Heterogeneous versus homogeneous palladium catalysts for ligandless Mizoroki-Heck reactions: A comparison of batch/microwave and continuous-flow processing

Article abstract of DOI:10.1002/chem.200802200

Mizoroki-Heck couplings of aryl iodides and bromides with butyl acrylate were investigated as model systems to perform transition-metal-catalyzed transformations in continuous-flow mode. As a suitable ligandless catalyst system for the Mizoroki-Heck coupl

Full text of DOI:10.1002/chem.200802200

FULL PAPER
DOI: 10.1002/chem.200802200
Heterogeneous Versus Homogeneous Palladium Catalysts for Ligandless
Mizoroki–Heck Reactions: A Comparison of Batch/Microwave and
Continuous-Flow Processing
[
a]
[b]
[a]
Toma N. Glasnov, Silvia Findenig, and C. Oliver Kappe*
Abstract: Mizoroki–Heck couplings of
aryl iodides and bromides with butyl
acrylate were investigated as model
systems to perform transition-metal-
catalyzed transformations in continu-
ous-flow mode. As a suitable ligandless
catalyst system for the Mizoroki–Heck
couplings both heterogeneous and ho-
mogeneous Pd catalysts (Pd/C and Pd
acetate) were considered. In batch
mode, full conversion with excellent se-
lectivity for coupling was achieved ap-
plying high-temperature microwave
conditions with Pd levels as low as
10 mol%. In continuous-flow mode
with Pd/C as a catalyst, significant Pd
leaching from the heterogeneous cata-
lyst was observed as these Mizoroki–
Heck couplings proceed by a homoge-
neous mechanism involving soluble Pd
colloids/nanoparticles. By applying low
levels of Pd acetate as homogeneous
Pd precatalyst, successful continuous-
flow Mizoroki–Heck transformations
were performed in a high-temperature/
pressure flow reactor. For both aryl io-
dides and bromides, high isolated prod-
uct yields of the cinnamic esters were
obtained. Mechanistic issues involving
the Pd-catalyzed Mizoroki–Heck reac-
tions are discussed.
À3
Keywords: cross-coupling
chemistry · heterogeneous catalysis ·
microwave-assisted reactions
·
flow
·
nanoparticles
nisms
·
reaction mecha-
[1,2]
Introduction
among the most prominent representatives.
During the
past decades, proper catalyst/ligand design has led to a vari-
ety of very efficient homogeneous catalytic systems for the
Mizoroki–Heck reaction that provide high reaction rates
and turn over numbers (TON), and often afford good selec-
tivities and product yields. Nevertheless, in particular from
the perspective of process development, the use of a ligand-
less heterogeneous transition-metal catalyst is often desir-
Transition-metal-catalyzed cross-coupling procedures have
revolutionized the art and practice of organic synthesis in
[1]
the last two decades. The in general mild reaction condi-
tions, high functional group tolerance and broad availability
of starting materials have contributed to the growing success
of, for example, Pd-catalyzed carbon–carbon and carbon–
heteroatom bond formation methods. Among the many dif-
ferent coupling protocols that have been reported till date,
the Mizoroki–Heck reaction involving the Pd-catalyzed
carbon–carbon coupling of aryl halides with alkenes is
[2]
AHCTUNGTRENNUGNa ble, primarily because of the ease of handling, and the
[3]
simple recovery/recycling of the metal catalyst. Notably,
Mizoroki–Heck transformations have been reported on an
industrial scale with comparatively inexpensive Pd/C as li-
[4]
gandless heterogeneous catalyst.
Since transition-metal-catalyzed cross-coupling reactions
using a heterogeneous, ligand-free catalytic system often re-
quire high temperatures and extended reaction times, the
use of microwave heating to improve these synthetic proto-
[
a] Dr. T. N. Glasnov, Prof. Dr. C. O. Kappe
Christian Doppler Laboratory for Microwave Chemistry (CDLMC)
and
Institute of Chemistry, Karl-Franzens-University Graz
Heinrichstrasse 28, 8010 Graz (Austria)
Fax : (+43)316-380-9840
[5–17]
cols has received considerable attention in recent years.
[
7–9]
Literature examples include the utilization of Pd/C,
Pd/
E-mail: oliver.kappe@uni-graz.at
[10]
[11,12]
[13,14]
SiO2, PdEnCat,
Pd/glass,
supported/stabilized Pd
[
b] S. Findenig
[15]
[16]
[17]
[18]
nanoparticles,
Ni/C,
Ni/graphite,
Cu/C,
and other
Institute of Chemistry, Analytical Chemistry
Karl-Franzens-University Graz, Universitꢀtsplatz 1
[19]
supported metal species in combination with microwave
dielectric heating for achieving highly efficient carbon–
carbon and carbon–heteroatom bond formation reactions.
For transformations involving a heterogeneous catalyst, the
8
010 Graz (Austria)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802200.
Chem. Eur. J. 2009, 15, 1001 – 1010
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1001

use of microwave heating appears to be particularly attrac-
tive, since heterogeneous metal catalysts (e.g., Pd/C) are
Et N as a base and Pd/C amounts as low as 0.4 mol%
3
(0.65 mmol 1a, 1.0 mL MeCN). For all coupling reactions
described herein, a Pd/C catalyst specifically optimized for
Mizoroki–Heck reactions was employed (E104CA/W
5% Pd), which is characterized by a high Pd dispersion, a
[20,21]
generally strongly microwave absorbing.
Therefore, se-
lective heating (“superheating”) of the heterogeneous cata-
lyst by microwave irradiation will occur under certain condi-
tions, which may result in differences in reaction rates and
selectivities compared to control experiments performed by
using conventional conductive heating at the same bulk tem-
[
27]
low reduction degree, and a high water content.
While
control experiments under reflux conditions (conventional
heating, ca. 808C) required 2–3 h for full conversion, sealed
vessel microwave heating at 1308C (3 bar) led to full conver-
sion after 5 min (GC-FID). Increasing the temperature to
1508C (6 bar) allowed shortening of the reaction time to
only 2 min to reach full conversion and provided the desired
cinnamic ester 3a in 96% isolated yield (TON=250, turn-
[8,11,14,22]
perature.
One disadvantage of microwave-assisted
synthesis, however, is the inability to scale the technology to
production quantities in a batch reactor, because of the lim-
[23]
ited penetration depth of microwave irradiation.
There-
fore, translating microwave chemistry to scalable continu-
[24]
À1
ous-flow processes is becoming increasingly important.
over frequency (TOF)=125 min ). Under all investigated
Herein we describe model studies involving Mizoroki–
Heck reactions using both a heterogeneous and homogene-
ous Pd catalyst [Pd/C and Pd ACHTUNGTRENN(UNG OAc) ] under ligandless condi-
2
conditions, this Mizoroki–Heck coupling was remarkably
clean with only trace amounts of dehalogenated product
(benzonitrile, <1%) and homocoupling product (4,4’-dicya-
nobiphenyl, ca. 3%) being observable by GC-FID analysis
of the crude reaction mixture. As expected, the analogous
coupling using aryl bromide 1b as starting material required
considerably higher temperatures (1808C) and extended re-
action times (20–30 min) to reach an approximate 85–90%
conversion. Full conversion and a high isolated product
yield (93%) could only be obtained using TBAB (tetrabut-
tions. Experiments were performed in batch mode with mi-
crowave dielectric heating and subsequently translated to
continuous-flow processes, employing dedicated flow reac-
tors designed for use at high temperatures and pressures,
thus mimicking the rapid heating and high temperature/
pressure conditions achieved in microwave batch processing.
The potential involvement of specific microwave effects in
these transition-metal-catalyzed transformations and mecha-
nistic aspects (homogeneous versus heterogeneous catalysis)
are discussed.
AHCTUNGTRENNUGNy lammonium bromide) as an additive (“Jeffrey condi-
[28]
tions”, see below for details).
To determine if microwave dielectric heating of the reac-
tion mixture will lead to selective heating (“superheating”)
[
20,21]
of the strongly absorbing Pd/C catalyst,
lead to specific microwave effects not reproducible by con-
and therefore
Results and Discussion
[8,11,14,22]
ventional heating at the same bulk temperature,
Microwave batch experiments: Our chosen model transfor-
mations involve the Mizoroki–Heck olefination of cyano-
substitued aryl iodide/bromide 1a,b with butyl acrylate (2)
to provide the corresponding cinnamic esters 3a,b
careful control experiments between microwave and con-
ventional heating for both Mizoroki–Heck couplings shown
in Scheme 1 were performed. By using a proper experimen-
tal set-up allowing for accurate internal temperature moni-
toring by a fiber-optic probe sensor in both the microwave
and oil bath experiments, kinetic studies at different tem-
perature regimes were performed. To allow an adequate ki-
netic analysis, the reaction temperatures for both the aryl
iodide and aryl bromide couplings were reduced to 105 and
[25,26]
(
Scheme 1).
Previous studies from our group have
[29]
1
758C, respectively (Table 1). For both aryl halide systems
we realized that not only the final reaction temperature ach-
ieved in both types of heating experiments, but also the
heating ramp to the maximum temperature must be similar
in order to provide meaningful data (see Figure S1 in the
Supporting Information). In addition, both Mizoroki–Heck
couplings proved very sensitive to small variations in the ex-
perimental parameters, in particular to the catalyst loading.
