Synthesis of new enantiopure fluorinated phenylcyclopropanecarboxylates - Potential chiral dopants for liquid-crystal compositions

Article abstract of DOI:10.1002/ejoc.200600579

The reaction of α-fluorostyrene (1a) with methyl phenyldiazoacetate in the presence of Rh₂(OAc)₄ gave a 64:36 mixture of diastereomeric monofluorinated cyclopropanes 5a and 6a. When using chiral Rh^II catalysts Rh₂

Full text of DOI:10.1002/ejoc.200600579

FULL PAPER
DOI: 10.1002/ejoc.200600579
Synthesis of New Enantiopure Fluorinated Phenylcyclopropanecarboxylates –
Potential Chiral Dopants for Liquid-Crystal Compositions
Svenja Hruschka,[a,b] Roland Fröhlich,[a] Peer Kirsch,[a] and Günter Haufe*[b]
Keywords: Asymmetric catalysis / Fluorine / Liquid crystals / Chirality / Cyclopropanes
The reaction of α-fluorostyrene (1a) with methyl phenyl-
diazoacetate in the presence of Rh2(OAc)4 gave a 64:36 mix-
ture of diastereomeric monofluorinated cyclopropanes 5a
and 6a. When using chiral RhII catalysts Rh2(TBSP)4 (7) and
vely in up to Ͼ99% ee for both (1R,2R)-5a and (1R,2S)-6a.
The fluorocyclopropane derivatives are of interest as dopants
to induce chirality in liquid-crystal mixtures.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Rh2(DOSP)4 (8), the products were obtained enantioselecti- Germany, 2007)
butyl diazoacetate and copper complexes of chiral bis(ox-
Introduction
azoline)s such as A (Figure 1) to give the corresponding cy-
clopropanecarboxylic esters 2 and 3 with good diastereo-
selectivity and high enantioselectivity (see Scheme 1).[20]
For a long time compounds containing a cyclopropane
ring have been of great interest. The unique bonding situa-
tion of the smallest carbocycle results in a specific geometry
of substituents and in a unique reactivity, which makes it a
valuable intermediate and starting material in organic
chemistry.[1–3] Cyclopropane derivatives are also known for
their strong biological activity, which is often related to the
high ring strain.[4]
Numerous publications dealing with the synthesis of the
cyclopropane moiety concentrate on convenient and enan-
tioselective access to this useful building block.[5] One of
the most widely applicable methods is the decomposition of
diazo compounds in the presence of olefins, catalyzed by
chiral transition-metal complexes.[6–9] Since Noyori et al.[10]
and Pfaltz et al.[11] introduced the first asymmetric reac-
tions of this type, much effort has been made to optimize
this pathway.[12–14]
Figure 1. Enantiopure ligand A.
However, only a few attempts have yet been made to syn-
thesize monofluorinated cyclopropanes[15,16] which promise
an even greater potential for interesting biological activities
since they combine the advantages of two known chemical
leads, namely the strained ring and the fluorine substituent.
In addition to potential biomedical applications, fluoro-
cyclopropane derivatives are also of interest as chiral dop-
ants for liquid-crystal compositions in liquid-crystal dis-
plays (LCDs).[17–19] Some time ago, we reported an enantio-
selective cyclopropanation of α-fluorostyrene (1a) with tert-
Scheme 1. Enantioselective cyclopropanation of α-fluorostyrene
(1a).[20]
These compounds have been converted into fluoro ana-
logues of the antidepressant tranylcypromine.[21–25] They
proved to be potent monoamine oxidase inhibitors, exhibit-
ing significant selectivity as tyramine oxidase inhibitors
compared to their potential to act as MAO A or MAO B
inhibitors.
Besides these known reactions of monosubstituted diazo-
acetates with α-fluorostyrene (1a), products derived from
disubstituted diazo compounds such as methyl phenyl-
diazoacetate may be attractive intermediates for the synthe-
sis of complex molecules, as well. Here we present our re-
cent results on the synthesis of polyfunctionalized cyclo-
propanes and their application as potent new enantiopure
dopants for liquid-crystal compositions.
[a] Organisch-Chemisches Institut, Westfälische Wilhelm-Uni-
versität Münster,
Corrensstrasse 40, 48149 Münster, Germany
[b] NRW Graduate School of Chemistry, University of Münster,
Corrensstrasse 36, 48149 Münster, Germany
[c] Merck Ltd. Japan, Atsugi Technical Center,
4084 Nakatsu, Aikawa-machi, Aiko-gun, 243-0303 Kanagawa,
Japan
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 141–148
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S. Hruschka, R. Fröhlich, P. Kirsch, G. Haufe
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The lower cis selectivity in the case of α-fluorostyrene
(1a) compared to that of the reaction with styrene (1b) pro-
vided both diastereomers as starting materials for further
reactions after chromatographic separation. These promis-
ing results encouraged us to extend our studies of polyfunc-
tionalized cyclopropanes towards enantioselective methods.
Optically active RhII carboxylate catalysts have ef-
ficiently been applied in the asymmetric cyclopropanation
with aryldiazoacetates and a broad range of alkenes.
Among them, N-(arylsulfonyl)prolinates proved to be the
most selective ones for carbene transfers from phenyldia-
zoacetates to styrene (1b).[5]
We applied the known catalysts Rh2(DOSP)4 (7) and
Rh2(TBSP)4 (8) (see Figure 3),[32] which can be prepared by
high-temperature ligand exchange from Rh2(OAc)4 and the
corresponding (arylsulfonyl)prolinate in refluxing chloro-
benzene with a modified Soxhlet apparatus (see Supporting
Information) equipped with an Na2CO3-filled thimble for
binding the excess acetic acid.
