2,2,6,6-Tetramethylpiperidine → (5-Bromo-2-fluorophenyl)(2-fluoro-3-(methoxymethoxy)-6-(neopentyloxy)pyridin-4-yl)methanone

HRID 455698Notes

Reaction equation

HRID 455698 reaction equation
C([Li])CCC.CC1(C)CCCC(C)(C)N1.[F:16][C:17]1[C:22]([O:23][CH2:24][O:25][CH3:26])=[CH:21][CH:20]=[C:19]([O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[N:18]=1.[Br:33][C:34]1[CH:35]=[CH:36][C:37]([F:42])=[C:38]([CH:41]=1)[CH:39]=[O:40].[NH4+].[Cl-].C[N+]1([O-])CCOCC1>C1COCC1.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.CCOC(C)=O>[Br:33][C:34]1[CH:35]=[CH:36][C:37]([F:42])=[C:38]([C:39]([C:21]2[CH:20]=[C:19]([O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[N:18]=[C:17]([F:16])[C:22]=2[O:23][CH2:24][O:25][CH3:26])=[O:40])[CH:41]=1

Participants

10

Reactant 6

HCID 130352,2,6,6-TetramethylpiperidineHCID 25517Ammonium ChlorideHCID 82029Methyl morpholine oxideHCID 7363275-Bromo-2-fluorobenzaldehydeHCID 574756602-Fluoro-3-(methoxymethoxy)-6-(neopentyloxy)pyridineHCID 178418339Butyllithium

Product 1

HCID 67383169(5-Bromo-2-fluorophenyl)(2-fluoro-3-(methoxymethoxy)-6-(neopentyloxy)pyridin-4-yl)methanone

Reagents, catalysts & solvents 3

HCID 178419074HCID 178419074, compoundCatalystHCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

A solution of n-butyllithium (1.6M in hexanes; 6.52 mL, 10.44 mmol) was added drop wise to a solution of 2,2,6,6-tetramethylpiperidine (1.897 mL, 11.24 mmol) in THF (30 mL) at −78° C. under nitrogen atmosphere. The reaction mixture was warmed to 0° C. and stirred for 25 min. The reaction mixture was cooled down again to −78° C. and a solution of 2-fluoro-3-(methoxymethoxy)-6-(neopentyloxy)pyridine (2.149 g, 8.83 mmol) in THF (5 mL) was added drop wise. The reaction mixture was kept for 1 h at −78° C., after which a solution of 5-bromo-2-fluorobenzaldehyde (1.63 g, 8.03 mmol) in THF (5 mL) was added. The reaction mixture was allowed to warm up to rt. Aqueous, saturated NH4Cl solution was added, followed by EtOAc. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the residue was dissolved in DCM (75 mL). 4-Methylmorpholine 4-oxide (1.176 g, 10.04 mmol) followed by tetrapropylammonium perruthenate (0.141 g, 0.401 mmol) were added. The reaction mixture was allowed to stir for 2 h at rt. The reaction mixture was filtered through a pad of celite and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (5-20% EtOAc/hexanes) to yield (5-bromo-2-fluorophenyl)(2-fluoro-3-(methoxymethoxy)-6-(neopentyloxy)pyridin-4-yl)methanone as a white solid.

Workup

  1. temperatureThe reaction mixture was cooled down again to −78° C.
  2. waitThe reaction mixture was kept for 1 h at −78° C.
  3. temperatureto warm up to rt
  4. customThe organic phase was separated
  5. dry with materialdried over MgSO4
  6. customThe solvent was removed under reduced pressure
  7. dissolutionthe residue was dissolved in DCM (75 mL)
  8. additionwere added
  9. stirringto stir for 2 h at rt
  10. filtrationThe reaction mixture was filtered through a pad of celite
  11. customthe solvent was removed under reduced pressure
  12. customThe residue was purified by flash chromatography (5-20% EtOAc/hexanes)

Sources & evidence

ORD record
ord-a038f6e6158a4015a4f140a5dfff4224
Source dataset
uspto-grants-2013_07
Patent number
US08497264B2

Reaction notes

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