Covalent and noncovalent immobilization of Arylid-BOX ligands and their derivatives: Evaluation in the catalytic asymmetric cyclopropanation of styrenes

Article abstract of DOI:10.1002/ejoc.201100781

The aim of this work was to immobilize an Arylid-BOX ligand on solid supports either by covalent attachment (to Wang resin) or by noncovalent attachment (on MK10 and SiO₂) and to evaluate the products in the catalytic asymmetric cyclopropanatio

Full text of DOI:10.1002/ejoc.201100781

FULL PAPER
DOI: 10.1002/ejoc.201100781
Covalent and Noncovalent Immobilization of Arylid-BOX Ligands and Their
Derivatives: Evaluation in the Catalytic Asymmetric Cyclopropanation of
Styrenes
Elisabete P. Carreiro,[a,b] Nuno M. M. Moura,[a,b] and Anthony J. Burke*[a,b]
Keywords: Heterogeneous catalysis / Supported catalysts / Asymmetric catalysis / Asymmetric synthesis / Arylid-BOX
The aim of this work was to immobilize an Arylid-BOX li-
gand on solid supports either by covalent attachment (to
Wang resin) or by noncovalent attachment (on MK10 and
SiO2) and to evaluate the products in the catalytic asymmet-
ric cyclopropanation (CACP) of styrene in the presence of
CuI and CuII. The synthetic strategy used to obtain the target
cled and reused up to four times. In the case of the hetero-
geneous CACP in the presence of [Cu(CH3CN)4]PF6 and tol-
uene, the yields, ees, des, and selectivities were maintained
over the four cycles. This heterogeneous catalyst was shown
to be very similar to the homogeneous catalyst with regard
to selectivity and activity. In the case of noncovalent immobi-
functionalized Arylid-BOX furnished a new, partially hydro- lization, both CuI and CuII Arylid-BOX complexes were im-
genated, Arylid-BOX derivative. Evaluation of this ligand in
the catalytic asymmetric cyclopropanation of styrene in the
presence of CuI gave a highest ee of 68%, a result better
than that obtained for the nonhydrogenated Arylid-BOX li-
gand. The new ligand was grafted to Wang resin; a loading
of 0.321 mmol of ligand per gram of polymer could be ob-
tained. [Cu(CH3CN)4]PF6 or Cu(OTf)2 were used in the
CACP of styrene with CH2Cl2 or toluene as solvents. A high-
est ee of 71% was obtained and the catalyst could be recy-
mobilized on Montmorillonite K10 (MK10) and silica gel
through noncovalent interactions. The obtained results de-
pended on the natures both of the chiral ligand and of the
support. In the case of MK10, enantioselectivities of 62% ee
(trans-cyclopropane) and 65% ee (cis-cyclopropane) could
be achieved, whereas in the case of the silica-gel-supported
catalyst, enantioselectivities of 50% ee (trans-cyclopropane)
and 43% ee (cis-cyclopropane) were obtained.
Bis(oxazoline) ligands have been shown to be very im-
portant in a wide range of catalytic asymmetric reactions,[4]
and as a consequence their immobilization has became an
important challenge over the last 10 years.
Introduction
Heterogeneous asymmetric catalysis is a field of great
interest both in academic and in industrial circles.[1] The
principle reason for this, and perhaps the most enduring, is
the importance of producing enantiomerically pure com-
pounds in the most efficient and cost-effective way possible.
By this technique it is possible to isolate and to recycle the
catalyst easily, thus reducing costs.[2] Through the choice of
a suitable support – organic and inorganic materials, for
example – a heterogeneous catalyst can be modified to give
high selectivities and activities. The role of the support has
changed from being that of an appendage to that of a well
defined material that can be used to influence the outcome
of the catalyzed reaction beneficially. For a long time now,
covalent immobilization of chiral complexes has been un-
equaled, due to the stabilities and recyclabilities of the re-
sulting immobilized catalysts. Besides this technique,
though, noncovalent immobilization has become quite so-
phisticated and highly promising.[3]
Several strategies have been used for covalent immobili-
zation of bis(oxazoline) ligands.[1–3] The first was developed
by Burguete et al.[5] and consisted of the polymerization of
bis(oxazoline) ligands (1 and 2, Figure 1) bearing vin-
ylbenzyl groups. The heterogeneous ligands were then
evaluated in the catalytic asymmetric cyclopropanation re-
action, giving low selectivities and enantioselectivities.
Some disadvantages were: i) that some ligands remained in
inaccessible positions on the support, and ii) that there was
unwanted steric hindrance at the C1 bridge with the oxazol-
ine rings. Mandoli et al.[6] used systems with less steric hin-
drance in the C1 bridge (ligand 3) thus ensuring more favor-
able binding with the metal. The results obtained in the
CACP were very good. Knight and Belcher[7] developed the
new bis(oxazoline) 4, containing a 1,3-dioxane unit to re-
strict the conformational mobility of the oxazoline units on
the C1 bridge. This ligand was grafted onto a Wang resin
and used in the CACP. The enantioselectivities were lower
than those achieved in the homogeneous reaction. Later,
Rieser and Mayoral[8] attached the AzaBOX ligands 5 to a
Tentagel resin. Some good results were obtained in the
[a] Centro de Química de Évora, Universidade de Évora,
59, Rua Romão Ramalho, 7000 Evora, Portugal
E-mail: ajb@uevora.pt
[b] Departamento de Química, Universidade de Évora,
59, Rua Romão Ramalho, 7000 Evora, Portugal
Fax: +351-266745303
518
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Immobilization of Arylid-BOX Ligands
CACP reaction. These ligands were easier to attach to the Henry reaction between nitromethane and benzalde-
support through the amine group, which is a good attach- hyde.[17b] The synthetic strategy to obtain these Arylid-BOX
ment point. Recently, Aranda et al. have immobilized cop- ligands 6 is a versatile one and highly modular in nature.
per–pyridine–oxazoline catalysts on a polymeric support;
the resulting systems showed good efficiency in the hetero-
geneous CACP.[9]
Figure 2. Arylid-BOXs 6–8 and the arylid-BOX derivative 9.
We decided to immobilize our rigid Arylid-BOX family
of ligands 6[14,15] on a Wang resin, expecting their inherent
Figure 1. Functionalized BOX ligands for immobilization on or-
rigidity to lead to good levels of metal binding within the
ganic supports.
support.
Here we describe for the first time our efforts with both
covalent and noncovalent immobilization of Arylid-BOX li-
gands (Figure 2) and their corresponding CuI catalysts on
solid supports and their evaluation as catalysts for asym-
metric catalysis by the simple CACP benchmark reaction,
which has become a standard preliminary screening reac-
tion in our laboratory.
In 1997, Mayoral and co-workers immobilized some
BOX-copper complexes noncovalently through ion-ex-
change on laponite and bentonite supports.[10] Testing in
the catalytic asymmetric cyclopropanation showed low
selectivities and enantioselectivities. Mayoral and Reiser in
2004 immobilized the AzaBOX 5 copper complexes on la-
ponite and Nafion-silica supports and the resulting systems
were used for the catalytic asymmetric cyclopropanation re-
action.[11] Three cycles were conducted, but both the yields
and the enantioselectivities dropped considerably from the
first cycle to the third.
