Straightforward synthesis of CF3-substituted triarylethenes by stereoselective threefold cross-coupling reactions

Article abstract of DOI:10.1002/anie.200703759

Any way round: The palladium-catalyzed threefold cross-coupling reaction of 1,1-dibromo-3,3,3-trifluoro-2-tosyloxypropene with aryl boronic acids provides a versatile route to CF₃-substituted triarylethenes (see scheme). The CF₃ group is essential for the high Z selectivity in the first coupling reaction, which is the key step in the process. Any of the ethene stereoisomers can be prepared simply by changing the order of the aryl boronic acids. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200703759

Angewandte
Chemie
DOI: 10.1002/anie.200703759
Cross-Coupling Reactions
Straightforward Synthesis of CF3-Substituted Triarylethenes by
Stereoselective Threefold Cross-Coupling Reactions**
Youhei Takeda, Masaki Shimizu,* and Tamejiro Hiyama
The incorporation of fluorine atoms into organic molecules
has been a powerful strategy for the improvement of parent
compounds in the fields of pharmaceuticals, agrochemicals,
and organic materials.[1] The preparation of panomifene[2] is
an example of the application of the strategy to triarylethenes,
which constitute an important class of nonsteroidal anti-
estrogens.[3] Although a few stereoselective syntheses of CF3-
substituted triarylethenes are known, the availability of the
CF3-containing starting substrates and/or the use of organo-
lithium or organomagnesium reagents limit their scope and
versatility.[4] We report herein that the threefold cross-
coupling reaction of 1,1-dibromo-3,3,3-trifluoro-2-tosyloxy-
propene (1)[5] with three kinds of aryl boronic acids provides a
simple and straightforward approach to the synthesis of CF3-
substituted triarylethenes 4 (Scheme 1). The presence of a
stitutes an efficient method for the stereoselective synthesis of
trisubstituted alkenes.[6] Meanwhile, the threefold cross-
2
1
1
2
=
coupling reaction of R(X )C C(X )2 (X , X = (pseudo)halo-
gens) leading to unsymmetrical tetrasubstituted alkenes has
no precedent, presumably because of the difficulty in
discriminating between the three leaving groups (X1 and X2)
in the first coupling reaction.[7] However, we anticipated that
the steric and/or electronic nature of a CF3 group might
overcome this difficulty.[8] Thus, we studied the palladium-
catalyzed reaction of 1 with an equimolar amount of
PhB(OH)2 to prove the viability of the approach.[9] Initial
experiments disclosed that both the stereoselectivity of 2 and
the production of dicoupled and side products were critical
issues to be solved.[5] After extensive optimization, we found
that monocoupled product 2a could be isolated in 94% yield
with high diastereoselectivity (92:8) when the reaction was
conducted in the presence of [PdCl2(PPh3)2] (5 mol%), P(m-
tolyl)3 (5 mol%), and 5m aqueous Cs2CO3 in toluene at 808C
(Table 1, entry 1). The stereochemistry of the major product
Table 1: Coupling reaction of 1 with Ar1B(OH)2.[a]
Entry
Ar1
2
Yield [%][b]
Z/E[c]
1
2
3
4
5
6
7
C6H5
2a
2b
2c
2d
2e
2 f
2g
2h
2i
94
74
73
89
85
96
78
87
80
92:8
p-MeOC6H4
p-MeC6H4
p-CF3C6H4
p-BrC6H4
p-PhC6H4
2-naphthyl
m-FC6H4
3-thienyl
90:10
89:11
87:13
88:12
88:12
89:11
89:11
90:10
Scheme 1. Approach for the synthesis of CF3-substituted triarylethenes
4. Ts=toluene-4-sulfonyl.
CF3 group is essential for both high chemical yields and high
Z selectivity in the first coupling reaction. This approach is
highly versatile, since any stereoisomers of 4 can be arbitrarily
synthesized in a stereochemically pure form simply by
changing the order of the coupling partners, and, furthermore,
a one-pot synthesis can also be achieved.
