
THE PREPARATION OF MESCALINE FROM EUCALYPT LIGNIN

[ CA 61, 8515 - Aust J Pharm, 45, 529 (1964) ] 

D. Amos, Australian Defence Scientific Service, Department of Supply,
Defence St Maribyrnong, Victoria, Australia.

Syringaldehyde has been prepared by the oxidation of eucalypt lignin with
nitrobenzene and alkali. It has been methylated with dimethyl sulphate and
mescaline has been synthesised from the 3,4,5-trimethoxybenzaldehyde so
formed.

Mescaline, 3,4,5-trimethoxyphenethylamine (IV), the hallucinatory principle
of "pellote", was isolated by Heffter (1896) in 1896, and its chemistry has
been studied in detail. Numerous syntheses have been developed (Downing,
1962) and many of these utilised 3,4,5-trimethoxybenzoic acid or one of
its derivatives as starting material. Other synthetic routes made use of
3,4,5-trimethoxybenzaldehyde (II), and Slotta and Heller (1930) and Slotta
(1932) prepared their starting material, 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.

Slotta and Szyska (1933; 1934) obtained mescaline directly by condensing II
with nitromethane and reducing electrolytically the w-nitrotrimethoxystyrene
(V). The latter also has been reduced with lithium aluminium hydride,
(Ramirez and Berger, 1950).

Pure crystalline mescaline has also been synthesised by condensation of
3,4,5-trimethoxybenzaldehyde with potassium cyanide followed by acetylation
and catalytic reduction to the amine (Kindler and Peschke, 1932).

Syringaldehyde,3.5-dimethoxy-4-hydroxy benzaldehyde (1), is an attractve
alternative starting material. Bland, Ho and Cohen (1950) reported its
preparation by the oxidation of certain eucalypt lignins with nitrobenzene
and alkali. Working on a small scale they showed that Eucalyptus regnans
(Mountain Ash), E. obliqiia (Messmate Stringybark) and E. diversicolor
(Karri) gave better than 5 per cent yields of syringaldehyde. It was decided,
therefore, to study the preparation of mescaline from these three species.

The first stage is the methylation of the free phenolic group of
syringaldehyde which can be accomplished either with dimethyl sulphate and
alkali, or with diazomethane. Only the first method was examined in detail,
since diazomethane would not bc favoured as a large-scale reagent. Both the
electrolytic and the lithium aluminium hydride reduction of V present
difficulties on a large scale, especially in the decomposition of the
lithium-alanate complex. On the other hand, cyanohydrin formation can be
performed quite readily by the reaction of potassium cyanide with the
aldehyde bisulphite compound, and catalytic reduction of III is
straight-forward and cheaper. This route was therefore preferred.

RESULTS AND DISCUSSION

75 g portions of air-dry sawdust from kiln-dried timber were oxidised with
nitrobenzene and alkali at 150°C according to the method of Bland (1950).
The mean yield of syringaldehyde from E. reanans was 4.9%,  from E. obliqua
3.1% and from E. diversicolor 3.2%. The use of a mechanical stirrer in the
autoclave would probably have increased the yields, which may also depend
on the particle size of the sawdust.

75 of sawdust gave the largest volume of solution which could be extracted
conveniently by hand. For larger volumes, a continuous extractor was used
in which hot benzene was allowed to flow through the aqueous phase, but
during the long period in which the benzene extract was kept at 80°C, a
large proportion of the he syringaldehyde decomposed. For large-scale
Operation, the benzene extract would have to be kept at a lower temperature
by the use of a climbing film or flash evaporator.

The crude extract which contained both syringaldehyde and vanillin was
analysed using a mass spectrometer. since spectrophotometric analyses are
of little use in distinguishing these two compounds. The syringealdehyde
was separated by fractional recrystallization from benzene until its mass
spectrum, compared with that of a mixture of syringaldehyde and vanillin in
known proportions, showed it to be at least 95% pure.

At first syringaldehyde was methylated with dimethyl sulphate for one hour
at 0-50°C, giving yields of 42%. It was found that heating at 70°C for a
further hour increased the yield of 3,4,5-trimethoxybenzaldehyde to 56%.
Heating above these temperatures lowered the yield, probably because of a
Canizzaro reaction. 3,4,5-trimethoxybenzaldehyde cyanohydrin was prepared
from 3,4,5-trimethoxybenzaldehyde according to the method of Kindler and
Peschke (1932) using the bisulphite compound as an intermediate. This
method eliminates the use of gaseous hydrogen cyanide and is considerably
safer. 3,4,5-trimethoxybenzaldehyde cyanohydrin acetate was prepared by
refluxing the cyanohydrin with acetic anhydride,

It has been reported (Kindler and Peschke, 1932) that if the cyanohydrin
acetate could be reduced catalytically in glacial acetic acid using
palladium black as the catalyst. However, when this system was used, no
mescaline was formed. Examination of the reaction mixture with a mass
spectrometer indicated that the active palladium black had removed boda
acetyl and cyanide groups from the 3,4,5-trimethoxybenzaldehyde cyanohydrin
acetate. The reduction was successful using a less active palladium black
and absolute ethanol as solvent. Mescaline was finally isolated as the
sulphate.

