Isobutyronitrile → 2-(4-Iodopyridin-2-yl)-2-methylpropanenitrile

HRID 331515Notes

Reaction equation

HRID 331515 reaction equation
Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[C:9](#[N:13])[CH:10]([CH3:12])[CH3:11].C[Si]([N-][Si](C)(C)C)(C)C.NC1N=CC(C2C=CN=C(C3(C#N)CCOCC3)C=2)=NC=1C1ON=C(C2C=CC(CNC)=CC=2)C=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:10]([CH3:12])([CH3:11])[C:9]#[N:13])[CH:7]=1

Participants

7

Reactant 4

HCID 6559IsobutyronitrileHCID 15165112-Chloro-4-iodopyridineHCID 3280088Npc316347HCID 708186554-[4-[5-Amino-6-[3-[4-(methylaminomethyl)phenyl]isoxazol-5-yl]pyrazin-2-yl]-2-pyridyl]tetrahydropyran-4-carbonitrile

Product 1

HCID 592937172-(4-Iodopyridin-2-yl)-2-methylpropanenitrileYield 65.1%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

An oven-dried flask was evacuated and back-filled with nitrogen three times. The flask was charged with 2-chloro-4-iodo-pyridine (3 g, 12.53 mmol) and isobutyronitrile (865.9 mg, 1.125 mL, 12.53 mmol) in anhydrous toluene (30.00 mL). The reaction mixture was cooled to 0° C. and treated with bis(trimethylsilyl)azanide in tetrahydrofuran (sodium ion (1)) (12.53 mL of 1 M, 12.53 mmol) over a period of 5 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred at this temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with 1 M hydrochloric acid. The aqueous layer was extracted with ethyl acetate (×3) and the combined organic extracts dried MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column) loaded with dichloromethane and eluted with 0 to 30% ethyl acetate/petroleum ether. Product fractions were combined and concentrated in vacuo to give the sub-title product as an off-white solid (2.22 g, 65% Yield). 1H NMR (400.0 MHz, DMSO-d6) δ 1.70 (s, 6H), 7.84 (dd, 1H), 7.98 (d, 1H) and 8.31 (d, 1H) ppm; LC/MS m/z 273.0 [M+H]+

Workup

  1. customAn oven-dried flask was evacuated
  2. additionback-filled with nitrogen three times
  3. temperatureto warm to ambient temperature
  4. washwashed with 1 M hydrochloric acid
  5. extractionThe aqueous layer was extracted with ethyl acetate (×3)
  6. filtrationthe combined organic extracts dried MgSO4, filtered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by column chromatography (ISCO Companion, 80 g column)
  9. washeluted with 0 to 30% ethyl acetate/petroleum ether
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-a1ed9dad63fe48b78fb9e18abeff9803
Source dataset
uspto-grants-2014_11
Patent number
US08877759B2

Reaction notes

Loading…