Continuous-flow Heck - Matsuda reaction: Homogeneous versus heterogeneous palladium catalysts

Article abstract of DOI:10.1021/jo501468z

This study describes extensive investigations of the Heck-Matsuda reaction carried out by continuous-flow chemistry between aryl diazonium salts generated in situ and methyl acrylate. Our optimized procedures enable sequential aniline diazotization/palladium-catalyzed Heck-Matsuda reaction using either Pd(OAc)₂ or PdEnCat 30 as respectively a homogeneous or a heterogeneous source of palladium. This safe chemistry that does not require the handling of hazardous aryl diazonium salts involves inexpensive reagents and solvents, under ligand- and base-free conditions. (Chemical Equation Presented)

Full text of DOI:10.1021/jo501468z

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Article
Continuous-Flow Heck-Matsuda Reaction: Homogeneous
versus Heterogeneous Palladium-Catalysts
Nicolas Oger, Erwan Le Grognec, and Francois-Xavier Felpin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501468z • Publication Date (Web): 04 Aug 2014
Downloaded from http://pubs.acs.org on August 10, 2014
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Continuous-Flow Heck-Matsuda Reaction: Homogeneous versus
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Heterogeneous Palladium-Catalysts
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Nicolas Oger,a Erwan Le Grognec,a François-Xavier Felpin*,a,b
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a Université de Nantes, UFR Sciences et Techniques, UMR CNRS 6230, CEISAM, 2 rue de la
Houssinière, BP 92208, 44322 Nantes Cedex 3, France.
Email: fx.felpin@univ-nantes.fr
b Institut Universitaire de France, 103 blvd St Michel, 75005 Paris Cedex 5, France
Graphical Abstract
Abstract
This study describes extensive investigations of the Heck-Matsuda reaction carried out by
continuous-flow chemistry between aryl diazonium salts generated in situ and methyl
acrylate. Our optimized procedures enable sequential aniline diazotization/palladium-
catalyzed Heck-Matsuda reaction using either Pd(OAc)2 or PdEnCat® 30 as respectively a
homogeneous or a heterogeneous source of palladium. This safe chemistry that do not require
the handling of hazardous aryl diazonium salts, involves inexpensive reagents and solvents,
under ligand- and base-free conditions.
Introduction
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The Heck-Matsuda reaction1 has found a growing interest from the synthetic community
these last years.2 This variant of the Heck-Mizoroki reaction, involves the use of aryl
diazonium salts as “super electrophiles” instead of traditional aryl halides or aryl sulfonates
(Scheme 1).
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Scheme 1. General equation of the Heck-Matsuda reaction
The high reactivity of aryl diazonium salts, easily accessed from diazotization of readily
available anilines, has been exploited for the development of transformations in mild
conditions, with hydrophilic solvents such as alcohols or water, and under ligand- and base-
free conditions.3 The major drawback associated with this high reactivity is the hazardous
character of some diazonium salts. Indeed, although it has been reported that aryl diazonium
salts suitably functionalized can be stable up to 600 °C,4 their stability rules are more or less a
black box. In order to increase the synthetic potential of these salts in palladium-catalysis, we
recently uncovered an innovative strategy based on the in-situ catalytic activation of anilines
into the corresponding diazonium salts.5 This approach, using catalytic amounts of both
palladium and acid (required for the diazonium formation), proceeds under mild conditions at
room temperature in methanol, and only produces t-BuOH, H2O, N2 as by-products. While
this bicatalytic strategy addresses the issue of the diazonium handling in safe conditions, slow
kinetics, requiring extensive reaction times (48-65 hours), still limit its use to a laboratory
scale. We reasoned that an approach significantly decreasing the reaction times should be
decisive for improving the synthetic potential of these transformations.
In this event, we felt that flow technology could considerably enhance kinetics due to
improved heat and mass transfer,6 while keeping the advantage of a safe handling of
diazonium salts. Such an approach has been pioneered by Wirth et al. with the development
of segmented flow conditions for the coupling of aryl diazonium salts, either prepared in-situ
or preformed, with methyl acrylate and styrenes.7 The reaction conditions required the use of
AcOH-DMF as mixture of solvents, Pd(OAc)2 (10 mol%) as catalyst, and alcanes as
segmenting phase, giving products in yields ranging from 18 to 90%. Improved mixing by
internal circulation was expected into segmented flow compared to laminar flow.
