3,4-dihydro-2H-chromen-2-ylmethanol

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

Procedure: 38.16 g (0.2 mol) of p-toluenesulphonyl chloride are added at room temperature while stirring to a solution of 31 g (0.189 mol) of 2-hydroxymethylchroman in 110 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature by means of an ice bath. The reaction mixture is stirred for a further 3 hours at room temperature and then poured onto ice-water. The oil which separates out is removed by decanting the aqueous phase, dissolved in diethyl ether and washed with ice-cold 2N hydrochloric acid and ice-water. The ethereal phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 58.15 g (96.6%) of 2-(p-toluenesulphonyloxymethyl)chroman are obtained in the form of a colourless oil. the slightly exothermic reaction poured onto ice-water The oil which separates out is removed by decanting the aqueous phase dissolved in diethyl ether washed with ice-cold 2N hydrochloric acid and ice-water The ethereal phases are dried over sodium sulphate concentrated by evaporation in vacuo

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

Procedure: At room temperature and while stirring, a solution of 36.4 g (0.19 mol) of 2-methoxycarbonylchroman in 400 ml of absolute tetrahydrofuran is added dropwise within a period of 1 hour to a suspension of 7.2 g (0.19 mol) of lithium aluminum hydride in 400 ml of absolute diethyl ether. After continuing to stir for a further 16 hours at room temperature, the reaction mixture is carefully decomposed with 7.2 ml of water, 7.2 ml of sodium hydroxide solution (15% strength) and 21.6 ml of water. The precipitate formed is filtered off with suction and the filtrate is concentrated by evaporation in vacuo. The oily residue is dissolved in diethyl ether. The ethereal solution is washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. 31 g (99.3%) of 2-hydroxymethylchroman are thus obtained in the form of a colourless oil. to stir for a further 16 hours at room temperature The precipitate formed is filtered off with suction the filtrate is concentrated by evaporation in vacuo The oily residue is dissolved in diethyl ether The ethereal solution is washed with water dried over sodium sulphate concentrated by evaporation in vacuo

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

Procedure: At room temperature and while stirring, a solution of 36.4 g (0.19 mol) of 2-methoxycarbonylchroman in 400 ml of absolute tetrahydrofuran is added dropwise within a period of 1 hour to a suspension of 7.2 g (0.19 mol) of lithium aluminum hydride in 400 ml of absolute diethyl ether. After continuing to stir for a further 16 hours at room temperature, the reaction mixture is carefully decomposed with 7.2 ml of water, 7.2 ml of sodium hydroxide solution (15% strength) and 21.6 ml of water. The precipitate formed is filtered off with suction and the filtrate is concentrated by evaporation in vacuo. The oily residue is dissolved in diethyl ether. The ethereal solution is washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. 31 g (99.3%) of 2-hydroxymethylchroman are thus obtained in the form of a colourless oil. to stir for a further 16 hours at room temperature The precipitate formed is filtered off with suction the filtrate is concentrated by evaporation in vacuo The oily residue is dissolved in diethyl ether The ethereal solution is washed with water dried over sodium sulphate concentrated by evaporation in vacuo

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

Procedure: To a stirred and cooled (0° C.) solution of 32.8 g of 3,4-dihydro-2H1-benzopyran-2-methanol in 71 ml of pyridine and 135 ml of benzene was added dropwise a solution of 41.9 g of 4-methyl-benzenesulfonyl chloride in 72.5 ml of benzene. Upon completion, stirring was continued for 25 hours. The reaction mixture was washed successively with a hydrochloric acid solution (10%), with water and with a sodium carbonate solution (10% ). The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 100%). The eluent of the desired fraction was evaporated, yielding 28.3 g of 3,4-dihydro-2H1-benzopyran-2-methanol 4-methylbenzenesulfonate (ester) as a solid residue, mp. 59.4° C. (interm. 1). Upon completion, stirring The reaction mixture was washed successively with a hydrochloric acid solution (10%), with water and with a sodium carbonate solution (10% ) The organic layer was dried filtered evaporated The residue was purified by column chromatography (silica gel; CHCl3 100%) The eluent of the desired fraction was evaporated

