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19th September 2012 @ 01:11

Experiment start time: ~11:00am, 19/9/2012.
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 4 h TLC showed trace amounts of starting material remaining. The black reaction mixture was cooled, dissolved in EtOAc (~40mL) and washed with water (3 x 20 mL) and brine (20 mL). The black oil was recrystallised from ethanol and water and left in the freezer overnight prior to filtration which gave a gold/beige solid (6.3 g). Mother liquors were concentrated in vacuo and found to contain impure product. A second recrystallisation was performed from aqueous ethanol and water. The mixture was left in the freezer for 4 days and then filtered and evaporated to give a second crop of beige/gold powder (3.6 g). Mother liquors still contain product but no further crystallisation was attempted.

Overall Yield: (9.9 g, 37.9 mmol, 60% yield)
N.B. Not necessary to purify prior to reduction so yield should be greater if repeated and used as crude in the hydrolysis step.

Risk and Hazard Assessmen:t
Risk Assessment

Previous Synthesis:
Upscaled Synthesis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (JRC 1-1)
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