Supported palladium catalysis using a heteroleptic 2-methylthiomethylpyridine-N,S-donor motif for Mizoroki-Heck and Suzuki-Miyaura coupling, including continuous organic monolith in capillary microscale flow-through mode

Article abstract of DOI:10.1016/j.tet.2009.07.013

Flow-through catalysis utilising (2-methylthiomethylpyridine)palladium(II) chloride species covalently attached to a macroporous continuous organic polymer monolith synthesised within fused silica capillaries of internal diameter 250 μm is described, together with related studies of ground bulk monolith compared with supported catalysis on Merrifield and Wang beads and homogeneous catalysis under identical conditions to bulk supported catalysis. The monolith substrate, poly(chloromethylstyrene-co-divinylbenzene), has a backbone directly related to Merrifield and Wang resins. The homogeneous precatalyst PdCl₂(L²) (L²=4-(4-benzyloxyphenyl)-2-methylthiomethylpyridine) contains the benzyloxyphenyl group on its periphery as a model for the spacer between the 'PdCl₂(N～S)' centre and the polymer substituent of the resins and monolith. Suzuki-Miyaura and Mizoroki-Heck catalysis exhibit anticipated trends in reactivity with variation of aryl halide reagents for each system, and show that supported catalysis on beads and monolith gives higher yields than for homogeneous catalysis. The synthesis of 2-methylthiomethylpyridines is presented, together with crystal structures of 4-bromo-2-bromomethylpyridine hydrobromide, 4-(4-hydroxyphenyl)-2-methylthiomethylpyridine (L¹), PdCl₂(L¹) and PdCl₂(L²). Hydrogen bonding occurs in 4-bromo-2-bromomethylpyridine hydrobromide as N-H?Br interactions, in 4-(4-hydroxyphenyl)-2-methylthiomethylpyridine as O-H?N to form chains, and in PdCl₂(L¹) as O-H?Cl interactions leading to adjacent π-stacked chains oriented in an antiparallel fashion.

Full text of DOI:10.1016/j.tet.2009.07.013

Tetrahedron 65 (2009) 7474–7481
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Supported palladium catalysis using a heteroleptic 2-methylthiomethyl-
pyridine–N,S–donor motif for Mizoroki–Heck and Suzuki–Miyaura
coupling, including continuous organic monolith in capillary
microscale flow-through mode
,
a
,
a,
Roderick C. Jones a , Allan J. Canty , Jeremy A. Deverell b, Michael G. Gardiner a,
*
*
Rosanne M. Guijt b, Thomas Rodemann c, Jason A. Smith a, Vicki-Anne Tolhurst a
a School of Chemistry, University of Tasmania, Private Bag 75, Hobart TAS 7001, Australia
b Australian Centre for Research on Separation Science (ACROSS), Private Bag 75, Hobart TAS 7001, Australia
c Central Science Laboratory (CSL), University of Tasmania, Private Bag 74, Hobart TAS 7001, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Flow-through catalysis utilising (2-methylthiomethylpyridine)palladium(II) chloride species covalently
attached to a macroporous continuous organic polymer monolith synthesised within fused silica capillaries
of internal diameter 250 mm is described, together with related studies of ground bulk monolith compared
Received 16 April 2009
Received in revised form 24 June 2009
Accepted 2 July 2009
with supported catalysis on Merrifield and Wang beads and homogeneous catalysis under identical con-
ditions to bulk supported catalysis. The monolith substrate, poly(chloromethylstyrene-co-divinylbenzene),
has a backbone directly related to Merrifield and Wang resins. The homogeneous precatalyst PdCl2(L2)
(L2¼4-(4-benzyloxyphenyl)-2-methylthiomethylpyridine) contains the benzyloxyphenyl group on its pe-
riphery as a model for the spacer between the ‘PdCl2(NwS)’ centre and the polymer substituent of the resins
and monolith. Suzuki–Miyaura and Mizoroki–Heck catalysis exhibit anticipated trends in reactivity with
variation of aryl halide reagents for each system, and show that supported catalysis on beads and monolith
gives higher yields than for homogeneous catalysis. The synthesis of 2-methylthiomethylpyridines is
presented, together with crystal structures of 4-bromo-2-bromomethylpyridine hydrobromide, 4-(4-
hydroxyphenyl)-2-methylthiomethylpyridine (L1), PdCl2(L1) and PdCl2(L2). Hydrogen bonding occurs in
4-bromo-2-bromomethylpyridine hydrobromide as N–H/Br interactions, in 4-(4-hydroxyphenyl)-2-
methylthiomethylpyridine as O–H/N to form chains, and in PdCl2(L1) as O–H/Cl interactions leading to
Available online 8 July 2009
Keywords:
Catalysis
Supported catalysis
Monolith
Flow-through microreactor
Pyridine
Methylthiomethylpyridine
adjacent p-stacked chains oriented in an antiparallel fashion.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
250 mm internal diameter) employing continuous macroporous
organic monolith as support for palladium-catalysed Suzuki–
We have recently examined the ability of palladium(II) com-
plexes of neutral 2-organothiomethylpyridine-N,S donor ligands to
facilitate Mizoroki–Heck catalysis, in order to explore potential
roles for heteroleptic ligands that may exhibit hemilabile activity
during the catalytic cycle (Fig. 1).1 The role of this ligand motif in
palladium catalysis has also been explored by Chelucci for addition
of diethylzinc to benzaldehyde2a,b and for allylic substitution,2a and
by Canovese for trimerisation of dimethylacetylene dicarboxylate,2c
and the stoichiometric synthesis of fluoranthenes2d–f and 2,4-di-
ene-6-ynes.2f We have recently commenced the development of
flow-through capillary3 and chip3b based microreactors (100–
Miyaura3 and Sonogashira3c reactions. This flow-through
B
A
a
b
N
SR
R
c
Figure 1. (A) 2-Organothiomethylpyridine ligands (R¼Me, Ph). (B) Polymeric supports
(i) Merrifield resin [R¼Cl, typically 2–3% divinylbenzene (DVB) crosslinker]; (ii) Wang
resin [R¼p-BrCH2C6H4O, typically 1% DVB]; and (iii) poly(chloromethylstyrene-co-di-
vinylbenzene) monolith (CMS/DVB, R¼Cl, typically CMS/DVB ratio w3:2 and (CMS/
DVB)/(porogen) ratio w2:3 in preparations to give highly porous continuous polymeric
monolith).
* Corresponding authors. Tel.: þ61 3 6226 2162; fax: þ61 3 6226 2858.
