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20th November 2011 @ 06:28
Synthesis of ethyl 2,5-dimethyl-1-(p-tolyl)-1H-pyrrole-3-carboxylate from condensation of p-toluidine with ethyl 2-acetyl-4-oxopentanoate.


Ethyl acetoacetate (2 mL, 15.7mmol, 1 equiv.) and K2CO3 (2.82 g, 20.4 mmol, 1.3 equiv.) in MeCN (30 mL) were mixed. Chloroacetone (1.6 mL, 17.2 mmol, 1.1 equiv.) and NaI (2.7 g, 18 mmol, 1.15 equiv.) were added and heated in an oil bath at 80°C. TLC showed reaction at completion after 2.5 hrs. After 3 hrs reflux, solution was allowed to cool to room temperature and then filtered and washed with EtOAc (30 mL). Mixture was concentrated under reduced pressure, dissolved in EtOAc (40 mL) and washed with water (20 mL), 1:1 water:brine (20 mL) and brine (20 mL). Crude product was then concentrated under reduced pressure. p-toluidine (2.02 g, 18.8 mmol, 1.2 equiv.) was added to crude intermediate and heated in an oil bath at 90°C. At 1.5 hrs, reaction was complete by TLC and reaction was allowed to cool to room temperature. Dark brown product was washed with EtOAc (2 x 20 mL), 10% citric acid (3 x 20 mL), water (2 x 20 mL) and brine (20 mL) and then concentrated under reduced pressure to form a black oil. Product was dissolved in EtOH and activated charcoal added to remove coloured impurities. Product was stirred for 1 hr then filtered and washed with EtOH. Filtrate was concentrated under reduced pressure to form a black oil. Oil was purified by chromatography on silica (2-10% EtOAc in petrol). Pure and impure fractions were taken separately and concentrated under reduced pressure to produce yellow and dark yellow oils respectively. Pure fraction crystallised overnight to a bright yellow crystalline solid (1.8 g, 45.6%).

Collected data: ethyl 2,5-dimethyl-1-(p-tolyl)-1H-pyrrole-3-carboxylate

mpt: 60-63oC
m/z (APCI+): 258 [M+H]+, 100%
1H-NMR (300 MHz, CDCl3): δ 7.29, 7.26 (d, 2H), 7.03, 7.06 (d, 2H), 6.36 (s, 1H), 4.24-4.31 (qr, 2H), 2.42 (s, 3H), 2.28 (s, 3H), 1.96 (s, 3H), 1.32-1.36 (t, 3H)
13C-NMR (75 MHz, CDCl3): δ 165.75, 138.46, 136.28, 135.12, 129.99, 128.78, 127.88, 111.31, 107.36, 59.17, 21.15, 14.59, 12.63, 12.36
IR: 767.43, 1080.99, 1218.07, 1411.09, 1515.22, 1693.11, 2982.09

For data files, refer to Synthesis of ethyl 2,5-dimethyl-1-(p-tolyl)-1H-pyrrole-3-carboxylate (LMW 6-1)

Compound known. No published data (11/11)
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