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

HRID 1431559Notes

Reaction equation

HRID 1431559 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([CH:8]=1)[NH2:7].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.[NH:78]1[CH2:83][CH2:82][O:81][CH2:80][CH2:79]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>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:78]2[CH2:83][CH2:82][O:81][CH2:80][CH2:79]2)=[CH:8][C:6]=1[NH2:7]

Participants

9

Reactant 5

HCID 8083MorpholineHCID 2733832Lithium HexamethyldisilazideHCID 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 8028TetrahydrofuranSolvent2×

Conditions

Temperature
60 °C

Procedure

A mixture of 5-bromo-2-chloroaniline (1.09 g, 5.29 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (202 mg, 0.42 mmol), tris(dibenzylideneacetone)dipalladium (0) (198 mg, 0.22 mmol), and morpholine (2.3 mL, 26.4 mmol) in dry THF (12 mL) was degassed by nitrogen. To this mixture was added lithium bis(trimethylsilyl)amide, 1.0M in THF (25.0 mL, 25.0 mmol) dropwise, and the resulting reaction was heated to 60° C. After 2.5 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic layers were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-45% EtOAc in hexanes) to yield 2-chloro-5-morpholinoaniline. 1H NMR (400 MHz, CDCl3) δ ppm 7.12 (1H, d, J=8.6 Hz), 6.42 (2H, m), 4.00 (2H, br. s.), 3.93 (4H, m), 3.22 (4H, m).

Workup

  1. customwas degassed by nitrogen
  2. customthe resulting reaction
  3. temperaturethe reaction was cooled to rt
  4. extractionAfter extracting twice with EtOAc and twice with DCM
  5. dry with materialthe combined organic layers were dried over anhydrous magnesium sulfate
  6. filtrationAfter filtration and concentration
  7. customthe residue was purified on silica gel (0-45% EtOAc in hexanes)

Sources & evidence

ORD record
ord-4113f4af20ca4ab0bd221b5e39b835fa
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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