Asymmetric cyclopropanation of vinyl fluorides: Access to enantiopure monofluorinated cyclopropane carboxylates

Article abstract of DOI:10.1055/s-2000-7103

The transition metal catalyzed cyclopropanation with alkyl diazoacetates of aliphatic or aromatic vinyl fluorides, prepared from the corresponding alkenes by bromofluorination and subsequent dehydrobromination, provides a smooth access to racemic I:1 mixt

Full text of DOI:10.1055/s-2000-7103

FEATURE ARTICLE
1479
Asymmetric Cyclopropanation of Vinyl Fluorides: Access to Enantiopure
Monofluorinated Cyclopropane Carboxylates
Oliver G. J. Meyer, Roland Fröhlich,+ Günter Haufe*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, D-48149 Münster, Germany
Received 12 May 2000
for the synthesis of the antibacterial quinolone, 7-[7(S)-7-
amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-
[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-
quinolinecarboxylic acid,5 an analogue of the highly po-
Abstract: The transition metal catalyzed cyclopropanation with
alkyl diazoacetates of aliphatic or aromatic vinyl fluorides, prepared
from the corresponding alkenes by bromofluorination and subse-
quent dehydrobromination, provides a smooth access to racemic 1:1
mixtures of cis/trans isomeric monofluorinated cyclopropane car- tent drug ciprofloxacin (Ciprobay®).
boxylates. The application of enantiopure bis(oxazoline) ligands
While continuing our research on the synthesis and reac-
and copper(I) triflate makes the reaction trans-diastereoselective
and enantioselective. For example, treatment of a-fluorostyrene
(3a) with tert-butyl diazoacetate in the presence of 2 mol% of the
catalyst prepared from (S)-tert-leucine-based 11b and CuOTf gave
a 4:1 mixture of trans-2-fluoro-2-phenylcyclopropanecarboxylate
(4e) with 93% ee and the corresponding cis-isomer 5e with 89% ee.
The absolute configuration of the trans-isomer 4e has been deter-
mined to be (1S,2S) by X-ray structure analysis of a derivative.
tions of vinyl fluorides,6 we became interested in their
ability to react in transition metal-catalyzed cyclopropa-
nations.7 A related method has been used for the synthesis
of fluorinated chrysanthemic acid derivatives, but the re-
actions suffered from low selectivity and moderate
yields.8 To the best of our knowledge, there have been no
previous reports on asymmetric cyclopropanations of
fluoro olefins. Herein we wish to report our results on
transition metal catalyzed cyclopropanation of vinyl fluo-
rides, which provide a smooth and efficient route to race-
mic or enantiopure monofluorinated cyclopropane
carboxylates.
Key words: [2+1]-cycloaddition, asymmetric metal catalysis, diazo
compounds, carbenoids, fluoroolefins
The cyclopropyl group is known to be one of the most im-
portant structural motifs of biological activity and hence
is found in a surprisingly large number of naturally occur-
ring compounds.1 Hence, this function is continuing to at-
tract a lot of attention in synthetic organic chemistry as
well as in medicinal and agricultural chemistry.2 Particu-
larly in pharmaceuticals and in insecticides, the three
membered ring frequently represents an important struc-
tural element.1
For several years monofluoroolefins proved to be valu-
able building blocks for the synthesis of new fluorinated
compounds by cycloadditions.6a-d,9 Such monofluoro ole-
fins are easily available by bromofluorination of alkenes
and subsequent dehydrobromination of the thus-formed
vicinal bromofluorides.10,11 As fluorination agents, tri-
alkylamine·HF complexes like Et3N·3HF have been used
in combination with N-bromosuccinimide (NBS) since
these reagents give high yields and are relatively safe to
handle.10 Our studies have shown that Me3N·3HF is more
reactive than Et3N·3HF and, moreover, led to significantly
higher regioselectivity. Bromofluorination of aromatic
olefins like 1a-c exclusively gave the Markovnikov prod-
uct either with Et3N·3HF or Me3N·3HF. In contrast, the
ratio of regioisomers derived from aliphatic terminal ole-
fins such as hexene was raised from 87:13 (Et3N·3HF) to
95:5 with Me3N·3HF. From these bromofluorides, the
corresponding vinyl fluorides have been prepared in good
On the other hand, it is known for biologically active mol-
ecules that the replacement of a C-H bond with a C-F
bond can cause dramatic effects on their physiological
properties.3 Therefore, the development of new synthetic
approaches to fluorinated compounds is an important field
of research.4 Almost nothing has been known about enan-
tioselective synthesis of monofluorinated cyclopropane
carboxylates until very recently, when Imura et al. de-
scribed the microbial resolution of cis-2-fluorocyclopro-
panecarboxylic acid, which is an important intermediate
Table 1 Bromofluorination of Olefins with NBS/Me3N∑3HF and Subsequent Dehydrobromination
Entry
Olefins 1
R1
R2
Bromo
Ratio of
Yield (%)
Vinyl
Yield (%)
Fluorides 2
Regioisomers
Fluoride 3
1
2
3
4
1a
1b
1c
1d
Ph
H
2a
2b
2c
2d
>99:1
>99:1
>99:1
95:5
96
98
92
95
3a
3b
3c
3d
80
64
71
64a
p-Cl-Ph
Ph
H
Me
H
C4H9
a Elimination was carried out without solvent and with KOH as base.
Synthesis 2000, No. 10, 1479–1490 ISSN 0039-7881 © Thieme Stuttgart · New York

1480
O. G. J. Meyer et al.
FEATURE ARTICLE
yield by treatment with potassium tert-butoxide applying the reaction of a fluorostyrene (3a) with ethyl diazoace-
the conditions given in ref.11 (Scheme 1 and Table 1).
tate (EDA) gave much higher yields with copper catalysts,
particularly with Cu(acac)2, than with Rh- or Pd-catalysts
(Scheme 2 and Table 2), which showed the best results
with non-fluorinated alkenes.12 Moreover, 1:1 mixtures of
the cis- and trans-isomers (The terms cis and trans with
regard to the phenyl and the carboxyl groups are used to
make the diastereoselectivity more comparable to the re-
sults obtained with non-fluorinated olefins.) were formed
independently of the catalyst used, whereas cyclopropa-
nation of styrene with EDA usually gives a 2:1 mixture fa-
voring the trans-isomer.12
Scheme 1
The cyclopropanations of 3a-3d were carried out with
Cu(acac)2 (Scheme 3 and Table 3). The reaction mixtures
were analyzed by GC and 19F NMR. Since an excess of
EDA was used in all reactions, small amounts of the ethyl
Initial cyclopropanation experiments showed that the con-
ditions and the results concerning the most efficient cata-
lyst reported for non-fluorinated olefins12 could not
simply be applied to vinyl fluorides. By way of example,
Biographical Sketches
Günter Haufe, born in medium- and large alicy- the University of Münster in
1949 in Saxony, Germany, clics in 1985. In the follow- 1991. His work was award-
studied at the University of ing year, he worked as a ed by the East German
Leipzig where he received a research fellow of CNRS Chemical Society with the
diploma in chemistry and with A. Laurent at the Uni- “Friedrich-Wöhler-Preis” in
his doctorate with J. Graefe versity Lyon I, France and 1985. In 1994, he was invit-
and M. Mühlstädt in 1975 as a guest researcher with J. ed as a Visiting Professor to
for work on the mechanism Paasivirta at the University the University of Lyon I,
of electrophilic additions. of Jyväskylä, Finland. Since France. His main areas of
After 18 months of basic 1988, he was a Lecturer of research relate to the devel-
military service, he returned Bioorganic Chemistry at the opment of selective fluori-
to the University of Leipzig University of Leipzig, until nation
methods
and
and completed his habilita- he was appointed to his synthesis of fluorinated ana-
tion on transannular cycliza- present position as a Profes- logues of natural products.
tions
of
unsaturated sor of Organic Chemistry at
Oliver Meyer, born in 1971 1997. He recently complet- his doctorate, he was work-
in Lemgo, Germany, stud- ed his dissertation on the ing as an assistant for the X-
ied chemistry in Münster stereoselective cyclopropa- ray crystallography depart-
and finished his diploma nation of vinyl fluorides un- ment at the Institute of Or-
thesis on dihalocarbene ad- der the supervision of ganic Chemistry.
dition to vinyl fluorides in Professor G. Haufe. During
Roland Fröhlich, born in studies at the Crystallo- senior scientist at the Uni-
1952 in Soest, Germany, graphic Institute of the Uni- versity of Münster and since
studied chemistry in Mün- versity of Karlsruhe, he 1994 a Lecturer of X-ray
ster and Cologne and re- worked as a sales and appli- crystallography at the Uni-
ceived his Dr. rer. nat. in cation manager for Enraf versity of Jyväskylä, Fin-
1982. After postdoctoral Nonius. Since 1993, he is a land.
Synthesis 2000, No. 10, 1479–1490 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Cyclopropanation of Vinyl Fluorides
1481
Table 2 Cyclopropanation of α-Fluorostyrene (3a) with EDA and Different Catalysts
Catalyst
PdCl2
16
Pd(OAc)2
11
RhCl3
6
Rh2(OAc)4
25
CuOTf◊½C6H6
Cu(OAc)2
62
Cu(acac)2
93
Yield 4a + 5a (%, GC)
39
Scheme 2
Scheme 4
ecules crystallize in the monoclinic space groups P21/c
(6a) or C2/c (7a), respectively. In the crystalline state,
both diastereomers exist as intermolecularly hydrogen-
bonded dimers across the carboxyl groups.
