Polymer-supported Bis(oxazoline)-copper Complexes as Catalysts in Cyclopropanation Reactions

Article abstract of DOI:10.1021/ol0066633

equation presented Bis(oxazolines) are easily immobilized by functionalization of the central methylene bridge with polymerizable groups and subsequent polymerization. Polymers are transformed into copper catalysts active in the cyclopropanation of styrene with ethyl diazoacetate. The results are similar or even better than those obtained with the similar homogeneous systems, and the catalysts can be easily recovered and reused. The substitution in the methylene bridge leads to a slight reduction in the enantioselectivity and an unexpected cis-preference.

Full text of DOI:10.1021/ol0066633

ORGANIC
LETTERS
2000
Vol. 2, No. 24
3905-3908
Polymer-Supported
Bis(oxazoline)−Copper Complexes as
Catalysts in Cyclopropanation Reactions
M. Isabel Burguete,† Jose´ M. Fraile,‡ Jose´ I. Garc´ıa,‡ Eduardo Garc´ıa-Verdugo,†
,†
,‡
Santiago V. Luis,* and Jose´ A. Mayoral*
Departamento de Qu´ımica Inorga´nica y Orga´nica, E.S.T.C.E., UniVersidad Jaume I,
E-12080 Castello´n, and Departamento de Qu´ımica Orga´nica, Instituto de Ciencia de
Materiales de Arago´n, Facultad de Ciencias, UniVersidad de Zaragoza-C.S.I.C.,
E-50009 Zaragoza, Spain
mayoral@posta.unizar.es
Received September 27, 2000
ABSTRACT
Bis(oxazolines) are easily immobilized by functionalization of the central methylene bridge with polymerizable groups and subsequent
polymerization. Polymers are transformed into copper catalysts active in the cyclopropanation of styrene with ethyl diazoacetate. The results
are similar or even better than those obtained with the similar homogeneous systems, and the catalysts can be easily recovered and reused.
The substitution in the methylene bridge leads to a slight reduction in the enantioselectivity and an unexpected cis-preference.
Enantioselective reactions promoted by chiral catalysts is a
topic of known importance in chemical research.1 The
development of heterogeneous catalysts able to promote
enantioselective organic reactions is an area of growing
interest due to the inherent advantages of heterogeneous over
homogeneous catalysts.2,3
Bis(oxazolines) are well-known chiral ligands with numer-
ous variations of substituents and which form complexes with
a variety of metals. This system has been used in a large
number of asymmetric reactions,4 and as a consequence, the
development of efficient methods to immobilize this type
of chiral ligand will open the way to the preparation of chiral
heterogeneous catalysts for those enantioselective reactions.
Different strategies and supports can be used for the
(3) Some examples of polymer-supported catalysts: (a) Schunicht, C.;
Biffs, A.; Wulff, G. Tetrahedron 2000, 56, 1693-1699. (b) Annis, D. A.;
Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 4147-4154. (c) Canali, L.;
Sherrington, D. C. Chem. Soc. ReV. 1999, 28, 85-93. (d) Hodge, P.; Sung,
D. W. L.; Stratford, P. W. J. Chem. Soc., Perkin Trans. 1 1999, 2335-
2342. (e) Peukert, S.; Jacobsen, E. N. Org. Lett. 1999, 1, 1245-1248.
(4) Recent reviews: (a) Gosh, A. K.; Mathivanan, P.; Capiello, J.
Tetrahedron: Asymmetry 1998, 9, 1-45. (b) Jørgensen, K. A.; Johannsen,
M.; Yao, S. L.; Audrain, H.; Thorhauge, J. Acc. Chem. Res. 1999, 32, 605-
613. (c) Pfaltz, A. Synlett 1999, 835-842. (d) Pfaltz, A. J. Heterocycl.
Chem. 1999, 36, 1437-1451. (e) Johnson, J. S.; Evans, D. A. Acc. Chem.
Res. 2000, 32, 325-335. (f) Fache, F.; Schulz, E.; Tommasino, M. L.;
Lemaire, M. Chem. ReV. 2000, 100, 2159-2231.
