Renaissance of immobilized catalysts. New types of polymer-supported catalysts, 'microencapsulated catalysts', which enable environmentally benign and powerful high-throughput organic synthesis

Article abstract of DOI:10.1039/b207445a

Immobilized catalysts have been reinvestigated from two aspects; as keys to environmentally benign chemical processes and high-throughput organic synthesis for combinatorial chemistry. While most known polymer-supported catalysts are less active than the

Full text of DOI:10.1039/b207445a

Renaissance of immobilized catalysts. New types of polymer-supported
catalysts, ‘microencapsulated catalysts’, which enable environmentally
benign and powerful high-throughput organic synthesis
Shu¯ Kobayashi* and Ryo Akiyama
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033,
Japan. E-mail: skobayas@mol.f.u-tokyo.ac.jp
Received (in Cambridge, UK) 30th August 2002, Accepted 7th October 2002
First published as an Advance Article on the web 12th December 2002
Immobilized catalysts have been reinvestigated from two
aspects; as keys to environmentally benign chemical proc-
esses and high-throughput organic synthesis for combinato-
rial chemistry. While most known polymer-supported cata-
lysts are less active than the corresponding original catalysts,
new types of polymer-supported catalysts, microencapsu-
lated catalysts, have been developed. The catalysts were
immobilized on to polymers using physical envelopment by
polymer backbones and interaction between p electrons of
benzene rings of the polystyrenes used as polymer backbones
and vacant orbitals of the catalysts. Microencapsulated Sc,
Os, Pd and Ru catalysts have been successfully prepared and
high activities have been attained. In all cases, no leaching of
the catalysts occurred, and the immobilized catalysts were
recovered quantitatively by simple filtration and reused
without loss of activity. It is noted that this method enables
direct immobilization of metals onto polymers, and that
normally unstable species such as Pd(0)(PPh3) can be kept
stable by this immobilization technique. It is expected that
other metal catalysts can be immobilized using this micro-
encapsulation technique.
reinvestigating immobilized catalysts mainly from two aspects.
First, chemical processes with little waste are expected using
immobilized catalysts, because they can be recovered and
reused. This leads to more environmentally benign chemical
processes. Second, use of immobilized catalysts is expected to
be a key to high-throughput organic synthesis. Recent advances
in combinatorial chemistry have required synthesis of large
numbers of structurally distinct compounds efficiently. For this
purpose, even modern organic synthesis with efficient reactions
which attain high yields and high selectivities does not work
well. We think new methodologies for the preparation of large
numbers of compounds (compound library) are needed.2 While
solid-phase syntheses provide one of the efficient methods, we
have recently proposed a new method for the synthesis of
compound libraries using immobilized catalysts.3
Through these research works, we have recognized the
importance of developing truly efficient polymer-supported
catalysts, and reached an idea of microencapsulated catalysts.
Microcapsules have been used for coating and isolating
substances until such time as their activity is needed, and their
application to medicine and pharmacy has been extensively
studied.4 Recently, much progress has been made in this field;
for example, the size of microcapsules achievable has been
reduced from a few mm to nanometers. Our idea is to apply this
microencapsulation technique to the immobilization of catalysts
onto polymers. That is, catalysts would be physically enveloped
by polymer thin films, and at the same time, immobilized by the
interaction between p electrons of benzene rings of the
polystyrene used as a polymer backbone and vacant orbitals of
the catalysts (metal compounds) (Fig. 1).
Introduction
Immobilized catalysts have been of great interest due to several
advantages, such as simplification of product work-up, separa-
tion, isolation, and reuse of the catalysts.1 However, their use in
organic synthesis has been rather limited because immobilized
catalysts are less active than the corresponding original catalysts
in many cases. On the other hand, we have recently been
In this article, use of new types of polymer-supported
catalysts, microencapsulated catalysts, is summarized.
Microencapsulated scandium
Shu¯ Kobayashi studied chemistry at the University of Tokyo and
received his Ph.D. in 1988 (Professor Teruaki Mukaiyama).
After spending 11 years at the Science University of Tokyo
(SUT), he moved to the Graduate School of Pharmaceutical
Sciences, the University of Tokyo, in 1998. His research
interests include development of new synthetic methods,
development of novel catalysts (especially chiral catalysts),
organic synthesis in water, solid-phase organic synthesis, total
synthesis of biologically interesting compounds, and organome-
tallic chemistry. He received the first Springer Award in
Organometallic Chemistry in 1997, IBM Award in 2001 and
Nagoya Silver Medal in 2002.
trifluoromethanesulfonate [MC Sc(OTf)3]
First, scandium triflate was chosen as a Lewis acid to be
immobilized.5 Sc(OTf)3 is a new type of water-compatible
Lewis acid,6 and many useful synthetic reactions using
Sc(OTf)3 have been developed.7 Microencapsulated Sc(OTf)3
(MC Sc(OTf)3) was prepared as follows: Polystyrene (1.000 g)
was dissolved in cyclohexane (20 mL) at 50–60 °C, and to this
solution was added powdered Sc(OTf)3 (0.200 g) as a core. The
mixture was stirred for 1 h at this temperature and then slowly
cooled to 0 °C. Coaservates were found to envelop the solid core
dispersed in the medium. Microcapsules formed at this stage
were physically soft, and hexane (30 mL) was added to harden
the capsule walls. The mixture was stirred at room temperature
for 1 h, and the capsules were washed with acetonitrile several
times and dried at 50 °C. Judging from the recovered Sc(OTf)3
(0.080 g), 0.120 g of Sc(OTf)3 was microencapsulated accord-
ing to this procedure. The weight of the capsules was 1.167 g
which contain acetonitrile. MC Sc(OTf)3 thus prepared can be
stored at room temperature for more than several months.
A scanning electron microscopy (SEM) micrograph and
scandium energy dispersive X-ray (EDX) map of MC Sc(OTf)3
revealed that small capsules of MC Sc(OTf)3 adhered to each
Ryo Akiyama was born in 1974 in Niigata. He studied chemistry
at the Science University of Tokyo (SUT), and took his Master
degree at SUT in 1999 and Ph.D. degree at the University of
Tokyo in 2002 under the supervision of Professor Shu¯
Kobayashi. He is now a postdoctoral fellow in Cambridge, UK
(Professor Steven V. Ley). His research interest includes
development of new synthetic methods and polymer-supported
catalysts.
This journal is © The Royal Society of Chemistry 2003
CHEM. COMMUN., 2003, 449–460
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amino ester, tetrahydroquinoline, a-aminonitrile and homo-
allylic amine derivatives, respectively, in high yields. Although
it is well known that most Lewis acids are trapped and
sometimes decomposed by basic aldimines and/or products,
MC Sc(OTf)3 effectively catalyzed the reactions in all cases.
One of the most remarkable and exciting points is that the ability
of MC Sc(OTf)3 to activate aldimines was superior to that of
monomeric Sc(OTf)3, which was shown by kinetic studies. The
polymer catalyst was recovered quantitatively by simple
filtration and could be reused. The activity of the recovered
catalyst did not decrease even after several uses.
MC Sc(OTf)3 has also been successfully used in three-
component reactions such as Mannich-type (Scheme 6),7h
Strecker (Scheme 7),7f and quinoline-forming (Scheme 8)
reactions,7i which provide efficient methods for the preparation
of biologically interesting compound libraries.9
Table 1 NMR experimentsa
Sample
45Sc NMR peak shift data/d
Sc(OTf)3
Sc(OTf)3 + 1,3,5-triphenylpentane
MC Sc(OTf)3
2182.2
2168.4
2163.9
a ScCl3 was used as an external standard (d = 0) in CD3CN.
Fig. 1 Microencapsulation technique.
other, probably due to the small size of the core, and that
Sc(OTf)3 was located all over the polymer surface. The
importance of the benzene rings of the polystyrene in im-
mobilizing Sc(OTf)3 was demonstrated by control experiments
using polybutadiene or polyethylene instead of polystyrene.
Whereas 43% of Sc(OTf)3 (where 100% is the amount of
Sc(OTf)3 immobilized by polystyrene) was bound using
polybutadiene, no Sc(OTf)3 was observed in the microcapsules
prepared using polyethylene.8
Scheme 2 Imino aldol reaction (flow system).
In addition, we measured the 45Sc NMR spectra of the
monomeric Sc(OTf)3, a mixture of Sc(OTf)3 and 1,3,5-triphe-
nylpentane and MC Sc(OTf)3. 1,3,5-Triphenylpentane was used
as a polystyrene analogue, which was synthesized from
trans,trans-dibenzylidenacetone according to Scheme 1. In the
presence of benzene rings, 45Sc NMR signals were shifted
downfield compared to monomeric Sc(OTf)3 (Table 1). These
results demonstrate that the interaction between Sc(OTf)3 and
the benzene rings of polystyrene is a key to immobilizing
Sc(OTf)3.
