Late Stage Difluoroethylation: Validated Protocol for Baran's DFES Reagent

Late Stage Difluoroethylation - Baran's DFES reagent

Procedure

  1. Assemble a 100 mL 3-neck reaction flask in a cooling bath with addition funnel and thermometer.
  2. Charge the 2-Quinoxalinol (Aldrich 260517, 5 mmol, 731 mg, 1.0 equiv), Sodium 1,1-difluoroethanesulfinate (DFES, Aldrich 7465405, 10 mmol, 1.521 g, 2.0 equiv) and Zinc chloride (Aldrich 211273, 7.5 mmol, 1.022 g, 1.5 equiv) to the reaction flask using a powder funnel.
  3. Charge dichloromethane (Aldrich 270997, 20 mL) and water (8 mL) to the reaction flask.
  4. Cool the reaction mixture to 0˚C using ice and salt.
  5. Charge p-Toluenesulfonic acid monohydrate (Aldrich 402885, 5 mmol, 951.1 mg, 1.0 equiv) to the reaction mixture at 0˚C.
  6. Charge tert-butyl hydroperoxide (Aldrich 458139, 70% solution in water, 3.2 mL, 5.0 equiv) to the addition funnel (metal needles should not be used as they decompose the reagent).
  7. Slowly add tert-butyl hydroperoxide to the reaction mixture at 0˚C for 15 minutes with vigorous stirring.
  8. Stir at 0˚C for additional 15 minutes after the addition.
  9. Warm the reaction mixture to room temperature and monitor by thin layer chromatography until reaction completion (Rf = 0.50, 50% EtOAc/hexanes).
  10. Reaction completed in 10 hours.
  11. The reaction was partitioned between CH2Cl2 (100.0 mL) and saturated NaHCO3 (100.0 mL).
  12. Dichloromethane layer was separated, and the aqueous layer was extracted with CH2Cl2 (3 x 100.0 mL).
  13. The organic layers were dried with Na2SO4, concentrated to obtain a yellow solid.
  14. The crude material was mixed with a minimal amount of silica gel and was purified by column chromatography (gradient from 15% to 30% EtOAc : hexanes).
  15. Removal of the solvent under vacuum provided white solid in 95% yield.

Materials

     

 Reference

  • Angew. Chem. Int. Ed. 2013, 52, 3949-3952.

 

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