Synthesis of trisubstituted alkenes via direct oxidative arene-alkene coupling

Article abstract of DOI:10.1021/jo401326f

The use of an inorganic oxidant with an acetic acid/acetonitrile solvent combination has been identified as optimal for direct arene/1,2-disubstituted alkene oxidative couplings, providing an efficient route to trisubstituted alkenes. The acetonitrile cosolvent dramatically accelerates the rate of reaction, and an insoluble inorganic oxidant limits unwanted oxidation of substrates. The scope of this procedure is illustrated with arenes and alkenes containing electron-donating and -withdrawing substituents resulting in a general synthetic strategy to trisubstituted alkenes. In situ ESI-MS analysis of the reaction components has identified the key Pd intermediates in the Fujiwara-Moritani catalytic cycle.

Full text of DOI:10.1021/jo401326f

Article
pubs.acs.org/joc
Synthesis of Trisubstituted Alkenes via Direct Oxidative Arene−
Alkene Coupling
Roderick C. Jones, Michał Gałęzowski, and Donal F. O’Shea*
School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
S
* Supporting Information
ABSTRACT: The use of an inorganic oxidant with an acetic acid/acetonitrile
solvent combination has been identified as optimal for direct arene/1,2-
disubstituted alkene oxidative couplings, providing an efficient route to
trisubstituted alkenes. The acetonitrile cosolvent dramatically accelerates the
rate of reaction, and an insoluble inorganic oxidant limits unwanted oxidation
of substrates. The scope of this procedure is illustrated with arenes and
alkenes containing electron-donating and -withdrawing substituents resulting
in a general synthetic strategy to trisubstituted alkenes. In situ ESI-MS analysis
of the reaction components has identified the key Pd intermediates in the
Fujiwara−Moritani catalytic cycle.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Transition-metal-promoted cross-coupling reactions of arenes
and alkenes offer an excellent means of synthesizing tri- and
tetrasubstituted alkenes. The importance of these trans-
formations can be recognized through their widespread
application in synthetic, medicinal, and materials chemistry.1
Classical methods such as the Suzuki−Miyaura (boronic acid/
halide), Negishi (zinc/halide), Stille (tin/halide), Hiyama
(silane/halide), and Mizoroki−Heck (aryl halide/alkene)
reactions involve using one or two preactivated coupling
components.2
The synthesis of trisubstituted alkenes via oxidative F-M arene/
alkene couplings offers a distinct set of challenges in identifying
a set of reaction conditions capable of capturing a broad
spectrum of substrate reactivity. Presuming the rate-limiting
step of the reaction is the Pd insertion into the arene C−H
bond, substrate reactivity would be expected to follow a similar
trend as electrophilic aromatic substitution with electron-rich
arenes more amenable to coupling than electron-deficient
arenes.7 Coupling with 1,2-disubstituted alkenes presents an
additional reactivity barrier as they are less reactive than
monosubstituted derivatives such as acrylates. Furthermore,
consideration must be given to the oxidant, which plays a
central role in the Pd catalytic cycle. Desirable, yet sometimes
difficult to reconcile, is the use of a relatively strong oxidant as
this must be done in the presence of alkene and arene
substrates that are susceptible to oxidation themselves.
Previously reported efforts have investigated metallic oxidants
such as AgOAc and Cu(OAc)2, with organic peroxides,
peroxyesters, and benzoquinones also utilized.4e The require-
ment for an oxidant limits the scope of ligands that can be
employed to enhance the Pd electrophilic reactivity due to their
instability under the reaction conditions. To date, the most
successful ligands employed have been heterocyclic pyridines
and amino acids.5a,e,h,i Previous reports of trisubstituted alkene
generation via F-M couplings have been restricted to benzene
or electron-rich arene substrates with oxygen/cocatalyst or
organic peroxides as the terminal oxidant.4d,5a,l−n
Recently, the selective activation of sp2 aryl C−H bonds
utilizing transition metals has attracted substantial research
focus as it provides opportunities for general approaches to
removing the necessity for preactivation of the cross-coupling
partners.3 When specifically applied to alkene derivatization, the
Fujiwara−Moritani (F-M) oxidative coupling via C−H arene
activation and alkene coupling offers the potential to have
neither cross-coupling partner activated.4 This direct approach
to increasing the substituent number on a carbon−carbon
double bond has been predominately explored for the
conversion of monosubstituted alkenes such as acrylates into
disubstituted products.5 Of late, our own research focus has
been the development of novel strategies for the synthesis of
tri- and tetrasubstituted alkenes.6 In this report we describe our
efforts toward a general set of reaction conditions for the direct
arylation of 1,2-disubstituted alkenes using a Pd-catalyzed
oxidative coupling approach. The use of C−H bond activation
for the synthesis of trisubstituted alkenes is rare in comparison
to 1,2-disubstituted derivatives, with no general approach yet
developed.
Received: June 19, 2013
© XXXX American Chemical Society
A
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Our oxidative coupling optimization strategy was to use
Pd(OAc)2 as palladium source and acetic acid as the primary
solvent, with potassium persulfate (K2S2O8) as an inexpensive
and relatively insoluble inorganic oxidant.8 The rationale for
selecting a sparingly soluble oxidant was that it would act with a
slow release mechanism during the course of the reaction. In
this way it was anticipated that the inorganic oxidant would
help facilitate the coupling of electron-deficient arenes, yet due
to its insolubility minimize unwanted oxidation of coupling
reactants and thereby also allow its use with electron-rich
arenes. It would be expected that in acetic acid alone there
would be insufficient reactivity to achieve F-M couplings with
electron-deficient arenes. As such, our approach was to identify
a cosolvent that would generally enhance reactivity and thereby
provide a broarder substrate scope for the synthesis of
trisubstituted alkenes.
The right balance for reaction rate and yield was struck using
MeCN as a cosolvent, though some oxidation byproducts could
be detected (entry 5). As such, the ratio of acetic acid/MeCN
was adjusted to 4:1, which gave a 79% yield (Z/E 7:1 ratio) in
an 8 h reaction time (entry 6). It was observed in successive
experiments that a reduction of the excess of arene 2a could be
achieved to 3.75 equiv with no detrimental effect on yield,
though reaction time lengthened to 24 h (entry 7). Illustrative
experiments were also conducted to highlight the benefits of
the chosen oxidant K2S2O8. For example, when the organic
soluble variants tetrabutylammonium persulfate (Bu4N)2S2O8
and ammonium persulfate (NH4)2S2O8 were utilized as the
oxidant, the alkene substrate 1a was consumed but very little
desired coupling product was detected (entries 8, 9). This can
be attributed to the competing oxidation of starting material by
the strong solubilized oxidants. In addition, the use of 1 atm of
O2 proved less effective than K2S2O8 with the reaction
conversion considerably slower though a 74% yield was
obtained after 48 h (entry 10).
The coupling of (E)-stilbene 1a and 1,4-dimethoxybenzene
2a was selected to identify reaction conditions and to screen
cosolvents for the formation of the triaryl-substituted alkene 3a
(Table 1). The preliminary reaction utilizing 5 mol % of
A more detailed assessment of the influence of acetonitrile
and dioxane cosolvents on the reaction was carried out by a
relative comparison of product formation for the first 8 h of
reaction (Figure 1). Acetic acid alone gave a steady conversion
Table 1. Optimization of Reaction Conditions
c
d
entry
solvent
oxidant
K2S2O8
time (h) Z/E % yield
a
1
AcOH
24
3
2:1
72
<5
70
74
75
79
75
<5
<5
74
a
2
AcOH/DMF (1:1)
AcOH/iPrOH (1:1)
AcOH/dioxane (1:1)
AcOH/MeCN (1:1)
AcOH/MeCN (4:1)
AcOH/MeCN (4:1)
AcOH/MeCN (4:1)
AcOH/MeCN (4:1)
AcOH/MeCN (4:1)
K2S2O8
a
3
K2S2O8
16
48
7
4:1
3:1
7:1
7:1
7:1
a
4
K2S2O8
a
5
K2S2O8
a
6
K2S2O8
8
b
7
K2S2O8
24
12
12
48
8
(Bu4N)2S2O8
(NH4)2S2O8
O2 (1 atm)
9
10
6:1
a
2 mmol (E)-stilbene, 15 mmol 1,4-dimethoxybenzene, 0.1 mmol
b
Pd(OAc)2, 4 mmol K2S2O8, 7.5 mmol 1,4-dimethoxybenzene.
Figure 1. Relative percentage of formation of 3a from 1a and 2a with
K2S2O8 at 80 °C over time in AcOH (green); AcOH/1,4-dioxane
(4:1) (blue); AcOH/MeCN (4:1) (red).
c
d
Determined by GC of crude product. Yield after chromatography.
Pd(OAc)2 and a 7.5-fold excess of arene in acetic acid was slow,
with consumption of the 1a taking 24 h (entry 1). Following
chromatography a 72% yield of the triaryl alkene 3a was
obtained with an Z/E selectivity of 2:1. It was noticeable that
during the course of the reaction a palladium mirror formed.
