Support effect on stereoselectivities of vinylogous mukaiyama-michael reactions catalyzed by immobilized chiral copper complexes

Article abstract of DOI:10.1021/cs400743n

Chiral bis(oxazoline)- and azabis(oxazoline)-copper complexes, used as homogeneous catalysts or immobilized onto laponite, are able to catalyze vinylogous Mukaiyama-Michael reactions between 2-(trimethylsilyloxy)furan and several electron-deficient alkenes. A study of the support effect has been conducted and different changes on the diastereoselectivities and enantioselectivities has been observed. The behavior of the catalyst is different, depending on the structure of the substrate (Michael acceptor). When diethyl benzylidenemalonate was used, the major diastereomer was that with syn configuration, but the homogeneous and the heterogeneous catalysts lead to opposite enantiomers (-80% ee in solution and 38% ee in the heterogeneous phase). This change represents a support effect of ～1.8 kcal/mol. With N-(E)-but-2-enoyloxazolidinone, the most relevant change is in the diastereomer preference. In solution, the anti isomer is the major one (anti/syn = 98/2); however, in contrast, syn isomer is preferred with the immobilized catalyst (anti/syn = 19/81). This syn preference has not been previously reported in the literature. Finally, in the case of α,β-unsaturated ketones, the homogeneous catalysts are not able to induce enantioselectivity, whereas the immobilized ones lead to moderate values (up to 70%), similar to those values described in the literature with organocatalysts.

Full text of DOI:10.1021/cs400743n

Research Article
pubs.acs.org/acscatalysis
Support Effect on Stereoselectivities of Vinylogous Mukaiyama−
Michael Reactions Catalyzed by Immobilized Chiral Copper
Complexes
Jose M. Fraile,* Nuria García, and Clara I. Herrerías
́
́ ́
Instituto de Síntesis Química y Catalisis Homogenea (ISQCH), CSIC-Universidad de Zaragoza, C/Pedro Cerbuna, 12,
50009-Zaragoza, Spain
S
* Supporting Information
ABSTRACT: Chiral bis(oxazoline)- and azabis(oxazoline)-copper com-
plexes, used as homogeneous catalysts or immobilized onto laponite, are
able to catalyze vinylogous Mukaiyama−Michael reactions between 2-
(trimethylsilyloxy)furan and several electron-deficient alkenes. A study of
the support effect has been conducted and different changes on the
diastereoselectivities and enantioselectivities has been observed. The
behavior of the catalyst is different, depending on the structure of the
substrate (Michael acceptor). When diethyl benzylidenemalonate was
used, the major diastereomer was that with syn configuration, but the homogeneous and the heterogeneous catalysts lead to
opposite enantiomers (−80% ee in solution and 38% ee in the heterogeneous phase). This change represents a support effect of
∼1.8 kcal/mol. With N-(E)-but-2-enoyloxazolidinone, the most relevant change is in the diastereomer preference. In solution,
the anti isomer is the major one (anti/syn = 98/2); however, in contrast, syn isomer is preferred with the immobilized catalyst
(anti/syn = 19/81). This syn preference has not been previously reported in the literature. Finally, in the case of α,β-unsaturated
ketones, the homogeneous catalysts are not able to induce enantioselectivity, whereas the immobilized ones lead to moderate
values (up to 70%), similar to those values described in the literature with organocatalysts.
KEYWORDS: asymmetric catalysis, bis(oxazolines), copper, supported catalyst, support effect
reaction parameters such as metal, solvent, or additives.10 In
INTRODUCTION
■
contrast, only a handful of examples dealing with immobilized
catalysts have been reported. Some examples described on
silica11 have been explained by the change in the coordinating
ability of the anion by hydrogen-bonding with the surface
silanols,12 which is a change that is also produced in the case of
supported ionic liquid phases.13
Enantioselective catalysis is, in theory, the most interesting
method to prepare organic compounds in enantiopure form. In
contrast with this idea, and apart from the cases of enzymatic
kinetic resolutions, the examples of industrial applications of
enantioselective catalysts are rather scarce and mostly
concentrated in a short number of hydrogenation reactions.1
One of the reasons adduced for this situation is the high cost
and low productivity of most of the enantioselective metal-
based catalysts.2 One method to improve their productivity is
the immobilization on solid supports,3−6 which, in principle,
should allow the recovery and reuse of the expensive
enantioselective catalyst, or even permit its use in continuous-
flow reactors.7 However, immobilization has an additional cost,
mainly in the most popular covalent method, because of the
required supplementary substitution on the ligand, which is also
a source of unexpected effects on enantioselectivity. The use of
noncovalent strategies of immobilization8 should help to
minimize its cost impact, since the same homogeneous catalysts
can be supported and the immobilization procedure is simple
and efficient. Moreover, additional advantages should be
obtained to compensate the preparation effort, even if not so
hard, of the immobilized catalyst (for example, modification of
the stereoselectivities of the reaction9). A good number of
examples have been described in which stereoselectivities in
homogeneous catalysis are reversed by modifications in
The mesoporous materials have been considered as suitable
supports for chiral catalysts, as the regular pore system would
restrict the conformational freedom of the catalysts and limit
the possible pathways for the attack of reagents14 in a sort of
confinement effect, invoked also in the case of catalysts
supported on zeolites.15 Another type of support for the
immobilization of chiral catalysts are the clays, which are
layered silicates that have been recognized for a long time as
interesting catalysts and supports for organic synthesis.16−18
Our group described, for the first time, the effect of the regular
flat surface of clays on the stereoselectivity of copper-catalyzed
reactions when the catalyst had been immobilized by
electrostatic interactions.9 In the case of cyclopropanation,
even the nonchiral catalyst had some influence on diaster-
eoselectivity,19 and the chiral catalysts with bis(oxazoline)
Received: August 28, 2013
Revised: September 27, 2013
Published: October 14, 2013
© 2013 American Chemical Society
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Figure 1. Ligands used in this work and an idealized view of the supported catalysts.
