Combined dealkoxycarbonylation and lactonisation of unsaturated malonates in ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2005.09.143

Heating unsaturated malonates with LiCl and water in [bmim][Br] or [bmim][BF₄]/[bmim][Br] produces unsaturated esters or lactones, respectively.

Full text of DOI:10.1016/j.tetlet.2005.09.143

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8087–8089
Combined dealkoxycarbonylation and lactonisation of unsaturated
malonates in ionic liquids
a
a,
a
b
*
Magalie F. Oswald, Andrew F. Parsons, Wei Yang and Martin Bowden
a
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Syngenta Ltd, PO Box A38, Leeds Road, Huddersfield, West Yorkshire HD1 2FF, UK
b
Received 4 August 2005; accepted 23 September 2005
Available online 10 October 2005
Abstract—Heating unsaturated malonates with LiCl and water in [bmim][Br] or [bmim][BF
esters or lactones, respectively.
4
]/[bmim][Br] produces unsaturated
Ó 2005 Elsevier Ltd. All rights reserved.
Decarboxylation is an important reaction in organic
synthesis. The preparation of many important target
molecules, including natural products, involves the
removal of unwanted carboxyl groups from carboxylic
of malonates with water and LiCl in 1-butyl-3-methyl-
imidazolium ([bmim]) ionic liquids. Ionic liquids have
4
recently emerged as a popular alternative to polar
organic solvents and they offer a potentially cleaner
1
5
acids and esters. Of particular synthetic importance is
liquid medium in which to conduct synthesis.
the decarboxylation of malonates, which traditionally
requires two steps—basic hydrolysis of the esters is fol-
lowed by treatment with acid and heating. Alternatively,
Krapcho showed that dealkoxycarbonylation is
achieved in a single step by heating the malonate with
Initial studies concentrated on decarboalkoxylation of
diallylmalonates 1a–b in [bmim][Br] (Scheme 1). Very
slow decarboxylation of 1a was observed (2a was iso-
lated in 82% yield after 5 days) although addition of
6
2
water and inorganic salts in DMSO or DMF. Besides
H O and/or particularly LiCl increased the rate of decar-
2
being a single-step procedure, the Krapcho approach
is milder than the traditional procedure and acid- or
base-sensitive functional groups survive the reaction
boalkoxylation. For example, heating 1a in [bmim][Br]
with LiCl (2 equiv) for ꢀ24 h gave 2a in 51% yield.
Decarboalkoxylation of methyl ester 1b was generally
faster than ethyl ester 1a (under the same conditions),
although 2b was isolated in only 47% yield after heating
for 2 h in [bmim][Br] with LiCl (2 equiv). This was
thought to be due to the volatility of 2b and so decarbo-
alkoxylation to form less volatile esters was investigated.
3
conditions.
One disadvantage to the Krapcho method is the use of
DMSO or DMF as the solvent. DMSO easily penetrates
the skin and it serves as a carrier for other chemicals, so
increasing their toxic effects, while DMF is toxic to the
liver. Industrial grade DMSO and DMF must be hand-
led with particular care and this, together with the
problems of removing these solvents from organic prod-
ucts (which generates large quantities of aqueous waste
or requires high temperatures), has detracted from the
use of these solvents on a large scale.
As shown in Scheme 2 and Table 1, demethoxycarbonyl-
ation of various dimethyl malonates proceeded in good
7
to excellent yield in [bmim][Br]. Methyl esters 4a–d
were isolated in comparable yields to those obtained
RO2C
CO2R
RO2C
H
[
bmim][Br], LiCl (0-2 eq.)
H2O (0-2 eq.), 160 ˚C
To overcome the problems of using DMSO or DMF in
the Krapcho reaction, this letter reports novel reactions
1
1
a; R = Et
b; R = Me
2a-b (47-82%)
Keywords: Decarboxylation; Ionic liquid; Lactonisation.
*
Corresponding author. Tel.: +44 1904 432608; fax: +44 1904
32516; e-mail: afp2@york.ac.uk
4
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.143