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More recently, while we were achieving our studies described in this paper, McGuire,
Organ et al. adapted reaction conditions we recently reported in batch,5a,5b into a flow
technology.8 They developed a multicomponent process whereby diazotization and cross-
coupling occurred in one single reactor. Diazonium salts were generated in situ from the
corresponding anilines with t-BuONO and MeSO3H as diazotizing agents. These salts were
reacted with acrylates and styrene in the presence of Pd(OAc)2 (2 mol%) as catalyst in a
mixture of MeOH and DMF. With such reaction conditions they were able to efficiently
couple electron-deficient and neutral anilines in excellent yields with flow rate ranging from 3
to 12 µL.min-1, corresponding respectively to 6.4 and 1.6 hours residence times. These
authors essentially studied ortho-subtituted anilines, likely because of the positive ortho-effect
we recently uncovered,5b and arylation with less reactive electron-rich anilines were
overlooked. Although this study was remarkably conducted, we opted for a significant
different procedure that led to higher throughputs. Ultimately, our procedure was extended
with the use of PdEncat®30 as an immobilized palladium catalyst.
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Results and Discussion
The first stage of our studies was to determine whatever a two-step flow sequence
involving sequential diazotation-coupling or a multicomponent process whereby diazotization
and coupling occur in a concomitant fashion (as described by Organ et al.) was the most
efficient way, considering reaction rates. To address this point, we initially studied these two
approaches in batch and monitored the reaction by 1H NMR.
The two-step one-pot coupling of 4-bromoaniline 1a with methyl acrylate requires, in a
first stage, the formation of 4-bromobenzene diazonium salt 2a, followed, in a second stage,
by the addition of methyl acrylate and Pd(OAc)2 as catalyst to carry out the Heck-Matsuda
coupling (Scheme 2). Since we previously showed that the Heck-Matsuda reaction was best
performed in MeOH, with t-BuONO and MeSO3H as diazotizing agents,5 we followed the
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formation of the diazonium salt 2a in MeOD-d4 by H NMR spectroscopy. As expected, the
diazotization proceeded smoothly at 25 °C with no formation of degradation product (see
Figure S1 in supporting information). Actually, the treatment of aniline with MeSO3H led
quickly and quantitatively to the formation of the corresponding anilinium 3a. As soon as t-
BuONO was added to the reaction mixture, the diazonium salt formation started (Figure 1). A
maximum conversion of 93% was reached after 90 min and no evolution was observed upon
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further stirring. At this time (90 min), the palladium catalyst and methyl acrylate was added to
the reaction mixture and the cross-coupling started immediately, as observed with the
vigorous nitrogen evolution (Scheme 2). The coupling was achieved in about 30 minutes,
giving >90% NMR yield and no significant evolution was observed upon further stirring. As a
consequence, a maximum of 120 minutes (90 + 30 min) were required to give >90% NMR
yield of 4a.
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SCHEME 2. Two-step one-pot coupling of 4-bromoaniline 1a with methyl acrylate
FIGURE 1. Kinetic of the formation of diazonium salt 2a
On the other hand the same coupling was studied with a procedure whereby all reactants
were introduced at one time (Scheme 3). The NMR recording of the crude reaction mixture
every hours showed a slower rate since after 90 min 30% of anilinium still remains in solution
while after 120 min of stirring only 75% conversion was observed for 4a (see Figure S2 in
supporting information). Actually, a total of 1080 min (18 h) was required to achieve the
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reaction in >90% NMR yield (Figure 2). Only trace amounts of diazonium salts can be
observed at any time of the NMR recording, suggesting that the coupling reaction is not the
rate limiting step of the process.
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SCHEME 3. Multicomponent coupling of 4-bromoaniline 1a with methyl acrylate
FIGURE 2. Kinetics for the formation of styrene 4a in a multicomponent mode
Interestingly, when 4-nitroaniline 1b was used as an electron-poor aniline, a complete
diazonium formation was observed in less than 5 minutes at room temperature, and the
subsequent coupling reaction, leading to styrene 4b, was achieved in half an hour (Scheme 4).
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SCHEME 4. Two-step one-pot coupling of 4-nitroaniline 1b with methyl acrylate
These particularly informative preliminary studies revealed us three important features: (1)
for unclear reasons, the diazonium formation is significantly slowed down in the
multicomponent process, compared to the two-step sequence; (2) the kinetics of the
diazotization-coupling sequence are highly dependent of the electronic nature of the anilines;
and (3) the diazotization is likely the rate determining step with neutral and electron-rich
anilines.
