Red-Al Reduction of Nitrostyrenes to Phenethylamines

J. Chem. Soc. Chem. Comm. 307 (1974)


β-Arylethylamines may be generated conveniently and in good yields by reduction of the corresponding styryl precursors with 'RedAl' [sodium bis-(2-methoxyethoxy) Aluminium dihydride].

β-Arylethylamines can be generated in good yield by a variety of synthetic procedures1. The most applicable method involves a Knoevenagel condensation of appropriately substituted benzaldehydes with nitroalkane2; LiAlH42 or Raney nickel reduction3 (elevated temperature, pressure) of the intermediate β-nitrostyryl derivative then affords the phenethylamine. Since we observed incomplete reduction of phenolic β-nitrostyrenes using LiAlH4 in ethereal solvents, we investigated the reactivities of the recently developed hydride reductants.

Table 1: Nitrostyrene Reduction
Substituents Yield mp
3,4-Methylenedioxy-β-Methyl 85% 180-181°Ca
3,5-Dimethyl-4-methoxy-β-Methyl 87% 255-257°Ca
3,5-Dimethyl-4-hydroxy-β-Methyl 75% 100-102°Cb
a As hydrochloride salt. b As free amine.

We describe a general preparative method for the generation of a pharmacologically interesting series using sodium bis-(2-methoxyethoxy)- aluminum dihydride (Red-Al) As the reductant. Aliphatic nitro-compounds are reduced to amines using this reducing agent4,5; by contrast, aryl nitro-compounds afford azo-, azoxy-, or hydrazo-compounds4,5 depending on conditions and manner of addition of the reductant. In our laboratory, β-nitrostyryl derivatives are smoothly reduced to β-phenethylamines in yields comparable to or greater than that afforded by other methods (Table 1).

Table 1: Nitrostyrene Synthesis
Substituents Yield Reflux (min)
3,5-Dimethyl-4-hydroxy- 81% 10
3,5-Dimethyl-4-methoxy- 88% 5
2,6-Dimethoxy-4-methyl- 85% 6

Preparation of two of the β-nitrostyrenes by generalized methods1 gave large amounts of dimeric byproducts, And instead we used a procedure, initially recorded by Ho et al6 which should find general application particularly where substitution on the benzaldehyde renders it electronically less reactive or sterically hindered to attack by nitroalkane anion, And the nitrostyryl derivative that does form begins to dimerize. Preliminary results in Table 2; reflux times are critical.


Reduction of Nitrostyrenes

Typically, a solution of the substituted benzaldehyde (1 mmol) and NH4OAc (1.25 mmol) in nitroethane was refluxed for the specified time. The mixture was cooled immediately in liquid N2 or Acetone-solid CO2, diluted with CH2Cl2, and filtered while cold. Solvent was removed in vacuo, and the remaining β-nitrostyrene was recrystallized by known procedures6.

Preparation of Nitrostyrenes

A solution of the β-nitrostyrene (1 mmol) in dry benzene is added at room temperature to Na(MeOCH2CH2)2AlH2 (8-10 mmol) in benzene and the mixture is heated under reflux for 2-17 h, cooled, hydrolysed with water, and filtered. Evaporation of benzene and 2-methoxyethanol followed by vacuum distillation affords the free amine in the case of non-phenolic compounds, while phenolic compounds are isolated by recrystallization or column chromatography.



  1. Review: K. A. Nieforth, J. Pharm. Sci., 1971, 60, 655; D. H. R. Barton, R. D. Bracho, and D. A. Widdowson, J.C.S. Chem. Comm., 1973, 781; J. H. Short, D. A. Dunnigan, and C. W. Ours, Tetrahedron, 1973, 29, 1931.
  2. F. A. Ramirez and A. Burger, J. Amer. Chem. Soc., 1951, 72, 2781; F. Benington and R. D. Morin, ibid., 1951, 73, 1353; M. Erne and F. Ramirez, Helv. Chim. Acta, 1950, 912; A: T. Shulgin, J. Med. Chem., 1966, 9, 445.
  3. G. Stochdorph and O. V. Schickh, German. Pat. 1952, 848,197; M. Kawanishi, Japan P. 1955, 5172; H. L. Curtis, U.S.P. 1965, 3,187,046.
  4. Kochloefl and Kraus, Tetrahedron Letters 3303 (1968); Kraus and Kochloefl, Coll. Czech. Chem. Comm. 34, 1823 (1969).
  5. J. F. Corbett, Chem. Comm., 1968, 1257.
  6. B. T. Ho, W. M. Mclsaac, R. An, W. Tansey, K. F. Walker and L. F. Englert, J. Med. Chem., 1970, 13, 26.