A novel use of the recyclable polymer-supported IBX: an efficient chemoselective and regioselective oxidation of phenolic compounds. The case of hydroxytyrosol derivatives.

Article abstract of DOI:10.1016/j.tetlet.2009.01.037

A useful and novel application of polymer-supported IBX for the chemoselective and regioselective oxidation of phenolic compounds has been described. Hydroxytyrosol and carboxymethylated hydroxytyrosol have been prepared in good conversions and yields und

Full text of DOI:10.1016/j.tetlet.2009.01.037

Tetrahedron Letters 50 (2009) 1307–1310
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Tetrahedron Letters
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A novel use of the recyclable polymer-supported IBX: an efficient
chemoselective and regioselective oxidation of phenolic compounds. The case
of hydroxytyrosol derivatives.
a
a
a
b
Roberta Bernini a, , Enrico Mincione , Fernanda Crisante , Maurizio Barontini , Giancarlo Fabrizi
*
a Dipartimento di Agrobiologia e Agrochimica, Università degli Studi della Tuscia, Via S. Camillo De Lellis snc, 01100 Viterbo, Italy
b Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli Studi di Roma La Sapienza, P.le A. Moro 5, 00185 Roma, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A useful and novel application of polymer-supported IBX for the chemoselective and regioselective oxi-
dation of phenolic compounds has been described. Hydroxytyrosol and carboxymethylated hydroxytyro-
sol have been prepared in good conversions and yields under green chemistry conditions in the presence
of dimethyl carbonate as the solvent. Polymer-supported reagent has been recovered by simple filtration,
regenerated and reused for more cycles of oxidation reactions without loss of efficiency.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 31 October 2008
Revised 16 December 2008
Accepted 9 January 2009
Available online 15 January 2009
Keywords:
Polymer-supported IBX
Dimethyl carbonate
Green process
Hydroxytyrosol
Carboxymethylated hydroxytyrosol
Polymer-supported reagents are a useful tool in synthetic or-
ganic chemistry. An attractive feature deriving from their use is
the easy work-up of the reactions. They can be separated from final
products by simple filtration avoiding common procedures of
extraction with toxic organic solvents. Additionally, polymer-sup-
ported reagents are generally reused for following reactions with
economic and environmental benefits.1
In the last 10 years, hypervalent iodine reagents have experi-
enced a wide development in organic chemistry. They have
received a growing interest due to their mild and highly chemose-
lective oxidizing properties combined with the commercial avail-
ability.2 The most important representative of pentavalent iodine
heterocycles is 2-iodoxybenzoic acid (1-hydroxy-1-oxo-1H-1k5-
benz[d][1,2]iodoxol-3-one, IBX, Figure 1) firstly prepared by Hart-
mann and Mayer3 and then by Santagostino et al. with a safe and
convenient procedure.4
IBX is an excellent reagent utilized under homogeneous condi-
tions for the oxidative conversion of phenols5 and phenolic methyl
aryl ethers into ortho-quinones.6 When the oxidation reaction was
followed by an in situ reduction, the catechol moiety was
obtained.5,6
The presence of this functionality is essential to increase the
biological activity of phenolic molecules, for example, the antioxi-
dant activity.7 Despite this peculiar capacity of IBX, only a few
examples of catecholic compounds of biological interest have been
prepared by this methodology. Between them, catecholestrogens8
and ( )-brazilin, a tinctorial compound found in the alcoholic ex-
tracts of the Brazil wood showing antitumoral activities.9
Recently, we have been involved in the optimization and appli-
cation of the IBX-oxidative procedure on a wide variety of natural
organic compounds to obtain bioactive catechol derivatives and in
the use of dimethyl carbonate as an ecofriendly solvent in alterna-
tive to common toxic reaction media.10 For example, we utilized
tyrosol 1 [2-(4-hydroxyphenyl)ethanol] and homovanillyl alcohol
2 [2-(4-hydroxy-3-methoxyphenyl)ethanol] as starting materials
for the preparation of hydroxytyrosol
3 [2-(3,4-dihydroxy-
phenyl)ethanol, Figure 2] and several lipophilic derivatives.11
Hydroxytyrosol 3 is a natural bioactive molecule found in extra
virgin olive oil12 and wastewaters13, which has been reported to
exhibit antioxidant properties.7a Because of this, it is widely used
in food14 and cosmetic applications.15 Hydroxytyrosol has also
been found to exert several pharmacological properties including
prevention and treatment of cardiovascular, hepatic, renal diseases
and cancer.16 Lipophilic derivatives are useful to extend the utiliza-
tion of hydroxytyrosol in nonaqueous media, in particular for cos-
metic applications.17 Between them, we have recently introduced
carboxymethylated hydroxytyrosol 4 [2-(3,4-dihydrophenyl)ethyl
methyl carbonate, Figure 2].10c,11 This new antioxidant exhibits
attractive properties. Preliminary biological data showed its major
effectiveness against the pulmonary carcinoma and melanoma
compared to hydroxytyrosol.18 Moreover, we described this
* Corresponding author. Tel./fax: +39 761 357230.
E-mail address: berninir@unitus.it (R. Bernini).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.037