Results and Discussion
Covalent Immobilization
BOX-copper complexes can also be immobilized on silica
gel supports through electrostatic interactions; this method
Our key objective was the immobilization of the BOX 7
was introduced by van Koten’s group[12] and employed by (Figure 2) on a polymeric support. For this reason an un-
the same group in the heterogeneous catalytic Diels–Alder successful attempt to convert 2-(4-hydroxybenzylidene)-
reaction and by McDonagh and O’Leary in the carbonyl- malonic acid (not shown) into the corresponding bis-amide
ene reaction.[13] The catalyst showed activity and enantio- by our standard method[14–16] was made.[18] It was assumed
selectivity similar to that observed in the homogeneous that the free hydroxy group was interfering with the reac-
phase for both reactions. However, a reversal of selectivity tion. In order to advance rapidly with this work, we at-
was observed, due to a change in the conformation of the tempted the synthesis of the analogous Arylid-BOX 8 (Fig-
catalyst on immobilization.
ure 2) by the method shown in Scheme 1. Although the
The Arylid-BOX family 6 of chiral nonracemic pseudo- TBDMS-protected dimethyl malonate ester 11 was success-
C2-symmetric bidentate bis-oxazoline ligands was intro- fully prepared from the p-TBDMS-protected hydroxymeth-
duced by us in 2006 (Figure 2).[14] They have shown signifi- ylbenzaldehyde derivative 10,[7] transformation into the cor-
cant applicability in some asymmetric catalytic reactions, responding protected diamide alcohol 13 proved impossible
such as styrene cyclopropanations,[15,16] the Friedel–Crafts despite our best efforts. Acid hydrolysis of the diester 11 by
alkylation of indole with phenylidenemalonates,[17a] and the the standard procedure[14–16] proved difficult, so we used
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519

E. P. Carreiro, N. M. M. Moura, A. J. Burke
FULL PAPER
Scheme 1. Attempted synthesis of 8.[19]
basic hydrolysis, leading to the disodium salt 12. Unfortu-
Compound 20 (Scheme 3) was obtained by the procedure
nately this intermediate failed to afford the diamide-alcohol reported by Evans et al.,[20] through a simple Knoevenagel
13 (Scheme 1), so the synthesis of 8 was abandoned.
condensation with dimethyl malonate and 4-benzyloxy-
Another approach was to attach the Aylid-BOX ligand benzaldehyde. Hydrolysis of 18 with NaOH in ethanol fur-
to a polymeric support by some elegant Suzuki–Miyaura nished the diacid 19.
chemistry with the commercially available polystyrene-im-
The synthesis of 21 was achieved through two important
mobilized phenylboronic acid 16b (Scheme 2). Study of the steps: formation of the malonamide 20 and subsequent cy-
conditions for this Suzuki–Miyaura reaction was first car- clization to afford 21 (Scheme 3). In order to deprotect 21
ried out with a homogeneous model system involving the and to convert it into 9 (Figure 2) we chose a palladium-
p-halo-Arylid-BOX ligands 15 and phenylboronic acid (16a, catalyzed debenzylation strategy as the method of choice,
Scheme 2). The p-bromo-Arylid-BOX 15a and p-chloro-Ar- even though many other methods exist for this transforma-
ylid-BOX 15b were prepared under our standard condi- tion (such as the use of Lewis acids), due to it being an
tions.[14,15] Unfortunately, after much experimentation with efficient, clean, and simple method. Catalytic hydrogenation
a variety of sets of conditions – which included the use of with Pd on activated charcoal was the method of choice.[21]
various palladium catalysts [e.g. Pd(OAc)2, Pd- It was assumed that the olefin unit would remain unsatu-
(dba)2, Pd(dppf)2, Pd(PPh3)4], bases, and ligands – it was rated, due to its high degree of conjugation with the two
not possible to obtain the phenylated Arylid-BOX 17a.[19]
oxazoline rings.[15] However, only starting material was re-
covered, as indicated by H NMR spectroscopy. The reac-
1
tion was repeated with heating at 50 °C, but, unexpectedly
for us, the partially hydrogenated Arylid-BOX derivative 9
(Figure 2 and Scheme 3) was obtained, as was confirmed
by 13C NMR (presence of C=N peaks at δ = 166.1 and
165.9 ppm) and high-resolution mass spectrometry. Other
hydrogenation methods were conducted, including the
method of Felix et al.,[22] involving a catalytic transfer hy-
drogenation with cyclohexa-1,4-diene as the hydrogen do-
nor at room temperature (25 °C) in the presence of Pd/C
(10%). However, the initial Arylid-BOX 21 was obtained in
all cases.
With this unexpected route to 9 now available to us, how-
ever, we decided to immobilize this ligand on Wang resin.
Immobilization of 9 on Wang resin (benzyloxybenzyl brom-
ide, 0.5–1 mmol Br per gram resin) was carried out with
NaH in DMF followed by addition of Br-Wang resin to
give the immobilized ligand 22 (Scheme 3). Microanalysis
of 22 indicated a loading of 0.321 mmol of ligand per gram
of resin. We chose Wang resin as the support because it is
Scheme 2. Suzuki–Miyaura coupling strategy to immobilize the
arylid-BOX ligand.
We decided in the end to return to our initial strategy
and to obtain ligand 7 from the benzyloxy-protected pre-
cursor 21 (Scheme 3). The Arylid-BOX 21 was prepared in
a good yield by our established method for the synthesis of
Arylid-BOX ligands (Scheme 3).[14–16]
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Immobilization of Arylid-BOX Ligands
Scheme 3. Reaction conditions: a) piperidine (5 mol-%), acetic acid (5 mol-%), benzene, Δ; b) NaOH (2.5 equiv.), EtOH, 0 °C. c) (COCl)2,
DMF, CH2Cl2; d) (R)-phenylglycinol, NEt3, CH2Cl2; e) MsCl, NEt3, CH2Cl2; f) Pd/C (10%), H2 (balloon), EtOH at 50 °C, 24 h; g) Wang
resin, NaH, DMF, 50 °C.
a well defined polymeric resin and because the active cata-
lytic sites on the resin were expected to be more accessible
during the reaction.
We also used our new procedure to convert the Arylid-
BOX 6a into the corresponding partially hydrogenated de-
rivative 23 (Scheme 4). Compound 23 was used as a refer-
ence to establish the efficiency of the immobilized Arylid-
BOX 22 in the CACP of styrenes.
Scheme 5. Asymmetric cyclopropanation of styrene Ϫ the bench-
mark reaction for this study.
The Arylid-BOX-derivatives 9 and 23 were also evaluated
in the CACP of styrene (Scheme 4). The best enantio-
selectivities were obtained with the ligand 9 – 68% ee for
cis-cyclopropane and 64% ee for the trans-cyclopropane –
but the yield and diastereoselectivity were inferior to those
obtained with ligand 23. The enantioselectivities were
slightly higher for the cis-cyclopropane (68% ee) than for
the trans-cyclopropane (64% ee), in a result that was the
opposite of that obtained with the Arylid-BOX ligand.[14,15]
Scheme 4. Synthesis of the arylid-BOX derivative 23.
Catalytic Asymmetric Cyclopropanation of Styrene
The polymer-supported Arylid-BOX-derivative 22 was CACP with the ligand 9 gave better enantioselectivities than
evaluated in the benchmark CACP of styrene. Three studies those obtained with the Arylid-BOX ligand 6a (Fig-
were carried out with [Cu(MeCN)4]PF6 and two different ure 2).[15] These results seem to indicate some inductive ef-
solvents: CH2Cl2 and toluene, and Cu(OTf)2 with CH2Cl2 fect by the hydroxy group in ligand 9. It should be noted
(Scheme 5 and Table 1). The objective was to compare these that the reaction in the presence of 6a had also been carried
reactions with those performed with the homogeneous sys- out in toluene, giving enantioselectivities of 54% and
tem and to verify which precatalyst was more suitable for 47% ee for the trans and cis isomers, respectively and a dia-
the heterogeneous reaction.
stereoselectivity of 30% de, with a yield of 20%.[14]
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E. P. Carreiro, N. M. M. Moura, A. J. Burke
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Table 1. Catalytic asymmetric cyclopropanation of styrene.[a]
.