Results and Discussion
Our first attempts at the cyclopropanation of α-fluoro-
styrene (1a) with methyl phenyldiazoacetate (4) dealt with
the synthesis of racemic products (Scheme 2). We carried
out the reaction with Rh2(OAc)4 as a catalyst and observed
the diastereomeric products in 92% yield with a cis/trans
ratio of 64:36.
Comparison of our results with those of Zwanenburg et
al.,[26] obtained with styrene (1b), showed that in terms of
reactivity and yields the fluorinated and non-fluorinated
substrates were similar, but they were different in diastereo-
selectivity (Scheme 2). The reaction of 1a led to a low selec-
tivity towards 5a, whereas 5b was present at a rate of 88%.
When performing the reaction at ambient temperature,
Davies et al. observed that 5b was formed almost exclu-
sively, but in lower yields.[27]
The high diastereoselectivity of the carbene transfer to
non-fluorinated olefins was explained by Doyle et al.[28]
Our results show that their hypothesis is not fully valid for
reactions of vinyl fluorides such as 1a. Additional factors
seem to be relevant in the mechanism. The discrepancy in
steric demand cannot be the only explanation for the dif-
ferent stereoselectivity, as fluorine and hydrogen are of sim-
ilar size (van der Waals radii of 1.20 Å vs. 1.47 Å, respec-
tively).[29] Another reason may be the ability of fluorine to
stabilize a developing electron-deficient centre in the α-posi-
tion,[30,31] which is the case for both the cis and trans transi-
tion states (Tcis, Ttrans; see Figure 2). However, in Tcis, the
interaction of the lone pair of the carbonyl oxygen atom
and the fluorinated electrophilic centre is weaker than it is
in the non-fluorinated case. Consequently, the energy differ-
Figure 3. Optically active RhII (arylsulfonyl)prolinate catalysts 7
and 8.[32]
The synthesized catalysts (0.01 equiv.) were used for the
ences of the transition states Tcis and Ttrans leading to 5a reaction of α-fluorostyrene (1a, 5.0 equiv.) with methyl
and 6a, respectively, are smaller than those leading to 5b phenyldiazoacetate (1.0 equiv.) at ambient temperature or
and 6b, resulting in lower diastereoselectivity.
–78 °C (see Table 1).
Scheme 2. Cyclopropanation of α-fluorostyrene (1a) and styrene (1b). Reagents and conditions: 1.0 equiv. of 1a, 1.55 equiv. of 4 (added
within 5–6 h), 2 mol-% of Rh2(OAc)4, refluxing CH2Cl2.
Figure 2. Transition states for the cyclopropanation of α-fluorostyrene (1a).
142
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New Enantiopure Fluorinated Phenylcyclopropanecarboxylates
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At room temperature, both catalysts showed similar dia- NOEs for HA and the phenyl ring ortho protons. Only the
stereoselectivities of about 75:25 in favour of the cis isomer spectrum of 5a showed a strong enhancement for the ester
5a. The enantioselectivities were similar as well, giving 83– signal, which leads to the conclusion that the ester group is
88% ee for 5a and about 80% ee for 6a. Compound 7 was in the vicinity of the fluorine atom.
less reactive than 8. With Rh2(TBSP)4 (7) as a catalyst, the
products were formed in a combined yield of 63%, while
application of Rh2(DOSP)4 (8) furnished the products in
79% at ambient temperature. We observed an increase in
yields to 81% with 7 and 91% with 8 at –78 °C due to
longer reaction times. The diastereoselectivities did not dif-
fer from those observed at room temperature, but the
enantioselectivities did. The effect of temperature and sol-
1
Figure 5. H-19F heteronuclear NOE analysis of 5a and 6a.
vent on cyclopropanations with 7 and 8 has been discussed
copiously in the literature.[32] These studies showed that the
less polar the solvent and the lower the temperatures were,
The absolute configurations we observed agree with the
the higher was the ee. Our results agree with these conclu- literature results for non-fluorinated compounds[33] con-
sions (see Table 1). Reduction of the temperature to –78 °C sidering that fluorine changes the priorities of substituents
and application of Rh2(DOSP)4 (8) as the catalyst caused a when introduced. Consequently, the mechanism proposed
significant increase in enantioselectivity to Ͼ99% ee for by Davies et al.[32] and other groups[34] is true for the fluori-
both diastereomers. This catalyst is commonly mentioned nated compounds, too. However, we found higher enantio-
to be the more selective one.[32,33]
selectivities at lower temperatures.
The absolute stereochemistry in all cases was (1R,2R) for
The D2-symmetric catalyst Rh2(DOSP)4 forms a (car-
5a and (1R,2S) for 6a, confirmed by X-ray data of the esters bene)metal complex with methyl phenyldiazoacetate, in
with abnormal dispersion. The crystal structures can be which the phenyl ring is blocked from the backside by one
seen in Figure 4.
of the chiral ligands. The ester group points back and is
The X-ray data confirmed the 1H-19F heteronuclear blocked itself by another ligand from the front. When α-
NOE experiments (see Figure 5), which were performed to fluorostyrene approaches the carbene complex, it can only
identify the diastereomers. Both compounds exhibited attack from the front. For a long time it was presumed that
Table 1. Effect of temperature and catalyst on asymmetric induction.
