SYNTHESIS: To a stirred solution of 25 g 3,6-dihydroxybenzonorbornane
(from Eastman Kodak Company) in 200 mL acetone there was added 200 mg
decyltriethylammonium iodide, 40 g of powdered anhydrous K2CO3, and 55
g methyl iodide. The mixture was held at reflux with a heating mantle
overnight. After re-moval of the solvent under vacuum, the residue
was added to 2 L of H2O, acidified with concentrated HCl, and
extracted with 3x100 mL CH2Cl2. The pooled extracts were washed with
2x150 mL 5% NaOH and once with dilute HCl, and the solvent was removed
under vacuum to give 19.0 g of a black oil as a residue. This was
distilled at 90-115 °C at 0.3 mm/Hg to yield 15.5 g of an orange oil
which set up as a crystalline solid. The product,
3,6-dimethoxybenzonorbornane, had a mp of 35-37 °C from hexane or
40-41 °C from MeOH. Anal. (C13H16O2) C,H.
A solution of 4.6 g POCl3 and 4.6 g N-methylformanilide was heated
briefly on the steam-bath until the color had become deep claret.
There was then added 3.05 g of 3,6-dimethoxybenzonorbornane and the
solution was heated on the steam bath for 12 h. The black, tarry
reaction mixture was poured into H2O, and after hydrolysis, the H2O
was decanted and the insoluble residues were washed alternately with
H2O and with CH2Cl2. The combined washes were separated, and the
aqueous phase extracted with 2x50 mL CH2Cl2. The combined organic
fractions were washed with 5% NaOH, and the solvent removed under
vacuum. The fluid, black residue was distilled at 130-140 °C at 0.3
mm/Hg to give 1.17 g of an almost white oil. This was dissolved in 1
mL MeOH, and cooled to -50 °C to give a white crystalline solid that
was removed by filtration and washed sparingly with -50 °C MeOH and
air dried. There was obtained 0.83 g
3,6-dimethoxy-4-formylbenzonorbornane with a mp of 37-40 °C which
could be increased, by wasteful recrystallization from MeOH, to 53-54
°C. An intimate mixture of this product with the starting diether (mp
40-41 °C) was a liquid at room temperature. Anal. (C14H16O3) C,H.
To a solution of 3.70 g 3,6-dimethoxy-4-formylbenzonorbornane in 20 g
nitromethane, there was added 1.3 g anhydrous ammonium acetate and the
mixture was heated on the steam bath for 45 min. The excess
reagent/solvent was removed under vacuum, and the residue was
dissolved in 20 mL boiling MeOH. A speck of seed crystal started a
heavy crystallization of orange crystals which were removed by
filtration and washed with MeOH. After drying, the product
3,6-dimethoxy-4-(2-nitrovinyl)benzonorbornane was yellow, weighed 3.47
g, and had a mp of 88-89 °C. Recrystallization of an analytical
sample from MeOH did not improve this mp. Anal. (C15H17NO4) C,H.
A solution of LAH (46 mL of a 1 M solution in THF) was cooled, under
He, to 0 °C with an external ice bath. With good stirring there was
added 1.25 mL 100% H2SO4 dropwise, to minimize charring. This was
followed by the addition of 3.4 g
3,6-dimethoxy-4-(2-nitrovinyl)benzonorbornane in 30 mL anhydrous THF.
After a few min further stirring, the temperature was brought up to a
gentle reflux on the steam bath for 10 min, and then all was cooled
again to 0 °C. The excess hydride was destroyed by the cautious
addition of 7 mL IPA, followed by 2 mL 15% NaOH and 5 mL H2O, which
gave an easily filtered white granular solid. This was removed by
filtration, and the filter cake was washed with THF. The combined
filtrate and washes were stripped of solvent under vacuum providing a
pale amber oil which was distilled at 150-160 °C at 0.3 mm/Hg to give
1.45 g of a white oil. This was dissolved in 7 mL IPA, and
neutralized with 15 drops of concentrated HCl. There was then added
25 mL anhydrous Et2O and, after a short delay, white crystals formed
spontaneously. These were removed by filtration, Et2O washed, and air
dried to constant weight, yielding 1.13 g of
3,6-dimethoxy-4-(2-aminoethyl)benzonorbornane hydrochloride (2C-G-5).
