A Complete Synthesis for TMA, Ecstasy's Close Relative
by Alexander Shulgin
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SYNTHESIS: To a solution of 39.2 g 3,4,5-trimethoxybenzaldehyde in 30 mL warm EtOH there was added 1 g
nitroethane followed by 1.5 mL n-butylamine. The reaction mixture was allowed to stand at 40 deg C f7 days. With
cooling and scratching, fine yellow needles were obtained which, after removal by filtration and airying, weighed 48 g.
Recrystallization from EtOH gave 2-nitro-1-(3,4,5-trimethoxyphenyl)propene as yellow crystals with a of 94-95
deg C. Anal. (C12H15NO5) C,H,N. Alternatively, a solution of 20 g of the aldehyde in 75 mL nitroethawas treated
with 4 g anhydrous ammonium acetate and heated on the steam bath until a deep red color had been gented.
Removal of the excess solvent/reagent under vacuum gave a red oil which was dissolved in an equal voe of boiling
MeOH. On cooling, yellow crystals of the nitropropene separated. Recrystallization from MeOH gave, ar air drying
to constant weight, 13.0 g with the same mp.
Under an inert atmosphere, 38 g LAH was wetted with 100 mL anhydrous Et2O, and then suspended in 1 Ly THF.
This was brought up to a gentle reflux, and there was added, slowly, a solution of 43.7 g
2-nitro-1-(3,4,5-trimethoxyphenyl)propene in 160 mL THF. Refluxing was continued for 36 h, and then reaction
mixture was cooled with an external ice bath. The excess hydride was destroyed by the cautious addit of 38 mL
H2O, and this was followed by 38 mL 15% NaOH, and finally another 114 mL H2O. The inorganic salts wh should
have ended up as a loose, granular, easily filterable mass, looked rather like library paste, but thwere filtered
nonetheless. Washing with THF was attempted, but it was not efficient. The combined filtrate and was were
stripped of solvent under vacuum giving 31.5 g of the crude base as an amber oil. This was dissolved 140 mL IPA,
neutralized with concentrated HCl (15 mL was required), and diluted with 650 mL anhydrous Et2O. Theras an
initial oily phase which on continued stirring changed to pale pink solids. These were finely groundder CH3CN to
give 15.2 g of 3,4,5-trimethoxyamphetamine hydrochloride (TMA) as white crystals that melted at 195- deg C. All
aluminum salts from everywhere were dissolved in dilute HCl, and 1 Kg of potassium sodium tartrate wadded.
There as added 25% NaOH allowed the pH to bring the pH to >9 without the precipitation of basic alum. Extraction
of this phase with CH2Cl2 was followed by removal of the solvent and salt formation as described abo allowed the
isolation of an additional 6.4 g TMA. The product prepared in this manner contains some 10-15%
3,5-dimethoxy-4-hydroxyamphetamine as an impurity. A solution of 20 g of the TMA made in this manner 200 mL
5% NaOH was extracted with 2x200 mL CH2Cl2. The pooled extracts were washed with 4x100 mL 5% NaOH, athe
aqueous washes were pooled with the original base phase. The organic phase was stripped of its CH2Clnder
vacuum to give an oil that was dissolved in 40 mL IPA, neutralized with concentrated HCl, and diluteith 400 mL
anhydrous Et2O. There was the immediate formation of spectacular white crystals of pure
3,4,5-trimethoxyamphetamine hydrochloride, weighing 15.4 g and having a mp of 220-221 deg C. The aqus phase
was brought to neutrality, treated with 10 g potassium di-hydrogen phosphate, brought to pH 9.0 withe careful
addition of NaOH, and extracted with 5x100 mL CH2Cl2. Evaporation of the solvent under vacuum gave ail that
spontaneously crystallized. This product, 3,5-dimethoxy-4-hydroxyamphetamine could be further purifiby
sublimation at 130 deg C at 0.2 mm/Hg. It was a white crystalline solid that slowly discolored in thir. The literature
describes a picrate salt with a mp of 225 deg C from EtOH.
DOSAGE: 100 - 250 mg.
DURATION: 6 - 8 h.
QUALITATIVE COMMENTS: (with 135 mg) I had no nausea, although I always vomit with mescaline. Somehow
personality was divided and exposed, and this allowed me to understand my psychic structure more cley. But maybe
others could look in there, too. The psychiatric use of this drug would be interesting to pursue. It not completely
pleasant, maybe because of this personal intimacy.
