4-(difluoromethyl)-2-oxa-3-azabicyclo[3.1.0]hex-3-ene

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a flame dried RBF was added a solution of n-butyllithium (2.5M in hexanes; 3.01 ml, 7.51 mmol) and diethyl ether (15 ml). The solution was cooled to −78° C., and 2-fluoro-6-iodotoluene (0.981 ml, 7.51 mmol) was added dropwise and the reaction was stirred at −78° C. for 10 minutes. A −78° C. premixed solution of 4-(difluoromethyl)-2-oxa-3-azabicyclo[3.1.0]hex-3-ene (1.00 g, 7.51 mmol) and boron trifluoride diethyl etherate (0.927 ml, 7.51 mmol) in toluene (10 ml) was added to the reaction via syringe. The reaction was stirred at −78° C. for 10 minutes, quenched with saturated ammonium chloride and warmed to RT. The reaction was diluted with water and EtOAc. The organic layer was separated and concentrated under reduced pressure. The crude residue was purified via silica gel flash chromatography eluting with 0-20% ethyl acetate in hexanes to afford 4-(difluoromethyl)-4-(3-fluoro-2-methylphenyl)-2-oxa-3-azabicyclo[3.1.0]hexane (0.81 g, 3.33 mmol, 44.3% yield). To a flame dried RBF was added to the reaction via syringe The reaction was stirred at −78° C. for 10 minutes quenched with saturated ammonium chloride warmed to RT The reaction was diluted with water and EtOAc The organic layer was separated concentrated under reduced pressure The crude residue was purified via silica gel flash chromatography eluting with 0-20% ethyl acetate in hexanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of potassium tert-butoxide (1.0 M in THF, 66.3 mL, 66.3 mmol) was added dropwise to a solution of 5-(chloromethyl)-3-(difluoromethyl)-4,5-dihydroisoxazole (16a rac, 9.0 g, 53.1 mmol) in THF (70 mL) at 0° C. The reaction mixture was stirred for 30 min, then aqueous saturated NH4Cl solution was added slowly. The mixture was extracted with Et2O (2×), and the combined organic extracts were dried over MgSO4. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-60% Et2O/pentane gradient) to give the title compound as an oil (5.29 g, 75% yield) The mixture was extracted with Et2O (2×) the combined organic extracts were dried over MgSO4 The filtrate was concentrated under reduced pressure The residue was purified by silica gel chromatography (0-60% Et2O/pentane gradient)