Preparation of nonsymmetrically substituted stilbenes in a one-pot two-step Heck strategy using ethene as a reagent

Article abstract of DOI:10.1021/jo800235c

(Chemical Equation Presented) We present here a strategy for the preparation of nonsymmetrically substituted stilbenes using a one-pot two-step double Heck strategy. First a protocol is developed for the selective preparation of a range of styrenes using ethene as the alkene coupling partner. Then conditions are found for the effective coupling of the styrenes with aryl halides using a 1:1 stoichiometric ratio of the two components. The use of the microwave apparatus to perform the reactions offers a convenient method for synthesis as well as for safely, easily, and accurately loading vessels with gaseous reagents.

Full text of DOI:10.1021/jo800235c

Preparation of Nonsymmetrically Substituted Stilbenes in a One-Pot
Two-Step Heck Strategy Using Ethene As a Reagent
Chad M. Kormos and Nicholas E. Leadbeater*
Department of Chemistry, UniVersity of Connecticut, Unit 3060, 55 North EagleVille Road, Storrs,
Connecticut 06269-3060
nicholas.leadbeater@uconn.edu
ReceiVed January 29, 2008
We present here a strategy for the preparation of nonsymmetrically substituted stilbenes using a one-pot
two-step double Heck strategy. First a protocol is developed for the selective preparation of a range of
styrenes using ethene as the alkene coupling partner. Then conditions are found for the effective coupling
of the styrenes with aryl halides using a 1:1 stoichiometric ratio of the two components. The use of the
microwave apparatus to perform the reactions offers a convenient method for synthesis as well as for
safely, easily, and accurately loading vessels with gaseous reagents.
Introduction
imagined in a Heck reaction. Also, the styrene and stilbene
products formed have a rich variety of chemical and biological
properties and so their synthesis is of interest in the organic
chemistry community.12
The palladium-catalyzed C-C coupling between aryl halides
or vinyl halides and activated alkenes in the presence of a base
is well-known now as the Heck reaction.1,2 There have been a
number of recent reviews of the scope and versatility of the
reaction.3–7 It finds wide applications from natural product to
fine chemicals synthesis as well as in the preparation of
functional polymers and their precursors.8–11 When looking in
the literature, the vast majority of the publications citing the
Heck reaction involve the reaction of aryl halides with mono-
substituted alkenes such as styrene and butyl acrylate. Generally
the alkene coupling partner is used in a stoichiometric excess
relative to the aryl halide component and a wide range of catalyst
systems have been developed for obtaining the Heck products
in good yields. An alkene that has received relatively little
attention is ethene; indeed, there are very few research papers
published using ethene as a substrate. This is despite the fact
that it is the simplest alkene coupling partner that could be
The reason behind the sparcity of reports using ethene as a
reagent in the Heck reaction is that it is fraught with difficulties.
The main problem is over-reaction with the aryl halide coupling
partner to give the symmetric stilbene product rather than the
monosubstituted alkene. It is therefore necessary to control
precisely the amount of gas used; this usually implies a complex
experimental setup. Another problem is that under the high
temperature/long reaction time conditions often used, polym-
erization of the desired monosubstituted alkene product can
occur. To circumvent these problems, liquid vinyltrialkylsilanes
and vinyltrialkoxysilanes have been used as ethene substitutes.
For example, a selective procedure for the construction of
symmetric and nonsymmetric trans-stilbene derivatives has been
reported based on two sequential Heck-type reactions using
vinyltrimethylsilane as ethene equivalent.13 More recently,
symmetric and nonsymmetric (E)-1,2-diarylethenes have been
prepared in consecutive palladium-catalyzed Hiyama-Heck
reactions.14
(1) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320–2322.
(2) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44, 581–
581.
(3) Whitcome, N. J.; Hii, K. K.; Gibson, S. E. Tetrahedron 2001, 57, 7449–
7476.
In our laboratory, we have had success performing Heck
reactions using water as a solvent in conjunction with microwave
heating.15,16 We also have the capability to perform microwave-
(4) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2–7.
(5) de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33,
2379–2411.
(6) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009–3066.
(7) Crisp, G. T. Chem. Soc. ReV. 1998, 27, 427–436.
