Diastereoselectivity of cyclopropanation of substituted α-fluorostyrenes versus styrenes by different methods

Article abstract of DOI:10.1016/j.jfluchem.2017.09.008

The diastereoselectivity of cyclopropanations of styrene and α-fluorostyrene with diazoacetate depends on the catalyst used and the presence or absence of the fluorine substituent. The Cu(acac)₂ catalyzed reaction of styrene with diazoacetate led to 3:1 selectivity in favor of trans-2-phenylcyclopropane carboxylate, while α-fluorostyrene gave a 1:1 mixture of cis/trans-isomers. A competition experiment proved that α-fluorostyrene reacted slower compared to styrene itself. With the bulkier tetraphenyl-iron(III)-porphyrin chloride as catalyst, 10:1 or 3:1 mixture, respectively, were obtained. An advantage of the latter protocol is the in situ formation of ethyl diazoacetate from ethyl glycinate hydrochloride in aqueous solution by diazotation avoiding the in-substance application of the potentially explosive ethyl diazoacetate. Accordingly, a series of diastereoisomeric ethyl 2-aryl-2-fluoro-cyclopropane carboxylates was synthesized from p- or m-substituted α-fluorostyrenes.

Full text of DOI:10.1016/j.jfluchem.2017.09.008

Accepted Manuscript
Title: Diastereoselectivity of cyclopropanation of substituted
␣-fluorostyrenes versus styrenes by different methods
Authors: Katharina Bartels, Benjamin Schinor, Gu¨nter Haufe
PII:
S0022-1139(17)30362-7
DOI:
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http://dx.doi.org/10.1016/j.jfluchem.2017.09.008
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Diastereoselectivity of cyclopropanation of substituted α-fluorostyrenes versus
styrenes by different methods
Katharina Bartels,1 Benjamin Schinor,1 Günter Haufe1,2 *
1 Organisch-Chemisches Institut, Universität Münster, Corrensstr. 40, 48149 Münster, Germany
2 Cells-in-Motion Cluster of Excellence, University of Münster, Waldeyerstr. 15, 48149 Münster,
Germany
Dedicated to Professor Antonio Togni, the 2017 recipient of the ACS award for Creativity in
Fluorine Chemistry
Graphical Abstract
Highlights
 Metal catalyzed cyclopropanations of substituted α-fluorostyrenes with diazoacetate
provide mixtures of cis/trans-isomeric 2-aryl-2-fluorocyclopropane carboxylates.
 In situ generation of diazoacetate in aqueous solution with subsequent iron porphyrin
catalyzed cyclopropanation is safe.
 Cu(acac)2 catalyzed cyclopropanation α-fluorostyrene proceeds slower than with styrene.
 The trans-diastereoselectivity of α-fluorostyrene is lower compared to styrene.
Abstract
The diastereoselectivity of cyclopropanations of styrene and α-fluorostyrene with diazoacetate
depends on the catalyst used and the presence or absence of the fluorine substituent. The
Cu(acac)2 catalyzed reaction of styrene with diazoacetate led to 3:1 selectivity in favor of trans-2-
phenylcyclopropane carboxylate, while α-fluorostyrene gave a 1:1 mixture of cis/trans-isomers. A
competition experiment proved that α-fluorostyrene reacted slower compared to styrene itself.
With the bulkier tetraphenyl-iron(III)-porphyrin chloride as catalyst, 10:1 or 3:1 mixture,
respectively, were obtained. An advantage of the latter protocol is the in situ formation of ethyl
diazoacetate from ethyl glycinate hydrochloride in aqueous solution by diazotation avoiding the
in-substance application of the potentially explosive ethyl diazoacetate. Accordingly, a series of
diastereoisomeric ethyl 2-aryl-2-fluoro-cyclopropane carboxylates was synthesized from p- or m-
substituted α-fluorostyrenes.
1. Introduction
1

For the synthesis of both fluorinated and non-fluorinated cyclopropanes plenty of methods do
exist, which were reviewed in recent years. Most frequently used methods involve the
intermediate formation of carbenes or metal carbenoides, which are generated by metal mediated
decomposition of diazo compounds and addition of the corresponding carbenes across non-
fluorinated [1] or fluorinated double bonds [2]. All these reactions can proceed enantioselectively
applying chiral, non-racemic auxiliaries in the substrates or in the respective ligands of catalysts
[1f,1h,2b,3].
Alternative to the photochemical reaction of diazomethane with fluoroacrylic carboxylates [4], the
Cu(acac)2 catalyzed reaction of diazoacetates with α-fluorostyrene has a couple of advantages in
safety and toxicity aspects. Accordingly, a series of mixtures of cis- and trans-2-fluoro-2-
phenylcyclopropane carboxylates were prepared in good yields, however, with low
diastereoselectivity in case of application of ethyl diazoacetate. Higher diastereoselectivity was
obtained applying tert-butyl diazoacetate [5]. The formed diastereomers were separated either
chromatographically or by recrystallization of the corresponding carboxylic acids. The latter
compounds [6] were shown to be versatile starting materials for the preparation of corresponding
fluorinated phenylcyclopropyl amines, which are highly potent monoamine oxidase inhibitors [7,8]
exhibiting better selectivity compared to the lead compound tranylcypromine®, a potent drug used,
for instance, for treatment of chronic depression [9].
However, the copper- or rhodium catalyzed cyclopropanations do have a general disadvantage,
which is connected to the application of low molecular weight, potentially explosive, diazocarbonyl
compounds. Therefore, several attempts were made to produce such diazo compounds in situ
and to couple its formation with a transition metal catalyzed cyclopropanation. In 2001, Barrett et
al. described a series of experiments with a rhodium-porphyrin catalyst. Thus, ethyl diazoacetate
formed in situ by diazotation of ethyl glycinate hydrochloride was used subsequently in Rh-
catalyzed cyclopropanation in a two-phase-system of water and methylene chloride at room
temperature [10]. No diastereoselectivity was observed and the products were isolated in
moderate yields after long reaction time of 4 days. A year later Wurz and Charette used a rhodium
catalyst in aqueous medium to generate a 3:2 mixture of cis- and trans-2-phenyl-
cyclopropanecarboxylic acid ethyl ester in 70% yield [11]. More efficient approach was the
iron(III)-porphyrin-catalyzed cyclopropanation of a series of styrenes substituted in aromatic
positions with diazoacetate generated in situ from ethyl glycinate hydrochloride in aqueous acetic
acid [12]. This approach was based on earlier investigations on iron-catalyzed cyclopropanations
with in situ generated diazomethane [13,14]. Very recently Arnold et al. reported on asymmetric
olefin-cyclopropanation reactions via carben transfer, catalyzed by engineered Cytochrome P450
enzymes giving mixtures of optically active ethyl or tert-butyl 2-arylcyclopropane carboxylates with
moderate yields and moderate to high diastereo- and enantioselectivities [15]. Similar examples
were highlighted by Roiban and Reetz recently [16].
2

For a couple of years, we have been involved in stereoselective syntheses of 2-aryl-2-fluoro-
cyclopropane carboxylates from α- and β-fluorostyrenes substituted in the aryl ring and alkyl
diazoacetates [5,17], its transformation to fluorinated arylcyclopropyl amines and investigation of
their potency and selectivity to inhibit monoamine oxidases [18] or lysine-specific demethylase 1
(LSD1) [19]. A recent paper of Carreira et al. [12] aroused our interests to investigate the tandem
diazotation/cyclopropanation reactions of substituted in the aryl ring α-fluorostyrenes in the
presence of tetraphenyl-iron(III)-porphyrin chloride (FeTPPCl).
Results and discussion
Our interest was to extend the scope of Carreira’s tandem diazotation/cyclopropanation protocol
of styrenes [12] to corresponding reactions of α-fluorostyrenes as an alternative approach to
copper- and rhodium-catalyzed cyclopropanations using diazoacetate [5,17-20]. Moreover, the
diastereoselectivity and the yields of these reactions will be compared.
Thus we reacted substituted styrenes 1 with ethyl glycinate hydrochloride and sodium nitrite in
the presence of 1 mol% of FeTPPCl in aqueous acetic acid (Scheme 1). The results of these
reactions are listed in Table 1 (column 5) and compared to results obtained by Carreira with the
corresponding non-fluorinated compounds. For comparison the results of similar
cyclopropanation reactions of the same fluorinated or non-fluorinated styrenes 1 with ethyl
diazoacetate catalyzed by Cu(acac)2 or Rh(OAc)4 in organic solvents are also included in Table
1 (column 7 and 9).
a
b
c
Yield of the mixture of diastereomers; 1 mol% FeTPPCl, NaNO2, AcOH, H2O, 40 °C, 14 h; 5 mol%
Cu(acac)2, CH2Cl2, 40 °C, 10 h; d 2 mol% Rh2(OAc)4, CH2Cl2, 40 °C, 6 h.
In most of the cases (except column 5, entries 8/9), the yields of the fluorinated products were
lower compared to the non-fluorinated parent compounds, and the diastereoselectivity was also
reduced. The cyclopropane carboxylates were formed as 1:3 mixtures of cis/trans-isomers, while
the ratio of the fluorine free counterparts was approximately 1:8 or even better (column 5). This
trend was observed already in our earlier studies of the copper-catalyzed cyclopropanations with
ethyl diazoacetate [5,7] (column 7) and a similar effect was observed also in some rhodium-
catalyzed cyclopropanations (column 9) [17,25].
We also investigated the relative reaction rates of Cu(acac)2 catalyzed cyclopropanation of
styrene and α-fluorostyrene with ethyl diazoacetate in methylene chloride using a competition
experiment with a 1:1 mixture of the alkenes. The progress of the reaction was monitored by gas
chromatography. Figure 1 shows the consumption of the styrenes and the formation of the
cis/trans-isomeric fluorinated and non-fluorinated ethyl 2-phenyl-cyclopropylcarboxylates 2.
Due to its higher HOMO (Highest Occupied Molecular Orbital) energy [26], styrene (1a) reacted
slightly faster than α-fluorostyrene (2b). The relative rate constant in this competition reaction was
3

calculated to be approximately 1.3 in favor of styrene using the equation (1). This equation was
applied already by Shell and Garner for the determination of the relative rate constant (kx/ky) for
the dibromocarbene addition across different alkenes [27].
Kx log(nx) / n(x,0)

