A flexible and versatile strategy for the covalent immobilization of chiral catalysts based on pyridinebis(oxazoline) ligands

Article abstract of DOI:10.1021/jo050504l

Flexible and versatile methods have been developed for the immobilization of chiral pyridinebis(oxazoline) ligands by covalent bonding to a solid support, either by grafting or by polymerization. Different spacers can easily be introduced to modulate the

Full text of DOI:10.1021/jo050504l

A Flexible and Versatile Strategy for the Covalent Immobilization
of Chiral Catalysts Based on Pyridinebis(oxazoline) Ligands
Alfonso Cornejo,† Jose´ M. Fraile,‡ Jose´ I. Garc´ıa,‡ Mar´ıa J. Gil,† Santiago V. Luis,§
V´ıctor Mart´ınez-Merino,*,† and Jose´ A. Mayoral*,‡
Departamento de Quı´mica Aplicada, Universidad Pu´blica de Navarra, E-31006 Pamplona, Departamento
de Quı´mica Orga´nica, Instituto Universitario de Cata´lisis Homoge´nea, Instituto de Ciencia de Materiales
de Arago´n, Universidad de Zaragoza-CSIC, E-50009 Zaragoza, and Departamento de Qu´ımica
Inorga´nica y Orga´nica, ESTCE, Universidad Jaume I, E-12080 Castello´n, Spain
merino@unavarra.es; mayoral@unizar.es
Received March 14, 2005
Flexible and versatile methods have been developed for the immobilization of chiral pyridinebis-
(oxazoline) ligands by covalent bonding to a solid support, either by grafting or by polymerization.
Different spacers can easily be introduced to modulate the support-ligand distance and the
electronic properties of the chiral ligand. As an example, 2,6-bis[(S)-4-isopropyloxazolin-2-yl]pyridine
has been immobilized on polystyrene resins, both on a Merrifield-type resin by grafting and on
supports prepared by polymerization of 4-vinyl-substituted ligands. The corresponding Ru complexes
have been tested as catalysts in the cyclopropanation reaction between styrene and ethyl
diazoacetate. The catalytic activity, the enantioselectivity, and the recyclability are strongly
dependent on the catalyst preparation method and the total exclusion of oxygen and moisture in
the filtration process. Under such optimized conditions, yields over 60% with up to 90% ee can be
obtained in four successive reactionssthe best cyclopropanation results described to date for a chiral
solid ruthenium catalyst.
Introduction
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 heterogeneous catalysts for several reactions.3 The
related pyridinebis(oxazoline) (pybox) ligands have also
shown wide applicability,4 and they are more suitable
than bis(oxazoline) ligands for some metals, such as
ruthenium or rhodium. However, the immobilization of
such systems has attracted considerably less attention
than that of bis(oxazolines). Our group published an
initial paper describing the synthesis and polymerization
of 4-vinyl-substituted pybox,5 and the subsequent graft-
ing of these materials onto silica supports6 was briefly
reported. On the other hand, Moberg and co-workers
described the immobilization of the same type of ligand
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 immobiliza-
tion of chiral complexes onto insoluble supports through
the formation of covalent bonds between the support and
the chiral ligand.2 Given that this type of immobilization
requires significant synthetic effort, it is of interest to
design general strategies that allow the immobilization
of chiral ligands with wide applicability. In this regard,
† Universidad Pu´blica de Navarra.
‡ Universidad de Zaragoza-CSIC.
(2) (a) Leadbeater, N. E.; Marco, M. Chem. Rev. 2002, 102, 3217-
3274. (b) McNamara, C. A.; Dixon, M. J.; Bradley, M. Chem. Rev. 2002,
102, 3275-3300. (c) Fan, Q.-H.; Li, Y.-M.; Chan, A. S. C. Chem. Rev.
2002, 102, 3385-3466. (d) Song, C. E.; Lee, S.-G. Chem. Rev. 2002,
102, 3495-3524.
§ Universidad Jaume I.
(1) Chiral Catalysts Immobilization and Recycling; De Vos, D. E.,
Vankelecom I. F. J., Jacobs, P. A., Eds.; Wiley-VCH: Weinheim,
Germany, 2000.
10.1021/jo050504l CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/15/2005
5536
J. Org. Chem. 2005, 70, 5536-5544

Covalent Immobilization of Chiral Catalysts
by grafting on TentaGel7 or by microcontact printing on
silicon chips.8 The analogous pincer 1,3-bis[(S)-4-isopro-
pyloxazolin-2-yl]benzene was immobilized on Wang resin
by solid-phase synthesis.9 In this paper we present a
complete overview of our efforts on the immobilization
of pybox ligands on polystyrene resins through two
complementary approaches, polymerization and grafting,
together with the importance of the complex preparation
method in the ruthenium-catalyzed cyclopropanation
reaction.
pared from chelidamic acid (1) in four steps (Scheme 1)
following the classical route11 with only minor modifica-
tions. The vinyl group was introduced by a Stille coupling
between 4-bromopyridinebis(oxazoline) 5a and tributylvi-
nylstannane to give the 4-vinylpybox 6 in 65% isolated
yield. It is worth noting that the analogous 4-chloropybox
5b did not react under the same conditions. To move the
catalyst further from the polymeric backbone, three more
functionalized ligands were prepared. The reaction be-
tween 4-bromostyrene and Sn2Bu6 gave the air-stable
tributyl(4-vinylphenyl)stannane, which undergoes a Stille
coupling reaction with 4-bromopybox 5a to give to the
corresponding 4-(4-vinylphenyl)pybox 7 (Scheme 1) in
55% isolated yield.
Another strategy was envisaged to introduce a longer
spacer between the support and ligand. 4-Halopyridines
react readily in SNAr reactions, and this behavior was
found to be useful to introduce phenoxide anions.6 One
possibility was substitution with p-bromophenol in a
basic medium (Scheme 1), which led to the 4-(p-bro-
mophenoxy)pybox intermediate 8. The aryl bromo group
was suitable for Stille coupling with tributylvinylstan-
nane, leading to 4-(p-vinylphenoxy)pybox 9. However,
this compound was obtained in a lower isolated yield
because its high solubility in hexane made purification
difficult. A longer spacer can be introduced by reaction
with a hydroquinone derivative, 4-(4-vinylbenzyloxy)-
phenol, in a basic medium, leading to the substituted
pybox 10 (Scheme 1). In this case the yield is lower than
with other phenols due to the occurrence of side reactions
involving the hydroquinone derivative.
