In Situ Generated Palladium on Aluminum Phosphate as Catalytic System for the Preparation of β,β-Diarylated Olefins by Matsuda-Heck Reaction

Article abstract of DOI:10.1021/acs.oprd.7b00279

In situ generated palladium on aluminum phosphate provides a novel and active catalytic system for the preparation of β,β-diarylated olefins using the Matsuda-Heck reaction. The reaction conditions of this catalytic protocol were optimized by a Response-Surface model.

Full text of DOI:10.1021/acs.oprd.7b00279

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Full Paper
In-situ Generated Palladium on Aluminum Phosphate as Catalytic System
for the Preparation of # ,# -Diarylated Olefins by Matsuda-Heck Reaction
Sandra Lucks, and Heiko Brunner
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00279 • Publication Date (Web): 10 Oct 2017
Downloaded from http://pubs.acs.org on October 11, 2017
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In-situ Generated Palladium on Aluminum Phosphate as
Catalytic System for the Preparation of β,β-Diarylated
Olefins by Matsuda-Heck Reaction
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Sandra Lucksa and Heiko Brunnera*
a Atotech Deutschland GmbH, Erasmusstrasse 20, Dꢀ10553 Berlin, Germany,
eꢀMail: Heiko.Brunner@atotech.com
KEYWORDS Palladium on Aluminum phosphate, bisarylation, MatsudaꢀHeck reaction, Design
of experiments
ABSTRACT In-situ generated palladium on aluminum phosphate provides a novel and active
catalytic system for the preparation of β,βꢀdiarylated olefins using the MatsudaꢀHeckꢀreaction.
The reaction conditions of this catalytic protocol were optimized by a ResponseꢀSurfaceꢀ model.
Introduction
Due to the high reactivity of aryldiazonium salts the MatsudaꢀHeck reaction1,2 is an important
tool for the arylation of olefinic substrates.3ꢀ6 Especially, for the synthesis of difficult accessible
synthetic targets like bisꢀarylated derivatives the MatsudaꢀHeck reaction seems to be very
auspicious.
Stimulated by the seminal work of Correia et al7,8. and motivated by our own investigations
regarding the development of improved catalytic systems9 we were interested in the synthesis of
bisꢀarylated olefinic substances. Despite the good to excellent yields in the synthesis of
symmetrical β,βꢀdiarylated acrylates using Correia’s protocol the synthetic approach suffers
from the utilization of high catalyst concentrations up to 7 molꢀ% and elevated temperatures up
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to 60 °C.7 Furthermore, only the bisarylation using electronꢀrich aryldiazonium salts as
electrophiles was reported.
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In the light of an industrial utilization of this synthetic access towards β,βꢀdiarylated olefins the
development of a more efficient protocol concerning low catalystꢀconcentrations, lower reaction
temperatures on the one hand and a broader scope of usable olefins on the other hand is
tempting.
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In previous investigations it could be stated that supported Pdꢀcatalysts and the utilized
supporting material show a tremendous impact on the reaction rates and yields of the Matsudaꢀ
Heck reaction.9,10
Even for the synthesis of β,βꢀdiarylated acrylates Correia and coꢀworkers could show improved
results by the utilization of Pd(OAc)2/C as catalyst (Scheme 1).7
Scheme 1. Diarylation of methyl acrylate using Correia protocol7
In the course of our investigations of novel and more active catalysts for the MatsudaꢀHeck
reaction9 we want to present a new catalytic system Pd(OAc)2/AlPO4. Despite of the low price
and its use as antacid in medicine it is interesting to notice that the utilization of aluminum
phosphate as supporting material for catalysts is scarce11. The new catalytic system was prepared
by a prereduction of Pd(OAc)2 by methanol in the presence of methyl acrylate and aluminum
phosphate before starting the MatsudaꢀHeck reaction. Investigations using scanning electron
microscopy (SEM) indicated the formation of Pdꢀspecies immobilized on aluminum phosphate
(Figure 1).
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Figure 1. SEM image of Pdꢀspecies immobilzed on AlPO4
Having this new catalytic system in our hands we applied the new catalyst in a MatsudaꢀHeck
reaction using methyl acrylate as olefine. During the reaction of 4ꢀmethoxyꢀbenzenediazonium
tertrafluoroborate with methyl acrylate on 10 mmol scale we could detect significant amounts of
bisꢀarylated product 4a (Scheme 2):
Scheme 2. Reaction of 4ꢀmethoxyꢀbenzenediazonium tertrafluoroborate with methyl acrylate
Whereas similar results could be obtained by the utilization of Pd(OAc)2/C as catalyst the
Pd(OAc)2/AlPO4ꢀsystem distinguished itself by significant higher reaction rates (1.49 mmol*mLꢀ
1**hꢀ1 vs. 0.67 mmol*mLꢀ1*hꢀ1). In previous investigations we could demonstrate that especially
for difficult synthetic targets the utilization of highly active catalytic systems is favourable.9,10
However, compared with our quite recently described Pd(OAc)2/Al2O3ꢀcatalyst9 the formation of
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bisꢀarylated product is pronounced in face of similar catalytic activity. Encouraged by these
findings we successfully conducted the arylation of Eꢀmethylꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀacrylate in
excellent yields using the new catalytic system (Scheme 3).
