2-Chloroacrylonitrile 3.474g (39.7mmol) was added dropwise into a solution of L-prolinol 4.216g (41.7mmol, 1.05eq.) in anh. THF 40mL at 0C over 5 min. The cooling bath was removed and the mixture was stitrred at 0C to RT for one hour and then at RT overnight (11 hours). The reaction mixture was cooled to 0C, a solution of potassium tert-butoxide 4.904g (43.7 mmol, 1.1eq.) in THF 40mL was added dropwise over 10 min, stirred at 0C for 30 min and the reaction was completed at RT (ambient water bath) for 30 min. The reaction was quenched by adding water 1mL, followed by anh. MgSO4 powder. The mixture was stirred for 15 min, filtered (the salts were washed with additional THF) and the filtrates were evaporated. The residue was purified on a column of silica (150g) in a mix dichloromethane-ethyl acetate 5:1 (3L total). Two pure products were obtained (with complete separation):
A: Faster isomer, axial CN, Y=2.006g (33%) of a white crystalline solid
1H(CDCl3, 400MHz): 4.709(dd, 3.5Hz, 0.8Hz, 1H), 3.968(dd, 10.9Hz, 3.1Hz, 1H), 3.649(app t, 10.1Hz, 1H), 3.150(m, 2H), 2.523(dd, 11.7Hz, 3.5Hz, 1H), 2.178(ddABX, 17.5Hz, 9.0Hz, 1H), 2.075(m, 1H), 1.806 (m, 3H), 1.415(m, 1H); 13C(CDCl3, 100MHz): 117.82, 69.50, 63.41, 61.55, 54.48, 53.53, 26.31, 20.82
B: Slower isomer, equatorial CN, Y=2.776g (46%) of a pale-yellow cryst solid
1H(CDCl3, 400MHz): 4.356(dd, 10.5Hz, 2.7Hz, 1H), 4.049(dd, 10.9Hz, 3.1Hz, 1H), 3.291(dd, 10.5Hz, 9.7Hz, 1H), 3.222(dd, 11.3Hz, 2.7Hz, 1H), 3.089(m, 1H), 2.530(t, 10.5Hz, 1H), 2.253(ddABX, 17.7Hz, 9.0Hz, 1H), 2.152(m, 1H), 1.774(m, 3H), 1.315(m,1H); 13C(CDCl3, 100MHz): 116.94, 71.93, 63.74, 60.86, 55.23, 25.87, 21.06 (All signals in proton spectra of the two stereoisomers were asigned based on COSY data)
(It was a pleasant surprise that the two nitrile diastereomers were quite far apart on silica. I don’t have a clear explanation why this is so but I think the axial cyano isomer may have reduced basicity, for stereoelectronical reasons.)
Using the same procedure, D-prolinol produced 2.110g (35%) of the axial nitrile and 2.716g (45%) of the equatorial nitrile. This cyclization procedure is quite general for secondary aminoalcohols. For example, N-Me-ethanolamine produced racemic 4-Me-morpholine-2-carbonitrile and diethanolamine produced racemic 4-(-2′-hydroxyethyl)-morpholine-2-carbonitrile, in good yelds.
The morpholine-2-carbonitriles are not very stable, they should be stored in a freezer – or better yet, used right away for the next step. For the preparation of the corresponding aminomethyl morpholines, LAH reduction works equally well as DIBAL (but it is easier to work up) and the LAH reduction results in no detectable epimerisation if the LAH addition is done at -78C and the reaction mixture is then allowed to gradualy warm up to 0C. (For racemic nitriles, hydrogenation over Adams catalyst on Parr shaker at 50 psi can be also used – but the LAH reduction gave better yields.)
One should be very careful with chloroacrylonitrile – acrylonitriles are nasty irritants and suspected carcinogens.