Transition-Metal-Free S_NAr-Type Synthesis of Chromones

Key words

chromones - O-arylation - S_NAr 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 S_NAr 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 R^² = aryl groups gave higher yields compared to R^² = aliphatic ones. Also, R^¹ = 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.