Model Guided Development of a Simple Catalytic Method for the Synthesis of Unsymmetrical Stilbenes by Sequential Heck Reactions of Aryl Bromides with Ethylene

Article abstract of DOI:10.1002/adsc.201800167

Stilbenes are important and useful structural moieties, but methods for their preparation typically possess numerous inefficiencies. Presented here is a methodology for the two-step, one pot preparation of unsymmetrical stilbenes via sequential Heck reactions. The first Heck reaction with ethylene gas was analysed as a function of temperature and pressure for electronically differentiated naphthyl bromides and model-aided reaction optimization was utilized to define the system. In addition, reactNMR was utilized to determine ethylene solubility in common organic solvents useful for Heck reactions. Finally, an optimized sequential Heck reaction process was developed and applied to a range of substrates allowing for efficient preparation of unsymmetrical stilbenes, including the natural antioxidant, pterostilbene. (Figure presented.).

Full text of DOI:10.1002/adsc.201800167

Title: Model guided development of a simple catalytic method for
the synthesis of unsymmetrical stilbenes by sequential Heck
reactions of aryl bromides with ethylene
Authors: Helen Barlow, Jonas Buser, Hendrik Glauninger, Carla
Luciani, Joseph Martinelli, Niall Oram, Nichole Thompson-Van
Hook, and Jeffery Richardson
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800167
Link to VoR: http://dx.doi.org/10.1002/adsc.201800167

10.1002/adsc.201800167
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Model Guided Development of a Simple Catalytic Method for
the Synthesis of Unsymmetrical Stilbenes by Sequential Heck
Reactions of Aryl Bromides with Ethylene
Helen Barlow b, Jonas Y. Buser a, Hendrik Glauninger a, Carla V. Luciani *a, Joseph R.
Martinelli* a, Niall Oram b, Nichole Thompson-Van Hook a and Jeffery Richardson* b
a
Small Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center,
Indianapolis, Indiana 46285, United States.
martinelli_joseph_r@lilly.com; luciani_carla_vanesa@lilly.com
Discovery Chemistry Research Technologies, Lilly Research Laboratories, Eli Lilly and Company, Erl Wood Manor,
b
Sunninghill Road, Windlesham, Surrey, GU20 6PH, United Kingdom.
richardson_jeffery@lilly.com
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Stilbenes are important and useful structural In addition, reactNMR was utilized to determine ethylene
moieties, but methods for their preparation typically possess solubility in common organic solvents useful for Heck
numerous inefficiencies. Presented here is a methodology for reactions. Finally, an optimized sequential Heck reaction
the two-step, one pot preparation of unsymmetrical stilbenes process was developed and applied to a range of substrates
via sequential Heck reactions. The first Heck reaction with allowing for efficient preparation of unsymmetrical
ethylene gas was analysed as a function of temperature and stilbenes, including the natural antioxidant, pterostilbene.
pressure for electronically differentiated naphthyl bromides
and model-aided reaction optimization was utilized to define
the system.
Keywords: Heck reaction; ethylene; cross-coupling;
unsymmetrical; stilbene; ethylene solubility; Pterostilbene
The mono-arylation of ethylene is well known with a
variety of catalyst systems that have been
Introduction
demonstrated to be effective for the synthesis of
[5]
Stilbenes are an important class of compounds[1] and
the methods used in their preparation are often used
as examples of poor atom economy. For example the
Wittig and Horner-Wadsworth-Emmons reactions
give rise to stoichiometric high molecular weight by-
products that must be removed and treated as waste.
During one of our drug discovery projects, we sought
a scalable batch synthesis of a stilbene derivative and
were attracted to the Heck reaction of styrenes with
aryl halides.[2] Recent efforts utilizing ethylene by our
colleagues in late phase development (Small
Molecule Design and Development) led to
discussions at a Pharmacat Consortium update
meeting which sparked a trans-Atlantic collaboration
between our groups.[3] The resulting methodology
represents an improvement in atom economy,
although is still far from perfect, but is limited by the
fact that styrene derivatives can be prone to
polymerization and be difficult to handle/purify.
styrene derivatives
and we were attracted by the
potential to perform the first Heck reaction then
simply discharge ethylene gas and charge a second
aryl halide allowing for formation of the desired
unsymmetrical stilbene. Not only does this two-step
approach utilize readily available and inexpensive
materials but it also eliminates the time and
equipment that would be required to isolate the
intermediate styrene derivative. A related advantage
to the two-step procedure is that it circumvents any
issues related to the potential instability of the
intermediate styrene derivative. The use of gaseous
ethylene under pressure also means that the arylation
of the styrene to form the undesired symmetrical
stilbene is minimized since ethylene is present in
significant excess.
This general approach has been described
previously, but none of the previously reported
methods were a truly one-pot method with broad
Thus a method that allows the synthesis of the
styrene and its one-pot conversion to the stilbene has
significant value and several methods for the in situ
generation of the styrene and subsequent Heck
coupling with an aryl halide have been described.[4]
substrate scope using nonspecialized equipment. A
[6]
report by Leadbeater et al
uses a N,N-
dimethylformamide (DMF, a substance of very high
concern by the European Chemicals Agency)[7] in a
specialized microwave system, high temperature and
1
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10.1002/adsc.201800167
Advanced Synthesis & Catalysis
pressure to afford modest yields of the desired
stilbenes. Similarly, the report by Monteiro and co-
workers[8] was only exemplified with aryl iodides,
uses DMF as solvent and would be operationally
complex on scale since transfer of the reaction
mixture to a new vessel for the second step is
required. Ley and co-workers developed a method
for this double arylation using continuous flow
techniques[9] but we were unable to apply this in our
synthesis since the appropriate equipment was not
immediately available. We therefore sought a low
pressure and temperature double Heck protocol to
prepare unsymmetrical stilbenes in a truly one-pot
manner using inexpensive phosphine ligands and
unsymmetrical stilbene. Similarly, in the second step,
the ethylene must efficiently be removed to minimize
the formation of a second, undesired styrene derivate.
Solubility data for ethylene in organic solvents
relevant to cross-coupling reactions is key to guiding
the design of the process to control these selectivity
elements. To the best of our knowledge, these data
were not readily accessible in the organic chemistry
1
literature, thus relevant data was generated using H
NMR.
1
The data resulting from these H NMR studies are
presented in Table 1 and Table 2. The solubility of
ethylene was measured using 1H flow/stop-flow
NMR techniques previously reported by Buser et al
[13]; four sets of conditions were evaluated, two
temperatures and two pressures (Table 1). As
expected, solubility of ethylene gas is generally lower
at higher temperatures and greater at higher pressures.
Interestingly and importantly, the addition of organic
base triethylamine (TEA) to acetonitrile (ACN) in a
ratio relevant to use as a reagent in a cross-coupling
reaction (100 mL ACN: 7.8 mL TEA; 12.8:1 v/v) did
not markedly impact the solubility of ethylene. In
addition, Henry constants were determined at 25 °C
and 50 °C and standard Van’t Hoff equations
parameters were estimated (Table 2).
