Cerium metal-mediated Reformatsky-type reaction with ethyl bromosuccinate for the synthesis of novel paraconic acid analogs

Article abstract of DOI:10.1016/j.tetlet.2012.08.155

The treatment of cerium metal with ethyl bromosuccinate (1) forms the stabilized organolanthanoid intermediate (2), which reacts with carbonyl compounds in a Reformatsky-type reaction, under mild conditions, to produce functionalized γ-substituted paraconic acids (4) in good yields.

Full text of DOI:10.1016/j.tetlet.2012.08.155

Tetrahedron Letters 53 (2012) 6136–6137
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cerium metal- mediated Reformatsky-type reaction with ethyl bromosuccinate
for the synthesis of novel paraconic acid analogs
⇑
Shirley M. M. Rodrigues , Viviani Nardini, Mauricio G. Constantino, Gil Valdo J. da Silva
Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Avenida dos Bandeirantes, 3900, 14040-901 Ribeirão Preto, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The treatment of cerium metal with ethyl bromosuccinate (1) forms the stabilized organolanthanoid
intermediate (2), which reacts with carbonyl compounds in a Reformatsky-type reaction, under mild con-
Received 17 August 2012
Revised 30 August 2012
Accepted 31 August 2012
Available online 8 September 2012
ditions, to produce functionalized
c
-substituted paraconic acids (4) in good yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ethyl bromosuccinate
Cerium metal
Reformatsky-type reaction
Paraconic acids
The synthesis of
c
-butyrolactones is important not only because
be stabilized, particularly if zinc is replaced by certain metals such
as cerium or samarium. In these cases, due to the relative position
of the groups, c-lactones are obtained instead of hydroxy-esters.
We have thus decided to study the synthesis of paraconic acids
through a Reformatsky-type reaction of ethyl bromosuccinate with
carbonyl compounds mediated by cerium, which could stabilize
the anion both as an enolate and as a complex with the b-carbonyl
ester group (Scheme 1).
they occur widely in nature, but also because they constitute a par-
ticularly useful class of synthons of numerous compounds possess-
ing biological activies.1
In this context, paraconic acids (bearing a carboxylic acid func-
tion at the position b to the carbonyl, see Scheme 1), constitute an
important class of
c-butyrolactones that showed antitumor and
antibiotic activies.2
Due to the important biological activities of paraconic acids,
several methods have been described for the synthesis of natural
The reaction as depicted in Scheme 2 was performed with ethyl
bromosuccinate, cerium metal, and several different carbonyl sub-
strates. Diols 5 form as by-products probably through free radical
dimerization8,16 of the carbonyl substrates. The results are summa-
rized in Table 1.17
products containing b-carboxylated c-butyrolactones, including a
variation of the Perkin–Fittig condensation,3 multicomponent
reactions,4 ring-closing metathesis of two electron deficient ole-
fins,5 free-radical-mediated conjugate additions,6 and aldol reac-
tions of dioxanes.7
O
Br
CO2Et
The Reformatsky reaction in its original form uses a-halo esters
as substrates to form the stabilized zinc enolates which will be
added to carbonyl compounds generating b-hydroxy esters. This
is a well-known synthetic methodology, with widespread use in
a number of multistep syntheses.8
Ce°
O
CO2Et
1
CO2H
Paraconic acid core
Many other metals have been used in Reformatsky-type reac-
tions, such as cerium,9–11 magnesium,12 nickel,13 lithium,14 and
mischmetal15 to allow the use of milder reaction conditions or
obtaining better yields.
O
CeBr
O
O
OEt
EtO
More recently, however, Fukuzawa and co-workers9 have dem-
onstrated that b-halo esters can also be used in a kind of homo-
Reformatsky reaction, because the anion in the b-position can also
2
O
R'
O
CO2Et
R
4a-h
R'
R
3
⇑
Corresponding author.
E-mail address: shirleymma@yahoo.com.br (S. M. M. Rodrigues).
Scheme 1.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.155

