Polytopic bis(oxazoline)-based ligands for the development of recoverable catalytic systems applied to the cyclopropanation reaction

Article abstract of DOI:10.1002/ejoc.201301510

New ditopic and tetratopic chiral ligands, based on the bis(oxazoline) moiety, have been synthesized and their copper complexes tested as catalysts in the benchmark asymmetric cyclopropanation reaction of styrene with ethyl diazoacetate. The polytopic nature of these ligands enables a release-capture strategy to efficiently recycle the enantioselective catalyst by precipitation of a coordination polymer at the end of the reaction. This strategy enables the self-supported catalyst to be reused up to 20 times leading to good yields and enantioselectivities. The use of polytopic chiral ligands complexes enables efficient recovery of reaction catalyst through precipitation by polymerization following cyclopropanation reactions. The catalyst can then be reused in further reaction cycles with excellent results. Copyright

Full text of DOI:10.1002/ejoc.201301510

FULL PAPER
DOI: 10.1002/ejoc.201301510
Polytopic Bis(oxazoline)-Based Ligands for the Development of Recoverable
Catalytic Systems Applied to the Cyclopropanation Reaction
José I. García,*[a] Jaime Gracia,[a] Clara I. Herrerías,*[a] José A. Mayoral,[a]
Ana C. Miñana,[a] and Carlos Sáenz[a]
Keywords: Coordination polymers / Copper / Polytopic ligands / Self-supported catalysts / Enantioselectivity /
Polymerization
New ditopic and tetratopic chiral ligands, based on the bis-
(oxazoline) moiety, have been synthesized and their copper
complexes tested as catalysts in the benchmark asymmetric
cyclopropanation reaction of styrene with ethyl diazoacetate.
ture strategy to efficiently recycle the enantioselective cata-
lyst by precipitation of a coordination polymer at the end of
the reaction. This strategy enables the self-supported catalyst
to be reused up to 20 times leading to good yields and
The polytopic nature of these ligands enables a release–cap- enantioselectivities.
We recently described the synthesis of several ditopic
(DAX, 2a and 2b) and tritopic (TAX, 3a and 3b) chiral
Introduction
Asymmetric catalysis is the most efficient method by ligands based on azabis(oxazoline), as well as a ditopic one
which to obtain enantiomerically pure compounds. How- bearing chiral bis(oxazoline) units (iPrDiBox) (2d) (Fig-
ever, chiral catalysts are usually expensive and, in many ure 1). These ligands were applied to the preparation of
cases, contain toxic metals. As a consequence, the easy sep- copper coordination polymers in order to promote a diver-
aration of such catalysts from their reaction products in sity of organic reactions in an enantioselective way, such
such a way as to avoid metal contamination, and their reuse as cyclopropanation of alkenes with ethyl diazoacetate,[12,13]
in further catalytic runs, increasing their productivity, has Henry or nitroaldol reactions,[14] and Kharasch–Sosnovsky
become an interesting goal from both academic and indus- allylic oxidation of cycloalkenes with peroxo esters.[15,16]
trial points of view.[1] In recent years growing interest has The application of a release–capture strategy allowed selec-
focused on the recycling and reuse of enantioselective cata- tive precipitation of the polymers after reaction completion
lysts using a variety of strategies.[2–7]
and product extraction by use of a non-coordinating sol-
Given the drawbacks usually associated with the use of vent. The polymer could then be recovered and reused in
chiral catalysts immobilized onto solid supports, an inter- subsequent reactions with good results.
esting alternative strategy involves carrying out the cata-
lyzed reaction in homogeneous phase, and then selectively
precipitating the catalyst, allowing its easy separation from
the crude reaction and subsequent reuse in consecutive re-
actions. Several methods have been described to accomplish
this goal. These include; a) linking of the chiral ligand to a
soluble polymer,[5] b) self-supporting the catalytic complex
through intercatalyst hydrogen bonding,[8,9] and c) coordi-
nation polymerization.[10,11] In most cases, selective precipi-
tation of the catalyst after the reaction is achieved by ad-
dition of a suitable solvent.
This strategy has the additional advantages of not requir-
ing chemical modification of the chiral ligand (simplifying
its synthesis and avoiding possible erosion of enantioselec-
tive capability) and of circumventing the use of an ad-
ditional support since the coordination polymer is self-sup-
porting.
In this work, we report the use of several monotopic,
ditopic and tetratopic bis(oxazoline)- and azabis(oxaz-
oline)-based ligands (Figure 1), including the three new di-
topic ligands tBuDiBox (2c), PhDiBox (2e) and InDiBox
(2f) and two new tetratopic ligands click-tBuQAX (4a) and
click-iPrQAX (4b) for the preparation of copper complexes
that are subsequently used as homogeneous catalysts in the
cyclopropanation of styrene with ethyl diazoacetate
(Scheme 1), the benchmark representative for cyclopropan-
ation chemistry. Copper complexes can then be separated
from the reaction medium by precipitation of the corre-
sponding coordination polymers [(L*Cu X2)n] at the end of
the reaction.
[a] Departamento de Catálisis y Procesos Catalíticos, Instituto de
Síntesis Química y Catálisis Homogénea (ISQCH)
(CSIC-Universidad de Zaragoza),
50009 Zaragoza, Spain
E-mail: jig@unizar.es
clarah@unizar.es
http://www.unizar.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301510.
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Figure 1. Structures of the different monotopic and polytopic chiral ligands.
