Hydrochloric Acid → Ethyl 5,6-dimethylpicolinate

HRID 1908840Notes

Reaction equation

HRID 1908840 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](Br)=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].Cl.O1CCOC[CH2:16]1>CC(=O)OCC.[CH3-].[CH3-].[Zn+2]>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:16])=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 58579426Ethyl 5-bromo-6-methylpyridine-2-carboxylate

Product 1

HCID 66933514Ethyl 5,6-dimethylpicolinate

Reagents, catalysts & solvents 2

HCID 11010DimethylzincCatalyst2×HCID 8857Ethyl AcetateSolvent

Procedure

Dimethyl zink (4.58 g, 48.0 mmol) is added to a solution of 5-bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester (11.7 g, 48.0 mmol, see preparation of 5-isobutyl-6-methyl-pyridine-2-carboxylic acid) and Pd(dppf) (392 mg, 0.48 mmol) in dioxane (40 mL). The mixture becomes warm and is stirred at rt for 1 h. Another portion of dimethyl zink (4.58 g, 48.0 mmol) is added. The mixture is stirred at 100° C. for 2 h, then at 80° C. for 72 h before it is cooled to rt, and diluted with EA (250 mL) and ice-water (150 mL). The mixture is acidified with 2 N aq. HCl, the org. phase is separated and the aq. phase is extracted with EA (3×100 mL) and DCM (2×75 mL). The combined org. extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by MPLC on silica gel (heptane:EA gradient) to give 5,6-dimethyl-pyridine-2-carboxylic acid ethyl ester (434 mg) as a brownish oil; LC-MS: tR=0.61 min, [M+1]+=179.98, 1H NMR (CDCl3): δ 1.45 (t, J=7.0 Hz, 3H), 2.37 (s, 3H), 2.62 (s, 3H), 4.48 (q, J=7.3 Hz, 2H), 7.55 (d, J=7.8 Hz, 1H), 7.90 (d, J=7.8 Hz, 1H).

Workup

  1. temperatureThe mixture becomes warm
  2. stirringThe mixture is stirred at 100° C. for 2 h
  3. temperatureat 80° C. for 72 h before it is cooled to rt
  4. customphase is separated
  5. extractionthe aq. phase is extracted with EA (3×100 mL) and DCM (2×75 mL)
  6. dry with materialextracts are dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude product is purified by MPLC on silica gel (heptane:EA gradient)

Sources & evidence

ORD record
ord-f44ad839d6cd47619c35cdf23ed44d14
Source dataset
uspto-grants-2013_12
Patent number
US08598208B2

Reaction notes

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