ligands were able to reverse both diastereoselectivity and
enantioselectivity.20 Since then this effect has been studied in-
depth by using different supports,21 ligand substituents,22
unsymmetrically substituted bis(oxazolines),22,23 monooxazo-
line ligands,24−26 and substrates and diazocompounds.22
Unfortunately, the system was revealed to be rather
unpredictable to get a full picture of the surface effect, probably
because of its high conformational flexibility, and different
effects on selectivities (enhancement, decrease, or reversal)
were obtained. In the meantime, effects on other reactions were
also observed. In the case of carbene insertions into C−H
bonds of cyclic ethers, stereoselectivities and also chemo-
selectivity were improved.27,28 An impressive effect, with
reversal of diastereoselectivity and great enhancement of
enantioselectivity, was observed in the case of the vinylogous
Mukaiyama aldol reaction using 2-(trimethylsilyloxy)furan.29
This enolsilane is very useful from a synthetic point of view,
because it leads to γ-butenolides30 that are present in a large
number of natural products. The related vinylogous Mukaiya-
ma−Michael reaction31,32 has been less explored, with only a
limited number of examples of the enantioselective version
catalyzed by bis(oxazoline)-metal complexes described in the
literature.33 In this case, it is also important to highlight that, to
our knowledge, there are no reported examples of using
heterogeneous catalysis to promote this reaction.
Scheme 1. Reaction between Diethyl Benzylidenemalonate
and 2-(Trimethylsilyloxy)furan
Table 1. Results of the Reaction between Diethyl
Benzylidenemalonate and 2-(Trimethylsilyloxy)furan
a
Homogeneous
Immobilized
yield
%ee
%ee
yield
%ee
%ee
b
b
b
b
ligand (%) syn/anti syn
anti
(%) syn/anti syn
anti
1a
1b
1c
1d
2b
2c
100
100
100
100
100
100
94/6
−52
−23
−83
−80
15
27
100
86
79/21
67/33
78/22
83/17
75/25
74/26
26
4
−6
1
79/21
90/10
94/6
−26
63
100
98
15
38
−3
2
21
17
−2
7
2
77/23
86/14
−50
50
71
−62
65
a
Reaction conditions: 1 mmol of diethyl benzylidenemalonate (226
In this paper, we present an extensive study of the surface
effect on enantioselective vinylogous Mukaiyama−Michael
reactions between 2-(trimethylsilyloxy)furan and several
electron-deficient alkenes, showing how the structure of the
substrate (Michael acceptor) conditions the results of both
diastereoselectivity and enantioselectivity. Cu(II) complexes of
different bis(oxazoline) (box)33 and azabis(oxazoline) (aza-
box)34,35 ligands (Figure 1) were tested as catalysts. Laponite,
which is a synthetic layered magnesio-silicate,36 was used as a
support for the immobilized catalysts. Immobilization was
carried out via the exchange of some of the Na+ cations by box-
Cu(OTf)2 complex in methanol,37 leading to a more disordered
material (Figure 1).38 The catalysts were characterized by
copper and elemental analysis (see the Supporting Informa-
tion) and by infrared (IR) spectroscopy,22,37,38 to confirm the
structural integrity of the complex after cation exchange.
μL), 1.5 mmol of HFIP (159 μL), catalyst (0.10 mmol of
homogeneous and 0.15 mmol of heterogeneous), 5 mL of anhydrous
toluene, slow addition (5 h) of 2 mmol of 2-(trimethylsilyloxy)furan
(347 μL) in 10 mL of anhydrous toluene at room temperature (rt).
Reaction time after addition: 5 h in the homogeneous phase and 24 h
b
in the heterogeneous phase. Considered positive when the major
product is that of lower retention time.
the chiral ligand reduces the diastereoselectivity, slightly in the
case of ligands with aromatic substituents (1a and 1d) and
more significantly in the case of ligands with aliphatic
t
substituents, and mainly with Bu (1b and 2b), leading to the
lowest diastereoselectivity values (around 78/22). With respect
to enantioselectivity, box ligands are slightly better than the
analogous azabox ones, whereas the worse results are obtained
with the tert-butyl substituted ligands. Under these conditions
(room temperature (rt), toluene solvent, 1,1,1,3,3,3-hexafluor-
oisopropanol (HFIP) additive), 1c and 1d (ee over 80%) are
the best ligands for the homogeneous reaction, despite the
better results described for 1b at low temperature. The
enantioselectivity in the minor anti isomer did not show any
correlation with that of the major syn isomer, with 63% ee as
the best value obtained with 1c.
RESULTS AND DISCUSSION
■
Reaction with Diethyl Benzylidenemalonate. The first
Michael acceptor considered was diethyl benzylidenemalonate
(Scheme 1), which had been used in nonvinylogous
Mukaiyama−Michael reactions catalyzed by the same type of
complexes.39 The results, both in homogeneous and heteroge-
neous phase, are collected in Table 1.