Alternatively, ligands 4, referred to as click-QAX, were
obtained following a click chemistry synthetic strategy al-
ready established in our group for the synthesis of click-
DAX ditopic ligands.[13] A similar strategy has been applied
to link azabis(oxazolines) to polymeric, dendrimeric, and
inorganic supports.[17–20] Copper-catalyzed [3 + 2] cycload-
dition[21–23] between 5 and 0.25 equiv. of 1,3-diazido-2,2-
Scheme 1. Cyclopropanation reaction between styrene and ethyl di-
azoacetate.
bis(azidomethyl)propane afforded
4
in good yield
(Scheme 2). Complete characterization data for these new
ligands prepared for this work are available in the Support-
ing Information.
Results and Discussion
It is worth mentioning that the synthesis of all these po-
lytopic ligands was very efficient and that the synthetic ef-
fort required for their preparation is equivalent to that
needed for the preparation of their counterpart monotopic
ligands used in traditional homogeneous catalysis.
Design and Synthesis of the Ligands
We started our study by synthesizing new polytopic li-
gands based on bis(oxazoline) and azabis(oxazoline) moie-
ties. In the context of DiBox ligands, the synthesis of
iPrDiBox (2d) had been previously reported by our
group;[14] similar synthetic schemes were applied for the
preparation of corresponding tBuDiBox (2c), PhDiBox (2e)
and InDiBox (2f). These ligands were prepared by conden-
Formation of the Coordination Polymers
For the preparation of the coordination polymer, copper
sation of two moieties of the corresponding bis(oxazoline), was used both as the point of ligand connection and as the
following deprotonation with one equivalent of tBuOK and catalytically active metal. Specifically Cu(OTf)2 was chosen
subjection to α,αЈ-dibromo-p-xylene (Scheme 2).
since this copper salt has provided excellent results in the
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Use of Polytopic Ligands in Cyclopropanation
Scheme 2. Synthesis of the different polytopic ligands: DiBox y click-QAX.
cyclopropanation reaction between styrene and ethyl diazo- was found to be different when forming the polymer with
acetate. In this sense, the low coordinating ability of the DiBox ligands (2) or with click-QAX (4). In the first case,
triflate anion fulfills two important requirements. First of a 1:1 molar ratio was found to be optimal. When working
all, it enables access to enantioselectivities higher than those with click-QAX, the optimal ratio for polymer induction
obtained with coordinating anions, such as chloride.[24,25] was found to be 1:2 because of the four coordination sites
Secondly, the use of a weak counter anion favors the simul- per ligand (Figure 2). A greater than optimal amount of
taneous coordination of two bis(oxazoline) or azabis(ox- copper in the reaction medium favored formation of shorter
azoline) moieties to one copper ion thereby enabling forma- polymers and monomers, thereby complicating catalyst re-
tion of the coordination polymer at the end of the reaction. covery by precipitation.
Other copper salts with a strong coordinating counterion,
such as CuCl, prevent recruitment of two azaBox ligands by
copper since the chloride anions remain within the copper
coordination sphere thereby restricting formation of the co-
Structural Studies of the Catalysts by FESEM
ordination polymer and the possibility of catalyst recov-
One of the most important features of a catalyst is its
structure given that both catalytic performance and recover-
ery.[12]
We found that coordination polymers were formed by ability are dictated by structural characteristics. X-ray dif-
mixing the corresponding polytopic bis(oxazoline) ligands fraction techniques have been profusely employed in the
2 or 4 with copper triflate salts in the appropriate Cu/L characterization of catalytic metal complexes. Disappoint-
molar ratio in CH2Cl2. The appropriate L/Cu molar ratio ingly, copper complexes involving polytopic ligands 2 and
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J. I. García, C. I. Herrerías et al.
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ning Electron Microscopy (FESEM). In the corresponding
micrographs the presence of fibers with a hierarchical struc-
ture is clearly observed (Figure 3). The fibrous microscopic
structure may reflect the molecular arrangement of ligand
and metal under the form of a linear coordination polymer.
Figure 2. Schematic representation of the self-assembled catalysts
from the coordination of copper cations with: a) DiBox ligands
(chains) and b) click-QAX ligands (3D structures).
Figure 3. FESEM micrograph of the iPrDiBox-Cu(OTf)2 [2d-Cu]n
complex in solid phase.
even 4 proved recalcitrant to crystallization techniques de-
spite having tried several crystallization techniques. Diffrac-
tion quality crystals for these complexes remain elusive
though efforts to obtain crystallographic data on any mem-
ber of this catalyst class remains a high priority for our
group.
Self-Supported Catalysts: Mode of Use
Coordination polymers are attractive for applications in
catalysis since they combine the beneficial attributes of both
Indirect techniques to elucidate coordination polymer homogeneous and heterogeneous catalysis. During the reac-
structures had previously proven successful in our research tion, the polymer disassembles due to competitive coordi-
group with metal complexes of 2a (tBuDAX) and 2b nation of either the reactants or the reaction solvent and
(iPrDAX). 1H NMR DOSY[26,27] experiments had been the resulting monomeric metal complexes become soluble
carried out using CuI and ZnII complexes of iPrDAX and thus allowing for the kinds of excellent results often associ-
similar DOSY experiments have been successfully applied ated with traditional homogeneous complexes. Upon com-
to the study of the size of molecular aggregates, metal–li- pletion of the catalytic reaction, a simple change in solvent
gand complexes, and metallosupramolecular architectures can trigger reassembly of the coordination polymer and
in solution.[28–31] Some experiments were done using the subsequent precipitation. The resulting heterogeneous self-
complex of Zn(OTf)2 with the monotopic ligand, and the supported catalyst in its resting state, is easily recoverable
corresponding complexes with ditopic ligand in different by decanting or other simple liquid/solid separation tech-
stoichiometries. When the Zn/2b ratio was adjusted to 1:1 niques.
