(R)-5-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-3,4-dihydroisoquinoline → (1S,3R)-5-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline

HRID 1854555Notes

Reaction equation

HRID 1854555 reaction equation
[CH3:1][Mg]Cl.[Br:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@H:8]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[N:9]=[CH:10]2>C(OCC)C>[Br:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][C@H:8]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[NH:9][C@H:10]2[CH3:1]

Participants

4

Reactant 2

HCID 123546513(R)-5-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-3,4-dihydroisoquinoline2×HCID 178418332HCID 178418332, compound

Product 1

HCID 118998349(1S,3R)-5-Bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-1,2,3,4-tetrahydroisoquinolineYield 170.8%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Conditions

Temperature
20 °C

Procedure

Add methylmagnesium chloride (0.66 L, 1.99 mol, 3M in THF) to a solution of (3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,4 dihydroisoquinoline (93.5 g, 0.24 mol) in diethyl ether (2.8 L) at −65° C. in an appropriate vessel. Then heat the reaction mixture to 20° C. over 2 hours and stir. After 16 hours, cool the mixture to 0° C. and quench the reaction with saturated aqueous ammonium chloride solution (2.5 L) and extract with ethyl acetate (2.5 L) and filter the mixture. Wash the combined organic extracts with brine (1 L), dry over anhydrous magnesium sulfate and concentrate under reduced pressure to give the crude title compound as an oil. Combine the oil with crude products from substantially same reactions run with 48 mmol and 229 mmol of [(3R)-5-bromo-3,4-dihydroisoquinolin-3-yl]methoxy-tert-butyl-dimethyl-silane and purify them by silica gel chromatography eluting with ethyl acetate in hexanes (gradient 5-65% ethyl acetate) to give the title compound (151 g, 0.41 mol). MS (m/z): 370.1 (M+1 (79Br)), 372.1 (M+1 (81Br)).

Workup

  1. temperaturecool the mixture to 0° C.
  2. customquench
  3. customthe reaction with saturated aqueous ammonium chloride solution (2.5 L)
  4. extractionextract with ethyl acetate (2.5 L)
  5. filtrationfilter the mixture
  6. washWash the combined organic extracts with brine (1 L)
  7. dry with materialdry over anhydrous magnesium sulfate
  8. concentrationconcentrate under reduced pressure
  9. customto give the crude title compound as an oil
  10. custompurify them by silica gel chromatography
  11. washeluting with ethyl acetate in hexanes (gradient 5-65% ethyl acetate)

Sources & evidence

ORD record
ord-e0eb07d1e3614624b1f03456bdaa133f
Source dataset
uspto-grants-2015_02
Patent number
US08962654B2

Reaction notes

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