2,5-Dichloropyridine → 5-Chloro-2-cyanopyridine

HRID 737005Notes

Reaction equation

HRID 737005 reaction equation
[CH3:1][N:2](C)C(=O)C.Cl[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=1>[Cl-].[Na+].O.[C-]#N.[Zn+2].[C-]#N.[Zn]>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:1]#[N:2])=[N:9][CH:10]=1

Participants

6

Reactant 2

HCID 276852,5-DichloropyridineHCID 31374Dimethylacetamide

Product 1

HCID 38339425-Chloro-2-cyanopyridineYield 59%

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 23994ZincCatalystHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
160 °C

Procedure

Add in a 22-L 3-neck round bottom equipped with overhead stirrer, reflux condenser, and thermometer, N,N-dimethylacetamide (DMAC, 6 L), 2,5-dichloropyridine (347.0 g, 2.34 mol), zinc cyanide (138.0 g, 1.17 mol), bis(diphenylphosphino)dipalladium II CH2Cl2 complex (DPPF, 20.8 g, 0.02 mol), and zinc dust (1.6 g, 0.02 mol). Slowly warm the reaction mixture to 160° C. As the temperature reaches 160° C., an exotherm (controllable) may result and the internal temperature may rise to 180-185° C. Remove the heat from the dark solution and cool the mixture slowly cool to room temperature. Extract the bulk reaction mixture by taking 2 L of the dark solution, diluting with brine (2 L), filtering over celite, and addition of ethyl acetate (4 L). Repeat the process 3 times to extract all material, and dry the combined organics over magnesium sulfate. Cautious concentration at 25-30° C. might give a dark liquid. (Note: Product volatility maybe observed at higher temperatures so the temperature upon concentration is kept low in all steps.) Stir the liquid and add water (5 L), resulting in a solid After 1 h, filter, and back-wash with water (2 L). Dry the filter cake to give 215 g of crude product. Extract the aqueous filtrate with ethyl ether (8 L). Dry the organics over magnesium sulfate and concentrate to provide 51 g of crude product. Combine with the 215 g lot and purify by chromatography over silica gel (biotage 150; eluting with 5% ethyl acetate in hexanes increasing to 10% ethyl acetate in hexanes) to provide a white solid of pure title compound (193 g, 59%); 1H NMR (CDCl3) δ 8.68 (d, J=2.0 Hz, 1H), 7.84 (dd, J=2.7, 8.6 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H).

Workup

  1. additionAdd in a 22-L 3-neck round bottom
  2. customequipped with overhead stirrer
  3. temperaturereflux condenser
  4. customreaches 160° C.
  5. customan exotherm (controllable) may result
  6. custommay rise to 180-185° C
  7. customRemove the
  8. temperatureheat from the dark solution
  9. temperaturecool the mixture
  10. temperatureslowly cool to room temperature
  11. extractionExtract
  12. customthe bulk reaction mixture
  13. filtrationfiltering over celite, and addition of ethyl acetate (4 L)
  14. extractionRepeat the process 3 times to extract all material
  15. dry with materialdry the combined organics over magnesium sulfate
  16. concentrationconcentration at 25-30° C.
  17. custommight give a dark liquid
  18. concentrationupon concentration
  19. additionadd water (5 L)
  20. customresulting in a solid After 1 h
  21. filtrationfilter
  22. washback-wash with water (2 L)
  23. customDry the filter cake
  24. customto give 215 g of crude product
  25. extractionExtract the aqueous filtrate with ethyl ether (8 L)
  26. dry with materialDry the organics over magnesium sulfate
  27. concentrationconcentrate
  28. customto provide 51 g of crude product
  29. customCombine with the 215 g lot and purify by chromatography over silica gel (biotage 150; eluting with 5% ethyl acetate in hexanes increasing to 10% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-d875dcdb28bc4a6e850d721df9242149
Source dataset
uspto-grants-2009_09
Patent number
US07595339B2

Reaction notes

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