E-mail addresses: rcj@utas.edu.au (R.C. Jones), allan.canty@utas.edu.au
(A.J. Canty).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.013

R.C. Jones et al. / Tetrahedron 65 (2009) 7474–7481
7475
technology to date has mainly utilised 1,10-phenanthroline and
N-methylimidazole moieties,3 e.g., attack by 5-amino-1,10-phe-
nanthroline at the benzylic chloride group of poly-
(chloromethylstyrene-co-divinylbenzene) monolith [CMS/DVB,
Fig. 1B(iii)], and with N-methylimidazole to most likely form pal-
ladium(II) carbene species on addition of PdCl2(NCMe)2.3c
anhydride to generate 4-bromo-2-trifluoroacetoxymethylpyridine,
followed by hydrolysis with NaOH)9a for synthesis of the 5-bromo
analogue to obtain known compound9b 3 (62%); bromination of 3
to give 4 (87%), a modification of the protocol of Canovese et al.
(reaction with thiomethoxide)10 for the synthesis of related com-
pounds to give 5 (72%); and Suzuki–Miyaura chemistry to give 6
(90%; overall yield 32%). Compound 7 was synthesised as a model
for the benzyl ether connectivity between ligand and the polymer
backbone (overall yield 30%), and palladium(II) complexes of 6 and
7, PdCl2(L1) (8) and PdCl2(L2) (9), respectively, were obtained on
reaction with PdCl2(NCMe)2 under reaction conditions identical to
those used to add palladium(II) to polymers functionalised with
compound 6.
The principles of flow-through organic synthesis at the mi-
croscale level in capillaries and chips of internal dimensions
<w1 mm have been elucidated recently.4 Advantages over con-
ventional reaction systems include high surface/volume ratio
leading to excellent heat transfer allowing higher concentrations
and better selectivity in reactions, environmental and safety ad-
vantages from use of less solvent and reagents, synthesis of
quantities of product sufficient for biological assay and integration
with analysis instrumentation, significant advantages in simplicity
of scale-out via multiple microreactors in parallel, together with
applications in combinatorial chemistry. For metal catalysis in
capillary5 and chip6 microreactors (internal diameter <w1 mm),
innovative systems developed to date have included homoge-
neous catalysis in open tubes/channels,5c,e,6c homogeneous with
gas/liquid interface,6e palladium as nanoparticles,5b palladium5d
or gold5h thin film on internal walls, palladium thin film together
with complex,5g palladium on metal oxide particles5a,6a,b and on
polysilane/metal oxide particles5f and, in our recent reports, pal-
ladium complexes supported on continuous organic polymer
monolith3 (e.g., Fig. 1B(iii)).3b,c For supported catalysis, the latter
approach avoids difficulties in filling capillaries with particles and
in confining particles within capillaries, difficulties associated
with swelling of polymer beads and compaction of particles if
high pressure is required for flow-through operation. The mono-
lith is fully anchored to walls during synthesis, the solid phase is
uniform with absence of particles, and the void volume fraction
for the monolith used in the present study is 79%. Organic poly-
mer monoliths have high surface area and excellent flow-through
properties.7
NO2
Br
1. AcBr, AcOH, 55 °C;
2. 120 °C, 90 min
N
O
N
O
1
2
1. TFAA, CH2Cl2, under Ar, 0 °C;
2. Reflux, 12 h;
3. 2 M NaOH, stir rt, 12 h
Br
Br
1. PBr3, CHCl3, 0 °C;
2. Reflux, 12 h
Br
N
N
H
OH
Br
4
3
NaSMe, KOH, EtOH, 12 h
OR
These promising developments are explored further here via
the synthesis and characterisation of an N,S-heteroleptic motif
known to be active in several palladium-catalysed processes and
organic syntheses functionalised by p-HOC6H4 at the 4-position
allowing covalent attachment to organic polymer supports
(Fig. 1A; R¼Me). Mizoroki–Heck and Suzuki–Miyaura cross-cou-
pling activity is examined for ‘[PdCl2(N,S)]’ complexes, and com-
pared with supported catalysis where the ligand is attached to
Merrifield and Wang beads (Fig. 1B(i) and B(ii)), ground bulk
monolith, and the dichloropalladium(II) complex of a closely re-
lated ligand as a homogeneous catalyst. To date, N,S-bidentate
ligands do not appear to have been explored in Suzuki–Miyaura
catalysis.
6: Na2CO3, p-HOC6H4B(OH)2,
Pd(PPh3)4 (6 mol %), 95 °C,
under Ar, 18 h
Br
7: Na2CO3, p-BnOC6H4B(OH)2,
Pd(PPh3)4 (6 mol %), 95 °C,
under Ar, 18 h
N
N
SMe
SMe
5
6: L1, R = H
7: L2, R = Bn
Scheme 1. Synthesis of 2-methylthiomethylpyridines 6 and 7.
NMR spectra were readily interpreted, noting that 6 alone,
containing the phenol group, undergoes deuterium exchange of the
methylene group in (CD3)2CO providing that D2O is present, at-
tributed to tautomeric and mesomeric effects encouraging ex-
change via IV, which is illustrated in Scheme 2; X-ray structural
data (see below) indicate little if any contribution from the ‘pyr-
idone’ form III in the solid state.
2. Results and discussion
2.1. Ligand synthesis
For the ligand motif A (R¼Me) (Fig. 1) the pyridine and thio-
methyl groups are anticipated to be unreactive towards the ben-
zylic halide group of the organic polymers B. A suitable reagent
containing this motif, and facilitating covalent attachment to the
polymers, could include a hydroxyl group. To achieve this, func-
tionalisation of the 4-position of the pyridine ring with a phenolic
group was considered desirable in order to minimise any steric
interaction between the phenolic group and the metal centre. The
synthesis in Scheme 1 was developed based on the reaction of
commercially available 1 with acetyl bromide to give 2 with slight
modification of a reported method8 (glacial acetic acid as solvent
rather than neat reagents) to increase the yield from 31 to 91%;
employing the protocol of van den Heuvel et al. (trifluoroacetic
OH
O
O
O
H
N
N
H
N
H
N
H
SMe
SMe
SMe
SMe
IV
I
II
III
Scheme 2.

