ethyl 3-(triphenyl-lambda5-phosphanylidene)propanoate

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

Procedure: Using a similar procedure to that described in Example 12, part c, except starting from 5-formylindole (prepared as described in the literature from 5-cyanoindole: F. Troxler, Helv. Chim. Acta., 51, 1616, (1968)), and using carbethoxyethylidene triphenylphosphorane, ethyl α-methylindol-5-acrylate was obtained (79%) as a low-melting white solid (mp about 50°); partial NMR(250 MHz, DMSO-d6): 1.28(t, 3H, CH2CH3), 2.13(d, J=1.0 Hz, 3H, CCH3), 4.19(q, 2H, CH2CH3), 6.49(m, 1H, H3 -indole), 11.28(br s, 1H, H1 -indole). prepared

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

Procedure: To a solution of 5.3 g (53.3 mmol) of sodium acetate mixed with about 100 ml of water was added under ice cooling 6.6 g (24.3 mmol) of 1,1-dibromo-3,3,3-trifluoroacetone, and the mixture was stirred at 70° C. for 20 minutes. The reaction mixture was cooled to room temperature, to which a solution of 5.8 g (21.5 mmol) of 2-fluoro-4-chloro-5-isopropoxyphenylhydrazine dissolved in about 20 ml of diethyl ether was added, and the mixture was stirred at room temperature for 1 hour. The ether layer was separated and then concentrated. About 60 ml of tetrahydrofuran (hereinafter referred to as THF) was added to the residue, to which 8.3 g (23.0 mmol) of (carbethoxyethylidene)triphenylphosphorane was added, and the mixture was heated under reflux for 2 hours. The THF was distilled out under reduced pressure, and the residue was subjected to silica gel column chromatography, which afforded 3.8 g (10.5 mmol) of 2-[2-fluoro-4-chloro-5-isopropoxyphenyl]-4-methyl-5-trifluoromethylpyridazin-3-one. was added the mixture was stirred at room temperature for 1 hour The ether layer was separated concentrated was added the mixture was heated under reflux for 2 hours The THF was distilled out under reduced pressure

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

Procedure: Then, 12.9 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-hydroxyphenylhydrazone) and 22.3 g of carbethoxyethylidenetriphenylphosphorane were dissolved in 110 ml of tetrahydrofuran, and the solution was heated under reflux for 3 hours. The solvent was distilled out under reduced pressure, and the residue was subjected to silica gel chromatography, which afforded 8.8 g of 2-(2-fluoro-4-chloro-5-hydroxyphenyl)-4-methyl-5-trifluoromethylpyridazin-3-one (compound 1-391). the solution was heated under reflux for 3 hours The solvent was distilled out under reduced pressure

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

Procedure: Then, 12.9 g of 3,3,3-trifluoro-2-oxopropanal (4-chloro-2-fluoro-5-hydroxyphenylhydrazone) and 22.3 g of carbethoxyethylidenetriphenylphosphorane were dissolved in 110 ml of tetrahydrofuran, and the solution was heated under reflux for 3 hours. The solvent was distilled out under reduced pressure, and the residue was subjected to silica gel chromatography, which afforded 8.8 g of 2-(2-fluoro-4-chloro-5-hydroxyphenyl)-4-methyl-5-trifluoromethylpyridazin-3 One (compound 1-391). the solution was heated under reflux for 3 hours The solvent was distilled out under reduced pressure

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

Procedure: Then, 12.9 g of 3,3,3-trifluoro-2-oxopropanal (4-chloro-2-fluoro-5-hydroxyphenylhydrazone) and 22.3 g of carbethoxyethylidenetriphenylphosphorane were dissolved in 110 ml of tetrahydrofuran, and the solution was heated under reflux for 3 hours. The solvent was distilled out under reduced pressure, and the residue was subjected to silica gel chromatography, which afforded 8.8 g of 2-(2-fluoro-4-chloro-5-hydroxyphenyl)-4-methyl-5-trifluoromethylpyridazin-3 One (compound 1-391). the solution was heated under reflux for 3 hours The solvent was distilled out under reduced pressure

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

Procedure: To a solution of 75.0 g (carbethoxyethylidene)triphenyl phosphorane in 350 ml of toluene, 23.2 g of salicylaldehyde was dropped in at 20° C. while cooling in an ice-bath. After stirring at room temperature for 90 mn., the reaction mixture was diluted with toluene and washed to neutrality with water. while cooling in an ice-bath washed

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

Procedure: To a solution of 75.0 g (carbethoxyethylidene)triphenyl phosphorane in 350 ml of toluene, 23.2 g of salicylaldehyde was dropped in at 20° C. while cooling in an ice-bath. After stirring at room temperature for 90 mn., the reaction mixture was diluted with toluene and washed to neutrality with water. while cooling in an ice-bath washed