Scheme 3
Table 3 Cyclopropanation of Vinyl Fluorides 3 with EDA Cata-
lyzed by Cu(acac)2
Surprisingly, b-fluorostyrene (8a), bearing the fluorine
substituent in the terminal position (synthesized as an E/
Z-mixture (86:14) by a Wittig-type reaction),14 showed a
completely different behavior compared to the vinyl fluo-
rides 3a-d. Independent of the catalyst used, only very
low conversion of 8 to 9 and 10 was found. Even after the
introduction of a p-methoxy group, in order to raise the
electron density of the double bond, the yield remained as
low as 17% (GC) after 6 hours at 40 °C (Scheme 5, shown
for the (E)-isomers 8). Elongation of the reaction time (20
hours) did increase the conversion of 8a slightly to 26%.
Entry Vinyl
Fluorides 3
R1
R2
Cyclopro-
panes 4 and 5 4:5
Ratio Yield
(%)
1
2
3
4
3a
Ph
H
H
4a + 5a
4b + 5b
50:50 87
50:50 91
3b
3c
3d
p-Cl-Ph
Ph
Me 4c + 5c
4d + 5d
33:67 63
42:58 36
C4H9
H
esters of maleic and fumaric acid were formed as byprod-
ucts.
It is noteworthy that the cyclopropanation of cis-1-fluoro-
1-phenylpropene (3c) gave an increased portion of 5c al-
though this isomer can be considered the sterically disfa-
vored one.
Furthermore, the diasteroselectivity of the cyclopropana-
tion of a-fluorostyrene (3a) was raised by using tert-butyl
diazoacetate as a more bulky carbene precursor. The tert-
butyl 2-fluoro-2-phenylcyclopropanecarboxylates (4e and
5e, not shown) were obtained with a trans/cis-ratio of
64:36. The application of Rh2(OAc)4·2H2O as the catalyst
gave the best yield (70%) in this particular case.
Scheme 5
These results can be attributed to the mechanism of the cy-
clopropanation and the different stabilization of cationic
positions. It is well known that a fluorine substituent sta-
bilizes cations in a-position by resonance, but destabilizes
b-cationic structures.15 Considering a concerted formation
of the cyclopropane carboxylates (Scheme 6, shown for
the trans-isomers), as proposed by Brookhart et al.16 and
Doyle et al.,17 the attack of the carbenoid at the terminal
position of a-fluorostyrene (3a) would create a stabilized
positive partial charge in the position a to the fluorine sub-
All cis- and trans-diastereomers were separated by col-
umn chromatography. Complete separation of the isomers
4a and 5a may also be achieved by fractional crystalliza-
tion of the corresponding acids 6a and 7a, which may be
obtained by saponification.
From both isomers (6a and 7a), single crystals were ob-
tained. X-ray structures13 are shown in Figure 1. The mol-
Synthesis 2000, No. 10, 1479–1490 ISSN 0039-7881 © Thieme Stuttgart · New York

1482
O. G. J. Meyer et al.
FEATURE ARTICLE
Figure 1 X-ray Structures of the Fluorinated Cyclopropane Carboxylic Acids 6a and 7a.
stituent. Subsequent ring closure by nucleophilic attack of stopped after 7 days. While CAL did not hydrolyse 4a,
the former carbenoid carbon atom and liberation of the PCL converted 15% of this compound to the carboxylic
metal catalyst leads to the cyclopropane carboxylate 4a.
acid 6a, however with only 6% ee. In contrast, hydrolysis
of racemic 4a with CRL reached 50% conversion after 7
days and yielded 49% of the corresponding cyclopropane
carboxylic acid 6a with 78% ee (Scheme 7). The enantio-
meric excesses of the cyclopropane carboxylic acids were
determined by 19F NMR spectroscopy after esterification
with enantiopure (-)-menthol using DCC. The absolute
configuration of 6a was assigned to be (1R,2R) by com-
parison of the 19F NMR spectra of the (-)-menthyl ester
with that formed from enantiopure (1S,2S)-6a (Table 4,
Entry 2, see also Scheme 11). It has to be stressed that un-
der the same conditions no hydrolysis of 5a took place
with any of the tested lipases.
In contrast, the analogous attack of the carbenoid to (E)-
b-fluorostyrene (8a) would lead to a cationic benzyl posi-
tion bearing a b-fluorine substituent. Fluorine in such a
position has a strong destabilizing effect and b-fluoro-
alkyl cations are not known in solution.15 This could be a
reason for the low conversion of 1-fluoroalkenes. On the
other hand, the alternative attack of the carbenoid to the
benzylic carbon of 8a leading to a primary homobenzylic
cationic structure, which is stabilized by the fluorine, also
does not seem to be much favoured. However, the small
amount of 9a is possibly formed in this way (Scheme 6).
Scheme 7
Thus, the asymmetric cyclopropanation of vinyl fluorides
using enantiopure catalysts was the way of choice to pre-
pare optically active fluorinated cyclopropane carboxy-
lates. During the last ten years, the asymmetric
cyclopropanation of olefins has developed to a very active
field of research.18,19 Nevertheless, there are no reports on
the stereoselective cyclopropanation of vinyl fluorides.
We expect this method to be a good approach to a wide
variety of optically active monofluorinated cyclopropane
derivatives.
Scheme 6
In order to obtain optically active monofluorinated cyclo-
propane carboxylates three different lipases, namely Can-
dida antarctica (CAL, Novozym® 435), Pseudomonas
cepacia (PCL, Amano PS) and Candida rugosa (CRL),
were screened for their ability to hydrolyze and deracem-
ize the esters 4a and 5a, which were separated by column
chromatography. Hydrolyses were carried out in phos-
phate buffer solution (c = 0.1 mol/L) at pH 7.0 and
Among the known ligand systems of enantiopure catalysts
for cyclopropanation of alkenes, the C2-symmetric semi-
corrins, first used by Pfaltz20 or bis(oxazolines), first used
by Masamune21 and Evans,22 proved to be highly effi-
cient. Many related catalysts have been shown to be useful
as well.19,23 Moreover, such catalysts have shown their
synthetic potential in a wide variety of different asymmet-
Synthesis 2000, No. 10, 1479–1490 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Cyclopropanation of Vinyl Fluorides
1483
ric reactions.24 While the enantioselectivity of the organo- more bulky diazo compound leads to higher diastereo-
metallic ligand is determined by the chiral topology of the and enantioselectivity but lower yields (Table 4, Entries 2,
catalytic complex, its electronic structure is responsible 4, and 5).
for the completion of the catalytic cycle.25
From other vinyl fluorides such as p-chloro-a-fluorosty-
The enantiopure bis(oxazolines) 11 and 12 were synthe- rene (3b), (E)-a-fluoro-b-methylstyrene (3c), and 2-fluo-
sized according to published procedures22,26 from the cor- rohex-1-ene (3d), the corresponding cis/trans-isomeric
responding amino alcohols, which are readily available cyclopropylcarboxylates have been synthesized in an
from the corresponding amino acids.27 The enantiopure analogous way (Scheme 9 and Table 5).
catalysts were formed in situ by mixing the bis(oxazoline)
ligand with a stoichiometric amount of CuOTf·½benzene
and used in an amount of 2 mol%. To the solution of the
catalyst and the corresponding vinyl fluoride, the diazoac-
etate was added over a period of about 6 hours at 40 °C
and the mixture was stirred for one more hour at this tem-
perature.
Scheme 9
Scheme 10 illustrates the proposed mechanism for the
asymmetric cyclopropanation (shown for the two enanti-
omers of 4a).20b The bis(oxazoline) ligand and the metal
carbene are orthogonal to each other. In case of a si-attack
by the olefin, a steric interaction with the bulky substitu-
ent R would hinder the turn of the ester-group into the
plane for cyclopropane formation. Since such an interac-
tion is absent for the re-attack, the latter pathway is fa-
vored.
In order to prove this mechanistic prediction we deter-
mined the absolute configuration of 4a from Entry 2, Ta-
ble 4. The pure ester 4a (89% ee) was hydrolyzed (KOH,
MeOH) to 6a which was recrystallized and subsequently
converted to the corresponding amide 13 under Schotten-
Scheme 8
Baumann conditions using 4-bromoaniline (Scheme 11).
The X-ray structure analysis13 of the obtained single crys-
tal (triclinic crystal system, space group: P1, enantiopol
parameter: -0.017(15) confirmed the configuration of 13
(and therefore of 4a) to be (1S,2S) as expected from the
proposed mechanism and assumptions regarding the
ligand's configuration. Figure 2 just shows one molecule
of the unit cell for clarity.
The results are summarized in Table 4. Entries 1 and 2 in-
dicate that the bulkiness of the ligand’s residue R has no
large influence on the diastereoselectivity, but a decisive
influence on enantioselectivity. In comparison, the differ-
ent ligand’s "backbones" of 11 and 12 (Table 4, Entries 1
and 3) seem to have almost no effect. Application of a
Table 4 Asymmetric Cyclopropanation of α-Fluorostyrene (3a) Catalyzed by Different Copper Catalysts
Entry
Ligands
R'
Cyclopropane
Ratio
Yield (%)
ee 4 (%)a
ee 5 (%)a
11 and 12
carboxylates 4 and 5
4:5
1
2
3
4
5
11a
11b
12
Et
4a + 5a
4a + 5a
4a + 5a
4e + 5e
4f + 5f
68:32
72:28
66:34
81:19
81:19
81
62
75
56
28c
69
54
80
Et
89
Et
70
54
11b
11b
tBu
93b
92d
89b
>98d
(–)-Menthyl
a The enantiomeric excesses of the cyclopropane carboxylates were determined by 19F NMR spectroscopy after hydrolysis and esterification
with enantiopure (–)-menthol using DCC.
b Determined by chiral GC.
c The cis-isomer 5f contains small amounts of the menthyl esters of maleic and fumaric acids as byproducts.
d de.