With these results in hand, we looked for implementing this chemistry into a flow device
using aniline 1a and methylacrylate as starting materials. Before developing a two-step
procedure in flow, a preliminary screening of solvents was required since we observed in
batch the rapid precipitation of insoluble palladium black in MeOH. This behavior likely
resulted from the instability of ligand-free palladium species in methanol. A more
coordinating solvent should be more suitable to address this issue. Indeed, we anticipated that
precipitation of palladium into the reaction coil of the flow device could lead to clogging
issues and severely compromise the flow efficiency. Since the diazonium salt has to be
prepared in MeOH, or eventually in water, a co-solvent was required for the Pd catalyst and
the olefin. Our initial reaction setup employed two ways equipped with 2 mL injection loops
(Table 1). Loop A was loaded with the diazonium salt, preformed in a flask in either MeOH or
H2O, and loop B was filled with a solution of Pd(OAc)2 and methyl acrylate. Pumping of each
way was initiated at 0.2 mL/min with two independent pumps. The flow streams met at a T-
shaped mixer (150 µL) before entering into the reaction coil (reactor A, 5 mL), these latter
being placed in an oven for an accurate control of the temperature. The use of MeOH as
solvent carrier effectively lead to the desired product in 60% NMR yield, but palladium
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deposit were observed on the side of the PFA tubing and the T-mixer clogged after a few runs
(entry 1). The use of environmentally friendly dimethyl carbonate marginally improved the
reaction yield but, most importantly, palladium deposit and clogging issues were not observed
(entry 2). The use of water as solvent for the diazonium stream, completely inhibited the
coupling, likely due to the immiscibility of water and DMC (entry 3). While 1,4-dioxane
displayed a similar behavior than DMC (entry 4), the use of THF significantly improved the
yield to 78% at 25 °C and even 90% at 40 °C, while keeping the flow device away from
clogging issue (entries 5-6).
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TABLE 1. Preliminary solvent screening with a two-stream flow device
Entry
Solvent A
MeOH
MeOH
H2O
Solvent B
MeOH
DMC
Temp. (°C)
Yield (%)a
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DMC
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MeOH
MeOH
MeOH
1,4-dioxane
THF
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90
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THF
a NMR yield. b Diazonium salt prepared in water (20 min, 100% conversion).
Having determined a suitable solvent combination, we further explored the two-step flow
diazotization-coupling sequence. In this event, a three-stream flow reactor was constructed as
depicted in Table 2. In the flow setup, 4-bromoaniline 1a and MeSO3H were loaded in loop A
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while t-BuONO was independently charged in loop B; these 5 mL loops being pumped with
MeOH as solvent. The two streams met at a T-mixer (150 µL) and entered into a PEEK
tubing reactor A (5 mL). Then the catalyst and methyl acrylate in solution in THF was
pumped into the system and met the diazonium salt at a second T-mixer (150 µL). The
resulting mixture was introduced into a PEEK reactor B (5 mL) and finally collected into a
fraction collector. An important slug flow stream was observed at the outlet due to N2 release.
All the tubing, including T-mixers and reaction coils were placed in an oven for an accurate
control of the reaction temperature. Initially, the flow rate was fixed at 0.2 mL/min,
corresponding to 12.5 and 8.3 min residence time for respectively the first and second tubing
reactor. At 25 °C a modest 22% NMR yield was obtained for the expected coupling product
4a (table 2, entry 1). When the flow rate of each pump was decrease to 0.1 mL/min, an
encouraging 40% yield was observed (entry 2). Increasing the temperature of both tubing
reactors at 40 °C and 60 °C improved the yield respectively to 65% (entry 3) and 90% (entry
4) with a total residence time of 41.7 min for the two-step sequence. The optimal
concentration of MeSO3H, methyl acrylate and Pd(OAc)2 was also deeply investigated in
order to ensure the highest efficiency and sustainability of our flow process. Interestingly, the
Pd concentration could be considerably lowered, up to 5 10-4 M (corresponding to a 0.5 mol%
loading) while keeping the same NMR yield (entry 6), and even concentration as low as 1 10-4
M (0.1 mol% Pd) still furnished compound 4a with a high yield (entry 7). While lower
concentration of the acrylate (0.22 M vs 0.44 M) significantly alter the reaction yield (entry
8), a different trend was observed when lowering the acid concentration from 0.23 M to 0.1
M, since it only marginally impacted the reaction efficiency (entry 9). Since excess of acid
might damage pump heads, especially when working on larger scale, we selected these last
conditions (entry 9) for our scope studies.