(the ideal stoichiometry for formation of a coordination
polymer), minimized diffusion coefficients were observed cyclopropanation of styrene with ethyl diazoacetate
indicating the presence of oligomeric species.[15]
(Scheme 1). All the coordination polymers prepared for this
This concept is demonstrated in the copper-catalyzed
To collect more information on the copper coordination work with polytopic ligands 2 or 4 and Cu(OTf)2 in a 1:1
polymers, analyses were conducted using high-resolution or 1:2 molar ratio, are insoluble in CH2Cl2 (reaction sol-
mass spectrometry (HRMS). These experiments were car- vent), but they are disassembled and hence solubilized, in
ried out with the complex CuI(OTf)-2a. HRMS revealed the presence of ethyl diazoacetate. Driving this solubiliza-
n+
the formation, in the gas phase, of [Cu-2a]n species (n = tion is the formation of copper carbenoid complexes, which
1–3), as well as other oligomeric species with three and four are known to be decisive intermediates in the title reac-
copper atoms linked to four or three ditopic ligands, respec- tion.[32–36] As a result, the catalytically active monomeric
tively.[13] These results strongly support the hypothesis that copper-ligand species are released and the cyclopropanation
the complexes formed in a non-coordinating solvent are in- reaction proceeds in the homogeneous phase with yields
deed coordination polymers.
and enantioselectivities similar to those described with the
In the case of the Cu-ditopic ligand complexes we pro- monotopic copper-bis(oxazoline) catalysts.
pose the formation of a linear polymer structure. Since no
After consumption of the ethyl diazoacetate the polymer
single crystal of these complexes could be obtained, we de- reassembles. Although in the first reaction cycle the poly-
cided to study the solids formed using Field Emission Scan- mer formation occurs in a short period of time, in the fol-
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Use of Polytopic Ligands in Cyclopropanation
lowing cycles it takes more time due to the presence of by-
Next, we evaluated the behavior of ditopic ligands based
products. Therefore, the procedure for catalyst recovery was on bis(oxazolines), referred to as DiBox. We started with
optimized. Catalyst recovery consists of evaporating most the tBuDiBox ligand, and results obtained with the corre-
of the CH2Cl2 and extracting the reaction products with n- sponding copper complex are gathered in Table 2.
hexane, in which the coordination polymer is nearly insolu-
ble. Following n-hexane extractions, a fine green powder ap-
pears at the bottom of the reaction vessel. After centrifuga-
tion, it is possible to decant the solvent where the products,
byproducts and residual starting materials are dissolved.
After drying the catalyst with argon, it can be reused in
consecutive reaction cycles by adding again CH2Cl2, styrene
and ethyl diazoacetate.
Table 2. Cyclopropanation reactions between styrene and ethyl di-
azoacetate catalyzed by Cu-tBuBox and Cu-tBuDiBox.[a]
Entry
Ligand
Run Yield
[%]
trans/cis
% ee % ee
trans
cis
1
tBuBox (1c)
tBuBox-2Bn (6a)
tBuDiBox (2c)
–
–
1
2
3
4
5
6
7
72
46
82
75
77
52
58
65
62
57
55
68
71:29
33:67
36:64
35:65
35:65
36:64
36:64
37:63
39:61
40:60
40:60
41:59
94
70
70
70
71
69
72
69
68
68
69
65
91
79
70
71
70
70
71
70
70
69
70
68
2[b]
3
4
5
6
7
8
9
10
11
12
Catalytic Studies
To explore the self-supporting catalytic possibilities of
new DiBox and click-QAX ligands, we used their corre-
sponding Cu(OTf)2 complexes in the benchmark asymmet-
ric cyclopropanation reaction of styrene with ethyl diazo-
acetate because of the huge amount of previous data avail-
able for this reaction.
For the sake of comparison we first studied the conven-
tional homogeneous reactions. Table 1 gathers the results
obtained in the cyclopropanation reaction catalyzed by
complexes of the monotopic bis(oxazoline) and azabis(ox-
azoline) ligands with Cu(OTf)2.
8
9
10
[a] Reagents and conditions: styrene (1 equiv.), ethyl diazoacetate
(1 equiv.), L-Cu(OTf)2 (1 mol-%), CH2Cl2, room temperature, yield
and selectivities were determined by gas chromatography (methyl
silicone and cyclodex-β columns). (1R,2R)-trans-cyclopropane and
(1R,2S)-cis-cyclopropane are the major isomers. [b] Taken from
ref.[37]
The most pronounced and noteworthy trend displayed
by these results is the diastereoselectivity inversion. When
the complex with monotopic ligand 1c was used as catalyst,
trans-cyclopropanes were the major isomers generated
(Table 2, Entry 1). However, when using the tBuDiBox-Cu
complex, cis-cyclopropanes constituted the predominant
products generated. This inversion of diastereoselectivity
has been previously observed in our group using homogen-
eous catalyst Cu-tBuBox (6a) which contains two benzyl
units in the bridge (Figure 4).[37]
Table 1. Cyclopropanation reactions between styrene and ethyl di-
azoacetate catalyzed by Cu-L.[a]
Entry
Ligand
Yield [%]
% ee trans
% ee cis
1
2
3
4
5
6
tBuBox (1c)
iPrBox(1d)
72
53
33
86
82
45
94
72
54
76
92
74
91
63
42
78
84
57
PhBox (1e)
InBox (1f)
tBuAzaBox(1a)
iPrAzaBox(1b)
[a] Reagents and conditions: styrene (1 equiv.), ethyl diazoacetate
(1 equiv.), L-Cu(OTf)2 (1 mol-%), CH2Cl2, room temperature, yield
and selectivities were determined by gas chromatography (methyl
silicone and Cyclodex-β columns). (1R,2R)-trans-cyclopropane and
(1R,2S)-cis-cyclopropane are the major isomers. The trans/cis ratio
is ca. 70:30 in all cases.
