Sodium hydride → ethyl N-[(4-phthalimidobutyl)oxy]acetimidate

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Reaction Steps

To a dried 100 mL 3-necked round-bottom flask equipped with an addition funnel and gas inlet was added sodium hydride (1.55 g, 39 mmol, 60% oil dispersion). The sodium hydride was washed three times with 10 mL portions of hexane and covered with 30 mL of dry tetrahydrofuran. The flask was placed over a magnetic stirrer, flushed with a slow stream of nitrogen, and stirred vigorously while ethyl N-hydroxyacetimidate (3.65 g, 35 mmol) (Aldrich Chemical Co., Milwaukee, Wis.) was added rapidly dropwise. After addition was complete and gas evolution had subsided, the suspension was heated at reflux for 18 hours. Upon cooling, the suspension was stirred while N-(4-bromobutyl)-phthalimide (10.0 g, 35 mmol) (Aldrich Chemical Co., Milwaukee, Wis.) in 30 ml of dry tetrahydrofuran (THF) was added rapidly dropwise. After addition was complete, the reaction mixture was refluxed for 48 hours under nitrogen. Thin-layer chromatography (TLC) of the crude reaction mixture in 95:5 chloroform:ethyl acetate showed conversion of the acetimidate into a product with Rf =0.45. The reaction suspension was treated with methanol (15 mL), and then with saturated aqueous ammonium chloride (50 mL). The organic solvents were removed on a rotary evaporator and the residue was transferred to a separatory funnel and partitioned between ethyl acetate and water. After three extractions with 100 mL portions of ethyl acetate, the combined layers were washed with brine, dried over magnesium sulfate and evaporated to yield a light yellow oil. Column chromatography on silica-gel (95:5 chloroform:ethyl acetate) yielded 7.8 g (25 mmol, 71%) of ethyl N-[(4-phthalimidobutyl)oxy]acetimidate (1) as a colorless oil. Single spot on TLC with Rf =0.45 (visualized with a hand-held ultraviolet lamp with output at about 280 nm). 1H NMR: δ7.7 (s, 4H), 3.8 (m, 4H), 3.6 (t, 2H), 1.8 (s, 3H), 1.6 (m, 4H), 1.1 (s, 3H).

Provenance & Evidence