Polymer-supported palladium catalysed Suzuki-Miyaura reactions in batch and a mini-continuous flow reactor system

Article abstract of DOI:10.1016/j.tet.2005.07.109

A polymer-supported palladium(II) salen-type complex exhibited catalytic activity in the cross-coupling reaction of various aryl bromides and heteroaryl bromides with phenylboronic acid in a mini-continuous flow reactor system at elevated temperatures in a phosphine-free system. The reaction was also performed in batch using a number of different solvent systems in order to optimise conditions. The catalytic mini-reactor can be used repeatedly over several cycles in the Suzuki-Miyaura cross-coupling reaction. While the diameter of the flow channel is 3 mm, the macroporous resin supported catalyst is solvent expanded to completely fill the channel. Consequently, the liquid path is through the micro channels of the macroporous resin structure. Intensification of the process over the stirred batch reaction is through increased reagent-catalyst contact and results in a 20-fold increase in the rate of reaction. The residence/space time on the reactor is 10.5 min, compared to 24 h in batch, which means that a diversity of starting materials can be screened over a short period of time. To demonstrate the utility of the system, a diversity of aryl and heteroaryl bromides have been studied.

Full text of DOI:10.1016/j.tet.2005.07.109

Tetrahedron 61 (2005) 12065–12073
Polymer-supported palladium catalysed Suzuki–Miyaura
reactions in batch and a mini-continuous flow reactor system
Nam T. S. Phan, Jamil Khan and Peter Styring
*
Department of Chemical and Process Engineering, The University of Sheffield, Mappin Street, Sheffield S1 3JD, UK
Received 17 June 2005; revised 18 July 2005; accepted 18 July 2005
Available online 20 October 2005
Abstract—A polymer-supported palladium(II) salen-type complex exhibited catalytic activity in the cross-coupling reaction of various aryl
bromides and heteroaryl bromides with phenylboronic acid in a mini-continuous flow reactor system at elevated temperatures in a phosphine-
free system. The reaction was also performed in batch using a number of different solvent systems in order to optimise conditions. The
catalytic mini-reactor can be used repeatedly over several cycles in the Suzuki–Miyaura cross-coupling reaction. While the diameter of the
flow channel is 3 mm, the macroporous resin supported catalyst is solvent expanded to completely fill the channel. Consequently, the liquid
path is through the micro channels of the macroporous resin structure. Intensification of the process over the stirred batch reaction is through
increased reagent-catalyst contact and results in a 20-fold increase in the rate of reaction. The residence/space time on the reactor is 10.5 min,
compared to 24 h in batch, which means that a diversity of starting materials can be screened over a short period of time. To demonstrate the
utility of the system, a diversity of aryl and heteroaryl bromides have been studied.
q 2005 Elsevier Ltd. All rights reserved.
7
1
. Introduction
and reused several times before they deactivate completely.
At the same time, the catalyst recovery also decreases
contamination of the desired products with hazardous or
harmful compounds, and also environmental pollution
caused by residual of toxic metals and organic and inorganic
Metal-catalysed cross-coupling reactions have gained
popularity over the past 30 years, in particular as convenient
techniques for the formation of carbon–carbon bonds.
Numerous reactions have been developed to achieve cross-
coupling, of which the Suzuki–Miyaura reaction is one of
the most efficient methods for the synthesis of biaryl and
1
8
waste can be reduced. So far, palladium metal immobilised
on cross-linked polystyrene resins and silica gels have been
9
,10
used in Suzuki–Miyaura reactions.
However, they
2
,3
heterobiaryl derivatives.
The tolerance of various
normally suffer from limited mass transfer, low specificity
and selectivity and leaching of the catalytic species from the
surface of the support. Recently new catalysts have been
described that go some way to achieving greener hetero-
geneous processing, in particular the now commercially
available EnCate polymer encapsulated palladium
functional groups in the coupling process, the diversity of
organoboron compounds that are environmentally safer than
other organometallic reagents, and the ease of handling and
removal of boron-containing by-products offer the Suzuki–
9
4
Miyaura reaction advantages over other related techniques.
