Preparation of 2,3,3-Triarylacrylic Acid Esters Using Suzuki-Miyaura Coupling Reactions

Article abstract of DOI:10.1055/s-0035-1560419

We report here a new strategy to produce 2,3,3-triarylacrylic acid esters, a class of 1,2,2-triarylethene compounds with an α,β-unsaturated ester functionality. Our approach requires the preparation of a gem-dibromoalkene precursor from an α-keto ester, followed by the installation of two aryl groups by Suzuki-Miyaura coupling reactions on the two C-Br bonds. Many 2,3,3-triarylacrylic acid esters with one, two, or three different aryl groups were obtained with complete regio- and stereocontrol in most cases.

Full text of DOI:10.1055/s-0035-1560419

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–O
paper
A
S. Cardinal, N. Voyer
Paper
Synthesis
Preparation of 2,3,3-Triarylacrylic Acid Esters Using Suzuki–
Miyaura Coupling Reactions
Sébastien Cardinal
Ar1
OR
Ar1
Ar2
Ar2
Normand Voyer*
Ar2
OR
Ar1
Ar1
Département de Chimie and PROTEO, Université Laval,
1045 avenue de la Médecine, Québec, QC, G1V OA6,
Canada
OR
O
Ar1
Ar1
O
O
Normand.voyer@chm.ulaval.ca
Br
OR
Ar2
Ar3
Br
Ar1
OR
Ar2
Ar1
Ar1
OR
O
O
Ar1
O
Received: 11.01.2016
Accepted: 24.01.2016
Published online: 17.02.2016
DOI: 10.1055/s-0035-1560419; Art ID: ss-2016-m0021-op
alkynes as starting materials, and form the 2,3,3-triary-
lacrylic acid ester moiety by strategies such as the double
addition of an organometallic reagent or the coupling with
an aryl iodide and an arylboronic acid.5–7 The latter strate-
gy, developed by Larock, showed good yields and compati-
bility with a range of substrates and has been used to pre-
pare different 2,3,3-triarylacrylic acid esters.6 However, this
multicomponent reaction often leads to moderate regiose-
lectivity, showing that it is challenging to control the geom-
etry when preparing tetrasubstituted alkenes with four C–C
bonds on the olefin scaffold.8 Recently, the Sawamura
group reported the synthesis of some 2,3,3-triarylacrylic
acid esters with stereocontrol over the olefin via an elegant
method that require the preparation of particular β-boryl-
α-silyl or α,β-diboryl acrylate templates.7a
Abstract We report here a new strategy to produce 2,3,3-triarylacrylic
acid esters, a class of 1,2,2-triarylethene compounds with an α,β-unsat-
urated ester functionality. Our approach requires the preparation of a
gem-dibromoalkene precursor from an α-keto ester, followed by the in-
stallation of two aryl groups by Suzuki–Miyaura coupling reactions on
the two C–Br bonds. Many 2,3,3-triarylacrylic acid esters with one, two,
or three different aryl groups were obtained with complete regio- and
stereocontrol in most cases.
Key words triarylethene, triarylacrylic acid, gem-dibromoalkene, dou-
ble Suzuki–Miyaura coupling, stereoselective Suzuki–Miyaura coupling
Triarylethene compounds have been widely studied.1
Tamoxifen, an antagonist of the estrogen receptor and a
commonly used anticancer agent, is surely the most famous
compound with the triarylethene moiety. Many synthetic
pathways for it have been developed, facilitating reactions
to produce various analogues.2 The 1,2,2-triarylethene π-
system has also been studied as a potential scaffold for the
design of functional materials with useful photophysical
properties.3 In the course of a project directed toward the
total synthesis of quebecol (1) [Figure 1 (a)], a natural prod-
uct found in maple syrup, we devised a synthetic strategy
to access efficiently the 1,2,2-triarylethene compound 2
[Figure 1 (b)], a key intermediate in the synthesis of natural
polyphenol 1.4
b)
a)
OMe
OMe
OMe
OMe
BnO
OBn
HO
OH
OEt
O
OH
BnO
HO
OMe
OMe
2
1
c)
Ar2
Ar3
While working on the construction of the 2,3,3-triaryl-
acrylic acid ester scaffold, a particular 1,2,2-triarylethene
moiety conjugated with an α,β-unsaturated ester function-
ality [Figure 1 (c)], we realized that there was a scarcity of
published synthetic methods for these compounds. Some of
the methods are only useful to prepare a limited number of
compounds. Most described synthetic pathways use
OR
Ar1
O
Figure 1 Structure of (a) quebecol (1), (b) its key precursor 2, and (c)
the general structure of the 2,3,3-triarylacrylic acid ester scaffold
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

B
S. Cardinal, N. Voyer
Paper
Synthesis
Herein, we report our most recent results aimed at the
preparation of various 2,3,3-triarylacrylic acid esters [Fig-
ure 1 (c)] with one, two, or even three different aryl groups,
in a way to access all possible arrangements of the aromatic
rings.
O
OR
Ar1
Ar1
OR
Ar2
OR
Ar1
Ar1
Ar3
Ar1
O
C-1
homologation
O
O
Our retrosynthetic approach towards 2,3,3-triarylacryl-
ic acid esters is presented in Scheme 1. It uses an α-keto es-
ter as an easily accessible starting material. The key se-
quence involves the formation of a gem-dibromoalkene
(Corey–Fuchs template)9 by a Wittig-like C-1 homologation
reaction, followed by Suzuki–Miyaura coupling (SMC) reac-
tions. As previously mentioned, we recently used this ap-
proach to prepare the symmetrically substituted 2,3,3-tri-
arylacrylic acid ethyl ester 2 (Figure 1).4 However, we
sought to prepare 2,3,3-triarylacrylic acid ester analogues
with various arrangements of aryl rings on the 1,2,2-triaryl-
ethene scaffold exploiting a single α-keto ester compound,
as shown in Scheme 1. For the sake of clarity, the five possi-
ble classes of compounds have been grouped in classes de-
noted A to E (Scheme 1).
The 2,3,3-triarylacrylic acid ester compounds with one
type of aryl group (Class A) can be prepared by a double
SMC reaction on the two C–Br bonds of the gem-dibro-
moalkene precursor, using an identically substituted aryl-
boronic acid.4 The use of two equivalents of a boronic acid
with an aromatic substituent different from the substrate
could lead to the preparation of triaryl compounds of Class
B.
Three other classes of compounds could potentially be
accessed by two consecutive SMC reactions with distinct
boronic acids. These transformations require the develop-
ment of efficient conditions for the preparation of 1,2-di-
aryl-2-bromoethene compounds with control over the ste-
reochemical outcome of the first coupling. Such reaction,
followed by another coupling, would open the way to the
preparation of 2,3,3-triarylacrylic acid esters with two
(Class C and D) or, most interestingly, three (Class E) types
of aryl groups with complete regio- and diastereocontrol
(Scheme 1).
The sequence involving for the formation of a gem-di-
bromoalkene followed by one or two SMC reactions has at-
tracted some interest in the past years, particularly in me-
dicinal chemistry and material science.10,11 Some triarylal-
kenes, other than 2,3,3-triarylacrylic acid esters, have
previously been prepared from gem-dibromoalkenes.3b,10c,12
However, few applications of this strategy starting from an
α-keto ester have been reported. Lu’s group has prepared a
series of ethyl esters of 3,3-diaryl-2-(trifluoromethyl)acryl-
ic acid from ethyl trifluoropyruvate, which is so far the clos-
est reported example of this reaction sequence to our syn-
thetic plan.13
class A
class E
sequential
SMC
Br
Ar1
Br
O
double
SMC
OR
sequential
SMC
double
SMC
Ar1
OR
Ar2
OR
Ar2
Ar1
Ar2
OR
Ar2
Ar1
Ar1
Ar1
O
O
O
class B
class C
class D
Scheme 1 Retrosynthetic approach towards the five possible classes of
2,3,3-triarylacrylic acid esters involving Suzuki–Miyaura coupling (SMC)
reactions
As mentioned, preparing compounds of classes C, D, and
E (Scheme 1) requires a diastereoselective reaction for the
installation of the first boronic acid on a gem-dibromo-
alkene. Such stereoselective reactions have been reported,
which shows that it is possible to discriminate between the
two C–Br bonds. Most of these have involved gem-dibromo-
alkenes derived from aldehydes and lead to (Z)-monobro-
moalkenes as products of the first SMC.14 A second coupling
results in trisubstituted alkenes.
Few examples of these sequences, which involve more
substituted gem-dibromoalkenes and lead to the diastereo-
selective preparation of tetrasubstituted alkenes, have been
reported.1b,10a,12a,15 Shimizu and co-workers synthesized pa-
nomifene and other CF3-substituted triarylethenes by a ste-
reoselective threefold cross-coupling reaction, the first two
couplings proceeding on 1,1-dibromo-3,3,3-trifluoro-2-(to-
syloxy)propene.1b According to the authors, the trifluoro-
methyl group is essential for the stereoselectivity of the
first coupling.15 Chapleur’s group prepared bioactive 1,1-di-
arylalkenes by two consecutive cross-couplings on a gem-
dibromoalkene functionality installed on a carbohydrate
scaffold.10a Recently, Tobrman reported stereoselective
cross-coupling reactions on a enolphosphate dibromide
template.12a Then, a coupling on the remaining C–Br bond
and further activation and coupling on the C–O bond pro-
vided access to all-carbon tetrasubstituted alkenes. Some
systems have also been developed using the opposite strat-
egy, where aryl bromides were selectively coupled on an
alkene with multiple metallic groups, leading to some tri-
and tetraarylethenes.7a,16
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

C
S. Cardinal, N. Voyer
Paper
Synthesis
As a first step, our strategy towards the desired 1,2,2-
triarylethene scaffold requires the preparation of gem-di-
bromoalkenes. These compounds can usually be obtained
with a PPh3/CBr4 Wittig-like C-1 homologation reaction on
the corresponding activated carbonyl precursor.17 Two aryl-
functionalized α-keto esters were prepared for this study
and chosen for their relevance in our synthetic plan to-
wards polyphenolic natural products.4 Scheme 2 presents
the synthesis of compounds 7 and 84,18 from a commercially
available mandelic acid analogue.
Br
Br
O
PPh3 (4 equiv)
CBr4 (2 equiv)
O
OR3
OR3
CH2Cl2
O
r.t., 12 h
R1
R1
R2
10 85% (R1 = H, R2 = H, R3 = Et)
7 (R1 = OBn, R2 = OMe, R3 = Bn) 11 91% (R1 = OBn, R2 = OMe, R3 = Bn)
8 (R1 = OBn, R2 = OMe, R3 = Et) 12 91% (R1 = OBn, R2 = OMe, R3 = Et)
R2
9 (R1 = H, R2 = H, R3 = Et)
Scheme 3 Preparation of gem-dibromoalkene compounds 10–12
OH
OH
a
hindered o-(aminomethyl)biaryl systems.20 For this double
OH
O
coupling, Pd2(dba)3 serves as the catalyst and 2-(dicyclo-
O
O
HO
HO
hexylphosphino)-2′,6′-dimethoxybiphenyl
(Buchwald’s
4
3
OMe
d
OMe
SPhos ligand) promotes coupling efficiently for this hin-
dered system.21 Scheme 4 shows the results of the SMC re-
actions on gem-dibromoalkenes 10–12 with such condi-
tions. As coupling partners, we used phenylboronic acid
(13) and 4-(benzyloxy)-3-methoxyphenylboronic acid (14),
which we have previously reported.4 Satisfying yields of 2,
15, and 16 were obtained when using 2.5 to 3 equivalents
of the boronic acids, proving the viability of the approach to
access Class A compounds (Scheme 4).18
b
OH
OH
O
OBn
O
O
BnO
BnO
5
6
OMe
OMe
c
e
O
O
R1
OBn
O
R2
O
O
(HO)2B
BnO
BnO
(2.5–3 equiv)
13 (R1 = H, R2 = H)
14 (R1 = OBn,
R2
R2
7
OMe
8
OMe
R1
R1
Scheme 2 Preparation of carbonyl compounds 7,8. Reagents and con-
ditions: (a) MeOH/H2O (10:1), Cs2CO3, pH 7, then EtBr (1.2 equiv), DMF,
r.t., 96 h, 77%; (b) BnBr (1.7 equiv), K2CO3 (1.7 equiv), acetone, reflux,
20 h, 84%; (c) Dess–Martin periodinane (2 equiv), CH2Cl2, 0 °C, 2 h,
99%; (d) BnBr (3.4 equiv), K2CO3 (3.4 equiv), acetone, reflux, 72 h, 54%;
(e) Dess–Martin periodinane (2 equiv), CH2Cl2, 0 °C, 2 h, 94%.
R
2 = OMe)
Pd2(dba)3 (8 mol%)
SPhos (16 mol%)
+
OR3
K3PO4 (3 equiv)
toluene, 110 °C
24 h
OR3
Br
Br
O
O
R1
R2
Only a few examples of PPh3/CBr4 C-1 homologation
have been previously reported for α-keto esters.13,19
Knochel’s work, in which ethyl 3,3-dibromo-2-phenylpro-
penoate (10) is prepared by this strategy, was of particular
interest.19b The conditions they described were tested on
model compound 9 and allowed us to obtain 10 efficiently.
Applying the same conditions to 7 and 8 led to the prepara-
tion of our desired gem-dibromoalkenes 11 and 124,18 in ex-
cellent yields (Scheme 3).
15 87% (R1 = H, R2 = H, R3 = Et)
16 84% (R1 = OBn, R2 = OMe, R3 = Bn)
2 85% (R1 = OBn, R2 = OMe, R3 = Et)
R1
R2
10 (R1 = H, R2 = H, R3 = Et)
11 (R1 = OBn, R2 = OMe, R3 = Bn)
12 (R1 = OBn, R2 = OMe, R3 = Et)
Scheme 4 Preparation of Class A compounds 2, 15, and 16
With gem-dibromoalkene compounds 10–12 in hand,
we investigated the preparation of a first series of 2,3,3-tri-
arylacrylic acid esters using a double coupling reaction to
unite three identical aromatic rings. Reported examples of
double SMC reactions on gem-dibromoalkenes used various
catalytic systems and conditions.1b,3b,10,11,12b,13,19 We chose
to adapt conditions used successfully in a natural product
synthesis related to our previous work on the synthesis of
The efficient double SMC reaction conditions were used
for the preparation of Class B compounds with two types of
aryl groups. We reacted the gem-dibromoalkene 10 with
both an electron-rich, and an electron-poor, arylboronic
acids 17 and 18, respectively, to explore the versatility of
our method. These two reactions, presented in Scheme 5,
led to compounds 19 and 20 in good isolated yields. Hence,
it can be concluded that these coupling conditions will al-
low the synthesis of a variety of triarylethenes.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

D
S. Cardinal, N. Voyer
Paper
Synthesis
Due to the undesired preference of the SPhos/Pd2(dba)3
catalytic system for the double addition product, we inves-
tigated other reaction conditions inspired by the reported
examples of diastereoselective coupling on a gem-dibro-
moalkene moiety.1b,10a,14,15 The PdCl2(PPh3)2/tri(2-fu-
ryl)phosphine (TFP) catalytic system reported by Chapleur10a
lead us to prepare bromodiarylethene 26a in a satisfying
yield and with good diastereoselectivity (Table 2, entry 1).
These conditions were also applicable to other boronic
acids [both a typical electron-rich one (Table 2, entry 3) and
a model electron-poor one (Table 2, entry 4)]. In all cases,
the (E)-single addition product was prepared as the major
product, but the formation of the double addition product
could not be avoided, suggesting that the monobromo-
alkenes undergo a second addition easily.
R1
(HO)2B
R1
R1
(3 equiv)
17 (R1 = OMe)
Pd2(dba)3 (8 mol%)
18 (R1 = CF3)
SPhos (16 mol%)
+
OEt
K3PO4 (3 equiv)
toluene, 110 °C
24 h
Br
Br
O
O
OEt
19 86% (R1 = OMe)
20 70% (R1 = CF3)
10
Scheme 5 Preparation of Class B compounds 19 and 20
The extension of our synthetic strategy to the prepara-
tion of 2,3,3-triarylacrylic acid esters of Classes C, D, and E
(Scheme 1) requires, as first step, the efficient preparation
of 1,2-diaryl-2-bromoethenes by a single SMC reaction, ide-
ally by a diastereoselective reaction.
The best yield of single addition product was observed
when using boronic acid 18, followed by 21, 13, and 17, il-
lustrating a clear connection between the electron-with-
drawing character of the para substituent on the boronic
acid and the formation of the desired bromodiarylethenes
(CF3 > F > H > OMe).22 This behavior might also be a conse-
quence of the greater tendency of electron-rich boronic ac-
ids to form double coupling products, as illustrated in Table
2.
The X-ray structure of compound 24a was obtained and
clearly establishes the stereochemical outcome of the single
coupling process for boronic acid 17 (Figure 2) Comparison
of the 1H NMR spectra for 24a and 24b (which differ in the
chemical shifts for E and Z ethyl groups) and the other pairs
of isomers of 23, 25, and 26 confirmed that the same ste-
reoselectivity was found for all four boronic acid single ad-
dition products. Preference for the coupling under an anti
configuration regarding the phenyl groups present on the
Since the SPhos/Pd2(dba)3 catalytic system worked well
in the preparation of the first 2,3,3-triarylacrylic acid es-
ters, we tried the same conditions for the single coupling
reactions. Table 1 presents the results of those coupling ex-
periments, using 1.1 equivalents of boronic acid. First, bo-
ronic acid 14 was used at room temperature, leading exclu-
sively to a low yield of double addition product 27 (Table 1,
entry 1). The use of reflux heating with the same boronic
acid only led to an increased yield in 27 (Table 1, entry 2).
We also tried boronic acids 17 and 21, but could not isolate
the product of single addition (Table 1, entries 3 and 4).
Products 19 and 28 were observed instead in good yield,
considering that the boronic acid was the limiting reagent
for their formation.
Table 1 Single Coupling Attempts on 10 Using a SPhos/Pd2(dba)3 Catalytic System
R2
R2
R2
R2
R1
R1
R2
R1 R1
Br
Br
R1
Pd2(dba)3 (8 mol%)
SPhos (16 mol%)
Br
Br
O
OEt
+
+
+
OEt
OEt
OEt
(HO)2B
K3PO4 (3 equiv)
toluene, 24 h
O
(1.1 equiv)
14, 17 or 21
10
O
O
22a–24a
19, 27 or 28
22b–24b
Entry
Boronic acid R1
R2
Temp
(°C)
(E)-Single addition product/ (Z)-Single addition product/ Double addition product/
yield (%)
yield (%)
yield (%)
1
2
3
4
14
14
21
17
OBn
OBn
OMe
OMe
25
110
110
110
22a/–a
22a/–a
23a/–a
24a/–a
22b/–a
22b/–a
23b/–a
24b/–a
27/18
27/27
28/41
19/38
F
H
H
OMe
a Product could not be isolated.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

E
S. Cardinal, N. Voyer
Paper
Synthesis
Table 2 Single Coupling Attempts on 10 Using a PdCl2(PPh3)2/TFP Catalytic System
R1 R1
R1
R1
Br
Br
O
R1
PdCl2(PPh3)2 (5 mol%)
TFP (30 mol%)
Br
Br
O
OEt
+
+
+
2 M K2CO3
DME, 85 °C, 24 h
OEt
OEt
OEt
(HO)2B
(1.1 equiv)
O
O
10
13, 17, 18, 21
23a–26a
15, 19, 20 or 28
23b–26b
Entry
Boronic acid
R1
Single addition products
Double addition product
isolated yield (%)
Isolated yielda (%)
(E)-Product/yieldb (%)
(Z)-Product/yieldb (%)
1
2
3
4
13
21
17
18
H
60
64
45
80
26a/52
23a/54
24a/39
25a/70
26b/8
15/20
28/26
19/32
20/14
F
23b/10
24b/6
OMe
CF3
25b/10
a Pure isolated yield of (E) + (Z) isomers.
b Determined by NMR analysis.
gem-dibromoalkene follows the same tendency as previ-
ously reported for stereoselective single couplings on such
moieties.14
With compounds 23a–26a in hand, we performed sec-
ond SMC reactions to investigate the preparation of other
classes of 1,2,2-triarylethene compounds. Class C com-
pounds, with two identically substituted aryl groups in a
syn relationship, can be synthesized by using, as partner for
the second coupling reaction, a boronic acid with the same
substituents as the gem-dibromoalkene precursor. Like-
wise, 2,3,3-triarylacrylic acid esters of Class C can be ob-
tained from 23a–25a by a SMC reaction with phenylboronic
acid, considering 23a–25a were all synthesized from α-keto
ester 9. The results of the preparation of compounds 29a–
31a are presented in Table 3.
Good conversions were obtained using the PdCl2(PPh3)2/
TFP catalytic system with an excess of boronic acid, show-
ing that this system was also efficient for the second cou-
pling. This matches what we expected due to our previous
obtention of undesirable double coupling products (Table
2).
Figure 2 X-ray diffraction structures of compound 24a
Table 3 Second SMC on Compound 23a–25a To Prepare 2,3,3-Triarylacrylic Acid Esters of Class C 29a–31a
R1
R1
R1
PdCl2(PPh3)2 (5 mol%)
TFP (30 mol%)
Br
+
+
B(OH)2
(2 equiv)
OEt
OEt
2 M K2CO3
DME, 85 °C, 24 h
OEt
13
O
O
O
29a–31a
29b–31b
23a–25a
Entry
Bromine compound
R1
(Z)-Product/yield (%)
(E)-Product/yield (%)
1
2
3
23a/b (E/Z 96:4)
F
29a/85
30a/36
31a/84
29b/4
30b/53
31b/0
24a
25a
OMe
CF3
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

F
S. Cardinal, N. Voyer
Paper
Synthesis
Due to its ease of use and efficiency, this system was
chosen for the second SMC on 1,2-diaryl-2-bromoethene
compounds. Using the same catalytic system for the first
and the second coupling is also advantageous, because it
opens the way to the one-pot preparation of 2,3,3-triaryl-
acrylic acid esters directly from a gem-dibromoalkene pre-
cursor.
screening of catalysts was necessary to reduce or avoid this
problem in these cases. Negishi even used these isomeriza-
tion phenomena to perform coupling reactions with com-
plete inversion of stereochemistry on dienylpalladium in-
termediates generated via oxidative addition.25 To the best
of our knowledge, there has been no extensive studies of
the isomerization of alkenyl halides in cross-coupling reac-
tions.
The preparation of compounds 29–31 established the
isomerization behavior of the functionalized 1,2-diaryl-2-
bromoethene compounds in the context of a second palla-
dium-catalyzed cross-coupling. As shown in Table 3, no
isomerization occurs in the case of 23a/b (Table 3, entry 1)
and 25a (Table 3, entry 3). Compound 31b was not formed
from 25a. The low yield of product 29b is due to the conver-
sion of 23b and parallels the amount of (Z) isomer present
in the starting material. A very different reactivity was ob-
served with 1,2-diaryl-2-bromoethene compound 24a, for
which the presence of 30b as the major second coupling
product indicates an undeniable case of isomerization. For
the structure of 24a, the conjugation of the electron-donat-
ing methoxy group with the ester functionality might sig-
nificantly reduce the double bond character of the olefin,23
thus permitting rotation at some point in the coupling
mechanism and facilitating the migration of the electron-
rich aryl group to a thermodynamically favored antiperi-
planar position from the electron-withdrawing ester.
To investigate the source of this isomerization event, we
performed two sets of control experiments with substrate
24a and product 30a. We solubilized 24a and 30a in DME
and heated the solutions at 85 °C for 16 hours. We also ex-
posed them to the single SMC conditions, but without the
presence of a boronic acid coupling partner. No isomeriza-
tion was observed for either experiment. This suggests that
isomerization occurs at a later stage of the catalytic cycle,
following the transmetalation step.
All the pairs of isomers of 2,3,3-triarylacrylic acid esters
are separable by chromatography. Consequently, our meth-
od provides access to 30a and to the other triarylethene
compounds with the 4-methoxyphenyl group in the syn
configuration with the ester, though the yield is compro-
mised by the isomerization of compound 24a in the context
of a second SMC.
Compounds of Class D can be synthesized from the 1,2-
diaryl-2-bromoethane compound 26a, a precursor that al-
ready has phenyl groups as two of the future three aryl
groups.26 Table 4 presents the preparation of 2,3,3-triaryl-
acrylic acid esters 29b–31b. We obtained excellent yields
and no isomerization of the double bond for all three prod-
ucts. In all three cases, the amount of (Z)-products 29a–31a
obtained was due to the presence of a minor amount of (Z)-
isomer 26b in the starting material. These results establish
the stability of compound 26a towards isomerization under
these SMC conditions, and illustrate that the nature of the
boronic acid chosen does not influence the geometry of the
second coupling product.
The preparation of 1,2,2-triarylethene moieties with
three differently substituted aryl groups provide a synthet-
ic challenge. We were particularly interested in preparing
such compounds to demonstrate the potential of our meth-
od, in terms of molecular diversity. Table 5 present the syn-
thesis of six different 2,3,3-triarylacrylic acid esters of Class
E from 1,2-diaryl-2-bromoethenes 23–25.
Other groups have also reported undesired erosion of
the double bond geometry of allyl halide compounds in the
context of cross-coupling reactions.12a,24 An extensive
As previously observed, excellent conversions were ob-
tained when using 2 equivalents of any of the arylboronic
acid (Table 5, entries 1–4). Compounds 23a and 25a reacted
Table 4 Second SMC on Compound 26a To Prepare 2,3,3-Triarylacrylic Acid Esters of Class D 29b–31b
R1
R1
R1
PdCl2(PPh3)2 (5 mol%)
TFP (30 mol%)
Br
+
+
OEt
B(OH)2
2 M K2CO3
DME, 85 °C, 24 h
OEt
OEt
(2 equiv)
17, 18, 21
O
O
O
26a/b
(E/Z 92:8)
29b–31b
29a–31a
Entry
Boronic acid
R1
(E)-Product/yield (%)
(Z)-Product/yield (%)
1
2
3
21
17
18
F
29b/91
30b/86
31b/92
29a/8
30a/7
31a/8
OMe
CF3
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

G
S. Cardinal, N. Voyer
Paper
Synthesis
Table 5 Preparation of 2,3,3-Triarylacrylic Acid Esters 32–34 of Class E
R3
R3
R1
R2
R1
R2
R1
R3
PdCl2(PPh3)2 (5 mol%)
TFP (30 mol%)
R2
Br
+
2 M K2CO3
DME, 85 °C, 24 h
OEt
OEt
OEt
B(OH)2
(2 equiv)
14, 17, 18, 21
O
O
O
23–25a
product 1
32–34a/b
product 2
Entry
Boronic Acid
R2
R3
Bromine compound
R1
Product 1/yield (%)
Product 2/yield (%)
1
17
21
18
17
14
OMe
H
23a/b (E/Z 96:4)
F
32a/96
32b/39
33a/38
33b/99
34a/74
32b/4
32a/56
33b/57
33a/0
2
F
H
24a
OMe
OMe
CF3
F
3
CF3
H
24a
4
OMe
OBn
H
25a
5a
OMe
23a/b (E/Z 96:4)
34b/4
a Coupling reaction proceeded with 1.5 equiv of boronic acid.
once again in a second SMC with complete retention of ge-
ometry (Table 5, entries 1, 4, and 5). Compound 24a showed
consistent isomerization behavior with all the arylboronic
acids investigated, confirming that the erosion of the dou-
ble bond geometry in the coupling procedure originates
from a geometric instability in the substrate (Table 5, en-
tries 2 and 3).
We were able to prepare 2.3.3-triarylacrylic acid esters
with all the possible substitution patterns (Class A to E)
with control over the stereochemistry of the desired prod-
uct. Even if the yields of the analogues with the 4-methoxy-
phenyl group in a syn relationship with the ester are low-
ered by isomerization during the second SMC, these com-
pounds can be easily accessed because all pairs of
diastereomers are separable by conventional flash chroma-
tography.
As previously mentioned, the use of the Pd-
Cl2(PPh3)2/TFP catalytic system for the first and second sin-
gle SMC reactions may work with a sequential one-pot pro-
cedure to prepare 2,3,3-triarylacrylic acid esters. We at-
tempted to prepare compound 32a by this procedure,
starting from gem-dibromoalkene precursor 10.
This one-pot experiment (Scheme 6) gave the desired
compound 32a as the main product (43%). Minor isomer
32b (11%) was also isolated from the crude reaction mix-
ture, as were double SMC products 19 and 28 (19% and 22%
respectively).
Even if this procedure leads to a more complex purifica-
tion step for the desired product, it surely represents a
more straightforward route to 2,3,3-triarylacrylic acid ester
X-ray diffraction structures of 32a, 32b (Figure 3), and
33a (see Supporting Information) were obtained to ensure
the double bond configuration and to confirm our stereo-
chemical assignments for the first coupling reactions on
gem-dibromoalkene precursor 10 with arylboronic acids
17, 18, and 21 (Table 2). Indeed, the comparison of these X-
1
ray crystal structures with the H and 19F NMR spectra of
the corresponding compounds have allowed us to unequiv-
ocally establish the spectral signatures of the 4-substituted
groups of compounds prepared in this study for the syn and
anti positions with relation to the ester functionality.
Separate syntheses of both diastereomers of 32a/32b
and 33a/33b (Table 5, entries 2, 3 and 3, 4) illustrated the
usefulness of our method to selectively prepare two diaste-
reomeric compounds by varying the order of the boronic
acids involved in the two consecutive SMC reactions.
MeO
F
OMe
MeO
F
F
OMe F
Br
Br
O
OEt a, b
OEt
OEt
OEt
OEt
+
+
+
O
O
O
O
10
28 22%
32a 43%
32b 11%
19 19%
Scheme 6 Synthesis of 32a from 10 by a one-pot procedure. Reagents and conditions: (a) 21 (1.1 equiv), PdCl2(PPh3)2 (5 mol%), TFP (30 mol%), 2 M
K2CO3, DME, 85 °C, 24 h; (b) addition of 17 (1.5 equiv), 85 °C, 24 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

H
S. Cardinal, N. Voyer
Paper
Synthesis
preparing 2,3,3-triarylacrylic acid esters covering the entire
range of substitution patterns on the alkene, according to
the nature of the aryl groups. We determined efficient con-
ditions to prepare 2,3,3-triarylacrylic acid esters with one
or two different aryl groups (Classes A and B) by double
SMC reactions. We varied the conditions to favor the single
coupling reaction and good diastereoselectivity in the for-
mation of (E)-1,2-diaryl-2-bromoethene products, then
used these in a subsequent single SMC reaction to provide
2,3,3-triarylacrylic acid esters with two (Classes C and D) or
three (Class E) different aryl groups.
Preliminary results showed that the two SMC reactions
can be performed sequentially in one pot. In most cases, the
1,2,2-triarylethene compounds in this study were efficient-
ly prepared with complete regio- and stereocontrol, except
for the candidates with a 4-methoxyphenyl group in a syn
relationship with the ester, for which the stereochemistry
was compromised by isomerization. More detailed mecha-
nistic studies and optimization of the catalytic system are
underway, especially concerning these isomerizable cases.
The ester functionality present on the 2,3,3-triarylacryl-
ic acid esters prepared by our method is an interesting
functional group as its transformation could lead to a vari-
ety of other 1,2,2-triarylethene moieties. We are currently
also exploring the use of other gem-dibromoalkene precur-
sors to extend the methodology developed to other types of
complex 1,2,2-triarylethene compounds.
Unless otherwise indicated, all starting materials were purchased
from commercial sources (Sigma-Aldrich and VWR) and used without
further purification. The reagents and the solvents were dried and
purified before use by the usual procedures and kept under argon. All
reagents were assembled under an inert atmosphere. 1H and 13C NMR
spectra were recorded on an Agilent DD2 500 MHz, a Varian 400
MHz, or a Bruker 300 MHz spectrometer. Melting points were taken
using a Standford Research Systems OptiMelt MPA 100 instrument.
Mass spectra were obtained on an Agilent 6210 LC Time of Flight
Mass Spectrometer in direct injection mode. IR spectra were taken on
a Bomem MB-Series Arid-Zone spectrophotometer (NaCl windows)
or a Thermo Nicolet 380 (ATR, ZnSe).
Figure 3 X-ray diffraction structures of compounds 32a (up) and 32b
(down)
32a. For this preliminary experiment, the yield obtained for
product 32a is slightly lower (43% vs. 52%) compared with
the overall yield of the stepwise synthesis (Table 2, entry 2
and Table 5, entry 1). Though optimization work is needed
to fully adapt this synthetic approach to one-pot condi-
tions, this procedure represents a promising extension of
our method for the rapid and selective preparation of com-
plex highly substituted 1,2,2-triarylethene compounds.
In summary, we have developed an efficient approach
for the selective preparation of 2,3,3-triarylacrylic acid es-
ters, by the installation of aryl groups on a gem-dibro-
moalkene compound using SMC reactions. Various ana-
logues can be obtained from a single precursor. We have
demonstrated the versatility of the synthetic strategy by
Preparation of Functionalized α-Keto Ester Compounds
Ethyl 4-Hydroxy-3-methoxymandelate (4)4
4-Hydroxy-3-methoxymandelic acid (3, 0.500 g, 2.52 mmol) was dis-
solved in MeOH/H2O (10:1, 5 mL) and then treated with 20% aq Cs2-
CO3 to adjust the pH to 7. After removal of the solvent, DMF (6 mL)
was added to the dry residue. After 5 min, EtBr (226 μL, 3.02 mmol)
was added and the mixture was stirred for 96 h or until completion
was shown by TLC (EtOAc/hexanes 50:50). 1 M HCl was then added
and the ester was extracted with CH2Cl2 (3 ×) The combined organic
layers were washed with brine, dried (Na2SO4), and concentrated in
vacuo to give an oil that was purified by flash chromatography
(EtOAc/hexanes 50:50, Rf 0.27) to yield 4 (0.438 g, 77%) as a white sol-
id; mp 76–79 °C.
IR (NaCl): 3436, 1731, 1516, 1274, 1206, 1152, 1031 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

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S. Cardinal, N. Voyer
Paper
Synthesis
1H NMR (500 MHz, CDCl3): δ = 6.94–6.88 (m, 3 H), 5.75 (br, 1 H), 5.08
(s, 1 H), 4.30–4.23 (m, 1 H), 4.22–4.15 (m, 1 H), 3.88 (s, 3 H), 1.24 (t,
J = 7.4 Hz, 3 H).
dried (MgSO4), and concentrated in vacuo. The crude product was pu-
rified by column chromatography (silica gel, EtOAc/hexanes 20:80, Rf
0.45) to yield 7 (0.802 g, 94%) as yellow needles; mp 57–62 °C.
13C NMR (125 MHz, CDCl3): δ = 145.8, 130.4, 119.9, 114.4, 108.8, 72.7,
62.2, 55.9, 14.0.
IR (NaCl): 1735, 1673, 1593, 1512, 1283, 1259, 1167, 1141, 1018, 744,
697 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C11H14NaO5: 249.0733; found:
249.0739.
1H NMR (500 MHz, CDCl3): δ = 7.54–7.50 (m, 2 H), 7.47–7.31 (m, 10
H), 6.91 (d, J = 6.9 Hz, 1 H), 5.41 (s, 2 H), 5.25 (s, 2 H), 3.88 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 184.7, 164.0, 154.1, 149.8, 135.8,
134.7, 128.7, 128.3, 127.2, 125.8, 125.7, 112.2, 111.2, 70.9, 67.6, 56.1.
Ethyl 4-(Benzyloxy)-3-methoxymandelate (5)4
HRMS (ESI): m/z [M + H]+ calcd for C23H21O5: 377.1384; found:
317.1378.
Ethyl 4-hydroxy-3-methoxymandelate (4, 1.00 g, 4.42 mmol) was dis-
solved in anhyd acetone (15 mL) in an oven-dried three-neck flask
under argon. K2CO3 (1.038 g, 7.51 mmol) was added. After 5 min,
BnBr (0.90 mL, 7.51 mmol) was added and the mixture was refluxed
for 20 h or until completion was shown by TLC (EtOAc/hexanes
50:50). The mixture was allowed to warm up to r.t., poured into sat.
K2CO3 and extracted with EtOAc (3 ×). The combined organic layers
were washed with brine, dried (MgSO4), concentrated in vacuo, and
purified by flash chromatography (EtOAc/hexanes 50:50, Rf 0.45) to
yield 5 (1.168 g, 84%) as a white solid; mp 118–121 °C.
Ethyl [4-(Benzyloxy)-3-methoxyphenyl](oxo)acetate (8)4
At r.t., 5 (1.15 g, 3.64 mmol) was dissolved in anhyd CH2Cl2 (160 mL)
in an oven-dried three-neck flask under argon. The flask was cooled
to 0 °C and Dess–Martin periodinane (3.08 g, 7.27 mmol) was added.
The mixture was stirred at 0 °C until completion was observed by TLC
(EtOAc/hexanes 20:80). The solution was then diluted with CH2Cl2
and a solution of 10% Na2S2O3 in sat. NaHCO3 (100 mL) was added. The
mixture was stirred for 15 min and the organic layer was separated,
dried (MgSO4), and concentrated in vacuo. The crude product (yellow-
ish solid) was purified by column chromatography (silica gel, EtOAc/
hexanes 20:80, Rf 0.37) to yield 8 (1.142 g, quantitative yield) as a
white solid; mp 71–73 °C.
IR (NaCl): 3467, 1735, 1513, 1263, 1225, 1206, 1156, 1139, 1031 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.46–7.28 (m, 5 H), 6.97 (s, 1 H), 6.98–
6.85 (m, 2 H), 5.16 (s, 2 H), 5.10 (s, 1 H), 4.30–4.23 (m, 1 H), 4.22–4.15
(m, 1 H), 3.90 (s, 3 H), 1.24 (t, J = 7.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 173.8, 149.7, 148.3, 137.0, 131.5,
128.6, 127.9, 127.3, 119.1, 113.7, 110.0, 72.7, 71.0, 62.2, 56.0, 14.1.
HRMS (ESI): m/z [2 M + Na]+ calcd for C36H40O10Na: 655.2514; found:
655.2531.
IR (NaCl): 1733, 1673, 1593, 1513, 1284, 1259, 1193, 1170, 1143,
1021 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.59–7.55 (m, 2 H), 7.45–7.31 (m, 5 H),
6.93 (d, J = 8.5 Hz, 1 H), 5.25 (s, 2 H), 4.43 (q, J = 7.3 Hz, 2 H), 3.95 (s, 3
H), 1.41 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 164.2, 154.1, 149.8, 135.9, 128.8,
128.3, 127.2, 126.0, 125.8, 112.2, 111.1, 70.9, 62.2, 56.1, 14.1.
Benzyl 4-(Benzyloxy)-3-methoxymandelate (6)
At r.t., 4-hydroxy-3-methoxymandelic acid (3, 1.00 g, 5.05 mmol) was
dissolved in anhyd acetone (15 mL) in an oven-dried three-neck flask
under argon. K2CO3 (2.09 g, 15.1 mmol) was added. After 5 min, BnBr
(1.80 mL, 15.14 mmol) was added and the mixture was refluxed for
72 h. The mixture was allowed to cooled to r.t., poured into sat. K2CO3
and extracted with EtOAc (3 ×). The combined organic layers were
washed with brine, dried (MgSO4), concentrated in vacuo, and puri-
fied by flash chromatography (EtOAc/hexanes 50:50, Rf 0.40) to yield
6 (1.03 g, 54%) as a white solid; mp 76–78 °C.
HRMS (ESI): m/z [M + H]+ calcd for C18H19O5: 315.1227; found:
315.1234.
Ethyl 3,3-Dibromo-2-phenylpropenoate (10); General Procedure
for the Preparation of gem-Dibromoalkenes
PPh3 (3.28 g, 12.5 mmol) was dissolved in anhyd CH2Cl2 (3 mL) in an
oven-dried three-neck flask under argon. The mixture was cooled to
0 °C and CBr4 (2.07 g, 6.25 mmol) in solution in anhyd CH2Cl2 (2 mL)
was added dropwise. The mixture was stirred at 0 °C for 30 min and a
solution of ethyl mandelate (9, 0.559 g, 3.12 mmol) in anhyd CH2Cl2
(1.5 mL) was added dropwise. The mixture was allowed to warm to
r.t. and stirred for 12 h or until completion was observed by TLC
(Et2O/hexanes 10:90). Pentane (50 mL) was added to the mixture,
which was stirred for 30 min. After filtration, the solvent was evapo-
rated in vacuo and the crude product was purified by column chro-
matography (silica gel, Et2O/hexanes 10:90, Rf 0.43) yielding 1019b
(0.880 g, 85%) as a colorless oil.
IR (NaCl): 3465, 1737, 1513, 1454, 1263, 1226, 1139, 742, 697 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.46–7.30 (m, 8 H), 7.24–7.20 (m, 2 H),
6.93–6.85 (m, 3 H), 5.20 (d, J = 6.1 Hz, 2 H), 5.17 (d, J = 2.1 Hz, 3 H),
3.90 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 173.6, 149.8, 148.3, 137.0, 135.1,
131.2, 128.6, 128.5, 128.0, 127.9, 127.3, 119.2, 113.8, 109.9, 72.7, 71.0,
67.6, 55.9.
HRMS (ESI): m/z [M – H2O + H]+ calcd for C23H21O4: 361.1434; found:
361.1465.
IR (ATR, ZnSe): 1722, 1284, 1199, 1037, 1021, 794, 693 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.40–7.38 (m, 5 H), 4.27 (q, J = 7.2 Hz, 2
H), 1.31 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 165.9, 141.6, 135.7, 129.0, 128.6,
128.2, 95.4, 62.3, 14.0.
.
Benzyl [4-(Benzyloxy)-3-methoxyphenyl](oxo)acetate (7)
At r.t., 6 (0.854 g, 2.26 mmol) was dissolved in anhyd CH2Cl2 (100 mL)
in an oven-dried three-neck flask under argon. The flask was cooled
to 0 °C and Dess–Martin periodinane (1.92 g, 4.51 mmol) was added.
The mixture was stirred at 0 °C until completion was observed by TLC
(EtOAc/hexanes 50:50). The solution was then diluted with CH2Cl2
and a solution 10% Na2S2O3 in sat. NaHCO3 (100 mL) was added. The
mixture was stirred for 15 min and the organic layer was separated,
HRMS (ESI): m/z [M]+ calcd for C11H10O2Br: 334.9056; found:
334.9091.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

J
S. Cardinal, N. Voyer
Paper
Synthesis
Benzyl 2-[4-(Benzyloxy)-3-methoxyphenyl]-3,3-dibromopropen-
oate (11)
IR (NaCl): 1714, 1599, 1511, 1237, 1168, 1140, 1025, 735, 697 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.45–7.24 (m, 20 H), 6.78–6.45 (m, 9
H), 5.14 (s, 2 H), 5.12 (s, 2 H), 5.10 (s, 2 H), 4.98 (s, 2 H), 3.73 (s, 3 H),
3.51 (s, 3 H), 3.48 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 171.0, 149.2, 149.1, 148.6, 148.4, 147.8,
145.3, 137.0, 136.9, 135.6, 133.7, 131.5, 131.2, 124.0, 123.2, 122.2,
122.1, 115.0, 113.8, 113.0, 112.9, 70.9, 70.8, 67.0, 55.7.
White solid (0.978 g, 91%) obtained upon purification by column
chromatography (silica gel, Et2O/hexanes 20:80, Rf 0.28); mp 73–
76 °C.
IR (NaCl): 3033, 1729, 1511, 1455, 1246, 1190, 1167, 1141, 1023, 736,
697 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.46–7.33 (m, 10 H), 6.93–6.89 (m, 3
HRMS (ESI): m/z [M + H]+ calcd for C52H47O8: 799.3265; found:
H), 5.25 (s, 2 H), 5.18 (s, 2 H), 3.84 (s, 3 H).
799.3416.
13C NMR (125 MHz, CDCl3): δ = 166.0, 149.3, 148.8, 140.9, 136.7,
134.9, 128.6, 128.2, 128.0, 127.3, 121.0, 113.3, 111.6, 95.1, 67.9, 56.0.
Ethyl 2,3,3-Tris(4-benzyloxy-3-methoxyphenyl)propenoate (2)4
HRMS (ESI): m/z [M + NH4]+ calcd for C24H24Br2NO4: 548.0048; found:
548.0040.
Orange solid (1.18 g, 85%) obtained upon purification by column
chromatography (silica gel, EtOAc/hexanes 40:60, Rf 0.29); mp (de-
comp).
Ethyl 2-[4-(Benzyloxy)-3-methoxyphenyl]-3,3-dibromopropen-
oate (12)4
IR (NaCl): 1711, 1511, 1463, 1454, 1262, 1236, 1139, 1129, 1027, 735
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.48–7.30 (m, 15 H), 6.86–6.52 (m, 9
H), 5.19 (s, 2 H), 5.13 (s, 2 H), 5.11 (s, 2 H), 4.04 (q, J = 7.1 Hz, 2 H), 3.82
(s, 3 H), 3.56 (s, 3 H), 3.50 (s, 3 H), 0.99 (t, J = 7.2 Hz, 3 H).
White solid (1.47 g, 91%) obtained upon purification by column chro-
matography (silica gel, Et2O/hexanes 20:80, Rf 0.25); mp 71–74 °C.
IR (NaCl): 1726, 1510, 1247, 1193, 1170, 1141, 1026, 734 cm–1
.
13C NMR (125 MHz, CDCl3): δ = 171.2, 149.1, 148.2, 147.8, 147.4,
144.8, 137.0, 136.9, 135.7, 133.7, 131.9, 131.1, 128.6, 127.9, 127.3,
124.0, 122.1, 115.0, 113.9, 113.5, 113.2, 113.0, 70.8, 61.0, 56.0, 55.7,
13.9.
HRMS (ESI): m/z [M + H]+ calcd for C47H45O8: 731.3109; found:
731.3126.
1H NMR (500 MHz, CDCl3): δ = 7.47–7.30 (m, 5 H), 6.90–6.88 (m, 3 H),
5.17 (s, 2 H), 4.29 (q, J = 7.2 Hz, 2 H), 3.90 (s, 3 H), 1.33 (t, J = 6.5 Hz, 3
H).
13C NMR (125 MHz, CDCl3): δ = 166.2, 149.3, 148.8, 141.3, 136.7,
128.6, 128.3, 128.0, 127.3, 120.9, 113.3, 111.7, 94.3, 70.9, 62.3, 56.1,
14.0.
HRMS (ESI): m/z [M + H]+ calcd for C19H19Br2O4: 470.9625; found:
470.9617.
Ethyl 3,3-Bis(4-methoxyphenyl)-2-phenylpropenoate (19)
Yellowish solid (0.354 g, 86%) obtained upon purification by column
chromatography (silica gel, EtOAc/hexanes 5:95, Rf 0.12); mp 117–
121 °C.
Ethyl 2,3,3-Triphenylacrylate (15); General Procedure for Double
Suzuki–Miyaura Coupling with the Pd2(dba)3/SPhos Catalytic Sys-
tem
IR (NaCl): 1713, 1606, 1510, 1249, 1217, 1174, 834 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.12 (m, 7 H), 6.96–6.92 (m, 2 H),
6.89–6.85 (m, 2 H), 6.69–6.64 (m, 2 H), 4.07 (q, J = 7.1 Hz, 2 H), 3.83 (s,
3 H), 3.74 (s, 3 H), 1.04 (t, J = 7.1 Hz, 3 H).
13C NMR (CDCl3, 100 MHz,): δ = 171.0, 159.6, 159.1, 145.7, 138.3,
135.3, 133.1, 132.5, 131.9, 130.7, 130.0, 130.6, 128.3, 127.1, 113.5,
113.1, 60.9, 55.3, 55.1, 13.9.
Ethyl 3,3-dibromo-2-phenylpropenoate (10, 0.150 g, 0.45 mmol),
phenylboronic acid (13, 0.165 g, 1.35 mmol), Pd2(dba)3 (0.034 g, 0.036
mmol), SPhos (0.030 g, 0.072 mmol), and K3PO4 (0.477 g, 2.25 mmol)
were poured into an oven-dried three-neck flask under argon. Three
vacuum/argon purges were performed and freshly distilled toluene
(10 mL) was added. The mixture was refluxed for 24 h and then al-
lowed to cool to r.t. and filtered on a Celite pad. The filtrate was con-
centrated in vacuo and the crude product was purified by column
chromatography (silica gel, Et2O/hexanes 20:80, Rf 0.40) to yield 15
(0.128 g, 87%) as a white solid; mp 117–121 °C.
HRMS (ESI): m/z [M + H]+ calcd for C25H25O4: 389.1747; found:
389.1742.
Ethyl 2-Phenyl 3,3-bis[4-(trifluoromethyl)phenyl]propenoate (20)
IR (NaCl): 1709, 1494, 1444, 1326, 1302, 1266, 1220, 1152, 1044,
1027 cm–1
.
White solid (0.392 g, 70%) obtained upon purification by column
chromatography (silica gel, EtOAc/hexanes 5:95, Rf 0.35); mp 126–
128 °C.
1H NMR (500 MHz, CDCl3): δ = 7.36–7.28 (m, 5 H), 7.21–7.12 (m, 8 H),
7.05–7.02 (m, 2 H), 4.05 (q, J = 7.2 Hz, 2 H), 0.99 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.5, 146.0, 142.5, 140.6, 137.0,
133.8, 130.9, 129.9, 129.2, 128.2, 128.1, 127.9, 127.7, 127.4, 61.0, 13.7.
HRMS (ESI): m/z [M + H]+ calcd for C23H21O2: 329.15361; found:
IR (NaCl): 1721, 1324, 1219, 1167, 1127, 1112, 1068 cm–1
.
1H NMR (CDCl3, 400 MHz,): δ = 7.63–7.59 (m, 2 H), 7.42–7.37 (m, 4 H),
7.24–7.21 (m, 3 H), 7.13–7.08 (m, 4 H), 4.05 (q, J = 7.1 Hz, 2 H), 0.99 (t,
J = 7.1 Hz, 3 H).
329.15517.
13C NMR (100 MHz, CDCl3): δ = 169.4, 145.2, 143.5, 142.49, 136.5,
136.2, 131.0, 129.6, 129.5, 128.5, 128.2, 125.3, 125.0, 122.6, 61.4, 13.6.
19F NMR (376 MHz, CDCl3): δ = –62.68 (s, 3 F), –62.75 (s, 3 F).
Benzyl 2,3,3-Tris[4-(benzyloxy)-3-methoxyphenyl]propenoate
(16)
Orange solid (1.18 g, 84%) obtained upon purification by column
chromatography (silica gel, Et2O/hexanes 70:30, Rf 0.13); mp 46–
55 °C.
HRMS (ESI): m/z [M + H]+ calcd for C25H19F6O2: 465.1284; found:
465.1298.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

K
S. Cardinal, N. Voyer
Paper
Synthesis
Ethyl3,3-Bis(4-benzyloxy-3-methoxyphenyl)-2-phenylpropenoate
(27)
1H NMR (500 MHz, CDCl3): δ = 7.51–7.42 (m, 6 H), 7.41–7.37 (m, 1 H),
6.91 (d, J = 8.8 Hz, 2 H), 4.00 (q, J = 7.1 Hz, 2 H), 3.85 (s, 3 H), 0.98 (t, J =
7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.1, 160.3, 137.7, 136.2, 132.7,
130.7, 130.0, 128.8, 128.3, 113.6, 61.4, 55.4, 13.7.
Obtained while attempting to perform single coupling with the
Pd2(dba)3/SPhos catalytic system (Table 1, entry 2); only 1.1 equiv of
arylboronic acid used for the coupling procedure. Orange solid (0.098
g, 27%) obtained upon purification by column chromatography (silica
gel, Et2O/hexanes 20:80 to >30:70); Rf 0.14 (Et2O/hexanes 30:70); mp
136–140 °C.
HRMS (ESI): m/z [M + H]+ calcd for C18H18BrO3: 363.0415; found:
363.0406.
Single crystals of 24a were recrystallized (hexanes) (see Supporting
IR (ATR, ZnSe): 1712, 1508, 1230, 1203, 1181, 1126, 1036, 1001, 748,
Information for checkCIF file); CCDC 1410092.27
698 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.50–7.45 (m, 2 H), 7.43–7.29 (m, 8 H),
7.25–7.12 (m, 5 H), 6.87–6.82 (m, 3 H), 6.70 (d, J = 8.3 Hz, 1 H), 6.55
(d, J = 2.1 Hz, 2 H), 5.19 (s, 2 H), 5.09 (s, 2 H), 4.04 (q, J = 7.1 Hz, 2 H),
3.82 (s, 3 H), 3.46 (s, 3 H), 0.99 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 171.0, 149.1, 148.4, 148.2, 147.9,
145.8, 138.3, 137.0, 136.9, 136.0, 133.3, 132.1, 129.8, 128.6, 128.5,
128.3, 127.9, 127.4, 127.3, 127.2, 124.2, 122.1, 115.1, 113.1, 113.0,
112.7, 70.8, 60.9, 56.0, 55.6, 13.9.
Ethyl (Z)-3-Bromo-3-(4-methoxyphenyl)-2-phenylpropenoate
(24b)
White solid (0.105 g, 6%) obtained upon purification by column chro-
matography (silica gel, EtOAc/hexanes 3:97 to> 10:90); Rf 0.43
(EtOAc/hexanes 10:90); mp 54–59 °C.
IR (NaCl): 1727, 1604, 1508, 1296, 1251, 1172, 1083 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.21–7.16 (m, 5 H), 7.16–7.11 (m, 2 H),
6.72–6.68 (m, 2 H), 4.35 (q, J = 7.1 Hz, 2 H), 3.75 (s, 3 H), 1.36 (t, J = 7.1
Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C39H37O6: 601.2585; found:
601.2706.
13C NMR (100 MHz, CDCl3): δ = 166.7, 137.3, 137.2, 136.4, 136.3,
130.5, 130.4, 129.3, 128.7, 128.6, 128.4, 115.4, 115.2, 61.6, 13.7.
HRMS (ESI): m/z [M + H]+ calcd for C18H18BrO3: 363.0415; found:
363.0361.
Ethyl 3,3-Bis(4-fluorophenyl)-2-phenylpropenoate (28)
Obtained while attempting to perform single coupling with the
Pd2(dba)3/SPhos catalytic system (Table 1, entry 3); only 1.1 equiv of
arylboronic acid used for the coupling procedure. White solid (0.090
g, 41%) obtained upon purification by column chromatography (silica
gel, EtOAc/hexanes 5:95 to >10:90); Rf 0.37 (EtOAc/hexanes 10:90);
mp 118–120 °C.
Ethyl (E/Z)-3-Bromo-3-(4-fluorophenyl)-2-phenylpropenoate
(23a/b)
White solid (0.667 g, 64%, E/Z 5.4:1) obtained upon purification by
column chromatography (silica gel, EtOAc/hexanes 3:97 to >10:90); Rf
(EtOAc/hexanes 3:97) 0.25.
IR (NaCl): 1718, 1601, 1507, 1221, 1158 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.25–7.19 (m, 2 H), 7.18–7.14 (m, 3 H),
7.09–7.04 (m, 2 H), 7.02–6.96 (m, 2 H), 6.95–6.89 (m, 2 H), 6.81–6.76
(m, 2 H), 4.02 (q, J = 7.1 Hz, 2 H), 0.99 (t, J = 7.1 Hz, 3 H).
Ethyl (E)-3-Bromo-3-(4-fluorophenyl)-2-phenylpropenoate (23a)
Early fractions were put aside during column chromatography (E/Z
96:4) for subsequent reactions and characterization of 23a; mp 62–
67 °C.
13C NMR (125 MHz, CDCl3): δ = 170.1, 163.6, 163.1, 161.6, 161.1,
143.5, 138.1, 137.2, 136.2, 134.1, 132.6, 130.9, 130.8, 129.7, 128.3,
127.6, 115.3, 115.1, 115.0, 114.9, 61.0, 13.7.
19F NMR (470 MHz, CDCl3): δ = –113.23 to –113.33 (m, 2 F).
HRMS (ESI): m/z [M + H]+ calcd for C23H19F2O2: 365.1348; found:
IR (NaCl): 2983, 1714, 1597, 1506, 1289, 1268, 1235, 1189, 837 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.51–7.38 (m, 7 H), 7.07 (m, 2 H), 3.97
(q, J = 7.1 Hz, 2 H), 0.95 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.7, 137.3, 137.2, 136.4, 136.3,
365.1349.
130.5, 130.4, 129.3, 128.7, 128.6, 128.4, 115.4, 115.2, 61.6, 13.6.
19F NMR (470 MHz, CDCl3): δ = –111.22 to –111.28 (m, 2 F).
HRMS (ESI): m/z [M + H]+ calcd for C17H15OBrFO2: 349.0234; found:
Ethyl (E)-3-Bromo-3-(4-methoxyphenyl)-2-phenylpropenoate
(24a); General Procedure for Single Suzuki–Miyaura Coupling with
the PdCl2(PPh3)2/TFP Catalytic System
Ethyl 3,3-dibromo-2-phenylpropenoate (10, 1.00 g, 2.99 mmol) and
4-methoxyphenylboronic acid (17, 0.500 g, 3.29 mmol) were poured
into an oven-dried three-neck flask under argon. Three vacuum/ar-
gon purges were performed, then anhyd DME (15 mL) and 2 M K2CO3
(3.89 mL, 7.77 mmol) were added at r.t. After 10 min, PdCl2(PPh3)2
(0.105 g, 0.150 mmol) and TFP (0.208 g, 0.897 mmol) were added and
the mixture was heated to 85 °C. After approx. 20 h the mixture was
allowed to cool to r.t. and diluted with CH2Cl2. 1 M HCl was then add-
ed and the ester was extracted with CH2Cl2 (3 ×) The combined organ-
ic layers were washed with brine, dried (MgSO4), and concentrated in
vacuo. The crude product was purified by flash chromatography
(EtOAc/hexanes 3:97 to >10:90) to yield 24a (0.631 g, 39%) as a white
solid; Rf 0.37 (EtOAc/hexanes 10:90); mp 81–85 °C.
349.0279.
Ethyl (Z)-3-Bromo-3-(4-fluorophenyl)-2-phenylpropenoate (23b)
Compound 23b could not be characterized because no fraction isolat-
ed during chromatography contained the (Z)-product as the major
isomer. The following spectral signatures (ethyl group and fluorine
atom) for 23b were found in the mixed E/Z fractions containing the
most (Z) isomer (E/Z 78:22).
1H NMR (400 MHz, CDCl3): δ = 4.37 (q, J = 7.1 Hz, 2 H), 1.38 (t, J = 7.1
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 61.9, 13.7.
19F NMR (470 MHz, CDCl3): δ = –111.29 to –111.36 (m, 1 F).
IR (NaCl): 1718, 1604, 1509, 1295, 1253, 1192, 1174, 1026, 833 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

