benzyl 2-(benzhydrylideneamino)acetate

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

Procedure: Tetrabutyl ammonium sulfate (3.0 g. 9 mmol) was added to a biphasic mixture consisting of 10% aqueous sodium hydroxide (75 mL). 2-[(diphenylmethylene)amino]acetic acid benzyl ester (3.05 g. 9.3 mmol) and 1,1-dimethylethyl 4-bromomethylbenzoate (3.0 g. 9 mmol) in dichloromethane (58 mL). After several hours of vigorous stirring at room temperature, the reaction mixture was diluted with ether (300 mL) and the layers were separated. The organic layer was washed with water (3×30 mL), dried (K2CO3) and filtered. Concentration provided an oil that was purified by HPLC on silica gel (the columns were pretreated with 10% triethylamine/hexanes, ethyl acetate and finally hexanes) eluting with a mixture of hexanes-ethyl acetate to give rac.-2-((diphenylmethylene)amino]-3-[4-[(1,1-dimethylethoxy) carbonyl]phenyl]propanoic acid benzyl ester, (1.7 g. 3 mmol) in 36% yield. the layers were separated The organic layer was washed with water (3×30 mL) dried (K2CO3) filtered Concentration provided an oil that was purified by HPLC on silica gel (the columns eluting with a mixture of hexanes-ethyl acetate

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

Procedure: Tetrabutyl ammonium sulfate (3.0 g. 9 mmol) was added to a biphasic mixture consisting of 10% aqueous sodium hydroxide (75 mL). 2-[(diphenylmethylene)amino]acetic acid benzyl ester (3.05 g. 9.3 mmol) and 1,1-dimethylethyl 4-bromomethylbenzoate (3.0 g. 9 mmol) in dichloromethane (58 mL). After several hours of vigorous stirring at room temperature, the reaction mixture was diluted with ether (300 mL) and the layers were separated. The organic layer was washed with water (3×30 mL), dried (K2CO3) and filtered. Concentration provided an oil that was purified by HPLC on silica gel (the columns were pretreated with 10% triethylamine/hexanes, ethyl acetate and finally hexanes) eluting with a mixture of hexanes-ethyl acetate to give rac.-2-((diphenylmethylene)amino]-3-[4-[(1,1-dimethylethoxy) carbonyl]phenyl]propanoic acid benzyl ester, (1.7 g. 3 mmol) in 36% yield. the layers were separated The organic layer was washed with water (3×30 mL) dried (K2CO3) filtered Concentration provided an oil that was purified by HPLC on silica gel (the columns eluting with a mixture of hexanes-ethyl acetate

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

Procedure: To a suspension of sodium hydride (0.41 grams, 17.1 mmole) in N,N-dimethylformamide (50 mL) at 0° C. is added dropwise a solution of N-diphenylmethylene glycine benzyl ester (7.8 mmole) in N,N-dimethylformamide (50 mL). After stirring for 30 minutes at room temperature, a solution of cis-2,5-bis(hydroxymethyl)-tetrahydrofuran ditosylate (4.1 grams, 9.3 mmole)(prepared by literature methods such as those described in JOC, 47, 2429-2435 (1982)) in N,N-dimethylformamide (50 mL) is added dropwise. The reaction mixture is gradually heated to 100° C. in an oil bath and stirred at this temperature overnight. The solvent is evaporated under vacuum and the residue is taken up in water and extracted twice with diethyl ether. The combined organic extracts are washed with brine, dried over magnesium sulfate and concentrated to a crude product. is added dropwise The reaction mixture is gradually heated to 100° C. in an oil bath stirred at this temperature overnight The solvent is evaporated under vacuum extracted twice with diethyl ether The combined organic extracts are washed with brine dried over magnesium sulfate concentrated to a crude product