(8) Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945–2963.
(9) Arisawa, M. Chem. Pharm. Bull. 2007, 55, 1099–1118.
(10) de Vries, J. G. Can. J. Chem. 2001, 79, 1086–1092.
(11) Koopmans, C.; Iannelli, M.; Kerep, P.; Klink, M.; Schmitz, S.; Sinnwell,
S.; Ritter, H. Tetrahedron 2006, 62, 4709–4714.
(12) Ferré-Filmon, K.; Delaude, L.; Demonceau, A.; Noels, A. F. Coord.
Chem. ReV. 2004, 248, 2323–2336.
(13) Jeffery, T.; Ferber, B. Tetrahedron Lett. 2003, 44, 193–197.
(14) Gordillo, A.; de Jesús, E.; López-Mardomingo, C. Chem. Commun. 2007,
4056–4058.
3854 J. Org. Chem. 2008, 73, 3854–3858
10.1021/jo800235c CCC: $40.75 2008 American Chemical Society
Published on Web 04/15/2008

Nonsymmetrically Substituted Stilbenes
FIGURE 1. Proposed one-pot two-step protocol for the preparation of nonsymmetric substituted stilbenes.
promoted reactions in the presence of a reactive gas.17–19 We
therefore wanted to take steps to address the problems of using
ethene in Heck coupling reactions and, in so doing, develop a
selective one-pot two-step protocol for the preparation of
nonsymmetric substituted stilbenes (Figure 1). We present our
results here.
To address this problem, we moved from palladium acetate
as a catalyst to palladium on carbon. This is known to discharge
small quantities of palladium into solution during the course of
a reaction. By dosing the reaction mixture with low levels of
palladium, we hoped to control the reaction and stop at the
styrene rather than over-react to form the stilbene. The result
from this was promising, giving a 10:64:26 ratio of unreacted
starting material, styrene, and stilbene, respectively. We moved
to using an ICP palladium standard as our catalyst source
because in previous studies we found that this is a very
convenient way of adding very small quantities of ligandless
palladium to reaction mixtures. Using 100 µL of a 1000 ppm
ICP standard allowed us to perform the reaction at a catalyst
loading of 0.1 mol%.
Results and Discussion
As a starting point, we decided to probe the Heck reaction
between iodobenzene and ethene using the conditions optimized
in our laboratory for other Heck couplings. This involved using
water (2 mL) as the solvent, tetrabutylammonium bromide (1
equiv) as a phase-transfer agent, potassium carbonate (3.7 equiv)
as base, heating the reaction mixture to 170 °C using microwave
irradiation, and holding it at this temperature for 10 min. We
knew from our previous studies that this protocol was quick,
used very low levels of a ligand-free palladium catalyst, and
was applicable to a range of substrates. Working on the 1 mmol
scale, we loaded all the reagents, with the exception of the
ethene, into a 10 mL microwave tube and then sealed the vessel
and placed it into our microwave unit. Using the gas-loading
accessory, we loaded 50 psi of ethene into the vessel. We then
attempted to heat the reaction mixture to the target temperature
of 170 °C. However, we found that when we reached a
temperature of just 120 °C we were already at the pressure limits
of the glass vessel (250 psi). Holding the reaction mixture at
this temperature for 10 min led, upon cooling and workup, to
a low yield of stilbene and only a trace of the desired styrene.
We knew from our previous studies that the Heck reaction under
these conditions was very temperature dependent, so in order
to be able to heat the reaction mixture to the desired temperature
of 170 °C, we decided to dose the reaction vessel with a much
lower ethene loading of 15 psi. Analysis of the product mixture
at the end of this reaction again showed a very low yield of
stilbene.
We turned our attention to the use of dimethylformamide
(DMF) as a solvent for the reaction. DMF has found use as a
solvent for Heck couplings before and its higher boiling point
meant that theoretically we could work at higher pressures of
ethene. Using palladium acetate as a catalyst and screening a
range of reaction conditions, we were unable to obtain significant
conversions to styrenes when using aryl bromides as substrates.
