A two-step sequence to ethyl α-fluorocyclopropanecarboxylates through MIRC reaction of ethyl dichloroacetate and highly regioselective fluorination

Article abstract of DOI:10.1002/ejoc.201300978

A two-step sequence to ethyl α-fluorocyclopropanecarboxylates has been developed. Ethyl α-chlorocyclopropanecarboxylates were first obtained through a Michael-initiated ring closure reaction of terminal electron-deficient olefins with ethyl 2,2-dichloroacetate under mild basic conditions. Subsequent smooth conversion into the corresponding monofluorinated analogues in good yields was through a halogen exchange reaction with potassium bifluoride. Further investigation clearly demonstrated that potassium bifluoride in this reaction system played a dual role of base and nucleophilic reagent. This is the first successful example reported hitherto for producing ethyl α-fluorocyclopropanecarboxylate directly through fluorination of its chlorinated analogue with alkali bifluoride. A convenient two-step method to prepare ethyl α-fluorocyclopropanecarboxylates has been developed. Ethyl α-chlorocycloproanecarboxylates were obtained through Michael-initiated ring closure reactions under mild reaction conditions in good yields before being smoothly converted into the corresponding monofluorinated analogues through halogen exchange reactions with potassium bifluoride in good yields. The reaction mechanism was also investigated. Copyright

Full text of DOI:10.1002/ejoc.201300978

Job/Unit: O30978
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Date: 23-09-13 18:21:10
Pages: 11
FULL PAPER
DOI: 10.1002/ejoc.201300978
A Two-Step Sequence to Ethyl α-Fluorocyclopropanecarboxylates Through
MIRC Reaction of Ethyl Dichloroacetate and Highly Regioselective
Fluorination
[a]
[a]
[b]
Min Zhang, Yuefa Gong,* and Weizhou Wang
Keywords: Synthetic methods / Fluorine / Small-ring systems / Elimination / Nucleophilic addition
A two-step sequence to ethyl α-fluorocyclopropanecarboxyl-
ates has been developed. Ethyl α-chlorocyclopropanecarb-
oxylates were first obtained through a Michael-initiated ring
closure reaction of terminal electron-deficient olefins with
ethyl 2,2-dichloroacetate under mild basic conditions. Subse-
quent smooth conversion into the corresponding monofluor-
inated analogues in good yields was through a halogen ex-
change reaction with potassium bifluoride. Further investiga-
tion clearly demonstrated that potassium bifluoride in this re-
action system played a dual role of base and nucleophilic
reagent. This is the first successful example reported hitherto
for producing ethyl α-fluorocyclopropanecarboxylate directly
through fluorination of its chlorinated analogue with alkali
bifluoride.
Introduction
Fluorinated cyclopropanes, which combine both the
unique properties of cyclopropane and fluorine, can be en-
visioned as new powerful scaffolds for building new bioac-
Cyclopropyl groups are found as a basic structural ele-
ment in a lot of biologically and pharmacologically active
[8]
tive molecules and therapeutic agents. Among them,
[
1,2]
substances.
Introduction of the cyclopropane moiety
monofluorinated cyclopropanes have received considerable
attention over recent years owing to their attractive bio-
logical activities, examples of which include monoamine
oxidase inhibitors, nitric oxide synthase inhibitors, anti-
virals, antibacterial agents, and mGluR inhibitors for the
into biologically active substances has been recognized as
an important chemical modification owing to its conforma-
tional rigidity and potential chemical reactivity.[ More-
over, various cyclopropane-containing unnatural products
have been prepared and used as versatile intermediates in
the synthesis of more functionalized cyclic and acyclic com-
3]
[9]
treatment of neurological disorders.
Synthetic methods of monofluorinated cyclopropanes[9]
reported previously mainly include [2+1] cycloaddition of
fluorocarbenes to olefins, [2+1] cycloaddition of carbenes
to fluoroalkenes, radical addition of ethyl iodofluoroacetate
with subsequent intramolecular nucleophilic substitution,
and direct fluorination with 5% F /N . Recently, Michael-
[
4]
pounds.
Owing to its unique properties – high electronegativity,
stable bonds to carbon, and small atomic radius similar to
that of hydrogen – fluorine is usually introduced into an
organic compound to drastically modify its chemical, physi-
cal and biological properties, such as solubility, lipophil-
icity, conformation, and metabolic stability.[ Today, fluor-
ine is frequently used to modulate the properties of a poten-
tial drug by medicinal chemists, and a growing number of
fluorinated drugs have found use in medical applications
over the past several decades.[ As a consequence, incorpo-
ration of fluorine into organic molecules has received con-
siderable interest in recent years as the number of biolo-
2
2
initiated ring closure (MIRC) reactions have been success-
fully applied to synthesize monofluorinated cyclopropane
5]
[
10]
compounds. Jubault et al. reported the reaction of ethyl
dibromofluoroacetate with electron-deficient olefins in the
[
11]
presence of diethylzinc or Zn/LiCl, and Hu et al.
devel-
6]
oped the first chiral monofluoromethylenation reagent, (R)-
N-tosyl-S-fluoromethyl-S-phenylsulfoximine, for the syn-
thesis of chiral monofluorinated cyclopropanes. Very re-
[
7]
gically active fluorinated compounds continues to grow.
[
12]
cently, Charette et al. reported the highly enantioselective
Simmons-Smith fluorocyclopropanation of allylic alcohols
by using difluoroiodomethane and ethylzinc iodide as the
[
a] School of Chemistry and Chemical Engineering, Huazhong
University of Science and Technology,
1
037 Luoyu Road, Wuhan 430074, People’s Republic of China substituted carbenoid precursors. Although the utility of
existing methods was demonstrated by the synthesis of sev-
b] College of Chemistry and Chemical Engineering, Luoyang eral types of biologically active compounds, the fluorine
E-mail: gongyf@mail.hust.edu.cn
www.hust.edu.cn
[
Normal University,
sources they used are rather limited. Therefore, it is still
interesting for us to develop mild and practical methods for
constructing monofluorinated cyclopropanes. Herein, we
Luoyang 471022, People’s Republic of China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300978.
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M. Zhang, Y. Gong, W. Wang
FULL PAPER
present a practical synthetic route of ethyl α-fluorocyclo- ucts trans/cis-3a, which were inseparable by silica-gel
propanecarboxylates by using KF or KHF as the fluorine column chromatography. Based on the Karplus equation,
2
sources.
trans-3a was easily distinguished from cis-3a from their dif-
ferent splitting constants JHa-F (2.7 Hz for the trans isomer,
and 18.7 Hz for the cis isomer) owing to their different dihe-
[
10a,15]
dral angles.
This assignment was further confirmed
Results and Discussion
by HSQC and HMBC experiments. To the best of our
knowledge, this is the first successful example related to
synthesis of ethyl α-fluorocyclopropanecarboxylates from
its chlorinated analogues.
According to the MIRC reaction pattern, we tried to ob-
tain ethyl α-fluorocyclopropanecarboxylate through the re-
action of ethyl bromofluoroacetate (1a) with 1-phenyl-2-
propenone (2a) in the presence of Cs CO in dimethylform-
2
3
amide (DMF). Unfortunately, no desired product ethyl 2-
benzoyl-1-fluorocyclopropanecarboxylate (3a) was detected
during this reaction even after various bases and solvents
were screened (Scheme 1). Further investigation demon-
strated that 1a was easily hydrolyzed into ethyl glyoxalate
under these reaction conditions, indicating that the failure
of the MIRC reaction for 1a could be attributed to the fac- Scheme 2. Fluorination of monochlorinated cyclopropane 4a.
ile elimination of bromide from its conjugate base.
To understand the effect of halogen properties well, ethyl
Encouraged by these preliminary results, we turned our
dichloroacetate (1b), a commercially available reagent, was attention to evaluate the reaction parameters and the sub-
used and assessed. Pleasingly, its reaction with 2a in aceto- strate scope suitable for this reaction. The MIRC reaction
nitrile took place smoothly in the presence of Cs CO at between ethyl dichloroacetate 1b and the enone 2a was cho-
2
3
room temperature, giving ethyl α-chlorocyclopropanecarb- sen as the model reaction to optimize the reaction condi-
oxylate (4a) in 64% yield (Scheme 1). Its steric structure tions including the base and solvent at room temperature.
was characterized by the heteronuclear single quantum cor- All the results are summarized in Table 1. The reaction pro-
relation (HSQC) and the heteronuclear multiple bond cor- ceeded smoothly in the presence of Cs CO with aceto-
2
3
relation (HMBC) experiments, and the main isomer was as- nitrile as the solvent (Table 1, Entry 1). Potassium carbon-
signed to be of trans-configuration.[
13]
ate, a common inorganic base, can readily promote the re-
With monochlorinated cyclopropane 4a in hand, the action at room temperature, but provided desired product
problem we faced was how to convert 4a into fluorinated 4a only in 16% yield with 4.8:1 dr value (Table 1, Entry 2).
analogue 3a. The common fluorination of chlorinated com- Strong base such as NaOH afforded product 4a only in 9%
pounds, except the direct substitution through an S 2 reac- yield (Table 1, Entry 3). Much stronger bases, NaH, EtONa
N
tion, is usually achieved by using anhydrous HF and fluor- and tBuOK were inferior for this reaction (Table 1, En-
inated Lewis acids such as SbF or SbF as the fluorinating tries 4, 6, 7), in which NaH could lead to further decompo-
3
5
[
14]
reagents.
