Hydrochloric Acid → 4-Chloromethyl-5-(4-methylphenyl)isoxazole

HRID 1794341Notes

Reaction equation

HRID 1794341 reaction equation
[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](OCC)=O)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[ClH:28]>O1CCCC1>[Cl:28][CH2:13][C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 21225700DiisobutylaluminumhydrideHCID 22220999Ethyl 5-(p-tolyl)isoxazole-4-carboxylate

Product 1

HCID 222209774-Chloromethyl-5-(4-methylphenyl)isoxazoleYield 94%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of ethyl 5-(4-methylphenyl)isoxazole-4-carboxylate (7.70 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (1.0 M toluene solution, 83 ml) at 0° C. and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in toluene (100 ml) and thionyl chloride (5.94 g) was added dropwise at 0° C., after which the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 4-chloromethyl-5-(4-methylphenyl)isoxazole (6.49 g, yield 94%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:9, volume ratio). NMR (CDCl3) δ: 2.44 (3H, s), 4.62 (2H, s), 7.34 (2H, d, J=8 Hz), 7.67 (2H, d, J=8 Hz), 8.35 (1H, s).

Workup

  1. customat 0° C.
  2. extractionthe mixture was extracted with ethyl acetate
  3. washThe ethyl acetate layer was washed with saturated brine
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated
  6. dissolutionThe residue was dissolved in toluene (100 ml)
  7. additionthionyl chloride (5.94 g) was added dropwise at 0° C.
  8. stirringafter which the mixture was stirred at room temperature for 1 hr
  9. concentrationThe reaction mixture was concentrated
  10. additionsaturated aqueous sodium hydrogencarbonate was added to the residue
  11. extractionthe mixture was extracted with ethyl acetate
  12. washThe ethyl acetate layer was washed with saturated brine
  13. dry with materialdried (MgSO4)
  14. concentrationconcentrated

Sources & evidence

ORD record
ord-91aff519db99489ca0a390c5d00774c6
Source dataset
uspto-grants-2006_04
Patent number
US07022725B2

Reaction notes

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