2,2,2'-TRIMETHYLPROPIONANILIDE

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2,2-dimethyl-N-o-tolyl-propionamide (30.0 g, 159 mmol) in dry THF (100 mL) was added dropwise n-BuLi (2.5 M, in hexane, 190 mL) at 15° C. The mixture was stirred overnight at 15° C., cooled in an ice-water bath and treated with saturated NH4Cl solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography to give 2-tert-butyl-1H-indole (23.8 g, 88%). cooled in an ice-water bath The organic layer was separated the aqueous layer was extracted with ethyl acetate The combined organic layers were dried over anhydrous Na2SO4 filtered concentrated in vacuum The residue was purified by column chromatography

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

Procedure: To a solution of o-tolylamine (21.4 g, 0.20 mol) and Et3N (22.3 g, 0.22 mol) in CH2Cl2 was added 2,2-dimethyl-propionyl chloride (25.3 g, 0.21 mol) at 10° C. The mixture was stirred overnight at room temperature, washed with aq. HCl (5%, 80 mL), saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated under vacuum to give 2,2-dimethyl-N-o-tolyl-propionamide (35.0 g, 92%). washed with aq. HCl (5%, 80 mL), saturated NaHCO3 solution and brine dried over Na2SO4 concentrated under vacuum

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2,2-dimethyl-N-o-tolyl-propionamide (30.0 g, 159 mmol) in dry THF (100 mL) was added dropwise n-BuLi (2.5 M, in hexane, 190 mL) at 15° C. The mixture was stirred overnight at 15° C., cooled in an ice-water bath and treated with saturated NH4Cl solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography to give 2-tert-butyl-1H-indole (23.8 g, 88%). cooled in an ice-water bath The organic layer was separated the aqueous layer was extracted with ethyl acetate The combined organic layers were dried over anhydrous Na2SO4 filtered concentrated in vacuum The residue was purified by column chromatography

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

Procedure: To a solution of o-tolylamine (21.4 g, 0.20 mol) and Et3N (22.3 g, 0.22 mol) in CH2Cl2 was added 2,2-dimethyl-propionyl chloride (25.3 g, 0.21 mol) at 10° C. The mixture was stirred overnight at room temperature, washed with aq. HCl (5%, 80 mL), saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated under vacuum to give 2,2-dimethyl-N-o-tolyl-propionamide (35.0 g, 92%). washed with aq. HCl (5%, 80 mL), saturated NaHCO3 solution and brine dried over Na2SO4 concentrated under vacuum

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

Procedure: A chilled solution (-4° C.) of 126 g of 2,2-dimethyl-N-[(2-methyl)phenyl]propanamide in 900 ml of tetrahydrofuran was treated dropwise over 1.5 hr with n-butyl lithium (500 ml of a 2.5M solution in hexanes). After the addition was complete, the resulting solution was stirred for 1 hr, with cooling, and was then treated over 0.5 hr with a solution of 91.77 g of 2-methylbenzaldehyde methyl imine. The reaction mixture was quenched by rapid addition of water. After concentration the residue was extracted with dichloromethane. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated. A 50 g portion of the residue (213 g) was acidified with 10% hydrochloric acid and partitioned with toluene. The aqueous layer was basified with a 50% sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. Upon standing under nitrogen overnight in a refrigerator a solid formed, which was triturated with hexane to give 2,2-dimethyl-N-[2 -[2-methylamino-2-(2-methylphenyl)ethyl]phenyl]propanamide, mp 77°-79° C. After the addition with cooling The reaction mixture was quenched by rapid addition of water After concentration the residue was extracted with dichloromethane The combined organic extract was dried over anhydrous sodium sulfate filtered concentrated partitioned with toluene extracted with dichloromethane The organic layer was dried over anhydrous sodium sulfate concentrated Upon standing under nitrogen overnight in a refrigerator a solid formed which was triturated with hexane

