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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. [b]Reaction Start time 1040 25/10/2012[/b] 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 R[size=8]f[/size] than SM. The reaction is now a dark brown solution, it was allowed to cool to room temperature before adding a solution of Na[size=8]2[/size]CO[size=8]3[/size] (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 MgSO[size=8]4[/size] 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. [b]1555 25-10-2012[/b] 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 R[size=8]f[/size] value than SM as well as another product of much lower R[size=8]f[/size]. The reaction is left in the freezer overnight. [b]1400 26-10-2012[/b] The reaction mixture is concentrated to a viscous dark brown oil (ca. 1.5 g, 375 % theory yield - excess caused by residual BrCCl[size=8]3[/size] 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. [i]Both product and intermediate are novel compounds[/i] [b]TLC (10% MeOH / DCM) with UV visualisation followed by UV staining[/b] [data]3622[/data][data]3624[/data] [b]Hazard assessment form[/b] [data]3596[/data] [b]References[/b] M. Pouliot, L. Angers, J. Hamel & J. Paquin, [i]Synthesis of 2-oxazolines and related N-containing heterocycles using [Et[size=8]2[/size]NSF[size=8]2[/size]]BF[size=8]4[/size] as a cyclodehydration agent[/i]. Tetrahedron letters. [b]53[/b] (2012), 4121-4123. [blog]4991[/blog] [blog]5019[/blog]
Attached Files
MJT 6-1 scheme
updated hirac
TLC cyclisation step
TLC oxidation step
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.