Isobutyronitrile → 2-(3-Chloro-5-hydroxymethyl-pyridin-2-yl)-2-methyl-propionitrile

HRID 1438309Notes

Reaction equation

HRID 1438309 reaction equation
[Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:12](#[N:16])[CH:13]([CH3:15])[CH3:14].C[Si](C)(C)[N-][Si](C)(C)C.[K+].B.C1COCC1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:3]([C:13]([CH3:15])([CH3:14])[C:12]#[N:16])=[N:4][CH:5]=[C:6]([CH2:7][OH:9])[CH:10]=1

Participants

9

Reactant 5

HCID 6559IsobutyronitrileHCID 11430Potassium CarbonateHCID 2479875,6-Dichloronicotinic acidHCID 2723981Borane;tetrahydrofuranHCID 3251421Potassium bis(trimethylsilyl)amide

Product 1

HCID 587640982-(3-Chloro-5-hydroxymethyl-pyridin-2-yl)-2-methyl-propionitrileYield 32.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
60 °C

Procedure

To a magnetically stirring solution of 5,6 dichloronicotinic acid (2.7 g, 14.06 mmol) in THF (70.0 mL), was added isobutyronitrile (6.37 mL, 69.66 mmol) followed by potassium hexamethyldisilazide 0.5 M in toluene (70 mL). The resulting orange mixture was stirred at 60° C. overnight. Solvents were removed and residue portioned between ethyl acetate (100 mL) and 1N HCl (100 mL). The layers of the resulting reaction mixture were separated and the aqueous layer was extracted three additional times with ethyl acetate. The organic layers were combined and dried over Na2SO4, filtered and concentrated in vacuo to a yellow solid (3.34 g). This crude residue was dissolved in THF (80 mL) and reaction cooled to 0° C. BH3.THF 1 M solution in THF (22.30 mL) was added and reaction stirred at 0° C. for 4 hours, then room temperature overnight. Solid K2CO3 (2 g) and water (100 mL) were added and the aqueous layer was extracted three additional times with ethyl acetate. The organics were combined dried over Na2SO4, filtered and concentrated in vacuo to a clear oil which was purified by silica gel chromatography (hexanes) to give the title compound as a white solid (0.95 g, 32%). ESIMS (MH+): 210.

Workup

  1. customSolvents were removed
  2. customThe layers of the resulting reaction mixture
  3. customwere separated
  4. extractionthe aqueous layer was extracted three additional times with ethyl acetate
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo to a yellow solid (3.34 g)
  8. dissolutionThis crude residue was dissolved in THF (80 mL)
  9. customreaction
  10. temperaturecooled to 0° C
  11. customreaction
  12. stirringstirred at 0° C. for 4 hours
  13. customroom temperature overnight
  14. extractionthe aqueous layer was extracted three additional times with ethyl acetate
  15. dry with materialThe organics were combined dried over Na2SO4
  16. filtrationfiltered
  17. concentrationconcentrated in vacuo to a clear oil which
  18. customwas purified by silica gel chromatography (hexanes)

Sources & evidence

ORD record
ord-85d99599087c4fe88abe71b15a2751fd
Source dataset
uspto-grants-2009_11
Patent number
US07622605B2

Reaction notes

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