9
Scheme 3. Arylation of Eꢀmethylꢀ3ꢀ(4ꢀmethoxyphenyl)acrylate
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While Correia et al. obtained quite similar resulst by applying 5 molꢀ% and 60 °C reaction
temperature7 the new catalyst pleasingly gave slightly better results by using 2 molꢀ% palladiumꢀ
concentration and 40 °C. Anyway, it had to be revealed that no significant reaction took place at
ambient temperature.
Based on these results we set out to apply this novel catalytic system on the optimized and
simple synthesis of β,βꢀdiarylated olefins using different aryldiazonium salts and alkenes.
Results and discussion
Optimization of reaction conditions. For the optimization of the bisarylation we used the
design of experiments (DoE) method. Despite of the usefulness it has to be stated that the
utilization of DoEꢀmethods for the optimization of MatsudaꢀHeck reactions is quite rare in
literature.12ꢀ14
As a model reaction we examined the β,βꢀdiarylation of methyl acrylate with 4ꢀmethoxyꢀ
benzenediazonium tetrafluoroborate 1a. At the beginning of this study we considered the
reaction temperature, the catalyst loading on the supporting material AlPO4, the prereduction
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time of the palladium acetate and the quantity of the utilized aryldiazonium salt as variables that
might have an impact on the outcome of the reaction.
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As DoEꢀmethod we chose a ResponseꢀSurfaceꢀmodel that is frequently used for the development
and optimization of processes and products in industry (see Supporting Information).15 Due to
our prior results shown in Scheme 3 the reaction should be optimized for 2 molꢀ% Pd(OAc)2 and
a maximum reaction temperature of 40 °C. All reactions were conducted under isothermic
conditions using the lab automation system EasyMax™ of MettlerꢀToledo. For obtaining the
most reactive Pd(0) on AlPO4 catalyst the preꢀcatalyst Pd(OAc)2 was reduced at the beginning of
the reaction at 25 °C for a dedicated time before starting the MatsudaꢀHeck reaction. The set of
experiments is outlined in Table 1.
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Table 1. Set of experiments for the DoE and results
entry
TR
32.5
32.5
40
WPd [%]
1.5
TR [min]’ nDZS [mmol] 3a [areaꢀ%]a
4a [areaꢀ%]a
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68
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1.0
0.5
ꢀ
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40
1.0
11
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0.5
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32.5
32.5
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1.0
1.0
0.5
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2
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a areaꢀ% HPLC
All reactions were run over 3.5h under the mentioned conditions. After separation of the catalyst,
quenching with water and extraction with methylene chloride the reaction mixtures were
analyzed by HPLC to provide the product distributions. According to table 1 the highest quantity
of bisꢀarylated product in the set of experiments is obtained by using a catalyst loading of 1.5
wt.ꢀ% palladium and 21 mmol diazonium salt at 40 °C (entry 19). For finding the optimized
process conditions all the results were evaluated by the JMP™ꢀ9.0ꢀsoftware. In figure 2 the
significance of the synthetic parameter based on probabilities of errors is presented.
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Figure 2. Significance of synthetic parameter
Referred to our DoE based on a ResponseꢀSurface model a reaction parameter has a significant
impact if the probability of error is p ≤ 0.05 in the tꢀtest. According to figure 2 it is obvious that
the yield of obtained bisꢀarylated methyl acrylate is significantly influenced by the reaction
temperature TR, the prereduction time tR, the molar quantity of diazonium salt nDZS, the squared
2
molar quantity of diazonium salt nDZS and the interaction between the reaction temperature and
the palladium loading TR*wPd. The error probability of the interaction between the molar
quantity of the diazonium salt and the palladium loading wPd*nDZS is 0.083. Therefore, a
significant impact can not be excluded. Thereby, these parameter may influence the process in a
positive or negative way. The impact of the parameter is shown in Figure 3.
