Synthesis of polymer bound azabis(oxazoline) ligands and their application in asymmetric cyclopropanations

Article abstract of DOI:10.1002/adsc.200505197

Aza(bisoxazoline) ligands were attached to various polymeric supports and the resulting immobilized ligands were evaluated in copper(I)-catalyzed asymmetric cyclopropanations. The efficiency of these transformations depends greatly on the polymeric support, on the protocol being applied for the immobilization of the ligands, and on the preparation of the catalysts.

Full text of DOI:10.1002/adsc.200505197

FULL PAPERS
DOI: 10.1002/adsc.200505197
Synthesis of Polymer Bound Azabis(oxazoline) Ligands and their
Application in Asymmetric Cyclopropanations
Heiko Werner,a Clara I. Herrerías,b Michael Glos,a Anja Gissibl,a Jose M. Fraile,b
b
b,
a,
´
Ignacio Perez, Jose A. Mayoral, * Oliver Reiser *
a
Institut für Organische Chemie, Universität Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany
Fax: (þ49)-941-943-4121, e-mail: oliver.reiser@chemie.uni-regensburg.de
b
´
´
Departamento de Química Organica, Instituto de Ciencia de Materiales de Aragon and Instituto Universitario de
´
´
Catalisis Homogenea, Facultad de Ciencias, Universidad de Zaragoza-C. S. I. C., 50009 Zaragoza, Spain
E-mail: mayoral@unizar.es
Received: May 18, 2005; Revised: October 18, 2005; Accepted: November 7, 2005
Abstract: Aza(bisoxazoline) ligands were attached to bilization of the ligands, and on the preparation of the
various polymeric supports and the resulting immobi- catalysts.
lized ligands were evaluated in copper(I)-catalyzed
asymmetric cyclopropanations. The efficiency of these Keywords: asymmetric cyclopropanation; azabis(oxa-
transformations depends greatly on the polymeric zolines); copper; immobilization; N ligand; polymer-
support, on the protocol being applied for the immo- supported catalyst
clays by ion exchange[6] and employed as catalysts. On
Introduction
the other hand, metal-aza(bisoxazoline) complexes dis-
play a reduced Lewis acidity compared to their bis(oxa-
Azasemicorrins 1[1] and bis(oxazolines) 3[2] have proved
to be privileged classes of chiral ligands, being able to
form complexes with a broad variety of metals that are
able to catalyze a great number of reactions with unpar-
alleled enantioselectivity.
Recently, we introduced azabis(oxazolines)[3] 2 which
can be viewed as structural hybrids of azasemicorrins 1
and bis(oxazolines) 3. They combine the advantage of
being accessible from the chiral pool like the bis(oxazo-
lines) 3 and the structural variability of azasemicorrins 1
due to the possibility of functionalizing the central nitro-
gen atom. Therefore, an attractive feature of these li-
gands is their potential for attachment to polymeric sup-
ports through alkylation of the central nitrogen, thus ar-
riving at recyclable catalysts. For example, 2c could be
attached to a polyethylene glycol support resulting in
4, which represented the first example of a bis(oxazo-
line) ligand being covalently immobilized.[3] Subse-
quently, there have been many more reports elegantly
demonstrating different strategies to attach bis(oxazo-
line) ligands of type 3 onto polymers.[4]
Since aza(bisoxazolines) 2 are considerably more
electron-rich than the corresponding bis(oxazolines) 3,
metal complexes of 2 are less prone to dissociate, thus di-
minishing ligand leaching. Therefore such complexes
can be immobilized in ionic liquids[5] and on nafion or Figure 1. Chiral N,N ligands for asymmetric catalysis.
Adv. Synth. Catal. 2006, 348, 125 – 132
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Heiko Werner et al.
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zoline) counterparts, as reflected, for example, in the in-
ability of Cu(II)-aza(bisoxazoline) complexes to cata-
lyze [4þ2]-cycloadditions in sharp contrast[7] to their
bis(oxazoline) analogues.
Immobilizing ligands on polyethylene glycol (MeO-
PEG5000) has the advantage that catalysts soluble in or-
ganic solvents such as dichloromethane are obtained.
