Synthesis of perfluoroalkyl-substituted bis(oxazolines) as ligands for catalytic enantioselective reactions

Article abstract of DOI:10.1002/ejoc.200390173

Two chiral perfluoroalkyl-substituted bis(oxazolines) (F-box) have been prepared for the first time by a reaction sequence that involved formation of the properly functionalized box followed by introduction of two (ligand 9) or four (ligand 6) n-C₈F₁₇ residues. The fluorine content of these F-box was 49.2 and 55.5%, respectively. These ligands were employed in the ene reaction between a-methylstyrene and ethylglyoxalate carried out in the presence of [Cu(OTf)₂] (up to 67% ee), and in the cyclopropanation of styrene in combination with CuOTf (up to 78% ee). In both cases the F-box with the lower fluorine content performed better than the more fluorinated one in terms of chemical yield and enantioselectivity. Ligand 9 was recovered by flash chromatography; ligand 6 by phase separation of the reaction solvents. Comparisons between the use of perfluoroalkyl groups and of soluble and insoluble polymers as solubility devices for the recovery and recycling of the bis(oxazoline) ligand are also reported. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390173

FULL PAPER
Synthesis of Perfluoroalkyl-Substituted Bis(oxazolines) as Ligands for
Catalytic Enantioselective Reactions
Rita Annunziata,[a] Maurizio Benaglia,*[a] Mauro Cinquini,[a,b] Franco Cozzi,[a,b] and
Gianluca Pozzi[b]
Keywords: Asymmetric catalysis / Biphasic catalysis / Fluorous ligands / Homogeneous catalysis / Supported catalysis
Two chiral perfluoroalkyl-substituted bis(oxazolines) (F-box)
have been prepared for the first time by a reaction sequence
that involved formation of the properly functionalized box
followed by introduction of two (ligand 9) or four (ligand 6)
n-C8F17 residues. The fluorine content of these F-box was
49.2 and 55.5%, respectively. These ligands were employed
the lower fluorine content performed better than the more
fluorinated one in terms of chemical yield and enantioselec-
tivity. Ligand 9 was recovered by flash chromatography; li-
gand 6 by phase separation of the reaction solvents. Compar-
isons between the use of perfluoroalkyl groups and of soluble
and insoluble polymers as solubility devices for the recovery
in the ene reaction between α-methylstyrene and ethylglyox- and recycling of the bis(oxazoline) ligand are also reported.
alate carried out in the presence of [Cu(OTf)2] (up to 67%
ee), and in the cyclopropanation of styrene in combination
with CuOTf (up to 78% ee). In both cases the F-box with
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
trol ability very similar (and in some instances even su-
perior) to those displayed by the nonsupported systems.[5]
In principle, a soluble and easily recoverable ligand can
also be obtained by the fluorous-phase approach,[9] i.e. by
the introduction of a sufficiently high number of perfluori-
nated ‘‘ponytails’’. To the best of our knowledge, no ex-
amples of perfluoroalkyl-substituted box (F-box) have been
reported in the literature.[10] Here, we report the first syn-
thesis of two derivatives of this class of compounds having
different fluorine content, and describe their use as chiral
ligands in two representative enantioselective catalytic reac-
tions. We compare the results obtained with these new F-
box with those obtained with related box, either nonsup-
ported or supported on various polymers, paying particular
attention to the recovery and recycling of the ligands.
The versatility of chiral bis(oxazolines) (box) to act as
ligands in a variety of catalytic enantioselective transform-
ations[1] has stimulated intense research activity devoted to
the immobilization of different representatives of this class
of compounds on various supports. This effort lies within
the framework of immobilization of ligands and catalysts
on polymeric matrixes,[2] that is currently regarded as a vi-
able tool to improve the efficiency of asymmetric catalysis[3]
by allowing simple catalyst recovery and recycling.
Generally, insoluble supports have been selected for the
immobilization of chiral box.[4] The immobilization of
classic (Evans-type)[5] and structurally new[6] box on modi-
fied poly(ethyleneglycol)s (PEGs) of high molecular weight
has been recently reported by Reiser’s group[6] and ours.[5]
The rationale behind the use of PEG as the support[7] stems
from the ability of this inexpensive and readily func-
tionalized polymer to act as a solubility device that com-
bines the advantages of running a reaction under homo-
geneous (and likely best-performing) catalysis conditions
with those of recovering and recycling a ligand or a catalyst
as if it were bound to an insoluble support.[8] The PEG-
supported species showed catalytic activity and stereocon-
Results
We designed the synthesis of the F-box ligands taking
into account: (i) the convenience of starting from a com-
mercially available box; (ii) the necessity of introducing a
spacer to separate the perfluorinated residues from the co-
ordination sites;[9f] and (iii) the need for disubstitution at
the box bridging atom, a feature known to enhance the
stereoselectivity of box-promoted reactions.[1] On the basis
of our previous experience in the synthesis of PEG-sup-
ported box,[5] we performed the reaction sequence outlined
in Scheme 1.
[a]
Centro di Eccellenza CISI e Dipartimento di Chimica Organica
e Industriale, UniversitaЈ degli Studi di Milano,
Via Golgi 19, 20133 Milano, Italy
Fax: (internat.) ϩ 39-02/50314159
E-mail: maurizio.benaglia@unimi.it
tert-Butyl-substituted box 1 was treated[4a] with MeLi
(2.2 mol-equiv. in THF, Ϫ55 °C, 90 min) and then alkylated
[b]
CNR-ISTM, UniversitaЈ degli Studi di Milano
Via Golgi 19, 20133 Milano, Italy
1191
Eur. J. Org. Chem. 2003, 1191Ϫ1197  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0407Ϫ1191 $ 20.00ϩ.50/0

R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi, G. Pozzi
FULL PAPER
perature, 15 h), afforded box 7 in 40% yield along with box
3 (35% yield). These were readily separated by flash chro-
matography and adduct 7 was transformed into perfluoro-
alkyl-substituted box 9 via the two reactions described
above, namely allyl removal (76% yield) and O-benzylation
with 5 (54% yield). The unoptimized overall yield of 9 from
1 was 16.5%. Recovered 3 was recycled to produce F-box 6.
