1-Acetylpiperazine → 4-(4-Acetylpiperazin-1-yl)-2-fluorobenzaldehyde

HRID 1505600Notes

Reaction equation

HRID 1505600 reaction equation
CC(C)([O-])C.[Na+].[N:7]1([C:13](=[O:15])[CH3:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[C:17]1[CH:22]=[CH:21][C:20]([CH:23](OC)[O:24]C)=[C:19]([F:28])[CH:18]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>[C:13]([N:7]1[CH2:12][CH2:11][N:10]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[C:19]([F:28])[CH:18]=2)[CH2:9][CH2:8]1)(=[O:15])[CH3:14]

Participants

7

Reactant 3

HCID 837951-AcetylpiperazineHCID 184268214-Bromo-1-(dimethoxymethyl)-2-fluorobenzeneHCID 23676156Sodium t-butoxide

Product 1

HCID 866906364-(4-Acetylpiperazin-1-yl)-2-fluorobenzaldehydeYield 60%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

Palladium(II) acetate (111 mg, 0.49 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (469 mg, 0.98 mmol) and sodium tert-butoxide (4.88 g, 49.2 mmol) were combined and the flask was purged with nitrogen. A solution of 1-piperazin-1-ylethanone (4.1 g, 32 mmol) and 4-bromo-1-(dimethoxymethyl)-2-fluoro-benzene (6.13 g, 24.6 mmol) in 1,4-dioxane (82 mL) was then added and the reaction was stirred at 100° C. for 16 hours. The reaction was then filtered through diatomaceous earth and concentrated. The resulting residue was dissolved in 50 mL of THF and 50 mL of 1 N aqueous HCl was added and the reaction was stirred at ambient temperature for 16 hours. The reaction was then neutralized with saturated aqueous Na2CO3 and extracted with dichloromethane (×3), dried with MgSO4, concentrated and purified by silica gel column chromatography (0-10% methanol in dichloromethane) to give 4-(4-acetylpiperazin-1-yl)-2-fluoro-benzaldehyde (3.68 g, 60% yield). LCMS (m/z) ES+ 251 [M+1]+.

Workup

  1. customthe flask was purged with nitrogen
  2. filtrationThe reaction was then filtered through diatomaceous earth
  3. concentrationconcentrated
  4. dissolutionThe resulting residue was dissolved in 50 mL of THF
  5. addition50 mL of 1 N aqueous HCl was added
  6. stirringthe reaction was stirred at ambient temperature for 16 hours
  7. extractionextracted with dichloromethane (×3)
  8. dry with materialdried with MgSO4
  9. concentrationconcentrated
  10. custompurified by silica gel column chromatography (0-10% methanol in dichloromethane)

Sources & evidence

ORD record
ord-ea071627445846a6b0062822ff2b26f4
Source dataset
uspto-grants-2015_12
Patent number
US09216988B2

Reaction notes

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