(1)
Ky log(ny) / n(y,0)
[n(x,0) or n(y,0) mean the molar amount of compounds X or Y at the starting
point (t = 0); n(x)/n(y) means the molar amount of compound X or Y at the
end of the measurement]
From styrene the cis- and trans-diastereoisomers were formed in a 1:3 ratio, which is in
agreement with earlier results by Kaiser et al. for the uncatalyzed thermal reaction of styrene with
diazoacetate [28] and Ahuja et al. for different Cu-catalyzed cyclopropanations [29].
The trans-selectivity of transition metal-catalyzed cyclopropanations of alkenes with different
diazoacetates was investigated by Doyle et al. [30].
The bulkier the substituent Z of the diazoacetate, favors the trans-configured transition state
leading to the trans-product. We observed similar results also for the Cu(acac)2 catalyzed
reactions of α-fluorostyrenes [5]. Doyle et al. obtained a diastereoselectivity as high as 2:98 in
favor of the trans-isomer using the extremely bulky 2,6-di-tert-butyl-4-methylphenyl diazoacetate
in a Rh-catalyzed cyclopropanation of styrene [31]. The maximum we achieved for the Cu-
catalyzed reaction of α-fluorostyrene with tert-butyl diazoacetate was 1:4 [5].
Doyle et al. also investigated electronic effects of double bonds on the diastereoselectivity of
cyclopropanation and found out that electron deficient double bonds exhibited higher trans-
diastereoselectivity because electron poor double bonds have to be arranged closer to the
carbenoid center, which causes increased steric repulsion in the cis-transition state and hence
favors the trans-arrangement [30].
In the above mentioned competition experiment the 2-fluoro-2-phenylcyclopropane carboxylates
were formed in 1:1 ratio, which is in agreement with earlier results [5] and also with Doyle’s results
on the electronic effects of the double bond. Due to the electron donating (+Iπ) effect of fluorine
on π-systems [32], the double bond of α-fluorostyrene is more electron-rich compared to styrene.
Therefore, the distance of the carbenoid center to the double bond is bigger and consequently
there is less steric congestion in the cis-transition state. Also the bigger van der Waals radius of
fluorine compared to hydrogen contributes to the lower diastereoselectivity in case of α-
fluorostyrene. Moreover, repulsion of the ester carbonyl group and the vinylic fluorine disfavors
the formation of the trans-transition state.
4

In addition to these effects also electronic interactions of the carbonyl oxygen with the forming
electrophilic center at the β-carbon in the alternative cis- and trans-transition states were
discussed [17,25]. In the trans-transition state of styrene an n-electron pair of the carbonyl oxygen
of the diazo compound interacts with the forming electrophilic β-carbon of styrene. This leads to
a stabilization, which is not possible in the cis-transition state. In the corresponding transition state
starting from α-fluorostyrene, the interaction of the forming electrophilic center of the trans-
transition state is also possible, but less efficient due to the stabilizing effect of a positive charge
by α-fluorine [32]. Consequently, the diastereoselectivity is lower (Figure 3).
Comparing the diastereoselectivity of the iron porphyrin-catalyzed reactions (Table 1, column 5)
the trans-diastereoselectivity is much more pronounced, in the styrene case, but also in the α-
fluorostyrene case a 1:3 selectivity was observed. The sterically more demanding iron-porphyrin
catalyst seems to favor the trans-transition states and the trans-configured 2-arylcyclopropane
carboxylates are the main products.
3. Conclusions
The iron(III)-porphyrin catalyzed cyclopropanation of α-fluorostyrene and several of its p- and m-
substituted derivatives with in situ generated ethyl diazoacetate in acidic aqueous medium has
advantages in spite of safety and economic issues compared to corresponding copper- or
rhodium catalyzed reactions using the potentially explosive ethyl diazoacetate in organic media.
While the diastereoselectivity is higher for the iron-porphyrin catalyzed reactions in favor of the
trans-products (3:1), the yields are lower compared to the Cu(acac)2 catalyzed reactions.
Moreover, the latter reaction with styrene is faster by a factor of 1.3 compared to that of α-
fluorostyrene. Here the ratio of trans- to cis-diastereomeric products is 3:1 from styrene and 1:1
for the α-fluorostyrene reactions.
4. Experimental
4.1 General remarks
NMR spectra were recorded on Bruker Avance II at 300 and 400 MHz, (1H), at 25 °C. TMS (1H
13
and C NMR) and CCl3F (19F NMR) were used as internal standards. Mass spectra (ESI-MS)
were measured on a MicroTof Bruker Daltonics. The reaction progress was monitored gas-
chromatographically using a gas-chromatograph Hewlett-Packard “HP 6890” with an FID, an
auto-sampler and data registration and reporting with the program “GC ChemStation Rev. B
02.01-SR1”. A 30 m quartz capillary “HP-1” with inner diameter of 0.32 mm and a film thickness
of 0.25 m was used. The same system was used to monitor the reaction progress and to
determine the cis/trans ratio of products in the competition experiment. Column chromatography
was carried out using silica gel 60 (Merck, particle size 0.040–0.063 mm). The used eluent is
mentioned in the respective experiment.
5

