Sodium Hydroxide → (+/-)-8-(cis 2-Phenyl-cyclohexyl)-1,4-dioxa-8-aza-spiro[4,5]decane

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Preparation of (+/−)-cis-1-(2-Phenyl-cyclohexyl)-piperidin-4-one. To a solution of 2-phenyl-cyclohexanone (46.0 g, 264 mmol) and 1,4-dioxa-8-aza-spiro[4,5]decane (31.5 g, 220 mmol) in toluene (380 ml), p-toluenesulphonic acid monohydrate (4.18 g, 22.0 mmol) was added and the mixture was heated to reflux in an apparatus equipped with a Dean-Stark trap for 24 h. The reaction mixture was then evaporated and the resulting crude enamine dissolved in 1,2-dichloroethane (900 ml) and acetic acid (8.00 ml). To this solution, sodium triacetoxyborohydride (69.0 g, 308 mmol) was added in portion. After a total reaction time of 2.5 h, the reaction mixture was treated with 2N NaOH (250 ml) and extracted with dichloromethane. The pooled organic extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated. Purification of the crude product over a silica gel plug (10:1) with n-heptane/ethyl acetate 10:1 then n-heptane/ethyl acetate 9:1 and finally ethyl acetate as eluent provided (+/−)-8-(cis-2-phenyl-cyclohexyl)-1,4-dioxa-8-aza-spiro[4,5]decane (44.8 g, 68%) as a yellow oil, MS (ISP): m/e=302.4 (M+H+).

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