Tetrahydrofuran → HCID 86610910, compound

HRID 2377033Notes

Reaction equation

HRID 2377033 reaction equation
[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([O:8][C@@H:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:12][N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10]1)=O.[CH2:37]1COCC1>C1(C)C=CC=CC=1.[CH3-].C[Al+]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+3]>[F:32][C:31]([F:34])([F:33])[C:29]1[CH:28]=[C:5]([C:6]([O:8][C@@H:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:12][N:11]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10]2)=[CH2:37])[CH:4]=[C:3]([C:2]([F:1])([F:35])[F:36])[CH:30]=1

Participants

5

Reactant 2

HCID 8028TetrahydrofuranHCID 86610909HCID 86610909, compound

Product 1

HCID 86610910HCID 86610910, compound

Reagents, catalysts & solvents 2

HCID 53384502mu-Chlorobis(eta5-cyclopentadienyl)(dimethylaluminum)-mu-methylenetitaniumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
0 °C

Procedure

In a 500 mL 3-neck round bottom flask equipped with septa, magnetic stir bar thermocouple, addition funnel and nitrogen line was placed a solution of tert-butyl (3R,4S)-3-{[3,5-bis(trifluoromethyl)benzoyl]oxy}-4-(4-fluorophenyl)pyrrolidine-1-carboxylate (product step A, 17.77 mmol) in 115 mL anhydrous THF. The solution was cooled to 0° C. with an ice/water bath. To the cooled solution was slowly added 45 mL (21.32 mmol) of a 0.5M solution of Tebbe reagent in toluene (commercially available) dropwise by addition funnel. After the addition was complete the funnel was rinsed with anhydrous toluene then THF and the resulting solution added to the reaction mixture. After stirring 1.5 h at 0° C., an additional 9.0 mL (4.5 mmol, 0.25 equiv.) of 0.5M solution of Tebbe reagent in toluene was added dropwise by addition funnel. The reaction was stirred an additional 15 min then carefully quenched by addition of 15 mL water drop by drop. The resulting mixture was transferred to a separatory funnel and extracted with ether/EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum. The residue dissolved in a minimal amount of methylene chloride filtered and the solvent removed under vacuum. The resulting oil was purified by column chromatography on silica gel eluting EtOAc/hexanes gradient (5/95 to 10/90) to afford the title compound as a yellow foam. 1H-NMR (CDCl3): δ: 1.54 (s, 9H), 3.46-4.01 (br. m, 6H), 4.0 (d, 1H), 4.61 (s, 1H), 4.91 (d, 1H), 7.08 (m, 2H), 7.22 (m, 2H), 7.83 (s, 1H), 8.0 (s, 2H)ppm.

Workup

  1. customIn a 500 mL 3-neck round bottom flask equipped with septa, magnetic stir bar thermocouple
  2. additionaddition funnel
  3. additiondropwise by addition funnel
  4. additionAfter the addition
  5. washwas rinsed with anhydrous toluene
  6. additionTHF and the resulting solution added to the reaction mixture
  7. additionan additional 9.0 mL (4.5 mmol, 0.25 equiv.) of 0.5M solution of Tebbe reagent in toluene was added dropwise by addition funnel
  8. stirringThe reaction was stirred an additional 15 min
  9. customthen carefully quenched by addition of 15 mL water drop by drop
  10. customThe resulting mixture was transferred to a separatory funnel
  11. extractionextracted with ether/EtOAc
  12. dry with materialdried over anhydrous sodium sulfate
  13. filtrationfiltered
  14. customthe solvent removed under vacuum
  15. dissolutionThe residue dissolved in a minimal amount of methylene chloride
  16. filtrationfiltered
  17. customthe solvent removed under vacuum
  18. customThe resulting oil was purified by column chromatography on silica gel
  19. washeluting EtOAc/hexanes gradient (5/95 to 10/90)

Sources & evidence

ORD record
ord-d0d99831c93c44de9a3482d235761e3a
Source dataset
uspto-grants-2008_12
Patent number
US07468437B2

Reaction notes

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