SYNTHESIS: To a solution of 9.5 g flaked KOH (10% excess) in 500 mL
95% EtOH there was added 20.4 g 4-methoxy-2-methylphenol (see under
2C-D for its preparation). This was followed with 23.5 g ethyl
iodide, and the mixture was held at reflux overnight. The solvent was
removed under vacuum and the residue suspended in 250 mL H2O. This
was made strongly basic with NaOH and extracted with 3x50 mL CH2Cl2.
Removal of the solvent gave 15.75 g of 2-ethoxy-5-methoxytoluene as an
amber oil, which was used in the following step without further
purification. Acidification of the aqueous phase followed by CH2Cl2
extraction gave, after removal of the solvent, crude recovered
starting phenol as a dark brown crystalline solid. The reasonably
pure phenol was best isolated by sequential extractions with portions
of 80 °C H2O which, on cooling, deposited the phenol as white
crystals.
A mixture of 38 mL POCl3 and 43 mL N-methylformanilide was allowed to
incubate for 1 h and then there was added to it 15.7 g
2-ethoxy-5-methoxytoluene. This was heated in the steam bath for 2 h,
then poured into 1 L H2O and allowed to stir overnight. The solids
that formed were removed by filtration and H2O washed, giving 20.7 g
of a crude, amber product. This was extracted with 2x150 mL boiling
hexane which gave crystals on cooling. These were filtered and hexane
washed, giving 12.85 g of 5-ethoxy-2-methoxy-4-methylbenzaldehyde as
pale cream-colored solids with a mp of 75-76 °C. Recrystallization of
an analytical sample from EtOH two times gave a product with a white
color, and a mp of 81-82 °C.
To a solution of 11.35 g 5-ethoxy-2-methoxy-4-methylbenzaldehyde in 48
mL glacial acetic acid containing 4 g anhydrous ammonium acetate there
was added 10 mL nitroethane, and the mixture heated on the steam bath
for 2 h. Standing at room temperature overnight allowed a heavy crop
of brilliant crystals to deposit. These were removed by filtration,
washed cautiously with acetic acid, and air dried to give 8.6 g
1-(5-ethoxy-2-methoxy-4-methylphenyl)-2-nitropropene with a mp of
118-120 °C. Recrystallization of all from 200 mL boiling MeOH gave
8.3 g of lustrous crystals with a mp of 121-122 °C.
To a gently refluxing suspension of 6.4 g LAH in 500 mL anhydrous Et2O
under a He atmosphere, there was added 8.1 g
1-(5-ethoxy-2-methoxy-4-methylphenyl)-2-nitropropene by allowing the
condensing ether to drip into a shunted Soxhlet thimble containing the
nitrostyrene. This effectively added a warm saturated solution of the
nitrostyrene dropwise. Refluxing was maintained overnight, and the
cooled reaction flask stirred for several additional days. The excess
hydride was destroyed by the cautious addition of 400 mL H2O
containing 40 g H2SO4. When the aqueous and Et2O layers were finally
clear, they were separated, and 160 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 3x50 mL CH2Cl2.
Evaporation of the solvent under vacuum produced an oil that was
dissolved in anhydrous Et2O and saturated with anhydrous HCl gas.
There appeared 5-ethoxy-2-methoxy-4-methylamphetamine hydrochloride
(IRIS) as fine white crystals. These weighed, after filtration, Et2O
washing, and air drying to constant weight, 5.3 g and had a mp of
192-193 °C. Recrystallization of an analytical sample from boiling
CH3CN gave lustrous crystals with a mp of 196-197 °C with
decomposition.
DOSAGE: greater than 9 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 7.5 mg) At about three hours I felt that
I was at threshold, but an hour later there was nothing.
(with 9 mg) Maybe a little light headed? Maybe not. Little effect
if any.
EXTENSIONS AND COMMENTARY: This is one of the ten Classic Ladies, the
ten possible homologues of DOM, which I had discussed under ARIADNE
(the first of the Ladies). The active level is unknown, but it is
higher than 9 milligrams (the highest dose tried) and since DOM itself
would have been smashingly active at this level, it is obvious that
IRIS is a homologue with decreased potency.
This lack of activity brings up a fascinating point. I have referred
to a drug's action on the mind, quite frequently in these notes, with
the phrase "reasonably complex." By that, I do not mean that a drug's
action simply shows many facets, and if these were to be tallied, the
drug-mind interaction would become clear. There is quite a bit of
importance intrinsically implied by the term, complex. Simple things,
as we have come to appreciate and depend upon them in our day-to-day
living, can have simple explanations. By this, I mean explanations
that are both completely satisfactory and satisfactorily complete.
Answers that have all the earmarks of being correct. What is the sum
of two plus three, you ask? Let's try five. And for most of our
needs, five is both factual and complete.
