4-Cyanopyridine → 4-(2,5-Difluorobenzoyl)pyridine

HRID 2260499Notes

Reaction equation

HRID 2260499 reaction equation
C([Li])CCC.CN(C)[CH2:8][CH2:9][N:10](C)[CH2:11][CH2:12]N(C)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.C(C1C=CN=CC=1)#N.C1C[O:37][CH2:36][CH2:35]1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[C:36]([C:35]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)=[O:37]

Participants

6

Reactant 5

HCID 75064-CyanopyridineHCID 8028Tetrahydrofuran3×HCID 108921,4-DifluorobenzeneHCID 18196PentamethyldiethylenetriamineHCID 178418339Butyllithium

Product 1

HCID 189984524-(2,5-Difluorobenzoyl)pyridineYield 51.5%

Conditions

Temperature
-75 °C

Procedure

Butyl lithium (70 ml of 2.22M solution, 155 mmole) was added to a solution of pentamethyldiethylenetriamine (23.3 ml, 155 mmole) in THF (250 ml) at -70° C. The solution was stirred for 5 min and 1,4-difluorobenzene (17.7 g, 155 mmole) in THF was added at -70° C. The solution was stirred for 2 hr during which time it was cooled to -75° C. and 4-cyanopyridine (15.6 g, 150 mmole) in THF was added at -75° C. The mixture was allowed to warm to 25° C. slowly and then quenched with ammonium chloride solution. The mixture was diluted with ether and the organic layer was separated. The organic layer was washed with water and 3N hydrochloric acid. The acid washes were stirred for 2 hr and basified with sodium hydroxide. The basic mixture was extracted with ether and the ether solution concentrated in vacuo. The crude product was purified by chromatography on silica eluting with ethyl acetate-hexane (20:1) to give 4-(2,5-difluorobenzoyl)pyridine (16.9 g, 51.5%).

Workup

  1. stirringThe solution was stirred for 2 hr during which time it
  2. temperatureto warm to 25° C. slowly
  3. customquenched with ammonium chloride solution
  4. additionThe mixture was diluted with ether
  5. customthe organic layer was separated
  6. washThe organic layer was washed with water and 3N hydrochloric acid
  7. stirringThe acid washes were stirred for 2 hr and basified with sodium hydroxide
  8. extractionThe basic mixture was extracted with ether
  9. concentrationthe ether solution concentrated in vacuo
  10. customThe crude product was purified by chromatography on silica eluting with ethyl acetate-hexane (20:1)

Sources & evidence

ORD record
ord-88d026e004ce49afb5f98138d1ed0b6f
Source dataset
uspto-grants-1995_12
Patent number
US05478828

Reaction notes

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