Stereoselectivity induced by support confinement effects. Aza-pyridinoxazolines: A new family of C1-symmetric ligands for copper-catalyzed enantioselective cyclopropanation reactions

Article abstract of DOI:10.1039/b919274c

Aza-pyridinoxazoline ligands, a new class of C₁-symmetric ligands, are described and tested in the heterogeneous enantioselective catalysis of a cyclopropanation reaction, with the aim of improving surface confinement effects by the clay support on the reaction stereoselectivity. In the case of trans/cis diastereoselectivity, these surface effects lead to a systematic reversal of selectivity, cis-cyclopropanes being favored. Regarding the enantioselectivities, support confinement has a positive effect in the case of major cis-cyclopropane products, leading to moderate enantioselectivity values (60% ee). A theoretical (DFT) mechanistic study is carried out to explain the origin of the enantioselectivity in the homogeneous phase at a molecular level, and to get insights on the geometries of the key intermediates and transition structures.

Full text of DOI:10.1039/b919274c

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/dalton | Dalton Transactions
Stereoselectivity induced by support confinement effects.
Aza-pyridinoxazolines: A new family of C1-symmetric ligands for
copper-catalyzed enantioselective cyclopropanation reactions†
Jose´ I. Garc´ıa,* Gonzalo Jime´nez-Ose´s,* Beatriz Lo´pez-Sa´nchez, Jose´ A. Mayoral and Andrea Ve´lez
Received 16th September 2009, Accepted 4th December 2009
First published as an Advance Article on the web 14th January 2010
DOI: 10.1039/b919274c
Aza-pyridinoxazoline ligands, a new class of C1-symmetric ligands, are described and tested in the
heterogeneous enantioselective catalysis of a cyclopropanation reaction, with the aim of improving
surface confinement effects by the clay support on the reaction stereoselectivity. In the case of trans/cis
diastereoselectivity, these surface effects lead to a systematic reversal of selectivity, cis-cyclopropanes
being favored. Regarding the enantioselectivities, support confinement has a positive effect in the case
of major cis-cyclopropane products, leading to moderate enantioselectivity values (60% ee). A
theoretical (DFT) mechanistic study is carried out to explain the origin of the enantioselectivity in the
homogeneous phase at a molecular level, and to get insights on the geometries of the key intermediates
and transition structures.
Introduction
Chiral catalysts immobilization is a powerful strategy to improve
the performance of catalytic systems, as well as separation and
contamination issues.1 It is usually thought that the interaction
between the catalytic complex and the support may reduce stere-
oselectivities, and hence the placement of the catalytic complex
Scheme 1 Benchmark cyclopropanation reaction between styrene and
ethyl diazoacetate.
far away from the surface is highly desirable in order to get
a homogeneous-like environment around the catalytic site. On
the other hand, some recent observations of support-induced
confinement effects on regio- and stereoselectivity of catalytic
reactions have opened the door to a new viewpoint, i.e., that steric
support effects can be beneficial for improving the stereoselectivity
marked cis preference, in contrast to the trans preference observed
in solution,5 was observed, and the asymmetric induction for the
major cis isomers was also reversed. As a consequence, the isomer
cis-(1S,2R) (4S) was preferably obtained instead of the major
of a reaction, or even to obtain stereoselectivities difficult to obtain
in homogeneous or traditional supported catalysis.2 Most known
examples of changes induced by support confinement effects are
referred to as non-covalent immobilization strategies, such as
entrapment, electrostatic or adsorptive methods.3,4
In this regard, the first unequivocally demonstrated con-
finement effect by the support surface on an enantioselective
reaction concerns the cyclopropanation reaction of styrene with
ethyl diazoacetate (Scheme 1),5 catalyzed by the C2-symmetric
bis(oxazoline) ligand bearing phenyl groups.6–8
trans-(1R,2R) (3R) obtained in solution. An extensive study on
the importance of the nature of the support has been recently
reported, confirming the need of having a lamellar anionic support
to observe such surface confinement effects.10 A simple model has
been proposed to explain those results, taking into account the
known cyclopropanation reaction mechanism11–21 and the strong
ion-pair interaction between the key copper-carbene intermediate
and the support surface, as well as the steric constraints of the
catalytic complex. From that model we proposed the synthesis
of chiral ligands without C2 symmetry as a method to enhance
the surface-complex proximity and hence the support-complex
interaction, allowing the surface to effectively shield one face
of the complex. Several 2-oxazolinylpyridine,22–24 8-oxazolinyl-
quinoline,25,26 and C1-symmetric bis(oxazoline)27 ligands have been
prepared and tested as chiral ligands for immobilized copper
complexes (Scheme 2).28–31
Complete reversal of stereoselectivities with regard to the
homogeneous phase catalytic reaction was observed when the
support was laponite, a synthetic clay with a lamellar structure.9 A
Departamento de Qu´ımica Orga´nica, Instituto de Ciencia de Materiales
de Arago´n and Instituto Universitario de Cata´lisis Homoge´nea, Facultad
de Ciencias, Universidad de Zaragoza-CSIC, E-50009, Zaragoza, Spain.
E-mail: jig@unizar.es, gjimenez@unizar.es; Fax: +34 976762077; Tel: +34
976762271
† Electronic supplementary information (ESI) available: Tables of elec-
tronic energies, as well as enthalpies, entropies, and Gibbs free energies
(the last three data series at 25 ◦C) for the different conformations of the
structures considered in this work. Calculated geometries of the structures
discussed in this paper. NMR spectra of the chiral ligands described. See
DOI: 10.1039/b919274c
From these studies, the enhancement of support confinement
effects with C1-symmetric ligands have been corroborated through
the observation of higher cis preference (up to 92% in cis-
cyclopropanes). However, changes in enantioselectivity were not
so good (up to 48% ee in the major product).
In this paper we report the preparation of a new family
of C1-symmetric ligands bearing the oxazoline motif, namely
2098 | Dalton Trans., 2010, 39, 2098–2107
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
Scheme 2 C1-symmetric ligands previously used in the heterogeneous
catalysis of cyclopropanation reactions by copper complexes.
aza-pyridinoxazolines (henceforth aza-pyox), their immobilized
copper complexes, and the surface effect in the benchmark
enantioselective cyclopropanation reaction of styrene with ethyl
diazoacetate (Scheme 1), together with a molecular modeling
study to explain the results obtained. The aim of this ligand design
is to combine the good coordinating abilities of aza-bis(oxazoline)
ligands32 with the planarity and chemical stability of the pyridine
ring, and a straightforward synthetic procedure.
Fig. 1 A possible mechanism to explain the low, but yet significant
enantioselectivities observed with C1-symmetric ligands: only one of four
main possible reaction channels is disfavored.
(Table 1, entries 5 and 6) has a slight positive effect on the
enantioselectivity with respect to their unsubstituted counterparts
10a,b (Table 1, entries 3 and 4). The next step was to test if
steric effects from the support can introduce changes in the
stereochemical reaction course, leading to better results.
Results and discussion
Experimental studies
Aza-pyox ligands were synthesized from 2-ethoxyoxazolines
8, obtained from the corresponding amino alcohol by the
method described by Reiser et al. (Scheme 3).33 The coupling
of each 2-ethoxyoxazoline with either 2-aminopyridine or 2-
amino-6-methylpyridine in the presence of p-toluenesulfonic
acid (pTsOH) and subsequent methylation at the aza bridge
with n-BuLi/MeI afforded the desired N-methyl-4-alkyl-N-
(pyridin-2-yl)-4,5-dihydrooxazol-2-amine ligands 10, henceforth
aza-pyox(R1,R2), R1 and R2 being the alkyl substituents at the
oxazoline and pyridine rings, respectively.
