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20th September 2011 @ 00:34
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.

Reaction Scheme

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:
TLC 30 min and 1.5 hours
TLC 20 hours of reflux
TLC stage 2, 2 hours


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

NMR:
1H NMR
13C NMR

1H, 13C NMR after recryst

1H intermediate diketoester
1H, 13C, 19F before recryst


IR:
IR spectra
IR JCAMP-DX


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


Risk and Hazard Assessement:
Risk assessment
Linked Posts
Attached Files
Risk assessment
Reaction Scheme
TLC 30 min and 1.5 hours
TLC 20 hours of reflux
TLC stage 2, 2 hours
1H, 13C, 19F before recryst
1H intermediate diketoester
13C NMR
1H NMR
1H, 13C NMR after recryst
IR spectra
IR JCAMP-DX