The polymers were prepared with the functionalized
monomer (m ) 6, 7, 9, or 10), styrene, and divinylben-
zene by block polymerization initiated by AIBN12 (Scheme
2). On the basis of previous results,5 toluene was chosen
as the solvent and the molar content of pybox was kept
constant at 7%. Highly cross-linked polymers (macrore-
ticular-type) were prepared by using 51% divinylbenzene
in the polymerization mixture. These materials are
denoted Pm51, where P stands for polymerized materials,
m is the pybox monomer, and the subscript is the cross-
linking degree (% of divinylbenzene). A gel-type polymer
was prepared from pybox monomer 6 by using only 2%
divinylbenzene (denoted as P62) for the sake of compari-
son with the Merrifield-grafted ligands. Most of the chiral
pybox was incorporated into the polymer, and the final
functionalization was in the range of 0.4-0.51 mmol g-1
(Table 1).
Immobilization of Chiral Pyridinebis(oxazoline)
Ligands by Grafting. The other general strategy to
immobilize chiral ligands through covalent bonding
involves the use of a preformed support. In the case of
polymers, the most widely used supports are probably
the Merrifield resins (MRs),13 which are poly(styrene-
divinylbenzene) polymers with a low cross-linking degree.
To tether the pybox ligand, it was necessary to introduce
Results and Discussion
Immobilization of Chiral Pyridinebis(oxazoline)
Ligands by Polymerization. In our preliminary paper,5
we reported the immobilization of pybox ligands by
polymerization. In that case it was necessary to introduce
a polymerizable vinyl group, and position 4 of the
pyridine ring was chosen to maintain the C2 symmetry
of the ligand, although it had been previously shown that
this is not a prerequisite to obtain good enantioselectivi-
ties.10 The key intermediates in the synthesis of 4-sub-
stituted pyridinebis(oxazolines) were the 4-bromo- and
4-chloropybox (5a and 5b) compounds, which were pre-
(3) (a) Burguete, M. I.; Fraile, J. M.; Garc´ıa, J. I.; Garc´ıa-Verdugo,
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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. Top. Catal. 2000,
13, 303-309. (c) Orlandi, S.; Mandoli, A.; Pini, D.; Salvadori, P. Angew.
Chem., Int. Ed. 2001, 40, 2519-2521. (d) Hallman, K.; Moberg, C.
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Mayoral, J. A. J. Org. Chem. 2001, 66, 8893-8901. (h) Park, J. K.;
Kim, S.-W.; Hyeon, T.; Kim, B. M. Tetrahedron: Asymmetry 2001, 12,
2931-2935. (i) 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. Bioorg. Med. Chem. Lett. 2002, 12, 1821-1824. (j)
Corma, A.; Garc´ıa, H.; Moussaif, A.; Sabater, M. J.; Zniber, R.;
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Fraile, J. M.; Garc´ıa, J. I.; Garc´ıa-Verdugo, E.; Herrer´ıas, C. I.; Luis,
S. V.; Mayoral, J. A.; Sa´nchez-Verdu´, P.; Tolosa J. Tetrahedron:
Asymmetry 2003, 14, 773-778.
(4) (a) Ghosh, A. K.; Mathivanan, P.; Capiello, J. Tetrahedron:
Asymmetry 1998, 9, 1-45. (b) Fache, F.; Schulz, E.; Tommasino, M.
L.; Lemaire, M. Chem. Rev. 2000, 100, 2159-2232. (c) Yao, S.;
Johannsen, M.; Audrias, H.; Hazell, R. G.; Jørgensen, K. A. J. Am.
Chem. Soc. 1998, 120, 8599-8605. (d) Evans, D. A.; Kozlowski, M. C.;
Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connel, B. N.; Staples, R.
J. J. Am. Chem. Soc. 1999, 121, 669-685. (e) Evans, D. A.; Burgey, C.
S.; Kozlowski, M. C.; Tregay, S. W. J. Am. Chem. Soc. 1999, 121, 686-
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P. V.; Miller, S. J.; Murry, J. A.; Norcross, R. D.; Shaughnessy, E. A.;
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H. C.; Greeves, N.; Smith, P. S. Tetrahedron Lett. 1999, 40, 1763-
1766. (h) Schaus, S. E.; Jacobsen, E. N. Org. Lett. 2000, 2, 1001-1004.
(i) Iwara, S.; Tsushima, S.; Shimada, T.; Nishiyama, H. Tetrahedron
2002, 58, 227-232.
(5) Cornejo, A.; Fraile, J. M.; Garc´ıa, J. I.; Garc´ıa-Verdugo, E.; Gil,
M. J.; Legarreta, G.; Luis, S. V.; Mart´ınez-Merino, V.; Mayoral, J. A.
Org. Lett. 2002, 4, 3927-3930.
(6) (a) Cornejo, A.; Fraile, J. M.; Garc´ıa, J. I.; Gil, M. J.; Mart´ınez-
Merino, V.; Mayoral, J. A. Mol. Diversity 2003, 6, 93-105. (b) Cornejo,
A.; Fraile, J. M.; Garc´ıa, J. I.; Gil, M. J.; Luis, S. V.; Mart´ınez-Merino,
V.; Mayoral, J. A. C. R. Chim. 2004, 7, 161-167.
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2003, 5, 3663-3665.
(8) Jo¨nsson, C.; Hallman, K.; Anderson, H.; Stemme, G.; Malkoch,
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J. Org. Chem, Vol. 70, No. 14, 2005 5537

Cornejo et al.
SCHEME 1. Preparation of Vinyl-Functionalized Pybox Ligandsa
a Reagents and conditions: (i) PX5, chlorobenzene, reflux, 14 h (55% for Br, 65% for Cl); (ii) for X ) Br, oxalyl chloride, CH2Cl2, rt, 7
h (90%); for X ) Cl, SOCl2, chlorobenzene, reflux, 3.5 h (95%); (iii) (S)-valinol, NEt3, CH2Cl2, rt, 24 h (75%, X ) Br; 80%, X ) Cl); (iv)
SOCl2, chloroform, reflux, 1.5 h (70%); (v) NaH, THF, 0 °C, 45 min (70%); (vi) tributylvinyltin, Pd(PPh3)2Cl2, toluene, 75 °C, 1 h (65%);
(vii) Pd(PPh3)2Cl2, toluene, reflux, 1.5 h (60%); (viii) p-bromophenol, K2CO3, DMF, 100 °C, 7 h (75%); (ix) tributylvinyltin, Pd(PPh3)4,
toluene, reflux, 48 h (25%); (x) K2CO3, DMF, 100 °C, 17 h (30%).
