Efficient MnIII-mediated synthesis of functionalized trans-3,4-disubstituted-γ-butyrolactones

Article abstract of DOI:10.1016/S0040-4039(02)01022-5

The Mn^III-induced addition of malonic acid (instead of acetic acid) to cinnamic esters affords in one step functionalized trans-3,4-disubstituted-γ-butyrolactones in a greatly improved yield which can be further optimized by conducting the reaction in either acetic or formic acid, depending on the substrate.

Full text of DOI:10.1016/S0040-4039(02)01022-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5301–5304
Efficient MnIII-mediated synthesis of functionalized
trans-3,4-disubstituted-g-butyrolactones
Alain Me´ou, Laurent Lamarque and Pierre Brun*
Laboratoire de Synthe`se Organique Se´lective, GCOMM, UMR-CNRS 6114, Faculte´ des Sciences de Luminy,
163 Avenue de Luminy, 13288 Marseille Cedex 9, France
Received 17 May 2002; accepted 30 May 2002
Abstract—The MnIII-induced addition of malonic acid (instead of acetic acid) to cinnamic esters affords in one step functionalized
trans-3,4-disubstituted-g-butyrolactones in a greatly improved yield which can be further optimized by conducting the reaction in
either acetic or formic acid, depending on the substrate. © 2002 Elsevier Science Ltd. All rights reserved.
The MnIII-promoted addition of acetic acid to 1,2-disub-
stituted alkenes enables the preparation, in a single step,
of g-butyrolactones possessing two contiguous stereo-
genic centers. Nevertheless, this synthetically attractive
reaction suffers from severe limitations which preclude
its general use: it is often poorly regio- and diastereose-
lective (giving rise to a mixture of isomers) and the yield
in isolated lactone(s) is seldom good due to the low
reactivity of many alkenes and/or the formation of side
products (mainly mono-, di- and hydroxyacetates).1
diastereomer of functionalized 2,3,4-trisubstituted-g-
butyrolactones, in good yield provided that the reaction
is carried out in either acetic or formic acid, depending
on the substrate.2
Owing to the continuing interest in the preparation of
3,4-disubstituted-g-butyrolactones of defined stereo-
chemistry, especially those possessing a 4-aryl sub-
stituent,3 we thought that we could capitalize on our
previous findings in order to also obtain stereo-
defined functionalized 3,4-disubstituted-g-lactones in a
practically useful yield. Few results concerning the addi-
tion of acetic acid to unsubstituted cinnamic derivatives
could be found in the literature: despite some dis-
However, we have shown previously that the MnIII-
induced addition of potassium monomethyl malonate to
substituted cinnamic esters furnishes a single (all-trans)
Scheme 1.
Keywords: manganese(III) acetate; oxidative addition; g-butyrolactones; malonic acid.
* Corresponding author. Tel.: (33)491829270; fax: (33)491829415; e-mail: brun@chimlum.univ-mrs.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01022-5