8
9[d]
[a] Reaction conditions: 2 (0.50 mmol), Ar1B(OH)2 (0.55 mmol), [PdCl2-
(PPh3)2] (25 mmol), P(m-tolyl)3 (25 mmol), 5m aq Cs2CO3 (1.0 mmol),
toluene (5 mL), 808C, 24 h. [b] Yield of isolated product. [c] The Z/E ratio
was determined by 19F NMR spectroscopic analysis of the crude
products. [d] (3-Thienyl)B(OH)2 (0.75 mmol) and 5m aq K3PO4
(1.0 mmol) as a base were used.
The twofold cross-coupling reaction of 1,1-dihalo-1-
=
alkenes (RHC CX2) with organometallic compounds con-
[*] Y. Takeda, Prof. Dr. M. Shimizu, Prof. Dr. T. Hiyama
Department of Material Chemistry
was unambiguously confirmed as Z by single-crystal X-ray
analysis,[5] which indicated that a bromine atom cis to the CF3
group was selectively substituted by a Ph group. Considering
that the steric parameters (A values) of CF3 and OTs groups
are 2.4–2.5 and 0.5 kcalmolÀ1, respectively,[10] it should be
noted that the coupling, in other words, an oxidative addition
of 1 to a Pd center, occurs at the more hindered site. The
optimized conditions were applicable to various aryl boronic
acids, thus giving rise to 2b–i in good to excellent yields
(Table 1, entries 2–9). In the case of thienylboronic acid, the
use of aqueous K3PO4 in place of aqueous Cs2CO3 resulted in
Graduate School of Engineering
Kyoto University
Kyoto University Katsura, Nishikyo-ku, Kyoto 615-8510 (Japan)
Fax: (+81)75-383-2445
E-mail: shimizu@npc05.kuic.kyoto-u.ac.jp
Homepage: http://npc.kuic.kyoto-u.ac.jp/e-index.htm
[**] This work was supported by a Grant-in-Aid for Creative Scientific
Research (no. 16GS0209) from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 8659 –8661
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8659
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Communications
a better yield of 2i (Table 1, entry 9). The Z/E selectivity
ranged from 87:13 to 92:8, and in all cases the E and Z isomers
of 2 could be easily separated by column chromatography on
silica gel or by recrystallization from hexane.
With stereochemically pure 2 in hand, we carried out the
second coupling reaction with Ar2B(OH)2 by using [Pd-
(PPh3)4] (5 mol%) and aqueous Cs2CO3 (2.0 equiv) in
toluene. The coupling reaction proceeded chemoselectively
with the remaining bromine atom rather than the tosyloxy
group at 1008C to give rise to 3 as a single diastereomer in
good to excellent yields (Table 2).
Table 2: Coupling reaction of 2 with Ar2B(OH)2.[a]
Entry
2
Ar1
Ar2
3
Yield [%][b]
1
2
3
2a
2a
2a
2a
2b
2b
2d
2h
2i
C6H5
C6H5
C6H5
C6H5
p-MeOC6H4
p-MeOC6H4
p-CF3C6H4
m-FC6H4
3-thienyl
C6H5
3aa
3ab
3ad
3ai
3ba
3bd
3da
3hb
3ig
97
88
83
60
82
70
97
90
88
p-MeOC6H4
p-CF3C6H4
3-thienyl
C6H5
p-CF3C6H4
C6H5
4[c]
5
6
7
8
9
p-MeOC6H4
2-naphthyl
Scheme 2. Synthesis of CF3-substituted triarylethenes 4.
[a] Reaction conditions: 2 (0.20 mmol), Ar2B(OH)2 (0.24 mmol), [Pd-
(PPh3)4] (10 mmol), 5m aq Cs2CO3 (0.40 mmol), toluene (2 mL), 1008C,
24 h. [b] Yield of isolated product. [c] (3-Thienyl)B(OH)2 (0.40 mmol)
and 5m aq K3PO4 (1.0 mmol) as a base were used.
