Palladium-catalyzed modular assembly of electron-rich alkenes, dienes, trienes, and enynes from (E)-1,2-dichlorovinyl phenyl ether

Article abstract of DOI:10.1021/jo1014678

We have devised a modular construction of electron-rich alkene derivatives from trichloroethylene (TCE). The three C-l bonds of TCE have sufficiently different reactivities that they can be sequentially and selectively functionalized. Following the substitution of one chlorine by phenol to generate (E)-1,2-dichlorovinyl ether, the C¹-Cl group next participates in palladium-catalyzed cross-coupling reactions with a variety of organometallic reagents. Subsequently, the C²-Cl group can engage in cross-couplings, while the C²-H may be deprotonated and quenched with an electrophile. Thus, isomerically pure tri- and tetrasubstituted electron-rich alkenes may be accessed in as few as two steps from simple and inexpensive starting materials. This method is ideally suited for diversity-oriented synthesis of highly conjugated molecules of interest as chromophores or as potential molecular electronics. It also gives access to diverse building blocks for further synthetic elaboration into high-value compounds.

Full text of DOI:10.1021/jo1014678

pubs.acs.org/joc
Palladium-Catalyzed Modular Assembly of Electron-Rich Alkenes,
Dienes, Trienes, and Enynes from (E)-1,2-Dichlorovinyl Phenyl Ether
Laina M. Geary and Philip G. Hultin*
Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2
hultin@cc.umanitoba.ca
Received July 26, 2010
We have devised a modular construction of electron-rich alkene derivatives from trichloroethylene
(TCE). The three C-Cl bonds of TCE have sufficiently different reactivities that they can be
sequentially and selectively functionalized. Following the substitution of one chlorine by phenol to
generate (E)-1,2-dichlorovinyl ether, the C1-Cl group next participates in palladium-catalyzed cross-
coupling reactions with a variety of organometallic reagents. Subsequently, the C2-Cl group can
engage in cross-couplings, while the C2-H may be deprotonated and quenched with an electrophile.
Thus, isomerically pure tri- and tetrasubstituted electron-rich alkenes may be accessed in as few as
two steps from simple and inexpensive starting materials. This method is ideally suited for diversity-
oriented synthesis of highly conjugated molecules of interest as chromophores or as potential
molecular electronics. It also gives access to diverse building blocks for further synthetic elaboration
into high-value compounds.
Introduction
metal-catalyzed synthesis of such electron-rich alkenes, in
contrast to the plethora of methods for assembling fully
carbon-substituted alkenes.2a,b Even so, this topic has begun
to receive more attention in the recent literature.5
Organ has pointed out that while most chemists think of
alkene synthesis in terms of forming the CdC bond, a
potentially better approach would be to build outward from
a suitable functionalized alkene unit.6 Based on this idea,
Organ et al. developed one-pot methods for selective and
Tri- and tetrasubstituted alkenes are ubiquitous structures
in organic chemistry, being found in biologically active
compounds such as the anticancer drug (Z)-tamoxifen.1 A
significant amount of research has gone into developing
syntheses of tri- and tetrasubstituted alkenes.2 Alkenes3
and dienes4 bearing electron-donating groups (e.g., enol
ethers) have many uses in organic synthesis, and one would
expect that methods for their efficient preparation would be
common. However, there have been few reports on the
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Published on Web 09/02/2010
DOI: 10.1021/jo1014678
r
2010 American Chemical Society

Geary and Hultin
JOCFeatured Article
SCHEME 1. Uses of Dichlorovinyl Ethers Derived from Trichloroethylene and Alcohols
sequential C-C bond formation reactions of 2,3-dibromo- or
2,3-dichloropropene or (E)-2-chloro-1-iodoethylene and have
explored the use of these “olefin templates” in target-oriented
syntheses.6,7 Others have likewise exploited the olefin tem-
plate concept. Yoshida et al. devised a small library of
tamoxifen analogues8 employing a vinyl pyridylsilane tem-
plate.9 Nishihara and co-workers obtained tri- and tetra-
substituted alkenes from alkynyl pinacolatoboronates via
highly substrate-dependent when the alkyne substrate was
unsymmetrical.
Trichloroethylene is a very inexpensive two-carbon
starting material.16 Much of the interest in its chemistry
derives from the ease with which it may be converted to
dichloroacetylene.17 Alcohols will add across dichloroacety-
lene, but the resultant (E)-dichlorovinyl ethers are generally
treated in situ with excess n-butyllithium and quenched to
give acetylenic ethers (Scheme 1, eq 1).18 The alkynes in
turn may be reduced or otherwise functionalized to give either
(E)- or (Z)-enol ethers.4hh,19 These methods, while both
general and useful, “waste” the stereo- and regiochemical
information inherent in the initial (E)-dichlorovinyl ethers.
A recent report noted that TCE underwent base-promoted
elimination/addition in the presence of iodide, affording
1-iodo-1,2-dichloroethylene, which then underwent palla-
dium-catalyzed methoxycarbonylation of the C-I group.20
We reasoned that the three C-Cl bonds of TCE might
zirconation and sequential cross-coupling reactions.10
A
series of papers by Ogilvie and co-workers has described the
stepwise elaboration of R,β-dihalo-R,β-unsaturated esters
leading to either tri- or tetrasubstituted alkenes.11
Many routes to electron-rich alkenes involve metal-pro-
moted addition across an alkyne. Jiang et al. prepared 2-halo
enol acetates via the silver-catalyzed reaction of ter-
minal acetylenes with N-halosuccinimides in the presence of
acetic anhydride.12 1,2-Disubstituted arylvinyl ethers13 and
sulfides14 have been synthesized via the gold-catalyzed addi-
tion of phenol- or copper-catalyzed addition of thiophenol
across an internal alkyne. Kato, Akita, and co-workers
recently published the palladium-catalyzed carbonylative
reaction of alkynes with methanol to give a variety of
“push-pull alkenes” (β-alkoxy-substituted R,β-unsaturated
esters).15 These processes were generally high yielding and
required as little as one step from commercially available
materials. However, the reported regioselectivity was often
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SCHEME 2. Ligand Screen for C1-Selective Cross-Coupling Reactions
Conditions: 0.2 M solution of 1 in THF, 65 °C, 1.05 equiv of boronic acid, 3.0 molar equiv of Cs2CO3, 2.5 mol % of Pd2dba3, 7.5 mol % of 4-6, or
5 mol % of 7-14, 4 h. The data for each experiment are normalized to 1.
actually be sufficiently different that they could be sequen-
tially addressed by appropriately chosen chemistry and that
the vinylic C-H could likewise be a handle for controlled
synthetic elaboration. We found that benzofurans may be
obtained by one-pot Suzuki coupling/direct arylation of di-
chlorovinyl ethers with organoboron compounds (Scheme 1,
eq 2).21 We now describe the simple, general, and modular
assembly of both tri- and tetrasubstituted alkenes via an
operationally simple combination of palladium-catalyzed cross-
coupling reactions and vinyllithium chemistry (Scheme 1, eq 3).
Our results demonstrate that trichloroethylene is an inexpensive
and versatile tetrafunctionalizable two-carbon linchpin for the
direct, rapid, and stereocontrolled synthesis of high-value pro-
ducts or molecular platforms for numerous6,22 synthetic trans-
formations.
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2916.
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TABLE 1. Regioselective Arylation and Vinylation at C1 of Dichloro-
vinyl Ether 1
Results and Discussion
Dichlorovinyl ethers derived from aliphatic alcohols have
been reported to be somewhat labile, even under the basic
conditions required for cross-couplings,23 so we decided to
develop this chemistry using phenol-based vinyl ethers. We21
and others24 have previously reported the reactions of var-
ious phenols with TCE to obtain the corresponding aryl 1,2-
dichlorovinyl ethers.
Selective C1-Cl Cross Coupling. The selective functiona-
lization of 1,1-dichloroalkenes25 has been looked at by
Minato and Tamao26 and, more recently, by both Negishi27
and Roulland.28 The regioselective functionalization of 1,2-
dihaloalkenes has been less explored,25 likely because they
are more challenging to prepare. Most examples of regiose-
lective cross-coupling reactions of 1,2-dihaloalkenes involve
R,β-unsaturated esters25,29 with only a few exceptions.30
To find conditions for C1 site-selective Suzuki-Miyaura
cross-coupling of a dichlorovinyl ether, we exposed dichloro-
vinyl phenol ether 131 and p-methoxyphenyl boronic acid to
Pd2dba3 and Cs2CO3 in hot THF in the presence of one of
several ligands (Scheme 2). Electron-rich monophosphines
P-t-Bu3 (4) and PCy3 (5) as well as monodentate biarylpho-
sphines JohnPhos (7) and S-Phos (8) led to unselective cross-
coupling; while monoarylated material 2 was produced,
substantial amounts of diarylated 6 also formed even before
complete consumption of 1. Additionally, the reactions
involving either P-t-Bu3 HBF4 (4)32 or JohnPhos (7) pro-
3
duced a second monoarylated product. Analysis of the
product mixture by GC/MS suggested that this was an
isomer of compound 2, likely resulting from competing C2
arylation and tentatively assigned the structure 20. The
catalyst incorporating monodentate ligand PhDavePhos
(6) was much more selective, leading only to product 2, but
it was rather inefficient giving only 42% conversion after 4 h.
The catalysts derived from either DPEphos (13) or Xant-
phos (14) were both extremely selective and were also the
most active, giving about 96% conversion from 1 to mono-
arylated 2 after 4 h of reaction time. Curiously, the catalyst
derived from tert-butyl-Xantphos (12) was the least active,
showing only 11% conversion. Of the remaining bidentate
ligands, DPPB (10) and DPPF (11) both afforded reasonably
competent catalysts (∼87% conversion), while the catalyst
incorporating DPPE (9) only led to ∼51% conversion.
The initial studies shown in Scheme 2 employed 3 molar
equiv of Cs2CO3 as a base, but other experiments showed
that 3 equiv of CsF were also moderately effective in many
instances. We discovered that using a mixture of Cs2CO3 and
CsF (3 equiv each) provided the most consistent results, and
we therefore employed this base couple in our remaining
studies without further optimization. While reactions em-
ploying either Xantphos or DPEphos ligands in THF (65 °C)
generally required 5.5 h to reach completion, reactions in
dioxane (100 °C) were complete in about 1 h, and so dioxane
became our solvent of choice.
Having established workable reaction conditions, we set
out to synthesize a number of C1-functionalized vinyl ethers.
As seen in Table 1, C1-aryl vinyl ethers 2 and 15-18 were
easily obtained using the Pd2dba3/DPEphos system. This
regioselectivity is consistent with the expectation that C1
would be relatively electron-poor, leading to preferential
oxidative insertion of Pd at this site. Further, other observa-
tions in aryl and heteroaryl systems show a related pref-
erence for oxidative insertion adjacent to a heteroatom.33
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S.; Taniyasu, R.; Takahashi, T.; Miyake, T.; Okano, M. Bull. Chem. Soc. Jpn.
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(31) The preparation of 1 is described in the Experimental Section.
(32) Similar unselectivity was noted in reactions using only CsF or KF,
and the overall conversion was lower with KF.
(33) (a) Schweizer, S. A.; Bach, T. Synlett 2010, 81–84. (b) Abid, O.-u.-R.;
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TABLE 2. Regioselective C1 Heteroarylation of Dichlorovinyl Ether 1
TABLE 3. Regioselective C1 Sonogashira Coupling Reactions of 1
SCHEME 3. C1-Selective Alkylations of 1
Curiously, the only other report we have found in which a
1,2-dichlorovinyl ether was the electrophile in a palladium-
catalyzed cross-coupling stated that a Sonogashira coupling
occurred at C2.23
Most of the heteroarylboronic acids we tested were com-
pletely unreactive toward the Pd/DPEphos catalytic system.
However, Pd(PPh3)4 in boiling THF and aqueous KOH6
promoted the cross-coupling of these stubborn boronic acids,
permitting us to prepare vinyl heteroaromatics 19-25 in
modest to good yields (Table 2). This catalytic system also
proved to be very effective for the C1-selective Suzuki-
Miyaura couplings shown in Table 1. The yields of these
reactions were similar to those obtained using Pd2dba3/DPE-
phos but proceeded much faster, requiring only 1 h or less.
C1-selective Sonogashira alkynylations were equally suc-
cessful (Table 3), using an adaptation of the procedure of
Tiano and Belmont34 for the alkynylation of 2-halobenzo-
furans and indoles. These conditions afforded compounds
26-30 in good yields from 1, although hydroxyl-substituted
products 28 and 29 slowly decomposed at room temperature.
We have only examined a few couplings of aliphatic organo-
metallic donors. Not surprisingly, attempts to cross-couple
cHex-B(OH)2 with 1 were unsuccessful.35 On the other hand,
31 was readily obtained using Roulland’s trialkylborane
procedure (Scheme 3, eq 1).28 Negishi cross-coupling with
diethylzinc27 likewise afforded C1 ethyl vinyl ether 32 in
excellent yield (Scheme 3, eq 2).
Cross-Couplings at C2: Synthesis of Trisubstituted Alkenes.
