1-Bromo 4-fluoronaphthalene → HCID 69417653, compound

HRID 1373550Notes

Reaction equation

HRID 1373550 reaction equation
C1(P(C2C=CC=CC=2C2C=CC=CC=2)C2CCCCC2)CCCCC1.Br[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([F:37])=[CH:29][CH:28]=1.[C:38]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:41]([O:40][C:38]([N:45]1[CH2:50][CH2:49][N:48]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([F:37])=[CH:29][CH:28]=2)[CH2:47][CH2:46]1)=[O:39])([CH3:44])([CH3:42])[CH3:43]

Participants

7

Reactant 4

HCID 676471-Bromo 4-fluoronaphthaleneHCID 143452tert-Butyl piperazine-1-carboxylateHCID 27342162-(Dicyclohexylphosphino)biphenylHCID 23676156Sodium t-butoxide

Product 1

HCID 69417653HCID 69417653, compoundYield 95.4%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

A first intermediate compound, 1-(4-Fluoro-naphthalen-1-yl)-piperazine, was produced as follows: A mixture of dicyclohexylphosphino biphenyl (0.155 g, 0.444 mmol, 0.1 mmol) and palladium acetate (0.099 g, 0.444 mmol, 0.1 equiv) in dry toluene (15 mL) was bubbled with N2 gas for two hours. To the resultant clear solution was added 1-bromo-4-fluoro naphthalene (1.0 g, 4.44 mmol, 1.0 equiv) followed by 1-Boc-piperazine (1.0 g, 5.33 mmol, 1.2 equiv). To this mixture was added NaOtBu (0.600 g, 6.22 mmol, 1.4 equiv) and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was taken up in CH2Cl2, filtered through a celite bed, and then rinsed with CH2Cl2. The combined filtrates were concentrated and purified by column chromatography on silica (20% EtOAc in hexane). 4-(4-Fluoro-naphthalen-1-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.4 g, impure) was obtained as a dark viscous liquid, which was used in the next step without further purification. 1H NMR: (400 MHz, CDCl3) δ 8.25 (m, 1H), 8.05 (m, 1H), 7.55 (m, 2H), 7.05–6.80 (m, 2H), 4.00 (br s, 4H), 3.00 (br s, 4H), 1.45(s, 9H). MS: ES+ 331.13 (M+H)+ (Exact mass: 330.17).

Workup

  1. customwas bubbled with N2 gas for two hours
  2. temperatureThe reaction mixture was cooled to room temperature
  3. customthe solvent was removed under reduced pressure
  4. filtrationfiltered through a celite bed
  5. washrinsed with CH2Cl2
  6. concentrationThe combined filtrates were concentrated
  7. custompurified by column chromatography on silica (20% EtOAc in hexane)

Sources & evidence

ORD record
ord-c6cdd4127f3a4a74be6b907c748cfa82
Source dataset
uspto-grants-2007_01
Patent number
US07160888B2

Reaction notes

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