Bromobenzene → tert-Butyl 4-(4-bromophenyl)-4-(4-chlorophenyl)-piperidine-1-carboxylate

HRID 521359Notes

Reaction equation

HRID 521359 reaction equation
[Cl-].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2(O)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C:12]2([C:9]3[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=3)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:29][CH:28]=1

Participants

5

Reactant 4

HCID 7961BromobenzeneHCID 90495Di-tert-butyl dicarbonateHCID 6451240Aluminum(III) ChlorideHCID 21997555tert-Butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate

Product 1

HCID 57691398tert-Butyl 4-(4-bromophenyl)-4-(4-chlorophenyl)-piperidine-1-carboxylateYield 51.5%

Conditions

Temperature
0 °C

Procedure

Solid aluminum trichloride (0.68 mL, 5.1 mmol) was added to a solution of tert-butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate (0.40 g, 1.3 mmol) in bromobenzene (5.4 mL, 51.3 mmol) at 0° C. under nitrogen. After being stirred at 0° C. for 4 hours, the mixture was quenched with ice and concentrated under reduced pressure. The mixture was dissolved in 1N LiOH (30 mL) and extracted with EtOAc (2×30 mL). The combined organics were dried with Na2SO4, filtered and concentrated. The crude product was directly taken up in EtOAc (4 mL) and aqueous Na2CO3 solution (2M, 4 mL). Di-tert-butyldicarbonate (0.851 g, 3.9 mmol) was added in one portion. The mixture was stirred at 23° C. overnight. The next day, two layers were separated, and the aqueous layer was further extracted with EtOAc (2×10 mL). The combined organics were dried over Na2SO4, concentrated, and purified by column chromatography (0-40% EtOAc/hexanes) to give tert-butyl 4-(4-bromophenyl)-4-(4-chlorophenyl)piperidine-1-carboxylate (0.302 g, 51% yield). 1H NMR (CDCl3, 400 MHz) δ 7.46 (d, J=7.2 Hz, 2H), 7.32 (d, J=6.9 Hz, 2H), 7.19 (d, J=7.0 Hz, 2H), 7.12 (d, J=7.3 Hz, 2H), 3.54 (br s, 2H), 2.35 (br s, 2H), 1.54 (br s, 2H), 1.43 (s, 11H). LCMS: M+1 452.2.

Workup

  1. customthe mixture was quenched with ice
  2. concentrationconcentrated under reduced pressure
  3. dissolutionThe mixture was dissolved in 1N LiOH (30 mL)
  4. extractionextracted with EtOAc (2×30 mL)
  5. dry with materialThe combined organics were dried with Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. stirringThe mixture was stirred at 23° C. overnight
  9. customThe next day, two layers were separated
  10. extractionthe aqueous layer was further extracted with EtOAc (2×10 mL)
  11. dry with materialThe combined organics were dried over Na2SO4
  12. concentrationconcentrated
  13. custompurified by column chromatography (0-40% EtOAc/hexanes)

Sources & evidence

ORD record
ord-59da350669634b2e9c70414e7803c558
Source dataset
uspto-grants-2016_05
Patent number
US09328091B2

Reaction notes

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