Carbon-carbon cross-coupling reactions under continuous flow conditions using poly(vinylpyridine) doped with palladium

Article abstract of DOI:10.1055/s-2008-1072579

Coordinative immobilization of an oxime-based pallada-cycle to poly(vinylpyridine)/glass composite materials shaped as Raschig rings or placed within the PASSflow microreactor affords technical devices that are well suited for performing palladium-catalyzed carbon-carbon cross-coupling reactions in the flow-through mode. Reusability of the immobilized precatalyst as well as applications in the microwave field were investigated. Experiments with thiol- and pyridine-based scavengers were carried out, which revealed that the active palladium species is likely to be composed of nanoparticles of unknown nature and that the poly(vinylpyridine) carrier has scavenging properties for these particles. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072579

PAPER
1589
Carbon–Carbon Cross-Coupling Reactions under Continuous Flow
Conditions Using Poly(vinylpyridine) Doped with Palladium
C
ross-Coupling Re
l
action
a
under Con
a
tinuous Flo
s
w Conditions Mennecke, Wladimir Solodenko, Andreas Kirschning*
Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1b, 30167 Hannover, Germany
E-mail: andreas.kirschning@oci.uni-hannover.de
Received 21 January 2008
Abstract: Coordinative immobilization of an oxime-based pallada-
cycle to poly(vinylpyridine)/glass composite materials shaped as
Raschig rings or placed within the PASSflowTM microreactor af-
fords technical devices that are well suited for performing palladi-
um-catalyzed carbon–carbon cross-coupling reactions in the flow-
through mode. Reusability of the immobilized precatalyst as well as
applications in the microwave field were investigated. Experiments
with thiol- and pyridine-based scavengers were carried out, which
revealed that the active palladium species is likely to be composed
Figure 1 Enabling technologies for organic synthesis
of nanoparticles of unknown nature and that the poly(vinylpyridine)
carrier has scavenging properties for these particles.
Suzuki cross-coupling reactions [using precipitated palla-
dium(0) nanoparticles,10 polyurea-encapsulated palladi-
um(II) acetate precatalyst,11 and salen-type palladium(II)
complexes12], Heck–Mizoroki and Sonogashira cross-
coupling reactions [using precipitated palladium(0)
nanoparticles9], Kumada–Corriu cross-coupling reactions
[using salen-type nickel(II) complex immobilized on
Merrifield resin13 or on functionalized silica gel14], and for
the kinetic resolution of terminal epoxides [using an im-
mobilized chiral cobalt(II)-salen complex15]. These exam-
ples illustrate the various techniques applied for
immobilization of metal catalysts inside continuous flow
devices. These are the physisorption on charcoal7,8 or or-
ganic polymers,10 and encapsulation within a polymer ma-
trix.11 Undoubtedly, the most popular method relies on
covalent attachment of ligands to a polymeric or inorganic
solid supports (grafting) followed by loading with the
transition-metal catalyst.9,13–15
Key words: palladium catalyst, immobilization, microreactor, mi-
crowave, C–C cross-coupling reactions
Advances in organic synthesis and catalysis from academ-
ic laboratories are often not rapidly transferred into indus-
trial applications.1,2 In many cases, developments from
research laboratories lack practicability as far as scale-up,
easy and rapid workup, product isolation, and recyclabili-
ty of catalysts are concerned. New synthetic methods need
to be combined with new techniques which are termed
‘enabling technologies for organic synthesis’ in order to
achieve better incorporation into industrial processes
(Figure 1). Microwave assistance,3 new solvent systems,4
continuous flow reactors,2,5 and immobilization of chem-
ically active species such as reagents and homogeneous
catalysts6 can be regarded as typical enabling technolo-
gies. Truly new synthetic technology platforms, however,
will not be based on the individual use of these new tech-
niques, but will require the integration of two or more of
these enabling techniques. By exploiting synergic effects
higher efficiency and better controlling of chemical pro-
cesses should be achieved. Various successful examples
of combining two or more of these techniques in order to
achieve faster synthesis or improved workup have recent-
ly appeared in the literature. Particularly the field of catal-
ysis with heterogenized homogeneous catalysts, which
are incorporated inside continuous flow reactors is a very
active area of research.2
For some time, we have been involved in the development
of continuous flow reactors suitable for organic synthesis.
Our PASSflowTM reactors contain a megaporous mono-
lithic glass/polymer composite material, which can be fur-
ther functionalized. This experimental set up allows an
almost workup-free procedure for carrying out many dif-
ferent reactions including nucleophilic substitutions, re-
ductive aminations, oxidations, Horner–Wadsworth–
Emmons, and palladium-catalyzed carbon–carbon cou-
pling reactions in the flow-through mode.16
From a technological point of view, particularly when up-
scaling and economical aspects are in focus, the mode of
immobilization should allow easy loading of the reactor
with active catalyst or precatalyst and simple removal,
and reloading after the catalytic species has lost its activi-
ty. In this context, ionic or coordinative interactions be-
tween the transition-metal complex and the solid phase
represent promising concepts. In both cases, the inactive
transition-metal complex or degradation products derived
For example, continuous flow processes with immobi-
lized catalysts were utilized for the reduction of organic
compounds (Pd/C-mediated hydrogenations7,8 and ruthe-
nium-catalyzed asymmetric transfer hydrogenations9),
SYNTHESIS 2008, No. 10, pp 1589–1599
x
x.
x
x
.
2
0
0
8
Advanced online publication: 07.04.2008
DOI: 10.1055/s-2008-1072579; Art ID: Z02308SS
© Georg Thieme Verlag Stuttgart · New York

1590
K. Mennecke et al.
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ous glass rod which is part of a PASSflowTM microreac-
tor,22 and c) megaporous glass Raschig rings coated with
this PVP matrix23 (Table 1). The powder was used in
batch processes while the two glass/polymer composites
were incorporated inside the reactor for being studied in
continuous flow processes. The Raschig ring microreactor
(case c) has an advantage over the rod-type reactor (case
b) because it can be easily unscrewed and functionalized
Raschig rings can be removed or fresh rings can be easily
inserted.
N
N
Mes
N
Mes
Cl
N
N
Pd
Cl
Ru
OH
Ph
Cl
N
1
2
Br
N
= polyvinyl pyridine (PVP)
Figure 2 Catalysts 1 and 2 (Mes = mesityl) bound to PVP
Table 1 Immobilization of Palladacycle 3 on Different PVP Matri-
ces
thereof can easily be removed by simple washing steps
before the solid phase is regenerated with a fresh portion
of the active complex under flow-through conditions.
OH
N , DMSO, r.t.
Cl
Pd Pd
Cl
HO
N
2
Recently, we have shown that poly(4-vinylpyridine)
(hereafter abbreviated as PVP) is a well suited solid phase
for immobilizing transition-metal complexes such as the
Grubbs III complex17 or Najera’s oxime-based palladacy-
cle.18 The resulting functionalized polymeric phases 1 and
2 showed very good activity in olefin metathesis17 and
N
3
Entry
Structure of the precatalyst 2
carbon–carbon cross-coupling reactions,19 respectively Case a
(Figure 2). In analogy to findings by Reetz and de Vries,20
we suggested that the latter complex 2 is a reservoir for
palladium nanoparticles of unknown nature, which are
Powder prepared by precipitation
polymerization22
Case b
formed after reduction. We further speculated that the pal-
Rod-shaped monolithic glass/polymer composite
material inside the flow-through reactor22
ladium(0) species can carry on the catalytic cycle or can
be recaptured by PVP. This hypothesis gained support
from ICP measurements of the cooled reaction mixture
because a residual palladium level as low as 1.1–2.1 ppb
was detected. The easy reusability of functionalized resin
2, its air-, moisture- and thermal stability in carbon–car-
bon cross-coupling reactions and the very low degree of
leaching makes this precatalyst an ideal study object for
Case c
Monolithic glass/polymer composite material
shaped as Raschig ring for batch as well as flow
reactions23
Applications in Palladium-Catalyzed Carbon–
Carbon Coupling Reactions
applications under continuous flow conditions. In fact,
when switching from batch to flow-through conditions
with heterogenized homogeneous catalytic systems, the
convective flow can strongly alter the reaction profile as
contact times between the solid phase and the fluid are
commonly shorter and leaching of metals can increase. In
this report, we disclose the studies on Suzuki–Miyaura
and Heck–Mizoroki reactions with PASSflowTM reactors
that are loaded with polymer 2. Additionally, we use the
flow-through device to shed light on how ‘homogeneous’
the carbon–carbon coupling reactions actually are by em-
ploying resins with scavenging properties, which are lo-
cated in a separate reactor.
First, we investigated the catalytic activity of precatalyst
2 loaded on the Raschig rings (optimized loading:
3.57 × 10–5 mmol Pd/mg ring as judged by elemental anal-
ysis). The composite rings were placed inside a flow-
through reactor (Table 1, case c) and Suzuki–Miyaura
cross-coupling reactions were performed under continu-
ous flow conditions. As the monolithic material doped
with palladium is composed of irregular microchannels
(£50 mm) one has to choose homogeneous conditions in
order to prevent clogging of the channels.
The results obtained are listed in Table 2. In some cases
(entries 2 and 3), an unusual solvent system consisting of
DMF–water–amyl alcohol (10:1:1) was employed. This
mixture guaranteed homogeneous conditions during the
whole process, however, with the price of prolonged reac-
tion times. Several boronic acids gave good to very good
yields with p-bromoacetophenone as coupling partner.
Aryl bromides that contain electron-donating substituents
(entries 7 and 8) gave only moderate yields of coupling
products with phenylboronic acid. The sterically congest-
ed 2,6-dimethylbromobenzene gave a low yield (9%) of
coupling product with phenylboronic acid (5a) while 2-
Preparation of Immobilized Palladium
Complex 2 was prepared by coordination of palladacycle
318 to PVP [cross-linked with 5.3% divinylbenzene
(DVB)] (Table 1).19 The proposed structure of this immo-
bilized precatalyst 2 is based on an X-ray study of a relat-
ed complex.21 We prepared three different types of
samples of precatalyst 2 using a) PVP as a powder pre-
pared by precipitation polymerization, b) the same PVP
matrix as a coating of the glass surface inside a megapor-
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Cross-Coupling Reactions under Continuous Flow Conditions
1591
Table 2 Continuous Flow Suzuki–Miyaura Reactions Using the Precatalyst 2 Immobilized on the Raschig Ringsa
R2
R2
2
R1
R1
R3
R3
Br
+
(HO)2B
4a–e
5a–e
6a–i
CN
Br
Br
Br
Br
Br
O
MeO
4c
4a
4b
4d
4e
SMe
OMe
O
O
(HO)2B
F3C
B(OH)2
B(OH)2
(HO)2B
(HO)2B
5a
5b
5c
5d
5e
Entry
ArBr
Boronic acid
Time (h)
Product
Yield (%)b
R2
R3
O
1
4a
4a
4a
4a
4a
5a
5b
5c
5d
5e
9
6a R2 = H; R3 = H
91
2c
3c
4
24 (24)
6b R2 = H; R3 = SMe
6c R2 = H; R3 = OMe
6d R2 = CF3; R3 = H
6e R2–R3 = OCH2O
87 (70)
73 (71)
99
30.5 (3.5)
24
3
5
94
R1
6
7
8
4b
4c
4d
5a
5a
5a
24
24
24
6f R1 = H
89
56
50
6g R1 = Me
6h R1 = OMe
CN
9
4e
5a
24
6i
75
a Conditions: Boronic acid (1.5 equiv), aryl bromide (1 equiv), CsF (2.4 equiv), 2 (1 mol% immobilized on Raschig rings; loading 3.57 × 10–5
mmol Pd/mg ring), DMF–H2O (10:1), 100 °C (preheated), flow rate 2 mL/min.
b Isolated yields.
c Solvent: DMF–H2O–amyl alcohol (10:1:1); time and yield in parentheses refer to DMF–H2O (10:1).
Synthesis 2008, No. 10, 1589–1599 © Thieme Stuttgart · New York

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K. Mennecke et al.
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bromothiazole, 3-bromothiophene or 2-bromothiophenol ous aryl bromides with acrylic acid esters, acrylonitrile,
practically are not suited for achieving cross-coupling and styrene as exemplified in Scheme 2 (in this case, the
products under continuous flow conditions.
reactions were carried out in screw-cap vials at 150 °C for
30–40 min). Thus, p-bromoacetophenone (4a) was trans-
formed into cyclohexyl (E)-3-(4-acetylphenyl)acrylate
(8a) within 30 minutes at 150 °C using doped PVP (1
mol% Pd; Table 1, case a) in DMF in the presence of
Et3N. The results obtained under these conditions for oth-
er aryl bromides are presented in Table 3.
Stability of the precatalyst 2 under conditions described
above was investigated using coupling of phenylboronic
acid with p-bromoacetophenone (4a) (Table 2, entry 1).
This reaction was repeated with the same Raschig rings
carrying the precatalyst 2, each run was carried out for 24
hours. The results clearly showed the good stability (after
the fifth run small degree of reduced activity was encoun- When microwave irradiation (300 W) was applied to carry
tered) of the catalyst. No formation of palladium black out the Heck–Mizoroki reaction between coupling part-
could be observed on the surface of the used rings after ners shown in Table 3, the results obtained were compara-
several runs.
ble to those observed for conventional thermal heating
except for a reduced E/Z ratio for 8e–g, and no product
formation in the case of the reaction of 4a with 7c.
The heterogeneous catalyst 2 was active also in the aryla-
tion of olefins with aryl halides (Heck–Mizoroki reac-
tion). The coupling between iodobenzene and methyl However, for conducting continuous flow experiments
acrylate in DMF at 110 °C in the presence of triethyl- these conditions had to be optimized so that homogeneous
amine as base and 2 [1 mol% immobilized on PVP (pow- conditions for the fluid are guaranteed throughout the
der)] under air (Scheme 1) proceeded quantitatively whole process. Poly(4-vinylpyridine) was incorporated
within 1.5 hours under batch conditions.
inside a rod-type PASSflowTM microreactor as well as in
a Raschig ring-type PASSflowTM microreactor and em-
ployed in Heck–Mizoroki reactions under continuous
flow conditions. Again, the reactors were preheated to
110–120 °C and the reaction mixture was circulated
through the reactors. Initially, iodobenzene (1 equiv) and
methyl acrylate were coupled in DMF inside the glass rod
microreactor, which resulted in quantitative conversion
(76% isolated yield) within 24 hours. As the performance
of both reactor types turned out to be comparable we
switched to the Raschig ring microreactor which can be
handled more conveniently (Table 4). Thus, under flow-
through conditions the Heck–Mizoroki reaction was car-
ried out in DMF at 120 °C [in order to prevent thermal de-
struction of some reactor parts (e.g., sealings)] and with
tributylamine (3 equiv) instead of triethylamine. The re-
sults are listed in Table 4.
The catalyst 2 after this reaction was washed with ethyl
acetate and used immediately for another Heck–Mizoroki
coupling between iodobenzene and tert-butyl acrylate un-
der similar conditions. Again, the reaction was completed
within 1.5 hours, and the product – trans-cinnamic acid
tert-butyl ester – was isolated in 93% yield. After washing
with ethyl acetate, the same portion of catalyst 2 was used
for the third Heck reaction of p-iodoanisole with methyl
acrylate. After completion of the reaction (6 h), the cou-
pling product – trans-4-methoxycinnamic acid methyl es-
ter – was isolated in 87% yield. Thus, precatalyst 2
showed high reusability, in contrast to the related cyclo-
palladated imine catalyst covalently immobilized on poly-
styrene resin, which completely lost all of its activity after
the first Heck coupling.24
These recycling experiments demonstrate the high affini-
ty of PVP to the palladium species with simultaneous
preservation of the catalytic activity. Precatalyst 2 (pow-
der) was also active in Heck–Mizoroki couplings of vari-
Aryl iodides gave satisfactory results. However, under
continuous flow conditions, aryl bromides furnished only
low to moderate yields of coupling products. For example,
only 64% and 72% of products 8e and 8k were isolated
I
COOMe
2 (1 mol%)
COOMe
+
Et3N (1.4 equiv),
DMF, 110 °C, air
1.2 equiv
93% (isolated)
Scheme 1 Heck coupling of iodobenzene with methyl acrylate under batch conditions
Br
N
N
Pd
Cl
O
OH
4a (1 equiv)
2 (powder)
O
CO2Cy
+
CO2Cy
Et3N (2 equiv), DMF,
150 °C, 30 min
or MW (300 W, 150 °C)
30 min
7a (1.2 equiv)
8a 99% (E/Z = 99:1)
Scheme 2 Heck–Mizoroki reaction of p-bromoacetophenone (4a) and acrylic ester 7a in batch mode (2, powder)
Synthesis 2008, No. 10, 1589–1599 © Thieme Stuttgart · New York

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Cross-Coupling Reactions under Continuous Flow Conditions
1593
Table 325 Heck–Mizoroki Reactions in Batch Mode Using the Precatalyst 2 in a Powder Form and Conventional Heatinga
R2
R1
R1
2
N
Br
R2
7a–e
+
CO2Cy
CO2Me
Ph
CO2t-Bu
CN
4a,b,e,f
8a–g
Br
4f
7a
7b
7c
7d
7e
Entry
ArBr
Alkene
Time (h)
Product
Yield (%)b
R2
O
1
2
3
4a
4a
4a
7a
7b
7c
0.5
0.5
0.5
8a R2 = CO2Cy
8b R2 = CO2t-Bu
8c R2 = CO2Me
99
64
99
99
(5.6:1)
4
5
4a
4b
7d
7e
0.5
0.6
8d R2 = CN
Ph
78
(18:1)
8e
8f
Ph
Ph
33
(14:1)
6
7
4e
4f
7e
7e
0.6
0.6
CN
86
(13:1)
N
8g
a For bromides also refer to Table 2. Conditions: Aryl bromide (1 equiv), alkene (1.2 equiv), Et3N (2 equiv), and precatalyst 2 (1 mol% immo-
bilized on powder with a loading of 0.8 mmol Pd/g resin) in DMF (3.5 mL/mmol aryl bromide), 150 °C in a screw-cap vial, 30–40 min.
b Isolated yield; unless otherwise noted, only the E-isomer was detected; data in parentheses refer to E/Z ratio.
when o-bromobenzonitrile (4e) or p-bromoacetophenone employed. De Vries et al. noted that the mechanism of
(4a), respectively, were coupled with styrene (7e) ligand-free palladium-catalyzed Heck reactions may
(Table 4, entries 4 and 8). When the other aryl bromides change when increasing reaction temperatures from
listed in Table 3 were employed in Heck–Mizoroki reac- 100 to 150 °C.20,25 At lower temperatures only aryl io-
tions with styrene, the yields did not exceed 50%.
dides react, likely on the solid surface while at higher tem-
peratures palladium particles released into solution are the
catalytically active species. Our flow-through experi-
ments were carried out at 120 °C because at higher tem-
peratures we encountered technical problems such as
damage of the reactor sealings.
For testing the stability of functionalized PVP 2, ten con-
secutive Heck–Mizoroki reactions of p-iodoacetophenone
(4g) with cyclohexyl acrylate (7a) were carried out in the
flow-through mode. For each run the same Raschig rings
containing palladium-doped PVP 2 was used. The catalyt-
ic performance of the polymeric material did not erode Reloading of inactive PVP phase was simply achieved by
under these conditions. The catalyst is stable for ten runs pumping dilute hydrochloric acid though the reactor
without loss of activity. Noteworthy, we observed some which leads to removal of the palladium species. This was
formation of palladium black on the surface of the glass/ followed by a washing protocol [aq 1 N NaOH, water (to
composite material an observation which contrasts to the neutral pH), methanol, and toluene]. At this point the pal-
corresponding test for the Suzuki–Miyaura cross-cou- ladacycle 3 could be recoordinated onto the polymeric
plings. This may be ascribed to the higher temperature phase as described above.
Synthesis 2008, No. 10, 1589–1599 © Thieme Stuttgart · New York

1594
K. Mennecke et al.
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Cl
B(OH)2
2 (1 mol%)
+
O
K2CO3 (2 equiv),
TBAB (0.5 equiv),
H2O, 100 °C, 16 h
O
4k
5a
6a 92%
Br
H
N
O
9
Scheme 3 Three-phase test with precatalyst 2 (PVP powder, batch mode)
On the Nature of the Catalytic Species
ca SBA-15, Mordenite and hydroxyapatite) have been re-
ported.26,27 This hypothesis was further supported by our
observation that higher loading of the PVP phase (0.8
mmol Pd/g polymer) yields a catalyst which more rapidly
loses its activity than PVP containing a smaller amount of
palladium. It can be concluded, that the higher concentra-
tion of palladium species on the polymeric phase more
rapidly leads to inactive palladium black under thermal
stress. De Vries and co-workers pointed out that also low
concentrations of palladium(0) in solution will aggregate
and deactivate much more slowly than high concentra-
tions.20,25 In order to gain further evidence on the double
role of PVP, we conducted several additional experi-
ments. First, we carried out the three phase test.28 Thus,
cross coupling of p-chloroacetophenone (4k) with phe-
nylboronic acid (5a) was performed in the presence of
polymer-bound aryl bromide 9. The latter halide should
be more reactive in Suzuki–Miyaura cross coupling reac-
tions than the former halide (Scheme 3). In fact, the an-
chored aryl bromide 9 did not react under the typical
reaction conditions, which could be an indication that low
level metal leaching occurred during catalysis and that
probably a biphasic process is under operation.29
Up to this point we have demonstrated that PVP is a ver-
satile solid phase for attaching palladacycles like 3 by di-
rect coordination. Under batch conditions, a highly active
catalytic species is present, which is even able to promote
Suzuki–Miyaura cross coupling reactions with activated
aryl chlorides. It can be repeatedly used and only a very
small amount of palladium (1.1–2.1 ppb) is present in the
cooled reaction mixture. However, when comparing the
results of the batch reactions with those observed under
continuous flow conditions one has to encounter that the
material performs less well under the latter conditions.
For the Heck–Mizoroki reaction this effect can be ex-
plained by the lower temperature used in the flow mode
(120 vs. 150 °C in the batch process).
We speculated that PVP may serve as a reservoir of a cat-
alytically active but ill-defined species of palladium(0)
which exerts its activity in solution.19,25 The low degree of
leaching observed could be ascribed to the possibility that
the catalytically active species is efficiently scavenged by
the large excess of uncoordinated pyridyl sites present
which would also retard the formation and growth of col-
loids. In fact similar observations for inorganic supports
(zeolites MCM-41, NaY and SAPO-31, mesoporous sili-
In order to get further insight, we coupled two microreac-
tors in a row. The first reactor contained palladium-doped
I
Raschig ring:
plain glass, 10,
11, 12, or 13, r.t.
O
O
2 (1 mol%),
120 °C
O
4l
+
8a
O
O
O
7a
N
N
SH
O
N
N
N
N
10
11
12
13
Scheme 4 Influence of the thiol- and pyridine-based scavengers on the course of the test Heck reaction
Synthesis 2008, No. 10, 1589–1599 © Thieme Stuttgart · New York

PAPER
Cross-Coupling Reactions under Continuous Flow Conditions
1595
ature. The polymeric phase of the Raschig rings incorpo-
rated into the second microreactor was functionalized
with groups that potentially are able to trap any soluble
palladium species from solution. As polymeric phase we
chose thiol 10, bispyridine 11, amino-bispyridine 12 (all
three based on polystyrene), or PVP 13. Additionally, we
also incorporated a blank Raschig ring (pure glass) in the
second reactor which served as a ‘dummy’ in order to
guarantee identical parameters for all experiments such as
the total volume of the reaction mixture, concentrations of
reactants, the flow inside the reactors, temperature gradi-
ents.
Table 4 Heck–Mizoroki Reactions in Continuous Flow Mode
Using the Precatalyst 2 Immobilized on the Raschig Ringsa
R1
X
2
R2
R1
4a,e,g–j
+
8a,b,d,h–k
7a,b,d,e
R2
I
I
I
I
O
MeO
NH2
The results of these experiments are summarized in
Figures 3 and 4. When the second microreactor contained
the ‘dummy’ rings the test Heck–Mizoroki reaction went
to completion within two hours. When the thiol scavenger
10 (one Raschig ring) was introduced the carbon–carbon
coupling reactions proceeded much slower and full trans-
formation was reached only after 23 hours. When three
thiol rings 10 were placed inside the second reactor, the
retardation of the reaction rate was even more pro-
nounced. Additionally, we observed a deposit of some
palladium black on the thiol Raschig rings. This deposit
showed no catalytic activity under batch as well as flow
conditions.
4g
4h
4i
4j
Aryl
halide
Time
(h)
Yield
(%)b
Entry
Alkene
Product
R2
O
1
2
4g
4g
7a
7b
2
4
8a R2 = CO2Cy
99
8b R2 = CO2t-Bu 99
In contrast, the pyridine-based scavengers 11–13 exerted
a much smaller influence on the test Heck–Mizoroki reac-
tion. Importantly, they had adopted high catalytic activity
after having served as scavenger inside the second mi-
croreactor. In fact, when these rings, after being applied in
the scavenging experiments, were used under the de-
scribed conditions, but with a ‘dummy’ ring in the first re-
actor, the Heck–Mizoroki reaction went to completion
within 4.5 hours for 11, 3.5 hours for 12, and 24 hours for
13 (81% isolated product).
97
(5:1)
3
4
4g
4a
7d
7e
4
8d R2 = CN
72
(24:1)
24
8k R2 = Ph
Ph
R1
5
6
4h
4i
7e
7e
24
24
8h R1 = Me
97
92
These results strongly support the role of the palladium-
doped PVP-phase 2 as a depot for active palladium spe-
cies which are released into solution (refer to Table 1).
8i R1 = OMe
Ph
R1
7
8
4j
7e
7e
8
8j R1 = NH2
8e R1 = CN
99
64
(29:1)
4e
24
a For other halides and alkenes, refer to Tables 1 and 2. Conditions:
Aryl halide (1 equiv), alkene (3 equiv), Bu3N (3 equiv), Pd precatalyst
2 (1 mol% immobilized on Raschig rings; loading 3.57 × 10–5 mmol
Pd/mg ring), DMF, 120 °C; flow rate 2 mL/min.
b Isolated yields; unless otherwise noted, only the E-isomer was de-
tected; data in parentheses refer to E/Z ratio.
Figure 3 Influence of the thiol scavenger 10 on the course of the test
Heck–Mizoroki reaction. Reagents and conditions: p-iodoacetophe-
none (1 equiv), cyclohexyl acrylate (3 equiv), Bu3N (3 equiv), Pd pre-
catalyst 2 (reactor 1:1 mol%, immobilized on Raschig rings, loading
3.57 × 10–5 mmol Pd/mg ring, 10 mmol Pd/Raschig ring), DMF,
120 °C, 2 mL/min flow rate; reactor 2: thiol scavenger 10 (0.185
PVP 2 (Raschig ring; loading 3.57 × 10–5 mmol Pd/mg of
ring, 10 mmol Pd/ring) while the second reactor contained
differently functionalized glass/polymer composite
Raschig rings (Scheme 4). The first reactor was heated at
120 °C while the second reactor was kept at room temper- mmol thiol groups/Raschig ring).
