1-(diethoxyphosphorylmethyl)-3-fluorobenzene

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-fluorobenzyl bromide (2 g) and triethyl phosphite (2.2 mL) was heated at 160° C. under nitrogen for 4 hours. After cooling, the were volatiles removed in vacuo and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give diethyl (3-fluorobenzyl)phosphonate (2.46 g) After cooling the were volatiles removed in vacuo the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100%

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

Procedure: Sodium hydride (0.245 g) was added portionwise to a solution of diethyl (3-fluorobenzyl)phosphonate (Intermediate 182, 1 g) in THF (40 mL) at 0° C. The mixture was stirred for 30 minutes then benzyl 4-oxopiperidine-1-carboxylate (0.947 g) was added at 0° C. The mixture was allowed to warm to room temperature and stirred for 21.5 hours. The mixture was partitioned between water and ethyl acetate and the organic layer was washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give benzyl 4-(3-fluorobenzylidene)piperidine-1-carboxylate (1.05 g) stirred for 21.5 hours The mixture was partitioned between water and ethyl acetate the organic layer was washed with brine dried (Na2SO4) filtered The filtrate was evaporated to dryness the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25%

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

Procedure: Prepared according to the method used to prepare diethyl 3-fluorobenzylphosphonate starting with 1-(bromomethyl)-2-fluorobenzene. 1H NMR (CDCl3) δ: 7.36 (t, J=7.5 Hz, 1H), 7.19-7.25 (m, 1H), 7.07-7.13 (m, 1H), 7.04 (t, J=9.2 Hz, 1H), 3.99-4.08 (m, 4H), 3.15-3.24 (m, 2H), 1.25 (td, J=7.0, 0.9 Hz, 6H). Prepared

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

Procedure: Prepared according to the same procedure as (4R,5R)-4-(2-bromopyridin-4-yl)-5-phenyloxazolidin-2-one, starting with diethyl 3-fluorobenzylphosphonate and 5-bromonicotinaldehyde. 1H-NMR (CDCl3, 500 MHz) δ 8.72 (d, J=2.1, 1H), 8.41 (d, J=1.8, 1H), 7.94 (dd, J=2.1, 1.8, 1H), 7.42 (ddd, J=7.9, 7.9, 5.8, 1H), 7.14 (ddd, J=8.6, 8.6, 2.4, 1H), 7.01-7.10 (m, 2H), 6.78 (bs, 1H), 5.27 (d, J=7.3, 1H), 4.81 (d, J=7.3, 1H). 13C-NMR (CDCl3, 126 MHz) δ 163.2 (d, J=249), 158.5, 152.0, 146.4, 138.5 (d, J=6.7), 136.7, 135.7, 131.1 (d, J=8.6), 121.6 (d, J=17), 116.8 (d, J=21), 113.0 (d, J=22), 84.8, 62.2. Mass spec.: 337.06 (MH)+. Prepared

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with 1-(bromomethyl)-3-fluorobenzene (7.5 mL, 61.1 mmol) and treated with triethylphosphite (21.39 mL, 122 mmol) dropwise with stirring. Upon completion of the addition, the reaction was fitted with a reflux condensor (no cooling) and a slow stream of nitrogen was passed over the reaction mixture. The reaction was slowly warmed to 150° C. and held there for 2 h. The reaction was cooled to room temperature and concentrated under high vacuum to remove most of the excess triethylphosphite. The resulting residue was purified by column chromatography (50%-->100% EtOAc/Hex) to give 15.13 g (quant.) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.29 (m, 1H), 7.10 (m, 1H), 7.05 (m, 1H), 6.97 (m, 1H), 4.06 (m, 4H), 3.16 (d, J=21.7, 2H), 1.28 (t, J=7.0, 6H). 13C-NMR (CDCl3, 126 MHz) δ 162.85 (dd, J=246, 3.8), 134.2 (t, J=8.6), 130.0 (dd, J=7.7, 2.9), 125.6 (dd, J=6.7, 2.9), 116.9 (dd, J=22, 6.7, 114.0 (dd, J=21, 2.9), 62.3 (d, J=6.7), 33.7 (dd, J=138, 1.9, 16.5 (d, J=5.8). Upon completion of the addition the reaction was fitted with a reflux condensor (no cooling) and a slow stream of nitrogen The reaction was cooled to room temperature concentrated under high vacuum to remove most of the excess triethylphosphite The resulting residue was purified by column chromatography (50%-->100% EtOAc/Hex) to give 15.13 g (quant.) as a colorless oil