The fluorine contents of F-box 6 and 9 were calculated
as 55.5 and 49.2%, respectively, Despite these similar values,
solubility studies revealed that while ligand 9 was readily
soluble in non-fluorinated solvents, the partition coef-
ficients of compound 6 in n-perfluorooctane/dichlorometh-
ane (50:50, v/v) and n-perfluorooctane/acetonitrile (50:50,
v/v) were gravimetrically determined as ca. 4.7 and 17.5,
respectively. Thus, the number of the perfluorinated pony-
tails, rather than the actual fluorine content, seems to be
the discriminating factor in determining the solubility
properties of perfluorinated compounds.[9]
Ligands 6 and 9 were then tested in the representative
enantioselective transformations reported in Scheme 2
[Equations (1) and (2)]. The results are collected in Table 1
(see the Exp. Sect. for methods of ee determination).
Scheme 1. Synthesis of F-box 6 and 9
with 4-allyloxybenzyl bromide (2)[5] (2.0 mol-equiv., Ϫ10
°C, 4.5 h) to afford adduct 3 in 74% isolated yield. Oxygen
deprotection was carried out at 90 °C with Pd(OAc)2 and
PPh3 in EtOH in the presence of SiO2 to give bis(phenol) 4
in 94% yield. Introduction of the perfluoroalkyl residues
was achieved by alkylation of 4 (Cs2CO3, DMF, 50 °C,
60 h) with a slight molar deficiency[11] of α-bromo-3,5-bi-
Scheme 2. Enantioselective reactions catalyzed by metal complexes
of F-box ligands 6 and 9
The ene reaction[13] [Equation (1), Scheme 2; Entry 1,
s(perfluorooctyl)toluene (5) (obtained in 60% yield from the Table 1] between α-methylstyrene (1 mol-equiv.) and ethyl
corresponding alcohol[12] with PBr3). Compound 6 was glyoxalate (50% solution in toluene, 10 mol-equiv.) carried
thus obtained in 37% unoptimized yield (26% overall yield out from 0 °C to room temp. for 18 h in CH2Cl2 in the
from 1).
presence of ligand 9 (11 mol%) and of [Cu(OTf)2] (10
Sequential treatment of similarly metallated 1, first with mol%) afforded adduct 10 in 99% yield and 67% ee (as de-
the benzyl bromide 2 (1 mol-equiv., Ϫ10 °C, 40 min) and termined by the Mosher ester method). When the reaction
then with MeI (3 mol-equiv., from Ϫ10 °C to room tem- was repeated under the same conditions using ligand 6 in a
Table 1. Enantioselective reactions catalyzed by F-box ligands 6 and 9
Entry
Eq. in Scheme 2
Catalyst (10 mol%)
Product
Isolated yield (%)
trans/cis[a]
ee (%)[b]
1
2
3
4
5
6
7
8
9
(1)
(1)
(2)
(2)
(2)
(2)
(2)
(2)
(1)
9/[Cu(OTf)2]
6/[Cu(OTf)2]
9/CuOTf
10
10
11
11
11
11
11
11
10
99
64
68
55
60
65
60
50
96
Ϫ
Ϫ
67
26
78
60
56
3
66
44
65
65:35
73:27
70:30
77:23
67:33
65:35
Ϫ
6/CuOTf
6/CuOTf[c]
6/CuOTf[d]
9/CuOTf[e]
6/CuOTf[f]
9/[Cu(OTf)2][g]
[a]
1
[b]
Determined by 300 MHz H NMR analysis of the crude reaction products.
Determined by the Mosher ester method (compound
10), or by HPLC on a chiral stationary phase (compound 11). In the case of adducts 11 the reported ee is that of the major isomer.[c] See
ref.[14]
.
Reaction carried out in a 1:1 mixture of acetonitrile/perfluorooctanes as solvent.[e] With a sample of ligand 9 recycled from the
[f] [g]
[d]
reaction of entry 3 (see text). With a sample of ligand 9 recycled from the reaction of entry 4 (see text). With a sample of ligand 9
recycled from the reaction of entry 1 (see text).
1192
Eur. J. Org. Chem. 2003, 1191Ϫ1197

Perfluoroalkyl-Substituted Bis(oxazolines) as Ligands for Catalytic Enantioselective Reactions
FULL PAPER
CH2Cl2/perfluorooctanes (1:1) mixture, the yield and the ee alkyl chains from the sites of chelation should effectively
dropped to 64 and 26%, respectively (Entry 2, Table 1).
prevent this effect.[9f,18]
Alternatively, we can hypothesize that the two heavily flu-
The cyclopropanation[14] [Equation (2), Scheme 2; Entry
3, Table 1] of styrene (5 mol-equiv.) carried out with ethyl orinated substituents at the bridging carbon atom in ligand
diazoacetate (1 mol-equiv., addition time ca. 10 h) in the 6 experience a strong repulsion, both steric and electronic
presence of ligand 9 (11 mol%) and CuOTf (10 mol%) in in origin. This should result in a reduced ‘‘bite angle’’ for
CH2Cl2 (12 h from the end of the addition of diazoacetate, the box moiety, and more difficult complexation of the cop-
room temp.) gave a 65:35 mixture of the trans/cis cyclopro- per ion.[19] Under this hypothesis, an undetermined amount
pane adducts in 68% yield. The major trans isomer 11 had of catalytically active copper() cations noncomplexed by 6
a 78% ee (as determined by HPLC on a chiral stationary could be present in the reaction medium, promoting a po-
phase). The use of ligand 6 in a CH2Cl2/perfluorooctanes orly enantioselective transformation. This negative effect
(1:1) mixture of solvent led to a 55% yield of the trans/cis should be felt more in the case of the ene reaction, which
(73:27) mixture, with the trans isomer being obtained in is known[20] to be catalyzed by a box/CuII complex adopting
60% ee (Entry 4, Table 1).[15] When ligand 6 was used in a a square-planar geometry particularly sensitive to the box
mixture of acetonitrile/perfluorooctanes (1:1) (Entry 6, ‘‘bite angle’’.[21] Since in ligand 9 the bridging substitution
Table 1), the ee of the trans adduct 11 was only 3% (65% is sterically less demanding than in 6, ligand/copper cation
yield, trans/cis ϭ 77:23).