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TABLE 2. Optimization studies with a three-stream flow device
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Entry
X
Temp.
[C1]
[C2]
[C3]
Yield
(%)e
22
(mL/min)a (°C)
(mol/L)b
0.23
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(mol/L)c
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0.22
0.44
(mol/L)d
4.4 10-3
4.4 10-3
4.4 10-3
4.4 10-3
1 10-3
5 10-4
1 10-4
5 10-4
5 10-4
1
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8
0.2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
25
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40
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40
65
90
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a
b
c
Total flow rate = 3X. Concentration of MeSO3H in MeOH. Concentration of methyl
acrylate in THF. d Concentration of Pd(OAc)2 in THF. e NMR yield.
The flow setup was then evaluated on a collection of both electron-poor and electron-rich
anilines (Table 3). Since electron-deficient anilines were converted into the corresponding
diazonium salt in a few seconds at 40 °C, reactor A was dimensioned according to the
electronic nature of the anilines. Thereby, while a 5 mL reactor A was used with electron-rich
and neutral anilines, it was downsized at 100 µL for the formation of electron-poor diazonium
salts. We observed that anilines bearing both electron-withdrawing and mildly electron-
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releasing groups underwent the diazotization-coupling sequence in good to high yields. The
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reaction advancement was monitored by H NMR in order to assure the complete
consumption of the diazonium salt. Remarkably, the mild experimental conditions tolerated a
variety of functional groups on the aniline, including bromo (4a), nitro (4b, 4d-g), ester (4c,
4h), and methoxy (4i). The conditions used in this transformation do not affect the bromo-
reactive functionality since no trace of coupling at the bromine atom was observed. Such high
regio- and chemoselective leave unaffected functionalities that could be further modified
using standard chemistry. The good yield obtained for heteroaromatic acrylate 4h suggest that
the scope of the method could be extended to relevant heterocyclic structures. The coupling of
aniline bearing electron-withdrawing groups proceed with a total residence time of only c.a.
17 min while mildly electron-rich anilines where diazotized and subsequently coupled with a
total residence time of c.a. 42 min. By contrast, the very deactivated 4-methoxy aniline were
less efficiently coupled in 54% yield, with a total residence time of c.a. 117 min. This last
result, revealed that the coupling of electron rich anilines proceeded with very slow kinetics
suggesting that continuous flow chemistry might be not suitable since temperature cannot be
raised above 60 °C due to the thermal instability of diazonium salts.
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TABLE 3. Scope of the Heck-Matsuda reaction using a three-stream flow devicea
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a
b
c
d
Isolated yield (average of at least two runs). 1.10-3 M Pd(OAc)2. 2.10-3 M Pd(OAc)2.
Flow rate/stream : 0.025 mL/min. e 4.10-3 M Pd(OAc)2.
To further explore the scope of the diazotization/Heck coupling sequence in flow and
develop a more practical and sustainable procedure, we considered the use of an immobilized
palladium-catalyst. Since Pd(OAc)2 was arguably the best homogeneous palladium-catalyst
for conducting Heck-Matsuda coupling in methanol,2b-d we opted for the use of commercially
available PdEncat® 30 which consist of palladium acetate microencapsulated in a polyurea
matrix.9 It should be noted that Heck-Matsuda reaction catalyzed by heterogeneous palladium
catalysts has neither been described with flow reactors, though it is known in batch.10
Accordingly, a three-stream flow reactor was elaborated as depicted in Table 4. The reaction
setup consisted of two injection loops containing the material required for the diazonium
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formation that met at a T-shaped mixer (150 µL) and enter in the coil reactor A (0.1 mL or 5
mL). Then, the flow stream containing the diazonium salt in MeOH met a solution of methyl
acrylate in MeOH at a second T-mixer (150 µL). The mixture was then transferred to an
Omnifit-type glass column loaded with PdEncat® 30 at a flow rate of 0.3 ml/min (0.1 mL/min
per pump) and maintained in an oven at the specified temperature (see Table 4). Since the
palladium catalyst was immobilized in a polyurea matrix, the use of THF was not required
anymore and the whole process was carried out in MeOH. A selection of representative
anilines were selected for the evaluation of this unprecedented flow setup. The results showed
that the yields for the coupled products were in the same range than those obtained with
Pd(OAc)2. As previously observed, electron-rich 4-methoxyaniline gave a modest yield of the
corresponding coupled product 4i (51%), and slowing down the flow rate to 0.05 mL/min per
pump did not affect the result. However, this approach features three decisive advantages
compared to the homogeneous conditions: (1) the total residence time is significantly lowered
up to only 225 seconds with electron-poor anilines; (2) the use of THF as solvent is not
required anymore; (3) the concentration of palladium, leached from the PdEncat® 30 catalyst
and measured by ICP-MS in the crude product solution, is in the range 1 to 7 ppm,
representing the acceptable limit for pharmaceutical ingredients. By comparison, under
homogeneous conditions, a one hundred times higher concentration of palladium was
measured for the synthesis of 4i.