SCHEME 2. Polymerization of Vinyl-Functionalized Pybox Ligands
a functional group, and position 4 of the pyridine ring
was again chosen for this purpose. The reactivity of the
halopyridines in SNAr reactions proved to be very con-
venient, and two different precursors were prepared
(Scheme 3). First, the 4-chloropybox 5b was reacted with
NaHS to give the 4-mercaptopybox 11 in high isolated
yield. The reactivity with phenols was used again, and
the reaction with p-aminophenol gave the amino-func-
tionalized pybox 12.
With regard to the grafting process, the benzyl chloride
on the Merrifield resin showed low reactivity toward both
the amino and the mercapto groups in 12 and 11,
respectively. In an attempt to increase the reactivity,
chlorine was replaced by bromine by nucleophilic sub-
stitution with NaBr using phase-transfer catalysis
(Scheme 4). This method leads to the brominated resin
MR-Br, with a substitution degree around 70-80% of
the initial chlorine. This solid showed enhanced reactivity
with the functionalized pybox ligands in the presence of
bases (Scheme 4). The resulting polymers, MR11 and
MR12am, reached a functionalization degree of 0.45-0.50
mmol of ligand g-1 (Table 1). In the case of the aminopy-
box 12 an alternative method was envisaged through
imine formation (MR12im), which allowed the introduc-
tion of a longer spacer between the pybox and the
polymer backbone. For this purpose the Merrifield resin
was initially converted into an aldehyde resin (MR-
CHO) by reaction with p-hydroxybenzaldehyde in a basic
medium (Scheme 4). However, the functionalization
degree in MR12im was much lower than in the resin
prepared by the alkylation method (MR12am).
Preparation of Ruthenium Catalysts. The first step
in the preparation of the catalysts was complexation of
the immobilized ligands with the stoichiometric amount
of [Ru(p-cymene)Cl2]2, the procedure used for the in situ
preparation of the homogeneous catalysts for cyclopro-
panation.14 The analyses of these solids, identified as
support-Ru, are gathered in Table 1. In the case of
5538 J. Org. Chem., Vol. 70, No. 14, 2005

Covalent Immobilization of Chiral Catalysts
TABLE 1. Solids Obtained by Polymerization (P) of Functionalized Pybox’s 6, 7, 9, and 10, or Grafting of Pybox’s 11
and 12 onto Merrifield Resin (MR)a
polymerization mixture (%)
styrene
concn, mmol/g
polymer
spacer (X)
pybox
DVB
pyboxb
Ruc
P651
7
7
7
7
7
42
91
42
42
42
51
2
51
51
51
0.443
0.514
0.400
0.315
0.421
0.512
0.450
0.155
0.274
0.402
0.265
0.214
0.342
0.436
0.421
0.094
P62
P751
P951
P1051
MR11
MR12am
MR12im
-C6H4-
-OC6H4-
-OC6H4OCH2C6H4-
-SCH2C6H4-
-OC6H4-NHCH2C6H4-
-OC6H4NdCHC6H4OCH2C6H4-
a Polymerization conditions: toluene/monomer mixture ) 1.5 (w/w), 80 °C, 24 h. The polymers were crushed and washed with THF in
a Soxhlet apparatus. b Calculated from nitrogen analysis. c Ru content after treatment with the stoichiometric amount of [RuCl2(p-cymene)]2
in CH2Cl2 for 24 h.
SCHEME 3. Synthesis of Functionalized Pybox Ligands for Graftinga
a Reagents and conditions: (i) NaHS, K2CO3, DMF, 75 °C, 6 h (85%); (ii) p-aminophenol, K2CO3, DMF, 100 °C, 24 h (75%).
polymerized ligands, the spacer length and the cross-
linking degree are the factors that control the function-
alization degree. In P651-Ru, which does not have a
spacer but has a high cross-linking degree, only 60% of
the pybox ligand is able to complex Ru. The introduction
of longer spacers, as in P751-Ru, P951-Ru and P1051-
Ru, increases the functionalization degree to 65%, 68%,
and 80%, respectively. The same high functionalization
level can be obtained with a gel-type polymer, as in the
case of P62-Ru, without the need for a spacer.
The same level of functionalizationsor even higher
(>90% in MR12am-Ru)scan be achieved in the case of
Merrifield-immobilized ligands. This result is consistent
with the better accessibility of the grafted ligands,
which are mostly located in the outer part of the polymer,
in comparison to the polymerized ones, a proportion
of which are located in the nonaccessible core of the
solid.
This type of complex was tested as a catalyst in our
preliminary paper.5 However, the yields obtained with
those immobilized complexes were not comparable to
those reported in solution.14 In fact, the results are
difficult to compare as they come from different ap-
proachessan in situ preparation of the complex in the
case of the homogeneous catalyst and an isolated complex
in the case of the immobilized one. Quantum mechanical
(DFT) calculations showed that, due to steric hindrance,
p-cymene cannot easily be accommodated in the coordi-
nation sphere of ruthenium once the pybox ligand is
coordinated. To simplify the calculations, a nonsubsti-
tuted pybox was chosen for the molecular modeling study.
The calculated structure of the pybox-RuCl2-ethylene
complex was in excellent agreement with the experimen-
tal (X-ray) geometry of an analogous pybox-RuCl2-
-
ethylene complex,14 as shown by overlaying the two
structures (Figure 1). On the other hand, the calculated
structure of the related pybox-RuCl2-p-cymene complex
shows that the p-cymene ligand is loosely bound to the
ruthenium center (Figure 2), and far from classical
metal-arene coordination. The calculated binding energy
(at the B3LYP/6-31G(d) level) is -25.3 kcal mol-1 for the
ethylene complex and +1.2 kcal mol-1 for the p-cymene
complex. The positive sign indicates that, in the latter
case, the coordination is disfavored. If we consider Gibbs
free energies (at 298 K), the relative differences are
maintained, but now the coordination of a p-cymene
molecule is still more disfavored (+15.8 vs -10.3 kcal
mol-1), due to the disfavorable entropic term. Obviously,
if we consider a chiral pybox, the coordination of the
p-cymene becomes still more difficult because of the new
steric interactions introduced by the substituents in the
stereogenic centers.
This loose coordination situation would easily lead to
a vacant site that, in the open air, would be occupied by
(14) Nishiyama, H.; Itoh, Y.; Sugawara, Y.; Matsumoto, H.; Auki,
K.; Itoh, K. Bull. Chem. Soc. Jpn. 1995, 68, 1247-1262.
J. Org. Chem, Vol. 70, No. 14, 2005 5539

Cornejo et al.