complexation should be easier and this should result in
more enantioselective reactions. It must be noted that this
behavior is not a general feature of chiral F-catalysts since
in other cases they were found to perform as efficiently as
their non-fluorinated counterparts.[10]
Discussion
The data collected in Table 1 showed that ligand 9 (the
We then studied the recovery of ligands 6 and 9. The
one with two perfluorinated ponytails) performed consist- solubility properties of these F-box (see above) required the
ently better than ligand 6 (four perfluorinated ponytails) in use of different procedures. First, both ligands were released
terms of enantioselectivity. Working with ligand 9, ee values from the copper cation by decomplexation with an aqueous
about 20% lower than those obtained with the best ligands solution containing cyanide ions, carried out on the crude
reported in the literature[13,14] were observed.[16] Indeed, the reaction mixture. After a standard workup, ligand 9 was
use of F-box 9 in the ene reaction led to product 10 in then recovered by filtration through a short silica-gel col-
67% ee compared with 89% ee obtained by Evans using the umn, whereas ligand 6 was recovered by separation of the
catalyst derived from the gem-dimethyl-substituted box (1 CH2Cl2/perfluorooctanes mixture and evaporation of the
with two methyl groups at the bridging carbon atom) at latter solvent. The ligands recovered from both the cyclo-
identical concentration.[13] In the cyclopropanation reaction propanation and the ene reaction were shown to be stable
1
a 78% ee was achieved for 11 working with ligand 9, while under the reaction and recovery conditions (they gave H
the same product was isolated in 99% ee[14] with the catalyst and 19F NMR spectra identical to those of fresh samples).
derived from the gem-dimethyl-substituted box.
However, F-box 6 and 9 recovered from the cyclopropan-
To attempt a rationalization of the obtained results, we ation reaction were found (by 1H NMR spectroscopy) to be
considered the influences exerted by the substitution pat- contaminated by considerable amounts of ethyl diazoacet-
tern at the box-bridging carbon atom, and by the introduc- ate derived decomposition products.[22] Indeed, recycling of
tion of the perfluoroalkyl ponytails. We studied the influ- the recovered ligand 9 in a second cyclopropanation reac-
ence of the substitution pattern in the case of ligand 6, i.e. tion (Entry 7, Table 1) led to the isolation of a trans/cis
the less effective one. By running the ene reaction of Equa- (67:33) mixture in 60% yield, with adduct 11 having a 66%
tion (1) (Scheme 1) in the presence of the catalyst derived ee. Further recovery/recycling showed a fast decrease of
from C2-symmetric box 3 and [Cu(OTf)2], adduct 11 was both the chemical yields and the ee of the product, as the
obtained in 71% yield and 82% ee.[17] Although slightly po- results of accumulation of the contaminants in recovered 9
orer than that obtained with the best performing box under (at the fourth cycle level: 40% yield, 37% ee). Similarly, one
similar conditions (89%),[13] the observed ee was clearly recycling of the recovered ligand 6 (Entry 8, Table 1), led to
higher than that obtained with either F-box 6 or 9 as li- adduct 11 in 44% ee.
gands.
In contrast, the F-box recovered from the ene reaction
This finding pointed to some negative effects exerted by were shown to be pure compounds (within the detection
1
the perfluorinated ponytails. Any explanation of these ef- limits of H and 19F NMR analysis). The recovery yields
fects must also account for the observed inverse relationship were 89% and 64% for compounds 6 and 9, respectively.[23]
existing between the fluorine loading of the ligands and the As expected, recycling of the latter in the reaction of Equa-
enantioselectivity of their reactions. In a first hypothesis we tion (1) (Entry 9, Table 1) afforded product 10 in 96% yield
can surmise that the fluorinated ponytails of 6 and 9 pre- and 65% ee; these values were very similar to those ob-
vent copper chelation by altering the electronic availability tained with a fresh sample of ligand (Entry 1, Table 1).
(and, hence, the chelating ability) of the box nitrogen atoms.
Finally, we compared different solubility devices em-
However, it seems likely that the long spacer (two phenyl ployed for the recovery and recycling of chiral box ligands.
rings and four saturated atoms) separating the perfluoro- The behavior of the soluble polymer-supported PEG-box
Eur. J. Org. Chem. 2003, 1191Ϫ1197
1193

R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi, G. Pozzi
FULL PAPER
12[5] (Figure 1) was considered an excellent term of com- ee,[4a] whereas recycling of 6, recovered by phase separation,
parison to that of F-box 9. These ligands share: (i) the sub- was prevented by ligand contamination (see above).
stitution pattern at the bridging carbon atom and at the
stereocenters; (ii) the location and the chemical nature of
the site of attachment of the solubility device; and (iii) the Conclusions
ready solubility in CH2Cl2. Comparison of the data in-
The synthesis of two perfluorinated bis(oxazolines) (F-
box) with different fluorine contents and solubility proper-
ties has been described for the first time. When these com-
pounds were employed as ligands in combination with CuI
and CuII triflates in two catalytic enantioselective trans-
formations (ene reaction and cyclopropanation), the prod-
ucts were obtained in similar chemical yield and about 20%
lower ee compared with the reactions carried out with the
best performing ligands. Recovery of the F-box was pos-
sible by two procedures, involving chromatography in one
case and phase separation in the other. While the ligands
recovered from the cyclopropanation reaction were con-
taminated by decomposition products, those recovered
from the ene reaction could be recycled, affording the prod-
uct in chemical yield and enantioselectivity almost identical
to those observed in the first cycle. The F-box were com-
pared to structurally related box supported on soluble and
insoluble polymers, in terms of chemical and stereochemical
efficiency, and of simplicity of recovery and recycling. As a
whole, the collected data indicated that the identification of
a ‘‘good-for-all’’ approach toward the development of an
easily recyclable enantioselective catalyst still requires an
extensive research effort.
cluded in Figure 1 and reported in Table 1 (Entries 1 and
9) for the ene reaction [Equation (1)] shows that, at the
same loading of catalyst, adduct 10 was obtained in very
high yield in both the first and the second cycles. As far as
the enantioselectivity is concerned, however, the reactions
carried out with PEG-box 12 gave a higher ee than those
carried out with F-box 9 (95 and 90% vs. 67 and 65%, for
the first and second runs, respectively). The trend was the
same, although with a smaller difference in enantioselectiv-
ity, for the cyclopropanation reaction [Equation (2); with
12/CuOTf: 91% ee, Figure 1; with 9/CuOTf: 78% ee, Entry
3, Table 1]. It is also worth mentioning that 12 was reco-
vered by precipitation and filtration, whereas 9 was reco-
vered by flash chromatography.
