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Copyright Syntheticpages ©2001




Preparation of imidazolidinones via cyclisation of ephedrine and urea; (4R, 5S)-1,5-dimethyl-4-phenyl imidazolidinone

SyntheticPage 67 (2001)
Submitted 13th Aug 2001, published 17th Aug 2001

Mala Mistry (m.mistry@sussex.ac.uk),
A contribution from the Caddick group Group, CPES, University of Sussex


Reaction Scheme

Chemicals Used
Urea (USB) (-) Ephedrine Hydrochloride (Aldrich)

Procedure
A mixture of (-) ephedrine hydrochloride (20.1 g, 0.1 mol,1 eq) and urea (18.1 g, 0.3 mol, 3 eq) was heated at 180oC in an oil bath. The two white solids melted to form a colourless melt and stirred for 45 minutes. The temperature of the oil bath was raised to 215oC and stirred for a couple of hours to give an orange melt. The reaction was cooled down and to which DCM was added slowly and then washed with distilled water. The aqueous layer was washed with DCM and the organic extracts were dried over MgSO4, filtered, reduced under pressure to afford an orange solid. Purification by column chromatography is necessary eluting with 2:1 PE:EtOAc to afford the imidazolidinone as a white solid (9.6 g, 50 %).

Author's Comments
Firstly it is vital to make sure the hot plate can reach such high temperatures as this is necessary for the fusion reaction to take place. It is noticed that not all hotplates can reach this temperature thus making this reaction ineffective. If you allow the melt to cool down too much it will form an orange solid which is extremely difficult to redissolve in DCM. It is best to add the DCM when the crude product is still a liquid, but add the DCM with caution as it will still be warm. Even though this fusion reaction is low yielding (45-50%), it is important to note that it is a very simple procedure to make this imidazoldinone, thus outweighing the poor yields. A by-product is also obtained from this fusion reaction [(4S,5R)-1,5-dimethyl-4-phenyloxazolidin-2-one] in about 28 % yield as a white solid. This reaction has been repeated at least three times on a large scale (18 g) and works very well. Due to the low yields (9 g, 50 %) I have never attempted to reduce the scale of the reaction. This experiment involves dealing with large quantities of starting materials, and the scale of apparatus used from the initial melting to the final purification are quite large and awkward to handle. But due to the fact that the yields are moderately low, it is necessary to carry out the reaction on this scale.

Data
1H NMR (300 MHz, CDCl3)0.67 (3H, d, J 7, CCH3) 2.66 (3H, s, NCH3) 3.73-3.75 (1H, m, PhCH) 4.46-4.58 (1H, br, s, NH) 4.61 (1H, d, J 9, CH3CH) 7.12-7.35 (5H, m, CHar)


Lead Reference
K. Jenkins, D.Phil Thesis, University of Sussex, 1999.

Other References
H. Roder, G. Helmchen, E. Peters, K. Peters, H. von Schnering; Angew. Chem. Int. Ed. Engl; 1984, 23, 11, 898-898. W.J. Close, J.Org. Chem, 1950, 1131-1134.

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User comments on this page

Kerry Jenkins
Mon, 5th Nov 2001 17:20:04
Effective stirring of this reaction is imperative. On larger scales it may be necessary to use mechanical stirring instead of magnetic stirring.

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