Iodine → 5-Benzyl-6-chloropyridin-3-ol

HRID 2075240Notes

Reaction equation

HRID 2075240 reaction equation
Br[C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[N:6][C:7]=1[Cl:8].II.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH2:12]([C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[N:6][C:7]=1[Cl:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1

Participants

8

Reactant 4

HCID 807IodineHCID 7498Benzyl BromideHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 145952265-Bromo-6-chloropyridin-3-ol2×

Product 1

HCID 584152845-Benzyl-6-chloropyridin-3-ol

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

Starting material (5-bromo-6-chloropyridin-3-ol) is available from a published 3-step procedure: Synthesis, 1990, 499-501. To an oven-dried flask was added zinc (2.45 g, 37.4 mmol) and a crystal of iodine. The mixture was heated with a heat gun for 10 min under vacuum and then allowed to cool under Ar atmosphere. After charging the flask with degassed DMF (10 mL), the mixture was cooled to 0° C., and benzyl bromide (2.96 mL, 24.9 mmol) was added. After stirring the resulting mixture at 0° C. for 30 min, a mixture of Pd2(dba)3 (0.571 g, 0.624 mmol), S-Phos (1.02 g, 2.49 mmol) and 5-bromo-6-chloropyridin-3-ol (2.60 g, 12.5 mmol) was added to the flask quickly, and then the reaction was flushed with Ar and placed in an oil bath at 60° C. for 4 h or until starting material was gone by LCMS. The reaction was cooled to rt and filtered through a fine fritted funnel. The filtrate was concentrated to afford a yellow oil that was adsorbed onto silica and purified by flash chromatography (25% EtOAc/Hex, ramped to 100% EtOAc). The product was further purified after the column by recrystallization from hexane and minimal cold chloroform to afford a white solid. MS (ESI) m/z: Calculated: 219.1; Observed: 220.0 (M++1).

Workup

  1. customSynthesis, 1990, 499-501
  2. temperatureThe mixture was heated with a heat gun for 10 min under vacuum
  3. temperatureto cool under Ar atmosphere
  4. additionwas added to the flask quickly
  5. customthe reaction was flushed with Ar
  6. waitplaced in an oil bath at 60° C. for 4 h
  7. temperatureThe reaction was cooled to rt
  8. filtrationfiltered through a fine fritted funnel
  9. concentrationThe filtrate was concentrated
  10. customto afford a yellow oil that
  11. custompurified by flash chromatography (25% EtOAc/Hex, ramped to 100% EtOAc)
  12. customThe product was further purified after the column
  13. customby recrystallization from hexane and minimal cold chloroform
  14. customto afford a white solid

Sources & evidence

ORD record
ord-64ad695c76034eccac94d65a4dcae7e0
Source dataset
uspto-grants-2011_04
Patent number
US07919519B2

Reaction notes

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