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From: sender@mit.edu
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Subject: PiHKAL: The Chemical Story. File 2 of 6
(I'm posting this for a friend.)
This is part 2 of 6 of the second half of PiHKAL: A Chemical Love
Story, by Alexander Shulgin and Ann Shulgin. Please forgive any typos
or misprints in this file; further, because of ASCII limitations,
many of the typographical symbols in the original book could not be
properly represented in these files.
If you are seriously interested in the chemistry contained in these
files, you should order a copy of the book PiHKAL. The book may be
purchased for $22.95 ($18.95 + $4.00 postage and handling) from
Transform Press, Box 13675, Berkeley, CA 94701. California residents
please add $1.38 State sales tax.
At the present time, restrictive laws are in force in the United
States and it is very difficult for researchers to abide by the
regulations which govern efforts to obtain legal approval to do work
with these compounds in human beings.... No one who is lacking legal
authorization should attempt the synthesis of any of the compounds
described in these files, with the intent to give them to man. To do
so is to risk legal action which might lead to the tragic ruination of
a life. It should also be noted that any person anywhere who
experiments on himself, or on another human being, with any of the
drugs described herin, without being familiar with that drug's action
and aware of the physical and/or mental disturbance or harm it might
cause, is acting irresponsibly and immorally, whether or not he is
doing so within the bounds of the law.
#30 2C-G-5; 3,6-DIMETHOXY-4-(2-AMINOETHYL)BENZONORBORNANE
SYNTHESIS: To a stirred solution of 25 g 3,6-dihydroxybenzonorbornane
(from Eastman Kodak Company) in 200 mL acetone there was added 200 mg
decyltriethylammonium iodide, 40 g of powdered anhydrous K2CO3, and 55
g methyl iodide. The mixture was held at reflux with a heating mantle
overnight. After re-moval of the solvent under vacuum, the residue
was added to 2 L of H2O, acidified with concentrated HCl, and
extracted with 3x100 mL CH2Cl2. The pooled extracts were washed with
2x150 mL 5% NaOH and once with dilute HCl, and the solvent was removed
under vacuum to give 19.0 g of a black oil as a residue. This was
distilled at 90-115 !C at 0.3 mm/Hg to yield 15.5 g of an orange oil
which set up as a crystalline solid. The product,
3,6-dimethoxybenzonorbornane, had a mp of 35-37 !C from hexane or
40-41 !C from MeOH. Anal. (C13H16O2) C,H.
A solution of 4.6 g POCl3 and 4.6 g N-methylformanilide was heated
briefly on the steam-bath until the color had become deep claret.
There was then added 3.05 g of 3,6-dimethoxybenzonorbornane and the
solution was heated on the steam bath for 12 h. The black, tarry
reaction mixture was poured into H2O, and after hydrolysis, the H2O
was decanted and the insoluble residues were washed alternately with
H2O and with CH2Cl2. The combined washes were separated, and the
aqueous phase extracted with 2x50 mL CH2Cl2. The combined organic
fractions were washed with 5% NaOH, and the solvent removed under
vacuum. The fluid, black residue was distilled at 130-140 !C at 0.3
mm/Hg to give 1.17 g of an almost white oil. This was dissolved in 1
mL MeOH, and cooled to -50 !C to give a white crystalline solid that
was removed by filtration and washed sparingly with -50 !C MeOH and
air dried. There was obtained 0.83 g
3,6-dimethoxy-4-formylbenzonorbornane with a mp of 37-40 !C which
could be increased, by wasteful recrystallization from MeOH, to 53-54
!C. An intimate mixture of this product with the starting diether (mp
40-41 !C) was a liquid at room temperature. Anal. (C14H16O3) C,H.
To a solution of 3.70 g 3,6-dimethoxy-4-formylbenzonorbornane in 20 g
nitromethane, there was added 1.3 g anhydrous ammonium acetate and the
mixture was heated on the steam bath for 45 min. The excess
reagent/solvent was removed under vacuum, and the residue was
dissolved in 20 mL boiling MeOH. A speck of seed crystal started a
heavy crystallization of orange crystals which were removed by
filtration and washed with MeOH. After drying, the product
3,6-dimethoxy-4-(2-nitrovinyl)benzonorbornane was yellow, weighed 3.47
g, and had a mp of 88-89 !C. Recrystallization of an analytical
sample from MeOH did not improve this mp. Anal. (C15H17NO4) C,H.
A solution of LAH (46 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath. With good stirring there was
added 1.25 mL 100% H2SO4 dropwise, to minimize charring. This was
followed by the addition of 3.4 g
3,6-dimethoxy-4-(2-nitrovinyl)benzonorbornane in 30 mL anhydrous THF.
After a few min further stirring, the temperature was brought up to a
gentle reflux on the steam bath for 10 min, and then all was cooled
again to 0 !C. The excess hydride was destroyed by the cautious
addition of 7 mL IPA, followed by 2 mL 15% NaOH and 5 mL H2O, which
gave an easily filtered white granular solid. This was removed by
filtration, and the filter cake was washed with THF. The combined
filtrate and washes were stripped of solvent under vacuum providing a
pale amber oil which was distilled at 150-160 !C at 0.3 mm/Hg to give
1.45 g of a white oil. This was dissolved in 7 mL IPA, and
neutralized with 15 drops of concentrated HCl. There was then added
25 mL anhydrous Et2O and, after a short delay, white crystals formed
spontaneously. These were removed by filtration, Et2O washed, and air
dried to constant weight, yielding 1.13 g of
3,6-dimethoxy-4-(2-aminoethyl)benzonorbornane hydrochloride (2C-G-5).
The mp was 199-200 !C. Anal. (C15H22ClNO2) C,H.
DOSAGE: 10 - 16 mg.
DURATION: 32 - 48 h.
QUALITATIVE COMMENTS: (with 14 mg) I was well aware of things at the
end of two hours, and I was totally unwilling to drive, or even go out
of the house. I was reminded continuously of 2C-B with its erotic
push, and the benign interplay of colors and other visual effects.
But it is so much longer lived. I am a full +++, very stoned, and
there is no believable sign of dropping for another several hours.
There is a good appetite (again, 2C-B like), and I managed to sleep
for a few hours, and all the next day I was spacey and probably still
a plus one. The day yet following, I was finally at a believable
baseline. Both of these days were filled with what might be called
micro doze-offs, almost like narcolepsy. Maybe I am just sleep
deprived.
(with 16 mg) The first effects were felt within one hour, and full
effects between 2 1/2 and 3 hours. Tremendous clarity of thought,
cosmic but grounded, as it were. This is not at all like LSD, and is a
lot mellower than the 2C-T family. For the next few hours it was
delightful and fun and I felt safe and good-humored. I got to sleep
without much difficulty while still at a plus three, and my dreams
were positive and balanced, but I awoke irritable and emotionally
flattened. I did not want to interact with anyone. The first 16
hours of this stuff were great, and the second 16 hours were a bit of
a drag. Just twice as long as it ought to be.
(with 16 mg) I was at full sparkle within three hours, and I
continued to sparkle for the longest time. The tiredness that comes
after a while probably reflects the inadequacy of sleep. I was aware
of something still going on some two days later.
EXTENSIONS AND COMMENTARY: In the eventual potency assessment of a
drug, there must be some consideration of not only the dosage needed,
but the duration of effects. The area under the curve, so to speak.
By these measures, this phenethylamine is a record breaker, in that it
is not only amongst the most potent, but it goes on and on and on.
There are a couple of chemical commentaries. One, the miserable
phenol-to-ether-to-aldehyde series of steps, so maddeningly
unsatisfactory in the 2C-G-4 process, was completely comfortable here.
The reactions rolled, and the yields were most satisfactory.
Secondly, this is one of the few phenethylamines that is a racemate.
The strange geometry of the norbornane ring carries within it a chiral
character, so this compound is potentially resolvable into two
optically active forms. That might be quite a task, but it would have
the value of providing for the first time a pair of isomers that were
asymmetric in the 3,4-aliphatic part of the molecule. To the extent
that some insight into the geometry of the receptor site can be
gleaned from the absolute configurations of active agonists, here is a
compound where the subtle variations are over there at the ring
substitution area of the structure, rather than at the well-explored
alpha-carbon atom. Some day I might try to resolve this drug into its
optical isomers. But I suspect that it might be quite difficult.
A number of chemical variations of 2C-G-5 are obvious. The
dihydroxybenzonorbornane compound that was the starting point of all
this was certainly the adduct of cyclopentadiene and benzoquinone,
with the double bond reduced. The same chemistry with
1,3-cyclohexadiene would give a two-carbon bridge instead of the
one-carbon bridge of norbornane and, after hydrogenation, would
provide a non-chiral analog with two ethylene bridges between the 3-
and 4-position carbons. This is a cyclohexane ring connected, by its
1- and 4-positions, to the two methyl groups of 2C-G. With six
carbons in this aliphatic mess, the compound is probably best called
2C-G-6. It should be easily made, and it is certain to be very
potent. And there are potentially several other Diels Alder dienes
that might serve with benzoquinone as the dieneophile. There are
aliphatic things such as hexa-2,4-diene and 2,3-dimethylbutadiene.
The textbooks are filled with dozens of diene candidates, and
benzquinone will always provide the two oxygens needed for the
eventual 2,5-dimethoxy groups of the phenethylamine.
#31 2C-G-N; 1,4-DIMETHOXYNAPHTHYL-2-ETHYLAMINE
SYNTHESIS: A solution of 17.5 g 1,4-naphthaquinone in 200 mL MeOH was
heated to the boiling point, and treated with 28.5 g stannous chloride
at a rate that maintained a continuous rolling boil. At the
completion of the addition, the reaction mixture was saturated with
anhydrous hydrogen chloride, and held at reflux on the steam bath for
2 h. The reaction mixture was poured into 700 mL H2O and treated with
aqueous NaOH. During the addition there was transient development of
a curdy white solid which redissolved when the system became strongly
basic. This was extracted with 3x200 mL CH2Cl2 and the pooled
extracts were washed first with H2O, then with dilute HCl, and finally
again with H2O. Removal of the solvent under vacuum yielded 15.75 g
of a low melting black flaky crystalline material which was distilled
at 160-180 !C at 0.05 mm/Hg to give 14.5 g of an amber, solid mass
with a mp of 78-86 !C. Recrystallization from 75 mL boiling MeOH
provided 1,4-dimethoxynaphthalene as white crystals melting at 87-88
!C.
A mixture of 20.0 g POCl3 and 22.5 g N-methylformanilide was allowed
to stand at room temperature for 0.5 h which produced a deep claret
color. To this there was added 9.4 g 1,4-dimethoxynaphthalene and the
mixture was heated on the steam bath. The reaction mixture quickly
became progressively darker and thicker. After 20 min it was poured
into 250 mL H2O and stirred for several h. The solids were removed by
filtration, and washed well with H2O. The wet crude product (a dull
yellow-orange color) was dissolved in 125 mL boiling EtOH to give a
deep red solution. On cooling, this deposited a heavy crop of
crystals that was removed by filtration, and washed with cold EtOH.
There was obtained, after air-drying to constant weight, 7.9 g
1,4-dimethoxy-2-naphthaldehyde as white crystals with a mp of 119-121
!C. This was not improved by further recrystallization. The
malononitrile derivative, from the aldehyde and malononitrile in EtOH
with a drop of triethylamine, had a mp of 187-188 !C.
A solution of 3.9 g 1,4-dimethoxy-2-naphthaldehyde in 13.5 g
nitromethane was treated with 0.7 g anhydrous ammonium acetate, and
heated on the steam bath for 1 h. The excess reagent/solvent was
removed under vacuum giving a residue that spontaneously crystallized.
This crude product was removed with the aid of a few mL MeOH, and
pressed on a sintered funnel with modest MeOH washing. There was
obtained 3.6 g (when dry) of old-gold colored crystals with a mp of
146-148 !C. Recrystallization from 140 mL boiling EtOH gave 3.0 g
1,4-dimethoxy-2-(2-nitro-vinyl)naphthalene as deep gold-colored
crystals with a mp of 146-147 !C. A small sample, upon
recrystalization from MeOH, melted at 143-144 !C. Anal. (C14H13NO4)
C,H.
A solution of LAH (50 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath. With good stirring there was
added 1.32 mL 100% H2SO4 dropwise, to minimize charring. This was
followed by the addition of 2.80 g
1,4-dimethoxy-2-(2-nitrovinyl)naphthalene in 40 mL anhydrous THF.
There was an immediate loss of color. After 1 h stirring at 0 !C, the
temperature was brought up to a gentle reflux on the steam bath for 20
min, then all was cooled again to 0 !C. The excess hydride was
destroyed by the cautious addition of 7 mL IPA followed by 5.5 mL 5%
NaOH. The reaction mixture was filtered, and the filter cake washed
with several portions of THF. The combined filtrate and washings were
stripped of solvent under vacuum providing 3.6 g of a pale amber oil
that was distilled at 145-160 !C at 0.2 mm/Hg to give 1.25 g of
product as an absolutely white oil. This was dissolved in 7 mL IPA,
and neutralized with concentrated HCl forming immediate crystals of
the hydrochloride salt in the alcohol solvent. Thirty mL of anhydrous
Et2O was added, and after complete grinding and mixing, the
hydrochloride salt was removed by filtration, Et2O washed, and air
dried to constant weight. The spectacular white crystals of
1,4-dimethoxynaphthyl-2-ethylamine hydrochloride (2C-G-N) weighed 1.23
g and had melting properties of darkening at 190 !C, and decomposing
in the 235-245 !C area. Anal. (C14H18ClNO2) C,H.
DOSAGE: 20 - 40 mg.
DURATION: 20 - 30 h.
QUALITATIVE COMMENTS: (with 24 mg) The effects were interestingly
colored by the reading of Alan WattsU Joyous Cosmology during the
coming-on period. The only body negatives were some urinary retention
and a feeling of a shallow but continuing amphetamine stimulation.
But not enough to be actually jingly, nor to interfere with sleep that
evening. There is not much psychedelic here, but there is something
really going on anyway. This has some similarities to the
antidepressant world.
(with 35 mg) Much writing, much talking, and there was considerable
residual awareness the next day. Somehow this material is not as
friendly as the other 2C-GUs.
(with 35 mg) Thinking is clear. No fuzziness, no feeling of being
pushed. None of the walking on the fine middle line between light and
dark that is the excitement and the threat of LSD. This is just a
friend, an ally, which invites you to do anything you wish to.
[comment added two days later] RMy sleep was not deep enough, but it
was pleasant and relatively resting. The whole next day I was feeling
happy, but with an overlay of irritability. Strange mixture. By
bedtime the irritability had become a mild depression. I feel that
there might have been a threshold continuing for a couple of days.
The character of my dreaming had the stamp of drug on it. This
compound, in retrospect, presents some problems that cause a faint
unease.
EXTENSIONS AND COMMENTARY: There is always a wish in the design of new
compounds to find something that is of interesting activity, with an
aromatic ring at some location pretty much away from the site of
activity. This would then allow some subtle fine-tuning of the nature
of the action by putting any of a wide range of electron pushing or
electron pulling groups on that ring. But here, with 2C-G-N, by the
time the ring got put into place, the activity was already on the
wane, and the action was too long, and there are indicators of some
not completely friendly effects. Ah well, some other molecule, some
other time.
#32 2C-H; 2,5-DIMETHOXYPHENETHYLAMINE
SYNTHESIS: A solution of 50 g 2,5-dimethoxybenzaldehyde in 100 g
nitromethane was treated with 5 g of anhydrous ammonium acetate, and
heated on the steam bath for 4 h. The solution was decanted from a
little insoluble material, and the solvent removed under vacuum. The
clear oily residue was dissolved in 100 mL boiling IPA which, after
standing a moment, set up as dense crystals. After returning to room
temperature, these were removed by filtration, the product was washed
with IPA and air dried, yielding 56.9 g 2,5-dimethoxy-'-nitrostyrene
as spectacular yum-yum orange crystals with a mp of 119-120 !C. An
analytical sample, from ethyl acetate, melted at 120-121 !C.
A suspension of 60 g LAH in 500 mL anhydrous THF was placed under an
inert atmosphere, stirred magnetically, and brought up to reflux
temperature. There was added, dropwise, 56 g of
2,5-dimethoxy-'-nitrostyrene dissolved in THF, and the reaction
mixture was maintained at reflux for 36 h. After being brought to
room tem-perature, the excess hydride was destroyed with 40 mL IPA,
followed by 50 mL of 15% NaOH. An additional 100 mL THF was required
for easy stirring, and an additional 150 mL H2O was needed for
complete conversion of the aluminum salts to a loose, white,
filterable consistency. This solid was removed by filtration, and the
filter cake washed with additional THF. The combined filtrate and
washes were stripped of solvent under vacuum, and the residue
dissolved in dilute H2SO4. Washing with 3x75 mL CH2Cl2 removed most
of the color, and the aqueous phase was made basic with aqueous NaOH
and reextracted with 3x100 mL CH2Cl2. Removal of the solvent yielded
39.2 g of a pale amber oil that was distilled. The fraction boiling
at 80-100 !C at 0.4 mm/Hg weighed 24.8 g and was water-white product
amine. As the free base, it was suitable for most of the further
synthetic steps that might be wanted, but in this form it picked up
carbon dioxide rapidly when exposed to the air. It was readily
converted to the hydrochloride salt by dissolution in 6 volumes of
IPA, neutralization with concentrated HCl, and addition of sufficient
anhydrous Et2O to produce a permanent turbidity. Crystals of
2,5-dimethoxyphenethylamine hydrochloride (2C-H) spontaneously formed
and were removed by filtration, washed with Et2O, and air dried. The
mp was 138-139 !C.
DOSAGE: unknown.
DURATION: unknown.
EXTENSIONS AND COMMENTARY: I know of no record of 2C-H ever having
been tried by man. It has been assumed by everyone (and probably
correctly so) that this amine, being an excellent substrate for the
amino oxidase systems in man, will be completely destroyed by the body
as soon as it gets into it, and thus be without action. In virtually
all animal assays where it has been compared with known psychoactive
drugs, it remains at the Rless-activeS end of the ranking.
It is, however, one of the most magnificent launching pads for a
number of rather unusual and, in a couple of cases, extraordinary
drugs. In the lingo of the chemist, it is amenable to Relectrophilic
attack at the 4-position.S And, in the lingo of the
psychopharmacologist, the R4-position is where the action is.S From
this (presumably) inactive thing have evolved end products such as
2C-B, 2C-I, 2C-C, and 2C-N. And in the future, many possible things
as might come from a carbinol group, an amine function, or anything
that can stem from a lithium atom.
#33 2C-I; 2,5-DIMETHOXY-4-IODOPHENETHYLAMINE
SYNTHESIS: A mixture of 7.4 g phthalic anhydride and 9.05 g of
2,5-dimethoxyphenethylamine (see the recipe for 2C-H for its
preparation) was heated with an open flame. A single clear phase was
formed with the loss of H2O. After the hot melt remained quiet for a
few moments, it was poured out into a crystallizing dish yielding 14.8
g of a crude solid product. This was recrystallized from 20 mL CH3CN,
with care taken for an endothermic dissolution, and an exothermic
crystallization. Both transitions must be done without haste. After
filtration, the solids were washed with 2x20 mL hexane and air dried
to constant weight. A yield of 12.93 g of
N-(2-(2,5-dimethoxyphenyl)ethyl)phthalimide was obtained as
electrostatic yellow crystals, with a mp of 109-111 !C. A sample
recrystallized from IPA was white, with a mp of 110-111 !C. Anal.
(C18H17NO4) C,H,N.
To a solution of 12.9 g N-(2-(2,5-dimethoxyphenyl)ethyl)phthalimide in
130 mL warm (35 !C) acetic acid which was being vigorously stirred,
there was added a solution of 10 g iodine monochloride in 40 mL acetic
acid. This was stirred for 1 h, while being held at about 30 !C. The
reaction mixture was poured into 1500 mL H2O and extracted with 4x75
mL CH2Cl2. The extracts were pooled, washed once with 150 mL H2O
containing 2.0 g sodium dithionite, and the solvent removed under
vacuum to give 16.2 g of
N-(2-(2,5-dimethoxy-4-iodophenyl)ethyl)phthalimide as yellow amber
solids with a mp of 133-141 !C. This mp was improved by
recrystallization from 75 mL CH3CN, yielding 12.2 g of a pale yellow
solid with mp 149-151 !C. A small sample from a large quantity of IPA
gives a white product melting at 155.5-157 !C.
A solution of 12.2 g
N-(2-(2,5-dimethoxy-4-iodophenyl)ethyl)phthalimide in 150 mL hot IPA
was treated with 6.0 mL of hydrazine hydrate, and the clear solution
was heated on the steam bath. After a few minutes there was the
generation of a white cottage cheese-like solid
(1,4-dihydroxyphthalizine). The heating was continued for several
additional h, the reaction mixture cooled, and the solids removed by
filtration. These were washed with 2x10 mL EtOH, and the pooled
filtrate and washes stripped of solvent under vacuum giving a residue
which, when treated with aqueous hydrochloric acid, gave 3.43 g of
voluminous white crystals. This, after recrystallization from 2
weights of H2O, filtering, washing first with IPA and then with Et2O,
and air drying, gave 2.16 g 2,5-dimethoxy-4-iodophenethylamine
hydrochloride (2C-I) as a white microcrystalline solid, with a mp of
246-247 !C. Anal. (C10H15ClINO2) C,H,N.
DOSAGE: 14 - 22 mg.
DURATION: 6 - 10 h.
QUALITATIVE COMMENTS (with 0 mg) I was present at a group meeting,
but was only an observer. With zero milligrams of 2C-I, I was able to
get to a delightful plus 2.5 in about five minutes after I arrived at
your place, and absorbed the ambience of the folks who had actually
imbibed the material. My level lasted about four hours and came down
at about the same time as did the others. There were no after-effects
experienced except for a pleasant languor.
(with 15 mg) Comfortable onset. Most notable are the visuals,
patterning like 2C-B (Persian carpet type), very colorful and active.
Much more balanced emotional character, but still no feeling of
insight, revelation, or progress toward the true meaning of the
universe. And at 5 1/2 hours drop-off very abrupt, then gentle
decline. I would like to investigate museum levels.
(with 16 mg) There was an immediate alert within minutes. As usual,
it was only an awareness, then nothing happened for a while. In
retrospect, I see some type of activity or awareness within 40
minutes, which then builds up over time. The peak was at 2 hours and
seemed to maintain itself for a while. Near the peak, there was some
hallucinogenic activity, though not a lot. The pictures in the dining
room had color and pattern movement that was fairly detailed.
Focusing on other areas, such as walls or the outside of the house,
produced little activity, though I tried. There was certainly a lot
of color enhancement. There was also that peculiar aspect of the
visual field having darkened or shadowed areas. These darker areas
seemed to shift around to some degree. That aspect seems to be
similar to 2C-B. I donUt think I was more than +2.5 at the peak.
Coming down was uneventful. I was down within 6 hours. I had no
problems driving home, nor were there any difficulties with sleep.
There were no body problems with this material. I ate like a horse.
(with 16 mg) The 16 was a bit much, I realized, because my body was
not sure of what to do with all the energy. Next time IUll try 14 or
15. However, my conversations were extremely clear and insightful.
The degree of honesty was incredible. I was not afraid to say
anything to anyone. Felt really good about myself. Very centered, in
fact. A bit tired at day's end. Early bedtime.
(with 20 mg) I think there is slightly less than full immersion in
the sensual, with this material, compared with 2C-B, but I suspect
it's more a matter of getting used to the language of 2C-I and the
feelings Q getting tuned to a slightly different frequency, really Q
rather than that the material is less sensual or less easy to use
sensually. Just different frequency, and we are very, very used to
2C-B. Good on the body. Transition, for me, not as strongly dark as
2C-B. But it could certainly take a lot more exploring, if we were
able to give the time (about 9 hours) to it. Next day: sleep
excellent. Energy next day unusually good. Quite tired by evening.
EXTENSIONS AND COMMENTARY: The frequent comparisons between 2C-I and
2C-B stem, without doubt, from a bit of chemical suggestion. The two
compounds have structures that are truly analogous, in technical
terms. In one, there is a strategically located iodine atom, and in
the other, an identically placed bromine atom. These are directly
above and below one-another in the periodic table. And what is
particularly maddening to the synthetic diddler, is that they cannot
be lengthened, or shortened, or squooshed around in any way. You
canUt make a longer and narrower version of a bromine atom, as you can
do with, say, a butyl group. YouUve got what youUve got, like it or
not. No subtle variations.
But, on the brighter side of the picture, you have a heavy atom here,
and this atom is intrinsic to the central activity of the compound.
So, these materials are naturals for radio-labelling experiments.
2C-I has been made radioactive with radio-iodine, but the most
impressive findings have been made with the 3-carbon analog, DOI.
One quotation from an observer of a group experiment is enclosed; an
experiment with zero milligrams being taken. This is a instructive
observation of what has been called a Rcontact high.
There is one Iodotweetio known. In Scrabble, would you challenge a
word that had seven of its eleven letters as vowels? Especially if
the vowels were, specifically, iooeeio? It sounds just a little like
the noise coming out of Old McDonald's farm. But a Tweetio there is,
namely, the 2-EtO-homologue of 2C-I. This is
2-ethoxy-4-iodo-5-methoxyphenethylamine, or 2CI-2ETO. The
hydrochloride salt was a white, crystalline product with a melting
point of 175-175.5 !C. The threshold level of activity was seen at an
oral dose of 5 milligrams, and the generated effects were completely
dispersed in a couple of hours. Most interestingly, larger doses, of
up to 50 milligrams orally, seem to produce no more intense an effect,
but simply to stretch out this threshold for an additional couple of
hours. At no level that has been tried, has 2CI-2EtO produced even a
plus-two response.
Where else can one go, from 2C-I? The iodine is the fourth, and the
last of the so-called halogens, at the bottom of the classical
periodic table. But, thanks to the miracles that have accompanied us
into the nuclear age, there is a fifth halide now known, Astatine.
All of its isotopes are radioactive, however, and it seems unlikely
that there will ever be an entry (other than this one) for
2,5-dimethoxy-4-astatophenethylamine. What might be speculated as to
its activity? Probably similar in potency to 2C-I, requiring maybe 10
or 20 milligrams. The duration would be dicey to measure, since the
isotope with the longest known half-life is half decayed in about 8
hours, and the longest lived natural isotope (for those who insist on
natural rather than man-made things) is half decayed in less than a
minute. Two predictions would be pretty solid. You might have quite
a job accumulating your 10 milligrams of Astatine, as the most that
has so far been made at one time is only about 0.05 micrograms,
approximately a millionth of the amount needed. And the second
prediction? You would not survive the screaming radiation that would
bombard you if you could get the needed 5 or 10 milligrams of
radio-astatine onto that magic 4-position, and the resulting 2C-A into
your tummy!
#34 2C-N; 2,5-DIMETHOXY-4-NITROPHENETHYLAMINE
SYNTHESIS: A cooled, stirred solution of 1.0 g
2,5-dimethoxyphenethylamine (see the recipe for 2C-H for its
preparation) in 20 mL glacial acetic acid was treated with 3.3 mL 70%
HNO3 in small portions, with the reaction temperature kept down with
periodic cooling. After the addition was completed, the stirring was
continued until there was the spontaneous separation of a yellow
solid. This was 2,5-dimethoxy-4-nitrophenethylamine nitrate (2C-N)
which was obtained after removal by filtration, washing with Et2O and
air drying, as a fluffy yellow solid. This weighed 1.04 g and melted,
with decomposition, in the area of 170-180 !C, depending on the rate
of heating. A solution of 0.8 g of this nitrate salt in 50 mL H2O was
made basic with aqueous NaOH. Extraction with 3x50 mL CH2Cl2, and
removal of the solvent under vacuum gave the free base as a residue.
This was distilled at 130-150 !C at 0.35 mm/Hg to give an orange-red
oil that weighed 0.5 g and set up as crystals. This was dissolved in
3 mL IPA, neutralized with 7 drops of concentrated HCl (the color
lightened considerably at the titration end point) and diluted with 5
mL anhydrous Et2O. There was the formation of the hydrochloride salt
which was a pumpkin-colored crystalline mass. After removal by
filtration, Et2O washing and air drying, these crystals weighed 0.44
g. The mp, 193-195 !C, was not improved by recrystallization from any
of several solvents (MeOH, IPA, CH3CN). The perchlorate salt was a
yellow solid from MeOH, with a mp of 211 !C, with decomposition.
Nitration of 2C-H in a mixture of acetic acid and acetic anhydride
produced the acetamide derivative of 2C-N as yellow crystals with a mp
142.5-143 !C. For the nitrate salt: Anal. (C10H15N3O7) C,H. This was
the form used for all human titrations.
DOSAGE: 100 - 150 mg.
DURATION: 4 - 6 h.
QUALITATIVE COMMENTS: (with 120 mg) This came on very fast Q I was
aware of it within a half hour, and it got as far as it would go by an
hour. There are similarities to MDMA, but missing is the benign
anti-stress component. I am light-headed, and there just might be a
little eye wiggling. And then it dropped right off to nothing within
a couple of hours.
