Polymer-micelle incarcerated scandium as a polymer-supported catalyst for high-throughput organic synthesis

Article abstract of DOI:10.1021/ja053176f

A novel immobilization technique for Sc(OTf)₃, a polymer-micelle incarcerated (PMI) method, has been developed. PMI Sc(OTf)₃ is highly active in several fundamental carbon-carbon bond-forming reactions. The catalyst is recovered quan

Full text of DOI:10.1021/ja053176f

Published on Web 08/31/2005
Polymer-Micelle Incarcerated Scandium as a Polymer-Supported Catalyst for
High-Throughput Organic Synthesis
Masahiro Takeuchi, Ryo Akiyama, and Shuj Kobayashi*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, The HFRE DiVision, ERATO, Japan Science
and Technology Agency (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received May 23, 2005; E-mail: skobayas@mol.f.u-tokyo.ac.jp
Table 1. Solvent Effects in Microencapsulation of Sc(OTf)3
High-throughput organic synthesis (HTOS) is a powerful tool
for lead discovery and lead optimization in modern medicinal
chemistry. Recently, many methodologies for HTOS, such as solid-
phase syntheses and solution-phase syntheses, using polymer-bound
reagents or scavengers have been reported.1,2 As one of the most
efficient methodologies for HTOS, the use of immobilized catalysts
has also attracted much attention.3 On the other hand, Lewis acid
catalysts are now of great interest because of their utility for
activation of various carbon-carbon bond-forming reactions and
others, and they provide among the most important methods in
organic syntheses.4 In this context, much effort has been devoted
to the development of solid-supported Lewis acid catalysts for
HTOS, and some immobilizing methods using organic polymers
or inorganic materials as solid supports have been reported.5
However, activities of such supported Lewis acids are lower in
many cases compared with those of the original Lewis acids,
presumably because rather strong interactions between the Lewis
acid metals and their supports, which work as Lewis bases, result
in decreasing Lewis acidities. Therefore, development of truly
efficient and general methods for immobilization of Lewis acids,
which can be applied to many reactions, is desired. We now report
here novel polymer-supported scandium triflate (Sc(OTf)3) utilizing
polymer micelles, which has high activity in several synthetically
useful carbon-carbon bond-forming reactions.
Since Sc(OTf)3 is a water-compatible Lewis acid and is now
one of the standard Lewis acids often used in organic synthesis,6
we decided to immobilize this Lewis acid onto polymers. Although
we and other groups have already synthesized some examples of
polymer-supported Sc(OTf)3 and derivatives,7 catalytic activity,
scope of reaction, and/or catalyst loadings are still unsatisfactory
in most cases. Recently, we developed a new immobilizing
technique for metal catalysts, a polymer incarcerated (PI) method.8
This method is based on microencapsulation and cross-linking, and
phosphine-free polymer incarcerated Pd(0) (PI Pd) was prepared
from Pd(PPh3)4. Since ligand exchanges were used for the prepara-
tion of PI Pd, it was not clear whether Lewis acids, such as Sc-
(OTf)3, could be immobilized utilizing this method.
Sc loading
(mmol/g)
entry
solvent
poor solvent
1
2
3
toluene
hexane
hexane
MeOH
0.191
THF-cHex (1:3)
0.185
CH2Cl2
not loaded
Figure 1. TEM images of 1-Sc(OTf)3 solutions in toluene (left) and THF-
cyclohexane.
Table 2. Comparison of Catalytic Activity of PI Sc(OTf)3 and PMI
Sc(OTf)3 in Mukaiyama Aldol Reaction
yield (%)
entry
solvent
Sc catalyst
1st
2nd
3rd
Sc leaching (%)
1
2
3
4
5
CH3CN
toluene
CH2Cl2
CH2Cl2
CH2Cl2
PI Sc(OTf)3
PI Sc(OTf)3
PI Sc(OTf)3
PI Sc(OTf)3
PMI Sc(OTf)3
85
87
64
83
85
71
83
NDb
NDb
NDb
NDc
NDc
70
83
84a
92a
96
94
We first examined several reaction conditions for the preparation
of polymer-supported Sc(OTf)3 based on the PI method. It was
found that choice of solvents at the stage of microencapsulation
was key to the preparation (Table 1). While toluene-hexane and
THF-cyclohexane-hexane were efficient for immobilizing Sc-
(OTf)3 (entries 1 and 2), the catalyst was not loaded at all in
microencapsulation before cross-linking using CH2Cl2-MeOH,
which was efficient for immobilization of Pd (entry 3).9 These
results suggest that Sc(OTf)3 may locate in hydrophilic parts of
random copolymer 1.8d,10 It is noted that the PI method can also be
successfully used for the preparation of immobilized Sc(OTf)3.
Moreover, interesting information was obtained by transmission
electron microscopic (TEM) analysis of the polymer solutions
(Figure 1). Although random aggregation of copolymer 1-Sc(OTf)3
a Corrected yield. Half of the crude compound was used for ICP analysis.