Henry’s constant (Hi) is defined as the infinite-
dilution limit of the ratio between the fugacity and
mole fraction of a solute. For gas-liquid equilibrium,
Henry constants provide a convenient way to relate
partial pressure of a gas (yiP) and saturation
concentration of the gas in the liquid (Ci).
environmentally benign solvent. We were attracted to
[10]
the Heck conditions described by Kiji
and
[11]
RajanBabu
and elected to begin our studies with
conditions based on the Kiji conditions employing
tris (o-tolyl)phosphine as the ligand.[3a, 10b, 12]
Results and Discussion
We decided to optimize these conditions and
then seek to understand the performance of the
optimal catalyst system on the second Heck reaction.
We began by optimizing the reaction in terms of
pressure and temperature and determining the
solubility of ethylene in relevant solvents. Building
from the previous work to study the synthesis of
Naproxen [3a], we chose to study three different
naphthyl halides with electronically different
substituents over a range of temperatures and
pressures (Scheme 1). The resulting data was then
used in modelling-aided reaction optimization and
reaction performance visualization to allow easy
examination of optimal conditions. The resulting
optimized conditions would then allow for a more
yi P  HiCi
(1)
While Henry’s constant as a function of
temperature is known for common gases such as O2
and N2 in a variety of organic solvents, the
availability for other gases is more limited. The data
below in Table 1 and Table 2 provide solubility data
for ethylene, and the related Henry's constants, in
organic solvents and a binary mixture that are
relevant to cross-coupling reactions. Equation (1)
allows the calculation of molar equivalents of the
ethylene in solution at a given pressure and
temperature. Thus, these data allow for the design of
each step of the process to ensure high solubility of
ethylene for the first step, during which high
equivalents of ethylene are desired, and for efficient
removal of ethylene after the first step.
efficient
two-step,
one
vessel
procedure.
Experimental details and further plots can be found in
the Supporting Information.
Scheme 1. Test cases examined to determine the effect of
temperature and pressure on product distribution in Heck
reactions with ethylene.
Ethylene Solubility
Key to the success of the two-step process is
selectivity of each step. In the first step, there must
be sufficiently high excess of dissolved ethylene to
minimize the undesired symmetrical stilbene, which
can be very difficult to separate from the desired
2
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10.1002/adsc.201800167
Advanced Synthesis & Catalysis
Table 1. Ethylene solubility in various organic solvents
(mM).
Solvent
25 C
100
50 C
50
50
100
psig
psig
psig
psig
ACN
ACN/TEA (12.8:1 v/v)
DMSO
399
403
155
287
423
778
475
840
305
332
146
285
325
434
399
619
606
Scheme 2. Reaction used for modeling purposes. R
represents electron donor, electron acceptor, or neutral
functional groups. D-catalyst represents the deactivated
catalyst species.
828
270
501
645
964
763
319
DMF
587
Using the aforementioned assumptions, the
species mass balances in the batch reactor were
written as follows:
Ethanol
829
THF
1237
1037
Toluene
d[Substrate]
P / P
ref
 k1[Substrate ]
 k2[Styrene][Substrate ]
 k2[Styrene][Substrate ]
dt
Hethylene
Table 2: Henry constants for ethylene in various organic
solvents.
d[Styrene]
P / P
ref
 k1[Substrate ]
dt
Hethylene
Solvent
Henry Constant (psi/mM)
Van’t Hoff Equation
50 C
25 C
d[Stilbene]
 k2[Styrene][Substrate ]
1144.9
dt
exp(
exp(
exp(
exp(
exp(
exp(
exp(
1.89)
1.75)
 0.85)
 0.01)
1.44)
1.81)
1.34)
ACN
7.05
5.23
5.24
2.33
4.38
6.54
8.00
5.48
T(C)  273.15

n


d[Catalyst ]
P / P
ref

 k3[Catalyst ]


dt
Hethylene

1101.4
ACN/TEA
(12.8:1
v/v)
6.98
2.69
4.96
8.63
11.08
7.06
T(C)  273.15
where k1, k2, and k3 represent the kinetic constants for
the formation of styrene, formation of stilbene, and
catalyst deactivation, respectively, P/Pref/Hethylene
represents the equilibrium concentration of dissolved
ethylene, where P is the ethylene pressure (Pref=25
psi) and Hethylene is the Henry constant. The catalyst
was assumed to deactivate over time and the impact
of such deactivation was stronger at high pressures.
The extent of deactivation was modeled by the use of
a coordination number n, which represents the order
of the deactivation reaction with respect to ethylene.
In order to incorporate the effect of catalyst
concentration on the reaction rates of styrene and
stilbene formation, kinetic parameters were assumed
to be impacted by catalyst with first order kinetics, as
follows:
546.7
DMSO
DMF
T(C)  273.15
474.1
T(C)  273.15
1072.5
Toluene
THF
T(C)  273.15
1257.8
T(C)  273.15
983.2
Ethanol
T(C)  273.15
k  k exp(E /(RT ))[C*]
1
10
1
k  k exp(E /(RT ))[C*]
2
20
2
Reaction Analysis and Model-Aided Optimization
The impact of the three substrates described in
Scheme 1 to the reaction performance and potential
optimization strategies were investigated with the
help of a simple mathematical model of the process.
For simplicity, the solvent was assumed to be
saturated in ethylene (i.e., very fast mass transfer
between liquid and gas phases was assumed) and the
step controlling the overall rate was assumed to be
first order with respect to the substrate. High ethylene
pressures were assumed to deactivate the catalyst by
coordination.[5h] A description of the reactions
considered by the model are presented in Scheme 2.
where k10 and k20, are the pre-exponential factors for
k1 and k2, respectively, and E1 and E2 are the
corresponding activation energies. While this model
is a very simplified version of the real system, it was
developed such that it captures the impact of key
process parameters on the overall reaction
performance and therefore can be used to explore
potential optimization strategies.
The model parameters listed in Table 3 were
determined by minimizing the sum of squared
deviations between experimental data and simulations.
Data used for modelling include seven experiments at
temperatures varying between 40 and 80 °C for
substrate containing methoxy (electron-donating)
3
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10.1002/adsc.201800167
Advanced Synthesis & Catalysis
Figure 1. Selected parity plot for substrate with: (a) 1a
(electron donating group) at 60 C; (b) 1c (electron
withdrawing group) at 40 C; (c) 1b (neutral group) at 40
C.
group,
H
(neutral), and an ester (electron-
withdrawing) group. A graphical summary of this
data is provided in the Supporting information. The
resulting model parameters for the three investigated
substrates are shown in Table 3.
Some of the resulting parity plots are shown in
Figure 1. In spite of the simplicity of the model, it
captures the main behavior of these three substrates.
Table 3: Model parameters
Parameter(a)
Value
Units(b)
Electron Donor Group
conc-1s-1
conc -1s-1
k /H
exp(6981.1/(T)  23.228)[C*]
exp(6884.3/(T)  20.353)[C*]
1
ethylene
k
2
n
concn s-1
k / H
exp(10739/(T)  29.249)
 0.0204(T  273.15)  2.586
3
ethylene
n
dimensionless
Electron Withdrawing Group
k /H
exp(4028.5/(T) 17.796)[C*]
1
ethylene
conc-1s-1
conc-1s-1
exp(1891.8/(T)  6.3453)[C*]
k
2
n
k / H
3
ethylene
2
concn s-1
1.7310
n
2.7334
dimensionless
Neutral Group
conc-1s-1
conc-1s-1
concn s-1
k /H
exp(2095.3/(T) 11.994)[C*]
1
ethylene
k
2.974
2
n
k / H
exp(16390/(T)  47.798)
 0.0645(T  273.15)  5.9512
3
ethylene
n
dimensionless
(a) For reaction in acetonitrile, the impact of temperature on Henry constant was combined
with the impact of temperature on reaction kinetics; (b) Reference concentration basis: 0.5
M for substrate and 0.01 M for catalyst.