Scheme 3 Aza Diels–Alder reaction (flow system).
Scheme 4 Cyanation reaction (flow system).
Scheme 1 Synthesis of 1,3,5-triphenylpentane.
Scheme 5 Allylation reaction (flow system).
MC Sc(OTf)3 was successfully used in several fundamental
and important Lewis acid-catalyzed carbon–carbon bond-
forming reactions. All reactions were carried out in a 0.5 mmol
scale in acetonitrile or nitromethane using MC Sc(OTf)3
containing ca. 0.120 g of Sc(OTf)3. The reactions could be
carried out in both batch (using normal vessels) and flow
systems (using circulating columns). It was found that MC
Sc(OTf)3 effectively activated aldimines. Imino aldol (Scheme
2),7d aza Diels–Alder (Scheme 3),7d,e cyanation (Scheme 4),7f
and alkylation (Scheme 5)7g reactions of aldimines proceeded
smoothly using MC Sc(OTf)3 to afford synthetically useful b-
Scheme 6 Mannich-type reaction (flow system).
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Scheme 7 Strecker reaction (flow system).
Scheme 13 Diels–Alder reaction (batch system).
requires more than a stoichiometric amount of a Lewis acid such
as aluminium chloride (AlCl3), due to consumption of the Lewis
acid by coordination to the products, aromatic ketones. It should
be noted that a catalytic amount of MC Sc(OTf)3 has high
activity in the Friedel–Crafts acylation and that MC Sc(OTf)3
can be recovered easily by simple filtration and reused without
loss of activity.
Scheme 8 Qinoline synthesis (flow system).
It was also found that MC Sc(OTf)3 can activate carbonyl
compounds such as aldehydes and a,b-unsaturated ketones.
Aldol reaction (Scheme 9),7i cyanation (Scheme 10), and
allylation (Scheme 11)7k of aldehydes proceeded smoothly
using MC Sc(OTf)3 to give the corresponding aldol, cyanohy-
dride, and homoallylic alcohol derivatives in high yields.
Michael reaction of an a,b-unsaturated ketone with a silyl enol
ether (Scheme 12)7j and a Diels–Alder reaction of an ox-
azolidinone derivatives with cyclopentadiene (Scheme 13)6 also
proceeded smoothly using MC Sc(OTf)3. Moreover, a Friedel–
Crafts acylation was performed to produce an aromatic ketone
in a good yield (Scheme 14).7l Friedel–Crafts alkylation and
acylation reactions are fundamental and important processes in
organic synthesis as well as in industrial chemistry.10 While the
alkylation reaction proceeds in the presence of a catalytic
amount of a Lewis acid, the acylation reaction generally
Scheme 14 Friedel–Crafts acylation (batch system).
MC Sc(OTf)3 was successfully used in other transformations.
Oriyama and coworkers reported that reactions of alcohols with
methallylsilanes proceeded smoothly in the presence of a
catalytic amount of MC Sc(OTf)3 to afford the corresponding
alkyl silyl ethers in high yields.11 It should be noted that MC
Sc(OTf)3 was more effective than monomeric Sc(OTf)3 (Table
2). In the cases of alcohols containing other functional groups
such as ketones, ethers, esters and acetals, the reactions worked
well using MC Sc(OTf)3, and the yields of the corresponding
TBS ethers were higher than those in the case of using
monomeric Sc(OTf)3.
Table 2 Synthesis of TBS ethers using MC Sc(OTf)3
Scheme 9 Aldol reaction (batch system).
ROH
Yield (%)a
98b
93 (59)c
92 (61)
95 (74)
85 (32)
Scheme 10 Cyanation reaction of aldehyde (batch system).
a Isolated yields. b 0.5 mol% of MC Sc(OTf)3 and 1.2 equiv. of
methallylsilane were used. The reaction was perfomed for 1 h. c Values in
parentheses are yields in the case of using monomeric Sc(OTf)3.
Scheme 11 Allylation reaction of aldehyde (Batch system).
Microencapsulated osmium tetroxide [MC OsO4]
Polystyrene-based MC OsO4 [PS-MC OsO4]
Osmium tetroxide (OsO4) is the most reliable reagent for the
dihydroxylation of olefins to give the corresponding vicinal
diols.12 The reaction proceeds in the presence of a catalytic
amount of OsO4 using a cooxidant such as metal chlorates,
hydrogen peroxide, tert-butyl hydroperoxide, potassium ferri-
cyanide, or most commonly, N-methylmorpholine N-oxide
(NMO). Although a number of substrates have been success-
fully applied to this dihydroxylation, few fruitful industrial
Scheme 12 Michael reaction (batch system).
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a
Table 4 Dihydroxylation of olefins using PS-MS OsO4
applications have been accomplished, probably because OsO4 is
highly toxic, expensive, volatile, and cannot be recovered.
Immobilized osmium catalysts are expected to solve these
problems, and indeed such efforts have been made; however,
recovery and reuse of polymer catalysts has not been sat-
isfactory in almost all cases.13 We intended to apply the
microencapsulation technique for immobilizing osmium tetr-
oxide.14 Styrene-based, microencapsulated osmium tetraoxide
(PS-MC OsO4) was easily prepared by the same procedure as
that of the preparation of MC Sc(OTf)3. One gram of
polystyrene and 200 mg of OsO4 were used, and ca. 180 mg of
OsO4 were immobilized. Unencapsulated OsO4 was recovered
from the washings.
PS-MC OsO4 was first used in dihydroxylation of cyclohex-
ene, and several solvents and cooxidants were examined (Table
3). All the reactions were carried out on a 10 mmol scale using
PS-MC OsO4 containing ca. 0.12 g of OsO4 (5 mol%) in a
bactch system. When a solvent such as H2O–acetone or H2O–
tBuOH (which is used in typical OsO4-catalyzed dihydroxyla-
tion) was used, lower yields were obtained. However, the yield
was dramatically improved when acetonitrile was added to the
H2O–acetone solution. We also examined several cooxidants.
While the reaction was successfully carried out using NMO,
only a moderate yield was obtained using trimethylamine N-
oxide, and much lower yield was observed using hydrogen
peroxide or potassium ferricyanide.
Olefin
Product
Yield (%)
n = 1; 84
n = 2; 81
R = (CH2)3CH3; 89
R = (CH2)7CH3; 68
83
84
78
74
76
R = CH3; 63
R = (CH2)3CH3; 83b
Table 3 Effect of solvents and cooxidants
a All reactions were carried out using PS-MC OsO4 (5 mol%) and NMO in
H2O–acetone–CH3CN (1+1+1) at room temperature for 6–48 h. b Carried
out at 60 °C.
Solvent
Cooxidant
Yield (%)
Table 5 Recovery and reuse of PS-MC OsO4
H2O–acetone (2+1)
NMO
NMO
NMO
Me3NO
H2O2
tBuOOH
K3Fe(CN)6
15
20
84
57
30
18
0
H2O–tBuOH (2+1)
H2O–acetone–CH3CN (1+1+1)
H2O–acetone–CH3CN (1+1+1)
H2O–acetone–CH3CN (1+1+1)
H2O–acetone–CH3CN (1+1+1)
H2O–acetone–CH3CN (1+1+1)
Run
1
2
3
4
5
Yield of product (%)
84
84
83
84
83
Recovery of catalyst (%)
quant. quant. quant. quant. quant.
Several examples of PS-MC OsO4-catalyzed dihydroxylation
of olefins in the presence of NMO in H2O–acetone–acetonitrile
are summarized in Table 4. Cyclic and acyclic exo as well as
internal olefins worked well under these conditions. Moreover,
bulky olefins such as 1-methylcyclohexene and 2-methyl-
2-butene also reacted smoothly in the presence of PS-MC OsO4
to afford the corresponding diols in high yields. The polymer
catalyst was recovered quantitatively by simple filtration and
could be reused several times without loss of activity (Table 5),
indicating that no OsO4 was released from the polymer catalyst
during or after the reaction. This was first comfirmed by the
qualitative analysis of OsO4 using iodometry as follows: PS-
MC OsO4 (1.12 g) was stirred in H2O–acetone–CH3CN (1+1+1,
9 mL) at room temperature for 24 h. After filtration, the
resulting filtrate was treated with potassium iodide and HCl.
The solution was titrated with sodium thiosulfate in the
presence of starch, and no formation of iodine was observed.
Since the titration is very sensitive, these results indicate that no
contamination OsO4 in the products occurred. No leaching of
OsO4 was also confirmed later by MIP-MS analysis. Finally, a
kinetic study on the conversion of the starting olefin was
performed by using OsO4 and PS-MC OsO4 in a model
dihydroxylation of cyclohexene using NMO as a cooxidant
(Table 6). It was found that the reaction proceeded slightly
faster using OsO4 than using PS-MC OsO4 (Fig. 2). While an
81% yield of the diol was obtained using OsO4 for 3 h, a 75%
yield was obtained using PS-MC OsO4 under the same reaction
conditions.
