Methyl 2-ethylbutyrate → 2-(4-Benzyloxy-3-methyl-phenyl)-2-ethyl-butyric acid methyl ester

Participants

Reaction Steps

To a mixture of 1-benzyloxy-4-iodo-2-methyl-benzene (494 mmoles; 160 g) and lithium bis(trimethylsilyl)amide (1.20 moles; 200 g) in 250 ml of toluene at 0-5° C. is added a solution of 2-ethyl-butyric acid methyl ester (988 mmoles; 129 g, Synthesis, 1985 (3), 320) in 250 ml of toluene over 30 m, causing the reaction to exotherm to 18 C. The cloudy yellow solution is allowed to warm to RT and stir for 20 m. Tri-tert-butylphosphine (4.94 mmoles; 1.30 mL; 1.00 g) in 200 ml of toluene and bis(dibenzylideneacetone)palladium (7.90 mmoles; 4.54 g) are added sequentially, and the dark mixture is stirred at ambient temperature for 62 h. The mixture is diluted with 1 L of EtOAc, filtered through a bed of Hyflo, and rinsed with another 1 L of EtOAc. The filtrate is concentrated. The dark orange oil (˜200 g) is purified by flash chromatography (10% EtOAc/hexanes, 1 kg of silica) to give the title compound as a light orange oil (72.4 g). The mixed fractions are combined and re-subjected to the same chromatography conditions to give the another batch of title compound as a yellow oil (50.6 g). 1H NMR (CDCl3) δ 7.40 (m, 5H), 7.02 (m, 2H), 6.83 (d, J=9.2 Hz, 1H), 5.06 (s, 3H), 3.64 (s, 3H), 2.27 (s, 3H), 2.02 (m, 4H), 0.73 (t, J=7.4 Hz, 6H).

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