Catalyst
T
Time
Solvent
Yield [%][a]
5a/6a
% ee (absolute configuration)[b]
5a
6a
Rh2(TBSP)4 (7)
Rh2(TBSP)4 (7)
Rh2(DOSP)4 (8)
Rh2(DOSP)4 (8)
room temp.
–78 °C
room temp.
–78 °C
5 h
5 d
5 h
5 d
pentane
63
81
79
91
75:25
79:21
74:26
75:25
83 (1R,2R)
84 (1R,2R)
88 (1R,2R)
Ͼ99 (1R,2R)
78 (1R,2S)
84 (1R,2S)
80 (1R,2S)
Ͼ99 (1R,2S)
[c]
CH2Cl2
pentane
pentane
[a] 5.0 equiv. of 1a, 1.0 equiv. of 4 (added within 30 min) and 1 mol-% of Rh2(OAc)4. [b] The enantiomeric excess (ee) was determined
by 19F NMR spectroscopy within an error of Ϯ1% after hydrolysis and subsequent esterification with (–)-menthol. Additionally, the ee
of 5a was determined by chiral GC with a Hydrodex®-β-PM column to confirm the 19F NMR results. [c] Because of the poor solubility
of 5 in pentane at –78 °C, dichloromethane was used as the solvent.
Figure 4. Crystal structures of (1R,2R)-5a and (1R,2S)-6a.
Eur. J. Org. Chem. 2007, 141–148
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S. Hruschka, R. Fröhlich, P. Kirsch, G. Haufe
FULL PAPER
the alkene attacks in a side-on approach, preferentially over
Chiral dopants are used to induce a cholesteric phase
the ester group. Further studies showed that the alkene at- in otherwise achiral, nematic, liquid-crystal mixtures. The
tacks in an end-on manner instead.[35] A bond is then ability to induce a chiral pitch depends on the concentra-
formed between the β-carbon atom and the carbene carbon tion of the dopant and on its so-called helical twisting
atom. Depending on the orientation of the phenyl ring of power (HTP). For common technical applications such as
α-fluorostyrene towards the catalyst, the cis or trans transi- displays based on the twisted nematic (TN) mode, a rela-
tion state is formed. While the reaction proceeds, the rho- tively small HTP (e.g. around 10–15 µm–1) and a low dop-
dium bond becomes weaker, and the cyclopropane ring is ant concentration (around 0.1%) are sufficient.[17,18]
built, leading to the products with the observed absolute higher HTP or increased concentrations are required for
configurations (Figure 6).
super-twisted nematic (STN) LCDs.[36,37] Also, LCDs based
A
The known reaction with non-fluorinated styrene was on ferroelectric liquid crystals in the smectic C* phase make
carried out at room temperature, giving similar enantio- use of chiral additives.[38] Some newer LCD modes such as
selectivities for 5b (91% ee)[27,33] as for 5a, but a diastereo- the surface-stabilized cholesteric texture (SSCT) mode,[39,40]
selectivity of 97:3. Consequently, fluorine does not signifi- use nematic liquid crystals with an extremely short pitch in
cantly influence the enantioselectivity but changes the dia- order to generate colour by the wavelength-selective reflec-
stereoselectivity of the cyclopropanation reaction.
tion of visible light. Another important application of chiral
Having the diastereomeric methyl 2-fluorocyclopro- dopants with very high HTP is cholesteric films (prepared
panecarboxylates (1R,2R)-5a and (1R,2S)-6a in hand, the by the polymerization of reactive mesogens including a chi-
corresponding acids were prepared by hydrolysis, which ral dopant) for improving, for example, the brightness of
subsequently were transformed into esters substituted with LCD panels or acting as polarizing reflectors.[41] For such
typical alcohol components[17] known to exhibit positive ef- applications, new dopants with very high HTP are in con-
fects on the properties of dopants for liquid-crystal compo- stant demand. Remarkably, although the first cholesteric
sitions in LCDs (Scheme 3).
liquid crystal was already reported in 1888,[42,43] the struc-
Figure 6. Mechanism of the enantioselective cyclopropanation of α-fluorostyrene (1a).
Scheme 3. Hydrolysis of diastereomeric methyl diphenylcyclopropanecarboxylates and esterification of the (1R,2R)-acid with a p-cyclohex-
ylphenol.
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New Enantiopure Fluorinated Phenylcyclopropanecarboxylates
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ringe pump. When Rh2(OAc)4·2H2O was used, the addition took
place at reflux within 5–6 h, followed by another 12 h of refluxing.
When chiral RhII catalysts were used, the diazo compound was
added within 30 min at room temperature or –78 °C, and the mix-
ture was stirred for 5 h or 5 d, respectively, at the same temperature.
Subsequently, the reaction mixture was diluted with dichlorometh-
ane and treated with a saturated sodium carbonate solution and
water. The organic layer was dried with magnesium sulfate before
removing the solvent under reduced pressure. The reactions carried
out at –78 °C were quenched at that temperature with silica gel
ture-property relationships of chiral dopants are still not
well understood. In general, molecules with a more liquid-
crystal-like shape seem to be more effective in inducing chi-
rality in a nematic host. Another rather general observation
concerns the location of the chiral substructure within the
dopant molecule; the more “central” the location, the
higher is the HTP of the resulting chiral compound. Thus,
we were interested to test the quality of enantiomerically
pure, fluorinated diphenylcyclopropanecarboxylates as a
new structural class of potential chiral dopants for liquid- before concentrating the mixture in vacuo. The crude product was
then purified by column chromatography on silica gel with pentane/
diethyl ether (20:1) as the eluent to give the diastereomeric product
as a white solid. The amounts of α-fluorostyrene, catalyst, diazo
compound and solvent are presented in that order in abbreviated
form. Diastereomeric ratios were determined by gas chromatog-
raphy (GC). After hydrolysis of 5a or 6a and esterification with
(–)-menthol, 19F NMR spectroscopy at 282 MHz was used to de-
termine the ee within an error of Ϯ1%, calculated with racemic 5a
and 6a. Additionally, the ee of 5a was determined by chiral GC
using a Hydrodex®-β-PM column from Macherey–Nagel, giving
crystal compositions.