Based on the weight of kiln-dried wood, the overall yields were 1% for E.
Tegnans and 0.7% for the other two species. As the synthetic route is
comparatively simple, it would appear that eucalypt sawdust can be used for
the economic production of mescaline on a large scale.


EXPERIMENTAL

3,5-Dimethoxy-4-hydroxybenzaldehyde

Air-dry sawdust (75 g) of the species tinder investigation, nitrobenzene
(45 ml) and sodium hydroxide solution (d1.51, 2N) were added to an
autoclave of 2 1 capacity. The bomb was sealed, shaken vigorously for a few
seconds and then agitated for 3 hours at 150°C. After cooling, the reaction
mixture from the oxidation was filtered and the residue washed twice with
distilled water (100 ml). The filtrate and washings were extracted with
benzene to remove nitrobenzene and its reduction products; the aqueous
solution was made acid with a 10% excess of concentrated hydrochloric acid
and was allowed to stand for 24 hours. It was then filtered to remove the
precipitate which had formed.

The clear filtrate was extracted with benzene, and the combined benzene
washings were concentrated to a convenient volume (50 ml). This concentrate
was extracted with sodium bisulphite solution (20 per cent) until no more
aldehyde could be detected in the washings by acidifying, boiling off the
sulphur dioxide, and testing with 2,4-dinitrophenylhydrazine in hydrochloric
acid (2N). The combined bisulphite washings were acidified with conc.
hydrochloric acid and the sulphur dioxide removed by heating in a current
of nitrogen; they were then extracted with benzene until free from
aldehyde. The benzene extracts were evaporated to dryness, and then
recrystallised from hot benzene. A second recrystallisation from hot water
gave syringaldehyde; m.p. 111°C.


3,4,5-Trimethoxybenzaldehyde

Syringaldehyde (10 g) was dissolved with gentle heating in a solution of
sodium hydroxide (3 g) in water (100 ml), and the mixture was then cooled
below 50°C in an ice-bath. Dimethyl sulphate (6 ml) was added dropwise with
vigorous mechanical stirring during one hour, the temperature being kept
below 50°C. The mixture was then heated for one hour in a water bath at
70°C, and was cooled and extracted twice with benzene (100 ml). The benzene
was evaporated and the residue was extracted with sodium bisulphite
solution (20 per cent) . After filtration, the aqueous extract was
acidified and the sulphur dioxide was removed by warming in a current of
nitrogen. The aldehyde was extracted with benzene and recrystallised from
aqueous ethanol. Yield, 6.0 g (56%); m.p. 70-71°C.


3,4,5-Trimethoxybenzaldehyde Cyanohydrin

Trimethoxybenzaldehyde (8.8 g) was dissolved with gentle warming in
saturated sodium bisulphite solution (20 ml). The resulting mixture was
allowed to reach room temperature, when the precipitated bisulphite
compound was removed by filtration and washed with absolute ethanol. The
bisulphite compound was dissolved in water (10 ml) and a solution of
potassium cyanide (6 g) in water (10 ml) was gradually added. The resulting
oil solidified on cooling, was collected by filtration, washed first with
bisulphite solution, then with water, and was finally dried over phosphorus
pentoxide. Yield, 9.7 g (96%); m.p. 81-82°C.


3,4,5-Trimethoxybenzaldehyde Cyanohydrin Acetate

3,4,5-Trimethoxybenzaldehyde cyanohydrin (10 g) was refluxed with acetic
anhydride (50 ml) for 2 hours. Excess anhydride was removed by distillation
under reduced pressure; the residue was taken up in ether and the ether
solution was washed with sodium carbonate solution (10 per cent), sodium
bisulphite solution (20 per cent) and water. The solution was then dried
over anhydrous potassium carbonate and the residue from the dried ether
distilled at 165-170°C (0.1 mm). Yield, 8.2 g (69%).


3,4,5-Trimethoxyphenethylamine

3,4,5-Trimethoxybenzaldehyde cyanohydrin acetate (1 g) was dissolved in
ethanol (15 ml) and concentrated sulphuric acid (0.4 ml) and palladium
black (140 mg) were added. The reduction was performed at room temperature
and atmospheric pressure, and was discontinued after 95% of the
calculated amount of hydrogen had been absorbed. The ethanol was eliminated
and the residue was taken up in water. After filtration and extraction with
ether, the aqueous solution was evaporated. The mescaline was isolated as
the sulphate and was recrystallised from water. Yield, 0.5 g (50 per cent),
m.p. 181-184°C; literature value 183-186°C (Reti, 1953).


ACKNOWLEDGEMENTS

The author is indebted to Mr. D. E. Bland for a gift of authentic
syringaldehyde. This paper is published by permission of the Chief
Scientist, Australian Defence Scientific Service, Department of Supply,
Melbourne, Victoria, Australia.


REFERENCES

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Ramirez, F. A. and Berger, A. (1950). J. Amer. Chem. Soc., 72, 2781.
Red L. (1953). The Alkaloids, ed. Manske, R. H. F. Academic Press, p. 313.
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