SYNTHESIS: A solution of 83 g bourbonal (also called ethyl vanillin,
or vanillal, or simply 3-ethoxy-4-hydroxybenzaldehyde) in 500 mL MeOH
was treated with a solution of 31.5 g KOH pellets (85% material)
dissolved in 250 mL H2O. There was then added 71 g methyl iodide, and
the mixture was held under reflux conditions for 3 h. All was added
to 3 volumes of H2O, and this was made basic with the addition of 25%
NaOH. The aqueous phase was extracted with 5x200 mL CH2Cl2. The
pooling of these extracts and removal of the solvent under vacuum gave
a residue of 85.5 g of the product 3-ethoxy-4-methoxybenzaldehyde,
with a mp of 52-53 °C. When this product was recrystallized from
hexane, its mp was 49-50 °C. When the reaction was run with the same
reactants in a reasonably anhydrous environment, with methanolic KOH,
the major product was the acetal, 3-ethoxy-a,a,4-trimethoxytoluene.
This was a white glistening product which crystallized readily from
hexane, and had a mp of 44-45 °C. Acid hydrolysis converted it to the
correct aldehyde above. The addition of sufficient H2O in the
methylation completely circumvents this by-product. A solution of 1.0
g of this aldehyde and 0.7 g malononitrile in 20 mL warm absolute
EtOH, when treated with a few drops of triethylamine, gave immediate
yellow color followed, in a few min by the formation of crystals.
Filtration, and washing with EtOH, gave bright yellow crystals of
3-ethoxy-4-methoxybenzalmalononitrile with a mp of 141-142 °C.
A well stirred solution of 125.4 g 3-ethoxy-4-methoxybenzaldehyde in
445 mL acetic acid was treated with 158 g 40% peracetic acid (in
acetic acid) at a rate at which, with ice cooling, the internal
temperature did not exceed 27 °C. The addition required about 45 min.
The reaction mixture was then quenched in some 3 L H2O. There was the
generation of some crystals which were removed by filtration. The
mother liquor was saved. The solid material weighed, while still wet,
70 g and was crude formate ester. A small quantity was recrystallized
from cyclohexane twice, to provide a reference sample of
3-ethoxy-4-methoxyphenyl formate with a mp of 63-64 °C. The bulk of
this crude formate ester was dissolved in 200 mL concentrated HCl
which gave a deep purple solution. This was quenched with water which
precipitated a fluffy tan solid, which was hydrated phenolic product
that weighed about 35 g, and melted in the 80-90 °C. range. The
mother liquors of the above filtration were neutralized with Na2CO3,
then extracted with 3x100 ml Et2O. Removal of the solvent gave a
residue of about 80 g that was impure formate (containing some
unoxidized aldehyde). To this there was added 500 mL 10% NaOH, and
the dark mixture heated on the steam bath for several h. After
cooling, the strongly basic solution was washed with CH2Cl2, and then
treated with 200 mL Et2O, which knocked out a heavy semi-solid mass
that was substantially insoluble in either phase. This was, again,
the crude hydrated phenol. The Et2O phase, on evaporation, gave a
third crop of solids. These could actually be recrystallized from
MeOH/H2O, but the mp always remained broad. When subjected to
distillation conditions, the H2O was finally driven out of the
hydrate, and the product 3-ethoxy-4-methoxyphenol distilled as a clear
oil at 180-190 °C at 0.8 mm/Hg. This product, 45.1 g, gave a fine NMR
spectrum, and in dilute CCl4 showed a single OH band at 3620 cm-1,
supporting the freedom of the OH group on the aromatic ring from
adjacent oxygen. Efforts to obtain an NMR spectrum in D2O immediately
formed an insoluble hydrate. This phenol can serve as the starting
material for either MEM (see below) or EEM (see separate recipe).
To a solution of 12.3 g 3-ethoxy-4-methoxyphenol in 20 mL MeOH, there
was added a solution of 4.8 g flaked KOH in 100 mL heated MeOH. To
this clear solution there was then added 10.7 g methyl iodide, and the
mixture held at reflux on the steam bath for 2 h. This was then
quenched in 3 volumes H2O, made strongly basic with 10% NaOH, and
extracted with 3x100 mL CH2Cl2. Removal of the solvent from the
pooled extracts under vacuum gave 9.4 g of an amber oil which
spontaneously crystallized. The mp of 1,4-dimethoxy-2-ethoxybenzene
was 42-43.5 °C, and was used, with no further purification, in the
following step.
