C-prenylated phenols are found in a diverse natural sources, especially in plant species. Small bioactive C-prenylated phenols such as benzoic, cinnamic and coumaric acid derivatives as well as prenylated ubiquinones/naphthaquinones, flavonoids and xanthones have attracted considerable scientific attentions due to its unique biological and pharmacological properties which are intimately associated with the presence of phenolic hydroxyl groups. Nevertheless, no single synthetic method encompassed the preparation of C-prenylated phenols, and some synthesis of prenylated phenols are reported to be challenging. Various synthetic methods has been developed so far for the preparation of ortho-alkyl phenols: Lewis acid catalyzed ortho-alkylation of phenol including the Friedel-Crafts type, Claisen rearrangement, metal-mediated coupling via metal-halogen exchange or directed ortho-metalation are popular strategies among them. In particular, ortho-alkylation of phenolate is a favored strategy for the preparation of terpenylated phenols especially for the prenylated. Although ortho-alkylation of phenolate is intuitive and tempting, possibly due to the advantages in terms of atom- and step-economy, it is often challenging because of the strong preference of competing O-alkylation and non-selective side reactions such as bisalkylation or para-alkylation depending on the structure. Herewith, we report our studies on the alkylation of phenolate in an organofluorine solvent and its application to the synthesis of bioactive natural products.

Studies on the alkylation of phenolate in an organofluorine solvent

253rd National Meeting (2017)

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