Potassium Fluoride → 2-(4-{2-[2-(2'-Methoxy-biphenyl-4-yl)-5-methyloxazol-4-yl]-ethoxy}-phenoxy)-2-methylpropionic acid ethyl ester

HRID 2228993Notes

Reaction equation

HRID 2228993 reaction equation
[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.[F-].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[O:33][CH3:32])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]

Participants

8

Reactant 4

HCID 522689Potassium FluorideHCID 27339582-Methoxyphenylboronic acidHCID 27342162-(Dicyclohexylphosphino)biphenylHCID 110273422-(4-{2-[2-(4-Bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester

Product 1

HCID 698714712-(4-{2-[2-(2'-Methoxy-biphenyl-4-yl)-5-methyloxazol-4-yl]-ethoxy}-phenoxy)-2-methylpropionic acid ethyl ester

Reagents, catalysts & solvents 3

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

Procedure

A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (300 mg, 0.614 mmol) (see Ex. 2, part B), o-methoxyphenylboronic acid (140 mg, 0.921 mmol), potassium fluoride (88.6 mg, 1.84 mmol), palladium acetate (1.3 mg, 0.14 μmol), and 2-(dicyclohexylphosphino)biphenyl (4.3 mg, 12.3 μmol) were combined under N2, to which anhydrous THF (1.23 mL) was added. The yellow mixture was heated at reflux for 12 h. After cooling to room temperature, the mixture was partitioned between Et2O (20 mL) and 1M NaOH (10 mL). The layers were separated, and the aqueous phase was back-extracted with Et2O (10 mL). Combined organic phases were dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (25 g SiO2, 1:4 ethyl acetate:hexanes) to yield 100.5 mg (32%) as an oil. Rf=0.38 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ7.97 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.33-7.29 (m, 2H), 7.01 (t, J=7.2 Hz, 1H), 6.97 (d, J=7.6 Hz, 1H), 6.80-6.74 (m, 4H), 4.20 (q, J=7.2 Hz, 2H), 4.17 (t, J=6.8 Hz, 2H), 3.80 (s, 3H), 2.94 (t, J=6.8 Hz, 2H), 2.34 (s, 3H), 1.50 (s, 6H), 1.24 (t, J=7.2 Hz, 3H); MS (EI) 538.2 (M+Na)+, 516.2 (M+H)+.

Workup

  1. additionwas added
  2. temperatureThe yellow mixture was heated
  3. temperatureat reflux for 12 h
  4. customthe mixture was partitioned between Et2O (20 mL) and 1M NaOH (10 mL)
  5. customThe layers were separated
  6. extractionthe aqueous phase was back-extracted with Et2O (10 mL)
  7. dry with materialCombined organic phases were dried over Na2SO4
  8. concentrationconcentrated
  9. customThe product was purified by silica gel chromatography (25 g SiO2, 1:4 ethyl acetate:hexanes)
  10. customto yield 100.5 mg (32%) as an oil

Sources & evidence

ORD record
ord-25e5caaa4ccc4706be6f386fe2f63130
Source dataset
uspto-grants-2002_07
Patent number
US06417212B1

Reaction notes

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