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

Procedure: To a stirred and cooled (0° C.) solution of 32.8 g of 3,4-dihydro-2H1-benzopyran-2-methanol in 71 ml of pyridine and 135 ml of benzene was added dropwise a solution of 41.9 g of 4-methyl-benzenesulfonyl chloride in 72.5 ml of benzene. Upon completion, stirring was continued for 25 hours. The reaction mixture was washed successively with a hydrochloric acid solution (10%), with water and with a sodium carbonate solution (10% ). The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 100%). The eluent of the desired fraction was evaporated, yielding 28.3 g of 3,4-dihydro-2H1-benzopyran-2-methanol 4-methylbenzenesulfonate (ester) as a solid residue, mp. 59.4° C. (interm. 1). Upon completion, stirring The reaction mixture was washed successively with a hydrochloric acid solution (10%), with water and with a sodium carbonate solution (10% ) The organic layer was dried filtered evaporated The residue was purified by column chromatography (silica gel; CHCl3 100%) The eluent of the desired fraction was evaporated

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

Procedure: Chroman-2-carboxylic acid (4.3 g, 24 mmol) in THF (70 mL) was combined with 1M LAH in THF (30 mL, 30 mmol) and stirred at room temperature for 2 h. The reaction mixture was quenched with water and then stirred for 2 hours. The THF solution was decanted from the solid, which was washed with fresh THF. The combined THF solution was dried (Na2SO4) and evaporated in vacuo to yield chroman-2-yl-methanol as an oil. The reaction mixture was quenched with water stirred for 2 hours The THF solution was decanted from the solid, which was washed with fresh THF The combined THF solution was dried (Na2SO4) evaporated in vacuo

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

Procedure: Chroman-2-carboxylic acid (4.3 g, 24 mmol) in THF (70 mL) was combined with 1M LAH in THF (30 mL, 30 mmol) and stirred at room temperature for 2 h. The reaction mixture was quenched with water and then stirred for 2 hours. The THF solution was decanted from the solid, which was washed with fresh THF. The combined THF solution was dried (Na2SO4) and evaporated in vacuo to yield chroman-2-yl-methanol as an oil. The reaction mixture was quenched with water stirred for 2 hours The THF solution was decanted from the solid, which was washed with fresh THF The combined THF solution was dried (Na2SO4) evaporated in vacuo

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Trifluoromethanesulfonic anhydride (19.6 g, 69.5 mmol) in DCM (15 mL) was added to a solution of the title compound from Step 1 (9.50 g, 57.9 mmol) in DCM (100 mL) and pyridine (11.0 g, 139 mmol) cooled to −5° C. The reaction was then stirred at 0° C. for 1 h. Water (150 mL) was added and the reaction was extracted with DCM (150 mL). The organic layer was washed with 1 M HCl (180 mL), water (100 mL), and NaHCO3 aqueous solution (100 mL). The organic phase was dried over Na2SO4, filtered and concentrated to give the title compound (13.5 g, 79%) as a pale-brown oil. 1H NMR (400 MHz, CDCl3): δ 7.12-7.04 (m, 2H), 6.90-6.83 (m, 2H), 4.66-4.61 (m, 2H), 4.36-4.31 (m, 1H), 2.96-2.79 (m, 2H), 2.09-2.03 (m, 1H), 1.95-1.84 (m, 1H). LCMS: 314 (M+NH4)+ the reaction was extracted with DCM (150 mL) The organic layer was washed with 1 M HCl (180 mL), water (100 mL), and NaHCO3 aqueous solution (100 mL) The organic phase was dried over Na2SO4 filtered concentrated

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

Procedure: A mixture of 4-oxochromene-2-carboxylic acid (20.0 g, 105 mmol) and Pd/C (3.0 g, w/w=10%) in AcOH (200 mL) was placed in Parr hydrogenation apparatus under H2 (50 psi) and stirred for 25 h at rt. It was then filtered and concentrated. The residue was suspended in water (300 mL), stirred for 10 min, filtered and dried to give 3,4-dihydro-2H-chromene-2-carboxylic acid (13.5 g, 72%) as a white solid. BH3 (57 mL, 114 mmol, 2.0 M in THF) was added slowly to a solution of this carboxylic acid in THF (120 mL) at 0° C. The reaction mixture was then warmed to rt and stirred for 5 h at this temperature. THF/H2O (30 mL, 1:1) was added drop wise while keeping the temperature between 0-5° C. and stirred for 20 min. K2CO3 (26.0 g, 189 mmol) was added and the reaction was vigorously stirred for 30 min. The THF layer was separated and concentrated to give the title compound (11.0 g, 89%) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 7.10-7.03 (m, 2H), 6.86-6.81 (m, 2H), 4.14-4.08 (m, 1H), 3.85-3.68 (m, 2H), 2.92-2.84 (m, 1H), 2.80-2.73 (m, 1H), 1.98-1.92 (m, 1H), 1.90-1.79 (m, 1H). LCMS: 165 (M+1)+ between 0-5° C. stirred for 20 min the reaction was vigorously stirred for 30 min The THF layer was separated concentrated