8088
M. F. Oswald et al. / Tetrahedron Letters 46 (2005) 8087–8089
MeO2C
CO2Me
R
MeO2C
H
R
Table 2. Products formed from heating 3a, 5a–f with LiCl (4 equiv)
and H O (2 equiv) in [bmim][BF
]/[bmim][Br] for ꢀ24 h
[
bmim][Br], LiCl (2 eq.)
2
4
Precursor
Product (yield (%)/d.r.)
Ph
a-d
160 ˚C, ~12 h
Ph
4a-d
O
MeO2C
Ph
CO2Me
CO2Me
3
Ph
O
Scheme 2.
3a
6
a(89% / 1.3:1)
Table 1. Demethoxycarbonylation of dimethyl malonates 3a–d
O
MeO2C
Ph
Precursor
R
Product
Yield (%)
Ph
O
3
3
3
3
a
b
c
–CH
–CH
–CH
–H
2
2
2
CH@CH
CH@CMe
Ph
2
4a
4b
4c
4d
99
82
a
2
84
95
5a
6b (93%)
d
O
a
O
2
Heating with LiCl (4 equiv) and H O (2 equiv) in DMSO for 22 h
gave 4b in 84% yield.
MeO2C
Ph
CO2Me
Ph
O
Ph
O
when using the Krapcho method. In all cases,
bmim][Br] was recovered in ꢀ70% yield after workup
and can be reused).
5b
[
(
6
c(45% / 1.3:1)
7a(45%)
O
MeO2C
Ph
CO2Me
O
Interestingly, a different product is formed when di-
methyl malonate 3a is heated with LiCl (4 equiv) and
Ph
O
Ph
O
H O (2 equiv) in
2
a 1:1 mixture of [bmim][Br]:
[
6
bmim][BF ]. After heating overnight, c-butyrolactone
a was isolated in an excellent 89% yield (as a 1.3:1 mix-
4
5c(E-:Z- = 5:1)
6d (49% / 1:1)
7b (34% / 1.9:1)
ture of diastereoisomers) after column chromatography
MeO2C
Ph
CO2Me
O
O
8
,9
(
Table 2). Similar reactions were observed for malo-
Ph
nates 5a–e and ester 5f. Lactones were generally isolated
in excellent yield and the size of the ring was shown to
depend on the position and substitution of the C@C
bond—this is consistent with an acid-promoted cyclisa-
tion (see later). Lactones were also isolated when unsat-
urated malonates or esters were heated solely in
O
Ph
O
6d (55% / 1.1:1)b
7b (5% / 1.7:1)
5d
CO2H
MeO2C
Ph
CO2Me
Ph
O
1
0
Ph
[
bmim][BF4] (although the reactions were generally
Ph
slower), with varying amounts of LiCl and/or H O,
O
2
and this proved that [bmim][BF ] plays a crucial role
4
in the formation of the lactones.
Ph
Ph
5e
e (15% / 1.3:1)c
6
8 (80%)
Formation of lactones in [bmim][BF ] is expected to
4
O
involve acid promoted cyclisation of the unsaturated
malonates (Scheme 3). For example, for formation of
c-butyrolactone 6a, regioselective protonation of the
C@C bond in 3a is expected to form a secondary carbo-
cation and nucleophilic attack by an ester or carboxylic
acid group produces the five-membered ring. Cyclisation
before and/or after demethoxycarbonylation of the
Ph
2
CO Et
Ph
O
5f
6
f (67% / 4.1:1)a
a
After heating for 4 h in [bmim][BF
80% yield).
4
] (the ionic liquid was recovered in
ꢀ
CO Me group is possible. (After short reaction times,
2
b
c
Presumably formed by initial isomerisation of 5d to give 5c.
The unexpected formation of the c-butyrolactone was confirmed by a
strong absorption band at 1768 cm (C@O) in the IR spectrum.
particularly with diethyl malonates, lactones containing
an ester group may be isolated—these lactones undergo
À1
dealkoxylation on further heating with LiCl, H O in
2
[
bmim][BF ].) It is likely that the acid responsible for
4
lactonisation of the unsaturated malonates is HF, which
has recently been shown to be formed on hydrolysis of
R1
Cl
OR1
O
1
1
12
[
bmim] ionic liquids, including [bmim][BF4].
Ph
6
a
R
Ph
O
+
R
O
1
This novel synthetic approach to lactones compares
favourably with other methods. Direct conversion of
R Cl
1
3
unsaturated esters into lactones is rare and normally
requires two steps—basic hydrolysis forms the unsatu-
rated carboxylic acid, which is subsequently converted
R = H or CO2Me; R1 = H or Me
Scheme 3.

