4-bromo-6-fluoro-2-methyl-2,3-dihydroinden-1-one

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of 48.4 g (199 mmol) of 4-bromo-6-fluoro-2-methylindan-1-one in 270 ml of a mixture of THF-methanol (2:1, vol.), 11.3 g (299 mmol) of NaBH4 was added in small portions, while vigorously stirring, over 2 h at 0° C. This mixture was stirred for 12 h at room temperature and then added to 500 ml of cold water. The organic layer was separated, the aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The residue was dissolved in 500 ml of toluene, and 2.0 g of p-TosOH was added. The resulting solution was refluxed for 4 h using a Dean-Stark trap to remove the water formed, and then it was passed through a short Silica Gel 60 column (40-63 um, d 100 mm, l 80 mm, eluent: hexanes). This column was additionally washed with 250 ml of toluene. The combined organic extract was evaporated to dryness. The residue was dried in vacuum to give the title compound. Yield 38.0 g (84%). This mixture was stirred for 12 h at room temperature The organic layer was separated the aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether The combined organic fractions were dried over K2CO3 evaporated to dryness The residue was dissolved in 500 ml of toluene 2.0 g of p-TosOH was added The resulting solution was refluxed for 4 h to remove the water formed This column was additionally washed with 250 ml of toluene The combined organic extract was evaporated to dryness The residue was dried in vacuum

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

Procedure: To a solution of 48.4 g (199 mmol) of 4-bromo-6-fluoro-2-methylindan-1-one in 270 ml of a mixture of THF-methanol (2:1, vol.), 11.3 g (299 mmol) of NaBH4 was added in small portions, while vigorously stirring, over 2 h at 0° C. This mixture was stirred for 12 h at room temperature and then added to 500 ml of cold water. The organic layer was separated, the aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The residue was dissolved in 500 ml of toluene, and 2.0 g of p-TosOH was added. The resulting solution was refluxed for 4 h using a Dean-Stark trap to remove the water formed, and then it was passed through a short Silica Gel 60 column (40-63 um, d 100 mm, l 80 mm, eluent: hexanes). This column was additionally washed with 250 ml of toluene. The combined organic extract was evaporated to dryness. The residue was dried in vacuum to give the title compound. Yield 38.0 g (84%). This mixture was stirred for 12 h at room temperature The organic layer was separated the aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether The combined organic fractions were dried over K2CO3 evaporated to dryness The residue was dissolved in 500 ml of toluene 2.0 g of p-TosOH was added The resulting solution was refluxed for 4 h to remove the water formed This column was additionally washed with 250 ml of toluene The combined organic extract was evaporated to dryness The residue was dried in vacuum

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

Procedure: To a solution of sodium ethoxide in ethanol obtained from 5.95 g (0.26 mmol) of sodium and 200 ml of anhydrous ethanol, a solution of 45.1 g (0.26 mmol) of diethyl methylmalonate in 200 ml of ethanol was added dropwise, while vigorously stirring, over 15 min. Then, 64.3 g (0.24 mmol) of 2-bromo-1-(bromomethyl)-4-fluorobenzene in 50 ml of ethanol was added dropwise with such a rate, so the reaction mixture would be slowly refluxing. The resulting mixture was additionally refluxed for 4 h, then cooled to room temperature, and a solution of 51.8 g of potassium hydroxide in 150 ml of water was added. This mixture was refluxed for 3 h, and then ethanol was distilled off at atmospheric pressure. The solution obtained was cooled to ambient temperature and acidified by saturated hydrochloric acid to pH 1. The precipitate formed was filtered off, washed with 2×150 ml of cold water, and dried in air. The dibacic acid obtained was then dehcarboxylated by heating it at 160° C. for 2 h. To the viscous oil obtained, 60 ml of SOCl2 was added, and the resulting mixture was stirred for 24 h at room temperature. The excess of SOCl2 was distilled off, and the residue was dissolved in 200 ml of anhydrous dichloromethane. The solution obtained was added dropwise to a suspension of 37.7 g (0.28 mmol) of AlCl3 in 800 ml of dichloromethane for 1 h at 0° C. The reaction mixture was refluxed for 3 h, then cooled to room temperature, poured on 300 cm3 of ice, and finally acidified by saturated HCl to pH 3. The organic layer was separated, and the aqueous layer was washed with 3×200 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The title product was isolated using flash chromatography (d 50 mm, l 800 mm, eluent: hexanes-CH2Cl2, 2:1, vol.). Yield 47.3 g (81%). so the reaction mixture would be slowly refluxing The resulting mixture was additionally refluxed for 4 h This mixture was refluxed for 3 h ethanol was distilled off at atmospheric pressure The solution obtained was cooled to ambient temperature The precipitate formed was filtered off washed with 2×150 ml of cold water dried in air The dibacic acid obtained by heating it at 160° C. for 2 h To the viscous oil obtained the resulting mixture was stirred for 24 h at room temperature The excess of SOCl2 was distilled off the residue was dissolved in 200 ml of anhydrous dichloromethane The solution obtained The reaction mixture was refluxed for 3 h cooled to room temperature The organic layer was separated the aqueous layer was washed with 3×200 ml of methyl-tert-butyl ether The combined organic fractions were dried over K2CO3 evaporated to dryness