4
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10.1002/adsc.201800167
Advanced Synthesis & Catalysis
Figure 2. Contour curves for substrate with electron donating group 1a, 1b, and 1c as a function of pressure and
temperature. (a) Styrene 2a; (b) Residual substrate 1a; (c) Stilbene 3aa. (d) Styrene 2b; (e) Residual substrate 1b; (f)
Stilbene 3bb. (g) Styrene 2c; (h) Residual substrate 1c; (i) Stilbene 3cc.The numbers indicate the relative percentage of the
species.
The model was used to analyze the data and to help
highlight process optimization strategies. To this
purpose, contour curves for the three investigated
substrates were generated (Figure 2). Having an
electron donating group in the substrate seems to
favor the formation of stilbene at low pressures (<30
psi) and intermediate temperatures (40-80 C) (Figure
2c). Interestingly, there are two operating regions that
favor the formation of high levels of styrene product:
one at low pressures and temperatures (50-75 psi/35-
40 C), and the other at high pressures and
temperatures (>300 psi/>95 C) (Figure 2a).
Correspondingly, residual starting material is
observed to be higher at the high pressure/low
temperature region as well as low pressure/higher
temperature region. This non-monotonic change in
reaction selectivity is due to the non-linear impact of
temperature and pressure on deactivation kinetics,
and the corresponding impact of such deactivation on
the main reaction rates.
When the substrate contains a neutral group, the
behavior is quite similar to that described for the
electron donating group. However, the two regions
promoting the formation of higher levels of styrene
product move closer to each other (Figure 2d). Higher
levels of stilbene are obtained at low pressure/low
temperature conditions (Figure 2f). In this case, levels
as high as 10% were obtained.
activation energy for the formation of styrene product
is lower than that for the other two substrates, which
explains why temperature has such a significant
impact to reaction selectivity. As expected, reaction
deactivation promotes higher levels of residual
starting material at low temperatures/high pressures
(Figure 2h). The levels of stilbene predicted for the
substrate with an electron withdrawing group are
much lower than those for neutral and electron
donating groups, but the formation of this compound
is also favored in the low temperature/low pressure
region (Figure 2i).
Experiment-Based Process Improvement
In order to perform a second Heck coupling the
catalyst would still need to be active at the end of the
first Heck reaction, so the ethylene pressure could be
discharged and a second aryl halide added. As such,
we sought to define our standard conditions for the
first Heck reaction, paying specific attention to the
fate of the catalyst. The data generated for the first
Heck reaction, and resulting process models, for
bromonaphthylene showed that the optimal reaction
temperature range for substrate conversion was 40-
80 °C (Figure 2d-f), it was noted that in these cases a
black precipitate was formed at the end of the
reaction at higher temperatures. Performing the
reaction at both 50 and 100 psi ethylene pressure
gave similarly high conversion, but significant
amounts of black precipitate were formed at both
pressures at 60 and 80 °C.
When an electron withdrawing group is present
in the substrate, the two regions of high selectivity
toward the styrene product merge into one single
region (Figure 2g). The higher the pressure, the
stronger the deactivation. This can be overcome by
increasing the reaction temperature. In this case, the
5
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10.1002/adsc.201800167
Advanced Synthesis & Catalysis
conditions would catalyse the second Heck coupling.
With so many of these variables predetermined by the
optimization of the first reaction, only temperature
could be easily varied (Fehler! Verweisquelle
konnte nicht gefunden werden.Table 4). Increasing
temperature lead to a significant increase in the
amount of 3aj formed according to HPLC analysis,
with almost all of the styrene intermediate consumed
after 16 h at 80 °C.
Scheme 3. Evaluation of catalyst lifetime in the
bromonaphthylene ethylene Heck reaction. aSignificant Pd
black formation observed.
Table 4. Development of a 1-pot, 2-step procedure; study
of the 2nd Heck reaction.
Since the goal was to utilize the same catalyst
for both steps, we aimed to understand how quickly
these reactions were complete so that we could
generate a good understanding of when ethylene
pressure should be discharged and the second aryl
halide added. At 60 °C, 50 psi the reaction with 1b,
bromonaphthylene was complete at a 7 hour time
point, while at 40 °C and the same pressure only
around 50% conversion was achieved.
We then sought to evaluate a small group of
electronically and sterically differentiated aryl
bromides under the more optimized conditions (50
psi, 60 °C) to understand the effect that these
properties would have on the rate of the first reaction,
Scheme 4.
Entry
Temp (°C)
1a:2a:3aj [a]
1
2
3
40
60
80
14:79:7
0:19:81
0:7:93
[a] ratio determined by HPLC analysis.
Further examination of this 2-Step, 1-pot synthesis,
revealed that it was better to charge the requisite base
for the second Heck at the same time as the second
aryl halide rather than adding it all at the beginning.
We also found that the preformed [(oTolyl)P]2PdCl2
complex (Pd-111; CAS 40691-33-6) served as a more
convenient precursor for these reactions, obviating
any issues with complex formation. Also, for the sake
of process robustness, it was decided to add a second
catalyst charge with the second aryl halide in the
styrene coupling step. This allowed us to take
advantage of the faster rates at higher temperatures
for the ethylene coupling step while minimizing the
impact of the catalyst deactivation observed at higher
temperatures. Overall this process still uses only 3
mol% of [(oTolyl)P]2PdCl2 and represents a simple
and practical method for these reactions.
100
80
60
40
1b
1d
1e
1f
1g
1h
1i
20
0
0
2
4
6
8
10
Time /h
Substrate Scope and Resveratrol Synthesis
The reaction conditions developed were
successful for a range of electronically and sterically
varied aryl halides affording the unsymmetrical
stilbenes in reasonable yield over the 2-steps. Typical
impurities in these materials were unreacted aryl
bromide(s) and symmetrical stilbenes, thus making
them very challenging to purify by chromatographic
means. While they could be crystallised in most
instances, it was difficult to obtain them in >98%
purity without significant loss of material. The order
in which each aryl bromide is introduced has some
impact on the overall yield (Scheme 5, 3bf, 3kl and
3fg), but these effects are relatively small in most
instances. A few examples were chosen where
identical products had been prepared by Leadbeater et
Scheme 4. Effect of aryl bromide on the progress of the
Heck reaction with ethylene under optimized conditions.
Unsurprisingly, the electron-deficient and
neutral aryl bromides (Scheme 4, 1b, 1e, 1h) were all
very fast, while those bearing electron donating
groups were somewhat slower, although close to full
conversion in 6-8 h. An ortho-positioned electron
donating group (Scheme 4, 1g) resulted in a reaction
that had not reached completion by the 8 h time point.
