Kinetic and thermodynamic control in the lithiation of 2,6-dimethylchromone, and selective lithiations in 2-(x-furyl)chromones and in furanochromones related to khellin

Abstract

The addition of 2,6-dimethylchromone to lithium di-isopropylamide (LDA) allows formation, under thermodynamic control, of the 2-methylene carbanion (3), but this seems to react at the carbonyl oxygen atom with carbon dioxide so no carboxylic acid can be isolated. With ethyl chloroformate (but not diethyl carbonate) this carbanion does afford the expected ethyl chromon-2-ylacetate (1d). The chromonylacetic acid is also obtainable if the starting chromone bears a free hydroxy group at position 5 as in (4a).From the addition of 2,6-dimethylchromone to a mixture of LDA and diethyl carbonate there results ethyl 2,6-dimethylchromone-3-carboxylate (9b) because the chromone 3-carbanion formed under kinetic control is trapped before it isomerises. The reaction resembles that found in flavones.Flavone (at the 3-position) and furan or benzofuran (at the 2-position) are about equally effective in competing for deprotonation by LDA. Khellin (14a) is probably deprotonated by LDA at both furan and pyrone sites but carboxylation affords only the furan carboxylic acid (14b) and unchanged khellin. This accords with the above results, as does the deprotonation and carboxylation of the phenol (15b), norvisnagin, which affords the chromonylacetic acid (16).With LDA followed by carbon dioxide the 2-(2-furyl)chromone (18a) surprisingly gives only the dicarboxylic acid (18b); apparently the dicarbanion is more stable than either monocarbanion. The isomeric 2-(3-furyl)chromone (20a) under similar conditions affords only the chromone-3-carboxylic acid (20b); the furan ring is untouched.