The fluorinated alcohol was necessary to accelerate the
reaction,39 but its role in the control of the enantiomeric excess
has not been described. Several fluorinated alcohols (2,2,2-
trifluoroethanol as a primary alcohol; 1,1,1,3,3,3-hexafluoro-2-
In the homogeneous phase, syn (unlike) products are the
major ones, as it happened in the reaction catalyzed by
Cu(OTf)2 (syn/anti = 98:2),40 but in general, the presence of
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Figure 2. (Left) Overimposed geometries (according to X-ray diffraction) of the [1a-Cu-benzylidenemalonate](SbF6)2 (green) and [1a-
Cu(H2O)2](OTf)2 (deep blue) complexes. Hydrogen atoms are omitted for the sake of clarity. (Right) Proposed attack route.
methyl-2-propanol as a tertiary one; 1,3-(2,2,2-trifluoroethoxy)-
2-propanol41 as a more hindered secondary one) were tested in
the reaction catalyzed by 1c-Cu(OTf)2. In all cases, the
selectivities were very similar, with a syn/anti ratio between
85:15 and 90:10 and an enantiomeric excess of the syn isomer
between 79% and 83%. This seems to indicate that the kinetic
effect is due to a change in the rate-determining step, but the
participation of fluorinated alcohol does not take place in the
stereoselectivity-determining step (furane attack) but in the
silane transfer step necessary to close the catalytic cycle.
Although crystals of the major syn isomer were obtained, they
were not suitable to determine the absolute configuration.
Hence, the sense of the asymmetric induction cannot be
inferred from experimental data. The structure of the 1a-Cu-
benzylidenemalonate complex has been described, albeit with
SbF6 anions,39 and this structure is very similar to that of the
diaquo complex with triflate anions.42 In fact, the over-
imposition of both structures (Figure 2) indicates that the
oxygens are nearly in the same position, slightly distorted from
the equatorial plane, and the anions are also in the same
position, irrespective from their nature. The only significant
variation corresponds to the rotation of the phenyl groups
around the bond to the oxazoline ring, probably due to the
presence of the benzylidenemalonate. Thus, it can be
speculated that the attack would take place through the Re
face of the benzylidenemalonate (Figure 2), leading to syn-3S as
the major product. However, in the related reaction between
benzylidenemalonate and indole catalyzed by 1c-Cu, the attack
through the Si face has been proposed to explain the induction
sense in nonpolar solvents,43 based on the square pyramidal
structure of the analogous [1b-Cu(H2O)2](OTf)2 complex.44
With this model, the major product would be syn-3R.
Interestingly, the induction sense in the syn isomers with all
the bis(oxazolines) is the same irrespective from the substituent
nature, in contrast with the result reported in the non-
vinylogous Mukaiyama−Michael reaction on the same
substrate.39
(syn/anti = 75:25)40 and the presence of the ligand does not
significantly modify this selectivity, with values in the range
from 67/33 to 83/17. At the same time, the sense of the
asymmetric induction in the major syn isomer was reversed with
respect to the homogeneous values and the major enantiomer
was that of opposite configuration. A similar effect had been
already observed in the case of cyclopropanation catalyzed by
bis(oxazoline)-Cu(I) complexes immobilized on laponite, and
it had been ascribed to the disposition of the complex with
respect to the surface of the support.20,26 In this case, the effect
is observed with Cu(II) catalytic complexes, showing its general
character. The most remarkable reversal was observed with 1d
ligand, from 80% ee in solution to 38% ee of the other
enantiomer with the immobilized catalyst. Such a change in
enantioselectivity represents a variation of ∼1.77 kcal/mol in
the relative energies of the corresponding transition states,
which must be due to the surface effect. In fact it can be
speculated that the box-Cu-benzylidenemalonate complex, once
the two anions have been exchanged by the negative charges of
the support, will be placed on the surface to minimize the steric
interactions, so probably the less hindered face in solution will
be shielded by the surface, explaining, in this way, the reversal
in the induction sense. The low enantioselectivity would be the
consequence of the shielding effect of the ligand on the less-
hindered face. However, this hypothesis, which considers the
intermediate as a rigid body, is a simplification, as demonstrated
in analogous examples.22,23,25,26
Reaction with N-(E)-but-2-enoyloxazolidinone. The N-
acyloxazolidinones are among the most-used Michael acceptors,
and specifically the reaction with 2-(trimethylsilyloxy)furan had
been described in the literature, using BINOL-lanthanides,45
bis(oxazoline) and pyridinebis(oxazoline) complexes with
different metals,46 or binaphthyldiimine−Ni47 chiral catalysts.
In our case, the results obtained with N-(E)-but-2-enoylox-
azolidinone (Scheme 2) and bis(oxazoline)-copper complexes
in solution and in heterogeneous phase are gathered in Table 2.
In this case, the major diastereomer has anti relative
configuration (syn/anti ratio from 8/92 to 2/98) in the
homogeneous reaction, in agreement with the results obtained
with other chiral catalysts45−47 and with Cu(OTf)2 or Lap-Cu
without chiral ligands.40 The use of the immobilized catalysts
In the case of the immobilized catalysts, the diastereose-
lectivity was generally lower than that obtained in solution with
their analogous catalysts. This immobilization effect had been
already observed with the nonchiral heterogeneous catalyst
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enantioselectivity can be ascribed to a disposition of the
complex with the less-hindered face toward the solid, leading to
a competition between the shielding effect of the ligand
substituent and the surface.
