Cesium fluoride → 1-(2-{4-[6-Benzyloxy-2-(4-trifluoromethanesulfonyl-phenyl)-benzo[b]thiophen-3-yloxy]-phenoxy}-ethyl)-piperidine

HRID 732828Notes

Reaction equation

HRID 732828 reaction equation
C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]2[C:35]([O:36][C:37]3[CH:51]=[CH:50][C:40]([O:41][CH2:42][CH2:43][N:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)=[CH:39][CH:38]=3)=[C:34](Br)[S:33][C:32]=2[CH:53]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC1(C)C(C)(C)OB([C:62]2[CH:67]=[CH:66][C:65]([S:68]([C:71]([F:74])([F:73])[F:72])(=[O:70])=[O:69])=[CH:64][CH:63]=2)O1.[F-].[Cs+]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]2[C:35]([O:36][C:37]3[CH:51]=[CH:50][C:40]([O:41][CH2:42][CH2:43][N:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)=[CH:39][CH:38]=3)=[C:34]([C:62]3[CH:63]=[CH:64][C:65]([S:68]([C:71]([F:73])([F:72])[F:74])(=[O:70])=[O:69])=[CH:66][CH:67]=3)[S:33][C:32]=2[CH:53]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1

Participants

7

Reactant 4

HCID 25953Cesium fluorideHCID 75806TricyclohexylphosphineHCID 673973674,4,5,5-Tetramethyl-2-(4-trifluoromethanesulfonylphenyl)-1,3,2-dioxaborolaneHCID 690745451-{2-[4-(6-Benzyloxy-2-bromo-benzo[b]thiophen-3-yloxy)-phenoxy]-ethyl}-piperidine

Product 1

HCID 597514351-(2-{4-[6-Benzyloxy-2-(4-trifluoromethanesulfonyl-phenyl)-benzo[b]thiophen-3-yloxy]-phenoxy}-ethyl)-piperidineYield 55.3%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6342AcetonitrileSolvent2×

Conditions

Temperature
90 °C

Procedure

Sonicate a suspension of palladium (II) acetate (146 mg, 0.65 mmol) and tricyclohexylphosphine (273 mg, 0.98 mmol) in acetonitrile (4 mL) for 10 minutes. In a separate flask, add a solution of 1-{2-[4-(6-benzyloxy-2-bromo-benzo[b]thiophen-3-yloxy)-phenoxy]-ethyl}-piperidine (350 mg, 0.65 mmol) and 4,4,5,5-tetramethyl-2-(4-trifluoromethanesulfonyl-phenyl)-[1,3,2]dioxaborolane (531 mg, 2.0 mmol) in acetonitrile (9 mL) to cesium fluoride (889 mg, 5.9 mmol). Add the sonicated catalyst mixture, and heat to 90° C. for 2 hours. Concentrate in vacuo and partition the residue between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (20 mL). Combine the organic layer with saturated aqueous ammonium chloride (20 mL) and filter. Wash the organic layer with brine (20 mL), dry with sodium sulfate, and concentrate in vacuo. Chromatbgraph the residue on a SiO2 column eluting with methanol in dichloromethane (0 to 3%) to give 240 mg of the title compound (55%) contaminated with tricyclohexylphosphine oxide. 1H NMR (CDCl3): δ 8.03-7.95 (m, 4H), 7.45-7.33 (m, 5H), 7.32 (d, J=2.3 Hz, 1H), 7.29 (d, J=8.9 Hz, 1H), 6.96 (dd, J=9.0, 2.2 Hz, 1H), 6.89-6.79 (m, 4H), 5.13 (s, 2H), 4.03 (t, J=6.0 Hz, 2H), 2.73 (t, J=6.0 Hz, 2H), 2.48 (bs, 4H), 1.96-1.18 (complex multiplet obscured by P(O)Cy3, 6H).

Workup

  1. customSonicate
  2. additionAdd the sonicated catalyst mixture
  3. concentrationConcentrate in vacuo
  4. custompartition the residue between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (20 mL)
  5. filtrationCombine the organic layer with saturated aqueous ammonium chloride (20 mL) and filter
  6. washWash the organic layer with brine (20 mL)
  7. dry with materialdry with sodium sulfate
  8. concentrationconcentrate in vacuo
  9. washChromatbgraph the residue on a SiO2 column eluting with methanol in dichloromethane (0 to 3%)

Sources & evidence

ORD record
ord-4d82703704a7446ea60ab1737cd98d33
Source dataset
uspto-grants-2009_09
Patent number
US07585977B2

Reaction notes

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