Phenethylamines from Benzyl Alcohols

Edgar F. Kiefer, J. Med. Chem. 15(2), 214 (1972)

Introduction

In view of the very broad pharmacological utility of substituted 2-phenylethylamines, we wish to contribute a synthetic procedure which, because of its versatility and convenience, may find considerable use. Although based entirely on standard synthetic methods, the overall scheme is specifically tailored to the properties of the benzylic intermediates involved, and eliminates the need for isolation of intermediates and other time- consuming operations. The procedure is described for the p-methoxy derivative; it is also applicable without substantive modification to other ring alkoxy-, alkyl-, and halogen-substituted phenethylamines.

Experimental Section

4-Methoxyphenylethylamine Hydrochloride

p-Anisyl alcohol (100 g, 0.725 mole) was shaken with 500 ml of concd HCl for 2 min. The org phase was washed with 1120, 5% NaHCO3 and H2O then added over 40 min to a stirred slurry of 49 g (1.0 mole) of NaCN in 400 ml of DMSO [1], with ice-water cooling to maintain the temp at 35-40°. After addn was complete, the cooling bath was removed, the mixt was stirred for 90 min and then added to 300 ml of H10, and the small upper phase sepd. The aq DMSO layer was extd with two 100-ml portions of Et2O which were combined with the product layer, and the whole was washed once with H20 and dried (MgSO4).

A dry flask was charged with ca. 600 ml of abs Et2O and chilled in ice as 80 g (0.6 mole) of anhyd AlCl3 was added portionwise, followed by 23 g (0.6 mole) of LAH (LAH alone and other metal hydride reagents are unsatisfactory for the reduction of benzylic nitriles to amines) [2]. The dried Et2O soln of crude p-methoxy- phenylacetonitrile was added at such a rate as to maintain gentle reflux without external heat (ca. 1 hr). The mixt was stirred for 2 hr, then chilled in ice, and treated dropwise with 25 ml of H2O followed by 250 ml of 20% of aq NaOH, with periodic addn of Et2O through the condenser to replenish losses and facilitate stirring. The resulting voluminous, granular ppt of NaCl and LiCl and aluminate was removed by filtration, washed well with Et2O and discarded. The filtrate was mixed with one-third its vol of abs EtOH and 60 ml of coned HCl was added slowly with continuous swirling and ice cooling. After chilling to 0°C, the cryst amine hydrochloride was collected, 101 g, mp 212-214°C. The overall yield was 75% from anisyl alcohol. The hydrochloride may be recrystd from Et2O-EtOH or i-PrOH.

N-Methyl-p-methoxyphenylethylamine Hydrochloride

p-Methoxyphenethylamine, generated from 100 g (0.536 mole) of the hydrochloride by stirring with concd aq NaOH, was treated with 100 ml of PhH and 70g (0.66 mole) of PhCHO. A mildly exothermic reaction began at once. The mixt was heated under reflux until no more H2O was present in the condensate (ca. 1 hr), then, without cooling, an attached Dean-Stark trap was removed and a soln of 82 g (0.65 mole) of Me2SO4 [3] in 200 ml of PhH was added through the condenser at such a rate as to maintain reflux (15 min). The 2-phase mixt was heated for 90 min on the steam bath, cooled slightly, treated with 200 ml of H20, and heated for an addn 20 min. After cooling in ice, the aq layer was washed twice with Et2O to remove unreacted PhCHO and made strongly basic with 50% aq NaOH. Two Et2O exts of the basic aq phase were added to the amine layer which sepd, and the resulting soln was evacd at the aspirator for 30 min, leaving 90 g (102%) of crude N-methyl-p-methoxyphenethylamine. This material was dissolved in 500 ml of 20% abs EtOH-Et 20 and treated with 50 ml of concd HCl with swirling and cooling to yield the white, cryst hydrochloride, which was washed thoroughly with ice-cold 20% EtOH-Et20 and dried, mp 185.5-186.5°C. The yield was 83 g (77%).

References

[1] R. A. Smiley and C. Arnold, J. Org. Chem., 25, 257 (1960)
[2] R. F. Nystrom, J. Amer. Chem. Soc., 77, 2544 (1955)
[3] J. J. Lucier, A. D. Harris, and P. S. Korosec, Org. Syn., 44, 72 (1964)