The identification of a supported counterpart of F-box 6
was less straightforward. Among the examples reported in
the literature,[4] the insoluble homopolymeric ligand 13 of
Luis and Mayoral[4a] (Figure 1) seemed the best choice. In-
deed, 13 and 6 have identical substituents at the bridging
carbon atom and at the stereocenters, and a very similar
mode of attachment of the solubility device. The major dif-
ference between these two systems resides in their solubility.
The data reported in Figure 1 showed that using 13/CuOTf
in the cyclopropanation reaction led to product in lower
yields (36%), different trans/cis ratio (37:63), and higher ee
(for the trans isomer 11: 78%) compared with those ob-
tained with F-box 6 (Entry 4, Table 1). Two recyclings of
the catalyst derived from 13, recovered by filtration, were
possible with only marginal decrease in chemical yield and
Experimental Section
General: 1H NMR spectra were recorded at 300 MHz in [D]chloro-
form (CDCl3) unless otherwise stated, and were referenced to tetra-
methylsilane (TMS) at δ ϭ 0.00 ppm. 13C NMR spectra were re-
corded at 75 MHz and were referenced to δ ϭ 77.0 ppm in CDCl3.
19F NMR spectra were recorded at 282 MHz in CDCl3 and were
referenced to hexafluorobenzene at δ ϭ 0.0 ppm. Optical rotations
were measured at the Na-D line in a 1-dm cell at 22 °C. IR spectra
were recorded from thin films or solutions in CH2Cl2. Compounds
2, 7, and 8 were prepared as described.[5] Adducts 10 and 11 are
known compounds of established absolute configurations.[13,14] The
1
ee of compound 10 was determined by H NMR spectroscopy of
the corresponding Mosher’s ester obtained by reaction with the (R)
enantiomer of the Mosher’s acid chloride. The esters gave signals
identical to those reported by Evans (see the Supporting Infor-
mation of ref.[13]). The diagnostic signals were those of the vinyl
protons that resonated at δ ϭ 5.40 and 5.22 ppm for the major
(R,R) isomer and at δ ϭ 5.23 and 5.02 ppm for the minor (S,R)
isomer. The ee of compound 11 was determined by HPLC on a
chiral stationary phase: column Chiracel OD; eluent: hexane/
iPrOH (85:15); flow rate: 1 mL/min; λ ϭ 210 nm. tR of the major
enantiomer: 4.83 min; tR of the minor enantiomer: 5.53 min.
1-(Bromomethyl)-3,5-bis(n-perfluorooctyl)benzene
(5):
PBr3
(0.3 mL, 3.2 mmol) was added by syringe over 5 min to a stirred
solution of 3,5-bis(n-perfluorooctyl)benzyl alcohol[12] (3.78 g,
4.0 mmol) in dry THF (40 mL), kept under nitrogen at 0 °C. The
turbid mixture was stirred at 0 °C for 1 h, then at room temp. for a
further 3 h. 1H NMR spectroscopy of the mixture showed complete
Figure 1. Structure of polymer-supported box 12 and 13
1194
Eur. J. Org. Chem. 2003, 1191Ϫ1197

Perfluoroalkyl-Substituted Bis(oxazolines) as Ligands for Catalytic Enantioselective Reactions
FULL PAPER
3
conversion of the starting alcohol. Concentration under reduced
pressure afforded a white solid that was dissolved in Et2O (40 mL).
The organic solution was washed with H2O (2 ϫ 15 mL) and brine
(15 mL), and dried with Na2SO4. Column chromatography of the
crude product with a hexanes/Et2O (85:15) mixture as eluent af-
2JH,H ϭ 9.8, JH,H ϭ 7.6 Hz, 2 H, 1 H of isoxazoline CH2), 4.08
3
2
3
(t, JH,H ϭ 7.6 Hz, 2 H, CHtBu), 4.16 (dd, JH,H ϭ 9.8, JH,H
7.6 Hz, 2 H, 1 H of isoxazoline CH2), 6.74 (A part of an AB sys-
tem, JH,H ϭ 8.5 Hz, 4 H, aromatic H ortho to O), 7.07 (B part of
ϭ
3
3
an AB system, JH,H ϭ 8.5 Hz, 4 H, aromatic H meta to O) ppm.
forded the product (2.49 g, 2.48 mmol, yield 62%) as a colorless
13C NMR: δ ϭ 25.1, 33.5, 38.0, 48.5, 68.2, 75.1, 114.6, 127.0, 131.1,
1
solid. M.p. 46Ϫ47 °C. H NMR: δ ϭ 4.58 (s, 2 H, CH2), 7.76 (s, 1 156.0, 166.5 ppm. C29H38N2O4 (478.6): calcd. C 72.77, H 8.00, N
H, aromatic H para to CH2), 7.86 (s, 2 H, aromatic H ortho to
CH2) ppm. 13C NMR: δ ϭ 29.8, 119.5Ϫ106.5 (m, fluorinated C),
125.4, 130.0 (t, 2JC,F ϭ 22.5 Hz), 131.0, 140.2 ppm. 19F NMR: δ ϭ
Ϫ81.2 (t, JF,F ϭ 10 Hz, 6 F), Ϫ111.5 (t, JF,F ϭ 14 Hz, 4 F),
Ϫ121.6 (br. s, 4 F), Ϫ122.3 (br. s, 12 F), Ϫ123.2 (br. s, 4 F), Ϫ126.6
(br. s, 4 F) ppm. C23H5BrF34 (1007.1): calcd. C 27.43, H 0.50;
found C 27.58, H 0.51.
5.85; found C 72.70, H 8.21, N 5.77.