Considering the instability of cyclopropane to sition of 4a, and EtONa or tBuOK preferred to add to en-
strong acids, we conducted a preliminary experiment with one 2a. Another common base, tetrabutylammonium fluo-
KF as the fluorine source, dimethyl sulfoxide (DMSO) as ride (TBAF) also gave 4a in a low yield (Table 1, Entry 5).
the solvent and 20 mol-% of tetrabutyl ammonium bromide Organic bases such as 1,4-diazabicyclo[2.2.2]octane
(TBAB) as the phase-transfer catalyst at 120 °C. As a con- (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in
sequence, compound 4a disappeared completely within four this reaction always caused oligomerization or a Rauhut-
[
16]
hours, and a new compound was generated with slightly Currier (RC) side-reaction
of 2a and gave a certain
higher polarity than 4a through TLC detection (Scheme 2). amount of oligomer or self-dimer 5a (Table 1, Entries 8–
Gratifyingly, further spectroscopic characterization of the 11). Therefore, Cs CO was the most promising base for
2
3
1
13
19
newly formed compound by H, C and F NMR spec- this MIRC reaction. Next, a group of solvents were further
troscopy demonstrated that it was desired fluorinated prod- assessed. Strong aprotic polar solvents commonly favored
Scheme 1. Reaction between ethyl dihaloacetate and 1-phenyl-2-propenone (2a).
2
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A Two-Steps Sequence to Ethyl α-Fluorocyclopropanecarboxylates
the formation of 4a (Table 1, Entries 12–13), and the iso- ceptor than MVK, worked well in this system to afford de-
lated yield reached 71% in DMF. However, the use of tetra- sired product 4h in good yield and excellent dr value
hydrofuran (THF) and 1,4-dioxane resulted in a significant (Table 2, Entry 8), whereas methyl methacrylate gave no de-
decrease in the chemical yield, and almost no desired prod- tectable MIRC product. The reaction of acrylamide was
uct was isolated (Table 1, Entries 14–15).
very slow, and gave only a little of the MIRC product. In
addition, we noticed that the trans/cis ratios for 4 listed in
Table 2 varied from 5.1:1 to 20:1 with the change of R
group, and the diastereoselectivity for 4h derived from
methyl acrylate was the best. Finally, for the practical use
of this protocol, we examined the model reaction of 1b and
Table 1. Optimization of the MIRC reaction between 1b and 2a.[a]
2a on a 10.0 mmol scale (20 times larger) and the same
good result was observed (Table 2, Entry 12).
Table 2. Scope of the MIRC reaction between 1b and 2.[a]
Entry
R
Product Time [h]
Yield [%][b] trans/cis[c]
Entry Base
Solvent
4a
yield [%]
5a
[b]
trans/cis[c] yield [%]
[b]
1
2
3
4
5
6
7
8
9
C
6
H
5
2a
4-MeC
4-MeOC
4-MeSC
4-ClC
4-BrC
Me 2g
MeO 2h
2-thienyl 2i
1-naphthyl 2j
4-PhC 2k
2a
4a
4b
4c
4d
4e
4f
4g
4h
4i
6
10
10
10
4
4
6
6
2
71
70
76
60
58
61
76
74
62
80
72
70
7.1:1
5.1:1
6.3:1
9.1:1
16.7:1
15.6:1
9.1:1
20:1
12.5:1
16.1:1
6.3:1
6.9:1
6
4
H 2b
1
2
3
4
5
6
7
8
9
Cs
K
2
2
CO
CO
3
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
64
16
9
trace
4
trace
trace
0
8
0
0
67
71
trace
7.1:1
4.8:1
5:1
–
4.8:1
–
–
–
4.9:1
–
–
0
0
0
0
0
0
0
12
6
6
trace
0
0
0
6
H
H
4
4
2c
2d
3
3
6
NaOH
NaH
TBAF
EtONa
tBuOK
DABCO
DBU
3
6
H
H
4
2e
2f
3
6
4
3
3
3
3
1
0
4j
4k
4a
5
5
6
3
1
12
1
6
H
4
10
DMAP
3
[d]
C
6
H
5
11
hydroquinine CH
3
1
2
Cs
Cs
Cs
Cs
2
CO
CO
CO
CO
3
DMSO
DMF
THF
6.9:1
7.1:1
–
[a] Reactions were carried out with 1b (0.5 mmol), 2 (0.5 mmol)
and Cs CO (0.6 mmol) in DMF (2 mL) at room temperature for
the given time. [b] Isolated yields. [c] Determined by H NMR spec-
troscopy of the crude product. [d] Reaction on a 10.0 mmol scale
of 2a.
1
3
2
3
2
3
1
1
4
2
3
15
2
3
1,4-dioxane trace
–
0
[
a] Reactions were carried out with 1b (0.5 mmol), 2a (0.5 mmol),
and base (0.6 mmol) in solvent (2 mL) at room temperature for 6 h.
1
Because chlorinated products 4a–4k could be conve-
niently obtained through the MIRC process, next we turned
our attention to the optimization of fluorination reaction
[b] Isolated yields. [c] Determined by H NMR spectroscopy of the
crude product.
Under the optimized reaction conditions, the diversity of conditions of these compounds. The reaction parameters
electron-deficient olefins was explored, and the results are including solvents, reaction temperature and amount of KF,
summarized in Table 2. The terminal electron-deficient ole- were screened by choosing the reaction of 4a as the model.
fins with a considerable degree of structure variations The results are described in Table 3. As mentioned above,
underwent the MIRC reaction smoothly to afford the ex- KF smoothly converted 4a into fluorinated analogue 3a in
pected products in moderate to good chemical yields with DMSO at 120 °C in 68% yield (Table 3, Entry 1). Further
good diastereoselectivities under the specified reaction con- experiments showed that the reaction temperature had a
ditions. The electronic nature of the substituent on the aro- significant influence on the reaction (Table 3, Entries 2–5).
matic ring did not exert any significant influence over the At room temperature, the reaction did not take place at all.
product yields, whereas electron-donating groups slowed When the temperature was elevated to 80 °C, the reaction
down the reaction rate (Table 2, Entries 1–6, 11). Enones 2i proceeded slowly, and only 55% of substrate 4a was con-
and 2j with heterocyclic 2-thienyl and fused-ring 1-naphthyl verted after 48 h. The reaction was markedly accelerated
groups were easily tolerated, and satisfying yields were when the reaction temperature was raised to 100 °C. A
achieved with excellent dr values (Table 2, Entries 9, 10). It slight decrease in the yield was observed when the reaction
is noteworthy that reaction of aliphatic enone, methyl vinyl temperature was further elevated to 140 °C, although sub-
ketone (MVK; 2g), proceeded smoothly, giving correspond- strate 4a was consumed completely in 2 h (Table 3, Entry 5).
ing product 4g in 76% yield with a good dr value (Table 2, Obviously, a temperature higher than 100 °C was crucial to
Entry 7). In contrast, cyclohexenone, a typical nonterminal this reaction, but too high a temperature is not beneficial.
enone, did not undergo the above MIRC reaction. More- Thus, the following experiments were performed at 120 °C.
over, methyl acrylate (MA; 2h), a less reactive Michael ac- DMSO turned out to be the promising solvent employed in
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M. Zhang, Y. Gong, W. Wang
FULL PAPER
this reaction (Table 3, Entries 1, 6–7). The amount of KF found during the reaction in the absence of K CO (Table 4,
2
3
used also influenced the reaction (Table 3, Entries 1, 8–9). Entries 5–8). Based on the yields observed (Table 4, En-
One equivalent of KF did not convert 4a completely, and tries 2 and 8), the addition of TBAB as the phase-transfer
gave only 48% yield of desired product 3a. However, no catalyst seems unnecessary for this reaction. In the absence
improvement in yield was observed when three equivalents of TBAB, the fluorination reaction of 4a with KHF was
2
of KF were used. Stereochemical analysis of the products smooth at 120 °C, and gave 3a in 75% yield after 12 h. The
clearly indicated there was an obvious decline in the dia- temperature and solvent also have great influence on this
stereoselectivity from 6.9:1 (dr for 4a) to 2.7:1 (dr for 3a; reaction, and the details are given in the Supporting Infor-
Table 3, Entry 1) during the fluorination process, although mation. The dose of KHF also had some effect on the
2
trans-3a remained the main isomer.
reaction, and the best result was obtained by using three
equivalents of KHF (Table 4, Entries 9–11). Thus, the opti-
2
Table 3. Optimization of the fluorination reaction of 4a with KF.[a] mized conditions for the fluorination reaction were ascer-
tained: KHF (3 equiv.) as the fluorine source and DMSO
2
as the solvent at 120 °C. It should be noted that there was
no marked effect on the diastereoselectivity of fluorination
process by the fluorine sources, and the trans/cis ratios
changed from 2.0:1 to 2.6:1.
Entry Solvent
T
°C]
Time
[h]
Conv. Yield
[%]
trans/
cis
Table 4. Optimization of fluorination of 4a with other fluorine
[%][
b]
[c]
[a]
[
sources.
1
2
3
4
5
6
7
8
9
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
PEG400
DMSO
DMSO
120
r. t.
80
100
140
120
120
120
120
4
26
48
20
2
2
4
100
0
55
68
0
69(38)
62(56)
55
34
0
48(43)
68
2.7:1
–
1.6:1
2.4:1
2.4:1
2.2:1
–
Entry Fluorine
source
T
[°C]
Time Conv. Yield
trans/
cis
[%][
b]
[c]
[h]
[%]
1[
2
3
4
5
6
7
8
d]
CsF
KHF
KHF
KHF
KHF
KHF
KHF
KHF2
KHF2
KHF2
KHF2
120
120
120
120
120
120
120
120
120
120
120
2
12
2
4
4
7
9
12
9
9
100
100
80
100
50
72
95
100
65
95
40
74
2.4:1
2.3:1
2.2:1
2.0:1
2.4:1
2.6:1
2.5:1
2.4:1
2.4:1
2.6:1
2.5:1
90
[
d]
e]
e]
2
2
2
2
2
2
100
100
100
90
[
25 (20)
8
92 (46)
88 (64)
82 (78)
75
80 (52)
85 (81)
83 (79)
[
[
[
d]
e]
4
4
1.8:1
2.5:1
100
[
a] Reactions were carried out with 4a (0.5 mmol), KF (2 equiv.
