Stereoselective synthesis of triarylethylenes via copper-palladium catalyzed decarboxylative cross-coupling: Synthesis of (Z)-tamoxifen

Article abstract of DOI:10.1039/c4cc03752a

The first Cu/Pd-catalyzed decarboxylative cross-coupling of 3,3-diarylacrylic acids with aryl bromides is described. Triarylethylenes were obtained in high yields with excellent stereoselectivities. This methodology was successfully applied to the stereos

Full text of DOI:10.1039/c4cc03752a

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Stereoselective synthesis of triarylethylenes via
copper–palladium catalyzed decarboxylative
cross-coupling: synthesis of (Z)-tamoxifen†
Cite this: Chem. Commun., 2014,
50, 8982
Received 16th May 2014,
Accepted 17th June 2014
Gerard Cahiez,*a Alban Moyeuxab and Mael Poizatb
´
¨
DOI: 10.1039/c4cc03752a
www.rsc.org/chemcomm
The first Cu/Pd-catalyzed decarboxylative cross-coupling of poor regio- and stereoselectivity. Moreover, the formation of
3,3-diarylacrylic acids with aryl bromides is described. Triarylethy- undesired homocoupling products often limits the synthetic
lenes were obtained in high yields with excellent stereoselectivities. efficiency of the reaction.5 The key step of the second strategy
This methodology was successfully applied to the stereoselective is the stereoselective carbometalation of diarylacetylenes. The
synthesis of (Z)-tamoxifen.
resulting vinylmetal is treated with iodine to form an alkenyl
iodide which is then alkylated via a Negishi procedure to give the
Stereo- and regioselective synthesis of tri- and tetrasubstituted final product.6 Other approaches like Pd-catalyzed three-
olefins is very challenging in organic synthesis.1 Indeed, con- component coupling7 or oxidative Heck coupling of methyl acrylate
struction of a congested double bond bearing three or four with arylboronic acids8 are also reported.9 As a rule, it should
different groups in a stereo- and regioselective manner has be noted that all the stereoselective methods require the use of
always been difficult to achieve. Many efforts were especially a stoichiometric amount of organometallic compounds. Based on
reported to synthesize triarylethylenes, an important family of these considerations, it was very tempting to try to perform the
nonsteroidal estrogen agonists and antagonists having inter- synthesis of triarylethylenes such as (Z)-tamoxifen via a decarb-
esting biological activities.2 Their field of application is very oxylative cross-coupling reaction. Indeed, the use of cheap and
large: fertility regulation, breast cancer, osteoporosis as well as readily available carboxylic acids as a source of nucleophiles instead
nervous central system, cardiovascular and lipid disorders. One of costly preformed stoichiometric organometallic reagents is very
of the best known triarylethylenes is (Z)-tamoxifen (Fig. 1), attractive.
which is an antagonist of the estrogen receptor used in the
treatment of breast cancer.3
As part of our ongoing research on decarboxylative cross-
coupling reactions, we have recently developed a new simple, cheap
Several syntheses of tamoxifen and its derivatives were and highly efficient copper-based catalytic system (CuBr–TMEDA)
published. Two strategies were mainly used. The first one is for the decarboxylation of aromatic carboxylic acids.10 This
based on the McMurry reaction in which two functionalized system was successfully used for the synthesis of biaryl com-
ketones are coupled by treating them with low-valent titanium pounds. The excellent results obtained encouraged us to
to form an alkene.4 However, the coupling takes place with extend the scope of the reaction to the stereoselective pre-
paration of triarylethylenes.
To the best of our knowledge, no attempt to perform the copper-
catalyzed decarboxylative coupling of 3,3-diarylacrylic acids has been
reported in the literature.11 It is quite surprising since such a
procedure seems very attractive to prepare bioactive molecules like
tamoxifen. This is probably due to the poor results obtained with
cinnamic acid, one of the simplest commercial arylacrylic acid
Fig. 1 (Z)-Tamoxifen.
which is probably frequently used as a model for preliminary
experiments. Indeed, our attempts to perform, under our condi-
tions, a Cu/Pd-catalyzed decarboxylative coupling reaction between
potassium cinnamate and bromobenzene led to an untractable
mixture of products resulting from both decarboxylative cross-
coupling and Heck reactions (Scheme 1). Thus, the yield of stilbene
never exceeded 18%.
a Institut de Recherche de Chimie Paris, CNRS – Chimie ParisTech, 11 rue Pierre et
Marie Curie, 75005 Paris, France. E-mail: gerard.cahiez@chimie-paristech.fr
b
´
´
Universite Paris 13, Sorbonne Paris Cite, 74 rue Marcel Cachin, 93017 Bobigny,
France
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra,
GC/MS analyses. See DOI: 10.1039/c4cc03752a
8982 | Chem. Commun., 2014, 50, 8982--8984
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Table 1 Scope of the decarboxylative cross-coupling reaction between
caesium (E)-b-anisylcinnamate and aryl halidesa
Scheme 1 Decarboxylative cross-coupling of potassium cinnamate with
bromobenzene.
