Diisopropylamine → Diethyl 3-(2-bromoethoxy)-1,1-difluoropropylphosphonate

Participants

Reaction Steps

An oven dried round-bottom flask was charged with dry THF (1.07 M) and diisopropylamine (2.0 equiv.). The flask was cooled in an acetone-dry ice bath, and was treated with n-butyllithium (1.6 equiv.) solution in cyclohexane (1.52 M) in dropwised fashion via syringe. The flask was transferred to an ice-water bath upon completion of the addition, and stirred for 30 minutes. The flask was then cooled back down to the dry ice-acetone bath, and was treated with a solution of diethyl difluoromethylphosphonate (1.0 equiv.) in HMPA (1:1 v/v) via syringe. The stirring was allowed to proceed for an hour. To the above reaction mixture, a cooled solution of 1-bromo-2-(2-bromoethoxy)ethane (3.0 equiv.) in THF (3 M) was added quickly through a syringe, and the reaction was allowed to stir for another 3 hours before quenching with 1 N HCl. The flask was warmed to room temperature, and the pH was adjusted to <4 with 1 N HCl. The mixture was extracted with EtOAc (3×). The combined organic extracts were dried over anhydrous Na2SO4, and concentrated in vacuo. The crude material was purified by Combiflash using 0-75% EtOAc in hexanes, followed by RP-HPLC (0.035% TFA in ACN:0.05% TFA in H2O, C18 column), to afford diethyl 3-(2-bromoethoxy)-1,1-difluoropropylphosphonate as a pale yellow oil.

Provenance & Evidence