Cesium fluoride → 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5,8-dichloro-7-(3,5-dimethyl-1,2-oxazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

HRID 577503Notes

Reaction equation

HRID 577503 reaction equation
[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:28])[C:20](Br)=[CH:21][C:22]=3[Cl:26])[C:17]2=[O:29])=[C:13]([CH3:30])[CH:12]=[C:11]([CH3:31])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][C:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[C:36]([CH3:47])[O:35][N:34]=1.[F-].[Cs+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:28])[C:20]([C:37]4[C:33]([CH3:32])=[N:34][O:35][C:36]=4[CH3:47])=[CH:21][C:22]=3[Cl:26])[C:17]2=[O:29])=[C:13]([CH3:30])[CH:12]=[C:11]([CH3:31])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 3

HCID 25953Cesium fluorideHCID 27586563,5-Dimethylisoxazole-4-boronic acid pinacol esterHCID 867237282-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-7-bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one

Product 1

HCID 867237292-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5,8-dichloro-7-(3,5-dimethyl-1,2-oxazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-oneYield 78%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-7-bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (253 g, 500 mg, 0.96 mmol), 3,5-Dimethylisoxazole-4-boronic acid pinacol ester (320 mg, 1.44 mmol), cesium fluoride (437 mg, 2.88 mmol) and tetrakis(triphenylphosphine)palladium(0) (70.0 mg, 0.06 mmol) in dioxane (20 mL) was degassed with nitrogen, then stirred at 100° C. for 18 hours. After cooling, the mixture was partitioned between water (15 mL) and ethyl acetate (3×20 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluting with 10:1 petroleum ether/ethyl acetate), affording 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5,8-dichloro-7-(3,5-dimethyl-1,2-oxazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (253h, 400 mg, 78% yield) as a yellow oil.

Workup

  1. customwas degassed with nitrogen
  2. temperatureAfter cooling
  3. customthe mixture was partitioned between water (15 mL) and ethyl acetate (3×20 mL)
  4. washThe combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL)
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated
  7. customThe residue was purified by silica gel chromatography (eluting with 10:1 petroleum ether/ethyl acetate)

Sources & evidence

ORD record
ord-0d5e0290fdd348a7a35adc3c0b302b3c
Source dataset
uspto-grants-2015_05
Patent number
US09040515B2

Reaction notes

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