Benzophenone imine → tert-Butyl 4-(5-aminopyridin-2-yl)piperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

To a suspension of 4-(5-bromopyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (6.45 g), palladium(II) acetate (533 mg), (±)-2-(di-tert-butylphosphino)-1,1′-binaphthyl (1.48 g), and tert-butoxysodium (2.74 g) in toluene (47 ml) was added benzophenone imine (3.35 ml), stirred at 120° C. for 3 hours, then ethanol (50 ml), water (50 ml), hydroxylamine monohydrate (5.28 g), and sodium acetate (9.35 g) were added thereto at room temperature, and stirred at room temperature for 2.5 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained residue was purified with basic silica gel chromatography (n-hexane/ethyl acetate) to give a mixture of 4-(5-aminopyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester and 4-(5-diphenylaminopyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester. To the obtained mixture were added ethanol (100 ml), water (50 ml), hydroxylamine monohydrate (2.64 g), and sodium acetate (4.67 g), and stirred at room temperature for 6.5 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained residue was purified with basic silica gel chromatography (n-hexane/ethyl acetate). To the obtained oil were added 1,4-dioxane (15 ml) and 10% palladium carbon (containing about 50% water, 1.7 g), stirred at room temperature for 3.5 hours under hydrogen atmosphere, and then stirred at 40° C. for 12 hours. The reaction solution was filtered through Celite, then the solvent was evaporated in vacuo, and the obtained residue was purified with basic silica gel chromatography (chloroform/methanol) to give 4-(5-aminopyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (2.8 g) as a yellow oil.

Provenance & Evidence