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Synlett 2010(8): 1273-1275  
DOI: 10.1055/s-0029-1219836
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Enamine-Based Domino Strategy for C-Acylation/Deacetylation of Acetoacetamides: A Practical Synthesis of β-Keto Amides

Plamen Angelov*
University of Plovdiv, Department of Organic Chemistry, 24 Tsar Asen Str., 4000 Plovdiv, Bulgaria
e-Mail: angelov@uni-plovdiv.bg;
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Publication History

Received 16 February 2010
Publication Date:
16 April 2010 (online)

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Abstract

A practical three-step route for C-acylation/deacetylation of acetoacetamides is described. Initial enamination of the acetoacetamides with Boc-monoprotected ethylenediamine provides β-enamino amides, which are acylated at the α-carbon with excellent selectivity. The C-acylated derivatives undergo domino fragmentation in acidic media to give the corresponding β-keto amides accompanied by 2-methyl-4,5-dihydro-1H-imidazole.

Key words

β-keto amide - enaminone - C-acylation - domino reaction - 1,3-dicarbonyl

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Preparation of β-Enamino Amides 2: The corresponding acetoacetamide 1 (5 mmol) was added to a solution of Boc-monoprotected ethylenediamine (5 mmol) in CH2Cl2 (20 mL) or MeOH (20 mL) for acetoacetamide 1h (1, R¹ = H) and the reaction mixture was stirred over anhyd Na2SO4 for 24 h at r.t. After that, the sulfate was filtered off and the solvent was removed by distillation. The residue was triturated with small amount of Et2O to give practically clean β-enamino amide in nearly quantitative yield (93-98%). Compound 2a (2, R¹ = Ph) has moderate solubility in CH2Cl2 and crystallizes out of the reaction mixture, so special care must be taken to wash it thoroughly off the drying agent. The β-enamino amides 2 are air-stable and can be stored safely at r.t., but they easily decompose on silica gel.

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Preparation of α-Acyl-β-enamino Amides 3; General Procedure: The corresponding acid chloride (1 mmol) was slowly added to a magnetically stirred solution of enamino amide 2 (1 mmol), DMAP (0.2 mmol, 25 mg) and Et3N (1 mmol, 0.14 mL) in CH2Cl2 (20 mL). The reaction mixture was stirred for 1 h at r.t. and after that was transferred to a separating funnel with additional 20 mL of CH2Cl2, where it was washed with 5% aq solution of AcOH (15 mL) and then with sat. aq NaHCO3 (15 mL). The organic phase was dried over Na2SO4 and the solvent was distilled off. The residue crystallized upon trituration with Et2O or Et2O-PE (1:1) to give the corresponding product 3 in 50-90% yield. Additional 10-30% were isolated from the ethereal washings after column chromatography on silica gel with Et2O as the eluent [increasing polarity to Et2O-MeOH (10:1) for products 3 with R¹ = H].

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Preparation of β-Keto Amides 6; General Procedure: The corresponding intermediate 3 (200 mg) was dissolved in TFA (2 mL), the solution was stirred for 40 min at r.t. and the reaction was quenched with aq solution of MeCOONa (3 mol/L, 20 mL). The resulting mixture was stirred for 20 min at r.t. and then extracted with CH2Cl2 [3 × 20 mL (5 × 20 mL for 6h and 10 × 20 mL for 6c and 6i)]. In the case of 6i the aqueous phase was saturated with NaCl prior to extraction. The combined organic layers were washed with sat. aq NaHCO3 (15 mL) and dried over Na2SO4. The solvent was distilled off to afford practically clean β-keto amides. In some cases enol tautomer was registered immediately after isolation, but it gradually converted to the keto form.

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All reactions were carried out in untreated CH2Cl2 and open to air.