Catalytic oxidation of catechins to p-benzoquinones with hydrogen peroxide/methyltrioxorhenium

Article abstract of DOI:10.1016/j.tetlet.2005.03.032

New p-benzoquinones were obtained by oxidation of catechin and epicatechin derivatives with the hydrogen peroxide/methyltrioxorhenium catalytic system. Reactions were carried out both in homogeneous and heterogeneous conditions and proceeded with high con

Full text of DOI:10.1016/j.tetlet.2005.03.032

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2993–2996
Catalytic oxidation of catechins to p-benzoquinones with
hydrogen peroxide/methyltrioxorhenium
a,b
Roberta Bernini,a,b, Enrico Mincione, Gianfranco Provenzanoa,b and
*
Giancarlo Fabrizic,*
a
`
Dipartimento A.B.A.C, Universita degli Studi della Tuscia, Via S. Camillo De Lellis, 01100 Viterbo, Italy
`
b
c
`
Unita di Ricerca VT2, Consorzio Interuniversitario La Chimica per l’Ambiente, Via della Liberta 5/12, 30175 Marghera (VE), Italy
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Universita degli Studi di Roma La Sapienza,
`
P.le A. Moro 5, 00185 Roma, Italy
Received 15 December 2004; revised 1 March 2005; accepted 7 March 2005
Available online 22 March 2005
Abstract—New p-benzoquinones were obtained by oxidation of catechin and epicatechin derivatives with the hydrogen peroxide/
methyltrioxorhenium catalytic system. Reactions were carried out both in homogeneous and heterogeneous conditions and pro-
ceeded with high conversion and moderate yields. Polymer-supported methyltrioxorhenium systems were used as heterogeneous
catalysts. After the first oxidation, the catalytic systems can be recovered and reused for five consecutive times without loss of
stability and efficiency.
Ó 2005 Elsevier Ltd. All rights reserved.
p-Benzoquinones are bioactive natural compounds
showing antimicrobial, antifungal, antibacterial, anti-
viral and anticancer activities.1 Furthermore, they are
useful chemicals in organic synthesis.2 Generally, they
are prepared by stoichiometric or catalytic oxidations
of inexpensive phenol and methoxybenzene derivatives.3
When hydrogen peroxide (H2O2) is used as the oxygen
atom donor, its activation is required. Among the cata-
lysts useful for this purpose, methyltrioxorhenium
(CH3ReO3, MTO) has been largely used in the last
few years being commercially available, stable in air
and efficient in many organic solvents.4 Hydrogen per-
oxide was converted into the mono(peroxo) mpRe and
bis(peroxo)rhenium complexes dpRe, the active catalytic
species in the oxidations (Scheme 1).5 A probable mech-
anism of the reaction, via an arene oxide as intermedi-
ate, was postulated to explain the conversion of simple
phenols and methoxybenzenes into the corresponding
p-benzoquinones.6
O
O
O
O
O
H2O2
H2O
H2O2
H2O
O
O
Re
Re
O
Re
O
H3C
O
O
O
H3C
H3C
mpRe
MTO
dpRe
Scheme 1. Activation of hydrogen peroxide by CH3ReO3 (MTO).
to obtain heterogeneous catalyst. Among the commer-
cial available supports, non-toxic and cheap polyvinyl-
pyridines (PVP) were described (Fig. 1).7 PVP-2%/
MTO and PVP-25%/MTO catalytic system were pre-
pared supporting MTO on poly(4-vinylpyridine) 2% or
25% cross-linked with divinylbenzene; PVPN-2%/MTO
on poly(4-vinylpyridine-N-oxide) 2% cross-linked with
divinylbenzene previously obtained by oxidation of the
PVP-2% with an excess of 3-chloroperbenzoic acid.8
All catalytic systems were characterized by a loading
factor that expresses the mmol of MTO for gram of
support.
It is well known that methyltrioxorhenium can be
bonded to polymers bearing oxygen and nitrogen atoms
Catechins (flavan-3-ols) constitute a large class of phen-
olic compounds ubiquitous in plants and widely found
in fruits, vegetables and beverages.9 In particular, they
are one of the major quality factors in grapes and then
in the resulting wine.10 During its elaboration, large
quantities of these compounds remain in the grapes
Keywords: Hydrogen peroxide/methyltrioxorhenium; Catalytic oxid-
ations; Catechins; p-Benzoquinones; Winery by-products; Renewable
sources; Agroindustrial wastes.
*
Corresponding authors. Tel./fax: +39 761 357230; e-mail:
berninir@unitus.it
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.032