According to previous results reported for 8-oxazolinyl-
quinoline29 and C1-symmetric bis(oxazoline)30,31 ligands, all
the aza-pyox ligands show a very similar behavior in the
homogeneous-phase cyclopropanation reactions (Table 1, entries
3–6, homogeneous phase results), achieving almost equal trans/cis
ratios and low values of enantioselectivity (8–30%) as expected for
chelating chiral ligands bearing only one stereocenter. These poor
enantioselectivities can be easily explained by invoking only one
disfavored reaction channel from four possible. Fig. 1 illustrates
this point, by showing the four main reaction channels possible
for a C1-symmetric ligand. Noteworthy, the presence of a methyl
group at the 6-position of the pyridine ring in ligands 10c,d
To this end, the copper complexes of ligands 10a–d were
prepared and immobilized onto laponite, following the same
protocol previously described for other similar complexes.28–31
Copper and nitrogen analyses, together with the IR spectra of
adsorbed species, confirmed that the complexes remained intact
after immobilization. These solids were tested as catalysts in the
same benchmark cyclopropanation reaction (Scheme 1), using
styrene as solvent. Table 1 gathers the most relevant results of
these reactions.
As can be seen, the reversal of trans/cis diastereoselectivity
demonstrates that there are important support confinement effects
in these catalytic systems. Thus, the ca. 70 : 30 trans-preference
in the homogeneous phase becomes ca. 20 : 80 cis-preference for
ligands 10a,b, and ca. 34 : 66 cis-preference for ligands 10c,d.
This is an interesting result from a synthetic point of view, since
there are relatively few catalytic systems described able to lead
preferentially to cis-cyclopropanes,34–38 and often they require the
use of structurally quite complex ligands.5,35
Unfortunately, in most cases the support confinement effect
does not have a strong effect on the enantioselectivities obtained
with the aza-pyox ligands. The only remarkable effects are
observed in the case of ligands 10b and 10c. With the former,
Scheme 3 Synthesis of chiral aza-pyridinoxazolines. (i) 2-aminopyridine (a,b compounds) or 2-amino-6-methylpyridine (c,d compounds), pTsOH,
toluene, reflux, 48 h; (ii) n-BuLi, THF, -78 ◦C; 15 min; (iii) MeI, THF, rt, 10 h.
This journal is
The Royal Society of Chemistry 2010
Dalton Trans., 2010, 39, 2098–2107 | 2099
©

View Article Online
Table 1 Results of the cyclopropanation between styrene and ethyl diazoacetate catalyzed by aza-pyox-copper complexes in the homogeneous phase
and supported on laponite
Homogeneous (CH2Cl2 as solvent)
Heterogeneous (styrene as solvent)
Entry
Ligand
Yield
3/4
%ee (3)c
%ee (4)d
1R/1Se
Yield
3/4
%ee (3)f
%ee (4)f
1R/1Se
1
2
3
4
5
6
7
8
9
6aa
7ab
10a
10b
10c
10d
11
65
58
48
48
48
57
53
45
56
58
68/32
68/32
73/27
70/30
63/37
57/43
70/30
71/29
55/45
74/26
48
29
30
28
29
30
72
71
35
97
28
8
16
8
35
34
63
55
38
92
71 : 29
61 : 39
63 : 37
61 : 39
66 : 34
66 : 34
85 : 15
83 : 17
68 : 32
98 : 2
59
60
52
52
53
58
88
48
38
54
23/77
15/85
20/80
24/76
32/68
33/67
22/78
39/61
32/68
45/55
24
13
10
10
23
~0
19
60
12
40
33
-48
~0
43
60
59
-62
41
57
8
65 : 35
31 : 69
51 : 49
68 : 32
74 : 26
70 : 30
29 : 71
74 : 26
71 : 29
61 : 39
12
13
14
10
a Results from Ref. 29. b Results from Ref. 30,31. c 3R was the major product. d 4R was the major product. e (3R+4R)/(3S+4S) ratio. f Negative sign
indicates that 1S-cyclopropanes (3S, 4S) are the major enantiomers.
the enantioselectivity in the 4R-cyclopropane goes from 8% ee in
the homogeneous phase to 43% ee in the heterogeneous phase
(Table 1, entry 4). Furthermore, cyclopropane 4R becomes the
major product in the heterogeneous phase, because of the above-
mentioned cis-preference induced by the support.
Similarly, with 10c, the enantioselectivity in the 4R-
cyclopropane goes from 29% ee in the homogeneous phase to
60% ee in the heterogeneous phase (Table 1, entry 5). It is worth
noting that this is the best enantioselectivity described to date for
a support confinement effect enhanced by the C1-symmetry of
the ligand in the cyclopropanation reaction catalyzed by copper
complexes, which validates the hypothesis that ad hoc ligand design
can be used to take advantage of the steric effect of the support to
obtain better stereoselectivities.
Another point deserves particular comment. There is a sig-
nificant difference in the behavior of ligands 6 and 10 with
regard to ligand 7. With the latter, there is a reversal of the
absolute configuration of the major cis-cyclopropane obtained
in the heterogeneous phase (4S) with regard to the catalytic
result in the homogeneous phase, similar to that described for
C2-symmetric bis(oxazoline) ligands.9,10,27 This reversal is not
observed neither for 6 nor for 10 ligands. This fact could be
related to the different structural features of bis(oxazoline)-
copper complexes, more prone to adopt boat-like geometries14,30
than either aza-bis(oxazoline)- and 8-oxazolinylquinoline-copper
complexes, which are much more rigid, leading to almost planar
geometries.14,29 In order to test this hypothesis, copper complexes
of both isopropyl-substituted39 C2-symmetric bis(oxazoline) (11)
and aza-bis(oxazoline) (12) chiral ligands (Fig. 2) were used in
the same conditions. The corresponding results are presented in
Table 1 (entries 7 and 8).
bis(oxazoline) ligand 11 a reversal in the absolute configuration of
the major cis-cylopropane (4S) is observed, this reversal does not
happen with the corresponding aza-bis(oxazoline) ligand 12. This
seems to indicate that both the geometrical constrains imposed
by the ligand to the complex and the support steric effects are
important to determine the enantiodiscrimination of the different
reaction pathways.
It has previously been proposed29–31 that the origin of these
moderate enantioselectivities probably lies in the existence of
several reaction channels of similar energy, leading to different
enantiomers, differing in the relative disposition of the copper
complex with regard to the support surface (as schematized in
the upper part of Fig. 3). Some experiments conducted using
reagents with different steric requirements have corroborated this
explanation.30,31 In order to obtain a more rigid disposition of the
copper complex and in an attempt to avoid turnarounds with
regard to the support surface, we designed and synthesized a
ditopic ligand, bearing two aza-pyox moieties, linked through a
1,4-phenylene bridge (13, Fig. 3). Provided the negative charges
on the support surface are placed at an adequate distance, di-
copper-carbene complex of 13 should be preferentially fixed
in the geometry allowing a better Coulombic interaction (as
schematized in Fig. 3), hence diminishing the number of reactive
approaches of styrene to this intermediate. We have recently
described the synthesis and use of this kind of ditopic ligand, in
their C2-symmetric form, to obtain self-supported catalysts.40 We
also included a ditopic aza-bis(oxazoline) (DAX) ligand, 14, for
comparative purposes. Table 1 collects the results obtained with
these ditopic ligands both in homogeneous and heterogeneous
catalysis experiments (entries 9 and 10).