Next, the addition of a series of cosolvents (iPrOH, DMF,
dioxane, CH3CN) was examined (entries 2−5). Clear trends
were observed when 1:1 ratios of acetic acid to cosolvent were
used such that dioxane significantly slowed the consumption of
1a, whereas DMF, CH3CN, and iPrOH all increased it. Yet
analysis of reaction products showed that DMF was the poorest
as only trace amount of desired product 3a was produced with
a complex mixture of oxidation byproducts observed (entry 2).
2-Propanol gave a 70% yield of 3a but only marginally
decreased reaction time when compared to acetic acid alone
(entry 3). 1,4-Dioxane (entry 4) gave 74% product yield and
minimal byproduct formation, but the rate of conversion was
considerably slower, taking 48 h to achieve complete
conversion of the starting material.
to product with a ∼40% product formation after 8 h. When 1,4-
dioxane was used as cosolvent the rate of conversion was
suppresed, reaching only ∼15% after 8 h. Encouragingly, the
use of MeCN as a cosolvent had a dramatic effect with more
than 85% conversion of the starting material in under 3 h with
reaction deemed complete at 8 h. This could be attributed to
the fact that MeCN can act as an effective ligand to Pd in the
presence of acetic acid. The rate enhancing effect of using
MeCN alone as solvent for the ortho-palladation of benzyl-
amines has been previously described.9 Overall, these results
reaffirmed that AcOH/MeCN (4:1) using K2S2O8 as an oxidant
provided the best results from the conditions screened.
Interestingly, an examination of the product Z/E ratio during
the course of the reaction in AcOH/MeCN showed a change
from 4:1 at earlier time points (1−2 h) to 7:1 upon reaction
completion. This is consistent with the palladium playing an
additional role in isomerizing the product 3a to the most stable
stereoisomer distribution during the course of the reaction. It is
also of note that the cosolvent had a significant effect on the
B
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reaction stereoselectivity as the Z/E ratio in acetic acid alone
was 2:1, whereas with dioxane as cosolvent it was 3:1 upon
reaction completion.
individually synthesized authentic samples showed it to be 1:2
ortho:para mixiture with no meta-isomer observed (Table 2). As
in the previous example above, the reaction in acetic acid alone
was considerably slower taking 24 h to reach completion and
with lower selectivity as all three regioisomers were obtained in
a ortho:meta:para ratio of 2:1:7.
a
Table 2. Analysis of Anisole Stilbene Cross-Coupling
Next, using benzene as a moderately reactive arene, the three
alkenes (E)-stilbene 1a, (E)-chalcone 1b, and (E)-methyl
cinnamate 1c were examined for their ability to participate in a
F-M coupling. The reaction was successful in each case, with
the trisubtituted olefins 3c−e isolated in good to moderate
yields of 48%, 59%, and 67%, respectively (Table 3, entries 1, 3,
4). As would be expected, cinnamate 1c was the most reactive
of the alkenes and stilbene 1a the least. Increasing the
equivalence of benzene to 20-fold for the coupling with stilbene
gave the product triphenylethylene 3c in an improved yield of
74% (entry 2).
b
c
entry
solvent
time (h) ortho:meta:para
% yield
1
2
AcOH/MeCN (4:1)
AcOH
7
1:0:2
2:1:7
84
76
24
a
Reaction conditions: 1a (2 mmol), 2b (15 mmol), K2S2O8 (4 mmol),
Pd(OAc)2 (5 mol %). Determined by GC. Yield after chromatog-
raphy.
b
c
In order to demonstrate the scope of the optimized reaction
conditions, the coupling of a series of activated and deactivated
arenes with these three alkenes was examined (Table 4). Direct
coupling of 1,4-dimethoxybenzene 1a with alkenes 1b and 1c
gave good yields of 66% and 80%, respectively, with reaction
times shorter than that observed for benzene (entries 1, 2). The
reactions of stilbene 1a with p-xylene and thiophene each gave
a good yield of isolated products (entry 3, 4). Encouragingly,
the electron-deficient 1,4-difluorobenzene 2f also effectively
coupled with each of the alkene substrates under the reaction
conditions, giving the trisubstituted olefin products 3j−l in 43−
56% yield (entries 5−7).10 Additionally, coupling of the 1,3,5-
trifluorobenzene 2g with cinnamate 1c gave a good 73% yield
of the coupling product 3m. Taken together these results give a
clear indication that the developed solvent/oxidant system can
be used for a variety of electron-rich and -deficient arenes. In
each case, the products 3f−m were isolated as a mixture of E/Z
isomers that could be characterized by comparison to literature
data or by NOE NMR experiments following stereoisomer
separation. In the case of 3m, both isomers were confirmed by
single crystal X-ray structure following separation by silica gel
chromatography (Supporting Information).
a
Table 3. Alkene Coupling with Benzene
c
entry
alkene
time (h)
product
R
% yield
1
2
3
4
1a
1a
1b
1c
48
24
40
24
3c
3c
3d
3e
Ph
Ph
48
74
59
67
b
COPh
CO2Me
a
Reaction conditions: 1a (2 mmol), 2c (15 mmol), K2S2O8 (4 mmol).
b
c
2c (40 mmol). Yield after chromatography.
The cross-coupling of 1a with anisole 2b was next examined
under the CH3CN cosolvent conditions. Anisole has the
potential to undergo palladium insertion at either the ortho,
meta, or para positions with previous reports showing that the
para position is the most favored followed by ortho, with meta
being the regioisomer least produced.4c,d Coupling of 1a and 2b
in AcOH/CH3CN as solvent system was complete in 7 h with
the mixture of isomeric products 3b isolated in an excellent
84% yield. Analysis by GC−MS and NMR with comparison to
As stilbene 1a was the least reactive of the three alkene
substrates examined, the two further substituted stillbenes (E)-
1,2-bis(4-methoxyphenyl)ethene 1d and (E)-1,2-bis(4-
fluorophenyl)ethene 1e were synthesized and tested for their
ability to undergo coupling reactions with both electron-rich
and -poor arenes (Table 5). It was of interest to explore if the
a
Table 4. Coupling of 1a−c with Electron-Rich and -Poor Arenes
c
entry
1
2
time (h)
3
R
Ar
% yield
1
2
3
4
5
6
7
8
b
c
a
a
a
b
c
c
a
a
d
e
f
7
7
f
g
h
i
COPh
CO2CH3
Ph
1,4-(OMe)2C6H3
1,4-(OMe)2C6H3
1,4-(Me)2C6H3
C4H3S
66
80
75
69
43
56
53
73
7
24
48
48
40
48
Ph
b
j
Ph
1,4-(F)2C6H3
b
f
k
l
COPh
CO2CH3
CO2CH3
1,4-(F)2C6H3
b
f
1,4-(F)2C6H3
b
g
m
1,3,5-(F)3C6H2
a
b
c
Conditions: 2 mmol of alkene, 15 mmol of arene, 5 mol % Pd(OAc)2, 4 mmol K2S2O8, AcOH/MeCN (4:1). 40 mmol of arene. Yield after
chromatography.
C
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a
Table 5. Coupling of 1d−e with Electron-Rich and -Poor Arenes
c
entry
1
2
time (h)
prod
Ar1
Ar2
% yield
1
2
3
4
5
d
d
e
e
e
a
f
3
24
48
48
48
3n
4-MeOC6H4
4-MeOC6H4
4-FC6H4
1,4-(MeO)2C6H3
69
0
b
1,4-(F)2C6H3
a
f
3o
3p
3q
1,4-(MeO)2C6H3
76
42
59
b
4-FC6H4
1,4-(F)2C6H3
b
g
4-FC6H4
1,3,5-(F)3C6H2
a
b
c
Conditions: 2 mmol of alkene, 15 mmol of arene, 5 mol % Pd(OAc)2, 4 mmol K2S2O8, AcOH/MeCN (4:1). 40 mmol of arene. Yield after
chromatography.
inclusion of electron-donating groups on the aryl rings of 1d
would increase formation of oxidation byproducts when reacted
with an electron-deficient arene of relatively low reactivity (a
reactivity mis-match), whereas the inclusion of an electron-
withdrawing fluorines in 1e may impede reactivity with an
electron-rich arene.
Oxidative coupling of 1d with dimethoxybenzene 2a (both
containing electron-donating substituents) gave a good 69%
yield following purification of olefin 3n after only 3 h reaction
time (Table 5, entry 1). In contrast, coupling of 1d with 1,4-
difluorobenzene 2f (alkene electron-donating and arene
electron-withdrawing substituents) for 24 h gave no coupling
product with only alkene degradation observed (entry 2).
