Suzuki cross-coupling reactions using reverse-phase glass beads in aqueous media

Article abstract of DOI:10.1016/S0040-4039(03)01128-6

Reverse-phase glass beads have been employed in Suzuki reactions to provide, in aqueous media, a route to diverse polar substrates in good yield and with low levels of palladium leaching.

Full text of DOI:10.1016/S0040-4039(03)01128-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5095–5098
Suzuki cross-coupling reactions using reverse-phase glass beads
in aqueous media
a
b
b
b
Kokovi M. Lawson Daku, Roger F. Newton, Simon P. Pearce, Julia Vile and
a,
Jonathan M. J. Williams *
a
Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
b
Maybridge plc, Trevillett, Tintagel, Cornwall PL34 0HW, UK
Received 13 March 2003; revised 25 April 2003; accepted 2 May 2003
Abstract—Reverse-phase glass beads have been employed in Suzuki reactions to provide, in aqueous media, a route to diverse
polar substrates in good yield and with low levels of palladium leaching. © 2003 Elsevier Science Ltd. All rights reserved.
Controlled-pore glass beads have been used in sup-
ported liquid-phase catalysis for a variety of transition
metal catalysed reactions. Generally, the hydrophilic
active catalyst. After removal of excess solvent, the
supported catalyst can be handled under a normal
atmosphere. We assume that the catalyst is still mobile
within a thin film of cyclohexane on the surface of the
glass bead, and that reaction occurs at the solvent
1
glass supports an aqueous film which contains a water-
2
soluble catalyst. However, straightforward derivatisa-
3
1
tion of the glass to provide a hydrophobic surface,
interface.
allows the support of non-polar solvents and conven-
tional non-polar catalysts. It is therefore possible to use
simple non-polar ligands such as PPh3 using the
reverse-phase glass bead methodology. We have previ-
ously reported the use of reverse-phase glass beads in
7
In a typical Suzuki reaction, boronic acid 1, 4-carb-
oxyphenyl boronic acid, was coupled with 4-iodobenz-
oic acid (Table 1, entry 1). The reaction was carried
out in water under the conditions indicated in Scheme
3.
4
Heck reactions and allylic substitution reactions.
The Suzuki reaction is a versatile and powerful tool for
After only 5 min, the coupled product was synthesised
in good yield (86%) and with minimal palladium leach-
ing (0.06%).
the formation of CꢀC bonds, and has previously been
5,6
8
reported using water-soluble palladium catalysts.
Herein, we wish to describe our results for the Suzuki
cross-coupling of boronic acids 1 to 3 (Scheme 1) with
various organohalides.
The boronic acid 1 was also coupled with a variety of
other aryl halides to provide the corresponding coupled
The derivatised glass beads were prepared by treatment
of the beads with octyl trimethoxysilane, following the
3
procedure reported previously. The commercially
,
available Davisil 500 A beads were used as the silica
support.
Scheme 2 illustrates the general conditions for the
conversion of the reverse-phase glass bead into an
Scheme 1.
Scheme 2.
Keywords: glass bead technology; Suzuki cross-coupling; aqueous
media; polar substrates.
*
Corresponding author. Tel.: +44-1225-383942; fax: +44-1225-
86231; e-mail: j.m.j.williams@bath.ac.uk
3
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01128-6

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096
K. M. Lawson Daku et al. / Tetrahedron Letters 44 (2003) 5095–5098
Table 1. Suzuki cross-coupling reactions of boronic acid 1 using the reverse-phase supported catalyst
found that even with rigorous exclusion of oxygen, the
self-coupling product was formed in similar yields.
We were pleased to find that the palladium leaching
levels observed for all of the compounds were low,
ranging from 0.06 to 0.63% of total palladium used. It
is important to determine the percentage of metal con-
tamination into the products, especially for possible
pharmaceutical applications.
Scheme 3.
The recycling of the catalyst with boronic acid 1 has
been briefly examined. Recycled catalyst was used in a
repeat reaction without any appreciable loss of activity
for entry 4. 97% then 94% of isolated yield of coupled
product was achieved using 3 mol% of supported cata-
lyst in water at reflux. The palladium leaching was
below 1 ppm.
products (Table 1). In general, reactions were run for
1
.5–4 h, although this is probably not a requirement.
Small amounts of self-coupling products were also
obtained in some cases. Moreno-Ma n˜ as et al. have
reported the influence of an inert atmosphere on the
The presence of the glass beads has a strong influence
on the rate of the reaction. Thus the reaction described
in Scheme 3 was demonstrated to proceed to comple-
9
formation of the homo-coupling product. In their
study, oxygen accelerates the reaction. However, we

