synthetic elaboration of chlorine-substituted 6. Conditions:
a) LiN(SiMe3)2, [Pd2(dba)3] (2.5 mol%), P(tBu)3 (5 mol%), toluene,
1008C, 12 h; b) HCl; c) NaO(tBu), [Pd2(dba)3] (5 mol%), 2-Cy2P-2’-
Me2N-biphenyl (12 mol%), toluene, 1008C, 18 h. dba=dibenzylidene-
acetone.
[9] The lithio-oxirane generated from styrene oxide by deprotona-
tion with sBuLi/TMEDA in THFat À988C was reportedly stable
at À988C for only 30 min; the presence of a CF3 group might
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[12] For the palladium-catalyzed coupling reaction of a-(trifluoro-
methyl)ethenyl boronic acid with aryl halides, see: a) B. Jiang,
In summary, we have demonstrated a convenient and
versatile synthetic strategy for CF3-substituted triaryl ethenes
through stereoselective preparation of 5 and its Pd-catalyzed
cross-coupling. In particular, water was found to be effective
in the acceleration of the Pd-catalyzed coupling reaction. This
method can be applied to diverse CF3-substituted triaryl
ethenes, including panomifene, a potent nonsteroidal anties-
trogen. Further studies on the preparation of organofluorine
compounds, taking advantage of CF3-substituted lithio-oxi-
ranes and alkenyl–metal compounds are in progress.
Received: October 8, 2003 [Z53032]
Angew. Chem. Int. Ed. 2004, 43, 879 –879
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
881

Communications
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[19] In reference [6e], acidic demethylation was reported to result in
the production of a 1:1 mixture of (E)- and (Z)-10.
882
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Angew. Chem. Int. Ed. 2004, 43, 879 –882