Synthesis, reactions and structural features of monofluorinated cyclopropanecarboxylates

Article abstract of DOI:10.1016/S0022-1139(02)00040-4

Monofluorinated cyclopropanecarboxylates are available in racemic or optically active form by transition metal-catalyzed reactions of vinylfluorides with diazoacetates. From α-fluorostyrene and tert-butyl diazoacetate in the presence of 2mol% of an enantiopure bis(oxazoline) copper complex, a 81:19 mixture of tert-butyl trans- and cis-2-fluoro-2-phenylcyclopropanecarboxylates was obtained with high enantiomeric excess (ee) of 93 or 89%, respectively. The corresponding racemic ethylesters were used as starting materials for the synthesis of carboxamides, of the cis- and trans-isomers of analogues of tranylcypromine, an anti-depressive drug and several of its homologous fluorinated cyclopropylmethyl and cyclopropylethyl amines. Corresponding enantiopure cyclopropylmethanols and several of their derivatives were synthesized also. Solid state structures of a selection of these compounds were examined by X-ray crystallography. Particularly, the cis-configurated fluorinated phenylcyclopropane derivatives showed extremely close intermolecular C-H···F-C contacts. The shortest of such distances (2.17A) was found in the N-(4-bromophenyl)carbamate of (1S,2R)-(2-fluoro-2-phenylcyclopropyl)methanol.

Full text of DOI:10.1016/S0022-1139(02)00040-4

Journal of Fluorine Chemistry 114 (2002) 189–198
Synthesis, reactions and structural features of monofluorinated
cyclopropanecarboxylates
a,*
Gunter Haufe , Thomas C. Rosen , Oliver G.J. Meyer , R. Frohlich , Kari Rissanen
a
a
a
b
¨
¨
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat, Corrensstrasse 40, D-48149 Munster, Germany
a
¨
¨
¨
bDepartment of Chemistry, University of Jyva¨skyla¨, P.O. Box 35, FIN-40351 Jyva¨skyla¨, Finland
Received 18 September 2001; received in revised form 24 January 2002; accepted 24 January 2002
Abstract
Monofluorinated cyclopropanecarboxylates are available in racemic or optically active form by transition metal-catalyzed reactions of
vinylfluorides with diazoacetates. From a-fluorostyrene and tert-butyl diazoacetate in the presence of 2 mol% of an enantiopure bis(oxazo-
line) copper complex, a 81:19 mixture of tert-butyl trans- and cis-2-fluoro-2-phenylcyclopropanecarboxylates was obtained with high
enantiomeric excess (ee) of 93 or 89%, respectively. The corresponding racemic ethylesters were used as starting materials for the synthesis of
carboxamides, of the cis- and trans-isomers of analogues of tranylcypromine, an anti-depressive drug and several of its homologous
fluorinated cyclopropylmethyl and cyclopropylethyl amines. Corresponding enantiopure cyclopropylmethanols and several of their
derivatives were synthesized also. Solid state structures of a selection of these compounds were examined by X-ray crystallography.
Particularly, the cis-configurated fluorinated phenylcyclopropane derivatives showed extremely close intermolecular CꢀH ꢁ ꢁ ꢁ FꢀC contacts.
˚
The shortest of such distances (2.17 A) was found in the N-(4-bromophenyl)carbamate of (1S,2R)-(2-fluoro-2-phenylcyclopropyl)methanol.
# 2002 Elsevier Science B.V. All rights reserved.
Keywords: Asymmetric synthesis; Transition metal-catalyzed reactions; Enantiopure bis(oxazoline) copper complexes; Cyclopropanation; Vinyl fluorides;
Fluorinated cyclopropanecarboxylates; X-ray structural analysis; Close intermolecular CꢀH ꢁ ꢁ ꢁ FꢀC contacts
1. Introduction
synthesis of monofluorinated or geminally difluorinated
cyclopropanes, which are based mainly on fluorocarbene
additions towards olefins [29–31,102]. Accordingly, gem-
inal difluorocyclopropyl methanols [32–36], difluorocyclo-
propane carboxylic acids and related amino acids were
synthesized ([37] and references cited therein). These latter
compounds gained particular interest as analogues of some
non-fluorinated methano amino acids. Such compounds are
currently attracting special attention because of their out-
standing biological activity and potential use in conforma-
tionally restricted peptides, providing biosynthetic and
mechanistic probes [38,39].
