Pivalic acid → 2-(4-Fluorophenyl)-6-methoxybenzo[b]thiophene

HRID 332848Notes

Reaction equation

HRID 332848 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.CC(C)(C)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[S:8][C:7]3[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:10]=2)=[CH:14][CH:15]=1

Participants

6

Reactant 4

HCID 6417Pivalic acidHCID 99931-Bromo-4-fluorobenzeneHCID 11430Potassium CarbonateHCID 136342376-Methoxy-1-benzothiophene

Product 1

HCID 235129082-(4-Fluorophenyl)-6-methoxybenzo[b]thiopheneYield 54.1%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Procedure

To a 5 mL microwave vial was added a solution of 6-methoxybenzo[b]thiophene (400 mg, 2.44 mmol) in anhydrous DMA (3 mL) followed by 1-bromo-4-fluorobenzene (448 mg, 2.56 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos palladacycle 1st generation, 97 mg, 0.12 mmol), trimethylacetic acid (746 mg, 7.31 mmol) and potassium carbonate (1.01 g, 7.31 mmol). The microwave vial was sealed, purged with nitrogen and subjected to microwave irradiation at 150° C. for 2 h. Upon completion the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified via trituration 2× with heptane and the remaining triturate (containing some product) was concentrated and purified by column chromatography (SiO2, 0-30% EtOAc/Heptane) to afford 2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene (340 mg, 1.32 mmol, 54% yield). 1H NMR (400 MHz, (CD3)2SO) δ ppm=3.79-3.93 (m, 3H), 7.01 (dd, J=8.59, 2.53 Hz, 1H), 7.24-7.42 (m, 2H), 7.56 (d, J=2.53 Hz, 1H), 7.67-7.86 (m, 4H). LC/MS (m/z, MH+): 258.8.

Workup

  1. customThe microwave vial was sealed
  2. custompurged with nitrogen
  3. customirradiation at 150° C. for 2 h
  4. additionUpon completion the reaction mixture was diluted with water
  5. extractionextracted with EtOAc
  6. washThe combined organic layers were then washed with brine
  7. dry with materialdried over anhydrous MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe resulting crude material was purified via trituration 2× with heptane
  11. customthe remaining triturate (
  12. additioncontaining some product)
  13. concentrationwas concentrated
  14. custompurified by column chromatography (SiO2, 0-30% EtOAc/Heptane)

Sources & evidence

ORD record
ord-11eed62bb434470ab9f180ea187a1535
Source dataset
uspto-grants-2014_11
Patent number
US08877801B2

Reaction notes

Loading…