1-(4-chlorophenyl)-3,3-dimethylbutan-2-one

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

Procedure: (b′) A 3 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, reflux condenser, and nitrogen inlet-outlet, is charged with 953 g (1.05 L) of a toluene solution containing 1-(4-chlorophenyl)-3,3-dimethyl-2-butanone and 173 g (200 mL) of toluene; then add by pump 232 g (259 mL) of N,N-dimethylformamide dimethyl acetal. The solution is heated to an internal temperature at 97-109° C. (reflux) and stirred at this temperature for 5 hours. One hundred (100) mL of solvent is distilled off over a period of 0.5 hours. After distillation is stopped, the mixture is heated to an internal temperature at 107-114° C. (reflux). The mixture is stirred at this temperature for an additional 1 hour. Three more distillations follow in a similar procedure. Then the reaction mixture is cooled to an internal temperature at 20-25° C. over 1 hour, and stirred at this temperature for 1 hour, filtered over a pad of 70 g of Celite and the pad was washed with 300 mL of toluene. Filtrates are combined and concentrated under vacuum (30-80 torr) at an internal temperature at 25-40° C. (maximum jacket temperature 50° C.) to collect about 800 g or 925 mL of solvent to afford 275 g of crude 2-(4-chlorophenyl)-1-(dimethylamino)-4,4-dimethyl-1-pentene-3-one (Theoretical yield: 173.6 g). This crude product is dissolved in 440 mL (380 g) of toluene and the removal of excess N,N-dimethylformamide dimethyl acetal is confirmed by 1H NMR. The solution can be held at 21-23° C. under nitrogen and then used in the next step. (b′) A 3 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer digital thermometer, reflux condenser, and nitrogen inlet-outlet (reflux) One hundred (100) mL of solvent is distilled off over a period of 0.5 hours After distillation the mixture is heated to an internal temperature at 107-114° C. (reflux) The mixture is stirred at this temperature for an additional 1 hour Then the reaction mixture is cooled to an internal temperature at 20-25° C. over 1 hour stirred at this temperature for 1 hour filtered over a pad of 70 g of Celite the pad was washed with 300 mL of toluene concentrated under vacuum (30-80 torr) at an internal temperature at 25-40° C. (maximum jacket temperature 50° C.) to collect about 800 g or 925 mL of solvent

Conditions: temp:103.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (b′) A 3 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, reflux condenser, and nitrogen inlet-outlet, is charged with 953 g (1.05 L) of a toluene solution containing 1-(4-chlorophenyl)-3,3-dimethyl-2-butanone and 173 g (200 mL) of toluene; then add by pump 232 g (259 mL) of N,N-dimethylformamide dimethyl acetal. The solution is heated to an internal temperature at 97-109° C. (reflux) and stirred at this temperature for 5 hours. One hundred (100) mL of solvent is distilled off over a period of 0.5 hours. After distillation is stopped, the mixture is heated to an internal temperature at 107-114° C. (reflux). The mixture is stirred at this temperature for an additional 1 hour. Three more distillations follow in a similar procedure. Then the reaction mixture is cooled to an internal temperature at 20-25° C. over 1 hour, and stirred at this temperature for 1 hour, filtered over a pad of 70 g of Celite and the pad was washed with 300 mL of toluene. Filtrates are combined and concentrated under vacuum (30-80 torr) at an internal temperature at 25-40° C. (maximum jacket temperature 50° C.) to collect about 800 g or 925 mL of solvent to afford 275 g of crude 2-(4-chlorophenyl)-1-(dimethylamino)-4,4-dimethyl-1-pentene-3-one (Theoretical yield: 173.6 g). This crude product is dissolved in 440 mL (380 g) of toluene and the removal of excess N,N-dimethylformamide dimethyl acetal is confirmed by 1H NMR. The solution can be held at 21-23° C. under nitrogen and then used in the next step. (b′) A 3 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer digital thermometer, reflux condenser, and nitrogen inlet-outlet (reflux) One hundred (100) mL of solvent is distilled off over a period of 0.5 hours After distillation the mixture is heated to an internal temperature at 107-114° C. (reflux) The mixture is stirred at this temperature for an additional 1 hour Then the reaction mixture is cooled to an internal temperature at 20-25° C. over 1 hour stirred at this temperature for 1 hour filtered over a pad of 70 g of Celite the pad was washed with 300 mL of toluene concentrated under vacuum (30-80 torr) at an internal temperature at 25-40° C. (maximum jacket temperature 50° C.) to collect about 800 g or 925 mL of solvent