Furthermore, 2-fluoro-cyclopropylamines have been
synthesized by Curtius degradation of 2-fluorocyclopropane-
carboxylic acid [40], which has been synthesized by direct
fluorination of tert-butyl cis-2-(phenylsulfinyl)cyclopropane-
1-carboxylate and subsequent reductive desulfonylation [41].
In order to synthesize enantiopure cis-2-fluoro-cyclopropy-
lamine, which is a key intermediate in syntheses of anti-
bacterial quinolones, analogous to the highly potent
antibiotic ciprofloxacin (Ciprobay1), several methods of
de-racemization of the precursor, cis-2-fluorocyclopropane-
carboxylic acid, have been reported [42,43]. Fluorinated
Among the structural motifs responsible for biological
activity of molecules, the cyclopropyl group is one of the
most important. There is a wide variety of naturally occur-
ring cyclopropane derivatives having important biological
functions [1–5]. Consequently, such compounds continue to
attract much attention in organic synthesis [6–8] as well as in
biological, agricultural and medicinal chemistry [1–5,9,10].
On the other hand, it has been demonstrated for numerous
compounds that replacement of a C–H moiety with a C–F
group can cause dramatic effects on their physicochemical
properties and their chemical reactivity [11,12]. Moreover,
for biologically active molecules, significant modifications
of their physiological properties are connected to selective
fluorination in strategic positions [13–22].
Therefore, the development of new synthetic approaches
to fluorinated compounds continues to be an important field
of research [23–28]. There are several methods for the
* Corresponding author. Tel.: þ49-251-83-33281;
fax: þ49-251-8339772.
E-mail address: haufe@uni-muenster.de (G. Haufe).
0022-1139/02/$ – see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 0 4 0 - 4

190
G. Haufe et al. / Journal of Fluorine Chemistry 114 (2002) 189–198
Scheme 1.
Scheme 3.
Scheme 2.
cyclopropylamines have also been obtained by direct cyclo-
propanation of enamines with fluorocarbene and subsequent
de-racemization [44] or by related auxiliary-directed asym-
metric cyclopropanation [45].
There are also some examples of additions of non-fluori-
nated carbenes towards fluorinated olefins. Addition of
dichlorocarbene towards vinylfluoride yielded 1,1-dichloro-
2-fluorocyclopropane [46]. Taguchi and co-workers demon-
strated the diastereoselective cyclopropanation of fluorinated
allylic alcohol derivatives using the Simmons–Smith reaction
[47,48] (Scheme 1) and Sloan and Kirk published a synthesis
of a racemic fluorinated ethyl cyclopropanecarboxylate from
a b-fluoro-a,b-unsaturated carboxylate and diazomethane
[49] (Scheme 2).
While continuing our research on reactions of vinyl
fluorides [50–57], we became interested in their ability to
react in transition metal-catalyzed cyclopropanations [58].
A related method starting from monofluorinated 1,3-dienes
has been used by Cottens and Schlosser in the synthesis of
fluorinated chrysanthemic acid derivatives, but the reactions
suffered from low selectivity and moderate yields [59]. To
the best of our knowledge, there have been no previous
reports on asymmetric cyclopropanations of prostereogenic
fluoroolefins.
Herein, we report further results on transition metal-
catalyzed cyclopropanations of a-fluorostyrene, which pro-
vide smooth and efficient entries to racemic or enantiopure
monofluorinated phenylcyclopropanecarboxylates. More-
over, the application of compounds prepared by this method
for further syntheses of other fluorinated cyclopropanes will
be demonstrated. Finally, the solid state structure of some of
these compounds, examined by X-ray crystallography, will
be discussed in terms of quite short XꢀH ꢁ ꢁ ꢁ FꢀC contacts.
Scheme 4.
sequence consisting of bromofluorination [60,61] with NBS/
Et3Nꢁ3HF and subsequent HBr elimination from the respec-
tive bromofluoro compounds [51,62,63], are valuable build-
ing blocks for the synthesis of new fluorinated compounds.
Simple vinyl fluorides, such as a-fluorostyrene are weak
dienophiles in Diels–Alder reactions and do react solely with
very reactive dienes, such as diphenylisobenzofuran [56]. On
the other hand, vinyl fluorides are more reactive in electro-
philic additions, both in stepwise ones, such as halofluorina-
tions and in dihalogen carbene additions [64] (Scheme 3).
Recently, we demonstrated that a-fluorostyrene (1) is a
good substrate for metal ion-catalyzed cyclopropanation
with ethyl diazoacetate (EDA) [58]. In contrast to the
non-fluorinated olefins [65–67], copper salts, particularly
Cu(acac)2, are superior to palladium or rhodium salts in this
particular reaction [68]1 (Scheme 4; Table 1). However, in
all reactions of 1 with EDA 1:1 mixtures of cis/trans
isomeric,2 fluorinated cyclopropane carboxylates 2 and 3
were formed [58], while with the non-fluorinated counter-
parts trans-selectivity was observed [65–67].
The ratio of diastereomers depends on the steric demand
of the ester groups and the nature of the metal/ligand system.
While the reactions with copper or rhodium catalysts and
EDA gave always 1:1 mixtures (Table 2), the tert-butyl- or
the (ꢀ)-menthyl diazoacetates led to 3:2 mixtures of the
diastereomers using rhodium acetate (Table 2).
1 A related carbene addition to a geminally difluorinated olefin was
catalyzed more effectively by Rh2(OAc)4 compared to Cu(acac)2.
2 The terms cis and trans with regard to the phenyl and the carboxyl
groups are used to make the diastereoselectivity comparable to the results
obtained for non-fluorinated olefins.
2. Results and discussion
Recently, we have shown that 2-fluoroalkenes, which are
readily available from terminal olefins applying a two-step

G. Haufe et al. / Journal of Fluorine Chemistry 114 (2002) 189–198
191
Table 1
the diastereo- and enantioselectivity for the cis- and trans-
isomers increased.
Cyclopropanation of a-fluorostyrene (1) with EDA and different catalysts
Catalyst
Yield 2a þ 3a (%, GC)
Pd(OAc)2
PdCl2
RhCl3
11
16
6
Rh2(OAc)4
CuOTfꢁ(1/2)C6H6
Cu(OAc)2
Cu(acac)2
25
39
62
93
Even better diastereo- and enantioselectivities were found
for the reaction of a-fluorostyrene (1) with tert-butyl diazo-
acetate (Table 3, entries 2 and 4). Finally, a double stereo-
differentiation applying the (ꢀ)-menthyl ester showed an
almost complete diastereoselectivity for the cis-diastereomer.
Scheme 5 illustrates the proposed mechanism of the
asymmetric cyclopropanation, shown for the two enantio-
mers of 3a [58]. 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 substituent R0
would hinder the turn of the ester group into the plane
necessary for cyclopropane formation. This steric repulsion
increases with the steric demand of R0. Since such an inter-
action is absent for the re-attack, the latter pathway is favored
and the selectivity increases with the size of R0 (Table 3).
In order to prove this mechanistic prediction, the absolute
configuration of the fluorinated ethyl trans-2-phenylcyclo-
propanecarboxylate (3a) formed, was determined. This ester
(89% ee) was hydrolyzed with KOH/MeOH and the formed
carboxylic acid 4 was treated with 4-bromoaniline under
Schotten–Baumann conditions. Recrystallization gave the
corresponding enantiopure 4-bromoanilide (6) (Scheme 6).
