CDRI Synthesis of TCMDC Aryl Pyrrole Analogues

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

Reaction time- 12-01-12:05 (IST) Experimental Procedure: To a 100 mL round bottom flask was added ethyl acetoacetate (2 mL, 15.7 mmol, 1 equiv) and K₂CO₃ (2.82 g, 20.4 mmol, 1.3 equiv) in MeCN (40 mL) under stirring. Subsequently chloroacetone (1.6 mL, 17.2 mmol, 1.1 equiv) and NaI (2.7 g, 18 mmol, 1.15 equiv) were added and the mixture was heated under stirring in an oil bath at 80 ^oC. TLC analysis at 2.5 h interval showed the presence of the starting material therefore the reaction was continued further. At 3 h interval the TLC analysis indicated completion of the reaction. The reaction mixture was filtered and washed with EtOAc (40 mL). The filtrate was concentrated under reduced pressure, dissolved in EtOAc (50 mL) and washed with brine (20 mL) and water (20 mL). Then organic layer was dried (Na₂SO₄) and concentrated under pressure over rotary evaporator. The yield of crude product was 3.60 g. Then intermediate (2.05 g, 11 mmol, 1 equiv.) and 3-fluoroaniline (1.26 mL, 13 mmol,1.2 equiv) was mixed and heated in an oil bath at 90 ^oC. After 2 h TLC analysis indicated incomplete reaction. After another 1 h, the TLC showed that the reaction was complete. The reaction mixture was allowed to cool to room temperature. A reaction mixture was observed to be a blackish yellow oil. The mixture was extracted with EtOAc ( 2× 25 ml) and the organic layer was washed with 10% citric acid (20 mL), water: brine (1:1) (2×20 mL). The collected organic layer was dried (Na₂SO₄) and concentrated under reduced pressure resulting in a dark yellow oil. The oil was purified via coloum chromatography on silica gel (60-120 mesh) using EtOAc/ hexane (3:97 to 5:95 v/v) as the eluent. The pure fractions were combined and evaporated under reduced pressure to afford the pure product as yellow oil (1.71 g, 50%).

TLC of SBBH-1-1(20% ethyl acetate in hexane) visualised using UV and I₂:

TLC of SBBH-1-3 (20% ethyl acetate in hexane) visualised using UV and vanillin:

TLC of SBBH-1-3 after column chromatography(20% ethyl acetate in hexane) visualised using UV and vanillin:

¹H NMR:

¹³C NMR: