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18th December 2012 @ 17:01

Reaction Scheme

4-fluoroaniline (5.2 mL, 55 mmol, 1.1 equiv.) and 2,5-hexanedione (5.85 mL, 50 mmol, 1 equiv.) were heated to 110 °C (oil bath temp.) for 19 hours. The reaction mixture was cooled and dissolved in hot EtOH (25 mL) and aqueous citric acid (10% w/v, 7.5ml). The solution was slowly cooled with occasional shaking to 10°C, whereupon tan and dark precipitates formed. The solution was filtered and washed with cold EtOH (10 mL) and water (200 mL), whereupon further tan precipitate formed in the filter flask. This filtrate was re-filtered, and the combined precipitates were washed with water (200 mL) to give a tacky brown solid (11.14 g, >99% yield, NMR PT-1-1-A). The solid was dissolved in DCM (100 mL) and washed with aqueous citric acid (5% w/v, 100 mL) dried over magnesium sulfate, then filtered and concentrated in vacuoto give a brown solid (8.571 g, 90.5% yield, NMR PT-1-1-B).

DataData in agreement with Paul Ylioja's and Alice Williamson's original reactions (see below for links)

PT-1-1-A.pdf
PT-1-1-B.pdf

References:

 

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11th December 2012 @ 23:35
AEW%2029-1.png

Ethyl acetoacetate (19.4 mL, 15.4 mmol, 1 equiv) was diluted in water (20 mL) and cooled to 0 ˚C with stirring. Aqueous ammonia (28%, 15.4 mL, 18.5 mmol, 1.2 equiv.) was added and the reaction mixture stirred for 5 mins at 0 ˚C, prior to the dropwise addition of chloroacetone (12.8 mL, 15.4 mmol, 1 equiv.) and the pale yellow solution stirred at 0 ˚C. The reaction mixture was stirred for 3 hours at rt and the white precipitate formed was filtered and washed with water to provide the desired product, 6.7 g. The filtrate (a red solution) was then left to stir at rt overnight and the resulting precipitate filtered and washed to give a red sludge containing a few crystals. The sludge was washed into the aqueous layers with DCM and then extracted (DCM x 3). Separating funnel broke and product lost to fumehood floor. Very unpleasant smelling compound so the mess was cleared up and no attempt was made to recover the product.
11th December 2012 @ 03:32
AEW%2028-2.png

AEW 3-5 (crude recovered from AEW 28-1, 173 mg) was dissolved in DMF (5 mL) at 0˚C and NaH (60% dispersed in mineral oil, 44 mg, 1.1 mmol, 1.2 equiv.) was added and the reaction mixture stirred at 0 ˚C for 30 minutes. Bromoacetonitrile (73 microlitres, 1.1 mmol, 1.2 equiv.) was added at 0 ˚C and the reaction mixture stirred for 5 minutes prior to the removal of the ice bath. After 2 hours, no reaction observed. After 5 hours, the reaction mixture turned black suggesting decomposition.

Hazard and Risk Assessment:
See: Synthesis of 2-((1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methoxy)acetonitrile (AEW 28-1). But with use of DMF instead of MeCN. DMF: Flammable, harmful by inhalation and in contact with skin, irritating to eyes and may cause harm to the unborn child. Risk Cat: 2, HU, Sl.
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11th December 2012 @ 02:35
AEW%2030-1.png

AEW 29-1 was dissolved in EtOH (1 mL) and 20% NaOH (0.5 mL) was added. The reaction mixture was stirred at room temperature overnight and no reaction occurred.Reaction mixture cooled in ice bath then acidified (pH 1) with 2M HCl and then cooled in an ice bath for 30 minutes. To be repeated at reflux on larger scale.

Risk and Hazard Assessment:
As for Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (PMY 8-1) but with different starting material, commercial but no MSDS found: Assume toxic, risk class 2, HU and Sl.
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10th December 2012 @ 03:38
AEW%2029-1.png

Ethyl acetoacetate (1.94 mL, 15.4 mmol, 1 equiv) was diluted in water (2 mL) and cooled to 0 ˚C with stirring. Aqueous ammonia (28%, 1.54 mL, 18.5 mmol, 1.2 equiv.) was added and the reaction mixture stirred for 5 mins at 0 ˚C, prior to the dropwise addition of chloroacetone (1.28 mL, 15.4 mmol, 1 equiv.) and the pale yellow solution stirred at 0 ˚C. The reaction mixture turned darker in hue and a white ppt crashed out. Stirred for 3 hours at 0 ˚C and 30 minutes whilst warming to room temperature. The white precipitate was filtered from the blood red reaction mixture and washed with water prior to drying at the high vac. The aqueous layer was then extracted with DCM, dried over MgSO4, filtered and evaporated to give a green/yellow oil.
1H NMR showed white solid (600 mg, 3.59 mmol, 23% yield) to be the desired product. Oil contained starting materials and impure product but no further purification was conducted:may be combined with residue from scale-up.

1H NMR:

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