The First Immobilization of Pyridine-bis(oxazoline) Chiral Ligands

Article abstract of DOI:10.1021/ol026787a

(Matrix Presented) A chiral pyridine-bis(oxazoline) ligand, functionalized with a vinyl group in the pyridine ring, can be polymerized with styrene and divinylbenzene to obtain supported chiral ligands. As proof of the usefulness of this supported ligands, the corresponding ruthenium complexes are catalysts for the cyclopropanation reaction of styrene with ethyl diazoacetate with up to 85% ee.

Full text of DOI:10.1021/ol026787a

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3927-3930
The First Immobilization of
Pyridine-bis(oxazoline) Chiral Ligands
Alfonso Cornejo,† Jose´ M. Fraile,‡ Jose´ I. Garc´ıa,‡ Eduardo Garc´ıa-Verdugo,§
Mar´ıa J. Gil,† Gorka Legarreta,† Santiago V. Luis,§ V´ıctor Mart´ınez-Merino,† and
,‡
Jose´ A. Mayoral*
Departamento de Qu´ımica Aplicada, UniVersidad Pu´blica de NaVarra,
E-31006 Pamplona, Spain, Departamento de Qu´ımica Orga´nica,
Instituto de Ciencia de Materiales de Arago´n, UniVersidad de Zaragoza-C.S.I.C.,
E-50009 Zaragoza, Spain, and Departamento de Qu´ımica Inorga´nica y Orga´nica,
E.S.T.C.E., UniVersidad Jaume I, E-12080 Castello´n, Spain
mayoral@posta.unizar.es
Received August 26, 2002
ABSTRACT
A chiral pyridine-bis(oxazoline) ligand, functionalized with a vinyl group in the pyridine ring, can be polymerized with styrene and divinylbenzene
to obtain supported chiral ligands. As proof of the usefulness of this supported ligands, the corresponding ruthenium complexes are catalysts
for the cyclopropanation reaction of styrene with ethyl diazoacetate with up to 85% ee.
The development of new chiral heterogeneous catalysts to
promote enantioselective reactions is a field of growing
interest as a result of the applications of heterogeneous
catalysts in the industrial preparation of fine chemicals and
specialities.1 The most widely used strategy to prepare chiral
heterogeneous catalysts is the immobilization of chiral
complexes onto insoluble supports. Given that the im-
mobilization process requires synthetic effort, it is of interest
to design general strategies that allow the immobilization of
chiral ligands with wide applicability. In this regard, the
immobilization of chiral catalysts based on bis(oxazoline)
ligands has received a great deal of attention in recent years
and has led to the development of efficient chiral hetero-
geneous catalysts for several reactions. Cationic bis(oxazo-
line) complexes have been immobilized onto inorganic,
organic, and hybrid anionic supports.2
Bis(oxazoline) ligands have been covalently bonded to
insoluble organic3 and inorganic materials,4 as well as soluble
polymers.5 The closely related azabis(oxazoline) ligands have
been immobilized by grafting onto a soluble organic
polymer.6 Finally, the recovery of bis(oxazoline)-copper
catalysts used in ionic liquids has also been described.7 From
the same family of ligands, C2-symmetric pyridine-bis-
(oxazoline) (pybox) compounds have shown their utility as
tridentate ligands in many asymmetric organic reactions.8
However, the immobilization of this type of chiral ligand
has not been described to date. In this communication, we
describe the first strategy to immobilize pybox by formation
of a covalent bond between the pyridine ring and the
insoluble support.
† Universidad Pu´blica de Navarra.
‡ Universidad de Zaragoza-C.S.I.C.
§ Universidad Jaume I.
(1) (a) Chiral Catalysts Immobilization and Recycling; De Vos, D. E.;
Vankelecom I. F. J.; Jacobs, P. A., Eds.; Wiley-VCH: Weinheim, 2000.
(b) Clapham, B.; Reger, T. S.; Janda, K. D. Tetrahedron 2001, 57, 4637.
(c) de Miguel, Y. R.; Brule´, E.; Margue, R. C. J. Chem. Soc., Perkin Trans.
1 2001, 3085.
The objective of the work described here was the
introduction of a vinyl group into the pybox ligand, with
10.1021/ol026787a CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/02/2002

