Ethyl-2-(2-chloroethyl)acrylate: A new very versatile α- cyclopropylester cation synthon. Efficient synthesis of cyclopropane ester derivatives by Michael addition-induced cyclization reaction

Article abstract of DOI:10.1016/j.tetlet.2011.04.046

We report here the use of the readily accessible ethyl-2-(2-chloroethyl) acrylate as a new very versatile α-cyclopropylester cation synthon, which reacts efficiently and selectively with carbon-, nitrogen-, sulfur- or phosphorus-centered nucleophiles through Michael addition followed by intramolecular capture of the incipient ester enolate to afford funtionalized cyclopropane esters in high yields.

Full text of DOI:10.1016/j.tetlet.2011.04.046

Tetrahedron Letters 52 (2011) 3219–3222
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Tetrahedron Letters
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Ethyl-2-(2-chloroethyl)acrylate: a new very versatile
a-cyclopropylester cation
synthon. Efficient synthesis of cyclopropane ester derivatives by Michael
addition-induced cyclization reaction
⇑
Mathilde Lachia, Sébastien Iriart, Myriam Baalouch, Alain De Mesmaeker, Renaud Beaudegnies
Syngenta Crop Protection AG, Crop Protection Research, Research Chemistry, Schaffhauserstrasse 101, CH-4332 Stein, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
We report here the use of the readily accessible ethyl-2-(2-chloroethyl)acrylate as a new very versatile a-
Received 10 March 2011
Revised 11 April 2011
Accepted 11 April 2011
Available online 18 April 2011
cyclopropylester cation synthon, which reacts efficiently and selectively with carbon-, nitrogen-, sulfur-
or phosphorus-centered nucleophiles through Michael addition followed by intramolecular capture of
the incipient ester enolate to afford funtionalized cyclopropane esters in high yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopropane
a-Cyclopropyl cation
Michael addition-initiated ring closure
reactions
Cyclopropanes occur widely in biologically active natural prod-
ucts as well as in pharmaceutical and agrochemical products.1
Therefore, a variety of methods to access these valuable target
molecules have been developed.2 Among these synthetic methods,
the Michael addition-initiated ring-closure reactions (MIRCs) are
usually performed on electron-deficient olefins carrying an elec-
tron withdrawing substituent at C1 and a leaving group at the C3
allylic position. 2e–j MIRC reactions of olefins having a homo allylic
leaving group at C1 have received less attention and only very spe-
cific examples have been reported.3,4 It is noteworthy that the syn-
thesis of optically pure cyclopropanes involving vinylsulfones
derived from carbohydrates has been investigated.5 However, a
systematic study on a general Michael acceptor is still missing.
Recently, we have reported the synthesis of spirocyclopropyl
O
Me
CO2Et
CO2Et
O
3
O
I
CO2Et
O
H
+
i
O
H
O
Me
1
2
4
Scheme 1. Reagents and conditions: (i) 2-acetyl-
(1.1 equiv), DMF, 0 °C to rt, 20 h.
c-butyrolactone 3 (1.0 equiv), NaH
variety of nucleophiles, leading to the corresponding cyclopropane
derivatives in very good yields.
cyclohexane-1,3-diones using the
a-cyclopropylester cation syn-
thon 1, derived from olefin 2 having both an ester and a homo
allylic leaving group attached at C1 (Scheme 1).6
Initially, we investigated the use of 2 with other nucleophiles 6
(Scheme 2 and Table 1). The derivative 2 is readily obtained in very
good yield from ethyl-2-(bromomethyl)acrylate 5, according to the
procedure described by Knochel.7 Although satisfactory results
were obtained with monosubstituted and unsubstituted ethyl ace-
toacetates (Table 1, entries a and b), it became obvious that, with
harder nucleophiles, SN2 and b-elimination processes are compet-
ing with the desired Michael-induced ring closure pathway. With
phthalimide as a nucleophile, the only product isolated was 8,
resulting from competitive SN2 reaction (Table 1, entry c).
We therefore turned our attention to the chloro analog 11 as a
This first example of the use of 2 as a a-cyclopropylester cation
synthon demonstrated its ability to undergo Michael addition with
a stabilized enolate. The subsequent intramolecular substitution
leads to the three-membered ring derivative 4, without any se-
verely competing reactions such as direct SN2 displacement of
the iodine and/or its b-elimination due to its homoallylic structure.
We report here the use of 2 and its improved chloro analog 11 as
a-cyclopropylester cation synthons, which react with a broad
⇑
a
-cyclopropylester cation synthon. Replacement of the iodine in 2
Corresponding author. Tel.: +41 62 8660276; fax: +41 62 8660860.
E-mail address: renaud.beaudegnies@syngenta.com (R. Beaudegnies).
by chlorine in 11 should decrease the rates of the intermolecular
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.046

