One-step synthesis of highly functionalized monofluorinated cyclopropanes from electron-deficient alkenes

Article abstract of DOI:10.1021/ol300687s

The unique combination of Zn/LiCl allowed generation of reactive zinc enolate from ethyl dibromofluoroacetate. This fluorinated enolate reacts efficiently with a wide range of functionalized electron-deficient alkenes to afford the corresponding monofluorinated cyclopropylcarboxylates in good yields.

Full text of DOI:10.1021/ol300687s

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2270–2273
One-Step Synthesis of Highly
Functionalized Monofluorinated
Cyclopropanes from Electron-Deficient
Alkenes
Pavel Ivashkin, Samuel Couve-Bonnaire, Philippe Jubault,* and Xavier Pannecoucke
ꢀ
INSA de Rouen, UMR 6014 & FR 3038, C.O.B.R.A. Universite de Rouen, 1 rue Tesniere
ꢁ
76131 Mont-Saint-Aignan Cedex, France
philippe.jubault@insa-rouen.fr
Received March 19, 2012
ABSTRACT
The unique combination of Zn/LiCl allowed generation of reactive zinc enolate from ethyl dibromofluoroacetate. This fluorinated enolate reacts
efficiently with a wide range of functionalized electron-deficient alkenes to afford the corresponding monofluorinated cyclopropylcarboxylates in
good yields.
Cyclopropane, the smallest cycloalkane with a unique
structural feature, is the basis core of many natural pro-
ducts and biological compounds.1 Incorporation of fluor-
ine atoms into the biologically active molecules modulates
their activity and often leads tosubstantial improvement in
bioavailability and biochemical stability.2 The combina-
tion of unique properties of cyclopropane and fluorine
thus gives birth to fluorinated cyclopropanes which can be
envisioned as new powerful scaffolds for building new
therapeutic agents or crop protection molecules. In parti-
cular, monofluorinated cyclopropanes have received con-
siderable attention over recent years due to their high
potency in the treatment of neurological disorders.3
Reported methods for the synthesis of monofluorinated
cyclopropanes include [2 þ 1]-cycloaddition of fluorocar-
benes to olefins,4 cyclopropanation of fluoroalkenes,5
radical addition of ethyl iodofluoroacetate,6 or Pd-cata-
lyzed allylation of ethyl 2-fluoroacetoacetate7 with subse-
quent intramolecular nucleophilic substitution. Also, one
example of 1,4-addition of fluorinated silyl ketene acetal
to cyclopentenone was used for the construction of the
6-fluorobicyclo[3.1.0]hexane core.6 Although the utility of
existing methods was demonstrated by the synthesis of
several types of biologically active compounds, the problem
of a general approach to the variously substituted mono-
fluorinated cyclopropanes has not yet been addressed.
In order to broaden the scope of accessible monofluori-
nated cyclopropanes we report here a new method based
on the Michael addition of zinc enolate 2 derived from
commercially available ethyl dibromofluoroacetate
(1) (a) Donaldson, W. A. Tetrahedron 2001, 57, 8589. (b) Pietruszka,
J. Chem. Rev. 2003, 103, 1051. (c) Fraust, R. Angew. Chem., Int. Ed.
2001, 40, 2251. (d) de Meijere, A. Top. Curr. Chem. 2000, 207, 1.
(2) Fluorine in Medicinal Chemistry and Chemical Biology; Ojima, I.,
Ed.; Wiley-Blackwell: 2009.
(4) Brahms, D. L. S.; Dailey, W. P. Chem. Rev. 1996, 96, 1585.
(5) (a) Morikawa, T.; Sasaki, H.; Mori, K.; Shiro, M.; Taguchi, T.
(3) (a) Chaki, S.; Yoshikawa, R.; Hirota, S.; Shimazaki, T.; Maeda,
M.; Kawashima, N.; Yoshimizu, T.; Yasuhara, A.; Sakagami, K.;
Okuyama, S.; Nakanishi, S.; Nakazato, A. Neuropharmacology 2004,
46, 457. (b) Sakagami, K.; Yasuhara, A.; Chaki, S.; Yoshikawa, R.;
Kawakita, Y.; Saito, A.; Taguchi, T.; Nakazato, A. Bioorg. Med. Chem.
2008, 16, 4359. (c) Hruschka, S.; Rosen, T. C.; Yoshida, S.; Kirk, K. L.;
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Chem. Pharm. Bull. 1992, 40, 3189. (b) Meyer, O. G. J.; Frohlich, R.;
Haufe, G. Synthesis 2000, 1479. (c) Nakazato, A.; Kumagai, T.;
Sakagami, K.; Yoshikawa, R.; Suzuki, Y.; Chaki, S.; Ito, H.; Taguchi,
T.; Nakanishi, S.; Okuyama, S. J. Med. Chem. 2000, 43, 4893.
(6) Saito, A.; Ito, H.; Taguchi, T. Tetrahedron 2001, 57, 7487.
(7) Zhang, F.; Song, Z. J.; Tschaen, D.; Volante, R. P. Org. Lett.
2004, 6, 3775.
€
Frohlich, R.; Wibbeling, B.; Haufe, G. Bioorg. Med. Chem. 2008, 7148.
(d) Pessah, N.; Bialer, M.; Wlodarczyk, B.; Finnell, R. H.; Yagen, B.
J. Med. Chem. 2009, 2233.
r
10.1021/ol300687s
Published on Web 04/23/2012
2012 American Chemical Society

