3-Aroyl-5-hydroxyflavones: Synthesis and transformation into aroylpyrazoles

Article abstract of DOI:10.1002/1099-0690(200211)2002:22<3807::AID-EJOC3807>3.0.CO;2-2

Treatment of 3-aroyl-5-benzyloxyflavones 4a-e with hydrazine afforded 3,5-diaryl-4-(2-benzyloxy-6-hydroxybenzoyl)pyrazoles 5a-e, together with 4-aroyl-5-aryl-3-(2-benzyloxy-6- hydroxyphenyl)pyrazoles 6a-e as minor products. The structures of all new compounds have been established by extensive NMR studies and the reaction mechanisms are discussed. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200211)2002:22<3807::AID-EJOC3807>3.0.CO;2-2

FULL PAPER
3-Aroyl-5-hydroxyflavones: Synthesis and Transformation into Aroylpyrazoles
[a]
[a]
[a]
´
Diana C. G. A. Pinto, Artur M. S. Silva,* Lucia M. P. M. Almeida,
[a]
[b]
´
´
Jose A. S. Cavaleiro, and Jose Elguero
Keywords: Chromones / Flavones / Hydrazine / Natural products / Nitrogen heterocycles
Treatment of 3-aroyl-5-benzyloxyflavones 4a−e with hydra-
zine afforded 3,5-diaryl-4-(2-benzyloxy-6-hydroxybenzoyl)-
tures of all new compounds have been established by extens-
ive NMR studies and the reaction mechanisms are discussed.
pyrazoles 5a−e, together with 4-aroyl-5-aryl-3-(2-benzyloxy-6- ( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
hydroxyphenyl)pyrazoles 6a−e as minor products. The struc-
2002)
Introduction
into 4-aroyl-3-aryl-5-(2-hydroxyaryl)-1-phenylpyrazoles.[30]
These compounds were obtained by treatment of 3-AFs
with hydroxylamine hydrochloride and phenylhydrazine, re-
spectively. The authors claimed that each reaction gave only
one pure product. However, considering the mechanism of
these types of reactions[31,32] Ϫ nucleophilic attack at C-2
of the chromone with subsequent heterocyclic ring-opening
Ϫ and the presence of two carbonyl groups in the structures
of the 3-AFs, one could reasonably expect the formation of
two isomers of isoxazoles and pyrazoles. In view of this, we
decided to revisit the reactions between 3-AFs and hydra-
zines and to study the effect of B-ring substituents on the
yields of the expected aroylpyrazoles.
Flavones are well known six-membered ring oxygen het-
erocyclic compounds and constitute one of the most com-
mon classes of natural flavonoids.[1] Several natural and
synthetic derivatives are responsible for a great variety of
biocidal,[2Ϫ4] pharmacological,[5Ϫ11] and antioxidant[5,12Ϫ16]
activities. It is worth mentioning that the presence of a 5-
hydroxy group in the flavone nucleus seems to be very im-
portant for some biological activities, such as pharmacolo-
gical and antioxidant properties.[16,17Ϫ19] Significant anti-
bacterial and antifungal activities for flavones bearing a 3-
aroyl group have been reported.[20]
It is worth mentioning that several promising pharmaco-
logical, agrochemical, and analytical applications have been
reported for some pyrazole derivatives.[33] Certain hydroxy-
phenylpyrazoles, for instance, can act as ultraviolet stabil-
izers,[34] as analytical reagents in the complexation of trans-
ition metal ions,[35] and as analgesic agents and platelet ag-
gregation inhibitors.[36] Others, such as 3-benzoylpyrazoles,
can act as precursors of other important heterocyclic com-
pounds (e.g., in the preparation of Cizolirtine, a potent an-
algesic).[37,38] This highlights the potential applications of
benzoylpyrazole derivatives and has stimulated the study of
their synthesis. With these possible applications and our
previous work on the synthesis of pyrazoles from chromone
precursors in mind,[31,32] a program aiming at the prepara-
tion of novel benzoylpyrazole derivatives from 3-AFs has
been set up. As a result we describe here our results on
the synthesis and structural characterization of 3- and 4-
aroylpyrazoles 5aϪe and 6aϪe.
Despite the important biocidal applications of 3-aroylfla-
vones (3-AFs), synthetic strategies affording these com-
pounds have not been widely explored. There are three
main synthetic routes: i) BakerϪVenkataraman rearrange-
ment of 2Ј,6Ј-diaroyloxyacetophenones,[21Ϫ24] ii) oxidation
of benzylideneflavanones with a number of oxidants,[25Ϫ27]
and iii) condensation of diaroylmethane derivatives with
aromatic aldehydes, followed by oxidation of the formed
products.[20,28,29] Only the BakerϪVenkataraman route has
been used for the synthesis of 3-aroyl-5-hydroxyflavones,
which always appear contaminated with the corresponding
5-hydroxyflavones. In this context, it would seem advant-
ageous if more studies were to appear on these topics and
if other derivatives were to become available for further
structure-activity relationship and reactivity studies. Two
Indian groups studied the transformation of 3-AFs into 4-
aroyl-5-aryl-3-(2-hydroxyaryl)isoxazoles[28,29] and also
[a]
Department of Chemistry, University of Aveiro,
3810Ϫ193 Aveiro, Portugal
Results and Discussion
Fax: (internat.) ϩ351Ϫ234Ϫ370714
E-mail: arturs@dq.ua.pt
[b]
Synthesis of 3-Aroyl-5-hydroxyflavones
´
´
Instituto de Quımica Medica,
c/Juan de la Cierva 3, 28006 Madrid, Spain
Fax: (internat.) ϩ34Ϫ(0)91Ϫ5644853
E-mail: iqm17@iqm.csic.es
3-Aroyl-5-hydroxyflavones 2aϪe were synthesized by the
BakerϪVenkataraman method.[39,40] This approach in-
Eur. J. Org. Chem. 2002, 3807Ϫ3815  2002 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/02/1122Ϫ3807 $ 20.00ϩ.50/0
3807

A. M. S. Silva et al.
FULL PAPER
volves the O-acylation of 2Ј,6Ј-dihydroxyacetophenone with with benzyl chloride in the presence of potassium carbonate
the appropriate benzoyl chlorides, either commercially and potassium iodide under reflux in acetone for 12 h, pro-
available or prepared in situ from benzoic acids and phos- viding 3-aroyl-5-benzyloxyflavones 4aϪe in good yields
phoryl oxychloride (Scheme 1). Treatment of these esters (82Ϫ97%) (Scheme 2). The lability of the 3-aroyl groups to
1aϪe with potassium carbonate in dry pyridine afforded alkaline media (vide supra) made us initiate our study with
the target 3-aroyl-5-hydroxyflavones 2aϪe as major prod- treatment of compounds 4aϪe with hydrazine generated
ucts (49Ϫ82%), with 5-hydroxyflavones 3aϪe as by-prod- slowly in situ by addition of potassium carbonate to hy-
ucts (2Ϫ20%). The formation of 3-aroylflavones 2aϪe in- drazinium sulfate, and this afforded 3,5-diaryl-4-(2-
volved the base-catalyzed rearrangement of 2Ј,6Ј-diaroyloxy- benzyloxy-6-hydroxybenzoyl)pyrazoles 5aϪe (55Ϫ69%) to-
acetophenones 1aϪe into 2,2-diaroyl-2Ј,6Ј-dihydroxyace- gether with 4-aroyl-5-aryl-3-(2-benzyloxy-6-hydroxyphenyl-
tophenone and 2-aroyl-2Ј,6Ј-dihydroxyacetophenone inter- )pyrazoles 6a and 6c-e (22Ϫ28%) (Scheme 2). The good
mediates, which underwent in situ cyclodehydration to give overall yields of these reactions prompted us to study the
products 2aϪe and 3aϪe, respectively.[23] This synthetic treatment of compounds 4aϪe with hydrazine hydrate,
route allowed the synthesis of 3-aroyl-5-hydroxyflavones which also gave 5aϪe and 6aϪe in better overall yields
2aϪe in better yields and in fewer steps than previously (72Ϫ98%). These results thus indicated that treatment of 3-
reported.[21Ϫ24] The BakerϪVenkataraman rearrangement aroylflavones with hydrazine gave rise to two aroylpyrazoles
was carried out under nitrogen atmosphere and the reaction and not only one as described by Chincholkar and Jam-
time was carefully controlled, in order to obtain the desired ode.[30]
3-aroyl-5-hydroxyflavones 2aϪe in good yields. After a re-
action time of one hour, for example, 1b yielded 4Ј-nitro-3-
(4-nitrobenzoyl)-5-hydroxyflavone (2b) (61%) and 4Ј-nitro-
5-hydroxyflavone (3b) (15%), but after two hours only 3b
(61%) was obtained. This indicates that after prolonged re-
action times there is a cleavage of the 3-aroyl group in the
alkaline medium. In order to confirm this cleavage, 4Ј-
chloro-3-(4-chlorobenzoyl)-5-benzyloxyflavone (2c) was
treated with potassium carbonate for 12 hours, and 4Ј-
chloro-5-hydroxyflavone (3c) was obtained as expected.
Scheme 2
The mechanism of reactions between chromones and hy-
drazine has been reported to involve a nucleophilic attack
at C-2 of the chromone nucleus, followed by ring-open-
ing.[31,32] In this case the formed intermediates 7 and 8 can
cyclise into pyrazoles by two possible pathways, thanks to
the presence of two carbonyl groups capable of undergoing
intramolecular dehydration reactions with the hydrazino
Scheme 1
group (Scheme 3). Our results suggest that the carbonyl of
the 3-aroyl group is more reactive than the chromone car-
bonyl group (C-4). This is confirmed by the higher propor-
Synthesis of Aroylpyrazoles
tion of pyrazoles 5aϪe with respect to 6aϪe and also by
Our previous studies on the use of chromone derivatives the absence of 3-(2-benzyloxy-6-hydroxyphenyl)-4-(4-nitro-
as starting materials in the synthesis of pyrazoles[31,32] re- benzoyl)pyrazole (6b) after treatment of 5-benzyloxy-3-(4-
vealed that it was necessary to protect the 5-hydroxyl group nitrobenzoyl)flavone (4b, bearing a strongly electron-with-
before treatment with hydrazine hydrate. This protection drawing substituent in the para-position of the 3-aroyl
was carried out by heating 3-aroyl-5-hydroxyflavones 2aϪe group) with the hydrazine produced in situ.
3808
Eur. J. Org. Chem. 2002, 3807Ϫ3815

3-Aroyl-5-hydroxyflavones
FULL PAPER
ances of the 5-OH proton at δ ϭ 11.76Ϫ12.24 ppm for
2aϪe, ii) the proton and carbon resonances of the methyl-
ene group of the benzyloxy substituent, appearing at δ ϭ
5.26Ϫ5.29 and 70.9Ϫ71.0 ppm, respectively, and iii) the res-
onances of the aroyl and chromone carbonyl groups, which
appear at δ ϭ 190.5Ϫ193.9 and 175.5Ϫ181.7 ppm, respect-
ively. The carbon resonances of the carbonyl groups of the
3-aroyl substituents were unequivocally assigned after ana-
lysis of the HMBC spectra of compounds 2aϪe and 4aϪe,
in which connectivities were observed between 2ЈЈ,6ЈЈ-H
and these carbonyl groups.