(with 150 mg) There may have been some visual changes, IUm not sure.
But the talking was extremely easy. If there were no other things to
use, this would be excellent, but there are other compounds available.
This doesnUt have too high a priority.
(with 150 mg) Am I enjoying it? Not exactly, but I am in a good
mood. There is not the light-filled energy that some other materials
can provide. By six hours, pretty much baseline. Strange material,
but okay. Final score: body +3, mind +2, barely.
EXTENSIONS AND COMMENTARY: A most consistent feature with 2C-N was the
fact that in every report, somewhere, there is the note that it
somehow came up just a little short of expectations. From the
esthetic point of view, the pure salt is yellow rather than the usual
white color, so the solutions that are to be consumed are by
definition also yellow colored. From the structural point of view,
the 4-nitro group, like the 4-bromo group of 2C-B, is a dead-end. It
cannot be stretched or compressed or lengthened or shortened. This
unique aspect demands that you have to live with what you have, as
there are no subtle ways of modifying the molecule. With 2C-B, the
end product was a total winner; there was no wish to modify it. With
2C-N the end product is something a little less, and there is no way
to modify it.
#35 2C-O-4; 2,5-DIMETHOXY-4-(i)-PROPOXYPHENETHYLAMINE
SYNTHESIS: To a solution of 3.10 g 85% KOH pellets in 30 mL warm MeOH
there was added 6.16 g 2,5-dimethoxyphenol (there was immediate
darkening) followed by 8.5 g isopropyl iodide. The reaction mixture
was heated on the steam bath for 3.5 h. White crystals of KI appeared
at the end of the first h. The mixture was poured into 800 mL H2O (it
was still basic) and acidified with HCl. This was extracted with
3x100 mL CH2Cl2, and the combined extracts washed with 2x100 mL 5%
NaOH. The organic phase was stripped of solvent under vacuum, and the
residual dark amber oil (6.4 g) distilled at 110-130 !C at 0.7 mm/Hg.
There was obtained 5.7 g of 1,4-dimethoxy-2-(i)-propoxybenzene as a
white oil.
A mixture of 10 g N-methylformanilide and 10 g POCl3 was heated on the
steam bath for 10 min producing a deep claret color. To this there
was added 5.1 g of 1,4-dimethoxy-2-(i)-propoxybenzene, and the
immediately exothermic reaction mixture was heated on the steam bath
for 45 min. It was then poured into 800 mL H2O which was stirred
until the dark oil changed into loose, light-colored solids. These
were removed by filtration giving 5.7 g of an amber crystalline
product with a mp of 76-78 !C. This was dissolved in an equal weight
of MeOH, and heated to a solution which was clear at the boiling
point. This was brought to 0 !C and held there for several hours,
yielding 2,5-dimethoxy-4-(i)-propoxybenzaldehyde as a fine, off-white
crystalline product which, after filtering and air drying, weighed
4.03 g. The mp was 79-80 !C with prior shrinking at 71 !C. Anal.
(C12H16O4) C,H.
A solution of 3.9 g 2,5-dimethoxy-4-(i)-propoxybenzaldehyde in 20 g
nitromethane was treated with 0.17 g anhydrous ammonium acetate and
heated on the steam bath for 1.25 h. The progress of the condensation
was readily followed by a TLC analysis of the reaction mixture. With
silica gel plates, the starting aldehyde and the product nitrostyrene
had Rf's of 0.16 and 0.50 resp., using CH2Cl2 as a developing solvent.
The excess solvent was removed under vacuum to give a red residue that
was dissolved in 10 mL boiling MeOH. The solution spontaneously
crystallized giving, after filteration and air drying, 4.1 g of orange
crystals of 2,5-dimethoxy-'-nitro-4-(i)-propoxystyrene.
A solution of LAH (60 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath. With good stirring there was
added 1.60 mL 100% H2SO4 dropwise, to minimize charring. This was
followed by the addition of 4.0 g
2,5-dimethoxy-'-nitro-4-(i)-propoxystyrene as a solid, perhaps 200 mg
at a time. There was an immediate loss of color after each addition.
The final pale salmon-colored solution was stirred for 2 h as it
returned to room temperature. The excess hydride was destroyed by the
cautious addition of 8 mL IPA, which was followed by 5 mL 15% NaOH
followed, in turn, by sufficient additional THF to make the suspension
of inorganic salts loose and filterable. The reaction mixture was
filtered, and the filter cake washed with additional THF. The
filtrate and washings were combined and stripped of solvent under
vacuum providing 4.6 g of a pale amber oil. This was dissolved in
dilute H2SO4, washed with 2x50 mL CH2Cl2, made basic with aqueous
NaOH, and extracted with 3x50 mL CH2Cl2. Removal of the solvent under
vacuum yielded 2.3 g of residue which was distilled at 115-125 !C at
0.3 mm/Hg to give 0.94 g of a clear white oil. This was dissolved in
5 mL IPA, neutralized with 12 drops of concentrated HCl, and diluted
with 10 mL anhydrous Et2O. White crystals of
2,5-dimethoxy-4-(i)-propoxyphenethylamine hydrochloride (2C-O-4)
separated, and were removed by filtration, Et2O washed, and air dried.
The final weight was 0.58 g.
DOSAGE: greater than 60 mg.
DURATION: unknown
QUALITATIVE COMMENTS: (with 60 mg) I became aware of something in the
front part of my head, and there was a lot of yawning. The body was
aware of the experiment. But also there was a general exhilaration
and excitement, which lasted for a few hours. At best, I am at a plus
one.
EXTENSIONS AND COMMENTARY: The full activity of 2C-O-4 is yet to be
discovered. It represents an interesting hybrid lying in between
several fascinating compounds.
First and foremost, all these carry the 2,4,5-trisubstitution which
has consistently proven to be the most interesting and the most active
of the phenethylamines. And with very few exceptions, the 2- and the
5- are methoxyl groups.
The sulfur analogues in this area, compounds with an alkylthio group
at the 4-position of the 2,5-dimethoxyphenethylamine backbone, are the
2C-T things. The replacement of a sulfur with an oxygen, quite
rightly, should give rise to the 2C-O counterparts. And they have
been given the same numbering system that was bestowed upon the RTS
series. 2C-T-4 was the 4-isopropylthio compound and one of the most
interesting of this family. And so, quite reasonably, the oxygen
coun-terpart should be the 2C-O-4 analogue, and should be one of the
first explored.
The extension of the 4-alkoxy-group led to the discovery of the TMA-2
Q MEM Q MIPM Q MPM Q MBM series of amphetamine analogues. The
2-carbon counterparts of these would be a fascinating series to
explore, I thought, if there was some encouragement to be had from a
preliminary try in this field.
This was a first shot in the dark, the actual trial example, and it
certainly didnUt provide much encouragement. The three-carbon
analogue, MIPM, was made (q.v.) but not explored, following the
disappointing trials of MPM. If this area is ever re-opened, the
numbering should reasonably follow the sulfur materials. The 4-ethoxy
material would be 2C-O-2, the 4-(n)-propoxy compound 2C-O-7, and the
4-(n)-butoxy compound 2C-O-19. These are the exact analogues of
2C-T-2, 2C-T-7, and 2C-T-19, resp., and the 2-carbon homologues of
MEM, MPM, and MBM. The simplest member of this series, the methyl
counterpart, is 2C-O, and it is the obvious analogue of 2C-T. This is
also called 2,4,5-TMPEA, and its story is presented elsewhere.
But, with the probable low eventual potency of 2C-O-4, I feel that the
2C-O series will not be an exciting one.
#36 2C-P; 2,5-DIMETHOXY-4-(n)-PROPYLPHENETHYLAMINE
SYNTHESIS: To a stirred solution of 138 g p-dimethoxybenzene in 400 mL
CH2Cl2 there was added a suspension of 172 g anhydrous AlCl3 in 500 mL
CH2Cl2 which contained 92.5 g propionyl chloride. After stirring for
1.5 h the reaction mixture was poured into 2 L H2O containing ice.
The phases were separated, and the aqueous fraction was extracted with
2x100 mL CH2Cl2. The organic phase and the extracts were pooled,
washed once with H2O, and then with 2x100 mL 5% NaOH. The solvent
from the organic phase was removed under vacuum, yielding a deeply
colored residue. This was distilled at 150-165 !C at 20 mm/Hg
yielding 170 g of 2,5-dimethoxypropiophenone as a pale amber-colored
oil. Acidification of the sodium hydroxide extract, extraction with
CH2Cl2, and evaporation of the solvent, yielded 3 g of an oil that
slowly crystallized. These solids, on recrystallization from MeOH,
provided 1.0 g of 2-hydroxy-5-methoxypropiophenone with a mp of 47-48
!C. The same Friedel Crafts reaction, conducted on the same scale in
CS2 rather than in CH2Cl2, required reduced temperature (5 !C) and a
24 h reaction period. This solvent variation, with the same workup
and isolation, gave 76 g of 2,5-dimethoxypropiophenone as a pale amber
oil boiling at 130-137 !C at 4 mm/Hg.
A total of 150 g mossy zinc was amalgamated by treatment with a
solution of 15 g mercuric chloride in 1 L H2O. After swirling for 0.5
h, the H2O phase was removed by decantation and the zinc added to a 1
L three neck flask. To this there was added 20 mL H2O and 20 mL
concentrated HCl, followed by 20 g of 2,5-di-methoxypropiophenone
dissolved in 50 mL EtOH. This mixture was held at reflux with a
heating mantle overnight, with the occasional addition of HCl as
needed to maintain acidic conditions. After cooling to room
temperature, the residual solids were removed by filtration, and the
filtrate extracted once with 100 mL CH2Cl2 (this was the upper phase).
Sufficient H2O was then added to allow extraction with 2x100 mL
additional CH2Cl2 with the organic solvent being the lower phase. The
combined organic extracts were washed twice with 5% NaOH, followed by
one washing with dilute acid. Removal of the solvent under vacuum
yielded 18 g of a dark brown oil that was distilled at the water pump
to yield 7.2 g of 2,5-dimethoxypropylbenzene as a light yellow oil
boiling at 90-130 !C.
A mixture of 22 g 2,5-dimethoxypropylbenzene, 23 g POCl3 and 22 g
N-methylformanilide was heated on the steam bath for 1.5 h. The hot,
dark reaction mass was poured into 1 L H2O, which allowed the eventual
separation of 2,5-dimethoxy-4-(n)-propylbenzaldehyde as a clear yellow
oil weighting 14 g. Although the homologous 4-ethyl and 4-butyl
benzaldehydes were clean crystalline solids, this propyl homologue
remained an oil. Gas chromatographic analysis showed it to be about
90% pure, and it was used as obtained in the nitrostyrene steps with
either nitromethane (here) or nitroethane (under DOPR).
To a solution of 13 g 2,5-dimethoxy-4-(n)-propylbenzaldehyde in 100 mL
nitromethane, there was added 1.3 g anhydrous ammonium acetate and the
mixture held at reflux for 1 h. Removal of the solvent/reactant under
vacuum yielded a spontaneously crystallizing mass of orange solids
that was removed with the help of a little MeOH. After filtering and
air drying there was obtained 7.5 g
2,5-dimethoxy-'-nitro-4-(n)-propylstyrene with a mp of 118-122 !C.
Recrystallization from CH3CN gave an analytical sample with a mp
123-124 !C. Anal. (C13H17NO4) N.
In a 1 L round bottomed flask with a magnetic stirrer under a He
atmosphere there was added 120 mL 1 M LAH in tetrahydrofuran. This
stirred solution was cooled with an external ice bath, and there was
added, dropwise, 3.2 mL of 100% H2SO4, freshly made by the addition of
13.5 g 20% fuming H2SO4 to 15.0 g of ordinary 96% concentrated H2SO4.
When the addition was complete, a total of 7.2 g of dry
2,5-dimethoxy-'-nitro-4-(n)-propylstyrene was introduced as solids in
several batches, against a flow of He, over the course of 20 min. The
reaction mixture was allowed to come to room temperature, and stirred
for an additional 0.5 h, then brought to reflux for 10 min on the
steam bath. The excess hydride was destroyed with 18 mL IPA, and then
sufficient 15% NaOH was added which made the aluminum oxides
distinctly basic and of a filterable texture. The inorganics were
removed by filtration, and the filter cake washed with additional THF.
The combined filrate and washes were stripped of solvent, yielding
several g of a pale yellow oil that was suspended in a large quantity
of dilute H2SO4. The aqueous phase was filtered free of insolubles,
washed with a little CH2Cl2, and made basic with aqueous NaOH. This
was extracted with 3x40 mL CH2Cl2 and, after the removal of the
solvent under vacuum, the residual 2 g of off-white oil was distilled.
A fraction that distilled at 100-110 !C at 0.3 mm/Hg was water white,
weighed 1.59 g and spontaneously crystallized. This fraction was
dissolved in 7.5 mL warm IPA and neutralized with 0.6 mL concentrated
HCl. The spontaneous crystals of
2,5-di-methoxy-4-(n)-propylphenethylamine hydrochloride (2C-P) were
suspended in 20 mL anhydrous Et2O, filtered, Et2O washed, and air
dried. The weight was 1.65 g and the mp was 207-209 !C with prior
sintering at 183 !C., Anal. (C13H22ClNO2) N.
DOSAGE: 6 - 10 mg.
DURATION: 10 - 16 h.
QUALITATIVE COMMENTS: (with 6 mg) I was not feeling so good.
Hangover, I guess. The material was so gentle in coming on, and soon
my body became jangled. Thinking was easy. Verbalizing was easy.
Being comfortable with my body was not. My back hurt and then my legs
hurt. My lower back was in spasm. At first I did not particularly
like what this drug was doing to my body, but took a good look at it
and decided that I was the culprit. Took a good look at my drinking
so much, and decided that I didnUt need it. So much energy was going
through me I didnUt know what to do with it. The whole day was spent
in physical discomfort. Food tasted good, and we nibbled all day. My
stomach was bloated. Next day I was more or less like a zombie. I
was wiped out.
(with 8 mg) Comes on slowly, not feeling intently until into 2nd
hour. I feel slight discomfort but override it responding to music.
I take in air, directing it inside to heal uncomfortable places, open
up my clogged sinuses. Wonderful experience of clean, fresh, healing
air. Find that discomfort zone is places where I think there is
something wrong with me. I dissolve these places with the feeling IUm
OK. Like myself better and better, and find more reasons to enjoy and
appreciate myself. I find this material powerful, and an excellent
working material. Under other circumstances, would probably spend
more time working alone inside, where there were great openings, and
some of the most beautiful visuals I have seen for a long time.
Usually I do not get visuals. I like the long action. I feel that
this material worked for a good week after the experience, with
internal processes taking place, many insights, and energy running.
At times the energy was a little uncom-fortable, but could always be
quelled by taking a moment for deep relaxation or looking directly at
the internal process. I feel that much good internal work has been
done, a lot of it unconscious.
(with 9 mg) At the one hour point, I am barely off of baseline. It
is not until almost the third hour that the experience is fully
developed, and once there it is maintained for another four hours. I
was well grounded but rather diffuse. I explored writing (which went
quite well), interpretation (pictures and reading both OK) and talking
(very good). This is an excellent level, and probably near the max.
(with 12 mg) Slow and even rise. At five minutes to seven (suddenly
the clock time makes no sense at all) I am at a 3+ and feel that I
have not yet plateauUd. Erotic was excellent. Music good.
Eyes-closed imagery very different place than usual experiences.
Slow, calm, strong images from an area that has no apparent connection
with usual waking world, yet underlies all of it. A cool, wise place
which has its own rules. All emotions and feeling available, but
there is a cool perspective which informs all thinking. Talking
superb and fun, and it was possible to feel our bodies healthy and
full of determination to remain so, despite obvious faults and
self-indulgences. Could do a lot of learning with this material, but
probably not a group thing. It would lend itself too easily to
hypnotic power-games, and it would be too easy to open up the shared
consciousness level, which would be frightening to a lot of people and
bring about necessary escapes such as sickness. Excellent feeling the
next day.
EXTENSIONS AND COMMENTARY: There is certainly a broad mixture of
experiences with 2C-P but, on the whole, probably more favorable than
not. There was one report of an experience in which a single dosage
of 16 mg was clearly an overdose, with the entire experiment labeled a
physical disaster, not to be repeated. A consistent observation is
that there may not be too much latitude in dosage between that which
would be modest, or adequate, and that which would be excessive. The
need for individual titration would be most important with this
compound.
#37 CPM; CYCLOPROPYLMESCALINE;
4-CYCLOPROPYLMETHOXY-3,5-DIMETHOXYPHENETHYLAMINE
SYNTHESIS: To a solution of 2.8 g homosyringonitrile (see under E for
synthesis) in 20 ml acetone containing about 50 mg
decyltriethylammonium iodide, there was added 3.0 g cyclopropylmethyl
chloride and 5.0 g NaI. Stirring was continued during a color change
from pale yellow to blue. There was then added 2.9 g of finely
powdered anhydrous K2CO3, resulting in a beautiful turquoise color.
The mixture was held at reflux on the steam bath for 3 h, which
discharged all color. The solvent was removed under vacuum, and the
residues were added to 100 mL H2O. This solution was extracted with
3x75 mL CH2Cl2, the extracts were pooled, washed with 2x50 mL 5% NaOH,
and the organic solvent removed under vacuum. The residual oil
weighed 4.2 g, and was distilled at 140-155 !C at 0.4 mm/Hg to yield
4-cyclopropylmethoxy-3,5-dimethoxyphenylacetonitrile as a colorless
oil weighing 2.8 g which spontaneously crystallized. Its mp was
44-44.5 !C after recrystallization from MeOH/H2O. Anal. (C14H17NO3)
C,H.
A suspension of 1.3 g LAH in 65 mL anhydrous THF under He was cooled
to 0 !C with stirring, and 0.85 mL of 100% H2SO4 was slowly added.
Then, with continued stirring, a THF solution of 2.7 g of
4-cyclopropylmethoxy-3,5-dimethoxyphenylacetonitrile in 50 mL THF was
added dropwise. After the addition was complete, the mixture was
brought to a boil briefly on the steam bath, cooled, and treated with
sufficient IPA to destroy the excess hydride. Then there was added an
amount of 15% NaOH sufficient to produce a loose filterable solid form
of aluminum oxide. This was removed by filtration, and the filter
cake washed with THF. The pooled filtrate and washes were stripped of
solvent, and the residue was dissolved in dilute H2SO4, washed with
2x50 mL CH2Cl2, made basic with aqueous NaOH, and then extracted with
2x50 mL of CH2Cl2. After removal of the solvent, the residue was
distilled at 128-140 !C at 0.4 mm/Hg to yield 2.5 g of a white oil.
This was dissolved in 10 mL IPA, and treated with 30 drops of
concentrated HCl which was just sufficient to demonstrate acidity as
judged by external dampened pH paper. The addition of 25 mL anhydrous
Et2O to the stirred solution allowed, in a few minutes, the product
4-cyclopropylmethoxy-3,5-dimethoxyphenethylamine hydrochloride (CPM)
to spontaneously crystallize as a fine white solid. The yield was 1.8
g, and a second crop of 0.8 g was obtained from the IPA/Et2O mother
liquors. The mp was 172-173 !C. Anal. (C14H22ClNO3) C,H.
DOSAGE: 60 - 80 mg.
DURATION: 12 - 18 h.
QUALITATIVE COMMENTS: (with 70 mg) I was surprised at the fast
development of this drug, with the knowledge that it was a
long-laster. Twenty minutes into it I was aware of some changes, and
by the end of one and a half hours there was a complete plus three.
The most remarkable property is the eyes-closed imagery. No, not just
imagery but fantasy. It is not completely benign, but it locks into
music with an extraordinary fit. I was at one moment keenly aware of
my body touching the rug, the tactile aspects of my surroundings, and
then I would find that my world was simply my personal sphere of
reality that kept engulfing everything about me, all completely
augmented by the music. Constructed by the music. I hoped that I
wouldnUt offend anyone else around me with this growing world of mine.
Eyes open, there was not that much of note. Not much insight. Not
much in the way of visuals. By the eighth hour an effort to sleep
showed me how exposed and vunerable I was, and when I closed my eyes I
needed my guards against this fantasy world. Even at the twelth hour
there was no easy way to relax and sleep. Use higher dosages with
caution.
(with 70 mg) There is a goodly amount of eyes-closed patterning but I
found external sounds to be irritating. Voices, and even music,
seemed to be intrusive. I didnUt want to share my space with anyone.
I was reminded of mescaline, in that I kept losing the awareness of
the drug's role in my experience. Visual exaggerations are probably
right around the corner. The residual effects were too much to
ignore, but 100 milligrams of phenobarb at about the twelth hour
allowed me to lie down quietly.
(with 80 mg) A wild day of profound philosophy, with discussions of
the art of molecules, the origins of the universe, and similar weighty
trivia. Much day-dreaming in erotic areas, but by and large, it went
on a bit too long. I was tired.
EXTENSIONS AND COMMENTARY: In the literary world, the guy who is on
your side, your leader, your champion, is the protagonist and the guy
he battles, your enemy, is the antagonist. These same roles are
played in the world of pharmacology, but the names are slightly
changed. A drug which does the needed or expected thing is called the
agonist rather than protagonist, but the drug that gets in its way is
still called the antagonist.
The cyclopropylmethyl group plays an interesting role in the world of
narcotics. There are numerous examples of opiates with a methyl group
attached to a nitrogen atom which are famous for being valuable in
producing analgesia and sedation. These run the gamut from natural
alkaloids such as morphine and codeine, to synthetic variants such as
Dilaudid and Percodan. And yet, with most of these narcotics, when
the methyl on the nitrogen is removed, and a cyclopropylmethyl group
put into its place, the agonist becomes an antagonist. Oxycodone (the
active narcotic thing in Percodan) becomes Naltrexone, a drug that
will immediately snap a heroin victim out of his overdose.
Cyclopropylmescaline (CPM) is a molecule that is very simply mescaline
itself, with a methyl group removed from an oxygen atom and a
cyclopropylmethyl group put on instead. Might CPM be not only
inactive, but actually block the action of mescaline? Interesting
concept. But it turned out to be entirely wrong.
The amphetamine analog of CPM should be easily made from the
alkyl-ation of syringaldehyde with cyclopropyl chloride, followed by
conventional reaction of the resulting aldehyde with nitroethane, and
finally a reduction step. There is no reason to believe that the
resulting compound 3,5-dimethoxy-4-cyclo-propyloxyamphetamine (3C-CPM)
would be any shorter acting than CPM.
#38 2C-SE; 2,5-DIMETHOXY-4-METHYLSELENEOPHENETHYLAMINE
SYNTHESIS: A suspension of 5.65 g 1,4-dimethoxybenzene in 100 mL
petroleum ether containing 6.5 mL N,N,NU,NU-tetramethylethylenediamine
was magnetically stirred, placed in an inert atmosphere, and cooled to
0 !C with an external ice bath. There was then added 27 mL of 1.6 M
butyllithium in hexane. The solids present went into solution, and
after a few min continued stirring, a fine precipitate appeared. The
reaction was allowed to stir while coming up to room temperature.
There was then added 4.8 g dimethyl diselenide which led to an
exothermic reaction, bringing the petroleum ether up to a reflux and
showing a color change from white to yellow, to light green, to an
eventual brown, all over the course of 30 min. After 2 h additional
stirring, the reaction was quenched by pouring into dilute NaOH. The
organic phase was separated, and the aqueous phase extracted with 2x75
mL Et2O. The pooled organics were washed first with dilute NaOH, then
with dilute HCl, and then the solvent was removed under vacuum.
Distillation of the residue at 0.4 mm/Hg gave an early fraction
(75-100 !C) that solidified in the receiver and was largely unreacted
dimethoxybenzene. A pale yellow oil distilled from 100 to 120 !C
which proved to be largely 2,5-dimethoxyphenyl methyl selenide.
Microanalysis gave C = 49.86, 49.69; H = 5.32, 5.47. As C9H12SeO2
requires C = 46.76, H = 5.23, there is approximately 13%
dimethoxybenzene present (C8H10O2 requires C = 69.54, H = 7.29). This
mixture was used as such, without further purification.
A mixture of 1.25 g POCl3 and 1.1 g N-methylformanilide was warmed on
the steam bath for several min until the color had become a deep
claret. There was then added 1.5 g of the 87% pure
2,5-dimethoxyphenyl methyl selenide and the steam bath heating
continued for an additional 25 min. The very tarry reaction mixture
was poured into 100 mL H2O, producing fine yellow solids almost
immediately. These were removed by filtration and distilled at 0.2
mm/Hg. A first fraction distilling up to 100 !C was a mixture of
unreacted ethers and what appeared to be 2,5-dimethoxybenzaldehyde. A
second cut distilled at 140-150 !C, solidified to a yellow solid in
the receiver, and weighed 1.2 g. A small amount of this product (with
mp 91-96 !C) was recrystallized from MeOH to give an analytic sample
of 2,5-dimethoxy-4-(methylseleneo)benzaldehyde with a mp 88-92 !C.
All efforts to achieve a tighter melting range were unsuccessful.
Anal. (C10H12O3 Se) C,H. Although this benzaldehyde migrates normally
on a silica gel TLC plate (Rf of 0.4 employing CH2Cl2 as a solvent)
when it is once completely dried on the plate, there seems to be some
irreversible reaction with the silica, and the spot will no longer
move at all.
To a solution of 0.85 g 2,5-dimethoxy-4-(methylseleneo)benzaldehyde in
10 mL nitromethane there was added 150 mg anhydrous ammonium acetate,
and the solution was heated for 35 min on the steam bath. Removal of
the volatiles under vacuum yielded brick-red solids (1.1 g) which were
ground under a small amount of MeOH, filtered, and air dried. This
yielded 0.88 g of solid 2,5-dimethoxy-4-methylseleneo-'-nitrostyrene
with a mp of 170.5-171.5 !C. Recrystallization from IPA or from
toluene gave no improvement of mp. Anal. (C11H13NO4Se) C,H.
A solution of LAH (20 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath. With good stirring there was
added 0.53 mL 100% H2SO4 dropwise, to minimize charring. This was
followed by the addition of 0.85 g
2,5-dimethoxy-4-methylseleneo-'-nitrostyrene in 20 mL hot anhydrous
THF. There was an immediate discoloring. After a few minutes further
stirring, the temperature was brought up to a gentle reflux on the
steam bath for 0.5 h, then all was cooled again to 0 !C. The excess
hydride was destroyed by the cautious addition of IPA and, when there
was no further activity, the reaction mixture was poured into 500 mL
dilute H2SO4. This was washed with 2x100 mL CH2Cl2, and then made
basic with 5% NaOH. The milky aqueous phase was extracted with 2x100
mL CH2Cl2, and extensive centrifuging was required to obtain a clear
organic phase. Evaporation of the pooled extracts gave 1.6 g of an
oil that crystallized. This was distilled at 130-140 !C at 0.15 mm/Hg
providing 0.6 g of a white oil that set to a crystalline solid melting
at 87-89 !C. This was dissolved in 4 mL boiling IPA, neutralized with
8 drops of concentrated HCl and the formed solids further diluted with
IPA with a little anhydrous Et2O. This crystalline product was
removed by filtration, washed with Et2O, and air dried to constant
weight, yielding 2,5-dimethoxy-4-methylseleneophenethylamine
hydrochloride (2C-SE) with a mp of 240-241 !C.
DOSAGE: perhaps 100 mg.
DURATION: 6 - 8 h.
QUALITATIVE COMMENTS: (with 50 mg) My tongue feels as if I had eaten
hot food. Overall I got up to a plus 1, and found the effects to be
completely benign. I wandered about within the Graves exhibit at the
Oakland Museum but there seemed to be only minor enhancement of the
visual input.
(with 70 mg) The water solution of this material has an unspeakable
smell. But there is no lasting taste, thank heaven. This is up to a
1.5 + and probably half again would be an effective dose. The first
awareness was at 45 minutes, and the plateau lasted from 1.5 hours to
about the fourth hour. I was at certain baseline at 8 hours.
EXTENSIONS AND COMMENTARY: With an entirely new hetero atom in the
molecule (the selenium), and with clear indications that large dosages
would be needed (100 milligrams. or more), some discretion was felt
desirable. There was certainly an odd taste and an odd smell. I
remember some early biochemical work where selenium replaced sulfur in
some amino acid chemistry, and things got pretty toxic. It might be
appropriate to get some general animal toxicity data before exploring
those dosages that might get to a +++.
What doors are opened by the observation that the selenium analog of
2C-T is an active compound? The potency appears to be in the same
ball park, whether there is a sulfur atom or a selenium atom there.
From the point of view of the thing that is hung onto the hetero-atom,
the selenium, the most active (and as first approximation the most
safe) analogue would be the same ones that are the most potent with
sulfur. These would probably be the Se-ethyl, the Se-propyl, or the
Se-isopropyl, the analogs of S-ethyl, S-propyl, and S-isopropyl. If
one were to be systematic, these would be called 2C-SE-2, 2C-SE-4, and
2C-SE-7. And a very special place might be held for 2C-SE-21, the
analogue of 2C-T-21. Not only is this of high potential potency, but
it would certainly be the first time that both fluorine and selenium
are in the same centrally active drug. In fact, might not this
compound, 2C-SE, be the first compound active within the human CNS
with a selenium atom in it? It is certainly the first psychedelic
with this atom in it!
