transmetallation process. The results show that Suzuki cross-
couplings are effected in organic solvent at low temperature and
n
without the need for excess Bu4NX salt.
Table 3 Continuous flow Suzuki reaction of iodobenzene and
p-tolylboronic acid with [PdEnCat] column in toluene–methanola
Supercritical carbon dioxide offers a cheaper, non-toxic and
environmentally more benign alternative to conventional organic
solvents for organic synthesis.6 There has been considerable
interest in hydrogenation7 and Pd-mediated C–C bond
formation reactions in this medium.8 Our previous studies
using [PdEnCat] to catalyse the Suzuki reaction of
bromobenzene and p-tolylboronic acid were carried out at
100 uC.5 For potential extension to continuous flow conditions a
lower temperature would be preferable. With this in mind batch
mode reactions in scCO2 were examined with various
additives (Table 2).
GC yield (%)
Cycle Cycle Cycle Cycle Cycle Cycle
6
Entry nBu4NX
T (uC) 1
2
3
4
5
1b
2c
3d
4e
5d
a
X 5 OAc 55
X 5 OH 55
X 5 OMe 55
X 5 F 55
X 5 OMe 70
4.7 7.5 11
3.1 13
12
—
—
—
—
14
—
—
—
—
15
—
—
—
—
70
85
55
—
12
36
100
48
40
—
At 100 uC (3000 psi), 4-methylbiphenyl was produced in almost
quantitative yields in the presence of stoichiometric amounts of
nBu4NX (X 5 OAc, OH and OMe) (Table 2, entries 1–3). At 40 uC
(1400 psi), the cross-coupled product was obtained in a good yield
of 66% with the use of nBu4NOMe (Table 2, entry 8). With
Reagents and conditions: 0.05
M solution of MePhB(OH)2
(1 mmol), PhI (1 mmol) and nBu4NX (1 mmol) in MePh–MeOH
20 cm3 (9:1, v:v); [PdEnCat] 40 column [5 cm (l) 6 0.45 cm (ID)];
flow rate: 0.2 cm3 min21 [residence time ca. 4 min]. Significant
b
c
d
e
n
nBu4NOH and Bu4NOMe, the hydroxide and methoxide anions
phase separation. Fine emulsion. Homogeneous solution. Phase
separation. See ESI.
are likely to react with CO2 to form the corresponding carbonates,
which may function as the active bases for these cross-coupling
reactions in scCO2.
respectively) after just three passes through the [PdEnCat]
column (Table 3, entries 2 and 3). Most impressive is the
performance of nBu4NOMe at 70 uC; a quantitative yield of
4-methylbiphenyl was obtained after a single pass through the
[PdEnCat] stationary bed (Table 3, entry 5). nBu4NOMe is
superior to the other bases examined as it does not lead to
phase separation of the reaction mixtures. The homogeneous
In chemical manufacturing processes, the operation costs and
labour required for continuous flow processes are generally less
than those for batch processes. As it has been shown that
[PdEnCat] can be recycled without significant loss of activity and
with minimal leaching{ of Pd from the microcapsules,4,5 cross-
coupling reactions with the immobilised [PdEnCat] catalyst as
the stationary phase under continuous flow conditions were
investigated.
n
mixtures observed with the use of Bu4NOMe allow maximum
interaction between the reagents and the catalyst. Methanol
formed in situ from the neutralisation of nBu4NOMe, may
solubilise the various species in the reaction mixture as a co-
solvent and maintain the reaction mixture as a homogeneous
solution.
The combination of microencapsulated Pd(OAc)2 [PdEnCat]2
n
40 and Bu4NX (X 5 OMe and OH) is demonstrated to be an
In the present work, experiments for ‘‘proof-of-concept’’ were
carried out by passing a stock reagent solution containing
n
iodobenzene, p-tolylboronic acid and Bu4NX (X 5 OAc, OH,
OMe and F) through an HPLC column packed with the
[PdEnCat] catalyst (Table 3). The cumulative yield of 4-methylbi-
phenyl was determined using GC.
The results of these preliminary results are extremely encour-
aging. Whilst low to moderate yields of 4-methylbiphenyl were
obtained at 55 uC in the presence of nBu4NOAc and nBu4NF
efficient and economical catalytic system for batch Suzuki cross-
couplings at low temperatures in both organic solvents and scCO2.
Continuous flow results are promising.
n
n
(Table 3, entries 1 and 4), the use of Bu4NOH and Bu4NOMe
gave rise to 4-methylbiphenyl in high yields (70% and 85%
We thank EPSRC for financial support and provision of the
Swansea Mass Spectrometry service and the Trustees of the
Ramsay Memorial Trust for a Ramsay Fellowship (to CKYL)
and ARC, CSIRO and VESKI (ABH). We thank AstraZeneca
and Dr D. Pears (Avecia) for generous support and provision of
the [PdEnCat] columns and pumps for the continuous flow
experiment.
Table 2 Batch-mode Suzuki reaction of bromobenzene and p-tolyl-
boronic acid catalysed by [PdEnCat]2 40 in scCO2
a
Entry
Method
nBu4NX
GC yield (%)
1
2
3
4
5
6
7
8
9
a
(i)
(i)
(i)
(i)
X 5 OAc
X 5 OH
X 5 OMe
X 5 F
X 5 OAc
X 5 OAc
X 5 OH
X 5 OMe
X 5 F
96b
97
97
74
Connie K. Y. Lee,a Andrew B. Holmes,*ab Steven V. Ley,*a
Ian F. McConvey,c Bushra Al-Duri,d Gary A. Leeke,d
Regina C. D. Santosd and Jonathan P. K. Sevilled
aDepartment of Chemistry, University of Cambridge, Lensfield Road,
Cambridge, UK CB2 1EW. E-mail: abh1@cam.ac.uk;
aholmes@unimelb.edu.au; svl1000@cam.ac.uk; Fax: +44 1223 334866;
Tel: +44 1223 334370
(i)
51
(ii)
(ii)
(ii)
(ii)
38b
16
66
,1c
bBio21 Institute, University of Melbourne, Parkville, Vic. 3010,
Australia
Reagents and conditions: [PdEnCat] (4.6% w/w Pd), nBu4NX
(1.0 mmol), PhBr (1.0 mmol), MePhB(OH)2 (1 mmol), scCO2;
cAstraZeneca Process Research and Development, Macclesfield,
Cheshire, UK SK10 2NA
b
method (i) 100 uC, 3000 psi, 21 h; (ii) 40 uC, 1400 psi, 2.5 d.
small quantity of MeOH (0.5 mL) was used as an additive.
A
dDepartment of Chemical Engineering, University of Birmingham,
Birmingham, UK B15 2TT
c
Reproducible result. See ESI.
2176 | Chem. Commun., 2005, 2175–2177
This journal is ß The Royal Society of Chemistry 2005