[f]
unless otherwise stated), TBAB (20 mol-%) in solvent (2 mL) at the
9
10[
11
g]
given temperature. [b] Yields based on converted 4a, and isolated
yields in parentheses. [c] Determined by H NMR spectroscopy of
the crude product. [d] KF (1 equiv.) was used. [e] KF (3 equiv.)
was used.
1
[h]
9
95
[
(
a] Reactions were carried out with 4a (0.5 mmol), fluorine source
2 equiv. unless otherwise stated) in DMSO (2 mL) at the given
temperature. [b] Yields based on converted 4a, isolated yields in
1
parentheses. [c] Determined by H NMR spectroscopy of the crude
product. [d] TBAB (20 mol-%) was used. [e] K CO (2 equiv.) was
2 3
The effect of different fluorine sources on the above reac-
tion was also investigated. Two common, commercially used. [f] KHF (1 equiv.) was used. [g] KHF (3 equiv.) was used.
2
2
[h] KHF
2
(4 equiv.) was used.
available, fluorine reagents CsF and KHF were utilized in
2
the following assessment. The results are summarized in
Table 4. Moderately basic CsF smoothly converted 4a into
fluorinated analogue 3a in DMSO at 120 °C within 2 h in
The above observations assured us that the fluorination
4
0% yield (Table 4, Entry 1). In contrast, potassium bi- reaction of 4a with KF or KHF could proceed smoothly
2
fluoride (KHF ), a weakly acidic reagent, gave a much under the basic reaction conditions. However, the direct nu-
2
higher yield of 3a under the same conditions despite a pro- cleophilic substitution of halogen by fluoride on a cyclopro-
[
17]
longed required reaction time (Table 4, Entry 2). From the pane ring has seldom been reported.
According to the
above observations, we were aware of a significant effect of features of this reaction, we realized there were two possible
the basicity for the fluorine source on the reaction. Thus, reaction pathways. One possibility is that both the electron-
we estimated the influence of basic K CO on the reaction, withdrawing carbonyl group and ester group on the cyclo-
2
3
and found its addition can markedly accelerate the con- propane ring of 4a might weaken the C–Cl bond together,
sumption rate of 4a, but disfavored formation of 3a which would make the direct nucleophilic fluorination
(Table 4, Entry 3). Moreover, the yield of 3a would be fur- smooth. Another possibility would be that the existence of
ther decreased with extended reaction times (Table 4, En- an acidic α-H of the carbonyl group for 4a leads to facile
try 4). These results indicate that fluorinated product 3a elimination of HCl, and then the generated cyclopropene
–
was not very stable and decomposed slowly during the reac- intermediate 6a combined regioselectively with HF2 or
–
tion under basic conditions. The side products formed were H F generated in situ to afford fluorinated product 3a
2
3
highly polar and hardly moved up on a TLC plate [mobile (Scheme 3).[18] Namely, the mechanistic ambiguity lies in
phase: petroleum/ethyl acetate, 10:1 (v/v)]. The same trend whether the reaction would undergo along the common
in the conversion ratio of 4a and in yield of 3a was also SN2 route or along an elimination/addition route. To solve
4
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A Two-Steps Sequence to Ethyl α-Fluorocyclopropanecarboxylates
Scheme 3. Mechanistic investigation for the fluorinated reaction of 4a.
this problem, some mechanistically pertinent experiments nating reaction system. As we expected, the reaction af-
were carried out.
forded Diels–Alder adduct 9a in 25% yield together with
Firstly, the effect of carbonyl group on the fluorinating monofluorinated product 3a in 35% yield [Scheme 3, Equa-
reaction was assessed. Substrate 4a was reduced to form tion (3)]. The successful capture of cyclopropene intermedi-
alcoholic compound 7a with sodium borohydride, which ate 6a strongly supports the opinion that fluorination pro-
was then treated with KF under the fluorinating conditions ceeds through an elimination/addition route (Scheme 3,
mentioned above. No fluorination reaction occurred at all Path b). Moreover, the experimental observations assured
in this case [Scheme 3, Equation (1)]. This result indicated us that the addition of 6a with HF2– or H F3 must be a
–
2
that a carbonyl group was vital to the fluorination process highly regioselective process owing to no detectable forma-
of 4a. Next, the role of the acidic α-H of 4a was examined. tion of 3a-I. Furthermore, this elimination/addition mech-
The acidic α-H of 4a was blocked through bromination in anistic proposal can rationalize why the original diastereo-
anhydrous acetic acid, and then the generated 8a was selectivity for 4a disappeared during the fluorination pro-
treated under the above fluorinating system. To our sur- cess. In general, because the size of fluorine atom is much
prise, no desired difluorinated compound 3a-II was formed smaller than that of chlorine, predominant formation of
[
Scheme 3, Equation (2)]. The above results show that trans-3a would be expected during the addition step
fluorination does not proceed along a S 2 mechanism through epimerization owing to less steric hindrance rela-
N
(Scheme 3, Path a). Lastly, we tried to capture cyclopropene tive to cis-3a. The dr values for 3a observed during the
intermediate 6a generated in situ possibly during the reac- fluorination process were relatively lower than that for 4a
tion by adding anthracene (2 equiv.) as a diene to the fluori- without exception. Although the real reason for this is still
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O30978
/KAP1
Date: 23-09-13 18:21:10
Pages: 11
M. Zhang, Y. Gong, W. Wang
FULL PAPER
unclear, the existence of weak H-bonding between cis-3a methodology is very practical owing to the quite-mild reac-
–
and the surrounding HF2 might be a potential factor bene- tion conditions and cheap reagents used. In addition, elec-
fitting the formation of cis-3a.
tron-deficient reactive cyclopropene intermediate 6, gener-
Next, various ethyl α-chlorocyclopropanecarboxylates ated in situ through a common 1,2-elimination, proved syn-
listed in Table 2 were chosen for subsequent fluorination thetically useful for accessing bicycloadducts, which are cur-
reaction to exploit the substrate scope under the above opti- rently being investigated in our laboratory.
mized fluorinating conditions. The results are given in
Table 5. Obviously, the electronic properties of the substitu-
ent groups at the cyclopropane ring had a marked effect on
the reaction. For substrates 4a–4f with substituted benzoyl
Experimental Section
groups, fluorination reactions with KHF gave high conver- General: Reactions were monitored by TLC analysis by using silica-
2
sions and high yields of products 3a–3f in each case gel 60 Å F-254 thin-layer plates. Flash column chromatography was
1
(
Table 5, Entries 1–5). Electron-donating p-methyl and p- performed on silica gel 60 Å, 10–40 μm. H NMR spectra were
recorded on a Bruker instrument (400 MHz). Chemical shifts are
reported in ppm from tetramethylsilane with the solvent resonance
as the internal standard. Data are reported as multiplicity (s: sing-
let, d: doublet, t: triplet, q: quartet, m: multiplet). C NMR spectra
were recorded with a Bruker instrument (101 MHz) with complete
proton decoupling. Chemical shifts are reported in ppm from the
tetramethylsilane with the solvent resonance as internal standard.
methoxy groups greatly retarded the reactions and electron-
withdrawing p-chloro and p-bromo groups accelerated the
reactions. In contrast, conversion of 4g with an acetyl group
was very slow, and yielded little product 3h (Table 5, En-
try 6). TLC analysis clearly indicated no reaction occurred
for substrates 4h with a methoxycarbonyl group under these
reaction conditions (Table 5, Entry 7). Substrates 4i–4k
1
3
19
F NMR spectra were recorded with a Bruker instrument
with 2-thienyl, 1-naphthyl or biphenyl groups were also tol- (376 MHz) with CDCl as the solvent. IR spectra were recorded
3
erated for this reaction, giving high yields of products 3i– with a Bruker FT-IR spectrometer. Melting points were recorded
3
k (Table 5, Entries 8–10). The trans/cis ratios for all the with a melting point detector. HRMS data were measured with a
Waters Micromass GCT Premier with an EI source and an Apex
fluorination products summarized in Table 5 were close to
III (7.0 Tesla) FTMS (Bruker, Billerica, MA, USA) equipped with
an ESI source.
that for 3a, and varied within a narrow range of 1.2:1 to
2.6:1, indicating little effect of the substrate structure and
original dr value.
Typical Procedure for Synthesis of Monochlorinated Cyclopropane
4: Terminal electron-deficient alkene 2a (0.5 mmol) was added to a
Table 5. Substrate scope of fluorination reaction with KHF
2
.[a]
solution of 1b (0.5 mmol) and Cs CO (0.6 mmol) in DMF (2 mL),
2
3
and the mixture was stirred at room temperature. The reaction was
followed by thin-layer chromatography until substrate 2a disap-
peared. The mixture was then washed with water and extracted
with CH
2 2
Cl . Combined extracts were dried with anhydrous
Na SO and concentrated under reduced pressure. The residue was
2
4
purified by silica-gel column chromatography to afford 90 mg of
compound 4a in 71% yield. Unless otherwise specified, all other
products 4 were synthesized according to this typical procedure.
Entry Product 3
Time
Conv.