Table 6 Kinetic study on the conversion of the starting olefin
Time/min
1
10
30
60
180
Yield (OsO4) (%)
Yield (PS-MC OsO4) (%)
11
—
79
7
78
37
78
55
81
75
ment of biological potency of Callystatin A, oxidative cleavage
of the olefin (1) using PS-MC OsO4 followed by NaIO4
treatment afforded hydroxyaldehyde 2 in 95% yield (Scheme
15).15a
In the synthesis of 2-acetoxypiperidines, the ene-carbamate
(3) was oxidized to give N-benzyloxycarbonyl-2,3-dihydrox-
ypiperidine (4) using OsO4.15b In this dihydroxylation proce-
dure, PS-MC OsO4 was observed to lead to the cis-diol without
epimerization at the 2-position, whereas epimerization occurred
when K2OsO4·2H2O was used (Table 7).
In addition, Oshima and coworkers used PS-MC OsO4 in
deprotection of an allyl ether (Scheme 16).15c Deallylation of
glycoside (5) using PdCl2 did not give Furanodictine A but
oxazoline as a major product. On the other hand, treatment of 5
with Wilkinson’s catalyst in 10% aqueous ethanol followed by
oxidative cleavage of 1-propenyl glycoside with PS-MC OsO4
allowed to complete the synthesis of Furanodictine A.
PS-MC OsO4 was successfully applied to several total
syntheses.15 For example, in analogue-syntheses and assess-
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Scheme 16 Deprotection of allyl ether. Reagents and conditions: (i)
RhCl(PPh3)3 (20 mol%), DABCO (20 mol%), EtOH–H2O (9+1), reflux, 2
h. (ii) PS–MC OsO4 (5 mol%), NMO (1.3 equiv.), H2O–acetone–CH3CN
(1+1+1), rt, 9 h (2 steps 56%).
Fig. 2 Kinetic study on dihydroxylation of cyclohexene.
Scheme 15 Oxidative cleavage of olefin (1). Reagents and conditions: (i)
PS-MC OsO4 (5 mol%), NMO (5.0 equiv.), H2O–acetone–CH3CN (1+1+1),
rt, 7 d. (ii) NaIO4 (5.0 equiv.), Et2O–H2O (1+1), rt, 1.5 h (2 steps 95%).
Table 7 Dihydroxylation of ene-carbamate (3)
Scheme 17 The first total synthesis of ( )-Linderol A.
In the initial studies, PS-MC OsO4 was applied to asymmetric
oxidation. After many trials, however, the yields and selectiv-
ities as well as recovery of the catalyst were not satisfactory, so
then the polymer support was changed. Several polymer
supports and preparative conditions were examined, and finally
the desired osmium catalyst for the catalytic asymmetric
dihydroxylation of olefins was prepared using an acryronitor-
ile–butadiene–styrene (ABS) copolymer and tetrahydrofuran
according to the general procedure.20
ABS-based OsO4 (ABS-MC OsO4) thus prepared was first
tested in achiral dihydroxylation of olefins. In the presence of
ABS-MC OsO4 (5 mol%), styrene was treated with N-
methylmorpholine N-oxide (NMO) in H2O–acetone–acetoni-
trile (1+1+1). Although styrene was not a good substrate in the
dihydroxylation using PS-MC OsO4 because styrene dissolved
PS-MC OsO4, the desired product, 1-phenyl-1,2-ethanediol,
was obtained in 93% yield using ABS-MC OsO4. The catalyst
was recovered quantitatively, and the recovered catalyst was
used in the second, third and fourth runs, and no loss of activity
was observed (93, 90, 87 and 89% yields, respectively, and
ABS-MC OsO4 was recovered quantitatively in all cases).
Several other olefins were then examined, and the results are
summarized in Table 8. Various olefins including cyclic and
acyclic, terminal, mono-, di-, tri- and tetra-substituted olefins
worked well to give the corresponding diols in high yields.
Encouraged by these promising results, asymmetric dihy-
droxylation of olefins was then performed according to the
Sharpless procedure.21 trans-Methylstyrene was chosen as a
model, and several reaction conditions were examined. When
1,4-bis(9-O-dihydroquinidinyl)phthalazine ((DHQD)2PHAL,
Fig. 3) was used as a chiral source and trans-methylstyrene was
Entry Conditions
Yield (%) cis+transa
1
2
PS-MC OsO4 (5 mol%), NMO
79
73
100+0
80+20
H2O–acetone–CH3CN (1+1+1)
K2OsO4·2H2O (1.7 mol%)
K3Fe(CN)6, K2CO3, tBuOH–H2O (1+1)
a Determined by 1H NMR.
Furthermore, PS-MC OsO4 was used in the first total
synthesis of ( )-Linderol A by Ohta and coworkers (Scheme
17).15d After Wittig olefination of the ketone with methylene-
triphenylphosphine, dihydroxylation using a catalytic amount
of PS-MC OsO4 in the presence of NMO afforded the
corresponding diol as a single isomer in quantitative yield.
Poly(acryronitryl-co-butadiene-co-styrene)-based MC
OsO4 [ABS-MC OsO4]
Osmium-catalyzed asymmetric dihydroxylation of olefins pro-
vides one of the most efficient methods for the preparation of
chiral diols.16 Although high yields and stereoselectivities have
been attained in many substrates, high cost of osmium and
ligands as well as high toxicity of osmium catalysts, which may
contaminate products, have obstructed the use in industry.
Soluble and insoluble polymer-supported ligands have been
developed by several groups,17,18 but complete recovery and
reuse of the osmium have not yet been accomplished.19
Microencapsulated osmium tetroxide, which has first achieved
complete recovery and reuse of the osmium component in
achiral oxidations, was then intended to apply to asymmetric
catalysis.
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a
Table 8 Achiral dihydroxylation of olefins using ABS-MC OsO4
Table 9 Reuse of ABS-MC OsO4
Olefin
Product
Yield (%)
94
Run
Yield (%)
Ee (%)
Recoverya,b
82
1
2
3
4
5
88
75
97
81
88
84
95
94
96
95
quant.
quant.
quant.
quant.
quant.
quant.
95
87
a Recovery of ABS-MC OsO4. b Recovery of (DHQD)2PHAL $95%.
Table 10 Asymmetric dihydroxylation using ABS-MC OsO4
83b
73
ABS-MC OsO4 Chiral ligand
Olefin
(mol%)
(mol%)
Yield (%) Ee (%)
5
2.5
1
10
5
2
75
90
97
91
91
92
86a
89b
74
82
1
2
5
5
98
78
5
5
64
86
77
5
5
5
5
90
85
36
60
63
85
a All reactions were carried out using ABS-MC OsO4 (5 mol%) and NMO
in H2O–acetone–CH3CN (1+1+1) at room temperature for 12 h. b Carried
out at 60 °C.
2.5
5
a 20 mmol-scale experiment was performed. b 100 mmol-scal experiment
was performed.
slowly added over 24 h to the mixture of ABS-MC OsO4,
(DHQD)2PHAL (5 mol% each) and NMO, the desired diol was
obtained in 88% yield with 84% ee. The osmium catalyst was
recovered quantitatively by simple filtration and the chiral
ligand was also recovered by simple acid/base extraction
( > 95% recovery). The recovered catalyst and the chiral source
were reused several times and no loss of activity was observed
even after the fifth use (Table 9). Higher enantioselectivities
were obtained in the second, third, fourth and fifth runs
compared to the 1st run. A clear explanation for these results has
not been made, but the following control experiment and the
standard Sharpless conditions that require an excess of a chiral
ligand to osmium may suggest a solution. The control
experiment performed was oxidation of trans-methylstyrene.
trans-Methylstyrene was slowly added over 24 h to a mixture of
fresh ABS-MC OsO4 (5 mol%), (DHQD)2PHAL (10 mol%)
and NMO, and the desired diol was obtained in 91% ee.
This system was applied to other olefins and the results are
summarized in Table 10. In most cases, the desired diols were
obtained in high yields with high enantiomeric excesses. The
yield and selectivities obtained are comparable to those
obtained using OsO4. For example, 73% yield and 95% ee were
obtained in the oxidation of trans-methylstyrene using 5 mol%
of unencapsulated OsO4, 10 mol% of (DHQD)2PHAL and
NMO (slow addition, 24 h).
The asymmetric reaction was conducted in a 100 mmol-scale
experiment. To a mixture of ABS-MC OsO4 (1.0 mmol, 1.0
mol%), (DHQD)2PHAL (2.0 mmol, 2.0 mol%) and NMO (130
mmol) was slowly added trans-methylstyrene (100 mmol) over
24 h. The desired diol was obtained in 91% yield with 89% ee,
and > 95% of ABS-MC OsO4 and the chiral ligand was
recovered.
