4466 lines
238 KiB
Plaintext
4466 lines
238 KiB
Plaintext
From: sender@mit.edu
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Newsgroups: sci.med,sci.chem,alt.drugs
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Subject: PiHKAL: The Chemical Story. File 2 of 6
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(I'm posting this for a friend.)
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This is part 2 of 6 of the second half of PiHKAL: A Chemical Love
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Story, by Alexander Shulgin and Ann Shulgin. Please forgive any typos
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or misprints in this file; further, because of ASCII limitations,
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many of the typographical symbols in the original book could not be
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properly represented in these files.
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If you are seriously interested in the chemistry contained in these
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files, you should order a copy of the book PiHKAL. The book may be
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purchased for $22.95 ($18.95 + $4.00 postage and handling) from
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Transform Press, Box 13675, Berkeley, CA 94701. California residents
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please add $1.38 State sales tax.
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At the present time, restrictive laws are in force in the United
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States and it is very difficult for researchers to abide by the
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regulations which govern efforts to obtain legal approval to do work
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with these compounds in human beings.... No one who is lacking legal
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authorization should attempt the synthesis of any of the compounds
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described in these files, with the intent to give them to man. To do
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so is to risk legal action which might lead to the tragic ruination of
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a life. It should also be noted that any person anywhere who
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experiments on himself, or on another human being, with any of the
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drugs described herin, without being familiar with that drug's action
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and aware of the physical and/or mental disturbance or harm it might
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cause, is acting irresponsibly and immorally, whether or not he is
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doing so within the bounds of the law.
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#30 2C-G-5; 3,6-DIMETHOXY-4-(2-AMINOETHYL)BENZONORBORNANE
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SYNTHESIS: To a stirred solution of 25 g 3,6-dihydroxybenzonorbornane
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(from Eastman Kodak Company) in 200 mL acetone there was added 200 mg
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decyltriethylammonium iodide, 40 g of powdered anhydrous K2CO3, and 55
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g methyl iodide. The mixture was held at reflux with a heating mantle
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overnight. After re-moval of the solvent under vacuum, the residue
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was added to 2 L of H2O, acidified with concentrated HCl, and
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extracted with 3x100 mL CH2Cl2. The pooled extracts were washed with
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2x150 mL 5% NaOH and once with dilute HCl, and the solvent was removed
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under vacuum to give 19.0 g of a black oil as a residue. This was
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distilled at 90-115 !C at 0.3 mm/Hg to yield 15.5 g of an orange oil
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which set up as a crystalline solid. The product,
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3,6-dimethoxybenzonorbornane, had a mp of 35-37 !C from hexane or
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40-41 !C from MeOH. Anal. (C13H16O2) C,H.
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A solution of 4.6 g POCl3 and 4.6 g N-methylformanilide was heated
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briefly on the steam-bath until the color had become deep claret.
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There was then added 3.05 g of 3,6-dimethoxybenzonorbornane and the
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solution was heated on the steam bath for 12 h. The black, tarry
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reaction mixture was poured into H2O, and after hydrolysis, the H2O
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was decanted and the insoluble residues were washed alternately with
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H2O and with CH2Cl2. The combined washes were separated, and the
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aqueous phase extracted with 2x50 mL CH2Cl2. The combined organic
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fractions were washed with 5% NaOH, and the solvent removed under
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vacuum. The fluid, black residue was distilled at 130-140 !C at 0.3
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mm/Hg to give 1.17 g of an almost white oil. This was dissolved in 1
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mL MeOH, and cooled to -50 !C to give a white crystalline solid that
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was removed by filtration and washed sparingly with -50 !C MeOH and
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air dried. There was obtained 0.83 g
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3,6-dimethoxy-4-formylbenzonorbornane with a mp of 37-40 !C which
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could be increased, by wasteful recrystallization from MeOH, to 53-54
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!C. An intimate mixture of this product with the starting diether (mp
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40-41 !C) was a liquid at room temperature. Anal. (C14H16O3) C,H.
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To a solution of 3.70 g 3,6-dimethoxy-4-formylbenzonorbornane in 20 g
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nitromethane, there was added 1.3 g anhydrous ammonium acetate and the
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mixture was heated on the steam bath for 45 min. The excess
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reagent/solvent was removed under vacuum, and the residue was
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dissolved in 20 mL boiling MeOH. A speck of seed crystal started a
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heavy crystallization of orange crystals which were removed by
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filtration and washed with MeOH. After drying, the product
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3,6-dimethoxy-4-(2-nitrovinyl)benzonorbornane was yellow, weighed 3.47
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g, and had a mp of 88-89 !C. Recrystallization of an analytical
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sample from MeOH did not improve this mp. Anal. (C15H17NO4) C,H.
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A solution of LAH (46 mL of a 1 M solution in THF) was cooled, under
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He, to 0 !C with an external ice bath. With good stirring there was
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added 1.25 mL 100% H2SO4 dropwise, to minimize charring. This was
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followed by the addition of 3.4 g
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3,6-dimethoxy-4-(2-nitrovinyl)benzonorbornane in 30 mL anhydrous THF.
