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A New Synthesis of Mescaline

Makepeace U. Tsao
J. Am. Chem. Soc. 5495-5496 (1951)

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Introduction

The cactus alkaloid, mescaline, β-(3,4,5-trimethoxyphenyl)-ethylamine, has been studied for some years, because of its most interesting effects on the psychic states of human subjects. Since the elucidation of the chemical structure of the alkaloid through the synthesis by Späth1, a few other methods of preparation have been published2-7. A simple synthesis utilizing lithium aluminum hydride is presented in this report.

The synthesis may be outlined as follows:

Gallic acid → 3,4,5-trimethoxybenzoic acid → Methyl 3,4,5-trimethoxybenzoate → 3,4,5-Trimethoxybenzyl alcohol → 3,4,5-Trimethoxybenzyl chloride → 3,4,5-Trimethoxyphenylacetonitrile → Mescaline.

Experimental

Methyl Ester of 3,4,5-Trimethoxybenzoic Acid

To a solution prepared from 100 g of 3,4,5-trimethoxybenzoic acid8 (0.47 mole), 20 g. of sodium hydroxide, 55 g. of sodium carbonate and 300 ml. of water is added, with stirring, 94 ml. of methyl sulfate (0.94 mole) during the course of 20 minutes. The reaction mixture is refluxed for one-half hour. The crude ester (65 g., 61 %) precipitates from the cold mixture. From the filtrate 38 g. of starting material is recovered upon acidification with diluted hydrochloric acid. The ester is further purified by solution in the minimum amount of methanol and treatment with norite. Usually it is necessary to repeat this treatment to obtain a colorless crystalline product that melts at 80-82C. Semmler9, who employed a different Process, reported mp 83-84C.

3,4,5-Trimethoxybenzyl Alcohol

To a suspension of 4.6 g (0.12 mole) of lithium aluminum hydride in 200 ml. of anhydrous ether is added, in the course of 30 minutes, a solution of 22.6 g (0.1 mole) of the methyl ester of 3,4,5-trimethoxybenzoic acid in 300 ml. of ether. The solid which forms is carefully decomposed first with 50 ml. of ice-water. After decantation of the ether, 250 ml of ice-cold 10% sulfuric acid is added. The product is extracted with 150 ml. Of ether. The combined extracts, after drying over sodium sulfate, are freed of ether and the residue distilled; bp 135-137°C/0.25mmHg; yield 14.7 g. (73%). This compound was obtained by a different method by Marx10; b.p. 228C (25 mm.).

3,4,5-Trimethoxybenzyl Chloride

A mixture of 25 g. of 3,4,5-trimethoxybenzyl alcohol and 125 ml. of ice-cold concentrated hydrochloric acid is shaken vigorously until a homogeneous solution is obtained. In a few minutes a turbidity develops, followed by a heavy precipitation of gummy product. After 4 hours and dilution with 100 ml. of icewater, the aqueous layer is decanted and extracted with three 50-ml. portions of benzene. Then the gummy organic residue is dissolved in the combined benzene extracts. The benzene solution is washed with water and dried over sodium sulfate.

The benzene solution is transferred to a distilling flask and the benzene is removed under diminished pressure. The red semi-solid residue is suspended in a small amount of ice-cold ether and filtered through a chilled funnel. The crystalline product, after washing with small portions of cold ether, weighs 9.7 g. The combined filtrates on standing in refrigerator yield more crystals. The total yield is 13.0 g. (48%). After four recrystallizations from benzene, colorless needles are obtained; m.p. 60-62C.

This compound is extremely soluble in ether, alcohol and acetone, but slightly soluble in petroleum ether. Standing at room temperature for a few weeks causes the crystals to turn into a red semi-solid. An alcoholic solution of pure material gives an instantaneous precipitation with alcoholic silver nitrate.

3,4,5-Trimethoxyphenylacetonitrile

A mixture of 9 g. of potassium cyanide in 35 ml. of water and 60 ml. of methanol and 9.7 g. of 3,4,5-trimethoxybenzyl chloride is heated for 10 minutes at 90'. The solvents are partially removed under diminished pressure. The residue is then extracted with 90 ml. of ether in three portions. The combined extracts are washed with water and dried over sodium sulfate. After the removal of the drying agent the ether solution is warmed on a steam-bath and the ether is removed with a stream of air. On chilling, the residue yields scale-like crystals. Recrystallization from ether gives rectangular prism; yield 2.5 g. (27%); m.p. 76-77C. Baker and Robinson11 reported a melting point of 77C for this compound.

Mescaline

In 150 ml. of anhydrous ether is suspended 0.85 g. of lithium aluminum hydride powder. With stirring, 2.0 g. of 3,4,5-trimethoxyphenylacetonitrile in 150 ml. of anhydrous ether was added during the course of 15 minutes. After 15 minutes stirring, 10 ml. of ice-water is dropped in carefully. Then a mixture of 10 g. of sulfuric acid in 40 ml. of water is added at a moderate rate. The aqueous layer is separated and treated with concentrated sodium hydroxide. The brown off is extracted with three portions of 30 ml. each of ether. The combined extracts are washed once with water and dried over stick potassium hydroxide. To the decanted ether solution is added a mixture of 1 g. of sulfuric acid and 25 ml. of ether. The white precipitate is washed several times with ether; yield 1.2 g. (40%). After two recrystallizations from 95% ethanol, the colorless long thin plates soften at 172C and melt at 183C.

References

  1. E. Spth, Monatsh., 40, 129 (1919)
  2. K. H. Slotta and H. Heller, Ber., 63B, 3029 (1930)
  3. H. Frisch and E. Waldmann, German Patent 545,853 (1930); Chem. Abs., 26, 35211 (1932)
  4. K. Kindler and W. Peschke, Arch. Pharm., 270, 410 (1932)
  5. K. H. Slotta and G. Szyzka, J. prakt. Chem., 137, 339 (1933)
  6. G. Hahn and H. Wassmuth, Ber., 67, 711 (1934)
  7. G. Hahn and F. Rumpf, Ber., 71B, 2141 (1938)
  8. A. H. Blatt, Organic Syntheses, Coll. Vol. 1, p. 537 (1946), 2nd ed., John Wiley & Sons, Inc., N.Y., N Y.
  9. F. W. Semmler, Ber., 41, 1774 (1908)
  10. M. Marx, Ann., 263, 254 (1891)
  11. Baker and R. Robinson, J. Chem, Soc., 160 (1929)