An improved method for the synthesis of γ-lactones using sodium bromate and sodium hydrogen sulfite

Article abstract of DOI:10.1016/S0040-4039(00)02341-8

o-Alkylbenzenecarboxylic acids are treated with a sodium bromate and sodium hydrogen sulfite reagent under a two-phase system using ethyl acetate as solvent, under mild conditions to give the corresponding cyclized phthalides in moderate to satisfactory yield. Intermediately the α-brominated alkylbenzenecarboxylic acids are formed by the in situ generated hypobromous acid. These α-brominated acids undergo an intramolecular nucleophilic substitution reaction to afford the corresponding γ-lactones.

Full text of DOI:10.1016/S0040-4039(00)02341-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1647–1649
An improved method for the synthesis of g-lactones using sodium
bromate and sodium hydrogen sulfite
Safdar Hayat,a Atta-ur-Rahman,a M. Iqbal Choudhary,a Khalid Mohammed Khana and
Ernst Bayerb,*
aH.E.J. Research Institute of Chemistry, International Center for Chemical Sciences, University of Karachi,
Karachi 75270, Pakistan
bInstitut fu¨r Organische Chemie der Universita¨t Tu¨bingen, Auf der Morgenstelle 18, D-72076 Tu¨bingen, Germany
Received 11 October 2000; revised 18 December 2000; accepted 20 December 2000
Abstract—o-Alkylbenzenecarboxylic acids are treated with a sodium bromate and sodium hydrogen sulfite reagent under a
two-phase system using ethyl acetate as solvent, under mild conditions to give the corresponding cyclized phthalides in moderate
to satisfactory yield. Intermediately the a-brominated alkylbenzenecarboxylic acids are formed by the in situ generated
hypobromous acid. These a-brominated acids undergo an intramolecular nucleophilic substitution reaction to afford the
corresponding g-lactones. © 2001 Published by Elsevier Science Ltd.
1. Introduction
The chemistry of the NaBrO3/NaHSO3 reagent has
been widely studied because it can serve as an effective
bromohydroxylation reagent of olefins,12 alkynes,
allylic alcohols.13 The oxidation of primary alcohols,14
diols, ethers15 and a-bromination of alkyl benzenes16
was also reported. In the course of our study to extend
the scope of the NaBrO3/NaHSO3 reagent in organic
synthesis, we have found that o-alkyl aromatic car-
boxylic acids are converted directly in a two-phase
system using ethyl acetate/water and ambient condi-
tions to the corresponding g-lactones (Scheme 1).
Many natural products have g-lactone skeletons,1 most
of which display a wide variety of significant biological
activity.2 They have also been employed as key interme-
diates for the synthesis of natural products.3 A number
of papers4–6 and reviews7 have been published on the
synthesis of phthalides. This reveals that the direct
preparation of g-lactones from the corresponding o-
alkyl aromatic carboxylic acid is very useful and impor-
tant. Thus, there have been extensive studies on the
preparation of such skeletons. Previously, Na2S2O8,
AgNO3 and CuX2 at 80°C,8 oxidative cyclization with
[bis(trifluoroacetoxy)iodo]benzene and iodine via aro-
matic carboxyloxy radicals9,10 and lactonization with
organohypervalent iodine compounds in the Suarez
system11 are reported for direct conversion of o-alkyl-
benzenecarboxylic acids to g-lactones.
2. Results and discussions
NaBrO3/NaHSO3 and most of the o-alkyl aromatic
carboxylic acids 1a–1e are commercially available
(Merck, Fluka, Aldrich). The required starting material
2-benzylbenzoic acid (1g) was prepared using literature
procedures17,18 whereas 2-ethylbenzoic acid (1f), 2-n-
propylbenzoic acid (1h) and 2-n-butylbenzoic acid (1i)
were prepared by the lithiation–alkylation of o-methyl-
benzoic acid.19,20 In a typical experiment, to a two-
In this communication we describe the conversion of
o-alkyl aromatic carboxylic acids into its corresponding
g-lactones by using the NaBrO3/NaHSO3 reagent at
room temperature under a two-phase system.
phase system comprised of
a
solution of
o-methylbenzoic acid (1a) in ethyl acetate and aqueous
NaBrO3 (3 equiv.) aqueous NaHSO3 (3 equiv.) was
added over a period of about 15 min and stirred at
room temperature for 40 h. The phthalide 2a was
obtained in 63% yield which is higher in comparison to
when using other oxidation agents.9,10 The yields using
Keywords: sodium bromate; sodium hydrogen sulfite; hypobromous
acid; intramolecular nucleophilic substitution; phthalide and deriva-
tives.
* Corresponding author. Fax: +49 7071 295034; e-mail:
ernst.bayer@uni-tuebingen.de
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(00)02341-8

1648
S. Hayat et al. / Tetrahedron Letters 42 (2001) 1647–1649
Scheme 1.
Table 1. Synthesis of g-lactones from o-alkylbenzenecar-
boxylic acids
Acknowledgements
Substrate
Lactone
Yield (%)
We express our gratitude to the Deutsche Akademische
Austauschdienst (DAAD, Bonn, Germany) for a sand-
wich-type scholarship granted to Safdar Hayat.
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2b
2c
2d
63
60
58
17
50/19
53
68
51
49
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2f
2g
2h
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