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After a few min further stirring, the temperature was brought up to a
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gentle reflux on the steam bath for 10 min, and then all was cooled
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again to 0 !C. The excess hydride was destroyed by the cautious
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addition of 7 mL IPA, followed by 2 mL 15% NaOH and 5 mL H2O, which
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gave an easily filtered white granular solid. This was removed by
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filtration, and the filter cake was washed with THF. The combined
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filtrate and washes were stripped of solvent under vacuum providing a
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pale amber oil which was distilled at 150-160 !C at 0.3 mm/Hg to give
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1.45 g of a white oil. This was dissolved in 7 mL IPA, and
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neutralized with 15 drops of concentrated HCl. There was then added
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25 mL anhydrous Et2O and, after a short delay, white crystals formed
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spontaneously. These were removed by filtration, Et2O washed, and air
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dried to constant weight, yielding 1.13 g of
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3,6-dimethoxy-4-(2-aminoethyl)benzonorbornane hydrochloride (2C-G-5).
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The mp was 199-200 !C. Anal. (C15H22ClNO2) C,H.
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DOSAGE: 10 - 16 mg.
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DURATION: 32 - 48 h.
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QUALITATIVE COMMENTS: (with 14 mg) I was well aware of things at the
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end of two hours, and I was totally unwilling to drive, or even go out
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of the house. I was reminded continuously of 2C-B with its erotic
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push, and the benign interplay of colors and other visual effects.
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But it is so much longer lived. I am a full +++, very stoned, and
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there is no believable sign of dropping for another several hours.
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There is a good appetite (again, 2C-B like), and I managed to sleep
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for a few hours, and all the next day I was spacey and probably still
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a plus one. The day yet following, I was finally at a believable
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baseline. Both of these days were filled with what might be called
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micro doze-offs, almost like narcolepsy. Maybe I am just sleep
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deprived.
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(with 16 mg) The first effects were felt within one hour, and full
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effects between 2 1/2 and 3 hours. Tremendous clarity of thought,
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cosmic but grounded, as it were. This is not at all like LSD, and is a
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lot mellower than the 2C-T family. For the next few hours it was
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delightful and fun and I felt safe and good-humored. I got to sleep
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without much difficulty while still at a plus three, and my dreams
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were positive and balanced, but I awoke irritable and emotionally
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flattened. I did not want to interact with anyone. The first 16
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hours of this stuff were great, and the second 16 hours were a bit of
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a drag. Just twice as long as it ought to be.
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(with 16 mg) I was at full sparkle within three hours, and I
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continued to sparkle for the longest time. The tiredness that comes
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after a while probably reflects the inadequacy of sleep. I was aware
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of something still going on some two days later.
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EXTENSIONS AND COMMENTARY: In the eventual potency assessment of a
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drug, there must be some consideration of not only the dosage needed,
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but the duration of effects. The area under the curve, so to speak.
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By these measures, this phenethylamine is a record breaker, in that it
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is not only amongst the most potent, but it goes on and on and on.
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There are a couple of chemical commentaries. One, the miserable
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phenol-to-ether-to-aldehyde series of steps, so maddeningly
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unsatisfactory in the 2C-G-4 process, was completely comfortable here.
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The reactions rolled, and the yields were most satisfactory.
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Secondly, this is one of the few phenethylamines that is a racemate.
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The strange geometry of the norbornane ring carries within it a chiral
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character, so this compound is potentially resolvable into two
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optically active forms. That might be quite a task, but it would have
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the value of providing for the first time a pair of isomers that were
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asymmetric in the 3,4-aliphatic part of the molecule. To the extent
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that some insight into the geometry of the receptor site can be
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gleaned from the absolute configurations of active agonists, here is a
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compound where the subtle variations are over there at the ring
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substitution area of the structure, rather than at the well-explored
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alpha-carbon atom. Some day I might try to resolve this drug into its
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optical isomers. But I suspect that it might be quite difficult.
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A number of chemical variations of 2C-G-5 are obvious. The
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dihydroxybenzonorbornane compound that was the starting point of all
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this was certainly the adduct of cyclopentadiene and benzoquinone,
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with the double bond reduced. The same chemistry with
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1,3-cyclohexadiene would give a two-carbon bridge instead of the
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one-carbon bridge of norbornane and, after hydrogenation, would
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provide a non-chiral analog with two ethylene bridges between the 3-
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and 4-position carbons. This is a cyclohexane ring connected, by its
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1- and 4-positions, to the two methyl groups of 2C-G. With six
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carbons in this aliphatic mess, the compound is probably best called
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2C-G-6. It should be easily made, and it is certain to be very
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potent. And there are potentially several other Diels Alder dienes
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that might serve with benzoquinone as the dieneophile. There are
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aliphatic things such as hexa-2,4-diene and 2,3-dimethylbutadiene.
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The textbooks are filled with dozens of diene candidates, and
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benzquinone will always provide the two oxygens needed for the
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eventual 2,5-dimethoxy groups of the phenethylamine.