The mp was 199-200 °C. Anal. (C15H22ClNO2) C,H.
DOSAGE: 10 - 16 mg.
DURATION: 32 - 48 h.
QUALITATIVE COMMENTS: (with 14 mg) I was well aware of things at the
end of two hours, and I was totally unwilling to drive, or even go out
of the house. I was reminded continuously of 2C-B with its erotic
push, and the benign interplay of colors and other visual effects.
But it is so much longer lived. I am a full +++, very stoned, and
there is no believable sign of dropping for another several hours.
There is a good appetite (again, 2C-B like), and I managed to sleep
for a few hours, and all the next day I was spacey and probably still
a plus one. The day yet following, I was finally at a believable
baseline. Both of these days were filled with what might be called
micro doze-offs, almost like narcolepsy. Maybe I am just sleep
deprived.
(with 16 mg) The first effects were felt within one hour, and full
effects between 2 1/2 and 3 hours. Tremendous clarity of thought,
cosmic but grounded, as it were. This is not at all like LSD, and is a
lot mellower than the 2C-T family. For the next few hours it was
delightful and fun and I felt safe and good-humored. I got to sleep
without much difficulty while still at a plus three, and my dreams
were positive and balanced, but I awoke irritable and emotionally
flattened. I did not want to interact with anyone. The first 16
hours of this stuff were great, and the second 16 hours were a bit of
a drag. Just twice as long as it ought to be.
(with 16 mg) I was at full sparkle within three hours, and I
continued to sparkle for the longest time. The tiredness that comes
after a while probably reflects the inadequacy of sleep. I was aware
of something still going on some two days later.
EXTENSIONS AND COMMENTARY: In the eventual potency assessment of a
drug, there must be some consideration of not only the dosage needed,
but the duration of effects. The area under the curve, so to speak.
By these measures, this phenethylamine is a record breaker, in that it
is not only amongst the most potent, but it goes on and on and on.
There are a couple of chemical commentaries. One, the miserable
phenol-to-ether-to-aldehyde series of steps, so maddeningly
unsatisfactory in the 2C-G-4 process, was completely comfortable here.
The reactions rolled, and the yields were most satisfactory.
Secondly, this is one of the few phenethylamines that is a racemate.
The strange geometry of the norbornane ring carries within it a chiral
character, so this compound is potentially resolvable into two
optically active forms. That might be quite a task, but it would have
the value of providing for the first time a pair of isomers that were
asymmetric in the 3,4-aliphatic part of the molecule. To the extent
that some insight into the geometry of the receptor site can be
gleaned from the absolute configurations of active agonists, here is a
compound where the subtle variations are over there at the ring
substitution area of the structure, rather than at the well-explored
alpha-carbon atom. Some day I might try to resolve this drug into its
optical isomers. But I suspect that it might be quite difficult.
A number of chemical variations of 2C-G-5 are obvious. The
dihydroxybenzonorbornane compound that was the starting point of all
this was certainly the adduct of cyclopentadiene and benzoquinone,
with the double bond reduced. The same chemistry with
1,3-cyclohexadiene would give a two-carbon bridge instead of the
one-carbon bridge of norbornane and, after hydrogenation, would
provide a non-chiral analog with two ethylene bridges between the 3-
and 4-position carbons. This is a cyclohexane ring connected, by its
1- and 4-positions, to the two methyl groups of 2C-G. With six
carbons in this aliphatic mess, the compound is probably best called
2C-G-6. It should be easily made, and it is certain to be very
potent. And there are potentially several other Diels Alder dienes
that might serve with benzoquinone as the dieneophile. There are
aliphatic things such as hexa-2,4-diene and 2,3-dimethylbutadiene.
The textbooks are filled with dozens of diene candidates, and
benzquinone will always provide the two oxygens needed for the
eventual 2,5-dimethoxy groups of the phenethylamine.
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