Boron trifluoride methanol

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

Procedure: A solution of 25 g of 1-benzyl-2-(2,6-dichlorophenyl)-5-oxopyrrolidin-3-carboxylic acid in 247 ml of boron trifluoride methanol was refluxed for 7 hours and then concentrated in vacuo to a solid. The solid was dissolved in chloroform and the chloroform washed with a saturated sodium carbonate solution and then with a saturated sodium bicarbonate solution. Drying (Na2SO4), filtration, and concentration in vacuo provided 18 g of off-white crystals, m.p. 97°-102°. concentrated in vacuo to a solid The solid was dissolved in chloroform the chloroform washed with a saturated sodium carbonate solution Drying (Na2SO4), filtration, and concentration in vacuo

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

Procedure: A solution of 25.0 gm. of 2-(3-methoxyphenyl)-5-oxo-1-phenylpyrrolidin-3-carboxylic acid in 200 ml 10-15% boron fluoride-methanol was refluxed for 8 hours and upon following the workup for example 1C the product was obtained as an oil. was obtained as an oil

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

Procedure: Two grams (0.005 mol) of 4-hydroxy-4-(p-bromophenyl)-6-methyl-4,5,6,7-tetrahydro-furano[2,3-c]pyridine were heated to 50° C. for four hours in 40 ml of a boron trifluoride/methanol mixture (20% BF3), and then the mixture was poured onto ice and neutralized with ammonia. The mixture was extracted with ether, and the ether was distilled off in vacuo. The residue was purified over silica gel [cyclohexane/ethyl acetate (75:25)]. The mixture was extracted with ether the ether was distilled off in vacuo The residue was purified over silica gel [cyclohexane/ethyl acetate (75:25)]

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

Procedure: 3-Trimethylsilyl alanine (J. Organomet. Chem., 628, (2001), 183–194; 19 mg, 0.118 mmol) was mixed with 3 ml BF3-MeOH (14%, 3.7 mmol) in a sealed tube and heated to 70° C. Analysis was performed using TLC (MeOH:DCM 1:9, stained w. ninhydrine in ethanol). The mixture was heated for 3 h and was then cooled to ambient temperature. The mixture was poured into a mixture of 3 ml EtOAc and 2 ml water containing Na2CO3. More Na2CO3 (5%-aq) was added until pH ca 7. The aqueous phase was washed with EtOAc (2×3 ml). The combined organic layers were washed with brine (1 ml), dried with Na2SO4 and evaporated. The product was obtained as a white film. Mass: 19 mg (92% yield). NMR (CDCl3): 0.1 (s, 9H), 1.2–1.4 (m, 2H), 3.8 (s, 3H), 4.2 (brs, 1H). The mixture was heated for 3 h was then cooled to ambient temperature The aqueous phase was washed with EtOAc (2×3 ml) The combined organic layers were washed with brine (1 ml) dried with Na2SO4 evaporated The product was obtained as a white film

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

Procedure: Boron trifluoride methanol (6.3 ml, 7.6 g) was added to a stirred solution of 5-bromofuran-2-carboxylic acid (10 g) in methanol (90 ml) and heated under reflux under nitrogen for 5 hours. More boron trifluoride methanol (5 ml) was added and the mixture heated under reflux for 5 hours, allowed to cool to room temperature and stand for 10 hours before the solvent was removed in vacuo and the residue poured into saturated sodium hydrogen carbonate solution (300 ml) and extracted with ethyl acetate (3×200 ml). The extract was washed with saturated sodium hydrogen carbonate solution (2×100 ml), dried over MgSO4, and the solvent removed in vacuo to give methyl 5-bromofuran-2-carboxylate, m.p. 62° C. heated under reflux under nitrogen for 5 hours the mixture heated under reflux for 5 hours was removed in vacuo the residue poured into saturated sodium hydrogen carbonate solution (300 ml) extracted with ethyl acetate (3×200 ml) The extract was washed with saturated sodium hydrogen carbonate solution (2×100 ml) dried over MgSO4 the solvent removed in vacuo

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

Procedure: Boron trifluoride methanol (6.3 ml, 7.6 g) was added to a stirred solution of 5-bromofuran-2-carboxylic acid (10 g) in methanol (90 ml) and heated under reflux under nitrogen for 5 hours. More boron trifluoride methanol (5 ml) was added and the mixture heated under reflux for 5 hours, allowed to cool to room temperature and stand for 10 hours before the solvent was removed in vacuo and the residue poured into saturated sodium hydrogen carbonate solution (300 ml) and extracted with ethyl acetate (3×200 ml). The extract was washed with saturated sodium hydrogen carbonate solution (2×100 ml), dried over MgSO4, and the solvent removed in vacuo to give methyl 5-bromofuran-2-carboxylate, m.p. 62° C. heated under reflux under nitrogen for 5 hours the mixture heated under reflux for 5 hours was removed in vacuo the residue poured into saturated sodium hydrogen carbonate solution (300 ml) extracted with ethyl acetate (3×200 ml) The extract was washed with saturated sodium hydrogen carbonate solution (2×100 ml) dried over MgSO4 the solvent removed in vacuo

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

Procedure: To a stirred suspension of (1E)-6-methoxy-N-[(methylsulfonyl)oxy]-2,3-dihydro-1H-inden-1-imine (1b, 27 g, 106 mmol), BF3/MeOH (14% in MeOH, 16.8 g, 170 mmol) and TiCl4 (32.3 g, 170 mmol) in dry DCM (200 mL) was added MsCl (20.9 g, 183 mmol) dropwise at 0° C. After the addition, the resulting solution was stirred at room temperature for 14 hours. To the reaction mixture was added DCM (200 mL) and the solution was washed with saturated NaHCO3 to pH ˜7. The organic layer was washed with brine (150 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (DCM/MeOH) to give 7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (1c, 22 g, 100%) as a gray solid. After the addition the solution was washed with saturated NaHCO3 to pH ˜7 The organic layer was washed with brine (150 mL) dried over Na2SO4 concentrated under vacuum The residue was purified by column chromatography (DCM/MeOH)

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

Procedure: To a stirred suspension of (1E)-6-methoxy-N-[(methylsulfonyl)oxy]-2,3-dihydro-1H-inden-1-imine (1b, 27 g, 106 mmol), BF3/MeOH (14% in MeOH, 16.8 g, 170 mmol) and TiCl4 (32.3 g, 170 mmol) in dry DCM (200 mL) was added MsCl (20.9 g, 183 mmol) dropwise at 0° C. After the addition, the resulting solution was stirred at room temperature for 14 hours. To the reaction mixture was added DCM (200 mL) and the solution was washed with saturated NaHCO3 to pH ˜7. The organic layer was washed with brine (150 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (DCM/MeOH) to give 7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (1c, 22 g, 100%) as a gray solid. After the addition the solution was washed with saturated NaHCO3 to pH ˜7 The organic layer was washed with brine (150 mL) dried over Na2SO4 concentrated under vacuum The residue was purified by column chromatography (DCM/MeOH)

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

Procedure: A solution of 25.0 gm. of 2-(3-methoxyphenyl)-5-oxo-1-phenylpyrrolidin-3-carboxylic acid in 200 ml 10-15% boron fluoride-methanol was refluxed for 8 hours and upon following the workup for example 1C the product was obtained as an oil. was obtained as an oil

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

Procedure: A solution of 25.0 gm. of 2-(3-methoxyphenyl)-5-oxo-1-phenylpyrrolidin-3-carboxylic acid in 200 ml 10-15% boron fluoride-methanol was refluxed for 8 hours and upon following the workup for example 1C the product was obtained as an oil. was obtained as an oil

Conditions: temp:83.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: As a comparison when other alkylating catalysts were used, the maximum yield was about 16% at reflux temperature 83° C. At 25° C. GC showed at most only a trace amount of product. Catalysts used included BF3 /CH3OH, BF3 /H2O, BF3 -Et2O, triethyl-aluminum, CF3CO2H, AlCl3, H2SO4 (no solvent) and TiCl4. Only the BF3 and BF3 /CH3OH catalyzed reactions provided any measurable amount of product under the reaction conditions illustrated below. At 25° C

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

Procedure: Into a boron trifluoride methanol complex methanol solution is added ethyl [2-(5-acetylamino-2-chloro-4-fluorophenoxy)phenoxy]acetate, and the mixture is heated while stirring. Thereafter, the reaction solution is concentrated, the residue is dissolved in ethyl acetate, and washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated to obtain ethyl [2-(5-amino-2-chloro-4-fluorophenoxy)phenoxy]acetate [Intermediate compound A3-23]. the mixture is heated Thereafter, the reaction solution is concentrated the residue is dissolved in ethyl acetate washed with saturated aqueous sodium bicarbonate dried over magnesium sulfate concentrated