Synthesis 2008, No. 10, 1589–1599 © Thieme Stuttgart · New York

1596
K. Mennecke et al.
PAPER
polymer support. Besides serving as an anchor for the pre-
catalyst 2, PVP also acts as a scavenger for the palladium
species that are released into solution in the course of the
catalytic reaction. Remarkably, the trapped palladium
species retain their catalytic activity. It is our belief that
PVP has a broad potential for the facile and repeated im-
mobilization of transition-metal complexes. However, the
fundamental problem of metal leaching is not prevented
with this phase.
All reactions were carried out in the air (in the absence of an inert
gas atmosphere). NMR spectra were recorded on a Bruker DPX-
400 spectrometer at 400 MHz (1H NMR) or 100 MHz (13C NMR)
in CDCl3 using TMS as internal standard. IR spectra were recorded
on a Bruker FT-IR Vector 22 apparatus using Golden-Gate-ATR
system on the film of the neat liquid compounds or on the com-
pressed samples for the solid substances. Mass spectra (EI) were ob-
tained at 70 eV on a VG Autospec apparatus. Melting points were
determined in open glass capillaries on an Electrothermal IA 9200
apparatus and are uncorrected. GC analyses were conducted using
a Hewlett-Packard HP 6890 Series GC System equipped with a SE-
54 capillary column (25 m, Macherey-Nagel) and a FID detector
19231 D/E. Microwave experiments were carried out in the appara-
tus Labmate Discover from CEM. Analytical TLC was performed
Figure 4 Influence of the pyridine-based scavengers 11–13 on the
course of the test Heck reaction. Reagents and conditions: p-iodoace-
tophenone (1 equiv), cyclohexyl acrylate (3 equiv), Bu3N (3 equiv),
Pd precatalyst 2 (reactor 1:1 mol%, immobilized on Raschig rings,
loading 3.57 × 10–5 mmol Pd/mg ring, 10 mmol Pd/Raschig ring),
DMF, 120 °C, 2 mL/min flow rate; reactor 2: scavengers 11–13 (load-
ing: 0.067 mmol/Raschig ring for 11, 0.046 mmol/Raschig ring for
12, and 0.181 mmol/Raschig ring for 13).
These species can be trapped by polymeric scavengers
10–13. In the case of thiol scavenger 10, the trapped pal- using precoated silica gel 60 F254 plates (Merck, Darmstadt), and the
spots were visualized with UV light at 254 nm or with vanillin re-
ladium is completely deactivated, while the pyridine-
agent. Merck silica gel 60 (230–400 mesh) was used for flash col-
umn chromatography. Pyridine-based scavengers 11 and 12
(Raschig rings) were purchased from Chelona GmbH (Potsdam).
Commercially available reagents and anhydrous solvents were pur-
chased from Fluka and Aldrich and used as received. Homogeneous
product samples were isolated via flash chromatography and their
based scavengers create palladium species still showing
excellent catalytic activity at elevated temperature. The
results prove that the PVP resin can serve as a solid phase
for immobilizing palladium precatalysts, which them-
selves create palladium particles during the Heck–
Mizoroki reaction conditions. Additionally, PVP is able to purity was checked by TLC, GC and NMR analyses. All products
are known and have been published with full characterization.
recapture these particles, which explains the low amount
Characterization of the products was commonly achieved spectro-
of palladium detected in the cooled solution.
scopically (1H and 13C NMR, IR, high-resolution mass spectrome-
try). Additionally, for known compounds the physical (e.g., melting
points) and spectroscopic data were compared with those in the lit-
erature.
At this point it has to be noted that our results contradict a
report by Jones et al.30 They considered PVP to be an ‘ef-
fective poison of active soluble palladium species in Heck
reactions’. This statement is based on the strong inhibition
of the reaction in the presence of a large excess of PVP
(molar ratio 1:300 of Pd to PVP). Similarly, Weck and co-
workers31 described a dramatic retardation of palladium-
catalyzed Suzuki–Miyaura reactions in the presence of a
large excess (molar ratio 1: 500) of either PVP or polysty-
rene (only about 15% conversion after 24 h for both res-
ins). In our case the ratio is about 1:15. Thus, we have
shown that retardation of the reaction not necessarily has
to be associated with poisoning properties of PVP, partic-
ularly as polystyrene is generally not considered to be a
poison for palladium catalysts.
The preparation of the PVP polymeric phase as a powder or as a
glass/polymer composite material (shaped as rods or as Raschig
rings) as well as immobilization of palladacycle 3 were described
previously.19,22b,23
Precatalyst 2 Immobilized on Glass/PVP Composite Raschig
Rings (Exemplified for Loading of 3.57 × 10–5 mmol Pd/mg
Raschig Ring)
Palladacycle 3 (128 mg, 0.23 mmol) and Raschig rings coated with
PVP19,23 (total weight 14.11 g, 0.55 mmol pyridine loading per ring)
were carefully shaken in DMSO (40 mL) at r.t. for 24 h. Then, the
Raschig rings were thoroughly washed with DMSO, then H2O, and
dried in vacuo. The loading was determined to be ca. 3.57 × 10–5
mmol Pd/mg ring as judged by weight increase and by Pd inductive-
ly coupled plasma mass spectrometry (ISP-MS).19 This corresponds
to a loading of ca. 10 mmol Pd/ring (all Raschig rings used had the
same standard size and weight). No decrease of catalytic activity of
precatalyst 2 immobilized on the Raschig rings was noted after stor-
ing for at least 7 months in the air at r.t.
