4-Chlorophenylboronic acid → 5-Chloro-4-(4-chlorophenyl)-2-fluoropyridine

HRID 2101393Notes

Reaction equation

HRID 2101393 reaction equation
[Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClC1C=CC(B(O)O)=CC=1>[Cl:1][C:2]1[C:3]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1

Participants

8

Reactant 2

HCID 742994-Chlorophenylboronic acidHCID 218653365-Chloro-2-fluoro-4-iodopyridine

Product 1

HCID 577994555-Chloro-4-(4-chlorophenyl)-2-fluoropyridineYield 107.4%

Reagents, catalysts & solvents 5

HCID 742994-Chlorophenylboronic acidCatalystHCID 178418397HCID 178418397, compoundCatalyst2×HCID 962WaterSolventHCID 1140TolueneSolventHCID 10340Sodium CarbonateSolvent

Conditions

Temperature
140 °C

Procedure

A suspension of 5-chloro-2-fluoro-4-iodopyridine (2.57 g, 10 mmol), 4-chlorophenylboronic acid (1.72 g, 11 mmol) and (Ph3P)4Pd (462 mg, 0.4 mmol) in a mixture of 2.0 M aqueous sodium carbonate (6 mL) and toluene (10 mL) was heated at 140° C. in a microwave oven for 30 min. Analysis by HPLC/MS indicated that the reaction was not complete. Additonal 4-chlorophenylboronic acid (0.156 g, 1 mmol) was added, followed by (Ph3P)4Pd (116 mg, 0.1 mmol). The reaction mixture was again heated at 140° C. in a microwave oven for 30 min. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (50 mL×3). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (120 g) eluted with a gradient of EtOAc (0-50%) in hexanes to afford 2.6 g of the product (˜60% pure) as an off-white solid. This was crystallized in EtOAc-hexanes to obtain the pure title compound (0.9 g) as a white solid. HPLC/MS: retention time=3.80 min, [M+H]+=242.0.

Workup

  1. temperatureThe reaction mixture was again heated at 140° C. in a microwave oven for 30 min
  2. temperatureAfter cooling to room temperature
  3. extractionextracted with EtOAc (50 mL×3)
  4. washThe combined EtOAc extracts were washed with saturated aqueous NaCl
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe crude product was purified
  9. washeluted with a gradient of EtOAc (0-50%) in hexanes

Sources & evidence

ORD record
ord-09a04d4aa3424593af13646bd0c4d352
Source dataset
uspto-grants-2009_08
Patent number
US07572808B2

Reaction notes

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