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5.25
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2
0
-2
-4
-6
-8
-3.42
-6.46
Figure 3. Impact of the reaction parameter
Figure 3 clearly indicates that the molar quantity of the utilized diazonium salt has the most
positive influence concerning the yield of the bisꢀarylated product 4a. On the other hand an
excessive usage of diazonium salt has a negative impact on the outcome and is illustrated by the
negative value of the squared molar quantity of diazonium salt (nDZS2). One reason might be that
the molarity exerts an effect on the mass transport of the reactants in the reaction mixture. Thus,
Felpin et al. reported a negative outcome in the MatsudaꢀHeck reaction utilizing high molar
quantities of diazonium salts6e. Furthermore, an extended prereduction time has a negative
impact on the formation of bisꢀarylated product 4a. In precedent investigations we could
demonstrate that prolonged prereduction times decrease the activity of the catalyst.9 Therefore,
the oxidative addition in the catalytic cycle and consequently the formation of bisꢀarylated
product are hampered. In addition the reaction temperature and the interaction of the reaction
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temperature with the palladium loading on AlPO4 have a positive impact on the obtained yield of
product 4a. Besides the classical kinetic effects this might be explained by a direct influence of
the temperature on the nature and consequently catalytic activity of the formed Pd(0)ꢀclusters
and their dissolution behaviour in the catalytic cycle. This is in accordance with precedent
observations described by Schmidt et al.16. A comparison of the reaction velocities at 30 °C and
40 °C clearly indicates that a higher reaction rate is obtained at 40 °C (3.719 mmol*mLꢀ1*hꢀ1 vs
1.476 mmol*mLꢀ1*hꢀ1) which is favourable to the formation of the bisꢀarylated product and is in
line with the observed product distribution as depicted in table 1. Hence, a higher reaction
temperature led to an improved product ratio between monoꢀarylated and bisꢀarylated products
that faciliates the product isolation and purification.
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The influence of the combination of the two reaction parameters on the yield of bisꢀarylated
product can be scrutinized by means of interactions shown in figure 4.
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Figure 4. Analysis of the interaction of the reaction parameters
The depicted set of diagrams in which the yield of bisꢀarylated product is presented as a function
of the interactions between two process variables. Thus, the twelve diagramed interactions are a
result of the four chosen process parameters reaction temperature TR, palladium loading wPd, the
prereduction time tR and the molar quantity of the utilized diazonium salt nDZS. In this study only
the interaction between the reaction temperature and the catalyst loading had a significant impact
on the yield of the bisꢀarylated product 4a (red labeled diagram in Figure 4). The diagram shows
two graphs. The blue graph displays the proportional dependency on the yield of bisꢀarylated
product as a function of the reaction temperature and catralyst loading of Pd(OAc)2/AlPO4 (wPd))
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of 1.5%. The red graph displays the outcome as a function of a catalyst loading of 0.5%.
Whereas the red graph clearly indicates a horizontal linear slope the blue graph displays a
significant ascending slope. The interception point of both graphs is located at a reaction
temperature of 35 °C. Hence, a obtained yield of 86% at a reaction temperature does not depend
on the catalyst loading. On the opposite the yield is diminished by 6% using 1.5% compared to
0.5% catalyst loading at 40 °C. By the means of an analysis of prediction the values of the
parameter concerning the maxima and minima or defined target value can be determined. In
figure 5 the influence of the target values reaction temperature (TR), the prereduction period (tR),
and the molar quantity of diazonium salt (nDZS) in the light of a desirability of 1 for a yield of
bisꢀarylated product of 95.0 ± 4.7% are shown.
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Figure 5. Prediction for the optimized reaction parameters
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According to Figure 5 the best results should be obtained by using an isothermic reaction
temperature of 40° C, a catalyst loading of 1.5 wt.ꢀ%, a prereduction time of 34 minutes and a
molar quantity of 21.5 mmol. A control test utilizing these optimized conditions gave an
outcome of 91.5% in HPLC and 89% isolated yield of bisꢀarylated product 4a and consequently
is on the one hand in a good agreement with the prediction and on the other hand comparable to
the results reported by Correia et al.7
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Scope of the catalytic system. These optimized reaction conditions were explored with various
aryldiazonium salts and methyl acrylate (Table 2).
Table 2. Preparation of ββꢀdiarylated methyl acrylates
R
N2BF4
COOMe
COOMe
Pd(OAc)2/AlPO4 (x molꢀ%)
R
MeOH, 40 °C
1 (2.15 eq.)
R
4
entry
1
R
Cat. [molꢀ%] Product
2
Yield
[%]
4ꢀOMe
89
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3
3,4ꢀ(OMe)2
2
2
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35
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OMe
3,4,5ꢀ
(OMe)3
MeO
MeO
COOMe
4c
OMe
MeO
OMe
OMe
4
3,4,5ꢀ
(OMe)3
4
64
MeO
MeO
COOMe
4c
OMe
MeO
OMe
5
6
3ꢀCl
4ꢀCl
2
2
76
41
7
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4ꢀNO2
2ꢀNO2
2
2
91
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With exception of the nitroꢀderivatives all bisꢀarylated products were obtained in moderate to
good yields. The diarylation of the nitro substituted aryldiazonium salts provided only
monoarylated Heck products in excellent yields due to the modest solubility of the nitro
cinnamic esters (entries 7 and 8, Table 2). However, we were pleased that the diarylation of
deactivated diazonium salts was successful. Thus, to our best knowledge the first preparation of
symmetrical diarylacrylates bearing chloroꢀfunctionalities by a MatsudaꢀHeckꢀreaction was
easily accessible. Strikingly the 3ꢀchloroꢀbenzenediazonium tetrafluoroborate provided a better
yield compared to its regioisomer (entries 5 and 6, Table 2). In the case of the highly substituted
3,4,5ꢀtrimethoxyꢀbenzenediazonium tetrafluoroborate an increase of the catalyst concentration
for obtaining a reasonable yield was necessary (entries 3 and 4, Table 2). However, it has to be
pointed out that the new catalytic system Pd(OAc)2/AlPO4 distinguishes itself by a higher
reactivity and enables benign diarylations of acrylates via MatsudaꢀHeckꢀcoupling. This is well
reflected in lower catalyst concentrations and temperatures. Encouraged by our findings utilizing
our novel catalytic system we prospected to alternative olefins. In a precedent publication one of
us described the utilization vinyl phosphonic esters in the MatsudaꢀHeck reaction.17 Synthetic
protocols towards the synthesis of bisꢀarylated vinylphosphonates are scarce in literature and all
procedures have moderate yields and a limited range of accessible substrates.18ꢀ23 Quite recently
Tsai et al. reported the first synthesis of bisꢀarylated vinylphosphonates via Heck reaction using
aryl iodides as electrophiles.24 Keeping in mind that the phosphonic ester moiety represents a
functional group that is isosteric to ester functionalities in medicinal chemistry the synthesis of
bisꢀarylated vinylphosphonates should be an auspicious target. The synthetic applicability of our
new catalytic procedure using the MatsudaꢀHeck reaction could be extended to the facile
synthesis of these compounds for the first time (Table 3).
