Sodium Iodide → tert-Butyl 4-(3-chlorophenyl)-4-cyanopiperidine-1-carboxylate

HRID 625069Notes

Reaction equation

HRID 625069 reaction equation
[H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1.C1OCCOCCOCCOCCOC1.[Na+].[I-].Cl[CH2:31][CH2:32][N:33]([CH2:41][CH2:42]Cl)[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2([C:11]#[N:12])[CH2:42][CH2:41][N:33]([C:34]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:40])[CH2:32][CH2:31]2)[CH:7]=[CH:8][CH:9]=1

Participants

9

Reactant 6

HCID 5238Sodium IodideHCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 3633615-Crown-5HCID 73722m-ChlorophenylacetonitrileHCID 11230235N-BOC-N,N-Bis(2-chloroethyl)amine

Product 1

HCID 49760302tert-Butyl 4-(3-chlorophenyl)-4-cyanopiperidine-1-carboxylateYield 79.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

60% NaH (2.31 g, 57.7 mmol) was added in 2 portions to a 0° C. solution of 2-(3-chlorophenyl)acetonitrile (3.50 g, 23.1 mmol) and 15-crown-5 (0.509 g, 2.31 mmol) in DMF (80 mL). The reaction mixture was warmed to room temperature while stirring for 35 minutes and then cooled back to 0° C. NaI (3.46 g, 23.1 mmol) was added, followed by the addition of a solution of freshly prepared tert-butyl bis(2-chloroethyl)carbamate (5.59 g, 23.1 mmol) in DMF (10 mL) by syringe. The reaction mixture warmed back to room temperature and stirred overnight (16 hours). The reaction mixture was poured into iced saturated NH4Cl and extracted with EtOAc. The extracts were dried (Na2SO4), filtered, and concentrated. The crude was flashed on silica (Biotage 40L, 9:1 hex:EA until prod, then gradient to 4:1 hexane:EtOAc) to give tert-butyl 4-(3-chlorophenyl)-4-cyanopiperidine-1-carboxylate (5.91 g, 79.8% yield) as a yellow foam. LC/MS (APCI+) m/z 221 [M-Boc+H]+.

Workup

  1. temperaturecooled back to 0° C
  2. temperatureThe reaction mixture warmed back to room temperature
  3. stirringstirred overnight (16 hours)
  4. extractionextracted with EtOAc
  5. dry with materialThe extracts were dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-8f6b1c16d3914afebf27a5ce7b53e55f
Source dataset
uspto-grants-2016_04
Patent number
US09303040B2

Reaction notes

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