4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butanal

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

Procedure: To the crude organic extract of 4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butyraldehyde (prepared as in Example 26, part F, 0.6 g, 2.88 mmol) in ether (5 mL) was added titanium (IV) ethoxide (2.63 g, 11.54 mmol) followed by (S)-(+)-toluene sulfinamide (0.537 g, 3.46 mmol) and the solution was heated to reflux for 5 h. The mixture was then cooled to 0° C. and water (35 mL) was added to precipitate titanium salts. The suspension was filtered through a pad of the Celite® reagent and the filter cake was washed with CH2Cl2. The layers of the filtrate were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated to obtain a crude yellow oil (1.05 g). The crude product was purified by the Biotage Flash™ 40 chromatography system, eluent: 1:9 EtOAc-hexanes, to afford 4-methyl-N-[(1Z)-4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butylidene]benzenesulfinamide as a yellow oil (0.41 g, 41.2%). Mass Spectrum (−ESI): 344 (M−H)−. the solution was heated to reflux for 5 h to precipitate titanium salts The suspension was filtered through a pad of the Celite® reagent the filter cake was washed with CH2Cl2 The layers of the filtrate were separated the aqueous layer was extracted with CH2Cl2 The combined organic extracts were dried over MgSO4 filtered concentrated to obtain a crude yellow oil (1.05 g) The crude product was purified by the Biotage Flash™ 40 chromatography system, eluent

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

Procedure: To the crude organic extract of 4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butyraldehyde (prepared as in Example 26, part F, 0.6 g, 2.88 mmol) in ether (5 mL) was added titanium (IV) ethoxide (2.63 g, 11.54 mmol) followed by (S)-(+)-toluene sulfinamide (0.537 g, 3.46 mmol) and the solution was heated to reflux for 5 h. The mixture was then cooled to 0° C. and water (35 mL) was added to precipitate titanium salts. The suspension was filtered through a pad of the Celite® reagent and the filter cake was washed with CH2Cl2. The layers of the filtrate were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated to obtain a crude yellow oil (1.05 g). The crude product was purified by the Biotage Flash™ 40 chromatography system, eluent: 1:9 EtOAc-hexanes, to afford 4-methyl-N-[(1Z)-4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butylidene]benzenesulfinamide as a yellow oil (0.41 g, 41.2%). Mass Spectrum (−ESI): 344 (M−H)−. the solution was heated to reflux for 5 h to precipitate titanium salts The suspension was filtered through a pad of the Celite® reagent the filter cake was washed with CH2Cl2 The layers of the filtrate were separated the aqueous layer was extracted with CH2Cl2 The combined organic extracts were dried over MgSO4 filtered concentrated to obtain a crude yellow oil (1.05 g) The crude product was purified by the Biotage Flash™ 40 chromatography system, eluent

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To sodium cyanide (0.425 g, 8.65 mmol) and ammonium carbonate (0.9 g, 11.54 mmol) in H2O (30 mL) was added 4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butyraldehyde (0.6 g, 2.88 mmol) in ethanol (30 mL). The black reaction mixture was heated to 90° C. After 1 h, the mixture became homogeneous and was stirred at 90° C. for 18 h. After cooling to 25° C., about 40 mL of solvent was removed in vacuo. Concentrated HCl (4 mL) was added to acidify the mixture to pH 1-2 and a precipitate formed. It was filtered. The mother liquor was washed with EtOAc (3×50 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain 5-(3,3,3-trifluoro-1-(2,2,2-trifluoroethyl)propyl) imidazolidine-2,4-dione as a brown oil (1.01 g, 100%). Mass Spectrum (+ESI): 279, 280 (M+H)+. The black reaction mixture After cooling to 25° C. about 40 mL of solvent was removed in vacuo Concentrated HCl (4 mL) was added a precipitate formed It was filtered The mother liquor was washed with EtOAc (3×50 mL) The organic layer was dried over MgSO4 filtered concentrated

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To sodium cyanide (0.425 g, 8.65 mmol) and ammonium carbonate (0.9 g, 11.54 mmol) in H2O (30 mL) was added 4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butyraldehyde (0.6 g, 2.88 mmol) in ethanol (30 mL). The black reaction mixture was heated to 90° C. After 1 h, the mixture became homogeneous and was stirred at 90° C. for 18 h. After cooling to 25° C., about 40 mL of solvent was removed in vacuo. Concentrated HCl (4 mL) was added to acidify the mixture to pH 1-2 and a precipitate formed. It was filtered. The mother liquor was washed with EtOAc (3×50 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain 5-(3,3,3-trifluoro-1-(2,2,2-trifluoroethyl)propyl) imidazolidine-2,4-dione as a brown oil (1.01 g, 100%). Mass Spectrum (+ESI): 279, 280 (M+H)+. The black reaction mixture After cooling to 25° C. about 40 mL of solvent was removed in vacuo Concentrated HCl (4 mL) was added a precipitate formed It was filtered The mother liquor was washed with EtOAc (3×50 mL) The organic layer was dried over MgSO4 filtered concentrated