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

Procedure: 3-Chloro-4-fluorobenzaldehyde (10 g, 63.1 mmol) was dissolved in 300 mL toluene. (Carboethoxyethylidene)triphenylphosphorane (25 g, 69.4 mmol) was added and the mixture was heated to reflux overnight. The solution was cooled, diluted with hexanes and the solid was filtered. The filtrate was evaporated in vacuo, and the residue was dissolved in ether and filtered through a plug of silica using ether as eluent. The solvent was evaporated in vacuo to afford the title compound (15.55 g) as a semi solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.56 (s, 1H), 7.44 (m, 1H), 7.23-7.32 (m, 1H), 7.16 (m, 1H), 4.28 (q, J=7.12 Hz, 2H), 2.09 (d, J=1.36 Hz, 3H), 1.35 (t, J=7.36 Hz, 3H). MS (DCI+) 243 (M+H). the mixture was heated to reflux overnight The solution was cooled the solid was filtered The filtrate was evaporated in vacuo the residue was dissolved in ether filtered through a plug of silica The solvent was evaporated in vacuo

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

Procedure: 3-Chloro-4-fluorobenzaldehyde (10 g, 63.1 mmol) was dissolved in 300 mL toluene. (Carboethoxyethylidene)triphenylphosphorane (25 g, 69.4 mmol) was added and the mixture was heated to reflux overnight. The solution was cooled, diluted with hexanes and the solid was filtered. The filtrate was evaporated in vacuo, and the residue was dissolved in ether and filtered through a plug of silica using ether as eluent. The solvent was evaporated in vacuo to afford the title compound (15.55 g) as a semi solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.56 (s, 1H), 7.44 (m, 1H), 7.23-7.32 (m, 1H), 7.16 (m, 1H), 4.28 (q, J=7.12 Hz, 2H), 2.09 (d, J=1.36 Hz, 3H), 1.35 (t, J=7.36 Hz, 3H). MS (DCI+) 243 (M+H). the mixture was heated to reflux overnight The solution was cooled the solid was filtered The filtrate was evaporated in vacuo the residue was dissolved in ether filtered through a plug of silica The solvent was evaporated in vacuo

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

Procedure: 2-Fluorobenzaldehyde (5.0 g, 40.3 mmol) was dissolved in 150 mL toluene. (Carboethoxyethylidene)triphenylphosphorane (42 g; 116 mmol) was added and the mixture was heated to reflux overnight. The solution was cooled, diluted with hexanes, and the solid was filtered. The filtrate was evaporated in vacuo, then dissolved in ether and filtered through a plug of silica gel using ether as eluent. The solvents were evaporated in vacuo to afford the title compound (10.57 g) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.70 (s, 1H), 7.26-7.38 (m, 3H), 7.17 (m, 2H), 4.28 (q, J=7.12 Hz, 2H), 2.04 (s, 3H), 1.35 (t, J=7.12 Hz, 3H). the mixture was heated to reflux overnight The solution was cooled the solid was filtered The filtrate was evaporated in vacuo dissolved in ether filtered through a plug of silica gel The solvents were evaporated in vacuo

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

Procedure: 2-Fluorobenzaldehyde (5.0 g, 40.3 mmol) was dissolved in 150 mL toluene. (Carboethoxyethylidene)triphenylphosphorane (42 g; 116 mmol) was added and the mixture was heated to reflux overnight. The solution was cooled, diluted with hexanes, and the solid was filtered. The filtrate was evaporated in vacuo, then dissolved in ether and filtered through a plug of silica gel using ether as eluent. The solvents were evaporated in vacuo to afford the title compound (10.57 g) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.70 (s, 1H), 7.26-7.38 (m, 3H), 7.17 (m, 2H), 4.28 (q, J=7.12 Hz, 2H), 2.04 (s, 3H), 1.35 (t, J=7.12 Hz, 3H). the mixture was heated to reflux overnight The solution was cooled the solid was filtered The filtrate was evaporated in vacuo dissolved in ether filtered through a plug of silica gel The solvents were evaporated in vacuo

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

Procedure: 4-Fluorobenzaldehyde (12 g, 97 mmol) was dissolved in toluene (500 mL). (Carboethoxyethylidene)triphenylphosphorane (42 g, 116 mmol) was added and the mixture was heated to reflux until the starting material was consumed. The solution was cooled, diluted with hexanes, and the solid was filtered. The filtrate was evaporated in vacuo. The remaining residue was dissolved in ether, and filtered through a plug of silica gel using ether as eluent. The solvents were evaporated in vacuo to afford the title compound (20 g, 99% yield) as a yellow solid. 1H NMR (DMSO-d6) δ ppm: 7.64 (s, 1H), 7.38 (dd, J=8.65, 5.59 Hz, 2H), 7.08 (t, J=8.65 Hz, 2H), 4.27 (q, J=7.12 Hz, 2H), 2.10 (d, J=1.36 Hz, 3H), 1.27-1.38 (m, 3H). MS (DCI+) 209 (M+H). the mixture was heated to reflux until the starting material was consumed The solution was cooled diluted with hexanes the solid was filtered The filtrate was evaporated in vacuo The remaining residue was dissolved in ether filtered through a plug of silica gel The solvents were evaporated in vacuo