4-Methoxybenzyl alcohol → 3-Bromo-2-fluoro-5-((4-methoxybenzyloxy)methyl)pyridine

HRID 1621439Notes

Reaction equation

HRID 1621439 reaction equation
[Br:1][C:2]1[C:3]([F:10])=[N:4][CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1.[Al]>CC#N.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Ag-]=O>[Br:1][C:2]1[C:3]([F:10])=[N:4][CH:5]=[C:6]([CH2:8][O:18][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:7]=1

Participants

7

Reactant 3

HCID 77384-Methoxybenzyl alcoholHCID 5359268AluminumHCID 595482443-Bromo-5-(bromomethyl)-2-fluoropyridine

Product 1

HCID 595482913-Bromo-2-fluoro-5-((4-methoxybenzyloxy)methyl)pyridineYield 24%

Reagents, catalysts & solvents 3

HCID 67553Tetrabutylammonium IodideCatalystHCID 178418778HCID 178418778, compoundCatalystHCID 6342AcetonitrileSolvent

Procedure

3-Bromo-5-(bromomethyl)-2-fluoropyridine (5.63 g, 20.9 mmol) was dissolved in MeCN (135 mL) and 4-methoxybenzyl alcohol (5.20 mL, 41.9 mmol), silver (I) oxide (7.169 g, 30.9 mmol), and tetrabutylammonium iodide (2.208 g, 5.98 mmol) were added. The reaction flask was covered with aluminum foil and the reaction was stirred under nitrogen at room temperature overnight. The reaction was filtered through a pad of Celite® (diatomaceous earth), washing with DCM, MeOH and MeCN. The filtrate was concentrated and purified on a silica gel column (3:1 to 2:1 to 3:2 hexanes/DCM to 3:2 DCM/hexanes to 2:1 DCM/hexanes to 3:1 DCM/hexanes to DCM) to give 3-Bromo-2-fluoro-5-((4-methoxybenzyloxy)methyl)pyridine (1.62 g, 24%). MS (ESI pos. ion) m/z 326/328 (M+H)+.

Workup

  1. filtrationThe reaction was filtered through a pad of Celite® (diatomaceous earth)
  2. washwashing with DCM, MeOH and MeCN
  3. concentrationThe filtrate was concentrated
  4. custompurified on a silica gel column (3:1 to 2:1 to 3:2 hexanes/DCM to 3:2 DCM/hexanes to 2:1 DCM/hexanes to 3:1 DCM/hexanes to DCM)

Sources & evidence

ORD record
ord-ab5a002a5d574e6f8c2231af6515db9c
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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