Interestingly, the reaction of difluorinated stilbene 1e with the
electron-rich and -poor arenes 2a, 2f, respectively, both gave
the corresponding trisubstituted alkenes 3o and 3p in yields of
76% and 42%. In both cases a longer reaction time of 48 h was
required. The results of this substituent study indicate that, in
the case of stilbene containing the electron-donating methoxy
groups, a substituent match with the arene is necessary in order
to facilitate a coupling reaction. In contrast, the electron-
deficient difluoro-substituted stilbene 1e could effectively react
with both electronically opposite arene classes under our
reaction conditions. Futher illustration of this point was
achieved with the synthesis of 4,4′-(1-(2,4,6-trifluorophenyl)-
ethene-1,2-diyl)bis(fluorobenzene) 3q from the direct coupling
of 1e with 1,3,5-trifluorobenzene 2g (entry 5). Overall, three of
the possible four substrate electron-donating/-withdrawing
substituents combinations could be successfully coupled
under our reaction conditions.
Figure 2. ESI(+)-MS of Pd(OAc)2 in AcOH/MeCN (4:1). (Top) MS
in range from 200 to 450 m/z. (Bottom) Expansion of most abundant
cluster at m/z 206.3.
The mechanistic cycle for the F-M reaction has been
investigated for the coupling of arenes with acrylates11 and
shown to first involve a C−H activation of the arene
component generating an ArPd(II)OAc intermediate. Alkene
insertion into the Pd-aryl bond followed by β-H elimination
yields the product and HPdOAc, which generates Pd(0), and the
catalytic cycle completes by its oxidation to Pd(II). To
investigate the catalytic cycle under our conditions, stilbene
1a and dimethoxybenzene 2a were used as substrates and the
reaction monitored by MS analysis.12 ESI(+)-MS analysis was
carried out on three key reagent and reaction compositions (i)
Pd(OAc)2 in acetic acid/CH3CN (ii) Pd(OAc)2 in acetic acid/
CH3CN with 2a and (iii) Pd(OAc)2 in acetic acid/CH3CN
with 1a, 2a and K2S2O8. In each case the MS analysis showed
intermediates consistent with the F-M catalytic cycle (Figures
2−4).
Analysis of composition (i) showed two main isotopic
clusters centered at m/z of 206.3 and 432.1 (Figure 2, top).
The mass and isotope distribution of the most abundant cluster
centered at m/z 206.3 was consistent with an acetonitrile-
bound monomeric palladium species [Pd(OAc)(CH3CN)]+,
with the 431.1 mass being that of a palladium dimer,
[Pd2(OAc)3CH3CN]+. In both cases it would be anticipated
that these mono positively charged species detected would arise
from a loss of a molecule of acetate. The predominance of the
monomeric palladium Pd(OAc)2(CH3CN)2 in the acetic acid/
CH3CN solvent mixture is consistent with the observed
increase in reactivity over acetic acid alone. This contrasts
sharply with the ESI-MS of Pd(OAc)2 in acetic acid alone,
which gave no discernible palladium species in this mass range,
in agreement with previous reports that it exists as a trimer in
acetic acid.13
D
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With the key monomeric palladium species for C−H
insertion step confirmed, the MS analysis of mixture (ii)
generated following the addition of 1,4-dimethoxybenzene 2a
to solution (i) was carried out. This showed the most abundant
m/z at 324.9, which can be assigned to [Pd(C8H9O2)-
(CH3CN)2]+, and is indicative of the intermediate from Pd
C−H insertion into 2a Pd(C8H9O2)(OAc)(CH3CN)2 having
lost an acetate (Figure 3, top and lower expansion).
Figure 4. ESI(+)-MS of Pd(OAc)2, 1a, 2a, and K2S2O8 in AcOH/
MeCN (4:1) after heating at 80 °C for 15 min. (Top) MS in range
from 200 to 450 m/z. (Bottom) Expansion of most abundant cluster at
m/z 422.8.
important role in accelerating the reaction. ESI-MS of in situ
reaction intermediates has identfied several of the key
organopalladium species expected for an F-M catalytic cycle.
The application of these coupling conditions to other C−H
bond activation processes is ongoing.
Figure 3. ESI(+)-MS of Pd(OAc)2 and 2a in AcOH/MeCN (4:1)
after heating at 80 °C for 15 min. (Top) MS in range from 200 to 450
m/z. (Bottom) Expansion of most abundant cluster at m/z 324.9.
EXPERIMENTAL SECTION
■
General Methods. All reactions involving air-sensitive reagents
were performed under nitrogen in oven-dried glassware using syringe-
septum cap technique. Chromatography was performed on silica gel
Interpretation of the next most abundant cluster centered at
m/z 283.9 supported this assignment as it could be attributed
to [Pd(C8H9O2)(CH3CN)]+ in accord with the loss of acetate
and acetonitrile from Pd(C8H9O2)(OAc)(CH3CN)2 (Figure 3,
top).
Following combination of all of the reaction components in
AcOH/MeCN and heating at 80 °C for 15 min, the most
abundant new cluster observed was at m/z of 422.8 in addition
to that of the arene C−H inserted Pd species (283.9)
previously observed in solution (ii). Provisionally, the m/z
422.8 could be attributed to [C22H20O2Pd]+, which would be in
agreement with the palladium/product complex as shown in
Figure 4 ,bottom panel. Overall this study confirms the a F-M
catalytic cycle is in operation under our reaction conditions for
1,2-disubstituted alkene substrates.
1
60 PF254 or aluminum oxide 90. H and 13C NMR spectrum were
recorded on a 400 or 500 MHz instrument. THF was dried over
sodium benzophenone before use. Substituted alkenes 1d and 1e were
prepared according to literature methods.14 Anhydrous iPrOH,
MeCN, and all other reagents were used as supplied. Preparative
HPLC separations were conducted on an OD (250 mm × 20 mm i.d.)
column. ES and EI HRMS measurements were taken on TOF mass
analyzers.
Synthesis of Authentic Product Standards. Synthesis of (E)-
(1-(2,5-Dimethoxyphenyl)ethene-1,2-diyl)dibenzene (E)-3a.15
(E)-1-Bromo-1,2-diphenylethene16 (150 mg, 0.58 mmol), Pd(OAc)2
(12.99 mg, 0.058 mmol), PPh3 (30.4 mg, 0.12 mmol), 2,5-
dimethoxyphenylboronic acid (158 mg, 0.87 mmol, 1.5 equiv),
KOH (65.1 mg, 1.2 mmol), iPrOH (3 mL), and THF (3 mL) were
combined in a flask under N2. The pale yellow solution was then
stirred at rt for 24 h after which 1 M NaOH was added (10 mL), and
the solution was extracted with Et2O (3 × 10 mL). The organic
fractions were combined, washed with brine (5 mL), dried over
Na2SO4, and filtered, and the solvent was removed in vacuo. The crude
material was purified by flash chromatography on silica gel with Et2O/
heptane (2:98) affording the product as a colorless oil (180 mg, 87%).
1H NMR (500 MHz, CDCl3): δ 7.24−7.19 (m, 5H), 7.15−7.12 (m,
CONCLUSION
■
In conclusion, we have developed an efficient protocol for
direct arene−1,2-disubstituted alkene couplings to generate
trisubstituted alkenes. Couplings were successful with a variety
of electron-rich and -deficient arenes with stilbenes, chalcones,
and cinnamates. Use of the reaction solvent mixture AcOH/
MeCN (4:1) and the inorganic oxidant K2S2O8 are key to
achieving positive reaction outcomes, with MeCN playing an
3H), 7.09−7.07 (m, 2H), 6.86−6.85 (m, 1H), 6.82−6.81 (m, 3H),
3.77 (s, 3H), 3.52 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 153.6,
151.7, 140.8, 140.2, 137.4, 134.9, 130.3, 129.5, 129.5, 128.0, 127.9,
E
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126.8, 126.6, 116.9, 113.6, 113.2, 56.6, 55.7. HRMS (EI) m/z [M]+:
found 316.1471 [C22H20O2]+, calcd 316.1463.
mg, 82%). 1H NMR (400 MHz, CDCl3): δ 7.36−7.24 (m, 6H), 7.13−
7.06 (m, 5H), 7.03−7.00 (m, 2H), 6.96−6.92 (m, 2H), 3.57 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 157.5, 142.8, 138.9, 137.6, 131.6,
129.0, 128.9, 128.8, 128.1, 127.9, 127.8, 127.2, 126.7, 126.5, 121.1,
111.7, 55.6. HRMS (ES) m/z [M + H]+: found 287.1430 [C21H19O]+,
calcd 287.1436.
Synthesis of (Z)-(1-(2,5-Dimethoxyphenyl)ethene-1,2-diyl)-
dibenzene (Z)-3a.15 1-Bromo-2,5-dimethoxybenzene (100 mg, 0.46
mmol), Pd(OAc)2 (10.34 mg, 0.046 mmol), PPh3 (24.1 mg, 0.092
mmol), (E)-(1,2-diphenylvinyl)boronic acid6b (155 mg, 0.69 mmol,
1.5 equiv), KOH (51.6 mg, 0.92 mmol, 2 equiv), iPrOH (3 mL), and
THF (3 mL) were combined in a flask under N2. The pale yellow
solution was then stirred at rt for 24 h after which 1 M NaOH was
added (10 mL), and the solution was extracted with Et2O (3 × 10
mL). The organic fractions were combined, washed with brine (5 mL),
dried over Na2SO4, and filtered, and the solvent was removed in vacuo.
