Hydrolytic kinetic resolution of terminal epoxides catalyzed by fluorous chiral Co(salen) complexes

Article abstract of DOI:10.1016/S0040-4020(02)00216-8

Cobalt complexes of fluorous chiral salen ligands have been synthesized and tested as catalysts in the hydrolytic kinetic resolution of terminal epoxides. Whereas the activity of heavily fluorinated complexes was found to be rather low, a 'light fluorous' complex was shown to be an efficient and highly selective catalyst for this asymmetric ring-opening reaction. Several strategies for the isolation of reaction products and the recovery of the fluorous catalyst are also discussed.

Full text of DOI:10.1016/S0040-4020(02)00216-8

TETRAHEDRON
Pergamon
Tetrahedron 58 52002) 3943±3949
Hydrolytic kinetic resolution of terminal epoxides catalyzed
by ¯uorous chiral Coꢀsalen) complexes
Marco Cavazzini, Silvio Quici and Gianluca Pozzip
Centro CNR Sintesi e Stereochimica di Speciali Sistemi Organici, via Golgi 19, 20133 Milano, Italy
Received 14 November 2001; revised 10 January 2002; accepted 16 January 2002
AbstractÐCobalt complexes of ¯uorous chiral salen ligands have been synthesized and tested as catalysts in the hydrolytic kinetic
resolution of terminal epoxides. Whereas the activity of heavily ¯uorinated complexes was found to be rather low, a `light ¯uorous' complex
was shown to be an ef®cient and highly selective catalyst for this asymmetric ring-opening reaction. Several strategies for the isolation of
reaction products and the recovery of the ¯uorous catalyst are also discussed. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
immobilization strategies for Mn5salen) complexes, the
most ef®cient chiral catalyst for this reaction, presented
several drawbacks.5 It was found that chiral Mn5salen)
complexes featuring per¯uoroalkyl substituents 5RF) in the
3,30- and 5,50-positions in the ligand could be utilized for
enantioselective epoxidation reactions carried out under FB
conditions. The ¯uorous layer in which the catalyst was
dissolved could be readily recovered and reused, but good
enantioselectivities were obtained for indene only.6 The
scope of the FB epoxidation has been recently widened
thanks to the synthesis of second-generation Mn5salen)
complexes that were designed taking into account the pos-
sible role of steric and electronic effects arising from the
presence of RF substituents in the proximity of the coordi-
nation sites of the ligand.7 These catalysts can be used in the
FB asymmetric epoxidation of several substrates, affording
results that compare favorably to those obtained with other
immobilized catalytic systems.8 The ¯uorous phase could be
used upto four times before signi®cant decline in yield and
enantioselectivity was observed. Nevertheless, effective
recycling of Mn5salen) complexes through a very high
number of reaction runs is limited by the tendency of
these compounds to undergo oxidative decomposition
under the reaction conditions. Application of a FB method-
ology can avoid this inconvenience only to some extent.
Asymmetric homogeneous catalysis is a powerful tool for
the ef®cient synthesis of enantiomerically enriched chiral
compounds.1 Application of this methodology on a wide
scale is often prevented by issues relating to puri®cation
of the reaction products and recyclability of the precious
chiral catalysts. The immobilization of chiral catalysts
onto insoluble supports 5both organic and inorganic) is an
attractive, but still challenging, strategy for overcoming
these limitations.2 Indeed, immobilized chiral catalysts
often show lower enantioselectivities and/or ef®ciencies
than their homogeneous parallels. In the case of homo-
geneous catalysts covalently attached to the support, the
practical advantages expected from heterogenization should
also compensate for the additional synthetic efforts required
to modify the structure of the chiral ligand.
Enantioselective reactions were recognized as a potential
target at a very early stage of development of ¯uorous
chemistry.3 Four years later, we succeeded in demonstrating
that the ¯uorous biphase 5FB) approach can be applied to the
immobilization of chiral catalysts.4 The asymmetric epoxi-
dation of alkenes was chosen as a model reaction in view of
its considerable importance and also because the reported
Scheme 1.
Keywords: cobalt and compounds; diols; epoxides; ¯uorine and compounds.
Corresponding author. Tel.: 139-2-5835-4163; fax: 139-2-5835-4159; e-mail: gianluca.pozzi@unimi.it
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020502)00216-8

3944
M. Cavazzini et al. / Tetrahedron 58 (2002) 3943±3949
terminal epoxides and 1,2-diols.12 The cobalt complex
5R,R)-1 5Fig. 1) and closely related polystyrene- or silica-
bound chiral Co5salen) complexes proved to be highly
ef®cient and enantioselective catalysts for this reaction.13,14
Two distinct sets of ¯uorous chiral salen ligands were
available from our previous studies.6±8 One is characterized
by a relatively low ¯uorine content 5F,50%) and by the
presence of bulky t-butyl substituents in the 3,30-positions,
as in the reference catalyst 5R,R)-1. Ligands of this kind
can be described as `light' or `minimally' ¯uorous com-
pounds.15,16 The second set is richer in ¯uorine 5F.60%)
thanks to the presence of more RF substituents. This allows
the ligands to be selectively soluble in per¯uorocarbons, as
required by FB applications, but the presence of RF sub-
stituents in the 3,30-positions can also have detrimental
effects on the enantioselectivities of the catalysts obtained
from these ligands, as exempli®ed by the behavior of
¯uorous Mn5salen) complexes in epoxidation reactions. In
the case of HKR, however, the enhanced Lewis acidity of
the metal site induced by the strongly electron-withdrawing
RF substituents might have a positive effect on the catalyst
activity.13 Therefore, cobalt complexes of ligands belonging
to both groups were prepared and tested 5Fig. 1).
Figure 1.
Since nitrogen-containing chiral ligands are increasingly
used in asymmetric catalysis,9 we decided to explore the
use of the readily accessible ¯uorous salen ligands in
reactions other than the epoxidation of alkenes. In the
frame of this program, it was shown that the hydrogen
transfer reduction of ketones in a mixture per¯uoroalkane/
isopropanol proceeds in the presence of [Ir5COD)Cl]2 asso-
Co5II) complexes 5R,R)-2±5R,R)-4 were readily obtained by
adding a solution of Co5OAc)2´4H2O in EtOH to the corre-
sponding ¯uorous ligand dissolved in hot toluene and
stirring the mixture for 3 h.17 The complexes were isolated
after crystallization from EtOH in 90±98% yield and were
characterized by UV±vis, FT-IR and elemental analysis.
As expected, the `light-¯uorous' complexes 5R,R)-3 and
5R,R)-4 5Fˆ45.3 and 48.6%, respectively) were found to
be soluble in common organic solvents such as CH2Cl2
and toluene and insoluble in per¯uorocarbons at room
temperature. The solubility behavior of 5R,R)-2 5Fˆ
63.0%) is less straightforward, the complex being insoluble
in common organic solvents, but also very slightly soluble
in per¯uorocarbons at room temperature 5e.g. 6.8£1025 M
in per¯uorooctane as evaluated by UV±vis spectroscopy).8
ciated with chiral ¯uorous salen ligands, affording optically
active carbinols with ees upto 60%.
10,11
Herein we report
the promising application of ¯uorous chiral Co5salen)
complexes to the hydrolytic kinetic resolution 5HKR) of
terminal epoxides 5Scheme 1).12 Due to the mild conditions
under which the HKR is performed, decomposition of the
catalyst is a minor problem with respect to epoxidation
reactions. The separation of the products from the catalyst
can be conducted by both ¯uorous and standard techniques.
The three complexes were examined for their ef®cacy in the
HKR of racemic 1-hexene oxide 5Table 1). In a ®rst series of
experiments 5entries 2±4), the ¯uorous Co5II) complexes
were oxidized by air prior to the reaction in the presence
of acetic acid, an effective promoter for the aerobic
2. Results and discussion
The HKR of terminal epoxides in the presence of chiral
Co5salen) complexes, discovered by Jacobsen in 1997,
provides a convenient access to both highly enantioenriched
Table 1. Hydrolytic kinetic resolution of 1-hexene oxide catalyzed by ¯uorous chiral Co5salen) complexes previously oxidized to the Co5III) state in the
presence of a promoter
Entry
Catalyst
Promoter
Time 5h)
Conversion 5%)a
ee diol 5%)b
ee epoxide 5%)c
1d
2
3
4
5
6
7
5R,R)-1
5R,R)-2
5R,R)-3
5R,R)-4
5R,R)-2
5R,R)-3
5R,R)-4
CH3COOH
CH3COOH
CH3COOH
CH3COOH
C8F17COOH
C8F17COOH
C8F17COOH
5
50e
10
0
43
29
10
46
98
81.4
±
96.9
84.8
62.4
$99
98
10.3
±
72.4
32.6
7.0
24
32
18
24
12
6
91.2
Reaction conditions: racemic epoxideˆ25 mmol 53 ml); H2Oˆ17.5 mmol 50.32 ml); catalystˆ0.05 mmol. Molar ratio epoxide/catalystˆ500.
a
Determined by GC analysis of the reaction mixture. See Section 4.
