Polytopic bis(oxazoline)-based ligands for recoverable catalytic systems applied to the enantioselective Henry reaction

Article abstract of DOI:10.1039/c5ob01033k

Several kinds of polytopic chiral ligands (including ditopic, tritopic and tetratopic), based on the bis(oxazoline) and azabis(oxazoline) motifs, have been tested in the preparation of recoverable catalytic systems for the Henry reaction. The results obta

Full text of DOI:10.1039/c5ob01033k

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Organic & Biomolecular Chemistry
PAPER
Polytopic bis(oxazoline)-based ligands for recoverable catalytic
systems applied to the enantioselective Henry reaction
Received 00th January 20xx,
Accepted 00th January 20xx
Beatriz Angulo, José I. García,* Clara I. Herrerías, José A. Mayoral and Ana C. Miñana
Several kinds of polytopic chiral ligands (including ditopic, tritopic and tetratopic), based on the bis(oxazoline) and
azabis(oxazoline) motifs, have been tested in the preparation of recoverable catalytic systems for the Henry reaction. The
results obtained with the different ligands are, in general, good, but they point to the existence of a delicate balance
between the coordinating ability of the ligand, the catalytic activity and the recovery of the catalyst by formation of the
coordination polymer, related to the easiness to form oligomeric species in solution.
DOI: 10.1039/x0xx00000x
www.rsc.org/
ligands to
a variety of organic reactions, such as the
Introduction
cyclopropanation reaction between styrene and ethyl
diazoacetate,18–20 the allylic oxidation of cycloalkenes with
tert-butyl perbenzoate,21 the
ketoesters,22 or the nitroaldolic Henry reaction between
aldehydes and nitro derivatives.23,24 Concerning the latter, only
two ditopic ligands were tested in our former work.23 The aim
of the current work is to explore the self-supported catalytic
possibilities of the family of polytopic ligands synthesized in
our group (Fig. 1) in nitroaldol reactions.
Asymmetric catalysis is one of the preferred methodologies to
obtain enantiomerically pure compounds. Nevertheless, chiral
catalysts are usually expensive and, therefore the
development of procedures for their easy recovery from the
reaction, allowing their reuse in further catalytic runs, has
become an interesting goal for both academia and industry.1 In
the past years a good number of strategies have been
proposed for the recycling and reuse of enantioselective
catalysts, including covalent and non-covalent bonding to solid
supports.2–7 However, given the drawbacks usually associated
with the use of chiral catalysts immobilized onto solid
α
-hydrazination of
β-
Results and discussion
supports, an appealing alternative consists of carrying out the Synthesis of polytopic ligands and preparation of coordination
catalysed reaction in homogeneous phase, and then selectively polymers
separating the catalyst and the product phases, allowing its
The synthesis of the polytopic ligands used in this work was
previously reported by our group.18–20,23 All the syntheses are
easy separation from the crude reaction and its reuse in
further cycles. Several methods have been described to
based on the condensation of the bis(oxazoline) or
accomplish this goal. For instance, the chiral ligand has been
azabis(oxazoline) moieties with different linking molecules.
tagged with either ionic8–10 or fluorous11,12 moieties to improve
Depending on the number of bis(oxazoline) moieties
its solubility in ionic liquids and fluorous solvents, respectively,
condensed in a single unit around the linker, ditopic, tritopic or
allowing easy product extraction in a second liquid phase.
tetratopic ligands are obtained. It is worth mentioning that the
Alternatively, selective precipitation of the catalyst to a solid
synthetic effort required to obtain these polytopic ligands is
phase has been accomplished by linking of the chiral ligand to
equivalent to that needed for the preparation of the analogous
a soluble polymer,5 self-supporting the catalytic complex
monotopic ligands used in conventional homogeneous
through intermolecular hydrogen bonding,13,14 and using
catalysis. In addition, the synthesis of all of these polytopic
coordination polymerization.15–17 In most cases, the
ligands is very efficient, reaching very good yields, even
precipitation of the catalyst after the reaction is achieved by
quantitative in some cases. For the preparation of the
adding a suitable solvent.
coordination polymers, copper was used as the ligand-
Our research group and others have described the
connecting metal. The copper salt chosen to this purpose was
application of the release-and-capture strategy using
Cu(OAc)2, since it provided excellent results in previously
reported nitroaldol reactions with related catalytic systems.23
coordination polymers of bis(oxazoline)-based polytopic
Acetate ion promotes the deprotonation of nitroalkanes,
avoiding the use of an additional base. Furthermore, the weak
coordinating ability of the acetate anion facilitates the
possibility of recruitment of two ligands by copper.
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Fig. 1 Structures of the chiral ligands used in this work.
Coordination polymers were formed by mixing the
corresponding polytopic ligand ( ) and Cu(OAc)2 in the
appropriate Cu/L molar ratio (Fig. 2). Thereby, for ditopic
ligands as DiBox ( ) and click-DAX ( ) a 1:1 molar ratio was
found to be optimal. In the case of the tritopic TAX ligand ( ),
3–6
3
4
5
the optimal ratio was 3:2 due to the presence of three
coordination sites per ligand. Finally, in the case of the
tetratopic click-QAX ligand (6), the optimal ratio for polymer
induction was found to be 2:1. An excess of copper in the
reaction media over the optimal amount could favour the
formation of shorter polymers, and even the presence in
solution of monomeric complexes, making catalyst
precipitation and recovery more complicated.
As mentioned in the Introduction, coordination polymers
are attractive for applications in catalysis since they combine
the advantages of both homogeneous and heterogeneous
catalysis. During the reaction, the polymer disassembles due to
competitive coordination of either the reactants or the
reaction solvent. The resulting soluble monomeric metal
complexes act as true homogeneous catalysts, leading to
results as good as those obtained using the traditional
homogeneous complexes. On other hand, when the catalytic
reaction has concluded, a simple change in the solvent can
promote the reassembly of the coordination polymer and his
subsequent precipitation. The resulting solid, which
constitutes the self-supported resting state of the catalyst, is
Fig. 2 Schematic representation of the self-assembled catalysts from the coordination
of copper cations with polytopic ligands. The optimal Cu:L ratio is highlighted.
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easily recoverable by simple liquid/solid separation DiBox(tBu)-Cu(OAc)2 complex, yields were similar to that
techniques.
obtained with the complex of the monotopic ligand 2a in the
first runs. The enantiomeric excess, however, was slightly
lower in the two first runs. When the catalyst was recovered
the enantioselectivity improved, reaching the same values as
those obtained with the monotopic ligand. This could indicate
that in the first two runs, there was free copper in the reaction
medium, that is, part of copper was not complexed with the
bis(oxazolines) moieties and then, the reaction was partially
catalysed in a non-enantioselective way. On the other hand,
reaction yields decreased after the sixth run. The recoverability
of this coordination polymer was fairly good, and it was
possible to recover it at least eight times without a significant
loss of enantioselectivity.
Catalytic studies
Trying to improve the recoverability of the catalytic systems
based on polytopic bis(oxazoline)-based ligands, three
different strategies were outlined. First, the use of ditopic
ligands with substituents different from isopropyl: DiBox
ligands (
substituents. Second, the use of a different ditopic ligand
bearing triazole units in the linker (click-DAX(iPr), ). Third, the
use of ligands with more than two coordination sites, i.e.
tritopic TAX(iPr) ( ) and tetratopic (click-QAX(iPr), ) ligands.
3) bearing tert-butyl (3a), phenyl (3b) and indanyl (3c)
4
5
6
Catalytic tests with DiBox ligands. The best results obtained in
our previous work on the Henry reaction catalysed by ditopic
ligands bearing bis(oxazoline) moieties were achieved with
DAX(iPr)-Cu(OAc)2 and DiBox(iPr)-Cu(OAc)2 complexes, using 4
mL of iPrOH.23 Yields over 75% and enantioselectivities around
70% ee were obtained in up to 11 consecutive runs in the case
of the DiBox(iPr)-Cu(OAc)2 complex, and over 90% yield and
90% ee in at least 11 runs in the case of using the DAX(iPr)-
Cu(OAc)2 as catalyst.23 Therefore, the evaluation of the
behaviour of the new ditopic ligands based on bis(oxazolines),
referred to as DiBox, was initially carried out using the same
reaction conditions for the reaction between o-anisaldehyde
and nitromethane.
Afterwards, DiBox(Ph)-Cu(OAc)2 was also tested as catalyst in
the same benchmark reaction. The corresponding results are
shown in Table 2.
Table 2 Henry reaction between o-anisaldehyde and nitromethane catalysed by
the complexes of Box(Ph) (2b) and DiBox(Ph) (3b) ligands with Cu(OAc)2.a
Entry
Ligand (L*)
Box(Ph)-Me2 (2b)
DiBox(Ph) (3b)
Run
—
1
Yield (%)b
% eec
19
1d
2
3
4
5
6
7
8
9
62
78
74
84
91
90
83
86
78
26
2
35
3
33
4
38
5
44
Table 1 Henry reaction between o-anisaldehyde and nitromethane catalysed by
the complexes of Box(tBu) (2a) and DiBox(tBu) (3a) ligands with Cu(OAc)2.a
6
38
7
37
8
40
a Reagents and conditions: o-anisaldehyde (1 mmol), nitromethane (10 mmol),
b
L*-Cu(OAc)2 (0.05 mmol, 5 mol %), i-PrOH (4 mL), room temperature, 24 h.
Yields were determined by 1H-NMR using an internal standard. c Enantiomeric
excesses were determined by HPLC using a Chiralcel OD-H column. (S)-1-(2-
d
methoxyphenyl)-2-nitroethanol was the major enantiomers in all cases.
Entry
Ligand (L*)
Run
—
1
Yield (%)b
% eec
84
Reaction carried out with 2 mL of i-PrOH.
1d
2
3
4
5
6
7
8
9
Box(tBu)-Me2 (2a)
DiBox(tBu) (3a)
55
50
67
60
50
55
33
32
26
71
As can be seen, yields from good to excellent were
obtained in all cases, even after eight runs, which indicates a
good recoverability of this catalyst. On the other hand modest
enantioselectivities were obtained with the Cu(II) complexes of
both monotopic and ditopic ligands. Nevertheless, the %ee is
significantly higher with the 3b-Cu(II) complex than with the
2b-Cu(II) complex.
