Phosphorus oxychloride → 2-Benzyl-5-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine

HRID 885075Notes

Reaction equation

HRID 885075 reaction equation
[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=O)[NH:13][CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[N:13][C:14]=2[Cl:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

3

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 223351906-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one

Product 1

HCID 468398932-Benzyl-5-chloro-1,2,3,4-tetrahydro-2,6-naphthyridineYield 85%

Conditions

Temperature
100 °C

Procedure

To 6-benzyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one (2.56 g, 10.65 mmol) was added POCl3 (20 mL, 215 mmol). The mixture was heated to 100° C. for 17 h and cooled to rt. The excess POCl3 was removed under reduced pressure, and the residue quenched with sat. NaHCO3 (150 mL) and partitioned with dichloromethane (100 mL) and stirred for 30 minutes. The dichloromethane layer was collected, and the aqueous layer was extracted with dichloromethane (2×100). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration, and the organic solution was concentrated under reduced pressure. The residue was purified by BIOTAGE® flash chromatography using a 5-30% EtOAc in hexanes gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give 2-benzyl-5-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine (2.334 g, 9.02 mmol, 85% yield) as a yellow oil. LC/MS: m/z 259.01 (M+H)+, 0.775 min (method 2). 1H NMR (500 MHz, chloroform-d) δ ppm 8.10 (d, J=4.88 Hz, 1H) 7.26-7.41 (m, 5H) 6.86 (d, J=4.88 Hz, 1H) 3.69 (s, 2H) 3.58 (s, 2H) 2.84-2.89 (m, 2H) 2.78-2.83 (m, 2H).

Workup

  1. temperaturecooled to rt
  2. customThe excess POCl3 was removed under reduced pressure
  3. customthe residue quenched with sat. NaHCO3 (150 mL)
  4. custompartitioned with dichloromethane (100 mL)
  5. customThe dichloromethane layer was collected
  6. extractionthe aqueous layer was extracted with dichloromethane (2×100)
  7. dry with materialThe combined organic layers were dried with Na2SO4
  8. customThe drying agent was removed by filtration
  9. concentrationthe organic solution was concentrated under reduced pressure
  10. customThe residue was purified by BIOTAGE® flash chromatography
  11. additionThe fractions containing the expected product
  12. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-b0137bd8e3764c49adbfc43a74b671ab
Source dataset
uspto-grants-2012_08
Patent number
US08242124B2

Reaction notes

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