(EDBFA, 1) followed by an in situ nucleophilic cyclization
(Scheme 1).
Table 1. Metalation of Ethyl Dibromofluoroacetate (1) in the
Presence of Benzyl Acrylate 3a
entry
[M]a
yield 4a,b %
drc
Scheme 1. Michael-Initiated Cyclopropanation Using the
Fluorinated Enolate 2
d
1
2
3
ZnEt2
traces
0
ꢀ
d
ZnEt2/RhCl(PPh3)3
iPrMgCl
ꢀ
17
3.8:1
(ꢀ94 to 0 °C)
iPrMgCl, ZnBr2
(ꢀ94 to 0 °C)
Mg (60 °C)e
4
30
2.4:1
5
traces
traces
0
ꢀ
6
Zn (60 °C)e
ꢀ
7
ZnꢀCu (rt)
ꢀ
8
Mg/ZnCl2/LiCl (0 °C)
Rieke-Zn (ꢀ20 °C)
Zn/LiCl (ꢀ20 °C)
30
2.8:1
2.1:1
2.6:1
In an initial set of experiments, we tried to generate pure
enolate 2 according to a halogenꢀmetal exchange, before
adding the Michael acceptor, by the treatment of 1 with
certain organometallics. Me2Znand Et2Zncannot giverise
to pure 2 as they require generally high temperatures for
metalꢀhalogen exchange. On the other hand, iPrMgCl
was found to react with 1 even at ꢀ94 °C; however
Mg-2 was found to be extremely unstable and undergoes
self-condensation, while reaction with benzyl acrylate
(3a, R1 = R2 = H, EWG = CO2Bn) leads to elimination
of benzyl alcohol as a result of a 1,2-addition. Only traces
of cyclopropane 4a (R1 = R2 = H, EWG = CO2Bn) were
obtainedalongwitha completedegradation ofboth benzyl
acrylate and EDBFA. Introduction of a MgꢀZn transme-
talation step allowed us to reduce the 1,2-addition, and
finally 20% of 4a were isolated. To improve the low
isolated yield and minimize the degradation, we decided
to switch the order of addition of reagents to generate the
reactive enolate 2 in the presence of a Michael acceptor
(Table 1).
Diethylzinc, successfully used8 in combination with 1 for
the synthesis of fluoroalkenes9 and oxiranes,10 proved to
be incompatible with benzyl acrylate (entries 1 and 2)
probably due to the fast polymerization of the acceptor
triggered by 1,4-addition of diethylzinc. Isopropylmagne-
sium chloride (entry 3) provided desired cyclopropane in a
low yield which can be slightly improved by the MgꢀZn
transmetalation (entry 4). Under these reaction conditions
benzyl acrylate is subject to intense polymerization along
with 1,2-addition (evidenced by formation of benzyl
alcohol). In order to reduce the degradation of the Michael
acceptor and increase the reaction yield, the non-nucleo-
philic Mg and Zn metals were used instead of organome-
tallics (entries 5ꢀ10).
9
35
10
88
a 0.5ꢀ1 mmol 1, 0.5 equiv of benzyl acrylate, THF. b Determined by
1H NMR of the crude reaction mixture using DMF as internal standard.
c Determined by 19F NMR of the crude product. d Various temperatures
in the range of ꢀ20 to 60 °C were tried. e No reaction was observed in a
reasonable time at <40 °C using standard metal activation procedures.
To our delight, the combination of zinc and lithium
chloride11 provided the best yield (88%) in very mild
conditions12 (entry 10) while the activated Mg and Zn
metals were found to be unreactive in the conditions
suitable for the cyclopropanation (with exception of
Rieke-Zn, entry 9). To our knowledge, that is the first
example of the application of the Zn/LiCl combination to
the metalation of R-halocarbonyl compounds.
We observed that zinc activation is a crucial step for
successful cyclopropanation; indeed insufficiently acti-
vated zinc requires a higher temperature for metalation
leading to poor isolated yields. The standard protic acid
activation was ineffective, while TMSCl/dibromoethane11
and DIBAL-H13 provided highly active zinc powder sui-
table for metalation at ꢀ20 °C. However, in our hands the
best results and the most reproducible procedure were
obtained after heating Zn/LiCl with 2 mol % DMSO
and 2 mol % TMSCl in THF.
Thus, with this optimized procedure in hand, a variety of
functionalized monofluorinated cyclopropanes 4 and 40
was obtained in moderate to very good yields (Table 2).
2-Alkyl- and aryl-substituted acrylates were not reactive
enough under the standard conditions but can be easily
converted to the corresponding cyclopropanes by increas-
ing the temperature14 (30 °C). More reactive alkenes
(3c, 3jꢀ3l) demand lower amounts of EDBFA. Noteworthy,
the simple alkenyl substituent (3e) and aryl halogenides
(3g, 3l) are tolerated.15
(8) In one case (Boc-ΔAla(N-Boc)-OCH3 3h), the expected cyclopro-
pane was obtained in 60% yield (cis/trans ratio: 65/35) using diethylzinc
in THF. In all other cases of Michael acceptor tested, the reaction failed.
The cyclopropane adduct 4h was used in a medicinal chemistry program
for the synthesis of glutamate analogs (mGluR4 receptor ligands);
application recently submitted for publication (BMC-D-12-00276).
(9) Lemonnier, G.; Zoute, L.; Dupas, G.; Quirion, J.-C.; Jubault, P.
J. Org. Chem. 2009, 74, 4124.
(10) Lemonnier, G.; Zoute, L.; Quirion, J.-C.; Jubault, P. Org. Lett.
2010, 12, 844.
(11) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 6040.
(12) THF provided the best yields compared to the other solvents
(MeCN, toluene, DCM, dioxane, DME, ether, DMF, DMSO, not
exceeding 20%). Other additives (LiBr, LiI, CsF, CsCl, ZnCl2, ZnBr2,
MgCl2, NEt3BnCl, HMPA) failed to promote the metalation of 1 in
THF at temperatures below 40 °C.
(13) Girgis, M. J.; Liang, J. K.; Du, Z.; Slade, J.; Prasad, K. Org.
Process Res. Dev. 2009, 13, 1094.
(14) See Supporting Information for optimization details.
(15) By contrast, metalation of 1 was inhibited in the presence of
β-nitrostyrene, N-acryloyloxazolidinone, and N,N-dimethylacrylamide.
Org. Lett., Vol. 14, No. 9, 2012
2271

