Cesium fluoride → Methyl 3-amino-2,6-bis(4-methoxyphenyl)isonicotinate

HRID 2410678Notes

Reaction equation

HRID 2410678 reaction equation
[NH2:1][C:2]1[C:11](Br)=[N:10][C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.[F-].[Cs+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[N:10][C:9]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]

Participants

5

Reactant 3

HCID 25953Cesium fluorideHCID 201262(4-Methoxyphenyl)boronic acidHCID 53419616Methyl 3-amino-2,6-dibromoisonicotinate

Product 1

HCID 66604440Methyl 3-amino-2,6-bis(4-methoxyphenyl)isonicotinateYield 44%

Reagents, catalysts & solvents 1

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalyst

Conditions

Temperature
80 °C

Procedure

A mixture of methyl 3-amino-2,6-dibromoisonicotinate (500 mg, 1.61 mmol), 4-methoxyphenylboronic acid (588 mg, 3.87 mmol), Tetrakis(triphenylphosphine)-palladium(0) (93 mg, 0.081 mmol) and cesium fluoride (1176 mg, 7.74 mmol) was placed in a vial and flushed with nitrogen. Dimethoxyethane (10 mL) was added and the reaction was heated at 80° C. for 48 hr. After cooling to room temperature, the reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated, washed with saturated aqueous sodium bicarbonate solution, brine, and then dried with sodium sulfate. Removal of the solvent followed by silica gel radial chromatography (step gradient elution with hexane containing 0 to 25% ethyl acetate) afforded methyl 3-amino-2,6-bis(4-methoxyphenyl)isonicotinate (258 mg, 0.708 mmol, 43.9% yield) as a yellow oil. MS (ESI) m/z 365.2 (M+H). 1H NMR (CDCl3) δ ppm 8.01 (1H, s), 7.91 (2H, d, J=8.85 Hz), 7.66 (2H, d, J=8.55 Hz), 7.02 (2H, d, J=8.55 Hz), 6.94 (2H, d, J=8.85 Hz), 5.93 (2H, br. s.), 3.94 (3H, s), 3.86 (3H, s), 3.83 (3H, s).

Workup

  1. customflushed with nitrogen
  2. additionDimethoxyethane (10 mL) was added
  3. temperatureAfter cooling to room temperature
  4. customthe reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution
  5. customThe organic phase was separated
  6. washwashed with saturated aqueous sodium bicarbonate solution, brine
  7. dry with materialdried with sodium sulfate
  8. customRemoval of the solvent
  9. washfollowed by silica gel radial chromatography (step gradient elution with hexane containing 0 to 25% ethyl acetate)

Sources & evidence

ORD record
ord-173e9b7cdab84842b60fb20333cc1797
Source dataset
uspto-grants-2014_08
Patent number
US08815840B2

Reaction notes

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