HCID 16113114, compound → 2-Hydroxyquinoline

HRID 1958218Notes

Reaction equation

HRID 1958218 reaction equation
OC1C=CC([C:8]2[NH:9][C:10](=[O:22])[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14](OC)=[CH:13][C:12]=3OC)=CC=1.C([Li])CCC>C1COCC1>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:8][N:9]=1.[NH:9]1[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]1=[O:22]

Participants

5

Reactant 2

HCID 16113114HCID 16113114, compoundHCID 178418339Butyllithium

Product 2

HCID 60382-HydroxyquinolineHCID 8405Isoquinoline

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a suspension of 2-methyl-4,6-dimethoxy benzoic acid (2.8 g, 14.27 mmol) in CH2Cl2 (30 mL), oxalyl chloride (3.62 g, 28.54 mmol) was added and the mixture was stirred at room temperature for 16 hours. The solvent and excess of oxalyl chloride were removed at reduced pressure. The solid was dissolved in CH2Cl2 (10 mL) and methyl amine hydrochloride (1.33 g, 42.81 mmol) was added on cooling and the mixture was stirred at room temperature for 4 hours. The solvent was removed and the crude product was purified by chromatography by using 5% methanol in CH2Cl2, to give 1.3 g of the amide intermediate in 43% yield. To a solution of the amide intermediate (1.29 g, 6.16 mmol) in THF (30 mL), n-butyl lithium (5.6 mL, 14.18 mmol, 2.5 M solution in hexane) was added slowly under nitrogen with cooling (ice-salt bath) maintaining the temperature below 20° C. The mixture was stirred for 1 h at 0° C., then cooled to −50° C. and a solution of 4-O-TBDMS-benzonitrile (1.58 g, 6.78 mmol) in THF (10 mL) was added quickly. The cooling bath was removed and allowed to warm to room temperature and stirred for 16 h at room temperature. Saturated aqueous NH4Cl solution was added with cooling, and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give the crude intermediate, which was purified by chromatography using 5% methanol in CH2Cl2, to give two products (1) 678 mg of isoquinoline in 26% yield and (2) 780 mg of quinolone product in 27% yield. To a suspension of the above quinolone product (2) (780 mg, 1.65 mmol) in ethanol (20 mL), conc. HCl (2 mL) was added and the mixture was heated at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and the solvent was removed and purified by chromatography using 5% methanol in CH2Cl2 to give 3-(4-hydroxyphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (215 mg, 44%). MS (ES) m/z: 297.93 (M); MP 245-247° C.

Workup

  1. temperaturemaintaining the temperature below 20° C
  2. temperaturecooled to −50° C.
  3. customThe cooling bath was removed
  4. temperatureto warm to room temperature
  5. stirringstirred for 16 h at room temperature
  6. additionSaturated aqueous NH4Cl solution was added
  7. temperaturewith cooling
  8. customthe layers were separated
  9. washThe organic layer was washed with water, brine
  10. dry with materialdried over Na2SO4
  11. concentrationconcentrated
  12. customto give the crude intermediate, which
  13. customwas purified by chromatography

Sources & evidence

ORD record
ord-bf6d04fa60f6402bb3a12e7200e7cd19
Source dataset
uspto-grants-2013_04
Patent number
US08410109B2

Reaction notes

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