1
1
complexes of Ley et al. and the Chitosan-supported
Catalysts used in the standard processes are generally based
on either homogeneous nickel or palladium phosphine
complexes, which are rarely recoverable without elaborate
and wasteful procedures, and, therefore, commercially
undesirable. Moreover, phosphine ligands are expensive,
toxic, and in large-scale applications the phosphines may be
a more serious economical burden than even the metal
1
2
materials reported by Hardy et al. Kwong and co-workers
have also described reactions using chloroaromatics at low
catalyst loading that give excellent turnover numbers and
yields but which is at present confined to homogeneous
catalysts with semi-labile phosphine ligands.
1
3
2
,5
6
Reactor miniaturisation, for example micro reactors in
which microlitre quantities of reagents are manipulated, has
been shown to confer many advantages over conventional
laboratory scale chemical apparatus. Micro reactor
technology clearly offers considerable advantages in
performing safer and more efficient chemical reactions. In
particular, the number of compounds that can be prepared
and screened can be considerably increased thereby
itself. In recent years there has been an increasing interest
in developing greener processes. In this context, hetero-
geneous catalysis is emerging as an alternative to
homogeneous processes so that catalysts can be recovered
1
4
Keywords: Suzuki–Miyaura; Palladium; Cross-coupling; Continuous flow.
*
Corresponding author. Tel.: C44 114 222 7571; fax: C44 114 222 7501;
e-mail: p.styring@sheffield.ac.uk
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.109

1
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N. T. S. Phan et al. / Tetrahedron 61 (2005) 12065–12073
5,16
1
enhancing the discovery phase.
Furthermore, the
reaction, albeit on a much smaller scale. This allows small
quantities of products to be prepared and screened quickly,
allowing diversity studies and high throughput synthesis to
be carried out. The compact design of the reactors also offer
the opportunity of scale-out through reactor parallelisation
although this will not be discussed in this paper.
capability of producing a parallel network of micro reactors,
the so-called ‘scaling out’ of the process, offers a clear route
to generating product volume on demand, at the point of
use, so reducing the need to store and transport hazardous or
1
7,18
highly reactive chemicals.
To date the scope of liquid
phase synthesis in micro reactors has, in the majority, been
limited to non metal-catalysed reactions, with the exception
1
9,20
of a few examples of heterogeneous catalysis.
There are
2. Results and discussion
2.1. Catalyst preparation
only a couple of reports of heterogeneously catalysed
Suzuki–Miyaura reactions in miniaturised continuous-flow
reactors. Greenway et al., have reported the Suzuki–
Miyaura reaction within a micro reactor operating under
electro osmotic flow, using palladium on silica as catalyst to
produce 4-cyanobiphenyl in 67% yield at room tempera-
The Merrifield resin-supported salen-type palladium(II)
complex was prepared according to previously reported
procedures (Scheme 1).
2
3
2
1
ture. However, the electric field played a major role in this
catalytic process as no reaction was observed in an identical
reactor system where EOF was replaced by pressure driven
flow. He et al., recently investigated the microwave-assisted
heterogeneous Suzuki–Miyaura reaction in a micro reactor,
with 99% yield of 4-cyanobiphenyl being achieved at
Inductively coupled plasma-atomic emission spectroscopy
(ICP-AES) analysis indicated there to be ca. 2% (wt/wt)
palladium on the Merrifield beads, corresponding to a
catalyst loading of 0.2 mmol palladium/g of resin. Initial
studies focused on the coupling reaction of 4-bromoanisole
and phenylboronic acid (Scheme 2) in stirred batch reactors
in order to obtain comparative data.
2
2
1
00 8C.