Elaboration of the remaining C2-Cl group was the next goal
we addressed. Treating compound 2 with 1.5 equiv of p-
fluorophenylboronic acid in the presence of Pd2dba3/DPE-
phos formed the expected diarylated vinyl ether 33, which was
isolated in 56% yield (Scheme 4). However, 2-(4-methoxy-
phenyl)benzofuran 34, formed via intramolecular C-H acti-
vation, was also isolated in 8% yield based on conversion
from 2. The development of this observation into a general
method for benzofuran synthesis has been described else-
where.21 In the context of the present investigation, competi-
tion from intramolecular arylation was problematic.
(34) Tiano, M.; Belmont, P. J. Org. Chem. 2008, 73, 4101–4109.
(35) Doucet, H. Eur. J. Org. Chem. 2008, 2013–2030.
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JOCFeatured Article
SCHEME 4. Pd/DPEphos-Promoted Cross-Coupling between Arylvinyl Chloride 2 and a Boronic Acid
TABLE 4. Synthesis of a Vinyl Ether and 1-Phenoxy-1,3-butadienes
from (Z)-2-Chloro-1-arylvinyl Ethers
TABLE 5. Synthesis of 2-Phenoxy-1,3-butadienes, Hexatrienes, and a
Dienyne from (Z)-1-Chloro-2-aryloxy-1,3-butadiene
aThe mass balance was recovered unreacted starting material (79%).
Our C1 arylation ligand screen (Scheme 2) had indicated
that the use of S-Phos (8) as a ligand in THF solution gave the
most diarylated product with no evidence of intramolecular
arylation, suggesting that these conditions might be appro-
priate for cross-coupling at C2. We therefore treated 15 with
threedifferentvinylboronic acidsin the presence of Pd(OAc)2/
S-Phos in hot toluene.27 Electron-rich dienes 35 and 36 were
obtained in this way in very good yields (Table 4), but the
cross-coupling with p-fluorostyrylboronic acid to form diene
37 remained problematic.
a65% unreacted starting material recovered as well.
phenylethynyl trifluoroborate, albeit in lower yield (entry 5).
In all cases, no other isomers or the corresponding benzofuran
could be detected, suggesting that for C1 alkenyl derivatives,
intermolecular Suzuki coupling is much faster than competing
intramolecular arylation at this concentration.37
In contrast to the reactions of the C1-arylated compounds
shown in Table 4, Suzuki cross-coupling at C2 of the C1
alkenyl derivative 18 under Pd/DPEphos catalysis proceeded
smoothly (Table 5). Good yields were obtained for C2-
arylated dienes 38 and 39 (entries 1 and 2). We also obtained
electron-rich trienes 40 and 41 in good yields (entries 3 and 4);
notably, the reaction tolerated the presence of an aryl
chloride (41, entry 4), leaving a useful handle for further
functionalization.36 Additionally, while we have been unable
to C2-alkynylate via standard Sonogashira chemistry (in con-
trast to the ready formation of C1-alkynyl derivatives 26-30,
and the single example reported previously by Schmidt
et al.23), dienyne 42 could be generated from 18 and potassium
Despite the difficulties of C2 alkynylation, reactions of
electron-rich enynes 26 and 30 with a variety of aryl-, hetero-
aryl-, and alkenylboronic acids proved facile (Table 6). We
observed that 30 was more labile under cross-coupling con-
ditions than was the phenylacetylene compound 26. How-
ever, 30 underwent cross-coupling in modest yields to give
enynes 43-45 (entries 1-3). Notably, 2-thiopheneboronic
(37) Normally, the direct arylation to benzofurans is done at a concen-
tration of 0.4 M in dioxane, and we have observed that this process is slowed
at lower concentrations.
(36) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176–4211.
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TABLE 6. Enynes and Dienynes from 1-Alkynyl Vinyl Ethers
formation of the 2-substituted thiophene 46 was accompanied
by production of 2-(phenylethynyl)benzofuran in 17% yield.
This may reflect the known lower reactivity of many hetero-
aryl-2-boronic acids, permitting the intramolecular direct
arylation to compete with the desired intermolecular Suzuki-
Miyaura coupling. As demonstrated in Table 6, alkenyl
boronic acids may be used as substrates, and substituted
dienynes 48-50 were generated in good yield (entries 6-8);
again, the tolerance for an aryl chloride group in this reaction
is noteworthy (50, entry 8).
The cross-coupling of 3-phenylpropenylboronic acid with
26 led to an interesting “downstream” reaction (Scheme 5),
affording biphenyl 52 as the sole identifiable product. We
assume this reaction forms the adduct 51, which then under-
goes an isomerization/electrocyclization to 52, although the
mechanistic details are not clear. This process may prove
useful for a modular and simple synthesis of highly substi-
tuted biaryl ethers, as an alternative to Buchwald-Hartwig
coupling.
Cross-couplings at C2 of C1-alkyl compounds were much
less facile than were the reactions shown in Tables 5 and 6.
The Pd/DPEphos catalyst in dioxane proved ineffective
in any attempted coupling of 31, but we were gratified to
find that 31 was smoothly converted to 53 in toluene using
the Pd(OAc)2/S-Phos catalyst (Table 7, entry 1). We were
initially surprised to find that cross-coupling of 31 with
potassium phenylethynyl trifluoroborate under these condi-
tions afforded 2-alkylbenzofuran 55 as the major product
(46%), and the desired enyne 54 was obtained in only 24%
yield (entry 3). The recent results of Lloyd-Jones,38 however,
show that slow cross-coupling should be expected under
conditions such as these, where only adventitious water is
available to hydrolyze the potassium alkyltrifluoroborate.
The Negishi coupling of 31 with diethyl zinc under the same
catalytic conditions (entry 4) proceeded sluggishly, affording
only 35% conversion after 23 h. The dialkylvinyl ether 56
was isolated in 33% yield.
Finally, we set out to see if the cross-couplings could be
done in one pot, increasing the efficiency of the reaction. As
the diarylated compounds could be synthesized fairly readily
in two steps using the Pd/DPEphos catalytic system for
both cross-couplings, our only concern for a one-pot process
was competing against direct arylation to the benzofuran
(cf. Scheme 4). With that in mind, we attempted the reaction
using the dichlorovinyl ether 57 derived from benzyl alcohol
rather than phenol.39 The one-pot sequential Suzuki-Miyaura
arylations proceeded very smoothly to give the fully elabo-
rated product 58 (Scheme 6). Other observations suggest
that even phenolic ethers should be able to participate
in this one-pot diarylation because cyclization by direct
arylation appears to be slower than cross-coupling pro-
vided that a second boronic acid is present in sufficient
concentration.
a1 equiv of vinyl chloride 26 or 30, 1.5 equiv of R-B(OH)2, 2.5 mol %
of Pd2dba3, 5 mol % of DPEphos, 3 equiv of CsF, 3 equiv of Cs2CO3,
0.4 M in dioxane, heated at 100 °C overnight. b1 equiv of vinyl chloride
26 or 30, 1.5 equiv of R-B(OH)2, 5 mol % of Pd(PPh3)4, 2.5 equiv of
c
KOH (aq), THF, 65 °C overnight. 15% recovered starting material.
d40% recovered starting material. eIsolated 17% of 2-(phenylethynyl)-
benzofuran as well.
C2-H Functionalization Leading to Tetrasubstituted Al-
kenes. Our overall concept was that all four substituent
groups of TCE were potential handles for synthetic elaboration.
acid could be cross-coupled using Pd/DPEphos, but 3-pyri-
dylboronic acid could not. Nevertheless, 3-pyridylboronic
acid did cross-couple with 22 under the aqueous Pd(PPh3)4
conditions.
Both heteroaryl- and ortho-substituted aryl boronic
acids underwent cross-coupling with enyne 26 using the
Pd/DPEphos method, giving 46 and 47 (entries 4 and 5). The
(38) Butters, M.; Harvey, J. N.; Jover, J.; Lennox, A. J. J.; Lloyd-Jones,
G. C.; Murray, P. M. Angew. Chem., Int. Ed. 2010, 49, 5156–5160.
(39) We have attempted sequential Suzuki coupling/direct arylation of
benzyl alcohol derivative using the Pd/DPEphos conditions and have found
that while Suzuki coupling is facile, intramolecular direct arylation to the six-
membered ring fails under these conditions.
6360 J. Org. Chem. Vol. 75, No. 19, 2010

Geary and Hultin
SCHEME 5. Production of Substituted Biaryl Ether 52 from the Reaction between Vinyl Chloride 26 and 3-Phenylpropenylboronic Acid
JOCFeatured Article
TABLE 7. Cross-Coupling at C2 of the Alkyl Derivative 31
TABLE 8. Synthesis of (E)-2-Substituted 1,2-Dichlorovinyl Ethers
aNo Cs2CO3 was added to this reaction. bOnly 35% conversion from
starting material by 1H NMR.
SCHEME 6. One-Pot Sequential Suzuki-Miyaura
Cross-Couplings of 57
SCHEME 7. One-Pot Alcohol Addition/Alkylation
While deprotonation at C2 was known to trigger elimina-
tion to form alkynyl ethers,19n19n appropriate control of the
reaction conditions would permit us to trap the vinyl anion
with various electrophiles. Indeed, Greene had reported
one such example in 2008.40
(E)-(1,2-Dichlorovinyloxy)benzene 1 was deprotonated
with BuLi and quenched with either methyl iodide or allyl
bromide to give adducts 59 or 60 in excellent yields (Table 8,
entries 1 and 2). The vinyllithium could also add to TMSCl,
giving vinylsilane 61 (entry 3), which is useful as a third
and orthogonal handle in subsequent palladium-catalyzed
chemistry41 and other processes.42 Ethyl chloroformate was
also a useful electrophile, giving 1,2-dichloro-1,2-unsatu-
rated ethyl ester 62 in good yield (entry 4). Quenching the
anion with aldehydes (entries 5 and 6) gave allyl alcohols 63
and 64 in excellent yields; the tolerance of an acidic R-proton
is notable (entry 5). This opens yet another pathway for
further synthetic transformation, as allyl alcohols are use-
ful substrates for Tsuji-Trost substitution reactions.43 We
(40) Darses, B.; Milet, A.; Philouze, C.; Greene, A. E.; Poisson, J.-F. Org.
Lett. 2008, 10, 4445–4447.
(41) Denmark, S. E.; Sweis, R. F. In Metal-Catalyzed Cross-Coupling
Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004;
Vol. 1, pp 163-216.
(42) (a) Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997, 97, 2063–
2192. (b) Blumenkopf, T. A.; Overman, L. E. Chem. Rev. 1986, 86, 857–873.
(43) Kazmaier, U.; Pohlman, M. In Metal-Catalyzed Cross-Coupling
Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004; Vol. 2, pp 531-584.
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SCHEME 8. Reaction Sequences Leading to Highly Substituted Ethylene Derivatives
SCHEME 9. Cross Coupling on C2-Methylated Compound
also found that while 1 added easily and cleanly to DMF,
the resultant R,β-unsaturated aldehyde (provisionally
identified from NMR spectra of the crude product) was
unstable and decomposed upon attempted column chro-
matography.
SCHEME 10. Functionalization of 2-Chloro-1-aryl-1-phenoxy-
ethylene
We have also found that the elimination/addition reaction
of a phenolate with TCE and deprotonation of the dichloro-
vinyl ether followed by electrophilic quench with ethyl
chloroformate can be done in one pot with no significant
change in the overall yield of R,β-unsaturated ester 62
(Scheme 7).
Withthe knowledgethatanion chemistry atC2 was feasible,
we envisaged three possible sequences leading to fully elabo-
rated alkenes (Scheme 8). We ruled out the pathway of eq 1 in
Scheme 8 after preliminary experiments showed that depro-
tonation of the trisubstituted ethylene intermediate (R1, R2 =
aryl) was problematic.
The route depicted in eq 2 (Scheme 8) also encountered
difficulties. The cross-coupling between C2-methylated com-
pound 59 and p-methoxyphenylboronic acid catalyzed by
Pd2dba3/DPEphos (Scheme 9) produced a mixture of what
appeared to be two isomers in an approximate 13:1 ratio
(52% yield). The major product was determined to be (Z)-65.
Given that Pd2dba3/DPEphos is unable to effect cross-
coupling between isolated (Z)-65 and boronic acids (vide
infra), it is unlikely that arylation is occurring at C2 here, and
we have a mixture of (E)-65 and (Z)-65 isomers. An analo-
gous cross coupling between 59 and (E)-styrylboronic acid
gave a similar mixture of products with incomplete con-
version. We were unable to induce Sonogashira cross-
coupling between the alkylated derivative 59 and terminal
alkynes.
C1-Cl cross-coupling. We therefore thought that the C1-Cl
should be activated by both substituents in a “push-pull”
fashion,44 and expected that cross-coupling of 62 should be
rapid and selective. We were surprised to find that cross-
coupling between 62 and p-MeOC6H4B(OH)2 gave mixtures
of products, similar the outcome observed with the 2-methyl-
substituted 59 (Scheme 9). We are currently trying to under-
stand the source of this difficultly and exploring alternative
catalytic systems.
As these results ruled out the route according to Scheme 8,
eq 2, we next examined C2-H functionalization from C1
arylated substrates. Deprotonation of vinyl ether 1 was
facile, and quenching with either iodomethane (to give 65)
or ethyl chloroformate (to give 66) proceeded smoothly
(Scheme 10).
