Org Prep Daily

September 22, 2006


Filed under: procedures — milkshake @ 2:02 am


Oven-dried 2L flask with a large egg-shaped stirbar was flushed with Ar and 95% sodium hydride 3.484g (138mmol) was quickly added (fire hazard!) followed by anh. THF 0.5L. Neat L-alaninol 9.865g (131.3 mmol) was added over 5 min (H2 evolution) without cooling. The obtained slurry of sodium aminoalcoholate was stirred under Ar for 45 min, then Ethyl chloroacetate 16.177g (132 mmol) was added. The mixture was stirred for 30 min at ambient temperature, then refluxed for 3 hours. The flask was cooled on ice bath, LAH 12g was carefully added in several portions (3x1g, then 3x3g) with cooling. 15 min after complete addition, the flask was placed on oil bath 95-100C and refluxed for 3 hours 30 min.The reaction mixture was cooled on ice bath, carefully quenched by dropwise addition of water 12 mL, diluted with THF (300mL), 15% NaOH 36 mL was added and the mixture was stirred overnight (16 hours). The solids were removed by filtration (and washed with additional THF) and the filtrates were carefully concentrated (ambient water bath, 60 Torr) The residue was distilled at normal pressure under Ar. After a smallTHF fraction, the pure product distilled, b.p. 136-8C (oil bath was 160-200C). Y=6.513g (49% th) of a clear liquid.

1H(CDCl3, 400MHz): 3.777 (br m, 1H), 3.732 (dd, 11.0Hz, 2.7Hz, 1H), 3.465 (app td, 11.4Hz(t), 2.3Hz(d), 1H), 3.083 (app t, 10.1Hz, 1H), 2.983(app td, 11.7Hz(t), 3.5Hz(d), 1H), 2.901(m, 1H), 2.805(br m, 1H), 0.958 (d, 6.3Hz, 3H);  13C-NMR(CDCl3, 100MHz): 73.99, 67.45, 50.62, 46.52, 18.11

In humid places like Florida, oil-free sodium hydride should be avoided because of its risk of self-ignition. It is helpful to use a dry test tube with a septa, as a disposable reagent container when weighing flammable powder reagents (NaH, LAH, etc.). The material in test tube is dumped into Ar-filled flask in a single portion. For LAH gradual addition, it is convenient to pre-weight several separate dump-portions and keep them under septa in a dessicator.


  1. I could be wrong (it wouldn’t the first, and won’t be the last, time), but isn’t this a *2* Methylmorpholine (start the numbering from the nitrogen?)

    Comment by SJB — September 22, 2006 @ 2:22 pm

  2. A solids addition funnel works well if you want to be even more careful about the rate of addition of powdered reagents.

    Comment by Come back, zinc! — September 22, 2006 @ 5:58 pm

  3. I bet alane (AlH3) would be higher yielding than LAH; it gives less C-N bond cleavage. Make it by adding half an eq of H2SO4 to cold LAH in THF (not as dangerous as it sounds, the actual reduction is more exothermic). Dont bother filtering off the Li2SO4.

    Comment by Handles — September 22, 2006 @ 10:02 pm

  4. LAH reduction is not the problem – the aminoalcohol is first alkylated on oxygen in presence of free NH2 by Et-chloroacetate. That’s where things crap up a bit (but the procedure is a simple one pot and the sideproducts fortunately do not distill).

    Comment by milkshake — September 22, 2006 @ 10:20 pm

  5. HI MS,

    I am getting a mixture of monoacylated as well as diacylated hydantoin when I react hydantoin with cinnamoyl chloride. The conditions were treatment of hydantoin with NaH, followed by tratement with cinnamoyl chloride. I have been working on milder conditions employing pyrdine as solvent /reagent. I am getting low yield of the desired monoacylated product. How can I get more amount of the desired momcoacylated product ?

    It would be really helpful if you can suggest to improve the yield.



    Comment by marto — August 23, 2011 @ 1:54 pm

    • One of the acyls in your diacylated hydantoins is going to be sensitive to hydrolysis – can you treat the mono+diacylated mix with diluted LiOH, or with methylamine solution in ethanol?

      Comment by milkshake — August 23, 2011 @ 10:04 pm

  6. Thanks very much for the suggestions.

    Comment by marto — August 24, 2011 @ 12:52 am

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