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

Procedure: To a solution of sodium ethoxide in ethanol obtained from 5.95 g (0.26 mmol) of sodium and 200 ml of anhydrous ethanol, a solution of 45.1 g (0.26 mmol) of diethyl methylmalonate in 200 ml of ethanol was added dropwise, while vigorously stirring, over 15 min. Then, 64.3 g (0.24 mmol) of 2-bromo-1-(bromomethyl)-4-fluorobenzene in 50 ml of ethanol was added dropwise with such a rate, so the reaction mixture would be slowly refluxing. The resulting mixture was additionally refluxed for 4 h, then cooled to room temperature, and a solution of 51.8 g of potassium hydroxide in 150 ml of water was added. This mixture was refluxed for 3 h, and then ethanol was distilled off at atmospheric pressure. The solution obtained was cooled to ambient temperature and acidified by saturated hydrochloric acid to pH 1. The precipitate formed was filtered off, washed with 2×150 ml of cold water, and dried in air. The dibacic acid obtained was then dehcarboxylated by heating it at 160° C. for 2 h. To the viscous oil obtained, 60 ml of SOCl2 was added, and the resulting mixture was stirred for 24 h at room temperature. The excess of SOCl2 was distilled off, and the residue was dissolved in 200 ml of anhydrous dichloromethane. The solution obtained was added dropwise to a suspension of 37.7 g (0.28 mmol) of AlCl3 in 800 ml of dichloromethane for 1 h at 0° C. The reaction mixture was refluxed for 3 h, then cooled to room temperature, poured on 300 cm3 of ice, and finally acidified by saturated HCl to pH 3. The organic layer was separated, and the aqueous layer was washed with 3×200 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The title product was isolated using flash chromatography (d 50 mm, l 800 mm, eluent: hexanes-CH2Cl2, 2:1, vol.). Yield 47.3 g (81%). so the reaction mixture would be slowly refluxing The resulting mixture was additionally refluxed for 4 h This mixture was refluxed for 3 h ethanol was distilled off at atmospheric pressure The solution obtained was cooled to ambient temperature The precipitate formed was filtered off washed with 2×150 ml of cold water dried in air The dibacic acid obtained by heating it at 160° C. for 2 h To the viscous oil obtained the resulting mixture was stirred for 24 h at room temperature The excess of SOCl2 was distilled off the residue was dissolved in 200 ml of anhydrous dichloromethane The solution obtained The reaction mixture was refluxed for 3 h cooled to room temperature The organic layer was separated the aqueous layer was washed with 3×200 ml of methyl-tert-butyl ether The combined organic fractions were dried over K2CO3 evaporated to dryness

