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

HRID 882053

Reaction equation

HRID 882053 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].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>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C:16]1[CH:15]=[CH:14][NH:13][C:12](=[O:20])[CH:17]=1

Participants

8

Reactant 4

HCID 13181,10-PhenanthrolineHCID 10796Cesium carbonateHCID 918672,4-Difluorobenzyl alcoholHCID 15165112-Chloro-4-iodopyridine

Product 1

HCID 220503904-(2,4-difluorobenzyloxy)-1H-pyridin-2-oneYield 44%

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 (2,4-difluorophenyl)methanol (4.86 g, 33.7 mmol), 2-chloro-4-iodopyridine (7.35 g, 30.7 mmol), Cs2CO3 (14.3 g, 43.8 mmol), CuI (5.83 g, 30.7 mmol) and 1,10-phenanthroline (1.11 g, 6.14 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, EtOAc (50 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 (8.21 g, 107 mmol) in 1:1 HCO2H/H2O (40 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 dried under reduced pressure to afford 3.16 g (44%) of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.14 (br s, 1H), 7.62 (br dd, J=15.3, 8.7 Hz, 1H), 7.33 (ddd, J=10.5, 10.5, 2.4 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 7.12 (ddd, J=8.4, 8.4, 1.8 Hz, 1H), 5.91-5.82 (m, 2H), 5.06 (s, 2H).

Workup

  1. customwas degassed
  2. customby bubbling N2 through the suspension for 15 min
  3. temperatureThe suspension was cooled
  4. additionEtOAc (50 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
  13. customdried under reduced pressure

Sources & evidence

ORD record
ord-0145a815c96d4349a087389612acb844
Source dataset
uspto-grants-2015_03
Patent number
US08993765B2

Linked notes

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