X-ray structure analysis of a single crystal confirmed the
configuration of 6 (and therefore, of 3a) to be (1S,2S) as
expected from the proposed mechanism and assumptions
regarding the ligand’s configuration [58].
Table 2
Cyclopropanation of a-fluorostyrene (1) with different diazoacetates and
rhodium catalysts
R
Ratio 2:3
(GC)
Combined
yield (%)
Rh2(OAc)4ꢁ2H2O
Rh2(OAc)4ꢁ2H2O
tBu
64:36
61:39
70
62
(ꢀ)-Menthyl
The application of chiral bis(oxazoline) ligands, first used
by Masamune and co-workers [69] and Evans et al. [70], for
catalytic copper complexes proved to be highly efficient and
allowed the asymmetric cyclopropanation of a-fluorostyrene
as shown in Table 3. Though this is a very active field of
research in non-fluorine series (for recent reviews see [71–
73]), there have been no reports on the asymmetric cyclo-
propanation of prostereogenic vinyl fluorides. We expected
this method to be a good approach to a variety of optically
active, monofluorinated cyclopropane derivatives.
As enantiopure ligands for the copper complexes, we used
the bis(oxazolines) A, B and C. While the enantioselectivity
of the cycloaddition is determined by the topology of the
catalyst, its electronic structure is responsible for the com-
pletion of the catalytic cycle [74]. The nature of the bridge
between the oxazoline rings has a quite weak influence on
yield, diastereo- and enantioselectivity (Table 3, entries 1 and
3). In contrast, the substituent R0 attached to the oxazoline
ring (isopropyl or tert-butyl, respectively) is important
(Table 3, entries 1 and 2). While the yield dropped, both
Due to the above-mentioned effects of a fluorine sub-
stituent on the properties of compounds, we established
pathways to synthesize monofluorinated cyclopropylamines
analogous to biogenic amines, such as the racemic trans-2-
Table 3
Asymmetric cyclopropanation of a-fluorostyrene (1) catalyzed by enantiopure copper catalysts
Entry
Ligand
R0
Products
Ratio 2:3
Yield (%)
ee of 2 (%)a
ee of 3 (%)a
1
2
3
4
5
A
B
C
B
B
Et
2a þ 3a
2a þ 3a
2a þ 3a
2b þ 3b
2c þ 3c
68:32
72:28
66:34
81:19
19:81
81
62
75
56
28c
69
54
80
Et
89
Et
tBu
70
54
93b
92d
89b
>98d
(ꢀ)-Menthyl
a The ee 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 3c contains small amounts of the (ꢀ)-menthyl esters of maleic and fumaric acids as byproducts.
d de.

192
G. Haufe et al. / Journal of Fluorine Chemistry 114 (2002) 189–198
Scheme 7.
of some of these compounds were proved by X-ray crystal-
lography.
The corresponding cyclopropylethyl amines have been
synthesized by a classical homologation methodology.
Reduction of carboxylic esters 2a and 3a gave the cyclo-
propylmethanol derivatives 15 and 16, which were tosylated
to give 17 and 18. Subsequent nucleophilic substitution led
to the nitriles 19 and 20, which were reduced with BH3 in
THF and the formed amines were precipitated as hydro-
chlorides 21 and 22 (Scheme 9) (see footnote 3).
Having a series of these fluorinated phenylcyclopropanes
in hands, we observed that it is very easy to assign the relative
configuration of such compounds by 19F NMR spectroscopy.
Fluorocyclopropane itself has a 19F NMR chemical shift of
ꢀ218.0 ppm relative to CFCl3. The trans-diastereomeric
compounds of this series showed chemical shifts in a quite
narrow range of 7 ppm between ꢀ187 and ꢀ194 ppm. The
cis-diastereomers on the other hand, exhibited a high field
shift in a range of ꢀ162 to ꢀ152 ppm compared to the trans-
isomers (Scheme 10).
Scheme 5.
Scheme 6.
phenylcyclopropylamine (Tranylcypromine1), which is an
anti-depressive drug.