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

Procedure: A chilled solution (-4° C.) of 126 g of 2,2-dimethyl-N-[(2-methyl)phenyl]propanamide in 900 ml of tetrahydrofuran was treated dropwise over 1.5 hr with n-butyl lithium (500 ml of a 2.5M solution in hexanes). After the addition was complete, the resulting solution was stirred for 1 hr, with cooling, and was then treated over 0.5 hr with a solution of 91.77 g of 2-methylbenzaldehyde methyl imine. The reaction mixture was quenched by rapid addition of water. After concentration the residue was extracted with dichloromethane. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated. A 50 g portion of the residue (213 g) was acidified with 10% hydrochloric acid and partitioned with toluene. The aqueous layer was basified with a 50% sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. Upon standing under nitrogen overnight in a refrigerator a solid formed, which was triturated with hexane to give 2,2-dimethyl-N-[2 -[2-methylamino-2-(2-methylphenyl)ethyl]phenyl]propanamide, mp 77°-79° C. After the addition with cooling The reaction mixture was quenched by rapid addition of water After concentration the residue was extracted with dichloromethane The combined organic extract was dried over anhydrous sodium sulfate filtered concentrated partitioned with toluene extracted with dichloromethane The organic layer was dried over anhydrous sodium sulfate concentrated Upon standing under nitrogen overnight in a refrigerator a solid formed which was triturated with hexane

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

Procedure: A stirred solution of N-[(2-methyl)phenyl]-2,2-dimethylpropanamide (95.6 g, 0.5 mol) in THF (500 ml, dried over 4 Å molecular sieves) was cooled to 0° C. and treated with 1.6M n-butyllithium in hexane (630 ml, 1.0 mol). The addition of n-butyllithium was complete after 45 minutes. During the addition, the temperature of the mixture was maintained below 10° C. with external cooling. The resultant dianion solution was aged (about 1-2 hrs) at 0° C. until the homogeneous orange solution became a white heterogeneous slurry. The dianion was then quenched with N-benzylidenemethylamine (63.7 g, 0.6 mol) and aged for 30 minutes at 15°-25° C. The reaction mixture was diluted with ether (200 ml), treated with crushed ice (200 g), and stirred for 15 minutes. The organic phase was separated, washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residual oil was crystallized from hexane (400 ml) at 5° C. to give N-[2-(2-methylamino-2-phenylethyl)phenyl]-2,2-dimethylpropanamide (121.2 g, 0.39 mol) in 78% yield. The product had a melting point of 85°-86° C. During the addition the temperature of the mixture was maintained below 10° C. with external cooling (about 1-2 hrs) at 0° C. aged for 30 minutes at 15°-25° C The organic phase was separated washed with saturated sodium chloride dried over anhydrous magnesium sulfate concentrated in vacuo The residual oil was crystallized from hexane (400 ml) at 5° C.

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

Procedure: A stirred solution of N-[(2-methyl)phenyl]-2,2-dimethylpropanamide (95.6 g, 0.5 mol) in THF (500 ml, dried over 4 Å molecular sieves) was cooled to 0° C. and treated with 1.6M n-butyllithium in hexane (630 ml, 1.0 mol). The addition of n-butyllithium was complete after 45 minutes. During the addition, the temperature of the mixture was maintained below 10° C. with external cooling. The resultant dianion solution was aged (about 1-2 hrs) at 0° C. until the homogeneous orange solution became a white heterogeneous slurry. The dianion was then quenched with N-benzylidenemethylamine (63.7 g, 0.6 mol) and aged for 30 minutes at 15°-25° C. The reaction mixture was diluted with ether (200 ml), treated with crushed ice (200 g), and stirred for 15 minutes. The organic phase was separated, washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residual oil was crystallized from hexane (400 ml) at 5° C. to give N-[2-(2-methylamino-2-phenylethyl)phenyl]-2,2-dimethylpropanamide (121.2 g, 0.39 mol) in 78% yield. The product had a melting point of 85°-86° C. During the addition the temperature of the mixture was maintained below 10° C. with external cooling (about 1-2 hrs) at 0° C. aged for 30 minutes at 15°-25° C The organic phase was separated washed with saturated sodium chloride dried over anhydrous magnesium sulfate concentrated in vacuo The residual oil was crystallized from hexane (400 ml) at 5° C.

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

Procedure: A biphasic solution of o-toluidine (107.2 g, 1.0 mol) in methylene chloride (500 ml) and water (150 ml) containing sodium carbonate (69 g, 0.65 mol) was treated with trimethylacetyl chloride (120.6 g, 1.0 mol). The rate of addition of trimethylacetyl chloride was adjusted so as to maintain the reaction at gentle reflux. After 45 minutes the addition was complete. The organic layer was separated, washed with water, and concentrated in vacuo. The crude N-[(2-methyl)phenyl]-2,2-dimethylpropanamide was slurried in 2% aqueous HCl, filtered and washed with H2O until the filtrate was neutral. After drying in vacuo (50° C., 20 mm), N-[(2-methyl)phenyl]-2,2-dimethylpropanamide (178 g, 0.93 mol) was obtained in 93% yield. (mp 109°-110° C.). to maintain the reaction at gentle reflux After 45 minutes the addition The organic layer was separated washed with water concentrated in vacuo filtered washed with H2O until the filtrate After drying in vacuo (50° C., 20 mm)

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

Procedure: A biphasic solution of o-toluidine (107.2 g, 1.0 mol) in methylene chloride (500 ml) and water (150 ml) containing sodium carbonate (69 g, 0.65 mol) was treated with trimethylacetyl chloride (120.6 g, 1.0 mol). The rate of addition of trimethylacetyl chloride was adjusted so as to maintain the reaction at gentle reflux. After 45 minutes the addition was complete. The organic layer was separated, washed with water, and concentrated in vacuo. The crude N-[(2-methyl)phenyl]-2,2-dimethylpropanamide was slurried in 2% aqueous HCl, filtered and washed with H2O until the filtrate was neutral. After drying in vacuo (50° C., 20 mm), N-[(2-methyl)phenyl]-2,2-dimethylpropanamide (178 g, 0.93 mol) was obtained in 93% yield. (mp 109°-110° C.). to maintain the reaction at gentle reflux After 45 minutes the addition The organic layer was separated washed with water concentrated in vacuo filtered washed with H2O until the filtrate After drying in vacuo (50° C., 20 mm)

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

Procedure: A chilled solution (-4° C.) of 126 g of 2,2-dimethyl-N-[(2-methyl)phenyl]propanamide in 900 ml of tetrahydrofuran was treated dropwise over 1.5 hr with n-butyl lithium (500 ml of a 2.5M solution in hexanes). After the addition was complete, the resulting solution was stirred for 1 hr, with cooling, and was then treated over 0.5 hr with a solution of 91.77 g of 2-methylbenzaldehyde methyl imine. The reaction mixture was quenched by rapid addition of water. After concentration the residue was extracted with dichloromethane. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated. A 50 g portion of the residue (213 g) was acidified with 10% hydrochloric acid and partitioned with toluene. The aqueous layer was basified with a 50% sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. Upon standing under nitrogen overnight in a refrigerator a solid formed, which was triturated with hexane to give 2,2-dimethyl-N-[2 -[2-methylamino-2-(2-methylphenyl)ethyl]phenyl]propanamide, mp 77°-79° C. After the addition with cooling The reaction mixture was quenched by rapid addition of water After concentration the residue was extracted with dichloromethane The combined organic extract was dried over anhydrous sodium sulfate filtered concentrated partitioned with toluene extracted with dichloromethane The organic layer was dried over anhydrous sodium sulfate concentrated Upon standing under nitrogen overnight in a refrigerator a solid formed which was triturated with hexane