Single-isomer trisubstituted olefins from a novel reaction of (E)-βchloro-α-iodo-α,β-unsaturated esters and amides

Article abstract of DOI:10.1021/jo8008325

(Chemical Equation Presented) (E)-β-Chloro-α-iodo-α, β-unsaturated esters are converted to single isomer trisubstituted olefins bearing three different carbon substituents by cross-coupling under reflux. Mechanistic investigations suggest that this process transfers a hydrogen from the boronic acid to the α-position of the substrate and then introduces an aryl group to the β-position of the intermediate template while replacing chloride. The reaction is highly stereoselective, showing preference for the E-isomer. The process proceeds through (E)-β-chloro-α-aryl-α, β-unsaturated esters that are transformed efficiently into the corresponding E-products through stereoselective Suzuki-type reactions giving single isomers. The observed stereo-chemistry is apparently enabled by the intermediacy of a palladium allenoate. The reaction involves a catalytic cycle in which Pd^II is reduced to Pd⁰ through the formation of biaryl-coupled products.

Full text of DOI:10.1021/jo8008325

Single-Isomer Trisubstituted Olefins from a Novel Reaction of
(E)-ꢀ-Chloro-r-iodo-r,ꢀ-unsaturated Esters and Amides
Julie Simard-Mercier, Jojo Liu Jiang, Michael L. Ho, Alison B. Flynn, and
William W. Ogilvie*
Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
wogilVie@uottawa.ca
ReceiVed April 15, 2008
(E)-ꢀ-Chloro-R-iodo-R,ꢀ-unsaturated esters are converted to single isomer trisubstituted olefins bearing
three different carbon substituents by cross-coupling under reflux. Mechanistic investigations suggest
that this process transfers a hydrogen from the boronic acid to the R-position of the substrate and then
introduces an aryl group to the ꢀ-position of the intermediate template while replacing chloride. The
reaction is highly stereoselective, showing preference for the E-isomer. The process proceeds through
(E)-ꢀ-chloro-R-aryl-R,ꢀ-unsaturated esters that are transformed efficiently into the corresponding
E-products through stereoselective Suzuki-type reactions giving single isomers. The observed stereo-
chemistry is apparently enabled by the intermediacy of a palladium allenoate. The reaction involves a
catalytic cycle in which PdII is reduced to Pd0 through the formation of biaryl-coupled products.
Introduction
Results and Discussion
The task of synthesizing trisubstituted olefins bearing three
different carbon-linked appendages is a significant challenge
in organic synthesis. Phosphorus-based reactions such as the
Wittig and Horner-Wadsworth-Emmons, while powerful,
provide mixtures of E and Z isomers.1 More successful are
indirect methods such as the carbometalation of alkynes
involving either alkyl or hydride transfer,2 the conversion of
existing olefin templates using cross couplings,3 or Heck-type
reactions.4 Selectivity issues may arise during these processes
producing isomeric mixtures that may be extremely difficult to
resolve. Thus, there exists a need for simple, direct methods to
prepare trisubstituted olefins that provide reliable means of
generating single isomer products.
We recently developed a mild and versatile method of
synthesizing acyclic, single isomer olefins bearing four different
carbon-linked substituents.5 These alkenes were obtained using
an (E)-ꢀ-chloro-R-iodo-R,ꢀ-unsaturated ester template that was
submitted to sequential Sonogashira coupling reactions to
produce trans ene-diynes. In order to improve the scope of
this process, the development of a Suzuki coupling process6
was initiated with the goal of introducing a wider variety of
(3) (a) Tan, Z.; Negishi, E. Angew. Chem., Int. Ed. 2006, 45, 762. (b) Tan,
Z.; Negishi, E.-I. Angew. Chem. 2006, 118, 776. (c) Marek, I. Chem. ReV. 2000,
100, 2887. (d) Hata, T.; Kitagawa, H.; Masai, H.; Kurahashi, T.; Shimizu, M.;
Hiyama, T. Angew. Chem. 2001, 113, 812. (e) Hata, T.; Kitagawa, H.; Masai,
H.; Kurahashi, T.; Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2001, 40,
790. (f) Kurahashi, T.; Hata, T.; Masai, H.; Kitagawa, H.; Shimizu, M.; Hiyama,
T. Tetrahedron 2002, 58, 6381. (g) Itami, K.; Mineno, M.; Muraoka, N.; Yoshida,
J. J. Am. Chem. Soc. 2004, 126, 11778. (h) Rossi, R.; Bellina, F.; Carpita, A.;
Mazzarella, F. Tetrahedron 1996, 52, 4095. (i) Normant, J. F.; Alexakis, A.
Synthesis 1981, 841. (j) Corey, E. J.; Katzenellenbogen, J. A. J. Am. Chem.
Soc. 1969, 91, 1851. (k) Negishi, E.-i.; Zhang, Y.; Cederbaum, F. E.; Webb,
M. B. J. Org. Chem. 1986, 51, 4080. (l) Itami, K.; Yoshida, J.-i. Bull. Chem.
Soc. Jpn. 2006, 79, 811. (m) Itami, K.; Yoshida, J.-i. Chem. Eur. J. 2006, 12,
3966.
(1) (a) Reiser, O. Angew. Chem., Int. Ed. 2006, 45, 2838. (b) Boutagy, J.;
Thomas, R. Chem. ReV. 1974, 74, 87.
(2) (a) Hayashi, T.; Inoue, K.; Taniguchi, N.; Ogasawara, M. J. Am. Chem.
Soc. 2001, 123, 9918. (b) Hall, D. G.; Chapdelaine, D.; Pre´ville, P.; Deslong-
champs, P. Synlett 1994, 660. (c) Houpis, I. N.; Lee, J. Tetrahedron 2000, 56,
817. (d) Qian, M.; Huang, Z.; Negishi, E. Org. Lett. 2004, 6, 1531. (e) Pommier,
A.; Stepanenko, V.; Jarowicki, K.; Kocienski, P. J. J. Org. Chem. 2003, 68,
4008. (f) Konno, T.; Daitoh, T.; Noiri, A.; Chae, J.; Ishihara, T.; Yamanaka, H.
Org. Lett. 2004, 6, 933. (g) Nishihara, Y.; Miyasaka, M.; Okamoto, M.;
Takahashi, H.; Inoue, E.; Tanemura, K.; Takagi, K. J. Am. Chem. Soc. 2007,
129, 12634.
(4) (a) Knowles, J. P.; Whiting, A. Org. Biomol. Chem. 2007, 5, 31. (b)
Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009.
(5) Lemay, A. B.; Vulic, K. S.; Ogilvie, W. W. J. Org. Chem. 2006, 71,
3615.
(6) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
10.1021/jo8008325 CCC: $40.75
Published on Web 06/25/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5899–5906 5899

Simard-Mercier et al.
TABLE 1. Attempted Generation of (Z)-ꢀ-Chloro-r,ꢀ-unsaturated
Ester 2 from (E)-ꢀ-Chloro-r-iodo-r,ꢀ-unsaturated Ester 1
TABLE 2. Formation of Trisubstituted Olefins from
(E)-ꢀ-Chloro-r-iodo-r,ꢀ-unsaturated Compounds and Boronic Acids
entrya
R
substrate
Ar
C6H5
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
4-MeC6H4
4-FC6H4
C6H5CHCH 10
2-thiophene 11
1-naphthyl
2-naphthyl
C6H5
product yieldb (%)
1
2
3
4
Mec
Me
Me
Me
Me
Me
Me
Me
Me
Me
Cy
1
1
1
1
1
1
1
1
1
1
14
3
5
6
7
8
9
99
83
79
98
76
entrya
catalyst
ligand
productb
1
2
3
Pd(PPh3)4
PdCl2(PPh3)2
PdCl2(dppf)
Pd2(dba)3
NR
NR
NR
NR
5
6d
7
69
88
4
P(t-Bu)3 ·HBF4
P(t-Bu)3 ·HBF4
5c
Pd2(dba)3
3 (99%)
8
9
82
a Conditions: 0.1 equiv of catalyst, 0.2 equiv of ligand, 4.0 equiv of
PhB(OH)2, 3.0 equiv of Cs2CO3, dioxane, rt. b Isolated yield in
parentheses. c Reaction performed at reflux.
