Asymmetric cyclopropanation in ionic liquids: Effect of anion and impurities

Article abstract of DOI:10.1016/j.tetasy.2003.10.011

Cyclopropanation of styrene with ethyl diazoacetate catalysed by copper triflate and a bis(oxazoline) occurs with good yield and enantioselectivity in a variety of ionic liquids. The catalyst solution can be recycled four times with little drop in yield o

Full text of DOI:10.1016/j.tetasy.2003.10.011

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 77–80
Asymmetric cyclopropanation in ionic liquids: effect of anion and
impurities
David L. Davies,a,* Sukhvinder K. Kandolaa and Raj K. Patelb
aDepartment of Chemistry, University of Leicester, Leicester LE1 7RH, UK
bSynthetic Chemistry, Chemical Development, GlaxoSmithKline, Powder Mills, Tonbridge, Kent TN11 9AN, UK
Received 21 August 2003; accepted 20 October 2003
Abstract—Cyclopropanation of styrene with ethyl diazoacetate catalysed by copper triflate and a bis(oxazoline) occurs with good
yield and enantioselectivity in a variety of ionic liquids. The catalyst solution can be recycled four times with little drop in yield or
selectivity. The purity of the ionic liquid has a marked effect on the yield and enantioselectivity.
ꢀ 2003Elsevier Ltd. All rights reserved.
Ionic liquids have negligible vapour pressure and hence
have attracted much study recently as replacements for
organic solvents for synthetic chemistry as part of a
strategy to reduce emissions of VOCꢀs.1 Ionic liquids
may also give benefits in terms of increased selectivity
and in separation and recycling of metal-containing
catalysts when the system is biphasic.2 The catalyst re-
mains in the ionic liquid phase and in some cases can be
reused several times with little reduction in activity. This
approach has also been applied in asymmetric catalysis
including epoxidation3 and dihydroxylation4 of alkenes,
ring opening of epoxides,5 allylic substitution6 and
particularly in hydrogenation of alkenes.7
enantioselectivity.10 Amongst these, the cyclopropana-
tion of styrene was studied by Evans et al. who
demonstrated that the catalytic activity and enantio-
selectivity was dependent on the nature of the anion
associated with the copper.11 Similar effects on activity
and selectivity of changing the anion and the solvent
have been observed by other workers.12 The use of
weakly coordinating anions was shown to be crucial in
Diels–Alder catalysis with copper bis(oxazoline)
complexes.13
Various strategies have been investigated for immobili-
sation and recycling of the copper oxazoline catalysts,14
including covalent attachment to an organic poly-
mer,15;16 ion-pairing with an anionic support15;17 and
covalent attachment to silica.18 During the course of our
work the use of imidazolium based ionic liquids for
immobilisation of bis(oxazoline) copper catalysts and
their use in cyclopropanation of styrene has been re-
ported and it was found that the nature of the cation
and anion of the ionic liquid effected the performance of
the catalysts.19 However, our results differ from those
published particularly in the case of ionic liquids con-
taining the BF4 anion. We report here the copper
bis(oxazoline) catalysed asymmetric cyclopropanation
of styrene in four different ionic liquids, attempts to
reuse the catalyst, and a reinterpretation of some of the
results described previously.
A problem that can arise in the use of ionic liquids for
immobilisation of transition metal based catalysts is that
at low catalyst concentrations impurities in the ionic
liquids, particularly halide ions, can have a significant
effect by coordinating to the metal and hence block-
ing an active site. For example, the rate of rhodium
catalysed biphasic hydrogenation of pent-1-ene in
[BMIM][BF4] (BMIM ¼ 1-butyl-3-methylimidazolium)
was significantly lower than in [BMIM][PF6] due to the
presence of chloride impurity in the [BMIM][BF4] ionic
liquid.8 Chloride impurities in [BMIM][BF4] also had a
marked effect on the metal catalysed Michael addition of
acetylacetone to methylvinyl ketone.9
Bis(oxazolines) in conjunction with various copper salts
catalyse a wide range of reactions with good to excellent
Evans et al. reported that cyclopropanation of styrene
with ethyl diazoacetate in chloroform catalysed by the
complex of bis(oxazoline) 1 with copper(I) triflate
(Scheme 1) gave the trans and cis cyclopropanes in a
* Corresponding author. E-mail: dld3@le.ac.uk
0957-4166/$ - see front matter ꢀ 2003Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.10.011