On the other hand, the low ligand loading that is ach-
ieved with this support (0.05–0.1 mmol ligand/g poly-
mer) as well as the necessity of precipitating the catalyst
by adding ether or pentane for its recovery makes the
use of other polymers desirable. In this study we report
the heterogenization of 2 on various polystyrene sup-
ports and evaluate the resulting ligands in copper(I)-cat-
alyzed cyclopropanation reactions in comparison with
the corresponding polyethylene glycol-supported or
free ligands.
Scheme 1. Synthesis of TentagelTM-bound azabis(oxazolines).
Reagents and conditions: a) 4-(bromomethyl)benzoyl chlor-
ide (10 equivs.), pyridine (40 equivs.), CH2Cl2, room temper-
ature, 48 h, 46%; b) i: 2 (3 equivs.), n-BuLi (3.3. equivs.),
THF, À788C, 10 min; ii: 5 (1 equiv.), THF, room tempera-
ture, 72 h, 85% (6a), 71% (6b).
Results and Discussion
Preparation of Polystyrene-Bound Azabis(oxazolines)
Based on our work with MeOPEG-bound azabis(oxazo-
lines), we chose as supports for this study (a) polystyr-
ene, being cross-linked with divinylbenzene (DVB), nated 2. Therefore, conversion of the chloromethyl to
and thus insoluble in organic solvents, and (b) Tenta- the more reactive bromomethyl group was necessary,
gelTM, being a hybrid polymer consisting ofa polystyrene which could be readily achieved by treatment of 7 with
backbone and a polyethylene glycol periphery, which NaBr/NBu4Br. Subsequent coupling of 8 with 2
displays, in spite of its heterogeneous character, homo- (Scheme 2, method A) proceeded cleanly to give rise
geneous properties due to the solubility of the polar to 9 with considerable higher ligand loading (0.5–
side chains to which the ligands will be attached. Two 0.56 mmol/g polymer) compared to 4 or 6. Alternatively,
strategies, which were also previously successful for con- 10 was copolymerized in the presence of styrene and di-
necting bis(oxazoline) ligands with polystyrene sup- vinylbenzene in a ratio aiming at a similar ligand loading
ports,[8] were applied for the immobilization of 2, i.e., in 11 as obtained previously in 9a, using the protocol for
´
the direct grafting of the ligand onto the polymer or the preparation of monolithic resins described by Fre-
the functionalization of the ligand with a styryl group chet and coworkers.[9]
which is subsequently polymerized.
Since azabis(oxazoline) ligands are readilybenzylated
on the central nitrogen, a benzylmoiety was chosen in all Asymmetric Cyclopropanations
cases as linker between polymer and ligand. Thus, com-
mercially available TentagelTM (0.26 mmol theoretical The so prepared polymer-bound azabis(oxazoline) li-
loading capacity/g polymer) was converted to 5, howev- gands were evaluated in copper(I)-catalyzed cyclopro-
er, despite using the coupling reagent 4-(bromomethyl)- panation reactions with ethyl diazoacetate and styrene
benzoyl chloride in a large excess the conversion could or 1,1-diphenylethylene, a common test reaction for
not be raised above 46% (Scheme 1). Subsequent reac- which also data from immobilized bis(oxazoline) li-
tion with the deprotonated azabox ligands 2 proceeded gands are available in the literature. Copper(II)-cata-
well (71–85% conversion) to give rise to the Tenta- lysts of TentagelTM-bound ligands 6 were prepared as
gelTM-bound ligands 6. The loading (0.1–0.12 mmol/g previously reported for MeOPEG bound ligands 4[3a] us-
polymer) onto the polymer was determined by elemen- ing an excess of ligand (2 equivs.). Employing ligand and
tal analysis, using the nitrogen content from the ligand as metal in equimolar amounts led to inferior results in the
the indicative value for the ligand attachment.