We therefore turned to the more reactive aryl iodides. As a
starting point, we used iodobenzene as substrate, 1 mol%
Pd(OAc)2 as catalyst, tributylamine as a base, and an initial
loading of 100 psi of ethene. Heating this reaction mixture to
175 °C and holding at this temperature for 10 min resulted in
consumption of starting material but formation of significant
quantities of stilbene rather than the desired styrene.
Keeping all other conditions the same, we obtained a 10:69:
21 ratio of unreacted starting material, styrene, and stilbene,
respectively. To increase further the selectivity of the reaction
toward formation of styrene, we turned our attention to the
reaction temperature and time. We postulated that if we slowed
the reaction down by reducing the temperature and extending
the time, we could favor formation of the styrene. Also, by
working at lower temperatures we could increase the initial
loading of ethene because the autogenic pressure generated
during the course of the reaction would be less. This would
also favor formation of the styrene product. Performing the
reaction at 125 °C for 1 h using 0.1 mol% palladium from the
ICP standard as catalyst and an ethene loading of 150 psi we
saw complete conversion of iodobenzene and obtained an 82:
18 ratio of styrene to stilbene respectively. Interestingly, the
reaction can be followed by monitoring the pressure. At the
start of the reaction the pressure increases to approximately 155
psi as the mixture is heated to the target temperature. It then
drops over time, indicating the consumption of ethene. In further
optimization studies we found that the catalyst loading could
be reduced to 0.02 mol% without a deleterous effect on product
yield. It was also possible to reduce the quantity of tributylamine
used in the reaction by adding a stoichiometric equivalent of
potassium carbonate. Although this modification is not essential,
it does make the subsequent step in the protocol easier
(conversion of styrenes to stilbenes). Using our optimal condi-
tions, we screened three further aryl iodides as representitive
examples as shown in Table 1.
We next needed to develop a protocol for preparing stilbenes
from styrenes. Generally, the alkene coupling partner is used
in excess relative to the aryl halide component in Heck
couplings. Because the styrenes in our studies were themselves
prepared from aryl halides in a Heck coupling, to make a one-
pot strategy successful, a challenge that faced us was to develop
a method for the stoichiometric conversion of these styrenes to
stilbenes. The first step of the protocol restricted us to using
DMF or DMF/cosolvent mixtures. Using a 1:1 stoichiometric
ratio of 4-bromoanisole and styrene as test coupling partners,
we screened a range of reaction conditions. It became clear that
using ligandless palladium sources as catalysts for the prepara-
tion of stilbenes from the stoichiometric combination of aryl
(15) Arvela, R. K.; Leadbeater, N. E. J. Org. Chem. 2005, 70, 1786–1790.
(16) Leadbeater, N. E.; Williams, V. A.; Barnard, T. M.; Collins, M. J. Synlett
2006, 47, 2953–2958.
(17) Kormos, C. M.; Leadbeater, N. E. Synlett 2007, 2006–2010.
(18) Kormos, C. M.; Leadbeater, N. E. Org. Biomol. Chem. 2007, 65–68.
(19) Kormos, C. M.; Leadbeater, N. E. Synlett 2006, 1663–1666.
J. Org. Chem. Vol. 73, No. 10, 2008 3855

Kormos and Leadbeater
TABLE 1. Conversion of Aryl Iodides to Styrenes Using a Heck
Reaction with Ethene as the Alkene Coupling Partnera
TABLE 2. Conversion of Aryl Bromides to Styrenes Using a Heck
Reaction with Ethene as the Alkene Coupling Partnera
a Initial microwave irradiation of 50 W was used, the temperature
being ramped from rt to 125 °C where it was then held for 60 min.
Reactions were run using 1 mmol aryl iodide, 150 psi ethene, 1.5 mL
DMF, and 0.25 mL tributylamine. ICP palladium standard was used as
catalyst (0.02 mol%). b Crude conversions were calculated by comparing
the integrations of styrene protons versus the total aromatic integration
in d6-DMSO.
halide and alkene was not going to be possible. However, the
palladium complex trans-bis(acetato)bis[o-(di-o-tolylphosphi-
no)benzyl]dipalladium(II) (called Herrmann’s catalyst and
marketed under the name CataCXium C) was catalytically active
under our conditions. We obtained complete conversion within
15 min at 175 °C in the coupling of 4-bromoanisole and styrene.