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Table 3. Preparation of ββꢀdiarylated vinylphosphonates
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8
R
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N2BF4
PO3Me2
PO3Me2
Pd(OAc)2/AlPO4 (x molꢀ%)
MeOH, 40 ° C
R
1 (2.15 eq.)
R
5
entry
1
R
Cat. [molꢀ%]
2
Product
Yield
[%]
4ꢀOMe
74
2
3,4,5ꢀ
(OMe)3
4
89
3
4
3ꢀCl
4ꢀCl
2
2
81
68
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O2N
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4ꢀNO2
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PO3Me2
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6e
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As depicted in Table 3 the diarylated vinylphosponates could be obtained in good yields.
It has to be pointed out that strikingly better results employing dimethylvinylphosphonate were
obtained in the case of the highly substituted 3,4,5ꢀtrimethoxyꢀbenzenediazonium and the
chlorinated benzenediazonium salts compared to the analogues acrylate derivatives (entries 2ꢀ4,
Table 3 vs. entries 4ꢀ6, Table 2). Similar to our prior findings utilizing methyl acrylate only
monosubstituted Heck product could be obtained in the case of nitro substituted diazonium salt
(entry 5, Table 3). Compared to the protocol published quite recently by Tsai et al. using aryl
iodides24 in the MizorokiꢀHeck reaction this procedure distinguishes itself by lower reaction
temperatures, lower palladium loadings and shorter reaction times. Furthermore, the presented
method is characterized by its simplicity, the broader scope of substrates and the higher yields
compared to the classical procedures described in literature. Besides methyl acrylate and
vinyldimethylphosphonic ester, a preliminary study with acrylonitrile was also carried out
(Scheme 4).
Scheme 4. β,βꢀDiarylation of acrylnitrile using 4ꢀmethoxyꢀbenzenediazonium tetrafluoroborate
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As depicted in Scheme 4, acrylonitrile could also be applied in the aboveꢀmentioned procedure.
However, for obtaining a reasonable yield the utilization of 50°C as reaction temperature seems
to be beneficial.
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Conclusion
In summary, we have first presented a novel catalytic system consisting of palladium
immobilized on aluminum phosphate that can be used for the preparation of β,βꢀdiarylated
olefins on gramꢀscale via MatsudaꢀHeckꢀreaction. The utilization of aluminum phosphate as
supporting material for catalyst in cross coupling was not reported so far and represents another
additional example for a targetꢀoriented tuning of catalysts in the MatsudaꢀHeck reaction. The
presented approach distinguishes itself by benign reaction conditions combined with high
catalytic activity and short reaction times. The efficiency of the new protocol could be elaborated
and validated by a ResponseꢀSurfaceꢀmodel. Besides an optimized procedure this study provides
valuable indications concerning the most important reaction parameter in the MatsudaꢀHeckꢀ
reaction.
Experimental Section
General methods. NMR spectra were recorded on Varian ECX 500 and V300b Varian Mercury
spectrometers. Chemical shifts in proton and carbon NMR spectra are reported in ppm relative to
the TMS peak at 0.00 ppm or relative to CDCl3 peak at 77.0 ppm, coupling constants (J) in Hz.
Infrared (IR) spectra were recorded as neat samples in ATR mode using a Spectrum One
(PerkinꢀElmer) spectrometer. Mass spectra were recorded on Bruker micrOTOFꢀQII. Yields
refer to isolated material determined to be pure by NMRꢀspectroscopy, mass spectrometry, and
thin layer chromatography (TLC), unless specified otherwise in the text. Flash chromatography
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(FC): Merck Silica Gel 60 (240ꢀ400 Mesh) and Merck Aluminium oxide 90 active neutral (70ꢀ
230 Mesh). Melting points were recorded using a Büchi Melting point apparatus Mꢀ560. The
scanning electron microscopy (SEM) image has been recorded with a Zeiss Gemini 1550
microscope. The catalyst was dispersed onto a carbon adhesive tape. Diazonium salts used in this
study were all known and prepared as described in the literature, see Ref. 10. Solvents and
chemicals were purchased from VWR or Aldrich and used as received.