78
D. L. Davies et al. / Tetrahedron: Asymmetry 15 (2004) 77–80
copper complexes (chloride or triflate) were added to
Cu(OTf)/(1)
Ph
Ph
CO2Et
CO2Et
Ph
Ph
CO2Et
CO2Et
[EMIM][BF4] the solution became a deep red colour and
some solid precipitated. In our hands addition of
[(Cu(s,s)tBu-box)OTf] to [BMIM][BF4] gives a clear blue
homogeneous solution as with all the other ionic liquids.
Halide anions are expected to coordinate more strongly
to copper than triflate and hence reduce or even stop
catalytic activity. Similar adverse effects of halide im-
purity on catalysis in ionic liquids have been noted
previously.8;9 To investigate this possibility we examined
the effect of added [BMIM]X (X ¼ Cl, Br) on the ca-
talysis. Addition of the catalyst to a solution of
[BMIM][BF4] with 5% [BMIM][Cl] added gave a ho-
mogeneous yellow-green solution, which was inactive
as a cyclopropanation catalyst though it did lead to
decomposition of the ethyl diazoacetate. If 5%
[BMIM][Br] was used a deep red/brown solution was
formed when the catalyst was added, this was also cat-
alytically inactive for cyclopropanation. Thus, we sug-
gest that the poor results observed previously for copper
catalysed cyclopropanation in [EMIM][BF4] are due to
the presence of [EMIM][Br] impurity in the ionic liquid.
The [EMIM][BF4] used was made from [EMIM][Br] and
NaBF4 and filtered through Celite to remove the NaBr
formed.19 Seddon et al. have shown, at least for chloride
salts that this procedure is inefficient at removing all the
unreacted dialkylimidazolium halide.21 We have ex-
tracted [BMIM][BF4] with chilled water (5 ꢁC), which
gives much lower levels of halide impurity.
2a
+
2b
+
+
O
O
N2CHCO2Et
N
N
3a
3b
But
tBu
1
Scheme 1.
73:27 ratio and 99% and 97% ee, respectively.11 Under
our conditions the trans:cis selectivity remains the same,
though the eeꢀs, 89% and 96%, respectively, are slightly
lower. The only variation to the literature conditions has
been to add the ethyl diazoacetate to the styrene and
catalyst at 10 ꢁC instead of 0 ꢁC before warming to 25 ꢁC
and to use a lower excess of styrene (1.5 equiv with re-
spect to diazoacetate rather than 5 equiv). These changes
were introduced to allow a direct comparison with the
reactions carried out in ionic liquids. Styrene is not
appreciably soluble in the ionic liquids, hence these re-
actions are biphasic and at 0 ꢁC the viscosity of the ionic
liquids makes magnetic stirring rather inefficient, how-
ever, much better mixing occurs at 10 ꢁC. The catalyst
solutions were prepared in chloroform before dissolu-
tion in the ionic liquid and then removal of the chlo-
roform under vacuum. After the reaction the products
were extracted from the ionic liquid with ether and fil-
tered through silica. The yield and stereoselectivity were
analysed by GC and the enantiomeric excess was de-
termined by GC–MS after conversion to the (R)-1-
phenylethylamides.11
Another important issue with the use of ionic liquids is
the possibility of recycling the catalyst solution. It was
noted that using the less polar [BMIM][OTf] and
[BMIM][NTf2] liquids some leaching of the catalyst
occurred in extraction of the products as judged by the
colour transferred to the ether layer, there was also a
faint blue spot on the baseline of the TLC plates used in
purification. [BMIM][BF4] and [BMIM][PF6] showed
minimal leaching and since the yields were better in the
BF4 liquid we chose that for experiments on recycling
and reusing the catalyst.
The results of the cyclopropanation are shown in Table
1. As can be seen, the yields are generally similar in all
the ionic liquids and in chloroform. The stereoselectivity
and enantioselectivity are similar in all the ionic liq-
uids and in chloroform, though the stereoselectivity is
somewhat less in the NTf2 liquid. A reduction in the
stereoselectivity in [EMIM][NTf2] (EMIM ¼ 1-ethyl-3-
methylimidazolium) was noted previously.19 How-
ever, the yields and enantioselectivities are significantly
higher than those (3–50% yield, 0–85% ee) observed
previously19 for the same reaction and catalyst20 in
[EMIM][BF4], [EMIM][NTf2] and [Oct3NMe][NTf2].
Notably in the previous study use of [EMIM][BF4] led
to very low yields and no enantioselectivity (see below).
In that case the authors noted that when bis(oxazoline)
To optimise the yield we wished to minimise the levels of
diethyl maleate and fumarate formed by carbene di-
merisation. This is often done by increasing the con-
centration of the styrene. However due to the limited
solubility of styrene in the ionic liquids we chose to
Table 1. Cyclopropanation of styrene with ethyl diazoacetate catalysed by Cu(OTf)/1
Solvent
Yield (%)a
trans:cis
Selectivity (%)
Enantioselectivity (%)b
89:96
CHCl3
59
73:27
97:95
75:25
63:37
75:25
––
BMIM[OTf]
BMIM[PF6]
BMIM[NTf2]
BMIM[BF4]
BMIM[BF4]/[Cl]c
BMIM[BF4]/[Br]c
5376:24
47
45
95:91
94:93
95:89
––
61
<1
<1
––
––
a Detemined by GC using decane as an internal standard.
b Determined by GC–MS after conversion to the 1-phenylethylamide; 3a was the major trans enantiomer and 2a the major cis enantiomer based on
retention times of the 1-phenylethylamides.
c Contains 5% [BMIM][X] (X ¼ Cl, Br).