Similarly, 3-bromopyridine (Scheme 4,1i) did not
fully react in this timeframe. For the majority of
these substrates, satisfactory conversion was
observed in a few hours under these conditions and so
we wanted to examine the second reaction of this 1-
pot, 2-step process using the same solvent, base and
catalyst to understand how effectively these
6
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10.1002/adsc.201800167
Advanced Synthesis & Catalysis
[6]
al
and in all instances the yield that we obtained
than hydroxyl groups lead us to believe the
methodology would have a better chance at success
given the potential for phenolates to cause catalyst
inhibition. Thus, pterostilbene was selected as a final
test for the generality of this procedure and we opted
to run this experiment in our Reaction
Characterization Lab to enable real-time monitoring
using this method compared favourably.
1
by H NMR and maximize our understanding of the
processes.
Scheme 6. FlowNMR experiment to prepare Pterostilbene.
We then sought to apply the general conditions
from the substrate scope evaluation (directly to the
synthesis of pterostilbene (Scheme 6). For the first
step of the process, the Heck reaction of 1-bromo-
3,5-dimethoxybenzene, 1n, was conducted with
ethylene to make 1,3-dimethoxy-5-vinylbenzene, 2n.
This reaction was performed on 2.5 g scale of 1n in a
100 mL Parr reactor and the reaction was
Scheme 5. Assessment of the general procedure for 2-step,
1-pot stilbene formation. Yield adjusted for purity. Purity
by HPLC in parentheses.
[13]
continuously monitored using FlowNMR.
The
reaction profile obtained via FlowNMR is shown in
Figure 6 and several interesting features of this
reaction are apparent.
Finally, we sought to demonstrate the utility of
this method by synthesizing a natural product and we
were attracted to the powerful antioxidants
resveratrol and pterostilbene (Figure 3).
As the profile clearly shows in Figure 6 the
reaction stalled around 6 h and 85% conversion. This
time point corresponds to when nearly all the ligand
had been oxidized (green shaded circles on secondary
axis of Figure 6, theoretical amount of ligand is 0.04
equiv.), presumably due to inadequate oxygen
removal. At this point, an additional portion of
catalyst and base were added to try to push the
reaction to completion. The addition of these
reagents resulted in progression to 95% conversion
(5% remaining 1n) and 85% in situ yield of 2n, as
measured by 1H NMR (flowNMR). The symmetrical
stilbene 3nn was observed at ~3%. The remaining
7% of the mole balance was unclosed.
Another benefit resulting from real-time reaction
observation by 1H flowNMR was the ability to
directly observe the solution concentration of
ethylene. In the first step, the level of ethylene
stabilized, i.e. reaches saturation, in less than 0.5 h.
The additional catalyst and base coincided with a
small increase in the saturation concentration of
ethylene, indicating the complexity of matrix effects
on solubility, despite the increase in system dilution,
the overall concentration of ethylene increased. Once
the concentration stabilized, the constant level shows
Figure 3. Naturally occurring antioxidants Resveratrol and
Pterostilbene.
Stilbene-derived compounds have a variety of
biological activity[14] and there is increasing interest
in the anticancer properties of polyphenols.[15]
Although resveratrol has received significant
attention as one of the main components in red wine,
we were attracted to pterostilbene as a test case for
two reasons. First, pterostilbene demonstrates much
of the same bioactivity as resveratrol and even
appears more attractive from a bioavailability
perspective.[16] Second, the fact that one half of the
molecule was decorated with methoxy groups rather
7
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10.1002/adsc.201800167
Advanced Synthesis & Catalysis
that the reaction is not mass transfer limited, ie. the
rate of consumption of ethylene is not faster than the
rate of diffusion of ethylene gas into the liquid phase.
The fact that the reaction was not mass transfer
limited was somewhat surprising, given the amount
of ethylene in the system. Using the reaction
temperature, pressure, and the solubility model
presented in above, Table 2, the relative amount of
ethylene was calculated to be 0.075 equiv. Note that
increase in the amount of 3nn that was produced.
While some 2n remained unconverted, it was decided
to work the reaction up and attempt to isolate the
product directly. Attempts to purify the product by
crystallization from ethanol:water were not successful.
The resulting orange-brown oil was 54.5% pure
Pterostilbene, corresponding to a 61.4% yield. To the
best of our knowledge, this constitutes the first direct
synthesis of Pterostilbene via sequential Heck
couplings utilizing ethylene.[17]
1
this value is lower than the amount observed by H
flowNMR, ~0.3 equiv. in Figure 4. These differences
can be attributed long T1 pre-magnetization and/or
relaxation of ethylene. This is a well-known source
of inaccurate quantitation in flowNMR.[13]
In
addition, ethylene solubility is sensitive to
temperature and additional solutes, ie. matrix effects.
Despite there being only 0.075 equiv. ethylene
dissolved in the saturated solution, the rate of
diffusion of ethylene gas in the reactor headspace,
containing a constant source of approximately 0.7
equiv., was fast enough keep up with the rate of
reaction. Overall, there was sufficient ethylene to
enable productive coupling to generate the desire
styrene, 2n. Under these conditions, only a small
amount of the symmetric stilbene, 3nn, was observed
(green + on secondary axis of Figure 4).
Figure 5. 1H NMR reaction profile for Heck reaction of 1o
and 2n to make Pterostilbene.
Conclusion
An efficient methodology for the two-step, one pot
preparation of unsymmetrical stilbenes via sequential
Heck reactions has been developed. The Heck
reaction with ethylene gas was analysed as a function
of temperature and pressure for electronically
differentiated naphthyl bromides and model-aided
reaction optimization was utilized to define the
system. In addition, ethylene solubility in common
Figure 4. 1H NMR reaction profile for Heck reaction of 1n
and ethylene to prepare 2n.
organic solvents useful for Heck reactions was
[13]
determined using flowNMR.
This data was also
used to develop a solubility model to facilitate
process design. Finally, an optimized sequential
Heck reaction process was developed and applied to a
range of substrates allowing for efficient preparation
of unsymmetrical stilbenes, including the natural
Once it was determined that the first reaction
was complete, the system was cooled to room
temperature and ethylene was removed until it was
not detectable by H NMR. For the second step of
the process, the Heck reaction of 1,3-dimethoxy-5-
1
antioxidant, Pterostilbene.
To the best of our
vinylbenzene, 2n, was conducted with 4-
knowledge, this constitutes the first direct synthesis
of Pterostilbene via sequential Heck couplings
utilizing ethylene
bromophenol, 1o, to make Pterostilbene.
This
reaction was carried out directly in the same 100 mL
Parr reactor and was also continuously monitored
using FlowNMR (Figure 5).