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R.C. Jones et al. / Tetrahedron 65 (2009) 7474–7481
2.2. X-ray crystal structures of reagents and palladium(II)
complexes as models for the supported catalyst
Aspects of the structure of reagents 4, 6 and complexes 8, 9 are
illustrated in Figures 2 and 3. The compounds containing a phenolic
hydroxy group (as well as the hydrobromide salt 4) exhibit hydrogen
bonding, for which refinement of the hydrogen atom positions in-
dicate N–H/Brꢀ interaction in 4, O–H/N in 6 and O–H/Cl in 8. The
N/Br distance in 4, 3.139(7) Å, is similar to that reported for 2,6-
bis(bromomethyl)pyridinium bromide, 3.242(2) Å.11 Other close
bromide contacts are a p-face of a pyridyl ring, a methylene proton,
a 6H-pyridyl and Br of a 2-CH2Br substituent. Molecules of 6 form
linear polymeric chains through O–H/N hydrogen bonding in-
volving the pyridyl nitrogen and phenolic substituent. These arrange
themselvesinto parallel runningstacks displaying limitedp-stacking
between adjacent pyridyl and aryl rings owing to disruptions
brought about by the positioning of the methylene protons and the
torsion angle of aromatic rings in the molecule. The O/N distance
(2.700(3) Å) is similar to that reported for 4-(3,5-dimethylpyridin-4-
yl)-3,5-dimethylphenol, 2.721(2) Å.12 Consistent with the presence
of C–O–H/N in 6, rather than C]O/H–N that could be anticipated
for tautomer III, the C–O and inter-ring C–C distances, 1.353(3) and
1.476(3) Å, respectively, are both much longer than quinoidal struc-
tures [w1.222 and w1.349 Å].13 The ring–ring dihedral angle,
29.9(2)ꢁ, is also supportive of the absence of inter-ring multiple
bonding.
Complexes 8 and 9 exhibit distorted square planar coordination
geometries (Fig. 3). As for the free ligand 6, molecules of 8 form
hydrogen-bonded linear polymeric chains in the solid state, though
these involve OH/Cl interactions involving a chloride ligand (trans
to S) and the phenolic substituent. In contrast to 6, these polymeric
strands stack antiparallel into dimeric units involving offset face–
Figure 3. Molecular structures of PdCl2(L1) (8) (A) and PdCl2(L2) (9) (C). For 8, the
partial packing diagram (B) shows the antiparallel arrangement of the linear polymeric
strands resulting from hydrogen bonding. Palladium–donor atom distances [N1
2.039(8), 2.037(3); S1 2.247(3), 2.2617(9); Cl1 (trans to S1) 2.321(3), 2.3305(9); Cl2
(trans to N1) 2.299(3), 2.2967(10) Å, for 8 and 9, respectively] and chelate angles
[84.5(2)ꢁ, 84.58(6)ꢁ] are similar to values reported for related Pd(II) complexes.14 The
pyridyl mean plane forms a dihedral angle of 16.2(4)ꢁ (8) and 18.9(1)ꢁ (9) with the
mean metal coordination plane, the aryl/pyridyl inter-ring dihedral angles are 8.1(7)ꢁ
(8) and 19.8(2)ꢁ (9), and the C–O and inter-ring C–C distances of both 8 and 9 are
within 1 esd of those for ligand 6.
for ‘[ECE]’ (E¼N, S) pincer complexes having a hydroxyl group hy-
drogen-bonded to a chloro-ligand in MCl{C6H2(CH2NMe2)2-2,6-
OH-4} (M¼Pt,16a,b Pd16c) and PdCl{C6H2(CH2SPh)2-2,6-OH-4}16c
,
face
p-stacking that is aided by the near planar aryl–pyridyl moi-
eties allowing an intermolecular distance of 3.43(2) Å. Palladium
coordination planes between paired sets of chains are close to being
directly aligned, but the Pd/Pd contact of 3.711(3) Å indicates the
absence of a metal–metal interaction (van der Waals radius
1.63 Å).15 The polymeric chain structure is similar to those reported
which have O–H/Cl with O/Cl 3.1040(18)–3.127(8) Å compared
with 3.002(8) Å in 8.
For complex 9, the linear polymeric chains noted for 6 and 8
are absent as hydrogen bonding is absent. Some packing features
are retained in that there is rough alignment of the, now, quite
extended polyaromatic ligand framework in the overall structure.
p
-Stacking between molecules is limited to the central aryl rings
(3.632 Å) that extends indefinitely. The limited -stacking, in
p
relation to complex 8, is presumably due to the influences of the
greater torsion angle between the pyridyl and aryl rings (19.8(2)ꢁ)
and the incorporation of the saturated benzylic carbon centre of
the ether substituent. Coplanarity of metal coordination planes
(3.633(2) Å) within these stacks is noted, however, the metal
centres are offset somewhat, giving a metal–metal separation of
5.133(1) Å.
2.3. Formation of polymer with supported precatalyst sites
As illustrated in Scheme 3, commercially obtained polymer
beads were treated with reagent 6 in ethanol at 60 ꢁC in the pres-
ence of excess base (i-Pr2NEt or Bu4NOH). Similar results were
obtained for both bases. Scanning electron micrographs of Merri-
field beads indicated considerable bead fragmentation after this
treatment, as reported for a recent study of catalyst immobilisa-
tion,17 but Wang beads were unaffected. Ground bulk monolith and
capillaries filled with continuous monolith, obtained as doc-
umented,3c were treated with ligand 6 in a similar manner, fol-
lowing the documented protocol,3c and for capillaries involved
flow-through of the solution in each direction. The base Bu4NOH
was used for ligand attachment to monolith as it promotes higher
solubility of 6 than does i-Pr2NEt, and thus minimises the possi-
bility of precipitation. Subsequently, the systems were treated with
Figure 2. Molecular structures of 4 (A) [symmetry code: (i) ꢀxꢀ1/2, yþ1/2, ꢀzþ1/2]
and 6 (B). For 6, the partial packing diagram shows a portion of the linear polymeric
strands resulting from hydrogen bonding.

R.C. Jones et al. / Tetrahedron 65 (2009) 7474–7481
7477
PdCl2(NCMe)2 under identical conditions, matching that for the
synthesis of PdCl2(L1) (8) and PdCl2(L2) (9). A scanning electron
micrograph of bulk monolith after attachment of ligand and pal-
ladium (Fig. 4) is unchanged in appearance from that prior to at-
tachment, and appears similar to monolith obtained on attachment
of other ligands.3c Palladium analysis showed levels of 0.75 wt %
(Merrifield resin), 0.32 wt % (Wang) and 1.19 wt % (bulk monolith).
Analysis for capillaries was not attempted as essentially identical
conditions were used for funtionalisation of the monolith in bulk
capillary of internal diameter 250
m
m filled with monolith of mass
1.76 mg and 1.19 wt % Pd, a void volume fraction of 79% results in an
effective mol % Pd of w51% for an aryl halide concentration of 0.1 M.
