Chiral C2-symmetric Cu(II) complex immobilized in ionic liquids: A recoverable catalytic system for enantioselective hetero-Diels-Alder reaction

Article abstract of DOI:10.1055/s-2007-1000830

Hydrophobic ionic liquids such as [Bmim]PF₆ and [Bmim]SbF ₆ were used successfully as powerful media for bis(oxazoline)-copper- catalyzed asymmetric hetero-Diels-Alder reactions. The reactivities and stereoselectivities were comparable (endo/exo up to 97:3 and up to 94% ee, respectively) to those of the corresponding homogeneous reactions. Furthermore, the reaction was remarkably accelerated in [Bmim]PF₆ compared to that in dichloromethane at 3 (±1)°C and metal-ligand complexes were recovered and recycled up to eight times exhibiting almost the same reactivity and selectivity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1000830

LETTER
89
Chiral C2-Symmetric Cu(II) Complex Immobilized in Ionic Liquids: A Reco-
verable Catalytic System for Enantioselective Hetero-Diels–Alder Reaction
C
hira
l
C
-Symmet
o
ric Cu(II) Co
n
mplexImm
o
g
bilizedinIonic Li
J
2
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, 151-747, Korea
Fax +82(2)8727505; E-mail: kimbm@snu.ac.kr
Received 6 November 2007
are often required and reduced catalytic activity and enan-
tioselectivity are associated.
Abstract: Hydrophobic ionic liquids such as [Bmim]PF6 and
[Bmim]SbF6 were used successfully as powerful media for bis(ox-
azoline)–copper-catalyzed asymmetric hetero-Diels–Alder reac-
tions. The reactivities and stereoselectivities were comparable
(endo/exo up to 97:3 and up to 94% ee, respectively) to those of the
corresponding homogeneous reactions. Furthermore, the reaction
was remarkably accelerated in [Bmim]PF6 compared to that in
dichloromethane at 3 ( 1) °C and metal–ligand complexes were re-
covered and recycled up to eight times exhibiting almost the same
reactivity and selectivity.
Recently, a new approach involving ionic liquids3 has
been developed for catalyst separation and recycling.4 In
ionic liquids, metal–ligand complex having ionic nature
could be solvated and immobilized without additional
structural modification. The immobilized catalyst could
be recycled by simple extraction of the ionic liquid with a
relatively nonpolar organic solvent after reaction. More-
over, in many asymmetric catalytic reactions, use of ionic
liquids could offer advantages over conventional volatile
organic solvents in terms of activity, enantioselectivity,
stability, and the reusability of the catalyst systems.5
Key words: enantioselective, hetero-Diels–Alder reaction, ionic
liquid, catalyst recycling, chiral bis(oxazoline)–copper complex
For the past decade, chiral bis(oxazoline) ligand–metal
complexes have received a noticeable attention from or-
ganic chemists due to their general applicability for mul-
tiple asymmetric catalytic reactions.1 However, these
versatile catalytic systems suffer from considerable draw-
backs such as requirement of a relatively large quantitiy of
the catalyst (generally 10 mol%), high cost, and a low
turnover number. As an effort to find a solution to these
problems, a number of heterogeneous systems have been
developed. In general, homogeneous asymmetric cata-
lysts have been anchored onto stationary supports such as
organic cross-linked polymers or inorganic materials.2 Al-
though these methods may offer several advantages such
as easy separation of products and recycling of the cata-
lyst, additional cumbersome modifications of the catalysts
The asymmetric hetero-Diels–Alder reactions (hetero-
DA)6 of unsaturated carbonyl compounds with enol ethers
is a facile method for the synthesis of substituted 3,4-di-
hydro-2H-pyrans, which are very useful precursors for the
preparation of chiral natural products.7 Herein we report
on highly efficient and recyclable asymmetric hetero-
Diels–Alder reactions utilizing chiral bis(oxazoline)–cop-
per complex immobilized in ionic liquid.
The enantioselective hetero-DA reaction of an unsaturat-
ed keto ester with ethyl vinyl ether was carried out using
the catalyst prepared from mixing ligand 3 (10.5 mol%
relative to the unsaturated keto ester) with Cu(OTf)2 in
various ionic liquids in situ for 3 hours (Scheme 1). The
reaction conditions8 for the hetero-DA reactions were tak-
en from those of the homogeneous counterparts reported
ligand 3 (10.5 mol%)
Ph
Ph
Cu(OTf)2 (10 mol%)
+
OEt
ionic liquid (0.5 M)
O
EtO2C
EtO2C
O
OEt
1
2
4
2+
Me
N
Me
N
Me
N
Me
N
–
2OTf
Cu
CMe3
CMe3
Me3C
Me3C
3
5
Scheme 1 Enantioselective hetero-Diels–Alder reaction of unsaturated keto ester 1 and enol ether 2 using chiral Cu(II) complex 5 in various
ionic liquids
SYNLETT 2008, No. 1, pp 0089–0093
x
x.
x
x.
2
0
0
7
Advanced online publication: 11.12.2007
DOI: 10.1055/s-2007-1000830; Art ID: U10807ST
© Georg Thieme Verlag Stuttgart · New York

