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

HRID 2167646Notes

Reaction equation

HRID 2167646 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.C(=O)=O.CC(C)=O.[F:20][CH:21]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[F:22].[Br:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36]Br>C1CCCCC1.CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[Br:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:21]([P:23](=[O:30])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])([F:22])[F:20]

Participants

9

Reactant 5

HCID 7912DiisopropylamineHCID 21521Bis(2-bromoethyl) etherHCID 2758305Phosphonic acid, (difluoromethyl)-, diethyl esterHCID 18522661Acetone cardiceHCID 178418339Butyllithium

Product 1

HCID 58166526Diethyl 3-(2-bromoethoxy)-1,1-difluoropropylphosphonate

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolvent2×HCID 8078CyclohexaneSolventHCID 12679HexamethylphosphoramideSolvent

Procedure

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.

Workup

  1. temperatureThe flask was cooled in an acetone-dry ice bath
  2. additionThe flask was transferred to an ice-water bath upon completion of the addition
  3. waitto proceed for an hour
  4. stirringto stir for another 3 hours
  5. custombefore quenching with 1 N HCl
  6. extractionThe mixture was extracted with EtOAc (3×)
  7. dry with materialThe combined organic extracts were dried over anhydrous Na2SO4
  8. concentrationconcentrated in vacuo
  9. customThe crude material was purified by Combiflash

Sources & evidence

ORD record
ord-e22f08fac831477991b38a7e74838a41
Source dataset
uspto-grants-2015_06
Patent number
US09045470B2

Reaction notes

Loading…