Detailed analysis of the 1H, 13C, and 2D HSQC and
HMBC NMR spectra of aroylpyrazoles 5aϪe and 6aϪe re-
vealed the presence of the pyrazole ring with an aroyl group
at position 4. Important features in the structural character-
ization of these aroylpyrazoles are the resonances of the
carbons atoms of the pyrazole ring, which appear at δ ϭ
143.5Ϫ144.8 ppm, 117.1Ϫ117.9, and 146.6Ϫ147.6 ppm for
C-3, C-4 and C-5, respectively, in aroylpyrazoles 6aϪe, and
at δ ϭ 145.3Ϫ148.1 and 119.3Ϫ122.1 ppm for C-3/5 and C-
4, respectively, for aroylpyrazoles 5aϪe. In the structural
characterization of aroylpyrazoles 5aϪe, it is important to
note that, due to the symmetry of the molecule, the carbons
C-3 and C-5 and the protons and carbons of the 3- and 5-
phenyl rings are equivalent. The most noticeable features to
1
report from their H NMR spectra are therefore a charac-
teristic AB spin system corresponding to the resonances of
2Ј,6Ј-H/3Ј,5Ј-H of aroylpyrazoles 5bϪe, at δ ϭ 7.14Ϫ7.51
and 6.66Ϫ8.18 ppm, respectively. Other important features
are: i) the doublets at δ ϭ 5.92Ϫ6.07 and 6.50Ϫ6.60 ppm,
which correspond to protons 3ЈЈ-H and 5ЈЈ-H, respectively,
ii) the triplet at δ ϭ 7.08Ϫ7.57 ppm, which corresponds to
proton 4ЈЈ-H, and iii) the singlet at δ ϭ 11.77Ϫ11.92 ppm,
due to the proton resonance of the 6ЈЈ-OH group, involved
Scheme 3
NMR Spectroscopy
The main resonances in the H and 13C NMR spectra of in a hydrogen bond with the carbonyl of the aroyl group.
2Ј,6Ј-dibenzoyloxyacetophenones 1aϪe are: i) the reson- These important data confirmed the presence of the 4-(2-
ances of the 2-CH3 proton and carbon atoms, which appear benzyloxy-6-hydroxybenzoyl) group, which is only compat-
at δ ϭ 2.44Ϫ2.48 and 31.2Ϫ31.4 ppm, respectively, ii) the ible with the structure shown for aroylpyrazoles 5aϪe
resonances of the ester and ketone carbonyl groups, which (Scheme 2).
1
appear at δ ϭ 162.8Ϫ164.6 and 197.6Ϫ198.6 ppm, respect-
The main characteristics for the structural characteriza-
ively, iii) the doublet at δ ϭ 7.20Ϫ7.29 ppm, attributable to tion of aroylpyrazoles 6aϪe that can be noted from their
the resonance of the equivalent 3Ј-H and 5Ј-H protons, and 1H NMR spectra are the proton resonances of 6Ј-OH and
iv) the triplet at δ ϭ 7.51Ϫ7.62 ppm, attributable to the NH at δ ϭ 11.77Ϫ11.94 and 9.29Ϫ10.47 ppm, respectively,
resonance of 4Ј-H, which appears at higher frequency than and the two characteristic AB spin systems corresponding
those of 3Ј,5Ј-H due to the mesomeric deshielding effect of to the resonances of 2ЈЈ,6ЈЈ-H/3ЈЈ,5ЈЈ-H of the phenyl group
the ketone carbonyl group.
at carbon C-5 and of 2ЈЈЈ,6ЈЈЈ-H/3ЈЈЈ,5ЈЈЈ-H of the aroyl
In the 1H NMR spectrum of each 5-hydroxyflavone 3aϪe group at carbon C-4 for 6bϪe. Because of the hydrogen
it is possible to observe the presence of two singlets at δ ϭ bond between the hydroxyl (6Ј-OH) proton and N-2 there
6.62Ϫ6.84 and 12.36Ϫ12.69 ppm, attributable to the reson- is no prototropy in these aroylpyrazoles 6bϪe.
ances of the 3-H and the 5-OH proton, respectively. Our
All these data and the connectivities found in the HMBC
previous work on 13C NMR assignments of 5-hydroxyfla- spectra of aroylpyrazoles 5aϪe and 6aϪe (Figure 1) provide
vones[41,42] and analysis of the HSQC and HMBC spectra unequivocal support for the proposed structures for these
of compounds 3aϪe enabled all their carbons to be as- two isomers.
signed.
The characterization of 3-aroyl-5-hydroxyflavones 2aϪe
and 3-aroyl-5-benzyloxyflavones 4aϪe was based on our
Conclusion
1
previous work.[24] The most noticeable features of the H
We have studied the reactions between 3-aroyl-5-
and 13C NMR spectra of these flavones are: i) the reson- benzyloxyflavones 4aϪe and either hydrazine, formed in
Eur. J. Org. Chem. 2002, 3807Ϫ3815
3809

A. M. S. Silva et al.
FULL PAPER
CϭO of 2Ј,6Ј-OCOC6H5), 198.4 (CϭO) ppm. EI-MS: m/z (%) ϭ
360 (12) [Mϩ·], 342 (1), 239 (4), 238 (5), 213 (4), 132 (3), 106 (33),
105 (100). C22H16O5 (360.10): calcd. C 73.33, H 4.48; found C
73.02, H 4.61.
The 2Ј,6Ј-dibenzoyloxyacetophenones 1bϪd were obtained in a
similar manner, from 2Ј,6Ј-dihydroxyacetophenone and appropriate
aroyl chlorides.
2Ј,6Ј-Bis(4-nitrobenzoyloxy)acetophenone (1b): Yield 98%. M.p.
1
208Ϫ210 °C (recrystallization from ethanol). H NMR: δ ϭ 2.47
Figure 1. Important connectivities found in the HMBC spectra of
(s, 3 H, 2-CH3), 7.29 (d, J ϭ 8.3 Hz, 2 H, 3Ј,5Ј-H), 7.62 (t, J ϭ
8.3 Hz, 1 H, 4Ј-H), 8.35 (AB, J ϭ 9.3 Hz, 4 H, 2,6-H of 2Ј,6Ј-
OCOC6H5), 8.38 (AB, J ϭ 9.3 Hz, 4 H, 3,5-H of 2Ј,6Ј-OCOC6H5)
ppm. 13C NMR: δ ϭ 31.4 (2-CH3), 120.9 (C-3Ј,5Ј), 123.9 (2 ϫ C-
3,5 of 2Ј,6Ј-OCOC6H5), 127.8 (C-1Ј), 131.5 (C-4Ј and 2 ϫ C-2,6 of
2Ј,6Ј-OCOC6H5), 133.8 (2 ϫ C-1 of 2Ј,6Ј-OCOC6H5), 147.7 (C-
2Ј,6Ј), 151.1 (2 ϫ C-4 of 2Ј,6Ј-OCOC6H5), 162.8 (2 ϫ CϭO of
2Ј,6Ј-OCOC6H5), 197.6 (CϭO) ppm. EI-MS: m/z (%) ϭ 450 (8)
[Mϩ·], 301 (1), 150 (100), 120 (9), 104 (19), 92 (7), 76 (7).
C22H14N2O9 (450.07): calcd. C 58.67, H 3.13, N 6.22; found C
58.33, H 3.17, N 6.60.
aroylpyrazoles 5aϪe and 6aϪe
situ from hydrazinium sulfate and sodium carbonate, or hy-
drazine hydrate. These reactions allowed us to establish new
synthetic methods for novel 3,4,5-trisubstituted pyrazoles,
3,5-diaryl-4-(2-benzyloxy-6-hydroxybenzoyl)pyrazoles
5aϪe and 4-aroyl-5-aryl-3-(2-benzyloxy-6-hydroxyphenyl)-
pyrazoles 6aϪe. These last were obtained as minor prod-
ucts, suggesting that the carbonyl group of the 3-aroyl
group is more reactive than the chromone carbonyl group
(C-4).
2Ј,6Ј-Bis(4-chlorobenzoyloxy)acetophenone (1c): Yield 92%. M.p.
1
138Ϫ140 °C (recrystallization from ethanol). H NMR: δ ϭ 2.45
(s, 3 H, 2-CH3), 7.23 (d, J ϭ 8.3 Hz, 2 H, 3Ј,5Ј-H), 7.50 (d, J ϭ
8.6 Hz, 4 H, 3,5-H of 2Ј,6Ј-OCOC6H5), 7.55 (t, J ϭ 8.3 Hz, 1 H,
4Ј-H), 8.10 (d, J ϭ 8.6 Hz, 4 H, 2,6-H of 2Ј,6Ј-OCOC6H5) ppm.
13C NMR: δ ϭ 31.3 (2-CH3), 120.7 (C-3Ј,5Ј), 127.0 (2 ϫ C-1 of
2Ј,6Ј-OCOC6H5), 128.2 (C-1Ј), 129.2 (2 ϫ C-3,5 of 2Ј,6Ј-OC-
OC6H5), 131.0 (C-4Ј), 131.7 (2 ϫ C-2,6 of 2Ј,6Ј-OCOC6H5), 140.8
(2 ϫ C-4 of 2Ј,6Ј-OCOC6H5), 147.9 (C-2Ј,6Ј), 163.7 (2 ϫ CϭO of
2Ј,6Ј-OCOC6H5), 198.1 (CϭO) ppm. EI-MS: m/z (%) ϭ 428 (10)
[Mϩ·], 247 (1), 139 (100), 111 (30), 75 (13). C22H14Cl2O5 (428.02):
calcd. C 61.56, H 3.29; found C 61.51, H 3.56.
Experimental Section
General Remarks: Melting points were measured in a Reichert
Thermovar apparatus fitted with a microscope, and are uncorrec-
ted. NMR spectra were recorded on Bruker AMX and DRX 300
spectrometers (300.13 for 1H and 75.47 MHz for 13C), in CDCl3
as solvent. Chemical shifts are reported (δ) in ppm and coupling
constants (J) in Hz; the internal standard was TMS. Unequivocal
13C assignments were made with the aid of 2D gHSQC (or
HETCOR) and gHMBC (delays for one bond and long-range J C/
H couplings were optimized for 145 and 7 Hz, respectively) experi-
ments. Electron impact (EI, 70 eV) MS were recorded on VG
Autospec Q and M spectrometers. Elemental analyses were ob-
tained with a CHNS 932 Leco analyzer (University of Aveiro). Pre-
parative thin layer chromatography was performed with Merck 60
DGF254 silica gel. Column chromatography was performed with
Merck 60 silica gel, 70Ϫ230 mesh.
2Ј,6Ј-Bis(4-methoxybenzoyloxy)acetophenone (1d): Yield 94%. M.p.
