A one-step synthesis of 5-hydroxyflavones

Article abstract of DOI:10.1055/s-1999-2844

5-hydroxy flavones were prepared in one step starting from 2,6- dihydroxyacetophenone. The latter was treated with an aroyl chloride in the presence of an excess of potassium carbonate to afford 5-hydroxyflavones.

Full text of DOI:10.1055/s-1999-2844

1480
LETTER
A One-Step Synthesis of 5-Hydroxyflavones
Frédéric Bois, Chantal Beney, Anne-Marie Mariotte, Ahcène Boumendjel*
Laboratoire de Pharmacognosie, Departement de Pharmacochimie Moléculaire. UMR-CNRS EP 811. Faculté de Pharmacie de Grenoble,
38706 La Tronche- France
Fax +33 (4) 76 63 71 65. E-mail: Ahcene.Boumendjel@ujf-grenoble.fr
Received 15 July 1999
taining sulfuric acid. Recent publications have reported
Abstract: 5-hydroxy flavones were prepared in one step starting
the preparation of diketone 2 in one step from substituted
from 2,6-dihydroxyacetophenone. The latter was treated with an
2-hydroxyacetophenone by consecutive treatment of the
latter with 2.2 equivalents of KOtBu and an aroyl chlo-
ride.7
aroyl chloride in the presence of an excess of potassium carbonate
to afford 5-hydroxyflavones.
Key words: 5-hydroxyflavones, one-step synthesis
O
R2
R1
R2
R1
OH
O
Flavonoids are a group of low molecular weight com-
pounds mainly occurring in the plant kingdom. One of the
most abundant being the flavones, which most commonly
occur in nature as hydroxyl derivatives or their partial me-
thyl ethers.1 Beside their well known antioxidant activity,
flavonoids are known to inhibit protein kinases.2 Recent
structure-activity relationship studies have correlated the
flavone activity with their ability to mimic the adenine
moiety of ATP where the 5-OH plays a critical role. This
analogy was recently demonstrated by the high resolution
X ray structure of cyclin-dependent protein kinase 2 co-
crystallized with a 8-substituted 5-hydroxyflavone,
(L868276).3 The 5-hydroxy group of L868276 was shown
to interact with as many as five residues normally interact-
ing with the 6-amino group of the adenine moiety of ATP,
whereas the vicinal 4-carbonyl appeared equivalent to the
1-nitrogen atom of adenine. The recent cocrystallization
of quercetin (5,7,3’,4’-tetrahydroxyflavonol) with ty-
rosine kinase Hck confirmed the role of A and C rings of
5-hydroxyflavone for mimicking the adenine moiety of
nucleotides.4 Our interest in the biological properties of
variably substituted 5-hydroxyflavones prompted us to re-
investigate their synthesis.
O
O
C
base
+
Cl
O
1
R2
R1
R1
R2
OH
O
O
O
H2SO4
AcOH
base
O
2
Conventional Baker-Venkataraman synthesis of flavones
Scheme 1
We have reinvestigated the Baker-Venkataraman reaction
and we would like to report here that 5-hydroxyflavones
can be obtained directly from 2,6-dihydroxyacetophenone
in reasonable yields. The synthesis of 5-hydroxyflavones
is shown on scheme 2. Treatment of 2,6-dihydroxyace-
tophenone with an excess of potassium carbonate in ace-
tone followed by addition of the aroylchloride and
refluxing for 24 h afford after subsequent hydrolysis, a
mixture of three compounds: A small amount of unreacted
2,6-dihydroxyacetophenone, the corresponding aroyl mo-
noester and the expected 5-hydroxyflavone which was
isolated by flash chromtography.
3'
2'
1'
4'
5'
1
B
8
O
2
7
6
6'
A
C
3
4
OH
5
O
K2CO3
OH
O
+
R
Cl
Acetone
reflux
5-hydroxyflavone
R
OH
O
O
OH
O
Scheme 2
Among the reported methods to synthesize flavones, the
Baker-Venkataraman is a largely applied one.5,6
In this method (scheme 1), a 2-hydroxyacetophenone is
converted to a benzoylester 1. The ester is treated with a
base to induce an intramolecular Claisen condensation
forming a 1,3-diketone 2 which is cyclized to the corre-
sponding flavone upon heating in glacial acetic acid con-
Although the overall yields of purified products are slight-
ly lower than those obtained by the conventional Baker-
Venkataraman sequence. It should be noted that the
