The synthesis of stereodefined trisubstituted olefins from olefin templates using Pd catalysis-synthesis of the antihypertensive isbogrel

Article abstract of DOI:10.1002/ejoc.201100849

A collection of highly functionalized, trisubstituted olefin building blocks (templates) have been developed for their Pd-catalyzed elaboration into more complex structures, including natural products and compounds of medicinal chemistry interest. The Pd-mediated transformations involve a combination of allylic substitution and cross-coupling reactions. The templates have been designed such that these processes proceed not only with a high degree of regio-and stereoselectivity, but the transformations can all be conducted sequentially in the same flask using the same catalyst. A strategy has been devised whereby small, highly functionalized olefin building blocks are systematically converted to a variety of products using the same catalyst.

Full text of DOI:10.1002/ejoc.201100849

FULL PAPER
DOI: 10.1002/ejoc.201100849
The Synthesis of Stereodefined Trisubstituted Olefins From Olefin Templates
Using Pd Catalysis – Synthesis of the Antihypertensive Isbogrel
Lawrence R. Rogers,[a] Zissis Konstantinou,[a] Madhav Reddy,[a] and Michael G. Organ*[a]
Keywords: Synthetic methods / Synthesis design / Stereoselective synthesis / Palladium / Cross-coupling / Allylic
substitution
A collection of highly functionalized, trisubstituted olefin
building blocks (templates) have been developed for their
tions. The templates have been designed such that these pro-
cesses proceed not only with a high degree of regio- and
Pd-catalyzed elaboration into more complex structures, in- stereoselectivity, but the transformations can all be con-
cluding natural products and compounds of medicinal chem-
istry interest. The Pd-mediated transformations involve a
combination of allylic substitution and cross-coupling reac-
ducted sequentially in the same flask using the same cata-
lyst.
Introduction
steps to get to the cross-coupling step. Further, in addition
to linear approaches being inefficient, the methods are often
example specific and not necessarily applicable across a
broader spectrum of molecular targets.
Although reasonable success has been achieved in the
stereoselective synthesis of 1,2-disubstituted olefins using
addition/elimination-based mechanisms, such as the Wit-
tig,[1] Peterson,[2] and Julia[3] olefination protocols, a general
strategy for the preparation of trisubstituted olefins has re-
mained elusive. With two substituents at one end of the
forming olefin, relative to the 1,2-disubstituted situation,
selectivity based primarily on steric differentiation is harder
to achieve in a predictable fashion. Alternatively, olefins can
be prepared using transition metal-mediated cross-coupling
strategies.[4] Here the coupling reactions are stereospecific,
that is, they proceed with retention of stereochemistry from
the precursor(s). Therefore, the stereoselectivity step has
been shifted to the preparation of the oxidative addition
and organometallic metal/metal exchange partners in-
volved. Conveniently, there are a number of highly stereo-
selective reactions to produce halogenated or metallated
olefins.
The linear synthesis of molecules containing olefin cross-
coupling moieties with the intent of coupling them closer
to the end of synthesis leads to a number of concerns. In-
stalling cross-coupling handles (i.e. halide or organometal
center) at a later stage in the synthesis can be a challenge
due to chemoselectivity concerns when incorporating such
reactive functional groups. Alternatively, if the functionality
is built in at an earlier stage, one must then be concerned
about carrying such reactive moieties through a number of
We,[5] and others,[6] have been developing a modular syn-
thetic approach to olefin targets based on metal-catalyzed
transformations for general use in synthesis. This approach
is applicable to the preparation of olefin-containing targets
as well as those derived from stereodefined olefin intermedi-
ates (e.g. cycloadditions involving olefins).[7] Here, the prod-
uct is derived from a small olefin-containing building block
(template) that is substituted with a number of functional
groups that are selectively and sequentially activated and
substituted by catalysis. Not only is the approach modular
because it can be used to make a wide variety of molecular
structures, it is highly convergent. Pieces of the target can
be constructed separately and then stitched together using
the olefin template as a lynch pin.[5,6,8] We have demon-
strated the utility of this approach in the synthesis of natu-
ral products that contain extensive polyene and enyne sub-
structures.[5b–5d] In these cases, we have focused on the use
of trans-1-chloro-2-iodoethylene to prepare disubstituted
olefin-containing products. We now wish to disclose our
strategy for the general preparation of trisubstituted olefin-
containing targets using a combination of Pd-catalyzed al-
lylic substitution and cross-coupling reactions.
With some notable exceptions,[9] allylic leaving groups
can be activated readily in the presence of vinylic oxidative
addition functionality. Thus, there should be no chemose-
lectivity issue for the first reaction of such templates. How-
ever, there is concern over the stereospecificity of allylic π-
allyl substitution chemistry (Figure 1). The π-allyl metal in-
termediate 4 is in equilibrium with the metal σ complexes
2 and 3. Bond rotation of 2 will introduce scrambling of
[a] Department of Chemistry, York University,
4700 Keele Street, Toronto, Ontario M3J 1P3, Canada
Fax: +1-416-736-5936
E-mail: organ@yorku.ca
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100849 or from
the author.
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Stereodefined Trisubstituted Olefins From Olefin Templates
the olefin geometry leading to alternative metal complexes regioselectivity in the attack of the nucleophile on the π-
6 and 7. This will result in the production of diastereomeric allyl complex. Thus, substituent A on template 1 would be
products (i.e. 5 vs. 8).
considerably larger than B (Figure 1). This means that π-
allyl complex 4 would dominate and product 5 would be
favored significantly. The second approach was to design
the template such that any isomerization would be unde-
tectable in the products, that is, to have the same functional
group at the two positions of the π-allyl complex (A = B).
In this way, 5 and 8 are the same. We have investigated both
of these strategies and they are discussed below.
Results and Discussion
Reactions with (Z)-1-Bromo-3-chloro-1-(trimethylsilyl)-1-
Figure 1. Stereochemical outcome of metal-catalyzed π-allyl substi- propene (Template 9)
tution with a trisubstituted olefin starting material.
Our initial foray into trisubstituted olefin template design
We envisioned two strategies for overcoming this con- centered on combining a vinyl organometallic moiety with
cern. The first involved the creation of a template with a a vinyl halide, in addition to the allylic leaving group. We
significant steric requirement at the substituted end of the performed several reaction sequences with template 9 and
π-allyl complex, which would minimize any concerns over the results are summarized in Table 1. Allylic substitution
Table 1. Pd-catalyzed allylic substitution/cross-coupling of template 9.
Entry
1
10
a
Coupling partner 12
Additives
Product
Yield of
Step 2[a]
Yield of independent
transformation sequence
(Step 1 ϫ Step 2)[a]
Yield of two step se-
quential catalysis[a]
1-hexyne (2.5 equiv.)
CuI (0.5%), piperidine
(3.0 equiv.)
13a
69
63
54
2
3
a
a
phenylboronic acid (2.0 equiv.) 1 m KOH (2.0 equiv.)
13b
13c
78
80
73
71
80
78
(p-methylphenyl)boronic acid
1 m KOH (2.0 equiv.)
(2.0 equiv.)
4
5
6
a
a
b
(p-methoxyphenyl)boronic acid 1 m KOH (2.0 equiv.)
(2.0 equiv.)
13d
13e
13f
99
69
54
91
63
46
99
57
54
(E)-1-hexenylboronic acid
(2.0 equiv.)
1 m KOH (2.0 equiv.)
1-hexyne (2.5 equiv.)
CuI (0.5%), piperidine
(3.0 equiv.)
7
8
b
b
phenylboronic acid (1.5 equiv.) 1 m KOH (2.0 equiv.)
13g
13h
63
63
54
54
65
63
(p-methylphenyl)boronic acid
1 m KOH (2.0 equiv.)
(1.5 equiv.)
9
b
b
(p-methoxyphenyl)boronic acid 1 m KOH (2.0 equiv.)
