Lithium Chloride → 2-(3-Fluoro-6-methylpyridin-2-yl)-5-methylpyridine 1-oxide

HRID 1522571Notes

Reaction equation

HRID 1522571 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-:9].C([Mg]Cl)(C)C.[Li+].[Cl-].Br[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([CH3:25])[N:19]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:24][C:23]1[C:18]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=2[O-:9])=[N:19][C:20]([CH3:25])=[CH:21][CH:22]=1

Participants

8

Reactant 4

HCID 433294Lithium ChlorideHCID 131787372-Bromo-5-methylpyridine 1-oxideHCID 248203182-Bromo-3-fluoro-6-methylpyridineHCID 178418918HCID 178418918, compound

Product 1

HCID 674695392-(3-Fluoro-6-methylpyridin-2-yl)-5-methylpyridine 1-oxideYield 187.2%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

To a cooled solution (−40 to −45° C.) of 2-bromo-5-methylpyridine 1-oxide (12 g, 63.8 mmol) in dry THF (250 mL) was added a solution of i-PrMgCl.LiCl (127 mL, 165.8 mmol, 1.3M) in THF and the reaction mixture was stirred for 1 hour at −40° C. Dry ZnCl2 (1 g, 127. mmol) was added and the reaction was warmed to room temperature and stirred for 1 hour. 2-Bromo-3-fluoro-6-methylpyridine (2 g, 127. mmol) and Pd(PPh3)4 (5. g, 4.4 mmol) were added and the reaction mixture was refluxed for 20 hours. The mixture was cooled 0° C. and stirred for 1 hour to afford a solid. The solid was collected by filtration and then dissolved in dichloromethane and washed with a saturated solution of ethylenediaminetetraacetic acid and saturated K2CO3 successively. The organic layers were separated, dried, and concentrated to give a residue which was purified by flash silica chromatography eluted with dichloromethane/MeOH (50:1) to give 2-(3-fluoro-6-methylpyridin-2-yl)-5-methylpyridine 1-oxide (4.3 g; 30.1%). 1HNMR (CDCL3): δ ppm 8.22 (s, 1H), 7.47-7.42 (m, 2H), 7.30-7.27 (m, 1H), 7.20-7.28 (m, 1H), 2.61 (s, 3H), 2.38 (s, 3H). MS [M+H] found 219.0.

Workup

  1. temperaturethe reaction mixture was refluxed for 20 hours
  2. temperatureThe mixture was cooled 0° C.
  3. stirringstirred for 1 hour
  4. customto afford a solid
  5. filtrationThe solid was collected by filtration
  6. dissolutiondissolved in dichloromethane
  7. washwashed with a saturated solution of ethylenediaminetetraacetic acid and saturated K2CO3 successively
  8. customThe organic layers were separated
  9. customdried
  10. concentrationconcentrated
  11. customto give a residue which
  12. customwas purified by flash silica chromatography
  13. washeluted with dichloromethane/MeOH (50:1)

Sources & evidence

ORD record
ord-38afd5a1f45f467194165429b96f01e0
Source dataset
uspto-grants-2015_07
Patent number
US09073918B2

Reaction notes

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