subsequent catalysis experiments, which we attributed
Likewise, the synthesis of polystyrene-bound azabis- to undesired complexation of copper to the glycol chains
(oxazolines) could be achieved (Scheme 2). However, in the polymer. In contrast, preparation of copper(II)
commercially available Merrifield resin proved not to complexes of polystyrene bound ligands 9 and 11
be reactive enough to undergo coupling with deproto- (~0.5 mmol/g polymer) were carried out with an excess
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Table 1. Cu(I)-catalyzed cyclopropanation of 12 in the pre-
sence of various azabis(oxazoline) ligands.[a]
Entry Ligand Run Time [h] Yield [%] 13: 14[b] % ee 13[c]
1
2
3
4
2b[d]
2d[d]
4[d]
6a
6b
9a
1
1
8
8
8
48
48
78
82
70–85
51
35
29–32
28
28
64: 36 66
73: 23 92
70: 30 86–91
64: 34 62
64: 34 47
70: 30 70–72
70: 30 88
67: 37 58
1–15
1
1
1–2 96
1
1
5
6[e]
7[e]
8[e]
9b
11
96
96
[a]
Reagent and conditions: 12 (6 equivs.), methyl diazoace-
tate (1 equiv.), catalyst (1.5 mol %), PhNHNH2
(1.8 mol %).
Determined by GC using a DB 1301 column.
Determined by GC using a CP-Chiralsil DEX CB column.
Ethyl diazoacetate was employed.
[b]
[c]
[d]
[e]
Scheme 2. Synthesis of polystyrene-divinylbenzene bound
azabis(oxazolines). Reagents and conditions: a) Merrifield
resin (loading 1–1.5 mmol/g), NaBr (~40 equivs.), NBu4Br
(~3 equivs.), H2O/benzene, 5 d, 608C; b) Method A: i) 2a
or 2c (7.5 equivs.), n-BuLi (8.25 equivs.), THF, À788C,
10 min; ii) 8 (1 equiv.), THF, room temperature, 72 h, 50%
(9a), 58% (9b); Method B: i) 2c (3.4 mmol), n-BuLi
(3.7 mmol), THF, À78 to 08C, 10 min; ii) 8 (1 g), THF, reflux,
40 h; c) 10 (1 equiv.), styrene (6 equivs.), DVB (7.3 equivs.),
cat. AIBN, toluene (monomers/toluene¼40/60 w/w), 808C,
24 h.
3 equiv of styrene, 1 mol % of ligand and 1.2 mol % of
PhNHNH2 were employed.
Table 2. Cu(I)-catalyzed cyclopropanation of 15 in the pre-
sence of various azabis(oxazoline) ligands.[a]
of metal (1.6 equivs.), since copper metal not bound to
the ligand molecules could be readily removed by ex-
traction with methanol, yielding catalysts with a copper
content of 0.2–0.3 mmol/g polymer. The copper(II)
complexes were reduced with phenylhydrazine prior
to every catalysis run and could be easily recovered by
simple filtration from the reaction mixture after comple-
tion of the reaction.
Cyclopropanations were performed with styrene (12,
Table 1) and 1,1-diphenylethylene (15, Table 2), using
1–1.5 mol % catalyst in all cases. As benchmark, reac-
tions with ligands 2b and 2d were also performed to al-
low a comparison between immobilized and non-immo-
bilized ligands. The MeOPEG-bound azabis(oxazoline)
ligand 4 gave very similar results (entry 3, Tables 1 and
2) as compared to the free ligand 2d (entry 2, Tables 1
and 2), giving consistently high selectivities and good
yields, and multiple sequential reactions could be car-
ried out without a noticeable loss of catalyst perform-
ance. Moving to the polystyrene bound catalysts, we
found that ligands 9 and 11 were considerably less active
(entries 6–8, Table 1; entries 9–11, Table 2), as reflected
by the long reaction time necessary for decomposition of
the diazoacetates, but also by the increased amounts of
Entry Ligand Run Time [h] Yield [%][b] % ee 16[c]
1
2
3
4
5
6
7
8
9
2b[d]
2d[d]
4[d]
6a
6b
6b
6b
6b
9b
9b
1
1
1–6
1
1
2
3
4
1
8
8
8
49
41
56
83
83–90
66
60
71
67
69
84
36–80[e]
83
72
48
48
72
72
96
96
96
70
76
78
85
34
28
30
10
11
2
3
77
79
9b
[a]
Reagent and conditions: 12 (6 equivs.), methyl diazoace-
tates (1 equiv.), catalyst (1 mol %), PhNHNH2
(1.2 mol %).
Determined by GC using a DB 1301 column.
Determined by GC using a CP-Chiralsil DEX CB column.
