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.

2′,4′‐Dihydroxy‐6′‐methoxy‐3′,5′‐dimethylchalcone (DMC), which is isolated from plants, has recently attracted much attention due to its beneficial pharmacological effects. The preparation of twelve 2′,4′,6′‐trimethoxy‐3′,5′‐dimethylchalcone (DMDMC) derivatives, which are dimethylated‐derivatives of DMC, is reported herein for the first time. Our synthetic method allowed the efficient construction of the DMDMC derivatives from phloroglucinol in 37.8%–46.5% overall yields. This promising approach would be advantageous for the production of many different DMDMC derivatives in a short period of time.