Diethyl 3-Bromobenzylphosphonate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To diethyl[(3-bromophenyl)methyl]phosphonate (100 g, 326 mmol) in a 2 L 3-neck flask with mechanical stirrer was added tetrahydrofuran (THF) (700 mL) followed by 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (71.4 g, 358 mmol) and potassium tert-butoxide (38.4 g, 342 mmol), portion-wise with ice-bath cooling to keep the temperature between 20° C. and 25° C. The mixture became more orange and was then stirred at room temperature under nitrogen. Some material was present as a suspension and it was slightly more viscous. Another 3.8 gm (0.1 eq) of potassium tert-butoxide was added. After 1.25 h the mixture had practically gelled and an extra 150 mL of THF were added. cooling the temperature between 20° C. and 25° C

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-bromo-3-(bromomethyl)benzene (100 g, 400 mmol) in a 500 mL round-bottom flask under nitrogen was added triethyl phosphite (69.6 mL, 400 mmol) and the solution was heated to 130° C. The apparatus was set up ready for distillation. As the heating block reached 130° C. the mixture began to reflux and a large volume of colourless liquid was allowed to distill off. Lab HPLC of the reaction after 40 min showed some starting material so another 0.5 eq of the phosphite was added, and heating with distillation continued. The reaction was then heated under vacuum and the excess phosphite was distilled off under vacuum (130° C. heater and 15 mbar, gradually going down to 0.5 mbar). This gave 120.8 g (98%) of a colourless oil that the lab HPLC showed to be 97% pure with a 2.20 min retention time. LC-MS m/z 307, 309 (M+H)+, 1.01 min (ret time). The apparatus was set up ready for distillation reached 130° C. to reflux to distill off Lab HPLC of the reaction after 40 min was added heating with distillation The reaction was then heated under vacuum the excess phosphite was distilled off under vacuum (130° C. heater and 15 mbar pure with a 2.20 min LC-MS m/z 307, 309 (M+H)+, 1.01 min (ret time)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-bromo-3-(bromomethyl)benzene (100 g, 400 mmol) in a 500 mL round-bottom flask under nitrogen was added triethyl phosphite (69.6 mL, 400 mmol) and the solution was heated to 130° C. The apparatus was set up ready for distillation. As the heating block reached 130° C. the mixture began to reflux and a large volume of colourless liquid was allowed to distill off. Lab HPLC of the reaction after 40 min showed some starting material so another 0.5 eq of the phosphite was added, and heating with distillation continued. The reaction was then heated under vacuum and the excess phosphite was distilled off under vacuum (130° C. heater and 15 mbar, gradually going down to 0.5 mbar). This gave 120.8 g (98%) of a colourless oil that the lab HPLC showed to be 97% pure with a 2.20 min retention time. LC-MS m/z 307, 309 (M+H)+, 1.01 min (ret time). The apparatus was set up ready for distillation reached 130° C. to reflux to distill off Lab HPLC of the reaction after 40 min was added heating with distillation The reaction was then heated under vacuum the excess phosphite was distilled off under vacuum (130° C. heater and 15 mbar pure with a 2.20 min LC-MS m/z 307, 309 (M+H)+, 1.01 min (ret time)

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

Procedure: To diethyl[(3-bromophenyl)methyl]phosphonate (100 g, 326 mmol) in a 2 L 3-neck flask with mechanical stirrer was added tetrahydrofuran (THF) (700 mL) followed by 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (71.4 g, 358 mmol) and potassium tert-butoxide (38.4 g, 342 mmol), portion-wise with ice-bath cooling to keep the temperature between 20° C. and 25° C. The mixture became more orange and was then stirred at room temperature under nitrogen. Some material was present as a suspension and it was slightly more viscous. Another 3.8 g (0.1 eq) of potassium tert-butoxide was added. After 1.25 h the mixture had practically gelled: an extra 150 mL of THF were added. The mixture was partitioned between water and ethyl acetate and the aqueous layer extracted well with ethyl acetate. The combined organics were washed with water, brine, dried (MgSO4), filtered and evaporated to give a pale yellow oil, 120.73 g. The crude product was purified on a 750 g Companion XL silica cartridge, eluting with 0-25% ethyl acetate in cyclohexane over 8 column volumes. This gave a colorless oil which became a white solid, 94.68 g (83%). HPLC 2.97 min (ret time), 99.5%; LC-MS m/z 352,354 (M+H)+, 3.96 min (ret time). cooling the temperature between 20° C. and 25° C The mixture was partitioned between water and ethyl acetate the aqueous layer extracted well with ethyl acetate The combined organics were washed with water, brine dried (MgSO4) filtered evaporated to give a pale yellow oil, 120.73 g The crude product was purified on a 750 g Companion XL silica cartridge eluting with 0-25% ethyl acetate in cyclohexane over 8 column volumes This gave a colorless oil which HPLC 2.97 min (ret time), 99.5% LC-MS m/z 352,354 (M+H)+, 3.96 min (ret time)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-bromo-3-(bromomethyl)benzene (100 g, 400 mmol) in a 500 mL round-bottom flask under nitrogen was added triethyl phosphite (69.6 mL, 400 mmol) and the solution was heated to 130° C. The apparatus was set up ready for distillation. As the heating block reached 130° C. the mixture began to reflux and a large volume of colourless liquid was allowed to distil off. Analysis of the reaction by hplc after 40 min showed some starting material so another 0.5 eq of the phosphite was added and heating with distillation continued. The reaction was then heated under vacuum: the excess phosphite was distilled off under vacuum (130° C. heater and 15 mbar, gradually going down to 0.5 mbar). This gave a colorless oil 120.8 g. HPLC 2.20 min (ret time), 97%; LC-MS m/z 307, 309 (M+H)+, 1.01 min (ret time). The apparatus was set up ready for distillation reached 130° C. to reflux to distil off Analysis of the reaction by hplc after 40 min was added heating with distillation The reaction was then heated under vacuum the excess phosphite was distilled off under vacuum (130° C. heater and 15 mbar

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

Procedure: To a solution of diethyl [(3-bromophenyl)methyl]phosphonate (3.07 g, 10 mmol) in THF (20 mL) was added 8-methyl-8-azabicyclo[3.2.1]octan-3-one (1.67 g, 12 mmol) then KOBu-t (1.234 g, 11 mmol). The reaction mixture was stirred at room temperature for 5 h before it was quenched with NH4Cl (5 mL, saturated aqueous). The organic layer of the reaction mixture was separated and the aqueous layer was extracted with DCM (5 mL). The combined organic layers were loaded onto a Combiflash Redisep silica gel column (40 g) and purified by Combiflash chromatograph to afford 2.48 g (85%) of the title compound. LC-MS m/z 292 (M+H)+. was quenched with NH4Cl (5 mL, saturated aqueous) The organic layer of the reaction mixture was separated the aqueous layer was extracted with DCM (5 mL) purified by Combiflash chromatograph

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

Procedure: 50 g (0.2 mol) of 3-bromobenzyl bromide and 33.2 g (0.2 mol) of triethyl phosphite were heated at 140° C. for 2 hours, during which ethyl bromide was distilled off. The product was distilled over a 30 cm Vigreux column. was distilled off The product was distilled over a 30 cm Vigreux column

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 50 g (0.2 mol) of 3-bromobenzyl bromide and 33.2 g (0.2 mol) of triethyl phosphite were heated at 140° C. for 2 hours, during which ethyl bromide was distilled off. The product was distilled over a 30 cm Vigreux column. was distilled off The product was distilled over a 30 cm Vigreux column