1,3-Bis(4-{[3,5-bis(perfluorooctyl)phenyl]methoxy}phenyl)-2,2-
bis[(4S)-4-(1,1-dimethylethyl)-1,3-oxazolin-2-yl]propane (6): Cesium
carbonate (0.344 g, 1.057 mmol), and benzyl bromide 5 (0.257 g,
0.272 mmol) were added to a solution of bis(phenol) 4 (0.072 g,
0.151 mmol) in DMF (2 mL) stirred under nitrogen at 50 °C. The
mixture was stirred at 50 °C for 60 h. The cooled mixture was
poured into water (5 mL) and extracted with Et2O (4 ϫ 10 mL).
The combined organic phases were washed with water (5 mL),
dried with Na2SO4, and concentrated under vacuum. The residue
was purified by flash chromatography with a hexanes/Et2O (8:2)
mixture as eluent to give the product (0.128 g, 0.056 mmol, 37%
yield). M.p. 48Ϫ50 °C. [α]2D2 ϭ Ϫ17.2 (c ϭ 0.9 in CHCl3). IR: ν˜ ϭ
3
3
Synthesis of F-box 6 and 9: These compounds were prepared by a
multistep synthesis starting from the commercially available box 1
and the known benzyl bromide 2.
2,2-Bis[(4S)-4-(1,1-dimethylethyl)-1,3-oxazolin-2-yl]-1,3-bis[4-(prop-
2-en-1-yloxy)phenyl]propane (3): MeLi in Et2O (0.52 mL of a 1.6 
solution, 0.826 mmol) was added dropwise to a stirred solution of
box 1 (0.100 g, 0.375 mmol) in dry THF (5 mL) cooled to Ϫ55 °C
under nitrogen. After 1 h of stirring at Ϫ55 °C, compound 2
(0.188 g, 0.826 mmol) in THF (3 mL) was added dropwise and the
reaction mixture was stirred for 4.5 h at Ϫ10 °C. The reaction was
quenched by the addition of a saturated aqueous solution of
NH4Cl (10 mL) and the resulting mixture was extracted with
CH2Cl2 (3 ϫ 10 mL). The combined organic phases were dried
with Na2SO4 and concentrated under vacuum. The residue was
purified by flash chromatography with a hexanes/EtOAc (9:1) mix-
ture as eluent to afford the product (0.155 g, 0.2775 mmol, 74%
yield) as a thick pale-yellow oil. [α]2D2 ϭ Ϫ73.8 (c ϭ 2.77 in CHCl3).
3051, 2955, 1657, 1510, 1266, 741 cmϪ1. H NMR: δ ϭ 0.86 (s, 18
H, tBu), 3.12 (A part of an AB system, JH,H ϭ 14.2 Hz, 2 H, 1 H
1
2
2
of PhCH2), 3.40 (A part of an AB system, JH,H ϭ 14.2 Hz, 2 H,
2
3
1 H of PhCH2), 3.83 (dd, JH,H ϭ 8.6, JH,H ϭ 10.0 Hz, 2 H, 1 H
2
3
of oxazoline CH2), 4.00 (t, JH,H ϭ 8.6, JH,H ϭ 8.6 Hz, 2 H, 1 H
3
of oxazoline CH2), 4.07 (dd, JH,H ϭ 8.6, 10.0 Hz, 2 H, CHtBu),
3
5.18 (s, 4 H, ArCH2O), 6.88 (A part of an AB system, JH,H
ϭ
8.7 Hz, 4 H, aromatic H ortho to O), 7.21 (B part of an AB system,
3JH,H ϭ 8.7 Hz, 4 H, aromatic H meta to O), 7.79 (s, 2 H, aromatic
H para to CH2O), 7.92 (s, 4 H, aromatic H ortho to CH2O) ppm.
13C NMR: δ ϭ 25.7, 33.9, 38.8, 48.4, 68.3, 68.5, 75.6, 114.3,
2
119.5Ϫ106.5 (m, C8F17), 124.9, 129.0, 130.4 (t, JC,F ϭ 22.0 Hz),
1
IR: ν˜ ϭ 2928, 2853, 1655, 1510, 1262 cmϪ1. H NMR: δ ϭ 0.86
131.7, 139.7, 156.8, 166.2 ppm. 19F NMR: δ ϭ Ϫ81.3, Ϫ111.4,
Ϫ121.6, Ϫ122.3, Ϫ123.2, Ϫ126.6 ppm. C75H46F68N2O4 (2331.1):
calcd. C 38.64, H 1.99, N 1.20; found C 38.43, H 2.03, N 1.24.
2
(s, 18 H, tBu), 3.11 (A part of an AB system, JH,H ϭ 14.2 Hz, 2
H, 1 H of PhCH2), 3.39 (B part of an AB system, 2JH,H ϭ 14.2 Hz,
2
3
2 H, 1 H of PhCH2), 3.81 (dd, JH,H ϭ 10.0, JH,H ϭ 8.6 Hz, 2 H,
3
1 H of isoxazoline CH2), 4.00 (t, JH,H ϭ 8.6 Hz, 2 H, CHtBu),
4.09 (dd, JH,H ϭ 10.0, JH,H ϭ 8.6 Hz, 2 H, 1 H of isoxazoline
CH2), 4.53 (dt, JH,H ϭ 5.2, JH,H ϭ 1.5 Hz, 4 H, OCH2CϭC),
5.36 (dq, JH,H ϭ 1.5, JH,H ϭ 10.2, JH,H ϭ 1.5 Hz, 2 H, H cis to
1-(4-{[3,5-Bis(perfluorooctyl)phenyl]methoxy}phenyl)-2,2-bis{2-
[(4S)-4-(1,1-dimethylethyl)-1,3-oxazolin-2-yl}propane (9): Cesium
carbonate (0.152 g, 0.468 mmol) and benzyl bromide 5 (0.156 g,
0.156 mmol) were added to a solution of phenol 8 (0.060 g,
0.156 mmol) in DMF (2 mL), stirred under nitrogen at 50 °C. The
mixture was stirred at 50 °C for 60 h. The cooled mixture was
poured into water (5 mL) and extracted with Et2O (4 ϫ 10 mL).
