Nitrogen → 5-Cyano-3-methyl-pyridine-2-carboxylic acid tert-butyl ester

HRID 627679Notes

Reaction equation

HRID 627679 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.N#N.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1(C)C=CC=CC=1.[CH3:38][N:39](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Zn]>[C:38]([C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1)#[N:39]

Participants

8

Reactant 5

HCID 947NitrogenHCID 1140TolueneHCID 6228DimethylformamideHCID 83681Tris(1,1-dimethylethyl)phosphine2×HCID 66665659Tert-butyl 5-bromo-3-methylpicolinate

Product 1

HCID 666658265-Cyano-3-methyl-pyridine-2-carboxylic acid tert-butyl esterYield 62.1%

Reagents, catalysts & solvents 2

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 23994ZincCatalyst

Conditions

Temperature
80 °C

Procedure

A mixture of tert-butyl 5-bromo-3-methylpicolinate (7.47 g, 27.4 mmol), zinc cyanide (2.26 g, 19.21 mmol) and zinc dust (0.179 g, 2.74 mmol) was suspended in DMF (55 ml). The suspension was purged with N2 and finally tri-tert-butylphosphine, 1.0M in toluene (2.196 ml, 2.196 mmol) was added under N2 gas. The reaction mixture was heated to 80° C. for 2.5 h. Then 0.8 g of tri-tert-butylphosphine was added to reaction mixture and it was heated to 80° C. for another 5.5 h. The mixture was then cooled to RT and the grey suspension was filtered out. Then 175 ml of MTBE and 40 ml of water were added. The aqueous layer was washed with 75 ml of MTBE. The organic layer was then washed with 100 ml of water and brine. It was dried on MgSO4 and concentrated. The crude material was concentrated to yield a yellow oil which was purified by chromatography through a Redi-Sep pre-packed silica gel column (330 g), eluting with a gradient of 20% to 30% to 40% (40% EtOAc in heptane) in heptane, to provide tert-butyl 5-cyano-3-methylpicolinate (3.72 g, 17.04 mmol, 62.1% yield) as white solid. MS m/z=241.2 (M+Na).

Workup

  1. additionwas added under N2 gas
  2. temperaturewas heated to 80° C. for another 5.5 h
  3. temperatureThe mixture was then cooled to RT
  4. filtrationthe grey suspension was filtered out
  5. additionThen 175 ml of MTBE and 40 ml of water were added
  6. washThe aqueous layer was washed with 75 ml of MTBE
  7. washThe organic layer was then washed with 100 ml of water and brine
  8. customIt was dried on MgSO4
  9. concentrationconcentrated
  10. concentrationThe crude material was concentrated
  11. customto yield a yellow oil which
  12. customwas purified by chromatography through a Redi-Sep pre-packed silica gel column (330 g)
  13. washeluting with a gradient of 20% to 30% to 40% (40% EtOAc in heptane) in heptane

Sources & evidence

ORD record
ord-db211924be9d4bb9af5c777ce01e28e7
Source dataset
uspto-grants-2016_04
Patent number
US09309263B2

Reaction notes

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