Tetrahydrofuran → 3-(4'-Ethoxy-2,2',3,3'-tetrafluorobiphenyl-4-yl)-6-(4-propylcyclohexyl)tetrahydropyran-2-one

HRID 1941724Notes

Reaction equation

HRID 1941724 reaction equation
C1COCC1.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[C:17]([F:25])[C:16]=2[F:26])=[C:11]([F:27])[C:10]=1[F:28])[CH3:7].C([Li])CCC.[CH2:34]([C@H:37]1[CH2:42][CH2:41][C@H:40]([CH:43]2[CH2:46][CH2:45]O2)[CH2:39][CH2:38]1)[CH2:35][CH3:36]>C(O)=O>[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:36][CH2:35][CH:34]([CH:37]4[CH2:38][CH2:39][CH:40]([CH2:43][CH2:46][CH3:45])[CH2:41][CH2:42]4)[O:23][C:22]3=[O:24])=[C:17]([F:25])[C:16]=2[F:26])=[C:11]([F:27])[C:10]=1[F:28])[CH3:7]

Participants

6

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 679923862-(4'-Ethoxy-2,2',3,3'-tetrafluorobiphenyl-4-yl)acetic acidHCID 178418339ButyllithiumHCID 178447926HCID 178447926, compound

Product 1

HCID 585356163-(4'-Ethoxy-2,2',3,3'-tetrafluorobiphenyl-4-yl)-6-(4-propylcyclohexyl)tetrahydropyran-2-oneYield 87%

Reagents, catalysts & solvents 1

HCID 284Formic AcidSolvent

Conditions

Temperature
-5 °C

Procedure

THF (50 ml) was added to 2-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)acetic acid (10) (2.0 g) prepared in the eighth step. The solution was cooled to −5° C., and n-butyllithium (1.59 M in n-hexane; 7.66 ml) was added dropwise. After the addition had been completed, the reaction mixture was returned to room temperature, and the stirring was continued for 30 minutes. The solution was then cooled to −65° C., and 2-(trans-4-propyl-cyclohexyl)-oxetane (5) (1.0 g) in a THF (5 ml) solution and a boron trifluoride-diethyl ether complex (0.86 g) were added dropwise. After the addition had been completed, the reaction mixture was returned to room temperature, and a 10% aqueous solution of formic acid (100 ml) was added to give two layers. The water layer was extracted with toluene (20 ml) three times and the combined organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 200 g, eluent: heptane/ethyl acetate=90/10 by volume) to give 3-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)-6-(4-propylcyclohexyl)tetrahydropyran-2-one (11) (2.35 g) in 86.1% yield.

Workup

  1. customprepared in the eighth step
  2. additionAfter the addition
  3. customwas returned to room temperature
  4. temperatureThe solution was then cooled to −65° C.
  5. additionAfter the addition
  6. customwas returned to room temperature
  7. customto give two layers
  8. extractionThe water layer was extracted with toluene (20 ml) three times
  9. washthe combined organic layer was washed with water
  10. dry with materialdried over anhydrous magnesium sulfate
  11. distillationThe solvent was distilled off under reduced pressure
  12. customThe residue was purified by silica gel chromatography (silica gel: 200 g, eluent: heptane/ethyl acetate=90/10 by volume)

Sources & evidence

ORD record
ord-d3d8b68963394fd8b466d1ea3f3d8c8f
Source dataset
uspto-grants-2013_03
Patent number
US08389073B2

Reaction notes

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