Total Syntheses of 4′,6′‐Dimethoxy‐2'‐Hydroxy‐3′,5′‐Dimethylchalcone Derivatives

Chalcone derivatives afford several pharmacological activities. However, a general synthetic method for 2',4'‐dihydroxy‐6'‐methoxy‐3',5'‐dimethylchalcone (DMC) derivatives has not been reported thus far. To address this, the preparation of 4',6'‐dimethoxy‐2'‐hydroxy‐3',5'‐dimethylchalcone (MDMC) derivatives, modified compounds of DMC, in excellent overall yields is reported herein. These compounds have recently attracted growing attention due to their various pharmacological activities. Di‐O‐methyl‐dimethylphloroacetophenone, the key intermediate containing the B‐ring moiety, was fabricated by four efficient reaction steps from commercially available phloroglucinol in a 50.1% isolated yield overall. Our synthetic route, which constructs the chalcone skeleton in the final stage via a Claisen–Schmidt condensation of the key intermediate with the desired benzaldehyde derivative, can rapidly produce a vast library of DMC derivatives. 4',6′‐Dimethoxy‐2'‐hydroxy‐3',5'‐dimethylchalcone (MDMC) derivatives were synthesized from commercially available phloroglucinol in excellent overall yields via Claisen‐Schmidt condensations of the key intermediate, di‐O‐methyl‐dimethylphloroacetophenone, with various benzaldehydes.