[%]
Yield
[%][
trans/
cis
b]
[c]
[h]
1
2
3
4
5
6
7
8
9
1
C
6
H
5
3a
4-MeC
4-MeOC
4-ClC
4-BrC
Me 3g
MeO 3h
9
95
84
83
96
94
15
0
86
84
85
85 (81)
92 (77)
86 (71)
89 (85)
81 (76)
trace
2.6:1
1.5:1
1.2:1
1.6:1
2.2:1
–
1
4
a: Colorless oil (90 mg, 71% yield). H NMR (400 MHz, CDCl
3
,
6
H
4
3b
3c
3e
3f
18
18
4
6
H
4
25 °C, TMS): δ = 7.99 (m, 2 H, ArH), 7.62 (m, 1 H, ArH), 7.50
(m, 2 H, ArH), 4.34 (q, J = 7.1 Hz, 2 H, COOEt), 3.53 (dd, J =
9.1, 7.9 Hz, 1 H, CH-cyclo), 2.23 (dd, J = 7.9, 5.6 Hz, 1 H, CH2-
6
H
4
6
H
4
4
24
24
5
15
11
cyclo), 1.98 (dd, J = 9.1, 5.6 Hz, 1 H, CH
7
2
-cyclo), 1.36 (t, J =
, 25 °C,
TMS): δ = 191.6, 168.7, 136.9, 133.7, 128.8, 128.5, 63.2, 43.7, 33.5,
–
–
.1 Hz, 3 H, COOEt) ppm. 13C NMR (101 MHz, CDCl
3
2-thienyl 3i
93 (80)
92 (77)
93 (79)
1.9:1
1.8:1
2.4:1
1-naphthyl 3j
2
1
9
2
1.9, 14.1 ppm. IR (neat): ν˜ = 3088, 2983, 2937, 1732, 1685, 1593,
0
6 4
4-PhC H 3k
450, 1380, 1367, 1276, 1223, 1178, 1133, 1090, 1056, 1009,
[
a] Reactions were carried out with 4 (0.5 mmol), KHF
2
(3 equiv.)
–1
+
3
79 cm . HRMS (EI): calcd. for C13H13ClO [M] 252.0553; found
in DMSO (2 mL) at 120 °C for the times given. [b] Yields based on
52.0559.
1
converted 4, isolated yields in parentheses. [c] Determined by
NMR spectroscopy of the crude product.
H
4b: White solid (93 mg, 70% yield); m.p. 27–28 °C. 1H NMR
400 MHz, CDCl , 25 °C, TMS): δ = 7.87 (d, J = 8.2 Hz, 2 H,
(
3
ArH), 7.28 (d, J = 8.0 Hz, 2 H, ArH), 4.32 (q, J = 7.1 Hz, 2 H,
COOEt), 3.51 (dd, J = 9.1, 8.0 Hz, 1 H, CH-cyclo), 2.41 (s, 3 H,
Conclusions
CH
3
), 2.21 (dd, J = 7.9, 5.6 Hz, 1 H, CH
.6 Hz, 1 H, CH -cyclo), 1.35 (t, J = 7.1 Hz, 3 H, COOEt) ppm.
C NMR (101 MHz, CDCl , 25 °C, TMS): δ = 191.1, 168.9, 144.7,
34.6, 129.5, 128.6, 63.2, 43.5, 33.5, 21.9, 21.7, 14.1 ppm. IR (neat):
2
-cyclo), 1.96 (dd, J = 9.1,
5
2
In summary, we have developed a convenient method for
preparing valuable ethyl α-fluorocyclopropanecarboxylates
that involves a convenient MIRC reaction between ethyl
dichloroacetate and various terminal electron-deficient alk-
1
3
3
1
ν˜ = 3100, 3032, 2983, 2936, 2873, 1740, 1727, 1682, 1607, 1448,
407, 1379, 1367, 1276, 1229, 1210, 1180, 1134, 1087, 1058, 1012,
1
–
1
+
enes and subsequent fluorination reaction with potassium 919 cm . HRMS (EI): calcd. for C H ClO [M] 266.0710; found
1
4
15
3
bifluoride through a 1,2-elimination/addition pathway. This 266.0712.
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30978
/KAP1
Date: 23-09-13 18:21:10
Pages: 11
A Two-Steps Sequence to Ethyl α-Fluorocyclopropanecarboxylates
1
1
4
2
8
c: Colorless oil (107 mg, 76% yield). H NMR (400 MHz, CDCl
3
,
3
4i: Colorless oil (80 mg, 62% yield). H NMR (400 MHz, CDCl ,
5 °C, TMS): δ = 7.95 (d, J = 8.9 Hz, 2 H, ArH), 6.95 (d, J =
.9 Hz, 2 H, ArH), 4.31 (q, J = 7.1 Hz, 2 H, COOEt), 3.86 (s, 3 H,
25 °C, TMS): δ = 7.79 (dd, J = 3.9, 0.9 Hz, 1 H, ArH), 7.72 (dd, J
= 4.9, 0.9 Hz, 1 H, ArH), 7.18 (dd, J = 4.9, 3.9 Hz, 1 H, ArH),
4.32 (m, 2 H, COOEt), 3.49 (dd, J = 9.1, 7.9 Hz, 1 H, CH-cyclo),
OCH
.0, 5.6 Hz, 1 H, CH
cyclo), 1.37 (t, J = 7.1 Hz, 3 H, COOEt) ppm. C NMR
101 MHz, CDCl , 25 °C, TMS): δ = 189.8, 168.9, 164.0, 130.9,
30.1, 113.9, 63.2, 55.5, 43.5, 33.3, 21.9, 14.1 ppm. IR (neat): ν˜ =
3
), 3.47 (dd, J = 9.1, 8.0 Hz, 1 H, CH-cyclo), 2.19 (dd, J =
8
2
-cyclo), 1.94 (dd, J = 9.1, 5.6 Hz, 1 H, CH
2
-
2.21 (dd, J = 7.9, 5.7 Hz, 1 H, CH
1 H, CH
-cyclo), 1.37 (t, J = 7.1 Hz, 3 H, COOEt) ppm. 13C NMR
(101 MHz, CDCl , 25 °C, TMS): δ = 183.9, 168.7, 144.2, 134.7,
2
-cyclo), 2.01 (dd, J = 9.1, 5.7 Hz,
13
2
(
3
3
1
3
1
9
2
133.0, 128.4, 63.2, 43.8, 34.0, 22.2, 14.1 ppm. IR (neat): ν˜ = 3102,
2981, 2964, 2906, 2873, 1741, 1724, 1663, 1516, 1466, 1445, 1414,
1381, 1367, 1279, 1239, 1215, 1132, 1087, 1065, 1020, 991 cm .
101, 3074, 2981, 2938, 2841, 1735, 1675, 1597, 1511, 1461, 1421,
379, 1367, 1309, 1266, 1170, 1133, 1086, 1057, 1023, 979, 920,
–
1
–1
+
S [M]+ 258.0117; found
03 cm . HRMS (EI): calcd. for C14
82.0661.
H15ClO
4
[M] 282.0659; found
HRMS (EI): calcd. for C11
258.0115.
H
11ClO
3
1
1
4
2
8
d: Colorless oil (90 mg, 60% yield). H NMR (400 MHz, CDCl
3
,
4j: Yellow oil (121 mg, 80% yield). H NMR (400 MHz, CDCl ,
3
5 °C, TMS): δ = 7.89 (d, J = 8.6 Hz, 2 H, ArH), 7.29 (d, J =
.6 Hz, 2 H, ArH), 4.33 (q, J = 7.1 Hz, 2 H, COOEt), 3.49 (dd, J ArH), 7.61 (m, 3 H, ArH), 4.36 (q, J = 7.1 Hz, 2 H, COOEt), 3.55
25 °C, TMS): δ = 8.74 (d, J = 8.7 Hz, 1 H, ArH), 7.99 (m, 3 H,
=
8
9.1, 8.0 Hz, 1 H, CH-cyclo), 2.52 (s, 3 H, SCH
.0, 5.6 Hz, 1 H, CH -cyclo), 1.98 (dd, J = 9.1, 5.6 Hz, 1 H, CH
cyclo), 1.38 (t, J = 7.1 Hz, 3 H, COOEt) ppm. C NMR
101 MHz, CDCl , 25 °C, TMS): δ = 190.4, 168.8, 146.9, 133.3,
28.9, 125.0, 63.2, 43.5, 33.4, 21.9, 14.7, 14.1 ppm. IR (neat): ν˜ =
099, 2983, 2924, 2871, 1736, 1676, 1587, 1436, 1402, 1377, 1366,
3
), 2.22 (dd, J =
(dd, J = 9.0, 7.9 Hz, 1 H, CH-cyclo), 2.38 (dd, J = 7.9, 5.6 Hz, 1
H, CH -cyclo), 2.09 (dd, J = 9.0, 5.6 Hz, 1 H, CH -cyclo), 1.39 (t, J
2
2
-
2
2
13
13
= 7.1 Hz, 3 H, COOEt) ppm. C NMR (101 MHz, CDCl , 25 °C,
3
(
3
TMS): δ = 194.2, 168.7, 135.4, 133.9, 133.6, 130.3, 129.1, 128.5,
1
3
1
128.3, 126.7, 125.7, 124.5, 63.2, 44.7, 36.5, 22.5, 14.2 ppm. IR
(neat): ν˜ = 3095, 3050, 2983, 2937, 2906, 1736, 1680, 1584, 1509,
1460, 1395, 1364, 1270, 1229, 1178, 1134, 1099, 1056, 1020,
–1
276, 1236, 1185, 1134, 1094, 1058, 1006, 975, 920 cm . HRMS
+
–1
+
(EI): calcd. for C14
H15ClO
3
S [M] 298.0430; found 298.0435.