(1.5 equiv.)
13i
13j
81
50
70
43
99
56
10
(E)-1-hexenylboronic acid
1 m KOH (2.0 equiv.)
(1.5 equiv.)
[a] Yields were determined on pure product following purification by silica gel chromatography. Reactions were performed in duplicate
and the average yield is reported.
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L. R. Rogers, Z. Konstantinou, M. Reddy, M. G. Organ
FULL PAPER
proceeded smoothly using soft anions (e.g. malonate-type stereoselectively. Template 9 will provide a complementary
nucleophiles 10) providing 11a and 11b as single stereoiso- route that allows the cross-coupling to be performed in the
mers, thus confirming our proposal about the steric role of reverse order when necessary. The trimethylsilyl moiety pro-
the relatively large trimethylsilyl group. Intermediates 11 vides a versatile handle for a wide array of transformations
were then reacted under Sonogashira (Table 1, entries 1 and by substitution with carbon groups.
6) and Suzuki–Miyaura reaction conditions (Table 1, en-
tries 2–5 and 7–10), and all transformations proceeded well
Reactions with 1,1,3-Tribromo-2-propene (Template 16)
giving rise to a variety of diverse structures including enyne
(13a and f), styryl (13b,c, d, g, h and i), and diene (13e and
j) products.
Next we turned our attention to tribromo template 16.
The reactivity profile of the functional groups on this tem-
plate to Pd catalysis should allow allylic substitution to take
place readily and selectively in the presence of both vinyl
bromides. Next, under cross-coupling conditions, the E Br
(i.e. BrA) should activate cleanly due to steric congestion
surrounding the Z Br site (i.e. BrB). There is precedence
in the literature for reacting structurally-related compounds
with Pd catalysis.[11] Treatment of 16 with sodium dimethyl
methylmalonate nucleophile (10a) and (PPh3)4Pd provided
17 (Scheme 2). We know this procedure to be Pd catalyzed
by performing appropriate control experiments; the uncata-
lyzed substitution does take place albeit at a greatly reduced
rate.
The stereochemistry of 13 was confirmed by performing
a stereospecific Pd-catalyzed formic acid reduction of the
Br on 11a (Scheme 1). Product 14 was identical to that ob-
tained from the Pd-catalyzed allylic substitution of 15, the
stereochemistry of which was determined readily by proton
NMR spectroscopy (i.e. large trans coupling constant for
the vinyl protons). Were isomerization of the Pd-organome-
tallic intermediate occurring during the cross-coupling pro-
cedures with 11, we would have anticipated seeing similar
isomerization during the reduction, at least to some extent,
but we do not observe any cis isomer from this reduction.
Scheme 2. Pd-catalyzed allylic alkylation with 16.
Attention was then turned to the selective oxidative ad-
dition and coupling of BrA on 17 with different aryl boronic
acid derivatives, which proved to be much more involved
than initially anticipated (Table 2). There is literature prece-
dence for the activation of this bromide with analogous
Scheme 1. Confirmation of stereochemistry of allylic substitution
products 11.
We have performed several two step reaction sequences substrates,[11] and mechanistically it would make sense that
with template 9 and these results are also outlined in it activates first. Indeed, it appears as though this site does
Table 1. One of our ultimate goals with this methodology activate first, but once the population of monocoupled
is to make this a one pot sequential reaction process to product (19) in solution begins to build up, subsequent oxi-
take maximum advantage of the common catalyst for allylic dative additions are less selective. That is, oxidative addition
substitution and cross-coupling. We were pleased to find of BrA on 17 to Pd, relative to addition of BrB on initially
that the two step reaction process was both selective and coupled product 19, appear to be competitive processes.
efficient, usually surpassing the yield of the two processes Bulkier ligands on Pd, such as diphenylphosphanylpropane
performed independently. This not only minimized product or (diphenylphosphanyl)butane (dppb) led to similar selec-
handling and vastly reduced the time to obtain the product, tivity. A similar reactivity profile with aryl dihalides has
but it heightened both the modularity and convergent as- been observed[12] using the highly reactive Pd–PEPPSI–IPr
pects of using this template strategy.
catalyst.[13] In that case the catalyst was deemed to be so
Another advantage of this particular template is that, fol- highly reactive that oxidative addition into the second,
lowing allylic substitution, it allows cross-coupling to take more hindered halide of the mono cross-coupled arene, still
place at the highly hindered position syn to the alkyl group. sitting inside the solvent cage, was faster than diffusion of
Panek and coworkers reported a similar linear strategy that the catalyst away from that product. Thus, only dicoupled
produces terminal olefins substituted with a TMS group products were observed when limiting amounts of organo-
that is syn to the rest of the structure and an anti iodide metallic coupling partner were used.[12] Interestingly, in our
(geminal to the TMS group).[10] They cross-coupled the io- study this selectivity issue seems to be more of an concern
dide, then converted the TMS group to an iodide after when the nucleophile is a boronic acid (vide infra). Again,
which they coupled it to produce trisubstituted olefins we were able to confirm the structure of 19 by performing
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Stereodefined Trisubstituted Olefins From Olefin Templates
Table 2. Selectivity in Suzuki–Miyaura coupling with intermediate 17.
Entry
Ar–X (18) (equiv.)
Base (3.0 equiv.)
Temp.
17 (% recovered)[a]
19 (% yield)[a]
21 (% yield)[a]
1
2
3
4
5
6
PhB(OH)2 (18a) (1.0)
KOH
23 °C
50 °C
50 °C
50 °C
50 °C
50 °C
38
62
21
28
0
31 (a)
31 (a)
57 (b)
58 (c)
83 (c)
62 (d)
31 (a)
6 (a)
22 (b)
14 (c)
17 (c)
21 (d)
PhB(OH)2 (18a) (1.25)
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
4-F–PhB(OH)2 (18b) (1.0)
4-Ac–PhB(OH)2 (18c) (1.0)
4-Ac–PhB(OH)2 (18c) (1.25)
4-MeO-PhB(OH)2 (18d) (1.0)
17
[a] Recoveries and yields were determined on pure product following purification by silica gel chromatography.
a Pd-catalyzed formic acid reduction of the remaining Br 24 with phenylzinc bromide and Pd0 with dppb provided
(i.e. BrB) and the trans alkene was produced exclusively monocoupled 25 cleanly in very good recovery (Scheme 4).
(JH,H of vinyl protons: 16 Hz).
The structure of 25 was confirmed by 1H NMR spec-
troscopy using NOESY and ROESY 2D subroutines. It is
interesting that 24 could be cross-coupled with complete
selectivity for the E Br site under Negishi conditions,[15]
whereas selectivity did not exceed 4:1 (mono/di-coupled)
when boronoic acids were used with geminal dibromide 17
(vide supra).
With the success of the first coupling in hand, we consid-
ered Suzuki–Miyaura and Stille–Migita couplings to install
the remaining pyridyl moiety. (3-Pyridyl)boronic acid 1,3-
propanediol cyclic ester (26a) was coupled using a biphasic
system (Method A: KOH in H2O/THF), which provided
Isbogrel methyl ester (27) in 70% yield, and a homogeneous
system (Method B: TBAF in THF) that proceeded in 78%
yield. The corresponding stannyl coupling partner (26b)
was prepared from sodium trimethyltin and 3-bromopyr-
idine. Under standard conditions (Method C) the coupling
proceeded with the best recovery. Saponification of the ester
and careful monitoring of the pH of the work up solution
facilitated the extraction of Isbogrel at its isoelectric point
into ethyl acetate. The NOESY and ROESY proton NMR
spectra corresponded to the assigned stereochemistry and
the melting point obtained was the same as the literature
value,[14] thus confirming the structure of 28.
