Enantioselective cyclopropanation reactions in ionic liquids

Article abstract of DOI:10.1016/S0957-4166(01)00315-9

The benchmark enantioselective cyclopropanation of styrene with ethyl diazoacetate, promoted by two different bis(oxazoline)-copper complexes, is studied in three ionic liquids. The nature of both the anion and cation influence the behaviour of the catalysts, which can be recovered and re-used.

Full text of DOI:10.1016/S0957-4166(01)00315-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1891–1894
Enantioselective cyclopropanation reactions in ionic liquids
a
a
a
a,
b
Jos e´ M. Fraile, Jos e´ I. Garc ´ı a, Clara I. Herrer ´ı as, Jos e´ A. Mayoral, * Daniel Carri e´ and
b,
Michel Vaultier *
a
Departamento de Qu ´ı mica Org a´ nica, Instituto de Ciencia de Materiales de Arag o´ n, Facultad de Ciencias,
Universidad de Zaragoza-CSIC, E-50009 Zaragoza, Spain
UMR 6510 du CNRS, Universit e´ de Rennes 1, Campus de Beaulieu, F-35042 Rennes Cedex, France
b
Received 18 June 2001; accepted 9 July 2001
Abstract—The benchmark enantioselective cyclopropanation of styrene with ethyl diazoacetate, promoted by two different
bis(oxazoline)-copper complexes, is studied in three ionic liquids. The nature of both the anion and cation influence the behaviour
of the catalysts, which can be recovered and re-used. © 2001 Elsevier Science Ltd. All rights reserved.
1
. Introduction
however, the solid counterion has a noticeable influence
7,8
on the stereochemical course of the reaction. In view
of this, the search for immobilisation methods that are
able to reduce the influence of the support is an open
field of great interest.
Enantioselective reactions promoted by chiral catalysts
constitute a topic of recognised importance in chemical
research. In this regard, the search for chiral ligands
1
with broad applicability is a particularly interesting
aspect in this field. Bis(oxazolines) are versatile chiral
ligands that are able to form complexes with different
metals, and these complexes are able promote a variety
of organic reactions. As a consequence, the immobili-
sation of bis(oxazoline)-based complexes opens the way
to obtain recoverable catalysts for a range of reactions.
Ionic liquids have proven to be excellent solvents for
many organic reactions. In catalysed reactions they
9
allow, in some cases, the catalyst to be re-used after
product extraction and, in this way, the use of these
solvents can be considered as an immobilisation
method without ligand modification. In spite of the fact
that this approach is a promising alternative for immo-
bilisation, there are very few examples describing its use
in enantioselective reactions promoted by chiral cata-
2
We have studied the immobilisation of bis(oxazoline)-
copper catalysts by two different strategies, namely by
3
,4
covalent grafting onto an organic polymer
ion-pairing with an anionic support.
or by
lysts. Most of these literature examples refer to hydro-
4,5
Recently the
10
genation reactions,
although some deal with
immobilisation of an aza-bis(oxazoline) by attachment
11
12
epoxidation or epoxide opening reactions. To the
best of our knowledge, there is only a single, unpub-
lished result that deals with the use of this methodology
in asymmetric CꢀC bond forming reactions. Herein,
we describe the immobilisation of bis(oxazoline)-copper
complexes in ionic liquids and the use of these com-
plexes to promote the benchmark cyclopropanation
6
to a soluble organic polymer has been described. In
both cases the immobilisation exerts a significant influ-
ence on the outcome of the reaction, particularly the
enantioselectivity. The changes observed after the graft-
ing process are due to the modification of the chiral
ligand, which is now bonded to a large polymeric
9d
‘
substituent’ whose presence would be expected to mod-
7
reaction between styrene and ethyl diazoacetate, a CꢀC
bond forming reaction.
