Polytopic oxazoline-based chiral ligands for cyclopropanation reactions: A new strategy to prepare highly recyclable catalysts

Article abstract of DOI:10.1002/adsc.201100213

New polytopic chiral copper complexes based on azabis(oxazoline) moieties have been synthesized and applied in cyclopropanation reactions of several alkenes. Excellent enantioselectivities have been obtained in all cases and additionally, the catalysts have been recovered in up to 14 cycles without noticeable loss of activity and selectivity. Analysis of the copper complexes by mass spectrometry suggests the formation of coordination polymers, representing the resting state of the catalysts. Copyright

Full text of DOI:10.1002/adsc.201100213

FULL PAPERS
DOI: 10.1002/adsc.201100213
Polytopic Oxazoline-Based Chiral Ligands for Cyclopropanation
Reactions: A New Strategy to Prepare Highly Recyclable
Catalysts
Josꢀ I. Garcꢁa,a,* Clara I. Herrerꢁas,a,b Beatriz Lꢂpez-Sꢃnchez,a,c Josꢀ A. Mayoral,a,b
and Oliver Reiserc
a
Instituto de Sꢁntesis Quꢁmica y Catꢃlisis Homogꢀnea, Dept. Quꢁmica Orgꢃnica, CSIC –Universidad de Zaragoza, Calle
Pedro Cerbuna 12, 50009 Zaragoza, Spain
Fax : (+34)-97-676-2077; phone: (+34)-97-676-2271; e-mail: jig@unizar.es
Instituto Universitario de Catꢃlisis Homogꢀnea, Universidad de Zaragoza, Calle Pedro Cerbuna 12, 50009 Zaragoza,
b
Spain
c
Institut fꢄr Organische Chemie, Universitꢅt Regensburg, Universitꢅtsstrasse 31, 93053 Regensburg, Germany
Received: March 25, 2011; Revised: May 13, 2011; Published online: August 29, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100213.
Abstract: New polytopic chiral copper complexes Analysis of the copper complexes by mass spectrom-
based on azabis(oxazoline) moieties have been syn- etry suggests the formation of coordination polymers,
thesized and applied in cyclopropanation reactions representing the resting state of the catalysts.
of several alkenes. Excellent enantioselectivities
have been obtained in all cases and additionally, the Keywords: bis(oxazoline) ligands; catalyst recovery;
catalysts have been recovered in up to 14 cycles cyclopropanation reaction; enantioselective catalysis;
without noticeable loss of activity and selectivity. multitopic chiral ligands; self-assembled catalysts
Introduction
effort is not always rewarded since the activity of the
catalyst, once immobilized, is usually lower and the
Enantioselective catalysis is a key strategy in order to selectivities can vary as well. These effects are also
obtain optically pure compounds.[1] In this respect, ho- observed when the immobilization is performed by
mogeneous catalysts have proved to exhibit high ac- non-covalent methods due to diffusion limitations or
tivity and selectivity in a great number of organic re- to distortion in the geometry of the active sites in the
actions.[2] However, this catalytic methodology is not solid matrix. These results stress the important role of
always the most efficient one for large scale applica- the support for the catalyst performance, which still
tions because of possible product contamination remains not well understood.[4]
caused by incomplete separation of the catalyst, and
However, in spite of the advantages of heterogene-
the frequently encountered difficulties of recovery ous catalysts, homogeneous catalysis generally offers
and reuse of the usually expensive chiral catalyst. better values of TON per reaction and better enantio-
This limitation can, in principle, be overcome by het- selectivities. In this context, it would be highly desira-
erogeneous catalysts, which bear the promise of facile ble to develop a strategy that allows us to join the
separation from a reaction mixture, in most cases by best of both worlds, in other words, to combine the
simple filtration, and their subsequent reuse.
high activity and selectivity provided by homogeneous
Over the last decades several approaches have catalysis with the possibility of separation and recov-
been developed for the successful immobilization of ery offered by heterogeneous catalysis.
highly effective homogeneous catalysts.[3] The most
An appealing possibility is the use of release-and-
common strategy consists in the covalent linkage of capture mechanisms, in which the catalyst remains
the catalyst onto a solid support. This approach usual- heterogeneous when it is in its resting state at the end
ly needs a structural modification of the catalyst with of the reaction, thus being easily recoverable and re-
the consequent increase in the number of steps for usable. On the other hand, in the catalytically active
their synthesis. Nevertheless, the cost of that extra state, the catalyst is dissolved in the reaction medium,
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so that catalysis is truly homogeneous. Some applica-
In addition, structural characterization of the spe-
tions of this approach are based on catalyst microen- cies involved in the formation of the coordination
capsulation in flexible polymer matrices, non-covalent polymers has been done by means of mass spectrome-
immobilization on nanoparticles, or selective precipi- try.
tation.[5]
Another possibility recently described for achiral
catalysts is the use of insoluble self-assembled coordi- Results and Discussion
nation polymers.[6] The strategy consists of the hetero-
genization of the homogeneous catalyst by the self-as- Design and Synthesis of the Ligands
sembly of multitopic ligands and the corresponding
metallic ions.
The aim of synthesizing multitopic ligands based on
In a preliminary communication,[7] we described the the azabis(oxazoline) (AzaBox) moiety was to take
application of this strategy to the enantioselective cy- advantage of its strong coordinating ability to copper
clopropanation reaction through the use of a new di- together with its ease of preparation and functionali-
topic ligand 3, coined as DAX. Herein, we describe zation.
protocols for the synthesis of new multitopic chiral li-
Thus, different linkers between azabis(oxazolines)
gands based on the azabis(oxazoline) moiety in order (Scheme 1) are readily introduced, which allows an
to form self-assembled coordination polymers with effective screening of different systems with respect
copper. The catalytic performance of these systems to their assembly, solubility and activity profile.
has been tested in the benchmark enantioselective cy-
The synthesis of diazabis(oxazolines) (DAX) li-
clopropanation reaction between styrene and ethyl di- gands was carried out following the methodology de-
azoacetate (Scheme 2), and has been extended to scribed in our previous work for tBuDAX.[7] Ligands
other cyclopropanation reactions.
3 were obtained in high purity by metalation of aza-
Scheme 1. Synthesis of the different multitopic ligands: diazabisoxazolines (DAX), triazabisoxazolines (TAX) and Click-dia-
zabisoxazolines (Click-DAX).