Poly(4-phenoxyethoxymethylstyrene-co-styrene)-based
MC OsO4 [PEM-MC OsO4]
ABS-MC OsO4 has achieved catalytic asymmetric dihydroxyla-
tion with complete recovery and reuse of the catalyst without
loss of activity. However, this reaction required a slow addition
of olefins, and hence incurred some problems such as a tedious
procedure and difficulty of using insoluble substances. Thus, it
was next planned to develop recoverable and reusable osmium-
catalyzed asymmetric dihydroxylation of olefins without slow
addition of olefins.22,23
In the initial studies, it was intended to apply ABS-MC OsO4
to the asymmetric dihydroxylation under Sharpless conditions:
i.e. two-phase conditions with potassium hexacyanoferrate
(K3Fe(CN)6) as a cooxidant (Table 11). In the presence of ABS-
MC OsO4 and (DHQD)2PHAL (5 mol% each), styrene was
treated with K3Fe(CN)6 (2.0 equiv.) and potassium carbonate
(2.0 equiv.) in H2O–tBuOH (1+1) for 5 h, and the desired diol
was obtained in 81% yield with 94% ee. The recovered catalyst
was reused three times, and no loss of activity was observed
(entry 1). However, it was revealed that a small amount of OsO4
was leached from the support.
1H NMR spectra of ABS-MC OsO4 was taken using a
swollen-resin magic angle spinning (SR-MAS) NMR tech-
nique.24 It was revealed that the olefin moiety of the ABS
polymer derived from the butadiene monomer was oxidized by
Fig. 3 (DHQD)2PHAL.
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Table 11 Study of several polymers
Yield (%) (ee (%), recovery (%))
Entry
MC OsO4
1st
2nd
3rd
1
2
3
ABSa
PSb
ASc
81 (94, 88)
4 (—, 97)
5 (—, 99)
83 (94, 74)
—
—
84 (94, 74)
—
—
a ABS = poly(acryronitrile-co-butadinen-co-styrne). b PS = polystyrene.
c AS = poly(acrylonitrile-co-styrene).
osmium tetroxide, presumably during the microcapsule forma-
tion (Fig. 4). Other polymer supports such as polystyrene (PS)
and poly(acrylonitrile-co-styrene) (AS) were then examined.
However, these polymers were not effective under the reaction
conditions. It was assumed that the diol moiety of the polymer
support was very effective in two-phase dihydroxylation,
probably due to the hydrophilic property of the cooxidant.
However, leaching of OsO4 occurred in ABS-MC OsO4,
because this polymer was too hydrophilic and a part of the
polymer was dissolved in the H2O–tBuOH solution. On the
other hand, PS and AS are lipophilic and were difficult to react
with the cooxidant.
Scheme 18 Synthesis of PEM-MC OsO4 (8).
Table 12 Effect of linkers and solvents
Yield (%) (ee (%), recovery (%))
Entry
Solventa 1st
2nd
3rd
1
A
A
B
C
D
D
D
77 (94, 94)
93 (93, 93)
65 (92, 86)
80 (80, 74)
35 (77, quant.)
44 (76, quant.)
85 (78, quant.)
37 (80, 86)
34 (90, 90)
4 (—, 82)
Trace (—, 61)
56 (79, quant.)
49 (78, 94)
NRd (—, 84)
3 (—, 83)
—
2b
3
4
—
5
6b
7c
53 (79, quant.)
60 (78, 90)
84 (78, quant.)
66 (78, quant.)
a A, H2O–tBuOH (1+1); B, H2O–iPrOH (1+1); C, H2O–THF (1+1); D,
H2O–acetone (1+1). b Polymer 7 was used instead of 6 (see Scheme 18).
c Cooxidant (2.0 equiv.) and base (2.0 equiv.) were added at first, and then
added again after 3 h. d NR = No reaction.
occurred, which were carefully confirmed by fluorescence X-
ray analysis.
In order to increase the chemical yields, separate addition of
the cooxidant and the base was examined, because it was
observed that the desired reaction stopped halfway (Table 12).
When K3Fe(CN)6 (2.0 equiv.) and potassium carbonate (2.0
equiv.) were added at first, and they were added again after 3 h,
the best result was obtained (entry 7).
Fig. 4 1H Swollen-Resin Magic Angle Spinning (SR-MAS) NMR spectra of
(a) ABS polymer and (b) ABS-MC OsO4 (CDCl3). /; Butadiene moiety.
This system was applied to other olefins, and the results are
summarized in Table 13. In most cases, the desired diols were
obtained in good yields with high enantiomeric excesses. It is
noteworthy that a wide variety of olefins were applicable in this
system and that the catalyst was recovered quantitatively by
simple filtration without loss of activity and that no leaching of
the osmium occurred.
Based on these experiments and consideration, a new
polymer, phenoxyethoxymethyl-polystyrene (PEM-polysty-
rene, 6), shown in Scheme 18 was designed. This polymer was
readily synthesized from chloromethyl-polystyrene by ether-
ification. PEM-based microencapsulated OsO4 was prepared
according to the standard procedure.
PEM-MC OsO4 (8) thus prepared was first tested in
asymmetric oxidation of styrene using (DHQD)2PHAL in H2O-
alcohol solutions (Table 12, entries 1–3). Although the desired
products were obtained in good yields in the first run, the
activity of the catalyst decreased significantly in the second and
third runs. In H2O–THF, the results were similar to those in
H2O-alcohols (entry 4). On the other hand, in H2O–acetone,
moderate chemical yields, good enantiomeric excesses, and
high recovery of the catalyst were obtained (entry 5). Use of
polymer 7 instead of 6 was not effective. It seemed that the
phenylether moiety of 6 was required for good recovery. It is
noted that the osmium catalyst 8 was recovered quantitatively
by simple filtration, and that no leaching of the osmium from 8
Microencapsulated palladium catalysts [MC
Pd(PPh3)]
While palladium catalysts find widespread utility in a variety of
transformations in organic synthesis,25 these are expensive, air-
sensitive, and cannot be recovered in many cases. Immobilized
palladium catalysts have been expected to solve these problems,
and several polymer-supported palladium catalysts have been
developed for allylic substitution,26,27a–c,f oligomeriza-
tion,26c,28,29 decarboxylation,26d hydrogenation,27h,29 isomer-
ization,30 telomerization,31 Suzuki coupling27c,d,i,32 and the
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Table 13 Asymmetric dihydroxylation of olefins using PEM-MC OsO4
(8)
Table 14 Effect of the amounts of triphenylphosphine
Entry
Olefin
Time/h
3 + 2
Yield (%)
85 (80)a
86
Ee (%)
78 (282)a
1
2
Yield (%) (recovery (%))
MC Pd(PPh3) PPh3
3 + 2
94
76
95
91
(mol%)
(mol%) 1st
2nd
3rd
5
5
0
5
0
10
20
40
60
0
—
—
3
4
5
3 + 2
5 + 4
3 + 2
85
85
41
97 (quant.)
0
94 (quant.)
83 (quant.)
92 (quant.)
69 (95)
75 (quant.)
—
61 (99)
90 (quant.)
81 (99)
58 (98)
57 (quant.)
—
20
20
20
20
20
30 (99)
84 (quant.)a
77 (quant.)
65 (99)
a 4th, 94 (quant.); 5th, 83 (quant.).
6b
7b
3 + 2 + 2 + 2c 66
3 + 2 51
> 99
> 99
stereoisomers (E+Z = 64+36), only E isomers were obtained in
the reactions of 10 with 12 and (Z)-carbonate 13. The recovery
was quantitative in all cases and the recovered catalyst could be
reused.
a (DHQ)2PHAL (5 mol%) was used instead of (DHQD)2PHAL. b Methane-
sulfonamide (1.0 equiv.) was added. c One equivalent each of K3Fe(CN)6
and K2CO3 was added four times.