Determined by capillary GC analysis of the isolated product on a HP ChiralÐ20% permethylated b-cyclodextrin column.
b
c
Optical purity of the isolated epoxide.
See Ref. 13: H2Oˆ0.55 equiv. Molar ratio epoxide/catalystˆ240.
d
e
Based on the ee of the recovered epoxide and diol. See Ref. 14.

M. Cavazzini et al. / Tetrahedron 58 (2002) 3943±3949
3945
Table 2. Hydrolytic kinetic resolution of terminal epoxides catalyzed by 5R,R)-4 previously oxidized to the Co5III) state in the presence of C8F17COOH
Entry
R
Time 5h)
Diol
Isolated yield 5%)a
Epoxide
Isolated yield 5%)a
ee 5%)b
ee 5%)c
1
2
3
4
5
CH3
15
6
15
15
15
49
41
47
40
46
75.2
$99
$99
98.3
79.4
±
±
CH35CH2)3
CH35CH2)5
ClCH2
55
51
56
51
91.2
$99
90.6
76.3
d
e
C6H5
Reaction conditions: racemic epoxideˆ25 mmol; H2Oˆ17.5 mmol; catalystˆ0.05 mmol. Molar ratio epoxide/catalystˆ500.
a
Products isolated by fractional distillation. See Section 4.
Determined by capillary GC analysis of the isolated product on a HP ChiralÐ20% permethylated b-cyclodextrin column.
Optical purity of the isolated epoxide.
Racemic 1,2-hexanediol 520 mol%) was added as a co-solvent. See Ref. 12.
CH2Cl2 53 ml) was added as a co-solvent.
b
c
d
e
oxidation of 5R,R)-1 and related compounds to the corre-
sponding catalytically active Co5III) species.14 Whereas the
literature procedure was suitable for the oxidation of 5R,R)-3
and 5R,R)-4, the Co5III) complex corresponding to 5R,R)-2
could be obtained only after prolonged treatment of a
suspension of the heavily ¯uorinated compound in a boiling
mixture toluene/acetic acid 9/1, v/v. Once formed, the
catalysts were isolated by removing the solvent under
reduced pressure. Rather surprisingly, the three ¯uorous
Co5III) complexes were soluble in neat 1-hexene oxide at
1.66£1022 M, a concentration yielding a molar ratio
epoxide/catalystˆ500 as used by Jacobsen in the HKR of
propylene oxide.12 Therefore, reactions could be carried out
at room temperature without addition of any co-solvent. A
sub-stoichiometric amount of water 50.7 equiv. with respect
to the epoxide) was added to the homogeneous solutions
that were gently stirred under aerobic conditions. The
progressive consumption of the epoxide was followed
by GC analysis, the only detectable products being
5S)-1,2-hexanediol and lower amounts of its R enantiomer.
5R,R)-2 was thus oxidized by air in the presence of
2 equiv. of per¯uorononanoic acid, affording the corre-
sponding Co5III)5salen)5C8F17COO) complex. Unfortu-
nately, also this species was found to be preferentially
soluble in neat 1-hexene oxide, the partition coef®cient
between the epoxide and n-per¯uorooctane determined by
UV±vis spectroscopy at 258C being .100, and so a possible
application of the FB approach was ruled out. The identity
of the counterion for the catalytically active Co5III)
complex had been proved to be important in the case of
the kinetic resolution of terminal epoxides with phenols.18
In that context, the presence of a per¯uorinated anion
55CF3)3CO2) enhances the activity of the Co5III) complex
generated from 5R,R)-1. A similar effect was observed in the
HKR of racemic 1-hexene oxide: the presence of the ¯uori-
nated counterion C8F17COO2 plays a bene®cial role, with
the ¯uorous Co5III) complexes consistently displaying
increased activities 5entries 5,6,7 vs 2,3,4). Again, the best
results were obtained with the Co5III) complex generated
from 5R,R)-4 which gave the enantiomerically enriched
R-epoxide and S-diol with eeˆ91.2 and ^99%, respec-
tively, at 46% conversion in 6 h.
The Co5III) complex generated from 5R,R)-4 5entry 4)
proved to be an ef®cient catalyst for the HKR of the
model compound, affording the enantiomerically enriched
epoxide and diol with eeˆ72.4 and 96.9%, respectively, and
conversionˆ43%. For sake of comparison, literature data
for the HKR of 1-hexene oxide catalyzed by the Co5III)
complex generated from 5R,R)-1 are reported 5entry 1).
The promising results obtained with 5R,R)-4 stand in deep
contrast with those obtained with 5R,R)-3 5entry 3), also
bearing t-butyl and RF substituents in the 3,30-positions
and 5,50-positions of the ligand, respectively. In that case,
the Co5III) species did not catalyze at all the epoxide ring-
opening reaction, even on an extended time scale. It appears
that the nature of the 1,2-diamine moiety of the ligand is
utterly important in determining the catalytic activity, as
also demonstrated by the results obtained with complex
5R,R)-2, derived from 5R,R)-1,2-diaminocyclohexane as
5R,R)-4 5entry 2). Although, contrary to our expectations,
the introduction of RF substituents in the 3,30-positions is
not bene®cial for the catalyst activity, a certain degree of
enantioselection was achieved even in the absence of the
sterical hindrance provided by the t-butyl groups.
Other terminal epoxides were subjected to HKR under the
optimized solvent-free conditions described above, and
results are summarized in Table 2. Reaction products were
isolated in good yields by fractional distillation, and the
con®gurations of the enantiomerically enriched epoxides
and diols 5established by comparison with authentic
samples) always corresponded to those reported in
Scheme 1.
The catalytic system based on the ¯uorous complex 5R,R)-4
usually gave clean reactions with no detectable traces of
by-products, affording highly selective kinetic resolutions
over reasonable reaction times even at a low catalyst
loading. In the case of epichlorohydrin, the diol could be
obtained in good enantiomeric purity, but the reaction was
sluggish and a low conversion of the epoxide 515.3%) was
observed. The low catalytic activity of the system was
ascribed to the low solubility of the ¯uorous catalyst in
the reaction mixture, since partial precipitation of the
¯uorous complex as a brown slurry was observed just
after the diol started to form. Addition of CH2Cl2 as a
solvent allowed to overcome this problem and the ring-
opening reaction proceeded in 15 h with conversionˆ
44% 5entry 4). It must be noted that epichlorohydrin is
We had found previously that the solubility of charged
Mn5III) ¯uorous complexes in per¯uorocarbons can be
strongly enhanced by choice of a ¯uorinated counterion.7

3946
M. Cavazzini et al. / Tetrahedron 58 (2002) 3943±3949
Table 3. Hydrolytic kinetic resolution of 1-hexene oxide catalyzed by
5R,R)-4 previously oxidized to the Co5III) state in the presence of
C8F17COOH. Recycling of the catalyst after fractional distillation of the
reaction mixture
lation of certain reaction mixtures is a delicate and time-
consuming task. The use of polymer-supported chiral
Co5salen) complexes has been proposed as a solution to
these problems.14 Polystyrene-bound catalysts could be
isolated from product mixtures by simple ®ltration and
continuous-¯ow reaction systems based on silica-bound
catalysts were also tested. Alternative solutions based on
the ¯uorous character of the catalyst can be envisaged. A
wide range of ¯uorous techniques complementary to the
standard FB approach have been introduced, providing
new options for separating reaction mixtures.19 Our interest
for these techniques was stimulated by the ®nding that a
chiral light ¯uorous phosphine can be conveniently used
in Pd50)-catalyzed asymmetric allylic substitutions. It was
shown that these reactions could be carried out under
homogeneous conditions in common organic solvents, the
products being subsequently recovered by simple liquid±
liquid extraction with a per¯uorocarbon.20 Unluckily,
neither the catalyst nor the ligand could be recycled, as
also observed by Curran and co-workers in the case of
phosphine-based light ¯uorous platinum complexes used
as catalysts in the allylation of benzaldehydes.15 This draw-
back is probably related to the sensitivity of the ligands used
and 5R,R)-4 seemed to be a better candidate for testing the
value of light ¯uorous techniques, due to its proved stability
under the reaction conditions here employed.