All experiments were therefore repeated several times to
ensure reproducibility and statistical relevance. As shown in
Table 1, for both Mizoroki–Heck couplings no significant
differences—within the experimental error of the experi-
ment—between microwave and conventional heating at the
same measured bulk reaction temperature was observed. In
an attempt to enforce an effect, we also performed an ex-
periment using “simultaneous cooling” of the reaction mix-
ture for the Mizoroki–Heck coupling of aryl iodide 1a with
Scheme 1. Mizoroki–Heck couplings in batch and continuous-flow mode.
found that microwave-assisted Mizoroki–Heck reactions of
aryl bromides of type 1b with acrylic acid can be effectively
carried out using Pd/C as a catalyst under ligandless condi-
tions at 1808C (MeCN, Et N) providing the corresponding
3
cinnamic acids in high yields after only 20 min reaction
[9]
time.
The starting point for our current investigation involved
the optimization of reaction conditions for the coupling of
aryl iodide 1a with butyl acrylate (2) under single-mode mi-
crowave conditions. In agreement with our previously pub-
[9]
lished results, we found that optimum coupling conditions
involved 1.5 equivalents of the acrylate, 1.5 equivalents of
1002
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Palladium Catalysts
FULL PAPER
[
24]
[33,34]
Table 1. Comparison of microwave heating (MW) and conventional heat-
microwave-driven
flow instrumentation).
The transi-
ing (conv) for the Mizoroki–Heck couplings of aryl halides 1a,b with
tion-metal-catalyzed flow Mizoroki–Heck reactions involv-
ing Pd/C were conducted in a high-pressure flow reactor (X-
in which the heterogeneous Pd catalyst is immo-
bilized in a pre-packed, replaceable stainless steel cartridge
60ꢂ4 mm i.d., ca. 310 mg Pd/C). The catalyst cartridge can
[
a]
butyl acrylate (2) (Scheme 1).
t
Heating
method
Aryl iodide 1a
Aryl bromide 1b
[35,36]
Cube),
[
b]
[b]
A[ min]
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A[ 105Æ28C]
H
U
G
E
N
N
A
H
U
G
R
N
U
G
[
c]
Conversion [%]
Conversion [%]
(
5
0
5
0
0
0
MW
conv
MW
conv
MW
conv
MW
conv
MW
conv
MW
conv
10/10
9/10
62/64
63/66/67
73/73
75/77/78
>99/>99
>99/>99
be heated to 2008C and the reaction mixture is pumped
1
1
2
3
4
43/44/46
42/42/48
through the cartridge using HPLC pumps at flow rates of
À1
[35]
0.1 to 3.0 mLmin and pressures of up to 150 bar.
Our flow experiments commenced with the optimization
of temperature, pressure, and flow rate for the Mizoroki–
Heck reaction of aryl iodide 1a and butyl acrylate (2)
(Scheme 1). Applying the exact same reaction composition
as processed in the batch experiments (0.65 mmol 1a in
mL MeCN, see above), full conversion based on consump-
tion of aryl iodide 1a was achieved at 1508C at a
.5 mLmin flow rate (20 bar set pressure). Lower temper-
60/63/64
59/61/68
79/81/82
78/81/87
84
1
86
[
a] Aryl iodide 1a (0.65 mmol), butyl acrylate (2; 1.5 equiv), Et
3
N
À1
0
(
1.5 equiv), MeCN (1 mL), Pd/C catalyst (E104CA/W 5% Pd;
atures and/or higher flow rates led to incomplete conver-
sions (see Table 2, entries 4, 5, and 7; see also Figure S4 in
the Supporting Information). Based on the measured dead
volume of about 300 mL of the filled catalyst cartridge (60ꢂ
0
.4 mol%). Microwave experiments were carried out by using a CEM
Discover system with a 10 mL fiber-optic probe set-up. Conventionally
heated experiments were performed in a pre-heated oil bath selecting an
appropriate bath temperature (see Figure S3 in the Supporting Informa-
tion). For further information see the Experimental Section. [b] Internal
reaction temperature measured by fiber-optic sensor. [c] Determined by
GC-FID analysis (peak area% of cinnamic ester 3). Entries reflect multi-
ple experiments.
4
mm i.d., 310 mg of Pd/C), a residence time over the cata-
lyst of approximately 30 s can be calculated applying a
À1
0.5 mLmin flow rate (the residence time in the complete
X-Cube system is ca. 8 min at this flow rate). We were sur-
prised to find, however, that the Mizoroki–Heck reactions
under flow conditions produced significantly more byprod-
ucts as compared to the batch experiments described above
(Table 2, compare entries 2 and 3). Under optimized condi-
tions for full conversion (1508C, 0.5 mLmin flow rate) the
formation of 7% dehalogenated side product (benzonitrile)
and 9% homocoupling product (4,4’-dicyanobiphenyl) was
[
29]
butyl acrylate (2).
Under “simultaneous cooling” condi-
tions, the reaction vessel is cooled from the outside by com-
pressed air, while being irradiated by microwaves. This
allows a higher level of microwave power to be directly ad-
ministered to the reaction mixture thereby potentially en-
hancing any specific microwave effects that are dependent
À1
[8,11,22,30,31]
on the electric field strength.
By monitoring inter-
nal reaction temperatures using fiber-optic probes and care-
fully adjusting the temperature and/or flow of the external
cooling gas, experiments can be performed in which for a
constant bulk reaction temperature distinctly different mi-
crowave power levels can be applied. For the Mizoroki–
Heck coupling of aryl iodide 1a with butyl acrylate (2) at
Table 2. Selectivities in the Pd/C-mediated Mizoroki–Heck coupling of
aryl iodide 1a with butyl acrylate (2) under batch and flow conditions
[
a]
(
Scheme 1).
Conditions
T
Flow rate
Conversion Selectivity
À1
[b]
[c]
[
8C]
A[ mLmin
H
U
G
R
N
N
]
[%]
P/D/H [%]
1
2
3
4
5
6
7
8
9
0
batch
batch
flow
flow
flow
flow
flow
batch
flow
flow
130/5 min
150/2 min
150
150
150
130
170
130/5 min
130
130
–
–
>99
>99
>99
93
43
98
>99
>99
>99
>99
95/3/2
96/<1/3
84/7/9
78/9/13
81/8/11
80/10/10
81/9/10
78/22/<1
84/12/4
0/19/73
1058C (10 min) a considerable higher amount of microwave
power was applied with cooling to reach and maintain the
same bulk temperature (80 W versus 32 W average power,
see Figure S2 in the Supporting Information). However, the
result both in terms of conversion and selectivity was virtu-
ally identical to the noncooled run (61% GC-FID conver-
sion). Although Pd/C itself is a strongly microwave absorb-
0.5
1.0
2.0
0.2
0.5
–
[d]
e]
[f]
[
0.2
0.2
[21]
1
ing material when irradiated under suitable conditions, for
the actual Mizoroki–Heck reaction mixtures containing sev-
eral other microwave-absorbing components (acetonitrile,
triethylamine, acrylic ester), an effect derived from selective
[a] Aryl iodide 1a (0.65 mmol), butyl acrylate (2; 1.5 equiv), Et
3
N
(
1.5 equiv), MeCN (1 mL), Pd/C catalyst (E104CA/W 5% Pd; 6.5 mg for
batch, 310 mg for flow experiments, see text for details). Batch experi-
ments were carried out by using either a CEM Discover system (entries 1
and 2) or in a pre-heated oil bath (entry 9). Flow experimentation
[32]
heating of the Pd/C catalyst could not observed.
(
20 bar) was performed in an X-Cube reactor. For further information
Continuous-flow processing by using a heterogeneous Pd
catalyst: Since for the Mizoroki–Heck couplings shown in
Scheme 1 no specific microwave effects could be observed,
our continuous-flow experiments therefore focused on the
use of a conventionally heated flow reactor (as opposed to
see the Experimental Section. [b] Determined by GC-FID (peak
area%). [c] Ratio determined by GC-FID (peak area%). P=cinnamic
ester product 3a, D=dehalogenated byproduct (benzonitrile) , H=ho-
mocoupling byproduct (4,4’-dicyanobiphenyl). [d] 310 mg Pd/C catalyst.
Experiment performed by conventional heating. [e] 2.0 equiv of butyl ac-
rylate. [f] 0.0 equiv of butyl acrylate.
Chem. Eur. J. 2009, 15, 1001 – 1010
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www.chemeurj.org
1003

C. O. Kappe et al.
detected by GC-FID analysis. In a preparative experiment
from a flow experiment in the X-Cube performed at room
the isolated yield of cinnamic ester 3a was reduced to 75%
temperature (at which no CÀC coupling occurs) did indeed
(
96% in batch), and along with the desired product, 10% of
,4’-dicyanobiphenyl was isolated (3% in batch). By using
indicate a chromatographic separation of the reaction mix-
ture as the first fractions eluting from the system contained
4
MeCN as solvent and Et N as base, the formation of these
only Et N and butyl acrylate (2) as monitored by GC-FID
3
3
byproducts could not be suppressed or even significantly in-
fluenced by variation of reaction temperature, pressure, or
flow rate (see Table 2 and Figure S5 in the Supporting Infor-
mation). The use of alternative solvents, such as EtOH,
NMP, DMF, or DMA, was also not successful.
analysis (see Table S1 in the Supporting Information). Ap-
parently, aryl iodide 1a is stronger retained/adsorbed on the
charcoal phase, compared to butyl acrylate.
