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

Abstract

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.

Total synthesis of 2′,4′,6′‐trimethoxy‐3′,5′‐dimethylchalcone derivatives

“…Trimethoxyxylene 6 was prepared from commercially available phloroglucinol by consecutive diformylation using N , N ‐dimethylformamide and phosphoryl chloride (POCl 3 ), Clemmensen reduction using zinc amalgam and concentrated HCl, and triple methylation using DMS and K 2 CO 3 in 65.4% overall isolated yield (Scheme 1). 27 Various Friedel‐Craft‐type conditions using a combination of Lewis acid catalysts, aluminum chloride and bismuth(III) trifluoromethanesulfonate, and acetylating agents, acetyl chloride and acetic anhydride, in several solvents have been investigated to directly introduce a C ‐acetyl group to the intermediate 6 to construct the key intermediate 3 . However, none of these reaction conditions gave satisfactory results in our trials.…”

“…To a solution of 7 27 (1.88 g, 8.39 mmol) and potassium carbonate (K 2 CO 3 ) (1.39 g, 10.06 mmol) in dry acetone (30 ml), DMS (0.95 ml, 10.06 mmol) was added in a two‐necked round‐bottomed flask under N 2 atmosphere and refluxed overnight. After the complete consumption of compound 7 , the reaction mixture was cooled to 25°C, extracted with ethyl acetate (EtOAc, 300 ml), and then washed with 1% hydrochloric acid (HCl) aqueous solution (200 ml), water (3 × 100 ml), and a saturated sodium chloride (NaCl) aqueous solution (200 ml).…”

“…Although structurally simple chalcones and trihydroxychalcone compounds have been synthesized by many researchers, [23][24][25][26] very few methods have been reported to date for the general syntheses of DMC derivatives. [27][28][29] This is because it is difficult to regioselectively introduce three hydroxy or methoxy groups and two methyl groups into the B-ring of the DMC derivative. However, since the two methyl groups bonded to the B-ring was discovered to play an important role for their antidiabetic activity in our previous study with cardamonin derivatives, 30 the synthesis of DMC derivatives became essential.…”

“…Although structurally simple chalcones and trihydroxychalcone compounds have been synthesized by many researchers, 23–26 very few methods have been reported to date for the general syntheses of DMC derivatives 27–29 . This is because it is difficult to regioselectively introduce three hydroxy or methoxy groups and two methyl groups into the B‐ring of the DMC derivative.…”

A Comparative Study of the Synthesis and Hydrolysis of sym-Triaminobenzene Homologues

“…These derivatives, and others, are important synthetic products that are finding application in various sectors of the chemical and pharmaceutical industries. For instance, phloroglucinol (1,3,5-trihydroxybenzene) and 2-methylphloroglucinol (2,4,6-trihydroxytoluene) are used in the manufacture of dyes and pigments [ 1 ], various polymers and pharmaceutical substances of different purpose [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ].…”