17 15 3
977 cm . HRMS (EI): calcd. for C H ClO [M] 302.0710; found
1
302.0709.
k: White solid (118 mg, 72% yield); m.p. 28–29 °C. 1H NMR
400 MHz, CDCl , 25 °C, TMS): δ = 8.09 (m, 2 H, ArH), 7.74 (m,
4
2
8
e: Colorless oil (83 mg, 58% yield). H NMR (400 MHz, CDCl
3
,
5 °C, TMS): δ = 7.91 (d, J = 8.6 Hz, 2 H, ArH), 7.46 (d, J =
.6 Hz, 2 H, ArH), 4.33 (q, J = 7.1 Hz, 2 H, COOEt), 3.48 (dd, J
9.1, 7.9 Hz, 1 H, CH-cyclo), 2.22 (dd, J = 7.9, 5.7 Hz, 1 H, CH
cyclo), 1.99 (dd, J = 9.1, 5.7 Hz, 1 H, CH -cyclo), 1.38 (t, J =
.1 Hz, 3 H, COOEt) ppm. 13C NMR (101 MHz, CDCl
, 25 °C,
TMS): δ = 190.5, 168.7, 140.3, 135.3, 129.9, 129.2, 63.3, 43.6, 33.4,
2.1, 14.1 ppm. IR (neat): ν˜ = 3100, 3060, 2982, 2933, 1734, 1686,
587, 1468, 1451, 1400, 1378, 1368, 1276, 1220, 1175, 1134, 1092,
2 3
008, 978, 919, 902, 843 cm . HRMS (EI): calcd. for C13H12Cl O
4
(
3
=
2
-
2
7
2
1
H, ArH), 7.66 (m, 2 H, ArH), 7.46 (m, 3 H, ArH), 4.38 (q, J =
.1 Hz, 2 H, COOEt), 3.61 (dd, J = 9.1, 8.0 Hz, 1 H, CH-cyclo),
2
7
3
.29 (dd, J = 8.0, 5.6 Hz, 1 H, CH
2
-cyclo), 2.04 (dd, J = 9.1, 5.6 Hz,
-cyclo), 1.41 (t, J = 7.1 Hz, 3 H, COOEt) ppm. 13C NMR
H, CH
, 25 °C, TMS): δ = 191.1, 168.8, 146.4, 139.7,
35.7, 129.1, 129.0, 128.4, 127.5, 127.3, 63.3, 43.7, 33.6, 22.1,
2
2
1
1
(101 MHz, CDCl
3
1
1
1
–1
4.2 ppm. IR (film): ν˜ = 3057, 3032, 2983, 2937, 1733, 1681, 1602,
+
[M] 286.0163; found 286.0165.
449, 1405, 1377, 1276, 1228, 1192, 1133, 1083, 1058, 1027, 1006,
–
1
+
1
19 17 3
978 cm . HRMS (EI): calcd. for C H ClO [M] 328.0866; found
4
2
8
f: Colorless oil (101 mg, 61% yield). H NMR (400 MHz, CDCl
3
,
3
28.0863.
Typical Procedure for Synthesis of Monofluorinated Cyclopropanes
: Fluorination with KHF : KHF (1.5 mmol) was added to a solu-
5 °C, TMS): δ = 7.85 (d, J = 8.6 Hz, 2 H, ArH), 7.65 (d, J =
.6 Hz, 2 H, ArH), 4.35 (q, J = 7.1 Hz, 2 H, COOEt), 3.49 (dd, J
9.0, 7.9 Hz, 1 H, CH-cyclo), 2.23 (dd, J = 7.9, 5.7 Hz, 1 H, CH
cyclo), 2.00 (dd, J = 9.0, 5.7 Hz, 1 H, CH -cyclo), 1.38 (t, J =
.1 Hz, 3 H, COOEt) ppm. 13C NMR (101 MHz, CDCl
, 25 °C,
TMS): δ = 190.7, 168.6, 135.7, 132.2, 130.0, 129.0, 63.3, 43.6, 33.4,
2.1, 14.1 ppm. IR (neat): ν˜ = 3099, 3057, 2983, 2906, 2873, 1743,
723, 1686, 1585, 1476, 1446, 1398, 1378, 1367, 1277, 1218, 1176,
134, 1111, 1070, 1006, 978, 919, 902, 840 cm . HRMS (EI): calcd.
=
2
-
3
2
2
2
tion of 4a (0.5 mmol) in DMSO (2 mL), and the mixture was
heated and stirred at 120 °C. The reaction was followed by TLC
until substrate 4a was almost exhausted (ultraviolet absorption of
7
3
2
1
1
4
a was almost invisible by TLC analysis). The mixture was then
washed with water and extracted with CH Cl . Combined extracts
were dried with anhydrous Na SO and concentrated under re-
2
2
–1
2
4
+
for C13
H12BrClO
3
[M] 329.9658; found 329.9654.
duced pressure. The residue was purified by silica-gel column
chromatography to afford 95 mg of compound 3a in 85% yield.
Unless otherwise specified, all products 3 were synthesized accord-
ing to this typical procedure.
1
4
2
9
5
1
g: Colorless oil (72 mg, 76% yield). H NMR (400 MHz, CDCl
3
,
5 °C, TMS): δ = 4.26 (q, J = 7.1 Hz, 2 H, COOEt), 2.91 (dd, J =
.0, 7.9 Hz, 1 H, CH-cyclo), 2.34 (s, 3 H, CH ), 1.96 (dd, J = 7.9,
.7 Hz, 1 H, CH -cyclo), 1.84 (dd, J = 9.0, 5.7 Hz, 1 H, CH -cyclo),
.32 (t, J = 7.1 Hz, 3 H, COOEt) ppm. C NMR (101 MHz,
, 25 °C, TMS): δ = 199.4, 168.6, 63.1, 43.1, 36.5, 31.6, 22.3,
4.0 ppm. IR (neat): ν˜ = 3102, 2985, 2939, 1722, 1420, 1381, 1368,
3
2
2
Fluorination with KF: KF (1.0 mmol) was added to a solution of
13
4a (0.5 mmol) and TBAB (20 mol-%) in DMSO (2 mL), and the
CDCl
1
1
3
mixture was heated and stirred at 120 °C. The reaction was worked-
up according to the above procedures. Compound 3a was afforded
in 68% yield, 80 mg.
–1
275, 1214, 1171, 1132, 1096, 1022, 985 cm . HRMS (ESI): calcd.
+
for C
8
H11ClNaO
3
[M + Na] 213.02889; found 213.02896.
3
3
1
a: Yellowish oil (total 95 mg, 81% yield). IR (neat): ν˜ = 3104,
1
4
2
h: Colorless oil (77 mg, 74% yield). H NMR (400 MHz, CDCl
3
,
063, 2983, 2984, 2936, 2874, 1746, 1684, 1597, 1536, 1449, 1369,
5 °C, TMS): δ = 4.22 (q, J = 7.1 Hz, 2 H, COOEt), 3.75 (s, 3 H,
COOMe), 2.66 (t, J = 8.6 Hz, 1 H, CH-cyclo), 1.95 (m, 2 H, CH -
2
cyclo), 1.32 (t, J = 7.1 Hz, 3 H, COOEt) ppm. C NMR
101 MHz, CDCl
–
1
302, 1274, 1220, 1178, 1157, 1096, 1043, 1019, 994 cm . HRMS
+
(
EI): calcd. for C13
H13FO
3
[M] 236.0849; found 236.0845.
, 25 °C, TMS): δ = 168.3, 167.5, 63.1, 52.6, 42.5, Major Isomer: H NMR (400 MHz, CDCl , 25 °C, TMS): δ = 8.00
0.6, 22.9, 14.0 ppm. IR (neat): ν˜ = 3107, 3056, 2986, 2955, 2910, (m, 2 H, ArH), 7.58 (m, 1 H, ArH), 7.49 (m, 2 H, ArH), 4.37 (q,
853, 1743, 1442, 1383, 1369, 1278, 1233, 1198, 1175, 1134, 1095, J = 7.1 Hz, 2 H, COOEt), 3.46 (ddd, J = 9.9, 8.2, 3.0 Hz, 1 H, CH-
13
1
(
3
3
3
2
1
–1
064, 1029, 983 cm .
cyclo), 2.46 (ddd, J = 18.5, 8.2, 6.3 Hz, 1 H, CH
2
-cyclo), 1.82 (m,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org 7

Job/Unit: O30978
/KAP1
Date: 23-09-13 18:21:10
Pages: 11
M. Zhang, Y. Gong, W. Wang
–183.65 (ddd, 18.7, 17.1,
FULL PAPER
1
H, CH
2
-cyclo), 1.37 (t, J = 7.1 Hz, 3 H, COOEt) ppm. 13C NMR
, 25 °C, TMS): δ = 190.5, 168.5 (d, J = 24 Hz),
37.2, 133.6, 128.8, 128.4, 77.6 (d, J = 243 Hz), 62.6, 31.2 (d, J =
CDCl
9.6 Hz) ppm.
3
,
25 °C, TMS):
δ
=
J =
(101 MHz, CDCl
3
1
1
1 Hz), 17.7 (d, J = 17 Hz), 14.2 ppm. 1 F NMR (376 MHz,
9
3e: Colorless oil (total 116 mg, 85% yield). IR (neat): ν˜ = 3103,
3
1
065, 2985, 2937, 2874, 1745, 1686, 1590, 1484, 1469, 1445, 1401,
378, 1335, 1307, 1275, 1218, 1178, 1157, 1093, 1041, 1014, 993,
CDCl
3
, 25 °C, TMS): δ = –205.96 (ddd, J = 18.6, 8.9, 2.7 Hz) ppm.
1
–1
+
Minor Isomer: H NMR (400 MHz, CDCl
3
, 25 °C, TMS): δ = 8.00
13 12 3
932, 851 cm . HRMS (EI): calcd. for C H ClFO [M] 270.0459;
(
m, 2 H, ArH), 7.58 (m, 1 H, ArH), 7.49 (m, 2 H, ArH), 4.02 (q, found 270.0456.