MC Pd(PPh3) was successfully used in other reactions. Allyl
acetate reacted with dimethyl phenylmalonate in the presence of
MC Pd(PPh3), PPh3, N,O-bis(trimethylsilyl)acetamide (BSA),
and a catalytic amount of potassium acetate, to afford the
corresponding adduct in 90% yield (Scheme 19). In addition,
Suzuki coupling reactions35 of boronic acids with aryl bromides
were found to proceed smoothly in the presence of MC
Pd(PPh3) to afford the corresponding adducts in high yields
(Scheme 20). 2-Bromothiophene also worked well. In these
reactions, the best results were obtained by using tri-o-
tolylphosphine (P(o-Tol)3) as an external ligand. A catalytic
asymmetric allylation reaction was also successfully carried out
using MC Pd(PPh3) and a chiral ligand (Scheme 21). The
Mizoroki–Heck reaction,27g,i,29c,33 etc. In these cases, however,
recovery and reuse of the polymer catalysts have not been
satisfactory.27 We have found that palladium catalyst was
successfully immobilized onto a polymer using the micro-
encapsulation technique.34
Preparation of the microencapsulated palladium catalyst was
performed according to the standard procedure. First, polysty-
rene (1.000 g) was dissolved in cyclohexane (20 mL) at 40 °C,
and to this solution was added tetrakis(triphenylphosphine-
)palladium(0) (Pd(PPh3)4, 0.200 g) as a core. Pd(PPh3)4 was
dissolved completely. The mixture was stirred for 1 h at this
temperature. The color of the mixture changed from brown to
black at this stage. The mixture was slowly cooled to 0 °C, and
coaservates (phase separation) were found to envelop the core
dispersed in the medium, and hexane (30 mL) was added to
harden the capsule walls. The mixture was left to stand at room
temperature for 12 h, and the catalyst capsules were then
washed with acetonitrile several times and dried at room
temperature for 24 h. From the washings, it was found that three
equivalents of triphenylphosphine (PPh3) were recovered and
one equivalent of PPh3 remained in the catalyst capsules. 31P
SR-MAS NMR spectra of the catalyst capsules were measured,
and only one peak of PPh3 coordinating to the palladium was
observed. From these results, it was assumed that the catalyst
was encapsulated as Pd(PPh3) (microencapsulated Pd(PPh3)).
Microencapsulated Pd(PPh3) (MC Pd(PPh3)) thus prepared
was first used in the allylation reaction of allyl methyl carbonate
(9) with dimethyl phenylmalonate (10). When 9 was combined
with 10 in the presence of 20 mol% MC Pd(PPh3), the reaction
did not proceed at all. However, it was found that the reaction
proceeded smoothly after adding PPh3 (external ligand). The
effect of the amounts of PPh3 was examined, and the results are
shown in Table 14. The best results were obtained when 20
mol% of PPh3 was used. It should be noted that the palladium
catalyst was recovered quantitatively and reused, and that the
high activity of the catalyst was maintained even after the fifth
use.
Table 15 Allylic substitution using MC Pd(PPh3)a
Allylic
carbonate
Yield
(%)
Entry
1
Nucleophile
Product
9
9
10
83
86
2
3
4
9
60
69
10
10
11
5
6
92b
79c
12
12
7
10
64b
Several examples of the MC Pd(PPh3)-catalyzed allylation
reactions of C-nucleophiles with allylic carbonates are summa-
rized in Table 15. Malonates and b-ketoesters smoothly reacted
under these conditions to afford the corresponding allylation
adducts in high yields. While the reaction of ethyl acetoacetate
with (E)-cinnamyl methyl carbonate (12) gave a mixture of E+Z
13
a All reactions were carried out using MC Pd(PPh3) (20 mol%) and PPh3 (20
mol%) in CH3CN at room temperature for 12 h. b E+Z = > 99+ < 1. c E+Z
= 64+36.
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reaction of 1,3-diphenyl-2-propen-1-yl ethyl carbonate (1.0
equiv.) with dimethyl malonate (3.0 equiv.) was performed in
the presence of MC Pd(PPh3) (20 mol%), 2-(o-diphenylphos-
phinophenyl)-(4R)-isopropyloxazoline (20 mol%),36 BSA (3.0
equiv.) and potassium acetate (0.10 equiv.) under reflux
conditions in acetonitrile. The allylation adduct was obtained in
87% yield with 83% ee.
applied to Sc, Os and Pd, it was decided to develop a new type
polymer-supported ruthenium catalyst based on the technique.
The idea is to utilize the benzene rings of polystyrene as
ligands to immobilize arene–metal complexes. However, it has
been known that arene-displacement reactions at Ru(II) are
6
often sluggish.44 Thus, [Ru(h -C6H5CO2Et)Cl2]2 (14) was
carefully chosen as the starting material, because it was reported
that an intramolecular arene exchange proceeded in good yield
6
using 14 instead of [Ru(h -p-cymene)Cl2]2.45 Dimer 14 was
easily prepared according to the literature procedure,44,45 and
treatment of 14 with triphenylphosphine or tricyclohexylphos-
6
phine gave [Ru(h -C6H5CO2Et)Cl2]2 (15a: R = Ph, 15b: R =
Cy) quantitatively (Scheme 22).
Scheme 19 Allylic substitution of allyl acetate with 10. Reagents and
conditions: MC Pd(PPh3) (20 mol%), PPh3 (20 mol%) BSA (3.0 equiv.),
KOAc (0.10 equiv.), CH3CN, reflux, 12 h.
Scheme 22 Preparation of monomeric catalysts 15.
Preparation of the polymer-supported arene ruthenium com-
plexes using 15 was successfully performed based on a
procedure, which is similar in part to that of formation of
microcapsules (Scheme 23).46 Polystyrene (5.00 g) was dis-
solved in cyclohexane (100 mL) at 65 °C, and to this solution
was added 15a (0.20 g). Complex 15a was not dissolved and a
suspension solution was obtained. The mixture was stirred at
120 °C for 24 h, and then at 65 °C for 1 h. The reaction was
monitored by TLC. Complex 15a disappeared and ethyl
benzoate appeared. The mixture was slowly cooled to 0 °C.
Coaservation (phase separation) occurred to envelop the core
dispersed in the medium to form catalyst capsules, and hexane
(100 mL) was added to harden the capsule walls. The mixture
was left to stand at room temperature for 12 h, and the catalysts
were then washed with acetonitrile several times and dried at
room temperature for 24 h to give polymer-supported ruthenium
complex 16a. The procedure for 16b is similar to the
preparation of 16a. The structure of 16 was confirmed by NMR
analysis. The 31P SR-MAS NMR spectra of the catalysts were
measured, and only one peak of PR3 (16a: R = Ph: d 25.7, 16b
R = Cy: d 28.5) coordinating to the ruthenium was observed.
Scheme 20 Suzuki coupling. Reagents and conditions: MC Pd(PPh3) (20
mol%), P(o-Tol)3 (20 mol%), K3PO4 (2.0 equiv.), CH3CN, reflux, 6 h.
Scheme 21 Asymmetric allylic substitution. Reagents and conditions: MC
Pd(PPh3) (20 mol%), chiral ligand (20 mol%), BSA (3.0 equiv.), KOAc
(0.10 equiv.), CH3CN, reflux, 12 h.
For the structure of MC Pd(PPh3), we assume 18-electron
Pd(0) that is coordinated by PPh3 and the benzene ring(s) of
polystyrene. After adding an external ligand, 14- or 16-electron
Pd(0) would be formed and the catalytic reaction proceeds. The
coordination of the external ligand to Pd(0) was confirmed by
31P SR-MAS NMR analysis, which revealed that the recovered
catalyst in Suzuki coupling reactions contained P(o-Tol)3.
6
[Ru(h -p-cymene)(PPh3)Cl2] was prepared and 31P NMR of
6
this complex was measured (d 23.1). [Ru(h -p-cymene)(P-
Cy3)Cl2] was reported in literature (d 26.0).42c From these
results, it was concluded that the catalyst was supported as
arene–RuCl2(PR3) (polymer-supported arene–RuCl2(PR3) (16,
PS-RuCl2(PR3))). To the best of our knowledge, this is the first
example of a polymer-supported ruthenium catalyst, in which
the benzene rings of the polymer coordinated to the ruthenium
to immobilize the catalyst onto the polymer.
Polymer-supported arene-ruthenium complexes
[PS-RuCl2(PR3)]
PS-RuCl2(PR3) (16) was first used in ring-closing olefin
metathesis (RCM). We prepared a polymer-supported cationic
ruthenium allenylidene complex according to the Dixneuf and
Fürstner method.42b,c Thus, PS-RuCl2(PPh3) (16a), tricyclohex-
ylphosphine (PCy3), 1,1-diphenyl-2-propynol (17) and sodium
Arene-ruthenium complexes are very useful precatalysts for
several organic reactions such as transfer hydrogenation,37
Diels–Alder reaction,38 olefin cyclopropanation,39 enol formate
formation,40 cyclization of dienylalkyne,41 and olefin met-
athesis,42 etc. While the catalysts prepared from the arene–
ruthenium complexes are air- and moisture-sensitive, ex-
pensive, and cannot be recovered in many cases, immobilized
catalysts are expected to solve these problems. Although several
polymer-supported ruthenium complexes have been reported,43
these involve problems such as tedious procedures for the
preparation of the complexes, low activity compared with the
original catalysts, and difficulty of applying the catalysts to
other reactions. Therefore, development of more versatile
polymer-supported ruthenium complexes is strongly demanded.
