Toluene → tert-Butyl 4-cyano-4-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

HRID 2102387Notes

Reaction equation

HRID 2102387 reaction equation
[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[N:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.[OH-].[Na+]>C1COCC1>[C:1]([C:3]1([C:39]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:40])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]

Participants

7

Reactant 5

HCID 1140TolueneHCID 14798Sodium HydroxideHCID 848104-Morpholinecarbonyl chlorideHCID 1514443Tert-butyl 4-cyanopiperidine-1-carboxylateHCID 3251421Potassium bis(trimethylsilyl)amide2×

Product 1

HCID 57803090tert-Butyl 4-cyano-4-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (9.46 g, 45 mmole) in dry THF (60 mL) was added 0.5M solution of KHMDS in toluene (100 Ml, 50 mmole) at −78° C. under argon with stirring. After addition of KHMDS, the reaction mixture was stirred for 1 h at −78° C. After this time, morpholine-4-carbonyl chloride (7.48 g, 50 mmole) was added. The resultant reaction mixture was stirred for 1 h at −78° C. and then 1 h at room temperature. The reaction mixture was then treated with cooled 1N NaOH (80 mL) and extracted with EtOAc (2×350 mL). The combined organic extracts were washed with brine (2×100 mL), dried over MgSO4, filtered, and concentrated to afford the title compound (I-2) as a white solid. This product was used in next step without further purification. Analytical LCMS: single peak (214 nm), 2.799 min.

Workup

  1. stirringthe reaction mixture was stirred for 1 h at −78° C
  2. customThe resultant reaction mixture
  3. stirringwas stirred for 1 h at −78° C.
  4. custom1 h
  5. customat room temperature
  6. additionThe reaction mixture was then treated
  7. extractionextracted with EtOAc (2×350 mL)
  8. washThe combined organic extracts were washed with brine (2×100 mL)
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-fd3be77030cc4177ae063f4090283083
Source dataset
uspto-grants-2009_08
Patent number
US07576083B2

Reaction notes

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