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

HRID 1523772Notes

Reaction equation

HRID 1523772 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]=[N: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.O.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[N:17]=[CH:18][C:13]([NH2:12])=[N:14][CH:15]=2)=[C:4]([F:11])[CH:3]=1

Participants

9

Reactant 4

HCID 1140TolueneHCID 10340Sodium CarbonateHCID 5995392-Amino-5-bromopyrazineHCID 4193595(4-Chloro-2-fluorophenyl)boronic acid

Product 1

HCID 802004855-(4-Chloro-2-fluorophenyl)pyrazin-2-amineYield 78.1%

Reagents, catalysts & solvents 4

HCID 11776TriphenylphosphineCatalystHCID 2733347Palladium(II) trifluoroacetateCatalystHCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
50 °C

Procedure

To a nitrogen flushed flask containing 4-chloro-2-fluorobenzene boronic acid (40.0 g, 229 mmol), 2-amino-5-bromopyrazine (39.9 g, 229 mmol), palladium(II) trifluoroacetate (1.5 g, 4.6 mmol), and triphenylphosphine (2.4 g, 9.2 mmol) were added sparged toluene (750 mL), ethanol (750 mL), and 2 M Na2CO3(aq) (418 mL, 836 mmol). The mixture was stirred and heated at 50° Celsius for 15 hours and then cooled to rt. Water (750 mL) was added and the layers were separated. The aqueous layer was washed with ethyl acetate (750 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated to dryness to give 55.4 g of crude product. The crude solid was crystallized from toluene (450 mL) to provide the title compound (40.0 g, 78%). MS (ESI): mass calcd. for C10H7ClFN3, 223.03; m/z found, 224.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (dd, J=2.6, 1.5, 1H), 8.03 (d, J=1.6, 1H), 7.89 (m, 1H), 7.52 (dd, J=11.3, 2.1, 1H), 7.38 (dd, J=8.5, 2.1, 1H), 6.79 (s, 2H).

Workup

  1. additionwere added
  2. temperaturecooled to rt
  3. customthe layers were separated
  4. washThe aqueous layer was washed with ethyl acetate (750 mL)
  5. washThe combined organic layers were washed with brine (500 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated to dryness
  9. customto give 55.4 g of crude product
  10. customThe crude solid was crystallized from toluene (450 mL)

Sources & evidence

ORD record
ord-c13a5db4a0d54da9a5d4d6849f8af09f
Source dataset
uspto-grants-2015_07
Patent number
US09079866B2

Reaction notes

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