Triethylamine → [(1-Bromonaphthalene-2-yl)-hydroxymethyl]phosphonic acid diethyl ester

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To a solution of 1-bromo-2-naphthaldehyde (0.740 g, 0.001 mole) in tetrahydrofuran (10 mL) was added triethylamine (0.150 mL, 0.001 mole) followed by diethylphosphite (0.330 mL, 0.002 mole). The reaction mixture was then stirred at room temperature under nitrogen gas for 18 hours. The volatiles then evaporated in vacuo and further dried under vacuum. The resulting solid was triturated with ether and the solid that separated out was collected and dried under vacuum to get 0.935 g of [(1-bromonaphthalene-2-yl)-hydroxymethyl]phosphonic acid diethyl ester B. This material was added to 40 mL of acetone. 20 eq. of manganese dioxide (4.31 g, 0.05 moles) was added and the mixture was stirred at room temperature for one hour. Another 20 eq. of manganese dioxide was added to it and it was stirred for another one hour. The solid manganese dioxide was filtered off on a Celite® pad and washed with hot acetone. Combined filtrates were evaporated to afford 0.6 g of crude (1-bromo-naphthalene-2-carbony)phosphonic acid diethyl ester. Flash chromatography on silica gel using 0-5% ethyl acetate/dichloromethane followed by drying of the product under high vacuum afforded 0.260 g of intermediate. C. To a solution of diethyl (1-bromonaphthalene-2-carbony)phosphonate ester in dichloromethane (2 mL) was added (diethylamino)sulfur trifluoride (1.3 mL, 0.01 mole) at 0° C. and it was allowed to come to room temperature then stirred for another 4 hours. The reaction mixture then was diluted with dichloromethane (50 mL) and washed with cold saturated aqueous sodium bicarbonate (NaHCO3, 25 mL), then dried over magnesium sulfate (MgSO4). Filtration and solvent evaporation provided 0.260 g of product. Flash chromatography on silica gel using 0-5% EtOAc/dichloromethane followed by drying of the product under high vacuum afforded 0.120 g of diethyl [(1-bromo-naphthalene-2-yl)difluoromethylphosphonate ester. Compound 80 was prepared from this corresponding diethyl ester using procedures similar to those of Example 40. 1H NMR: (DMSO-d6, 400 MHz) δ 8.52 (d, 1H, J=8.4 Hz) 8.11 (m, 2H), 7.79 (m, 3H). MS (ion spray): m/z 337.00 (M+H)

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