Methyl phenylacetate → Tert-butyl 4-(3-oxo-4-phenylbutanoyl)piperidine-1-carboxylate

HRID 1593009Notes

Reaction equation

HRID 1593009 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)N[Si](C)(C)C.[Li].[C:27]1([CH2:33][C:34](OC)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[CH2:15][C:34](=[O:35])[CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 7559Methyl phenylacetateHCID 109879834-Acetyl-piperidine-1-carboxylic acid tert-butyl esterHCID 57426343Lithium bis(trimethylsilyl)amide

Product 1

HCID 18187492Tert-butyl 4-(3-oxo-4-phenylbutanoyl)piperidine-1-carboxylateYield 14.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

4-Acetyl-piperidine-1-carboxylic acid tert-butyl ester (1.00 g) was dissolved in anhydrous THF (6 mL) and cooled to 0° C. To this was added a solution of lithium hexamethyldisilazane (1.0M in hexanes; 4.84 mL). This was left to stir at 0° C. for 10 minutes before addition of a THF solution (2 mL) of methyl phenylacetate (0.661 g). The reaction mixture was left to stir for a total of 4 hours before being quenched by the addition of 1M aqueous HCl (50 mL). The reaction mixture was extracted with Et2O (3×75 mL) then the combined organic extracts were dried over magnesium sulfate and filtered. Evaporation of solvents under reduced pressure gave a thick yellow oil which was purified by column chromatography on silica gel, using an increasingly polar gradient of Et2O in DCM as eluent. Evaporation of solvents under reduced pressure gave the desired 4-(3-oxo-4-phenyl-butyryl)-piperidine-1-carboxylic acid tert-butyl ester as a clear oil (0.225 g); NMR (CDCl3): 1.45 (s, 9H), 1.54 (m, 2H), 1.76 (d, 2H), 2.28 (tt, 1H), 2.71 (br t, 2H), 3.61 (s, 2H), 4.12 (br d, 2H), 5.44 (s, 1H), 7.12-7.36 (m, 5H), 15.30 (s, 1H); MS: 344 (M−1−).

Workup

  1. waitThis was left
  2. waitThe reaction mixture was left
  3. custombefore being quenched by the addition of 1M aqueous HCl (50 mL)
  4. extractionThe reaction mixture was extracted with Et2O (3×75 mL)
  5. dry with materialthe combined organic extracts were dried over magnesium sulfate
  6. filtrationfiltered
  7. customEvaporation of solvents under reduced pressure
  8. customgave a thick yellow oil which
  9. customwas purified by column chromatography on silica gel
  10. customEvaporation of solvents under reduced pressure

Sources & evidence

ORD record
ord-44bde3ecefec43dcb9294f63a2003ef2
Source dataset
uspto-grants-2007_11
Patent number
US07294636B2

Reaction notes

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