1-Methoxy-1-trimethylsilyloxypropene → Methyl 2-(6-chloro-2-methoxypyridin-3-yl)propanoate

HRID 922577

Reaction equation

HRID 922577 reaction equation
Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1(C)C=CC=CC=1.[CH3:31][O:32]/[C:33](/[O:36][Si](C)(C)C)=[CH:34]\[CH3:35]>CN(C=O)C.[F-].[Zn+2].[F-]>[Cl:8][C:5]1[N:4]=[C:3]([O:9][CH3:10])[C:2]([CH:34]([CH3:35])[C:33]([O:32][CH3:31])=[O:36])=[CH:7][CH:6]=1

Participants

6

Reactant 3

HCID 108557751-Methoxy-1-trimethylsilyloxypropeneHCID 532174543-Bromo-6-chloro-2-methoxypyridineHCID 66647975Tri-t-butylphosphine toluene

Product 1

HCID 117992989Methyl 2-(6-chloro-2-methoxypyridin-3-yl)propanoateYield 64%

Reagents, catalysts & solvents 2

HCID 10129912Zinc(II) fluorideCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
85 °C

Procedure

To a dry flask was added 3-bromo-6-chloro-2-methoxypyridine (9.7 g, 43.7 mmol), palladium(0)bis(dibenzylideneacetone) (1.3 g, 2.2 mmol), and zinc fluoride (3.4 g, 32.7 mmol). The mixture was degassed with nitrogen. A solution of tri-tert-butylphoshine/toluene (1.0 M, 4.4 mL, 4.4 mmol) in DMF (146 mL) was then added to the degassed mixture. After stirring, (E)-(1-methoxyprop-1-enyloxy)trimethylsilane (15.2 mL, 65 mmol) was added and the reaction was heated at 85° C. for 18 h. The mixture was partitioned between MTBE and brine. The aqueous layer was extracted with MTBE. The combined organic layers were dried over Na2SO4 and concentrated. Purification by silica gel column chromatography (330 g RediSep Gold column, 30-65% DCM/heptanes) provided methyl 2-(6-chloro-2-methoxypyridin-3-yl)propanoate (6.4 g, 64%); 1H NMR (600 MHz, CDCl3) δ: 1.44 (d, 3H), 3.67 (s, 3H), 3.91 (q, 1H), 3.95 (s, 3H), 6.89 (d, 1H), 7.45 (d, 1H).

Workup

  1. customThe mixture was degassed with nitrogen
  2. customThe mixture was partitioned between MTBE and brine
  3. extractionThe aqueous layer was extracted with MTBE
  4. dry with materialThe combined organic layers were dried over Na2SO4
  5. concentrationconcentrated
  6. customPurification by silica gel column chromatography (330 g RediSep Gold column, 30-65% DCM/heptanes)

Sources & evidence

ORD record
ord-e8e07004844e4b09aedabc9266e5beff
Source dataset
uspto-grants-2016_03
Patent number
US09278953B2

Linked notes

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