Imidazole → HCID 66661663, compound

HRID 336648Notes

Reaction equation

HRID 336648 reaction equation
[OH:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:14].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>CN(C=O)C>[Si:22]([O:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:14])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]

Participants

6

Reactant 4

HCID 795ImidazoleHCID 962WaterHCID 28928tert-Butyldimethylsilyl chlorideHCID 65453727HCID 65453727, compound

Product 1

HCID 66661663HCID 66661663, compoundYield 54%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 4-(2-hydroxy-2-methylpropoxy)-3,5-dimethyl benzonitrile (2.90 g, 13.2 mmol) in anhydrous DMF (20 mL) was added imidazole (2.7 g, 40 mmol) and tert-butyldimethylsilylchloride (2.19 g, 14.6 mmol). The reaction mixture was stirred at room temperature under nitrogen for 3 d. Water (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude compound was purified by column chromatography to give 4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylbenzonitrile (2.24 g, 54%). N-Butyl lithium (6.2 mL, 6.6 mmol, 1.6 M solution in hexanes) was added to a solution of 2,4-dimethoxy-6-N-dimethylbenzamide (0.9 g, 4.3 mmol) in anhydrous THF (10 mL) drop-wise at −10° C. over a period of 10 min under nitrogen. The stirring was continued at 0° C. for 1 h. The reaction mixture was cooled to −50° C. A solution of 4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylbenzonitrile (1.58 g, 4.73 mmol) in anhydrous THF (5 mL) was quickly added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The stirring was continued at room temperature for 1 h. An aqueous ammonium chloride solution (10 mL) was added followed by ethyl acetate (100 mL). The organic layer was separated, washed with water (10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 0-5% methanol in CH2Cl2 as eluent) to give 3-{4-[2-(tert-butyldimethylsilanyloxy)-2-methylpropoxy]-3,5-dimethylphenyl}-6,8-dimethoxy-2H-isoquinolin-1-one (0.82 g, 37%), as a white solid.

Workup

  1. extractionthe mixture was extracted with ethyl acetate (200 mL)
  2. washThe organic layer was washed with water (2×100 mL) and brine (100 mL)
  3. dry with materialdried over anhydrous Na2SO4
  4. customThe solvent was removed under reduced pressure
  5. customthe crude compound was purified by column chromatography

Sources & evidence

ORD record
ord-3b31ebc34968418c8fa08dff08d84d3e
Source dataset
uspto-grants-2014_11
Patent number
US08889698B2

Reaction notes

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