The HTP (determined from a 1% w/w solution of the
chiral component in the Merck liquid-crystal mixture
MLC-6260) of the methyl esters (1R,2R)-5a (–8.7 µm–1) and
(1R,2S)-6a (–7.5 µm–1) was found to be relatively small.
However, the introduction of a more liquid-crystal-like phe-
nol moiety into the ester afforded a significantly higher
HTP of +24.0 µm–1 for (1R,2R)-13a. Although this value is
higher than that of many commercially used chiral dop-
ants,[18] there are several compounds known with an even the same results as obtained by 19F NMR spectroscopy.
higher HTP.[44–46] Nevertheless, esters of chiral diphenylcy-
General Procedure for the Determination of Enantiomeric Excesses:
A diastereomeric mixture of 5a and 6a (50 mg, 0.18 mmol) and
KOH (99 mg, 1.8 mmol, 10 equiv.) were dissolved in THF/H2O
clopropanecarboxylic acids show some promise as a versa-
tile structural scaffold. So far, only modification of the ester
group has been investigated to a very limited extent. The (1:1, 3 mL) and heated for 24 h. The reaction mixture was then
cooled to room temperature and subsequently acidified with HCl
(pH = 1). The aqueous phase was extracted with dichloromethane,
and the combined organic layers were dried before removing the
solvent under reduced pressure. The crude product, dicyclohex-
ylcarbodiimide (DCC, 0.05 g, 0.22 mmol), (–)-menthol (0.09 g,
0.6 mmol) and some grains of DMAP were dissolved in absolute
dichloromethane (2 mL) and stirred at room temperature over-
night. The precipitate was filtered and washed with dichlorometh-
ane before removing the solvent in vacuo. The resulting product
was analyzed by 19F NMR spectroscopy.
systematic exploration of the two phenyl moieties with com-
binatorial methodology may disclose even more efficient
chiral dopants.
Experimental Section
General Remarks: Methyl phenyldiazoacetate, α-fluorostyrene (1a)
and tetrakis[N-(phenylsulfonyl)-(S)-prolinato]dirhodium(II) cata-
lysts Rh2(TBSP)4 (7) and Rh2(DOSP)4 (8) were prepared according
to refs.[47–49] All other starting materials and reagents were ob-
tained from ABCR, Acros, Fluka or Sigma–Aldrich. Dichloro-
methane was dried with and distilled from P2O5, whereas toluene
was dried with and distilled from sodium with benzophenone as an
indicator. Both solvents were stored over molecular sieves (0.4 nm).
Mass spectra were measured with a Waters-Micromass GCT in-
strument operating at 70 eV or with a Waters-Micromass Quattro
LC-Z instrument. NMR spectra were recorded with a Varian 600
Unity Plus (600.0 MHz for 1H, 150.66 MHz for 13C and
564.3 MHz for 19F), Varian INOVA 500 (499.84 MHz for 1H,
125.70 MHz for 13C and 470.28 MHz for 19F), Bruker ARX300
(؎)-Methyl 2α-Fluoro-1β,2β-diphenylcyclopropanecarboxylate [(؎)-
5a] and (؎)-Methyl 2α-Fluoro-1α,2β-diphenylcyclopropanecarboxyl-
ate [(؎)-6a]: α-Fluorostyrene (1a, 610 mg, 5 mmol) was treated
with Rh2(OAc)4·2H2O (68 mg, 0.155 mmol) and methyl phenyldia-
zoacetate (4, 1.365 g, 7.75 mmol) in dichloromethane (20 mL). Pu-
rification of the crude diastereomeric product gave 1.232 g (92%
yield) of a mixture of (Ϯ)-5a and (Ϯ)-6a (64:36). The diastereomers
were separated by MPLC with pentane/diethyl ether (20:1) and
each isomer was recrystallised from pentane, giving 682 mg (50%
yield) of (Ϯ)-5a as colourless, tetragonal columns and 328 mg (24%
yield) of (Ϯ)-6a as colourless, hexagonal plates, respectively. (Ϯ)-
1
(300.13 MHz for H, 75.48 MHz for 13C and 282.37 MHz for 19F)
1
5a: M.p. 93 °C (pentane). H NMR (600 MHz, CDCl3): δ = 2.10
1
and Bruker AC250 (250.1 MHz for H and 235.3 MHz for 19F) in
(dd, J = 7.8 and 11.7 Hz, 1 H), 2.77 (dd, J = 7.7 and 21.9 Hz), 3.73
(s, 3 H), 6.97–7.15 (m, 10 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 21.3 (dt, J = 21.3 Hz), 42.6 (ds, J = 13.8 Hz), 52.8 (q), 83.7 (ds,
J = 224.3 Hz), 125.6 (dd, J = 7.2 Hz), 127.4 (d), 127.7 (dd, J =
0.9 Hz), 127.8 (d), 128.0 (dd, J = 1.4 Hz), 130.9 (dd, J = 2.2 Hz),
134.0 (ds, J = 3.7 Hz), 134.2 (s), 168.6 (ds, J = 3.7 Hz) ppm. 19F
NMR (282 MHz, CDCl3): δ = –176.95 (dd, J = 12.1 and 24.3 Hz,
1 F) ppm. MS (EI): m/z (%) = 270 [M]+ (25), 251 (4), 250 (38), 235
(35), 218 (14), 209 (23), 191 (47), 189 (41), 178 (28), 165 (22), 140
(10), 139 (100), 133 (55), 115 (13), 109 (33), 105 (71), 89 (24), 77
(57), 63 (37), 51 (45). C17H15FO2 (270.30): calcd. C 75.54, H 5.59;
CDCl3 solution with TMS or CFCl3 as internal standards, respec-
tively. Thin layer chromatography was performed with 60 F254 TLC
plates (Merck). Column chromatography was performed with silica
gel (Merck, particle size 0.063–0.200 mm, 70–230 mesh), and pre-
parative MPLC was carried out on silica gel (Merck, particle size
0.040–0.063 mm, 230–400 mesh) with a solvent flow rate of 50 mL/
min.
