Benzyl Alcohol → 3,5-Bis(benzyloxy)picolinonitrile

HRID 1908285Notes

Reaction equation

HRID 1908285 reaction equation
[CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Cl[C:14]1[C:15]([C:21]#[N:22])=[N:16][CH:17]=[C:18](Cl)[CH:19]=1>C1COCC1>[CH2:1]([O:8][C:14]1[C:15]([C:21]#[N:22])=[N:16][CH:17]=[C:18]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 244Benzyl AlcoholHCID 24758Sodium hydrideHCID 27696993,5-Dichloro-2-cyanopyridineHCID 178418361HCID 178418361, compound

Product 1

HCID 534879943,5-Bis(benzyloxy)picolinonitrileYield 94%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To an 80 mL microwave pressure vessel is charged dry THF (30 mL) and benzyl alcohol (6.32 mL, 61.1 mmol). The solution is cooled to 0° C. and sodium hydride (2.44 g of a 60% dispersion in mineral oil, 61.1 mmol) is added in portions. The reaction mixture is gradually allowed to warm to room temperature with efficient stirring until the evolution of hydrogen gas ceases. The solution is re-cooled to 0° C. and 3,5-dichloro-2-cyanopyridine (5.00 g, 29.1 mmol) is added, and the solution is transferred to an unfocussed Mars 5 CEM microwave reactor to 190° C., 300 W and held for 5 hours. The reaction mixture is quenched with H2O, concentrated under reduced pressure, diluted with EtOAc and washed with 2M Na2CO3, H2O and saturated aqueous NaCl. The organic layer is dried (MgSO4), filtered and concentrated under reduced pressure to give a brown solid. The crude solid is purified over silica (EtOAc:heptane, gradient 1:1 to 1:0) to afford 8.6 g (94% yield) of the desired compound as an orange solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.96 (1H, d, J=2.2 Hz), 7.25-7.37 (10H, m), 6.78 (1H, d, J=2.2 Hz), 5.10 (2H, s), 5.03 (2H, s). HPLC-MS: m/z 317 [M+H]+.

Workup

  1. temperatureto warm to room temperature
  2. temperatureThe solution is re-cooled to 0° C.
  3. customis transferred to an unfocussed Mars 5 CEM microwave reactor to 190° C.
  4. customThe reaction mixture is quenched with H2O
  5. concentrationconcentrated under reduced pressure
  6. additiondiluted with EtOAc
  7. washwashed with 2M Na2CO3, H2O and saturated aqueous NaCl
  8. dry with materialThe organic layer is dried (MgSO4)
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customto give a brown solid
  12. customThe crude solid is purified over silica (EtOAc:heptane, gradient 1:1 to 1:0)

Sources & evidence

ORD record
ord-f958edb359fd451893ddcd5e1819b457
Source dataset
uspto-grants-2013_12
Patent number
US08598210B2

Reaction notes

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