Bromoacetonitrile → 1-tert-Butyl 4-methyl 4-(cyanomethyl)piperidine-1,4-dicarboxylate

HRID 1848431Notes

Reaction equation

HRID 1848431 reaction equation
[N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.[Li+].[CH3:19][CH:20]([N-:22]C(C)C)C.BrCC#N>C1COCC1>[C:20]([CH2:19][C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]1)#[N:22]

Participants

5

Reactant 3

HCID 11534BromoacetonitrileHCID 3928701-N-Boc-4-Piperidinecarboxylic acid methyl esterHCID 2724682Lithium diisopropylamide

Product 1

HCID 713056681-tert-Butyl 4-methyl 4-(cyanomethyl)piperidine-1,4-dicarboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-65 °C

Procedure

To a solution of commercially available 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (200 g, 0.82 mol) in anhydrous THF (2 L) was added LDA (2M in THF, 575 mL, 1.15 mol) drop-wise at −65° C. under N2. The mixture was stirred at −65° C. for 1.5 h. To the mixture was added bromoacetonitrile (148 g, 1.23 mol) in anhydrous THF (500 mL) at −65° C. The mixture was stirred at −65° C. for 1 h, then warmed up to room temperature and stirred overnight. The reaction was quenched with water (800 mL) at 0° C. and the combined reaction mixture was concentrated in vacuum to give a crude product, which was extracted with ethyl acetate (1 L three times). The combined organic phases were washed with brine (1 L) and dried over Na2SO4. The organic layer was filtered and the filtrate was concentrated under vacuum to give a crude product, which was purified by column chromatography on silica gel eluting with petroleum ether/ethyl acetate (from petroleum ether to 2/1) to give the title compound. 1H-NMR (400 MHz, CDCl3) δ 3.900-3.750 (m, 5H), 3.120-3.000 (m, 2H), 2.612-2.562 (m, 2H), 2.190-2.111 (m, 2H), 1.590-1.502 (m, 2H), 1.402 (s, 9H).

Workup

  1. stirringThe mixture was stirred at −65° C. for 1 h
  2. temperaturewarmed up to room temperature
  3. stirringstirred overnight
  4. customThe reaction was quenched with water (800 mL) at 0° C.
  5. customthe combined reaction mixture
  6. concentrationwas concentrated in vacuum
  7. customto give a crude product, which
  8. extractionwas extracted with ethyl acetate (1 L three times)
  9. washThe combined organic phases were washed with brine (1 L)
  10. dry with materialdried over Na2SO4
  11. filtrationThe organic layer was filtered
  12. concentrationthe filtrate was concentrated under vacuum
  13. customto give a crude product, which
  14. customwas purified by column chromatography on silica gel eluting with petroleum ether/ethyl acetate (from petroleum ether to 2/1)

Sources & evidence

ORD record
ord-ae2abbca0d294d339397c7ee8ac1c4b0
Source dataset
uspto-grants-2015_02
Patent number
US08952166B2

Reaction notes

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