Entry Precatalyst
Ligand Solvent
Cycle
Yield[b]
[%]
cis/trans[c]
ee[c]
cis [%]
ee[c]
trans [%]
Products/
dimers[c]
1[14]
2[14]
3
4
5
6
7
8
[Cu(MeCN)]4PF6
[Cu(MeCN)]4PF6
Cu(OTf)2
[Cu(MeCN)]4PF6
[Cu(MeCN)]4PF6
[Cu(MeCN)]4PF6
6a
6a
6a
23[e]
9
CH2Cl2
toluene[d]
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene[d]
toluene[d]
toluene[d]
toluene[d]
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
–
–
–
–
30
20
5
35:65
35:65
27:73
29:71
37:63
32:68
30:70
32:68
32:68
33:67
33:67
36:64
36:64
32:68
31:69
28:72
30:70
45
47
53
52
68
45
50
44
36
62
61
58
57
52
47
13
17
57
54
63
59
64
68
67
69
47
71
71
66
64
68
70
36
22
n.d.
n.d.
n.d.
63
31
61
38
57
44
30
26
36
33
5
92:8
93:7
99:1
89:11
97:3
97:3
98:2
91:9
91:9
90:10
76:24
95:5
72:28
81:19
–
22
first
second
third
fourth
first
second
third
fourth
first
second
third
fourth
9[f]
10
11
12
13[g]
14
15
16
17[h]
[Cu(MeCN)]4PF6
Cu(OTf)2
22
22
47
19
24
[a] Styrene (4 equiv.), [Cu(MeCN)4]PF6 or Cu(OTf)2 (0.027 mmol, 2 mol-%), ligand (2.2 mol-%), EDA (1 equiv.), solvent (5 mL), room
temp., 48 h. [b] Calculated by determining the product weight. [c] Determination by GC analysis; n.d. = not determined. [d] Temperature
was 40 °C. [e] Determined with use of an internal standard. [f] ICP-OES 0.204 mmol Cug–1 after the fourth cycle (before the first cycle
0.265 mmol Cug–1). [g] ICP-OES 0.137 mmol Cug–1 after the fourth cycle (before the first cycle 0.265 mmol Cug–1). [h] ICP-OES
0.109 mmol Cug–1 after the fourth cycle (before the first cycle 0.266 mmol Cug–1).
The polymeric ligand 22 was complexed with both CuI isomer 71% ee) were very similar, although there were slight
and CuII precatalysts. The results obtained in the hetero- decreases in the yield and the selectivity. In the third cycle
geneous CACP of styrene in the presence of [Cu(MeCN)]4- there were also slight decreases in the enantioselectivities
PF6 with EDA and CH2Cl2 showed that the enantio- and the diastereoselectivity, but the yield was larger by
selectivity for production of the cis-cyclopropane decreased, 10%. The results obtained in the fourth cycle were closer
but that for the trans-cyclopropane remained the same as to those of the third cycle. The supported CuI complex iso-
that obtained in the homogeneous CACP with 9 (Table 1, lated after the fourth cycle was analyzed by ICP-OES and
Entries 5 and 6). The diastereoselectivity increased in the a loading of 0.137 mmol Cu g–1 was determined; 48% of
heterogeneous system. In the second cycle the ee of the cis- the CuI had leached out over the four cycles. This was prob-
cyclopropane was increased as well as the diastereoselectiv- ably due to the higher temperature used.
ity, but the yield was less, due to a decrease in selectivity
On comparing the results obtained for the CACP in tolu-
(i.e., the amounts of maleate/fumerate side products in- ene and in CH2Cl2, it was toluene that gave the more con-
creased due to increased dimerization under these condi- sistent enantioselectivities over the four cycles. In the case
tions). This behavior could imply reduced levels of or no of CH2Cl2 the enantioselectivities became progressively
free copper in the mixture. In the third cycle, the enantio- lower with the number of cycles.
selectivity of the cis-cyclopropane production had de-
For the CACP of styrene with 22-Cu(OTf)2, EDA, and
creased, but the yield and selectivity had increased. These CH2Cl2 the enantioselectivities and diastereoselectivities re-
results were very similar to those encountered in the first mained almost constant between the first (cis isomer
cycle. In the fourth cycle both the enantioselectivities and 52% ee and trans isomer 68% ee) and the second cycles (cis
the yield had decreased, particularly for the trans-cyclopro- isomer 47% ee and trans isomer 70% ee), but the yield and
pane. The diastereoselectivity and selectivity remained con- the selectivity significantly increased. After the second cycle
stant. After the last cycle the supported-ligand 22-[Cu- the enantioselectivities, yield, and selectivity decreased
(MeCN)4]PF6 complex was analyzed by ICP-OES, and it more than half.
was determined to have a loading of 0.204 mmol Cug–1,
this result indicating only 23% leaching of CuI over the four in CH2Cl2, the yields and enantioselectivities (after the sec-
reaction cycles.
ond cycle) were in general lower for the CuII catalyst. It is
On comparison of the results obtained for CuII with CuI
Toluene was used as the solvent in the CACP of styrene not known for sure why this was the case.
in the presence of [Cu(MeCN)4]PF6-polymer supported li-
gand 22 and the reactions were carried out at 50 °C. In
terms of enantioselectivity, the results were better than in
the homogeneous case (vide supra).[14] They were also bet-
ter than when CH2Cl2 was used (vide infra). Heating was
necessary to activate the catalyst.[13] The results obtained
Noncovalent Immobilization
Arylid-BOX-Copper Complexes Immobilized by Ion
Exchange on MK10
The Arylid-BOXs 6a and 6b were prepared by our pro-
for the first and second cycles (cis isomer 61% ee and trans cedure.[15,16] Some of the chiral complexes were obtained
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Immobilization of Arylid-BOX Ligands
Table 2. Catalytic asymmetric cyclopropanation of styrene in the presence of 6a-CuII(OTf)2 and 6b-[CuI(MeCN)4]PF6 immobilized on
MK10.
Catalyst type
Cycle
Solvent
DCM
Cu[a]
Yield[b]
[%]
ee[c]
cis [%]
ee[c]
trans [%]
cis/trans[c]
Products/
[mmolg–1]
[%]
dimers[c] [%]
Homogeneous
Heterogeneous
Heterogeneous
Heterogeneous
n.a.
first
second
third
–
–
–
5
53
46
45
35
63
38
46
23
27:73
34:66
36:64
40:60
n.d.
80:20
87:13
91:9
19
30
37
0.053
Homogen-
n.a.
–
25
39
47
35:65
n.d.
toluene
eous[d][15,16]
Heterogeneous[d]
Heterogeneous[d]
first
second
–
25
11
43
43
50
19
41:59
39:61
86:14
85:15
0.045
[a] Determined by ICP-OES analysis after the corresponding run. [b] Determined by mass isolation. [c] Determined by GC analysis.