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1484
O. G. J. Meyer et al.
FEATURE ARTICLE
Table 5 Asymmetric Cyclopropanation of Vinyl Fluorides 3b, 3c, and 3d with EDA and the Copper Catalyst Formed from Ligand 11b
Entry
Vinyl
Fluoride
R1
R2
Cyclopropane
carboxylates
Yield (%)
Ratio
4:5
ee 4 (%)a
ee 5 (%)a
6
7
8
3b
3c
3d
p-Cl-Ph
Ph
H
4b + 5b
4c + 5c
4d + 5d
64
62
28
81:19
82:18
64:36
93
65
16
91
–
Me
H
C4H9
–
a The enantiomeric excesses of the cyclopropane carboxylates were determined by 19F NMR spectroscopy after hydrolysis and esterification
with enantiopure (–)-menthol using DCC.
Figure 2 X-ray Structure of (1S,2S)-2-Fluoro-2-phenylcyclopro-
panecarboxylic Acid (4-Bromophenyl)amide (13).
Scheme 10
Scheme 12
8b were prepared by Wittig-type olefination of the corresponding
benzaldehydes using n-tributylphosphine and trichlorofluoro-
methane.14 While (1R,3R,4S)-(-)-menthyl diazoacetate was pre-
pared following the literature procedure,20b tert-butyl diazoacetate
Scheme 11
was synthesized by a modified diazo transfer reaction with p-aceta-
midobenzenesulfonyl azide.33 The bis(oxazoline) ligands 11a, 11b
and 12 were prepared with little variation according to literature
procedures.22,26 All reagents were obtained from Acros, Merck, or
The thus-formed fluorinated cyclopropane carboxylates 4
are shown to serve as precursors for fluorinated analogues
Fluka chemicals. CH2Cl2 was distilled from P4O10. All cyclopro-
panation reactions were performed under Ar atm in flame-dried
of biogenic amines. By way of example, a fluorinated ra-
cemic analogue 15 of the monoamine oxidase inhibitor
tranylcypromine has been prepared by Curtius-degrada-
tion of racemic 6a (Scheme 12).
glassware.
If not stated otherwise, 1H (300.13 MHz), 13C (75.47 MHz) and 19
F
1
NMR (282.4 MHz): Bruker WM 300. For some marked cases H
(600 MHz) and 19F NMR (564.3 MHz): Varian 600 MHz apparatus
Unity Plus. Carbon multiplicities have been assigned by distortion-
less enhancement by polarization transfer (DEPT) experiments. Un-
less otherwise stated, the spectra were obtained in CDCl3 solutions.
Bromofluoroalkanes 2a-d and vinyl fluorides 3a-d were synthe-
sized according to literature procedures.10,11 However, in bromo-
fluorinations Me3N∑3HF was used instead of Et3N∑3HF and elimi-
nation of 1-bromo-2-fluorohexane (2d) was achieved without sol-
vent using KOH as the base. The spectroscopic data of the
bromofluoroalkanes 2a,28 2c,28 2d29 and vinyl fluorides 3a,30 3c,31
3d32 are in accordance with published data. b-Fluorostyrenes 8a and
TMS was used as internal standard for H-, CDCl3 for 13C- and
1
CFCl3 for 19F NMR spectroscopy. Mass spectra (70 eV): GC/MS
coupling: Varian GC 3400/MAT 8230 and data system SS 300 of
Finnigan MAT and Varian GC 3400/Varion Saturn IT (Ion Trap)
and data system NIST. Elemental analysis: Mikroanalytisches
Laboratorium, OC, Universität Münster.
Synthesis 2000, No. 10, 1479–1490 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Cyclopropanation of Vinyl Fluorides
1485
3
1-(2-Bromo-1-fluoroethyl)-4-chlorobenzene (2b)
Prepared from p-chlorovinylbenzene (9.7 g, 70 mmol) according to
ref.10 but using Me3N·3HF as fluorinating agent. Yield: 16.4 g
(98%).
1H NMR (600 MHz): d = 0.96 (t, 3H, JH,H = 7.2 Hz, CH3), 1.77
(ddd, 1H, 2JH,H = 7.1 Hz, 3JH,H(cis) = 10.4 Hz, 3JH,F(cis) = 19.3 Hz, HB),
1.95 (ddd, 1H, JH,H = 7.1 Hz, JH,H(trans) = 7.6 Hz, JH,F(trans) = 12.4
Hz, HA), 2.50 (ddd, 1H, JH,H(cis) = 10.4 Hz, JH,H(trans) = 7.6 Hz,
3JH,F(cis) = 18.1 Hz, HX), 3.9 (q, 2H, 3JH,H = 7.2 Hz, 5-CH2), 7.3-7.5
(m, 5H, Harom.).
2
3
3
3
3
2
1H NMR: d = 3.44-3.59 (m, 2H, CH2), 5.57 (ddd, 1H, JH,F = 46.5
Hz, 3JH,H = 4.5 Hz, 3JH,H = 7.2 Hz, CH), 7.20-7.40 (m, 4H, Harom.).
13C NMR: d = 13.9 (q, C-6), 16.4 (dt, 2JC,F = 10.2 Hz, C-3), 27.9 (dd,
13C NMR: d = 33.7 (dt, 2JC,F = 28.0 Hz, C-8), 91.7 (dd, 1JC,F = 179.3
Hz, C-7), 127.0 (dd, 3JC,F = 6.4 Hz, C-2/6), 128.7 (d, C-3/5), 134.9
(s, C-4), 135.4 (ds, 2JC,F = 20.4 Hz, C-1).
2JC,F = 17.3 Hz, C-1), 60.7 (t, C-5), 83.0 (ds, 1JC,F = 221.3 Hz, C-2),
2
126.3 (ds, JC,F = 20.4 Hz, C-7), 128.2 (d, C-8/12), 128.4 (d, C-9/
11), 129.2 (d, C-10), 168.8 (s, C-4).
3
3
19F NMR: d = -174.0 (ddd, JH,F = 17.2 Hz, JH,F = 22.9 Hz,
19F NMR (564.3 MHz): d = -154.8 (m).
MS (GC/MS): m/z (%) = 208 (M+, 78), 180 (McLafferty, 20), 163
(M+-C2H5O, 16), 160 (180-HF, 16), 153 (42), 135 (M+-C3H5O2,
100), 133 (60), 125 (88), 115 (70), 105 (22), 77 (11), 51 (6).
2JH,F = 46.5 Hz).
MS (GC/MS): m/z (%) = 40/238/236 (M+, 4/13/10), 145/143 (M+-
+
CH2Br, 38/100), 121 (3), 107 (M+-HCl, 4), 101 (6), 75 (C6H3 , 5),
+
51 (C4H3 , 4), 50 (4).
Anal. Calcd for C12H13FO2 (208.23, mixture of 4a and 5a): C,
69.22; H, 6.29. Found: C, 69.17; H, 6.55.
1-Chloro-4-(1-fluorovinyl)benzene (3b)
Prepared from 2b (5.0 g, 21 mmol) according to ref.11 Yield: 2.1 g
(64%).
Ethyl 2-(4-Chlorophenyl)-2-fluorocyclopropanecarboxylates
(4b, 5b)
The reaction was carried out following typical procedure I, from 3b
(0.64 g, 4.1 mmol). Separation of the crude product by column chro-
matography (silica gel, pentane/CH2Cl2, 1:1) afforded the pure iso-
mers 4b and 5b as colorless oils.
1H NMR: d = 4.85 (dd, 1H, 3JH,F(cis) = 17.9 Hz, 2JH,H = 3.6 Hz, HA),
3
2
5.00 (dd, 1H, JH,F(trans) = 49.4 Hz, JH,H = 3.8 Hz, HB), 7.30-7.50
(m, 5H, Harom.).
13C NMR: d = 90.0 (dt, 2JC,F = 22.9 Hz, C-8), 126.0 (d, C-3/5), 128.7
(d, C-2/6), 130.5 (ds, 2JC,F = 29.2 Hz, C-4), 135.3 (d, C-1),162.0 (ds,
1JC,F = 250.5 Hz, C-7).
4b:
Yield: 0.54 g (55%).
19F NMR: d = -108.17 (dd, 3JH,F(trans) = 49.4 Hz, 3JH,F(cis) = 17.9 Hz).
MS (GC/MS): m/z (%) = 158/156 (M+, 40/100), 121 (M+-Cl, 55),
3
1H NMR: d = 1.29 (t, 3H, JH,H = 7.2 Hz, CH3), 1.58 (ddd, 1H,
3
3
2JH,H = 7.1 Hz, JH,H(cis) = 9.5 Hz, JH,F(trans) = 10.7 Hz, HA), 2.15
+
+
(ddd, 1H, JH,H(cis) = 9.5 Hz, 3JH,H(trans) = 7.9 Hz, 3JH,F(trans) = 3.0 Hz,
3
101 (121-HF, 40), 75 (C6H3 , 12), 51 (C4H3 , 16), 50 (8).
2
3
HX), 2.29 (ddd, 1H, JH,H = 7.1 Hz, JH,H(trans) = 7.9 Hz,
3JH,F(cis) = 20.0 Hz, HB), 4.15-4.35 (m, 2H, JH,H = 7.2 Hz, 5-CH2),
3
Ethyl 2-Fluoro-2-phenylcyclopropanecarboxylates (4a+5a);
Typical Procedure I
7.15-7.45 (m, 4H, Harom.).