From the point of view of the hetero-atom itself, there are two more
known below selenium in the Periodic Table. Each deserves some
special comment. The next atom, directly below selenium, is
tellurium. It is more metallic, and its com-pounds have a worse smell
yet. I heard a story about a German chemist, many years ago, who was
carrying a vial of dibutyl telluride in his pocket in a passenger
coach from here to there in Germany, back at about the turn of the
century. It fell to the floor and broke. No one could remain in the
car, and no amount of decontamination could effectively make the smell
tolerable. Scratch one railway coach. But the compound, 2C-TE, would
be readily makeable. Dimethyl ditelluride is a known thing.
However, the atom below tellurium (and at the bottom of that
particular column of the Periodic Table) is the element polonium.
Here one must deal in terms of theory, as far as human activity goes,
since there are no non-radioactive isotopes of polonium. The only
readily available isotope is that with mass 210, which is also called
Radium F, and is an alpha-particle emitter. If this were ever to be
put into a living organism, and if it were to seek out and hang around
some particular site of action, that area would be thoroughly and
completely cooked by alpha-particle emission. It would be a fun
academic exercise to make 2C-PO
(2,5-dimethoxy-4-methylpoloneophenethylamine), but in no way could it
ever go into anyone. I knew an eminent physiologist named Dr. Hardin
Jones (now dead) who always argued that the continuing use of drugs
would burn out the pleasure center of the brain. It is a certainty
that 2C-PO would, quite literally, do this. If I ever made it, I
would call it HARDINAMINE in his honor.
There was an interesting observation associated with the making of
2C-SE. In the synthesis of many of the sulfur compounds (of the 2C-T
family) is was quite common to find, when there was a quantity of some
organic sulfide let go as a by-product of a reaction on a warm summer
night, a number of flies coming into the lab to pay a visit. On the
first synthesis of the starting material for 2C-SE, a quantity of
CH3SeH was let go into the environment. Within minutes, there were
two beautiful dragonflies in the lab. A coincidence certainly, but
somehow, it was a nice message to receive.
#39 2C-T ; 2,5-DIMETHOXY-4-METHYLTHIOPHENETHYLAMINE
SYNTHESIS: A solution of 149 g sodium thiosulfate in 300 mL H2O was
vigorously stirred. To this there was added, over the course of 10
min, a solution of 43.2 g benzoquinone in 200 mL acetic acid. After
an additional 1 h stirring at room temperature, all volatiles were
removed under vacuum. The residual syrup slowly set up as crystals
which, after grinding under brine, were removed by filtration and
washed with additional brine. These were dissolved in MeOH, clarified
by filtration through a Celite bed, and the clear filtrate stripped of
solvent under vacuum. The yellow, powdery sodium
2,5-hydroxyphenylthiosulfate weighed 67 g when dry. This intermediate
was dissolved in aqueous HCl (50 g in 200 mL H2O containing 400 mL
concentrated HCl), cooled with an external ice bath, and treated with
250 g zinc dust added at a rate that kept the temperature below 60 !C.
About 1.5 h were required, and caution must be taken concerning the
poisonous hydrogen sulfide that evolves. An additional 50 mL
concentrated HCl was added, and the aqueous phase decanted from the
unreacted zinc metal. This was extracted with 6x100 mL Et2O, and
these extracts were pooled, washed with brine, and the solvent removed
under vacuum to yield 33.1 g of 2,5-dihydroxythiophenol as pale yellow
needles with a mp of 118-119 !C.
A solution of 118.6 g KOH pellets in 200 mL H2O was placed under N2,
and to it was added 24.0 g 2,5-dihydroxythiophenol. With vigorous
stirring, there was then added 160 g methyl sulfate at a rate that
maintained the temperature at about 60 !C. This took about 2 h.
After the addition was complete, the mixture was held at reflux for 3
h, and allowed to stir at ambient temperature overnight. It was then
filtered, and the filtrate extracted with 6x100 mL Et2O, the extracts
pooled, washed with 2x50 mL brine, dried over anhydrous Na2SO4, and
the solvent removed under vacuum. The residue was distilled at 86-88
!C at 0.04 mm/Hg to provide 25.9 g of 2,5-dimethoxythioanisole as a
white oil that crystallized on standing. Its mp was 33-34 !C. An
alternate preparation of this compound follows the direct methylation
of 2,5-dimethoxythiophenol (see under 2C-T-2 for the preparation of
this common intermediate) with methyl iodide.
To 40 mL dry CH2Cl2 there was added 6.07 g 2,5-dimethoxythioanisole,
and this was cooled to 0 !C under N2. To this well stirred solution
there was added 13.02 g stannic chloride over the course of 2 min.
This was followed by the drop-wise addition of dichloromethyl methyl
ether over 5 min, and the reaction mixture allowed to stir for an
additional 15 min. After returning to room temperature, it was
stirred for an additional 1 h. The reaction mixture was poured over
15 g ice, and the organic phase separated, washed with 3x25 mL 3 N
HCl, with 3x50 mL brine and, after drying over anhydrous Na2SO4, the
solvent was removed under vacuum. The residue was a solid and, after
recrystallization from MeOH/H2O, gave 5.86 g
2,5-dimethoxy-4-(methylthio)benzaldehyde with a mp of 95-97 !C.
Purification via the bisulfite complex provided an analytical sample
with mp of 99-100 C. Anal. (C10H12O3S) C,H,S. The malononitrile
derivative (from equal weights of the aldehyde and malononitrile in
EtOH with a drop of triethylamine as catalyst) was recrystallized from
an equal volume of EtOH to give orange crystals with a mp of 185-186
!C. Anal. (C13H12N2O2S) C,H,N,S.
A solution of 2.1 g 2,5-dimethoxy-4-(methylthio)benzaldehyde in 7.5 mL
nitromethane was treated with 0.45 g anhydrous ammonium acetate and
held at steam bath temperature for 6 h. The deep red solution was
stripped of solvent to give a residue that spontaneously crystallized.
This was ground up under 12 mL MeOH, filtered, and washed with MeOH to
yield, after air-drying, 1.7 g of
2,5-dimethoxy-4-methylthio-'-nitrostyrene as orange solids.
Recrystallization from EtOH provided rust-orange colored crystals with
a mp of 165.5-166 !C. Anal. (C11H13NO4S) C,H,N; S: calcd, 12.56;
found, 11.96.
To a gently refluxing mixture of 1.4 g LAH in 40 mL anhydrous THF
under an inert atmosphere there was added, dropwise, 1.7 g
2,5-dimethoxy-4-methylthio-'-nitrostyrene in 25 mL THF. The refluxing
was continued for 18 h, and the stirring continued for another day at
room temperature. There was then added 1.5 mL H2O (diluted with a
little THF), 1.5 mL 15% NaOH, and finally 4.5 mL H2O. The white
aluminum oxide salts were removed by filtration, and the filter cake
washed with THF. The filtrate and washings were combined and stripped
of solvent under vacuum yielding a straw-colored residue that
crystallized (mp 81-92 !C without purification). This residue was
dissolved in 25 mL IPA and neutralized with concentrated HCl. The
slightly pink solution spontaneously crystallized. There was added
100 mL anhydrous Et2O, and the white crystalline mass of
2,5-dimethoxy-4-methylthiophenethylamine hydrochloride (2C-T) was
removed by filtration, washed with Et2O, and air dried. The final
weight was 1.0 g, and had a mp of 232-237 !C. Recrystallization from
EtOH provided an analytical sample with mp 240-241 !C. IPA was not a
good recrystallization solvent. Anal. (C11H18ClNO2S) C,H,N,S.
DOSAGE: 60 - 100 mg.
DURATION: 3 - 5 h.
QUALITATIVE COMMENTS: (with 60 mg) Poetry was an easy and natural
thing. Both the reading of it and the writing of it. This is a
potential MDMA substitute since it opens things up but it doesnUt do
anything to get in the way.
(with 75 mg) I am already aware at a quarter of an hour into it! It
develops very quickly but very quietly. There are no visuals at all
but, rather, a tactile sensitivity, with warm close feelings. This
could be very erotic. There is some fantasy to music, but nothing
very demanding. The viewing of pictures doesnUt do much either. The
drop-off was extremely relaxed, with a good body feeling. At the
fifth hour I was able to drift into an excellent, deep sleep with busy
dreams. In the morning I felt refreshed and active, without apparent
deficit.
(with 75 mg) I got up to a thin and fragile plus two, but there was a
continuing feeling of a hooded cloak brought down over my head.
Nothing obvious Q it is transparent Q but it somehow separated me from
everything around me. I do not think the overall experiment was worth
it.
(with 100 mg) Material all right, but a little bit along the lines of
a 'generic' psychedelic effect. Sharper edges than 2C-B. The one
true negative, which has been pretty consistent with this drug, is
that there is a certain emotional removal. One teeny step removed.
One is connected with feelings, certainly, but there is a tendency for
the intellect to be more evident, in me, than the heart. All this is
moderately so. Nothing extreme. Pretty good material, but there are
more inter-esting ones. However, if you are looking for a really
short one, this is one of the answers. For most people. For me, itUs
still around 5 to 6 hours long. I wish we had more shorties, indeed.
(with 125 mg) There was some physical tummy uncertainty, but once
that was past, talking was extremely easy. This is probably really
psychedelic, but I am not really sure why, as there is not much in the
way of visuals. Dropping was noted just after hour number three, and
I was at baseline three hours later.
EXTENSIONS AND COMMENTARY: The earliest work with the sulfur atom was
with the three-carbon chain materials, the ALEPHs. It was only after
a considerable time of working with them, and trying to come to peace
with their property of being so different from person to person as to
potency, that the two-carbon homologues were looked at. Although the
first of these (this compound, called 2C-T) was prepared at the same
time as ALEPH-1, there was a lapse of about four years between their
trials. The relatively low potency of 2C-T was a bit discouraging.
But the methodical pursuit of the higher 2C-T's (to parallel the
higher ALEPHs) proved to be a treasure house, and they have been
explored much further than any of the ALEPHs.
A note on the RTS in 2C-T. Many, in fact most, of the 2C's have their
name based on the last letter of the amphetamine prototype. 2C-B from
DOB, 2C-C from DOC, 2C-I from DOI, 2C-N from DON, etc. And since the
original name for ALEPH-1 was DOT (the desoxy- and a thiomethyl group
at the 4-position), the 2C-T naming followed this general pattern.
And as a note on the subsequent numbering, they (both the ALEPHs and
the 2C-TUs) are assigned numbers as they are thought up. There is no
structural significance in the number but they have been, like the
houses on the streets in residential Tokyo, assigned numbers in strict
historical order, documenting the sequence of construction rather than
the relative position down the side of the street.
Both of the homologous mono-ethoxy Tweetios of 2C-T have been
synthesized and evaluated. The 2-EtO-homologue of 2C-T is
2-ethoxy-5-methoxy-4-methylthiophenethylamine, or 2CT-2ETO. The
benzaldehyde (2-ethoxy-5-methoxy-4-(methylthio)benzaldehyde) was an
oil, the nitrostyrene intermediate had a melting point of 137-138 !C,
and the final hydrochloride a melting point of 215-216 !C. The
effects were felt very quickly, and there was a blurring of vision.
However, the highest dose tried, 50 milligrams, was not able to
produce a greater-than-plus one state, and what did occur, lasted for
only 4 hours.
The 5-EtO-homologue of 2C-T is
5-ethoxy-2-methoxy-4-methylthio-phenethylamine, or 2CT-5ETO. The
benzaldehyde (5-ethoxy-2-methoxy-4-(methyl-thio)benzaldehyde) was
impure, and had a melting point of about 66 !C, the nitrostyrene
intermediate a melting point of 133-134 !C, and the final
hydrochloride a melting point of 184-185 !C. There was a body
awareness and modest eyes-closed visuals following the use of 30
milligrams of 2CT-5ETO. The experience was quiet, peaceful,
contemplative, and insightful. The duration was perhaps 15 hours and
Halcion was needed to allow sleep. There were a lot of dreams, and
the next day was restful.
#40 2C-T-2; 2,5-DIMETHOXY-4-ETHYLTHIOPHENETHYLAMINE
SYNTHESIS: To a solution of 165 g 1,4-dimethoxybenzene in 1 L of
CH2Cl2, in a well ventilated place and well stirred, there was
cautiously added 300 mL chlorosulfonic acid. With about half the acid
chloride added, there was a vigorous evolution of HCl gas and the
generation of a lot of solids. As the addition was continued, these
redissolved to form a clear, dark green solution. Towards the end of
the addition, some solids were again formed. When everything was
stable, there was added 2 L H2O, a few mL at a time, commensurate with
the vigor of the reaction. The two phases were separated, and the
aqueous phase extracted with 2x75 mL CH2Cl2. The original organic
phase and the extracts were combined and the solvent removed under
vacuum. The residue weighed 162 g and was quite pure
2,5-dimethoxybenzenesulfonyl chloride, a yellow crystalline solid with
a mp of 115-117 !C. It need not be further purified for the next
step, and it appears to be stable on storage. The sulfonamide, from
this acid chloride and ammonium hydroxide, gave white crystals from
EtOH, with a mp of 147.5-148.5 !C.
The following reaction is also a very vigorous one and must be
performed in a well ventilated place. To a solution of 400 mL 25%
H2SO4 (V/V) in a beaker at least 2 L in size, there was added 54 g of
2,5-dimethoxybenzenesulfonyl chloride, and the mixture was heated on a
steam bath. The yellow crystals of the acid chloride floated on the
surface of the aqueous layer. There should be 80 g of zinc dust at
hand. A small amount of Zn dust was placed at one spot on the surface
of this chapeau. With occasional stirring with a glass rod, the
temperature was allowed to rise. At about 60 or 70 !C an exothermic
reaction took place at the spot where the zinc was placed. Additional
dollups of zinc were added, and each small exothermic reaction site
was spread about with the glass stirring rod. Finally, the reaction
spread to the entire solid surface layer, with a melting of the acid
chloride and an apparent boiling at the H2O surface. The remainder of
the 80 g of zinc dust was added as fast as the size of the reaction
container would allow. After things subsided again, the heating was
continued for 1 h on the steam bath. After the reaction mixture had
cooled to room temperature, it was filtered through paper in a Buchner
funnel, and the residual metal washed with 100 mL CH2Cl2. The
two-phase filtrate was separated, and the lower, aqueous phase was
extracted with 2x75 mL CH2Cl2. The addition of 2 L H2O to the aqueous
phase now made it the upper phase in extraction, and this was again
extracted with 2x75 mL CH2Cl2. The organic extracts were pooled (H2O
washing is more trouble than it is worth) and the solvent removed
under vacuum. The light amber residue (30.0 g) was distilled at 70-80
!C at 0.3 mm/Hg to yield 25.3 g 2,5-dimethoxythiophenol as a white
oil. This chemical is certainly not centrally active, but it is a
most valuable precursor to all members of the 2C-T family.
To a solution of 3.4 g of KOH pellets in 75 mL boiling EtOH, there was
added a solution of 10.0 g 2,5-dimethoxythiophenol in 60 mL EtOH
followed by 10.9 g ethyl bromide. The reaction was exothermic with
the immediate deposition of white solids. This was heated on the
steam bath for 1.5 h, added to 1 L H2O, acidified with HCl, and
extracted with 3x100 mL CH2Cl2. The pooled extracts were washed with
100 mL of 5% NaOH, and the solvent removed under vacuum. The residue
was 2,5-dimethoxyphenyl ethyl sulfide which was a pale amber oil,
weighed about 10 g and which was sufficiently pure for use in the next
reaction without a distillation step.
A mixture of 19.2 POCl3 and 18.0 g N-methylformanilide was heated
briefly on the steam bath. To this claret-colored solution there was
added the above 2,5-dimethoxyphenyl ethyl sulfide, and the mixture
heated an additional 20 min on the steam bath. This was then added to
500 mL of well-stirred warm H2O (pre-heated to 55 !C) and the stirring
continued for 1.5 h by which time the oily phase had completely
solidified to a brown sugar-like consistency. The solids were removed
by filtration, and washed with additional H2O. After being sucked as
dry as possible, these solids were dissolved in 50 mL boiling MeOH
which, after cooling in an ice-bath, deposited almost-white crystals
of 2,5-dimethoxy-4-(ethylthio)-benzaldehyde. After filtration, modest
washing with cold MeOH, and air drying to constant weight, there was
obtained 11.0 g of product with a mp of 86-88 !C. Recrystallization
of a small sample again from MeOH provided an analytical sample with
mp 87-88 !C. Anal. (C11H14O3S) C,H.
To a solution of 11.0 g 2,5-dimethoxy-4-(ethylthio)benzaldehyde in 100
g of nitromethane there was added 0.5 g of anhydrous ammonium acetate,
and the mixture was heated on the steam bath for 80 min (this reaction
progress must be monitored by TLC, to determine the point at which the
starting aldehyde has been consumed). The excess nitromethane was
removed under vacuum leaving a residue that spontaneously set to
orange-red crystals. These were scraped out to provide 12.9 g crude
2,5-dimethoxy-4-ethylthio-'-nitrostyrene with a mp of 152-154 !C. A
sample recrystallized from toluene was pumpkin colored and had a mp of
148-149 !C. Another sample from acetone melted at 149 !C sharp, and
was light orange. From IPA came spectacular fluorescent orange
crystals, with a mp 151-152 !C. Anal. (C12H15NO4S) C,H.
A suspension of 12.4 g LAH in 500 mL anhydrous THF was stirred under
He. To this there was added 12.4 g
2,5-dimethoxy-4-ethylthio-'-nitrostyrene in a little THF, and the
mixture was held at reflux for 24 h. After the reaction mixture had
returned to room temperature, the excess hydride was destroyed by the
cautious addition of 60 mL IPA, followed by 20 mL of 5% NaOH followed,
in turn, by sufficient H2O to give a white granular character to the
oxides. The reaction mixture was filtered, and the filter cake washed
first with THF and then with MeOH. Removing the solvents from the
combined filtrate and washings under vacuum provided 9.5 g of a yellow
oil. This was added to 1 L dilute HCl and washed with 2x100 mL CH2Cl2
which removed all color. After making the aqueous phase basic with
25% NaOH, it was extracted with 3x100 mL CH2Cl2, the extracts pooled,
and the solvent removed under vacuum to provide 7.3 g of a pale amber
oil. Distillation at 120-130 !C at 0.3 mm/Hg gave 6.17 g of a clear
white oil. This was dissolved in 80 mL IPA and neutralized with
concentrated HCl, forming immediate crystals of
2,5-dimethoxy-4-ethylthiophenethylamine hydrochloride (2C-T-2). An
equal volume of anhydrous Et2O was added and, after complete grinding
and mixing, the salt was removed by filtration, washed with Et2O, and
air dried to constant weight. The resulting white crystals weighed
6.2 g.
DOSAGE: 12 - 25 mg.
DURATION: 6 - 8 h.
QUALITATIVE COMMENTS: (with 12 mg) I donUt feel this for fully an
hour, but when I do it is quite a weight. It feels good to work it
through. It is OK to be with pain. You canUt eliminate it. And it
is OK to contact your deep pools of anger. And all of it stems from
the lack of acknowledgment. All the macho carrying on, the fights,
the wars, are ways of demanding attention, and getting even for not
having had it in one's life. I am experiencing more deeply than ever
before the importance of acknowledging and deeply honoring each human
being. And I was able to go through and resolve some judgments with
particular persons.
(with 20 mg) I chose 2C-T-2 at this dose level because the lateness
of getting started, and I wanted a shorter experience with my daughter
and her family around. I feel, however, that I have somewhat less of
a body load with 2C-T-7. Today I was badly in need of the help that
might possibly come from this material, and today it was my ally. I
sorely needed the type of help that it afforded. The result was to
work off the heavy feeling of tiredness and lack of motivation that
had been hounding me. The next day I felt that I had dropped my
burden.
(with 20 mg) There is a neutralness to this. I am at the maximum,
and I am asking myself, 'Am I enjoying this?' And the answer is, 'No,
I am experiencing it.' Enjoyment seems beside the point. It is a
rather intensely matter-of-fact +3. Is it interesting? Yes, but
mostly in expectation of further developments. Is it inspiring? No.
Is it negative? No. Am I glad I took it? Yes. Not glad. Satisfied
and contented. This is a controlled +3. No threat. The body is all
right. Not superbly healthy Q but OK. Of no interest, either way.
If I were to define the body's state, I would have to define it in
image. The image is of a not comfortable state of being clenched.
Clenched? Well, carefully bound in control.
(with 22 mg) A slow onset. It took an hour for a plus one, and
almost another two hours to get to a +++. Very vivid fantasy images,
eyes closed, but no blurring of lines between RrealityS and fantasy.
Some yellow-grey patterns a la psilocybin. Acute diarrhea at about
the fourth hour but no other obvious physical problems. Erotic
lovely. Good material for unknown number of possible uses. Can
explore for a long time. Better try 20 milligrams next time.
(with 25 mg) I was at a +++ in an hour! It is most difficult to do
even ordinary things. I took notes but now I canUt find them. This
is much too high for anything creative, such as looking at pictures or
trying to read. Talking is OK. And to my surprise I was able to get
to sleep, and a good sleep, at the seven hour point.
EXTENSIONS AND COMMENTARY: There is a considerable parallel between
2C-T-2 and 2C-T-7, and both have proven to be excellent tools for
introspection. The differences are largely physical. With 2C-T-2,
there is more of a tendency to have physical disturbances such as
nausea and diarrhea. And the experience is distinctly shorter. With
2C-T-7, physical disturbances are less common, but you are into the
effects for almost twice as long. Both have been frequently used in
therapy as follow-ups to MDMA.
A point of potential misidentification should be mentioned here.
2C-T-2 has occasionally been called, simply, T-2. This abbreviated
nickname has also been used for T-2 Toxin, a mycotoxin of the
Tricothecene group, formed mainly by the Fusarium spp. This is the
infamous Rwarfare agentS in Southeast Asia, which was finally
identified as bee feces rather than a Soviet military adventure. T-2
and 2C-T-2 are radically different compounds.
All three Tweetios of 2C-T-2 have been made and looked at through
human eyes. The 2-EtO-homologue of 2C-T-2 is
2-ethoxy-4-ethylthio-5-methoxyphenethylamine, or 2CT2-2ETO. The
benzaldehyde (2-ethoxy-4-ethylthio-5-methoxybenzaldehyde) had a
melting point of 73-75 !C, the nitrostyrene intermediate a melting
point of 122-123 !C, and the final hydrochloride a melting point of
202-204 !C. Fifty milligrams was a completely effective level. The
effects were felt very quickly. Vision was blurred, and there were
intense eyes-closed visuals and the generation of a pleasant,
contemplative mood. Baseline was re-established in five or six hours,
but sleep was restless, with weird dreams. Nasal administration
showed considerable variation between individuals, but a typical dose
was 10 milligrams.
The 5-EtO-homologue of 2C-T-2 is
5-ethoxy-4-ethylthio-2-methoxyphenethylamine, or 2CT2-5ETO. The
benzaldehyde (5-ethoxy-4-ethylthio-2-methoxybenzaldehyde) had a
melting point of 49 !C, but it was impure. The nitrostyrene
intermediate melted at 107-108 !C, and the final hydrochloride had a
melting point of 180 !C. At levels of 20 milligrams, there was a
slow, gentle climb to a full effect at the third or fourth hour. The
flooding of thoughts and easy conversation lasted for many hours, and
on some occasion a sedative was needed at the 16 hour point. There
was a feeling of being drained for the following day or two. Some
intoxication was still noted in the second day. Again it is true
here, as had been stated as a generality, that the 5-Tweetio analogues
have potencies similar to that of the parent compound, but show a much
longer duration. The nickname of Rforever yoursS had been applied.
There may indeed be insight, but 24 hoursU worth is an awful lot of
insight.
The 2,5-DiEtO-homologue of 2C-T-2 is
2,5-diethoxy-4-ethylthiophen-ethylamine, or 2CT2-2,5DIETO. The
benzaldehyde, 2,5-diethoxy-4-(ethylthio)benzaldehyde, had a melting
point of 84-85 !C, the nitrostyrene intermediate a melting point of
123-124 !C, and the final hydrochloride a melting point of 220-221 !C.
Levels that were evaluated from 10 to 50 milligrams were not
particularly different in intensity, but were progressively longer in
duration. At 50 milligrams there was a nervousness and edginess
during the early part of the experience, but for the next several
hours there was evident both energy and high attentiveness. There
were few if any sensory alterations. There were no negatives on the
following day. The duration was perhaps nine hours.
#41 2C-T-4; 2,5-DIMETHOXY-4-(i)-PROPYLTHIOPHENETHYLAMINE
SYNTHESIS: To a solution of 2.5 g of KOH pellets in 40 mL hot EtOH,
there was added 5.4 g 2,5-dimethoxythiophenol (see under 2C-T-2 for
its preparation) and 8.7 g isopropyliodide. White solids appeared in
a few min, and the reaction mixture was heated on the steam bath
overnight. This mixture was added to 200 mL H2O followed by
additional aqueous NaOH to raise the pH to a deep purple-blue on
universal pH paper. This was extracted with 3x75 mL CH2Cl2. The
pooled extracts were stripped of solvent under vacuum, and the residue
distilled at 100-110 !C at 0.2 mm/Hg to yield 6.9 g of
2,5-dimethoxyphenyl isopropyl sulfide as a pale yellow oil. It has a
very light, pleasant smell of apples.
A mixture of 4.8 g POCl3 and 4.5 g N-methylformanilide was stirred and
allowed to stand at room temperature for 1 h To this claret-colored
solution was added 3.0 g of 2,5-dimethoxyphenyl isopropyl sulfide,
producing an exothermic reaction and immediate reddening. This was
heated for 0.5 h on the steam bath, then quenched in 200 mL of warm
H2O producing immediate crystals. Stirring was continued for a few
min, and then the solids were removed by filtration, washed with H2O
and sucked as dry as possible. When they were ground up under an
equal weight of cold MeOH, refiltered and air dried, they gave 2.35 g
of 2,5-dimethoxy-4-(i-propylthio)benzaldehyde as pale yellow solids
(in some runs this was a pale lime-green color) with a mp of 89-90 !C.
A wasteful recrystallization from MeOH gave pale yellow crystals with
a mp of 90 !C sharp.
To a solution of 6.7 g 2,5-dimethoxy-(i-propylthio)benzaldehyde in 40
g of nitromethane there was added 0.10 g of anhydrous ammonium
acetate, and the mixture was heated on the steam bath for 2 h. The
excess reagent/solvent was removed under vacuum yielding 8.9 g of
orange solids. This was recrystallized from 200 mL boiling MeOH
providing 6.2 g of 2,5-dimethoxy-'-nitro-4-(i-propyl-thio)styrene as
lustrous golden orange platelets.
A solution of LAH (80 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath. With good stirring there was
added 2.1 mL 100% H2SO4 dropwise, to minimize charring. This was
followed by the addition of 5.74 g
2,5-dimethoxy-'-nitro-4-(i-propylthio)styrene as a solid, a bit at a
time. After 15 min further stirring, the temperature was brought up
to a gentle reflux on the steam bath for another 15 min, then allowed
to stand at room temperature overnight. After cooling again to 0 !C,
the excess hydride was destroyed by the addition of 7 mL IPA followed
by 6 mL 15% NaOH which was sufficent to give a white granular
character. The reaction mixture was filtered and the filter cake
washed with THF. The filtrate and washings were pooled, stripped of
solvent under vacuum providing 3.9 g of a pale amber oil which was
dissolved in 250 mL dilute H2SO4. This was washed with 3x75 mL CH2Cl2
which removed the residual yellow color. After making basic with 25%
NaOH, the product was extracted with 3x75 mL CH2Cl2 and the solvent
removed under vacuum to give 2.72 g of a residue which was distilled
at 140-145 !C at 0.2 mm/Hg to give 2.42 g of a clear white oil. This
was dissolved in 25 mL IPA, and neutralized with concentrated HCl.
This gave a clear solution which, with good stirring, was diluted with
100 anhydrous Et2O to provide 2.40 g
2,5-dimethoxy-4-(i)-propyl-thiophenethylamine hydrochloride (2C-T-4)
as white crystals.
DOSAGE: 8 - 20 mg.
DURATION: 12 - 18 h.
QUALITATIVE COMMENTS: (with 8 mg) Visual effects set in at about two
hours. There was much color enhancement, particularly of green, and
some flowing of colors. The bright impressionistic picture of the
little girl, in the bathroom, was particularly good for the visuals to
take over, especially when I was concentrating on urinating. The
shadows in the large picture above the fireplace would change
constantly. I could not either control or turn off these effects
during the middle period (3-6 hours). From the physical point of
view, something early in the experience simply didnUt feel right.
Both my lower legs tended to fall asleep, and this seemed to spread to
my hands and lower arms. It was uncomfortable and although I was
apprehensive at first it didnUt get any worse with time so I ignored
it. This is not one my favorite materials, and it takes too long to
wear off. If I were to do it again I would settle for 4 or 5
milligrams. It may well cut out the extremity problem amd still allow
for a pleasant experience.
