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An Improved Synthesis of Mescaline

Fred Benington and Richard D. Morin
J. Am. Chem. Soc. 73, 1353 (1951)

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In connection with certain studies of the synthesis of phenethylamines, we have had the occasion to prepare mescaline, β-(3,4,5-trimethoxyphenyl)-ethylamine, an alkaloid which occurs naturally in the cacti Anhalonium. The literature cites the synthesis of this alkaloid by two methods, neither of which gives a satisfactory yield.

Slotta and Heller1 synthesized mescaline in four steps from 3,4,5-trimethoxybenzaldehyde in an overall yield of 28%. A more direct method via the condensation of 3,4,5-trimethoxybenzaldehyde with nitromethane, followed by the reduction of the resulting nitrostyrene, was employed by Spth2. The nitrostyrene was first reduced to the corresponding aldoxime, which on further reduction gave mescaline. The two-stage reduction gave a 24.9% yield, and the overall yield of mescaline from the aldehyde was only 20.8%.

An elegant method for reduction of β-nitrostyrenes to phenethylamines with lithium aluminum hydride has been reported3. Reduction of 3,4,5-trimethoxy-β-nitrostyrene by this method resulted in an 89% yield of mescaline hydrochloride. The over-all yield from 3,4,5-trimethoxybenzaldehyde has been increased to 65%.

Experimental4

3,4,5-Trimethoxybenzaldehyde

Gallic acid was converted to trimethylgallic acid in 80% yield by methylation with methyl sulfate5.

Trimethylgalloyl chloride was prepared in 81% yield by the action of phosphorus pentachloride on trimethylgallic acid.1 The acid chloride was purified by distillation and redistillation under reduced pressure; bp 131-133C/2 mmHg; mp 83-84C.

Rosenmund reduction of 3,4,5-trimethoxybenzoyl chloride (trimethylgalloyl chloride) was carried out as described1 using 52 g of 3% Pd-BaSO4 catalyst per mole of acid chloride. Dry xylene was the solvent. The product was recovered by removal of the catalyst by filtration, stripping off the xylene and fractional distillation of the residue under reduced pressure. A forerun of pyrogallol trimethyl ether, bp 82-100C/0.1 mmHg, was obtained, and 3,4,5-trimethoxybenzaldehyde was collected as the fraction boiling at 106-112C/0.1 mmHg. After crystallization from alcohol the aldehyde melted at 73-74C; yield 59%.

3,4,5-Trimethoxy-β-nitrostyrene

This compound was prepared by the procedure of Spth2 in 82.7% yield; mp 121-122C after recrystallization from alcohol.

Mescaline Hydrochloride

Reduction of 7.2 g (0.03 mole) of 3,4,5-trimethoxy-β-nitrostyrene with 5.7 g. of lithium aluminum hydride was carried out as described3a for 4-hydroxy-3-methoxy-β-nitrostyrene. The yield of mescaline picrate, mp 210-212C, was 11.4 g (86%).

After recrystallization from alcohol, the picrate melted at 214-216C; reported2 216-218C. The mescaline picrate was converted to mescaline hydrochloride as described3a in 92% yield; mp 180-181C (after recrystallization from alcohol); reported1 181C.

References

  1. K. H. Slotta and H. Heller, Chem. Ber. 63, 3029 (1930)
  2. E. Spth, Monatsh., 40, 129 (1919)
  3.  
    1. F. A. Ramirez and A. Burger, J. Am. Chem. Soc., 72, 2781 (1950)
    2. R. F. Nystrom and W. G. Brown, J. Am. Chem. Soc., 70, 3738 (1948)
    3. K. E. Hamlin and A. W. Weston, J. Am. Chem. Soc., 71, 2210 (1949)
  4. All melting and boiling points uncorrected.
  5. H. Gilman and A. H. Blatt, Organic Syntheses, Coll. Vol. I, p. 537, John Wiley & Sons, New York, N. Y. (1941)