But some years ago, a mathematician named Gödel devised a proof for a
theorem that anything that is reasonably complex cannot enjoy this
luxury (I believe he used the word "interesting" rather than
reasonably complex). If your collection of information is factual, it
cannot be entirely complete. And if it is complete, it cannot be
entirely factual. In short, we will never know, we cannot ever know,
every fact that constitutes an explanation of something. A complete
book of knowledge must contain errors, and an error-free book of
knowledge must be incomplete.
There is a small warning light deep inside me that starts flashing any
time I hear someone begin to advance an explanation of some reasonably
complex phenomenon with an air of confidence that implies, "Here is
how it works." What the speaker usually has is an intense familiarity
with one particular discipline or specialty and the phenomenon is
viewed through those eyes, often with the assurance that looking at it
that way, intently enough and long enough, will reveal the complete
explanation. And be attentive to the phrase, "We are not yet
com-pletely sure of exactly how it works." What is really meant is,
"We haven't the slightest idea of how it really works."
I must admit to some guilt in this matter, certainly as much as the
next person. I am a chemist and I suspect that the way that the
psychedelic drugs do their thing can eventually be understood through
a comparison of the structures of the molecules that are active and
those that are inactive. I put those that have methoxyl groups in
pigeon hole #1, and those that are bicyclic into pigeon hole #2. And
then, if pigeon hole #2 becomes more and more cluttered, I will
subdivide the contents into pigeon hole #2A for bicyclics with
heteroatoms and pigeon hole #2B for bicyclics without heteroatoms.
The more information I can accumulate, the more pigeon holes I need.
But in the adjoining lab, there is a molecular biologist who feels
that the eventual explanation for the action of the psychedelic drug
will come from the analysis and understanding of the intimate geometry
of the places in the brain where they act. These classification
pigeon holes are called receptor sites. But they, too, can become
more and more subdivided as they become cluttered. One reads of a new
sub-sub type quite regularly in the literature. The favorite
neurotransmitter of the moment, as far as the current thinking of how
these marvelous drugs work, is serotonin, or 5-HT (for
5-hydroxytryptamine). There are 5-HT1 and 5-HT2A and 5-HT2B and (for
all I know right now) 5-HT2C and 5-HT2D receptors, and I don't really
think that either he or I have come much closer to understanding the
mechanism of action.
And, since the mind is a reasonably complex system, Gödel has already
informed us both that neither of us will be completely successful.
Sometimes I feel that the pigeon hole approach to the classification
of knowledge might actually limit our views of the problem. A Harvard
Professor of Medicine recently noted: RWe must recognize for what it
is, man's predilection for dividing things into tidy categories,
irrespective of whether clarity is gained or lost thereby.
No. No one will ever have it all together. It is like sitting down
in front of a jigsaw with a zillion zillion pieces spread all over the
kitchen table. With diligent searching you will occasionally find a
piece that matches another, but it rarely provides any insight into
the final picture. That will remain a mystery, unless you had the
chance to see the cover of the box in some other incarnation. But Oh
my, what fun it is, whenever you do happen to find a new piece that
fits!
This harangue is really a lengthy prelude to the story of putting an
ethoxy group in place of a methoxy on the 2,5-dimethoxy skeleton of
these psychedelic families. The making of IRIS was the first move in
this direction, done back in 1976. One can have a pigeon hole that is
named "Ethoxy In Place of Methoxy" and toss in there the names of
perhaps twenty pairs of compounds, which differ from one another by
just this feature. Yet when they are looked at from the potency point
of view, there are some which show a decrease in potency (which is the
case with IRIS and most of the Tweetios) and there are some which seem
to maintain their potency (such as the TMA-2/MEM pair) and there are
some where there is a distinct potency increase (the
mescaline/escaline pair, for example).
What does one do to clarify the contents of this particular pigeon
hole? The current fad would be to subdivide it into three
subdivisions, maybe something like "Ethoxy in Place of Methoxy if 2-
or 5-located" and "Ethoxy in Place of Methoxy if 4-located and other
things 2,5" and "Ethoxy in Place of Methoxy if 4-located, and other
things 3,5." The end point that soon becomes apparent, down the line,
will be to have as many pigeon holes as compounds! And at the moment,
this particular piece of the jigsaw puzzle doesn't seem to fit
anywhere at all.
Perhaps both my neighboring molecular biologist and I are asking the
wrong questions. I am looking at the molecules and asking, "What are
they?" And he is following them and asking, "Where do they go?" And
neither of us is fully attentive to the question, "What do they do?"
It is so easy to replace the word "mind," in our inquiries, with the
word "brain."
Yup. The operation of the mind can certainly be classified as a
"reasonably complex" phenomenon. I prefer Gödel's term. The mind is
without question an "interesting" phenomenon.
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