General Procedure for RhII-Catalyzed Decompositions of Methyl
Phenyldiazoacetate in the Presence of α-Fluorostyrene: α-Fluorosty-
rene (1a, 1–5 equiv.) and RhII catalyst [Rh2(OAc)4·2H2O,
Rh2(TBSP)4 (7) or Rh2(DOSP)4 (8), 0.01–0.02 equiv., relative to found C 75.49; H 5.34. (Ϯ)-6a: M.p. 68 °C (pentane). 1H NMR
the diazo compound] were dissolved in absolute dichloromethane
or pentane under argon at room temperature or –78 °C. A solution
of methyl phenyldiazoacetate (1–1.55 equiv.) was added with a sy-
(500 MHz, CDCl3): δ = 2.01 (dd, J = 7.3 and 20.1 Hz, 1 H), 2.62
(dd, J = 7.3 and 12.9 Hz, 1 H), 3.27 (s, 3 H), 7.31–7.56 (m, 10 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 21.4 (dt, J = 9.4 Hz), 41.7
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S. Hruschka, R. Fröhlich, P. Kirsch, G. Haufe
(1R,2S)-2α-Fluoro-1α,2β-diphenylcyclopropanecarboxylic Acid
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(ds, J = 14.2 Hz), 52.4 (q), 84.0 (ds, J = 227.4 Hz), 127.9 (d), 128.2
(d), 128.2 (dd, J = 0.6 Hz), 128.3 (dd, J = 1.1 Hz), 129.2 (dd, J =
2.6 Hz), 131.3 (d), 133.8 (ds, J = 21.1 Hz), 134.3 (ds, J = 3.2 Hz),
169.4 (ds, J = 1.9 Hz) ppm. 19F NMR (282 MHz, CDCl3): δ =
–156.87 (dd, J = 12.7 and 20.8 Hz, 1 F) ppm. MS (EI): m/z (%) =
270 [M]+ (66), 251 (5), 250 (75), 235 (35), 219 (11), 218 (30), 210
(43), 209 (49), 191 (73), 189 (48), 178 (38), 165 (36), 163 (14), 139
(100), 133 (80), 115 (23), 109 (90), 105 (63), 89 (39), 77 (67), 63
(52), 51 (66). C17H15FO2 (270.30): calcd. C 75.54, H 5.59; found C
75.41, H 5.39.
[(1R,2S)-10a]: Compound (1R,2S)-6a (0.100 g, 0.37 mmol) gave
88 mg (92% yield) of (1R,2S)-10a as colourless needles. M.p.
131 °C (cyclohexane/ethyl acetate). [α]2D0 = +249.6 (c = 1.0, CHCl3,
Ͼ99% ee). 1H NMR (400 MHz, CDCl3): δ = 2.03 (dd, J = 7.3 and
19.8 Hz, 1 H), 2.53 (dd, J = 7.2 and 13.4 Hz, 1 H), 7.30–7.52 (m,
10 H) ppm. 13C NMR (75 MHz CDCl3): δ = 22.0 (dt, J = 8.3 Hz),
41.0 (ds, J = 13.4 Hz), 84.6 (ds, J = 228.3 Hz), 128.0 (d), 128.2 (d),
128.3 (d), 128.4 (d), 129.3 (dd, J = 2.8 Hz), 131.2 (d), 133.1 (ds, J
= 19.4 Hz), 134.8 (ds, J = 2.7 Hz), 174.5 (s) ppm. 19F NMR
(282 MHz, CDCl3): δ = –153.79 (dd, J = 13.6 and 21.6 Hz, 1 F)
ppm. MS (ESI/daughter ion experiment): m/z (%) = 257 (22) [M +
H]+, 237 (4), 219 (100), 191 (5), 105 (4). MS (EI, as trimethylsilyl
ester): m/z (%) = 328 (11) [M]+, 313 (1), 308 (13), 239 (4), 238 (51),
236 (1), 218 (2), 210 (20), 209 (23), 192 (9), 191 (38), 189 (17), 179
(2), 178 (2), 165 (3), 163 (1), 133 (7), 131 (4), 115 (1), 109 (7), 105
(76), 103 (23), 102 (1), 89 (5), 77 (31), 75 (14), 73 (100), 63 (4), 63
(9), 47 (4), 45 (17). C16H13FO2 (256.28): calcd. C 74.99, H, 5.11;
found C 74.37, H 4.94.
