Hexamethylphosphoramide → tert-Butyl 2-methyl-4-oxopiperidine-1-carboxylate

HRID 1815833Notes

Reaction equation

HRID 1815833 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][Mg]Cl.CN(C)P(N(C)C)(N(C)C)=O.FC(F)(F)S(N(C1C=CC(Cl)=CN=1)S(C(F)(F)F)(=O)=O)(=O)=O>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH:13]1[CH3:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 4

HCID 12679HexamethylphosphoramideHCID 388544N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-trifluoromethanesulfonylmethanesulfonamideHCID 22495568tert-Butyl 4-oxo-3,4-dihydropyridine-1(2H)-carboxylateHCID 178418332HCID 178418332, compound2×

Product 1

HCID 12992764tert-Butyl 2-methyl-4-oxopiperidine-1-carboxylateYield 44.4%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 4.0 gm (20.28 mMol) 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydropyridin-4-one and 4.21 gm (20.48 mMol) copper(I) bromide-dimethylsulfide complex in 160 mL tetrahydrofuran was cooled to −780C. To this solution was added 7.43 mL (22.31 mMol) methyl magnesium chloride (3.0 M in tetrahydro-furan). After stirring for 1 hour at −78° C. an additional equivalent of methyl magnesium chloride was added and stirring continued for an additional 30 minutes. The reaction mixture was then treated with 10 mL hexamethylphosphoramide followed by the addition of a solution of 15.93 gm (40.56 mMol) 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine in 50 mL tetrahydrofuran. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature overnight. The reaction mixture was then diluted with 1.5 L diethyl ether and was washed sequentially with 2×500 mL saturated aqueous oxalic acid, 500 mL water, 2×500 mL saturated aqueous sodium bicarbonate, and 500 mL saturated aqueous sodium chloride. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was suspended in hexanes and then filtered. The filtrate was concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with a gradient of hexane containing 0-50% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 1.92 gm of the title compound as an oil that gradually formed a crystalline mass.

Workup

  1. additionwas added
  2. stirringwas stirred at room temperature overnight
  3. washwas washed sequentially with 2×500 mL saturated aqueous oxalic acid, 500 mL water, 2×500 mL saturated aqueous sodium bicarbonate, and 500 mL saturated aqueous sodium chloride
  4. dry with materialThe remaining organics were dried over magnesium sulfate
  5. concentrationconcentrated under reduced pressure
  6. filtrationfiltered
  7. concentrationThe filtrate was concentrated under reduced pressure
  8. washeluting with a gradient of hexane containing 0-50% ethyl acetate
  9. additionFractions containing product
  10. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-d3e92b616f9d49679658ccb136ce50b9
Source dataset
uspto-grants-2005_04
Patent number
US06881733B1

Reaction notes

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