ify the conformational preferences and, as a conse-
quence, the relative energies of the different transition
states. Electrostatic immobilisation eliminates this
drawback because the chiral ligand is not modified;
2
. Results and discussion
In this study we used three different ionic liquids
Scheme 1), an approach that allows evaluation of the
(
*
Corresponding authors. Tel./fax: +34 976 76 20 77 (J.A.M.); tel.:
33 02 99 28 62 74; fax: +33 02 99 28 69 55 (M.V.); e-mail:
mayoral@posta.unizar.es; michel.vaultier@univ-rennes1.fr
influence of both cation and anion, namely
[Emim][NTf2], [Emim][BF4], and [Oct NMe][NTf ]
+
3
2
0
957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00315-9

1
892
J. M. Fraile et al. / Tetrahedron: Asymmetry 12 (2001) 1891–1894
Table 1, along with those obtained using the same
7,8
N
N
catalysts in dichloromethane. It is known that the
nature of the copper counterion has a decisive influence
on the behaviour of chiral bis(oxazoline)-copper cata-
lysts in cyclopropanation reactions, as shown by the
results in entries 1, 2, 7 and 13. It seems logical that in
an ionic liquid, the most abundant copper species will
bear the counterion of the solvent. This effect is demon-
strated by the result obtained with 5a-CuCl2 in
N
X
NTf2
[
Emim][X]
X = NTf2, BF4
[Oct3NMe][NTf2]
Scheme 1.
Emim=1-ethyl-3-methylimidazolium, Oct NMe-NTf2
methyltri-n-octylammonium). The catalysts were
obtained by treating the chiral bis(oxazoline) ligand
with different copper salts, namely Cu(OTf)2 and
(
=
3
[
Emim][NTf ] (entry 3). Both yield and enantioselectivi-
2
ties are very similar to those obtained with the corre-
sponding triflate in dichloromethane (entry 1) and
clearly better than those observed with the same chlo-
ride complex (entry 2). This seems to indicate that the
CuCl . Most of the catalysts were prepared in
2
dichloromethane, the solvent was evaporated under
reduced pressure and the complex was dissolved in the
ionic liquid. In some other cases the complex was
directly prepared in the ionic liquid and readily used as
catalyst. When the complexes were not completely solu-
ble clear bluish–green solutions (except in the case of
Emim][BF4], as will be commented later) were
obtained, after decanting the supernatant solution from
the insoluble material.
active species is 5a-CuNTf , obtained by reduction of
2
5
a-Cu(NTf ) with ethyl diazoacetate. Thus NTf anion
2
2
2
behaves more similarly to triflate than to chloride. This
complex dissolved in [Emim][NTf ] was successfully
2
recycled twice without loss of activity or selectivities
(
entries 4 and 5). These experiments demonstrate the
[
possibility of easy recycling of these complexes by
means of the use of ionic liquids as solvents. Another
clear advantage is the possibility of using the inexpen-
The results obtained in the cyclopropanation reaction
of styrene 1 with ethyl diazoacetate 2 are gathered in
sive CuCl instead of the expensive and moisture-sensi-
tive Cu(OTf)2.
2
Table 1. The asymmetric cyclopropanation of styrene 1 with ethyl diazoacetate 2 promoted by bis(oxazoline)-copper
a
complexes
R
R
S
S
O
O
Ph
COOEt
COOEt
Ph
5
a: R = Ph
3
R
3S
4S
t
cat.
N
N
5b: R = Bu
+
N CHCOOEt
2
Ph
R
R
1
2
S
R
R
S
Ph
COOEt
Ph
COOEt
4
R
Entry
Ligand
CuX
Solvent
Run
% Yieldb,c
trans/cisb
% E.e. transd
% E.e. cise
1
2
3
4
5
6
7
8
9
5a
5a
5a
Cu(OTf)2
CuCl2
CuCl2
CH Cl
1
1
1
2
3
1
1
1
2
3
1
1
1
33
19
34
32
33
18
61
38
38
37
3
68:32
67:33
67:33
66:34
66:34
67:33
71:29
64:36
64:36
65:35
7:3
60
17
55
53
53
49
91
66
66
64
0
51
13
47
45
44
41
88
64
64
62
0
2
2
CH Cl
2
2
[Emin][NTf2]
5a
5b
5b
CuCl2
Cu(OTf)2
Cu(OTf)2
[Oct NMe][NTf ]
3
2
CH Cl
2
2
[Emim][NTf2]
10
11
12
13
14
15
5b
5b
5b
5b
Cu(OTf)2
Cu(OTf)2
CuCl2
[Emim][BF4]
[Oct NMe][NTf ]
18
24
50
42
63:37
7:3
62:38
6:4
23
2
86
55
22
7
85
56
3
2
CH Cl
2
2
f
CuCl2
[Emim][NTf2]
1
2
a
b
c
d
e
f
Using equimolecular amounts of styrene and ethyl diazoacetate and 1% catalyst.
Determined by GC.
Total conversion of ethyl diazoacetate.
Determined by GC with a Cyclodex B column; 3S was the major product.
Determined by GC with a Cyclodex B column; 4S was the major product.