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#31 2C-G-N; 1,4-DIMETHOXYNAPHTHYL-2-ETHYLAMINE
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SYNTHESIS: A solution of 17.5 g 1,4-naphthaquinone in 200 mL MeOH was
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heated to the boiling point, and treated with 28.5 g stannous chloride
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at a rate that maintained a continuous rolling boil. At the
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completion of the addition, the reaction mixture was saturated with
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anhydrous hydrogen chloride, and held at reflux on the steam bath for
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2 h. The reaction mixture was poured into 700 mL H2O and treated with
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aqueous NaOH. During the addition there was transient development of
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a curdy white solid which redissolved when the system became strongly
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basic. This was extracted with 3x200 mL CH2Cl2 and the pooled
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extracts were washed first with H2O, then with dilute HCl, and finally
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again with H2O. Removal of the solvent under vacuum yielded 15.75 g
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of a low melting black flaky crystalline material which was distilled
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at 160-180 !C at 0.05 mm/Hg to give 14.5 g of an amber, solid mass
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with a mp of 78-86 !C. Recrystallization from 75 mL boiling MeOH
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provided 1,4-dimethoxynaphthalene as white crystals melting at 87-88
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!C.
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A mixture of 20.0 g POCl3 and 22.5 g N-methylformanilide was allowed
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to stand at room temperature for 0.5 h which produced a deep claret
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color. To this there was added 9.4 g 1,4-dimethoxynaphthalene and the
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mixture was heated on the steam bath. The reaction mixture quickly
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became progressively darker and thicker. After 20 min it was poured
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into 250 mL H2O and stirred for several h. The solids were removed by
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filtration, and washed well with H2O. The wet crude product (a dull
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yellow-orange color) was dissolved in 125 mL boiling EtOH to give a
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deep red solution. On cooling, this deposited a heavy crop of
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crystals that was removed by filtration, and washed with cold EtOH.
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There was obtained, after air-drying to constant weight, 7.9 g
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1,4-dimethoxy-2-naphthaldehyde as white crystals with a mp of 119-121
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!C. This was not improved by further recrystallization. The
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malononitrile derivative, from the aldehyde and malononitrile in EtOH
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with a drop of triethylamine, had a mp of 187-188 !C.
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A solution of 3.9 g 1,4-dimethoxy-2-naphthaldehyde in 13.5 g
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nitromethane was treated with 0.7 g anhydrous ammonium acetate, and
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heated on the steam bath for 1 h. The excess reagent/solvent was
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removed under vacuum giving a residue that spontaneously crystallized.
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This crude product was removed with the aid of a few mL MeOH, and
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pressed on a sintered funnel with modest MeOH washing. There was
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obtained 3.6 g (when dry) of old-gold colored crystals with a mp of
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146-148 !C. Recrystallization from 140 mL boiling EtOH gave 3.0 g
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1,4-dimethoxy-2-(2-nitro-vinyl)naphthalene as deep gold-colored
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crystals with a mp of 146-147 !C. A small sample, upon
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recrystalization from MeOH, melted at 143-144 !C. Anal. (C14H13NO4)
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C,H.
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A solution of LAH (50 mL of a 1 M solution in THF) was cooled, under
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He, to 0 !C with an external ice bath. With good stirring there was
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added 1.32 mL 100% H2SO4 dropwise, to minimize charring. This was
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followed by the addition of 2.80 g
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1,4-dimethoxy-2-(2-nitrovinyl)naphthalene in 40 mL anhydrous THF.
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There was an immediate loss of color. After 1 h stirring at 0 !C, the
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temperature was brought up to a gentle reflux on the steam bath for 20
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min, then all was cooled again to 0 !C. The excess hydride was
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destroyed by the cautious addition of 7 mL IPA followed by 5.5 mL 5%
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NaOH. The reaction mixture was filtered, and the filter cake washed
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with several portions of THF. The combined filtrate and washings were
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stripped of solvent under vacuum providing 3.6 g of a pale amber oil
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that was distilled at 145-160 !C at 0.2 mm/Hg to give 1.25 g of
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product as an absolutely white oil. This was dissolved in 7 mL IPA,
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and neutralized with concentrated HCl forming immediate crystals of
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the hydrochloride salt in the alcohol solvent. Thirty mL of anhydrous
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Et2O was added, and after complete grinding and mixing, the
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hydrochloride salt was removed by filtration, Et2O washed, and air
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dried to constant weight. The spectacular white crystals of
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1,4-dimethoxynaphthyl-2-ethylamine hydrochloride (2C-G-N) weighed 1.23
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g and had melting properties of darkening at 190 !C, and decomposing
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in the 235-245 !C area. Anal. (C14H18ClNO2) C,H.
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DOSAGE: 20 - 40 mg.
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DURATION: 20 - 30 h.
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QUALITATIVE COMMENTS: (with 24 mg) The effects were interestingly
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colored by the reading of Alan WattsU Joyous Cosmology during the
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coming-on period. The only body negatives were some urinary retention
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and a feeling of a shallow but continuing amphetamine stimulation.