To a solution of 3a (0.50 g, 4.1 mmol) and Cu(acac)2 (32 mg, 0.12
mmol) in anhyd CH2Cl2 (5 mL), a solution of ethyl diazoacetate
(0.64 mL, 6.15 mmol) in anhyd CH2Cl2 (3 mL) was added at 40 °C
through a syringe pump over a period of 6-7 h. After stirring for
one more hour and addition of CH2Cl2 (100 mL), the mixture was
washed successively with sat. NaHCO3 (2 ¥ 50 mL) and H2O
(2 ¥ 50 mL). After drying (MgSO4), the solvent was removed by
evaporation (rotary evaporator). Separation of the crude product by
column chromatography (silica gel, pentane/Et2O, 40:1) afforded
the pure isomers 4a and 5a as colorless oils.
13C NMR: d = 14.2 (q, C-6), 18.8 (dt, 2JC,F = 12.7 Hz, C-3), 29.0 (dd,
2JC,F = 11.5 Hz, C-1), 61.2 (t, C-5), 80.3 (ds, 1JC,F = 228.9 Hz, C-2),
126.0 (dd, 3JC,F = 6.35 Hz, C-8/12), 128.8 (d, C-9/11), 134.3 (s, C-
10), 136.1 (ds, 2JC,F = 22.9 Hz, C-7), 167.4 (s, C-4).
3
3
19F NMR: d = -188.22 (pseudo dd, JH,F(trans) = 10.7 Hz, JH,F(trans)
not resolved, 3JH,F(cis) = 20.0 Hz).
MS (GC/MS): m/z (%) = 244/242 (M+, 19/36), 216/214 (McLaffer-
ty, 14/32), 187 (40), 185 (34), 171/169 (M+-C3H5O2, 30/96), 159
(92), 151/149 (171/169-HF, 18/31), 139 (28), 134 (66), 133 (169-
HCl, 100), 131 (24), 115 (18), 107 (18), 101 (13), 83 (5), 66 (14),
39 (6).
4a:
Yield: 0.37 g (44%).
3
1H NMR (600 MHz): d = 1.26 (t, 3H, JH,H = 7.2 Hz, CH3), 1.58
5b:
(ddd, 1H, 2JH,H = 7.1 Hz, 3JH,H(cis) = 9.4 Hz, 3JH,F(trans) = 10.7 Hz, HA),
2.15 (ddd, 1H, 3JH,H(cis) = 9.4 Hz, 3JH,H(trans) = 7.8 Hz, 3JH,F(trans) = 2.9
Hz, HX), 2.26 (ddd, 1H, JH,H = 7.1 Hz, JH,H(trans) = 7.8 Hz,
3JH,F(cis) = 20.4 Hz, HB), 4.2 (m, 2H, 3JH,H = 7.2 Hz, 5-CH2), 7.2-7.4
(m, 5H, Harom.).
Yield: 0.36 g (36%).
1H NMR: d = 1.00 (t, 3H, JH,H = 7.2 Hz, CH3), 1.81 (ddd, 1H,
3
2
3
2JH,H = 7.2 Hz, JH,H(cis) = 10.5 Hz, JH,F(cis) = 19.3 Hz, HB), 1.94
3
3
2
3
3
(ddd, 1H, JH,H = 7.2 Hz, JH,H(trans) = 7.6 Hz, JH,F(trans) = 12.4 Hz,
3
3
HA), 2.55 (ddd, 1H, JH,H(cis) = 10.5 Hz, JH,H(trans) = 7.6 Hz,
3JH,F(cis) = 17.9 Hz, HX), 3.94 (q, 2H, 3JH,H = 7.2 Hz, 5-CH2), 7.30-
7.50 (m, 4H, Harom.).
13C NMR: d = 14.1 (q, C-6), 18.9 (dt, 2JC,F = 12.2 Hz, C-3), 29.0 (dd,
2JC,F = 12.7 Hz, C-1), 61.1 (t, C-5), 80.8 (ds, 1JC,F = 226.3 Hz, C-2),
3
13C NMR: d = 14.0 (q, C-6), 16.6 (dt, 2JC,F = 10.2 Hz, C-3), 28.0 (dd,
124.6 (dd, JC,F = 5.1 Hz, C-8/12), 128.2 (d, C-10), 128.6 (d, C-9/
11), 137.5 (ds, 2JC,F = 20.4 Hz, C-7), 167.7 (s, C-4).
2JC,F = 16.5 Hz, C-1), 60.8 (t, C-5), 82.3 (ds, 1JC,F = 221.3 Hz, C-2),
3
19F NMR (564.3 MHz): d = -188.33 (ddd, JH,F(trans) = 10.7 Hz,
3
128.5 (d, C-9/11), 129.6 (dd, JC,F = 3.8 Hz, C-8/12), 131.7 (ds,
2JC,F = 20.3 Hz, C-7), 135.2 (s, C-10), 168.6 (s, C-4).
3JH,F(trans) = 2.9 Hz, 3JH,F(cis) = 20.4 Hz).
19F NMR: d = -155.35 (not resolved ddd, JH,F(cis) = 19.3 Hz,
3
MS (GC/MS): m/z (%) = 208 (M+, 56), 180 (McLafferty, 18), 163
(M+-C2H5O, 20), 160 (180-HF, 14), 153 (40), 135 (M+-C3H5O2,
100), 133 (53), 125 (66), 115 (62) [135-HF], 105 (20), 77 (10), 51
(10).
3JH,F(trans) = 12.4 Hz, 3JH,F(cis) = 17.9 Hz).
MS (GC/MS): m/z (%) = 244/242 (M+, 18/36), 216/214 (McLaffer-
ty, 14/32), 187 (40), 185 (34), 171/169 (M+-C3H5O2, 31/96), 159
(92), 151/149 (171/169-HF, 17/31), 139 (27), 134 (66), 133 (169-
HCl, 100), 131 (25), 115 (17), 107 (18), 101 (17), 66 (15), 39 (5).
5a:
Yield: 0.36 g (43%).
Synthesis 2000, No. 10, 1479–1490 ISSN 0039-7881 © Thieme Stuttgart · New York

1486
O. G. J. Meyer et al.
FEATURE ARTICLE
HRMS: m/z calcd for C12H12O2ClF (4b) 242.05098. Found:
242.05057.
118 (14), 117 (41), 111 (20), 105 (55), 95 (60), 88 (40), 85 (36), 73
(C3H5O2 , 100), 55 (60), 43 (86), 41 (96), 39 (40).
+
5d:
Ethyl 2-Fluoro-3-methyl-2-phenylcyclopropanecarboxylates
(4c, 5c)
The reaction was carried out following typical procedure I, from 3c
(0.55 g, 4.0 mmol). Separation of the crude product by column chro-
matography (silica gel, pentane/Et2O, 10:1) afforded the pure iso-
mers 4c and 5c as colorless oils.
Yield: 0.15 g (16%).
1H NMR: d = 0.84 (t, 3H, JH,H = 7.2 Hz, 10-CH3), 1.2 (t, 3H,
3
3JH,H = 7.2 Hz, 6-CH3), 1.1-1.6 (m, 6H, 7/8/9-CH2), 1.7-2.15 (m,
3H, HA,HB,HX), 4.08 (q, 2H, 3JH,H = 7.2 Hz, 5-CH2).
13C NMR: d = 14.2 (q, C-10), 14.6 (q, C-6), 18.6 (dt, 2JC,F = 10.2 Hz,
C-3), 22.7 (t, C-9), 25.4 (dd, 2JC,F = 15.3 Hz, C-1), 27.9 (t, C-8), 29.8
(dt, 2JC,F = 20.3 Hz, C-7), 61.1 (t, C-5), 83.5 (ds, 1JC,F = 223.8 Hz, C-
2), 171.1 (s, C-4).
4c:
Yield: 0.21 g (24%).
3
4
1H NMR: d = 0.93 (dd, 3H, JH,H = 6.7 Hz, JH,F = 1.7 Hz, 7-CH3),
19F NMR: d = -169.2 (m).
1.30 (t, 3H, 3JH,H = 7.2 Hz, 6-CH3), 2.10 (dd, 1H, 3JH,F(trans) = 7.4 Hz,
3JH,H(trans) = 3.1 Hz, HB), 2.38-2.56 (m, 1H, JH,F(cis) = 22.2 Hz,
3
MS (GC/MS): m/z (%) = 188 (M+, 3), 168 (M+-HF, 5), 160
(McLafferty, 16), 159 (M+-C2H5, 16), 146 (M+-C3H6, 100), 143
(30, M+-C2H5O), 118 (29), 117 (73), 111 (33), 105 (55), 101 (41),
95 (49), 88 (53), 85 (32), 73 (84, C3H5O2 ), 55 (32), 44 (26), 42
(C3H6 , 29).
3JH,H = 6.7 Hz, HA), 4.20 (q, 2H, 3JH,H = 7.2 Hz, CH2), 7.30-7.50 (m,
5H, Harom.).
+
13C NMR: d = 12.8 (q, C-7), 14.1 (q, C-6), 25.1 (dd, 2JC,F = 15.3 Hz,
+
2
C-3), 29.0 (dd, JC,F = 17.8 Hz, C-1), 61.2 (t, C-5), 85.4 (ds,
1JC,F = 228.9 Hz, C-2), 128.3 (dd, 3JC,F = 5.1 Hz, C-9/13), 128.5 (d,
tert-Butyl 2-Fluoro-2-phenylcyclopropanecarboxylates (4e, 5e)
The reaction was carried out following typical procedure I, from 3a
(0.50 g, 4.1 mmol), Rh2(OAc)4·2H2O (59 mg, 0.123 mmol) and tert-
butyl diazoacetate (0.87 mL, 6.15 mmol). Separation of the crude
64:36 mixture of 4e and 5e by column chromatography (silica gel,
pentane/Et2O, 40:1) afforded the pure isomers as colorless oils.
