with methyl crotonate (14) and then quenching the reaction
with acetic anhydride10 afforded an 88% yield of the
xanthone 15 (Table 1). Similarly, condensation of 5 with
Scheme 2
Table 1. Products and Yields from Condensation of the
Benzopyranone-phthalide 5 with Various Michael Acceptorsa
expectation that the benzopyranonephthalide 5 might undergo
condensation with Michael acceptors 6 to afford 7.
If successful, this approach would provide an alternative
and ultimately more general approach to the preparation of
xanthones and extended aromatic systems with a xanthone
fragment. An immediate question was whether 5 would
exhibit the desired condensation chemistry.
To explore this point, we prepared the benzopyrano-
nephthalide 5 (Scheme 3). The procedure reported by
Scheme 3
a Reaction of 5 with 16 was not quenched with Ac2O.
cyclohexenone 16 provided an 82% yield of the expected
linear benzoxanthanone 17. We next investigated the poten-
tial of the reaction for angular polycyclic aromatic synthesis.
Condensation of 5 with coumarin (18) gave a 67% yield of
the product 19. Recently, we reported the use of ortho-
quinonemonoketals as acceptors in phthalide condensa-
tions.11 Condensation of the ortho-quinonemono-ketal 20
with 5 afforded a 78% yield of the angular polycyclic product
21.
In summary, this annelation provides a general, high-
yielding route to not only xanthones but also xanthone-
containing polycyclic aromatic systems. We expect that this
methodology will be useful for the preparation of angular
polycyclic aromatic natural products and currently are
exploring this possibility.
Zagorevskii et al.9 provided an 84% yield of the chromanone
10 from o-hydroxypropiophenone 8 and ethyl chlorooxo-
acetate 9. NBS bromination of 10 gave the bromomethyl
intermediate (95%), which on reaction with thiophenoxide
afforded the thiophenylated product 11. Hydrolysis of the
ester followed by MCPBA oxidation gave the sulfoxide acid
12. As expected, Pummerer reaction of 12 in acetic anhydride
resulted in intramolecular trapping of the sulfenium inter-
mediate 13, directly providing the thiophenyl-substituted
benzopyranonephthalide 5.
Acknowledgment. This work was supported by the
National Cancer Institute of the National Institutes of Health
under Grant CA 181411.
With 5 in hand, we explored its condensation chemistry.
Treatment of 5 with LiOtBu in THF at -78 °C afforded a
deep blue-colored solution of the anion. Reaction of the anion
OL0354876
(10) Acetylation prevents oxidation of the initially formed product.
(11) Hauser, F. M.; Dorsch, W. A.; Mal, D. Org. Lett. 2002, 4, 2237-
2239. Hauser, F. M.; Liao, H.; Sun, Y. Org. Lett. 2002, 4, 2241-2243.
(9) Zagorevskii, V. A.; Zykov, D. A.; Orlova, E. K. Zhurnal Obschchei
Khimii (Engl. Trans.) 1961, 31, 568.
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Org. Lett., Vol. 5, No. 20, 2003