Sodium hydride → 5-Formyl-2-{[(1R)-1-methylpropyl]oxy}benzonitrile

HRID 423324

Reaction equation

HRID 423324 reaction equation
[CH3:1][C@@H:2]([OH:5])[CH2:3][CH3:4].[H-].[Na+].F[C:9]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:10]=1[C:11]#[N:12]>CN(C=O)C>[CH:17]([C:14]1[CH:15]=[CH:16][C:9]([O:5][C@H:2]([CH3:1])[CH2:3][CH3:4])=[C:10]([CH:13]=1)[C:11]#[N:12])=[O:18]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 84682(-)-2-ButanolHCID 27695822-Fluoro-5-formylbenzonitrile

Product 1

HCID 866414345-Formyl-2-{[(1R)-1-methylpropyl]oxy}benzonitrileYield 11.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

(2R)-2-Butanol (0.99 g, 0.013 mol) was dissolved in DMF (50 ml) and the solution cooled to 0° C. To this was added sodium hydride, 60% dispersion in mineral oil (1.54 g, 0.036 mol) in a portion-wise manner, the mixture was stirred at 0° C. for 10 minutes after complete addition. 2-Fluoro-5-formylbenzonitrile (2.0 g, 0.013 mol) was then added and the reaction mixture allowed to warm to room temperature (slowly within the ice bath) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then cooled to 0° C., quenched with brine and diluted with EtOAc (˜25 ml). The mixture was partitioned and the organic fraction extracted with water (˜30 ml), the combined organics were dried by passing through a phase separating cartridge and evaporated to dryness under reduced pressure to give the crude product. The crude residue was purified on a 40+M Biotage cartridge, eluting with a 20 to 50% mixture of EtOAc in hexane. This gave the title compound (310 mg) as a yellow oil. δH (d6-DMSO, 400 MHz): 9.88 (1H, s), 8.30 (1H, s), 8.15 (1H, d), 7.49 (1H, d), 4.73-4.81 (1H, m), 1.63-1.79 (2H, m), 1.33 (3H, d), 0.95 (3H, t) ppm.

Workup

  1. additionafter complete addition
  2. stirringwas stirred overnight at room temperature
  3. temperatureThe reaction mixture was then cooled to 0° C.
  4. customquenched with brine
  5. additiondiluted with EtOAc (˜25 ml)
  6. customThe mixture was partitioned
  7. extractionthe organic fraction extracted with water (˜30 ml)
  8. customthe combined organics were dried
  9. customseparating cartridge
  10. customevaporated to dryness under reduced pressure
  11. customto give the crude product
  12. customThe crude residue was purified on a 40+M Biotage cartridge
  13. washeluting with a 20 to 50% mixture of EtOAc in hexane

Sources & evidence

ORD record
ord-261e3f0ad46e4b05ae721972548880b3
Source dataset
uspto-grants-2012_01
Patent number
US08101775B2

Linked notes

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