Selective and efficient oxidative modifications of flavonoids with 2-iodoxybenzoic acid (IBX)

Article abstract of DOI:10.1016/j.tet.2010.06.014

2-Iodoxybenzoic acid (IBX), a mild and efficient hypervalent iodine oxidant, has been utilised in different reaction conditions to perform several efficient oxidative modifications of flavonoids. Fine-tuning of the reaction conditions allowed remarkably selective modifications of these compounds. At room temperature, IBX proved to be an excellent reagent for a highly regioselective aromatic hydroxylation of monohydroxylated flavanones and flavones, generating the corresponding catecholic derivatives showing high antioxidant activity. At 90 °C, IBX efficiently dehydrogenated a large panel of methoxylated flavanones to their corresponding flavones exhibiting anticancer activity. IBX polystyrene has also been utilised to increase the recovery of highly polar compounds. Following the first oxidation, the reagent was recovered and reused in several runs without loss of efficiency and selectivity. The first example of an application of IBX polystyrene in a dehydrogenation reaction has been described.

Full text of DOI:10.1016/j.tet.2010.06.014

Tetrahedron 66 (2010) 6047e6053
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Selective and efficient oxidative modifications of flavonoids with 2-iodoxybenzoic
acid (IBX)
,
a
b
Maurizio Barontini a, Roberta Bernini a , Fernanda Crisante , 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:
2-Iodoxybenzoic acid (IBX), a mild and efficient hypervalent iodine oxidant, has been utilised in different
reaction conditions to perform several efficient oxidative modifications of flavonoids. Fine-tuning of the
reaction conditions allowed remarkably selective modifications of these compounds. At room temper-
ature, IBX proved to be an excellent reagent for a highly regioselective aromatic hydroxylation of
monohydroxylated flavanones and flavones, generating the corresponding catecholic derivatives show-
ing high antioxidant activity. At 90 ꢀC, IBX efficiently dehydrogenated a large panel of methoxylated
flavanones to their corresponding flavones exhibiting anticancer activity. IBX polystyrene has also been
utilised to increase the recovery of highly polar compounds. Following the first oxidation, the reagent
was recovered and reused in several runs without loss of efficiency and selectivity. The first example of
an application of IBX polystyrene in a dehydrogenation reaction has been described.
Received 1 February 2010
Received in revised form 20 May 2010
Accepted 7 June 2010
Available online 15 June 2010
Dedicated to Professor Enrico Mincione on
the occasion of his retirement
Keywords:
Catecholic flavonoids
Methoxylated flavones
Aromatic hydroxylation
Dehydrogenation reaction
2-Iodoxybenzoic acid (IBX)
IBX polystyrene
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Various structureeactivity relationship studies of flavonoids have
pointed to the importance of the number and location of the phe-
Flavonoids constitute one of the major groups of secondary
metabolites and play important roles in plant development,
reproduction and defence. Structurally, they have a common, basic
C6eC3eC6 skeleton structure consisting of two aromatic rings
(A and B) and a heterocyclic ring (C) containing one oxygen atom.
More than 4,000 compounds have been isolated and characterised
as a consequence of the wide variety of functional group sub-
stitutions into these three rings.1 These compounds are important
components of the human diet, being present in food (fruit, vege-
tables) and beverages (tea, wine).2
nolic groups present for effective radical scavenging activity.5
A recent publication reported that the ortho-dihydroxyl (catechol)
substitution is one of the essential features to increase this activity,
while isolated monohydroxyl or meta-dihydroxyl substitutions do
not have this effect.6 Moreover, the catecholic group imparts ap-
preciable activity when it is found on either ring A or ring B. For
example, 7,8-dihydroxyflavone and 5,7,30,40-tetrahydroxyflavone
(luteolin) are more active than the corresponding 7-hydroxy-
flavone and 5,7,40-trihydroxyflavone (apigenin, Fig. 1).6
Although a number of methods are available for the synthesis of
flavonoids, they are not ideal for the preparation of catecholic de-
rivatives because the phenolic hydroxyl groups of the starting
materials must be derivatized as esters or ethers and then cleaved
for regeneration. This often results in only partial deprotection of
the phenolic hydroxyl groups, which lowers the overall yield and
complicates the product isolation procedure.7 As an alternative,
catecholic flavonoids could be prepared by an oxidative pathway
from the corresponding phenol derivatives. The selective hydrox-
ylation of aromatic compounds is amongst the most challenging
chemical reactions in synthetic chemistry and has gained in-
creasing attention in recent years, particularly because of the use of
hydroxylated aromatics as precursors for pharmaceuticals. In
Many studies have shown that they are biologically active
molecules
exhibiting
antiviral,
anti-inflammatory,
hep-
atoprotective, antioxidant, antithrombotic, vasodilating, antiviral
and anticarcinogenic activities.3 Recently, the majority of interest
has focused on their antioxidant property, which is due to their
ability to reduce free radical formation and to scavenge free radi-
cals.4 In view of this capability, they have attracted attention as
potential therapeutic agents against free radical-mediated diseases.