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Polytopic Oxazoline-Based Chiral Ligands for Cyclopropanation Reactions
ordination polymers. Accordingly, the correct combi-
nation of anion salt and solvent was found to be criti-
cal to obtain the desired self-supported catalysts. The
use of Cu(I) or Cu(II) triflate with dichloromethane
turned out to be a perfect choice for obtaining the de-
sired polymers (Figure 1). Hence, coordination poly-
mers were formed by mixing the corresponding poly-
topic oxazoline ligands 3–5 with copper triflate salts
in the appropriate L:Cu molar ratio in CH2Cl2 in all
the cases. Both Cu(I) and Cu(II) are amenable for
Scheme 2. Cyclopropanation reaction between styrene and
ethyl diazoacetate.
ACHTUNGTRENNUNG
bis(oxazoline) 1[8] with butyllithium and subsequent these processes.
trapping with a,a’-dibromo-p-xylene, followed by re-
crystallization in acetone (>80% yield).
Encouraged by these results, we decided to extend
the procedure to the preparation of threefold ligands,
namely triazabis(oxazoline) ligands
Scheme 1). In this case, the linker between the aza-
bis(oxazolines) was derived from 1,3,5-tris(bromo-
methyl)benzene giving rise to 4 in up to 93% yield.
It is noteworthy to point out that the total number
4
(TAX;
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
of steps needed for the synthesis of DAX or TAX li-
gands is the same as those for simple alkylated azabi-
s(oxazoline) ligands that are commonly employed as
chiral ligands in homogeneous catalysts. In other
words, no extra synthetic effort is required to prepare
the polytopic ligands described in this study.
Alternatively ligands 5 were obtained following a
click-synthetic strategy that had already been applied
to link azabis(oxazolines) to polymeric, dendrimeric,
and inorganic supports.[8] The same strategy has also
been described for the immobilization of other chiral
ligands.[9] Copper-catalyzed [3+2]cycloaddition[10] be-
tween 2 and two equivalents of 1,4-bis(azidomethyl)-
benzene were reacted to give rise to 5 in approxi-
mately 90% yield. Complete information on the char-
Figure 1. Schematic representation of the self-assembled cat-
alysts from the coordination of copper cations with: A)
DAX or Click-DAX ligands (chains) and B) TAX ligands
(layers).
acterization of all the new ligands prepared is avail- Structural Studies of the Catalysts by Mass
able in the Supporting Information.
Spectrometry
One of the most important features of a catalyst is its
structure given that the catalytic performance and its
recoverability are directly dependent on it. X-ray dif-
Formation of the Coordination Polymers
For the formation of coordination polymers based on fraction techniques have been profusely employed in
azabis(oxazolines) 3–5 we chose copper as the ligand- the characterization of metal complexes acting as cat-
connecting metal ion since monomeric copper-aza- alysts. Disappointingly, obtaining a single crystal with
ACHTUNGTRENNUNGbis(oxazoline) complexes have proved to be outstand- copper complexes of multitopic ligands 3–5 has
ing catalysts in several enantioselective reactions, in- proved to be not possible despite several crystalliza-
cluding cyclopropanation reactions.[11] The copper tion techniques that have been tried.
salts to be employed must be chosen carefully be-
In order to collect more information on the copper
cause the coordination strength of the anions could coordination polymers, some analyses were conducted
prevent coordination polymers from forming. Strongly by mass spectrometry. Even though those studies
coordinating counter ions such as chloride prevent were carried out with most of the polymers obtained,
the recruiting of two AzaBox ligands by copper since the more detailed study was performed with the
the chloride anions remain in its coordination spher- tBuDAX-Cu polymeric catalyst ACTHNUTRGENUG[N 3a·Cu]n since it has
e.[8a] A similar consideration must be applied to the shown the best performance in the promotion of the
solvent: Those with strong coordinating ability, for ex- cyclopropanation reaction (vide infra).
ample, methanol or acetonitrile, can compete for the
The electrospray ionization technique calls for dis-
copper and consequently impede the assembly of co- solving the sample in methanol or acetonitrile, both
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coordinating solvents. In these conditions the solvent
All the species observed in previous experiments in
would coordinate to the copper centers in the a standard ESI-MS-spectrometer were also detected
tBuDAX-Cu(I) complex, and polymeric or oligomeric using the spectrometer with the ion trap. In addition,
species would disaggregate in monomers. Indeed, peaks at m/z=1100.2, 1247.3, and 1368.8 were detect-
using electrospray ionization mass spectrometry (ESI- ed, which could be assigned based on their isotopic
MS) carried out in a device with a single octupole so- patterns (for a detailed analysis see Supporting Infor-
lution of tBuDAX-Cu(I)
major species detected corresponds with 1:1 (or n:n ride is attributed to the complex formation being car-
oligomers) [tBuDAX-Cu(I)]+ species at m/z=699.6.[7] ried
out in dichloromethane), [tBuDAX3-
Other relevant species identified were 2:1 [DAX- Cu4A
(OTf)2MeOH]2+ and [tBuDAX4-Cu3]2+species, re-
[3a·Cu]n in methanol the mation) as [tBuDAX3-Cu4Cl]2+ (the presence of chlo-
ACHTUNGTRENNUNG
CTHUNGTRENNUNG
Cu(I)-DAX]+ at m/z=1336.1 and 1:2 [Cu(I)-DAX- spectively.
Cu(I)]2+ species at m/z=381.4, being in agreement
Especially noteworthy, the peak at 700.4 displaying
with previously reported ESI mass spectra of mono- an isotopic distribution with a peak every third of a
topic Box and Azabox ligands, in which [L-Cu] and unit indicates the presence of a threefold-charged spe-
3+
[L2-Cu] species were found.[12]
cies that can be attributed as the [tBuDAX-Cu]3
In order to detect the presence of oligomers in the ion. The signals of such multi-charged species result
mass spectra, we therefore conducted experiments from superimposition of a mixture of species with the
with saturated methanolic solutions of tBuDAX- same m/z ratio but different z values. Thus, the iso-
CuACHTUNGTRENNUNG(OTf) complex ACHTUNGTERN[NUGN 3a·Cu]n in an ESI-MS device in- topic distribution of the signal at m/z=700.4, shown
cluding an ion trap as analyzer. In its maximum reso- on the top of the Figure 3, is different from the one
lution mode 1,650 u/sec, this device is able to resolve that would be theoretically expected for [tBuDAX-
3+
2+
multicharged species up to 4+ ions. Under these con- Cu]3
because the ions [tBuDAX-Cu]2
and
ditions it was indeed possible to obtain spectra with [tBuDAX-Cu]+ are contributing to the overall signal
resolved peaks, allowing their deconvolution based on as well.
n+
isotopic patterns of the species. Thus, the presence of
The detection of [tBuDAX-Cu]n species (n=1–3)
higher order copper-ligand species of ACTHGUNTRNE[NUG 3a·Cu] could by mass spectrometry strongly supports the hypothe-
be unambiguously proved. Figure 2 shows a typical sis that the complexes formed in a non-coordinating
mass spectrum in which several characteristic peaks solvent are indeed coordination polymers. The same
that are indicative for such higher order species conclusion is reached for the analysis of analogous
appear with prominent intensity.