3220
M. Lachia et al. / Tetrahedron Letters 52 (2011) 3219–3222
CO2Et
CO2Et
I
CO2Et
i,ii
iii
Br
NuH
+
Nu
5
2
6
7
Scheme 2. Reagents and conditions: (i) Zn (1.0 equiv), 1,2-dibromoethane (0.04 equiv), trimethylchlorosilane (0.03 equiv), diiodomethane (1.0 equiv), THF, rt, 5 h; (ii) ethyl-
2-(bromomethyl)acrylate 5 (1.0 equiv), LiI (2.3 equiv), CuI (1.2 equiv), THF, rt, 16 h, 80% (over two steps); (iii) NaH (1.1 equiv), NuH 6 (1.0 equiv), DMF, 0 °C, 1 h, then 2
(1.0 equiv), 0 °C to rt, 16 h.
Table 1
rine should not affect the Michael addition reaction. Furthermore,
the capture of the incipient ester enolate through intramolecular
SN2 reaction should proceed readily, even in the case of chloride
as the leaving group, due to the entropically favored three-mem-
bered ring cyclization reaction (Scheme 3). Indeed, we have ob-
tained high yields of cyclopropane derivatives by reaction of
various stabilized enolates with 11 (Scheme 3, Table 2).
Reactivity of 2 with various nucleophiles 6
Entry
NuH 6
Yielda (%)
Product
CO2Et
O
CO2Et
Me
CO2Et
Me
a
48
Me
O
Me
The ethyl-2-(2-chloroethyl)acrylate 11 is conveniently prepared
on multigram scale by reaction of the bromide 5 with indium and
formaldehyde.8 The alcohol 9 is then transformed into the corre-
sponding chloride 11 by treatment with the chloroenamine 10
(Ghosez’s reagent).9
7a
O
CO2Et
CO2Et
CO2Et
Me
b
c
50
29
O
Esters, amides, aryls, sulfones and ketones are suitable activat-
ing groups for carbon-centered nucleophiles to react with 11, giv-
ing the desired cyclopropane derivatives in high yields (Table 2).
An additional alkyl substituent on the methylene moiety does
not alter the course of the cyclopropanation reaction, as previously
observed with the iodo analog 2 (Table 2, entry a and Table 1, entry
Me
7b
O
O
NH
CO2Et
N
O
O
8
a, respectively). The
a-fluoro ethyl acetoacetate delivers the ex-
a
pected cyclopropane 7c in good yield (Table 2, entry c). In contrast,
Yields refer to isolated compounds after purification by chromatography on
a mixture of compounds is obtained from the corresponding
a
silicagel.
-chloro ethyl acetoacetate.10
It is noteworthy that in all examples in Table 2, the desired
substitution reaction (SN2), as well as the elimination reaction of
the homoallylic halogen (E2). However, changing iodine into chlo-
pathway preferentially leading to the cyclopropane derivatives is
followed by the stabilized nucleophiles (Scheme 4, equations A
CO2Et
CO2Et
Cl
CO2Et
HO
i
CO2Et
iii
ii
Br
Me
Me
Cl
NuH
Nu
5
9
11
6
7
NMe2
10
CO2Et
H
+
H
1
Scheme 3. Reagents and conditions: (i) ethyl-2-(bromomethyl)acrylate 5 (1.0 equiv), indium (1.1 equiv), formaldehyde (1.8 equiv), EtOH/H2O (1:1), rt, 22 h, 79%; (ii) 9
(1.0 equiv), chloroeneamine 10 (1.0 equiv), CH2Cl2, rt, 1 h, 80%; (iii) NaH (1.1 equiv), NuH 6 (1.0 equiv), DMF, 0 °C, 1 h, then 11 (1.0 equiv), 0 °C to rt, 12 h.
O
Na+
Na+
CO2Et
O
Cl
CO2Et
Cl
A
B
OEt
CO2Me
CO2Me
MeO2C
+
CO2Me
OMe
11
12
13
7g
CO2Me
H+ exchange
SN2
E2
C
D
E
CO2Me
CO2Et
Cl
CO2Et
F
CO2Et
CO2Et
MeO2C
MeO2C
CO2Me
CO2Me
16
Na+
O
MeO
14
15
17
Scheme 4. Possible reaction pathways for the reaction of 11 and 12.

