methyl 4-(2,2,2-trifluoroethoxymethyl)benzoate

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

Procedure: 2,2,2-Trifluoroethanol (0.35 mL, 4.80 mmol) was dissolved in THF (2 mL) and cooled to 0 C under nitrogen. Sodium hydride (60% dispersion in mineral oil, 0.192 g, 4.80 mmol) was added portionwise and the mixture stirred for 10 min. A solution of methyl 4-(bromomethyl)benzoate in THF (3 mL) was added, the mixture was warmed to room temperature and then heated to 50 C for 3 h. The mixture was then diluted with water (15 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous neutralised with 1M hydrochloric acid. The aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to afford the title compound as a colourless oily residue (1.05 g, 97%). 1H NMR (500 MHZ, CDCl3) δ ppm 7.95 (2H, d), 7.33 (2H, d), 4.64 (2H, s), 3.83 (3H, s) and 3.77 (2H, q). cooled to 0 C under nitrogen heated to 50 C for 3 h The organic layer was separated The aqueous layer was further extracted with EtOAc (2×20 mL) The combined organic layers were dried over sodium sulfate concentrated under vacuum

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

Procedure: Methyl 4-[(2,2,2-trifluoroethoxy)methyl]benzoate (Intermediate 249, 1.05 g, 4.23 mmol) was dissolved in MeOH (10 mL), 2M aq. sodium hydroxide (6.4 mL, 12.69 mmol) was added and the mixture was stirred at room temperature for 3 h. THF (2 mL) was then added and the mixture stirred at room temperature over the weekend. The mixture was then concentrated under vacuum and the residue acidified by adding 2M hydrochloric acid. The mixture was diluted with a little water and extracted with DCM (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to afford the title compound as a white solid (0.974 g, 98%). 1H NMR (500 MHZ, CDCl3) δ ppm 8.14 (2H, d), 7.49 (2H, d), 4.79 (2H, s) and 3.91 (2H, q). the mixture stirred at room temperature over the weekend The mixture was then concentrated under vacuum by adding 2M hydrochloric acid The mixture was diluted with a little water extracted with DCM (3×20 mL) The combined organic layers were dried over sodium sulfate concentrated under vacuum

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

Procedure: 2,2,2-Trifluoroethanol (0.35 mL, 4.80 mmol) was dissolved in THF (2 mL) and cooled to 0 C under nitrogen. Sodium hydride (60% dispersion in mineral oil, 0.192 g, 4.80 mmol) was added portionwise and the mixture stirred for 10 min. A solution of methyl 4-(bromomethyl)benzoate in THF (3 mL) was added, the mixture was warmed to room temperature and then heated to 50 C for 3 h. The mixture was then diluted with water (15 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous neutralised with 1M hydrochloric acid. The aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to afford the title compound as a colourless oily residue (1.05 g, 97%). 1H NMR (500 MHZ, CDCl3) δ ppm 7.95 (2H, d), 7.33 (2H, d), 4.64 (2H, s), 3.83 (3H, s) and 3.77 (2H, q). cooled to 0 C under nitrogen heated to 50 C for 3 h The organic layer was separated The aqueous layer was further extracted with EtOAc (2×20 mL) The combined organic layers were dried over sodium sulfate concentrated under vacuum

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

Procedure: 2,2,2-Trifluoroethanol (0.35 mL, 4.80 mmol) was dissolved in THF (2 mL) and cooled to 0 C under nitrogen. Sodium hydride (60% dispersion in mineral oil, 0.192 g, 4.80 mmol) was added portionwise and the mixture stirred for 10 min. A solution of methyl 4-(bromomethyl)benzoate in THF (3 mL) was added, the mixture was warmed to room temperature and then heated to 50 C for 3 h. The mixture was then diluted with water (15 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous neutralised with 1M hydrochloric acid. The aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to afford the title compound as a colourless oily residue (1.05 g, 97%). 1H NMR (500 MHZ, CDCl3) δ ppm 7.95 (2H, d), 7.33 (2H, d), 4.64 (2H, s), 3.83 (3H, s) and 3.77 (2H, q). cooled to 0 C under nitrogen heated to 50 C for 3 h The organic layer was separated The aqueous layer was further extracted with EtOAc (2×20 mL) The combined organic layers were dried over sodium sulfate concentrated under vacuum

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

Procedure: Methyl 4-[(2,2,2-trifluoroethoxy)methyl]benzoate (Intermediate 249, 1.05 g, 4.23 mmol) was dissolved in MeOH (10 mL), 2M aq. sodium hydroxide (6.4 mL, 12.69 mmol) was added and the mixture was stirred at room temperature for 3 h. THF (2 mL) was then added and the mixture stirred at room temperature over the weekend. The mixture was then concentrated under vacuum and the residue acidified by adding 2M hydrochloric acid. The mixture was diluted with a little water and extracted with DCM (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to afford the title compound as a white solid (0.974 g, 98%). 1H NMR (500 MHZ, CDCl3) δ ppm 8.14 (2H, d), 7.49 (2H, d), 4.79 (2H, s) and 3.91 (2H, q). the mixture stirred at room temperature over the weekend The mixture was then concentrated under vacuum by adding 2M hydrochloric acid The mixture was diluted with a little water extracted with DCM (3×20 mL) The combined organic layers were dried over sodium sulfate concentrated under vacuum

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

Procedure: 2,2,2-Trifluoroethanol (0.35 mL, 4.80 mmol) was dissolved in THF (2 mL) and cooled to 0 C under nitrogen. Sodium hydride (60% dispersion in mineral oil, 0.192 g, 4.80 mmol) was added portionwise and the mixture stirred for 10 min. A solution of methyl 4-(bromomethyl)benzoate in THF (3 mL) was added, the mixture was warmed to room temperature and then heated to 50 C for 3 h. The mixture was then diluted with water (15 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous neutralised with 1M hydrochloric acid. The aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to afford the title compound as a colourless oily residue (1.05 g, 97%). 1H NMR (500 MHZ, CDCl3) δ ppm 7.95 (2H, d), 7.33 (2H, d), 4.64 (2H, s), 3.83 (3H, s) and 3.77 (2H, q). cooled to 0 C under nitrogen heated to 50 C for 3 h The organic layer was separated The aqueous layer was further extracted with EtOAc (2×20 mL) The combined organic layers were dried over sodium sulfate concentrated under vacuum

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

Procedure: Methyl 4-[(2,2,2-trifluoroethoxy)methyl]benzoate (Intermediate 249, 1.05 g, 4.23 mmol) was dissolved in MeOH (10 mL), 2M aq. sodium hydroxide (6.4 mL, 12.69 mmol) was added and the mixture was stirred at room temperature for 3 h. THF (2 mL) was then added and the mixture stirred at room temperature over the weekend. The mixture was then concentrated under vacuum and the residue acidified by adding 2M hydrochloric acid. The mixture was diluted with a little water and extracted with DCM (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to afford the title compound as a white solid (0.974 g, 98%). 1H NMR (500 MHZ, CDCl3) δ ppm 8.14 (2H, d), 7.49 (2H, d), 4.79 (2H, s) and 3.91 (2H, q). the mixture stirred at room temperature over the weekend The mixture was then concentrated under vacuum by adding 2M hydrochloric acid The mixture was diluted with a little water extracted with DCM (3×20 mL) The combined organic layers were dried over sodium sulfate concentrated under vacuum