Cesium fluoride → 1-(2-(4-(6-Methoxy-2-(thiophen-2-yl)naphthalen-1-yloxy)phenoxy)ethyl)piperidine

HRID 445204Notes

Reaction equation

HRID 445204 reaction equation
FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[C:8]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:22][CH:21]=1)(=O)=O.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1B(O)O.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[F-].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:24][CH:25]=1)=[C:7]([C:38]1[S:37][CH:41]=[CH:40][CH:39]=1)[CH:16]=[CH:15]2

Participants

7

Reactant 4

HCID 25953Cesium fluorideHCID 75806TricyclohexylphosphineHCID 27339602-Thiopheneboronic acidHCID 116133766-Methoxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-yl trifluoromethanesulfonate

Product 1

HCID 583385531-(2-(4-(6-Methoxy-2-(thiophen-2-yl)naphthalen-1-yloxy)phenoxy)ethyl)piperidineYield 73.7%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6342AcetonitrileSolvent

Conditions

Temperature
80 °C

Procedure

Combine 6-methoxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-yl trifluoromethanesulfonate (6.0 g, 11.4 mmol), Thiophene-2-boronic Acid (4.4 g, 34.3 mmol), tricyclohexylphosphine (1.1 g, 4.0 mmol), palladium (II) acetate (0.51 g, 2.3 mmol), cesium fluoride (15.6 g, 102.8 mmol) and acetonitrile (150 mL; degas with nitrogen for 30 minutes) to a round bottom flask under nitrogen. Warm the resulting mixture to 80° C. and stir for 40 minutes. Filter off solids and wash with acetonitrile. Combine the filtrate and washes and concentrate in vacuo. Dissolve the residue in methanol and load onto an SCX acidic ion exchange column. Flush the column with methanol then elute with 2M ammonia in methanol. Concentrate the ammonia containing eluent in vacuo to give a light brown solid. Purify the solid by silica gel flash chromatography to obtain the title compound (3.88 g, 8.4 mmol). 1H NMR (d6-DMSO) δ29 (dd, J=5.9, 11.2 Hz, 2H), 1.43-1.37 (m, 5H), 2.32 (s, 4H), 2.52 (t, J=5.9 Hz, 2H), 3.87 (t, J=6.1 Hz, 2H), 6.62-6.60 (m, 2H), 6.76-6.74 (m, 2H), 7.09-7.03 (m, 2H), 7.37 (d, J=2.6 Hz, 1H), 7.48-7.47 (m, 1H), 7.62-7.59 (m, 2H), 7.76 (d, J=8.8 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H).

Workup

  1. filtrationFilter off solids
  2. washwash with acetonitrile
  3. concentrationconcentrate in vacuo
  4. dissolutionDissolve the residue in methanol
  5. customFlush the column with methanol
  6. washthen elute with 2M ammonia in methanol
  7. concentrationConcentrate the ammonia containing eluent in vacuo
  8. customto give a light brown solid
  9. customPurify the solid by silica gel flash chromatography

Sources & evidence

ORD record
ord-9af1a5268c164bfea05399d354a09216
Source dataset
uspto-grants-2013_07
Patent number
US08476300B2

Reaction notes

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