Three-component synthesis of functionalized five-membered ring lactones under Barbier-like conditions

Article abstract of DOI:10.1016/j.tetlet.2009.07.038

Five-membered ring lactones have been synthesized using a straightforward three-component reaction among in situ-generated arylzinc reagents, dimethyl itaconate and aromatic aldehydes. This Barbier-like procedure, which is characterized by its simplicity,

Full text of DOI:10.1016/j.tetlet.2009.07.038

Tetrahedron Letters 50 (2009) 5456–5458
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Three-component synthesis of functionalized five-membered ring lactones
under Barbier-like conditions
*
Camille Le Floch, Carine Bughin, Erwan Le Gall , Eric Léonel, Thierry Martens
Électrochimie et Synthèse Organique, Institut de Chimie et des Matériaux Paris-Est, UMR 7182 CNRS-Université Paris 12 Val-de-Marne, 2-8 rue Henri Dunant, 94320 Thiais, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Five-membered ring lactones have been synthesized using a straightforward three-component reaction
among in situ-generated arylzinc reagents, dimethyl itaconate and aromatic aldehydes. This Barbier-like
procedure, which is characterized by its simplicity, allows the concise synthesis of a range of highly func-
Received 8 June 2009
Revised 29 June 2009
Accepted 1 July 2009
Available online 5 August 2009
tionalized 4,5-substituted c-butyrolactones.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reactions
Barbier-like conditions
c-Butyrolactones
Aryl bromides
Aromatic aldehydes
Dimethyl itaconate
Substituted
c-butyrolactones, in particular those bearing a car-
aldehyde 17 to induce the formation of an alcoholate which would
boxyl group at the b position (paraconic acids) constitute an
important family of biologically active compounds displaying anti-
tumour and antibiotic activities.1 They also represent important
building blocks in the preparation of natural products of pharma-
ceutical interest.2 Accordingly, during the last years, numerous
procedures have been developed for the synthesis of paraconic
acids and derivatives.3
further cyclize to provide the expected
1).
c-butyrolactone 3 (Scheme
In a preliminary experiment, we tried to undergo a three-com-
ponent cascade reaction between benzaldehyde 1a, dimethyl itac-
onate and 4-bromoanisole 2a. We chose to employ experimental
conditions similar to those described in a previous work regarding
the in situ activation of aryl bromides into the corresponding aryl-
zinc compounds8 and their three-component reaction with alde-
hydes and amines.6e Thus, 2a was allowed to react with dimethyl
itaconate and benzaldehyde 1a in the presence of zinc dust and co-
balt bromide at room temperature (Scheme 2).
Surprisingly, although multicomponent reactions provide a ra-
pid access to highly functionalized scaffolds4 such processes have
not been employed so far for the synthesis of functionalized 4,5-
substituted c
-butyrolactones.5
Recently, our group has developed a Mannich-type three-compo-
nent reaction among organozinc reagents, amines and aldehyde
derivatives.6 As a prospect, we envisaged to extend this methodol-
ogy to an array of multicomponent reactions involvingin situ-gener-
ated arylzinc reagents as nucleophiles. Thus, as a first disclosure, we
describe herein a cascade conjugate addition-aldolization-cycliza-
FG
O
O
Zn dust
CoBr2, cat.
OMe
MeO
O
O
H
O
+
Ar
FG
OMe
tion process as a useful tool for the synthesis of
c-butyrolactones.
Ar
H
Br
O
1
2
3
The putative synthesis of -butyrolactones was based on the
c
observation that the addition of arylzinc compounds to aldehyde
1 is generally slow. Thus, we conceived that a 1,4 addition of these
organometallic reagents, generated in situ from aryl bromides 2,
on a suitable Michael acceptor like dimethyl itaconate might be
the faster pathway. The resulting enolate might then react with
FG
FG
FG
Ar
MeO
O
O
MeO
O
O
BrZn
OMe
MeO
ZnO
H
H
O
ZnO
Ar
OMe
O
OMe
* Corresponding author. Tel.: +33 0 149781135; fax: +33 0 149781148.
E-mail address: legall@glvt-cnrs.fr (E.L. Gall).
Scheme 1. Principle of the three-component cascade reaction.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.038

