Potassium Carbonate → 2-(4-Benzylpiperazin-1-yl)-6-fluorobenzaldehyde

HRID 1648355Notes

Reaction equation

HRID 1648355 reaction equation
F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH2:20]2)[C:3]=1[CH:4]=[O:5]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 759941-BenzylpiperazineHCID 1362842,6-Difluorobenzaldehyde

Product 1

HCID 152899492-(4-Benzylpiperazin-1-yl)-6-fluorobenzaldehydeYield 74.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Combine 2,6-difluorobenzaldehyde (5.00 g, 35.2 mmol), 1-benzylpiperazine (7.30 mL, 42.2 mmol) and potassium carbonate (5.83 g, 42.2 mmol) in dry N,N-dimethylformamide (10 mL) under an atmosphere of nitrogen. Heat the reaction to 80° C. for 4 hours. Cool the reaction to room temperature (20° C.) and stir overnight. Quench the reaction with water (100 mL) and extract with ethyl acetate (3×100 mL). Combine the organic extracts, wash with saturated ammonium chloride (4×100 mL), dry over anhydrous magnesium sulfate/sodium sulfate, filter and concentrate under vacuum to provide the crude product as a yellow oil. Purify the crude material by flash chromatography (ethyl acetate:hexane, 30:70, TLC Rf =0.40) followed by recrystallization from hot ethyl acetate (50 mL). Collect the crystals by suction filtration and rinse with hexane to yield 5.16 g. Concentrate the mother liquor and recrystallize the solid from ethyl acetate (15 mL). Isolate the crystals as above to yield 1.71 g. Repeat the above process to yield an additional 0.95 g. This provides the 2-fluoro-6-[4-benzylpiperazin-1-yl]-benzaldehyde (7.82 g) as yellow crystals, mp 94°-95° C.; 1H NMR (CDCl3) δ 10.26 (1H,-s), 7.44 (1H, td, J=8.1, 6.3 Hz). 7.34 (4H, m), 7.29 (1H, m), 6.84 (1H, d, J=8.3 Hz), 6.74 (1H, dd, J=8.3, 8.0 Hz), 3.59 (2H, s), 3.12 (4H, m), 2.66 (4H, m); 13C NMR (CDCl3) δ 187.63, 187.56, 165.73, 162.27, 155.82, 137.82, 135.62, 135.46, 129.20, 128.27, 127.18, 116.91, 116.82, 114.26, 114.22, 109.38, 109.09, 62.95, 53.51, 52.96; 19F NMR CDCl3) δ -115.94 (m); IR (KBr) 2825, 1690, 1607, 1462, 1005 cm-1 ; EI/MS (70eV) 298(80%), 91(100%).

Workup

  1. temperatureHeat
  2. customthe reaction to 80° C. for 4 hours
  3. temperatureCool
  4. customthe reaction to room temperature (20° C.)
  5. customQuench
  6. customthe reaction with water (100 mL)
  7. extractionextract with ethyl acetate (3×100 mL)
  8. washCombine the organic extracts, wash with saturated ammonium chloride (4×100 mL)
  9. dry with materialdry over anhydrous magnesium sulfate/sodium sulfate
  10. filtrationfilter
  11. concentrationconcentrate under vacuum
  12. customto provide the crude product as a yellow oil
  13. customPurify the crude material by flash chromatography (ethyl acetate:hexane, 30:70, TLC Rf =0.40)
  14. customfollowed by recrystallization from hot ethyl acetate (50 mL)
  15. customCollect the crystals
  16. filtrationby suction filtration
  17. washrinse with hexane
  18. customto yield 5.16 g
  19. concentrationConcentrate the mother liquor
  20. customrecrystallize the solid from ethyl acetate (15 mL)
  21. customIsolate the crystals as above
  22. customto yield 1.71 g
  23. customRepeat the above process to yield an additional 0.95 g

Sources & evidence

ORD record
ord-eb4556f0071c4322a8c51b0e4049c51e
Source dataset
uspto-grants-1995_07
Patent number
US05436246

Reaction notes

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