Potassium Phosphate, Tribasic → 2-Chloro-5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoropyridine

HRID 575619Notes

Reaction equation

HRID 575619 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Br[C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[O:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[F:36].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:21]2[CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=[CH:19][C:20]=2[O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])=[CH:4][N:3]=1

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 532167992-Chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineHCID 867049232-Bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene

Product 1

HCID 1180223532-Chloro-5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoropyridineYield 57.3%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (170 mg, 0.66 mmol), 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene (326 mg, 0.98 mmol), Pd2(dba)3 (30 mg, 5%), and tricyclohexylphosphine (280 mg, 10%) was suspended in 1,4-dioxane (4 mL) and aqueous 1M K3PO4 (2 mL). The mixture was heated to 70° C. using microwave irradiation (normal) for 45 min. The crude reaction mixture was filtered through a short plug of celite and the celite plug was washed with EtOAc (˜50 mL). The filtrate was washed with water (2×30 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (12 g ISCO, gradient 05-75% EtOAc in hexanes) to afford the free base of the desired product, 2-chloro-5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoropyridine as a yellow solid (144 mg, 57%). LCMS (M+H)+=381.

Workup

  1. custommicrowave irradiation (normal) for 45 min
  2. customThe crude reaction mixture
  3. filtrationwas filtered through a short plug of celite
  4. washthe celite plug was washed with EtOAc (˜50 mL)
  5. washThe filtrate was washed with water (2×30 mL), brine
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe resulting residue was purified by silica gel column chromatography (12 g ISCO, gradient 05-75% EtOAc in hexanes)

Sources & evidence

ORD record
ord-7398a183d48745e1964deff5e872cae6
Source dataset
uspto-grants-2015_05
Patent number
US09034900B2

Reaction notes

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