Figure 4. Structures of tBuBox-2Bn (6a) and PhBox-2Bn (6b).
As can be seen, high yields and enantioselectivities are
It is clear that the presence of the benzyl group modifies
obtained when the chiral ligands display tert-butyl substitu- the geometry of the catalytic intermediate and this is re-
ents. It can be also observed that, in almost all cases, the flected by the results in Table 2. This not only impacts
enantioselectivities for trans-cyclopropanes are slightly bet- trans/cis selectivity; the enantioselectivity obtained with Cu-
ter than those for the cis products.
It is worth noting that in all reactions a 1:1 styrene:ethyl with the complex with ligand 6a than that with ligand 1c.
diazoacetate molar ratio was used leading to low yields in The coordination polymer with Cu-tBuDiBox can be re-
tBuDiBox complex more closely resembles that obtained
some cases; the likely cause of this observation is competi- covered during at least 10 runs and recovered catalyst was
tive dimerization of the diazo-compound. Even so, good found capable of delivering results that are on par with the
yields are obtained with the complexes of those ligands first cycle (Table 2, Entries 3–12). Erratic reaction yields
bearing tert-butyl and indanyl substituents. Of course, these were observed along the recycling experiments though these
yields could be further improved by increasing the olefin:di- could be attributed to incomplete product extractions with
azo compound ratio, as is often done in synthetically-ori- hexane after some of the reactions. These products are envi-
ented works.
sioned to possibly accumulate in the reaction medium and,
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J. I. García, C. I. Herrerías et al.
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subsequently, can be extracted in a successive run. The in- lyst Cu-PhDiBox (2e) was found to effective enabling acqui-
fluence of this particular behavior on yields was also ob- sition of the same values with Cu-1e and Cu-6b complexes
served in experiments with all the other coordination poly- over the course of 10 cycles. Curiously, in this case, the ef-
mers used in this work. Some tests sought to increase the fect of the benzyl group in the bridge was negligible, only
number of times that catalyst was washed, so as to improve small changes in diastereoselectivity were observed, from a
the product extraction methodology. The problem was that, value of 70:30 with ligands 1e or 6b, to a value of 65:35 in
if the catalyst was washed more than three times, not only the case of 2e. Even the enantioselectivity obtained with
the products and by-products are extracted but part of the complex 2e, which included the ditopic ligand, was found
polymer is also dissolved. Thus, it became necessary to to be slightly better than that obtained with homologous
reach a compromise between properly cleaning up catalyst complexes, in contrast to the behavior of complexes 2c and
versus inadvertently inducing its loss during the extraction 2d.
process. Even so, the yields in all reaction cycles were found
to be superior to those obtained with complex Cu-6a.
Table 4. Cyclopropanation reactions between styrene and ethyl di-
azoacetate catalyzed by Cu-PhBox and Cu-PhDiBox.[a]
Afterwards, Cu-iPrDiBox was also used as the catalyst
in the cyclopropanation reaction; the results are shown in
Table 3.
Entry
Ligand
Run Yield trans/cis
% ee
trans
% ee
cis
[%]
1
PhBox (1e)
PhBox-2Bn (6b)
PhDiBox (2e)
–
–
1
2
3
4
5
6
7
8
9
10
11
33
32
38
44
42
52
50
32
36
32
30
22
16
71:29
70:30
69:31
66:34
65:35
64:36
64:36
64:36
62:38
61:39
61:39
61:39
63:37
54
50
60
63
62
58
58
58
58
58
53
53
52
42
40
45
50
50
51
53
54
56
56
54
54
54
Table 3. Cyclopropanation reactions between styrene and ethyl di-
2[b]
3
azoacetate catalyzed by Cu-iPrBox and Cu-iPrDiBox.[a]
4
5
6
7
8
9
10
11
12
13
Entry
Ligand
Run Yield trans/cis % ee
% ee
cis
[%]
trans
1
2
3
4
5
6
7
8
iPrBox (1d)
iPrDiBox (2d)
–
1
2
3
4
5
6
7
8
53
39
35
49
41
47
41
45
39
39
28
70:30
57:43
57:43
54:46
52:48
52:48
51:49
52:48
53:47
52:48
50:50
72
59
62
63
62
61
62
62
62
63
60
63
61
63
63
62
60
60
60
61
63
62
[a] Reagents and conditions: styrene (1 equiv.), ethyl diazoacetate
(1 equiv.), L-Cu(OTf)2 (1 mol-%), CH2Cl2, room temperature, yield
and selectivities were determined by gas chromatography (methyl
silicone and cyclodex-β columns). (1R,2R)-trans-cyclopropane and
(1R,2S)-cis-cyclopropane are the major isomers. [b] Taken from
ref.[37]
9
10
11
9
10
[a] Reagents and conditions: styrene (1 equiv.), ethyl diazoacetate
(1 equiv.), L-Cu(OTf)2 (1 mol-%), CH2Cl2, room temperature, yield
and selectivities were determined by gas chromatography (methyl
silicone and cyclodex-β columns). (1R,2R)-trans-cyclopropane and
(1R,2S)-cis-cyclopropane are the major isomers.