3 equivs. of styrene, 1 mol % of ligand and 1.2 mol % of
PhNHNH2 were employed.
[b]
[d]
[d]
[e]
Run 1: 80%, Run 2: 78%, Run 3: 36%, Run 4: 50%, Run
5: 80%, Run 6: 61%.
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maleate and fumarate formed as by-products. Neverthe-
less, the enantioselectivity observed with these ligands
compared reasonably well with the non-immobilized
counterparts. Moreover, we found that the immobilized
azabis(oxazoline) ligands 9 obtained by direct grafting
onto the Merrifield resin gave better results than 11,
which was obtained by copolymerization of styrene
and DVB with the monomer 10. Consistent with the me-
dium degree of heterogenization, the TentagelTM-bound
ligands 6 displayed higher reactivity than the polystyr-
ene-supported ligands 9 and 11, but less activity than
the polyethylene glycol-supported ligand 4. However,
the enantioselectivities obtained with 6 were compara-
tively low, suggesting, that copper ions, not being bound
to the aza(bisoxazoline) ligands but possibly to the poly-
ethylene glycol chains, could not be completely removed
in the course of the catalyst preparation. A similar effect
has been observed also with bis(oxazoline) ligands at-
tached to polystyrene being cross-linked with bis(p-vi-
nylbenzyl) poly(ethylene glycol).[10] In agreement with
this analysis, in sequential reactions the enantioselectiv-
ity improved to some degree after the initial first cycle,
which could be rationalized in that copper ions not being
bound to the chiral ligand are removed within the wash-
ing cycles upon recovery of the catalyst. It is worth not-
ing that this complication is not encountered with poly-
ethylene glycol-bound aza(bisoxazoline) or bis(oxazo-
line) ligands but seems to be a particular problem of in-
soluble supports.
Comparing these results with the ones obtained for
Cu(I)-catalyzed cyclopropanations using polystyrene-
immobilized bis(oxazolines)[10] attached via a benzyl
linker, it becomes evident that azabis(oxazolines) are
advantageous over bis(oxazolines) regarding immobili-
zation on such supports (Figure 2). When copper com-
plexes of 17 and 19 are used to promote the reaction of
styrene (12) with ethyl diazoacetate, both grafted or co-
polymerized catalysts led to greatly reduced enantiose-
lectivities in comparison to the corresponding non-im-
Figure 2. Enantioselectivities of the major trans-diastereomer
21 obtained for the cyclopropanation of styrene (12) with eth-
yl diazoacetate with polystyrene-immobilized bis(oxazoline)
ligands.[10–12]
mobilized ligand. The best results were obtained with substitution pattern that was assumed to mimick best
homopolymers 17 (no cross-linking agent used) but the gem-dimethyl substitution in the box-bridge, gave
even with these supports enantioselectivities for the cy- 21 in 93% ee, being the highest selectivity reported for
clopropane 21 did not exceed 78% ee[10] [>99% ee with the title reaction with polymer-bound box ligands to
non-immobilized t-Bu-bis(oxazoline) ligands[2b]], clear- date. The same argument could also explain the better
ly worse than 88% ee for 13 obtained with 9b [92% ee selectivity obtained with 20[12] in comparison to 19.
withnon-immobilized t-Bu-azabis(oxazoline) ligands[3a]].
The best enantioselectivities, in some cases even
We attribute the difference in the performance of poly- slightly higher than in the homogeneous phase, are ob-
styrene-bound bis(oxazoline) and azabis(oxazoline) li- tained with the ligands 9 grafted on a Merrifield resin.
gands to the higher binding affinity of the latter towards In spite of the higher selectivity, these PS-DVB-immobi-
copper, thus reducing leaching and consequently cataly- lized catalysts as well as the corresponding bis(oxazo-
sis by non-ligand-bound metal centers during the reac- line)-based catalysts 17–18 suffer from a low catalytic
tion. However, another important factor has also to be activity and a poor chemoselectivity as evidenced by
taken into account, which was pointed out by Salvadori the formation of considerable amounts of fumarate
and co-workers,[11] i.e., the change of the optimal ligand and maleate as by-products, resulting in longer reaction
geometry imposed by the gem-dimethyl substitution in times and lower yields of cyclopropanes. This can be due
the bis(oxazoline) bridge by sterically more bulky to the low loading of copper catalyst onto the polymer,
groups being used as linkers. Indeed, using 18 having a given that the content Cu(I)·9 prepared by method A
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Table 3. Consecutive cyclopropanation reactions catalyzed by 9b’-Cu(I) prepared by method B.[a]
Entry
Alkene
Run
% yield
trans/cis
% ee trans[b]
% ee cis[b]
1
2
3
4
12
12
25
15
28
12
12
28
12
1
2
3
4
5
6
7
1
2
94
87
74
96
26
3
2
32
70
74: 26
74: 26
55: 45
–
65: 35
n.d.