C. L. Floch et al. / Tetrahedron Letters 50 (2009) 5456–5458
5457
Under these conditions, we were satisfied to observe the forma-
tion of the expected lactone in good yield, as a one-to-one ratio of
diastereoisomers.
We then started to investigate the scope of this reaction system.
In a first series of experiments, dimethyl itaconate and 4-bromo-
anisole 2a, taken as the model halide, were allowed to react with
a range of aromatic aldehydes 1 for 0.75–2 h.9 Results are reported
in Table 1.
OMe
MeO2C
O
CO2Me
Zn dust (3 eq.)
CoBr2 (13%)
O
Br
H
+
Ph CHO
Ph
CH3CN, r.t.
71%
MeO
CO2Me
1a
2a
3a
Scheme 2. Preliminary experiment involving 4-bromoanisole, benzaldehyde and
dimethyl itaconate.
Yields obtained with benzaldehyde derivatives generally range
from moderate to excellent and it can be noted that the reaction
tolerates an important variety of functionalized aromatic alde-
hydes bearing electron-withdrawing as well as electron-donating
groups. Starting from heteroaromatic aldehydes, the corresponding
lactones are obtained in satisfactory to good yields except starting
from 3-pyridine carboxaldehyde (Table 1, entry 7). In that case, no
coupling is observed, even after 24 h at 60 °C.
In a second set of experiments, we turned our attention to the
variation of the aromatic bromide. Results are reported in Table 2.
Very satisfactory yields are generally obtained with both elec-
tron-rich and electron-deficient aryl bromides. Moreover, we were
Table 1
Scope of aromatic aldehydesa
MeO2C
OMe
O
CO2Me
Zn dust
CoBr2, cat.
O
Br
+
H
Ar
Ar CHO
CH3CN
MeO
CO2Me
1
2a
3a-h
Yieldb (%)
Entry
Aromatic aldehyde
Product 3
Table 2
OMe
Scope of aromatic bromidesa
O
CHO
O
H
1
95
O
MeO2C
CO2Me
Zn dust
O
CO2Me
CoBr2, cat.
+
H
Ph
3a
Br
FG
OMe
CH3CN
Ph CHO FG
O
CO2Me
CHO
O
H
1a
2
3i-n
2
3
4
5
6
7
41
98
79
56
75
MeO
CO2Me
OMe
Entry
1
Aromatic bromide
Product 3
Yield (%)b
3b
MeO
O
O
CHO
O
Br
O
H
H
64
99
52
95
46
69
F
Ph
CO2Me
O
CO2Me
3i
3c
F
OMe
CO2Me
O
Br
Me
CHO
O
O
O
H
2
3
4
5
H
Ph
Me
MeO2C
CO2Me
CO2Me
O
3j
3d
OMe
O
CO2Me
Br
CHO
CF3
O
H
H
Ph
CO2Me
CO2Me
CO2Me
O
3k
3e
CF3
OMe
OMe
O
Br
CHO
CHO
O
O
O
O
H
H
Ph
S
MeO
CO2Me
CO2Me
O
S
3f
3l
OMe
O
O
F3C
Br
c
H
CF3
—
H
Ph
N
CO2Me
CO2Me
O
3m
3g
N
OMe
Me
O
Br
CHO
O
8
49
H
O
6
H
O
Me
Ph
CO2Me
CO2Me
3h
3n
a
All experiments were conducted with 20 mL of acetonitrile, 2.7 g (15 mmol) of
bromoanisole, 10 mmol of the aldehyde, 7.9 g (50 mmol) of dimethyl itaconate, 3 g
(46 mmol) of zinc dust and 0.44 g (2 mmol) of CoBr2. Reactions were carried out for
0.75–2 h.
a
All experiments were conducted with 20 mL of acetonitrile, 15 mmol of the aryl
bromide, 1.1 g (10 mmol) of benzaldehyde, 7.9 g (50 mmol) of dimethyl itaconate,
3 g (46 mmol) of zinc dust and 0.44 g (2 mmol) of CoBr2. Reactions were carried out
for 1–3 h.
b
Isolated yield.
No reaction.
b
c
Isolated yield.

5458
C. L. Floch et al. / Tetrahedron Letters 50 (2009) 5456–5458
2007, 349, 943–950; (g) Bazin, S.; Feray, L.; Vanthuynne, N.; Siri, D.; Bertrand, M.
P. Tetrahedron 2007, 63, 77–85. and references cited therein; (h) Fortzato, C.;
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pling, even if in this case a slight decrease of the reaction yield (Ta-
ble 2, entries 3 and 5) is noticed.
In summary, we have developed a simple and efficient method
for the synthesis of 4,5-substituted c-butyrolactones via a multi-
component one-pot reaction between dimethyl itaconate, aryl bro-
mides and carbonyl compounds. This cascade procedure, which
involves in the same experimental step the formation of an organo-
zinc reagent, a Michael addition, an aldol coupling and a final cycli-
zation provides a reliable access to a wide variety of lactones,
making this strategy suitable for parallel synthesis. Further devel-
opments of this promising reaction system are currently in
progress.
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a-amino-
butyrolactones, see: Park, S. J.; Keum, G.; Kang, S. B.; Koh, H. Y.; Kim, Y.
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References and notes
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9. General procedure: a dried 100 mL round-bottomed flask was flushed with argon
and charged with acetonitrile (20 mL). Dodecane (0.2 mL), zinc dust (3 g,
46 mmol), dimethylitaconate (7.9 g, 50 mmol), aromatic aldehyde (10 mmol)
and aryl bromide (15 mmol) were added under stirring. Cobalt bromide (0.44 g,
2 mmol), trifluoroacetic acid (0.1 mL) and 1,2-dibromoethane (0.2 mL) were
added successively to the mixture which was heated at 60 °C until complete
consumption of the aryl bromide (45 min to 3 h, monitored by gas
chromatography). The reaction mixture was then filtered through Celite.
Celite was washed several times with diethyl ether and the combined organic
fractions were concentrated in vacuo. The crude reaction product was purified
via flash column chromatography over silica gel using a pentane/diethyl ether
mixture (1:0 to 0:1) as an eluant to afford the pure lactone 3.