A new synthesis of flavonoids via Heck reaction

Article abstract of DOI:10.1016/j.tetlet.2003.10.060

Several naturally occuring flavonoids have been synthesised following a new proposed method based on the use of the Heck reaction. The key step involves the coupling of an aryl vinyl ketone with an aryl iodide. This procedure affords the flavonoid moiety in a single step.

Full text of DOI:10.1016/j.tetlet.2003.10.060

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9107–9109
A new synthesis of flavonoids via Heck reaction
Armandodoriano Bianco, Claudia Cavarischia,* Angela Farina, Marcella Guiso and Carolina Marra
Dipartimento di Chimica Universita` ‘La Sapienza’, Istituto di Chimica Biomolecolare del CNR, Piazzale Aldo Moro 5,
I-00185 Roma, Italy
Received 1 August 2003; revised 4 October 2003; accepted 10 October 2003
Abstract—Several naturally occurring flavonoids have been synthesised following a new proposed method based on the use of the
Heck reaction. The key step involves the coupling of an aryl vinyl ketone with an aryl iodide. This procedure affords the flavonoid
moiety in a single step.
© 2003 Elsevier Ltd. All rights reserved.
The flavonoids are a very well known family of natural
products found almost exclusively in the plant king-
dom, most of them are highly coloured and, as a
consequence, play a vital role in the ecology of plants
by making flowers and fruits attractive to bees and
birds. Many naturally occurring and synthetic
flavonoids are known to have significant biological
activities.1–3 The anti-inflammatory, antiviral and anti-
neoplastic activity of flavonoids have been reported.4–6
obtained by dehydrogenation of flavanones which are
readily accessible via the spontaneous cyclisation of the
isomeric chalcones.14
The alternative classic method involves the synthesis of
the intermediate 2-hydroxychalcone15 which undergoes
cyclisation to a flavanone and then dehydrogenation to
a flavone. The required chalcone is prepared by con-
densation of o-hydroxyacetophenone with an aryl alde-
hyde, benzaldehyde is the most widely used.16
Flavanone synthesis is well documented and no routine
examples are given here.17
Flavonoids have the same basic skeleton and the key
feature which distinguishes one structural type from the
other is the oxidation level of the various carbons in the
heterocyclic ring which results in a large number of
individuals.7 Much of our fundamental knowledge of
the flavonoids is due to the classical researches of Von
In addition to the classic routes, several alternative
syntheses have been recently developed. Flavones have
been prepared via several methods including condensa-
tion of phenylpropiolic acid with phenols18–20 and heat-
ing 2-iodophenols with arylacetylenes in the presence of
PdCl2[bis(diphenylphosphino)ferrocene] (dppf)2 gives
flavones.21 The palladium-catalysed carbonylative cou-
pling of 2-hydroxyaryliodides and ethynylarenes has
been carried out using Pd(OAc)2 (dppf)2 as the catalyst
8
Kostanecki and Perkin.9
The classic synthetic pattern for flavonoids follows two
main schemes of reaction. The first one involves acid-
catalysed cyclisation of an intermediate 1,3-diketone to
the flavone structure.10–13 Flavones may be easily
Scheme 1. Reagents and conditions: (i) Pd(OAc)2, Ph3P, CH3CN, Et3N.
Keywords: Heck reaction; flavonoids; palladium.
* Corresponding author. E-mail: claudia.cavarischia@uniroma1.it
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.060