Clearly, the use of a ditopic ligand based on a starting
C2-symmetric building block (14) does not introduce any ad-
vantage over the traditional C2-symmetric bis(oxazoline) and
aza-bis(oxazoline) ligands (11 and 12, for instance). Similarly,
the use of the ditopic aza-pyox derived ligand (13) results in
almost identical trans/cis diastereoselectivities and enantiose-
lectivities of the major cyclopropanes. These results seem to
point to a more complex situation than that ideally depicted in
Fig. 3, probably due to the fact that negative charge distribu-
tion on the support surface does not match with the distance
between positive charges in the di-copper complexes, and also
Fig. 2 C2-symmetric bis(oxazoline) and aza-bis(oxazoline) ligands.
As can be seen, both C2-symmetric ligands display a different
behavior when used in supported catalysis. Whereas with the
2100 | Dalton Trans., 2010, 39, 2098–2107
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
calculated: (1) the ester group of the carbene moiety can be
placed in both anti and syn dispositions with respect to the alkyl
group of the oxazoline ring; (2) two main rotamers arise from
the ester group, one with the carbonyl pointing to the alkyl
group of the oxazoline ring (I) and the other with the carbonyl
group oriented in the reverse direction (II); (3) the approach of
the olefin to the copper-carbene intermediate bows the chelate
Cu(I) complex to two different boat conformations, either towards
the alkyl group of the oxazoline ring (K) or in the opposite
direction (V); (4) finally, the nucleophilic attack of the incoming
olefin can take place by the Re and Si faces of the Cu(I)-
carbene plane, which determines the absolute configuration of
the carbon bearing the ester group in the resulting cyclopropanes.
Scheme 4 summarizes the different approximations of the olefin
and conformers considered in the calculations, that is, four starting
carbenes (15) and sixteen transition structures (ts15) overall for
each aza-pyox(R1,R2) ligand.
The theoretical ratio of cyclopropane products was calculated
through the energy of the different diastereomeric transition states
using a Maxwell–Boltzmann distribution. It must be noted that
the resulting cyclopropanes using ethylene as olefin are achiral, so
the theoretical ratio of 1R/1S cyclopropanes is only an estimation
of the hypothetical enantioselectivity that would be obtained with
a substituted olefin (i.e. styrene) which, on the other hand, are
the only experimental data available. As described later on, it was
demonstrated that a proper selection of both the ligand models
and the theoretical method is necessary to obtain reliable results.
Thus, a methyl group in the oxazoline ring (ligand 10a¢) is enough
to model the reaction experimentally carried out with 10a and
10b, but a bulkier tert-butyl group is necessary to account for the
experimental behavior of 10c and 10d (ligand 10c¢ bearing a methyl
group gives worse results). From the methodological point of view,
single-point energy calculations using the recently developed M05-
2X functional41–48 carried out on B3LYP49,50 optimized geometries
led to much better relative energies, which is necessary to account
for the subtle energy differences involved in enantioselective
processes. It has been reported that the hybrid meta functional
M05-2X shows a superior performance with respect to classical
functionals in the field of transition metal thermochemistry, which
is of particular interest in our theoretical study.41–48 Fig. 4 shows
some selected examples of calculated TS structures and the relative
energies of all the calculated TS (a few structures could not be
properly converged) are presented in Table 2, together with the
calculated enantioselectivities.
Fig. 3 C1-symmetric aza-pyox and C2-symmetric aza-bis(oxazoline)
ditopic ligands. Proposed disposition of the copper complexes of ditopic
ligand 13, compared to a generic C1-symmetric ligand, with regard to the
laponite surface.
that the conformational flexibility of the latter is greater than
supposed.31
Theoretical studies
With the aim of rationalizing the experimental results described
above, and to have a better understanding of the geometries
of the key intermediates and transition structures (TS), a the-
oretical study of the different reaction channels of the copper-
catalyzed cyclopropanation reaction with C1-symmetric aza-pyox
ligands was performed. Apart from the well-known drawbacks in
modeling the cyclopropanation reaction with styrene due to the
flatness of the potential energy surface,11–15 our main interest in
this work was to evaluate the enantioselectivity of the process;
therefore, all the calculations were carried out using ethylene as
the olefin. In addition, as in previous studies, methyl diazoacetate
was used in the calculations instead of ethyl diazoacetate. The lack
of symmetry of the ligand and, as demonstrated by preliminary
calculations, the high flexibility of the Cu(I)-carbene complex
increased significantly the number of reaction channels to be
The first observation made from the energy values presented
in Table 2 is that conformations labeled as K are always less
favored than the corresponding V. In addition, an inspection of the
transition structures revealed that the lowest energy conformations
are always associated to a distal disposition of the carbonyl group
with regard to the incoming alkene. Regarding enantioselectivity,
it can be seen that the calculated ratio of cyclopropanes 1R and 1S
are in good qualitative agreement with the experimental values (ca.
60 : 40, Table 1, entries 3–6) obtained in homogeneous conditions
(Table 1). In particular, and although slightly overestimated,
the enantioselectivity calculated from the aza-pyox(Me,H)-Cu(I)-
carbene complexes (15a¢) agrees quite well with that obtained
experimentally with aza-pyox(iPr,H) (10a) and aza-pyox(tBu,H)
(10b) ligands irrespective of the theoretical method used (calcu-
lated 1R/1S = 66 : 34 with B3LYP functional). In contrast, the
This journal is
The Royal Society of Chemistry 2010
Dalton Trans., 2010, 39, 2098–2107 | 2101
©

View Article Online
Scheme 4
This erroneous inversion of the calculated enantioselectivity
with respect to the experimental values obtained with aza-
pyox(iPr,Me) (10c) and aza-pyox(tBu,Me) (10d) ligands, is prob-
ably due to an incorrect evaluation by the B3LYP functional
of relatively small steric interaction differences in the TS. Bet-
ter values can be obtained by performing single-point energy
calculations through the recently developed M05-2X functional
on the B3LYP optimized transition structures. Hence, the re-
evaluation of the energies of transition structures ts15d through
this methodology allowed an outstanding improvement on the
calculated enantioselectivity towards values very close to the
experimental ones (Tables 1 and 2).
The source of this method-dependent reversal on the enantios-
electivity calculated through 6-methylpyridine-derived catalysts
was located on the overstabilization of the syn-I-Si reaction
trajectories at the expense of the syn-II-Re ones. The origin of
this special stability of the ts15c,d-syn-I-Si-V transition structures
is not clear, moreover when large steric interactions between
the 6-methyl group and the incoming alkene and between the
ester moiety and the alkyl group of the oxazoline should take
place; on the contrary, these interactions appear to be attractive
under the B3LYP scheme. In this sense, the proper evaluation
of dispersion forces is widely recognized as one of the more
important drawbacks of classical functionals like B3LYP. As a
consequence, and despite the remarkable success of the B3LYP
functional in classical organic and organometallic systems, this
method has failed when treating problems in which dispersion
forces are relevant. In these cases, the use of new functionals like
Truhlar’s hybrid meta-GGA M05-2X results are advantageous.