The reaction could be performed either in DMF or a 1:1 DMF/
water mix as solvent. Putting this in context, CataCXium C has
been used previously in Heck reactions with success, but when
using an excess of the alkene coupling partner.20–23
Before performing a screening of aryl halides for the synthesis
of stilbenes, we wanted to revisit the preparation of styrenes
using aryl bromides as coupling partners in conjunction with
CataCXium C as the catalyst. This would then allow us to use
both iodo- and bromo-arenes in the first step of the process.
We found that we could indeed achieve this but that the reaction
temperature had to be increased from 125 °C, as was used in
the case of the ligandless palladium catalyzed coupling of aryl
iodides with ethene, to 150 °C. This was successful for a range
of aryl bromides as shown in Table 2. Of note is that while
product conversions are generally high, small-scale isolation of
styrenes from the DMF solution is difficult. Also, with activated
substrates such as 4-bromoacetophenone, the high reaction
temperature required (150 °C) resulted in polymerization of the
styrene product. We also screened 4-chlorotoluene and 4-chlo-
a Initial microwave irradiation of 50 W was used, the temperature
being ramped from r.t. to 125 °C where it was then held for 60 min.
Reactions were run using 1 mmol aryl bromide, 150 psi ethene, 1.5 mL
DMF and 0.25 mL tributylamine. CataCXium C was used as catalyst
(0.5 mol%) b Crude conversions were calculated by comparing the
integrations of styrene protons versus the total aromatic integration in
d6-DMSO. c Substituted styrene products were isolated by silica gel
chromatography following aqueous/organic work-up using diethyl ether.
roanisole as representative aryl chloride substrates in the reaction
but found that product conversions were very low (<5%)
indicating the limitations of the methodology.
With routes for all the desired steps in hand, we screened
different pairs of aryl halides in the one-pot two-step synthesis
of nonsymmetrical stilbenes. Results are gathered in Table 3.
We present data for isolated product yields as well as product
purity. As with any synthetic protocol, product purity is
important and especially when considering the one-pot two-
step approach used here. The product mixtures from our
reactions in some cases contained up to 10 mol% of the
symmetrically substituted stilbene arising from reaction of a
second equivalent of the first aryl halide with the styrene
product. We find that the easiest method for product isolation
is recrystallization from ethanol/water, this allowing for separa-
tion of the stilbenes from other constituents in the product
mixture such as unreacted aryl halide and remaining amine base
and DMF. As a strategy for increasing the product yield while
limiting competitive formation of the undesired symmetric
stilbene we find that its is prudent to use the less reactive aryl
halide in the first (styrene forming) step. That way, the first
step of the process results in a high styrene to symmetric stilbene
(20) Herrmann, W. A.; Bohm, V. P. W.; Reisinger, C. P. J. Organomet.
Chem. 1999, 576, 23–41.
(21) Bohm, V. P. W.; Herrmann, W. A. Chem. Eur. J. 2001, 7, 4191–4197.
(22) Herrmann, W. A.; Brossmer, C.; Reisinger, C. P.; Priermeier, T.; Ofele,
K.; Beller, M. Chem. Eur. J. 1997, 3, 1357–1364.
(23) Herrmann, W. A.; Brossmer, C.; Ofele, K.; Reisinger, C. P.; Priermeier,
T.; Beller, M.; Fischer, H. Angew. Chem., Int. Ed. 1995, 34, 1844–1848.
3856 J. Org. Chem. Vol. 73, No. 10, 2008

Nonsymmetrically Substituted Stilbenes
TABLE 3. One-Pot Two-Step Synthesis of Nonsymmetrical Stilbenesa
a If an aryl iodide is used in the styrene-forming step, ICP palladium standard is employed as the catalyst, DMF as solvent and potassium carbonate,
and tributylamine as bases. The reaction is heated to 125 °C using an initial microwave power of 50 W and held at that temperature for 60 min. If an
aryl bromide is used in the styrene forming step, CataCXium C is employed as the catalyst, DMF as the solvent, and tributylamine as the base. The
reaction is heated to 125 °C using an initial microwave power of 50 W and held at that temperature for 60 min. In both cases, the reaction vessel is
prepressurized with 150 psi of ethene. In the stilbene-forming step, potassium carbonate, CataCXium C, and the second aryl halide coupling parner are
added to the styrene-containing reaction mixture, and this is heated to 175 °C using an initial microwave power of 5-25 W and held at that temperature
for 15 min to give the desired product. b Stilbene products were isolated directly by recrystallization from ethanol/water. c Required silica gel
chromatography (5–10% ethyl acetate in hexanes as eluent). d Required silica gel chromatography (100% dichloromethane as eluent).
