Late Stage Difluoromethylation: Validated Protocol for Baran's DFMS Reagent

Late Stage Difluoroethylation - Baran's DFMS Reagent


  1. Assemble a 100 ML 3-neck reaction flask in a cooling bath with addition funnel topped with a large bore stopcock leading to nitrogen bubbler and thermometer.
  2. Charge the 4-chloropyridine hydrochloride (Aldrich C70223, 5 mmol, 750 mg, 1.0 equiv) and Zinc difluoromethanesulfinate (DFMS, Aldrich 767840, 15 mmol, 4.433 g, 3.0 equiv) to the reaction flask using the 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 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).
  6. Slowly add tert-butyl hydroperoxide to the reaction mixture at 0˚C for 15 minutes with vigorous stirring.
  7. Stir at 0˚C for additional 15 minutes after the addition.
  8. Warm the reaction mixture to room temperature and monitor by thin layer chromatography until reaction completion (Rf = 0.55, 20% EtOAc/hexanes).
  9. Reaction completed in 12 hours.
  10. The reaction was partitioned between CH2Cl2 (100.0 mL) and saturated NaHCO3 (100.0 mL).
  11. Dichloromethane layer was separated, and the aqueous layer was extracted with CH2Cl2 (3 x 100.0 mL).
  12. The organic layers were dried with Na2SO4, concentrated to obtain yellow oil.
  13. NMR yield (80%) based on internal standard of 1,4-dimethoxybenzene (Aldrich D131350).




  • Nature, 492, 95-99, (06 December 2012)


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