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

Procedure: (a′) A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, addition funnel, heating mantle and a condenser with nitrogen inlet-outlet, is charged with 100.0 g of sodium t-butoxide and 300 mL of dry toluene. The mixture is stirred at 23-27° C. and added to a solution of 1.48 g of palladium acetate and 125.0 g of 4-bromochlorobenzene in 850 mL of dry toluene. The mixture is heated to a temperature at 95-100° C. using a heating mantle temperature set at about 95-125° C. over a period of 40 minutes. A solution of 98.1 g of pinacolone in 300 mL of toluene is added over a period of 45 minutes to 1 hour while maintaining the internal temperature at 95-100° C. The mixture is stirred for an additional 9 hours, then cooled to an internal temperature at 23-25° C. over a period of 30 minutes. Six hundred (600) g of 15% ammonium chloride solution is added over a period of 10 minutes while maintaining the internal temperature at 20-27° C. The mixture is stirred, the organic layer separated, and washed with 600 mL of saturated sodium chloride solution. The organic layer is charged into a 5 L, 4-necked, round-bottomed flask equipped with a mechanical stirrer, digital thermometer, addition funnel, heating mantle and a condenser with nitrogen inlet-outlet, and a solution of 150.0 g of L-cysteine in 900 mL of water is added. The mixture is heated to an internal temperature at 84-90° C. over a period of 40 minutes to achieve reflux, then stirred for an additional 5 hours. After cooling, the aqueous layer is removed, and the organic layer filtered over a Buchner funnel containing a pad of 20.0 g of Celite. After washing the Celite pad with 200 mL of toluene, and saving the filtrate, to the filtrate is added a solution of 75.0 g of L-cysteine and 2.5 g of sodium thiosulfate pentahydrate in 600 mL of water. The mixture is heated to an internal temperature at 78-82° C. White solids formed gradually. The triphasic mixture is stirred at this temperature for an additional 5 hours, then cooled, and the organic layer is separated. The organic layer is filtered over a pad of 20.0 g of Celite and the pad is washed with 200 mL of toluene. The combined filtrates is washed again with 400 mL of saturated NaCl solution. The organic layer is filtered and concentrated to collect about 800 mL of solvent to afford about 1.0 L of crude 1-(4-chlorophenyl)-3,3-dimethyl-2-butanone in toluene, which is used directly in the next step, theoretical Yield: 137.6 g (Pd 2 ppm). (a′) A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer digital thermometer, addition funnel heating mantle and a condenser with nitrogen inlet-outlet The mixture is heated to a temperature at 95-100° C. while maintaining the internal temperature at 95-100° C The mixture is stirred for an additional 9 hours cooled to an internal temperature at 23-25° C. over a period of 30 minutes while maintaining the internal temperature at 20-27° C The mixture is stirred the organic layer separated washed with 600 mL of saturated sodium chloride solution The organic layer is charged into a 5 L 4-necked, round-bottomed flask equipped with a mechanical stirrer digital thermometer, addition funnel heating mantle and a condenser with nitrogen inlet-outlet a solution of 150.0 g of L-cysteine in 900 mL of water is added The mixture is heated to an internal temperature at 84-90° C. over a period of 40 minutes to achieve reflux stirred for an additional 5 hours After cooling the aqueous layer is removed the organic layer filtered over a Buchner funnel containing a pad of 20.0 g of Celite After washing the Celite pad with 200 mL of toluene to the filtrate is added a solution of 75.0 g of L-cysteine and 2.5 g of sodium thiosulfate pentahydrate in 600 mL of water The mixture is heated to an internal temperature at 78-82° C White solids formed gradually The triphasic mixture is stirred at this temperature for an additional 5 hours cooled the organic layer is separated The organic layer is filtered over a pad of 20.0 g of Celite the pad is washed with 200 mL of toluene The combined filtrates is washed again with 400 mL of saturated NaCl solution The organic layer is filtered concentrated to collect about 800 mL of solvent