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Trifluoromethanesulfonic anhydride (19.6 g, 69.5 mmol) in DCM (15 mL) was added to a solution of the title compound from Step 1 (9.50 g, 57.9 mmol) in DCM (100 mL) and pyridine (11.0 g, 139 mmol) cooled to −5° C. The reaction was then stirred at 0° C. for 1 h. Water (150 mL) was added and the reaction was extracted with DCM (150 mL). The organic layer was washed with 1 M HCl (180 mL), water (100 mL), and NaHCO3 aqueous solution (100 mL). The organic phase was dried over Na2SO4, filtered and concentrated to give the title compound (13.5 g, 79%) as a pale-brown oil. 1H NMR (400 MHz, CDCl3): δ 7.12-7.04 (m, 2H), 6.90-6.83 (m, 2H), 4.66-4.61 (m, 2H), 4.36-4.31 (m, 1H), 2.96-2.79 (m, 2H), 2.09-2.03 (m, 1H), 1.95-1.84 (m, 1H). LCMS: 314 (M+NH4)+ the reaction was extracted with DCM (150 mL) The organic layer was washed with 1 M HCl (180 mL), water (100 mL), and NaHCO3 aqueous solution (100 mL) The organic phase was dried over Na2SO4 filtered concentrated

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Trifluoromethanesulfonic anhydride (19.6 g, 69.5 mmol) in DCM (15 mL) was added to a solution of the title compound from Step 1 (9.50 g, 57.9 mmol) in DCM (100 mL) and pyridine (11.0 g, 139 mmol) cooled to −5° C. The reaction was then stirred at 0° C. for 1 h. Water (150 mL) was added and the reaction was extracted with DCM (150 mL). The organic layer was washed with 1 M HCl (180 mL), water (100 mL), and NaHCO3 aqueous solution (100 mL). The organic phase was dried over Na2SO4, filtered and concentrated to give the title compound (13.5 g, 79%) as a pale-brown oil. 1H NMR (400 MHz, CDCl3): δ 7.12-7.04 (m, 2H), 6.90-6.83 (m, 2H), 4.66-4.61 (m, 2H), 4.36-4.31 (m, 1H), 2.96-2.79 (m, 2H), 2.09-2.03 (m, 1H), 1.95-1.84 (m, 1H). LCMS: 314 (M+NH4)+ the reaction was extracted with DCM (150 mL) The organic layer was washed with 1 M HCl (180 mL), water (100 mL), and NaHCO3 aqueous solution (100 mL) The organic phase was dried over Na2SO4 filtered concentrated

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Trifluoromethanesulfonic anhydride (19.6 g, 69.5 mmol) in DCM (15 mL) was added to a solution of the title compound from Step 1 (9.50 g, 57.9 mmol) in DCM (100 mL) and pyridine (11.0 g, 139 mmol) cooled to −5° C. The reaction was then stirred at 0° C. for 1 h. Water (150 mL) was added and the reaction was extracted with DCM (150 mL). The organic layer was washed with 1 M HCl (180 mL), water (100 mL), and NaHCO3 aqueous solution (100 mL). The organic phase was dried over Na2SO4, filtered and concentrated to give the title compound (13.5 g, 79%) as a pale-brown oil. 1H NMR (400 MHz, CDCl3): δ 7.12-7.04 (m, 2H), 6.90-6.83 (m, 2H), 4.66-4.61 (m, 2H), 4.36-4.31 (m, 1H), 2.96-2.79 (m, 2H), 2.09-2.03 (m, 1H), 1.95-1.84 (m, 1H). LCMS: 314 (M+NH4)+ the reaction was extracted with DCM (150 mL) The organic layer was washed with 1 M HCl (180 mL), water (100 mL), and NaHCO3 aqueous solution (100 mL) The organic phase was dried over Na2SO4 filtered concentrated