One step preparation of bromo-2-pyrones via bromo-decarboxylation of 2-pyrone-carboxylic acids

Article abstract of DOI:10.1016/S0040-4039(00)02182-1

Synthetically valuable 3-bromo-2-pyrone, 3-bromocoumarin, 5-bromo-2-pyrone, and 3,5-dibromo-2-pyrone were prepared in one step from readily available 2-pyrone-carboxylic acids via bromo-decarboxylation in good to fair yiels.

Full text of DOI:10.1016/S0040-4039(00)02182-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1065–1067
One step preparation of bromo-2-pyrones via
bromo-decarboxylation of 2-pyrone-carboxylic acids
Cheon-Gyu Cho,* Jung-Sang Park, In-Hak Jung and Haiwon Lee
Department of Chemistry, Hanyang University, Seoul 131-791, South Korea
Received 25 September 2000; revised 21 November 2000; accepted 24 November 2000
Abstract—Synthetically valuable 3-bromo-2-pyrone, 3-bromocoumarin, 5-bromo-2-pyrone, and 3,5-dibromo-2-pyrone were pre-
pared in one step from readily available 2-pyrone-carboxylic acids via bromo-decarboxylation in good to fair yields. © 2001
Elsevier Science Ltd. All rights reserved.
Various substituted 2-pyrones1 have been used as key
synthons for the synthesis of many natural and unnatu-
ral complex molecules including taxol and a series of
vitamin D3 analogs,2 taking advantage of their excellent
stereochemical control in the Diels–Alder cycloaddition
steps.3 Brominated 2-pyrones have an additional inter-
esting feature in that they can act as ‘chameleon
dienes’,3 meaning that they can react with both electron
poor and rich dienophiles. As thoroughly investigated
by Posner et al.,4,5 they can undergo either normal or
inverse electron-demand D-A cycloadditions, depend-
ing on the type of dienophiles being encountered, as the
bromine atom at 3 or 5 position on the 2-pyrone ring
can withdraw or donate electron density to the pyrone
Table 1. Hundsdiecker reactions of 2-pyrone-carboxylic acids
Keywords: Hundsdiecker reaction; halo-decarboxylation; Diels–Alder cycloaddition; 2-pyrones.
* Corresponding author. Fax: 82 2 2290 0762; e-mail: ccho@email.hanyang.ac.kr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02182-1