(with 9 mg) An important characteristic of this experience was the
sense of letting go and flowing with it. Just follow where it leads.
This seemed to lead to a growing euphoria, a feeling of clearing out
of body residues, and the handling of very impressive insights. My
thinking continued to grow in clarity, visual perception was crystal
clear, and it was a joy to simply look over the scenery, enjoy the
beauty, enjoy the companionship, and ponder whatever came to mind.
This clarity of body and mind lasted the rest of the evening with a
wonderful feeling of peace and centeredness. I still felt a lot of
push from the chemical at bed time, causing some tiredness, and
allowing very little sleep. I kept working at what had taken place,
all night, just to release the experience.
(with 14 mg) Very rational, benign, and good humored. The insight
and calm common to the 2C-T's are present, with less of the push of
body-energy which makes 2C-T-2 difficult for some people. There are
no particular visuals, but then I tend to screen them out
consistently, except in cases of mescaline and LSD and psilocybin, so
I canUt judge what others would experience in the visual area. The
eyes-closed imagery is very good without being compelling. The
decline is as gradual and gentle as the onset. I am fully capable of
making phone calls and other normal stuff. Music is marvelous, and
the body feels comfortable throughout.
(with 14 mg) Persistent cold feet, and an uncertain stomach when
moving around. Brilliant color trails reminiscent of 2C-B. But a
change is occurring and I canUt talk myself out of it. There are dark
corners. If I were with other people, this would bring out the worst
in me, which can be pretty bad.
(with 19 mg) I was caught by the TV. Leonard Bernstein conducting
West Side Story. I think I know every note. This was a 1985
rehearsal with the goofs and the sweat. And now Peter, Paul and Mary,
grown older along with the songs we all sang. Where Have All the
Flowers Gone Q and an audience of grown-older people singing Puff the
Magic Dragon like earnest children and probably crying along with me.
It is good to have lived through the 60's and not to be in them now.
Now there's a new song about El Salvador and itUs the battle all over
again on a different field, but it will always be so, until and
unless. Now, in the 80Us, I donUt get really angry anymore. I am
more warrior than angry protester, and that's a much better way to be.
In fact, I am quite happy to be where I am. I know a lot more about
the game, and what it is, and why it is played, and I have a good idea
about my part in it, and I like the part IUve chosen.
(with 22 mg) The transition took place over three hours, an alert in
30 minutes followed by a slow and gentle climb. I found it difficult,
not physically but mentally since I was for a while locked into the
illogical and disconnected aspects of human experiences and
expressions, particularly laws and pronouncements and unseeing
prejudices, most of which I was picking up from reading the Sunday
paper book reviews. As time went on, things became less pushy and I
came to be at ease with very positive feelings about everything going
on. No self-rejecting aspect at all. Sleep was excellent, but the
next day things went slowly and I had to nap a bit. Next time, maybe
18 milligrams.
EXTENSIONS AND COMMENTARY: There are shades of the variability of the
Alephs. Some observers are overwhelmed with colors and visual
activity; others volunteer their absence. And a very wide range of
dosages represented, from an estimated 4 or so milligrams for full
effects, to something over 20 milligrams without any loss of control.
That is an unusually wide lattitude of activity. And a rich variety
of effects that might be experienced. The same wide range of
effective dosages was also observed with the corresponding Tweetio.
The 2-EtO-homologue of 2C-T-4 is
2-ethoxy-5-methoxy-4-(i)-propylthiophenethylamine, or 2CT4-2ETO. The
benzaldehyde (2-ethoxy-5-methoxy-4-(i-propylthio)benzaldehyde had a
melting point of 43-44 !C, the nitrostyrene intermediate a melting
point of 77-79 !C, and the final hydrochloride a melting point of
153.5-154 !C. There were practically no differences between trials at
5 milligram increments within the 10 and 25 milligram range. Each
produced a gentle plus two level of effect which lasted for some 10
hours. A code name of RtendernessS was felt to be appropriate, as
there was a peaceful meditative inner receptiveness and clarity noted,
with an honest connection felt with those who were present during the
experience. Sleep was not comfortable.
I have heard 2C-T-4 referred to as T-4. There is a potent explosive
used by terrorists called cyclotrimethylenetrinitramine, known by the
code name RDX, or T-4. There is also a T-4 term that refers to
thyroxine, an amino acid in the body. The drug 2C-T-4 is neither an
explosive nor an amino acid, I am happy to say.
#42 Y-2C-T-4; 2,6-DIMETHOXY-4-(i)-PROPYLTHIOPHENETHYLAMINE)
SYNTHESIS: A stirred solution of 8.3 g 3,5-dimethoxy-1-chlorobenzene
and 7.2 g isopropylsulfide in 100 mL anhydrous Et2O was cooled with an
external ice bath, and then treated with 67 mL 1.5 M lithium
diisopropylamide in hexane which was added over the course of 10 min.
The reaction mixture was allowed to return to room temperature and the
stirring was continued for 0.5 h. The mixture was poured into dilute
H2SO4, the organic layer was separated, and the aqueous phase
extracted with 3x75 mL EtOAc. The organic phases were combined, dried
over anhydrous K2CO3, and the solvent removed under vacuum. The
resulting 4.54 g of almost colorless oil was distilled at 85-95 !C at
0.1 mm/Hg to give 4.2 g of 3,5-dimethoxyphenyl isopropyl sulfide as a
colorless oil, showing a single spot on TLC with no indication of
starting chlorobenzene. The product formed a picrate salt, but this
had an unsatisfactory mp character (partly melting at 45-47 !C, and
then completely at about 80-90 !C). The microanalysis for this picrate
was low in the carbon value, although the hydrogen and nitrogen were
excellent. Anal. (C17H19N3O9S) H,N; C: calcd, 46.25; found, 44.58,
44.45.
To a well-stirred solution of 4.1 g 3,5-dimethoxyphenyl isopropyl
sulfide and 3.5 mL N,N,NU,NU-tetramethylethylenediamine in 25 mL
anhydrous Et2O that had been cooled to -78 !C with a dry-ice/acetone
bath, there was added 10 mL 2.5 M hexane solution of butyllithium.
The mixture was allowed to return to room temperature, and there was
added 3.5 mL DMF which caused the yellow color to progressively
darken. The reaction mixture was poured into dilute H2SO4, the Et2O
layer was separated, and the aqueous phase extracted with 3x75 mL
EtOAc. The solvent was removed from the combined organic phases, and
the residue distilled at 0.15 mm/Hg to give two fractions. One,
boiling at 120-140 !C, was 0.98 g of a pale yellow mobile liquid,
which was part starting sulfide and part product aldehyde by TLC. The
second cut, boiling at 160-180 !C, was a viscous liquid, weighed 1.66
g, and was largely 2,6-dimethoxy-4-(i-propylthio)benzaldehyde. This
formed a crystalline anil with 4-methoxyaniline (by fusing equimolar
amounts of the two with a flame) which, after recrystallization from
MeOH, gave fine yellow crystals with a mp of 87.5-89 !C. Anal.
(C19H23NO3S) C,H.
A solution of 0.8 g 2,6-dimethoxy-4-(i-propylthio)benzaldehde in 10 mL
nitromethane was treated with 0.2 g anhydrous ammonium acetate and
heated on the steam bath for 1 h. The excess reagent/solvent was
removed under vacuum, and the residue spontaneously solidified. This
was recrystallized from 5 mL MeOH to give 0.70 g
2,6-dimethoxy-'-nitro-4-(i)-propylthiostyrene as a pale yellow fluffy
solid, with a mp of 83-84.5 !C. Anal. (C13H17NO4S) C,H.
A solution of LAH (20 mL of a 1 M solution in THF) was cooled, under
He to 0 !C with an external ice bath. With good stirring there was
added 0.54 mL 100% H2SO4 dropwise, to minimize charring. This was
followed by the addition of 0.54 g
2,6-dimethoxy-'-nitro-4-(i)-propylthiostyrene in a small volume of
anhydrous THF. The color was discharged immediately. After a few
minutes further stirring, the temperature was brought up to a gentle
reflux on the steam bath for about 10 min, and then all was cooled
again to 0 !C. The excess hydride was destroyed by the cautious
addition of IPA followed by sufficent 15% NaOH to give a white
granular character to the oxides, and to assure that the reaction
mixture was basic. The reaction mixture was filtered, and the filter
cake washed well with THF. The filtrate was stripped of solvent under
vacuum and the residue dissolved in 100 mL of dilute H2SO4. This was
washed with 2x50 mL CH2Cl2 (the washes were saved, see below), made
basic with aqueous NaOH, and then extracted with 2x50 mL CH2Cl2. The
residue remaining after the removal of the solvent was distilled at
130-140 !C at 0.05 mm/Hg to give 0.11 g of a white oil. This was
dissolved in 10 mL IPA, neutralized with 5 drops of concentrated HCl
and diluted with 50 mL anhydrous Et2O. After filtration of the formed
crystals, Et2O washing, and air drying, there was obtained 80 mg of
2,6-dimethoxy-4-(i)-propylthiophenethylamine hydrochloride (y-2C-T-4)
as fine white crystals. The removal of the solvent from the CH2Cl2
washes of the dilute H2SO4 solution gave a H2O-soluble white solid
that proved to be the sulfate salt of the product. This provided,
after making the H2O solution basic, extraction with CH2Cl2, and
solvent removal, the free base that was converted, as described above,
to a second crop of the hydrochloride salt.
DOSAGE: above 12 mg.
DURATION: probably short.
QUALITATIVE COMMENTS: (with 8 mg) I might actually be up to a plus 1,
and with a very good feeling. But I cannot say how long it lasted,
and it was probably pretty short. It just sort of faded away.
(with 12 mg) At the 25 minute point I am reminded of the experiment,
and in another quarter hour I am into something. Will this be another
forever threshold? I feel very good, but there is no sparkle.
EXTENSIONS AND COMMENTARY: Here is another example of the presentation
of a compound for which there has not yet been an effective level
determined. Why? For a very good reason. This is an example of a
whole class of compounds that I have called the pseudos, or the
y-compounds. Pseudo- as a prefix in the literary world generally
stands for Rfalse.S A pseudopod is a thing that looks like a foot, but
isnUt one. A pseudonym is a fictitious name. But in chemistry, it
has quite a different meaning. If something has a common name, and
there is a second form (or isomer, or shape, or orientation) that is
possible and it doesnUt have a common name, it can be given the name
of the first form with a Rpseudo-S attached. Ephedrine is the
erythro-isomer of N-methyl-'-hydroxyamphetamine. There is a second
stereoisomer, the threo- isomer, but it has no trivial name. So it is
called pseudoephedrine, or the RSudafedS of sinus decongestant fame.
The pseudo-psychedelics are the 2,4,6-trisubstituted counterparts of
the 2,4,5-trisubstituted psychedelics. Almost all of the
2,5-dimethoxy-4-something-or-other compounds are active and
interesting whether they be phenethylamines or amphetamines, and it is
an exciting fact that the 2,6-dimethoxy-4-something-or-other compounds
are going be just as active and just as interesting. A number of
examples have already been mentioned. TMA-2 is
2,4,5-trimethoxyamphetamine (a 2,5-dimethoxy-substituted compound with
a methoxyl at the 4-position). The pseudo- analogue is TMA-6
(2,4,6-trimethoxyamphetamine) and it is every bit as potent and
fascinating. Z-7 could be called pseudo-DOM, and although it is quite
a bit down in potency, it is an active drug and will both demand and
receive much more clinical study some day.
Will the other 2,4,5-things spawn 2,4,6-things that are active?
Without a shadow of a doubt. Chemically, they are much more difficult
to synthesize. The 2,5-dimethoxy orientation made the 4-position a
natural and easy target. The 2,6-dimethoxy orientation pushes for
3-substitution, and the 4-position is completely unnatural. Tricks
are needed, but tricks have now been found. The above synthesis of
pseudo-2C-T-4 shows one such trick. This is, in my opinion, the
exciting chemistry and psychopharmacology of the next decade. Well
over half of all the psychedelic drugs mentioned in Book II are
2,4,5-trisubstituted compounds, and every one of them has a
(potentially active) 2,4,6-pseudo-counterpart.
It goes yet further. The antidepressant series of RAriadneS compounds
are 1-phenyl-2-aminobutanes. But the 1-phenyl is again a
2,4,5-trisubstituted compound. The 2,4,6-isomer will give rise to a
pseudo-Ariadne family, and I will bet that they too will be
antidepressants. The 1-phenyl-2-aminobutane analog of y-2C-T-4 is the
2,4,6-analogue and it has been prepared as far as the nitrostyrene.
It has not yet been reduced, so it is not yet been evaluated, but it
could be a most remarkable psycho-pharmacological probe.
And it goes yet yet further. Think back to the six possible TMAUs.
TMA and TMA-3 were relatively inactive. And TMA-2 and TMA-6 were the
interesting ones. The first gave rise to the last twenty years of
psychedelic chemistry, and the other (as speculated upon above) will
give rise to the forthcoming ten years. But what of TMA-4 and TMA-5?
Both showed activity that was more than TMA but less than that of the
-2 or -6 isomers. Could they, some day, provoke yet other families of
psychedelics? Maybe the 3-position of these two might be focal points
of leverage as to psychological activity. What are the letters that
follow y in the Greek alphabet? If I remember correctly, the next
letter is the last letter, omega. So, I guess that Nature is trying
to tell us something, that the -4 and -5 isomers will not engender
interesting families. What a pity. The chemistry is so unthinkably
difficult that it would have been a true challenge. My next
incarnation, maybe?
#43 2C-T-7; 2,5-DIMETHOXY-4-(n)-PROPYLTHIOPHENETHYLAMINE
SYNTHESIS: To a solution of 3.4 g of KOH pellets in 50 mL hot MeOH,
there was added a mixture of 6.8 g 2,5-dimethoxythiophenol (see under
the recipe for 2C-T-2 for its preparation) and 7.4 g (n)-propylbromide
dissolved in 20 mL MeOH. The reaction was exothermic, with the
deposition of white solids. This was heated on the steam bath for 0.5
h, added to 800 mL H2O, additional aqueous NaOH added until the pH was
basic, and extracted with 3x75 mL CH2Cl2. The pooled extracts were
washed with dilute NaOH, and the solvent removed under vacuum. The
residue was 2,5-dimethoxyphenyl (n)-propyl sulfide which was obtained
as a pale yellow oil, and which weighed 8.9 g. It had a light
pleasant fruity smell, and was sufficiently pure for use in the next
reaction without distillation.
A mixture of 14.4 g POCl3 and 13.4 g N-methylformanilide was heated
for 10 min on the steam bath. To this claret-colored solution was
added 8.9 g of 2,5-dimethoxyphenyl (n)-propyl sulfide, and the mixture
heated an additional 25 min on the steam bath. This was then added to
800 mL of well-stirred warm H2O (pre-heated to 55 !C) and the stirring
continued until the oily phase had completely solidified (about 15
minutes). The resulting brown sugar-like solids were removed by
filtration, and washed with additional H2O. After sucking as dry as
possible, they were dissolved in an equal weight of boiling MeOH
which, after cooling in an ice-bath, deposited pale ivory colored
crystals. After filtration, modest washing with cold MeOH, and air
drying to constant weight, there was obtained 8.3 g of
2,5-dimethoxy-4-(n-propyl-thio)benzaldehyde with a mp of 73-76 !C.
Recrystallization from 2.5 volumes of MeOH provided a white analytical
sample with mp 76-77 !C. The NMR spectrum in CDCl3 was textbook
perfect, with the two aromatic protons showing singlet signals at 6.81
and 7.27 ppm, giving assurance that the assigned location of the
introduced aldehyde group was correct.
To a solution of 4.0 g 2,5-dimethoxy-(n-propylthio)benzaldehyde in 20
g of nitromethane there was added 0.23 g of anhydrous ammonium
acetate, and the mixture was heated on the steam bath for 1 h. The
clear orange solution was decanted from some insoluble material and
the excess nitromethane removed under vacuum. The orange-yellow
crystalline material that remained was crystallized from 70 mL boiling
IPA which, on slow cooling, deposited
2,5-dimethoxy-'-nitro-4-(n)-propylthiostyrene as orange crystals.
After their removal by filtration and air-drying to constant weight,
they weighed 3.6 g, and had a mp of 120-121 !C. Anal. (C13H17NO4S)
C,H.
A solution of LAH (132 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath. With good stirring there was
added 3.5 mL 100% H2SO4 dropwise, to minimize charring. This was
followed by the addition of 8.4 g
2,5-dimethoxy-'-nitro-4-(n)-propylthiostyrene in 50 mL anhydrous THF.
There was an immediate loss of color. After a few min further
stirring, the tem-perature was brought up to a gentle reflux on the
steam bath, then all was cooled again to 0 !C. The excess hydride was
destroyed by the cautious addition of IPA (21 mL required) followed by
sufficent 5% NaOH to give a white granular character to the oxides,
and to assure that the reaction mixture was basic (15 mL was used).
The reaction mixture was filtered and the filter cake washed first
with THF and then with IPA. The filtrate and washes were combined and
stripped of solvent under vacuum providing about 6 g of a pale amber
oil. Without any further purification, this was distilled at 140-150
!C at 0.25 mm/Hg to give 4.8 g of product as a clear white oil. This
was dissolved in 25 mL IPA, and neutralized with concentrated HCl
forming immediate crystals of the hydrochloride salt in the alcohol
solvent. An equal volume of anhydrous Et2O was added, and after
complete grinding and mixing,
2,5-dimethoxy-4-(n)-propylthiophenethylamine hydrochloride (2C-T-7)
was removed by filtration, Et2O washed, and air dried to constant
weight. The resulting spectacular white crystals weighed 5.2 g.
DOSAGE: 10 - 30 mg.
DURATION: 8 - 15 h.
QUALITATIVE COMMENTS (with 20 mg) A wonderful day of integration and
work. Took about 2 hours for the onset. Some nausea on and off Q
that seemed to cycle periodically throughout the day. Visuals were
great, much like mescaline but less sparkly. Lots of movement and
aliveness Q velvety appearance and increased depth perception. Neck
and shoulder tension throughout the day along with legs. I would
periodically notice extreme tightness of muscles, and then relax.
Working was very integrative. Back and forth constantly between
wonderful God-space Q similar to MDMA but more grounded Q then always
back to sadness. I felt that it really showed me where I was
unfinished, but with self-loving and tolerance. Tremendous processing
and letting go. Seeing things very clearly and also able to laugh at
my trips. Lots of singing. In spite of shoulder tension, vocal
freedom and facility were very high. I felt my voice integrated and
dropped in a way it never had before, and that remained for several
days. Able to merge body, voice, psyche and emotions with music and
then let go of it as a role. I also realized and gave myself
permission to do whatever it takes to get free. I let go of Dad with
tragic arias. The next day I let go of Mom by singing Kaddish for
her, and merging with it.
(with 20 mg) I lay down with music, and become engrossed with being
as still as possible. I feel that if I can be totally, completely
still, I will hear the inner voice of the universe. As I do this, the
music becomes incredibly beautiful. I see the extraordinary
importance of simply listening, listening to everything, to people and
to nature, with wide open receptivity. Something very, very special
happens at the still point, so I keep working on it. When I become
totally still, a huge burst of energy is released. And it explodes so
that it takes enormous effort to quiet it all down in order to be
still again. Great fun.
(with 25 mg) This was a marvelous and strange evening. This 2C-T-7
is good and friendly and wonderful as I remember it. I think it is
going to take the place of 2C-T-2 in my heart. It is a truly good
material. I got involved with a documentary on television. It was
about certain people of Bolivia, people living in the high mountains
and about a small village which Q perhaps alone among all the places
in the country Q maintains the old Inca ways, the old traditions, the
old language. Which is, I gather, against the law in Bolivia. It
showed a yearly meeting of shamans and it was quite clear that
hallucinogens played a major part in this meeting. The shaman faces,
male and female, were startling in their intensity and earthy depth.
The Virgin Mary is worshipped as another version of the ancient Pacha
Mama, the Earth Mother. Wonderful dark, vivid look at places and
people who are not usually to be seen or even known about.
(with 30 mg) The visuals have an adaptable character to them. I can
use them to recreate any hallucinogenic substance I have known and
loved. With open eyes, I can go easily into LSD flowing visuals, or
into the warm earth world of Peyote, or I can stop them altogether.
With closed eyes, there are Escher-like graphics with a lot of
chiaroscuro, geometric patterns with oppositional play of sculptured
light and dark values. Green light.
EXTENSIONS AND COMMENTARY: If all the phenethylamines were to be
ranked as to their acceptability and their intrinsic richness, 2C-T-7
would be right up there near the top, along with 2C-T-2, 2C-B,
mescaline and 2C-E. The range is intentionally extended on the lower
side to include 10 milligrams, as there have been numerous people who
have found 10 or so milligrams to be quite adequate for their tastes.
One Tweetio related to 2C-T-7 has been made and evaluated. This is
the 2-EtO-homologue of 2C-T-7,
2-ethoxy-5-methoxy-4-(n)-propylthiophenethyl-amine, or 2CT7-2ETO. The
benzaldehyde (2-ethoxy-5-methoxy-4-(n-propyl-thio)benzaldehyde had a
melting point of 69-71 !C, the nitrostyrene intermediate a melting
point of 106-106.5 !C, and the final hydrochloride a melting point of
187-189 C!. At the 20 milligram level, the effects were felt quickly,
and the eyes-closed visuals were modest but real. It was very
short-lived, with baseline recovery at about the fifth hour. The next
day there was an uncomfortable headache which seemed on an intuitive
level to be an after-effect of the compound.
The unusual properties of a number of N-methyl-N-(i)-propyltryptamines
suggested the possibility of something like a similar set of
N-methyl-N-(i)-propylphenethylamines. Why not try one from 2C-T-7?
The thought was, maybe N-methylate this compound, then put on an
isopropyl group with reductive alkylation, using acetone as the carbon
source and sodium cyanoborohydride. Towards this end, the free base
of 2C-T-7 (from one gram of the hydrochloride) was refluxed for 2 h in
1.3 g butyl formate, and on removing the solvent/reactant the residue
spontaneously crystallized. This formamide (0.7 g) was reduced with
lithium hydride in cold THF to provide
2,5-dimethoxy-4-(n)-propyl-N-methyl-phenethylamine, METHYL-2C-T-7,
which distilled at 150-170 !C at 0.4 mm/Hg. A very small amount of
the hydrochloride salt was obtained (65 milligrams) and it had a brown
color. Too small an amount of an impure product; the entire project
was dropped.
#44 2C-T-8; 2,5-DIMETHOXY-4-CYCLOPROPYLMETHYLTHIOPHENETHYLAMINE
SYNTHESIS: To a solution of 2.8 g of KOH pellets in 25 mL hot MeOH,
there was added a mixture of 5.9 g 2,5-dimethoxythiophenol (see under
2C-T-2 for its preparation) and 5.0 g of cyclopropylmethyl bromide.
There was an immediate exothermic reaction with spontaneous boiling
and the formation of white crystals. This was heated on the steam
bath for 4 h, and then added to 400 mL of H2O. After extraction with
3x75 mL CH2Cl2, the pooled extracts were washed first with dilute
NaOH, then with saturated brine, then the solvent was removed under
vacuum. The residue, 8.45 g of crude 2,5-dimethoxyphenyl cyclopropyl
methyl sulfide, was distilled at 120-140 !C at 0.3 mm/Hg to give a
white oil weighing 7.5 g.
A mixture of 13.5 g POCl3 and 13.5 g N-methylformanilide was heated
for 10 min on the steam bath. To this claret-colored solution was
added 7.28 g of 2,5-dimethoxyphenyl cyclopropylmethyl sulfide, and the
spontaneously exothermic mixture was heated for an additional 10 min
on the steam bath, and then quenched in 400 mL of 55 !C H2O with good
stirring. After a few minutes a reddish solid phase separated. This
was removed by filtration, and washed with additional H2O. After
sucking as dry as possible, this 8.75 g of ochre-colored solid was
dissolved in 14 mL of boiling MeOH, and after cooling, filtering,
washing sparsely with MeOH, and air drying, gave 7.27 g of white solid
crystals of 2,5-dimethoxy-4-(cyclopropylmethylthio)benzaldehyde. The
proton NMR spectrum was impeccable; CHO 9.38, ArH 7.27, 6.81 2 s.,
OCH3 3.93, 3.90 2 s., SCH2 t. 2.96, CH2, m. 1.72, and CH2, t. 1.11.
To a solution of 6.6 g 2,5-dimethoxy-4-(cyclopropylthio)benzaldehyde
in 82 g of nitromethane there was added 0.12 g of anhydrous ammonium
acetate, and the mixture was heated on the steam bath for 6 h. The
reaction mixture was allowed to stand overnight producing a heavy
crystallization crop. Filtration, washing lightly with MeOH, and air
drying gave 4.72 g of orange crystals of
2,5-dimethoxy-4-cyclopropylmethylthio-'-nitrostyrene as yellow
crystals. The evaporation of the mother liquors and grinding of the
resulting solids with MeOH provided another 2.0 g of the product.
A solution LAH (40 mL of a 1 M solution in THF) was cooled, under He,
to 0 !C with an external ice bath. With good stirring there was added
1.05 mL 100% H2SO4 dropwise over 10 min, to minimize charring. This
was followed by the addition of 2.95 g
2,5-dimethoxy-4-cyclopropylmethylthio-'-nitrostyrene as a solid, over
the course of 10 min. After a few min further stirring, the
temperature was brought up to a gentle reflux on the steam bath, then
all was cooled again to 0 !C. The excess hydride was destroyed by the
cautious addition of 6 mL IPA followed by 3 mL 15% NaOH which gave the
aluminum oxide as a curdy white solid. The reaction mixture was
filtered, and the filter cake washed with additional THF. The
filtrate and washes were stripped of solvent under vacuum providing
about 1.8 g of a colorless oil. The addition of dilute H2SO4 produced
a thick mass of white solids. This was washed with CH2Cl2, and the
remaining aqueous phase, still containing solids, was made basic with
25% NaOH. The aqueous phase was extracted with 3x75 mL CH2Cl2, and
the combined extracts stripped of solvent under vacuum. The result
was 1.4 g of colorless oil. This was distilled at 150-165 !C at 0.2
mm/Hg to give 1.2 g of a white oil. This was dissolved in 6 mL IPA,
neutralized with 0.6 mL concentrated HCl producing spontaneous white
crystals. These were diluted with 8 mL additional IPA, and suspended
under 60 mL anhydrous Et2O to provide, after filtering and air drying,
1.13 g of 2,5-dimethoxy-4-cyclo-propylmethylthiophenethylamine
hydrochloride (2C-T-8) as white crystals.
DOSAGE: 30 - 50 mg.
DURATION: 10 - 15 h.
QUALITATIVE COMMENTS: (with 30 mg) Bad taste, worse smell. But I
like it. I can paint easily, and wouldnUt hesitate to take a little
more next time, but this is enough with no one to talk to. Manual
dexterity good. Body rather warm. WouldnUt mind fooling around. In
retrospect, it has a smooth onset, and is not too stimulating. This
is a good one.
(with 40 mg) This is beginning to develop at one and a half hours
into it. High energy, good feeling. I have had a heavy, dense
feeling between me and my work for several days now, but this is
rapidly dissolving, and with this loss, the day continues into one of
the most remarkable experiences I have ever had. Excellent feelings,
tremendous opening of insight and understanding, a real awakening as
if I had never used these materials effectively before. For the next
several hours it was an internal journey for me; I wished to interact
with myself. I cannot recall all the details, but I did review many
aspects of myself and my personal relations. I know that I am the
better for all of this.
(with 40 mg) I first noted the effects at three quarters of an hour,
and at two hours I have pain in my sinuses. My head is split in two Q
this is not being two or three different people Q this is one person
with a head living in two different universes at the same time. Not a
crisis experience, but one of extreme and prolonged discomfort.
Hypersensitivity to light, noise, motion, with the belief that it
would not go away when the chemical wore off. My visual and spatial
perceptions were divided in two along a vertical axis, with both
halves moving in uncoordinated ways. A feeling that the eyes were
working independently of each other. Nausea without vomiting, even
when I tried to. Vertigo became intolerable if I closed my eyes or
lay down, so I felt that I would never lie down or close my eyes
again. Problems with 'boundaries.' The outside environment seemed to
be getting inside my head. The parts of myself seemed to either
separate uncontrollably or run together into someone I didnUt know. A
late movie, and Tranxene, and a little sleep all helped me out of
this. However, a buzzing in the head, an uncertain balance, and an
out-of-it feeling lasted for 3 days, and was still faintly present
after a week.
(with 43 mg) For the first two hours I rocked in place and felt quite
happy not trying to 'do' anything useful or expected, but watched some
excellent programs on TV. Later I sat at the typewriter and felt the
energy and the opening of the particular kind of thinking-connection
that I associate with 2C-T-2. I felt this very strongly; I was fully
into my own energy and capable of being aggressive if I decided to. I
was very good humored and completely anchored to the earth. In the
late evening I went to bed and felt that I would not allow myself to
sleep, since the tendency to go completely out of conscious body was
quite strong. However, before I could get up and continue happily
writing, as I intended, I fell asleep. I slept thoroughly, well, and
woke up the next day with good energy and a willingness to get on with
the day.