Entry
1
Product
Yield (%)
91
Selectivity
96 : 4
We obtained very similar results by using the conditions
described by Goossen12 and Miura.13 In spite of these discouraging
results, we tried to perform the reaction with 3,3-diarylacrylic acids.
Indeed, we thought that it would give better results since the Heck
reaction would be less competitive with these substrates. Indeed, as
expected we found that, under our conditions, the cross-coupling
between potassium 3,3-diphenylacrylate 1a and bromobenzene
gives only the expected coupling product 2 in high yield at 170 1C
(Scheme 2). The reaction takes place at a lower temperature (140 1C)
upon using the corresponding caesium carboxylate 1b in DMPU.
2
3
4
90
90
86
99 : 1
99 : 1
97 : 3
Scheme 2 Decarboxylative cross-coupling reaction between potassium
or caesium 3,3-diphenylacrylates and bromobenzene.
These results prompted us to develop a new stereoselective
synthesis of triarylethylenes. At first, we coupled caesium
(E)-3-anisylcinnamate 3 with bromobenzene to study the stereo-
selectivity of the decarboxylative cross-coupling reaction under
our conditions (Scheme 3).
Interestingly, we found that the reaction is quite stereoselective
under our conditions (E/Z = 90 : 10). Replacement of Pd(acac)2 by
Pd(OAc)2 as a precatalyst leads to the expected product 4a in 90–91%
yield with an excellent E/Z ratio (94 : 6 to 96 : 4) (Scheme 3).
To investigate the scope of the reaction we applied this
procedure to various functionalized aryl bromides. As shown in
Table 1, the decarboxylative cross-coupling reaction with caesium
(E)-3-anisylcinnamate is very efficient (yields ranging from 72% to
91%) and chemoselective since aldehyde, ester and nitrile are
5
6
72
94 : 6
84
87
98 : 2
96 : 4
7
a
For a typical procedure see supporting information.
tolerated (Table 1, entries 3 to 5). Furthermore, excellent stereo-
selectivities were obtained (E/Z ratio ranges from 96 : 4 to 99 : 1).
We also used various caesium 3,3-diarylacrylates (Scheme 4).
As a rule, excellent yields and stereoselectivities were obtained,
and it should be noted that 3,3-diarylacrylates bearing a chloro,
a fluoro or an acetamido group reacted successfully.
Scheme 3 Optimization of the stereoselectivity of the coupling between
caesium (E)-3-anisylcinnamate 3 and bromobenzene.
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and ethyl bromide. These two compounds then react rapidly to
give (Z)-tamoxifen 10 in 70% yield. This original one-pot
procedure allows complete retention of the configuration of
the starting alkenylbromide (Z Z 93%).
In summary, we have developed the first decarboxylative
cross-coupling of 3,3-diarylacrylic acids with aryl halides by
using a simple and cheap decarboxylation catalytic system
CuBr–TMEDA. This procedure is very efficient to prepare very
stereoselectively various simple and functionalized triarylethy-
lenes in excellent yields. In addition, the reaction displays a
high functional group tolerance.
We successfully applied this procedure to the synthesis of
Z-tamoxifen.
Notes and references
1 A. B. Flynn and W. W. Ogilvie, Chem. Rev., 2007, 107, 4698.
2 S. Ray, Drugs Future, 2004, 29, 185.
Scheme 4 Synthesis of various substituted triarylethylenes via a decar-
boxylative cross-coupling procedure.
3 (a) Early Breast Cancer Trialists’ Collaborative Group, The Lancet,
1998, 351, 1451; (b) B. Fisher, J. P. Costantino, D. L. Wickerham,
C. K. Redmond, M. Kavanah, W. M. Cronin, V. Vogel, A. Robidoux,
N. Dimitrov, J. Atkins, M. Daly, S. Wieand, E. Tan-Chiu, L. Ford,
N. Wolmark, o. N. S. A. Breast and B. P. Investigators, J. Natl. Cancer
Inst., 1998, 90, 1371; (c) V. C. Jordan, Nat. Rev. Drug Discovery, 2003,
2, 205; (d) V. C. Jordan, J. Med. Chem., 2003, 46, 883.
