2,5-dimethoxy-'-nitro-3,4-(tetramethylene)styrene with a mp of 151.5-152.5 !C. Anal. (C14H17NO4) C,H.
DOSAGE: unknown.
DURATION: unknown
EXTENSIONS AND COMMENTARY: The road getting to this final product reminded me of the reasons why, during the first few billion years of the universe following the big bang, there was only hydrogen and helium. Nothing heavier. When everything had expanded enough to cool things sufficiently for the first actual matter to form, all was simply very energetic protons and neutrons. These were banging into one-another, making deuterium nuclei, and some of these got banged up even all the way to helium, but every time a helium nucleus collided with a particle of mass one, to try for something with mass five, the products simply couldnUt exist. Both Lithium-5 and Helium-5 have the impossible half-lives of 10 to the minus 21 seconds. Hence, in the primordial soup, the only way to get into something heavier than helium was to have a collision between a couple of the relatively scarcer heavy nuclei, or to have a three body collision. Both of these would be extremely rare events, statistically. And if a few got through, there was another forbidden barrier at mass 8, since Beryllium-8 has a half life of 10 to the minus 16 seconds. So everything had to wait for a few suns to burn down so that they could process enough helium into heavy atoms, to achieve some nuclear chemistry that was not allowed in the early history of the universe.
And in the same way, there were two nearly insurmountable barriers encountered in getting to 2C-G-4 and G-4. The simple act of methylating an aromatic hydroxyl group provided mixtures that could only be resolved into components by some pretty intricate maneuvers.
And when that product was indeed gotten, the conversion of it into a simple aromatic aldehyde resisted the classic procedures completely, either giving complex messes, or nothing. And even now, with these two hurdles successfully passed, the presumed simple last step has not yet been done. The product 2C-G-4 lies just one synthetic step (the LAH reduction) away from completion, and the equally fascinating G-4
also that one last reduction step from being completed. Having gotten through the worst of the swamp, let's get into the lab and finish up this challenge. They will both be active compounds.
From: [email protected]
Newsgroups: sci.med,sci.chem,alt.drugs Subject: PiHKAL: The Chemical Story. File 2 of 6
(I'm posting this for a friend.)
This is part 2 of 6 of the second half of PiHKAL: A Chemical Love Story, by Alexander Shulgin and Ann Shulgin. Please forgive any typos or misprints in this file; further, because of ASCII limitations, many of the typographical symbols in the original book could not be properly represented in these files.
If you are seriously interested in the chemistry contained in these files, you should order a copy of the book PiHKAL. The book may be purchased for $22.95 ($18.95 + $4.00 postage and handling) from Transform Press, Box 13675, Berkeley, CA 94701. California residents please add $1.38 State sales tax.
At the present time, restrictive laws are in force in the United States and it is very difficult for researchers to abide by the regulations which govern efforts to obtain legal approval to do work with these compounds in human beings.... No one who is lacking legal authorization should attempt the synthesis of any of the compounds described in these files, with the intent to give them to man. To do so is to risk legal action which might lead to the tragic ruination of a life. It should also be noted that any person anywhere who experiments on himself, or on another human being, with any of the drugs described herin, without being familiar with that drug's action and aware of the physical and/or mental disturbance or harm it might cause, is acting irresponsibly and immorally, whether or not he is doing so within the bounds of the law.
30 2C-G-5; 3,6-DIMETHOXY-4-(2-AMINOETHYL)BENZONORBORNANE
SYNTHESIS: To a stirred solution of 25 g 3,6-dihydroxybenzonorbornane (from Eastman Kodak Company) in 200 mL acetone there was added 200 mg decyltriethylammonium iodide, 40 g of powdered anhydrous K2CO3, and 55
g methyl iodide. The mixture was held at reflux with a heating mantle overnight. After re-moval of the solvent under vacuum, the residue was added to 2 L of H2O, acidified with concentrated HCl, and extracted with 3x100 mL CH2Cl2. The pooled extracts were washed with 2x150 mL 5% NaOH and once with dilute HCl, and the solvent was removed under vacuum to give 19.0 g of a black oil as a residue. This was distilled at 90-115 !C at 0.3 mm/Hg to yield 15.5 g of an orange oil which set up as a crystalline solid. The product, 3,6-dimethoxybenzonorbornane, had a mp of 35-37 !C from hexane or 40-41 !C from MeOH. Anal. (C13H16O2) C,H.
