N-bromobutanimide → tert-Butyl 4-(1-bromo-2-methoxy-2-oxoethyl)piperidine-1-carboxylate

HRID 1410523Notes

Reaction equation

HRID 1410523 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:29][Si](C)(C)C.BrN1C(=O)CCC1=O>C1COCC1>[Br:29][CH:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)[C:15]([O:17][CH3:18])=[O:16]

Participants

6

Reactant 4

HCID 67184N-bromobutanimideHCID 76113BromotrimethylsilaneHCID 1514280tert-Butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylateHCID 2733832Lithium Hexamethyldisilazide

Product 1

HCID 23655672tert-Butyl 4-(1-bromo-2-methoxy-2-oxoethyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

Commercially available methyl 2-(1-tert-butoxycarbonyl-4-piperidinyl)-acetate (Astatech, 2.57 g, 10.0 mmol) was dissolved in anhydrous THF (20 mL) under argon, cooled to −78° C., treated dropwise with a 1N solution of LHMDS in THF (20 mL), and stirred under positive Ar pressure for 30 mins. Bromotrimethylsilane (2.10 mL, 15.9 mmol) was added dropwise via dry syringe over 5 mins, then a solution of freshly recrystallized N-bromosuccinimide (2.14 g, 12.0 mmol) in anhydrous THF (20 mL) was added in one portion from an addition funnel. The reaction was kept at −78° C. for 2 hrs then warmed to ambient temperature. The crude reaction was concentrated in vacuo then partitioned between saturated aq. NaHCO3 and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers washed with brine, dried over Na2SO4, filtered, and filtrate concentrated in vacuo giving 4.7 g of orange slurry. This was purified by flash column chromatography on silica gel (0 to 10% EtOAc/DCM step gradient elution), and the combined TLC-pure fractions were concentrated and dried in vacuo giving the title compound as a viscous, pale yellow oil. 1H NMR (CHLOROFORM-d) δ: 4.05-4.26 (m, 2H), 4.02 (d, J=8.8 Hz, 1H), 3.79 (s, 3H), 2.70 (br. s., 2H), 1.97-2.10 (m, 4H), 1.57-1.68 (m, 2H), 1.45 (s, 9H), 1.13-1.32 (m, 3H).

Workup

  1. customvia dry syringe over 5 mins
  2. waitThe reaction was kept at −78° C. for 2 hrs
  3. temperaturethen warmed to ambient temperature
  4. customThe crude reaction
  5. concentrationwas concentrated in vacuo
  6. customthen partitioned between saturated aq. NaHCO3 and ethyl acetate
  7. extractionThe aqueous layer was extracted twice with ethyl acetate
  8. washthe combined organic layers washed with brine
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationfiltrate concentrated in vacuo
  12. customgiving 4.7 g of orange slurry
  13. customThis was purified by flash column chromatography on silica gel (0 to 10% EtOAc/DCM step gradient elution)
  14. concentrationthe combined TLC-pure fractions were concentrated
  15. customdried in vacuo

Sources & evidence

ORD record
ord-63e83d78737048a29354c29ff6b9cdbf
Source dataset
uspto-grants-2014_12
Patent number
US08921559B2

Reaction notes

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