J = 7.1 Hz, 2 H, COOEt), 3.18 (ddd, J = 19.4, 10.8, 9.3 Hz, 1 H,
CH-cyclo), 2.22 (td, J = 9.5, 6.9 Hz, 1 H, CH -cyclo), 1.85 (m, 1
-cyclo), 1.00 (t, J = 7.1 Hz, 3 H, COOEt) ppm. 1 C NMR
H, CH
101 MHz, CDCl , 25 °C, TMS): δ = 190.8, 166.6 (d, J = 18 Hz),
36.2, 133.7, 128.8, 77.5 (d, J = 236 Hz), 62.0, 33.3 (d, J = 9 Hz),
7.1 (d, J = 10 Hz), 13.8 ppm. 19F NMR (376 MHz, CDCl
, 25 °C,
1
3
Major Isomer: H NMR (400 MHz, CDCl , 25 °C, TMS): δ = 7.92
2
3
(d, J = 8.6 Hz, 2 H, ArH), 7.46 (d, J = 8.6 Hz, 2 H, ArH), 4.36 (q,
J = 7.1 Hz, 2 H, COOEt), 3.40 (ddd, J = 9.4, 8.3, 2.9 Hz, 1 H, CH-
cyclo), 2.45 (ddd, J = 18.5, 8.1, 6.4 Hz, 1 H, CH
1 H, CH -cyclo), 1.37 (t, J = 7.1 Hz, 3 H, COOEt) ppm. C NMR
101 MHz, CDCl , 25 °C, TMS): δ = 189.3, 168.3 (d, J = 24 Hz),
40.1, 135.5, 129.8, 129.1, 77.6 (d, J = 244 Hz), 62.7, 31.1 (d, J =
2
(
1
1
3
2
-cyclo), 1.84 (m,
1
3
2
3
(
3
TMS): δ = –183.43 (ddd, J = 18.7, 17.0, 9.6 Hz) ppm.
1
1
9
3
2
1
b: Yellowish oil (total 97 mg, 77% yield). IR (neat): ν˜ = 3104,
11 Hz) 17.8 (d, J = 10 Hz), 14.1 ppm. F NMR (376 MHz, CDCl3,
25 °C, TMS): δ = –205.75 (ddd, J = 18.6, 9.8, 2.6 Hz) ppm.
984, 2928, 2872, 1747, 1683, 1607, 1447, 1403, 1373, 1335, 1301,
–
1
262, 1225, 1211, 1179, 1157, 1116, 1097, 1043, 1018, 934 cm .
1
+
Minor Isomer: H NMR (400 MHz, CDCl
3
, 25 °C, TMS): δ = 7.95
HRMS (EI): calcd. for C14
H15FO
3
[M] 250.1005; found 250.1007.
(
d, J = 8.6 Hz, 2 H, ArH), 7.46 (d, J = 8.6 Hz, 2 H, ArH), 4.04 (q,
J = 7.1 Hz, 2 H, COOEt), 3.13 (ddd, J = 19.1, 10.7, 9.4 Hz, 1 H,
CH-cyclo), 2.21 (td, J = 9.5, 7.0 Hz, 1 H, CH -cyclo), 1.86 (m, 1
H, CH -cyclo), 1.03 (t, J = 7.1 Hz, 3 H, COOEt) ppm. C NMR
101 MHz, CDCl , 25 °C, TMS): δ = 189.7, 166.7 (d, J = 25 Hz),
40.2, 134.6, 129.7, 129.2, 77.4 (d, J = 237 Hz), 62.1, 33.1 (d, J =
1
Major Isomer: H NMR (400 MHz, CDCl
3
, 25 °C, TMS): δ = 7.91
(
m, 2 H, ArH), 7.29 (m, 2 H, ArH), 4.37 (q, J = 7.1 Hz, 2 H,
COOEt), 3.44 (ddd, J = 9.4, 8.3, 3.0 Hz, 1 H, CH-cyclo), 2.45 (m,
H, CH -cyclo), 2.43 (s, 3 H, CH ), 1.81 (m, 1 H, CH -cyclo), 1.38
t, J = 7.1 Hz, 3 H, COOEt) ppm. C NMR (101 MHz, CDCl
2
13
2
1
(
2
3
2
(
3
13
3
,
1
1
2
2
1
5 °C, TMS): δ = 190.0, 168.6 (d, J = 24 Hz), 144.6, 134.8, 129.5,
28.5, 77.5 (d, J = 243 Hz), 62.5, 31.2 (d, J = 11 Hz), 21.7, 17.7 (d,
19
0 Hz), 17.1 (d, J = 9 Hz), 13.8 ppm. F NMR (376 MHz, CDCl
5 °C, TMS): δ = –183.41 (m) ppm.
3
,
19
J = 11 Hz), 14.2 ppm. F NMR (376 MHz, CDCl
δ = –206.13 (ddd, J = 18.2, 8.9, 2.7 Hz) ppm.
3
, 25 °C, TMS):
3
3
1
f: Yellowish oil (total 120 mg, 76% yield). IR (neat): ν˜ = 3101,
066, 2958, 2922, 2869, 2851, 1742, 1685, 1585, 1465, 1398, 1378,
308, 1272, 1217, 1178, 1156, 1095, 1069, 1010, 932, 847, 777 cm .
1
Minor Isomer: H NMR (400 MHz, CDCl
3
, 25 °C, TMS): δ = 7.91
–1
(
m, 2 H, ArH), 7.29 (m, 2 H, ArH), 4.02 (q, J = 7.1 Hz, 2 H,
COOEt), 3.16 (ddd, J = 19.9, 10.8, 9.4 Hz, 1 H, CH-cyclo), 2.42
s, 3 H, CH ), 2.21 (td, J = 9.5, 6.9 Hz, 1 H, CH -cyclo), 1.81 (m,
H, CH
-cyclo), 1.01 (t, J = 7.1 Hz, 3 H, COOEt) ppm. 1 C NMR
101 MHz, CDCl , 25 °C, TMS): δ = 190.4, 166.7 (d, J = 25 Hz),
44.6, 133.8, 129.5, 128.5, 77.4 (d, J = 235 Hz), 62.0, 33.3 (d, J =
Hz), 21.7, 17.0 (d, J = 10 Hz), 13.8 ppm. 19F NMR (376 MHz,
25 °C, TMS): –183.45 (ddd, 19.1, 17.4,
.8 Hz) ppm.
+
HRMS (EI): calcd. for C13
13.9958.
H12BrFO
3
[M] 313.9954; found
3
(
1
(
1
9
3
2
1
3
3
Major Isomer: H NMR (400 MHz, CDCl , 25 °C, TMS): δ = 7.84
2
(
d, J = 8.6 Hz, 2 H, ArH), 7.63 (d, J = 8.6 Hz, 2 H, ArH), 4.36 (q,
J = 7.1 Hz, 2 H, COOEt), 3.39 (ddd, J = 9.4, 8.2, 2.9 Hz, 1 H, CH-
cyclo), 2.44 (ddd, J = 18.5, 8.1, 6.4 Hz, 1 H, CH -cyclo), 1.84 (m,
3
2
1
3
1
H, CH
2
-cyclo), 1.37 (t, J = 7.1 Hz, 3 H, COOEt) ppm. C NMR
, 25 °C, TMS): δ = 189.5, 168.3 (d, J = 24 Hz),
35.9, 132.1, 129.9, 128.9, 77.6 (d, J = 244 Hz), 62.7, 31.1 (d, J =
CDCl
9
3
,
δ
=
J =
(101 MHz, CDCl
3
1
1
3
3
1
8
2
c: Yellowish oil (total 95 mg, 71% yield). IR (neat): ν˜ = 3105,
052, 2982, 2938, 2912, 2843, 1745, 1675, 1601, 1578, 1511, 1464,
423, 1380, 1368, 1304, 1262, 1229, 1174, 1114, 1024, 993, 932,
49 cm . HRMS (EI): calcd. for C14
66.0952.
19
1 Hz), 17.9 (d, J = 11 Hz), 14.2 ppm. F NMR (376 MHz,
CDCl
3
, 25 °C, TMS): δ = –205.70 (ddd, J = 18.6, 9.8, 2.6 Hz) ppm.
–1
+
1
H15FO
4
[M] 266.0954; found Minor Isomer: H NMR (400 MHz, CDCl
3
, 25 °C, TMS): δ = 7.87
(d, J = 8.6 Hz, 2 H, ArH), 7.63 (d, J = 8.6 Hz, 2 H, ArH), 4.04 (q,
J = 7.1 Hz, 2 H, COOEt), 3.13 (ddd, J = 19.1, 10.7, 9.3 Hz, 1 H,
1
Major Isomer: H NMR (400 MHz, CDCl
(
3
, 25 °C, TMS): δ = 7.98
CH-cyclo), 2.21 (td, J = 9.5, 7.0 Hz, 1 H, CH
H, CH -cyclo), 1.03 (t, J = 7.1 Hz, 3 H, COOEt) ppm. C NMR
101 MHz, CDCl , 25 °C, TMS): δ = 189.9, 166.5 (d, J = 25 Hz),
35.0, 132.2, 129.8, 129.0, 77.4 (d, J = 237 Hz), 62.1, 33.1 (d, J =
2
-cyclo), 1.84 (m, 1
d, J = 8.9 Hz, 2 H, ArH), 6.97 (d, J = 8.9 Hz, 2 H, ArH), 4.37 (q,
J = 7.1 Hz, 2 H, COOEt), 3.88 (s, 3 H, OCH ), 3.41 (ddd, J = 9.5,
.2, 3.1 Hz, 1 H, CH-cyclo), 2.44 (ddd, J = 18.5, 8.2, 6.2 Hz, 1 H,
CH -cyclo), 1.79 (m, 1 H, CH -cyclo), 1.38 (t, J = 7.1 Hz, 3 H,
COOEt) ppm. 13C NMR (101 MHz, CDCl
, 25 °C, TMS): δ =
88.7, 168.7 (d, J = 24 Hz), 130.7, 130.3, 113.9, 77.4 (d, J =
13
2
3
(
3
8
1
1
2
2
2
19
0 Hz), 17.1 (d, J = 9 Hz), 13.8 ppm. F NMR (376 MHz, CDCl
5 °C, TMS): δ = –183.37 (m) ppm.
