Improvement of ligand economy controlled by polymer morphology: The case of polymer-supported bis(oxazoline) catalysts

Article abstract of DOI:10.1016/S0960-894X(02)00259-7

A functionalized chiral bis(oxazoline) is used as a chiral monomer in polymerization reactions leading to homo- and copolymers of different morphology. Polymers with a high content of chiral monomer lead to enantioselectivities that are higher than those obtained with the soluble ligand, but the chiral ligand is not used in an optimal way. A hyperbranched polymer, obtained by using a hexavinyldendrimer as the cross-linker, leads to the same enantioselectivities with a more efficient use of the chiral ligand.

Full text of DOI:10.1016/S0960-894X(02)00259-7

Bioorganic & Medicinal Chemistry Letters 12 (2002) 1821–1824
Improvement of Ligand Economy Controlled by
Polymer Morphology: The Case of Polymer-Supported
Bis(oxazoline) Catalysts
M. I. Burguete,a E. Dıez-Barra,b,* J. M. Fraile,c J. I. Garcıa,c E. Garcıa-Verdugo,a
R. Gonzalez,b C. I. Herrerıas,c S. V. Luisa,* and J. A. Mayoralc,*
a
´
Dep. Quımica Inorganica y Organica, E.S.T.C.E., Universidad Jaume I, E-12080 Castellon, Spain
´
Dep. Quımica Organica, Universidad de Castilla-La Mancha, E-13071 Ciudad Real, Spain
´
´
b
´
´
Dep. Quımica Organica, Instituto de Ciencia de Materiales de Aragon, Universidad de Zaragoza-C.S.I.C., E-50009 Zaragoza, Spain
c
´
´
´
Received 26 November 2001; accepted 7 February 2002
Abstract—A functionalized chiral bis(oxazoline) is used as a chiral monomer in polymerization reactions leading to homo- and
copolymers of different morphology. Polymers with a high content of chiral monomer lead to enantioselectivities that are higher
than those obtained with the soluble ligand, but the chiral ligand is not used in an optimal way. A hyperbranched polymer,
obtained by using a hexavinyldendrimer as the cross-linker, leads to the same enantioselectivities with a more efficient use of the
chiral ligand. # 2002 Elsevier Science Ltd. All rights reserved.
The development of new heterogeneous catalysts to
promote enantioselective organic reactions is an area of
great interest given the importance of asymmetric
synthesis in the industrial preparation of fine chemicals
and specialities.1 In this context, several strategies for
the immobilization of bis(oxazoline)–metal complexes
have been developed by our group2,3 and other
authors.4 Immobilization of the cationic complexes by
electrostatic interaction with an anionic support does
not require modification of the chiral ligand and this
process can be carried out very easily,2 but there is a
limit in the enantioselectivity that can be reached in the
benchmark cyclopropanation reaction between styrene
and ethyl diazoacetate. In order to overcome this limi-
tation, we explored the immobilization of bis(oxazo-
line)–copper complexes on organic polymers and found
that the best results were obtained with homopolymers.3
In these polymers, however, most of the chiral ligand is
occluded in inaccessible parts of the polymer, meaning
that only a small proportion of the chiral information is
used in the asymmetric reaction. In this paper, we com-
pare homopolymers and different copolymers in order
to demonstrate the importance of the correct selection
of monomers to improve ligand economy without
reduction in catalytic activity and enantioselectivity.
This initial comparison was carried out with derivatives
of the cheap methylenebis[(S)-4-phenyl-2-oxazoline].
The complexes with Cu(OTf)2 were tested in the bench-
mark cyclopropanation reaction between styrene and
ethyl diazoacetate (Scheme 1), one of the reactions in
which bis(oxazoline)–copper complexes have led to
excellent results in the homogeneous phase.5
Double benzylation on the central methylene bridge was
easily accomplished with benzyl chloride in the presence
of methyllithium, leading to the soluble ligand 6 to be
*Corresponding author. Tel.: +34-976-762077; fax: +34-976-762077.
E-mail: luiss@mail.uji.es (S.V. Luis); mayoral@posta.unizar.es (J.A.
Mayoral); ediez@qino-cr.uclm.es (E. Dıez-Barra)
Scheme 1. Cyclopropanation reaction between styrene (1) and ethyl
diazoacetate (2).
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00259-7