Saponification of the racemic, diastereopure fluorinated
ethyl cis- and trans-2-phenylcyclopropylcarboxylates 2a
and 3a gave the corresponding cyclopropanecarboxylic
acids 4 and 5, which subsequently served as precursors
for the fluorinated analogues 9 and 10 of tranylcypromine
(Scheme 7). Curtius-type degradation of 4 and 5, and
reaction of the intermediary isocyanates with tert-butanol
gave the Boc-protected fluorinated cyclopropylamines 7 and
8. Deprotection with HCl in HOAc led to the hydrochlorides
of both diastereomers of the fluorinated analogues 9 and 10
of the 2-phenylcyclopropylamines.
There are also significant differences between the cis-
and the trans-configurated compounds in the 1H NMR
3
spectra. Most significantly, there is only one large JHF in
the trans-compound indicating the relative cis-configuration
The homologues (13 and 14) of 9 and 10 were synthesized
as shown in Scheme 8. The diastereopure carboxylic acids 4
and 5, were transformed to the corresponding acid chlorides,
which were treated without isolation with ammonia to give
the carboxamides 11 and 12. These compounds were
reduced with borane in THF. After work-up, the hydro-
chlorides 13 and 14 of the corresponding amines were
obtained by treatment with dry HCl gas.3 The structures
3 Complete synthetic details and spectroscopic data will be published in
combination with results of biological studies.
Scheme 8.

G. Haufe et al. / Journal of Fluorine Chemistry 114 (2002) 189–198
193
known as a very strong proton acceptor [85], the ‘organic’
C–F group seems to be rarely involved in hydrogen bonding
compared to C–O or C–N moieties. Recently, the question,
whether or not C–F groups can function as hydrogen bridge
acceptors have been discussed quite controversially [86–92].
Dunitz and Taylor [89] defined a XꢀH ꢁ ꢁ ꢁ FꢀC distance
˚
<2.3 A and an XꢀH ꢁ ꢁ ꢁ F angle >908 as criteria for a ‘‘real’’
hydrogen bridge. They analyzed almost 6000 C–F bonds in
more than 1200 crystal structures of fluorinated, organic
(excluding organometallic) compounds found in the Cam-
bridge Crystallographic Data Collection (CCDC) and iden-
tified only 37 (0.6%) which meet these criteria. Among these
compounds, only two were identified by these authors as
exhibiting true hydrogen bridges. Thus, it seems extremely
rare that C–F moieties act as hydrogen bond acceptors.
On the other hand, Howard et al. identified 40 mono-
fluorinated compounds from the same source in 1996 having
Scheme 9.
˚
XꢀH ꢁ ꢁ ꢁ FꢀC contacts (X ¼ O, N) <2.35 A [88]. Recently,
several close intermolecular XꢀH ꢁ ꢁ ꢁ FꢀC contacts below
these limits were described [93–95]. Other authors regarded
a distance of about the sum of the van der Waals radii
˚
(2.67 A) [96] or even longer as hydrogen bridges [97,98].
Furthermore, a quite short intramolecular NꢀH ꢁ ꢁ ꢁ FꢀC
˚
distance of 2.27 A has been found for N-(fluoroacetyl)phe-
nylglycine in the crystalline state recently [99]. This interest
in short XꢀH ꢁ ꢁ ꢁ FꢀC contacts led us to examine the X-ray
structures4 of several of the crystalline, fluorinated 2-phe-
nylcyclopropane derivatives.5
As expected, the two diastereomeric racemic carboxylic
acids formed dimers in the crystalline state. There are strong
hydrogen bridges between the two acid groups, but there are
also CꢀH ꢁ ꢁ ꢁ FꢀC distances, which are close to the sum of
Scheme 10.
of fluorine and one of the vicinal hydrogens. In contrast, two
3
˚
large JHF are found in the cis-compounds indicating the
the van der Waals radii, namely 2.62 A to the C–H of the
˚
cyclopropane ring and 2.65 A to an aromatic hydrogen, in
relative cis-configuration of fluorine to two vicinal hydro-
gens. Moreover, there are 3JCF couplings of about 7–11 Hz
to the g-carbon atoms only, in most of the trans-compounds.
