Toluene → 5-(4-Chloro-2-fluorophenyl)pyridin-2-amine

HRID 1523899Notes

Reaction equation

HRID 1523899 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([F:11])[CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][N:14]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[CH:17]=[CH:18][C:13]([NH2:12])=[N:14][CH:15]=2)=[C:4]([F:11])[CH:3]=1

Participants

8

Reactant 4

HCID 1140TolueneHCID 10340Sodium CarbonateHCID 706222-Amino-5-bromopyridineHCID 4193595(4-Chloro-2-fluorophenyl)boronic acid

Product 1

HCID 802010835-(4-Chloro-2-fluorophenyl)pyridin-2-amineYield 71.2%

Reagents, catalysts & solvents 3

HCID 11776TriphenylphosphineCatalystHCID 2733347Palladium(II) trifluoroacetateCatalystHCID 702EthanolSolvent

Conditions

Temperature
80 °C

Procedure

Solid 4-chloro-2-fluorobenzeneboronic acid (10.0 g, 57.4 mmol), 2-amino-5-bromopyridine (9.92 g, 57.4 mmol), palladium (II) trifluoroacetate (0.381 g, 1.15 mmol), and triphenylphosphine (0.602 g, 2.29 mmol) were combined in a 1 L flask under nitrogen, then toluene (150 mL), EtOH (150 mL), and 2 M Na2CO3 (100 mL) were added. The mixture was sparged with nitrogen for 30 min using a gas dispersion tube, then heated at 80° Celsius for 20 hours with vigorous stirring. The mixture was cooled to rt, diluted with EtOAc (200 mL), and transferred to a separatory funnel. The aqueous phase was removed, and the organic phase washed with brine. The combined aqueous phases were extracted with an equal volume of EtOAc, and the combined organic phases were dried and concentrated to dryness. The residue was subjected to FCC to provide 5-(4-chloro-2-fluorophenyl)pyridin-2-amine (9.10 g, 71%). MS (CI): mass calcd. for C11H8CFN2, 222.04; m/z found, 223.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.54-8.22 (s, 2H), 8.22-8.18 (d, J=2.1, 1H), 8.15-8.10 (m, 1H), 7.68-7.58 (m, 2H), 7.48-7.38 (m, 1H), 7.16-7.06 (d, J=9.3, 1H).

Workup

  1. customThe mixture was sparged with nitrogen for 30 min
  2. temperatureThe mixture was cooled to rt
  3. additiondiluted with EtOAc (200 mL)
  4. customtransferred to a separatory funnel
  5. customThe aqueous phase was removed
  6. washthe organic phase washed with brine
  7. extractionThe combined aqueous phases were extracted with an equal volume of EtOAc
  8. customthe combined organic phases were dried
  9. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-8ee0bfd9ade840d08fa952639e9a5c9a
Source dataset
uspto-grants-2015_07
Patent number
US09079866B2

Reaction notes

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