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M. I. Burguete et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1821–1824
Table 1. Immobilized catalysts prepared with Cu(OTf)2 and the
polymers obtained by polymerization of the chiral monomer 7a
Polymer Box (7) Styrene Cross-
Box
Cu
(mmol gÀ1
)
Box/Cu
linker (mmol gÀ1
)
8b
9
100
100
80
50
10
10
10
10
5
—
—
20
50
90
70
70
70
85
—
—
—
—
—
20
20
20
10
1.85
1.74
1.60
1.49
0.56
0.60
0.37
0.50
0.21
0.01
0.14
0.16
0.09
0.39
0.19
0.18
0.04
0.08
185
12.4
10.0
16.5
1.6
3.2
2.1
12.5
2.6
10
11
12
13
14
15
16c
aPolymerization conditions: at 80 ꢀC using a 60% (w/w) of a mixture
toluene/1-dodecanol (1/5, w/w) and 1% AIBN. Treatment with
Cu(OTf)2 in methanol at room temperature for 24 h, followed by fil-
tration, thorough washing with methanol and dichloromethane and
drying under vacuum at 60 ꢀC.
bUsing only 60% (w/w) toluene.
cIn toluene/dodecanol/DMF (1/4/1).
azoline) groups. The accessibility and, as a consequence,
the copper loading were improved when a porogenic
mixture of toluene and 1-dodecanol was used, as shown
by the higher copper content of polymer 9. This latter
porogenic mixture was therefore used in the preparation
of the different copolymers.
Three different copolymers (10–12) were obtained using
styrene and the chiral monomer 7 as the cross-linker
(Scheme 2). The bis(oxazoline) content of the polymer
clearly decreases with the amount of chiral monomer in
the polymerization mixture, but at the same time the
copper content either remains essentially unchanged
(polymers 10 and, 11) or greatly increases (12). These
results show that only in the cases where a small amount
of chiral monomer is used in the polymerization mixture
is most of the bis(oxazoline) accessible for Cu(OTf)2.
The greater flexibility of the less cross-linked polymer
may account for this behavior. It seems clear that the
use of the chiral monomer as the cross-linker makes
most of the ligand inaccessible for copper-complexa-
tion, a situation that may be due to the incorporation of
the ligand in the inner part of the polymer. Taking this
information into account, we tested the incorporation
of a different cross-linker into the polymerization mix-
ture (polymers 13–15, Scheme 3). The use of these cross-
linkers did not improve the copper functionalization
and, in the case of polymer 15, it even had a detrimental
effect. It is clear that the nature of the cross-linker is
also an important factor and, in view of this, we decided
to test a completely new type of cross-linker, namely a
dendrimer (polymer 16, Scheme 3).
Scheme 2. Preparation of homopolymers of bis(oxazoline) and
copolymers of styrene and bis(oxazoline).
used for comparison with the immobilized systems.
The alkylation with p-vinylbenzyl chloride led to the C2-
symmetric chiral monomer 7, which was subsequently
used to prepare different homo- and copolymers. Poly-
merizations were carried out in the presence of AIBN,
following the general protocol developed by Frechet for
the preparation of monolithic resins6 (Scheme 2).
Polymers were characterized by both FTIR and Raman
spectroscopy7 and, in all cases, the bands corresponding
to the bis(oxazoline) ligand were observed. Nitrogen
analysis indicated the complete incorporation of the
bis(oxazoline) into the polymeric network. Catalysts
were obtained by treatment of the corresponding poly-
mer with an equimolecular amount of Cu(OTf)2 in
methanol, followed by filtration, washing and drying.
Table 1 shows the compositions of the different poly-
merization mixtures, together with the bis(oxazoline)
and copper contents of the final polymeric catalysts.
The use of dendrimers in the synthesis of polymer-
bound enantioselective catalysts is a field of very recent,
but growing, interest.8 In general, the chiral ligand
occupies a cross-linking position in this kind of poly-
mer, a situation that would be detrimental in our case,
as indeed we have seen. On the other hand, to the best
of our knowledge, this is the first time that a non-chiral
dendrimer has been used as a cross-linker unit in the
preparation of a polymer-immobilized chiral catalyst.9
The results obtained indicate that the degree of incor-
poration of copper noticeably depends on the morphol-
ogy of the polymer. For example, with the
homopolymer prepared in toluene (8) only a very low
degree of copper functionalization was obtained, a fact
that must be due to the low accessibility of the bis(ox-