Recently we reported the synthesis and characterisation of
an unsymmetrical salen-type palladium(II) complex and its
immobilisation onto a polystyrene–divinylbenezene cross-
2.2. Solvent studies in batch
2
3
linked Merrifield resin. The supported catalyst was air-
and moisture-stable, and could be reused several times
without a significant degradation in catalytic activity in the
Suzuki–Miyaura reaction of 4-bromoanisole and phenyl-
boronic acid at 90 8C. Importantly, the reaction was carried
out successfully without the need for intrinsic or added
phosphine ligands. Leaching of the palladium into solution
The combination of K PO suspended in DMF and the
4
3
palladium resin catalyst has been shown to produce the
desired coupling product, that is, 4-methoxybiphenyl, in
2
4
satisfactory yields. However, in order to transfer the
reaction to a continuous flow reactor, a totally homogeneous
mixture was necessary as any solid in the flowing liquid
would potentially cause blockages in the reactor. It was,
therefore, decided to investigate a number of solvent-base
combinations in order to optimise the process. Reactions
were carried out in a Radley’s Carousel Parallel Synthesiser
fitted with a fuzzy logic temperature controller, using DME/
water 1:1, ethanol/water 1:1 and PEG-300/water 1:1 and 4:1
2
4
from the supported catalyst proved almost negligible. In
this paper we report for the first time, to the best of our
knowledge, the cross-coupling reactions of various aryl
bromides and heteroaryl bromides with phenylboronic acid
in a mini-continuous flow reactor system using the
heterogeneously polymer-supported homogeneous palla-
dium catalyst. The use of the polymer-supported catalyst
in the continuous flow system enabled product streams to be
palladium free as leaching was minimised, removing the
requirement for downstream catalyst separation. Reason-
able conversions could be achieved in a matter of minutes,
compared to conversions obtained after 24 h in a batch
with sodium carbonate as base and also DMF/H O 1:1 with
2
N,N-diisopropyl ethyl amine as the base. In each case the
reaction time was set to 24 h and the temperature
thermostated at 100 8C. Yields were determined by GC
against standard calibrations for each of the expected
products. These data were used to determine the turnover
frequencies (TOFs) before transferring the optimised
Scheme 1. The immobilisation of the salen-type palladium(II) complex.
Scheme 2. The Suzuki–Miyaura reaction of 4-bromoanisole and phenylboronic acid.

N. T. S. Phan et al. / Tetrahedron 61 (2005) 12065–12073
12067
conditions to the continuous flow system. All reactions were
carried out under a nitrogen atmosphere to prevent oxidation
of the boronic acid to the phenol, which leads to the
formation of the homocoupled product, unsubstituted
biphenyl.
Reactions in PEG-300/water 1:1 and ethanol/water 1:1
failed to yield any product while DME/water 1:1 gave only
5
% yield, although the homocoupled product was detected.
It was, therefore, decided to use a procedure modified from a
method that originally involved microwave heating of the
2
5
reaction solution. The original procedure used palladium(II)
chloride in a mixture of PEG-400/water. Reactions were
attempted using PEG-300/water in the ratio 4:1 using the
Figure 1. Study of the conversion dependence on flow rates in the
continuous Suzuki–Miyaura reaction between 4-bromoanisole and phenyl-
boronic acid at 100 8C.
palladium resin catalyst as well as homogeneous PdCl . The
2
reactions were studied over a 24 h period and the kinetics
studied as well as determining the TOFs. For the
homogeneous catalyst a pseudo-first order overall rate
The Omnifit reactor is a low pressure liquid chromatography
column, which is packed with the catalyst particles; these
are held in place by 25 mm pore size stainless steel frits
integrated in to the screw caps that connect the column to
the fluidic system, at the reactor entrance and exit. The
catalyst particles swell in the solvent to tightly pack into the
reactor body. Solvent removal allows the particles to de-
swell. The design of the reactor system makes catalyst
filling and removal an extremely easy and quick process.
The reactor was heated by immersing it in a water bath at
K5 K1
constant of 1.4!10
sodium carbonate as the base. The heterogeneous resin
s
was determined at 100 8C using
supported catalyst showed an enhanced rate with a pseudo-
under the
K5 K1
s
first order overall rate constant of 3!10
same conditions. TOF studies also revealed some interesting
characteristics of the heterogeneous catalyst relative to
PdCl . All reactions were performed using 1.0 mmol of
2
4
-bromoanisole and 1.1 mmol benzene boronic acid with an
accurately weighed quantity of catalyst. A higher mole
fraction of the homogeneous salt was required (28 mol%)
giving a typical TOF of 0.18 h . For the resin-supported
100 8C. Reactants from a syringe at room temperature were
K1
then pumped through 0.8 mm internal diameter PTFE
tubing at 100 8C and then through the palladium resin
catalyst in the flow reactor at known flow rates for 5 h.