* Corresponding author. Tel.: þ39 761 357452; fax: þ39 761 357230; e-mail
address: berninir@unitus.it (R. Bernini).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.014

6048
M. Barontini et al. / Tetrahedron 66 (2010) 6047e6053
OH
OH
O
OH
No product
HO
O
O
HO
HO
O
OH O
1
OH O
7,8-Dihydroxyflavone
Luteolin
O
O
OH
HO
O
HO
HO
HO
O
O
O
OH O
3
2
OH O
OH
O
HO
O
7-Hydroxyflavone
Apigenin
Figure 1. Some bioactive flavones.
O
4
O
5
flavonoid metabolism, cytochrome P450 monooxygenases catalyse
the aromatic hydroxylation of large panels of derivatives.8
OH
OCH3
OH
Our previous studies were concerned with the oxidative
chemistry of flavonoids by the hydrogen peroxide/methyltrioxo-
rhenium catalytic system for the generation of bioactive com-
pounds; however, no catecholic derivatives were isolated.9
Recently, Selenski and Pettus reported the synthesis of (ꢁ)-diinsi-
ninone, a biologically active compound having the flavanone
skeleton.10 A key step is the aromatic hydroxylation of 5,7,40-tri-
hydroxyflavanone (naringenin) to 5,7,30,40-tetrahydroxyflavanone
OH
HO
O
HO
O
OH O
7
OH O
6
Scheme 1. Aromatic hydroxylation of flavanones 1, 2, 4 and 6.
(eriodictyol) performed with 1-hydroxy-1-oxo-1H-1l
5-benz[d]
conditions, the substrate 1 was unreactive (Table 1, entry 1).
A similar behaviour was observed heating the reaction mixture to
60 ꢀC (Table 1, entry 2). This unexpected result may be explained by
the establishment of the well-known hydrogen bond between the
hydroxyl group in C-5 and the oxygen atom of the carbonyl group in
[1,2]iodoxol-3-one (2-iodoxybenzoic acid, IBX, Fig. 2), followed by
reductive work-up of the resulting ortho-quinone with sodium
dithionite (Na2S2O4). This one-pot two step chemical process
mimics the enzyme flavanone-3-hydrolase in flavan biosynthesis.11
O OH
I
Table 1
Experimental data of oxidation depicteda,b in Scheme 1
O
Entry
Substrate
Product
T (ꢀC)
Reaction
time (h)a
Conv. (%)
Yieldsc (%)
O
1a
2a
3a
4a
5a
6a
7b
1
1
2
4
4
6
6
d
d
3
5
5
25
60
25
25
60
25
25
24
24
1
24
24
2
d
d
Figure 2. 2-Iodoxybenzoic acid (IBX).
d
d
IBX is a long-established reagent first prepared in 1893 by
>98
84
88
>98
>98
95
80
84
70
95
Hartman and Mayer,12 but only after the development of an
13
improved method for its synthesis
did it become a powerful
7
7
reagent for several organic transformations.14 Both the aromatic
2
15
hydroxylation of phenols
and the oxidative demethylation of
a
16
Oxidant: IBX.
Oxidant: IBX-polystyrene.
