Dimethyl methylphosphonate → (S)-(+)-dimethyl (2-oxo-3-phenylbutyl)phosphonate

HRID 59703Notes

Reaction equation

HRID 59703 reaction equation
[CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[C:13]1([C@H:19]([CH3:25])[C:20](OCC)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.OS([O-])(=O)=O.[K+]>C1COCC1>[O:21]=[C:20]([C@H:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:25])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]

Participants

6

Reactant 4

HCID 12958Dimethyl methylphosphonateHCID 516920Potassium bisulfateHCID 7204861ethyl (2S)-2-phenylpropanoateHCID 178418339Butyllithium

Product 1

HCID 13345710(S)-(+)-dimethyl (2-oxo-3-phenylbutyl)phosphonateYield 72%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirring solution consisting of dimethyl methylphosphonate (1.392 g, 11.22 mmol) in THF (20 mL) at −78° C. was slowly added n-butyllithium solution (6.6 mL, 11 mmol, 1.6 M solution in hexane). The mixture was stirred for 30 minutes, after which time a mixture consisting of (S)-ethyl 2-phenylpropanoate (1.0 g, 5.6 mmol) in THF (10 mL) was slowly added, and the mixture stirred at −78° C. for two hours before being allowed to rise to room temperature overnight. The reaction mixture was treated with 5% aqueous KHSO4 and extracted with ethyl acetate three times. The combined organic layer was twice washed with a solution of 50:50 water-brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane (80:20 v/v) afforded the title compound (1.03 g, 72%) as a colorless oil; TLC Rf 0.4 (solvent system 80:20 v/v ethyl acetate-heptane); MS (ESI+) m/z 257.1 (M+H)+; 1H NMR (CD3OD) δ 7.37-7.22 (m, 5H), 4.01 (q, J=6.71 Hz, 1H), 3.74-3.69 (m, 6H), 3.27-3.2 (m, 1H), 3.09-2.97 (m, 1H), 1.37-1.34 (m, 3H); [α]Tλ=α/cl, [α]21.9D=0.946/(0.01859 g/1.5 mL)(0.5)=+152.6° (c=1.24, CHCl3).

Workup

  1. additionwas slowly added
  2. stirringthe mixture stirred at −78° C. for two hours
  3. waitto rise to room temperature overnight
  4. extractionextracted with ethyl acetate three times
  5. washThe combined organic layer was twice washed with a solution of 50:50 water-brine
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated under vacuum
  8. customThe residue was purified by silica gel chromatography
  9. washElution with ethyl acetate-heptane (80:20 v/v)

Sources & evidence

ORD record
ord-640c85069d084afb96e7d6a6cbc1c9d6
Source dataset
uspto-grants-2016_09
Patent number
US09440919B2

Reaction notes

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