(with 140 mg) There were not the color changes of mescaline there, but certainly a good humor and aner-appreciation of jokes. The images behind the eyes were remarkable and tied in with the music, adIbecame
annoyed at other people's conversations that got in the way. I was out of it in eight hours. I woulduate this to 300 or
350 milligrams of mescaline and I rather think that I would prefer the latter.
(with 225 mg) There was quite a bit of nausea in the first hour. Then I found myself becoming emotioly quite volatile,
sometimes gentle and peaceful, sometimes irritable and pugnacious. It was a day to be connected in oway or
another with music. I was reading Bernstein's 'Joy of Music' and every phrase was audible to me. On radio,
Rachmaninoff's 2nd piano concerto on the radio put me in an eyes-closed foetal position and I was toly involved
with the structure of the music. I was suspended, inverted, held by fine filigreed strands of the mu which had been
woven from the arpeggios and knotted with the chords. The commercials that followed were irritating,d the next
piece, Slaughter on Fifth Avenue, made me quite violent. I was told that I had a, 'Don't cross me ifu know what is
good for you,' look to me. I easily crushed a rose, although it had been a thing of beauty.
EXTENSIONS AND COMMENTARY: TMA was the very first totally synthetic psychedelic phenethylamine that
found to be active in man, for which there had been any attempt to describe such drug effects in anytail. This was the
report of research done in Canada, and it appeared in 1955, six years before my own report on the maial. There was
an earlier report on TMPEA which is mentioned in the appropriate recipe, but there were few details en. Also there
had been interest in reports that adrenalin that had become old and discolored seemed to elicit cent effects in man.
The oxidation products were identified as the deeply colored indolic compound adrenochrome and the crless
analogue adrenolutin. The controversy that these reports created just sort of died away, and the adrchrome family
has never been accepted as being psychedelic. No one in the scientific community today is looking ind about the
area, and at present this is considered as an interesting historical footnote. But, in any case, there not
phenethylamines and so not part of this book.
The Canadian studies with TMA involved the use of a stroboscope as a tool for the induction of visuahenomena.
These experiments used levels in the 50-150 milligram range, and generally employed pre-treatment wiDramamine
for the successful prevention of nausea. There was reported giddiness and light-headedness, and somemarkable
flash-induced visualizations. With higher levels, the visual syntheses are present without external mulation. But
there is a thread of negativity that seems to pervade the experience at these higher levels, and thepearance of a
publication that emphasized the possible antisocial nature to TMA seemed to discourage further medicexploration.
Military interest was maintained however, apparently, as TMA became a part of the chemical warfare sies where it
was referred to with the code name EA-1319. It had been used in human trials with psychiatric patien but no details
of these experiments have been published.
The presence of a potentially active impurity in TMA deserves some comment. In the Canadian work, thaterial used
was described as melting at 219-220 deg C, which is the property given for the impurity-free materiabove. If this
was the actual material used in those studies, this impurity (3,5-dimethoxy-4-hydroxyamphetamine) warobably
not present. The Army studies use a material of unreported melting point. In my own studies, the lowmelting product
was used. There is an intriguing and unanswered question: what contribution did this phenolic compon make to the
nature of the observed effects of TMA? Assays on the isolated contaminant could answer that, but theave not yet
There is an old saying that has gotten many people into trouble: If one is good, then two is better.d if a statement of
the measure of worth of a compound can be made from its potency, then TMA is a step in the right dirion. And this
was a chemically simple direction to follow further. Looking at mescaline as a compound with no carb on its
side-chain, and TMA as a mescaline molecule with one carbon on its side chain, then what about a comnd with two
carbons there, or three, or nine carbons?
Using this pattern of naming, TMA can be seen as alpha-methylmescaline, or AMM. And the two carbon hlogue
would be alpha-ethyl mescaline, or AEM. Its proper name is 2-amino-1-(3,4,5-trimethoxyphenyl)butane. and its
several higher homologues are discussed in a separate recipe entry called AEM (#1).