K1
palladium catalyst TOFs of 0.40 and 0.38 h
were
determined at 5 and 18 mol%, respectively. Further
reactions were studied using 18 mol% of the resin-
supported catalyst with increasing amounts of starting
materials, maintaining a 10% excess of the boronic acid. At
2.0 and 5.0 mmol 4-bromoanisole respective TOFs of 0.74
and 1.84 were determined. However, after due consideration
The reaction was carried out in the continuous flow reactor
at different flow rates to investigate the effect of the
residence time of the reagents within the catalyst bed on the
coupling process. The results of conversion dependence on
flow rates are shown in Figure 1. It was found that
it was decided to use DMF/H O 1:1 and N,N-diisopropyl
2
ethyl amine as the solvent/base system in the flow reactor.
Although this organic amine has been shown to be less
effective than Na CO or K PO in the Suzuki–Miyaura
4-methoxybiphenyl was formed in a yield of only 46% at a
flow rate of 13 ml/min. This indicates that the residence time
at this flow rate was too fast for the continuous Suzuki–
Miyaura reaction, reducing reagent contact with the catalyst
bed. Increasing the flow rate to more than 13 ml/min resulted
in a significant drop in reaction conversion, with only 27 and
2
1
3
3
3
4
reaction in batch, it is totally soluble under the reaction
conditions used in the continuous flow reactor and showed
satisfactory results in our batch studies. Using a mole
2
4
fraction of only 0.5 mol%, a TOF of 6.4 was determined.
The results from the TOF studies are summarised in Table 1.
2
2
2% of 4-methoxybiphenyl being produced at flow rates of
0 and 25 ml/min, respectively. As expected, decreasing the
flow rate to less than 13 ml/min increased the conversion to
52% at a 6 ml/min flow rate and up to 56% conversion for
2
.3. Mini flow reactor studies
3
ml/min. Since the reaction conditions such as concen-
The continuous Suzuki–Miyaura reaction was carried out in
a pressure driven mini flow reactor (bed sizeZ25 mm!
3 mm) constructed from Omnifit glassware with back-
pressure being supplied by a syringe pump (RAZAL A-99).
tration, ratio of phenylboronic acid to 4-bromoanisole, base,
solvent and temperature remained unchanged in all cases,
the observed increase in conversion with decreasing flow
rate was obviously due to an effective increase in residence
Table 1. Turnover frequencies (TOF) in the Suzuki–Miyaura reaction of 4-bromoanisole with 1.1 equiv PhB(OH)
base and solvent under stirred batch conditions (based on GC–S data)
2
at 100 8C with different palladium catalysts,
K1
Substrate concn (mol)
Catalyst (mol%)
PdCl (28)
Pd resin (5)
Pd resin (18)
Pd resin (18)
Pd resin (18)
Pd resin (0.5)
Solvent system
Base
TOF (h
)
1.0
1.0
1.0
2.0
5.0
1.0
2
PEG300/H
PEG300/H
PEG300/H
PEG300/H
PEG300/H
2
2
2
2
2
O (4:1)
O (4:1)
O (4:1)
O (4:1)
O (4:1)
Na
Na
Na
Na
2
CO
2
CO
2
CO
2
CO
2
CO
3
3
3
3
3
0.18
0.40
0.38
0.74
1.84
6.40
Na
i
DMF/H
2
O (1:1)
2
Pr NEt

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N. T. S. Phan et al. / Tetrahedron 61 (2005) 12065–12073
with that of the batch reaction under the same reaction
conditions. For the batch reaction, aliquots were withdrawn
at different time intervals to measure the corresponding
conversion. The data were then analysed using the first order
reaction design equation (Eq. 1), where x is the mole
fraction of 4-methoxybiphenyl produced and t is the
corresponding reaction time (Fig. 3). The reaction was
shown to be pseudo first order overall with respect to the
bromide, giving an observed overall rate constant of 5!
K5 K1
K1
1
0
s
(0.18 h ). It should be noted that in a continuous
flow reactor, the mean residence time is also the reaction
time and that the residence time in the mini flow reactor is
much shorter than in the batch process. The continuous
reaction was also assumed to be pseudo first order because
the mechanism in batch and flow modes should be the same,
so comparisons were made using this assumption. The
residence time of the solution within the catalyst bed was
Figure 2. Study of the conversion against reactor run time in the continuous
Suzuki–Miyaura reaction at the flow rate of 3 ml/min over 6 h. The actual
residence time was 21 min.
