Acetone Cyanohydrin → (E)-4-(1-(4-fluorophenyl)cyclohexyl)but-3-enenitrile

HRID 1506296Notes

Reaction equation

HRID 1506296 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(/[CH:14]=[CH:15]/[CH2:16]O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:37]([C:44](OCC)=O)=NC(OCC)=O.OC(C)(C)C#N>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(/[CH:14]=[CH:15]/[CH2:16][C:44]#[N:37])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 6406Acetone CyanohydrinHCID 11776TriphenylphosphineHCID 220568ethyl N-ethoxycarbonyliminocarbamateHCID 67167810(E)-3-(1-(4-fluorophenyl)cyclohexyl)prop-2-en-1-ol

Product 1

HCID 67169431(E)-4-(1-(4-fluorophenyl)cyclohexyl)but-3-enenitrileYield 80.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (E)-3-(1-(4-fluorophenyl)cyclohexyl)prop-2-en-1-ol (Intermediate I-11A, 912 mg, 3.89 mmol) and triphenylphosphine (1531 mg, 5.84 mmol) in THF (20 mL) at −20° C. was added diethyl azodicarboxylate (0.924 mL, 5.84 mmol) dropwise and the mixture was stirred at a temperature in the range of from about 20 to about −10° C. for 20 mins. Then 2-hydroxy-2-methylpropanenitrile (0.109 mL, 1.196 mmol) was added slowly at −20° C., and the mixture was stirred for 1 hr at a temperature in the range of from about −20 to about 10° C. and for 20 hrs at room temperature. The reaction was quenched with a few drops of methanol and stirred for 20 mins. After evaporation of the solvent the residue was purified by column chromatography (80 g silica gel) eluting with 1:9 followed by 2:8 ethyl acetate-hexane to give the desired (E)-4-(1-(4-fluorophenyl)cyclohexyl)but-3-enenitrile (760 mg, 80% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.25-7.30 (2H, m), 7.01 (2H, t, J=8.80 Hz), 5.85 (1H, d, J=15.63 Hz), 5.10 (1H, ddd, J=15.74, 5.72, 5.61 Hz), 3.06 (2H, dd, J=5.61, 1.65 Hz), 1.98-2.06 (2H, m), 1.77-1.86 (2H, m), 1.41-1.60 (6H, m).

Workup

  1. stirringthe mixture was stirred for 1 hr at a temperature in the range of from about −20 to about 10° C. and for 20 hrs at room temperature
  2. customThe reaction was quenched with a few drops of methanol
  3. stirringstirred for 20 mins
  4. customAfter evaporation of the solvent the residue
  5. customwas purified by column chromatography (80 g silica gel)
  6. washeluting with 1:9

Sources & evidence

ORD record
ord-ee4798b6e92a4111bd61ab2b0ef44aa1
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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