A simple method to prepare single isomer tetrasubstituted olefins by successive Suzuki-Miyaura cross-couplings of E-β-chloro-α-iodo-α,β-unsaturated esters

Article abstract of DOI:10.1016/j.tet.2008.04.004

A convenient method of synthesizing tetrasubstituted olefins as single isomers is described. E-β-Chloro-α-iodo-α,β-unsaturated esters are first converted into the corresponding E-β-chloro-α,β-unsaturated esters using Suzuki-Miyaura coupling reactions with arylboronic acids and alkenylboronic acids. These transformations gave complete selectivity, and proceeded with substitution at the more activated α-iodide position. These compounds, isolated as single isomers, were then transformed into tetrasubstituted olefins by Suzuki-Miyaura couplings with arylboronic acids, alkenylboronic acids, and alkyl boranes to afford the corresponding tetrasubstituted olefins as single isomers. During this coupling process, it was discovered that the use of small ligands, such as PMe₃ or PEt₃, was critical for efficient coupling. The stereochemistry and regiochemistry of the products were unequivocally established using NMR methods.

Full text of DOI:10.1016/j.tet.2008.04.004

Tetrahedron 64 (2008) 5472–5481
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A simple method to prepare single isomer tetrasubstituted olefins by successive
Suzuki–Miyaura cross-couplings of E-
b
-chloro-a-iodo-a,b-unsaturated esters
*
Julie Simard-Mercier, Alison B. Flynn, William W. Ogilvie
Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient method of synthesizing tetrasubstituted olefins as single isomers is described. E-
b-Chloro-
Received 20 February 2008
Received in revised form 31 March 2008
Accepted 1 April 2008
a
-iodo- -unsaturated esters are first converted into the corresponding E- -chloro- -unsaturated
a
,
b
b
a,b
esters using Suzuki–Miyaura coupling reactions with arylboronic acids and alkenylboronic acids. These
transformations gave complete selectivity, and proceeded with substitution at the more activated
Available online 8 April 2008
a-iodide position. These compounds, isolated as single isomers, were then transformed into tetrasub-
stituted olefins by Suzuki–Miyaura couplings with arylboronic acids, alkenylboronic acids, and alkyl
boranes to afford the corresponding tetrasubstituted olefins as single isomers. During this coupling
process, it was discovered that the use of small ligands, such as PMe3 or PEt3, was critical for efficient
coupling. The stereochemistry and regiochemistry of the products were unequivocally established using
NMR methods.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
R1
R4
R3
R2
R1
R2
a
b
1
The efficient regio- and stereodefined synthesis of tetrasub-
stituted olefins bearing four different carbon-linked appendages
presents a significant challenge.1 The congested nature of the
double bond often makes it difficult for reagents to approach each
other, reducing the utility of many ‘traditional’ olefin-producing
reactions. The majority of the methods that have been developed to
produce tetrasubstituted olefins rely either on the carbometallation
of alkynes or on the use of olefin templates in cross-coupling re-
actions. Alkyne carbometallation is perhaps the most widely used
method,1,2 and because of the convergent nature of the strategy, in
principle it provides maximum structural variation (Scheme 1a).
Tetrasubstituted double bonds can also be prepared by manipu-
lating a pre-existing olefin template (Scheme 1b).1,3 Generating the
template is often the most difficult aspect of this approach,
requiring the installation of directing elements for chemo-, regio-,
and stereocontrol. Selectivity issues may arise during the sub-
sequent cross-coupling stages that can lead to the production of
isomeric mixtures that may be extremely difficult to resolve.
Many natural products4 and pharmaceuticals3b,5,6 contain tet-
rasubstituted olefins as important structural elements. Tetrasub-
stituted olefins can also be used as intermediates in asymmetric
transformations that generate quaternary centers such as osmyla-
tions,7 epoxidations,8 and conjugate additions.9 Compounds
2
R1
Y
R
R1
R4
R3
R2
2
X
2
3
Scheme 1. General strategies for tetrasubstituted olefin formation.
containing tetrasubstituted alkenes have been employed as di-
peptide mimetics10 as well as polymerization substrates and cata-
lysts.11 Material science makes use of these functionalities because
of their physical,12 structural, and electronic properties;13 and these
moieties have often been used to form molecular switches14 or
optical storage devices.15 All of these applications require pre-
parative chemical transformations that are reliable, simple to per-
form, and that deliver the products as single isomers.
We have recently developed a mild and versatile method of
synthesizing acyclic, single isomer olefins bearing four different
carbon-linked substituents.16 These alkenes were obtained using
a differentially halogenated template that was submitted to se-
quential Sonogashira coupling reactions to produce trans ene–
diynes. Herein, we describe the optimization of sequential Suzuki
coupling reactions to these templates using arylboronic acids and
alkylboranes, a challenging task given the steric demands of the
substrates and reagents. An extensive package of tetrasubstituted
olefins formed by a simple, regioselective and stereoselective,
three-step method is disclosed as well.
* Corresponding author. Tel.: þ1 613 562 5800; fax: þ1 613 562 5170.
E-mail address: wogilvie@uottawa.ca (W.W. Ogilvie).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.004

J. Simard-Mercier et al. / Tetrahedron 64 (2008) 5472–5481
5473
2. Results and discussion
variety of palladium catalyst precursors suggested that selectivity
was possible in this process, however the efficiency of the reaction
was very sensitive to the palladium source. The use of PdCl2(PPh3)2
(entry 3) gave a moderate improvement in yield compared to the
Pd2(dba)3 that was used originally (entry 1), while the use of
Pd(dppf)Cl2 alone resulted in a lower product recovery (entry 2).
Using Pd(OAc)2 as a palladium source (entry 4) afforded the highest
yield when using PtBu3 as the ligand.
Using the best conditions described above as a starting point, an
optimization of the reaction solvent was then performed (Table 2).
Interestingly, the use of polar solvents such as acetonitrile (entry 1),
DMSO (entry 2) or DMF (entry 3) did not lead to any of the desired
product. Performing the reaction in other common solvents such as
THF, benzene or CHCl3 gave modest amounts of product, but the
use of these solvents did not produce any advantages over the di-
oxane originally used (entries 4–9). A slight but significant increase
in the yield of the monosubstituted product 8 was realized when
reactions were performed in EtOAc or in toluene (entries 10–12),
with toluene giving the best conversion to products.
The efficient synthesis of E-b-chloro-a-iodo-a,b-unsaturated
esters by the exposure of 2-alkynyl esters to Bu4NI in refluxing
dichloroethane represents a versatile entry into tetrasubstituted
olefin production.17 This method gives
b-chloro-a-iodo olefin
templates such as 5 with complete control of regio- and stereo-
chemistry. This process is directed by the presence of an electron-
withdrawing group on the alkyne and provides the starting point
for subsequent organometallic coupling reactions that convert the
template into a single isomer, all carbon-linked alkene (Scheme 2).
R1
CO2Et
Bu4NI
DCE, Δ
I
R1
Cl
4
5
CO2Et
67 - 92%
Scheme 2. Generation of single isomer E-
b-chloro-
a
-iodo- -unsaturated esters.
a,b
During these optimization studies, significant amounts of the
tetrasubstituted olefin were produced. Because this product was
the result of an over-reaction at the b-position, we investigated the
The introduction of substituents onto the E-b-chloro-a-iodo
templates can be done selectively and smoothly. Sonogashira re-
actions were first explored to obtain intermediate trisubstituted
olefins, a task that required some optimization in order to obtain
good yields and, importantly, single isomers.16 Starting with tem-
plates 5, submission to typical Sonogashira conditions produced
the desired products 6 that were isolated as single isomers in good
yield (Scheme 3).
possibility of improving the selectivity by lowering the reaction
temperature. As shown in Table 3, lowering the temperature of the
reaction to 0 ꢀC did not lead to any improvement in reaction se-
lectivity (entry 2). Raising the temperature slightly, however,
resulted in a significant increase in the amount of tetrasubstituted
product 10 that was formed (entry 3). As there was no advantage in
lowering the reaction temperature compared to performing the
reactions at room temperature, the more practical conditions were
employed for the next set of experiments.
The ligand was found to have a profound impact on reaction
efficiency (Table 4). Initial experiments were carried out using
Pd(OAc)2 and PtBu3$HBF4. These conditions delivered a modest
yield of the desired product 9, together with a small amount of
tetrasubstituted adduct 10 (entry 1). Reducing the size of the ligand
resulted in the production of significant amounts of the double-
coupled material (entries 2–4). Unfortunately, the use of other
hindered ligands such as PCy3 did not improve selectivity, nor did
the use of PPh3 or bidentate ligands such as DPPF (entries 5–7). Use
of the biphenyl ligand S-PHOS produced a remarkably selective
reaction (entry 8), a result that was unequaled by a related ligand
R1
R1
R2
R2
I
Pd(PPh3)2Cl2
CuI, iPr2NEt
Dioxane
Cl
Cl
CO2Et
CO2Et
5
6
Scheme 3. Sonagashira coupling of E-b-chloro-a-iodo-a,b-unsaturated esters to pro-
duce trisubstituted olefin templates.
These results were significant in that they demonstrated that
selectivity could be achieved in the cross-coupling of dihalogenated
templates such as 5. Of particular interest was the facile and pref-
erential displacement of the
bearing identical halogens at both the
react at the more activated
-position first,18 a trend reversed in the
a
-iodo substituent. Related templates
a
- and -position invariably
b
b
present series due to the increased reactivity of the iodide relative
to the chloride.