Concerning support effects, the most significant feature, apart
from the well-documented preference toward cis-cyclopropanes, is
the lack of inversion in the absolute configuration of the major cis-
cyclopropanes with regard to the homogeneous phase reactions,
Fig. 4 Selected geometries of the lowest energy ts15d transition structures,
leading to both enantiomeric cyclopropane products. Most hydrogen
atoms are omitted for clarity.
addition of a methyl group in the 6-position of the pyridine
made the calculations of the enantioselectivity fail when the
B3LYP functional was used: calculated 1R/1S = 33 : 67 from aza-
pyox(Me,Me)-Cu(I)-carbene complexes (15c¢) and 1R/1S = 25 : 75
with aza-pyox(tBu,Me)-Cu(I)-carbene complexes (15d) (see ESI†).
2102 | Dalton Trans., 2010, 39, 2098–2107
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
Table 2 Calculated (M05-2X/6-31G(d)//B3LYP/6-31G(d)) relative en-
ergies a(kcal mol-1) and enantioselectivities of the carbene addition step
of the cyclopropanation reaction of styrene with methyl diazoacetate,
catalyzed by the 10a-d-Cu(I) complexes
coordinates were kept fixed. Single point energy calculations were
then carried out at the ONIOM(M05-2X/6-31G(d):UFF) level,
to give better relative energy values. Fig. 5 shows the calculated
geometries for the lowest energy Re and Si TS, in the case of ts15d.
As can be seen, ts15d-syn-II-Re-V (Fig. 5a) allows a closer ion
pair disposition between the copper complex and the negatively
charged support, without significant geometry change. On the
other hand, both the anti and syn TS in the Si approach (ts15d-
anti-II-Si-V and ts15d-syn-II-Si-V, Fig. 5b and 5c, respectively)
have problems in accommodating the surface. In the first case,
the Cu–Ccarbene bond must be rotated to avoid steric interactions
between the ester group and the surface. In the second one, the
complex disposition results in a larger cation–anion separation.
Both circumstances are reflected in the higher energy of the Si TS
with respect to the Re TS (10.9 and 12.3 kcal mol-1, respectively),
in agreement with the experimental behavior observed. Of course,
these results must be taken with caution, because of the simplicity
of the model used, but they support at least qualitatively the
connection between the TS-support geometrical disposition, and
the resulting relative energies.
DDE‡/
kcal mol-1a % mol % mol
Cumulative Cyclopropane
TS
configuration
ts15a¢-anti-I-Re-K
1.6
3.8
10.8
0.0
1.1
—
0.2
—
74.0
26.0
49.3
50.7
66.0
34.0
1R
ts15a¢- anti-I-Re-V 1.0
ts15a¢- anti-II-Re-K 4.3
ts15a¢-anti-II-Re-V 2.4
ts15a¢-syn-I-Re-K
ts15a¢-syn-I-Re-V
ts15a¢-syn-II-Re-K
ts15a¢-syn-II-Re-V
ts15a¢-anti-I-Si-K
ts15a¢-anti-I-Si-V
ts15a¢-anti-II-Si-K
ts15a¢-anti-II-Si-V
ts15a¢-syn-I-Si-K
ts15a¢-syn-I-Si-V
ts15a¢-syn-II-Si-K
ts15a¢-syn-II-Si-V
ts15c¢-anti-I-Re-K
ts15c¢- anti-I-Re-V
—
3.4
—
0.0
—
4.4
1.2
1.1
2.6
1.2
3.9
3.1
2.4
0.7
58.1
—
1S
1R
1S
1R
1S
0.0
7.7
8.9
0.8
8.1
0.1
0.3
0.6
10.1
0.0
1.8
1.1
3.2
1.2
31.4
—
1.1
0.8
17.1
0.6
30.9
0.0
0.2
1.5
2.8
0.6
—
0.0
5.9
0.2
55.0
0.0
0.5
0.0
21.6
0.0
10.9
0.0
1.1
ts15c¢- anti-II-Re-K 5.6
ts15c¢-anti-II-Re-V 1.7
ts15c¢-syn-I-Re-K
ts15c¢-syn-I-Re-V
ts15c¢-syn-II-Re-K
ts15c¢-syn-II-Re-V
ts15c¢-anti-I-Si-K
ts15c¢-anti-I-Si-V
ts15c¢-anti-II-Si-K
ts15c¢-anti-II-Si-V
ts15c¢-syn-I-Si-K
ts15c¢-syn-I-Si-V
ts15c¢-syn-II-Si-K
ts15c¢-syn-II-Si-V
ts15d-anti-I-Re-K
ts15d-anti-I-Re-V
ts15d-anti-II-Re-K
ts15d-anti-II-Re-V
ts15d-syn-I-Re-K
ts15d-syn-I-Re-V
ts15d-syn-II-Re-K
ts15d-syn-II-Re-V
ts15d-anti-I-Si-K
ts15d-anti-I-Si-V
ts15d-anti-II-Si-K
ts15d-anti-II-Si-V
ts15d-syn-I-Si-K
ts15d-syn-I-Si-V
ts15d-syn-II-Si-K
ts15d-syn-II-Si-V
2.0
1.4
1.9
0.0
—
2.0
2.2
0.4
2.3
0.0
4.1
3.1
2.1
1.8
2.7
—
6.0
1.3
3.3
0.0
6.4
2.9
5.0
0.6
4.5
1.0
5.1
2.4
a Calculated ZPE-corrected energies with thermal corrections at 298.15 K.
similar to that observed for quinolinoxazoline ligands,29 but op-
posite to that observed with bisoxazoline ligands.31 This result can
be rationalized if the lowest energy TS in the homogeneous phase
is also the lowest energy one in the heterogeneous phase. To shed
some light on this point, we carried out some calculations taking
into account the effect of the support. Given the huge size of such
systems, weused a low theoreticallevelfor geometryoptimizations.
Thus, we first selected the lowest energy calculated TS for the Re
and Si approaches of the alkene, and reoptimized them in the pres-
ence of a model of the clay support at the ONIOM(PM6:52UFF)
theoretical level. The inorganic support was left in the molecular
mechanics part of the ONIOM calculation, and their atomic
Fig. 5 Possible dispositions of the lowest energy ts15d transition struc-
tures with regard to the support surface, leading to both enantiomeric
cyclopropane products. Most hydrogen atoms are omitted for clarity.
Conclusions
We have synthesized a series of chiral aza-pyridinoxazoline lig-
ands, a new class of C1-symmetric ligands with a single stereogenic
This journal is
The Royal Society of Chemistry 2010
Dalton Trans., 2010, 39, 2098–2107 | 2103
©

View Article Online
center, through a general synthetic method. These ligands have
been tested in the enantioselective supported catalysis of the
cyclopropanation reaction of styrene with ethyl diazoacetate, with
the aim to improve surface confinement effects of the clay support
on the reaction stereoselectivity, due to a better adaptation of the
chiral complex to the surface. In the case of trans/cis diastere-
oselectivity, the support confinement effects result in a reversal
of selectivity, leading to good cis-selectivity values. On the other
hand, in general, the enantioselectivities do not display important
variations upon catalyst supports, except in the case of ligand 10c,
for which a fairly good enantioselectivity (60% ee) is obtained
in the major cis-cyclopropane. These results suggest the existence
of multiple dispositions of the complex reaction intermediates
with regard to the support surface. As a consequence, more work
is necessary to improve the ligand design to take advantage of
surface confinement effects in the enantioselective catalysis of this
reaction. As a general conclusion, it can be said that depending
on the structure of the C1-oxazoline-based ligand (bisoxazoline,
quinolinoxazoline, aza-pyridinoxazoline), coming from the same
chiral aminoalcohol, either (1R)- or (1S)-cis-cyclopropanes can
be selectively obtained in heterogeneous catalysis, illustrating
the interplay between the chiral ligand structure and support
confinement effects.
