TCMDC_ArylPyrrole

 

Product obtained in 61% yield.

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Synthesis of ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate from condensation of 4-fluoroaniline with ethyl 2-acetyl-4-oxopentanoate.



Experiment start time: 11.00 EST 20/09/11
Ethyl acetoacetate (2.00 mL, 15.7 mmol, 1 equiv.) and K₂CO₃ (2.82 g, 20.4 mmol, 1.3 equiv.) in acetonitrile (30 mL) were cooled ice/brine. Chloroacetone (1.39, 17.2 mmol, 1.1 equiv.) was added dropwise. After stirring for 15 minutes, reaction was allowed to warm to room temperature. After 15 minutes, no reaction by TLC. Sodium iodide (2.58 g, 17.2 mmol, 1.1 equiv.) was added. After stirring for 1.5 hours, reaction is now a pale yellow suspension. TLC shows some products and SM. Heated to reflux. After 20 hours at reflux, reaction was allowed to cool and then filtered. The filtrate was concentrated under reduced pressure and then dissolved in EtOAc (40 mL). Washed with water (2 × 20 mL), 1:1 brine/water (20 mL) to break emulsion, brine and dried (MgSO₄ then concentrated to brown oil (3.41 g). Azeotrope with Et₂O, brown oil (2.95 g). ¹H NMR consistant with product¹ which was used without further purification.

4-fluoroaniline (1.78 mL, 18.8 mmol, 1.2 equiv.) was added and the reaction heated to 90 °C. After 2 hours, reaction complete by TLC. Reaction cooled. Black oil with colouless liquid (water). Dissolved in EtOAc (30 mL) and washed with 10% citric acid (3 × 15 mL), water (3 × 15 mL) and brine then dried (MgSO₄) and concentrated under reduced pressure (3.70 g). Recrystallised from EtOH/water; Dissolved in warm EtOH (4 mL) and cooled in ice until crystallisation initiated, then 40% EtOH (16 mL) added slowly with stirring. Cooled in ice for 30 minutes to complete crystallisation and filtered. Red/brown crystals washed with 20% EtOH and dried under vacuum (2.77 g, 61% over 2 steps).

TLC (25% EtOAc/petrol) visualised with UV and vanillin:


Mass Spectrometry:
m/z (ESI+) 262 [M+H]^-, 100%.

NMR:




IR:


References:

1. doi: 10.1021/jo00391a003
   
2. doi: 10.1016/S0040-4020(01)81514-3
   

Risk and Hazard Assessement: