Acetic Acid → 4-Acetyl-piperidine-1-carboxylic acid tert-butyl ester

Participants

Reaction Conditions

Reaction Steps

A solution of 1-(tert-butoxycarbonyl)-4-(N-methyl-N-methoxycarboxamido)piperidine (from Piperidine 8, Step A) in anhydrous ether (400 mL) at 0° C. was treated with 55 mL of 1.4 M methyl magnesium bromide in 3:1 toluene and THF over 30 min. After stirring at 0° C. for 1 h, the reaction was poured into a mixture of ice water (400 mL) and acetic acid (8 mL, 150 mmol). The layers were separated and the aqueous layer was extracted twice with ether. The combined organic layers were washed with 0.1 N HCl (200 mL), 3% sodium bicarbonate (200 mL), water (200 mL) and brine (200 mL), dried over sodium sulfate, and concentrated to give the crude product (14.322 g). Flash chromatography (20–80% ethyl acetate in hexanes) gave the title compound as a yellowish oil. Rf: 0.27 (25% ethyl acetate in hexanes). Some starting Weinreb amide was also recovered. Rf: 0.10 (25% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ 4.07–4.14 (m, 2H), 2.75–2.83 (m, 2H), 2.46 (tt, J=11.3 and 3.8 Hz, 1H), 2.17 (s, 3H), 1.82–1.87 (m, 2H), 1.48–1.57 (m, 2 H), 1.46 (s, 9H).

Provenance & Evidence