SCHEME 4. Grafting of Functionalized Pybox onto Merrifield Resins (MRs)a
a Reagents and conditions: (i) NaBr, Et4NBr, benzene/water, 80 °C, 7 d; (ii) p-hydroxybenzaldehyde, KOH, Bu4NOH, o-dichlorobenzene/
water, 100 °C, 4 d; (iii) 4-mercaptopybox 11, NaH, DMF, 100 °C, 72 h; (iv) 4-aminophenoxypybox 12, K2CO3, Bu4NI, 18C6, DMF, 90 °C,
4 d; (v) 4-aminophenoxypybox 12, ethanol, reflux, 2 d.
Catalytic Results. The Ru complexes were tested in
the benchmark asymmetric cyclopropanation reaction
between styrene and ethyl diazoacetate, and the most
interesting results are gathered in Table 2. Three dif-
ferent sets of conditions were tested with complexes
derived from MR11 polymer to assess their effect. In the
first attempt, the complex MR11-Ru, prepared directly
from the precursor [Ru(p-cymene)Cl2]2 (entry 2), led to a
low yield (24%), good trans/cis selectivity (84/16), and
modest to low enantioselectivities, 61% ee in the trans
and 30% ee in the cis isomers. In an attempt to reproduce
the homogeneous conditions, the complex was prepared
31G*) (red) and the experimental (X-ray) (blue) structures of
FIGURE 1. Overlay between the calculated (B3LYP/SDD-6-
under an ethylene atmosphere (entry 3), and this change
led to a considerable increase in yield (41%) and enan-
tioselectivities, both in the trans (75% ee) and in the cis
isomers (51% ee). However, the results were much worse
after recycling (entry 4), with a loss of activity and
selectivity. Finally, the catalyst was prepared in the same
way, but all the filtration and recycling manipulations
were carried out under an inert atmosphere (entry 5).
In the first reaction the results were not too different
from those obtained with the catalyst filtered in the open
air. In contrast, the recycling process was much better
(entries 6-8), and an even better yield (47%) was
obtained and the selectivities improved (up to 83% ee in
the trans isomers). These figures were maintained in a
second recycling stage but were lower in the third one.
The lower selectivities in the first run can be ascribed to
the presence of residual non-pybox-complexed ruthenium
centers, which are completely removed after the first
catalytic run. In fact, the filtrate after the first run was
slightly colored and showed some residual catalytic
activity when ethyl diazoacetate was added, demonstrat-
ing some ruthenium leaching.
the nonsubstituted pybox-RuCl2-ethylene complex.
FIGURE 2. Some geometrical parameters of the calculated
(B3LYP/SDD-6-31G*) structures of the pybox-RuCl2-ethylene
and pybox-RuCl2-p-cymene complexes. Hydrogen atoms
omitted for clarity.
water, oxygen, or another small molecule that would be
difficult to replace with the diazoacetate. In view of this
finding, we tried to reproduce the preparation of a stable
catalytic complex by bubbling ethylene in the solution
in which the immobilized complex was being prepared.
This process gave the immobilized complexes denoted as
support-Ru-// (// represents the coordinated ethylene).
These complexes were filtered off and washed, either in
the open air or under an inert atmosphere.
In view of these results, the previously described P651
polymer5 was used to prepare the corresponding ruthe-
nium complex under the optimized conditions under an
5540 J. Org. Chem., Vol. 70, No. 14, 2005

Covalent Immobilization of Chiral Catalysts
TABLE 2. Results Obtained in the Cyclopropanation Reactiona
yieldc
(%)
ee (%),d
ee (%),d
entry
catalystb
spacer (X)
-SCH2C6H4-
run
trans/cisc
trans
cis
1
2
pybox-Ru
MR11-Ru
MR11-Ru-//
34
24
41
10
38
47
41
36
21
25
20
14
37
15
31
28
11
40
53
50
45
36
17
26
69
52
54
8
12
24
25
21
14
32
27
5
52
67
70
68
32
90/10
84/16
87/13
79/21
86/14
88/12
88/12
84/16
81/19
87/13
84/16
77/23
86/14
79/21
85/15
84/16
75/25
87/13
88/12
87/13
87/13
85/15
80/20
80/20
88/12
88/12
86/14
82/18
64/36
82/18
85/15
85/15
79/21
86/14
83/17
72/28
88/12
90/10
90/10
90/10
88/12
88
61
75
46
77
83
81
56
57
75
60
45
73
28
85
84
45
87
88
87
87
69
52
63
86
79
75
42
12
59
64
64
46
67
54
25
85
91
89
87
74
70
30
51
11
43
54
50
23
19
35
27
14
45
12
41
40
20
63
70
58
62
49
28
24
67
58
57
24
0
31
27
39
16
33
22
8
54
67
64
63
63
1
1
2
1
2
3
4
1
2
3
4
1
2
1
2
3
1
2
3
4
5
6
1
2
3
4
5
1
2
3
4
5
1
2
3
1
2
3
4
5
3
-SCH2C6H4-
4
5
MR11-Ru-//e
-SCH2C6H4-
6
7
8
9
MR12am-Ru-//e
-OC6H4NHCH2C6H4-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
MR12im-Ru-//
P651-Ruf
-OC6H4NdCHC6H4OCH2C6H4-
P651-Ru-//e
P751-Ru-//e
P951-Ru-//e
-C6H4-
-OC6H4-
P1051-Ru-//
P62-Ru-//e
-OC6H4OCH2C6H4-
a Reaction conditions: 5 mmol of styrene, 1 mmol of ethyl diazoacetate (slow addition), 3% Ru, CH2Cl2, rt. The catalyst was filtered off,
washed, and dried before reuse. b The catalysts were prepared by treatment of the ligand with [RuCl2(p-cymene)]2 in CH2Cl2. The catalysts
marked as Ru-// were prepared by bubbling ethylene for 1 h and stirring under an ethylene atmosphere for 23 h. c Determined by GC
at total conversion of diazoacetate. d Determined by GC with a Cyclodex-B column. 13R and 14R are the major products. e All the filtrations
were carried out under an inert atmosphere. f Data from ref 5.
ethylene atmosphere (entry 18). The results obtained in
the first run were only slightly better than those obtained
for the nonoptimized conditions (entry 15), but the most
relevant differences were found after recycling (entries
19-23). The moderate yield, around 50%, together with
the high enantioselectivity, 87% ee in the trans isomers,
was maintained until the fourth run before declining in
the fifth one. This set of results confirms the sensitivity
of the Ru complex to ambient moisture and/or oxygen.