A mixture of 17.3 g N-methylformanilide and 19.6 g POCl3 was allowed
to stand for 0.5 h, producing a deep claret color. To this there was
added 9.2 g 1,4-dimethoxy-2-ethoxybenzene, and the mixture was held on
the steam bath for 2 h. It was then poured into chipped ice and, with
mechanical stirring, the dark oily phase slowly became increasingly
crystalline. This was finally removed by filtration, providing a
brown solid mat which showed a mp of 103.5-106.5 °C. All was
dissolved in 75 mL boiling MeOH which, on cooling, deposited fine
crystals of 2,5-dimethoxy-4-ethoxybenzaldehyde that were colored a
light tan and which, after air drying to constant weight, weighed 8.5
g and had a mp of 108-109.5 °C. Search was made by gas chromatography
for evidence of the other two theoretically possible positional
isomers, but none could be found. The NMR spectrum showed the two
para-protons as clean singlets, with no noise suggesting other
isomers. There was a single peak by GC (for the recrystallized
product) but the mother liquors showed a contamination that proved to
be N-methylformanilide. A 0.3 g sample, along with 0.3 g
malononitrile, was dissolved in 10 mL warm absolute EtOH, and treated
with a drop of triethylamine. There was the immediate formation of a
yellow color followed, in 1 min, by the deposition of fine yellow
needles. Filtering and air drying gave 0.25 g of
2,5-dimethoxy-4-ethoxybenzalmalononitrile, with a mp of 171-172 °C.
A solution of 7.3 g 2,5-dimethoxy-4-ethoxybenzaldehyde in 25 g glacial
acetic acid was treated with 3.6 g nitroethane and 2.25 g anhydrous
ammonium acetate, and heated on the steam bath. After two h, the
clear solution was diluted with an equal volume of H2O, and cooled in
an ice bucket. There was the formation of a heavy crop of orange
crystals which were removed by filtration. The dry weight of
1-(2,5-dimethoxy-4-ethoxyphenyl)-2-nitropropene was 4.8 g and the mp
was 120-124 °C. Recrystallization of an analytical sample from MeOH
gave a mp of 128-129 °C. Anal. (C13H17NO5) C,H.
To a gently refluxing suspension of 3.3 g LAH in 400 mL anhydrous Et2O
under a He atmosphere, there was added 4.3 g
1-(2,5-dimethoxy-4-ethoxy)-2-nitropropene by allowing the condensing
Et2O to drip into a shunted Soxhlet thimble apparatus containing the
nitrostyrene, thus effectively adding a warm saturated ether solution
of it to the hydride mixture. The addition took 2 h. Refluxing was
maintained for 5 h, and then the reaction mixture was cooled to 0 °C
with an external ice bath. The excess hydride was destroyed by the
cautious addition of 300 mL of 1.5 N H2SO4. When the aqueous and Et2O
layers were finally clear, they were separated, and 100 g of potassium
sodium tartrate was dissolved in the aqueous fraction. Aqueous NaOH
was then added until the pH was >9, and this was then extracted with
3x100 mL CH2Cl2. Evaporation of the solvent from the pooled extracts
produced an almost white oil that was dissolved in 100 mL anhydrous
Et2O and saturated with anhydrous HCl gas. There was deposited a
white crystalline solid of 2,5-dimethoxy-4-ethoxyamphetamine
hydrochloride (MEM) which weighed 3.1 g and had a mp of 171-172.5 °C.
Anal. (C13H22ClNO3) C,H,N.
DOSAGE: 20 - 50 mg.
DURATION: 10 - 14 h.
QUALITATIVE COMMENTS: (with 20 mg) I experienced some physical
discomfort, but doesn't that tell us about the work to be done, rather
than the property of the material? The breakthrough I had was the
following day (and this seems to be the way MEM operates, i.e., first
the energy and expansion, next day insight) was of the highest value
and importance for me. I was given a methodology for dealing with my
shadow parts. No small gift. And I did it all alone and the results
were immediate. I am so grateful.
(with 20 mg, at 1.5 h following 120 mg MDMA) RThe transition was very
smooth, with no obvious loss of the MDMA experience. I felt less of a
need to talk, but the intimate closeness with the others was
maintained. The experience continues to grow more profound and
euphoric and I prayed, in the latter part of the afternoon, that it
wouldn't stop. It continued until midnight with marvelous feelings,
good energy, and much hilarity. And it abated very little over the
next several days leaving me with the feeling of lasting change with
important insights still coming to mind one week later.
