1,3,3-trimethoxybutane

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

Procedure: To a mixture containing 3-chloroaniline (1.59 g), ferric chloride hexahydrate (5.4 g), zinc chloride (0.2 g), ethanol (20 ml of 95% aqueous solution) preheated to 60° C. was added 1,3,3-trimethoxybutane (1.48 g). The resulting mixture was refluxed for two hours and allowed to stand overnight. The volatile matrials were then removed in vacuo and the residue rendered basic with 10% aqueous sodium hydroxide. The resulting mixture was partitioned between water and diethyl ether (3 times). The combined ether layer was dried over magnesium sulfate. Rotary evaporation of the ether solution gave a dark liquid. The liquid was added to a silica gel column and eluted with hexane/ethyl acetate (3:1) to give the desired product as tan crystals. preheated to 60° C. The resulting mixture was refluxed for two hours The volatile matrials were then removed in vacuo The resulting mixture was partitioned between water and diethyl ether (3 times) The combined ether layer was dried over magnesium sulfate Rotary evaporation of the ether solution gave a dark liquid The liquid was added to a silica gel column eluted with hexane/ethyl acetate (3:1)

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

Procedure: To a mixture containing 3-chloroaniline (1.59 g), ferric chloride hexahydrate (5.4 g), zinc chloride (0.2 g), ethanol (20 ml of 95% aqueous solution) preheated to 60° C. was added 1,3,3-trimethoxybutane (1.48 g). The resulting mixture was refluxed for two hours and allowed to stand overnight. The volatile matrials were then removed in vacuo and the residue rendered basic with 10% aqueous sodium hydroxide. The resulting mixture was partitioned between water and diethyl ether (3 times). The combined ether layer was dried over magnesium sulfate. Rotary evaporation of the ether solution gave a dark liquid. The liquid was added to a silica gel column and eluted with hexane/ethyl acetate (3:1) to give the desired product as tan crystals. preheated to 60° C. The resulting mixture was refluxed for two hours The volatile matrials were then removed in vacuo The resulting mixture was partitioned between water and diethyl ether (3 times) The combined ether layer was dried over magnesium sulfate Rotary evaporation of the ether solution gave a dark liquid The liquid was added to a silica gel column eluted with hexane/ethyl acetate (3:1)

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

Procedure: Commercially available 2-chloroaniline (200 g, 1.56 mol) was dissolved in 600 ml ethanol, and dry HCl gas was bubbled through for 10 minutes to give 2-chloroaniline hydrochloride. A new flask was charged with 2-chloroaniline hydrochloride (130 g, 0.793 mol), ferric chloride hexahydrate (25.7 g, 0.095 mol), anhydrous zinc chloride (10.9 g, 0.0799 mol) and 500 ml 2B ethanol. The mixture was heated to 60° C. for 10 minutes and 1,3,3-trimethoxy butane was added dropwise over a period of one hour. The mixture was then refluxed for two hours and allowed to stand overnight at room temperature. Most of the alcohol was removed by distillation and the residue was made alkaline with 25% sodium hydroxide solution. The reaction was cooled, filtered, and the filter pad washed with toluene. The toluene was concentrated to dryness. The product was recrystallized from dichloromethane/pentane to obtained a spectroscopically pure sample (mp: 110° C., 37.0 g, 25% overall yield). The mixture was then refluxed for two hours Most of the alcohol was removed by distillation The reaction was cooled filtered the filter pad washed with toluene The toluene was concentrated to dryness The product was recrystallized from dichloromethane/pentane to obtained a spectroscopically pure sample (mp: 110° C., 37.0 g, 25% overall yield)

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

Procedure: A mixture of 2,5-dimethyl-4-nitroaniline (0.96 g), ferric chloride hexahydrate (2.50 g), zinc chloride (0.094 g), concentrated hydrochloric acid (0.481 mL), and ethanol (8 mL) is heated to 60° C. 1,3,3-trimethoxybutane (0.73 mL) is added dropwise while the reaction mixture is kept at 60° C. The reaction mixture is heated at reflux overnight and cooled to room temperature. A solution of 10% aqueous sodium hydroxide is added, and the mixture is extracted three times with methylene chloride. The combined organic layers are dried over sodium sulfate, filtered and evaporated to afford a crude product. The crude product is purified by flash chromatography using 25% ethyl acetate in hexane as eluent, providing 6-nitro-4,5,8-trimethylquinoline. is kept at 60° C The reaction mixture is heated at reflux overnight cooled to room temperature the mixture is extracted three times with methylene chloride The combined organic layers are dried over sodium sulfate filtered evaporated to afford a crude product The crude product is purified by flash chromatography

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

Procedure: To a mixture containing 3-chloroaniline (1.59 g), ferric chloride hexahydrate (5.4 g), zinc chloride (0.2 g), ethanol (20 ml of 95% aqueous solution) preheated to 60° C. was added 1,3,3-trimethoxybutane (1.48 g). The resulting mixture was refluxed for two hours and allowed to stand overnight. The volatile materials were then removed in vacuo and the residue rendered basic with 10% aqueous sodium hydroxide. The resulting mixture was partitioned between water and diethyl ether (3 times). The combined ether layer was dried over magnesium sulfate. Rotary evaporation of the ether solution gave a dark liquid. The liquid was added to a silica gel column and eluted with hexane/ethyl acetate (3:1) to give the desired product as tan crystals. preheated to 60° C. The resulting mixture was refluxed for two hours The volatile materials were then removed in vacuo The resulting mixture was partitioned between water and diethyl ether (3 times) The combined ether layer was dried over magnesium sulfate Rotary evaporation of the ether solution gave a dark liquid The liquid was added to a silica gel column eluted with hexane/ethyl acetate (3:1)