The crude material was purified by flash chromatography on silica gel
with toluene/heptane (50:50) affording the product as a colorless oil
(75.7 mg, 52%). 1H NMR (500 MHz, CDCl3): δ 7.38−7.36 (m, 2H),
7.32−7.30 (m, 2H), 7.26−7.25 (m, 1H), 7.15−7.11 (m, 3H), 7.07−
7.05 (m, 3H), 6.88 (s, 2H), 6.68 (s, 1H), 3.69 (s, 3H), 3.51 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 154.0, 151.7, 142.5,138.6, 137.5,
Synthesis of (Z)-(1-(4-Methoxyphenyl)ethene-1,2-diyl)-
dibenzene ((Z)-p-3b). 1-Iodo-4-methoxybenzene (100 mg, 0.46
mmol), Pd(OAc)2 (10.34 mg, 0.046 mmol), PPh3 (24.1 mg, 0.092
mmol), (E)-(1,2-diphenylvinyl)boronic acid6b (155 mg, 0.69 mmol,
1.5 equiv), KOH (51.6 mg, 0.92 mmol, 2 equiv), iPrOH (3 mL), and
THF (3 mL) were combined in a flask under N2. The pale yellow
solution was then stirred at rt for 24 h after which 1 M NaOH was
added (10 mL), and the solution was extracted with Et2O (3 × 10
mL). The organic fractions were combined, washed with brine (5 mL),
dried over Na2SO4, and filtered, and the solvent was removed in vacuo.
The crude material was purified by flash chromatography on silica gel
with Et2O/heptane (2:98) affording the product as a colorless oil (104
mg, 79%). 1H NMR (400 MHz, CDCl3): δ 7.34−7.26 (m, 5H), 7.14−
7.05 (m, 7H), 6.90 (s, 1H), 6.85 (d, 6.6 Hz, 2H), 3.82 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 185.9, 143.8, 142.3, 137.7, 132.5, 131.6,
129.5, 128.2, 127.9, 127.8, 127.7, 127.5, 126.6, 114.0, 55.2. HRMS
(ES) m/z [M + H]+: found 287.1431 [C21H19O]+, calcd 287.1436.
General Experimental Procedure for Pd-Mediated Arene/
1,2-Disubstituted Alkene Coupling. Pd(OAc)2 (22.0 mg, 5 mol
%), K2S2O8 (0.81 g, 3 mmol), 1,2-disubstituted alkene (2 mmol),
arene (15 mmol, 7.5 equiv unless otherwise specified), acetic acid (8
mL), and MeCN (2 mL) were placed in a 20-mL scintillation vial
containing a magnetic stir bar. The flask was sealed with a Teflon-lined
crimped cap, and the reaction solution was stirred vigorously at 80 °C
until alkene had been consumed as indicated by TLC and GC. The
reaction solution was then filtered, the solvent was removed in vacuo,
and the residue was purified by column chromatography on silica gel.
Synthesis of (E/Z)-(1-(2,5-Dimethoxyphenyl)ethene-1,2-
diyl)dibenzene (3a). Prepared by the general procedure using (E)-
stilbene 1a (359 mg, 2 mmol), 1,4-dimethoxybenzene (2.07 g, 15
mmol), Pd(OAc)2 (21.4 mg), K2S2O8 (0.81 g, 3 mmol), acetic acid (8
mL), and MeCN (2 mL). Complete conversion of the starting alkene
was achieved after 8 h. Purification by silica gel column
chromatography using cyclohexane/EtOAc (95:5) gave the product
as a colorless oil (499 mg, 79%). 1H and 13C NMR spectral data of the
isolated material matched the spectral data obtained for authentically
synthesized samples described above.
130.3, 129.0, 128.9, 128.2, 127.9, 127.2, 126.2, 126.8, 126.6, 116.9,
114.0, 113.2, 56.4, 55.7. HRMS (EI) m/z [M]+: found 316.1475
[C22H20O2]+, calcd 316.1463.
Synthesis of (E)-(1-(2-mMethoxyphenyl)ethene-1,2-diyl)-
dibenzene ((E)-o-3b). (E)-1-Bromo-1,2-diphenylethene16 (150 mg,
0.58 mmol), Pd(OAc)2 (12.99 mg, 0.058 mmol), PPh3 (30.4 mg, 0.12
mmol), 2-methoxyphenylboronic acid (158 mg, 0.87 mmol, 1.5 equiv),
KOH (65.1 mg, 1.2 mmol, 2 equiv), iPrOH (3 mL), and THF (3 mL)
were combined in a flask under N2. The pale yellow solution was then
stirred at rt for 24 h after which 1 M NaOH was added (10 mL), and
the solution was extracted with Et2O (3 × 10 mL). The organic
fractions were combined, washed with brine (5 mL), dried over
MgSO4, and filtered, and the solvent was removed in vacuo. The crude
material was purified by flash chromatography on silica gel with Et2O/
heptane (2:98) affording the product as a colorless oil (140 mg, 84%).
1H NMR (400 MHz, CDCl3): δ 7.29−7.25 (m, 2H), 7.22−7.17 (m,
5H), 7.13−7.09 (m, 3H), 7.08−7.06 (m, 2H), 6.95 (dt, 1.0, 7.5 Hz,
1H), 6.87 (dd, 1.0, 7.4 Hz, 1H), 6.79 (s, 1H), 3.59 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 157.3, 141.1, 140.4, 137.5, 133.7, 131.1, 130.2,
129.6, 129.5, 128.8, 128.0, 127.9, 126.7, 126.6, 120.6, 111.8, 55.7.
HRMS (ES) m/z [M + H]+: found 287.1434 [C21H19O]+, calcd
287.1436.
Synthesis of (E)-(1-(4-Methoxyphenyl)ethene-1,2-diyl)-
dibenzene ((E)-p-3b). (E)-1-Bromo-1,2-diphenylethene16 (150 mg,
0.58 mmol), Pd(OAc)2 (12.99 mg, 0.058 mmol), PPh3 (30.4 mg, 0.12
mmol), 4-methoxyphenylboronic acid (158 mg, 0.87 mmol, 1.5 equiv),
KOH (65.1 mg, 1.2 mmol, 2 equiv), iPrOH (3 mL), and THF (3 mL)
were combined in a flask under N2. The pale yellow solution was then
stirred at rt for 24 h after which 1 M NaOH was added (10 mL), and
the solution was extracted with Et2O (3 × 10 mL). The organic
fractions were combined, washed with brine (5 mL), dried over
Na2SO4, and filtered, and the solvent was removed in vacuo. The crude
material was purified by flash chromatography on silica gel with Et2O/
heptane (2:98) affording the product as a colorless oil (131 mg, 79%).
1H NMR (400 MHz, CDCl3): δ 7.33−7.28 (m, 3H), 7.27−7.23 (m,
2H), 7.21−7.19 (m, 2H), 7.12−7.07 (m, 3H), 7.01−6.99 (m, 2H),
6.89 (s, 1H), 6.84 (m, 2H), 3.80 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 159.3, 142.1, 140.6, 137.6, 136.1, 130.4, 129.4, 128.8, 128.6,
127.9, 127.3, 126.5, 126.4, 113.6, 55.3. HRMS (ES) m/z [M + H]+:
found 287.1426 [C21H19O]+, calcd 287.1436.
Synthesis of (Z)-(1-(2-Methoxyphenyl)ethene-1,2-diyl)-
dibenzene ((Z)-o-3b). 1-Iodo-2-methoxybenzene (100 mg, 0.46
mmol), Pd(OAc)2 (10.34 mg, 0.046 mmol), PPh3 (24.1 mg, 0.092
mmol), (E)-(1,2-diphenylvinyl)boronic acid6b (155 mg, 0.69 mmol,
1.5 equiv), KOH (51.6 mg, 0.92 mmol, 2 equiv), iPrOH (3 mL), and
THF (3 mL) were combined in a flask under N2. The pale yellow
solution was then stirred at rt for 24 h after which 1 M NaOH was
added (10 mL), and the solution was extracted with Et2O (3 × 10
mL). The organic fractions were combined, washed with brine (5 mL),
dried over Na2SO4, and filtered, and the solvent was removed in vacuo.
The crude material was purified by flash chromatography on silica gel
with Et2O/heptane (2:98) affording the product as a colorless oil (108
Synthesis of (E/Z)-(Methoxyphenyl)ethene-1,2-diyl)-
dibenzene (Mixture of (E/Z)-o-3b and (E/Z)-p-3b). Prepared by
the general procedure using (E)-stilbene 1a (360 mg, 2 mmol, 1.0
equiv), anisole (1.63 mL, 15 mmol, 7.5 equiv), Pd(OAc)2 (22.5 mg),
K2S2O8 (0.82 g, 3 mmol), acetic acid (8 mL), and MeCN (2 mL).
Complete conversion of the starting alkene was achieved after 7 h.
Purification by silica gel column chromatography using cyclohexane/
EtOAc (95:5) gave the (E/Z) product as a pale yellow oil (515 mg,
84%). 1H and 13C NMR spectral data of the isolated material matched
the spectral data obtained for authentically synthesized samples
described above.