Scheme 2. Reaction between N-(E)-but-2-
enoyloxazolidinone and 2-(Trimethylsilyloxy)furan
The explanation for the reversal of the diastereoselectivity is,
by far, more difficult to justify, mainly because the reaction
mechanism is not well understood. The enantioselectivity is
explained by the disposition of the Michael acceptor in an s-cis
conformation, in agreement with X-ray diffraction (XRD)
data,48 and the approach of furan by the less-hindered Si face
(Figure 3). However, the disposition of furan, with respect to
the acceptor, is still a matter of debate. Both open transition
states and cyclic ones (similar to the Diels−Alder transition
states) have been proposed to explain the stereochemical
outcome of Mukaiyama-type reactions of silyloxyfurans.49
Open-chain transition states allow one to explain the results
of uncatalyzed Mukaiyama−Michael reactions with qui-
nones,50,51 but they have been also proposed for Sc-catalyzed
reactions with unsaturated ketones,52 although in that case, a
coordination of furan to Sc has been also envisaged. Diels−
Alder-like transition states have been always proposed in both
Lewis-acid-catalyzed Mukaiyama aldol53 and Mukaiyama−
Michael54 reactions. In the case of copper catalyzed reactions
of simple enolsilanes with N-acyloxazolidinones, a mechanism
through a hetero-Diels−Alder state has been observed, but in
that case the Michael acceptor acts as heterodiene and the
enolsilane as dienophile.55,56
When all the possible approaches of furan by the Si face of
the Michael acceptor are represented (Figure 3), no clear
preference for any of the transition states can be observed. In
the case of Diels−Alder-like transition states (TS-DA), the one
leading to the major anti diastereomer corresponds to the endo
approach, the kinetically favored in a Diels−Alder reaction,57
although it has been described that reactions with furan as a
diene are reversible up to −20 °C.58 The presence of HFIP
might prevent this reversibility and TS-DA would explain the
observed diastereoselectivity. Regarding the open-chain tran-
sition states (TS1 and TS2), the antiperiplanar disposition of
the double bonds in TS1 has been always proposed as the most
favorable approach. TS1-anti has also the advantage over TS1-
syn that H atoms are in antiperiplanar, minimizing the steric
interactions between the substituents. However, TS1-anti
places the bulky TMS group toward the catalytic complex
Table 2. Results of the Reaction between N-(E)-but-2-
enoyloxazolidinone and 2-(Trimethylsilyloxy)furan
a
Homogeneous
Immobilized
yield
ligand (%)
syn/
anti
%ee
b
%ee
yield
%ee
%ee
c
c
b
syn
anti
(%) syn/anti syn
anti
1a
1b
1c
1d
2b
2c
100
100
100
100
100
100
2/98
7/93
7/93
8/92
7/93
4/96
69
19
23
34
13
21
36
62
16
59
92
26
81
70
64/36
35/65
81/19
67/33
35/65
57/43
32
32
20
52
46
29
28
2
0
100
76
52
15
9
85
81
a
1.5 mmol of HFIP (159 μL), catalyst (0.10 mmol of homogeneous
phase and 0.15 mmol of heterogeneous phase), 5 mL of anhydrous
toluene, slow addition (5 h) of 2 mmol of 2-(trimethylsilyloxy)furan
(347 μL) in 10 mL of anhydrous toluene at rt. Reaction time after
addition: 5 h in the homogeneous phase and 24 h in the
b
c
heterogeneous phase. syn-4SR is the major syn isomer. anti-4SS is
the major anti isomer.
promotes the formation of the syn isomer in different degrees,
depending on the chiral ligand usedfrom syn/anti 35/65 with
tert-butyl substituted ligands 1b and 2b up to syn/anti 81/19
with 1c, showing that this result is a combined effect of the
support and the ligand. This is a remarkable result since, to the
best of our knowledge, none of the catalysts described in the
literature promotes the formation of the syn isomer.
Unfortunately, enantioselectivities are always lower than those
obtained with the homogeneous catalysts, especially for the
major syn isomer. The only exception is the result with Indane
box 1d, leading to moderate diastereoselectivities (67/33 d.r.)
and enantioselectivities (52% ee for syn). Again, the decrease in
Figure 3. Possible approaches of 2-(trimethylsilyloxy)furan to the Si face of coordinated N-(E)-but-2-enoyloxazolidinone.
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and higher enantioselectivity than that obtained would be
expected. TS2 present a synclinal disposition of the two double
bonds, and it has never been considered as a possibility in the
reaction mechanism.49−52 TS-DAanti and TS2-syn would present
a correct disposition for a hetero-Diels−Alder mechanism.55
In the case of the heterogeneous catalysts, the proximity of
the support surface eliminates the C2 symmetry of the complex,
and two dispositions can be considered (Figure 4). If the
expected, the homogeneous reactions do not produce any
asymmetric induction (ee <5%). In contrast, the immobilized
catalysts lead to modest but significant enantioselectivities,
although, unfortunately, in the minor syn diastereomer.
Isopropyl-substituted ligands 1c and 2c show the best
performance, 64% and 71% ee for the syn isomer, respectively,
combined with a lower anti preference. This encouraging result
prompted us to test the effect of the substituent size in both
positions of the unsaturated ketone.