Dimethylvinylphosphonate was pruchased from BASF SE.
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The statistical design of experiment was carried out with the Software JMP® 9.0
(SAS Institute Inc.) (see Supporting Information).
General Procedure for Synthesis of β,β-diarylated methyl acrylates 4a-e.
In a 100mL EasyMax™ reactor, equipped with a reflux condenser and a magnetc stirrer bar,
0.2 mmol palladium acetate (45 mg), 11.4 mmol (1.39 g) aluminum phosphate and 10
mmol (870 mg) methyl acrylate were dispersed in 68 mL methanol. The mixture was
stirred (350 rpm) for 34 minutes at 25°C (isothermic conditions). After this pre-reduction
of palladium actetate 21.5 mmol of aryldiazonium salt were added and the reaction mixture
was heated to 40 °C within 1 min. Reaction development was monitored by heat flow
control and gas evolution. When reaction was finalized, reaction mixture was filtrated
through celite, poured into ice-water and the water phase was extracted with methylene
chloride (3x50 mL). The combined organic phases were dried over anhydrous MgSO4 and
then concentrated under reduced pressure. The obtained residues were purified by flash
chromatography to obtain the desired product.
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Methylꢀ3,3ꢀbis(4ꢀmethoxyphenyl)ꢀacrylate (4a). The product was purified by flash
5
6
7
chromatography with cyclohexane/ethyl acetate (9:1 and 8:2) as eluent to give the desired
8
9
product: 89%, 2.65 g (rose solid); mP: 59.0 °C; 1H NMR (500 MHz, CDCl3, ppm) δ 7.24 (d, 3JHH
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3
3
3
= 8.5 Hz, 2H), 7.16 (d, JHH = 8.5 Hz, 2H), 6.92 (d, JHH = 8.5 Hz, 2H), 6.85 (d, JHH = 8.5 Hz,
13
2H), 6.24 (s, 1H), 3.85 (s, 3H); 3.82 (s, 3H), 3.63 (s, 3H); C NMR (125 MHz, CDCl3, ppm)
δ 166.70, 160.74, 159.64, 156.82, 133.75, 131.03, 130.80, 129.96, 114.19, 113.65, 113.16, 55.28,
55,13, 51.06; IR: 2959, 1722, 1604, 1511, 1246, 1172, 1162, 1152, 1029, 828; ESIꢀMS m/z
(Intensity): 299 [MH+] (22), 267 (100).
Methylꢀ3,3ꢀbis(3,4ꢀdimethoxyphenyl)ꢀacrylate (4b). The product was purified by flash
chromatography with cyclohexane/ethyl acetate (9:1 and 8:2) as eluent to give the desired
1
product: 78%, 2.79 g (orange viscous oil); H NMR (500 MHz, CDCl3, ppm) δ 6.91 – 6.79 (m,
3
5H), 6.73 (d, JHH = 1.9 Hz,, 1H), 6.25 (s, 1H), 3.93 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H); 3.63 (s,
3H); 13C NMR (125 MHz, CDCl3, ppm) δ 166.66, 156.67, 150.37, 149.10, 148.62, 148.22,
133.77, 131.15, 122.37, 122.09, 114.60, 112.73, 111.14, 110.55, 110.27, 55.89, 55,86, 55.74,
51.16; IR: 2947, 2837, 2376, 2281, 2038, 1719, 1514, 1253, 1216, 1142, 1129, 1024, 859, 811,
766; ESIꢀMS m/z (Intensity): 259 [MH+] (61), 327 (100).
Methylꢀ3,3ꢀbis(3,4,5ꢀtrimethoxyphenyl)ꢀacrylate (4c). For the preparation of 4c 4 molꢀ%
Pd(OAc)2 were used. The product was purified by flash chromatography with cyclohexane/ethyl
acetate (9:1 and 8:2) as eluent to give the desired product: 64%, 2.65 g (white); mP: 100.4°C; 1H
NMR (500 MHz, CDCl3, ppm) δ 6.53 (s, 2H), 6.45 (s, 2H), 6.27 (s, 1H), 3.92 (s, 3H), 3.88 (s,
3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.65 (s, 3H); 13C NMR (125 MHz, CDCl3, ppm) δ 166.44,
156.35, 152.91, 152.67, 139.48, 138.12, 136.12, 133.77, 116.21 106.82, 60.92, 56.18, 51.33; IR:
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2952, 2839, 2376, 1696, 1583, 1505, 1421, 1339, 1287, 1248, 1125, 1005, 980, 818; ESIꢀMS
m/z (Intensity): 419 [MH+] (34), 387 (100); HRꢀMS (ESI): m/z = 419.1698 [MH+], calcd. for
C22H26O8 : 419.17067.