[d] The temperature was 40 °C. n.a.: not applied. n.d.: not determined.
with use of equimolecular amounts of Cu(OTf)2 and 6a in gents.[24] It was hypothesized that potentially important ste-
dry CH2Cl2. The ion exchange was carried out by stirring a ric effects between the surface and the incoming alkene en-
suspension of non-activated MK10 (used without any acid able the transition state leading to the cis-cyclopropane
treatment) in CH2Cl2 (Scheme 6). The quantity of Cu im- product to be freer from steric interactions. In the case of
mobilized in the MK10 was analyzed by ICP-OES. The the immobilized 6b the ee values are similar but rather in-
quantity of ligand immobilized in MK10 was also analyzed ferior in the first cycle and decreased in the second cycle.
by microanalysis. In the case of ligand 6b, it was complexed The catalytic asymmetric cyclopropanation with the hetero-
with [Cu(MeCN)4]PF6 in CH2Cl2. The ion exchange was geneous catalyst 6b-CuI(MeCN)4 and styrene was carried
carried out with MK10 (Scheme 6). From the analysis of out with 2.05 mol-% catalyst, practically the same amount
the immobilized Cu in the MK10 support, the immobiliza- that was used in the original homogeneous catalysis (2 mol-
tion of 6b-[Cu(MeCN)4]PF6 was more effective than that %).[14,15] The enantioselectivity obtained with this immobi-
for the 6a-Cu(OTf)2 complex, despite the fact that the same lized catalyst was lower than for the homogeneous catalytic
amount of complex was immobilized in 50 mg less MK10 system. The results obtained for the first cycle were very
support. The catalysts 6a-Cu(OTf)2 and [Cu(MeCN)4]PF6 close to those obtained in the homogeneous reaction, the
cannot be compared, however, because the ligands used main difference being the higher yield obtained in the
were different, but are compared with the homogeneous heterogeneous phase, which is accounted for on the basis of
systems. Both 6a-Cu(OTf)2 MK10 and 6b-[Cu(MeCN)4]- the reduced level of maleate/fumarate side-product forma-
PF6 MK10 were screened in the heterogeneous benchmark tion in the case of the heterogeneous reaction. With this
cyclopropanation of styrene with EDA (Scheme 5 and immobilized catalyst we observed once again that the yield
Table 2). We conducted four cycles in each case, but only and the stereoselectivities drop from one cycle to the next.
the first two cycles were of significance and are listed in
Table 2. In terms of enantioselectivity, it is obvious from
these results that immobilized 6a gives results closer to
those seen with the homogeneous phase. On going from the
first cycle to the second cycle, there were significant drop-
offs both in the enantioselectivities and in the yield. This
we believe to be a consequence of leaching of the catalyst
from the support, because ICP analysis of the recovered
supported catalyst after the fourth cycle revealed a 35% loss
of catalyst. The quantity of nitrogen in the 6a-Cu(OTf)2 on
MK10 recovered after the fourth cycle was determined by
elemental analysis and implied that it was only the Cu that
Scheme 6. Ion-exchange of the Cu complexes on MK10.
was being leached out and not the full catalyst, because the
quantity of nitrogen remained constant. We cannot explain
this result, but it might be because the copper is not bound
to the BOX ligand, and can be removed easily. Curiously,
the cis-cyclopropane was obtained with better enantio-
selectivity than the trans-cyclopropane in these reactions.
Mayoral’s group has reported a similar result in the case of
analogous BOX-derived Cu catalysts on other clay sup-
ports.[23] To explain this phenomenon Mayoral and co-
There was also a gradual increase in the proportion of
cis-cyclopropane produced on going from the first to the
second cycle.
Arylid-BOX-CuII(OTf)2 Complex Immobilized by
Hydrogen Bonding with SiO2
The 6a-Cu(OTf)2 complex in dichloromethane was im-
workers have proposed a working model involving key ste- mobilized on silica gel by the rapid method introduced by
reochemical interactions between the catalyst and the rea- van Koten[12] (Scheme 7). The electrostatically immobilized
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E. P. Carreiro, N. M. M. Moura, A. J. Burke
FULL PAPER
Scheme 7. Representation of the immobilization of 6a-Cu(OTf)2 on silica gel and its subsequent reduction to CuI.
Table 3. Catalytic asymmetric cyclopropanation of styrene in the presence of complex 6a-Cu(OTf)2 immobilized on silica gel.
Catalyst type
Run
Complex
Cu
t [h]
Yield[a]
[%]
ee[b]
cis
[%]
ee[b]
trans
[%]
cis/trans[b]
[%]
Products/
dimers[b]
[%]
[mmolg–1]
Homogeneous
Heterogeneous
Heterogeneous
n.a.
first
second
6a-Cu(OTf)2
–
20
45
45
5
31
18
53
65
47
63
62
46
27:73
32:68
38:62
n.d.
94:6
87:13
0.133[c]
–
Homogeneous[16]
Heterogeneous
Heterogeneous
n.a.
first
second
6b-[Cu(MeCN)4]PF6
–
24
45
45
100
22
14
41
39
26
50
45
37
31:69
34:66
40:60
95:5
83:17
82:18
0.171[c]
–
[a] Determined by GC with use of di-n-butyl ether as the internal standard. [b] Determined by chiral GC analysis. [c] Determined by
ICP-OES analysis before the first run. n.d.: not determined.
catalyst was tested in the benchmark catalytic asymmetric catalyst reuse. There was, yet again, a preference for the
cyclopropanation (Scheme 5) in both CH2Cl2 and toluene formation of the cis-cyclopropane with this support.
as solvents (Table 3).
In the case of the reactions run in CH2Cl2, the enantio-
selectivities were lower in the case of the supported reac-
tions, although the yields increased from the first to the
Conclusions
third cycles. There were also gradual increases in the
The covalent immobilization method described in this
amounts of cis-cyclopropane produced on going from the paper is a simple way to immobilize bis(oxazoline) ligands
homogeneous phase to the last cycle. In this case, the quan- on polymeric supports. Evaluation of the polymeric ligand
tities of maleate/fumarate side-product decreased on going 22 in the CACP showed that the activity of the CuI catalyst
from the first to the third cycles. There was also significant and its selectivity remained constant over four cycles,
leaching in this case, of approximately 81% in immobilized achieving similar results to the homogeneous system. This
Cu from the first to the third cycles (it was estimated on was one of the advantages of this system over the Knight
the basis of the quantity of ligand and catalyst used that and Belcher[7] system.
there was initially approximately 0.28 mmol of Cu immobi-
lized on the support).
The covalent immobilization method described in this
paper has many advantages over the grafting technique by
With regard to the copper oxidation state, because the polymerization documented in the literature.[5] Burguete
catalyst is constantly maintained under anhydrous condi- et al.[5b] could only obtain a highest enantioselectivity of
tions, it is assumed that it remains in the CuI oxidation state 33% ee (in relation to our highest of 71% ee) with their
throughout. The color of the solid was always green.
immobilized ligand 2 (Figure 1). The immobilized catalyst
When toluene was used, the enantioselectivity achieved gave results similar to those achieved with the non-immobi-
in the first run was slightly better than that obtained with lized catalyst in the CACP of styrene with [Cu(MeCN)4]-
the homogeneous phase. Although the enantioselectivities PF6.
and the yields for the cis-cyclopropane were constant in the
If the results obtained for the noncovalent immobilized
first and second cycles, the enantioselectivities for the trans- Arylid-BOX catalysts and for the covalently immobilized
cyclopropane and the yields dropped drastically in the sec- catalyst are compared, the latter was superior in all aspects:
ond cycle. Once again there was significant leaching, of the activity, selectivity, and recycling. Leaching of the catalyst
order of 84%, indicating that this method of weak immobi- was less than that observed in the noncovalent immobiliza-
lization with this catalytic system is not very applicable for tion process.
524
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 518–528

Immobilization of Arylid-BOX Ligands
2-(4-Benzyloxybenzylidene)malonic Acid (19): A solution of 18
(6.580 g, 0.020 mol) in ethanol (50 mL) was added to a solution of
NaOH (2.016 g, 0.050 mol) in ethanol (150 mL) and the mixture
was stirred for 4 d at 0 °C. The ethanol was removed under reduced
pressure and the residue was dissolved in H2O (until the solution
became clear), allowed to cool, and cautiously acidified with concd.