ratio and then in the second step when the more reactive aryl
halide is added, the formation of the desired nonsymmetrical
stilbene is favored. Conversely, if the more reactive aryl halide
is used, it tends to over-react in the first stage yielding symmetric
J. Org. Chem. Vol. 73, No. 10, 2008 3857

Kormos and Leadbeater
saturate the solvent before heating. The switch must be reset to
Run before the microwave heating can be resumed. This capability
was generally found not to be necessary for this methodology (see
Supporting Information).
stilbene and then any remaining aryl halide reacts competitively
in the second step giving a double-hit to the yield of the desired
product. The difference between the two strategies is clearly
seen in the case of the 4-bromoacetophenone and 4-bromoani-
sole as the two aryl halide components for the preparation of
4-acetyl-4′-methoxystilbene (Table 3, entries 6 and 11).
In summary, we present here a strategy for the preparation
of nonsymmetrical stilbenes using a one-pot two-step double
Heck strategy. Several significant obstacles were overcome.
First, a protocol was developed for the selective preparation of
a range of styrenes using ethene as the alkene coupling partner.
Then conditions were found for the effective coupling of the
styrenes with aryl halides using a 1:1 stoichiometric ratio of
the two components unlike the majority of cases in the literature
where an excess of the alkene component is used. Our optimal
conditions involve starting with the less reactive aryl halide to
form the styrene. In this step, if an aryl iodide is used, ICP
palladium standard is employed as the catalyst, DMF as solvent
and potassium carbonate and tributylamine as bases. The
reaction is run at 125 °C for 60 min. If an aryl bromide is used
in the styrene forming step, trans-bis(acetato)bis[o-(di-o-
tolylphosphino)benzyl]dipalladium(II) (called Herrmann’s cata-
lyst and marketed under the name CataCXium C) is employed
as the catalyst, DMF as the solvent and potassium carbonate
and tributylamine as bases. The reaction is run at 125 °C for
60 min. In both cases, the reaction vessel is prepressurized with
150 psi of ethene. In the stilbene-forming step, potassium
carbonate, CataCXium C, and the second aryl halide coupling
parner are added to the styrene-containing reaction mixture and
this heated to 175 °C for 15 min to give the desired product.
Microwave heating was used as a tool for performing the
reaction. As well as the inherent advantages of rate acceleration,
the use of the microwave apparatus offers a convenient method
for safely, easily, and accurately loading vessels with gaseous
reagents and monitoring the progress of reactions.
Representative Procedure 1. Preparation of Styrenes from
Aryl Iodides: 4-Methoxystyrene from 4-Iodoanisole. In a 10 mL
microwave tube were placed 4-iodoanisole (1 mmol, 234 mg),
anhydrous potassium carbonate (1 mmol, 138 mg), dimethylfor-
mamide (1.5 mL), and tributylamine (0.25 mL). The mixture was
stirred with a magnetic stir bar as palladium ICP standard (20 uL
of a 1000 ppm solution in 5% HCl, 0.02 mol% Pd) was added.
Using the gas-loading manifold, a pressure of 150 psi ethene as
set at the cylinder regulator was introduced into the vessel by slowly
turning the switch from “Run” to “Load”, then back to “Run”,
isolating the reaction vessel. A second brief switch back to “Load”
was sometimes necessary for the manifold analog pressure gauge
to read 150 psi. The reaction mixture was heated to 125 °C with
stirring using an initial microwave power of 50 W and held at
that temperature for 60 min. The reaction mixture was cooled
to 40 °C, and the remaining pressure was carefully vented. This
crude mixture was carried on directly to a stilbene synthesis
(procedure 3).