Table 2. Scope of the Cyclopropanation Reaction Using Zn/LiCl in THF
a Overall isolated yield (see Supporting Information for the isolated yields of individual isomers). b Based on 19F NMR of the crude product. c 2 equiv
of 1, ꢀ20 °C. d 1.1 equiv of 1, ꢀ20 °C. e 3 equiv of 1, 30 °C. f 2 equiv of 1, 0 °C. g Large-scale procedure: 0.1 mol of Michael acceptor, 1.6 equiv of 1, 0 °C. h
1.1 equiv of 1, 0 °C.
Remarkably, our method was successfully applied to the
synthesis of the fluorinated amino acid 4h on a 0.1 mol
scale (30.1 g of Michael acceptor) with 93% isolated yield.
A similar amino acid 4i was synthesized with a better dr
due to the more sterically demanding tert-butyl ester
group. In contrast, when tert-butyl dibromofluoroacetate
instead of ethyl dibromofluoroacetate was used during the
cyclopropanation process, no improvement of diastereos-
electivity was observed16 (benzyl acrylate 3a: dr 75:25 for
tBu-DBFA, 72:28 for EDBFA; diethyl benzylidenemalo-
nate 3k: dr 64:36 for tBu-DBFA, 69:31 for EDBFA).
Reactions with both dibenzyl fumarate (E)-3j and di-
benzyl maleate (Z)-3j lead to exclusive formation of the
same trans-isomer of 4j with comparable yields. In a
control experiment no cisꢀtrans isomerization of dibenzyl
maleate (Z)-3j was observed under the reaction conditions
(standard protocol except using ZnBr2 in place of 1). Then,
we tried to isolate the intermediate using diethyl benzyli-
dene malonate 3k. Quenching the reaction at ꢀ20 °C leads
to the exclusive formation of a minor isomer of cyclopro-
pane 4k0 along with the noncyclized intermediate 5k which
can be trapped by protonation upon aqueous workup
(Scheme 2). When allowed to warm to rt, this intermediate
is converted quantitatively into the major isomer of cyclo-
propane 4k. Based on the above experiments, we can
assume that cyclopropanation with EDBFA-Zn/LiCl pro-
ceeds via the 1,4-addition-nucleophilic substitution and
does not involve the formation of the corresponding
ethoxycarbonylfluorocarbene.
Interestingly, reaction with oxyindol derivative 3l leads
to the formation of the same mixture of four stereoisomers
when either (Z)-3l or (E)-3l is used. Unlike dibenzyl
maleate, (Z)-3l and (E)-3l undergo interconversion under
reaction conditions. Therefore, identical stereochemical
outcomes for both isomers of 3l can result from the
equilibrium of the reactive and nonreactive isomers of 3l.17
(16) Independence of stereoselectivity on the size of R in silyl ketene
acetals derived from CFBr2CO2R (R = Me, Et, iPr) was reported earlier
for 1,2-addition to aldehydes: Iseki, K.; Kuroki, Y.; Kobayashi, Y.
Tetrahedron 1999, 55, 2225.
2272
Org. Lett., Vol. 14, No. 9, 2012