HCl to a pH of 3.0. The acid was extracted with EtOAc
(3ϫ75 mL), and the organic layers were dried (MgSO4), filtered,
and concentrated to afford the 19 as a pale yellow solid (3.410 g,
Experimental Section
General Remarks: 2-Phenyl-1,1-bis[(S)-4-phenyloxazoline-2-yl]eth-
ene (6a),[15] 2-(2-methoxyphenyl)-1-[(S)-4-phenyloxazoline-2-yl]eth-
ane (23)[21] and the α-amino alcohol (R)-phenylglycinol[25] were pre-
pared by previously described methods. Solvents were dried by
common laboratory methods. All reagents were obtained from Ald-
rich, Fluka, Alfa Aesar, or Acros. Column chromatography was
carried out on silica gel (sds, 70–200 μm), as was flash column
chromatography (Merck, 40–63 μm and sds, 40–63 μm). TLC was
carried out on aluminium-backed Kieselgel plates (Merck,
60 F254). Plates were visualized either under UV light or by use of
phosphomolybdic acid in ethanol. The melting points were re-
corded with a Barnstead Electrothermal 9100 apparatus and are
uncorrected. The NMR spectra were recorded either with a Bruker
AMX 300 (1H: 300.13 MHz and 13C: 75 MHz) instrument or with
a Bruker Avance instrument (1H: 400 MHz and 13C: 100 MHz) in
CDCl3 or [D6]DMSO as solvents. Mass spectra were recorded with
a Waters-Micromass GC-TOF and a MicroTOF Focus (Bruker
Daltonics) instrument by the TOF technique and electron spray
ionization (ESI) mass spectra were recorded with a Bruker Dalton-
ics Apex-Qe instrument. Infrared spectra were measured with a
Perkin–Elmer Paragon 1000 model. Gas chromatographic (GC)
analyses of the products were performed with a Hewlett–Packard
(HP) 6890 series instrument and a flame ionization detector (FID).
The chromatograph was fitted with a cyclosil-B capillary column
(30 m, 250 μm, 0.25 μm, Agilent 112–2532). ICP-OES analyses
were performed with a Perkin–Elmer Optima 4300 DV instrument
at CACTI, Universidad de Vigo. Elemental analysis was performed
with an EA 1108 CHNS-O Fisons instrument. Specific rotations
were measured with a Perkin–Elmer 241 polarimeter.
1
57%); m.p. 186 °C. H NMR (300 MHz, [D6]DMSO): δ = 7.56 [d,
J = 8.7 Hz, 2 H, CH(Ar)], 7.47–7.33 [m, 6 H, CH(Ar), RCH=CR2],
7.07 [d, J = 8.4 Hz, 2 H, CH(Ar)], 5.15 (s, 2 H, OCH2Ph) ppm. 13
C
NMR (100 MHz): δ = 168.3, 165.5, 160.1, 138.4, 136.6, 131.3,
128.5, 128.0, 127.8, 125.8, 125.4, 115.3, 69.4 ppm. IR (KBr): ν
˜
max
= 3346, 2979, 1728, 1665, 1514, 1436, 1280, 1217, 1067, 1174,
837 cm–1. MS (ESI-TOF): m/z = 299.10 [M + 1]+.
2-(4-Bromophenyl)-1,1-bis[(S)-4-phenyloxazolin-2-yl]ethene (15a): A
100 mL round-bottomed flask containing a magnetic stirring bar
was charged with malonic acid (3.0 g, 28.8 mmol) and p-bro-
mobenzaldehyde (5.3 g, 28.8 mmol). The mixture was heating at
80 °C for 24 h. The mixture was allowed to cool to room tempera-
ture and extracted with Et2O (15 mL) and NaOH (1 m, 25 mL).
The aqueous layer was washed with Et2O (10 mL), a solution of
concd. HCl was added until pH 1, and the aqueous layer was ex-
tracted with EtOAc (3ϫ10 mL). The organic layer was collected,
dried with anhydrous MgSO4, filtered, and concentrated under vac-
uum to give 2-(4-bromobenzylidene)malonic acid as a white solid
1
(1.8 g, 24%). H NMR (300 MHz, [D6]DMSO): δ = 7.87 (s, 1 H,
ArCH=CR2), 7.72–7.65 [m, 2 H, CH(Ar)], 7.52–7.49 [m, 2 H,
CH(Ar)] ppm.
The 2-(4-bromobenzylidene)malonic acid (1.8 g, 6.6 mmol) was
placed in a dry 25 mL two-necked round-bottomed flask contain-
Dimethyl 2-[4-(tert-Butyldimethylsilanoxy)benzylidenemethyl]mal-
onate (11): A dry round-bottomed flask fitted with a Dean–Stark
trap and condenser and containing a magnetic stirring bar was
charged with acetic acid (0.4 mL, 5 mol-%), piperidine (0.6 mL,
5 mol-%), dimethyl malonate (1.58 mL, 0.024 mol), 4-[(tert-butyldi-
methylsilyl)methoxy]benzaldehyde (10)[7] (3.5 g, 0.014 mol), and
benzene (60 mL). The solution was stirred at reflux. The cooled
reaction mixture was washed with water and brine, dried with
MgSO4, and concentrated in vacuo to give 11 as a yellow solid
ing
a magnetic stirring bar, dimethylformamide (0.06 mL,
0.86 mmol), and CH2Cl2 (20 mL). The solution was cooled to 0 °C,
oxalyl chloride (1.5 mL, 16.6 mmol) was added dropwise over
30 min, and the solution was then stirred at room temperature until
the evolution of gas had ceased. The solution was concentrated in
vacuo to give the 4-bromobenzylidenemalonyl chloride intermedi-
ate as a yellow semi-solid (2.0 g, 97%). A 25 mL two-necked round-
bottomed flask containing a magnetic stirring bar was charged
with a solution of (S)-phenylglycinol (0.6 g, 4.4 mmol) and dry
CH2Cl2 (15 mL) and the solution was cooled to 0 °C with an ice
bath. Dry triethylamine (0.92 mL, 6.6 mmol) was added by syringe.
1
(4.83 g, 95%); m.p. 59–60 °C. H NMR (300 MHz): δ = 7.77 (s, 1
H, ArCH=CR2), 7.41–7.33 [m, 4 H, CH(Ar)], 4.76 (s, 2 H, OCH2-
OTBDMS), 3.85 (s, 6 H, –CO2CH3), 0.95 [s, 9 H, –C(CH3)3], 0.11
[s, 6 H, Si(CH3)2] ppm. 13C NMR (100 MHz): δ = 167.4, 164.7,
144.7, 143.0, 131.5, 129.6, 126.4, 125.1, 64.6, 52.7, 26.1, 18.5,
A
solution of crude 2-(4-bromobenzylidene)malonyl chloride
(0.85 g, 2.78 mmol) in CH2Cl2 (5 mL) was slowly added by syringe
to the vigorously stirred reaction mixture over 30 min. The ice bath
was removed, and the reaction mixture was stirred at room tem-
perature for 2 h. The reaction mixture was washed with HCl (2 m,
12 mL) and saturated aqueous NaHCO3 (15 mL) and the aqueous
layer was back-extracted with CH2Cl2 (10 mL). The combined or-
–5.2 ppm. IR (KBr): ν
= 2955, 1733, 1702, 1631, 1440, 1230,
˜
max
1100, 838, 774 cm–1.