The Synthesis of Isbogrel (28)
We developed this multistep, Pd-mediated reaction se-
quence to apply to the preparation of natural products and
compounds of interest in medicinal chemistry. Isbogrel,[14]
an antihypertensive agent, was a suitable target to showcase
the use of the geminal dibromide selective coupling se-
quence. Compound 24 was generated from ε-caprolactone
(22) using the sequence outlined in Scheme 3. Treatment of
Scheme 3. Conversion of 22 into geminal dibromide 24.
Scheme 4. Cross-coupling sequence to produce 28.
Eur. J. Org. Chem. 2011, 5374–5382
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L. R. Rogers, Z. Konstantinou, M. Reddy, M. G. Organ
FULL PAPER
dry THF (2 mL), sodium hydride (19.3 mg, 60% dispersion in oil,
0.48 mmol), and dimethyl methylmalonate (64.2 mg, 58.4 μL,
0.44 mmol). Following hydrogen gas evolution, the mixture was
Conclusions
In conclusion, we have developed a general strategy for
conducting multistep reaction sequences using polyfunc- stirred for 15 min. and Pd(PPh3)4 (25.4 mg, 5 mol-%, 0.029 mmol)
was added. After the orange solution was stirred for 10 min, 9
(100 mg, 0.44 mmol) was added and the reaction followed by TLC
until it was judged complete at which time it was quenched with
saturated NH4Cl, extracted into diethyl ether (3ϫ), and the pooled
organic layers were washed with water. After drying with anhy-
drous MgSO4, the organic layer was filtered and the solvent re-
moved in vacuo. The crude product was purified by flash
chromatography (5% ether in hexanes) providing 134 mg of 11a
tionalized olefin templates as building blocks for trisubsti-
tuted olefin-containing products. The concept is to use the
smallest possible building block to serve as the focal point
in a synthesis, thus making the approach both modular and
compatible for two and three step sequences that can all be
catalysed by the same catalyst. It is interesting and puzzling
that the same catalyst would produce different selectivites
in the cross-coupling of terminal dibromides, such as 17
and 24, when the organometallic partner is changed from
(91%) as a clear oil. IR (thin film): ν = 1736 cm–1. 1H NMR
˜
(CDCl3, 300 MHz): δ = 6.11 (t, J = 6.6 Hz, 1 H), 3.68 (s, 6 H),
boron to zinc. We have looked at other dibromides that do 2.82 (d, J = 7.4 Hz, 2 H), 1.39 (s, 3 H), 0.12 (s, 9 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 172.0, 135.7, 135.4, 53.2, 52.6, 38.4,
20.2, –2.0 ppm. C12H21BrO4Si (337.29): calcd. C 42.74, H 6.28;
found C 43.13, H 6.34.
not have the ester group(s) (e.g. an alkyl-phenyl chain off
the olefin) and analogous results were obtained. Thus, the
answer does not seem to be related to any chelating effect
to the ester group(s). We are continuing to investigate the
origin of this effect.
(Z)-Ethyl 1-[3-Bromo-3-(trimethylsilyl)allyl]-2-oxocyclopentanecarb-
oxylate (11b): To a flame-dried flask equipped with a stir bar was
added dry THF (2 mL), sodium hydride (38.7 mg, 60% dispersion
in oil, 0.97 mmol), and ethyl-2-oxocyclopentane carboxylate
(137 mg, 130 μL, 0.88 mmol). After initial hydrogen gas evolution
the mixture was stirred for 15 min. after which Pd(PPh3)4 (30.5 mg,
3 mol-%, 0.026 mmol) was added. After the orange solution was
stirred for 10 min, 9 (200 mg) was added and the reaction followed
by TLC until it was judged complete. The reaction mixture was
quenched with saturated NH4Cl, extracted into diethyl ether,
washed with water, and the organic layer dried with anhydrous
MgSO4. Following filtration and solvent removal in vacuo, the
crude product was purified by flash chromatography (5% diethyl
ether in hexanes) providing 328 mg of 11b (86%) as a clear oil. IR
Experimental Section
Preparation of Olefin Template 9
(Z)-3-Bromo-3-(trimethylsilyl)-2-propen-1-ol:
A flask containing
dry ether (28 mL) and Red-Al (2 mL, 65% toluene solution,
10.1 mmol) was cooled to 0 °C and 1-hydroxy-3-(trimethylsilyl)-2-
propyne (1.0 g, 7.79 mmol) was added dropwise. The reaction mix-
ture was allowed to warm to room temp. over 2 h at before it was
cooled to 0 °C again and N-bromosuccinimide (1.8 g, 10.1 mmol)
was added. After stirring for 2 h, the reaction mixture was
quenched with saturated NH4Cl and extracted into diethyl ether
(3ϫ). The pooled organic layers were washed with water and dried
with anhydrous MgSO4. Following filtration and solvent removal
in vacuo, the product was purified by flash chromatography on
silica gel (1% diethyl ether in hexanes) providing 1.34 g (63%) of
the intermediate bromide product as a clear oil. This material was
(thin film): ν = 1753, 1728 cm–1. 1H NMR (CDCl , 300 MHz): δ =
˜
3
6.15 (t, J = 7.4 Hz, 1 H), 4.04–4.13 (m, 2 H), 1.76–2.79 (m, 8 H),
1.17 (t, J = 7.4 Hz, 3 H), 0.09 (s, 9 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 213.8, 170.8, 136.3, 135.1, 61.3, 59.3, 37.7, 35.7,
32.3, 19.5, 14.0, –2.1 ppm. HRMS calcd. for C14H23BrO3Si: [M +
H]+ 347.0600, found 347.0645.
then used as outlined below for the preparation of 9. IR (thin film):
Independent Coupling Reactions of (E)-3-[1,1-Bis(dimethoxycarb-
onyl)ethyl]-1-bromo-1-(trimethylsilyl)-1-propene (11a) with Different
Nucleophiles
1
ν = 3316 (br) cm–1. H NMR (CDCl , 300 MHz): δ = 6.46 (t, J =
˜
3
5.2 Hz, 1 H), 4.34 (d, J = 5.2 Hz, 2 H), 0.15 (s, 9 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 142.6, 133.7, 65.0, –0.6 ppm.
(E)-Dimethyl 2-Methyl-2-[3-(trimethylsilyl)non-2-en-4-ynyl]malon-
ate (13a): To a flame-dried flask was added dry THF (2 mL), 11a
(37.1 mg, 0.11 mmol), Pd(PPh3)4 (6.3 mg, 5 mol-%, 0.006 mmol),
1-hexyne (22.5 mg, 31.5 μL, 0.28 mmol, 2.5 equiv.), piperidine
(28.1 mg, 32.6 μL, 0.33 mmol, 3.0 equiv.), and CuI (0.4 mg,
0.002 mmol, 0.5 mol-%). The reaction mixture was heated to reflux
for 3 h, quenched on silica gel (ca. 1 scoopula), and the solvent
removed in vacuo. The resultant crude product/silica gel mixture
was dry-loaded atop a silica gel column and purified by flash
chromatography (2% ether in hexanes) providing 26 mg of 13a as
a clear, colorless oil (69%). Spectral data are identical to those
listed below in the two step reaction sequences.
(Z)-(1-Bromo-3-chloroprop-1-enyl)trimethylsilane (9): To a flask
containing CH2Cl2 (50 mL) at 0 °C was added dimethyl sulfide
(890 mg, 1.05 mL, 14.2 mmol) and N-chlorosuccinimide (1.92 g,
14.2 mmol). The white solution was stirred for 15 min. after which
(Z)-3-bromo-3-(trimethylsilyl)-2-propen-1-ol (2.0 g, 9.6 mmol) was
added. The reaction mixture was allowed to come to room temp.
over 4 h and it was quenched with water and extracted into
CH2Cl2. The pooled organic layers were washed with water and
dried with anhydrous Na2SO4. Following filtration and solvent re-
moval in vacuo, the crude mixture was purified by flash chromatog-
raphy on silica gel (100% hexanes) providing 1.67 g of 9 (77%) as
a clear oil. IR (thin film): ν = 1615 cm–1. 1H NMR (CDCl3,
˜
(E)-Dimethyl 2-Methyl-2-[3-phenyl-3-(trimethylsilyl)allyl]malonate
(13b): To a flame-dried flask was added dry THF (2 mL), 11a
(25 mg, 0.074 mmol), and Pd(PPh3)4 (4.3 mg, 5%, 0.004 mmol). To
this solution was added phenylboronic acid (18 mg, 0.15 mmol,
2.0 equiv.) and 2 m KOH solution (100 μL, 0.15 mmol, 2.0 equiv.).
The reaction mixture was heated to reflux for 3 h, quenched on
silica gel (ca. 1 scoopula), and the solvent removed in vacuo. The
300 MHz): δ = 6.40 (t, J = 6.6 Hz, 1 H), 4.17 (d, J = 6.6 Hz, 2 H),
0.19 (s, 9 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 136.7, 135.7,
42.8, –2.2 ppm. C6H12BrClSi (227.60): calcd. C 31.66, H 5.31;
found C 31.89, H 5.32.
Independent Trials of Palladium-Catalyzed Allylic Substitution Re-
actions on Template 9
(Z)-Dimethyl 2-[3-Bromo-3-(trimethylsilyl)allyl]-2-methylmalonate resultant crude product/silica gel mixture was dry-loaded atop a
(11a): To a flame-dried flask equipped with a stir bar was added silica gel column and purified by flash chromatography (4% ether
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Stereodefined Trisubstituted Olefins From Olefin Templates
in hexanes) providing 20 mg of 13c as a clear oil (78%). Spectral
data are identical to those listed below in the two step reaction
sequences.
removed in vacuo. The resultant crude product/silica gel mixture
was dry-loaded atop a silica gel column and purified by flash
chromatography (4% ether in hexanes) providing 21.8 mg of 13g
as a clear oil (63%). Spectral data are identical to those listed below
in the two step reaction sequences.
(E)-Dimethyl 2-Methyl-2-[3-(4-methylphenyl)-3-(trimethylsilyl)allyl-
]malonate (13c): To a flame dried flask was added dry THF (2 mL),
11a (25 mg, 0.074 mmol), and Pd(PPh3)4 (4.3 mg, 5 mol-%,
0.004 mmol). To the solution was added p-tolylboronic acid
(20.2 mg, 0.15 mmol, 2.0 equiv.) and 2 m KOH solution (100 μL,
0.15 mmol, 2.0 equiv.). The reaction mixture was heated to reflux
for 3 h, quenched on silica gel (ca. 1 scoopula), and the solvent
removed in vacuo. The resultant crude product/silica gel mixture
was dry-loaded atop a silica gel column and purified by flash
chromatography (4% ether in hexanes) providing 19 mg of 13b as
a clear oil (80%). Spectral data are identical to those listed below
in the two step reaction sequences.
(E)-Ethyl 2-Oxo-1-[3-(4-methylphenyl)-3-(trimethylsilyl)allyl]cyclo-
pentanecarboxylate (13h): To a flame-dried flask was added dry
THF (2 mL), 11b (40 mg, 0.12 mmol), and Pd(PPh3)4 (6.6 mg,
5 mol-%, 0.006 mmol). To this solution was added p-tolylboronic
acid (23.4 mg, 0.17 mmol, 1.5 equiv.) and 2 m KOH solution
(115 μL, 0.23 mmol, 2.0 equiv.). The reaction mixture was heated
to reflux for 3 h, quenched on silica gel (ca. 1 scoopula), and the
solvent removed in vacuo. The resultant crude product/silica gel
mixture was dry-loaded atop a silica gel column and purified by
flash chromatography (4% ether in hexanes) providing 26 mg of
13h as a clear oil (63%). Spectral data are identical to those listed
below in the two step reaction sequences.
(E)-Dimethyl 2-Methyl-2-[3-(4-methoxyphenyl)-3-(trimethylsilyl)all-
yl]malonate (13d): To a flame-dried flask was added dry THF
(2 mL), 11a (25 mg, 0.074 mmol), and Pd(PPh3)4 (4.3 mg, 5%,
0.004 mmol). To the solution was added (p-methoxyphenyl)boronic
acid (22.5 mg, 0.15 mmol, 2.0 equiv.) and 2 m KOH solution
(100 μL, 0.15 mmol, 2.0 equiv.). The reaction mixture was heated
to reflux for 3 h, quenched on silica gel (ca. 1 scoopula), and the
solvent removed in vacuo. The resultant crude product/silica gel
mixture was dry-loaded atop a silica gel column and purified by
flash chromatography (4% ether in hexanes) providing 27 mg of
13d as a clear oil (99%). Spectral data are identical to those listed
below in the two step reaction sequences.
(E)-Ethyl 2-Oxo-1-[3-(4-methoxyphenyl)-3-(trimethylsilyl)allyl]cy-
clopentanecarboxylate (13i): To a flame-dried flask was added dry
THF (2 mL), 11b (40 mg, 0.12 mmol), and Pd(PPh3)4 (6.6 mg,
5 mol-%, 0.006 mmol). To the solution was added (p-meth-
oxyphenyl)boronic acid (26.2 mg, 0.17 mmol, 1.5 equiv.) and 2 m
KOH solution (115 μL, 0.23 mmol, 2.0 equiv.). The reaction mix-
ture was heated to reflux for 3 h, quenched on silica gel (ca. 1
scoopula), and the solvent removed in vacuo. The resultant crude
product/silica gel mixture was dry-loaded atop a silica gel column
and purified by flash chromatography (4% diethyl ether in hexanes)
providing 35 mg of 13i as a clear oil (81%). Spectral data are iden-
tical to those listed below in the two step reaction sequences.
Dimethyl 2-Methyl-2-[(2E,4E)-3-(trimethylsilyl)nona-2,4-dienyl]mal-
onate (13e): To a flame-dried flask was added dry THF (2 mL),
11a (25 mg, 0.074 mmol), and Pd(PPh3)4 (4.3 mg, 5 mol-%,
0.004 mmol). To the solution was added (E)-1-hexenylboronic acid
(16.5 mg, 0.15 mmol, 2.0 equiv.) and 2 m KOH solution (100 μL,
0.15 mmol, 2.0 equiv.). The reaction mixture was heated to reflux
for 3 h, quenched on silica gel (ca. 1 scoopula), and the solvent
removed in vacuo. The resultant crude product/silica gel mixture
was dry-loaded atop a silica gel column and purified by flash
chromatography (4% ether in hexanes) providing 17.4 mg of 13e as
a clear oil (69%). Spectral data are identical to those listed below
in the two step reaction sequences.
Ethyl 2-Oxo-1-[(2E,4E)-3-(trimethylsilyl)nona-2,5-dienyl]cyclopent-
anecarboxylate (13j): To a flame-dried flask was added dry THF
(2 mL), 11b (40 mg, 0.12 mmol), and Pd(PPh3)4 (6.6 mg, 5 mol-%,
0.006 mmol). To the solution was added (E)-1-hexeneboronic acid
(21.4 mg, 0.17 mmol, 1.5 equiv.) and 2 m KOH solution (115 μL,
0.23 mmol, 2.0 equiv.). The reaction mixture was heated to reflux
for 3 h, quenched on silica gel (ca. 1 scoopula), and the solvent
removed in vacuo. The resultant crude product/silica gel mixture
was dry-loaded atop a silica gel column and purified by flash
chromatography (4% diethyl ether in hexanes) providing 20 mg of
13j as a clear oil (50%). Spectral data are identical to those listed
below in the two step reaction sequences.