Encouraged by our success with the Sonogashira coupling re-
action, efforts were then directed to the development of a Suzuki
coupling process19 in order to introduce a larger variety of nucleo-
Table 2
Effect of the solvent in the Suzuki coupling reactions of 7
OMe
OMe
philes at the a-position of substrate 7 (Table 1). The testing of a
Me
Me
(HO)2B
I
Cl
Cl
t
Pd(OAc)2, P Bu3·HBF4
Cs2CO3, Solvent
CO2Et
Table 1
CO2Et
8
Effect of the palladium source in Suzuki coupling reactions at the
a
-position of 7
7
OMe
Entrya
Solvent
Yield (%)
OMe
Me
Me
(HO)2B
catalyst, ligand
Cs2CO3, Dioxane
1
2
3
4
CH3CN
DMSO
DMF
CH2Cl2
THF
NR
NR
NR
Trace
26
I
Cl
Cl
CO2Et
CO2Et
7
8
5
6
7
8
9
10
11
12
Benzene
CHCl3
Trifluorotoluene
tBuOMe
Dioxane
EtOAc
17
34
38
35
45
50
60
Entrya
Catalyst
Ligand
Yieldb (%)
1
2
3
4
Pd2(dba)3
PtBu3$HBF4
d
17
10
35
45
Pd(dppf)Cl2
PdCl2(PPh3)2
Pd(OAc)2
PtBu3$HBF4
PtBu3$HBF4
Toluene
a
Conditions: 0.1 equiv of catalyst, 0.2 equiv of ligand, 4.0 equiv of boronic acid,
4.0 equiv of Cs2CO3, and dioxane, 23 ꢀC.
Conditions: 0.1 equiv of Pd(OAc)2, 0.2 equiv of PtBu3$HBF4, 4.0 equiv of boronic
a
b
Tetrasubstituted (15–25%) olefin was also obtained in each of these reactions.
acid, 4.0 equiv of Cs2CO3, and 23 ꢀC.

5474
J. Simard-Mercier et al. / Tetrahedron 64 (2008) 5472–5481
Table 3
Effect of temperature on the efficiency of the Suzuki coupling reaction of 7
Me
Me
+
Me
Pd(OAc)2
Me
Me
Me
t
P Bu3·HBF4
I
+
Cl
Cl
Cs2CO3
Toluene
CO2Et
CO2Et
CO2Et
Me
B(OH)2
7
9
10
Entrya
Temperature (ꢀC)
Yield 9 (%)
Yield 10 (%)
1
2
3
23
0
45
21
23
18
3
2
13
a
Conditions: 0.1 equiv of Pd(OAc)2, 0.2 equiv of PtBu3$HBF4, 2.0 equiv of boronic acid, 2.0 equiv of Cs2CO3, and toluene.
Table 4
Effect of the ligand in the Suzuki coupling of
b
-chloro-
a
-iodo-
a
,
b-unsaturated ester 7
Me
Me
Me
Pd(OAc)2
ligand
Me
Me
Me
I
+
+
Cl
Cl
Cs2CO3
toluene
CO2Et
CO2Et
CO2Et
10
Me
B(OH)2
7
9
Entrya
Ligand
PtBu3$HBF4
Yield 9b (%)
Yield 10b (%)
1
2
3
4
5
6
7
8
9
10
21
16
23
20
21
10
7
81 (99)
45 (65)
Trace
3
30
20
27
43
12
19
Trace
15
PtBuMe2$HBF4
PEt3$HBF4
PMe3$HBF4
PCy3$HBF4
PPh3
DPPF
S-PHOS
Dave-PHOS
None
65 (99)
a
Conditions: 0.1 equiv of Pd(OAc)2, 0.2 equiv of ligand, 2.0 equiv of boronic acid, 2.0 equiv of Cs2CO3, toluene, and 23 ꢀC.
Yields in parentheses are corrected for unreacted starting material.
b
(entry 9). By using ligand-free conditions, clean conversion to the
tetrasubstituted alkenes bearing four different groups was then
explored. Some -alkynyl- -chloro substrates such as 6 have pre-
tetrasubstituted olefin product 10 was achieved (entry 10). This
result suggested a simple method of carrying out the subsequent
conversion of chlorides such as 9 into the ultimately desired single
isomer tetrasubstituted products 10.
a
b
viously been subjected to Suzuki coupling conditions to generate
a variety of tetrasubstituted alkenes.16 However, the
a-aryl-b-
The reaction with a variety of substrates and coupling partners
Table 5
was then investigated (Table 5). Selective coupling at the
of the -chloro- -iodo-substituted substrates was observed for all
examples, demonstrating that this position was more activated
toward oxidative addition than was the -position. Coupling with
a-position
Suzuki coupling of
acids
a
-iodo-
b
-chloro-
a
,
b
-unsaturated esters with a variety of boronic
b
a
R1
R1
R2B(OH)2, Pd(OAc)2
S-PHOS, Cs2CO3, Toluene
R2
b
I
Cl
Cl
phenylboronic acid resulted in a full conversion of the unsaturated
ester 7 to product 11 (entry 2). Substitution on the phenyl ring of
the boronic acid gave very good yields with electron-donating
groups such as methoxy at the para, meta and even at the sterically
demanding ortho position (entries 3–5). An aryl group substituted
with fluorine at the para position reacted smoothly (entry 6), as did
the sterically hindered 1-naphthyl (entry 7) and 2-naphthyl (entry
8) moieties. We were delighted to observe that heterocycles such as
thiophene (entry 9) could be added, giving the corresponding tri-
substituted product 17. We further expanded the scope of the re-
action to vinyl Suzuki processes, and successfully introduced both
a styrenyl substituent and an alkenyl group (entries 10 and 11). The
CO2Et
CO2Et
Entrya
Substrate
R1
R2
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
7
7
7
7
7
7
7
7
7
7
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
p-MeC6H4
C6H5
p-OMeC6H4
o-OMeC6H4
m-OMeC6H4
p-FC6H4
1-Naphthyl
2-Naphthyl
2-Thiophenyl
Styrenyl
9
11
8
12
13
14
15
16
17
18
81 (99)
100
84
93
65 (98)
82c
94
95
64 (100)
85d
substituent at the b-position of the olefin could be varied to include
11
7
Me
19
75d
( )5
bulky functions such as a cyclohexyl group (entry 12) or function-
alized alkyl chains (entry 13), illustrating that the nature of the R1
substituent did not significantly impact the reactivity of the tem-
plate. In all cases the reaction was regioselective and stereo-
selective, giving single isomers during the process.
12
13
20
22
Cy
CH2OTBS
p-OMeC6H4
p-OMeC6H4
21
23
79
74
a
Conditions: 0.1 equiv of Pd(OAc)2, 0.2 equiv of S-PHOS, 4.0 equiv of boronic acid,
4.0 equiv of Cs2CO3, toluene, and 23 ꢀC.
b
Yields in parentheses are corrected for unreacted starting material.
(E)-ethyl 3-(4-fluorophenyl)-but-2-enoate (14%) was also obtained.
Reaction run at 5 ꢀC.
c
With a successful strategy in hand to make the appropriate
trisubstituted olefin templates, the synthesis of all carbon
d

J. Simard-Mercier et al. / Tetrahedron 64 (2008) 5472–5481
5475
Table 7
chloro substituted compounds such as 8 were much more crowded
than the -alkynyl- -chloro substrates 6, and so we undertook
Single isomer tetrasubstituted olefins prepared using the Suzuki reaction
a
b
R1
R1
investigations to develop practical conditions to introduce the re-
quired aryl substituents. The ligand-free conditions that had pre-
viously been found to promote the formation of tetrasubstituted
olefins directly from substrate 7 (Table 4, entry 10) were in-
vestigated first. Although the use of Pd(OAc)2 alone in dioxane/
water had previously given very high conversions of 7 to the tet-
rasubstituted product 10, the application of these conditions to the
transformation of 8 to 24 was unsuccessful (Table 6, entry 1). Be-
cause Pd(OAc)2 alone did not give any of the tetrasubstituted
product, the effect of ligand size was investigated as a means of
R3B(OH)2
R2
R2
Cl
R3
Pd(OAc)2, PMe3·HBF4
Cs2CO3, Dioxane
CO2Et
CO2Et
Entrya Substrate R1
R2
R3
Product Yieldb (%)
1
2
3
4
5
6
7
8
8
8
8
8
8
8
Me
Me
Me
Me
Me
Me
Me
p-OMeC6H4 p-OMeC6H4
p-OMeC6H4 o-OMeC6H4
p-OMeC6H4 m-OMeC6H4
p-OMeC6H4 C6H5
p-OMeC6H4 p-FC6H4
p-MeC6H4
24
25
26
27
28
10
29
95
91
79
96
92
93
85
p-MeC6H4
introducing groups at the b-position of chloride-containing sub-
p-OMeC6H4 Styrenyl
strates such as 8. As shown, the use of large ligands such as PtBu3 or
PtBuMe2 did not result in the production of significant amounts of
tetrasubstituted olefin 24 (entries 2 and 3). The use of PPh3 was also
unfruitful, as all of the starting material was returned unchanged
(entry 6). Smaller ligands such as PEt3 or PMe3 were, however, very
efficient in promoting the cross-coupling, giving an excellent yield
of tetrasubstituted olefin 24 as a single stereoisomer (entries 4 and
5). The use of small ligands such as PMe3 in cross-couplings is
unusual, but in the production of congested materials such as 24,
these ligands appear to afford significant advantages.
8
8
Me
p-OMeC6H4
30
100
( )5
9
8
8
9
21
23
Me
Me
Me
Cy
p-OMeC6H4 2-Thiophenyl
p-OMeC6H4 2-Naphthyl
p-MeC6H4
d
NR
92
47 (67)
63 (79)
97
10
11
12
13
31
32
33
34
1-Naphthyl
p-OMeC6H4 C6H5
CH2OTBS p-OMeC6H4 C6H5
a
Conditions: 0.1 equiv of Pd(OAc)2, 0.2 equiv of PMe3$HBF4, 2.0 equiv of boronic
acid, 2.0 equiv of Cs2CO3, dioxane, and 23 ꢀC.
b
Yields in parentheses are corrected for unreacted starting material.