(with 25 mg, at 2 h following 120 mg MDMA) RI found that sounds in
general were distracting. No, they were out-and-out annoying. I may
have been in an introspective mood, but I really wanted to be alone.
No body problems at all. Felt good. I developed some color changes
and some pattern movement. Not much, but then I didn't explore it
much. The wine party afterwards was certainly most pleasant. The
soup was a great pleasure. And that hard bread was good. The
material was clearly not anorexic, or at least I overcame whatever
anorexia there might have been.
(with 30 mg) I was aware of this in thirty minutes and it slowly
developed from there to an almost +++ in the following hour. There
were visual phenomena, with some color enhancement and especially a
considerable enhancement of brights and darks. The first signs of
decline were at about six hours, but there was something still working
there after another six hours had passed. A slow decline, certainly.
(with 50 mg) I came into the experience knowing that yesterday had
been a very fatiguing and tense day. I felt this material within the
first ten minutes which is the fastest that I have ever felt anything.
The ascent was rapid and for the first hour I tended to an inward
fantasying with a distinct sensual tinge. There was a persistent
queasiness that never left me, and it contrasted oddly with a good
feeling of outward articulation and lucidity which succeeded in coming
to the fore after the introverted first hour. Sleep was difficult,
but the next day was calm and clear.
(with 50 mg) Lots of energy, best directed into activity. Clear
imaging, thinking. Intense yet serene. Good feeling of pleasantness
and some euphoria. I felt the need to keep moving. Hard to stay
still.
(with 70 mg, in two parts) RThe effects of the 40 milligrams were
muted by another drug experiment yesterday morning, and I never got
much over a plus 1. There is an erotic nature, tactile sensitivity
perhaps not as delicate as with 2C-B, but it is there. At the 2 hour
point, an additional 30 milligrams increased the body impact (a
distinct tremor and sensitivity) but somehow not a lot more mental. I
have been compromised by yesterday.
EXTENSIONS AND COMMENTARY: MEM was both a valuable and dramatic
compound, as well as a drug that played a watershed role. The
completion of all the possible trimethoxyamphetamines (the TMA's)
showed that only two of them combined the values of dependability of
positive psychedelic effects with a reasonably high potency. Both
TMA-2 and TMA-6 are treasures, both active in similar dosages, and
both offer methoxyl groups that are begging to be replaced by other
things. The first focus was on TMA-2, partly because the needed
synthetic chemistry was better known, and partly because I had
discovered its activity earlier. But there were three entirely
different and distinct methoxyl groups to work on, in TMA-2. There is
one at the 2-position, one at the 4-position, and one at the
5-position. The most obvious thing to do, it seemed, was to make each
of them one carbon longer. Replace a methoxy with an ethoxy. And a
logical naming pattern could follow the use of M for methoxy, and E
for ethoxy, in sequence right around the ring from the 2- to the 4- to
the 5-positions. The first group to be compared, then, would be EMM,
MEM, and MME. And of these three, it was only MEM that was right up
there in drama and in potency. But, by the time that became apparent,
I had already completed the diethoxy possibilities (EEM, EME, and MEE)
as well as the triethoxy homologue, EEE. With the discovery that the
4-position was the magic leverage point, and that the homologues at
positions 2- and 5- were clearly less interesting, all emphasis was
directed at this target, and this has led to the many 4-substituted
families that are now known to be highly potent and felt by many to be
personally valuable.
Why put such emphasis on potency, I am frequently asked? Why should it
matter how much of a compound you take, as long as the effective level
is much lower than its toxic level? Well, in a sense, that is the
very reason. There are no guides as to what the toxic levels of any
of these many compounds might really be in man. There is simply no
way of determining this. Only a few have been explored in animals in
the pursuit of an LD-50 level. Most of them are similar to
one-another, in that they are, in mice, of relatively low toxicity
and, in rat, of relatively high toxicity. But this toxicity appears
not to be related to potency in man. So, if one might extrapolate
that they are of more or less the same risk to man (from the toxic
point of view) then the lower the dosage, the greater the safety.
Maybe. In the absence of anything factual, it makes a reasonable
operating hypothesis.
Many of the reports of MEM effects have been with experiments in which
an effective dose of MDMA had been taken shortly earlier. There has
developed a concept, embraced by a number of researchers, that the
ease and quietness usually seen with the development of the MDMA
experience can mitigate some of the physically disturbing symptoms
sometimes seen with other psychedelics. This may be partly due to a
familiar entry into a altered place, and partly due to a lessening of
dosage usually required for full effects. MEM seems to have had more
trials using this combination than many of the other psychedelic
drugs.
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