n.d.
60: 40
70: 30
99
96
91
75
90
90
81
–
67
n.d.
n.d.
82
67
5
64
6
n.d.
n.d.
90
7[c]
8
9
76
[a]
Reagent and conditions: alkene (1 equiv.), ethyl diazoacetate (1 equiv.), 9b’-Cu(OTf)2 (1 mol %), 24 h.
Determined by GC using a CP-Chiralsil DEX CB column or HPLC using a Chiralpack AD-H column.
Polymer treated again with Cu(OTf)2.
[b]
[c]
(Scheme 2) was only 0.2 mmol/g. Although employing a in the cyclopropanation of a-methylstyrene (25) (entry
larger amount of polymer 9 can increase the number of 3), comparing quite well even to the best results ob-
catalytic sites, the possible diffusion limitations imposed tained for this substrate with homogeneous catalysts.[14]
by the high dispersion of the catalytic sites would not be In the fourth run 1,1-diphenylethylene (15) was cyclo-
avoided.
propanted in almost quantitative yield and good enan-
Consequently, we tried to increase the degree of func- tioselectivity, comparable with the homogeneous results
tionalization of the resin by changing the immobiliza- obtained earlier (see Table 2). The situation was
tion conditions (Scheme 2, method B). The loading of changed when an aliphatic alkene was tried. 1-Octene
Cu(I)·9b’ onto the resin could be increased three-fold (28) is much less reactive and as a consequence dimeri-
(0.74 mmol/g) when the brominated resin 8 and the de- zation (and probably polymerization) of diazoacetate
protonated chiral azabis(oxazoline) 2c were reacted in interferes, leading to low yield and only moderate enan-
THF under reflux and the complexation with Cu(OTf)2 tioselectivities. Furthermore, those by-products are
was carried out in methanol instead of dichloromethane. known to poison the copper catalysts[8a] as is clearly
This new solid was tested under more exigent condi- shown by the results in the sixth run again with styrene.
tions, employing only stoichiometric amounts of al- The catalyst was rendered completely inactive, which is
kene[13] and, moreover, leaving out the commonly em- not due to copper leaching as demonstrated by analysis
ployed activation of the catalyst with phenylhydrazine. of the solution and the lack of activity of the polymer re-
In spite of these disadvantageous conditions the results charged with copper (entry 7). Also carrying out the cy-
were excellent (Table 3) leading to 94% yield with clopropanation of 1-octene (21) with freshly prepared
99% ee for the major trans product 21 (entry 1) in the re- catalyst (entry 8) gave low yields of cyclopropanation
action of styrene with ethyl diazoacetate, which is the adducts, albeit with better selectivity compared to the
best performance of a heterogeneous catalyst ever de- reused catalyst (entry 5). Upon recyclization of the cat-
scribed in this cyclopropanation but also exceeds the alyst followed by a second cyclopropanation with styr-
best results achieved with non-polymer-bound azabis- ene (entry 9) the catalyst was still active in contrast to
(oxazolines).
the results obtained in entry 6, but nevertheless signifi-
Moreover, the catalyst could be recovered and reused cant poisoning clearly had occurred when compared to
in cyclopropanation reactions with various alkenes. In the results obtained for entries 1–4. Consequently, it
the second run with styrene (entry 2) the behavior was can be concluded that catalyst deactivation occurs also
almost identical with respect to yield and enantioselec- to some extent with aromatic substrates but, due to their
tivity. Subsequently, the recovered catalyst was tested high reactivity, catalyst recycling and multiple cycles
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2 d the brown solid was filtered off, washed with tetrahydrofur-
an and dried to obtain TentaGel-bound-ligand 6a (loading
0.12 mmol/g. as deduced from the elemental analysis taking
into account the nitrogen content which is unique to the ligand:
C 62.86%, H 9.04%, N 0.50%) and 6b (loading 0.10 mmol/g, as
deduced from the elemental analysistaking into accountthe ni-
trogen content which is unique to the ligand: C 62.99%, H
9.07%, N 0.42%).
