methyl (E)-3-methoxyprop-2-enoate

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

Procedure: A solution of (E)-methyl 3-methoxyacrylate (290 mg, 280 mL, 2.51 mmol) in 1:1 mixture of dioxane/water (4 mL) was treated with NBS (507 mg, 2.85 mmol) at 0° C. and stirred for 1 hour. The mixture was transferred to a flask containing the thioamide 337 (593 mg, 2.28 mmol) at room temperature and the resulting mixture was refluxed for 1.5 hours. It was cooled down, quenched by adding saturated NH4Cl solution (5 mL) and concentrated. Obtained material was partitioned between EtOAc and water. Organic phase was dried with Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography using 60% EtOAc in hexanes as an eluent, to afford the title compound 338 (602 mg, 77% yield). MS: calc: 342.1; found: 343.1 (M+H) The mixture was transferred to a flask the resulting mixture was refluxed for 1.5 hours It was cooled down quenched by adding saturated NH4Cl solution (5 mL) concentrated Obtained material was partitioned between EtOAc and water Organic phase was dried with Na2SO4 filtered concentrated The crude product was purified by flash chromatography

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

Procedure: A solution of (E)-methyl 3-methoxyacrylate (290 mg, 280 mL, 2.51 mmol) in 1:1 mixture of dioxane/water (4 mL) was treated with NBS (507 mg, 2.85 mmol) at 0° C. and stirred for 1 hour. The mixture was transferred to a flask containing the thioamide 337 (593 mg, 2.28 mmol) at room temperature and the resulting mixture was refluxed for 1.5 hours. It was cooled down, quenched by adding saturated NH4Cl solution (5 mL) and concentrated. Obtained material was partitioned between EtOAc and water. Organic phase was dried with Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography using 60% EtOAc in hexanes as an eluent, to afford the title compound 338 (602 mg, 77% yield). MS: calc: 342.1; found: 343.1 (M+H) The mixture was transferred to a flask the resulting mixture was refluxed for 1.5 hours It was cooled down quenched by adding saturated NH4Cl solution (5 mL) concentrated Obtained material was partitioned between EtOAc and water Organic phase was dried with Na2SO4 filtered concentrated The crude product was purified by flash chromatography

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

Procedure: To a solution of tert-butyl N-(2-formyl-6-methoxyphenyl)carbamate (2.85 g, 11.35 mmol) [described in Org. Lett. 2002, 4(1), 39-42] and methyl trans-3-methoxyacrylate (2.70 mL, 24.96 mmol) dissolved in 60 ml of methanol, was added slowly 40 mL of an aqueous solution of hydrochloric acid 3M. The resulting mixture was stirred under reflux for 3 hours. The reaction mixture was then cooled to room temperature and neutralised by adding Na2CO3. The aqueous solution was extracted with CH2Cl2 (4×70 mL). The combined organic layers were dried over MgSO4, filtered and evaporated under vacuum giving 2.12 g of compound of molecular formula C12H11NO3. The crude product was used without further purification in the next stage. Aspect: orange powder. under reflux for 3 hours The aqueous solution was extracted with CH2Cl2 (4×70 mL) The combined organic layers were dried over MgSO4 filtered evaporated under vacuum

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

Procedure: To a solution of tert-butyl N-(2-formyl-3-methoxyphenyl)carbamate (7.8 g, 31 mmol) [described in Adv. Synth. Catal. 2003, 345, 743-765] and methyl trans-3-methoxyacrylate (7.4 mL, 68.4 mmol) dissolved in 150 ml of methanol, was added slowly 100 mL of an aqueous solution of hydrochloric acid 3M. The resulting mixture was stirred under reflux for 3 hours. The reaction mixture was then cooled to room temperature and neutralised by adding Na2CO3. The aqueous solution was extracted with CH2Cl2 (4×150 mL). The combined organic layers were dried over MgSO4, filtered and evaporated under vacuum. The crude product was then filtered on silica gel (AcOEt:cyclohexane/1:1) to afford 5.6 g of compound of molecular formula C12H11NO3. Aspect: yellow powder. under reflux for 3 hours The aqueous solution was extracted with CH2Cl2 (4×150 mL) The combined organic layers were dried over MgSO4 filtered evaporated under vacuum The crude product was then filtered on silica gel (AcOEt:cyclohexane/1:1)

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

Procedure: To a solution of tert-butyl N-(2-formyl-3-methoxyphenyl)carbamate (7.8 g, 31 mmol) [described in Adv. Synth. Catal. 2003, 345, 743-765] and methyl trans-3-methoxyacrylate (7.4 mL, 68.4 mmol) dissolved in 150 ml of methanol, was added slowly 100 mL of an aqueous solution of hydrochloric acid 3M. The resulting mixture was stirred under reflux for 3 hours. The reaction mixture was then cooled to room temperature and neutralised by adding Na2CO3. The aqueous solution was extracted with CH2Cl2 (4×150 mL). The combined organic layers were dried over MgSO4, filtered and evaporated under vacuum. The crude product was then filtered on silica gel (AcOEt:cyclohexane/1:1) to afford 5.6 g of compound of molecular formula C12H11NO3. Aspect: yellow powder. under reflux for 3 hours The aqueous solution was extracted with CH2Cl2 (4×150 mL) The combined organic layers were dried over MgSO4 filtered evaporated under vacuum The crude product was then filtered on silica gel (AcOEt:cyclohexane/1:1)