The last ditopic ligand prepared and used in this work
was InDiBox (2f). The results obtained with its correspond-
In this case, there was no apparent inversion in the ing copper complex are collected in Table 5.
trans/cis ratio when we consider the complex with the di-
In this case, for comparison, we also synthesized the li-
topic ligand. However, a loss of diastereoselectivity was ob- gand InBox modified in the bridge with one benzyl group
served (from 70:30 to 55:45). This effect could be attributed (7) (Figure 5). The rationale for introducing just one benzyl
to the benzyl group present in the DiBox ligand as was the group, was so that the structure of 7 would be closer to its
case for tBuDiBox (2c). However, the enantioselectivities homologous ditopic ligand 2f. Consequently, the behavior
obtained using Cu-iPrDiBox complex were the same as of 7 should be more similar to 2f than in the absence of the
with the Cu-iPrBox complex, especially in the case of the additional benzyl moiety. Comparing those results with
cis-isomers. This indicates that the benzyl effect, in this case, data obtained with Cu-1f, it was observed that a small de-
is not as influential as that observed in Table 2.
crease in yield and diastereoselectivity values was evident
Recovery of the catalyst in this case was excellent, yields although, contrary to this general trend, enantioselectivity
were moderated in all cases due to the chemoselectivity of increased slightly. The results obtained with Cu-2f are sim-
the reaction, as we have described above. However, ob- ilar to those obtained with Cu-7, and also to those pre-
served enantioselectivities were as good as those obtained viously described with analogous dibenzylated ligand 8,[37]
with the monotopic liganded complex. The quality of reac- indicating again that the presence of the benzyl group in
tion results with Cu-iPrDiBox was easily retained over the the bridge is decisive in setting complex geometry and
course of 10 runs, as anticipated.
therefore, in the mechanistic stage where selectivity is deter-
On the other hand, when complexes with phenyl-substi- mined.
tuted ligands were used (Cu-1e, Cu-2e and Cu-6b), results
The recoverability and reapplication of the catalyst Cu-
were found to be moderated (Table 4). Not only yields, but 2f was also found to be very good. It was possible to use
also ee values for both diastereomers were found to be less this catalyst in up to 12 cycles of cyclopropanation without
than 60%. Despite these poor results, the recovery of cata- suffering any loss of activity or selectivity.
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Use of Polytopic Ligands in Cyclopropanation
Table 5. Cyclopropanation reactions between styrene and ethyl di-
azoacetate catalyzed by Cu-InBox and Cu-InDiBox.[a]
Table 6. Cyclopropanation reactions of styrene and ethyl diazoacet-
ate as catalyzed by Cu-tBuAzabox and Cu-click-tBuQAX.[a]
Entry
Ligand
Run Yield trans/cis
% ee
trans
% ee
cis
Entry
Ligand
Run Yield trans/cis % ee
% ee
cis
[%]
[%]
trans
1
InBox (1f)
–
–
–
1
2
3
4
5
6
7
8
9
10
11
12
86
62
49
69
50
59
59
77
79
63
70
65
71
76
49
62:38
57:43
58:42
50:50
50:50
48:52
45:55
47:53
46:54
46:54
46:54
46:54
46:54
46:54
46:54
78
85
83
73
83
70
77
81
64
79
73
72
70
69
65
76
85
86
74
79
86
82
87
82
81
80
78
78
74
74
1
2
3
4
5
6
7
8
tBuAzabox (1a)
click-tBuQAX (4a)
–
1
2
3
4
5
6
7
8
9
82
98
96
87
95
90
84
83
76
86
73:27
75:25
74:26
73:27
72:28
71:29
71:29
70:30
69:31
69:31
69:31
68:32
67:33
67:33
67:33
67:33
67:33
66:34
66:34
66:34
66:34
92
99
99
99
98
98
97
98
98
99
98
99
99
96
96
96
97
96
95
95
91
84
90
90
89
89
88
88
87
87
86
85
85
85
84
85
84
85
85
84
85
84
2
InBox-Bn (7)
InBox-2Bn (8)
InDiBox (2f)
3[b]
4
5
6
7
8
9
9
10
11
12
13
14
15
10
11
12
13
14
15
16
17
18
19
20
21
10 79
11 73
12 84
13 81
14 85
15 73
16 90
17 62
18 81
19 77
20 50
[a] Reagents and conditions: styrene (1 equiv.), ethyl diazoacetate
(1 equiv.), L-Cu(OTf)2 (1 mol-%), CH2Cl2, room temperature, yield
and selectivities were determined by gas chromatography (methyl
silicone and cyclodex-β columns). (1R,2R)-trans-cyclopropane and
(1R,2S)-cis-cyclopropane are the major isomers. [b] Taken from
ref.[37]
[a] Reagents and conditions: styrene (1 equiv.), ethyl diazoacetate
(1 equiv.), L-Cu(OTf)2 (1 mol-%), CH2Cl2, room temperature, yield
and selectivities were determined by gas chromatography (methyl
silicone and cyclodex-β columns). (1R,2R)-trans-cyclopropane and
(1R,2S)-cis-cyclopropane are the major isomers.