Dimethyl 2-[4-(Benzyloxy)benzylidene]malonate (18): A dry round-
bottomed flask fitted with a Dean–Stark trap and condenser and
containing a magnetic stirring bar was charged with acetic acid
(0.068 mL, 1.2 mmol, 5 mol-%), piperidine (0.11 mL, 1.2 mmol, ganic extracts were washed with brine (15 mL) and the aqueous
5 mol-%), dimethyl malonate (2.7 mL, 0.024 mol), 4-(benzyloxy)-
benzaldehyde (5 g, 0.024 mol), and benzene (60 mL). The solution
was stirred at reflux until 0.43 mL of H2O had been removed. The
cooled reaction mixture was washed with water and brine, dried
with MgSO4, and concentrated in vacuo to give 18 as a pale yellow
layer was back-extracted with CH2Cl2 (15 mL). The combined or-
ganic extracts were dried with anhydrous MgSO4, filtered, and con-
centrated in vacuo to give (S,S)-N,NЈ-bis(2-hydroxy-1-phenylethyl)-
2-(4-bromobenzylidene)malonamide as a yellow solid. The crude
product was purified by column chromatography (silica gel,
EtOAc) to afford the amide as a white solid (0.46 g, 41%); m.p.
1
solid (8.13 g, 95%); m.p. 54–55 °C. H NMR (300 MHz, CDCl3):
δ = 7.70 (s, 1 H, ArCH=CR2), 7.39–6.83 [m, 9 H, CH(Ar)], 4.50 86–87 °C. [α]2D4 = –66 (c = 0.81, CHCl3). 1H NMR (400 MHz,
(s, 2 H, OCH2Ph), 3.87 (s, 3 H, –CO2CH3), 3.84 (s, 3 H, CDCl3): δ = 7.90 (d, J = 8 Hz, 1 H, NH), 7.85 (d, J = 8 Hz, 1 H,
–CO2CH3) ppm. 13C NMR (100 MHz): δ = 167.7, 164.9, 142.6,
136.3, 131.6, 128.7, 128.3, 127.5, 125.6, 123.0, 115.3, 70.2, 52.7,
NH), 7.42 (s, 1 H, ArCH=CR2), 7.31–7.25 [m, 10 H, CH(Ar)], 7.13
[d, J = 8 Hz, 2 H, CH(Ar)], 7.00 [d, J = 8 Hz, 2 H, CH(Ar)], 5.30–
2.25 (m, 1 H, CH), 5.21–5.16 (m, 1 H, CH), 3.88–3.69 (m, 4 H,
CH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.1, 164.7, 138.4,
52.6 ppm. IR (KBr): ν
= 3004, 2952, 1712, 1598, 1380, 1228,
˜
max
1181, 1063, 147 cm–1. MS (ESI-TOF): m/z = 327.05 [M + H]+.
Eur. J. Org. Chem. 2012, 518–528
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
525

E. P. Carreiro, N. M. M. Moura, A. J. Burke
FULL PAPER
138.3, 137.6, 132.0, 131.9, 131.8, 131.0, 129.0, 128.9, 128.2, 128.0,
5.37 (m, 1 H, CH), 5.23–5.22 (m, 1 H, CH), 4.91 (s, 2 H,
–OCH2Ph), 3.86–3.79 (m, 2 H, CH2), 3.66 (dd, J = 9.7, 11.6 Hz, 2
H, CH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.8, 165.3,
159.8, 139.3, 138.3, 137.6, 136.3, 131.7, 128.7, 128.6, 128.1, 128.1,
127.7, 127.7, 127.4, 127.3, 126.5, 125.4, 114.5, 69.7, 65.7, 65.5,
127.2, 126.7, 124.3, 66.2, 65.7, 56.4, 56.1 ppm. IR (KBr): ν
=
˜
max
3271, 2929, 1737, 1662, 1531, 1261, 1073, 819, 757, 700 cm–1. MS
(ESI-TOF): m/z = 509.1052 [M + 1]+. HRMS (ESI): calcd. for
C26H26BrN2O4 [M + H]+ 509.10522; found 509.10705.
56.1 ppm. IR (KBr): ν
= 3274, 2930, 1736, 1659, 1602, 1511,
˜
max
A solution of methanesulfonyl chloride (0.14 g, 1.25 mmol) in dry
CH2Cl2 (1 mL) was added dropwise over 20 min to a solution of
the malonamide (0.25 g, 0.5 mmol) and dry triethylamine (0.42 mL,
3.0 mmol) in dry CH2Cl2 (20 mL) and the solution was stirred be-
tween –5 and –10 °C. The reaction mixture was allowed to warm to
room temperature and stirring was continued for 3 d. The reaction
mixture was then poured into a saturated aqueous NH4Cl solution
(10 mL). The organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (2ϫ10 mL). The combined organic lay-
ers were washed with brine, dried (MgSO4), filtered, and concen-
trated to afford the crude product. The crude product was purified
by column chromatography (silica gel, EtOAc/hexane 1:1) to give
bis[(S)-4-phenyloxazoline-2-yl]-2-(4-bromophenyl)ethene (15a) as a
yellow solid (0.07 g, 30%); m.p. 134–135 °C. [α]2D4 = +42.7 (c = 0.93,
1177, 1026, 829, 753, 699 cm–1. MS (ESI-TOF): m/z = 537.24 [M
+ H]+. HRMS (ESI): calcd. for C33H33N2O5 [M + H]+ 537.23696;
found 537.23840.
2-(4-Benzyloxyphenyl)-1,1-bis[(R)-4-phenyloxazoline-2-yl]ethane
(21): A solution of methanesulfonyl chloride (0.166 g, 1.45 mmol)
in dry dichloromethane (1 mL) was added dropwise over 20 min
to a solution of the malonamide 20 (0.354 g, 0.66 mmol) and dry
triethylamine (0.55 mL, 3.96 mmol) in dry dichloromethane
(20 mL) and the solution was stirred between –5 and –10 °C. The
reaction mixture was allowed to warm to room temperature and
stirring was continued for 3 d. The reaction mixture was then
poured into a saturated aqueous NH4Cl solution (10 mL). The or-
ganic layer was separated and the aqueous layer was extracted with
CH2Cl2 (2ϫ10 mL). The combined organic layers were washed
with brine, dried (MgSO4), filtered, and concentrated to afford the
crude product. The crude product was purified by column
chromatography [silica gel, EtOAc/hexane 1:1] to give bis[(R)-4-
phenyloxazoline-2-yl]-2-(4-benzyloxyphenyl)ethane (21) as a white
solid (0.11 g, 60%); m.p. 68 °C (decomposition). [α]2D0 = +50.3 (c =
1.89, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.68 (s, 1 H,
R2C=CHR), 7.50 [d, J = 8.8 Hz, 2 H, CH(Ar)], 7.42–7.23 [m, 15
H, CH(Ar)], 6.93 [d, J = 8.7 Hz, 2 H, CH(Ar)], 5.43 (dd, J = 9 Hz,
2 H, 2ϫ CHH), 5.08 (s, 2 H, –OCH2Ph), 4.88 (dd, J = 9, 10 Hz,
1 H, CHH), 4.81 (dd, J = 9, 12 Hz, 1 H, CHH), 4.31 (t, J = 8.4 Hz,
1 H, CH), 4.20 (t, J = 8.2 Hz, 1 H, CH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 163.7, 162.2, 160.2, 142.3, 141.9, 141.4, 136.4, 131.5,
128.7, 128.6, 128.6, 128.2, 127.5, 127.0, 126.8, 126.7, 74.9, 74.8,
CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 7.68 (s, 1 H,
ArCH=CR2), 7.46–7.26 [m, 14 H, Ar(H)], 5.44–5.36 (m, 2 H,
–CH2–), 4.3 (t, J = 8.4 Hz, 1 H, –CH–), 4.22 (t, J = 8.4 Hz, 1 H,
–CH–) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.3, 161.6, 142.1,
141.8, 140.6, 133.1, 132.0, 131.0, 128.8, 128.7, 127.7, 127.0, 126.8,
124.3, 119.5, 75.1, 75.0, 70.4, 70.3 ppm. IR (KBr): ν
= 2869,
˜
max
1672, 1634, 1615, 1182, 1024, 760, 702 cm–1. MS (ESI-TOF): m/z
= 473.09 [M + 1, Br79]+, 474.09 [M + 2, Br79]+, 475.09 [M + 1,
Br81]+, 476.09 [M
+
2, Br81]+. HRMS (ESI): calcd. for
C26H22BrN2O2 [M + H]+ 473.08538; found 473.08592.