(1R,2R)-Methyl 2α-Fluoro-1β,2β-diphenylcyclopropanecarboxylate
[(1R,2R)-5a] and (1R,2S)-Methyl 2α-Fluoro-1α,2β-diphenylcyclopro-
panecarboxylate [(1R,2S)-6a]. Method A [with Rh2(TBSP)4 (7)]: α-
Fluorostyrene (1a, 610 mg, 5 mmol) was treated with Rh2(TBSP)4
(7, 14 mg, 0.01 mmol) and methyl phenyldiazoacetate (4, 176 mg,
1 mmol) in dichloromethane (–78 °C) or pentane (room temp.,
4 mL). The reaction at room temp. furnished 170 mg (63% yield)
of diastereomeric (1R,2R)-5a and (1R,2S)-6a [75:25, 83% ee
(1R,2R)-5a and 78% ee (1R,2S)-6a], while the reaction at –78 °C
yielded 220 mg (81% yield) of (1R,2R)-5a and (1R,2S)-6a [79:21,
84% ee (1R,2R)-5a and 84% ee (1R,2S)-6a]. Method B [with
Rh2(DOSP)4 (8)]: α-Fluorostyrene (1a, 610 mg, 5 mmol) was
treated with Rh2(DOSP)4 (8, 19 mg, 0.01 mmol) and methyl phen-
yldiazoacetate (4, 176 mg, 1 mmol) in pentane (4 mL). The reaction
at room temp. furnished 214 mg (79% yield) of diastereomeric
General Procedure for Esterification with (–)-Menthol: Compound
(1R,2R)-9a or (1R,2S)-10a (1 mmol), N,N-dicyclohexylcarbodi-
imide (DCC, 1.25 mmol, 1.25 equiv.), (–)-menthol (1.1 mmol,
1.1 equiv.) and a catalytic amount of 4-(N,N-dimethylamino)pyri-
dine (DMAP) were dissolved in absolute dichloromethane (6 mL).
The reaction mixture was stirred at room temp. overnight before
(1R,2R)-5a and (1R,2S)-6a [74:26, 88% ee (1R,2R)-5a and 80% ee the precipitate formed was filtered and washed with dichlorometh-
(1R,2S)-6a], while the reaction at –78 °C yielded 246 mg (91%
yield) of (1R,2R)-5a and (1R,2S)-6a [75:25, Ͼ99% ee (1R,2R)-5a
and Ͼ99% ee (1R,2S)-6a]. (1R,2R)-5a: [α]2D0 = +62.7 (c = 1.0,
CHCl3), Ͼ99% ee. (1R,2S)-6a: [α]2D0 = +287.5 (c = 1.0, CHCl3),
Ͼ99% ee.
ane (2 mL). The filtrate was concentrated in vacuo. After determi-
nation of the ratio of diastereomers by 19F NMR spectroscopy, the
crude product was purified by column chromatography.
(–)-Menthyl (1R,2R)-2-Fluoro-1,2-diphenylcyclopropanecarboxylate
[(1R,2R)-11a]: Compound (1R,2R)-9a (182 mg, 80% ee,
0.71 mmol) gave 146 mg (80% de, 52% yield) of (1R,2R)-11a as a
colourless oily liquid after column chromatography with pentane/
General Procedure for Hydrolysis: KOH (1.12 g, 20 mmol,
10 equiv.) was added to a solution of methyl 2-fluoro-1,2-diphenyl-
cyclopropanecarboxylate 5a or 6a (0.541 g, 2 mmol) in THF/H2O
(1:1, 60 mL). The resulting mixture was heated to reflux for 24 h.
Subsequently, it was poured into iced water (60 mL), and the
phases were separated. The aqueous layer was extracted with
dichloromethane (2ϫ25 mL) and then acidified with HCl (pH =
1) and extracted with ethyl acetate (3ϫ30 mL). The combined ethyl
acetate layers were dried with sodium sulfate and concentrated in
vacuo. Crystallization from cyclohexane/ethyl acetate (10:1) fur-
nished the corresponding acids.
1
dichloromethane (5:1) as the eluent. H NMR (500 MHz, CDCl3):
δ = 0.76–0.91 (m, 2 H), 0.82 (d, J = 6.9 Hz, 3 H), 0.84 (d, J =
6.5 Hz, 3 H), 0.95 (d, J = 7.0 Hz, 3 H), 1.02–1.11 (m, 1 H), 1.37–
1.50 (m, 2 H), 1.63–1.69 (m, 2 H), 1.88–1.92 (m, 1 H), 2.02 (m, 1
H), 2.06 (dd, J = 7.6 and 11.4 Hz, 1 H), 2.72 (dd, J = 7.8 and
21.7 Hz, 1 H), 4.74 (ddd, J = 4.4, 11.0 and 11.0 Hz, 1 H), 6.96–
7.18 (m, 10 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.6 (q),
20.7 (q), 21.0 (dt, J = 10.5 Hz), 21.9 (q), 23.7 (t), 26.6 (d), 31.3 (d),
34.2 (t), 40.3 (t), 43.2 (ds, J = 14.2 Hz), 46.9 (d), 76.0 (d), 83.5 (ds,
J = 224.2 Hz), 125.5 (dd, J = 6.5 Hz), 127.3 (d), 127.7 (d), 127.8
(d), 128.0 (d), 130.8 (d), 134.3 (s), 134.6 (s), 180.5 (s) ppm. 19F
NMR (282 MHz, CDCl3): δ = –176.55 (dd, J = 22.1 and 11.5 Hz,
1 F) ppm. MS (EI): m/z (%) = 394 (0) [M]+, 374 (2), 372 (15), 341
(1), 313 (1), 255 (1), 231 (1), 199 (1), 189 (4), 163 (27), 162 (100),
150 (21), 131 (29), 129 (22), 115 (16), 103 (34), 91 (17), 77 (6), 69
(7), 57 (11), 55 (14), 43 (16).