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Methylꢀ3,3ꢀbis(3ꢀchlorphenyl)ꢀacrylate (4d). The product was purified by flash
chromatography with cyclohexane/ethyl acetate (9:1 and 8:2) as eluent to give the desired
1
product: 76%, 2.33 g (colorless viscous liquid); H NMR (500 MHz, CDCl3, ppm) δ 7.40 ꢀ 7.24
(m, 5H), 7.18 (s, 1H), 7.14 (d, 3JHH = 7.5 Hz, 1H), 7.10 (d, 3JHH = 7.5 Hz, 1H), 6.36 (s, 1H), 3.63
(s, 3H), 3.36 (s, 3H); 13C NMR (125 MHz, CDCl3, ppm) δ 165.71, 153.82, 141.93, 139.82,
134.66, 134.07, 129.78, 129.67, 129.34, 128.98, 128.60, 128.12, 127.28, 126.37, 118.66, 51.51;
IR: 2959, 1726, 1564, 1261, 1162, 1162, 878, 789, 702; ESIꢀMS m/z (Intensity): 307 [MH+]
(45), 275 (100); HRꢀMS (ESI): m/z = 307.03124 [MH+], calcd. for C16H12Cl2O2: 307.02934.
Methylꢀ3,3ꢀbis(4ꢀchlorphenyl)ꢀacrylate (4e). The product was purified by flash
chromatography with cyclohexane/ethyl acetate (9:1 and 8:2) as eluent to give the desired
1
product: 41%, 1.25 g (white solid); mP: 118.1 °C; H NMR (500 MHz, CDCl3, ppm) δ 7.37 (d,
3JHH = 8.5 Hz,, 2H), 7.31 (d, 3JHH = 8.5 Hz, 2H), 7.20 (d, 3JHH = 8.5 Hz, 2H), 7.13 (d, 3JHH = 8.5
Hz, 2H), 6.34 (s, 1H), 3.63 (s, 3H); 13C NMR (125 MHz, CDCl3, ppm) δ 165.98, 154.56, 138.85,
136.66, 135.88, 134.55, 130.54, 129.52, 128.75, 128.34, 117.52, 51.43; IR: 2957, 1717, 1623,
1490, 1263, 1159, 1089, 1014, 834; ESIꢀMS m/z (Intensity): 307 [MH+] (45), 275 (100); HRꢀMS
(ESI): m/z = 307.03144 [MH+], calcd. for C16H12Cl2O2: 307.02934.
Methylꢀ3ꢀ(2ꢀnitrophenyl)ꢀacrylate (3f). The product was obtained as yellow solid: 91%,
1
3
1.88 g; mP: 72.5 °C (lit.mp 71 – 73 °C)25.; H NMR (500 MHz, CDCl3, ppm) δ 8.12 (d, JHH
=
15.8 Hz, 1H), 8.04 (d, 3JHH = 8.0 Hz, 1H), 7.68 – 7.65 (m, 1H), 7.64 (d, 3JHH = 8.0 Hz, 1H), 7.57
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– 7.53 (m, 1H), 6.37 (d, JHH = 15.8 Hz, 1H), 6.84 (s, 3H); C NMR (125 MHz, CDCl3, ppm)
δ 165.17, 147.31, 139.12, 132.49, 129.54, 129.29, 128.10, 123.89, 121.86, 50.99; IR: 2956,
1718, 1520, 1345, 1332, 1292, 1208, 1196, 1180, 975, 756; ESIꢀMS m/z (Intensity): 208 [MH+]
(19), 176 (100).
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Methylꢀ3ꢀ(4ꢀnitrophenyl)ꢀacrylate (3g). The product was obtained as yellow solid: 91%,
1.88 g; mP: 136ꢀ137 °C (lit mp.: 137.8ꢀ138.8 °C)26.; 1H NMR (500 MHz, CDCl3, ppm) δ 8.25 (d,
3
3
3JHH = 8.7 Hz, 2H), 7.70 (d, JHH = 16.0 Hz, 1H), 7.67 (d, JHH = 8.7 Hz, 2H), 7.57 – 7.53 (m,
3
13
1H), 6.57 (d, JHH = 16.0 Hz, 1H), 3.63 (s, 3H); C NMR (125 MHz, CDCl3, ppm) δ 166.44,
148.49, 141.88, 140.45, 128.51, 123.90, 122.06, 52.31; IR: 2957, 1722, 1510, 1343, 1314, 1193,
1172, 847, 706; ESIꢀMS m/z (Intensity): 207 [M] (18), 176 (100).
General
Procedure
for
Synthesis
of
β,β-diarylated
dimethyl
vinylphosphonates 5a-d.
