Potassium Carbonate → 4-Methylene-6-chloro-8-difluoromethoxychromane

HRID 353249Notes

Reaction equation

HRID 353249 reaction equation
CP(=O)(OC)OC.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([O:24][CH:25]([F:27])[F:26])[CH:23]=1)[O:20]CCC2=O.[NH4+].[Cl-].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CCCCCC.O>[CH2:11]=[C:10]1[C:16]2[C:21](=[C:22]([O:24][CH:25]([F:27])[F:26])[CH:23]=[C:14]([Cl:13])[CH:15]=2)[O:20][CH2:8][CH2:9]1

Participants

9

Reactant 5

HCID 11430Potassium CarbonateHCID 12958Dimethyl methylphosphonateHCID 25517Ammonium ChlorideHCID 227083496-Chloro-8-difluoromethoxychroman-4-oneHCID 178418339Butyllithium

Product 1

HCID 227083434-Methylene-6-chloro-8-difluoromethoxychromaneYield 47%

Reagents, catalysts & solvents 3

HCID 962WaterSolvent3×HCID 8028TetrahydrofuranSolvent2×HCID 8058HexaneSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of dimethyl methylphosphonate (8.9 g, 71.1 mmol) in dry THF (55 mL) under N2 was added, dropwise over 1 h at −70° C., n-butyllithium in hexane (1.6M, 49.2 mL). The mixture was stirred for 30 minutes at −70° C., whereafter a solution of 6-chloro-8-difluoromethoxychroman-4-one (6.8 g, 27.35 mmol, from step (v) above) in dry THF (15 mL) was added, dropwise over 30 minutes at −70° C. The reaction mixture was stirred for 2 h at −70° C., whereafter NH4Cl (aq., sat., 110 mL) was added, and then water (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was dissolved in DMF (85 mL). To the solution was added anhydrous potassium carbonate (27.4 g, 201.0 mmol) and water (3.6 ml). The mixture was warmed for 2 h at 120° C. (oil-bath). After the mixture had reached room temperature water (80 mL) was added. The mixture was extracted with EtOAc. The combined organic layers were washed with citric acid (aq., 10%) and with brine, dried (Na2SO4) and evaporated. The crude product was chromatographed on silica gel, eluting with heptane:methylene chloride (8:2), to afford 3.2 g (47%) of the sub-title compound.

Workup

  1. additionwas added, dropwise over 30 minutes at −70° C
  2. additionwas added
  3. customThe layers were separated
  4. extractionthe aqueous phase was extracted with EtOAc
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated
  8. dissolutionThe residue was dissolved in DMF (85 mL)
  9. customhad reached room temperature
  10. additionwas added
  11. extractionThe mixture was extracted with EtOAc
  12. washThe combined organic layers were washed with citric acid (aq., 10%) and with brine
  13. dry with materialdried (Na2SO4)
  14. customevaporated
  15. customThe crude product was chromatographed on silica gel
  16. washeluting with heptane:methylene chloride (8:2)

Sources & evidence

ORD record
ord-87ef1862bf0d44eb894c6ed975f921b5
Source dataset
uspto-grants-2004_06
Patent number
US06750243B1

Reaction notes

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