Another important issue with immobilized catalysts is
the accessibility to the catalytic sites. From the Ru
analysis, it seems that longer spacers make the access
easier, and this factor was studied with Merrifield-
immobilized catalysts. In contrast with the initial hy-
pothesis, MR12am and MR12im led to catalysts that were
less active, less enantioselective, and less stable than
MR11 (entries 9-14). However, in this case the change
of spacer is also associated with a modification in the
atom directly linked to the pyridine ring, i.e., sulfur in
MR11 and oxygen in both MR12 systems. A detrimental
effect of electron-donating substituents in position 4 of
the pyridine ring has been reported.15 This may be one
factor that leads to the lower yield and enantioselectivity,
(15) Park, S.-B.; Murata, K.; Matsumoto, H.; Nishiyama, H. Tetra-
hedron: Asymmetry 1995, 6, 2487-2494.
J. Org. Chem, Vol. 70, No. 14, 2005 5541

Cornejo et al.
filtered through a Celite pad, and the pad was washed with
hexanes. The solvent was evaporated under reduced pressure,
and the resulting oil was purified twice by column chroma-
tography (hexanes). Tributyl(4-vinylphenyl)tin (1.50 g, 35%)
although the presence of new coordinating atoms in the
polymer cannot be excluded as an additional factor.
In view of these features, the polymerized ligands that
do not include donor atoms directly linked to the pyridine
ring would be expected to perform better. To test this
hypothesis, we prepared three catalysts from highly
cross-linked polymers P751, P951, and P1051, with spacers
bonded to the pyridine ring through carbon in the case
of 7 and oxygen atoms in 9 and 10. First of all, it is worth
noting the poor result obtained with P751 in the first run
(entry 24). This was due to incomplete removal of the
non-pybox-complexed ruthenium, as shown by the extent
of Ru leaching after the reaction and the significant
activity of the filtrate for nonenantioselective cyclopro-
panation. The spacer length in P751 and P951 is markedly
different, but catalyst P751-Ru-// was much more active
and enantioselective (entries 25-28) than P951-Ru-//
(entries 29-33)sa situation in agreement with the donor
character of the spacer in 9. In fact, the catalytic activity
of P751-Ru-// is even better than that of MR11-Ru-//,
which bears a sulfur atom. The P751-Ru-// results are
better in terms of both yield, around 50%, and enanti-
oselectivity, 86% ee for the trans-cyclopropanes in the
first run. After recycling, only the enantioselectivity was
slightly lower, with the catalytic activity maintained in
the second run before showing significant deactivation
in the third run. The use of a longer spacer in P1051
(entries 34-36) does not significantly improve on the
results obtained with a shorter spacer in P951.
1
was obtained as a colorless solid. H NMR (CDCl3): δ 7.42-
7.27 (m, 4H), 6.68 (dd, 1H, J ) 11.0 Hz, J ) 17.6 Hz), 5.74
(dd, 1H, J ) 0.7 Hz, J ) 17.6 Hz), 5.20 (dd, 1H, J ) 0.7 Hz, J
) 11.0 Hz), 1.64-1.52 (m, 6H), 1.49-1.21 (m, 6H), 1.04-0.99
(m, 6H), 0.87 (t, 9H, J ) 7.3 Hz).
To a stirred solution of tributyl(4-vinylphenyl)tin (760 mg,
1.93 mmol) in anhydrous toluene (15 mL) were added 4-bromo-
2,6-bis[(S)-4-isopropyloxazolin-2-yl]pyridine (5a) (668 mg, 1.76
mmol) and Pd(PPh3)2Cl2 (31 mg, 0.04 mmol). The mixture was
heated under reflux for 1.5 h. After cooling, the solution was
filtered through a Celite pad, and the pad was washed with
ethyl acetate. The solvent was evaporated under reduced
pressure, and the resulting solid was dissolved in acetonitrile
(20 mL). The solution was washed with hexane (5 × 20 mL).
The acetonitrile solution was evaporated under reduced pres-
sure, and the yellow solid was purified by flash chromatogra-
phy on alumina (hexanes/ethyl acetate, 3:1) and subsequent
crystallization from hexanes. 2,6-Bis[(S)-4-isopropyloxazolin-
2-yl]-4-(4-vinylphenyl)pyridine (390 mg, 55%) was obtained as
a yellow solid. 1H NMR (CDCl3): δ 8.43 (s, 2H), 7.73 (d, 2H, J
) 8.4 Hz), 7.50 (d, 2H, J ) 8.4 Hz), 6.75 (dd, 1H, J ) 11.0 Hz,
J ) 17.6 Hz), 5.83 (d, 1H, J ) 17.6 Hz), 5.33 (d, 1H, J ) 11.0
Hz), 4.54 (dd, 2H, J ) 7.7 Hz, J ) 9.2 Hz), 4.30-4.10 (m, 4H),
2.16-1.83 (m, 2H), 1.04 (d, 6H, J ) 6.6 Hz), 0.96 (d, 6H, J )
6.6 Hz). 13C NMR (CDCl3): δ 162.4, 149.4, 147.5, 139.0, 136.0,
135.9, 129.7, 129.2, 127.5, 127.3, 127.0, 123.6, 123.2, 115.4,
73.0, 71.0, 33.0, 19.3, 18.4. IR (KBr, cm-1): 3093, 2956, 1641,
1603, 1401. Mp: 113 °C. Anal. Calcd for C25H29N3O2: C, 74.41;
H, 7.24; N, 10.41. Found: C, 74.64; H, 7.45; N, 10.22.
From all these results we considered that the proper-
ties necessary to obtain a recoverable highly active and
enantioselective catalyst are as follows: improved acces-
sibility, absence of donor atoms directly bonded to the
pyridine ring, preparation of the ethylene-ruthenium
complex, and manipulations under an inert atmosphere.
Thus, monomer 6, with a C-C bond to the matrix, was
used to prepare the polymer P62, which had a low cross-
linking degree to ensure accessibility to the catalytic
centers. The resulting catalyst was P62-Ru-//, and this
gave the best overall results in four consecutive runs
(entries 37-41), leading to improved yields in the range
of 52-70%, trans/cis selectivity of 90/10, and enantiose-
lectivity around 85-91% ee for the trans-cyclopropanes.
Even in the best case, however, the catalyst is finally
deactivatedslosing both activity and enantioselectivity.
Ruthenium leaching does not account for this deactiva-
tion. In fact, only 6% Ru is lost from P751-Ru-// after
five runs and 13% Ru from P1051-Ru-// after three runs,
whereas the loss in activity is far more pronounced. This
deactivation may be caused by poisoning through the
adsorption of byproducts (diethyl maleate and fumarate,
or their polymerization products), the adsorption of traces
of moisture and/or oxygen during recycling, or pore
blocking by polymerized byproducts. These possibilities
are currently under investigation.