Besides the synthetic aspects, it is also interesting to gain
insights into the structure of such fluorinated compounds.
During the past years, there has been an enormous interest in
the question, whether or not a fluorine substituent in organic
compounds can function as a hydrogen bridge acceptor with
acidic X–H bonds, such as O–H, N–H or even C–H moieties.
A hydrogen bridge in organic compounds is a particular
type of a chemical bond, which is formed between a
covalently bound hydrogen atom and a free electron pair
of an electronegative atom. In terms of macroscopic proper-
ties of a compound, hydrogen bridges do influence the
physical properties, such as the melting point, the boiling
point as well as the dipole moment [75]. Moreover, hydro-
gen bridges contribute to the formation of particular crystal
structures and to the arrangement of supramolecular ensem-
bles [76]. Most importantly, hydrogen bridges determine the
active conformation of enzymes and the interactions of
substrates and their receptors in the body [75–83] and can
be applied to steer selectivity in organic synthesis (non-
covalent synthesis [84]). While the ‘inorganic’ fluoride ion is
the case of the racemic trans-compound 4 (Fig. 1).
Due to the different crystal type, the structure of the
enantiopure trans-configurated carboxylic acid (S,S)-4
revealed a shorter contact to the C–H of the cyclopropane
˚
ring (2.39 A), while the distance to the aromatic hydrogen
became longer compared to the racemate (Fig. 2).
In the corresponding p-bromocarboxamide 6, which was
prepared in order to assign the absolute configuration of the
carboxylic acid (S,S)-4 (Fig. 2), an even shorter contact of
4 A detailed discussion of the X-ray structures of these compounds will
be matter of a separate future paper. The H atoms in the studied
compounds (presented in Figs. 1–8) have been calculated into their
idealized positions and the C–H, O–H and N–H distances have been
normalized to their neutron diffraction distances during the refinements,
˚
e.g. C–H to 1.08 A, O–H and N–H to 1.00 A, using the SHELXL
˚
command AFIX.
5 Crystallographic data (excluding structure factors) for the structures in
this paper have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication nos. CCDC 145029–145031 and
170381–170385. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Fax:
þ44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk

194
G. Haufe et al. / Journal of Fluorine Chemistry 114 (2002) 189–198
Fig. 1. trans-(Æ)-2-Fluoro-2-phenylcyclopropanecarboxylic acid (4).
Fig. 4. cis-(Æ)-2-Fluoro-2-phenylcyclopropanecarboxylic acid (5).
The structures of the two diastereomeric carboxamides 11
and 12 are quite different in crystalline state. The trans-
compound 11 shows a symmetric arrangement of the dimers
˚
(1.92 A for the NꢀH ꢁ ꢁ ꢁ O¼C) and an intermolecular
CꢀH ꢁ ꢁ ꢁ FꢀC distance to one of the methylene hydrogens
˚
of the cyclopropane ring, which is longer (2.76 A) than the
sum of the van der Waals radii (Fig. 5).
On the other hand, the cis-isomer 12 crystallized in a
much more complicated structure. There are no very short
CꢀH ꢁ ꢁ ꢁ FꢀC contacts and no clear dimeric moieties, but a
‘‘network’’ of hydrogen bridges and short contacts of one of
the N–H bonds to a carbonyl oxygen were found. Three
different hydrogen bridges of this type have been identified,
Fig. 2. (1S,2S)-2-Fluoro-2-phenylcyclopropanecarboxylic acid, (S,S)-4.
˚
2.35 Awas found to one C–H group of the cyclopropane ring
(Fig. 3).
For the cis-configurated carboxylic acid 5, two different
˚
short distances of 2.41 or 2.28 A, were found to one of the
methylene hydrogens of the cyclopropane ring (Fig. 4).