Catalyst prepared directly in the ionic liquid.

J. M. Fraile et al. / Tetrahedron: Asymmetry 12 (2001) 1891–1894
1893
+
In order to improve the results, the more efficient
bis(oxazoline) 5b was used. The effect of the copper
line)-Cu] -anion ion pair, which reduces both catalytic
activity and selectivity. The use of [Oc NMe][NTf ]
7
3
2
counterion in this case is more dramatic, as shown by
the very different results obtained with triflate and
chloride in dichloromethane (entries 7 and 13). This
sensitivity is also demonstrated by the modest result
obtained with 5b-Cu(OTf) in [Emim][NTf ] (entry 8),
with 5b-Cu(OTf)2 (entry 12) leads to an even more
important reduction in yield and enantioselectivities,
which is in agreement with the more important influ-
ence of the counterion in the reactions promoted by
5b-Cu catalysts. Thus not only the counterion but also
the solvent properties are important in this system.
2
2
leading to reduced yield and enantioselectivities (64–
6% e.e.). The tendency of NTf to reduce the enan-
6
2
tioselectivity is the same as that observed with 5a but
the magnitude is much more important with 5b. How-
ever, this catalyst is fully recovered twice (entries 9 and
3. Conclusions
10) with the same performance.
The results obtained show that ionic liquids are promis-
ing tools for the immobilisation of chiral cationic cata-
lysts without modification of the chiral ligand. The
fine-tuning of both the coordinating ability of the
cation and the polarity of the liquid will allow the
optimisation of the behaviour and applicability of these
systems.
In this case, another strategy was used. The relatively
long time spent for the preparation of the complex
5
b-Cu in dichloromethane and its use as catalyst made
us attempt the synthesis of the complex 5b-CuCl2
directly in [Emim][NTf ]. With this method fairly good
2
results in yield and enantioselectivities (86% e.e.) were
obtained in the first reaction (entry 14). The similarity
of the results with those obtained with the triflate in
dichloromethane (entry 7) demonstrates the existence of
a fast counterion exchange, owing to the very low
enantioselectivity obtained with 5b-CuCl2 (entry 13).
4. Experimental
4.1. Preparation of the ionic liquids
Moreover, the similar behaviour of triflate and NTf is
4.1.1. 1-Ethyl-3-methylimidazolium tetrafluoroborate
2
again demonstrated. However, this catalyst is not fully
recoverable, showing a partial loss of enantioselectivity
[Emim][BF ]. This ionic liquid was prepared according
4
13
to the method of Suarez et al. [Emim][Br] (4.40 g, 23.0
mmol) and sodium tetrafluoroborate (2.83 g, 23.0
mmol) were mixed in acetone (25 mL). After stirring
the mixture for 24 h, the reaction mixture was filtered
through a pad of Celite and acetone evaporated in
vacuo. Extraction of the residue with CH Cl (50 mL),
(
entry 15) and leading to results similar to those
obtained using the catalyst prepared by the other
approach. It is difficult to offer an explanation for these
results, which suggest the existence of complex equi-
libria between different catalytic species. This point
deserves further investigation.
2
2
filtration, evaporation of the solvent under reduced
pressure and drying under high vacuum (10 torr) at
−
2
In order to test the influence of the anion of the ionic
50°C for 24 h afforded [Emim][BF ] as a clear oil (16.9
g, 81%).
4
liquid, [Emim][BF ] was used and its behaviour
4
deserves a particular comment. When complexes 5a-
CuCl and 5b-Cu(OTf) were added to [Emim][BF ] the
4.1.2. 1-Ethyl-3-methylimidazolium bis(trifluoromethyl-
2
2
4
solutions took a brownish deep red colour with some
suspended solid. These suspensions were able to decom-
pose ethyl diazoacetate under the reaction conditions
but they were almost inactive for cyclopropanation.
Although we cannot yet offer an explanation for this
behaviour, the colour change might be caused by the
formation of Cu(0) in a redox reaction. The fact that
the formation of the red colour occurs prior to the
addition of the diazoacetate seems to rule out the
participation of a dismutation from Cu(I).
sulfonyl)amide [Emim][NTf ]. This ionic liquid has been
2
1
4
obtained according to the procedure of Bonh oˆ te et al.
[Emim][Br] (13.16 g, 68.9 mmol) and LiNTf (20.5 g,
2
68.9 mmol) were mixed in hot water (50 mL at 70°C).