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

Procedure: To a suspension of sodium hydride (6.56 grams. 0.164 mole) in ethylene glycol dimethyl ether (150 mL) at 0° C. is added a solution of the N-(diphenylmethylene)glycine benzyl ester (0.07398 mole) in ethylene glycol dimethyl ether (50 mL) dropwise via addition funnel. A solution of 2-bromoethyl ether (23.21 grams, 0.090 mole) in ethylene glycol dimethyl ether (50 mL) is then added, in 10 mL portions over approximately 5 minutes, to the ethylene glycol dimethyl ether solution. The ice bath is removed and the reaction is stirred at room temperature for 16 hours. The mixture is diluted with diethyl ether and washed with water. The aqueous layer is extracted with diethyl ether. The combined organic extracts are washed with brine, dried over magnesium sulfate, and concentrated to afford crude product. Chromatography on silica gel eluting first with 4 L of 5% ethyl acetate/hexane followed by 4 liters of 10% ethyl acetate/hexane provides 4-[N-(diphenylmethylene)amino]tetrahydropyran-4-carboxylic acid benzyl ester as a clear yellow oil. dropwise via addition funnel The ice bath is removed The mixture is diluted with diethyl ether washed with water The aqueous layer is extracted with diethyl ether The combined organic extracts are washed with brine dried over magnesium sulfate concentrated to afford crude product

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

Procedure: To a suspension of sodium hydride (0.41 grams, 17.1 mmole) in N,N-dimethylformamide (50 mL) at 0° C. is added dropwise a solution of N-diphenylmethylene glycine benzyl ester (7.8 mmole) in N,N-dimethylformamide (50 mL). After stirring for 30 minutes at room temperature, a solution of cis-2,5-bis(hydroxymethyl)-tetrahydrofuran ditosylate (4.1 grams, 9.3 mmole) (prepared by literature methods such as those described in JOC, 47, 2429-2435 (1982)) in N,N-dimethylformamide (50 mL) is added dropwise. The reaction mixture is gradually heated to 100° C. in an oil bath and stirred at this temperature overnight. The solvent is evaporated under vacuum and the residue is taken up in water and extracted twice with diethyl ether. The combined organic extracts are washed with brine, dried over magnesium sulfate and concentrated to a crude product. is added dropwise The reaction mixture is gradually heated to 100° C. in an oil bath stirred at this temperature overnight The solvent is evaporated under vacuum extracted twice with diethyl ether The combined organic extracts are washed with brine dried over magnesium sulfate concentrated to a crude product

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

Procedure: To a suspension of sodium hydride (6.56 grams. 0.164 mole) in ethylene glycol dimethyl ether (150 mL) at 0° C. is added a solution of the N-(diphenylmethylene)glycine benzyl ester (0.07398 mole) in ethylene glycol dimethyl ether (50 mL) dropwise via addition funnel. A solution of 2-bromoethyl ether (23.21 grams, 0.090 mole) in ethylene glycol dimethyl ether (50 mL) is then added, in 10 mL portions over approximately 5 minutes, to the ethylene glycol dimethyl ether solution. The ice bath is removed and the reaction is stirred at room temperature for 16 hours. The mixture is diluted with diethyl ether and washed with water. The aqueous layer is extracted with diethyl ether. The combined organic extracts are washed with brine, dried over magnesium sulfate, and concentrated to afford crude product. Chromatography on silica gel eluting first with 4 L of 5% ethyl acetate/hexane followed by 4 liters of 10% ethyl acetate/hexane provides 4-[N-(diphenylmethylene)amino]tetrahydropyran-4-carboxylic acid benzyl ester as a clear yellow oil. dropwise via addition funnel The ice bath is removed The mixture is diluted with diethyl ether washed with water The aqueous layer is extracted with diethyl ether The combined organic extracts are washed with brine dried over magnesium sulfate concentrated to afford crude product