Of key importance in any homogeneous or heterogeneous
transition-metal-catalyzed process on a preparative scale is
the amount of metal catalyst that remains in the product. In
this context, we performed ICP-MS trace analyses for Pd in
the cinnamic ester products obtained from batch and contin-
uous-flow experiments. Analysis of the crude cinnamic ester
derived from the preparative-flow experiment described in
Table 2, entry 3 (0.65 mmol 1a, 1 mL MeCN) revealed the
presence of substantial amounts of Pd in the processed reac-
tion mixture (ca 300 mg), corresponding to a calculated Pd
We ascribe the increased formation of the dehalogenated
and homocoupling byproducts under flow conditions to the
fact that the catalyst quantity in the flow experiments using
the X-Cube is significantly higher than in the batch environ-
ment for processing the same amount (0.65 mmol) of start-
[37]
ing materials (310 mg versus 6.5 mg Pd/C). The fact that
higher catalyst loadings will often lead to increased byprod-
uct formation (dehalogenation, homocoupling) in Mizoroki–
Heck reactions has been observed previously (see also
below), and may be explained by the high concentration of
[40]
leaching from the catalyst cartridge of ca. 2.5%. Notably,
ICP-MS analysis of the cinnamic ester resulting from the
corresponding batch experiment (Table 2, entry 2) per-
formed on an identical scale—after hot filtration from the
Pd/C catalyst—showed significantly lower amounts of Pd
contamination (17 mg). This discrepancy is not surprising
given the much lower amount of Pd/C catalyst employed in
the batch experiment (6.5 versus 310 mg).
II
ArPd species in solution and the therefore increased ratio
II
[38]
of ArPd /olefin. Alternatively, previous studies have sug-
gested that the increased formation of dehalogenated side
products in Mizoroki–Heck transformations involving a het-
erogeneous Pd catalyst such as Pd/C is connected to mecha-
nisms involving the surface of solid Pd metal particles and/
[39]
or radical processes. Whatever the reason, a control ex-
periment with 300 mg of Pd/C (18 mol%) for the Mizoroki–
Heck reaction of aryl iodide 1a and butyl acrylate (2) in
batch mode led to the formation of 22% dehalogenated
benzonitrile product. In direct comparison, the batch experi-
ment with 6.5 mg Pd/C (0.4 mol%) only furnished a trace
amount of dehalogenated product (Table 2, compare en-
tries 1 and 8).
Surprisingly, however, the batch experiment with high cat-
alyst loading did not lead to significant amounts of homo-
coupling product as seen in the flow processing mode in the
X-Cube. In this context it is tempting to speculate that pass-
ing a reaction mixture under pressure through a cylindrical
cartridge densely packed with high-surface-area material
To investigate the amount of Pd leaching from the Pd/C
catalyst cartridge in the X-Cube in more detail we per-
formed a preparative Mizoroki–Heck coupling using the op-
timized conditions (Table 2, entry 3) starting from a stock
solution containing aryl iodide substrate 1a (20 mmol) and
MeCN (30 mL) as solvent (ca. 40 mL total reaction
volume). The conversion and product composition were
constantly monitored by GC-FID collecting 12 fractions of
about 3.5 mL volume. For the first six fractions (10 mmol
substrate) full conversion under the reaction conditions was
maintained. From the seventh fraction onwards the conver-
sion started to drop continuously, ultimately reaching only
24% in the 12th and last fraction (Table S2 in the Support-
ing Information). The degree of conversion in this experi-
ment is clearly related to Pd leaching from the catalyst car-
tridge, since ICP-MS analysis of the material contained in
the used cartridge confirmed that 89% of Pd had leached
from the Pd/C catalyst, comparing ICP-MS data obtained
(
here Pd/C) can induce a chromatographic separation of the
reaction mixture, similar to a flash chromatography experi-
ment. For the Mizoroki–Heck reaction mixture (Scheme 1)
this may lead to a local depletion of, for example, the acry-
late component in the catalyst cartridge, thus leading to an
increased formation of aryl iodide homocoupling product.
To substantiate this hypothesis a set of control experiments
under flow conditions were conducted. Applying flow condi-
tions that provide a high degree of selectivity for the forma-
[40]
from the fresh
and used cartridges. The substantial Pd
leaching from the cartridge was also evident by inspecting
the fraction collection vials kept overnight from similar
runs, which showed a distinct Pd mirror (Figure S6, Support-
ing Information).
tion of the desired cinnamic ester 3a (e.g., 1308C,
In this context, the question must be addressed as to
whether the Mizoroki–Heck reactions shown in Scheme 1
using Pd/C as a catalyst involve catalysis on solid surfaces or
soluble Pd species (homogeneous versus heterogeneous cat-
alysis). There is substantial evidence in the literature that
transition-metal-catalyzed coupling reactions with Pd/C as a
catalyst (in particular for the Mizoroki–Heck reaction) do in
À1
0.2 mLmin ) an increase in the stoichiometry of butyl acry-
late from 1.5 to 2.0 equivalents led to a decrease in the yield
of homocoupling product (Table 2, compare entries 6 and
9). Conversely, elimination of the acrylate building block
from the reaction mixture mainly provided the homocou-
pling product (73%) along with dehalogenated byproduct
[41,42]
(
Table 2, entry 10). Importantly, collecting small fractions
fact involve homogeneous Pd species.
The insoluble Pd/
1004
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Palladium Catalysts
FULL PAPER
C catalyst acts as a reservoir of soluble, active Pd species,
generated under the reaction conditions by chemical interac-
tion of the catalyst with one or more of the components of
Pd/C catalyst only occurred for runs that included aryl
iodide 1a and Et N base (entries 6 and 8). Reaction mix-
3
tures that contained solvent, Et N and the acrylate building
3
[41,42]
the liquid phase.
For the catalyst used in this investiga-
block 2 showed some background leaching (<10 mg Pd, en-
tries 1, 2, 3, and 5), while a somewhat higher degree of
leaching was obtained for mixtures that contained aryl
tion (E104CA/W 5% Pd), extensive studies by Kçhler and
co-workers have indicated that in Mizoroki–Heck reactions
a quasihomogeneous reaction mechanism involving soluble
Pd species and a dissolution/re-adsorption mechanism is in
iodide 1a, but no Et N base (<50 mg Pd entries 4 and 7). In
3
contrast, strikingly high levels of Pd were found for the full
Mizoroki–Heck reaction mixture leading to cinnamic ester
3a (entry 8) and for the mixture missing the acrylate compo-
nent (entry 6). In the latter case the homocoupling product
4,4’-dicyanobiphenyl is obtained in high yields (see Table 2,
[
27]
operation.
species in the coupling of aryl iodide 1a with butyl acrylate
To confirm the involvement of a soluble Pd
[43]
(
2), we performed a three-phase test experiment
using
polystyrene-bound acrylate 4 as a precursor (Scheme 2).
Using reaction conditions (nonoptimized) similar to the ex-
periment in the solution phase (Table 2, entry 1), the corre-
entry 10). The critical role of the Et N base is clearly evident
3
comparing entries 4 and 6.
[21]
sponding cinnamic acid 5 was isolated in 47% yield after
The results obtained in the studies described herein are in
good agreement with the currently accepted mechanistic
theories involving Mizoroki–Heck reactions catalyzed by
acidic cleavage from the resin.
[27,41,42]
Pd/C.
Catalysis essentially proceeds through dissolu-
tion/re-adsorption of Pd from the support, the Pd concentra-
tion in solution being the highest at the beginning of the re-
[27]
action. The mechanism is quasi-homogeneous with small
0
Pd species (colloids/nanoparticles) in solution acting as the
[41,42]
catalytically active species.
Presumably, the heterogene-
Scheme 2. Mizoroki–Heck couplings with polymer-supported acrylate
(
three-phase test).
ous Pd catalyst is initially solubilized by oxidative addition
of the aryl halide and enters the catalytic cycle in the form
[41,42]
of soluble Pd species.
As already mentioned above, for
Based on the leaching studies described above it occurred
aryl bromide 1b the Mizoroki–Heck reaction with butyl ac-
rylate 2 is significantly slower relative to aryl iodide 1a, re-
quiring extended reaction times (20–30 min) and consider-
to us that flow processing in combination with Pd trace anal-
ysis presents an unique opportunity to investigate mechanis-
tic aspects of transition-metal-catalyzed transformations. In
the experiments described in Table 3 we have determined
the leaching of Pd from a standard X-Cube catalyst car-
tridge (310 mg Pd/C) during the Mizoroki–Heck coupling of
aryl iodide 1a with butyl acrylate (2) under optimized flow
conditions (Table 2, entry 3). Keeping temperature, pressure,
and flow rate constant, the only changes made were related
to the composition of the reaction mixture processed
through the catalyst cartridge. As can be seen from the ICP-
MS data presented in Table 3, significant leaching from the
AHCTUNGTRENNUNGa bly higher temperatures (1808C) in the batch experiments
(Scheme 1, Table 1). Even under these forcing conditions
(0.4 mol% Pd), full conversion could not be achieved. Only
[28]
by using TBAB as an additive (“Jeffrey conditions”),
complete conversion, high selectivity for carbon–carbon
coupling (>98%) and a high isolated product yield of cin-
namic ester 3b (93%) was obtained (1808C, 30 min,
0.4 mol% Pd/C). Since for aryl bromides oxidative addition
[1,2]
is slower as compared to aryl iodides,
Pd colloids/nano-
particles can accumulate over time which ultimately leads to
[41,42]
the formation of Pd black of low catalytic activity.
TBAB has been demonstrated to stabilize Pd nanoparticles
through electrostatic stabilization by the bromide anion and
Table 3. Leaching of Pd from Pd/C catalyst for the Mizoroki–Heck cou-
pling of aryl iodide 1a with butyl acrylate (2) under X-Cube flow condi-
tions (Scheme 1).
steric stabilization by the tetrabutylammonium cation, there-
[
a]
[41,42]
fore preventing the formation of Pd black.
Under con-
[
b]
Reaction mixture composition
MeCN
Leaching [mg Pd]
tinuous-flow conditions in the X-Cube the residence time of
the reaction mixture in the heated catalyst cartridge (60ꢂ
1
2
3
4
5
6
7
8
1.6
4.8
MeCN/Et
3
N
4
mm i.d.) apparently is too short to allow the efficient cou-
MeCN/2
MeCN/1a
MeCN/Et
MeCN/Et
MeCN/1a/2
MeCN/Et N/1a/2
1.0
17.2
7.2
1370
46
220
pling of aryl bromide 1b with butyl acrylate (2) under any
set of available reaction conditions. At 1808C and
3
N/2
N/1a
À1
0.5 mLmin flow rate (ca. 30 s residence time) a conversion
3
of about 50% was obtained, with poor selectivity for the
cinnamic ester product (13% by GC-FID).
3
[
a] Complete reaction mixture composition: Aryl iodide 1a (0.65 mmol),
butyl acrylate (2; 1.5 equiv), Et N (1.5 equiv), MeCN (1 mL), Pd/C cata-
3
Continuous-flow processing with a homogeneous Pd preca-
talyst: At this stage it became apparent that performing the
Mizoroki–Heck reactions shown in Scheme 1 in a continu-
ous-flow reactor with immobilized Pd/C in a pre-packed cat-
lyst in cartridge (E104CA/W 5% Pd; 310 mg). Conditions: 1508C,
À1
2
0 bar, 0.5 mLmin flow rate. A fresh cartridge was used for every run.
See the Supporting Information for details. [b] Determined by ICP-MS
analysis of the product contained in a 4 mL fraction.
Chem. Eur. J. 2009, 15, 1001 – 1010
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1005

C. O. Kappe et al.
alyst cartridge was not a viable strategy, mainly because of
Pd leaching and the comparatively short residence times
possible in the X-Cube flow reactor, in which only the cata-
lyst cartridge is heated. Continuous-flow processing with the
specific Pd/C preparation optimized by Kçhler et al. for
quired when using Pd/C (see above). In line with previous
studies on ligand-free Mizoroki–Heck transformations with
[48]
low Pd loadings (“homeopathic doses”), we were able to
reduce the Pd level down to 0.01 mol% (Table 4). Although
the reduction of Pd catalyst loading resulted in the require-
ment of a prolonged reaction time in order to achieve full
conversion (25 min versus 2 min at 1508C), gratifyingly the
selectivity for coupling was appreciably increased, leading to
less dehalogenation and homocoupling byproducts (compare
entries 1, 2, and 3). To regain the advantages of a fast reac-
tion, the temperature ultimately was increased to 1708C
(10 bar). Under these newly optimized batch conditions
(0.01 mol% Pd, 1708C) full conversion with near perfect se-
lectivity for Mizoroki–Heck coupling was obtained after
10 min reaction time (entry 8), and resulted in a 96% isolat-
ed product yield of cinnamic ester 3a. The increase in selec-
tivity on going to lower catalyst loadings is in good agree-
ment with the experiments described above employing Pd/C
as a Pd source. As demonstrated in Table 2 (entry 8), raising
the amount of Pd/C to 18 mol% resulted in a dramatic in-
crease in dehalogenation byproduct (22%). It was also pos-
sible to lower the amount of Pd catalyst further to
0.001 mol% and still obtain full conversion coupled with
perfect selectivity, but this required increasing the tempera-
ture to 1908C (12 bar) and extending the reaction time to
[27]
Mizoroki–Heck chemistry as a solid catalyst therefore ap-
pears to be unsuitable for coupling reactions that proceed
by the above mentioned dissolution/re-precipitation path-
way, since under flow conditions the active Pd catalyst will
be leached and transported away from the support, there-
fore constantly reducing the activity of the Pd/C catalyst
[44,45]
and contaminating the product with the metal.
In a con-
ventional batch experiment the Pd will also be leached, but
at the end of the reaction is likely to be redeposited on the
[27]
support. This may provide for a high degree of precious
metal recovery from the reaction mixture, which is of partic-
[4]
ular importance working on an industrial scale.
Since we have demonstrated that the Mizoroki–Heck
transformations described above using Pd/C as a catalyst in-
volve a homogeneous mechanism, we next employed Pd-
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) as a direct soluble Pd source, allowing a far better
2
control of the amount of Pd metal entering the catalytic
cycle. For this purpose, the coupling experiments involving
aryl iodide 1a and butyl acrylate (2; Scheme 1) at 1508C
[46,47]
were reoptimized under batch microwave conditions
employing different concentrations of Pd(OAc) (Table 4).
5
À1
A
H
U
G
R
N
U
G
15 min (TON=10 , TOF 6667 min ; entry 9). Notably, full
conversion under these conditions was only achievable in
the presence of 10 mol% of TBAB, providing improved sta-
bility for the presumably formed Pd colloids/nanoparticles
2
Apart from changing the Pd source, the composition of the
reaction mixture and general conditions were identical. It
was quickly established that the amount of Pd-metal catalyst
necessary source could be reduced significantly by using a
homogeneous Pd compared to the quantity (0.4 mol%) re-
[28,48]
(“Jeffrey conditions”).
To ensure that the results shown in Table 4 obtained by
microwave dielectric heating
were reproducible by conven-
Table 4. Selectivities in the Mizoroki–Heck coupling of aryl iodide 1a with butyl acrylate (2) under batch and
flow conditions using Pd ACHTUNGTRENNUNG( OAc) as Pd source.
2
tional autoclave technology, a
control experiment was per-
formed in an oil bath by using
the experimental setup de-
scribed in Table 1. Conducting
the Mizoroki–Heck coupling
with 0.01 mol% Pd at 1508C
for 25 min in an oil bath pro-
duced the same result com-
pared to the analogous experi-
ment run with microwave heat-
ing (compare Table 4, entries 6
and 10). The optimized batch
conditions were then translated
to a flow protocol by using the
[
a]
Conditions
Pd
A
H
U
G
R
N
U
(OAc)
2
T [8C]/t [min]
Flow rate
Conversion
[%]
Selectivity
P/D/H [%]
À1
[b]
[c]
A
H
U
G
R
N
U
G
A[ mLmin
H
U
G
R
N
U
G
]
1
2
3
4
5
6
7
8
9
0
1
batch
batch
batch
batch
batch
batch
batch
batch
batch
batch
flow
0.4
0.1
150/2
150/2
150/5
150/10
150/20
150/25
170/5
170/10
190/15
150/25
170
–
–
–
–
–
–
–
–
>99
>99
>99
63
95
>99
87
>99
>99
>99
99
89/5/6
93/2/5
98/1/1
0.05
0.01
0.01
0.01
0.01
0.01
0.001
0.01
0.01
99/<1/0
99/<1/0
99/<1/0
99/<1/0
99/<1/0
99/<1/0
99/<1/0
99/<1/<1
[
[
d]
g]
[e]
–
–
0.4
[36]
[
f]
X-Cube Flash reactor.
Simi-
1
1
lar to the X-Cube system, the
X-Cube Flash is a high-temper-
[
3 2
a] Aryl iodide 1a (0.65 mmol), butyl acrylate (2; 1.5 equiv), Et N (1.5 equiv), MeCN (1 mL), Pd ACHTGUNTERNUN(G OAc)
(
0.001–0.4 mol%). Batch experiments were carried out by using a CEM Discover system with internal fiber- ature, high-pressure flow unit
optic probe temperature measurement. Flow experimentation (70 bar) was performed in an X-Cube Flash re- (maximum conditions 3508C,
actor with a 4 mL stainless steel coil. For further information see the Experimental Section. [b] Determined by
2
00 bar) that can be used for
GC-FID (peak area%). [c] Ratio determined by GC-FID (peak area%). P=cinnamic ester product 3a, D=
dehalogenated byproduct (benzonitrile) , H=homocoupling byproduct (4,4’-dicyanobiphenyl). [d] 96% isolat-
ed product yield. [e] In the presence of 10 mol% TBAB. [f] Experiment performed by conventional heating,
see Table 1 one for details. [g] 94% isolated product yield.
processing homogeneous reac-
tion mixtures.
the X-Cube in which the reac-
[36]
In contrast to
1006
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ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1001 – 1010

Palladium Catalysts
FULL PAPER
tion mixture is passed through a heated stainless steel car-
tridge filled, for example, with an immobilized catalyst, the
X-Cube Flash reactor uses stainless steel coils (i.d. 1.0 mm)
of variable length (4, 8, and 16 mL total dead volume) that
can be heated across their full length to temperatures up to
option when considering the scale-up of Mizoroki–Heck re-
actions of this type. Both flow experiments provided nearly
identical results as obtained in the batch experiment in
terms of selectivity (>99%) and isolated product yields of
3b (ca. 91%). Using a homogeneous Pd precatalyst in con-
trolled quantities (here 0.01 mol%), the issue of Pd leaching
is not a concern and small residual amounts of Pd can easily
be removed by in-line flow purification by employing suit-
3508C. This allows for significantly higher residence times in
the system as compared to the X-Cube, in which only the
relatively short catalyst cartridge possessing a small dead
volume (typically ca. 300 mL) is heated.
[44,49]
AHCTUNGERTNNUNGa ble scavenger resins.
Gratifyingly, passing the Mizoroki–Heck reaction mixture
through the X-Cube Flash system employing the 4 mL stain-
À1
less steel coil at a 0.4 mLmin flow rate (10 min residence
Conclusion
time) provided full conversion at a measured coil tempera-
ture of 1708C (Table 4, entry 11). Lower temperatures and/
or higher flow rates led to incomplete conversions. The
same high level of selectivity for Mizoroki–Heck coupling as
in the batch microwave experiments was obtained, produc-
ing a 94% isolated product yield of cinnamic ester 3a after
purification by flash chromatography. It should be noted
that the required reaction time of 10 min in the batch runs
corresponds nicely to the calculated residence time of
In summary, we have demonstrated that Mizoroki–Heck re-
actions of both aryl iodides and bromides with an acrylate
building block can be successfully performed under continu-
ous-flow conditions by using ligandless Pd catalysts. Since
employing immobilized Pd/C as heterogeneous catalyst
under flow processing leads to significant leaching of the Pd
metal from the support, the use of a homogeneous precata-
lyst in controlled quantities is the preferred option. By using
10 min in the flow experiment (compare entries 8 and 11).