(with 50 mg) The whole experience was somewhat negative,
self-doubting, paranoid. Basically, I am not in a good place. No
constructive values ever knit, and although there was a lot of
talking, nothing positive developed. I was glad of sleep at about
twelve hours into it, and this aspect of it was completely friendly.
Next day, no deficit. Strange. Maybe too much.
EXTENSIONS AND COMMENTARY: With 2C-T-8, there are as many negatives as
there are positives, and the particular substitution pattern is not
one to set the world on fire. The first step was made towards the
synthesis of the 3-carbon counterpart,
2,5-dimethoxy-4-cyclopropylmethylthioamphetamine, ALEPH-8. The above
benzaldehyde (2.2 g) was cooked overnight on the steam bath in
nitroethane (20 mL) containing ammonium acetate (0.4 g) and when the
solvent was removed, the residue was converted to orange crystals by
the addition of a little MeOH. This was not pursued further.
Although the cyclopropylmethyl group was quite something on the
mescaline oxygen atom, it is less appealing on the 2C-T-X sulfur atom,
and there is even less enthusiasm to put it into an ALEPH. That's the
way it is, and who could have guessed!
#45 2C-T-9; 2,5-DIMETHOXY-4-(t)-BUTYLTHIOPHENETHYLAMINE
SYNTHESIS: To a well-stirred ice-cold suspension of 2.8 g
p-dimethoxybenzene and 3.2 mL N,N,NU,NU-tetramethylethylenediamine in
100 mL petroleum ether under an inert atmosphere of He, there was
added 13 mL of a 1.6 N solution of butyllithium in hexane. The
suspended dimethoxybenzene became opaque and there was a pale yellow
color generated. The reaction mixture was warmed to room temperature
which converted it to light white solids. After an additional 0.5 h
stirring, there was added, slowly, 3.6 g of di-(t)-butyldisulfide.
The yellow color deepened, the solids dissolved and, after 1 h, the
color was a clear deep brown. This solution was poured into 100 mL
dilute HCl and the organic phase was separated. The aqueous fraction
was extracted with 3x75 mL CH2Cl2. The combined organic phases were
washed with dilute aqueous NaOH, with H2O, and then stripped of
solvents under vacuum. The residue was distilled at 95-105 !C at 0.5
mm/Hg to provide 3.7 g of 2,5-dimethoxyphenyl (t)-butyl sulfide as a
white, mobile liquid. Anal. (C12H18O2S) C,H. A solid derivative was
found in the nitration product,
2,5-dimethoxy-4-(t)-butylthio-1-nitrobenzene, which came from the
addition of 0.11 mL of concentrated HNO3 to a solution of 0.23 g of
the above sulfide in 5 mL ice cold acetic acid. Dilution with H2O
provided yellow solids which, on recrystallization from MeOH, had a mp
of 92-93 !C. Anal. (C12H17NO4S) C,H. Attempts to make either the
picrate salt or the sulfonamide derivative were not satisfactory.
A mixture of 72 g POCl3 and 67 g N-methylformanilide was heated for 10
min on the steam bath. To this claret-colored solution was added 28 g
of 2,5-dimethoxyphenyl (t)-butyl sulfide, and the mixture heated for
10 min on the steam bath. This was then added to 1 L of H2O and
stirred overnight. The residual brown oil was separated from the
water mechanically, and treated with 150 mL boiling hexane. The
hexane solution was decanted from some insoluble tars, and on cooling
deposited a dark oil which did not crystallize. The remaining hexane
was removed under vacuum and the residue combined with the above
hexane-insoluble dark oil, and all distilled at 0.2 mm/Hg. An early
fraction (70-110 !C) was largely N-methyl-formanilide and was
discarded. Crude 2,5-dimethoxy-4-(t-butylthio)benzaldehyde came over
at 120-130 !C and weighed 12.0 g. This was never satisfactorily
crystallized despite the successful formation of seed. It was a
complex mixture by TLC, containing several components. It was used
for the next step as the crude distilled fraction.
To a solution of 10 g impure 2,5-dimethoxy-(t-butylthio)benzaldehyde
in 75 mL of nitromethane there was added 1.0 g of anhydrous ammonium
acetate, and the mixture was heated on the steam bath 1.5 h. Removal
of the excess solvent/reagent under vacuum produced an orange oil that
was (not surprisingly) complex by TLC and which would not crystallize.
A hot hexane solution of this oil was allowed to slowly cool and stand
at room temperature for several days, yielding a mixture of yellow
crystals and a brown viscous syrup. The solids were separated and
recrystallized from 40 mL MeOH to give 3.7 g
2,5-dimethoxy-4-(t)-butylthio-'-nitrostyrene as fine lemon-yellow
crystals, with a mp of 93-94 !C. A second crop of 1.4 g had a mp of
91-92 !C. Anal. (C14H19NO4S) C,H.
A solution of LAH (70 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath. With good stirring there was
added 2.1 mL 100% H2SO4 dropwise, over the course of 20 min. This was
followed by the addition of 4.7 g
2,5-dimethoxy-4-(t)-butylthio-'-nitrostyrene in 20 mL anhydrous THF.
There was an immediate loss of color. After a few min further
stirring, the mixture was allowed to come to room temperature, and the
stirring was continued for 5 h. The excess hydride was destroyed by
the cautious addition of 10 mL IPA followed by 6 mL 15% NaOH and
finally 6 mL H2O. The loose white solids were removed by filtration,
and the filter cake washed with THF. The filtrate and washes were
combined and, after stripping off the solvent under vacuum, there was
obtained 4.66 g of a pale yellow oil. Without any further
purification, this was distilled at 0.2 mm/Hg. A first fraction came
over at up to 120 !C and was a light colorless oil that was not
identified. The correct product distilled at 130-160 !C as a pale
yellow viscous oil that weighed 1.66 g. This was dissolved in 10 mL
IPA, neutralized with 20 drops of concentrated HCl and diluted with 80
mL anhydrous Et2O. After standing a few min there was the spontaneous
generation of white crystals of
2,5-dimethoxy-4-(t)-butylthiophenethylamine hydrochloride (2C-T-9)
which were removed by filtration, and air dried. The weight was 1.10
g.
DOSAGE: 60 - 100 mg.
DURATION: 12 - 18 h.
QUALITATIVE COMMENTS: (with 90 mg) 2C-T-9 tastes the way that old
crank-case motor oil smells. I was up to something above a plus two
at the third hour. Although there were no visuals noted, I certainly
would not choose to drive. Somehow this does more to the body than to
the head. I feel that the effects are waning at maybe the sixth hour,
but there is a very strong body memory that makes sleeping difficult.
Finally, at sometime after midnight and with the help of a glass of
wine, some sleep.
(with 125 mg) There was a steady climb to a +++ over the first couple
of hours. So far, the body has been quite peaceful without any strong
energy push or stomach problems, although my tummy insists on being
treated with quiet respect, perhaps out of habit, perhaps not. At the
fifth hour, the body energy is quite strong, and I have the choice of
focusing it into some activity, such as love-making or writing, or
having to deal with tapping toes and floor-pacing. For a novice this
would be a murderously difficult experience. Too much energy, too
long a time. I suppose I could get used to it, but let me judge by
when I get to sleep, and just what kind of sleep it is. It turned out
that sleep was OK, but for the next couple of days there was a
continuing awareness of some residue in the body Q some kind of
low-level poisoning. I feel in general that there is not the
excitement or creativity to connect with, certainly not enough to
justify the cost to the body.
EXTENSIONS AND COMMENTARY: The three-carbon analog of 2C-T-9 (this
would be one of the ALEPH series) has never been made and, for that
matter, none of the higher numbered 2C-T's have had the amphetamine
counterparts synthesized. They are, as of the present time, unknown
compounds. This nifty reaction with di-(t)-butyl disulfide worked so
well, that three additional disulfides that were at hand were
immediately thrown into the chemical program, with the quick
assignment of the names 2C-T-10, 2C-T-11, and 2C-T-12.
The lithiated dimethoxybenzene reaction with 2,2-dipyridyl disulfide
produced 2,5-dimethoxyphenyl 2-pyridyl sulfide which distilled at
135-150 !C at 0.4 mm/Hg and could be recrystallized from cyclohexane
containing 2% EtOH to give a product that melted at 66-67.5 !C. Anal.
(C13H13NO2S) C,H. This would have produced
2,5-dimethoxy-4-(2-pyridylthio)phenethylamine (2C-T-10) but it was
never pursued.
The same reaction with di-(4-bromophenyl) disulfide produced
2,5-dimethoxyphenyl 4-bromophenyl sulfide which distilled at 150-170
!C at 0.5 mm/Hg and could be recrystallized from MeOH to give a
product that melted at 72-73 !C. Anal. (C14H13BrO2S) C,H. This was
being directed towards
2,5-dimethoxy-4-(4-bromophenylthio)phenethylamine (2C-T-11) but it
also was abandoned.
The same reaction with N,N-dimorpholinyl disulfide produced virtually
no product at all, completely defusing any plans for the synthesis of
a novel sulfur-nitrogen bonded base
2,5-dimethoxy-4-(1-morpholinothio)phenethylamine (2C-T-12). One
additional effort was made to prepare a 2C-T-X thing with a
sulfur-nitrogen bond. The acid chloride intermediate in the
preparation of 2,5-dimethoxythiophenol (as described in the recipe for
2C-T-2) is 2,5-dimethoxybenzenesulfonyl chloride. It reacted smoothly
with an excess of diethylamine to produce
2,5-dimethoxy-N,N-diethylbenzenesulfonamide which distilled at 155 !C
at 0.13 mm/Hg and which could be recrystallized from a 4:1 mixture of
cyclohexane/benzene to give a product with a melting point of 41-42 !C
and an excellent proton NMR. This amide proved totally refractory to
all efforts at reduction, so the target compound,
2,5-dimethoxy-4-diethylaminothiophenethylamine, has not been made. It
has not even been given a 2C-T-X number.
#46 2C-T-13; 2,5-DIMETHOXY-4-(2-METHOXYETHYLTHIO)PHENETHYLAMINE
SYNTHESIS: To a solution of 3.25 g of KOH pellets in 25 mL hot MeOH,
there was added 6.8 g of 2,5-dimethoxythiophenol (see under 2C-T-2 for
its preparation) followed by 4.73 g of 2-methoxyethylchloride. This
mixture was heated on the steam bath for 0.5 h, then added to 500 mL
H2O. This very basic aqueous phase was extracted with 3x100 mL
CH2Cl2, the extracts pooled, and back-washed with 5% NaOH. The
solvent was removed under vacuum to give 8.82 g of a white oil.
Distillation gave 2,5-dimethoxyphenyl 2-methoxyethyl sulfide with a bp
115-125 !C at 0.3 mm/Hg, and a weight of 6.65 g.
A mixture of 10 g POCl3 and 10 g N-methylformanilide was heated for 10
min on the steam bath. To this claret-colored solution was added 6.16
g of 2,5- dimethoxyphenyl 2-methoxyethyl sulfide. There was an
immediate exothermic reaction and gas evolution. The mixture was
heated for 15 min on the steam bath, at which time there was no
starting sulfide present by TLC. This was then added to 500 mL of
well-stirred warm H2O (pre-heated to 55 !C) and the stirring continued
until only a thin oily phase remained. This was extracted with
CH2Cl2, the extracts were combined, and the solvent removed under
vacuum. The residue was extracted with 5 sequential 20 mL portions of
boiling hexane which deposited crystals on cooling. Filtering gave a
total of 4.12 g crystalline solids. Recrystallization from MeOH gave
a poor yield of a cream-colored crystal with a mp of 68-69 !C. A more
efficient purification was achieved by distillation (155-168 !C at 0.3
mm/Hg) yielding 3.50 g of
2,5-dimethoxy-4-(2-methoxyethylthio)benzaldehyde as a pale yellow
solid, with a mp of 67-68 !C. A faster moving (by TLC) trace
component with an intense fluo-rescence persisted throughout the
entire purification scheme, and was still present in the analytical
sample. Anal. (C12H16O4S) C,H.
To a solution of 3.41 g
2,5-dimethoxy-4-(2-methoxyethylthio)benzaldehyde in 50 g of
nitromethane there was added 0.11 g of anhydrous ammonium acetate, and
the mixture was heated on the steam bath for 2 h, at which time the
starting aldehyde had largely disappeared by TLC (silica gel plates
with CH2Cl2 as the developing solvent) and a faster moving
nitrostyrene product was clearly visible. The clear orange solution
was stripped of the excess nitromethane under vacuum producing a
yellow oil that crystallized yielding 3.97 g of a yellow solid with a
mp of 99-104 !C. Recrystallization of a small sample from MeOH
produced (when dry) yellow electrostatic crystals of
2,5-dimethoxy-4-(2-methoxyethylthio)-'-nitrostyrene with a mp of 107
!C sharp. From IPA the product is a burnished gold color with the mp
106-107 !C. Anal. (C13H17NO5S) C,H.
A solution of LAH (40 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath. With good stirring there was
added 1.05 mL 100% H2SO4 dropwise, to minimize charring. This was
followed by the addition of 3.07 g
2,5-dimethoxy-4-(2-methoxyethylthio)-'-nitrostyrene in small portions,
as a solid, over the course of 10 min. There was a considerable
amount of gas evolved, and a little bit of charring. After a few min
further stirring, the temperature was brought up to a gentle reflux on
the steam bath, and then all was cooled again to 0 !C. The excess
hydride was destroyed by the cautious addition of 8 mL IPA followed by
3 mL 15% NaOH which gave the reaction mixture a curdy white granular
character. The reaction mixture was filtered, the filter cake washed
with THF, and filtrate and washes were stripped of solvent under
vacuum providing about 3 g of a pale amber oil. This was dissolved in
about 40 mL CH2Cl2 and extracted with 200 mL dilute H2SO4 in three
portions. All of the color remained in the organic phase. The pooled
aqueous extracts were washed with CH2Cl2, then made basic with 25%
NaOH, extracted with 3x75 mL CH2Cl2, and the combined extracts pooled
and stripped of solvent under vacuum. The 2 g pale yellow oily
residue was distilled at 155-165 !C at 0.2 mm/Hg to give 1.23 g of a
clear white oil. This was dissolved in IPA, neutralized with
concentrated HCl, and diluted with anhydrous Et2O to produce crystals
of 2,5-dimethoxy-4-(2-methoxyethylthio)phenethylamine hydrochloride
(2C-T-13). After filtration, washing with Et2O, and air drying, this
white crystalline product weighed 0.89 g.
DOSAGE: 25 - 40 mg.
DURATION: 6 - 8 h.
QUALITATIVE COMMENTS: (with 25 mg) I felt it was somewhat noisy as we
went into the experience. This noisiness lasted only about an hour,
then stopped. At the peak, which seemed to be at about 1 to maybe 1.5
hours, some eyes-closed visuals appeared. There was a white field
with colored visuals, at times geometric in shape. These eye-closed
images were pleasant and I enjoyed them when I did not concern myself
with, or listen to, the conversation. There was an eyes-open change
in color, the ivy became a little lighter or maybe a little stronger
in color. IUm not sure which. I felt there was a gradual diminishing
of activity (whatever that undefined activity was) starting at 2 to
2.5 hours, and coming close to baseline at 6 PM. The descent was
pleasant and I would say pleasurable. The experience did not lead to
any confusion which I sometimes notice in other experiences. There
was no problem with anorexia. We ate constantly during the
experience. The grapes and other fruit were lovely. This is one of
the few times I would say that I would try a higher dose. Maybe 30 or
33 milligrams. I suspect the experience would be similar, with just a
heightened peak at 1 hour and perhaps a little more body effect. It
may well be one to try with one's wife.
(with 28 mg) There was a strange, disturbing twinge exactly eight
minutes after starting this, that asked me, TShould I have done this?U
I answered, TYesU and the twinge disappeared. And then there was
nothing until the expected time of development, at a half hour when I
felt a light head and slight dizziness. There was a solid plus two
for a couple of hours. I paid careful attention for auditory oddities
that I had noted before, but they were not there. In an earlier trial
(with 20 milligrams) the radio had the sound of being located in the
outdoors with the sounds coming through the wall and into the room
where I was. I was at a neutral baseline at about seven hours.
(with 35 mg) There was a quiet climb, but it was marred with some
tummy unquiet, and an annoying persistence of diarrhea. I was very
impressed with eyes-closed patterning, which seemed to do its own
thing independently of the music. I was clearly up to a +++, but
there was a feeling that as soon as it got there it started to go away
again. There was no there, there. Yet there were a couple of touches
of introspection, of seriousness which I had to respect.
(with 40 mg) There were four of us, and the entry was individual for
each of us. Two of us were nauseous. One volunteered a statement,
almost a confession, of too much food and drink in the immediate past.
One of us needed his cigarette right now, and then he saw that he was
killing himself, and he swore off. DonUt know if it will last,
however. At the two and a half hour point there is a consensus that
this has gone its route and will lose its impact, so three of us
decided to supplement on 2C-T-2. Six milligrams proves to be a little
light so, some four hours later, we each took another six milligrams.
Excellent. In a while we discoved that we were very hungry, and food
tasted marvelous. Headaches acknowledged in the early evening, but
the extension from T-13 to T-2 seemed to be absolutely correct. And
as of the next day, the non-smoker was still a non-smoker.
EXTENSIONS AND COMMENTARY: Most of the synthetic adventures of putting
a basic something aways out from the benzene ring, at the
four-position, have involved subtle things such as unsaturated bonds
or three-membered rings. This was the first try with the actual use
of a different atom (an oxygen). What about other heteroatoms such as
sulfur or nitrogen or silicon or phosphorus, or some-such?
The sulfur counterpart of 2C-T-13 was named 2C-T-14, and was
immediately launched. The reaction of 2,5-dimethoxythiophenol and KOH
with 2-methyl-thioethyl chloride in hot MeOH gave 2,5-dimethoxyphenyl
2-methylthioethyl sulfide as a white oil (boiling point of 140-160 !C
at 0.3 mm/Hg). This underwent a normal Vilsmeier reaction
(phosphorous oxychloride and N-methylformanilide) to give
2,5-dimethoxy-4-(2-methylthioethylthio)benzaldehyde with a melting
point of 64-64.5 !C from MeOH. This, in nitromethane containing a
little ammonium acetate, was heated on the steam bath for 10 hours and
worked up to give an excellent yield of
2,5-dimethoxy-4-(2-methylthioethylthio))-'-nitrostyrene as garish
orange-red RLas VegasS colored crystals from acetonitrile, with a
melting point of 126-127 !C. And as of the moment, this is sitting on
the shelf waiting to be reduced to the target compound
2,5-dimethoxy-4-(2-methylthioethylthio)phenethylamine hydrochloride,
or 2C-T-14. Will it be active? I rather suspect that it will be, and
IUll bet it will be longer-lived than the oxygen model, 2C-T-13.
#47 2C-T-15; SESQUI; 2,5-DIMETHOXY-4-CYCLOPROPYLTHIOPHENETHYLAMINE
SYNTHESIS: To a solution of 3.3 g of KOH pellets in 150 mL hot MeOH,
there was added 10 g 2,5-dimethoxythiophenol (see recipe for 2C-T-2
for its preparation) followed by 10 g 1-bromo-3-chloropropane. The
reaction was exothermic, and immediately deposited white solids of
KCl. The reaction mixture was warmed for a few min on the steam bath,
and then quenched in H2O. The basic reaction mixture was extracted
with 3x75 mL CH2Cl2. The pooled extracts were stripped of solvent
under vacuum. The residual oil was distilled at 145-155 !C at 0.2
mm/Hg to give 16.5 g of 2,5-dimethoxyphenyl 3-chloropropyl sulfide as
a clear, colorless oil.
A solution of the lithium amide of 2,2,6,6-tetramethylpiperidine was
prepared by the addition of 20 mL of 2.6 M butyllithium in hexane to a
well stirred hexane solution of the piperidine in 100 mL hexane, under
an atmosphere of He. The reaction was exothermic, formed a white
solid precipitate, and was allowed to continue stirring for a few min.
There was then added 6.5 g 2,5-dimethoxphenyl 3-chloropropyl sulfide,
and a strongly exothermic reaction ensued. This was stirred for 30
min and then poured into dilute H2SO4 (the progress of the reaction
must be followed by TLC, silica gel plates, CH2Cl2:petroleum ether
50:50 to determine when it is done; in one run over 2 h were required
for completion of the reaction). The organic phase was separated, and
the aqueous phase extracted with 3x75 mL EtOAc. The combined organic
phases were washed first with dilute NaOH, then with dilute HCl, then
the solvents were removed under vacuum. The residue was distilled to
provide 2,5-dimethoxyphenyl cyclopropyl sulfide as a pale yellow
liquid that boiled at 100-115 !C at 0.1 mm/Hg. The use of other bases
to achieve this cyclization were less successful. Incomplete
cyclization resulted from the use of lithium diisopropyl amide and, if
the conditions were made more vigorous, there was dehydrohalogenation
to the allyl sulfide. An unexpected difficulty was that the allyl
sulfide (from elimination) and the 3-chloropropyl sulfide (starting
material) behaved in an identical manner on TLC analysis. They were
easily separated, however, by GC analysis.
A completely different approach to the synthesis of this sulfide was
explored through the reaction of cyclopropyllithium with an aromatic
disulfide, thus avoiding the base-promoted cyclization step. A
solution of 2.6 g di-(2,5-dimethoxyphenyl)disulfide (from
2,5-dimethoxythiophenol and hydrogen peroxide, bp 220-230 !C at 0.3
mm/Hg) was made in anhydrous Et2O, and well stirred. In a separate
flask, under an atmosphere of He, 4 mL of 2.6 M butyllithium was added
to a solution of 1.2 g cyclopropyl bromide in 20 mL anhydrous Et2O.
This mildly exothermic combination turned a bit cloudy, was stirred
for 1 h, then trans-ferred with an air-tight syringe to the
above-described Et2O solution of the aromatic disulfide. A heavy
precipitate formed, and stirring was continued for an additional 0.5
h. The reaction mixture was then poured into H2O, the layers
separated, and the aqueous phase extracted with CH2Cl2. The extracts
were pooled, washed with dilute aqueous KOH, and the solvents removed
under vacuum. Distillation gave 0.7 g of 2,5-dimethoxyphenyl
cyclopropyl sulfide with identical gas chromatographic behavior to the
sample prepared by the cyclization of the chloropropylthio compound.
A mixture of 7.2 g POCl3 and 6.7 g N-methylformanilide was heated on
the steam bath until it was claret red. To this there was added 4.5 g
of 2,5-di-methoxyphenyl cyclopropyl sulfide, and the exothermic
combination heated on the steam bath for about 5 min. The deep red,
bubbling reaction mixture was added to 150 mL H2O and stirred until
all oils had been converted into loose solids. These were then
removed by filtration, washed with H2O, and sucked as dry as possible.
They were dissolved in boiling MeOH which, after cooling in an
ice-bath, deposited yellow crystals of
2,5-dimethoxy-4-(cyclopropylthio)benzaldehyde that weighed 3.43 g
after air drying, and had a mp of 97-99 !C. Anal. (C12H14O3S) C,H.
To a solution of 3.0 g 2,5-dimethoxy-4-(cyclopropylthio)benzaldehyde
in 40 g of nitromethane there was added 0.2 g of anhydrous ammonium
acetate, and the mixture was heated on the steam bath for 3 h. The
excess nitromethane was removed under vacuum yielding 3.4 g orange
crystals. These were recrystallized from 150 mL boiling IPA
containing a little toluene. After cooling, filtering, and air drying
there were obtained 2.75 g of
2,5-dimethoxy-4-cyclopropylthio-'-nitro-styrene as pumpkin-colored
crystals with a mp of 159-160 !C. Anal. (C13H15NO4S) C,H.
A solution of LAH (40 mL of a 1 M. solution in THF) was cooled, under
He, to 0 !C with an external ice bath. With good stirring there was
added 1.05 mL 100% H2SO4 dropwise, to minimize charring. This was
followed by the addition of 2.5 g
2,5-dimethoxy-4-cyclopropylthio-'-nitrostyrene in 40 mL anhydrous THF
over the course of 15 min. There was an immediate loss of color.
After a few min further stirring, the temperature was brought up to a
gentle reflux on the steam bath and held there for 2 h. After
recooling, there was added IPA (to destroy the excess hydride)
followed by sufficent 15% NaOH to give a white granular character to
the oxides, and to assure that the reaction mixture was basic. The
reaction mixture was filtered, and the filter cake washed with THF.
The filtrate and washes were stripped of solvent under vacuum
providing a yellow oil that was treated with dilute H2SO4. This
produced a flocculant white solid, apparently the sulfate salt of the
product. This was washed with 4x75 mL CH2Cl2 which removed most of
the yellow color. The aqueous phase was made basic with aqueous NaOH
and extracted with 3x75 mL CH2Cl2. Removal of the solvent under
vacuum gave a light yellow colored oil that was distilled at 0.3
mm/Hg. The fraction boiling at 140-150 !C was a colorless, viscous
oil that weighed 1.97 g. This was dissolved in a few mL IPA, and
neut-ralized with concentrated HCl forming immediate cottage
cheese-like crystals of the hydrochloride salt. This was diluted by
suspension in anhydrous Et2O, removed by filtration, and air dried to
give 1.94 g of 2,5-dimethoxy-4-cyclopropylthiophenethylamine
hydrochloride (2C- T-15) that had a mp of 203-5-204.5 !C. Anal.
(C13H20ClNO2S) C,H.
DOSAGE: greater than 30 mg.
DURATION: several hours.
QUALITATIVE COMMENTS: (at 30 mg) I was somewhere between a threshold
and a plus one for several hours, and appeared to be quite talkative
in the evening.
EXTENSIONS AND COMMENTARY: The commonly used name for 2C-T-15, during
its synthesis, was SESQUI. The general name for a 15-carbon terpene
is sesquiterpene, from the Latin prefix for one and a half. The
active level of 2C-T-15 is not known. The highest level yet tried was
30 milligrams orally, and there had been threshold reports pretty
regularly all the way up from 6 milligrams. But no definite activity
yet. This compound is isosteric with the isopropyl group as seen in
the analogous compound 2C-T-4 (the three carbons are in exactly the
same positions, only the electrons are located differently) and it is
a little surprising that the potency appears to be considerably less.
Just over 20 milligrams of the latter compound was overwhelmingly
psychedelic.
The entire mini-project of hanging cyclic things onto the sulfur atom
was an interesting problem. This is the three carbon ring. The six
carbon ring (the cyclohexyl homologue) was discussed as 2C-T-5 in the
recipe for of ALEPH-2. The cyclobutyl and cyclopentyl homologs were
assigned the names of 2C-T-18 and 2C-T-23, respectively, and their
preparations taken as far as the nitrostyrene and the aldehyde stages,
respectively, before the project ran out of steam.
Towards the cyclobutyl homologue, a solution of
2,5-dimethoxythiophenol and cyclobutyl bromide in DMSO containing
anhydrous potassium carbonate was stirred for several hours at room
temperature and yielded 2,5-dimethoxyphenyl cyclobutyl sulfide as a
white oil that boiled at 135-140 !C at 0.3 mm/Hg. Anal. (C12H16O2S)
C,H. This was brought to react with a mixture of phosphorus
oxy-chloride and N-methylformanilide producing
2,5-dimethoxy-4-(cyclobutylthio)benzaldehyde that had a melting point
of 108-109.5 !C from MeOH. Anal. (C13H16O3S) C,H. Coupling with
nitromethane in the presence of ammonium acetate produced
2,5-dimethoxy-4-cyclobutylthio-'-nitrostyrene as lustrous orange
crystals from boiling acetonitrile, melting point 160-161 !C. Anal,
(C14H17NO4S) C,H. This will some day be reduced to
2,5-dimethoxy-4-cyclobutylthiophenethylamine hydrochloride, 2C-T-18.
Towards the cyclopentyl homologue, a solution of
2,5-dimethoxythiophenol and cyclopentyl bromide in DMSO containing
anhydrous potassium carbonate was stirred for several hours at room
temperature and yielded 2,5-dimethoxyphenyl cyclopentyl sulfide as a
white oil that boiled at 135-145 !C at 0.3 mm/Hg. This was brought to
react with a mixture of phosphorus oxychloride and N-methylformanilide
producing 2,5-dimethoxy-4-(cyclopentylthio)benzaldehyde as yellow
crystals from MeOH. This will some day be converted to the
nitrostyrene and then reduced to
2,5-dimethoxy-4-cyclopentylthiophenethylamine hydrochloride, 2C-T-23.