This second reaction in this sequence was
relatively straightforward. The desired coupling
occurred fairly rapidly, essentially reaching
completion in approximately 2 h, Figure 5. Also at
this time point, it appeared that the Pterostilbene
concentration had dropped, potentially indicating
precipitation of product from solution (as flow to and
from NMR had stopped as a result of solids in
transfer lines). There was also a 2.5- to 3-fold
Experimental Section
All reagents purchased from commercial suppliers
and used as received. Solvents were purchased from
Aldrich, anhydrous, sure-seal quality, and used with
no further purification. The ligands, bases, solvents,
ethylene, and aryl halides were purchased from
commercial sources and used without further
purification. Ethylene was purchased from either
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800167
Advanced Synthesis & Catalysis
Argo International or AirGas Inc. Anhydrous
acetonitrile was purchased from either Acros or
Aldrich. Triethylamine was purchased from either
Aldrich or Fisher Chemical. Dichlorobis(tri-o-
tolylphosphine) palladium (II) was purchased from
either Aldrich or Alfa Aesar. Palladium (II) acetate
and tri-o-tolylphosphine were purchased from
General Procedure for Temperature and Pressure
Screening (Data used in Reaction Analysis and
Model-Aided Optimization Figures 1-4)
To Biotage Endeavor glass liners were charged with
all solid reagents: Pd(OAc)2(0.02 equiv), P(o-tol)3
(0.04 equiv), and the required aryl halide. 2-Bromo-
6-methoxynaphthalene, 2-bromonaphthalene, or
Methyl 6-bromo-2-naphthoate (1 mmol). The tubes
were then transferred into a glovebox where degassed
liquid reagents were added: Et3N (2.0 equiv),
CH3CN (2 mL). The tubes were then loaded in the
the Endeavor, sealed, further inerted with nitrogen
pressure / vent cycles (3x), then heated to the target
temperature and finally pressurized with C2H4, to the
target pressure. The reactions were allowed to stir at
least 12 h. The crude reactions were analysed by
HPLC using toluene as an internal standard and
diluting with ethyl acetate / acetonitrile. The data are
summarized in supporting information.
Aldrich.
2-Bromo-6-methoxynaphthalene
was
purchased from Oakwood Products Inc. Methyl 6-
bromo-2-naphthoate and 4-bromophenol were
purchased from Acros. 2-bromonaphthalene, 1-
bromo-4-methoxybenzene, methyl 4-bromobenzoate,
1-bromo-4-nitrobenzene,
3-bromopyridine,
4-
bromoacetophenone, 1-bromo-4-methylbenzene and
1-bromo-2-methoxybenzene were purchased from
Aldrich. 2-Bromothiophene was purchased from
Fluorochem. 1-Bromo-3,5-dimethoxybenzene was
purchased from Acela.
Flash column chromatography was carried out
using silica gel columns with a Teledyne ISCO
CombiFlash Companion system.
General Procedure for Experiments Illustrated in
Scheme 4.
1H and 13C NMR spectra were recorded on a
Bruker AV-HD 400 spectrometer. Signal positions
were recorded in δ ppm with the abbreviations s, d, t,
q, dd, dt and m denoting singlet, doublet, triplet,
quartet, doublet of doublets, doublet of triplets and
In to 8 separate Biotage Endeavour tubes containing a
stir bar was weighed Pd(OAc)2 (7 mg, 0.02 equiv),
P(o-tol)3 (18 mg, 0.04 equiv), and aryl halide (1.5
mmol) and these were purged with nitrogen. Et3N
(0.5 mL, 2.5 equiv), CH3CN (3 mL), were added via
syringe using the ports in the Endeavour, washed
through with CH3CN (<0.1 mL). The tubes were then
pressurised with ethylene gas (50 psig) and heated to
60 °C. Every hour, heating was stopped and the
ethylene discharged from sequential vials until all
vials were no longer under an ethylene atmosphere.
The conversion in each vial was then determined by
HPLC analysis and plotted as shown in Scheme 4.
1
multiplet respectively. All H NMR chemical shifts
were referenced to SiMe4 as an internal standard
(0.00 ppm). All 13C NMR chemical shifts in CDCl3
were referenced to the residual solvent peak at 77.00
ppm. All 13C NMR chemical shifts in (CD3)2SO were
referenced to the residual solvent peak at 39.52 ppm.
All coupling constants, J, are quoted in Hz. Infra-red
spectra were recorded on
a
Nexus FT-IR
spectrometer with Nicolet OMNI sampler using a
neat sample. Melting points were obtained using a
DSC 1 STARe system and high resolution mass
spectrometry (HRMS) data were recorded under
electrospray ionisation conditions.
General Procedure for Experiments Illustrated in
Table 4
Pd(OAc)2 (5 mg, 0.02 equiv), P(o-tol)3 (12 mg, 0.04
equiv), and 2-bromonapthalene (207 mg, 1 mmol)
were added to three microwave vials which were
purged with nitrogen. Et3N (0.35 mL, 2.5 equiv),
CH3CN (2 mL, 8 vols), were added to each
microwave vial via syringe and the vials were then
degassed. The contents of each vial was then injected
in to a separate, ethylene purged reaction vials on the
Biotage Endeavour via syringe using the injection
ports, washed through with CH3CN (<0.1 mL). The
vials were then charged with ethylene (50 psig) and
heated to 60 °C. After 4 hours the reaction mixtures
were cooled to 25 °C and purged with nitrogen. Three
degassed solutions of bromobenzene (105 L, 1
1H flowNMR experiments were carried out as
described in the literature.[13] And the resulting data
was utilized to generate the solubility data presented
in Table 1 and Table 2.
All screening reactions were performed using an
Argonaut
Technologies,
Inc.
EndeavorTM
(Indianapolis) or Biotage® EndeavorTM (Erl Wood).
The reactions were performed in Biotage® glass
liners (Part No. 900676) and using Biotage® blade
type impellers (part no. 900543) for overhead
agitation.
HPLC analyses were performed on an Agilent
Series 1100 HPLC eluting through Waters XBridge™
C18 2.5 μm 4.6 x 75 mm column or Waters XBridge
Shield RP18 2.5 μm 4.6 x 75 mm column.
mmol) in
CH3CN (1 mL) were added via the
injection port (one in each initial reaction) and and
heated to the temperature specified in table 4 for 16 h
under a nitrogen atmosphere.
9
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800167
Advanced Synthesis & Catalysis
1-Bromo-4-methoxybenzene,
Ar2Br
=
2-
General Procedure for g-scale Preparative
Reactions (Scheme 5):
bromonaphthalene). The crude product was
recrystallized from a mixture of ethanol and water.
The solid was collected by filtration, washing with
ethanol. Dried in a vacuum oven at 40 °C to obtain
product (0.87 g, 58% yield based on 93% purity by
HPLC). 1H (400 MHz CDCl3) δ 7.85‐7.77 (m, 4H),
7.71 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 8 Hz, 2H), 7.49-
7.41 (m = 2H), 7.20 (d, J = 16.2 Hz, 1H), 7.13 (d, J =
16.2 Hz, 1H), 6.92 (d, J = 8.6 Hz, 2H), 3.84 (s, 3H).
13C NMR (100 MHz CDCl3) δ 159.4, 135.2, 133.8,
132.9, 130.2, 128.6, 128.3, 127.9, 127.8, 127.7, 126.7,
126.3, 126.1, 125.7, 123.5, 114.2, 55.5. NMR data
All g-scale preparative reactions were performed in
an oven-dried 250 mL ACE Glass pressure flask (Part
number 8415-21), equipped with magnetic stir bar
and fitted with a modified PTFE stopper serving as
gas inlet and sampling/addition port. Liquids and
slurries were transferred via syringe.
