Ammonia → 4-(6-Methoxy-pyridin-3-yl)-benzoic acid ethyl ester

HRID 430896Notes

Reaction equation

HRID 430896 reaction equation
[Li][CH2:2][CH2:3]CC.CCCCCC.Br[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=1.C([C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-:29])=[O:28])=[C:25](I)[CH:24]=1)C.N>C1COCC1.O.[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH2:2]([O:29][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([C:13]2[CH:18]=[N:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:31][CH:30]=1)[CH3:3]

Participants

10

Reactant 5

HCID 222AmmoniaHCID 8058HexaneHCID 27348955-Bromo-2-methoxypyridineHCID 183515044-Ethyl-iodobenzoateHCID 178418339Butyllithium

Product 1

HCID 186177044-(6-Methoxy-pyridin-3-yl)-benzoic acid ethyl ester

Reagents, catalysts & solvents 4

HCID 3007855ZincchlorideCatalystHCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

A 1.6 M solution of nBuLi in hexane (9.53 mL, 15.24 mmol) is added dropwise to a stirred solution of 5-Bromo-2-methoxy-pyridine (2.72 g, 14.52 mmol) in THF (50 mL) at −78° C. The resulting mixture is stirred for 15 minutes at −78° C. To this is added a 0.5 M solution of ZnCl2 in THF (29.04 mL, 14.52 mmol) and the resulting mixture allowed to warm to room temperature. In a separate flask tetrakis(triphenylphosphine)palladium(O) (0.58 g, 0.50 mmol) is stirred in THF (10 mL). To this is added 4-ethyl-iodobenzoate (3.61 g, 13.07 mmol). The contents of the two flasks are combined and stirred for 1 hour at room temperature. A 5% solution of ammonia in water (150 mL) is added with stirring. The mixture is extracted with EtOAc (3×). The organics are combined and dried over MgSO4, filtered and concentrated. The crude product is purified by flash chromatography (2.5% EtOAc/hexane to 5% EtOAc/hexane) to give the product as a white solid (2.43g, 9.44 mmol). 1H NMR (CDCl3, 300 MHz) d 8.41 (d, 1H), 8.08 (d, 2H), 7.82 (dd, 1H), 7.60 (d, 2H), 6.82 (d, 1H), 4.38 (q, 2H), 3.98 (s, 3H), 1.40 (t, 3H).

Workup

  1. temperatureto warm to room temperature
  2. stirringstirred for 1 hour at room temperature
  3. stirringwith stirring
  4. extractionThe mixture is extracted with EtOAc (3×)
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude product is purified by flash chromatography (2.5% EtOAc/hexane to 5% EtOAc/hexane)

Sources & evidence

ORD record
ord-96de34abbbc64a3abd07226715bf9833
Source dataset
uspto-grants-2001_11
Patent number
US06323227B1

Reaction notes

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