9108
A. Bianco et al. / Tetrahedron Letters 44 (2003) 9107–9109
affording mixtures of flavones and aurones in varying
yields, depending on the substituents on both
reactants.22
ple steps (Scheme 2), in contrast to that recently
reported by Lebedev et al.,24 modifying the procedure
previously described by Stetter et al.25 The first step is a
Friedel–Crafts reaction on resorcinol dimethyl ether
using b-bromopropionyl chloride as acylating agent
and TiCl4 as the Lewis acid.26 The second step involves
dehydro-alogenation of the intermediate product of
acylation 10 (78% yield).27
A new efficient method to obtain the basic skeleton of
flavonoids is described herein. The key step involves the
use of the Heck reaction for the synthesis of the inter-
mediate chalcone.
Hydrolysis of the acetyl group of the intermediate
chalcone 3,28 was followed by demethylation performed
with sodium ethanethiolate which gave a mixture of
chalcones and flavanones in racemic form,29 as shown
in Scheme 3. All the compounds described are natural
flavonoids and were identified by NMR spectroscopy
and by comparison with literature data.30 Compound 5
is 4,4%-dihydroxy-2%-methoxychalcone, a stress metabo-
lite of Pisum sativum, isolated from Caesalpinia japon-
ica; compound 6 is 2%,4-dihydroxy-4%-methoxychalcone,
isolated from Xanthorrhoea australis; compound 7 is
Results
The synthetic strategy we propose, as shown in Scheme
1, consists of the use of the Heck coupling reaction
between an a,b-unsaturated ketone, such as 1, and an
aryl iodide, like 2.
In a typical experiment equimolar quantities (0.34
mmol) of compound 1 (65 mg) and compound 2 (88
mg) were dissolved in 3.5 ml of acetonitrile; Et3N (1
ml), Pd(OAc)2 (0.75 mg) and PPh3 (5.24 mg) were
added and the mixture was stirred at reflux (85°C)
under argon. The reaction appeared to be complete
after 4 h and was quenched by addition of ice and
acidification with 1N HCl. Extraction with diethyl ether
and standard work-up gave 120 mg of the crude mate-
rial which was purified by silica-gel chromatography
using CHCl3 as eluent, affording the pure protected
chalcone 3 in 94% yield (103 mg, 0.32 mmol).23
4%-hydroxy-7-methoxyflavanone,
a
constituent of
Bauhinia manca and Xanthorrhoea sp., isolated also in
racemic form from Platymiscium praecox; compound 8
is isoliquiritigenin, widespread in the Leguminosae and
Compositae and compound 9 is liquiritigenin which can
be isolated from all Leguminosae.
The first example of the use of the Heck reaction for
the synthesis of flavonoids has been presented here. The
procedure is very simple and suggests the possibility of
preparing the flavonoid skeleton with a wide variety of
substitution patterns, without secondary products. The
The a,b-unsaturated ketone 1 used in this example was
chosen in order to achieve the natural pattern of
hydroxy substitution. It was prepared in two very sim-
Scheme 2. Reagents and conditions: (i) TiCl4, CH2Cl2; (ii) DBU, benzene.
Scheme 3. Reagents and conditions: (i) MeONa, THF/MeOH; (ii) EtSNa, DMF.

A. Bianco et al. / Tetrahedron Letters 44 (2003) 9107–9109
9109
reported reaction proceeds in a short time (about 4 h)
affording the flavonoid moiety in a very satisfactory
yield (94%).
22. Ciattini, P. G.; Morera, E.; Ortar, G.; Strano Rossi, S.
Tetrahedron 1991, 47, 6449.
23. Compound 3: 1H NMR (CDCl3): l=2.30 (s, 3H,
OCOCH3), 3.84 (s, 3H, CH3O), 3.88 (s, 3H, CH3O), 6.47
(d, 1H, J=2.1 Hz, H-3%), 6.54 (dd, 1H, J=8.4 Hz, J=2.1
Hz, H-5%), 7.10 (d, 2H, J=8.4 Hz, H-5, H-3), 7.45 (d, 1H,
J=16.2 Hz, H-a), 7.58 (d, 2H, J=8.7 Hz, H-2, H-6), 7.63
(d, 1H, J=15.9 Hz, H-b), 7.74 (d, 1H, J=8.4 Hz, H-6%);
13C NMR (CDCl3): l=21.1 (OCOCH3), 55.4, 55.6 (2×
OCH3), 98.4 (C-3%), 105.1 (C-5%), 121.8 (C-3, C-5, C-1%),
127.2 (C-a), 129.1 (C-2, C-6), 132.7 (C-6%), 133.0 (C-1),
140.4 (C-b), 151.6 (C-4), 160.2 (C-2%), 164.0 (C-4%), 168.9
(OCOCH3), 189.8 (CO). Compound 3 afforded satisfac-
tory elemental analysis.
Acknowledgements
NMR spectra, Mr. Francesco Piccioni. Financial sup-
port, MIUR and CNR.
References
24. Lebedev, M. V.; Nenajdenko, V. G.; Balenkova, E. S.
Synthesis 1998, 89.
1. Jurd, L. In The Chemistry of Flavonoid Compounds,
Geissman, T. A., Ed.; Pergamon Press: New York, 1962;
pp. 107–155.
25. Stetter, H.; Nienhaus, J. Chem. Ber. 1978, 111, 2825.
26. To a solution of resorcinol dimethyl ether (300 mg, 2.27
mmol) in anhydrous CH2Cl2 (4 ml) were added at 0°C,
0.6 ml of TiCl4 diluted in 0.5 ml of anhydrous CH2Cl2
and b-bromopropionyl chloride in 0.5 ml of anhydrous
CH2Cl2 slowly. The mixture was allowed to stir at room
temperature for about 30 min, then the reaction was
quenched by addition of ice. Standard work-up afforded
the crude product 10 (644 mg) in quantitative yield. 1H
NMR (CDCl3): l=2.95 (t, 2H, J=8.0 Hz, CH2CO), 3.20
(t, 2H, J=8.0 Hz, CH2Br), 3.83, 3.86 (2s, CH3O), 6.46 (d,
1H, J=2.2 Hz, H-3), 6.56 (dd, 1H, J=8.4 Hz, J=2.2 Hz,
H-5), 7.81 (d, 1H, J=8.4 Hz, H-6). Compound 10
afforded satisfactory elemental analysis.
27. Compound 10 (644 mg) was dissolved in 3 ml of dry
benzene and 0.389 ml of DBU in 1 ml of dry benzene was
added dropwise. The reaction was complete after 20 min
stirring under argon at 80°C. Standard work-up afforded
the crude a,b-unsaturated ketone 1 (436 mg) which was
purified by column chromatography on silica gel eluting
with CHCl3 (340 mg, 78% yield).
28. Removal of acetyl group was achieved by adding a
catalytic amount of sodium methoxide in anhydrous
THF–MeOH and stirring under a stream of argon for
about 1 h. The reaction mixture was acidified with citric
acid until pH 5–6 and extracted twice with diethyl ether.
Standard work-up gave 66 mg of crude 4 in quantitative
yield.
29. Chalcone 4 (66 mg, 0.23 mmol) in dry DMF (5 ml) and
2.7 mmol of EtSNa was stirred at reflux under argon for
about 3 h. The reaction was quenched by cooling and
adding 2N HCl in brine. Standard work-up afforded 71
mg of a crude material. The residue was purified by
column chromatography on silica gel eluting with
CHCl3–Et2O (1:1) to give 9 mg of compound 5, 22 mg of
compound 6, 2 mg of compound 7, 6 mg of compound 8
and 2 mg of compound 9. All the isolated compounds
afforded satisfactory elemental analysis
2. Donnelly, D. M. X.; Meegan, M. J. In Comprehensive
Heterocyclic Chemistry; Katritzky, A. R.; Rees, C. W.,
Eds.; Pergamon Press: Oxford, 1984; Vol. 4, pp. 657–712.
3. Middleton, E.; Kandaswami, C. In The Flavonoids
Advances in Research Since 1986, Harborne, J. B., Ed.;
Chapman & Hall Press: London, 1994; pp. 619–652.
4. Ito, M.; Ishimoto, S.; Nishida, Y.; Shiramizu, T.;
Yunoki, H. Agric. Biol. Chem. 1986, 50, 1073.
5. Meyer, N. D.; Haemers, A.; Mishra, L.; Pandey, H. K.;
Pieters, I. A. C.; Berghe, D. A. V.; Vlietinck, A. J. J.
Med. Chem. 1991, 34, 736.
6. Beutler, J. A.; Cardellina, J. H.; Lin, C. Y.; Hamel, E.;
Cragg, J. M.; Boyd, M. R. Biorg. Med. Chem. Lett. 1993,
3, 581.
7. Geissman, T. A. In Comprehensive Biochemistry, Florkin,
M.; Stotz, E. M., Eds.; Elsevier: Amsterdam, 1963; Vol.
9, pp. 213–265.
8. Tambor, J. Ber. 1912, 45, 1683.
9. Robinson, R. J. Chem. Soc. 1938, 1738.
10. Wheeler, T. S. Org. Synth. 1963, CV4, 478.
11. Baker, W. J. Chem. Soc. 1933, 1381.
12. Mahal, H. S.; Venkataraman, K. J. Chem. Soc. 1934,
1767.
13. Mahal, H. S.; Venkataraman, K. J. Chem. Soc. 1935,
868.
14. Bargellini, G.; Marini-Bettolo, G. B. Gazz. Chim. Ital.
1940, 70, 170.
15. Ramakrishnan, V. T.; Kagan, J. J. Org. Chem. 1970, 35,
2901.
16. Keane, D. D.; Marathe, K. G.; O’Sullivan, W. I.;
Philbrin, E. M. J. Org. Chem. 1970, 35, 2286.
17. Harborne, J. B.; Mabry, T. J.; Mabry, H. The Flavonoids;
Chapman and Hall: London, 1975.
18. Okajima, Y. Yakugaku Zasshi 1960, 80, 322.
19. Hasebe, N. Nippon Kagaku Zasshi 1957, 78, 1102.
20. Reichel, L.; Proksch, G. Ann. 1971, 745, 59.
21. Kalinin, V. N.; Shostakovskii, M. V.; Ponomarev, A. B.
Tetrahedron Lett. 1990, 31, 4073.
30. Dictionary of Natural Products; J. Buckingham, Ed.;
Chapman & Hall: London, 1994.