Palladium-catalyzed stereoselective synthesis of E- and Z-1,1-diaryl or triarylolefins

Article abstract of DOI:10.1016/S0040-4039(03)00459-3

A stereoselective and flexible synthesis of various E- and Z-1,1-diaryl and triarylolefins 3 was achieved from readily available vinylstannanes 1 via stereospecific iodo-destannylation and subsequent palladium-catalyzed Negishi-type cross-coupling reaction with arylzinc reagents under mild conditions.

Full text of DOI:10.1016/S0040-4039(03)00459-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2789–2794
Palladium-catalyzed stereoselective synthesis of E- and
Z-1,1-diaryl or triarylolefins
Fre´de´ric Liron, Marina Gervais, Jean-Franc¸ois Peyrat, Mouaˆd Alami* and Jean-Daniel Brion
Laboratoire de Chimie The´rapeutique, BioCIS-CNRS (UMR 8076), Universite´ Paris-Sud, Faculte´ de Pharmacie,
rue J.B. Cle´ment 92296 Chaˆtenay-Malabry Cedex, France
Received 12 February 2003; revised 17 February 2003; accepted 19 February 2003
Abstract—A stereoselective and flexible synthesis of various E- and Z-1,1-diaryl and triarylolefins 3 was achieved from readily
available vinylstannanes 1 via stereospecific iodo-destannylation and subsequent palladium-catalyzed Negishi-type cross-coupling
reaction with arylzinc reagents under mild conditions. © 2003 Elsevier Science Ltd. All rights reserved.
Trisubstituted arylated olefins has attracted consider-
able attention of organic chemists in recent years not
only for their interesting physical properties,1 but also
for their occurrence in natural and biological active
substances. In this respect, the growing interest in ary-
lated olefin derivatives of general structure 3 (Scheme 1)
is connected with the hormonal,2 retinoidal,3 antimi-
totic,4 antiviral5 and anticonvulsant6 activities. Despite
their broad applications, the search for more simple
and efficient methods for the stereocontrolled synthesis
of trisubstituted arylated olefins bearing non-identical
aromatic rings remains an ongoing challenge in the area
of synthetic organic chemistry.
dihaloalkenes using Grignard11 or arylstannane12
derivatives. While these reactions are suitable methods,
many of them either display low stereoselectivity when
olefins bear non-identical aromatic rings or do not
tolerate sensitive functionality and/or requires harsh
conditions (high temperatures, long reaction times). A
stereoselective protocol for the synthesis of triaryl
olefins has been reported which is based on the palla-
dium-catalyzed hydroarylation of disubstituted alky-
nes.13 However, in many instances,
a
lack of
regioselectivity was observed from unsymmetrical alky-
nes and a mixture of regioisomers was obtained except
in the case of hydroarylation of unsymmetrical alkynes
conjugated to an electron withdrawing group such as
arylpropiolamides14 and related compounds.15 More
recently, 2-pyridyldimethyl(vinyl)silane has been suc-
cessfully used as synthetic precursors of triaryl olefins
by the palladium-catalyzed sequential double-Heck/
Hiyama coupling reactions.16
Several synthetic methods have been developed for the
preparation of
3
such as Wittig-type reactions,7
McMurry coupling of carbonyl compounds,8 Heck
reactions,9 or palladium-catalyzed coupling reactions of
organometallic reagents with organic halides10 particu-
larly, those involving sequential arylation of 1,1-
We had previously reported an unprecedented ortho-
directing effect (ODE) in unsymmetrical substituted
arylalkynes17 or diarylalkynes18 which promotes
regioselective addition of tributyltin hydride to the
triple bond to afford efficiently disubstituted vinylstan-
nane derivatives 1. An important aspect of our ongoing
research on the synthetic utility of these disubstituted
vinylstannanes as intermediates in organic synthesis is
their elaboration via further coupling under palladium
catalysis into trisubstituted arylated olefins 3. Conse-
quently, our goal during this work was to provide a
clean, high-yielding and general synthesis of trisubsti-
tuted arylated olefins 3 of defined configuration by
direct coupling of 1 with aryl halides (Stille reaction) or
Scheme 1.
* Corresponding author. Tel.: +33(1)46835887; fax: +33(1)46835828;
e-mail: mouad.alami@cep.u-psud.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00459-3

