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20th November 2011 @ 06:41
Synthesis of ethyl 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate from condensation of aniline with ethyl 2-acetyl-4-oxopentanoate


Ethyl acetoacetate (6 mL,47 mmol, 1 equiv.) and K2CO3 (8.45 g, 61.1 mmol, 1.3 equiv.) were mixed in MeCN (55 mL). NaI (7.05 g, 47 mmol, 1 equiv.) and Chloroacetone (4.8 mL, 51.7 mmol, 1.1 equiv.) were added and mixture heated to 80oC in an oil bath. TLC at 2 hours showed reaction at completion. Reaction was allowed to cool to room temperature. Mixture washed with EtOAc (2 x 20 mL), water (2 x 20 mL), 1:1 water:brine (2 x 20 mL) and brine (2 x 20 mL) and dried with MgSO4 and concentrated under reduced pressure to form a yellow oil. Ethyl 2-acetyl-4-oxopentanoate intermediate (2 mL, 10.7 mmol, 1 equiv.) was added to Aniline (1.17 mL, 12.89 mmol, 1.2 equiv.) and heated at 80oC in an oil bath for 1.25 hrs. TLC at 1 hour showed reaction at completion and reaction was allowed to cool to room temperature. Product was washed with EtOAc (2 x 20 mL), 10% citric acid (3 x 20 mL), water (20 mL) and brine (2 x 20 mL) and then concentrated under reduced pressure to form a dark brown oil. Product was purified by chromatography on silica (2-15% EtOAc in petrol – suggest a lower % EtOAc). Product containing fractions concentrated under reduce pressure to produce a yellow oil (952 mg, approximate yield 37%). Product did not crystallise.

Collected data: ethyl 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate

mpt: n/a
m/z (APCI+): 244 [M+H]+, 100%
1H-NMR (300 MHz, CDCl3): δ 7.41-7.50 (qn, 2H), 7.15, 7.18 (m, 2H), 6.38 (s, 1H), 4.20-4.32 (sx, 2H), 2.29 (s, 3H), 1.97 (s, 3H), 1.27-1.36 (qn, 3H)
13C-NMR (75 MHz, CDCl3): δ 165.72, 137.76, 136.16, 129.39, 129.19, 128.93, 128.68, 128.53, 128.18, 111.49, 107.55, 59.21, 14.59, 12.64, 12.37
IR: 696.57, 770.6, 1072.8, 121.34, 1411.26, 1693.25, 2978.29

For data files, refer to Synthesis of ethyl 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate (LMW 8-1) and Synthesis of ethyl 2-acetyl-4-oxopentanoate intermediate. (LMW 7-1)

References:
doi: 10.1016/0040-4020(80)80102-5
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