Yields were given on the isolated product.
phenolic methyl aryl ethers can be performed with high regio-
selectivity; catecholic compounds can be isolated in excellent
yields and high purity. According to the previously reported ionic
mechanism, the first step of the aromatic hydroxylation reaction of
phenols is an intramolecular electrophilic aromatic substitution
b
c
C-4 on 5-hydroxyflavanone 1,18 which evidently hindered the for-
mation of the
5-iodanyl complex. On the basis of this possible
and the key intermediate is a l
5-iodanyl complex between the io-
l
dine atom of IBX and the phenolic functionality of the substrate.15,16
explanation, we decided to try the IBX-oxidative procedure on
flavanones having one or more hydroxyl groups in different posi-
tions on the A ring. The oxidation of 6-hydroxyflavanone 2 with IBX
and the subsequent reduction with Na2S2O4 in aqueous solution
generated an oxidation product with quantitative conversion and
This unique example of aromatic hydroxylation of flavonoid
10
derivatives reported by Selenski and Pettus
as well as the ex-
perience of our own research group both in the oxidative chemistry
9
of flavonoids
and in the preparation of naturally occurring
yield after only 1 h (Table 1, entry 3). Spectroscopic data (1H and 13
C
catecholic compounds with IBX,17 prompted us to exploit their
utilisation in order to prepare a large panel of biologically active
polyhydroxylated flavonoids.
NMR) and gas-mass spectrometry (GC-MS) analysis confirmed the
structure of 5,6-dihydroxyflavanone 3. Under similar experimental
conditions, the oxidation of 7-hydroxyflavanone 4 proceeded with
satisfactory conversion and yield to give a compound after a longer
reaction time (Table 1, entries 4 and 5). By comparison of our
spectroscopic data with data in the literature,19 this compound was
identified as 7,8-dihydroxyflavanone 5.
It is worth noting that the aromatic hydroxylation of
6-hydroxyflavanone 2 and 7-hydroxyflavanone 4 with IBX pro-
ceeded with full regioselectivity. As shown previously by Selenski
2. Results and discussion
First, we applied the IBX-oxidative procedure to flavanones
(Scheme 1). 5-Hydroxyflavanone 1 was solubilised in dimethyl
sulfoxide, then IBX was added. The mixture was kept at room
temperature under stirring for 24 h. Under these experimental

M. Barontini et al. / Tetrahedron 66 (2010) 6047e6053
6049
and Pettus,10 this could be rationalised by the theory of Dewar,20
Table 2
Experimental data of oxidation depicteda,b in Scheme 2
which has been widely investigated in relation to several electro-
philic aromatic substitution reactions, e.g., the bromination of
phenols and indane derivatives21 and the amino-methylation of
bicyclic phenols.22 According to Dewar, 1,2,4-trisubstitued ben-
zenes, wherein an electron withdrawing and an electron donating
substituent are ortho to each other and an electron donating sub-
stituent is at the 4-position, will yield the 1,2,3,4-monosubstition
product. This phenomenon has been ascribed to the conjugation
between the adjacent 1- and 2-substituent, which tends to increase
the bond order of the annular bond. Then, starting with
6-hydroxyflavanone 2 and 7-hydroxyflavanone 4, the presence of
an hydroxyl group on the A ring (an electron donating group),
a carbonyl group (an electron withdrawing substituent) and a pyr-
anic oxygen (an electron donating substituent) in ortho position on
the A ring directed the substitution to the carbon C-5 of compound
2 and C-8 for 4. Finally, 5,7,40-trihydroxy-30methoxyflavanone 6
(hesperetin) was treated with IBX. A selective demethylation at the
C-30 position of the B ring resulted in the production of 5,7,30,40-
tetrahydroxyflavanone 7 (eriodictyol)23,24 in 70% yield (Table 1,
entry 6). As already observed by us with other phenolic com-
pounds,17c,d the demethylation reaction of phenolic methyl aryl
ethers is quick and probably proceeded with the mechanism
already reported in the literature.16 No hydroxylation products on
the aromatic ring A were observed.
Entry
Substrate
Product
T (ꢀC)
Reaction
time (h)a
Conv. (%)
Yieldsc (%)
1a
2a
3a
4a
5b
8
9
11
13
13
d
80
25
80
25
25
24
1
24
1
d
d
10
12
14
14
>98
>98
>98
>98
>98
>98
72
2
95
a
Oxidant: IBX.
Oxidant: IBX-polystyrene.
Yields were given on the isolated product.
b
c
HIV activities of compounds 10 and 12 have been extensively
studied.26 A selective ortho-hydroxylation of the B ring of com-
pound 13 gave rise to 5,7,30,40-tetrahydroxyflavone 14 (luteolin) in
72% yield (Table 2, entry 4).