2
73
3
91
4
89
5
93
6
78
7
76
8
87
a Reagents and conditions: o-anisaldehyde (1 mmol), nitromethane (10 mmol),
The last ditopic ligand tested was DiBox(In) (3c). Catalytic
results obtained with its corresponding copper complex in the
same benchmark reaction are collected in Table 3.
b
L*-Cu(OAc)2 (0.05 mmol, 5 mol %), i-PrOH (4 mL), room temperature, 24 h.
Yields were determined by 1H-NMR using an internal standard. c Enantiomeric
excesses were determined by HPLC using a Chiralcel OD-H column. (S)-1-(2-
The monotopic 2c-Cu(II) complex led to good values of
yield and enantioselectivity. In addition, when the reaction
was carried out with the complex 3c-Cu(II), the results
obtained were similar to those obtained with 2c-Cu(II), high
yields around 80% and from moderate to good
enantioselectivities. As happened with ligand 3a (Table 1),
enantiomeric excesses in the two first runs were lower,
improving throughout recoveries. In this case, it was possible
to recover the self-supported catalytic system at least seven
times, with a decreasing yield from the fifth run.
d
methoxyphenyl)-2-nitroethanol was the major enantiomer in all cases.
Reaction carried out with 2 mL of i-PrOH.
We started the study with the DiBox(tBu) ligand (3a), and
the catalytic results obtained with the corresponding Cu(II)
complex, including their recovery and reuse, are gathered in
Table 1. The results obtained with the corresponding
monotopic ligand (2a) have also been included for comparison.
When the complex with the monotopic ligand 2a was used
as catalyst,
a moderate yield (55%) and a fairly good
enantioselectivity (84%) were obtained. When using the
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Table 3 Henry reaction between o-anisaldehyde and nitromethane catalysed by
complexes of Box(In) (2c) and DiBox(In) (3c) ligands with Cu(OAc)2.a
with the latter complex. Recoverability in this case was poor;
up to three runs were performed with this catalytic system,
but yield dramatically decreased from 70% to 29% in the
second run.
Entry
Ligand (L*)
Box(In)-Me2 (2c)
DiBox(In) (3c)
Run
—
1
Yield (%)b
% eec
82
1d
2
3
4
5
6
7
8
92
67
88
84
73
79
42
38
With the 3b-Cu(OAc)2 complex, enantiomeric excesses and
anti/syn ratios obtained were comparable to the values
achieved with its homologous 2b-Cu(OAc)2 complex. However,
yields were significantly better. These results were maintained
during four runs.
60
2
67
3
71
4
76
5
80
6
86
Table 4 Henry reaction between o-anisaldehyde and nitroethane catalysed by
the complexes of Box-Me2(2a-c), Box(In)-Bn (8) and DiBox (3a-c) ligands with
Cu(OAc)2.a
7
75
a Reagents and conditions: o-anisaldehyde (1 mmol), nitromethane (10 mmol),
b
L*-Cu(OAc)2 (0.05 mmol, 5 mol %), i-PrOH (4 mL), room temperature, 24 h.
Yields were determined by 1H-NMR using an internal standard. c Enantiomeric
excesses were determined by HPLC using a Chiralcel OD-H column. (S)-1-(2-
d
methoxyphenyl)-2-nitroethanol was the major enantiomers in all cases.
Reaction carried out with 2 mL of i-PrOH.
Yield
(%)b
13
70
29
28
49
80
72
70
60
94
34
86
95
85
77
64
62
64
47
50
80
40
89
75
69
%ee
%ee
Entry
Ligand (L*)
Run
Anti/Syn
(anti)c,d (syn)c,e
As a general remark of this first series of experiments, the
1f
2
Box(tBu)-Me2 (2a)
DiBox(tBu) (3a)
—
1
92/8
89
63
65
68
19
16
39
13
43
49
15
66
62
66
70
72
74
74
72
73
70
72
71
70
70
9
results obtained with copper complexes of DiBox ligands (
did not outperform those obtained in our previous work with
DAX(iPr)-Cu(OAc)2 (
, Fig. 3) complexes,23 especially respecting
3)
62/38
63/37
63/37
57/43
59/41
67/33
59/41
68/32
58/42
61/39
72/28
65/35
67/33
69/31
70/30
71/29
71/29
72/28
72/28
70/30
72/28
66/34
67/33
67/33
70
76
74
42
46
54
52
61
90
80
78
79
77
78
80
81
82
77
77
76
75
74
72
72
7
3
2
4
5f
3
recoverability, which could be extended at best up to eight
reaction cycles.
Box(Ph)-Me2 (2b)
DiBox(Ph) (3b)
—
1
6
7
2
8
3
9
4
10f
11f
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Box(In)-Me2(2c)
Box(In)-Bn (8)
DiBox(In) (3c)
—
—
1
2
3
Fig. 3 Structure of DAX(iPr) ligand.
