Trifluoroacetic acid → 1-[3-(Methyloxy)-4-nitrophenyl]-4-(1-piperidinylmethyl)piperidine

Participants

Reaction Steps

1,1-dimethylethyl 4-(1-piperidinylmethyl)-1-piperidinecarboxylate (1.25 g, 4.43 mmol) in DCM (40 mL) was cooled with an ice/H2O bath. TFA (8.80 mL, 115 mmol) was added dropwise via pipette. Upon completion by TLC the reaction was quenched with 1N NaOH (115 mL) and extracted with EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and concentrated. The combined aqueous layer was treated with 1N NaOH, extracted with DCE/iso-propanol (4:1), dried (MgSO4) and concentrated. The crude material was added to 5-fluoro-2-nitrophenyl methyl ether (Example 22, step A) (0.833 g, 4.87 mmol) and K2CO3 (0.992 g, 7.17 mmol) in DMSO (15 mL) and stirred at rt overnight. Upon completion by TLC, the reaction was diluted with EtOAc (250 mL), washed with H2O (three times), dried (MgSO4) and concentrated. Purification by flash chromatography provided the title compound (0.890 g, 2.66 mmol, 60% over two steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.14 (m, 2H), 1.30-1.41 (m, 2H), 1.42-1.50 (m, 4H), 1.72-1.83 (m, 3H), 2.07 (d, J=7.0 Hz, 2H), 2.27 (br. s., 4H), 2.93 (td, J=12.7, 2.2 Hz, 2H), 3.88 (s, 3H), 4.00 (d, J=13.6 Hz, 2H), 6.45 (d, J=2.6 Hz, 1H), 6.55 (dd, J=9.5, 2.6 Hz, 1H), 7.85 (d, J=9.5 Hz, 1H).

Provenance & Evidence