A final comment. But maybe a long one! Elsewhere, I have made comparisons between myristicin and MMDand
between safrole and MDA. And here there is a similar parallel between elemicin and TMA. What are therelationships between the essential oils and the amphetamines? In a word, there are some ten essentioils that have
a three carbon chain, and each lacks only a molecule of ammonia to become an amphetamine. So, maybe se essential
oils, or almost amphetamines, can serve as an index for the corresponding real amphetamine counterpa. I had
originally called this family the natural amphetamines, but my son suggested calling them the essent amphetamines,
and I like that. At the time that I had synthesized TMA, back there in the '50s, I had the impulse txplore this body
of Essential Amphetamines. As the old folk-wisdom says: Nature is trying to tell us something.
One of the banes of the archivist is having to choose one pattern of organization over another. The k store owned by
a language scholar will have the German poets and playwrights and novelists here, and the French onever there.
Next door, the book store is run by a letters scholar, and the poetry of the world is here, and the ys of the world are
there, regardless of the language of origin. The same obtains with spices, and essential oils, and aetamines. The
spice cabinet is a rich source of chemical treasures, each source plant containing a host of com-pou, some of which
are true essential oils. And the next spice from the next plant has some of the same components and e new ones.
Does one organize by plant (spice or herb) or by essential oil (amphetamine)? Let's do it by the rinubstitution
pattern of the amphetamine, and gather the spices and oils as a secondary collection.
(1) The 4-methoxy pattern. The pivotal essential oil is 4-allylanisole, or methyl chavicol, or estrae (called esdragol
in the old literature). This allyl compound is found in turpentine, anise, fennel, bay, tarragon, anasil. Its smell is light,
and reminiscent of fennel. The propenyl analogue is called anethole, or anise camphor, and it is fouin both anise and
camphor. It is a waxy solid, and has a very intense smell of anise or fennel. At low concentrations, is sweet, as in
magnolia blossoms, where it is also found. The drinks that turn cloudy with water dilution (Pernod-l liqueurs, and
ouzo and roki), are heavy with it, since it was the natural flavoring in the original absinthe. Thatink was very popular
in the last century, as an intoxicant which produced an altered state of consciousness beyond that wh could be
ascribed to alcohol alone. It contained wormwood, which proved to be neurologically damaging. The flrings, such as
anethole, are still big things in synthetic liqueurs such as vermouth. Old anethole, when exposed tor and light, gets
thick and sticky and yellowish, and becomes quite disagreeable to taste. Maybe it is polymerizing, oaybe oxidizing
to stuff that dimerizes. Whatever. These changes are why old spices in the cabinet are best discardeAnd adding
ammonia to any of these natural product oils produces, in principle, 4-methoxyamphetamine, 4-MA.
(2) The 3,4-dimethoxy pattern. The main actor here is methyleugenol, or 4-allyl-1,2-dimethoxybenzenehis is
located in almost every item in the spice cabinet. It is in citronella, bay (which is laurel, which myrtle), pimiento,
allspice, pepper, tree-tea oil, and on and on. It has a faint smell of cloves, and when dilute is imiately mistaken for
carnations. The propenyl analogue is, not unreasonably, methylisoeugenol, a bit more scarce, and seeto always be
that little minor peak in any essential oil analysis. The compounds missing that methyl group on theoxygen are
famous. The allyl material is eugenol, 4-allylguaiacol, and it is in cinnamon, nutmeg, cloves, sassas and myrrh. You
taste it and it burns. You smell it and think immediately of cloves. And its property as an anesthet in the form of a
clove, is well known in the folk-treatment of toothaches. Actually, flowers of clove (the gillyflowelike the carnation)
are the small, pointy things that decorate baked hams and, when stuck into apples, make pomander bal This
anesthetic property has recently led to a drug abuse fad, called clove cigarettes. Very strong, veryavorful, and very
corrosive things from Southeast Asia. The eugenol that is present numbs the throat, and allows many ong cigarettes
to be smoked without pain. The propenyl analogue is isoeugenol, with a smell that is subtle but veryng lasting, used
more in soaps and perfumes than in foods. The amine addition to the methyleugenol world produces
3,4-dimethoxyamphetamine, or 3,4-DMA. The isomer with the other methyl group missing is chavibetol
(3-hydroxy-4-methoxyallylbenzene) and is found in the pepper leaf that is used with betel nut. A cou of positional
rearrangement isomers of methyleugenol are known in the plant world. The 2,4-isomer is called osmorrole, and the
conjugated form is isoosmorrhizole or nothosmyrnol; both are found in carrot-like vegetables. They, h ammonia,
would give 2,4-DMA. And the 3,5-dimethoxyallylbenzene isomer from artemisia (a pungent herb commonlylled
mugwort) and from sage, would give rise to 3,5-DMA. This is an unexplored isomer which would be both antidote
for opium as well as a stimulant, if the classical reputation of mugwort is transferred to the ampheine.