The results of cross-couplings of relatively electron-rich
65 and electron-poor 66 are summarized in Tables 9 and 10.
The electron-rich alkene 65 did not participate in any
Suzuki-Miyaura cross-coupling in hot dioxane in the
presence of Pd/DPEphos. However, the Pd(OAc)2/S-Phos
catalyst in toluene proved able to promote Suzuki-
Miyaura couplings of 65, and adducts 67-69 were ob-
tained in good yields (Table 9). Cross-coupling occurred
We also explored cross-coupling reactions between the
dichlorovinyl ester 62 and arylboronic acids. Cross-coupling
is known to favor the β position in R,β-unsaturated esters
(i.e., C1 in 62).11c11c Furthermore, we have already noted the
directing effect of the C1-phenoxy substituent for selective
(44) Kleinpeter, E. J. Serb. Chem. Soc. 2006, 71, 1–17.
6362 J. Org. Chem. Vol. 75, No. 19, 2010

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TABLE 9. Tetrasubstituted Alkenes from Cross-Coupling with Electron-Rich Alkene 65
readily with an electron-rich (entry 1), an electron-
deficient (entry 2), and an ortho-substituted (entry 3)
arylboronic acid. Similarly, electron-rich tetrasubstitu-
ted dienes 70-72 were easily assembled in high yields
(entries 4-6).
Pd(OAc)2/S-Phos/toluene conditions gave higher yields of
these adducts (Table 10, conditions B, entries 2, 4, 6, 8, and
10). Cross-coupling with vinylboronic acids provided buta-
dienes 76-80. As in the synthesis of trisubstituted alkenes
(Tables 5 and 6), an aryl chloride substituent was tolerated
by either catalyst examined (entries 11 and 12) giving butadiene
78 in excellent yields. Finally, alkyl-substituted vinyl boro-
nic acids could be utilized, giving butadienes 79 and 80 in
moderate to good yield (entries 13 and 14). In all cases, only
one isomer could be detected in the 1H NMR spectra
of the crude material and the pure isolated product. Un-
saturated esters 73-80 are also generally referred to as
Analogous reactions of R-chloro-R,β-unsaturated ester
65 catalyzed by Pd/DPEphos typically gave the tetrasub-
stituted unsaturated esters 73-78 in good yields (Table 10,
conditions A, entries 1, 3, 5, 7, 9, and 11). However, in
some cases 2-(4-methoxyphenyl)-3-carboxyethylbenzofuran
was also produced in competition, as detected by TLC
1
and H NMR analysis of the crude products. Generally, the
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TABLE 10. Push-Pull Alkenes from Cross-Coupling with 65
aA: 1 equiv of 66, 1.5 equiv of RB(OH)2, 2.5 mol % of Pd2dba3, 5 mol % of DPEphos, 3 equiv of CsF-Cs2CO3, dioxane, 100 °C, overnight. B: 1 equiv
of 66, 1.5 equiv of RB(OH)2, 5 mol % of Pd(OAc)2, 10 mol % of S-Phos, 2.2 equiv of Cs2CO3, toluene, 110 °C, overnight.
push-pull alkenes45 and are reactive to both electrophiles
and nucleophiles,45 making them highly useful targets. The
method described here provides a nice complement to the
published procedures for the synthesis of trisubstituted
unsaturated esters.46
(46) (a) Nakatsuji, H.; Nishikado, H.; Ueno, K.; Tanabe, Y. Org. Lett.
2009, 11, 4258–4261. (b) Nakatsuji, H.; Ueno, K.; Misaki, T.; Tanabe, Y.
Org. Lett. 2008, 10, 2131–2134.
(45) Lloyd, D.; McNab, H. Angew. Chem., Int. Ed. 1976, 15, 459–468.
6364 J. Org. Chem. Vol. 75, No. 19, 2010

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Conclusions
acid (1.3550 g, 8.9 mmol, 1.05 equiv), Pd2dba3 (194.6 mg, 0.212
mmol, 2.5 mol %), DPEphos (228.8 mg, 0.425 mmol, 5 mol %),
CsF (3.87 g, 25.5 mmol, 3 equiv), and Cs2CO3 (8.31 g, 25.5 mmol,
3 equiv) were placed into a one-piece, round-bottom flask/
condenser, sealed with a septum, and purged with argon for 20-
30 min. A solution of the 1,2-dichlorovinyl ether 1 (1.6068 g,
8.5 mmol) in dioxane (25 mL) was added. The solution was
vigorouslystirred andbroughttoreflux. When complete(6 h), the
reaction was cooled and partitioned between water and dichloro-
methane. The layers were separated, and the aqueous layer
was extracted with dichloromethane once more. The combined
organic layers were dried with magnesium sulfate, filtered, and
concentrated onto silica gel, applied to a column, and eluted with
9:1 hexanes/dichloromethane. NMR were consistent with pre-
viously published data:21 Rf = 0.29 (9:1 hexanes/ethyl acetate);
1H NMR (300 MHz, CDCl3) δ 7.40 (d, 2H), 7.28-7.21 (m, 2H),
7.00-6.95 (m, 3H), 6.83 (d, 2H), 6.30 (s, 1H), 3.78 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 160.3, 156.1, 151.1, 129.6, 127.7,
127.1, 125.7, 122.2, 115.9, 114.2, 105.1, 55.3.
We have developed a modular and efficient synthesis of
tri- and tetrasubstituted electron-rich alkenes from the two-
carbon building block trichloroethylene. In general, C-C bond
formation at C1 was best accomplished using a DPEphos-based
catalyst in dioxane, while C2 functionalization could be
achieved using an S-Phos-based catalyst in toluene solution.
Cross-coupling heteroaryl boronic acids was the exception to
those generalizations, and Pd(PPh3)4 in THF/KOH (aq) was
the most efficient catalyst for cross-coupling heteroarylboronic
acids at either C1 or C2. This method efficiently installs alkyl,
alkenyl, alkynyl, and (hetero)aryl groups at C1 and C2 of TCE.
This is one of the most general approaches we know of to access
alkoxy-substituted stilbenes, dienes, trienes, enynes, and
related conjugated structural motifs.
Experimental Section
(Z)-1-Chloro-2-phenoxy-2-(4-methylphenyl)ethylene (15).
This compound was prepared according to representative
procedure A on a 5.4 mmol scale to give 1.26 g of 15 (95%
yield). Purified via flash chromatography using a gradient of
hexanes to 14:1 hexanes/dichloromethane as an eluent: Rf =
0.62 (9:1 hexanes/dichloromethane); 1H NMR (300 MHz,
CDCl3) δ 7.43 (d, 2H, J = 8 Hz), 7.34-7.29 (m, 2H), 7.19 (d,
2H, J = 8 Hz), 7.08-7.02 (m, 3H), 6.54 (s, 1H), 2.38 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 156.2, 151.4, 139.3, 130.4,
129.6, 129.5, 125.6, 122.3, 116.0, 106.2, 21.3; HRMS calcd
for C15H13ClO 244.0655, found 244.0659.
(Z)-1-Chloro-2-phenoxy-2-(4-fluorophenyl)ethylene (16). This
compound was prepared according to representative procedure
A on a 5 mmol scale. NMR were consistent with previously
published data:21 Rf = 0.5 (9:1 hexanes/ethyl acetate); 1H NMR
(300 MHz, CDCl3) δ 7.49 (m, 2H), 7.31 (m, 2H), 7.07-7.00
(m, 5H), 6.41 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 164.8,
161.5, 155.9, 150.5, 129.7, 129.4, 122.5, 116.1, 115.9, 115.8,
106.8, 106.8.
General Considerations. All glassware was oven-dried and
cooled in a desiccator before use. All reactions were carried
out under argon using standard syringe techniques. THF
and toluene were purified by passage through two columns of
activated alumina under argon pressure47 and degassed via
sparging with argon before use. Anhydrous dioxane was de-
gassed via sparging with argon before use. Boronic acids were
generally used as received, but trans-2-phenylvinylboronic acid
and 2-thiopheneboronic acid were recrystallized before use.
Alkynes were generally used as purchased, or in the case of
phenylacetylene, were passed through a short column of acti-
vated alumina first. All palladium reagents, as well as phosphine
ligands, cesium fluoride, and cesium carbonate, were used as
received. Flash chromatography employed 230-400 mesh silica
gel. Rf values refer to TLC on precoated 0.2 mm silica gel plates
1
obtained using the eluent indicated. H NMR (300 MHz) and
13C NMR (75 MHz) were recorded in CDCl3 solutions. Chemi-
cal shifts for 1H and 13C are reported in parts per million (ppm)
downfield from TMS, using residual CDCl3 (7.27 ppm and
triplet at 77.0 ppm, respectively) as an internal standard.
(E)-1,2-Dichloro-1-phenoxyethylene (1). This compound was
prepared according to our published procedure.21a21a KH (2.05
equiv) was weighed into a round-bottom flask and washed with
three portions of either pentane or petroleum ether. The KH was
then suspended in THF (ca. 2.4 mL per mmol of KH). A
solution of the phenol (1.0 equiv) in THF (ca. 1.25 mL per
mmol of phenol) was added dropwise (vigorous gas evolution
was noted), and the reaction was allowed to stir for 30-120 min.
The suspension was cooled to approximately -50 °C (CHCl3/
CO2(s) bath). Trichloroethylene (1.5 equiv) was then added
dropwise. The reaction was allowed to warm gradually to room
temperature overnight. The reaction was diluted with petroleum
ether and quenched with ice-cold water. The phases were
separated, and the aqueous phase was extracted once more with
petroleum ether. The organic layers were combined, dried with
sodium sulfate, filtered, and concentrated to give a yellow to
dark brown oil. The crude oil was applied to a silica column
pretreated with triethylamine (ca. 2.5 vol% with respect to the
volume of dry silica) and eluted with petroleum ether: 1H NMR
(300 MHz, CDCl3) δ 7.43-7.36 (m, 2H), 7.22-7.17 (m, 1H),
7.13-7.08 (m, 2H), 5.97 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
154.0, 140.1, 129.8, 124.5, 117.1, 103.8.
(Z)-1-Chloro-2-phenoxy-2-phenylethylene (17). Viscous, col-
orless oil prepared according to Representative Procedure A on
a 0.38 mmol scale. Purified via flash chromatography on TEA-
treated silica using 9:1 hexanes/dichloromethane as an eluent to
give 75.5 mg of 17 (60% yield): Rf = 0.57 (9:1 hexanes/ethyl
1
acetate); H NMR (300 MHz, CDCl3) δ 7.52-7.49 (m, 2H),
7.36-7.25 (m, 5H), 7.04-7.00 (m, 3H), 6.47 (s, 1H). The
structure of this compound has been confirmed by its transfor-
mation into the known compound 2-phenylbenzo[b]furan.21
(1Z,3E)-1-Chloro-2-phenoxy-4-phenylbuta-1,3-diene (18).
This compound is a clear oil and was prepared according to
representative procedure A. NMR were consistent with pre-
viously published data:21 Rf = 0.49 (9:1 hexanes/ethyl acetate);
1H NMR (300 MHz, CDCl3) δ 7.43-7.27(m, 7H), 7.12-7.06 (m,
3H), 6.83 (d, 1H, J = 16 Hz), 6.72 (d, 1H, J = 16 Hz), 6.22
(s, 1H); 13C NMR (75 MHz, CDCl3) δ156.5, 151.1, 136.0, 131.1,
129.7, 128.8, 128. 5, 126.9, 122.3, 120.3, 115.2, 110.6.
Representative Procedure B for Suzuki-Miyaura Cross-
Coupling Using Pd(PPh3)4: (Z)-2-(2-Chloro-1-phenoxyvinyl)-
benzo[b]thiophene (19). The boronic acid (308.4 mg, 1.73 mmol,
1.05 equiv) and tetrakis(triphenylphosphine)palladium(0) (95.3 mg,
82.5 μmol, 5 mol %) were placed into a one-piece, round-bottom
flask-condenser, sealed with a septum, and purged with argon
for 20 min. A 1.0 equiv portion of the dichlorovinyl ether 1
(311.9 mg, 1.65 mmol, 1 equiv) in THF (5 mL) was added, and
then a degassed 1.0 M aqueous solution of KOH (3.5 mL, 3,5
mmol, 2.1 equiv) was added. The solution was vigorously stirred
and brought to reflux. When complete (14 h), the reaction was
cooled and partitioned between water and dichloromethane.
The layers were separated, and the aqueous layer was extracted
Representative Procedure A for Suzuki-Miyaura Cross-
Coupling Reactions Using Pd/DPEphos: Synthesis of (Z)-1-
Chloro-2-phenoxy-2-(4-methoxyphenyl)ethylene (2). The boronic
(47) Pangborn, A. B.; Giardello, M.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518–1520.
