Reaction Steps
To a cold (−20° C.) solution of 8.9 mL (63.7 mmol) of diisopropylamine in 100 mL of diethyl ether under argon was added 28.1 mL (63.7 mmol; 2.27 M solution in hexanes) of n-BuLi via syringe and the solution was stirred at 0° C. for 45 min. In a separated flask, 3.315 g (25.5 mmol) of freshly distilled ethyl acetoacetate and 50 mL of diethyl ether were added and the solution was cooled to −78° C. To it, the above LDA solution was added via cannula, then 3.84 mL (25.5 mmol) of N,N,N′,N′-tetramethylethylenediamine (TMEDA) (distilled from LiAlH4) was added via syringe, and the solution was stirred at 0° C. for 3 h. To this dianion solution, a solution of 5.0 g (25.5 mmol) of methyl 3,4-dimethoxybenzoate in 50 mL of diethyl ether was added via cannula and the reaction solution was warmed to room temperature and stirred for 40 h. The reaction mixture was filtered through fritted funnel, and the solid (desired product) was saved. The organic filtrate from the above filtration was washed with a solution of 50 mL of 1 N HCl and 50 mL of distilled water, and then with 80 mL of brine, dried (MgSO4), and concentrated to give the desired product, 5-(3,4-dimethoxy-phenyl)-3,5-dioxopentanoic acid. The solid obtained above was dissolved in 80 mL of distilled water and 10 mL of 1 N HCl solution, and washed twice with methylene chloride (100 mL each). The water layer was further acidified with 100 mL of 1 N HCl, extracted twice with methylene chloride (50 mL each). The combined methylene chloride extract was washed with 80 mL of brine, dried (MgSO4), concentrated to give the desired carboxylic acid [5-(3,4-dimethoxyphenyl)-3,5-dioxopentanoic acid]. This acid and the above acid from the filtrate were combined and dissolved in 50 mL of CH2Cl2, cooled over ice-water bath, and a solution of diazomethane in diethyl ether was added dropwise until the carboxylic acid was no longer present. The solution was concentrated on a rotary evaporator and dried under vacuum, and column chromatographed on silica gel using a gradient mixture of hexane and ethyl acetate as eluant to give 3.798 g (56% yield) of pure 13B. 1H NMR δ7.51 (dd, J=8.5 Hz, 2 Hz, 1 H, C5′ H, Ar), 7.45 (d, J=2 Hz, 1 H, C2′ H), 6.9 (d, J=8.5 Hz, 1 H, C6′ H), 6.24 (s, 1 H, ═CH of enol at C4&5), 3.95 (s, 6 H, 2 OMe on Ar ring), 3.77 (s, 3 H, MeO), 3.47 (s, 2 H, CH2); 13C NMR δ186.18 (s, C3 C═O), 184.05 (s, C5═C—O), 168.21 (s, C═O ester), 153.16 (s, C4′Ar), 149.07 (s, C3′Ar), 127.04 (s, Cl′Ar), 121.49 (d, C2′), 110.56 (d, C5′), 109.66 (d, C6′), 96.17 (d, C4═CH), 56.06 (q, OMe), 56.0 (q, OMe), 52.32 (q, OMe of ester), 44.89 (t, CH2); MS.FAB, m/z 281 (M+1), 280 (M+).
