1-Butanol → Butyl methylphosphonate

Participants

Reaction Conditions

Reaction Steps

To a flask containing 1H-tetrazole (˜0.002 g, 0.028 mmol) was added a solution of n-butanol (0.041 g, 0.55 mmol) in 0.33 mL of DCM, followed by a solution of 3,5-lutidine (0.090 g, 0.84 mmol) in 0.33 mL of DCM. The resulting clear solution was cooled to 0° C. then added, under an atmosphere of N2, a solution of methylphosphonic dichloride (0.073 g, 0.55 mmol) in 0.33 mL of DCM. The resulting white suspension was stirred to ambient temperature overnight. To a cooled (0° C.) solution of rapamycin (0.1 g, 0.11 mmol) in 0.5 mL of DCM was added a solution of 3,5-lutidine (0.090 g, 0.84 mmol) in 0.5 mL of DCM, followed immediately by the phosphorylating reagent (yellow solution with white precipitate) and a 1.0 mL DCM wash. The resulting yellow solution was stirred at 0° C. for 1.0 h (followed by MS). The cold (0° C.) reaction solution was diluted with ˜20 mL EtOAc then transferred to a separatory funnel containing EtOAc (120 mL) and saturated NaHCO3 (100 mL). Upon removing the aqueous layer, the organic layer was washed successively with ice cold 1N HCl (1×100 mL), saturated NaHCO3 (3×100 mL), and brine (1×100 mL), then dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 0.25:10:3:3 then 0.5:10:3:3 MeOH/DCM/EtOAc/hexane) then RP HPLC (85% MeOH/H2O) to provide 0.063 g of a white solid (˜2:1 diastereomeric mixture): 1H NMR (300 MHz, CDCl3) d 4.15 (m, 1Ha, 1Hb), 4.11–3.89 (m, 3Ha, 3Hb), 3.04 (m, 1Ha, 1Hb); 31P NMR (121 MHz, CDCl3) d 32.1, 29.9; 1071 m/z (M+Na).

Provenance & Evidence