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with dichloromethane once more. The combined organic layers
were washed with brine, dried with sodium sulfate, filtered, and
concentrated. The crude residue was purified via flash chroma-
tography using 14:1hexanes/dichloromethaneasaneluenttogive
0.50 g of 19: Rf=0.65 (9:1 hexanes/diethyl ether). This material
could not be separated from traces of 2,20-dibenzo[b]thiophene
arising from homocoupling of benzothiophene-2-boronic acid:
1H NMR (300 MHz, CDCl3) δ 7.80-7.67 (m, 2H), 7.42-7.29 (m,
10H), 7.13-7.05 (m, 3H), 6.57 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 156.2, 146.9, 139.4, 135.9, 133.9, 133.6, 129.7, 128.7,
128.6, 128.5, 125.5, 124.8, 124.2, 122.8, 122.7, 122.2, 115.5, 108.6;
HRMS calcd for C16H11ClOS 286.0219, found 286.0227.
(Z)-3-(2-Chloro-1-phenoxyvinyl)benzo[b]thiophene (20). Vis-
cous, colorless oil prepared according to representative proce-
dure B on a 1.59 mmol scale. Purified via flash chromatography
on TEA-treated silica using 14:1 hexanes/dichloromethane as an
eluent to give 0.31 g of 20 (68% yield): Rf = 0.53 (9:1 hexanes/
diethyl ether); 1H NMR (300 MHz, CDCl3) δ 8.15 (d, 1H, J =
8 Hz), 7.86 (d, 1H, J = 8 Hz), 7.62 (s, 1H), 7.51-7.38 (m, 2H),
7.30-7.22 (m, 2H), 7.07 (m, 2H), 7.00 (m, 1H), 6.44 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 155.8, 147.9, 140.4, 136.2, 129.7,
129.6, 127.2, 125.0, 123.1, 123.0, 122.7, 116.3, 107.8; HRMS
calcd for C16H11ClOS 286.0219, found 286.0207.
(Z)-2-(2-Chloro-1-phenoxyvinyl)thiophene (25). This com-
pound was prepared according to representative procedure B.
It decomposes at room temperature. NMR were consistent with
previously reported data:21a21a 1H NMR (300 MHz, CDCl3) δ
7.33-7.24 (m, 3H), 7.13 (m, 1H), 7.07-7.02 (m, 3H), 6.96 (m,
1H), 6.42 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 156.1, 146.7,
136.4, 129.7, 127.6, 126.2, 125.9, 122.6, 115.8, 106.1 (also
contains a trace of decomposed material).
Representative Procedure C for Sonogashira Cross-Coupling:
Synthesis of (Z)-1-Chloro-2-phenoxy-4-phenylbut-1-en-3-yne (26).
Pd(PPh3)4 (286.0 mg, 0.25 mmol, 5 mol %) and CuI (95.2 mg,
0.5 mmol, 10 mol %) were placed into an oven-dried one-piece,
round-bottom flask/condenser, sealed with a septum, and purged
with argon for 20 min. A dichlorovinyl ether 1 (946.3 mg, 4.95
mmol, 1 equiv) in THF (5 mL) was added, followed by TEA
(1.4 mL, 9.9 mmol, 2.0 equiv) and phenylacetylene (0.61 mL,
5.4 mmol, 1.1 equiv). The solution was stirred at room tempera-
ture for 12 h, after which it was diluted with ethyl acetate, filtered
through Celite, concentrated, and purified via flash chromato-
graphy using 9:1 hexanes/ethyl acetate as an eluant. NMR were
consistent with previously published data.21a21a Rf = 0.48 (9:1
1
hexanes/ethyl acetate); H NMR (300 MHz, CDCl3) δ 7.41-
7.26 (m, 7H), 7.18-7.13 (m, 3H), 6.21 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 155.2, 136.5, 131.5, 129.4, 129.2, 128.4, 123.8,
121.4, 118.4, 111.3, 94.0, 81.3.
(Z)-2-(2-Chloro-1-phenoxyvinyl)benzo[b]furan (21). Viscous,
colorless oil prepared according to representative procedure B
on a 1.62 mmol scale. Purified via flash chromatography on
TEA-treated silica using 14:1 hexanes/dichloromethane as an
eluent to give 175.8 mg of 21 (40% yield): Rf = 0.28 (14:1
hexanes/dichloromethane); 1H NMR (300 MHz, CDCl3) δ
7.70-7.59 (m, 1H), 7.51 (m, 2H), 7.41-7.33 (m, 4H), 7.28-
(Z)-1-Chloro-2-phenoxy-6-(tert-butyldiphenylsilyloxy)hex-1-
en-3-yne (27). This compound is a colorless oil and was pre-
pared according to representative procedure C. NMR were
consistent with previously published data:21a21a Rf = 0.61 (9:1
1
hexane/ethyl acetate); H NMR (300 MHz, CDCl3) δ 7.72-
7.22 (m, 1H), 7.13-7.08 (m, 3H), 6.90 (s, 1H), 6.71 (s, 1H); 13
C
7.67 (m, 4H), 7.51-7.40 (m, 6H), 7.34-7.28 (m, 2H), 7.12-7.05
NMR (75 MHz, CDCl3) δ 156.4, 155.0, 149.5, 143.2, 129.8,
128.6, 128.1, 125.5, 125.1, 123.4, 123.4, 122.8, 121.6, 121.4,
115.3, 111.3, 111.2, 109.7, 105.2, 103.7; HRMS calcd for
C16H11ClO2 270.0448, found 270.0447.
(m, 3H), 6.04 (s, 1H), 3.71 (t, 2H), 2.51 (t, 2H), 1.09 (s, 9H); 13
C
NMR (75 MHz, CDCl3) δ 155.2, 136.2, 135.6, 135.6, 133.5,
129.8, 129.3, 127.8, 123.5, 117.9, 111.0, 92.8, 74.0, 61.8, 26.8,
23.4, 19.2.
(Z)-1-(tert-Butoxycarbonyl)-2-(2-chloro-1-phenoxyvinyl)indole
(22). Viscous, colorless oil prepared according to representative pro-
cedure B on a 2.75 mmol scale. Purified via flash chromatography
on TEA-treated silica using 4:1 hexanes/dichloromethane as an elu-
ent to give 524.5 mg of 22 (52% yield): Rf = 0.36 (9:1 hexanes/
diethyl ether); 1H NMR (300 MHz, CDCl3) δ8.17 (d, 1H, J=8 Hz),
7.56 (d, 1H, J = 7.5 Hz), 7.41-7.34 (m, 2H), 7.25 (m, 3H), 7.03 (m,
3H), 6.80 (s, 1H), 6.28 (s, 1H), 1.78 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ155.3, 149.4, 146.2, 137.4, 131.3, 129.4, 128.0, 125.6, 123.2,
123.1, 121.0, 117.2, 115.4, 115.4, 114.2, 108.0, 84.4, 28.0; HRMS
calcd for C21H20ClNNaO3 392.1024, found 392.0989.
(Z)-5-(2-Chloro-1-phenoxyvinyl)indole (23). Viscous, color-
less oil prepared according to representative procedure B on a
0.53 mmol scale. Purified via flash chromatography on TEA-
treated silica using 4:1 hexanes/ethyl acetate as an eluent to give
65.7 mg of 23 (49% yield): Rf = 0.15 (9:1 hexanes/ethyl acetate);
1H NMR (300 MHz, CDCl3) δ 8.21 (br s, 1H), 7.80 (s, 1H),
7.35-7.23 (m, 4H), 7.20 (t, 1H, J = 2.8 Hz), 7.07 (m, 2H), 6.98
(m, 1H), 6.54 (br t, 1H, J = 2.4 Hz), 6.39 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 156.4, 152.6, 136.2, 129.6, 127.9, 125.2, 125.2,
122.1, 120.0, 118.8, 116.1, 111.4, 104.6, 103.3. This compound
gradually decomposes at room temperature, and we were unable
to get satisfactory HRMS.
(Z)-2-Fluoro-5-(2-chloro-1-phenoxyvinyl)pyridine (24). This
compound was a colorless oil prepared according to represen-
tative procedure B on a 0.38 mmol scale. NMR were consistent
with previously published data:21a21a Rf = 0.10 (9:1 hexanes/
ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.38 (d, 1H, J = 2
Hz), 7.85 (ddt, 1H, J = 1 Hz, 2 Hz, 7 Hz), 7.32-7.26 (m, 2H),
7.04 (dt, 1H, J = 1 Hz, 7 Hz), 6.97 (dd, 1H, J = 1 Hz, 8 Hz), 6.90
(dd, 1H, J = 3 Hz, 8 Hz), 6.46 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 165.3, 162.09, 155.4, 148.0, 145.3, 145.1, 138.4, 138.3,
129.9, 127.6, 127.5, 123.0, 116.0, 110.1, 109.6, 108.4, 108.4.
(Z)-1-Chloro-2-phenoxy-6-hydroxyhex-1-ene-3-yne (28). This
compound is a colorless oil and was prepared according to
representative procedure C. NMR were consistent with pre-
viously published data:21a21a Rf = 0.17 (9:1 hexane/ethyl acet-
ate; dec at room temperature; 1H NMR (300 MHz, CDCl3)
δ 7.39-7.32 (m, 2H), 7.17-7.12 (m, 1H), 7.10-7.05 (m, 2H),
6.04 (s, 1H), 3.56 (t, 2H), 2.47 (t, 2H), 1.61 (br s, 1H); 13C NMR
(75 MHz, CDCl3) δ 155.1, 136.3, 129.3, 123.9, 118.5, 110.5, 92.4,
74.7, 60.5, 23.6.
(Z)-1-Chloro-2-phenoxy-4-(2-hydroxymethylphenyl)but-1-en-
3-yne (29). Viscous, colorless oil prepared on a 0.8 mmol scale
according to representative procedure C. Purified via flash chro-
matography on TEA-treated silica using hexanes as an eluent to
give 171.8 mg of 29: Rf = 0.33 (hexanes); 1H NMR (300 MHz,
CDCl3) δ 7.45-7.32 (m, 5H), 7.28-7.16 (m, 4H), 6.22 (s, 1H),
4.39 (s, 2H), 1.57 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ
155.2, 142.8, 136.5, 132.1, 129.6, 129.6, 127.4, 127.2, 124.2,
119.3, 118.8, 111.2, 91.7, 85.7, 63.2; HRMS calcd for C17H13-
ClO2 284.0604, found 284.0601.
(Z)-1-Chloro-2-phenoxyoct-1-en-3-yne (30). This compound
is a colorless oil and was prepared according to representative
procedure C. NMR were consistent with previously pub-
lished data:21a21a Rf = 0.63 (9:1 hexane/ethyl acetate); 1H
NMR (300 MHz, CDCl3) δ 7.37-7.31 (m, 2H), 7,15-7.06 (m,
3H), 6.01 (s, 1H), 2.22 (t, 2H), 1.44-1.34 (m, 2H), 1.30-1.18 (m,
2H), 0.84 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 155.2, 136.5,
129.2, 123.5, 118.3, 109.9, 95.9, 73.0, 30.0, 21.7, 18.8, 13.5.
(Z)-1-Chloro-2-phenoxy-5-phenylpent-1-ene (31). An oven-
dried one piece round-bottom flask/condenser was sealed with
a septum and purged with argon for 20-30 min. Allylbenzene
(0.64 mL, 4.8 mmol, 1.2 equiv) was added followed by a 0.5 M
solution of 9-BBN in THF (9.6 mL, 4.8 mmol, 1.2 equiv) and the
mixture stirred at room temperature. After 1 h, Pd2dba3 (91.7 mg,
6366 J. Org. Chem. Vol. 75, No. 19, 2010

Geary and Hultin
JOCFeatured Article
0.10 mmol, 2.5 mol %), Xantphos (115.7 mg, 0.20 mmol,
5 mol %), CsF (1.82 g, 12 mmol, 3 equiv), and Cs2CO3 (3.91 g,
12 mmol, 3 equiv) were added as solids, followed by 1.0 equiv
of vinyl chloride 1 (0.7561 g, 4 mmol) in THF (8 mL). The
suspension was brought to reflux and stirred for 12 h. When
complete, the reaction was cooled and partitioned between
water and dichloromethane. The layers were separated, and
the aqueous layer was extracted with dichloromethane once
more. The combined organic layers were dried with magnesium
sulfate, filtered and concentrated onto silica gel for purification
via flash chromatography using 14:1 hexanes/ethyl acetate as
an eluant: Rf = 0.62 (9:1 hexanes/ethyl acetate); 1H NMR (300
MHz, CDCl3) δ 7.43-7.00 (m, 10H), 5.81 (s, 1H), 2.70 (m, 2H),
2.33 (s, 2H), 1.90 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 155.2,
152.9, 141.5, 129.7, 128.5, 126.0, 122.7, 116.7, 104.3, 35.0, 30.9,
27.9; HRMS calcd for C17H17ClO 272.0968, found 272.0956.
Representative Procedure D for Negishi Cross-Coupling
with Et2Zn: Synthesis of (Z)-1-Chloro-2-phenoxybut-1-ene (32).