1
141Ϫ142 °C (recrystallization from ethanol). H NMR: δ ϭ 2.46
(s, 3 H, 2-CH3), 3.89 (s, 6 H, 2 ϫ 4-OCH3 of 2Ј,6Ј-OCOC6H5),
6.98 (d, J ϭ 9.0 Hz, 4 H, 3,5-H of 2Ј,6Ј-OCOC6H5), 7.20 (d, J ϭ
8.2 Hz, 2 H, 3Ј,5Ј-H), 7.51 (t, J ϭ 8.2 Hz, 1 H, 4Ј-H), 8.12 (d, J ϭ
9.0 Hz, 4 H, 2,6-H of 2Ј,6Ј-OCOC6H5) ppm. 13C NMR: δ ϭ 31.3
(2-CH3), 55.5 (2 ϫ 4-OCH3 of 2Ј,6Ј-OCOC6H5), 120.5 (C-3Ј,5Ј),
120.9 (C-1Ј), 114.0 (2 ϫ C-3,5 of 2Ј,6Ј-OCOC6H5), 128.5 (2 ϫ C-
1 of 2Ј,6Ј-OCOC6H5), 130.7 (C-4Ј), 132.5 (2 ϫ C-2,6 of 2Ј,6Ј-OC-
OC6H5), 148.0 (C-2Ј,6Ј), 164.2 (2 ϫ C-4 and 2 ϫ CϭO of 2Ј,6Ј-
OCOC6H5), 198.6 (CϭO) ppm. EI-MS: m/z (%) ϭ 420 (38) [Mϩ·],
402 (13), 373 (5), 243 (17), 152 (8), 135 (100), 107 (5), 92 (6), 77
(10). C24H20O7 (420.12): calcd. C 68.57, H 4.80; found C 68.35,
H 4.82.
Synthesis of 2Ј,6Ј-Dibenzoyloxyacetophenones 1aϪd
Synthesis of 2Ј,6Ј-Dibenzoyloxyacetophenone (1a): Benzoyl chloride
(4.6 mL, 39.4 mmol) was added to a solution of 2Ј,6Ј-dihydroxyace-
tophenone (2.0 g, 13.3 mmol) in dry pyridine (20 mL). The solution
was stirred at room temperature for 12 h; after that period the solu-
tion was poured into ice and water, and the pH was adjusted to 4
with hydrochloric acid. The obtained solid was removed by filtra-
Synthesis of 2Ј,6Ј-Bis(4-methylbenzoyloxy)acetophenone (1e): p-
Methylbenzoic acid (1.12 g, 8.23 mmol), thionyl chloride (1.8 mL,
tion, dissolved in dichloromethane (100 mL), washed with water, 24.7 mmol), and one drop of pyridine were heated (60Ϫ70 °C) for
and purified by silica gel column chromatography with dichlorome-
thane as eluent. The solvent was evaporated to dryness in each
case, and the residue was crystallized from ethanol, yielding 1a
4 h. After this period, benzene (50 mL) was added and the reaction
solvents were evaporated to dryness. The obtained residue was ad-
ded to
a solution of 2Ј,6Ј-dihydroxyacetophenone (0.50 g,
(4.07 g, 85%). 1a: M.p. 103Ϫ104 °C (recrystallization from eth-
anol). H NMR: δ ϭ 2.48 (s, 3 H, 2-CH3), 7.23 (d, J ϭ 8.0 Hz, 2 room temperature for 12 h; after that period the solution was
3.29 mmol) in dry pyridine (20 mL). The solution was stirred at
1
H, 3Ј,5Ј-H), 7.51 (d, J ϭ 7.3 Hz, 4 H, 3,5-H of 2Ј,6Ј-OCOC6H5),
poured into ice and water, and the pH was adjusted to 4 with hy-
7.54 (t, J ϭ 8.0 Hz, 1 H, 4Ј-H), 7.66 (t, J ϭ 7.3 Hz, 2 H, 4-H of drochloric acid. The obtained solid was removed by filtration, dis-
2Ј,6Ј-OCOC6H5), 7.82 (d, J ϭ 7.3 Hz, 4 H, 2,6-H of 2Ј,6Ј-OC-
solved in dichloromethane (100 mL), washed with water, and puri-
OC6H5) ppm. 13C NMR: δ ϭ 31.4 (2-CH3), 120.6 (C-3Ј,5Ј), 124.4 fied by silica gel column chromatography with dichloromethane as
(C-1Ј), 128.7 (2 ϫ C-1 of 2Ј,6Ј-OCOC6H5), 128.8 (2 ϫ C-3,5 of eluent. The solvent was evaporated to dryness and the residue was
2Ј,6Ј-OCOC6H5), 130.3 (2 ϫ C-2,6 of 2Ј,6Ј-OCOC6H5), 130.9 (C-
4Ј), 134.1 (2 ϫ C-4 of 2Ј,6Ј-OCOC6H5), 148.0 (C-2Ј,6Ј), 164.6 (2 ϫ 100Ϫ102 °C (recrystallization from ethanol). H NMR: δ ϭ 2.44
crystallized from ethanol, yielding 1e (2.12 g, 69%). 1e: M.p.
1
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Eur. J. Org. Chem. 2002, 3807Ϫ3815

3-Aroyl-5-hydroxyflavones
FULL PAPER
(s, 6 H, 2 ϫ 4-CH3 of 2Ј,6Ј-OCOC6H5), 2.47 (s, 3 H, 2-CH3), 7.21 vone (3d) (20%) displayed spectroscopic and analytical data ident-
(d, J ϭ 8.3 Hz, 2 H, 3Ј,5Ј-H), 7.30 (d, J ϭ 8.3 Hz, 4 H, 3,5-H of
2Ј,6Ј-OCOC6H5), 7.52 (t, J ϭ 8.3 Hz, 1 H, 4Ј-H), 8.05 (d, J ϭ
8.3 Hz, 4 H, 2,6-H of 2Ј,6Ј-OCOC6H5) ppm. 13C NMR: δ ϭ 21.7
(2 ϫ 4-CH3 of 2Ј,6Ј-OCOC6H5), 31.2 (2-CH3), 120.5 (C-3Ј,5Ј),
125.8 (2 ϫ C-1 of 2Ј,6Ј-OCOC6H5), 128.4 (C-1Ј), 129.4 (2 ϫ C-3,5
of 2Ј,6Ј-OCOC6H5), 130.3 (2 ϫ C-2,6 of 2Ј,6Ј-OCOC6H5), 130.7
(C-4Ј), 144.9 (2 ϫ C-4 of 2Ј,6Ј-OCOC6H5), 147.9 (C-2Ј,6Ј), 164.5
(2 ϫ CϭO of 2Ј,6Ј-OCOC6H5), 198.4 (CϭO) ppm. EI-MS: m/z
(%) ϭ 388 (5) [Mϩ·], 227 (1), 119 (100), 91 (28), 65 (9). C24H20O5
(388.13): calcd. C 74.21, H 5.19; found C 73.95, H 5.40.
ical to those previously reported.[24]
5-Hydroxy-4Ј-methyl-3-(4-methylbenzoyl)flavone (2e): Yield 82%.
M.p. 222Ϫ225 °C (recrystallization from ethanol). H NMR: δ ϭ
1
2.34 (s, 3 H, 4Ј-CH3), 2.39 (s, 3 H, 4ЈЈ-CH3), 6.85 (dd, J ϭ 8.3, 0.6
Hz, 1 H, 6-H), 7.03 (br. d, J ϭ 8.3 Hz, 1 H, 8-H), 7.17 (d, J ϭ
8.2 Hz, 2 H, 3Ј,5Ј-H), 7.24 (d, J ϭ 8.2 Hz, 2 H, 3ЈЈ,5ЈЈ-H), 7.55 (d,
J ϭ 8.2 Hz, 2 H, 2Ј,6Ј-H), 7.60 (t, J ϭ 8.3 Hz, 1 H, 7-H), 7.85 (d,
J ϭ 8.2 Hz, 2 H, 2ЈЈ,6ЈЈ-H), 12.24 (s, 1 H, 5-OH) ppm. 13C NMR:
δ ϭ 21.5 (4Ј-CH3), 21.8 (4ЈЈ-CH3), 107.1 (C-8), 110.1 (C-10), 111.8
(C-6), 120.7 (C-3), 128.4 (C-1Ј), 128.5 (C-2Ј,6Ј), 129.6 (6C, C-
3Ј,5Ј,2ЈЈ,3ЈЈ,5ЈЈ,6ЈЈ), 134.5 (C-1ЈЈ), 135.9 (C-7), 142.6 (C-4Ј), 145.2
(C-4ЈЈ), 156.2 (C-9), 160.9 (C-5), 163.6 (C-2), 181.7 (C-4), 192.3
(CϭO) ppm. EI-MS: m/z (%) ϭ 370 (100) [Mϩ·], 369 (28), 355 (13),
341 (65), 327 (15), 279 (30), 235 (7), 206 (9), 185 (10), 143 (49), 119
(65), 91 (63), 65 (24). C24H18O4 (370.12): calcd. C 77.82, H 4.90;
found C 77.62, H 5.27.
Synthesis of 3-Aroyl-5-hydroxyflavones 2aϪe
Synthesis of 3-Benzoyl-5-hydroxyflavone (2a): Anhydrous potas-
sium carbonate (1.355 g, 9.80 mmol) was added to a solution of
2Ј,6Ј-dibenzoyloxyacetophenone (1a, 2.05 g, 4.90 mmol) in dry pyr-
idine (15 mL). The mixture was heated (120Ϫ130 °C) under nitro-
gen for 2 h; after this period it was poured into a mixture of ice
(100 g), water (50 mL), and concentrated hydrochloric acid (pH ad-
justed to 3Ϫ4). The obtained solid was filtered, dissolved in dichlo-
romethane (100 mL), washed with water, and purified on preparat-
ive thin layer chromatographic plates, eluting several times with a
(1:1) mixture of dichloromethane/light petroleum. Two very close
spots were collected; these were, with increasing Rf values, 3-
benzoyl-5-hydroxyflavone 2a (53%) and 5-hydroxyflavones 3a
(16%), which displayed spectroscopic and analytical data identical
to those previously reported.[24,42]
5-Hydroxy-4Ј-methylflavone (3e): Yield 2%. M.p. 183Ϫ185 °C
(recrystallization from ethanol). 1H NMR: δ ϭ 2.44 (s, 3 H, 4Ј-
CH3), 6.70 (s, 1 H, 3-H), 6.80 (dd, J ϭ 8.3, 0.8 Hz, 1 H, 6-H), 6.99
(dd, J ϭ 8.3, 0.8 Hz, 1 H, 8-H), 7.32 (d, J ϭ 8.3 Hz, 2 H, 3Ј,5Ј-
H), 7.53 (t, J ϭ 8.3 Hz, 1 H, 7-H), 7.80 (d, J ϭ 8.3 Hz, 2 H, 2Ј,6Ј-
H), 12.61 (s, 1 H, 5-OH) ppm. 13C NMR: δ ϭ 21.6 (4Ј-CH3), 105.5
(C-3), 107.0 (C-8), 110.9 (C-10), 111.4 (C-6), 126.4 (C-3Ј,5Ј), 128.5
(C-1Ј), 129.9 (C-2Ј,6Ј), 135.3 (C-7), 142.8 (C-4Ј), 156.5 (C-9), 160.9
(C-5), 164.8 (C-2), 183.6 (C-4) ppm. EI-MS: m/z (%) ϭ 252 (100)
[Mϩ·], 251 (26), 237 (20), 224 (32), 195 (12), 181 (13), 137 (15), 136
(59), 115 (42), 108 (56). C16H12O3 (252.26): calcd. C 76.18, H 4.79;
found C 76.36, H 4.71.