The reaction was compatible with a large variety of functional-
ities, and substitution at the para, meta, and even the ortho position
of the boronic acid component resulted in successful reactions
(Table 7, entries 1–3). A simple phenyl group was easily installed, as
were aromatic groups substituted with fluorine or methyl at the
para position (entries 4–6). The reaction could be extended to in-
clude alkenyl substituents bearing alkyl or aromatic functionalities
(entries 7 and 8), although we were unable to introduce hetero-
cycles such as thiophene (entry 9). Hindered naphthyl groups could
be added, but the yield of the process depended on the attachment
point to the naphthyl moiety (entries 10 and 11). As before,
branched substituents were tolerated at the R1 position, and
substituted alkyl groups could also be present on the olefin tem-
plate (entries 12 and 13). All of the reactions were stereoselective
and all products were isolated as single isomers.
The scope of the functionalities available was further expanded
by investigating alkyl-Suzuki coupling reactions on the tri-
substituted alkenyl chlorides (Table 8). The use of a typical catalyst
and base for this conversion, under anhydrous conditions, was
unsuccessful (entry 1). The use of bidentate ligands such as DPPF,
DPPM, DPPE, DPPP, or DPPB in THF with K3PO4 as a base also met
with failure. The biphenyl ligand XANTPHOS was tested, but the use
of this material did not result in the formation of a tetrasubstituted
olefin. The addition of H2O to the reaction mixture ultimately led to
a successful reaction. Using the hydrated form of K3PO4 resulted in
the isolation of a small amount of the desired alkyl substituted
product 36 (entry 2). The addition of water to the reaction when
using anhydrous K3PO4 as the base also resulted in the production
of this desired material (entry 3). Finally, the use of dioxane, rather
than THF as the principal solvent was tested in combination with
water. These conditions produced
a 64% yield of the alkyl
substituted product 36, rendering the process synthetically useful
(entry 4).
These optimized conditions were successfully applied to
a number of different substrates and alkyl boranes (Table 9). Simple
alkyl chains coupled smoothly to substrates bearing a trimethyl-
silyl-substituted acetylene (entry 1) as well as to compounds pos-
sessing a phenyl terminus on the triple bond (entry 2). Products
bearing more polar alkyl chains were easily obtained from different
substrates (entries 3 and 4). Aryl substituted olefins obtained by
Suzuki couplings at the a-position were also good substrates for
this transformation (entries 5 and 6), giving the desired products 40
and 41 in good yields. In these latter reactions, the use of PMe3 was
required in order to achieve efficient coupling. As in all of the other
coupling processes developed by our group, the reactions were
stereoselective and the products were obtained as single isomers.
The regio- and stereochemistry of all final products were con-
firmed by NOE methods. This analysis was performed at every stage
of the coupling process to confirm the stereochemical and
Table 6
Effect of ligand size on the generation of tetrasubstituted olefins
B(OH)2
Table 8
OMe
OMe
Production of tetrasubstituted olefins by alkyl-Suzuki cross-coupling reactions with
chloride 35
Me
Me
MeO
Cl
Pd(OAc)2, ligand
Cs2CO3, Dioxane
B
( )7
CO2Et
24
CO2Et
8
Me
TMS
Me
( )7
36
TMS
MeO
Cl
35
Pd(dppf)Cl2
CO2Et
Base
CO2Et
base, solvent
Entrya
Ligand
Yield (%)
1
2
3
4
5
6
None
NR
22
NR
85
99
NR
Entrya
Solvent
Yield (%)
PtBu3$HBF4
PtBuMe2$HBF4
PEt3$HBF4
PMe3$HBF4
PPh3
1
2
3
4
K3PO4
K3PO4$H2O
K3PO4
THF
THF
NR
19
12
64
THF/H2O
Dioxane/H2O
K3PO4
a
a
Conditions: 0.1 equiv of Pd(OAc)2, 0.2 equiv of ligand, 2.0 equiv of boronic acid,
2.0 equiv of Cs2CO3, dioxane, and 23 ꢀC.
Conditions: 0.05 equiv of Pd(dppf)Cl2, 3.0 equiv of alkyl borane, 2.0 equiv of
base, and 20 ꢀC.

5476
J. Simard-Mercier et al. / Tetrahedron 64 (2008) 5472–5481
Table 9
treated in a similar manner and gave consistent results, thus cor-
roborating the stereochemical assignments for these materials.
Alkyl substituents incorporated via the alkyl-Suzuki reaction into tetrasubstituted
olefins
B
R2
3. Conclusion
Me
Me
R1
R1
R2
A simple, high yielding, and convenient method for the prepa-
ration of single isomer tetrasubstituted olefins has been developed.
This method utilizes E-b-chloro-a-iodo-a,b-unsaturated esters as
Cl
PdCl2(DPPF)
K3PO4
Dioxane/H2O
CO2Et
CO2Et
templates for further cross-coupling reactions. The templates are
constructed as single isomers by the exposure of the corresponding
alkynyl esters to Bu4NI in refluxing dichloroethane. Once prepared,
these templates are readily converted to tetrasubstituted olefins
using cross-coupling reactions. By carefully controlling the reaction
Entrya
1
Substrate
R1
R2
Product
Yield (%)
64
35
36
TMS
( )7
2
37
38
48
( )7
conditions, Suzuki-type coupling reactions can be done at the
a-
position selectively, giving E- -chloro- -aryl- -unsaturated es-
b
a
a,b
AcO
ters as single isomers in excellent yields. The use of these coupling
methods gives a facile way to prepare such olefins linked directly to
3
4
37
8b
8b
39
40
41
75
96
76
( )5
( )5
( )5
sp2 hybridized carbons at the position
a
-to the ester group. Sub-
sequent cross-couplings have been successfully accomplished at
the
-position of the template using sp, sp2- or sp3-hybridized
substituents, giving a wide scope to the process. In the case of the
Suzuki process at the -chloro center, a direct dependence between
AcO
BzO
p-OMeC6H4
p-OMeC6H4
5
b
a
Conditions: 0.05 equiv of Pd(dppf)Cl2, 3.0 equiv of alkyl borane, 2.0 equiv of
K3PO4, and 20 ꢀC.
b
b
ligand size and coupling success was observed in which small li-
gands gave the best conversions and yields of these hindered
products. In all cases single isomers were obtained, eliminating the
need for a tedious and difficult separation of isomeric products.
This technology provides a simple, convenient method of making
single isomer tetrasubstituted olefins bearing four different carbon-
linked appendages using inexpensive reagents and only a few
synthetic steps.
Conditions: 0.1 equiv of Pd(OAc)2, 0.2 equiv of PMe3$HBF4, 4.0 equiv of alkyl
borane, 4.0 equiv of K3PO4, and 20 ꢀC.
regiochemical identity of the materials. In a typical example,
a sample of 8 was isomerized by brief photolysis, and the mixture of
E/Z isomers 8 and 42 was then analyzed using NOE networks
(Scheme 4). A NOESY spectrum of the pure sample of 8 was sepa-
rately recorded in order to verify the identity of the initial material.
NOE enhancements were observed between the methyl and aro-
matic group of 8, indicating a cis-relationship between these sub-
stituents. Isomer 42 did not give enhancements between these
groups. Instead, NOE interactions were only noted between the
aromatic hydrogens and the methoxy group. This network of NOE
enhancements was only possible if the stereochemistry of 8 was Z,
as shown. The other compounds in Table 5 displayed NOE networks
consistent with the assigned configurations. This corroborated the
4. Experimental
4.1. General
Reactions were performed under nitrogen in flame-dried
glassware equipped with a magnetic stirbar and a rubber septem.
Solvents were freshly distilled prior to use as follows: THF and
toluene over sodium/benzophenone; dioxane over calcium hy-
dride. All other reagents were obtained from commercial sources
and used without further purification unless otherwise indicated.
Reactions were monitored by TLC analysis using aluminum plates
precoated with silica gel 60 F254. The plates were visualized using
ultraviolet light, potassium permanganate, ceric ammonium mo-
lybdate, and/or p-anisaldehyde stains. Flash chromatography was
carried out on 230–400 mesh silica gel 60. 1H and 13C NMR spectra
were acquired on a Bruker Avance 400 MHz instrument in the
specified solvent, reporting chemical shifts downfield from tetra-
methylsilane. Infrared spectra were acquired from neat films on
a sodium chloride cell using a Bomen Michaelson 100 FTIR spec-
trometer. High resolution mass spectra were obtained using an
Analytical Concept spectrometer using either electron impact (EI)
or chemical ionization (CI). High resolution mass spectroscopy
(HRMS) was performed with an electron beam of 70 eV, or using
a double focusing magnetic sector mass spectrometer. Melting
points were determined using an Electrothermal Meltemp appa-
ratus and are uncorrected.
stereochemical assignments for the
such as 8.
b
-chloro alkenyl intermediates
OMe
OMe
Cl
Me
hν
Cl
Me
CH2Cl2
CO2Et
CO2Et
42
8
OMe
OMe
Me
hν
Me
CH2Cl2
CO2Et
CO2Et
43
27
Scheme 4. Stereochemical analysis of a,b-unsaturated esters 8 and 27.
Similar analyses were performed with the tetrasubstituted
products. Thus, a NOESY spectrum of tetrasubstitued olefin 27 was
first recorded, that showed interactions between the allylic methyl
group and both of the pendant aromatic rings as indicated. Clear
NOE interactions between the methyl group of 43 and the neigh-
boring phenyl ring were noted, while the p-methoxyphenyl moiety
only displayed NOE interactions with the phenyl group. This pat-
tern of interactions was consistent with the Z configuration shown
for compound 27. Related compounds in Tables 7 and 9 were
4.2. General procedure for the Suzuki cross-coupling reaction
of
b-chloro-a-iodo-a,b-unsaturated esters. (Z)-Ethyl 3-chloro-
2-(4-methylphenyl)but-2-enoate (9)
A
flame-dried flask charged with Pd(OAc)2 (12.0 mg,
0.018 mmol, 0.1 equiv), S-PHOS (14.8 mg, 0.036 mmol, 0.2 equiv),
Cs2CO3 (118.3 mg, 0.54 mmol, 2.0 equiv), and p-tolylboronic acid
(48.9 mg, 0.36 mmol, 2.0 equiv) was purged for 10 min with N2. To

J. Simard-Mercier et al. / Tetrahedron 64 (2008) 5472–5481
5477
this mixture was added toluene (2.0 mL) and the resulting solution
was sparged for 20 min with N2. To the solution was added (E)-ethyl
3-chloro-2-iodobut-2-enoate (7)16 (50.0 mg, 0.18 mmol, 1.0 equiv)
and the reaction was stirred at room temperature for 16 h. The
mixture was partitioned between water and Et2O. The combined
organic extracts were washed with water and brine, and then dried
over anhydrous MgSO4. The product was purified by flash chro-
matography (1% Et2O in hexanes then 5% Et2O in hexanes) to give
the title product as clear oil (35.2 mg, 81%). 1H NMR (400 MHz,
(CH3), 15.4 (CH3); IR (neat) 1728 cmꢁ1; MS 254.1 (Mþ); HRMS calcd
for C13H15ClO3 (Mþ) 254.0710, found 254.0717.
4.7. (Z)-Ethyl 3-chloro-2-(4-fluorophenyl)but-2-enoate (14)
Prepared from compound 7 (50 mg, 0.18 mmol) using a pro-
cedure similar to that described above for compound 9 that pro-
vided the title product as clear oil (22.0 mg, 82%). 1H NMR
(400 MHz, acetone-d6):
8.8, 8.8 Hz, 2H), 4.22 (q, J¼7.2 Hz, 2H), 2.14 (s, 3H), 1.25 (t, J¼7.2 Hz,
3H); 13C NMR (100 MHz, acetone-d6):
168.0 (C), 164.4 (d,
d
7.40 (dd, J¼8.8, 5.6 Hz, 2H), 7.21 (dd, J¼
acetone-d6):
d
7.25–7.20 (m, 4H), 4.21 (q, J¼7.2 Hz, 2H), 2.34 (s, 3H),
2.15 (s, 3H), 1.25 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, acetone-d6):
d
d
168.3 (C), 140.1 (C), 135.3 (C), 133.6 (C), 131.1 (CH), 130.3 (CH), 62.7
J¼246.2 Hz, C), 135.0 (C), 134.1 (C), 132.6 (d, J¼8.3 Hz, CH), 130.4 (d,
J¼8.5 Hz, C), 117.4 (d, J¼21.8 Hz, CH), 62.9 (CH2), 24.6 (CH3), 15.3
(CH3); IR (neat) 1727 cmꢁ1; MS 242.1 (Mþ); HRMS calcd for
(CH2), 24.4 (CH3), 22.2 (CH3), 15.3 (CH3); IR (neat) 1716 cmꢁ1; MS
238.1 (Mþ); HRMS calcd for C13H15ClO2 (Mþ) 238.0761, found
238.0753.
C
12H12ClFO2 (Mþ) 242.0510, found 242.0507.
4.3. (Z)-Ethyl 3-chloro-2-phenylbut-2-enoate (11)
4.8. (Z)-Ethyl 3-chloro-2-(naphthalen-1-yl)but-2-enoate (15)
Prepared from compound 7 (30 mg, 0.12 mmol) using a pro-
cedure similar to that described above for 9 with the following
modifications: Pd(OAc)2 (16.2 mg, 0.024 mmol, 0.2 equiv) and
S-PHOS (19.7 mg, 0.048 mmol, 0.4 equiv). The title product was
obtained as a clear oil (30 mg, 100%). 1H NMR (400 MHz, acetone-
Prepared from compound 7 (50 mg, 0.18 mmol) using a pro-
cedure similar to that described above for compound 9 that pro-
vided the title product as a clear oil (49.9 mg, 94%). 1H NMR
(400 MHz, acetone-d6):
1.2 Hz, 1H), 4.16 (q, J¼7.1 Hz, 2H), 1.92 (s, 3H), 1.18 (t, J¼7.1 Hz, 3H);
13C NMR (100 MHz, acetone-d6):
167.8 (C), 136.9 (C), 135.8 (C),
d
7.97 (m, 3H), 7.58 (m, 3H), 7.48 (dd, J¼7.0,
d6):
d
7.45–7.33 (m, 5H), 4.22 (q, J¼7.2 Hz, 2H), 2.15 (s, 3H), 1.25 (t,
d
J¼6.8 Hz, 3H); 13C NMR (100 MHz, acetone-d6):
d
168.2 (C), 136.5
134.5 (C), 133.3 (C), 133.1 (C), 130.8 (CH), 130.3 (CH), 129.1 (CH),
128.6 (CH), 128.1 (CH), 127.4 (CH), 126.9 (CH), 62.8 (CH2), 25.1 (CH3),
15.3 (CH3); IR (neat) 1727 cmꢁ1; MS 274.1 (Mþ); HRMS calcd for
(C), 135.3 (C), 134.3 (C), 130.5 (CH), 130.4 (CH), 130.2 (CH), 62.8
(CH2), 24.5 (CH3), 15.3 (CH3); IR (neat) 1727 cmꢁ1; MS 224.1 (Mþ);
HRMS calcd for C12H13ClO2 (Mþ) 224.0604, found 224.0587.
C
16H15ClO2 (Mþ) 274.0761, found 274.0770.
4.4. (Z)-Ethyl 3-chloro-2-(4-methoxyphenyl)but-2-enoate (8)
4.9. (Z)-Ethyl 3-chloro-2-(naphthalen-2-yl)but-2-enoate (16)
Prepared from compound 7 (50 mg, 0.18 mmol) using a pro-
cedure similar to that described above for compound 9 that pro-
vided the title product as a clear oil (39 mg, 84%). 1H NMR
Prepared from compound 7 (50 mg, 0.18 mmol) using a pro-
cedure similar to that described above for compound 9 that pro-
vided the title product as a clear oil (50 mg, 95%). 1H NMR
(400 MHz, benzene-d6):
2H), 4.21 (q, J¼7.2 Hz, 2H), 3.82 (s, 3H), 2.15 (s, 3H), 1.25 (t, J¼7.2 Hz,
3H); 13C NMR (100 MHz, benzene-d6):
167.1 (C), 160.0 (C), 133.6
d
7.26 (d, J¼9.0 Hz, 2H), 6.97 (d, J¼9.0 Hz,
(400 MHz, acetone-d6):
1.8 Hz, 1H), 4.24 (q, J¼7.1 Hz, 2H), 2.21 (s, 3H), 1.25 (t, J¼7.1 Hz, 3H);
13C NMR (100 MHz, acetone-d6):
166.4 (C), 133.4 (C), 133.3 (C),
d
7.92 (m, 4H), 7.55 (m, 2H), 7.45 (dd, J¼8.5,
d
d
(C), 132.2 (C), 130.2 (CH), 114.3 (CH), 61.2 (CH2), 54.7 (CH3), 23.1
(CH3), 14.0 (CH3); IR (neat) 1727 cmꢁ1; MS 254.1 (Mþ); HRMS calcd
for C13H15ClO3 (Mþ) 254.0710, found 254.0702.
133.0 (C), 133.0 (C), 132.2 (C), 128.4 (CH), 128.1 (CH), 127.9 (CH),
127.7 (CH), 126.8 (CH), 126.7 (CH), 126.1(CH), 61.0 (CH2), 22.9 (CH3),
13.5 (CH3); IR (neat) 1716 cmꢁ1; MS 274.1 (Mþ); HRMS calcd for
C
16H15ClO2 (Mþ) 274.0761, found 274.0758.
4.5. (Z)-Ethyl 3-chloro-2-(2-methoxyphenyl)but-2-enoate (12)
4.10. (E)-Ethyl 3-chloro-2-(thiophen-2-yl)but-2-enoate (17)
Prepared from compound 7 (30 mg, 0.12 mmol) using a pro-
cedure similar to that described above for 9 with the following
modifications: Pd(OAc)2 (16.2 mg, 0.024 mmol, 0.2 equiv) and
S-PHOS (19.7 mg, 0.048 mmol, 0.4 equiv). The product was obtained
Prepared from compound 7 (50.0 mg, 0.18 mmol) using a pro-
cedure similar to that described above for compound 9 that pro-
vided the title product as a clear oil (27 mg, 64%). 1H NMR
as a clear oil (28.0 mg, 93%); 1H NMR (400 MHz, acetone-d6):
d
7.33
(400 MHz, acetone-d6):
d
7.58 (dd, J¼4.6, 1.9 Hz, 1H), 7.10 (m, 2H),
(ddd, J¼8.3, 7.4, 1.7 Hz, 1H), 7.24 (dd, J¼7.6,1.7 Hz, 1H), 7.04 (dd,
J¼8.4, 0.8 Hz, 1H), 6.99 (ddd, J¼7.5, 7.5, 1.1 Hz, 1H), 4.15 (q, J¼7.1 Hz,
2H), 3.81 (s, 3H), 2.07 (s, 3H), 1.19 (t, J¼7.1 Hz, 3H); 13C NMR
4.27 (q, J¼7.1 Hz, 2H), 2.34 (s, 3H), 1.29 (t, J¼7.1 Hz, 3H); 13C NMR
(100 MHz, acetone-d6):
d 165.9 (C), 134.8 (C), 132.6 (C), 128.4 (CH),
127.5 (C),127.3 (CH), 127.2 (CH), 61.3 (CH2), 23.1 (CH3),13.5 (CH3); IR
(neat) 1732 cmꢁ1; MS 230.0 (Mþ); HRMS calcd for C10H11ClO2S
(Mþ) 230.0168, found 230.0169.