Pd2dba3 (14.2 mg, 15.5 μmol, 2.5 mol %) and DPEphos (17.0 mg,
31 μmol, 5 mol %) were placed into an oven-dried, one-piece,
round-bottom flask condenser, sealed with a septum, and purged
with Ar for 20 min. A 1.0 equiv portion of dichlorovinyl ether 1
(118.5 mg, 0.62 mmol) as a solution in DMF or THF (2 mL) was
added, followed by Et2Zn as a 1.0 M solution in hexanes (0.68
mL, 0.68 mmol, 1.1 equiv). The resulting solution was stirred at
room temperature for 12 h. When complete, water was added to
the reaction and extracted three times with diethyl ether. The
organic layers were combined, washed with brine, dried with
magnesium sulfate, filtered, and concentrated. The crude oil
obtained was applied to a silica gel column that was pretreated
with 2.5 vol % of triethylamine and eluted with 14:1 hexanes/
diethyl ether to yield the corresponding 1-ethyl-2-chlorovinyl ether
32 as a colorless oil: Rf = 0.71 (9:1 hexanes/dichloromethane); 1H
NMR (300 MHz, CDCl3) δ 7.38-7.31 (m, 2H), 7.11-7.05 (m,
1H), 7.03-6.99 (m, 2H), 5.77 (t, 1H, J = 1.2 Hz), 2.28 (dd, 2H,
J1 = 7.5 Hz, J2 = 1.2 Hz), 1.11 (t, 3H, J = 7.5 Hz); 13C NMR (75
MHz, CDCl3) δ 155.3, 154.7, 129.6, 122.6, 116.7, 103.4, 24.9, 11.2.
We were unable to get satisfactory HRMS of this compound.
(Z)-1-Phenoxy-1-(4-methoxyphenyl)-2-(4-fluorophenyl)ethylene
(33). Colorless solid prepared according to representative proce-
dure A on 0.38 mmol scale. Purified via flash chromatography
using 9:1 hexanes/dichloromethane as an eluent to give 68.9 mg of
(s, 3H), 1.08 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 157.8, 147.7,
147.0, 137.9, 132.5, 129.5, 129.3, 125.3, 121.5, 119.2, 116.9, 115.9,
33.6, 29.6, 21.2; HRMS calcd for C21H24O 292.1827, found 292.1827.
(1Z,3E)-1-Phenoxy-1-(4-methylphenyl)-4-phenylbuta-1,3-diene
(36). Colorless solid prepared according to representative proce-
dure E on a 0.26 mmol scale. Purified via flash chromatography
using 14:1 hexanes/dichloromethane as an eluent to give 53.1 mg
of 36: Rf = 0.10 (14:1 hexanes/dichloromethane); 1H NMR (300
MHz, CDCl3) δ 7.51 (m, 2H), 7.43 (m, 2H), 7.36-7.14 (m, 8H),
7.09-6.98 (m, 3H), 6.78-6.66 (m, 2H), 2.37 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 157.9, 149.8, 138.4, 137.5, 132.7, 132.0, 129.7,
129.4, 128.6, 127.6, 126.5, 125.5, 123.2, 121.8, 116.6, 115.2, 21.3;
HRMS calcd for C23H20O 312.1514, found 312.1517.
(1Z,3E)-1-Phenoxy-1-(4-methylphenyl)-4-(4-fluorophenyl)buta-
1,3-diene (37). Colorless solid prepared according to representa-
tive procedure E on a 0.26 mmol scale. Purified via flash chroma-
tography using 14:1 hexanes/dichloromethane to give 12.7 mg of
1
37: Rf = 0.10 (14:1 hexanes/dichloromethane); H NMR (300
MHz, CDCl3) δ 7.49 (d, 2H), 7.38 (m, 2H), 7.31-7.25 (m, 3H),
7.15 (d, 2H), 7.09-6.97 (m, 6H), 6.71-6.62 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 163.9, 160.7, 157.9, 149.8, 138.5, 133.7, 132.0,
131.4, 129.7, 129.4, 128.0, 127.9, 125.5, 122.89, 122.86, 121.8,
116.4, 116.4, 115.9 115.7 115.4, 21.3; HRMS calcd for C23H19FO
330.1420, found 330.1427.
(1Z,3E)-1-(4-Methylphenyl)-2-phenoxy-4-phenylbuta-1,3-diene
(38). Pale yellow solid prepared according to representative
procedure A on a 0.38 mmol scale. Purified via flash chromatog-
raphy using 14:1 hexanes/dichloromethane as an eluent to give
1
64.7 mg of 38: Rf = 0.14 (14:1 hexanes/dichloromethane); H
NMR (300 MHz, CDCl3) δ 7.53 (d, 2H, J = 8 Hz), 7.42 (m, 2H),
7.38-7.24 (m, 5H), 7.16-7.10 (m, 4H), 7.03 (m, 1H), 6.87 (d, 1H,
J = 16 Hz), 6.71 (d, 1H, J = 16 Hz), 6.40 (s, 1H), 2.34 (s, 3H); 13
C
NMR (75 MHz, CDCl3) δ 156.5, 148.5 137.6, 136.7, 131.8, 130.1
129.7, 129.3, 129.1, 128.7 127.8, 126.7 124.6, 121.8, 121.3 115.3,
21.3; HRMS calcd for C23H20O 312.1514, found 312.1514.
(1Z,3E)-1-(4-Methoxyphenyl)-2-phenoxyl-4-phenylbuta-1,3-
diene (39). Pale yellow solid prepared according to represen-
tative procedure A on a 0.38 mmol scale. Purified via flash
chromatography using 9:1 hexanes/ethyl acetate as an eluent
to give 100.4 mg of 39: Rf = 0.38 (9:1 hexanes/ethyl acetate);
1H NMR (300 MHz, CDCl3) δ 7.58 (d, 2H, J = 8 Hz),
7.43-7.23 (m, 7H), 7.14 (d, 2H, J = 8 Hz), 7.03 (t, 1H), 6.86
(m, 3H), 6.68 (d, 1H, J = 16 Hz), 6.37 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 159.0, 156.5, 147.5, 136.8, 130.6, 129.8, 129.5,
128.6, 127.7, 127.4, 126.6, 124.6, 121.8, 120.9, 115.3, 114.1,
55.2; HRMS calcd for C23H20O2 328.1463 found 328.1465.
(1E,3Z,5E)-1-Phenyl-3-phenoxy-6-(4-methylphenyl)hexa-
1,3,5-triene (40). Colorless solid prepared according to repre-
sentative procedure A on a 0.21 mmol scale. Purified via flash
chromatography using 9:1 hexanes/ethyl acetate as an eluent to
1
33: Rf = 0.45 (9:1 hexanes/ethyl acetate); H NMR (300 MHz,
CDCl3) δ 7.66-7.60 (m, 2H), 7.56-7.52 (m, 2H), 7.30-7.23 (m,
2H), 7.06-6.96 (m, 5H), 6.90-6.85 (m, 2H), 6.55 (s, 1H), 3.81 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 163.3, 160.0, 159.9, 156.3,
149.2, 131.3, 131.2, 130.4, 130.3, 129.7, 128.3, 127.4, 122.1, 116.3,
115.6, 115.3, 114.1, 113.8, 55.3; HRMS calcd for C21H17FO2
321.1284, found 321.1285.
Representative Procedure E for Suzuki-Miyaura Cross-Cou-
pling with Pd/S-Phos Catalytic System: Synthesis of (1Z,3E)-1-
Phenoxy-1-(4-methylphenyl)-5,5-dimethylhexa-1,3-diene (35).
The boronic acid (50.2 mg, 0.39 mmol, 1.5 equiv), Pd(OAc)2
(2.9 mg, 0.013 mmol, 5 mol %), S-Phos (10.7 mg, 0.026 mmol,
10 mol %), and Cs2CO3 (187.6 mg, 0.58 mmol, 2.2 equiv) were
placed in a one-piece, round-bottom flask/condenser, sealed
with a septum and purged with argon for 20 min. A solution of
the vinyl chloride 15 (64.0 mg, 0.26 mmol, 1 equiv) in toluene
(2.5 mL) was added and the suspension was refluxed overnight.
When complete, the reaction was cooled and partitioned between
dichloromethane and water. The layers were separated, and the
water layer was extracted twice more with dichloromethane. The
organic layers were combined, dried with magnesium sulfate,
filtered, and concentrated onto silica gel, which was applied to a
silica gel column and eluted with 14:1 hexanes/dichloromethane
to give 66.7 mg of 35: Rf = 0.25 (9:1 hexanes/dichloromethane);
1H NMR (300 MHz, CDCl3) δ 7.46 (d, 2H), 7.29 (t, 2H), 7.14 (d,
2H), 7.06-6.97 (m, 3H), 6.48-6.34 (m, 2H), 5.96 (d, 1H), 2.36
1
give 27.7 mg of 40: Rf = 0.50 (9:1 hexanes/ethyl acetate); H
NMR (300 MHz, CDCl3) δ 7.39-7.17 (m, 13H), 7.09 (m, 2H),
7.04-6.98 (m, 2H), 6.81-6.62 (m, 3H), 6.28 (d, 1H, J = 11 Hz);
13C NMR (75 MHz, CDCl3) δ 158.2, 149.7, 137.3, 136.6, 133.3,
130.3, 129.7, 128.6, 128.6, 127.9, 127.8, 126.7, 123.3, 122.9, 122.1,
121.8, 115.3; HRMS calcd for C25H22O 338.1671, found
338.1672.
(1E,3Z,5E)-1-Phenyl-3-phenoxy-6-(4-chlorophenyl)hexa-
1,3,5-triene (41). Pale yellow solid prepared according to re-
presentative procedure A on a 0.19 mmol scale. Purified via flash
chromatography using 9:1 hexanes/dichloromethane as an eluent
to give 44.6 mg of 41: Rf = 0.14 (hexanes/dichloromethane); 1H
NMR (300 MHz, CDCl3) δ 7.43-7.25 (m, 12H), 7.13-6.98 (m,
4H), 6.83-6.70 (m, 2H), 6.62 (d, 1H, J = 16 Hz), 6.29 (d, 1H, J =
11 Hz); 13C NMR (75 MHz, CDCl3) δ 158.2, 150.2, 136.5, 135.8,
133.3, 131.8, 130.7, 129.8, 128.8, 128.7, 128.1, 127.7, 126.8, 123.5,
123.2, 121.9, 121.7, 115.3; HRMS calcd for C24H19ClO 358.1124,
found 358.1126.
J. Org. Chem. Vol. 75, No. 19, 2010 6367

Geary and Hultin
JOCFeatured Article
(1E,3Z)-1,6-Diphenyl-3-phenoxyhexa-1,3-dien-5-yne (42). Pale
yellow solid prepared according to representative procedure A on
a 0.19 mmol scale. Purified via flash chromatography using 9:1
hexanes/dichloromethane as an eluent to give 13.2 mg of 42: Rf =
0.10 (9:1 hexanes/dichloromethane); 1H NMR (300 MHz,
CDCl3) δ 7.48 (m, 2H), 7.41-7.06 (m, 14H), 7.02 (d, 1H, J =
16 Hz), 6.84 (d, 1H, J = 16 Hz), 5.70 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 159.1, 157.3, 136.1, 132.0, 131.3, 129.5, 128.8, 128.5,
128.1, 127.1, 123.3, 123.0, 122.2, 116.4, 99.7, 98.9, 85.5; HRMS
calcd for C24H18O 322.1358, found 322.1373.
(Z)-1-(3-Acetylphenyl)-2-(phenoxy)oct-1-ene-3-yne (43). Color-
less solid prepared according to representative procedure A on a
85 μmol scale. Purified via flash chromatography using 10:1
hexanes/ethyl acetate to give 11.3 mg of 43: Rf = 0.19 (9:1
hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.15 (m,
1H), 7.84 (m, 1H), 7.78 (m, 1H), 7.40-7.31 (m, 3H), 7.14-7.08
(m, 3H), 6.23 (s, 1H), 2.54 (s, 3H), 2.23 (t, 2H), 1.42-1.32 (m,
2H), 1.29-1.17 (m, 2H), 0.82 (t, 3H); 13C NMR (75 MHz,
CDCl3) δ 198.0, 155.3, 137.3, 135.8, 135.2, 133.2, 129.3, 129.0,
128.7, 126.8, 123.4, 118.9, 118.5, 94.4, 76.3, 30.1, 26.6, 21.7, 18.9,
13.5; HRMS calcd for C22H22O2 318.1620, found 318.1625.
(Z)-1-(3-Pyridinyl)-2-(phenoxy)oct-1-ene-3-yne (44). Color-
less oil prepared according to representative procedure B on
0.28 mmol scale. Purified via flash chromatography on TEA-
treated silica using 4:1 hexanes/ethyl acetate as an eluent: Rf =
0.33 (2:1 hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ
8.73 (d, 1H, J = 2.2 Hz), 8.44 (dd, 1H, J1 = 1.5 Hz, J2 = 5 Hz),
8.08 (dt, 1H, J1 = 2 Hz, J2 = 8 Hz), 7.40-7.34 (m, 2H), 7.25-
7.21 (m, 1H), 7.18-7.12 (m, 2H), 6.17 (s, 1H), 2.26 (t, 2H, J =
7 Hz), 1.44-1.35 (m, 2H), 1.31-1.19 (m, 2H), 0.85 (t, 2H, J =
7 Hz); 13C NMR (75 MHz, CDCl3) δ 155.11 150.0, 147.9, 137.0,
135.4, 130.9, 129.2, 123.7, 123.4, 118.8, 115.8, 94.9, 76.0, 30.1,
21.7, 18.9, 13.5; HRMS calcd for C19H19NO 277.1467, found
277.1476.
hexanes/dichloromethane as an eluent to give 45.2 mg of 48: Rf =
0.10 (20:1 hexanes/dichloromethane); 1H NMR (300 MHz,
CDCl3) δ 7.48 (m, 2H), 7.43-7.12 (m, 14H), 6.71 (d, 1H, J =
16 Hz), 6.41 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 156.3, 137.2,
134.0, 133.2, 131.5, 129.4, 128.7, 128.7, 128.4, 128.0, 126.8, 123.8,
123.2, 122.1, 118.1, 93.3, 85.2; HRMS calcd for C24H18O
322.1358, found 322.1359.