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But not enough to be actually jingly, nor to interfere with sleep that
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evening. There is not much psychedelic here, but there is something
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really going on anyway. This has some similarities to the
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antidepressant world.
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(with 35 mg) Much writing, much talking, and there was considerable
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residual awareness the next day. Somehow this material is not as
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friendly as the other 2C-GUs.
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(with 35 mg) Thinking is clear. No fuzziness, no feeling of being
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pushed. None of the walking on the fine middle line between light and
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dark that is the excitement and the threat of LSD. This is just a
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friend, an ally, which invites you to do anything you wish to.
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[comment added two days later] RMy sleep was not deep enough, but it
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was pleasant and relatively resting. The whole next day I was feeling
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happy, but with an overlay of irritability. Strange mixture. By
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bedtime the irritability had become a mild depression. I feel that
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there might have been a threshold continuing for a couple of days.
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The character of my dreaming had the stamp of drug on it. This
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compound, in retrospect, presents some problems that cause a faint
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unease.
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EXTENSIONS AND COMMENTARY: There is always a wish in the design of new
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compounds to find something that is of interesting activity, with an
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aromatic ring at some location pretty much away from the site of
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activity. This would then allow some subtle fine-tuning of the nature
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of the action by putting any of a wide range of electron pushing or
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electron pulling groups on that ring. But here, with 2C-G-N, by the
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time the ring got put into place, the activity was already on the
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wane, and the action was too long, and there are indicators of some
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not completely friendly effects. Ah well, some other molecule, some
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other time.
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#32 2C-H; 2,5-DIMETHOXYPHENETHYLAMINE
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SYNTHESIS: A solution of 50 g 2,5-dimethoxybenzaldehyde in 100 g
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nitromethane was treated with 5 g of anhydrous ammonium acetate, and
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heated on the steam bath for 4 h. The solution was decanted from a
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little insoluble material, and the solvent removed under vacuum. The
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clear oily residue was dissolved in 100 mL boiling IPA which, after
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standing a moment, set up as dense crystals. After returning to room
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temperature, these were removed by filtration, the product was washed
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with IPA and air dried, yielding 56.9 g 2,5-dimethoxy-'-nitrostyrene
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as spectacular yum-yum orange crystals with a mp of 119-120 !C. An
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analytical sample, from ethyl acetate, melted at 120-121 !C.
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A suspension of 60 g LAH in 500 mL anhydrous THF was placed under an
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inert atmosphere, stirred magnetically, and brought up to reflux
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temperature. There was added, dropwise, 56 g of
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2,5-dimethoxy-'-nitrostyrene dissolved in THF, and the reaction
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mixture was maintained at reflux for 36 h. After being brought to
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room tem-perature, the excess hydride was destroyed with 40 mL IPA,
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followed by 50 mL of 15% NaOH. An additional 100 mL THF was required
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for easy stirring, and an additional 150 mL H2O was needed for
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complete conversion of the aluminum salts to a loose, white,
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filterable consistency. This solid was removed by filtration, and the
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filter cake washed with additional THF. The combined filtrate and
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washes were stripped of solvent under vacuum, and the residue
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dissolved in dilute H2SO4. Washing with 3x75 mL CH2Cl2 removed most
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of the color, and the aqueous phase was made basic with aqueous NaOH
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and reextracted with 3x100 mL CH2Cl2. Removal of the solvent yielded
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39.2 g of a pale amber oil that was distilled. The fraction boiling
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at 80-100 !C at 0.4 mm/Hg weighed 24.8 g and was water-white product
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amine. As the free base, it was suitable for most of the further
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synthetic steps that might be wanted, but in this form it picked up
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carbon dioxide rapidly when exposed to the air. It was readily
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converted to the hydrochloride salt by dissolution in 6 volumes of
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IPA, neutralization with concentrated HCl, and addition of sufficient
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anhydrous Et2O to produce a permanent turbidity. Crystals of
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2,5-dimethoxyphenethylamine hydrochloride (2C-H) spontaneously formed
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and were removed by filtration, washed with Et2O, and air dried. The
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mp was 138-139 !C.
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DOSAGE: unknown.
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DURATION: unknown.
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EXTENSIONS AND COMMENTARY: I know of no record of 2C-H ever having
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been tried by man. It has been assumed by everyone (and probably
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correctly so) that this amine, being an excellent substrate for the
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amino oxidase systems in man, will be completely destroyed by the body
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as soon as it gets into it, and thus be without action. In virtually
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all animal assays where it has been compared with known psychoactive
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drugs, it remains at the Rless-activeS end of the ranking.
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It is, however, one of the most magnificent launching pads for a
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number of rather unusual and, in a couple of cases, extraordinary
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drugs. In the lingo of the chemist, it is amenable to Relectrophilic
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attack at the 4-position.S And, in the lingo of the
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psychopharmacologist, the R4-position is where the action is.S From
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this (presumably) inactive thing have evolved end products such as
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2C-B, 2C-I, 2C-C, and 2C-N. And in the future, many possible things
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as might come from a carbinol group, an amine function, or anything
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that can stem from a lithium atom.