Cycle
Time 5h) Conversion 5%)a ee diol 5%)b ee epoxide 5%)c
1
2
3
4
6
6
6
8
46
44
45
46
$99
97.2
97.4
96.9
91.2
90.6
90.8
90.5
Reaction conditions: racemic epoxideˆ25 mmol 53 ml); H2Oˆ17.5 mmol
50.32 ml); catalystˆ0.05 mmol. Molar ratio epoxide/catalystˆ500.
a
Determined by GC analysis of the reaction mixture. See Section 4.
Determined by capillary GC analysis of the isolated product on a HP
b
ChiralÐ20% permethylated b-cyclodextrin column.
Optical purity of the isolated epoxide.
c
susceptible to racemization upon distillation of the reaction
mixture.14 Accordingly, the optical purity of the isolated
epoxide was found to be 90.6% against eeˆ97% as
measured by chiral GC analysis of the reaction mixture.
Having established the effectiveness of 5R,R)-4 as a catalyst
precursor, recycling of this light ¯uorous complex was
investigated. A methodology analogous to that proposed
by Jacobsen and coworkers for the reference complex
5R,R)-1 was applied at ®rst 5Table 3).13 The non-volatile
residue obtained after distillation of the reaction mixture
deriving from the HKR of 1-hexene oxide was taken upin
toluene and treated with C8F17COOH in air. The Co5III)
species was thus regenerated as shown by UV±vis spectro-
scopy. Evaporation of the solvent under reduced pressure
afforded a dark brown material that was dissolved in a new
batch of racemic 1-hexene oxide. Water was added to
the solution that was stirred 6 h at room temperature. GC
analysis of the organic phase showed the almost complete
consumption of the reactive S-epoxide and the formation of
the S-diol with 97.2% ee 5entry 2). As judged by comparison
with the results obtained with fresh 5R,R)-4 5entry 1), the
catalyst could be recycled as described at least 3 times with
only minor loss in activity and selectivity.
Three different ¯uorous separation methods were compared,
using again the HKR of 1-hexene oxide as a model reaction:
5A) liquid±liquid extraction at room temperature, in the
presence of a ¯uorinated co-solvent;
5B) liquid±liquid extraction in a continuous extractor;
5C) solid phase extraction.
The results obtained are summarized in Table 4.
As discussed above, complex 5R,R)-4 is insoluble in n-per-
¯uorooctane at room temperature and rather soluble in
1-hexene oxide. However, the solubility of the spent catalyst
in the products mixture is decreased by the presence of the
more polar 1,2-hexanediol and can be further decreased by
addition of CH3CN, a ¯uorophobic solvent able to dissolve
both reaction products. When 10 ml of n-per¯uorooctane
This simple and effective recycling procedure, however,
presents some limitations, as in the case of products prone
to racemization or non-volatile. Moreover, fractional distil-
Table 4. Hydrolytic kinetic resolution of 1-hexene oxide catalyzed by 5R,R)-4 previously oxidized to the Co5III) state in the presence of C8F17COOH.
Recycling of the catalyst using ¯uorous techniques
Entry
Methoda
Time 5h)
Conversion 5%)b
ee diol 5%)c
Co loss 5%)
1d
2
3
4
±
6
46
50
47
36
41
$99
$99
95.2
$99
90.9
±
A
B
24
15
50
36
16e
14f
50h
33h
Cg
Ci
5
Reaction conditions: racemic epoxideˆ25 mmol 51.5 ml); H2Oˆ17.5 mmol 50.32 ml); fresh catalystˆ0.05 mmol 566 mg); C8F17COOHˆ0.1 mmol 546 mg).
Initial molar ratio epoxide/catalystˆ500.
a
See main text.
Determined by GC analysis of the reaction mixture. See Section 4.
Determined by capillary GC analysis of the reaction mixture on a HP ChiralÐ20% permethylated b-cyclodextrin column.
Fresh catalyst.
Colorimetric essay of the ¯uorous extract after the ®rst reaction cycle. See Ref. 8 for the method used.
ICP analysis of the recovered material after the second reaction cycle.
Extraction of the spent catalyst adsorbed on a ¯uorous reverse phase silica with cold toluene.
ICP analysis of the extracted silica.