A solution of 4.6 g POCl3 and 4.6 g N-methylformanilide was heated briefly on the steam-bath until the color had become deep claret.
There was then added 3.05 g of 3,6-dimethoxybenzonorbornane and the solution was heated on the steam bath for 12 h. The black, tarry reaction mixture was poured into H2O, and after hydrolysis, the H2O
was decanted and the insoluble residues were washed alternately with H2O and with CH2Cl2. The combined washes were separated, and the aqueous phase extracted with 2x50 mL CH2Cl2. The combined organic fractions were washed with 5% NaOH, and the solvent removed under vacuum. The fluid, black residue was distilled at 130-140 !C at 0.3
mm/Hg to give 1.17 g of an almost white oil. This was dissolved in 1
mL MeOH, and cooled to -50 !C to give a white crystalline solid that was removed by filtration and washed sparingly with -50 !C MeOH and air dried. There was obtained 0.83 g 3,6-dimethoxy-4-formylbenzonorbornane with a mp of 37-40 !C which could be increased, by wasteful recrystallization from MeOH, to 53-54
!C. An intimate mixture of this product with the starting diether (mp 40-41 !C) was a liquid at room temperature. Anal. (C14H16O3) C,H.
To a solution of 3.70 g 3,6-dimethoxy-4-formylbenzonorbornane in 20 g nitromethane, there was added 1.3 g anhydrous ammonium acetate and the mixture was heated on the steam bath for 45 min. The excess reagent/solvent was removed under vacuum, and the residue was dissolved in 20 mL boiling MeOH. A speck of seed crystal started a heavy crystallization of orange crystals which were removed by filtration and washed with MeOH. After drying, the product 3,6-dimethoxy-4-(2-nitrovinyl)benzonorbornane was yellow, weighed 3.47
g, and had a mp of 88-89 !C. Recrystallization of an analytical sample from MeOH did not improve this mp. Anal. (C15H17NO4) C,H.
A solution of LAH (46 mL of a 1 M solution in THF) was cooled, under He, to 0 !C with an external ice bath. With good stirring there was added 1.25 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 3.4 g
3,6-dimethoxy-4-(2-nitrovinyl)benzonorbornane in 30 mL anhydrous THF.
After a few min further stirring, the temperature was brought up to a gentle reflux on the steam bath for 10 min, and then all was cooled again to 0 !C. The excess hydride was destroyed by the cautious addition of 7 mL IPA, followed by 2 mL 15% NaOH and 5 mL H2O, which gave an easily filtered white granular solid. This was removed by filtration, and the filter cake was washed with THF. The combined filtrate and washes were stripped of solvent under vacuum providing a pale amber oil which was distilled at 150-160 !C at 0.3 mm/Hg to give 1.45 g of a white oil. This was dissolved in 7 mL IPA, and neutralized with 15 drops of concentrated HCl. There was then added 25 mL anhydrous Et2O and, after a short delay, white crystals formed spontaneously. These were removed by filtration, Et2O washed, and air dried to constant weight, yielding 1.13 g of 3,6-dimethoxy-4-(2-aminoethyl)benzonorbornane hydrochloride (2C-G-5).
The mp was 199-200 !C. Anal. (C15H22ClNO2) C,H.
DOSAGE: 10 - 16 mg.
DURATION: 32 - 48 h.
QUALITATIVE COMMENTS: (with 14 mg) I was well aware of things at the end of two hours, and I was totally unwilling to drive, or even go out of the house. I was reminded continuously of 2C-B with its erotic push, and the benign interplay of colors and other visual effects.
But it is so much longer lived. I am a full +++, very stoned, and there is no believable sign of dropping for another se
veral hours.
There is a good appetite (again, 2C-B like), and I managed to sleep for a few hours, and all the next day I was spacey and probably still a plus one. The day yet following, I was finally at a believable baseline. Both of these days were filled with what might be called micro doze-offs, almost like narcolepsy. Maybe I am just sleep deprived.
(with 16 mg) The first effects were felt within one hour, and full effects between 2 1/2 and 3 hours. Tremendous clarity of thought, cosmic but grounded, as it were. This is not at all like LSD, and is a lot mellower than the 2C-T family. For the next few hours it was delightful and fun and I felt safe and good-humored. I got to sleep without much difficulty while still at a plus three, and my dreams were positive and balanced, but I awoke irritable and emotionally flattened. I did not want to interact with anyone. The first 16
hours of this stuff were great, and the second 16 hours were a bit of a drag. Just twice as long as it ought to be.
(with 16 mg) I was at full sparkle within three hours, and I continued to sparkle for the longest time. The tiredness that comes after a while probably reflects the inadequacy of sleep. I was aware of something still going on some two days later.
EXTENSIONS AND COMMENTARY: In the eventual potency assessment of a drug, there must be some consideration of not only the dosage needed, but the duration of effects. The area under the curve, so to speak.
By these measures, this phenethylamine is a record breaker, in that it is not only amongst the most potent, but it goes on and on and on.
There are a couple of chemical commentaries. One, the miserable phenol-to-ether-to-aldehyde series of steps, so maddeningly unsatisfactory in the 2C-G-4 process, was completely comfortable here.
The reactions rolled, and the yields were most satisfactory.
Secondly, this is one of the few phenethylamines that is a racemate.
The strange geometry of the norbornane ring carries within it a chiral character, so this compound is potentially resolvable into two optically active forms. That might be quite a task, but it would have the value of providing for the first time a pair of isomers that were asymmetric in the 3,4-aliphatic part of the molecule. To the extent that some insight into the geometry of the receptor site can be gleaned from the absolute configurations of active agonists, here is a compound where the subtle variations are over there at the ring substitution area of the structure, rather than at the well-explored alpha-carbon atom. Some day I might try to resolve this drug into its optical isomers. But I suspect that it might be quite difficult.
A number of chemical variations of 2C-G-5 are obvious. The dihydroxybenzonorbornane compound that was the starting point of all this was certainly the adduct of cyclopentadiene and benzoquinone, with the double bond reduced. The same chemistry with 1,3-cyclohexadiene would give a two-carbon bridge instead of the one-carbon bridge of norbornane and, after hydrogenation, would provide a non-chiral analog with two ethylene bridges between the 3-
and 4-position carbons. This is a cyclohexane ring connected, by its 1- and 4-positions, to the two methyl groups of 2C-G. With six carbons in this aliphatic mess, the compound is probably best called 2C-G-6. It should be easily made, and it is certain to be very potent. And there are potentially several other Diels Alder dienes that might serve with benzoquinone as the dieneophile. There are aliphatic things such as hexa-2,4-diene and 2,3-dimethylbutadiene.
The textbooks are filled with dozens of diene candidates, and benzquinone will always provide the two oxygens needed for the eventual 2,5-dimethoxy groups of the phenethylamine.
31 2C-G-N; 1,4-DIMETHOXYNAPHTHYL-2-ETHYLAMINE
SYNTHESIS: A solution of 17.5 g 1,4-naphthaquinone in 200 mL MeOH was heated to the boiling point, and treated with 28.5 g stannous chloride at a rate that maintained a continuous rolling boil. At the completion of the addition, the reaction mixture was saturated with anhydrous hydrogen chloride, and held at reflux on the steam bath for 2 h. The reaction mixture was poured into 700 mL H2O and treated with aqueous NaOH. During the addition there was transient development of a curdy white solid which redissolved when the system became strongly basic. This was extracted with 3x200 mL CH2Cl2 and the pooled extracts were washed first with H2O, then with dilute HCl, and finally again with H2O. Removal of the solvent under vacuum yielded 15.75 g of a low melting black flaky crystalline material which was distilled at 160-180 !C at 0.05 mm/Hg to give 14.5 g of an amber, solid mass with a mp of 78-86 !C. Recrystallization from 75 mL boiling MeOH
provided 1,4-dimethoxynaphthalene as white crystals melting at 87-88
!C.
A mixture of 20.0 g POCl3 and 22.5 g N-methylformanilide was allowed to stand at room temperature for 0.5 h which produced a deep claret color. To this there was added 9.4 g 1,4-dimethoxynaphthalene and the mixture was heated on the steam bath. The reaction mixture quickly became progressively darker and thicker. After 20 min it was poured into 250 mL H2O and stirred for several h. The solids were removed by filtration, and washed well with H2O. The wet crude product (a dull yellow-orange color) was dissolved in 125 mL boiling EtOH to give a deep red solution. On cooling, this deposited a heavy crop of crystals that was removed by filtration, and washed with cold EtOH.
