Phenylphosphonic dichloride → (S)-1-(2-thiopheneacetyl)-3-piperidinonitrile

HRID 432829Notes

Reaction equation

HRID 432829 reaction equation
[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([CH:15]=O)[CH2:10]1)=[O:8].Cl.[NH2:18]O.C1(P(Cl)(Cl)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl.N1C=CC=CC=1.CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]#[N:18])[CH2:10]1)=[O:8]

Participants

8

Reactant 4

HCID 69990Phenylphosphonic dichlorideHCID 443297Hydroxyamine hydrochlorideHCID 516892Sodium BicarbonateHCID 28271707(S)-1-(2-thiopheneacetyl)-3-piperidinecarboxaldehyde

Product 1

HCID 70029059(S)-1-(2-thiopheneacetyl)-3-piperidinonitrileYield 60.9%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 1049PyridineSolventHCID 6344DichloromethaneSolvent2×

Procedure

(S)-1-(2-thiopheneacetyl)-3-piperidinecarboxaldehyde (117.4 mg. 0.50 mmol) was dissolved in dichloromethane (2.5 ml). Anhydrous methanol (80 l), dry pyridine (100 g), and hydroxylamine hydrochloride (38.2 mg; 0.55 mmol) were added and the mixture was allowed to stir at ambient temperature for 1 hour. The mixture was then evaporated under reduced pressure at ambient temperature. The residue was suspended in fresh dichloromethane (3 ml). Dry pyridine (80 μl) was added to this mixture, followed by dropwise addition of commercially available phenylphosphonic dichloride (140 μl; 1.0 mmol). After addition was complete, the mixture was allowed to stir at ambient temperature for 22 hours. Saturated sodium bicarbonate solution was then added. The mixture was diluted with dichloromethane and washed with fresh saturated sodium bicarbonate solution. The dichloromethane was then washed with saturated sodium chloride solution, dried with anhydrous potassium carbonate, and evaporated under reduced pressure at ambient temperature. The crude product was purified by chromatography on silica eluting with 50% ethyl acetate/50% hexane, giving (S)-1-(2-thiopheneacetyl)-3-piperidinonitrile (71.4 mg) as a pale yellow oil. MS m/z (positive ion) 235 (MH+; 100).

Workup

  1. customThe mixture was then evaporated under reduced pressure at ambient temperature
  2. additionDry pyridine (80 μl) was added to this mixture
  3. additionAfter addition
  4. stirringto stir at ambient temperature for 22 hours
  5. washwashed with fresh saturated sodium bicarbonate solution
  6. washThe dichloromethane was then washed with saturated sodium chloride solution
  7. dry with materialdried with anhydrous potassium carbonate
  8. customevaporated under reduced pressure at ambient temperature
  9. customThe crude product was purified by chromatography on silica eluting with 50% ethyl acetate/50% hexane

Sources & evidence

ORD record
ord-1583475833b54c489ea94d7e64d98e3f
Source dataset
uspto-grants-2003_12
Patent number
US06664271B1

Reaction notes

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