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

Procedure: To a solution of 48.4 g (199 mmol) of 4-bromo-6-fluoro-2-methylindan-1-one in 270 ml of a mixture of THF-methanol (2:1, vol.), 11.3 g (299 mmol) of NaBH4 was added in small portions, while vigorously stirring, over 2 h at 0° C. This mixture was stirred for 12 h at room temperature and then added to 500 ml of cold water. The organic layer was separated, the aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The residue was dissolved in 500 ml of toluene, and 2.0 g of p-TosOH was added. The resulting solution was refluxed for 4 h using a Dean-Stark trap to remove the water formed, and then it was passed through a short Silica Gel 60 column (40-63 um, d 100 mm, l 80 mm, eluent: hexanes). This column was additionally washed with 250 ml of toluene. The combined organic extract was evaporated to dryness. The residue was dried in vacuum to give the title compound. Yield 38.0 g (84%). This mixture was stirred for 12 h at room temperature The organic layer was separated the aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether The combined organic fractions were dried over K2CO3 evaporated to dryness The residue was dissolved in 500 ml of toluene 2.0 g of p-TosOH was added The resulting solution was refluxed for 4 h to remove the water formed This column was additionally washed with 250 ml of toluene The combined organic extract was evaporated to dryness The residue was dried in vacuum

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

Procedure: To a solution of sodium ethoxide in ethanol obtained from 5.95 g (0.26 mmol) of sodium and 200 ml of anhydrous ethanol, a solution of 45.1 g (0.26 mmol) of diethyl methylmalonate in 200 ml of ethanol was added dropwise, while vigorously stirring, over 15 min. Then, 64.3 g (0.24 mmol) of 2-bromo-1-(bromomethyl)-4-fluorobenzene in 50 ml of ethanol was added dropwise with such a rate, so the reaction mixture would be slowly refluxing. The resulting mixture was additionally refluxed for 4 h, then cooled to room temperature, and a solution of 51.8 g of potassium hydroxide in 150 ml of water was added. This mixture was refluxed for 3 h, and then ethanol was distilled off at atmospheric pressure. The solution obtained was cooled to ambient temperature and acidified by saturated hydrochloric acid to pH 1. The precipitate formed was filtered off, washed with 2×150 ml of cold water, and dried in air. The dibacic acid obtained was then dehcarboxylated by heating it at 160° C. for 2 h. To the viscous oil obtained, 60 ml of SOCl2 was added, and the resulting mixture was stirred for 24 h at room temperature. The excess of SOCl2 was distilled off, and the residue was dissolved in 200 ml of anhydrous dichloromethane. The solution obtained was added dropwise to a suspension of 37.7 g (0.28 mmol) of AlCl3 in 800 ml of dichloromethane for 1 h at 0° C. The reaction mixture was refluxed for 3 h, then cooled to room temperature, poured on 300 cm3 of ice, and finally acidified by saturated HCl to pH 3. The organic layer was separated, and the aqueous layer was washed with 3×200 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The title product was isolated using flash chromatography (d 50 mm, l 800 mm, eluent: hexanes-CH2Cl2, 2:1, vol.). Yield 47.3 g (81%). so the reaction mixture would be slowly refluxing The resulting mixture was additionally refluxed for 4 h This mixture was refluxed for 3 h ethanol was distilled off at atmospheric pressure The solution obtained was cooled to ambient temperature The precipitate formed was filtered off washed with 2×150 ml of cold water dried in air The dibacic acid obtained by heating it at 160° C. for 2 h To the viscous oil obtained the resulting mixture was stirred for 24 h at room temperature The excess of SOCl2 was distilled off the residue was dissolved in 200 ml of anhydrous dichloromethane The solution obtained The reaction mixture was refluxed for 3 h cooled to room temperature The organic layer was separated the aqueous layer was washed with 3×200 ml of methyl-tert-butyl ether The combined organic fractions were dried over K2CO3 evaporated to dryness

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of 48.4 g (199 mmol) of 4-bromo-6-fluoro-2-methylindan-1-one in 270 ml of a mixture of THF-methanol (2:1, vol.), 11.3 g (299 mmol) of NaBH4 was added in small portions, while vigorously stirring, over 2 h at 0° C. This mixture was stirred for 12 h at room temperature and then added to 500 ml of cold water. The organic layer was separated, the aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The residue was dissolved in 500 ml of toluene, and 2.0 g of p-TosOH was added. The resulting solution was refluxed for 4 h using a Dean-Stark trap to remove the water formed, and then it was passed through a short Silica Gel 60 column (40-63 um, d 100 mm, l 80 mm, eluent: hexanes). This column was additionally washed with 250 ml of toluene. The combined organic extract was evaporated to dryness. The residue was dried in vacuum to give the title compound. Yield 38.0 g (84%). This mixture was stirred for 12 h at room temperature The organic layer was separated the aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether The combined organic fractions were dried over K2CO3 evaporated to dryness The residue was dissolved in 500 ml of toluene 2.0 g of p-TosOH was added The resulting solution was refluxed for 4 h to remove the water formed This column was additionally washed with 250 ml of toluene The combined organic extract was evaporated to dryness The residue was dried in vacuum