90
Y. J. Shin et al.
LETTER
earlier by Evans9 and the results are summarized in in Figure 1, the reaction was remarkably faster in
Table 1. First, we investigated how different ionic liquids [Bmim]PF6 than in CH2Cl2. Several factors were suggest-
(IL) affect the reaction. The enantioselectivity and the re- ed for the rate acceleration in ionic liquid such as high in-
activity were strongly influenced by the inherent nature of ternal pressure,12a hydrogen bonding,12b solvent
the anion. When hydrophilic10 ionic liquids, such as polarity,12c and Lewis acidity.12d Recently, a report,
[Bmim]BF4, [Bmim]OTf,11 were used, the DA adduct was through computational investigation,13 has indicated that
obtained in very low yields, i.e., 5% and 6%, respectively, the cationic part of the ionic liquid is responsible for the
as a 93:7 endo/exo mixture (Table 1, entries 1 and 2) and rate enhancement through hydrogen bonding with sub-
in poor enantiomeric enrichments (29% and 49% ee). strate and relative stabilization of a transition state. Ac-
However, in the hydrophobic10 ionic liquids such as cording to this suggestion, in our case the heterodiene
[Bmim]PF6 and [Bmim]SbF6,11 the desired adducts were would interact with the Bmim+, and the intensity of hydro-
obtained in excellent yields and enantioselectivities gen bonding might be maximized in the hydrophobic ion-
(Table 1, entries 3 and 4). When the reactions were carried ic liquid.
out at 3 ( 1) °C (entry 5), sightly improved endo/exo se-
Since reactions in ionic liquids were significantly acceler-
lectivity and ee were observed and more improvement
ated, we wondered whether the catalyst loading could be
was observed with increasing the equivalent of enol ether
reduced while maintaining the reactivity. Reactions were
(entry 6). Using 0.44 mmol of unsaturated ester 1, the
run with gradually diminishing amount of the ligand–met-
al complex, and the results are shown in Table 2. For con-
endo product of 93% ee was obtained in quantitative yield
(Table 1, entry 7). The product obtained in dichlo-
trol reactions, one DA reaction was run without any ligand
romethane at –78 °C exhibited 97.5% ee (entry 9).
nor metal complex at all in [Bmim]PF6 (entry 1) and an-
To examine the rate acceleration in ionic liquid, the rates other with only Cu(OTf)2 (entry 2), giving 0.3% and 25%
of the reactions between 1 and 2 in [Bmim]PF6 and yields, respectively, of the product with no enantioselec-
dichloromethane were compared at 3 ( 1) °C. As shown tivity. The latter result indicates that the cupric triflate it-
Table 1 Results of the Cycloaddtion between Heterodiene 1 and Enol ether 2 Catalyzed by 5a
ligand 3 (10.5 mol%)
Ph
Ph
Cu(OTf)2 (10 mol%)
+
OEt
ionic liquid (0.5 M)
O
EtO2C
EtO2C
O
OEt
1
2
4
2+
Me
N
Me
N
Me
N
Me
N
–
2OTf
Cu
CMe3
CMe3
Me3C
Me3C
3
5
Entry
Solvent
EVE (equiv)
Temp (°C)
20
Yield (%)d,e
5 (7)
endo/exof
93:7
ee (%)f
29
1
[Bmim]BF4
[Bmim]OTf
[Bmim]PF6
[Bmim]SbF6
[Bmim]PF6
[Bmim]PF6
[Bmim]SbF6
CH2Cl2
1.5
1.5
1.5
1.5
1.5
2
2
20
6 (8)
93:7
49
3
20
96 (100)
93 (94)
99 (100)
100 (100)
99 (100)
(100)
82:18
93:7
89
4
20
89
5
3 ( 1)
3 ( 1)
3 ( 1)
–78
96:4
91
6b
7
97:3
94
1.5
1.5
94:6
93
8c
>99:1
97.5
a All reactions were performed using 0.220 mmol of unsaturated keto ester 1 at 0.5 M concentration for 1 h.
b This reaction was performed using 0.441 mmol of 1 for 5 min.
c See ref. 6d.
d The values in parentheses indicate conversion of starting material determined by 1H NMR (300 MHz) or GC using a chiral stationary phase.
e Yields of isolated product.
f Enantiomeric excess and endo/exo ratios were determined by HPLC using Chiralcel OD-H column (0.5 mL/min, 0.4% i-PrOH in hexane) and
NMR, respectively.
Synlett 2008, No. 1, 89–93 © Thieme Stuttgart · New York

LETTER
Chiral C2-Symmetric Cu(II) Complex Immobilized in Ionic Liquids
Table 3 Result of the Cycloaddtion between Heterodiene 1 and
91
a
Enol Ether 2 at 3 ( 1) °C Using Recycled 5 and [Bmim]PF6.
Run
1
Time
5 min
Conversion (%)e endo/exof
ee (%)f
100 (100)d
100 (99)d
100 (95)d
100 (94)d
100 (95)d
100 (96)d
100 (94)d
99 (95)d
31
97:3
97:3
96:4
96:4
96:4
96:4
96:4
96:4
98:2
97:3
95:5
93:7
95:5
97:3
97:3
96:4
94
94
94
94
94
94
94
94
85
83
74
–
2
10 min
10 min
10 min
10 min
10 min
15 min
20 min
20 min
90 min
180 min
12 h
3
4
5
6
Figure 1 Comparison of the hetero-DA reaction rates in CH2Cl2 and
[Bmim]PF6 at 3 ( 1) °C
7
8
Table 2 Influence of Ligand–Metal-to-Substrate Ratio on the Cy-
cloaddtion between Heterodiene 1 and Enol Ether 2 Catalyzed by 5a
9
Entry
Ligand 3/metal Yield
(mol%)
endo/exod
ee
10
11
14b
15c
17
18
20
20
(%)b,c
(%)d
7
1
2
3
4
5
6
–/–
0.3 (0.7)
98:2
64:36
97:3
97:3
97:3
93:7
0
0
1
–/10
25 (28)
100 (100)
99 (99)
15 min
20 min
50 min
120 min
99
92
92
89
89
10.5/10
10/8
94
88
83
42
94
80
7/5
58 (67)
43
2.8/2.5
1.8 (2.4)
a All reactions were performed on 0.441 mmol scale at 0.5 M concen-
tration with 2 equiv of ethyl vinyl ether.
a All reactions were carried out at 3 ( 1) °C for 1 h.
b Yields of isolated products.
b Additional ligand 3 (0.1 equiv) was added at this run.
c Additional Cu(OTf)2 (0.1 equiv) and ligand 3 (0.1 equiv) were added
at this run.
c Values in parentheses are determined through 1H NMR (300 MHz)
analysis based on remaining starting material.
d The ee and endo/exo ratios were determined through HPLC and
NMR spectroscopic analyses, respectively.
d Yields of isolated products.
e Determined through 1H NMR (300 MHz) analysis of the crude prod-
uct based on remaining starting material.
f The ee and endo/exo ratios were determined through HPLC and
NMR spectroscopic analyses, respectively.
self is somewhat effective in catalyzing the reaction
without the ligand. As the amount of the catalyst de-
creased, the reactivity and the stereoselectivity of the het-
ero-DA reactions diminished gradually (entries 3–6) and
eventually very low enantioselectivity was observed with
2.5 mol% of metal complex (entry 6). In order to obtain
maximum enantioselectivity of the reaction, the ligand
catalyst was kept at 10 mol% level.
long presumably due to leaching of the catalyst from the
ionic liquid (cycles 16–20). It was found that a small
amount of ionic liquid was lost through extraction with di-
ethyl ether in every recycle, thus the concentration of the
reaction mixture became higher and higher. Presumably,
the concentration change might have affected the catalytic
system in ionic liquid (in comparison with our experiment
of 0.5 M concentration between 1 and 2, product of 7%
yield after one hour was observed in 1 M concentration
and only 5% yield was obtained in 1.5 M concentration).
However, more detailed studies are required to clarify
these phenomena.
Recognizing that copper–chiral bis(oxazoline) complex
could be immobilized in ionic liquid,14 we examined the
recycling capability of the catalyst 5, and the results are
summarized in Table 3. The recycling process8 was ex-
tremely straightforward; the ionic liquid containing the
catalyst was reused successfully up to eight times (cycles
1–8). After the eighth reaction, noticeable decreases in
both reactivity and enantioselectivity were observed (cy-
cles 9–13). Although the additional ligand 3 was added at
the fourteenth run, only a trace amount of the product was
obtained (cycle 14). This presumably indicates that the
concentration of the copper(II) reagent is quite low at this
time. When fresh Cu(OTf)2 and ligand 3 were added in the
fifteenth recycle, the catalytic system was fully restored
(cycle 15). However, these recycling system did not last
Encouraged with the successful results between unsatur-
ated keto ester 1 and ethyl vinyl ether 2 (Table 4, entries 1
and 2), we examined the scope of this hetero-DA reaction
further using various substrates, and the results are shown
in Table 4. When a,b-unsaturated keto ester 1 and dihy-
drofuran were employed under the same reaction condi-
tions, better results in yield and endo/exo selectivity were
observed than those of the corresponding homogeneous
Synlett 2008, No. 1, 89–93 © Thieme Stuttgart · New York