The combined organic phases were washed with water (5 mL),
dried with Na2SO4, and concentrated under vacuum. The residue
was purified by flash chromatography with a CH2Cl2/Et2O (8:2)
mixture as eluent to give the product (0.111 g, 0.084 mmol, 54%
yield) as a pale yellow viscous oil. [α]2D2 ϭ Ϫ18.8 (c ϭ 0.48 in
2
3
3
4
2
3
4
2
3
4
H in CHϭCH2), 5.42 (dq, JH,H ϭ 1.5, JH,H ϭ 17.2, JH,H
ϭ
1.5 Hz, 2 H, H trans to H in CHϭCH2), 6.06 (m, 2 H, CHϭCH2),
3
6.82 (A part of an AB system, JH,H ϭ 8.5 Hz, 4 H, aromatic H
3
ortho to O), 7.17 (B part of an AB system, JH,H ϭ 8.5 Hz, 4 H,
aromatic H meta to O) ppm. 13C NMR: δ ϭ 25.8, 33.9, 38.6, 48.5,
68.3, 68.8, 75.1, 114.2, 117.4, 129.4, 131.5, 133.5, 157.3, 166.3 ppm.
C35H46N2O4 (558.8): calcd. C 75.23, H 8.30, N 5.01; found C 75.62,
H 8.51, N 4.92.
2,2-Bis[(4S)-4-(1,1-dimethylethyl)-1,3-oxazolin-2-yl]-1,3-bis(4-
hydroxyphenyl)propane (4): A solution of compound 3 (0.559 g,
1 mmol) in ethanol (15 mL) containing Pd(OAc)2 (0.045 g,
CHCl3). IR: ν˜ ϭ 3054, 2981, 1657, 1510, 1266, 741 cmϪ1 1H
.
NMR: δ ϭ 0.85 (s, 9 H, tBu), 1.43 (s, 3 H, Me at bridging C), 3.17
2
(A part of an AB system, JH,H ϭ 14.0 Hz, 1 H, 1 H of PhCH2),
2
0.2 mmol) and PPh3 (0.231 g, 0.88 mmol) was refluxed for 90 min. 3.37 (A part of an AB system, JH,H ϭ 14.0 Hz, 1 H, 1 H of
3
The resulting mixture was cooled to room temperature and SiO2
(2 g) was added in one portion. After stirring at room temperature
for 40 min, the mixture was filtered through a Celite plug, the sol-
vent was evaporated under vacuum, and the residue was purified
PhCH2), 3.82 (dd, JH,H ϭ 8.5, 10.0 Hz, 1 H, CHtBu), 3.90 (dd,
3JH,H ϭ 8.5, 10.0 Hz, 1 H, CHtBu), 4.05 (t, JH,H ϭ 8.5, JH,H
ϭ
3
2
8.5 Hz, 1 H, remaining H of 2 CH2O of oxazolines), 4.23Ϫ4.12 (m,
3 H, 3 H of 2 CH2O of oxazolines), 5.17 (s, 2 H, ArCH2O), 6.87
3
by flash chromatography with a CH2Cl2/EtOAc (6:4) mixture as (A part of an AB system, JH,H ϭ 8.5 Hz, 2 H, aromatic H ortho
eluent to give the product (0.45 g, 0.94 mmol, 94% yield). M.p. 200
to O), 7.13 (B part of an AB system, 3JH,H ϭ 8.5 Hz, 2 H, aromatic
H meta to O), 7.77 (s, 1 H, aromatic H para to CH2O), 7.91 (s, 2
H, aromatic H ortho to CH2O) ppm. 13C NMR: δ ϭ 21.1 25.7,
°C (dec). [α]2D2 ϭ ϩ129.3 (c ϭ 0.65 in CHCl3). [α]2D2 ϭ Ϫ99.1 (c ϭ
0.6 in MeOH). IR: ν˜ ϭ 3583, 3054, 1648, 1515, 1438, 1266 cmϪ1
.
1H NMR ([D6]EtOH): δ ϭ 0.88 (s, 18 H, tBu), 3.07 (A part of an 33.7, 33.9, 41.2, 43.5, 68.5, 68.7, 75.4, 75.6, 114.4, 119.5Ϫ106.5 (m,
2
AB system, JH,H ϭ 14.2 Hz, 2 H, 1 H of PhCH2), 3.31 (B part of
C8F17), 124.9, 129.0, 129.3, 130.2 (t, 2JC,F ϭ 22.5 Hz), 131.8, 139.7,
156.9, 167.2, 167.7 ppm. 19F NMR: δ ϭ Ϫ81.3, Ϫ111.4, Ϫ121.6,
2
an AB system, JH,H ϭ 14.2 Hz, 2 H, 1 H of PhCH2), 3.76 (dd,
Eur. J. Org. Chem. 2003, 1191Ϫ1197
1195

R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi, G. Pozzi
FULL PAPER
Ϫ122.3, Ϫ123.2, Ϫ126.6 ppm. C46H38F34N2O3 (1312.8): calcd. C
[5]
R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi, M. Pitillo,
J. Org. Chem. 2001, 66, 3160Ϫ3166.
M. Glos, O. Reiser, Org. Lett. 2000, 2, 2045Ϫ2048.
Review: D. J. Gravert, K. D. Janda, Chem. Rev. 1997, 97,
489Ϫ509.
42.09, H 2.92, N 2.13; found C 42.33, H 2.96, N 2.11.
[6]
[7]
Stereoselective Syntheses Promoted by F-box Ligands 6 and 9: The
reactions carried out with ligand 9 are illustrative of the procedure.
[8]
For the immobilizaton of other chiral ligands and catalysts on
[8a]
modified PEG see;
H. Han, K. D. Janda, Tetrahedron Lett.
Ene Reaction: A solution was prepared by dissolving under nitro-
gen ligand 9 (0.039 g, 0.030 mmol) and [Cu(OTf)2] (0.012 g,
0.033 mmol) in dry CH2Cl2 (2 mL). The resulting dark-green solu-
tion was stirred at room temperature for 4 h and then added to a
mixture of α-methylstyrene (0.039 mL, 0.3 mmol) and ethylgly-
oxalate (0.595 mL of a 50% solution in toluene, 3.0 mmol), cooled
to 0 °C. The resulting mixture was stirred overnight while the tem-
perature was allowed to slowly increase from 0 °C to room tem-
perature. The mixture was then concentrated under vacuum, and
the residue was dissolved in CH2Cl2 (5 mL), dried with Na2SO4,
filtered, and concentrated under vacuum to give the crude product,
which was purified by flash chromatography with a hexanes/Et2O
(7:3) mixture as eluent. Yields and ee of adduct 10 are reported
in Table 1.
