Sodium Iodide → Tert-butyl 4-(4-chloro-3-fluorophenyl)-4-cyanopiperidine-1-carboxylate

HRID 532782Notes

Reaction equation

HRID 532782 reaction equation
[H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][C:5]=1[F:13].C1OCCOCCOCCOCCOC1.[Na+].[I-].Cl[CH2:32][CH2:33][N:34]([CH2:42][CH2:43]Cl)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38]>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:43][CH2:42][N:34]([C:35]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:41])[CH2:33][CH2:32]2)=[CH:6][C:5]=1[F:13]

Participants

7

Reactant 5

HCID 5238Sodium IodideHCID 24758Sodium hydrideHCID 3633615-Crown-5HCID 38044142-(4-Chloro-3-fluorophenyl)acetonitrileHCID 11230235N-BOC-N,N-Bis(2-chloroethyl)amine

Product 1

HCID 66618032Tert-butyl 4-(4-chloro-3-fluorophenyl)-4-cyanopiperidine-1-carboxylateYield 54.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

60% NaH (1.07 g, 26.7 mmol) was added in 2 portions to a 0° C. solution of 2-(4-chloro-3-fluorophenyl)acetonitrile (1.81 g, 10.7 mmol) and 15-crown-5 (0.235 g, 1.07 mmol) in DMF (45 mL). The reaction mixture was warmed to room temperature and stirred for 35 minutes. The reaction mixture was then cooled to 0° C. NaI (1.60 g, 10.7 mmol) was added, and then a solution of freshly prepared tert-butyl bis(2-chloroethyl)carbamate (2.58 g, 10.7 mmol) in DMF (10 mL) was added by syringe. The reaction mixture was warmed to room temperature and stirred overnight (19 hours). The reaction mixture was poured into ice saturated NH4Cl, and the mixture was extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was flashed on silica (Biotage 40 L, 9:1 hex:EtOAc until product eluted, then 6:1 hex:EtOAc to elute product) to give tert-butyl 4-(4-chloro-3-fluorophenyl)-4-cyanopiperidine-1-carboxylate (1.96 g, 54.2% yield) as a yellow oil. LC/MS (APCI+) m/z 239 [M−Boc+H]+.

Workup

  1. temperatureThe reaction mixture was then cooled to 0° C
  2. temperatureThe reaction mixture was warmed to room temperature
  3. stirringstirred overnight (19 hours)
  4. additionThe reaction mixture was poured into ice saturated NH4Cl
  5. extractionthe mixture was extracted with EtOAc
  6. dry with materialThe combined extracts were dried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. washEtOAc until product eluted
  10. wash6:1 hex:EtOAc to elute product)

Sources & evidence

ORD record
ord-7257fda6078c4e74b71a88f9d4ff9285
Source dataset
uspto-grants-2014_10
Patent number
US08853199B2

Reaction notes

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