Picolinic acid → Diethyl 2-(6-methoxypyridin-2-yl)malonate

HRID 535664Notes

Reaction equation

HRID 535664 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.N1C=CC=CC=1C(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[C:25]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[NH4+].[Cl-]>O1CCOCC1.[Cu]I.C(OCC)(=O)C>[CH3:9][O:8][C:4]1[N:3]=[C:2]([CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:25]([O:33][CH2:34][CH3:35])=[O:32])[CH:7]=[CH:6][CH:5]=1

Participants

9

Reactant 5

HCID 1018Picolinic acidHCID 7761Diethyl MalonateHCID 10796Cesium carbonateHCID 25517Ammonium ChlorideHCID 2568102-Bromo-6-methoxypyridine

Product 1

HCID 59636709Diethyl 2-(6-methoxypyridin-2-yl)malonate

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

A slurry of 2-bromo-6-methoxypyridine (1.8 g, 9.57 mmol), copper(I) iodide (0.16 g, 0.86 mmol), 2-picolinic acid (0.21 g, 1.72 mmol), cesium carbonate (4.7 g, 14.4 mmol) and diethyl malonate (4.4 mL, 28.7 mmol) in dioxane (15 mL) was heated at 95° C. for 4 days. After cooling to room temperature, ethyl acetate and saturated aqueous NH4Cl were added. The organic phase was separated and the aqueous phase extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated. The product was purified twice by flash chromatography (SiO2; heptane/ethyl acetate, gradient 0-80% and second chromatography using heptane/ethyl acetate gradient 0-20%) giving the product. Yield: 1.1 g (43%).

Workup

  1. customThe organic phase was separated
  2. extractionthe aqueous phase extracted with ethyl acetate
  3. dry with materialThe combined organic phases were dried over Na2SO4
  4. concentrationconcentrated
  5. customThe product was purified twice by flash chromatography (SiO2; heptane/ethyl acetate, gradient 0-80% and second chromatography using heptane/ethyl acetate gradient 0-20%)
  6. customgiving the product

Sources & evidence

ORD record
ord-5b48b19c3ad64b2e866dd840931f9f3c
Source dataset
uspto-grants-2014_10
Patent number
US08859534B2

Reaction notes

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