Aromatic ring hydroxylation of flavanones by dimethyldioxirane

Article abstract of DOI:10.1016/S0040-4039(99)02236-4

The selective and efficient oxidation of flavanones with dimethyldioxirane (DMD) is reported. Aromatic rings carrying methoxy groups were selectively hydroxylated in neutral and acidic media. In the latter case inversion of chemoselectivity with respect to the benzylethereal position was observed. This behaviour was exploited to obtain polyhydroxylated flavanones, which are compounds with potential antioxidant and biological properties. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02236-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1087–1090
Aromatic ring hydroxylation of flavanones by dimethyldioxirane
Roberta Bernini,a,∗,† Enrico Mincione,a Anna Sanetti,a Maurizio Mezzetti a and
Paolo Bovicelli b,∗
aDipartimento A.B.A.C., Università della Tuscia, Via S. Camillo de Lellis, 01100 Viterbo, Italy
bCentro CNR di Studio per la Chimica delle Sostanze Organiche Naturali,‡ Dip. di Chimica, Università ‘La Sapienza’,
P.le A. Moro, 5–00185 Roma-Box 34, Roma 62, Italy
Received 30 July 1999; revised 18 November 1999; accepted 29 November 1999
Abstract
The selective and efficient oxidation of flavanones with dimethyldioxirane (DMD) is reported. Aromatic rings
carrying methoxy groups were selectively hydroxylated in neutral and acidic media. In the latter case inversion of
chemoselectivity with respect to the benzylethereal position was observed. This behaviour was exploited to obtain
polyhydroxylated flavanones, which are compounds with potential antioxidant and biological properties. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: dioxirane; flavanones; hydroxylation.
Flavonoids are phenol derivatives present in substantial amounts (0.5–1.5%) in plants1 in which
they carry out important functions for their biochemistry and physiology.2 These compounds contribute
colour, flavour and processing characteristics important in many foods (vegetables, fruits) and in drinks
(tea, wine). Food from common plants contain from traces up to several grams of flavonoids per kilogram
fresh weight.3 In particular, flavanones (2,3-dihydro-2-phenyl-4H-1-benzopyran-4-one derivatives) are
present in the fruits of genus Citrus4 and are present in wastes and residues obtained during the industrial
processing of lemons.5 Biological properties of flavonoids and their pharmaceutical potencies have been
widely investigated and extensively reviewed during the past 30 years.6 Recently it has been reported
that their antioxidant activity, involving efficiency in capturing free radicals, is highly influenced by the
presence of oxygenated groups (hydroxyls, methoxyls) on the aromatic rings; an ortho-dihydroxy system
is of particular interest.7
Our group has been working for several years on selective oxidation of natural products by dimethyl-
dioxirane (DMD).8 This peroxide inserts oxygen into C–H bonds very efficiently and can discriminate
between different sites in the same molecule. Selectivities are often as high as those that enzymes are
∗
Corresponding authors. Fax +39(0)649913628; e-mail: berninir@unitus.it (R. Bernini), bovicelli@uniroma1.it (P. Bovicelli)
Research fellow for Consorzio I.N.C.A. — Venezia.
Associated to Istituto Nazionale Chimica dei Sistemi Biologici-CNR, Italy.
†
‡
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02236-4
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able to achieve. We planned to exploit such efficiencies and selectivities to perform transformations of
readily available compounds to obtain more interesting products.
In a previous paper we reported on a new route to flavylium salts based on the high selectivity of DMD
for the oxidation of benzyl ethereal carbons;9 we now report efficient oxygen insertion into activated
aromatic rings of flavanones, the regio- and chemoselectivity of the insertion strongly depends on the
neutral or acidic reaction conditions.
The model compound considered first, 5-methoxyflavanone 1, reacted with DMD to give, in satis-
factory yield, a polar compound and spectroscopic analysis showed it to be the 6-hydroxy derivative 2
(Scheme 1).10
Scheme 1.
With the aim of making DMD more electrophilic and so more reactive towards aromatic centres, we
performed the reactions in acidic medium, namely in a 2N solution of HCl. In this case the reaction
took a different course with formation of the dihydroxylated product 310 in almost quantitative yield.
40-Methoxyflavanone 4 reacted with DMD, under neutral conditions, at the benzyl ethereal position,9,11
but when the reaction was carried out under acidic conditions selective oxidation of the aromatic ring B
occurred to give 7.12 This reaction was quantitative and occurred in a few minutes.

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The inversion of chemoselectivity under neutral conditions is worthy of note: protonation of the ben-
zopyranic oxygen probably caused deactivation of the C-2 position while protonated dimethyldioxirane
was more electrophilic and was then able to carry out aromatic ring oxidation.
With more substituted flavanones such as 8, DMD reacted under neutral conditions to give essentially
two compounds (910, 1013), one of which lacked a methyl substituent (Scheme 2). With a further equiv.
of DMD 9 was quantitatively transformed into 10, a most interesting and specific demethylation.
Scheme 2.
This reaction may occur via a radical process and the carbonyl group should play a determining role
in favouring the process (e.g. via dipolar interaction with DMD). Under acidic conditions 10 was not
produced, but after just one minute the reaction led to a quantitative yield of the C-6, C-8 dihydroxy
derivative 11.12 On forcing the reaction further, functionalisation occurred on the ring B ortho to the
methoxy group to give compound 12.12 Evidently in acidic media radical pathways were suppressed and
cleavage of the O–O bond of DMD is favoured.
In summary, the utilisation of acid media in DMD oxidation reactions on flavanones allows their
quantitative transformation into polyhydroxylated compounds.
Other authors14 previously reported different behaviour in the acid-catalysed oxidation of meth-
oxybenzenes by DMD, obtaining mainly p-benzoquinones. In our case a simple aromatic substitution
occurs in which an electrophilic oxygen inserts on an highly activated carbon atom. In the light of their
promising biological activity as antioxidants and anticancer agents, the method appears as a direct route
to polyhydroxylated flavonoids starting from material largely available in nature, and more work is in
progress to exploit its potential.
Acknowledgements
We are grateful to Consorzio I.N.C.A. — Venezia who have supported this research with a grant. We
are grateful to Prof. O. Attanasi of the University of Urbino-Italy for a gift of cardanol.

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Phytochemistry 1978, 17, 1363 and references cited therein). A methoxy substituent on an aromatic system lies in the plane
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the aromatic ring. The methyl carbon is then shielded by the conjugated electrons and chemical shifts occur between 55.0
and 56.5 ppm. When the methoxy group is between bulky substituents, this conformation is disfavoured, the oxygen is not
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11. Compound 6 was identified with data reported in literature (Adam, W.; Golsch, D.; Hadjiarapoglou, L.; Patonay, T. J. Org.
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signal should be at 187 ppm.
14. Adam, W.; Shimizu, M. Synthesis 1994, 560.