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TABLE 4. Scope of the Heck-Matsuda reaction using Pd Encat® 30 as an immobilized
catalyst.
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a Total residence time including reactor A and reactor B. b Isolated yield.
Conclusion
In summary, we have deeply investigated the two-step diazotization/Heck-Matsuda reaction
using a dedicated flow reactor. We provided strong evidences for preferentially conducting
the diazotization/Heck-Matsuda reaction sequentially rather than as a multicomponent process
whereby diazotization and coupling occur in a concomitant fashion. The experimental
simplicity and the mild conditions render this flow approach highly competitive and safer
compared to traditional batch approaches. This work allows a better understanding of the
scope and limitation of the Heck-Matsuda reaction conducted in a flow reactor. For instance,
the uncovered use of an immobilized catalyst considerably increase the throughput of the
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process with residence time as low as 225 seconds for the sequential two-step
diazotization/Heck-Matsuda reaction while limiting to low ppm levels the contamination of
the crude products by palladium residues. From a larger perspective, we provided important
advances for considering in a safer environment the rich chemistry of aryl diazonium salts in
palladium-catalyzed transformations under continuous-flow conditions.
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Experimental section
General methods. All commercial reagents were used as received. Silica gel (40-63 µm) was
used in flash column chromatography. Analytical thin-layer chromatography (TLC) was
performed on silica gel plates (TLC silica gel 60 F254), visualized with a UV lamp (254 nm),
and stained with a basic solution of KMnO4. Solvent systems and flash column
chromatography are reported as percent by volume values. 1H and 13C NMR were recorded at
300 MHz or 400 MHz and 75 MHZ or 100 MHz respectively. Proton chemical shifts were
internally referenced to the residual proton resonance in CDCl3 (δ 7.26 ppm). Carbon
chemical shifts were internally referenced to the deuterated solvent signals in CDCl3 (δ 77.2
ppm). FT-IR spectra were recorded with samples loaded as KBr plates. Low resolution mass
spectroscopy (LRMS) was performed using chemical ionization (CI). High resolution mass
spectroscopy (HRMS) was recorded on an orbitrap spectrometer. Sample loops and reactors
were made out of PEEK with a 0.75 mm internal diameter. T-mixers were made out of PEEK
with an internal volume of 150 µL and connecting tubbing was made out of PFA with a 0.75
mm internal diameter.
General procedure for the two-step one-pot coupling of 4-bromoaniline with methyl
acrylate in batch. To a solution of aniline (1.0 mmol, 172 mg) in MeOD-d4 (5 mL) were
added methanesulfonic acid (2.3 mmol, 150 µL) and t-BuONO (1.5 mmol, 180 µL) at 25 °C.
The resulting mixture was stirred for 90 minutes and then, methyl acrylate (2.2 mmol, 200
µL) and palladium acetate (2.2 mol%, 5 mg) were added and the reaction was conducted at 25
°C.
General procedure for the multicomponent coupling of 4-bromoaniline with methyl
acrylate in batch. To a solution of aniline (1.0 mmol, 172 mg) in MeOD-d4 (3 mL) were
added methanesulfonic acid (2.3 mmol, 150 µL) and t-BuONO (1.5 mmol, 180 µL) at 25 °C.
Then, methyl acrylate (2.2 mmol, 200 µL) and palladium acetate (2.2 mol%, 5 mg) were
added with MeOD-d4 (2 mL). The reaction was conducted at 25 °C.
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General procedure for the two-step one-pot coupling of 4-nitroaniline with methyl
acrylate in batch. To a solution of aniline (1.0 mmol, 138 mg) in MeOD-d4 (5 mL) were
added methanesulfonic acid (2.3 mmol, 150 µL) and t-BuONO (1.5 mmol, 180 µL) at 25 °C.
The resulting mixture was stirred for 90 minutes and then, methyl acrylate (2.2 mmol, 200
µL) and palladium acetate (2.2 mol%, 5 mg) were added and the reaction was conducted at 25
°C.