MS-ESI experiments conducted for click-DAX 5a
(see Supporting Information).
Figure 2. Infusion ESI-mass spectrum of the [tBuDAX-CuOTf] complex carried out in an ion trap spectrometer.
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Polytopic Oxazoline-Based Chiral Ligands for Cyclopropanation Reactions
copper carbenoids, which are known to be decisive in-
termediates in the title reaction.[14] As a consequence
soluble copper-DAX species are formed allowing the
cyclopropanation to proceed in the homogeneous
phase with similar high enantioselectivities and yields
as are known from monomeric copper-bis(oxazoline)
catalysts. After consumption of ethyl diazoacetate
AHCTUNGTERGNUN[N 3a·Cu]n reassembles again and as a consequence pre-
cipitates from the reaction mixture, from which it can
be recovered by filtration and subsequently reused. In
all cases, we found that the first cyclopropanation re-
action lasted 24 h from the end of the reagents addi-
tion until the final precipitation of the polymer, which
agrees with the usual cyclopropanation reaction time.
However, the formation of the copper polymer in the
subsequent reactions required two to three days
mainly because of the presence of by-products diethyl
maleate and fumarate formed in the course of the re-
action. This period can be considerably shortened by
evaporating most of dichloromethane and extracting
the reaction products with n-hexane, in which the co-
ordination polymer is nearly insoluble. An additional
advantage of using the latter strategy is the ability of
dichloromethane to dissolve monomeric and oligo-
meric copper complexes (as indicated by the green
color of the reaction solution), so it is impossible to
avoid partial loss of catalytic species in the recovering
procedure. We also tested the possible solubilization
of catalytic species in n-hexane, leading to catalyst
leaching. After carrying out a reaction with styrene
and evaporating the dichloromethane, an extraction
was performed with n-hexane. The hexane was subse-
quently removed and the sample redissolved in di-
chloromethane. Then, 1-octene and ethyl diazoacetate
were added to the resulting solution. After four days
of reaction, only a marginal activity of cyclopropana-
tion (less than 0.5% yield) was observed, which indi-
cates that the amount of complex lost during the recy-
cling is almost negligible (see Supporting Information
for details).
Figure 3. Enlargement of the signal at m/z=700.4 (top) and
theoretical simulated pattern for several [tBuDAX-Cu]n
species (below).
n+
Maleate and fumarate are known to act as a cata-
lyst poison in the title reaction by competing with li-
gands and substrates in coordination to copper, which
has been recognized as a limiting factor for the reuse
Catalytic Studies
Coordination polymers are attractive for applications of conventional polymer-bound copper-box com-
in catalysis since they can represent the resting state plexes. The ultimate formation of the insoluble coor-
of a catalyst that precipitates in the absence of reac- dination polymer ACTHNURGTNEUNG[3a·Cu]n, calling for coordination of
tants or by change of solvent.[13] In the presence of copper by two ligand molecules, drives the equilibri-
the latter the polymers disassemble due to competi- um away from copper species being coordinated with
tive coordination of the reactants and thus become maleate or fumarate, thus, allowing the reuse of
soluble and catalytically active. This concept is dem-
onstrated for the copper-catalyzed cyclopropanation selectivity (Table 1, entries 3–16).
of styrene with ethyl diazoacetate (Scheme 2). The co- Notably, the catalysts with DAX ligands
ordination polymer [3a·Cu]n (obtained from mixing and [3b·Cu]n compare well with the performance of
3a and Cu
(OTf)2 in a 1:1 ratio)[7] being insoluble in their monomeric analogues 7a·Cu and 7b·Cu, respec-
ACHTUNGTERN[NUNG 3a·Cu]n for at least 14 runs without loss of activity of
AHCTUNGTERN[GNUN 3a·Cu]n
N
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
CH2Cl2, is broken up and thus solubilized in the pres- tively, both with respect to yields and selectivities. It
ence of ethyl diazoacetate due to the formation of became furthermore apparent that for the tert-butyl-
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Table 1. Cyclopropanation reactions between styrene and
ethyl diazoacetate catalyzed by tBuDAX-Cu and iPrDAX-
Cu.[a]
obtained with 6b·Cu, 7b·Cu and ACTHNUTRGNEG[NU 3b·Cu]n. (note that
in the case of 7b·Cu, in Table 1, entry 19, the yield
corresponds to a reaction in which a 3:1 styrene:dia-
zocompound ratio has been used).
Entry Catalyst Run Yield [%] % ee trans % ee cis
Concerning the erratic reaction yields observed
along the recycling experiments, they could be attrib-
uted to an incomplete extraction of the products with
hexane after some of the reactions. These products
would accumulate in the reaction medium and subse-
quently, they would be extracted in the successive
run. This particular behavior on the yields was also
observed sometimes in the experiments with catalysts
1
2
3
4
5
6
7
8
6a·Cu
7a·Cu
1
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1
82
54
55
60
60
60
58
56
46
65
67
69
71
78
59
58
45
78
44
29
41
50
10
92
98
98
97
97
97
97
97
96
97
96
96
96
95
96
96
71
66
62
75
69
69
n.d.
84
90
91
90
90
89
89
89
89
89
87
87
87
87
87
86
55
44
47
58
60
59
n.d.
A
A
ACHTUNGERTN[NUNG 5a·Cu]n (Table 2 and Table 3).
9
10
11
12
13
14
15
16
17
18[b]
19[b]
20
21
22
23
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
attribute to a better solubility and thus less efficient
precipitation of the former.
6b·Cu
6b·Cu
7b·Cu
1
1
1
2
3
4
Since the recycling of the catalysts directly corre-
sponds with the efficient formation and precipitation
of their coordination polymers, we next studied the
TAX-ligands 4a that should be capable of forming
two- rather than one-dimensional coordination poly-
mers as described with DAX-ligands 3. Copper com-
A
[a]
Reagents and conditions: styrene (1 equiv.), ethyl diazo-
acetate (1 equiv.), DAX-Cu(OTf)2 (1 mol%), CH2Cl2,
room temperature. Yield and selectivities were deter-
mined by gas chromatography (methyl silicone and cyclo-
plexes with 4a were prepared by mixing Cu
and 4a in a ratio of 3:2.
ACHTUNGTRENNUNG(OTf)2
G
ACHTUNGTRENNUNG
Indeed, catalyst ACTHNURGTNEUNG[4a·Cu]n also performed well in the
dex-b columns). (1R,2R)-trans-cyclopropane and (1R,2S)- cyclopropanation of styrene, giving even higher enan-
cis-cyclopropane are the major isomers. The trans/cis
ratio is ca. 70:30 in all cases.
tioselectivities than previously obtained with ACTHUNRGTNEUNG[3a·Cu]n
(Table 2), which remained unaltered in eleven consec-
utive cycles. The catalyst recovery procedure was ex-
[b]
Taken from ref.[5a], 3 equiv. of styrene were used.
Table 2. Cyclopropanation reactions between styrene and
substituted azabis(oxazoline) ligands a significant in-
crease in enantioselectivity is achieved upon switching
the alkyl substituent at the central nitrogen from
methyl to benzyl (Table 1, entries 1–3),[15] which is
nearly retained upon subsequent multiple reuse of
ethyl diazoacetate catalyzed by tBuTAX-Cu ACTHNUTRGNEUNG
[4a·Cu]n.[a]
Entry
Run
Yield [%]
% ee trans
% ee cis
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
57
51
54
57
71
49
51
53
27
29
41
99
98
98
98
98
98
98
98
98
98
98
93
92
92
91
92
91
92
92
91
92
91
catalyst
ACHTUNGTRENNUNG
obtained with ACHTUNGTRENNUNG
they are closer to those obtained with 7a·Cu
(Figure 4). These results suggest that, under identical
À
conditions, catalysts with the N Me motif lead to
À
higher yields than those with the N Bn motif. Similar
conclusions can be reached by examining the results
9
10
11
9
10
11
[a]
Reagents and conditions: styrene (1 equiv.), ethyl diazo-
acetate (1 equiv.), tBuTAX-Cu(OTf)2 (1 mol%), CH2Cl2,
N
ACHTUNGTRENNUNG
room temperature. Yield and selectivities were deter-
mined by gas chromatography (methyl silicone and cyclo-
dex-b 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. Azabox ligands used in the homogeneous phase.
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Polytopic Oxazoline-Based Chiral Ligands for Cyclopropanation Reactions
actly the same as that used with ACTHNUTRGNEN[UG 3a·Cu]n, that is, par- 2,5-Dimethyl-2,4-hexadiene for its importance in the
tial evaporation of dichloromethane and extraction of synthesis of pyrethroids, 1-octene as a linear and a-
the reaction products with several portions of n- methylstyrene as a branched alkene with a larger
hexane.
steric hindrance on only one side of the double bond
Azabis(oxazoline)-copper complexes containing tri- were chosen as representative substrates. After each
azole linkers have been found to be less soluble in or- reaction cycle, with one of these substrates the cata-
ganic solvents and to readily crystallize.[8a] Conse- lyst was reused in the reaction with styrene in order
quently, we synthesized ligands 5 of the DAX-type to assess its performance in the benchmark reaction
that were connected via additional triazole units initially studied. The results of these experiments are
rather than just xylyl linkers. By mixing 5a and Cu- disclosed in Table 4 and Table 5.
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Table 4. Cyclopropanation reactions of several alkenes with
ethyl diazoacetate catalyzed by tBuDAX-Cu
[3a·Cu]n.[a]
G
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Run Alkene
Yield
[%]
trans/ % ee
cis trans
% ee
cis
G
ACHTUNGTRENNUNG
bly faster from CH2Cl2, moreover, the remaining solu-
tion was almost colorless, indicating indeed a lower
solubility profile of
1
2
styrene
2,5-dimethyl-2,4-
hexadiene
56
35
73/27 99
79/21 63
92
70
G
ACHTUNGTNER[NUNG 3a·Cu]n.
Indeed, recovery of AHCTUNGTRENNUNG
reactions proved to be exceptionally facile. Thus, in
initially performed 10 cycles with styrene the catalyst
readily precipitated at the end of the reaction and
was reused. However, the enantioselectivities ob-
3
4
5
6
1-octene
a-methylstyrene
styrene
2,5-dimethyl-2,4-
hexadiene
1-octene
75
37
47
35
68/32 93
52/48 91
75/25 98
77/23 68
93
86
89
61
tained with
and more erratic than those obtained with catalyst
[3a·Cu]n. This effect might be caused by the presence
ACHTUNGTRENNUNG[5a·Cu]n (Table 3) were somewhat lower
7
8
9
52
41
52
68/32 95
52/47 92
73/27 98
92
87
89
a-methylstyrene
styrene
ACHTUNGTRENNUNG
of the triazole rings in the ligand, which seem to be
capable of coordinating copper,[8a,16] giving rise to
non-enantioselective catalytic sites.
[a]
Reagents and conditions: alkene (1 equiv.), ethyl diazo-
acetate (1 equiv.), tBuDAX-Cu(OTf)2 (1 mol%), CH2Cl2,
A
ACHTUNGTRENNUNG
room temperature. Yield and selectivities were deter-
mined by gas chromatography (methyl silicone and cyclo-
dex-b 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.
Having identified ACTHNUTRGENNUG[3a·Cu]n and ACHTUNGTREN[NUGN 5a·Cu]n to be most
efficient in cyclopropanation reactions, we explored
the scope of these catalysts, addressing especially the
question if different substrates can be used with the
catalyst used in a previous run with another substrate.
Table 5. Cyclopropanation reactions between several al-
kenes and ethyl diazoacetate catalyzed by tBuclickDAX-Cu
Table 3. Cyclopropanation reactions between styrene and
ethyl diazoacetate catalyzed by tBuclick-DAX-Cu
ACHTUNGTRENNUNG[5a·Cu]n.
