Picolinic acid → Diethyl 2-(6-chloro-5-methylpyridin-3-yl)malonate

HRID 592183Notes

Reaction equation

HRID 592183 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([Cl:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].N1C=CC=CC=1C(O)=O.[C:25]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>[Cu]I>[Cl:8][C:5]1[N:6]=[CH:7][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:3][C:4]=1[CH3:9]

Participants

6

Reactant 4

HCID 1018Picolinic acidHCID 7761Diethyl MalonateHCID 10796Cesium carbonateHCID 2854345-Bromo-2-chloro-3-methylpyridine

Product 1

HCID 58447937Diethyl 2-(6-chloro-5-methylpyridin-3-yl)malonate

Reagents, catalysts & solvents 1

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst

Conditions

Temperature
96 °C

Procedure

To a flask were added 5-bromo-2-chloro-3-methylpyridine 156-1 (4.13 g, 20 mmol), CuI (380 mg, 2.00 mmol), Cs2CO3 (18 g, 60 mmol), 2-picolinic acid (480 mg, 4.00 mmol). The flask was evacuated and backfilled with argon 3 times. Anhydrous dioxane (40 mL) was added to the flask, followed by diethyl malonate 156-2 (6 mL, 40 mmol). The mixture was stirred at 96° C. for 36 hours under argon. After cooled to room temperature, the mixture was partitioned between ethyl acetate and water. The organic portion was dried over Na2SO4, filtered and concentrated by rotary evaporation. The crude product was purified by flash chromatography, eluted with 20% ethyl acetate in hexanes to give diethyl 2-(6-chloro-5-methylpyridin-3-yl)malonate 156-3 as colorless oil. MS m/z 286.1 (M+1).

Workup

  1. customThe flask was evacuated
  2. additionAnhydrous dioxane (40 mL) was added to the flask
  3. temperatureAfter cooled to room temperature
  4. customthe mixture was partitioned between ethyl acetate and water
  5. dry with materialThe organic portion was dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated by rotary evaporation
  8. customThe crude product was purified by flash chromatography
  9. washeluted with 20% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-c47f6c9e180b40ec8c2947ef21cfdd91
Source dataset
uspto-grants-2016_01
Patent number
US09238646B2

Reaction notes

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