Versatile Conversions of Substituents in Guaiazulene: Synthesis of Carboxylic Acid Derivatives with Controlled Regiospecific Reactivities

Abstract Azulene derivatives such as guaiazulene have unique properties and thus play important roles in electronic materials. However, the application of these materials is limited by the lack of functionalization approaches for guaiazulene extracted from natural products. Herein, we report a method for the synthesis of three guaiazulene carboxylic acid derivatives in four to five steps by controlling the reactivity of guaiazulene. 7-Isopropyl-4-methylazulene-1-carboxylic acid was prepared by protecting the C-3 position of guaiazulene with an ester group to inhibit unexpected reactions. We also introduced a carboxyl group at the inactive C-2 position of guaiazulene using a boryl group as a key intermediate. The C4-methyl group of guaiazulene was converted to a formyl group utilizing the acidity of the protons on the C4-methyl group. By protecting the C-3 position of guaiazulene with a tosyl group, 7-isopropyl-1-methylazulene-4-carboxylic acid was synthesized via Kraus-Pinnick oxidation. Ultraviolet/visible spectra of the synthesized guaiazulene carboxylic acids indicate that the longest wavelength at maximum absorption varied depending on the substitution position of the carboxyl group in guaiazulene. Guaiazulene carboxylic derivatives will serve as building blocks for the development of guaiazulene-based materials because the carboxyl group can be converted to various functional groups.