ACHTUNGTRENNUNG
[a]
Yield
[%]
trans/ % ee
cis trans
% ee
cis
Entry
Run
Yield [%]
% ee trans
% ee cis
1
2
3
4
5
6
7
8
9
10
1
2
3
4
5
6
7
8
46
48
53
62
91
58
49
30
55
51
97
89
85
84
83
83
83
92
89
84
82
78
75
73
71
73
74
76
78
76
1
2
styrene
58
31
74/26 94
78/22 66
89
65
2,5-dimethyl-2,4-
hexadiene
1-octene
a-methylstyrene
styrene
1-octene
a-methylstyrene
styrene
3
4
5
6
7
8
9
10
54
66
41
56
68
60
57
54
68/32 90
52/48 92
74/26 97
68/32 95
51/49 93
73/27 93
51/49 91
72/28 94
86
88
84
87
88
84
87
89
9
10
a-methylstyrene
styrene
[a]
Reagents and conditions: styrene (1 equiv.), ethyl diazo-
acetate (1 equiv.), tBuClick-DAX-Cu(OTf)2 (1 mol%),
[a]
G
G
Reagents and conditions: alkene (1 equiv.), ethyl diazo-
acetate (1 equiv.), tBuClickDAX-Cu(OTf)2 (1 mol%),
CH2Cl2, room temperature. Yield and selectivities were
determined by gas chromatography (methyl silicone and
cyclodex-b columns). (1R,2R)-trans-cyclopropane and
(1R,2S)-cis cyclopropane are the major isomers
CH2Cl2, room temperature. Yield and selectivities were
determined by gas chromatography (methyl silicone and
cyclodex-b 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.
G
ACHTUNGTRENNUNG
Adv. Synth. Catal. 2011, 353, 2691 – 2700
ꢆ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2697

Josꢀ I. Garcꢁa et al.
FULL PAPERS
tallized from acetone; isolated yield: 87%; mp 198–1998C;
For all alkenes employed, both with ACTHNUTRGENUG[N 3a·Cu]n as
well as with ACHTUNGTRENNUNG[5a·Cu] high enantioselectivites were ach-
1
[a]2D0: À24.6 (c 0.85, CH2Cl2). H NMR (400 MHz, CDCl3):
d=7.34 (s, 4H), 5.05 (d, 2H, J=15.2 Hz), 4.96 (d, 2H, J=
15.2 Hz), 4.29 (dd, 4H, J=8.8, 9.2 Hz), 4.18 (dd, 4H, J=6.4,
8.4 Hz), 3.77 (dd, 4H, J=6.4, 9.2 Hz), 0.79 (s, 36H);
13C NMR (100 MHz, CDCl3): d=157.2, 136.5, 127.8, 73.4,
70.1, 52.9, 34.0, 25.5; MS (ESI+): m/z=637 [M+H]+; IR
ieved in all runs, comparing well with the commonly
employed copper-azabox catalysts. The moderate
enantioselectivities achieved with 2,5-dimethyl-2,4-
hexadiene are typical for this substrate, in fact, this
reaction is usually carried out with bulkier diazocom-
pounds to achieve better enantioselectivities.[17]
(C=N):
n
=1640 cmÀ1
;
elemental Analysis: calcd.
(C36H56N6O4): C 67.89, H 8.86, N 13.20, O 10.05; found: C
67.98, H 8.48, N 13.11, O 10.43.
Conclusions
Synthesis of (4S,4’S)-N,N’-[1,4-phenylenebis-
(methylene)]bis{4-isopropyl-N-[4-isopropyl-N-(4-
isopropyl-4,5-dihydrooxazol-2-yl]-4,5-dihydrooxazol-
2-yl}amine (iPrDAX) (3b)
We have described the synthesis of several coordina-
tion polymers based on the copper-azabis(oxazoline)
moiety. The multitopic complexes were able to act as
self-supported catalysts in cyclopropanation reactions
through a capture-release mechanism, combining the
advantages of both homogeneous and heterogeneous
catalysis. Facile recovery of the catalysts by reforming
its self-assembling polymeric structure which is insolu-
ble in dichloromethane or hexane has been demon-
strated in up to 14 cycles without a noticeable loss of
activity or enantioselectivity. Structural information
on the copper complexes was obtained by ESI-mass
spectra, carried out in an ion trap spectrometer,
proved the presence of oligomeric species, supporting
the hypothesis that the solids formed in a non-coordi-
nating solvent are coordination polymers.
The procedure is the same as for the synthesis of 3a using
(S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-(4,5-dihydro-oxazol-
2-yl)-amine (1.00 mmol, 239 mg); isolated yield: 83%; mp
114–1168C; [a]D20: À66.7 (c 0.99, CH2Cl2). 1H NMR
(400 MHz, CDCl3): d=7.30 (s, 4H), 5.02 (d, 2H, J=
15.2 Hz), 4.96 (d, 2H, J=15.2 Hz), 4.34 (dd, 4H, J=8.4,
9.2 Hz), 4.08 (dd, 4H, J=6.8, 8.4 Hz), 3.85 (m, 4H), 1.67 (m,
4H), 0.86 (d, 12H, J=6.8 Hz), 0.78 (d, 12H, J=6.8 Hz);
13C NMR (100 MHz, CDCl3): d=157.1, 136.5, 127.6, 71.3,
69.9, 52.6, 32.8, 18.6, 17.7; MS (ESI+): m/z=581 [M+H]+;
IR (C=N): n=1641 cmÀ1
;
elemental analysis: calcd.
(C32H48N6O4): C 66.18, H 8.33, N 14.47, O 11.02, found: C
66.15, H 8.21, N 14.21, O 11.43.
Synthesis of (4S,4’S,4’’S)-N,N’,N’’-[Benzene-1,3,5-
triyltris(methylene)]tris[4-tert-butyl-N-(4-tert-butyl-
4,5-dihydrooxazol-2-yl)-4,5-dihydrooxazol-2-yl]amine
(tBuTAX) (4a)
Experimental Section
General Remarks
The procedure is the same as for the synthesis of 3a using
1,3,5-tris(bromomethyl)benzene (0.34 mmol, 121 mg) instead
of a,a’-dibromo-p-xylene to give 4a; yield: 93%; mp 99–
1018C; [a]2D0: À16.0 (c 1.2, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=7.27 (s, 3H), 5.04 (d, 3H, J=15.1 Hz), 4.92 (d,
3H, J=15.1 Hz), 4.29 (dd, 6H, J=8.6, 9.3 Hz), 4.17 (dd,
6H, J=6.8, 8.4 Hz), 3.76 (dd, 6H, J=6.8, 9.4 Hz), 0.79 (s,
54H); 13C NMR (100 MHz, CDCl3): d=157.3, 137.4, 126.1,
73.3, 70.1, 52.9, 33.9, 25.5; MS (ESI+): m/z=917 [M+H]+;
All reactions were carried out under an argon atmosphere
in oven-dried glassware. Dichloromethane, tetrahydrofuran
and toluene were dried in an SPS-Device. Ethanol was dis-
tilled from magnesium. Amino acids were used as commer-
cially available. The starting azabis(oxazolines) and 1,4-bi-
s(azidomethyl)benzene were prepared according to litera-
ture procedures.[8]
IR (C=N): n=1640 cmÀ1
;
elemental analysis: calcd.