#48 2C-T-17; NIMITZ; 2,5-DIMETHOXY-4-(s)-BUTYLTHIOPHENETHYLAMINE
SYNTHESIS: To a solution of 2.6 g of KOH pellets in 50 mL hot MeOH,
there was added a mixture of 6.8 g 2,5-dimethoxythiophenol (see under
2C-T-2 for its preparation) and 5.8 g (s)-butyl bromide. The reaction
was exothermic, with the deposition of white solids. This was heated
on the steam bath for a few h, the solvent removed under vacuum, and
the resulting solids dissolved in 250 mL H2O. Additional aqueous NaOH
was added to bring universal pH paper to a full blue color. This was
extracted with 3x40 mL CH2Cl2, the extracts pooled, and the solvent
removed under vacuum. The residue was 2,5-dimethoxyphenyl (s)-butyl
sulfide which was a pale yellow oil, weighing 10.12 g. It was
sufficiently pure for use in the next reaction without a distillation
step.
A mixture of 15.1 g POCl3 and 14.1 g N-methylformanilide was heated
for 10 min on the steam bath. To this claret-colored solution was
added 9.4 g of 2,5-dimethoxyphenyl (s)-butyl sulfide, and the mixture
heated for 35 min on the steam bath. This was then added to 200 mL of
well-stirred warm H2O (pre-heated to 55 !C) and the stirring continued
until the oily phase had completely solidified (about 15 min). These
light brown solids were removed by filtration, and washed with
additional H2O. After sucking as dry as possible, these solids (12.14
g wet) were ground under an equal weight of MeOH which produced a
yellowish crystalline solid with a mp of 76-81 !C. Recrystallization
of a 0.4 g sample from an equal weight of boiling MeOH provided 0.27 g
of 2,5-dimethoxy-4-(s-butylthio)benzaldehyde as a pale cream-colored
crystalline material with a mp of 86-87 !C.
To a solution of 8.0 g of the crude
2,5-dimethoxy-4-(s-butylthio)benzaldehyde in 40 g of nitromethane
there was added 0.38 g of anhydrous ammonium acetate, and the mixture
was heated on the steam bath for 1 h. The reddish colored solution
was decanted from some insoluble tan material and the excess
nitromethane removed under vacuum. The heavy red oil that remained
was diluted with an equal volume of boiling MeOH, and allowed to
return to room temperature. The orange-colored crystals that slowly
formed were removed by filtration and, after air drying, weighted 6.24
g. This was again recrystallized from an equal volume of MeOH,
yielding 2,5-dimethoxy-4-(s-butylthio)-'-nitrostyrene as yellow,
somewhat beady crystals that weighed (when dry) 3.50 g and which had a
mp of 62-65 !C. A small portion of this fraction was crystallized yet
again from MeOH to provide an analytical sample that was yellow-orange
in color, and had an mp of 68-69 !C. Anal. (C13H17NO4S) C,H.
A solution of LAH (120 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath. With good stirring there was
added 3.3 mL 100% H2SO4 dropwise, to minimize charring. This was
followed by the addition of 8.83 g
2,5-dimethoxy-4-(s-butylthio)-'-nitrostyrene in 80 mL anhydrous THF
dropwise over the course of 2 h. After a few min further stirring,
the temperature was brought up to a gentle reflux on the steam bath,
and then all was cooled again to 0 !C. The excess hydride was
destroyed by the cautious addition of 18 mL IPA followed first by 5 mL
of 15% NaOH and then by 15 mL of H2O. The reaction mixture was
filtered, and the filter cake washed with THF. The filtrate and
washing were combined and stripped of solvent under vacuum providing
about 8.5 g of a pale amber oil. Without any further purification,
this was distilled at 135-150 !C at 0.4 mm/Hg to give 6.12 g of a
clear white oil. This was dissolved in 30 mL IPA, and neutralized
with 2.1 mL of concentrated HCl forming crystals immediately. Another
10 mL of IPA was added to allow the solids to be finely dispersed, and
then about 100 mL of anhydrous Et2O were added. The solids were
removed by filtration, Et2O washed, and air dried to constant weight.
The product, 2,5-dimethoxy-4-(s)-butylthiophenethylamine hydrochloride
(2C-T-17) was obtained as spectacular white crystals, weighing 5.67 g.
DOSAGE: 60 - 100 mg.
DURATION: 10 - 15 h.
QUALITATIVE COMMENTS: (with 60 mg) This material took fully three
hours to get into its maximum effect. I never was at a +++, quite,
and I am not sure why it is really active, but I know it is. There
does not seem to be any interference with my concentration or mental
coordination, but I wouldnUt want to drive right now. Good appetite
in the evening, for a Chicago-style pizza, and there was no Tomso
effects (the rekindling of a psychedelic effect with alcohol) with a
glass of wine. An over-all good and instructive ++, no visuals,
totally benign. There is no hesitation in doing it again some day.
(with 100 mg) A small fragment hadnUt dissolved when I drank the
solution, and it must have stuck to the back of my mouth, because it
made a searing spot that burned for 5 minutes. The first central
effects were noted at an hour. The plateau stretched from the 3rd to
the 7th hour, then tapered off quite quickly. My sleep was fitful,
with some hints of nervous sensitivity. I felt that there were some
residuals even into the next morning. A truly heavy psychedelic, but
with very few explicit sensual changes or unusual perceptions to
justify that comment. Why is it heavy? It just is. This dosage is
high enough.
EXTENSIONS AND COMMENTARY: An interesting, and quite logical, habit
that seems to always pop up when a lot of talk and energy become
directed at a specific compound, is the habit of using a nickname for
it. The Tweetios are an example, and in the 2C-T-X family I had
mentioned the term SESQUI. Here, this compound was called NIMITZ, for
the obvious reason that the major freeway from Oakland to San Jose,
the Nimitz freeway, was also called State Highway 17. Its name has
been changed to Interstate 880, and I guess it could now only be used
as a reference point if efforts were being made for a 2C-T-880.
The reason that 2C-T-17 is of special theoretic interest is that it is
one of the very first of the active psychedelic compounds (along with
2C-G-5) to have a potential optically active center on the side of the
ring away from the nitrogen atom. One of the oldest and best studied
variants of the phenethylamine chain are the alpha-methyl homologues,
the substituted amphetamines. Here there is an asymmetric carbon atom
right next to the amine group, allowing the molecule to be prepared in
either a right-hand way or a left-hand way. The RRS or the RSS
isomer. And in the several studies that have looked at such isomers
separately, it has always been the RRS isomer that has carried the
psychedelic effects. This probably says something about the nitrogen
end, the metabolic end, the RnorthS end of the receptor site that
recognizes these compounds, and suggests that there is some intrinsic
asymmetry in the area that binds near to the basic nitrogen atom.
But very little is known of the receptor's RsouthS end, so to speak,
the geometry of the area where the opposite end of the molecule has to
fit. Here, with 2-C-17, there is a secondary butyl group, and this
contains an asymmetric carbon atom. But now this center of asymmetry
is clear across the benzene ring from the nitrogen, and should
certainly be in some entirely new part of the receptor site. Why not
make this compound with the RRS and the RSS forms in this new and
unusual location? Why not, indeed! Why not call them the right-lane
and the left lane of the Nimitz? Fortunately, both RRS and RSS
secondary butyl alcohols were easily obtained, and the synthesis given
above for the racemic compound was paralleled for each of these
isomers, separately. Is there any chemistry that is different with
the specific optical isomers from that which has been reported with
the racemic? There certainly is for the first step, since the butyl
alcohols rather than the butyl bromides must be used, and this first
step must go by inversion, and it cannot be allowed any racemization
(loss of the optical purity of the chiral center).
The synthesis of 2C-T-17 RRS required starting with the RSS isomer of
secondary butanol. The RSS 2-butanol in petroleum ether gave the
lithium salt with butyllithium which was treated with tosyl chloride
(freshly crystallized from naphtha, hexane washed, used in toluene
solution) and the solvent was removed. The addition of
2,5-dimethoxythiophenol, anhydrous potassium carbonate, and DMF
produced RSS 2,5-dimethoxyphenyl s-butyl sulfide. The conversion to
RRS 2,5-dimethoxy-4-(s-butyl-thio)benzaldehyde (which melted at 78-79
!C compared to 86-87 !C for the racemic counterpart) and its
conversion in turn to the nitrostyrene,
RSS-2,5-dimethoxy-4-(s)-butylthio-'-nitrostyrene which melted at 70-71
!C compared to 68-69 !C for the racemic counterpart, followed the
specific recipes above. The preparation of the intermediates to
2C-T-17 RSS follows the above precisely, but starting with RRS
2-butanol instead. And it is at these nitrostyrene stages that this
project stands at the moment.
It would be fascinating if one of the two optically active 2C-T-17Us
carried all of the central activity, and the other, none of it. What
is more likely is that the spectrum of effects will be teased apart,
with one isomer responsible for some of them and the other isomer
responsible for the others. Then, again, maybe the south end of the
receptor site in the brain is totally symmetric, and the two optical
antipodes will be indistinguishable.
An incidental bit of trivia Q yet another bit of evidence that we are
all totally asymmetric in our personal body chemistry. RRS and RSS
secondary butanols smell different. The RRS has a subtle smell, which
is rather fragrant . The RSS is stronger, hits the nasal passages
harder, and reminds one of isopropanol more than does the RSS isomer.
#49 2C-T-21; 2,5-DIMETHOXY-4-(2-FLUOROETHYLTHIO)PHENETHYLAMINE
SYNTHESIS: To a solution of 6.9 g of KOH pellets in 100 mL hot MeOH,
there was added 13.0 g 2,5-dimethoxythiophenol (see under 2C-T-2 for
its preparation) followed by 9.6 g 2-fluoroethyl bromide. The
reaction was exothermic, with the immediate deposition of white
solids. This was allowed to stand for 2 h, added to 1 L H2O, and
extracted with 3x75 mL CH2Cl2. The extracts were pooled and the
solvent removed under vacuum. The residue was 2,5-dimethoxyphenyl
2-fluoroethyl sulfide which was a colorless oil and weighed 17.2 g.
It was sufficiently pure for use in the next reaction without a
distillation step.
A mixture of 26.8 g POCl3 and 24.8 g N-methylformanilide was heated
for 10 min on the steam bath. To this claret-colored solution was
added 17.0 g of 2,5- dimethoxyphenyl 2-fluoroethyl sulfide, and the
mixture heated an additional 25 min on the steam bath. This was then
added to 1.5 L of well-stirred warm H2O (pre-heated to 55 !C) and the
oily phase that formed solidified almost immediately. This brown
sugar-like product was removed by filtration, and washed with
additional H2O. After sucking as dry as possible, the residual solids
(weighing 19.0 g wet) were dissolved in an equal weight of boiling
MeOH which, after cooling in an ice-bath, deposited pale ivory colored
crystals of 2,5-dimethoxy-4-(2-fluoroethylthio)benzaldehyde. This was
air dried to constant weight, which was 15.1 g.
To a solution of 15.0 g 2,5-dimethoxy-(2-fluoroethylthio)benzaldehyde
in 75 mL nitromethane there was added 1.35 g of anhydrous ammonium
acetate, and the mixture was heated on the steam bath for 70 min (the
progress of the reaction must be followed by continuous TLC
monitoring). The clear deeply-colored solution was decanted from some
insoluble material and the excess nitromethane removed under vacuum.
There resulted 17.78 g of almost dry brick-red crystals which were
dissolved in 110 mL boiling EtOAc. After cooling overnight in the
refrigerator, the crystalline product was removed, washed with EtOAc,
and air dried. There was obtained 14.33 g of
2,5-dimethoxy-4-(2-fluoroethylthio)-'-nitro-styrene as bright orange
crystals.
A solution of LAH (140 mL of a 1 M solution in THF) was cooled, under
He, to 0 !C with an external ice bath. With good stirring there was
added 3.7 mL 100% H2SO4 dropwise, to minimize charring. This was
followed by the addition of 8.9 g
2,5-dimethoxy-4-(2-fluoroethylthio)-'-nitrostyrene in 40 mL of hot
anhydrous THF (a heat lamp was needed to keep the nitrostyrene in
solution). As the nitrostyrene entered the hydride solution, there
was an immediate loss of color. After 1 h stirring at room
temperature, the temperature was brought up to a gentle reflux on the
steam bath, then all was cooled again to 0 !C. The excess hydride was
destroyed by the cautious addition of 15 mL IPA and the inorganic
solids were made white and filterable by the addition of 15 ml 15%
NaOH. The loose cottage-cheesy solids were removed by filtration, and
washed with additional THF. The filtrate and washes were pooled and
stripped of solvent under vacuum providing 7.39 g of a pale amber oil.
This was dissolved in 600 mL dilute H2SO4, and washed with 3x50 mL
CH2Cl2 (which removed the light yellow color). The aqueous phase was
made strongly basic with 25% NaOH, extracted with 3x75 mL CH2Cl2 and,
after pooling, the solvent was removed under vacuum leaving 4.91 g of
product as an oil. This was distilled at 145-160 !C at 0.4 mm/Hg
giving 3.91 g of a white oil. This was dissolved in 40 mL IPA and
neutralized with 35 drops of concentrated HCl. The beautiful white
solids that formed were removed by filtration, and washed with IPA.
All were suspended in, and ground under, 40 mL anhydrous Et2O,
refiltered and air dried. The final weight of
2,5-dimethoxy-4-(2-fluoroethylthio)phenethylamine hydrochloride
(2C-T-21) was 4.07 g of glistening white crystals.
DOSAGE 8 - 12 mg.
DURATION: 7 - 10 h.
QUALITATIVE COMMENTS: (with 6 mg) I noticed something undefined
within five minutes which went away. Within 15 minutes I noticed a
definite awareness of activity. There was a progressive increase in
awareness of something happening over the next two hours with a
plateau of perhaps an hour then occurring. The nature of the
happening, as usual, was not clear. During the experience I was more
talkative than I usually am. I seemed to be interacting with all
others. There was no euphoria but, then, there was no body load or
nausea, nor was there any nystagmus. I found a little mental
confusion at the peak and there was some searching in my memory bank
for the right chips at times. I lost the entire line of one of my
conversations at one point during the plateau and had to ask what I
was talking about. I tested my visual field on a painting and with
sufficient concentration I could get the center part to wiggle a
little. I didnUt try to observe anything with my eyes closed. I feel
that there was something physical about the eyes. In the evening,
after-images were quite intense, and the next day my eyes seemed tired
or bothered. What can I say? The material was pleasant and I
certainly got the feeling of being high but not getting too much out
of it. There were no insights or Rah-hahs.S I wonder if periodic and
frequent use (say twice a day) at the one or two milligram level would
be a positive mood enhancer?S
(with 8 mg) Comes on very gradually and slowly. Takes about an hour
to feel. Reasonably intense in two hours, ++. Very pleasant
material, enhancing communication, clear thinking, good feeling.
There is a feeling of closeness; the bondedness with the group grows
steadily during the day, reaching a highly rewarding level. For me a
couple of firsts regarding food. I was hungry only two hours into it.
I usually donUt want food 'til well down as I usually feel that it
interferes with the experience. And, also, I nibbled constantly as I
felt that there was nothing in my body. And I enjoyed it thoroughly,
feeling only the warmth and energy, with no contrary developments.
There was a nice feeling of inner strength and peace.
(with 8 mg) It was very difficult to fix the times of ascent or
descent. Some chilling during onset but not later. And there was
some yawning and ear-popping. It is easy on the body, in no way
threatening. This time I am very relaxed and somewhat lethargic; the
visuals are not too pronounced. Excellent sleep.
(with 10 mg) I find I can use it if I set my energy in a direction I
really want to go in. Otherwise I can just be stoned and
self-indulgent. Not out-of-body cosmic at all. But it's good
material, an ally, not presenting hidden negatives.
(with 12 mg) Well ... 12 milligrams is quite enough for a +3, which
was established within the first hour and plateauUd by the end of the
second. Body felt quite safe, again, but there was considerable push
of energy. I did not feel par-ticularly interested in doing anything
like writing and in fact preferred to watch television while rocking a
bit on the couch, to ease the push. Mood was faintly grim, but not
more than faintly. I noted something that I hadnUt seen before with
this material: time slowing. The first two hours seemed to last a
very long time. There was no anorexia. It wasnUt until 10 PM [fifth
hour] that the idea of writing had any appeal at all. By then, I was
still +3 but a lot more at ease. I wrote two letters and enjoyed the
process. Sleep was fine. My mood next day was slightly introverted,
not very spontaneous for a while. Late in the afternoon, it was a lot
better.
EXTENSIONS AND COMMENTARY: This is about as potent a phenethylamine as
they come. There are a couple in the 2C-G family that are similar in
potency, but they are much longer lived. The motivation for the use
of the beta-fluoroethyl group can be seen under the discussion of
DOEF, where there was an amalgamation of two lines of reasoning: the
imitation of potent serotonin agonists with a need of including an
atom (the fluorine) that is potentially labelable with a positron
emitter. And the mass-18 isotope of fluorine, with a half-life of
just under 2 hours, is ideal for many biological studies. In fact,
much of the research work being carried out by the Nuclear Medicine
group in Berkeley is based on the analogy between a halogen atom and a
beta-fluoroethyl group. There are some similarities in pharmacology
so that if there is a bromine or an iodo atom present in a drug, it is
a fair guess that the corresponding beta-fluoroethyl would also be
active. In a sense, the cute (and chemically impossible) idea of
putting a bromo atom on the sulfur of the 2C-T family is nicely
satisfied by using the beta-fluoroethyl group instead (which is
chemically completely possible).
A logical extension of 2C-T-21 is the three carbon amphetamine
analogue which should be, by comparing structures and activities, a
very potent and in-teresting material in its own rights. This would
be 2,5-dimethoxy-4-(2-fluoroethylthio)amphetamine or, following the
nomenclature used with the earlier members of this series, ALEPH-21.
A solution of 2,5-dimethoxy-4-(2-fluoroethylthio)benzaldehyde (see
earlier in this recipe) in nitroethane with ammonium acetate gave
1-(2,5-dimethoxy-4-(2-fluoroethylthio)phenyl)-2-nitropropene as
yellow-orange crystals from MeOH with a melting point of 102-104 !C.
And that is where the project now stands. It has not yet been reduced
to the amine.
This phenethylamine, 2C-T-21, was the last of the 2C-T's to be
completed. A couple of other sulfur analogues have been given
numbers, and have been started, but the syntheses are still at some
intermediate state.
The (n)-butyl compound, named 2C-T-19, has been taken to the
nitrostyrene stage. Reaction between 2,5-dimethoxythiophenol and
(n)-butylbromide with KOH gave 2,5-dimethoxyphenyl (n)-butyl sulfide
as a colorless oil. This, with phosphorus oxychloride and
N-methylformanilide, provided
2,5-dimethoxy-4-(n-butylthio)benzaldehyde as pale orange solids from
MeOH, with a melting point of 78-79 !C. This, with nitromethane and
ammonium acetate, gave 2,5-dimethoxy-4-(n-butylthio)-'-nitrostyrene,
with a melting point of 133-134 !C from either IPA or acetonitrile.
The 2,2,2-trifluoroethyl compound, which I have named 2C-T-22, has
been taken to the benzaldehyde stage. Reaction between
2,5-dimethoxythiophenol and 2,2,2-trifluoroethyliodide with KOH gives
2,5-dimethoxyphenyl 2,2,2-trifluoroethyl sulfide as a very pale amber
oil. This, with phosphorus oxychloride and N-methylformanilide
provided 2,5-dimethoxy-4-(2,2,2-trifluoroethyl)benzaldehyde as
crystals that proved to be exceedingly difficult to purify. Yellow
solids can be obtained from several solvents, and they melt in the 70
!C area. The initially isolated fraction melted at 69-72 !C and
showed three major spots by both TLC and GCMS. The largest GC peak
was the correct product with a parent peak of 280 m/e, and cracking
fragments at 154 and 234 m/e. A small sample was finally obtained
from hexane with a melting point of 78-79 !C but I am not sure that
even it is particularly pure. Not surprisingly, the reaction of this
crude benz-aldehyde with nitromethane and ammonium acetate gave a
nitrostyrene product that was a complex mixture. And there that
project also rests.
A couple of additional efforts warrant comment. The reaction between
trifluoromethyliodide and 2,5-dimethoxythiophenol should have produced
2,5-dimethoxyphenyl trifluoromethyl sulfide, but it didnUt produce
anything. And one more. What about a bare thio group at the
4-position in this 2C-T-family? Maybe this can be protected through
everything as the disulfide, and be reduced at the last step! The
disulfide, 2,5-dimethoxyphenyl disulfide (see under 2C-T-15) was aimed
towards the needed bis-aldehyde with phosphorus oxychloride and
N-methylformanilide, but all that came out of this were black oils and
tars. This has also been abandoned for now.
And it has just occurred to me that there is yet another effort that
is certain-ly worth making, inspired by the observation that
2,2-difluoroethyl iodide is commercially available and not
prohibitively expensive. It, with 2,5-dimethoxythiophenol, and
following the obvious steps to the aldehyde, the nitrostyrene, and the
final amine, would produce
2,5-dimethoxy-4-(2,2-difluoroethylthio)phenethylamine hydrochloride.
It lies exactly half way between the highly potent 2C-T-21 (the
mono-fluoro), and the yet to be finished 2C-T-22 (the trifluoro).
Let's be weird, and call it 2C-T-21.5. I will wager mucho that it
will be very potent.
#50 4-D; 3,5-DIMETHOXY-4-TRIDEUTEROMETHOXY-PHENETHYLAMINE
SYNTHESIS: To a solution of 34.0 g homosyringonitrile
(3,5-dimethoxy-4-hydroxyphenylacetonitrile, see under ESCALINE for its
preparation) in 350 mL acetone containing 0.5 g decyltriethylammonium
iodide, there was added 25 g trideuteromethyl iodide followed by 50 g
of finely powdered anhydrous K2CO3. This mixture was held at reflux
on a steam bath for 12 h, added to 2 L of dilute HCl, and extracted
with 3x100 mL of CH2Cl2. The extracts were washed with 5% NaOH, and
the solvent removed under vacuum, yielding 28.0 g yellow solids.
These were distilled at 135-150 !C at 0.5 mm/Hg providing 19.4 g
3,5-dimethoxy-4-trideuteromethoxyphenylacetonitrile which melted at
76.5-77.5 !C after crystallization from toluene, or 77-78 !C from
methylcyclohexane/CHCl3 3:1. The mp of the proteo-reference compound,
from toluene, was 77-78.5 !C. The OCD3 stretch in the infra-red
occured at 2072 cm-1.
A solution of 275 mL of 1.0 M LAH in THF was cooled under He to 0 !C
and treated with 7.25 mL 100% H2SO4 added very slowly with vigorous
stirring. A solution of 19.3 g
3,5-dimethoxy-4-trideuteromethoxyphenylacetonitrile in 200 mL
anhydrous THF was added slowly, and following the addition stirring
was continued for 20 min. The reaction mixture was brought to a
reflux for 30 min on a steam bath, cooled again to 0 !C, and the
excess hydride destroyed with 25 mL IPA. About 15 mL of 15% NaOH was
required to convert the solids to a filterable white consistency.
These were removed by filtration, the cake washed with IPA, the
filtrates and washes were combined, and the solvent removed under
vacuum leaving a white oil as residue. This was dissolved in 1.5 L
dilute H2SO4, washed with 3x75 mL CH2Cl2, made basic with aqueous
NaOH, and then extracted with 3x75 mL CH2Cl2. Removal of the solvent
from these extracts under vacuum yielded 18.5 g of a colorless oil
which was distilled at 120-150 !C at 0.5 mm/Hg to provide 13.5 g of a
white oil. This was dissolved in 70 ml IPA and neutralized with
concentrated HCl, producing spontaneous crystals. These were removed
by filtration, washed first with IPA then with anhydrous Et2O. After
air drying, the final yield of
3,5-dimethoxy-4-trideuteromethoxyphenethylamine hydrochloride (4-D)
was 13.50 g.
DOSAGE: 200 - 400 mg (as the sulfate salt); 178 - 356 mg (as the
hydrochloride salt).
DURATION: 12 h.
QUALITATIVE COMMENTS: (with 275 mg) The onset was smooth and gradual.
Within the hour, the slight queasiness I experienced (not as much as
with mescaline) completely disappeared. Some visual enhancement, good
energy, good communication. It was a very special day for me as I was
in a good place pretty much the whole day, and able to communicate
clearly without deeper feelings getting in the way. While most
enjoyable, and at times remarkable fun, I did not experience the
intensity I am familiar with, with mescaline.
(with 300 mg) The taste was bitter to a moderate degree but faded
fast. About 40 minutes later the first stirrings of pleasurable
experience came on. It was very mild. Twenty minutes after that an
unease of the stomach was apparent, and it stayed with me until I ate
some crackers an hour or so later. I got no sharpened visual
reactions and no physical instability at any time. I did feel a
quickening of thought and verbal flow; again, this was mild and unlike
my earlier mescaline patter.
(with 350 mg) A rapid onset Q alert in 20 minutes. Climbed to a plus
two in about one hour and stayed there. During the first two hours
had a slight queasiness or pre-nausea, and cold hands and feet, but
this all disappeared completely and I became very hungry during the
whole latter half of the experience. I did not eat much at any one
time, but did a lot of snacking and everything tasted good. Very
pleasant after the plateau was reached. Pretty good visuals with eyes
closed, but not as bright as 2C-B. Very little visuals with eyes open
Q some movement and flow of objects Q pupils dilated. Spent most of
the day lying down Q had no aversion to conversation but it felt good
just to be still. I was in a funny place I canUt quite describe Q I
was in an 'alert lassitude,' a state of 'interested detachment,' or a
place of 'vibrating equanimity' or whatever. While trying to
recapture the day, it seemed to me that it was a good day, but that
nothing much had really transpired. However, upon reflection, I am
startled to find that several important shifts took place. It was a
day that allowed some peaceful gear-shifting in the mind.
(with 400 mg) Not a great taste. Some type of awareness at approx.
20 minutes. Considerable nausea peaking at about 1 hr. Some nausea
continued through the experience but became quite low. I enjoyed the
color show considerably. Trees outside would change color in a
wave-like manner. The book-covers upstairs would also change colors
and become distorted. Brightly lighted items would undergo the same
thing. Believed I could suppress the vision, but concentrating on
something would cause it to easily undergo the color and visual
changes. Evidently I had little problem following the conversation
downstairs, but I remained somewhat quiet. Had an element of
confusion that seemed to last for some 4 or 5 hours. Had no problems
dropping off to sleep that evening.
EXTENSIONS AND COMMENTARY: The effects of 4-D and '-D are similar to
one-another, both as to dosage and effect. And with both, there is a
close parallel to those reported from mescaline. It is reasonable to
assume that the human body handles these materials in the same manner,
although no metabolic studies have ever been published.
A similar deuterium substitution pattern is of course completely
feasible with TMA and related 3,4,5-trimethoxy-substituted analogues.
Some studies have supported the idea that the ability to remove methyl
groups from such aromatic ethers might be correlated to endogenous
schizophrenia. It is possible to imagine that, in such individuals,
the effects of substituting trideuteromethyl groups for normal methyl
groups might result in psychopharmacological differences of action.
Two reports exist that describe metabolic products of mescaline that
have lost this methyl group on the 4-position oxygen. It is possible
that these might be produced in abnormal quantities in mentally ill
subjects. There are also similar reports of the 3-methoxyl group
being demethylated in man. Here, studies with 3,5-D
(3,5-bis-trideuteromethoxy-4-methoxyphenethylamine) might reveal some
differences in quantitative responses in man. These are extremely
minor metabolites, however. I suspect that more extensive studies
will establish that 4-D, 3,5-D and '-D all have properties
indistinguishable from one-another, at least in healthy subjects.
#51 '-D; 3,4,5-TRIMETHOXY-','-DIDEUTEROPHENETHYLAMINE
SYNTHESIS: To a solution of 13.6 g homosyringonitrile (see under
ESCALINE for its preparation) in 150 mL acetone containing 200 mg
decyltriethylammonium iodide and 30 g of finely powdered anhydrous
K2CO3, there was added 20 g methyl iodide. The mixture was held at
reflux for 18 h in a heating mantle with effective stirring. This was
added to 1 L H2O, acidified with concentrated HCl, and extracted with
3x75 mL CH2Cl2. The extracts were pooled, washed with 2x100 mL 5%
NaOH, once with dilute HCl, once with saturated brine, and the solvent
was removed under vacuum. The pale yellow residue was distilled at
130-150 !C at 0.3 mm/Hg to yield 12.9 g of
3,4,5-trimethoxyphenylacetonitrile as an off-white solid. Upon
crystallization from methylcyclohexane/CHCl3 it was white and had a mp
of 77-78 !C. Attempts to prepare this compound by the theoretically
appealing route from 3,4,5-trimethoxybenzaldehyde to
N,N-dimethyl-3,4,5-tri-methoxybenzylamine (reductive amination with
dimethylamine), to 3,4,5-trimethoxy-N,N,N-trimethylbenzylammonium
iodide (methylation with methyl iodide), and then to 3,4,5-
trimethoxyphenylacetonitrile (with some source of cyanide ion) gave
excellent yields in the first two steps, and no product at all in the
last step.
A solution of 20.6 g of 3,4,5-trimethoxphenylacetonitrile in 70 g
pyridine was treated with 15 mL 99+% D2O and held at reflux for 24 h.
