Tris(1,1-dimethylethyl)phosphine → 2-(2,6-Difluorophenyl)-3-fluoro-6-methylpyridine

HRID 705232ノート

反応式

HRID 705232 の反応式
Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1B(O)O.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[BH4-].[Na+]>C1COCC1.O.CCO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1

参加物

10

反応物 5

HCID 83681Tris(1,1-dimethylethyl)phosphineHCID 522689Potassium FluorideHCID 27343362,6-Difluorophenylboronic acidHCID 4311764Sodium borohydrideHCID 248203182-Bromo-3-fluoro-6-methylpyridine

生成物 1

HCID 592265082-(2,6-Difluorophenyl)-3-fluoro-6-methylpyridine収率 86%

試薬・触媒・溶媒 4

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 702Ethanol溶媒HCID 962Water溶媒HCID 8028Tetrahydrofuran溶媒

反応条件

温度
60 °C

実験手順

To a solution of 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) in THF and Water (10:1, 0.2 M) was added 2,6-difluorophenylboronic acid (2.0 equiv.) and potassium fluoride (3.3 equiv.). The reaction was degassed for 10 minutes, then Pd2(dba)3 (0.05 equiv.) was added, followed by tri-t-butylphosphine (0.1 equiv.). The reaction was stirred to 60° C. for 1 hour at which point, all starting material was consumed as indicated by LC/MS. The reaction was allowed to cool to room temperature, partitioned with ethyl acetate and water, the organic phase was dried with sodium sulfate, filtered, and concentrated. The crude material was diluted in EtOH to 0.1 M, and 0.5 equiv. of NaBH4 was added to reduce the dba. The reaction was stirred for one hour at room temperature, then quenched with water and concentrated under vacuo to remove the ethanol. The product was extracted in ether, washed with brine, the organics were dried over sodium sulfate, filtered, and concentrated. The crude material was loaded on silica gel and purified via column chromatography (ISCO) eluting with hexanes and ethyl acetate (0%-10% ethyl acetate). The pure fractions were combined, and concentrated to yield 2-(2,6-difluorophenyl)-3-fluoro-6-methylpyridine as a light yellow oil in 86% yield. LC/MS=224.0 (M+H), Rt=0.84 min.

後処理

  1. customThe reaction was degassed for 10 minutes
  2. customall starting material was consumed
  3. temperatureto cool to room temperature
  4. custompartitioned with ethyl acetate and water
  5. dry with materialthe organic phase was dried with sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. additionwas added
  9. stirringThe reaction was stirred for one hour at room temperature
  10. customquenched with water
  11. concentrationconcentrated under vacuo
  12. customto remove the ethanol
  13. extractionThe product was extracted in ether
  14. washwashed with brine
  15. dry with materialthe organics were dried over sodium sulfate
  16. filtrationfiltered
  17. concentrationconcentrated
  18. custompurified via column chromatography (ISCO)
  19. washeluting with hexanes and ethyl acetate (0%-10% ethyl acetate)
  20. concentrationconcentrated

出典と根拠

ORDレコード
ord-23727fdb60bf4f428b3852a033a3ee08
出典データセット
uspto-grants-2015_11
特許番号
US09173883B2

反応ノート

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