M. F. Oswald et al. / Tetrahedron Letters 46 (2005) 8087–8089
8089
O
R. Eur. J. Org. Chem. 2003, 1779; (c) Wolan, A.;
Zaidlewicz, M. Org. Biomol. Chem. 2003, 1, 3724; (d)
Branco, L. C.; Afonso, C. A. M. J. Org. Chem. 2004, 69,
MeO2C
CO2Me
NaH, [bmim][BF4],
BnBr, 0 ˚C to r.t.
Ph
O
4
381.
then [bmim][Br],
LiCl, H2O, 160 ˚C
6
. [Bmim][Br] has a mp of 78 °C: Nishida, T.; Tashiro, Y.;
Yamamoto, M. J. Fluorine Chem. 2003, 120, 135.
. Typical procedure: dimethyl allylbenzylmalonate 3a
(131 mg, 0.50 mmol), lithium chloride (42 mg, 1.0 mmol)
and [bmim][Br] (0.5 g) were heated at 160 °C for 14 h.
After cooling, the mixture was partitioned between water
and diethyl ether. The aqueous layer was extracted with
further diethyl ether and the combined organic extracts
were washed with brine, dried, filtered, evaporated and
purified by column chromatography (silica). This gave
methyl 2-benzylpent-4-enoate 4a (101 mg, 99%) as a
colourless oil.
6a (29% / 1.1:1)
7
Scheme 4.
1
4
into the lactone by selenolactonisation, iodolactonisa-
tion,1 or by heating with strong acids. In comparison,
5
16
heating in [bmim][BF ]/[bmim][Br] with LiCl and H O
4
2
offers a direct and efficient approach to variously substi-
tuted lactones from malonates. This is expected to be
useful to synthetic chemists because alkylation of malo-
nates followed by decarboalkoxylation is a well-used
strategy for regioselective a-alkylation of carbonyls.
Indeed, alkylation of dialkyl malonates can be combined
with decarboalkoxylation and lactonisation in a one-pot
procedure (Scheme 4).
8
9
. All new compounds gave consistent spectral and HRMS
data.
. Typical procedure: dimethyl allylbenzylmalonate 3a
(
131 mg, 0.50 mmol), lithium chloride (85 mg, 2.0 mmol),
water (18 mg, 1.0 mmol), [bmim][Br] (0.5 g) and
[bmim][BF ] (0.5 mL) were heated at 160 °C for 22 h.
4
After cooling, the mixture was partitioned between water
and diethyl ether. The aqueous layer was extracted with
further diethyl ether and the combined organic extracts
were washed with brine, dried, filtered, evaporated and
purified by column chromatography (silica). This gave 3-
benzyl-5-methyl-dihydrofuran-2-one 6a (85 mg, 89%) as a
colourless oil as a 1.3:1 mixture of diastereoisomers (from
Acknowledgements
We would like to thank the EPSRC, Syngenta and the
R e´ gion Rh oˆ ne-Alpes for funding.
1
the H NMR spectrum).
1
1
0. Similar results were obtained when [bmim][PF
in place of [bmim][BF4].
6
] was used
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