Since microencapsulation techniques have been successfully
Scheme 23 Synthesis of polymer-supported arene–RuCl2(PR3) (16).
Reagents and conditions: (i) cyclohexane, 65 °C, 1 h. (ii) 15a or 15b, 120
°C, 24 h then 65 °C, 1 h then 0 °C.
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Table 17 Reactivation conditions of the catalyst
hexafluorophosphate (NaPF6) were mixed in several solvents,
and the mixture was stirred for 1 h under reflux conditions.
Signals of the 31P SR-MAS NMR spectra of the activated
ruthenium catalyst (18a, Fig. 5) thus prepared were observed at
Yield (%)
Entry
Method Conditions
1st
2nd
3rd
1
2
3
A
B
C
PCy3, 17, reflux, 1 h
40
63
69
72
56
73
77
49
85
PCy3, NaPF6, 17, rt, 12 h
PCy3, 17, reflux, 1 h then
NaPF6, rt, 12 h
As above
As above
As above
4c
C
C
C
75
71
97
80
81
85
18
—
98f
88
12
—
5c,d
6c,e
7c,g
Fig. 5 Activated ruthenium catalyst 18a.
d 50.8 and –144.0. The 31P NMR spectrum of the monomeric
a Catalyst 18a was reactivated under method A–C in iPrOH–hexane (1+10).
b Recovery of the catalysts was quantitative. c Hexane–toluene (10+1) was
used as a solvent in RCM. d 10 mol% of 18a was used. e 5 mol% of 18a was
used. f 4th, 83% (recovery: quant.); 5th, 82% (recovery: quant.); 6th, 89%
(recovery: quant.); 7th, 92% (recovery: quant.). g [(p-cymene)RuCl(P-
Cy3)(NCNCNCPh2)]+[PF6}2 was used instead of 18a.
ruthenium complex has already been measured [31P NMR
(CDCl3): d 58.8 (PCy3), –140.8 (PF6 )].40c,47 Catalyst 18a was
–
then tested in RCM of N,N-diallyl-p-toluensulfonamide (19) in
hexane (Table 16). It was found that the choice of solvents was
crucial. While the desired product was obtained in good yield in
the first run in iPrOH–hexane (1+1), the activity of the catalyst
decreased significantly in the second and third runs (entry 2).
On the other hand, the yield of the desired product was very low
in iPrOH (entry 1). In iPrOH–hexane (1+10), moderate chemical
yields were obtained. The activity of the catalyst was main-
tained even after the third use (entries 3 and 4). In all reactions,
no leaching of ruthenium metal were confirmed by fluorescence
X-ray analysis.
Table 18 Ring-closing olefin metathesis using 18aa
Yield
Entry
1
Substrate
Product
(%)
98
Table 16 Effect of solvents in the preparation of the active catalyst
2
3
92
57b
4
5
6
72
66
82
Yield (%) (recovery (%))
Entry Solvent
1st
2nd
3rd
a All reactions were carried out using 18a (20 mol%) in hexane–toluene
1
2
3
4
iPrOH
8 (quant.)
78 (quant.)
9 (quant.)
—
(10+1) under reflux conditions for 12 h. b Reaction was carried out for 24
iPrOH–hexane (1+1)
48 (quant.)
69 (quant.)
72 (quant.)
16 (quant.)
71 (quant.)
77 (quant.)
h.
iPrOH–hexane (1+10) 42 (quant.)
iPrOH–hexane (1+10)a 49 (98)
a 16b was used intead of 16a.
PS-RuCl2(PPh3) (16a) was successfully used in other
reactions. Acetophenone was reduced smoothly in the presence
of 16a to afford the corresponding alcohol in high yield
(Scheme 24). In addition, 16a catalyzed cyclization of dieny-
lalkyne (20) in good yield (Scheme 25).
In order to increase the chemical yields, reactivation
conditions of the recovered catalysts in RCM were next
examined (Table 17). After careful investigations, the best
results were obtained when a mixture of the recovered catalyst,
PCy3, and 17 was stirred for 1 h under reflux conditions and,
after addition of NaPF6, further stirred for 12 h at room
temperature (method C). Several other examples of the PS Ru-
catalyzed ring-closing metathesis of olefins were then tested,
and the results are summarized in Table 18. Six- as well as five-
membered rings were smoothly formed under these conditions,
while sterically hindered diethyl diallylmalonate was less
reactive (entry 4). It should be noted that recovery of the catalyst
was quantitative in all cases, and that the recovered catalyst
could be reused without loss of activity. In addition, the
structure of the recovered catalyst was confirmed by 31P SR-
MAS NMR analysis. Signals were observed at d 50.8 and
2144.0, which were completely consistant with those of the
original catalyst 18a.
Scheme 24 Hydrogenation of acetophenon using 16a.
Scheme 25 Cyclization of dienylalkye using 16a.
458
CHEM. COMMUN., 2003, 449–460

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(c) S. Kobayashi, Synlett, 1994, 689. For selected examples (d) S.
Kobayashi, M. Araki, H. Ishitani, S. Nagayama and I. Hachiya, Synlett,
1995, 233; (e) S. Kobayashi, H. Ishitani and S. Nagayama, Synthesis,
1995, 1195; (f) S. Kobayashi, H. Ishitani and M. Ueno, Synlett, 1997,
115; (g) S. Kobayashi and S. Nagayama, J. Am. Chem. Soc., 1997, 119,
10049; (h) S. Kobayashi, M. Araki and M. Yasuda, Tetrahedron Lett.,
1995, 36, 5773; (i) S. Kobayashi, H. Ishitani and S. Nagayama, Chem.
Lett., 1995, 423; (j) S. Kobayashi, I. Hachiya, H. Ishitani and M. Araki,
Synlett, 1993, 472; (k) I. Hachiya and S. Kobayashi, J. Org. Chem.,
1993, 58, 6958; (l) A. Kawada, S. Mitamura and S. Kobayashi, Synlett,
1994, 545.
8 Steric factors (physical envelopment) would also contribute the
remarkable immobilizeing ability of polystyrene compared to poor
immobilization of polybutadiene and polyethylene.
9 (a) I. Ugi, A. Dömling and W. Hörl, Endeavour, 1994, 18, 115; (b) R.
W. Armstrong, A. P. Combs, P. A. Tempest, S. D. Brown and T. A.
Keating, Acc. Chem. Res., 1996, 29, 123; (c) S. Kobayashi, H. Ishitani
and S. Nagayama, Chem. Lett., 1995, 423.
10 For leading references on Friedel–Crafts acylation, see: (a) G. A. Olah,
Friedel–Crafts Chemistry, Wiley-Interscience, New York, 1973; (b) H.
Heaney, in Comprehensive Organic Synthesis, ed. B. M. Trost,
Pergamon Press, Oxford, 1991, vol. 2, p. 733; (c) G. A. Olah, R.
Krishnamurti and G. K. S. Prakash, in Comprehensive Organic
Synthesis, ed. B. M. Trost, Pergamon Press, Oxford, 1991, vol. 3, p. 293;
(d) S. Kobayashi, I. Komoto and J.-i. Matsuo, Adv. Synth. Catal., 2001,
343, 71.
Conclusion
New types of polymer-supported catalysts, microencapsulated
catalysts, have been discussed. The catalysts were developed
based on a microencapsulation technique for binding catalysts
to polymers utilizing physical envelopment by polymer back-
bones and interaction between p electrons of benzene rings of
the polystyrenes used as polymer backbones and vacant orbitals
of the catalysts. They are indeed unprecedented polymer-
supported catalysts, and immobilization of Sc, Os, Pd and Ru
catalysts has been demonstrated, and high activities have been
attained. In all cases, no leaching of the catalysts occurred, and
the immobilized catalysts were recovered quantitatively by
simple filtration and reused without loss of activity. It is noted
that this method enables direct immobilization of metals onto
polymers, and that normally unstable species such as
Pd(0)(PPh3) can be kept stable by this immobilization tech-
nique. It is expected that other metal catalysts can be
immobilized using this micriencapsulation technique, and that
these catalysts contribute to environmentally benign and
powerful high-throughput organic synthesis.
Notes in proof
11 T. Suzuki, T. Watahiki and T. Oriyama, Tetrahedron Lett., 2000, 41,
8903.
After completing this article, Gibson and Swamy reported a
microencapsulated metathesis catalyst.48 Ley and coworkers
also published elegant examples of polyurea-encapsulated
palladium catalysts.49 Furthermore, Lattanzi and Leadbeater
prepared microencapsulated VO(acac)2 (MC VO(acac)2),
which was used in epoxidation of allylic alcohols using tert-
butyl hydroperoxide as an oxidant (Scheme 26).50 The reactions
proceeded smoothly in hexane at room temperature. The MC
VO(acac)2 was reusable without significant loss of activity.