3
,
3
1
2
1
42 Hz), 62.5, 55.5, 31.0 (d, J = 11 Hz), 17.6 (d, J = 10 Hz), 3i: Yellowish oil (total 97 mg, 80% yield). IR (neat): ν˜ = 3104, 2976,
4.2 ppm. 19F NMR (376 MHz, CDCl
, 25 °C, TMS): δ = –206.22
2928, 1745, 1664, 1516, 1466, 1446, 1413, 1371, 1335, 1307, 1240,
3
–
1
(m) ppm.
1157, 1085, 1064, 1050, 1016, 982, 915, 854, 731 cm . HRMS (EI):
calcd. for C11
H11FO
3
S [M]+ 242.0413; found 242.0415.
1
Minor Isomer: H NMR (400 MHz, CDCl
3
, 25 °C, TMS): δ = 7.99
1
(
(
m, 2 H, ArH), 6.97 (m, 2 H, ArH), 4.02 (m, 2 H, COOEt), 3.88 Major Isomer: H NMR (400 MHz, CDCl , 25 °C, TMS): δ = 7.81
3
s, 3 H, OCH
.20 (td, J = 9.5, 6.9 Hz, 1 H, CH
cyclo), 1.01 (t, J = 7.1 Hz, 3 H, COOEt) ppm. C NMR
101 MHz, CDCl , 25 °C, TMS): δ = 189.3, 163.9 (d, J = 18 Hz),
30.7, 129.4, 114.0, 77.4 (d, J = 235 Hz), 61.9, 55.5, 33.2 (d, J =
0 Hz), 17.0 (d, J = 10 Hz), 13.8 ppm. 19F NMR (376 MHz,
3
), 3.13 (ddd, J = 19.8, 10.9, 9.3 Hz, 1 H, CH-cyclo),
(m, 1 H, ArH), 7.70 (m, 1 H, ArH), 7.16 (m, 1 H, ArH), 4.35 (q,
J = 7.1 Hz, 2 H, COOEt), 3.35 (ddd, J = 9.6, 8.2, 2.7 Hz, 1 H, CH-
2
2
-cyclo), 1.81 (m, 1 H, CH
2
-
13
cyclo), 2.43 (ddd, J = 18.5, 8.0, 6.4 Hz, 1 H, CH
1 H, CH -cyclo), 1.36 (t, J = 7.1 Hz, 3 H, COOEt) ppm. C NMR
(101 MHz, CDCl , 25 °C, TMS): δ = 182.9, 168.4 (d, J = 24 Hz),
2
-cyclo), 1.83 (m,
1
3
(
3
2
1
1
3
144.5, 134.6, 132.7, 128.4, 77.5 (d, J = 245 Hz), 62.6, 31.7 (d, J =
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30978
/KAP1
Date: 23-09-13 18:21:10
Pages: 11
A Two-Steps Sequence to Ethyl α-Fluorocyclopropanecarboxylates
1 Hz), 17.9 (d, J = 11 Hz), 14.1 ppm. 19F NMR (376 MHz,
1
190.4, 166.7 (d, J = 25 Hz), 146.3, 139.6, 135.0, 129.0, 128.4, 127.4,
127.3, 77.5 (d, J = 234 Hz), 62.0, 33.3 (d, J = 9 Hz), 17.1 (d, J =
CDCl
3
, 25 °C, TMS): δ = –205.87 (ddd, J = 18.8, 8.9, 2.3 Hz) ppm.
1
9
1
9 Hz), 13.8 ppm. F NMR (376 MHz, CDCl
183.34 (ddd, J = 19.1, 17.3, 9.8 Hz) ppm.
3
, 25 °C, TMS): δ =
Minor Isomer: H NMR (400 MHz, CDCl
3
, 25 °C, TMS): δ = 7.81
–
(m, 1 H, ArH), 7.70 (m, 1 H, ArH), 7.16 (m, 1 H, ArH), 4.08 (m,
2
2
H, COOEt), 3.16 (ddd, J = 19.0, 10.8, 9.3 Hz, 1 H, CH-cyclo), Ethyl 1-Chloro-2-[hydroxy(phenyl)methyl]cyclopropanecarboxylate
.22 (td, J = 9.5, 7.0 Hz, 1 H, CH
2
-cyclo), 1.83 (m, 1 H, CH
2
-
(7a): To a solution of 4a (0.5 mmol) in CH OH (1 mL) was added
3
13
cyclo), 1.06 (t, J = 7.1 Hz, 3 H, COOEt) ppm. C NMR
101 MHz, CDCl , 25 °C, TMS): δ = 183.6, 166.5 (d, J = 25 Hz),
43.5, 134.5, 132.9, 128.4, 77.5 (d, J = 235 Hz), 62.1, 33.5 (d, J =
1 Hz), 17.2 (d, J = 10 Hz), 13.8 ppm. 19F NMR (376 MHz,
, 25 °C, TMS): δ = –183.16 (m) ppm.
NaBH (0.5 mmol) slowly under an ice-water bath with continuous
4
(
1
1
3
stirring. The reaction was followed by thin-layer chromatography
and stopped when substrate 4a disappeared. The mixture was then
washed with water and extracted with CH Cl . Combined extracts
2
2
CDCl
3
2 4
were dried with anhydrous Na SO and concentrated under re-
duced pressure. The residue was purified by silica-gel column
3
2
1
7
2
j: Yellowish oil (total 111 mg, 77% yield). IR (neat): ν˜ = 3057,
chromatography to afford compound 7a as colorless oil (127 mg,
958, 2921, 2851, 1743, 1680, 1592, 1574, 1508, 1462, 1399, 1376,
333, 1301, 1274, 1230, 1177, 1157, 1101, 1018, 920, 864, 785, 764,
1
in 100% yield). H NMR (400 MHz, CDCl
3
, 25 °C, TMS): δ =
–1
+
7.39 (m, 5 H, ArH), 4.58 (d, J = 9.5 Hz, 1 H, CH), 4.21 (q, J =
49 cm . HRMS (EI): calcd. for C17
86.1001.
H15FO
3
[M] 286.1005; found
7
.1 Hz, 2 H, COOEt), 2.91 (s, 1 H, OH), 2.23 (ddd, J = 10.1, 9.6,
.2 Hz, 1 H, CH-cyclo), 1.82 (dd, J = 10.2, 5.9 Hz, 1 H, CH
-cyclo), 1.30 (t, J = 7.1 Hz, 3 H, CO-
OEt) ppm. 13C NMR (101 MHz, CDCl
, 25 °C, TMS): δ = 169.8,
41.9, 128.6, 128.1, 126.2, 74.8, 62.7, 44.3, 35.9, 23.8, 14.1 ppm. IR
neat): ν˜ = 3492, 3088, 3062, 3030, 2983, 2935, 2905, 1720, 1603,
8
2
-
1
Major Isomer: H NMR (400 MHz, CDCl
3
, 25 °C, TMS): δ = 8.64
cyclo), 1.30 (m, 1 H, CH
2
(
(
d, J = 8.7 Hz, 1 H, ArH), 8.03 (d, J = 8.4 Hz, 1 H, ArH), 7.96
dd, J = 7.2, 1.1 Hz, 1 H, ArH), 7.90 (dd, J = 7.7, 1.2 Hz, 1 H,
3
1
(
ArH), 7.63 (m, 1 H, ArH), 7.56 (m, 2 H, ArH), 4.38 (q, J = 7.1 Hz,
H, COOEt), 3.43 (ddd, J = 9.4, 8.2, 2.8 Hz, 1 H, CH-cyclo), 2.61
ddd, J = 18.4, 8.1, 6.3 Hz, 1 H, CH -cyclo), 1.92 (m, 1 H, CH
cyclo), 1.39 (t, J = 7.1 Hz, 3 H, COOEt) ppm. C NMR
101 MHz, CDCl , 25 °C, TMS): δ = 193.5, 168.3 (d, J = 24 Hz),
35.9, 133.9, 133.3, 130.5, 130.1, 128.5, 128.2, 126.7, 125.6, 124.5,
8.2 (d, J = 201 Hz), 62.6, 34.6 (d, J = 11 Hz), 18.2 (d, J = 10 Hz),
2
(
1
1
493, 1451, 1394, 1372, 1302, 1250, 1220, 1175, 1142, 1117, 1081,
2
2
-
056, 1020, 968, 916, 860, 767, 740, 701, 509 cm . HRMS (EI):
–1
13
+
calcd. for C13
H15ClO
3
[M] 254.0710; found 254.0713.
(
3
Ethyl 2-Benzoyl-2-bromo-1-chlorocyclopropanecarboxylate (8a): To
a solution of 4a (2 mmol) in CH COOH (1 mL) was added drop-
wise a mixture of Br (130 μL, 2.5 mmol) and CH COOH (250 μL)
1
7
1
3
4.2 ppm. 1 F NMR (376 MHz, CDCl
9
2
3
3
, 25 °C, TMS): δ = –205.34
at 118 °C. The mixture was reacted at that temperature for 3 h.