(5) (a) Sung, D. W. L.; Hodge, P.; Stratford, P. W. J. Chem. Soc., Perkin
Trans. 1 1999, 1463-1472. (b) Altava, B.; Burguete, M. I.; Garc´ıa-Verdugo,
E.; Luis, S. V.; Salvador, R. V.; Vincent, M. J. Tetrahedron 1999, 55,
12897-12906. (c) Altava, B.; Burguete, M. I.; Garc´ıa-Verdugo, E.; Luis,
S. V.; Pozo, O.; Salvador, R. V. Eur. J. Org. Chem. 1999, 2263-2267. (d)
Fraile, J. M.; Mayoral, J. A.; Royo, A. J.; Salvador, R. V.; Altava, B.; Luis,
S. V.; Burguete, M. I. Tetrahedron 1996, 52, 9853-9862.
† Universidad Jaume I.
‡ Universidad de Zaragoza-C.S.I.C.
(1) (a) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer-Verlag: Berlin-Heidelberg, 1999. (b)
Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New, York,
1994.
(2) (a) Blaser, H.-U.; Pugin, B. In Chiral Reactions in Heterogeneous
Catalysis; Jannes, G., Dubois, V., Eds.; Plenum Press: New York, 1995;
pp 33-57. (b) Sherrington, D. C.; Hodge, P. Synthesis and Separations
using Functional Polymers; Wiley: New York, 1988 (c) Ford, W. T.
Polymeric Reagents and Catalysts; ACS Symposium Series 308; American
Chemical Society: Washington, DC, 1986. (d) Shuttleworth, S. J.; Allin,
S. M.; Sharma, P. K. Synthesis 1997, 1217-1239. (e) Pu, L. Tetrahedron:
Asymmetry 1998, 9, 1457-1477.
10.1021/ol0066633 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/10/2000

immobilization process, and it has to be taken into account
that the methodology can have a definite effect on the activity
and selectivity of the resulting catalysts.5
Scheme 1
We have shown that bis(oxazoline)-Cu(II) complexes can
be immobilized by formation of ion pairs with anionic solids6
and that the solids obtained promote enantioselective cyclo-
propanation reactions. Whereas the immobilized 2,2′-
isopropylidenebis[(4R)-4-phenyl-2-oxazoline]-Cu(II) com-
plex is stable, leads to good results, and can be reused, the
steric interactions with the support limit the applicability of
this strategy to immobilize the 2,2′-isopropylidenebis[(4S)-
4-tert-butyl-2-oxazoline].
Very recently a family of related chiral ligands, aza-bis-
(oxazolines), has been described.7 These ligands can be
attached to soluble polymeric supports, forming soluble
catalysts which can be recovered by precipitation. The utility
of this strategy has been demonstrated also in enantioselective
cyclopropanation reactions.
In this Letter, we present the first results on the im-
mobilization of bis(oxazoline)-Cu(II) complexes by forma-
tion of covalent bonds between the ligand and an organic
polymer and the use of these solids as insoluble catalysts in
enantioselective cyclopropanation, one of the reactions in
which these ligands form excellent catalysts in the homo-
geneous phase.8
Different strategies of covalent bonding of the bis-
(oxazoline) to a polymeric support were initially tested with
a ligand bearing phenyl groups (1a).
Double alkylation in the methylene bridge was carried out
with methyllithium in THF as a base (Scheme 1). In this
way the model ligand 2a for a homogeneous test was
prepared. In the preparation of polymer-supported enanti-
oselective catalysts, polymerization was shown to provide,
in some cases, advantages over grafting.5b,9 Dialkylation with
p-vinylbenzyl chloride led to 3a which was used in different
polymerization processes. The use of this monomer was
considered advantageous with regard to the C2 symmetry of
the chiral ligand.10 This monomer was used in a copolym-
erization process with styrene using AIBN as a radical
initiator and 1-dodecanol/toluene as the porogenic mixture
(polymeric ligand 4a) using the general protocol for the
preparation of the monolithic resins developed by Fre´chet.11
It was also used in three different homopolymerization
processes: in the first one the monomer is left to polymerize
thermally (ligand 5a) and in the second and third ones AIBN
was used to initiate the reaction and toluene (ligand 6a) or
a mixture of 1-dodecanol/toluene (ligand 7a) was used as
porogenic agent.