A theoretical mechanistic study has been carried out to explain
the origin of the enantioselectivity in the homogeneous and
heterogeneous phase at a molecular level. The theoretical study
allows us to conclude that steric interactions different from those
originated at the stereogenic centers of the chiral ligand might
also be important in determining the final enantioselectivity of
the catalyst. This knowledge can aid in the design of more efficient
chiral ligands, lacking C2 symmetry. The theoretical results also
help to explain the low enantioselectivity values obtained in
most cases with supported catalysts. The presence of different
chelate complex conformations increases the number of possible
reaction channels, making the selective formation of a single
cyclopropane enantiomer more difficult. However, as the lowest
energy TS in the homogeneous phase is also the one displaying
better accommodation with the support surface, no inversion in
the absolute configuration of the major cyclopropane is observed,
which is also corroborated by the molecular modelling studies.
chromatography on neutral alumina using ethyl acetate–hexane
(7 : 3) and 5% Et3N as eluent.
(S)-4-isopropyl-N-(pyridin-2-yl)-4,5-dihydrooxazol-2-amine (9a)
Prepared according to the general procedure, reaction of (S)-2-
ethoxy-4-isopropyl-4,5-dihydrooxazol and 2-aminopyridine gave
the title compound as a colorless solid in a yield after purification
of 20%.
◦
1
Mp: 116.5–117.6 C; [a]2D0 (c 0.99, CH2Cl2) +130.0; H NMR
(400 MHz, CDCl3, d ppm) d 8.21 (ddd, 1H; J = 0.8 Hz, J = 2 Hz,
J = 5.1 Hz), 7.54 (td, 1H; J = 2 Hz, 7.8 Hz), 6.95 (d, 1H; J =
7.8 Hz), 6.76(t, 1H; J = 5.2 Hz), 4.36(t, 1H; J = 8.5 Hz), 4.05 (dd,
1H; J = 6.2 Hz, 8.5 Hz), 3.76 (dd, 1H; J = 6.8 Hz, J = 14.7 Hz),
1.74(m, 1H), 0.95 (d, 3H; J = 6.7 Hz), 0.88 (d, 3H; J = 6.7 Hz);
13C NMR (100 MHz, CDCl3, d ppm) d 146.0, 137.0, 120.0, 116.5,
112.5, 67.5, 61.0, 32.5, 31.0, 29.8, 18.5, 18.0; m/z (ESI+) 206; IR
(cm-1): 1587 Anal. Calcd. for C11H15N3O: C, 64.3; H, 7.3; N, 20.5.
Found: C, 63.7; H, 7.0; N, 19.8.
(S)-4-tert-butyl-N-(pyridin-2-yl)-4,5-dihydrooxazol-2-amine (9b)
Prepared according to the general procedure, reaction of (S)-2-
ethoxy-4-tert-butyl-4,5-dihydrooxazol and 2-aminopyridine pro-
vided the title compound as a colorless solid in a yield after
purification of 17%.
◦
Mp: 93.3–94.1 C; [a]2D0 (c 0.90, CH2Cl2) +121.3; 1H NMR
(400 MHz, CDCl3, d ppm) d 8.2 (dd, 1H; J = 1.89 Hz, J =
5 Hz), 7.48 (t, 1H; J = 7.58 Hz), 6.95 (d, 1H; J = 7.9 Hz), 6.76
(dd, 1H; J = 0.8 Hz, 11.75 Hz), 4.28 (t, 1H; J = 8.7 Hz), 4.15
(dd, 1H; J = 5 Hz, 8.8 Hz), 3.7 (dd, 1H; J = 5.4 Hz, J = 8.5 Hz),
0.9 (s, 9H); 13C NMR (100 MHz, CDCl3, d ppm) d 146.0, 137.5,
120.5, 116.5, 66.0, 64.2, 50.3, 35.1, 33.7, 25.1; m/z (ESI+) 220; IR
(cm-1): 1587. Anal. Calcd. for C12H17N3O: C, 65.75; H, 7.75; N,
19.18. Found: C, 66.88; H, 8.20; N, 17.81.
(S)-4-isopropyl-N-(6-methylpyridin-2-yl)-4,5-dihydrooxazol-2-
amine (9c)
Prepared according to the general procedure, reaction of (S)-2-
ethoxy-4-isopropyl-4,5-dihydrooxazol and 2-aminopycoline pro-
vided the title compound as a colorless solid in a yield after
purification of 16%.
Experimental
◦
Mp: 83.6–84.3 C; [a]2D0 (c 0.98, CH2Cl2) +128,2; 1H NMR
(400 MHz, CDCl3, d ppm) d 7.38 (t, 1H; J = 7.7 Hz), 6.83 (d, 1H;
J = 7.7 Hz), 6.69 (d, 1H; J = 7.7 Hz), 4.43(t, 1H; J = 8.4 Hz),
4.04 (dd, 1H; J = 6.4 Hz, J = 8.4 Hz), 3.80 (dd, 1H; J = 7.4 Hz,
J = 14.6 Hz), 2.38 (s, 3H), 1.79(m, 1H), 1.03 (d, 3H; J = 6.6 Hz),
0.95 (d, 3H; J = 6.6 Hz).13C NMR (100 MHz, CDCl3, d ppm) d
137.5, 117.2, 115.7, 68.0, 61.0, 32.5, 24.5, 18.5, 18.2.; m/z (ESI+)
220; IR (cm-1): 1648. Anal. Calcd. for C12H17N3O: C, 65.75; H,
7.75; N, 19.18. Found: C, 63.54; H, 7.23; N, 19.24.
General methods
All reactions were carried out under an argon atmosphere
in oven-dried glassware. Dichloromethane, tetrahydrofuran and
toluene were dried in an SPS-Device. Ethanol was distilled from
magnesium. Amino acids were used as commercially available. 2-
Ethoxyoxazolines (8a,b) were synthesized by the method described
by Reiser et al.33 Aminopyridines are commercially available, and
were distilled prior use.
(S)-4-tert-butyl-N-(6-methylpyridin-2-yl)-4,5-dihydrooxazol-2-
General procedure for the synthesis of the aza-pyridinoxazolines
amine (9d)
Ethoxyoxazoline (7.5 mmol), aminopyridine (7.5 mmol) and a
catalytic amount of p-toluensulfonic acid (20 mg) were dissolved
in toluene (40 ml) and heated at reflux for 60 h. After this
period, the solution was concentrated in vacuum and purified by
Prepared according to the general procedure, reaction of (S)-2-
ethoxy-4-tert-butyl-4,5-dihydrooxazol and 2-aminopycoline pro-
vided the title compound as a colorless solid in a yield after
purification of 19%.
2104 | Dalton Trans., 2010, 39, 2098–2107
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
◦
Mp: 74.5–75.6 C; [a]2D0 (c 1.2, CH2Cl2) +121.6; 1H NMR
[a]2D0 (c 0.90, CH2Cl2)–10.3; 1H NMR (400 MHz, CDCl3, d ppm)
d 7.60 (d, 1H; J = 8.3 Hz), 7.50 (t, 1H; J = 7.8 Hz), 6.80 (d, 1H;
J = 7.3 Hz), 4.34 (dd, 1H; J = 8.1 Hz, 8.9 Hz), 4.09 (dd, 1H; J =
6.9 Hz, 8.0 Hz), 3.7 (td, 1H; J = 6.5 Hz, J = 8.9 Hz), 3.54 (s,
3H), 2.49 (s, 3H), 1.02 (d, 3H, J = 6.7 Hz), 0.93 (d, 3H, J = 6.7);
13C NMR (100 MHz, CDCl3, d ppm) d 156.3, 154.5, 137.2, 117.2,
113.7, 70.5, 70.4, 35.2, 33.3, 24.4, 18.9, 17.9; m/z (ESI+) 234; IR
(cm-1): 1648. Anal. Calcd. for C13H19N3O: C, 66.9; H, 8.1; N, 22.8.