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C.-G. Cho et al. / Tetrahedron Letters 42 (2001) 1065–1067
Scheme 1.
diene unit. Unfortunately, however, the versatility and
usefulness of bromo-2-pyrones are much overshadowed
by their difficult syntheses. For example, synthesis of
3-bromo-2-pyrone requires total three steps, starting
from expensive 5,6-dihydro-2-pyrone, in an overall yield
of 32%.4a 5-Bromo-2-pyrone is also prepared from the
same starting material, either as a by-product during the
synthesis of 3-bromo-2-pyrone or directly, both in less
than 36% yield.4b,c
5-bromo-2-pyrone and 3,5-dibromo-2-pyrone, along
with the recovered starting pyrone carboxylic acid. A
series of studies were conducted to increase the product
yield and, at the same time, to suppress the formation
of 3,5-dibromo-2-pyrone by varying reaction condi-
tions. Ultimately, we isolated the desired 5-bromo-2-
pyrone in 35% yield, along with 3,5-dibromo-2-pyrone
and the recovered starting acid in 15 and 10%, respec-
tively, when 2 equiv. of both NBS and LiOAc were used
in CH3CN–H2O (5:1) as a solvent after 3 days at rt. We
presume that 3,5-dibromo-2-pyrone was produced from
the competitive aromatic bromination at carbon 3 of the
starting pyrone, followed by bromo-decarboxylation,
judged from a separate control experiment that showed
5-bromo-2-pyrone did not undergo bromination at car-
bon 3 under the same reaction conditions (Scheme 1).
In the search for a more affordable and convenient way
of synthesis, we undertook a systematic study on the
bromo-decarboxylation of the readily available 2-
pyrone-carboxylic acids. Under the conditions with
metal ion catalysts or without, various aromatic and
a,b-unsaturated carboxylic acids have been successfully
converted to the corresponding aryl and alkenyl
halides.5 No examples on the carboxylic acids with
internal ester systems were, however, reported. Jor-
gensen et al.5e reported, in fact, that coumarin-3-car-
boxylic acid (entry 2 in Table 1) was completely inert
under their highly effective NBS/PhIO system for halo-
decarboxylation of a,b-unsaturated carboxylic acids.
Although the yield of 5-bromo-2-pyrone here is only
compatible to the literature method,4a our method
would still be more attractive in that coumalic acid is
much cheaper. Use of more than 2 equiv. of NBS to
complete the reaction increased the formation of 3,5-di-
bromo-2-pyrone only, without much effect on 5-bromo-
2-pyrone. In fact, we obtained 3,5-dibromo-2-pyrone as
a main product, in an isolated yield of 75%, when 2.5
equiv. of both NBS and LiOAc were used. Noteworthy
is that we now have a practical method for 3,5-dibromo-
2-pyrone, which is expected to be an ambiphilic diene,
similar to 3- or 5-bromo-2-pyrone. Known since 1969,
3,5-dibromo-2-pyrone has not been studied as a diene,
despite the potency as an ambiphilic diene, primarily
due to the intensive labor and extremely low yield in its
synthesis.4b,6 Our subsequent study showed that 3,5-
dibromo-2-pyrone is indeed ambiphilic, undergoing
normal and inverse electron demand D-A [4+2]
cycloadditions with both methyl acrylate and benzyl
vinyl ether to give rise to the highly functionalized
bicyclolactones with excellent stereocontrol (Scheme 2).
It turned out to be a bit more reactive and stereoselec-
tive than 3- or 5-bromo-2-pyrone. We are currently
While most of the literature methods5 failed on our
2-pyrone system, Roy’s condition5c using NBS and
catalytic LiOAc in aqueous CH3CN was found to be
working, furnishing small amounts of the desired 3-
bromo-2-pyrone from 2-pyrone-3-carboxylic acid.3b The
reaction itself was extremely slow, thus resulting in the
gradual decomposition of the product. While increasing
the reaction temperature led to the decomposition of the
product, excessive use of LiOAc facilitated the reaction
rate. Thus, when the reaction was conducted in aqueous
CH3CN, with NBS and 1.2 equiv. of LiOAc, 2-pyrone-
3-carboxylic acid was cleanly converted into 3-bromo-2-
pyrone in 42% yield (entry 1), 10% better than the
conventional three step method. Under the conditions,
coumarin-3-carboxylic acid (entry 2) was also bromo-
decarboxylated to 3-bromo-coumarin in 67% yield.
Reaction on coumalic acid (entry 3) provided both
Scheme 2.

C.-G. Cho et al. / Tetrahedron Letters 42 (2001) 1065–1067
1067
investigating its scope and limitation as a diene through
the reactions with a series of electronically and steri-
cally distinct dienophiles.
J. L.; Dolan, P.; Kensler, T. W. J. Org. Chem. 1997, 62,
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1995, 60, 4617. (c) Nicolaou, K. C.; Yang, Z.; Liu, J. J.;
Ueno, H. et al. Nature 1994, 367, 630.
In conclusion, we prepared synthetically useful 3-
bromo-2-pyrone, 5-bromo-2-pyrone, and 3,5-dibromo-
2-pyrone including 3-bromo-2-coumarine7 in one step
from readily available 2-pyrone-carboxylic acids with
good to reasonable yields.
3. (a) Posner, G. H.; Wettlaufer, D. G. J. Am. Chem. Soc.
1986, 108, 7373; (b) Cho, C.-G.; Posner, G. H. Bull.
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D. B. Bull. Soc. Chim. Fr. 1990, 127, 830; (d) Marko, I. E.;
Evans, G. R. Tetrahedron Lett. 1994, 35, 2767.
Acknowledgements
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Org. Chem. 1994, 59, 3543; (f) Izawa, T.; Nishiyama, S.;
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Chem. 1999, 64, 1033; (b) Mitra, A. K.; De, A.; Karchaud-
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This work was supported through a grant from the
Ministry of Science and Technology, National Research
Laboratory (99-N-NL-01-C-103) in Korea. We are also
grateful to Professor K. Afarinkia at King’s College for
helpful discussions.
References
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mura, H.; Shimizu, H.; Nakamura, Y.; Iwagawa, T.;
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