4.2 Syntheses
4.2.1 Cyclopropanation of styrene and α-fluorostyrene derivatives with FeTPPCl (General
procedure)
Analogously to the protocol by Carreira et al. [12], FeTPPCl (7 mg, 0.01 mmol) was dissolved in
the corresponding styrene (1 mmol) and ethyl glycinate hydrochloride (419 mg, 3 mmol, 3 equiv),
water (10 mL) and acetic acid (9 mg, 0.15 mmol, 0.15 equiv) were added. To this heterogenic
mixture sodium nitrite (497 mg, 7.2 mmol, 2.4 equiv) was added in one portion under stirring at
40 °C. Stirring was continued at this temperature for 15 hours. Then water (15 mL) was added
and the mixture was extracted with dichloromethane (3  15 mL). The combined organic phase
was washed with 5% bicarbonate solution (5 mL), water (10 mL) and dried with magnesium
sulfate. After evaporation of the solvent, the crude product mixture was analyzed by GC and
separated by column chromatography (n-pentane/diethyl ether).
4.2.1.1 Ethyl 2-phenylcyclopropanecarboxylate (2a)
From styrene (100 mg, 0.96 mmol), ethyl glycinate hydrochloride (268 mg, 1.92 mmol) and
sodium nitrite (159 mg, 2.3 mmol) in acidified water (4.5 mL) in the presence of FeTPPCl (7 mg,
0.01 mmol) a 1:10 mixture of cis-2a and trans-2a was formed as colorless oil. Yield: 133 mg
(73%). The stereoisomers were separated chromatographically (n-pentane/diethyl ether, 20:1).
The spectroscopic data of both diastereoisomers agree with published values [33].
4.2.1.2 Ethyl 2-fluoro-2-phenylcyclopropanecarboxylate (2b)
From α-fluorostyrene (50 mg, 0.41 mmol), ethyl glycinate hydrochloride (127 mg, 1.23 mmol) and
sodium nitrite (69 mg, 1.0 mmol) in acidified water (2 mL) in the presence of FeTPPCl (3 mg,
0.004 mmol) a 1:3-mixture of cis-2b and trans-2b was formed as colorless oil. Yield: 45 mg (53%).
The stereoisomers were separated chromatographically (n-pentane/diethyl ether, 20:1). The
spectroscopic data of both diastereoisomers agree with published values [5].
4.2.1.3 Ethyl 2-fluoro-2-(4-methoxyphenyl)cyclopropanecarboxylate (2c)
From p-methoxy-α-fluorostyrene (50 mg, 0.33 mmol), ethyl glycinate hydrochloride (138 mg, 0.99
mmol) and sodium nitrite (55 mg, 0.79 mmol) in the presence of FeTPPCl (3 mg, 0.004 mmol) in
acidified water (2 mL) a 1:3 mixture of cis-2c and trans-2c was formed as colorless oil. Yield: 55
mg (70%). The stereoisomers were separated chromatographically (cyclohexane/ethyl acetate,
15:1). The spectroscopic data of both diastereoisomers agree with published values [18b].
4.2.1.4 Ethyl 2-fluoro-2-(3-methoxyphenyl)cyclopropanecarboxylate (2d)
From m-methoxy-α-fluorostyrene (50 mg, 0.33 mmol), ethyl glycinate hydrochloride (138 mg, 0.99
mmol) and sodium nitrite (55 mg, 0.79 mmol) in the presence of FeTPPCl (3 mg, 0.004 mmol) in
6

acidified water (2 mL) a 1:3 mixture of cis-2c and trans-2c was formed as colorless oil. Yield: 42
mg (55%). The stereoisomers were separated chromatographically (cyclohexane/ethyl acetate,
15:1).
1
Ethyl cis-2-fluoro-2-(3-methoxyphenyl)cyclopropanecarboxylate (cis-2d). H NMR (400 MHz,
3
2
3
CDCl3): δ 1.03 (t, JH,H = 7.1 Hz, 3 H, 12-CH3), 1.81 (ddd, JH,H(B) = 7.1, JH,H(X) = 10.3,
2
3
3
3JH,F(cis) = 19.3 Hz, 1 H, HA), 1.97 (ddd, JH,H(A) = 7.1, JH,H(X) = 7.7, JH,F(trans) = 12.4 Hz, 1 H, HB),
2.54 (ddd, 3JH,H(B) = 7.7, 3JH,H(A) = 10.3, 3JH,F(cis) = 18.1 Hz, 1 H, HX), 3.81 (s, 3 H, 13-CH3), 3.94 (qd,
3
4
4
3
2JH,H = 1.6, JH,H = 7.1 Hz, 2 H, 11-CH2), 6.91 (ddd, JH,H = 1.4, JH,H = 2.5, JH,H = 8.3 Hz, 1 H,
4
4
4
4
6-CH), 7.02 (dt, JH,H = 1.5, JH,H = 2.8 Hz, 1 H, 10-CH), 7.03 (dtd, JH,H = 0.9, JH,H = 1.6,
13
3JH,H = 7.6 Hz, 1 H, 8-CH), 7.27 (m, 1 H, 7-CH). C NMR (101 MHz, CDCl3): δ 14.0 (q, C-12),
16.6 (d, 2JC,F = 10.4 Hz, C-3), 28.0 (d, 2JC,F = 16.4 Hz, C-2), 55.4 (q, C-13), 60.8 (t, C-11), 83.1 (d,
1JC,F = 221.4 Hz, C-4), 113.9 (d, 3JC,F = 4.1 Hz, C-10), 115.2 (d, 3JC,F = 2.6 Hz, C-6), 120.5 (s, C-
4
2
4
8), 129.3 (d, JC,F = 1.3 Hz, C-7), 134.4 (d, JC,F = 19.9 Hz, C-5), 159.4 (d, JC,F = 1.2 Hz, C-9),
3
3
168.9 (d, JC,F = 1.7 Hz, C-1). 19F NMR (282 MHz, CDCl3): δ -154.12 (ddd, JH,F(trans) = 12.4,
3JH,F(cis) = 18.1, 3JH,F(cis) = 19.5 Hz, 1 F, 4-CF). MS (GC/EI): m/z (%) 238.1 (45) [M]+, 193.1 (30) [M-
C2H5O]+, 165.1 (100) [M-COOC2H5]+, 115.1 (40) [C9H8F-HF]+. MS (ESI+, exact mass): m/z
261.0902 [M+Na]+, calcd for C13H15FO3Na+: 261.0897.
1
Ethyl trans-2-fluoro-2-(3-methoxyphenyl)-cyclopropanecarboxylate (trans-2d). H NMR (300
3
2
3
MHz, CDCl3): δ 1.29 (t, JH,H = 7.1 Hz, 3 H, 12-CH3), 1.63 (ddd, JH,H(A) = 6.8, JH,H(X) = 8.9,
3
3
3
3JH,F(trans) = 10.7 Hz, 1 H, HB), 2.18 (ddd, JH,F(trans) = 3.2, JH,H(A) = 7.8, JH,H(B) = 8.9 Hz, 1 H, HX),
2.31 (ddd, 2JH,H(B) = 6.8, 3JH,H(X) = 7.8, 3JH,F(cis) = 19.9 Hz, 1 H, HA), 3.83 (s, 3 H, 13-CH3), 4.23 (qd,
2JH,H = 1.8, 3JH,H = 7.2 Hz, 2 H, 11-CH2), 6.80-6.85 (m, 1 H, 6-CH), 6.87-6.90 (m, 2 H, 8/10-CH),
7.29 (dt, 4JH,H = 0.9, 3JH,H = 7.9 Hz, 1 H, 7-CH). 13C NMR (75 MHz, CDCl3): δ
19.2 (d, 2JC,F = 12.3 Hz, C-3), 29.2 (d, 2JC,F = 11.6 Hz, C-2), 55.3 (q, C-13), 61.2 (t, C-11), 80.5 (d,
14.2 (q, C-12),
3
4
1JC,F = 228.3 Hz, C-4), 110.7 (d, JC,F = 7.3 Hz, C-10), 113.6 (d, JC,F = 1.4 Hz, C-7), 116.5 (d,
2
3JC,F = 6.5 Hz, C-6), 129.7 (d, C-8), 139.3 (d, JC,F = 21.3 Hz, C-5), 159.8 (s, C-9), 167.7 (d,
3JC,F = 2.3 Hz, C-1). 19F NMR (282 MHz, CDCl3): δ -188.36 (ddd, 3JH,F(trans) = 3.2, 3JH,F(trans) = 10.7,
3JH,F(cis) = 20.4 Hz, 1 F, 4-CF). MS (GC/EI): m/z (%) 238.1 (40) [M]+, 193.1 (25) [M-C2H5O]+, 165.1
(100) [M-COOC2H5]+, 115.1 (40) [C9H8F-HF]+. MS (ESI+, exact mass): m/z 261.0902 [M+Na]+,
calcd for C13H15FO3Na+: 261.0897.
4.2.1.5 Ethyl 2-fluoro-2-(4-nitrophenyl)cyclopropanecarboxylate (2e)
From 4-nitro-α-fluorostyrene (500 mg, 3.0 mmol), ethyl glycinate hydrochloride (1,260 mg, 9.0
mmol) and sodium nitrite (500 mg, 7.2 mmol) in the presence of FeTPPCl (20 mg, 0.03 mmol)
in acidified water (15 mL) a 1:2 mixture of cis-2e and trans-2e was formed as colorless oil. The
stereoisomers were separated chromatographically (n-pentane/diethyl ether, 20:1).
7

