Ethyl 2,5-dimethyl-1-[p-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate

Ethyl 2,5-dimethyl-1-[p-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate 


HAS A TRIFLUORO GP


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 80^oC 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 p-(trifluoromethyl)aniline (1.62 mL, 12.9 mmol, 1.2 equiv.) and heated at 80^oC 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%).


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

mpt: 66-68^oC

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), Methyls on pyrrole ring
1.99 (s, 3H), Methyls on pyrrole ring
1.33-1.37 (t, 3H)  CH2CH3


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


NMR Spectra:

1H NMR.........http://malaria.ourexperiment.org/data/704.html

13C NMR..........http://malaria.ourexperiment.org/data/706.html

19F NMR........http://malaria.ourexperiment.org/data/708.html

WITHOUT THE FLUORO GP

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 80^oC 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 80^oC 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.

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

NOW WITH A METHYL

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: 60-63^oC
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