12 (a) M. Schröder, Chem. Rev., 1980, 80, 187; (b) H. S. Singh, in Organic
Synthesis by Oxidation with Metal Compounds, ed. W. J. Mijs, Plenum,
New York, 1986, ch. 12; (c) A. H. Haines, in Comprehensive Organic
Synthesis, ed. B. M. Trost, Pergamon Press, Oxford, 1991, vol. X, p.
437.
13 (a) G. Cainelli, M. Contento, F. Manescalahi and L. Plessi, Synthesis,
1989, 45; (b) W. A. Herrmann, R. M. Kratzer, J. Blumel, H. B.
Friedrich, R. W. Fischer, D. C. Apperley, J. Mink and O. Berkesi, J.
Mol. Catal., A, 1997, 120, 197.
14 S. Nagayama, M. Endo and S. Kobayashi, J. Org. Chem., 1998, 63,
6094.
15 (a) N. Murakami, M. Sugimoto and M. Kobayashi, Bioorg. Med. Chem.,
2001, 9, 57; (b) O. Okitsu, R. Suzuki and S. Kobayashi, J. Org. Chem.,
2001, 66, 809; (c) H. Kikuchi, Y. Saito, J. Komiya, Y. Takaya, S.
Honma, N. Nakahata, A. Ito and Y. Oshima, J. Org. Chem., 2001, 66,
6982; (d) M. Yamashita, N. Ohta, I. Kawasaki and S. Ohta, Org. Lett.,
2001, 3, 1359; (e) S. Aoki, K. Matsui, K. Tanaka, R. Satari and M.
Kobayashi, Tetrahedron, 2001, 56, 9945.
16 (a) H. C. Kolb, M. S. Van Nieuwenhze and K. B. Sharpless, Chem. Rev.,
1994, 94, 2483; (b) G. Poil and C. Scolastico, in Stereoselective
Synthesis, ed. G. Helmchen, Thieme, Stuttgart, 1996, p. 4547; (c) R. A.
Johnson and K. B. Sharpless, in Catalytic Asymmetric Synthesis, ed. I.
Ojima, VCH, Weinheim, 2nd edn., 2000, pp. 357–398.
17 For reviews, see: (a) D. J. Gravert and K. D. Janda, Chem. Rev., 1997,
97, 489; (b) C. Bolm and A. Gerlach, Eur. J. Org. Chem., 1998, 21, 1;
(c) P. Salvsdori, D. Pini and A. Petri, Synlett, 1999, 1181.
18 (a) H. M. Lee, S.-W. Kim, T. Hyeon and B. M. Kim, Tetrahedron:
Asymmetry, 2001, 12, 1537; (b) I. Motorina and C. M. Crudden, Org.
Lett., 2001, 3, 2325; (c) B. M. Choudary, N. S. Chowdari, K. Jyothi, N.
S. Kumar and M. L. Kantam, Chem. Commun., 2002, 586.
19 Since amine ligands coordinate to osmium under equilibium conditions,
recovery of the osmium using polymer-supported ligands is generally
difficult.
Scheme 26 Allylic alcohol epoxidation using MC VO(acac)2.
Acknowledgements
Our work shown in this article was partially supported by
CREST and SORST, Japan Science and Technology Corpora-
tion (JST), and a Grant-in-Aid for Scientific Research from
Japan Society of the Promotion of Science.
Notes and references
20 S. Kobayashi, M. Endo and S. Nagayama, J. Am. Chem. Soc., 1999, 121,
1 For reviews, see: (a) D. C. Bailey and S. H. Langer, Chem. Rev., 1981,
81, 109; (b) A. Akelah and D. C. Sherrington, Chem. Rev., 1981, 81,
557; (c) J. M. J. Frechet, Tetrahedron, 1981, 37, 663.
2 (a) S. Kobayashi, Chem. Soc. Rev., 1999, 28, 1; (b) S. Kobayashi, Curr.
Opin. Chem. Biol., 2000, 4, 338.
3 (a) S. Kobayashi and S. Nagayama, J. Am. Chem. Soc., 1996, 118, 8977.
For other Sc catalysts, see (b) S. Kobayashi and S. Nagayama, J. Org.
Chem., 1996, 61, 2256; (c) S. Kobayashi, S. Nagayama and T.
Busujima, Tetrahedron Lett., 1996, 51, 9221; (d) S. Kobayashi and S.
Nagayama, Synlett, 1997, 653; (e) S. Nagayama and S. Kobayashi,
Angew. Chem., Int. Ed., 2000, 39, 567.
4 M. Donbrow, Microcapsules and Nanocapsules in Medicine and
Pharmacy, CRC Press, Boca Raton, FL, 1992.
5 S. Kobayashi and S. Nagayama, J. Am. Chem. Soc., 1998, 120, 2985.
6 S. Kobayashi, I. Hachiya, M. Araki and H. Ishitani, Tetrahedron Lett.,
1993, 34, 3755.
7 (a) S. Kobayashi, Eur. J. Org. Chem., 1999, 15; (b) S. Kobayashi, M.
Sugiura, H. Kitagawa and W. W.-L. Lam, Chem. Rev., 2002, 102, 2227;
11229.
21 J. S. M. Wai, I. Markó, J. S. Svendsen, M. G. Finn, E. N. Jacobsen and
K. B. Sharpless, J. Am. Chem. Soc., 1989, 111, 1123.
22 S. Kobayashi, T. Ishida and R. Akiyama, Org. Lett., 2001, 3, 2649.
23 Recently, osmium tetroxide was immobilized onto a silica-anchored
tetrasubstited olefin or by an ion-exchange technique, respectively: (a)
A. Sevrens, D. E. De Vos, L. Fiermans, F. Verpoort, P. J. Grobet and P.
A. Jacobs, Angew. Chem., Int. Ed., 2001, 40, 586; (b) B. M. Choudary,
N. S. Chowdari, K. Jyothi and M. L. Kantam, J. Am. Chem. Soc., 2002,
124, 5341.
24 The usefulness of the SR-MAS NMR technique for structure determina-
tion of resins directly without cleavage from polymer supports has been
demonstrated through the development of several useful reactions using
the cross-linked polystyrene-based resins in the solid-phase in our
laboratories: (a) S. Kobayashi, R. Akiyama, T. Furuta and M. Moriwaki,
Mol. Online, 1998, 2, 35; (b) S. Kobayashi and Y. Aoki, Tetrahedron
Lett., 1998, 39, 7345; (c) S. Kobayashi and R. Akiyama, Tetrahedron
CHEM. COMMUN., 2003, 449–460
459

View Online
Lett., 1998, 39, 9211; (d) S. Kobayashi, T. Furuta, K. Sugita, O. Okitsu
and H. Oyamada, Tetrahedron Lett., 1999, 40, 1341; (e) Y. Aoki and S.
Kobayashi, J. Comb. Chem., 1999, 1, 371; (f) O. Okitsu, H. Oyamada,
T. Furuta and S. Kobayashi, Heterocycles, 2000, 52, 1143; (g) S.
Kobayashi, R. Akiyama and H. Kitagawa, J. Comb. Chem., 2000, 2,
438.
35 (a) A. Suzuki, Pure Appl. Chem., 1985, 57, 1749; (b) A. Suzuki, Pure
Appl. Chem., 1994, 66, 91; (c) N. Miyaura and A. Suzuki, Chem. Rev.,
1995, 95, 2457.
36 (a) P. von Matt and A. Pfaltz, Angew. Chem., Int. Ed., 1993, 32, 566; (b)
J. Sprinz and G. Helmchen, Tetrahedron Lett., 1993, 34, 1769; (c) G. J.
Dawson, C. G. Frost, J. M. J. Williams and S. W. Coate, Tetrahedron
Lett., 1993, 34, 3149.
37 (a) S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya and R. Noyori, J. Am.
Chem. Soc., 1995, 117, 7562; (b) R. Noyori and S. Hashiguchi, Acc.
Chem. Res., 1997, 30, 97; (c) Y. Jiang, Q. Jiang and X. J. Zhang, J. Am.
Chem. Soc., 1998, 120, 3817.
38 (a) D. L. Davies, J. Fawcett, S. A. Garratt and D. A. Russell, Chem.
Commun., 1997, 1352; (b) D. Carmona, C. Cativiela, S. Elipe, F. J.
Lahoz, M. P. Lamata, M. P. L.-R. Víu, L. A. Oro, C. Vega and F. Viguri,
Chem. Commun., 1997, 2352.
25 For reviews, see: (a) R. F. Heck, Palladium Reagents in Organic
Synthesis, Academic Press, New York, 1985; (b) J. Tuji, Palladium
Reagents and Catalysts, John Wiley and Sons, Chichester, 1995; (c) B.