2
6
measured according to a standard literature procedure ,
giving a value of 10.5 min at the flow rate of 6 ml/min. This
means that the observed rate constant of the coupling
K3 K1
time within the continuous reactor and hence an increase in
the reaction time. It should be noted that because of the
solvent induced swelling of the catalyst particles, the
catalyst tightly packs the body of the reactor causing fluid
and reagent flow through the internal macroporous structure
of the resin as well as, to some extent, around the particles.
reaction was considerably faster, with kobsZ1!10
(
s
3.6 h ) using the continuous mini flow reactor. This
K1
represents an enhancement of the reaction rate of 20 times
as compared to the batch reaction. This enhancement of the
rate can be reconciled with the fact that the actual relative
catalyst concentration within the element of the continuous
flow reactor, relative to the reactants, is much higher than in
the stirred batch reactor system. This means that there is
much more efficient contacting of the reactants with the
catalyst surface, and interior, as the reaction solution if
The conversion data presented in Figure 1 were achieved
using a total 5 h reaction time (i.e., the average conversion
over this period). However, it became clear that the reaction
conversion changed during the period. The continuous
reactor using the supported palladium catalyst was run
continuously for 6 h at the flow rate of 3 ml/min with product
samples being collected every hour. The results of this study
are shown in Figure 2. It was found that 4-methoxybiphenyl
was produced in a yield of approximately 40% over the first
hour while an average conversion of approximately 60%
was achieved over the subsequent 4 h. The lower conversion
achieved in the first hour is most likely due to an induction
period that corresponds to the delay required for the
reduction of the catalyst precursor Pd(II) to the catalytically
active Pd(0) oxidation state, although a complete reaction
pathway for the Suzuki–Miyaura reaction using the
polymer-supported salen-type palladium(II) catalyst is on-
going and still remains to be elucidated. As the palladium
catalyst could be reused in the batch reaction without a
significant degradation in activity, we decided to test the
activity of the recycled catalyst after this 6 h period of
reaction in the continuous flow reactor. The palladium
catalyst was washed several times with DMF, water and
THF to remove any excess or surface deposited reagents,
and dried under vacuum prior to re-use. A similar trend in
activity was observed for the recycled catalyst.
2
.4. Kinetics studies
Many chemical reactions have been demonstrated to show
improved reactivity, product yield and selectivity when
performed in micro reactors, compared with those generated
1
4–17
using conventional laboratory practices.
We, therefore,
decided to investigate if there was an enhancement of the
observed rate constant for the continuous flow reaction of
Figure 3. Kinetic data of the Suzuki–Miyaura reaction in a stirred batch
reactor using the palladium resin catalyst over 7 h at 100 8C, showing an
K5 K1
4
-bromoanisole and phenylboronic acid, when compared
observed pseudo first order rate constant of 5!10
s
.

N. T. S. Phan et al. / Tetrahedron 61 (2005) 12065–12073
12069
pumped through the fixed bed when compared to the batch
system, which is dependent on mass transport phenomena
between the liquid and solid phases.
A favourable effect of electron-withdrawing substituents is
normally observed in palladium-catalysed coupling
2
7
reactions. However, the continuous Suzuki–Miyaura
reaction of 4-bromonitrobenzene failed with the coupling
product being detected only in trace amount (entry 5),
despite the fact that the nitro group is strongly electron-
withdrawing. All attempts to carry out the reaction of
4-bromoaniline (entry 6) were also unsuccessful. Similarly,
1
kobsZK½lnð1KxÞꢀ! t
(1)
2
.5. Substrate diversity studies
5-bromoisatin, which possesses a secondary amine function
The study was then extended to several substituted
bromobenzenes containing both electron-withdrawing and
electron-donating groups using the palladium resin catalyst,
in order to test the tolerance of functional groups as well as
their effects on the conversion. The reactions in the
continuous flow reactor were run for 5 h at the flow rate
of 6 ml/min at 100 8C. The results are shown in Table 2. As
and two carbonyl groups (entry 7), was also completely
unreactive. This unexpected behaviour with this catalytic
system still remains to be clarified but further studies are on-
going. 4-Bromotoluene, which is electron-rich, still afforded
the coupling product in a good conversion of 68% (entry 8).