M. I. Burguete et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1821–1824
1823
Table 2. Results obtained from the cyclopropanation reaction
between styrene (1) and ethyl diazoacetate (2) catalyzed by polymeric
catalystsa,e
Ligand Run Yield (%)b 3+4/Cuc 3+4/boxc trans/cisb ee (%)d
trans cis
6
1
1
1
1
1
1
1
1
1
1
2
32
28
40
26
18
28
11
32
12
35
25
3.2
1932
204
54.1
66.8
24.1
19.4
30.4
51.4
3.2
10.4
17.0
5.4
4.0
15.1
6.1
14.5
4.1
70.8
50.4
71:29
66:34
52:48
57:43
57:43
60:40
71:29
67:33
58:42
57:43
58:42
50
61
57
56
57
46
18
8
40
55
53
51
51
42
18
8
8e
9
10
11
12
13e
14e
15
16
50
58
52
46
56
56
184
131
aUsing equimolecular amounts of styrene and ethyl diazoacetate.
Reaction carried out at room temperature unless otherwise indicated.
bDetermined by GC. Total conversion of ethyl diazoacetate.
cmmol/mmol ratio.
dDetermined by GC. 3R and 4R are the major enantiomers.
eReaction carried out at 60 ꢀC.
cyclopropanes does not provide information about the
catalytic activity of the different polymers but does
indicate the chemoselectivity of the conversion of the
intermediate carbene, either to cyclopropane products
or to diethyl maleate and fumarate. Both reagents were
used in equimolecular amounts. Although these are not
the best synthetic conditions, they were selected to
increase the variability in yield and allow a better com-
parison between the different catalysts. Table 2 gathers
the results obtained in these reactions, including the
yield in cyclopropanes and the different selectivities. In
order to illustrate the principle of ligand economy, the
yield is also expressed as mmol of cyclopropanes per
mmol of copper and bis(oxazoline) ligand present in the
polymeric catalyst.
Scheme 3. Preparation of copolymers of styrene, bis(oxazoline) and
different cross-linkers.
The synthesis of dendrimer 16 was achieved using a
convergent methodology to ensure highly pure pro-
ducts. The synthesis required the preparation of a den-
dron with a hydroxymethyl group at the focal point.
This dendron was synthesized by reaction of 3,5-dihy-
droxybenzyl alcohol with 4-vinylbenzyl bromide (Wil-
liamson synthesis). Connection of this unit to the core
(1,3,5-trischlorocarbonylbenzene) was performed in the
presence of 4-dimethylaminopyridine.10 This strategy
constitutes a very interesting approach, since it allows
hyperbranched systems to be obtained with a morphol-
ogy that is completely different to that obtained with
normal cross-linkers. Due to the low solubility of the
dendrimer, DMF was added to the porogenic mixture
and the amount of cross-linker and chiral monomer was
reduced in order to maintain the same cross-linker/
chiral monomer ratio.
The two homopolymers (8 and 9) led to very good
enantioselectivities, which were even better than those
observed with the homogeneous ligand 6, although the
trans/cis selectivity was lower. However, polymer 8
showed low catalytic activity and it was necessary to
heat the reaction, a fact that is probably due to the low
copper content. Copolymers (10–12) show a quite dif-
ferent and characteristic behavior. The efficiency in the
use of the chiral ligand was found to increase as the
amount of chiral monomer was decreased, showing the
same trend as the copper functionalization. However,
whereas the trans/cis selectivity remained almost con-
stant, the enantioselectivities were observed to decrease
with the content of chiral monomer. The use of an
additional cross-linker demonstrated that the nature of
this molecule has a crucial influence on the results of the
reaction. The polymer obtained with divinylbenzene
(13) was not very active and heating at 60 ꢀC was
required. Moreover, the enantioselectivity was very low.
The polymer prepared with divinylbenzylpolyethyl-
eneglycol (14) showed similar behavior and led to an
even lower enantioselectivity. In contrast, the use of
All of the polymers (8–16), as well as the analogous
homogeneous ligand 6, were tested in the benchmark
cyclopropanation reaction (Scheme 1) in order to assess
the effect of the polymeric matrix on the catalytic per-
formance in comparison to other cases.11 It is important
to note that the ethyl diazoacetate was completely con-
sumed in all the reactions, meaning that the yield in
divinylbenzylresorcinol (15) gave rise to
a more
enantioselective catalyst, but the yield and, as a con-
sequence, the ligand utilization was very low. In fact, all

1824
M. I. Burguete et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1821–1824
of the polymers studied are worse than homopolymer 9
with regard to the use of the chiral ligand. It may be
speculated that the differences in reactivity of the dif-
ferent monomers might be responsible for this effect.
Fraile, J. M.; Garcıa, J.; Garcıa, J. I.; Martınez, J. I.; Mayoral,
J. A.; Sanchez, M. C. Langmuir 2000, 16, 5607. (c) Fraile,
J. M.; Garcıa, J. I.; Harmer, M. A.; Herrerıas, C. I.; Mayoral,
J. A. J. Mol. Catal. A. 2001, 165, 211. (d) Fernandez, A. I.;
Fraile, J. M.; Garcıa, J. I.; Herrerıas, C. I.; Mayoral, J. A.;
Salvatella, L. Catal. Commun. 2001, 2, 165.
In contrast to these results, the hyperbranched polymer
16, which incorporates a dendrimer as the cross-linker,
gave yields and enantioselectivities that are comparable
to those obtained with homopolymer 9. In fact this is
the only polymer with a low content of chiral monomer
that was able to reproduce those results. Therefore, the
enantioselectivities obtained with polymers 9 and 16
were similar but 16 gave the highest amount of cyclo-
propanes per mmol of bis(oxazoline), which represents a
significant improvement in the ligand economy in com-
parison with the other polymeric catalysts. This beha-
vior was essentially retained in a second reaction run
with the same polymer.
3. (a) Fernandez, M. J.; Fraile, J. M.; Garcıa, J. I.; Mayoral,
J. A.; Burguete, M. I.; Garcıa-Verdugo, E.; Luis, S. V.; Har-
mer, M. A. Topics Catal. 2000, 13, 303. (b) Burguete, M. I.;
Fraile, J. M.; Garcıa, J. I.; Garcıa-Verdugo, E.; Luis, S. V.;
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4. (a) Orlandi, S.; Mandoli, A.; Pini, D.; Salvadori, P. Angew.
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In conclusion, it has been shown that polymer mor-
phology plays a crucial role in the chemo- and stereo-
selectivities of enantioselective reactions promoted by
chiral catalysts immobilized onto polymeric networks.
The use of dendrimers bearing several different vinyl
groups as cross-linkers leads to hyperbranched polymers,
which in this particular case present the best properties
in terms of ligand economy and enantioselectivity.
5. Pfaltz, A. In Comprehensive Asymmetric Catalysis; Jacob-
sen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
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Acknowledgements
8. Oosterom, G. E.; Reek, J. N. H.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M. Angew. Chem., Int. Ed. Engl. 2001, 40,
1828 and references cited therein.
9. During the revision of the proofs a paper dealing with
the use of a similar immobilization strategy for TADDOL
appeared: Sellner, H.; Rheiner, P. B.; Seebach, D. Helv. Chim.
Acta 2002, 85, 352.
This work was made possible by the generous financial
support of the C.I.C.Y.T. (project MAT99–1176) and
the Generalitat Valenciana (project GV99–64–1–02).
C.I.H. is indebted to the M.C.Y.T. for a grant.
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