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				   Many Mescaline Syntheses
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                          A New Synthesis of Mescaline
                              By Makepeace U. Tsao
                                JACS 5495 (1951)

The cactus alkaloid, mescaline, beta-(3,4,5trimethoxyphenyl)-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 Späth, a few other methods of
preparation have been published. 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 acid (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 80-82°.
Semmler, who employed a different Process, reported m.p. 83-84°.

3,4,5-Trimethoxybenzyl Alcohol

To a suspension of 4.6 g. (012 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;
b.p.135-137' (0.25 mm.); yield 14.7 g. (73%). This compound was obtained by a
different method by Marx; b.p. 228° (25 mm.).

3,4,5-Trimethoxybenzyl Chloride 

A mixture of 25 g. of 3,4,5trimethoxybenzyl 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. 60-62°.

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. 76-77°C. Baker and Robinson reported a melting point of 77°C 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 172° and melt at 183°C.


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Synthesis of Mescaline [J Prakt Chem 137, 339 (1933)]

0) 3,4,5-trimethoxy-benzoic acid [Org Syn Coll Vol 1, p 537 (1941)]

To a cold solution of 80g (2 moles) of sodium hydroxide in 500ml water in 
a 1000ml flask is added 50g (0.266 mole) of gallic acid. The flask is 
immediately tightly stoppered (to prevent the solution from darkening, due 
to oxidation by atmospherical oxygen. Oxygen must not enter the reaction 
flask at any time!), and the mixture is shaken occasionally until all the 
acid has dissolved. 89g (67 ml) of dimethyl sulfate (0.71 mole) is then 
added (Caution! Dimethylsulfate is very toxic, and all spills must be 
neutralized with ammonia solution!), and the flask is shaken for twenty 
minutes, and cooled by means of cold water in order to prevent the 
temperature to rise above 30-35°C. Occasionally the stopper is raised to 
release any pressure. A second portion of 89g of dimethyl sulfate is added 
and shaking continued for ten minutes longer. During the second addition 
the temperature may rise to 40-45°C. The flask is then fitted with a reflux 
condenser and the contents boiled for two hours. In order to saponify the 
small amount of ester which is produced, a solution of 20g of sodium 
hydroxide in 30 ml of water is themn added and the boiling continued for 
two additional hours. The reaction mixture is then cooled and acidified 
with dilute hydrochloric acid; the precipitated trimethylgallic acid is 
filtered with suction and wased well with cold water. The yield is around 
50g (90%). 

1) 3,4,5-Trimethoxybenzoyl Chloride.

Five hundred grams of 3,4,5-trimethoxybenzoic acid (ef. Gilman-Blatt,
"Organic Syntheses," John Wiley & Sons, New York 1941, Collective Volume I,
537) is added to 285 cc of thionyl chloride freshly distilled over linseed
oil and the mixture is heated for 2 hours on a water bath. The still-hot
mixture is then distilled under reduced pressure from a Claisen-flask,
avoiding rubber stoppers. There is obtained 510 g. (93 % of theory) of
trimethoxybenzoyl chloride boiling at 185 deg C (18 mm.).

2) 3,4,5-Trimethoxybenzaldehyde.

To a solution of 200 g. of 3,4,5-trimethoxy benzoyl chloride in 1000 cc of
xylene freshly distilled over sodium, there is added 60 g. of a 5 %
palladium-barium sulfate catalyst. The mixture is heated in an oil bath
maintained at 150 deg C and a vigorous stream of hydrogen is introduced
into the boiling solution. The hydrogen should be washed with aqueous
permanganate and the dried with sulfuric acid. After 60-80 hours the
reaction is complete. The solution is filtered and the aldehyde
conveniently isolated as its bisulfite compound. Yield 120 g. (70.6 % of
theory), m.p. 74 deg C.

3) 3:4:5-Trimethoxy-nitrostyrene.

A solution of 40 cc of nitromethane and 100 g. of trimethoxybenzaldehyde in
200 cc alcohol is cooled to 0 deg C and while it is stirred mechanically
there is introduced a solution of 45 g. pure potassium hydroxide in 45 cc
water and 90 cc methanol at the rate of about one drop per second, care
being taken that the temperature does not rise. Fifteen minutes after the
addition is completed the solution is poured into 500 cc concentrated
hydrochloric acid mixed with sufficient fee to assure its presence
throughout the slow addition and to maintain the temperature of -10 deg C.
The precipitated nitrostyrene is separated by filtration and washing and 
may be purified by recrystallizing from 700 cc alcohol. The pale yellow 
plates which melt at 120-121 deg C are obtained in a yield of approximately 
78% of theory.

4) Mescaline.

(A)  APPARATUS

A cell of porous porcelain (PC) (external dimensions 75x160 mm) with a
glazed rim is placed in a glass jar of 500 cc capacity, surrounded by a
cooling bath. The anode is a lead or carbon rod, surrounded by a glass
coil; the cooling water flows through the coil and discharges into the
cooling bath. The cathode is a sheet of lead (220x90x2 mm.), which previous
to each experiment is electrolytically coated with lead peroxide, in a bath
of dilute sulfuric acid.

(B) REDUCTION

The cathode liquor consists of a solution of 30g. 3,4,5-trimethoxy-
nitrostyrene in 100 cc glacial acetic acid and 100 cc alcohol, to which 50
cc conc. hydrochloric acid has been added. The anode compartment is filled,
to the same level occupied by the catholyte, with a solution of 25 cc conc.
sulfuric acid in 175 cc water.

The reduction requires 12 hours, using a current of 5-6 amperes; the
cathode current density should be about 3 amperes per square centimeter.
The temperature is regulated by the flow of the cooling water and the
catholyte should be kept at 20 deg C for the first six hours; the temp is
then allowed to rise until it reaches 40 deg C at the end of the reduction.

When the reduction is complete, the catholyte is filtered, evaporated in
vacuum and the residue taken up in 300 cc water Unreduced nitrostyrene is
extracted sucessively with ethyl acetate and with ether. The crude
mescaline hydrochloride solution in a separatory funnel is then treated
with a cold concentrated solution of 100 g. of sodium hydroxide and the
liberated base exhaustively extracted with ether. The somewhat concentrated
and dried (potassium carbonate) solution is treated with a stream of dry
hydrogen chloride and the separated hydrochloride twice recrystallized 
from absolute alcohol. The pure mescaline hydrochloride, thus obtained in 
77% yield, forms white leaflets melting at 184°C.

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Synthesis of Mescaline [Arch Pharm 270, 410 (1932)]

1) 3,4,5-Trimethoxyacetylmandelonitrile.

Twenty grams 3,4,5-trimethoxybenzaldehyde, prepared according to Slotta
[Ber 63, 3029 (1930)], is mixed with 40 cc of saturated sodium bisulfite
solution. The separated bisulfite compound in a slurry with water is
treated with a solution of 9.5 g. of potassium cyanide in 20 cc water. The
resulting nitrile is filtered, washed first with bisulfite solution then
with water, and finally dried on a porous plate.

The mandelonitrile is acetylated by boiling for 1 hour with 100 cc of
acetic anhydride. The excess anhydride is distilled, the residue is
dissolved in ether, and the solution washed successively with sodium
carbonate solution, with bisulfite solution, and with water. The residue
from the dried ether solution distills at 163-165 deg C (0.1 mm); yield
82% based on the 3,4,5-trimethoxybenzaldehyde.

2) Mescaline.

Twenty-two grams of 3,4,5-trimethoxyacetylmandelonitrile is dissolved in
200 cc glacial acetic acid and the solution dropped into a suspension of 3
g. palladium black in 75 cc acetic acid and 5 cc concentrated sulfuric acid
(for apparatus see Arch. Pharm. 1931, 74). The introduction is made with
agitation, at 18 deg C, and under a hydrogen pressure of 2 atm. In 2.5
hours, 95% of the calculated amount of hydrogen is absorbed. An amount of
potassium carbonate equivalent to the sulfuric acid is added, the acetic
acid is eliminated in vacuo, and the residue dissolved in water. The
aqueous solution is washed twice with ether, treated with excess potassium
hydroxide, and the separated mescaline taken up in ether. The residue from
the ether extract distills at 173°C (10 mmHg) and solidifies to white
crystals, mp 35-36°C.

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                A Novel Route for the Synthesis of Mescaline
                   M. Nabil Aboul-Enein and Attiat I. Eid
                    Acta Chem. Scand. 16, 267-270 (1979)

                ABSTRACT: A new plausible synthetic pathway for
                the synthesis of the peyote alkaloid mescaline
                in a satisfactory overall yield is reported.

The hallucinogen mescaline (I) is the main alkaloid isolated from the
cactus plant Anhalonium Lewinii Hennings or Lophophora Williamsii Lemaire
[1]. Several methods have been reported describing the total synthesis of
this alkaloid [2-7]. However, all these procedures were found to be tedious
and costly as well as giving low overall yields of the alkaloid. In the
present work, we would like to report a convenient new simple, facile and
non-costly synthetic pathway of mescaline (I) leading to comparatively high
overall yields. The scheme illustrates the route resorted to to achieve the
base, starting from the inexpensive and easily available 2,6-dimethoxy-
phenol (II): II was allowed to undergo Mannich reaction to give the base
III. Subsequent quaternization to IV, nucleophilic substitution to V and
methylation resulted in 3,4,5-trimethoxybenzyl cyanide (VI) in high yields.
Lithium aluminum hydride reduction of the latter afforded the alkaloid
mescaline isolated as the hydrochloride in 42% overall yield.

