2-Methyl-3-buten-2-ol → (3E)-4-[(1S,3R)-3-[[[(1,1-Dimethylethyl)dimethylsilyl]oxy]methyl]-1,2,3,4-tetrahydro-1-methyl-5-isoquinolinyl]-2-methyl-3-buten-2-ol

HRID 1854560Notes

Reaction equation

HRID 1854560 reaction equation
Cl.Br[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][C@H:6]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[NH:7][C@H:8]2[CH3:13].[CH3:23][C:24]([OH:28])([CH:26]=[CH2:27])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CN(C)C=O>[Si:16]([O:15][CH2:14][C@H:6]1[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2/[CH:27]=[CH:26]/[C:24]([CH3:25])([OH:28])[CH3:23])[C@H:8]([CH3:13])[NH:7]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]

Participants

7

Reactant 3

HCID 82572-Methyl-3-buten-2-olHCID 11430Potassium CarbonateHCID 122412747(1S,3R)-5-Bromo-3-[[(tert-butyldimethylsilyl)oxy]methyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride

Product 1

HCID 131732505(3E)-4-[(1S,3R)-3-[[[(1,1-Dimethylethyl)dimethylsilyl]oxy]methyl]-1,2,3,4-tetrahydro-1-methyl-5-isoquinolinyl]-2-methyl-3-buten-2-olYield 63.4%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
125 °C

Procedure

Add (1S,3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (310 g, 723.83 mmol) and 2-methylbut-3-en-2-ol (508.95 g, 5.79 mol) to N,N-dimethylformamide (1.08 L) in an appropriate vessel and degas by bubbling nitrogen through the solution for 10 minutes. Add potassium carbonate (315.12 g, 2.28 mol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (15.32 g, 36.19 mmol) and palladium (II) acetate (8.29 g, 36.19 mmol) and degas by bubbling nitrogen through the mixture for 15 minutes then heat to 125° C. After 16 hours, cool the mixture to 20° C. and dilute with ethyl acetate (1.5 L) and water (2.5 L). Wash the ethyl acetate layer with brine (2.5 L), then dry over sodium sulfate and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography, eluting with 0-50% ethyl acetate in isohexanes to give the title compound (193 g, 459.1 mmol). MS (m/z): 376(M+1).

Workup

  1. customdegas
  2. customby bubbling nitrogen through the solution for 10 minutes
  3. customby bubbling nitrogen through the mixture for 15 minutes
  4. temperaturecool the mixture to 20° C.
  5. additiondilute with ethyl acetate (1.5 L) and water (2.5 L)
  6. washWash the ethyl acetate layer with brine (2.5 L)
  7. dry with materialdry over sodium sulfate
  8. concentrationconcentrate under reduced pressure
  9. customto give a residue
  10. customPurify the residue by flash chromatography
  11. washeluting with 0-50% ethyl acetate in isohexanes

Sources & evidence

ORD record
ord-970d0761181244398a049f7f455675ba
Source dataset
uspto-grants-2015_02
Patent number
US08962654B2

Reaction notes

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