To a 250 mL ACE Glass round-bottom flask was
added Ar1Br (1.0 g), triethylamine (2.5 equiv.) and
acetonitrile (20 mL). The mixture was degassed with
subsurface nitrogen purge for 5 minutes and
dichlorobis(tri-o-tolylphosphine) palladium (II) (2
mol%) was added. The flask was purged three times
by pressurizing with nitrogen (20 psig) followed by
ethylene (20 psig). The flask was filled with ethylene
to 50 psig and the reaction mixture in an oil bath at
70 °C overnight.
The reaction mixture was then allowed to cool to
ambient temperature, residual ethylene was vented
and the mixture sampled under a nitrogen blanket.
Complete conversion to the vinyl intermediate was
determined by GC-MS. The reaction mixture was
degassed with subsurface nitrogen purge for fifteen
minutes.
were consistent with literature data [18]
.
Methyl 4-[(E)-2-(4-nitrophenyl)vinyl]benzoate
(3kl). Prepared according to the general procedure
(Ar1Br = methyl 4-bromobenzoate, Ar2Br = 1-
Bromo-4-nitrobenzene). The crude product was
recrystallized from a mixture of ethanol and water.
The solid was collected by filtration, washing with
ethanol. Dried in a vacuum oven at 40 ºC to obtain
desired product (0.79 g, 60%, 100% purity by HPLC).
Also prepared with inverted order of aryl halides
according to the general procedure (Ar1Br = 1-
In a separate round-bottom flask a solution of Ar2Br
(1.1 equiv.), triethylamine (1.0 equiv.) and
acetonitrile (4 mL) was degassed with subsurface
nitrogen purge for five minutes. Dichlorobis(tri-o-
tolylphosphine) palladium (II) (1 mol%) was added,
the flask was sealed with a septum and the contents
further degassed with three cycles of vacuum and
nitrogen refill. The contents were transferred to the
styrene solution above via syringe and the reaction
vessel was sealed, and heated at 80 °C (external
temp) overnight. The reaction mixture was allowed
to cool to ambient temperature and the mixture
sampled under a nitrogen blanket. Conversion to the
stilbene product was determined by HPLC analysis
The reaction mixture was partitioned between ethyl
acetate (150 mL) and water (50 mL). The organic
layer was washed with dilute aqueous hydrochloric
acid (1M, 50 mL) then water (50 mL) then saturated
aqueous brine solution (50 mL). The organic layer
was dried over magnesium sulfate, filtered and
evaporated to obtain the crude product.
Bromo-4-nitrobenzene, Ar2Br
bromobenzoate). The crude
=
methyl 4-
product was
recrystallized from a mixture of ethanol and water.
The solid was collected by filtration, washing with
ethanol. Dried in a vacuum oven at 40 °C to obtain
desired product (1.12 g, 80%, 100% purity by
HPLC).1H (400 MHz CDCl3) δ 8.24 (d, J = 8.2 Hz,
1H), 8.06 (d, J = 7.8 Hz, 2H), 7.66 (d, J = 8.2 Hz,
2H), 7.61 (d, J = 7.8 Hz, 2H), 7.33-7.20 (m, 2H), 3.94
13
(s, 3H). C NMR (100 MHz CDCl3) δ 166.6, 147.2,
143.2, 140.5, 132.1, 130.2, 130.1, 128.7, 127.2, 126.9,
124.2, 52.2. NMR data were consistent with literature
data [19]
.
3-[(E)-2-(2-naphthyl)vinyl]pyridine (3bi). Prepared
according to the general procedure (Ar1Br = 3-
bromopyridine, Ar2Br = 2-bromonaphthalene), except
the aq. HCl was omitted from the work-up. The crude
product was triturated in warm methanol. The beige
solid was collected by filtration, washing with
ethanol. The liquors were loaded to the top of Biotage
SCX-2 cartridge. Washed with several column
volumes of methanol, followed by several column
volumes of 2M methanolic ammonia solution. The
methanolic ammonia fractions were evaporated to
and combined with the solids from the filtration and
dried under vacuum at 40 °C to obtain desired
product (1.25 g, 85%, 93% purity by HPLC). 1H (400
MHz CDCl3) δ 8.78 (s, 1H), 8.5 (d, J = 4.3 Hz, 1H),
7.9-7.8 (m, 5H), 7.74 (d, J = 8.8 Hz, 1H), 7.52-7.44
(m, 2H), 7.37-7.27 (m, 2H), 7.2 (d, J = 16.4 Hz, 1H).
13C NMR (100 MHz CDCl3) δ 148.6, 134.1, 133.6,
133.3, 133.1, 132.7, 130.9, 128.5, 128.1, 127.8, 127.1,
2-[(E)-2-(4-methoxyphenyl)vinyl]naphthalene
(3bf). Prepared according to the general procedure
(Ar1Br = 2-bromonaphthalene, Ar2Br = 1-Bromo-4-
methoxybenzene). The crude product was
recrystallised from a mixture of ethanol and water.
The solid was collected by filtration, washing with
ethanol and dried under vacuum at 40 ºC to obtain
product (0.89 g, 66% yield based upon 93% purity by
HPLC). Also prepared with inverted order of aryl
halides according to the general procedure (Ar1Br =
10
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800167
Advanced Synthesis & Catalysis
126.5, 126.3, 125.2, 123.6, 123.3. NMR data were
J = 8.6 Hz, 2H), 7.35 (d, J = 16.4 Hz, 1H), 7.22 (t, J
= 7.8 Hz, 1H), 7.06 (d, J = 16.4 Hz, 1H), 6.96 (d, J =
7.6 Hz, 1H), 6.91-6.86 (m, 3H), 3.88 (s, 3H), 3.82 (s,
3H) ppm. NMR data were consistent with literature
consistent with literature data [20]
.
1-[4-[(E)-2-(4-
data [21]
.
methoxyphenyl)vinyl]phenyl]ethanone
(3fh).
Prepared according to the general procedure (Ar1Br =
4-bromoacetophenone,
methoxybenzene).
Ar2Br
The crude product was
=
1-bromo-4-
1-methoxy-2-[(E)-2-(4-
methoxyphenyl)vinyl]benzene
(3fg).
Prepared
recrystallized from a mixture of ethanol and water.
The solid was collected by filtration, washing with
ethanol. Dried under vacuum at 40 °C to obtain
product (0.99 g, 74%, 94% purity by HPLC). 1H
(400 MHz CDCl3) δ 7.93 (d, J = 8.4 Hz, 2H), 7.55 (d,
J = 8.4 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.18 (d, J =
16.4 Hz, 1H), 6.99 (d, J = 16.4 Hz, 1H), 6.91 (d, J =
8.6 Hz, 2H), 3.84 (s, 3H), 2.60 (s, 3H). NMR data
according to the general procedure (Ar1Br = 1-
bromo-4-methoxybenzene, Ar2Br
=
1-bromo-2-
methoxybenzene), except that the first Heck reaction
was run for an additional 5 h at 70 °C with an
additional charge of catalyst (1 mol%) to drive first
Heck to completion. The crude product was
recrystallized from a mixture of methanol and water.