Synthesis of Triphenylethylene (3c).17 Prepared by the general
procedure using (E)-stilbene 1a (361 mg, 2 mmol, 1.0 equiv), benzene
(3.57 mL, 40 mmol, 20 equiv), Pd(OAc)2 (22.6 mg), K2S2O8 (0.82 g,
3 mmol), NaOAc (324 mg, 4 mmol), acetic acid (8 mL), and MeCN
(2 mL). Complete conversion of the starting alkene was achieved after
48 h. Purification by silica gel column chromatography using
cyclohexane (100%) gave the product as a colorless oil (646 mg,
74%). 1H NMR (500 MHz, CDCl3): δ 7.35−7.28 (m, 8H), 7.22−7.19
(m, 2H), 7.14−7.10 (m, 3H), 7.04−7.02 (m, 2H), 6.97 (s, 1H). 13C
NMR (100 MHz, CDCl3): δ 143.4, 142.6, 140.3, 137.4, 130.4, 129.5,
128.6, 128.2, 128.1, 127.9, 127.6, 127.5, 127.4, 126.7. HRMS (ES) m/z
[M + H]+: found 257.1328 [C20H17]+, calcd 257.1330.
Synthesis of 3,3-Diphenylacrylophenone (3d).18 Prepared by
the general procedure using (E)-chalcone 1b (418 mg, 2 mmol, 1.0
equiv), benzene (1.34 mL, 15 mmol, 7.5 equiv), Pd(OAc)2 (21.8 mg),
K2S2O8 (0.81 g, 3 mmol), NaOAc (327 mg, 4 mmol), acetic acid (8
F
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Article
mL), and MeCN (2 mL). Complete conversion of the starting alkene
was achieved after 40 h. Purification by silica gel column
chromatography using cyclohexane/Et2O (90:10) gave the product
127.9, 127.5, 119.9, 116.8, 114.6, 113.4, 56.4, 55.7, 51.2. HRMS (ES)
m/z [M + H]+: found 299.1208 [C18H19O4]+, calcd 299.1205.
Synthesis of (E/Z)-1-(2,5-Dimethylphenyl)-1,2-diphenyle-
thene (3h).20 Prepared by the general procedure using (E)-stilbene
1a (350 mg, 2 mmol, 1.0 equiv), p-xylene (1.85 mL, 15 mmol, 7.5
equiv), Pd(OAc)2 (22.9 mg), K2S2O8 (0.82 g, 3 mmol), acetic acid (8
mL), and MeCN (2 mL). Complete conversion of the starting alkene
was achieved after 7 h. Purification by silica gel column
chromatography using cyclohexane (100%) gave the product was as
a mixture of known (E/Z) isomers in a ratio of 20:80 (414 mg, 75%).
1H NMR (500 MHz, CDCl3): δ 7.34−7.23 (m), 7.19 (m), 7.16−7.07
1
as a pale yellow solid, mp 90−91 °C (403 mg, 59%). H NMR (500
MHz, CDCl3): δ 7.91 (dd, 1.5, 7.0 Hz, 2H), 7.48−7.46 (m, 1H),
7.40−7.35 (m, 7H), 7.27−7.25 (m, 3H), 7.18−7.16 (m, 2H), 7.11 (s,
1H). 13C NMR (100 MHz, CDCl3): δ 192.7, 154.7, 141.4, 139.0,
138.2, 132.6, 129.7, 129.3, 128.7, 128.6, 128.4, 128.3, 128.0, 124.0,
110.0. HRMS (EI) m/z [M]+: found 284.1205 [C21H16O]+, calcd
284.1201.
Synthesis of Methyl 3,3-Diphenyl-2-propenoate (3e).19
Prepared by the general procedure using methyl (E)-cinnamate 1c
(323 mg, 2 mmol, 1.0 equiv), benzene (1.34 mL, 15 mmol, 7.5 equiv),
Pd(OAc)2 (21.8 mg), K2S2O8 (0.81 g, 3 mmol), NaOAc (329 mg, 4
mmol), acetic acid (8 mL), and MeCN (2 mL). Complete conversion
of the starting alkene was achieved after 24 h. Purification by silica gel
column chromatography using cyclohexane/EtOAc (20:1) gave the
(m), 7.05−7.03 (m), 6.97−6.94 (m), 2.32 (s, CH3, minor), 2.28 (s,
CH3, major), 2.07 (s, CH3, minor), 1.99 (s, CH3, major). 13C NMR
(100 MHz, CDCl3): δ 143.8, 143.1, 142.5, 141.4, 140.3, 139.5, 137.5,
137.5, 137.4, 135.8, 135.0, 133.3, 133.1, 130.8, 130.5 130.4, 130.3,
129.9, 129.8, 129.4, 128.9, 128.4, 128.3, 128.2, 128.1, 127.9, 127.3,
127.1, 126.8, 126.7, 126.6, 21.0, 20.9, 20.0, 19.1. HRMS (EI) m/z
[M]+: found 284.1569 [C22H20]+, calcd 284.1565.
1
product as a pale yellow oil (318 mg, 67%). H NMR (500 MHz,
Synthesis of (E/Z)-2-(1,2-Diphenylethenyl)thiophene (3i).21
Prepared by the general procedure using (E)-stilbene 1a (359 mg, 2
mmol, 1.0 equiv), thiophene (1.20 mL, 15 mmol, 7.5 equiv),
Pd(OAc)2 (22.4 mg), K2S2O8 (0.82 g, 3 mmol), acetic acid (8 mL),
and MeCN (2 mL). Complete conversion of the starting alkene was
achieved after 24 h. Purification by silica gel column chromatography
using cyclohexane (100%) gave the product was as a mixture of known
CDCl3): δ 7.39−7.28 (m, 8H), 7.22−7.20 (m, 2H), 6.37 (s, 1H), 3.61
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 166.4, 157.0, 140.8, 138.8,
129.4, 129.0, 128.4, 128.3, 128.2, 127.9, 116.8, 51.2 HRMS (ES) m/z
[M + H]+: found 239.1069 [C16H14O2]+, calcd 239.1072.
Synthesis of (E/Z) 3-(2,5-Dimethoxyphenyl)-1,3-diphenyl-
propenone (3f). Prepared by the general procedure using (E)-
chalcone 1b (417 mg, 2 mmol, 1.0 equiv), 1,4-dimethoxybenzene
(2.072 g, 15 mmol, 7.5 equiv), Pd(OAc)2 (22.4 mg), K2S2O8 (0.81 g, 3
mmol), acetic acid (8 mL), and MeCN (2 mL). Complete conversion
of the starting alkene was achieved after 7 h. Purification by silica gel
column chromatography using cyclohexane/EtOAc (95:5) gave the
product as a mixture of (E/Z) isomers in a ratio of 85:15 (489 mg,
66%). The two isomers were separated by preparative HPLC using
heptane/2-propanol (99.5:0.5) as a mobile phase. Isomer assignments
were determined by 1D NOESY and 2D NMR techniques.
1
(E/Z) isomers in a ratio of 35:65 (361 mg, 69%). H NMR (500
MHz, CDCl3): δ 7.42−7.29 (m), 7.21−7.15 (m), 7.11, 7.07 (m), 7.05
(s), 7.00 (dd, 3.5 Hz, 5.1 Hz), 6.96 (m), 6.93 (dd, 3.5 Hz, 5.1 Hz),
6.88 (dd, 1.1 Hz, 3.5 Hz), 6.73 (dd, 1.1 Hz, 3.5 Hz). 13C NMR (100
MHz, CDCl3): δ 147.9, 143.2, 141.6, 140.6, 139.4, 137.2, 136.6, 136.2,
135.2, 130.4, 129.9,129.4, 129.3, 128.8, 128.4, 128.2, 128.1, 128.0,
127.9, 127.8, 127.5, 127.4, 127.1, 127.1, 126.8, 126.4, 126.3, 126.0,
124.7. HRMS (ES) m/z [M + H]+: found 262.0811 [C18H14S]+, calcd
262.0816.
Synthesis of (E/Z)-(1-(2,5-Difluorophenyl)ethene-1,2-diyl)-
dibenzene (3j). Prepared by the general procedure using (E)-
stilbene 1a (351 mg, 2 mmol, 1.0 equiv), 1,4-difluorobenzene (4.11
mL, 40 mmol, 20 equiv), Pd(OAc)2 (22.5 mg), K2S2O8 (0.82 g, 3
mmol), acetic acid (8 mL), and MeCN (2 mL). Complete conversion
of the starting alkene was achieved after 48 h. Purification by silica gel
column chromatography using cyclohexane (100%) gave the product
as a mixture of (E/Z) isomers in a ratio of 60:40 (245 mg, 43%). The
two isomers were separated by preparative HPLC using heptane:2-
propanol (99.8:0.2) as a mobile phase. Isomer assignments were
determined by 1D NOESY and 2D NMR techniques.