4
5
Next, the evaluation of the new ligands was extended to
the reaction between o-anisaldehyde and nitroethane, which
allows studying both enantioselectivity and syn/anti
diastereoselectivity. The results obtained are gathered in Table
4. In the case of the indanyl-substituted ligand 3c, we also
6
7
8
9
10
11
12
13
14
include the results obtained with the monotopic ligand
8 for
the sake of comparison (Fig. 4). The rationale behind the
introduction of a single benzyl group in the bis(oxazoline)
bridge was to make the structure of the monotopic ligand
closer to that of the homologous ditopic ligand.
a
Reagents and conditions: o-anisaldehyde (1 mmol), nitroethane (10 mmol), L*-
Cu(OAc)2 (0.05 mmol, 5 mol %), i-PrOH (4 mL), room temperature, 24 h. b Yields
were determined by 1H-NMR using an internal standard. c Enantiomeric excesses
d
were determined by HPLC using
a
Chiralpak AD-H column. (1S,2R)-1-(2-
e
methoxyphenyl)-2-nitropropan-1-ol was the major enantiomer. (1S,2S)-1-(2-
methoxyphenyl)-2-nitropropan-1-ol was the major enantiomer. f Reactions carried
out with 2 mL of i-PrOH.
On the other hand, the 3c-Cu(OAc)2 complex afforded
yields and enantiomeric excesses at least as good as those
obtained with 2c-Cu(OAc)2, satisfactory in the case of yields
(70±16.7% average yield) and fairly good in case of
enantiomeric excesses of the anti and syn diastereomers
(average values of 70±3.4% ee and 77±3.0% ee, respectively, in
14 reaction cycles). Slightly better anti/syn diastereo-
selectivities were obtained with the ditopic ligand with regard
Fig. 4 Structure of ligand 8, a monobenzylated Box(In).
Regarding the 3a-Cu(OAc)2 complex, both yield (70%) and
enantioselectivity of the syn diastereomer (70% ee) were
noticeably improved in comparison with 2a-Cu(OAc)2.
However, anti/syn ratio (98/2) and %ee anti (89%) were better
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to the monotopic one (2c). Recoverability according to the complex in the reaction between o-anisaldehyde and
release and capture strategy with 3c was excellent, and the nitromethane are gathered in Table 5.
catalyst could be reused up to 14 runs without a dramatic
As can be seen, the use of the complex 4-Cu(OAc)2
decrease of yield, diastereo- or enantioselectivity. These provided excellent results in both yield and enantioselectivity
results clearly outperform those previously described with the (96% and 91%, respectively). These results were comparable to
DAX(iPr) ligand
7 (57±16.8% average yield, and 61±11.7% and those obtained with the complex with the monotopic ligand 1-
88±3.8% ee average anti and syn enantioselectivities in 8 Cu(OAc)2. Recoverability of the catalyst was excellent as well; it
reaction cycles).23
could be recovered by formation of the insoluble coordination
It is worth noting that the monotopic ligand
8, which has a polymer up to 12 runs without loss of enantioselectivity, and
chemical structure closer to 3c, leads to significantly worse with only a slight decrease in yield after ninth cycle. This drop
results of yield and anti enantioselectivity, so correlations in yield was probably due to small losses of chiral complex in
between the structural features of the chiral ligand and the the reaction handling, necessary for catalyst recovery. In order
reaction results are not straightforward.
to verify this hypothesis, an additional 0.2% mol of 4-Cu(OAc)2
Catalytic tests with the click-DAX ligand. It has been complex was added in the 12th run, and as can be seen in entry
demonstrated that bis(oxazoline) and azabis(oxazoline) ligands 13 of Table 5, an important improvement in the yield, reaching
have different coordinating abilities towards copper.25–28 the values obtained in the first runs, was immediately
Azabis(oxazoline)-copper complexes are stronger than their observed, which corroborates the above hypothesis. Overall,
analogous bis(oxazoline)-copper complexes. As a consequence, this ligand displays comparable performance to that from
the recoverability of the coordination polymers formed with DAX(iPr) ligand,23 with slightly better average yield (92±1.8%
azabis(oxazoline) moieties is better, since the coordination vs. 87±4.8%) and slightly lower enantioselectivity (83±11.1%
equilibrium is more shifted towards the complex.
vs. 87±6.3% ee).
In view of the good results of yield and enantioselectivity
Table 5 Henry reaction between o-anisaldehyde and nitromethane catalysed by
complexes of Azabox(iPr)-Me (1) and Click-DAX(iPr) (4
) ligands with Cu(OAc)2.a
obtained with the complex 4-Cu(OAc)2, we decided to evaluate
the scope of the Henry reaction using this catalyst. We carried
out several experiments with other substrates, and the results
are collected in Table 6.
Entry
1d
2
Ligand (L*)
Run
—
1
Yield (%)b
93
% eec
94
91
90
90
94
94
94
93
92
90
90
90
90
Azabox(iPr)-Me (1)
Click-DAX(iPr) (4)
96
Table 6 Henry reaction between several aromatic aldehydes and nitromethane
3
2
95
catalysed by complexes of Azabox(iPr)-Me (
Cu(OAc)2.a
1) and Click-DAX(iPr) (
4) ligands with
4
3
95
5
4
94
6
5
90
7
6
80
8
7
80
Yield (%)b
% eec
94
91
90
74
89
89
90
90
92
46
90
91
9
8
78
Entry
1d
Ligand (L*)
R
10
11
12
13e
9
75
Azabox(iPr)-Me (1) o-MeO
93
92
40
76
75
68
10
11
12
70
2d
H
3d
p-MeO
p-NO2
p-Cl
65
4d
95
5d
a Reagents and conditions: o-anisaldehyde (1 mmol), nitromethane (10 mmol),
6d
p-Me
b
L*-Cu(OAc)2 (0.05 mmol, 5 mol %), i-PrOH (4 mL), room temperature, 24 h.