M. Lachia et al. / Tetrahedron Letters 52 (2011) 3219–3222
3221
Table 2
Table 3
Reactivity of 11 with various carbon-centered nucleophiles 6
Reactivity of 11 with various heteroatom-centered nucleophiles 6. Reaction condi-
tions: see Scheme 3
Entry
NuH 6
Yielda (%)
Product
CO2Et
Entry
a
NuH 6
Yielda (%)
90
Product
O
CO2Et
S
CO2Et
Me
CO2Et
SH
SH
Me
a
77
Me
18
O
CO2Et
S
Cl
Me
7a
O
CO2Et
bb
64
70
CO2Et
CO2Et
Me
19
b
c
62
70
CO2Et
O
Me3Si
Me
SH
7b
c
S
7k
O
CO2Et
CO2Et
SiMe3
CO2Et
Me
O
CO2Et
O
F
F
O
Me
NH
N
7c
d
52
O
O
CO2Et
O
O
O
NMe2
Me
7l
NMe2
O
CO2Et
O
d
e
f
77
77
83
O
e
f
50
60
NH
Me
N
7d
CO2Et
O
O
7m
O
O
O
S
O
CO2Et
S
Me
OEt
EtO
P
H
P
OEt
O
OEt
Me
7e
O
7n
O
CO2Et
a
Yields refer to isolated compounds after purification by chromatography on
silicagel.
b
Me
Et3N was used as the base instead of NaH.
O
pathway (Scheme 4, equation E). Although this reaction proceeds
through the more stabilized malonate anion 16, the resulting
cyclopentane product 17 is not observed (Scheme 4, equation
F).11,12
One of the advantages of the present method is that diactivated
methylene derivatives can be successfully used, allowing the sub-
sequent introduction of an additional group by reaction with vari-
ous electrophiles. Finally, the phenyl dithiane derivative illustrates
the broad scope of carbon-centered nucleophiles which can react
with 11 to form cyclopropanes (Table 2, entry j).
Me
7f
MeO2C
CO2Me
CO2Et
CO2Me
CO2Me
g
94
71
7g
7h
CO2Et
CO2Et
h
CO2Et
The present method involving 11 as a a-cyclopropylester cation
O
CO2Et
O
O
S
O
S
synthon can be extended to nitrogen-, phosphorous-, and sulfur-
centered nucleophiles (Scheme 3 and Table 3). With thiophenol
as the nucleophile, we obtained the substitution product 18 under
our standard conditions (NaH, DMF) (Table 3, entry a). In contrast,
when triethylamine was used as a base, the Michael addition prod-
uct 19 was isolated (Table 3, entry b). Treatment of the Michael
adduct 19 with NaH in DMF converted it in very good yield into
18. Similar results were obtained with thioacetic acid as the nucle-
ophile. These results suggest that thiophenol and thioacetic acid
are undergoing fast and reversible Michael addition to the acrylate
11. We assume that, in the presence of triethylamine, the incipient
intermediate ester enolate does not cyclize into the corresponding
cyclopropane but is rather reprotonated in situ to give 19. How-
ever, in the presence of NaH, the enolate of 19 undergoes fast ret-
ro-Michael addition of the thiolate which reacts further in SN2
manner to give 18. In agreement with this hypothesis, the less
labile 2-(trimethylsilyl)-ethanethiol gives the desired cyclopropa-
nation product 7k (Table 3, entry c).
MeO2C
i
j
96
63
CO2Me
7i
CO2Et
S
S
S
S
7j
a
Yields refer to isolated compounds after purification by chromatography on
silicagel.
and B). Side reactions such as SN2 and E2 (Scheme 4, equations C
and D, respectively) are not competing with the Michael-induced
ring closure pathway. For example, the incipient enolate 13 cy-
clizes readily into the cyclopropane 7g and neither intra- nor in-
ter-molecular proton exchange occurs as potentially competing
An example of the improved chemoselectivity of the chloro
derivative 11 compared to the iodo analog 2 is observed with

