N,N,N',N'-Tetramethylethylenediamine → HCID 21878154, compound

HRID 896137Notes

Reaction equation

HRID 896137 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:5]=[C:6]([F:8])[CH:7]=1.CN(C)CCN(C)C.C([Li])CCC.[S:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]1>C1COCC1>[OH:36][C:33]1([C:7]2[C:2]([F:1])=[CH:3][C:4]([NH:9][C:10](=[O:16])[O:11][CH2:12][CH:13]([CH3:14])[CH3:15])=[CH:5][C:6]=2[F:8])[CH2:34][CH2:35][S:30][CH2:31][CH2:32]1

Participants

6

Reactant 4

HCID 8037N,N,N',N'-TetramethylethylenediamineHCID 66173Tetrahydrothiopyran-4-oneHCID 21878207HCID 21878207, compoundHCID 178418339Butyllithium

Product 1

HCID 21878154HCID 21878154, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

A stirred solution of isobutyl 3,5-difluorophenylcarbamate (Step A, 10.0 g, 43.6 mmol) and N,N,N′,N′-tetramethylethylenediamine (13.7 mL, 87.3 mmol) in anhydrous THF (87 mL) at −78° C. under N2 is treated n-butyllithium (1.6M in hexanes, 35.8 mL, 89.4 mmol) dropwise over 35 mins. The mixture is stirred at −78° C. for 20 mins and is then treated with a solution of tetrahydro-2H-thiopyran-4-one (5.32 g, 45.8 mmol) in anhydrous THF (15 mL) dropwise over 10 mins. After 45 mins at −78° C., the cooling bath is removed and the mixture is allowed to warm to ambient temperature and is then quenched by the slow addition of saturated aqueous ammonium chloride (50 mL). Water (50 mL) and EtOAc (100 mL) are added, the layers are separated, and the organic phase is washed with water (100 mL) and saline (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product is triturated and filtered from EtOAc (approx. 25 mL) to remove an insoluble impurity, and the filtrate is chromatographed on two Flash 40M 90 g silica gel cartridges, eluting with EtOAc/heptane (20/80). Pooling and concentration of those fractions with an Rf=0.26 by TLC (EtOAc/hexanes, 25/75) gives the title compound, mp 103-104° C.

Workup

  1. waitAfter 45 mins at −78° C.
  2. customthe cooling bath is removed
  3. temperatureto warm to ambient temperature
  4. customis then quenched by the slow addition of saturated aqueous ammonium chloride (50 mL)
  5. additionWater (50 mL) and EtOAc (100 mL) are added
  6. customthe layers are separated
  7. washthe organic phase is washed with water (100 mL) and saline (50 mL)
  8. dry with materialdried over anhydrous magnesium sulfate
  9. concentrationconcentrated under reduced pressure
  10. customThe crude product is triturated
  11. filtrationfiltered from EtOAc (approx. 25 mL)
  12. customto remove an insoluble impurity
  13. customthe filtrate is chromatographed on two Flash 40M 90 g silica gel cartridges
  14. washeluting with EtOAc/heptane (20/80)

Sources & evidence

ORD record
ord-bff3a01e010e4c118e3f1af7c04598e2
Source dataset
uspto-grants-2005_07
Patent number
US06919329B2

Reaction notes

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