(5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methanol

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

Procedure: To a solution of (5-fluoro-2,3-dihydrobenzofuran-2-yl)methanol (854) (1.0 g, 6.0 mmol) in dimethylformamide (130.0 mL) was added 60% NaH in mineral oil (0.480 g, 12.0 mmol) and MeI (1.12 mL, 18.0 mmol). The suspension was stirred at room temperature for 24 h and diluted with water (50 mL), and extracted with ethyl acetate (2×25 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (0-10% EtOAc in hexanes) to provide the desired 5-fluoro-2-(methoxymethyl)-2,3-dihydrobenzofuran (855) (0.650 g, 59.5%) as a colorless oil. extracted with ethyl acetate (2×25 mL) dried over sodium sulfate filtered concentrated in vacuo The residue was purified by chromatography (0-10% EtOAc in hexanes)

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

Procedure: To a solution of (5-fluoro-2,3-dihydrobenzofuran-2-yl)methanol (854) (1.0 g, 6.0 mmol) in dimethylformamide (130.0 mL) was added 60% NaH in mineral oil (0.480 g, 12.0 mmol) and MeI (1.12 mL, 18.0 mmol). The suspension was stirred at room temperature for 24 h and diluted with water (50 mL), and extracted with ethyl acetate (2×25 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (0-10% EtOAc in hexanes) to provide the desired 5-fluoro-2-(methoxymethyl)-2,3-dihydrobenzofuran (855) (0.650 g, 59.5%) as a colorless oil. extracted with ethyl acetate (2×25 mL) dried over sodium sulfate filtered concentrated in vacuo The residue was purified by chromatography (0-10% EtOAc in hexanes)

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

Procedure: To an ice cold solution of 2-allyl-4-fluorophenol (853) (6.0 g, 36.2 mmol) in CHCl3 (180.0 mL) was added slowly the suspension of 77% 3-chloroperoxybenzoic acid (8.1 g, 36.2 mmol) in CHCl3 (36.2 mL). The resulting mixture was stirred at 0° C. for 2 hours, then washed with NaHCO3 (100 mL), water (2×100 mL), brine (100 mL) and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (30-40% EtOAc in hexanes) to provide the desired product (5-fluoro-2,3-dihydrobenzofuran-2-yl)methanol (854) (3.8 g, 57.7%) as a yellow oil. washed with NaHCO3 (100 mL), water (2×100 mL), brine (100 mL) dried over sodium sulfate filtered concentrated in vacuo The residue was purified by flash chromatography on silica gel (30-40% EtOAc in hexanes)

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

Procedure: To a solution of (5-fluoro-2,3-dihydrobenzofuran-2-yl)methanol (854) (1.0 g, 6.0 mmol) in dimethylformamide (130.0 mL) was added 60% NaH in mineral oil (0.480 g, 12.0 mmol) and MeI (1.12 mL, 18.0 mmol). The suspension was stirred at room temperature for 24 h and diluted with water (50 mL), and extracted with ethyl acetate (2×25 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (0-10% EtOAc in hexanes) to provide the desired 5-fluoro-2-(methoxymethyl)-2,3-dihydrobenzofuran (855) (0.650 g, 59.5%) as a colorless oil. extracted with ethyl acetate (2×25 mL) dried over sodium sulfate filtered concentrated in vacuo The residue was purified by chromatography (0-10% EtOAc in hexanes)

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

Procedure: To an ice cold solution of 2-allyl-4-fluorophenol (853) (6.0 g, 36.2 mmol) in CHCl3 (180.0 mL) was added slowly the suspension of 77% 3-chloroperoxybenzoic acid (8.1 g, 36.2 mmol) in CHCl3 (36.2 mL). The resulting mixture was stirred at 0° C. for 2 hours, then washed with NaHCO3 (100 mL), water (2×100 mL), brine (100 mL) and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (30-40% EtOAc in hexanes) to provide the desired product (5-fluoro-2,3-dihydrobenzofuran-2-yl)methanol (854) (3.8 g, 57.7%) as a yellow oil. washed with NaHCO3 (100 mL), water (2×100 mL), brine (100 mL) dried over sodium sulfate filtered concentrated in vacuo The residue was purified by flash chromatography on silica gel (30-40% EtOAc in hexanes)

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

Procedure: To a 500 ml round-bottomed flask that contained a solution of (5-fluoro-2,3-dihydro-benzofuran-2-yl)-methanol (3.0 g, 17.8 mmol) in 100 ml of acetonitrile was added a solution of potassium bicarbonate (7.14 g, 71.4 mmol, 4 eq) in 30 ml of water. The mixture was cooled to 0° C. and TEMPO (56 mg, 0.36 mmol, 2 mol %) was added, followed by the dropwise addition of NaOCl(aq) (60 ml, 1.1 eq). The mixture was then stirred for 1.5 hours at room temperature. The pH was then adjusted to 4 using aqueous hydrogen chloride (3N). The mixture was then extracted with 3×80 ml of ethyl acetate. The organic fractions were combined, dried over magnesium sulfate, filtered and then concentrated under vacuum to provide 2.0 grams of the crude product as a yellow solid. To a 500 ml round-bottomed flask that contained The mixture was then extracted with 3×80 ml of ethyl acetate dried over magnesium sulfate filtered concentrated under vacuum

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 500 ml round-bottomed flask that contained a solution of 2-allyl-4-fluoro-phenol (10.0 g, 65.7 mmol) in 300 ml of chloroform was added m-CPBA (11 g, 64 mmol, ˜0.96 eq). The mixture was heated at 60° C. (oil bath) for 6 hours. The contents were cooled to room temperature and the solids were filtered off and washed with 3×20 ml of chloroform The filtrate was washed with saturated aqueous NaHCO3 (2×100 mL) to remove traces of m-CPBA, dried over magnesium sulfate, filtered, and then concentrated under vacuum. The crude residue was then chromatographed on silica gel using petroleum ether/ethyl acetate to elute. The product-containing fractions were combined and concentrated under vacuum to afford 8.5 grams of the alcohol as a yellow oil (77%); 1H NMR (300 MHz, CDCl3): δ 6.91-6.88 (m, 1H), 6.84-6.78 (m, 1H), 6.72-6.68 (m, 1H), 4.99-4.90 (m, 1H), 3.90-3.85 (dd, J=3.3 Hz, 12 Hz, 1H), 3.78-3.70 (dd, J=3.3 Hz, 12 Hz, 1H), 3.29-3.21 (dd, J=9.3 Hz, 15.9 Hz, 1H), 3.01-3.08 (dd, J=7.5 Hz, 15.9 Hz, 1H). Into a 500 ml round-bottomed flask that contained The contents were cooled to room temperature the solids were filtered off washed with 3×20 ml of chloroform The filtrate was washed with saturated aqueous NaHCO3 (2×100 mL) to remove traces of m-CPBA dried over magnesium sulfate filtered concentrated under vacuum The crude residue was then chromatographed on silica gel to elute concentrated under vacuum

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

Procedure: To a solution of (5-fluoro-2,3-dihydrobenzofuran-2-yl)methanol (854) (1.0 g, 6.0 mmol) in dimethylformamide (130.0 mL) was added 60% NaH in mineral oil (0.480 g, 12.0 mmol) and MeI (1.12 mL, 18.0 mmol). The suspension was stirred at room temperature for 24 h and diluted with water (50 mL), and extracted with ethyl acetate (2×25 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (0-10% EtOAc in hexanes) to provide the desired 5-fluoro-2-(methoxymethyl)-2,3-dihydrobenzofuran (855) (0.650 g, 59.5%) as a colorless oil. extracted with ethyl acetate (2×25 mL) dried over sodium sulfate filtered concentrated in vacuo The residue was purified by chromatography (0-10% EtOAc in hexanes)

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

Procedure: To an ice cold solution of 2-allyl-4-fluorophenol (853) (6.0 g, 36.2 mmol) in CHCl3 (180.0 mL) was added slowly the suspension of 77% 3-chloroperoxybenzoic acid (8.1 g, 36.2 mmol) in CHCl3 (36.2 mL). The resulting mixture was stirred at 0° C. for 2 hours, then washed with NaHCO3 (100 mL), water (2×100 mL), brine (100 mL) and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (30-40% EtOAc in hexanes) to provide the desired product (5-fluoro-2,3-dihydrobenzofuran-2-yl)methanol (854) (3.8 g, 57.7%) as a yellow oil. washed with NaHCO3 (100 mL), water (2×100 mL), brine (100 mL) dried over sodium sulfate filtered concentrated in vacuo The residue was purified by flash chromatography on silica gel (30-40% EtOAc in hexanes)