0.01 mol% of Pd AHCTUNGERTNNUNG( OAc) as a precatalyst, full conversion
2
The residence time in the flow experiments can be easily in-
creased by selecting a longer flow coil. This allows the use
of higher flow rates and therefore increases the throughput
combined with high selectivity for Mizoroki–Heck couplings
was obtained under flow conditions for both aryl iodides
and aryl bromides. At the comparatively high reaction tem-
peratures applied in the high-pressure flow reactor (170–
2008C), the homogeneous Pd precatalyst rapidly converts
into Pd colloids/nanoparticles with high catalytic activity
that can additionally be stabilized by a phase-transfer cata-
lyst such as TBAB. Flow processing under these conditions
results in a easily scalable method for performing Mizoroki–
Heck couplings. Although no specific or nonthermal micro-
wave effects were observed for the coupling reactions inves-
tigated, batch microwave processing has proven helpful in
effectively optimizing conditions for subsequent flow pro-
(
see below).
Finally, we investigated the possibility to perform
ACHTUNGTRENNUNGM izoroki–Heck reactions of aryl bromide 1b with butyl ac-
rylate (2) under continuous-flow conditions. As mentioned
above, for aryl bromide 1b the Mizoroki–Heck reaction is
significantly slower as compared to aryl iodide 1a, requiring
extended reaction times and considerably higher tempera-
tures in the batch experiments with Pd/C (Scheme 1,
Table 1). A rapid re-optimization with Pd ACHTUNGTERNN(UNG OAc) as source
2
of Pd demonstrated that full conversion with complete se-
lectivity for cinnamic ester 3b (>99%) was readily achiev-
ACHTUNGTRENNUNG
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
able within 30 min at 1808C (12 bar) or within 16 min at
2
008C (15 bar) by using 0.01 mol% Pd(OAc) in combina-
ACHTUNGTRENNUNG
2
tion with 10 mol% TBAB. Small amounts of tributylamine
as a result of an Hofmann elimination from TBAB at those
high temperatures were identified by GC-MS, but this did
Experimental Section
not influence the
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
Mizoroki–Heck coupling. We noticed,
1
General remarks: H NMR spectra were recorded on a Bruker 360 MHz
however, that in contrast to the Mizoroki–Heck reactions in-
volving aryl iodide 1a, a solid precipitate was formed at the
end of the reaction. Since heterogeneous reaction condi-
tions/precipitates are a major concern in continuous-flow
instrument. Low-resolution mass spectra were obtained on an Agilent
1100 LC/MS instrument by using atmospheric pressure chemical ioniza-
tion (APCI) in positive or negative mode. Analytical HPLC analysis was
carried out on a Shimadzu LC-10 system using a LiChrospher 100 C18
reversed-phase analytical column (119ꢂ3 mm, 5 mm particle size) at
[33]
processing this issue needed to be addressed before start-
2
58C, by using mobile phase A (water/MeCN 9:1 (v/v)+0.1% TFA) and
phase B (MeCN+0.1% TFA), with linear gradient from 30% B to
00% B in 8 min and 2 min with 100% phase B. GC-FID analysis was
ing flow experiments. The precipitate was identified as Et N
3
1
hydrobromide and changing the base from Et N to diisopro-
3
performed on a Trace-GC (ThermoFisher) with a flame ionization detec-
pylethylamine (DIEA) eliminated the problem of precipita-
tion without effecting conversion or selectivity. Translation
of the 2008C/16 min batch reaction conditions to flow pro-
tor using a HP5 column (30 mꢂ0.250 mmꢂ0.025 mm). After 1 min at
À1
5
08C the temperature was increased in 258Cmin steps up to 3008C and
kept at 3008C for 4 min. The detector gas for the flame ionization is H2
and compressed air (5.0 quality). Pd was determined at m/z 105 with an
Agilent 7500ce inductively coupled plasma mass spectrometer (ICP-MS)
from Agilent Technologies. The sample was dispatched from the auto-
sampler through an integrated sample introduction system (ISIS) from
Agilent Technologies to an Ari Mist HP nebulizer (Burgener Research
International) and further into the ICP-MS. Calibration was performed
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
cessing was possible in the X-Cube Flash by using either the
À1
8
mL stainless steel coil applying a 0.5 mLmin flow rate,
À1
or the 16 mL coil at a flow rate of 1.0 mLmin (16 min resi-
dence time for both cases). As a higher flow rate will lead
to an increased throughput, the latter setup is the preferred
Chem. Eur. J. 2009, 15, 1001 – 1010
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1007

C. O. Kappe et al.
3
3
with external calibration curves established from a standard 1.000 g Pd/L
CPI International). Microwave irradiation experiments were carried out
in a CEM Discover instrument with appropriate internal fiber-optic tem-
16 Hz, 1H; CH), 7.50 (t,
16 Hz, 1H; CH), 7.65 (d,
J
J
A
H
U
G
R
N
U
G
J
J
ACHTUNGTRENNUNG( H,H)=
ACHTUNGTRENNUNG( H,H)=
3
3
(
8 Hz, 2H; CH), 7.78 ppm (s, 1H; CH); MS (pos-APCI): m/z (%): 230
(100) [M+1].
[
29]
perature control. Flow experiments were performed either on an X-
Cube instrument, with 5% Pd/C (Degussa-type, E 104 CA/W 5% Pd)
CatCart cartridge or on a X-Cube Flash instrument equipped with a stan-
Method B—with Pd
A
H
U
G
R
N
U
G
2
as precatalyst: 3-Bromobenzonitrile (1a;
(0.01 mol%, from a 2.7 mm stock solution
0
.65 mmol, 120 mg), Pd
A
H
U
G
E
N
N
[
35,36]
dard 4, 8, or 16 mL heated stainless steel coil.
separations were performed on a Biotage SP1 instrument using petro-
leum ether/ethyl acetate mixtures as eluent. All products synthesized in
Flash chromatography
in MeCN), n-butyl acrylate (2; 0.98 mmol, 1.50 equiv, 142 mL), tetrabuty-
lammonium bromide (0.065 mmol, 10 mol%, 21 mg), and triethylamine
0.98 mmol, 1.5 equiv, 137 mL) were mixed together in that sequence with
MeCN (1 mL) in a 10 mL Pyrex glass microwave vial containing a mag-
netic stir bar and were stirred for 20 s. The vial was sealed tight by using
the CEM Discover pressure/fiber-optic attenuator and heated by micro-
wave irradiation at 1808C for 30 min. After cooling the vessel to ambient
conditions by compressed air, the crude reaction mixture was analyzed
by GC-FID. Product isolation (139 mg, 92%) was performed as described
above (Method A).
ACHTUNGTRENNUNG
(
this study are known in the literature and have been characterized by
1
H NMR spectroscopy and MS analysis. Pd/C (E 104 CA/W 5% Pd) was
obtained from Aldrich Chem. Co (Catalog no. 643181-10G) and used as
À1
received. REM acrylate resin 4 (50–100 mesh, loading 1.1 mmolg ) was
obtained from NOVABiochem (Catalog no. A35565811) and used as re-
ceived. All other chemicals were obtained from Aldrich or Alfa Aesar
and were used as received. HPLC-grade acetonitrile was used in all mi-
crowave and flow experiments.
Three-phase test (Scheme 2): 4-Iodobenzonitrile (1a; 0.22 mmol, 2 equiv,
1 mg), Pd/C (0.0035 mmol, 3 mol%, 8 mg 5% Pd/C (20% H O)), and
2
triethylamine (0.22 mmol, 31 mL) were mixed together with DMF/MeCN
(1:1 mixture, 1 mL) in a 10 mL Pyrex glass microwave vial containing a
magnetic stir bar and stirred for 20 s. Thereafter pre-swollen REM acry-
Mizoroki–Heck coupling of aryl iodide (1a) with butyl acrylate (2) under
batch microwave conditions (Scheme 1)
5
Method A—with Pd/C as catalyst: 4-Iodobenzonitrile (1a; 0.65 mmol,
1
50 mg), Pd/C (0.0029 mmol, 0.4 mol%, 6.5 mg 5% Pd/C (20% H
n-butyl acrylate (2; 0.98 mmol, 1.50 equiv, 142 mL), and triethylamine
0.98 mmol, 1.5 equiv, 137 mL) were mixed together in that sequence with
2
O)),
late resin (100 mg, 1.1 mmolg loading) was added and the reaction mix-
(
ture was again stirred for 20 s. The vial was sealed tight by using the
CEM Discover pressure/fiber-optic attenuator and heated by microwave
irradiation at 1308C for 15 min. After cooling the vessel to ambient con-
ditions by compressed air, the reaction mixture was filtered and the resi-
due was washed with DMF/MeCN (1:1 mixture, 2ꢂ5 mL) followed by
MeOH (2ꢂ5 mL), and CH Cl (2ꢂ10 mL). The recovered resin was sub-
MeCN (1 mL) in a 10 mL Pyrex microwave vial containing a magnetic
stir bar and were stirred for 20 s. The vial was sealed tight by using the
CEM Discover pressure/fiber-optic attenuator and heated by microwave
irradiation at 1508C for 2 min (fiber-optic temperature control, time
refers to hold time at 1508C). After cooling the vessel to ambient condi-
tions by compressed air, the crude reaction mixture was transferred to a
silica-samplet, was dried for 2 h at 708C in a drying oven, and was sub-
jected to automated flash chromatography with petroleum ether/ethyl
acetate (0 to 45% gradient) as eluent to provide 144 mg (96%) of butyl
2
sequently transferred to a round bottom flask, containing a mixture of
TFA/CH Cl (10 mL of 20% v/v) and gently stirred for 2 h to cleave the
formed cinnamic acid from the resin. The resin was then filtered off and
washed with CH Cl (2ꢂ5 mL) followed by MeOH (2ꢂ5 mL). The fil-
2
2
2
2
3
-(4-cyanophenyl)acrylate (3a). M.p. 42–448C, lit. [50] m.p. 43–468C;
trate and the washings were combined and the solvent removed under re-
duced pressure to result in 9 mg (47%) of 3-(4-cyanophenyl)acrylic acid
1
3
H NMR (360 MHz, [D
H; CH ), 1.38–1.48 (m, 2H; CH
(H,H)=7 Hz, 2H; CH
(H,H)=16 Hz, 1H; CH), 7.60 (d, J
1
]CHCl
3
, 258C, TMS): d=0.96 (t, J
A
H
U
G
R
N
N
(H,H)=7 Hz,
3
1
3
3
2
3
), 1.65–1.73 (m, 2H; CH
2
), 4.22 (t, J-
(5). M.p. 257–2598C; lit.[21] m.p. 255–2608C; H NMR (360 MHz, [D ]
6
3
3
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
), 6.51 (d, J
A( H,H)=16 Hz, 1H; CH), 7.65 (d, J-
H
U
G
E
N
N
DMSO, 258C, TMS): d=6.70 (d,
J AHCTUNGTRENNUN(G H,H)=16 Hz, 1H; CH), 7.64 (d, J-
3
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
H
U
G
R
N
U
G
ACHTUNGTR(NENNUG H,H)=16 Hz, 1H; CH), 7.86–7.91 (m, 4H; CH), 12.64 ppm (s, 1H;
3
J
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
OH); MS (pos-APCI): m/z (%): 174 (100) [M+1].