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#33 2C-I; 2,5-DIMETHOXY-4-IODOPHENETHYLAMINE
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SYNTHESIS: A mixture of 7.4 g phthalic anhydride and 9.05 g of
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2,5-dimethoxyphenethylamine (see the recipe for 2C-H for its
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preparation) was heated with an open flame. A single clear phase was
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formed with the loss of H2O. After the hot melt remained quiet for a
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few moments, it was poured out into a crystallizing dish yielding 14.8
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g of a crude solid product. This was recrystallized from 20 mL CH3CN,
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with care taken for an endothermic dissolution, and an exothermic
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crystallization. Both transitions must be done without haste. After
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filtration, the solids were washed with 2x20 mL hexane and air dried
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to constant weight. A yield of 12.93 g of
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|
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!
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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#45 2C-T-9; 2,5-DIMETHOXY-4-(t)-BUTYLTHIOPHENETHYLAMINE
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SYNTHESIS: To a well-stirred ice-cold suspension of 2.8 g
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p-dimethoxybenzene and 3.2 mL N,N,NU,NU-tetramethylethylenediamine in
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100 mL petroleum ether under an inert atmosphere of He, there was
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added 13 mL of a 1.6 N solution of butyllithium in hexane. The
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suspended dimethoxybenzene became opaque and there was a pale yellow
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color generated. The reaction mixture was warmed to room temperature
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which converted it to light white solids. After an additional 0.5 h
|
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stirring, there was added, slowly, 3.6 g of di-(t)-butyldisulfide.
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The yellow color deepened, the solids dissolved and, after 1 h, the
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color was a clear deep brown. This solution was poured into 100 mL
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dilute HCl and the organic phase was separated. The aqueous fraction
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was extracted with 3x75 mL CH2Cl2. The combined organic phases were
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washed with dilute aqueous NaOH, with H2O, and then stripped of
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solvents under vacuum. The residue was distilled at 95-105 !C at 0.5
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mm/Hg to provide 3.7 g of 2,5-dimethoxyphenyl (t)-butyl sulfide as a
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white, mobile liquid. Anal. (C12H18O2S) C,H. A solid derivative was
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found in the nitration product,
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2,5-dimethoxy-4-(t)-butylthio-1-nitrobenzene, which came from the
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addition of 0.11 mL of concentrated HNO3 to a solution of 0.23 g of
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the above sulfide in 5 mL ice cold acetic acid. Dilution with H2O
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provided yellow solids which, on recrystallization from MeOH, had a mp
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of 92-93 !C. Anal. (C12H17NO4S) C,H. Attempts to make either the
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picrate salt or the sulfonamide derivative were not satisfactory.
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A mixture of 72 g POCl3 and 67 g N-methylformanilide was heated for 10
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min on the steam bath. To this claret-colored solution was added 28 g
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of 2,5-dimethoxyphenyl (t)-butyl sulfide, and the mixture heated for
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10 min on the steam bath. This was then added to 1 L of H2O and
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stirred overnight. The residual brown oil was separated from the
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water mechanically, and treated with 150 mL boiling hexane. The
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hexane solution was decanted from some insoluble tars, and on cooling
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deposited a dark oil which did not crystallize. The remaining hexane
|
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was removed under vacuum and the residue combined with the above
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hexane-insoluble dark oil, and all distilled at 0.2 mm/Hg. An early
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fraction (70-110 !C) was largely N-methyl-formanilide and was
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discarded. Crude 2,5-dimethoxy-4-(t-butylthio)benzaldehyde came over
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at 120-130 !C and weighed 12.0 g. This was never satisfactorily
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crystallized despite the successful formation of seed. It was a
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complex mixture by TLC, containing several components. It was used
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for the next step as the crude distilled fraction.
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To a solution of 10 g impure 2,5-dimethoxy-(t-butylthio)benzaldehyde
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in 75 mL of nitromethane there was added 1.0 g of anhydrous ammonium
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acetate, and the mixture was heated on the steam bath 1.5 h. Removal
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of the excess solvent/reagent under vacuum produced an orange oil that
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was (not surprisingly) complex by TLC and which would not crystallize.
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A hot hexane solution of this oil was allowed to slowly cool and stand
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at room temperature for several days, yielding a mixture of yellow
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crystals and a brown viscous syrup. The solids were separated and
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recrystallized from 40 mL MeOH to give 3.7 g
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2,5-dimethoxy-4-(t)-butylthio-'-nitrostyrene as fine lemon-yellow
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crystals, with a mp of 93-94 !C. A second crop of 1.4 g had a mp of
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91-92 !C. Anal. (C14H19NO4S) C,H.
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A solution of LAH (70 mL of a 1 M solution in THF) was cooled, under
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He, to 0 !C with an external ice bath. With good stirring there was
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added 2.1 mL 100% H2SO4 dropwise, over the course of 20 min. This was
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followed by the addition of 4.7 g
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2,5-dimethoxy-4-(t)-butylthio-'-nitrostyrene in 20 mL anhydrous THF.