[8b]
1997, 38, 1527Ϫ1530, and references therein.
Gerlach, Eur. J. Org. Chem. 1998, 21Ϫ27, and references ther-
C. Bolm, A.
[8c]
ein.
T. S. Reger, K. D. Janda, J. Am. Chem. Soc. 2000, 122,
[8d]
6929Ϫ6934.
M. Benaglia, G. Celentano, F. Cozzi, Adv.
Synth. Catal. 2001, 343, 171Ϫ173. [8e] R. W. Flood, T. P. Geller,
S. A. Petty, S. M. Roberts, J. Skidmore, M. Volk, Org. Lett.
[8f]
2001, 3, 683Ϫ686.
Q. H. Fan, G. J. Deng, C. C. Lin, A. S.
[8g]
C. Chan, Tetrahedron: Asymmetry 2001, 12, 1241Ϫ1247.
P. Guerreiro, V. Ratovelomanana-Vidal, J.-P. Genet, P. Dellis,
[8h]
Tetrahedron Lett. 2001, 42, 3423Ϫ3426.
Y. Q. Kuang, S. Y.
[8i]
Zhang, L. L. Wei, Tetrahedron Lett. 2001, 42, 5925Ϫ5927.
H. Guo, X. Shi, Z. Qiao, S. Hou, M. Wang, Chem. Commun.
[8j]
2002, 118Ϫ119.
M. Benaglia, G. Celentano, M. Cinquini,
A. Puglisi, F. Cozzi, Adv. Synth. Catal. 2002, 344, 149Ϫ152.
[8k]
M. Benaglia, M. Cinquini, F. Cozzi, A. Puglisi, G. Celen-
tano, Adv. Synth. Catal. 2002, 344, 533Ϫ542. For the immobili-
zaton of achiral ligands and catalysts on modified PEG see: [8l]
Q. Yao, Angew. Chem. Int. Ed. 2000, 39, 3896Ϫ3898; Angew.
Chem. 2000, 112, 4060Ϫ4062. [8m] R. Annunziata, M. Benaglia,
M. Cinquini, F. Cozzi, G. Tocco, Org. Lett. 2000, 2,
1737Ϫ1739. [8n] M. Benaglia, M. Cinquini, F. Cozzi, G. Tocco,
Tetrahedron Lett. 2002, 43, 3391Ϫ3393.
Cyclopropanation: A solution was prepared by stirring under nitro-
gen ligand 9 (0.039 g, 0.030 mmol) and commercially available
CuOTf·0.5PhH (0.008 g, 0.033 mmol) in dry CH2Cl2 (2 mL) at
room temperature for 2 h. To the resulting pale-yellow solution,
freshly distilled styrene (0.157 mL, 1.5 mmol) was added. Ethyl di-
azoacetate (0.034 mL, 0.3 mmol), dissolved in CH2Cl2 (1 mL), was
added over a period of 10 h by a syringe pump, and the mixture
was stirred for 20 h at room temperature. The mixture was then
concentrated under vacuum, and the residue was dissolved in
CH2Cl2 (5 mL), dried with Na2SO4, filtered, and concentrated un-
der vacuum to give the crude product, which was purified by flash
chromatography with a hexanes/EtOAc (95:5) mixture as eluent.
Yields and ee of adduct 11 are reported in Table 1.
[9]
Reviews on fluorous biphase chemistry: [9a] I. T. Horvath, Acc.
[9b]
Chem. Res. 1998, 31, 641Ϫ650.
L. P. Barthel-Rosa, J. A.
[9c]
Gladysz, Coord. Chem. Rev. 1999, 190Ϫ192, 587Ϫ605.
M.
Cavazzini, F. Montanari, G. Pozzi, S. Quici, J. Fluorine Chem.
1999, 94, 183Ϫ193. [9d] D. P. Curran, Synlett 2001, 1488Ϫ1496.
[9e]
Reviews on fluorous biphase catalysis:
Koten, B.-J. Deelman, Chem. Soc. Rev. 1999, 28, 37Ϫ41.
E. de Wolf, G. van
[9f]
E.
G. Hope, A. M. Stuart, J. Fluorine Chem. 1999, 100, 75Ϫ83.
[9g]
R. H. Fish, Chem. Eur. J. 1999, 5, 1677Ϫ1680. For defi-
nitions in this field: [9h] J. A. Gladysz, D. P. Curran, Tetrahedron
2002, 58, 3823Ϫ3825.
Acknowledgments
This work was supported by MIUR (Progetto Nazionale Stereose-
lezione in Sintesi Organica, Metodologie ed Applicazioni) and
CNR.
[10]
Review on perfluoroalkyl-substituted chiral ligands and cata-
[10a]
lysts:
G. Pozzi, M. Cavazzini, S. Quici, D. Maillard, D.
Sinou, J. Mol. Catal. A: Chem. 2002, 182Ϫ183, 455Ϫ461. For
[10b]
other examples not included in ref.[10a] see:
S. Quici, G. Pozzi, Tetrahedron 2002, 58, 3943Ϫ3949.
Tian, Q. C. Yang, T. C. W. Mak, K. S. Chan, Tetrahedron 2002,
M. Cavazzini,
[10c]
Y.
[1]
Review: A. K. Ghosh, P. Mathivanan, J. Cappiello, Tetra-
[10d]
58, 3951Ϫ3961.
Y. Nakamura, S. Takeuchi, K. Okumura,
hedron: Asymmetry 1998, 9, 1Ϫ45.
R. Noyori, Asymmetric Catalysis in Organic Synthesis, John
[10e]
Y. Ohgo, D. P. Curran, Tetrahedron 2002, 58, 3963Ϫ3969.
[2]
D. Maillard, G. Pozzi, S. Quici, D. Sinou, Tetrahedron 2002,
Wiley & Sons, New York, 1994.
Chiral Catalyst Immobilization and Recycling (Eds.: D. E. De
[10f]
58, 3971Ϫ3976.
Y. Nakamura, S. Takeuchi, S. Zhang, K.
[3]
Okumura, Y. Ohgo, Tetrahedron Lett. 2002, 43, 3053Ϫ3056.