the aim of preparing polymers using the chiral ligand as a
co-monomer. The similarity in the reactivities of 4-vinylpy-
ridine and styrene, and the fact that 4-position in the pyridine
ring of pybox is free, prompted us to try the introduction of
a vinyl group in that position by means of a Stille coupling
reaction. It was therefore necessary to first prepare the
corresponding 4-bromopybox. The synthetic pathway, adapted
from that described in the literature,9 is represented in
Scheme 1. Bromination of chelidamic acid (1) with POBr3
led to 4-bromopyridine-2,6-dicarboxylic acid (2). This acid
was used in the synthesis of diamide 3 with (S)-valinol. The
4-bromopybox 5 was obtained in two steps by substitution
of the hydroxyl groups by chloride groups and subsequent
cyclization with sodium hydride. The desired 4-vinylpybox
7 could be prepared either by direct reaction of 5 with
tributylvinyltin in the presence of a palladium catalysts or
by reaction of intermediate 4 and cyclization of the resulting
vinyldiamide 6. Vinylpybox 7 was used in different block
copolymerizations with styrene and divinylbenzene using a
porogen and AIBN as a radical initiator, according to the
general protocol described by Fre´chet for the preparation of
monolithic resins.10 Three different polymers (P1-P3) were
obtained from vinylpybox 7 by changing the degree of cross-
linking and the porogen (Table 1). In all cases, the pybox
Scheme 1a
(2) (a) Fraile, J. M.; Garc´ıa, J. I.; Mayoral, J. A.; Tarnai, T. Tetrahe-
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J. A.; Tarnai, T. Tetrahedron: Asymmetry 1998, 9, 3997. (c) Fraile, J. M.;
Garc´ıa, J. I.; Mayoral, J. A.; Tarnai, T.; Harmer, M. A. J. Catal. 1999,
186, 214. (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. (e) Fraile,
J. M.; Garc´ıa, J. I.; Harmer, M. A.; Herrer´ıas, C. I.; Mayoral, J. A. J. Mol.
Catal. A 2001, 165, 211. (f) Ferna´ndez, A. I.; Fraile, J. M.; Garc´ıa, J. I.;
Herrer´ıas, C. I.; Mayoral, J. A.; Salvatella, L. Catal. Commun. 2001, 2,
165. (g) Hutchings, G. J.; Langham, C.; Piaggio, P.; Taylor, S.; McMorn,
P.; Willock, D. J.; Bethell, D.; Bulman-Page, P. C.; Sly, C.; Hancock, F.
E.; King, F. Stud. Surf. Sci. Catal. 2000, 130, 521. (h) Taylor, S.; Gullick,
J.; McMorn, P.; Bethell, D.; Bulman-Page, P. C.; Hancock, F. E.; King, F.;
Hutchings, G. J. J. Chem. Soc., Perkin Trans. 2 2001, 1714.
(3) (a) Burguete, M. I.; Fraile, J. M.; Garc´ıa, J. I.; Garc´ıa-Verdugo, E.;
Luis, S. V.; Mayoral, J. A. Org. Lett. 2000, 2, 3905. (b) Ferna´ndez, M. J.;
Fraile, J. M.; Garc´ıa, J. I.; Mayoral, J. A.; Burguete, M. I.; Garc´ıa-Verdugo,
E.; Luis, S. V.; Harmer, M. A. Topics Catal. 2000, 13, 303. (c) Orlandi,
S.; Mandoli, A.; Pini, D.; Salvadori, P. Angew. Chem. 2001, 113, 2587. (d)
Hallman, K.; Moberg, C. Tetrahedron: Asymmetry 2001, 12, 1475. (e)
Burguete, M. I.; D´ıez-Barra, E.; Fraile, J. M.; Garc´ıa, J. I.; Garc´ıa-Verdugo,
E.; Gonza´lez, R.; Herrer´ıas, C. I.; Luis, S. V.; Mayoral, J. A. Biorg. Med.
Chem. Lett. 2002, 12, 1821. (f) Reiser, O. Chim. Oggi 2002, 73.
(4) (a) Rechavi, D.; Lemaire, M. Org. Lett. 2001, 3, 2493. (b) Clarke,
R. J.; Shannon, I. J. Chem. Commun. 2001, 1936. (c) Burguete, M. I.; Fraile,
J. M.; Garc´ıa, J. I.; Garc´ıa-Verdugo, E.; Herrer´ıas, C. I.; Luis, S. V.; Mayoral,
J. A. J. Org. Chem. 2001, 66, 8893.
a Reagents and conditions: (a) POBr3, chlorobenzene, reflux, 14
h (55%); (b) oxalyl chloride, CH2Cl2, rt, 7 h (90%); (c) (S)-valinol,
NEt3, CH2Cl2, rt, 24 h (75%); (d) SOCl2, chloroform, reflux, 1.5 h
(70%); (e) NaH, THF, 0 °C, 45 min (70%); (f) tributylvinyltin,
Pd(PPh3)2Cl2, toluene, 60 °C, 6 h (55%); (g) NaH, THF, 45 °C,
1.5 h (65%); (h) tributylvinyltin, Pd(PPh3)2Cl2, toluene, 75 °C, 1 h
(65%).
ligand was incorporated into the polymer with high yield
(75-95%), as shown by the elemental analysis data. The
polymers were also characterized by IR spectroscopy, with
the spectra showing in all cases the typical bands corre-
sponding to the pybox ligand (1640 and 1599 cm-1). These
polymers were transformed into immobilized ruthenium
catalysts by treatment with [RuCl2(p-cymene)]2. According
to metal analyses, about 50-60% of the chiral pybox was
functionalized with Ru, which seems to indicate that a
significant proportion of the ligand is situated in inaccessible
sites within the polymer. This situation is particularly evident
in the case of P3, in which Ru functionalization is even
lower. Another polymeric catalyst (P4) was obtained by
(5) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Pitillo, M. J.
Org. Chem. 2001, 66, 3160.
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D.; Vaultier, M. Tetrahedron: Asymmetry 2001, 12, 1891.
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E. A.; Campos, K. R. J. Am. Chem. Soc. 1999, 121, 7582. (g) Aspinall, H.
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3928
Org. Lett., Vol. 4, No. 22, 2002