The fact that switching from batch to flow-through condi-
tions leads to a less active catalytic system can be ascribed
to shorter contact times between the solid phase and the
fluid and a more pronounced wash-out effect for the re-
leased palladium particles.
Suzuki–Miyaura Cross-Coupling Reactions Under Continuous
Flow Conditions Using Precatalyst 2; General Procedure
A solution of aryl halide (1 mmol), arylboronic acid (1.5 mmol),
and CsF (364 mg, 2.4 mmol) in DMF–H2O (10:1, 5 mL) was circu-
lated (flow rate 2.5 mL/min) through the reactor charged with one
Pd-doped PVP Raschig ring 2 (10 mmol Pd) at 100 °C. After com-
We have demonstrated that PVP is well suited to accom-
modate Najera’s palladium precatalyst. It can be em-
ployed in continuous flow devices for Suzuki–Miyaura
cross-coupling and Heck–Mizoroki reactions. The use of
additional scavenger reactors shed light on the role of the
Synthesis 2008, No. 10, 1589–1599 © Thieme Stuttgart · New York

PAPER
Cross-Coupling Reactions under Continuous Flow Conditions
1597
pletion of the reaction (GC monitoring), the reactor was washed
with DMF–H2O (10:1, 40 mL). The combined reaction mixture and
washings were diluted with H2O (50 mL), and extracted with
EtOAc (3 × 20 mL). The combined organic phases were dried
(MgSO4) and concentrated in vacuo. The products were commonly
sufficiently pure. Final purification was possible by flash column
chromatography on silica gel. The reactor was ready for use in the
next experiment.
through the reactor (flow rate: 2 mL/min) charged with a Raschig
ring bearing immobilized precatalyst 2 (3.57 × 10–5 mmol Pd/mg,
10 mmol Pd). After completion of the reaction (GC-monitoring),
the reactor was rinsed with DMF (40 mL). The solution was diluted
with H2O (80 mL), extracted with EtOAc (3 × 50 mL), and the com-
bined EtOAc layers were dried (MgSO4). After concentration in
vacuo, the products were commonly sufficiently pure. Final purifi-
cation was possible by flash column chromatography on silica gel.
The reactor was ready for use in the next experiment.
Heck–Mizoroki Reaction Using Precatalyst 2 Immobilized on
PVP; General Procedure A (Powder, Batch Mode, Convention-
al Heating)
Three-Phase Test for Suzuki–Miyaura Cross-Coupling Reac-
tions (Batch Mode)
A mixture of aryl iodide (1 mmol), acrylic acid ester (1.2 mmol),
palladium precatalyst 2 (10 mg of powder, 1 mol%), and Et3N (142
mg, 1.4 mmol) in DMF (2 mL) was stirred at 110 °C. After comple-
tion of the reaction (GC monitoring), the mixture was diluted with
EtOAc (5 mL) and filtered. The filtrate was diluted with H2O (10
mL) and extracted with EtOAc (2 × 15 mL). The combined organic
extracts were washed with H2O (10 mL), dried (MgSO4), and con-
centrated in vacuo. The products were commonly sufficiently pure.
Final purification was possible by flash column chromatography on
silica gel. The recovered precatalyst 2 (on filter paper) was carefully
washed with EtOAc and immediately used for the next Heck–
Mizoroki reaction.
Polymer-bound aryl bromide 9 (loading 0.72 mmol/g) was prepared
according to a literature protocol28b using aminomethylated polysty-
rene (0.9 mmol/g, 1% DVB, 200–400 mesh) and p-bromobenzoyl
chloride. For the 3-phase test, a mixture of p-chloroacetophenone
(4k; 1 mmol), phenylboronic acid (5a; 1.5 mmol), K2CO3 (2 mmol),
TBAB (0.5 mmol), precatalyst 2 (1 mol%; immobilized on PVP,
powder), and polymer-bound aryl bromide 9 (0.4 mmol) in H2O (5
mL) was stirred for 17 h at 100 °C. The polymers were filtered off
and washed with several portions of EtOAc and H2O. 4-Acetyl-1,1¢-
diphenyl (6a) was isolated from the combined filtrates in 92% yield
after the usual workup. The polymer was extracted in a Soxhlet with
CHCl3 for 12 h, dried in vacuo, and heated in an excess of 2 M KOH
in EtOH–H2O (2:1) for 4 days at 90 °C. The solution was neutral-
ized with aq 2 N HCl and extracted with CH2Cl2 (3 × 10 mL). The
combined CH2Cl2 layers were concentrated, and the residue was an-
alyzed by GC-MS.
Heck–Mizoroki Reactions Using Precatalyst 2 Immobilized on
PVP; General Procedure B (Powder, Batch Mode, Convention-
al Heating)
A mixture of aryl bromide (1 mmol), alkene (1.2 mmol), palladium
precatalyst 2 (10 mg of powder, 1 mol%), and Et3N (202 mg, 2
mmol) in DMF (3.5 mL) was stirred at 150 °C in a sealed tube. After
completion of the reaction (GC monitoring), the mixture was dilut-
ed with EtOAc (5 mL), and filtered. The filtrate was diluted with
H2O (10 mL) and extracted with EtOAc (2 × 15 mL). The combined
organic extracts were washed with H2O (10 mL), dried (MgSO4),
and concentrated in vacuo. The products were commonly sufficient-
ly pure. Final purification was possible by flash column chromatog-
raphy on silica gel.