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

Procedure: Tetrabutyl ammonium sulfate (3.0 g, 9 mmol) was added to a biphasic mixture consisting of 10% aqueous sodium hydroxide (75 mL), 2-[(diphenylmethylene)amino]acetic acid benzyl ester (3.05 g, 9.3 mmol) and 1,1-dimethylethyl 4-bromomethylbenzoate (3.0 g, 9 mmol) in dichloromethane (58 mL). After several hours of vigorous stirring at room temperature, the reaction mixture was diluted with ether (300 mL) and the layers were separated. The organic layer was washed with water (3×30 mL), dried (K2CO3) and filtered. Concentration provided an oil that was purified by HPLC on silica gel (the columns were pre-treated with 10% triethylamine/hexanes, ethyl acetate and finally hexanes) eluting with a mixture of hexanes-ethyl acetate to give rac.-2- [(diphenylmethylene)amino]-3-[4-[(1,1-dimethylethoxy) carbonyl]phenyl]propanoic acid benzyl ester, (1.7 g, 3 mmol) in 36% yield. the layers were separated The organic layer was washed with water (3×30 mL) dried (K2CO3) filtered Concentration provided an oil that was purified by HPLC on silica gel (the columns were pre-treated with 10% triethylamine/hexanes, ethyl acetate and finally hexanes) eluting with a mixture of hexanes-ethyl acetate

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

Procedure: Tetrabutyl ammonium sulfate (3.0 g, 9 mmol) was added to a biphasic mixture consisting of 10% aqueous sodium hydroxide (75 mL), 2-[(diphenylmethylene)amino]acetic acid benzyl ester (3.05 g, 9.3 mmol) and 1,1-dimethylethyl 4-bromomethylbenzoate (3.0 g, 9 mmol) in dichloromethane (58 mL). After several hours of vigorous stirring at room temperature, the reaction mixture was diluted with ether (300 mL) and the layers were separated. The organic layer was washed with water (3×30 mL), dried (K2CO3) and filtered. Concentration provided an oil that was purified by HPLC on silica gel (the columns were pre-treated with 10% triethylamine/hexanes, ethyl acetate and finally hexanes) eluting with a mixture of hexanes-ethyl acetate to give rac.-2-](diphenylmethylene)amino]-3-[4-[(1,1-dimethylethoxy)carbonyl]phenyl]propanoic acid benzyl ester, (1.7 g, 3 mmol) in 36% yield. the layers were separated The organic layer was washed with water (3×30 mL) dried (K2CO3) filtered Concentration provided an oil that was purified by HPLC on silica gel (the columns were pre-treated with 10% triethylamine/hexanes, ethyl acetate and finally hexanes) eluting with a mixture of hexanes-ethyl acetate

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

Procedure: To a suspension of sodium hydride (6.56 grams. 0.164 mole) in ethylene glycol dimethyl ether (150 mL) at 0° C. is added a solution of the N-(diphenylmethylene)glycine benzyl ester (0.07398 mole) in ethylene glycol dimethyl ether (50 mL) dropwise via addition funnel. A solution of 2-bromoethyl ether (23.21 grams, 0.090 mole) in ethylene glycol dimethyl ether (50 mL) is then added, in 10 mL portions over approximately 5 minutes, to the ethylene glycol dimethyl ether solution. The ice bath is removed and the reaction is stirred at room temperature for 16 hours. The mixture is diluted with diethyl ether and washed with water. The aqueous layer is extracted with diethyl ether. The combined organic extracts are washed with brine, dried over magnesium sulfate, and concentrated to afford crude product. Chromatography on silica gel eluting first with 4 L of 5% ethyl acetate/hexane followed by 4 liters of 10% ethyl acetate/hexane provides 4-[N-(diphenylmethylene)amino]tetrahydropyran-4-carboxylic acid benzyl ester as a clear yellow oil. dropwise via addition funnel The ice bath is removed The mixture is diluted with diethyl ether washed with water The aqueous layer is extracted with diethyl ether The combined organic extracts are washed with brine dried over magnesium sulfate concentrated to afford crude product