12
13
15
17
19
21
23
96
10
11
12
13
14
15e
16e
549
71
TBSO(CH2)2 16
BnO(CH2)2 18
TIPSO(CH2)2 20
Me(CH2)5
Me(CH2)5
C6H5
C6H5
C6H5
C6H5
81
96
SCHEME 1. Elucidation of the Structure of Trisubstituted
Olefin 3
9510
99
22
22
4-MeOC6H4 24
92
a Conditions: 0.1 equiv of Pd2(dba)3, 0.2 equiv of P(t-Bu)3 ·HBF4,
10.0 equiv of ArB(OH)2, 7.5 equiv of Cs2CO3, dioxane, reflux, 4 h.
b Isolated yield. c 4.0 equiv of ArB(OH)2 and 3.0 equiv of Cs2CO3 were
used. d P(t-Bu)Me2 ·HBF4 was used in place of P(t-Bu)3 ·HBF4.
e Weinreb amide was used; Pd(OAc)2 was used in place of Pd2(dba)3.
substituents to the R-position of the substrate.7 An initial
experiment performed using Pd(PPh3)4 in dioxane gave no
conversion to the desired product 2 (Table 1, entry 1). Similar
results were obtained using PdCl2(PPh3)2 and with the bidentate
ligand DPPF (entries 2 and 3), while the use of P(t-Bu)3 as a
ligand also was unsuccessful (entry 4). In order to increase
reactivity, we carried out a coupling reaction using Pd2(dba)3
and P(t-Bu)3 in refluxing dioxane. As shown in entry 5, a clean
conversion of all of the starting material was realized.
compounds and if the stereochemistry of the initial product 3
was E as shown.8
In order to establish the scope of this unusual reaction, the
effect of changing the boronic acid and of changing the
substituent at the ꢀ-position of the template was explored (Table
2.) In addition to the simple phenyl moiety, aryl groups
containing a variety of substituents could be introduced to the
(E)-ꢀ-chloro-R-iodo template 1 to give the corresponding
trisubstituted olefins. The presence of electron-donating groups
on the aryl boronic acid was well tolerated, and excellent yields
of the trisubstituted products were realized, even if the sub-
stituent was in the meta or ortho position (entries 2-5). The
presence of a fluorine at the para position of the phenylboronic
acid resulted in a lower recovery of the trisubstituted product,
and a modest improvement in yield was realized by using P(t-
Bu)Me2 as the ligand in this case. Vinyl boronic acids underwent
the process affording a very good recovery of the trisubstituted
olefin product bearing a styrenyl appendage (entry 7). Hetero-
cycles such as thiophene were compatible with the reaction,
and we were pleased to note that hindered substituents such as
1- and 2-naphthyl groups could be successfully introduced
(entries 8-10).
The product of the reaction was isolated as a single isomer,
and spectroscopic analysis immediately indicated that it was
not the anticipated product 2. Instead, a trisubstituted olefin was
obtained in which a phenyl group and hydrogen had been
introduced onto the olefin moiety. Using NOESY analysis, we
established that the product of the reaction was the trisubstituted
olefin 3. This process also produced a quantitative amount of
biphenyl, a result that became important when considering the
mechanism of the process (see below).
As shown in Scheme 1, the key reaction product 3 gave NOE
interactions between the methyl and phenyl groups and between
the phenyl and olefinic hydrogen. Photoisomerization of com-
pound 3 gave olefin 4 that displayed enhancements between
the phenyl and methyl hydrogens and between the methyl and
olefinic hydrogen. This network of NOE effects indicated that
the phenyl and olefinic hydrogen were cis in adduct 3. The
regiochemistry of compound 3 was established from the
magnitude of the coupling constant between this hydrogen and
the methyl group (1.3 Hz) and by the observation that the
olefinic hydrogen gave only one NOE interaction for both
isomers (3 and 4). The phenyl residue of product 3 displayed
two NOE effects, one with the methyl group and one with the
olefinic hydrogen, and the methyl group of 4 experienced the
two NOE enhancements shown. This network would only be
possible if the phenyl was ꢀ to the ester group in both
Substitution on the substrate template was tolerated as
branched alkyl groups could be present in addition to function-
alized alkyl moieties (entries 11-14). The reaction conditions
(8) Similar analyses were carried out for all products described in this work.
(9) 14% of a tetrasubstituted olefin product was obtained.
(10) 5% of a tetrasubstituted olefin product was produced.
(7) Simard-Mercier, J.; Flynn, A. B.; Ogilvie, W. W. Tetrahedron 2008, 64,
5472.
5900 J. Org. Chem. Vol. 73, No. 15, 2008

Single-Isomer Trisubstituted Olefins
SCHEME 2. Possible Elimination/Addition Mechanism To
Account for the Formation of Products of Type 27 from 1
SCHEME 3. Possible Reaction Intermediates Subjected to
the Conditions Used To Form Trisubstituted Olefins
TABLE 3. Alkynyl Esters Submitted to the Conditions Used To
Prepare Trisubstituted Esters
entrya
boronic acid
ratio(3:28)
combined yield (%)
1
PhB(OH)2
PhB(OD)2
PhB(OH)2
PhB(OH)2
3:1
2:1
3:1
2:1
10
10b
50
2
3c
4d
30
a Conditions: 0.1 equiv of Pd2(dba)3, 0.2 equiv of P(t-Bu)3 ·HBF4, 4.0
equiv of ArB(OH)2, 3.0 equiv of Cs2CO3, dioxane, reflux, 4 h. b 46%
Deuterium incorporation. c 7.1 equiv of water was added. d 0.1 equiv of
1 was added.
were compatible with the presence of other electron-withdrawing
groups on the substrates as the use of a Weinreb amide in place
of an ester group (compound 22) gave excellent conversions to
products (entries 15 and 16). In all of the examples shown in
Table 2, the products were isolated as single isomers suggesting
a highly specific or stereocontrolled reaction.
The observation of single isomers, in which the configuration
of the olefin was “inverted” with respect to the starting substrate,
was intriguing, and the mechanism by which this transformation
had occurred was not immediately evident. The source of
hydrogen was also unclear. This could have been introduced
by simple protonation, or as part of a catalytic cycle involving
palladium that would imply hydride transfer from a reductive
elimination. To resolve these issues, a mechanistic analysis was
carried out.
The fact that the aryl group and hydrogen were introduced
in a cis fashion suggested a mechanism involving an intermedi-
ate alkyne. This process could have happened through an initial
oxidative addition of Pd into the C-I bond of 1 followed by
the elimination of chloride11 to afford an alkynyl ester such as
26 (Scheme 2.) Such materials have been reported as side
products during Negishi couplings of R,ꢀ-dibromo-R,ꢀ-unsatur-
ated esters.3h The alkynyl ester would then suffer Pd-catalyzed
aryl addition, followed by hydrogen transfer to form the products
observed.12
To test whether such an elimination/addition mechanism was
operative in the present process, alkynyl ester 26 was subjected
to the reaction conditions. As shown in Table 3, when alkynyl
ester 26 was treated with PhB(OH)2 in the presence of palladium
catalyst, a very low conversion to products was observed (entry
1). More importantly, the reaction produced a 3:1 mixture of
trisubstituted olefin 3 and the regioisomer 28,13 a product that
was not formed when 1 was used as a substrate. Performing
the reaction with PhB(OD)2 gave the analogous deuterated
products, but the level of D incorporation in the products was
only 46% (entry 2), suggesting that traces of water were
implicated in the process. When a small amount of water was
introduced to the medium, the yield was increased, but the same
two regioisomers (3 and 28) were formed in similar ratios to
the reaction performed without water (entries 1 and 3). To
explore the possibility that substrate 1 was perhaps forming some
sort of catalytic entity that was responsible for the selectivity
noted (relative to the reaction without 1), 10 mol % of 1 was
added to the reaction mixture. In this experiment, the combined
yield of products 3 and 28 was slightly increased (relative to
the reaction performed without 1); however, no significant
change in product distribution was noticed (entry 4). Overall,
these results suggested that the formation of trisubstituted olefins
from (E)-ꢀ-chloro-R-iodo-R,ꢀ-unsaturated esters did not involve
the intermediacy of an alkynyl ester such as 26.