(R,R)-2-(4-Benzyloxybenzylidene)-N,NЈ-bis(2-hydroxy-1-phenyl-
ethyl)malonamide (20): A dry 25 mL two-necked round-bottomed
flask containing a magnetic stirring bar was charged with 2-(4-
benzyloxybenzylidene)malonic acid (19) (1 g, 3.35 mmol), dimeth-
ylformamide (0.03 mL, 0.44 mmol), and CH2Cl2 (10 mL). The
solution was cooled to 0 °C, oxalyl chloride (0.73 mL, 8.38 mmol)
was added dropwise over 30 min, and the solution was stirred at
room temperature until the evolution of gas had ceased. The solu-
tion was evaporated in vacuo to give 4-benzyloxybenzylidenema-
lonyl chloride as a yellow semi-solid (because of the unstable nature
of this compound it was stored in the freezer at –10 °C). A 25 mL
two-necked round-bottomed flask containing a magnetic stirring
bar was charged with a solution of (R)-phenylglycinol (1.22 g,
8.88 mmol) and dry CH2Cl2 (15 mL) and the solution was cooled
to 0 °C with an ice bath. Dry triethylamine (1.24 mL, 8.88 mmol)
was added by syringe. A solution of crude 2-(4-benzyloxybenzylid-
ene)malonyl chloride (1.28 g, 3.35 mmol) in CH2Cl2 (5 mL) was
slowly added to the vigorously stirred reaction mixture by syringe
over 30 min. The ice bath was removed and the reaction mixture
was stirred at room temperature for 4 h. The reaction mixture was
washed with HCl (2 m, 12 mL) and saturated aqueous NaHCO3
(15 mL) and the aqueous layer was back-extracted with CH2Cl2
(10 mL). The combined organic extracts were washed with brine
(15 mL) and the aqueous layer was back-extracted with CH2Cl2
(15 mL). The combined organic extracts were dried with anhydrous
MgSO4, filtered, and concentrated in vacuo to give (R,R)-N,NЈ-
bis(2-hydroxy-1-phenylethyl)-2-(4-benzyloxybenzylidene)malon-
amide (20) as a yellow solid. The crude product was purified by
column chromatography (silica gel, EtOAc) to afford the amide 20
as a white solid (0.955 g, 53%); m.p. 90–91 °C. [α]2D0 = +62.2 (c =
1.03, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.40 (d, J =
70.2, 70.1, 70.0 ppm. IR (KBr): ν
= 2958, 1739, 1670, 1633,
˜
max
1601, 1509, 1250, 1173, 1013, 741, 699 cm–1. MS (ESI-TOF): m/z
= 501.22 [M + H]+. HRMS (ESI): calcd. for C33H29N2O3
[M + H]+ 501.21786; found 501.21727.
2-(4-Hydroxyphenyl)-1,1-bis[(R)-4-phenyloxazoline-2-yl]-ethane (9):
A dry 50 mL round-bottomed flask containing a magnetic stirring
bar was charged with the Arylid-BOX 21 (0.371 g, 0.74 mmol), dry
ethanol (25 mL), and Pd on activated carbon (0.186 g, 0.5 equiv.).
The mixtures were warmed to 50 °C and a balloon filled with hy-
drogen was attached to the flask. The mixture was stirred for 24 h
and then allowed to cool to room temp., filtered through a celite
filter, and washed with CH2Cl2 (30 mL), and the solvent was re-
moved under vacuum. The crude product was purified by column
chromatography (silica gel, EtOAc/hexane 91:9) to give 9 as a col-
1
orless semi-solid (0.14 g, 46%). [α]2D5 = –177 (c = 0.1, CHCl3). H
NMR (400 MHz, CDCl3): δ = 7.43–7.23 [m, 10 H, CH(Ar)], 6.98–
6.93 [m, 2 H, CH(Ar)], 6.29 [d, J = 8.3 Hz, 2 H, CH(Ar)], 5.21 (dd,
J = 9, 18 Hz, 2 H, 2ϫ CHH), 4.7 (dd, J = 8.6, 10 Hz, 2 H, 2ϫ
CH), 4.24 (t, J = 8 Hz, 1 H, CH), 4.17–4.09 (m, 2 H, 2ϫ CHH),
3.34–3.28 (m, 1 H, CHH), 3.27–3.22 (m, 1 H, CHH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 166.1, 165.9, 155.9, 141.6, 141.4,
129.7, 128.7, 127.8, 127.7, 127.7, 126.9, 126.6, 126.4, 115.6, 75.5,
75.4, 69.3, 68.9, 41.9, 34.9 ppm. IR (KBr): νmax = 3200, 2925, 1736,
˜
1657, 1613, 1516, 1239, 994, 823, 761, 700 cm–1. MS (ESI-TOF):
m/z = 413.19 [M + H]+. HRMS (ESI): calcd. for C26H25N2O3 [M
+ H]+ 413.18625; found 413.18597.
8.9 Hz, 1 H, NH), 7.84 (d, J = 8.4 Hz, 1 H, NH), 7.41–7.30 [m, 6 Wang-Resin-Supported 2-(4-Hydroxyphenyl)-1,1-bis[(R)-4-phenyl-
H, R2C=CHR, CH(Ar)], 7.26–7.18 [m, 10 H, CH(Ar)], 7.03 [d, J oxazoline-2-yl]ethane (22): The bis(oxazoline) (130 mg,
= 8.8 Hz, 2 H, CH(Ar)], 6.52 [d, J = 8.8 Hz, 2 H, CH(Ar)], 5.39– 0.315 mmol) was dissolved in dry DMF (5 mL), and NaH (60%,
9
526
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 518–528

Immobilization of Arylid-BOX Ligands
27 mg, 0.63 mmol) was added in one portion. The mixture became
yellow and the suspension was stirred for 30 min at room temp.
Wang-Br resin (0.5–1 mmolg–1, 0.630 g, 0.315 mmol) was added to
the reaction mixture, which was stirred under nitrogen overnight at
50 °C. The resin was filtered off and washed successively with
[Cu(MeCN)4]PF6 (22.51 mg, 0.06 mmol) were dissolved in CH2Cl2
(3 mL). The resulting complex (36 mg, 0.05 mmol) was immobi-
lized in MK10 (250 mg), and after washing the immobilized cata-
lyst, it was dried thoroughly, giving a final mass of 227 mg. It was
calculated to contain Cu (0.171 mmol per gram support) and N
MeOH (3 mL), THF/H2O (1:1, 3 mL), H2O (3 mL), CH2Cl2 (0.419 mmol per gram support) (as determined by EA).
(3 mL), and MeOH (3 mL). The supported ligand 22 was dried at
Heterogeneous Catalytic Asymmetric Cyclopropanation with the
40 °C under vacuum for several hours, giving a final mass of
MK10-Supported Catalysts
0.598 g, with a loading of 0.321 mmol of ligand per gram polymer.
