Benzene → 2,3-difluoro-6-nitro-{[(R)-2-(tetrahydropyran-2-yl)oxypropyl]oxy}benzene

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Reaction Steps

To an ice-cooled suspension of 720 mg of sodium hydride (60%) in 12 ml of anhydrous toluene was added dropwise a solution of 2.88 g of 2-O-tetrahydropyranyl-(R)-propane-1,2-diol (IIIR, Rc=THP) in 12 ml of anhydrous toluene, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 10 minutes. The mixture was added dropwise to a solution of 2.66 g of 2,3,4-trifluoronitrobenzene in 12 ml of anhydrous toluene with stirring under cooling with ice. The mixture was stirred at an external temperature of 5° C. for 24 hours. To the mixture were added ice-water and benzene, and the resulting mixture was shaken. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to yield 2,3-difluoro-6-nitro-{[(R)-2-(tetrahydropyran-2-yl)oxypropyl]oxy}benzene (IR, Xa=Xb=F, Rc=THP) in quantitative yield. This compound was dissolved in 38 ml of anhydrous ethanol and to this was added 450 mg of pyridinium tosylate. The mixture was heated under refluxing for 1 hour. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate. This solution was washed successively with 1 N hydrochloric acid, a 5% sodium bicarbonate aqueous solution and water, then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield 3.20 g of the oily titled compound.

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