3-Aroyl-5-hydroxyflavones 2cϪe and 5-hydroxyflavones 3cϪe were
obtained from 1cϪe in a similar manner. In the case of 5-hydroxy-
4Ј-nitro-3-(4-nitrobenzoyl)flavone (2b) and 5-hydroxy-4Ј-nitrofla-
vone 3b, treatment of 2Ј,6Ј-bis(4-nitrobenzoyloxy)acetophenone 1b
with base was carried out only for 1 h.
Synthesis of 3-Aroyl-5-benzyloxyflavones 4aϪe
Synthesis of 3-Benzoyl-5-benzyloxyflavone (4a): Anhydrous potas-
sium carbonate (1.113 g, 8.05 mmol), potassium iodide (0.67 g,
4.03 mmol), and benzyl chloride (0.37 mL, 3.22 mmol) were added
5-Hydroxy-4Ј-nitro-3-(4-nitrobenzoyl)flavone (2b): Yield 61%. M.p.
1
245Ϫ247 °C (recrystallization from ethanol). H NMR: δ ϭ 6.93
to
a solution of 3-benzoyl-5-hydroxyflavone (2a, 0.92 mg,
(d, J ϭ 8.4 Hz, 1 H, 6-H), 7.07 (d, J ϭ 8.4 Hz, 1 H, 8-H), 7.68 (t,
J ϭ 8.4 Hz, 1 H, 7-H), 7.79 (d, J ϭ 8.8 Hz, 2 H, 2Ј,6Ј-H), 8.07 (d,
J ϭ 8.8 Hz, 2 H, 2ЈЈ,6ЈЈ-H), 8.26 (d, J ϭ 8.8 Hz, 2 H, 3Ј,5Ј-H), 8.30
(d, J ϭ 8.8 Hz, 2 H, 3ЈЈ,5ЈЈ-H), 11.76 (s, 1 H, 5-OH) ppm. 13C
NMR: δ ϭ 107.3 (C-8), 110.2 (C-10), 112.9 (C-6), 121.8 (C-3),
124.1 (C-3Ј,5Ј), 124.3 (C-3ЈЈ,5ЈЈ), 129.8 (C-2Ј,6Ј), 130.2 (C-2ЈЈ,6ЈЈ),
136.6 (C-1Ј), 137.0 (C-7), 140.9 (C-1ЈЈ), 149.7 (C-4Ј), 151.0 (C-4ЈЈ),
156.1 (C-9), 161.0 (C-5), 162.3 (C-2), 181.1 (C-4), 190.5 (CϭO)
ppm. EI-MS: m/z (%) ϭ 432 (100) [Mϩ·], 403 (42), 357 (12), 310
(12), 174 (10), 150 (12), 128 (7), 104 (14), 92 (6), 78 (40), 63 (45).
C22H12O8N2 (432.06): calcd. C 61.12, H 2.80, N 6.48; found C
61.32, H 3.01, N 6.53.
2.68 mmol) in acetone (150 mL). The mixture was heated under
reflux under nitrogen for 12 h. After this period the inorganic salts
were filtered and the acetone was evaporated to dryness. The ob-
tained residue was dissolved in dichloromethane (20 mL) and puri-
fied by silica gel column chromatography, with dichloromethane
as eluent, giving 3-benzoyl-5-benzyloxyflavone (4a, 0.95 mg, 82%).
1
M.p. 203Ϫ204 °C (recrystallization from ethanol). H NMR: δ ϭ
5.27 (s, 2 H, 5-OCH2C6H5), 6.88 (d, J ϭ 8.4 Hz, 1 H, 6-H), 7.14
(d,
J
ϭ
8.4 Hz,
1
H, 8-H), 7.24Ϫ7.56 (m, 11 H,
3Ј,4Ј,5Ј,2ЈЈ,3ЈЈ,4ЈЈ,5ЈЈ,6ЈЈ-H and 3,4,5-H of 5-OCH2C6H5), 7.57 (t,
J ϭ 8.4 Hz, 1 H, 7-H), 7.64 (d, J ϭ 7.4 Hz, 2 H, 2,6-H of 5-
OCH2C6H5), 7.95 (d, J ϭ 7.6 Hz, 2 H, 2Ј,6Ј-H) ppm. 13C NMR:
δ ϭ 70.9 (5-OCH2C6H5), 108.8 (C-6), 110.3 (C-8), 114.4 (C-10),
123.7 (C-3), 126.7 (C-2,6 of 5-OCH2C6H5), 127.7 (C-4 of 5-
OCH2C6H5), 128.4 (C-2Ј,6Ј), 128.6 (C-2ЈЈ,6ЈЈ), 128.7 (C-3ЈЈ,5ЈЈ and
C-3,5 of 5-OCH2C6H5), 129.5 (C-3Ј,5Ј), 131.2 (C-4Ј), 131.5 (C-4ЈЈ),
133.6 (C-1ЈЈ), 134.2 (C-1Ј), 136.3 (C-1 of 5-OCH2C6H5), 137.0 (C-
7), 158.1 (C-9), 158.9 (C-5), 159.9 (C-2), 176.0 (C-4), 193.9 (CϭO)
ppm. EI-MS: m/z (%) ϭ 432 (50) [Mϩ·], 431 (14), 342 (30), 326
(22), 313 (26), 297 (33), 129 (27), 105 (29), 91 (100), 77 (41), 65
(14), 51 (11). C29H20O4·H2O (450.16): calcd. C 77.32, H 4.92; found
C 77.28, H 4.81.
5-Hydroxy-4Ј-nitroflavone (3b): Yield 15%. M.p. 296Ϫ298 °C
1
(recrystallization from ethanol). H NMR: δ ϭ 6.82 (s, 1 H, 3-H),
6.86 (d, J ϭ 8.4 Hz, 1 H, 6-H), 7.03 (d, J ϭ 8.4 Hz, 1 H, 8-H), 7.60
(t, J ϭ 8.4 Hz, 1H. 7-H), 8.09 (d, J ϭ 8.8 Hz, 2 H, 2Ј,6Ј-H), 8.39
(d, J ϭ 8.8 Hz, 2 H, 3Ј,5Ј-H), 12.32 (s, 1 H, 5-OH) ppm. 13C NMR:
δ ϭ 108.2 (C-3), 107.1 (C-8), 111.0 (C-10), 112.1 (C-6), 127.4 (C-
2Ј,6Ј), 124.3 (C-3Ј,5Ј), 136.0 (C-7), 137.1 (C-1Ј), 149.8 (C-4Ј), 156.4
(C-9), 161.0 (C-5), 161.7 (C-2), 183.2 (C-4) ppm. EI-MS: m/z (%) ϭ
283 (100) [Mϩ·], 253 (8), 237 (22), 152 (6), 136 (6), 108 (15), 83
(46), 72 (14), 59 (28). C22H12O8N2 (283.05): calcd. C 63.61, H 3.20,
N 4.95; found C 63.41, H 3.31, N 5.27.
The 3-aroyl-5-benzyloxyflavones 4bϪd were obtained from 3-aroyl-
5-hydroxyflavones 2bϪd in a similar manner.
4Ј-Chloro-3-(4-chlorobenzoyl)-5-hydroxyflavone (2c) (58%), 4Ј-
Chloro-5-hydroxyflavone (3c) (18%), 5-Hydroxy-4Ј-methoxy-3-(4- 5-Benzyloxy-4Ј-nitro-3-(4-nitrobenzoyl)flavone (4b): Yield 97%.
1
methoxybenzoyl)flavone (2d) (49%), and 5-Hydroxy-4Ј-methoxyfla-
Eur. J. Org. Chem. 2002, 3807Ϫ3815
M.p. 244Ϫ246 °C (recrystallization from ethanol). H NMR: δ ϭ
3811

A. M. S. Silva et al.
5.29 (s, 2 H, 5-OCH2C6H5), 6.95 (d, J ϭ 8.4 Hz, 1 H, 6-H), 7.16 H, 2,6-H of 5-OCH2C6H5), 7.55 (t, J ϭ 8.3 Hz, 1 H, 7-H), 7.55 (d,
FULL PAPER
(d, J ϭ 8.4 Hz, 1 H, 8-H), 7.30 (t, J ϭ 7.4 Hz, 1 H, 4-H of 5-
OCH2C6H5), 7.36 (t, J ϭ 7.4 Hz, 2 H, 3,5-H of 5-OCH2C6H5), 7.51
J ϭ 8.1 Hz, 2 H, 2Ј,6Ј-H), 7.85 (d, J ϭ 8.1 Hz, 2 H, 2ЈЈ,6ЈЈ-H) ppm.
13C NMR: δ ϭ 21.5 (4Ј-CH3), 21.8 (4ЈЈ-CH3), 70.9 (5-OCH2C6H5),
(d, J ϭ 7.4 Hz, 2 H, 2,6-H of 5-OCH2C6H5), 7.65 (t, J ϭ 8.4 Hz, 108.6 (C-6), 110.3 (C-8), 114.4 (C-10), 123.3 (C-3), 126.7 (C-2,6 of
1 H, 7-H), 7.79 (d, J ϭ 8.9 Hz, 2 H, 2Ј,6Ј-H), 8.10 (d, J ϭ 8.9 Hz, 5-OCH2C6H5), 127.6 (C-4 of 5-OCH2C6H5), 128.3 (C-2Ј,6Ј), 128.6
2 H, 2ЈЈ,6ЈЈ-H), 8.24 (d, J ϭ 8.9 Hz, 2 H, 3Ј,5Ј-H), 8.28 (d, J ϭ (C-1Ј and C-3,5 of 5-OCH2C6H5), 129.4 (C-3Ј,5Ј and C-3ЈЈ,5ЈЈ),
8.9 Hz, 2 H, 3ЈЈ,5ЈЈ-H) ppm. 13C NMR: δ ϭ 70.9 (5-OCH2C6H5), 129.7 (C-2ЈЈ,6ЈЈ), 134.0 (C-7), 134.7 (C-1ЈЈ), 136.3 (C-1 of 5-
109.3 (C-6), 110.2 (C-8), 114.2 (C-10), 124.2 (C-3), 124.0 (C-3Ј,5Ј), OCH2C6H5), 141.7 (C-4Ј), 144.5 (C-4ЈЈ), 158.1 (C-9), 158.8 (C-5),
124.2 (C-3ЈЈ,5ЈЈ), 126.6 (C-2,6 of 5-OCH2C6H5), 127.9 (C-4 of 5-
159.7 (C-2), 176.0 (C-4), 193.8 (CϭO) ppm. EI-MS: m/z (%) ϭ 460
OCH2C6H5), 128.7 (C-3,5 of 5-OCH2C6H5), 129.6 (C-2Ј,6Ј), 130.3 (41) [Mϩ·], 442 (9), 370 (15), 356 (20), 341 (18), 325 (22), 311 (6),
(C-2ЈЈ,6ЈЈ), 135.2 (C-7), 135.8 (C-1 of 5-OCH2C6H5), 136.8 (C-1Ј), 279 (5), 143 (16), 119 (29), 91 (100), 65 (17). C31H24O4 (478.19):
141.0 (C-1ЈЈ), 149.3 (C-4Ј), 150.7 (C-4ЈЈ), 157.9 (C-9), 158.7 (C-5),
158.9 (C-2), 175.5 (C-4), 192.0 (CϭO) ppm. EI-MS: m/z (%) ϭ 523
(12) [Mϩ·], 460 (5), 307 (30), 289 (15), 212 (7), 180 (5), 154 (100),
137 (67), 136 (65), 120 (12), 107 (20), 91 (30), 77 (17), 65 (7).
