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24th October 2012 @ 05:07
Cyclodehydration of serine methyl ester coupled pyrazole core MJT5-1 using XtalFluor-E in 1,2-DCE and subsequent oxidation to oxazole using bromotrichloromethane and DBU.

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Reaction Start time 1040 25/10/2012
MJT6-1 (442 mg, 1.37 mmol, 1 equiv.) was stirred in 1,2-dichloroethane (20 mL) giving a colourless solution. XtalFluor-E (640 mg, 2.8 mmol, 2 equiv.) was added and the mixture heated to reflux at 90°C under a nitrogen atmosphere.

After 40 minutes TLC showed consumption of SM and formation of a new product of higher Rf than SM. The reaction is now a dark brown solution, it was allowed to cool to room temperature before adding a solution of Na2CO3 (1:1 saturated soln/water, approx 30 mL). The reaction was stirred for 10 minutes and then separated.
The aqueous layer was washed with DCM (3 x 20 mL) and the combined organic extracts washed with brine (approx 20 mL) before drying over anhydrous MgSO4 and concentration to give the intermediate ( 0.4655g, 1.53 mmol, 112% of theory yield) as a viscous dark brown oil.
TLC of worked up product again showed only one spot. NMR analysis is consistent with expected product but with solvent peak at 3.731 ppm (1,2-DCE) and at 7.26 ppm (DCM). ca 50 mg of intermediate is retained for characterisation.

1555 25-10-2012
Intermediate (0.4013 g, 1.32 mmol, 1 equiv.) is dissolved in DCM (15 mL) to give a brown solution. Bromotrichloromethane (0.39 mL, 3.96 mmol, 3 equiv.) and DBU (0.59 mL, 3.96 mmol, 3 equiv.) are added and the reaction stirred under a nitrogen atmosphere. After 45 minutes, TLC showed consumption of starting materials and formation of a product with a higher Rf value than SM as well as another product of much lower Rf. The reaction is left in the freezer overnight.

1400 26-10-2012
The reaction mixture is concentrated to a viscous dark brown oil (ca. 1.5 g, 375 % theory yield - excess caused by residual BrCCl3 and DBU). Column chromatography (acetone / hexane, 5%; 10%) is used to isolate MJT6-1 as a white solid (ca. 0.4 g, '101%'), NMR consistent with expected structure but with some contaminant signals. This columned product is left in the freezer over the weekend.

Both product and intermediate are novel compounds

TLC (10% MeOH / DCM) with UV visualisation followed by UV staining

TLC cyclisation step
TLC oxidation step


Hazard assessment form
updated hirac


References

M. Pouliot, L. Angers, J. Hamel & J. Paquin, Synthesis of 2-oxazolines and related N-containing heterocycles using [Et2NSF2]BF4 as a cyclodehydration agent. Tetrahedron letters. 53 (2012), 4121-4123.

Cyclodehydration of carboxamide PMY 67-1 (PMY 58-3)

EDC Couplng of pyrazole carboxylic acid MJT 3-2 with serine methyl ester (MJT 5-1)
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Attached Files
HIRAC
MJT 6-1 scheme
updated hirac
TLC cyclisation step
TLC oxidation step
Comments
Re: Cyclodehydration of coupled pyrazole core MJT5-1 and subsequent oxidation to oxazole (MJT 6-1) by Paul Ylioja
24th October 2012 @ 05:15
HIRAC approved. Requirement for ammonia gas cylinder shown on hirac is an error.