92
Y. J. Shin et al.
LETTER
Table 4 Results on the Cycloaddition between Various Heterodienes and Enol Ethers Catalyzed by 5 3 ( 1) °C a
Ph
2
OEt
EtO2C
O
OEt
Ph
O
Ph
H
H
6
4
cat. 5
O
[Bmim]PF6
EtO2C
O
EtO2C
O
Ph
8
SPh
1
7
EtO2C
O
SPh
9
Ph
Ph
2
OEt
O
(MeO)2P
(MeO)2P
O
OEt
cat. 5, [Bmim]PF6
O
O
11
10
Entry
1
Product
Yield (%)c
endo/exod
97:3
ee (%)d
94
4
4
100
93
99
96
91
91
91
88
2a
3
>20:1
95:5
97
7
93
4a
5
7
16:1
97
9
99:1
95
6a
7
9
>20:1
96:4
99
11
11
93
8b
32:1
94
a See ref. 6c.
b See ref. 9.
c Yields of isolated products after chromatographic purification.
d The ee and endo/exo ratios were determined through HPLC and NMR spectroscopic analyses.
reaction, and comparable enantioselectivity value (93% times exhibiting almost the same activity and selectivity.
vs. 97% ee in the control reaction) was obtained (entries 3 The stability of copper complex in ionic liquid was also
and 4). In the case when phenyl vinyl sulfide was used as verified, thus these results could be extended to a practical
dienophile, better diastereoselectivity than that of the ho- application.
mogeneous reaction was observed, and similar results
were obtained in reactivity and enantioselectivity (entries
5 and 6). In the case utilizing a,b-unsaturated acyl phos-
phonate 10 and enol ether 2, also good results were afford-
Acknowledgment
Generous financial support from the Korea Research Fund (KRF-
2005-041-C00247) is gratefully acknowledged.
ed like other cases (entries 7 and 8).
In summary, it has been demonstrated that hydrophobic
ionic liquids such as [Bmim]PF6 and [Bmim]SbF6 were
used successfully as powerful media for copper–bis(ox-
azoline)-catalyzed asymmetric hetero-Diels–Alder reac-
tions. Both the reactivity and the stereoselectivity were
comparable to those of the corresponding homogeneous
reaction. Moreover, in ionic liquids the reaction was sig-
nificantly faster than in dichloromethane and the metal–
ligand complexes were recovered and recyled up to eight
References and Notes
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Synlett 2008, No. 1, 89–93 © Thieme Stuttgart · New York

LETTER
Chiral C2-Symmetric Cu(II) Complex Immobilized in Ionic Liquids
93
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