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There was an immediate loss of color. After a few min further
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stirring, the mixture was allowed to come to room temperature, and the
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stirring was continued for 5 h. The excess hydride was destroyed by
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the cautious addition of 10 mL IPA followed by 6 mL 15% NaOH and
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finally 6 mL H2O. The loose white solids were removed by filtration,
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and the filter cake washed with THF. The filtrate and washes were
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combined and, after stripping off the solvent under vacuum, there was
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obtained 4.66 g of a pale yellow oil. Without any further
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purification, this was distilled at 0.2 mm/Hg. A first fraction came
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over at up to 120 !C and was a light colorless oil that was not
|
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identified. The correct product distilled at 130-160 !C as a pale
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yellow viscous oil that weighed 1.66 g. This was dissolved in 10 mL
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IPA, neutralized with 20 drops of concentrated HCl and diluted with 80
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mL anhydrous Et2O. After standing a few min there was the spontaneous
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generation of white crystals of
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2,5-dimethoxy-4-(t)-butylthiophenethylamine hydrochloride (2C-T-9)
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which were removed by filtration, and air dried. The weight was 1.10
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g.
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DOSAGE: 60 - 100 mg.
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DURATION: 12 - 18 h.
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QUALITATIVE COMMENTS: (with 90 mg) 2C-T-9 tastes the way that old
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crank-case motor oil smells. I was up to something above a plus two
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at the third hour. Although there were no visuals noted, I certainly
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would not choose to drive. Somehow this does more to the body than to
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the head. I feel that the effects are waning at maybe the sixth hour,
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but there is a very strong body memory that makes sleeping difficult.
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Finally, at sometime after midnight and with the help of a glass of
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wine, some sleep.
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(with 125 mg) There was a steady climb to a +++ over the first couple
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of hours. So far, the body has been quite peaceful without any strong
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energy push or stomach problems, although my tummy insists on being
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treated with quiet respect, perhaps out of habit, perhaps not. At the
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fifth hour, the body energy is quite strong, and I have the choice of
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focusing it into some activity, such as love-making or writing, or
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having to deal with tapping toes and floor-pacing. For a novice this
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would be a murderously difficult experience. Too much energy, too
|
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long a time. I suppose I could get used to it, but let me judge by
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when I get to sleep, and just what kind of sleep it is. It turned out
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that sleep was OK, but for the next couple of days there was a
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continuing awareness of some residue in the body Q some kind of
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low-level poisoning. I feel in general that there is not the
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excitement or creativity to connect with, certainly not enough to
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justify the cost to the body.
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EXTENSIONS AND COMMENTARY: The three-carbon analog of 2C-T-9 (this
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would be one of the ALEPH series) has never been made and, for that
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matter, none of the higher numbered 2C-T's have had the amphetamine
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counterparts synthesized. They are, as of the present time, unknown
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compounds. This nifty reaction with di-(t)-butyl disulfide worked so
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well, that three additional disulfides that were at hand were
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immediately thrown into the chemical program, with the quick
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assignment of the names 2C-T-10, 2C-T-11, and 2C-T-12.
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The lithiated dimethoxybenzene reaction with 2,2-dipyridyl disulfide
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produced 2,5-dimethoxyphenyl 2-pyridyl sulfide which distilled at
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135-150 !C at 0.4 mm/Hg and could be recrystallized from cyclohexane
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containing 2% EtOH to give a product that melted at 66-67.5 !C. Anal.
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(C13H13NO2S) C,H. This would have produced
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2,5-dimethoxy-4-(2-pyridylthio)phenethylamine (2C-T-10) but it was
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never pursued.
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The same reaction with di-(4-bromophenyl) disulfide produced
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2,5-dimethoxyphenyl 4-bromophenyl sulfide which distilled at 150-170
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!C at 0.5 mm/Hg and could be recrystallized from MeOH to give a
|
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product that melted at 72-73 !C. Anal. (C14H13BrO2S) C,H. This was
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being directed towards
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2,5-dimethoxy-4-(4-bromophenylthio)phenethylamine (2C-T-11) but it
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also was abandoned.
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The same reaction with N,N-dimorpholinyl disulfide produced virtually
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no product at all, completely defusing any plans for the synthesis of
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a novel sulfur-nitrogen bonded base
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2,5-dimethoxy-4-(1-morpholinothio)phenethylamine (2C-T-12). One
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additional effort was made to prepare a 2C-T-X thing with a
|
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sulfur-nitrogen bond. The acid chloride intermediate in the
|
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preparation of 2,5-dimethoxythiophenol (as described in the recipe for
|
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2C-T-2) is 2,5-dimethoxybenzenesulfonyl chloride. It reacted smoothly
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with an excess of diethylamine to produce
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2,5-dimethoxy-N,N-diethylbenzenesulfonamide which distilled at 155 !C
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at 0.13 mm/Hg and which could be recrystallized from a 4:1 mixture of
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cyclohexane/benzene to give a product with a melting point of 41-42 !C
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and an excellent proton NMR. This amide proved totally refractory to
|
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all efforts at reduction, so the target compound,
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2,5-dimethoxy-4-diethylaminothiophenethylamine, has not been made. It
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has not even been given a 2C-T-X number.