Extraction with CH Cl2 (2×50 mL), concentration
2
under reduce pressure and drying under high vacuum
−
2
(10 torr) at 100°C for 24 h afforded [Emim][NTf2]
(23.9 g, 89%).
4.1.3. Methyltrioctylammonium bis(trifluoromethyl)-
sulfonylamide [Oc NMe][NTf ]. The same procedure as
3
2
®
We also investigated the influence of the cation present
in the ionic solvent by using the same complex 5a-
CuCl in [Oc NMe][NTf ]. In principle the active spe-
for [Emim][BF ] was used: Aliquat 336 (4.04 g, 10
4
mmol) and LiNTf (1.54 g, 10 mmol) were dissolved in
2
acetone (50 mL) at rt. After stirring the mixture for 24
h, the reaction mixture was filtered through a plug of
Celite. The solvent was removed under reduce pressure
2
3
2
cies should be the same as in [Emim][NTf ], but the
2
results (entry 6) are different, with lower yield and
slightly lower enantioselectivities. The change of cation
noticeably influences the polarity of the ionic liquid,
which decreases when the polar character of the cation
−
2
and the ionic liquid dried under high vacuum (10
torr) at 70°C for 24 h giving a clear oil (4.37 g, 85%).
1
H NMR (acetone-d , 300 MHz, l ppm/TMS): 3.49 (m,
6
9
e
is decreased. In this regard, the use of methyltri-n-
octylammonium instead of 1-ethyl-3-methylimida-
zolium must reduce the polarity of the reaction
6H), 3.21 (s, 3H), 1.90 (brs, 6H), 1.38 (m, 36H), 0.88 (t,
13
J=6.6 Hz, 9H). C NMR (acetone, 50 MHz, l ppm/
TMS): 123.51, 118.52, 92.48, 62.52, 32.59, 32.41, 26.48,
23.30, 23.23, 22.78, 14.32. Positive-ion LSIMS (m/z):
1014.8, 1042.9, 1070.8, 1098.9, 1126.9, 1154.8.
8
medium. It has been described that the use of less
polar solvents increases the strength of the [bis(oxazo-

1
894
J. M. Fraile et al. / Tetrahedron: Asymmetry 12 (2001) 1891–1894
4.2. Preparation of the catalysts
Acknowledgements
The bis(oxazoline)-copper complexes were prepared by
dissolving the copper salt (CuCl ·2H O or Cu(OTf) :
This work was made possible by the generous finan-
cial support of the CICYT (project MAT99-1176). C.
I. H. thanks the MCYT for a grant.
2
2
2
0.6 mmol) and the ligand (5a or 5b: 0.6 mmol) in
anhydrous dichloromethane (4 mL). After 1 h, the
insoluble materials were removed by microfiltration,
the solvent was evaporated under reduced pressure
and the bluish–green solid was dried under vacuum.
A sample of each catalyst (100 mg) was dissolved in
the ionic liquid (2 mL). When the complex was not
completely soluble, the clear solution was decanted
from the solid and used in the cyclopropanation reac-
tions.
References
1. (a) Comprehensive Asymmetric Catalysis; Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H., Eds.; Springer: Berlin, 1999;
(b) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994.
2
. For recent reviews, see: (a) Gosh, A. K.; Mathivanan, P.;
Capiello, J. Tetrahedron: Asymmetry 1998, 9, 1–45; (b)
Jørgensen, K. A.; Johannsen, M.; Yao, S. L.; Audrain,
H.; Thorhauge, J. Acc. Chem. Res. 1999, 32, 605–613; (c)
Pfaltz, A. Synlett 1999, 835–842; (d) Pfaltz, A. J. Hetero-
cyclic Chem. 1999, 36, 1437–1451; (e) Johnson, J. S.;
Evans, D. A. Acc. Chem. Res. 2000, 32, 325–335; (f)
Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M.
Chem. Rev. 2000, 100, 2159–2231.
In some cases the complex was prepared by dissolving
the copper salt (0.038 mmol) and the ligand (0.038
mmol) in the ionic liquid (0.5 mL). The mixture was
stirred at rt until a clear pale green solution was
obtained. In these cases the catalyst was immediately
used in a cyclopropanation reaction.
4.3. Cyclopropanation reaction
3. Burguete, M. I.; Fraile, J. M.; Garc ´ı a, J. I.; Garc ´ı a-Ver-
dugo, E.; Luis, S. V.; Mayoral, J. A. Org. Lett. 2000, 2,
3905–3908.
