Ethanol → 6-(4-Fluorophenyl)picolinic acid

HRID 2117138Notes

Reaction equation

HRID 2117138 reaction equation
Br[C:2]1([C:8]([OH:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.C([O-])([O-])=O.[Na+].[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21](B2OCC(C)(C)CO2)=[CH:20][CH:19]=1.CCO>COCCOC.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>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:4]2[N:3]=[C:2]([C:8]([OH:10])=[O:9])[CH:7]=[CH:6][CH:5]=2)=[CH:20][CH:19]=1

Participants

7

Reactant 4

HCID 702EthanolHCID 10340Sodium CarbonateHCID 110200772-(4-Fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinaneHCID 210815642-Bromo-picolinic acid

Product 1

HCID 210817086-(4-Fluorophenyl)picolinic acidYield 46%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
100 °C

Procedure

A solution of 2-bromo-picolinic acid (2.02 g, 10 mmol, Aldrich) in DME containing 4 mL of 10% aq. Na2CO3 was purged with Ar gas, treated with Pd(PPh3)4 followed by 2-(4-fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane (2.40 g, 11.5 mmol, Aldrich) and EtOH (20 mL). This mixture was then also purged with Ar gas. The reaction mixture was heated at 100° C. for 2.5 h in a sealed tube. Additional 2-bromo-picolinic acid (900 mg) and Pd(PPh3)4 was added, and after purging with Ar gas it was heated at 100° C. for 4.5 h. Trifluoroacetic acid (20 mL) was added to the reaction and the mixture was concentrated in vacuo. MeOH (150 mL) was added to the residue and the insoluble material was filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash column chromatography on silica gel eluting with EtOAc/MeOH (9:1) followed by EtOAc/MeOH/HOAc (14:30:1) to afford the desired product (1.0 g, 40% based on borinane starting material) as a white solid. 1H NMR (CD3OD) δ 8.01 (d, 1H, J=7.7 Hz), 7.94-7.87 (m, 3H), 7.73 (d, 1H, J=7.7 Hz), 7.13 (t, 2H, J=8.8 Hz); MS(ESI+) m/z 234 (M+H)+.

Workup

  1. customThis mixture was then also purged with Ar gas
  2. additionAdditional 2-bromo-picolinic acid (900 mg) and Pd(PPh3)4 was added
  3. customafter purging with Ar gas it
  4. temperaturewas heated at 100° C. for 4.5 h
  5. additionTrifluoroacetic acid (20 mL) was added to the reaction
  6. concentrationthe mixture was concentrated in vacuo
  7. additionMeOH (150 mL) was added to the residue
  8. filtrationthe insoluble material was filtered
  9. concentrationThe filtrate was concentrated in vacuo
  10. customthe resulting residue was purified by flash column chromatography on silica gel eluting with EtOAc/MeOH (9:1)

Sources & evidence

ORD record
ord-8700df460232488597d2ad76054dc0d6
Source dataset
uspto-grants-2008_10
Patent number
US07439246B2

Reaction notes

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