benzene-1,3,5-triol;dihydrate

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

Procedure: Sodium nitrite (14.0 g, 0.2 mol) was added to a solution of the dibromide 2 (17.25 g, 0.05 mol) and phloroglucinol dihydrate (16.2 g, 0.1 mol) in DMSO (100 mL) and stirred for 8 h. The reaction mixture was poured into water and extracted with ethyl acetate (3×150 mL). The ethyl acetate solution was washed with water (2×100 mL) sodium chloride solution (2×100 mL), and dried (Na2SO4). Evaporation of ethyl acetate gave an oil, which was purified by silica gel chromatography, (hexane/ethyl acetate, 7/3). Fractions (Rf=0.73 were collected and evaporated to give 3 as a foamy solid. Yield: 2.8 g (22%). extracted with ethyl acetate (3×150 mL) The ethyl acetate solution was washed with water (2×100 mL) sodium chloride solution (2×100 mL) dried (Na2SO4) Evaporation of ethyl acetate gave an oil, which was purified by silica gel chromatography, (hexane/ethyl acetate, 7/3) Fractions (Rf=0.73 were collected evaporated

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

Procedure: Chloroacetonitrile (4 ml, 63.2 mmol) was added dropwise to a stirred solution containing phloroglucinol dihydrate (10 g, 61.7 mmol) and zinc chloride (8.5 g, 62.4 mmol) in anhydrous ether (100 ml) at room temperature. The resulting solution was then saturated with hydrogen chloride gas. After stirring at room temperature for 24 hours, the orange precipitates were filtered and washed with anhydrous ether (50 ml). The precipitates were then dissolved in water (100 ml) and heated at 100° C. for 1 hr. The solution was allowed to cool to ambient temperature, and aqueous sodium hydroxide (20% w/v) (10 ml) was then added. After stirring at room temperature for an additional 30 minutes, the reaction mixture was acidified by adding dilute hydrochloric acid (1M, 50 ml) and was extracted with ethyl acetate (2×250 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a light orange solid which was then recrystallized from ethyl acetate to give 4,6-dihydroxy-3-benzofuranone as a light orange powder (9.5 g, 93%). the orange precipitates were filtered washed with anhydrous ether (50 ml) The precipitates were then dissolved in water (100 ml) heated at 100° C. for 1 hr to cool to ambient temperature aqueous sodium hydroxide (20% w/v) (10 ml) was then added After stirring at room temperature for an additional 30 minutes by adding dilute hydrochloric acid (1M, 50 ml) was extracted with ethyl acetate (2×250 ml) The combined organic extracts were washed with brine dried over magnesium sulfate filtered concentrated in vacuo to afford a light orange solid which was then recrystallized from ethyl acetate

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

Procedure: Sodium nitrite (14.0 g, 0.2 mol) was added to a solution of the dibromide 2 (17.25 g, 0.05 mol) and phloroglucinol dihydrate (16.2 g, 0.1 mol) in DMSO (100 mL) and stirred for 8 h. The reaction mixture was poured into water and extracted with ethyl acetate (3×150 mL). The ethyl acetate solution was washed with water (2×100 mL) sodium chloride solution (2×100 mL), and dried (Na2SO4). Evaporation of ethyl acetate gave an oil, which was purified by silica gel chromatography, (hexane/ethyl acetate, 7/3). Fractions (Rf=0.73 were collected and evaporated to give 3 as a foamy solid. Yield: 2.8 g (22%). extracted with ethyl acetate (3×150 mL) The ethyl acetate solution was washed with water (2×100 mL) sodium chloride solution (2×100 mL) dried (Na2SO4) Evaporation of ethyl acetate gave an oil, which was purified by silica gel chromatography, (hexane/ethyl acetate, 7/3) Fractions (Rf=0.73 were collected evaporated

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

Procedure: Sodium nitrite (14.0 g, 0.2 mol) was added to a solution of the dibromide 2 (17.25 g, 0.05 mol) and phloroglucinol dihydrate (16.2 g, 0.1 mol) in DMSO (100 mL) and stirred for 8 h. The reaction mixture was poured into water and extracted with ethyl acetate (3×150 mL). The ethyl acetate solution was washed with water (2×100 mL) sodium chloride solution (2×100 mL), and dried (Na2SO4). Evaporation of ethyl acetate gave an oil, which was purified by silica gel chromatography, (hexane/ethyl acetate, 7/3). Fractions (Rf=0.73 were collected and evaporated to give 3 as a foamy solid. Yield: 2.8 g (22%). extracted with ethyl acetate (3×150 mL) The ethyl acetate solution was washed with water (2×100 mL) sodium chloride solution (2×100 mL) dried (Na2SO4) Evaporation of ethyl acetate gave an oil, which was purified by silica gel chromatography, (hexane/ethyl acetate, 7/3) Fractions (Rf=0.73 were collected evaporated