Application of (6a)-Cu(OTf)2 MK10: Ethyl diazoacetate (EDA,
0.032 mg, 0.28 mmol) was added under nitrogen to a mixture con-
Catalytic Asymmetric Cyclopropanation of Styrene
[Cu(MeCN)4]PF6 as Precatalyst
taining the immobilized (6a)-Cu(OTf)2 catalyst (0.172 g,
0.0228 mmol, 1.6 mol-%) in dry CH2Cl2 (4 mL). This was followed
by the addition of styrene (580 mg, 5.6 mmol). The reaction mix-
ture was stirred for 15 min, followed by the addition of EDA
(0.159 mg, 1.4 mmol) in CH2Cl2 (1 mL) by syringe pump over 6 h.
It was found that the color of the insoluble supported catalyst
changed from grey to greenish. The reaction mixture was stirred
under nitrogen for 45 to 47 h. The solid was filtered off and washed
with CH2Cl2 and EtOAc, and the volatiles were then removed in
vacuo. The crude product was analyzed by GC with di-n-butyl
ether as an internal standard (Table 2). For the other runs the same
procedure was used, but because of the powdery nature of the sup-
ported catalyst some of the immobilized catalyst was inevitably
lost. However, although the quantity of supported catalyst used in
the subsequent cycles was reduced, the proportions were always the
same. In order to conduct these catalytic reactions rapidly it was
assumed that there was negligible catalyst leaching.
Representative Asymmetric Cyclopropanation of Styrene: The im-
mobilized catalyst 22 (92 mg, 0.029 mmol, 2.2 mol-%) was added
to a suspension of [Cu(MeCN)4]PF6 (10 mg, 0.027 mmol, 2 mol-
%) in solvent (4 mL). After 1 h, styrene (0.58 mL, 5.6 mmol,
4 equiv.) was added to the resulting green solution. A solution of
ethyl diazoacetate (159 mg, 1.4 mmol, 1.0 equiv.) in solvent (1 mL)
was added to the reaction vessel by syringe pump over 8 h. The
reaction mixture was stirred at room temperature for 40 h and was
filtered off and washed with CH2Cl2 to collect the products. The
yellow solid was dried under vacuum and used again in subsequent
catalytic cycles. The crude product was analyzed by GC. For the
other runs the same procedure was used, but because of the pow-
dery nature of the supported catalyst some of the immobilized cata-
lyst was inevitably lost. Although the quantity of supported catalyst
used in the subsequent cycles was reduced, however, the pro-
portions were always the same. In order to conduct these catalytic
reactions rapidly it was assumed that there was negligible catalyst
leaching. All cyclopropane products were obtained as mixtures of
cis and trans diastereomers, and the ratios were determined by GC
analysis. Isolated yields, diastereoselectivities, and enantioselectivi-
ties are given in Table 1.
Application of (6b)-[Cu(MeCN)4]PF6 MK10: Styrene (580 mg,
5.6 mmol) was added under nitrogen to a mixture containing the
immobilized (6b)-[Cu(MeCN)4]PF6 catalyst (0.168 g, 0.0287 mmol,
2.05 mol-%) in dry CH2Cl2 (4 mL). The reaction mixture was
stirred for 15 min, followed by the addition of EDA (0.159 mg,
1.4 mmol) in CH2Cl2 (1 mL) by syringe pump over 6 h. The reac-
tion mixture was stirred under nitrogen for 45 to 47 h. The solid
was filtered off and washed with CH2Cl2 and EtOAc, and the vola-
tiles were removed in vacuo. The crude product was analyzed by
GC with di-n-butyl ether as an internal standard (Table 2). For the
other runs the same procedure was used.
Cu(OTf)2 as a Precatalyst
Representative Asymmetric Cyclopropanation of Styrene: Ethyl di-
azoacetate (EDA, 0.032 mg, 0.28 mmol) was added under nitrogen
to a suspension of Cu(OTf)2 (9.6 mg, 0.027 mmol, 2 mol-%) in
CH2Cl2 (4 mL) together with immobilized catalyst 22 (92 mg,
0.029 mmol, 2.2 mol-%) in dry CH2Cl2 (4 mL). This was followed
by the addition of styrene (580 mg, 5.6 mmol). The reaction mix-
ture was stirred for 15 min, followed by the addition of EDA
(0.159 mg, 1.4 mmol) in CH2Cl2 (1 mL) by syringe pump over 6 h.
The reaction mixture was stirred under nitrogen for 48 h. The solid
was filtered off and washed with CH2Cl2, and the volatiles were
then removed in vacuo. The crude product was analyzed by GC.
All cyclopropane products were obtained as mixtures of cis and
trans diastereomers, the ratios of which were determined by GC
analysis. Isolated yields, diastereoselectivities, and enantioselectivi-
ties are given in Table 1.
Heterogeneous Catalytic Asymmetric Cyclopropanation with Cata-
lysts Supported on Silica Gel: A mixture of the Arylid-BOX 6a
(11.8 mg, 0.03 mmol) and Cu(OTf)2 (10.1 mg, 0.028 mmol) was dis-
solved in dry CH2Cl2 (2 mL) under nitrogen in a Schlenk tube and
stirred for 30 min at room temp. The catalyst complex solution was
filtered and the filtrate was added under nitrogen to pre-dried silica
gel (100 mg, 63–20 μm, dried for 1 h under vacuum at 70 °C) in
a dry Schlenk tube. The mixture was stirred until the color had
disappeared from the solution. The silica gel (which was now col-
ored) was allowed to settle and washed with dry dichloromethane
(2 mL) and then left under the appropriate dry reaction solvent
(2 mL) and nitrogen. EDA (0.032 mg, 0.28 mmol) was added under
nitrogen to the mixture containing the immobilized catalyst com-
plex, along with more dry solvent (1 mL), followed by styrene
(580 mg, 5.6 mmol). The reaction mixture was stirred for 15 min,
followed by the addition of EDA (0.159 mg, 1.4 mmol) in an appro-
priate dry reaction solvent (1 mL) by syringe pump over 6 h. The
reaction mixture was stirred under nitrogen for 91.5 h. The solvent
layer was removed with a Pasteur pipette and filtered through Ce-
lite, the remaining solid was then washed with dry solvent
(2ϫ5 mL), and the washings were filtered through Celite under
reduced pressure. The silica gel catalyst was left under a dry solvent
(1 mL) and nitrogen for subsequent catalytic runs. The combined
extracts were concentrated under reduced pressure to give the crude
Immobilization of the Cu Catalysts on MK10
Immobilization of (6a)-Cu(OTf)2: The Arylid-BOX 6a (20 mg,
0.05 mmol), Cu(OTf)2 (18 mg, 0.05 mmol), and dry CH2Cl2 (3 mL)
were placed in a flask under nitrogen. The mixture was stirred for
2 h. The solvent was removed. Montmorillonite K10 (300 mg) was
added to the complex (38 mg, 0.05 mmol) together with dry
CH2Cl2 (5 mL). The resulting suspension was stirred for 24 h. The
solid was filtered, washed with CH2Cl2, and dried under vacuum.
Immobilized catalyst (279 mg) was obtained and was calculated
(ICP-OES analysis) to contain Cu (0.133 mmol per gram support)
and N (0.296 mmol per gram support) (as determined by EA).
Immobilization of (6b)-[Cu(MeCN)4]PF6: By the same procedure as
described previously, the Arylid-BOX 6b (25.5 mg, 0.06 mmol) and
Eur. J. Org. Chem. 2012, 518–528
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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527

E. P. Carreiro, N. M. M. Moura, A. J. Burke
FULL PAPER
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Acknowledgments
We are grateful for financial support from the Fundação para a
Ciência e a Tecnologia (FCT) (project; PPCDT/QUI/55779/2004)
through POCI 2010, supported by the European community,
Fundo Europeu de Desenvolvimento Regional (FEDER). FCT is
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Received: June 1, 2011
Published Online: November 30, 2011
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Eur. J. Org. Chem. 2012, 518–528