Morpholine → 2-Chloro-5-(morpholin-4-yl)aniline

HRID 1431575Notes

Reaction equation

HRID 1431575 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([CH:8]=1)[NH2:7].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.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].O>[Cl:9][C:5]1[CH:4]=[CH:3][C:2]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:8][C:6]=1[NH2:7]

Participants

8

Reactant 4

HCID 8083MorpholineHCID 38307312-Chloro-5-bromoanilineHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 672859322-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

Product 1

HCID 176073522-Chloro-5-(morpholin-4-yl)aniline

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of 5-bromo-2-chloroaniline (2.0 g, 9.74 mmol), morpholine (4.3 mL, 49 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (0.37 g, 0.79 mmol), and tris(dibenzylideneacetone)dipalladium (0) (0.37 g, 0.4 mmol) in dry THF (20 mL) was degassed by nitrogen. To this mixture was added 1.0M lithium bis(trimethylsilyl)amide in THF (54 mL) dropwise, and the resulting reaction was heated to 60° C. After 2 h, the reaction was cooled to rt then cond under reduced pressure to ˜5 mL. After pouring into water, the mixture was extracted twice with EtOAc and twice with DCM. After the combined organic layers were dried over anhydrous magnesium sulfate, filtration, and concentration, the residue was purified on silica gel (0-30% EtOAc in hexanes) to yield 2-chloro-5-morpholinoaniline. 1H NMR (400 MHz, CDCl3) δ ppm 7.19 (1H, m), 6.41 (2H, m), 4.00 (2H, br. s.), 3.93 (4H, m), 3.22 (4H, m).

Workup

  1. customwas degassed by nitrogen
  2. additionTo this mixture was added 1.0M lithium bis(trimethylsilyl)amide in THF (54 mL) dropwise
  3. customthe resulting reaction
  4. temperaturethe reaction was cooled to rt
  5. extractionthe mixture was extracted twice with EtOAc and twice with DCM
  6. dry with materialAfter the combined organic layers were dried over anhydrous magnesium sulfate, filtration, and concentration
  7. customthe residue was purified on silica gel (0-30% EtOAc in hexanes)

Sources & evidence

ORD record
ord-a531dddb1390436b948788f58208e71f
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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