Toluene → 1-[4-(Phenylmethoxy)phenyl]-4-[4-(trifluoromethoxy)phenoxy]piperidine

HRID 1039608Notes

Reaction equation

HRID 1039608 reaction equation
[F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][CH:21]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C(O)C.O>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:15]=[CH:16][C:4]([O:3][C:2]([F:1])([F:17])[F:18])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)=[CH:21][CH:22]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1

Participants

10

Reactant 4

HCID 1140TolueneHCID 1388351-Bromo-4-phenylmethoxybenzeneHCID 161154394-[4-(Trifluoromethoxy)phenoxy]piperidineHCID 23676156Sodium t-butoxide

Product 1

HCID 684830771-[4-(Phenylmethoxy)phenyl]-4-[4-(trifluoromethoxy)phenoxy]piperidineYield 91.7%

Reagents, catalysts & solvents 5

HCID 167845palladium(II) acetateCatalystHCID 23136663Tri-tert-butylphosphonium TetraphenylborateCatalystHCID 702EthanolSolventHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

4-[4-(Trifluoromethoxy)phenoxy]piperidine (26.1 g), benzyl 4-bromophenyl ether (26.3 g), palladium (II) acetate (22.4 mg), Tri-tert-butyl phosphonium tetraphenyl borate (52.3 mg), sodium tert-butoxide (10.6 g) and toluene (130 mL) were placed in a vessel and heated to reflux for 4 hr under Ar. The reaction mixture was then cooled to room temperature and water (260 mL) and ethyl acetate (260 mL) were added. The organic material was taken up in ethyl acetate. The organic layer was washed two times with water (260 mL×2). The organic layer was filtered to remove a harz and then the organic layer was condensed under reduced pressure to give 43.34 g (97.82% crude yield, 97.34% HPLC purity) of the pale yellow product. The crude product (43.3 g) and ethanol (433 mL) were placed in a vessel and heated until to dissolve and then the mixture was allowed to cool to 0° C. for 1 hr. The mixture was then filtered and the crystalline powder washed with cooled ethanol (43 mL) and then dried at 40° C. for 15 hr to afford 39.7 g (91.7% yield) of a pale yellow crystal target compound.

Workup

  1. temperatureheated
  2. temperatureto reflux for 4 hr under Ar
  3. washThe organic layer was washed two times with water (260 mL×2)
  4. filtrationThe organic layer was filtered
  5. customto remove a harz
  6. customcondensed under reduced pressure
  7. customto give 43.34 g (97.82% crude yield, 97.34% HPLC purity) of the pale yellow product
  8. temperatureheated until
  9. dissolutionto dissolve
  10. temperatureto cool to 0° C. for 1 hr
  11. filtrationThe mixture was then filtered
  12. washthe crystalline powder washed with cooled ethanol (43 mL)
  13. customdried at 40° C. for 15 hr

Sources & evidence

ORD record
ord-63d8341440b348c087626f2f3d2f5ff6
Source dataset
uspto-grants-2013_10
Patent number
US08552188B2

Reaction notes

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