Found: C, 65.7; H, 7.7; N, 21.2.
(400 MHz, CDCl3, d ppm) d 7.45 (t, 1H; J = 7.7 Hz), 6.83 (d, 1H;
J = 8.1 Hz), 6.69 (d, 1H; J = 7.3 Hz), 4.34 (t, 1H; J = 8.8 Hz), 4.20
(dd, 1H; J = 5.4 Hz, 8.9 Hz), 3.8 (dd, 1H; J = 5.4 Hz, J = 8.7 Hz),
2.44 (s, 3H), 0.95 (s, 9H); 13C NMR (100 MHz, CDCl3, d ppm) d
153.6, 137.0, 122.4,120.6, 114.9, 64.9, 44.5, 32.7, 30.0, 24.1, 23.5
m/z (ESI+) 234; IR (cm-1): 1644. Anal. Calcd. for C12H17ON3:
C,66.95; H,8.15; N,18.03. Found: C, 57.23; H, 8.8; N, 12.78.
General procedure for the methylation of aza-pyridinoxazolines
(S)-4-tert-butyl-N-methyl-N-(6-methylpyridin-2-yl)-4,5-
The corresponding aza-pyridinoxazoline (1 mmol) was dissolved
in THF (10 ml) and a 15% solution of n-butyl lithium in hexane
(1.5 N, 688 mL) was added at -78 ◦C. After stirring for 20 min
iodomethane (2.5 mmol, 355 mg) was added. The cooling bath
was removed and stirring at room temperature continued for
10 h. After evaporation of the solvent the residue was partitioned
between CH2Cl2 (10 ml) and saturated NaHCO3 (10 ml). The
aqueous phase was extracted with CH2Cl2 (2 ¥ 5 ml) and the com-
bined organic phases dried over NaSO4. Evaporation of the solvent
yielded the corresponding products as yellow oils.
dihydrooxazol-2-amine (10d)
Prepared according to the general procedure using 220 mg of 9d
to yield 98%.
[a]2D0 (c 0.90, CH2Cl2) +15.1; H NMR (400 MHz, CDCl3, d
1
ppm) d 7.61 (t, 1H; J = 8.3 Hz), 7.47 (dd, 1H; J = 7.4 Hz, 8.3 Hz),
6.76 (d, 1H; J = 7.3 Hz), 4.25 (dd, 1H; J = 8.5 Hz, 9.2 Hz), 4.17
(dd, 1H; J = 6.4 Hz, 8.4 Hz), 3.86 (dd, 1H; J = 6.4 Hz, J = 9.3 Hz),
3.5 (s, 3H), 2.5 (s, 3H), 0.91 (s, 9H); 13C NMR (100 MHz, CDCl3,
d ppm) d 156.3, 154.5, 137.2, 117.1, 113.5, 74.1, 68.9, 35.1, 34.1,
30.9, 25.7, 24.4 m/z (ESI+) 248; IR (cm-1): 1654. Anal. Calcd. for
C14H21N3O: C, 71.8; H, 7.8; N,14.8. Found: C, 72.4; H, 7.5; N,
15.7.
(S)-4-isopropyl-N-methyl-N-(pyridin-2-yl)-4,5-dihydrooxazol-2-
amine (10a)
Prepared according to the general procedure using 220 mg of 9a
(S)-N,N-(1,4-phenylenebis(methylene))bis(4-tert-butyl-N-
(6-methyl-pyridin-2-yl)-4,5-dihydrooxazol-2-amine (13)
to yield 98%.
1
[a]2D0 (c 0.81, CH2Cl2); -19.4; H NMR (400 MHz, CDCl3, d
248 mg (1 mmol) of 9d was dissolved in tetrahydrofuran (10 ml)
and a 15% solution of n-butyl lithium in hexane (1.5 N,
688 mL) was added at -78 ◦C. After stirring for 20 min a,a¢-
Dibromo-p-xylene (0.45 mmol, 11.88 mg) was added. The cooling
bath was removed and stirring at room temperature continued
for 10 h. After evaporation of the solvent the residue was
partitioned between CH2Cl2 (10 ml) and saturated NaHCO3
(10 ml). The aqueous phase was extracted with CH2Cl2 (2 ¥
5 ml) and the combined organic phases dried over Na2SO4.
After evaporation of the solvent, the product was purified by
chromatography on neutral alumina using ethyl acetate–hexane
7/3 and 5% Et3N as eluent to yield 70% of 13 as a yellow
oil.
ppm) d 8.26 (ddd, 1H; J = 0.8 Hz, J = 1.9 Hz, J = 4.9 Hz), 7.8
(dt, 1H; J = 0.8 Hz, 8.5 Hz), 7.52 (ddd, 1H; J = 1.9 Hz, J =
6.9 Hz, J = 7.20 Hz), 6.84 (ddd, 1H; J = 0.9 Hz, J = 4.9 Hz, J =
7.2 Hz), 4.28 (dd, 1H; J = 8.2 Hz, J = 8.9 Hz), 4.01 (dd, 1H; J =
7 Hz, 8 Hz), 3.76 (td, 1H; J = 6.7 Hz, J = 9 Hz), 3.45 (s, 3H),
1.7 (m, 1H), 0.94 (d, 3H; J = 6.7 Hz), 0.85 (d, 3H; J = 6.7 Hz);
13C NMR (100 MHz, CDCl3, d ppm) d 147.3, 136.9, 124.9, 117.9,
116.9,70.7, 70.5, 33.3, 19.0, 18.0, 16.3; m/z (ESI+) 220; IR (cm-1):
1650 Anal. Calcd. for C12H17N3O: C, 65.7; H, 7.8; N, 19.2. Found:
C, 63.7; H, 7.5; N, 17.3.
(S)-4-tert-butyl-N-methyl-N-(pyridin-2-yl)-4,5-dihydrooxazol-2-
amine (10b)
1
[a]2D0 (c 0.99, CH2Cl2) +12.3; H NMR (400 MHz, CDCl3, d
Prepared according to the general procedure using 220 mg of 9b
ppm) d 7.67 (d, 1H; J = 8.3 Hz), 7.47 (dd, 1H; J = 7.4 Hz,
8.3 Hz), 6.75 (d, 1H; J = 7.3 Hz), 5.3 (q, 2H; J = 15.1 Hz),
4.15 (m, 2H), 3.84 (dd, 1H; J = 6.2 Hz, 9.3 Hz), 2.42 (s, 3H),
0.85 (s, 9H); 13C NMR (100 MHz, CDCl3, d ppm) d 158.6, 156.2,
153.6, 137.6, 137.3, 127.5, 117.2, 113.7, 74.2, 68.7, 49.9, 34.1, 30.9,
29.7, 25.6, 24.3; m/z (ESI+) 569; IR (cm-1): 1649 Anal. Calcd.
for C34H44N6O2: C, 71.8; H, 7.8; N,14.8. Found: C, 73.7; H, 6.7;
N,15.3.
to yield 98%.