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

Procedure: 1-(4-Chlorophenyl)-3,3-dimethyl-butan-2-one (30 mmol) and tert-butoxybis-(dimethylamino)methane (31.5 mmol) are heated together at reflux overnight. The reaction mixture is then cooled to RT and the excess tert-butoxybis(dimethylamino)methane removed under reduced pressure to give 2-(4-chlorophenyl)-1-dimethylamino-4,4-dimethyl-pent-1-en-3-one. at reflux overnight the excess tert-butoxybis(dimethylamino)methane removed under reduced pressure

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

Procedure: 1-(4-Chlorophenyl)-3,3-dimethyl-butan-2-one (30 mmol) and tert-butoxybis-(dimethylamino)methane (31.5 mmol) are heated together at reflux overnight. The reaction mixture is then cooled to RT and the excess tert-butoxybis(dimethylamino)methane removed under reduced pressure to give 2-(4-chlorophenyl)-1-dimethylamino-4,4-dimethyl-pent-1-en-3-one. at reflux overnight the excess tert-butoxybis(dimethylamino)methane removed under reduced pressure

Conditions: temp:103.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (b′) A 3 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, reflux condenser, and nitrogen inlet-outlet, is charged with 953 g (1.05 L) of a toluene solution containing 1-(4-chlorophenyl)-3,3-dimethyl-2-butanone and 173 g (200 mL) of toluene; then add by pump 232 g (259 mL) of N,N-dimethylformamide dimethyl acetal. The solution is heated to an internal temperature at 97-109° C. (reflux) and stirred at this temperature for 5 hours. One hundred (100) mL of solvent is distilled off over a period of 0.5 hours. After distillation is stopped, the mixture is heated to an internal temperature at 107-114° C. (reflux). The mixture is stirred at this temperature for an additional 1 hour. Three more distillations follow in a similar procedure. Then the reaction mixture is cooled to an internal temperature at 20-25° C. over 1 hour, and stirred at this temperature for 1 hour, filtered over a pad of 70 g of Celite and the pad was washed with 300 mL of toluene. Filtrates are combined and concentrated under vacuum (30-80 torr) at an internal temperature at 25-40° C. (maximum jacket temperature 50° C.) to collect about 800 g or 925 mL of solvent to afford 275 g of crude 2-(4-chlorophenyl)-1-(dimethylamino)-4,4-dimethyl-1-pentene-3-one (Theoretical yield: 173.6 g). This crude product is dissolved in 440 mL (380 g) of toluene and the removal of excess N,N-dimethylformamide dimethyl acetal is confirmed by 1H NMR. The solution can be held at 21-23° C. under nitrogen and then used in the next step. (b′) A 3 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer digital thermometer, reflux condenser, and nitrogen inlet-outlet (reflux) One hundred (100) mL of solvent is distilled off over a period of 0.5 hours After distillation the mixture is heated to an internal temperature at 107-114° C. (reflux) The mixture is stirred at this temperature for an additional 1 hour Then the reaction mixture is cooled to an internal temperature at 20-25° C. over 1 hour stirred at this temperature for 1 hour filtered over a pad of 70 g of Celite the pad was washed with 300 mL of toluene concentrated under vacuum (30-80 torr) at an internal temperature at 25-40° C. (maximum jacket temperature 50° C.) to collect about 800 g or 925 mL of solvent