(1R,2R)-2α-Fluoro-1β,2β-diphenylcyclopropanecarboxylic
Acid
[(1R,2R)-9a]: Compound (1R,2R)-5a (0.541 g, 2 mmol) gave
515 mg (Ͼ99% yield) of (1R,2R)-9a as colourless needles. M.p.
189 °C (cyclohexane/ethyl acetate). [α]2D0 = +71.3 (c = 1.0, CHCl3,
Ͼ99% ee). 1H NMR (400 MHz, CDCl3): δ = 2.15 (dd, J = 7.9 and
11.8 Hz, 1 H), 2.79 (dd, J = 7.7 and 21.8 Hz, 1 H), 6.97–7.16 (m,
10 H), 10.81 (br. s) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.6
(dt, J = 9.6 Hz), 42.3 (ds, J = 12.4 Hz), 84.4 (ds, J = 227.0 Hz),
125.7 (dd, J = 9.0 Hz), 127.7 (d), 127.8 (d), 128.2 (d), 131.0 (d),
133.6 (s), 133.9 (ds, J = 22.2 Hz), 174.4 (ds, J = 4.3 Hz) ppm. 19F
NMR (282 MHz, CDCl3): δ = –176.95 (dd, J = 10.0 and 19.6 Hz,
1 F) ppm. MS (ESI/daughter ion experiment): m/z (%) = 257 (12)
[M + H]+, 219 (100), 191 (15), 105 (8). MS (EI, as trimethylsilyl
ester): m/z (%) = 328 (14) [M]+, 313 (3), 308 (39), 239 (4), 238 (60),
236 (9), 235 (1), 218 (3), 210 (27), 209 (36), 197 (2), 192 (9), 191
(–)-Menthyl trans-(1R,2S)-2-Fluoro-1,2-diphenylcyclopropanecar-
boxylate [(1R,2S)-12a]: Compound (1R,2S)-10a (0.039 g, 94% ee,
0.15 mmol) gave 29 mg (94% de, 49% yield) of (1R,2S)-12a as a
white solid after column chromatography with pentane/diethyl
ether (80:1) as the eluent. M.p. 95 °C (pentane/diethyl ether). 1H
NMR (500 MHz, CDCl3): δ = 0.24 (dd, J = 12.2 and 23.2 Hz, 1
3
H), 0.43 (d, J = 6.9 Hz, 3 H), 0.70 (d, J = 6.5 Hz, 3 H), 0.76 (d, J
= 7.0 Hz, 3 H), 0.67 (m, 1 H), 0.85 (m, 1 H), 1.08 (m, 1 H), 1.21
(38), 189 (32), 179 (15), 178 (13), 165 (8), 163 (2), 152 (2), 133 (13), (m, 1 H), 1.34–1.39 (m, 1 H), 1.45 (m, 1 H), 1.51 (m, 2 H), 2.02
131 (9), 115 (2), 109 (15), 105 (72), 103 (37), 102 (2), 89 (11), 77 (dd, J = 7.3 and 20.3 Hz, 1 H), 2.64 (dd, J = 7.3 and 13.3 Hz, 1
(58), 75 (36), 73 (100), 65 (1), 63 (9), 62 (1), 47 (9), 45 (27). H), 4.29 (ddd, J = 4.4, 10.9 and 10.9 Hz, 1 H), 7.32–7.57 (m, 10
C16H13FO2 (256.28): calcd. C 74.99, H, 5.11; found C 74.50, H
5.03.
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 16.0 (q), 20.7 (q), 20.9
(dt, J = 9.3 Hz), 21.8 (q), 23.0 (t), 25.8 (d), 31.0 (d), 33.9 (t), 39.6
146
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 141–148

New Enantiopure Fluorinated Phenylcyclopropanecarboxylates
FULL PAPER
(t), 42.0 (ds, J = 14.2 Hz), 46.4 (d), 75.3 (d), 84.0 (ds, J = 226.9 Hz),
parameter –0.5(3), max. residual electron density 0.15 (–0.14) e·Å–3
127.7 (d), 128.1 (d), 128.2 (d), 128.3 (d), 129.1 (ds, J = 2.7 Hz), and hydrogen atoms calculated and refined as riding atoms.
