Toluene → 4-Methyl-3-[(1-methylpiperidin-4-yl)oxy]aniline

HRID 1821997Notes

Reaction equation

HRID 1821997 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([CH:15]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.C(=[NH:30])(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>C1COCC1.Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][C:5]1[CH:4]=[CH:3][C:2]([NH2:30])=[CH:15][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1

Participants

8

Reactant 3

HCID 1140TolueneHCID 136809Benzophenone imineHCID 57893591HCID 57893591, compound

Product 1

HCID 450976834-Methyl-3-[(1-methylpiperidin-4-yl)oxy]anilineYield 93%

Reagents, catalysts & solvents 4

HCID 634876Binap, (A+-)-CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 313Hydrochloric AcidSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

Combine 4-(5-bromo-2-methyl-phenoxy)-1-methyl-piperidine (preparation 20, 3.90 g, 13.7 mmol), benzophenone imine (2.98 g, 16.44 mmol), Pd2(dba)3 (251 mg, 0.27 mmol), BINAP (512 mg, 0.82 mmol), sodium f-butoxide (1.843 g, 19.18 mmol) and toluene (40 mL) and heat at 85° C. After 9 hr., quench the reaction with saturated NaHCO3 solution, extract with ethylacetate three times, combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Dissolve the residue in THF (55 mL) and add 5N HCl (5.5 mL) and stir. After 1 hr., dilute the mixture with 0.1N HCl, extract with ethylacetate/hexanes (1:2) twice, keep aqueous layer, adjust pH>11 with 5N NaOH, extract with methylene dichloride three time. Combine methylene dichloride layers, dry over Na2SO4, filter and concentrate to give a residue. Purify by silica gel chromatography, eluting with 6.5% 2M NH3-methanol in methylene dichloride to give the title compound as a yellow oil (2.80 g, 93%). Mass spectrum (ion spray): m/z=221.1 (M+1); 1H NMR (CDCl3, ppm): 6.79 (d, 1H), 6.09 (m, 2H), 4.16 (m, 1H), 3.41 (s, br, 1H), 2.53 (m, 2H), 2.24 (m, 2H), 2.19 (s, 3H), 2.00 (s, 3H), 1.93-1.68 (m, 4H).

Workup

  1. custom, quench
  2. customthe reaction with saturated NaHCO3 solution
  3. extractionextract with ethylacetate three times
  4. dry with materialdry over Na2SO4
  5. filtrationfilter
  6. concentrationconcentrate
  7. customto give a residue
  8. waitAfter 1 hr
  9. extractionextract with ethylacetate/hexanes (1:2) twice
  10. extractionextract with methylene dichloride three time
  11. dry with materialCombine methylene dichloride layers, dry over Na2SO4
  12. filtrationfilter
  13. concentrationconcentrate
  14. customto give a residue
  15. customPurify by silica gel chromatography
  16. washeluting with 6.5% 2M NH3-methanol in methylene dichloride

Sources & evidence

ORD record
ord-4e82acdab76b4a56bd6c7623b9bd5fa9
Source dataset
uspto-grants-2009_10
Patent number
US07608629B2

Reaction notes

Loading…