3,4-dihydro-1H-isochromen-1-ol

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

Procedure: To a solution of methyl-3-(2'-formyl-3'-6'-dimethoxy)phenyl-2-methoxyisopropyloxy-propionate (4.2 g, 12.4 mmol) in THF (75 ml) containing water (4 ml) was added pyridinium p-toluenesulfonate (230 mg). After stirring at room temperature for 1.75 hours, triethylamine (3 ml) and saturated NH4Cl solution (60 ml) were added. THF was removed at 25° C. and the mixture was extracted with ether (3×150 ml). Ether extract was washed with brine, dried and evaporated yielding 3.9 g of 1-hydroxyisochroman (95%) (quite pure from NMR spectrum). (MP. 127°-129° C.) THF was removed at 25° C. the mixture was extracted with ether (3×150 ml) Ether extract was washed with brine dried evaporated

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

Procedure: To a stirred solution of crude product from step 5 (1.89 g; 5.49 mmol) in a mixture of acetone (80 ml) and water (25 ml) was added p-toluene sulfonic acid monohydrate (70 mg; 0.37 mmol). After stirring at room temperature for 3 hours, triethylamine (2 ml; 1.43 mmol) was added and stirred for 5 minutes. The mixture was evaporated until volume went down to 10 ml. A mixture of acetone (80 ml) and water (15 ml) was added followed by addition of p-toluene sulfonic acid monohydrate (70 mg; 0.37 mmol). After 3.5 hours, triethylamine (3 ml; 2.15 mmol) was added, evaporated to a small volume, extracted with ether (3×100 ml). The extract was washed with brine (50 ml), dried over MgSO4 and evaporated yielding quite pure 1-hydroxyisochroman (1.3 g; 94%), (MP. 136°-138° C.). NMR (CDCl3 ; 300 MHz) δ:2.32 (3H, s, CH3O), 2.51 (1H, dd, J=12.4, 17.5 Hz, H-4), 2.97 (1H, d, J=3.5 Hz; --OH), 3.06 (1H, dd, J=4.1, 17.5 Hz, H-4), 3.77, 3.82 (3H, s each, ArOCH3), 4.70 (1H, dd, J=4.1, 12.4 Hz, H-3), 6.22 (1H, d, J=3.4 Hz, 1H), 6.71, 6.76, (1H, d each, J=9.0 Hz, ArH). stirred for 5 minutes The mixture was evaporated until volume A mixture of acetone (80 ml) and water (15 ml) was added After 3.5 hours evaporated to a small volume extracted with ether (3×100 ml) The extract was washed with brine (50 ml) dried over MgSO4 evaporated

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

Procedure: 2-(2-Fluoro-phenyl)-ethylamine (0.34 mL) was added to a solution of iso-chroman-1-ol (0.26 g) and acetic acid (0.1 mL) in methanol (5 mL). After stirring for 1 hour, sodium cyanoborohydride (0.17 g) was added and stirred for 18 hours. A few drops of 0.880 ammonia solution was added and the resulting mixture concentrated. The residue was dissolved in methanol (5 mL) and loaded onto a conditioned SCX cartridge (10 g Varian). The cartridge was washed with methanol (3×20 mL), then eluted with a methanolic ammonia solution (2×15 mL) and the combined elution fractions evaporated. The residue was dissolved in dimethylformamide (5 mL) and triethylamine (0.37 mL) added, followed by di-tert-butyl dicarbonate (0.57 g) and the resulting mixture was stirred for 72 hours. The reaction was concentrated, partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organic phase was separated and the aqueous phase extracted with ethyl acetate (2×50 mL). The combined organics were washed sequentially with water (50 mL), brine (50 mL), dried (magnesium sulfate) and concentrated. Purification on silica, eluting with a gradient of iso-hexane:ethyl acetate [1:0 to 4:1], afforded the subtitle compound as a yellow oil (250 mg). stirred for 18 hours the resulting mixture concentrated The residue was dissolved in methanol (5 mL) The cartridge was washed with methanol (3×20 mL) eluted with a methanolic ammonia solution (2×15 mL) the combined elution fractions evaporated The residue was dissolved in dimethylformamide (5 mL) triethylamine (0.37 mL) added the resulting mixture was stirred for 72 hours The reaction was concentrated partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL) The organic phase was separated the aqueous phase extracted with ethyl acetate (2×50 mL) The combined organics were washed sequentially with water (50 mL), brine (50 mL) dried (magnesium sulfate) concentrated Purification on silica eluting with a gradient of iso-hexane