present method is simple and is less time-consuming. This
Synlett 1999, No. 9, 1480–1482 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A One-Step Synthesis of 5-Hydroxyflavones
1481
procedure also avoids the acid-catalyzed cyclization In the case of 2-hydroxyacetophenone bearing no hydrox-
which could be incompatible with the presence of acid yl group in the 6-position, the ester 3b is formed and rear-
sensitive substituents. Table 1 indicates the different 5-hy- ranges to give the diketone 4b which may adopt the more
droxyflavones prepared by this method.
stable form 4c (on account of chelation of the hydroxyl
group by the enolized ketone) 8, thus avoiding the cycliza-
tion to 5b. In this case, a strong acidic treatment becomes
necessary in order to break the hydrogen bonding and al-
low the formation of the conformer 4d required for the cy-
clization.
O
O
R - OH
K2CO3
O
O
C
R
O
O
R
4b
3b
O
H
O
O
O
X
O
R
4c
5b
R
O
Substrates with no hydroxyl group or with a masked OH
in the 6-position of the 2-hydroxyacetophenone, when
subjected to the same experimental conditions do not give
flavones. In this contest, b-diketone is the main product.
In order to rationalize the difference in reactivity between
2,6-dihydroxyacetophenone and 2-hydroxyacetophenone,
the following mechanism is proposed. When 2,6-dihy-
droxyacetophenone is treated with K2CO3 and one equiv-
alent of an aroyl chloride, the ester 3a is obtained. In the
presence of a base, the enolate of the acetyl group is
formed and attacks the carbonyl of the ester to give mainly
the diketone 4a which may be in equilibrium with the cy-
clic intermediate 5a. When the reaction mixture is hydro-
lyzed, the intermediate 6 becomes the first compound
formed. The protonated hydroxyl group now being a good
leaving group, is eliminated to give 5-hydroxyflavone.
H+
O
OH
O
R
O
R
O
4d
Scheme 4
In summary, a convenient and short preparation of 5-hy-
droxyflavones has been developed. This reaction has been
successfully applied to the convenient synthesis of a num-
ber of 5-hydroxyflavones.
Synthesis of 5-hydroxyflavones, general procedure: To
a solution of 2,6-dihydroxyacetophenone in dry acetone
(5mL/mmol) was added anhydrous potassium carbonate
(5 eq). The solution was stirred at room temperature for 10
min and aroylchloride (1eq) was added. The mixture was
stirred at reflux for 24 h. After cooling to room tempera-
ture, water was added and the acetone was evaporated.
Extraction with ethyl acetate, washing with water and
brine afforded the crude material which was purified by
column chromatography using hexane:ethyl acetate (4:1)
as eluent.
O
OH
O
O
O
+
Cl
OH
O
OH
3a
O
O
O
K2CO3
O
O
5a
O
O
O
H
H
4a
References and Notes
O
O
H2O
(1) Harborne, J. B. In The flavonoids: Advances in Research
Since 1986: Chapman and Hall: London, 1994.
OH
(2) (a). Levitzki, A.; Gazit, A. Science 1995, 267, 1782.
(b). Cushman, M. ; Zhu, H.; Geahlen, R. L.; Kraker, A. J.
J. Med. Chem. 1994, 37, 3353. (c). Cunningham, B. D.;
O
O
O
O
H
H
6
Scheme 3
Synlett 1999, No. 9, 1480–1482 ISSN 0936-5214 © Thieme Stuttgart · New York

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F. Bois et al.
LETTER
(6) Linuma, M.; Tanaka, L.; Matsuura, S. Chem. Pharm. Bull.
Threadgill, M. D. Groundwater, P. W. Dale, I. L.; Hickman, J.
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(3) De Azevedo, W. F. Jr.; Mueller-Dieckmann, H. J.; Schulze-
Gahmen, U.; Worland, P. J.; Sausville, E.; Kim, S. H. Proc.
Natl. Acad. Sci. USA. 1996, 93, 2735.
(7) Ares, J. J.; Outt, P. E.; Kakodkar, S. V.; Bass, R. C.; Geiger, J.
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(4) Sicheri, F.; Moarefi, I.; Kuriyan, J. Nature 1997, 385, 602.
(5) For reviews see Ref 1 and Gripenberg, J. In The Chemistry of
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Article Identifier:
1437-2096,E;1999,0,09,1480,1482,ftx,en;G16199ST.pdf
Synlett 1999, No. 9, 1480–1482 ISSN 0936-5214 © Thieme Stuttgart · New York