C-10/12), 129.0 (d, C-11), 133.9 (s, C-8), 168.4 (s, C-4).
3
19F NMR (564.3 MHz): d = -168.87 (dd, JH,F(cis) = 22.2 Hz,
4JH,F = 1.7 Hz).
MS(GC/MS): m/z (%) = 222 (M+, 14), 204 (4), 177 (M+-OC2H5,
15), 153 (36), 149 (M+-C3H5O2, 100), 129 (149-HF, 34), 125 (20),
77 (4), 51 (4).
4e:
5c:
Yield: 0.40 g (41%).
Yield: 0.35 g (39%).
1H NMR: d = 1.48 (s, 9H, C(CH3)3), 1.50-1.57 (m, 1H, HA), 2.11
1H NMR: d = 1.17 (t, 3H, JH,H = 7.2 Hz, 6-CH3), 1.31 (dd, 3H,
(ddd, 1H, JH,H(cis) = 9.3 Hz, 3JH,H(trans) = 7.6 Hz, 3JH,F(trans) = 3.1 Hz,
3
3
4JH,F = 1.7 Hz, 3JH,H = 6.92 Hz, 7-CH3), 2.10-2.30 (m, 1H, HA), 2.49
HX), 2.21 (ddd, 1H, JH,H = 6.9 Hz, JH,H(trans) = 7.6 Hz,
2
3
(dd, 1H, 3JH,F(cis) = 19.1 Hz, JH,H = 11.2 Hz, Hx), 3.90-4.2 (m, 2H,
3JH,F(cis) = 20.0 Hz, HB), 7.2-7.4 (m, 5H, Harom.).
3
CH2), 7.30-7.50 (m, 5H, Harom.).
13C NMR: d = 18.8 (dt, 2JC,F = 12.7 Hz, C-3), 28.1 (q, C-6/7/8), 30.1
(dd, 2JC,F = 12.7 Hz, C-1), 80.6 (ds, 1JC,F = 227.6 Hz, C-2), 81.2 (s,
C-5), 124.3 (dd, 3JC,F = 6.4 Hz, C-10/14), 128.0 (d, C-12), 128.5 (d,
C-11/13), 137.9 (ds, 2JC,F = 21.6 Hz, C-9), 166.7 (s, C-4).
13C NMR: d = 9.7 (q, C-7), 14.1 (q, C-6), 25.7 (dd, 2JC,F = 12.72 Hz,
2
C-3), 31.2 (dd, JC,F = 12.7 Hz, C-1), 60.3 (t, C-5), 85.9 (ds,
1JC,F = 218.7 Hz, C-2), 128.5 (d, C-9/13), 129.6 (d, C-11), 130.8 (d,
C-10/12), 131.2 (d, C-8), 168.9 (s, C-4).
19F NMR (564.3 MHz): d = -136.56 (pseudo t, 3JH,F(cis) = 19.1 Hz).
MS (GC/MS): m/z (%) = 222 (M+, 18), 177 (M+-OC2H5, 12), 153
(42), 149 (M+-C3H5O2, 100), 133 (10), 129 (149-HF, 34), 125
(25), 109 (10), 77 (4), 51 (4).
19F NMR (188.29 MHz): d = -190.24 (m).
MS (GC/MS): m/z (%) = 236 (M+, 0), 221 (M+-CH3, 2), 207 (1),
180 (McLafferty, 33), 163 (M+-C4H9O, 10), 160 (180-HF, 31),
135 (M+-C5H9O2, 43), 125 (19), 115 (135-HF, 31), 105 (22), 77
+
+
(C6H5 , 4), 57 (C4H9 , 100), 41 (34).
Anal. Calcd for C13H15FO2 (222.25, mixture of 4c and 5c): C, 70.25;
5e:
H, 6.80. Found: C, 70.29; H, 6.94.
Yield: 0.28 g (29%).
1H NMR: d = 1.15 (s, 9H, C(CH3)3), 1.71 (ddd, 1H, 2JH,H = 7.2 Hz,
3
3JH,H(cis) = 10.3 Hz, JH,F(cis) = 19.3 Hz, HB), 1.95 (ddd, 1H,
Ethyl 2-Butyl-2-fluoro-cyclopropanecarboxylates (4d, 5d)
The reaction was carried out following typical procedure I, from 3d
(0.50 g, 4.9 mmol). Separation of the crude product by column chro-
matography (silica gel, pentane/Et2O, 40:1) afforded the pure iso-
mers 4d and 5d as colorless oils.
3
3
2JH,H = 7.2 Hz, JH,H(trans) = 7.6 Hz, JH,F(trans) = 12.2 Hz, HA), 2.46
(ddd, 1H, 3JH,H(cis) = 10.3 Hz, 3JH,H(trans) = 7.6 Hz, 3JH,F(cis) = 18.6 Hz,
HX), 7.3-7.5 (m, 5H, Harom.).
13C NMR: d = 15.9 (dt, 2JC,F = 10.2 Hz, C-3), 27.9 (q, C-6/7/8), 28.8
(dd, 2JC,F = 15.3 Hz, C-1), 81.6 (s, C-5), 82.9 (ds, 1JC,F = 221.3 Hz,
C-2), 128.1 (d, C-10/14), 128.7 (d, C-11/13), 129.1 (d, C-12), 133.3
(ds, 2JC,F = 20.4 Hz, C-9), 167.8 (s, C-4).
4d:
Yield: 0.18 g (20%).
3
1H NMR: d = 0.93 (t, 3H, JH,H = 7.2 Hz, 10-CH3), 1.05 (ddd, 1H,
3
3
2JH,H = 6.4 Hz, JH,H(cis) = 9.0 Hz, JH,F(trans) = 11.0 Hz, HA), 1.27 (t,
3H, 3JH,H = 7.2 Hz, 6-CH3), 1.3-1.9 (m, 8H, 7-9-CH2/HB/HX), 4.1-
4.2 (m, 2H, 3JH,H = 7.2 Hz, 5-CH2).
19F NMR (188.29 MHz): d = -153.80 (m).
MS (GC/MS): m/z (%) = 236 (M+, 0), 221 (M+-CH3, 2), 193 (2),
180 (McLafferty, 48), 163 (M+-C4H9O, 11), 160 (180-HF, 39),
135 (M+-C5H9O2, 59), 125 (31), 115 (135-HF, 26), 105 (16), 77
13C NMR: d = 13.8 (q, C-10), 14.2 (q, C-6), 17.2 (dt, 2JC,F = 12.7 Hz,
C-3), 22.2 (t, C-9), 25.3 (dd, 2JC,F = 12.7 Hz, C-1), 27.3 (t, C-8), 35.0
(dt, 2JC,F = 20.3 Hz, C-7), 60.7 (t, C-5), 81.6 (ds, 1JC,F = 231.4 Hz, C-
2), 168.6 (s, C-4).
+
+
+
(C6H5 , 5), 57 (C4H9 , 100), 51 (C4H3 , 6), 41 (24).
Anal. Calcd for C14H17FO2 (236.28, mixture of 4e and 5e): C, 71.17;
H, 7.25. Found: C, 71.20; H, 7.45.
19F NMR: d = -191.0 (m).
MS(GC/MS): m/z (%) = 188 (M+, 1), 160 (McLafferty, 5), 159
2-Fluoro-2-phenylcyclopropanecarboxylic Acids (6a, 7a)
To a solution of KOH (1.51 g, 27 mmol) in dry MeOH (10 mL) a
1:1 mixture of 4a and 5a (0.57 g, 2.7 mmol) was added slowly at
(M+-C2H5, 8), 146 (M+-C3H6, 36), 143 (M+-C2H5O, 22), 133 (10),
Synthesis 2000, No. 10, 1479–1490 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Cyclopropanation of Vinyl Fluorides
1487
0 °C. After strirring at r.t. overnight, the mixture was poured into ice
water (50 mL) and extracted successively with CH2Cl2 (2 ¥ 25 mL).
The aqueous phase was adjusted with 2 N hydrochloric acid to pH
1 and extracted with CH2Cl2 (3 ¥ 25 mL). Drying of the latter ex-
tracts (MgSO4) and removing of the solvent by evaporation (rotary
evaporator) afforded a mixture of 6a and 7a as colorless crystals (to-
tal yield: 0.45 g, 93%).
(M+-C3H5O2, 100), 133 (20), 116 (9), 115 (52), 109 (8), 89 (6), 77
+ +
(5) [C6H5 ], 73 (6), 63 (4), 51 (C4H3 , 6).
Ethyl 2-Fluoro-3-(4-methoxyphenyl)cyclopropanecarboxylates
(9b+10b)
The reaction was carried out following typical procedure I, from 8b
(0.60 g, 4.1 mmol) which was synthesized as an E/Z-mixture
(86:14) by a Wittig-type reaction.14 Three of the four possible dia-
stereomers were found in the crude product by 19F NMR spectros-
copy and GC/MS. Since the mass spectra of the three isomers are
almost identical, just one is given below. Because of low conver-
sion, the esters 9b and 10b were not isolated, but the configuration
can be assigned from the 19F NMR spectrum of the mixture.
Complete separation of isomers 6a and 7a can be achieved by frac-
tional crystallization from CH2Cl2. One single crystal of each iso-
mer was used for X-ray analysis.
6a:
Mp: 102 °C (CH2Cl2).
