Acetic Acid → 4-Piperidineacetic acid

Participants

Reaction Steps

4-pyridine acetic acid (50 g, 0.314 mole) was dissolved in H2O (50 mL), and HOAc (100 mL), PtO2 (1 g) was added and the mixture was hydrogenated at 55 psi for 72 h. An additional 1 g of PtO2 was added after 48 h. The solution was filtered through celite, the cake was washed with H2O and the filtrate was evaporated, using heptane to azeotrope off excess HOAc. The 4-piperidine acetic acid was obtained as a white solid. Rf (9:1 EtOH/H2O) 0.11.1H NMR (400 MHz, CD3OD) δ3.36 (bd, 2H), 330 (bt, 2H), 2.3 (d, J=7 Hz, 2H), 2.08 (m, 1H), 1.99 (bd, 2H), 1.47 (m, 2H). This solid was dissolved in H2O (200 mL), and dioxane (200 mL), treated with triethylamine (76 mL, 0.546 mole), and di-t-butyldicarbonate (59.5 g, 0.273 mole) and stirred for 96 h. After 72 h, an additional equivalent of triethylamine and 10 g of di-t-butyldicarbonate was added. The organic solvent was evaporated and the remaining aqueous solution was brought to pH 10 with saturated NaHCO3, washed with 3×50 mL EtOAc, acidified with 10% KHSO4 to pH 2-3, extracted with 3×100 mL EtOAc, dried with MgSO4, filtered and evaporated to give 4-(N-t-butyloxycarbonyl)piperidine acetic acid. Rf (9:1 EtOH/H2O) 0.68. 1H NMR (CDCl3) δ4.1 (bs, 2H), 2.7 (bt, 2H), 2.27 (d, J=7 Hz, 1.95 (m, 1H), 2.7 (bd, 2H), 1.45 (s, 9H), 1.18 (m, 2H). This acid was reduced with borane to yield 2-(4-N-t-butyloxycarbonylpiperidine)ethanol, 1-5, as an oil. 1H NMR (400 MHz, CDCl3) δ4.08 (bd, J=12 Hz, 2H), 3.7 (t, J=6.5 Hz, 2H), 2.4 (bt, 12 Hz, 2H), 1.67 (bd, 2H), 1.6-1.45 (m, 3H), 1.45 (s, 9H), 1.12 (m, 2H).

Provenance & Evidence