1-Bromo-4-tert-butylbenzene → rel-(3R,5S)-1-[4-(1,1-Dimethylethyl)phenyl]-3,5-dimethylpiperazine

HRID 1727079Notes

Reaction equation

HRID 1727079 reaction equation
[CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[C:9]([C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([N:6]2[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]2)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]

Participants

7

Reactant 4

HCID 775951-Bromo-4-tert-butylbenzeneHCID 634876Binap, (A+-)-HCID 6950261rel-(2R,6S)-2,6-dimethylpiperazineHCID 178418730sodium 2-methylpropan-2-olate

Product 1

HCID 57565204rel-(3R,5S)-1-[4-(1,1-Dimethylethyl)phenyl]-3,5-dimethylpiperazineYield 37.3%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of cis-2,6-dimethylpiperazine (1 g, 8.7 mmol) in toluene (35 mL) was added 4-(tert-butyl)bromobenzene (1.86 g, 8.7 mmol), followed by BINAP (0.81 g, 1.3 mmol) and t-BuONa (1.5 g, 15.6 mmol) in one portion each. The resulting mixture was degassed twice. To the mixture was added Pd2(dba)3 (0.79 g, 0.87 mmol) in one portion and the mixture was heated to 100° C. overnight. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3×100 mL), washed with water (1×100 mL), and brine (1×50 mL), dried over Na2SO4 and concentarted in vacuo. The residue was purified by silica gel column chromatography (0-20% MeOH in dichloromethane) to afford 0.8 g 1-(4-tert-Butyl-phenyl)-cis-3,5-dimethyl-piperazine. 1H NMR (400 MHz, CDCl3) δ 7.29-7.26 (m, 2H), 6.88-6.86 (m, 2H), 3.49-3.46 (m, 2H), 3.08-3.00 (m, 2H), 2.33-2.27 (m, 2H), 2.15 (1H, br), 1.29 (s, 9H), 1.13 (d, 6H).

Workup

  1. customThe resulting mixture was degassed twice
  2. temperatureThe reaction mixture was cooled to room temperature
  3. extractionextracted with ethyl acetate (3×100 mL)
  4. washwashed with water (1×100 mL), and brine (1×50 mL)
  5. dry with materialdried over Na2SO4
  6. customThe residue was purified by silica gel column chromatography (0-20% MeOH in dichloromethane)

Sources & evidence

ORD record
ord-e71cf70d6e8d4327a251a3e329f8d3f4
Source dataset
uspto-grants-2009_02
Patent number
US07494999B2

Reaction notes

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