with such substrates are possible with similar perform-
ance in each run. In contrast, with the less reactive acy-
clic alkenes, significant amounts of by-products are pro-
duced that rapidly poison the catalyst.
Conclusion
Azabis(oxazolines) can be efficiently immobilized onto
insoluble polymers by either grafting or copolymeriza-
tion of vinylbenzyl-substituted ligands. Copolymeriza-
tion does not show any advantage over grafting, whereas
Merrifield resin clearly is a better support than Tenta-
Gel. The catalytic results greatly depend on the immobi-
lization conditions and the complexation method.
Moreover, due to the higher binding affinity towards
copper immobilized azabis(oxazolines) are far superior
compared to the corresponding bis(oxazolines). Under
the optimal conditions, the immobilized azabis(oxazo-
line) 9b’ leads to the most effective immobilized catalyst
described so far for enantioselective cyclopropanations
of aromatic substrates, rivaling the best results obtained
with homogeneous chiral catalysts.
Synthesis of Cu(OTf)2 ·6
Ligand 6 (0.1 g) was suspended in dichloromethane (15 mL)
and a solution of Cu(OTf)2 (0.48 equivs.) in dichloromethane
(10 mL) was added. After shaking for 24 h the green solid
was filtered, washed several times with methanol and tetrahy-
drofuran, and dried under vacuum to obtain Cu(OTf)2 ·6a
(loading 0.044 mmol/g, determined by plasma emission spec-
trometry) and Cu(OTf)2 ·6b (loading 0.054 mmol/g, deter-
mined by plasma emission spectrometry).
Synthesis of Cu(OTf)2 ·9
Merrifield resin (1 g) was suspended in benzene and treated
with a solution of NaBr (4.12 g, 40 mmol) and Bu4NBr
(0.97 g, 3 mmol) in water. The mixture was stirred at 608C
for 5 days. The solid was filtered and washed with THF to yield
the brominated resin 8.
Experimental Section
Method A: Azabis(oxazoline) 2a or 2c (0.375 mmol) was dis-
solved in tetrahydrofuran (5 mL) and cooled to À788C. Via sy-
ringe n-BuLi (258 mL, 0.412 mmol, 1.6 M in hexane) was added
dropwise and the mixture was allowed to warm to room tem-
perature. After stirring for 2 h the reaction mixture was trans-
ferred slowly to a suspension of 8 (500 mg) in tetrahydrofuran
(8 mL). After shaking the suspension for further 2 d the solid
was filtered off, washed with tetrahydrofuran and dichlorome-
thane, and dried under vacuum at 508C overnight to obtain PS-
bound-ligand 9a (loading 0.50 mmol/g, as deduced from the el-
emental analysis taking into account the nitrogen content
which is unique to the ligand: C 87.96%, H 6.73%, N 2.11%)
and 9b (loading 0.56 mmol/g, as deduced from the elemental
analysis taking into account the nitrogen content which is
unique to the ligand: C 87.35%, H 6.51%, N 2.38%).
The resins (0.1 g) were suspended in dichloromethane
(15 mL) and a solution of Cu(OTf)2 (0.18 mmol) in dichloro-
methane (300 mL) was added. After shaking for 24 h, the solid
was filtered off, washed with dichloromethane, methanol and
tetrahydrofuran, and dried under vacuum at 508C overnight
to obtain Cu(OTf)2 ·9a (loading 0.20 mmol Cu/g, determined
by plasma emission spectrometry) and Cu(OTf)2 ·9b (loading
0.22 mmol/g, determined by plasma emission spectrometry).
Method B: Azabis(oxazoline) 2c (0.41 g, 1.7 mmol) was dis-
solved in tetrahydrofuran (5 mL) and cooled to À788C. Via sy-
ringe n-BuLi (1.17 mL, 1.87 mmol. 1.6 M in hexane) was added
dropwise and the mixture was allowed to warm to room tem-
perature. After stirring for 10 min the reaction mixture was
slowly transferred to a suspension of 8 (500 mg) in tetrahydro-
furan (8 mL) and the resulting mixture was heated under reflux
for 40 h. The solid was filtered off, washed with tetrahydrofur-
an, dichloromethane and methanol, and dried under vacuum at
508C overnight to obtain PS-bound-ligand 9b (loading
General Remarks
The copper analysis is carried out by plasma emission spec-
trometry measuring at 224.7 nm after dissolving completely a
sample (25–50 mg) of the polymer in an acidic aqueous solu-
tion (nitric acid, sulfuric acid, HF) under microwave irradia-
tion. Elemental analyses were carried out on a Perkin-Elmer
2400 elemental analyzer. Compound 4 was prepared as descri-
bed in ref.[3a]
Synthesis of 5
TentaGel-S-OH (2.0 g, loading 0.26 mmol/g) was suspended in
dichloromethane (20 mL) and pyridine (2 mL). To this suspen-
sion 4-bromomethylbenzoyl chloride (1.2 g, 5 mmol) dissolved
in dichloromethane (15 mL) was added dropwise. After shak-
ing of the reaction mixture for two days at room temperature,
the polymer was isolated by filtration, and washed with meth-
anol, tetrahydrofuran and dichloromethane. The resulting col-
orless solid was dried under vacuum; yield: 2.06 g (loading¼
0.12 mmol/g).
Synthesis of 6
Azabis(oxazoline) 2a or 2c (0.9 mmol) was dissolved in tetra-
hydrofuran (5 mL) and cooled to À788C. Via syringe n-BuLi
(621 mL, 0.99 mmol, 1.6 M in hexane) was added dropwise
and the mixture was allowed to warm to room temperature. Af-
ter stirring for 2 h the reaction mixture was transferred slowly
to a suspension of 5 (500 mg, loading 0.12 mmol/g) in tetrahy-
drofuran (15 mL). After shaking of the suspension for further
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Adv. Synth. Catal. 2006, 348, 125 – 132

Polymer Bound Azabis(oxazoline) Ligands
FULL PAPERS
0.99 mmol/g as deduced from the elemental analysis taking
into account the nitrogen content which is unique to the ligand:
C 83.72%, H 6.33%, N 4.16%).
The resin (0.1 g) was suspended in a solution of Cu(OTf)2
(0.1 mmol) in methanol (1.7 mL) and shake for 24 h at room
temperature. After this time the solid was filtered off, washed
with methanol, and dried under vacuum to yield Cu(OTf)2 ·9b
(loading 0.73 mmol/g, determined by plasma emission spec-
trometry).
vessel, and activated by addition of phenylhydrazine (22 mL
of a 5% solution in dichloromethane). Styrene (312 mg,
3 mmol, 345 mL) and methyl diazoacetate (1 mmol, 1 mL of
an 8% solution in dichloromethane diluted with 7 mL di-
chloromethane) were added for the next cycle as described
above.
Representative Procedure for Cyclopropanations of
Alkenes with Tentagel-Bound Azabis(oxazolines) 6
Cu(OTf)2 ·6a (35 mg, 0.015 mmol) was mixed with dichloro-
methane (3 mL) and shaken for 2 h. Phenylhydrazine (33 mL
of a5% solution indichloromethane) and, after 15 min, styrene
(12) (625 mg, 6 mmol, 690 mL) were added. Methyl diazoace-
tate (1 mmol, 8 mL of a 1% solution in dichloromethane)
was added over 8 h using a syringe pump. Stirring was contin-
ued for 40 h (total reaction time 48 h). The catalyst was filtered
off, the filtrate was concentrated, and the residue was purified
on silica (3ꢀ25 cm silica, 9:1 hexanes/EtOAc as eluant). The
products 13 and 14 were obtained as clear oils showing identi-
cal spectroscopic properties as described in the literature.[2b]
Immobilization by Polymerization
Azabis(oxazoline) 2a (1.0 mmol) was dissolved in tetrahydro-
furan (3 mL) and cooled to À788C. Via syringe n-BuLi
(687 mL, 1.1 mmol, 1.6 M in hexane) was added dropwise and
the mixture was allowed to warm to room temperature. After
stirring for 2 h the reaction mixture was added to a solution
of p-vinylbenzyl bromide (1.0 mmol) in tetrahydrofuran
(3 mL) and the resulting mixture was stirred overnight. The
solution was treated with saturated NaHCO3 solution
(10 mL) and extracted with dichloromethane (3ꢀ10 mL).
