Triphenylphosphine → 3-(4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(3-thiophen-3-yl-phenoxy)-propionic acid ethyl ester

HRID 1393500Notes

Reaction equation

HRID 1393500 reaction equation
BrC1C=C(C=CC=1)OC(C)(CC1C=CC(OCCC2N=C(C3CCCCC3)OC=2C)=CC=1)C(O)=O.[S:36]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].[K+].[CH2:65]([O:67][C:68](=[O:100])[C:69]([CH3:99])([O:92][C:93]1[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=1)[CH2:70][C:71]1[CH:76]=[CH:75][C:74]([O:77][CH2:78][CH2:79][C:80]2[N:81]=[C:82]([CH:86]3[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]3)[O:83][C:84]=2[CH3:85])=[CH:73][CH:72]=1)[CH3:66]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH2:65]([O:67][C:68](=[O:100])[C:69]([CH3:99])([O:92][C:93]1[CH:94]=[CH:95][CH:96]=[C:97]([C:38]2[CH:39]=[CH:40][S:36][CH:37]=2)[CH:98]=1)[CH2:70][C:71]1[CH:72]=[CH:73][C:74]([O:77][CH2:78][CH2:79][C:80]2[N:81]=[C:82]([CH:86]3[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]3)[O:83][C:84]=2[CH3:85])=[CH:75][CH:76]=1)[CH3:66]

Participants

9

Reactant 5

HCID 11776TriphenylphosphineHCID 522689Potassium FluorideHCID 581760Thiophene-3-boronic acidHCID 208231432-Methyl-3-(4-{2-[5-methyl-2-cyclohexyl-oxazol-4-yl]-ethoxy}-phenyl)-2-phenoxypropionic Acid Ethyl EsterHCID 223400282-(3-Bromo-phenoxy)-3-(4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionic acid

Product 1

HCID 208231423-(4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-(3-thiophen-3-yl-phenoxy)-propionic acid ethyl ester

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

Add palladium acetate (8 mg, 0.04 mmol) to a solution of 2-(3-Bromo-phenoxy)-3-{4-[2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-propionic acid (0.204 g, 0.36 mmol), thiophene-3-boronic acid (91 mg, 0.71 mmol), triphenylphosphine (19 mg, 0.07 mmol), and potassium fluoride (51 mg, 1.07 mmol) in anhydrous THF (3 mL). Reflux the reaction mixture for 18 h under an atmosphere of nitrogen. Dilute the cooled reaction mixture with ethyl acetate and wash with water and brine. The organic layer was dried over Na2SO4, concentrated in vacuo, and purified by flash column chromatography (9% acetone in hexanes) to provide a mixture of the titled compound and 3-{4-[2-(2-Cyclohexyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionic acid ethyl ester (70 mg, 34%). 1H NMR (400 MHz, CDCl3): δ 7.38-7.19 (m, 5H), 7.13 (d, 2H, J=8.60 Hz), 7.07 (m, 1H), 6.80 (2H, J=8.60 Hz), 6.73-6.70 (m, 1H), 4.19 (q, 2H, J=7.04 Hz), 4.12 (t, 2H, J=6.65 Hz), 3.27 (d, 1H, J=13.69 Hz), 3.11 (d, 1H, J=13.69 Hz), 2.85 (t, 2H, J=6.65 Hz), 2.70-2.63 (m, 1H,), 2.22 (s, 3H), 2.01 (d, 2H, J=11.73 Hz), 1.79-1.76 (m, 2H), 1.67 (h, 1H, J=11.73 Hz), 1.59 (s, 3H), 1.56-1.46 (m, 2H), 1.41 (s, 3H), 1.37-1.23 (m, 2H), 1.20 (t, 3H, J=7.04 Hz). MS [EI+] 574 (M+H)+. Rf=0.08 in 9% ethyl acetate in hexanes.

Workup

  1. temperatureReflux the reaction mixture for 18 h under an atmosphere of nitrogen
  2. additionDilute
  3. washwash with water and brine
  4. dry with materialThe organic layer was dried over Na2SO4
  5. concentrationconcentrated in vacuo
  6. custompurified by flash column chromatography (9% acetone in hexanes)
  7. customto provide

Sources & evidence

ORD record
ord-57c9d352ab38495a912acff26e52a448
Source dataset
uspto-grants-2008_03
Patent number
US07345070B2

Reaction notes

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