Pyrrolidine → Ethyl 3-chloro-4-(pyrrolidin-1-yl)benzoate

HRID 2189771Notes

Reaction equation

HRID 2189771 reaction equation
Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[Cl:13].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.CC(C)([O-])C.[Na+].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>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]>[Cl:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]

Participants

7

Reactant 4

HCID 31268PyrrolidineHCID 634876Binap, (A+-)-HCID 12594301Ethyl 4-bromo-3-chlorobenzoateHCID 23676156Sodium t-butoxide

Product 1

HCID 59316744Ethyl 3-chloro-4-(pyrrolidin-1-yl)benzoateYield 24.6%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

A mixture of ethyl 4-bromo-3-chlorobenzoate (D16) (2.53 g, 9.62 mmol), pyrrolidine (1.03 mL, 12.5 mmol), sodium tert-butoxide (1.29 g, 13.5 mmol), BINAP (196 mg, 0.29 mmol) and tris(dibenzylideneacetone)dipalladium(0) (58 mg, 0.10 mmol) in toluene (120 mL) was heated to reflux under argon for 3 h. The reaction was allowed to cool and was filtered. The solid was washed with toluene and then the filtrate was concentrated. The residue was partitioned between ethyl acetate (150 mL) and water (100 mL) with aqueous sodium bicarbonate (50 mL) added. The organic phase was dried (phase separator) and concentrated to give an orange oil. The oil was purified by reverse phase chromatography, eluting 5-100% acetonitrile in water to give the title compound as an orange oil (600 mg). This contained some impurities. MS (ES): C13H1635ClNO2 requires 253; found 254 (MH+).

Workup

  1. temperaturewas heated
  2. temperatureto reflux under argon for 3 h
  3. temperatureto cool
  4. filtrationwas filtered
  5. washThe solid was washed with toluene
  6. concentrationthe filtrate was concentrated
  7. customThe residue was partitioned between ethyl acetate (150 mL) and water (100 mL) with aqueous sodium bicarbonate (50 mL)
  8. additionadded
  9. customThe organic phase was dried (phase separator)
  10. concentrationconcentrated
  11. customto give an orange oil
  12. customThe oil was purified by reverse phase chromatography
  13. washeluting 5-100% acetonitrile in water

Sources & evidence

ORD record
ord-a4617cf816f942ab810552f63b085bb0
Source dataset
uspto-grants-2012_12
Patent number
US08324254B2

Reaction notes

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