1
(E)-3f: pale yellow oil. H NMR (500 MHz, CDCl3): δ 7.93−7.92
(m, 2H), 7.45−7.43 (m, 1H), 7.35−7.33 (m, 2H), 7.16 (ps, 5H), 6.97
(s, 1H), 6.88 (ps, 2H), 6.78 (s, 1H), 3.74 (s, 3H), 3.64 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 193.8, 153.4, 151.7, 150.5, 139.6, 137.9,
132.6, 132.2, 129.1, 128.9, 128.2, 127.9, 127.7, 127.4, 116.9, 114.5,
113.3, 56.5, 55.7.HRMS (ES) m/z [M + H]+: found 345.1494
[C23H21O3]+, Calc. Mass: 345.1491.
1
(Z)-3f: pale yellow oil. H NMR (500 MHz, CDCl3): δ 7.91−7.89
(m, 2H), 7.48−7.46 (m, 1H), 7.42−34 (m, 7H), 7.22 (s, 1H), 6.80−
6.74 (m, 2), 6.61 (d, 3.01 Hz, 1H), 3.68 (s, 3H), 3.49 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 192.1, 153.3, 150.8, 150.1, 140.8, 138.4,
132.4, 129.0, 128.5, 128.4, 128.2, 127.8, 124.7, 116.6, 114.2, 112.2,
110.0, 55.9, 55.7. HRMS (ES) m/z [M + H]+: found 345.1500
[C23H21O3]+, calcd 345.1491.
(E)-3j: colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.29−7.28 (m,
3H), 7.19−7.18 (m, 2H), 7.15−7.14 (m, 3H), 7.05−7.04 (m, 2H),
7.01 (dt, 4.6 Hz, 9.0 Hz, 1H), 6.95−6.88 (m, 3H). 13C NMR (100
MHz, CDCl3): δ 158.5 (dd, 1.9 Hz, 209.1 Hz), 156.1 (dd, 2.0 Hz,
213.3 Hz), 139.5, 136.6, 136.1, 132.9−132.7 (m), 132.5, 132.4, 129.7,
129.5, 128.6, 128.0, 127.6, 127.2, 117.4 (dd, 3.6 Hz, 24.2 Hz), 116.9
(dd, 8.8 Hz, 25.9 Hz,), 115.1 (dd, 8.7 Hz, 24.0 Hz,). 19F NMR (376
MHz, CDCl3): δ −119.4 (m, 1F), −120.1 (m, 1F). HRMS (EI) m/z
[M]+: found 292.1062 [C20H14F2]+, calcd 292.1064.
Synthesis of (E/Z) (2,5-Dimethoxyphenyl)-3-phenylacrylic
Acid Methyl Ester (3g). Prepared by the general procedure using
methyl (E)-cinnamate 1c (320 mg, 2 mmol, 1.0 equiv), 1,4-
dimethoxybenzene (2.08 g, 15 mmol, 7.5 equiv), Pd(OAc)2 (20.2
mg), K2S2O8 (0.80 g, 3 mmol), acetic acid (8 mL), and MeCN (2
mL). Complete conversion of the starting alkene was achieved after 7
h. Purification by silica gel column chromatography using cyclo-
hexane/EtOAc (90:10) gave the product as a mixture of (E/Z)
isomers in a ratio of 60:40 (530 mg, 80%). The two isomers were
separated by preparative HPLC using heptane/2-propanol (99:5:0.5)
as a mobile phase. Isomer assignments were determined by 1D
NOESY and 2D NMR techniques.
(Z)-3j: colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.34−7.29 (m,
5H), 7.20−7.15 (m, 3H), 7.13 (s, 1H), 7.07−7.01 (m, 4H), 6.89 (ddd,
2.9 Hz, 5.3 Hz, 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 158.7
(d, 242.1 Hz), 156.3 (d, 241.0 Hz), 141.5, 136.6, 134.9, 130.9, 129.2
(m), 128.9, 128.4, 128.2, 127.8, 127.4, 126.7, 118.5 (dd, 4.2 Hz, 23.7
Hz), 117.1 (dd, 8.9 Hz, 25.1 Hz,), 116.0 (dd, 8.4 Hz, 24.0 Hz). 19F
NMR (376 MHz, CDCl3): δ −118.7 (m, 1F), −119.5 (m, 1F). HRMS
(EI) m/z [M]+: found 292.1058 [C20H14F2]+, calcd 292.1064.
Synthesis of (E/Z)-3-(2,5-Difluorophenyl)-1,3-diphenylpro-
penone (3k). Prepared by the general procedure using (E)-chalcone
1b (414 mg, 2 mmol, 1.0 equiv), 1,4-difluorobenzene (4.11 mL, 40
mmol, 20 equiv), Pd(OAc)2 (23.0 mg, 5 mol %), K2S2O8 (0.82 g, 3
mmol), NaOAc (340 mg, 4 mmol), acetic acid (8 mL), and MeCN (2
mL). Complete conversion of the starting alkene was achieved after 48
h. Purification by silica gel column chromatography using cyclo-
hexane/Et2O (90:10) gave the product as a mixture of (E/Z) isomers
1
(E)-3g: colorless oil. H NMR (500 MHz, CDCl3): δ 7.36−7.28
(m, 5H), 6.89−6.88 (m, 2H), 6.64−6.61 (m, 1H), 6.45 (s, 1H), 3.75
(s, 3H), 3.64 (s, 3H), 3.61 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
166.7, 153.4, 152.9, 150.9, 139.9, 129.3, 129.1, 128.4 127.5, 117.8,
115.9, 113.8, 112.4, 56.5, 55.7, 51.2. HRMS (ES) m/z [M + H]+:
found 299.1211 [C18H19O4]+, calcd 299.1205.
1
(Z)-3g: colorless oil. H NMR (500 MHz, CDCl3): δ 7.32−7.28
(m, 3H), 7.25−7.21 (m, 2H), 6.85−6.81 (m, 2H), 6.71−6.68 (d, 5 Hz,
1H), 6.28 (s, 1H), 3.73 (s, 3H), 3.61 (s, 3H), 3.57 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 166.7, 154.1, 153.3, 151.5, 139.5, 132.1, 128.6,
G
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in a ratio of 80:20 (E:Z) (357 mg, 56%). (E)-Isomer purification was
achieved using preparative HPLC with heptane/2-propanol (99.5:0.5)
as a mobile phase. The (Z)-isomer was not isolated in sufficient
quantities. Isomer assignments were determined by 1D NOESY and
2D NMR techniques.
(m, 1F), −109.08 (m, 2F). HRMS (ES) m/z [M + Na]+: found
315.0609 [C16H11O2F3Na]+, calcd 315.0617.
Single crystals of (E)-3m and (Z)-3m were grown by slow
evaporation of dicholomethane. CIF files of the obtained structures
can be found in Supporting Information.
1
Synthesis of (E/Z)-4,4′-(1-(2,5-Dimethoxyphenyl)ethene-1,2-
diyl)bis(methoxybenzene) (3n). Prepared by the general procedure
using (E)-4,4′-dimethoxystilbene 1d (487 mg, 2 mmol, 1.0 equiv), 1,4-
dimethoxybenzene (2.07 g, 15 mmol, 7.5 equiv), Pd(OAc)2 (22.2 mg),
K2S2O8 (0.81 g, 3 mmol), acetic acid (8 mL), and MeCN (2 mL).
Complete conversion of the starting alkene was achieved after 3 h.
Purification by silica gel column chromatography using cyclohexane/
EtOAc (90:10) gave the product was as a mixture of (E/Z) isomers in
a ratio of 80:20 (526 mg, 69%). Isomer separation was not achieved.
(E)-3k: yellow oil. H NMR (500 MHz, CDCl3): δ 7.90 (dd, 1.1
Hz, 8.2 Hz, 2H), 7.49−7.46 (m, 1H), 7.36 (t, 7.7 Hz, 2H), 7.24−7.20
(m, 3H), 7.18−7.15 (m, 2H), 7.10 (td, 4.5 Hz, 9.3 Hz, 1H), 7.06−7.03
(m, 1H), 7.02 (s, 1H), 6.89 (ddd, 3.0 Hz, 5.8 Hz, 8.8 Hz, 1H). 13C
NMR (100 MHz, CDCl3): δ 193.3, 158.3 (dd, 2.5 Hz, 241.7 Hz),
156.3 (dd, 2.6 Hz, 245.1 Hz), 145.9, 138.1, 137.4, 132.9, 130.6−130.4
(m), 129.0, 128.9, 128.8, 128.6, 128.4, 128.2, 117.9 (dd, 3.0 Hz, 24.4
Hz), 117.3 (dd, 8.6 Hz, 25.7 Hz), 116.7 (dd, 8.6 Hz, 23.9 Hz). 19F
NMR (376 MHz, CDCl3): δ −118.5 (m, 1F), −119.6 (m, 1F). HRMS
(ES) m/z [M + H]+: found 321.1086 [C21H15OF2]+, calcd 321.1091.