2
1H NMR (250.0 MHz): d = 1.71 (ddd, 1H, JH,H = 6.9 Hz,
2
3
19F NMR: d = -218.13 (ddd, JH,F = 64.9 Hz, JH,F(trans) = 7.6 Hz,
3JH,F(cis) = 19.1 Hz), ethyl t-2-fluoro-t-3-(4-methoxyphenyl)cyclo-
propane-r-1-carboxylate (not shown in Scheme 5); -214.44 (ddd,
3
3JH,H(cis) = 9.2 Hz, JH,F(trans) = 11.3 Hz, HA), 2.20 (ddd, 1H,
3
3
3JH,H(cis) = 9.2 Hz, JH,H(trans) = 7.6 Hz, JH,F(trans) = 2.9 Hz, HX), 2.33
(ddd, 1H, 2JH,H = 6.9 Hz, 3JH,H(trans) = 7.6 Hz, 3JH,F(cis) = 20.1 Hz, HB),
7.30-7.44 (m, 5H, Harom.).
3
3
2JH,F = 62.9 Hz, JH,F(trans) = 3.8 Hz, JH,F(cis) = 22.9 Hz), ethyl c-2-
fluoro-t-3-(4-methoxyphenyl)cyclopropane-r-1-carboxylate (9b);
2
3
3
13C NMR (62.9 MHz): d = 19.4 (dt, 2JC,F = 12.4 Hz, C-4), 28.7 (dd,
-206.06 (ddd, JH,F = 62.9 Hz, JH,F(cis) = 17.2 Hz, JH,F(cis) = 22.9
Hz), ethyl t-2-fluoro-c-3-(4-methoxyphenyl)cyclopropane-r-1-
carboxylate (10b); (ratio 23:29:48).
1
2JC,F = 11.6 Hz, C-2), 81.5 (ds, JC,F = 229.8 Hz, C-3), 124.8 (dd,
3JC,F = 6.2 Hz, C-6/10), 128.6 (d, C-8), 128.7 (d, C-7/9), 132.5 (ds,
2JC,F = 19.9 Hz, C-5), 174.2 (s, C-1).
MS (GC/MS): m/z (%) = 238 (M+, 22), 218 (M+-HF, 6), 209 (M+-
CHO/M+-C2H5, 4), 193 (M+-C2H5O, 10), 189 (209-HF, 3), 165
(M+-C3H5O2, 100), 145 (15), 133 (7), 121 (5), 101 (4), 91 (5), 77
(3), 59 (4), 51 (3).
19F NMR: d = -186.58 (m).
MS (GC/MS) after silylation: m/z (%) = 253 (MH+, 6), 252 (M+,
26), 237 (M+-CH3, 42), 197 (37), 162 (C10H7OF+, 52), 134 (15),
133 (15), 117 (C4H9O2Si+, 5), 116 (33), 115 (50), 105 (40), 77
+
(C6H5 , 32), 73 (C3H9Si+, 100).
Lipase-Catalyzed Hydrolysis of Racemic 4a in a Phosphate
Buffer
7a:
Compound 4a (104 mg, 0.50 mmol) was suspended in a phosphate
buffer solution (20 mL, 0.1 M, pH 7.0) and the respective enzyme
(20 mg) was added. The reaction mixture was stirred at r.t. for 7 d.
After addition of 2 N HCl (5 mL), the mixture was extracted with
CH2Cl2 (3 x 20 mL) and the conversion was determined by 19F
NMR spectroscopy. Afterwards, the combined organic layers were
extracted with sat. NaHCO3∑2 N HCl was added to the combined
NaHCO3 layers until pH 1-2 was reached and this mixture was ex-
tracted twice with CH2Cl2. After drying (MgSO4) and removal of
the solvent, the enantiomerically enriched (1R,2R)-6a (hydrolysis
of racemic 4a with CRL: 88 mg, 49%) was isolated. The enantio-
meric excess of the remaining ester (1S,2S)-4a was not determined.
Mp: 95 °C (CH2Cl2).
1H NMR (250.0 MHz): d = 1.87 (m, 2H, HA/HB), 2.49 (ddd, 1H,
3
3
3JH,H(trans) = 7.6 Hz, JH,H(cis) = 10.2 Hz, JH,F(cis) = 17.6 Hz, HX),
7.29-7.45 (m, 5H, Harom.).
13C NMR (62.9 MHz): d = 17.3 (dt, 2JC,F = 10.4 Hz, C-4), 27.5 (dd,
2JC,F = 17.3 Hz, C-2), 83.6 (ds, 1JC,F = 221.9 Hz, C-3), 128.3 (d, C-
8), 128.3 (d, C-7/9), 128.4 (dd, 3JC,F = 5.6 Hz C-6/10), 132.5 (ds,
2JC,F = 19.9 Hz, C-5), 175.0 (s, C-1).
19F NMR: d = -152.06 (m).
MS (GC/MS) after silylation: m/z (%) = 253 (MH+, 9), 252 (M+,
39), 237 (M+-CH3, 41), 236 (17), 207 (11), 197 (51), 162
(C10H7OF+, 68), 134 (20), 133 (20), 117 (C4H9O2Si+, 5), 116 (30),
Determination of the Enantiomeric Excesses of Carboxylic
Acids 6
115 (52), 105 (49), 77 (C6H5 , 32), 73 (C3H9Si+, 100).
+
According to ref.,34 the fluorocarboxylic acids 6 (0.5 mmol) pre-
pared from the esters 4 by saponification (KOH, MeOH) and enan-
tiopure (-)-menthol (224 mg, 1.5 mmol) were dissolved in anhyd
CH2Cl2 (2 mL). N,N-dicyclohexyl carbodiimide (113 mg, 0.55
mmol) and a catalytic amount of 4-(N,N-dimethylamino)pyridine
(approx. 5 mg) was added and the mixture was stirred at r.t. for 12
h. The precipitated dicyclohexyl urea was filtered off and washed
with CH2Cl2 (1 mL). The combined organic layer was evaporated
and the diastereomeric excess of the crude esters was determined by
19F NMR spectroscopy.
Anal. Calcd for C10H9FO2 (180.17, mixture of 6a and 7a): C, 66.66;
H, 5.03. Found: C, 66.69; H, 5.35.
Ethyl 2-Fluoro-3-phenylcyclopropanecarboxylates (9a+10a)
The reaction was carried out following general procedure I, from 8a
(0.50 g, 4.1 mmol) which was synthesized as an E/Z-mixture
(86:14) by a Wittig-type reaction.14 Three of the four possible dia-
stereomers were found in the crude product by 19F NMR spectros-
copy and GC/MS. Since the mass spectra of the three isomers are
almost identical, just one is given below. Because of low conver-
sion, the esters 9a and 10a were not isolated, but the configuration
can be assigned from the 19F NMR spectrum of the mixture.
Asymmetric Cyclopropanation ofa-Fluorostyrene (3a); Typical
Procedure II
2
3
19F NMR: d = -218.11 (ddd, JH,F = 64.9 Hz, JH,F(trans) = 7.6 Hz,
The bis(oxazoline) ligand 11a, 11b or 12 (0.15 mmol) and
CuOTf·½benzene (30 mg, 0.12 mmol) were dissolved in anhyd
CH2Cl2 (5 mL) and stirred at r.t. for 1 h. Then 3a (0.50 g, 4.1 mmol)
was added. Afterwards, a solution of diazoacetate (6.15 mmol) in
anhyd CH2Cl2 (3 mL) was added at 40 °C through a syringe con-
trolled by a syringe pump over a period of 6-7 h. After stirring for
one more hour and addition of CH2Cl2 (100 mL), the mixture was
washed successively with sat. Na2CO3 (2 ¥ 50 mL) and H2O (2 ¥ 50
mL). After drying (MgSO4) and evaporation of the solvent, the
crude product was purified by column chromatography (silica gel,
3JH,F(cis) = 19.1 Hz), ethyl t-2-fluoro-t-3-phenylcyclopropane-r-1-
2
carboxylate (not shown in Scheme 5); -214.11 (ddd, JH,F = 64.9
Hz, 3JH,F(trans) = 3.8 Hz, 3JH,F(cis) = 21.0 Hz), ethyl c-2-fluoro-t-3-phe-
2
nylcyclopropane-r-1-carboxylate (9a); -206.72 (ddd, JH,F = 61.0
Hz, 3JH,F(cis) = 17.2 Hz, 3JH,F(cis) = 21.0 Hz), ethyl t-2-fluoro-c-3-phe-
nylcyclopropane-r-1-carboxylate (10a); (ratio 27:28:45).
MS (GC/MS): m/z (%) = 208 (M+, 20), 188 (M+-HF, 7), 179 (M+-
CHO/M+-C2H5, 2), 163 (M+-C2H5O, 20), 160 (6), 136 (20), 135
Synthesis 2000, No. 10, 1479–1490 ISSN 0039-7881 © Thieme Stuttgart · New York

1488
O. G. J. Meyer et al.
FEATURE ARTICLE
Table 6 Optical Rotations of Enantiomerically Enriched Mono-
C-2), 128.2 (d, C-6/7/9/10), 129.1 (d, C-8), 133.2 (ds, 2JC,F = 19.4
fluorinated Cyclopropane Carboxylates
Hz, C-5), 168.2 (s, C-4).
19F NMR: d = -153.56 (m) [(1R,2R)-5f]; -154.85 (m) [(1S,2S)-5f];
Compounds ee 4
ee 5
[%]
[a]2D0
4
[a]2D0
5
(ratio 1:99).
[%]
(c 1, CH2Cl2) (c 1, CH2Cl2)
MS (GC/MS): m/z (%) = 318 (M+, 0), 180 (McLafferty, 26), 160
(180-HF, 12), 139 (C10H19+, 32), 135 (M+-C11H19O2, 15), 115
(135-HF, 12), 105 (8), 97 (19), 83 (100), 71 (6), 69 (32), 57 (28),
55 (38), 41 (20).
a
c
d
e
89
65
16
93
80
-161.0
-30.2
-34.8
152.3
-29.8
-1.2
-42.4
n.d.
n.da
n.d.
