p-Toluenesulfonic acid → N-(1-(2-(Benzyloxy)-3-tert-butylphenyl)ethyl)2-methoxyaniline

HRID 41339Notes

Reaction equation

HRID 41339 reaction equation
[CH2:1]([O:8][C:9]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[C:24]([NH2:29])=[CH:25][CH:26]=[CH:27][CH:28]=1.[C:30]1(C)C=CC(S(O)(=O)=O)=CC=1.C[Mg+].[Br-]>C1COCC1.O.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]([NH:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH3:21])[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

8

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 70002-MethoxyanilineHCID 115435672-(Benzyloxy)-3-(tert-butyl)benzaldehydeHCID 178418689HCID 178418689, compound

Product 1

HCID 67105469N-(1-(2-(Benzyloxy)-3-tert-butylphenyl)ethyl)2-methoxyanilineYield 85%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

A mixture of 21 (1.88 g, 7 mmol, 1.0 equiv), o-anisidine (0.86 g, 0.79 mL, 7 mmol, 1.0 equiv), toluene (35 mL) and a crystal of p-toluenesulfonic acid was refluxed for 4 hr with H2O removal (Dean-Stark trap). The mixture was cooled to room temperature and concentrated under reduced pressure to give crude imine 22 as a yellow-brown oil. Crude 22 was dissolved in THF (25 mL) and the solution cooled to ˜2° C. 3M MeMgBr in THF (5 mL, 15 mmol, 2.15 equiv) was added dropwise via syringe. A green color developed followed by a yellow-brown color. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to ˜10° C., quenched by the slow, dropwise addition of saturated NH4Cl solution (10 mL) then partitioned between EtOAc (100 mL) and H2O (20 mL). The organic phase was washed with brine (2×40 mL), dried over Na2SO4, filtered and the solution concentrated under reduced pressure to give a brown oil. The crude product was absorbed onto silica gel using dichloromethane and dry-loaded onto a column of silica gel (30 g) packed in heptanes. The column was eluted with heptanes (100 mL), 2% EtOAc/heptanes (200 mL) and 3% EtOAc/heptanes (200 mL). Product fractions were concentrated under reduced pressure to give 2.3 g (85%) 23 as a yellow oil.

Workup

  1. concentrationconcentrated under reduced pressure
  2. customto give crude imine 22 as a yellow-brown oil
  3. temperaturethe solution cooled to ˜2° C
  4. temperatureto warm to room temperature
  5. temperatureThe mixture was cooled to ˜10° C.
  6. customquenched by the slow,
  7. additiondropwise addition of saturated NH4Cl solution (10 mL)
  8. customthen partitioned between EtOAc (100 mL) and H2O (20 mL)
  9. washThe organic phase was washed with brine (2×40 mL)
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. concentrationthe solution concentrated under reduced pressure
  13. customto give a brown oil
  14. customThe crude product was absorbed onto silica gel
  15. washThe column was eluted with heptanes (100 mL), 2% EtOAc/heptanes (200 mL) and 3% EtOAc/heptanes (200 mL)
  16. concentrationProduct fractions were concentrated under reduced pressure

Sources & evidence

ORD record
ord-451c0257a7a24b38a8145b4d87a8d739
Source dataset
uspto-grants-2013_09
Patent number
US08530593B2

Reaction notes

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