(C51H81N9O6): C 66.85, H 8.91, N 13.76, O 10.48; found: C
67.30, H 8.41, N 13.64, O 10.71.
Synthesis of (4S,4’S)-N,N’-[1,4-Phenylenebis(methyl-
ene)]bis[4-tert-butyl-N-(4-tert-butyl-N-(4-tert-butyl-
4,5-dihydrooxazol-2-yl)-4,5-dihydrooxazol-2-yl]amine
(tBuDAX) (3a)
Synthesis of (4S,4’S,4’’S)-N,N’,N’’-[Benzene-1,3,5-
triyltris(methylene)]tris[4-isopropyl-N-(4-isopropyl-
4,5-dihydrooxazol-2-yl)-4,5-dihydrooxazol-2-yl]amine
(iPrTAX) (4b)
(S)-4-tert-Butyl-4,5-dihydro-oxazol-2-yl)-(4,5-dihydrooxazACTHNUTRGENUGoN l-
2-yl)-amine (1.00 mmol, 267 mg) was dissolved in tetrahy-
drofuran (10 mL) and a 15% solution of n-butyllithium in
hexane (1.50M, 688 mL) was added at À788C. After stirring
for 20 min a,a’-dibromo-p-xylene (0.45 mmol, 11.9 mg) was
added. The cooling bath was removed and stirring at room
temperature continued for 10 h. After evaporation of the
solvent the residue was partitioned between CH2Cl2 (10 mL)
and saturated NaHCO3 (10 mL). The aqueous phase was ex-
tracted with CH2Cl2 (2ꢇ5 mL) and the combined organic
phases were dried over MgSO4. Evaporation of the solvent
yielded the product as colorless solid which could be recrys-
The procedure is the same as for the synthesis of 3b using
1,3,5-tris(bromomethyl)benzene (0.34 mmol, 121 mg) instead
of a,a-dibromo-p-xylene as an oil; isolated yield: 93%; [a]2D0:
À48.1 (c 0.95, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=
7.23 (s, 3H), 5.00 (d, 3H, J=15.1 Hz), 4.92 (d, 2H, J=
15.1 Hz), 4.33 (dd, 6H, J=8.4, 9.2 Hz), 4.07 (dd, 6H, J=6.8,
8.4 Hz), 3.84 (m, 6H), 1.67 (m, 6H), 0.86 (d, 18H, J=
6.8 Hz), 0.78 (d, 18H, J=6.8 Hz); 13C NMR (100 MHz,
CDCl3): d=157.0, 137.3, 125.8, 71.2, 70.0, 52.7, 32.8, 18.7,
2698
asc.wiley-vch.de
ꢆ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 2691 – 2700

Polytopic Oxazoline-Based Chiral Ligands for Cyclopropanation Reactions
17.7; MS (ESI+): m/z=833 [M+H]+; IR (C=N): n=
1641 cmÀ1; elemental analysis: calcd. (C45H69N9O6): C 64.95,
H 8.36, N 15.15, O 11.54; found: C 65.10, H 8.48, N 14.95, O
11.47.
precipitate, and could be used as in the catalytic tests with-
out further treatment.
General Procedure for the Cyclopropanation
Reactions
Synthesis of (4S,4’S)-N,N’-[1,1’-(1,4-Phenylenebis-
(methylene)]bis[1H-1,2,3-triazole-4,1-diyl)]bis-
(methylene)bis{4-tert-butyl-N-[(S)-4-tert-butyl-4,5-
dihydrooxazol-2-yl]-4,5-dihydrooxazol-2-yl}amine
(tBuclick-DAX) (5a)
Ethyl diazoacetate (2.00 mmol) was slowly added via syringe
pump to
a
solution of the corresponding alkene
(2.00 mmol), n-decane (100 mg; internal standard) and the
polymeric catalyst (0.02 mmol) in 2 mL of anhydrous di-
chloromethane at room temperature. During the addition of
the ethyl diazoacetate the solid polymer disappeared and a
clear solution appeared instead. After total consumption of
the diazoacetate (approx. 24 h) the polymer catalyst precipi-
tated again. The solution was concentrated to 0.5 mL and
the solid washed with n-hexane and dried. In these condi-
tions the catalyst was ready to be used again in a new reac-
tion. Reactions were monitored by gas chromatography
using an FID detector connected to a Hewlett–Packard
5890II chromatograph, using a cross-linked methyl silicone
column: 25 mꢇ0.25 mmꢇ0.25 mm; helium was used as carri-
er gas. Column pressure: 20 psi; injector temperature:
2308C; detector temperature: 2508C; oven program: 708C
(3 min), 158C minÀ1 to 2008C (5 min). The enantioselectivi-
ties of the reactions were also determined in all cases by gas
chromatography using a Cyclodex-b column. Temperature
program: 1258C isotherm. Specific chromatographic condi-
tions, retention times and some typical chromatograms are
gathered in the Supporting Information.
(S)-4-tert-Butyl-N-[(S)-4-tert-butyl-4,5-dihydrooxazol-2-yl]-
N-(prop-2-ynyl)-4,5-dihydrooxazol-2-amine (2) (2.00 mmol,
610 mg) and 1,4-bis(azidomethyl)benzene (1.00 mmol,
188 mg) were dissolved in 16 mL of CH2Cl2 and 4 mL of
Et3N. The mixture was stirred during 20 h at room tempera-
ture. After this time, the solvent was evaporated under re-
duced pressure and the residue partitioned between 10 mL
of CH2Cl2 and a 1% EDTA (ethylenediaminetetraacetic
acid) aqueous solution. The aqueous phases were extracted
with CH2Cl2 and the combined organic phases dried over
anhydrous Na2SO4 and subsequently, evaporated under
vacuum. A recrystallization in acetone yielded dark brown
crystals of the product; isolated yield: 85; mp 220–2218C;
1
[a]2D0: +46.6 (c 0.96, CH2Cl2). H NMR (400 MHz, CDCl3):
d=7.56 (s, 2H), 7.22 (s, 4H), 5.46 (s, 4H), 5.12 (s, 4H), 4.30
(t, 4H, J=9.0 Hz), 4.19 (t, 4H, J=7.6 Hz), 3.76 (m, 4H),
0,76 (s, 36H); 13C NMR (100 MHz, CDCl3): d=156.9, 145.0,
135.3, 128.7, 123.0, 73.4, 70.3, 53.5, 45.4, 33.9, 25.6; IR
ACHTUNGTRENNUNG ; HR-MS (ESI+): m/z=799.5080
(C=N): n=1638 cmÀ1
[MH+], calcd. for C42H62O12N4: 799.5090.
