Org Prep Daily

October 1, 2006

(S,S) and (S,R)-9-Aza-2-Oxa-[4,3,0]-Bicyclononane-3-Carbonitrile

Filed under: procedures — milkshake @ 11:16 pm


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.


  1. can you explain in more detail that stereoelectronic reasons influencing basicity of axial isomer?

    Comment by petr — October 2, 2006 @ 6:03 am

  2. I am not Kirby – I wrote that I don’t have a clear explanation. Maybe it has to do with the alignment of the cyano group with the N lone pair – but I am not quite sure. The stereoelectronic effects through 2 carbons are going to be weak though it could be enough to differentiate the two epimers on silica by their basicity – considering that N-alkylated morpholines are actually not quite that basic to begin with. (If you are at Ch.Uni, ask Dr. Trnka, he may know the answer.)

    Comment by milkshake — October 2, 2006 @ 6:39 am

  3. One has to wonder if the observed behavior is simply do to the fact that the axial CN structure may be more compact in nature (precluding SiO2 – CN interaction) whereas the equatorial is a more open one favoring CN – silica interactions.

    Comment by milo — October 2, 2006 @ 4:17 pm

  4. I think you are right, it is another perfectly believable explanation. You know, it would be great if someone schooled in discussing this kind of electronic effects (a sugar chemist for example) could step forward and write: “these orbitals overlap here and there and therefore the argument about the nitrile effect on the amine basicity is bunk.” But we got over 1400 visits today (before 4pm Florida time) and almost everybody’s shy.

    Comment by milkshake — October 2, 2006 @ 4:38 pm

  5. I know the feeling… I have had > 10000 visits and far fewer comments. It is fun to see who visits from where 😉

    Comment by milo — October 2, 2006 @ 4:45 pm

  6. 1,500 now. Almost everybody is visiting from the goddamned Tenderbutton last post – If this does not stop soon, the WordPress servers will get tired of hosting me for free.

    Comment by milkshake — October 2, 2006 @ 4:53 pm

  7. Don’t worry, as long as there are no gossipy posts, it should die down in a day or two.

    Comment by milo — October 2, 2006 @ 6:11 pm

  8. I think it is quite reasonable that using stereoelectronic arguments to explain this difference. Assuming the sigma bond of C-N matchs better with the antibond of C-CN in energy than that of C-H ( I am not very sure about this though), the electron density of C-N bond will be more likely released into the antibond of C-CN in the equatorial isomer and make it longer, more ionic.

    Comment by MissingSnow — October 2, 2006 @ 7:59 pm

  9. Well, yes – but isn’t it going to make the equatorial nitrile rather less basic on nitrogen? – I mean if the R2N-C sigma backdonates into C-CN antibonding sigma, the sigma bond N-C electron density will slightly decrease, as if one would have some electron-withdrawing substituent R2N-C-EWG (which is a pretty good way of making amine less basic, not more).

    Comment by milkshake — October 2, 2006 @ 8:54 pm

  10. I will be the platitude-artist here and say the needful: “I think that this is a result of kinetic control and not thermodynamic control”.

    The next person to say anything about kinetic/thermodynamic control without knowing what it means will get shot.

    The rest of you: nod your heads like sheep when you hear “kinetic/thermodynamic control”.

    Comment by Davy — January 20, 2007 @ 7:13 pm

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