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13th November 2012 @ 22:32

Ethyl acetoacetate (8.2 mL, 62.8 mmol, 1 equiv.), K2CO3 (11.4 g, 82.4 mmol, 1.3 equiv.) and sodium iodide (10.3 g, 68.9 mmol, 1.1 equiv.) were dissolved in acetonitrile (120 mL) and cooled in ice water. A yellow colour was observed in the mixture. Chloroacetone (6.4 mL, 79.9 mmol, 1.3 equiv.) was added dropwise and the reaction mixture stirred for 5 minutes prior to heating to reflux. Followed by TLC - after four hours reaction had reached completion and was left to reach room temperature and concentrated under reduced pressure to leave an orange liquid. The liquid was dissolved in ethyl acetate (~90 mL) and washed with water (2 x 20 mL) and brine (20 mL). The organic layer containing the intermediate was concentrated under reduced pressure to a brown liquid and 4-fluoroaniline (8.2 mL, 63.8 mmol, ~0.6 equiv.) was added. This mixture was heated to 90 °C, after 3.5 hours reaction was complete. The black reaction mixture was cooled, dissolved in EtOAc (40mL) and washed with water (3 × 20 mL) and brine (20 mL), dried over MgSO4, filtered and evaporated to give a crude brown solid containing dark brown crystals (14.2 g, ~54 mmol, ~87%)

Overall CRUDE Yield: (14.2 g, ~54 mmol, ~87% yield)

TLC (1:1, EtOAc/Hexane, Vanillin:
Formation of ethyl 2-acetyl-4-oxopentanoate intermediate
AEW 7-2, intermediate, vanillin.jpg
AEW 7-2, intermediate, UV.jpg

TLC (1:3, EtOAc/Hexane, UV:
AEW 7-2, FP.jpg

Risk and Hazard Assessment:
Risk Assessment

Previous Synthesis:
Synthesis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (AEW 7-1)
Upscaled Synthesis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (JRC 1-1)
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Attached Files
AEW 7-2, intermediate, UV.jpg
AEW 7-2, intermediate, vanillin.jpg
AEW 7-2, FP.jpg