L
S. Cardinal, N. Voyer
Paper
Synthesis
Ethyl (E)-3-Bromo-2-phenyl-3-[4-(trifluoromethyl)phenyl]prop-
enoate (25a)
Ethyl (Z)-3-(4-Fluorophenyl)-2,3-diphenylpropenoate (29a); Gen-
eral Procedure for Second Suzuki–Miyaura Coupling with the Pd-
Cl2(PPh3)2/TFP Catalytic System
White solid (0.651 g, 54%) obtained upon purification by column
chromatography (silica gel, EtOAc/hexanes 3:97 to >10:90); Rf 0.36
(EtOAc/hexanes 3:97); mp 66–71 °C.
IR (NaCl): 2985, 1719, 1327, 1265, 1193, 1166, 1114, 1068, 837 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.67–7.59 (m, 4 H), 7.51–7.38 (m, 5 H),
3.96 (q, J = 7.1 Hz, 2 H), 0.90 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.3, 143.8, 138.2, 136.9, 128.8,
128.7, 128.4, 125.3, 61.7, 13.5.
19F NMR (376 MHz, CDCl3): δ = –62.80 (s, 3 F).
HRMS (ESI): m/z [M + H]+ calcd for C18H15BrF3O2: 401.0183; found:
401.0209.
Ethyl (E/Z)-3-bromo-3-(4-fluorophenyl)-2-phenylpropenoate (23a/b
96:4, 0.075 g, 0.215 mmol) and phenylboronic acid (13, 0.053 g, 0.430
mmol) were poured into an oven-dried three-neck flask under argon.
Three vacuum/argon purges were performed, then anhyd DME (3 mL)
and 2 M K2CO3 (0.280 mL, 0.559 mmol) were added at r.t. After 10
min, PdCl2(PPh3)2 (0.008 g, 0.011 mmol) and tri(2-furyl)phosphine
(TFP) (0.015 g, 0.065 mmol) were added and the mixture was heated
to 85 °C. After approx. 24 h, the mixture was allowed to cool to r.t. and
diluted with CH2Cl2. 1 M HCl was then added and the ester was ex-
tracted with CH2Cl2 (3 ×). The combined organic layers were washed
with brine, dried (MgSO4), and concentrated in vacuo. The crude
product was purified by flash chromatography (EtOAc/hexanes 2:98
to >10:90) to yield 29a (0.063 g, 85%) as a white solid; Rf 0.32 (EtOAc/
hexanes 4:96); mp 130–132 °C.
.
Ethyl (Z)-3-Bromo-2-phenyl-3-[4-(trifluoromethyl)phenyl]prop-
enoate (25b)
IR (ATR, ZnSe): 1709, 1505, 1219, 1156, 1023, 873, 843, 773, 756, 696
Compound 25b could not be isolated as pure isomer during chroma-
tography, thus compromising its complete characterization. The fol-
lowing spectral signatures (ethyl group and fluorine atoms) and
properties for 25b were found in the mixed E/Z fractions containing
the most (Z) isomer (E/Z 1:1); Rf 0.3 (EtOAc/hexanes 3:97).
1H NMR (400 MHz, CDCl3): δ = 4.38 (q, J = 7.1 Hz, 2 H), 1.38 (t, J = 7.1
Hz, 3 H).
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.29–7.23 (m, 2 H), 7.21–7.08 (m, 8 H),
7.06–6.95 (m, 4 H), 4.06 (q, J = 7.1 Hz, 2 H), 1.03 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.4, 163.8, 161.3, 144.7, 140.3,
138.4, 137.3, 134.0, 131.0, 130.8, 129.8, 128.2, 127.9, 127.8, 127.5,
115.2, 115.0, 61.0, 29.7, 13.8.
19F NMR (376 MHz, CDCl3): δ = –111.55 to –111.63 (m, 1 F).
HRMS (ESI): m/z [M + H]+ calcd for C23H20FO2: 347.1442; found:
13C NMR (100 MHz, CDCl3): δ = 62.1, 14.1.
19F NMR (376 MHz, CDCl3): δ = –62.85 (s, 3 F).
347.1462.
Ethyl (E/Z)-3-Bromo-2,3-diphenylpropenoate (26a/b)
Ethyl (E)-3-(4-Fluorophenyl)-2,3-diphenylpropenoate (29b)
White solid (0.602 g, 60%, E/Z 6.5:1) obtained upon purification by
column chromatography (silica gel, EtOAc/hexanes 3:97 to >10:90); Rf
(EtOAc/hexanes 3:97) 0.24.
Pinkish solid (0.071 g, 91%) obtained upon purification by column
chromatography (silica gel, EtOAc/hexanes 2:98 to >10:90); Rf 0.23
(EtOAc/hexanes 4:96); mp 110–114 °C.
IR (NaCl): 1712, 1601, 1505, 1219, 1158, 1044, 1026, 837 cm–1
.
Ethyl (E)-3-Bromo-2,3-diphenylpropenoate (26a)
1H NMR (500 MHz, CDCl3): δ = 7.38–7.33 (m, 3 H), 7.32–7.28 (m, 2 H),
7.25–7.18 (m, 3 H), 7.17–7.12 (m, 2 H), 7.02–6.98 (m, 2 H), 6.86–6.81
(m, 2 H), 4.05 (q, J = 7.1 Hz, 2 H), 0.98 (t, J = 7.1 Hz, 3 H).
Early fractions were put aside during column chromatography (E/Z
92:8) for subsequent reactions and characterization of 26a; mp 55–
60 °C.
13C NMR (125 MHz, CDCl3): δ = 170.3, 163.1, 161.1, 144.9, 142.3,
137.4, 136.5, 133.9, 132.8, 132.7, 129.8, 129.1, 128.3, 128.2, 127.5,
114.8, 61.0, 13.7.
19F NMR (470 MHz, CDCl3): δ = –113.50 to –113.58 (m, 1 F).
HRMS (ESI): m/z [M + H]+ calcd for C23H20FO2: 347.1442; found:
IR (NaCl): 1722, 1445, 1286, 1267, 1234, 1191, 1040 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.52–7.49 (m, 4 H), 7.46–7.35 (m, 6 H),
3.95 (q, J = 7.1 Hz, 2 H), 0.89 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 166.9, 140.3, 137.4, 136.9, 130.7,
129.2, 128.8, 128.5, 128.4, 128.2, 61.5, 13.5.
.
347.1423.
HRMS (ESI): m/z [M + H]+ calcd for C17H16BrO2: 333.0309; found:
333.0251.
Ethyl (Z)-3-(4-Methoxyphenyl)-2,3-diphenylpropenoate (30a)
Yellowish solid (0.054 g, 36%) obtained upon purification by column
chromatography (silica gel, EtOAc/hexanes 5:95, Rf 0.18); mp 102–
106 °C.
Ethyl (Z)-3-Bromo-2,3-diphenylpropenoate (26b)
Compound 26b could not be characterized because no fraction isolat-
ed during chromatography contained the (Z)-product as the major
isomer. The following spectral signatures (ethyl group) for 26b were
found in the mixed E/Z fractions containing the most (Z) isomer (E/Z
83:17).
IR (NaCl): 1714, 1245, 1216, 1038, 1025, 775, 721, 696 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.25–7.08 (m, 10 H), 7.05–7.00 (m, 2
H), 6.89–6.84 (m, 2 H), 4.08 (q, J = 7.1 Hz, 2 H), 3.83 (s, 3 H), 1.05 (t, J =
7.1 Hz, 3 H).
1H NMR (500 MHz, CDCl3): δ = 4.38 (q, J = 7.1 Hz, 2 H), 1.40 (t, J = 7.1
13C NMR (125 MHz, CDCl3): δ = 170.9, 159.6, 145.7, 140.8, 137.8,
134.9, 132.9, 131.0, 130.5, 129.9, 129.6, 128.1, 127.8, 127.6, 127.2,
120.6, 115.3, 113.5, 60.9, 55.3, 13.9.
Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 62.0, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C24H23O3: 359.1642; found:
359.1644.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