Eliminating alkynes such as 26 as reaction intermediates
indicated that the process must involve sequential replacement
of the halogens during palladium-catalyzed couplings. Previous
experience with (E)-ꢀ-chloro-R-iodo-R,ꢀ-unsaturated esters had
shown that the iodide was always replaced first during related
cross-coupling reactions.5,7 Experiments were performed to
elucidate the order of substitution in the current process by
subjecting possible intermediates to the reaction conditions. If
the chloride at the ꢀ-position of 1 had been replaced first, then
iodide 29 should be converted to 3 (Scheme 3.) When (E)-R-
iodo-R,ꢀ-unsaturated ester 2914 was treated with 4-MeOC6H4-
B(OH)2 under the reaction conditions, tetrasubstituted olefin 30
was obtained as the sole product in 85% yield. The formation
of the tetrasubstituted product 30, rather than the trisubstituted
derivative 3, suggested that 29 could not be a reaction
intermediate and that the iodide was indeed displaced first when
substrates such as 1 were coupled with boronic acids under the
present conditions.
(11) Organ, M. G.; Ghasemi, H.; Valente, C. Tetrahedron 2004, 60, 9453.
(12) (a) Oh, C. H.; Jung, H. H.; Kim, K. S.; Kim, N. Angew. Chem., Int. Ed.
2003, 42, 805. (b) Gupta, A. K.; Kim, K. S.; Oh, C. H. Synlett. 2005, 457.
(13) Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc. 1975, 97,
5434.
(14) Prepared following a procedure similar to that described in: Klein, J.;
Levene, R. J. Chem. Soc., Perkin Trans. 2 1973, 1971.
(15) (a) Conrow, R. E.; Marshall, J. A. Synth. Commun. 1981, 11, 419. (b)
Jones, D. E.; Morris, R. O.; Vernon, C. A.; White, R. F. M. J. Chem. Soc. 1960,
2349. (c) Hatch, L. F.; Perry, R. H. J. Am. Chem. Soc. 1955, 77, 1136.
J. Org. Chem. Vol. 73, No. 15, 2008 5901

Simard-Mercier et al.
TABLE 4. Deuterium-Labeling Experiments To Elucidate the
Source of Hydrogen Transfer
If the initial step of the reaction was the replacement of the
iodide by hydrogen, the intermediate ꢀ-chloro-R,ꢀ-unsaturated
esters thus formed (31 or 32) should be cleanly converted to
product 3. Subjecting the cis-chloride 3115 to the reaction
conditions produced the expected trisubstituted olefin 3 in good
yield as a single isomer. In the case of the trans ꢀ-chloro
substrate 32,13 a low conversion to products was observed.
Moreover, this reaction produced a 1.7:1 mixture of stereoiso-
mers 3 and 4. The fact that 31 was efficiently converted to
product 3, whereas the use of 32 led to an erosion in both
selectivity and yield, indicated that the stereochemistry of the
product was most likely established during the first step of the
process and that intermediates such as 31 were implicated. A
thermodynamic component to the process was suggested when
the Z product isomer 416 was subjected to the reaction
conditions. The observation of only the E product 3 from this
experiment suggested that 3 was thermodynamically favored
at reflux in the presence of the reaction components. However,
the selective formation of 3 from 1 could not simply be a
consequence of thermodynamic control in the product, as
suggested by the experiments involving the intermediate chlo-
rides 31 and 32.
That the stereochemistry of the product was indeed a
consequence of the iodide replacement step was further sug-
gested by performing a coupling reaction with the (Z)-ꢀ-chloro-
R-iodo-R,ꢀ-unsaturated ester 33 that delivered the E-trisubsti-
tuted olefin 17 as the sole product in excellent yield. Interestingly,
it was found that the reaction of the cis isomer 33, with
PhB(OH)2 in the presence of Pd2(dba)3, P(t-Bu)3 ·HBF4, and
Cs2CO3 in refluxing dioxane, was more facile than the conver-
sion of the trans isomer 16 to products. The cis compound 33
could be converted to product 17 by a reaction performed at
room temperature, whereas the trans material 16 required
refluxing conditions to transform into the adduct 17 (Table 2,
entry 12). If the intermediate chloride structure was indeed an
E isomer similar to 31 (and not to the Z isomer 32), then the
reaction of the (E)-ꢀ-chloro-R-iodo-R,ꢀ-unsaturated ester 31,
possessing the same relative stereochemical arrangement of
substituents, would perhaps be expected to proceed faster than
that of the corresponding Z isomer. The results obtained with
substrate 33 therefore also supported the intermediacy of 31 in
the process.17
entrya
boronic acid
solvent
product
yield (%)
1
2
3
4
5
6
7
8
9
PhB(OH)2
PhB(OH)2
PhB(OH)2
C6D5B(OH)2
PhB(OD)2
dioxane
CH3CN
CD3CN
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
3
3
3
35
99
35
32
98
89
88
87
NR
40
3:34 (48:52)b
3:34 (33:67)
3:34 (48:52)b
c
PhB(OH)2
d
PhB(OD)2
e
PhBpin
e,c
PhBpin
34
a Conditions: 0.1 equiv of Pd2(dba)3, 0.2 equiv of P(t-Bu)3 ·HBF4, 4.0
equiv of ArB(OH)2, 3.0 equiv of Cs2CO3, dioxane, reflux, 2 h. b 52%
deuterium-labeled boronic acid was used. c 7.1 equiv of D2O added.
d Reaction performed in the presence of 4 Å molecular sieves. e PhBpin
) phenylboronic acid pinacol ester.
the source of hydrogen. The next possibility examined was
the boronic acid (entry 5). Using C6H5B(OD)2 as the coupling
partner resulted in the formation of adduct 34 in which the
level of deuterium incorporation (52%) matched that of the
starting boronic acid (52%), suggesting that the hydrogen
could be derived from the boronic acid component. When a
reaction using C6H5B(OH)2 was performed in the presence
of 7 equiv of D2O, deuterated product 34 was also formed.
The ratio of 3 to 34 approximately matched the ratio of
PhB(OH)2 to D2O in this experiment, suggesting that the
hydrogen source could have been either the boronic acid,
water, or the -ate complex formed from the water and boronic
acid (entry 6). Although the reactions depicted in Table 2
were all performed under anhydrous conditions, it was
possible that traces of water could be involved. An experi-
ment using PhB(OD)2 was therefore done in the presence of
4 Å molecular sieves, which produced a mixture of 3 and 34
in the same ratio as that observed previously (entries 5 and
7). When the pinacol ester of the boronic acid was used (entry
8), no product was formed consistent with the requirement
for boronic acid as the hydrogen source. The same experi-
ment, performed in the presence of 7 equiv of D2O. resulted
in the formation of product 34 indicating that hydrogen could
be transferred from a boron-ate complex or from traces of
water in the medium (entry 9).6
The possible sources of hydrogen were investigated using
a series of isotopic-labeling experiments (Table 4.) Perform-
ing the reaction in deuterated acetonitrile resulted in no
deuterium incorporation, indicating that the solvent was not
the source of hydrogen. Although the yield of this process
was lower than the standard reaction in dioxane, trisubstituted
olefin 3 was obtained as the sole product of the reaction (as
a single isomer) and the efficiency of the process was
unaffected by the use of labeled solvent (entries 2 and 3).
