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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.

LMW%209-1.png

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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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
LMW%208-1.png

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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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.
LMW%206-1withNaI.png

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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20th November 2011 @ 06:19
Vilsmeier-Haack Synthesis of 2,5-dimethyl-1H-(p-tolyl)-pyrrole-3-carboxaldehyde

Vilsmeier%20(methyl%20aniline%20derivati

DMF (1.5 mL, 19.4 mmol, 6.5 equiv.) was stirred under a nitrogen atmosphere in an ice-bath. Phosphoryl chloride (0.308 mL, 3.3 mmol, 1.1 equiv.) was added and the reaction stirred for 30 minutes. Reaction mixture was a very pale yellow. A solution of 2,5-dimethyl-1H-(p-tolyl)-pyrrole (556 mg, 3 mmols, 1 equiv.) in DMF (2 mL) was added dropwise over 1 minute. After 5 minutes, flask removed from ice and reaction stirred for a further 55 mins. TLC at 1 hr showed reaction at completion. Reaction mixture was then poured onto ice (50 mL) and 1M NaOH added (pH 11), until adjusted to pH 6. Total volume approximately 50 mL after ice has melted and solution was pH 3 the next day. 20% NaOH was added to achieve pH 11 and flask bathed in a brine ice-bath for 20 minutes. Product filtered and washed with water to produce a wet brown paste. Product was dissolved in MeCN and concentrated under a nitrogen atmosphere. Brown solution with precipitation of fine crystals was observed overnight. Solution was cooled in an ice bath and filtered. Filter cake washed with water (3 x 10 mL). Filtered product was then dried under vacuum to produce a lumpy grey-brown powder (423 mg, 71%).

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

mpt: 109-111oC
1H-NMR (300 MHz, CDCl3): δ 9.86 (s, 1H), 7.30, 7.33 (d, 2H), 7.06, 7.09 (d, 2H), 6.37 (s, 1H), 2.44 (s, 3H), 2.27 (s, 3H), 1.98 (s, 3H)
13C-NMR (75 MHz, CDCl3): δ 185.18, 138.98, 138.94, 134.30, 131.08, 130.18, 127.65, 121.82, 105.63, 21.19, 12.64, 11.19
m/z (ESI+/-): 214 [M+H]+, 100%
IR: 810.51, 1421.53, 1514.85, 1651.24, ~3934.95

For data files, refer to Vilsmeier Haack Synthesis of 2,5-dimethyl-1-(4-methylphenyl)-1H-pyrrole-3-carbaldehyde (LMW 5-1)

References:
doi: 10.1002/cmdc.200600026
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20th November 2011 @ 06:12
Vilsmeier Haack synthesis of 2,5-dimethyl-1H-phenyl pyrrole-3-carboxaldehyde.

Vilsmeier%20(aniline%20derivative)2.png

DMF (1.5 mL, 19.4 mmol, 6.5 equiv.) was stirred under a nitrogen atmosphere in an ice-bath. Phosphoryl chloride (0.308 mL, 3.3 mmol, 1.1 equiv.) was added and the reaction stirred for 30 minutes. Reaction mixture was a very pale yellow. A solution of 2,5-dimethyl-1H-phenyl-pyrrole (514 mg, 3 mmols, 1 equiv.) in DMF (2 mL) was added dropwise over 1 minute. After 5 minutes, the flask was removed from ice and reaction stirred for a further 55 mins. TLC at 1 hr showed reaction to be complete. Reaction mixture was poured onto ice (50 mL) and 1M NaOH added (pH 11), until adjusted to pH 6. Total volume approximately 50 mL after ice has melted and was pH 3 the next day. 20% NaOH was added to achieve pH 11 and flask bathed in a brine ice-bath for 20 minutes. Product was filtered and washed with water to produce a wet brown paste. Product was dissolved in MeCN and concentrated under a nitrogen atmosphere. Brown-green solution with slight precipitation was observed overnight. Product was then extracted using a mixture of EtOAc (2 × 20 mL), Et2O (20 mL), water (20 mL) and brine (20 mL). Product was concentrated under reduced pressure and cooled in refrigerator overnight to crystallise. Product was dissolved in EtOH (3 mL) in a water bath at 40°C. Solution was cooled in a brine ice bath and filtered. Filter cake was washed with water (3 × 10 mL) and product dried under vacuum to give a grey free-flowing powder (407 mg, 64%).

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

mpt: 88-90oC
1H-NMR (300 MHz, CDCl3): δ 9.88 (s, 1H), 7.55-7.50 (qn, 3H), 7.19, 7.22 (t, 2H), 6.39 (s, 1H), 2.28 (s, 3H), 1.99 (s, 3H)
13C-NMR (75 MHz, CDCl3): δ 185.29, 138.85, 136.99, 131.01, 129.58, 128.91, 127.97, 121.91, 105.84, 12.65, 11.22
m/z (ESI +/-): 200 [M+H]+, 100%
IR: 668.92, 703.93, 801.29, 1422.13, 1650.27

For data files, refer to Vilsmeier Haack Synthesis of 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carbaldehyde (LMW 4-1)

References:
doi: 10.1002/cmdc.200600026
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