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

Procedure: 3-Fluoroaniline (50 g, 450 mmol) was dissolved in toluene (500 ml) and 25% NaOMe in MeOH (120 ml) and methyl (2E)-3-(methyloxy)-2-propenoate (57.4 ml, 495 mmol) were added. The mixture was then heated to 70° C. and stirred at this temperature for 2.5 hours. The solvent was then reduced to around a quarter of the original volume and the reaction was then treated with NH4Cl until pH 7 was reached (approx 500 ml used). EtOAc was added to the reaction and the layers separated, the aqueous layer was then extracted three times with EtOAc and the combined organic layers dried with MgSO4. The solvents were removed and the crude residues were purified by column chromatography on silica gel using a 30-50% EtOAc/40-60 petroleum ether gradient. Fractions containing product were concentrated to afford the desired compound (40.68 g, 40%) and a less pure batch (6.17 g, 6%) the layers separated the aqueous layer was then extracted three times with EtOAc the combined organic layers dried with MgSO4 The solvents were removed the crude residues were purified by column chromatography on silica gel using a 30-50% EtOAc/40-60 petroleum ether gradient Fractions containing product were concentrated

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

Procedure: 3-Fluoroaniline (50 g, 450 mmol) was dissolved in toluene (500 ml) and 25% NaOMe in MeOH (120 ml) and methyl (2E)-3-(methyloxy)-2-propenoate (57.4 ml, 495 mmol) were added. The mixture was then heated to 70° C. and stirred at this temperature for 2.5 hours. The solvent was then reduced to around a quarter of the original volume and the reaction was then treated with NH4Cl until pH 7 was reached (approx 500 ml used). EtOAc was added to the reaction and the layers separated, the aqueous layer was then extracted three times with EtOAc and the combined organic layers dried with MgSO4. The solvents were removed and the crude residues were purified by column chromatography on silica gel using a 30-50% EtOAc/40-60 petroleum ether gradient. Fractions containing product were concentrated to afford the desired compound (40.68 g, 40%) and a less pure batch (6.17 g, 6%) the layers separated the aqueous layer was then extracted three times with EtOAc the combined organic layers dried with MgSO4 The solvents were removed the crude residues were purified by column chromatography on silica gel using a 30-50% EtOAc/40-60 petroleum ether gradient Fractions containing product were concentrated

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

Procedure: 1.27 g of 3-(4-fluorophenyl)-1-isopropyl-1H-indole, 1.16 g of methyl trans-3-methoxyacrylate and 12 mL of glacial acetic acid were mixed, then, 797 mg of 30 wt % hydrogen bromide/acetic acid solution was added dropwise into the mixture at an inner temperature of 25° C., the mixture was stirred for 5 hours at the same temperature to cause a reaction. After completion of the reaction, the same post treatment was conducted as in Example 1 to obtain 0.15 g of methyl trans-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrylate (yellow solid). Yield: 8%. a reaction After completion of the reaction

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

Procedure: 2.53 g of 3-(4-fluorophenyl)-1-isopropyl-1H-indole, 2.32 g of methyl trans-3-methoxyacrylate, 0.3 g of water and 15 mL of acetonitrile were mixed, then, 2.51 g of phosphorus oxychloride was added dropwise into the mixture at an inner temperature of 25° C., the added mixture was stirred for 19 hours at the same temperature to cause a reaction. After completion of the reaction, the same post treatment was conducted as in Example 1 to obtain 2.17 g of methyl trans-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrylate (yellow solid). Yield: 65%. a reaction After completion of the reaction

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

Procedure: 0.31 g of 3-(4-fluorophenyl)-1-isopropyl-1H-indole, 0.28 g of methyl trans-3-methoxyacrylate, 36 mg of water and 6 mL of acetonitrile were mixed, then, 164 mg of phosphorus oxychloride was added dropwise into the mixture at an inner temperature of 25° C., the added mixture was stirred for 22 hours at the same temperature to cause a reaction. After completion of the reaction, the same post treatment was conducted as in Example 1 to obtain 0.21 g of methyl trans-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrylate (yellow solid). Yield: 51%. a reaction After completion of the reaction

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

Procedure: 2.53 g of 3-(4-fluorophenyl)-1-isopropyl-1H-indole, 2.32 g of methyl trans-3-methoxyacrylate, 0.3 g of water and 15 mL of acetonitrile were mixed, then, 2.51 g of phosphorus oxychloride was added dropwise into the mixture at an inner temperature of 25° C., the added mixture was stirred for 19 hours at the same temperature to cause a reaction. After completion of the reaction, the same post treatment was conducted as in Example 1 to obtain 2.17 g of methyl trans-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrylate (yellow solid). Yield: 65%. a reaction After completion of the reaction

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

Procedure: 0.62 g of 3-(4-fluorophenyl)-1-isopropyl-1H-indole, 0.57 g of methyl trans-3-methoxyacrylate, 46 mg of water and 6.4 mL of glacial acetic acid were mixed, then, 66 mg of phosphorus oxychloride was added dropwise into the mixture at an inner temperature of 25° C., the added mixture was stirred for 21 hours at the same temperature to cause a reaction. After completion of the reaction, the same post treatment was conducted as in Example 1 to obtain 0.65 g of methyl trans-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrylate (yellow solid). Yield: 79%. a reaction After completion of the reaction