(100 MHz, benzene-d6):
d 167.5 (C), 158.9 (C), 137.2 (C), 132.6 (CH),
131.8 (C), 131.0 (CH), 126.4 (C), 122.2 (CH), 113.2 (CH), 62.2 (CH2),
56.9 (CH3), 25.9 (CH3), 15.4 (CH3); IR (neat) 1725 cmꢁ1; MS 254.1
(Mþ); HRMS calcd for C13H15ClO3 (Mþ) 254.0710, found 254.0704.
4.11. (Z)-Ethyl 3-chloro-2-((E)-styrenyl)but-2-enoate (18)
4.6. (Z)-Ethyl 3-chloro-2-(3-methoxyphenyl)but-2-enoate (13)
A
flame-dried flask charged with Pd(OAc)2 (6.1 mg,
0.0091 mmol, 0.1 equiv), S-PHOS (7.5 mg, 0.018 mmol, 0.2 equiv),
Cs2CO3 (89.1 mg, 0.27 mmol, 3.0 equiv), and (E)-styrenylboronic
acid (27.2 mg, 0.18 mmol, 2.0 equiv) was purged for 10 min with N2.
To this mixture was added toluene (1.0 mL), and the resulting so-
lution was sparged for 20 min with N2 The mixture was cooled to
0 ꢀC before (E)-ethyl 3-chloro-2-iodobut-2-enoate (7) (25.0 mg,
0.091 mmol, 1.0 equiv) was added. The reaction mixture was stirred
at 5 ꢀC for 16 h and then the solution was partitioned between
water and Et2O. The organic extracts were washed with water and
Prepared from compound 7 (50 mg, 0.18 mmol) using a pro-
cedure similar to that described above for compound 9 that pro-
vided the title product as a clear oil (30.3 mg, 65%). 1H NMR
(400 MHz, acetone-d6):
d
7.34 (ddd, J¼8.2, 8.2, 0.6 Hz, 1H), 6.95
(ddd, J¼8.2, 2.6, 0.9 Hz,1H), 6.89 (m, 2H), 4.22 (q, J¼7.1 Hz, 2H), 3.82
(s, 3H), 2.16 (s, 3H), 1.26 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz, ace-
tone-d6):
d 168.1 (C), 161.7 (C), 137.7 (C), 135.1 (C), 134.4 (C), 131.6
(CH), 122.6 (CH), 115.9 (CH), 115.8 (CH), 62.8 (CH2), 56.6 (CH3), 24.6

5478
J. Simard-Mercier et al. / Tetrahedron 64 (2008) 5472–5481
brine, then dried over anhydrous MgSO4. The product was purified
by flash chromatography (1% Et2O in hexanes then 5% Et2O in
hexanes) to give the title product as clear oil (19.4 mg, 85%). 1H
MgSO4, filtered, and concentrated in vacuo. The product was pu-
rified by flash chromatography (2% Et2O in hexanes then 20% Et2O
in hexanes) to give the title product as a clear oil (11.4 mg, 95%). 1H
NMR (400 MHz, acetone-d6):
d
7.55 (m, 2H), 7.32 (m, 3H), 7.10 (d,
NMR (400 MHz, acetone-d6):
d
7.29 (d, J¼8.4 Hz, 2H), 7.27 (d,
J¼16.2 Hz,1H), 7.01 (d, J¼16.2 Hz,1H), 4.35 (q, J¼7.2 Hz, 2H), 2.40 (s,
J¼8.8 Hz, 2H), 6.97 (d, J¼8.8 Hz, 2H), 6.92 (d, J¼8.8 Hz, 2H), 3.87 (q,
J¼6.8 Hz, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 2.03 (s, 3H), 0.90 (t, J¼7.2 Hz,
3H), 1.35 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, acetone-d6):
d 168.1
(C), 138.5 (C), 135.2 (C), 133.7 (CH), 132.7 (C), 130.6 (CH), 130.1 (CH),
128.6 (CH), 122.9 (CH), 62.8 (CH2), 23.1 (CH3), 15.4 (CH3); IR (neat)
1722, 1624 cmꢁ1; MS 250.1 (Mþ); HRMS calcd for C14H15ClO2 (Mþ),
250.0761, found 250.0776.
3H); 13C NMR (100 MHz, acetone-d6):
d 171.2 (C), 161.1 (C), 151.0 (C),
142.3 (C), 137.2 (C), 134.2 (C), 132.2 (CH), 131.6 (C), 130.3 (CH), 115.5
(CH), 115.3 (CH), 61.7 (CH2), 56.5 (CH3), 56.5 (CH3), 23.0 (CH3), 15.1
(CH3); IR (neat) 1739 cmꢁ1; MS 326.4 (Mþ); HRMS calcd for
C
20H22O4 (Mþ) 326.1518, found 326.1533.
4.12. (2Z,3E)-Ethyl 2-(1-chloroethylidene)dec-3-enoate (19)
4.16. (Z)-Ethyl 3-(2-methoxyphenyl)-2-(4-methoxyphenyl)-
but-2-enoate (25)
Prepared from compound 7 (25.0 mg, 0.091 mmol, 1.0 equiv)
using a procedure similar to that described above for compound 18
that provided the title product as a clear oil (17.7 mg, 75%). 1H NMR
Prepared from compound 8 (10.0 mg, 0.039 mmol) using a pro-
cedure similar to that described above for compound 24 that pro-
vided the title product as a yellow oil (11.6 mg, 91%). 1H NMR
(400 MHz, acetone-d6):
d
6.28 (ddd, J¼15.7, 3.0, 1.5 Hz, 1H), 5.65
(ddd, J¼15.7, 14.3, 7.1 Hz, 1H), 4.26 (q, J¼7.2 Hz, 2H), 2.23 (s, 3H),
2.17–2.11 (m, 2H), 1.42–1.36 (m, 2H), 1.32–1.27 (m, 9H), 0.87 (t,
(400 MHz, acetone-d6):
d
7.26–7.16 (m, 8H), 3.84 (q, J¼7.2 Hz, 2H),
J¼7.2 Hz, 3H). 13C NMR (100 MHz, acetone-d6):
d 168.2 (C), 136.8
2.35 (s, 3H), 2.33 (s, 3H), 2.03 (s, 3H), 0.87 (t, J¼7.2 Hz, 3H); 13C NMR
(CH), 134.9 (C), 130.0 (C), 124.4 (CH), 62.7 (CH2), 34.7 (CH2), 33.5
(CH2), 30.7 (CH2), 30.5 (CH2), 24.2 (CH2), 22.7 (CH3), 15.5 (CH3), 15.4
(CH3). IR (neat) 1733 cmꢁ1; MS 258.2 (Mþ); HRMS calcd for
(100 MHz, acetone-d6):
d 170.9 (C), 143.1 (C), 142.1 (C), 138.9 (C),
138.9 (C), 136.4 (C), 134.7 (CH), 130.9 (CH), 130.8 (CH), 130.5 (CH),
129.0 (CH), 61.7 (CH2), 23.0 (CH3), 22.2 (CH3), 22.1 (CH3), 15.0 (CH3);
IR (neat) 1720 cmꢁ1; MS 326.4 (Mþ); HRMS calcd for C20H22O4 (Mþ)
326.1518, found 326.1535.
C
14H23ClO2 (Mþ) 258.1387, found 258.1383.
4.13. (Z)-Ethyl 3-chloro-3-cyclohexyl-2-(4-methoxyphenyl)-
acrylate (21)
4.17. (Z)-Ethyl 3-(3-methoxyphenyl)-2-(4-methoxyphenyl)-
Prepared from compound 2016 (30 mg, 0.088 mmol) using
a procedure similar to that described above for compound 9 that
provided the title product as a clear oil (22 mg, 79%). 1H NMR
but-2-enoate (26)
Prepared from compound 8 (10.0 mg, 0.039 mmol) using a pro-
cedure similar to that described above for compound 24 that pro-
vided the title product as a yellow oil (10.0 mg, 79%). 1H NMR
(500 MHz, acetone-d6):
d
7.23 (d, J¼9.0 Hz, 2H), 6.98 (d, J¼9.0 Hz,
2H), 4.19 (q, J¼7.5 Hz, 2H), 3.82 (s, 3H), 2.63–2.55 (m, 1H), 1.73–1.57
(400 MHz, acetone-d6):
d 7.32–7.25 (m, 3H), 7.00–6.96 (m, 2H),
(m, 2H), 1.62–1.57 (m, 5H), 1.24 (t, J¼7.5 Hz, 3H), 1.05–1.20 (m, 3H);
13C NMR (125 MHz, acetone-d6):
d 168.6 (C),161.7(C),142.6 (C),134.0
6.91–6.86 (m, 3H), 3.85 (q, J¼7.2 Hz, 2H), 3.83 (s, 3H), 3.81 (s, 3H),
2.05 (s, 3H), 0.87 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, acetone-d6):
(C),131.4 (CH),128.5 (C),116.0 (CH), 62.2 (CH2), 56.6 (CH), 43.6 (CH3),
32.1 (CH2), 27.2 (CH2), 15.4 (CH3); IR (neat) 1727 cmꢁ1; MS 322.1
(Mþ); HRMS calcd for C18H23ClO3 (Mþ) 322.1336, found 322.1344.
d
170.9 (C), 161.5 (C), 161.1 (C), 146.5 (C), 142.6 (C), 134.6 (C), 132.2
(C), 131.3 (CH), 131.0 (CH), 121.4 (CH), 115.5 (CH), 114.7 (CH), 61.7
(CH2), 56.6 (CH3), 56.5 (CH3), 22.9 (CH3), 15.0 (CH3); IR (neat)
;
1713 cmꢁ1 MS 326.4 (Mþ); HRMS calcd for C20H22O4 (Mþ)
4.14. (Z)-Ethyl 4-(tert-butyldimethylsilyloxy)-3-chloro-2-
(4-methoxyphenyl)but-2-enoate (23)
326.1518, found 326.1531.