M
S. Cardinal, N. Voyer
Paper
Synthesis
Ethyl (E)-3-(4-Methoxyphenyl)-2,3-diphenylpropenoate (30b)
1H NMR (500 MHz, CDCl3): δ = 7.30–7.25 (m, 2 H), 7.22–7.18 (m, 3 H),
7.15–7.12 (m, 2 H), 7.06–7.01 (m, 2 H), 6.92–6.89 (m, 2 H), 6.69–6.65
(m, 2 H), 4.05 (q, J = 7.1 Hz, 2 H), 3.75 (s, 3 H), 1.02 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 170.6, 163.6, 161.6, 159.2, 144.7,
138.8, 137.8, 132.4, 131.0, 130.0, 128.3, 127.3, 115.2, 115.0, 113.3,
60.9, 55.1, 13.8.
Brownish solid (0.067 g, 86%) obtained upon purification by column
chromatography (silica gel, EtOAc/hexanes 5:95, Rf 0.24); mp 114–
118 °C.
IR (NaCl): 1716, 1606, 1509, 1249, 1217, 1151, 1042, 831 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.38–7.29 (m, 5 H), 7.25–7.14 (m, 5 H),
6.98–6.90 (m, 2 H), 6.71–6.64 (m, 2 H), 4.03 (q, J = 7.1 Hz, 2 H), 3.75 (s,
3 H), 0.97 (t, J = 7.1 Hz, 3 H).
19F NMR (470 MHz, CDCl3): δ = –113.61 to –113.70 (m, 1 F).
HRMS (ESI): m/z [M + H]+ calcd for C24H22FO3: 377.1547; found:
13C NMR (125 MHz, CDCl3): δ = 170.8, 159.1, 146.0, 142.9, 138.0,
132.9, 132.7, 132.4, 129.9, 129.3, 128.3, 128.1, 128.0, 127.2, 113.2,
60.9, 55.1, 13.7.
377.1479.
Single crystals of 32a were recrystallized (hexanes) (see Supporting
Information for checkCIF file); CCDC 1410093.27
HRMS (ESI): m/z [M + H]+ calcd for C24H23O3: 359.1642; found:
359.1656.
Ethyl (E)-3-(4-Fluorophenyl)-3-(4-methoxyphenyl)-2-phenylpro-
penoate (32b)
Ethyl (Z)-2,3-Diphenyl-3-[4-(trifluoromethyl)phenyl]propenoate
(31a)
Yellowish solid (0.061 g, 39%) obtained upon purification by column
chromatography (silica gel, EtOAc/hexanes 4:96, Rf 0.16); mp 100–
104 °C.
White solid (0.067 g, 84%) obtained upon purification by column
chromatography (silica gel, EtOAc/hexanes 4:96, Rf 0.46); mp 128–
132 °C.
IR (ATR, ZnSe): 1719, 1504, 1252, 1207, 1174, 1159, 1142, 1031, 838,
801, 770, 703 cm–1
.
IR (NaCl): 1718, 1325, 1219, 1160, 1127, 1110, 1066 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.23–7.17 (m, 5 H), 7.12–7.08 (m, 2 H),
7.01–6.96 (m, 2 H), 6.89–6.80 (m, 4 H), 4.08 (q, J = 7.1 Hz, 2 H), 3.83 (s,
3 H), 1.05 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 170.7, 163.1, 161.1, 159.7, 144.6,
137.6, 136.8, 134.6, 133.0, 132.9, 132.8, 130.5, 129.8, 128.3, 127.4,
114.9, 114.8, 113.6, 61.0, 55.3, 13.9.
1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 8.0 Hz, 2 H), 7.40 (d, J = 8.0
Hz, 2 H), 7.23–7.08 (m, 8 H), 7.00–6.94 (m, 2 H), 4.03 (q, J = 7.1 Hz, 2
H), 0.97 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 169.9, 146.1, 144.4, 139.8, 136.9,
135.0, 130.8, 129.8, 129.5, 128.8, 128.3, 128.0, 127.8, 126.3, 125.1,
61.2, 13.6.
19F NMR (470 MHz, CDCl3): δ = –113.65 to –113.73 (m, 1 F).
19F NMR (376 MHz, CDCl3): δ = –62.55 (s, 3 F).
HRMS (ESI): m/z [M + H]+ calcd for C24H22FO3: 377.1547; found:
HRMS (ESI): m/z [M + H]+ calcd for C24H20O2F3: 397.1410; found:
377.1480.
397.1427.
Single crystals of 32b were recrystallized (hexanes) (see Supporting
Information for checkCIF file); CCDC 1410094.27
Ethyl (E)-2,3-Diphenyl-3-[4-(trifluoromethyl)phenyl]propenoate
(31b)
Ethyl (Z)-3-(4-Methoxyphenyl)-2-phenyl-3-[4-(trifluorometh-
yl)phenyl]propenoate (33a)
White solid (0.070 g, 92%) obtained upon purification by column
chromatography (silica gel, EtOAc/hexanes 4:96, Rf 0.26); mp 115–
118 °C.
White solid (0.034, 38%) obtained upon purification by column chro-
matography (silica gel, EtOAc/hexanes 4:96, Rf 0.17); mp 70–72 °C.
IR (NaCl): 2925, 1719, 1324, 1218, 1166, 1125, 1067, 1043, 1021, 723,
IR (NaCl): 1718, 1607, 1510, 1324, 1250, 1218, 1166, 1125, 1110,
701 cm–1
.
1067, 1028, 874 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.43–7.39 (m, 2 H), 7.38–7.35 (m, 3 H),
7.31–7.28 (m, 2 H), 7.24–7.21 (m, 3 H), 7.17–7.13 (m, 4 H), 4.07 (q, J =
7.1 Hz, 2 H), 1.00 (t, J = 7.1 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.38 (d, J = 8.0 Hz, 2 H), 7.21–7.17 (m, 5
H), 7.16–7.12 (m, 2 H), 7.11–7.07 (m, 2 H), 6.87 (d, J = 8.8 Hz, 2 H),
4.09 (q, J = 7.1 Hz, 2 H), 3.83 (s, 3 H), 1.06 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 170.0, 144.3, 144.1, 141.6, 136.8,
135.3, 131.2, 129.7, 129.1, 128.4, 128.3, 127.9, 124.8, 122.9, 77.3, 61.1,
13.7.
13C NMR (100 MHz, CDCl3): δ = 170.3, 159.8, 144.6, 143.7, 137.0,
134.3, 134.0, 131.3, 130.5, 129.7, 128.4, 127.7, 124.7, 113.7, 61.1, 55.3,
13.9.
19F NMR (376 MHz, CDCl3): δ = –62.62 (s, 3 F).
19F NMR (376 MHz, CDCl3): δ = –62.61 (s, 3 F).
HRMS (ESI): m/z [M + H]+ calcd for C24H20F3O2: 397.1410; found:
HRMS (ESI): m/z [M + H]+ calcd for C25H22F3O3: 427.1516; found:
397.1415.
427.1529.
Single crystals of 33a were recrystallized (hexanes) (see Supporting
Information for checkCIF file); CCDC 1410095.27
Ethyl (Z)-3-(4-Fluorophenyl)-3-(4-methoxyphenyl)-2-phenylpro-
penoate (32a)
Brownish solid (0.078 g, 96%) obtained upon purification by column
chromatography (silica gel, EtOAc/hexanes 4:96, Rf 0.23); mp 100–
106 °C.
Ethyl (E)-3-(4-Methoxyphenyl)-2-phenyl-3-[4-(trifluorometh-
yl)phenyl]propenoate (33b)
Brownish solid (0.079 g, 99%) obtained upon purification by column
chromatography (silica gel, EtOAc/hexanes 4:96, Rf 0.25); mp 114–
118 °C.
IR (ATR, ZnSe): 1710, 1509, 1251, 1213, 1145, 1037, 1024, 830, 764,
730, 702 cm–1
.
IR (NaCl): 1717, 1606, 1509, 1325, 1250, 1217, 1165, 1125, 1066,
1040, 832 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

N
S. Cardinal, N. Voyer
Paper
Synthesis
1H NMR (500 MHz, CDCl3): δ = 7.62 (d, J = 8.1 Hz, 2 H), 7.44 (d, J = 8.0
Hz, 2 H), 7.28–7.15 (m, 5 H), 6.91 (d, J = 8.8 Hz, 2 H), 6.69 (d, J = 8.8 Hz,
2 H), 4.04 (q, J = 7.1 Hz, 2 H), 3.75 (s, 3 H), 0.97 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 170.2, 159.3, 146.5, 144.4, 137.4,
133.9, 132.3, 132.1, 129.9, 129.6, 128.4, 127.6, 125.1, 113.4, 61.0, 55.1,
13.6.
mixture was stirred for an extra 24 h before the mixture was allowed
to cool to r.t. and diluted with CH2Cl2. 1 M HCl was then added and the
ester was extracted with CH2Cl2 (3 ×). The combined organic layers
were washed with brine, dried (MgSO4), and concentrated in vacuo.
The crude product was purified by flash chromatography
(EtOAc/hexanes 10:90) to yield 32a (0.144 g, 43%).
19F NMR (376 MHz, CDCl3): δ = –62.49 (s, 3 F).
HRMS (ESI): m/z [M + H]+ calcd for C25H22F3O3: 427.1516; found:
427.1525.
Acknowledgment
The authors thank Charles Racine-Berthiaume and Pierre-Alexandre
Paquet Côté for bringing new insights to the project, and Dr. Wenhua
BI for X-ray crystallography experiments. This work was supported
by the NSERC of Canada, the FQRNT of Quebec, PROTEO and Universi-
té Laval. SC is also indebted to NSERC of Canada and PROTEO for post-
graduate scholarships and for a travel award.
Ethyl (E)-3-(4-Benzyloxy-3-methoxyphenyl)-3-(4-fluorophenyl)-
2-phenylpropenoate (34a)
Brownish solid (0.315 g, 74%) obtained upon purification by column
chromatography (silica gel, EtOAc/hexanes 15:85, Rf 0.32); mp 110–
114 °C.
IR (ATR, ZnSe): 1713, 1505, 1250, 1221, 1206, 1182, 1131, 1039, 1023,
852, 748, 730, 698 cm–1
.
Supporting Information
1H NMR (400 MHz, CDCl3): δ = 7.44–7.31 (m, 4 H), 7.35–7.16 (m, 6 H),
7.18–7.11 (m, 2 H), 7.03 (t, J = 8.7 Hz, 2 H), 6.69 (d, J = 8.3 Hz, 1 H),
6.54–6.42 (m, 2 H), 5.08 (s, 2 H), 4.05 (q, J = 7.1 Hz, 2 H), 3.45 (s, 3 H),
1.02 (t, J = 7.1 Hz, 3 H).
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560419. SupoirtIngformioatnSupoirtIngformiaotn
13C NMR (100 MHz, CDCl3): δ = 170.6, 163.9, 161.4, 148.5, 148.0,
145.0, 138.5, 138.0, 136.8, 133.1, 133.0, 131.1, 131.0, 129.7, 128.5,
128.4, 127.9, 127.4, 127.3, 124.0, 115.2, 115.0, 114.9, 112.8, 70.8, 61.0,
55.6, 13.8.
19F NMR (470 MHz, CDCl3): δ = –113.43 to –113.55 (m, 1 F).
HRMS (ESI): m/z [M + H]+ calcd for C31H28FO4: 483.1966; found:
References
(1) (a) Doni, E.; Zhou, S.; Murphy, J. A. Molecules 2015, 20, 1755;
http://www.mdpi.com/journal/molecules.
(b) Takeda,
Y.;
Shimizu, M.; Hiyama, T. Angew. Chem. Int. Ed. 2007, 46, 8659.
(c) Uddin, M. J.; Rao, P. N. P.; McDonald, R.; Knaus, E. E. Bioorg.
Med. Chem. Lett. 2005, 15, 439. (d) Liu, X. Y.; Shimizu, M.;
Hiyama, T. Angew. Chem. Int. Ed. 2004, 43, 879. (e) Hellwinkel,
D.; Goke, K.; Karle, R. Synthesis 1994, 973.
483.1953.
Ethyl (Z)-3-(4-Benzyloxy-3-methoxyphenyl)-3-(4-fluorophenyl)-
(2) (a) Shoda, T.; Okuhira, K.; Kato, M.; Demizu, Y.; Inoue, H.; Naito,
M.; Kurihara, M. Bioorg. Med. Chem. 2014, 24, 87. (b) Ganapathy,
D.; Sekar, G. Org. Lett. 2014, 16, 3856. (c) Christodoulou, M. S.;
Fokialakis, N.; Passarella, D.; Garcia-Argaez, A. N.; Gia, O. M.;
Pongratz, I.; Dalla Via, L.; Haroutounian, S. A. Bioorg. Med. Chem.
2013, 21, 4120. (d) Abdellatif, K. R. A.; Belal, A.; Omar, H. A.
Bioorg. Med. Chem. Lett. 2013, 23, 4960. (e) Matsumoto, K.;
Shindo, M. Adv. Synth. Catal. 2012, 354, 642. (f) Shiina, I.; Sano,
Y.; Nakata, K.; Suzuki, M.; Yokoyama, T.; Sasaki, A.; Orikasa, T.;
Miyamoto, T.; Ikekita, M.; Nagahara, Y.; Hasome, Y. Bioorg. Med.
Chem. 2007, 15, 7599. (g) Jordan, V. C. Nat. Rev. Drug Discovery
2003, 2, 205. (h) Itami, K.; Kamei, T.; Yoshida, J. J. Am. Chem. Soc.
2003, 125, 14670.
(3) (a) Nagata, T.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2014,
79, 8960. (b) Zhu, Y.; Sun, P.; Yang, H. L.; Lu, L. H.; Yan, H.; Creus,
M.; Mao, J. C. Eur. J. Org. Chem. 2012, 4831. (c) Itami, K.;
Tonogaki, K.; Nokami, T.; Ohashi, Y.; Yoshida, J. Angew. Chem.
Int. Ed. 2006, 45, 2404. (d) Itami, K.; Ohashi, Y.; Yoshida, J. J. Org.
Chem. 2005, 70, 2778.
2-phenylpropenoate (34b)
White solid (0.017 g, 4%) obtained upon purification by column chro-
matography (silica gel, EtOAc/hexanes 15:85, Rf 0.24); mp 144–
147 °C.
IR (ATR, ZnSe): 1720, 1508, 1204, 1143, 1134, 1024, 1004, 820, 748,
697 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.45 (d, J = 1.6 Hz, 2 H), 7.40–7.36 (m, 2
H), 7.34–7.29 (m, 1 H), 7.22–7.17 (m, 3 H), 7.09 (m, 2 H), 6.99 (m, 2 H),
6.87–6.76 (m, 5 H), 5.18 (s, 2 H), 4.04 (q, J = 7.1 Hz, 2 H), 3.81 (s, 3 H),
0.99 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 170.7, 163.1, 161.1, 149.2, 148.3,
144.5, 137.5, 136.9, 136.4, 135.3, 133.2, 132.8, 129.8, 128.6, 128.3,
127.9, 127.4, 127.3, 122.0, 115.0, 114.8, 113.2, 112.8, 70.8, 61.0, 56.0,
13.9.
19F NMR (470 MHz, CDCl3): δ = –113.50 to –113.58 (m, 1 F).
HRMS (ESI): m/z [M + H]+ calcd for C31H28FO4: 483.1966; found:
483.1979.
(4) Cardinal, S.; Voyer, N. Tetrahedron Lett. 2013, 54, 5178.
(5) Strategies involving the uncatalyzed double addition of an
organometallic compound on an alkyne: (a) Zhou, C.; Larock, R.
C. J. Org. Chem. 2006, 71, 3184. (b) Shimizu, K.; Takimoto, M.;
Mori, M.; Sato, Y. Synlett 2006, 3182. (c) Zhou, C.; Larock, R. C.
Org. Lett. 2005, 7, 259. (d) Takahashi, T.; Xi, C.; Ura, Y.; Nakajima,
K. J. Am. Chem. Soc. 2000, 122, 3228. (e) Oda, H.; Morishita, M.;
Fugami, K.; Sano, H.; Kosugi, M. Chem. Lett. 1996, 25, 811.
(f) Ossor, H.; Pfeffer, M. J. Chem. Soc., Chem. Commun. 1985,
1540.
One-Pot Preparation of 2,3,3-Triarylacrylic Acid Ester 32a from
gem-Dibromoalkene Precursor 10
Ethyl 3,3-dibromo-2-phenylpropenoate (10, 0.300 g, 0.898 mmol)
and 4-fluorophenylboronic acid (21, 0.126 g, 0.898 mmol) were
poured into an oven-dried three-neck flask under argon. Three vacu-
um/argon purges were performed, then anhyd DME (10 mL) and 2 M
K2CO3 (1.16 mL, 2.33 mmol) were added at r.t. After 10 min,
PdCl2(PPh3)2 (0.032 g, 0.045 mmol) and TFP (0.063 g, 0.269 mmol)
were added and the mixture was heated to 85 °C. After 20 h, 4-meth-
oxyphenylboronic acid (17, 0.205 g, 1.347 mmol) was added and the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O