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
Mizoroki–Heck coupling of aryl iodide (1a) with butyl acrylate (2) under
continuous-flow conditions (X Cube Flash) (Table 4, Entry 11): 4-Iodo-
benzonitrile (1a; 150 mg, 0.65 mmol), n-butyl acrylate (2; 126 mg,
(
A
H
U
G
E
N
N
2
1
2
142 mL, 0.98 mmol, 1.5 equiv), Pd ACHTUNEGRTNNUNG( OAc) (0.01 mol%, from a 2.7 mm
gether in that sequence with MeCN (1 mL) in a 10 mL Pyrex glass micro-
wave vial containing a magnetic stir bar and were stirred for 20 s. The
vial was sealed tight by using the CEM Discover pressure/fiber-optic at-
tenuator and heated by microwave irradiation at 150–2008C for 2–25 min
stock solution in MeCN, and triethylamine (100 mg, 137 mL, 0.98 mmol,
1.5 equiv) were mixed together with MeCN (1 mL) into a 5 mL glass vial
and stirred for 2 min. The X Cube Flash instrument was equipped with a
stainless steel reaction coil (4 mL volume, 10 min residence time at
À1
(
Table 4). After cooling the vessel to ambient conditions by compressed
0.4 mLmin flow rate). The reaction parameters—temperature (1708C),
À1
air, the crude reaction mixture was analyzed by GC-FID. Product isola-
tion (Table 4, entry 8) wass performed as described above (Method A).
flow rate (0.4 mLmin ), and pressure (50 bar)–-were selected on the
flow reactor and the processing was started, whereby only pure solvent
was pumped through the system until the instrument had achieved the
desired reaction parameters and stable processing was assured. At that
point the inlet tube was switched to the vial containing the freshly pre-
pared reaction mixture. After processing through the flow reactor, the
inlet tubing was dipped back into a vial with pure solvent and processed
for a further 10 min, thus washing the system from any remaining reac-
tion mixture. The processed reaction mixture was then combined with
the washings and the solvent was removed under vacuum. The residue
was dissolved in acetone (2 mL) and transferred to a silica-samplet, was
dried for 2 h at 708C in a drying oven, and was then subjected to auto-
mated flash chromatography with petroleum ether/ethyl acetate (0 to
Mizoroki–Heck coupling of aryl bromide (1b) with butyl acrylate (2)
under microwave conditions (Scheme 1)
Method A—with Pd/C as catalyst: 3-Bromobenzonitrile (1b; 0.65 mmol,
1
2
20 mg), Pd/C (0.0029 mmol, 0.4 mol%, 6.5 mg 5% Pd/C (20% H O)),
n-butyl acrylate (2; 0.98 mmol, 1.50 equiv, 142 mL), tetrabutylammonium
bromide (0.65 mmol, 1.0 equiv, 210 mg), and triethylamine (0.98 mmol,
1
.5 equiv, 137 mL) were mixed together in that sequence with MeCN
(
1 mL) in a 10 mL Pyrex glass microwave vial containing a magnetic stir
bar and were stirred for 20 s. The vial was sealed tight by using the CEM
Discover pressure/fiber-optic attenuator and heated by microwave irradi-
ation at 1808C for 30 min (fiber-optic temperature control, time refers to
hold time at 1508C). After cooling the vessel to ambient conditions by
compressed air, the crude reaction mixture was transferred to a silica-
samplet, was dried for 2 h at 708C in a drying oven, and was subjected to
automated flash chromatography with petroleum ether/ethyl acetate (0
4
5% gradient) as eluent to provide 141 mg (94%) of butyl 3-(4-cyano-
phenyl)acrylate (3b).
Mizoroki–Heck coupling of aryl bromide (1b) with butyl acrylate (2)
under continuous-flow conditions (X Cube Flash): 3-Bromobenzonitrile
to 45% gradient) as eluent to provide 141 mg (93%) of butyl 3-(3-cyano-
2
(1a; 0.65 mmol, 120 mg), Pd ACHUTNGTNERGUN( OAc) (0.01 mol%, from a 2.7 mm stock so-
1
phenyl)acrylate (3b) as a colorless oil. H NMR (360 MHz, [D
1
]CHCl
3
,
lution in MeCN), n-butyl acrylate (2; 0.98 mmol, 1.50 equiv, 142 mL), tet-
rabutylammonium bromide (0.065 mmol, 10 mol%, 21 mg), and diisopro-
pylethylamine (0.98 mmol, 1.5 equiv, 161 mL) were mixed together with
3
2
58C, TMS): d=0.96 (t,
J
A
H
U
G
R
N
N
3
), 1.38–1.48 (m, 2H;
3
CH ), 1.64–1.72 (m, 2H; CH
2
2
ACHTUNGTRNENUNG( H,H)=
1008
www.chemeurj.org
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Chem. Eur. J. 2009, 15, 1001 – 1010

Palladium Catalysts
FULL PAPER
MeCN (1 mL) in a 5 mL glass vial and stirred for 2 min. The X Cube
Flash instrument was equipped with a stainless steel reaction coil (16 mL
[4] a) D. Schils, F. Stappers, G. Solberghe, R. van Heck, M. Coppens, D.
Van den Heuvel, P. van der Donck, T. Callewaert, F. Meeussen, E.
De Bie, K. Eersels, E. Schouteden, Org. Process Res. Dev. 2008, 12,
530, and references therein; b) J. G. de Vries, Can. J. Chem. 2001,
79, 1086.
À1
volume, 16 min residence time at 1.0 mLmin flow rate). The reaction
À1
parameters—temperature (2008C), flow rate (1.0 mLmin ), and pressure
(
60 bar)—were selected on the flow reactor and the processing was start-
ed, whereby only pure solvent was pumped through the system until the
instrument had achieved the desired reaction parameters and stable pro-
ACHTUNGTRENNUNGc essing was assured. At that point the inlet tube was switched to the vial
[5] For general reviews on microwave-assisted transition-metal catalysis,
see: a) P. Appukkuttan, E. van der Eycken, Eur. J. Org. Chem. 2008,
1133; b) P. Nilsson, K. Olofsson, M. Larhed, Top. Curr. Chem. 2006,
266, 103; c) N. E. Leadbeater, Chem. Commun. 2005, 2881; d) C. O.
Kappe, Angew. Chem. 2004, 116, 6408; Angew. Chem. Int. Ed. 2004,
43, 6250; e) M. Larhed, C. Moberg, A. Hallberg, Acc. Chem. Res.
2002, 35, 717.
[6] B. Desai, C. O. Kappe, Top. Curr. Chem. 2004, 242, 177.
[7] a) M. G. Organ, S. Mayer, F. Lepifre, B. N’Zemba, Mol. Diversity
2003, 7, 211; b) G. Palmisano, W. Bonrath, L. Boffa, D. Garella, A.
Barge, G. Cravotto, Adv. Synth. Catal. 2007, 349, 2338; c) X. Xie, J.
Lu, B. Chen, J. Han, X. She, X. Pan, Tetrahedron Lett. 2004, 45, 809.
[8] R. K. Arvela, N. E. Leadbeater, Org. Lett. 2005, 7, 2101.
[9] A. Stadler, B. H. Yousefi, D. Dallinger, P. Walla, E. van der Eycken,
N. Kaval, C. O. Kappe, Org. Process Res. Dev. 2003, 7, 707.
[10] a) M. S. Pillai, A. Wali, S. Satish, US Patent 2003 100625, 2003; b) P.
He, S. J. Haswell, P. D. I. Fletcher, Appl. Catal. A 2004, 274, 111.
[11] I. R. Baxendale, C. M. Griffith-Jones, S. V. Ley, G. K. Tranmer,
Chem. Eur. J. 2006, 12, 4407.
