Org Prep Daily

October 4, 2006


Filed under: procedures — milkshake @ 1:02 am


1-benzyl-4-hydroxypiperidine-4-carbonitrile hydrochloride 10.03g (39.68mmol, Aldrich) was suspended in neat morpholine 100mL and the mixture was stirred in a closed flask at 60C for 4 hours. The reaction mixture was concentrated on highvac, the obtained solid residue was suspended in water 100mL with sonication (10 min), the precipitated product was collected by filtration, squashed with a spatula on the filter, washed with cold water 50mL and dried on highvac. Y = 10.692g (94.5%) of a white microcrystalline solid (a very light, static-electricity-flying fluff)

1H(CDCl3, 400MHz): 7.298 (m, 5H), 3.734(t, 4.7Hz, 4H), 3.528(s, 2H), 2.870(m, 2H), 2.628(t, 4.7Hz, 4H), 2.304(br t, 13.7Hz, 2H), 2.104(br d, 12.1Hz, 2H), 1.731(br t, 12.9Hz, 2H); 13C(CDCl3, 100MHz): 138.37, 129.09(2C), 128.50(2C), 127.36, 118.54, 67.22(br, 2C), 62.84, 60.73(br), 50.04(br, 2C), 47.49(2C), 33.94(br, 2C)

The nitrile intermediate 10.585g (37.0mmol) was added to concentrated sulfuric acid 100g (96%) and the mixture was stirred until complete dissolution of the starting material occurred (this may take several hours, depending on size of the chunks). The obtained solution was then stirred at 60C for 5 hours. The mixture was cooled to RT, poured onto ice 400g and made basic with conc. aqueous ammonia 300mL with intense stirring and cooling on ice bath. The resulting mixture was stirred on ice bath for additional 30 minutes, the precipitated product was collected by filtration, washed with ice-cold 1:2 diluted ammonia, dried by suction and on highvac. Y=8.830g (78.5%) of a white crystalline product.

1H(CDCl3, 400MHz): 7.294(m, 5H), 6.447(br s, 1H), 5.736(br s, 1H), 3.680(t, 4.4Hz, 4H), 3.490(s, 2H), 2.743(m, 2H), 2.581(t, 4.4Hz, 4H), 2.386(m, 2H), 2.211(br s, 1H), 1.832(m, 4H); 13C(CDCl3, 100MHz): 177.03, 138.50, 129.21(2C), 128.22(2C), 127.03, 67.91(2C), 64.45, 63.10, 50.56(2C), 47.03(2C), 29.58(2C)


  1. I spent awhile trying to get this reaction to work with diethyl amine in place of morpholine, but it never worked for me. Pyrrolidine worked okay though

    Comment by Atompusher — October 4, 2006 @ 9:16 pm

  2. Sometimes it takes a mild acid to get Strecker going (with less reactive amines or hindered ketones). I remember doing N-subst-piperidone Strecker with anilines in straight acetic acid as solvent, with spooning in solid zinc cyanide at 10C and warming up to RT overnight in a closed flask (to keep the Death in), and it worked quite nicely.

    Comment by milkshake — October 5, 2006 @ 12:06 am

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