C29H18N2O8 (540.13): calcd. C 64.44, H 3.73, N 5.18; found C
64.68, H 3.82, N 5.50.
calcd. C 77.81, H 5.48; found C 77.48, H 5.58.
Synthesis of 3,5-Diaryl-4-(2-benzyloxy-6-hydroxybenzoyl)pyrazoles
5aϪe and 4-Aroyl-5-aryl-3-(2-benzyloxy-6-hydroxyphenyl)pyrazoles
6aϪe
Synthesis of 4-(2-Benzyloxy-6-hydroxybenzoyl)-3,5-diphenylpyrazole
(5a) and 4-Benzoyl-3-(2-benzyloxy-6-hydroxyphenyl)-5-phenylpyr-
azole (6a):
5-Benzyloxy-4Ј-chloro-3-(4-chlorobenzoyl)flavone (4c): Yield 85%.
1
M.p. 231Ϫ233 °C (recrystallization from ethanol). H NMR: δ ϭ
5.27 (s, 2 H, 5-OCH2C6H5), 6.90 (dd, J ϭ 8.4, 0.8 Hz, 1 H, 6-H),
7.12 (dd, J ϭ 8.4, 0.8 Hz, 1 H, 8-H), 7.27Ϫ7.34 (m, 3 H, 3,4,5-H
of 5-OCH2C6H5), 7.34 (d, J ϭ 6.7 Hz, 2 H, 3Ј,5Ј-H), 7.38 (d, J ϭ
6.7 Hz, 2 H, 3ЈЈ,5ЈЈ-H), 7.53 (d, J ϭ 7.1 Hz, 2 H, 2,6-H of 5-
OCH2C6H5), 7.56 (d, J ϭ 6.7 Hz, 2 H, 2Ј,6Ј-H), 7.59 (t, J ϭ 8.4 Hz,
1 H, 7-H), 7.87 (d, J ϭ 6.7 Hz, 2 H, 2ЈЈ,6ЈЈ-H) ppm. 13C NMR:
δ ϭ 71.0 (5-OCH2C6H5), 108.9 (C-6), 110.2 (C-8), 114.3 (C-10),
123.4 (C-3), 126.7 (C-2,6 of 5-OCH2C6H5), 127.8 (C-4 of 5-
OCH2C6H5), 128.6 (C-3Ј,5Ј), 129.2 (C-3ЈЈ,5ЈЈ and C-3,5 of 5-
OCH2C6H5), 129.6 (C-2Ј,6Ј), 129.7 (C-1Ј), 130.8 (C-2ЈЈ,6ЈЈ), 134.5
(C-7), 135.3 (C-1ЈЈ), 136.1 (C-1 of 5-OCH2C6H5), 137.8 (C-4Ј),
140.3 (C-4ЈЈ), 157.9 (C-9), 158.9 (C-2 and C-5), 175.7 (C-4), 192.6
(CϭO) ppm. EI-MS: m/z (%) ϭ 500 (18) [Mϩ·], 482 (5), 410 (5),
394 (5), 365 (8), 163 (10), 139 (16), 111 (17), 91 (100), 75 (8), 65
(11). C29H18Cl2O4 (518.08): calcd. C 67.06, H 3.88; found C 67.03,
H 3.81.
Method A: Hydrazinium sulfate (0.997 g, 7.67 mmol) was added to
a
solution of 3-benzoyl-5-benzyloxyflavone (4a, 550 mg,
1.28 mmol) in methanol (50 mL). The mixture was heated (80 °C)
under nitrogen, and a saturated solution of potassium carbonate
in methanol (100 mL) was slowly added, then the mixture was
heated for 20 h. After this period the reaction mixture was poured
into water and extracted with chloroform (3 ϫ 100 mL). The solv-
ent was evaporated to dryness and the residue was dissolved in
dichloromethane and chromatographed on preparative thin layer
chromatographic plates, eluting several times with dichlorome-
thane. Two very close spots were collected, representing, with in-
creasing Rf values, 4-(2-benzyloxy-6-hydroxybenzoyl)-3,5-di-
phenylpyrazole (5a, 320 mg, 56%) and 4-benzoyl-3-(2-benzyloxy-6-
hydroxyphenyl)-5-phenylpyrazole (6a, 160 mg, 28%).
Method B: Hydrazine hydrate (0.37 mL, 7.67 mmol) was added to
a
solution of 3-benzoyl-5-benzyloxyflavone (4a, 550 mg,
5-Benzyloxy-4Ј-methoxy-3-(4-methoxybenzoyl)flavone (4d): Yield
90%. M.p. 155Ϫ157 °C (recrystallization from ethanol). H NMR:
1
1.28 mmol) in methanol (50 mL). The mixture was heated (80 °C)
under nitrogen for 20 h. After this period the reaction mixture was
poured into water and extracted with chloroform (3 ϫ 100 mL).
The solvent was evaporated to dryness and the residue was dis-
solved in dichloromethane and chromatographed on preparative
thin layer chromatographic plates, eluting several times with dichlo-
romethane. Two very close spots were collected, representing, with
increasing Rf values, 4-(2-benzyloxy-6-hydroxybenzoyl)-3,5-di-
phenylpyrazole (5a, 297 mg, 52%) and 4-benzoyl-3-(2-benzyloxy-6-
hydroxyphenyl)-5-phenylpyrazole (6a, 171 mg, 30%).
δ ϭ 3.78 (s, 3 H, 4Ј-OCH3), 3.82 (s, 3 H, 4ЈЈ-OCH3), 5.26 (s, 2 H,
5-OCH2C6H5), 6.84 (d, J ϭ 6.0 Hz, 2 H, 3ЈЈ,5ЈЈ-H), 6.85 (d, J ϭ
6.5 Hz, 2 H, 3Ј,5Ј-H), 6.86 (d, J ϭ 8.5 Hz, 1 H, 6-H), 7.12 (dd, J ϭ
8.5, 0.9 Hz, 1 H, 8-H), 7.26 (t, J ϭ 7.2 Hz, 1 H, 4-H of 5-
OCH2C6H5), 7.35 (t, J ϭ 7.2 Hz, 2 H, 3,5-H of 5-OCH2C6H5), 7.55
(d, J ϭ 7.2 Hz, 2 H, 2,6-H of 5-OCH2C6H5), 7.55 (t, J ϭ 8.5 Hz,
1 H, 7-H), 7.63 (d, J ϭ 6.5 Hz, 2 H, 2Ј,6Ј-H), 7.93 (d, J ϭ 6.0 Hz,
2 H, 2ЈЈ,6ЈЈ-H) ppm. 13C NMR: δ ϭ 55.3 (4Ј-OCH3), 55.4 (4ЈЈ-
OCH3), 70.9 (5-OCH2C6H5), 108.6 (C-6), 110.3 (C-8), 113.9 (C-
3Ј,5Ј), 114.1 (C-3ЈЈ,5ЈЈ), 114.4 (C-10), 122.7 (C-3), 123.7 (C-1Ј),
126.7 (C-2,6 of 5-OCH2C6H5), 127.6 (C-4 of 5-OCH2C6H5), 128.6
(C-3,5 of 5-OCH2C6H5), 130.1 (C-2Ј,6Ј), 130.4 (C-1ЈЈ), 131.9 (C-
2ЈЈ,6ЈЈ), 133.9 (C-7), 136.3 (C-1 of 5-OCH2C6H5), 158.0 (C-9),
158.8 (C-5), 159.3 (C-2), 161.8 (C-4Ј), 163.9 (C-4ЈЈ), 176.0 (C-4),
192.8 (CϭO) ppm. EI-MS: m/z (%) ϭ 492 (96) [Mϩ·], 474 (12), 402
(46), 386 (28), 373 (22), 357 (40), 295 (10), 278 (15), 159 (24), 135
(93), 107 (7), 91 (94), 78 (91), 63 (100). C31H24O6 (510.18): calcd.
C 72.93, H 5.13; found C 72.83, H 5.34.
4-(2-Benzyloxy-6-hydroxybenzoyl)-3,5-diphenylpyrazole (5a): Yield
56%. M.p. 150Ϫ152 °C (recrystallization from methanol). 1H
NMR: δ ϭ 4.51 (s, 2 H, 2ЈЈ-OCH2C6H5), 5.94 (br. d, J ϭ 8.3 Hz,
1 H, 3ЈЈ-H), 6.52 (dd, J ϭ 8.3, 0.6 Hz, 1 H, 5ЈЈ-H), 6.89Ϫ6.92 (m,
2 H, 2,6-H of 2ЈЈ-OCH2C6H5), 7.14Ϫ7.33 (m, 8 H, 2Ј,3Ј,4Ј,5Ј,6Ј-H
and 3,4,5-H of 2ЈЈ-OCH2C6H5), 7.57 (t, J ϭ 8.3 Hz, 1 H, 4ЈЈ-H),
11.90 (s, 1 H, 2ЈЈ-OH) ppm. 13C NMR: δ ϭ 70.0 (2ЈЈ-OCH2C6H5),
101.8 (C-3ЈЈ), 110.0 (C-5ЈЈ), 113.0 (C-1ЈЈ), 120.0 (C-4), 126.6 (C-2,6
of 2ЈЈ-OCH2C6H5), 127.8 (C-4 of 2ЈЈ-OCH2C6H5), 127.9 (2 ϫ C-
2Ј,6Ј), 128.2 (C-3,5 of 2ЈЈ-OCH2C6H5), 128.3 (2 ϫ C-3Ј,5Ј), 128.6
(2 ϫ C-4Ј), 130.3 (2 ϫ C-1Ј), 135.7 (C-1 of 2ЈЈ-OCH2C6H5), 136.2
5-Benzyloxy-4Ј-methyl-3-(4-methylbenzoyl)flavone (4e): Yield 94%.
