Toluene → 5-(4-Cyano-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid methyl ester

HRID 240740Notes

Reaction equation

HRID 240740 reaction equation
Br[C:2]1[C:3]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([B-](F)(F)F)=[CH:35][CH:34]=1)#[N:32].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)[C:3]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:4][CH:5]=1

Participants

8

Reactant 4

HCID 1140TolueneHCID 10796Cesium carbonateHCID 23716872Potassium (4-Cyanophenyl)trifluoroborateHCID 66686828Methyl 5-bromo-6-(2,2,2-trifluoroethoxy)nicotinate

Product 1

HCID 712941715-(4-Cyano-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid methyl esterYield 84%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 11371790Bis(adamantan-1-yl)(butyl)phosphaneCatalystHCID 962WaterSolvent2×

Conditions

Temperature
120 °C

Procedure

In a 50 mL 4-necked flask, methyl 5-bromo-6-(2,2,2-trifluoroethoxy)nicotinate (1 g, 3.18 mmol, Eq: 1.00, CAN 1211589-51-3) and cesium carbonate (3.11 g, 9.55 mmol, Eq: 3) were combined with toluene (25 ml) and water (2.8 ml) to give a colorless solution. The reaction mixture was 3× degassed and purged with argon; then palladium(II) acetate (14.3 mg, 63.7 μmol, Eq: 0.02), potassium (4-cyanophenyl)trifluoroborate (732 mg, 3.5 mmol, Eq: 1.1, CAN 850623-36-8) and butyldi-1-adamantylphosphine (68.5 mg, 191 μmol, Eq: 0.06) were successively added. The degassing-purging cycle was repeated after each addition. The reaction mixture was then heated to 120° C. for 5 hours. After cooling, the reaction mixture was poured into 50 mL H2O and extracted with AcOEt (2×50 mL). The organic layers were washed with H2O/NaCl solution, combined, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (silica gel, 50 g, 50% to 100% CH2Cl2 in heptane) yielded finally 898 mg of the title compound as white foam; MS (EI) 337.2 (M+H)+.

Workup

  1. customto give a colorless solution
  2. customdegassed
  3. custompurged with argon
  4. additionafter each addition
  5. temperatureAfter cooling
  6. extractionextracted with AcOEt (2×50 mL)
  7. washThe organic layers were washed with H2O/NaCl solution
  8. dry with materialdried over Na2SO4
  9. concentrationconcentrated in vacuo
  10. customPurification by flash chromatography (silica gel, 50 g, 50% to 100% CH2Cl2 in heptane)

Sources & evidence

ORD record
ord-dc44f5e065444ece94d9413a13e1bcd4
Source dataset
uspto-grants-2014_02
Patent number
US08648099B2

Reaction notes

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