Hydrochloric Acid → 2-(4-Bromo-2,5-dichloro-phenoxy)-nicotinic acid

HRID 1877418Notes

Reaction equation

HRID 1877418 reaction equation
Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([OH:19])=[C:14]([Cl:20])[CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C1(C)C=CC=CC=1.O.CC#N.CC#N.CC#N.CC#N.F[P-](F)(F)(F)(F)F.[Cu+]>[Br:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([O:19][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[C:14]([Cl:20])[CH:13]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 10796Cesium carbonateHCID 160224-Bromo-2,5-dichlorophenolHCID 762582-Chloronicotinic acid

Product 1

HCID 673686592-(4-Bromo-2,5-dichloro-phenoxy)-nicotinic acid

Reagents, catalysts & solvents 3

HCID 11068737tetrakis(acetonitrile)copper(I) hexafluorophosphateCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
140 °C

Procedure

To a solution of 2-chloro-nicotinic acid (100 mg, 0.64 mmol, 1.0 equiv; [CAS RN 2942-59-8]) and 4-bromo-2,5-dichloro-phenol (184 mg, 0.76 mmol, 1.2 equiv; [CAS RN 1940-42-7]) in toluene (1 mL) was added caesium carbonate (517 mg, 1.59 mmol, 2.5 equiv; [CAS RN 534-17-8]) and tetrakis(acetonitrile)copper(I) hexafluorophosphate (47 mg, 0.13 mmol, 0.2 equiv; [CAS RN 64443-05-6]). The reaction mixture was heated by microwave irradiation to 140° C. for 1 h. The solvent was evaporated under reduced pressure and the crude reaction product taken up in water (100 mL) acidified to pH 1 by addition of a solution of 1 M HCl and extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of dichloromethane/methanol affording 170 mg (73%) of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO): δ7.21 (dd, J=−7.6 Hz, J=4.8 Hz, 1H), 7.42 (s, 1H), 7.76 (s, 1H), 8.29 (dd, J=4.8 Hz, J=1.9 Hz, 1H), 8.50 (dd, J=7.7 Hz, J=2.0 Hz, 1H). MS (ISN): 362.0 [M−H]−.

Workup

  1. customThe solvent was evaporated under reduced pressure
  2. customthe crude reaction product
  3. extractionextracted with ethyl acetate (3×100 mL)
  4. dry with materialThe combined organic phases were dried over MgSO4
  5. customthe product purified by silica column chromatography
  6. washeluting with a gradient of dichloromethane/methanol affording 170 mg (73%) of the title compound as an off-white solid

Sources & evidence

ORD record
ord-a48e7d51f1ae4036a78adcf91a89e126
Source dataset
uspto-grants-2012_11
Patent number
US08309734B2

Reaction notes

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