On the basis of our previous experience on the use of IBX
polystyrene (Fig. 3) for the construction of catecholic com-
pounds,17def we utilised this heterogeneous oxidant to increase the
yield of eriodictyol 7 and luteolin 14 being the work-up favourable
to the recovery of highly polar products. After the oxidation re-
action, the polymer was recovered by simple filtration; compounds
7 and 14 were quantitatively isolated (Table 1, entry 7; Table 2,
entry 5). Polymer-supported IBX was regenerated and reused for
five runs without loss of efficiency and selectivity.
On the basis of these satisfactory results, we extended the oxi-
dative procedure to 5-hydroxyflavone 8, 6-hydroxyflavone 9,
7-hydroxyflavone 11 and 5,7,40-trihydroxyflavone 13 (Scheme 2).
O
OH
O
I
O
Figure 3. IBX polystyrene27
.
O
No product
Finally, we exploited the ability of IBX to perform oxidations
adjacent to carbonyl functionalities to obtain -unsaturated car-
a,b
OH O
8
bonyl compounds in the presence of an excess of the reagent and
under elevated temperatures. Mechanistic investigations demon-
strated that these reactions were initiated by single-electron
transfer from the substrate to IBX to form a radical cation, which
reacted further to give the final products.28 We then planned the
dehydrogenation of the catecholic flavanones 3, 5 and 7 in order to
directly obtain the corresponding flavones 10,12 and 14. As a model
substrate, we utilised 5,6-dihydroxyflavanone 3 (Scheme 3). The
substrate was solubilised in DMSO and an excess of IBX was added at
high temperature. Unfortunately, the expected 5,6-dihydroxy-
O
O
HO
HO
HO
HO
O
9
OH O
10
OH
O
O
O
11
O
12
O
O
a) or b)
OH
HO
HO
OH
OH
OH O
3
OH O
10
HO
O
HO
O
a) IBX, DMSO, 90 °C, 24 h
Not isolated
b) IBX/NMO, DMSO, 25 °C, 24 h
OH O
14
OH O
13
Scheme 3.
Scheme 2. Aromatic hydroxylation of flavones 8, 9, 11 and 13.
flavone 10 was not isolated from the complex reaction mixture. To
exclude that this result was due to the instability of the catecholic
compound in these harsh conditions, we tried the dehydrogenation
reaction at room temperature by using N-methyl morpholine-N-
oxide (NMO).29 However, also under these experimental conditions,
the desired product 5,6-dihydroxyflavone 10 could not be isolated.
On the basis of these results, we considered the protection of the
phenolic groups of flavanones to be appropriate before performing
the dehydrogenation reaction. The methylation reactionwas chosen
in order to obtain methoxylated flavones as final products, a class of
biologically active flavonoids.30 Recently, Walle and colleagues
We observed a similar trend to that of flavanones. 5-Hydroxy-
flavone 8 was also unreactive, even at high temperature (Table 2,
entry 1); 6-hydroxyflavone 9 and 7-hydroxyflavone 11 selectively
yielded the corresponding catecholic compounds 5,6-dihydroxy-
flavone 10 and 7,8-dihydroxyflavone 12 in quantitative yields
(Table 2, entries 2 and 3). 7-Hydroxyflavone 11 was less reactive,
requiring a high reaction temperature. A recent publication repor-
ted the oxidation of 5-hydroxyflavone with potassium persulfate to
a trace amount of 5,6-dihydroxyflavone 10 (yield of 5%).25 The anti-

6050
M. Barontini et al. / Tetrahedron 66 (2010) 6047e6053
reported that these compounds show in vivo cancer chemo-
preventive properties superior to the more common unmethoxy-
lated derivatives 31 These effects are attributed to their high hepatic
metabolic stability as well as high intestinal absorption in humans,
which increase the oral bioavailability in vivo. 5,6-Dihydroxy-
flavanone 3 was firstly methylated under classical conditions with
dimethyl sulfate in basic conditions to obtain 5,6-dimethoxy-
flavanone 15 (Scheme 4). This compound was solubilised in DMSO
and treated with IBX at high temperature. After 24 h, the corre-
sponding 5,6-dimethoxyflavone 16 was isolated in quantitative
yield (Table 3, entry 1). This efficient procedure was successfully
extended to 7,8-dimethoxyflavanone 17, methylated hesperetin 19,
methylated naringenin 22 previously prepared by us and to com-
mercially available 5-methoxyflavanone 24, 6-methoxyflavanone
26 and 7-methoxyflavanone 28. The corresponding methoxylated
flavones 18, 20, 23, 25, 27 and 29 were isolated in satisfactory to
excellent yields (Table 3, entries 3, 5, 7, 11 and 13).