All volatiles were stripped first under vacuum and finally with a hard
vacuum at room temperature in a Kugelrohr apparatus. The dark residue
was treated again with another 30 mL pyridine and another 15 mL 99+%
D2O. The flask was protected with a drying tube and held at reflux
for another 24 h. Again, all volatiles were stripped, and the residue
distilled at 110-130 !C at 0.25 mm/Hg to yield 16.77 g of an almost
white solid. The GCMS verified this chemical to be
3,4,5-trimethoxy-','-dideuterophenylacetonitrile, with a parent peak
at m/e 209 and no visible peak at m/e 207.
A solution of 250 mL of 1 M LAH in THF was cooled under He to 0 !C and
treated with 6.8 mL 100% H2SO4 added very slowly with vigorous
stirring. A solution of 18.23 g
3,4,5-trimethoxy-','-dideuterophenyl-acetonitrile in 200 mL anhydrous
THF was added slowly, and following the addition stirring was
continued for 20 min. The reaction mixture was brought to a reflux
for 30 min on a steam bath, cooled again to 0 !C, and the excess
hydride destroyed with 15 mL IPA. About 10 mL of 15% NaOH was
required to convert the solids to a filterable white consistency.
These were removed by filtration, the cake washed with IPA, the
filtrates and washes were combined, and the solvent removed under
vacuum leaving 17 g of a white oil as residue. This was dissolved in
2 L dilute H2SO4, washed with 3x75 mL CH2Cl2, made basic with aqueous
NaOH, and then extracted with 3x75 mL CH2Cl2. Removal of the solvent
from these extracts under vacuum yielded 10.3 g of a colorless oil
which was distilled at 120-130 !C at 0.3 mm/Hg to provide 9.2 g of a
white oil. This was dissolved in 50 ml IPA and neutralized with
concentrated HCl, producing spontaneous crystals. These were diluted
with 50 mL anhydrous Et2O, removed by filtration, washed first with
Et2O/IPA, and then with anhydrous Et2O. After air drying, the final
yield of 3,4,5-trimethoxy-','-dideuterophenethylamine hydrochloride
('-D) was 10.0 g of white needles.
DOSAGE: 200 - 400 mg (as the sulfate salt); 178 - 356 mg (as the
hydrochloride salt).
DURATION: 12 h.
QUALITATIVE COMMENTS: (with 200 mg) The onset was very gradual and
very gentle. At about an hour and a half I was rather out of my body
(at least I wasnUt aware of my body, it felt so light). I was
listening to Berlioz Requiem, and it took me to the highest realm. I
was totally caught up in the magnificence of the music, of the genius
it took to compose it, the love it took to complete it, and the
devotion of the composer. I felt as though this music had been
written for me. What came next is hard to remember because I was so
taken with this experience which came only 1 1/2 hours after
ingestion. I wondered what time it was and how come I was having a
peak experience so soon, because this material was supposed to reach
its peak after two hours. Well, now we can revise the records, heh?
Incidentally this material is really good for interior work. It was a
magnificent experience Q one of the best.
(with 275 mg) I begin to feel it in 15 minutes, stomach getting
squeamish. Looking up into the clouds, becoming absorbed in them,
watching light grow in intensity, stomach feelings disappeared.
Became totally absorbed by the music. Listening to Boito's Prologue
to Mephistopheles Q exquisitely beautiful, dramatic. Lying on the
couch, the music continuing, I was suddenly filled with enormous
power. I realized that raw, male power was pouring through me as I
had never before experienced it. I was wild, totally self satisfied,
and completely oblivious of others and their needs. I wanted to
strike out, to win, to conquer. I felt what conquerers have felt in
the past, the unbridled passion to vanquish everything. I could see
how such misguided power could lead nations to war. Wanting still
more power, I was about to find out if God would grant me the power to
destroy the world if I wished it, when I felt a gentle kiss on my
brow. My wife had leaned over just in time to save the world.
(with 275 mg) Never had I had such a magnificent appreciation of God.
It was clear that if I minded my business and turned to Him to learn
as I had been doing today, then I could continue to grow and learn in
a most wonderful way. It became crystal clear to me that I didnUt
have to help anybody or heal anybody, as everyone can turn directly to
the source for their needs. An earth-shaking experience.
(with 300 mg) I had extreme nausea, and vomited. This had a very
hard impact on me, and I had to retreat with a paranoia that swept
over me without warning. I lay down and let it sweep on, and through
this came several very important insights. At least they were
important to me. It was about the fourth hour before I could emerge
from my retreat, and at that time I knew that I had answered some
troublesome personal problems. It was a satisfactory day, but I
probably shall not repeat it.
(with 350 mg) Strong body awareness started within 15 minutes.
Visual activity started within half an hour. Visuals were typical
kinds, but seemed to arrive earlier. A strong experience of
pleasantness started and continued throughout the experience. I
tended to internalize to some extent. Ended on a water bed at maybe
an hour and a half, pulled covers over me, and went inward with
considerable visuals but not much insight. I felt good about where I
was. I would not mind being there again, so something was going well.
I am not sure how long this continued. The visuals decreased
somewhere around the 5th or 6th hour. After 8 or 9 hours, activity
considerably decreased. I felt quite clear and reasonably centered.
Would I do this again? The answer is yes.
(with 500 mg) I consumed the material over a period of twenty
minutes, and at the 1 hour 45 minute point, havenUt had any nausea,
but I am still careful not to bounce around. Am absolutely grounded
even though I am completely into the experience. No more that state
in which it is possible to seriously consider trying to rise two
inches above the floor and skim, as I do so expertly in dreams. As a
matter of fact I havenUt had those dreams for some time now. This
material doesnUt allow the straddling of realities as does ordinary
mescaline. I know where my realities are, and reality is, basically,
where my center is. Thus I am grounded in the physical reality even
when the doors are open to non-physical levels.
EXTENSIONS AND COMMENTARY: The 4-D and the '-D are two of five obvious
deuterium isomer derivatives of mescaline. The three remaining are:
(1) 3,5-D (4-methoxy-3,5-bis-trideuteromethoxyphenethylamine); (2)
2,6-D (2,6-di-deutero-3,4,5-trimethoxyphenethylamine); and (3) a-D
(a.a-dideutero-3,4,5-tri-methoxyphenethylamine). I fully expect both
3,5-D and 2,6-D to be indistinguishable from mescaline in effect,
since it is known that not much metabolism takes place in man at these
locations of the molecule.
The last compound, a-D, could be quite a different matter. The
principal metabolite of mescaline is 3,4,5-trimethoxyphenylacetic
acid, and this product requires enzymatic attack at the exact position
where the deuteriums will be located. To the extent that they are
harder to remove (come off more slowly or to a lesser degree), to that
extent the molecule will be more potent in man, and the dosage
required for effects will be less. The compound will be easily made
by the reduction of 3,4,5-trimethoxyphenylacetonitrile with lithium
aluminum deuteride. And if there is a believable difference between
a-D and mescaline, it will be necessary to synthesize each of the two
optically active a-mono-deutero analogs. That will be quite a
challenge.
Some years ago I performed a fascinating series of experiments with
another isotopically labeled mescaline derivative. This was '-14C
labeled material, which I self-administered on three occasions, at
three different levels. One dosage was with 350 milligrams, a second
a few weeks later was with 4 milligrams, and a third was a few weeks
later yet, with about 60 micrograms. In each case, exactly the same
absolute quantity of radioactivity was administered, so the metabolic
distribution was equally visible. Only the weight dosage was
different. Urinary analysis was run for each experiment for the
presence of unchanged mescaline, and for the primary metabolite,
3,4,5-trimethoxyphenylacetic acid. The smaller the dosage, the
proportionately larger amount of mescaline was oxidized to the
inactive acetic acid, and the smaller amount was excreted in an
unchanged state. It seemed to me that there might be a finite
capacity of the body to oxidatively deaminate mescaline, and at larger
and larger dosages, this capacity became increasingly depleted.
Perhaps this is why mescaline requires such a large dosage to be
effective in man.
#52 DESOXY; 3,5-DIMETHOXY-4-METHYLPHENETHYLAMINE
SYNTHESIS: To a well-stirred solution of 31 g 2,6-dimethoxytoluene in
200 mL CH2Cl2 there was added 11 mL elemental bromine, a portion at a
time. There was a copious evolution of HBr and the color gradually
faded from deep red to straw. The reaction mixture was poured into
500 mL H2O, and the organic layer separated, washed first with dillute
NaOH and finally with dilute HCl. The solvent was removed under
vacuum, and the residue distilled at 85-90 !C at 0.4 mm/Hg to provide
44 g of 3-bromo-2,6-dimethoxytoluene as a white oil.
A well-stirred solution of 42 mL diisopropylamine in 100 mL petroleum
ether was placed in a He atmosphere and cooled to 0 !C with an
external ice-water bath. There was then added 120 mL of a 2.5 M
solution of n-butyllithium in hexane, producing a clear but viscous
solution of the lithium amide. Maintaining this temperature, there
was added 100 mL of anhydrous THF, followed by 10 mL dry CH3CN, which
produced an immediate white precipitate. A solution of 23 g of
3-bromo-2,6-dimethoxytoluene in 75 mL anhydrous THF was then added
which produced a light red color. The reaction mixture was allowed to
come to room temperature. The color became progressively darkened,
eventually becoming a deep red-brown. After 0.5 h, the reaction
mixture was poured into 500 mL of dilute H2SO4, the layers were
separated, and the aqueous layer extracted with 2x75 mL CH2Cl2. The
organics were combined, the solvent removed under vacuum, and the
residue distilled. Discarding a first fraction, the cut boiling at
125-165 !C at 0.3 mm/Hg was collected. This light yellow fraction
spontaneously crystallized and weighed 11.0 g. Trituration under 20
mL petroleum ether provided 1.72 g of
3,5-dimethoxy-4-methylphenylacetonitrile as a yellowish solid.
A solution of LAH in anhydrous THF under nitrogen (20 mL of a 1.0 M
solution) was cooled to 0 !C and vigorously stirred. There was added,
dropwise, 0.54 mL 100% H2SO4, followed by 1.5 g
3,5-dimethoxy-4-methylphenylacetonitrile as a solid. The reaction
mixture was stirred at 0 !C for a few min, then brought to room
temperature for 1 h, and finally to a reflux on the steam bath for 30
min. After cooling back to 0 !C there was added IPA until no more
hydrogen was evolved, followed by sufficient 15% NaOH to produce a
granular texture. The white solids were removed by filtration, and
washed with THF. The filtrate and washes were stripped of solvent
under vacuum, the residue added to 150 mL dilute H2SO4 and washed with
2x50 mL CH2Cl2. The aqueous phase was made basic with 25% NaOH, and
extracted with 3x100 mL CH2Cl2. These extracts were pooled, the
solvent removed under vacuum, and the residue distilled at 110-120 !C
at 0.45 mm/Hg to give a colorless viscous oil. This was dissolved in
10 mL of IPA, neutralized with 10 drops of concentrated HCl and
diluted with 20 mL anhydrous Et2O. The product was removed by
filtration, washed with Et2O, and air dried to give 0.55 g
3,5-dimethoxy-4-methylphenethylamine (DESOXY) as white crystals.
DOSAGE: 40 - 120 mg.
DURATION: 6 - 8 h.
QUALITATIVE COMMENTS: (with 40 mg) Initially I felt very chilled, so
I lay down under a blanket. Eyes-closed imagery became very
dream-like and my general state was felt as having lost my center.
Also, not much in touch with feelings, sense of strangeness, almost
alien view of the world. Not through recog-nizable eyes. Neither
pleasant nor unpleasant, just strange. Was able to drift into sleep
very easily, or sleep-like trance state, with disconnected, far-out
imagery. After 3 hours the nausea was gone, I was able to get up and
explore. A little food went down well. No drive, no strong focus in
any direction. Feel this was a quite fascinating experience.
Completely down by six hours. Would go a bit slowly because of slight
hints of neurological sensitivity Q the instant chilling and a
tendency to dart on going to sleep. The nervous system does not feel
over-exposed, but all of a sudden there will be a millisecond of
auditory hallucination, or an out-of-the-blue startle. So take it
easy going up.S [Some 24 hours after this experiment had been
completed, and a normal baseline re-established, a complex and
psycho-logically disruptive syndrome occurred, that lasted for the
better part of a week. The temporal juxtaposition between the use of
desoxy and the subsequent Rspiritual crisisS initially suggested some
possible connection, but in retrospect the events seem to be
unrelated].
(with 40 mg) I have offered to be a control on an experiment where
there had been a close relationship between a trial with desoxy and
what might have been a psychotic break, or some kind of so-called
spiritual emergency. These two events lay within a day of one
another. I was aware of my 40 milligram dosage at about
three-quarters of an hour into the experiment, and felt that there was
no more in-tensification at the two-hour point. At that time I felt
distinctly spaced but with a very good feeling, and I could see no
reason not to increase the dosage at some future time. There was a
good and mellow mood, and enjoyment in escapist reading. The only
physical oddity that I noted was that there had been no urge to
urinate, and only a small amount of quite concentrated urine was
passed rather late in the experiment. I was at baseline at the fifth
hour, and there was nothing unusual at any time during the following
week.
(with 100 mg) The stuff has a sweet taste! There was a slight
heart-push in the early awareness period, with a pulse up to 100 and a
feeling of pressure in the chest. There were no apparent visual
enhancements, but the eyes-closed imagery to music was noteworthy.
Thinking skills and conversation seemed to be fully under control, if
not enhanced. There was none of the colorful psychedelic world of
mescaline, but this might be just around the corner; perhaps with a
larger dose. This is a comfortable in-between level. Sleep was not
possible at the sixth hour, but two hours later, it was easy and very
restful. There was no negative price to pay the next day.
EXTENSIONS AND COMMENTARY: All substituents that are involved with the
several drugs being discussed in this writing are really things that
are stuck like warts on the benzene ring that is central to every
phenethylamine. Some of these warts are things attached with a oxygen
atom; there are some of these in every single compound in this story.
No oxygen atom, no psychedelic effect. Without them, one has
stimulants or, more frequently, no effects at all.
But the removal of an oxygen atom (in those cases where there is more
than one) can radically change the nature of the effects seen. This
is the exact meaning of the term Rdesoxy.S RDesS, without, and RoxyS,
the oxygen. Since this drug is simply the structure of mescaline with
the oxygen at the 4-position plucked out of the picture, the first
impulse was to abbreviate this compound as DOM for des-oxymescaline.
However, a long, long time ago, in a universe far, far away, a
compound was synthesized that had a methoxy group replaced by a
methyl, and it was already named DOM. This was the first of the STP
analogs, and the initials stood for desoxy (DO, losing an oxygen) and
methyl (M, having it replaced with a methyl group). These are two
different worlds. One M stands for Mescaline, and the other M stands
for Methyl. Let's call it 4-desoxymescaline, or simply DESOXY, and be
exact.
This drug is a prime example of a pharmacological challenge directed
to the metabolic attack at the 4-position as a mechanism for the
expression of biological activity. A methoxy group there would allow
easy removal of the methyl group from the oxygen by some demethylation
process, but a bare methyl group there cannot be removed by any simple
process. It must be removed by a very difficult oxidation.
This is not the first time that oxygen atoms have been removed from
the mescaline molecule. Both the 3,5-dideoxymescaline
(3,5-dimethyl-4-methoxyphenethylamine) and 3,4,5-trideoxymescaline
(also called desoxymescaline in the literature, but really
tri-desoxymescaline or 3,4,5-trimethylphenethylamine) have been
studied in the cat, and have shown extraordinary pharmacological
profiles of CNS action. The trimethyl compound showed behavior that
was interpreted as being intense mental turmoil, accompanied by a
startling rise in body temperature. The significance is hard to
determine, in that LSD gave similar responses in the cat, but
mescaline was without effects at all. No human studies have been made
on these compounds, just animal studies. But they might prove upon
trial in man to be most revealing. They would have to be performed
with exceptional care.
The 3-carbon chain amphetamines that correspond to these mescaline
look-alikes with one or more methoxy groups replaced with methyl
groups, are largely untested and would require independent and novel
syntheses. The 3,4,5-trimethylamphetamine is known, and is known to
be very hard on experimental cats.
A mescaline analogue with a bromo atom in place of the 4-methoxyl
group is an analogue of mescaline in exactly the same way that DOB (a
very potent am-phetamine) is an analog of TMA-2 (the original
trisubstituted amphetamine). This analogue,
3,5-dimethoxy-4-bromoamphetamine, has been found to be a most
effective serotonin agonist, and it is a possibility that it could be
a most potent phenethylamine. But, as of the present time, it has
never been assayed in man.
#53 2,4-DMA; 2,4-DIMETHOXYAMPHETAMINE
SYNTHESIS: To a solution of 10 g 2,4-dimethoxybenzaldehyde in 50 mL
nitroethane there was added 0.5 g anhydrous ammonium acetate, and the
mixture was heated on the steam bath for 2 h. The excess
solvent/reagent was removed under vacuum, and the residue oil
dissolved in 25 mL boiling MeOH. On cooling, this deposited yellow
crystals of 1-(2,4-dimethoxyphenyl)-2-nitropropene that, after
filtering, MeOH washing, and air drying, weighed 10.2 g and had a mp
of 78-79 !C.
A magnetically stirred suspension of 6.0 g LAH in 300 mL anhydrous
Et2O was brought up to a gentle reflux under a He atmosphere. A total
of 8.5 g 1-(2,4-dimethoxyphenyl)-2-nitropropene was introduced into
the reaction mixture by allowing the condensed Et2O to leach it from a
modified Soxhlet condenser. After the addition was complete, the
reaction was held at reflux for an additional 24 h. After cooling
with an external ice bath, the excess hydride was destroyed by the
cautious addition of H2O. When the exothermic reaction had subsided,
there was added 500 mL H2O, 150 g potassium sodium tartrate, and
sufficient base to bring the pH above 9. The phases were separated,
the organic phase dried over anhydrous MgSO4, the drying agent removed
by filtration, and the clear filtrate then saturated with anhydrous
HCl gas to produce white crystals of 2,4-dimethoxyamphetamine
hydrochloride (2,4-DMA) with a mp of 146-147 !C.
DOSAGE: greater than 60 mg.
DURATION: short.
QUALITATIVE COMMENTS: (with 60 mg) This is definitely threshold, or
even a bit more. There is a lot of amphetamine-like component, and a
certain blush of euphoria. There is also a diffusion of association,
so it's more than just amphetamine, no question about it. At the
three-hour point, it is definitely quieting down.
EXTENSIONS AND COMMENTARY: What can one say as to the active dosage of
2,4-DMA? Nothing. What can one say as to the duration? Probably
short. The 60 milligram report given above is the highest level that
I personally know of having been tried in man, and there is no hint as
to what might be found at a fully active dose, or just where that dose
might be. It might be fully speedy. It might be fully psychedelic.
It might give a cardiovascular push that would be scary. Studies of
2,4-DMA on vascular strips (associated with serotonin action) were not
impressive in comparison with structurally related psychedelics, and
it seems as if its action might involve norepinephrine release. It is
a reasonable guess that there would be cardio-vascular activity at
higher levels. But it will only be with human trials, someday, that
the answer will be known for sure.
The meta-orientation of the two methoxyl groups does, however, greatly
increase the susceptibility of the aromatic ring to electrophilic
attack. This is one of the three possible meta-dimethoxy substituted
amphetamines, and it is the best studied one in the pursuit of
potential radio-halogen substituted brain blood-flow agents. This
strategy is discussed under IDNNA; the other two meta-compounds are
discussed under 3,4-DMA.
The homologues of 2,4-DMA that were iodinated (or occasionally
fluor-inated) were mono- or di-alkylated on the nitrogen, and the
precursor that was common to all was the corresponding acetone. The
above nitrostyrene, 1-(2,4-dimethoxyphenyl)-2-nitropropene, was
reduced in acetic acid with elemental iron, and the base-washed
extracts stripped of solvent and distilled (125-145 !C at 0.5 mm/Hg)
to give 2,4-dimethoxyphenylacetone as a water-white oil. The
principal reductive amination product of this, the one that was most
thoroughly explored with various halogenation schemes, was obtained by
the reaction of 2,4-dimethoxyphenylacetone with dimethylamine and
sodium cyanoborohydride. This product,
2,4-dimethoxy-N,N-dimethylamphetamine or 2,4-DNNA, distilled at
105-115 !C at 0.4 mm/Hg and formed a perchlorate salt that melted at
98-98.5 !C. This could be iodinated with the radio-iodide anion, when
oxidized with chloramine-T in buffered sulfuric acid, to give the
iodinated analogue (2,4-dimethoxy-N,N-dimethyl-5-iodoamphetamine) in
an excellent yield. Radio-fluorination with acetyl hypofluorite gave
the 5-fluoroanalogue (2,4-dimethoxy-N,N-dimethyl-5-fluoroamphetamine)
in an acceptable yield. Both compounds went into a rat's brain to a
pretty good extent, but both of them washed out too rapidly to be
clinically interesting.
A large family of other N-substituted homologues of 2,4-DMA were
similarly prepared from the above ketone and sodium cyanoborohydride.
Methylamine, ethylamine, propylamine, isopropylamine and hexylamine
gave the corresponding N-alkyl homologues. The N,N-diethyl homologue
was made from the primary amine, 2,4-DMA itself, with acetaldehyde and
sodium cyanoborohydride but the product,
N,N-diethyl-2,4-dimethoxyamphetamine, could not be converted into a
crystalline hydrochloride salt.
Yet another variation on these structures was launched, again with the
design of making radio-iodination targets which are not psychedelic
and thus might be useful clinically. In this variation, the nitrogen
atom substitution pattern was held constant, with two methyl groups,
as were the ring locations of the two oxygen atoms. But the
identities of the alkyl groups on these oxygen atoms were varied. The
synthetic procedure followed was to make the appropriate
2,4-dialkoxybenzaldehyde, convert it to the nitrostyrene with
nitroethane, reduce this to the phenylacetone with elemental iron, and
then reductively aminate this ketone with dimethylamine. Following
this reaction scheme, five amphetamine homologues of 2,4-DMA were
made, three with the 4-methoxy group maintained but the 2-position
extended, and two with both groups extended symmetrically. These are:
(1) N,N-dimethyl-2-ethoxy-4-methoxyamphetamine; (2)
2-(n)-butyloxy-N,N-dimethyl-4-methoxy-amphetamine; (3)
2-(n)-decyloxy-N,N-dimethylamphetamine; (4)
2,4-diethoxy-N,N-dimethylamphetamine; and (5)
N,N-dimethyl-2,4-di-(i)-propoxyamphetamine. I believe that most of
these have been iodinated and assayed in rats, and several of them
appear quite promising. But none of them have been assayed in man,
yet. The bromination product of 2,4-DMA
(5-bromo-2,4-dimethoxyamphetamine, 5-Br-2,4-DMA) is way down in
activity (see its recipe, separately). Since all iodo analogues are
of about the same potency as the bromo counterparts, and since the
addition of two methyl groups on the nitrogen does not appear to
enhance central activity, I feel the iodination products of these
N,N-dialkyl-dialkoxyamphetamines would not have any interesting
psychopharmacology.
There is something vaguely counterproductive, in my evaluation of
things, when the goal of a research project is to avoid activity
rather than to create it. Although this chemistry was completely
fascinating and could have produced the world's best
positron-emitting, brain-scanning diagnostic compound, I feel it quite
unlikely that it would have produced the world's best
insight-revealing, empathy-enhancing psychedelic, so this research
direction never totally caught my fancy. I went on to other things.
#54 2,5-DMA; DMA; 2,5-DIMETHOXYAMPHETAMINE
SYNTHESIS: A solution of 10.0 g 2,5-dimethoxybenzaldehyde in 50 mL
glacial acetic acid was treated with 6.8 g of nitroethane and 4.0 g of
anhydrous ammonium acetate. This mixture was heated on the steam bath
for 3 h and then the reagent/solvent was removed under vacuum. The
residue was suspended in H2O and extracted with CHCl3. Removal of the
solvent from the pooled extracts yielded 11.2 g of an impure
1-(2,5-dimethoxyphenyl)-2-nitropropene which, on recrystallization
from 75 mL boiling MeOH, gave 6.7 g of product with a mp of 73-75 !C.
Anal. (C11H13NO4) C,H,N. This nitrostyrene has been periodically
available commercially from a number of sources.
A solution of 17.0 g of 1-(2,5-dimethoxyphenyl)-2-nitropropene was
prepared in 500 mL anhydrous Et2O. This solution was added slowly to
a well-stirred suspension of 12.0 g LAH in 700 mL anhydrous Et2O. The
mixture was then brought up to a reflux and maintained there for 20 h,
cooled with an external ice bath, and the excess hydride destroyed by
the cautious addition of H2O. Finally, a total of 500 mL H2O was
added, followed by the addition of 300 g potassium sodium tartrate,
and sufficient aqueous NaOH to bring the pH above 9. The two phases
were separated, and the ether phase dried by the addition of anhydrous
MgSO4. The drying agent was removed by filtration, and the clear
filtrate saturated with a stream of anhydrous HCl gas. The formed
crystals of 2,5-dimethoxyamphetamine hydrochloride (2,5-DMA) were
removed by filtration, washed with anhydrous Et2O, and dried to
constant weight of 16.3 g. Recrystallization from EtOH gave an
analytical sample with a mp of 114-116 !C. The hydrobromide salt is
reported to melt at 129-131 !C.
DOSAGE: 80 - 160 mg.
DURATION: 6 - 8 h.
EXTENSIONS AND COMMENTARY: The qualitative information on 2,5-DMA is
very sparse. I was up to a 1+ with 80 milligrams of the
hydrochloride, and since it appeared to be totally a physical trip
with tremors and some cardiovascular push and nothing of a sensory
nature, I chose to explore it no further. A report from South America
found the intoxication to be largely pleasant (this, at 75
milligrams), with an enhanced interest in one's surroundings, but no
perceptual changes, no overt stimulation, and no gross physiological
effects other than a slight mydriasis (dilation of the pupils). I
have also been told of a single trial of 250 milligrams of the
tartrate (this is equivalent to somewhere in the 150-200 milligram
range of the hydrochloride salt, depending upon the acid/base ratio of
the tartrate salt) with some RspeedyS effects but still no sensory
changes. A seizure of capsules reported by the drug law enforcement
authorities some 20 years ago found that each contained some 200
milligrams of the hydrobromide salt. This is equivalent to 170
milligrams of the hydrochloride salt, and suggests that level may be
an effective dosage.
An intriguing, but little studied, analogue of 2,5-DMA is the compound
with methyls in place of the methoxyls. 2,5-Dimethylamphetamine has
been looked at, in man, as a potential anorexic, but there is little
effect even at 150 milligrams. The 3,4-isomer,
3,4-dimethylamphetamine or xylopropamine, is an adrenergic agent and
it has been found to be an analgesic in man at as little as 10
milligrams. This was assayed, rather remarkably, by attaching
electrodes to the tooth fillings of the experimental subjects. But
with this base, cardiovascular effects were not observed until doses
of about 100 milligrams were administered, and toxic effects (nausea
and vomiting) were reported at 150 milligrams. There was no
suggestion of anything psychedelic.
All three isomers of monomethylamphetamine have also been looked at in
man. The ortho- and meta-isomers, 2-methyl- (and 3-methyl- )
amphetamine are weak anorexics. At doses of up to 150 milligrams
orally, there were signs of stimulation noted Q talkativeness and loss
of appetite. The para-isomer, 4-methyl-amphetamine or Aptrol, is more
potent. At 75 milligrams (orally, in man) there is clear adrenergic
stimulation, and at twice this dosage there are signs of mild toxicity
such as salivation, coughing and vomiting.
There is a mystery, at least to me, concerning the commercial
production of 2,5-DMA. At regular intervals, there is a public
announcement of the production quotas that are requested or allowed by
the Drug Enforcement Administration, for drugs that have been placed
in Schedules I or II. In the Schedule I category there are usually
listed amounts such as a gram of this, and a few grams of that. These
are probably for analytical purposes, since there are no medical uses,
by definition, for drugs in this Schedule. But there is a staggering
quantity of 2,5-DMA requested, regularly. Quantities in the many tens
of millions of grams, quantities that vie with medical mainstays such
as codeine and morphine. I have heard that this material is used in
the photographic industry, but I have no facts. Somewhere I am sure
that there is someone who has to keep a lot of very careful books!
In the area of psychedelic drugs, the value of 2,5-DMA is mainly in
its role as a precursor to the preparation of materials that can come
from a direct electrophilic attack on the activated 4-position. These
uses can be found under things such as DOB and DOI and DON. The
radio-halogenation of N-substituted homologues of 2,5-DMA with
hypoiodite or hypofluorite is part of an extensive study underway in
the search for radio-labeled brain blood flow agents. The rationale
for this work is to be found in the commentary under IDNNA. In
essence it has been found that the N-substitution or
N,N-disubstitution of 2,5-DMA where the 4-position is unsubstituted
and thus available for the introduction of a radioactive nucleus can
give rise to potentially useful drugs. Most of these 2,5-dimethoxy
exploratory compounds were made by the reductive alkylation of
2,5-dimethoxy-4-(radio)iodophenylacetone, using various mono or
dialkyl amines. This, too, is described under IDNNA.
