Hydrochloric Acid → Ethyl α-cyano-5-methoxy-2-nitrobenzeneacetate

HRID 1358291Notes

Reaction equation

HRID 1358291 reaction equation
[C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].CC(C)([O-])C.[K+].F[C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].Cl>C1COCC1.O>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([C:1]#[N:2])[C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[CH3:8]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 7764Ethyl cyanoacetateHCID 5656543-Fluoro-4-nitroanisoleHCID 23665647Potassium tert-butoxide

Product 1

HCID 10754073Ethyl α-cyano-5-methoxy-2-nitrobenzeneacetateYield 107.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To an ice-cold solution of ethyl cyanoacetate (10.9 mL, 102.4 mmol) in anhydrous THF (170 mL) under N2 is added of potassium tert-butoxide (12.07 g, 107.5 mmol). The formed white suspension is stirred for 15 min then treated with 3-fluoro-4-nitroanisole [Halfpenny, P. R.; Horwell, D. C.; Hughes, J.; Hunter, J. C.; Rees, D. C. J. Med. Chem. (1990), 33, 286-91] (8.86 g, 51.2 mmol). The suspension is heated at reflux for 1.5 h. The solution is poured into H2O; and the aqueous mixture is acidified to pH 2 with concentrated HCl. The mixture is extracted three times with ether then the combined organic phases are dried (MgSO4) and concentrated to an oil that is pumped at 0.3 mm for 2 days. The oil is dissolved in dichloromethane and purified by flash silica gel chromatography eluting with dichloromethane. The product fractions are combined and concentrated to leave cyano-(5-methoxy-2-nitrophenyl)acetic acid ethyl ester (14.5 g) as a light yellow oil that is about 93-95% pure. 1H NMR (CDCl3): δ8.29 (1H, d, J=9.2 Hz), 7.22 (1H, d, J=2.7 Hz), 7.04 (1H, dd, J=9.2, 2.7 Hz), 5.69 (1H, s), 4.31 (2H, q, J=7.0 Hz), 1.34 (3H, t, J=7.2 Hz).

Workup

  1. temperatureThe suspension is heated
  2. temperatureat reflux for 1.5 h
  3. extractionThe mixture is extracted three times with ether
  4. dry with materialthe combined organic phases are dried (MgSO4)
  5. concentrationconcentrated to an oil that
  6. waitis pumped at 0.3 mm for 2 days
  7. dissolutionThe oil is dissolved in dichloromethane
  8. custompurified by flash silica gel chromatography
  9. washeluting with dichloromethane
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-608e4c41501d43cdbc7c1e85360ec9d7
Source dataset
uspto-grants-2003_07
Patent number
US06596726B1

Reaction notes

Loading…