Finally, we tested the efficiency and selectivity of IBX poly-
styrene as oxidant in the dehydrogenation reaction. After 24 h, the
conversion of the substrate and the yield of the final product 16
were comparable to those obtained with homogeneous IBX
(Table 3, compare entry 1 with entry 2). At the end of the reaction,
IBX polystyrene was regenerated and reused. In this case, the effi-
ciency and selectivity of the reagent persisted for only three runs,
probably due to the high temperature of the reaction (90 ꢀC).
Similar results were obtained from methylated flavanones 17,19, 21,
22, 24, 26, 28 obtaining flavones 18, 20, 23, 25, 27 and 29 (Table 3,
entries 4, 6, 8, 10, 12 and 14). To the best of our knowledge, this is
O
O
O
b)
a)
HO
H3CO
H3CO
OH O
3
O
16
O
15
CH3O
CH3O
OCH3
OH
OCH3
H3CO
O
HO
HO
O
H3CO
O
a)
b)
O
18
O
5
O
17
OCH3
OH
OCH3
OCH3
OCH3
OCH3
O
H3CO
O
H3CO
O
a)
b)
OH O
6
O
19
O
20
CH3O
CH3O
OH
OCH3
OCH3
HO
O
b)
H3CO
O
H3CO
O
a)
a)
OH O
O
22
O
23
CH3O
CH3O
21
O
O
O
24
O
25
CH3O
CH3O
O
O
a)
H3CO
H3CO
H3CO
O
26
O
27
O
H3CO
O
a)
O
28
O
29
a) K2CO3, (CH3)2SO4, acetone, 25 °C, 24 h (Conv. and yields: >98%)
b) IBX, DMSO, 90 °C, 24 h (Conv. and yields: see Table 3)
Scheme 4. Dehydrogenation reaction of methylated flavonoids 15, 17, 19, 22, 25, 27, 29.

M. Barontini et al. / Tetrahedron 66 (2010) 6047e6053
6051
which was then stirred at room temperature or 60 ꢀC for 1e24 h
depending on the substrate. During the reaction, a chromatic
change from yellow to brown was observed. At the end, H2O
(10 mL) and an excess of Na2S2O4 were added and the solution was
left under stirring until it became yellow. Ethyl acetate was added
to the mixture, then it was treated with pH 8.5 buffer solution to
remove o-iodobenzoic acid. The aqueous phase was extracted with
ethyl acetate. The organic phases were washed with a saturated
solution of NaCl and dried over Na2SO4. After evaporation of the
solvent, the catecholic flavonoids were isolated by chromato-
graphic purification on silica gel (230e400 mesh).
Oxidation with IBX polystyrene. The substrate (1.0 mmol) was
solubilised in DMSO (10 mL) at room temperature under magnetic
stirring and then commercial polymer-supported IBX (3.0 mmol)
was added. When the substrate disappeared, the polymer was
recovered by simple filtration and the remaining solution was
treated with water (10 mL) and an excess of Na2S2O4. The products
were extracted with ethyl acetate. The organic phases were washed
with a saturated solution of NaCl and dried over Na2SO4. After
evaporation of the solvent, catecholic compounds were isolated.
Polymer-supported IBX was regenerated by treating the filtered
resin with a solution of tetrabutylammonium oxone and meth-
anesulfonic acid according to the procedure reported by us
previously.17d,e
Table 3
Dehydrogenation of methoxylated flavanonesb
Entry
Substrate
Product
Conv. (%)
Yieldsc (%)
1a
15
15
17
17
19
19
22
22
24
24
26
26
28
28
16
16
18
18
20
20
23
23
25
25
27
27
29
29
>98
95
>98
95
92
90
90
92
>98
92
85
95
92
>98
95
90
88
88
90
>98
92
80
2b
3a
4b
5a
6b
7a
8b
9a
10b
11a
12b
13a
14b
84
80
78
80
75
78
a
Oxidant: IBX.
Oxidant: IBX-polystyrene.