Prepared from compound 2216 (50 mg, 0.18 mmol) using a pro-
cedure similar to that described above for compound 9 that pro-
vided the title product as a clear oil (35.0 mg, 74%). 1H NMR
4.18. (Z)-Ethyl 2-(4-methoxyphenyl)-3-phenylbut-
2-enoate (27)
(400 MHz, acetone-d6):
d
7.31 (d, J¼8.8 Hz, 2H), 6.99 (d, J¼8.8 Hz,
A
flame-dried flask charged with Pd(OAc)2 (2.6 mg,
2H), 4.34 (s, 2H), 4.26 (q, J¼6.8 Hz, 2H), 3.83 (s, 3H),1.28 (t, J¼7.2 Hz,
0.0039 mmol, 0.1 equiv), PMe3$HBF4 (1.3 mg, 0.0079 mmol,
0.2 equiv), Cs2CO3 (50.8 mg, 0.059 mmol, 4.0 equiv), and phenyl-
boronic acid (19.2 mg, 0.059 mmol, 4.0 equiv) was purged with N2
for 10 min. Dioxane (0.3 mL) was added, the resulting mixture was
sparged with N2 for 10 min before chloride 8 (10.0 mg, 0.039 mmol,
1.0 equiv) was added as a solution in dioxane (0.5 mL). After 5 h,
additional portions of phenylboronic acid (9.6 mg, 0.030 mmol,
2.0 equiv) and Cs2CO3 (25.4 mg, 0.030 mmol, 2.0 equiv) were added
to the solution. After 16 h, the reaction mixture was partitioned
between Et2O and H2O. The organic layer was separated and dried
over anhydrous MgSO4, filtered, and concentrated in vacuo. The
product was purified by flash chromatography (2% Et2O in hexanes
then 20% Et2O in hexanes) to give the title product as a clear oil
3H), 0.90 (s, 9H), 0.06 (s, 6H); 13C NMR (100 MHz, acetone-d6):
d
168.2 (C), 162.1 (C), 137.0 (C), 135.1 (C), 131.6 (CH), 127.6 (C), 115.9
(CH), 65.2 (CH2), 62.9 (CH2), 56.7 (CH3), 27.1 (CH3), 19.8 (C), 15.3
(CH3), ꢁ4.2 (CH3); IR (neat) 1720 cmꢁ1; MS 327.1 (MþꢁC4H9);
HRMS calcd for C15H20ClO4Si (MþꢁC4H9) 327.0819, found 327.0837.
4.15. General procedure for the generation of tetrasubstituted
olefins via Suzuki coupling reaction. (Z)-Ethyl 2,3-bis-
(4-methoxyphenyl)but-2-enoate (24)
A
flame-dried flask charged with Pd(OAc)2 (2.6 mg,
0.0039 mmol, 0.1 equiv), PMe3$HBF4 (1.3 mg, 0.0079 mmol,
0.2 equiv), Cs2CO3 (25.6 mg, 0.079 mmol, 2.0 equiv), and
p-methoxyphenylboronic acid (12.0 mg, 0.079 mmol, 2.0 equiv)
was purged with N2 for 10 min. Dioxane (0.3 mL) was added, and
the mixture was sparged with N2 for 10 min before 8 (10.0 mg,
0.039 mmol, 1.0 equiv) was added as a solution in dioxane (0.5 mL).
After 16 h, the reaction mixture was partitioned between Et2O and
H2O. The organic layer was separated and dried over anhydrous
(11.1 mg, 96%). 1H NMR (400 MHz, acetone-d6):
d 7.38–7.18 (m, 7H),
6.97 (d, J¼8.8 Hz, 2H), 3.82 (q, J¼7.2 Hz, 2H), 3.82 (s, 3H), 2.05 (s,
3H), 0.82 (t, J¼6.8 Hz, 3H); 13C NMR (100 MHz, acetone-d6):
d 170.9
(C), 161.1 (C), 145.1 (C), 143.0 (C), 134.7 (C), 132.2 (CH), 131.3 (C),
129.9 (CH), 129.1 (CH), 129.0 (CH), 115.5 (CH), 61.7 (CH2), 56.5 (CH3),
23.1 (CH3), 14.9 (CH3); IR (neat) 1709 cmꢁ1; HRMS calcd for
C
19H20O3 (Mþ) 296.1412, found 296.1405.

J. Simard-Mercier et al. / Tetrahedron 64 (2008) 5472–5481
5479
4.19. (Z)-Ethyl 3-(4-fluorophenyl)-2-(4-methoxyphenyl)but-2-
enoate (28)
7.54–7.49 (m, 3H), 7.37–7.34 (m, 2H), 7.02–7.00 (m, 2H), 3.84 (s, 3H),
3.79 (q, J¼7.2 Hz, 2H), 2.16 (s, 3H), 0.72 (t, J¼7.2 Hz, 3H); 13C NMR
(100 MHz, acetone-d6):
d 170.9 (C), 161.1 (C), 143.0 (C), 142.7 (C),
Prepared from compound 8 (10.0 mg, 0.039 mmol) using a pro-
cedure similar to that described above for compound 27 that pro-
vided the title product as a yellow oil (11.3 mg, 92%). 1H NMR
135.2 (C), 134.6 (C), 132.3 (CH), 131.4 (C), 129.8 (CH), 129.5 (CH),
129.4 (CH), 128.1 (CH), 127.9 (CH), 127.7 (CH), 127.6 (CH), 115.6 (CH),
61.7 (CH2), 56.6 (CH3), 23.1 (CH3), 14.9 (CH3); IR (neat) 1710 cmꢁ1
;
(400 MHz, acetone-d6):
d
7.37 (dd, J¼8.9, 5.4 Hz, 2H), 7.30 (d,
MS 346.6 (Mþ); HRMS calcd for C23H22O3 (Mþ) 346.1569, found
346.1586.
J¼8.9 Hz, 2H), 7.14 (dd, J¼8.9, 8.9 Hz, 2H), 6.98 (d, J¼8.9 Hz, 2H), 3.86
(q, J¼7.1 Hz, 2H), 3.83 (s, 3H), 2.05 (s, 3H), 0.88 (t, J¼7.1 Hz, 3H); 13
C
NMR (100 MHz, acetone-d6):
d
170.8 (C), 164.0 (d, J¼244.3 Hz, C),
4.24. (Z)-Ethyl 2-(4-methylphenyl)-3-(naphthalen-1-yl)-
but-2-enoate (32)
161.1 (C), 142.0 (C), 141.3 (d, J¼3.3 Hz, C), 135.1 (C), 132.2 (CH), 131.2
(C), 130.9 (d, J¼8.1 Hz, CH), 116.5 (d, J¼21.5 Hz, CH), 115.3 (CH), 61.8
(CH2), 56.5 (CH3), 23.2 (CH3), 15.0 (CH3); IR (neat) 1715 cmꢁ1; MS
314.1 (Mþ); HRMS calcd forC19H19FO3 (Mþ) 314.1318, found314.1318.
Prepared from compound 9 (10.0 mg, 0.042 mmol) using a pro-
cedure similar to that described above for compound 27 that pro-
vided the title product as a yellow oil (6.4 mg, 47%). 1H NMR
4.20. (Z)-Ethyl 2,3-di-(4-methylphenyl)but-2-enoate (10)
(400 MHz, acetone-d6): d 8.00–7.98 (m, 1H), 7.94–7.92 (m, 1H), 7.85
(d, J¼8.2 Hz, 1H), 7.55–7.47 (m, 3H), 7.41 (d, J¼8.2 Hz, 2H), 7.34 (dd,
J¼7.0, 1.2 Hz, 1H), 7.29 (d, J¼7.8 Hz, 2H), 3.60–3.50 (m, 2H), 2.39 (s,
3H), 2.13 (s, 3H), 0.40 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, acetone-
Prepared from compound 7 (10.0 mg, 0.042 mmol) using a pro-
cedure similar to that described above for compound 27 that pro-
vided the title product as a yellow oil (11.5 mg, 93%). 1H NMR
d6):
d 170.2 (C), 143.9 (C), 143.1 (C), 139.1 (C), 136.0 (C), 135.6 (C),
(400 MHz, acetone-d6):
d
7.01–6.88 (m, 8H), 4.22 (q, J¼7.2 Hz, 2H),
131.2 (C), 131.2 (CH), 130.8 (CH), 130.1 (CH), 129.1 (CH), 127.8 (CH),
127.6 (CH), 127.4 (CH), 127.2 (CH), 126.3 (CH), 61.3 (CH2), 24.3 (CH3),
22.2 (CH3), 14.5 (CH3); IR (neat) 1711 cmꢁ1; MS 330.4 (Mþ); HRMS
calcd for C23H22O2 (Mþ) 330.1620, found 330.1628.
2.24 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H), 1.25 (t, J¼7.2 Hz, 3H); 13C NMR
(100 MHz, acetone-d6): d 171.0 (C),143.2 (C),140.9 (C),138.4 (C),138.1
(C), 136.4 (C),133.8 (C), 131.4 (CH), 130.5 (CH), 130.3 (CH), 62.1 (CH2),
24.3 (CH3), 22.1 (CH3), 15.5 (CH3); IR (neat) 1716 cmꢁ1; MS 294.2
(Mþ); HRMS calcd for C20H22O2 (Mþ) 294.1620, found 294.1633.