This is in accordance with the results of Ikegami et al.,
where 4-bromotoluene was found to be more reactive than
2
4
28
with the batch reactions, it was found that electron-
deficient substrates such as 4-bromobenzaldehyde (entry 1),
4-bromoanisole in the Suzuki–Miyaura reaction. How-
ever, conversely Leadbeater et al. have also reported that the
reaction of 4-bromoanisole and phenylboronic acid gave a
better yield.
4
(
-bromoacetophenone (entry 2) and 4-bromobenzonitrile
entry 4) were more reactive than 4-bromoanisole, giving
2
9,30
higher yields of 74, 67 and 77%, respectively. The ester
function (entry 3) survived the reaction, giving the ester-
substituted coupled product in a yield of 65% with no
detectable traces of the corresponding carboxylic acid.
Because of the synthetic importance of heterobiaryl
derivatives, we also wished to carry out the Suzuki–
Miyaura reactions of bromopyridines, bromothiophenes
Table 2. The Suzuki–Miyaura reaction of aryl bromides in the continuous flow reactor using the palladium resin catalyst, 1.5 equiv PhB(OH)
diisopropyl ethyl amine in DMF/water 1:1 at 100 8C, at the flow rate of 6 ml/min
2
, 3 equiv N,N-
Entry
Substrate
Product
Conversion (%)
1
74
2
3
65
65
4
5
6
77
Trace
0
7
8
0
68
37
71
1
1
0
1
a
76
12
The data represent conversions of the bromides to cross-coupling products (based on GC–S data).
a
DMF/water 3:1 was used instead of DMF/water 1:1.

12070
N. T. S. Phan et al. / Tetrahedron 61 (2005) 12065–12073
3
4
and bromofurans with phenylboronic acid in the continuous
flow reactor using the palladium resin catalyst (Table 3).
Palladium was previously found to possess strong thiophi-
licity, which was reflected in the poisoning effect of the
sulphur atom on some palladium-catalysed reactions. This
poisoning effect was also observed in the presence of
by Molander and Biolatto. However, over 10% of both 2-
and 3-bromothiophene ended up in the corresponding
homo-coupling product, which was not observed in the
Suzuki–Miyaura reaction of any other organobromide used
in this study. It is possible there is a substrate–metal
interaction in one of the possible catalytic transition states
that is affecting the outcome. However, a complete reaction
pathway still remains to be elucidated. It is interesting that
in general no homocoupled product was observed, even
though the continuous flow reactions were not carried out in
a nitrogen atmosphere. Therefore, the reaction in the mini-
reactor is more selective than the reaction in batch.
3
1
nitrogen atoms. For this reason, the position of the
bromide on a heteroaromatic ring should have an important
effect on the coupling reaction. Due to the electronegativity
of the nitrogen atom, it was reasoned that 2-bromopyridine
should be more reactive towards the oxidative addition,
which is normally the rate-limiting step of the reaction, than
3
2
3
-bromopyridine. In fact, a conversion of 70% was
achieved for the reaction of 3-bromopyridine with
phenylboronic acid (entry 15), while 2-bromopyridine
remained almost unreacted under the same reaction
conditions (entry 14). The same trend in the reactivity
between substitution in the 2- and 3-postitions has also been
observed by others, although the difference in reactivity
between the two isomers of bromopyridines was much less
Wiles et al. have recently reported a Michael addition
reaction in a micro reactor under EOF conditions, in which
enhancements in conversions through the application of the
3
5
stopped flow technique were achieved. This procedure
involved the mobilisation of reagents through the glass
micro reactor device for a designated period of time using
an applied electric field, and the flow was subsequently
paused by the removal of the applied field, prior to re-
applying the field. The authors proposed that the observed
increase in conversion, when using the technique of stopped
flow, was due to an effective increase in residence time
within the reactor. We, therefore, decided to apply the
stopped-flow technique to the Suzuki–Miyaura reaction of
4-bromobenzaldehyde with phenylboronic acid using the
palladium resin catalyst in the continuous flow reactor. In
fact, this technique is an alternative route to decreasing the
flow rate to increase the space time of reagents within
the catalyst bed. The results are shown in Figure 4. As the
residence time was found to be 10.5 min at a flow rate of
3
1–34
significant.