Representative Procedure 2. Preparation of Styrenes from
Aryl Bromides: 4-Methoxystyrene from 4-Bromoanisole. In a
10 mL microwave tube were placed 4-bromoanisole (1.00 mmol,
187 mg), anhydrous potassium carbonate (1.00 mmol, 138 mg),
CataCXium C (2.3 mg, 0.50 mol% Pd), dimethylformamide (1.5
mL), and tributylamine (0.25 mL, 1.05 mmol). The mixture was
stirred briefly, then the vessel was sealed and loaded with ethylene
gas (150 psi) using the method outlined in procedure 1. The reaction
mixture was heated to 150 °C using an initial microwave power of
50 W and held at that temperature for 60 min. The reaction mixture
was cooled to 40 °C, and the remaining pressure was carefully
vented. This crude mixture can be carried on directly to a stilbene
synthesis (procedure 3). Otherwise, the reaction was poured into
diethyl ether (50 mL) and water (25 mL). The organic layer was
washed with 2 M HCl (15 mL). The evaporated organic residue
was purified by silica gel chromatography (40 g, 5% ethyl acetate
in hexanes) to isolate 4-methoxystyrene (90 mg, 67% yield) as a
clear, colorless oil.
Experimental Section
Representative Procedure 3. Preparation of Stilbenes from
Styrenes:4-Methoxy-4′-MethylstilbenefromCrude4-Methoxy-
styrene. To the crude, cooled mixture from procedure 1 or 2 was
added anhydrous potassium carbonate (1.00 mmol, 138 mg),
CataCXium C (2.3 mg, 0.50 mol% Pd), and 4-bromotoluene (1.00
mmol, 171 mg). The reaction mixture was heated to 175 °C with
stirring using an initial microwave power of 5–25 W and held at
that temperature for 15 min. The presence of iodide greatly
increased the microwave absorptivity of the sample, so when the
styrene was prepared from an aryl iodide, careful monitoring was
required to prevent overheating. The reaction mixture was cooled
to 40 °C and poured into diethyl ether (50 mL) and water (25 mL).
The organic layer was washed with 2 M HCl (2 × 15 mL). The
evaporated organic layer yields a solid which can be recrystallized
from ethanol and water to yield 4-methoxy-4′-methylstilbene
(55–57% yield, >90% purity).
General Experimental Details. All materials were obtained from
commercial suppliers and used without further purification. All
reactions were carried out in air. Reactions were conducted using
a scientific microwave unit. The machine consists of a continuously
focused microwave power delivery system with operator selectable
power output from 0 to 300 W (CEM Discover). Reactions were
performed in thick-walled glass vessels (capacity 10 mL, maximum
working volume 5 mL). The vessel was sealed with a septum with
ports for pressure and temperature measurement devices. The
pressure is measured by a load cell connected directly to the vessel.
The pressure limit was set to 200 psi for all reactions, beyond which
the apparatus shuts down. The temperature of the contents of the
vessel was monitored using a calibrated fiber-optic probe inserted
into the reaction vessel by means of a sapphire immersion well. In
all cases, the contents of the vessel were stirred by means of a
rotating magnetic plate located below the floor of the microwave
cavity and a Teflon-coated magnetic stir bar in the vessel. Gas
loading is achieved through a manifold coupled with the pressure
sensor. The manifold allows isolation of the reaction vessel, loading
of gas, purging to vacuum, and a vent option that opens the vessel
to a vent line in the back of the manifold. A built-in analog pressure
gauge conveniently indicates the pressure inside the vessel, even
during loading. Once a reaction method has been started, switching
the manifold off the Run position to the Fill position pauses the
microwave heating but maintains reaction stirring. This can be used
to stir a reaction under an open source of gas, allowing gas to
Acknowledgment. We thank the American Chemical Society
Petroleum Research Foundation (45433-AC1) for funding and
CEM Corporation for equipment support.
Supporting Information Available: Photographs of the gas
loading apparatus and NMR spectral data for the styrene and
stilbene products. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO800235C
3858 J. Org. Chem. Vol. 73, No. 10, 2008