2-methyl-2-phenylpropanal

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

Procedure: To a stirred solution of 2.5 g of 2,2-dimethyl-3-phenyloxirane (16 mmol) in 85 mL of anhydrous benzene is added 0.415 g (0.362 mmol, 5 mol %) of tris(pentafluorophenyl) borane. The light yellow solution is stirred at 25° C. for 19 hours. The reaction mixture containing the 2-methyl-2-phenylpropanal is then treated with (S)-p-toluenesulfinamide (2.3 g, 15 mmol) followed by a solution of 16 mL (73 mmol) titanium ethoxide in 155 mL of benzene. The yellow solution is stirred at 25° C. for 24 hours then cooled to 5-10° C. and quenched with 245 mL of water. The mixture is filtered through diatomaceous earth, and the filter cake washed with methylene chloride (4×50 mL). The aqueous layer is washed with methylene chloride (1×25 mL). The combined organic layers are dried (MgSO4) and concentrated under reduced pressure to give 3.74 g (81%) of the desired product as a white solid. The product is used without further purification in the next step. The yellow solution is stirred at 25° C. for 24 hours then cooled to 5-10° C. quenched with 245 mL of water The mixture is filtered through diatomaceous earth the filter cake washed with methylene chloride (4×50 mL) The aqueous layer is washed with methylene chloride (1×25 mL) The combined organic layers are dried (MgSO4) concentrated under reduced pressure

Conditions: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of potassium cyanide (103 g, 1.56 mol) and methylamine hydrochloride (106 g, 1.56 mol) in water (1000 mL) is added a solution of 2-methyl-2-phenylpropanal (222 g, 1.50 mol) in methanol (1000 mL) over a period of 30 minutes. An ice-water bath is used occasionally to maintain the reaction temperature between 20-25° C. The mixture is stirred at room temperature for 25 hours. Water (2000 mL) is then added and the reaction mixture is extracted with CH2Cl2 (3×800 mL). The combined organic extracts are washed with brine (500 mL) and dried over Na2SO4. The organic extracts are filtered and concentrated to give 3-methyl-2-(methylamino)-3-phenylbutanenitrile as an oil (274 g, 95% yield, 76.6% by HPLC area, NMR (>95%)). Evidence of decomposition on the HPLC/GC column is noted. An ice-water bath is used occasionally the reaction mixture is extracted with CH2Cl2 (3×800 mL) The combined organic extracts are washed with brine (500 mL) dried over Na2SO4 The organic extracts are filtered concentrated

Conditions: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of potassium cyanide (103 g, 1.56 mol) and methylamine hydrochloride (106 g, 1.56 mol) in water (1000 mL) is added a solution of 2-methyl-2-phenylpropanal (222 g, 1.50 mol) in methanol (1000 mL) over a period of 30 minutes. An ice-water bath is used occasionally to maintain the reaction temperature between 20-25° C. The mixture is stirred at room temperature for 25 hours. Water (2000 mL) is then added and the reaction mixture is extracted with CH2Cl2 (3×800 mL). The combined organic extracts are washed with brine (500 mL) and dried over Na2SO4. The organic extracts are filtered and concentrated to give 3-methyl-2-(methylamino)-3-phenylbutanenitrile as an oil (274 g, 95% yield, 76.6% by HPLC area, NMR (>95%)). Evidence of decomposition on the HPLC/GC column is noted. An ice-water bath is used occasionally the reaction mixture is extracted with CH2Cl2 (3×800 mL) The combined organic extracts are washed with brine (500 mL) dried over Na2SO4 The organic extracts are filtered concentrated

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-methyl-2-phenylpropanenitrile (290 g, 2.00 mol) in hexane (2000 mL) at 0° C. under N2 is added diisobutylaluminum hydride (DIBAL-H) (2600 mL, 1M in hexane) over a period of 80 minutes. The reaction mixture is stirred at 6-14° C. for 15 minutes, then allowed to warm to room temperature and stirred for 4 hours. The reaction mixture is cooled to 0° C. and H2O (50 mL) is added slowly during 1 hour. Aqueous HCl (900 mL, 15%) is then added slowly to maintain a gentle reflux. The reaction mixture is stirred for 17 hours and the organic phase is separated. The aqueous layer is extracted with ethyl acetate (400 mL) and the combined organic layers are washed with water (300 mL), brine (300 mL) and dried over Na2SO4. The organic extracts are filtered and concentrated to give 2-methyl-2-phenylpropanal as an oil (275 g, 92.8% yield, 98.2% by HPLC area). to warm to room temperature stirred for 4 hours The reaction mixture is cooled to 0° C. to maintain a gentle reflux The reaction mixture is stirred for 17 hours the organic phase is separated The aqueous layer is extracted with ethyl acetate (400 mL) the combined organic layers are washed with water (300 mL), brine (300 mL) dried over Na2SO4 The organic extracts are filtered concentrated