After the reaction was complete, water was added to quench the
(m) ppm.
1
Minor Isomer: H NMR (400 MHz, CDCl
3
, 25 °C, TMS): δ = 8.96
d, J = 8.0 Hz, 1 H, ArH), 8.19 (dd, J = 7.3, 1.1 Hz, 1 H, ArH),
reaction. The mixture was then extracted with CH
with 10% aqueous Na CO . Combined extracts were dried with
anhydrous Na SO and concentrated under reduced pressure. The
2 2
Cl and washed
(
2
3
8
.05 (d, J = 8.7 Hz, 1 H, ArH), 7.96 (dd, J = 7.2, 1.1 Hz, 1 H,
2
4
ArH), 7.64 (ddd, J = 8.6, 3.5, 1.6 Hz, 1 H, ArH), 7.56 (m, 2 H,
ArH), 4.06 (tdd, J = 10.8, 7.1, 3.6 Hz, 2 H, COOEt), 3.32 (ddd, J
=
residue was purified by silica-gel column chromatography to afford
compound 8a as colorless oil (330 mg, in 50% yield). 1H NMR
19.8, 10.8, 9.3 Hz, 1 H, CH-cyclo), 2.36 (ddd, J = 9.9, 9.3, 6.9 Hz,
H, CH -cyclo), 1.92 (m, 1 H, CH -cyclo), 1.03 (t, J = 7.1 Hz, 3
, 25 °C, TMS): δ =
93.3, 166.7 (d, J = 25 Hz), 134.2, 134.0, 133.4, 130.4, 130.1, 128.5,
(
1
=
400 MHz, CDCl
3
, 25 °C, TMS): δ = 7.98 (m, 2 H, ArH), 7.60 (m,
H, ArH), 7.49 (m, 2 H, ArH), 3.82 (m, 2 H, COOEt), 2.88 (d, J
8.3 Hz, 1 H, CH -cyclo), 1.91 (d, J = 8.3 Hz, 1 H, CH -cyclo),
1
2
2
13
H, COOEt) ppm. C NMR (101 MHz, CDCl
3
2
2
1
1
9
2
13
0
.93 (t, J = 7.1 Hz, 3 H, COOEt) ppm. C NMR (101 MHz,
CDCl , 25 °C, TMS): δ = 187.5, 165.7, 134.0, 132.6, 129.5, 128.8,
3.3, 47.7, 43.4, 29.7, 13.4 ppm. IR (film): ν˜ = 3094, 3064, 2982,
965, 2926, 1748, 1726, 1690, 1596, 1449, 1398, 1370, 1316, 1267,
28.4, 126.7, 126.0, 124.4, 78.3 (d, J = 258 Hz), 62.1, 35.5 (d, J =
3
Hz), 17.7 (d, J = 9 Hz), 13.9 ppm. 19F NMR (376 MHz, CDCl
5 °C, TMS): δ = –182.16 (ddd, J = 19.3, 17.5, 10.0 Hz) ppm.
,
3
6
2
–
1
3k: Yellow solid (total 123 mg, 79% yield); m.p. 30–31 °C. IR
1225, 1179, 1132, 1069, 1026, 943, 805, 696 cm . HRMS (ESI):
calcd. for
352.95545.
+
(film): ν˜ = 3106, 3073, 3011, 2983, 2875, 1744, 1665, 1603, 1560,
C
13
H
12BrClNaO
3
[M + Na] 352.95506; found
1
1
C
516, 1482, 1448, 1402, 1383, 1367, 1335, 1298, 1230, 1176, 1098,
–1
021, 935, 908, 858, 758, 697 cm . HRMS (EI): calcd. for
Capture Experiment of Cyclopropene Intermediate 6a: To a solution
of 4a (0.3 mmol) and TBAB (20 mol-%) in DMSO (1 mL) was
added KF (0.6 mmol) and anthracene (0.6 mmol), and the mixture
was heated and stirred at 120 °C. The reaction was detected by
thin-layer chromatography until substrate 4a disappeared. The mix-
+
19
H17FO
3
[M] 312.1162; found 312.1164.
1
Major Isomer: H NMR (400 MHz, CDCl
3
, 25 °C, TMS): δ = 8.10
(m, 2 H, ArH), 7.74 (m, 2 H, ArH), 7.65 (m, 2 H, ArH), 7.50 (m,
2
3
8
H, ArH), 7.43 (m, 1 H, ArH), 4.41 (q, J = 7.1 Hz, 2 H, COOEt),
.52 (ddd, J = 9.4, 8.2, 3.0 Hz, 1 H, CH-cyclo), 2.52 (ddd, J = 18.5,
ture was then washed with water and extracted with CH
2 2
Cl . Com-
.2, 6.3 Hz, 1 H, CH
2
-cyclo), 1.87 (m, 1 H, CH
2
-cyclo), 1.41 (t, J
, 25 °C,
TMS): δ = 190.0, 168.5 (d, J = 24 Hz), 146.3, 139.7, 136.0, 129.0,
bined extracts were dried with anhydrous Na SO and concentrated
2
4
=
7.1 Hz, 3 H, COOEt) ppm. 13C NMR (101 MHz, CDCl
3
under reduced pressure. The residue was purified by silica-gel col-
umn chromatography to afford 25 mg of yellowish oil 3a and 30 mg
of white solid 9a, respectively, in 35% and 25% yield.
1
1
28.4, 127.4, 127.3, 77.6 (d, J = 243 Hz), 62.6, 31.3 (d, J = 11 Hz),
7.8 (d, J = 10 Hz), 14.2. 19F NMR (376 MHz, CDCl
, 25 °C,
3
1
Compound 9a: H NMR (400 MHz, CDCl
3
, 25 °C, TMS): δ = 7.84
TMS): δ = –205.80 (m) ppm.
(
m, 2 H, ArH), 7.58 (m, 2 H, ArH), 7.46 (t, J = 7.7 Hz, 2 H, ArH),
1
Minor Isomer: H NMR (400 MHz, CDCl
3
, 25 °C, TMS): δ = 8.10
7.32 (m, 2 H, ArH), 7.23 (m, 2 H, ArH), 7.11 (m, 3 H, ArH), 4.95
(s, 1 H, CH-cyclo), 4.59 (s, 1 H, CH-cyclo), 4.02 (m, 2 H, COOEt),
(m, 2 H, ArH), 7.74 (m, 2 H, ArH), 7.64 (m, 2 H, ArH), 7.50 (m,
2
H, ArH), 7.43 (m, 1 H, ArH), 4.07 (m, 2 H, COOEt), 3.22 (ddd,
1.98 (d, J = 5.8 Hz, 1 H, CH
COOEt), 0.95 (d, J = 5.8 Hz, 1 H, CH
(101 MHz, CDCl , 25 °C, TMS): δ = 195.2, 171.6, 144.6, 143.1,
141.3, 139.8, 135.9, 133.0, 129.2, 128.5, 126.9, 126.8, 125.9, 125.8,
2
-cyclo), 1.11 (t, J = 7.1 Hz, 3 H,
1
3
J = 19.4, 10.8, 9.3 Hz, 1 H, CH-cyclo), 2.28 (td, J = 9.5, 6.9 Hz, 1
H, CH -cyclo), 1.88 (m, 1 H, CH -cyclo), 1.06 (t, J = 7.1 Hz, 3 H,
COOEt) ppm. 13C NMR (101 MHz, CDCl
, 25 °C, TMS): δ =
2
-cyclo) ppm. C NMR
2
2
3
3
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O30978
/KAP1
Date: 23-09-13 18:21:10
Pages: 11
M. Zhang, Y. Gong, W. Wang
FULL PAPER
1
1
1
1
25.5, 125.0, 124.7, 124.3, 61.1, 48.7, 46.4, 46.1, 37.7, 25.6,
3.9 ppm. IR (film): ν˜ = 3066, 3022, 2957, 2924, 2852, 1721, 1679,
596, 1460, 1371, 1348, 1315, 1291, 1249, 1218, 1172, 1150, 1114,
ChemBioChem 2004, 5, 628–635; f) K. L. Kirk, Org. Process
Res. Dev. 2008, 12, 305–321.
[
6] a) R. Filler, in: Organofluorine Compounds in Medicinal Chem-
istry and Biomedical Applications (Ed.: R. Filler), Elsevier, New
York, 1993, p. 1–23; b) J. R. McCarthy, Fluorine in Drug De-
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22 3
069, 1019, 976, 887, 753 cm . HRMS (EI): calcd. for C27H O
+
[M] 394.1569; found 394.1567.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed information for the optimization of the fluorination
reaction; copies of H, C, F, HSQC and HMBC NMR spectra
for all compounds; X-ray structure of 4b.
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www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30978
/KAP1
Date: 23-09-13 18:21:10
Pages: 11
A Two-Steps Sequence to Ethyl α-Fluorocyclopropanecarboxylates
Fluorinated Cyclopropane
M. Zhang, Y. Gong,* W. Wang ...... 1–11
A Two-Step Sequence to Ethyl α-Fluoro-
cyclopropanecarboxylates Through MIRC
Reaction of Ethyl Dichloroacetate and
Highly Regioselective Fluorination
A convenient two-step method to prepare
ethyl α-fluorocyclopropanecarboxylates
has been developed. Ethyl α-chlorocyclo-
proanecarboxylates were obtained through
Michael-initiated ring closure reactions un-
der mild reaction conditions in good yields
before being smoothly converted into the
corresponding monofluorinated analogues
through halogen exchange reactions with
potassium bifluoride in good yields. The
reaction mechanism was also investigated.
Keywords: Synthetic methods / Fluorine /
Small-ring systems / Elimination / Nucleo-
philic addition
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11