Acknowledgements
Synthesis of (4S,4’S)-N,N’-(1,1’-[1,4-Phenylenebis-
A(methylene)]bis(1H-1,2,3-triazole-4,1-
This work was supported by the Ministerio de Ciencia e In-
novaciꢀn (projects CTQ2008-05138 and Consolider Ingenio
2010 CSD2006-0003), the Aragon Government, the European
Commission (European Regional Development Funds), the
and the Deutsche Forschungsgemeinschaft (RE 948–8/1
“GLOBUCAT”). One of the authors (B. L.-S.) thanks the
Deutscher Akademischer Austausch Dienst for a grant. The
authors are also indebted to Dr. Jesffls Orduna (ICMA) for
helpful discussions and help to interpret the mass spectometry
experiments.
diyl)bis(methylene)bis{4-isopropyl-N-[(S)-4-isopropyl-
4,5-dihydrooxazol-2-yl]}-4,5-dihydrooxazol-2-yl)amine
(iPrclick-DAX) (5b)
The procedure is the same as for the synthesis of 5a using
(S)-4-isopropyl-N-((S)-4-isopropyl-4,5-dihydrooxaz-ol-2-yl)-
N-(prop-2-ynyl)-4,5-dihydrooxazol-2-amine (2) (2.00 mmol,
554 mg); isolated yield: 88%; mp 168–170; [a]2D0: À102.5 (c
1
1.00, CH2Cl2). H NMR (400 MHz, CDCl3): d=7.54 (s, 2H),
7.22 (s, 4H), 5.46 (s, 4H), 5.14 (d, 2H, J=15.3 Hz), 5.06 (d,
2H, J=15.3 Hz), 4.35 (t, 4H, J=8.8 Hz), 4.09 (t, 4H, J=
7.5 Hz), 3.84 (m, 4H), 1.69–1.63 (m, 4H), 0.85 (d, 12H, J=
6.5 Hz), 0.77 (d, 12H, J=6.5 Hz); 13C NMR (100 MHz,
CDCl3): d=156.6, 145.0, 135.0, 128.6, 123.1, 70.9, 70.0, 51.8,
45.1, 33.3, 19.3, 18.7; MS (ESI+): m/z=743; IR (C=N): n=
References
[1] E. N. Jacobsen, A. Pfaltz, H. Yamamoto, (Eds.), Com-
prehensive Asymmetric Catalysis, Springer-Verlag,
Berlin, 2001.
1640 cmÀ1
;
HR-MS: m/z=743.4486 [MH+], calcd. for
C38H54O12N4: 743.4464.
[2] P. W. N. M. van Leeuwen, (Ed.), Homogeneous cataly-
sis: Understanding the art, Kluwer Academic Publish-
ers, Dordrecht, 2004.
[3] a) K. Ding, Y. Uozumi, (Eds.), Handbook of Asymmet-
ric Heterogeneous Catalysis, Wiley-VCH, Weinheim,
2008; b) D. J. Cole-Hamilton, R. P. Tooze, (Eds.), Cata-
lyst Separation Recovery and Recycling: Chemistry and
Process Design, Springer, Berlin, 2006; c) J. M. Fraile,
J. I. Garcꢁa, J. A. Mayoral, Chem. Rev. 2009, 109, 360–
417; d) J. M. Fraile, J. I. Garcꢁa, J. A. Mayoral, Coord.
General Procedure for the Preparation of the
Copper(II)-Ligand Coordination Polymers
The ligand-copper coordination polymers were prepared by
dissolving 0.02 mmol of CuACHTNUTRGENNG(U OTf)2 and either 0.02 mmol of
the corresponding ditopic ligand or 0.013 mmol of TAX in
1 mL of anhydrous dichloromethane. The resulting clear so-
lution was stirred for 15 min. After this time the correspond-
ing coordination polymer formed appeared as a green solid
Adv. Synth. Catal. 2011, 353, 2691 – 2700
ꢆ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2699

Josꢀ I. Garcꢁa et al.
FULL PAPERS
Chem. Rev. 2008, 252, 624–646; e) A. Schꢅtz, O. Reiser,
W. Stark, Chem. Eur. J. 2010, 16, 8950–8967.
[4] J. M. Fraile, J. I. Garcꢁa, C. I. Herrerꢁas, J. A. Mayoral,
E. Pires, Chem. Soc. Rev. 2009, 38, 695–706, and refer-
ences cited therein.
pan, T. Olbrich, O. Reiser, Adv. Synth. Catal. 2009, 351,
1961–1967; c) C. C. Paluti, E. S. Gawalt, J. Catal. 2009,
267, 105–113; d) J. Lim, S. N. Riduan, S. S. Lee, J. Y.
Ying, Adv. Synth. Catal. 2008, 350, 1295–1308; e) J. M.
Fraile, I. Pꢀrez, J. A. Mayoral, J. Catal. 2007, 252, 303–
311; f) J. M. Fraile, I. Pꢀrez, J. A. Mayoral, O. Reiser,
Adv. Synth. Catal. 2006, 348, 1680–1688; g) C. Geiger,
P. Kreitmeier, O. Reiser, Adv. Synth. Catal. 2005, 347,
249–254.
[5] a) M. Glos, O. Reiser, Org. Lett. 2000, 2, 2045–2048;
b) A. Cornejo, J. M. Fraile, J. I. Garcꢁa, M. J. Gil, V.
Martꢁnez-Merino, J. A. Mayoral, Tetrahedron 2005, 61,
12107–12110; c) B. W. T. Gruijters, M. A. C. Broeren,
F. L. van Delft, R. P. Sijbesma, P. H. H. Hermkens,
F. P. J. T. Rutjes, Org. Lett. 2006, 8, 3163–3166; d) D.-W.
Kim, S.-G. Lim, C.-H. Jun, Org. Lett. 2006, 8, 2937–
2940; e) L. Shi, X. Wang, C. A. Sandoval, M. Li, Q. Qi,
Z. Li, K. Ding, Angew. Chem. 2006, 118, 4214–4218;
Angew. Chem. Int. Ed. 2006, 45, 4108–4112; f) S. Witt-
mann, A. Schꢅtz, R. N. Grass, W. J. Stark, O. Reiser,
Angew. Chem. 2010, 122, 1911–1914; Angew. Chem.
Int. Ed. 2010, 49, 1867–1870; g) D. E. Bergbreiter, J.