3222
M. Lachia et al. / Tetrahedron Letters 52 (2011) 3219–3222
B. Angew. Chem., Int. Ed. 2010, 49, 486–488; (g) den Hartog, T.; Rudolph, A.;
Macia, B.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2010, 132, 14349–
14351; (h) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051–3060; (i)
Doyle, M. P. Angew. Chem., Int. Ed. 2009, 48, 850–852; (j) Johansson, C. C. C.;
Bremeyer, N.; Ley, S. V.; Owen, S. C.; Smith, S. C.; Gaunt, M. J. Angew. Chem., Int.
Ed. 2006, 45, 6024–6028.
phthalimide as the nucleophile. This reactant furnished the desired
cyclopropane 7l in 52% yield from 11, compared to the substitution
product 8 obtained with the iodo compound 2 (Table 3, entry d and
Table 1, entry c, respectively). Other nucleophiles successfully led
to the desired three-membered ring products as exemplified in en-
tries e and f with pyrrolidone and diethyl phosphite. However, the
reaction with oxygen-centered nucleophiles such as sodium meth-
oxide failed to give the desired product, probably due to competing
elimination reactions.
3. (a) Childs, R. F.; Johnson, A. W. J. Chem. Soc. 1966, 1950–1955; (b) Lavilla, R.;
Coll, O.; Nicolàs, M.; Sufi, B. A.; Torrents, J.; Bosch, J. Eur. J. Org. Chem. 1999, 2,
2997–3003. and references cited therein; (c) Afarinkia, K.; Mahmood, F.
Tetrahedron Lett. 2000, 41, 1287–1290.
4. Joshi, R. A.; Ravindranathan, T. Indian J. Chem. 1984, 23B, 260–262.
5. Atta, A. K.; Pathak, T. J. Org. Chem. 2009, 74, 2710–2717.
6. Beaudegnies, R.; De Mesmaeker, A.; Mallinger, A.; Baalouch, M.; Goetz, A.
Tetrahedron Lett. 2010, 51, 2741–2744.
7. Knochel, P.; Chou, T.-S.; Chen, H. G.; Yeh, M. C. P.; Rozema, M. J. J. Org Chem.
1989, 54, 5202–5204.
8. Nagano, H.; Kuwahara, R.; Yokoyama, F. Tetrahedron 2007, 63, 8810–8814.
9. Devos, A.; Remion, J.; Frisque-Hesbain, A.-M.; Colens, A.; Ghosez, L. J. Chem. Soc.,
Chem. Commun. 1979, 1180–1181.
In conclusion, we have reported the use of ethyl-2-(2-chloro-
ethyl)acrylate 11 as an
a-cyclopropylester cation synthon, which
offers clear improvements in terms of chemoselectivity as well as
increased isolated yields compared to the iodo analog 2 that we
used initially.6 The very good accessibility of 11 as well as its abil-
ity to react efficiently with a broad variety of carbon-, nitrogen-,
sulfur- and phosphorous-centered nucleophiles allowed successful
applications of this strategy to the preparation of cyclopropyl ester
targets difficult to access by standard methods. We are now gener-
alizing the described method to other Michael acceptors to synthe-
size a variety of highly substituted small rings.
10.
a
-Chloro acetates are known to produce cyclopropane derivatives by Michael
addition on electron deficient olefins, as reported in the McCoy reaction;
McCoy, L. L. J. Am. Chem. Soc. 1958, 80, 6568. In our case, the reaction of
a-
chloro acetates with 2 or 11 led to a mixture of products which were not
characterized.
11. In the case of methyl cyanoacetate as the nucleophile, the desired
cyclopropane derivative is obtained along with side products which might
result from proton exchange (Scheme 4, equation E). The intramolecular
proton exchange through
a six-membered ring between the negatively
References and notes
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by the ester enolate.
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