Ammonium Chloride → 1-(Tetrahydro-2H-pyran-4-yl)ethanone

HRID 2088909Notes

Reaction equation

HRID 2088909 reaction equation
[CH:1]([Mg]Cl)(C)C.[O:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14]C)=O)[CH2:8][CH2:7]1.Cl.CNOC.[Cl-].[NH4+].C[Mg]Cl>O1CCCC1>[O:6]1[CH2:7][CH2:8][CH:9]([C:12](=[O:14])[CH3:1])[CH2:10][CH2:11]1

Participants

7

Reactant 5

HCID 25517Ammonium Chloride2×HCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 27735202H-Pyran-4-carboxylic acid, tetrahydro-, methyl esterHCID 178418332HCID 178418332, compoundHCID 178418918HCID 178418918, compound

Product 1

HCID 98773651-(Tetrahydro-2H-pyran-4-yl)ethanoneYield 75%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent4×

Procedure

Add 2 M isopropylmagnesium chloride in tetrahydrofuran (520.22 mL, 3.0 eq) to a mixture of methyl tetrahydro-2H-pyran-4-carboxylate (46.30 mL, 346.81 mmol) and N,O-dimethylhydroxylamine hydrochloride (52.44 g, 1.6 eq) in tetrahydrofuran (2.43 L) during 15 minutes at −20° C. under nitrogen. After 30 min, add saturated aqueous ammonium chloride (400 mL) to the reaction at −20° C. Extract the aqueous solution with methyl tert-butyl ether (250 mL×3). Wash the combined organics with saturated aqueous sodium chloride. Dry over anhydrous magnesium sulfate and concentrate in vacuo. Add dichloromethane (500 mL), filter through Celite® and concentrate in vacuo. Add tetrahydrofuran (700 mL), then add 3 M methyl magnesium chloride in tetrahydrofuran (231.21 mL, 2.0 eq) dropwise over 15 minutes at 7° C. After 40 minutes, add saturated aqueous ammonium chloride (250 mL) to the reaction. Extract the aqueous solution with methyl tert-butyl ether (250 mL×2). Dry over anhydrous magnesium sulfate and concentrate in vacuo. Purify by silica gel chromatography, eluting with 2:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate, to give 1-(tetrahydro-pyran-4-yl)-ethanone (33.18 g, 75%). 1H NMR (300 MHz, DMSO-d6) δ 3.98 (m, 2H), 3.42 (m, 2H), 2.52 (m, 1H), 2.15 (s, 3H), 1.74 (m, 4H).

Workup

  1. customto the reaction at −20° C
  2. extractionExtract the aqueous solution with methyl tert-butyl ether (250 mL×3)
  3. washWash the combined organics with saturated aqueous sodium chloride
  4. dry with materialDry over anhydrous magnesium sulfate
  5. concentrationconcentrate in vacuo
  6. filtrationAdd dichloromethane (500 mL), filter through Celite®
  7. concentrationconcentrate in vacuo
  8. waitAfter 40 minutes
  9. customto the reaction
  10. extractionExtract the aqueous solution with methyl tert-butyl ether (250 mL×2)
  11. dry with materialDry over anhydrous magnesium sulfate
  12. concentrationconcentrate in vacuo
  13. customPurify by silica gel chromatography
  14. washeluting with 2:1 hexanes

Sources & evidence

ORD record
ord-ac22e7b65ac94e198f99caf19fe23e63
Source dataset
uspto-grants-2013_05
Patent number
US08436002B2

Reaction notes

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