M. Trost, Chem. Rev., 1996, 96, 395; (d) I. P. Beletskaya and A. V.
Cheprakov, Chem. Rev., 2000, 100, 3009; (e) G. Poli, G. Giambastiani
and A. Heumann, Tetrahedron, 2000, 56, 5959.
26 (a) B. M. Trost and E. Keinan, J. Am. Chem. Soc., 1978, 100, 7779; (b)
D. E. Bergbreiter, B. Chen and T. J. Lynch, J. Org. Chem., 1983, 48,
4179; (c) D. E. Bergbreiter and D. A. Weatherford, J. Org. Chem., 1989,
54, 2726; (d) D. E. Bergbreiter, B. Chen and D. A. Weatherford, J. Mol.
Catal., 1992, 74, 409; (e) B. M. Trost and R. W. Warner, J. Am. Chem.
Soc., 1982, 104, 6112; (f) B. M. Trost and R. W. Warner, J. Am. Chem.
Soc., 1983, 105, 5940.
27 Recently, some excellent polymer-supported palladium catalysts for
allylic substitution have been reported: (a) Y. Uozumi, H. Danjo and T.
Hayashi, Tetrahedron Lett., 1997, 38, 3557; (b) Y. Uozumi, H. Danjo
and T. Hayashi, Tetrahedron Lett., 1998, 39, 8303; (c) H. Danjo, D.
Tanaka, T. Hayashi and Y. Uozumi, Tetrahedron, 1999, 55, 14341, as
well as for Suzuki coupling (d) S. B. Jang, Tetrahedron Lett., 1997, 38,
1793; (e) I. Fenger and C. L. Drian, Tetrahedron Lett., 1998, 39, 4287.
For using biphasic systems (f) D. E. Bergbreiter, Y. S. Liu and P. L.
Osburn, J. Am. Chem. Soc., 1998, 120, 4250; (g) D. E. Bergbreiter, P. L.
Osburn and Y. S. Liu, J. Am. Chem. Soc., 1999, 121, 9531; (h) V.
Chechik and R. M. Crooks, J. Am. Chem. Soc., 2000, 122, 1243; (i) D.
E. Bergbreiter, P. L. Osburn, A. Wilson and E. M. Sink, J. Am. Chem.
Soc., 2000, 122, 9058.
39 (a) F. Simal, A. Demonceau and A. F. Noels, Tetrahedron Lett., 1998,
39, 3493; (b) F. Simal, J. Dominique, A. Demonceau and A. F. Noels,
Tetrahedron Lett., 1999, 40, 1653.
40 M. Neveaux, C. Bruneau and P. H. Dixneuf, J. Chem. Soc., Perkin
Trans. 1, 1991, 1197.
41 A. M. Craig and E. P. Malinda, J. Am. Chem. Soc., 1996, 118, 11319.
42 For ring-closing olefin metathesis, see: (a) E. L. Dias and R. H. Grubbs,
Organometallics, 1998, 17, 2758; (b) A. Fürstner, M. Picquet, C.
Bruneau and P. H. Dixneuf, Chem. Commun., 1998, 1315; (c) A.
Fürstner, M. Liebl, C. W. Lehmann, M. Picquet, R. Kunz, C. Bruneau,
D. Touchard and P. H. Dixneuf, Chem. Eur. J., 2000, 6, 1847; for ring-
opening metathesis polymerization, see (d) A. Hafner, A. Mühlebach
and P. A. van der Schaaf, Angew. Chem., Int. Ed., 1997, 36, 2121; (e) A.
Demonceau, A. W. Stumpf, E. Saive and A. F. Noels, Macromolecules,
1997, 30, 3127.
43 For ring-closing olefin metathesis, see: (a) M. Ahmed, A. G. M. Barrett,
D. C. Braddock, S. M. Cramp and P. A. Procopiou, Tetrahedron Lett.,
1999, 40, 8657; (b) Q. Yao, Angew. Chem., Int. Ed., 2000, 39, 3896; (c)
S. C. Schürer, S. Gessler, N. Buschmann and S. Blechert, Angew.
Chem., Int. Ed., 2000, 39, 3898; (d) J. S. Kingsbury, S. B. Garber, J. M.
Giftos, B. L. Gray, M. M. Okamoto, R. A. Farrer, J. T. Fourkas and A.
H. Hoveyda, Angew. Chem., Int. Ed., 2001, 40, 4251; for asymmetric
hydrogenation, see (e) Q. H. Fan, C. Y. Ren, C. H. Yeung, W. H. Hu and
A. S. C. Chan, J. Am. Chem. Soc., 1999, 121, 7407; (f) T. Ohkuma, H.
Takeno and R. Noyori, Adv. Synth. Catal., 2001, 343, 369; (g) Q. H. Fan,
G. J. Deng, C. C. Lin and A. S. C. Chan, Tetrahedron: Asymmetry, 2001,
12, 1241; for other reactions, see (h) N. E. Leadbeater, K. A. Scott and
L. J. Scott, J. Org. Chem., 2000, 65, 3231; (i) N. E. Leadbeater, J. Org.
Chem., 2001, 66, 2168.
28 (a) C. U. Pittman, S. K. Wuu and S. E. Jacobson, J. Catal., 1976, 44, 87;
(b) C. U. Pittman, Jr. and Q. Ng, J. Organomet. Chem., 1978, 153,
85.
29 (a) H. Bruner and J. C. Bailar, Inorg. Chem., 1973, 12, 1465; (b) M.
Terasawa, K. Kaneda, T. Imanaka and S. Teranishi, J. Catal., 1978, 51,
406; (c) K. Kaneda, M. Terasawa, T. Imanaka and S. Teranishi,
Fundam. Res. Homogeneous Catal., 1973, 3, 671; (d) E. Baralt and N.
Holy, J. Org. Chem., 1984, 49, 2626; (e) G. Bar-Sela and A.
Warshawsky, J. Polym. Sci., Part A: Polym. Chem., 1990, 28, 1303; (f)
R. Mani, V. Mahadevan and M. Srinvasan, React. Polym., 1991, 14,
263; (g) Y. Zhang, S. Liao and Y. Xu, Tetrahedron Lett., 1994, 35, 4599;
(h) P. C. Selvaraj, V. Mahadevan and M. Srinvasan, J. Polym. Sci., Part
A: Polym. Chem., 1997, 35, 105; (i) R. J. Card, C. E. Liesner and D. C.
Neckers, J. Org. Chem., 1979, 44, 1095.
44 M. A. Bennett and A. K. Smith, J. Chem. Soc., Dalton Trans., 1974,
233.
30 (a) R. J. Card and D. C. Neckers, J. Org. Chem., 1978, 43, 2958; (b) R.
B. King and R. M. Hanse, J. Org. Chem., 1979, 44, 1092.
31 K. Kaneda, H. Kurosaki, M. Terasawa, T. Imanaka and S. Teranishi, J.
Org. Chem., 1981, 46, 2356.
45 B. Therrien, T. R. Ward, M. Pilkington, C. Hoffmann, F. Gilardoni and
J. Weber, Organometallics, 1998, 17, 330.
46 R. Akiyama and S. Kobayashi, Angew. Chem., Int. Ed., 2002, 42,
2602.
32 Y. Uozumi, H. Danjo and T. Hayashi, J. Org. Chem., 1999, 64, 3384.
33 (a) M. Terasawa, K. Kaneda, T. Imanaka and S. Teranishi, J.
Organomet. Chem., 1978, 162, 403; (b) C.-M. Andersson, K. Karabelas
and A. Hallberg, J. Org. Chem., 1985, 50, 3891; (c) Z. Y. Zhang, H. W.
Hu and T. Y. Kao, React. Polym., Ion Exch. Solvents, 1988, 9, 249; (d)
Z. Y. Zhang, Y. Pan, H. W. Hu and T. Y. Kao, Synth. Commun., 1990,
20, 3563; (e) S. B. Jang, Tetrahedron Lett., 1997, 3, 4421.
34 R. Akiyama and S. Kobayashi, Angew. Chem., Int. Ed., 2001, 40,
3469.
47 A. Fürstner, O. Guth, A. Düffels, G. Seidel, M. Liebl, B. Gabor and R.
Mynott, Chem. Eur. J., 2001, 7, 4811.
48 S. E. Gibson and V. M. Swamy, Adv. Synth. Catal., 2002, 344, 619.
49 (a) C. Ramarao, S. V. Ley, S. C. Smith, I. M. Shirley and N. DeAlmeida,
Chem. Commun., 2002, 1132; (b) S. V. Ley, C. Ramarao, R. S. Gordon,
A. B. Holmes, A. J. Morrison, I. F. McConvey, I. M. Shirley, S. C. Smith
and M. D. Smith, Chem. Commun., 2002, 1134.
50 A. Lattanzi and N. E. Leadbeater, Org. Lett., 2002, 4, 1519.
460
CHEM. COMMUN., 2003, 449–460