4. Fern a´ ndez, M. J.; Fraile, J. M.; Garc ´ı a, J. I.; Mayoral, J.
A.; Burguete, M. I.; Garc ´ı a-Verdugo, E.; Luis, S. V. Top.
Catal. 2000, 13, 303–309.
5. (a) Fraile, J. M.; Garc ´ı a, J. I.; Mayoral, J. A.; Tarnai, T.
Tetrahedron: Asymmetry 1997, 8, 2089–2092; (b) Fraile, J.
M.; Garc ´ı a, J. I.; Mayoral, J. A.; Tarnai, T. Tetrahedron:
Asymmetry 1998, 9, 3997–4008; (c) Fraile, J. M.; Garc ´ı a,
J. I.; Mayoral, J. A.; Tarnai, T.; Harmer, M. A. J. Catal.
1999, 186, 214–221.
6. Glos, M.; Reiser, O. Org. Lett. 2000, 2, 2045–2048.
7. Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M.
M. J. Am. Chem. Soc. 1991, 113, 726–728.
To the solution (0.5 mL) of the corresponding sup-
ported catalyst (approx. 0.038 mmol) under an Ar
atmosphere, styrene (395 mg, 3.8 mmol) was added.
Ethyl diazoacetate (433 mg, 3.8 mmol) was slowly
added (2 h) using a syringe pump. The reaction was
stirred at rt for
5 h ([Emim][NTf2]) or 20 h
(
[Oct NMe][NTf ]). After this time the products were
3
2
extracted with hexane (3×4 mL) and n-decane (100
mg) was added to the hexane solution as an internal
standard for the GC analysis. The remaining solution
of the catalyst in the ionic liquid was reused following
the same method.
The results of the reactions were determined by gas
chromatography. FID from Hewlett–Packard 5890II;
cross-linked methyl silicone column: 25 m×0.2 mm×
8. Fraile, J. M.; Garc ´ı a, J. I.; Mayoral, J. A.; Tarnai, T. J.
Mol. Catal. A 1999, 144, 85–89.
9. For recent reviews, see: (a) Seddon, K. R. J. Chem. Tech.
Biotechnol. 1997, 68, 351–356; (b) Welton, T. Chem. Rev.
1999, 99, 2071–2083; (c) Holbrey, J.; Seddon, K. R. Clean
Prod. Proc. 1999, 1, 223–226; (d) Earle, M. J.; Seddon, K.
R. Pure Appl. Chem. 2000, 72, 1391–1398; (e) Wasser-
scheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39,
3772–3789.
10. (a) Chauvin, Y.; Mußmann, L.; Olivier, H. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 2698–2700; (b) Monteiro, A. L.;
Zinn, F. K.; de Souza, R. F.; Dupont, J. Tetrahedron:
Asymmetry 1997, 8, 177–179.
11. Song, C. E.; Roh, E. J. Chem. Commun. 2000, 837–838.
12. Song, C. E.; Oh, C. R.; Roh, E. J.; Choo, D. J. Chem.
Commun. 2000, 1743–1744.
13. Suarez, P. A. Z.; Dullius, J. E. L.; Einloft, S.; de Souza,
R. F.; Dupont, J. Polyhedron 1996, 15, 1217–1219.
14. Bonh oˆ te, P.; Dias, A.-P.; Papageorgiou, N.; Kalyanasun-
daram, K.; Gr a¨ tzel, M. Inorg. Chem. 1996, 35, 1168–1178.
0
.33 mm; helium as carrier gas, 20 psi; injector tem-
perature: 230°C; detector temperature: 250°C; oven
−
1
temperature program: 70°C (3 min), 15°C min to
00°C (5 min); retention times: ethyl diazoacetate 4.28
2
min, styrene 5.03 min, n-decane 6.93 min, cis-cyclo-
propanes 4 11.84 min, trans-cyclopropanes 3 12.35
min.
The asymmetric inductions of the reactions were also
determined by gas chromatography. FID from
Hewlett–Packard 5890II, Cyclodex B column: 30 m×
0.25 mm×0.25 mm; helium as carrier gas, 20 psi; injec-
tor temperature: 230°C; detector temperature: 250°C;
oven temperature program: 125°C isotherm; retention
times: (1S,2R)-cyclopropane 4S 28.9 min, (1R,2S)-
cyclopropane 4R 29.8 min, (1R,2R)-cyclopropane 3R
34.3 min, (1S,2S)-cyclopropane 3S 34.9 min.