There was obtained, after air-drying to constant weight, 7.9 g 1,4-dimethoxy-2-naphthaldehyde as white crystals with a mp of 119-121
!C. This was not improved by further recrystallization. The malononitrile derivative, from the aldehyde and malononitrile in EtOH
with a drop of triethylamine, had a mp of 187-188 !C.
A solution of 3.9 g 1,4-dimethoxy-2-naphthaldehyde in 13.5 g nitromethane was treated with 0.7 g anhydrous ammonium acetate, and heated on the steam bath for 1 h. The excess reagent/solvent was removed under vacuum giving a residue that spontaneously crystallized.
This crude product was removed with the aid of a few mL MeOH, and pressed on a sintered funnel with modest MeOH washing. There was obtained 3.6 g (when dry) of old-gold colored crystals with a mp of 146-148 !C. Recrystallization from 140 mL boiling EtOH gave 3.0 g 1,4-dimethoxy-2-(2-nitro-vinyl)naphthalene as deep gold-colored crystals with a mp of 146-147 !C. A small sample, upon recrystalization from MeOH, melted at 143-144 !C. Anal. (C14H13NO4) C,H.
A solution of LAH (50 mL of a 1 M solution in THF) was cooled, under He, to 0 !C with an external ice bath. With good stirring there was added 1.32 mL 100% H2SO4 dropwise, to minimize charring. This was followed by the addition of 2.80 g
1,4-dimethoxy-2-(2-nitrovinyl)naphthalene in 40 mL anhydrous THF.
There was an immediate loss of color. After 1 h stirring at 0 !C, the temperature was brought up to a gentle reflux on the steam bath for 20
min, then all was cooled again to 0 !C. The excess hydride was destroyed by the cautious addition of 7 mL IPA followed by 5.5 mL 5%
NaOH. The reaction mixture was filtered, and the filter cake washed with several portions of THF. The combined filtrate and washings were stripped of solvent under vacuum providing 3.6 g of a pale amber oil that was distilled at 145-160 !C at 0.2 mm/Hg to give 1.25 g of product as an absolutely white oil. This was dissolved in 7 mL IPA, and neutralized with concentrated HCl forming immediate crystals of the hydrochloride salt in the alcohol solvent. Thirty mL of anhydrous Et2O was added, and after complete grinding and mixing, the hydrochloride salt was removed by filtration, Et2O washed, and air dried to constant weight. The spectacular white crystals of 1,4-dimethoxynaphthyl-2-ethylamine hydrochloride (2C-G-N) weighed 1.23
g and had melting properties of darkening at 190 !C, and decomposing in the 235-245 !C area. Anal. (C14H18ClNO2) C,H.
DOSAGE: 20 - 40 mg.
DURATION: 20 - 30 h.
QUALITATIVE COMMENTS: (with 24 mg) The effects were interestingly colored by the reading of Alan WattsU Joyous Cosmology during the coming-on period. The only body negatives were some urinary retention and a feeling of a shallow but continuing amphetamine stimulation.
But not enough to be actually jingly, nor to interfere with sleep that evening. There is not
much psychedelic here, but there is something really going on anyway. This has some similarities to the antidepressant world.
(with 35 mg) Much writing, much talking, and there was considerable residual awareness the next day. Somehow this material is not as friendly as the other 2C-GUs.
(with 35 mg) Thinking is clear. No fuzziness, no feeling of being pushed. None of the walking on the fine middle line between light and dark that is the excitement and the threat of LSD. This is just a friend, an ally, which invites you to do anything you wish to.
[comment added two days later] RMy sleep was not deep enough, but it was pleasant and relatively resting. The whole next day I was feeling happy, but with an overlay of irritability. Strange mixture. By bedtime the irritability had become a mild depression. I feel that there might have been a threshold continuing for a couple of days.
The character of my dreaming had the stamp of drug on it. This compound, in retrospect, presents some problems that cause a faint unease.
EXTENSIONS AND COMMENTARY: There is always a wish in the design of new compounds to find something that is of interesting activity, with an aromatic ring at some location pretty much away from the site of activity. This would then allow some subtle fine-tuning of the nature of the action by putting any of a wide range of electron pushing or electron pulling groups on that ring. But here, with 2C-G-N, by the time the ring got put into place, the activity was already on the wane, and the action was too long, and there are indicators of some not completely friendly effects. Ah well, some other molecule, some other time.
Pihkal Page 76
