Citric Acid → Methyl 3-chloro-5-cyclopropylbenzoate

HRID 878273Notes

Reaction equation

HRID 878273 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](I)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br-].[CH:14]1([Zn+])[CH2:16][CH2:15]1.CN1CCN(C)C1=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:14]2[CH2:16][CH2:15]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]

Participants

7

Reactant 4

HCID 311Citric Acid2×HCID 66611,3-Dimethyl-2-imidazolidinone2×HCID 24721134Methyl 3-chloro-5-iodobenzoateHCID 178419765HCID 178419765, compound2×

Product 1

HCID 70663348Methyl 3-chloro-5-cyclopropylbenzoateYield 63.2%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
50 °C

Procedure

To a solution of methyl 3-chloro-5-iodobenzoate (0.5 g, 1.69 mmol) in THF (5 mL) were added cyclopropylzinc(II)bromide (3.71 mL, 1.86 mmol), PEPPSI-IPr (22.9 mg, 33.7 μmol, CAS RN 905459-27-0) and 1,3-dimethyl-2-imidazolidinone (DMI) (1 mL) and the turbid light brown solution was stirred at 50° C. for 2.25 hours. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 50 g column using an MPLC (Flasmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 70:30). The obtained fraction (light yellow oil, 315 mg) was dissolved in THF (5 mL), to the clear solution were added cyclopropylzinc(II) bromide (3.71 mL, 1.86 mmol), PEPPSI-IPr (22.9 mg, 33.7 μmol, CAS RN 905459-27-0) and 1,3-dimethyl-2-imidazolidinone (DMI) (1 mL) and the reaction mixture was heated at 50° C. for 2.25 hours. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 40:60) to give the title compound as a light brown oil (0.225 g; 63%) containing 3,5-dicyclopropyl-benzoic acid methyl ester.

Workup

  1. customthe layers were separated
  2. extractionThe aqueous layer was extracted twice with EtOAc
  3. washThe organic layers were washed with brine
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. additiontreated with silica gel
  7. customevaporated
  8. customThe compound was purified by silica gel chromatography on a 50 g column
  9. washeluting with a gradient of n-heptane:EtOAc (100:0 to 70:30)
  10. dissolutionThe obtained fraction (light yellow oil, 315 mg) was dissolved in THF (5 mL), to the clear solution
  11. temperaturethe reaction mixture was heated at 50° C. for 2.25 hours
  12. customthe layers were separated
  13. extractionThe aqueous layer was extracted twice with EtOAc
  14. dry with materialThe organic layers were dried over MgSO4
  15. filtrationfiltered
  16. additiontreated with silica gel
  17. customevaporated
  18. customThe compound was purified by silica gel chromatography on a 10 g column
  19. washeluting with a gradient of n-heptane:EtOAc (100:0 to 40:60)

Sources & evidence

ORD record
ord-060c2592c29c49778b4a8749011a6a2a
Source dataset
uspto-grants-2015_03
Patent number
US08987307B2

Reaction notes

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