1,4-Difluorobenzene → HCID 66849804, compound

HRID 658413Notes

Reaction equation

HRID 658413 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.N1([C:15](=[O:25])[C@@H:16]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH3:17])CCOCC1.C(NC(C)C)(C)C.[Li]>C1COCC1.C1COCC1.CCCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:15](=[O:25])[C@@H:16]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[CH3:17]

Participants

6

Reactant 3

HCID 108921,4-DifluorobenzeneHCID 14978394HCID 14978394, compoundHCID 45051747Lithium diisopropylamine

Product 1

HCID 66849804HCID 66849804, compoundYield 46.2%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 21263495Tetrahydrofuran heptaneSolvent

Conditions

Temperature
0 °C

Procedure

1,4-Difluorobenzene (1.8 g; 15.8 mmol) and (2S)-1-Morpholin-4-yl-2-(tetrahydro-pyran-2-yloxy)-propan-1-one (3 g; 10.5 mmol) are dissolved in dry THF (15 ml). The mixture is cooled to 0° C. and then lithium diisopropylamine (7.9 ml of a 2M solution in THF/Heptane; 15.8 mmol) is added dropwise over a period of 20 minutes. The mixture is stirred for another 2 hours at 0° C. The reaction is then quenched with a saturated ammonium chloride solution. The reaction mixture is extracted with ethyl acetate. The organic phase is washed with water and brine and then dried over magnesium sulfate. The solids are filtered off and the solvent is removed under reduced pressure. The crude product is chromatographed over silicagel (eluent: Petrol ether/Ethyl acetate 50:1 to 30:1). 1.31 g of yellow crystalline material (yield 44.8%) is obtained with a HPLC purity of 96.2%. NMR: (CDCl3; 400 MHz): 7.53-7.47 (m; 1H); 7.24-7.16 (m; 1H); 7.15-7.07 (m; 1H); 5.10 (qd; J=7.2 Hz; 2.0 Hz; ½H); 4.85 (q; J=7.2 Hz; ½H); 4.74 (m; ½H); 4.64 (m; ½H); 3.89 (m; ½H); 3.71 (m; ½H); 3.51 (m; ½H); 3.34 (m; ½H); 1.90-1.48 (m; 6H); 1.47 (d; J=7.2 Hz; 1.5H); 1.42 (d; J=7.2 Hz; 1.5H).

Workup

  1. addition15.8 mmol) is added dropwise over a period of 20 minutes
  2. customThe reaction is then quenched with a saturated ammonium chloride solution
  3. extractionThe reaction mixture is extracted with ethyl acetate
  4. washThe organic phase is washed with water and brine
  5. dry with materialdried over magnesium sulfate
  6. filtrationThe solids are filtered off
  7. customthe solvent is removed under reduced pressure
  8. customThe crude product is chromatographed over silicagel (eluent: Petrol ether/Ethyl acetate 50:1 to 30:1)

Sources & evidence

ORD record
ord-0c7ca4f9daf64248bbab031567dabfad
Source dataset
uspto-grants-2011_12
Patent number
US08076494B2

Reaction notes

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