Tian, C. Hongfa, Chem. Rev. 2009, 109, 530–582.
[6] a) S. W. Chen, J. H. Kim, C. E. Son, S. G. Lee, Org.
Lett. 2007, 9, 3845–3848; b) S. W. Chen, J. H. Kim, H.
Shin, S. G. Lee, Org. Biomol. Chem. 2008, 6, 2676–
2678; c) Z. Wang, G. Chen, K. Ding, Chem. Rev. 2009,
109, 322–359.
[12] a) M. Hager, S. Wittmann, A. Schꢅtz, F. Pein, P. Kreit-
meier, O. Reiser, Tetrahedron: Asymmetry 2010, 21,
1194–1198; b) E. Zocher, R. Dietiker, P. Chen, J. Am.
Chem. Soc. 2007, 129, 2476–2481.
[13] One of the referees raised the question of the role of
alkene coordination. From Kochiꢉs seminal work it is
well known that olefins have a high affinity for cop-
per(I), so an 18-electron ligand-copper-olefin is usually
proposed as the resting state of the catalyst. In our
system, when pure styrene was added to the solid coor-
dination polymer formed in dichloromethane, no ap-
preciable changes were noticed (neither dissolution of
the solid nor coloring of the liquid phase). On the
other hand, when the same experiment was performed,
but adding ethyl diazoacetate instead of styrene, a
rapid dissolution of the solid, accompanied with color
change and dinitrogen evolution, was observed. These
experiments support our hypothesis that, in the case of
ditopic ligands, the coordination polymer is the actual
resting state of the catalyst. For the role of copper
olefin complexes in the catalytic cycle, see: a) R. G.
Salomon, J. K. Kochi, J. Am. Chem. Soc. 1973, 95,
3300–3310; b) M. M. Dꢁaz-Requejo, T. R. Belderrain,
M. C. Nicasio, F. Prieto, P. J. Pꢀrez, Organometallics
1999, 18, 2601–2609.
[14] a) H. Fritschi; U. Leutenegger; A. Pfaltz, Helv. Chim.
Acta 1988, 71, 1553–1565; b) B. F. Straub; P. Hofmann;
Angew. Chem. 2001, 113, 1328–1330; Angew. Chem.
Int. Ed. 2001, 40, 1288–1290; c) J. M. Fraile, J. I. Garcꢁa,
J. A. Mayoral, L. Salvatella, J. Am. Chem. Soc. 2001,
123, 7616–7625; d) X. Dai, T. H. Warren, J. Am. Chem.
Soc. 2004, 126, 10085–10094; e) P. Hofmann, I. V. Shish-
kov, F. Rominger, Inorg. Chem. 2008, 47, 11755–11762.
[15] Cf. a) H. Werner, C. I. Herrerꢁas, M. Glos, A. Gissibl,
J. M. Fraile, I. Pꢀrez, J. A. Mayoral, O. Reiser, Adv.
Synth. Catal. 2006, 348, 125–132; b) J. M. Fraile, I.
Pꢀrez, J. A. Mayoral, O. Reiser, Adv. Synth. Catal.
2006, 348, 1680–1688.
[7] J. I. Garcꢁa, B. Lꢂpez-Sꢃnchez, J. A. Mayoral, Org. Lett.
2008, 10, 4995–4998.
[8] a) A. Gissibl, M. G. Finn, O. Reiser, Org. Lett. 2005, 7,
2325–2328; b) A. Gissibl, C. Padiꢀ, M. Hager, F. Jaros-
chik, R. Rasappan, E. Cuevas-YaÇez, C.-O. Turrin, A.-
M. Caminade, J.-P. Majoral, O. Reiser, Org. Lett. 2007,
9, 2895–2898; c) H. Werner, R. Vicha, A. Gissibl, O.
Reiser, J. Org. Chem. 2003, 68, 10166–10168; d) A.
Schꢅtz, M. Hager, O. Reiser, Adv. Funct. Mater. 2009,
19, 2109–2115.
[9] a) K. M. Kacprzak, N. M. Maier, W. Lindner, Tetrahe-
dron Lett. 2006, 47, 8721–8726; b) A. Bastero, D. Font,
M. A. Pericꢈs, J. Org. Chem. 2007, 72, 2460–2468; c) M.
Tilliet, S. Lundgren, C. Moberg, V. Levacher, Adv.
Synth. Catal. 2007, 349, 2079–2084; d) D. Popa, R.
Marcos, S. Sayalero, A. Vidal-Ferran, M. A. Pericꢈs,
Adv. Synth. Catal. 2009, 351, 1539–1556; e) A. R.
McDonald, N. Franssen, G. P. M. van Klink, G. van Ko-
ten, J. Organomet. Chem. 2009, 694, 2153–2162; f) B. S.
Rana, S. L. Jain, B. Singh, A. Bhaumik, B. Sain, A. K.
Sinha, Dalton Trans. 2010, 39, 7760–7767.
[10] a) C. W. Tornøe, M. Meldal, Peptidotriazoles: Cop-
per(I)-catalyzed 1,3-dipolar cycloadditions on solid-
phase, in: Peptides: The Wave of the Future, (Eds.: M.
Lebl, R. A. Houghten), American Peptide Society and
Kluwer Academic Publishers, San Diego, 2001, pp 263–
264; b) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B.
Sharpless, Angew. Chem. 2002, 114, 2708–2711; Angew.
Chem. Int. Ed. 2002, 41, 2596–2599; c) C. W. Tornøe, C.
Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057–
3064.
[16] a) A. Bastero, D. Font, M. A. Pericꢈs, J. Org. Chem.
2007, 72, 2460–2468; b) S. OzÅubukÅu, E. Ozkal, C.
Jimeno, M. A. Pericꢈs, Org. Lett. 2009, 11, 4680–4683.
[17] a) M. Itagaki, K. Masumoto, K. Suenobu, Y. Yamamo-
to, Org. Process Res. Dev. 2006, 10, 245–250; b) M. Ita-
gaki, K. Masumoto, Y. Yamamoto, J. Org. Chem. 2005,
70, 3292–3295; c) M. Itagaki, K. Hagiya, M. Kamita-
mari, K. Masumoto, K. Suenobu, Y. Yamamoto, Tetra-
hedron 2004, 60, 7835–7843.
[11] a) A. Schꢅtz, R. N. Grass, Q. Kainz, W. Stark, O.
Reiser, Chem. Mater. 2010, 22, 305–310; b) R. Rasap-
2700
asc.wiley-vch.de
ꢆ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 2691 – 2700