Table 7. Cyclopropanation reactions between styrene and ethyl di-
azoacetate catalyzed by Cu-iPrAzabox and Cu-click-iPrQAX.[a]
Entry
Ligand
Run Yield trans/cis % ee
% ee
cis
[%]
trans
1
2
3
4
5
6
7
8
iPrAzabox (1b)
–
1
2
3
4
5
6
7
8
9
45
75
74
69
86
82
71
81
63
64
71:29
67:33
68:32
69:31
68:32
69:31
63:37
63:37
68:32
67:33
66:34
66:34
66:34
66:34
74
26
53
82
75
76
78
80
86
83
84
80
85
86
57
21
39
53
56
60
60
63
64
66
65
68
69
69
Figure 5. Structure of InBox-Bn (7).
click-iPrQAX (4b)
The main objective of the preparation of coordination
polymers and the use of a release–capture strategy was to
develop highly recoverable catalytic systems. In our pre-
vious studies, we found that the use of ligands with more
than two units of azabis(oxazoline) [TAX (3)] improved re-
coverability of the catalyst, probably due to more facile for-
mation of the polymer at the end of the reaction.[13] For
this reason, we went one step beyond and designed a new
family of tetratopic ligands where the azabis(oxazoline)
units are connected to a tetrahedral quaternary carbon
using a click chemistry-based synthetic strategy [click-QAX
(4)].
9
10
11
12
13
14
10 77
11 67
12 62
13 48
[a] Reagents and conditions: styrene (1 equiv.), ethyl diazoacetate
(1 equiv.), L-Cu(OTf)2 (1 mol-%), CH2Cl2, room temperature, yield
and selectivities were determined by gas chromatography (methyl
silicone and cyclodex-β columns). (1R,2R)-trans-cyclopropane and
(1R,2S)-cis-cyclopropane are the major isomers.
According to the results presented in Table 1, the best
cyclopropanation outcomes correlate to the use of ligands
As shown in Table 6, results obtained with complex Cu-
bearing tBu and iPr groups. Accordingly, we carried out the 4a are remarkable; both the yield and the enantioselectivity
synthesis of the new click-QAX ligands containing these are close to 100% (Table 6, Entry 2), a substantial improve-
two different substituents. The resulting ligands were com- ment over data found using complex Cu-1a (Table 6, Entry
plexed with Cu(OTf)2 in the appropriated 2:1 Cu/Ligand 1). In addition, the quality of data obtained using Cu-4a
stoichiometry in order to obtain the corresponding coordi- was, to a large extent, retained over the course of the 19
nation polymer. The results obtained with these two ligands subsequent runs with recovered catalyst. Only in the last
together with those obtained using the corresponding run was any substantial decrease in yield observed (50%)
monotopic ligand are depicted in Table 6 and Table 7.
(Table 6, Entry 21). Run 21 data notwithstanding it is im-
Eur. J. Org. Chem. 2014, 1531–1540
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1537

J. I. García, C. I. Herrerías et al.
FULL PAPER
solution of 2,2Ј-methylene-bis[(4S)-4-phenyl-4,5-dihydrooxazole]
(306 mg, 1 mmol) in anhydrous tetrahydrofuran (5 mL) was com-
bined with another solution of tBuOK (112 mg, 1 mmol) also in
anhydrous tetrahydrofuran (5 mL). After stirring for 1 h at room
temperature, α,αЈ-Dibromo-p-xylene (132 mg, 0.5 mmol) was
added. The mixture was stirred at 77 °C overnight. The solvent was
evaporated under reduced pressure and the residue was partitioned
between ethyl acetate (10 mL) and a saturated NaCl solution
(10 mL). The aqueous phase was extracted with ethyl acetate (3ϫ
10 mL) and the combined organic phases were dried with anhy-
portant to point out that these results are the best yet ob-
tained for this reaction and this type of catalyst complex.
Finally, complex Cu-4b was applied to the cycloprop-
anation reaction (Table 7). As shown in the Table, although
product yields during all the cycles are better than those
obtained using monotopic ligand complex Cu-1b, the
enantioselectivity found in the first two cycles was exceed-
ingly low. Interestingly, after the second cycle of reaction,
enantioselectivity induced by Cu-4b increased, even ex-
ceeding the enantioselectivity induced during cyclopropan- drous MgSO4. Evaporation of the solvent yielded the product as a
light yellow solid.
ations with Cu-1b. We attribute this change in Cu-4b-in-
duced enantioselectivity to the presence of free copper in
the reaction medium introduced during initial complex-
ation. Free Cu(OTf)2 catalyzes the racemic reaction and this
would explain the poor ee values noted for runs 1 and 2
with Cu-4b (Table 7, Entries 2 and 3). We envision that,
after two reaction cycles, all unbound copper would have
been extracted. Consequently, enantioselectivity values as-
sociated with Cu-4b (generated during runs 3–20) would
now be comparable to those noted for complex Cu-1b.
As with the other coordination polymers, the recoverabi-
lity of Cu-4b was found to be excellent. In this case, up to
13 runs could be carried out affording both good yields and
enantioselectivities.
1,4-Bis{2,2-bis[(S)-4-tertbutyl-4,5-dihydrooxazol-2-yl]ethyl}benzene
(tBuDiBox) (2c): Yellow solid in almost quantitative yield. [α]2D0
=
–72.3 (c = 2.3, CH2Cl2); m.p. 75–77 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.12 (s, 4 H), 4.06 (m, 8 H), 3.78 (m, 4 H), 3.37 (m, 2
H), 3.14 (m, 4 H), 0.89 (s, 9 H), 0.83 (s, 9 H), 0.82 (s, 9 H), 0.77
(s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.11, 164.06,
163.8, 163.7, 136.39, 136.3, 130.4, 130.0, 129.0, 128.5, 75.6, 75.5,
68.85, 68.80, 41.3, 41.2, 35.4, 33.9, 33.75, 33.70, 33.54, 25.85, 25.83,
25.69, 25.68, 25.66, 25.64 ppm. IR (C=N): ν = 1654 cm–1. HRMS
˜
(ESI+): m/z = 635.4531 [M + H]+, calcd. for C38H58N4O4H:
635.4536.