Thiol Scavenger 10
A solution of thiourea (2.04 g, 26.5 mmol) in DMA (50 mL) was
added to Raschig rings (10 g, coated with a Merrifield-type poly-
mer, 5.3% DVB, loading 0.53 mmol benzyl chloride groups/g com-
posite material). The mixture was degassed and then heated at 85 °C
for 24 h under N2. After cooling to r.t., the Raschig rings were thor-
oughly washed with i-PrOH, dioxane, a mixture of dioxane–H2O
(1:1), finally with i-PrOH, and dried in high vacuo. The Raschig
rings were immersed in a mixture of pyrrolidine–dioxane (1:4, 50
mL), the mixture was degassed and then heated at 110 °C for 3 h un-
der N2. After cooling, the Raschig rings were thoroughly washed
with DMA and i-PrOH, and dried under high vacuum. According to
combustion analyses (S: 1.8%), the Raschig rings prepared were
loaded with thiol groups (0.56 mmol/g).
Heck–Mizoroki Reactions Using Precatalyst 2 Immobilized on
PVP; General Procedure (Powder, Batch Mode, Microwave
Irradiation)
The reactions were carried out as described above for the general
procedure B, but employing microwave irradiation at 300 W to
reach 150 °C within 3 min, which was then kept for 30 min. After
cooling to r.t., the coupling products were isolated using the usual
workup procedure.
Continuous Flow Heck–Mizoroki Reaction Using Precatalyst 2
Immobilized on Raschig Rings in Combination with Scavenger
Rings; General Procedure
A solution of aryl halide (1 mmol), alkene (3 mmol) and Bu3N (556
mg, 3 mmol) in anhyd DMF (3 mL) was pumped through the two
consecutive connected flow-through reactors at the flow rate 2 mL/
min in a cycle mode. The first reactor was charged with a Raschig
ring bearing immobilized precatalyst 2 (3.57 × 10–5 mmol Pd/mg,
10 mmol Pd) and held at 120 °C. The second reactor was charged
with a Raschig ring bearing scavenger 10, 11, 12, or 13, or ‘dummy’
and was held at r.t. (in the course of circulation, the temperature in-
creased slowly to ca. 50 °C because of the heat transfer from the
first reactor). After completion of the reaction (GC-monitoring), the
reactors were rinsed with DMF (ca. 40 mL). The solution was dilut-
ed with H2O (80 mL), extracted with EtOAc (3 × 50 mL), and dried
(MgSO4). After concentration in vacuo, the pure coupling product
was isolated by flash chromatography on silica gel.
Heck–Mizoroki Reactions Using Precatalyst 2 Immobilized on
PVP General Procedure (Monolithic PASSflowTM Reactor,
Continuous Flow)
A solution of iodobenzene (306 mg, 1.5 mmol), tert-butyl acrylate
(269 mg, 2.1 mmol) and Et3N (212 mg, 2.1 mmol) in anhyd DMF
(3 mL) was circulated through the PASSflowTM microreactor (2.5
mL/min) loaded with the precatalyst 2 (ca. 0.8 mmol)19 at 110 °C
(oven temperature). After completion of the reaction (24 h), the mi-
croreactor was rinsed with DMF (10 mL) and EtOAc (15 mL). The
solution was diluted with EtOAc (50 mL), washed with H2O (2 × 50
mL), and dried (MgSO4). After concentration in vacuo, the products
were commonly sufficiently pure. Final purification was possible
by flash column chromatography on silica gel.
Heck–Mizoroki Reactions Using Precatalyst 2 Immobilized on
PVP; General Procedure (Raschig Ring PASSflowTM Reactor,
Continuous Flow)
A solution of aryl halide (1 mmol), alkene (3 mmol), and Bu3N (556
mg, 3 mmol) in anhyd DMF (3 mL) was circulated at 120 °C
Catalytic Activity Test of Scavenger Rings after Heck–Mizoroki
Reaction (Continuous Flow Mode)
After performing the Heck–Mizoroki reaction with two linearly
linked reactors as described above, the Raschig ring bearing precat-
alyst 2 was removed from the first reactor and replaced with a ‘dum-
Synthesis 2008, No. 10, 1589–1599 © Thieme Stuttgart · New York

1598
K. Mennecke et al.
PAPER
(8) Yoswathananont, N.; Nitta, K.; Nishiuchi, Y.; Sato, M.
my’ Raschig ring. Then, a solution of aryl halide (1 mmol), alkene
(3 mmol), and Bu3N (556 mg, 3 mmol) in anhyd DMF (3 mL) was
circulated through the connected reactors under the general condi-
tions. Conversion was determined by GC (Figures 3 and 4).
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Test of Catalytic Activity of Thiol Raschig Rings 10 after Heck–
Mizoroki Coupling (Batch Mode)
A solution of aryl halide (1 mmol), alkene (3 mmol) and Bu3N (556
mg, 3 mmol) in anhyd DMF (3 mL) was added to the thiol Raschig
ring 10, which was previously used as a scavenger in the linear re-
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Supporting Information
Supporting information on further coupling reactions carried out
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Acknowledgment
The work was funded by the DFG (Ki 397/6-1) and the Fonds der
Chemischen Industrie. We are grateful to U. Kunz (Institute of Che-
mical Engineering, Technical University of Clausthal, Germany)
for supporting us in all the issues concerning precipitation poly-
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Synthesis 2008, No. 10, 1589–1599 © Thieme Stuttgart · New York