1
M.p. 174Ϫ177 °C (recrystallization from ethanol). H NMR: δ ϭ
2.32 (s, 3 H, 4Ј-CH3), 2.36 (s, 3 H, 4ЈЈ-CH3), 5.27 (s, 2 H, 5- (C-4ЈЈ), 148.0 (C-3,5), 159.2 (C-2ЈЈ), 163.0 (C-6ЈЈ), 195.2 (CϭO)
OCH2C6H5), 6.87 (d, J ϭ 8.3 Hz, 1 H, 6-H), 7.13 (d, J ϭ 8.3 Hz, ppm. EI-MS: m/z (%) ϭ 446 (98) [Mϩ·], 428 (22), 311 (53), 247
1 H, 8-H), 7.14 (d, J ϭ 8.1 Hz, 2 H, 3Ј,5Ј-H), 7.18 (d, J ϭ 8.1 Hz,
(16), 233 (9), 221 (33), 104 (9), 91 (100), 77 (12), 65 (14).
2 H, 3ЈЈ,5ЈЈ-H), 7.26Ϫ7.29 (m, 1 H, 4-H of 5-OCH2C6H5), 7.35 (t, C29H22N2O3 (446.16): calcd. C 78.01, H 4.97, N 6.27; found C
J ϭ 7.6 Hz, 2 H, 3,5-H of 5-OCH2C6H5), 7.54 (d, J ϭ 7.6 Hz, 2 78.12, H 4.99, N 6.23.
3812
Eur. J. Org. Chem. 2002, 3807Ϫ3815

3-Aroyl-5-hydroxyflavones
FULL PAPER
4-Benzoyl-3-(2-benzyloxy-6-hydroxyphenyl)-5-phenylpyrazole (6a):
(23), 91 (51), 77 (20). EI-HRMS: calcd. for C29H20O3N2Cl2 (Mϩ·
)
Yield 28%. Yellow oil Ϫ 1H NMR: δ ϭ 4.71 (s, 2 H, 2Ј- 536.1332, found 536.1334.
OCH2C6H5), 6.20 (d, J ϭ 8.1 Hz, 1 H, 3Ј-H), 6.62 (d, J ϭ 8.1 Hz,
4-(2-Benzyloxy-6-hydroxybenzoyl)-3,5-bis(4-chlorophenyl)-
pyrazole (5c): M.p. 108Ϫ110 °C (recrystallization from methanol).
1H NMR: δ ϭ 4.51 (s, 2 H, 2ЈЈ-OCH2C6H5), 5.99 (br. d, J ϭ
8.2 Hz, 1 H, 3ЈЈ-H), 6.54 (dd, J ϭ 8.2, 0.6 Hz, 1 H, 5ЈЈ-H), 6.89
(m, 2 H, 2,6-H of 2ЈЈ-OCH2C6H5), 7.13 (AB, J ϭ 8.3 Hz, 4 H, 2
ϫ 3Ј,5Ј-H), 7.16 (AB, J ϭ 8.3 Hz, 4 H, 2 ϫ 2Ј,6Ј-H), 7.10Ϫ7.20
(m, 4 H, 4ЈЈ-H and 3,4,5-H of 2ЈЈ-OCH2C6H5), 11.77 (s, 1 H, 2ЈЈ-
OH) ppm. 13C NMR: δ ϭ 70.0 (2ЈЈ-OCH2C6H5), 101.9 (C-3ЈЈ),
110.3 (C-5ЈЈ), 112.8 (C-1ЈЈ), 120.4 (C-4), 126.7 (C-2,6 of 2ЈЈ-
OCH2C6H5), 127.9 (C-4 of 2ЈЈ-OCH2C6H5), 128.3 (C-3,5 of 2ЈЈ-
OCH2C6H5), 128.4 (2 ϫ C-1Ј), 128.5 (2 ϫ C-3Ј,5Ј), 129.0 (2 ϫ C-
2Ј,6Ј), 134.8 (2 ϫ C-4Ј), 135.5 (C-1 of 2ЈЈ-OCH2C6H5), 136.7 (C-
4ЈЈ), 147.0 (C-3,5), 159.0 (C-2ЈЈ), 163.0 (C-6ЈЈ), 194.6 (CϭO) ppm.
EI-MS: m/z (%) ϭ 514 (32) [Mϩ·], 379 (6), 289 (5), 91 (100), 65 (6).
C29H20Cl2N2O3 (514.09): calcd. C 67.58, H 3.91, N 5.44; found C
67.23, H 4.11, N 5.26.
1 H, 5Ј-H), 6.99 (t, J ϭ 8.1 Hz, 1 H, 4Ј-H), 7.09Ϫ7.14 (m, 5 H,
2,3,4,5,6-H of 2Ј-OCH2C6H5), 7.16Ϫ7.25 (m, H,
5
3ЈЈ,4ЈЈ,5ЈЈ,3ЈЈЈ,5ЈЈЈ-H), 7.30 (t, J ϭ 7.6 Hz, 1 H, 4ЈЈЈ-H), 7.38Ϫ7.41
(m, 2 H, 2ЈЈ,6ЈЈ-H), 7.65 (d, J ϭ 7.6 Hz, 2 H, 2ЈЈЈ,6ЈЈЈ-H), 9.29 (br.
s, 1 H, NH), 11.87 (br. s, 1 H, 6Ј-OH) ppm. 13C NMR: δ ϭ 69.8
(2Ј-OCH2C6H5), 104.4 (C-3Ј), 107.3 (C-1Ј), 110.4 (C-5Ј), 117.9 (C-
4), 126.7 (C-2,6 of 2Ј-OCH2C6H5), 127.6 (C-4 of 2Ј-OCH2C6H5),
127.8 (C-3,5 of 2Ј-OCH2C6H5), 128.4 (C-3ЈЈ,5ЈЈ), 128.5 (C-2ЈЈ,6ЈЈ
and C-3ЈЈЈ,5ЈЈЈ), 128.9 (C-4ЈЈ), 129.4 (C-1ЈЈЈ), 129.7 (C-2ЈЈЈ,6ЈЈЈ),
130.6 (C-4Ј), 132.7 (C-4ЈЈЈ), 136.7 (C-1 of 2Ј-OCH2C6H5), 137.3
(C-1ЈЈ), 144.8 (C-3), 147.6 (C-5), 156.1 (C-6Ј), 156.3 (C-2Ј), 192.5
(CϭO) ppm. EI-MS: m/z (%) ϭ 446 (85) [Mϩ·], 429 (7), 369 (8),
341 (61), 311 (5), 193 (5), 105 (85), 91 (100), 77 (17), 65 (6). EI-
HRMS: calcd. for C29H22N2O3 (Mϩ·) 446.1630, found 446.1631.
3,5-Diaryl-4-(2-benzyloxy-6-hydroxybenzoyl)pyrazoles 5cϪe and 4-
aroyl-5-aryl-3-(2-benzyloxy-6-hydroxyphenyl)pyrazoles 6cϪe were
obtained from 3-aroyl-5-benzyloxyflavone 2bϪe in a similar man-
ner. The yields obtained were listed in Table 1
3-(2-Benzyloxy-6-hydroxyphenyl)-4-(4-chlorobenzoyl)-5-
1
(4-chlorophenyl)pyrazole (6c): Yellow oil. H NMR: δ ϭ 4.63 (s, 2
H, 2Ј-OCH2C6H5), 6.16 (d, J ϭ 8.3 Hz, 1 H, 3Ј-H), 6.40 (d, J ϭ
8.3 Hz, 1 H, 5Ј-H), 6.86 (t, J ϭ 8.3 Hz, 1 H, 4Ј-H), 7.01Ϫ7.05 (m,
6 H, 3ЈЈ,5ЈЈ,3ЈЈЈ,5ЈЈЈ-H and 2,6-H of 2Ј-OCH2C6H5), 7.09Ϫ7.18 (m,
5 H, 2ЈЈ,6ЈЈ-H and 3,4,5-H of 2Ј-OCH2C6H5), 7.49 (d, J ϭ 8.5 Hz,
2 H, 2ЈЈЈ,6ЈЈЈ-H), 10.36 (br. s, 1 H, NH), 11.77 (br. s, 1 H, 6Ј-OH)
ppm. 13C NMR: δ ϭ 69.9 (2Ј-OCH2C6H5), 104.1 (C-3Ј), 106.3 (C-
1Ј), 109.7 (C-5Ј), 117.1 (C-4), 126.9 (C-2,6 of 2Ј-OCH2C6H5), 127.6
(C-4 of 2Ј-OCH2C6H5), 128.1 (C-3ЈЈ,5ЈЈ), 128.3 (C-3,5 of 2Ј-
OCH2C6H5), 128.5 (C-3ЈЈЈ,5ЈЈЈ), 129.6 (C-2ЈЈ,6ЈЈ), 130.7 (C-4Ј),
130.9 (C-2ЈЈЈ,6ЈЈЈ), 134.7 (C-4ЈЈ), 135.4 (C-1ЈЈЈ), 136.3 (2 ϫ C-1ЈЈ
and C-1 of 2Ј-OCH2C6H5), 139.1 (C-4ЈЈЈ), 143.5 (C-3), 147.3 (C-
5), 155.4 (C-6Ј), 156.0 (C-2Ј), 191.7 (CϭO) ppm. EI-MS: m/z (%) ϭ
514 (20) [Mϩ·], 375 (11), 139 (36), 111 (7), 91 (100), 65 (7). EI-
Table 1. Yields of 5b؊e and 6b؊e
Compounds
5b
6b
5c
6c
5d
6d
5e
6e
Method A (%)
Method B (%)
64
48
Ϫ
24
55
57
22
40
69
51
25
37
61
58
24
40
4-(2-Benzyloxy-6-hydroxybenzoyl)-3,5-bis(4-nitrophenyl)-
pyrazole (5b): M.p. 202Ϫ204 °C (recrystallization from methanol).
1H NMR: δ ϭ 4.55 (s, 2 H, 2ЈЈ-OCH2C6H5), 6.07 (d, J ϭ 8.3 Hz,
1 H, 3ЈЈ-H), 6.60 (d, J ϭ 8.3 Hz, 1 H, 5ЈЈ-H), 6.95 (d, J ϭ 7.6 Hz,
2 H, 2,6-H of 2ЈЈ-OCH2C6H5), 7.23 (t, J ϭ 8.3 Hz, 1 H, 4ЈЈ-H),
7.29Ϫ7.35 (m, 3 H, 3,4,5-H of 2ЈЈ-OCH2C6H5), 7.51 (d, J ϭ 7.7 Hz,
2 H, 2Ј,6Ј-H), 8.18 (d, J ϭ 7.7 Hz, 2 H, -3Ј,5Ј-H), 11.85 (s, 1 H,
2ЈЈ-OH) ppm. 13C NMR: δ ϭ 70.6 (2ЈЈ-OCH2C6H5), 102.0 (C-3ЈЈ),
110.8 (C-5ЈЈ), 112.7 (C-1ЈЈ), 122.1 (C-4), 123.8 (2 ϫ C-3Ј,5Ј), 127.5
(C-2,6 of 2ЈЈ-OCH2C6H5), 128.4 (2 ϫ C-2Ј,6Ј and C-3,4,5 of 2ЈЈ-
OCH2C6H5), 135.1 (C-1 of 2ЈЈ-OCH2C6H5), 137.6 (2 ϫ C-1Ј and
C-4ЈЈ), 145.3 (C-3,5), 147.8 (2 ϫ C-4Ј), 159.2 (C-2ЈЈ), 163.6 (C-6ЈЈ),
194.5 (CϭO) ppm. EI-MS: m/z (%) ϭ 536 (44) [Mϩ·], 506 (12), 416
(5), 352 (8), 310 (29), 296 (9), 280 (30), 176 (7), 160 (10), 91 (100),
78 (7), 69 (13). C29H20N4O7 (536.13): calcd. C 64.92, H 3.76, N
10.44; found C 64.87, H 4.00, N 10.67.
