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20th November 2011 @ 07:05
Synthesis of ethyl 2,5-dimethyl-1-[p-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate from condensation of p-(trifluoromethyl)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 (LMW 7-1) (2 mL, 10.7 mmol, 1 equiv.) was added to p-(trifluoromethyl)aniline (1.62 mL, 12.9 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. Brown oil was dissolved in 20 mL EtOH and heated before filtering under heat to remove residual salts and washing with hot EtOH. Filtrate was concentrated under reduced pressure and purified by chromatography on silica (2-15% EtOAc in petrol). Pure fractions were taken and concentrated under reduced pressure to produce a light yellow oil. Product was cooled in a refrigerator overnight forming a pale yellow crystalline solid (1.85 g, 55%).

Collected data: ethyl 2,5-dimethyl-1-[p-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate

mpt: 66-68oC
m/z (APCI+): 312[M+H]+, 100%
1H-NMR (300 MHz, CDCl3): δ 7.77, 7.80 (d, 1H), 7.32, 7.35 (d, 1H),6.41 (s, 1H), 4.25-4.32 (qr, 2H), 2.30 (s, 3H), 1.99 (s, 3H), 1.33-1.37 (t, 3H)
13C-NMR (75 MHz, CDCl3): δ 165.5 140.98, 135.85, 131.00, 128.76, 128.47, 126.64, 126.59, 125.50, 121.89, 112.24, 108.24, 59.38, 14.52, 12.65, 12.35
19F-NMR (280 MHz, CDCl3): δ -62.65
IR: 770.27, 840.98, 1065.03, 119.55, 1215.36, 1322.48, 1413.83, 1613.74, 1681.96, 2928.23

For data files, refer to Synthesis of ethyl 2,5-dimethyl-1-[p-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate (LMW 9-1) and Synthesis of ethyl 2-acetyl-4-oxopentanoate intermediate. (LMW 7-1)

Compound known. No published data (11/11)
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