However, an approximate comparison between beads, bulk
monolith and homogeneous catalysis is feasible as the homoge-
neous catalysis can be conducted using the same mol % precatalyst.
To ascertain whether palladium was not simply adhered to the solid
phase, support materials that had not been treated in any way, or
treated with ligand only, or treated with PdCl2(NCMe)2 only fol-
lowed by flushing, did not act as catalysts in Mizoroki–Heck re-
actions, and for these trials palladium could not be detected in the
supports by ICP-MS analysis.
and in capillaries. The capillaries (internal diameter 250
30 cm) were cut to 10 cm lengths for catalytic studies.
mm, length
Reactions studied are illustrated in Scheme 4 and results are
presented in Tables 1 and 2. For beads, bulk monolith and homo-
geneous systems the preferred base Na2CO3 was used, but for
capillaries Et3N was used as Na2CO3 has low solubility that may
lead to blockages.
6, Bu4NOH or Et(i-Pr)2N,
PdCl2(NCMe)2,
EtOH, 60 oC
MeCN, rt
X
Y
Y
O
N
O
Suzuki-Miyaura catalysis
[Pd]
R1
X
B(OH)2
R1
+
10
N
Mizoroki-Heck catalysis
SMe
Cl Pd SMe
Cl
R1
[Pd]
R2
Scheme 3. Functionalisation of Merrifield resin and monolith (X¼CH2Cl, Y¼CH2) or
Wang resin (X¼CH2OC6H4CH2Br, Y¼CH2OC6H4CH2).
R1
X
+
CO2Bu
11
R2
CO2Bu
10
12
Scheme 4.
For both Suzuki–Miyaura and Mizoroki–Heck reactions using
beads and bulk monolith (Table 1), similar results are obtained for
each support, with trends on variation of reagent as expected, in
particular aryl iodides>bromides>chlorides, e.g., for Suzuki–
Miyaura (PhI>PhBr>p-AcC6H4Cl, entries 1–3); and for Mizoroki–
Heck (PhI>PhBr>p-TolBr>p-AcC6H4Cl and PhCl, entries 5–9, and
PhI>PhBr, entries 10 and 11). High yields of the trisubstituted Miz-
oroki–Heck product were obtained (entries 10 and 11). Moderate
activation of 4-chloroacetophenone in the Mizoroki–Heck reaction
(entry 3) indicates that further development of catalyst design may
lead to improved aryl chloride activation. For both catalysis systems,
the solid supports provide higher yield than comparable homoge-
neous catalysis (entries 2, 4 and 6, 12), and the homogeneous sys-
tems provide lower yields than widely used phosphine systems.18
Detailed comparison of values obtained from different bulk
supports is difficult in view of the differing mol % of precatalyst and
differences in anticipated access of reagents to precatalyst sites,
e.g., observed fracture of the Merrifield beads compared with un-
altered appearance of Wang beads, and anticipated better access to
interior sites for monolith than for beads. However, for bulk re-
actions the trend in loadings (monolith>Merrifield>Wang) is
reflected in the same trend in yield (entries 3, 5–7, 10). If it is as-
sumed that precatalyst sites have identical activities for the three
supported systems, trends in turnover number (TON) may reflect
the accessibility of sites. Thus, it is of interest to note that, except
where yields are >99% or very low (entry 9, Wang entries 3 and 8),
turnover numbers (TON, moles of product/moles of palladium) for
Merrifield and Wang beads are greater than those for monolith
(entries 3, 6–8,11), even when the yield is lower for beads (entries 3
and 8). Leaching of palladium could not be detected by ICP-MS
analysis above background levels that were obtained in blank runs
using reagents and the three supports without precatalyst.
Figure 4. Scanning electron micrograph of ground bulk monolith after attachment of
ligand and palladium (ꢂ3000, accelerating voltage 3.0 kV).
2.4. Studies of Suzuki–Miyaura and Mizoroki–Heck catalysis
In addition to the supported systems, catalysis using the model
complex PdCl2(L2) (9) was undertaken as the ligand L2 contains the
same benzyl ether linker on its periphery as that present in the
ligand motif attached to solid supports. Direct comparison between
catalysis for this complex, the resins, bulk monolith and capillary
systems is problematic, mainly due to the different experimental
protocol required for flow-through studies. Microreactors have
a much higher effective mol % precatalyst in the flow-through ar-
chitecture, as noted previously.17 Thus, for the 10 cm length

7478
R.C. Jones et al. / Tetrahedron 65 (2009) 7474–7481
Table 1
Comparison of Suzuki–Miyaura and Mizoroki–Heck catalysis for Merrifield and Wang beads and ground monolith with anchored palladium(II) precatalyst, and homogeneous
catalysis using PdCl2(L2) (9) as precatalysta
Entry
X
10 (R1)
11 (R2)
Yield (%)
TON
Merrifield
Wang
Monolith
Suzuki–Miyaura, beads and monolith
1
2
3
I
H
>99
>99
8
>99
85
>99
>99
12
8512, 19,950,
5365
8512, 16,958,
5365
Br
Cl
H
Ac
<1
681, <199, 644
Suzuki–Miyaura, homogeneous, identical mol % loading as analogous supported catalysis
4
Br
H
57
6.4
64
4852, 1227,
3434
Mizoroki–Heck, beads and monolith
5
6
7
8
I
H
H
H
H
H
>99
95
>99
86
>99
93
8512, 19,950,
5365
8086, 17,157,
4989
7235, 13,965,
4185
1021, <199,
804
Br
Br
Cl
H
Me
Ac
85
70
78
12
<1
15
9
10
Cl
I
H
H
H
Ph
<1
>99
<1
>99
1
>99
<85, <199, 54
8512, 19,950,
5365
11
Br
H
Ph
85
72
87
11
7235, 14,364,
4668
Mizoroki–Heck, homogeneous, identical mol % loading as analogous supported catalysis
12 Br
H
H
6
<1
511, <199, 590
a
Reagents shown in Scheme 3. Suzuki–Miyaura conditions: ArX (10, 0.3 M), p-TolB(OH)2 (0.45 M), polymer (5 mg), Na2CO3 (0.6 M) in DMF/H2O (3:1, 10 mL), 80 ꢁC, 24 h.
Mizoroki–Heck conditions: ArX (10, 0.3 M), alkene (11, 0.45 M), polymer (5 mg), Na2CO3 (0.6 M), Bu4NCl (0.45 M) in DMA (10 mL), 120 ꢁC, 48 h. Merrifield beads and
homogeneous catalysis: 0.012 mol % Pd. Wang beads and homogeneous catalysis: 0.005 mol % Pd, monolith and homogeneous catalysis: 0.019 mol % Pd.
other reagents (Aldrich) were used as received. Bulk monolith and
fused silica capillaries (internal diameter 250 m, outer surface
Table 2
Suzuki–Miyaura and Mizoroki–Heck catalysis in capillary microreactorsa
m
10 (R1)
11 (R2)
Yield (%)
coated with polyimide (Polymicro Technologies, Phoenix, Arizona))
filled with monolith bonded to the walls were prepared as repor-
ted.3c Bulk monolith was ground, resulting in a range of particle sizes
up to w200 m
m. NMR spectra were recorded at 20 ꢁC on a Varian
Entry
X
Suzuki–Miyaura
1
2
I
Br
H
H
96
65
Mercury Plus 300 spectrometer and chemical shifts are reported in
parts per million relative to TMS; assignments were facilitated by
gHMBC, gHMQC and gCOSY techniques. For 6 and 8 the C6H4 group
atoms are denoted H4b and H4c; for 7 and 9 the phenyl group atoms
are denoted H4b–d2. Microanalyses, LSIMS mass spectra, scanning
electron micrographs (FEI Quanta 600 MLA ESEM) and ICP-MS (EL-
EMENT high resolution) allowing detection down to 0.1 ppb were
performed by the Central Science Laboratory. GC–MS measurements
were performed using a Varian 3800 gas chromatograph coupled
with a triple quadrupole mass spectrometer; GC-FID measurements
were performed on a Shimadzu GC-2014 AFsc gas chromatograph
equipped with a 25 m length (ID 0.32 mm) ID-BPX5 SGE capillary
column. Standards were purchased or synthesised using conven-
tional techniques, and mixtures with different concentration ratios
were used for calibration. The mass of monolith in a capillary was
Mizoroki–Heck
3
4
I
Br
H
H
H
H
98
45
a
w39 min contact time of reagent solution within capillaries of internal diameter
m, length 10 cm, flow rate 0.1
L minꢀ1; w51 mol % Pd. Suzuki–Miyaura con-
250
m
m
ditions: ArX (10, 0.10 M), p-TolB(OH)2 (0.15 M), Et3N (0.2 M) in DMF/H2O (3:1), 80 ꢁC,
24 h. Mizoroki–Heck conditions: ArX (10, 0.10 M), alkene (11, 0.15 M), Et3N (0.2 M) in
DMA, 120 ꢁC, 24 h.
Results for the bulk studies demonstrate that the N,S-bidentate
system facilitates catalysis. The capillary microreactor was exam-
ined for reaction of iodo- and bromobenzene, and the same trend in
reactivity was observed for both catalyses (entries 1, 2 and 3, 4)
(Table 2), illustrating the feasibility of this microreactor technology.
Assuming that the palladium loading is identical to that of the bulk
monolith, leaching of Pd over a 24 h period corresponded to
w0.05% for the Suzuki–Miyaura and Mizoroki–Heck reactions.
determined using a Sartorius SE2 Ultra-Microbalance (0.1 mg read-
ability), and the void volume fraction was determined as described
previously.3c For palladium analyses, samples (50–100 mg) were
digested in freshly prepared aqua regia (4 mL) for 18 h with soni-
cation, diluted to a final mass of 30 g, indium (100 ppb) was added as
an internal standard, and measurements performed on the low
3. Experimental section
3.1. General techniques
resolution setting of 300m (D
m)ꢀ1 at 10% valley definition, and
All solvents were dried and distilled by conventional methods
prior to use. 4-Nitro-2-picoline N-oxide (Oakwood), 4-hydroxy-
phenylboronic acid (Boron Molecular), (chloromethyl)polystyrene
palladium was measured as a total of isotopes 105, 106 and 108.
For microreactor catalysis, as reported,3c controlled solvent
pumping was performed using a Harvard Apparatus model PHD
2000 (Holliston, Massachusetts, USA) twin syringe pump and
250
capillaries and syringes were connected using Upchurch Scientific
(Merrifield Resin, 200–400 mesh, 37–74
thylphenoxymethyl)polystyrene (Wang Resin, 100–200 mesh, 74–
149 m) (Novabiochem), ultra high purity argon (BOC Gases) and
mm) (Fluka), (4-bromome-
m
L Hamilton (Reno, Nevada, USA) GastightÒ glass syringes. All
m

R.C. Jones et al. / Tetrahedron 65 (2009) 7474–7481
7479
(Oak Harbor, Washington, USA) capillary connections. Capillaries
were heated using a Waters Millipore (Billerica, Massachusetts,
USA) 112/WTC-120 temperature controlled column heater. Leading
and trailing capillary sections were used to ensure that the whole
microreactor was inside the column heater.
3.2.4. 4-Bromo-2-methylthiomethylpyridine (5)
A stirred solution of NaOMe (0.35 g, 4.97 mmol) in dry EtOH
(50 mL) was added dropwise over 10 min to a stirred solution of 4
(1.50 g, 4.52 mmol) and powdered KOH (0.76 g, 13.56 mmol) in dry
EtOH (100 mL). Stirring was continued for 12 h after which the
EtOH was removed in vacuum resulting in a pale brown oil. Water
(25 mL) was added and the product extracted with CH2Cl2
(3ꢂ25 mL). The organic phase was washed with brine and dried
over Na2SO4. The solvent was removed in vacuum to give a pale
brown oil, which was purified by column chromatography [40%
EtOAc in hexanes], to give a pale yellow oil (0.75 g, 72%). 1H NMR
3.2. Synthetic procedures
3.2.1. 4-Bromo-2-methylpyridine N-oxide (2)
Acetyl bromide (34.6 mL, 0.46 mol) was added in small portions
to a solution of 4-nitro-2-picoline N-oxide (2.47 g, 0.02 mol) in
glacial AcOH (35 mL) at 55 ꢁC. The resulting solution was heated to
120 ꢁC with stirring for 2.5 h in air. After cooling to rt the solution
was poured into crushed ice and made basic with K2CO3 and the
product extracted with CH2Cl2 (4ꢂ30 mL). The combined organic
phases were washed with brine, and dried over Na2SO4. The solvent
was removed in vacuum resulting in a pale orange oil, which was
used without further purification (2.75 g, 91%). 1H NMR (300 MHz,
(300 MHz, CDCl3):
H3), 7.34 (dd, J¼5.4, 1.8 Hz, 1H, H5), 3.76 (s, 2H, CH2), 2.06 (s, 3H,
SCH3); 13C{1H} NMR (75.4 MHz, CD3OD):
159.1 (C2), 148.6 (C6),
132.7 (C4), 125.4 (C3), 124.4 (C5), 38.5 (CH2), 14.2 (SCH3). MS (EI)
d
8.34 (d, J¼5.4 Hz, 1H, H6), 7.56 (d, J¼1.8 Hz, 1H,
d
m/z 218 [M]þ,
[ S
12C7H879Br14N32 218]. HRMS (EI) m/z [Mþ]
216.95611, [C7H8BrNS]þ requires 216.95608.
CDCl3):
d
8.11 (d, J¼6.9 Hz, 1H, H6), 7.41 (d, J¼2.4 Hz, 1H, H3), 7.27
3.2.5. 4-(4-Hydroxyphenyl)-2-methylthiomethylpyridine (6)
(dd, J¼6.9, 2.4 Hz, 1H, H5), 2.48 (s, 3H, CH3); 13C{1H} NMR
Pd(PPh3)4 (0.397 g, 5 mol %) and 5 (1.50 g, 6.88 mmol) in toluene
(28.0 mL) were treated with a degassed solution of Na2CO3 (1.60 g,
13.11 mmol, 2.2 equiv) in H2O (14.0 mL), followed by a solution of
p-HOC6H4B(OH)2 (1.42 g, 10.32 mmol) in MeOH (10.0 mL). The
resulting mixture was stirred at 95 ꢁC under Ar; after 6 h another
0.5 equiv of p-HOC6H4B(OH)2 and a further 1 mol % of catalyst was
added to the solution, and after 12 h the solution was cooled to rt
and treated with a saturated solution of Na2CO3. The product was
extracted with CH2Cl2 (3ꢂ25 mL), the organic phase was washed
with saturated NaCl solution, dried over Na2SO4 and the solvent
removed in vacuum to give a dark oil. The oil was dissolved in
CH2Cl2 (5 mL) and hexane added to precipitate a tan solid (1.56 g,
98%). The product was recrystallised from hot EtOH to give a dark
(75.4 MHz, CDCl3):
d 150.6 (C2), 140.2 (C6), 129.6 (C3), 127.0 (C5),
119.4 (C4), 17.9 (CH3). MS (EI) m/z 187 [Mþ], [12C6H679Br14N16O 187].
HRMS (EI) m/z [MꢀH]þ 186.96339, [C6H6BrNO]þ requires
186.96328.
3.2.2. 4-Bromo-2-hydroxymethylpyridine (3)
Under argon, TFAA (9.24 mL, 66.48 mmol) was added drop-
wise (with extreme caution) to
a solution of 2 (2.50 g,
13.30 mmol) in dry CH2Cl2 (40 mL) at 0 ꢁC, and the resulting so-
lution refluxed for 12 h with stirring. After cooling to rt the TFAA
and CH2Cl2 were removed in vacuum to give a dark yellow oil;
CH2Cl2 (40 mL) was added followed by 2 M NaOH with vigorous
stirring until the resulting biphasic mixture was basic (pH 12–14).
Vigorous stirring was continued for 12 h under Ar, and the mix-
ture extracted with CH2Cl2 (3ꢂ30 mL). The organic phase was
washed with brine and dried over Na2SO4. The solvent was re-
moved in vacuum resulting in a dark brown oil, which was used
without further purification. (1.55 g, 62%). 1H NMR (300 MHz,
brown solid (1.43 g, 90%). 1H NMR (300 MHz, (CD3)2CO):
d 9.01 (s,
1H, OH), 8.47 (dd, J¼5.1, 1.5 Hz, 1H, H6), 7.66 (m, 3H, H3, H4b), 7.47
(dd, J¼5.1, 1.5 Hz, 1H, H5), 6.83 (d, J¼8.7 Hz, 2H, H4c), 3.82 (s, 2H,
CH2), 2.08 (s, 3H, SCH3); 13C{1H} NMR (75.4 MHz, (CD3)2CO):
d 159.7
(C2), 158.1 (COH), 149.8 (C6), 149.7 (C4), 128.7 (C4a), 128.4 (C4b),
119.8 (C3), 119.0 (C5), 116.3 (C4c), 39.8 (CH2), 14.5 (SCH3). MS (APCI)
m/z 232 [MþH]þ, [12C13H1414N16O32S 232]. HRMS (EI) m/z [MþH]þ
232.07941, [C13H14NOS]þ requires 232.07961. Anal. Calcd for
C13H13NSO: C, 67.50; H, 5.66; N, 6.06. Found: C, 67.54; H, 5.62; N,
6.11.
CDCl3):
d
8.36 (d, J¼5.4 Hz, 1H, H6), 7.52 (dd, J¼1.8 Hz, 1H, H3),
7.39 (dd, J¼5.4, 1.8 Hz, 1H, H5), 4.75 (s, 2H, CH2), 4.16 (s, 1H, OH);
13C{1H} NMR (75.4 MHz, CDCl3):
d 161.1 (C2), 149.2 (C6), 134.1
(C4), 126.0 (C5), 124.3 (C3), 63.9 (CH2). MS (EI) m/z 187 [MꢀH]þ,
[
12C6H579Br14N16
O
186]. HRMS (EI) m/z [MꢀHþ] 185.95554,
[C6H5BrNO]þ requires 185.95545.
3.2.6. 4-(4-Benzyloxy)-2-methylthiomethylpyridine (7)
This compound was prepared from 5 (1.50 g, 6.88 mmol) and
4-BnOC6H4B(OH)2 (2.35 g, 10.32 mmol) using a similar procedure
to that described for 6. The product was purified by column
chromatography (40% EtOAc in hexanes) to remove contamination
by BnOPh to give a pale yellow oil (1.88 g, 85%). 1H NMR (300 MHz,
3.2.3. 4-Bromo-2-bromomethylpyridine hydrobromide (4)
PBr3 (5.55 mL, 59.03 mmol) was added dropwise (with extreme
caution) to a solution of 3 (1.85 g, 9.84 mmol) in dry CHCl3 (50 mL)
at 0 ꢁC, and the resulting solution was heated to reflux for 12 h with
vigorous stirring. After cooling to rt the suspension was poured into
crushed ice and made basic (pHw14) with K2CO3, and the product
was extracted with CH2Cl2 (4ꢂ50 mL). The organic phase was
washed with brine and dried over Na2SO4. The solvent was re-
moved in vacuum, and the resulting pale brown oil was then dis-
solved in Et2O and with vigorous stirring; HBr/AcOH solution was
added dropwise to precipitate an off white solid, which was col-
lected by filtration and washed thoroughly with Et2O (2.84 g, 87%).