In a 100mL EasyMax™ reactor, equipped with a reflux condenser and a magnetc stirrer bar,
0.2 mmol palladium acetate (45 mg), 11.4 mmol (1.39 g) aluminum phosphate and 10
mmol (1.36 g) dimethylvinylphosphonate were dispersed in 68 mL methanol. The mixture
was stirred (350 rpm) for 34 minutes at 25 °C (isothermic conditions). After this pre-
reduction of palladium actetate 21.5 mmol of aryldiazonium salt were added and the
reaction mixture was heated to 40 °C within 1 min. Reaction development was monitored
by heat flow control and gas evolution. When reaction was finalized, reaction mixture was
filtrated through celite, poured into ice-water and the water phase was extracted with
methylene chloride (3x50 mL). The combined organic phases were dried over anhydrous
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MgSO4 and then concentrated under reduced pressure. The obtained residues were
purified by flash chromatography to obtain the desired product.
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Dimethylꢀ(2,2ꢀbis(4ꢀmethoxyphenyl)vinyl)ꢀphosphonate (5a). The product was purified
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by flash chromatography with methylene chloride/ethyl acetate (9:1 and 8:2) as eluent to give the
1
desired product: 74%, 2.56 g (yellow viscous liquid); H NMR (500 MHz, CDCl3, ppm) δ 7.32
(d, 3JHH = 9.0 Hz,, 2H), 7.23 (d, 3JHH = 8.5 Hz, 2H), 6.92 (d, 3JHH = 8.5 Hz; 2H), 6.84 (d, 3JHH
=
3
9.0 Hz, 2H), 5.99 (d, JHP = 15.7 Hz, 1H), 3.85 (s, 3H); 3.82 (s, 3H), 3.53 (s, 3H), 3.51 (s, 3H);
13C NMR (125 MHz, CDCl3, ppm) δ 160.76, 160.28, 160.04, 134.20, 134.02, 131.34, 129.81,
31
113.60, 113.17, 111.02, 109.46, 55.26, 52,04; P NMR (202 MHz, CDCl3, ppm) δ 21.20; IR:
3667, 2965, 1606, 1510, 1248, 1175, 1028, 861, 834, 817, 800; ESIꢀMS m/z (Intensity): 349
[MH+] (100); HRꢀMS (ESI): m/z = 349.12111 [MH+], calcd. for C18H21O5P: 349.12056.
Dimethylꢀ(2,2ꢀbis(3,4,5ꢀtrimethoxyphenyl)vinyl)ꢀphosphonate
(5b).
For
the
preparation of 5b 4 molꢀ% Pd(OAc)2 were used. The product was purified by flash
chromatography with methylene chloride/ethyl acetate (9:1 and 8:2) as eluent to give the desired
product: 89%, 4.17 g (brownish solid); mP: 93.4 °C; 1H NMR (500 MHz, CDCl3, ppm) δ 6.71 (s,
2H), 6.53 (s, 2H), 6.04 (d, 3JHP = 15.4 Hz, 1H), 3.91 (s, 12H); 3.89 (s, 3H), 3.87 (s, 6H), 3.81 (s,
13
6H), 3.56 (s, 3H), 3.54 (s, 3H); C NMR (125 MHz, CDCl3, ppm) δ 160.58, 152.85, 152.52,
31
139.50, 138.52, 136.62, 136.44, 133.80, 113.51, 111.96, 107.41, 105.92, 60.87, 56.22, 52.20; P
NMR (121 MHz, CDCl3, ppm) δ 20.65; IR: 2955, 2843, 1582, 1572, 1505, 1360, 1242, 1121,
849, 794; ESIꢀMS m/z (Intensity): 468 [M+] (100); HRꢀMS (ESI): m/z = 469.16286 [MH+],
calcd. for C22H29O9P : 469.16282.
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Dimethylꢀ(2,2ꢀbis(3ꢀchlorphenyl)vinyl)ꢀphosphonate (5c). The product was purified by
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flash chromatography with methylene chloride/ethyl acetate (9:1 and 8:2) as eluent to give the
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9
1
desired product: 81%, 2.89 g (yellow liquid); H NMR (500 MHz, CDCl3, ppm) δ 7.44 – 7.24
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(m, 7H), 7.13 (d, 3JHH = 7.8 Hz, 1H), 6.20 (d, 3JHP = 14.5 Hz, 1H), 3.57 (s, 3H), 3.54 (s, 3H); 13C
NMR (125 MHz, CDCl3, ppm) δ 157.46, 142.42, 142.25, 134.60, 134.00, 129.73, 129.69,
31
129.37, 129.09, 127.97, 127.77, 127.77, 127.75, 126.22, 116.88, 115.34, 55.26; P NMR (202
MHz, CDCl3, ppm) δ 18.54; IR: 2952, 2849, 1562, 1251, 1053, 1029, 859, 824, 790, 691; ESIꢀ
MS m/z (Intensity): 358 [MH+] (67), 356 (100); HRꢀMS (ESI): m/z = 357.02191 [MH+], calcd.
for C16H15Cl2O3P: 357.02149.