The substituent in α-position of the ketone (R3) should be
placed close to the metal center, with a deep effect on the
coordination mode. In fact, when 4-phenylbut-3-en-2-one (R1 =
Ph, R2 = H, R3 = Me (5b)) is used, the diastereoselectivity is
significantly modified in the heterogeneous phase, despite the
similar results obtained in solution. Even a slight syn preference
is observed, mainly with 1c ligand (syn/anti 64/36), a
preference only observed in nonenantioselective reactions
using iodine as a catalyst.61 With regard to enantioselectivity,
the presence of the methyl instead of phenyl in α position of
the carbonyl group produces a lower effect in the syn isomers
(up to 47% ee with 2b) but a higher effect in the anti (up to
37% ee with 2c). Azabis(oxazolines) perform significantly
better than the analogous bis(oxazolines), and again the
isopropyl-substituted ligand 2c leads to the best overall results:
∼40% ee in both isomers.
In contrast, when 1-phenylbut-2-en-1-one is used as a
substrate (R1 = Me, R2 = H, R3 = Ph (5c)), the
diastereoselectivity is not modified with respect to chalcone,
and the effect of immobilization on enantioselectivity is only
marginal (up to 10% ee). These results demonstrate that the
substituent in β position plays a key role in the interaction with
the surface, and the larger phenyl group shows a more
important effect than the methyl group to promote
enantioselectivity under heterogeneous conditions.
Given the improvement of enantioselectivity by the presence
of aromatic rings in both ends of the conjugated system, a 2-
naphthyl group was introduced in α position to the carbonyl
(5d), in an attempt to enhance the effect. However, this
substitution does not have any positive effect. Diastereose-
lectivity is only moderate, without reversal of the major
diastereomer, and enantioselectivity is only obtained in the
minor syn isomer but up to values (52% ee) lower than in the
case of chalcone.
Although the methyl groups were detrimental for the surface
effect when compared with aromatics, mesityl oxide (5e) was
used as an example of double substitution in the terminal
position of the conjugated system, which, in principle, should
force its s-cis conformation. Immobilization again produces a
modest enhancement of the enantioselectivity, up to 43% ee
with ligand 2c, which is the ligand that has consistently shown
the best results in all cases. This result is much better than that
obtained with 1-phenylbut-2-en-1-one (R1 = Me, R2 = H, R3 =
Ph (5c)), and analogous to the result with 4-phenylbut-3-en-2-
one (R1 = Ph, R2 = H, R3 = Me (5b)). This seems to indicate
that the enantioselectivity obtained is representative of the s-cis
Figure 4. Possible orientations of the intermediate box-Cu-acceptor,
with respect to the laponite surface: a) oxazolidinone (Ox) toward the
surface; b) the double bond (thick line) toward the surface.
oxazolidinone ring were placed close to the surface (Figure 4a),
the steric hindrance of the surface would work in the same
direction as the substituent of the ligand, and enantioselectivity
should increase in all the cases. As the effect of immobilization
is the opposite, the disposition with the double bond close to
the surface (Figure 4b) seems to be more probable, and, in that
case, each face of the double bond would be shielded by one
element, either the surface or the oxazoline substituent, with a
decrease in enantioselectivity. Moreover, the angle of the
chelate plane, with respect to the surface, would also force the
furan to react close to the surface, leading to a change in the
diastereoselectivity. Of course, this model is an oversimplifica-
tion, since it considers the intermediate complex as a rigid
model. In fact, the proximity of the surface might also change
the geometry of the complex, for example in a distortion of the
chelate or even favoring the s-trans conformation of the Michael
acceptor. In such case, the conformational equilibrium would
control the stereoselectivity of the process. This might be very
interesting in the case of substrates with poor control of the
conformational equilibrium in solution, for example those
unable to form chelate complexes, such as α,β-unsaturated
ketones, where the support might help to this control, leading
to an enhanced enantioselectivity.
Reaction with α,β-Unsaturated Ketones. Excellent
results have been obtained in this type of reaction using
organocatalysts, mainly with unsaturated aldehydes59 or also in
the direct Michael reaction with γ-butenolide.60 However, the
results with metal catalysts are scarce,52 probably by the poor
control of the s-cis/s-trans equilibrium and the possible
formation of intermediate complexes with different stoichiom-
etry.
The results of the study with α,β-unsaturated ketones
(Scheme 3) are gathered in Table 3. The first substrate chosen
was chalcone (R1 = R3 = Ph, R2 = H (5a)). The
diastereoselectivity obtained in the homogeneous phase is
slightly better (syn/anti up to 14/86) than that observed with
Cu(OTf)2 in the absence of ligand (syn/anti = 29:71).40 As
Scheme 3. Reaction between α,β-Unsaturated Ketones and 2-(Trimethylsilyloxy)furan
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a
Table 3. Results of the Reaction between α,β-Unsaturated Ketones and 2-(Trimethylsilyloxy)furan
Homogeneous
Immobilized
b
b
b
b
ligand
yield (%)
syn/anti
%ee syn
%ee anti
yield (%)
syn/anti
%ee syn
%ee anti
Substrate 5a
c
1a
100
100
100
100
100
100
15/85
19/81
19/81
16/84
14/86
23/77
1
4
−3
−2
−2
1
100
82
22/78
21/79
38/62
28/72
27/73
35/65
16
15
64
9
−10
−2
−5
−4
c
1b
c
1c
4
100
78
c
1d
−1
0
c
2b
2
80
20
71
−7
c
2c
2
2
83
−1
Substrate 5b
1a
100
100
100
100
100
100
21/79
25/75
23/77
25/75
23/77
20/80
1
0
0
2
0
1
0
0
98
79
99
88
71
78
48/52
51/49
64/36
48/52
52/48
56/44
5
15
11
4
−1
21
24
−6
0
1b
1c
0
1d
−1
0
2b
47
43
2c
0
37
Substrate 5c
1a
100
24/76
0
0
0
89
82
77
84
26/74
28/72
27/73
28/72
−10
1
9
−3
4
1c
1d
−9
1
2c
2
Substrate 5d
1a
100
26/74
0
68
70
55
73
32/68
27/73
36/64
44/56
−19
−8
−15
−52
0
2
8
1
1c
1d
2c
Substrate 5e
1a
1b
1c
1d
2b
2c
100
100
100
100
100
100
0
0
0
0
0
0
100
83
−1
−11
−18
−17
−12
−43
100
77
85
79
a
Reaction conditions: 1 mmol of α,β-unsaturated ketone, 1.5 mmol of HFIP (159 μL), catalyst (0.10 mmol of homogeneous phase and 0.15 mmol
of heterogeneous phase), 5 mL of anhydrous toluene, slow addition (5 h) of 2 mmol of 2-(trimethylsilyloxy)furan (347 μL) in 10 mL of anhydrous
b
toluene at rt. Reaction time after addition: 5 h in the homogeneous phase and 24 h in the heterogeneous phase. Considered positive when the
c
major product is that of lower retention time. In this case, the major anti isomer has RR configuration when the sign is negative.