Ethyl cis-2-fluoro-2-(4-nitrophenyl)cyclopropanecarboxylate (cis-2e). Yield: 114 mg (15%). 1H
3
2
NMR (300 MHz, CDCl3): δ 1.06 (t, JH,H = 7.1 Hz, 3 H, 12-CH3), 1.95 (ddd, JH,H(B) = 7.4,
3JH,H(X) = 10.5, 3JH,F(cis) = 19.5 Hz, 1 H, HA), 2.07 (dt, 3JH,H(X) = 7.7, 3JH,F(trans) = 13.0 Hz, 1 H, HB),
3
3
3
2
2.65 (ddd, JH,H(B) = 7.9, JH,H(A) = 10.5, JH,F(cis) = 18.4 Hz, 1 H, HX), 3.95 (qd, JH,H = 3.7,
3JH,H = 7.2 Hz, 2 H, 11-CH2), 7.61-7.66 (m, 2 H, 6/10-CH), 8.20-8.25 (m, 2 H, 7/9-CH). 13C
NMR (75 MHz, CDCl3): δ 14.0 (q, C-12), 17.3 (d, 2JC,F = 9.8 Hz, C-3), 29.0 (d, 2JC,F = 15.9 Hz,
1
3
C-2), 61.2 (t, C-11), 81.9 (d, JC,F = 221.9 Hz, C-4), 123.3 (d, C-7/9), 128.7 (d, JC,F = 5.2 Hz,
C-6/10), 140.2 (d, 2JC,F = 20.7 Hz, C-5), 148.1 (s, C-8), 168.3 (d, 3JC,F = 1.8 Hz, C-1). 19F NMR
3
3
3
(282 MHz, CDCl3): δ -160.61 (ddd, JH,F(trans) = 13.0, JH,F(cis) = 18.6, JH,F(cis) = 19.6 Hz, 1 F,
4-CF). MS (GC/EI): m/z (%) 253.1 (20) [M]+, 225.1 (10) [M-C2H5]+, 208.0 (20) [M-C2H5O]+,
188.0 (40) [M-C10H7FNO3-HF]+, 180.1 (20) [M-COOC2H5]+, 134.1 (85) [C9H8F]+, 133.1 (100)
[C9H7F]+, 115.1 (12) [C9H7F-HF]+. MS (ESI+, exact mass): m/z 276.0657 [M+Na]+, calcd for
C12H12FNO4Na+: 276.0643.
Ethyl trans-2-fluoro-2-(4-nitrophenyl)-cyclopropanecarboxylate (trans-2e). Yield: 138 mg (0.54
1
3
mmol, 18 %). H NMR (300 MHz, CDCl3): δ 1.28 (t, JH,H = 7.1 Hz, 3 H, 12-CH3), 1.72 (ddd,
3
3
3
2JH,H(A) = 7.3, JH,H(X) = 9.5, JH,F(trans) = 10.5 Hz, 1 H, HB), 2.28 (ddd, JH,F(trans) = 3.1,
3JH,H(A) = 8.0, 3JH,H(B) = 9.4 Hz, 1 H, HX), 2.42 (ddd, 2JH,H(B) = 7.2, 3JH,H(X) = 8.0,
3JH,F(cis) = 20.2 Hz, 1 H, HA), 4.19-4.27 (m, 2 H, 11-CH2), 7.38-7.41 (m, 2 H, 6/10-CH), 8.20-
8.25 (m, 2 H, 7/9-CH). 13C NMR (75 MHz, CDCl3): δ 14.2 (q, C-12), 20.1 (d, 2JC,F = 11.8 Hz, C-
2
1
3), 30.4 (d, JC,F = 11.2 Hz, C-2), 61.6 (t, C-11), 79.8 (d, JC,F = 229.8 Hz, C-4), 123.9 (d,
3
2
4JC,F = 1.4 Hz, C-7/9), 124.5 (d, JC,F = 7.7 Hz, C-6/10), 145.1 (d, JC,F = 21.6 Hz, C-5), 147.5
3
(s, C-8), 166.8 (d, JC,F = 2.4 Hz, C-1). 19F NMR (282 MHz, CDCl3): δ -193.22 (ddd,
3
3
3JH,F(trans) = 3.0, JH,F(trans) = 10.7, JH,F(cis) = 20.4 Hz, 1 F, 4-CF). MS (GC/EI): m/z (%)
253.1 (15) [M]+, 225.1 (8) [M-C2H5]+, 208.0 (20) [M-C2H5O]+, 188.1 (30) [M-C10H7FNO3-
HF]+, 180.1 (20) [M-COOC2H5]+, 134.1 (80) [C9H8F]+, 133.1 (100) [C9H7F]+, 115.1 (12) [C9H7F-
HF]+. MS (ESI+, exact mass): m/z 276.0657 [M+Na]+, calcd for C12H12FNO4Na+: 276.0643.
4.2.1.6 Ethyl 2-fluoro-2-(3-nitrophenyl)cyclopropanecarboxylate (2f)
From 3-nitro-α-fluorostyrene (50 mg, 0.3 mmol), ethyl glycinate hydrochloride (126 mg, 0.9
mmol) and sodium nitrite (50 mg, 0.72 mmol) in the presence of FeTPPCl (3 mg, 0.004 mmol)
in acidified water (2 mL) a 1:2 mixture of cis-2f and trans-2f was formed as colorless oil. Yield:
65 mg (86%). The stereoisomers were separated chromatographically (n-pentane/diethyl
ether, 30:1 → 10:1).
1
Ethyl cis-2-fluoro-2-(3-nitrophenyl)cyclopropanecarboxylate (cis-2f). H NMR (300 MHz,
3
2
3
CDCl3): δ 1.08 (t JH,H = 7.1 Hz, 1 H, 12-CH3), 1.94 (ddd, JH,H(B) = 7.0, JH,H(X) = 10.5,
3JH,F(cis) = 19.5 Hz, 1 H, HA), 2.06 (ddd, 2JH,H(A) = 7.3, 3JH,H(X) = 7.4, 3JH,F(trans) = 12.3 Hz, 1 H, HB),
2.63 (ddd, 3JH,H(B) = 7.7, 3JH,H(A) = 10.5, 3JH,F(cis) = 18.1 Hz, 1 H, HX), 3.96 (q, 3JH,H = 7.5 Hz, 2 H,
8

11-CH2), 7.55-7.67 (m, 1 H, 7-CH), 7.79-7.83 (m, 1 H, 6-CH), 8.19-8.26 (m, 1 H, 8-CH),
8.35-8.37 (dt, 3JH,H = 1.5, 4JH,F = 2.8 Hz, 1 H, 10-CH). 13C NMR (75 MHz, CDCl3): δ 14.0 (q, C-
2
2
12), 17.1 (d, JC,F = 9.9 Hz, C-3), 28.3 (d, JC,F = 16.0 Hz, C-2), 61.3 (t, C-11), 81.1 (d,
1JC,F = 221.4 Hz, C-4), 123.1 (d, C-7), 124.1 (d, C-8), 129.3 (d, C-6), 129.8 (d, C-10), 134.1 (d,
3JC,F = 4.2 Hz, C-9), 135.3 (d, 2JC,F = 21.1 Hz, C-5), 165.3 (s, C-1). 19F NMR (282 MHz, CDCl3):
δ -158.78 (m, 1 F, 4-CF). MS (GC/EI): m/z (%) 253.1 (10) [M]+, 208.1 (20) [M-C2H5O]+, 188.1
(40) [208.1-HF]+, 180.1 (15) [M-C3H5O2]+, 134.1 (60) [C9H7F]+, 133.1 (100) [C9H6F]+. MS (ESI+,
exact mass): m/z 276.0642 [M+Na]+, calcd for C12H12FNO4Na+: 276.0643.
Ethyl trans-2-fluoro-2-(3-nitrophenyl)-cyclopropanecarboxylate (trans-2f). 1H NMR (300 MHz,
3
2
3
CDCl3): δ 1.31 (t, JH,H = 7.1 Hz, 3 H, 12-CH3), 1.72 (ddd, JH,H(A) = 7.3, JH,H(X) = 9.4,
3JH,F(trans) = 10.4 Hz, 1 H, HB), 2.28 (ddd, 3JH,F(trans) = 3.0, 3JH,H(A) = 7.9, 3JH,H(B) = 9.4 Hz, 1 H, HX),
2
3
3
2
2.42 (ddd, JH,H(B) = 7.2, JH,H(X) = 8.0, JH,F(cis) = 20.2 Hz, 1 H, HA), 4.26 (qd, JH,H = 3.1,
3JH,H = 7.1 Hz, 2 H, 11-CH2), 7.55-7.67 (m, 1 H, 7-CH), 8.12-8.13 (m, 3 H, 6/8/10-CH). 13C
NMR (75 MHz, CDCl3): δ 14.2 (q, C-12), 19.4 (d, 2JC,F = 12.0 Hz, C-3), 29.7 (d, 2JC,F = 11.4 Hz,
1
3
C-2), 61.6 (t, C-11), 79.8 (d, JC,F = 229.4 Hz, C-4), 119.2 (d, JC,F = 7.7 Hz, C-10), 123.1 (d,
C-8), 129.8 (d, C-7), 130.2 (d, 3JC,F = 6.9 Hz, C-6), 148.5 (s, C-9), 167.0 (d, 3JC,F = 2.4 Hz, C-
1). 19F NMR (282 MHz, CDCl3): δ
-191.26 (ddd, 3JH,F(trans) = 3.1, 3JH,F(trans)
=
10.6,
3JH,F(cis) = 20.4 Hz, 1 F, 4-CF). MS (GC/EI): m/z (%) 253.1 (10) [M]+, 208.1 (20) [M-C2H5O]+,
188.1 (40) [208.1-HF]+, 180.1 (15) [M-C3H5O2]+, 134.1 (60) [C9H7F]+, 133.1 (100) [C9H6F]+. MS
(ESI+, exact mass): m/z 276.0642 [M+Na]+, calcd for C12H12FNO4Na+: 276.0643.
4.2.1.7 Ethyl 2-fluoro-2-(4-acetoxyphenyl)cyclopropanecarboxylate (2g)
From 3-nitro-α-fluorostyrene (50 mg, 0.28 mmol), ethyl glycinate hydrochloride (117 mg, 0.84
mmol) and sodium nitrite (46 mg, 0.67 mmol) in the presence of FeTPPCl (3 mg, 0.004 mmol)
in acidified water (3 mL) a 1:3 mixture of cis-2g and trans-2g was formed as colorless oil. Yield:
63 mg (47%). The stereoisomers were separated chromatographically (n-pentane/diethyl
ether, 10:1).
1
Ethyl cis-2-fluoro-2-(4-acetoxyphenyl)cyclopropanecarboxylate (cis-2g). H NMR (300 MHz,
3
2
3
CDCl3): δ 1.02 (t, JH,H = 7.2 Hz, 3 H, 14-CH3), 1.83 (ddd, JH,H(B) = 7.1, JH,H(X) = 10.3,
3JH,F(cis) = 19.1 Hz, 1 H, HA), 1.97 (ddd, 2JH,H(A) = 7.1, 3JH,H(X) = 7.3, 3JH,F(trans) = 12.6 Hz, 1 H, HB),
2.29 (s, 3 H, 12-CH3), 2.57 (ddd, 3JH,H(B) = 7.3, 3JH,H(A) = 10.4, 3JH,F(cis) = 17.8 Hz, 1 H, HX), 3.92
(q, 3JH,H = 7.1 Hz, 2 H, 13-CH2), 7.09-7.12 (m, 2 H, 6/10-CH), 7.45-7.50 (m, 2 H, 7/9-CH). 13C
NMR (75 MHz, CDCl3): δ 13.9 (q, C-12), 16.7 (d, 2JC,F = 10.3 Hz, C-3), 21.1 (q, C-14), 28.0 (d,
2JC,F = 16.5 Hz, C-2), 60.8 (t, C-13), 82.4 (d, 1JC,F = 221.9 Hz, C-4), 121.4 (d, 4JC,F = 1.3 Hz, C-
7/9), 129.5 (d, 3JC,F = 4.0 Hz, C-6/10), 130.7 (d, 3JC,F = 20.6 Hz, C-5), 151.2 (s, C-8), 168.7 (d,
3JC,F = 1.8 Hz, C-1), 169.1 (s, C-11). 19F NMR (282 MHz, CDCl3): δ -154.3 (ddd,
3JH,F(trans) = 12.3, 3JH,F(cis) = 17.2, 3JH,F(cis) = 19.9 Hz, 1F, 4-CF). MS (GC/EI): m/z (%) 266.1 (50)
9

[M]+, 224.1 (40) [M-C2H3O]+, 195.0 (30) [224.3-C2H5]+, 151.1 (90) [195.3-CO2]+, 131.3 (40) [M-
C6H5O]+, 103.1 (100) [C4H4FO2]+. MS (ESI+, exact mass) m/z 289.0848 [M+Na]+, calcd for
C14H15FO4Na+: 289.0847.
1
Ethyl trans-2-fluoro-2-(4-acetoxyphenyl)cyclopropanecarboxylate (trans-2g). H NMR (300
2
3
3
MHz, CDCl3): δ 1.25 (ddd, JH,H(A) = 7.1, JH,H(X) = 9.1, JH,F(trans) = 12.7 Hz, 1 H, HB), 1.30 (t,
3JH,H = 7.1 Hz, 3 H, 14-CH3), 1.61 (ddd, 3JH,F(trans) = 3.1 Hz, 3JH,H(A) = 7.0, 3JH,H(B) = 9.2, 1 H, HX),
2.20 (ddd, 2JH,H(B) = 7.2, 3JH,H(X) = 7.0, 3JH,F(cis) = 19.5 Hz, 1 H, HA), 2.31 (s, 3 H, 12-CH3), 4.08-
4.26 (m, 2 H, 13-CH2), 7.09-7.12 (m, 2 H, 6/10-CH), 7.31-7.34 (m, 2 H, 7/9-CH). 13C NMR (75
2
MHz, CDCl3): δ 14.2 (q, C-14), 18.8 (d, JC,F = 12.4 Hz, C-3), 21.0 (q, C-12), 28.9 (d,
2JC,F = 11.6 Hz, C-2), 61.2 (t, C-13), 80.5 (d, 1JC,F = 227.2 Hz, C-4), 118.7 (d, C-7), 121.8 (d,
3
C-9), 126.0 (d, 3JC,F = 6.3 Hz, C-6), 129.2 (d, C-10), 135.0 (d, JC,F = 22.0 Hz, C-5), 150.5 (s,
C-8), 167.6 (d, 3JC,F = 2.2 Hz, C-1), 169.3 (s, C-11). 19F NMR (282 MHz, CDCl3): δ -187.4 (ddd,
3JH,F(trans) = 3.1, 3JH,F(trans) = 10.2, 3JH,F(cis) = 20.6 Hz, 1 F, 4-CF). MS (GC/EI): m/z (%) 266.1 (60)
[M]+, 224.1 (50) [M-C2H3O]+, 195.0 (30) [224.3-C2H5]+, 151.1 (100) [195.3-CO2]+, 131.3 (40)
[M-C6H5O]+, 103.1 [C4H4FO2]+. MS (ESI+, exact mass): m/z 289.0848 [M+Na]+, calcd for
C14H15FO4Na+: 289.0847.
4.2.1.8 Ethyl 2-fluoro-2-(4-methylphenyl)cyclopropanecarboxylate (2h)
From 4-methyl-α-fluorostyrene (50 mg, 0.37 mmol), ethyl glycinate hydrochloride (155 mg,
1.11 mmol) and sodium nitrite (61 mg, 0.89 mmol) in the presence of FeTPPCl (3 mg, 0.004
mmol) in acidified water (2 mL) a 1:4 mixture of cis-2h and trans-2h was formed as colorless
oil. Yield: 20 mg (24%). The stereoisomers were separated chromatographically (n-
pentane/diethyl ether, 20:1). The spectroscopic data of both diastereoisomers agree with
published values [18b].
4.2.1.9 Ethyl 2-fluoro-2-(4-chlorophenyl)cyclopropanecarboxylate (2i)
From 4-methyl-α-fluorostyrene (50 mg, 0.32 mmol), ethyl glycinate hydrochloride (134 mg,
0.96 mmol) and sodium nitrite (53 mg, 0.77 mmol) in the presence of FeTPPCl (3 mg, 0.004
mmol) in acidified water (3 mL) a 1:3 mixture of cis-2i and trans-2i was formed as colorless oil.
Yield: 16 mg (21%). The stereoisomers were separated chromatographically (n-
pentane/diethyl ether, 20:1). The spectroscopic data of both diastereoisomers agree with
published values [5].
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft (DFG), Collaborative Research
Center 656 (Molecular Cardiovascular Imaging, Project B1) and Cells-in-Motion Cluster of
Excellence (EXC 1003 – CIM), University of Münster is gratefully acknowledged.
10