The final coupling of 3 with Ar3B(OH)2 to give 4 was
accomplished by applying the conditions developed by
Buchwald and co-workers.[11] We succeeded in isolating
diverse compounds 4 as single stereoisomers in high to
excellent yields (Scheme 2). Since it has been reported that
4aba can be converted into panomifene,[4c] its preparation is
equivalent to the formal synthesis of panomifene. The striking
versatility of the present strategy is that both the E and Z
isomers as well as any olefinic constitutional isomers of 4 can
be synthesized at will simply by changing the order of the
three aryl boronic acids employed, as demonstrated by the
preparation of 4abd, 4adb, and 4bad.
Scheme 3. Reagents and conditions: a) [PdCl2(PPh3)2] (5 mol%), P(m-
tolyl)3 (5 mol%), 5m aq Cs2CO3, toluene, 808C, 24 h; b) 5m aq
Cs2CO3, 1008C, 24 h; c) Pd(OAc)2 (5 mol%), 2-dicyclohexylphosphino-
2’,4’,6’-triisopropylbiphenyl (10 mol%), 2m aq K3PO4, 808C, 12 h.
Table 3: Cross-coupling reaction of dibromoalkenes 5.[a]
Entry
5
R1
R2
6 (Z/E)[b]
7[b]
8[b]
Another advantage of the designed sequence is the
feasibility of a one-pot synthesis. Thus, panomifene precursor
4aba was obtained from 1 in 69% yield without isolation of
2a or 3ab, although the conditions have not been optimized
(Scheme 3).
To gain insight into the effect of the CF3 group on the first
coupling reaction we carried out the reaction of 5a–c with
PhB(OH)2 under the optimum conditions (Table 3). The
reaction of non-fluorinated dibromoalkene 5a resulted in a
lower yield of the isolated product and a lower Z/E selectivity
of the monocoupled product 6a (Table 3, entry 1). Ethoxy-
carbonyl-substituted ethene 5b gave 6b in moderate yield
together with fair amounts of the dicoupled product 7b and
acetylene 8 as by-products (Table 3, entry 2). In the case of 5c,
1
5a
5b
5c
CH3
EtO2C
CF3
OTs
OTs
(CH2)2Ph
70 (68:32)
57 (96:4)
15 (81:19)
0
16
47
–
21
–
2
3[c]
[a] Reaction conditions: 5 (1.0 equiv), PhB(OH)2 (1.1 equiv), [PdCl2-
(PPh3)2] (5 mol%), P(m-tolyl)3 (5 mol%), 5m aq Cs2CO3, toluene, 808C,
24 h. [b] Yield of isolated product. [c] 5c was recovered in 31% yield.
diphenylated ethene 7c was formed as the major product
(Table 3, entry 3). Thus, these results indicate the high Z
selectivity of 2 can be attributed to the presence of a CF3
group, while both the CF3 and tosyloxy groups are indispen-
sable for suppressing the second coupling reaction. While
elucidation of the origin of the stereochemical outcome
8660 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 8659 –8661
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Angewandte
Chemie
[4] a) W. J. Middleton, D. Metzger, J. A. Snyder, J. Med. Chem.
awaits further study, a Pd···F interaction in the oxidative
addition step may be operative.[12]
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In summary, we have developed a straightforward stereo-
controlled synthesis of CF3-substituted triarylethenes. Further
study of the coupling reactions of 1,1-dibromo-3,3,3-trifluoro-
2-tosyloxypropene with other kinds of nucleophiles is in
progress.
[5] See the Supporting Information.
Received: August 6, 2007
[6] a) T. Sugihara in Handbook of Organopalladium Chemistry for
Organic Synthesis, Vol. 1 (Ed.: E. Negishi), Wiley, New York,
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Published online: October 8, 2007
Keywords: alkenes · boron · cross-coupling · fluorine ·
.
synthetic methods
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Angew. Chem. Int. Ed. 2007, 46, 8659 –8661
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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