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

Procedure: To a solution of oxalylchloride (4.1 ml) in dichloromethane (100 ml) was added dropwise a solution of dimethylsufoxide (7.14 g) in dichloromethane (10 ml) at -60° C., and the mixture was stirred for 10 minutes. To the resultant mixture was added a solution of 2-methyl-2-phenylpropanol (6.16 g) in dichloromethane (15 ml) at the same temperature. After stirring for one hour, to the mixture was added triethylamine (20.7 g). The mixture was further stirred for 30 minutes and allowed to room temperature. After adding water, the mixture was extracted with dichloromethane. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant residue was subjected to silica gel (40 g) column chromatography and elution with 2% ethyl acetate hexane solution gave 4.93 g of 2-methyl-2-phenylpropanal. After stirring for one hour, to the mixture The mixture was further stirred for 30 minutes allowed to room temperature the mixture was extracted with dichloromethane The extract was washed with a saturated aqueous solution of sodium chloride dried over anhydrous magnesium sulfate concentrated under reduced pressure The resultant residue was subjected to silica gel (40 g) column chromatography and elution with 2% ethyl acetate hexane solution

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 2-methyl-2-phenyl-propan-1-ol (13.3 g, 87.0 mmol) in DMSO (150 mL) was added triethylamine (24.7 mL, 178.0 mmo) at rt, followed by pyridine sulfuric oxide (28.6 g, 180.0 mmol). The mixture was stirred for 2.5 h at rt. Water was added and the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product 2-methyl-2-phenyl-propionaldehyde (12.0 mg, 91.6%), which was used to the next step without further purification. the resulting mixture was extracted with dichloromethane The organic layer was dried over anhydrous sodium sulfate concentrated

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

Procedure: To a solution of 2-methyl-2-phenyl-propan-1-ol (13.3 g, 87.0 mmol) in DMSO (150 mL) was added triethylamine (24.7 mL, 178.0 mmo) at rt, followed by pyridine sulfuric oxide (28.6 g, 180.0 mmol). The mixture was stirred for 2.5 h at rt. Water was added and the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product 2-methyl-2-phenyl-propionaldehyde (12.0 mg, 91.6%), which was used to the next step without further purification. the resulting mixture was extracted with dichloromethane The organic layer was dried over anhydrous sodium sulfate concentrated

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

Procedure: To a stirred solution of 2.5 g of 2,2-dimethyl-3-phenyloxirane (16 mmol) in 85 mL of anhydrous benzene is added 0.415 g (0.362 mmol, 5 mol %) of tris(pentafluorophenyl) borane. The light yellow solution is stirred at 25° C. for 19 hours. The reaction mixture containing the 2-methyl-2-phenylpropanal is then treated with (S)-p-toluenesulfinamide (2.3 g, 15 mmol) followed by a solution of 16 mL (73 mmol) titanium ethoxide in 155 mL of benzene. The yellow solution is stirred at 25° C. for 24 hours then cooled to 5–10° C. and quenched with 245 mL of water. The mixture is filtered through diatomaceous earth, and the filter cake washed with methylene chloride (4×50 mL). The aqueous layer is washed with methylene chloride (1×25 mL). The combined organic layers are dried (MgSO4) and concentrated under reduced pressure to give 3.74 g (81%) of the desired product as a white solid. The product is used without further purification in the next step. The yellow solution is stirred at 25° C. for 24 hours then cooled to 5–10° C. quenched with 245 mL of water The mixture is filtered through diatomaceous earth the filter cake washed with methylene chloride (4×50 mL) The aqueous layer is washed with methylene chloride (1×25 mL) The combined organic layers are dried (MgSO4) concentrated under reduced pressure