4-Fluoroiodobenzene → C-(4-Fluorophenyl)-C-(1-pyrrolidin-1-yl-cyclobutyl)-methylamine

HRID 560198Notes

Reaction equation

HRID 560198 reaction equation
C([Li])(C)(C)C.[F:6][C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=1.[N:14]1([C:19]2([C:23]#[N:24])[CH2:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>C(OCC)C>[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH:23]([NH2:24])[C:19]2([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:20][CH2:21][CH2:22]2)=[CH:9][CH:8]=1

Participants

7

Reactant 5

HCID 96054-FluoroiodobenzeneHCID 516892Sodium BicarbonateHCID 4311764Sodium borohydrideHCID 438027731-Pyrrolidin-1-yl-cyclobutanecarbonitrile2×HCID 178418306HCID 178418306, compound

Product 1

HCID 59197920C-(4-Fluorophenyl)-C-(1-pyrrolidin-1-yl-cyclobutyl)-methylamineYield 86.8%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent2×

Conditions

Temperature
-75 °C

Procedure

tert-Butyllithium (1.6M in pentane, 65 mL, 104 mmol) was added during 30 min at −75° C. to −60° C. to a solution of 4-fluoroiodobenzene (13 g, 59 mmol) in 40 mL diethylether. The reaction mixture was stirred at −75° C. for 45 min. 1-Pyrrolidin-1-yl-cyclobutanecarbonitrile (intermediate F) (5 g, 29 mmol) in 5 mL diethylether was added slowly. The reaction mixture was allowed to slowly warm up and was poured into cold saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The residue was dissolved in 100 mL methanol and sodiumborohydride (2.3 g, 59 mmol) was added portion-wise at 0° C. The reaction mixture was stirred at room temperature for 2 hours and quenched by addition of water. The solvent was evaporated off. The residue was taken up in water and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on amine silica gel with dichloromethane yielded the title compound as a yellow oil (6.25 g, 85%), MS: m/e=249.2 [(M+H)+].

Workup

  1. temperatureto slowly warm up
  2. extractionThe mixture was extracted three times with ethyl acetate
  3. customThe combined organic phases were dried on sodium sulfate
  4. filtrationfiltered
  5. customevaporated
  6. dissolutionThe residue was dissolved in 100 mL methanol
  7. stirringThe reaction mixture was stirred at room temperature for 2 hours
  8. customquenched by addition of water
  9. customThe solvent was evaporated off
  10. extractionethyl acetate and was extracted three times with ethyl acetate
  11. customThe combined organic phases were dried on sodium sulfate
  12. filtrationfiltered
  13. customevaporated
  14. customPurification of the residue by flash chromatography on amine silica gel with dichloromethane

Sources & evidence

ORD record
ord-bc481d628578493cb5edeb480e44f762
Source dataset
uspto-grants-2011_11
Patent number
US08063098B2

Reaction notes

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