conformation on the surface, which is favored by the single
substitution in β position with a phenyl group and its steric
interaction with the surface. The second phenyl group in the α
position of chalcone increases this enantioselectivity even more,
probably by a double steric interaction, although with an
unknown geometry.
Table 4. Recycling Experiments in the Reactions of 2-
(Trimethylsilyloxy)furan and Diethyl Benzylidenemalonate
or N-(E)-but-2-enoyloxazolidinone
run
yield (%)
syn/anti
%ee syn
%ee anti
a
Diethyl Benzylidenemalonate Substrate, Ligand 1c
1
2
3
100
100
31
78/22
76/24
77/23
77/23
15
24
22
21
25
22
0
Recycling Experiments. Although recycling was not the
main objective of this work, some experiments were carried out
in a similar way to those performed with the analogous
nonchiral catalyst.40 Two combinations were tested, diethyl
benzylidenemalonate as substrate with Lap-Cu-1c catalyst, and
N-(E)-but-2-enoyloxazolidinone with Lap-Cu-1d. As can be
seen in Table 4, the catalysts were recoverable once,
irrespective of the chiral ligand and the substrate, whereas its
activity decreases significantly in the third run while
maintaining the same selectivities. These results demonstrate
that deactivation is due to poisoning of the Lewis acid sites by
coordination, as it happened in the case of the analogous
nonchiral catalyst.40 In that case, the catalyst was reactivated by
Soxhlet extraction with THF, which enabled elimination of the
coordinated products. However, when the chiral catalyst was
treated in the same way, the activity was fully recovered but
enantioselectivity was lost, indicating the decomplexation of the
b
3
100
0
c
N-(E)-but-2-enoyloxazolidinone Substrate, Ligand 1d
1
2
3
76
73
12
67/33
66/34
67/33
52
50
50
46
49
49
a
b
Reaction conditions as described in Table 1. The catalyst used was
c
extracted with THF in a Soxhlet apparatus. Reaction conditions as
described in Table 2.
chiral ligand in the process. Attempts of recomplexation with
new chiral ligand after Soxhlet extraction were unsuccessful,
probably by the difficulty in replacing the solvent molecules,
presumably THF, from the coordination sphere of the metal
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with a stoichiometric amount of ligand. Alternative methods are
currently under study.
Diethyl (S*,R*)-2-[(5-Oxo-2,5-dihydrofuran-2-yl)(phenyl)-
methyl]-malonate (syn-3). The reaction crude was purified
by column chromatography on silica, using hexane/iPrOH 7:3
as an eluent. The enantiomeric excess was determined by
HPLC: Chiralpak IB column, 210 nm, n-hexane/iPrOH 9:1, 1
mL/min, tR syn1 = 13.0 min and tR syn2 = 14.9 min, mp 71−72
°C; 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 7.30−7.09
(m, 6H), 5.78 (dd, J1 = 5.7 Hz, J2 = 2.1 Hz, 1H), 5.54−5.53 (m,
1H), 4.27 (q, J = 7.1 Hz, 2H), 4.22 (d, J = 11.8 Hz, 1H), 3.89−
3.83 (m, 3H), 1.30 (t, J = 7.1 Hz, 3H), 0.87 (t, J = 7.1 Hz, 3H).
13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 172.5, 168.0,
167.1, 154.8, 133.6, 128.9, 128.4, 128.1, 122.1, 82.2, 62.1, 61.5,
53.6, 47.3, 14.0, 13.5. HR-MS (ESI+): m/z (%): 333.1335
[M+−H]. Calcd. for C18H21O6: 333.1333.
Diethyl (R*,R*)-2-[(5-Oxo-2,5-dihydrofuran-2-yl)(phenyl)-
methyl]-malonate (anti-3) (from the Spectrum of an anti/
syn Mixture). The reaction crude was purified by column
chromatography on silica, using hexane/iPrOH 7:3 as an eluent.