capacity for 2-bromopyridine to complex to the palladium
It was previously presumed that the
3
4
catalyst prevented the coupling reaction. The reaction of
-bromopyrimidine, although it is an electron-poor hetero-
5
aryl bromide, proceeded with low yield (entry 16). The
Suzuki–Miyaura reaction of 5-bromo-2-furaldehyde pro-
ceeded with very good conversion being achieved (entry
3
1,32
1
3), in accordance with results of Feuerstein et al.
It was
found that the reaction of 2-bromothiophene led to a high
yield of over 80% (entry 17), while a conversion of only
3
1
9% was afforded in the reaction of 3-bromothiphene (entry
8). This is in accordance with results previously reported
Table 3. The Suzuki–Miyaura reaction of heteroaryl bromides in the continuous flow reactor using the palladium resin catalyst, 1.5 equiv PhB(OH)
N,N-diisopropyl ethyl amine in DMF/water 1:1 at 100 8C, at the flow rate of 6 ml/min
2
, 3 equiv
Entry Substrate
Product
Conversion (%)
91
13
1
1
1
4
5
6
1
70
42
17
18
19
20
82
39
a
88
a
55
The data represent conversions of the bromides to cross-coupling products (based on GC–S data).
a
4-Methoxybenzeneboronic acid was used instead of benzeneboronic acid.

N. T. S. Phan et al. / Tetrahedron 61 (2005) 12065–12073
12071
palladium(II) complex was synthesised according to
previously published methods. Mass Spectra were
2
0
recorded by Jane Stanbra and Simon Thorpe, ICP-ES
analyses were performed on a Spectro Ciros
CDD
instrument
Spectro Analytical, UK) by Ian Staton from the Depart-
(
ment of Chemistry, The University of Sheffield. GC–MS
analyses were performed using a Perkin Elmer GC–MS with
a 30 m!0.25 mm!0.25 mm Phenomenex-2B5 column.
K1
The temperature program was 60–260 8C at 10 8C min
with a final temperature isothermal hold for 10 min. The MS
mass limit was set between 50 and 450 Da.
4.2. Catalyst preparation
A yellow solution of palladium complex (0.20 g,
0.54 mmol) in dry DMF (40 ml) and THF (20 ml) was
added dropwise at room temperature to a dispersion of
excess 60% sodium hydride in mineral oil (0.06 g,
Figure 4. Study of stopped flow technique in the Suzuki–Miyaura reaction
of 4-bromobenzaldehyde using the continuous flow reactor at the low rate
of 6 ml/min, with the regime of 10 min on and between 0 and 20 min off.
1
.5 mmol) and the resulting mixture stirred for 10 min. A
suspension of Merrifield resin (2 g, 200–400 mesh,
.7 mmol-Cl/g, 3.4 mmol) that had been pre-swelled in
6
1
ml/min, reactants were pumped through the reactor for
0 min and the flow was subsequently paused for a
1
designated period of time, prior to re-injecting the solution.
The syringe pump was controlled using an automated cyclic
timer unit, which was designed and constructed in-house.
Using the regime of 10 min on and 5 min off, the
conversions were slightly improved to 76%. Lengthening
the stopped flow period to 10 min resulted in a further
increase to around 80% conversion. The conversion could
be improved to 83 and 86% by stopping the flow for 15 and
DMF (40 ml) for 30 min was then added and the mixture
stirred gently at room temperature for 24 h. The initially
white Merrifield resin beads became yellow and the
solution turned pale yellow. The beads were filtered off,
washed several times with water (3!50 ml), triturated
several times for a total of 24 h with DMF (5!50 ml),
THF (3!50 ml), diethyl ether (3!50 ml) to remove
physically adsorbed palladium complex and air-dried to
yield yellow beads (2.0 g). Inductively coupled plasma-
atomic emission spectroscopy (ICP-AES) measurements
showed there to be ca. 2% (wt/wt) palladium on the
Merrifield beads, corresponding to a catalyst loading of
2
0 min, respectively. No by-products were observed, the
mass balance being completed by unreacted starting
material.