Table 1. Polymers Used in This Worka
Table 2. Results Obtained in the Cyclopropanation Reactiona
polymerization
mixture (%)
mmol/g
polymer pybox (7) styrene DVB porogen
pyboxb Ruc
P 1
P 2
P 3
P 4
7
7
7
7e
42
63
42
42
51
30
51
51
toluene
tol/dodecd 0.426 0.258
tol/dodecd 0.405 0.143
0.443 0.274
toluene
0.247
catalystb run % yieldc trans/ cisc % ee trans % ee cisd
a Polymerization conditions: porogen/monomers mixture ) 1.5 (w/w),
80 °C, 24 h. Polymers were crushed and washed with THF in a Soxhlet.
b Calculated from nitrogen analysis. c Ru content after treatment with a
stoichiometric amount of [RuCl2(p-cymene)]2 in CH2Cl2 for 24 h. d Mixture
of toluene/1-dodecanol ) 1/5 (w/w). e Polymerization with the complex
prepared with pybox (7) and [RuCl2(p-cymene)]2 in CH2Cl2.
P 1-Ru
1
2
3
1
2
3
1
2
1
2
1
1
31
28
11
32
35
28
26
39
17
9
85/15
84/16
75/25
78/22
85/15
75/25
77/23
72/28
81/19
78/22
87/13
90/10
85
84
45
76
75
44
54
30
80
84
92
88
41
40
20
41
42
18
18
13
29
30
71
70
P 2-Ru
P 3-Ru
polymerization of the complex 7-Ru, which was formed in
solution prior to polymerization. In this case, the elemental
analysis was not accurate due to the presence of Ru.
P 4
5-Ru
10-Rue
45
34
Excellent results have been reported for homogeneous
phase cyclopropanation reactions with analogous pybox-
Ru catalysts.11 Thus, the benchmark reaction between styrene
and ethyl diazoacetate was used as a test of the catalyst
properties. However, in the homogeneous phase, the reported
results were obtained using the pybox ligand in either 2 or
4 molar excess over Ru. It is quite difficult to obtain a local
excess of chiral ligand on a heterogeneous catalyst, so the
polymers were compared with the homogeneous catalysts
prepared with equimolecular amounts of pybox and Ru. The
results are gathered in Table 2. In all cases, the heterogeneous
catalyst was filtered off and an additional quantity of ethyl
diazoacetate was added to the solution to confirm the
heterogeneous character of the catalyst.12
a Reaction conditions: 5 mmol of styrene, 1 mmol of ethyl diazoacetate
(slow addition), 3% Ru, CH2Cl2, rt. Catalyst was filtered, washed, and dried
before reuse. b Catalysts were prepared by treatment of the ligand with
[RuCl2(p-cymene)]2 in CH2Cl2. c Determined by GC at total conversion of
diazoacetate. d Determined by GC with a cyclodex-B column. Compounds
8R and 9R were the major products. e Result with the pybox without
substitution at the 4-position.
of the reactive sites. Thus, the polymer morphology, which
is controlled by cross-linking and the nature of the porogen,
determines the performance of the immobilized catalyst, a
situation that has been described in other cases.13 The best
catalysts were reused twice, with similar efficiencies ob-
served in the first recycle but a marked decrease in both
selectivities and activity in the case of P1. The coordination
of byproducts may be responsible for this deactivation, with
a partial decoordination of Ru from the chiral ligand, which
can act as a bidentate ligand with a corresponding decrease
in enantioselectivity. Finally, the polymer prepared by
polymerization of the complex 7-Ru is clearly less active
