Dimethylformamide → Tert-butyl 4-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate

HRID 1487863Notes

Reaction equation

HRID 1487863 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][N:23](C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[C-]#N.[Zn+2]>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[N:23]

Participants

5

Reactant 2

HCID 6228DimethylformamideHCID 183795571-Boc-4-(4-bromo-phenyl)-piperidin-4-ol2×

Product 1

HCID 59003435Tert-butyl 4-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylateYield 75%

Reagents, catalysts & solvents 2

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
80 °C

Procedure

A mixture of tert-butyl 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate (compound 13.1, 36 g, 101 mmol), Pd(PPh3)4 (11.7 g, 10.1 mmol), and Zn(CN)2 (17.9 g, 152.4 mmol) in DMF (400 mL) under nitrogen was stirred overnight at 80° C. The mixture was cooled to ambient temperature, then the reaction was quenched by the addition of 600 mL of FeSO4 (aq., sat.) and diluted with ethyl acetate. The resulting mixture was stirred vigorously then filtered through Celite® and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with potassium carbonate (aq., sat., 200 mL), followed by brine (200 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:200-1:5) as the eluent to yield 23 g (75%) of the title compound as a white solid.

Workup

  1. temperatureThe mixture was cooled to ambient temperature
  2. customthe reaction was quenched by the addition of 600 mL of FeSO4 (aq., sat.)
  3. additiondiluted with ethyl acetate
  4. stirringThe resulting mixture was stirred vigorously
  5. filtrationthen filtered through Celite®
  6. washwashed with 1 M FeSO4, water, and ethyl acetate
  7. customThe layers were separated
  8. extractionthe aqueous phase was extracted with ethyl acetate (2×300 mL)
  9. washThe combined organic layers were washed with potassium carbonate (aq., sat., 200 mL)
  10. dry with materialdried (Na2SO4)
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure
  13. customThe residue was purified

Sources & evidence

ORD record
ord-3be99079be904a00a35b5eae6297f879
Source dataset
uspto-grants-2016_08
Patent number
US09428502B2

Reaction notes

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