Extraction in continuous of the spent catalyst adsorbed on a ¯uorous reverse phase silica with warm toluene.
b
c
d
e
f
g
h
i

M. Cavazzini et al. / Tetrahedron 58 (2002) 3943±3949
3947
and 2 ml of a,a,a-tri¯uorotoluene were added to the reac-
tion mixture diluted with 30 ml of CH3CN, two distinct
layers formed. After stirring for 30 min at room tempera-
ture, the mixture was poured into a separating funnel. The
upper layer was subjected to a second extraction and the
combined brown ¯uorous layers were collected, washed
with 10 ml of CH3CN and evaporated to dryness under
reduced pressure. The recovered catalyst was regenerated
by treatment with C8F17COOH as previously described, and
used in a second run 5entry 2). Quantitative colorimetric
analysis of a diluted solution of the recovered Co5III)5salen)
species taken before the second reaction cycle showed an
absorption decrease of 16% with respect to a fresh catalyst
solution.8 The partial loss of catalyst during the extraction
was con®rmed by the results of the second run. Although
the enantioselectivities in epoxide and diol were not
affected, a signi®cant reduction of activity was observed,
50% conversion of the racemic epoxide being achieved
only after 24 h.
different, more ¯uorophilic solvent 5e.g. CH2Cl2, toluene or
Et2O). In the case of toluene, the best solvent among those
tested, 50% of the initial cobalt remained attached to the
silica as determined by elemental analysis. The recovered
material still showed catalytic activity, but as expected
reaction rate was reduced 5entry 4). Extraction in continuous
of the ¯uorous silica gel with toluene in a Sohxlet apparatus
also gave disappointing results: elemental analysis of the
extracted silica showed that 33% of the cobalt initially intro-
duced was still adsorbed and this was associated with both
decreased catalytic activity and enantioselectivity 5entry 5).
The high af®nity of the ¯uorous complex for the modi®ed
silica prompted us to explore the use of this material as an
insoluble support for 5R,R)-4, with the practical advantage
that no modi®cation of the ligand for the covalent attach-
ment to the heterogeneous matrix was required. Two
methods were tested in parallel: 5a) adsorption of a solution
of 5R,R)-4 in toluene onto the ¯uorous silica followed by
aerobic oxidation in the presence of C8F17COOH, and 5b)
adsorption of the complex previously oxidized in solution to
a Co5III) species. In both cases, the brown solid material
was thoroughly rinsed with CH3CN, CH2Cl2 and 1-hexene
oxide and dried under vacuum before using it in the HKR of
1-hexene oxide. Elemental analysis indicated incorporation
of 42 and 40 mmol of Co per gram of silica, respectively.
Both heterogeneous materials were found to be devoid of
catalytic activity, neither consumption of 1-hexene oxide
nor formation of 1,2-diol being detected by GC analysis
after 48 h, in striking contrast with the excellent results
reported in the case of silica-bound Co5salen) complexes
featuring the covalent attachment of the ligand to the
inorganic support.16 Site isolation resulting from the low
catalyst loading on the ¯uorous silica might explain
this remarkable difference. Indeed, the HKR of terminal
epoxides is likely to proceed through a cooperative
bimetallic mechanism, which is effective only in the case
of physical proximity of the catalyst molecules. The access
of water to the catalytically active Co5III) sites might be
also dif®cult because of the hydrophobic character of the
¯uorous silica gel.
Crich and co-workers suggested the use of a jacketed con-
tinuous extraction apparatus to overcome the low tendency
to partition in the ¯uorous phase of light ¯uorous
compounds.16 This method was tested after diluting the
reaction mixture with CH3CN 57.5 ml) as in the case of
liquid±liquid extraction at room temperature, but this time
no co-solvent was added to n-per¯uorooctane 535 ml) that
was re¯uxed in the receiver ¯ask. Cold water kept the two
phases cold and immiscible in the jacketed return arm of the
apparatus, but a brown solid was clearly visible at the inter-
face of the two layers. The extraction was halted after a
period of 2 h and evaporation of the ¯uorous phase afforded
only a few milligrams of an orange solid which was identi-
®ed as a Co5II)5salen) complex by the presence of two
characteristic UV±vis absorption bands at 407 and 344.
Better results were obtained with a common continuous
extractor the upper part of which became progressively
hotter as the extraction proceeded. Hot n-per¯uorooctane
readily dissolved the brown solid when crossing the inter-
face between the organic and the ¯uorous layers. After 2 h
the n-per¯uorooctane solution in the receiver ¯ask was
cooled to room temperature affording an orange precipitate
592 mg against 112 mg of 5R,R)-4 plus C8F17COOH initially
used). Ten milligrams of pale-orange solid was also
obtained from the liquid phase after evaporation under
reduced pressure. The recovered material was reoxidized
and recycled as described before. However, reduction of
the catalytic activity was still observed 5entry 3). Elemental
analysis 5ICP) of the solid recovered after the second
reaction cycle showed a Co loss of 14 % with respect to
the fresh catalyst.
