Formaldehyde → 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine-4-carboxylic acid

Participants

Reaction Steps

Lithium diisopropylamide was prepared by the addition of 2.45M N-butyllithium (69 mL, 168.8 mmol) in hexanes to a solution diisopropylamine (24 mL, 171.2 mmmol) in tetrahydrofuran (40 mL) at 0° C. with stirring for 20 minutes. Then a solution of N-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (18 g, 78.5 mmol) in tetrahydrofuran (35 mL) was added to the solution of lithium diisopropylamide over 15 minutes to form a slurry, followed by hexamethylphosphoramide (2 mL). The resulting solution was stirred for 25 minutes, then stream of gaseous formaldehyde (prepared by heating paraformaldehyde (16.4 g, 189 mmol) at 175-200° C. over 5-10 minutes) was passed through the solution, which was allowed to immediately warm to room temperature. The slurry was concentrated at ambient temperature, acidified to pH 4 with 6M hydrochloric acid, saturated with solid sodium chloride, and extracted with ethyl acetate (8×100 mL). The combined organic layers were dried over magnesium sulfate, concentrated in vacuo. Chromatography over silica gel, and eluting with 1% methanol/methylene chloride, afforded N-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine-4-carboxylic acid as a white solid (4 g, 20%). mp 156.6-157.3° C.; 1HNMR (DMSO-d6) δ 1.25-1.37 (m, 2H), 1.38 (s, 9H), 1.85 (dm, J=13.7 Hz, 2H), 2.78-2.94 (br m, 2H), 3.41 (s, 1H), 3.70 (dm, J=12.8 Hz, 2H), 4.87 (br s, 1H), 12.34 (s, 1H); Anal. Calcd. for C12H21NO5 : C, 55.58; H, 8.16; N, 5.40. Found: C, 55.72; H, 8.10; N, 5.53.

Provenance & Evidence