TCMDC_ArylPyrrole

Total yield: 3.34 g, 73% yield. Better yield on 2 g scale.

DMF (10.0 mL) was stirred under a nitrogen atmosphere in an ice-bath. Phosphoryl chloride (2.36 mL, 25.4 mmol, 1.2 equiv.) was added and the reaction stirred for 25 minutes. Reaction still colourless. A solution of pyrrole AEW 10-2 (4.00 g, 21.0 mmol, 1 equiv.) in DMF (10 mL) was added dropwise over 10 minutes. The reaction was removed from the ice-bath and allowed to warm to room temperature. 

After 1 h 20 mins, reaction was complete by TLC. Poured over ice (200 ml). pH adjusted to 9 (meant to be 6) (approx. 20% NaOH) and left stirring overnight. In the morning pH was 1. 20% NaOH added until pH 11 and the reaction mixture was left to stir for a further 40 minutes. The solid was filtered and washed with water to form a wet beige paste. Recrystallised from (MeCN/water) to give a free-flowing pale brown solid (2.36 g, 10.9 mmol, 52% yield). Second crop of crystals was still paste-like, they were dissolved in EtOAc and combined with the mother liquor. MeCN and EtOAc was removed under reduced pressure and the aqueous layer was extracted with EtOAC, washed with brine, dried (MgSO₄) filtered and evaporated to yield a brown solid (976 mg, 4.49 mmol, 21% yield). Both fractions = good by ¹H NMR. 

Data:

Original Experiment:
Scale up (11 mmol): Formylation of 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole (PMY 2-4)

Starting material synthesis:
Repeat Preparation of 1-(4-Fluoro-phenyl)-2,5-dimethyl-1H-pyrrole (AEW 1-1)

References:

1. Gangjee, A.; Patel, J.; Kisliuk, R. L.; Gaumont, Y; J. Med. Chem., 1992, 35 (20), 3678–3685. doi:10.1021/jm00098a013

• Manetti, F.; Magnani, M.; Castagnolo, D.; Passalacqua, L.; Botta, M.; Corelli, F.; Saddi, M.; Deidda, D; De Logu, A. ChemMedChem, 2006, 1, 973–989. doi: 10.1002/cmdc.200600026
  

InChI=1S/C12H12FN/c1-9-3-4-10(2)14(9)12-7-5-11(13)6-8-12/h3-8H,1-2H3
gave
InChI=1S/C13H12FNO/c1-9-7-11(8-16)10(2)15(9)13-5-3-12(14)4-6-13/h3-8H,1-2H3

Hazard and Risk Assessment: