N-Methoxy-N-methylacetamide → Ethanone, 1-(2-chloro-8-quinolinyl)-

HRID 1055839Notes

Reaction equation

HRID 1055839 reaction equation
Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[CH:8]=[CH:7]2.[Li]CCCC.CON(C)[C:21](=[O:23])[CH3:22]>C1COCC1>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([C:21](=[O:23])[CH3:22])[CH:3]=[CH:4][CH:5]=2)[N:10]=1

Participants

5

Reactant 3

HCID 537505N-Methoxy-N-methylacetamideHCID 109557558-Bromo-2-chloroquinolineHCID 178418339Butyllithium

Product 1

HCID 89782085Ethanone, 1-(2-chloro-8-quinolinyl)-Yield 43%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 8-bromo-2-chloroquinoline (Biofine International, Vancouver, BC; 10.0 g, 41.2 mmol) in 200 mL THF in a dry ice/acetone bath was added nBuLi solution (2.5 M in hexanes; 18.14 ml, 45.4 mmol) slowly (dropwise) via addition funnel such that the internal temperature did not exceed −72° C. After 15 min, N-methoxy-N-methylacetamide (Aldrich; 5.05 ml, 49.5 mmol) was added via syringe such that the internal temperature did not exceed −72° C. The dry ice/acetone bath was removed and the reaction was quenched with 200 mL saturated aq. NH4Cl and diluted with 300 mL Et2O. The organic layer was washed 1× brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (240 g column) using 0-20% EtOAc/hexanes until less polar impurities elute, then 20-40% EtOAc/hexanes to elute desired material. Fractions were combined and concentrated to give 1-(2-chloroquinolin-8-yl)ethanone (3.63 g, 17.65 mmol, 43% yield) as a peach-colored solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.16 (1H, d, J=8.6 Hz), 8.06 (1H, dd, J=7.2, 1.6 Hz), 7.96 (1H, dd, J=8.0, 1.6 Hz), 7.59-7.66 (1H, m), 7.46 (1H, d, J=8.6 Hz), 2.98 (3H, s). m/z (ESI, +ve) 206.0 (M+H)+.

Workup

  1. additionvia addition funnel such that the internal temperature
  2. customdid not exceed −72° C
  3. customdid not exceed −72° C
  4. customThe dry ice/acetone bath was removed
  5. customthe reaction was quenched with 200 mL saturated aq. NH4Cl
  6. additiondiluted with 300 mL Et2O
  7. washThe organic layer was washed 1× brine
  8. dry with materialdried over anhydrous MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. additionThe material was treated with DCM
  12. custompurified by silica gel chromatography (240 g column)
  13. washelute
  14. wash20-40% EtOAc/hexanes to elute desired material
  15. concentrationconcentrated

Sources & evidence

ORD record
ord-00f9284633a84495be382b3228d4ed14
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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