The solid was collected by filtration, washing with
ethanol. Dried under vacuum at 40 °C to obtain
product (0.81 g, 57%, 90% purity by HPLC). 1H
(400 MHz CDCl3) δ 7.57 (d, J = 7.6 Hz, 1H), 7.47 (d,
J = 8.6 Hz, 2H), 7.35 (d, J = 16.4 Hz, 1H), 7.22 (t, J
= 7.8 Hz, 1H), 7.06 (d, J = 16.4 Hz, 1H), 6.96 (d, J =
7.6 Hz, 1H), 6.91-6.86 (m, 3H), 3.88 (s, 3H), 3.82 (s,
3H) ppm.
were consistent with literature data [21]
.
1-[4-[(E)-2-(p-tolyl)vinyl]phenyl]ethanone (3dh).
Prepared according to the general procedure (Ar1Br =
4-bromoacetophenone,
methylbenzene). The
Ar2Br
crude
=
1-bromo-4-
product was
recrystallized from a mixture of ethanol and water.
The solid was collected by filtration, washing with
ethanol. Dried in a vacuum oven at 40 °C to obtain
desired product (0.87 g, 71%, 96% purity by HPLC).
1H (400 MHz CDCl3) (400 MHz, CDCl3) δ 7.94 (d,
J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.44 (d, J =
8.0 Hz, 2H), 7.21 (d, J = 16.4 Hz, 1H), 7.19 (d, J =
8.0 Hz, 2H), 7.10 (d, J = 16.4 Hz, 1H), 2.60 (s, 3H),
2.37 (s, 3H). NMR data were consistent with
2-[(E)-2-(4-nitrophenyl)vinyl]thiophene (3km) [22]
Prepared according to the general procedure (Ar1Br =
2-bromothiophene, Ar2Br = 1-bromo-4-nitrobenzene).
The crude product was recrystallized from a mixture
of ethanol and water. The solid was collected by
filtration, washing with ethanol. Dried under vacuum
at 40 °C to obtain product (0.78 g, 48%, 94% purity
literature data [21]
.
by HPLC). H (400 MHz CDCl3) δ 8.20 (d, J = 8.6
1
Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 16.2
Hz, 1H), 7.30 (d, J = 4.7 Hz, 1H), 7.18 (d, J = 3.1 Hz,
1H), 7.05 (t, J = 4.1 Hz, 1H), 6.95 (d, J = 16.2 Hz,
1H).
Pterostilbene. A 100 mL pear shaped flask was
charged with 1-bromo-3,5-dimethoxybenzene (2.522
1-methoxy-2-[(E)-2-(4-
methoxyphenyl)vinyl]benzene
(3fg).
Prepared
according to the general procedure (Ar1Br = 1-
bromo-2-methoxybenzene, Ar2Br
=
1-bromo-4-
methoxybenzene), except that the first Heck reaction
was run for an additional 4.5 h at 70 °C with an
additional charge of catalyst (1 mol%) to drive first
Heck to completion. The crude product was
recrystallized from a mixture of methanol and water.
The solid was collected by filtration, washing with
ethanol. Dried under vacuum at 40 °C to obtain
product (0.62 g, 44%, 91% purity by HPLC). Also
prepared with inverted order of aryl halides according
to the general procedure (Ar1Br = 1-bromo-4-
g,
11.27
mmol)
and
dichlorobis(tri-o-
tolylphosphine)palladium(II) (182.5 mg, 0.225 mmol,
0.02 equiv, 2 mol%). A second 100 mL pear shaped
flask was charged with 4-bromophenol (2.552 g,
14.75 mmol, 1.3 equiv.) and dichlorobis(tri-o-
tolylphosphine)palladium(II) (111.5 mg, 0.138 mmol,
0.012 equiv, 1.2 mol%). The flasks were sealed with
rubber septa and the air atmosphere was exchanged
for nitrogen via vacuum/nitrogen cycles on a high
vacuum line using 18G needles (3 cycles for each
flask).
To the first flask, containing 1-bromo-3,5-
dimethoxybenzene, was added acetonitrile (35 mL,
degassed prior to use via subsurface nitrogen sparge).
The contents of this flask were then emptied into the
100 mL Parr vessel body. The pear shaped flask was
rinsed with acetonitrile (15 mL, total added is 50 mL,
20 vols). Triethylamine was added via syring (4 mL,
28.7 mmol, 2.55 equiv., degassed prior to use via
methoxybenzene,
Ar2Br
=
1-bromo-2-
methoxybenzene), except that the first Heck reaction
was run for an additional 5 h at 70 °C with an
additional charge of catalyst (1 mol%) to drive first
Heck to completion. The crude product was
recrystallized from a mixture of methanol and water.
The solid was collected by filtration, washing with
ethanol. Dried under vacuum at 40 °C to obtain
product (0.81 g, 57%, 90% purity by HPLC). 1H
(400 MHz CDCl3) δ 7.57 (d, J = 7.6 Hz, 1H), 7.47 (d,
11
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800167
Advanced Synthesis & Catalysis
cross-functional collaborations which allowed this group
to pursue this project. Jeff Levy and Jacques Zimmowitch
are gratefully acknowledged for sponsoring the MQ
Science intern program and providing opportunities for
talented undergraduates (NTvH and HG). The reviewers
are acknowledged for their helpful suggestions.
subsurface nitrogen sparge). The Par reactor was
immediately sealed with the head of the autoclave
and the system was inerted by nitrogen pressure /
vent cycles (3 cycles, 25 psig nitrogen). The
remaining necessary tubing was connected for
continuous monitoring by 1H flowNMR. The system
was heated to 70 °C and pressurized to 50 psig with
ethylene. The reaction was monitored and allowed to
proceed uninterrupted until it stalled around 6h and
References
[1] Likhtenshtein, G. in Stilbenes: Applications in
Chemistry, Life Sciences and Materials Science, Wiley-
VCH Verlag GmbH & Co. KGaA, Weinheim, Germany,
2009.
[2] a) I. P. Beletskaya, A. V. Cheprakov, Chem. Rev.
2000, 100, 3009-3066; b) N. J. Whitcombe, K. K. Hii, S. E.
Gibson, Tetrahedron, 2001, 57, 7449-7476; c) J. G. de
Vries, Can. J. Chem., 2001, 79, 1086-1092.
85% conversion.
At this point, additional
dichlorobis(tri-o-tolylphosphine)palladium(II) (39.8
mg, 0.05 mmol, 0.0044 equiv, 0.44 mol%) and
trimethylamine (1 mL, 7.18 mmol, 0.637 equiv.) was
charged. The reaction was allowed to continue
overnight, ultimately reaching 95% conversion. At
this point, the reaction was cooled to ambient
temperature, then ethylene was slowly vented. The
ethylene was further removed using nitrogen pressure
/ vent cycles (3 cycles, 25 psig nitrogen) until no
more ethylene was observed by 1H flowNMR.
[3] a) M. L. Abrams, J. Y. Buser, J. R. Calvin, M. D.
Johnson, B. R. Jones, G. Lambertus, C. R. Landis, J. R.
Martinelli, S. A. May, A. D. McFarland, J. R. Stout, Org.
Proc. Res. Dev., 2016, 20, 901-910; b) The PharmaCat
Consortium, http://www.imperial.ac.uk/pharmacat/
[4] a) N. Sharma, A. Sharmaꢀ, A. Shard, R. Kumar,
Saima, A. K. Sinha, Chem. Eur. J., 2011, 17, 10350-
10356; b) A. Sharma, N. Sharma, R. Kumar, A. Shard, A.