131.3 (d), 134.0 (ds, J = 21.3 Hz), 134.8 (ds, J = 3.3 Hz), 168.3 (s)
Data sets were collected with a Nonius KappaCCD diffractometer.
ppm. 19F NMR (282 MHz, CDCl3): δ = –156.63 (dd, J = 19.8 and
Programs used: data collection: COLLECT (Nonius B.V., 1998);
13.4 Hz, 1 F) ppm. MS (GCToF/EI): m/z (%) = 394 (0) [M]+, 256
data reduction: Denzo-SMN;[50] absorption correction: SOR-
(4), 237 (4), 236 (24), 220 (8), 218 (21), 207 (6), 202 (10), 193 (1),
TAV[51] and DENZO;[52] structure solution: SHELXS-97;[53] struc-
192 (15), 191 (24), 189 (34), 178 (6), 165 (6), 163 (4), 139 (4), 138
ture refinement: SHELXL-97;[54] graphics: SCHAKAL.[55] CCDC-
(23), 131 (10), 123 (23), 121 (9), 109 (9), 105 (18), 95 (100), 93 (11),
610521 to -610523 contain the supplementary crystallographic data
82 (15), 81 (86), 79 (21), 77 (14), 76 (4), 68 (10), 67 (57), 57 (5), 55
for this paper. These data can be obtained free of charge from The
(31), 53 (10), 50 (4), 44 (10), 41 (24).
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
4-(trans-4-n-Pentylcyclohexyl)phenyl (1R,2R)-2α-Fluoro-1β,2β-di-
phenylcyclopropanecarboxylate : A solution of (1R,2R)-9a (2.00 g,
7.7 mmol), 4-(trans-4-n-pentylcyclohexyl)phenol (1.90 g, 7.7 mmol)
and DMAP (120 mg) in absolute toluene (30 mL) was treated drop-
wise at 10 °C with DCC (1.75 g, 8.48 mmol) in toluene (10 mL).
The mixture was stirred at room temp. for 18 h. Oxalic acid dihy-
drate (200 mg) was added. After stirring for 1 h, the precipitate was
filtered off, washed with toluene, and the solution was concentrated
in vacuo to give a viscous yellow oil. The crude product was chro-
matographed with toluene on a short silica gel column and crys-
tallized from ethanol after the addition of a small amount of tolu-
ene, yielding 2.5 g (67% yield, 99.4% pure by HPLC) of a colour-
less solid. M.p. 113 °C (ethanol). [α]2D0 = –48.6 (c = 1.0, CH2Cl2).
1H NMR (250 MHz, CDCl3, 298 K): δ = 0.89 (t, J = 6.8 Hz, 3 H),
0.95–1.08 (m, 2 H), 1.21–1.50 (m, 11 H), 1.93–1.87 (m, 4 H), 2.20
(dd, J = 8.0 and 11.7 Hz, 1 H), 2.44 (mc, 1 H), 2.87 (dd, J = 7.8
and 21.9 Hz, 1 H), 6.94–7.00 (m, 2 H), 7.03–7.07 (m, 2 H), 7.12–
7.25 (m, 10 H) ppm. 19F NMR (235 MHz, CDCl3, 300 K): δ =
–176.23 (dd, J = 11.4 and 21.8 Hz, 1 F) ppm. MS (EI): m/z (%) =
484 (13) [M]+, 420 (5), 238 (100), 219 (6), 210 (9), 191 (14), 133
(12), 109 (13), 104 (21).
data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis of catalysts 7 and 8, 1H,19F-Hetero-NOE experi-
ments, extended X-ray data of compounds (1R,2R)-5a, (1R,2S)-6a
and (1R,2S)-9a.
Acknowledgments
This work was supported by the NRW Graduate School of Chemis-
try (GSC-MS), Münster, Germany. We thank Andreas Ruhl, Jörg
Haas and Kerstin Altenburg (Merck KGaA, Darmstadt, Germany)
for technical assistance.
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X-ray Crystal Structure Analysis for Compound (1R,2R)-5a:
C17H15FO2, M = 270.29, colourless crystal, 0.30ϫ0.10ϫ0.10 mm,
a = 5.705(1) Å, b = 15.307(1) Å, c = 15.496(1) Å, V = 1353.2(3) Å3,
ρcalcd. = 1.327 gcm–3, µ = 0.782 mm–1, empirical absorption correc-
tion (0.799 Յ T Յ 0.926), Z = 4, orthorhombic, space group
P212121 (No. 19), λ = 1.54178 Å, T = 223 K, ω and φ scans, 6020
reflections collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] = 0.58 Å–1, 2073 inde-
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182 refined parameters, R = 0.031, wR2 = 0.080, Flack parameter
0.23(16), max. residual electron density 0.12 (–0.12) e·Å–3 and hy-
drogen atoms calculated and refined as riding atoms.
X-ray Crystal Structure Analysis for Compound (1R,2S)-6a:
C17H15FO2, M = 270.29, colourless crystal, 0.35ϫ0.35ϫ0.15 mm,
a = 8.127(1) Å, b = 10.301(1) Å, c = 16.501(1) Å, V = 1381.4(2) Å3,
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P212121 (No. 19), λ = 1.54178 Å, T = 223 K, ω and φ scans, 9078
reflections collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] = 0.60 Å–1, 2451 inde-
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182 refined parameters, R = 0.031, wR2 = 0.085, Flack parameter
0.03(13), max. residual electron density 0.12 (–0.14) e·Å–3 and hy-
drogen atoms calculated and refined as riding atoms.
X-ray Crystal Structure Analysis for Compound (1R,2R)-9a:
C16H13FO2, M = 256.26, colourless crystal, 0.20ϫ0.10ϫ0.03 mm,
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absorption correction (0.860 Յ T Յ 0.977), Z = 2, monoclinic,
space group P21 (No. 4), λ = 1.54178 Å, T = 223 K, ω and φ scans,
6406 reflections collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] = 0.58 Å–1, 1748
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Received: July 6, 2006
Published Online: November 6, 2006
148
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Eur. J. Org. Chem. 2007, 141–148