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a) L. Huang, Y. Chen, G.-Y Gao, X.P. Zhang, Diastereoselective and enantioselective cyclopropanation
of alkenes catalyzed by cobalt porphyrins, J. Org. Chem. 68(21) (2003) 8179-8184; b) M.L. Rosenberg, E.
Langseth, A. Krivokapic, N.S. Gupta, M. Tilset, Investigation of ligand steric effects on a highly cis-selective Rh(I)
cyclopropanation catalyst, New J. Chem. 35(9) (2011) 2306-2313.
13

Figure 1. Competition experiment of Cu(acac)2 catalyzed cyclopropanation of styrene (1a) and
α-fluorostyrene (1b) with ethyl diazoacetate (EDA) in methylene chloride at room temperature to
form ethyl cis- and trans-2-phenylcyclopropanecarboxylates (cis- and trans-2a) and ethyl cis- and
trans-2-fluoro-2-phenylcycopropanecarboxylates (cis- and trans-2b), respectively (GC analysis).
14

Figure 2. Transition states of the formation of cis/trans-isomeric cyclopropane carboxylates [30]
Figure 3. Transition states of the cyclopropanation of styrene and α-fluorostyrene
15

Scheme 1. Iron-porphyrin-catalyzed cyclopropanations of styrenes and α-fluorostyrenes
16

Table 1. Results of iron-porphyrin-catalyzed cyclopropanations of styrenes and α-fluorostyrenes
and comparison to alternative copper- or rhodium catalyzed reactions
Yielda 2 [%]b
(c/t-ratio)
Yielda 2 [%]c
(c/t-ratio)
Yielda 2 [%]d
(c/t-ratio)
Entry Compound
R
H
X
H
Ref.
12
Ref.
21
Ref.
21
1
2
3
4
5
1a
1a
1b
1c
1d
71
(1:10)
71
(1:2.6)
93
(1:1.6)
H
H
F
H
F
73
(1:10)
this
work
65
(1:2)
22
5
92
(1:1.5)
22
21
23
H
53
(1:3)
this
work
87
(1:1)
25
(1:1)
p-OMe
p-OMe
79
(1:8)
12
87
(1:7)
70
this
89
18e
(1:3)
work
(1:1)
6
7
1e
1f
m-OMe
p-NO2
m-NO2
m-NO2
p-OAc
F
F
H
F
H
55
(1:3)
this
work
62
(1:1)
24
24
33
(1:2)
this
work
40
(1:1)
8
1g
1h
1i
55
(1:6)
12
9
86
(1:2)
this
work
51
(1:1)
24
10
68
(1:8)
47
12
78
(1:5)
23
23
this
work
11
12
1j
p-OAc
p-Me
F
(1:3)
1k
H
74
(1:9)
24
12
90
(1:2)
20
20
5
89
(1:8)
this
work
13
14
1l
p-Me
p-Cl
F
F
90
(1:2)
(1:4)
21
(1:3)
this
work
1m
91
(1:1)
17