3. Conclusions
The hydrolytic kinetic resolution 5HKR) of terminal
epoxides can be performed under solvent-free conditions
in the presence of small amounts of ¯uorous chiral
Co5salen) complexes. The best results were obtained using
a light ¯uorous catalyst featuring sterically hindered t-butyl
substituents in the 3,30-positions of the ligand. Catalytic
activities and enantioselectivities were comparable to
those reported for a similar non-¯uorous catalytic system,
and recycling of the spent catalyst could also be performed
analogously. In addition, application of ¯uorous techniques
provided alternative methods for the separation of the
catalyst from reaction mixtures under mild conditions.
Solid±liquid extraction was found to be the quickest and
operationally simplest way to get rid of the catalyst: it did
not require the use of a ¯uorous solvent and could be useful
for parallel synthesis. Liquid±liquid extraction, both in the
presence of a co-solvent and in a continuous extractor, was
less effective. Indeed, the compounds here investigated are
Fluorous compounds can be quickly separated from
standard organic molecules using a particular kind of
solid±liquid extraction based on the adsorbing properties
of `¯uorous reverse phase silica gel'.21 In a third series of
recycling experiments, the crude reaction mixture was
charged to 1 g of silica gel modi®ed with a per¯uoroalkyl
residue, placed in a plastic syringe.22 Elution with 6 ml of
CH3CN removed 1-hexene oxide and 1-2-hexanediol in a
few minutes, with no trace of Co5salen) detectable by
UV±vis spectroscopy. However, only a fraction of the
¯uorous catalyst was recovered by a second elution with a

3948
M. Cavazzini et al. / Tetrahedron 58 (2002) 3943±3949
poorly soluble in per¯uorocarbons despite the presence of
long ¯uorous ponytails and their relatively high ¯uorine
content. We are currently trying to extend this comparison
to other chiral ¯uorous catalytic systems.
4.2. HKR of terminal epoxides: general procedure
The ¯uorous Co5II) complex 50.05 mmol) was dissolved in
toluene 54 ml). Solid C8F17COOH 546.4 mg, 0.1 mmol) was
added and the mixture was stirred while open to the air for
1 h at room temperature. This procedure was carried out in
re¯uxing toluene in the case of 5R,R)-2. The solvent was
removed by evaporation under reduced pressure and the
brown residue was dried under vacuum. Racemic epoxide
525 mmol) was added and the mixture was stirred for 5 min.
H2O 50.32 ml, 17.5 mmol) was added in one portion and the
mixture was stirred at room temperature. The outcome of
the HKR was followed by GC analysis of aliquots taken at
different times 5columnˆHP-5). Conversion was evaluated
by comparison of the relative area of the epoxide and diol
peaks with a calibration curve built with mixtures of the two
products in known amounts. The values obtained were
found to be in good agreement with those calculated from
GC measurement of the ee of the unreacted epoxide and
formed diol 5column HP-Chiral 20%).14 After the reaction
times reported in Tables 1 and 2, the products were isolated
by fractional distillation of the reaction mixture in a
Kugelrhor apparatus with dry-ice cooled receivers. The
following compounds were distilled under vacuum:
3-chloro-1,2-propane diol 5bp 838C, 2 mmHg),23 1-octene
oxide 5bp51±54 8C, 10 mmHg),24 1,2-octane diol 5bp
103±1048C, 0.5 mmHg),25 1-phenyl-1,2-ethane diol 5bp
828C, 1 mmHg).26 The solid residue was recycled as
described in the text if required.
4. Experimental
Solvents were puri®ed by standard methods and dried if
necessary, except for n-per¯uorooctane 5Galden D-100, a
generous gift from Ausimont S.p.A. Bollate, Italy), which
was used as received. All commercially available reagents
were used as received. TLC was carried out on silica gel 60
F254. Column chromatography was carried out on SI 60
silica gel, mesh size 0.040±0.063, Merck, Darmstadt,
Germany. Melting points 5uncorrected) were determined
with a BuÈchi SMP-20 capillary melting point apparatus.
