2-Bromo-5-hydroxypyridine → 6-(4-Bromo-2-fluorophenyl)-3-pyridinol

HRID 423531Notes

Reaction equation

HRID 423531 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([F:19])[CH:11]=1>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[N:3]=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=2)=[C:12]([F:19])[CH:11]=1

Participants

5

Reactant 2

HCID 27628652-Bromo-5-hydroxypyridineHCID 27733334-Bromo-2-fluorobenzeneboronic acid

Product 1

HCID 666732076-(4-Bromo-2-fluorophenyl)-3-pyridinolYield 10.9%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Procedure

A mixture of Pd(PPh3)2Cl2 (0.42 g, 0.57 mmol) and 2-bromo-5-hydroxypyridine (1.0 g, 5.75 mmol) in DME (20 mL) was degassed with N2. 2M Na2CO3 (10 mL) was added, and the mixture was stirred at ambient temperature for 10 minutes. 4-Bromo-2-fluorobenzeneboronic acid (1.48 g, 6.61 mmol) was added. The reaction mixture was degassed again, purged with N2 and heated at 80° C. overnight, then cooled to ambient temperature, and partitioned between water and EtOAc. Concentrated HCl was added carefully to adjust aqueous pH to about 8, the mixture was filtered thought Celite®, and the EtOAc layer was separated and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a dark brown oil. The crude product was purified by chromatography on a silica gel column eluted with 20% EtOAc/hexane to give 0.168 g of 6-(4-bromo-2-fluorophenyl)-3-pyridinol as an off-white solid. The impure fractions were combined, concentrated and further purified with 1:5 acetone/hexane to give additional 78 mg of 6-(4-bromo-2-fluorophenyl)-3-pyridinol (0.246 g overall, 16% yield). 1H NMR (400 MHz, CD3OD): δ 8.20 (d, 1H, J=2.7 Hz), 7.75-7.65 (m, 1H), 7.62 (dd, 1H, Ja=8.7 Hz, Jb=2.1 Hz), 7.50-7.40 (m, 2H), 7.28 (dd, 1H, Ja=8.5 Hz, Jb=2.9 Hz); LRMS (ESI), m/z 268/270 (M+H).

Workup

  1. customwas degassed with N2
  2. addition2M Na2CO3 (10 mL) was added
  3. customThe reaction mixture was degassed again
  4. custompurged with N2
  5. temperatureheated at 80° C. overnight
  6. temperaturecooled to ambient temperature
  7. custompartitioned between water and EtOAc
  8. additionConcentrated HCl was added carefully
  9. filtrationthe mixture was filtered
  10. customthe EtOAc layer was separated
  11. washwashed with brine
  12. dry with materialdried over Na2SO4
  13. filtrationfiltered
  14. concentrationthe filtrate was concentrated
  15. customto give the crude product as a dark brown oil
  16. customThe crude product was purified by chromatography on a silica gel column
  17. washeluted with 20% EtOAc/hexane

Sources & evidence

ORD record
ord-9525fd8432284335ad98615100363610
Source dataset
uspto-grants-2012_01
Patent number
US08101634B2

Reaction notes

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