HRMS: calcd. for C29H2035Cl2N2O3 (Mϩ·
514.0858.
) 514.0851, found
4-(2-Benzyloxy-6-hydroxybenzoyl)-3,5-bis(4-methoxyphenyl)-
pyrazole (5d): M.p. 94Ϫ97 °C (recrystallization from methanol). 1H
NMR: δ ϭ 3.74 (s, 6 H, 2 ϫ 4Ј-OCH3), 4.51 (s, 2 H, 2ЈЈ-
OCH2C6H5), 5.94 (dd, J ϭ 8.4, 0.7 Hz, 1 H, 3ЈЈ-H), 6.51 (dd, J ϭ
8.4, 0.7 Hz, 1 H, 5ЈЈ-H), 6.66 (d, J ϭ 8.8 Hz, 4 H, 2 ϫ 3Ј,5Ј-H),
6.89 (m, 2 H, 2,6-H of 2ЈЈ-OCH2C6H5), 7.09 (t, J ϭ 8.4 Hz, 1 H,
4ЈЈ-H), 7.13Ϫ7.17 (m, 3 H, 3,4,5-H of 2ЈЈ-OCH2C6H5), 7.20 (d, J ϭ
8.8 Hz, 4 H, 2 ϫ 2Ј,6Ј-H), 11.81 (s, 1 H, 2ЈЈ-OH) ppm. 13C NMR:
δ ϭ 54.9 (2 ϫ 4Ј-OCH3), 69.7 (2ЈЈ-OCH2C6H5), 101.9 (C-3ЈЈ), 109.8
(C-5ЈЈ), 113.0 (C-1ЈЈ), 113.5 (2 ϫ C-3Ј,5Ј), 119.3 (C-4), 122.7 (2 ϫ
C-1Ј), 126.3 (C-2,6 of 2ЈЈ-OCH2C6H5), 127.6 (C-4 of 2ЈЈ-
OCH2C6H5), 128.1 (C-3,5 of 2ЈЈ-OCH2C6H5), 129.2 (2 ϫ C-2Ј,6Ј),
135.8 (C-1 of 2ЈЈ-OCH2C6H5), 135.9 (C-4ЈЈ), 148.1 (C-3,5), 159.0
(C-2ЈЈ), 159.5 (2 ϫ C-4Ј), 162.6 (C-6ЈЈ), 195.1 (CϭO) ppm. EI-MS:
m/z (%) ϭ 506 (100) [Mϩ·], 488 (14), 415 (13), 370 (38), 307 (6),
280 (66), 265 (6), 91 (62). C31H26N2O5 (506.18): calcd. C 73.50, H
5.17, N 5.53; found C 73.23, H 4.91, N 5.31.
3-(2-Benzyloxy-6-hydroxyphenyl)-4-(4-nitrobenzoyl)-5-(4-nitro-
1
phenyl)pyrazole (6b): Yellow oil. H NMR (DMSO): δ ϭ 4.96 (s, 2
H, 2Ј-OCH2C6H5), 6.30 (d, J ϭ 8.3 Hz, 1 H, 5Ј-H), 6.38 (d, J ϭ
8.3 Hz, 1 H, 3Ј-H), 6.98 (t, J ϭ 8.3 Hz, 1H. 4Ј-H), 7.27Ϫ7.33 (m,
5 H, 2,3,4,5,6-H of 2Ј-OCH2C6H5), 7.68 (d, J ϭ 8.6 Hz, 2 H,
2ЈЈ,6ЈЈ-H), 7.88 (d, J ϭ 8.7 Hz, 2 H, 2ЈЈЈ,6ЈЈЈ-H), 7.94 (d, J ϭ
8.6 Hz, 2 H, 3ЈЈ,5ЈЈ-H), 8.22 (d, J ϭ 8.7 Hz, 2 H, 3ЈЈЈ,5ЈЈЈ-H), 9.95 3-(2-Benzyloxy-6-hydroxyphenyl)-4-(4-methoxybenzoyl)-
(NH), 13.75 (OH) ppm. 13C NMR (DMSO): δ ϭ 69.5 (2Ј- 5-(4-methoxyphenyl)pyrazole (6d): Yellow oil. 1H NMR: δ ϭ 3.66
OCH2C6H5), 102.9 (C-3Ј), 105.0 (C-1Ј), 108.2 (C-5Ј), 117.1 (C-4), (s, 3 H, 4ЈЈ-OCH3), 3.71 (s, 3 H, 4ЈЈЈ-OCH3), 4.67 (s, 2 H, 2Ј-
122.7 (C-3ЈЈ,5ЈЈ), 123.4 (C-3ЈЈЈ,5ЈЈЈ), 127.2 (C-2,6 of 2Ј-
OCH2C6H5), 6.15 (d, J ϭ 8.2 Hz, 1 H, 3Ј-H), 6.56 (d, J ϭ 8.2 Hz,
OCH2C6H5), 127.7 (C-4 of 2Ј-OCH2C6H5), 128.4 (C-3,5 of 2Ј- 1 H, 5Ј-H), 6.61 (d, J ϭ 7.1 Hz, 2 H, 3ЈЈЈ,5ЈЈЈ-H), 6.66 (d, J ϭ
OCH2C6H5), 129.4 (C-2ЈЈЈ,6ЈЈЈ), 129.9 (C-2ЈЈ,6ЈЈ), 131.1 (C-4Ј), 8.8 Hz, 2 H, 3ЈЈ,5ЈЈ-H), 6.91 (t, J ϭ 8.2 Hz, 1 H, 4Ј-H), 7.06Ϫ7.10
136.9 (C-1 of 2Ј-OCH2C6H5), 139.6 (C-1ЈЈЈ), 140.5 (C-3), 143.4 (C- (m, 2 H, 2,6-H of 2Ј-OCH2C6H5), 7.14Ϫ7.19 (m, 3 H, 3,4,5-H of
1ЈЈ), 146.8 (C-4ЈЈЈ), 148.8 (C-4ЈЈ), 149.6 (C-5), 156.1 (C-6Ј), 156.7 2Ј-OCH2C6H5), 7.26 (d, J ϭ 8.8 Hz, 2 H, 2ЈЈ,6ЈЈ-H), 7.66 (d, J ϭ
(C-2Ј), 189.6 (CϭO) ppm. FABϩ-MS: m/z (%) ϭ 537 (20) [[M ϩ 7.1 Hz, 2 H, 2ЈЈЈ,6ЈЈЈ-H), 10.26 (br. s, 1 H, NH), 11.84 (br. s, 1 H,
H]ϩ·], 536 (7), 307 (23), 289 (13), 154 (100), 136 (70), 120 (13), 107
6Ј-OH) ppm. 13C NMR: δ ϭ 55.1 (4ЈЈ-OCH3), 55.2 (4ЈЈЈ-OCH3),
Eur. J. Org. Chem. 2002, 3807Ϫ3815
3813

A. M. S. Silva et al.
FULL PAPER
[5]
[6]
[7]
E. Middleton Jr., C. Kandaswami, in The Flavonoids-Advances
in Research Since 1986 (Ed.: J. B. Harborne), Chapman and
Hall, London, 1994, p. 619Ϫ652.
E. S. C. Wu, J. T. Loch III, B. H. Toder, A. R. Borrelli, D.
Gawlak, L. A. Radov, N. P. Gensmantel, J. Med. Chem. 1992,
35, 3519Ϫ3525.
J. Morris, D. G. Wishka, A. H. Lin, W. R. Humphrey, A. L.
Wiltse, R. B. Gammill, T. M. Judge, S. N. Bisaha, N. L. Olds,
C. S. Jacob, C. L. Bergh, M. M. Cudahy, D. J. Williams, E. E.
Nishizawa, E. W. Thomas, R. R. Gorman, C. W. Benjamin, R.
J. Shebuski, J. Med. Chem. 1993, 36, 2026Ϫ2032.
69.6 (2Ј-OCH2C6H5), 104.2 (C-3Ј), 107.4 (C-1Ј), 109.9 (C-5Ј), 113.1
(C-3ЈЈЈ,5ЈЈЈ), 113.7 (C-3ЈЈ,5ЈЈ), 117.2 (C-4), 121.7 (C-1ЈЈ), 126.6 (C-
2,6 of 2Ј-OCH2C6H5), 127.3 (C-4 of 2Ј-OCH2C6H5), 128.2 (C-3,5
of 2Ј-OCH2C6H5), 129.6 (C-2ЈЈ,6ЈЈ), 130.1 (C-1ЈЈЈ), 130.3 (C-4Ј),
132.0 (C-2ЈЈЈ,6ЈЈЈ), 136.9 (C-1 of 2Ј-OCH2C6H5), 144.5 (C-3), 146.6
(C-5), 155.9 (C-6Ј), 156.2 (C-2Ј), 159.7 (C-4ЈЈ), 163.1 (C-4ЈЈЈ), 191.7
(CϭO) ppm. EI-MS: m/z (%) ϭ 506 (58) [Mϩ·], 489 (6), 415 (10),
399 (18), 371 (29), 308 (10), 280 (8), 225 (5), 152 (5), 135 (100),
112 (22), 91 (70), 77 (16), 65 (16), 56 (42). EI-HRMS: calcd. for
C31H26N2O5 (Mϩ·) 506.1842, found 506.1845.
[8]
[9]
4-(2-Benzyloxy-6-hydroxybenzoyl)-3,5-bis(4-methylphenyl)-
pyrazole (5e): M.p. 143Ϫ144 °C (recrystallization from methanol).
1H NMR: δ ϭ 2.26 (s, 6 H, 2 ϫ 4Ј-CH3), 4.49 (s, 2 H, 2ЈЈ-
OCH2C6H5), 5.92 (d, J ϭ 8.2 Hz, 1 H, 3ЈЈ-H), 6.50 (d, J ϭ 8.2 Hz,
1 H, 5ЈЈ-H), 6.85 (m, 2 H, 2,6-H of 2ЈЈ-OCH2C6H5), 6.93 (d, J ϭ
8.0 Hz, 4 H, 2 ϫ 3Ј,5Ј-H), 7.08 (t, J ϭ 8.2 Hz, 1 H, 4ЈЈ-H),
7.10Ϫ7.15 (m, 3 H, 3,4,5-H of 2ЈЈ-OCH2C6H5), 7.14 (d, J ϭ 8.8 Hz,
4 H, 2 ϫ 2Ј,6Ј-H), 11.92 (s, 1 H, 2ЈЈ-OH) ppm. 13C NMR: δ ϭ
21.2 (2 ϫ 4Ј-CH3), 69.8 (2ЈЈ-OCH2C6H5), 101.8 (C-3ЈЈ), 109.9 (C-
5ЈЈ), 113.0 (C-1ЈЈ), 119.7 (C-4), 126.4 (C-2,6 of 2ЈЈ-OCH2C6H5),
127.7 (2 ϫ C-1Ј,2Ј,6Јand C-4 of 2ЈЈ-OCH2C6H5), 128.2 (C-3,5 of
C. Wolfman, H. Viola, M. Marder, C. Wasowski, P. Ardenghi,
I. Izquierdo, A. C. Paladini, J. H. Medina, Eur. J. Parmacol.
1996, 318, 23Ϫ30.
