3,3,3-trifluoropropan-1-ol

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

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

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

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

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

Procedure: To a solution of 3,3,3-trifluoro-propan-1-ol (1.1 g, 10.0 mmol) in DCM (10 mL) are added p-toluenesulfonyl chloride (2.3 g, 12.0 mmol), N,N-dimethylaminopyridine (0.1 g, 1.0 mmol) and triethyl amine (2.8 mL, 20.0 mmol). The reaction is stirred at room temperature for 3 d, then poured into water and extracted with DCM. The combined organic extracts are washed with 1N aqueous HCl solution, saturated aqueous NaHCO3 solution, brine and dried over Na2SO4, filtered and concentrated to afford 2.34 g of title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.47 (3H, s), 2.47-2.6 (2H, m), 4.22 (2H, t, J=6.4 Hz), 7.36 (2H, d, J=8.08 Hz), 7.8 (2H, d, J=7.8 Hz) extracted with DCM The combined organic extracts are washed with 1N aqueous HCl solution, saturated aqueous NaHCO3 solution, brine dried over Na2SO4 filtered concentrated

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

Procedure: The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 3,3,3-trifluoropropanol in analogy to Example 9c): MS (ISP): 492.2 and 494.2 (M+H)+, 392.0 and 394.0 ((M-Boc)+H)+ (100%).

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

Procedure: 3,3,3-Trifluoropropanol (0.338 g, 2.96 mmol) was dissolved in THF (5 mL) and cooled to 0 C under nitrogen. Potassium tert-butoxide (0.332 g, 2.96 mmol) was added and the mixture stirred for 5 min. Ethyl 6-chloronicotinate (0.500 g, 2.69 mmol) was added, the mixture was warmed to room temperature and stirred for 3 h. Brine (10 mL) was added and the mixture extracted with EtOAc (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated to yield a yellow oil. This was purified by FCC, eluting with a gradient of 0-10% EtOAc in heptane to afford the title compound as a colourless oil (0.240 g, 34%), which was used in the next step without further purification. NMR shows approximately 15% unreacted ethyl 6-chloronicotinate. 1H NMR (500 MHZ, MeOH-d4) δ ppm 8.75 (1H, d), 8.11 (1H, dd), 6.71 (1H, d), 4.55 (2H, t), 4.31 (2H, q), 2.57 (2H, m) and 1.33 (3H, t). cooled to 0 C under nitrogen stirred for 3 h the mixture extracted with EtOAc (3×10 mL) The combined organic layers were dried over sodium sulfate concentrated to yield a yellow oil This was purified by FCC eluting with a gradient of 0-10% EtOAc in heptane

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

Procedure: To a stirred solution of 4-hydroxybenzaldehyde (0.36 g, 2.93 mmol), 3,3,3-trifluoropropanol (0.5 g, 4.39 mmol) and triphenylphosphine (1.15 g, 4.39 mmol) in dry THF (10 ml) at 0° C. under an atmosphere of argon was added dropwise diisopropylazodicarboxylate (0.89 g, 4.39 mmol). On completion of the addition, the reaction mixture was stirred at room temperature for 60 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (4:1 Hexane/EtOAc) to give the title compound (0.25 g, 46%) as a colourless solid. On completion of the addition The solvent was removed under reduced pressure the residue was purified by flash chromatography (4:1 Hexane/EtOAc)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.00 g (5.75 mmol) 2-bromo-5-hydroxypyridine, 0.66 g (5.75 mmol) 3,3,3-trifluoro-1-propanol and 1.51 g (5.75 mmol) triphenylphosphine are added to 50 mL THF. Then 1.32 g (5.75 mmol) di-tert-butyl azodicarboxylate are added and the reaction mixture is stirred at 60° C. for 3 h. The solvent is removed in vacuo and the crude product is purified by column chromatography (silica gel, PE/EtOAc). The solvent is removed in vacuo the crude product is purified by column chromatography (silica gel, PE/EtOAc)

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

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

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

Procedure: The same reactions as in Example 9 (9a) and (9b) were conducted using methyl 4-hydroxybenzoate (1.52 g, 9.99 mmol) and 3,3,3-trifluoropropan-1-ol (1.14 g, 9.99 mmol) to give 385 mg of the title compound (white powder, yield: 14%).