Hydrochloric Acid → (3-Benzyloxy-5-bromophenyl)-acetic acid ethyl ester

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Reaction Steps

Malonic acid tert-butyl ester ethyl ester (10.2 mL, 53.8 mmol) was added dropwise to a suspension of NaH (2.2 g of a 60% suspension in mineral oil, 53.8 mmol) in dioxane (200 mL) at room temperature and the mixture was stirred at this temperature for 1 hour before CuBr (7.7 g, 53.8 mmol) and 1-benzyloxy-3,5-dibromobenzene (9.2 g, 26.9 mmol) were added. The reaction mixture was heated to reflux for 5 h. HCl solution (1M aq, 100 mL) was carefully added and the mixture was extracted with iso-hexane (×3). The combined organic extracts were washed with HCl solution (1 M aq), water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc:petroleum ether) to give, in order of elution, recovered 1-benzyloxy-3,5-dibromobenzene (3.2 g, 9.4 mmol) in 35% yield and 2-(3-benzyloxy-5-bromo-phenyl)-malonic acid tert-butyl ester ethyl ester (7.2 g, contains 1.4 equivalent malonic acid tert-butyl ester ethyl ester, 10 mmol) as a colourless liquid in 37% yield. 2-(3-Benzyloxy-5-bromophenyl)malonic acid tert-butyl ester ethyl ester (7.2 g, contains 1.4 equivalent malonic acid tert-butyl ester ethyl ester, 10 mmol) was dissolved in glacial AcOH (50 mL) and heated to reflux for 12 hours. The AcOH was removed under reduced pressure. The residue was poured into Na2CO3 solution (sat. aq.) and the mixture was extracted with EtOAc (×3). The combined organic extracts were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure to give (3-benzyloxy-5-bromo-phenyl-)acetic acid ethyl ester (6.8 g, 9.7 mmol) as a yellow liquid in 97% yield. 1H NMR (CDCl3) δ 7.44-7.30 (m, 5H), 7.07-7.03 (m, 2H), 6.87-6.84 (m, 1H), 5.03 (s, 2H), 4.15 (q, 2H), 3.54 (s, 2H), 1.26 (t, 3H).

Provenance & Evidence