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with 1-(bromomethyl)-3-fluorobenzene (7.5 mL, 61.1 mmol) and treated with triethylphosphite (21.39 mL, 122 mmol) dropwise with stirring. Upon completion of the addition, the reaction was fitted with a reflux condensor (no cooling) and a slow stream of nitrogen was passed over the reaction mixture. The reaction was slowly warmed to 150° C. and held there for 2 h. The reaction was cooled to room temperature and concentrated under high vacuum to remove most of the excess triethylphosphite. The resulting residue was purified by column chromatography (50%-->100% EtOAc/Hex) to give 15.13 g (quant.) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.29 (m, 1H), 7.10 (m, 1H), 7.05 (m, 1H), 6.97 (m, 1H), 4.06 (m, 4H), 3.16 (d, J=21.7, 2H), 1.28 (t, J=7.0, 6H). 13C-NMR (CDCl3, 126 MHz) δ 162.85 (dd, J=246, 3.8), 134.2 (t, J=8.6), 130.0 (dd, J=7.7, 2.9), 125.6 (dd, J=6.7, 2.9), 116.9 (dd, J=22, 6.7, 114.0 (dd, J=21, 2.9), 62.3 (d, J=6.7), 33.7 (dd, J=138, 1.9, 16.5 (d, J=5.8). Upon completion of the addition the reaction was fitted with a reflux condensor (no cooling) and a slow stream of nitrogen The reaction was cooled to room temperature concentrated under high vacuum to remove most of the excess triethylphosphite The resulting residue was purified by column chromatography (50%-->100% EtOAc/Hex) to give 15.13 g (quant.) as a colorless oil

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with 1-(bromomethyl)-3-fluorobenzene (7.5 mL, 61.1 mmol) and treated with triethylphosphite (21.39 mL, 122 mmol) dropwise with stirring. Upon completion of the addition, the reaction was fitted with a reflux condensor (no cooling) and a slow stream of nitrogen was passed over the reaction mixture. The reaction was slowly warmed to 150° C. and held there for 2 h. The reaction was cooled to room temperature and concentrated under high vacuum to remove most of the excess triethylphosphite. The resulting residue was purified by column chromatography (50%-->100% EtOAc/Hex) to give 15.13 g (quant.) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.29 (m, 1H), 7.10 (m, 1H), 7.05 (m, 1H), 6.97 (m, 1H), 4.06 (m, 4H), 3.16 (d, J=21.7, 2H), 1.28 (t, J=7.0, 6H). 13C-NMR (CDCl3, 126 MHz) δ 162.85 (dd, J=246, 3.8), 134.2 (t, J=8.6), 130.0 (dd, J=7.7, 2.9), 125.6 (dd, J=6.7, 2.9), 116.9 (dd, J=22, 6.7, 114.0 (dd, J=21, 2.9), 62.3 (d, J=6.7), 33.7 (dd, J=138, 1.9, 16.5 (d, J=5.8). Upon completion of the addition the reaction was fitted with a reflux condensor (no cooling) and a slow stream of nitrogen The reaction was cooled to room temperature concentrated under high vacuum to remove most of the excess triethylphosphite The resulting residue was purified by column chromatography (50%-->100% EtOAc/Hex) to give 15.13 g (quant.) as a colorless oil

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-fluorobenzyl bromide (2 g) and triethyl phosphite (2.2 mL) was heated at 160° C. under nitrogen for 4 hours. After cooling, the were volatiles removed in vacuo and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give diethyl (3-fluorobenzyl)phosphonate (2.46 g) After cooling the were volatiles removed in vacuo the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100%

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

Procedure: Sodium hydride (0.245 g) was added portionwise to a solution of diethyl (3-fluorobenzyl)phosphonate (Intermediate 182, 1 g) in THF (40 mL) at 0° C. The mixture was stirred for 30 minutes then benzyl 4-oxopiperidine-1-carboxylate (0.947 g) was added at 0° C. The mixture was allowed to warm to room temperature and stirred for 21.5 hours. The mixture was partitioned between water and ethyl acetate and the organic layer was washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give benzyl 4-(3-fluorobenzylidene)piperidine-1-carboxylate (1.05 g) stirred for 21.5 hours The mixture was partitioned between water and ethyl acetate the organic layer was washed with brine dried (Na2SO4) filtered The filtrate was evaporated to dryness the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25%