Previous reports involving rhodium-catalyzed additions of
aryl boronic acids to alkynes had suggested that the phenyl
ring of the boronic acid could serve as a supply of hydrogen
atoms in some cases.2a When C6D5B(OH)2 was used as a
coupling partner, compound 35 was obtained as the sole
product with no deuterium incorporation noted on the alkene
moiety (entry 4). This indicated that the aryl ring was not
Several pathways were considered to account for the
introduction of hydrogen onto the trisubstituted olefin product
3. In principle, the hydrogen could be transferred formally
as a hydride through reductive elimination from a palladium
species (Scheme 4, pathways a and b) or by simple
protonolysis (Scheme 4c). Two sequences were examined
when considering the possibility of hydride transfer. Oxida-
tive addition of Pd into the H-O bond of ArB(OH)2 would
generate species such as 36.10,18 This could be followed by
a Heck-type addition pathway19 delivering the hydride to
(16) A 10:1 mixture of 4 and 3 was used.
(17) The results obtained using 31, 32, and 33 as substrates are consistent
with the intermediacy of a product in which the hydrogen and chloride were
cis. This suggests that the thermodynamic preference for the E isomer 3 (scheme
3) may be coincidental.
(18) Shirakawa, E.; Otsuka, H.; Hayashi, T. Chem. Commun. 2005, 47, 5885.
(19) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 4156.
5902 J. Org. Chem. Vol. 73, No. 15, 2008

Single-Isomer Trisubstituted Olefins
SCHEME 4. Possible Pathways Considered To Account for
the Introduction of Hydrogen
SCHEME 5. Isolation of a Biphenyl Byproduct during the
Formation of Trisubstituted Olefin 3 from Substrate 1
the stereochemistry of the products. This mechanism would
be compatible with the results obtained with substrates 31
and 32, which showed that the cis-chloride 31 was efficiently
converted to 3, whereas trans-chloride 32 showed erosions
in both yield and stereochemistry during the final coupling
phase. The difficulty with this mechanism was that such a
protonolysis (42 f 31) would result in the production of a
palladium(II) species (38) that would need some mechanism
of conversion to the catalytically capable palladium(0)
complex.
The formation of biphenyl compounds such as 43 as
byproducts in the coupling reaction of 1, in amounts equal to
the amount of products formed, provided a means to account
for this (Scheme 5.) Successive transmetalation steps involving
excess boronic acid in the medium could ultimately form a diaryl
palladium species that would suffer reductive elimination to
regenerate the active Pd0 catalyst while expelling biphenyl 43.
The observation of a stoichiometric amount of biphenyl byprod-
uct 43 from the reaction of 1 with phenylboronic acid is
consistent with this hypothesis.
On the basis of these results, a plausible mechanism
involving two catalytic cycles is proposed that accounts for
the formation of one single trisubstituted isomer from the
Suzuki reaction of (E)-ꢀ-chloro-R-iodo-R,ꢀ-unsaturated esters
such as 1 (Scheme 6.) The first step involves oxidative
addition of the palladium into the carbon-iodine bond of 1
to form an (E)-alkenyl PdII species 40. Under reflux condi-
tions, this species would be in equilibrium with the palladium
allenoate 41 and the isomeric (Z)-alkenylpalladium complex
42. A protonolysis step involving the boronic acid would
form the PdII intermediate 44, while selectively generating
chloride 31. Successive transmetalation steps involving excess
boronic acid in the medium could ultimately form the diaryl
palladium species 45 that would suffer reductive elimination
to regenerate the active Pd0 catalyst while expelling biphenyl
43. The observation of a stoichiometric amount of biphenyl
product 43 from the reaction of 1 with phenylboronic acid
is consistent with this hypothesis. The second catalytic cycle
would follow the usual Suzuki-Miyaura mechanism using
the (E)-ꢀ-chloro-R,ꢀ-unsaturated ester 31 as an entry point.
The fact that 31 was efficiently converted to the final product
3 suggested that 31 was implicated in the cycle and not the
isomeric chloride 32.
form 37 as an intermediate (sequence a). A subsequent
elimination of 38 from this material would form 31, which
would then undergo cross coupling to afford 3. Although this
mechanism could account for the stereochemistry of the
products, electronically this process would be expected to
favor regioisomers such as 28 rather than the observed
products 3 as the hydride would be expected to add in a
conjugate fashion to the R,ꢀ-unsaturated ester. In addition,
if this mechanism were operative, (Z)-ꢀ-chloro-R-iodo-R,ꢀ-
unsaturated esters would be expected to form products such
as 4 selectively. As the reaction of 32 was inefficient and
condensation of 33 gave the E-trisubstituted product 17 and
not the Z isomer, an alternative process was indicated.
This second possibility would involve an exchange between
the initial Pd hydride 36 and the substrate 1 to afford a precursor
(39) for reductive elimination (sequence b). One difficulty with
this sequence was that it predicted the formation of the Z
products and of the intermediacy of 32 rather than 31 from the
reductive elimination.20 A more serious difficulty with this
pathway was the fact that a transient palladium(IV) species
would be implicated during the conversion of 36 to 39, making
this route an unlikely possibility.
A sequence considered was that initial oxidative addition
of palladium(0) into the carbon-iodine bond of 1 would form
an intermediate (40) that was formally a palladium enolate
(sequence c). Introduction of the hydrogen could proceed by
simple protonolysis,21 a mechanism that would also provide
a means of establishing the stereochemistry of the intermedi-
ates and products. At reflux, the palladium structure 40 could
exist in equilibrium with the corresponding palladium alle-
noate 41 and therefore with isomeric palladium species 42.
Protonation of compound 42, if more facile than the
protonation of the initial intermediate 40, could account for
A regiospecific and stereoselective palladium-catalyzed cross-
coupling reaction of organoboronic acids onto ꢀ-chloro-R-iodo-
R,ꢀ-unsaturated esters has been developed to produce single isomer
trisubstituted olefins in excellent yields. This methodology is
potentially a very useful synthetic tool as it gives single isomers
and therefore avoids problematic olefin isomer separation. The
mechanism of this process is somewhat unusual and involves
protonolysis of an intermediate palladium allenoate in a highly
stereoselective manner to afford intermediate (E)-ꢀ-chloro-R,ꢀ-
unsaturated esters. This protonolysis is mediated by the boronic
acid component in the mixture. The (E)-ꢀ-chloro-R,ꢀ-unsaturated
(20) Related couplings using these substrates always proceed with retention
of configuration. See refs5 and.7
(21) Lautens, M.; Yoshida, M. Org. Lett. 2002, 4, 123.
J. Org. Chem. Vol. 73, No. 15, 2008 5903

Simard-Mercier et al.
SCHEME 6. Proposed Catalytic Cycle
59.4 (CH2), 54.8 (CH3), 17.1 (CH3), 13.8 (CH3); IR (neat) 1708,
1628 cm-1; MS 220.1 (M+); HRMS calcd for C13H16O3 (M+)
220.1099, found 220.1086.
ester intermediates then rapidly undergo a stereoselective Suzuki-
type coupling to deliver the final products as single isomers. The
protonolysis and final coupling are “matched” in that the isomer
produced in the initial proton transfer is the substrate most
efficiently converted to products by the cross-coupling process.
(E)-Ethyl 3-(2-Methoxyphenyl)but-2-enoate (7). Prepared from
1 (30 mg, 0.11 mmol), 2-methoxyphenylboronic acid (166 mg, 1.1
mmol), and Cs2CO3 (289 mg, 0.89 mmol) using a procedure similar
to that described for compound 3 that provided the title compound
Experimental Section
1
as a colorless oil (24 mg, 98%): H NMR (400 MHz, acetone-d6)
δ 7.35-7.31 (m, 1H), 6.97 (dd, J ) 7.6, 1.6 Hz, 1H), 7.04 (d, J )
8.4 Hz, 1H), 6.97-6.93 (m, 1H), 5.82 (q, 1.2 Hz, 1H), 4.16 (q, J
) 7.2 Hz, 2H), 3.84 (s, 3H), 2.45 (d, J ) 1.2 Hz, 3H), 1.26 (t, J
) 7.2 Hz, 3H); 13C NMR (100 MHz, acetone-d6) δ 167.8 (C), 158.3
(C), 158.1 (C), 134.6 (C), 131.5 (CH), 130.4 (CH), 122.4 (CH),
120.7 (CH), 113.2 (CH), 61.1 (CH2), 56.8 (CH3), 21.0 (CH3), 15.6
(CH3); IR (neat) 1712, 1630 cm-1; MS 220.1 (M+); HRMS calcd
for C13H16O3 (M+) 220.1099, found 220.1091.