T. Akama, H. Ishida, Y. Shida, U. Kimura, K. Gomi, H. Saito,
E. Fuse, S. Kobayashi, N. Yoda, M. Kasai, J. Med. Chem. 1997,
40, 1894Ϫ1900.
J. A. Manthey, N. Guthrie, K. Grohmann, Curr. Med. Chem.
2001, 8, 135Ϫ153.
J. M. Gee, I. T. Johnson, Curr. Med. Chem. 2001, 8,
1245Ϫ1255.
C. A. Rice-Evans, N. J. Miller, G. Paganga, Free Rad. Biol.
Med. 1996, 20, 933Ϫ956.
W. Bors, W. Heller, C. Michel, K. Stettmaier, in Handbook of
Antioxidants (Ed.: E. Cadenas and L. Packer), Marcel Dekker,
New York, 1996, p. 409Ϫ466.
C. A. Rice-Evans, L. Packer, Flavonoids in Health and Disease,
Marcel Dekker, New York, 1998.
C. Rice-Evans, Curr. Med. Chem. 2001, 8, 797Ϫ807.
P.-G. Pietta, J. Nat. Prod. 2000, 63, 1035Ϫ1042.
F. Shahidi, M. Naczk, Food Phenolics Ϫ Sources, Chemistry,
Effects, Applications, Technomic Publishing AG, Basel, 1995,
p. 171Ϫ198.
N. R. Guz, F. R. Stermitz, J. B. Johnson, T. D. Beeson, S.
Willen, J.-F. Hsiang, K. Lewis, J. Med. Chem. 2001, 44,
261Ϫ268.
G. Comte, J.-B. Daskiewicz, C. Bayet, G. Conseil, A. Viornery-
Vanier, C. Dumontet, A. D. Pietro, D. Barron, J. Med. Chem.
2001, 44, 763Ϫ768.
M. B. Hogale, B. N. Pawar, B. P. Nikam, J. Indian Chem. Soc.
1987, 64, 486Ϫ487.
J. H. Looker, W. W. Hanneman, J. Org. Chem. 1962, 27,
3261Ϫ3263.
J. H. Looker, J. R. Edman, I. Dappen, J. Heterocycl. Chem.
1964, 1, 141Ϫ144.
E. M. Gaydou, J.-P. Bianchini, Bull. Soc. Chim. Fr. 1978, II,
43Ϫ47.
A. M. Cardoso, A. M. S. Silva, C. M. F. Barros, L. M. P.
M. Almeida, A. J. Ferrer-Correia, J. A. S. Cavaleiro, J. Mass
Spectrom. 1997, 32, 930Ϫ939.
[10]
[11]
[12]
[13]
2ЈЈ-OCH2C6H5), 128.8 (2
ϫ C-3Ј,5Ј), 135.7 (C-1 of 2ЈЈ-
OCH2C6H5), 135.9 (C-4ЈЈ), 138.2 (2 ϫ C-4Ј), 148.1 (C-3,5), 159.2
(C-2ЈЈ), 162.9 (C-6ЈЈ), 195.3 (CϭO) ppm. EI-MS: m/z (%) ϭ 474
(65) [Mϩ·], 456 (15), 384 (9), 338 (24), 275 (8), 248 (60), 202 (5),
121 (9), 91 (100), 65 (13). C31H26N2O3 (474.19): calcd. C 78.46, H
5.52, N 5.90; found C 78.42, H 5.63, N 5.92.
[14]
[15]
[16]
[17]
3-(2-Benzyloxy-6-hydroxyphenyl)-4-(4-methylbenzoyl)-5-
1
(4-methylphenyl)pyrazole (6e): Yellow oil. H NMR: δ ϭ 2.17 (s, 3
H, 4ЈЈ-CH3), 2.21 (s, 3 H, 4ЈЈЈ-CH3), 4.62 (s, 2 H, 2Ј-OCH2C6H5),
6.10 (d, J ϭ 8.2 Hz, 1 H, 3Ј-H), 6.52 (d, J ϭ 8.2 Hz, 1 H, 5Ј-H),
6.86 (t, J ϭ 8.2 Hz, 1 H, 4Ј-H), 6.89 (d, J ϭ 7.0 Hz, 2 H, 3ЈЈ,5ЈЈ-
H), 6.91 (d, J ϭ 8.1 Hz, 2 H, 3ЈЈЈ,5ЈЈЈ-H), 7.04Ϫ7.07 (m, 2 H, 2,6-
H of 2Ј-OCH2C6H5), 7.11Ϫ7.22 (m, 5 H, 2ЈЈ,6ЈЈ-H and 3,4,5-H of
2Ј-OCH2C6H5), 7.58 (d, J ϭ 8.1 Hz, 2 H, 2ЈЈЈ,6ЈЈЈ-H), 10.47 (br. s,
1 H, NH), 11.94 (br. s, 1 H, 6Ј-OH) ppm. 13C NMR: δ ϭ 21.1 (4ЈЈ-
CH3), 21.5 (4ЈЈЈ-CH3), 69.5 (2Ј-OCH2C6H5), 104.0 (C-3Ј), 107.2 (C-
1Ј), 109.8 (C-5Ј), 117.3 (C-4), 126.5 (C-2,6 of 2Ј-OCH2C6H5), 127.2
(C-4 of 2Ј-OCH2C6H5), 127.7 (C-1ЈЈ), 128.1 (C-2ЈЈ,6ЈЈ), 128.2 (C-
3,5 of 2Ј-OCH2C6H5), 128.5 (C-3ЈЈЈ,5ЈЈЈ), 128.9 (C-3ЈЈ,5ЈЈ), 129.7
(C-2ЈЈЈ,6ЈЈЈ), 130.0 (C-4Ј), 134.8 (C-1ЈЈЈ), 136.8 (C-1 of 2Ј-
OCH2C6H5), 138.4 (C-4ЈЈ), 143.2 (C-4ЈЈЈ), 144.4 (C-3), 147.0 (C-5),
155.9 (C-6Ј), 156.0 (C-2Ј), 192.6 (CϭO) ppm. EI-MS: m/z (%) ϭ
474 (45) [Mϩ·], 384 (6), 367 (8), 355 (30), 248 (5), 207 (5), 119 (100),
91 (85), 65 (14). EI-HRMS: calcd. for C31H26N2O3 (Mϩ·) 474.1943,
found 474.1946.
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
H. M. Chawla, S. K. Sharma, Synth. Commun. 1990, 20,
301Ϫ306.
Acknowledgments
´
´
´
C. Nemes, A. Levai, T. Patonay, G. Toth, S. Boros, J. Halasz,
Sincere thanks are expressed to the University of Aveiro and the
W. Adam, D. Golsch, J. Org. Chem. 1994, 59, 900Ϫ905.
M. G. Dhara, S. K. De, A. K. Mallik, Tetrahedron Lett. 1996,
37, 8001Ϫ8002.
M. M. Chincholkar, V. S. Jamode, Indian J. Chem. 1979, 17B,
510Ϫ511.
J. T. Ganvir, V. N. Ingle, J. Indian Chem. Soc. 1988, 65,
878Ϫ879.
M. M. Chincholkar, V. S. Jamode, Acta Ciencia 1982, VIIc,
63Ϫ65.
D. C. G. A. Pinto, A. M. S. Silva, J. A. S. Cavaleiro, C. Foces-
Foces, A. L. Llamas-Saiz, N. Jagerovic, J. Elguero, Tetrahedron
1999, 55, 10187Ϫ10200.
ˆ
‘‘Fundaca˜o para a Ciencia e Tecnologia’’, Portugal, for funding the
¸
Organic Chemistry Research Unit.
[1]
The Flavonoids-Advances in Research Since 1986 (Ed.: J. B.
Harborne), Chapman and Hall, London, 1994.
K. V. Rao, S. K. Chattopadhyay, G. C. Reddy, J. Agric. Food
[2]
Chem. 1990, 38, 1427Ϫ1430.
[3]
M. Weidenborner, H. C. Jha, Pestic. Sci. 1993, 38, 347Ϫ351.
[4]
A. M. S. Silva, M. Weidenbörner, J. A. S. Cavaleiro, Mycol.
Res. 1998, 102, 638Ϫ640.
3814
Eur. J. Org. Chem. 2002, 3807Ϫ3815

3-Aroyl-5-hydroxyflavones
FULL PAPER
[32]
[37]
[38]
´
´
´
D. C. G. A. Pinto, A. M. S. Silva, J. A. S. Cavaleiro, J. Hetero-
J. A. Hueso-Rodrıguez, J. Berrocal, B. Gutierrez, A. J. Farre,
J. Frigola, Bioorg. Med. Chem. Lett. 1993, 3, 269Ϫ272.
A. Torrens, J. A. Castrillo, A. Claparols, J. Redondo, Synlett
1999, 765Ϫ767.
cycl. Chem. 2000, 37, 1629Ϫ1634.
J. Elguero, in Comprehensive Heterocyclic Chemistry II (Eds: A.
[33]
R. Katritzky, C. W. Rees, E. F. Scriven), Pergamon, Oxford,
[39]
[40]
W. B a ke r, J. Chem. Soc. 1933, 1381Ϫ1389.
H. S. Mahal, K. Venkataraman, J. Chem. Soc. 1934,
1767Ϫ1769.
A. M. S. Silva, D. C. G. A. Pinto, J. A. S. Cavaleiro, Tetrahed-
ron Lett. 1994, 35, 5899Ϫ5902.
1996, vol. 3, p. 1Ϫ75.
[34]
´
´
J. Catalan, F. Fabero, R. M. Claramunt, M. D. Santa Marıa,
´
M. C. Foces-Foces, F. H. Cano, M. Martınez-Ripoll, J. El-
[41]
[42]
guero, R. Sastre, J. Am. Chem. Soc. 1992, 114, 5039Ϫ5048.
R. Ahmad, N. Ahmad, M. Zia-Ul-Haq, A. Wahid, J. Chem.
Soc. Pak. 1996, 18, 38Ϫ41.
[35]
[36]
D. C. G. A. Pinto, A. M. S. Silva, J. A. S. Cavaleiro, J. Hetero-
cycl. Chem. 1996, 33, 1887Ϫ1893.
K. Takagi, M. Tanaka, Y. Murakami, H. Morita, T. Aotsuka,
Received May 8, 2002
Eur. J. Med. Chem.- Chim. Ther. 1986, 21, 65Ϫ69.
[O02250]
Eur. J. Org. Chem. 2002, 3807Ϫ3815
3815