b Determined by XRF analysis (ND ) not detected in all runs (<2.2%)).
c Determined by ICP analysis after the first use (ND < 0.05%).
was observed in toluene, spherical micelles were formed in THF-
cyclohexane, and Sc(OTf)3 seemed to be encapsulated into these
spherical micelles. These different shapes are ascribed to the polarity
of the solvents. To distinguish these catalysts, the former was named
as polymer incarcerated Sc(OTf)3 (PI Sc(OTf)3) and the latter as
polymer-micelle incarcerated Sc(OTf)3 (PMI Sc(OTf)3).
PI Sc(OTf)3 and PMI Sc(OTf)3 were first used in the Mukaiyama
aldol reaction11 to compare their catalytic activity (Table 2). PI Sc-
(OTf)3 worked well in several solvents, and the desired product
was obtained in good yields (entries 1-3). Moreover, it was
9
13096
J. AM. CHEM. SOC. 2005, 127, 13096-13097
10.1021/ja053176f CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Mannich-type Reaction Using PMI Sc(OTf)3
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from Japan Society of the
Promotion of Science (JSPS).
Supporting Information Available: Tables of details in Mu-
kaiyama aldol, Mannich-type, and Michael reactions, and experimental
details (PDF). This material is available free of charge via Internet at
http://pubs.acs.org.
entry
R1
X
R2
R3
Y
time (h)
yield (%)
1
Ph
Ph
Ph
NHBz
NHBz
Ph
Me
Me
Me
Me
H
Me
Me
Me
Me
H
OMe
SEt
OMe
OMe
Ph
3
4
24
24
3
96b,c
97
2a
3a
4a
5a
2-thienyl
PhCH2CH2
EtO2C
80
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73
Ph
80
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confirmed by XRF and ICP analyses that no leaching of Sc
occurred. On the other hand, PMI Sc(OTf)3 was found to be more
effective (entry 5). We tested other substrates, and in all cases,
PMI Sc(OTf)3 had higher catalytic activity than PI Sc(OTf)3.12 The
higher activity of PMI Sc(OTf)3 compared with that of PI Sc(OTf)3
may be ascribed to construct the larger catalytic surface area in
PMI Sc(OTf)3 by formation of spherical micelles shown in Figure
1. Moreover, PMI Sc(OTf)3 showed higher activity than MC Sc-
(OTf)3, previously developed by our group.7c,12 It is noted that these
catalysts were recovered quantitatively by simple filtration and that
the same levels of yields were obtained even after the third use.
PMI Sc(OTf)3 was successfully used as a catalyst in other re-
actions, such as Mannich-type13 and Michael14 reactions (Tables 3
and 4). Although it is well-known that most Lewis acids are trapped
and sometimes decomposed by basic compounds, PMI Sc(OTf)3
was effective for the activation of imines to form amines, and no
Sc leaching was observed (Table 3). PMI Sc(OTf)3 was also
available for the reaction of less reactive acylhydrazones (entries
3 and 4).12,15 Moreover, it was confirmed that PMI Sc(OTf)3 was
an effective catalyst for Michael reactions (Table 4), one of the
powerful methods for the synthesis of 1,5-dioxo units.14 In the
presence of 5 mol % of PMI Sc(OTf)3, the desired Michael reactions
proceeded smoothly,12,16 and again, no Sc leaching was observed.
It is noted that, to our knowledge, the highest catalytic activity in
terms of TON (>7500) has been attained in the Michael reaction.
In summary, we have developed a novel immobilization tech-
nique for Sc(OTf)3, a polymer-micelle incarcerated (PMI) method.
To the best of our knowledge, this is the first example of
immobilization of Lewis acids utilizing polymer micelles. PMI Sc-
(OTf)3 is highly active in several fundamental carbon-carbon bond-
forming reactions. The catalyst is recovered quantitatively by simple
filtration and reused several times without loss of catalytic activity,
and no Sc leaching was observed in all reactions (<0.1 ppm).17 In
addition, several solvents are available, and these aspects are suitable
for HTOS. The PMI method is operationally simple and might be
applied to a wide range of Lewis acid catalysts. Further study into
the immobilization of other Lewis acid catalysts is now in progress.
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XRF analysis. See Supporting Information for details.
(10) Control experiments strongly suggested that the tetraethyleneglycol
moieties in copolymer 1 played an important role in the immobilization
of Sc(OTf)3. See Supporting Information for details.
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(16) PMI Sc(OTf)3 is also available and reusable in CH2Cl2 or toluene.
(17) Metal leaching is a serious issue especially in pharmaceutical industry.
However, most literature of immobilized Lewis acids ignores this important
aspect. As far as we know, this is the lowest leaching level so far reported.
JA053176F
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