1-(2-chloro-3-fluorophenyl)ethanone

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

Procedure: To a solution of 1-(2-chloro-3-fluorophenyl)ethanone (31.21 g, 181 mmol) in tetrahydrofuran (500 mL) was added (R)-2-methylpropane-2-sulfinamide (32.9 g, 271 mmol) and titanium(IV) isopropoxide (111 mL, 371 mmol). The mixture was heated to 65° C. overnight. LCMS showed 25% starting material remaining. Additional 16 g sulfinamide and 30 mL Ti(OPr)4 was added and the reaction was continued at 70° C. overnight. The mixture was diluted with brine (600 mL), and EtOAc. The solid was filtered through a pad of celite and washed with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (330 g, 0-60% EtOAc-hexane in 20 min) to give (R,Z)-N-(1-(2-chloro-3-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (40.8 g, 82% yield) as yellow oil. MS m/z=276 [M+H]+. Calculated for C12H15ClFOS: 275.8. The solid was filtered through a pad of celite washed with EtOAc The organic layer was washed with brine dried over sodium sulfate filtered concentrated in vacuo The crude material was purified by silica gel chromatography (330 g, 0-60% EtOAc-hexane in 20 min)

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

Procedure: To a solution of 1-(2-chloro-3-fluorophenyl)ethanone (31.21 g, 181 mmol) in tetrahydrofuran (500 mL) was added (R)-2-methylpropane-2-sulfinamide (32.9 g, 271 mmol) and titanium(IV) isopropoxide (111 mL, 371 mmol). The mixture was heated to 65° C. overnight. LCMS showed 25% starting material remaining. Additional 16 g sulfinamide and 30 mL Ti(OPr)4 was added and the reaction was continued at 70° C. overnight. The mixture was diluted with brine (600 mL), and EtOAc. The solid was filtered through a pad of celite and washed with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (330 g, 0-60% EtOAc-hexane in 20 min) to give (R,Z)-N-(1-(2-chloro-3-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (40.8 g, 82% yield) as yellow oil. MS m/z=276 [M+H]+. Calculated for C12H15ClFOS: 275.8. The solid was filtered through a pad of celite washed with EtOAc The organic layer was washed with brine dried over sodium sulfate filtered concentrated in vacuo The crude material was purified by silica gel chromatography (330 g, 0-60% EtOAc-hexane in 20 min)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 2L flask was added 2-chloro-3-fluoro-N-methoxy-N-methylbenzamide (41.49 g, 191 mmol) and tetrahydrofuran (800 mL). The solution was cooled to 0° C., then methylmagnesium chloride, 3.0M solution in THF (254 mL, 763 mmol) was added dropwise through addition funnel. The mixture was gradually warmed to 5° C. The reaction was quenched with 5N HCl (190 mL) until it is acidic and extracted with EtOAc twice. The organic solution was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by flash chromatography on silica gel (330 g, 0-50% EtOAc/hexane in 20 min) to give 1-(2-chloro-3-fluorophenyl)ethanone as a colorless oil (31.3 g, 95% yield). MS m/z=173 [M+H]+. Calculated for C8H6ClFO: 172.6. The mixture was gradually warmed to 5° C The reaction was quenched with 5N HCl (190 mL) until it extracted with EtOAc twice The organic solution was washed with brine dried over sodium sulfate filtered concentrated in vacuo The crude was purified by flash chromatography on silica gel (330 g, 0-50% EtOAc/hexane in 20 min)

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

Procedure: To a solution of 1-(2-chloro-3-fluorophenyl)ethanone (31.21 g, 181 mmol) in tetrahydrofuran (500 mL) was added (R)-2-methylpropane-2-sulfinamide (32.9 g, 271 mmol) and titanium(IV) isopropoxide (111 mL, 371 mmol). The mixture was heated to 65° C. overnight. LCMS showed 25% starting material remaining. Additional 16 g sulfinamide and 30 mL Ti(OPr)4 was added and the reaction was continued at 70° C. overnight. The mixture was diluted with brine (600 mL), and EtOAc. The solid was filtered through a pad of celite and washed with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (330 g, 0-60% EtOAc-hexane in 20 min) to give (R,Z)-N-(1-(2-chloro-3-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (40.8 g, 82% yield) as yellow oil. MS m/z=276 [M+H]+. Calculated for C12H15ClFOS: 275.8. The solid was filtered through a pad of celite washed with EtOAc The organic layer was washed with brine dried over sodium sulfate filtered concentrated in vacuo The crude material was purified by silica gel chromatography (330 g, 0-60% EtOAc-hexane in 20 min)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 2L flask was added 2-chloro-3-fluoro-N-methoxy-N-methylbenzamide (41.49 g, 191 mmol) and tetrahydrofuran (800 mL). The solution was cooled to 0° C., then methylmagnesium chloride, 3.0M solution in THF (254 mL, 763 mmol) was added dropwise through addition funnel. The mixture was gradually warmed to 5° C. The reaction was quenched with 5N HCl (190 mL) until it is acidic and extracted with EtOAc twice. The organic solution was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by flash chromatography on silica gel (330 g, 0-50% EtOAc/hexane in 20 min) to give 1-(2-chloro-3-fluorophenyl)ethanone as a colorless oil (31.3 g, 95% yield). MS m/z=173 [M+H]+. Calculated for C8H6ClFO: 172.6. The mixture was gradually warmed to 5° C The reaction was quenched with 5N HCl (190 mL) until it extracted with EtOAc twice The organic solution was washed with brine dried over sodium sulfate filtered concentrated in vacuo The crude was purified by flash chromatography on silica gel (330 g, 0-50% EtOAc/hexane in 20 min)