1308
R. Bernini et al. / Tetrahedron Letters 50 (2009) 1307–1310
O OH
I
O
O
Figure 1. Chemical structure of 2-iodoxybenzoic acid (IBX).
as the solvent) of phenolic compounds to obtain bioactive catechol
H3CO
HO
OH
OH
OH
derivatives. In particular, we verified the efficiency of polymer-
supported IBX as inFigure 3 in the oxidative insertion of a hydroxyl
into tyrosol derivatives 1 and 5 as well as in the demethylation
reaction of homovanillyl alcohol derivatives 2 and 6 to prepare
HO
1
3
2
4
hydroxytyrosol
3 and carboxymethylated hydroxytyrosol 4
HO
HO
HO
HO
O
O
OCH3
through an one-pot procedure (Scheme 1). After the oxidation/
reduction steps, the polymeric reagent was recovered, regenerated
and reused for several oxidation reactions without lack of effi-
ciency to give the final products in excellent yields. Cycles of poly-
mer recycling are superior to those reported in the literature.20a It
is remarkable that polymer-supported IBX oxidized directly tyrosol
derivatives 1 and 5 into the corresponding hydroxytyrosol deriva-
tives with a regioselectivity similar to those of enzymes.21 At the
same time, we have noticed an improvement as far as the yield
is concerned compared to the only previous chemical procedure.22
Similarly, homovanillyl alcohol derivatives 2 and 6 were demethy-
lated with high regioselectivity. Moreover, polymer-supported IBX
showed an excellent chemoselectivity not previously evidenced in
the literature,20 the free alcoholic chain present in compounds 1
and 3 was not oxidized.
Tyrosol 1 or freshly prepared carboxymethylated tyrosol 5 (1.0
mmol)10c was solubilized in dimethyl carbonate (10 ml) at room
temperature under magnetic stirring and then commercial poly-
mer supported-IBX (2.1 mmol) was added.23 When the substrate
disappeared (1 h), the polymer was recovered by simple filtration
and the remaining solution was treated with sodium dithionite
(Na2S2O4). After the work-up, hydroxytyrosol 3 and carboxymethy-
lated hydroxytyrosol 4 were isolated. It is interesting to point out
that under heterogeneous conditions, these compounds were ob-
tained in quantitative yield and conversion. On the contrary, the
direct oxidation of tyrosol 1 into hydroxytyrosol 3 under homoge-
neous conditions proceeded in only 30% yield. This was due to
practical problems of extraction of the final products from the
aqueous medium after the reductive step. Under these experimen-
tal conditions, a chemoselective esterification of the aliphatic chain
of tyrosol 1 was necessary to diminish the hydrophilic character of
the catecholic compounds.11
Figure 2. Chemical structures of some bioactive phenolic compounds.
compound as a precursor of hydroxytyrosol by hydrolysis under
basic conditions11 and of the new 2-arylhydroxytyrosol derivatives
via Suzuki–Miyaura cross-coupling with arylboronic acids.19
Recently, various research groups have reported on the immobi-
lization of IBX onto solid polymeric supports.20 Between them,
Rademann and co-workers20a employed 4-hydroxy-2-iodobenzoic
acid and Merrifield resin as solid supports to prepare the corre-
sponding supported-IBX derivative (Fig. 3). The periodinane re-
agent was immobilized to methyl polystyrene cross-linked with
1% divinylbenzene via an aryl ether linkage. Janda and co-workers
used a similar procedure to attach 4-hydroxybenzoic acid to a set
of soluble and insoluble polymer supports.20b These polymers were
characterized by a loading factor defined as mmol of IBX per gram
of resin.
To the best of our knowledge, the oxidation properties of these
supported-periodinane reagents and their reuse have been investi-
gated only for the conversion of benzylic, allylic, terpene alcohols
and carbamate-protected aminoalcohols into respective carbonylic
compounds.20a,b
Therefore, as another useful application of polymer-supported
IBX, we describe here the first example of chemoselective and reg-
ioselective oxidation under green conditions (dimethyl carbonate
O OH
O
I
O
Polymer-supported IBX was regenerated by treating the filtered
resin with a solution of tetrabutylammonium oxone and methane-
sulfonic acid according to the procedure reported in the litera-
ture20a in the presence of dimethyl carbonate as the solvent
O
Figure 3. Polymer-supported IBX.20a,b
Polymer: regeneration
Solution: Na2S2O4 reduction
Filtration
Polymer-supported IBX
OR1
R2
HO
HO
OR1
Oxidation in DMC or DMC/H2O
HO
3: R1=H
4: R1=CO2CH3
1: R1=R2=H
2: R1=H; R2=OCH3
5: R1=CO2CH3; R2=H
6: R1=CO2CH3; R2=OCH3
Scheme 1. Conversion of phenolic compounds 1, 2, 5 and 6 into hydroxytyrosol derivatives 3 and 4 by polymer-supported IBX.

R. Bernini et al. / Tetrahedron Letters 50 (2009) 1307–1310
1309
carbonate) was utilized. Hydroxytyrosol and carboxymethylated
hydroxytyrosol are useful compounds in both cosmetic and phar-
maceutical applications.
Works are in progress in our laboratory to apply this advanta-
geous oxidative methodology to a wide number of phenolic com-
pounds for the preparation of the corresponding bioactive
catechol derivatives.
Acknowledgments
The authors like to thank Ministero delle Politiche Agricole e
Forestali (MIPAF, National Project ‘Estrazione di oli vergini di oliva
da paste denocciolate: miglioramento della qualità e delle rese e
valorizzazione dei residui—Valorolio’) and Interuniversity Consor-
tium ‘Chemistry for the Environment’ (INCA) for financial support.
Figure 4. Yields of 3 and 4 after the recycling experiments of oxidation of tyrosol
derivatives 1 and 5 by polymer-supported IBX.
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