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

Procedure: 2-(2-Fluoro-phenyl)-ethylamine (0.34 mL) was added to a solution of iso-chroman-1-ol (0.26 g) and acetic acid (0.1 mL) in methanol (5 mL). After stirring for 1 hour, sodium cyanoborohydride (0.17 g) was added and stirred for 18 hours. A few drops of 0.880 ammonia solution was added and the resulting mixture concentrated. The residue was dissolved in methanol (5 mL) and loaded onto a conditioned SCX cartridge (10 g Varian). The cartridge was washed with methanol (3×20 mL), then eluted with a methanolic ammonia solution (2×15 mL) and the combined elution fractions evaporated. The residue was dissolved in dimethylformamide (5 mL) and triethylamine (0.37 mL) added, followed by di-tert-butyl dicarbonate (0.57 g) and the resulting mixture was stirred for 72 hours. The reaction was concentrated, partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organic phase was separated and the aqueous phase extracted with ethyl acetate (2×50 mL). The combined organics were washed sequentially with water (50 mL), brine (50 mL), dried (magnesium sulfate) and concentrated. Purification on silica, eluting with a gradient of iso-hexane:ethyl acetate [1:0 to 4:1], afforded the subtitle compound as a yellow oil (250 mg). stirred for 18 hours the resulting mixture concentrated The residue was dissolved in methanol (5 mL) The cartridge was washed with methanol (3×20 mL) eluted with a methanolic ammonia solution (2×15 mL) the combined elution fractions evaporated The residue was dissolved in dimethylformamide (5 mL) triethylamine (0.37 mL) added the resulting mixture was stirred for 72 hours The reaction was concentrated partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL) The organic phase was separated the aqueous phase extracted with ethyl acetate (2×50 mL) The combined organics were washed sequentially with water (50 mL), brine (50 mL) dried (magnesium sulfate) concentrated Purification on silica eluting with a gradient of iso-hexane

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

Procedure: Manganese(IV) oxide (1.43 g) was added to a solution of 2-(2-hydroxymethyl-phenyl)-ethanol (0.5 g) in dichloromethane (25 mL) and stirred for 18 hours under nitrogen. The reaction was filtered through celite, the filter pad washed with dichloromethane (2×20 mL), and the combined filtrates evaporated. Purification on silica, eluting with a gradient of iso-hexane:ethyl acetate [1:0 to 4:1], afforded the subtitle compound as a yellow oil (263 mg). The reaction was filtered through celite the filter pad washed with dichloromethane (2×20 mL) the combined filtrates evaporated Purification on silica eluting with a gradient of iso-hexane

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

Procedure: To a solution of methyl-3-(2'-formyl-3'-6'-dimethoxy)phenyl-2-methoxyisopropyloxy-propionate (4.2 g, 12.4 mmol) in THF (75 ml) containing water (4 ml) was added pyridinium p-toluenesulfonate (230 mg). After stirring at room temperature for 1.75 hours, triethylamine (3 ml) and saturated NH4Cl solution (60 ml) were added. THF was removed at 25° C. and the mixture was extracted with ether (3×150 ml). Ether extract was washed with brine, dried and evaporated yielding 3.9 g of 1-hydroxyisochroman (95%) (quite pure from NMR spectrum). (MP. 127°-129° C.) THF was removed at 25° C. the mixture was extracted with ether (3×150 ml) Ether extract was washed with brine dried evaporated

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

Procedure: To a stirred solution of crude product from step 5 (1.89 g; 5.49 mmol) in a mixture of acetone (80 ml) and water (25 ml) was added p-toluene sulfonic acid monohydrate (70 mg; 0.37 mmol). After stirring at room temperature for 3 hours, triethylamine (2 ml; 1.43 mmol) was added and stirred for 5 minutes. The mixture was evaporated until volume went down to 10 ml. A mixture of acetone (80 ml) and water (15 ml) was added followed by addition of p-toluene sulfonic acid monohydrate (70 mg; 0.37 mmol). After 3.5 hours, triethylamine (3 ml; 2.15 mmol) was added, evaporated to a small volume, extracted with ether (3×100 ml). The extract was washed with brine (50 ml), dried over MgSO4 and evaporated yielding quite pure 1-hydroxyisochroman (1.3 g; 94%), (MP. 136°-138° C.). NMR (CDCl3 ; 300 MHz) δ:2.32 (3H, s, CH3O), 2.51 (1H, dd, J=12.4, 17.5 Hz, H-4), 2.97 (1H, d, J=3.5 Hz; --OH), 3.06 (1H, dd, J=4.1, 17.5 Hz, H-4), 3.77, 3.82 (3H, s each, ArOCH3), 4.70 (1H, dd, J=4.1, 12.4 Hz, H-3), 6.22 (1H, d, J=3.4 Hz, 1H), 6.71, 6.76, (1H, d each, J=9.0 Hz, ArH). stirred for 5 minutes The mixture was evaporated until volume A mixture of acetone (80 ml) and water (15 ml) was added After 3.5 hours evaporated to a small volume extracted with ether (3×100 ml) The extract was washed with brine (50 ml) dried over MgSO4 evaporated

