Carbon Dioxide → 3,5-Difluorobiphenyl-4-carboxylic acid

HRID 2224732Notes

Reaction equation

HRID 2224732 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Li]N1C(C)(C)CCCC1(C)C.[Li]CCCC.CC1CCCN(C)C1(C)C.[C:41](=[O:43])=[O:42].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[C:7]=1[C:41]([OH:43])=[O:42]

Participants

8

Reactant 6

HCID 280Carbon DioxideHCID 14798Sodium HydroxideHCID 130223913,5-Difluorobiphenyl2×HCID 187617721,2,2,3-TetramethylpiperidineHCID 178418339ButyllithiumHCID 178418821HCID 178418821, compound2×

Product 1

HCID 463147683,5-Difluorobiphenyl-4-carboxylic acidYield 77%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

Dissolve crude 3,5-difluorobiphenyl (1.3 g, 6.83 mmol) in THF (14 mL) and cool to −78° C. Prepare LiTMP from the addition of BuLi (1.6 M soln in hexanes, 5.33 mL) to tetramethyl piperidine (1.4 mL, 1.25 equiv) at −78° C. in THF (14 mL). Cannulate the cooled LiTMP into the cooled 3,5-difluorobiphenyl and stir the reaction at −78° C. for 1 hour. Bubble carbon dioxide gas through the solution for 5 minutes, warn the reaction to room temperature, pour into 50 mL of 1M NaOH, and extract with 50 mL EtOAc. Discard the organic layer. Acidify the remaining aqueous layer with conc. HCl and extract twice with EtOAc. Dry the organics over MgSO4, filter, and evaporate to give 1.22 g of the title compound as a white solid (77%). MS (ES): m/z 233.1 (M−H).

Workup

  1. customthe reaction at −78° C. for 1 hour
  2. customthe reaction to room temperature
  3. extractionextract with 50 mL EtOAc
  4. extractionextract twice with EtOAc
  5. dry with materialDry the organics over MgSO4
  6. filtrationfilter
  7. customevaporate

Sources & evidence

ORD record
ord-d681f97ef96e4688a0fb9d7a29806afd
Source dataset
uspto-grants-2008_05
Patent number
US07378447B2

Reaction notes

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