The enantiomeric excess was determined by HPLC: Chiralpak
IB column, 210 nm, n-hexane/iPrOH 9:1, 1 mL/min, tR anti1 =
18.9 min and tR anti2 = 19.6 min. 1H NMR (400 MHz, CDCl3,
25 °C, TMS): δ = 7.30−7.09 (m, 6H), 6.05 (dd, J1 = 5.8 Hz, J2
= 2.0 Hz, 1H), 5.39 (dt, J1 = 8.0 Hz, J2 = 1.8 Hz, 1H), 4.23−
4.18 (m, 3H), 3.94−3.82 (m, 2H), 3.70 (dd, J1 = 9.6 Hz, J2 =
8.0 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.1 Hz, 3H).
13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 171.9, 167.8,
166.9, 154.7, 136.0, 128.9, 128.8, 128.3, 121.9, 84.2, 62.0, 61.5,
54.4, 48.8, 13.8, 13.6.
(R*,S*)-3-(2,5-Dihydro-5-oxo-2-furyl)butanoyl-1,3-oxazo-
lidin-2-one (syn-4) (from the Spectrum of an anti/syn
Mixture). The reaction crude was purified by column
chromatography on silica, using hexane/ethyl acetate 8:2 as
an eluent. The enantiomeric excess was determined by HPLC:
Chiralpak AD-H column, 245 nm, n-hexane/iPrOH 66:34, 0.5
mL/min, tR syn1 (R,S) = 28.1 min and tR syn2 (S,R) = 43.5 min.
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 7.45 (dd, J1 =
5.8 Hz, J2 = 1.5 Hz, 1H), 6.17 (dd, J1 = 5.8 Hz, J2 = 2.1 Hz,
1H), 5.20−5.18 (m, 1H), 4.44 (t, J = 8.1 Hz, 2H), 4.03 (t, J =
8.1 Hz, 2H), 2.90 (dd, J1 = 17.5 Hz, J2 = 6.4 Hz, 1H), 2.68−
2.58 (m, 1H), 0.94 (d, J = 7 Hz, 3H). 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 172.9, 171.6, 155.7, 153.4, 122.6,
85.3, 62.1, 42.5, 38.0, 32.0, 13.9. HR-MS (ESI+): m/z (%):
240.0869 [M+−H]. Calcd. for C10H14NO5: 240.0872.
CONCLUSIONS
■
The presence of the support greatly conditions the stereo-
chemical course of vinylogous Mukaiyama−Michael reactions
of 2-(trimethylsilyloxy)furan and different Michael acceptors
catalyzed by bis(oxazoline) and azabis(oxazoline) copper
complexes immobilized onto laponite clay. The modification
of the stereoselectivities depends on the structure of the
Michael acceptor, probably by the differences in the disposition
of the intermediate complex with respect to the surface,
although this point is difficult to assess. With ethyl
benzylidenemalonate, an intermediate with forced s-trans
conformation is formed, which leads to a reversal in
enantioselectivity from solution to the heterogeneous phase,
with values of −80% and 38% ee in the most relevant case. In
the case of N-(E)-but-2-enoyloxazolidinone, the total reversal
of diastereoselectivity leads to the unprecedented syn selectivity,
up to a diastereomeric ratio of 81/19. The possible effect of the
surface on the s-cis/s-trans conformational equilibrium seems to
be confirmed by the enantioselectivity obtained in the reaction
with α,β-unsaturated ketones. Although the homogeneous
catalysts are unable to induce enantioselectivity, the supported
ones lead to variable enantiomeric excess, depending on the
substitution in the unsaturated ketone and the chiral ligand.
These results demonstrate that it is possible to use the
immobilization of chiral catalysts not only to facilitate their
recovery and recycling, but also to modify the reaction
stereoselectivities with respect to those obtained in solution,
even to obtain new (stereomeric) products, which can be an
added value to the immobilization.
EXPERIMENTAL SECTION
■
General. Chiral box (1a−1d) and azabox ligands (2b and
2c) were prepared by methods described in the literature.34,35,62
Laponite clay was obtained as a generous gift from Rockwood
Additives. All the Michael acceptors were purchased from
Aldrich and used without further purification, except N-(E)-
but-2-enoyloxazolidinone, which was prepared according to the
literature.63
General Procedure of the Heterogeneous Vinylogous
Mukaiyama−Michael Reaction. The dried immobilized
catalyst (0.15 mmol Cu) was added to a mixture of the
corresponding Michael acceptor (1 mmol) and 1,1,1,3,3,3-
hexafluoroisopropanol (160 μL, 1.5 mmol) in 5 mL of
anhydrous toluene under argon atmosphere. Then, a solution
of 2-(trimethylsilyloxy)furan (347 μL, 2 mmol) in 10 mL of
solvent was slowly added with a syringe pump to the
suspension for 5 h. The mixture was stirred at room
temperature for 24 h. At the end of the reaction, the catalyst
was removed by filtration and washed with anhydrous
dichloromethane (10 mL). The reaction crude was purified
by column chromatography on silica. Yield and diastereose-
(R*,S*)-5-(3-Oxo-1,3-diphenylpropyl)furan-2(5H)-one
(syn-5a) (from the Spectrum of an anti/syn Mixture). The
reaction crude was purified by column chromatography on
silica, using hexane/ethyl acetate 95:5 as an eluent. The
enantiomeric excess was determined by HPLC: Chiralpak AD-
H column, 245 nm, n-hexane/iPrOH 66:34, 0.5 mL/min, tR
1
syn1 = 14.5 min and tR syn2 = 16.9 min. H NMR (400 MHz,
CDCl3, 25 °C, TMS): δ = 7.90 (m, 2H), 7.52−7.11 (m, 9H),
5.77 (dd, J1 = 5.7 Hz, J2 = 2.1 Hz, 1H), 5.37 (m, 1H), 3.88 (m,
1H), 3.73 (dd, J1 = 18.0 Hz, J2 = 8.3 Hz, 1H), 3.37 (dd, J1 =
13.1 Hz, J2 = 5.0 Hz, 1H). 13C NMR (100 MHz, CDCl3, 25 °C,
TMS): δ = 197.8, 172.8, 155.2, 139.7, 137.2, 133.5, 128.9,
128.7, 128.3, 128.0, 127.6, 122.0, 84.3, 42.9, 40.1. HR-MS (ESI
+, of the anti/syn mixture): m/z (%): 293.1176 [M+−H].
