Toluene → 3-(3-Methoxyphenyl)-2-propenenitrile

HRID 530901Notes

Reaction equation

HRID 530901 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.C1(C)C=CC=CC=1.C([O-])(=O)C.[NH4+].[C:23]([CH2:25]C(O)=O)#[N:24]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH:25][C:23]#[N:24]

Participants

6

Reactant 4

HCID 1140TolueneHCID 9740Cyanoacetic acidHCID 115693-MethoxybenzaldehydeHCID 517165Ammonium Acetate

Product 1

HCID 342413-(3-Methoxyphenyl)-2-propenenitrile

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

3-Methoxybenzaldehyde (20.8 g, 0.15 mol) was treated with toluene (dry, 140 mL), pyridine (dry, 60 mL), ammonium acetate (0.59 g) and cyanoacetic acid (11.9 g, 0.14 mol) and then heated under reflux with a Dean-Stark trap for 71 h according to the procedure of Montgomery et. al (J. Med. Chem. 1993, 36, 55). The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with 10% aq. HCl, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel, eluting with 2-5% EtOAc in hexanes to give 3-methoxycinnamonitrile, 14.65 g (60%). This material was dissolved in EtOH (75 mL) and conc. HCl (15 mL) and hydrogenated with 10% Pd/C (2.0 g) at 70 psi on a Parr shaker for 67 h. The reaction mixture was filtered over Celite. The filtrate was extracted with EtOAc, and the EtOAc layer was concentrated under vacuum to give the hydrochloride salt of 3-(3-methoxyphenyl)propylamine as a waxy white solid, 17.3 g (93%). HPLC—(Method B)—tr=1.28 min. [M+H]+=166.30. 1H-NMR (300 MHz, CDCl3/CD3OD): δ=7.14-7.19 (m, 1H), 6.70-6.77 (m, 3H), 4.51-4.58 (m, 2H), 3.75 (s, 3H, OMe), 2.85-2.91 (m, 2H), 2.63-2.68 (m, 2H), 1.95-2.01 (m, 2H).

Workup

  1. temperatureheated
  2. temperatureunder reflux with a Dean-Stark trap for 71 h
  3. concentrationThe reaction mixture was concentrated under reduced pressure
  4. dissolutionThe residue was dissolved in dichloromethane
  5. washwashed with 10% aq. HCl
  6. dry with materialdried over anhydrous sodium sulfate
  7. concentrationconcentrated under reduced pressure
  8. customThe crude product was purified by flash chromatography on silica gel
  9. washeluting with 2-5% EtOAc in hexanes

Sources & evidence

ORD record
ord-44d720f4640c411eacc7a46017915ad5
Source dataset
uspto-grants-2016_05
Patent number
US09353112B2

Reaction notes

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