It is known in the literature, that methylene hydrogens of
cyclopropanes are quite acidic and can form intermolecular
hydrogen bridges towards oxygen functions of an imide
˚
˚
˚
one is 1.96 A, the second is 1.91 A and the shortest is 1.88 A.
Surprisingly, there are also three different and very short
distances between a C–F group and the second amide
˚
hydrogen. There is one of 2.10 A, another one of 2.09 A
˚
˚
and the third one is even as short as 2.07 A. These, to the best
˚
(particularly CꢀH ꢁ ꢁ ꢁ O¼C distances of 2.27 or 2.37 A)
of our knowledge [89,101], are the shortest intermolecular
contacts ever observed for monofluorinated compounds,
which can be considered as real hydrogen bridges, because
[100]. Thus, we obtained very similar CꢀH ꢁ ꢁ ꢁ FꢀC dis-
tances.
Fig. 3. (1S,2S)-2-Fluoro-2-phenylcyclopropanecarbox(4-bromophenyl)a-
mide (6).
Fig. 5. trans-(Æ)-2-Fluoro-2-phenylcyclopropanecarboxamide (11).

G. Haufe et al. / Journal of Fluorine Chemistry 114 (2002) 189–198
195
Fig. 6. cis-(Æ)-2-Fluoro-2-phenylcyclopropanecarboxamide (12).
Fig. 7. N-(4-Bromophenyl)carbamate of (1R,2R)-(2-fluoro-2-phenylcyclo-
propyl)methanol (24).
Fig. 8. N-(4-Bromophenyl)carbamate of (1S,2R)-(2-fluoro-2-phenylcyclo-
propyl)methanol (25).
also the bond angles of 158–1678 meet the criteria of Dunitz
and Taylor [89] (Fig. 6).
After reduction of the diastereopure esters 2a and 3a to the
corresponding cyclopropyl methanols 15 and 16 and enzyme-
catalyzed (Pseudomonas cepacia lipase (PCL)) resolution of
the racemates, we synthesized the corresponding enantiopure
p-bromophenylcarbamates 24 and 25 in order to determine
the absolute configuration. In Scheme 11, the sequence is
shown for the cis-isomer 25 (see footnote 3).
While the trans-isomer 24 showed a CꢀH ꢁ ꢁ ꢁ FꢀC con-
tact, which is only slightly shorter than the sum of the van
˚
der Waals radii (2.55 A, Fig. 7), in the cis-diastereomer 25
significantly shorter distances were found (Fig. 8). One is
˚
˚
2.19 A and the other one is 2.17 A. These are the shortest
contacts of this type found so far.
Scheme 11.

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G. Haufe et al. / Journal of Fluorine Chemistry 114 (2002) 189–198
3. Experimental
[I > 2sðIÞ];R1¼ 0:0616, wR2¼ 0:0909;Rindices(alldata),
R1 ¼ 0:1260, wR2 ¼ 0:1108, absolute structure para-
Synthesis and complete spectroscopic data of compounds
1–10 have been published [58]. Synthesis and complete
spectroscopic data of compounds 11–25 will be published
in combination with results of biological studies.
X-ray crystal data sets were collected with Nonius CAD4
or KappaCCD diffractometers.
meter ¼ 0:ꢀ0032ð11Þ, largest diff. peak and hole ¼ 0:428=
˚
ꢀ0:599 e A
.
References
[1] H.-W. Liu, C.T. Walsh, Biochemistry of the cyclopropyl group, in:
Z. Rappoport (Ed.), The Chemistry of the Cyclopropyl Group,
Wiley, New York, 1987, pp. 959–1025.
Compound (S,S)-4 (CCDC 170381): C10H9FO2,
˚
f:w: ¼ 180:17, T ¼ 223ð2Þ K, l ¼ 1:54178 A. Monoclinic
˚
˚
˚
P21, a ¼ 12:054ð1Þ A, b ¼ 5:609ð1Þ A, c ¼ 12:994ð1Þ A,
[2] C.J. Suckling, Angew Chem. 100 (1988) 555;
C.J. Suckling, Angew Chem. Int. Ed. Engl. 27 (1988) 537.