Yields were determined by 1H-NMR using an internal standard. c Enantiomeric
7e
Click-DAX(iPr) (4)
o-MeO
52
36
20
29
40
34
8e
H
excesses were determined by HPLC using a Chiralcel OD-H column. (S)-1-(2-
d
9e
p-MeO
p-NO2
p-Cl
methoxyphenyl)-2-nitroethanol was the major enantiomers in all cases.
Reaction carried out with 2 mL of i-PrOH. e Adding 0.2% mol of Cu-4 complex.
10e
11e
12e
p-Me
Having in mind the improvement of results and
recoverability obtained with the DAX(iPr) ligand, we carried
out the abovementioned Henry reactions using other polytopic
ligands bearing azabis(oxazoline) moieties. Azabis(oxazoline)-
copper complexes containing triazole linkers have been found
to be less soluble in organic solvents and to readily precipitate.
This feature could favour the recovering of the coordination
polymer, so we started this study by using a ditopic ligand in
which the connecting unit between the azabisoxazoline
a
Reagents and conditions: aldehyde (1 mmol), nitromethane (10 mmol), L*-
Cu(OAc)2 (0.05 mmol, 5 mol %), i-PrOH (4 mL), room temperature, 24 h. b Yields
were determined by 1H-NMR using an internal standard. Enantiomeric
c
excesses were determined by HPLC using Chiralcel OD-H and Chiralpak IB
columns. (S)-product was the major enantiomer in all cases.23 d Reaction carried
e
out with 2 mL of i-PrOH at room temperature. Reaction carried out at
controlled temperature (20 ºC).
In this Table we have also included the results obtained
moieties has two triazole groups, named as click-DAX(iPr) (
4).
with all the substrates using the ligand Azabox(iPr) (1) for
comparison, which we reported in a previous article.23 It has to
The coordination polymer 4-Cu(OAc)2 was proved to
precipitate considerably faster than his analogous 7-Cu(OAc)2
in non-coordinating solvents.19 The results obtained with this
be mentioned that the reactions promoted by
to be conducted at controlled temperature (20
4
-Cu(OAc)2 had
º
C) since room
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temperature those days in our laboratory was higher than 35 monotopic ligand,
ARTICLE
1
-Cu(OAc)2. From the fourth run,
º
C, and we noticed a significant effect on the results, especially enantioselectivity values were recovered as in precedent
on the enantioselectivity. It can be seen (Table 6) that in these cases.
conditions, the enantioselectivities obtained with -Cu(OAc)2 Catalyst recoverability with this complex was fairly good,
are very similar to those reached with the -Cu(OAc)2 complex and 12 catalytic runs could be achieved with yields better than
4
1
as we also observed in Table 5 for the reaction with o- those obtained with the classical homogeneous complex. On
1
anisaldehyde. Yields were relatively lower but in the H-NMR the other hand, enantiomeric excesses were slightly lower, and
experiments no by-products were detected, only the reaction clearly decreased after the eleventh run. Overall, these results
product and the starting aldehyde, which indicates that the are better than those obtained with the DAX(iPr) ligand in the
reactions at 20
values to those obtained with
reported by other authors.9 Overall, the results showed that Catalytic tests with TAX and click-QAX ligands. In our previous
the catalytic system formed by -Cu(OAc)2 can be successfully studies about the use of the release-capture strategy through
º
C need more than 24 hours to reach similar same reaction,23 with better average yield and comparable
1
-Cu(OAc)2, as previously enantioselectivities.
4
applied to the Henry reaction with other aromatic aldehydes. the formation of coordination polymers, we found that the use
The position of the substituent in the aromatic ring of the of ligands with more than two azabis(oxazoline) units
aldehydes shows an influence in the activity of the catalyst; improved recoverability of the catalyst, probably due to easier
the change of a methoxy group from an ortho to a para formation of the polymer at the end of the reaction.23 Because
position reduces significantly the yield (Table 6, entries 7 and of that, we continued our study with the copper complexes of
9). There is not a clear rationale for the fluctuations observed, TAX(iPr)
(5), a tritopic ligand, and click-QAX(iPr) (6), a
as other authors showed in similar studies.9 Variations in tetratopic one. The results of the reactions between o-
enantioselectivity seem to be less dependent on the aromatic anisaldehyde and nitromethane, catalysed by the
substitution, and only the p-NO2 derivative showed a lower complex are shown in Table 8.
selectivity, a fact also observed in similar studies.9,29
5-Cu(OAc)2
Table 8 Henry reaction between o-anisaldehyde and nitromethane catalysed by
complexes of Azabox(iPr)-Me (
1
) and TAX(iPr) (
5
) ligands with Cu(OAc)2.a
Next, we studied the behaviour of the same catalyst in the
reaction between o-anisaldehyde and nitroethane. The
corresponding results are gathered in Table 7.