1
[a]2D0 (c 1.05, CH2Cl2) +12.5; H NMR (400 MHz, CDCl3, d
ppm) d 8.3 (ddd, 1H; J = 0.76 Hz, J = 1.91 Hz, J = 4.89 Hz), 7.9
(d, 1H; J = 8.54 Hz), 7.5 (dd, 1H; J = 1.98 Hz, J = 7.18 Hz), 6.8
(ddd, 1H; J = 0.87 Hz, 4.92 Hz, J = 7.20 Hz), 4.2 (dd, 1H; J =
8.49 Hz, J = 9.30 Hz), 4.1 (dd, 1H; J = 6.54 Hz, 8.39 Hz), 3.78
(dd, 1H; J = 6.5 Hz, J = 9.4 Hz), 3.5 (s, 3H) 0.86 (s, 9H);(hacer);
13C NMR (400 MHz, CDCl3, d ppm) d 146.0, 137.5, 120.5, 116.5,
66.0, 64.2, 50.3, 35.1, 33.7, 25.1; m/z (ESI+) 234; IR (cm-1): 1653.
Anal. Calcd. for C13H19ON3: C,66.9; H,8.2; N, 18.0. Found: C,67.3;
H,7.9; N,17.6.
Preparation of immobilized catalysts
The complex for cationic exchange was prepared by mixing
Cu(OTf)2 (65.1 mg, 0.18 mmol) with a solution of the corre-
sponding 10 ligand (0.20 mmol) in dichloromethane (2 ml). After
stirring for 30 min under an inert atmosphere, the solution was
filtered through a syringe PTFE microfilter, and the solvent was
evaporated under reduced pressure. The residue was redissolved in
anhydrous methanol (3 ml), and dried laponite (500 mg) was added
(S)-4-isopropyl-N-methyl-N-(6-methylpyridin-2-yl)-4,5-
dihydrooxazol-2-amine (10c)
Prepared according to the general procedure using 220 mg of 9c
to yield 99%.
This journal is
The Royal Society of Chemistry 2010
Dalton Trans., 2010, 39, 2098–2107 | 2105
©

View Article Online
to this solution. The suspension was stirred at room temperature
for 24 h, and the solid was filtered and washed with anhydrous
methanol (7 ml) and dichloromethane (10 ml). The resulting
freshly exchanged catalyst was dried under vacuum overnight.
The catalysts were characterized by elemental analysis, copper
analysis, and transmission FT-IR spectroscopy of self-supported
wafers evacuated (<10-4 Torr) at 50 ◦C.
Acknowledgements
This work was made possible by the generous financial support
of the Ministerio de Ciencia e Innovacio´n (MICINN, projects
CTQ2008-05138 and Consolider Ingenio 2010 CSD 2006-0003).
We thank the Supercomputation Center of Catalonia (CESCA)
and the Supercomputacio´n Center of Galicia (CESGA) for
computing facilities.
Catalytic tests
Notes and references
Homogeneous phase. The complex was prepared by mixing
Cu(OTf)2 (65.1 mg, 0.18 mmol) with a solution of the correspond-
ing ligand (0.20 mmol) in dichloromethane (2 ml). After stirring
for 30 min under an inert atmosphere, the solution was filtered
through a syringe PTFE microfilter and added to a solution of
styrene (2 mL, 2.0 mmol) and n-decane (50 mg, internal standard)
in anhydrous dichloromethane (1 ml). Ethyl diazoacetate (two
additions of 2.5 mmol) was then slowly added with a syringe
pump at room temperature. The reaction was monitored by gas
chromatography. FID from Hewlett-Packard 5890-II, cross-linked
methyl silicone column (SPB): 25 m ¥ 0.2 mm ¥ 0.33 mm; helium
as carrier gas. 20 psi; injector temperature: 230 ◦C; ◦detector
1 D. E. De Vos, I. F. J. Vankelecom, P. A. Jacobs, (ed.), Chiral Catalysts
Immobilization and Recycling, Wiley-VCH, Weinheim, 2000.
2 J. M. Fraile, J. I. Garc´ıa, C. I. Herrer´ıas, J. A. Mayoral and E. Pires,
Chem. Soc. Rev., 2009, 38, 695–706.
3 For a recent review on non-covalent immobilization of enantioselective
catalysts, see: J. M. Fraile, J. I. Garc´ıa and J. A. Mayoral, Chem. Rev.,
2009, 109, 360–417.
4 D. Rechavi and M. Lemaire, Chem. Rev., 2002, 102, 3467–3494.
5 For a review on stereoselective cyclopropanation reactions, see: H.
Lebel, J.-F. Marcoux, C. Molinaro and A. B. Charette, Chem. Rev.,
2003, 103, 977–1050.
6 G. C. Hargaden and P. J. Guiry, Chem. Rev., 2009, 109, 2505–2550.
7 R. Rasappan, D. Laventine and Oliver Reiser, Coord. Chem. Rev., 2008,
252, 702–714.
8 G. Desimoni, G. Faita and K. A. Jørgensen, Chem. Rev., 2006, 106,
3561–3651.
◦
◦
temperature: 250 C; oven program: 70 C (3 min), 15 C min-1
to 200 ◦C (5 min); retention times: ethyl diazoacetate 3.2 min,
styrene 3.82 min, n-decane 5.47 min, diethyl maleate 7.84 min,
diethyl fumarate 8.02 min, cis-cyclopropanes 10.91 min, trans-
cyclopropanes 11.41 min. The asymmetric inductions of the
reactions were also determined by gas chromatography with a
Cyclodex-b column. Oven temperature program: 125 ◦C isotherm;
retention times: (1S,2R)-cyclopropane (4S) 28.9 min, (1R,2S)-
cyclopropane (4R) 29.8 min, (1R,2R)-cyclopropane (3R) 34.3 min,
(1S,2S)-cyclopropane (3S) 34.9 min.
9 A. I. Ferna´ndez, J. M. Fraile, J. I. Garc´ıa, C. I. Herrer´ıas, J. A. Mayoral
and L. Salvatella, Catal. Commun., 2001, 2, 165–170.
10 M. R. Castillo, L. Fousse, J. M. Fraile, J. I. Garc´ıa and J. A. Mayoral,
Chem.–Eur. J., 2007, 13, 287–291.
11 Theoretical mechanistic studies: J. M. Fraile, J. I. Garc´ıa, V. Mart´ınez-
Merino, J. A. Mayoral and L. Salvatella, J. Am. Chem. Soc., 2001, 123,
7616–7625.
`
12 T. Rasmussen, J. F. Jensen, N. Estergaard, D. Tanner, T. Ziegler and
P.-O. Norrby, Chem.–Eur. J., 2002, 8, 177–184.
13 J. M. Fraile, J. I. Garc´ıa, M. J. Gil, V. Mart´ınez-Merino, J. A. Mayoral
and L. Salvatella, Chem.–Eur. J., 2004, 10, 758–765.
14 J. I. Garc´ıa, G. Jime´nez-Ose´s, V. Mart´ınez-Merino, J. A. Mayoral,
E. Pires and I. Villalba, Chem.–Eur. J., 2007, 13, 4064–4073.
15 G. Drudis-Sole´, F. Maseras, A. Lledo´s, A. Vallribera and M. Moreno-
Man˜as, Eur. J. Org. Chem., 2008, 5614–5621.
16 Experimental mechanistic studies: B. F. Straub and P. Hofmann,
Angew. Chem., Int. Ed., 2001, 40, 1288–1290.
17 B. F. Straub, I. Gruber, F. Rominger and P. Hofmann, J. Organomet.
Chem., 2003, 684, 124–143.