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General procedure for the solvent screening using a two-stream flow device. A solution
of p-bromobenzene diazonium salt (0.2 M) was prepared using p-bromoaniline (2.0 mmol,
344 mg) with methanesulfonic acid (2.3 equiv., 300 µL) and t-BuONO (1.5 equiv., 360 µL) in
MeOH (10 mL) at 25 °C. In another flask, a solution containing methyl acrylate (0.44 M, 400
µL) and palladium acetate (0.0044 M, 10 mg) was prepared in solvent B (10 mL) at 25 °C.
Then, each sample loops were filled with the solutions previously prepared and the reaction
was conducted at the corresponding temperature. The collected product 4a was analyzed by
1H NMR.
General procedure for the optimization studies with a three-stream flow device. To a
solution of p-bromoaniline (0.1 M, 172 mg) was added methanesulfonic acid ([C1]) in MeOH
(10 mL) at 25 °C. In another flask, a solution of t-BuONO (0.15 M, 180 µL) was prepared in
MeOH (10 mL) at 25 °C. Both of them were injected into two different sample loops (5 mL).
A solution of methyle acrylate ([C2]) and palladium acetate ([C3]) prepared in THF at 25 °C
was continuously added on a third pump. The reaction was conducted at the corresponding
temperature. The collected product 4a was analyzed by 1H NMR.
General procedure for the homogeneous Heck-Matsuda cross-coupling using a flow
device. A solution of aniline (0.1 M) and methanesulfonic acid (0.1 M, 65 µL) in MeOH (10
mL) at 25 °C was loaded in loop A (5 mL). A solution of t-BuONO (0.15 M, 180 µL) in
MeOH (10 mL) at 25 °C was loaded in loop B (5 mL). A solution of methyle acrylate (0.44
M) and palladium acetate (0.0005 M, 0.5 mol%) prepared in THF at 25 °C was continuously
added on a third pump. The reaction is conducted at the corresponding temperature. Na2CO3
(0.5 mmol ) was added to the collected product and then, the solvent was removed. The crude
product was purified by flash chromatography to give the corresponding coupling product.
General procedure for the heterogeneous Heck-Matsuda cross-coupling using a flow
device. A solution of aniline (0.2 M) and methanesulfonic acid (0.2 M, 130 µL) in MeOH (10
mL) at 25 °C was loaded in loop A (5 mL). A solution of t-BuONO (0.3 M, 360 µL) in MeOH
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(10 mL) at 25 °C was loaded in loop B (5 mL). A solution of methyle acrylate (0.44 M)
prepared in MeOH at 25 °C was continuously added on a third pump. The resulting flow
stream went through the packed bed containing the heterogeneous catalyst (PdEnCat®30,
0.38 mmol). The reaction is conducted at the corresponding temperature. Na2CO3 (1.0 mmol )
was added to the collected product and then, the solvent was removed. The crude product was
purified by flash chromatography to give the corresponding coupling product.
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(E)-Methyl-4-bromocinnamate (4a). This compound was prepared according to the general
cross-coupling procedures. Purification by flash chromatography (5% AcOEt-petroleum
ether) gave a white solid (homogeneous procedure: 94 mg, 78%). mp 89 °C [Lit.3h 88-93 °C].
1
IR: ν 1490, 1587, 1633, 1710, 2833, 2948, 2997, 3032, 3064 cm-1. H NMR (CDCl3, 300
MHz): δ 3.81 (s, 3H), 6.43 (d, 1H, J = 16.0 Hz), 7.39 (d, 2H, J = 8.4 Hz), 7.52 (d, 2H, J = 8.5
Hz), 7.62 (d, 1H, J = 16.0 Hz). 13C NMR (CDCl3, 75 MHz): δ 52.0, 118.7, 124.7, 129.6,
79
81
+ 79
132.3, 133.5, 143.7, 167.4. MS (CI) m/z 240 (M, Br), 242 (M, Br), 258 (M+NH4 , Br),
+
260 (M+NH4 , 81Br).
