Citric Acid → (1S,2R)-1-(3-Fluorophenyl)-1,2-cyclopropanedimethanol

HRID 1482781Notes

Reaction equation

HRID 1482781 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C@:8]23[CH2:13][C@H:12]2[CH2:11][O:10][C:9]3=[O:14])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+].C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.CCCCCCC>[F:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH2:9][OH:14])[CH2:13][C@H:12]2[CH2:11][OH:10])[CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 4

HCID 311Citric AcidHCID 8028TetrahydrofuranHCID 4148881Lithium borohydrideHCID 67281781(1S,5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexan-2-one

Product 1

HCID 67282266(1S,2R)-1-(3-Fluorophenyl)-1,2-cyclopropanedimethanol

Reagents, catalysts & solvents 1

HCID 21899848Ethylacetate heptaneSolvent

Conditions

Temperature
-7.5 °C

Procedure

(1S,5R)-1-(3-fluorophenyl)-3-oxabicyclo[3.1.0]hexan-2-one (4, 10.08 g, 0.052 mol, 1.0 equiv.) was dissolved in 2-methyl-THF (75.60 mL) under nitrogen. The solution was cooled to −5 to −10° C., and 2.0 M Lithium tetrahydroborate in THF (39.34 mL, 0.079 mol, 1.5 equiv.) was added to the reaction mixture while maintaining the internal temperature below 0° C. The reaction was stirred at 20-25° C. for 14-16 hours and monitored by HPLC and TLC (EtOAc/Heptane=1/1). Once the reaction was completed, the reaction mixture was cooled to 0-5° C. and reverse quenched into a pre-cooled (0-5° C.) 20% aqueous citric acid solution (50.40 mL, 1.67 equiv.) at such a rate as to maintain the internal temperature below 5° C. Once the quench was complete, the reaction mixture was warmed to 20-25° C. and stirred for at least 20 min. The aqueous layer was back extracted once with 2-methyl-THF (50.40 mL). The organic layers were combined and washed once with saturated aqueous sodium bicarbonate solution (20.16 mL) and once with 20% aqueous NaCl (20.16 mL). The solvent was removed under reduced pressure then azeotroped with 2-methyl-THF until KF is less than 1500 ppm to afford the title compound, ((1S,2R)-1-(3-fluorophenyl)cyclopropane-1,2-diyl)dimethanol; 5 (10.29 g).

Workup

  1. temperaturewhile maintaining the internal temperature below 0° C
  2. temperaturethe reaction mixture was cooled to 0-5° C.
  3. customreverse quenched into
  4. temperatureto maintain the internal temperature below 5° C
  5. temperaturethe reaction mixture was warmed to 20-25° C.
  6. stirringstirred for at least 20 min
  7. extractionThe aqueous layer was back extracted once with 2-methyl-THF (50.40 mL)
  8. washwashed once with saturated aqueous sodium bicarbonate solution (20.16 mL) and once with 20% aqueous NaCl (20.16 mL)
  9. customThe solvent was removed under reduced pressure
  10. customthen azeotroped with 2-methyl-THF until KF

Sources & evidence

ORD record
ord-39f8c3ab5b9e454faa4ef208604712e0
Source dataset
uspto-grants-2016_08
Patent number
US09416109B2

Reaction notes

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