Single crystals for X-ray and elemental analysis were grown from
vapour diffusion of Et2O into MeNO2. 1H NMR (300 MHz, CD3OD):
(CD3)2SO):
d
8.53 (d, J¼5.4 Hz, 1H, H6), 7.76 (dd, J¼5.4, 1.8 Hz, 1H,
H5), 7.60 (d, J¼8.7 Hz, 2H, H4b), 7.56 (d, J¼1.8 Hz, 1H, H3), 7.46–
7.34 (m, 5H, H4b2, H4c2, H4d2), 7.07 (d, J¼8.7 Hz, 1H, H4c), 5.12 (s,
2H, OCH2), 3.86 (s, 2H, SCH2), 2.10 (s, 3H, SCH3); 13C{1H} NMR
(75.4 MHz, (CD3)2SO):
d 160.1 (C2), 158.9 (C4d), 149.4 (C6), 149.1
(C4), 136.8 (C4a2), 128.9 (C4b), 128.6 (C4c2), 128.4 (C4d2), 127.7
(C4b2), 120.7 (C5), 119.8 (C3), 115.7 (C4c), 70.0 (OCH2), 40.0 (SCH2),
22.9 (SCH3). MS (EI) m/z 321 [M]þ, [12C20H1914N16O32S 321]. HRMS
(EI) m/z [Mþ] 321.11868, [C20H19NOS]þ requires 321.11873. Anal.
Calcd for C13H13NSO: C, 67.50; H, 5.66; N, 6.06. Found: C, 67.54; H,
5.62; N, 6.11.
d
8.70 (d, J¼6.3 Hz, 1H, H6), 8.42 (d, J¼2.1 Hz, 1H, H3), 8.21 (dd,
J¼6.3, 2.1 Hz, 1H, H5), 4.81 (s, 2H, CH2); 13C{1H} NMR (75.4 MHz,
CD3OD):
d
153.4 (C2), 144.1 (C4), 143.7 (C6), 130.9 (C5), 130.1 (C3),
3.2.7. Dichloro{4-(4-hydroxyphenyl)-2-methylthiomethyl-
pyridine}palladium(II) (8)
PdCl2(NCMe)2 (0.15 g, 0.64 mmol) was added to a stirred sus-
pension of 6 (0.18 g, 0.77 mmol) in dry MeCN (30 mL) and the
brown suspension was stirred for 12 h at 50 ꢁC. The solvent was
24.8 (CH2). MS (EI) m/z 251 [MꢀHBr]þ, [12C6H579Br214N 251]. HRMS
(EI) m/z [MꢀHBr]þ 248.87875, [C6H5Br2N]þ requires 248.87887.
Anal. Calcd for C6H6Br2N: C, 21.72; H, 1.82; N, 4.22. Found: C, 22.12;
H, 1.78; N, 4.20.

7480
R.C. Jones et al. / Tetrahedron 65 (2009) 7474–7481
then reduced in vacuum to w5 mL and Et2O was added to pre-
cipitate the title complex as a yellow solid, which was collected by
filtration and washed with Et2O (0.23 g, 87%). Single crystals suit-
able for X-ray structure determination and elemental analysis were
grown from a vapour diffusion of Et2O into MeNO2. 1H NMR
(5 mL) were stirred for 24 h at rt, filtered under vacuum, resus-
pended in MeCN, stirred for 30 min and recovered again by fil-
tration. The polymer was washed twice more with EtOH and
dried in vacuum.
(300 MHz, (CD3)2SO):
d
10.18 (s, 1H, OH), 8.99 (dd, J¼6.6, 1.8 Hz, 1H,
3.5. Suzuki–Miyaura catalysis for resins and bulk monolith
H6), 8.04 (d, J¼1.8 Hz, 1H, H3), 7.83 (dd, J¼6.6, 1.8 Hz, 2H, H5), 7.78 (d,
J¼9.0 Hz, 2H, H4b), 6.91 (d, J¼8.7 Hz, 2H, H4c), 4.76, 4.47 (AB spin
system, J¼16.5 Hz, 2H, CH2), 2.55 (s, 3H, SCH3); 13C{1H} NMR
Aryl halide (3.0 mmol) was added to a solution of p-Tol-
B(OH)2 (0.612 g, 4.5 mmol), Na2CO3 (0.5 g, 6.0 mmol), catalyst
(5.0 mg) in a 3:1 DMF/H2O mixture (10 mL) under Ar. The
resulting mixture was stirred at 80 ꢁC for 24 h under Ar. Once
cooled to rt, Ph2O (0.17 g, 1.0 mmol) was added and an aliquot
(1.50 mL) was taken and diluted with CH2Cl2, washed three
times with a saturated NaCl solution. The organic layer was
extracted, dried over MgSO4 and filtered, and analysed by GC-
FID and GC–MS.
(75.4 MHz, (CD3)2SO): d 163.8 (C2), 160.9 (HOC), 151.7 (C6), 150.5 (C4),
129.7 (C4b), 125.7 (C4a), 120.7 (C5), 120.4 (C3), 117.0 (C4c), 45.3 (CH2),
22.9 (SCH3). MS (LSIMS) m/z 373 [MꢀCl]þ, [12C13H1335Cl14N32S16O 373].
HRMS (EI) m/z [MꢀCl]þ 371.94412, [C13H13ClNSO]þ requires
371.94521. Anal. Calcd for PdC13H13NSOCl2: C, 38.21; H, 3.21; N, 3.43;
S, 7.85. Found: C, 38.30; H, 3.07; N, 3.67; S, 7.45.
3.2.8. Dichloro{4-(4-Benzyloxy)-2-methylthiomethyl-
pyridine}palladium(II) (9)
3.6. Mizoroki–Heck catalysis for resins and bulk monolith
PdCl2(NCMe)2 (0.15 g, 0.64 mmol) was added to a stirred sus-
pension of 7 (0.25 g, 0.77 mmol, 1.2 equiv) in dry MeCN (30 mL),
instantly affording a bright yellow suspension, which was stirred
for 12 h at rt. The solvent was reduced in vacuum to w5 mL and
Et2O was added. The title complex was collected by filtration as
a bright yellow solid and washed with Et2O (0.27 g, 85%). Single
crystals suitable for elemental analysis were grown from hot
Aryl halide (3.0 mmol) was added to a solution of n-butyla-
crylate (0.75 mL, 4.5 mmol) (or n-butylcinnamate for entries 10
and 11 in Table 1), Na2CO3 (0.5 g, 6.0 mmol), catalyst (5.0 mg) and
n-Bu4NCl (1.25 g, 4.5 mmol) in DMA (10 mL) under Ar. The result-
ing mixture was stirred at 120 ꢁC for 48 h under Ar. The cooled
mixture was treated and analysed as for Suzuki–Miyaura catalysis
by GC-FID and GC–MS.
