N-tert-butoxycarbonyl-3-methoxy-2-methylaniline → 1-[2-(Tert-butoxycarbonylamino)-6-methoxyphenyl]-2-butanone

HRID 1280812Notes

Reaction equation

HRID 1280812 reaction equation
C([Li])(CC)C.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH3:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].CON(C)[C:26](=[O:29])[CH2:27][CH3:28]>C1CCCCC1.C1COCC1>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH2:22][C:26](=[O:29])[CH2:27][CH3:28])=[O:12])([CH3:9])([CH3:8])[CH3:7]

Participants

6

Reactant 3

HCID 10609918N-tert-butoxycarbonyl-3-methoxy-2-methylanilineHCID 11344007N-Methoxy-N-methylpropionamideHCID 178418400CID 53628100

Product 1

HCID 107324851-[2-(Tert-butoxycarbonylamino)-6-methoxyphenyl]-2-butanoneYield 96.6%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8078CyclohexaneSolvent

Conditions

Temperature
-60 °C

Procedure

A solution of 140 mL (0.18 mol) of 1.3M sec-butyl lithium in cyclohexane was added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (21.3 g, 0.09 mol) in 250 mL of THF keeping the temperature below −40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to 0° C. and then the bath replaced. After the temperature has cooled to −60° C., 18.5 g (0.18 mol) of N-methoxy-N-methylpropanamide in an equal volume of THF was added dropwise. The reaction mixture was stirred 5 minutes, the cooling bath removed and stirring continued an additional 18 hours. It was then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HCl. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated at reduced pressure to give 25.5 g of crude 1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-butanone. This material was dissolved in 250 mL of methylene chloride and 50 mL of trifluoroacetic acid and stirred for a total of 17 hours. The mixture was concentrated at reduced pressure and ethyl acetate and water added to the remaining oil. The ethyl acetate was separated, washed with brine, dried (MgSO4) and concentrated. The residue was chromatographed three times on silica eluting with 20% EtOAc/hexane to give 13.9. g of 2-ethyl-4-methoxy-1H-indole.

Workup

  1. customThe bath was removed
  2. customto rise to 0° C.
  3. customthe cooling bath removed
  4. stirringstirring
  5. waitcontinued an additional 18 hours
  6. additionIt was then poured into a mixture of 300 mL of ether and 400 mL of 0.5N HCl
  7. customThe organic layer was separated
  8. washwashed with water, brine
  9. dry with materialdried over MgSO4
  10. concentrationconcentrated at reduced pressure

Sources & evidence

ORD record
ord-4e10052b00dc46028aff70f0e4adc912
Source dataset
uspto-grants-2002_09
Patent number
US06451839B1

Reaction notes

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