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

Procedure: To a solution of 48.4 g (199 mmol) of 4-bromo-6-fluoro-2-methylindan-1-one in 270 ml of a mixture of THF-methanol (2:1, vol.), 11.3 g (299 mmol) of NaBH4 was added in small portions, while vigorously stirring, over 2 h at 0° C. This mixture was stirred for 12 h at room temperature and then added to 500 ml of cold water. The organic layer was separated, the aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The residue was dissolved in 500 ml of toluene, and 2.0 g of p-TosOH was added. The resulting solution was refluxed for 4 h using a Dean-Stark trap to remove the water formed, and then it was passed through a short Silica Gel 60 column (40-63 um, d 100 mm, l 80 mm, eluent: hexanes). This column was additionally washed with 250 ml of toluene. The combined organic extract was evaporated to dryness. The residue was dried in vacuum to give the title compound. Yield 38.0 g (84%). This mixture was stirred for 12 h at room temperature The organic layer was separated the aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether The combined organic fractions were dried over K2CO3 evaporated to dryness The residue was dissolved in 500 ml of toluene 2.0 g of p-TosOH was added The resulting solution was refluxed for 4 h to remove the water formed This column was additionally washed with 250 ml of toluene The combined organic extract was evaporated to dryness The residue was dried in vacuum

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

Procedure: To a solution of sodium ethoxide in ethanol obtained from 5.95 g (0.26 mmol) of sodium and 200 ml of anhydrous ethanol, a solution of 45.1 g (0.26 mmol) of diethyl methylmalonate in 200 ml of ethanol was added dropwise, while vigorously stirring, over 15 min. Then, 64.3 g (0.24 mmol) of 2-bromo-1-(bromomethyl)-4-fluorobenzene in 50 ml of ethanol was added dropwise with such a rate, so the reaction mixture would be slowly refluxing. The resulting mixture was additionally refluxed for 4 h, then cooled to room temperature, and a solution of 51.8 g of potassium hydroxide in 150 ml of water was added. This mixture was refluxed for 3 h, and then ethanol was distilled off at atmospheric pressure. The solution obtained was cooled to ambient temperature and acidified by saturated hydrochloric acid to pH 1. The precipitate formed was filtered off, washed with 2×150 ml of cold water, and dried in air. The dibacic acid obtained was then dehcarboxylated by heating it at 160° C. for 2 h. To the viscous oil obtained, 60 ml of SOCl2 was added, and the resulting mixture was stirred for 24 h at room temperature. The excess of SOCl2 was distilled off, and the residue was dissolved in 200 ml of anhydrous dichloromethane. The solution obtained was added dropwise to a suspension of 37.7 g (0.28 mmol) of AlCl3 in 800 ml of dichloromethane for 1 h at 0° C. The reaction mixture was refluxed for 3 h, then cooled to room temperature, poured on 300 cm3 of ice, and finally acidified by saturated HCl to pH 3. The organic layer was separated, and the aqueous layer was washed with 3×200 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The title product was isolated using flash chromatography (d 50 mm, l 800 mm, eluent: hexanes-CH2Cl2, 2:1, vol.). Yield 47.3 g (81%). so the reaction mixture would be slowly refluxing The resulting mixture was additionally refluxed for 4 h This mixture was refluxed for 3 h ethanol was distilled off at atmospheric pressure The solution obtained was cooled to ambient temperature The precipitate formed was filtered off washed with 2×150 ml of cold water dried in air The dibacic acid obtained by heating it at 160° C. for 2 h To the viscous oil obtained the resulting mixture was stirred for 24 h at room temperature The excess of SOCl2 was distilled off the residue was dissolved in 200 ml of anhydrous dichloromethane The solution obtained The reaction mixture was refluxed for 3 h cooled to room temperature The organic layer was separated the aqueous layer was washed with 3×200 ml of methyl-tert-butyl ether The combined organic fractions were dried over K2CO3 evaporated to dryness