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

Procedure: 1,3,3-Trimethoxybutane (145.4 g, 0.98 mol) is combined with 1 N aqueous hydrochloric acid (50.0 mL, 0.05 mol) and stirred for 1-2 h at RT under a nitrogen atmosphere. THF (1.5 L) is added and the solvent is evaporated at standard atmospheric pressure below 70° C. twice. THF (1.5 L) is added to prepare a solution of 4-methoxybutan-2-one in THF. (S)-(−)-2-Methyl-2-propanesulfinamide (124.4 g, 1.03 mol) and titanium (IV) ethoxide (447.0 g, 1.96 mol) are added and the reaction heated to 65-70° C. for 16-17 h. The reaction mixture is cooled to −10 to 0° C. Sodium borohydride (37.0 g, 0.98 mol) is added in portions, and then the mixture is stirred for 1-2 h at the same temperature. The reaction mixture is warmed to RT and stirred for 1-2 h. It is then cooled to 10-20° C. and methanol (100 mL) is added dropwise over 1-2 h. 25% Aqueous sodium chloride (300 mL) is added and the mixture is warmed to RT. Ethyl acetate (500 mL) is added. The mixture is stirred for 1-2 h at RT and then filtered. The filtercake is rinsed with additional ethyl acetate (807 mL). The layers are separated and the organic phase is washed with 25% aqueous sodium chloride (1.0 L). The aqueous phase is extracted with ethyl acetate (500 mL). The organic portions are combined, and the solvent is distilled at atmospheric pressure (no vacuum) below 75° C. to arrive at a solution of 300-500 mL total volume. Ethyl acetate (600 mL) and sodium thiosulfate (150.0 g) are added and the mixture is stirred for 1-2 h at 20-30° C. The mixture is filtered and the filtrate is concentrated. The diastereomers are separated by supercritical fluid chromatography to afford the title compound as a yellow oil (205.0 g, 65%). Column. ChiralPak® AD 10 μm, 50×300 mm; Elution mode: Isocratic; Mobile phase: CO2/ethanol; Flow rate: 280 mL/min; UV detection: 215.16 nm; Loading: 300 mg/mL. The first eluting peak is the minor diastereomer, TR=15.17 min. The second eluting peak is the major diastereomer representing the title compound, TR=17.11 min. the solvent is evaporated at standard atmospheric pressure below 70° C. twice THF (1.5 L) is added to prepare a solution of 4-methoxybutan-2-one in THF the reaction heated to 65-70° C. for 16-17 h The reaction mixture is cooled to −10 to 0° C the mixture is stirred for 1-2 h at the same temperature The reaction mixture is warmed to RT stirred for 1-2 h It is then cooled to 10-20° C. the mixture is warmed to RT The mixture is stirred for 1-2 h at RT filtered The filtercake is rinsed with additional ethyl acetate (807 mL) The layers are separated the organic phase is washed with 25% aqueous sodium chloride (1.0 L) The aqueous phase is extracted with ethyl acetate (500 mL) the solvent is distilled at atmospheric pressure (no vacuum) below 75° C. Ethyl acetate (600 mL) and sodium thiosulfate (150.0 g) are added the mixture is stirred for 1-2 h at 20-30° C The mixture is filtered the filtrate is concentrated The diastereomers are separated by supercritical fluid chromatography

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

Procedure: A mixture of 2,5-dimethyl-4-nitroaniline (0.96 g), ferric chloride hexahydrate (2.50 g), zinc chloride (0.094 g), concentrated hydrochloric acid (0.481 mL), and ethanol (8 mL) is heated to 60° C. 1,3,3-trimethoxybutane (0.73 mL) is added dropwise while the reaction mixture is kept at 60° C. The reaction mixture is heated at reflux overnight and cooled to room temperature. A solution of 10% aqueous sodium hydroxide is added, and the mixture is extracted three times with methylene chloride. The combined organic layers are dried over sodium sulfate, filtered and evaporated to afford a crude product. The crude product is purified by flash chromatography using 25% ethyl acetate in hexane as eluent, providing 6-nitro-4,5,8-trimethylquinoline. is kept at 60° C The reaction mixture is heated at reflux overnight cooled to room temperature the mixture is extracted three times with methylene chloride The combined organic layers are dried over sodium sulfate filtered evaporated to afford a crude product The crude product is purified by flash chromatography

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

Procedure: To a mixture containing 3-chloroaniline (1.59 g), ferric chloride hexahydrate (5.4 g), zinc chloride (0.2 g), ethanol (20 ml of 95% aqueous solution) preheated to 60° C. was added 1,3,3-trimethoxybutane (1.48 g). The resulting mixture was refluxed for two hours and allowed to stand overnight. The volatile matrials were then removed in vacuo and the residue rendered basic with 10% aqueous sodium hydroxide. The resulting mixture was partitioned between water and diethyl ether (3 times). The combined ether layer was dried over magnesium sulfate. Rotary evaporation of the ether solution gave a dark liquid. The liquid was added to a silica gel column and eluted with hexane/ethyl acetate (3:1) to give the desired product as tan crystals. preheated to 60° C. The resulting mixture was refluxed for two hours The volatile matrials were then removed in vacuo The resulting mixture was partitioned between water and diethyl ether (3 times) The combined ether layer was dried over magnesium sulfate Rotary evaporation of the ether solution gave a dark liquid The liquid was added to a silica gel column eluted with hexane/ethyl acetate (3:1)