4-[2-[[4-(trifluoromethyl)phenyl]methoxy]ethyl]piperidine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:99.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(R)-pyrrolidinyl]methoxy]pyridine (210 mg, 0.59 mmol) and 4-[2-[4-(trifluoromethyl)benzyloxy]ethyl]piperidine (186 mg, 0.65 mmol, 1.1 equiv.) in anhydrous toluene (2 mL) were added successively sodium tert-butoxide (93 mg, 0.97 mmol, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium(0) (11.8 mg, 13 μmol, 0.02 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 22.4 mg, 39 μmol, 0.06 equiv.). The mixture was degassed and purged with Ar (3 cycles), then warmed to 98-100° C. for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc, and the solution was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by CC on SiO2 with CH2Cl2/EtOAc 4:1, then 1:1. The product (371 mg, 100%) was obtained as a dark yellow oil. The mixture was degassed purged with Ar (3 cycles) After cooling to room temperature the mixture was diluted with EtOAc the solution was washed with brine dried over Na2SO4 evaporated The residue was purified by CC on SiO2 with CH2Cl2/EtOAc 4:1

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(tert-butoxycarbonyl)-4-[2-[4-(trifluoromethyl)benzyloxy]ethyl]piperidine (496 mg, 1.28 mmol) in MeOH (0.5 mL) was added 2N anhydrous HCl/ether (2.0 mL, 4.0 mmol). The reaction mixture was stirred overnight. After evaporation, the residue was dissolved in deionized water. EtOAc was used to wash the aqueous layer before the pH was altered to approx. 9-10. The aqueous layer was extracted three times with CH2Cl2 and dried over Na2SO4. After evaporation, 4-[2-[4-(trifluoromethyl)benzyloxy]ethyl]piperidine (321 mg, 87%) was obtained as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.56 (d, 2H, J=8.4 Hz), 7.41 (d, 2H, J=8.0 Hz), 4.51 (s, 2H), 3.50 (t, 2H, J=6.0 Hz), 3.39 (br, 1H), 3.07 (d, 2H, J=12.0 Hz), 2.59 (t, 2H, J=11.6 Hz), 1.66 (d, 2H, J=12.8 Hz), 1.54 (m, 3H), 1.20 (m, 2H). After evaporation the residue was dissolved in deionized water to wash the aqueous layer before the pH The aqueous layer was extracted three times with CH2Cl2 dried over Na2SO4 After evaporation

Conditions: temp:0.00; pressure:0.00; stir: