tetramethylazanium;hydroxide

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

Procedure: To a 20 L round bottom flask was added isobutyric acid (1300 mL, 14 mol), and an aqueous solution of 25% tetramethylammonium hydroxide (5 L, 14 mol). The water was removed under reduced pressure, and azeotroped with toluene (2×2 L) to leave the product (15) as an amber liquid, which was used without further purification. The water was removed under reduced pressure azeotroped with toluene (2×2 L)

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

Procedure: To a 20 L, round bottom flask was added isobutyric acid (1300 mL, 14 mol), and an aqueous solution of 25% tetramethylammonium hydroxide (5 L, 14 mol). The water was removed under reduced pressure, and azeotroped with toluene (2×2 L) to leave the product (4b) as an amber liquid, which was used without further purification. The water was removed under reduced pressure azeotroped with toluene (2×2 L)

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

Procedure: To a 20 L, round bottom flask was added isobutyric acid (1300 mL, 14 mol), and an aqueous solution of 25% tetramethylammonium hydroxide (5 L, 14 mol). The water was removed under reduced pressure, and azeotroped with toluene (2×2 L) to leave the product (1b) as an amber liquid, which was used without further purification. The water was removed under reduced pressure azeotroped with toluene (2×2 L)

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

Procedure: Under an atmosphere of nitrogen, 4.2 ml of anhydrous N,N-dimethylformamide was added dropwise to 0.279 g of 3-carboxymethyl-5-benzylidenerhodanine (prepared as described in Example 1) at room temperature, and then 1.14 ml of methanol solution of 91.15 mg of tetramethylammonium hydroxide was added dropwise. After the mixture was stirred at room temperature for 20-30 minutes, 0.075 ml of ethyl bromide was added dropwise to the reaction mixture. The mixture was stirred at the same temperature for about 2 hours, and then concentrated under reduced pressure. The residue was diluted with 15 ml of water and extracted with ethyl acetate. The extract was washed with 50 ml of aqueous solution of sodium bicarbonate, 50 ml of water and 50 ml of aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and n-hexane (1:3) to obtain 14 mg of the titled compound. The mixture was stirred at the same temperature for about 2 hours concentrated under reduced pressure The residue was diluted with 15 ml of water extracted with ethyl acetate The extract was washed with 50 ml of aqueous solution of sodium bicarbonate, 50 ml of water and 50 ml of aqueous solution of sodium chloride dried over magnesium sulfate concentrated under reduced pressure The residue was recrystallized from a mixture of ethyl acetate and n-hexane (1:3)

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

Procedure: Di-tert-butyl phospohite (40.36 mmole) was combined with potassium bicarbonate (24.22 mmole) in 35 ml of water. The solution was stirred in an ice bath and potassium permanganate (28.25 mmole) was added in three equal portions over one hour's time, The reaction as then allowed to continue at room temperature for an additional half hour, Decolorizing carbon (600 mg) was then incorporated as the reaction was heated to 60° C. for 15 minutes. The reaction was then vacuum filtered to remove solid magnesium dioxide. The solid was washed several times with water. The filtrate was then combined with one gram of decolorizing carbon and heated at 60° C. for an additional twenty minutes. The solution was again filtered to yield a colorless solution, which was then evaporated under vacuum to afford crude Di-tert-butyl phosphate potassium salt. Di-tert-butyl phosphate potassium salt (5 g, 20.14 mmole) was dissolved in methanol (15 g): to this solution at 0° C., a slight excess of concentrated HCl is slowly added with efficient stirring at 0° C. The addition of acid causes the precipitation of potassium chloride. The solid is then filtered and washed with methanol. The compound in the mother liquor is then converted to the ammonium form by adding an equal molar amount of tetramethylammonium hydroxide (3.65 g, 20.14 mmole) while keeping the reaction cooled by a salt/ice bath with efficient stirring. The resulting clear solution is placed under reduced pressure to give the elude product. To the tetramethylammonium di-tert-butyl-phosphate dissolved in refluxing dimethoxyethane is then added 4.3 grams of chloroiodomethane (24.16 mmole) and stirred for 1-2 hours. The reaction is then filtered and the filtrate is placed under reduced pressure to concentrate the solution in DME. The chloromethyl di-tert-butyl phosphate 12-16% in DME is used in the synthesis of 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium without further purifications (60% yield): 1HNMR (CD3OD, 300 MHz) δ 1.51 (s, 12H, 5.63 (d, 2H, J=14.8). 31P-NMR (CD3OD, 300 MHz) δ −11.3 (s, 1 P). The addition of acid the precipitation of potassium chloride The solid is then filtered washed with methanol cooled by a salt/ice bath with efficient stirring to give the elude product stirred for 1-2 hours The reaction is then filtered to concentrate the solution in DME The chloromethyl di-tert-butyl phosphate 12-16% in DME is used in the synthesis of 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium without further purifications (60% yield)

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

Procedure: A solution of 6 mmol (3.2 g) of the bromo compound obtained in (2), 10 mmol (0.72 g) of acrylic acid, and 10 mmol (1.8 g) of tetramethylammonium hydroxide (pentahydrate) in 30 ml of DMF was stirred for 10 hours at room temperature. To the resulting reaction solution was added water and then extracted with ether. The extract was concentrated, and the concentrate was purified by column chromatography to obtain 2.2 g of the objective monomer (3b). (Yield: 71%)

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

Procedure: A solution of 6 mmol (3.2 g) of the bromo compound obtained in (2), 10 mmol (0.72 g) of acrylic acid, and 10 mmol (1.8 g) of tetramethylammonium hydroxide (pentahydrate) in 30 ml of DMF was stirred for 10 hours at room temperature. To the resulting reaction solution was added water and then extracted with ether. The extract was concentrated, and the concentrate was purified by column chromatography to obtain 2.2 g of the objective monomer (3b). (Yield: 71%)

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

Procedure: Into a 100 ml. flask, equipped with a magnetic stirrer, thermometer, condensor, and static nitrogen head, was placed 13.6 g. of 2-octanone, 11 g. of propionitrile, 61 g. of calcium oxide and 0.3 g. of 25% tetramethyl ammonium hydroxide in water. The mixture was held at reflux (103° C.) for 16 hours at which time gas chromatographic analysis showed 7% product nitrile relative to starting ketone. flask, equipped with a magnetic stirrer

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

Procedure: Into a 100 ml. flask, equipped with a magnetic stirrer, thermometer, condensor, and static nitrogen head, was placed 13.6 g. of 2-octanone, 11 g. of propionitrile, 61 g. of calcium oxide and 0.3 g. of 25% tetramethyl ammonium hydroxide in water. The mixture was held at reflux (103° C.) for 16 hours at which time gas chromatographic analysis showed 7% product nitrile relative to starting ketone. flask, equipped with a magnetic stirrer

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

Procedure: Into a 100 ml. flask, equipped with magnetic stirrer, thermometer, condensor and static nitrogen head, was placed 23.6 g. of 2-octanone (0.18 m), 22 g. of propionitrile (0.4 m), 7 g. of Ca(OH)2 (0.09 m), 7 g, of CaO (0.12 m), and 0.6 g. of 25% tetramethyl ammonium hydroxide in water. The solution was held at reflux for 64 hours, whereupon a gas chromatographic analysis of a sample of the reaction mixture showed 10.7% conversion of the ketone to the product nitrile. flask, equipped with magnetic stirrer at reflux for 64 hours, whereupon a gas chromatographic analysis of a sample of the reaction mixture

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

Procedure: Into a 100 ml. flask, equipped with magnetic stirrer, thermometer, condensor and static nitrogen head, was placed 23.6 g. of 2-octanone (0.18 m), 22 g. of propionitrile (0.4 m), 7 g. of Ca(OH)2 (0.09 m), 7 g, of CaO (0.12 m), and 0.6 g. of 25% tetramethyl ammonium hydroxide in water. The solution was held at reflux for 64 hours, whereupon a gas chromatographic analysis of a sample of the reaction mixture showed 10.7% conversion of the ketone to the product nitrile. flask, equipped with magnetic stirrer at reflux for 64 hours, whereupon a gas chromatographic analysis of a sample of the reaction mixture

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

Procedure: Into a 100 ml flask equipped with magnetic stirrer were placed 2.45 g (0.01 mol) of 4-nitrophenylsulfonylacetic acid and 50 ml of acetone. Stirring was begun and upon dissolution of the acid, 4.0 g of a 25% methanolic solution (i.e., 1.00 g, 0.011 mol) of tetramethylammonium hydroxide was slowly added, dropwise over a 15 min period. A precipitate formed in the dark red solution. Filtration, washing with acetone (10 ml) and drying in air afforded 2.9 g (91%) of tetramethylammonium 4-nitrophenylsulfonylacetate (Compound C1-A1). 1H and 13C NMR were in agreement with the proposed structure. Into a 100 ml flask equipped with magnetic stirrer was slowly added, dropwise over a 15 min period A precipitate formed in the dark red solution Filtration washing with acetone (10 ml) drying in air