Dichloromethane → Methyl 6-hydroxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxylate

HRID 1392281Notes

Reaction equation

HRID 1392281 reaction equation
[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6](Br)[CH:5]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)(O)[O-].[K+].ClCCl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=2)[C:7]([OH:10])=[CH:8][CH:9]=1)=[O:12]

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 516893Potassium BicarbonateHCID 27343894-(Trifluoromethyl)phenylboronic acidHCID 4778958Methyl 3-bromo-4-hydroxybenzoate

Product 1

HCID 69196371Methyl 6-hydroxy-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxylateYield 76%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 312751,4-DioxaneSolvent2×

Procedure

To a solution of 3-bromo-4-hydroxy-benzoic acid methyl ester (4.50 g, 19.5 mmol) and 4-trifluoromethylbenzene boronic acid (4.07 g, 21.4 mmol) in dioxane (75 mL) was added 2 M potassium bicarbonate solution (29.2 mL, 58.4 mmol) and a second portion of dioxane (75 mL, 150 mL total volume added). This mixture was then degassed by bubbling dry nitrogen through the mixture for 5 minutes. After degassing, [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium (II), complex 1:1 with dichloromethane (DPPF; 0.40 g, 0.49 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 hour. The mixture was then heated to reflux for 5 hours, allowed to cool back to ambient temperature for 14 hours and then refluxed for an additional 5 hours. After cooling back to ambient temperature, the mixture was partitioned between 1 M hydrochloric acid (100 mL) and ethyl acetate. The layers were separated and the aqueous layer was adjusted to pH 3. The aqueous layer was extracted with two additional portions of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered through Celite and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using diethyl ether/hexanes (0/100 gradient to 20/80) to give 6-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (3.40 g, 76%) as a white powder. 1H NMR (400 MHz, DMSO-d6); δ 10.76 (s, 1H), 7.87 (s, 1H), 7.84 (d, 1H), 7.76 (s, 4H), 7.06 (d, 1H), 3.79 (s, 3H).

Workup

  1. customThis mixture was then degassed
  2. customby bubbling dry nitrogen through the mixture for 5 minutes
  3. customAfter degassing
  4. temperatureThe mixture was then heated
  5. temperatureto reflux for 5 hours
  6. temperatureto cool back to ambient temperature for 14 hours
  7. temperaturerefluxed for an additional 5 hours
  8. temperatureAfter cooling back to ambient temperature
  9. customthe mixture was partitioned between 1 M hydrochloric acid (100 mL) and ethyl acetate
  10. customThe layers were separated
  11. extractionThe aqueous layer was extracted with two additional portions of ethyl acetate
  12. dry with materialdried over anhydrous magnesium sulfate
  13. filtrationfiltered through Celite
  14. concentrationconcentrated under reduced pressure
  15. customThe crude material was purified by flash chromatography through silica gel

Sources & evidence

ORD record
ord-b6fbdd4c13b3481682b403d3fb092265
Source dataset
uspto-grants-2008_03
Patent number
US07342039B2

Reaction notes

Loading…