Calcd. for C19H17O3: 293.1172.
(S*,S*)-5-(4-Oxo-4-phenylbut-2-yl)furan-2(5H)-one (anti-
5c) (from the Spectrum of an anti/syn Mixture). The reaction
crude was purified by column chromatography on silica, using
hexane/ethyl acetate 95:5 as an eluent. The enantiomeric
1
lectivity were determined by GC in the case of 3, and by H
NMR using mesitylene as a standard. In the case of 4 and 5a−
5e, the enantioselectivity was determined by high-pressure
liquid chromatography (HPLC), using chiral columns.
The products anti-4, anti-5a, anti-5b, syn-5b, and 5e were
identified according to data in the literature45,52,64 (see the
Supporting Information).
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ACS Catalysis
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excess was determined by HPLC: Chiralpak AD-H column, 210
nm, n-hexane/iPrOH 95:5, 1 mL/min, tR anti1 = 46.6 min and
tR anti2 = 50.3 min. 1H NMR (400 MHz, CDCl3, 25 °C, TMS):
δ = 7.89 (d, J = 8.3 Hz, 1H), 7.57−7.52 (m, 2H), 7.50−7.42
(m, 3H), 6.17 (dd, J1 = 5.7 Hz, J2 = 1.9 Hz, 1H), 5.05 (dt, J1 =
7.5 Hz, J2 = 1.8 Hz, 1H), 3.04 (dd, J1 = 17.5 Hz, J2 = 5.3 Hz,
1H), 2.85 (dd, J1 = 17.5 Hz, J2 = 7.3 Hz, 1H), 2.72−2.62 (m,
1H), 1.15 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3, 25
°C, TMS): δ = 198.1, 172.6, 155.3, 136.5, 133.2, 133.1, 128.5,
127.8, 127.1, 121.3, 86.7, 39.5, 32.4, 16.7. HR-MS (ESI+, of the
anti/syn mixture): m/z (%): 231.1016 [M+−H]. Calcd. for
C14H15O3: 231.1013.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jmfraile@unizar.es.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Spanish Ministerio de Economia y
Competitividad (Project No. CTQ2011-28124) and the
■
́
́
́
Diputacion General de Aragon (E11 Group cofinanced by
the European Regional Development Funds) is gratefully
acknowledged.
(R*,S*)-5-(4-Oxo-4-phenylbut-2-yl)furan-2(5H)-one (syn-
5c) (from the Spectrum of an anti/syn Mixture). The reaction
crude was purified by column chromatography on silica, using
hexane/ethyl acetate 95:5 as an eluent. The enantiomeric
excess was determined by HPLC: Chiralpak AD-H column, 210
nm, n-hexane/iPrOH 95:5, 1 mL/min, tR syn1 = 56.9 min and tR
syn2 = 61.9 min. 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ
= 7.94 (d, J = 8.1 Hz, 1H), 7.57−7.53 (m, 2H), 7.50−7.42 (m,
3H), 6.08 (m, 1H), 5.20 (m, 1H), 3.10 (dd, J1 = 17.6 Hz, J2 =
6.9 Hz, 1H), 2.94 (dd, J1 = 17.6 Hz, J2 = 6.5 Hz, 1H), 2.79−
2.73 (m, 1H), 0.88 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 198.3, 172.9, 155.2, 136.5, 133.2,
133.1, 128.5, 127.8, 127.1, 121.3, 86.7, 39.5, 32.4, 16.7.
(S*,S*)-5-(3-(2-Naphthyl)-3-oxo-1-phenylpropyl)furan-
2(5H)-one (anti-5d) (from the Spectrum of an anti/syn
Mixture). The reaction crude was purified by column
chromatography on silica, using hexane/ethyl acetate 95:5 as
an eluent. The enantiomeric excess was determined by HPLC:
Chiralpak IB column, 210 nm, n-hexane/iPrOH 85:5, 0.8 mL/
min, tR anti1 = 36.8 min and tR anti2 = 37.8 min. 1H NMR (400
MHz, CDCl3, 25 °C, TMS): δ = 8.41 (m, 1H), 8.03−7.84 (m,
4H), 7.60−7.53 (m, 2H), 7.39−7.22 (m, 6H), 6.09 (dd, J1 = 5.7
Hz, J2 = 1.9 Hz, 1H), 5.31 (dt, J1 = 7.5 Hz, J2 = 1.8 Hz, 1H),
3.78−3.73 (m, 1H), 3.63−3.58 (m, 2H). 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 197.7, 172.7, 155.6, 139.6, 135.7,
133.9, 132.4, 129.7, 129.5, 128.9, 128.6, 128.5, 128.3, 128.1,
127.7, 126.6, 122.0, 85.8, 44.5, 40.1. HR-MS (ESI+, of the anti/
syn mixture): m/z (%): 343.1261 [M+−H]. Calcd. for
C23H19O3: 343.1257.
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