(3) The 3,4-methylenedioxy pattern. One of the most famous essential oils is safrole, or
4-allyl-1,2-methylenedioxybenzene. This is the mainstay of sassafras oil, and it and its conjugated mer isosafrole
have a smell that is immediately familiar: root beer! These are among the most widely distributed estial oils, being
present in most of the spices, including the heavies such as cinnamon and nutmeg. I am not aware of 2,3-isomer
ever having been found in nature. Adding ammonia to either would give MDA.
(4) The 3-methoxy-4,5-methylenedioxy pattern. The parent compound is myristicin,
5-allyl-1-methoxy-2,3-methylenedioxybenzene, and the source of this is nutmeg (or the botanically palel
material, mace). The nutmeg is the seed of the tree Myristica fragrans and mace is the fibrous cover of the seed. The
two spices are virtually identical as to their chemical composition. Myristicin and the conjugated ier isomyristicin
are also found in parsley oil, and in dill. This was the oil that was actually shown to be converted MMDA by the
addition of ammonia by passage through an in vitro liver preparation. So here is the major justifican for the equation
between the essential oils and the Essential Amphetamines. Care must be taken to make an exact distiion between
myristicin (this essential oil) and myristin (the fat) which is really trimyristin or glyceryl trimytate from nutmeg and
coconut. This is the fat from myristic acid, the C-14 fatty acid, and these two similar names are of interchanged
even in the scientific literature.
(5) The 2-methoxy-3,4-methylenedioxy pattern. This is the second of the three natural methoxy methyldioxy
orientations. Croweacin is 2-methoxy-3,4-methylenedioxyallylbenzene, and it takes its name from the omial for
the plant Eriostemon crowei from the worlds of rue and the citrus plants. It corresponds to the esseal amphetamine
MMDA-3a. This oil is found in plants of the Family Rutaceae. My memories of this area of botany are Ruta
graveolens, the common rue, whose small leaves smelled to me, for all the world, like cat urine. Thilant has always
fascinated me because of a most remarkable recipe that I was given by a very, very conservative fellclub member,
one evening, after rehearsal. He told me of a formula that had provided him with the most complete ref from arthritic
pain he had ever known. It was a native decoction he had learned of many years eariler, when he was veling in
Mexico. One took equal quantities of three plants, Ruta graveolens (or our common rue), Rosmarinus ocinalis (better
known as rosemary), and Cannabis sativa (which is recognized in many households simply as marijuana)hree plants
all known in folklore, rue as a symbol for repentance, rosemary as a symbol of remembrance, and pot,ll, I guess it is
a symbol of a lot of things to a lot of people. Anyway, equal quantities of these three plants are awed to soak in a
large quantity of rubbing alcohol for a few weeks. Then the alcoholic extracts are clarified, and aled to evaporate in
the open air to a thick sludge. This then was rubbed on the skin, where the arthritis was troublesomand always
rubbed in the direction of the extremity. It was not into, but onto the body that it was applied. Alhis from a very
conservative Republican friend!
The methoxy-methylenedioxy pattern is also found in nature with the 2,4,5-orientation pattern. The
allyl-2,4,5-isomer is called asaricin. It, and its propenyl-isomer, carpacin, are from the Carpano t which grows in
the Solomon Islands. All these plants are used in folk medicine. These two systems, the 2,3,4- and t2,4,5-orientations, potentially give rise, with ammonia, to MMDA-3a and MMDA-2.
(6) The 3,4,5-trimethoxy pattern. Elemicin is the well studied essential oil, 5-allyl-1,2,3-trimethoenzene,
primarily from the oil of elemi. It is, like myristicin, a component of the Oil of Nutmeg, but it isso found in several of
the Oils of Camphor, and in the resin of the Pili in the Philippines. This tree is the source of thel of Elemi. I had found
a trace component in nutmeg many years ago that proved to be 5-methoxyeugenol, or elemicin without t4-methyl
group; it is also present in the magnolia plant. The aldehyde that corresponds to this is syringaldee, and its prefix
has been spun into many natural products. Any natural product with a syring somewhere in it has a hyxy between
two methoxys. The amphetamine base from elemicin or isoelemicin would be TMA, the topic of this verycipe.