                                Experimental

Melting points were determined on a Kofler melting point apparatus and are
uncorrected. Infrared spectra were recorded on a Perkin-Elmer Model 257
grating spectrophotometer and were consistent with the assigned structures.
Microanalyses were performed at the National Research Centre, Dokki, Cairo,
Egypt. Analytical results obtained were within +-0.4% of the calculated value.

4-Dimethylaminomethyl-2,6-dimethoxyphenol (III)

To a solution of 23.1 g (0.15 mol) of 2,6-dimethoxyphenol (II) in 150 ml of
methanol was added 17.1 g of 40% aqueous solution of dimethylamine and
12.75 g of 35% formaldehyde solution. The whole mixture was left well
closed in the dark at room temperature for 10 days with occasional shaking.
Thereafter, the methanol was driven off in vacuo and 45 ml of water was
added to the residue. The separated product was filtered and recrystallized
from petroleum-ether (bp 60-80°C), mp 79-80°C, yield 25.3 g (80 %).

Quaternization of III to IV

To a solution of 21 g (0.099 mol) of III in 90 ml of absolute ethanol, 28.2
g (0.198 mol) of methyl iodide was added under stirring and cooling,
resulting in an exothermic reaction accompanied by the precipitation of the
product IV. After complete addition, the reaction mixture was allowed to
stand overnight. The separated solid was recrystallized from ethanol, mp
185-187°C, yield 35g (99%) .

3,5-Dimethoxy-4-hydroxybenzyl cyanide (V)

A solution of 35.3g (0.1 mol) of the methiodide IV and 26g (0.4 mol) of KCN
in 200 ml of water was refluxed for 2.5 h. After cooling, the solution was
cautiously acidified with 2 M HCl and extracted with CHCl3. The CHCl3
extract was dried (Na2SO4) and the solvent removed in vacuo to give 15.4 g
of an oil (80 %), which is used as such without further purification in the
next step.

3,4,5-Trimethoxybenzyl cyanide (Vl)

To a solution of 30g (0.156 mol) of V in 200 ml of dry acetone was added
27.6g (0.2 mol) of K2CO3 and 31.2g (0.22 mol) of methyl iodide. The mixture
was refluxed for 20 h. After cooling and filtration, the filtrate was
evaporated in vacuo. The residue was extracted with CHCl3. The CHCl3
extract was washed with 2M NaOH, 10% Na2S2O3, and then with water. After
drying over Na2SO4 and removal of the solvent, the crystalline was
recrystallized from petroleum-ether (60-80°C), mp 76-77°C, yield 27g (83.8
%) (Lit. [4] 76-77°C).  VI was further identified by comparing mixed
melting point and comparative IR spectrum with an authentic sample.

Mescaline hydrochloride (I)

To a suspension of 10 g LiAlH4 in 300 ml of dry tetrahydrofuran was added a
solution of 20.7 (0.1 mol) of VI in 60ml of dry tetrahydrofuran over a
period of 30 min. After complete addition, the whole mixture was refluxed
for 3 h and then cooled. The complex and excess hydride were decomposed
with saturated Na2SO4 solution and filtered. The combined filtrate and
washings were evaporated in vacuo. The calculated amount of methanolic
hydrogen chloride was added to the residue and the mescaline hydrochloride
was recrystallized from 2-propanol, mp 180-181°C, yield 19.5g (79%) (Lit.
[8] 180-181°C). Mescaline hydrochloride was further identified by comparing
mixed melting point and comparative IR spectrum with an authentic sample.

References

[1]     A. Hoffer and H. Osmond, The Hallucinogens, Academic Press (1967)
[2]     E. Späth, Monatsh. Chem. 40,129 (1919)
[3]     K. H. Slotta and H. Helter, Chem. Ber. 63, 3029 (1930)
[4]     M. U. Tsao, J. Am Chem. Soc. 73, 5495 (1951)
[5]     K. Banholzer and T. W. Campbell, Helv. Chim. Acta 35, 1577 (1952)
[6]     J. Hadacek, J. Michalsky and L. Macholan, Chem. Listy 49, 271 (1955)
[7]     D. Amos, Aust. J. Chem. 46, 58 (1904)
[8]     F. Benington and R. D. Morin, J. Am. Chem. Soc. 73, 1353 (1951)

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