Trifluoroacetic acid → 4-(Benzyloxy)piperidine

Participants

Reaction Steps

Trifluoroacetic acid (5 ml) was added to a solution of 1-(tert-butoxycarbonyl)-4-benzyloxypiperidine (2.08 g, 7.14 mmol) in dichloromethane (20 ml) and the solution stirred for 30 minutes at room temperature under nitrogen. The solution was concentrated in vacuo, the residue was redissolved in dichloromethane (20 ml) and treated with trifluoroacetic acid (20 ml). The solution was stirred for 30 minutes, partially evaporated and poured into saturated aqueous potassium carbonate solution (50 ml). The mixture was diluted with water (50 ml) and extracted with dichloromethane (2×100 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo to give crude 4-benzyloxypiperidine (1.29 g), as an amber oil. A portion of this material (0.59 g, 3.08 mmol) was dissolved in dimethylformamide (15 ml). Potassium carbonate (0.85 g, 6.15 mmol) and 2-(chloromethyl) benzimidazole (0.46 g, 2.76 mmol) were added to the solution and the mixture stirred at room temperature, under nitrogen, overnight. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate (2×100 ml). The extracts were washed with brine (100 ml), combined, dried (MgSO4) and the residue after evaporation purified by flash chromatography, eluting with 7.5% methanol in dichloromethane, to give the title compound (0.26 g, 30%) as a pale yellow solid. Recrystallisation from ethyl acetate afforded very pale yellow needles, m.p. 190.5°-191° C.; (Found: C, 74.83; H, 7.17; N, 13.00. C20H23N3O requires C, 74.74; H, 7.21; N, 13.07%); δH (DMSO-d6) 1.56 (2H, m, piperidinyl H), 1.88 (2H, m, piperidinyl H), 2.21 (2H, m, piperidinyl H), 2.74 (2H, m, piperidinyl H), 3.40 (1H, m, piperidinyl CH-O), 3.69 (2H, s, CH2N), 4.49 (2H, s, OCH2Ph), 7.12 (2H, m, ArH), 7.27 (5H, m, ArH), 7.48 (2H, br s, ArH), and 12.23 (1H, br s, NH); m/z (CI+, NH3) 322 (M+H)+.

Provenance & Evidence