Formaldehyde → 4-(1-Cyano-2-hydroxy-ethylidene)-piperidine-1-carboxylic acid tert-butyl ester

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To a solution of 2,6-diphenylphenol (10.5 g, 42 mmol) in 60 mL CH2Cl2 at room temperature was added AlMe3 (2.0 M in hexane, 10.5 mL, 21 mmol). Gas evolution was observed and the mixture was stirred at room temperature for 30 min. The solution was cooled to 0° C. and 1,3,5-trioxane (630 mg, 7 mmol) in 6 mL CH2Cl2 was added dropwise and the solution was stirred for 1 h. In a separate flask 4-(bromo-cyano-methylidene)-piperidine-1-carboxylic acid tert-butyl ester (2.1 g, 7 mmol) was dissolved in 20 mL THF at −40° C. and to this solution was added isopropylmagnesium bromide (1M in THF, 8.4 mL, 8.4 mmol) dropwise. The mixture was stirred at −40° C. to −30° C. for 1.5 h. The above freshly prepared Grignard reagent was added dropwise to the formaldehyde solution and the mixture was stirred at 0° C. for 1 h. Water was carefully added and the mixture was extracted with ethyl acetate. Purification by chromatography (EtOAc/hexanes=1:1) yielded the title compound (800 mg, 45%) as a white solid. MS 253 (M+H).

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