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

Procedure: Chloroacetonitrile (4 ml, 63.2 mmol) was added dropwise to a stirred solution containing phloroglucinol dihydrate (10 g, 61.7 mmol) and zinc chloride (8.5 g, 62.4 mmol) in anhydrous ether (100 ml) at room temperature. The resulting solution was then saturated with hydrogen chloride gas. After stirring at room temperature for 24 hours, the orange precipitates were filtered and washed with anhydrous ether (50 ml). The precipitates were then dissolved in water (100 ml) and heated at 100° C. for 1 hr. The solution was allowed to cool to ambient temperature, and aqueous sodium hydroxide (20% w/v) (10 ml) was then added. After stirring at room temperature for an additional 30 minutes, the reaction mixture was acidified by adding dilute hydrochloric acid (1M, 50 ml) and was extracted with ethyl acetate (2×250 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a light orange solid which was then recrystallized from ethyl acetate to give 4,6-dihydroxy-3-benzofuranone as a light orange powder (9.5 g, 93%). the orange precipitates were filtered washed with anhydrous ether (50 ml) The precipitates were then dissolved in water (100 ml) heated at 100° C. for 1 hr to cool to ambient temperature aqueous sodium hydroxide (20% w/v) (10 ml) was then added After stirring at room temperature for an additional 30 minutes by adding dilute hydrochloric acid (1M, 50 ml) was extracted with ethyl acetate (2×250 ml) The combined organic extracts were washed with brine dried over magnesium sulfate filtered concentrated in vacuo to afford a light orange solid which was then recrystallized from ethyl acetate

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

Procedure: A solution of phloroglucinol dihydrate (20 g) and ethyl 2-benzylacetoacetate (27.5 ml) in ethanol (320 ml) was treated with dry HCl at 0° C. for five hours and the solution was kept at that temperature overnight. The yellow solution was concentrated and triturated with water, the solids filtered, washed with water and dried. The resulting hydrate was thrice evaporated to dryness from toluene, triturated with petroleum ether (bp. 40-60° C.) and filtered. Yield 33,4 g (96%). Melting point 258-260° C. was kept at that temperature overnight The yellow solution was concentrated triturated with water the solids filtered washed with water dried evaporated to dryness from toluene triturated with petroleum ether (bp. 40-60° C.) filtered

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

Procedure: Sodium nitrite (14.0 g, 0.2 mol) was added to a solution of the dibromide 2 (17.25 g, 0.05 mol) and phloroglucinol dihydrate (16.2 g, 0.1 mol) in DMSO (100 mL) and stirred for 8 h. The reaction mixture was poured into water and extracted with ethyl acetate (3×150 mL). The ethyl acetate solution was washed with water (2×100 mL) sodium chloride solution (2×100 mL), and dried (Na2SO4). Evaporation of ethyl acetate gave an oil, which was purified by silica gel chromatography, (hexane/ethyl acetate, 7/3). Fractions (Rf=0.73 were collected and evaporated to give 3 as a foamy solid. Yield: 2.8 g (22%). extracted with ethyl acetate (3×150 mL) The ethyl acetate solution was washed with water (2×100 mL) sodium chloride solution (2×100 mL) dried (Na2SO4) Evaporation of ethyl acetate gave an oil, which was purified by silica gel chromatography, (hexane/ethyl acetate, 7/3) Fractions (Rf=0.73 were collected evaporated

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

Procedure: A solution of phloroglucinol dihydrate (20 g) and ethyl 2-benzylaceto-acetate (27.5 ml) in ethanol (320 ml) was treated with dry HCl at 0° C. for five hours and the solution was kept at that temperature overnight. The yellow solution was concentrated and triturated with water, the solids filtered, washed with water and dried. The resulting hydrate was thrice evaporated to dryness from toluene, triturated with pethroleum ether (bp. 40-60° C.) and filtered. Yield 33.4 g (96%). Melting point 258-260° C. was kept at that temperature overnight The yellow solution was concentrated triturated with water the solids filtered washed with water dried evaporated to dryness from toluene triturated with pethroleum ether (bp. 40-60° C.) filtered

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

Procedure: A solution of phloroglucinol dihydrate (20 g) and ethyl 2-benzylaceto-acetate (27.5 ml) in ethanol (320 ml) was treated with dry HCl at 0° C. for five hours and the solution was kept at that temperature overnight. The yellow solution was concentrated and triturated with water, the solids filtered, washed with water and dried. The resulting hydrate was thrice evaporated to dryness from toluene, triturated with pethroleum ether (bp. 40-60° C.) and filtered. Yield 33,4 g (96%). Melting point 258-260° C. was kept at that temperature overnight The yellow solution was concentrated triturated with water the solids filtered washed with water dried evaporated to dryness from toluene triturated with pethroleum ether (bp. 40-60° C.) filtered

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under argon, 112 g (690 mmol) of 1,3,5-trihydroxybenzene dihydrate are dissolved in 230 ml abs. dimethylformamide, 28.82 g (230 mmol) of methyl cyclopropylideneacetate (Example 41A) and 20 g of 4 Å molecular sieve (as powder) are added and the mixture is stirred at a bath temperature of 130° C. overnight. 1 liter of 1 N hydrochloric acid is then added, and the mixture is extracted repeatedly with ethyl acetate. The combined organic phases are washed once with water and once with saturated sodium chloride solution, dried over sodium sulfate and concentrated. 230 ml (2.99 mol) of trifluoroacetic acid are added to the product obtained, and the mixture is heated to 75° C. and stirred for 8 hours. The mixture is then cooled, water is added and the mixture is extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is purified on silica gel (mobile phase: dichloromethane/methanol 100:1→100:3). The product fractions are combined and concentrated. Dichloromethane is added to the residue obtained, the mixture is stirred briefly and the precipitate is filtered off with suction and dried under high vacuum. This gives 2.25 g (5% of theory) of the target compound. The mother liquor is then purified again on a silica gel column (mobile phase: dichloromethane/methanol 100:1). This gives a further 3.41 g (7% of theory) of the title compound. the mixture is extracted repeatedly with ethyl acetate The combined organic phases are washed once with water and once with saturated sodium chloride solution dried over sodium sulfate concentrated obtained the mixture is heated to 75° C. stirred for 8 hours The mixture is then cooled the mixture is extracted repeatedly with ethyl acetate The combined organic phases are washed twice with saturated sodium chloride solution dried over sodium sulfate filtered concentrated The residue is purified on silica gel (mobile phase: dichloromethane/methanol 100:1→100:3) concentrated Dichloromethane is added to the residue obtained the mixture is stirred briefly the precipitate is filtered off with suction dried under high vacuum The mother liquor is then purified again on a silica gel column (mobile phase: dichloromethane/methanol 100:1)

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

Procedure: 8 g (49.34 mmol) of 1,3,5-trihydroxybenzene dihydrate and 6.64 g (59.21 mmol) of cyclo-butylideneacetic acid (Example 40A) are initially charged, 25 ml (197.4 mmol) of boron trifluoride/diethyl ether complex are added and the mixture is then heated to 70° C. After three hours, the mixture is cooled, poured into 600 ml of ice-water, acidified with 6 N hydrochloric acid and extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is taken up in dichloromethane and stirred, and insoluble solid is then filtered off. Silica gel is added to the filtrate, the mixture is concentrated and the residue is purified chromatographically on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 5:1). This gives 4.7 g (43% of theory) of the title compound. 25 ml (197.4 mmol) of boron trifluoride/diethyl ether complex are added the mixture is cooled extracted repeatedly with ethyl acetate The combined organic phases are washed twice with saturated sodium chloride solution dried over sodium sulfate filtered concentrated insoluble solid is then filtered off Silica gel is added to the filtrate the mixture is concentrated the residue is purified chromatographically on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 5:1)

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

Procedure: Chloroacetonitrile (4 ml, 63.2 mmol) was added dropwise to a stirred solution containing phloroglucinol dihydrate (10 g, 61.7 mmol) and zinc chloride (8.5 g, 62.4 mmol) in anhydrous ether (100 ml) at room temperature. The resulting solution was then saturated with hydrogen chloride gas. After stirring at room temperature for 24 hours, the orange precipitates were filtered and washed with anhydrous ether (50 ml). The precipitates were then dissolved in water (100 ml) and heated at 100° C. for 1 hr. The solution was allowed to cool to ambient temperature, and aqueous sodium hydroxide (20% w/v) (10 ml) was then added. After stirring at room temperature for an additional 30 minutes, the reaction mixture was acidified by adding dilute hydrochloric acid (1M, 50 ml) and was extracted with ethyl acetate (2×250 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a light orange solid which was then recrystallized from ethyl acetate to give 4,6-dihydroxy-3-benzofuranone as a light orange powder (9.5 g, 93%). the orange precipitates were filtered washed with anhydrous ether (50 ml) The precipitates were then dissolved in water (100 ml) heated at 100° C. for 1 hr to cool to ambient temperature aqueous sodium hydroxide (20% w/v) (10 ml) was then added After stirring at room temperature for an additional 30 minutes by adding dilute hydrochloric acid (1M, 50 ml) was extracted with ethyl acetate (2×250 ml) The combined organic extracts were washed with brine dried over magnesium sulfate filtered concentrated in vacuo to afford a light orange solid which was then recrystallized from ethyl acetate