Dimethylꢀ(2,2ꢀbis(4ꢀchlorphenyl)vinyl)ꢀphosphonate (5d). The product was purified by
flash chromatography with methylene chloride/ethyl acetate (9:1 and 8:2) as eluent to give the
desired product: 68%, 2.43 g (yellow liquid); 1H NMR (500 MHz, CDCl3, ppm) δ 7.38 (d, 3JHH
=
3
3
3
8.5 Hz, 2H), 7.30 (d, JHH = 2.1 Hz, 2H), 7.29 (d, JHH = 2.1 Hz; 2H), 7.18 (d, JHH = 8.5 Hz,
2H), 6.14 (d, 3JHP = 14.6 Hz, 1H), 3.55 (s, 3H); 3.52 (s, 3H); 13C NMR (125 MHz, CDCl3, ppm)
δ 158.12, 139.35, 139.17, 136.68, 136.62, 135.91, 135.10, 130.95, 129.36, 128.69, 128.29,
31
115.40, 113.86, 52.23; P NMR (202 MHz, CDCl3, ppm) δ 19.09; IR: 3668, 2969, 1588, 1491,,
1251, 1090, 1053, 1030, 1014, 926, 862, 825, 761; ESIꢀMS m/z (Intensity): 358 [MH+] (70), 356
(100); HRꢀMS (ESI): m/z = 357.02232 [MH+], calcd. for C16H15Cl2O3P: 357.02149.
Dimethylꢀ3ꢀ(4ꢀnitrophenyl)vinyl phosphonate (6e). The product was obtained as yellow
solid: 95%, 2.45 g; mP: 109.9 °C (lit28: 97ꢀ100 °C); 1H NMR (500 MHz, CDCl3, ppm) δ 8.26 (d,
3JHH = 8.5 Hz, 2H), 7.66 (d, 3JHH = 8.5 Hz 2H), 7.59 (d, 3JHH = 17.6 Hz, 1H), 7.54 (d, 3JHH = 17.6
3
Hz, 1H), 6.37 (d, 3JHH = 8.5 Hz, 1H), 7.59 – 7.52 (m, 2H), 6.41 (t, JHH = 17.6 Hz, 1H), 3.82 (s,
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3H), 3.80 (s, 3H); C NMR (125 MHz, CDCl3, ppm) δ 148.55, 146.33, 140.57, 128.34, 124.14,
5
6
7
31
118.71, 117.10, 52.66, 52.62; P NMR (202 MHz, CDCl3, ppm) δ 20.65; IR: 3073, 2956, 2849,
8
9
1514, 1345, 1246, 1043, 1019, 995, 853, 832, 766, 743; ESIꢀMS m/z (Intensity): 258 [M+] (100).
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3,3ꢀBis(4ꢀmethoxyphenyl)acrylnitrile (7). In a 100mL EasyMax™ reactor, equipped with
a reflux condenser and a magnetc stirrer bar, 0.2 mmol palladium acetate (45 mg), 11.4 mmol
(1.39 g) aluminum phosphate and 10 mmol (870 mg) acrylonitrile were dispersed in 68 mL
methanol. The mixture was stirred (350 rpm) for 34 minutes at 25 °C (isothermic conditions).
After this prereduction of palladium actetate 21.5 mmol of aryldiazonium salt were added and
the reaction mixture was heated to 50 °C within 1 min. Reaction development was monitored by
heat flow control and gas evolution. When reaction was finalized, reaction mixture was filtrated
through celite, poured into iceꢀwater and the water phase was extracted with methylene chloride
(3x50 mL). The combined organic phases were dried over anhydrous MgSO4 and then
concentrated under reduced pressure. The product was purified by flash chromatography with
methylene chloride/ethyl acetate (9:1 and 8:2) as eluent to give the desired product: 57%, 1.51 g
mP: 109.3 °C (lit mp: 105ꢀ108 °C)27; 1H NMR (500 MHz, CDCl3, ppm) δ 7.40 (d, 3JHH = 8.5 Hz,
3
3
3
2H), 7.24 (d, JHH = 8.5 Hz, 2H), 6.95 (d, JHH = 8.5 Hz, 2H), 6.88 (d, JHH = 8.5 Hz, 2H), 5:54
13
(s, 1H), 3.85 (s, 3H); 3.83 (s, 3H); C NMR (125 MHz, CDCl3, ppm) δ 162.21, 161.36, 160.87,
131.55, 131.19, 130.97, 130.06, 129.43, 118.68, 113.88, 113.75, 91:41, 55,33, 55.26; IR: 3041,
2202, 1601, 1584, 1514, 1253, 1176, 1028, 838, 806; HRꢀMS (ESI): m/z = 266.11803 [MH+],
calcd. for C17H16NO2: 266.11818.
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Supporting Information
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Corresponding Author
*Eꢀmail: heiko.brunner@atotech.com
Acknowledgements
S.L. thanks the Atotech Deutschland GmbH for a scholarship for her Master thesis.
Notes
The authors declare no competing financial interest.
Acknowledgement
Sandra Lucks thanks the Atotech Deutschland GmbH for a scholarship for her Master thesis.
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