2994
R. Bernini et al. / Tetrahedron Letters 46 (2005) 2993–2996
pounds and on the chemical valorization of molecules
present into renewable sources as the agroindustrial
wastes,13 we report here the first catalytic oxidation of
the catechins derivatives to new A-ring p-benzoquinones
with the catalytic system H2O2/CH3ReO3 in homo-
geneous and heterogeneous conditions (Scheme 2). First,
we tried the oxidation on the non-methylated (ꢀ)-epi-
catechin 1 and (+)-catechin 2. When we added these sub-
strates to the yellow solution of H2O2/MTO in ethanol,
a purple-violet colour appeared. Similarly, as reported
for the simple catechol,14 this colour can be attributed
to the condensation reaction between the MTO and
the ortho-hydroxyl group of the B ring of catechins;
the following oxidative opening of this complex afforded
a complex and useless mixture of polar compounds.15
Therefore, we performed the oxidation reaction on the
methylated (ꢀ)-epicatechin 5,7,30,40-tetramethyl ether 3
and on the (+)-catechin 5,7,30,40-tetramethyl ether 5 in
different experimental conditions. As reported in Table
1, our best results were obtained in acetic acid, in terms
of conversion, reaction time and yield. In fact, using
ethanol or dichloromethane as solvents, the oxidation
MTO
O
MTO
O
MTO
N
MTO
N
N
N
n
n
PVP-2%/MTO
PVP-25%/MTO
PVPN-2%/MTO
Figure 1. Polymer-supported methyltrioxorhenium catalysts.
pomace consisting of skins, seeds and stems.11 Recently,
these winery by-products have attracted great attention
in nutrition, health and medicine areas.12
Continuing our studies on the environmentally friendly
oxidative conversion of flavonoids into bioactive com-
OR5
OR5
OR6
OR6
O
8
R4O
O
R4O
O
H2O2/Catalyst
A
R2
R1
R2
R1
6
OR3
O
1, 2, 3, 5, 7, 9
1: R1=R3=R4=R5=R6=H; R2=OH; 2: R1=OH; R2=R3=R4=R5=R6=H
4, 6, 8, 10
3: R1=H; R2=OH; R3=R4=R5=R6=CH3;4: R1=H; R2=OH; R4=R5=R6=CH3
5: R1=OH; R2=H; R3=R4=R5=R6=CH3; 6: R1=OH; R2=H; R4=R5=R6=CH3
7: R1=H; R2=OAc; R3=R4=R5=R6=CH3; 8: R1=H; R2=OAc; R4=R5=R6=CH3
9: R1=OAc; R2=H; R3=R4=R5=R6=CH3; 10: R1=OAc; R2=H; R4=R5=R6=CH3
Scheme 2. Oxidation of catechin derivatives 3, 5, 7, 9 to p-benzoquinones 4, 6, 8, 10 with H2O2/MTO catalytic system.
Table 1. Experimental data of the oxidations of catechins derivatives 3, 5, 7 and 9
Catalysta
Solvent
T (°C)
Time (h)
Conversion (%)
Yieldc (%)
b
H2O2 (equiv)
Entry
Substrate
Product
1
3
3
3
3
3
3
5
5
5
5
5
5
7
7
7
9
9
9
4
4
MTO
MTO
MTO
8
8
EtOH
CH2Cl2
AcOH
AcOH
AcOH
AcOH
EtOH
CH2Cl2
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
70
25
25
50
50
50
70
25
25
50
50
50
25
50
50
25
50
50
24
24
0.5
6
65
98
98
98
98
98
92
98
98
79
98
98
98
98
98
98
98
98
21 (33)
24
42
2
3
4
2
4
4
PVP-2%/MTO
PVPN-2%/MTO
PVP-25%/MTO
MTO
6
26
27
5
4
6
8
6
4
10
8
6
38
7
6
24
48
2
16 (17)
23
38
8
6
MTO
MTO
10
2
9
6
10
11
12
13
14
15
16
17
18
6
PVP-2%/MTO
PVPN-2%/MTO
PVP-25%/MTO
MTO
6
24
24
24
4
25 (32)
23
36
6
10
6
6
8
2
44
28
8
PVP-2%/MTO
PVP-25%/MTO
MTO
6
24
24
4
8
6
38
42
10
10
10
2
PVP-2%/MTO
PVP-25%/MTO
6
24
24
26
35
6
a MTO (5 mol %); loading factor of PVP-2%/MTO, PVPN-2%/MTO and PVP-25%/MTO: 1.0.
b H2O2 (50% aqueous solution).
c In brackets calculated yields on converted substrate were reported.