[12] a) A. K. Sharma, J. K. Gowdahalli, S. Amin, J. Org. Chem. 2007, 72,
8987; b) J. Gil-Moltꢄ, S. Karlstrçm, C. Najera, Tetrahedron 2005, 61,
12168.
[13] C. Schmçger, T. Szuppa, A. Tied, F. Schneider, A. Stolle, B. On-
druschka, ChemSusChem 2008, 1, 339.
[14] a) G. Shore, S. Morin, M. G. Organ, Angew. Chem. 2006, 118, 2827;
Angew. Chem. Int. Ed. 2006, 45, 2761; b) E. Comer, M. G. Organ, J.
Am. Chem. Soc. 2005, 127, 8160; c) C. Valente, S. Baglione, D. Can-
dito, C. J. OꢅBrien, M. G. Organ, Chem. Commun. 2008, 735; d) G.
Shore, S. Morin, D. Mallik, M. G. Organ, Chem. Eur. J. 2008, 14,
1351.
[15] a) B. M. Choudary, S. Madhi, N. S. Chowdari, M. L. Kantam, B.
Sreedhar, J. Am. Chem. Soc. 2002, 124, 14127; b) K. Mennecke, R.
Cecilia, T. N. Glasnov, S. Gruhl, C. Vogt, A. Feldhoff, M. A. L.
Vargas, C. O. Kappe, U. Kunz, A. Kirschning, Adv. Synth. Catal.
2008, 350, 717; c) A. Barau, V. Budarin, A. Caragheorgheopol, R.
Luque, D. J. Macquarrie, A. Prelle, V. S. Teodorescu, M. Zaharescu,
containing the freshly prepared reaction mixture. After processing
through the flow reactor, the inlet tubing was dipped back into a vial
with pure solvent and processed for a further 10 min, thus washing the
system from any remaining reaction mixture. The processed reaction mix-
ture was then combined with the washings and the solvent was removed
under vacuum. The residue was dissolved in acetone (2 mL) and trans-
ferred to a silica-samplet, was dried for 2 h at 708C in a drying oven, and
was then subjected to automated flash chromatography with petroleum
ether/ethyl acetate (0 to 45% gradient) as eluent to provide 138 mg
(
91%) of butyl 3-(3-cyanophenyl)acrylate (3b).
Pd leaching studies (ICP-MS): 4-Iodobenzonitrile (1a; 0.65 mmol,
50 mg), Pd/C (0.0029 mmol, 0.4 mol%, 6.5 mg 5% Pd/C (20% H O)),
n-butyl acrylate (2; 0.98 mmol, 1.50 equiv, 142 mL), and triethylamine
0.98 mmol, 1.5 equiv, 137 mL) were mixed together in that sequence with
1
2
(
MeCN (1 mL) in a 10 mL Pyrex microwave vial containing a magnetic
stir bar and stirred for 20 s. The vial was sealed tight by using the CEM
Discover pressure/fiber-optic attenuator and heated by microwave irradi-
ation at 1508C for 2 min (fiber-optic temperature control, time refers to
hold time at 1508C). After the reaction was completed, the mixture was
cooled down to 608C and quickly filtered through a sintered disk filter
funnel (D3) to remove the heterogeneous Pd/C catalyst. After washing
with MeCN (5 mL), the clear filtrate was transferred into a 25 mL round
bottom flask and the solvent was removed under reduced pressure. The
residue was subsequently dissolved in conc. HNO
ferred into a 60 mL Teflon vessel of an MLS ETHOS 1600 microwave re-
actor (EMLS/Milestone). An additional quantity of conc. HNO (4 mL)
3
(5 mL) and trans-
3
and conc. HCl (1 mL) were added and the resulting mixture was heated
for 30 min at a power of 500 W. For the Pd-determination the samples
were further diluted with 10% (v/v) nitric acid. Samples resulting from
flow experiments were analyzed in an analogous way.
Pd/C-samples from the fresh catalyst (dried at 1208C) and from the used
catalyst (removed from the CatCart-cartridge after usage and dried at
1
0
208C) were analyzed in a similar way: An aliquot (ꢀ50 mg, weighed to
ˇ
ˇ
.1 mg) of the samples were mixed with conc. HCl (1 mL) and conc.
Catal. Lett. 2008, 124, 204; d) J. Demel, S.-E. Park, J. Cejka, P. St eˇ p-
ni cˇ ka, Catal. Today 2008, 132, 63.
HNO
3
(4 mL) and digested in an MLS Ultraclave III microwave reactor
(
EMLS/Milestone) at 2508C for 30 min. The digested samples were fur-
[16] B. H. Lipshutz, B. A. Frieman, C.-T. Lee, A. Lower, D. M. Nihan,
B. R. Taft, Chem. Asian J. 2006, 1, 417.
ther diluted and Pd determined with ICP-MS as mentioned above.
[
17] a) T. A. Butler, E. C. Swift, B. H. Lipshutz, Org. Biomol. Chem.
2
1
008, 6, 19; b) B. H. Lipshutz, T. Butler, E. Swift, Org. Lett. 2008,
0, 697.
[
18] B. H. Lipshutz, J. B. Unger, B. R. Taft, Org. Lett. 2007, 9, 1089.
Acknowledgement
[19] a) U. Kazmaier, S. Hꢀhn, T. D. Weiss, R. Kautenburger, W. F. Maier,
Synlett 2007, 2579; b) S. P. Andrews, A. F. Stepan, H. Tanaka, S. V.
Ley, M. D. Smith, Adv. Synth. Catal. 2005, 347, 647.
This work was supported by a grant from the Christian Doppler Society
(
CDG). We thank Thales Nanotechnology Inc. for the provision of the
[20] a) D. R. Baghurst, D. M. P. Mingos, Chem. Soc. Rev. 1991, 20, 1;
b) C. Gabriel, S. Gabriel, E. H. Grant, B. S. Halstead, D. M. P.
Mingos, Chem. Soc. Rev. 1998, 27, 213; c) M. Gupta, E. Wong Wei
Leong, Microwaves and Metals, Wiley, New York, 2007.
X-Cube reactors and CatCarts.
[
1] a) Transition Metals for Organic Synthesis, 2nd ed. (Eds.: M. Beller,
C. Bolm), Wiley-VCH, Weinheim, 2004; b) Metal-Catalyzed Cross-
Coupling Reactions, Vol. 1–2, 2nd ed. (Eds.: A. de Meijere, F. Die-
derich), Wiley-VCH, Weinheim, 2004; c) M. Beller, A. Zapf in
Handbook of Organopalladium Chemistry for Organic Synthesis,
Vol. 1 (Ed.: E.-I. Negishi), Wiley, New York, 2002, pp. 1209–1222.
2] a) I. Beletskaya, A. Cheprakov, Chem. Rev. 2000, 100, 3009; b) V.
Farina, Adv. Synth. Catal. 2004, 346, 1553; c) A. de Meijere, F. Die-
derich, Metal-Catalysed Cross-Coupling Reactions, 2nd ed., Wiley-
VCH, Weinheim, 2004; d) J. Tsuji, Palladium Reagents and Cata-
lysts—New Perspectives for the 21st Century, Wiley, New York, 2004.
3] a) L. Yin, J. Liebscher, Chem. Rev. 2007, 107, 133, and references
therein; b) V. Polshettiwar, A. Molnꢃr, Tetrahedron 2007, 63, 6949.
[21] T. Razzaq, J. M. Kremsner, C. O. Kappe, J. Org. Chem. 2008, 73,
6321; see in particular the Supporting Information, Figure S14 and
S15.
[22] For examples of selective heating of Pd/C catalysts using microwave
irradiation in hydrogenation reactions, see: a) G. S. Vanier, Synlett
2007, 0131; b) E. Heller, W. Lautenschlꢀger, U. Holzgrabe, Tetrahe-
dron Lett. 2005, 46, 1247; c) A. N. Parvulescu, E. van der Eycken,
P. A. Jacobs, D. E. De Vos, J. Catal. 2008, 255, 206.
[23] J. D. Moseley, P. Lenden, M. Lockwood, K. Ruda, J. -P-Sherlock,
A. D. Thomson, J. P. Gilday, Org. Process Res. Dev. 2008, 12, 30, and
references therein.
[24] For reviews on microwave-assisted continuous-flow processing, see:
a) I. R. Baxendale, J. J. Hayward, S. L. Ley, Comb. Chem. High
[
[
Chem. Eur. J. 2009, 15, 1001 – 1010
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1009

C. O. Kappe et al.
Throughput Screening 2007, 10, 802; b) T. N. Glasnov, C. O. Kappe,
Macromol. Rapid Commun. 2007, 28, 395; c) See also: B. K. Singh,
N. Kaval, S. Tomar, E. van der Eycken, V. S. Parmar, Org. Process
Res. Dev. 2008, 12, 468.
cal cartridge is exposed to stoichiometric amounts of the catalyst. In
flow format, the TON of the “catalyst” is therefore dependent on
how much material is actually processed through the catalyst car-
tridge. For the Mizoroki–Heck reaction of 1a on a 0.65 mmol scale
the formal TON is only 6.
[
[
[
25] a) D. Williams, G. Bradley, H. Lombard, C. W. Holzapfel, Synth.
Commun. 2001, 31, 2077; b) L. J. Goossen, J. Paetzold, Angew.
Chem. 2002, 114, 1285; Angew. Chem. Int. Ed. 2002, 41, 1237;
c) G. K. Datta, K. S. A. Vallin, M. Larhed, Mol. Diversity 2003, 7,
[38] a) C.-M. Andersson, A. Hallberg, G. D. Davis, Jr., J. Org. Chem.
1987, 52, 3529; b) K. S. A. Vallin, M. Larhed, A. Hallberg, J. Org.
Chem. 2001, 66, 4340.