4.25. (Z)-Ethyl 3-cyclohexyl-2-(4-methoxyphenyl)-3-
phenylacrylate (33)
4.21. (2Z,4E)-Ethyl 2-(4-methoxyphenyl)-3-methyl-5-
phenylpenta-2,4-dienoate (29)
Prepared from compound 21 (10.0 mg, 0.031 mmol) using
a procedure similar to that described above for compound 27 that
provided the title product as a yellow oil (7.0 mg, 63%). 1H NMR
Prepared from compound 8 (10.0 mg, 0.039 mmol) using a pro-
cedure similar to that described above for compound 27 that pro-
vided the title product as a yellow oil (10.7 mg, 85%). 1H NMR
(400 MHz, acetone-d6):
d
7.36–7.18 (m, 5H), 7.17 (d, J¼6.4 Hz, 2H),
6.98 (d, J¼8.8 Hz, 2H), 3.84 (s, 3H), 3.68 (q, J¼7.2 Hz, 2H), 2.59–2.52
(m, 1H), 1.68–1.60 (m, 3H), 1.52–1.47 (m, 1H), 1.12–1.05 (m, 3H),
0.93–0.85 (m, 3H), 0.72 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, ace-
(400 MHz, acetone-d6):
d
7.56 (d, J¼16.0 Hz, 1H), 7.53 (d, J¼8.0 Hz,
2H), 7.38 (dd, J¼7.2, 7.2 Hz, 2H), 7.29 (tt, J¼6.8, 1.2 Hz, 1H), 7.22 (d,
J¼8.8 Hz, 2H), 6.96 (d, J¼16.8 Hz, 1H), 6.97 (d, J¼8.8 Hz, 2H), 4.24 (q,
J¼7.2 Hz, 2H), 3.83 (s, 3H), 1.97 (s, 3H), 1.25 (t, J¼7.2 Hz, 3H); 13C
tone-d6):
d 169.7 (C), 140.9 (C), 132.0 (CH), 131.1 (CH), 129.0 (CH),
128.6 (CH), 125.5 (C), 115.5 (C), 61.4 (CH2), 56.5 (CH3), 43.4 (CH),
NMR (100 MHz, acetone-d6):
d
170.3 (C), 161.0 (C), 139.5 (C), 139.2
33.0 (CH2), 27.7 (CH2), 27.4 (CH2), 14.9 (CH3); IR (neat) 1712 cmꢁ1
;
(C), 135.6 (C), 133.8 (CH), 132.3 (CH), 131.5 (C), 130.6 (CH), 130.0
(CH), 129.9 (CH), 128.6 (CH), 115.4 (CH), 62.2 (CH2), 56.5 (CH3), 17.2
(CH3), 15.6 (CH3); IR (neat) 1712 cmꢁ1; MS 322.2 (Mþ); HRMS calcd
for C21H22O3 (Mþ) 322.1569, found 322.1587.
MS 364.2 (Mþ); HRMS calcd for C24H28O3 (Mþ) 364.2038, found
364.2063.
4.26. (E)-Ethyl 4-(tert-butyldimethylsilyloxy)-2-
(4-methoxyphenyl)-3-phenylbut-2-enoate (34)
4.22. (2Z,4E)-Ethyl 2-(4-methoxyphenyl)-3-methylundeca-
2,4-dienoate (30)
Prepared from compound 23 (10.0 mg, 0.026 mmol) using
a procedure similar to that described above for compound 27 that
provided the title product as a yellow oil (10.8 mg, 97%). 1H NMR
Prepared from compound 8 (10.0 mg, 0.039 mmol) using a pro-
cedure similar to that described above for compound 27 that pro-
vided the title product as a yellow oil (12.9 mg, 100%). 1H NMR
(400 MHz, acetone-d6):
d
7.41 (d, J¼8.8 Hz, 2H), 7.37–7.30 (m, 5H),
6.99 (d, J¼8.8 Hz, 2H), 4.44 (s, 2H), 3.85 (q, J¼7.2 Hz, 2H), 3.84 (s,
(400 MHz, acetone-d6):
d
7.16 (d, J¼8.8 Hz, 2H), 6.93 (d, J¼8.8 Hz,
3H), 0.84 (t, J¼7.2 Hz, 3H), 0.77 (s, 9H), ꢁ0.15 (s, 6H); 13C NMR
2H), 6.70 (dt, J¼15.6,1.6 Hz,1H), 6.04 (dt, J¼15.6, 7.2 Hz,1H), 4.17 (q,
J¼7.2 Hz, 2H), 3.81 (s, 3H), 2.19 (ddd, J¼7.2, 7.2, 1.6 Hz, 2H), 1.81 (s,
3H), 1.47–1.29 (m, 8H), 1.21 (t, J¼7.2 Hz, 3H), 0.89 (t, J¼6.8 Hz, 3H);
(100 MHz, acetone-d6): d 170.7 (C), 161.6 (C), 144.0 (C), 144.2 (C),
136.9 (C), 132.2 (CH), 130.3 (CH), 130.0 (C), 129.5 (CH), 129.2 (CH),
115.5 (CH), 65.3 (CH2), 61.9 (CH2), 56.6 (CH3), 27.1 (CH3), 19.7 (C),
14.9 (CH3), ꢁ4.4 (CH3); IR (neat) 1720 cmꢁ1; MS 426.2 (Mþ); HRMS
calcd for C25H34O4Si (Mþ) 426.2226, found 426.2232.
13C NMR (100 MHz, acetone-d6):
d 170.5 (C),160.9 (C),139.1 (C),136.4
(CH),133.4 (C),132.3(CH),131.6(C),131.5(CH),115.4 (CH), 62.0 (CH2),
56.5 (CH3), 34.9 (CH2), 33.5 (CH2), 31.0 (CH2), 30.6 (CH2), 24.3 (CH2),
17.1 (CH3), 15.5 (CH3), 15.3 (CH3); IR (neat) 1713 cmꢁ1; MS 330.2
(Mþ); HRMS calcd for C21H30O3 (Mþ) 330.2195, found 330.2196.
4.27. General procedure for the alkyl-Suzuki coupling
reaction of b-chloro-a,b-unsaturated olefins. (Z)-Ethyl
3-methyl-2-(phenylethynyl)undec-2-enoate (38)
4.23. (Z)-Ethyl 2-(4-methoxyphenyl)-3-(naphthalen-2-yl)-
but-2-enoate (31)
To a solution of 1-octene (0.05 mL, 0.30 mmol, 3.0 equiv) in THF
(1.0 mL)
was
added
9-borabicyclo[3.3.1]nonane
(0.6 mL,
Prepared from compound 8 (10.0 mg, 0.039 mmol) using a pro-
cedure similar to that described above for compound 27 that pro-
vided the title product as a yellow oil (12.4 mg, 92%). 1H NMR
0.30 mmol, 3.0 equiv, 0.5 M in THF) and the mixture was stirred for
0.5 h. A separate flask was charged with PdCl2(DPPF) (3.7 mg,
0.005 mmol, 0.05 equiv) and K3PO4 (42.4 mg, 0.20 mmol,
2.0 equiv). To this were added sequentially dioxane (1.0 mL) and
(400 MHz, acetone-d6):
d
7.92–7.89 (m, 3H), 7.83 (d, J¼1.5 Hz, 1H),

5480
J. Simard-Mercier et al. / Tetrahedron 64 (2008) 5472–5481
3716 (25.0 mg, 0.10 mmol, 1.0 equiv). The 9-octyl-9-bora-bicy-
clo[3.3.1]nonane solution was introduced via canula, H2O (0.3 mL)
was added, and the reaction mixture was stirred for 18 h. The
mixture was partitioned between EtOAc and H2O and the aqueous
layer was extracted with EtOAc (3ꢂ20 mL). The combined organic
layers were dried over anhydrous MgSO4, filtered, and concen-
trated in vacuo. The product was purified by column chromatog-
raphy on silica gel, eluting with hexanes to 5% EtOAc in hexanes to
afford the product as a colorless oil (15.7 mg, 48%). 1H NMR
purified by flash chromatography (hexanes then 1% ether in hex-
anes) to afford the product as a colorless oil (13.1 mg, 96%). 1H NMR
(400 MHz, acetone-d6): d 7.14–7.10 (m, 2H), 6.92–6.89 (m, 2H), 4.11
(q, J¼7.1 Hz, 2H), 4.05 (t, J¼6.7 Hz, 2H), 3.80 (s, 3H), 2.40–2.36 (m,
2H), 2.00 (s, 3H), 1.69 (s, 3H), 1.67–1.57 (m, 4H), 1.47–1.40 (m, 2H),
1.19 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz, acetone-d6):
d 172.0 (C),
170.3 (C), 160.7 (C), 146.1 (C), 132.2 (CH), 115.3 (CH), 65.7 (CH2), 61.7
(CH2), 56.5 (CH3), 37.5 (CH2), 29.6 (CH2), 27.6 (CH2), 21.8 (CH3), 21.3
(CH3), 15.5 (CH3); IR (neat) 1713 cmꢁ1; MS 348.2 (Mþ); HRMS calcd
for C20H28O5 (Mþ) 348.1937, found 348.1950.