Entry
1d
2
Ligand (L*)
Run
Yield (%)b
% eec
Azabox(iPr)-Me (1)
TAX(iPr) (5)
—
1
93
71
82
80
76
79
65
53
18
16
8
94
91
90
90
88
87
82
82
80
79
78
Table 7 Henry reaction between o-anisaldehyde and nitroethane catalysed by
) ligands with Cu(OAc)2.a
3
2
complexes of Azabox-Me (
1) and Click-DAX(iPr) (
4
4
3
5
4
Yield
Run
%ee
%ee
Entry
Ligand (L*)
Anti/Syn
(%)b
(anti)c,d (syn)c,e
6
5
7
6
1f
2
Azabox(iPr)-Me (1)
Click-DAX(iPr) (4)
—
1
47
98
88
70
80
65
62
60
65
78
78
73
73
57/43
72/28
69/31
57/43
63/37
62/38
63/37
62/38
64/36
62/38
59/41
61/39
64/36
77
8
91
54
57
54
65
66
83
86
86
84
84
64
52
8
7
9
8
3
2
22
47
71
72
73
74
63
60
50
44
43
10
11
9
4
3
10
5
4
a Reagents and conditions: o-anisaldehyde (1 mmol), nitromethane (10 mmol),
6
5
b
L*-Cu(OAc)2 (0.05 mmol, 5 mol %), i-PrOH (4 mL), room temperature, 24 h.
Yields were determined by 1H-NMR using an internal standard. c Enantiomeric
7
6
8
7
excesses were determined by HPLC using a Chiralcel OD-H column. (S)-1-(2-
9
8
d
methoxyphenyl)-2-nitroethanol was the major enantiomers in all cases.
10
11
12
13
9
Reaction carried out with 2 mL of i-PrOH.
10
11
12
Catalyst
reaction studied, leading to high enantioselectivities, similar to
those obtained with the -Cu(OAc)2 complex, and with the
previously reported -Cu(OAc)2 complex. Yields were good,
5-Cu(OAc)2 performed well in the nitroaldol
a Reagents and conditions: o-anisaldehyde (1 mmol), nitroethane (10 mmol), L*-
Cu(OAc)2 (0.05 mmol, 5 mol %), i-PrOH (4 mL), room temperature, 24 h. b Yields
were determined by 1H-NMR using an internal standard. c Enantiomeric excesses
1
7
d
were determined by HPLC using
a
Chiralpak AD-H column. (1S,2R)-1-(2-
over 70% in the first five runs, but displayed a progressive
decrease in the following reactions, droping to 8% in the tenth
e
methoxyphenyl)-2-nitropropan-1-ol was the major enantiomer. (1S,2S)-1-(2-
f
methoxyphenyl)-2-nitropropan-1-ol was the major enantiomer. Reactions
run. As we previously discussed in case of the
4-Cu(OAc)2
carried out with 2 mL of i-PrOH.
complex, this diminishing of yield may be attributed to a loss
of complex during the recovery of the catalyst.
Enantioselectivity was kept nearly constant for five runs as
well, and then a slight decrease was also observed in
subsequent runs (average value of 85±5.0% ee in 10 reaction
cycles). Contrary to our expectations, the recoverability of
In this case, with the
4
-Cu(OAc)2 complex yields were much
higher as compared with that obtained with the
1-Cu(OAc)2
complex. We were able to reach 98% yield and a good
diastereoselectivity anti/syn in the first run (72/28). However,
during the first three runs, enantioselectivity was worse as
compared with that obtained using the complex with the
catalytic
5
-Cu(OAc)2 complex was not improved compared to
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that of the complex of the equivalent ditopic ligand DAX(iPr) the reaction yield. As this experiment represented the 12th run
).23
conducted with the same catalyst sample, the poor yield
Table 9 shows the results obtained in the reaction of o- obtained could also be ascribed to catalyst losses along the
anisaldehyde with nitroethane, catalysed by the -Cu(OAc)2 consecutive recoveries, as mentioned previously. In these
complex. As can be seen, good yields were achieved in up to conditions, even if the disassembly of the polymer had
12 runs, better than those obtained with -Cu(OAc)2. However, increased, the amount of catalytically active species in reaction
as happened in case of click-DAX(iPr) ligand ), the media would not be enough to warrant a high yield in the
enantioselectivities were somewhat lower than those obtained same reaction time. Hence, an additional 0.25% mol of Cu-
with the complex of the monotopic Azabox(iPr) ligand ( ).
complex was added in the 13th run. As can be seen in entry 14
(
7
5
1
(
4
6
1
(Table 10), although enantioselectivity was as good as in all
previous cases, yield was not substantially improved (50%).
Table 9 Henry reaction between o-anisaldehyde and nitroethane catalysed by
complexes of Azabox-Me ( ) and TAX(iPr) (
) ligands with Cu(OAc)2.a
1
5
Table 10 Henry reaction between o-anisaldehyde and nitromethane catalysed by
Yield
(%)b
47
%ee
%ee
Entry
Ligand (L*)
Run
Anti/Syn
the complexes of Azabox(iPr)-Me
Cu(OAc)2.a
(
1
)
and Click-QAX(iPr)
(
6
)
ligands with
(anti)c,d (syn)c,e
1f
2
Azabox(iPr)-Me (1)
TAX(iPr) (5)
—
1
57/43
64/36
56/44
55/45
55/45
57/43
63/38
67/31
53/47
58/42
55/45
56/44
58/42
77
18
31
60
63
68
65
67
59
65
56
46
49
91
53
73
70
76
85
84
82
80
73
75
73
69
88
Entry
1d
Ligand (L*)
Run
—
1
Yield (%)b
93
% eec
94
92
91
90
92
91
89
90
89
89
90
89
87
86
80
94
91
3
2
85
Azabox(iPr)-Me (1)
Click-QAX(iPr) (6)
4
3
80
2
51
5
4
75
3
2
68
6
5
73
4
3
68
7
6
60
5
4
71
8
7
70
6
5
69
9
8
77
7
6
75
10
11
12
13
9
73
8
7
76
10
11
12
69
9
8
69
65
10
11
12
13e
14f
15g
16g
17h
9
60
65
10
11
12
13
1
54
64
a Reagents and conditions: o-anisaldehyde (1 mmol), nitroethane (10 mmol), L*-
Cu(OAc)2 (0.05 mmol, 5 mol %), i-PrOH (4 mL), room temperature, 24 h. b Yields
were determined by 1H-NMR using an internal standard. c Enantiomeric excesses
46
50
d
70
were determined by HPLC using
a
Chiralpak AD-H column. (1S,2R)-1-(2-
e
2
50
methoxyphenyl)-2-nitropropan-1-ol was the major enantiomer. (1S,2S)-1-(2-
f
methoxyphenyl)-2-nitropropan-1-ol was the major enantiomer. Reactions
1
80
carried out with 2 mL of i-PrOH.
a Reagents and conditions: o-anisaldehyde (1 mmol), nitromethane (10 mmol),
b
L*-Cu(OAc)2 (0.05 mmol, 5 mol %), i-PrOH (4 mL), room temperature, 24 h.
Yields were determined by 1H-NMR using an internal standard. c Enantiomeric
Finally, we tested the use of a tetratopic ligand, namely
excesses were determined by HPLC using a Chiralcel OD-H column. (S)-1-(2-
click-QAX(iPr) (6). The 6-Cu(OAc)2 complex was used as catalyst
d
methoxyphenyl)-2-nitroethanol was the major enantiomers in all cases.
in the nitroaldol Henry reaction between nitromethane and o-
anisaldehyde, and the corresponding results are shown in
Table 9. Due to the structural resemblance between this
Reaction carried out with 2 mL of i-PrOH. e Reactions carried out with 6 mL of i-
PrOH. f Adding 0.25% mol of fresh 6-(OAc)2 complex. g Reaction was carried out
with a 1:3 ligand/copper proportion. h Reactions carried out with fresh catalyst
and 6 mL of i-PrOH.
molecule and click-DAX(iPr) (4), results with the 6-Cu(OAc)2
complex should be expected to be comparable to those
obtained with its analogous ditopic ligand (Table 5). In fact,
For the optimal preparation of the coordination polymer
enantioselectivities were as good as those obtained with
Cu(OAc)2. On the other hand, yields obtained were somewhat
lower (average value of 66±8.0% in eleven runs with
Cu(OAc)2 vs. 83% with -Cu(OAc)2). This fact might be due to
4-
with the tetratopic ligand click-QAX(iPr) (6), a ligand/copper
ratio of 1:2 was used. However, a larger amount of copper
could be utilized to favour the disassembly of the polymer and
in this way, increase the reaction yield. Then, the reaction was
carried out with a 1:3 ligand/copper ratio. The results of these
experiments are shown in entries 15 and 16 of Table 10. In the
first run (entry 15), yield increased to 70% but, on the
contrary, enantioselectivity decreased to 80%, probably
indicating the presence of free copper in solution catalysing
the reaction in a non-enantioselective way. In the second run
(entry 16), free copper seems to have been extracted during
catalyst recovery, so the enantiomeric excess increased to
values as good as those obtained using a 1:2 ligand/copper
ratio for the preparation of the complex. Regrettably, yield
6-
4
an incomplete disassembly of the coordination polymer in the
reaction conditions, because of the complexity of the
polymeric structure in this case, which would lead to a lower
concentration of catalytically active species in solution.
To verify this hypothesis, several experiments were carried
out in different conditions. Firstly, an additional run was
carried out (entry 13 in Table 10), but using 6 mL of i-PrOH, the
reaction solvent. As we proved in our previous work,23 an
increase in solvent concentration in the reaction media is able
to shift the polymer assembly-disassembly equilibrium
towards the monomeric species, the one catalytically active.
Unfortunately, this change did not result in an improvement of
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decreased again to the same value as that obtained in the 13th
run (50%).
Experimental
General Methods
According to the experience acquired working with
coordination polymers, the obtaining of moderate yields
indicates an incomplete release of catalytically active species
due to partial decomplexation of the coordination polymer.
For this reason, one more experiment was conducted using 6
mL of iPrOH, but using freshly prepared catalyst in this case.
The results of this experiment are shown in entry 17 of Table
10. This time not only the enantiomeric excess was good (91%
ee), but yield also increased with regard to the previous values
(80% vs. 66% average yield), although without achieving the
good results obtained with the click-DAX(iPr) ligand (96% in
the first run, Table 5).
All reactions were carried out under argon atmosphere in
oven-dried glassware. Anhydrous solvents such as
dichloromethane, hexane and Et2O were obtained from a SPS-
device; however, i-PrOH was distilled from calcium hydride.
