Sulfuric Acid → Ethyl-5-(4-[2-fluorobenzyloxy]phenyl)-3,4-dihydro-2H-pyrrole-2-carboxyate

HRID 410003Notes

Reaction equation

HRID 410003 reaction equation
[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH:13]=[CH2:14])=[CH:8][CH:7]=1.C1(C(C2C=CC=CC=2)=[N:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])C=CC=CC=1.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1.CC([C@@H]1N=C([C]2[C](P(C3C=CC=CC=3)C3C=CC=CC=3)[CH][CH][CH]2)OC1)C.[CH]1[CH][CH][CH][CH]1.[Fe].C1CCN2C(=NCCC2)CC1>[CH2:32]([O:31][C:29]([CH:28]1[CH2:14][CH2:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]3[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=3[F:1])=[CH:7][CH:8]=2)=[N:27]1)=[O:30])[CH3:33]

Participants

8

Reactant 4

HCID 1118Sulfuric AcidHCID 319508Ethyl 2-(diphenylmethyleneamino)acetateHCID 516892Sodium BicarbonateHCID 533483441-(4-[2-Fluorobenzyloxy]phenyl)-2-propen-1-one

Product 1

HCID 53348357Ethyl-5-(4-[2-fluorobenzyloxy]phenyl)-3,4-dihydro-2H-pyrrole-2-carboxyateYield 84%

Reagents, catalysts & solvents 3

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneCatalystHCID 72376438(2R)-1-[(4S)-4,5-Dihydro-4-(1-methylethyl)-2-oxazolyl]-2-(diphenylphosphino)ferroceneCatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
22.5 °C

Procedure

(S)-4-Isopropyl-2-[(S)-2-(diphenylphosphino)ferrocen-1-yl]oxazoline (18.8 mg, 0.039 mmol) and Cu(MeCN)4PF6 (14.5 mg, 0.039 mmol) were added to a dried, nitrogen swept reaction vessel. Anhydrous, degassed, BHT inhibited THF (5.0 mL) was then added and the mixture was stirred for 30 minutes at 20-25° C. The resulting solution was then cooled to −78° C. and a solution of 1-(4-[2-fluorobenzyloxy]phenyl)-2-propen-1-one (P4, 2.0 g, 7.80 mmol) and ethyl N-(diphenylmethylidene)glycinate (2.29 g, 8.58 mmol) in THF (15 mL total volume) was added over 1-2 minutes. After 3-5 minutes, a solution of DBU (5.9 mg, 0.039 mmol) in THF (0.5 mL total volume) was added. The solution was then stirred for 8-12 hours at −78° C. The reaction mixture was then warmed to 0-5° C. and 1 M H2SO4 (aq., 25 mL) was then added. The reaction mixture was then warmed to 20-25° C. and mixed vigorously for 2 hours. The mixture was then poured into a rapidly stirring solution of NaHCO3 (saturated, enough to bring the pH to 7.0). After 5 minutes of stirring, the mixture was extracted twice with TBME and the organic extracts were pooled, dried over Na2SO4, and concentrated to near dryness. The resulting residue was purified by flash column chromatography eluting with 0→40% acetone/hexanes (gradient). Concentration of the fractions containing the title compound gave a crystalline solid (2.23 g, 84% yield).

Workup

  1. customreaction vessel
  2. customAnhydrous, degassed
  3. additionwas then added
  4. temperatureThe resulting solution was then cooled to −78° C.
  5. waitAfter 3-5 minutes
  6. stirringThe solution was then stirred for 8-12 hours at −78° C
  7. temperatureThe reaction mixture was then warmed to 0-5° C.
  8. temperatureThe reaction mixture was then warmed to 20-25° C.
  9. additionmixed vigorously for 2 hours
  10. stirringAfter 5 minutes of stirring
  11. extractionthe mixture was extracted twice with TBME
  12. dry with materialdried over Na2SO4
  13. concentrationconcentrated
  14. customThe resulting residue was purified by flash column chromatography
  15. washeluting with 0→40% acetone/hexanes (gradient)
  16. additionConcentration of the fractions containing the title compound

Sources & evidence

ORD record
ord-0100347d752e421d8562ff874cd3558d
Source dataset
uspto-grants-2014_06
Patent number
US08759542B2

Reaction notes

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