(3Z,5E)-1-Phenyl-3-phenoxy-6-(4-methylphenyl)hex-1-yne-
3,5-diene (49). Pale yellow solid prepared according to repre-
sentative procedure A on a 0.18 mmol scale. Purified via flash
chromatography using 20:1 hexanes/dichloromethane as
an eluent to give 39.1 mg of 49: Rf = 0.10 (20:1 hexanes/
1
dichloromethane); H NMR (300 MHz, CDCl3) δ 7.42-7.35
(m, 4H), 7.32-7.25 (m, 6H), 7.22-7.11 (m, 5H), 6.68 (d, 1H,
J = 16 Hz), 6.40 (m, 1H), 2.37 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 156.4, 138.0, 134.4, 133.5, 133.3, 131.5, 129.43,
129.37, 128.7, 128.3, 126.7, 124.2, 123.1, 122.2, 121.2, 118.0,
93.1, 85.3, 21.4; HRMS calcd for C25H20O 336.1514, found
336.1515.
(3Z,5E)-1-Phenyl-3-phenoxy-6-(4-chlorophenyl)hex-1-yne-3,5-
diene (50). Pale yellow solid prepared according to representative
procedure A on a 0.18 mmol scale. Purified via flash chroma-
tography using 20:1 hexanes/dichloromethane as an eluent to
1
give 29.5 mg of 50: Rf = 0.40 (9:1 hexanes/ethyl acetate); H
NMR(300 MHz, CDCl3) δ 7.42-7.12 (m, 15H), 6.63 (d, 1H, J =
16 Hz), 6.36 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 156.2, 135.7,
134.5, 133.5, 131.6, 131.5, 129.4, 128.9, 128.8, 128.4, 127.9, 123.3,
123.2, 122.7, 122.0, 118.2, 93.6, 85.0; HRMScalcd for C24H17ClO
356.0968, found 356.0962.
3-Benzyl-5-phenoxybiphenyl (52). Colorless solid prepared
according to representative procedure A on a 0.18 mmol scale.
Purified via flash chromatography using 20:1 hexanes/dichloro-
methane as an eluent to give 25.7 mg of 52: Rf = 0.13 (20:1
1
hexanes/dichloromethane); H NMR (300 MHz, CDCl3) δ
7.40-7.25 (m, 8H), 7.20-7.06 (m, 5H), 7.03-6.98 (m, 2H),
6.95-6.90 (m, 3H), 4.05 (s, 2H); 13C NMR (75 MHz, CDCl3)
δ 157.3, 155.7, 144.7, 141.3, 141.2, 129.9, 129.7, 129.4, 128.4,
128.1, 128.0, 127.2, 127.1, 125.48, 125.45, 123.0, 118.5,
117.9, 33.0; HRMS calcd for C25H20O 336.1514, found
336.1517.
(Z)-1-(2-Thiophene-yl)-2-(phenoxy)oct-1-ene-3-yne (45). Col-
orless oil prepared according to representative procedure B on a
0.28 mmol scale. Purified via flash chromatography using 9:1
hexanes/dichloromethane as an eluent to give 23.2 mg of 45:
Rf = 0.18 (9:1 hexanes/dichloromethane); 1H NMR (300 MHz,
CDCl3) δ 7.38-7.32 (m, 2H), 7.28-7.25 (m, 1H), 7.18-7.09
(m, 4H), 7.02-6.98 (m, 1H), 6.58 (s, 1H), 2.27 (t, 2H), 1.47-1.37
(m, 2H), 1.34-1.23 (m, 2H), 0.85 (t, 3H); 13C NMR (75 MHz,
CDCl3) δ 155.1, 137.4, 132.4, 129.2, 127.1, 126.9, 126.4, 123.2,
118.1, 115.1, 94.9, 75.9, 30.2, 21.7, 19.0, 13.5; HRMS calcd for
C18H18OS 282.1078, found 282.1072.
(Z)-1-(4-Methoxyphenyl)-2-phenoxy-5-phenylpent-1-ene (53).
Colorless oil prepared according to representative procedure E
on a 0.34 mmol scale. Purified via flash chromatography using
24:1 hexanes/ethyl acetate as an eluent to give 48.3 mg of 53:
1
Rf = 0.18 (24:1 hexanes/ethyl acetate); H NMR (300 MHz,
CDCl3) δ 7.51 (m, 2H), 7.37-7.28 (m, 5H), 7.25-7.18 (m, 3H),
7.10-7.04 (m, 3H), 6.84 (m, 2H), 5.94 (s, 1H), 3.81 (s, 3H), 2.70
(t, 2H), 2.36 (t, 2H), 1.92 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
158.3, 155.5, 150.5, 142.1, 129.7, 128.5, 128.3, 127.8, 125.8,
122.2, 117.0, 115.1, 113.8, 55.2, 35.1, 32.7, 28.7. We were unable
to obtain satisfactory HRMS of this compound.
(Z)-1,7-Diphenyl-4-phenoxyhept-1-yne-3-ene (54). Colorless
oil prepared according to representative procedure E on a 0.34
mmol scale. Purified via flash chromatography using 24:1
hexanes/ethyl acetate as an eluent to give 27.8 mg of 54: Rf =
0.28 (20:1 hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ
7.43-7.05 (m, 15H), 5.32 (d, 1H, J = 0.6 Hz), 2.72 (t, 2H, J =
7.5 Hz), 2.37 (t, 2H, J = 7.5 Hz), 1.94 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 163.2, 156.0, 141.7, 131.3, 129.4, 128.44, 128.40,
127.7, 125.9, 123.6, 122.8, 118.0, 94.3, 93.1, 84.3, 35.1, 33.2, 28.4.
We were unable to obtain satisfactory HRMS of this com-
pound.
(Z)-1-(2-Thiophene-yl)-2-phenoxy-4-phenylbut-1-en-3-yne (46).
Colorless solid prepared according to representative procedure A
on a 0.28 mmol scale. Purified via flash chromatography using
20:1 hexanes/dichloromethane to give 24.3 mg of 46: Rf = 0.55
(20:1 hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ
7.42-7.36 (m, 2H), 7.33-7.13 (m, 11H), 7.04 (m, 1H), 6.77 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 155.2, 137.2, 132.2, 131.4,
129.3, 128.7, 128.3, 127.8, 127.6, 126.6, 123.5, 122.1, 118.3, 116.3,
93.4, 84.6. We were unable to obtain satisfactory HRMS of this
compound.
(Z)-1-[2-(Methylthio)phenyl]-2-phenoxy-4-phenylbut-1-en-3-
yne (47). Colorless solid prepared according to representative
procedure A on a 0.20 mmol scale. Purified via flash chroma-
tography using 3% diethyl ether in hexanes to give 27.7 mg of
47: Rf = 0.26 (24:1 hexanes/ethyl acetate); 1H NMR (300
MHz, CDCl3) δ 8.01 (m, 1H), 7.43-7.14 (m, 13H), 6.89 (s,
1H), 2.55 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 155.6, 137.1,
135.4, 133.2, 131.5, 129.8, 129.3, 128.7, 128.3, 128.1, 127.2,
125.5, 123.5, 118.7, 117.8, 92.4, 85.2, 16.9. We were unable to
obtain satisfactory HRMS of this compound.
(Z)-4-Phenoxy-7-phenylhept-3-ene (56). Colorless oil pre-
pared according to representative procedure E on a 0.34 mmol
scale. Purified via flash chromatography using a gradient of
hexanes to 4:1 hexanes/dichloromethane as an eluent to give
(3Z,5E)-1,6-Diphenyl-3-phenoxyhex-1-yne-3,5-diene (48). Pale
yellow solid prepared according to representative procedure A on
a 0.18 mmol scale. Purified via flash chromatography using 20:1
1
30.2 mg of 56: Rf = 0.20 (9:1 hexanes/dichloromethane); H
NMR (300 MHz, CDCl3) δ 7.35-7.29 (m, 4H), 7.24-7.19
6368 J. Org. Chem. Vol. 75, No. 19, 2010

Geary and Hultin
JOCFeatured Article
(m, 3H), 7.05-6.98 (m, 3H), 5.08 (t, 1H, J = 7.2 Hz), 2.67 (t, 2H,
J = 7.6 Hz), 2.22 (t, 2H, J = 8 Hz), 2.09 (t, 2H, J = 7 Hz), 1.84
(m, 2H), 1.00 (t, 3H, J = 8 Hz); 13C NMR (75 MHz, CDCl3) δ
156.8, 149.7, 142.2, 129.5, 128.5, 128.3, 125.8, 121.4, 118.3,
115.9, 35.2, 31.9, 28.5, 18.7, 14.1. We were unable to obtain
satisfactory HRMS of this compound.
methane, dried with magnesium sulfate, filtered, and concen-
trated. The crude residue was applied to a silica gel column
pretreated with 2.5 volume% of triethylamine and eluted with
hexanes to yield 1.21 mg of 59 as a colorless oil: Rf = 0.7 (9:1
1
hexanes/ethyl acetate); H NMR (300 MHz, CDCl3) δ7.41-
7.34 (m, 2H), 7.19-7.13 (m, 1H), 7.09-7.04 (m, 2H), 2.30 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 154.5, 134.9, 129.7, 124.0,
116.6, 116.5, 21.6; HRMS calcd for C9H8Cl2O 201.9952, found
201.9944.
(E)-1-Benzyloxy-1,2-dichloroethylene (57). KH (2.74 g, 20.5
mmol, 2.05 equiv) was weighed into a round-bottom flask and
washed with three portions of petroleum ether. The KH was
then suspended in 40 mL THF, benzyl alcohol (1.0 mL, 10
mmol) was added dropwise, and the reaction was allowed to stir
for 15 min. The suspension was cooled to approximately -50 °C
(CHCl3/CO2 (s) bath). Trichloroethylene (1.35 mL, 15 mmol,
1.5 equiv) was then added dropwise. The reaction was allowed to
warm gradually to room temperature overnight. The reaction
was cooled to 0 °C, diluted with petroleum ether, and then
quenched with ice-cold water. The phases were separated, and
the aqueous phase was extracted once more with petroleum
ether. The organic layers were combined, dried with sodium
sulfate, filtered, and concentrated to give a yellow to dark brown
oil. The crude oil was applied to a silica column pretreated with
triethylamine (ca. 2.5 vol % with respect to the volume of dry
silica) and eluted with hexanes to give 1.00 g of 57: Rf = 0.55 (9:1
(E)-1,2-Dichloro-1-phenoxy-1,4-pentadiene (60). Clear oil
prepared according to representative procedure F on a 0.80
mmol scale using 2.5 equiv of allyl bromide. Purified via flash
chromatography using 9:1 hexanes/dichloromethane as an
eluent to give 107.11 mg of 60 (66% yield). Rf = 0.55 (9:1
hexanes/dichloromethane); 1H NMR (300 MHz, CDCl3) δ
7.41-7.34 (m, 2H), 7.19-7.13 (m, 1H), 7.08-7.03 (m, 2H),
5.97-5.83 (m, 1H), 5.32-5.22 (m, 2H), 3.33 (dd, 1H); 13C
NMR (75 MHz, CDCl3) δ 154.3, 135.5, 129.8, 124.1, 118.7,
118.1, 116.5, 39.0. We were unable to obtain satisfactory
HRMS for this compound.
(E)-1,2-Dichloro-1-(trimethylsilyl)-2-phenoxyethylene (61).
Clear oil prepared according to representative procedure F on
a 0.88 mmol scale using 2.0 equiv of chlorotrimethylsilane as
the electrophile. Purified via flash chromatography using 17:1
hexanes: ethyl acetate as an eluent to give 205.8 mg of 61 (89%
yield): Rf = 0.55 (9:1 hexanes/dichloromethane); 1H NMR
(300 MHz, CDCl3) δ 7.42-7.36 (m, 2H), 7.21-7.15 (m, 1H),
7.09-7.05 (m, 2H), 0.41 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
154.0, 143.6, 129.8, 124.2, 117.9, 117.0, -0.97; HRMS calcd
for C11H14Cl2OSi 260.0191, found 260.0194.
1
hexanes/ethyl acetate). H and 13C NMR data are consistent
with literature values:48 1H NMR (300 MHz, CDCl3) δ 7.48-
7.37 (m, 5H), 5.53 (s, 1H), 5.07 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 143.4, 134.7, 128.8, 128.6, 128.6, 98.9, 73.4.
One-Pot Double Suzuki Coupling: Synthesis of (Z)-1-[3-[1-
(Benzyloxy)-2-p-tolylvinyl)phenyl]ethanone (58). Pd2dba3 (3.6 mg,
3.9 μmol, 2.5 mol %), DPEphos (4.3 mg, 7.8 μmol, 5 mol %),
3-acetylphenylboronic acid (22.7 mg, 0.137 mmol, 1.05 equiv),
CsF (59.5 mg, 0.39 mmol, 3 equiv), and Cs2CO3 (127.6 mg, 0.39
mg, 3 equiv) were added to an oven-dried test tube and sealed
with a septum. The test tube was purged with argon for 10 min.