Yields were given on the isolated product.
b
c
the first example of an application of IBX polystyrene on the
dehydrogenation reaction of carbonyl compounds.
3. Conclusions
This paper has described some useful and efficient applications
of IBX to the oxidative chemistry of flavonoids to obtain bioactive
compounds in high yields. Fine-tuning of the reaction conditions
allowed remarkably selective modifications of these compounds.
Under controlled conditions (IBX: 1.2 equiv, room temperature),
a regioselective aromatic hydroxylation of a large panel of flava-
nones and flavones generated the corresponding ortho-dihy-
droxylated flavonoids with powerful antioxidant properties. In the
presence of an excess of oxidant and under elevated temperatures,
an efficient dehydrogenation reaction of methoxylated flavanones
generated the corresponding flavones with anticancer properties.
IBX polystyrene showed similar efficiency and selectivity in the
oxidation reactions in comparison to homogeneous IBX, allowing
the quantitative isolation of high polar compounds. This is the first
example of a dehydrogenation reaction performed by this hetero-
geneous oxidant to be reported.
4.2.1. 5,6-Dihydroxyflavanone (3). Yellow solid (243 mg; yield:
95%). Mp 154e155 ꢀC. 1H NMR (200 MHz, CDCl3)
d 2.86 (dd, 1H,
J1¼3.2 and J2¼17.3 Hz), 3.11 (dd, 1H, J1¼12.9 and J2¼17.3), 5.39 (dd,
1H, J1¼3.1 and J2¼12.9), 6.44 (d,1H, J¼8.8 Hz), 7.08 (d,1H, J¼8.8 Hz),
7.36e7.47 (m, 5H). 13C NMR (50 MHz, CDCl3)
d 44.0, 79.3, 106.9,
108.0, 123.5, 126.1, 126.1, 128.8, 128.9, 138.3, 138.4, 147.5, 154.2,
198.7. m/z 256 (Mþ, 25),152 (100),124 (12). Anal. Calcd for C15H12O4
(256.25): C, 70.31; H, 4.72; O, 24.97. Found: C, 70.37; H, 4.69; O,
24.94.
4.2.2. 7,8-Dihydroxyflavanone (5). Yellow solid (205 mg. Yield:
80%). Mp 162e164 ꢀC (lit.32 164e166 ꢀC). Spectroscopic data were
according to the literature.19
4.2.3. 5,7,30,40-Tetrahydroxyflavanone (7) (eriodictyol). Yellow oil
(288 mg; yield: >98%). Mp 282e284 ꢀC (lit.32 281e282 ꢀC). Spec-
troscopic data were according to the authentic commercial sample.
4. Experimental
4.1. General
4.2.4. 5,6-Dihydroxyflavone (10). Yellow solid (254 mg. Yield:
>98%). Mp 189e191 ꢀC (lit.25 193e195 ꢀC). 1H NMR (200 MHz,
Hydroxylated flavonoids 1, 2, 4, 6, 8, 9, 11, 13 and 14 and
methoxylated flavonoids 24, 26 and 28 were commercially supplied
(Aldrich, ApinChemicals). All chemicals used wereofanalyticalgrade.
Homogeneous IBX was prepared in our laboratory as described in the
literature.13 IBX polystyrene was purchased from Novabiochem
(loading factor¼1.1 mmol/gram). Silica gel 60 F254 plates and silica gel
60wereobtainedfromMerck.1HNMRand13C NMR were recorded on
a Bruker 200 MHz spectrometer using CDCl3 and CD3OD as solvents.
CDCl3)
d
6.70 (s, 1H), 6.96 (d, 1H, J¼8.9 Hz), 7.27 (d, 1H, J¼8.9 Hz),
7.45e7.54 (m, 3H), 7.89 (m, 2H). 13C NMR (50 MHz, CDCl3)
d
105.1,
106.8, 110.8, 121.4, 126.4, 129.1, 131.4, 132.0, 140.1, 145.4, 149.6, 165.1,
183.7. m/z 256 (Mþ, 20), 152 (100), 124 (4). Anal. Calcd for C15H10O4
(254.24): C, 70.87; H, 3.96; O, 25.17. Found: C, 70.79; H, 4.01; O,
25.20.
