Sodium Carbonate → (E)-2-Bromo-4-(2,5-difluorostyryl)-5-fluoropyridine

HRID 2362410Notes

Reaction equation

HRID 2362410 reaction equation
[Br:1][C:2]1[CH:7]=[C:6](B(O)O)[C:5]([F:11])=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH:20]=[CH2:21].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:7]=[C:6](/[CH:21]=[CH:20]/[C:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=2[F:12])[C:5]([F:11])=[CH:4][N:3]=1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 218718902,5-DifluorostyreneHCID 44631046(2-Bromo-5-fluoropyridin-4-yl)boronic acid

Product 1

HCID 86673436(E)-2-Bromo-4-(2,5-difluorostyryl)-5-fluoropyridine

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

A suspension of 2-bromo-5-fluoropyridin-4-ylboronic acid (1.569 g, 7.14 mmol) and 1,4-difluoro-2-vinylbenzene (1 g, 7.14 mmol) in dimethylformamide (20 mL) was flushed with a balloon of oxygen. To this was added sodium carbonate (1.51 g, 14.3 mmol) and palladium(II) acetate (0.16 g, 0.71 mmol) as solids in one portion. The flask was flushed with another balloon of oxygen and fitted with a balloon of oxygen. The reaction was warmed to 50° C. After 1 h, the reaction was treated with a second portion of sodium carbonate (0.75 g) and boronic acid (1.6 g). This process was repeated twice more (total boronic acid addition=6.3 g). The reaction was cooled to room temperature, diluted with ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (2.5%→5% EtOAc/Hex) gave 89 mg (4.0%) as a white solid. 1H NMR (CDCl3) Shift: 8.28 (d, J=1.8 Hz, 1H), 7.68 (d, J=5.5 Hz, 1H), 7.49 (d, J=16.5 Hz, 1H), 7.33 (ddd, J=8.9, 5.8, 3.1 Hz, 1H), 7.17 (d, J=16.8 Hz, 1H), 6.98-7.14 (m, 2H). 19F NMR (CDCl3) Shift: −118.54 (d, J=13.0 Hz, 1F), −122.71 (br. s., 1F), −135.71 (br. s., 1F). Mass spec.: 314.0 (MH)+.

Workup

  1. customwas flushed with a balloon of oxygen
  2. customThe flask was flushed with another balloon of oxygen
  3. customfitted with a balloon of oxygen
  4. additionthe reaction was treated with a second portion of sodium carbonate (0.75 g) and boronic acid (1.6 g)
  5. addition(total boronic acid addition=6.3 g)
  6. temperatureThe reaction was cooled to room temperature
  7. additiondiluted with ether
  8. washwashed with water (3×)
  9. dry with materialbrine, dried over magnesium sulfate
  10. concentrationconcentrated
  11. customColumn chromatography (2.5%→5% EtOAc/Hex) gave 89 mg (4.0%) as a white solid

Sources & evidence

ORD record
ord-8b865149f148479fa42156c999021f92
Source dataset
uspto-grants-2014_04
Patent number
US08691821B2

Reaction notes

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