A solution of benzyl dichlorovinyl ether 57 (26.5 mg, 0.13
mmol, 1 equiv) in 0.65 mL of THF was added to the test tube,
and the reaction mixture was brought to reflux. When the first
cross-coupling was deemed complete as judged by TLC
(approximately 12 h), the reaction mixture was cooled to room
temperature, and 4-methylphenylboronic acid (26.9 mg, 0.19
mmol, 1.5 equiv) was added as a solid. The reaction mixture
reheated to reflux. After 20 h, the reaction mixture was cooled
and partitioned between dichloromethane and water. The
layers were separated, and the aqueous layer was reextracted
with dichloromethane twice more. The organic layers were
combined, dried with magnesium sulfate, filtered, and concen-
trated. The crude residue was applied to a silica gel column
eluted with 9:1 hexanes/ethyl acetate to give 33.4 mg 58 (75%
Ethyl (E)-2,3-Dichloro-3-phenoxyacrylate (62). Clear oil pre-
pared according to representative procedure F on 1.2 mmol
scale using 2.5 equiv of ethylchloroformate. Purified via flash
chromatography using 9:1 hexanes/dichloromethane as an elu-
ent to give 174.4 mg of 62 (56% yield): Rf = 0.50 (9:1 hexanes/
1
ethyl acetate); H NMR (300 MHz, CDCl3) δ 7.42-7.35 (m,
2H), 7.25-7.19 (m, 1H), 7.09-7.04 (m, 2H), 4.35 (m, 2H), 1.38
(t, 3H); 13C NMR (75 MHz, CDCl3) δ 161.8, 153.4, 145.7, 129.9,
125.4, 118.6, 109.8, 62.6, 14.1; HRMS calcd for C11H10Cl2O3
260.0007, found 260.0006.
(E)-1,2-Dichloro-1-phenoxy-3-hydroxy-4-methylpentene (63).
Clear oil prepared according to representative procedure F on a
0.83 mmol scale using 2.0 equiv of isobutyraldehyde. Purified
via flash chromatography using 9:1 hexanes/ethyl acetate as
an eluent to give 200.1 mg of 63 (92% yield): Rf = 0.21 (9:1
1
hexanes/ethyl acetate); H NMR (300 MHz, CDCl3) δ 7.40-
7.33 (m, 2H), 7.19-7.13 (m, 1H), 7.07-7.02 (m, 2H), 4.43 (m,
1H), 2.07 (br d, 1H), 2.04-1.94 (m, 1H), 1.16 (d, 3H, J = 6.6
Hz), 0.98 (d, 3H, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ
154.0, 136.5, 129.8, 124.3, 122.3, 116.9, 76.3, 32.8, 19.0, 18.5;
HRMS calcd for C12H14Cl2O2 260.0371, found 260.0362.
(E)-1,2-Dichloro-1-phenoxy-3-(4-methylphenyl)propen-3-ol (64).
Clear oil prepared according to representative procedure F on a
0.70 mmol scale using 1.5 equiv of p-tolualdehyde. Purified via
flash chromatography using 9:1 hexanes/ethyl acetate as an eluent
to give 203.1 mg of 64 (94% yield): Rf = 0.18 (9:1 hexanes/ethyl
acetate); 1H NMR (300 MHz, CDCl3) δ 7.47-7.38 (m, 4H), 7.28
(d, 2H, J = 8 Hz), 7.25-7.19 (m, 1H), 7.12-7.08 (m, 2H), 6.11 (br
s, 1H), 2.61 (br s, 1H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
154.1, 138.1, 136.7, 136.5, 129.9, 129.4, 125.6, 124.5, 122.5, 117.0,
71.5, 21.2; HRMS calcd for C16H14Cl2O2 308.0371, found
308.0373.
1
yield): Rf = 0.40 (4:1 hexanes/ethyl acetate); H NMR (300
MHz, CDCl3) δ 8.18 (m, 1H), 7.93 (m, 1H), 7.81 (m, 1H), 7.67
(d, 2H), 7.51 (t, 1H), 7.42-7.33 (m, 5H), 7.17 (m, 2H), 6.29 (s,
1H), 4.79 (s, 2H), 2.62 (s, 3H), 2.37 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 198.0, 153.2, 137.5, 137.5, 137.1, 136.9, 132.6, 130.8,
129.2, 128.9, 128.6, 128.1, 127.98, 127.95, 126.3, 114.8, 26.7,
21.3; HRMS calcd for C24H22O2 342.1620, found 342.1622.
Representative Procedure F for Synthesis of 2-Substituted 1,2-
Dichlorovinyl Ethers from Dichlorovinyl Ether 1: Synthesis of
(E)-1,2-Dichloro-1-phenoxypropene (59). A solution of the di-
chlorovinyl ether 1 (149.3 mg, 0.79 mmol, 1 equiv) in 4 mL of
THF was cooled to -78 °C. n-BuLi as a 1.6 M solution in
hexanes (0.56 mL, 0.89 mmol, 1.13 equiv) was added dropwise
and stirred for 5 min. Iodomethane (98 μL, 1.58 mmol, 2 equiv)
was added dropwise. The solution was allowed to stir at -78 °C
for 1 h and allowed to warm to room temperature. The reaction
was quenched with NH4Cl, extracted twice with dichloro-
Procedure for the One-Pot Synthesis of 62 from Phenol. KH
(2.74 g, 20.5 mmol, 2.05 equiv) was weighed into a round-
bottom flask and washed with three 5 mL portions of petroleum
ether. The KH was then suspended in 20 mL of THF. A solution
of phenol (0.9411 g, 10 mmol, 1.0 equiv) in 5 mL of THF was
added dropwise, and the reaction was allowed to stir at room
(48) Dudley, G. B.; Takaki, K. S.; Cha, D. D.; Danheiser, R. L. Org. Lett.
2000, 2, 3407–3410.
J. Org. Chem. Vol. 75, No. 19, 2010 6369

Geary and Hultin
JOCFeatured Article
temperature for 60 min. The suspension was cooled to approxi-
mately -50 °C (CHCl3/CO2 (s) bath), and trichloroethylene
(TCE) (1.35 mL, 15 mmol, 1.5 equiv) was then added dropwise.
The reaction was allowed to warm gradually to room tempera-
ture overnight. The solution of the dichlorovinyl ether was
cooled to -78 °C. n-BuLi (7.5 mL of 1.6 M solution in hexanes,
1.13 equiv) was added dropwise and stirred for 5 min. Ethyl
chloroformate (2.0 mL, 20 mL, 2.0 equiv) was added dropwise.
The solution was allowed to stir at -78 °C for 5 h before being
quenched with H2O. The mixture was extracted twice with
dichloromethane, and the combined organic extracts were dried
with magnesium sulfate, filtered, and concentrated. The crude
residue was applied to a silica gel column pretreated with 2.5 vol
% of triethylamine, which was then eluted with 14:1 hexanes/
diethyl ether to yield 1.32 g of adduct 62.
Cross-Coupling between Vinyl Chloride 59 and p-Methoxy-
phenylboronic Acid. This reaction was performed according to
representative procedure A on a 0.37 mmol scale. The product
was purified via flash chromatography using 9:1 hexanes/di-
chloromethane as an eluent to give 54.1 mg of (Z)-65 and 4.0 mg
of a minor product identified by its 1H and 13C NMR spectra as
(E)-65.
0.31 mmol, 1 equiv) in toluene (0.75 mL) was added, and the
suspension was refluxed overnight. When complete, the reaction
was cooled, partitioned between dichloromethane and water. The
layers were separated, and the water layer was extracted twice
more with dichloromethane. The organic layers were combined,
dried with magnesium sulfate, filtered, and concentrated onto
silica gel, which was applied to a silica gel column and eluted with
14:1 hexanes/dichloromethane to give 83.6 mg of 67: Rf = 0.24
(9:1 hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.46
(m, 2H), 7.17 (t, 2H, J = 7.5 Hz), 7.05-6.85 (m, 7H), 6.77 (m,
1H), 5.93 (s, 2H), 3.81 (s, 3H), 2.22 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 159.1, 157.3, 147.2, 146.2, 145.0, 134.5, 131.0, 129.2,
128.0, 122.5, 121.3, 121.2, 117.0, 113.5, 108.6, 108.0, 100.8, 55.2,
20.2; HRMS calcd for C23H20O4 360.1362, found 360.1362.
(Z)-1-Phenoxy-1-(4-methoxyphenyl)-2-[3,5-bis(trifluoromethyl)-
phenyl]propene (68). This compound was prepared according to
representative procedure H on a 0.30 mmol scale. Purified via
flash chromatography using 14:1 hexanes to ethyl acetate as an
eluent to give 115.2 mg of 68: Rf = 0.32 (14:1 hexanes/ethyl
acetate); 1H NMR (300 MHz, CDCl3) δ 7.94 (s, 2H), 7.72 (s, 1H),
7.50 (m, 2H), 7.16 (m, 2H), 6.95-6.82 (m, 5H), 3.83 (s, 3H), 2.30
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.7, 156.7, 147.7, 142.7,
131.3, 131.0, 129.3, 128.3, 128.3, 126.9, 125.6, 121.9, 121.6, 120.3,
120.3, 119.8, 116.7, 113.7, 55.2, 19.5; 19F NMR (282 MHz,
CDCl3) δ -62.92; HRMS calcd for C24H18F6O2 452.1211, found
452.1216.
(Z)-1-Phenoxy-1-(4-methoxyphenyl)-2-[2-(methylthio)phenyl]-
propene (69). This compound was prepared according to repre-
sentative procedure H on a 0.30 mmol scale. Purified via flash
chromatography using 12:1 hexanes to ethyl acetate as an eluent
to give 78.5 mg of 69: Rf = 0.31 (12:1 hexanes/ethyl acetate); 1H
NMR (300 MHz, CDCl3) δ 7.51 (m, 2H), 7.23-7.04 (m, 6H),
6.90-6.84 (m, 4H), 6.79 (m, 1H), 3.80 (s, 3H), 2.48 (s, 3H), 2.18
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.2, 157.3, 146.3, 140.3,
136.7, 130.9, 128.8, 128.5, 127.4, 127.3, 125.6, 124.7, 122.7, 121.1,
117.3, 113.5, 55.2, 19.6, 15.9; HRMS calcd for C23H22O2S
362.1341, found 362.1348.
(1Z,3E)-1-Phenoxy-1-(4-methoxyphenyl)-2-methyl-5-phenyl-
penta-1,3-diene (70). This compound was prepared according
to representative procedure H on a 0.30 mmol scale. Purified via
flash chromatography using a gradient of neat hexanes to 14:1
hexanes to ethyl acetate as an eluent to give 100.9 mg of 70: Rf =
0.34 (14:1 hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3)
δ 7.42 (m, 2H), 7.36-7.31 (m, 7H), 7.00-6.84 (m, 7H), 6.03-
5.92 (m, 1H), 3.81 (s, 3H), 3.52 (d, 2H, J = 7.7 Hz), 2.04 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 159.2, 157.5, 146.0, 140.8, 131.0,
129.6, 129.4, 128.6, 128.6, 128.5, 128.3, 127.7, 126.1, 121.5,
121.0, 116.7, 113.4, 55.2, 39.9, 14.5. We were unable to obtain
satisfactory HRMS for this compound.
(1Z,3E)-1-Phenoxy-1-(4-methoxyphenyl)-2-methyl-4-phenyl-
buta-1,3-diene (71). This compound was prepared according to
representative procedure H on a 0.30 mmol scale. Purified via
flash chromatography using a gradient of neat hexanes to 9:1
hexanes to ethyl acetate as an eluent to give 78.5 mg of 71: Rf =
0.25 (9:1 hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ
7.54 (d, 1H, J = 16 Hz), 7.47-7.41 (m, 4H), 7.34-7.28 (m, 2H),
7.25-7.19 (m, 3H), 7.00-6.83 (m, 5H), 6.71 (d, 1H, J = 16 Hz),
3.80 (s, 3H), 2.16 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.3,
157.5, 147.9, 138.0, 131.2, 129.4, 128.7, 128.6, 127.6, 127.3,
126.5, 126.1, 121.8, 121.2, 117.0, 113.5, 55.2, 14.6; HRMS calcd
for C24H22O2 342.1620, found 342.1625.
(Z)-1-(2-Chloro-1-phenoxyprop-1-enyl)-4-methoxybenzene
((Z)-65): Rf = 0.48 (9:1 hexanes/ethyl acetate); H NMR (300
1
MHz, CDCl3) δ 7.37 (m, 2H), 7.24-7.18 (m, 2H), 6.97-6.92 (m,
3H), 6.84 (m, 2H), 3.77 (s, 3H), 2.32 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 159.7, 156.2, 145.4, 130.5, 129.4, 125.8, 122.1, 119.5,
116.5, 113.8, 55.2, 22.1; HRMS calcd for C16H15ClO2 274.0761,
found 274.0767.