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3
˚
b ¼94:56ð1Þ8, V ¼875:75ð18Þ A , Z ¼ 4, Dc ¼ 1:367 Mg/
m3, refl. coll. 3932, of which independent 1969
[RðintÞ ¼ 0:0238]. Full-matrix least-squares refinement on
F2 with 238 parameters, S ¼ 1:086, final R indices
[I > 2sðIÞ]; R1 ¼ 0:0378, wR2 ¼ 0:1011; R indices (all
data), R1 ¼ 0:0398, wR2 ¼ 0:1036, absolute structure
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parameter ¼ 0:11ð17Þ, extinction coefficient ¼ 0ꢀ:03116ð17Þ,
´
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˚
largest diff. peak and hole ¼ 0:237/(ꢀ0.304) e A
.
Compound 11 (CCDC 170382): C10H10FNO,
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˚
f:w: ¼ 179:19, T ¼ 223ð2Þ K, l ¼ 1:54178 A. Monoclinic
˚
˚
˚
P21/c, a ¼ 17:620ð3Þ A, b ¼ 5:251ð1Þ A, c ¼ 9:720ð1Þ A,
3
[9] J.T. Welch, Tetrahedron 43 (1987) 3123.
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˚
b ¼ 93:68ð1Þ8, V ¼ 897:5ð2Þ A , Z ¼ 4, Dc ¼ 1:326 Mg/
m3, refl. coll. 1944, of which independent 1825
[RðintÞ ¼ 0:0210]. Full-matrix least-squares refinement on
F2 with 118 parameters, S ¼ 0:967, final R indices
[I > 2sðIÞ]; R1 ¼ 0:0525, wR2 ¼ 0:1247; R indices (all
data), R1 ¼ 0:1432, wR2 ¼ 0:1675, largest diff. peak and
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ꢀ3
˚
hole ¼ 0:155/(ꢀ0.186) e A
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Compound 12 (CCDC 170383): C10H10FNO,
˚
f:w: ¼ 179:19, T ¼ 198ð2Þ K, l ¼ 0:71073 A. Triclinic
˚
˚
˚
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P1, a ¼ 9:241ð1Þ A, b¼ 9:859ð2Þ A, c¼ 15:262ð3Þ A, a ¼
3
˚
78:06ð1Þ8, b¼ 80:61ð1Þ8, g ¼78:47ð1Þ8, V ¼ 1322:1ð4Þ A ,
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pendent 3429 [RðintÞ ¼ 0:1654], Full-matrix least-squares
refinement on F2 with 352 parameters, S ¼ 1:034, final R
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ꢀ3
˚
and hole ¼ 0:235/(ꢀ0.266) e A
.
Compound 24 (CCDC 179384): C17H15BrFNO2,
˚
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f:w: ¼ 364:21, T ¼ 198ð2Þ K, l ¼ 0:71073 A. Orthorhom-
˚
˚
˚
bicP21212,a¼8:840ð1Þ A,b¼34:535ð1Þ A,c¼5:054ð1Þ A,
3
3
˚
V ¼ 1542:9ð4Þ A , Z ¼ 4, Dc ¼ 1:568 Mg/m , refl. coll.
8237, of which independent 3553 [RðintÞ ¼ 0:0510]. Full-
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0:0895; R indices (all data), R1 ¼ 0:0823, wR2 ¼ 0:1019,
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ꢀ3
˚
and hole ¼ 0:364/(ꢀ0.619) e A
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Compound 25 (CCDC 170385): C17H15BrFNO2,
˚
f:w: ¼ 364:21, T ¼ 198ð2Þ K, l ¼ 0:71073 A. Monoclinic
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˚
˚
˚
P21, a ¼ 16:186ð1Þ A, b ¼ 5:348ð1Þ A, c ¼ 18:294ð1Þ A,
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˚
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