1,4-Bis{2,2-bis[(S)-4-isopropyl-4,5-dihydrooxazol-2-yl]ethyl}benzene
(iPrDiBox) (2d): Transparent oil in almost quantitative yield: [α]2D5
= –57.5 (c 0.54, CHCl3); 1H NMR (400 MHz, CDCl3): δ = 7.10 (s,
4 H), 4.28–4.06 (m, 4 H), 4.01–3.79 (m, 8 H), 3.76–3.63 (m, 2 H),
3.25–3.05 (m, 4 H), 1.79–155 (m,4 H), 0.89 (d, J = 6.8 Hz, 6 H),
0.82 (d, J = 6.8 Hz, 6 H), 0.81 (d, J = 6.8 Hz, 6 H), 0.75 (d, J =
6.8 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.0, 163.9,
136.4, 128.9, 71.82, 71.81, 70.05, 70.04, 41.3, 35.4, 32.3, 32.2, 18.6,
Conclusions
In this work we have described the preparation of several
new polytopic chiral ligands based on bis(oxazoline) units,
both ditopic (tBuDiBox, PhDiBox, and InDiBox) and
tetratopic (click-tBuQAX and click-iPrQAX). The copper
complexes of these ligands have been tested in a benchmark
asymmetric cyclopropanation reaction, using a release–cap-
ture strategy based on the formation of coordination poly-
mers at the end of the reaction to recover and recycle cata-
lysts. The use of this strategy has allowed, in the case of the
tetratopic ligands, the recovery and reuse of catalysts in at
least up to 20 reaction cycles leading to very good yields
and enantioselectivities. These results are among the best
described thus far for a recoverable catalyst in this kind of
reaction. These findings broaden the scope of application
for this recycling strategy and also highlight its strength as
a convergence of the best of the homogeneous and hetero-
geneous catalysis worlds.
18.5, 17.8, 17.7 ppm. IR (C=N): ν = 1665.2 cm–1. HRMS(ESI+)
˜
m/z = 579.3931 [M + H]+, calcd. for C34H50N4O4 + H 579.3910.
1,4-Bis{2,2-bis[(4S)-4-phenyl-4,5-dihydrooxazol-2-yl]ethyl}benzene
(PhDiBox) (2e): Light yellow solid in almost quantitative yield.
[α]2D5 = –42.0 (c 0.6, CH3OH); m.p. 86–89 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.36–4.14 (m, 20 H), 7.09–6.99 (m, 4 H), 5.26–5.11
(m, 4 H), 4.69–4.55 (m, 4 H), 4.20–4.12 (m, 2 H), 4.11–3.95 (m, 4
H), 3.48–3.35 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
165.49, 165.37, 141.96, 141.90, 136.39, 130.72, 129.27, 128.65,
128.59, 127.56, 127.53, 126.78, 126.75, 126.66, 126.61, 125.47,
125.44, 75.34, 75.15, 69.53, 69.54, 41.4, 35.4 ppm. IR (C=N): ν
˜
= 1657 cm–1. HRMS(ESI+) m/z = 715.3288 [M + H]+, calcd. for
C46H43N4O4 + H 715.3284.
1,4-Bis{2,2-bis[(3aR,8aS)-8,8a-dihydro-3aH-indeno[1,2-d]oxazol-2-
yl]ethyl}benzene (InDiBox) (2f): Yellow solid in almost quantitative
yield. [α]2D5 = –209.5 (c 0.58, CH3OH); m.p. 88–91 °C; 1H NMR
(400 MHz, CDCl3): δ = 7.50–7.45 (m, 2 H), 7.40–7.15 (m, 18 H),
5.51 (d, J = 7.8 Hz, 2 H), 5.47 (d, J = 7.6 Hz, 2 H), 5.29–5.21 (m,
4 H), 3.46 (t, J = 8.4 Hz, 2 H), 3.35–3.25 (m, 4 H), 3.05–2.87 (m,
8 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.2, 164.8, 164.5,
164.4, 141.6, 139.8, 139.7, 139.5, 135.3, 135.2, 134.0, 129.9, 128.4,
128.3, 128.0, 127.5, 127.3, 125.6, 125.5, 125.2, 125.0, 83.4, 83.1,
76.4, 76.3, 76.2, 41.2, 41.1, 39.6, 39.5, 39.2, 38.3, 35.1, 29.7 ppm.
Experimental Section
General Information: All reactions were carried out under an argon
atmosphere in oven-dried glassware. Anhydrous solvents such as
tetrahydrofuran, dichloromethane, and hexane were obtained from
an SPS-device. The purchased reagents were used as received with-
out further purification. Amino acids were used as commercially
available. The starting azabis(oxazolines) and 1,3-diazido-2,2-bis-
(azidomethyl)propane were prepared according to literature pro-
cedures.[17–20,38] The chemical shifts were relative to TMS as an
IR (C=N): ν = 1652 cm–1. HRMS(ESI+) m/z = 763.3296 [M +
˜
H]+, calcd. for C50H43N4O4 + H 763.3285.
Synthesis of 2,2Ј-(2-Phenyletano-1,1-diyl)bis(8,8a-dihydro-3aH-
indano[1,2-d]oxazol) (InBox-Bn) (7): A solution of bis[(3aR,8aS)-
8,8a-dihydro-3aH-indeno[1,2-d]oxazol-2-yl]methane
(200 mg,
1
internal reference for H NMR spectroscopy.