89
Determination of the Absolute Configuration of (1S,2S)-2-Fluo-
ro-2-phenylcyclopropanecarboxylic (4-Bromophenyl)amide
(13)
a n.d = not determined.
Enantiopure compound 6a (315 mg, 1.75 mmol), prepared by sa-
ponification of 4a (89% ee) and recrystallization, and SOCl2 (0.30
mL, 4.14 mmol) were dissolved in dry benzene (10 mL) and heated
under reflux for 5 h. After removing the solvent and excess SOCl2
by evaporation, the residue was dissolved in CH2Cl2 (3 mL). This
solution was added slowly to a cold (0 °C) solution of 4-bromo-
aniline (310 mg, 1.8 mmol) and Et3N (0.5 mL) in CH2Cl2 (5 mL)
and stirred overnight. The mixture was poured into sat. NH4Cl (20
mL) and extracted with CH2Cl2 (3 ¥ 10 mL). The organic phase was
washed successively with sat. NaHCO3, H2O, and brine (50 mL
each). After drying (MgSO4), the solvent was removed by evapora-
tion (rotary evaporator). Purification of the crude product by recrys-
tallization from EtOAc afforded 13 (400 mg, 69%) as white
crystals; mp 160 °C (sublimation). One of the single crystals of 13
was used for X-ray analysis.
same eluents as for the racemic products). The spectroscopic data of
all optically active products agree with those obtained for the corre-
sponding racemic compounds. If not stated otherwise (cf. Table 4),
the enantiomeric excess was determined by 19F NMR spectroscopy
after saponification of the cyclopropane carboxylates (KOH in
MeOH) and esterification with enantiopure (-)-menthol using the
above described method. The enantiomeric excesses and optical ro-
tations are given in Table 6.
(-)-Menthyl 2-Fluoro-2-phenylcyclopropanecarboxylate (4f,
5f)
4f:
2
1H NMR (acetone-d6): d = 1.69 (ddd, 1H, JH,H = 6.7 Hz,
Yield: 0.29 g (22%).
3
3JH,H(cis) = 9.1 Hz, JH,F(trans) = 10.3 Hz, HA), 2.32 (ddd, 1H,
3
1H NMR: d = 0.80 (d, 3H, JH,H = 6.9 Hz, CH3), 0.90 (d, 3H,
3
3
2JH,H = 6.7 Hz, JH,H(trans) = 7.6 Hz, JH,F(cis) = 20.3 Hz, HB), 2.42
3JH,H = 6.9 Hz, CH(CH3)2), 0.91 (d, 3H, 3JH,H = 6.4 Hz, CH(CH3)2),
(ddd, 1H, JH,H(cis) = 9.1 Hz, 3JH,H(trans) = 7.6 Hz, 3JH,F(trans) = 4.0 Hz,
3
2
0.83-1.15 (m, 3H), 1.34-1.54 (m, 2H), 1.59 (ddd, 1H, JH,H = 6.7
Hz, 3JH,H(cis) = 9.3 Hz, 3JH,F(trans) = 10.7 Hz, HA), 1.64-1.76 (m, 2H),
HX), 7.31-7.48 (m, 7H, Harom.), 7.62-7.70 (m, 2H, Harom.).
3
13C NMR: d = 18.3 (dt, 2JC,F = 12.7 Hz, C-3), 32.9 (dd, 2JC,F = 12.7
Hz, C-1), 82.0 (ds, 1JC,F = 225.1 Hz, C-2), 116.3 (s, C-8), 122.0 (dd,
3JC,F = 6.4 Hz, C-12/16), 125.0 (dd, 4JC,F = 6.4 Hz, C-13/15), 129.0
(d, C-14), 129.7 (d, C-6/10), 132.7 (d, C-7/9), 139.8 (ds, 2JC,F = 21.6
Hz, C-11), 140.0 (s, C-5), 165.0 (s, C-4).
1.82-1.98 (m, 1H), 2.0-2.1 (m, 1H), 2.16 (ddd, 1H, JH,H(cis) = 9.3
3
3
Hz, JH,H(trans) = 7.8 Hz, JH,F(trans) = 3.2 Hz, HX), 2.28 (ddd, 1H,
2JH,H = 6.7 Hz, JH,H(trans) = 7.8 Hz, JH,F(cis) = 20.0 Hz, HB), 4.75-
4.88 (m, 1H, 11-CH), 7.2-7.5 (m, 5H, Harom.).
3
3
2
13C NMR: d = 16.5 (q, CH(CH3)2), 18.5 (dt, JC,F = 12.7 Hz, C-3),
19F NMR: d = -189.97 (m).
20.6 (q, CH(CH3)2), 22.0 (q, C-17), 23.7 (t, C-14), 26.5 (d, C-18),
29.4 (dd, 2JC,F = 11.5 Hz, C-1), 31.4 (d, C-15), 34.3 (t, C-13), 41.0
(t, C-16), 47.1 (d, C-12), 75.2 (d, C-11), 80.7 (ds, 1JC,F = 227.6 Hz,
C-2), 124.7 (dd, 3JC,F = 6.4 Hz, C-6/10), 128.3 (d, C-8), 128.6 (d, C-
7/9), 137.7 (ds, 2JC,F = 21.6 Hz, C-5), 167.2 (s, C-4).
MS (GC/MS): m/z (%) = 336/334 (M++H, 12/14), 335/333 (M+, 70/
68), 315/313 (M+-HF, 7/6), 280/278 (10/12), 260/258 (280/278-
HF, 4/5), 213/211 (C8H6NOBr+, 18/20), 173/171 (C6H6NBr+, 30/
32), 162 (M+-C6H6NBr, 78), 135 (C9H8F+, 82), 115 (135-HF,
100), 109 (18), 91 (15), 76 (8), 63 (14), 39 (12).
19F NMR: d = -187.35 (m) [(1S,2S)-4f]; -188.59 (m) [(1R,2R)-4f];
(ratio 96:4).
MS (GC/MS): m/z (%) = 318 (M+, 0), 180 (McLafferty, 25), 160
(180-HF, 12), 139 (C10H19+, 24), 135 (M+-C11H19O2, 14), 115
(135-HF, 14), 105 (6), 97 (16), 83 (100), 71 (6), 69 (32), 57 (28),
55 (31), 43 (12), 41 (12).
Anal. Calcd for C16H13NBrFO (334.18): C, 57.51; H, 3.92; N, 4.19.
Found: C, 57.15; H, 3.99; N, 3.94.
trans-N-(2-Fluoro-2-phenylcyclopropyl)carbamic Acid tert-
Butyl Ester (14)
A two-neck 250 mL flask, which had been thoroughly dried,
pumped and purged with Ar, was charged with racemic 6a (834 mg,
4.55 mmol), anhyd cyclohexane (85 mL), Et3N (0.73 mL, 5.31
mmol, freshly distilled from CaH2), t-BuOH (4.38 mL, 46.1 mmol,
freshly distilled from CaH2), and diphenylphosphoryl azide (1.0
mL, 4.8 mmol). The mixture was heated at 70 °C for 18 h under Ar
and then di-tert-butyl dicarbonate (1.55 mL, 6.8 mmol) was added,
and the mixture was heated for a further 2 h. The reaction was then
cooled to r.t., and the solvent was removed by evaporation (rotary
evaporator) leaving a thick oil. EtOAc (120 mL) was added, and the
organic layer was washed successively with 5% aqueous citric acid,
H2O, sat. NaHCO3, and brine (75 mL each). The excess dicarbonate
was removed by Kugelrohr distillation (60 °C at 1.2∑10–1 mbar),
and the residue was purified by column chromatography (silica gel,
EtOAc/cyclohexane, 6:1) to give 14 (0.68 g, 60%) as a white solid;
mp 103 °C (EtOAc).
5f:
Yield: 0.15 g (6%).
1H NMR: d = 0.47 (d, 3H, JH,H = 6.9 Hz, CH3), 0.79 (d, 3H,
3
3JH,H = 7.2 Hz, CH(CH3)2), 0.80 (d, 3H, 3JH,H = 6.4 Hz, CH(CH3)2),
0.8-1.0 (m, 3H), 1.14-1.37 (m, 3H), 1.45-1.70 (m, 3H), 1.78 (ddd,
1H, 2JH,H = 7.1 Hz, 3JH,H(cis) = 10.5 Hz, 3JH,F(cis) = 19.8 Hz, HB), 2.01
2
3
3
(ddd, 1H, JH,H = 7.1 Hz, JH,H(trans) = 7.6 Hz, JH,F(trans) = 12.6 Hz,
3
3
HA), 2.54 (ddd, 1H, JH,H(cis) = 10.5 Hz, JH,H(trans) = 7.6 Hz,
3JH,F(cis) = 18.1 Hz, HX), 4.3-4.5 (m, 1H, 11-CH), 7.3-7.5 (m, 5H,
Harom.).
13C NMR: d = 15.9 (q, CH(CH3)2), 16.1 (dt, JC,F = 9.7 Hz, C-3),
20.7 (q, CH(CH3)2), 21.9 (q, C-17), 23.2 (t, C-14), 26.0 (d, C-18),
28.5 (dd, 2JC,F = 16.64 Hz, C-1), 31.2 (d, C-15), 34.1 (t, C-13), 40.4
(t, C-16), 46.8 (d, C-12), 74.6 (d, C-11), 83.1 (ds, 1JC,F = 220.6 Hz,
2
Synthesis 2000, No. 10, 1479–1490 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Cyclopropanation of Vinyl Fluorides
1489
1H NMR: d = 1.35-1.68 (m, 3H, HA/HB/HX), 1.47 (s, 9H, C(CH3)3),
7.25-7.41 (m, 5H, Harom.).