(7) The 2,4,5-trimethoxy pattern. There is an essential oil called asarone that is
2,4,5-trimethoxy-1-propenylbenzene. It is the trans- or alpha-isomer, and the cis-isomer is known asta-asarone. It is the isomerization analogue of the much more rare 1-allyl-2,4,5-trimethoxybenzene
gamma-asarone, or euasarone, or sekishone. Asarone is the major component of Oil of Calamus obtainedom the
rhizomes of Acorus calamus, the common Sweet Flag that grows wild on the edges of swamps throughout th
America, Europe, and Asia. It has been used as a flavoring of liqueurs and, as almost every other pl known to man,
has been used as a medicine. In fact, in Manitoba this plant was called Rat-root by the Cree Indians the Lake
Winnipeg area known as New Iceland, and Indian-root by the Icelandic pioneers. It was used externallor the
treatment of wounds, and internally for most illnesses. There apparently is no report of central effs. The
corresponding propanone, acoramone (or 2,4,5-trimethoxyphenylacetone), is also present in Oil of Cals. The
styrene that corresponds to asarone is found in a number of plants, and is surprisingly toxic to brishrimp. The older
literature describes an allyl-trimethoxy benzene called calamol, but it has never been pinned down ao structure. The
isolation of gamma-asarone or euasarone from Oil of Xixin (from wild ginger) has given rise to a potial problem of
nomenclature. One of the Genus names associated with wild ginger is Asiasarum which looks very much e the name
asarone, which comes from the Genus Acorus. And a second Genus of medical plants also called wild gir is simply
called Asarum. There is an Asarum forbesi from central China, and it is known to give a pleasant smeto the body.
And there is Asarum seiboldi which is largely from Korea and Manchuria. It has many medical uses, inding the
treatment of deafness, epilepsy, and rheumatism. The amphetamine that would arise from this natural asure chest is
(8) The 2,5-dimethoxy-3,4-methylenedioxy pattern. The parent allyl benzene is apiole (with a final R or parsley
camphor, and it is the major component of parsley seed oil. Its conjugated isomer is called isoapioland they are
valuable as the chemical precurors to the amination product, DMMDA. Whereas both of these essential s are white
solids, there is a green oily liquid that had been broadly used years ago in medicine, called green, liquid apiol
(without the final ReS). It comes from the seeds of parsley by ether extraction, and when the chloroll has been
removed, it is known as yellow apiol. With the fats removed by saponification and distillation, the term for the
medicine was apiolin. I would assume that any of these would give rise to white, crystalline apiole careful
distillation, but I have never tried to do it. The commercial Oil of Parsley is so readily available
(9) The 2,3-dimethoxy-4,5-methylenedioxy pattern. The second of the three tetraoxygenated essential s is
1-allyl-2,3-dimethoxy-4,5-methylenedioxybenzene, commonly called dillapiole and it comes, not surprigly, from
the oils of any of the several dill plants around the world. It is a thick, almost colorless liquid,t its isomerization
product, isodillapiole, is a white crystalline product which melts sharply. This, by the theoreticaldition of ammonia,
(10) The tetramethoxy pattern. The third and last of the tetra-oxygenated essential oils, is
1-allyl-2,3,4,5-tetramethoxybenzene. This is present as a minor component in the oil of parsley, but is much more
easily obtained by synthesis. It, and its iso-compound, and the amination product, are discussed undthe last of
theTen Essential Amphetamines, TA.
One must remember that the term RessentialS has nothing to do with the meaning of needed, or requireThe word's
origin is essence, something with an odor or smell. Thus, the essential oils are those oils that hav fragrance, and the
Essential Amphetamines are those compounds that can, in principle, be made from them by the addition ammonia in
There were a few interesting experimental trials that were based on these natural oils. Methoxyeugenwas assayed
up to a 10 milligram level, and asarone at up to a 70 milligram level, and neither had any effects all. And, in an
attempt to challenge the Roil-to-amphetamineS concept, I made up a mixture of 1 part MDA, 2 parts TMnd 5 parts
MMDA. A total of 100 milligrams of this combination (which I had named the RPseunut CocktailS for pso-nutmeg)
should be equivalent to the safrole, elemicin and myristicin that would be in 5 grams of nutmeg. And0 milligrams
indeed produced quite a sparkle and considerable eye-dilation. But then, I have never taken 5 grams nutmeg, so I
cannot make any comparisons.