4-(4-Bromophenoxy)-2,6-bis[(S)-4-isopropyloxazolin-2-
yl]pyridine (8). To a suspension of anhydrous K2CO3 (186
mg, 1.35 mmol) in anhydrous DMF (1 mL) was added p-
bromophenol (233 mg, 1.35 mmol), and the mixture was stirred
at room temperature for 30 min. 4-Bromo-2,6-bis[(S)-4-isopro-
pyloxazolin-2-yl]pyridine (5a) (380 mg, 1 mmol) was then
added, and the mixture was heated at 100 °C for 7 h. After
cooling, the mixture was poured onto iced water (20 mL), the
resulting solid was collected by filtration, dissolved in ethyl
acetate (50 mL), and washed with 3% KOH (3 × 40 mL). The
organic phase was dried with MgSO4 and evaporated under
reduced pressure to give a white solid, which was purified by
crystallization from hexanes to give 4-(4-bromophenoxy)-2,6-
bis[(S)-4-isopropyloxazolin-2-yl]pyridine (354 mg, 75%). 1H
NMR (CDCl3): δ 7.71 (s, 2H), 7.53 (d, 2H, J ) 8.8 Hz), 6.98
(d, 2H, J ) 8.8 Hz), 4.49 (dd, 2H, J ) 8.1 Hz, J ) 9.5 Hz),
4.23-4.02 (m, 4H), 1.82 (dt, 2H, J ) 13.2 Hz, J ) 7.0 Hz),
1.01 (d, 6H, J ) 6.6 Hz), 0.88 (d, 6H, J ) 6.6 Hz).
2,6-Bis[(S)-4-isopropyloxazolin-2-yl]-4-(4-vinylphenoxy)-
pyridine (9). To a stirred solution of tributylvinyltin (475 mg,
1.50 mmol) in anhydrous toluene (25 mL) were added 8 (354
mg, 0.75 mmol) and Pd(PPh3)4 (130 mg, 0.112 mmol). The
resulting solution was heated under reflux for 48 h. After
cooling, the solution was filtered through a Celite pad. The
solvent was evaporated under reduced pressure to give a dark
yellow oil, which was dissolved in acetonitrile (30 mL). The
solution was washed with hexane (6 × 10 mL). The acetonitrile
solution was evaporated under reduced pressure, and the
yellow semisolid was purified by flash chromatography on
alumina (hexanes/ethyl acetate, 2:1) to give 2,6-bis[(S)-4-
isopropyloxazolin-2-yl]-4-(4-vinylphenoxy)pyridine (80 mg, 25%).
1H NMR (CDCl3): δ 7.68 (s, 2H), 7.46 (d, 2H, J ) 8.9 Hz),
7.05 (d, 2H, J ) 8.9 Hz), 6.72 (dd, 1H, J ) 11.0 Hz, J ) 17.6
Hz), 5.72 (d, 1H, J ) 17.6 Hz), 5.27 (d, 1H, J ) 11.0 Hz), 4.49
(t, 2H, J ) 8.4 Hz), 4.22-4.02 (m, 4H), 1.91-1.70 (m, 2H),
1.01 (d, 6H, J ) 6.5 Hz), 0.90 (d, 6H, J ) 6.6 Hz). 13C NMR
(CDCl3): 170.0, 164.7, 161.2, 152.6, 148.1, 135.0, 134.5, 127.4,
119.9, 113.3, 72.2, 70.3, 32.2, 18.6, 17.6. IR (KBr, cm-1): 2950,
2873, 1731, 1664, 1581, 1225.
Experimental Section
2,6-Bis[(S)-4-isopropyloxazolin-2-yl]-4-(4-vinylphenyl)-
pyridine (7). To a stirred solution of hexabutylditin (5.94 mL,
11.17 mmol) in anhydrous toluene (50 mL) were added
4-bromostyrene (1.46 mL, 11.17 mmol) and Pd(PPh3)4 (323 mg,
0.28 mmol) at room temperature. The resulting solution was
heated under reflux for 2.5 h. After cooling, the solution was
5542 J. Org. Chem., Vol. 70, No. 14, 2005

Covalent Immobilization of Chiral Catalysts
TABLE 3. Composition of the Polymerization Mixtures
2,6-Bis[(S)-4-isopropyloxazolin-2-yl]-4-[4-(4-vinylben-
zyloxy)phenoxy]pyridine (10). To a stirred solution of
hydroquinone (3.52 g, 32 mmol) in acetone (70 mL) were added
4-vinylbenzyl chloride (1.25 mL, 8 mmol), K2CO3 (1.10 g, 8
mmol), and Aliquat 336 (323 mg, 0.8 mmol). The resulting
mixture was heated under reflux for 24 h. To the cold solution
was added chloroform (25 mL), and the solution was filtered
through a silica pad. The filtrate was concentrated under
vacuum, and the resulting oil was purified by column chro-
matography (hexanes/ethyl acetate, 9:1) to give 4-(4-vinylben-
zyloxy)phenol (780 mg, 44%) as a solid.
To a stirred suspension of NaH (54 mg, 1.35 mmol) in
anhydrous DMF (1 mL) was added 4-(4-vinylbenzyloxy)phenol
(305 mg, 1.35 mmol), and the mixture was stirred at room
temperature for 10 min. 4-Chloro-2,6-bis[(S)-4-isopropyloxazo-
lin-2-yl]pyridine (5b) (335 mg, 1 mmol) was added, and the
mixture was heated at 100 °C for 2.5 h. After cooling, the
mixture was poured onto cold water (25 mL), and the resulting
white solid was filtered off. The solid was dissolved in ethyl
acetate (25 mL) and washed with water (3 × 25 mL). The
filtrate was extracted with ethyl acetate (2 × 25 mL), and the
combined organic phases were dried with MgSO4 and evapo-
rated under reduced pressure. The resulting oil was purified
by flash chromatography on alumina (hexanes/ethyl acetate,
3:1) to give 2,6-bis[(S)-4-isopropyloxazolin-2-yl]-4-[4-(4-vinyl-
benzyloxy)phenoxy]pyridine (125 mg, 24%) as a solid. 1H NMR
(CDCl3): δ 7.69 (s, 2H), 7.45 (d, 2H, J ) 8.4 Hz), 7.39 (d, 2H,
J ) 8.4 Hz), 7.02 (s, 4H), 6.73 (dd, 1H, J ) 10.8 Hz, J ) 17.5
Hz), 5.77 (d, 1H, J ) 17.5 Hz), 5.27 (d, 1H, J ) 10.8 Hz), 5.07
(s, 2H), 4.49 (dd, 2H, J ) 7.7 Hz, J ) 8.9 Hz), 4.24-4.03 (m,
4H), 1.83 (m, 2H), 1.02 (d, 6H, J ) 6.7 Hz), 0.90 (d, 6H, J )
6.7 Hz). 13C NMR (CDCl3): 166.2, 162.0, 156.4, 148.7, 147.1,
137.4, 136.3, 136.1, 127.7, 126.4, 121.8, 116.3, 114.2, 113.5,
72.8, 70.9, 70.2, 32.8, 19.1, 18.2. IR (KBr, cm-1): 3088, 2958,
1664, 1641, 1583, 1503, 1210, 984. Mp: 124 °C. Anal. Calcd
for C32H35N3O4: C, 73.12; H, 6.67; N, 7.99. Found: C, 73.26;
H, 6.68; N, 7.96.