13C NMR: d = 20.2 (dt, 2JC,F = 11.4 Hz, C-3), 28.3 (q, C-6/7/8), 34.0
(br s, C-1), 79.1 (ds, 1JC,F = 219.2 Hz, C-2), 80.0 (s, C-5), 125.0 (d,
C-10/14), 128.1 (d, C-12), 128.5 (d, C-11/13), 137.5 (ds,
2JC,F = 20.3 Hz, C-9), 156.3 (s, C-4).
tion via SORTAV (0.591 £ T £ 0.867), Z = 2, triclinic, space group
P1 (No. 1), l = 0.71073 Å, T = 198 K, w and j scans, 4298 reflec-
tions collected ( h, k, l), [(sinq)/l] = 0.65 Å-1, 3298 independent
(Rint = 0.041) and 2933 observed reflections [I ≥ 2 s(I)], 367 refined
parameters, R = 0.050, wR2 = 0.129, max. residual electron density
0.45 (-0.43) e Å-3, Flack parameter -0.02(2), hydrogens calculated
and refined as riding atoms.
19F NMR: d = -191.04 (m).
MS (GC/MS): m/z (%) = 251 (M+, 1), 250 (M+-H, 1), 236 (M+-
Acknowledgement
CH3, 1), 195 (McLafferty, 6), 175 (195 - HF, 4), 151 (C9H10NF+,
+
+
18), 130 (70), 103 (16), 77 (C6H5 , 14), 59 (CHNO2 , 40), 57
We would like to thank the Degussa AG, Hanau and Allied Signal
Specialty Chemicals, Riedel-de Haën GmbH, Seelze, for the kind
donation of chemicals. O. G. J. M. is grateful to the Deutsche For-
schungsgemeinschaft for a stipend (Graduiertenkolleg "Hochreak-
tive Mehrfachbindungssysteme") and the Deutscher Akademischer
Austauschdienst for funding.
+
+
(C4H9 , 100), 51 (C4H3 , 20), 41 (56).
Anal. Calcd for C14H18FNO2 (251.30): C, 66.91; H, 7.22; N, 5.57.
Found: C, 66.70; H, 7.00; N, 5.55.
trans-(2-Fluoro-2-phenylcyclopropyl)amine Hydrochloride
(15)
A suspension of 14 (145 mg, 0.58 mmol) in 1.2 N HCl/HOAc (5
mL) was stirred at r.t. for 1 h. After evaporation, HOAc (10 mL)
was added twice and evaporated to remove traces of HCl. Washing
of the residue with Et2O (5 mL) and drying of the solid at r.t./15
mbar for 1 h yielded 50 mg (46%) of 15 as a white solid (46%); mp
160 °C (decomposition).
1H NMR (methanol-d4): d = 1.79-1.96 (m, 2H, CH2), 3.05-3.15
(m, 1H, CH), 7.40-7.50 (m, 5H, Harom.).
References
+
X-ray structures
(1) Liu, H. -W.; Walsh, C. T. Biochemistry of the Cyclopropyl
Group. In The Chemistry of the Cyclopropyl Group;
Rappoport, Z., Ed.; Wiley: New York, 1987; pp 959-1025.
Salaün, J. Top. Curr. Chem. 2000, 207, 1.
(2) For recent reviews, see: Houben-Weyl, 4th ed., Vol. E17a/b;
de Meijere, A., Ed.; Thieme: Stuttgart, 1997.
(3) Biomedical Frontiers of Fluorine Chemistry; Ojima, I.;
McCarthy, J. R.; Welch, J. T., Eds.; ACS Symposium Series
639, Washington DC, 1996.
2
13C NMR (methanol-d4): d = 18.1 (dt, JC,F = 12.7 Hz, C-3), 32.7
2
1
(dd, JC,F = 10.2 Hz, C-1), 79.5 (ds, JC,F = 218.7 Hz, C-2), 127.0
3
(dd, JC,F = 6.4 Hz, C-5/9), 130.2 (d, C-6/8), 130.5 (d, C-7), 136.8
(ds, 2JC,F = 20.3 Hz, C-4).
Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications; Filler, R.; Kobayashi, Y.;
Yagupolski, L. M., Eds.; Elsevier: Amsterdam, 1993.
Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1991.
19F NMR (methanol-d4): d = -187.94 (m).
MS (direct inlet): m/z (%) = 188/186 (M+, 0/0), 151 (M+-HCl, 12),
150 (C9H9FN+, 22), 131 (12), 130 (150-HF, 100), 103 (32), 99 (11),
+
+
77 (C6H5 , 16), 74 (18), 57 (11), 51 (C4H3 , 13).
(4) Asymmetric Fluoroorganic Chemistry. Synthesis,
Applications, and Future Directions; Ramachandran, P. V.,
Ed.; ASC Symposium Series 746: American Chemical
Society: Washington, DC, 2000.
Anal. Calcd for C9H11ClFN (187.64): C, 57.61; H, 5.91; N, 7.46.
Found: C, 57.34; H, 5.95; N, 7.29.
X-Ray Crystal Data
6a:
Enantiocontrolled Synthesis of Fluoro-Organic Compounds;
Soloshonok, V. A., Ed.; Wiley: New York, 1999.
Chemistry of Organic Fluorine Compounds II; Hudlický, M.;
Pavlath, A. E., Eds.; ACS Monograph 187: Washington, DC,
1995.
Formula
C10H9O2F,
M = 180.17,
colorless
crystal
0.40 ¥ 0.20 ¥ 0.20 mm, a = 5.492(1), b = 7.569(2), c = 20.451(2)
Å, b = 93.78(1)∞, V = 848.3(2) Å3, rcalc = 1.411 g cm-3 m = 1.12
cm-1, no absorption correction (0.957 £ T £ 0.978), Z = 4, mono-
clinic, space group P21/c (No. 14), l = 0.71073 Å, T = 293 K, w/2q
scans, 1654 reflections collected (+h, +k, l), [(sinq)/l] = 0.59 Å-1,
1489 independent (Rint = 0.009) and 1118 observed reflections
[I ≥ 2 s(I)], 120 refined parameters, R = 0.029, wR2 = 0.079, max.
residual electron density 0.18 (-0.16) e Å-3, hydrogens calculated
and refined as riding atoms.
Organofluorine Chemistry; Banks, R. E.; Smart, B. E.;
Tatlow, J. C., Eds.; Plenum Press: New York, 1994.
Synthetic Fluorine Chemistry; Olah, G. A.; Chambers, R. D.;
Prakash, G. K. S., Eds.; Wiley: New York, 1992.
(5) Imura, A.; Itoh, M.; Miyadera, A. Tetrahedron: Asymmetry
1998, 9, 3047.
(6) a) Ernet, T.; Haufe, G. Tetrahedron Lett. 1996, 37, 7251.
b) Ernet, T.; Haufe, G. Synthesis 1997, 953.
7a:
c) Laue, K. W.; Haufe, G. Synthesis 1998, 1453.
d) Laue, K. W.; Mück-Lichtenfeld, C.; Haufe, G. Tetrahedron
1999, 55, 10413.
e) Bogachev, A. A.; Kobrina, L. S.; Meyer, O. G. J.; Haufe, G.
J. Fluorine Chem. 1999, 97, 135.
Formula
C10H9O2F,
M = 180.17, colorless crystal
0.5 ¥ 0.05 ¥ 0.05 mm, a = 24.124(3), b = 5.543(1), c = 40.282(6)
Å, b = 98.20(1)∞, V = 5331.4(14) Å3, rcalc = 1.347 g cm-3, m = 9.05
cm-1, no absorption correction, Z = 24, monoclinic, space group
C2/c (No. 15), l = 1.54178 Å, T = 223 K, w/2q scans, 4032 reflec-
tions collected ( h, -k, -l), [(sinq)/l] = 0.56 Å-1, 3961 independent
(Rint = 0.141) and 2023 observed reflections [I ≥ 2 s(I)], 355 refined
parameters, R = 0.068, wR2 = 0.170, max. residual electron density
0.39 (-0.34) e Å-3, hydrogens calculated and refined as riding
atoms.
f) Kovtonyuk V. N.; Kobrina, L. S.; Gatilov, Y. V.;
Bagryanskaya, I. Y.; Fröhlich, R.; Haufe, G. J. Chem. Soc.,
Perkin Trans. I 2000, in press.
(7) Meyer, O. G. J.; Haufe, G. presented in part at the 12th
European Symposium on Fluorine Chemistry, Berlin, 1998,
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13:
(8) Cottens, S.; Schlosser, M. Tetrahedron 1988, 44, 7127.
(9) Buddrus, J.; Nerdek, F.; Hentschel, P.; Klamann, D.
Tetrahedron Lett. 1966, 5379.
Formula
C16H13NOFBr,
M = 334.18,
colorless
crystal
0.20 ¥ 0.10 ¥ 0.05 mm, a = 5.706(1), b = 7.890(1), c = 15.613(4)
Å, a = 90.55(1), b = 94.90(1), g = 91.84(2)∞, V = 699.9(2) Å3,
r
calc = 1.586 g cm-3, m = 29.42 cm-1, empirical absorption correc-
Synthesis 2000, No. 10, 1479–1490 ISSN 0039-7881 © Thieme Stuttgart · New York

1490
O. G. J. Meyer et al.
FEATURE ARTICLE
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Article Identifier:
1437-210X,E;2000,0,10,1479,1490,ftx,en;H03300SS.pdf
Synthesis 2000, No. 10, 1479–1490 ISSN 0039-7881 © Thieme Stuttgart · New York