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F. Liron et al. / Tetrahedron Letters 44 (2003) 2789–2794
via coupling of the corresponding vinyl iodides 2 with
organometallic reagents (Scheme 1). The results of this
study are reported now.
bromide in the presence of Pd(dba)2 (5 mol%) and PPh3
(10 mol%) in refluxing THF provided the allylated
products 5a–c in moderate to good yields (44–75%, entries
4–6).
Although Stille coupling of vinylstannanes with organic
halides have already been established as an efficient
method for the formation of carbonꢀcarbon bonds, the
coupling reactions in the case of sterically hindering
1-substituted vinylstannanes is well known to be
sluggish19 and often require specific conditions for differ-
ent substrates. Thus several reported Stille conditions
wereexaminedforthecouplingof1witharyliodidesusing
various combinations of Pd/solvent/additive mixtures
(e.g. Pd(PPh3)4, PdCl2L2 (L: MeCN or PPh3), Pd(dba)2/
(furyl)3P, AsPh3, Ar3P with or without CuI). After much
study,20 it was found that the use of CuI as co-catalyst,
which may facilitate the rate-determining transmetalla-
tion step, in combination with palladium catalyst that
incorporate bulky phosphines resulted in optimal condi-
tions. Thus, in the presence of Pd(dba)2 (5 mol%),
P(o-Tol)3 (10 mol%), CuI (10 mol%) in refluxing aceto-
nitrile for 15 h the reaction of 1a (1.5 equiv.) having a
free hydroxyl group21 with 4-iodo-nitrobenzene 4a
afforded the coupling product 3a in 66% yield (Table 1,
entry 1). Unfortunately, under these conditions, all our
attempts to prepare trisubstituted olefins 3b–c from
unreactive aryl iodides such as hindered ortho-substituted
aryl iodides (i.e. 4b) or deactivated aryl iodides bearing
an electron-donating group (i.e. 4c) resulted in unsatisfac-
tory yields (27–42%, entries 2 and 3). It may be pointed
out that Stille coupling of a-substituted vinyl stannanes
1b–d with highly reactive organic halides such as allylic
Difficulties in obtaining trisubstituted arylated olefins 3
in good yields by direct coupling of sterically encumbered
a-substituted vinyl stannanes 1 with unreactive aryl
iodides led us to explore their halodestannylation chem-
istry and subsequent palladium-catalyzed cross-coupling
reaction with various organometallic reagents (Mg, Zn,
Sn…). Of particular interest, our attention was drawn to
arylzinc derivatives (Negishi reaction)22 since they are
mild nucleophiles, well-known for their compatibility
with most functional groups and are good candidates for
transmetallations to organopalladium(II) complexes.
Stereospecific iodo-destannylation of a-substituted vinyl
stannanes 1 with ca. 1 equiv. of iodine in dichloromethane
at 20°C allows cleanly and rapidly the synthesis of the
corresponding E-vinyl iodides23 2 as a single isomer, an
interesting class of compounds which has been difficult
to obtain in a stereoselective manner.24 These latter are
suitable electrophiles for further cross-coupling reactions.
Thus, reaction of 2 with arylzinc chlorides in the presence
of a catalytic amount of PdCl2(PPh3)2 (5%) occurs rapidly
in THF at room temperature and provided in excellent
yields within 2 to 4 h, the corresponding trisubstituted
arylated olefins 3 as isomerically pure materials.23 The
coupling reaction was effective with either (E)-a-iodo
substituted styrenes 2a–e or (E)-iodostilbenes 2f–i. As
shown in Table 2, the reaction tolerates sensitive func-
Table 1. Palladium-catalyzed Stille coupling reaction of vinyl stannanes 1 with organic halides

F. Liron et al. / Tetrahedron Letters 44 (2003) 2789–2794
2791
Table 2. Palladium-mediated cross coupling reaction between arylzinc chloridesa and trisubstituted vinyl iodides 2

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F. Liron et al. / Tetrahedron Letters 44 (2003) 2789–2794
tional groups in the substrates and was even successful
in the absence of hydroxy protecting groups (entries 3–6)
except in the case of vinyl iodide 2f. The coupling reaction
from 2f demonstrated the need for protecting the benzylic
alcohol function. Indeed, without protection, the product
of the reaction 3g is mainly obtained as a mixture of
E and Z-isomers (E/Z: 35/65, entry 7). However,
when the same reaction was conducted from the corre-
sponding silyloxy derivatives 2g, triaryl olefins 3h and 3i
were formed in high yields as a single isomer (entries 8
and 9).
in Table 3. The installation of aromatic groups at the
desired olefins carbon can be achieved by simply changing
the order of addition of aromatic groups. Thus, starting
from terminal alkyne 6 this four-step sequence afforded
the desired E- and Z-isomers of arylated olefins 3 in good
overall yields. It may be pointed out that in the conversion
of 1 to 3, the intermediate vinyl iodides 2 could be used
in the further coupling step without purification.
The favorable results obtained above in the alkenyl-aryl
coupling reactions prompted us to study and com-
pare related procedures particularly those involving aryl
Grignard reagents, arylstannanes and arylboranes. Sev-
eral points are worth noting from the above results
summarized in Table 4. More reactive organometallics
The flexibility of this procedure was further demonstrated
bythesynthesisofbothE-andZ-isomersoftrisubstituted
arylated olefins 3 in an independent fashion as illustrated
Table 3. Synthesis of E- and Z-1,1-diaryl or triarylolefins 3a

