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Mescaline (3,4,5-Trimethoxyphenethylamine)

Manske & Holmes, The Alkaloids, Vol III, p 324-328, Academic Press (1953)

Mescaline, the active hallucinatory principle of the "mescal buttons" or "pellote," was isolated by Heffter (96) in 1896. Pellote (Anhalonium lewinii Hennings) contains up to 6% mescaline. Reti (97, 98) observed the presence of mescaline in the Argentine cactus Trichocereus terscheckii, Britton and Rose, which contains 0.2 % trichocereine (dimethylmescaline) and 0.05% mescaline. Herrero-Ducloux (99) has assumed that one of the bases extracted from Echinocactus gibbosus D.C., (Glymnocalycium gibbosum Pfeiff.) was mescaline.

The free base is a colorless strongly alkaline oil or crystals having mp 35-36°C (Kindler and Peschke, 103), bp 180°C (12 mmHg). It is soluble in water, alcohol, and chloroform, but only slightly so in ether. It readily absorbs carbon dioxide from the air forming the solid carbonate. The hemisulfate hydrate is particularly suited for isolation since it is insoluble in alcohol, only slightly soluble in cold water but very soluble in hot water; it forms brilliant prisms, mp 183-186°C. The hydrochloride forms colorless crystals, mp 184°C; picrate, mp 222°C.

Heffter (104, 105,106) determined the empirical formula of mescaline and found that upon oxidation the base yields trimethylgallic acid. Unfortunately, mescaline behaves in methylimino determinations as though it contained an N-methyl group. Heffter (107) synthesized 3,4,5-trimethoxybenzylmethylamine and found that it was not identical but isomeric with mescaline.

The irregularity mentioned was confirmed by Späth (3) who, guided by biogenetical considerations, arrived at the correct structure, in spite of the confusing analytical evidence. In Späth's mescaline synthesis 3,4,5-trimethoxybenzoyl chloride was reduced by the Rosenmund method (108) to the corresponding aldehyde, which when condensed with nitromethane yielded beta-nitro-3,4,5-trimethoxystyrene. This was reduced with zinc dust and acetic acid to the corresponding oxime and the latter was further reduced, by sodium amalgam, to 3,4,5-trimethoxyphenethylamine (mescaline). Subsequently a number of improved syntheses have been reported.

Slotta and Heller (109, 110) prepared their starting material, viz., trimethoxyphenylpropionic acid by condensation of the substituted benzaldehyde with malonic acid and reduction of the resulting cinnamic acid. Mescaline was then obtained by Hofmann degradation of the trimethoxyphenylpropionamide. Kindler and Peschke (103) synthesized very pure, crystallized mescaline by condensation of 3,4,5-trimethoxybenzaldehyde with potassium cyanide, acetylation, and catalytic reduction to the amine. Slotta and Szyska (111, 112) improved Späth's first synthesis, obtaining mescaline directly by the electrolytic reduction of beta-nitro-trimethoxystyrene. Hahn and Wassmuth (113, 114) started from elemicin and first prepared trimethoxyphenylacetaldehyde by ozonization. The oxime was then reduced to mescaline. Kindler (115) and Kindler and Peschke (38, 103) improved the catalytic reduction of beta-nitrostyrenes. Kindler (115) and Kindler and Peschke (38, 103) improved the catalytic reduction of beta-nitro-styrenes to the corresponding phenethylamines. Hahn and Rumpf (116) described the preparation of mescaline by reduction of beta-nitro-trimethoxystyrene with Adam's catalyst. A review has been published by Jensch (117).

An improved synthesis of mescaline has been described by Benington and Morin (175). 3,4,5-Trimethoxy-beta-nitrostyrene (176) was reduced with lithium aluminum hydride, using a method described by Ramirez and Burger (177). The yield was of 86%.

A new synthesis of mescaline has been recently elaborated by Tsao (178). The synthesis is outlined as follows: gallic acid - 3,4,5-trimethoxybenzoic acid - methyl ester of the 3,4,5-trimethoxybenzoic acid - 3,4,5-trimethoxybenzyl alcohol - 3,4,5-trimethoxybenzyl chloride - 3,4,5-trimethoxyphenylacetonitrile - mescaline. The reduction of the methyl ester and of the nitrile has been achieved using lithium aluminum hydride.


[3] Monatsh 40, 129 (1919)
[38] Arch Pharm 270, 340 (1932)
[96] Ber 29, 216 (1896)
[97] Atti Congr Intern Chim 10th Congr Rome 1938, 5, 396 (1939)
[98] J Am Chem Soc 73, 1767 (1951)
[99] Rev Facultad Cienc Quim Univ Nac La Plata 6, 75 (1930)
[103] Arch Pharm 270, 410 (1932)
[104] Ber 27, 2975 (1894)
[105] Ber 31, 1193 (1898)
[106] Ber 34, 3004 (1901)
[107] Ber 38, 3634 (1905)
[109] J Prakt Chem 133 129 (1932)
[110] Ber 63, 3029 (1930)
[111] J Prakt Chem 137, 339 (1933)
[112] Ber 67, 1106 (1934)
[113] Ber 67, 1210 (1934)
[114] Ber 67, 696 (1934)
[115] Arch Pharm 265, 389 (1927)
[116] Ber 71, 2141 (1938)
[117] Med U Chem Abhandl Med Chem Forschungstätten I G Farben 3, 408 (1936)
[175] J Am Chem Soc 73, 1353 (1951)
[176] Monatsch 40, 144 (1919)
[177] J Am Chem Soc 72, 2781 (1950)
[178] J Am Chem Soc 73, 5495 (1951)