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19th September 2011 @ 07:29
A procedure for the synthesis of 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carbaldehyde by Vilsmeier-Haack formylation of 1-(4-Fluoro-phenyl)-2,5-dimethyl-1H-pyrrole.

Reaction Scheme PY14.png

DMF (5.0 mL) was stirred under a nitrogen atmosphere in an ice-bath. Phosphoryl chloride (1.18 mL, 12.7 mmol, 1.2 equiv.) was added and the reaction stirred for 25 minutes. Reaction still colourless. A solution of pyrrole PMY 1-6 (2.00 g, 10.5 mmol, 1 equiv.) in DMF (5 mL) was added dropwise over 5 minutes. The reaction was removed from the ice-bath and allowed to warm to room temperature. After 45 minutes, reaction was complete by TLC. Poured over ice (100 ml). pH adjusted to 6 (approx. 20% NaOH) and left stirring overnight. In the morning, pH was 3. 20% NaOH added until pH 11 and left for a further 30 minutes. The solid was filtered and washed with water. The solid was a wet beige paste. Recrystallised (MeCN/water) to obtain a first crop of tan free-flowing powder (2.05 g, 89%).

Data:
300 MHz

IR JCAMP-DX

IR spectra

m/z (APCI+) 218 [M+H]+, 100%.
mpt: 117-118 °C (MeCN/water)

Starting material synthesis:
Preparation 1-(4-Fluoro-phenyl)-2,5-dimethyl-1H-pyrrole

Original Experiment:
Scale up (11 mmol): Formylation of 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole (PMY 2-4)

References:

Gangjee, A.; Patel, J.; Kisliuk, R. L.; Gaumont, Y; J. Med. Chem., 1992, 35 (20), 3678–3685. doi:10.1021/jm00098a013

Manetti, F.; Magnani, M.; Castagnolo, D.; Passalacqua, L.; Botta, M.; Corelli, F.; Saddi, M.; Deidda, D; De Logu, A. ChemMedChem, 2006, 1, 973–989. doi: 10.1002/cmdc.200600026

Bill from Creative Chemistry.


Structural Information:
InChI=1S/C12H12FN/c1-9-3-4-10(2)14(9)12-7-5-11(13)6-8-12/h3-8H,1-2H3
gives: InChI=1S/C13H12FNO/c1-9-7-11(8-16)10(2)15(9)13-5-3-12(14)4-6-13/h3-8H,1-2H3
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7th September 2011 @ 01:35
A procedure for the Paal-Knorr synthesis of 1-(4-Fluoro-phenyl)-2,5-dimethyl-1H-pyrrole.

Reaction Scheme

4-fluoroaniline (10.4 mL, 110 mmol, 1.1 equiv.) and 2,5-hexanedione (11.7 mL, 100 mmol, 1 equiv.) were heated to 110 °C (oil bath temp.). After 15 hours, reaction was cooled to room temperature. The mixture was dissolved in hot EtOH (15 mL) and a mixture of EtOH (30 mL) and aqueous solution of 10% citric acid (15 mL). The reaction was slowly cooled to approx. 10 °C with periodic shaking. The resulting crystals were filted and washed with water (approx. 200 mL) to obtain the product as pale tan crystals (14.98 g, 79%) after drying under vacuum at room temperature. A further crop of brown crystals (1.89 g, 10%) could be obtained from mother liquor.

Data:
1H and 13C 300 MHz Data

mpt: 48-49 °C (EtOH/water)
m/z (APCI+) 190 [M+H]+, 100%.

References:

Manetti, F.; Magnani, M.; Castagnolo, D.; Passalacqua, L.; Botta, M.; Corelli, F.; Saddi, M.; Deidda, D; De Logu, A. ChemMedChem, 2006, 1, 973–989. doi: 10.1002/cmdc.200600026

Original Experiment:
Scale-up (100 mmol) of Paal-Knorr Synthesis of 1-aryl-2,5-dimethyl Pyrrole Core (PMY 1-6)

Structural Information
InChI=1S/C6H6FN/c7-5-1-3-6(8)4-2-5/h1-4H,8H2
and
InChI=1S/C6H10O2/c1-5(7)3-4-6(2)8/h3-4H2,1-2H3
gives: InChI=1S/C12H12FN/c1-9-3-4-10(2)14(9)12-7-5-11(13)6-8-12/h3-8H,1-2H3
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