chromones - O-arylation - SNAr reaction
Significance
This report represents a caveat publication.
Aiming to develop a copper-catalyzed synthesis of chromones 2 via an intramolecular Ullmann
O-arylation of (ortho-halophenyl)propane-1,3-diones 1, Fu and co-workers, to their credit,
carried out a control experiment without a copper catalyst. This
led to the discovery that the O-arylation proceeded more efficiently
without the aid of a transition metal, thus representing a normal
intramolecular SNAr process. The reaction was carried
out under basic conditions (K2CO3, Na2CO3,
K3PO4) in polar aprotic solvents (DMF, DMSO,
NMP); the combination of K2CO3 and DMF giving
the best results. Surprisingly, aryl bromides were more
reactive than aryl chlorides, although both gave good to high yields
of chromone products. Starting materials 1 with
R² = aryl groups gave higher yields
compared to R² = aliphatic ones. Also,
R¹ = EDG showed lower reactivity. Control
experiments showed that 1) oxygen has no effect on the reaction
and 2) the reaction does not proceed through a radical pathway.
Surprisingly, the simple intermolecular O-arylation of 1-bromo-2-nitrobenzene
with phenol under the same conditions failed.
Comment
Aryl ethers are classically prepared by copper-mediated
Ullmann and palladium-catalyzed Buchwald-Hartwig
coupling reactions of aryl halides with phenols. Intramolecular
metal-catalyzed O-arylation couplings have been applied to the synthesis
of various heteroaromatics including chromones (Q. Yang, H. Alper J. Org. Chem. 2010, 75, 948). Chromones are ubiquitous in
Nature, especially in the class of plant secondary metabolites,
for example flavonoids (see Book below). Metal-free strategies to
chromones often suffer from harsh conditions, poor substituent tolerance
and low yields (see Review below). A recent synthesis of chromones
involves the sequential intramolecular anionic ortho-Fries rearrange-ment-Michael addition
of 2-but-2-ynoyl aryl O-carbamates
(T. K. Macklin, J. Panteleev, V. Snieckus Angew.
Chem. Int. Ed. 2008, 47,
2097). The present method represents a convenient and efficient
access to chromones 2 starting from 1 prepared via a simple Claisen condensation
between methyl ortho-halobenzoate derivatives
and ketones. This work teaches the necessity for execution of control
experiments in all studies concerned with transition-metal-catalyzed
C-C, C-O, and C-N couplings.
Book: J. B. Harborne, H. Baxter The Handbook of Natural Flavonoids, Vol.
1; John Wiley & Sons: Chichester, UK, 1999.
Review: N.-G. Li, Z.-H. Shi, Y.-P. Tang,
H.-Y. Ma, J.-P. Yang, B.-Q. Li, Z.-J. Wang, S.-L. Song, J.-A.
Duan J. Heterocycl. Chem. 2010, 47, 785-798.