However, the study of various direct iodinations and fluoridations
that would have the N,N-dimethyl substitution on the amphetamine
nitrogen atom, would require the 4-proteo- analogue, and this was made
from the above nitrostyrene. A solution of the above nitrostyrene,
22.3 g 1-(2,5-dimethoxyphenyl)-2-nitropropene in 100 mL acetic acid
was added to a suspension of elemental iron in acetic acid (45 g in
250 mL) and worked up with water and base washing to give, after
distillation at 92-106 !C at 0.35 mm/Hg, 13.8 g
2,5-dimethoxyphenylacetone as a pale yellow oil. This underwent
reductive amination with dimethylamine hydrochloride in MeOH solution,
using sodium cyanoborohydride, to give the target compound
2,5-dimethoxy-N,N-dimethylamphetamine oxalate with a melting point of
133-134 !C (4.6 g ketone gave 1.38 g of salt). Anal. (C15H23NO6) C,H.
It has also been prepared by the N,N-dimethylation of 2,5-DMA
directly, with formaldehyde and formic acid. This has been called
2,5-DNNA, or IDNNA without the RI.S This intermediate, 2,5-DNNA,
underwent direct radioiodination with labeled iodine monochloride in
the presence of perchloric acid to give IDNNA with a 40% incorporation
of isotope. Reaction with labeled acetyl hypofluorite, on the other
hand, gave only a 2% in-corporation of the radio-isotope. This latter
compound is, chemically,
4-fluoro-2,5-dimethoxy-N,N-dimethylamphetamine and, using the
reasoning suggested above and with IDNNA, might best be encoded FDNNA.
The 2,5-dimethylamphetamine analogue mentioned above was also explored
in this IDNNA concept. The commercially available
2,5-dimethylbenzaldehyde was converted to the nitrostyrene with
nitroethane (1-(2,5-dimethylphenyl)-2-nitropropene, yellow crystals
with a melting point of 24.5-25.5 !C) which reacted with elemental
iron in acetic acid to give the ketone 2,5-dimethylphenylacetone
(boiling at 140-150 !C at 0.4 mm/Hg). Reductive amination with
dimethylamine and sodium cyanoborohydride gave 2,5-DMNNA
(2,5,N,N-tetramethylamphetamine) as a clear oil with a boiling point
of 115-125 !C at 0.35 mm/Hg. It gave poor yields of the 4-fluoro
analogue with acetyl hypofluorite.
All of these latter materials remain unevaluated in man.
#55 3,4-DMA; 3,4-DIMETHOXYAMPHETAMINE
SYNTHESIS: A solution of 33.2 g of veratraldehyde in 15.0 g
nitroethane was treated with 0.9 g of n-amylamine and placed in a dark
place at room temperature. In a day or so, separated H2O was apparent
and, after a couple of weeks, the mixture completely solidified. The
addition of 50 mL EtOH and heating effected complete solution and, on
cooling, this provided 1-(3,4-dimethoxyphenyl)-2-nitropropene as
yellow crystals, 29.0 g, with mp of 70-71 !C. The more conventional
reaction scheme, 6 h heating of a solution of the aldehyde and
nitroethane in acetic acid with ammonium acetate as catalyst, gave a
much inferior yield of product (33.2 g gave 14.8 g) of the same
purity. Recrystallization from MeOH increased the mp to 72-73 !C.
To a refluxing suspension of 7 g LAH in 600 mL anhydrous Et2O, stirred
and under an inert atmosphere, there was added 7.5 g
1-(3,4-dimethoxyphenyl)-2-nitropropene by allowing the returning
condensed ether to leach out the material as a warm solution from a
Soxhlet thimble. Following the completion of the addition of the
nitrostyrene, refluxing was maintained for 24 h, and the reaction
mixture allowed to stand several days at room temperature. The excess
hydride was destroyed by the cautious addition of 500 mL H2O
containing 40 g H2SO4, and the phases were separated. The aqueous
phase was washed with both Et2O and CH2Cl2. There was then added 200
g potassium sodium tartrate, and the pH brought above 9 by the
addition of aqueous NaOH. This clear solution was extracted with
3x150 mL CH2Cl2, the extracts were pooled, and the solvent removed
under vacuum to give a residual oil. This was dissolved in Et2O,
saturated with anhydrous HCl gas, and the resulting solids removed by
filtration. Recrystallization from 10 mL acetone gave 1.35 g
3,4-dimethoxyamphetamine hydrochloride (3,4-DMA) as beautiful white
crystals with a mp of 144-145 !C.
DOSAGE: a few hundred milligrams.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 70 mg i.v.) [One patient received 0.004
mM/Kg of the hydrochloride salt intravenously and exhibited only
slight increase in psychiatric symptoms; a comparable dosage in a
second individual also elicited only insignificant changes.]
(with 700 mg i.v.) [When one of these patients was reinjected at a
later date with approximately 0.04 mM/Kg of 3,4-DMA a definite
Tmescaline-likeU state was induced. The symptoms included colored
hallucinations of geometric figures and occasional structured forms.
The other individual experienced visual distortions, notable
after-imagery, feelings of unreality, and paranoid ideas. Marked
mydriasis and gross body tremors also occurred but apparently no
hallucinations were experienced.]
EXTENSIONS AND COMMENTARY: These RQualitative CommentsS are not
explicit quotations from people who had taken 3,4-DMA. They are
written descriptions by the observers who had given 3,4-DMA to
psychiatric patients. This is one of the most outrageous chapters in
the books on military medicine. The chemical warfare group within the
U.S. Army explored many potential psychedelics by administering them
to innocent patients with not even a thought of obtaining informed
consent. These experiments took place at the New York State
Psychiatric Institute (amongst other places) in the early 1960Us. The
Edgewood Arsenal code name for 3,4-DMA was EA-1316. A few
non-military studies have indicated that 3,4-DMA is orally active at
160 milligrams, and so probably its potency by this more conventional
route would fall midway between that of mescaline and of MDA. The
3-methoxy-4-other-than-methoxy things (such as hydroxy, ethoxy,
allyloxy and methyl) are mentioned in the recipe for MEPEA. The
alpha-ethyl homologue of 3,4-DMA,
2-amino-1-(3,4-dimethoxyphenyl)butane, and of other DMA's are
discussed under the recipe for ARIADNE.
There are a total of six possible amphetamine molecules with two
methoxyl groups attached. The 3,4-orientation has always been the
most appealing to the life scientists as this is the positional
substitution pattern found in the natural neuro-chemicals dopamine,
norepinephrine and epinephrine. These latter two are called
noradrenalin and adrenalin in England. Two adjacent hydroxy groups
represent the catechol in the well known word catecholamines. You
might read in a textbook, RThis is where nature placed the groups when
she put the compounds in our brains. So that is where the groups
might be the most interesting in a psychedelic.S Why? I have never
understood this kind of reasoning. If a possible psychedelic has just
the exact oxygen positioning of a neurotransmitter, then, voila,
that's why it is active. And if a possible psychedelic has some
positioning of these oxygen atoms that is different than that of a
neurotransmitter? Then voila again. That's why it is active. Both
sound equally reasonable to me, and neither one even begins to address
the fundamental question, how do the psychedelic drugs do what they
do? A study in the human animal of the intimate effects of one of
these neurotransmitter analogues might bring us a little bit closer to
answering this fundamental question. But maybe it wouldnUt, after
all. Nothing has made much sense so far! Anyway, 3,4-DMA is one of
the ten essential amphetamines that can, in theory, arise from the ten
essential oils of the spice and herb trade. In this case, the origins
are methyl eugenol and methyl isoeugenol.
Two of these RdifferentS isomers, 2,4-DMA and 2,5-DMA, have already
been discussed in their own separate recipes. And the remaining three
of the six possible DMA's that are RdifferentS have been made and
studied pharmacologically in animals but not in man. These are the
2,3-DMA, 2,6-DMA and the 3,5-DMA isomers. The products of their
reaction with elemental bromine are discussed under META-DOB.
Both the 2,6- and the 3,5-isomers, as the N,N-dimethyl homologues,
have been looked at as potential radio-halogen recipients in the
search for positron-emitting brain blood-flow indicators, as discussed
in the recipe for IDNNA. Both were made from the appropriate
nitrostyrene via the corresponding phenylacetone.
The 2,6-isomer was derived from 2,6-dimethoxybenzaldehyde. This, in
nitroethane and ammonium acetate, gave the nitrostyrene as
canary-yellow crystals from MeOH that melted at 101.5-102.5 !C.
Elemental iron in acetic acid converted this nitrostyrene to
2,6-dimethoxyphenylacetone (a water-white oil with boiling point of
95-105 !C at 0.4 mm/Hg. Anal. (C11H14O3) C,H) and reductive amination
with dimethylamine and sodium cyanoborohydride gave
2,6-dimethoxy-N,N-di-methylamphetamine perchlorate (2,6-DNNA) with a
melting point of 109-110 !C. This base was readily fluorinated with
18F acetylhypofluorite and iodinated with chloramine-T-oxidized 122I
iodide ion. It was also halogenated with (non-radioactive) bromine
and iodine monochloride to give the corresponding 3-bromo-(and
3-iodo)-2,6-dimethoxy-N,N-dimethylamphetamines but these, in turn, did
not react with radioactive acetyl hypofluorite.
The 3,5-isomer followed precisely the same flow sheet.
3,5-Dimethoxybenzaldehyde gave the nitrostyrene (with a melting point
of 87-88 !C), the phenylacetone (with a boiling point of 110-130 !C at
0.3 mm/Hg) and the product 3,5-dimethoxy-N,N-dimethylamphetamine
perchlorate (3,5-DNNA) with a melting point of 100-101 !C. This also
reacted readily with 18F acetylhypofluorite and 122I-hypoiodite.
Several alpha-ethyl homologues of these compounds have also been
discussed in the recipe for ARIADNE.
#56 DMCPA; 2-(2,5-DIMETHOXY-4-METHYLPHENYL)CYCLOPROPYLAMINE
SYNTHESIS: To a solution of 25 g 2,5-dimethoxy-4-methylbenzaldehyde
(see the recipe for 2C-D for the preparation) and 29.2 g malonic acid
in 50 mL anhydrous pyridine, there was added 2 mL piperidine and this
was heated on the steam bath for several h. The mixture was added to
a solution of 125 mL concentrated HCl in 500 mL H2O at 0 !C, and the
solid product that was formed was removed by filtration, and washed
with H2O. Recrystallization from aqueous EtOH yielded 31 g
2,5-dimethoxy-4-methylcinnamic acid with a mp of 163-166 !C. Anal.
(C12H14O4) C,H.
In a cooled high-pressure reaction vessel there was placed a
suspension of 30 g 2,5-dimethoxy-4-methylcinnamic acid in 150 mL
liquid isobutene. This was treated dropwise with 0.6 mL concentrated
H2SO4, then sealed and brought to room temperature. After 48 h
shaking, the vessel was cooled again to -10 !C, opened, and poured
into 200 mL of 10% Na2CO3. This was extracted with hexane, the pooled
extracts washed with H2O, and the solvent removed to yield 17.0 g of
(t)-butyl 2,5-dimethoxy-4-methylcinnamate as an amber oil. Anal.
(C16H22O4) C,H.
The cyclopropane ester was prepared by the reaction between 16 g
(t)-butyl 2,5-dimethoxy-4-methylcinnamate and dimethylsulfoxonium
methylide, prepared as described in the Kaiser reference in the
acknowledgements. Hydrolysis of this ester gave 53%
trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropanecarboxylic acid
which, after recrystallization from a MeOH/H2O mixture, had a mp of
136 !C. Anal. (C13H16O4) C,H.
A suspension of 4 g of
trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropanecarboxylic acid in
an equal volume of H2O, was treated with sufficient acetone to effect
complete solution. This was cooled to 0 !C and there was added,
first, 2.0 g triethylamine in 35 mL acetone, followed by the slow
addition of 2.5 g ethyl chloroformate in 10 mL acetone. This was
stirred for 0.5 h, and then there was added a solution of 1.7 g NaN3
in 6 mL H2O, dropwise. After 1 h stirring at 0 !C, the mixture was
quenched by pouring into H2O at 0 !C. The separated oil was extracted
with Et2O, and extracts dried with anhydrous MgSO4. Removal of the
solvent under vacuum gave a residue of the azide, which was dissolved
in 10 mL anhydrous toluene. This solution was heated on the steam
bath until the nitrogen evolution was complete, and the removal of the
solvent under vacuum gave a residue of crude isocyanate as an amber
oil. This intermediate isocyanate was dissolved in 5.4 g benzyl
alcohol and the reaction mixture was heated on the steam bath for 6 h.
The excess benzyl alcohol was removed by distillation, yielding
trans-2-(2,5-dimethoxy-4-methylphenyl)carbobenzoxyamidocyclopropane as
a crystalline residue. This was recrystallized from an EtOAc/hexane
mixture to give 6.13 g of a crystalline product with a mp of 107-108
!C. Anal. (C20H23NO4) C,H,N.
A solution of 1.5 g
trans-2-(2,5-dimethoxy-4-methylphenyl)carbobenzoxyamidocyclopropane in
120 mL MeOH containing 200 mg 10% Pd/C was shaken under hydrogen gas
at 35 psig for 45 min. The solution was filtered through celite, and
a sufficient amount of a solution of 5% HCl in EtOH was added to the
filtrate to make it acidic. Removal of all volatiles under vacuum
gave a solid residue that was recrystallized from an EtOH/ether
mixture to give 0.98 g of
trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine hydrochloride
(DMCPA) as white crystals with a mp of 210-211 !C.
DOSAGE: 15 - 20 mg.
DURATION: 4 - 8 h.
QUALITATIVE COMMENTS: (with 10 mg) The effects were quite real at an
hour, but very hard to define. Nothing left at four hours, but my
sleep was filled with bizarre and colorful dreams. Something was
still working somewhere, at some level.
(with 20 mg) I found myself lightheaded, and the thinness seemed to
be, rather remarkably, on the left side of my brain. The experience
was flighty. I was reminded of the aura that has been described
preceding a convulsion. I was decoupled from my experience and from
my environment. Not all of the control is there, and I am
uncomfortable. But in an hour, there is complete control again, and I
can relax my conscious guard which allows an easy plus three. With
this, there was easy fantasy, erotic, quite a bit of movement in the
visual field, and mild anorexia. The residual hyperreflexive thinness
is largely gone, and not at all worrisome. This stuff is complicated,
with a little too much of the physical. The next day was without any
residues at all.
EXTENSIONS AND COMMENTARY: Most of the human trials took place in the
fifteen to twenty milligram range. Several reports describe some
muscular tremor, especially in the earliest part of the experience,
but this never seemed to be a concern. The efforts to lock imagery to
music were not too successful. All of these clinical studies were
conducted on the trans-compound, but on the racemic mixture. This has
been resolved into the two optical isomers, but they have not been
compared in man. The cis-mixture is unknown.
This material is intimately related to tranylcypromine, a clinically
proven antidepressant. This drug is a known monoamine oxidase
inhibitor, and it is certainly possible that some of this
pharmacological property might be found in DMCPA if it were to be
looked for. The hints of physical toxicity at the higher doses
assayed might suggest some such activity.
This compound, DMCPA, was modeled directly after the structure of DOM,
with the 2,5-dimethoxy-4-methyl substitution pattern. Another
analogue of tranylcypromine, similarly modeled, is
3,4,5-trimethoxytranylcypromine, or
trans-2-(3,4,5-trimethoxyphenyl)cyclopropylamine (TMT). It has been
evaluated at levels of only 13 milligrams orally, and at this dose
there were no hints of central activity.
#57 DME; 3,4-DIMETHOXY-'-HYDROXYPHENETHYLAMINE
SYNTHESIS: To a solution of 10.2 g 3,4-dimethoxybenzaldehyde in 10 mL
EtOH, cooled to 0 !C, there was added a solution of 4.2 g KCN in 40 mL
H2O. With good stirring, there was slowly added 10 mL concentrated
HCl (caution: HCN is evolved) and the two-phase reaction mixture was
allowed to continue stirring until there was the spontaneous formation
of crystals. After a few days standing, these were removed by
filtration and well washed with H2O. All was recrystallized from 75
mL of 50% MeOH and air dried to provide 6.95 g of the cyanohydrin
3,4-dimethoxy-a-hydroxyphenylacetonitrile. The mp was 104-106 !C,
which can be increased to 109 !C by recrystallization from benzene.
A well-stirred suspension of 4.7 g LAH in 500 mL anhydrous Et2O was
brought up to a gentle reflux, and 4.7 g
3,4-dimethoxy-a-hydroxyphenylacetonitrile was leached in from a
Soxhlet thimble, over the course of 3 h. The color of the ether
solution progressed from yellow to green, to an eventual blue. The
reflux was maintained for 16 h. After cooling again, there was added
(carefully) a solution of 27 g H2SO4 in 500 mL H2O. The completely
clear two-phase mixture was separated, and the aqueous phase treated
with 87 g potassium sodium tartrate. The addition of 25% NaOH brought
the pH >9, and this phase was extracted with 4x100 mL CH2Cl2. Removal
of all the organic solvents under vacuum gave a residue that was part
oil and part solid. This was extracted with 4x50 mL boiling Et2O, the
extracts pooled, and saturated with anhydrous HCl gas. The 0.95 g of
pale-yellow crystals that formed were removed by filtration, and
finely ground under 5 mL CH3CN. There remained, after refiltration
and air drying, 0.85 g of 3,4-dimethoxy-'-hydroxyphenethylamine
hydrochloride, DME, with a mp of 170-172 !C.
DOSAGE: greater than 115 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 115 mg) I was faintly nauseous about an
hour after taking the compound, and perhaps I was more alert than
usual in the evening. Substantially no effects.
EXTENSIONS AND COMMENTARY: The rationale for exploring the
beta-hydroxylated phenethylamines, especially those with oxygens at
the biologically important 3- and 4-positions, has already been
presented. Norepinephrine is a '-hydroxylated phenethylamine with
oxygens at these two ring positions. With DME, these are masked as
two methyl ethers, and the initials DME stand for
3,4-dimethoxyphenyl-'-ethanolamine. This is an alternate name for
3,4-dimethoxy-'-hydroxyphenethylamine.
An exactly analogous compound is 3,4-methylenedioxy-'-ethanolamine,
where the masking is done with the biologically more fragile
methylenedioxy ether. Originally I had called this compound MDE
(methylenedioxyethanolamine) but that code has been, since 1975, used
exclusively for 3,4-methylenedioxy-N-ethylamphetamine, which is a
recipe all by itself. Under the discussion of members of the BOX
series, there is a methylenedioxyphenethylamine with a methoxyl group
at the '-position, and it is called BOH (q.v.). There, a reasonable
code name for this specific compound is given, namely BOHH. RBOS
stands for the beta-oxygen function on a phenethylamine; this is the
heart of the BOX family. The RHS which is the third letter of BOHH
stands for the free hydroxyl group. And the final RHS is for
homopiperonylamine (which is the trivial name for the compound without
the hydroxyl group). BOHH, or
3,4-methylenedioxy-'-hydroxyphenethylamine, or
3,4-methylenedioxy-'-ethanolamine, has also be assayed in man at up to
100 milligrams without any effects, and must be considered, as of now,
to be inactive centrally. The possible toxic roles of '-ethanolamines
as potential adrenolytic agents, have been discussed in the BOHD
recipe. And beware of the use of the code name MDE in the very old
literature. It might be this BOHH compound.
#58 DMMDA; 2,5-DIMETHOXY-3,4-METHYLENEDIOXYAMPHETAMINE
SYNTHESIS: Apiole, as the crystalline essential oil
1-allyl-2,5-dimethoxy-3,4-methylenedioxybenzene, is isolated directly
from commercial Oil of Parsley, by careful fractional distillation.
It is the fraction that boils at 165-167 !C at 27 mm/Hg. A solution
of 19.8 g apiole in a mixture of 43 g KOH and 60 mL hot EtOH was
heated in the steam bath for 24 h. With vigorous stirring, it was
diluted with H2O, at a rate which the crystals that formed
spontaneously could accumulate from the turbidity that was generated.
When no more H2O could be added (there was persistent oiling out of
material) the reaction mixture was filtered to give 12.1 g of an amber
solid material. This was recrystallized from 20 mL boiling hexane,
which was filtered while hot to remove insolubles. From the cooled
filtrate, there was obtained 9.3 g of
2,5-dimethoxy-3,4-methylenedioxy-1-propenylbenzene, isoapiole, as pale
cream-colored solids.
A stirred solution of 8.8 g
2,5-dimethoxy-3,4-methylenedioxy-1-propenylbenzene and 3.9 g pyridine
in 45 mL acetone was cooled to ice-bath temperatures, and treated with
7.9 g tetranitromethane. This extremely dark reac-tion was stirred at
0 !C for 5 min, then quenched with a solution of 2.6 g KOH in 45 mL
H2O. With continued stirring, there appeared yellow crystals of
1-(2,5-dimethoxy-3,4-methylenedioxyphenyl)-2-nitropropene which, after
filtering, washing with 50% acetone and air drying, weighed 8.0 g and
had a mp of 110-111 !C.
To a well-stirred and gently refluxing suspension of 6.3 g LAH in 500
mL anhydrous Et2O, under an inert atmosphere, there was added 7.5 g
1-(2,5-dimethoxy-3,4-methylenedioxyphenyl)-2-nitropropene by leaching
out the nitrostyrene from a thimble in a modified Soxhlet condenser
apparatus. The addition took 1.5 h, and the refluxing was maintained
for an additional 3 h. After cooling, the excess hydride was
destroyed by the cautious addition of 300 mL of 1.5 N H2SO4. The
aqueous phase was brought to a pH of 6 with Na2CO3. This was heated
to 80 !C and clarified by filtration though paper. The addition of a
stochiometric amount of picric acid in boiling EtOH gave rise to
precipitation of the product picrate as globs that did not
crystallize. These were washed with cold H2O, then dissolved in 30 mL
5% NaOH. Extraction with 2x75 mL Et2O, and the stripping of the
solvent from the pooled extracts, gave 3.1 g of an oily residue which,
upon dissolving in 250 mL Et2O and saturation with anhydrous HCl gas,
gave white crystals. These were removed by filtration, Et2O-washed,
and air dried, to give 2.9 g of
2,5-dimethoxy-3,4-methylenedioxyamphetamine hydrochloride (DMMDA) that
melted in the 165-175 !C range.
DOSAGE: 30 - 75 mg.
DURATION: 6 - 8 h.
QUALITATIVE COMMENTS: (with 25 mg) The intoxication was there at an
hour and a quarter, and I was hit with nausea with no particular
warning. I am shaky, a little dilated in the eyes, and there is a
modest depersonalization (reminding me of LSD). Time might be
slightly slowed, and there is a mild ataxia in the legs. A couple of
hours later, all effects are going away fast. I ate an apple, but
maybe my mouth didnUt work quite right. The apple was incredibly
noisy.
(with 32 mg) I am up to a 2 1/2 plus at something after two hours,
with no apparent visuals, no push, no erotic. And a few hours later
it is quietly slipping away. It felt completely safe, and without any
conspicuous psychedelic action, at least at this level.
(with 50 mg) I took graded doses of 10 milligrams every thirty
minutes for a total of 50 milligrams, and there were no effects at
all.
(with 50 mg) In the middle of this all, I found myself getting into
abstract thinking, and maybe some imagery as well. The effects were
disappointingly light.
(with 75 mg) This was equal to somewhere between 75 and 100
micrograms of LSD. I was caught up with the imagery, and there was an
overriding religious aspect to the day. The experience had an
esthetic value. I liked it.
EXTENSIONS AND COMMENTARY: DMMDA was the first of the tetraoxygenated
amphetamine derivatives that was ever explored in man, back in 1962.
And it is not easy to find an acceptable single phrase to describe its
action or an acceptable number to describe its potency. I have put
the value of 10 mescaline units (M.U.) into the literature and this
would imply that maybe 30 milligrams was an active dose. This is
probably too low, and some day I would like to run an experiment with
the entire research group with this compound to see just what it
really does.
The essential oil that corresponds to DMMDA is, of course, apiole from
the Oil of Parsley, which again ties together the spice world and the
amphetamine world. And there is isoapiole, also a natural thing.
This pair represents the ring-substitution pattern of one of the ten
essential oils and DMMDA is one of the ten essential amphetamines.
Several people have asked me what I thought about the potential
activity of a compound with a methyl group added to DMMDA. One of
these possibilities would be the N-methylated derivative,
2,5-dimethoxy-N-methyl-3,4-methylenedioxyamphetamine, or METHYL-DMMDA
(or DMMDMA for the dimethoxy-methylenedioxy-methamphetamine
nomenclature). It is a MDMA analogue, and is described in the recipe
for METHYL-MMDA-2.
The placement of an added methyl group onto the '-position of DMMDA,
rather than on the nitrogen atom, produces a pair of stereoisomeric
homologues. These are the threo- (or-trans-) and erythro- (or
cis)-2,5-dimethoxy-'-methyl-3,4-methylenedioxyamphetamines. They have
never been assigned trivial names (my original codes for them were
S-1495 and S-1496 which is not too intuitively informative). Their
chemically proper names would have the 2-amino-3-substituted
phenylbutane form. The synthesis of these DMMDA homologues started
with the reduction of the nitrosyrene to the ketone (see under
METHYL-MMDA-2 for this preparation), followed by methylation with
fresh sodium isopropoxide and methyl iodide, to give the beta-methyl
product. This formed the two possible oximes, one with a mp of 120
!C, and the other from MeOH with a mp of 146 !C. The 120 !C oxime,
with fresh sodium ethoxide gave
threo-2-amino-3-(2,5-dimethoxy-3,4-methylenedioxyphenyl)butane
hydrochloride. This salt had a mp of 247-249 !C. The 146 !C oxime
gave erythro-2-amino-3-(2,5-dimethoxy-3,4-methylenedioxyphenyl)butane
hydrochloride with a mp of 188-189 !C. The threo-isomer showed a
possible threshold effect at 80 milligrams, with hyperventilation and
perhaps some mental muddiness. The erythro-isomer showed no effects,
but it had been taken up only to 10 milligrams.
The only other '-methyl homologue of an active material that was
explored chemically, was related to MDA. The ketone
(3,4-piperonylacetone, see under MDMA) was methylated with sodium
isopropoxide and methyl iodide, and a crystalline oxime was obtained.
Reduction with Zn dust gave what appeared to be
2-amino-3-(3,4-methylenedioxyphenyl)butane hydrochloride, but there
were sufficient uncertainties (possible dimethylation, only one oxime
isolated, the need of strong reducing conditions) that the entire
project was placed in, and still is in, an indefinite holding pattern.
The similar analogues for DOM are the two Classic Ladies, DAPHNE and
ELVIRA, and they, too, are for some time in the future.
#59 DMMDA-2; 2,3-DIMETHOXY-4,5-METHYLENEDIOXYAMPHETAMINE
DOSAGE: about 50 mg.
DURATION: unknown.
QUALITATIVE COMMENTS: (with 50 mg) I am into it; it is much like
MDA.
EXTENSIONS AND COMMENTARY: This is pretty sparse information upon
which to build a picture of biological activity. First, the synthesis
was done by someone else and, as I have not been able to find where
the notes are, this will be the one recipe in the footnote without
explicit directions incorporated. The procedure used was exactly the
same as that described for DMMDA, except that the starting material
was dillapiole rather than apiole. The dillapiole was obtained by the
careful fractionation of Oil of Dill (as opposed to the isolation of
apiole from the careful fractionation of Oil of Parsley).
Isomerization to isodillapiole, nitration with tetra-nitromethane to
give 1-(2,3-dimethoxy-4,5-methylenedioxyphenyl)-2-nitropropene, and
its reduction with LAH in ether to give
2,3-dimethoxy-4,5-methylenedioxyamphetamine hydrochloride (DMMDA-2)
proceeded in a precisely analogous manner to the preparation of DMMDA.
And the pharmacological part is rather thin as well. I was not the
taster, and can only quote what I had been given. This same observer
found a threshold at 28 milligrams. Under other circumstances, this
comment on DMMDA-2 would have been tucked into the commentary on DMMDA
where it belongs, but the activity level was called for in a large
review article, and on the basis of the above, both its initials and
the value of 5x the potency of mescaline were permanently enshrined in
the published literature. What is it really like? I donUt know. Its
structure is an appealing amalgamation of that of MMDA and MMDA-2, and
it might be quite a winner if the dosage and the duration were known.
It is, after all, one of the ten essential amphetamines, since
dillapiole is one of the ten essential oils.
At the time that DMMDA and DMMDA-2 were synthesized, I had visions of
doing the same thorough study with these as I had set up with the
TMA's (six possible, six done) and the MMDAUs (six possible, five
done). Here, too, with a pair of methoxy groups on an amphetamine
skeleton, with a methylenedioxy ring thrown in, six isomers are
possible but only these two have been prepared. The unknown ones will
certainly be called DMMDA-3, -4, -5 and -6, but the assignments of
code to structure havenUt even been thought out yet. The remarkable
and totally unexpected activity of DOM was discovered at about this
time and it was a much more tempting direction to follow. The
remaining four possible DMMDA's have been left to that famous time, a
future Rrainy day.