Divergent approach to flavones and aurones via dihaloacrylic acids. unexpected dependence on the halogen atom

Article abstract of DOI:10.1021/ol1023294

The reaction of phenols with 7a led to the synthesis of aurones, while the reaction of phenols with 7b led to the synthesis of flavones.

Full text of DOI:10.1021/ol1023294

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5278-5280
Divergent Approach to Flavones and
Aurones via Dihaloacrylic Acids.
Unexpected Dependence on the Halogen
Atom
George A. Kraus* and Vinayak Gupta
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011, United States
gakraus@iastate.edu
Received September 27, 2010
ABSTRACT
The reaction of phenols with 7a led to the synthesis of aurones, while the reaction of phenols with 7b led to the synthesis of flavones.
Flavones are natural products common to many plant
genuses.1 Examples of this important family include flavones
1-5 shown in Figure 1. Natural and synthetic flavones
exhibit a range of biological activity, including anti-inflam-
matory,2 anticancer,3 and antioxidant4 activity. As a result,
a number of useful synthetic methods have been reported.
The majority of these methods falls into the category of either
oxidative cyclization of various substituted 2′-hydroxychal-
cones or cyclodehydration of substituted 1-(2-hydroxyphe-
nyl)-3-phenylpropane-1,3-diones.5,6
flavones that would be amenable to the creation of functional
libraries. In view of the ready availability of substituted aryl
boronic acids, we examined the disconnection shown in
Figure 2.
As part of an interdisciplinary effort to understand the
modes of action of components of botanical dietary supple-
ments,7 we needed to develop a convergent synthesis of
Figure 1. Structures of flavones.
(1) Atmani, D.; Chaher, N.; Berboucha, M.; Debbache, N.; Boudaoud,
H. Curr. Nutr. Food Sci. 2009, 5, 225–237.
(2) Theoharides, T. C. Chemistry and Molecular Aspects of Drug Design;
Rekka, E. A., Kourounakis, P. N., Eds.; CRC Press: Boca Raton, FL, 2008;
pp 215-226.
The synthesis began with the coupling of commercially
available phenol 6a with 3,3-dibromoacrylic acid (7a)8 using
DCC and DMAP in 71% yield.9 A Fries rearrangement using
aluminum chloride in 1,2-dichloroethane produced ketone
10 in 41% yield, accompanied by products derived from Fries
rearrangement and demethylation. Cyclization of 10 with
dilute sodium hydroxide in THF afforded a bromoketone,
originally assigned as 11a. However, Suzuki coupling with
(3) Liu, H. L.; Jiang, W. B.; Xie, M. X. Recent Pat. Anti-Cancer Drug
DiscoVery 2010, 5, 152–164.
(4) Carneiro, C. D.; Amorim, J. C.; Cadena, S. M. S. C.; Noleto; et al.
Food Chem. Toxicol. 2010, 48, 2380–2387.
(5) Marais, J. P. J.; Ferreira, D.; Slade, D. Phytochemistry 2005, 66,
2145–2176.
(6) Barton, D. H. R.; Offis, W. D., Editor: Staunton, J. ComprehensiVe
Organic Chemistry 1979, 4, 659.
10.1021/ol1023294  2010 American Chemical Society
Published on Web 10/20/2010

(7b),12 in part because its preparation was more conducive
to scale up. As shown in Scheme 2, esters 13a and 13b
Scheme 2. Synthesis of Flavones
Figure 2. Retrosynthetic analysis.
phenylboronic acid (8a) provided a compound whose NMR
spectrum was different from an authentic sample of 4
prepared by the literature method.10 After considering
alternate structures, the structure of 11a was revised to 11b.
This implies that the Suzuki coupling led to aurone 12a, and
this was confirmed. Using the same protocol, aurones 12b
and 12c were produced in 81% and 80% yields, respectively,
and were confirmed by comparison with literature spectra
(Scheme 1).11
While this chemistry was being pursued, a parallel series
of reactions was conducted using 3,3-dichloroacrylic acid
Scheme 1. Synthesis of Aurones
underwent Fries rearrangements to afford ketones 14a and
14b in 40% and 60% yields, respectively. The dichloro
ketones were treated with dilute base to generate chromones
15a and 15b in good yields. Although the Suzuki reaction
is more commonly conducted with aryl bromides or io-
dides,13 the reaction of 15b with boronic acid 8a afforded
flavone 1 in 74% yield.14 Our NMR spectrum matched the
spectrum of an independently synthesized sample.10 In a
similar manner, flavones 2-5 were synthesized in good
yields and compared to literature standards.10,15a-c
(7) Kraus, G. A.; Wei, J.; Thite, A. Synthesis 2008, 2427–2431.
(8) Rappe, C.; Anderson, K. Ark. Kemi 1965, 24, 303–313.
(9) (a) Bringmann, G.; Menche, D.; Kraus, J.; Mu¨hlbacher, J.; Peters,
K.; Peters, E. M.; Brun, R.; Bezabih, M.; Abegaz, B. M. J. Org. Chem.
2002, 67, 5595–5610. (b) The synthesis and spectral data are reported in
the Supporting Information.
(10) Liao, H. L.; Hu, M.-K. Chem. Pharm. Bull. 2004, 52, 1162–1165.
(11) (a) Morimoto, M.; Fukumoto, H.; Nozoe, T.; Hagiwara, A.; Komai,
K. J. Agric. Food Chem. 2007, 55, 700–705. (b) The synthesis and spectral
data are reported in the Supporting Information.
(12) Schroth, W.; Schmiedl, D.; Jahn, U.; Spitzner, R. Z. Chem. 1989,
29, 419–420.
(13) Corbet, J.-P.; Mignani, G. Chem. ReV. 2006, 106, 2651–2710.
(14) Hollick, J. J.; Rigoreau, L. J. M.; Cano-Soumillac, C.; Cockcroft,
X.; Curtin, N. J.; Frigerio, M.; Golding, B. T.; Guiard, S.; Hardcastle, I. R.;
Hickson, I.; Hummersone, M. G.; Menear, K. A.; Martin, N. M. B.;
Matthews, I.; Newell, D. R.; Ord, R.; Richardson, C. J.; Smith, G. C. M.;
Griffin, R. J. J. Med. Chem. 2007, 50, 1958–1972.
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The rationale for the remarkable divergence remains
unclear. We speculate that intramolecular cyclization of 10
might be slow relative to dehydrobromination to a bromo
acetylenic ketone. The bromo acetylenic ketone could then
cyclize to 11b, the precursor to the aurones.
will permit the synthesis of both natural and synthetic
flavones and aurones.
Acknowledgment. We thank the Department of Chemistry
at Iowa State University for partial support of this work.
In summary, we have devised a synthetic route which is
direct and proceeds in good overall yield. This procedure
Supporting Information Available: Representative ex-
perimental procedures and spectral data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) (a) Kutney, J. P.; Hanssen, H. W. Phytochemistry 1971, 10, 3298–
3302. (b) Righi, G.; Antonioletti, R.; Silvestri, I. P.; D’Antona, N.; Lambusta,
D.; Bovicelli, P. Tetrahedron 2010, 66, 1294–1298. (c) Sutthanut, K.;
Sripanidkulchai, B.; Yenjai, C.; Jay, M. J. Chromatogr. A 2007, 1143, 227–
233.
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