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

Procedure: To a suspension of sodium hydride (0.41 grams, 17.1 mmole) in N,N-dimethylformamide (50 mL) at 0° C. is added dropwise a solution of N-diphenylmethylene glycine benzyl ester (7.8 mmole) in N,N-dimethylformamide (50 mL). After stirring for 30 minutes at room temperature, a solution of cis-2,5-bis(hydroxymethyl)-tetrahydrofuran ditosylate (4.1 grams, 9.3 mmole,)(prepared by literature methods such as those described in JOC, 47, 2429-2435 (1982)) in N,N-dimethylformamide (50 mL) is added dropwise. The reaction mixture is gradually heated to 100° C. in an oil bath and stirred at this temperature overnight. The solvent is evaporated under vacuum and the residue is taken up in water and extracted twice with diethyl ether. The combined organic extracts are washed with brine, dried over magnesium sulfate and concentrated to a crude product. is added dropwise The reaction mixture is gradually heated to 100° C. in an oil bath stirred at this temperature overnight The solvent is evaporated under vacuum extracted twice with diethyl ether The combined organic extracts are washed with brine dried over magnesium sulfate concentrated to a crude product

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

Procedure: To a suspension of sodium hydride (6.56 grams. 0.164 mole) in ethylene glycol dimethyl ether (150 mL) at 0° C. is added a solution of the N-(diphenylmethylene)glycine benzyl ester (0.07398 mole) in ethylene glycol dimethyl ether (50 mL) dropwise via addition funnel. A solution of 2-bromoethyl ether (23.21 grams, 0.090 mole) in ethylene glycol dimethyl ether (50 mL) is then added, in 10 mL portions over approximately 5 minutes, to the ethylene glycol dimethyl ether solution. The ice bath is removed and the reaction is stirred at room temperature for 16 hours. The mixture is diluted with diethyl ether and washed with water. The aqueous layer is extracted with diethyl ether. The combined organic extracts are washed with brine, dried over magnesium sulfate, and concentrated to afford crude product. Chromatography on silica gel eluting first with 4 L of 5% ethyl acetate/hexane followed by 4 liters of 10% ethyl acetate/hexane provides 4-[N-(diphenylmethylene)amino]tetrahydropyran-4-carboxylic acid benzyl ester as a clear yellow oil. dropwise via addition funnel The ice bath is removed The mixture is diluted with diethyl ether washed with water The aqueous layer is extracted with diethyl ether The combined organic extracts are washed with brine dried over magnesium sulfate concentrated to afford crude product

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

Procedure: Lithium bis(trimethylsilyl)amide (1M in THF, 10.5 mL, 10.5 mmol) was added to N-(diphenylmethylene)glycine benzyl ester (3.28 g, 10 mmol) in tetrahydrofuran (10 mL) at −78° C. under argon. The reaction mixture was stirred at this temperature for about 1 hr. Propionyl chloride (0.913 mL, 10.5 mmol) in tetrahydrofuran (5 mL) was slowly added into the above mixture and stirred for 30 minutes. The reaction mixture was warmed up to room temperature and let stir overnight. After the completion of the above reaction, the reaction mixture was cooled to −40° C. quenched with 50 mL dilute hydrochloride acid (3N) and stirred at room temperature for 2 hr. After removal of tetrahydrofuran, the aqueous solution was extracted with ethyl acetate (3×50 mL), ether (1×50 mL) and CH2Cl2 (50 mL). The aqueous solution was concentrated in vacuo to about ½ volume and lyophilized to give 2-amino-4-methyl-3-oxo-butanoic acid benzyl ester hydrochloride salt, which was used in the next step without further purification. stirred for 30 minutes let stir overnight After the completion of the above reaction the reaction mixture was cooled to −40° C. quenched with 50 mL dilute hydrochloride acid (3N) stirred at room temperature for 2 hr After removal of tetrahydrofuran the aqueous solution was extracted with ethyl acetate (3×50 mL), ether (1×50 mL) and CH2Cl2 (50 mL) The aqueous solution was concentrated in vacuo to about ½ volume