(E)-1-(2-Chloro-1-phenoxyprop-1-enyl)-4-methoxybenzene
((E)-65): 1H NMR (300 MHz, CDCl3) δ 7.33-7.26 (m, 5H),
7.09-7.04 (m, 1H), 7.02-6.98 (m, 1H), 6.80 (m, 2H), 3.76 (s, 3H),
2.24 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.6, 155.3, 135.2,
130.5, 130.4, 129.5, 129.4, 128.8, 116.7, 113.5, 55.2, 20.2.
Representative Procedure G for Lithiation and Electrophilic
Quenching of 1-Aryl-2-chlorovinyl Ethers: Synthesis of (Z)-1-
(2-Chloro-1-phenoxyprop-1-enyl)-4-methoxybenzene (65) from 2.
This procedure is similar to representative procedure F for the
alkylation of 1,2-dichlorovinyl ethers. A solution of the chloro-
vinyl ether 2 (800 mg, 3.06 mmol, 1 equiv) in 46 mL of THF was
cooled to -78 °C. n-BuLi as a 1.6 M solution in hexanes (2.2 mL,
3.47 mmol, 1.13 equiv) was added dropwise, and the mixture was
stirred for 30 min. The iodomethane (0.38 mL, 6.1 mmol,
2 equiv) was then added dropwise. The solution was allowed to
stir at -78 °C for 10 min and then was quenched with water. It
was then extracted twice with dichloromethane, dried with
magnesium sulfate, filtered, and concentrated. The crude residue
was applied to a silica gel column pretreated with 2.5 vol % of
triethylamine and eluted with 9:1 hexanes/ethyl acetate to yield
832.1 mg of 65. NMR data are listed above.
Ethyl (Z)-3-Phenoxy-3-(4-methoxyphenyl)-2-chloroacrylate
(66). Clear oil prepared on a 3.06 mmol scale according to
representative procedure G. Purified via flash chromatography
using 9:1 hexanes/ethyl acetate as an eluent to give 938.8 mg of
66: Rf = 0.25 (9:1 hexanes/ethyl acetate); 1H NMR (300 MHz,
CDCl3) δ 7.32 (m, 2H), 7.21 (m, 2H), 6.98 (m, 1H), 6.92 (m, 2H),
6.80 (m, 2H), 4.15 (q, 2H), 3.77 (s, 3H), 1.13 (t, 3H); 13C NMR
(75 MHz, CDCl3) δ 164.1. 160.9, 158.8, 155.0, 131.1, 129.5,
124.9, 123.4, 118.5, 113.5, 113.5, 110.7, 61.9, 55.2, 13.8; HRMS
calcd for C18H17ClO4 332.0815, found 332.0815.
Representative Procedure H for the Synthesis of Tetrasub-
stituted Alkenes: (Z)-1-Phenoxy-1-(4-methoxylphenyl)-2-(3,4-
methylenedioxyphenyl)propene (67). The boronic acid (77.5
mg, 0.46 mmol, 1.5 equiv), Pd(OAc)2 (3.4 mg, 0.015 mmol,
5 mol %), S-Phos (12.5 mg, 0.031 mmol, 10 mol %), and Cs2CO3
(218.8 mg, 0.67 mmol, 2.2 equiv) were placed in a one-piece,
round-bottom flask/condenser, sealed with a septum, and purged
with argon for 20 min. A solution of the vinyl chloride 65 (83.8 mg,
(1Z,3E)-1-Phenoxy-1-(4-methoxyphenyl)-2-methyl-4-(4-methyl-
phenyl)-buta-1,3-diene (72). This compound was prepared accord-
ing to representative procedure H on a 0.30 mmol scale. Purified
via flash chromatography using a gradient of neat hexanes to
9:1 hexanes/ethyl acetate as an eluent to give 78.5 mg of 72: Rf =
1
0.25 (9:1 hexanes/ethyl acetate); H NMR (300 MHz, CDCl3)
δ7.49-6.81 (m, 14H) 6.68 (d, 1H, J = 16 Hz),3.79 (s, 3H), 2.34
6370 J. Org. Chem. Vol. 75, No. 19, 2010

Geary and Hultin
JOCFeatured Article
(s, 3H), 2.14 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.2, 157.6,
147.5, 137.1, 135.2, 131.1, 129.6, 129.4, 129.3, 128.9, 127.7, 126.4,
125.1, 121.7, 121.3, 117.0, 113.5, 55.2, 21.2, 14.4; HRMS calcd for
C25H24O2 356.1776, found 136.1780.
2H), 7.31-7.12 (m, 6H), 7.02-6.87 (m, 6H), 6.64 (d, 1H, J = 16
Hz), 4.33 (q, 2H), 3.83 (s, 3H), 2.37 (s, 3H), 1.21 (t, 3H); 13C NMR
(75 MHz, CDCl3) δ 168.0, 160.4, 156.8, 151.6, 137.6, 134.5, 131.6,
131.1, 129.4, 129.2, 126.4, 125.1, 122.6, 122.4, 121.3, 117.8, 113.9,
61.2, 55.3, 21.3, 14.1; HRMS calcd for C27H26O4 414.1831, found
414.1835.
Ethyl (E)-3-Phenoxy-3-(4-methoxyphenyl)-2-(4-fluorophenyl)-
acrylate (73). This compound was prepared according to repre-
sentative procedure H on a 0.30 mmol scale. Purified via flash
chromatography using a gradient of 12:1 to 9:1 hexanes/ethyl
acetate as an eluent to give 85.0 mg of 73: Rf = 0.35 (4:1 hexanes/
ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.42-7.36 (m, 4H),
7.19-7.13 (m, 2H), 7.00-6.86 (m, 5H), 6.82-6.78 (m, 2H), 4.10
(q, 2H), 3.77 (s, 3H), 1.06 (t, 3H); 13C NMR (75 MHz, CDCl3) δ
169.4, 163.7, 160.5, 156.2, 154.6, 130.6, 130.4, 129.4, 126.8, 122.6,
121.0, 117.9, 115.4, 115.1, 113.7, 61.2, 55.2, 13.9; HRMS calcd for
C24H21FO4 392.1424, found 392.1437.
Ethyl (E)-3-Phenoxy-3-(4-methoxyphenyl)-2-(4-methylphenyl)-
acrylate (74). This compound was prepared according to repre-
sentative procedure H on a 0.30 mmol scale. Purified via flash
chromatography using a 10:1 hexanes to ethyl acetate as an eluent
to give 102.1 mg of 74: Rf = 0.36 (4:1 hexanes/ethyl acetate); 1H
NMR (300 MHz, CDCl3) δ7.44(m, 2H), 7.35(m, 2H), 7.23-7.11
(m, 4H), 6.97-6.92 (m, 3H), 6.83 (m, 2H), 4.14 (q, 2H), 3.80 (s,
3H), 2.35 (s, 3H), 1.11 (t, 3H); 13C NMR (75 MHz, CDCl3) δ
169.7, 160.3, 156.5, 153.5, 137.4, 131.6, 130.3, 129.3, 129.0, 128.4,
127.1, 122.4, 122.3, 118.0, 113.7, 61.1, 55.2, 21.3, 13.9; HRMS
calcd for C25H24O4 388.1675, found 388.1674.
(1E,3E)-1-Phenoxy-1-(4-methoxyphenyl)-2-(carboxyethyl)-
4-(4-chlorophenyl)buta-1,3-diene (78). This compound was pre-
pared according to representative procedure H on a 0.30 mmol
scale. Purified via flash chromatography using 7:1 hexanes/ethyl
acetate as an eluent to give 81.4 mg of 78: Rf = 0.35 (4:1 hexanes/
ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.47 (m, 2H),
7.32-7.28 (m, 5H), 7.21 (m, 3H), 7.00-6.88 (m, 6H), 6.60 (d, 1H,
J = 16 Hz), 4.33 (q, 2H), 3.83 (s, 3H), 1.21 (t, 3H); 13C NMR (75
MHz, CDCl3) δ167.8, 160.6, 156.6, 152.8, 135.8, 133.2, 131.6, 129.6,
129.2, 128.8, 127.6, 124.8, 122.9, 122.5, 122.1, 117.9, 114.0, 61.2,
55.3, 14.1; HRMS calcd for C26H23ClO4 434.1285, found 434.1287.
(1E,3Z)-1-Phenoxy-1-(4-methoxyphenyl)-2-(carboxyethyl)-
penta-1,3-diene (79). This compound was prepared according
to representative procedure H on a 0.30 mmol scale. Purified via
flash chromatography using 7:1 hexanes/ethyl acetate as an
eluent to give 81.4 mg of79: Rf = 0.35(4:1 hexanes/ethyl acetate);
1H NMR (300 MHz, CDCl3) δ 7.38 (m, 2H), 7.24-7.18 (m, 2H),
7.00-6.91 (m, 3H), 6.81 (m, 2H), 6.24 (m, 1H), 5.78-5.67 (m,
1H), 4.14 (q, 2H), 3.79 (s, 3H), 1.70 (dd, 3H, J1 = 2 Hz, J2 =
7 Hz), 1.14 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 169.5, 160.4,
156.0, 154.4, 130.4, 129.4, 128.9, 126.5, 122.5, 122.4, 119.3, 117.6,
113.6, 61.1, 55.2, 14.9, 13.8; HRMS calcd for C21H22O4 338.1518,
found 338.1527.
(1E,3E)-1-Phenoxy-1-(4-methoxyphenyl)-2-(carboxyethyl)-5-
phenylpenta-1,3-diene (80). This compound was prepared ac-
cording to representative procedure H on a 0.30 mmol scale.
Purified via flash chromatography using a gradient of 9:1 to 7:1
hexanes/ethyl acetate as an eluent to give 81.4 mg of 80: Rf =
0.28 (4:1 hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ
7.45-7.19 (m, 10H), 7.02-6.93 (m, 3H), 6.82 (m, 2H). 6.66 (m,
2H), 6.09-5.98 (m, 1H), 4.15 (q, 2H), 3.79 (s, 3H), 3.52 (d, 2H,
J = 7.2 Hz), 1.09 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 168.6,
160.3, 156.6, 150.8, 140.0, 132.1, 130.8, 129.9, 129.5, 128.6,
128.5, 126.8, 126.2, 126.1, 123.7, 122.4, 122.0, 117.9, 113.7,
113.3, 61.1, 55.2, 39.7, 13.9; HRMS calcd for C27H26O4
414.1831, found 414.1828.
Ethyl (E)-3-Phenoxy-3-(4-methoxyphenyl)-2-(2-methylphenyl)-
acrylate (75). This compound was prepared according to repre-
sentative procedure H on a 0.30 mmol scale. Purified via flash
chromatography using 9:1 hexanes/ethyl acetate as an eluent to
1
give 104.5 mg of 75: Rf = 0.36 (4:1 hexanes/ethyl acetate); H
NMR (300 MHz, CDCl3) δ 7.46 (d, 2H), 7.30 (m, 1H), 7.19-7.07
(m, 5H), 6.89-6.79 (m, 5H), 4.08 (q, 2H), 3.80 (s, 3H), 2.35 (s,
3H), 1.06 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 168.8, 160.5,
157.8, 156.3, 137.1, 134.8, 130.9, 130.0, 129.9, 129.1, 127.7, 126.8,
125.5, 122.4, 120.5, 118.3, 113.5, 60.8, 55.3, 20.0, 13.9; HRMS
calcd for C25H24O4 388.1675, found 388.1676.
(1E,3E)-1-Phenoxy-1-(4-methoxyphenyl)-2-(carboxyethyl)-4-
phenylbuta-1,3-diene (76). This compound was prepared accord-
ing to representative procedure H on a 0.30 mmol scale. Purified
via flash chromatography using 9:1 hexanes/ethyl acetate as an
eluent to give 93.7 mg of 76: Rf = 0.38 (4:1 hexanes/ethyl
1
acetate); H NMR (300 MHz, CDCl3) δ 7.44-7.40 (m, 4H),
7.33-7.19 (m, 7H), 7.01-6.94 (m, 3H), 6.82-6.72 (m, 2H), 4.21
(q, 2H), 3.78 (s, 3H), 1.12 (t, 3H); 13C NMR (75 MHz, CDCl3) δ
168.5, 160.4, 156.6, 152.1, 137.4, 130.8, 130.0, 129.6, 128.6,
127.7, 126.7, 122.6, 122.4, 121.2, 117.5, 113.8, 61.3, 55.2, 13.9;
HRMS calcd for C26H24O4 400.1675, found 400.1674.
(1E,3E)-1-Phenoxy-1-(4-methoxyphenyl)-2-(carboxyethyl)-
4-(4-methylphenyl)buta-1,3-diene (77). This compound was
prepared according to representative procedure H on a 0.30
mmol scale. Purifiedvia flash chromatography using 7:1 hexanes/
ethyl acetate as an eluent to give 113.4 mg of 77: Rf = 0.38 (4:1
hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.49 (m,
Acknowledgment. This work was supported by a Discovery
Grant to P.G.H. from the Natural Sciences and Engineering
Research Council of Canada and by NSERC Postgraduate
Fellowships to L.M.G. We thank Dr. Peter Budzelaar for
helpful suggestions, Dr. Kirk Marat for advice on NMR, and
Mr. Xiao Feng (Dalhousie University) for acquiring HRMS.
Supporting Information Available: Original 1H and 13C
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 19, 2010 6371