0.61 mmol) in anhydrous tetrahydrofuran (5 mL) was combined
Synthesis of 1,4-Bis{2,2-bis[(4S)-4-phenyl-4,5-dihydrooxazol-2- with another solution of tBuOK (67.8 mg, 0.61 mmol) also in an-
yl]ethyl}benzene (PhDiBox) (2e) as a representative procedure: A hydrous tetrahydrofuran (5 mL). After stirring for 1 h at room tem-
1538
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1531–1540

Use of Polytopic Ligands in Cyclopropanation
perature, benzyl bromide (103.6 mg, 0.61 mmol) was added. The
clear solution appeared instead. After total consumption of the
mixture was stirred at 77 °C overnight. The solvent was evaporated diazoacetate (approx. 24 h) the polymer catalyst precipitated again.
under reduced pressure and the residue was partitioned between
ethyl acetate (10 mL) and a saturated NaCl solution (10 mL). The
aqueous phase was extracted with ethyl acetate (3ϫ 10 mL) and
the combined organic phases were dried with anhydrous MgSO4.
The product was purified by medium pressure liquid chromatog-
raphy. A light yellow solid is obtained with 68% of isolated yield.
[α]2D0 = –252.0 (c = 0.7, CH3OH); m.p.161–163 °C; 1H NMR
The solution was concentrated to 0.5 mL and the solid washed with
n-hexane and dried. In these conditions the catalyst was ready to
be used again in a new reaction. Reactions were monitored by gas
chromatography using an FID detector connected to a Hewlett–
Packard 5890 II chromatograph, using a cross-linked methyl sili-
cone column: 25 mϫ0.25 mmϫ0.25 μm; helium was used as car-
rier gas. Column pressure: 20 psi; injector temperature: 230 °C; de-
(400 MHz, CDCl3): δ = 7.52–7.50 (m, 1 H), 7.35–7.20 (m, 7 H), tector temperature: 250 °C; oven program: 70 °C (3 min), 15 °C
6.99–6.85 (m, 5 H), 5.54 (d, J = 8 Hz, 1 H), 5.50 (d, J = 7.6 Hz, 1
min–1 to 200 °C (5 min). The enantioselectivities of the reactions
H), 5.32–5.24 (m, 2 H), 3.59 (t, J = 8.4 Hz, 1 H), 3.33 (dd, J = 9.6, were also determined in all cases by gas chromatography using a
J = 18 Hz, 1 H), 3.31 (dd, J = 10, J = 18 Hz, 1 H), 3.18–2.93 (m,
4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.7, 164.3, 141.6,
141.6; 139.7, 139.5, 137.4, 128.7, 128.4, 128,3; 128,0; 127,3; 126,3;
125,6; 125,5; 125,2; 125,1; 83,5; 83,2; 76,6; 76.3, 41.3, 39.6, 39.5,
Cyclodex-β column. Temperature program: 120 °C isotherm. Spe-
cific chromatographic conditions, retention times and some typical
chromatograms are gathered in the Supporting Information.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra of the new ligands. Typical gas chro-
matograms of the cyclopropanation reaction between styrene and
ethyl diazoacetate.
35.6 ppm. IR (C=N): ν = 1647.61 cm–1. HRMS (μ-TOF) m/z =
˜
421.1911 [M + H]+, calcd. for C28H24N2O2H = 421.1916.
Synthesis of (click-tBuQAX) (4a) as a Representative Procedure: (S)-
4-tert-Butyl-N-[(S)-4-tert-butyl-4,5-dihydrooxazol-2-yl]-N-(prop-2-
ynyl)-4,5-dihydrooxazol-2-amine (4) (1.00 mmol, 291.4 mg), 1,3-di-
azido-2,2-bis(azidomethyl)propane (0.25 mmol, 59 mg) and CuI
(0.05 mmol, 9.5 mg) were dissolved in 9 mL of CH2Cl2 and 2 mL
of Et3N. The mixture was stirred during 20 h at room temperature.
After this time, the solvent was evaporated under reduced pressure
and the residue partitioned between 10 mL of CH2Cl2 and a 1%
EDTA-2Na (ethylenediaminotetraacetic acid disodium salt) aque-
ous solution. The aqueous phases were extracted with CH2Cl2 and
the combined organic phases dried with anhydrous Na2SO4 and
subsequently, evaporated under vacuum. A recrystallization in
acetone yielded dark brown crystals of the product in almost quan-
titative yield.
Acknowledgments
Financial support from the Spanish Ministerio de Economía y
Competitividad (MINECO) (project number CTQ2011-28124-
C02-01), the European Social Fund (ESF) and the Gobierno de
Aragón (Grupo Consolidado E11) is gratefully acknowledged. The
authors also thank Ana C. Gallego, from the Service of Electron
Microscopy of Materials of the University of Zaragoza for her
valuable assistance in the FESEM experiments. One of the authors
(ACM) is indebted to the Consejo Superior de Investigaciones
Científicas for a grant (CSIC JAE-Pre program).
click-tBuQAX (4a): Brown solid. [α]2D0 = –59 (0.7, CH2Cl2); m.p.
73–75 °C; 1H NMR (400 MHz, CDCl3): δ = 8.10–8.07 (m, 4 H),
5.23–5.10 (m, 8 H), 4.36–4.29 (m, 16 H), 4.25–4.19 (m, 8 H), 3.82–
3.76 (m, 8 H), 0.85–0.80 (m, 72 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 156.9, 144.2, 130.2, 73.2, 70.3, 51.4, 45.2, 33.9, 29.7,
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Eur. J. Org. Chem. 2014, 1531–1540
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1539

J. I. García, C. I. Herrerías et al.
FULL PAPER
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Received: October 7, 2013
Published Online: December 19, 2013
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