R. Bernini et al. / Tetrahedron Letters 46 (2005) 2993–2996
2995
proceeded sluggish (compare entries 1, 2 with entry 3
and entries 7, 8 with entry 9). In the absence of the cat-
alyst, less of 5% conversion of substrate took place in
identical conditions. In all cases, the oxidation reactions
proceed with high regioselectivity at C-8 position, the C-
6 being unaffected. The disappearance of the two doub-
let at 6.08 and 6.16 ppm in the proton NMR of 3, given
to C-8 and C-6 positions and the appearance of a singlet
Noteworthy, in all the reported experiments the epicate-
chin tetramethyl ether 3 reacted faster than the catechin
tetramethyl ether 5, especially in heterogeneous catalytic
conditions (Table 1, compare entries 4, 5, 6 with 10, 11,
12). This higher reaction rate of 3 can be reasonably
ascribed to a more efficient coordination of the bulky
rhenium–polyvinylpyridine complex with the C-3 OH
group oriented in the more accessible a-axial orientation
(Fig. 2).19 In fact, when we performed the same reaction
with the C-3 acetate 7 of the (ꢀ)-epicatechin 5,7,30,40-
tetramethyl ether 3, the reactivity significantly slow
down, the reaction time became similar to the catechin
derivative 9 (Table 1, entries 14, 15, 17 and 18).
1
at 5.85 ppm in the H NMR spectrum of product 4 and
of two signals at 175.6 and 186.5 ppm in its 13C NMR
spectrum,16 confirmed the presence of a quinone moiety
in the A ring of 4. Specifically, the p-benzoquinonic
structure was fully assigned with HMQC, HMBC and
NOESY spectroscopy.17 Similar spectroscopic data were
obtained for the quinone 6.18
The oxidation of catechins is an important route to new
potential bioactive molecules and chemical intermedi-
ates for the synthesis of polyphenolic compounds.20
To the best of our knowledge, we described the first cat-
alytic benign methodology to obtain new A-ring p-ben-
zoquinones. Work is in progress in our laboratory to
test their potential biological activities.
Successively, we performed the oxidations of 3 and 5 in
heterogeneous conditions using the PVP-2%/MTO,
PVPN-2%/MTO and PVP-25%/MTO catalysts. Under
the reported experimental conditions, both catalysts
were effective in the oxidation of 3 and 5 to the corre-
sponding quinones 4 and 6. Better results were obtained
using the PVP-25%/MTO, evidencing the influence of
the morphologic properties of the polymeric support
on the efficiency of the catalyst (compare entries 4, 5
with entry 6 and entries 10, 11 with entry 12). This cat-
alyst was then recovered by filtration, washed with ethyl
acetate and reused in successive oxidations under identi-
cal conditions. Table 2 shows its efficiency to perform
five recycling experiments with similar conversion, yield
and selectivity.
References and notes
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Table 2. Yields (%) of the quinones 4 and 6 using the recycled PVP-
25%/MTO for the oxidation of the (ꢀ)-epicatechin 5,7,30,40-tetra-
methyl ether 3 and the (+)-catechin 5,7,30,40-tetramethyl ether 5 with
hydrogen peroxide
Substrate
Run 1
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Run 3
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5
38
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32
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(-)-Epicatechin-5,7,3',4'-tetramethyl ether 3
OCH3
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O
H3CO
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(+)-Catechin-5,7,3',4'-tetramethyl ether 5
Figure 2. Stable conformations of 3 and 5.19

2996
R. Bernini et al. / Tetrahedron Letters 46 (2005) 2993–2996
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4a,4b); 3.78 (3H, s, OCH3); 3.86 (3H, s, OCH3); 3.87
(3H, s, OCH3); 4.21–4.23 (1H, m, H-3), 4.96–4.99 (1H, m,
H-2); 5.85 (1H, s, H-6); 6.85–7.00 (3H, m, H-20,50,60); dC
(CDCl3, 200 MHz): 26.7 (C-4); 55.9 (OCH3); 56.0 (OCH3);
56.3 (OCH3), 65.2 (C-3), 79.7 (C-2), 106.9 (C-6), 109.3
(C-20), 111.3 (C-50), 116.4 (C-7), 118.5 (C-60), 128.4
(C-10), 149.2 (C-30), 149.3 (C-40), 151.3 (C-10), 157.0
(C-9); 175.6 (C-8), 186.5 (C-5).
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17. For example, no cross peaks between vinylic proton at
5.85 ppm and the aromatic protons in the C ring were
observed in different NOESY experiments, performed
with mixing time ranging from 400 to 1200 ms, suggesting
˚
an interprotonic distance greater than 5 A, clearly in
agreement with the p-benzoquinonic structure respect to
the o-quinonic.
18. p-Benzoquinone 6: yellow solid. Mp 211–212 °C. 1H
NMR dH (CDCl3, 200 MHz): 2.48 (1H, dd, J = 18.4 and
8.2 Hz, H-4a); 2.89 (1H, dd, J = 18.5 and 5.4 Hz, H-4b);
3.79 (3H, s, OCH3); 3.85 (3H, s, OCH3); 3.86 (3H, s,
OCH3); 4.01–4.12 (1H, m, H-3), 4.75 (1H, d, J = 7.7 Hz,
H-2); 5.84 (1H, s, H-6); 6.84–6.94 (3H, m, H-20,50,60); dC
(CDCl3, 200 MHz): 29.3 (C-4); 55.9 (OCH3); 56.0 (OCH3);
56.4 (OCH3); 66.7 (C-3); 82.8 (C-2); 107.0 (C-6); 109.9
(C-20); 111.3 (C-50); 117.3 (C-7); 119.8 (C-60); 128.4
(C-10); 149.4 (C-30); 149.5 (C-40); 151.4 (C-10); 157.2
(C-9); 175.8 (C-8); 185.9 (C-5).
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NMR dH (CDCl3, 200 MHz): 2.61–2.87 (2H, m, H-