(E)-Methyl 4-nitrocinnamate (4b). This compound was prepared according to the general
cross-coupling procedures. Purification by flash chromatography (20% AcOEt-petroleum
ether) gave a white solid (homogeneous procedure: 73 mg, 71%; heterogeneous procedure:
1
137 mg, 66%). mp 161 °C [Lit.10c 161 °C]. IR: ν 1638, 1721, 2958, 3041 cm-1. H NMR
(CDCl3, 300 MHz): δ 3.84 (s, 3H), 6.57 (d, 1H, J = 16.1 Hz), 7.68 (d, 2H, J = 8.7 Hz), 7.71 (s,
1H, J = 16.1 Hz), 8.25 (d, 2H, J = 8.8 Hz). 13C NMR (CDCl3, 75 MHz): δ 52.3, 122.3, 124.4,
128.8, 140.7, 142.1, 148.7, 166.6. HRMS (ESI) calcd for C10H9NO4 [M]+: 207.0532, found:
207.0533.
(E)-Methyl 4-methoxycarbonylcinnamate (4c). This compound was prepared according to
the general cross-coupling procedures. Purification by flash chromatography (15% AcOEt-
petroleum ether) gave a white solid (homogeneous procedure: 81 mg, 74%; heterogeneous
procedure: 176 mg, 80%). mp 124 °C [Lit.3h 124 °C]. IR: ν 1641, 1720, 2958 cm-1. 1H NMR
(CDCl3, 300 MHz): δ 3.82 (s, 3H), 3.93 (s, 3H), 6.52 (d, 1H, J = 16.1 Hz), 7.58 (d, 2H, J = 8.3
Hz), 7.70 (d, 1H, J = 16.1 Hz), 8.04 (d, 2H, J = 8.4 Hz). 13C NMR (CDCl3, 75 MHz): δ 52.1,
52.5, 120.4, 128.1, 130.3, 131.6, 138.8, 143.6, 166.6, 167.1. HRMS (ESI) calcd for
C12H12O4Na [M+Na]+: 243.0633, found: 243.0629.
(E)-Methyl 2-nitrocinnamate (4d). This compound was prepared according to the general
cross-coupling procedures. Purification by flash chromatography (20% AcOEt-petroleum
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ether) gave a yellow solid (homogeneous procedure:73 mg, 71%). mp 71-72 °C [Lit.3h 72 °C].
IR: ν 1637, 1719, 2953, 3024 cm-1. 1H NMR (CDCl3, 300 MHz): δ 3.83 (s, 3H), 6.37 (d, 1H, J
= 15.8 Hz), 7.51-7.57 (m, 1H), 7.61-7.68 (m, 2H), 8.03 (d, 1H, J = 7.8 Hz), 8.11 (d, 1H, J =
15.8 Hz). 13C NMR (CDCl3, 75 MHz): δ 52.2, 123.0, 125.1, 129.3, 130.5, 130.7, 133.7, 140.3,
148.5, 166.4. HRMS (ESI) calcd for C10H9NO4Na [M+Na]+: 230.0429, found: 230.0429.
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(E)-Methyl 4-methyl-2-nitrocinnamate (4e). This compound was prepared according to the
general cross-coupling procedures. Purification by flash chromatography (20% AcOEt-
petroleum ether) gave a yellow solid (homogeneous procedure: 83 mg, 75%; heterogeneous
procedure: 147 mg, 67%). mp 73-75 °C [Lit.5a 71-72 °C]. IR: ν 1527, 1635, 1716, 2952,
1
3012, 3070 cm-1. H NMR (CDCl3, 300 MHz): δ 2.47 (s, 3H), 3.82 (s, 3H), 6.35 (d, 1H, J =
15.8 Hz), 7.45 (app. d, 1H, J = 8.0 Hz), 7.53 (d, 1H, J = 8.0 Hz), 7.84 (s, 1H), 8.07 (d, 1H, J =
15.8 Hz). 13C NMR (CDCl3, 75 MHz): δ 21.3, 52.1, 122.3, 125.4, 127.8, 129.0, 134.4, 140.2,
141.6, 148.6, 166.6. HRMS (ESI) calcd for C11H11NO4Na [M+Na]+: 244.0586, found:
244.0584.
(E)-Methyl 4-methoxy-2-nitrocinnamate (4f). This compound was prepared according to
the general cross-coupling procedures. Purification by flash chromatography (15% AcOEt-
petroleum ether) gave a yellow solid (homogeneous procedure: 103 mg, 87%). mp 90-91 °C
[Lit.5a 90-91 °C]. IR: ν 1639, 1725, 2957, 3005 cm-1. 1H NMR (CDCl3, 300 MHz): δ 3.82 (s,
3H), 3.91 (s, 3H), 6.32 (d, 1H, J = 15.8 Hz), 7.17 (dd, 1H, J = 2.7 Hz, J = 8.7 Hz), 7.50 (d, 1H,
J = 2.6 Hz), 7.58 (d, 1H, J = 8.7 Hz), 8.04 (d, 1H, J = 15.8 Hz). 13C NMR (CDCl3, 75 MHz): δ
52.1, 56.2, 109.6, 120.2, 121.2, 122.7, 130.2, 139.7, 149.6, 161.1, 166.7. HRMS (ESI) calcd
for C11H11O5NNa [M+Na]+: 260.0529, found: 260.0525.
(E)-Methyl 2-methoxy-4-nitrocinnamate (4g). This compound was prepared according to
the general cross-coupling procedures. Purification by flash chromatography (15% AcOEt-
petroleum ether) gave a yellow solid (homogeneous procedure: 88 mg, 74%; heterogeneous
procedure: 201 mg, 85%). mp 108 °C [Lit.5a 108 °C]. IR: ν 1635, 1719, 2957, 3098 cm-1. 1H
NMR (CDCl3, 300 MHz): δ 3.83 (s, 3H), 4.00 (s, 3H), 6.64 (d, 1H, J = 16.2 Hz), 7.64 (d, 1H,
J = 8.5 Hz), 7.76 (d, 1H, J = 2.1 Hz), 7.84 (dd, 1H, J = 2.1 Hz, J = 8.5 Hz), 7.95 (d, 1H, J =
16.2 Hz). 13C NMR (CDCl3, 75 MHz): δ 52.1, 56.4, 106.4, 116.0, 122.5, 129.2, 129.9, 138.0,
149.6, 158.5, 167.2. HRMS (ESI) calcd for C11H11NO5Na [M+Na]+: 260.0535, found:
260.0540.
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(E)-Methyl (2-methoxycarbonyl-3thienyl)acrylate (4h). This compound was prepared
according to the general cross-coupling procedures. Purification by flash chromatography
(20% AcOEt-petroleum ether) gave a white solid (homogeneous procedure: 85 mg, 75% and
95 mg, 84%; heterogeneous procedure: 157 mg, 69%). mp 89-91 °C. IR: ν 1525, 1628, 1702,
1726, 2955, 3007, 3103 cm-1. 1H NMR (CDCl3, 300 MHz): δ 3.80 (s, 3H), 3.90 (s, 3H), 6.37
(d, 1H, J = 16.2 Hz), 7.34 (dd, 1H, J = 0.3 Hz, J = 5.3 Hz), 7.46 (dd, 1H, J = 0.6 Hz, J = 5.3
Hz), 8.50 (d, 1H, J = 16.2 Hz). 13C NMR (CDCl3, 75 MHz): δ 52.0, 52.5, 121.8, 126.8, 131.0,
131.3, 136.9, 142.0, 162.4, 167.3. HRMS (ESI) calcd for C10H10O4NaS [M+Na]+: 249.0197,
found: 249.0198.
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(E)-Methyl-4-methoxycinnamate (4i). This compound was prepared according to the
general cross-coupling procedure. Purification by flash chromatography (20% AcOEt-
petroleum ether) gave a white solid (homogeneous procedure: 52 mg, 54%; heterogeneous
procedure: 98 mg, 51%). mp 86 °C [Lit.5c 94 °C]. IR: ν 1513, 1603, 1637, 1718, 2843, 2948,
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3000, 3031 cm-1. H NMR (CDCl3, 300 MHz): δ 3.79 (s, 3H), 3.83 (s, 3H), 6.32 (d, 1H, J =
13
16.0 Hz), 6.91 (d, 2H, J = 8.8 Hz), 7.47 (d, 2H, J = 8.7 Hz), 7.64 (d, 1H, J = 16.0 Hz). C
NMR (CDCl3, 75 MHz): δ 51.8, 55.5, 114.5, 115.4, 127.3, 129.9, 144.7, 161.6, 167.9. HRMS
(ESI) calcd for C11H13O3 [M+H]+: 193.0859, found: 193.0860.
Acknowledgments
We gratefully acknowledge the “Université de Nantes”, the “Centre National de la Recherche
Scientifique (CNRS)”, and the “Région Pays de la Loire” in the framework of a “Recrutement
sur poste stratégique” for the financial support to this project and C. Douchet (Université
Montpellier) for ICPMS analyses. F.-X. Felpin is member of the “Institut Universitaire de
France (IUF)”.
Supporting Information
1
Figure S1, Figure S2, H, 13C NMR and HRMS spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
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