0.2 mmol palladium/g of resin.
3. Conclusions
4
.3. ICP analysis of the supported catalysts
The polymer-supported palladium(II) complex exhibited
catalytic activity in the cross-coupling reactions of various
aryl bromides and heteroaryl bromides with phenylboronic
acid in a mini-continuous flow reactor system without the
need for phosphine ligands. Using the mini-flow reactor
system, reasonable conversions can be achieved in a matter
of minutes. Although simple in design and concept, with
easily replaceable catalyst beds and interchangeable
reagents premixes, as there is no reaction in the absence
of the catalyst, the mini-flow reactor system provides a
powerful tool in catalyst screening and a route to high
throughput synthesis. Therefore, the mini flow system is
ideal for the rapid production of small inventories of
reagents. Products can be generated on demand, at the point
of use, so reducing the need to store and transport hazardous
chemicals. Furthermore, we have demonstrated that the use
of stopped-flow techniques are applicable to the Suzuki–
Miyaura reaction, leading to increased residence time in the
reactor and an increase in product yield.
Calibration against palladium standards and a blank was
linear, using 2% nitric acid solutions containing 0, 1, 5 and
10 ppm palladium made from a 1000 ppm stock solution
(Aristar). Weighed samples (20.0 mg) of immobilised
palladium catalysts were placed in glass tubes and digested
3
at 180 8C in a mixture of concentrated nitric acid (5 cm ,
3
Aristar) and concentrated perchloric acid (0.5 cm , Aristar).
Three parallel samples were digested in 2, 4 and 6 h,
respectively. The yellow palladium catalyst became a white
residue after digestion. The digest was then diluted to
3
5
0 cm with water. Analysis showed that all the palladium
was removed from the support within 2 h as increasing the
digestion time to 4 and 6 h achieved no increase in the
amount of the palladium in the digest.
4
4
.4. Catalysis studies
.4.1. Batch reactions. Unless otherwise stated, a solution
of 4-bromoanisole (0.0561 g, 0.3 mmol) in DMF (0.75 ml)
was added to a Radley’s Carousel reaction tube constaining
the palladium resin catalyst (7.5 mg, 0.0015 mmol). A
solution of N,N-diisopropyl ethyl amine (0.116 g,
0.9 mmol) in water (1.5 ml) and a solution of phenylboronic
acid (0.054 g, 0.45 mmol) in DMF (0.75 ml) were then
added and the tube was heated at 100 8C for 24 h with
magnetic stirring under a nitrogen atmosphere. To work-up,
4
. Experimental
4
.1. General
Chemicals were obtained from Aldrich and Fisher and
were used as received. The unsymmetrical salen-type

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N. T. S. Phan et al. / Tetrahedron 61 (2005) 12065–12073
the mixture was allowed to cool to room temperature
and saturated aqueous NaCl solution (3 ml) was added. The
organic components were extracted into diethyl ether (3!
time within the catalyst bed was found to be 10.5 min at the
flow rate of 6 ml/min.
3
ml), which was dried over anhydrous MgSO and the
4
resulting solution analysed by GC and GC–MS with
reference to standard solutions of 4-methoxybiphenyl.
Acknowledgements
We wish to thank the Vietnamese Government for financial
support in the form of a studentship to NTSP and to
Oz MacFarlane for construction of the cyclic timer.
4
.4.2. Micro flow reactions. Unless otherwise stated, the
Suzuki–Miyaura coupling reaction of 4-bromoanisole with
phenylboronic acid was carried out in a pressure driven
micro flow reactor (lengthZ25 mm; I.D.Z3 mm) build up
from Omnifit glassware containing the Merrifield resin-
supported palladium catalyst (110 mg). Standard HPLC
connectors allowed one end of the reactor to be connected to
a disposable solvent-resistant syringe, while the other end
was attached to a syringe needle leading to a quenching
vessel containing diethyl ether and saturated aqueous
References and notes
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3
2
2. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
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9
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5
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Figure 5. The outlet absorbance distribution versus time at the wavelength
of 520 nm and the flow rate of 6 ml/min using CoCl in DMF/H O.
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