General Procedure for the Synthesis of Trisubstituted
Alkenes from (E)-3-Chloro-2-iodo-2-alkenoates. (E)-Ethyl
2-Methyl-3-phenylbut-2-enoate (3). To an oven-dried, 10 mL,
round-bottom flask equipped with a Teflon sleeve and a water-
cooled condenser were added Pd2(dba)3 (16 mg, 0.018 mmol), P(t-
Bu)3 ·HBF4 (21 mg, 0.072 mmol), PhB(OH)2 (88 mg, 0.72 mmol),
and Cs2CO3 (176 mg, 0.54 mmol) under a nitrogen atmosphere.
Freshly distilled dioxane was added (2.0 mL) followed by (E)-
ethyl 3-chloro-2-iodobut-2-enoate 15 (50 mg, 0.18 mmol), and the
resulting mixture was heated at reflux for 4 h. The solution was
cooled, diluted with Et2O, and washed with brine. The organic phase
was dried over anhydrous MgSO4, filtered, and concentrated in
vacuo. The pure product22 (34 mg, 99%) was obtained as a clear
oil by flash chromatography (hexanes then 1% Et2O in hexanes):
1H NMR (400 MHz, acetone-d6) δ 7.58-7.55 (m, 2H), 7.42-7.40
(m, 3H), 6.13 (q, J ) 1.3 Hz, 1H), 4.17 (q, J ) 7.0 Hz, 2H), 2.56
(d, J ) 1.4 Hz, 3H), 1.27 (t, J ) 7.0 Hz, 3H).
(E)-Ethyl 3-p-Tolylbut-2-enoate (8). Prepared from 1 (30 mg,
0.11 mmol), p-tolylboronic acid (149 mg, 1.1 mmol), and Cs2CO3
(289 mg, 0.89 mmol) using a procedure similar to that described
for compound 3 that provided the title compound as a colorless oil
1
(17 mg, 76%): H NMR (400 MHz, acetone-d6) δ 7.48-7.45 (m,
2H), 7.24-7.22 (m, 2H), 6.12 (q, J ) 1.2 Hz, 1H), 4.16 (q, J )
7.2 Hz, 2H), 2.55 (d, J ) 1.2 Hz, 3H), 2.35 (s, 3H), 1.27 (t, J )
7.2 Hz, 3H); 13C NMR (100 MHz, acetone-d6) δ 168.0 (C), 156.9
(C), 141.0 (C), 140.9 (C), 131.1 (CH), 128.0 (CH), 117.8 (CH),
61.1 (CH2), 22.1 (CH3), 18.7 (CH3), 15.6 (CH3); IR (neat) 1712,
1626 cm-1; MS 204.1 (M+); HRMS calcd for C13H16O2 (M+)
204.1150, found 204.1165.
(E)-Ethyl 3-(4-Methoxyphenyl)but-2-enoate (5). Prepared from
1 (30 mg, 0.11 mmol), 4-methoxyphenylboronic acid (166 mg, 1.1
mmol), and Cs2CO3 (289 mg, 0.89 mmol) using a procedure similar
to that described for compound 3 that provided the title compound
(E)-Ethyl 3-(4-Fluorophenyl)but-2-enoate (9). Prepared from
1 (50 mg, 0.18 mmol), 4-fluorophenylboronic acid (255 mg, 1.8
mmol), and Cs2CO3 (445 mg, 1.4 mmol) using a procedure similar
to that described for compound 3 that provided the title compound
1
as a colorless oil (20 mg, 83%): H NMR (400 MHz, acetone-d6)
δ 7.57-7.53 (m, 2H), 6.98-6.96 (m, 2H), 6.11 (q, J ) 1.2 Hz,
1H), 4.15 (q, J ) 7.2 Hz, 2H), 3.83 (s, 3H), 2.55 (d, J ) 1.2 Hz,
3H), 1.26 (t, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, acetone-d6) δ
168.1 (C), 162.6 (C), 156.4 (C), 135.7 (C), 129.5 (CH), 116.7 (CH),
115.8 (CH), 61.0 (CH2), 56.7 (CH3), 18.5 (CH3), 15.7 (CH3); IR
(neat) 1709, 1626 cm-1; MS 220.1 (M+); HRMS calcd for C13H16O3
(M+) 220.1099, found 220.1098.
1
as a colorless oil (26 mg, 69%): H NMR (400 MHz, acetone-d6)
δ 7.66-7.63 (m, 2H), 7.21-7.16 (m, 2H), 6.12 (q, J ) 1.2 Hz,
1H), 4.17 (q, J ) 7.2 Hz, 2H), 2.56 (d, J ) 1.2 Hz, 3H), 1.27 (t,
J ) 7.2 Hz, 3H); 13C NMR (100 MHz, acetone-d6) δ 167.9 (C),
165.1 (d, J ) 245 Hz, C), 155.7 (C), 140.1 (d, J ) 3.1 Hz, C),
130.3 (d, J ) 8.4 Hz, CH), 118.7 (CH), 117.2 (d, J ) 21.6 Hz,
CH), 61.3 (CH2), 18.8 (CH3), 15.6 (CH3); IR (neat) 1713, 1631
cm-1; MS 208.1 (M+); HRMS calcd for C12H13FO2 (M+) 208.0900,
found 208.0905.
(2E,4E)-Ethyl 3-Methyl-5-phenylpenta-2,4-dienoate (10). Pre-
pared from 1 (30 mg, 0.11 mmol), trans-styrenylboronic acid (161
mg, 1.1 mmol), and Cs2CO3 (289 mg, 0.9 mmol) using a procedure
similar to that described for compound 3 that provided the known
compound23 as a colorless oil (21 mg, 88%): 1H NMR (400 MHz,
acetone-d6) δ 7.61-7.59 (m, 2H), 7.40-7.36 (m, 2H), 7.33-7.29
(E)-Ethyl 3-(3-Methoxyphenyl)but-2-enoate (6). Prepared from
1 (30 mg, 0.11 mmol), 3-methoxyphenylboronic acid (166 mg, 1.1
mmol), and Cs2CO3 (289 mg, 0.89 mmol) using a procedure similar
to that described for compound 3 that provided the title compound
1
as a colorless oil (19 mg, 79%): H NMR (400 MHz, acetone-d6)
δ 7.33 (dd, J ) 8.1, 0.3 Hz, 1H), 7.13 (ddd, J ) 7.7, 1.7, 0.9 Hz,
1H), 7.09 (dd, J ) 2.3, 0.3 Hz, 1H), 6.97 (ddd, J ) 8.2, 2.6, 0.9
Hz, 1H), 6.13 (q, 1.3 Hz, 1H), 4.17 (q, J ) 7.1 Hz, 2H), 3.84 (s,
3H), 2.55 (d, J ) 1.3 Hz, 3H), 1.27 (t, J ) 7.1 Hz, 3H); 13C NMR
(100 MHz, acetone-d6) δ 166.1 (C), 160.0 (C), 155.1 (C), 143.6
(C), 129.6 (CH), 118.5 (CH), 117.0 (CH), 114.7 (CH), 111.8 (CH),
(23) Albaugh-Robertson, P.; Katzenellenbogen, J. A. J. Org. Chem. 1983,
48, 5288.
(22) Paraskar, A. S.; Sudalai, A. Tetrahedron 2006, 62, 4907.
5904 J. Org. Chem. Vol. 73, No. 15, 2008

Single-Isomer Trisubstituted Olefins
(m, 1H), 7.13-7.02 (m, 2H) 5.98 (s, 1H), 4.14 (q, J ) 7.2 Hz,
2H), 2.40 (d, J ) 1.3 Hz, 3H), 1.26 (t, J ) 7.2 Hz, 3H).
(E)-Ethyl 5-(Benzyloxy)-3-chloro-2-iodopent-2-enoate (18). A
solution of ethyl 5-(benzyloxy)pent-2-ynoate24 (500 mg, 2.16 mmol,
1.0 equiv) and tetrabutylammonium iodide (2.25 g, 6.09 mmol, 3.0
equiv) in dichloroethane (20 mL) was heated at reflux for 18 h.
The reaction mixture was cooled, diluted with Et2O, and washed
with NaHSO3 (20% solution), saturated NaHCO3, and brine. The
organic phase was then dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The pure product was obtained as a colorless
oil (614 mg, 72%) by flash chromatography (hexanes and then 5%
(E)-Ethyl 3-(Thiophen-2-yl)but-2-enoate (11). Prepared from
1 (50 mg, 0.18 mmol), thiophen-2-ylboronic acid (233 mg, 1.8
mmol), and Cs2CO3 (482 mg, 1.4 mmol) using a procedure similar
to that described for compound 3 that provided the title compound
1
as a colorless oil (29 mg, 82%): H NMR (400 MHz, acetone-d6)
δ 7.54 (dd, J ) 5.1, 0.9 Hz, 1H), 7.48 (dd, J ) 3.7, 1.0 Hz, 1H),
7.11 (dd, J ) 5.1, 3.8 Hz, 1H), 6.22 (q, J ) 1.1 Hz, 1H), 4.15 (q,
J ) 7.1 Hz, 2H), 2.58 (d, J ) 1.2 Hz, 3H), 1.25 (t, J ) 7.1 Hz,
3H); 13C NMR (100 MHz, acetone-d6) δ 165.9 (C), 145.6 (C), 145.0
(C), 128.3 (CH), 127.5 (CH), 127.3 (CH), 113.8 (CH), 59.4 (CH2),
16.4 (CH3), 13.8 (CH3); IR (neat) 1716, 1607 cm-1; MS 196.1 (M+);
HRMS calcd for C10H12SO2 (M+) 196.0558, found 196.0552.
(E)-Ethyl 3-(Naphthalene-2-ylbut-2-enoate (12). Prepared from
1 (30 mg, 0.11 mmol), naphthalen-1-ylboronic acid (188 mg, 1.1
mmol), and Cs2CO3 (289 mg, 0.89 mmol) using a procedure similar
to that described for compound 3 that provided the title compound
1
ether in hexanes): H NMR (400 MHz, acetone-d6) δ 7.39-7.25
(m, 5H), 4.57 (s, 2H), 4.26 (q, J ) 7.2 Hz, 2H), 3.76 (dd, J ) 6.3,
6.3 Hz, 2H), 3.02 (dd, J ) 6.3, 6.3 Hz, 2H), 1.29 (t, J ) 7.2 Hz,
3H); 13C NMR (100 MHz, acetone-d6) δ 166.8 (C), 140.5 (C), 136.2
(C), 130.1 (CH), 129.3 (CH), 129.2 (CH), 84.7 (C), 74.3 (CH2),
63.8 (CH2), 43.0 (CH2), 15.2 (CH3); IR (neat) 1728, 1618 cm-1
;
MS 360.0 (M+ - Cl); HRMS calcd for C14H16ClIO3 (M+ - Cl)
360.0222, found 360.0224.
(E)-Ethyl 5-(Benzyloxy)-3-phenylpent-2-enoate (19). Prepared
from 18 (50 mg, 0.12 mmol), phenylboronic acid (149 mg, 1.2
mmol), and Cs2CO3 (324 mg, 0.92 mmol) using a procedure similar
to that described for compound 3 that provided the title compound
1
as a colorless oil (25 mg, 96%): H NMR (400 MHz, acetone-d6)
δ 7.95-7.87 (m, 3H), 7.56-7.47 (m, 3H), 7.34 (dd, J ) 7.0, 1.1
Hz, 1H), 5.90 (q, J ) 1.4 Hz, 1H), 4.20 (q, J ) 7.1 Hz, 2H), 2.58
(d, J ) 1.4 Hz, 3H), 1.27 (t, J ) 7.1 Hz, 3H); 13C NMR (100
MHz, acetone-d6) δ 165.7 (C), 156.7 (C), 142.0 (C), 133.9 (C),
130.0 (C), 128.5 (CH), 128.2 (CH), 126.4 (CH), 126.1 (CH), 125.4
(CH), 125.1 (CH), 124.3 (CH), 120.4 (CH), 59.5 (CH2), 20.9 (CH3),
13.8 (CH3); IR (neat) 1721, 1715 cm-1; MS 240.1 (M+); HRMS
calcd for C16H16O2 (M+) 240.1150, found 240.1148.
1
as a colorless oil (38 mg, 96%): H NMR (400 MHz, acetone-d6)
δ 7.58-7.56 (m, 2H), 7.42-7.40 (m, 3H), 7.31-7.23 (m, 5H), 6.11
(s, 1H), 4.46 (s, 2H), 4.17 (q, J ) 7.1 Hz, 2H), 3.59 (ddd, J )
12.8, 6.7, 0.7 Hz, 2H), 3.49-3.47(m, 2H), 1.26 (t, J ) 7.1 Hz,
3H); 13C NMR (100 MHz, acetone-d6) δ 167.6 (C), 159.0 (C), 143.1
(C), 140.8 (C), 130.8 (CH), 130.4 (CH), 130.0 (CH), 129.1 (CH),
129.0 (CH), 128.7 (CH), 120.4 (CH), 73.9 (CH2), 70.8 (CH2), 61.4
(CH2), 33.0 (CH2), 15.6 (CH3); IR (neat) 1705, 1622 cm-1; this
compound did not give satisfactory mass spectral data.
(E)-Ethyl 3-(Naphthalene-2-yl)but-2-enoate (13). Prepared
from 1 (30 mg, 0.11 mmol), naphthalen-2-ylboronic acid (188 mg,
1.1 mmol), and Cs2CO3 (289 mg, 0.89 mmol) using a procedure
similar to that described for compound 3 that provided the title
(E)-Ethyl 3-Chloro-2-iodo-5-(triisopropylsilyloxy)pent-2-enoate
(20). Prepared from (E)-ethyl 5-(triisopropylsiloxy)pent-2-ynoate25
(500 mg, 1.7 mmol) and tetrabutylammonium iodide (1.9 g, 5.0
mmol) using a procedure similar to that described for compound
18 that provided the title compound as a colorless oil (237 mg,
1
compound as a colorless oil (14 mg, 54%): H NMR (400 MHz,
acetone-d6) δ 8.13 (d, J ) 1.6 Hz, 1H), 8.00-7.91 (m, 3H), 7.72
(dd, J ) 8.7, 2.0 Hz, 1H), 7.57-7.53 (m, 2H), 6.31 (dd, J ) 2.6,
1.3 Hz, 1H), 4.20 (q, J ) 7.1 Hz, 2H), 2.68 (d, J ) 1.3 Hz, 3H),
1.29 (t, J ) 7.1 Hz, 3H); 13C NMR (100 MHz, acetone-d6) δ 166.1
(C), 154.8 (C), 139.2 (C), 133.7 (C), 133.4 (C), 128.6 (CH), 128.2
(CH), 127.5 (CH), 126.6 (CH), 126.5 (CH), 126.0 (CH), 123.9 (CH),
117.3 (CH), 59.4 (CH2), 16.9 (CH3), 13.8 (CH3); IR (neat) 1721,
1640 cm-1; MS 240.1 (M+); HRMS calcd for C16H16O2 (M+)
240.1150, found 240.1147.
1
31%): H NMR (400 MHz, acetone-d6) δ 4.25 (q, J ) 7.1 Hz,
2H), 4.03 (t, J ) 6.2 Hz, 2H), 2.97 (t, J ) 6.2 Hz, 2H), 1.29 (t, J
) 7.1 Hz, 3H), 1.13-1.08 (m, 21H); 13C NMR (100 MHz, acetone-
d6) δ 166.8 (C), 63.7 (CH2), 62.0 (CH2), 45.8 (CH2), 19.4 (CH3),
15.2 (CH2), 13.7 (CH3); IR (neat) 1732, 1620 cm-1; MS 418.0
(MH+ - C3H7); HRMS calcd for C13H24ClIO3Si (MH+ - C3H7)
418.0228, found 417.9758.
(E)-Ethyl 3-Cyclohexyl-3-phenylacrylate (15). Prepared from
145 (28 mg, 0.08 mmol), phenylboronic acid (99 mg, 0.82 mmol),
and Cs2CO3 (216 mg, 0.61 mmol) using a procedure similar to that
described for compound 3 that provided the title compound as a
(E)-Ethyl 3-Phenyl-5-(triisopropylsiloxy)pent-2-enoate (21).
Prepared from 20 (50 mg, 0.11 mmol), phenylboronic acid (132
mg, 1.1 mmol), and Cs2CO3 (287 mg, 0.81 mmol) using a procedure
similar to that described for compound 3 that provided the title
1
colorless oil (15 mg, 71%): H NMR (400 MHz, acetone-d6) δ
1
compound as a colorless oil (39 mg, 95%): H NMR (400 MHz,
7.39-7.33 (m, 3H), 7.23-7.21 (m, 2H), 5.61 (q, J ) 1.2 Hz, 1H),
4.16 (q, J ) 7.2 Hz, 2H), 3.78 (ddt, J ) 23.7, 11.8, 3.2 Hz, 1H),
1.76-1.62 (m, 5H), 1.42-1.23 (m, 4H), 1.26 (t, J ) 7.2 Hz, 3H),
1.13-1.06 (m, 1H); 13C NMR (100 MHz, acetone-d6) δ 168.2 (C),
167.3 (C), 143.2 (C), 129.7 (CH), 129.4 (CH), 129.3 (CH), 120.3
(CH), 61.3 (CH2), 42.3 (CH), 33.3 (CH2), 28.2 (CH2), 27.6 (CH2),
15.6 (CH3); IR (neat) 1715, 1628 cm-1; MS 258.2 (M+); HRMS
calcd for C17H22O2 (M+) 258.1620, found 258.1626.
acetone-d6) δ 7.59-7.57 (m, 2H), 7.44-7.38 (m, 3H), 6.11 (s, 1H),
4.17 (q, J ) 7.1 Hz, 2H), 3.85 (dd, J ) 6.8, 6.8 Hz, 2H), 3.42 (dd,
J ) 6.8, 6.8 Hz, 2H), 1.27 (t, J ) 7.1 Hz, 3H), 1.03-0.99 (m,
21H); 13C NMR (100 MHz, acetone-d6) δ 167.6 (C), 159.1 (C),
143.3 (C), 130.8 (CH), 130.4 (CH), 128.8 (CH), 120.4 (CH), 64.4
(CH2), 61.3 (CH2), 36.2 (CH2), 19.3 (CH3), 15.6 (CH), 13.7 (CH3);
IR (neat) 1716, 1629 cm-1; MS 333.2 (M+ - C3H7); HRMS calcd
for C19H29O3Si (M+ - C3H7), 333.1886, found 333.1894.
(E)-Ethyl 5-(tert-butyldimethylsiloxy)-3-phenylpent-2-enoate
(17). Prepared from 165 (20 mg, 0.05 mmol), phenylboronic acid
(58 mg, 0.48 mmol), and Cs2CO3 (126 mg, 0.36 mmol) using a
procedure similar to that described for compound 3 that provided
the title compound as a colorless oil (13 mg, 81%): 1H NMR (400
MHz, acetone-d6) δ 7.58-7.55 (m, 2H), 7.44-7.39 (m, 3H), 6.11
(s, 1H), 4.17 (q, J ) 7.2 Hz, 2H), 3.74 (dd, J ) 6.8, 6.8 Hz 2H),
3.70 (dd, J ) 6.8, 6.8 Hz, 2H), 1.27 (t, J ) 7.2 Hz, 3H), 0.82 (s,
9H), -0.02 (s, 6H); 13C NMR (100 MHz, acetone-d6) δ 167.6 (C),
159.0 (C), 143.2 (C), 130.8 (CH), 130.4 (CH), 128.7 (CH), 120.3
(CH), 63.9 (CH2), 61.3 (CH2), 36.1 (CH2), 27.2 (CH3), 19.7 (CH),
15.6 (CH3), -4.3 (CH3); IR (neat) 1716, 1618 cm-1; MS 277.1
(M+ - C4H9); HRMS calcd for C15H21O3Si (M+ - C4H9) 277.1260,
found 277.1269.
(E)-3-Chloro-2-iodo-N-methoxy-N-methylnon-2-enamide (22).
To a solution of 1-hexyne (2.6 mL, 17.7 mmol) in hexanes (150
mL) at -78 °C was added a solution of butyllithium (2.26 M in
THF, 8.63 mL, 19.5 mmol). After 1 h, a solution of N-methoxy-
N-methylcarbamoyl chloride26 (2.40 g, 19.4 mmol) in THF (20 mL)
was slowly added via canula. The reaction was stirred for 1 h at
-78 °C, and then the reaction was quenched by the dropwise
addition of 10% HCl. The mixture was allowed to warm to room
(24) Yadav, J. S.; Srihari, P. Tetrahedron: Asymmetry 2004, 15, 81.
(25) Boukouvalas, J.; Cheng, Y.-X.; Robichaud, J. J. Org. Chem. 1998, 63,
228.
(26) Smith, A. B., III; Beiger, J. J.; Davulcu, A. H.; Cox, J. M. Org. Synth.
2005, 82, 147.
J. Org. Chem. Vol. 73, No. 15, 2008 5905

Simard-Mercier et al.
temperature for 1 h and was then diluted with ether. The organic
layer was washed sequentially with a saturated solution of sodium
bicarbonate and brine, dried over anhydrous MgSO4, filtered, and
concentrated. The pure amide was obtained by chromatography
eluting with 5% EtOAc in hexanes then 20% EtOAc in hexanes to
give a pale yellow oil (3.02 g, 87%): 1H NMR (400 MHz, CDCl3)
δ 3.40 (s, 3H), 2.94 (s, 3H), 2.03 (t, J ) 6.4 Hz, 2H), 1.36 - 1.14
(m, 8H), 0.93 (t, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
73.0 (CH3), 61.8 (CH3), 31.1 (CH2), 30.8 (CH2), 28.4 (CH2), 27.6
(CH2), 22.4 (CH2), 18.8 (CH2), 13.6 (CH3); IR (neat) 2237, 1644
cm-1; MS 197.1 (M+); HRMS calcd for C11H19NO2 (M+) 197.1416,
found 197.1405. This material was transformed into the title
compound using a procedure similar to that described above for
compound 18 that provided the desired material as a colorless oil
(5.05 g, 92%): 1H NMR (400 MHz, C6D6) δ 3.22 (s, 3H), 2.82 (s,
3H), 2.46 (br, 2H), 1.48 - 1.45 (m, 2H), 1.19 - 1.14 (m, 6H), 0.84
(t, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, C6D6) δ 166.3 (C), 135.1
(C), 82.7 (C), 60.8 (CH3), 40.4 (CH2), 32.4 (CH3), 31.8 (CH2), 28.3
(CH2), 27.1 (CH2), 22.8 (CH2), 14.1 (CH3); IR (neat) 2954, 2930
cm-1; MS 359.0 (M+); HRMS calcd for C11H19ClINO2 (M+)
359.0149, found 359.0201.
was washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The pure product was obtained as a clear
oil (152 mg, 96%) by flash chromatography (5% Et2O in hexanes):
1H NMR (400 MHz, acetone-d6) δ 7.36-7.33 (m, 3H), 7.25-7.22
(m, 2H), 3.88 (q, J ) 7.1 Hz, 2H), 2.37 (s, 3H), 0.88 (t, J ) 7.1
Hz, 3H); 13C NMR (100 MHz, acetone-d6) δ 168.1 (C), 152.2 (C),
142.7 (C), 130.1 (CH), 129.9 (CH), 128.8 (CH), 63.1 (CH2), 16.6
(CH3), 14.7 (CH3); IR (neat) 1720, 1629 cm-1; MS 316.0 (M+);
HRMS calcd for C12H13IO2 (M+) 315.9960, found 315.9980.