F. Liron et al. / Tetrahedron Letters 44 (2003) 2789–2794
2793
Table 4. Palladium-catalyzed arylation of vinyl iodides 2 with aryl Grignard, arylstannane or arylboronic acid reagents
such as organomagnesium derivatives suffer from a
moderate functional tolerance when compared to
organozinc compounds. Moreover, in most cases stud-
ied the cross coupling products were contaminated with
15–20% of 1,2-diarylstilbenes arising probably from
metal–halogen exchange reaction26 (Table 4 entries 1–
3). With less reactive organometallic species such as
arylstannane or arylboronic acid compounds (entries
5–7), the coupling can occur stereospecifically to pro-
duce the desired arylated olefins 3 in good yields. It
should be pointed out that for efficient coupling,
Suzuki reaction typically requires heating to ꢀ90°C for
several hours, whereas Stille reaction proceed at room
temperature.
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triarylolefins from readily available vinylstannanes. The
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Acknowledgements
The CNRS is gratefully thanked for support of this
research. Thanks are also due to the ADIR (Servier
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spectra of the products indicated the presence of one
isomer in each cases.
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25. Typical procedure: To a stirred solution of vinyl stannane
1 (1 equiv.) in dry CH2Cl2 (2 mL per mmol of substrate)
was added at 0°C sublimed finely divided I2 (1.05 equiv.)
and the dark wine solution was vigorously stirred at room
temperature until all of the substrate had been consumed.
Saturated aqueous Na2S2O3 was added to remove excess
of iodine followed by potassium fluoride aqueous solution.
After stirring at room temperature for 1 h, the resulting
white precipitate of tributyltin fluoride was removed by
filtration and the filtrate was extracted with ether. The
combined organic layer was washed with brine, dried over
MgSO4 and concentrated (the crude vinyl iodide 2 could
be used in the further step without purification). Filtration
through silica gel afforded pure vinyl iodide 2.
2b: 1H NMR (200 MHz, CDCl3) d 7.47 (2H, d, J=8.9 Hz),
6.84 (2H, d, J=8.9 Hz), 6.49 (1H, t, J=7.6 Hz), 3.81 (3H,
s), 3.65 (2H, t, J=6.3 Hz), 2.27 (2H, q, J=7.6 Hz), 1.48
(1H, br.s); 13C NMR (50 MHz, CDCl3) d 159.2, 138.9,
134.0, 130.0, 113.6, 97.6, 61.5, 55.3, 35.4.
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1
2c: H NMR (200 MHz, CDCl3) d 7.30 to 7.17 (5H, m),
6.47 (1H, t, J=7.5 Hz), 3.57 (2H, t, J=6.4 Hz), 2.20 (2H,
q, J=7.5 Hz), 1.89 (1H, br.s); 13C NMR (50 MHz, CDCl3)
d 141.3, 139.2, 128.5, 128.1, 128.0, 97.0, 61.2, 35.2.
To a solution of vinyl iodide 2, PdCl2(PPh3)2 (5 mol%) in
THF was added at room temperature ArZnCl (2 equiv.)
prepared by transmetallation from the corresponding
Grignard reagent (2 equiv.) and anhydrous ZnCl2 (2.1
equiv.). The reaction was stirred at room temperature and
monitored by TLC until complete consumption of starting
materials (2 to 4 h). The reaction was hydrolyzed at 0°C
with aqueous HCl (1N), extracted with Et2O, the organic
extract was dried over MgSO4 and the solvent was removed
in vacuo. Pure arylated olefin was isolated by simple
filtration through silica gel.
E-3m: 1H NMR (200 MHz, CDCl3) d 7.46 to 7.35 (3H, m),
7.26 to 7.20 (4H, m), 6.86 (2H, d, J=9.0 Hz), 6.08 (1H,
t, J=7.6 Hz), 3.83 (3H, s), 3.73 (2H, t, J=6.6 Hz), 2.42
(2H, q, J=7.6 Hz), 1.94 (1H, s); 13C NMR (50 MHz,
CDCl3) d 158.7, 143.5, 140.0, 135.0, 129.7, 128.2, 128.1,
126.9, 123.4, 113.4, 62.5, 55.2, 33.2.
1
Z-3m: H NMR (200 MHz, CDCl3) d 7.18 (5H, m), 7.05
(2H, d, J=8.3 Hz), 6.84 (2H, d, J=8.3 Hz), 6.00 (1H, t,
J=7.3 Hz), 3.76 (3H, s), 3.66 (2H, t, J=6.5 Hz), 2.36 (2H,
q, J=7.0 Hz); 13C NMR (50 MHz, CDCl3) d 158.5, 143.4,
142.7, 132.1, 130.9, 127.9, 127.2, 126.9, 125.1, 113.5, 62.3,
55.0, 33.2.
20. Under Stille’s standard conditions (PdCl2(RCN)2 (R=Me,
Ph), DMF or NMP, 20°C), no coupling reaction occurred
and the starting material was recovered. Increasing the
reaction time to 24 h and temperature to 110°C resulted
in decomposition of reactant.
26. Rottla¨nder, M.; Boymond, L.; Cahiez, G.; Knochel, P. J.
Org. Chem. 1999, 64, 1080–1081.
21. The coupling of a similar stannane compound having the
alcohol group protected as MOM ether was reported, see: