Hexamethylenetetramine → Methyl 2-(difluoromethyl)-1,3-oxazole-4-carboxylate

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To a cooled (0° C.) suspension of copper(II) bromide (5.95 g, 26.6 mmol) in DCM (50 ml) was added hexamethylenetetramine (3.73 g, 26.6 mmol, Aldrich) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (4.0 ml, 26.8 mmol, Aldrich). After 20 min a solution of methyl 2-(difluoromethyl)-4,5-dihydrooxazole-4-carboxylate (1.59 g, 8.88 mmol) in DCM (5 mL) was added and the reaction mixture was allowed to warm to rt and stirred for 2 h. The mixture was filtered and the filtrate was concentrated to dryness. The residue was partitioned between EtOAc and 1:1 satd NH4Cl-conc NH4OH. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were washed consecutively with 1:1 satd NH4Cl-conc NH4OH (1×), 10% citric acid (1×), satd NaHCO3 (1×) and brine (1×). The organic layer was dried over MgSO4. The filtrate was purified by silica gel flash chromatography, eluting with 25% EtOH/EtOAc:hexanes (0:1→1:0) to give 708 mg (45%) of a white crystalline solid. MS m/z=178 [M+H]+. Calculated for C6H5F2NO3:177.

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