2,6-Bis[(S)-4-isopropyloxazolin-2-yl]-4-mercaptopyri-
dine (11). To a suspension of NaHS‚H2O (90%, 332 mg, 4.03
mmol) in anhydrous DMF (1.7 mL) were successively added
K2CO3 (556 mg, 4.03 mmol) and 5b (1.0 g, 2.98 mmol). The
mixture was heated at 80 °C for 7 h until completion (TLC on
alumina, hexanes/ethyl acetate, 1:2). After cooling, the mixture
was poured onto iced water (20 mL) and stirred for 10 min.
The resulting solid was collected by filtration, dissolved in
ethyl acetate (45 mL), and washed with water (3 × 15 mL).
The organic phase was dried with MgSO4 and evaporated
under reduced pressure to obtain 2,6-bis[(S)-4-isopropyl-
oxazolin-2-yl]-4-mercaptopyridine (887 mg, 89%). 1H NMR
(CDCl3): δ 8.13 (s, 2H), 4.37 (t, 2H, J ) 8.8 Hz), 4.26-4.05
(m, 4H), 1.98-1.75 (m, 3H), 1.01 (d, 6H, J ) 6.7 Hz), 0.91 (d,
6H, J ) 6.6 Hz). 13C NMR (CDCl3): 161.2, 148.5, 147.1, 121.6,
73.0, 70.9, 32.9, 19.1, 18.2. Mp: 95 °C. IR (cm-1, KBr): 2952,
2870, 1641, 1378, 1118. Anal. Calcd for C17H23N3O2S: C, 61.23;
H, 6.95; N, 12.60. Found: C, 61.47; H, 7.12; N, 12.70.
composition (mg)
polymer
pybox
styrene
DVB
toluene
AIBN
P651
P751
P951
P1051
P62
50.0
60.2
69.1
69.0
49.0
91.4
91.9
142.6
141.4
132.3
132.4
13.5
436.0
451.8
436.2
436.0
392.1
2.9
3.1
2.8
2.8
3.0
97.2
97.0
219.3
J ) 6.6 Hz), 0.88 (d, 6H, J ) 6.6 Hz). 13C NMR (CDCl3): 166.4,
161.9, 148.4, 144.2, 121.6, 116.2, 113.1, 72.6, 70.8, 32.7, 19.1,
18.2. Mp: 181 °C. IR (KBr): 3405, 3354, 2958, 1645, 1582,
1507, 1213. Anal. Calcd for C23H28N4O3: C, 67.65; H, 6.86; N,
13.73. Found: C, 67.45; H, 7.10; N, 13.80.
Polymerization Procedure. A solution of the monomers
and AIBN in toluene (Table 3) was heated at 80 ( 2 °C in a
test tube for 24 h. The resulting solid was washed with THF,
dried by suction, and crushed in a mortar. The polymer was
washed in a Soxhlet apparatus with THF for 24 h and dried
under vacuum at 50 °C overnight. Typical yields were in the
range 75-95%.
Grafting Procedures. The starting material was a Mer-
rifield resin (MR-Cl, chloromethylated poly(styrene-divinyl-
benzene) copolymer, 200-400 mesh) 2% cross-linked with a
Cl content of 1.3 mmol g-1
.
A. MR-Br. To a solution of NaBr (12.12 g, 117.6 mmol) in
water (45 mL) were added tetrabutylammonium bromide (3.15
g, 13.82 mmol), benzene (45 mL), and MR-Cl (1.5 g, 1.95 mmol
Cl). The mixture was heated under reflux for 7 d. After cooling,
the resin was filtered off and washed with toluene (120 mL),
methanol (120 mL), water (120 mL), water/THF (1:3, 120 mL),
acetone (120 mL), and diethyl ether (120 mL). The resin was
dried under vacuum at 50 °C for 24 h. Anal. Found C, 84.57;
H, 6.97; Cl, 1.25; Br, 7.01.
B. MR-CHO. To a solution of KOH (2.53 g, 45.1 mmol) in
water (5.5 mL) were successively added 1,2-dichlorobenzene
(16.5 mL), p-hydroxybenzaldehyde (5.5 g, 45.1 mmol), aqueous
tetrabutylammonium hydroxide (40%, 0.1 mL), and MR-Cl
(1 g, 1.3 mmol Cl). The suspension was heated at 100 °C for 4
d. After cooling, the resin was filtered off and washed with
methanol (120 mL), water (200 mL), water/THF (1:3, 250 mL),
and acetone (250 mL). The resin was dried under vacuum at
60 °C for 3 d.
C. MR11. To a suspension of NaH (20 mg, 0.5 mmol) in
anhydrous DMF (10 mL) was added 11 (120 mg, 0.36 mmol)
at room temperature, and the mixture was stirred for 15 min.
MR-Br (200 mg) was then added, and the mixture was heated
at 90 °C for 72 h. After cooling, MR9 was collected by filtration
and washed with DMF (50 mL), ethanol (75 mL), water (75
mL), water/THF (1:3, 75 mL), THF (75 mL), dichloromethane
(75 mL), and diethyl ether (75 mL). The resin was dried under
vacuum at 50 °C for 24 h.
D. MR12am. To a suspension of K2CO3 (76 mg, 0.55 mmol)
in anhydrous DMF (10 mL) were successively added tetrabu-
tylammonium iodide (6 mg, 0.018 mmol), 18C6, 12 (225 mg,
0.55 mmol), and MR-Br (150 mg). The mixture was heated
at 85 °C for 4 d. After cooling, MR12am was collected by
filtration and washed with DMF (50 mL), methanol (75 mL),
water (75 mL), water/THF (1:3, 100 mL), dichloromethane (75
mL), and diethyl ether (75 mL). The resin was dried under
vacuum at 50 °C for 24 h.