(Z)-Ethyl 2-(4-Methoxyphenyl)-3-phenylbut-2-enoate (30).
Prepared from 29 (70 mg, 0.22 mmol), phenylboronic acid (270
mg, 2.2 mmol), and Cs2CO3 (586 mg, 1.7 mmol) using a procedure
similar to that described for compound 3 that provided the title
1
compound as a colorless oil (50 mg, 85%): H NMR (400 MHz,
acetone-d6) δ 7.38-7.18 (m, 7H), 6.97 (d, J ) 8.8 Hz, 2H), 3.82
(q, J ) 7.2 Hz, 2H), 3.82 (s, 3H), 2.05 (s, 3H), 0.82 (t, J ) 6.8 Hz,
3H); 13C NMR (100 MHz, acetone-d6) δ 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, 1602 cm-1; MS 296.1 (M+); HRMS
calcd for C19H20O3 (M+) 296.1412, found 296.1405.
(E)-Ethyl 3-Phenyl-2-deuterobut-2-enoate (34). Prepared from
1 (50 mg, 0.18 mmol) and C6H5B(OD)227 (89 mg, 0.72 mmol) using
a procedure similar to that described for compound 3 that provided
the title compound as a colorless oil (21 mg, 60%): 1H NMR (400
MHz, acetone-d6) δ 7.58-7.56 (m, 2H), 7.45-7.39 (m, 3H), 6.13
(q, J ) 1.3 Hz, 0.48H), 4.17 (q, J ) 7.2 Hz, 2H), 2.57 (s, 3H),
1.27 (t, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, acetone-d6) δ 167.9
(C), 156.9 (C), 143.8 (C), 130.9 (CH), 130.4 (CH), 128.1 (CH),
118.7 (CH), 61.2 (CH2), 18.8 (CH3), 15.6 (CH3); IR (neat) 1711,
1617 cm-1; MS 191.1 (M+); HRMS calcd for C12H13DO2 (M+)
191.1057, found 191.1043.
(E)-N-Methoxy-N-methyl-3-phenylnon-2-enamide (23). Pre-
pared from 22 (50 mg, 0.11 mmol), phenylboronic acid (132 mg,
1.1 mmol), and Cs2CO3 (287 mg, 0.81 mmol) using a procedure
similar to that described for compound 3 that provided the title
1
compound as a colorless oil (39 mg, 99%): H NMR (400 MHz,
C6D6) δ 7.35 (dd, J ) 6.6, 1.6 Hz, 2H), 7.15-7.08 (m, 3H), 6.65
(s, 1H), 3.34 (t, J ) 7.7 Hz, 2H), 3.06 (s, 3H), 2.97 (s, 3H),
1.65-1.57 (m, 2H), 1.45-1.38 (m, 2H), 1.24-1.19 (m, 4H), 0.83
(t, J ) 7.5 Hz, 3H); 13C NMR (100 MHz, C6D6) δ 167.1 (C), 158.0
(C), 143.1 (C), 128.7 (CH), 128.3 (CH), 127.1 (CH), 117.0 (CH),
60.9 (CH3), 54.8 (CH3), 31.9 (CH2), 31.4 (CH2), 29.8 (CH2), 29.5
(CH2), 23.0 (CH2), 14.2 (CH3); IR 1731, 1649 cm-1; MS 275.1
(M+); HRMS calcd for C17H25NO2 (M+) 275.1885, found 275.1891.
(E)-N-Methoxy-3-(4-methoxyphenyl)-N-methylnon-2-enam-
ide (24). Prepared from 22 (50 mg, 0.11 mmol), 4-methoxyphe-
nylboronic acid (132 mg, 1.1 mmol), and Cs2CO3 (287 mg, 0.81
mmol) using a procedure similar to that described for compound 3
that provided the title compound as a colorless oil (39 mg, 92%):
1H NMR (400 MHz, C6D6) δ 7.37 (d, J ) 8.8 Hz, 2H), 6.74 (d, J
) 8.8 Hz, 2H), 6.71 (s, 1H), 3.39 (t, J ) 7.6 Hz, 2H), 3.27 (s, 3H),
3.10 (s, 3H), 3.00 (s, 3H), 1.73-1.69 (m, 2H), 1.49-1.44 (m, 2H),
1.27-1.24 (m, 4H), 0.84 (t, J ) 7.5 Hz, 3H); 13C NMR (100 MHz,
C6D6) δ 168.0 (C), 160.6 (C), 157.6 (C), 135.1 (C), 128.3 (CH),
115.3 (CH), 114.2 (CH), 60.9 (CH3), 54.8 (CH3), 32.0 (CH2), 31.3
(CH2), 29.9 (CH2), 29.7 (CH2), 23.0 (CH2), 14.3 (CH3); IR 1731,
1649 cm-1; MS 305.2 (M+); HRMS calcd for C18H27NO3 (M+)
305.1991, found 305.1988.
(E)-Ethyl 2-Iodo-3-phenylbut-2-enoate (29). To an oven-dried,
25 mL, round-bottom flask equipped with a magnetic stirring bar
were added CuI (96 mg, 0.503 mmol), freshly distilled tetrahydro-
furan (4.0 mL), and methyllithium (1.6 M in Et2O, 0.63 mL, 1.00
mmol), and the resulting mixture was cooled to -78 °C. To this
mixture was added, via cannula, a solution of ethyl 3-phenylpro-
piolate (88 mg, 0.5 mmol) in tetrahydrofuran (1.0 mL). The resulting
mixture was stirred at -78 °C for 1 h, and then iodine (381 mg,
1.50 mmol) was introduced. The solution was stirred briefly at -78
°C and was then allowed to warm to 0 °C and was stirred at that
temperature for 2 h. The reaction mixture was then diluted with
Et2O and washed with saturated aqueous NH4Cl. The organic phase
(E)-Ethyl 3-(Pentadeuterophenyl)but-2-enoate (35). Prepared
from 1 (50 mg, 0.18 mmol) and C6D5B(OH)2 (89 mg, 0.72 mmol)
using a procedure similar to that described for compound 3 that
1
provided the title compound as a colorless oil (33 mg, 98%): H
NMR (400 MHz, acetone-d6) δ 6.14 (dd, J ) 1.4 Hz, 1H), 4.17 (q,
J ) 7.2 Hz, 2H), 2.56 (dd, J ) 1.4 Hz, 3H), 1.27 (t, J ) 7.2 Hz,
3H); 13C NMR (100 MHz, acetone-d6) δ 167.9 (C), 156.9 (C), 143.8
(C), 129.9 (CD, J ) 14.7 Hz), 127.7 (CD, J ) 14.7 Hz), 118.6
(CH), 61.2 (CH2), 18.8 (CH3), 15.6 (CH3); IR (neat) 1712, 1626
cm-1; MS 195.1 (M+); HRMS calcd for C12H9D5O2 (M+) 195.1308,
found 195.1308.
Acknowledgment. We thank the Natural Science and Engi-
neering Research Council of Canada (NSERC), the Canadian
Foundation for Innovation, the Ontario Innovation Trust, and
the University of Ottawa for generous funding. J.L.J. and M.L.H.
thank NSERC for undergraduate student research awards.
Supporting Information Available: Experimental proce-
1
dures and product characterization data for E isomers. H and
13C spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO8008325
(27) C6H5B(OD)2 was prepared by recrystallizing C6H5B(OH)2 from boiling
D2O. The boronic acid so obtained was dried under vacuum over P2O5 for 16 h
before use. NMR indicated 52% deuterium incorporation.
5906 J. Org. Chem. Vol. 73, No. 15, 2008