Synthesis of N-(1-Isopropyl-vinyl)-N-(4-methoxy-benzyl)-malonamic acid methyl ester; Enamides

John P. McDonagh ([email protected]),
A contribution from the Clark Group, Warwick

Chemicals Used
3-methyl-2-butanone,p-methoxybenzylamine, Methyl malonyl chloride, N,N-diethylaniline

Procedure
A solution of 3-methyl-2-butanone (1.1 ml, 10 mmol) and the p-methoxybenzylamine (1.3 ml, 10 mmol) in toluene (20 ml) was stirred under reflux in a Dean and Stark apparatus until no starting material could be detected by tlc analysis (typically 4 hours). The solution was then cooled to 0°C with stirring. Methyl malonyl chloride (1.1 ml, 10 mmol) was added dropwise to this solution, followed by the slow, dropwise addition of N,N-diethylaniline (1.6 ml, 10 mmol). The reaction was then stirred for 2 hours at room temperature and dropped onto H₂O (30 ml). The organic layer was washed with 10% aq.HCl (10 ml), H₂O (10 ml) dried over MgSO₄ and concentrated in vacuo to give a residue which was purified by column chromatography, petroleum ether : ethyl acetate (1:1)(1.9 g, 63 %).

Author's Comments
Slow addition of both the acylating agent and base is important in this procedure for successful N-acylation over competitive C-acylation. A side product in this reaction has been indentified as 2-Isopropyl-3-(4-methoxy-benzyl)-6-methoxycarbonylmethyl-2-methyl-4-oxo-3,4-dihydro-2H-[1,3]oxazine-5-carboxylic acid methyl ester (~10 %). The imine intermediate can be isolated and stored if required.

Data
¹H NMR (250 MHz, CDCl₃) d 7.17 (2H, d, J = 8.8 Hz, CHCHCOCH₃), 6.76 (2H, d, J = 8.8 Hz, CH=COCH₃), 4.98 (1H, s, CHH=C), 4.64 (1H, s, CHH=C), 4.60 (2H, br s, CH₂N), 3.72 (3H, s, OCH₃), 3.67 (3H, s, OCH₃), 3.44 (2H, s, COCH₂CO), 2.39 (1H, sep, J = 6.7 Hz, CH(CH₃)₂), 1.04 (6H, d, J = 6.7 Hz, CH(CH₃)₂)

Lead Reference
D. T. Davies, N. Kapur, A. F. Parsons, Tetrahedron, 2000, 56, 3941

Other References

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