K. M. Lawson Daku et al. / Tetrahedron Letters 44 (2003) 5095–5098
5097
Scheme 4.
tion in less than 5 min using the supported catalyst,
while the conventional catalyst Pd(PPh3)4 gave only
5
0% conversion after 7.5 h. The increased reaction rate
Scheme 5.
can be attributed to the large contact area between the
water and the organic phase when beads are present.
the reagents were solubilised by adding extra equiva-
lents of base. Therefore it was important to find a
system of solvents that would allow a good solubility of
both reagents. Acetonitrile was chosen as a co-solvent,
Other boronic acids (2 and 3) have been successfully
coupled using the reverse-phase glass beads. Both
reagents have lower water solubility than 1, therefore a
higher palladium leaching was expected in their final
coupled products.
11
as it has been used in similar reactions.
The most successful results were obtained using a
water/acetonitrile (7:3) mixture as solvent, with Na CO
In particular, boronic acid 2 has been coupled with a
selection of aryl halides under the conditions described
in Scheme 4.
2
3
to deprotonate the carboxylic acid and CsF to promote
the Suzuki reaction. It was interesting to note that the
leaching level was higher than in earlier examples. We
speculate that the pyridine may be able to act as a
ligand to draw palladium into the aqueous layer. Addi-
tionally, the lower polarity of the water/acetonitrile
solvent may have an effect on partitioning.
Although the solubility of boronic acid 2 is lower than
boronic acid 1 in water, the isolated yields obtained are
moderate to good (Table 2). In addition no self-cou-
pling product has been observed for this boronic acid.
Whilst aryl iodides and aryl bromides were satisfactory
coupling partners, only small amounts of coupled
product (6%) were obtained when using 4-chlorobenz-
oic acid with boronic acid 2, and no product formed at
all with 1. Alternative non-polar ligands for palladium
have not been examined, although reverse-phase glass
bead methodology could, in principle, be applied to
The majority of the reactions described in this commu-
nication were performed on a small scale, typically 0.5
mmol. We carried out one reaction on a larger scale.
Compound 7 was produced in high yield and with low
level of palladium leaching (Scheme 6).
10
other non-polar ligands.
In summary, a supported catalyst derived from
Pd(PPh ) gave an efficient Suzuki cross coupling of
3
4
The reaction with 4-pyridinylboronic acid 3 was exam-
ined (Scheme 5). The first attempt at cross coupling
with 4-iodobenzoic acid in water did not provide any
product. This was probably due to a poor solubility of
the boronic acid. We reasoned that in order to achieve
the best reactivity both reagents should be well solu-
bilised. When the reaction was run exclusively in water,
boronic acids with several organohalides, in good yields
and with low levels of palladium leaching, even though
these levels are higher than for ordinary-phase glass
4
beads. In addition, the recycling of the reverse-phase
glass beads has been investigated. Initial results showed
that the catalyst could be recycled at least once without
any loss of activity.
Table 2. Suzuki cross-coupling of 2 with organohalides
using the reverse-phase supported catalyst
Scheme 6.

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K. M. Lawson Daku et al. / Tetrahedron Letters 44 (2003) 5095–5098
Acknowledgements
added Na CO (2 M, 250 mL, 0.50 mmol) and supported
2
3
catalyst (174 mg, 3 mol%). Then a solution of boronic
acid (91.3 mg, 0.55 mmol) and Na CO3 (260 mL, 0.55
2
We are grateful to Maybridge for a studentship (to
mmol) in water (5 mL) was added. The solution was
heated at reflux until completion of the reaction (<5 min).
The supported catalyst was separated from the mixture
by centrifugation and the remaining solution was aci-
dified with concentrated HCl to give 4,4%-biphenyldicarb-
oxylic acid (104.2 mg, 86%) as a white solid which was
isolated after filtration under vacuum. lH (300 MHz,
K.L.D.) and for supplying boronic acids 2, 3, 5 and
1
2
reagent 6.
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7