Optical rotations were measured using a Perkin±Elmer
241 polarimeter. UV±vis spectra were measured using a
Lambda 6 Perkin±Elmer spectrometer. GC analyses were
performed on a Hewlett-Packard 5890 instrument 5column:
30 m£0.32 mm HP-5 5% phenyl methyl siloxane or 30 m£
0.25 mm HP ChiralÐ20% permethylated b-cyclodextrin
column). Elemental analysis: Departmental Service of
Microanalysis 5University of Milano, C, H, N) and Redox
S.n.c. 5Monza, Italy, ICP determination of Co).
4.1. Synthesis of ¯uorous CoꢀII)ꢀsalen) complexes:
general procedure
4.3. Preparation of ¯uorous reverse phase silica gel
To a solution of salen ligand6,8 50.5 mmol) in toluene 57 ml)
heated at 1008C under nitrogen was added dropwise
Co5OAc)2´4H2O 50.25 g, 1 mmol) in aqueous 95%-ethanol
515 ml). The yellow solution turned orange and a precipitate
was formed. The mixture was stirred for 4 h, after which the
solvent was evaporated under reduced pressure. The residue
was crystallized from EtOH 515 ml) affording the Co5II)
complex as a bright orange solid.
The procedure described in Ref. 22 was followed, with
slight modi®cations. Flash chromatography grade silica
59 g, Silica Gel 40 m, Mallinckrodt Baker) was dried at
1208C in a vacuum oven for 8 h and poured into a ¯ask
containing dry toluene 525 ml), imidazole 52.87 g, 42
mmol) and 1H,1H,2H,2H-per¯uorooctyldimethylchloro-
silane 515 g, 34 mmol). The mixture was heated for 80 h
at 1008C and gently shaken with care occasionally. After
cooling, the solid was ®ltered on a sintered glass ®lter,
washed sequentially with toluene, MeOH, MeOH/H2O,
Et2O, CH3CN and dried at 1208C in a vacuum oven for
8 h to yield 13.5 g of ¯uorous reverse phase silica gel.
20
4.1.1. Cobalt complex ꢀR,R)-2. Yieldˆ93.6%; [a]D
ˆ
2411 5cˆ0.002, CCl2FCClF2); mp.2508C; UV±vis 56.8£
1025 M, CCl2FCClF2): lmax 5log 1)ˆ403 53.68), 353
53.71), 243 53.93); FT-IR 5KBr): 3555, 2955, 1620, 1550,
1458, 1356, 1211, 1150 cm21; C52H16CoF68N2O2 52051.5):
calcd C 30.44, H 0.79, N 1.37; found C 29.96, H 1.03, N
1.27.
4.4. Solid±liquid extraction over ¯uorous reverse phase
silica gel
A 5 ml plastic syringe ®tted with a stopcock was packed
with ¯uorous reverse phase silica 51 g) as described in
Ref. 22. To this column the dark reaction mixture diluted
with CH3CN 51 ml) was loaded. A pale yellow liquid was
eluted at ®rst, while the topof the silica bed became almost
black. The column was then eluted with further 6 ml of
CH3CN, thus completely removing 1-hexene oxide and
1-2-hexanediol.
20
4.1.2. Cobalt complex ꢀR,R)-3. Yieldˆ98.4%; [a]D
ˆ
1192 5cˆ0.01, CH2Cl2); mpˆ1968C; UV±vis 51.8£
1025 M, CH2Cl2): lmax 5log 1)ˆ414 54.12), 347 54.14),
244 54.40); FT-IR 5KBr): 3365, 2958, 1619, 1601, 1540,
1292, 1246, 1205, 1148 cm21; C52H36CoF34N2O2 51425.7):
calcd C 43.81, H 2.55, N 1.91; found C 43.54, H 2.61, N
1.88.
20
4.1.3. Cobalt complex ꢀR,R)-4. Yieldˆ89.6%; [a]D
ˆ
2534 5cˆ0.01, CH2Cl2); mpˆ2448C; UV±vis 53.8£
1025 M, CH2Cl2): lmax 5log 1)ˆ407 54.05), 344 54.10),
245 54.67); FT-IR 5KBr): 3441, 2955, 1607, 1543, 1210,
1151 cm21; C44H34CoF34N2O2 51327.6): calcd C 39.81, H
2.58, N 2.11; found C 39.73, H 2.70, N 1.93.
Acknowledgements
The ®nancial contribution of the European Commission
through the Human Potential Programme 5Contract
no. HPRN-CT-2000-00002, Development of Fluorous

M. Cavazzini et al. / Tetrahedron 58 (2002) 3943±3949
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