Synthesis of (E/Z)-(2,5-Difluorophenyl)-3-phenylacrylic Acid
Methyl Ester (3l). Prepared by the general procedure using methyl
(E)-cinnamate 1c (316 mg, 2 mmol, 1.0 equiv), 1,4-difluorobenzene
(4.11 mL, 40 mmol, 20 equiv), Pd(OAc)2 (23.0 mg, 5 mol %), K2S2O8
(0.808 g, 3 mmol), NaOAc (327 mg, 4 mmol), acetic acid (8 mL), and
MeCN (2 mL). Complete conversion of the starting alkene was
achieved after 40 h. Purification by silica gel column chromatography
using cyclohexane/Et2O (95:5) gave the product as a mixture of (E/Z)
isomers in a ratio of 80:20 (280 mg, 53%). The two isomers were
separated by preparative HPLC using heptane/2-propanol (99.5:0.5)
as a mobile phase. Isomer assignments were determined by 1D
NOESY and 2D NMR techniques.
1
(E/Z)-3n: colorless oil. H NMR (500 MHz, CDCl3): δ 7.28 (m),
7.11 (d, 8.6 Hz), 7.03 (d, 8.6 Hz), 6.97−6.91 (m), 6.89−6.86 (m),
6.84−6.76 (m), 6.70−6.65 (m), 3.80 (s, CH3), 3.78 (s, CH3), 3.76 (s,
CH3), 3.74 (s, CH3), 3.70 (s, CH3), 3.54 (s, CH3), 3.53 (s, CH3). 13
C
NMR (100 MHz, CDCl3): δ 158.8, 158.4, 158.2,154.1, 153.6, 151.8,
151.7, 144.1, 138.0, 135.9, 135.4, 133.4, 130.8, 130.7, 130.4, 130.2,
130.1, 129.3, 127.5, 126.6, 116.9, 116.8, 113.8, 113.7, 113.5, 113.4,
113.3, 112.9, 56.8, 56.5, 55.7, 55.3, 55.1, 55.0. HRMS (ES) m/z [M +
H]+: found 377.1764 [C24H25O4]+, calcd 377.1753.
Synthesis of (E/Z)-4,4′-(1-(2,5-Dimethoxyphenyl)ethene-1,2-
diyl)bis(fluorobenzene) (3o). Prepared by the general procedure
using (E)-4,4′-difluorostilbene 1e (432 mg, 2 mmol, 1.0 equiv), 1,4-
dimethoxybenzene (2.073 g, 15 mmol, 7.5 equiv), Pd(OAc)2 (22.4
mg), K2S2O8 (0.80 g, 3 mmol), acetic acid (8 mL), and MeCN (2
mL). Complete conversion of the starting alkene was achieved after 3
h. Purification by silica gel column chromatography using cyclo-
hexane/EtOAc (95:5) gave the product as a mixture of (E/Z) isomers
in a ratio of 85:15 (535 mg, 76%). The two isomers were separated by
preparative HPLC using heptane/2-propanol (99.5:0.5) as a mobile
phase. Isomer assignments were determined by 1D NOESY NMR.
1
(E)-3l: pale yellow oil. H NMR (500 MHz, CDCl3): δ 7.38−7.36
(m, 3H), 7.24−7.21 (m, 2H), 7.06−6.97 (m, 2H), 6.80 (ddd, 3.1 Hz,
5.9 Hz, 8.9 Hz, 1H), 6.35 (s, 1H), 3.62 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 166.0, 158.4 (dd, 2.1 Hz, 208.5 Hz), 155.9 (dd, 2.0 Hz,
215.1 Hz), 149.5, 138.0, 130.2 (dd, 2.6 Hz, 22.0 Hz), 128.7, 128.6,
128.0, 127.8, 121.7, 117.7 (dd, 2.9 Hz, 24.8 Hz), 117.3 (dd, 8.6 Hz,
25.7 Hz), 116.9 (dd, 8.8 Hz, 24.0 Hz). 19F NMR (376 MHz, CDCl3):
δ −118.5 (m, 1F), −119.2 (m, 1F). HRMS (ES) m/z [M + Na]+:
found 297.0695 [C16H12O2F2Na]+, calcd 297.0703.
1
(E)-3o: pale green oil. H NMR (500 MHz, CDCl3): δ 7.31−7.28
(m, 2H), 6.98 (m, 5H), 6.88 (pd, 1.7 Hz, 2H), 6.82 (pt, 8.8 Hz, 2H),
6.63 (pt, 1.7 Hz, 1H), 3.69 (s, 3H), 3.52 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 163.1 (d, 246.0 Hz), 160.7 (d, 248.0 Hz), 154.0, 151.5,
138.5 (d, 3.2 Hz), 137.4 (d, 1.9 Hz), 133.5 (d, 3.4 Hz), 130.4 (d, 7.9
Hz), 129.6, 128.1 (d, 8.0 Hz), 127.4 (d, 1.6 Hz), 116.9, 115.0 (d, 21.0
Hz), 114.8 (d, 21.0 Hz), 114.0, 113.1 56.2, 55.7. 19F NMR (376 MHz,
CDCl3): δ −114.78 (m, 1F), −115.33 (m, 1F). HRMS (EI) m/z
[M]+: found 352.1284 [C221H18F2O2]+, calcd 352.1275.
1
(Z)-3l: pale yellow oil. H NMR (500 MHz, CDCl3): δ 7.39−7.31
(m, 5H), 7.10−7.04 (m, 2H), 6.84 (ddd, 2.9 Hz, 5.4 Hz, 8.4 Hz, 1H),
6.52 (s, 1H), 3.66 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 165.5,
158.6 (dd, 2.3 Hz, 228.3 Hz), 155.5 (dd, 2.5 Hz, 241.9 Hz), 149.0,
138.8, 129.9, 128.6, 127.7 (dd, 8.2 Hz, 19.3 Hz), 127.6, 119.2, 117.1
(dd, 3.7 Hz, 24.6 Hz), 116.4 (m), 116.2 (m), 51.5. 19F NMR (376
MHz, CDCl3): δ −119.3 (m, 1F), −120.9 (m, 1F). HRMS (ES) m/z
[M + Na]+: found 297.0701 [C16H12O2F2Na]+, calcd 297.0703.
Synthesis of (E/Z)-(2,4,6-Trifluorophenyl)-3-phenylacrylic
Acid Methyl Ester (3m). Prepared by the general procedure using
methyl (E)-cinnamate 1c (322 mg, 2 mmol, 1.0 equiv), 1,3,5-
trifluorobenzene (4.14 mL, 40 mmol, 20 equiv), Pd(OAc)2 (22.2 mg),
K2S2O8 (0.81 g, 3 mmol), NaOAc (317 mg, 4 mmol), acetic acid (8
mL), and MeCN (2 mL). Complete conversion of the starting alkene
was achieved after 48 h. Purification by silica gel column
chromatography using cyclohexane/Et2O (95:5) gave the product as
a mixture of (E/Z) isomers in a ratio of 75:25 (424 mg, 73%). The two
isomers were separated by preparative HPLC using heptane/2-
propanol (99.8:0.2) as a mobile phase. Individual isomer assignments
were determined by 1D NOESY and 2D NMR techniques and single
crystal X-ray spectrometry.
(Z)-3o: pale yellow oil. H NMR (500 MHz, CDCl3): δ 7.12 (dd,
5.6 Hz, 8.6 Hz, 2H), 7.02 (dd, 5.6 Hz, 8.6 Hz, 2H), 6.92 (t, 8.8 Hz,
2H), 6.86−6.81 (m, 5H), 6.74 (s, 1H), 3.78 (s, 3H), 3.52 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 161.8 (d, 247.0 Hz), 161.5 (246.0 Hz),
153.6, 151.5, 139.2, 136.5 (d, 3.4 Hz), 134.3, 133.2 (d, 3.4 Hz), 131.1
(d, 11.5 Hz), 131.0 (d, 12.0 Hz), 129.2, 116.9, 115.0 (d, 21.3 Hz),
114.9 (d, 22.3 Hz), 113.3, 56.4, 55.7. 19F NMR (376 MHz, CDCl3): δ
−114.8 (m, 1F), −115.2 (m, 1F). HRMS (EI) m/z [M]+: found
352.1276 [C22H18F2O2]+, calcd 352.1275.
Synthesis of (E/Z)-4,4′-(1-(2,5-Difluorophenyl)ethene-1,2-
diyl)bis(fluorobenzene) (3p). Prepared by the general procedure
using (E)-4,4′-difluorostilbene 1e (430 mg, 2 mmol, 1.0 equiv), 2,4-
difluorobenzene (4.11 mL, 40 mmol, 20 equiv), Pd(OAc)2 (21.8 mg),
K2S2O8 (0.82 g, 3 mmol), acetic acid (8 mL), and MeCN (2 mL). The
reaction was stopped after 48 h; however, complete conversion of the
starting alkene was not achieved. Purification by silica gel column
chromatography using heptane/Et2O (99.8:0.2) gave the product as a
mixture of (E/Z) isomers in a ratio of 65:35 (276 mg, 42%). The two
isomers were separated by preparative HPLC using heptane/2-
propanol (99.8:0.2) as a mobile phase. Isomer assignments were
determined by 1D NOESY and 2D NMR techniques.
