Potassium bis(trimethylsilyl)amide → 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5-bromo-8-chloro-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one

HRID 577520Notes

Reaction equation

HRID 577520 reaction equation
[Br:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]([Cl:16])=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:17].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:28]([O:35][C:36]1[C:41]([CH2:42]Cl)=[C:40]([CH3:44])[CH:39]=[C:38]([CH3:45])[N:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCOCC1>[CH2:28]([O:35][C:36]1[C:41]([CH2:42][N:6]2[CH2:5][CH2:4][C:3]3[C:8](=[C:9]([Cl:16])[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:11][C:2]=3[Br:1])[C:7]2=[O:17])=[C:40]([CH3:44])[CH:39]=[C:38]([CH3:45])[N:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1

Participants

5

Reactant 3

HCID 3251421Potassium bis(trimethylsilyl)amideHCID 612578682-(Benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridineHCID 867237465-bromo-8-chloro-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one

Product 1

HCID 867237472-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5-bromo-8-chloro-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-oneYield 44%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

To a solution of 5-bromo-8-chloro-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (77d, 188 mg, 0.590 mmol) in anhydrous 1,4-dioxane (10 mL) was added KHMDS (2.00 mL, 2.00 mmol). Upon addition, a dark red paste was formed. After stirring at room temperature for 30 minutes, 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 170 mg, 0.649 mmol) was added. The resulting reaction mixture was stirred at 100° C. for 5 hours. After cooling to room temperature, the reaction mixture was quenched with water, and extracted with ethyl acetate (2×50 mL). The combined organic phases were dried over sodium sulfate, concentrated under vacuum, and purified by column chromatography (0-40% EtOAc/heptanes) to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5-bromo-8-chloro-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (77e, 140 mg, 44%).

Workup

  1. additionUpon addition
  2. customa dark red paste was formed
  3. customThe resulting reaction mixture
  4. stirringwas stirred at 100° C. for 5 hours
  5. temperatureAfter cooling to room temperature
  6. customthe reaction mixture was quenched with water
  7. extractionextracted with ethyl acetate (2×50 mL)
  8. dry with materialThe combined organic phases were dried over sodium sulfate
  9. concentrationconcentrated under vacuum
  10. custompurified by column chromatography (0-40% EtOAc/heptanes)

Sources & evidence

ORD record
ord-ae844b6725bd499f9c3a697293e3274a
Source dataset
uspto-grants-2015_05
Patent number
US09040515B2

Reaction notes

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