2,2,2-trifluoro-1-(4-fluorophenyl)ethanone

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:

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

Procedure: A solution of TiCl4 (0.0299 ml, 0.271 mmol) in CH2Cl2 (0.5 ml) was added to a solution of N-(cyclopropylmethyl)-2-(piperidin-4-ylidene)acetamide hydrochloride (125 mg, 0.542 mmol) prepared in EXAMPLE 22e, triethylamine (0.225 ml, 1.63 mmol) and 2,2,2,4′-tetrafluoroacetophenone (0.0770 ml, 0.542 mmol) in CH2Cl2 (3.5 ml), and the whole was stirred for 9 hours. A solution of sodium cyanoborohydride (102 mg, 1.63 mmol) in methanol (1 ml) was added to the reaction mixture and the whole was stirred for 30 minutes. After the reaction was quenched with aqueous 2 N NaOH solution (15 ml), the aqueous phase was extracted with ethyl acetate (30 ml×2) and the combined organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/n-hexane: 35/65 to 55/45) to give N-(cyclopropylmethyl)-2-(1-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)piperidin-4-ylidene)acetamide (52 mg, 26%) as a yellow solid: LCMS: 371 {M+1}+. 1H NMR (DMSO-d6)□ δ: 0.11 (m, 2H), 0.37 (m, 2H), 0.85 (m, 1H), 2.17 (m, 2H), 2.43-2.68 (m, 4H), 2.91 (m, 4H), 4.70 (m, 1H), 5.57 (s, 1H), 7.26 (m, 2H), 7.45 (m, 2H), 7.87 (t, 1H). the whole was stirred for 30 minutes After the reaction was quenched with aqueous 2 N NaOH solution (15 ml) the aqueous phase was extracted with ethyl acetate (30 ml×2) the combined organic phase was dried over MgSO4 filtered concentrated in vacuo The residue was purified by column chromatography (ethyl acetate/n-hexane: 35/65 to 55/45)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product. heated for another 10 min the reaction mixture was cooled to 0° C was added dropwise After complete addition extracted in diethyl ether (4×50 mL) dried over Na2SO4 concentrated at 25° C. to obtain the product

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

Procedure: To a −78° C. toluene (25 mL)/dichloromethane (25 mL) solution of 2,2,2,4′-tetrafluoroacetophenone (2.5 g, 13.01 mmol) and 1M S-methyl CBS oxazaborolidine catalyst (1.3 mL, 1.3 mmol) was added freshly distilled catecholborane (1.66 mL, 15.62 mmol). The reaction mixture was maintained at −78° C. for 16 h at which time 4N HCl (5 mL in dioxane) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and washed with a saturated brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated to provide a solid. The solid was suspended in hexanes and filtered off. The hexanes filtrate containing the desired product was concentrated and the residue subjected to flash chromatography (10 hexanes:1 ethylacetate) to provide the title compound as colorless oil (2.2g, 87% yield). The ratio of enantiomers was determined to be 95:5 by chiral HPLC (Chiralcel OD column, 95 hexanes:5 isopropanol mobile phase. Ret. time major product 6.757 min. Ret. time minor isomer 8.274 min.). was added washed with a saturated brine solution The organic layer was dried over magnesium sulfate filtered concentrated to provide a solid filtered off The hexanes filtrate containing the desired product was concentrated

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

Procedure: To a −78° C. toluene (25 mL)/dichloromethane (25 mL) solution of 2,2,2,4′-tetrafluoroacetophenone (2.5 g, 13.01 mmol) and 1M S-methyl CBS oxazaborolidine catalyst (1.3 mL, 1.3 mmol) was added freshly distilled catecholborane (1.66 mL, 15.62 mmol). The reaction mixture was maintained at −78° C. for 16 h at which time 4N HCl (5 mL in dioxane) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and washed with a saturated brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated to provide a solid. The solid was suspended in hexanes and filtered off. The hexanes filtrate containing the desired product was concentrated and the residue subjected to flash chromatography (10 hexanes:1 ethylacetate) to provide the title compound as colorless oil (2.2g, 87% yield). The ratio of enantiomers was determined to be 95:5 by chiral HPLC (Chiralcel OD column, 95 hexanes:5 isopropanol mobile phase. Ret. time major product 6.757 min. Ret. time minor isomer 8.274 min.). was added washed with a saturated brine solution The organic layer was dried over magnesium sulfate filtered concentrated to provide a solid filtered off The hexanes filtrate containing the desired product was concentrated

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2,2,2,4′-tetrafluoroacetophenone (10 g, 52.1 mmol) in methanol (50 mL) was added NaBH4 (0.98 g, 26.5 mmol) at 0° C. After stirring at 25° C. for 2 h, the reaction mixture was quenched by adding 1N HCl (100 mL) and then extracted with ethyl ether. The ether extract was washed with brine, dried with MgSO4, and concentrated to give 2,2,2-trifluoro-1-(4-fluorophenyl)ethanol (11.32 g) which was used in next step without further purification. the reaction mixture was quenched by adding 1N HCl (100 mL) extracted with ethyl ether The ether extract was washed with brine dried with MgSO4 concentrated

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

Procedure: To a −78° C. toluene (25 mL)/dichloromethane (25 mL) solution of 2,2,2,4′-tetrafluoroacetophenone (2.5 g, 13.01 mmol) and 1M S-methyl CBS oxazaborolidine catalyst (1.3 mL, 1.3 mmol) was added freshly distilled catecholborane (1.66 mL, 15.62 mmol). The reaction mixture was maintained at −78° C. for 16 h at which time 4N HCl (5 mL in dioxane) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and washed with a saturated brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated to provide a solid. The solid was suspended in hexanes and filtered off. The hexanes filtrate containing the desired product was concentrated and the residue subjected to flash chromatography (10 hexanes: 1 ethylacetate) to provide the title compound as colorless oil (2.2 g, 87% yield). The ratio of enantiomers was determined to be 95:5 by chiral HPLC (Chiralcel OD column, 95 hexanes: 5 isopropanol mobile phase. Ret. time major product 6.757 min. Ret. time minor isomer 8.274 min.). was added washed with a saturated brine solution The organic layer was dried over magnesium sulfate filtered concentrated to provide a solid filtered off The hexanes filtrate containing the desired product was concentrated

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

Procedure: To a −78° C. toluene (25 mL)/dichloromethane (25 mL) solution of 2,2,2,4′-tetrafluoroacetophenone (2.5 g, 13.01 mmol) and 1M S-methyl CBS oxazaborolidine catalyst (1.3 mL, 1.3 mmol) was added freshly distilled catecholborane (1.66 mL, 15.62 mmol). The reaction mixture was maintained at −78° C. for 16 h at which time 4N HCl (5 mL in dioxane) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and washed with a saturated brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated to provide a solid. The solid was suspended in hexanes and filtered off. The hexanes filtrate containing the desired product was concentrated and the residue subjected to flash chromatography (10 hexanes: 1 ethylacetate) to provide the title compound as colorless oil (2.2 g, 87% yield). The ratio of enantiomers was determined to be 95:5 by chiral HPLC (Chiralcel OD column, 95 hexanes: 5 isopropanol mobile phase. Ret. time major product 6.757 min. Ret. time minor isomer 8.274 min.). was added washed with a saturated brine solution The organic layer was dried over magnesium sulfate filtered concentrated to provide a solid filtered off The hexanes filtrate containing the desired product was concentrated