O
S. Cardinal, N. Voyer
Paper
Synthesis
(6) Examples involving the palladium-catalalyzed coupling of an
internal alkyne with an aryl iodide and an arylboronic acid:
(a) Scanlan, T. S.; Iijima, T. US 8236987, 2012. (b) Jiang, H.-F.;
Xu, Q.-X.; Wang, A. Z. J. Supercrit. Fluids 2009, 49, 377. (c) Zhou,
C.; Larock, R. C. J. Org. Chem. 2005, 70, 3765. (d) Zhou, C.;
Emrich, D. E.; Larock, R. C. Org. Lett. 2003, 5, 1579.
(7) Miscellaneous methods starting from different starting materi-
als: (a) Nagao, K.; Ohmiya, H.; Sawamura, M. Org. Lett. 2015, 17,
1304. (b) Zhu, D.; Wu, Y.; Wu, B.; Luo, B.; Ganesan, A.; Wu, F.-H.;
Pi, R.; Huang, P.; Wen, S. Org. Lett. 2014, 16, 2350. (c) Oliva-
Madrid, M.-J.; García-López, J.-A.; Saura-Llamas, I.; Bautista, D.;
Vicente, J. Organometallics 2014, 33, 19. (d) Zhou, L.; Zhang, W.;
Jiang, H. Sci. China, Ser. B: Chem. 2008, 51, 241. (e) Nakatsuji, H.;
Ashida, Y.; Hori, H.; Sato, Y.; Honda, A.; Taira, M.; Tanabe, Y. Org.
Biomol. Chem. 2015, 13, 8205. (f) Banert, K.; Hagedorn, M.;
Pester, T.; Siebert, N.; Staude, C.; Tchernook, I.; Rathmann, K.;
Hollóczki, O.; Friedrich, J. Chem. Eur. J. 2015, 21, 14911.
(14) (a) Chelucci, G.; Capitta, F.; Baldino, S.; Pinna, G. A. Tetrahedron
Lett. 2007, 48, 6514. (b) Molander, G. A.; Yokoyama, Y. J. Org.
Chem. 2006, 71, 2493. (c) Shen, W. Synlett 2000, 737. (d) Roush,
W. R.; Brown, B. B.; Drozda, S. E. Tetrahedron Lett. 1988, 29,
3541.
(15) Shimizu, M.; Takeda, Y.; Hiyama, T. Bull. Chem. Soc. Jpn. 2011, 84,
1339.
(16) (a) Jiao, J.; Hyodo, K.; Hu, H.; Nakajima, K.; Nishihara, Y. J. Org.
Chem. 2014, 79, 285. (b) Shimizu, M.; Nakamaki, C.; Shimono,
K.; Schelper, M.; Kurahashi, T.; Hiyama, T. J. Am. Chem. Soc.
2005, 127, 12506.
(17) Desai, N. B.; McKelvie, N.; Ramirez, F. J. Am. Chem. Soc. 1962, 84,
1745.
(18) Preparation of compound 2 as well as synthesis of precursors 8
and 12 has been previously reported by our group.4 They are
presented in this paper to show the complete current scope of
this synthetic strategy.
(8) Flynn, A. B.; Ogilvie, W. W. Chem. Rev. 2007, 107, 4698.
(9) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(10) Selected examples in medicinal chemistry: (a) Novoa, A.;
Pellegrini-Moise, N.; Bourg, S.; Thoret, S.; Dubois, J.; Aubert, G.;
Cresteil, T.; Chapleur, Y. Eur. J. Med. Chem. 2011, 46, 3570.
(b) Koh, M.; Park, S. B. Mol. Diversity 2011, 15, 69. (c) Bauer, A.;
Miller, M. W.; Vice, S. F.; McCombie, S. W. Synlett 2001, 254.
(11) Selected examples in material science: (a) Zeng, Z. B.; Sung, Y.
M.; Bao, N. N.; Tan, D.; Lee, R.; Zafra, J. L.; Lee, B. S.; Ishida, M.;
Ding, J.; Navarrete, J. T. L.; Li, Y.; Zeng, W. D.; Kim, D.; Huang, K.
W.; Webster, R. D.; Casado, J.; Wu, J. S. J. Am. Chem. Soc. 2012,
134, 14513. (b) Pola, S.; Kuo, C. H.; Peng, W. T.; Islam, M. M.;
Chao, I.; Tao, Y. T. Chem. Mater. 2012, 24, 2566. (c) Loo, Y. L.;
Hiszpanski, A. M.; Kim, B.; Wei, S. J.; Chiu, C. Y.; Steigerwald, M.
L.; Nuckolls, C. Org. Lett. 2010, 12, 4840. (d) Ramana, C. V.;
Reddy, B. K. K.; Reddy, C. N.; Gonnade, R. G.; Gurjar, M. K. Synlett
2007, 127. (e) Bures, F.; Schweizer, W. B.; May, J. C.; Boudon, C.;
Gisselbrecht, J. P.; Gross, M.; Biaggio, I.; Diederich, F. Chem. Eur.
J. 2007, 13, 5378.
(19) (a) Morken, P. A.; Bachand, P. C.; Swenson, D. C.; Burton, D. J.
J. Am. Chem. Soc. 1993, 115, 5430. (b) Vu, V. A.; Marek, I.;
Knochel, P. Synthesis 2003, 1797.
(20) Boudreault, P. L.; Cardinal, S.; Voyer, N. Synlett 2010, 2449.
(21) (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem. Int. Ed. 2004, 43, 1871. (b) Barder, T. E.; Walker, S.
D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127,
4685.
(22) Ritchie, C. D.; Sager, W. F. Prog. Phys. Org. Chem. 1964, 2, 323.
(23) (a) de Vaal, P.; Dedieu, A. J. Organomet. Chem. 1994, 478, 121.
(b) Amatore, C.; Bensalem, S.; Ghalem, S.; Jutand, A.
J. Organomet. Chem. 2004, 689, 4642.
(24) (a) Krijnen, E. S.; Zuilhof, H.; Lodder, G. J. Org. Chem. 1994, 59,
8139. (b) Rossi, R.; Bellina, F.; Carpita, A.; Mazzarella, F. Tetrahe-
dron 1996, 52, 4095. (c) Shi, J.-c.; Zeng, X.; Negishi, E.-i. Org. Lett.
2003, 5, 1825. (d) Simard-Mercier, J.; Jiang, J. L.; Ho, M. L.; Flynn,
A. B.; Ogilvie, W. W. J. Org. Chem. 2008, 73, 5899.
(25) Zeng, X.; Hu, Q.; Qian, M.; Negishi, E.-i. J. Am. Chem. Soc. 2003,
125, 13636.
(12) (a) Kotek, V.; Dvořáková, H.; Tobrman, T. Org. Lett. 2015, 17, 608.
(b) Gu, S.; Xu, H.; Zhang, N.; Chen, W. Chem. Asian. J. 2010, 5,
1677.
(26) For the synthesis of 2,3,3-triarylacrylic acid esters of Class D
from trans vic-dibromoalkenes see: Zhou et al. 2008 (ref. 7d).
(27) CCDC 1410092, CCDC 1410093, CCDC 1410094, and CCDC
1410095 contain the supplementary crystallographic data for
24a, 32a, 32b, and 33a, respectively. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
(13) Li, Y. H.; Zhao, X. M.; Lu, L. J. Fluorine Chem. 2004, 125, 1821.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–O