1,10-Phenanthroline → 4-(4-Chloro-2-fluorobenzyloxy)pyridin-2(1H)-one

HRID 474943Notes

Reaction equation

HRID 474943 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([F:10])[CH:3]=1.Cl[C:12]1[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=[O:20].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.[Cu]I.C(O)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:16]2[CH:15]=[CH:14][NH:13][C:12](=[O:20])[CH:17]=2)=[C:4]([F:10])[CH:3]=1

Participants

8

Reactant 4

HCID 13181,10-PhenanthrolineHCID 10796Cesium carbonateHCID 15165112-Chloro-4-iodopyridineHCID 2773609(4-Chloro-2-fluorophenyl)methanol

Product 1

HCID 580922574-(4-Chloro-2-fluorobenzyloxy)pyridin-2(1H)-oneYield 28%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 1140TolueneSolventHCID 18673298Formic acid--water (1/1)Solvent

Conditions

Temperature
105 °C

Procedure

A suspension of (4-chloro-2-fluorophenyl)methanol (3.24 g, 20.1 mmol), 2-chloro-4-iodopyridine (4.40 g, 18.3 mmol), Cs2CO3 (7.76 g, 23.8 mmol), CuI (3.48 g, 18.7 mmol) and 1,10-phenanthroline (659 mg, 3.66 mmol) in toluene (20 mL) was degassed by bubbling N2 through the suspension for 15 min. The suspension was put under N2 and heated at 105° C. for 18 h. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was passed through a plug of SiO2. The resulting solution was concentrated under reduced pressure. Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. A suspension of the white solid and NH4OAc (2.66 g, 34.6 mmol) in 1:1 HCO2H/H2O (20 mL) was heated at reflux with stirring for 4 d. The solution was cooled and concentrated under reduced pressure. The resulting residue was made basic with saturated NaHCO3 solution, and the resulting suspension was filtered. The solid was washed with H2O and CH2Cl2, and dried under reduced pressure to afford 1.28 g (28%) of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.14 (br s, 1H), 7.59 (dd, J=8.1, 8.1 Hz, 1H), 7.52 (dd, J=10.2, 1.8 Hz, 1H), 7.36 (dd, J=8.1, 1.8 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 5.89 (d, J=7.2, 2.4 Hz, 1H), 5.83 (d, J=2.4 Hz, 1H), 5.06 (s, 2H).

Workup

  1. customwas degassed
  2. customby bubbling N2 through the suspension for 15 min
  3. temperatureThe suspension was cooled
  4. addition9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added
  5. concentrationThe resulting solution was concentrated under reduced pressure
  6. customFlash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid
  7. temperaturewas heated
  8. temperatureat reflux
  9. temperatureThe solution was cooled
  10. concentrationconcentrated under reduced pressure
  11. filtrationthe resulting suspension was filtered
  12. washThe solid was washed with H2O and CH2Cl2
  13. customdried under reduced pressure

Sources & evidence

ORD record
ord-f80e00a10e7d45f59d925ce174a8a82f
Source dataset
uspto-grants-2014_01
Patent number
US08637501B2

Reaction notes

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