Finally, we applied our procedure to the synthesis of
(Z)-tamoxifen (Scheme 5). At first, decarboxylative cross-coupling
of caesium carboxylate 6 with bromobenzene afforded compound
7 in 84% yield with a high stereoselectivity (E/Z = 97 : 3).
4 J. E. McMurry and M. P. Fleming, J. Am. Chem. Soc., 1974,
96, 4708.
5 P. L. Coe and C. E. Scriven, J. Chem. Soc., Perkin Trans. 1, 1986, 475.
6 (a) N. F. McKinley and D. F. O’Shea, J. Org. Chem., 2006, 71, 9552;
(b) Y. Nishihara, M. Miyasaka, M. Okamoto, H. Takahashi, E. Inoue,
K. Tanemura and K. Takegi, J. Am. Chem. Soc., 2007, 129, 12634;
(c) R. B. Miller and M. I. Al-Hassan, J. Org. Chem., 1985, 50, 2121;
(d) T. Studemann and P. Knochel, Angew. Chem., Int. Ed. Engl., 1997, 36, 93.
7 C. Zhou and R. C. Larock, J. Org. Chem., 2005, 70, 3765.
According to the procedure developed by Nunes et al.,14
bromination of 7 in dichloromethane, followed by recrystalliza-
tion in hexanes, gave the E isomer 8 (E Z 93%) in 60% yield.
Generally, (Z)-tamoxifen is prepared from 8 via a Negishi
reaction with ethylzinc bromide or chloride. We propose herein
a new and simple way. Alkenylbromide 8 was treated with 1.05
equivalents of ethyllithium. The reaction starts by a lithium–
bromide exchange which leads to a mixture of alkenyllithium 9
¨
8 Z. He, S. Kirchberg, R. Frohlich and A. Studer, Angew. Chem., Int. Ed.,
2012, 51, 3699.
´
9 For various other approaches, see: (a) M. Yus, D. J. Ramon and
´
I. Gomez, Tetrahedron, 2003, 59, 3219; (b) I. Shiina, Y. Sano,
K. Nakata, T. Kikuchi, A. Sasaki, M. Ikekita and Y. Hasome, Bioorg.
Med. Chem. Lett., 2007, 17, 2421; (c) I. Shiina, M. Suzuki and
K. Yokoyama, Tetrahedron Lett., 2004, 45, 965; (d) S. D. Brown and
R. W. Armstrong, J. Org. Chem., 1997, 62, 7076; (e) R. A. Pilli and
L. G. Robello, J. Braz. Chem. Soc., 2004, 15, 938; ( f ) M. Shindo,
K. Matsumoto and K. Shishido, Synlett, 2005, 176.
10 G. Cahiez, A. Moyeux, O. Gager and M. Poizat, Adv. Synth. Catal.,
2013, 355, 790.
11 On the other hand, it should be noted that the copper-catalyzed
protodecarboxylation of 3,3-diarylacrylic acid has already been
reported. For instance: F. Bergmann, E. Dimant and H. Japhe,
J. Am. Chem. Soc., 1948, 70, 1618.
12 (a) N. Rodriguez and L. J. Goossen, Chem. Soc. Rev., 2011, 40, 5030;
(b) L. J. Goossen, N. Rodriguez, B. Melzer, C. Linder, G. Deng and
L. M. Levy, J. Am. Chem. Soc., 2007, 129, 4824.
13 Miura reported the palladium-catalyzed decarboxylative cross-
coupling between cinnamic acids and vinyl bromide:
M. Yamashita, K. Hirano, T. Satoh and M. Miura, Org. Lett., 2009,
12, 592. However, this procedure cannot be used with aryl halides
since we have found that, in this case, the reaction mainly gives the
Heck product. See also M. Yamashita, K. Hirano, T. Satoh and
M. Miura, Adv. Synth. Catal., 2011, 353, 631.
Scheme 5 Synthesis of Z-tamoxifen: (a) PhBr, CuBr-TMEDA (10 mol%),
Pd(OAc)2 (3 mol%), DMPU, 140 1C, 16 h (84%, Z/E= 97 : 3). (b) Br2
(1.2 equiv.), Et3N (3 equiv.), CH2Cl2, 0 1C, 16 h (60%, E/Z = 93 : 7). (c) EtLi
(1.05 equiv.), THF, À78 1C - RT, 1 h (70%, E/Z = 93 : 7).
14 A. L. Monteiro, M. C. Nunes, J. Limberger, S. Poersch and M. Seferin,
Synthesis, 2009, 2761.
8984 | Chem. Commun., 2014, 50, 8982--8984
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