Vos, I. F. J. Vankelecom, P. A. Jacobs), Wiley-VCH,
[10g]
After acceptance of this paper, a synthesis of fluorous
Weinheim, 2000.
chiral box was published: J. Bayardon, D. Sinou, Tetrahedron
Lett. 2003, 44, 1449Ϫ1451.
The use of a deficiency of 5 greatly simplified the chromato-
graphic purification of box 6, which showed a retention factor
very similar to that of the benzyl alcohol derived from 5
upon workup.
[4]
[4a] M. I. Burguete, J. M. Fraile, J. I. Garcia, E. Garcia-Verdugo,
C. I. Herrerias, S. V. Luis, J. A. Mayoral, J. Org. Chem. 2001,
[11]
[4b]
66, 8893Ϫ8901, and references therein.
D. Rechavi, M. Le-
maire, Org. Lett. 2001, 3, 2493Ϫ2496. [4c] K. Hallman, C. Mob-
erg, Tetrahedron: Asymmetry 2001, 12, 1475Ϫ1478.
Park, S.-W. Kim, T. Hyeon, B. M. Kim, Tetrahedron: Asym-
[4d]
J. K.
[12]
[13]
[4e]
S. Colonna, N. Gaggero, F. Montanari, G. Pozzi, S. Quici, Eur.
J. Org. Chem. 2001, 181Ϫ186.
metry 2001, 12, 2931Ϫ2935.
S. Orlandi, A. Mandoli, D.
Pini, P. Salvadori, Angew. Chem. Int. Ed. 2001, 40, 2519Ϫ2521;
[4f]
D. A. Evans, S. W. Tregay, C. S. Burgey, N. A. Paras, V. I.
Vojkovsky, J. Am. Chem. Soc. 2000, 122, 7936Ϫ7943.
Angew. Chem. 2001, 113, 2587Ϫ2589.
R. J. Clarke, I. J.
Shannon, Chem. Commun. 2001, 1936Ϫ1937. [4g] A. Corma, H.
Garcia, A. Moussaif, A. M. J. Sabater, R. Zniber, A. Redouane,
Chem. Commun. 2002, 1058Ϫ1059. For the immobilization of
box on polymer supports containing dendrimeric cross-linkers
see: [4h] M. I. Burguete, E. Diez-Barra, J. M. Fraile, J. I. Garcia,
E. Garcia-Verdugo, R. Gonzalez, C. I. Herrerias, S. V. Luis, J.
A. Mayoral, Bioorg. Med. Chem. Lett. 2002, 12, 1821Ϫ1824.
[14] [14a]
D. A. Evans, K. A. Woerpel, M. N. Hinman, M. M. Faul,
[14b]
J. Am. Chem. Soc. 1991, 113, 726Ϫ728. See also:
R. E.
Lowenthal, A. Abiko, S. Masamune, Tetrahedron Lett. 1990,
31, 6005Ϫ6009.
These results were obtained preparing the catalyst in the
CH2Cl2/perfluorooctanes mixture and then adding the re-
agents. When the catalyst was prepared in neat perfluoro-
octanes and the reagents were subsequently added in CH2Cl2
[15]
[4i]
D. Rechavi, M. Lemaire, J. Mol. Catal. A: Chem. 2002,
182Ϫ183, 239Ϫ247.
1196
Eur. J. Org. Chem. 2003, 1191Ϫ1197

Perfluoroalkyl-Substituted Bis(oxazolines) as Ligands for Catalytic Enantioselective Reactions
FULL PAPER
marginally different results were observed (60% yield,
trans/cis ϭ 70:30, 56% ee; see Entry 5, Table 1).
When the [Cu(OTf)2] complexes of ligands 6 and 9 were em-
ployed to catalyze the DielsϪAlder cycloaddition between
cyclopentadiene and N-acryloyloxazolidinone, the correspond-
ing cycloadducts were obtained in high yield, excellent endo
diastereoselectivity, and low ee.
Box featuring gem-dibenzyl substitution at the bridging carbon
atom are also known to promote cyclopropanation reactions
less stereoselectively than the corresponding gem-dimethyl-sub-
stituted ligands (see ref.[4a]).
For a discussion on the insulating effects of structurally differ-
ent spacers in perfluorinated ligands see: I. T. Horvath, G. Kiss,
R. A. Cook, J. E. Bond, P. A. Stevens, J. Rabai, E. J. Mozeleski,
J. Am. Chem. Soc. 1998, 120, 3133Ϫ31453.
The transition state of the enantioselective box/CuI-catalyzed
cyclopropanation reaction has been recently calculated: J. M.
Fraile, J. I. Garcia, V. Martinez-Merino, J. A. Mayoral, L. Sal-
vatella, J. Am. Chem. Soc. 2001, 123, 7616Ϫ7625, showing that
the catalytic complex adopts a trigonal geometry.
For examples of the influence of even small changes of the
box ‘‘bite angle’’ on the enantioselectivity of chiral box/CuII-
promoted reactions see: I. W. Davies, R. J. Deeth, R. D. Larsen,
P. J. Reider, Tetrahedron Lett. 1999, 40, 1233Ϫ1236.
For a similar observation of diazoacetate-derived decompo-
sition products contaminating polymer-supported box ligands
see ref.[4h]
Preliminary results showed that ligand 9 could also be reco-
vered by filtration through a short (ca. 3 cm) plug of fluorous
reverse-phase silica gel prepared according to: S. Kainz, Z. Y.
Luo, D. P. Curran, W. Leitner, Synthesis 1998, 1425Ϫ1527.
While the recovery yield was very high (90%), a fraction of
ligand 9 was contaminated by traces of product 10. Improve-
ment of the recovery procedure is currently under investigation.
Received October 31, 2002
[16]
[21]
[17]
[18]
[19]
[22]
[23]
For a recent discussion on the influence of the substitution
pattern at the box-bridging carbon atom on the steric course
of box-mediated asymmetric syntheses see: S. E. Denmark, C.
M. Stiff, J. Org. Chem. 2000, 65, 5875Ϫ5878, and references
therein.
[20]
J. S. Johnson, D. A. Evans, Acc. Chem. Res. 2000, 33, 325Ϫ335.
[O02604]
Eur. J. Org. Chem. 2003, 1191Ϫ1197
1197