Morpholine → 2-Methoxy-6-methyl-4-morpholin-4-yl-phenylamine

HRID 905573Notes

Reaction equation

HRID 905573 reaction equation
C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[K+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.Br[C:42]1[CH:47]=[C:46]([CH3:48])[C:45]([NH2:49])=[C:44]([O:50][CH3:51])[CH:43]=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].C1(C)C=CC=CC=1>[CH3:51][O:50][C:44]1[CH:43]=[C:42]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:47]=[C:46]([CH3:48])[C:45]=1[NH2:49]

Participants

7

Reactant 4

HCID 8083MorpholineHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 106802184-Bromo-2-methoxy-6-methylanilineHCID 23665647Potassium tert-butoxide

Product 1

HCID 674062832-Methoxy-6-methyl-4-morpholin-4-yl-phenylamineYield 29%

Reagents, catalysts & solvents 2

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumCatalystHCID 1140TolueneSolvent

Procedure

Bis(dibenzylideneacetone)palladium (0.63 g) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (0.68 g) were added to dry toluene (100 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (3.70 g), morpholine (4.0 mL) and 4-bromo-2-methoxy-6-methyl-phenylamine (3.40 g) were added subsequently. The reaction mixture was heated to reflux for 16 hours under argon, cooled and filtered through silica (50 g). Sodium hydroxide (2 M, 200 mL) was added and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with brine (1×200 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 1.0 g (29% yield) of the title compound as a black oil. 1H NMR (500 MHz, DMSO-d6): 2.05 (s, 3H), 2.91 (t, 4H), 3.69 (t, 4H), 3.74 (s, 3H), 3.95 (s, 2H), 6.23 (d, 1H), 6.39 (d, 1H).

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureto reflux for 16 hours under argon
  3. temperaturecooled
  4. filtrationfiltered through silica (50 g)
  5. additionSodium hydroxide (2 M, 200 mL) was added
  6. extractionthe mixture was extracted with ethyl acetate (3×200 mL)
  7. washThe combined organic phases were washed with brine (1×200 mL)
  8. dry with materialdried over magnesium sulfate
  9. concentrationconcentrated in vacuo
  10. customThe crude product was purified by flash chromatography

Sources & evidence

ORD record
ord-a09d413b69a54336b79f7aa552dff6ae
Source dataset
uspto-grants-2011_09
Patent number
US08012962B2

Reaction notes

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