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

Procedure: 2-(2-Fluoro-phenyl)-ethylamine (0.34 mL) was added to a solution of iso-chroman-1-ol (0.26 g) and acetic acid (0.1 mL) in methanol (5 mL). After stirring for 1 hour, sodium cyanoborohydride (0.17 g) was added and stirred for 18 hours. A few drops of 0.880 ammonia solution was added and the resulting mixture concentrated. The residue was dissolved in methanol (5 mL) and loaded onto a conditioned SCX cartridge (10 g Varian). The cartridge was washed with methanol (3×20 mL), then eluted with a methanolic ammonia solution (2×15 mL) and the combined elution fractions evaporated. The residue was dissolved in dimethylformamide (5 mL) and triethylamine (0.37 mL) added, followed by di-tert-butyl dicarbonate (0.57 g) and the resulting mixture was stirred for 72 hours. The reaction was concentrated, partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organic phase was separated and the aqueous phase extracted with ethyl acetate (2×50 mL). The combined organics were washed sequentially with water (50 mL), brine (50 mL), dried (magnesium sulfate) and concentrated. Purification on silica, eluting with a gradient of iso-hexane:ethyl acetate [1:0 to 4:1], afforded the subtitle compound as a yellow oil (250 mg). stirred for 18 hours the resulting mixture concentrated The residue was dissolved in methanol (5 mL) The cartridge was washed with methanol (3×20 mL) eluted with a methanolic ammonia solution (2×15 mL) the combined elution fractions evaporated The residue was dissolved in dimethylformamide (5 mL) triethylamine (0.37 mL) added the resulting mixture was stirred for 72 hours The reaction was concentrated partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL) The organic phase was separated the aqueous phase extracted with ethyl acetate (2×50 mL) The combined organics were washed sequentially with water (50 mL), brine (50 mL) dried (magnesium sulfate) concentrated Purification on silica eluting with a gradient of iso-hexane

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

Procedure: Manganese(IV) oxide (1.43 g) was added to a solution of 2-(2-hydroxymethyl-phenyl)-ethanol (0.5 g) in dichloromethane (25 mL) and stirred for 18 hours under nitrogen. The reaction was filtered through celite, the filter pad washed with dichloromethane (2×20 mL), and the combined filtrates evaporated. Purification on silica, eluting with a gradient of iso-hexane:ethyl acetate [1:0 to 4:1], afforded the subtitle compound as a yellow oil (263 mg). The reaction was filtered through celite the filter pad washed with dichloromethane (2×20 mL) the combined filtrates evaporated Purification on silica eluting with a gradient of iso-hexane

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

Procedure: To a solution of methyl-3-(2'-formyl-3'-6'-dimethoxy)phenyl-2-methoxyisopropyloxy-propionate (4.2 g, 12.4 mmol) in THF (75 ml) containing water (4 ml) was added pyridinium p-toluenesulfonate (230 mg). After stirring at room temperature for 1.75 hours, triethylamine (3 ml) and saturated NH4Cl solution (60 ml) were added. THF was removed at 25° C. and the mixture was extracted with ether (3×150 ml). Ether extract was washed with brine, dried and evaporated yielding 3.9 g of 1-hydroxyisochroman (95%) (quite pure from NMR spectrum). (MP. 127°-129° C.) THF was removed at 25° C. the mixture was extracted with ether (3×150 ml) Ether extract was washed with brine dried evaporated

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

Procedure: To a stirred solution of crude product from step 5 (1.89 g; 5.49 mmol) in a mixture of acetone (80 ml) and water (25 ml) was added p-toluene sulfonic acid monohydrate (70 mg; 0.37 mmol). After stirring at room temperature for 3 hours, triethylamine (2 ml; 1.43 mmol) was added and stirred for 5 minutes. The mixture was evaporated until volume went down to 10 ml. A mixture of acetone (80 ml) and water (15 ml) was added followed by addition of p-toluene sulfonic acid monohydrate (70 mg; 0.37 mmol). After 3.5 hours, triethylamine (3 ml; 2.15 mmol) was added, evaporated to a small volume, extracted with ether (3×100 ml). The extract was washed with brine (50 ml), dried over MgSO4 and evaporated yielding quite pure 1-hydroxyisochroman (1.3 g; 94%), (MP. 136°-138° C.). NMR (CDCl3 ; 300 MHz) δ:2.32 (3H, s, CH3O), 2.51 (1H, dd, J=12.4, 17.5 Hz, H-4), 2.97 (1H, d, J=3.5 Hz; --OH), 3.06 (1H, dd, J=4.1, 17.5 Hz, H-4), 3.77, 3.82 (3H, s each, ArOCH3), 4.70 (1H, dd, J=4.1, 12.4 Hz, H-3), 6.22 (1H, d, J=3.4 Hz, 1H), 6.71, 6.76, (1H, d each, J=9.0 Hz, ArH). stirred for 5 minutes The mixture was evaporated until volume A mixture of acetone (80 ml) and water (15 ml) was added After 3.5 hours evaporated to a small volume extracted with ether (3×100 ml) The extract was washed with brine (50 ml) dried over MgSO4 evaporated