1
2
07; d) M. Mayr, M. R. Buchmeister, Macromol Rap. Commun.
004, 25, 231; e) Ai-E. Wang, J.-H. Xie, L.-X. Wang, Q.-L. Zhoe, Tet-
[39] a) L. Djakovitch, M. Wagner, C. G. Hartung, M. Beller, K. Kçhler,
J. Mol. Catal. A 2004, 219, 121; b) F. Zhao, M. Arai, React. Kinet.
Catal. Lett. 2004, 81, 281.
[40] The amount of Pd in a fresh sample of the commercially available
(Aldrich 643181-10G) Degussa Pd/C catalyst (E 104 CA/W 5% Pd)
was determined by ICP-MS analysis. The dry catalyst (20% deter-
mined water content) has a loading of 4.8% Pd. A 60ꢂ4 mm i.d. X-
Cube catalyst cartridge filled with 310 mg of the (wet) catalyst
therefore contains 12 mg of Pd.
rahedron 2005, 61, 259.
26] a) R. S. Dubbaka, P. Vogel, Chem. Eur. J. 2005, 11, 2633; b) X. Cui,
Z. Li, C.-Z. Tao, Y. Xu, J. Li, L. Liu, Q.-X. Guo, Org. Lett. 2006, 8,
2
467; c) R. S. Dubbaka, D. Zhao, Z. Fei, C. M. R. Volla, P. J. Dyson,
P. Vogel, Synlett 2006, 3155; d) X. Cui, Y. Zhou, N. Wang, L. Leiu,
Q.-X. Guo, Tetrahedron Lett. 2007, 48, 163; e) X. Cui, J. Li, L. Liu,
Q.-X. Guo, Chin. Chem. Lett. 2007, 18, 625; f) X. Cui, J. Li, Z.-P.
Zhang, Y. Fu, L. Liu, Q.-X. Guo, J. Org. Chem. 2007, 72, 9342.
[41] For a critical review, see: N. T. S. Phan, M. van der Sluys, C. W.
Jones, Adv. Synth. Catal. 2006, 348, 609.
27] a) R. G. Heideneich, K. Kçhler, J. G. E. Krauter, J. Pietsch, Synlett
2
002, 1118; b) K. Kçhler, R. G. Heidereich, J. G. E. Krauter, J.
[42] For other key references, see: a) A. Biffis, M. Zecca, M. Basato, J.
Mol. Catal. A 2001, 173, 249; b) D. Astruc, F. Lu, J. R. Aranzaes,
Angew. Chem. 2005, 117, 8062; Angew. Chem. Int. Ed. 2005, 44,
7852; c) J. G. de Vries, Dalton Trans. 2006, 421; d) D. Astruc, Inorg.
Chem. 2007, 46, 1884; e) A. M. Trzeciak, J. J. Ziꢄłkowski, Coord.
Chem. Rev. 2007, 251, 1281; f) A. Svennebring, P. J. R. Sjoeberg, M.
Larhed, P. Nilsson, Tetrahedron 2008, 64, 1808.
Pietsch, Chem. Eur. J. 2002, 8, 622; c) R. G. Heideneich, J. G. E.
Krauter, J. Pietsch K. Kçhler, Mol. Catal. A 2002, 182, 499.
[
[
28] T. Jeffrey, J. Chem. Soc. Chem. Commun. 1984, 1287.
29] a) M. Hosseini, N. Stiasni, V. Barbieri, C. O. Kappe, J. Org. Chem.
2
007, 72, 1417; b) M. A. Herrero, J. M. Kremsner, C. O. Kappe, J.
Org. Chem. 2008, 73, 36.
[
30] a) B. L. Hayes, M. J. Collins, Jr., World Patent 2004, WO 04002617;
b) B. L. Hayes, Aldrichimica Acta 2004, 37, 66.
[43] a) I. W. Davies, L. Matty, D. L. Hughes, P. J. Reider, J. Am. Chem.
Soc. 2001, 123, 10139; b) M. Parisien, D. Valette, K. Fagnou, J. Org.
Chem. 2005, 70, 7578; c) C. S. Consorti, F. R. Flores, J. Dupont, J.
Am. Chem. Soc. 2005, 127, 12054; d) J. M. Richardson, C. W. Chris-
topher, Adv. Synth. Catal. 2006, 348, 1207.
[44] Leaching effects in continuous-flow Mizoroki–Heck reactions in-
volving immobilized forms of Pd have been previously observed
(ref. [34]). In some cases the leached metal can be efficiently re-
moved online by the use of scavenger resins (ref. [34a]). In other in-
stances the support itself (e.g. poly(vinylpyridine)) has been demon-
strated to be able to recapture the Pd metal to some extent
(ref. [34b]).
[45] If the leaching observed for the specific preparation of Pd/C in Miz-
oroki–Heck chemistry under flow conditions is a general phenomen-
on also valid for other immobilized Pd species and/or other transi-
tion-metal-catalyzed transformations will be the subject of further
investigations.
[46] For recent examples of microwave-assisted Mizoroki–Heck reactions
using ligandless Pd, see: a) R. K. Arvela, N. E. Leadbeater, J. Org.
Chem. 2005, 70, 1786; b) R. K. Arvela, N. E. Leadbeater, M. J. Col-
lins, Tetrahedron 2005, 61, 9349; c) M. D. Bowman, J. L. Holcomb,
C. M. Kormos, N. E. Leadbeater, V. A. Williams, Org. Process Res.
Dev. 2008, 12, 41; d) M. D. Bowman, J. R. Schmink, C. M. McGo-
wan, C. M. Kormos, N. E. Leadbeater, Org. Process Res. Dev. 2008,
12, 1078; e) J. D. Moseley, E. K. Woodman, Org. Process Res. Dev.
2008, 12, 967. See also ref. [7b].
[
31] a) B. K. Singh, P. Appukkuttan, S. Claerhout, V. S. Parmar, E. van
der Eycken, Org. Lett. 2006, 8, 1863; b) P. Appukkuttan, M. Husain,
R. K. Gupta, V. S. Parmar, E. van der Eycken, Synlett 2006, 1491;
c) B. Singh, V. P. Mehta, V. S. Parmar, E. van der Eycken, Org.
Biomol. Chem. 2007, 5, 2962.
[
[
32] The selective heating of metal particles under microwave conditions
is a complex phenomenon depending on the type of support, parti-
cle size (surface-to-volume ratio), electromagnetic field strength
(power density), and a variety of other factors; for more details, see:
R. Cecilia, U. Kunz, T. Turek, Chem. Eng. Process. 2007, 46, 870,
and references therein.
33] For selected reviews on continuous-flow processing in organic syn-
thesis, see: a) G. Jas, A. Kirschning, Chem. Eur. J. 2003, 9, 5708;
b) P. Watts, S. J. Haswell, Drug Discovery Today 2003, 8, 586; c) I. R.
Baxendale, M. R. Pitts, Chim. Oggi 2006, 24, 41; d) A. Kirschning,
W. Solodenko, K. Mennecke, Chem. Eur. J. 2006, 12, 5972; e) A.
Chighine, G. Sechi, M. Bradley, Drug Discovery Today 2007, 12,
4
2
59; f) B. Ahmed-Omer, J. C. Brandt, T. Wirth, Org. Biomol. Chem.
007, 5, 733; g) C. Wiles, P. Watts, Eur. J. Org. Chem. 2008, 1655.
[
34] For closely related Mizoroki–Heck reactions in continuous-flow
format using immobilized Pd species, see: a) N. Nikbin, M. Ladlow,
S. V. Ley, Org. Process Res. Dev. 2007, 11, 458 (monolithic nanopar-
ticles); b) K. Mennecke, W. Solodenko, A. Kirschning, Synthesis
2
008, 1589 (immobilized palladacycles); c) N. Karbass, V. Sans, E.
Garcia-Verdugo, M. I. Burguete, S. V. Luis, Chem. Commun. 2006,
095 (immobilized Pd catalysts on monolithic polymers/ionic liquid
[47] For Mizoroki–Heck reactions performed in a microfluidic device,
see: a) B. Ahmed, D. Barrow, T. Wirth, Adv. Synth. Catal. 2006, 348,
1043; b) S. Liu, T. Fukuyama, M. Sato, I. Ryu, Org. Process Res.
Dev. 2004, 8, 477.
[48] M. T. Reetz, J. G. de Vries, Chem. Commun. 2004, 1559, and refer-
ences therein; see also references [41] and [42].
3
fragments); d) W. Solodenko, H. Wen, S. Leue, F. Stuhlmann, G.
Sourkouni-Argirusi, G. Jas, H. Schoenefeld, U. Kunz, A. Kirschning,
Eur. J. Org. Chem. 2004, 3601 (monolithic nanoparticles); e) See
also reference [14d].
[
[
[
35] For a detailed description, see: C. Csajꢃgi, B. Borcsek, K. Niesz, I.
[49] A. Hinchcliffe, C. Hughes, D. A. Pears, M. R. Pitts, Org. Process
Res. Dev. 2007, 11, 477; see also reference [44].
[50] Q. Yao, E. P. Kinney, C. Zheng, Org. Lett. 2004, 6, 2997.
Kovꢃcs, Z. Szꢆkelyhidi, Z. Bajkꢄ, L. ꢇrge, F. Darvas, Org. Lett.
2
008, 10, 1589.
36] The X-Cube and X-Cube Flash product series are available from
Thales Nanotechnology Inc. (Budapest, Hungary. For further infor-
mation, please refer to http://www.thalesnano.com.
37] In fact, each portion of the reaction mixture passing through the mi-
crochannels formed by the packed Pd/C catalyst inside the cylindri-
Received: October 24, 2008
Published online: December 10, 2008
1010
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1001 – 1010