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

Procedure: A solution of 4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butan-1-ol (1.5 g, 7.14 mmol) in CH2Cl2 saturated with water (30 mL) was stirred under nitrogen at 0° C. Dess-Martin periodinane reagent (6.35 g, 14.99 mmol) was added in one portion. The resulting suspension was stirred at 25° C., monitoring the progress of reaction by TLC analysis (1:2 EtOAc/hexane). As the rate of conversion of the starting material slowed, additional 2 mL portions of CH2Cl2 saturated with water were added (three portions over 15 min). After 19 h at 25° C., the reaction was complete by TLC. The solution was diluted with Et2O (50 mL) and a solution of sodium thiosulfate, Na2S2O3 (73.33 mmol, 11.6 g, 11 eq) in 80% saturated aqueous sodium bicarbonate solution (50 mL) was added. The mixture was stirred rapidly for 10 min until both phases were clear. The layers were separated and the aqueous phase was extracted with ether (30 mL). The combined organic layers were washed sequentially with saturated aqueous sodium bicarbonate (10 mL) and brine (15 mL), then dried over MgSO4, filtered and concentrated to 50% of its original volume to give 4,4,4-trifluoro-2-(2,2,2-trifluoro-ethyl)-butyraldehyde as a solution (20 mL). Mass Spectrum (+ESI): (M+H)+. The mixture was stirred rapidly for 10 min until both phases The layers were separated the aqueous phase was extracted with ether (30 mL) The combined organic layers were washed sequentially with saturated aqueous sodium bicarbonate (10 mL) and brine (15 mL) dried over MgSO4 filtered concentrated to 50% of its original volume

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4,4,4-trifluoro-N-methoxy-N-methyl-2-(2,2,2-trifluoroethyl)-butyramide (2.67 g, 10 mmol) in CH2Cl2 (10 mL), diisobutylaluminum hydride (2.9 mL, 16 mmol) was added over 10 min at −70° C. The reaction mixture was stirred at −70° C. for 40 min, then transferred via a cannula to a flask containing 30 mL of 2N HCl at 0° C. 10 mL of conc. HCl was added and the mixture was stirred at 25° C. for 30 min. Phases were split and the aqueous phase was extracted with 5 mL of CH2Cl2. The combined organic phase was washed with brine and dried over MgSO4. NMR analysis of the solution using an internal standard indicated formation of the title product in 65% yield. The solution was used as such for further transformations. transferred via a cannula to a flask the mixture was stirred at 25° C. for 30 min Phases were split the aqueous phase was extracted with 5 mL of CH2Cl2 The combined organic phase was washed with brine dried over MgSO4

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

Procedure: To a solution of 4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butan-1-ol (5.0 g, 24 mmol) in CH2Cl2 (80 mL) was added Dess-Martin periodinane reagent (10 g, 24 mmol). The reaction mixture was subsequently stirred for 20 hours at 25° C. The solution was diluted with Et2O (200 mL) and a 1:1 mixture of 10% sodium thiosulfate and saturated NaHCO3 (200 mL) was added. The mixture was stirred rapidly for 10 min until both phases were clear. The layers were separated and the aqueous phase was extracted with Et2O (100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to 50% of its original volume to give 4,4,4-trifluoro-2-(2,2,2-trifluoro-ethyl)-butyraldehyde that was used as is for the subsequent reaction. was added The mixture was stirred rapidly for 10 min until both phases The layers were separated the aqueous phase was extracted with Et2O (100 mL) The combined organic layers were washed with brine (100 mL) dried over Na2SO4 filtered concentrated to 50% of its original volume

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

Procedure: To the crude organic extract of 4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butyraldehyde (prepared as in Example 26, part F, 0.6 g, 2.88 mmol) in ether (5 mL) was added titanium (IV) ethoxide (2.63 g, 11.54 mmol) followed by (S)-(+)-toluene sulfinamide (0.537 g, 3.46 mmol) and the solution was heated to reflux for 5 h. The mixture was then cooled to 0° C. and water (35 mL) was added to precipitate titanium salts. The suspension was filtered through a pad of the Celite® reagent and the filter cake washed with CH2Cl2. The layers of the filtrate were separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated to obtain a crude yellow oil (1.05 g). The crude product was purified by the Biotage Flash™ 40 chromatography system, eluent: 1:9 EtOAc-hexanes, to afford 4-methyl-N-[(1Z)-4,4,4-trifluoro-2-(2,2,2-trifluoroethyl)butylidene]benzenesulfinamide as a yellow oil (0.41 g, 41.2%). Mass Spectrum (−ESI): 344 (M−H)−. the solution was heated to reflux for 5 h to precipitate titanium salts The suspension was filtered through a pad of the Celite® reagent the filter cake washed with CH2Cl2 The layers of the filtrate were separated the aqueous layer was extracted with CH2Cl2 The combined organic extracts were dried over MgSO4 filtered concentrated to obtain a crude yellow oil (1.05 g) The crude product was purified by the Biotage Flash™ 40 chromatography system, eluent