Independent Coupling Reactions of (E)-1-Bromo-4-[1-(ethoxy-
carbonyl)-2-oxocyclopent-1-yl]-1-(trimethylsilyl)-1-propene
with Different Nucleophiles
(11b)
Tandem Reactions of Trisubstituted Olefins
General Procedure for Two Step Reaction Sequences: To a flame-
dried flask equipped with a stir bar was added dry THF (2 mL),
sodium hydride (1.0 equiv.), and dimethyl methylmalonate or ethyl-
2-oxocyclopentane carboxylate (1.0 equiv.). After initial hydrogen
gas evolution the mixture was stirred for 15 min. To this solution
was added Pd(PPh3)4 (5 mol-%) and the orange solution was stirred
for 10 min, then 9 (1.1 equiv.) was added. The reaction was fol-
lowed by TLC until complete. Once complete, the cross-coupling
partner (3.0 equiv. of hexyne or 3.0 equiv. of the corresponding
boronic acid unless indicated otherwise) and 3.0 equiv. of base
(piperidine for the Sonagashira coupling or a 2 m KOH solution
for the Suzuki–Miyaura couplings unless indicated otherwise) were
added. The resultant mixture was heated to reflux for 3 h,
quenched with saturated NH4Cl, and extracted into diethyl ether
(3ϫ). The pooled organic layers were washed with water and dried
with anhydrous MgSO4. Following filtration and solvent removal
in vacuo, the crude mixture was purified by flash chromatography
providing the desired product.
(E)-Ethyl 2-Oxo-1-[3-(trimethylsilyl)non-2-en-4-ynyl]cyclopentane-
carboxylate (13f): To a flame-dried flask was added dry THF
(2 mL), 11b (76.3 mg, 0.22 mmol), Pd(PPh3)4 (6.6 mg, 5 mol-%,
0.006 mmol), 1-hexyne (45.1 mg, 63.1 μL, 0.55 mmol, 2.5 equiv.),
piperdine (56.1 mg, 65.2 μL, 0.66 mmol), and CuI (0.4 mg,
0.002 mmol, 0.5 mol-%). The reaction mixture was heated to reflux
for 3 h, quenched on silica gel (ca. 1 scoopula), and the solvent
removed in vacuo. The resultant crude product/silica gel mixture
was dry-loaded atop a silica gel column and purified by flash
chromatography (2% ether in hexanes) providing 41 mg of 13f as
a clear, colorless oil (54%). Spectral data are identical to those
listed below in the two step reaction sequences.
(E)-Ethyl
2-Oxo-1-[3-phenyl-3-(trimethylsilyl)allyl]cyclopentane-
carboxylate (13g): To a flame-dried flask was added dry THF
(2 mL), 11b (40 mg, 0.12 mmol), and Pd(PPh3)4 (6.6 mg, 5 mol-%,
0.006 mmol). To this solution was added phenylboronic acid
(21 mg, 0.17 mmol, 1.5 equiv.) and 2 m KOH solution (115 μL,
0.23 mmol, 2.0 equiv.). The reaction mixture was heated to reflux
for 3 h, quenched on silica gel (ca. 1 scoopula), and the solvent
(Z)-Dimethyl 2-[3-Bromo-3-(trimethylsilyl)allyl]-2-methylmalonate
(13a): Following the general procedure for the two step reaction
Eur. J. Org. Chem. 2011, 5374–5382
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5379

L. R. Rogers, Z. Konstantinou, M. Reddy, M. G. Organ
FULL PAPER
sequence,
9
(50.0 mg, 0.22 mmol), sodium hydride (9.7 mg,
(19.3 mg, 0.48 mmol, 60% dispersion in oil), dimethyl methylma-
0.24 mmol, 60% dispersion in oil), dimethyl methylmalonate
lonate (64.2 mg, 58.4 μL, 0.044 mmol), Pd(PPh3)4 (25.4 mg, 5 mol-
(34.3 mg, 32.5 μL, 0.22 mmol), Pd(PPh3)4 (12.6 mg, 5 mol-%, %, 0.022 mmol), (E)-1-hexenylboronic acid (128 mg, 0.88 mmol),
0.01 mmol), 1-hexyne (45.1 mg, 63.1 μL, 0.55 mmol), piperdine
(56.1 mg, 65.2 μL, 0.066 mmol), and CuI (0.4 mg, 0.002 mmol)
gave, after flash chromatography (2% ether in hexanes), 41.6 mg of
and 2 m KOH (439 μL, 0.88 mmol) gave, after flash chromatog-
raphy (2% ether in hexanes) 84 mg of 13e as a clear, colorless oil
(57%). IR (thin film): ν = 1737 cm–1. 1H NMR (CDCl , 300 MHz):
˜
3
13a as a clear, colorless oil (54%). IR (thin film): ν = 1737 cm–1.
δ = 6.28 (d, J = 15.5 Hz, 1 H), 5.61 (dt, J = 15.4, 7.4 Hz, 1 H),
˜
1H NMR (CDCl3, 300 MHz): δ = 6.30 (t, J = 7.4 Hz, 1 H), 3.70 5.51 (t, J = 7.4 Hz, 1 H), 2.67 (s, 6 H), 2.77 (d, J = 7.4 Hz, 2 H),
(s, 6 H), 2.76 (d, J = 7.4 Hz, 2 H), 2.29 (t, J = 6.6 Hz, 2 H), 1.39– 2.09 (q, J = 6.6 Hz, 2 H), 1.32–1.38 (m, 7 H), 0.89 (t, J = 6.6 Hz,
1.23 (m, 4 H), 1.38 (s, 3 H), 0.95 (t, J = 3.7 Hz, 3 H), 0.19 (s, 9 H) 3 H), 0.09 (s, 9 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 172.4,
ppm. 13C NMR (CDCl3, 75 MHz): δ = 172.1, 145.1, 127.8, 83.1,
53.4, 52.6, 52.3, 37.7, 31.6, 31.2, 22.1, 19.3, 13.6, –0.1 ppm. HRMS
calcd. for C18H30O4Si: 338.1914, found 338. 1873. Reduced product
(Br to H, 14a) could not be separated from 13a thus the yield was
determined from the areas of the peaks in the proton NMR spec-
trum of the product.
143.0, 134.2, 133.1, 128.0, 53.7, 52.4, 34.5, 33.3, 31.8, 22.2, 20.0,
13.9, –0.6 ppm. HRMS calcd. for C12H32O4Si: 340.2071; found
340.2070.
(E)-Ethyl 2-Oxo-1-[3-(trimethylsilyl)non-2-en-4-ynyl]cyclopentane-
carboxylate (13f): Following the general procedure for the two step
reaction sequence, 9 (50.0 mg, 0.22 mmol), sodium hydride (9.7 mg,
0.24 mmol, 60% dispersion in oil), ethyl 2-oxocyclopentanecarbox-
ylate (34.3 mg, 32.5 μL, 0.22 mmol), Pd(PPh3)4 (12.6 mg, 5 mol-%,
0.01 mmol), 1-hexyne (45.1 mg, 63.1 μL, 0.55 mmol), piperdine
(56.1 mg, 65.2 μL, 0.66 mmol), and CuI (0.4 mg, 0.002 mmol) gave,
after flash chromatography (2% ether in hexanes) 41.6 mg of 13f
(E)-Dimethyl 2-Methyl-2-[3-phenyl-3-(trimethylsilyl)allyl]malonate
(13b): Following the general procedure for the two step reaction
sequence,
9 (25.0 mg, 0.11 mmol), sodium hydride (4.8 mg,
0.12 mmol), dimethyl methylmalonate (16.1 mg, 14.6 μL,
0.11 mmol), Pd(PPh3)4 (6.4 mg, 5 mol-%, 0.005 mmol), phenyl-
boronic acid (64.0 mg, 0.33 mmol), and 2 m KOH (165 μL,
0.33 mmol) gave, after flash chromatography (2% ether in hexanes),
as a clear, colorless oil (54%). IR (thin film): ν = 1762, 1727 cm–1.
˜
1H NMR (CDCl3, 300 MHz): δ = 6.27 (t, J = 8.1 Hz, 1 H), 4.15
(q, J = 7.2 Hz, 2 H), 2.85–1.35 (m, 14 H), 1.22 (t, J = 7.4 Hz, 3
H), 0.89 (t, J = 6.6 Hz, 3 H), 0.18 (s, 9 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 214.3, 170.9, 145.8, 127.8, 91.7, 61.5, 60.0, 59.8, 40.8,
35.6, 32.3, 32.1, 31.1, 14.0, 14.0, 13.9, –1.3 (one carbon signal is
overlapping) ppm. HRMS calcd. for C20H32O3Si: 348.2122; found
348.2120. Reduced product (Br to H, 14b) could not be separated
from 13f thus the yield was determined from the areas of the peaks
in the proton NMR spectrum of the product.
29.3 mg of 13b as a clear, colorless oil (80%). IR (thin film): ν =
˜
1
3076, 1734 cm–1. H NMR (CDCl3, 300 MHz): δ = 7.13–7.29 (m,
3 H), 6.84 (d, J = 7.4 Hz, 2 H), 5.79 (t, J = 6.6 Hz, 1 H), 3.66 (s,
6 H), 2.48 (d, J = 7.4 Hz, 2 H), 1.32 (S, 3 H), 0.00 (s, 9 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 172.4, 149.1, 141.7, 134.1, 128.1,
127.6, 125.5, 53.3, 52.4, 35.7, 20.1, –1.7 ppm. HRMS calcd. for
C18H26O4Si: 334.1597, found 334.1597.
(E)-Dimethyl 2-Methyl-2-[3-(4-methylphenyl)-3-(trimethylsilyl)allyl-
]malonate (13c): Following the general procedure for the two step
reaction sequence, 9 (50.0 mg, 0.22 mmol), sodium hydride (9.6 mg,
0.24 mmol, 60% dispersion in oil), dimethyl methylmalonate
(32.0 mg, 29.2 μL, 0.22 mmol), Pd(PPh3)4 (12.8 mg, 5 mol-%,
0.01 mmol), p-tolylboronic acid (44.8 mg, 0.66 mmol), and 2 m
KOH (165 μL, 0.66 mmol) gave, after flash chromatography (2%
(E)-Ethyl
carboxylate (13g): Following the general procedure for the two step
reaction sequence, (300.0 mg, 1.32 mmol), sodium hydride
2-Oxo-1-[3-phenyl-3-(trimethylsilyl)allyl]cyclopentane-
9
(58.0 mg, 1.45 mmol, 60% dispersion in oil), ethyl 2-oxocyclopen-
tanecarboxylate (206 mg, 195 μL, 1.32 mmol), Pd(PPh3)4 (76 mg,
5 mol-%, 0.068 mmol), phenylboronic acid (241 mg, 1.32 mmol),
and 2 m KOH (988 μL, 1.98 mmol) gave, after flash chromatog-
raphy (2% diethyl ether in hexanes) 253 mg of 13g as a clear, color-
ether in hexanes), 57.7 mg of 13c as a clear, colorless oil (78%). IR
1
(thin film): ν = 1737 cm–1. H NMR (CDCl , 300 MHz): δ = 7.06
˜
3
less oil (65%). IR (thin film): ν = 1759, 1739 cm–1. 1H NMR
˜
(d, J = 8.1 Hz, 2 H), 6.72 (d, J = 8.1 Hz, 2 H), 5.77 (t, J = 6.6 Hz,
1 H), 3.65 (s, 6 H), 2.48 (d, J = 6.6 Hz, 2 H), 2.39 (s, 3 H), 1.34 (s,
3 H), –0.01 (s, 9 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 172.4,
149.1, 138.6, 134.9, 134.1, 128.8, 127.4, 53.4, 52.4, 35.6, 21.1, 20.1,
–1.7 ppm. HRMS calcd. for C19H28O4Si: 348.1753, found
348.1749.
(CDCl3, 300 MHz): δ7.19 (dt, J = 7.4, 6.6 Hz, 3 H), 6.86 (d, J =
8.1 Hz, 2 H), 5.85 (t, J = 7.4 Hz, 1 H), 4.11–4.15 (m, 2 H), 0.84–
2.55 (m, 11 H), 0.01 (s, 9 H). 13C NMR (CDCl3, 75 MHz): δ =
214.3, 170.9, 149.1, 141.8, 134.8, 128.1, 127.5, 125.5, 63.3, 59.9,
37.9, 33.3, 31.6, 22.6, 19.3, 14.1, –1.7. HRMS calcd. for
C20H28O4Si: 344.1808; found 334.1807.
(E)-Dimethyl 2-Methyl-2-[3-(4-methoxyphenyl)-3-(trimethylsilyl)all-
yl]malonate (13d): Following the general procedure for the two step
reaction sequence, 9 (25.0 mg, 0.11 mmol), sodium hydride (5 mg,
0.12 mmol, 60% dispersion in oil), dimethyl methylmalonate
(16.1 mg, 14.6 μL, 0.11 mmol), Pd(PPh3)4 (6.4 mg, 5 mol-%,
0.005 mmol), (p-methoxyphenyl)boronic acid (50 mg, 0.33 mmol),
and 2 m KOH (165 μL, 0.33 mmol) gave, after flash chromatog-
raphy (5% diethyl ether in hexanes), 39.6 mg of 13d a clear oil
(E)-Ethyl 2-Oxo-1-[3-(4-methylphenyl)-3-(trimethylsilyl)allyl]cyclo-
pentanecarboxylate (13h): Following the general procedure for the
two step reaction sequence, 9 (50.0 mg, 0.22 mmol), sodium hydride
(9.7 mg, 0.24 mmol, 60% dispersion in oil), ethyloxocyclopentane
carboxylate (34.3 mg, 32.5 μL, 0.22 mmol), Pd(PPh3)4 (12.6 mg,
5 mol-%, 0.01 mmol), p-tolylboronic acid (44.8 mg, 0.34 mmol),
and 2 m KOH (219 μL, 0.43 mmol) gave, after flash chromatog-
raphy (2% ether in hexanes) 49.3 mg of 13h as a clear, colorless oil
(99%). IR (thin film): ν = 1735 cm–1. 1H NMR (CDCl , 300 MHz):
(63%). IR (thin film): ν = 1751, 1727 cm–1. 1H NMR (CDCl3,
˜
3
˜
δ = 6.80 (q, J = 8.8 Hz, 4 H), 5.78 (t, J = 7.4 Hz, 1 H), 3.78 (s, 3
H), 3.66 (s, 6 H), 2.50 (d, J = 6.6 Hz, 2 H), 1.31 (s, 3 H), 0.00 (s,
9 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 172.4, 157.6, 148.7,
134.4, 135.9, 128.6, 113.6, 55.2, 53.4, 52.4, 35.6, 29.7, 20.1, –1.7
ppm. HRMS calcd. for C19H28O5Si: 364.1702; found 364.1703.
300 MHz): δ = 7.07 (d, J = 8.1 Hz, 2 H), 6.74 (d, J = 8.1 Hz, 2 H),
5.82 (t, J = 6.6 Hz, 1 H), 4.09–4.19 (m, 2 H), 1.57–2.55 (m, 11 H),
1.22 (t, J = 7.4 Hz, 3 H), 0.00 (s, 9 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 216.1, 172.6, 150.7, 140.2, 136.5, 136.4, 130.5, 129.1,
62.9, 61.6, 39.5, 34.9, 33.9, 22.7, 20.9, 15.7, –0.08 ppm. C21H30O3Si:
C, 70.34; H, 8.34;; found C, 70.22; H, 8.48.
Dimethyl
malonate (13e): Following the general procedure for the two step
reaction sequence, (100 mg, 0.44 mmol), sodium hydride
2-Methyl-2-[(2E,4E)-3-(trimethylsilyl)nona-2,4-dienyl]-
(E)-Ethyl 2-Oxo-1-[3-(4-methoxyphenyl)-3-(trimethylsilyl)allyl]cy-
clopentanecarboxylate (13i): Following the general procedure for
9
5380
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 5374–5382

Stereodefined Trisubstituted Olefins From Olefin Templates
the two step reaction sequence, 9 (50.0 mg, 0.22 mmol), sodium
hydride (9.7 mg, 0.25 mmol, 60% dispersion in oil), ethyloxocyclo-
pentane carboxylate (34.3 mg, 132.5 μL, 0.22 mmol), Pd(PPh3)4
added to magnesium turnings (1.4 equiv., 1.4 mmol, 34 mg), and
the suspension stirred at room temp. for 1 h. The resultant Grig-
nard was transferred by cannula to a solution of anhydrous ZnCl2
(12.7 mg, 5 mol-%, 0.01 mmol), (p-methoxyphenyl)boronic acid (191 mg, 1.4 equiv., 1.4 mmol) in THF (2 mL) [the anhydrous
(100 mg, 0.66 mmol), and 2 m KOH (329 μL, 0.66 mmol) gave after
flash chromatography (5% diethyl ether in hexanes) 81.3 mg of 13i
ZnCl2 was prepared by heating the powder at 140 °C for 4 h under
high vacuum (0.2 Torr)]. The resulting solution was stirred for 1.5 h
as a clear oil (99%). IR (thin film): ν = 1751, 1725 cm–1. 1H NMR at room temp. during which time a white precipitate (MgX2)
˜
(CDCl3, 300 MHz): δ = 6.75–6.83 (m, 4 H), 5.83 (t, J = 6.6 Hz, 1
formed, indicating that metal–metal exchange had taken place. A
H), 4.11–4.16 (m, 2 H), 3.77 (s, 3 H), 1.61–2.56 (m, 8 H), 1.23 (t, solution of 24 (1.0 equiv., 1.0 mmol, 300 mg) and PdCl2dppb
J = 5.2 Hz, 3 H), 0.00 (s, 9 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 214.4, 170.9, 157.6, 148.7, 135.1, 133.9, 128.6, 113.6, 61.5, 60.0,
55.2, 37.9, 33.2, 32.3, 19.3, 14.1, –1.7 ppm. HRMS calcd. for
C21H30O4Si: 374.5426, found 374.5467.
(0.1 equiv., 0.1 mmol, 60 mg) in THF (5 mL) was transferred by
cannula to the phenylzinc halide mixture at 0 °C. The ice bath was
removed and the reaction mixture was stirred for 5 h after which
distilled water (10 mL) was added. The layers were separated and
the aqueous layer was extracted into Et2O (3ϫ20 mL). The com-
bined organic extracts were dried with anhydrous MgSO4, filtered,
and the solvent was removed in vacuo. The crude product was puri-
fied by flash chromatography (5% Et2O in pentane eluent) provid-
Ethyl 2-Oxo-1-[(2E,4E)-3-(trimethylsilyl)nona-2,5-dienyl]cyclopent-
anecarboxylate (13j): Following the general procedure for the two
step reaction sequence, 9 (50 mg, 0.22 mmol), sodium hydride
(9.7 mg, 0.24 mmol, 60% dispersion in oil), ethyloxocyclopentane
carboxylate (34.3 mg, 32.5 μL, 0.22 mmol), Pd(PPh3)4 (12.6 mg,
5 mol-%, 0.01 mmol), (E)-1-hexenylboronic acid (48.1 mg,
0.34 mmol), and 2 m KOH (219 μL, 0.44 mmol) gave, after flash
ing 250 mg (85% yield) of 25 as a yellow oil. IR (neat): ν = 1732
˜
1
cm–1. H NMR (CDCl3, 400 MHz): δ = 7.51 (d, J = 9.2 Hz, 2 H),
7.31 (m, 3 H), 6.19 (t, J = 7.0 Hz, 1 H), 3.68 (s, 3 H), 2.38 (m, 4 H),
1.73 (m, 2 H), 1.55 (m, 2 H) ppm. 13C NMR (CDCl3, 100 MHz): δ
= 174.0, 140.0, 131.1, 128.3, 128.2, 127.5, 125.8, 51.5, 33.9, 32.1,
27.9, 24.5 ppm. C14H17BrO2 (297.19): calcd. C 56.58, H 5.77, Br
26.89; found C 56.73, H 5.86, Br 27.01.
chromatography (2% ether in hexanes) 44.8 mg of 13j as a clear,
1
colorless oil (56%). IR (thin film): ν = 1753, 1726 cm–1. H NMR
˜
(CDCl3, 300 MHz): δ = 6.26 (d, J = 15.4 Hz, 1 H), 5.56 (dt, J =
15.4, 6.6 Hz, 1 H), 4.09–4.17 (m, 2 H), 1.26–2.87 (dd, J = 14.7,
7.4 Hz, 1 H), 2.55–1.80 (m, 10 H), 1.35 (m, 2 H), 1.22 (t, J =
6.6 Hz, 3 H), 0.87 (t, J = 7.4 Hz, 3 H), 0.00 (s, 9 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 214.6, 170.9, 142.9, 134.2, 133.8, 128.0, 61.4,
60.2, 38.3, 33.3, 32.4, 32.2, 31.7, 22.2, 19.6, 14.1, 13.9, –0.6 ppm.
C20H32O3Si (348.56): calcd. C 68.53, H 9.77; found C 68.83, H
9.85.
(Z)-Methyl 7-Phenyl-7-(pyridin-3-yl)hept-6-enoate (27). Procedure
A: To a solution of 25 (1.0 equiv., 150 mg, 0.505 mmol) in THF
(2.5 mL) was added (3-pyridyl)boronic acid 1,3-propanediol cyclic
ester (26a, 1.3 equiv., 97.8 mg, 0.657 mmol), Pd(PPh3)4 (0.1 equiv.,
58.4 mg, 0.051 mmol), and 1.0 m aqueous KOH solution (1.32 mL,
2.6 equiv., 1.32 mmol). The resulting solution was heated to reflux
for 16 h, cooled to room temp., diluted with water (10 mL), and
the layers separated. The aqueous layer was extracted into ethyl
acetate (3ϫ30 mL), the organic layers combined, dried with anhy-
drous MgSO4, filtered, and concentrated in vacuo. The crude prod-
uct was purified by flash chromatography (12% EtOAc in pent-
anes) providing 105 mg (70%) of 27 as a yellow oil.
Methyl 6-Oxohexanoate (23): ε-Caprolactone (22, 1.0 equiv.,
100 mmol, 11.41 g) was dissolved in MeOH (300 mL) and conc.
H2SO4 (5 mL) was added. The resulting mixture was heated to re-
flux for 16 h, after which it was cooled to room temp. and the
volume concentrated to approximately 20 mL. Distilled water
(100 mL) was added and the pH was adjusted to 7. The aqueous
layer was then extracted into Et2O (3ϫ), and the combined organic
layers dried with anhydrous MgSO4, filtered, and concentrated in
vacuo. The resulting crude methyl 6-hydroxyhexanoate was taken
up in CH2Cl2 (300 mL) and sodium acetate (2.6 g, 0.32 equiv.,
32 mmol) and PCC (32.7 g, 1.5 equiv., 150 mmol) were added. Af-
ter stirring at room temp. for 1.5 h, pentane (1.2 L) was added, the
mixture was filtered through Florisil, and the solvent was removed
in vacuo. The crude mixture was distilled (80 °C at 0.2 Torr) to
yield 11.5 g (80% yield) of 23. The physical and spectroscopic data
were in accordance with the literature.[16]
Procedure B: To a solution of 25 (1.0 equiv., 150 mg, 0.505 mmol)
in THF (2.5 mL) was added (3-pyridyl)boronic acid 1,3-propane-
diol cyclic ester (26a, 1.2 equiv., 90.2 mg, 0.606 mmol), Pd(PPh3)4
(0.1 equiv., 58.35 mg, 0.051 mmol), and 1.0 m solution of TBAF in
THF (760 μL, 1.5 equiv., 0.76 mmol). The reaction was heated at
50 °C for 15 h, cooled to room temp., and distilled water (10 mL)
added. The layers were separated and the aqueous layer extracted
into EtOAc (3ϫ30 mL). The organic layers were combined, dried
with anhydrous MgSO4, filtered, and concentrated in vacuo. The
crude product was purified by flash chromatography (10% EtOAc
in pentanes) providing 117 mg (78%) of 27 as a yellow oil.
Methyl 7,7-Dibromohept-6-enoate (24): To a solution of carbon tet-
rabromide (23.0 g, 2.0 equiv., 69.35 mmol) in CH2Cl2 (175 mL) was
added triphenylphosphane (36.4 g, 4.0 equiv., 138.75 mmol) at
room temp. The mixture was stirred for 30 min, cooled to 0 °C, 23
(5.0 g, 1.0 equiv., 34.7 mmol) added, and the resulting solution was
stirred for 5 min. After the addition of pentane (800 mL), the mix-
ture was stirred for 30 min. and then filtered. The filtrate was con-
centrated in vacuo and the crude product was purified by flash
chromatography on silica gel (2% Et2O in pentane) providing 9.9 g
Procedure C: To a solution of 3-(trimethylstannyl)pyridine (26b,
1.5 equiv., 183 mg, 0.757 mmol) and lithium chloride (3.0 equiv.,
96.5 mg, 2.27 mmol) in dioxane (2.5 mL) was added by cannula
a solution of 25 (1.0 equiv., 150 mg, 0.505 mmol) and Pd(PPh3)4
(0.1 equiv., 58.4 mg, 0.051 mmol) in dioxane (1.5 mL). The reaction
was heated to reflux for 16 h and then cooled to room temp., The
mixture was washed with 2.0 m KF aqueous solution (10 mL) and
the resultant aqueous layer extracted into ethyl acetate (3ϫ30 mL).
The combined organic layers were combined, dried with anhydrous
MgSO4, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography (10% EtOAc in pentanes)
(95%) of 24 as a clear oil. IR (neat): ν = 1733 cm–1. 1H NMR
˜
(CDCl3, 400 MHz): δ = 6.38 (t, J = 7.3 Hz, 1 H), 3.66 (s, 3 H),
2.33 (t, J = 7.4 Hz, 2 H), 2.12 (m, 2 H), 1.65 (m, 2 H), 1.46 (m, 2
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 173.8, 138.1, 89.1, 51.5,
33.7, 32.6, 27.2, 24.3 ppm. C8H12Br2O2 (299.99): calcd. C 32.03, H
4.03, Br 53.27; found C 32.15, H 4.07, Br 53.40.
providing 132 mg (88%) of 27 as a yellow oil. IR (neat): ν = 1732
˜
cm–1. 1H NMR (CDCl3, 400 MHz): δ = 8.59 (s, 1 H), 8.49 (s, 1 H),
7.51 (d, J = 9.5 Hz, 1 H), 7.31 (m, 4 H), 7.20 (d, J = 7.5 Hz, 2 H),
6.18 (t, J = 6.9 Hz, 1 H), 3.68 (s, 3 H), 2.29 (t, J = 7.7 Hz, 2 H),
Methyl (Z)-7-Bromo-7-phenylhept-6-enoate (25): A solution of bro-
mobenzene (1.10 equiv., 1.1 mmol, 116 μL) in THF (1 mL) was
Eur. J. Org. Chem. 2011, 5374–5382
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5381

L. R. Rogers, Z. Konstantinou, M. Reddy, M. G. Organ
FULL PAPER
2.14 (m, 2 H), 1.65 (m, 2 H), 1.50 (m, 2 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 177.6, 149.3, 146.9, 141.6, 138.5, 138.0, 136.4, 131.8,
129.6, 128.3, 127.3, 127.1, 123.7, 55.5, 34.0, 29.4, 29.1, 24.4 ppm.
C19H21NO2 (295.38): calcd. C 77.26, H 7.17, N 4.74; found C
77.28, H 7.21, N 4.83.
[5] a) M. G. Organ, J. T. Cooper, L. R. Rogers, F. Soleymanzadeh,
T. Paul, J. Org. Chem. 2000, 65, 7959–7970; b) H. Ghasemi,
L. M. Antunes, M. G. Organ, Org. Lett. 2004, 6, 913–2916; c)
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d) M. G. Organ, L. M. Antunes, Tetrahedron Lett. 2003, 44,
6805–6808.
[6] a) V. Ratovelomanana, D. Guillerm, G. Limstrumelle, Tetrahe-
dron Lett. 1984, 25, 6001–6004; b) P. Magnus, R. T. Lewis, J. C.
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[7] For examples of the use of olefin templates to prepare olefin
intermediates that were used in, for example, epoxidation reac-
tions, see: a) M. G. Organ, S. W. Kaldor, C. Dixon, D. J. Parks,
U. Singh, D. J. Lavorato, P. K. Isbester, M. G. Siegel, Tetrahe-
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(Z)-7-Phenyl-7-(pyridin-3-yl)hept-6-enoic Acid (Isbogrel, 28): To a
solution of 27 (1.0 equiv., 220 mg, 7.43 mmol) in EtOH (4 mL) was
added aqueous KOH solution (4 mL, 1 m). The mixture was heated
to reflux for 2.5 h and cooled to room temp. Concentrated aqueous
HCl was then added dropwise until the pH of the solution was
lowered to 4.5. The mixture was extracted into EtOAc (3ϫ50 mL)
and the organic layers were combined, dried with anhydrous
MgSO4, filtered, and concentrated in vacuo. Isbogrel (28) was iso-
lated as a grayish-white solid (162 mg, 87%) by decanting; m.p. 94–
95 °C (ref.[14] 93–94 °C). IR (neat): ν = 3368 (br), 1682 cm–1. 1H
˜
NMR (CDCl3, 400 MHz): δ = 12.16 (br. s, 1 H), 8.62 (s, 1 H) 8.49
(s, 1 H), 7.58 (d, J = 7.8 Hz, 1 H), 7.41 (d, J = 5.0 Hz, 1 H), 7.28
(m, 3 H), 7.21 (m, 2 H), 6.20 (t, J = 7.7 Hz, 1 H), 2.33 (t, J =
7.4 Hz, 2 H), 2.14 (m, 2 H), 1.66 (m, 2 H), 1.55 (m, 2 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 177.6, 149.3, 146.9, 141.6, 138.5,
138.0, 136.4, 131.8, 129.6, 128.3, 127.3, 127.1, 123.7, 34.0, 29.4,
29.1, 24.4 ppm. C18H19NO2 (281.35): calcd. C 76.84, H 6.81, N
4.98; found C 76.88, H 6.89, N 5.06.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for the compounds reported.
[11] For activation of the E-configured bromide of terminal vinyl
dibromide substrates, see: a) W. R. Roush, B. B. Brown, S. E.
Drozda, Tetrahedron Lett. 1988, 29, 3541–3544; b) G. Chelucci,
F. Capitta, S. Baldino, Tetrahedron 2008, 64, 10250–10257; c)
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Acknowledgments
We thank the Natural Sciences and Engineering Research Council
of Canada (NSERC) and the Ontario Research and Development
Challenge Fund (ORDCF) for funding.
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C. Valente, Synthesis 2008, 2776–2797; b) M. Abdel-Hadi, S.
Avola, I. Dubovyk, N. Hadei, E. A. B. Kantchev, C. J. O’Brien,
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Received: June 12, 2011
Published Online: August 5, 2011
5382
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 5374–5382