E. MR12im. To a suspension of MR-CHO (500 mg) in
anhydrous toluene (35 mL) was added 12 (229 mg, 0.56 mmol),
and the mixture was heated under reflux in a Dean-Stark
apparatus for 72 h. After cooling, MR12im was collected by
filtration and washed with toluene (100 mL), dichloromethane
(75 mL), THF (100 mL), and diethyl ether (100 mL). The resin
was dried under vacuum at 50 °C for 24 h. Compound 12 (190
mg) was recovered from the filtrate.
4-(4-Aminophenoxy)-2,6-bis[(S)-4-isopropyloxazolin-2-
yl]pyridine (12). To a suspension of anhydrous K2CO3 (186
mg, 1.35 mmol) in anhydrous DMF (1 mL) was added p-
aminophenol (147 mg, 1.35 mmol), and the mixture was stirred
at room temperature for 30 min. 5b (335 mg, 1 mmol) was
then added, and the mixture was heated at 100 °C for 17 h.
After cooling, the mixture was poured onto iced water (20 mL),
and the resulting solid was collected by filtration, dissolved
in ethyl acetate (50 mL), and washed with water (3 × 40 mL).
The organic phase was dried with MgSO4 and evaporated
under reduced pressure to give a black solid, which was
purified by column chromatography to give 4-(4-aminophe-
noxy)-2,6-bis[(S)-4-isopropyloxazolin-2-yl]pyridine (285 mg,
1
70%). H NMR (CDCl3): δ 7.66 (s, 2H), 6.88 (d, 2H, J ) 7.7
Hz), 6.70 (d, 2H, J ) 7.7 Hz), 4.47 (t, 2H, J ) 8.8 Hz), 4.21-
4.05 (m, 4H), 3.75 (br s, 2H), 1.87-1.77 (m, 2H), 1.00 (d, 6H,
Preparation of the Catalysts. The support-Ru complexes
were prepared by adding the corresponding amount of polymer
J. Org. Chem, Vol. 70, No. 14, 2005 5543

Cornejo et al.
(0.06 mmol of pybox) to a prefiltered solution of [Ru(p-cymene)-
Cl2]2 (18.7 mg, 0.03 mmol) in methylene chloride (5 mL). The
suspension was stirred at room temperature for 24 h. The solid
was filtered off, thoroughly washed with methylene chloride,
and dried under vacuum at 50 °C overnight.
The support-Ru-// complexes were prepared in the same
way, but ethylene was bubbled through the suspension for 1
h, and the stirring was carried out in an ethylene atmosphere.
The filtration was carried out either in the open air or under
nitrogen (see Table 2).
Cyclopropanation Reactions. To a suspension of the
corresponding supported catalyst (0.03 mmol Ru) in a solution
of styrene (0.57 mL, 5.00 mmol) and n-decane (ca. 25 mg) in
anhydrous degassed methylene chloride (5 mL) was added
ethyl diazoacetate (57 mg, 0.50 mmol) in methylene chloride
(1 mL) over 6 h using a syringe pump. The reaction was
monitored by gas chromatography, and after complete con-
sumption of the diazoacetate, a second portion of this reagent
was added in the same way. After the reaction had finished
the catalyst was filtered off, washed with methylene chloride,
and dried. The recovered catalysts were reused following the
same method.
Yields and trans/cis selectivities were determined with a
cross-linked methyl silicone column: 25 m × 0.2 mm × 0.33
µm. Oven temperature program: 70 °C (3 min), 15 °C/min to
200 °C (5 min). Retention times: ethyl diazoacetate, 4.28 min;
styrene, 5.03 min; n-decane, 6.93 min; diethyl fumarate, 8.73
min; diethyl maleate, 9.04 min; cis-cyclopropanes 14, 11.84
min; trans-cyclopropanes 13, 12.35 min. The asymmetric
induction (Figure 2) was determined with a Cyclodex-B
column: 30 m × 0.25 mm × 0.25 µm. Oven temperature
program: 125 °C isotherm. Retention times: (1S,2R)-cyclo-
propane 14S, 28.3 min; (1R,2S)-cyclopropane 14R, 29.1 min;
(1R,2R)-cyclopropane 13R, 33.9 min; (1S,2S)-cyclopropane
13S, 34.3 min.
the length of the spacer, and the electronic properties of
the ligand. In the chosen example, ruthenium catalysts
for enantioselective cyclopropanation reactions, the prepa-
ration of an efficient heterogeneous catalyst requires
careful control of all of these properties. The organic
support must be of a gel type and have a low cross-linking
degree (2% divinylbenzene) to allow excellent accessibil-
ity, as shown by the high functionalization (around 80%)
achieved during the complex preparation. It is also very
important that there is no electron-donating effect on
the pyridine ring, a situation achieved by the formation
of a C-C bond between the support and the ligand.
4-Vinylpybox 6 and its polymer P62 fulfill all of these
requirements. Finally, the complex preparation method
is crucial to obtain high catalytic performance and good
recyclability. The presence of ethylene during the prepa-
ration of the ruthenium complex is an important requisite
to prevent rapid deactivation of the catalyst, which can
even be completely suppressed when the filtration and
all the other manipulations of the complex are carried
out under an inert atmosphere. Under such optimized
conditions, a highly active (40-65% yield) and enanti-
oselective (87-91% ee) catalyst is obtained, which can
be reused at least three times without a reduction in its
performance. This represents the best result obtained
with an enantioselective heterogeneous ruthenium cata-
lyst.
All of the parameters related to support type and
spacer properties could be easily modified in the design
of solid catalysts for other enantioselective reactions with
different requirements.
Theoretical Calculations. Theoretical DFT calculations
were carried out using the B3LYP hybrid functional.16 This
functional has already been successfully used in calculations
for other ruthenium complexes.10b,17 A hybrid basis set (denoted
as SDD-6-31G*) consisting of the Stuttgart-Dresden effective
core potential (ECP)18 was used for ruthenium and chlorine
atoms, and the standard 6-31G(d) basis set was used for the
remaining atoms. All the calculations were carried out using
the Gaussian 03 program.19
Acknowledgment. This work was made possible
by the generous financial support of the C.I.C.Y.T.
(Project PPQ2002-04012) and the Diputacio´n General
de Arago´n.
Supporting Information Available: Description of the
general experimental procedures. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO050504L
Conclusions
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