K. Sinha, Chem. Commun., 2010, 46, 3283-3285; c) J. P.
Das, S. Roy, J. Org. Chem., 2002, 67, 7861-7864; d) J.
McNulty, P. Das, Eur. J. Org. Chem., 2009, 4031-4035; e)
A. S. Saiyed, A. V. Bedekar, Tetrahedron Lett., 2010, 51,
6227-6231; f) A. Shard, N. Sharma, R. Bharti, S. Dadhwal,
R. Kumar, A. K. Sinha, Angew. Chem. Int. Ed., 2012, 51,
12250-12253.
[5] a) S. B. Atla, A. A. Kelkar, V. G. Puranik, W. Bensch,
R. V. Chaudhari, J. Organomet. Chem., 2009, 694, 683-
690; b) R. A. DeVries, A. Mendoza, Organometallics,
1994, 13, 2405-2411; c) S. Gibson, D. F. Foster, G. R.
Eastham, R. P. Tooze, D. J. Cole-Hamilton, Chem.
Commun., 2001, 779-780; d) G. E. Southard, K. A. Van
Houten, G. M. Murray, Synthesis, 2006, 2475-2477; e) R.
F. Heck, Organic Reactions., 2005, 27:2:345–390; f) T.
Izumi, Y. Nishimoto, K. Kohei, A. Kasahara, J. Het.
Chem,. 1990, 27, 1419-1424; g) M. T. Reetz, G. Lohmer,
R. Schwickardi, Angew. Chem. Int. Ed., 1998, 37, 481-483;
h) J. E. Plevyak, R. F. Heck, J. Org. Chem., 1978, 43,
2454-2456.
At this point, acetonitrile (5 mL, degassed prior to use
via subsurface nitrogen sparge) and trimethylamine
(2 mL, 14.3 mmol, 1.275 equiv.) were added to the
flask containing 4-bromophenol.
The resulting
mixture was added to the Parr reactor by sealing the
Parr reactor vent with a rubber septa and adding the
mixture via syringe through the vent. The flask was
rinsed with acetonitrile (4 mL, total added in step 2 is
9 mL, 3.6 vols; total in reaction is 23.6 vols) and the
rinse was added to the reaction vessel in the same
manner. The system was sealed and inerted by
nitrogen pressure / vent cycles (3 cycles, 25 psig
nitrogen), then heated to 80 °C. The reaction was
allowed to stir overnight with constant monitoring by
1H flowNMR; as shown in Figure 7 if the main text,
no change was observed in the profile after
approximately 3 h. After stirring overnight, the
reaction was cooled and worked up. Ethyl acetate
(400 mL) and D.I. water (125 mL) were added to the
crude reaction mixture and the resulting biphasic
mixture was transferred to a 1 L separatory funnel.
The mixture was agitated and the layers were
separated. The organic layer was washed with D.I.
water (125 mL), dilute aqueous HCl (1 M, 125 mL),
D.I water (125 mL) and saturated aqueous brine
solution (125 mL). The organic layer was then dried
over magnesium sulfate, filtered and evaporated to
obtain the crude product as an orange oil. The oil
was further dried on the high vacuum line to remove
residual solvent. Total mass of the crude product was
[6] C. M. Kormos, N. E. Leadbeater, J. Org. Chem.,
2008, 73, 3854-3858.
[7] J. Petuškova, M. Patil, S. Holle, C. W. Lehmann, W.
Thiel, M. Alcarazo, J. Am. Chem. Soc., 2011, 133, 20758.
[8] S. M. Nobre, M. N. Muniz, M. Seferin, W. M. da
Silva, A. L. Monteiro, App. Organomet. Chem., 2011, 25,
289-293.
[9] a) S. L. Bourne, M. O'Brien, S. Kasinathan, P. Koos,
P. Tolstoy, D. X. Hu, R. W. Bates, B. Martin, B. Schenkel,
S. V. Ley, ChemCatChem, 2013, 5, 159-172; b) S. L.
Bourne, P. Koos, M. O’Brien, B. Martin, B. Schenkel, I. R.
Baxendale, S. V. Ley, Synlett 2011, 2643-2647.
[10] a) J. Kiji, T. Okano, T. Hasegawa, J. Mol. Cat. A.,
1995, 97, 73-77; b) J. Kiji, T. Okano, A. Ooue, J. Mol. Cat.
A., 1999, 147, 3-10.
1
3.181 g, 54.5% potency by H NMR, corrected yield
of product 61.4%.
Acknowledgements
[11] C. R. Smith, T. V. RajanBabu, Tetrahedron, 2010, 66,
1102-1110.
Bret Huff, Alan Palkowitz and all of SMDD and DCRT
management are gratefully acknowledged for supporting
12
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10.1002/adsc.201800167
Advanced Synthesis & Catalysis
[12] M. Hiroaki, K. Makoto, Vol. JP2002167350 (A) ―
2002-06-11 Adchemco Corp, Japan, 2002.
[13] J. Y. Buser, A. D. McFarland, Chem. Commun., 2014,
50, 4234-4237.
[14] G. Elisa, R. Sebastiano, G. Laura, R. Maurizio, R.
Marinella, Curr. Med. Chem., 2016, 23, 2439-2489.
[15] J. M. Estrela, S. Mena, E. Obrador, M. Benlloch, G.
Castellano, R. Salvador, R. W. Dellinger, J. Med. Chem.
2017, 60, 9413–9436.
[17] A decarboxylative Heck reaction using acrylic acid
has been used to prepare this compound. See: A. Shard, N.
Sharma, R. Bharti, S. Dadhwal, R. Kumar, A. K. Sinha,
Angew. Chem. Int. Ed., 2012, 51, 12250-12253.
[18] L. Kötzner, M. J. Webber, A. Martínez, C. De Fusco,
B. List, Angew. Chem. Int. Ed., 2014, 53, 5202-5205.
[19] E. N. Durantini, Synth. Commun., 1999, 29, 4201-
4222.
[20] R. Kumar, A. Shard, R. Bharti, Y. Thopate, A. K.
Sinha, Angew. Chem. Int. Ed., 2012, 51, 2636-2639.
[16] a) J. M. Estrela, A. Ortega, S. Mena, M. L. Rodriguez,
M. Asensi, Crit. Rev. Clin. Lab. Sci., 2013, 50, 65-78; b) R. [21] C. M. Kormos, N. E. Leadbeater, J. Org. Chem.,
Kosuru, U. Rai, S. Prakash, A. Singh, S. Singh, Eur. J.
Pharm., 2016, 789, 229-243.
2008, 73, 3854-3858.
[22] W. Freund, J. Chem. Soc., 1953, 2889-2891.
13
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FULL PAPER
Model guided development of a simple catalytic
method for the synthesis of unsymmetrical
stilbenes by sequential Heck reactions of aryl
bromides with ethylene.
Adv. Synth. Catal. Year, Volume, Page – Page
Helen Barlow, Jonas Y. Buser, Hendrik
Glauninger, Carla V. Luciani, Joseph R.
Martinelli,* Niall Oram, Nichole Thompson-Van
Hook and Jeffery Richardson.*
14
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