D. L. Davies et al. / Tetrahedron: Asymmetry 15 (2004) 77–80
79
reduce the rate of addition of the ethyl diazoacetate (5 h)
and to keep the reaction mixture at 10 ꢁC throughout
this period and lower the concentration of the catalyst
by using twice the amount of ionic liquid. Using these
conditions gave increased yields of products. The results
of performing the reaction eight times in the same batch
of ionic liquid are displayed in Table 2. As can be seen
for the first four runs the yield and enantioselectivity are
comparable. After the fourth run, the yield drops with a
slight reduction in selectivity though the enantioselec-
tivity generally remains high.
propylidenebis-[(4S)-4-tert-butyl-2-oxazoline] (0.0497 g
0.168 mmol) in chloroform (1.4 mL) for 3h after which
time the solution was filtered through glass wool. A
measured portion (200 lL) of this solution was added to
the ionic liquid (2 mL) and the bluish-green homoge-
neous solution was stirred for 30 min after which time
the chloroform was removed under vacuum. Styrene
(344 lL, 3mmol) was added and the resultant biphasic
system was stirred for 10 min before addition of the
ethyl diazoacetate (210 lL, 2 mmol) over 2 h using a
syringe pump. The reaction mixtures were allowed to
equilibrate to 25 ꢁC over 4 h and stirred for a further
10 h. The product was extracted using diethyl ether
(6 · 3mL), the combined extracts were filtered over silica
and concentrated in vacuo to a pale yellow oil. The
yields and trans:cis selectivity were determined at this
stage by GC using decane as an internal standard. The
esters were converted to the R-1-phenylethylamides by
the literature method,11 the amide fraction was sepa-
rated by preparative TLC and this fraction was used to
determine the enantioselectivity.
Table 2. Repeated cyclopropanation reactions of styrene with ethyl
diazoacetate catalysed by Cu(OTf)/(1) in [BMIM][BF4]a
Run
Yield (%)
trans:cis
Selectivity (%)
Enantioselectivity (%)
1
2
3
4
5
6
7
8
88
88
90
85
69
71
55
51
75:25
75:25
73:27
72:28
65:35
66:34
69:31
69:31
97:94
95:93
93:91
98:98
76:77
81:78
76:72
77:78
Acknowledgements
a Yield, stereoselectivity and enantioselectivity measured as for Table 1.
We thank the EPSRC and GlaxoSmithKline for a
CASE award (S.K.K.) and Professor K. R. Seddon for
providing advice and training to S.K.K. in the prepa-
ration and purification of ionic liquids.
In conclusion we have shown that copper catalysed cy-
clopropanation can be carried out in ionic liquids with
high yield and enantioselectivity. The catalyst solution
can be recycled at least four times before there is a sig-
nificant drop in yield. The purity of the ionic liquids has
a marked effect on the catalysis. Particular care should
be taken in the purification of hydrophilic ionic liquids
prepared by metathetical anion exchange to ensure that
all the dialkyl imidazolium halide is removed.
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