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#46 2C-T-13; 2,5-DIMETHOXY-4-(2-METHOXYETHYLTHIO)PHENETHYLAMINE
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SYNTHESIS: To a solution of 3.25 g of KOH pellets in 25 mL hot MeOH,
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there was added 6.8 g of 2,5-dimethoxythiophenol (see under 2C-T-2 for
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its preparation) followed by 4.73 g of 2-methoxyethylchloride. This
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mixture was heated on the steam bath for 0.5 h, then added to 500 mL
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H2O. This very basic aqueous phase was extracted with 3x100 mL
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CH2Cl2, the extracts pooled, and back-washed with 5% NaOH. The
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solvent was removed under vacuum to give 8.82 g of a white oil.
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Distillation gave 2,5-dimethoxyphenyl 2-methoxyethyl sulfide with a bp
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115-125 !C at 0.3 mm/Hg, and a weight of 6.65 g.
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A mixture of 10 g POCl3 and 10 g N-methylformanilide was heated for 10
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min on the steam bath. To this claret-colored solution was added 6.16
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g of 2,5- dimethoxyphenyl 2-methoxyethyl sulfide. There was an
|
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immediate exothermic reaction and gas evolution. The mixture was
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heated for 15 min on the steam bath, at which time there was no
|
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starting sulfide present by TLC. This was then added to 500 mL of
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well-stirred warm H2O (pre-heated to 55 !C) and the stirring continued
|
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until only a thin oily phase remained. This was extracted with
|
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CH2Cl2, the extracts were combined, and the solvent removed under
|
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vacuum. The residue was extracted with 5 sequential 20 mL portions of
|
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boiling hexane which deposited crystals on cooling. Filtering gave a
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total of 4.12 g crystalline solids. Recrystallization from MeOH gave
|
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a poor yield of a cream-colored crystal with a mp of 68-69 !C. A more
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efficient purification was achieved by distillation (155-168 !C at 0.3
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mm/Hg) yielding 3.50 g of
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2,5-dimethoxy-4-(2-methoxyethylthio)benzaldehyde as a pale yellow
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solid, with a mp of 67-68 !C. A faster moving (by TLC) trace
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component with an intense fluo-rescence persisted throughout the
|
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entire purification scheme, and was still present in the analytical
|
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sample. Anal. (C12H16O4S) C,H.
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To a solution of 3.41 g
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2,5-dimethoxy-4-(2-methoxyethylthio)benzaldehyde in 50 g of
|
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nitromethane there was added 0.11 g of anhydrous ammonium acetate, and
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the mixture was heated on the steam bath for 2 h, at which time the
|
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starting aldehyde had largely disappeared by TLC (silica gel plates
|
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with CH2Cl2 as the developing solvent) and a faster moving
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nitrostyrene product was clearly visible. The clear orange solution
|
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was stripped of the excess nitromethane under vacuum producing a
|
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yellow oil that crystallized yielding 3.97 g of a yellow solid with a
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mp of 99-104 !C. Recrystallization of a small sample from MeOH
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produced (when dry) yellow electrostatic crystals of
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2,5-dimethoxy-4-(2-methoxyethylthio)-'-nitrostyrene with a mp of 107
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!C sharp. From IPA the product is a burnished gold color with the mp
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106-107 !C. Anal. (C13H17NO5S) C,H.
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A solution of LAH (40 mL of a 1 M solution in THF) was cooled, under
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He, to 0 !C with an external ice bath. With good stirring there was
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added 1.05 mL 100% H2SO4 dropwise, to minimize charring. This was
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followed by the addition of 3.07 g
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2,5-dimethoxy-4-(2-methoxyethylthio)-'-nitrostyrene in small portions,
|
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as a solid, over the course of 10 min. There was a considerable
|
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amount of gas evolved, and a little bit of charring. After a few min
|
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further stirring, the temperature was brought up to a gentle reflux on
|
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the steam bath, and then all was cooled again to 0 !C. The excess
|
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hydride was destroyed by the cautious addition of 8 mL IPA followed by
|
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3 mL 15% NaOH which gave the reaction mixture a curdy white granular
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character. The reaction mixture was filtered, the filter cake washed
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with THF, and filtrate and washes were stripped of solvent under
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vacuum providing about 3 g of a pale amber oil. This was dissolved in
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about 40 mL CH2Cl2 and extracted with 200 mL dilute H2SO4 in three
|
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portions. All of the color remained in the organic phase. The pooled
|
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aqueous extracts were washed with CH2Cl2, then made basic with 25%
|
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NaOH, extracted with 3x75 mL CH2Cl2, and the combined extracts pooled
|
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and stripped of solvent under vacuum. The 2 g pale yellow oily
|
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residue was distilled at 155-165 !C at 0.2 mm/Hg to give 1.23 g of a
|
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clear white oil. This was dissolved in IPA, neutralized with
|
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concentrated HCl, and diluted with anhydrous Et2O to produce crystals
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of 2,5-dimethoxy-4-(2-methoxyethylthio)phenethylamine hydrochloride
|
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(2C-T-13). After filtration, washing with Et2O, and air drying, this
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white crystalline product weighed 0.89 g.
