Hydrogen Bromide → 2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine

HRID 2376308Notes

Reaction equation

HRID 2376308 reaction equation
Br[C:2]1[C:3]([CH3:20])=[C:4]([NH:12]C(=O)OC(C)(C)C)[C:5]([CH3:11])=[C:6]([CH3:10])[C:7]=1[O:8]C.[CH2:21]([Li])[CH2:22][CH2:23][CH3:24].C[CH:27](C)[C:28]([C:30]1[CH:35]=CC(C)=[CH:32][CH:31]=1)=O.Br.[OH-].[Na+].[CH2:41]1COCC1>O>[CH3:24][C:23]1([CH3:41])[CH:22]([C:21]2[CH:32]=[CH:31][C:30]([CH3:35])=[CH:28][CH:27]=2)[C:2]2[C:3]([CH3:20])=[C:4]([NH2:12])[C:5]([CH3:11])=[C:6]([CH3:10])[C:7]=2[O:8]1

Participants

8

Reactant 6

HCID 260Hydrogen BromideHCID 8028TetrahydrofuranHCID 14798Sodium HydroxideHCID 5768291-Propanone, 2-methyl-1-(4-methylphenyl)-HCID 21961344HCID 21961344, compoundHCID 178418339Butyllithium

Product 1

HCID 106853092,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amineYield 62%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

To a solution of tert-butyl 3-bromo-4-methoxy-2,5,6-trimethylphenylcarbamate synthesized in Reference Example 129 (27.8 g, 80.8 mmol) in THF (150 mL) was added n-butyllithium (1.6 M, 110 mL, 176 mmol) hexane solution at −78° C. and the mixture was stirred at the same temperature for 20 minutes. 2-Methyl-1-(4-methylphenyl)propane-1-one (13.1 g, 80.7 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Water (150 mL) was poured into the reaction mixture, which was three times extracted with ethyl acetate, the combined organic layer was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain the crude product 26.0 g of tert-butyl 3-(1-hydroxy-2-methyl-1-(4-methylphenyl)propyl)-4-methoxy-2,5,6-trimethylphenylcarbamate. A mixture of this compound and 47% hydrobromic acid (100 mL) was heated under reflux under argon atmosphere for 4 hours. The reaction mixture was cooled to room temperature, and then was neutralized with a 8 N aqueous sodium hydroxide solution. The product was twice extracted with ethyl acetate, and the combined extract was washed with a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was crystallized from isopropyl ether-hexane to obtain 14.8 g (yield 62%) of the title compound. Melting point: 114-115° C.

Workup

  1. stirringthe mixture was stirred at room temperature for 1 hour
  2. extractionextracted with ethyl acetate
  3. washthe combined organic layer was washed with water
  4. dry with materialdried over magnesium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customto obtain the crude product 26.0 g of tert-butyl 3-(1-hydroxy-2-methyl-1-(4-methylphenyl)propyl)-4-methoxy-2,5,6-trimethylphenylcarbamate
  7. temperaturewas heated
  8. temperatureunder reflux under argon atmosphere for 4 hours
  9. extractionThe product was twice extracted with ethyl acetate
  10. extractionthe combined extract
  11. washwas washed with a saturated sodium hydrogen carbonate solution
  12. dry with materialdried over magnesium sulfate
  13. concentrationconcentrated under reduced pressure
  14. customThe residue was crystallized from isopropyl ether-hexane

Sources & evidence

ORD record
ord-e92dfe3fd7634e39bcdf392921a64159
Source dataset
uspto-grants-2008_12
Patent number
US07465815B2

Reaction notes

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