All the polymers showed the FT-IR bands corresponding
to the bis(oxazoline) ligand, mainly the CdN band at ca.
1655 cm-1. The polymeric catalysts were obtained by
treatment of resins 4-7 with Cu(OTf)2, and the copper
contents were determined by plasma emission spectroscopy.
The solids were tested as catalysts in the cyclopropanation
reaction of styrene and ethyl diazoacetate in equimolecular
amounts (Scheme 2). Table 1 compares the results obtained
with the homogeneous and the different polymeric catalysts.
The solid obtained by copolymerization with styrene 4a
(6) (a) Fraile, J. M.; Garc´ıa, J. I.; Mayoral, J. A.; Tarnai, T. Tetrahe-
dron: Asymmetry 1997, 8, 2089-2092. (b) Fraile, J. M.; Garc´ıa, J. I.;
Mayoral, J. A.; Tarnai, T. Tetrahedron: Asymmetry 1998, 9, 3997-4008.
(c) Fraile, J. M.; Garc´ıa, J. I.; Mayoral, J. A.; Tarnai, T.; Harmer, M. A. J.
Catal. 1999, 186, 214-221. (d) Alonso, P. J.; Fraile, J. M.; Garc´ıa, J.;
Garc´ıa, J. I.; Mart´ınez, J. I.; Mayoral, J. A.; Sa´nchez, M. C. Langmuir 2000,
16, 5607-5612.
(7) Glos, M.; Reiser, O. Org. Lett. 2000, 2, 2045-2048.
(8) (a) Lowenthal, R. E.; Abiko, A.; Masamune, S. Tetrahedron Lett.
1990, 31, 6005-6008. (b) Lowenthal, R. E.; Masamune, S. Tetrahedron
Lett. 1991, 32, 7373-7376. (c) Evans, D. A.; Woerpel, K. A.; Hinman, M.
M.; Faul, M. M. J. Am. Chem. Soc. 1991, 113, 726-728. (d) Bedekar, A.
V.; Andersson, P. G. Tetrahedron Lett. 1996, 37, 4073-4076. (e) Bedekar,
A. V.; Koroleva, E. B.; Andersson, P. G. J. Org. Chem. 1997, 62, 2518-
2526. (f) End, N.; Pfaltz, A. Chem. Commun. 1998, 589-590. (g) Boulch,
R.; Scheurer, A.; Mosset, P.; Saalfrank, R. W. Tetrahedron Lett. 2000, 41,
1023-1026.
(9) (a) Itsuno, S.; Sakurai, Y.; Ito, K.; Maruyama, T.; Nakahama, S.;
Fre´chet, J. M. J. J. Org. Chem. 1990, 55, 304-310. (b) Kamahori, K.; Tada,
S.; Ito, K.; Itsuno, S. Tetrahedron: Asymmetry 1995, 6, 2547-2555.
(10) Halm, C.; Kurth, M. J. Angew. Chem., Int. Ed. Engl. 1998, 37, 510-
512.
(11) (a) Svec, F.; Fre´chet, J. M. J. Chem. Mater. 1995, 7, 707-715. (b)
Svec, F.; Fre´chet, J. M. J. Science 1996, 273, 205-211. (c) Xie, S.; Svec,
F.; Fre´chet, J. M. J. Chem. Mater. 1998, 10, 4072-4078. (d) Svec, F.;
Fre´chet, J. M. J. Ind. Eng. Chem. Res. 1999, 38, 34-48. (e) Hird, N.;
Hughes, I.; Hunter, D.; Morrison, M. G. J. T.; Sherrington, D. C.; Stevenson,
L. Tetrahedron 1999, 55, 9575-9584.
(12) (a) Altava, B.; Burguete, M. I.; Fraile, J. M.; Garc´ıa, J. I.; Luis, S.
V.; Mayoral, J. A.; Vicent, M. J. Angew. Chem., Int. Ed. 2000, 39, 1503-
1506. (b) Breysse, E.; Pinel, C.; Lemaire, M. Tetrahedron: Asymmetry 1998,
9, 897-900.
(13) (a) Altava, B.; Burguete, M. I.; Escuder, B.; Luis, S. V.; Salvador,
R.; Fraile, J. M.; Mayoral, J. A.; Royo, A. J. J. Org. Chem. 1997, 62, 3126-
3134. (b) Hodge, P. In InnoVation and PerspectiVes in Solid-Phase Synthesis;
Epton, R., Ed.; SPCC (UK) Ltd.: Birmingham, 1990; pp 273-292.
3906
Org. Lett., Vol. 2, No. 24, 2000

immobilized catalysts are very easily recovered by filtration
and washing in the open air. In fact, the catalyst obtained
from polymer 5a can be recovered 5 times with final
deactivation due to the presence of byproducts from ethyl
diazoacetate. These products are detected by IR spectroscopy,
because of the presence of an intense band at 1739 cm-1 in
the used catalyst. Ester groups from diethyl maleate or
polymeric products can form chelate complexes with copper.
To improve the accessibility to the reactive sites, a
porogenic mixture of 1-dodecanol/toluene was used. The
resulting resin 7a showed an increase in the copper loading
and a higher catalytic activity (entries 8 and 9). The
enantioselectivity is similar to that obtained with 6a although
the catalyst is not fully recoverable, probably due to pore
blocking by polymeric byproducts derived from ethyl dia-
zoacetate. It is worth noting that the stereoselectivity obtained
with 7a is higher than that shown by the homogeneous
analogue. This is one of the very first examples in which
the polymeric network plays a positive effect on the
enantioselectivity of the reaction. Most often the immobiliza-
tion process is accompanied by a decrease of the enantiose-
lectivity.13
The results obtained with the bis(oxazoline) bearing phenyl
groups show that the best enantioselectivity is obtained with
the homopolymers. Therefore, the same strategy was used
to immobilize two different bis(oxazolines), namely, those
bearing tert-butyl (1b) and indan (1c) groups. The results
are gathered in Table 1.
Surprisingly, the homogeneous catalyst obtained from 2b
leads to a clear cis preference (entry 10), whereas the bis-
(oxazoline) with an isopropylidene bridge gives rise to about
72/28 trans preference.8,14 This is the first cis preference
described for a bis(oxazoline)-copper catalyst in solution
and shows that the substitution in the methylene bridge has
a noticeable influence on the stereochemical course of the
Scheme 2
(entries 2 and 3) leads to results close to those obtained with
the homogeneous catalyst (entry 1) and the most significant
difference is the reduction in trans/cis selectivity. Interest-
ingly, the results obtained with the homopolymers depend
on the method of preparation. With the homopolymer
obtained by thermal polymerization, 5a (entries 4 and 5),
both yield and enantioselectivity are higher than those
obtained with the copolymer 4a and with the homogeneous
catalyst 2a, despite a lower amount of catalyst being used.
However, the trans/cis selectiVity is reduced, showing a slight
preference for the cis isomer. This illustrates the very
important role that the polymeric matrix can play in the
stereochemical outcome of reactions in using polymer-
supported species.12 With the homopolymer prepared using
toluene as the porogenic agent 6a (entries 6 and 7), it was
necessary to heat the reaction to obtain a noticeable
transformation yield. This can be related to the very low
amount of copper introduced. Most likely, this is a result of
the low accessibility of the bis(oxazoline) groups that,
according to the divinylic nature of 3, must be located in
highly cross-linked regions. The use of toluene as a porogen
produces, in general, polymer networks of high surface area
and small porosity (low pore size distribution).11 Despite the
higher reaction temperature, the enantioselectivity is better
than that obtained with 5a. As shown in entries 2-7, the
Table 1. Results Obtained from the Cyclopropanation Reaction between Styrene (8) and Ethyl Diazoacetate (9) Catalyzed by the
Immobilized Catalystsa
entry
ligand
Cu (mmol/g)
9/Cu
run
yield (%)b
trans/cisb
% ee (trans)c,d
% ee (cis)c,e
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
2a
4a
10
185
1
1
2
1
2
1
2
1
2
1
1
2
1
2
1
2
32
28
24
45
39
28f
27f
40
20
46
51
56
34
36
35
22i
70/30
60/40
60/40
47/53
46/54
66/34
64/36
53/47
53/47
32/68
35/65
37/63
39/61
39/61
44/56
44/56
50
46
43
51
50
61
58
57
47
70
75
74
77
77
69g
69g
40
42
41
52
52
55
52
53
50
79
72
70
73
73
75h
75h
0.39
0.21
0.01
0.14
5a
6a
7a
330
6900
510
2b
5b
50
490
0.13
0.07
0.03
6b
7c
910
2630
a Using equimolecular amounts of styrene and diazoacetate, at room temperature. Results after 24 h. b Determined by GC. Total conversion of ethyl
diazoacetate. c Determined by GC with a Cyclodex-B column. d 10S is the major isomer. e 11S is the major isomer. f At 60 °C. g 10R is the major isomer.
h 11R is the major isomer. i After 36 h.
Org. Lett., Vol. 2, No. 24, 2000
3907

reaction. In fact, the enantioselectivity is reduced in com-
parison with that described for the bis(oxazoline) with an
isopropylidene bridge.14 It is important to note that the
changes in trans/cis and enantioselectivities are, from an
energetic point of view, of the same order of magnitude
(about 1 kcal/mol). This change from trans to cis selectivity
with copper catalysts had been described with clays ex-
changed with Cu(II)15 and bis(oxazoline)-Cu(II) complexes.6
The homopolymers obtained by thermal polymerization,
5b (entries 11 and 12), and with AIBN, 6b (entries 13 and
14), were compared. The first one was able to coordinate a
larger amount of copper, and as a consequence it was more
active. However, the differences are not so noticeable as in
the case of the bis(oxazoline) bearing phenyl groups, 5a and
6a. Both solids are very good catalysts, leading to similar
or even better results than the homogeneous ligand 2b,
especially taking into account the high 9/Cu ratio used. It is
remarkable that both catalysts, obtained from 5b and 6b, can
be easily recovered and reused, with the same activity and
selectivity, by filtration in the open air.
To demonstrate the generality of this methodology of
immobilization by homopolymerization, we have applied it
also to the bis(oxazoline) derived from indan 7c (entries 15
and 16). In this case the homopolymer prepared with AIBN/
1-dodecanol/toluene showed a catalytic activity similar to
that of the other homopolymers and selectivities comparable
to those obtained with the ligand bearing tert-butyl groups.
A slight cis preference is again observed. The catalyst can
be also recovered and reused without loss of enantioselec-
tivity.
changing the reaction conditions. The use of a 5-fold excess
of styrene leads to better yields, namely, 65% with 5a, 58%
with 7a, and 76% with 5b. The recovery of 7a and 5b is
complete until the fifth reaction, whereas when equimolecular
amounts of both reagents are used, 7a cannot be efficiently
recovered more than three times.
In conclusion, the homopolymerization of chiral bis-
(oxazolines) functionalized in the methylene bridge is an easy
and general strategy to immobilize these ligands and to obtain
insoluble and easily recoverable enantioselective catalysts.
Changes in the polymerization conditions that affect to the
morphology of the polymer have important effects on the
activity and the selectivity of the catalysts. The corresponding
chiral heterogeneous catalysts are even more enantioselective
than their homogeneous counterparts in cyclopropanation
reactions. Although higher enantioselectivities have been
described with soluble catalysts, the reduction in the enan-
tioselectivity is not due to the immobilization process but to
the nature of the functional groups in the methylene bridge
of the ligand. This modification has also a unexpected
influence on the trans/cis selectivity and allows one to obtain
the highest cis preference described for a homogeneous bis-
(oxazoline)-copper catalyst. Further work is in progress to
optimize the activity and enantioselectivity of the catalysts.
Acknowledgment. This work was made possible by the
generous financial support of the CICYT (project MAT99-
1176) and the Generalitat Valenciana (project GV99-64-1-
02).
Finally, both yield and recovery can be improved by
Supporting Information Available: Experimental pro-
cedures and spectra of the new ligands. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) Fraile, J. M.; Garc´ıa, J. I.; Mayoral, J. A.; Tarnai, T. J. Mol. Catal.
A 1999, 144, 85-89.
(15) Fraile, J. M.; Garc´ıa, J. I.; Mayoral, J. A. Chem. Commun. 1996,
1319-1320.
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3908
Org. Lett., Vol. 2, No. 24, 2000