4.2.5. 7,8-Dihydroxyflavone (12). Yellow solid (254 mg; yield:
>98%). Mp 248e250 ꢀC (lit.33 250e251 ꢀC). Spectroscopic data
were according to the literature.34
All chemical shifts are expressed in parts per million (d scale) and
coupling constants in hertz. GCeMS analysis was performed on
a Shimatzu VG 70/250S apparatus equipped with a CP-SIL 8 CB-MS
column (25 m, 0.25 mm and 0.25 mm film thickness). The analyses
were performedusing anisothermaltemperatureprofileof 100 ꢀC for
2 min, followed by a 10 ꢀC/min temperature gradient for 15 min until
280 ꢀC. The injector temperature was 280 ꢀC.
4.2.6. 5,7,30,40-Tetrahydroxyflavone (14) (luteolin). Yellow solid
(206 mg; yield: 72%). Mp 325e328 ꢀC (lit.35 328e330 ꢀC). Spec-
troscopic data were according to the literature.36
4.3. General procedure for the methylation of flavanones
4.2. General procedure for the aromatic hydroxylation of
flavanones and flavones
The substrate (1.0 mmol) was solubilised in acetone (10 mL) at
room temperature. Then, potassium carbonate (1.5 mmol per hy-
droxyl group) and dimethyl sulfate (6 mmol per hydroxyl group)
were added. The reaction was monitored by TLC. When the
Oxidation with homogeneous IBX. To a solution of substrate
(1.0 mmol) solubilised in DMSO (10 mL) was added IBX (1.2 equiv),

6052
M. Barontini et al. / Tetrahedron 66 (2010) 6047e6053
substrate disappeared (24 h), the acetone was evaporated under
reduced pressure. The mixture was neutralised by 1 M HCl and the
product was extracted with ethyl acetate (3ꢂ10 mL). The organic
layers were washed with a saturated solution of NaCl and dried
over dry Na2SO4. The product was obtained pure in quantitative
yield.
H-7,8,30,40,50), 7.86e7.91 (2H, m, H-20,60). 13C NMR (50 MHz, CDCl3):
d
57.2, 61.9, 108.0, 113.4, 117.2, 119.1, 126.1, 129.0, 131.4, 133.8, 147.9,
150.0, 151.6, 161.6, 178.1. m/z: 282 (Mþ, 33), 267 (100), 239 (29), 165
(21), 133 (43), 102 (35), 77 (40). Anal. Calcd for C17H14O4 (282.29): C,
72.33; H, 5.00; O, 22.67. Found: C, 72.40; H, 5.08; O, 22.52.
4.4.2. 7,8-Dimethoxyflavone (18). Yellow solid (282 mg; yield:
>98%). Mp 145e147 ꢀC (lit.40 147e148 ꢀC). 1H NMR (200 MHz,
4.3.1. 5,6-Dimethoxyflavanone (15). Yellow solid (270 mg; yield:
95%). Mp 140e142 ꢀC (lit.37 142e144 ꢀC). 1H NMR (200 MHz, CDCl3)
CDCl3)
d
3.99 (s, 3H), 4.00 (s, 3H), 6.77 (s, 1H), 7.04 (d, 1H, J¼9.0 Hz),
d
2.81 (dd, 1H, J1¼16.7 and J2¼3.2 Hz), 3.02 (dd, 1H, J1¼16.7 and
7.51e7.54 (m, 3H), 7.93e7.98 (m, 3H). 13C NMR (50 MHz, CDCl3)
J2¼12.9 Hz), 3.79 (s, 3H), 3.88 (s, 3H), 5.36 (dd, 1H, J1¼3.2 and
J2¼12.9 Hz), 6.76 (d, 1H, J¼9.0 Hz), 7.10 (d, 1H, J¼9.0 Hz), 7.31e7.46
d 56.5, 61.6, 106.9, 109.9, 118.6, 121.0, 126.2, 129.1, 131.5, 131.9, 137.0,
150.6, 156.7, 163.0, 178.1. m/z 282 (Mþ, 100), 267 (33), 239 (17), 165
(53),137 (59), 109 (37), 66 (30). Anal. Calcd for C17H14O4 (282.29): C,
72.33; H, 5.00; O, 22.67. Found: C, 72.38; H, 5.08; O, 22.54.