Liquid o-anisaldehyde was obtained from different commercial
sources and distilled before use. EtNO2 was distilled from
potassium carbonate. The rest of purchased reagents were
used as received without further purification. All the ligands
used in this work were prepared according to literature
procedures.18–20,23 The chemical shifts were relative to TMS as
an internal reference for 1H NMR.
General Procedure for Henry Reactions Promoted by Monotopic
Azabis(oxazoline) or Bis(oxazoline)−copper Complexes
Conclusions
A solution of Cu(OAc)2 (9.07 mg, 0.05 mmol) and the
A family of polytopic chiral ligands, based on the bis(oxazoline)
motif, have been tested in the reactions of o-anisaldehyde
with nitromethane and nitroethane, catalysed by the Cu(OAc)2
complexes of these ligands. In all cases, the release−capture
strategy for the recovery and reuse of enantioselective
catalysts, based on the precipitation of an insoluble
coordination polymer at the end of each reaction, has been
shown to be effective, allowing up to fourteen catalyst uses in
the best case. Given the wide structural diversity of the ligands
used, these results support the generality of this catalyst
recycling strategy.
corresponding monotopic ligand (1, 2a, 2b or 2c) (0.055 mmol)
in 2 mL of anhydrous dichloromethane was stirred at room
temperature for 30 min. Then the mixture was microfiltered to
eliminate the remaining Cu(OAc)2. Afterwards, the
dichloromethane was removed under vacuum, and 2 mL of
anhydrous isopropyl alcohol together with o-anisaldehyde (1
mmol) and the nitroderivative (10 mmol) were added. The
reaction solution was stirred at room temperature for 24 h,
and then it was filtered through a silica pad to eliminate the
catalyst. After that, the silica pad was washed with
dichloromethane, and the resulting solution was concentrated
under vacuum. Yield was determined by 1H-NMR using
mesitylene as internal standard. Enantiomeric excesses were
Compared with the results previously described with the
DAX(iPr) ditopic ligand, improved performance has been
obtained with the click-DAX(iPr) ditopic ligand in the reactions
with nitromethane, and with the DiBox(In), click-DAX(iPr) and
TAX(iPr) ligands in the reactions with nitroethane. In particular,
the DiBox(In)-Cu(OAc)2 complex has been used in 14 reaction
determined by HPLC using
a chiral column. Specific
chromatographic conditions, retention times, and some typical
chromatograms have been described elsewhere.23
General Procedure for Henry Reactions Promoted by Politopic
Azabis(oxazoline) or Bis(oxazoline)−copper Complexes
cycles without
a clear decrease in yield and enantio-
selectivities, which compares favourably with the 8 reaction
cycles achieved with the DAX(iPr) ligand. It is worth noting that A solution of Cu(OAc)2 (9.07 mg, 0.05 mmol) and either the
the results obtained with these polytopic ligands are corresponding ditopic ligand (3a 3b 3c or ) (0.055 mmol),
significantly better than those recently reported by Bellemin- tritopic ligand ( ) (0.037 mmol) or tetratopic ligand ( ) (0.027
,
,
4
5
6
Laponnaz and co-workers, using analogous DiBox-, TriBox- and mmol) in 4 mL of anhydrous isopropyl alcohol was stirred at
TetraBox-Cu(AOc)2 complexes in the reaction of o- room temperature for 30 min. Afterwards, the corresponding
nitrobenzaldehyde with nitromethane.24
aldehyde (1 mmol) and the nitroderivative (10 mmol) were
In the case of the tetratopic QAX(iPr) ligand, the easiness of added. The resulting solution was stirred at room temperature
the formation of coordination polymeric and oligomeric for 24 h and then concentrated under vacuum. The residue
species, tough desirable for catalyst recovery, is detrimental was extracted with an anhydrous mixture of hexane/Et2O (1:1)
for the catalytic activity, because of the decrease of (3 × 2 mL) in order to separate the products from the solid
catalytically active species in solution. This drawback can be polymer, which had already precipitated. The polymer was
overcome by increasing the dilution of the catalyst in the then dried under argon atmosphere. Under these conditions,
reaction medium. Nevertheless, given the good results the catalyst was ready to be used again in a new reaction by
obtained with the analogous and simpler ditopic ligand click- adding new portions of solvent and reagents. The product
DAX(iPr), this should be the logical choice for practical solution was concentrated under vacuum, and the
applications.
determination of the results was carried out as described
previously.
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22 M. Torres, A. Maisse-François and S. Bellemin-Laponnaz,
ChemCatChem, 2013, 5, 3078–3085.
Acknowledgements
Financial support from the Spanish MINECO (project CTQ2011-
28124-C02-01, the European Social Fund (ESF) and the
Gobierno de Aragón (Grupo Consolidado E11) is gratefully
acknowledged.
23 B. Angulo, J. I. García, C. I. Herrerías, J. A. Mayoral and A. C.
Miñana, J. Org. Chem., 2012, 77, 5525–5532.
24 M. Torres-Werlé, A. Nano, A. Maisse-François and S. Bellemin-
Laponnaz, New J. Chem., 2014, 38, 4748–4753.
25 J. M. Fraile, J. I. Garcia, C. I. Herrerias, J. A. Mayoral, O. Reiser,
A. Socuellamos and H. Werner, Chem.- Eur. J., 2004, 10, 2997–
3005.
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