S. M. M. Rodrigues et al. / Tetrahedron Letters 53 (2012) 6136–6137
6137
O
Unsymmetrical ketones (R1–R2, Scheme 2) can produce stereo-
isomers both of the butyrolactone (4) and of the by-product diol
(5). This is the case for entries 1, 3, and 8. The presence of both pos-
sible stereoisomers was confirmed by 1H and 13C NMR of the crude
products. Separation of the isomers followed by purification and
more detailed analysis, however, was only performed for products
4a and 4c (Fig. 1).
The relative configuration for each stereoisomer was deter-
mined by comparing NOEDIFF experiments for each isomer. Partic-
ularly significant is the interaction between the hydrogens of the
CH3 group and the hydrogens of OCH2 of the ester group: this
interaction is observed only in isomers 4a1 and 4c1 (Fig. 1), in
which the CH3 and the ester group are on the same face of the ring.
In conclusion, the treatment of ketones with the organocerium
from ethyl bromosuccinate proved to be a mild and efficient meth-
OH
R2
R2
Br
CO2Et
CO2Et
Ce°
O
R1
R1
O
CO2Et
R1
R2
HO
R1
R2
3
4
5
1
Scheme 2.
Table 1
Reaction of ethyl bromosuccinate with various carbonyl compounds mediated by
cerium
Entry
Carbonyl compound
4
5
(Isolated yield, %)
4a (58)
1
2
3
4
5
6
7
8
Acetophenone
Benzophenone
Hex-5-en-2-one
Diethyl ketone
Cyclopentanone
Cyclohexanone
Cycloheptanone
4,4-Dimethylcyclo
hex-2-en-1-one
Benzaldehyde
5a (14)
—
od for the synthesis of
acid core.
c-butyrolactones containing the paraconic
4b (43)
4c (51)
4d (41)
4e (30)
4f (45)
4g (42)
4h (20)
—
5d (10)
5e (16)
5f (20)
5g (18)
5h (8)
Acknowledgment
We are grateful to FAPESP, CNPq, and CAPES for financial
support.
9
10
11
0
0
0
—
—
—
Crotonaldehyde
Isobutyraldehyde
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
155.
O
O
O
O
HO
OH
Ce°
References and notes
CO2Et
ethyl
bromosuccinate
THF
1. Petragnani, N.; Ferraz, H. M. C.; Silva, G. V. J. Synthesis 1986, 157.
2. Le Floch, C.; Le Gall, E.; Léonel, E.; Martens, T.; Cresteil, T. Bioorg. Med. Chem.
Lett. 2011, 21, 7054.
3. Lawlor, J. M.; McNamee, M. B. Tetrahedron Lett. 1983, 24, 2211.
4. Le Floch, C.; Bughin, C.; Le Gall, E.; Léonel, E.; Koubaa, J.; Martens, T.; Retailleau,
P. Eur. J. Org. Chem. 2010, 5279.
30%
16%
20%
3e
4e
5e
6
Scheme 3.
5. Selvakumar, N.; Kumar, P. K.; Reddy, K. C. S.; Chary, B. C. Tetrahedron Lett. 2007,
48, 2021.
6. Sibi, M. P.; Liu, P.; Ji, J.; Hajra, S.; Chen, J. J. Org. Chem. 2002, 67, 1738.
7. Barros, M. T.; Maycock, C. D.; Ventura, M. R. Org. Lett. 2003, 5, 4097.
8. (a) Shriner, R. L. Organic React. 1942, 1, 1–37; (b) Fürstner, A. In Organozinc
Reagents; Knochel, P., Jones, P., Eds.; Oxford University Press: New York, 1999;
p 287.
O
O
O
O
CO2Et
CO2Et
H3C
R
H3C
R
9. Fukuzawa, S.; Sumimoto, N.; Fujinami, T.; Sakai, S. J. Org. Chem. 1990, 55, 1628.
10. Fukuzawa, S.-I.; Fujinami, T.; Sakai, S. J. Chem. Soc., Chem. Commun. 1986, 475.
11. Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.; Hatanaka, Y.;
Yokoyama, M. J. Org. Chem. 1984, 49, 3904.
4a1
4c1
4a2
4c2
R= Ph
R= CH2CH2CH=CH2
12. Moriwake, T. J. Org. Chem. 1996, 31, 983.
13. Inaba, S.-I; Rieke, R. D. Tetrahedron Lett. 1985, 26, 155.
14. Villieras, J.; Perriot, P.; Bourgain, M.; Normant, J. F. J. Organomet. Chem. 1975,
102, 129.
Figure 1. Diastereoisomers and observed effect NOE.
15. Lannou, M.-I.; Hélion, F.; Namy, J.-L. Tetrahedron 2003, 59, 10551.
16. Yokoo, K.; Fujiwara, Y.; Fukagawa, T.; Taniguchi, H. Polyhedron 1983, 2, 1101.
17. General procedure: cerium metal powder (3 mmol) recently prepared with a
rasp (caution: the cerium metal can easily ignite in air when it is scraped) was
activated with a trace of iodine under nitrogen atmosphere. A few drops of a
solution of ethyl bromosuccinate (3 mmol) in THF (2 mL) were added and, after
a mild reaction started, the reaction mixture was cooled in an ice bath and the
remaining ethyl bromosuccinate solution was added dropwise. This mixture
was stirred for 30 min at 0 °C. A solution of the carbonyl compound (3 mmol)
in THF (3 mL) was added to the dark brown reaction mixture, followed by
additional THF (5 mL), stirring for 30 min at 0 °C and then at room temperature
for 3 h. The mixture was filtered, acidulated with dilute HCl, and extracted
with diethyl ether. The organic layer was washed with brine and dried over
Aromatic, linear, and cyclic ketones reacted smoothly to furnish
-butyrolactones (4) in moderate to good yields (entries 1–8). In
c
the case of 4,4-dimethylcyclohex-2-en-1-one (entry 8), that could
give 1,2- or 1,4-adducts, only the 1,2-adduct was obtained. Cyclo-
pentanone (entry 5) gave a rather low yield mainly because the
Reformatsky reagent acted as a base, forming the enolate of the ke-
tone, resulting in aldol condensation (6) (Scheme 3).
Each one of the ketones (3) gave, in reasonable amount, the ex-
pected
c-butyrolactone. Rather intriguingly, however, aldehydes
were destroyed but gave no lactone at all. This is possibly due to
the readiness for aldehydes to form a radical anion which can give
a number of by-products.16
MgSO4. The solvent was removed by evaporation, and
c-butyrolactone and
diols were isolated by column chromatography on silica gel (hexane: ethyl
acetate gradient from 9.5: 0.5 to 8: 2 v/v).