MeNO2. 1H NMR (300 MHz, (CD3)2SO):
d
9.02 (dd, J¼6.3, 1.8 Hz, 1H,
H6), 8.10 (d, J¼1.8 Hz, 1H, H3), 7.89 (m, 3H, H5, H4b), 7.39 (m, 5H,
H4b2, H4c2, H4d2), 7.19 (d, J¼8.7 Hz, 1H, H4c), 5.19 (s, 2H, OCH2),
4.77, 4.48 (AB spin system, J¼16.8 Hz, 2H, SCH2), 2.55 (s, 3H, SCH3);
3.7. Ligand and palladium attachment to monolith in
capillaries
13C{1H} NMR (75.4 MHz, (CD3)2SO):
d 163.9 (C2), 161.3 (C4d), 151.7
(C6), 150.2 (C4), 137.3 (C4a2), 129.6 (C4b), 129.2 (C4c2), 128.7
(C4d2), 128.5 (C4b2), 127.6 (C4a), 121.1 (C5), 120.9 (C3), 116.4 (C4c),
The monolith filled capillary was flushed with EtOH for 30 min
at 60 ꢁC (2.0 L minꢀ1). A filtered solution of 6 (85 mg) and Bu4NOH
m
70.1 (OCH2), 45.3 (SCH2), 22.9 (SCH3). MS (LSIMS) m/z 463
(1.5 mL) in EtOH (3.5 mL) was pumped through the capillary at
60 ꢁC for 18 h (0.2 L minꢀ1), then the capillary was reversed and
the solution was pumped through for a further 8 h (0.5
L minꢀ1).
The capillary was washed with EtOH for 1 h at rt (2.0
L minꢀ1) to
remove unreacted ligand and base. The monolith filled capillary
was flushed with MeCN for 30 min at rt (2.0
L minꢀ1), prior to
a filtered solution of PdCl2(NCMe)2 (10 mg) in MeCN (2 mL) being
pumped through the capillary at rt for 8 h (0.5
L minꢀ1), then the
capillary was reversed and the solution was pumped through for
a further 18 h (0.2
L minꢀ1). The capillary was flushed with MeCN
for 1 h (2.0
L minꢀ1).
[MꢀCl]þ,
[
C
H1935Cl14N32S16
O
463]. HRMS m/z [MꢀCl]þ
12
20
m
461.99107, [C20H19ClNSO]þ requires 461.99215. Anal. Calcd for
PdC20H19NSOCl2: C, 48.16; H, 3.84; N, 2.81. Found: C, 47.89; H, 3.74;
N, 2.72.
m
m
m
3.3. Structural determinations
m
Data for 4, 6 and 8 were collected at ꢀ80 ꢁC with an Enraf
Nonius TurboCAD4 with Mo Ka radiation (0.71073 Å) on crystals
m
of 4, 6 and 8 mounted on glass fibres. Data for 9 were collected at
ꢀ173 ꢁC for crystals mounted on a Hampton Scientific cryoloop at
the PX1 beamline of the Australian Synchrotron. Views of the
structures are shown in Figures 2 and 3. The structures were
solved by direct methods with SHELXS-97, refined using full-
matrix least-squares routines against F2 with SHELXL-97,19 and
visualised using X-SEED.20 All non-hydrogen atoms were refined
anisotropically. Nitrogen-bound and O-bound hydrogen atoms
were positionally refined and other hydrogen atoms were placed
in calculated positions and refined using a riding model with
fixed C–H distances of 0.95 Å (sp2C–H), 0.99 Å (CH2), 0.98 Å
(CH3). The thermal parameters of all hydrogen atoms were es-
timated as Uiso(H)¼1.2 Ueq(C) except for CH3 where
Uiso(H)¼1.5 Ueq(C).
m
3.8. Suzuki–Miyaura catalysis for capillaries
To equilibrate the microreactor prior to the reaction, the capil-
lary (10 cm) was flushed with DMF/H2O (3:1) for 1 h at rt
(2.0
for 2 h at 80 ꢁC (2.0
pre-heated column heater. The reaction mixtures were passed
through the capillary at a flow rate of 0.1
L minꢀ1 for 24 h. The
m
L minꢀ1), then with solvent mixture containing 2 M of Et3N
m
L minꢀ1) with the microreactor placed in the
m
product was collected from the opposing end and analysed by GC-
FID.
3.9. Mizoroki–Heck Catalysis for capillaries
3.4. Attachment of ligand and palladium to resins and
bulk monolith
A similar procedure was followed, using DMA initially, then
DMA with Et3N, and reactions were carried out at 120 ꢁC for
248 h.
A suspension of polymer (0.05 g), 6 (0.08 g) and Bu4NOH
(1.75 mmol) in EtOH (5 mL) was stirred at 60 ꢁC for 24 h, after
which the resin was filtered under vacuum, resuspended in EtOH
and stirred for 30 min, and recovered again by filtration. The
polymer was washed twice more with EtOH and dried in vac-
uum. The modified polymer and PdCl2(NCMe)2 (0.70 g) in MeCN
4. Supplementary data
Crystallographic data for 4, 6, 8 and 9 have been deposited with
the Cambridge Crystallographic Data Centre with deposition

R.C. Jones et al. / Tetrahedron 65 (2009) 7474–7481
7481
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Morin, S.; Organ, M. G. Angew. Chem., Int. Ed. 2006, 45, 2761; (e) Shi, G.; Hong, F.;
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M.; Suzuki, T.; Naito, T.; Oyamada, H.; Kobayashi, S. Chem. Commun. 2008, 1647;
(g) Shore, G.; Morin, S.; Mallik, D.; Organ, M. G. Chem.dEur. J. 2008, 14, 1351;
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numbers CCDC 726966–726969; data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
The present research was supported by the Australian Research
Council, Dr. R.M.G. is the recipient of an ARC APD fellowship; Dr. A.
Townsend (CSL) and Julian Adams (Australian Synchrotron) are
acknowledged for technical support. Data for the structure of 9
were obtained on the PX1 beamline at the Australian Synchrotron,
Victoria, Australia. The views expressed herein are those of the
authors and are not necessarily those of the owner or operator of
the Australian Synchrotron.
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References and notes
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