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

Procedure: (a′) A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, addition funnel, heating mantle and a condenser with nitrogen inlet-outlet, is charged with 100.0 g of sodium t-butoxide and 300 mL of dry toluene. The mixture is stirred at 23-27° C. and added to a solution of 1.48 g of palladium acetate and 125.0 g of 4-bromochlorobenzene in 850 mL of dry toluene. The mixture is heated to a temperature at 95-100° C. using a heating mantle temperature set at about 95-125° C. over a period of 40 minutes. A solution of 98.1 g of pinacolone in 300 mL of toluene is added over a period of 45 minutes to 1 hour while maintaining the internal temperature at 95-100° C. The mixture is stirred for an additional 9 hours, then cooled to an internal temperature at 23-25° C. over a period of 30 minutes. Six hundred (600) g of 15% ammonium chloride solution is added over a period of 10 minutes while maintaining the internal temperature at 20-27° C. The mixture is stirred, the organic layer separated, and washed with 600 mL of saturated sodium chloride solution. The organic layer is charged into a 5 L, 4-necked, round-bottomed flask equipped with a mechanical stirrer, digital thermometer, addition funnel, heating mantle and a condenser with nitrogen inlet-outlet, and a solution of 150.0 g of L-cysteine in 900 mL of water is added. The mixture is heated to an internal temperature at 84-90° C. over a period of 40 minutes to achieve reflux, then stirred for an additional 5 hours. After cooling, the aqueous layer is removed, and the organic layer filtered over a Buchner funnel containing a pad of 20.0 g of Celite. After washing the Celite pad with 200 mL of toluene, and saving the filtrate, to the filtrate is added a solution of 75.0 g of L-cysteine and 2.5 g of sodium thiosulfate pentahydrate in 600 mL of water. The mixture is heated to an internal temperature at 78-82° C. White solids formed gradually. The triphasic mixture is stirred at this temperature for an additional 5 hours, then cooled, and the organic layer is separated. The organic layer is filtered over a pad of 20.0 g of Celite and the pad is washed with 200 mL of toluene. The combined filtrates is washed again with 400 mL of saturated NaCl solution. The organic layer is filtered and concentrated to collect about 800 mL of solvent to afford about 1.0 L of crude 1-(4-chlorophenyl)-3,3-dimethyl-2-butanone in toluene, which is used directly in the next step, theoretical Yield: 137.6 g (Pd 2 ppm). (a′) A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer digital thermometer, addition funnel heating mantle and a condenser with nitrogen inlet-outlet The mixture is heated to a temperature at 95-100° C. while maintaining the internal temperature at 95-100° C The mixture is stirred for an additional 9 hours cooled to an internal temperature at 23-25° C. over a period of 30 minutes while maintaining the internal temperature at 20-27° C The mixture is stirred the organic layer separated washed with 600 mL of saturated sodium chloride solution The organic layer is charged into a 5 L 4-necked, round-bottomed flask equipped with a mechanical stirrer digital thermometer, addition funnel heating mantle and a condenser with nitrogen inlet-outlet a solution of 150.0 g of L-cysteine in 900 mL of water is added The mixture is heated to an internal temperature at 84-90° C. over a period of 40 minutes to achieve reflux stirred for an additional 5 hours After cooling the aqueous layer is removed the organic layer filtered over a Buchner funnel containing a pad of 20.0 g of Celite After washing the Celite pad with 200 mL of toluene to the filtrate is added a solution of 75.0 g of L-cysteine and 2.5 g of sodium thiosulfate pentahydrate in 600 mL of water The mixture is heated to an internal temperature at 78-82° C White solids formed gradually The triphasic mixture is stirred at this temperature for an additional 5 hours cooled the organic layer is separated The organic layer is filtered over a pad of 20.0 g of Celite the pad is washed with 200 mL of toluene The combined filtrates is washed again with 400 mL of saturated NaCl solution The organic layer is filtered concentrated to collect about 800 mL of solvent

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

Procedure: 1-(4-Chlorophenyl)-3,3-dimethyl-butan-2-one (30 mmol) and tert-butoxybis-(dimethylamino)methane (31.5 mmol) are heated together at reflux overnight. The reaction mixture is then cooled to RT and the excess tert-butoxybis(dimethylamino)methane removed under reduced pressure to give 2-(4-chlorophenyl)-1-dimethylamino-4,4-dimethyl-pent-1-en-3-one. at reflux overnight the excess tert-butoxybis(dimethylamino)methane removed under reduced pressure