Scheme 2. Stepwise Cyclopropanation of Diethyl Benzylidene-
malonate 3k
Figure 1. X-ray structure of 4l.
of indole alkaloids.19 To our knowledge, this is the first
example of spiro-oxyindole fluorinated in a nonaromatic
position.
The scope of the Zn/LiCl-promoted cyclopropanation
can be further extended to the highly valuable fluorinated
cyclopropylphosphonates as exemplified by the synthesis
of an R-fluoro-phosphonate 6 (Scheme 3).
In conclusion, a straightforward single step procedure
for the preparation of monofluorinated cyclopropanes
using ethyl dibromofluoroacetate 1 as a commercially
available fluorine source was developed. The combination
of Zn and LiCl proved to be essential for the generation of
a highly reactive organozinc reagent 2 for the cyclopropa-
nation of a wide range of Michael acceptors. Further
developments especially devoted to an asymmetric version
of this cyclopropanation process are currently under in-
vestigation in our laboratory.
Scheme 3. Synthesis of Fluorinated Cyclopropyl Phosphonate 6
The stereochemistry of the products 4 and 6 was eluci-
dated based on the known trends of HꢀF and CꢀF
spinꢀspin coupling in fluorinated cyclopropanes and
Acknowledgment. This work was supported by MESR
0
ꢁ
ꢀ
(Ministere de l Enseignement Superieur et de la Recherche),
the Region Haute-Normandie (CRUNCH program),
ꢀ
19
1Hꢀ F HOESY (4h, 4h0) and was independently con-
CNRS, University of Rouen and INSA of Rouen. This
work was also supported by ERDF funding through the IS:
CE-Chem project and Interreg IV A France -(Channel)-
England Program. Both are gratefully thanked for their
financial support (grant to P.I.).
firmed by the X-ray analysis of oxyindole derivative 4l
(Figure 1). This type of spiro-oxyindols is of particular
interest because of the biological activity of similar non-
fluorinated compounds18 and possible use in the synthesis
(17) Under identical reaction conditions (addition of EDBFA over
40 min) a 61% yield was obtained from (E)-3l compared to 71% for (Z)-
3l. Diastereomeric composition of cyclopropane was the same for both
(E)-3l and (Z)-3l. See Supporting Information for mechanistic proposal.
(18) (a) Chen, L.; Feng, L.; He, Y.; Huang, M.; Yun, H. WO 2011/
070039 A1, 2011. (b) He, Y.; Jiang, T.; Kuhen, K. L.; Ellis, D. A.; Wu, B.;
Wu, T. Y.-H.; Bursulaya, B. WO 2004/037247, 2004.
Supporting Information Available. Detailed experimen-
tal procedures, spectral data for the new compounds,
crystallographic information. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) (a) Meyers, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42,
694. (b) Zhang, D.; Song, H.; Qin, Y. Acc. Chem. Res. 2011, 44, 447.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
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