(m, 5H). 13C NMR (50 MHz, CDCl3)
d 46.2, 57.2, 60.4, 79.0, 112.8,
116.0, 121.2, 126.1, 128.7, 128.8, 138.8, 147.7, 149.7, 156.1, 190.9. m/z
284 (Mþ, 36.5),180 (100), 165 (84),137 (39),109 (12). Anal. Calcd for
C17H16O4 (284.31): C, 71.82; H, 5.67; O, 22.51. Found: C, 71.90; H,
5.72; O, 22.38.
4.4.3. 5,7,30,40-Tetramethoxyflavone (20) (methylated luteolin). Yel-
low oil (281 mg; yield: 90%). Mp 190e194 ꢀC (lit.41 193 ꢀC). Spec-
troscopic data were according to the literature.41
4.3.2. 7,8-Dimethoxyflavanone (17). Yellow solid (284 mg; yield:
>98%). Mp 112e115 ꢀC (lit.38 114 ꢀC). Spectroscopic data were
according to the literature.38
4.4.4. 5,7,30-Trimethoxyflavone (23) (methylated apigenin). Yellow
solid (275 mg; yield: 88%). Mp 154e156 ꢀC (lit.41 157 ꢀC). Spectro-
scopic data were according to the literature.41
4.3.3. 5,7,30,40-Tetramethoxyflavanone (19) (methylated hesperetin).
Yellow oil (327 mg; yield: 95%). Spectroscopic data were according
to the literature.9a,b
4.4.5. 5-Methoxyflavone (25). White solid (252 mg; yield: >98%).
Mp 130e134 ꢀC (lit.42 131 ꢀC). Spectroscopic data were according to
the authentic commercial sample.
4.3.4. 5,7,30-Trimethoxyflavanone (22) (methylated naringenin).
Yellow oil (314 mg; yield: >98%). Spectroscopic data were accord-
ing to the literature.9a,b
4.4.6. 6-Methoxyflavone (27). White solid (202 mg; yield: 80%). Mp
164 ꢀC (lit.43 161e163 ꢀC). Spectroscopic data were according to the
authentic commercial sample.
4.4. General procedure for the dehydrogenation of
methylated flavanones
4.4.7. 7-Methoxyflavone (29). White solid (189 mg; yield: 75%). Mp
109e110 ꢀC (lit.44 110 ꢀC). Spectroscopic data were according to the
authentic commercial sample.
Dehydrogenation with homogeneous IBX. To a solution of sub-
strate (1.0 mmol) solubilised in DMSO (10 mL) was added IBX
(2.0 equiv), which was then stirred at 90 ꢀC for 24 h. At the end,
ethyl acetate was added to the mixture, then it was treated with
a solution of NaHCO3. The aqueous phase was extracted with ethyl
acetate. The organic phases were washed with a saturated solution
of NaCl and dried over Na2SO4. After evaporation of the solvent, the
corresponding flavones were isolated by chromatographic purifi-
cation on silica gel (230e400 mesh).
Acknowledgements
The authors are grateful to Dr. Gianfranco Provenzano for the
preparation of some samples. The University of Tuscia and Minis-
tero della Ricerca Scientifica e Tecnologica are acknowledged for
their financial support.
Dehydrogenation with homogeneous IBX and NMO. IBX
(1.2 mmol) and NMO (1.2 mmol) were added to DMSO (2.5 mL) and
stirred at room temperature until complete dissolution
(15e60 min). Then, the substrate was added (1.0 mmol), the mix-
ture was stirred and the reaction was monitored by TLC. The mix-
ture was diluted with a solution of NaHCO3 and extracted with
diethyl ether. The organic extracts were evaporated and dried over
Na2SO4. Finally, the organic phase was concentrated and the
product was purified by a chromatographic column of silica gel.
Dehydrogenation with polymer-supported IBX. The substrate
(1.0 mmol) was solubilised in DMSO (10 mL) at 90 ꢀC under mag-
netic stirring, then commercial polymer-supported IBX (3.0 mmol)
was added. When the substrate disappeared, the polymer was re-
covered by simple filtration. The products were extracted with
ethyl acetate. The organic phases were washed with a saturated
solution of NaCl and dried over Na2SO4. After evaporation of the
solvent, the corresponding flavones were isolated. Polymer-sup-
ported IBX was regenerated by treating the filtered resin with
a solution of tetrabutylammonium oxone and methanesulphonic
acid according to the procedure reported by us previously.17d,e
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