Heterogeneous phase. Ethyl diazoacetate (228 mg, 2.0 mmol)
was slowly added with a syringe pump over 2 h to a suspension of
laponite catalyst (150 mg) in styrene (2 mL, 2.0 mmol) containing
n-decane (internal standard, 50 mg) at room temperature. The
reaction was monitored by gas chromatography with SPB and
Cyclodex-b columns. After total consumption of the diazoacetate
the solid catalyst was filtered off. Additional ethyl diazoacetate
(228 mg, 2.0 mmol) was slowly added to the filtrate, and the
absence of reaction was tested by GC.
18 X. Dai and T. H. Warren, J. Am. Chem. Soc., 2004, 126, 10085–
10094.
19 Y. M. Badiei and T. H. Warren, J. Organomet. Chem., 2005, 690, 5989–
6000.
20 P. Hofmann, I.V. Shishkov and F. Rominger, Inorg. Chem., 2008, 47,
11755–11762.
21 I.V. Shishkov, F. Rominger and P. Hofmann, Organometallics, 2009, 28,
1049–1059.
22 G. Chelucci, S. Medici and A. Saba, Tetrahedron: Asymmetry, 1997, 8,
3183–3184.
Theoretical calculations
23 G. Chelucci, M. G. Sanna and S. Gladiali, Tetrahedron, 2000, 56, 2889–
Quantum chemical calculations were carried out by means of the
B3LYP49,50 and M05-2X41–48 hybrid functionals. Full geometrical
optimizations using the 6-31G(d) basis set were carried out with
the Gaussian 03 package.51 Analytical frequencies were calculated
at the same level used in the geometry optimization, and the
nature of the stationary points was determined in each case
according to the right number of negative eigenvalues of the
Hessian matrix. Hard data on electronic energies, enthalpies, and
Gibbs free energies of the different conformations of all structures
considered are available as ESI.† ONIOM calculations with the
PM6 semiempirical method52 were carried out with the Gaussian
09 package.53
2893.
24 K. Schwekendiek and F. Glorius, Synthesis, 2006, 2996–3002.
25 X.-Y. Wu, X.-H. Li and Q.-L. Zhou, Tetrahedron: Asymmetry, 1998, 9,
4143–4150.
26 X.-G. Li, L.-X. Wang and Q.-L. Zhou, Chin. J. Chem., 2002, 20, 1445–
1449.
27 J. I. Garc´ıa, J. A. Mayoral, E. Pires and I. Villalba, Tetrahedron:
Asymmetry, 2006, 17, 2270–2275.
28 A. Cornejo, J. M. Fraile, J. I. Garc´ıa, M. J. Gil, C. I. Herrer´ıas,
G. Legarreta, V. Martinez-Merino and J. A. Mayoral, J. Mol. Catal.
A: Chem., 2003, 196, 101–108.
29 J. M. Fraile, J. I. Garc´ıa, G. Jime´nez-Ose´s, J. A. Mayoral and M. Rolda´n,
Organometallics, 2008, 27, 2246–2251.
30 J. M. Fraile, J. I. Garc´ıa, A. Gissibl, J. A. Mayoral, E. Pires, O. Reiser,
M. Rolda´n and I. Villalba, Chem.–Eur. J., 2007, 13, 8830–8839.
2106 | Dalton Trans., 2010, 39, 2098–2107
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
31 J. I. Garc´ıa, B. Lo´pez-Sa´nchez, J. A. Mayoral, E. Pires and I. Villalba,
J. Catal., 2008, 258, 378–385.
32 J. M. Fraile, J. I. Garc´ıa, C. I. Herrer´ıas, J. A. Mayoral, O. Reiser,
A. Socue´llamos and H. Werner, Chem.–Eur. J., 2004, 10, 2997–3005.
33 H. Werner, R. Vicha, A. Gissibl and O. Reiser, O., J. Org. Chem., 2003,
68, 10166–10168.
34 For some examples of cis-selective cyclopropanation catalysts, see:
M. L. Rosenberg, A. Krivokapic and M. Tilset, Org. Lett., 2009, 11,
547–550.
35 H. Suematsu, S. Kanchiku, T. Uchida and T. Katsuki, J. Am. Chem.
Soc., 2008, 130, 10327–10337, and references therein.
36 C. Bonaccorsi and A. Mezzetti, Organometallics, 2005, 24, 4953–4960.
37 M. M. Diaz-Requejo, T. R. Belderrain, S. Trofimenko and P. J. Pe´rez,
J. Am. Chem. Soc., 2001, 123, 3167.
38 W. Hu, D. J. Simmons and M. P. Doyle, Org. Lett., 2002, 4, 901–904.
39 Isopropyl-substituted ligands were used instead of the tert-butyl-
substituted ones because it is well-known that the copper complexes
of the tert-butyl-bearing bis(oxazoline) ligand are more difficult to
support, and decomplexation and loss of the chiral ligand is often
observed. See Ref. 10 and: J. M. Fraile, J. I. Garc´ıa, C. I. Herrer´ıas, J. A.
Mayoral and M. A. Harmer, J. Catal., 2004, 221, 532–540.
40 J. I. Garc´ıa, B. Lo´pez-Sa´nchez and J. A. Mayoral, Org. Lett., 2008, 10,
4995–4998.
50 A. D. Becke, J. Chem. Phys., 1993, 98, 5648–5652.
51 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A.
Robb, J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N.
Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone,
B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H.
Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,
M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X.
Li, J. E. Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo,
J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin,
R. Cammi, C. Pomelli, J. Ochterski, P. Y. Ayala, K. Morokuma, G. A.
Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich,
A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck,
K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul,
S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P.
Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-
Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill,
B. G. Johnson, W. Chen, M. W. Wong, C. Gonzalez and J. A. Pople,
GAUSSIAN 03 (Revision E.01), Gaussian, Inc., Wallingford, CT,
2004.
52 J. J. P. Stewart, J. Mol. Model., 2007, 13, 1173–1213.
53 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson,
H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J.
Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota,
R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao,
H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro,
M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov,
R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant,
S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E.
Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts,
R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J.
Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth,
P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas,
J. B. Foresman, J. V. Ortiz, J. Cioslowski and D. J. Fox, GAUSSIAN 09
(Revision A.2), Gaussian, Inc., Wallingford, CT, 2009.
41 Y. Zhao, N. E. Schultz and D. G. Truhlar, J. Chem. Theory Comput.,
2006, 2, 364–382.
42 Y. Zhao and D. G. Truhlar, J. Phys. Chem. A, 2006, 110, 10478–10486.
43 Y. Zhao and D. G. Truhlar, J. Phys. Chem. A, 2006, 110, 5121–5129.
44 Y. Zhao and D. G. Truhlar, J. Chem. Theory Comput., 2006, 2, 1009–
1018.
45 Y. Zhao and D. G. Truhlar, J. Org. Chem., 2007, 72, 295–298.
46 Y. Zhao and D. G. Truhlar, J. Chem. Theory Comput., 2007, 3, 289–300.
47 Y. Zhao and D. G. Truhlar, Org. Lett., 2006, 8, 5753–5755.
48 Y. Zhao and D. G. Truhlar, Acc. Chem. Res., 2008, 41, 157–167.
49 C. Lee, W. Yang and R. Parr, Phys. Rev. B: Condens. Matter, 1988, 37,
785–789.
This journal is
The Royal Society of Chemistry 2010
Dalton Trans., 2010, 39, 2098–2107 | 2107
©