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DOSAGE: 25 - 40 mg.
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DURATION: 6 - 8 h.
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QUALITATIVE COMMENTS: (with 25 mg) I felt it was somewhat noisy as we
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went into the experience. This noisiness lasted only about an hour,
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then stopped. At the peak, which seemed to be at about 1 to maybe 1.5
|
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hours, some eyes-closed visuals appeared. There was a white field
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with colored visuals, at times geometric in shape. These eye-closed
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images were pleasant and I enjoyed them when I did not concern myself
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with, or listen to, the conversation. There was an eyes-open change
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in color, the ivy became a little lighter or maybe a little stronger
|
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in color. IUm not sure which. I felt there was a gradual diminishing
|
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of activity (whatever that undefined activity was) starting at 2 to
|
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2.5 hours, and coming close to baseline at 6 PM. The descent was
|
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pleasant and I would say pleasurable. The experience did not lead to
|
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any confusion which I sometimes notice in other experiences. There
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was no problem with anorexia. We ate constantly during the
|
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experience. The grapes and other fruit were lovely. This is one of
|
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the few times I would say that I would try a higher dose. Maybe 30 or
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33 milligrams. I suspect the experience would be similar, with just a
|
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heightened peak at 1 hour and perhaps a little more body effect. It
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may well be one to try with one's wife.
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(with 28 mg) There was a strange, disturbing twinge exactly eight
|
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minutes after starting this, that asked me, TShould I have done this?U
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I answered, TYesU and the twinge disappeared. And then there was
|
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nothing until the expected time of development, at a half hour when I
|
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felt a light head and slight dizziness. There was a solid plus two
|
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for a couple of hours. I paid careful attention for auditory oddities
|
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that I had noted before, but they were not there. In an earlier trial
|
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(with 20 milligrams) the radio had the sound of being located in the
|
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outdoors with the sounds coming through the wall and into the room
|
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where I was. I was at a neutral baseline at about seven hours.
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(with 35 mg) There was a quiet climb, but it was marred with some
|
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tummy unquiet, and an annoying persistence of diarrhea. I was very
|
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impressed with eyes-closed patterning, which seemed to do its own
|
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thing independently of the music. I was clearly up to a +++, but
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there was a feeling that as soon as it got there it started to go away
|
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again. There was no there, there. Yet there were a couple of touches
|
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of introspection, of seriousness which I had to respect.
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|
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(with 40 mg) There were four of us, and the entry was individual for
|
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each of us. Two of us were nauseous. One volunteered a statement,
|
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almost a confession, of too much food and drink in the immediate past.
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One of us needed his cigarette right now, and then he saw that he was
|
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killing himself, and he swore off. DonUt know if it will last,
|
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however. At the two and a half hour point there is a consensus that
|
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this has gone its route and will lose its impact, so three of us
|
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decided to supplement on 2C-T-2. Six milligrams proves to be a little
|
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light so, some four hours later, we each took another six milligrams.
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Excellent. In a while we discoved that we were very hungry, and food
|
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tasted marvelous. Headaches acknowledged in the early evening, but
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the extension from T-13 to T-2 seemed to be absolutely correct. And
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as of the next day, the non-smoker was still a non-smoker.
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EXTENSIONS AND COMMENTARY: Most of the synthetic adventures of putting
|
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a basic something aways out from the benzene ring, at the
|
|
four-position, have involved subtle things such as unsaturated bonds
|
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or three-membered rings. This was the first try with the actual use
|
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of a different atom (an oxygen). What about other heteroatoms such as
|
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sulfur or nitrogen or silicon or phosphorus, or some-such?
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The sulfur counterpart of 2C-T-13 was named 2C-T-14, and was
|
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immediately launched. The reaction of 2,5-dimethoxythiophenol and KOH
|
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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
|
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2,5-dimethoxy-4-(2-methylthioethylthio)benzaldehyde with a melting
|
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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
|
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orange-red RLas VegasS colored crystals from acetonitrile, with a
|
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melting point of 126-127 !C. And as of the moment, this is sitting on
|
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the shelf waiting to be reduced to the target compound
|
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2,5-dimethoxy-4-(2-methylthioethylthio)phenethylamine hydrochloride,
|
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or 2C-T-14. Will it be active? I rather suspect that it will be, and
|
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IUll bet it will be longer-lived than the oxygen model, 2C-T-13.
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#47 2C-T-15; SESQUI; 2,5-DIMETHOXY-4-CYCLOPROPYLTHIOPHENETHYLAMINE
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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
|
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reaction was exothermic, and immediately deposited white solids of
|
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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.
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|
|
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.
|
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There was then added 6.5 g 2,5-dimethoxphenyl 3-chloropropyl sulfide,
|
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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
|
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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.
|
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|
|
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.
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#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.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|