(E)-3m: colorless waxy solid. 1H NMR (500 MHz, CDCl3): δ 7.33
(m, 3H), 7.27 (m, 2H), 6.69 (m, 2H), 6.13 (s, 1H), 3.64 (s, 1H). 13C
NMR (125 MHz, CDCl3): δ 165.5, 162.5 (dt, 15.4 Hz, 251.4 Hz),
160.2 (ddd, 9.4 Hz, 15.0 Hz, 251.6 Hz), 143.5, 137.7, 128.6, 128.1,
127.9, 123.8, 115.5 (m), 100.6 (m), 51.5. 19F NMR (376 MHz,
CDCl3): δ −106.85 (m, 1F), −108.62 (m, 2F). HRMS (ES) m/z [M +
Na]+: found 315.0595 [C16H12O2F2Na]+, calcd 315.0609.
1
(E)-3p: colorless oil. H NMR (500 MHz, CDCl3): δ 7.16−7.12
(Z)-3m: colorless waxy solid. 1H NMR (500 MHz, CDCl3): δ 7.37
(m, 5H), 6.74 (m, 2H), 6.62 (s, 1H), 3.68 (s, 3H) 13C NMR (125
MHz, CDCl3): δ 165.3, 162.7 (dt, 14.9 Hz, 250.3 Hz), 159.9 (ddd,
10.2 Hz, 14.9 Hz, 249.5 Hz), 143.6, 138.1, 130.0, 128.8, 126.9, 120.8,
111.9 (m), 100.2 (m), 51.6. 19F NMR (376 MHz, CDCl3): δ −107.71
(m, 2H), 7.04−6.97 (m, 5H), 6.97−6.92 (m, 1H), 6.91−6.83 (m, 4H).
13C NMR (100 MHz, CDCl3): δ 162.0 (dd, 39.1 Hz, 246.0 Hz), 158.4
(dd, 2.2 Hz, 240.0 Hz), 156.2 (dd, 2.4 Hz, 243.0 Hz), 135.1 (d, 3.5
Hz), 134.9, 132.4 (d, 3.5 Hz), 131.5, 131.4 (d, 8.1 Hz), 131.2 (d, 7.9
Hz), 117.3 (dd, 3.5 Hz, 24.2 Hz), 117.0 (dd, 8.04, 25.0 Hz), 115.8,
H
dx.doi.org/10.1021/jo401326f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
115.6, 115.4 (dd, 8.2 Hz, 23.0 Hz), 115.2, 115.0. 19F NMR (376 MHz,
CDCl3): δ −113.7 (m, 1F), −113.8 (m, 1F), −119.2 (m, 1F), −120.0
(m, 1F), −120.1 (m, 1F). HRMS (EI) m/z [M]+: found 328.0870
[C20H12F4]+, calcd 328.0875.
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1
(Z)-3p: colorless oil. H NMR (500 MHz, CDCl3): δ 7.48−7.43
(m, 2H), 7.30−7.26 (m, 1H), 7.07−6.99 (m, 6H), 6.98 (s, 1H), 6.91−
6.82 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 162.4 (dd, 21.4 Hz,
247.6 Hz), 161.8 (td, 15.8 Hz, 247.0 Hz), 158.7 (dd, 2.4 Hz, 254.5
Hz), 156.3 (dd, 2.71 Hz, 255.7 Hz), 132.6 (d, 3.6 Hz) 130.5 (d, 7.8
Hz), 129.5 (m), 128.3 (d, 8.0 Hz), 127.8 (d, 8.0 Hz), 127.2 (m), 118.3
(dd, 3.9 Hz, 23.7 Hz), 117.3 (dd, 8.7 Hz, 25.1 Hz), 116.3 (8.3 Hz, 24.0
Hz), 115.7, 115.5, 115.4 (dd, 14.1 Hz, 21.4 Hz). 19F NMR (376 MHz,
CDCl3): δ −114.21 (m, 1F), −118.31 (m, 1F), −119.54 (m, 1F).
HRMS (EI) m/z [M]+: found 328.0882 [C20H12F4]+, calcd 328.0875.
Synthesis of (E/Z)-4,4′-(1-(2,4,6-Trifluorophenyl)ethene-1,2-
diyl)bis(fluorobenzene) (3q). Prepared by the general procedure
using (E)-4,4′-difluorostilbene 1e (432 mg, 2 mmol, 1.0 equiv), 1,3,5-
trifluorobenzene (4.14 mL, 40 mmol, 20 equiv), Pd(OAc)2 (22.6 mg),
K2S2O8 (0.81 g, 3 mmol), acetic acid (8 mL), and MeCN (2 mL). The
reaction was stopped after 48 h, without complete consumption of the
starting alkene. Purification by silica gel column chromatography using
cyclohexane:EtOAc (90:10) gave the product as a mixture of (E/Z)
isomers in a ratio of 65:35 (408 mg, 59%). The two isomers were
separated by preparative HPLC using heptane/2-propanol (99.8:0.2)
as a mobile phase. Isomer assignments were determined by 1D
NOESY and 2D NMR techniques.
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(E)-3q: pale yellow oil. H NMR (500 MHz, CDCl3): δ 7.16 (m,
2H), 7.06 (m, 2H), 6.95 (pt, 8.70 Hz, 2H), 6.88 (pt, 8.71 Hz, 2H),
6.68 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 162.1(d, 246.1 Hz),
161.9 (d, 246.8 Hz), 161.8 (dt, 15.2 Hz, 248.1 Hz), 160.6 (ddd, 9.6
Hz, 14.8 Hz, 249.4 Hz), 134.9 (d, 3.6 Hz), 133.2, 132.0 (d, 3.5 Hz),
131.1 (d, 8.1 Hz), 130.8 (d, 8.0 Hz), 128.1, 115.6 (d, 21.5 Hz), 115.2
(d, 21.48 Hz), 100.4 (m). 19F NMR (376 MHz, CDCl3): δ −108.63
(m, 1F), −109.43 (m, 2F), −113.56 (m, 1F), −113.89 (m, 1F). HRMS
(EI) m/z [M]+: found 346.0792 [C20H11F5]+, calcd 346.0781.
(Z)-3q: pale yellow oil. 1H NMR (500 MHz, CDCl3): δ 7.31−7.27
(m, 2H), 7.14 (s, 1H), 7.06−7.00 (m, 4H), 6.90 (pt, 8.7 Hz, 2H), 6.70
(m, 2H). 13C NMR (100 MHz, CDCl3): δ 162.7 (dt, 15.3 Hz, 250.8
Hz), 162.6 (d, 247.9 Hz) 162.0 (d, 248.4 Hz), 160.6 (ddd, 10.5 Hz,
14.7 Hz, 250.4 Hz), 136.8 (d, 3.1 Hz), 132.8 (d, 3.4 Hz), 131.7, 129.9
(d, 8.1 Hz), 127.8 (d, 8.0 Hz), 127.6, 115.42 (m), 110.8 (m). 19F
NMR (376 MHz, CDCl3): δ −107.4 (m, 1F), −107.9 (m, 2F), −113.3
(m, 1F), −114.1 (m, 1F). HRMS (EI) m/z [M]+: found 346.0789
[C20H11F5]+, calcd 346.0781.
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ASSOCIATED CONTENT
■
S
* Supporting Information
All 1H, and 13C NMR spectra and X-ray crystallographic data in
CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: donal.f.oshea@ucd.ie or donalfoshea@rcsi.ie.
(9) Kurzeev, S. A.; Kazankov, G. M.; Alexander D. Ryabov, A. D.
Inorg. Chim. Acta 2002, 340, 192−196.
Notes
The authors declare no competing financial interest.
(10) For examples of F-M coupling with polyfluorinated arenes and
their medicinal applications, see: (a) Zhang, X.; Fan, S.; He, C.-Y.;
Wan, X.; Min, Q.-Q.; Yang, J.; Jiang, Z.-X. J. Am. Chem. Soc. 2010, 132,
4506−4507. (b) Zhang, W.; Sviripa, V.; Chen, X.; Shi, J.; Yu, T.;
Hamza, A.; Ward, N. D.; Kril, L. M.; Vander Kooi, C. W.; Zhan, C.-G.;
Evers, B. M.; Watt, D. S.; Liu, C. ACS Chem. Biol. 2013, 8, 796−803.
(11) Boutadla, Y.; Davies, D. L.; Macgregor, S. A.; Poblador-
Bahamonde, A. I. Dalton Trans. 2009, 5820.
ACKNOWLEDGMENTS
■
We thank the European Research Association ERA-Chemistry
and the Irish Research Council (IRC) (EMPOWER post-
doctoral fellowship PD/2011/2132) for financial support.
Thanks to Dr. Y. Ortin for NMR support and Dr. H. Muller-
Bunz for X-ray crystallography.
̈
(12) For MS study of acrylate coupling, see: Vasseur, A.; Harakat, D.;
Muzart, J.; Le Bras, J. J. Org. Chem. 2012, 77, 5751−5758.
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