(400 MHz, acetone-d6):
d
7.49–7.37 (m, 5H), 4.22 (q, J¼7.2 Hz, 2H),
2.61 (dd, J¼9.6, 7.6 Hz, 2H), 2.19 (s, 3H), 1.55–1.50 (m, 2H), 1.33–1.29
(m, 10H), 1.31 (t, J¼7.2 Hz, 3H), 0.89 (t, J¼6.8 Hz, 3H); 13C NMR
4.31. (Z)-8-Ethoxy-7-(4-methoxyphenyl)-6-methyl-8-oxooct-
6-enyl benzoate (41)
(100 MHz, acetone-d6): d 166.5 (C), 163.6 (C), 132.9 (CH), 130.4 (CH),
130.1 (CH), 125.4 (C), 114.6 (C), 95.8 (C), 87.8 (C), 62.3 (CH2), 36.9
(CH2), 33.6 (CH2), 31.4 (CH2), 31.4 (CH2), 31.1 (CH2), 30.1 (CH2), 24.4
(CH3), 24.3 (CH2), 15.5 (CH3), 15.3 (CH3); IR (neat) 1719 cmꢁ1; MS
326.2 (Mþ); HRMS calcd for C22H30O2 (Mþ) 326.2246, found
326.2232.
Prepared from compound 8 (10.0 mg, 0.039 mmol) using a pro-
cedure similar to that described above for compound 40 that pro-
vided the title product as a yellow oil (12.0 mg, 76%). 1H NMR
(400 MHz, acetone-d6):
d 8.06–8.03 (m, 2H), 7.67–7.62 (m, 1H),
7.54–7.50 (m, 2H), 7.13–7.10 (m, 2H), 6.93–6.87 (m, 2H), 4.35 (t,
J¼6.6 Hz, 2H), 4.11 (q, J¼7.1 Hz, 2H), 3.80 (s, 3H), 2.44–2.40 (m, 2H),
1.84 (quint, J¼6.6 Hz, 2H), 1.69 (s, 3H), 1.71–1.63 (m, 2H), 1.60–1.53
(m, 2H), 1.17 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz, acetone-d6):
4.28. (Z)-Ethyl 3-methyl-2-((trimethylsilyl)ethynyl)undec-2-
enoate (36)
Prepared from compound 35 (50.0 mg, 0.20 mmol) using a pro-
cedure similar to that described above for compound 38 that pro-
vided the title product as a colorless oil (41.3 mg, 64%). 1H NMR
d
170.3 (C), 146.0 (C), 134.8 (C), 132.5 (C), 132.2 (CH), 131.1 (CH),
130.4 (CH), 113.4 (CH), 66.4 (CH2), 61.7 (CH2), 56.4 (CH3), 37.5 (CH2),
29.6 (CH2), 27.7 (CH2), 27.7 (CH2), 21.2 (CH3), 15.5 (CH3); IR (neat)
;
1711 cmꢁ1 MS 410.2 (Mþ); HRMS calcd for C25H30O5 (Mþ)
(400 MHz, benzene-d6):
d
4.00 (q, J¼7.2 Hz, 2H), 2.58 (dd, J¼9.6,
8.0 Hz, 2H), 2.02 (s, 3H), 1.46–1.22 (m, 12H), 0.99 (t, J¼7.2 Hz, 3H),
410.2093, found 410.2113.
0.89 (t, J¼6.8 Hz, 3H), 0.16 (s, 9H); 13C NMR (100 MHz, benzene-d6):
d
165.0 (C), 163.7 (C), 113.9 (C), 102.5 (C), 99.4 (C), 60.6 (CH2), 35.6
Acknowledgements
(CH2), 32.2 (CH2), 30.1 (CH2), 29.8 (CH2), 29.6 (CH2), 28.7 (CH2), 23.5
(CH3), 23.0 (CH2), 14.3 (CH3), 14.1 (CH3), 0.1 (CH3); IR (neat)
1721 cmꢁ1; MS 322.2 (Mþ); HRMS calcd for C19H34SiO2 (Mþ)
322.2328, found 322.2347.
We thank the Natural Science and Engineering Research Council
of Canada (NSERC), Canada Foundation for Innovation, Ontario In-
novation Trust, and the University of Ottawa for generous funding.
4.29. (Z)-Ethyl 8-acetoxy-3-methyl-2-(phenylethynyl)oct-2-
enoate (39)
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.04.004.
Prepared from compound 37 (800.0 mg, 2.53 mmol) using
a procedure similar to that described above for compound 38 that
provided the title product as a colorless oil (648.9 mg, 75%). 1H NMR
References and notes
(400 MHz, acetone-d6): d 7.48–7.46 (m, 2H), 7.39–7.37 (m, 3H), 4.23
(q, J¼7.2 Hz, 2H), 4.04 (t, J¼6.8 Hz, 2H), 2.63 (dd, J¼9.6, 7.6 Hz, 2H),
1. Flynn, A. B.; Ogilvie, W. W. Chem. Rev. 2007, 107, 4698.
2.20 (s, 3H),1.99 (s, 3H),1.69–1.54 (m, 4H),1.46–1.38 (m, 2H), 1.31 (t,
2. (a) Normant, J. F.; Alexakis, A. Synthesis 1981, 841; (b) Doyle, M. P. Compre-
hensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G.,
Hegedus, L., Eds.; Pergamon: Oxford, 1995; Vol. 12, p 387.
J¼7.2 Hz, 3H); 13C NMR (100 MHz, acetone-d6):
d 171.9 (C), 166.5
(C), 163.4 (C), 132.9 (CH), 130.4 (CH), 130.1 (CH), 125.4 (C), 114.7 (C),
95.9 (C), 87.7 (C), 65.6 (CH2), 62.3 (CH2), 36.8 (CH2), 30.2 (CH2), 29.6
(CH2), 27.7 (CH2), 24.4 (CH3), 21.8 (CH3), 15.5 (CH3); IR (neat) 1738,
3. (a) Itami, K.; Mineno, M.; Muraoka, N.; Yoshida, J. J. Am. Chem. Soc. 2004, 126,
11778; (b) Itami, K.; Kamei, T.; Yoshida, J. J. Am. Chem. Soc. 2003, 125, 14670; (c)
Nishihara, Y.; Miyasaka, M.; Okamoto, M.; Takahashi, H.; Inoue, E.; Tanemura,
K.; Takagi, K. J. Am. Chem. Soc. 2007, 129, 12634; (d) Takeda, Y.; Shimizu, M.;
Hiyama, T. Angew. Chem., Int. Ed. 2007, 46, 8659; (e) Shimizu, M.; Nakamaki, C.;
Shimono, K.; Schelper, M.; Kurahashi, T.; Hiyama, T. J. Am. Chem. Soc. 2005, 127,
12506; (f) Shimizu, M.; Fujimoto, T.; Liu, X.; Minezaki, H.; Hata, T.; Hiyama, T.
Tetrahedron 2003, 59, 9811; (g) Itami, K.; Tonogaki, K.; Ohashi, Y.; Yoshida, J.
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Kamei, T.; Yoshida, J. J. Am. Chem. Soc. 2001, 123, 11577; (i) Itami, K.; Yoshida, J.
Bull. Chem. Soc. Jpn. 2006, 79, 811; (j) Selle`s, P. Org. Lett. 2005, 7, 605.
4. Takahashi, A.; Kirio, Y.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc.
1989, 111, 643.
1718 cmꢁ1
;
MS 342.2 (Mþ); HRMS calcd for C21H26O4 (Mþ)
342.1831, found 342.1841.
4.30. (Z)-Ethyl 8-acetoxy-2-(4-methoxyphenyl)-3-methyloct-
2-enoate (42)
A
solution of pent-4-enylacetate (20.3 mg, 0.158 mmol,
4.0 equiv) and 9-borabicyclo[3.3.1]nonane (0.32 mL, 0.158 mmol,
4.0 equiv, 0.5 M in THF) was stirred for 2 h. A separate flask was
charged with Pd(OAc)2 (2.6 mg, 0.004 mmol, 0.1 equiv), PMe3$HBF4
(1.3 mg, 0.0079 mmol, 0.2 equiv), and Cs2CO3 (51.1 mg, 0.158 mmol,
4.0 equiv). To this was added sequentially dioxane (0.7 mL) and 8
(10.0 mg, 0.039 mmol, 1.0 equiv). The reaction was sparged for
20 min. The 9-octyl-9-bora-bicyclo[3.3.1]nonane solution was in-
5. (a) Al-Hassan, M. I. Synthesis 1987, 816; (b) Tessier, P. E.; Penwell, A. J.; Souza, F.
E. S.; Fallis, A. G. Org. Lett. 2003, 5, 2989.
6. (a) Caturla, F.; Amat, M.; Reinoso, R. F.; Cordoba, M.; Warrellow, G. Bioorg. Med.
Chem. Lett. 2006, 16, 3209; (b) Wadman, M. Nature 2006, 440, 277; (c) Prasit, P.;
Wang, Z.; Brideau, C.; Chan, C. C.; Charleson, S.; Cromlish, W.; Ethier, D.; Evans,
J. F.; Ford-Hutchinson, A. W.; Gauthier, J. Y. Bioorg. Med. Chem. Lett. 1999, 9, 1773.
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troduced via canula, H2O (2.8 mL) was added, and the reaction
8. Katsuki, T.; Martin, V. Org. React. 1996, 48, 1.
9. Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829.
10. Oishi, S.; Miyamoto, K.; Niida, A.; Yamamoto, M.; Ajito, K.; Tamamura, H.; Otaka,
A.; Kuroda, Y.; Asai, A.; Fujii, N. Tetrahedron 2006, 62, 1416.
11. (a) Misumi, Y.; Masuda, T. Macromolecules 1998, 31, 7572 and references cited
therein; (b) Hall, H. K. J. Angew. Chem., Int. Ed. Engl. 1983, 22, 440.
mixture was stirred for 18 h. The mixture was partitioned between
ether and H2O and the aqueous layer was extracted with ether
(3ꢂ20 mL). The combined organic phases were dried over anhy-
drous MgSO4, filtered, and concentrated in vacuo. The product was

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