Propanal → 1-Benzyl-2,6-diethylpiperidin-4-one

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Reaction Conditions

Reaction Steps

A 1 L, 3-necked round-bottom flask, equipped with a mechanical stirrer, reflux condenser, thermometer and addition funnel was charged with a solution of propionaldehyde (25.3 g, 0.4 mol) in water (150 mL) and stirred. The solution was cooled in an ice-bath to 5° C. The solution was treated with benzylamine hydrochloride (37.2 g, 0.26 mol) and stirred at 5° C. for 30 min. Solid acetone dicarboxylic acid 89 (31.6 g, 0.2 mol) was added at 5° C., followed within 5 min with a solution of sodium acetate (7.65 g, 0.093 mol) in water (60 mL). The reaction mixture was stirred at 5° C. for 1 hour and then allowed to warm up to rt and stirred for 70 hours. CH2Cl2 (350 mL) was added and the pH of the mixture was adjusted to 9 by cautious addition of solid sodium carbonate. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (300 mL). The combined extracts were washed with sat. aq. sodium bicarbonate (200 mL), water (200 mL), brine (200 mL) and dried over anhydrous Na2SO4. The solution was filtered and evaporated to give a brown liquid, ca. 57 g. This was diluted with CH2Cl2 (100 mL) and filtered through a plug of basic alumina (ca. 3×2 in), washing with CH2Cl2 (1 L). The combined filtrates were evaporated to give the product 123 as a light orange liquid, 50.1 g, which was used without further purification.

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