than the other catalysts, although a high enantioselectivity
in the trans isomers is observed. In this case, the possible
inclusion of the complex in nonaccessible sites would lead
to a lower activity due to the lower effective amount of
catalyst in the reaction mixture. This low activity may also
be due to the complexation of Ru by AIBN, which would
also explain the need for an excess of AIBN to promote the
polymerization of the 7-Ru complex (see Supporting
Information).
As can be seen, the use of dodecanol in the porogenic
mixture seems to be detrimental to the trans/cis selectivity
and enantioselectivity (P1 vs P3), probably due to the
reduced accessibility of the sites, as evidenced by the lower
Ru functionalization. In fact, high trans/cis selectivity and
enantiomeric excess (85% ee trans) were obtained with the
polymer prepared in toluene, and these results are only
slightly lower than those obtained with the homogeneous
ligands. In contrast, the enantioselectivity for the cis isomer
is reduced to 41% ee, demonstrating an effect of the
immobilization on this particular selectivity. It is difficult
to offer an explanation for this effect, although it is clear
that the support has a different influence on the energy of
the four diastereomeric transition states. The detrimental
effect of dodecanol is not particularly important when a lower
degree of cross-linking is used (P2). This seems to confirm
that the observed effects are related to lower accessibility
In conclusion, we have developed a simple and efficient
methodology for the immobilization of chiral pybox systems.
This new route opens the way for the preparation of a range
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Am. Chem. Soc. 1994, 116, 2223. (b) Nishiyama, H.; Itoh, Y.; Sugawara,
Y.; Matsumoto, H.; Aoki, K.; Itoh, K. Bull. Chem. Soc. Jpn. 1995, 68,
1247. (c) Park, S.-B.; Sakata, N.; Nishiyama, H. Chem. Eur. J. 1996, 2,
303. (d) Nishiyama, H.; Soeda, N.; Naito, T.; Motoyama, Y. Tetrahedron:
Asymmetry 1998, 9, 2865. (e) Iwasa, S.; Takezawa, F.; Tuchiya, Y.;
Nishiyama, H. Chem. Commun. 2001, 59
(13) (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.
(b) Breysse, E.; Pinel, C.; Lemaire, M. Tetrahedron: Asymmetry 1998, 9,
897. (c) Altava, B.; Burguete, M. I.; Collado, M.; Garc´ıa-Verdugo, E.; Luis,
S. V.; Salvador, R. V.; Vicent, M. J. Tetrahedron 1999, 55, 12897. (d)
Altava, B.; Burguete, M. I.; Garc´ıa-Verdugo, E.; Luis, S. V.; Vicent, M. J.;
Mayoral, J. A. React. Funct. Polym. 2001, 48, 25.
(12) Sheldon, R. A.; Wallau, M.; Arends, I. W. C. E.; Schuchardt, U.
Acc. Chem. Res. 1998, 31, 485
Org. Lett., Vol. 4, No. 22, 2002
3929

of different supported pybox-based catalysts for a wide
variety of enantioselective reactions
Supporting Information Available: Experimental details
for the synthesis of compounds 2-7 and polymerization and
cyclopropanation reactions. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was made possible by the
generous financial support of the CICYT (Project MAT99-
1176). A.C. is indebted to the M.C.Y.T. for a grant.
OL026787A
3930
Org. Lett., Vol. 4, No. 22, 2002