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A. Me´ou et al. / Tetrahedron Letters 43 (2002) 5301–5304
Scheme 2.
crepancies (due in particular to the different reaction
conditions employed and to the mode of assessment of
the yield), a single or a highly predominant trans-3,4-
disubstituted-g-lactone seemed to be formed in moder-
ate yield.4 Moreover, this oxidative addition failed with
the only substituted cinnamic substrate tested, 3,4-
methylenedioxycinnamyl acetate.4d
malonic acid relative to the alkene were used and
cinnamates were not among the few substrates tested).6
Yet, when using methylmalonic acid (which could not
obviously give rise to spirodilactones), Kurosawa
cleanly obtained a-methyl-a-carboxy-g-lactones in
moderate to good yields (AcOH, 100°C, 2.5–10 min).
Three of them were subsequently decarboxylated by
prolonged heating (5.5–9 h) in refluxing acetic acid,
allowing the preparation of a-methyl-g-butyrolactones
(in 34–72% yield over two steps) from styrene or 1,1-
diarylethenes. Interestingly, in one instance (AcOH,
70°C, 14 days) the a-methyl-g-lactone was directly
obtained in 81% yield.7 These results prompted us to
investigate more systematically the addition of malonic
acid to cinnamic esters aiming to define an experimental
procedure which could lead to a less time-consuming
one-pot synthesis of lactones 2. After much effort, we
were pleased to find that, by employing the modified
protocol depicted in Scheme 2 (R=CH3) and Table 2,
no spirodilactone was ever observed: the only products
are the two lactones 2 and (when formed, entries 4 and
5) 3.5b
Our preliminary study was thus focused on re-examin-
ing the addition of acetic acid to a series of cinnamic
esters possessing diverse substitution patterns, under
standardized conditions, while measuring the yield in
isolated lactone(s) relative to the starting alkene
(Scheme 1 and Table 1).5a
As expected, the addition of acetic acid to cinnamic
esters 1a–f is totally regioselective and highly
diastereoselective, giving the two epimeric lactones 2
and 3 (readily separable by flash chromatography) with
2:3]96:4. However, the yield in isolated lactone 2 is
moderate (42–46%) in three cases (entries 2–4) and poor
(10–29%) in three others (entries 1, 5 and 6). Finally,
when starting from 1g, no lactone was ever detected
after 24 h. The incomplete consumption of 1 (entries
1–3) and the formation of side products 4 and 5 (entries
4–6) both account for the overall unsatisfactory yield in
lactone 2. Clearly, a more reactive substitute of acetic
acid was needed in order to obtain better yields of the
desired 2. In addition, this could also allow us to
perform the reaction in formic acid (which proved
highly beneficial for the preparation of trisubstituted
g-lactones).2 Malonic acid seemed a good candidate
provided that the first-formed a-carboxylactone could
be readily decarboxylated under the reaction condi-
tions. The use of malonic acid had previously been
examined but abandoned as an alternative for prepar-
ing monolactones presumably because, in each instance,
it gave overwhelmingly spirodilactones (0.5 equiv. of
The comparison between Tables 1 and 2 shows that, for
each entry, 1 is consumed to a greater extent and the
yield in 2 is consistently better (34–55%) when using
malonic acid. Furthermore, under these conditions, lac-
tone 2g (entry 7) is formed and can be isolated in fair
yield (55%).
To gain an overview of the benefits afforded by the use
of malonic acid, we then completed our study by carry-
ing out the same reactions in refluxing formic acid
(Scheme 2, R=H).5b The results are displayed in Table
3.
In this solvent, no lactone is formed in two instances
(entries 5 and 6). In all the other entries, except for
Table 1. Addition of acetic acid to cinnamates 1a–g
Entry
Cinnamate
Time (h)
2:3:4:5a
2 (yield, %)b
4 (yield, %)c
5 (yield, %)b
Unreacted 1 (%)b
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
4
6
6
3.5
4
1.5
24
97:3:0:0
97:3:0:0
97:3:0:0
69:3:28:0
20:0:26:54
35:0:65:0
–
29
43
46
42
10
18
–
–
–
–
–
–
–
–
18
–
–
32
29
38
16
13
22
62
12 (50:50)
11 (67:33)
23 (47:53)
–
1g
a Determined by 1H NMR on the crude product.
b Pure isolated compound.
c Inseparable mixture of erythro:threo diastereomers.

A. Me´ou et al. / Tetrahedron Letters 43 (2002) 5301–5304
Table 2. Addition of malonic acid to cinnamates 1a–g in acetic acid
5303
Entry
Cinnamate
Time (h)
2:3a
2 (yield, %)b
3 (yield, %)b
Unreacted 1 (%)b
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
3
2
100:0
100:0
100:0
98:2
87:13
100:0
100:0
50
46
54
55
43
34
55
–
–
–
–
7
–
–
12
32
25
19
9
2.5
2.5
2
2.5
2.5
9
28
1g
a Determined by 1H NMR on the crude product.
b Pure isolated compound.
Table 3. Addition of malonic acid to cinnamates 1a–g in formic acid
Entry
Cinnamate
Time (h)
2:3a
2 (yield, %)b
3 (yield, %)b
Unreacted 1 (%)b
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
3
3
3
2.5
3
100:0
86:14
77:23
88:12
38
60
48
59
–
–
7
14
8
–
–
10
–
3
–
c
–
–
c
3
4
–
18
–
3
–
40
1g
87:13
a Determined by 1H NMR on the crude product.
b Pure isolated compound.
c Complex mixture of unidentified compounds.
entry 1, the addition is far less diastereoselective giving
more lactone 3 than in acetic acid. Nonetheless, from a
practical point of view, in two cases the yield in isolated
2 is even better in formic than in acetic acid (entries 2
and 4).
2. Lamarque, L.; Me´ou, A.; Brun, P. Tetrahedron Lett. 1998,
39, 8283–8284.
3. (a) Lawlor, J. M.; McNamee, M. B. Tetrahedron Lett.
1983, 24, 2211–2212; (b) Frenette, R.; Kakushima, M.;
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We have thus demonstrated that, by a simple experi-
mental modification combining the use of malonic acid
(instead of acetic acid) and the proper choice of the
solvent (acetic or formic acid), it is possible to conve-
niently and rapidly prepare diverse racemic trans-3,4-
disubstituted-g-butyrolactones in greatly enhanced
isolated yield (from 0–46 to 34–60%) by a one-pot
free-radical oxidative addition/decarboxylation from
readily accessible starting materials. Current work is in
progress toward the generalization of this protocol
(including further yield improvements) in order to syn-
thesize other types of substituted g-butyrolactones and
toward the development of an asymmetric version.
4. (a) Heiba, E. I.; Dessau, R. M.; Rodewald, P. G. J. Am.
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D. A. J. Chem. Soc., Perkin Trans. 1 1992, 185–190.
5. General procedure for the preparation of 2: (a) Cinnamic
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