The combined organic phases were dried over MgSO4 and
the solvent eliminated under reduced pressure. A mixture of
this residue with styrene and divinylbenzene (7:42:51 molar
ratio) was dissolved in toluene (monomers:toluene ratio¼
40:60 w/w), placed in a glass mold, and purged with N2 in the
presence of AIBN (1% w/w). The mold was closed and heated
at 808C for 24 h. The mold was broken and the solid was ex-
tracted with THF in a Soxhlet apparatus. The ligand loading
was 0.52 mmol/g. This polymer (0.5 g) was added to a solution
of Cu(OTf)2 (0.42 mmol) in THF (17 mL) and the mixture was
shake for 3 days at room temperature. The solid wasfiltered off,
washed with THF and methanol and dried under vacuum to
yield Cu(OTf)2 ·11 (0.31 mmol/g, determined by plasma emis-
sion spectrometry).
Representative Procedure for Cyclopropanations of
Alkenes with Merrifield-Bound Azabis(oxazolines) 9
Cu(OTf)2 ·9b (70 mg, 0.015 mmol) was mixed with dichloro-
methane (3 mL) and shaken for 2 h. Phenylhydrazine (33 mL
of a5% solution indichloromethane) and, after 15 min, styrene
(12) (625 mg, 6 mmol, 690 mL) were added. Methyl diazoace-
tate (1 mmol, 8 mL of a 1% solution in dichloromethane)
was added over 8 h using a syringe pump. Stirring was contin-
ued for 40 h (total reaction time 88 h). The catalyst was filtered
off, the filtrate was concentrated, and the residue was purified
on silica (3ꢀ25 cm silica, 9:1 hexanes/EtOAc as eluant). The
products 13 and 14 were obtained as clear oils showing identi-
cal spectroscopic properties as described in the literature.[2b]
Representative Procedure for Cyclopropanations of
Alkenes with MeOPEG-Bound Azabis(oxazolines) 4
Acknowledgements
Under a nitrogen atmosphere Cu(OTf)2 (3.6 mg, 0.01 mmol)
and 12 (200 mg, 0.02 mmol ) were dissolved in dichlorome-
thane (5 mL). Phenylhydrazine (22 mL of a 5% solution in di-
chloromethane) and styrene (312 mg, 3 mmol, 345 mL) were
added. Methyl diazoacetate (1 mmol, 8 mL of a 1% solution
in dichloromethane) was added over 8 h using a syringe
pump. Stirring was continued for 3 h and the reaction mixture
was transferred via cannula to a 250-mL septum-capped flask.
The reaction vessel was rinsed with 3 mL dry dichloromethane.
The volume of the solvent was reduced to approximately 5 mL
by applying vacuum and 100 mL of dry diethyl ether were add-
ed to precipitate the polymer-supported catalyst. After cooling
with ice for 15 min the catalyst was separated from the products
by filtration through a sintered glass funnel under a nitrogen at-
mosphere. The filtrate was evaporated under vacuum to give a
slightly yellow oil, which was purified by chromatography on
silica (3ꢀ25 cm silica, 9:1 hexanes/EtOAc as eluant). The
products 13 and 14 were obtained as clear oils showing identi-
cal spectroscopic properties as described in the literature.[2b]
For the following reaction cycle the catalyst was dissolved in
10 mL dry dichloromethane, transferred into a new reaction
This workwas supported by the Fonds der Chemischen Indus-
trie, the DAAD (Accion Integrada HA2001–0096), the
C.I.C.Y.T. (project PPQ2002–04012), the DGA, and through
generous chemical gifts by Degussa AG. I.P. is indebted to the
MEC for a grant.
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Adv. Synth. Catal. 2006, 348, 125 – 132
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
131

Heiko Werner et al.
FULL PAPERS
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132
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 125 – 132